摘要:

ISSN 0265-0568 NPRRDF 14(6) 559-682 (1 997) Natural Product Reports A journal of current developments in bioorganic chemistry ~~ Volume 14 Number 6 CONTENTS ... 111 Hot off the press Robert A. Hill and Andrew R. Pitt Reviewing the recent literature on natural products and bioorganic chemistry 559 Recent progress in the chemistry of the monoterpenoid indole alkaloids J. Edwin Saxton Reviewing the literature published in 1996 591 Isopentenyl diphosphate isomerase a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function Ana C. Ramos-Valdivia Robert van der Heijden and Robert Verpoorte 605 Quinoline quinazoline and acridone alkaloids Joseph P. Michael Reviewing the literature published between July 1995 and June 1996 619 Indolizidine and quinolizidine alkaloids Joseph P.Michael Reviewing the literature published between July 1995 and June 1996 637 Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids David O’Hagan Reviewing the literature published between 1995 and 1996 653 Pyrrolizidine alkaloids J. Richard Liddell Reviewing the literature published in 1995 661 Tri terpenoids Joseph D. Connolly and Robert A. Hill Reviewing the literature published between July 1995 and June 1996 681 Book review Phytochemical diversity. A source of new industrial products eds. S. Wrigley M. Hayes R. Thomas and E. Chrystal (reviewed by David O’Hagan) Cumulative Contents of Volume 14 Number 1 1 Brassinosteroids Shozo Fujioka and Akira Sakurai 11 Quinoline quinazoline and acridone alkaloids (July 1994 to June 1995) Joseph P.Michael 21 Indolizidine and quinolizidine alkaloids (July 1994 to June 1995) Joseph P. Michael 43 Lignans neolignans and related compounds (January 1994 to December 1995) Robert S. Ward 75 Cyclopeptide alkaloids (January 1985 to December 1995) Dimitris C. Gournelis Gregory G. Laskaris and Robert Verpoorte Number 2 83 Recent advances in chemical ecology (July 1992 to December 1995) Jeffrey B. Harborne 99 The role of carbohydrates in biologically active natural products Alexander C. Weymouth-Wilson I1 1 The biosynthesis of C,-C, terpenoid compounds (1993 to 1995) Paul M. Dewick 145 Natural sesquiterpenoids (1995) Braulio M. Fraga 163 Fatty acids fatty acid analogues and their derivatives (1988 to 1995) Marcel S.F. Lie Ken Jie Mohammed Khysar Pasha and M. S. K. Syed-Rahmatullah 191 Diterpenoid and steroidal alkaloids (mid 1994 to the beginning of 1996) Atta-ur-Rahman and M. Iqbal Choudhary Number 3 205 Synthesis of amino acids incorporating stable isotopes (1990 to mid 1996) Nicholas M. Kelly Andrew Sutherland and Christine Willis 221 The biosynthesis of the gibberellin plant hormones (up to September 1996) Jake MacMillan 245 Diterpenoids (1995)James R. Hanson 259 Marine natural products (1995) D. John Faulkner 303 Amaryllidacae alkaloids (1995) John R. Lewis Number 4 309 Chemistry and biosynthesis of clavulanic acid and other clavams Keith H. Baggaley Allan Brown and Christopher J. Schofield 335 Biosynthesis of fatty acids and related metabolites (up to end 1994) Bernard J.Rawlings 359 Biosynthesis of plant alkaloids and nitrogenous microbial metabolites (1995) Richard B. Herbert 373 Steroids reactions and partial synthesis (1995) James R. Hanson 387 Phenethylamine and isoquinoline alkaloids (July 1995 to June 1996) Kenneth Bentley 413 Recent progress in chemistry of non-monoterpenoid indole alkaloids (July 1995 to June 1996) Masataka Ihara and Keiichiro Fukumoto 431 Book review Analysis of steroids by L. John Gould and Toshihiro Akihisa (reviewed by James R. Hanson) 432 Corrigendum Number 5 433 Natural products derived from unusual variants of the shikimate pathway Heinz G. Floss 453 Secondary metabolites from marine microorganisms bacteria protozoa algae and fungi Francesco Pietra 465 Coumarins (January 1995 to December 1996) Ana EstCvez-Braun and Antonio G.Gonzalez 477 Monoterpenoids (part 1993 all 1994 part 1995) David H. Grayson 523 Biosynthesis of polyketides (mid 1993 to end 1994) Bernard J. Rawlings 557 Book review Biochemical aspects of marine pharmacology eds. P. Lazarovici M. E. Spira and E. Zlotkin (reviewed by John Mann) 558 Corrigendum Number 6 559 Recent progress in the chemistry of the monoterpenoid indole alkaloids (1996) J. Edwin Saxton 591 Isopentenyl diphosphate isomerase a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function Ana C. Ramos-Valdivia Robert van der Heijden and Robert Verpoorte 605 Quinoline quinazoline and acridone alkaloids (July 1995 to June 1996) Joseph P. Michael 619 Indolizidine and quinolizidine alkaloids (July 1995 to June 1996) Joseph P. Michael 637 Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids (1994 to 1996) David O’Hagan 653 Pyrrolizidine alkaloids (1 995) J. Richard Liddell 661 Triterpenoids (July 1995 to June 1996) Joseph D. Connolly and Robert A. Hill 681 Book review Phytochemical diversity. A source of new industrialproducts eds. S. Wrigley M. Hayes R. Thomas and E. Chrystal (reviewed by David O’Hagan)

ISSN:0265-0568    

DOI:10.1039/NP99714FP011

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

The Royal Society of Chemistry 1998 National Congress and Young Researchers' Meeting University of Durham 6 -9 April 1998 MAIN THEMES Structure-Activity Relationships of Inorganic and Organometallic Systems Tailor-Made Molecules Polymorphism and Related Phenomena in Molecular Solids Macromolecules PLENARY SPEAKERS Professor Sir Harry Kroto (Sussex UK) Professor A Simon (Max-Planck lnstitut fur Festkorperforschung Germany) Professor R Hoff mann (Cornell USA) The organisation of this National Congress (which follows three years after the last annual meeting) represents a radical departure from previous arrangements. The key points are A core two-day programme of four symposia on interdisciplinary themes. Participation of the Analytical Division the Solid State Chemistry Subject Group of the RSC and the Macro Group (UK) of the RSC and SCI in three of the symposia.Symposia sessions arranged to allow participants to follow a cross-theme consistently Special invited lectures on Science and Politics and Science and the Media. A one-day Young Researchers' Meeting to precede the symposia to incorporate the 35th Research and Development Topics meeting (organised by the Analytical Division) and with special participation of the Macro Group (UK) and Solid State Chemistry Subject Groups. An RSC Awards meeting representing outstanding achievements in Chemistry to follow the symposia. This will feature presentations to be given by Professor Sir Jack Baldwin (Oxford UK) Professor G Wegner (Max-Planck lnstitut fur Polymerforschung Germany) and Professor D E Fenton (Sheffield UK).It is expected that the symposia sessions will be organised as far as possible so that participants can if they prefer cross between the themes according to their interests. The cross-themes envisaged are Theory and Modelling Characterisation and Analysis Synthesis and Transformations Industrial Aspects The Society is anxious to encourage poster andlor oral presentations for the Young Researchers' Meeting and poster presentations for the National Congress. To this end all those whose contributions are accepted will have their registration fee waived. Anyone wishing to contribute a paper should submit not later than 14 November 1997 a title and three copies of a synopsis (ca. 100 words) to Dr Gerry Montgomery 1998 Annual Congress The Royal Society of Chemistry Burlington House London W1V OBN.Further details will be given in the Second Circular (available in December 1997) a copy of which can be obtained from Dr Gerry Montgomery 1998 National Congress The Royal Society of Chemistry Burlington House Piccadilly London W1V OBN Fax +44 (0)171-734 1227 E-Mail montgomeryg43 rsc.org using the subject header 98CNGIICC Furtherdetails can also be viewed on the World-Wide Web http://chemistry.rsc.org/rsc/ncong98.htm 12th INTERNATIONAL CONFERENCE ON ORGANIC SYNTHESIS (ICOS-12) VENEZIA Italy JUNE 28 -JULY 2,1998 The conference will emphasize all important aspects of the creative science of Modern Organic Synthesis.Plenary Lectures S.G. Davies (United Kingdom) D.N. Reinhoudt (The Netherlands) S.E. Denmark (USA) P. Sinay (France) D. Kahne (USA) A.B. Smith 111(USA) J. Mulzer (Austria) A. Togni (Switzerland) L. Paquette (USA) H. Yamamoto (Japan) Thieme-IUPAC Prize winner Invited Lectures V. Aggarwal (United Kingdom) M. D. Bachi (Israel) M. Balci (Turkey) J.J. Baldwin (USA) F. Balkenhohl (Germany) Y. Belokon (Russia) K.Bock (Denmark) A. Brandi (Italy) W.Brieden (Switzerland) G. Bringmann (Germany) R. Brueckner (Germany) L. Colombo (flaly) J.P.Genet (France) S. Gibson Thomas (United Kingdom) J.M. Gonziles (Spain) E.M. Gordon (USA) E. Guitian (Spain) T. Hayashi (Japan) R. Haner (Switzerland) H. Hiemstra (The Netherlands) J. Iqbal (India) K.D.Janda (USA) K.A. Jorgenscn (Denmark) E. Juaristi (Mexico) S. Kobayashi (Japan) A.M.P. Koskinen (Finland) M. Lebl (USA) X. Lu (China) N. Mongclli (Italy) W.B. Motherwell (United Kingdom) F. Naso (Italy) I. Patcrson (United Kingdom) R.A. Pilli (Brasil) M. Prato (Italy) P. Rcnaud (Switzerland) A. Ricci (Italy) T. Rossi (Italy) V. Snicckus (USA) A. Solladi&Cavallo (France) A. Umani Ronchi (Italy) G. van Koicn (7'he Netherlands) Y. Yamamoto (.Japan) Contributed Papers The scientific program will include conlribulcd papcrs as oral and poster presentations Further informations and second circular will be available in internet http://www.cilea.it/icosl2 or contacting the 0rgani zi ng Secretariat Scientific Secretariat DEPHA CONGRESS SRL Professor Francesco Nicotra Palazzo Tiepolo Dipartimento di Chimica Organica e IndustriaIe Via Cassanese 224 Via Venezian 21 1-20090 Segrate (MI) (Italy) 1-20133Milano (Italy) fax. +39-2-26.92.9 1.63 tel+39-2-2 169 121 fax. + 39-2-23.64.369 e- mail deph adu@ mbox.vol.it e-mail nicotra@imiucca.csi.unimi.it

ISSN:0265-0568    

DOI:10.1039/NP99714BP013

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann U n iversi ty of Reading Professor D. J. Robins U n ive rsi ty of Glasg ow Dr C. J. Schofield University of Oxford Dr D. A. Whiting University of Notting ham Editorial Staff Editorial Office Dr. Sheila R. Buxton The Royal Society of Chemistry Managing Editor Thomas Graham House Dr Roxane M. Owen Science Park Deputy Editor Milton Road Miss Nicola P. Coward Cambridge Production Editor UK CB4 4WF Dr Carmel M. McNamara Technical Editor Telephone +44 (0) 1223 420066 Mrs Dawn J. Webb Facsimile +44 (0) 1223 420247 Miss Karen L. White E-mail perkin@ rsc.org Edit0 ria I Se ere ta ries RSC Server h tt p://chem ist ry.rsc. org/rsc/ Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bioorganic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis biological activity and chemistry of the major groups of natural products-alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. This is augmented by frequent reviews of the wider context of bioorganic chemistry including developments in enzymology nucleic acids genetics chemical ecology primary and secondary metabolism and isolation and analytical techniques which will be of general interest to all workers in the area.Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the Chairman for consideration at meetings of the Board. Natural Product Reports (ISSN 0265-0568) is published bimonthly by The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF. 1997 Annual subscription rate €355.00; US$640.00. Customers in Canada will be charged the sterling price plus a surcharge to cover GST. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. UK SG6 1HN. Air freight and mailing in the USA by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003.US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11 003. Periodicals postage paid at Jamaica NY 11 431 -9998. All other despatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the UK. Members of the Royal Society of Chemistry should order the journal from The Membership Manager The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge UK CB4 4WF. 0 The Royal Society of Chemistry 1997 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by Henry Ling Ltd at the Dorset Press Dorchester Dorset.

ISSN:0265-0568    

DOI:10.1039/NP99714FX025

出版商:RSC    

年代:1997

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99714BX027

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

Recent progress in the chemistry of the monoterpenoid indole alkaloids J. Edwin Saxton School of Chemistry University of Leeds Leeds UK LS2 9JT Covering 1996 Previous review 1996 13 327 1 General 2 2.1 Monoterpenoid indole alkaloids Corynantheine heteroyohimbine group and related oxindoles and yohimbine 2.2 Sarpagine ajmaline and gelsemine group 2.3 Strychnine group 2.4 Ellipticine uleine and apparicine group 2.5 Aspidospermine group 2.6 Vincamine group 2.7 Catharanthine and ibogamine group 3 Bisindole alkaloids 4 Biogenetically related quinoline alkaloids 4.1 Cinchona group 4.2 Campto thecin 5 References 1 General Volume 48 in the Manske-Cordell series of monographs includes a very useful survey by Sevenet and Pusset of the alkaloids from the medicinal plants of New Caledonia which naturally contains reference to a wide range of monoterpenoid indole alkaloids and two superb surveys of progress in the chemistry of the Strychnos alkaloids during the last seven years (Bosch and his collaborators) and the Aristotelia alkaloids since 1983 (Borschberg).' 2 Monoterpenoid indole alkaloids 2.1 Corynantheine heteroyohimbine and yohimbine group and related oxindoles The bark of Strychnos mellodora S.Moore collected in the Chirinda rain forest of Zimbabwe contains strictosidine Edwin came to my room one day and asked for a back issue of Natural Product Reports 'X (a distinguished alkaloid chemist) has just published a paper on an Aspidosperma alkaloid.I need to check but I am sure he has got the stereochemistry at C-20 wrong.' If you know Edwin and his formidable memory and meticu- lous attention to accuracy you will know that he was right about the C-20 stereochemistry. Edwin has had a distinguished career in alkaloid chemistry founded in research he did with Sir Robert Robinson and R. B. Woodward. He was first Senior Reporter for the Specialist Periodical Reports on The Alkaloids and here and later in Natural Product Reports reviewed the indole alkaloids in a scholarly and comprehensive way. He has been the energetic editor of several definitive monographs on the indole alkaloids. If you worked with him on these you were reminded quietly about good English accurate science and schol- arship.Edwin has now decided that this is the last report he will write for NPR. We shall miss his distinguished contributions. Richard Herbert July 1997 dolichantoside and palicoside,2 and (1 6S)-(E)-isositsirikine is one of twelve alkaloids of the root bark of Tanzanian Strych- nos panganensis Gilg3 Its epimer (1 6R)-(E)-isositsirikine has been isolated together with (5S)-5-methoxycarbonyl-strictosidine 1 from the suspension culture of hybrid cells "&o .. Me02C 1 (5S)-5-Methoxycarbonylstrictosidine derived from RauwolJia serpentina and Rhazya stricta; these alkaloids have not been found in either of the parent plants which thus shows that the function of alkaloid biosynthesis is retained after hybrid f~rmation.~ The bark of Strychnos guaianensis (Aubl.) Mart.collected at Manaus (Brazil) contains5 9-methoxygeissoschizol 2 while its isomer 10-methoxygeissoschizol occurs together with P-yohimbine and two new bisindole akaloids in the stem bark and seeds of Aspidosperma ramiflorum Muel1.-Arg. from Porto Ferreira Brazil6 OMe I \c&H OH 2 9-Methoxygeissoschizol 3 Deppeaninol Deppeaninol3 is a new alkaloid which has been found in a Brazilian Rubiaceae Deppea blumenaviensis S~humann;~ its structure was determined by analysis of its NMR spectrum and comparison with that of tetrahydroakagerine. Hirsuteine hirsutine and 3a-dihydrocadambine have been isolated from the callus cultures of Uncaria rhynchophylla Miq.; this last alkaloid was obtained in amounts 50 times greater than have been observed in the hooks and stems of this plant which are the active ingredients of the crude drug 'chotoko' used in traditional medicine as a spasmolytic analgesic and sedative and for the treatment of a variety of ailments including hypertension dizziness cerebral arteriosclerosis and convulsions.* The roots of Catharanthus roseus have again been reported to contain ajmalicine,'" while the stem bark of Panamanian Stemmadenia obovata Benth.contains an unusual mixture of iboga and heteroyohimbine alkaloids the latter group being represented by ajmalicine and an epimeric mixture of ajmali- cinine and 17-epiajmalicinine 4; this last alkaloid has not been previously described. 9b Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids HH OH OH 4 17-Epiajmalicinine 5 18-Hydroxyepialloyohimbine Me02C CH20H 6 16-Hydroxymethylpleiocarpamine Yohimbine and p-yohimbine are two of the constituents of the aerial parts of Texan Haplophyton crooksii L.Benson." 18-Hydroxyepialloyohimbine5 has been found in the air-dried leaves of Peruvian RauwoQia sprucei Muell.-Arg. and 3-epi-a- yohimbine in the air-dried stems.' la Apparently no trace of the alkaloids claimed earlier to be present in this species purely on the basis of a paper chromatographic examin- ation by Korzun et al.,llh could be found. Finally 16-hydroxymethylpleiocarpamine 6 is one of three new alkaloids isolated from the stem bark of Kopsia deverrei;I2 its structure was confirmed by deformylation with sodium hydride in toluene which gave pleiocarpamine.A new approach to indoloquinolizidine synthesis involves as the critical stage the cyclization of a tetrahydro-P-carboline cyanoaldehyde 7 generated in situ by the decarboxylative ring opening of a carboxyisoxazole 8 (Scheme 1).l3 Other workersI4 have generated the indoloquinolizidine system as in 9 en route 10 Me ii iii H H' Iv Me0 0 I II H H' U U MeO$AC02Me 9 Scheme 2 Reagents i PdCI2(PPh3), DIBAL THF heat; ii NaOH EtOH H20 heat; iii LDA THF then ClCO,Me 25 "C; iv H, PtO, EtOH; v ClCH,CON(OMe)Me Nal K,CO, MeCN 45°C; vi Red-Al PhMe -25 "C; vii Et,SiH TFA CH,CI, heat HH HH OHC Me 1 la Strictosamide 3a-H 12a Naucleidinal 3a-H 11b Vincosamide 3P-H 12b 3-Epinaucleidinal 3P-H -'Q-qNH H N Q-QNH H \ N Scheme 3 Reagents i P-Glucosidase; ii 10% pyIH,O 110 'C 5 h f I H02C+) NC*CHKIJ N-0 7 8 I t -CN Scheme 1 Reagent i DMF 100 "C to the Corynanthe alkaloids by the Pdo-catalysed coupling of a 2-indolylzinc derivative 10 with a 2-halopyridine followed by deprotection stereoselective hydrogenation of the pyridine ring N-alkylation and cyclization stages (Scheme 2).A biomimetic conversion of strictosamide lla into nauclei- dinal 12a the alkaloid of Nauclea latifolia and N. oficinalis has been achieved by removal of the glucose unit and heating the resulting strictosamide aglycone in aqueous pyridine (Scheme 3).15 The stereochemistry of the product was estab- lished by the observation of a NOE between H-15and H-19 and by the large J,,,, and J15,, coupling constants which argues for an axial arrangement of hydrogen atoms at C-15 560 Natural Product Reports 1997 C-19 and C-20; further the CD spectrum reveals that nauclei- dinal contains a-hydrogen at C-3.Similarly vincosamide llb the 3C)-H epimer of lla gives 3-epinaucleidinal 12b which has so far not been found in nature. New syntheses of flavopereirine 13 and deplancheine have been reported. The flavopereirine synthesis16 makes further use of the previously prepared tetracyclic allylic acetate 14.l7 A Polonovski-Potier reaction on the N-oxide of 14 followed by elimination of acetic acid resulted in the aromatisation of ring D with formation of 5,6-dihydroflavopereirine15 the conver- sion of which by means of DDQ into flavopereirine 13 is already known (Scheme 4).Alternatively reduction of the immediate Polonovski-Potier product by means of sodium borohydride gave a mixture of (E)-and (2)-14,15-didehydroplancheine 16a and 16b. Similar treatment of the malonyl ester 17a gave a mixture of products which included 16a 16b the parent allylic alcohol a trace of deplancheine and its 15,2O-double bond isomer. l8 The same group have also continued their investigations into the possibility of applying the Claisen rearrangement to the synthesis of corynantheine drivatives.'' Here the orthoma- lonate 18a derived from the same parent allylic alcohol as 14 and 17a was rearranged thermally in dry 1,4-dioxane or toluene to give a mixture of the malonic ester derivative 19a (on 14) H H' H H" A Et "rl.OR 15 5,6-Dihydroflavopereirine Me 14 R=Ac 1 21 \C02Me 17a R = COCH2C02Me iv i ii1 Et 13 Flavopereirine v 1 (from 17a) \. l5 \ '\ Oy% $q-+ Deplancheine 16a 14,15-Didehydro-(E)-deplancheine + 16b 14,15-Didehydro-(Z)-deplancheine Scheme 4 Reagents i rn-CPBA; ii TFAA; iii MeOH HC1 H,O rt; iv DDQ; v NaBH with a 192 configuration of the 19,20-double bond together with its stereoisomer 20 and the 19R ester 17c (Scheme 5). Similarly the 19s epimer 18b gave a mixture of 19b and 17b. This would appear to be the first example of the successful use of orthomalonates in Claisen ester rearrangements.By use of methods previously published,20 21 Lounasmaa and his co-workers have prepared22 the four possible deformylgeissoschizines 21 together with their N tert-butoxycarbonyl (N,-Boc) derivatives their cis Nb-oxides and two of their trcrns Nb-oxides. The predominant conformations i ii or i iii ___) % H H" OH of these compounds were determined from their NMR spectra full details of which were given together with assignments. These data will be valuable in future determinations of stereostructures of geissoschizine derivatives. The earlier synthesis of the geissoschizine isomers" by Lounasmaa and his co-workers has been refined and has resulted in a reasonably efficient synthesis of ( f)-(a-geissoschizine itself.23 The easily accessible mixture of ( f)-(2)-geissoschizine 22 and ( f)-3-epi-(E)-geissoschizine23 was Me02C3 OR OR 22 R=H 23 R=H 24 R=Boc 25 R= BoC i-iii H y+y H Me02C+ ' MeO2c3 ' OBoc OH 26 27 (E)-Geissoschizine Scheme 6 Reagents i rn-CPBA; ii TFAA Ar -16 "C then 0 "C; iii NaBH, MeOH; iv HC0,H H H' Et02C7" EtO OEd 18a 19R 9s 18b1 4 f Et02C*C02Et Et0& *COdEt Et02C70 19a 15a-H 20 17c 19R 19b 15P-H 17b 19s Scheme 5 Reagents i EtO,CCH,C(OEt), AcOH; ii dry 1,4-dioxane heat; iii PhMe heat Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids converted into a mixture of 0-Boc derivatives 24 and 25 which was isomerized by a Polonovski-Potier reaction on the related N,-oxides followed by reduction by means of sodium boro- hydride (Scheme 6).The product proved to be a mixture of unchanged 24 and 25 together with the 0-Boc derivative of 0A ( f)-(E)-geissoschizine 26 from which ( f)-(E)-geissoschizine + 27 could readily be obtained by hydrolysis. Repetition of this SPh sequence of reactions on 24 and 25 gave more (&)-(a-geissoschizine 27 which was eventually obtained in 40% yield. This isomerization presumably proceeds by appropriate pro- ton exchanges on the 21,Nb- or 3,Nb-iminium ions generated in the Polonovski-Potier reaction. A new synthesis of ( f)-geissoschizine 27 has been designed specifically to circumvent the problems usually associated with generating the desired relative stereochemistry at C-3 and C-15 by incorporating these centres at bridgehead positions in the intermediate 28 constructed as shown in Scheme 7.In common with earlier experience in this area borohydride reduction of the acid derived from 28 gave the required E alkene 29. Ring C was then closed by Pummerer cyclization of the related sulfoxide and the product was then converted into deformylgeissoschizine 30 by methanolysis of the lactam ring followed by removal of the phenylthio There is ample precedent for the con- version of deformylgeissoschizine 30 into geissoschizine 27.25 The general strategy outlined in Scheme 7 has also been used in the preparation of derivatives of apogeissoschizine. Here the tetracyclic intermediate 31 prepared in similar fashion to 28 was debenzylated and simultaneously hydrogenated to give the amino ester 32 which was then reacted with bis(methy1- thio)acetaldehyde and the thioacetal so produced was cyclized by means of dimethyl(methy1thio)sulfonium tetrafluoroborate (Scheme 8).Hydrogenation of the product then gave tetra- hydroapogeissoschizine 33. Alternatively ring C could be closed by photocyclization of the N,-ChlOrOaCetamlde derived from 32 which gave the pentacyclic 2-hydroxyindoline derivative 34. Dehydration of 34 gave an unstable indole but reduction of 34 by sodium cyanoborohydride gave the pentacyclic indoline 35.26 2,7-Dihydroxyapogeissoschizine36 the alkaloid recently isolated from the root bark of Strychnos go~sweileri,'~ has been synthesised by acid-catalysed cyclization of geis- soschizine methyl ether 37 and hydroxylation of the apogeis- soschizine 38 so formed (Scheme 9).27Contrary to the earlier proposal 2,7-dihydroxyapogeissoschizineis now formulated with a cis-quinolizidine ring junction; this is consistent with the NOE data and with molecular orbital calculations which show that a cis-quinolizidine conformation is favoured.H' ___) 'H .'H Et C02Me C02Me 31 32 vi vii viii t- C02Me C02Me 35 34 C02Me I \C02Me SPh SPh I l iii iv H-c-H" 'H 29 28 \C02Me v vi 1 SPh vii viii ___t 0 'H Me02C/ 30 (Ref. 25) I 27 Geissoschizine Scheme 7 Reagents i LDA THF; ii TsOH PhH LiI THF rt; iii 2.5 M. HCl 100 "C; iv NaBH, MeOH 0 "C; v TFA then rn-CPBA -70 "C; vi TMSOTf PrI2 NEt CH,CI, rt; vii NaOMe MeOH THF rt; viii Bu,SnH AIBN PhH heat Details of the synthesis" of (+)-vallesiachotamine and ( -)-isovallesiachotamine by Amann et al.have been published.28 SMe I H" H' . Et 'H 'H C02Me C02Me 1" C02Me 33 Scheme 8 Reagents i separation of C-16 epimers; ii H, Pd(OH), MeOH; iii (Me S) CHCHO NaBH,CN MeOH rt; iv DMTSF CH,Cl,; v H, Pd/C MeOH; vi ClCH,COCl NEt, THF 0 "C; vii hv MeOH H,O rt; viii NaBH,CN MeOH HCl 0 "C 562 Natural Product Reports I997 I Me02C OMe C02Me 37 Geissoschizine methyl ether 38 Apogeissoschizine ii iii I OH C02Me 36 2,7-Dihydroxyapogeissoschizine Scheme 9 Reugmts i conc. HCI AcOH rt; ii OsO, py THF 0 "C; iii NaHSO The oxidative rearrangement of yohimbine 39 has been reinvestigated and the course of the reaction has been clari- fied.29 In consonance with previous reports treatment of yohimbine with tert-butyl hypochlorite gives a mixture of two 7-chloroindolenine derivatives 40 and 41 of which the latter is now shown from NMR evidence to have a cis-quino-lizidine C/D ring junction a conclusion that was confirmed by extensive force-field calculations.Methanolysis of the 7-chloroindolenine derivative 40 under appropriate conditions gives exclusively the imino ether 42 which on acid hydrolysis gives a mixture of the oxindole derivatives 43 and 44 (Scheme 10). In contrast the behaviour of the 7-chloroindolenine 41 was complex the products depending on the reaction conditions.When heated in methanol 41 gave the isomeric imino ethers 42 and 45 but when heated with sodium meth- oxide in methanol 42 and 45 were accompanied by the 3,14-didehydro derivative 46 some yohimbine and the 3,4,5,6- tetradehydro salt 47. Other observations included the ready equilibration of the imino ethers 42 and 45 in methanol or chloroform and the exclusive formation of the oxindole B derivative 44 with retention of configuration at C-7 by the hydrolysis of 45 in the presence of a very strong acid. The divergent reactivity of the chloroindolenines 40 and 41 was further examined by extensive force-field calculations and semi-empirical calculations of various conformers of compounds 40-42 and 45.The isomerization of the spiro-oxindole alkaloids mitraphyl- line 48 isomitraphylline 49 pteropodine isopteropodine 0-0 50a It - 0- 49 50b Scheme 11 speciophylline and uncarine F in aqueous solution has been investigated and the rate coefficients have been determined.30 The results are consistent with the participation of a zwitter- ionic intermediate 50 stabilised by polar solvents and show that protonation of the alkaloids inhibits isomerization (Scheme 11). This paper also includes details of the X-ray crystal structure determination of pteropodine 51. The stereochemistry of mitragynine pseudoindoxyl 52 yohimbine pseudoindoxyl53a and P-yohimbine pseudoindoxyl 53b has been deduced from their NMR and CD ~pectra.~' Reduction of reserpine by means of sodium cyanoboro- hydride in trifluoroacetic acid gives the 2,7-dihydro derivative 54 which on reaction with formaldehyde and sodium cyanoborohydride gives the N,-methyl derivative 55.Further HO HO 47 46 Scheme 10 Reugents i Bu'OC1 CH2C12 -17 "C; ii NaOMe MeOH 25 "C;iii 10%AcOH H20 heat; iv 0.5 M NaOMe MeOH heat; v MeOH heat 40 h; vi MeOH or CHC1,; vii CF,.SO,H CH,Cl, H,O 25 "C 6 h Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids H Me rN-0 nTflNH2 H 'Br i-iii TMS H 51 Pteropodine v-viii .t.-H Et H- 'H Me02C OMe 52 Mitragynine pseudoindoxyl Me02C -~ HO 53a Yohimbine pseudoindoxyl a-OH 53b P-Yohimbine pseudoindoxyl P-OH methylation with the same reagents occurred in the presence of trifluoroacetic acid to give the dimethyldihydro derivative 56;32 however this last compound could be obtained more efficiently MeO2C-OCO -@:Me OMe OMe 54 R' = R2 = H 55 R' =Me; R2= H 56 R' = R2 = Me from reserpine in a one-pot reaction by treating a solution of the alkaloid in trifluoroacetic acid with sodium cyanoboro- hydride at 25 OC followed by an excess of formaldehyde at -5 "C.3-Isoreserpine and tetraphylline behaved similarly. Lounasmaa and his co-workers have completed the first ab initio synthesis33 of 1 0-methoxydihydrocorynantheol 57; previously it had only been obtained by transformation vii viii v c- OH 57 10-Methoxydihydrocorynantheol20P-H 61 10-Methoxycorynantheidol 20a-H w 63 QYTH H,' 65 Yohimbane P-H 66 Alloyohimbane a-H Scheme 13 Reagents i Na,CO, EtOH rt; ii hexa-3,5-dienoyl chlo- ride NEt, CH,Cl, -78 "C; iii Boc,O DMAP CH,Cl, rt; iv 20 mol% Ni(COD), 60 mol% P(O'C,HF,), THF 25 "C; v RhCI(PPh,), H, CH,CI, rt; vi TsOH MeCN THF H,O heat; vii POCl, C,H, heat; viii NaBH, MeOH; ix,H, PtO, EtOH from quinine.The synthesis proceeds via the quaternary salt 58 prepared from 5-methoxytryptophyl bromide and 3-acetylpyridine. Reduction of 58 followed by cyclization re-aromatization and a further reduction stage then gave a mixture of 19-epimeric allylic alcohols from which the desired epimer 59 was separated by chromatography. A Claisen rearrangement on the orthoacetate derived from 59 then gave 1 O-methoxy- 16-deformyl-(Z)-geissoschizine 60 which was reduced to a separable mixture of 10-methoxydi-hydrocorynantheol 57 and 1 0-methoxycorynantheidol 61 (Scheme 12).Wender and Smith34 have developed a novel method for the construction of the yohimbane ring system which in its critical vi I OH \C02Me 60 59 Scheme 12 Reagents i Na,S,O, NaHCO, H,O MeOH; ii AcCl MeOH N, 0 "C;iii maleic acid Pd/C H,O N, heat; iv NaBH, H,O MeOH; v separation of epimers; vi MeC(OMe), AcOH l,bdioxane 95 "C; vii LiAlH, THF; viii H, PtO, MeOH 564 Natural Product Reports 1997 stage involves a Nio-catalysed intramolecular cycloaddition. H Me02C ,,CH20H The N-acyltryptamine derivative 62 prepared in three stages from tryptamine as shown in Scheme 13 was cyclized at room temperature in the presence of bis( 1,5-cyclooctadiene)nickel and tris(hexafluoroisopropyl)phosphite to give the tetracyclic amide 63 in 88% yield the electron-withdrawing phosphite ligand exerting an accelerating effect on the cycloaddition.Selective hydrogenation of the less highly substituted double bond in 63 followed by protiodesilylation of the vinylsilane 70 1O-Methoxy-N,-methylpericyclivine 71a 16-Epideacetylakuammiline function with concomitant removal of the tert-butoxycarbonyl group gave an intermediate which on Bischler-Napieralski cyclization and reduction by sodium borohydride gave 19,20- didehydroyohimbane 64. Hydrogenation of 64 then gave an equimolecular mixture of ( f )-yohimbane 65 and ( f )- alloyohimbane 66.An independent synthesis of Stork's ring E intermediate 67 from methyl vanillate constitutes a new formal synthesis of 71b te~i.~' 16-Epideacetylakuammiline 71a is one of three new alkaloids extracted from the stem bark of Kopsia deverrei;'* its structure was confirmed by deformylation with sodium hydride in toluene which gave a mixture of strictamine 16-epistrictamine and a dimeric species 71b which is simply an esterification product from 16-epideacetylakuammiline and 16-epistrict-amine. The most recent extractions of the bark of Alstonia angustifolia have revealed the presence of alsto-phyllne 19,2O-didehydro- 1O-methoxytalcarpine affinisine and norma~usine-B,~~ while the leaves and stems of Peruvian RauwoIJia spruce? lU contain lochnerine 18-hydroxylochnerine lochneram and perakine; the stems of this species also contain spegatrine the Nb-methosalt of sarpagine.The roots of RauwoIJia sellowii Muel1.-Arg. are used in Brazilian folk medicine as the source of a hypotensive drug. Previous extractions have yielded ajmalidine and ajmalinine but a more recent investigation on plants collected in two locations in Brazil has resulted in the isolation of two differ- ent sets of alkaloid^.^' The leaves of a specimen from Curitiba Parana were shown to contain raucaffrinoline perakine perakine dimethyl acetal (which was admitted to be an artefact) and a new alkaloid sellowiine 72 which H 72 Sellowiine Me-0 H 73 19a-Hydroxygelsamydine contains the same ring system as suaveoline.On the other hand the leaves of a specimen from Marcelino Ramos Rio Grande do Sul yielded sellowiine vomilenine picrinine and 12-demethoxytabernulosine(1 O-methoxypicrinine). Yet another new alkaloid 19a-hydroxygelsamydine 73 has been isolated from Gelsemium elegans grown in the Guangxi Province of China.41 Jokela and Lo~nasmaa~~ have presented complete proton and I3C NMR data for normacusine B (E)-akuammidine pericyclivine polyneuridine and voachalotine. Several earlier misinterpretations in the literature have been corrected and reserpine.35 Me02COH 5 O OMe 67 H Lounasmaa and Hanhir~en~~ have attempted to prepare the pentacyclic sarpagan ring system by an intramolecular cyclization of a 5,Nb-iminium ion e.g.68 derived from the corresponding tertiary base by a Polonovski reaction on the corresponding cis Nb-oxide. The reaction was attempted on four substrates related to 68 but no cyclization was observed in any of the examples chosen although the formation of 5-cyano derivatives e.g. 69 showed that the desired iminium ion had been formed (Scheme 14). i ii Et02ChCOpEt EtO2C*Co2Et 68 ji' liii Et02C Et02C*C02Et 69 Scheme 14 Reagents i m-CPBA CH2Cl,; ii TFAA CH2CI, Ar -17 "C; iii KCN H20 2.2 Sarpagine ajmaline and gelsemine group 1O-Methoxy-N,-methylpericyclivine 70 is a new alkaloid which occurs together with akuammidine lanceomigine and its N-oxide and eleven other alkaloids in the aerial parts of Haplophyton crooksii.lo Dregamine tabernaemontanine akuammiline and deacetylakuammiline have been isolated from the bark of Kopsia macrophylla Hook. f.;37 the last two alkaloids have also been found in the stem bark of Kopsia Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids the data for polyneuridine are now claimed to be reported for the first time the earlier published data now being regarded as those relating to its C-16 epimer (E)-akuammidine. The authors also record authentic data for (a-akuammidine and state that the earlier reported data were not those of this alkaloid but those of a different unidentified base. Earlier attempts to construct the akuammilan ring system have foundered owing to the failure to form the 6,7-bond or the 7,16-bond in appropriate tetracyclic intermediates.One of the more recent essays in this area involved the compound 74 which was prepared43 as shown in Scheme 15 However all attempts to form the 6,7-bond by chemical processes on 74 or its N,-methoxycarbonyl derivative failed and photocyclization of the related N-chloroacetyl derivative 75 gave a lactone 76 in which two additional carbon atoms had been introduced. Since some parent secondary amine related to 75 was also isolated it tractable substrate for the completion of the akuammiline skeleton and may have the advantage that it could also serve as a late intermediate in a synthesis of alkaloids of the echitamine series. For this purpose the intermediate 77 pre-pared by exactly the same route as 74 was quaternized by reaction with phenylsulfinylacetyl choride and the resulting isogramine derivative suffered elimination to give a dihydro- carbazole derivative which was reduced to the tetrahydro- carbazole 78.Oxidation to the related sulfoxide 79 followed by a Pummerer rearrangement gave an acyloxysulfoxide which cyclized on to the P-position of the indole ring when heated in dichloromethane; reduction of the methyleneindoline double bond in the product then gave the indoline 80. Removal of the phenylthio group then gave the 3,Nb-secoakuammilan derivative 81 (Scheme 1 5).44 ( -)-Anhydromacrosalhine methine 82 one of the compo- nents of the bisindole alkaloid macrocarpamine has been obtained by partial synthesis from (+)-ajmaline 83 and also by total synthesis.45 The hemicaetal 84 previously prepared46 from ajmaline as shown in Scheme 16 was first dehydrated to C02Me deoxyalstonerine 85.Since allylic bromination at C-19 in 85 failed it was subjected to regioselective oxyselenation by means of N-(phenylseleny1)phthalimide.Oxidative elimination of the phenylselenyl group in the product 86 then gave the a*, allylic alcohol 87 which on dehydration gave anhydromacro- COCHzCI '0 salhine methine 82 (Scheme 16). For the total synthesis 75 76 is clear that the chloroacetic acid released in its formation reacts with 75 or its immediate cyclization product to give eventually 76. In view of these results an alternative approach was adopted,44 in which the 6,7-bond was formed in a 3,Nb- seco derivative of 74; the product was thus a 3,Nb-secoakuammilan derivative which may prove to be a more OAc C02Me I of 82 Gan and Cook45 took advantage of the availability of ( -)-alstonerine 88 by enantioselective synthesis from ~-(+)-tryptophan.~'Reduction of 88 by means of sodium borohydride followed by dehydration then gave ( -)-anhydromacrosalhine methine 82 (Scheme 16).Bosch and his co-workers have developed a short route to the silicine-methuenine group of alkaloids,48 and have applied it in a synthesis49 of ( f)-6-oxo-l6-episilicine 89. The synthesis begins with the familiar condensation of a pyridinium salt 90 ii-iv I + QTl I H ( COZMe C02Me \CO2Me OAc 74 OH 80 CH2Ph PhCH2 PhCH2 0 0 77 78 79 Me 81 Scheme 15 Reagents i LDA THF N, -70 "C then -40 "C; ii MeOH 10% KOH H,O; iii HCI H,O; iv NaBH, MeOH; v PhSCH,COCl PhMe heat; vi Et,SiH TFA; vii rn-CPBA CH,Cl, -70 "C; viii TFAA CH,Cl,; ix NaBH,CN; x Raney Ni EtOH 566 Natural Product Reports 1997 83 (+)-Ajmaline 84 1 ii H H aTq iiiaTq \ NMe f-\ NMe / Me I OH SePh Me ,H H 86I iv 85 U H 87 82 Anhydromacrosalhine methine vi v 88 (-)-Alstonerine Scheme 16 Reagents i see ref.46; ii TsOH PhH heat; iii N-(phenylselenyl)phthalimide,TsOH CH,C12 H,O; iv NaIO, THF H,O; v TsOH THF; vi NaBH, THF with the anion from a 2-acylindole. The product 91 was regioselectively hydrogenated then cyclized by means of trimethylsilyl polyphosphate to give the desired ring system 92.Subsequent stages included Barton decarboxylation of the acid derived from 92 removal of the N-benzyl group and reduction of the enamine double bond which gave a mixture of ( f)-6-oxo- 16-episilicine 89 and the related alcohol Me i-iv O y PhH2C 0 PhH2C C02Me 90 0 93 X=H,OH xii K89 6-0x0-16-episilicine X = 0 93 which could be reoxidised to 89 by manganese dioxide (Scheme 17). In another application of this synthetic approach the same workers have completed a synthesis5' of 19,20-didehydroervatamine 94. Here the dihydropyridine derivative 95 was prepared exactly as was 91; selective hydrogenation of 95 followed by obvious stages then gave the intermediate diol 96. At this point the final carbon atom for the ervatamine ring system was introduced by reaction of 96 with Eschenmoser's salt and ring C was closed by internal alkylation of the enamine system.Reduction of the product 97 gave ( f)-19-hydroxy-20-epiervatamine 98 which on elimination gave ( f)-19,2O-didehydroervatamine94; alternatively removal of the secondary hydroxy group in 98 gave ( f)-2O-epiervatamine99 (Scheme 18). Since 19,2O-didehydroervatamine94 has already been converted into ervatamine this work also constitutes a formal synthesis of ervatamine. The asymmetric synthesis of ( -)-suaveoline 100 by Bailey and Morgan," starts essentially with the nitrile 101 prepared by obvious stages from L-tryptophan and is a relatively brief synthesis in which the key stage is the exclusive formation of the cis-tetrahydrocarbazole derivative 102 by reaction of 101 with a protected P-hydroxypropionaldehydein a cis-selective kinetically-controlled Pictet-Spengler cyclization.Conven-tional stages then led to the unsaturated bis-nitrile 103 which was cyclized by base to the tetracyclic bis-nitrile 104. Con-trolled reduction of 104 to the diimine was accompanied by oxidative cyclization to N-benzylsuaveoline 105 which on debenzylation of its hydrochloride gave ( -)-suaveoline 100 (Scheme 19). The fourth synthesis of gelsemine 106 (Scheme 20) to be recorded is a lengthy one of some 30 stages in which the central bicyclo[3.2. llheptane framework is constructed in a stereocontrolled reaction by a divinylcyclopropane-cycloheptadiene rearrangement.52 The initial stage involved the condensation of methyl acetoacetate with sorbic aldehyde followed by protection of the secondary alcohol so formed as an acetal 107.Conversion of 107 into a diazo derivative and copper-catalysed insertion of the derived carbenoid into one of the double bonds then gave the cyclopropyl ester 108 which was converted into the aldehyde 109 by conventional stages. The oxindole function was now introduced by condensation of 109 with 4-iodooxindole the exclusive product having the desired geometry shown in 110. Further unexceptional stages then gave the divinylcyclopropane intermediate 111 which was thermally rearranged to the cycloheptadiene derivative 112a. The structure of 112a was established by the X-ray crystal structure analysis of the corresponding bromide 112b ~ q M e v QyLQMe 0 \ PhH2C o i C02Me C02Me 91 0 0 C02Me 92 Scheme 17 Reagents i LDA THF -30°C; ii (Cl,C-CO),O 0°C; iii separation of isomers; iv MeONa MeOH; V H, PtO, EtOAc; vi trimethylsilyl polyphosphate 110 "C; vii LiOH MeOH H20 heat then 1 M HCl; viii 2,2'-dithiobis(pyridine N-oxide) Bu,P CH,Cl, rt; ix Bu'SH hv 5-20 "C;x AlCl, PhH rt; xi NaBH,CN MeOH AcOH rt; xii MnO, CHCl Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids u IVlt! 95 C02Me C02Me @ T G M e -a-))Me MeP"OH OH Me/.'OH OH Me/-.OH 98 97 zQ)-Jy C02Me HI 0 Me/"OMs Me 99 20-Epiervatamine 94 19,20-Didehydroervatamine Scheme 18 Reagents i H, PtO, MeOH THF; ii AlCl,; iii LiBEt,H; iv CH,=N+Me,I- CH,Cl,; v MeI DMSO rt then 70 "C; vi NaBH,CN MeOH; vii MnO, CHCl,; viii MsCl NEt,; ix LEI MeCOMe heat; x Bu",SnH AIBN PhH heat; xi DBU PhMe 80 "C prepared by exactly the same route.Manipulation of 112a as which has not previously been encountered from a natural shown in Scheme 20 eventually gave the urethane 113 the last source has been extracted from the leaves of RuuwoEJu sellowii stage in this sequence involving a modified Curtius reaction. collected at Marcelino Ramos Brazil.40 Compactinervine Replacement of the ally1 ester group in 113 by a chlorocarbo- occurs in the leaves of Peruvian Rauwo@u sprucei,"" and nyl group gave the substrate 114 for closure of the five- 14~-hydroxycondylocarpine (14aH-hydroxycondylocarpine) membered ring encompassing Nb.This was achieved by an 118b a new alkaloid in the stem bark of Kopsia deverrei.I2 The unprecedented cyclization when 114 was treated with silver configuration of the hydroxy group in 118b follows from its 5.0 Hz, triflate and silver carbonate which gave the unusually stable NMR spectrum since H-14 exhibits J3ax,14=J3eq,14= carbinolamine derivative 115. Decomposition of 115 with acid and H-15 exhibits J,4,15=2.5 Hz appropriate to an equatorial gave the aldehyde 116 which on reaction with Tebbe's reagent (a) hydrogen at C-14 provided that ring D assumes a chair gave the vinyl derivative 117. The gelsemine ring system was conformation. Of the 12 alkaloids of the root bark of Strych-then completed by internal oxymercuration of the 3,14-d0uble nos panganensis from Tanzania six belong to this group; these bond in 117; deprotection and reduction stages finally gave are 12-hydroxy-1 1 -methoxydiaboline N-deacetylretuline gelsemine 106 (Scheme 20).52 N-deacetylisoretuline and three new alkaloids which were identified as N-deacetylspermostrychnine 119 12-hydroxy-1 1 -methoxynor-C-fluorocurarine 120 and 12-hydroxy-l l-2.3 Strychnine group methoxy-N-acetylnor- C-fluorocurarimine 121.This last Akuammicine and tubotaiwine have been found in the aerial alkaloid seems likely to be an artefact since ammonia was used parts of Haplophyton crooksii together with a new alkaloid in the extraction 16-decarbomethoxyvinervinine (strictly decarbomethoxy-2,16- 12-Hydroxymalagashanine 122 is a new alkaloid which dihydrovinervinine) 118a" and 19a,2Oa-epoxyakuammicine occurs together with malagashanine in Strychnos myrtoides ~ Qj-YHc~ NCH2Ph -iii-v vi vii NCH2Ph QTTcN H HI Me 101 I\/OSiPh2But 102 Et CN 103 viii 1 q Me AQ T Me H' P h CN aTw ay-Et Et Et 100 (-)-Suaveoline 105 104 Scheme 19 Reagents i OHCCH,CH,OSi Ph,Bu' CH,Cl, 3 8,mol sieves 0 T;ii TFA -78 "C to rt; iii PhCH,Br 70 OC; iv MeI NaH DMF 0°C; v TBAF THF rt; vi (COCI), DMSO CH,Cl, -6O"C then NEt, -60°C to rt; vii EtC(CN)PO(OEt),; viii KOBu' THF 0°C; ix DIBAL CH,Cl, 0 "C to rt; x EtOH HCl; xi H, PdC EtOH 568 Natural Product Reports 1997 iv CH3COCH2C02Me h i ii *Jo N2 C02Me MeCH=CH-CHr CH-CHO 0 107 108 v-viii -flLq fl'?I &H xii C02Me I c-C02Me I c-P C C02Me x,xi jx HO Me02C \/ 0 HO HO 111 110 109 HvC02B~' Me!&MoM '-xvii xviii vi ____) CH20Ac xix-xxi NHC02Et ,NHC02Et 3-OM xxv xxiv Me' xxii xxiii Me" "&-I f-t-CH20H \ / 116 115 114 113 xxvi xxvii xxviii xxix xxx xxxi 117 21-0xogelsemine 106 Gelsemine Scheme 20 Reagents i NaH THF 0 "C then BuLi 0-23 "C; ii EtOCH=CH, POCl, CH,CI,; iii TsN, NEt, CH,Cl,; iv Cu(acac) (cat.) CuSO, PrH 85 "C; v NaBH, MeOH 0 "C; vi Ac,O py; viii TsOH Pr'OH H,O; viii 0, 10% MeOH CH,Cl, -78 "C then Me,S -78 "C to +23 "C; ix 4-iodooxindole piperidine MeOH; x DCC DMSO pyCF,CO,H; xi NEt, CH,Cl,; xii PhMe MeCN 90 "C; xiii Bu,SnH AIBN PhMe 95 "C; xiv (EtO),POCH,CO,Bu' BuLi THF 65 OC; xv MOMCI Bu'OK; xvi MeNH, MeOH; xvii ClCO,CH,CH=CH, py DMAP CH,Cl,; xviii LiBH, LiBEt,H THF; xix HC0,H; xx CICO,Et NEt, THF; xxi Bu,N.N, PhMe NEt, heat then EtOH; xxii Pd(PPh,), PPh, pyrrolidine CH,Cl,; xxiii COCl, 2,6-lutidine CH,Cl,; xxiv AgOTf Ag,CO, CH,Cl,; xxv 3 M HCl THF; xxvi Cp,TiCH,AlClMe, THF -40 "C to 0 "C; xxvii Hg (OTf), PhNMe, MeNO, then satd.NaCl H,O; xxviii NaBH, 10% NaOH H,O BuNEt,Cl CH,Cl,; xxix Me,SiI NaI; xxx MeOH NEt, 55 "C; xxxi DIBAL PhMe 0 "C Gilg. et Buss.S3 The structure of 122 is based on the revised I3C and proton chemical shifts in both amide rotamers of structure 123 for malagashanine which became clear from strychnobrasiline have been made.57 an X-ray crystal structure determinati~n~~ and from a re-Bosch and his co-workers have reported the first enantiose- examination of its NMR spectrum.53 Malagashanine is likely lective synthesis of ( -)-tubifoline," together with syntheses to be derived from spermostrychnine 124 which occurs with of ( f)-norfluorocurarine ( f )-ak~ammicine,~~ ( f)-malagashanine in Strychnos mostueoides via oxidation of an tubifolidine ( f)-19,2O-dihydroakuammicine and a second Nb,21-dehydro derivative followed by N,-methylation and synthesis of ( f )-akuammicine.60 For the synthesis5' of ( -)-esterification.tubifoline 125 the essential starting material (I?)-( +)-3-A reverse phase HPLC method has been developed for the pyridylethanol 126 was prepared by preferential enzyme-separation and quantitative assay of strychnine and brucine in catalysed trans-esterification of the racemic alcohol with vinyl seeds of Strychnos nux vomica and S.ignatii.'' The results acetate promoted by lipase PS followed by separation and are said to be reproducible and superior to the spectrophoto- methanolysis. Benzylation and reduction stages on 126 then metric method and can also be used to differentiate the two replacement of the N-benzyl group by a benzyloxycarbonyl species. group gave an allylic alcohol 127 which enabled the chirality The "N chemical shifts and long range 'H-I5N coupling to be transferred to position 4 of the piperidine ring by Claisen pathways for strychnine brucine and holstiine have rearrangement of an orthoacetate. Smith indolization of the been e~tablished,'~ and complete assignments of all the product 128 and removal of the benzyloxycarbonyl group gave Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids 126 127 'C02Me 118a 16-Decarbomethoxyvinervinine 118b 14a-Hydroxycondylocarpine 128 CICHzCO I 119 N-DeacetylspermostrychnineR = H 124 Spermostrychnine R = Ac IF I 120 12-Hydroxy-l l-methoxynor-Cfluorocurarine R1 = 0; R2 = H 121 12-Hydroxy-l l-methoxy-N-acetylnor-C-fluorocurarimine R1=NH; R2=Ac 122 12-Hydroxymalagashanine R = OH 123 Malagashanine R = H an indole 129 whose chloroacetyl derivative 130 could be photocyclized to the tetracyclic indole 131.Reduction stages then gave 132 accompanied surprisingly by a small amount of (-)-tubifoline. Finally oxidation of 132 with oxygen in the presence of platinum oxide gave ( -)-tubifoline 125.This oxidative cyclization was not entirely regiospecific since minor amounts of condyfoline 133 were also obtained (Scheme 21).58 The synthesis59 of norfluorocurarine and akuammicine is remarkably brief and begins with the alkylation of the arylhexahydroindolone derivative 134 previously prepared,21 by means of (2)-1 -bromo-2-iodobut-2-ene. Treatment of the product 135 with nickel bis(cyc1ooctadiene) in the presence of lithium cyanide effected the closure of ring D (formation of the 15,20-bond) and brought about the reductive cyclization of the a-(o-nitropheny1)ketone grouping to give the pentacyclic base ( & )-didehydrotubifoline 136 in a single step (Scheme 22). The final stages to ( f)-akuammicine 138 simply involved N,-methoxycarbonylation of 136 followed by photoisomeri- zation of the product 137.In a second sequence of reactions the alkylated arylhexahydroindolone 135 was treated with nickel bis(cyc1ooctadiene) and lithium cyanide and the result- ing intermediate was immediately trapped with (chloromethyl- idene)dimethylammonium chloride in a one-pot reaction. Under these conditions the pentacyclic aldehyde 139 was formed and could be transformed into ( f)-norfluorocurarine 140 by photoisomerization (Scheme 22). An interesting point relating to the structure of bharhingine an alkaloid from Rhazya stricta,6' emerged from these studies. Synthesis of the 2 isomer 141 of 139 by an exactly analogous route gave a product which has the structure postulated earlier for bharhingine.In fact the NMR data for 141 are clearly 570 Natural Product Reports I997 \ 130 129 viii I 0 H H H H 131 132 J xi 125 (-)-Tubifoline Scheme 21 Reagents i PhCH,Cl MeOH 80 "C;ii NaBH, MeOH; iii CICO,CH,Ph CH,Cl, heat; iv MeC(OMe), DME pivalic acid heat; v o-MeC,H,NHSiMe, Bu"Li hexane heat then 128 THF -78 "C to rt; vi Me,SiI MeCN 0 "C; vii CICH,COCI 2 M NaOH CH,Cl,; viii hv Na,CO, H,O MeOH; ix LiAlH, THF heat; x H, PtO, EtOH; xi O, PtO, EtOAc 133 Condyfoline different from those observed for bharhingine; hence the structure for this alkaloid needs to be re-examined. The synthesis of ( &)-tubifolidine 142 ( f)-19,20-dihydroakuammicine 143 and ( f)-akuammicine 138 from the same laboratory is equally brief.60 Alkylation of the arylhexahydroindolone derivative 134 by 1 -iodo-4-(trimethyl- silyl)but-2-yne gave the acetylenic silane 144 which on cyclization in the presence of a Lewis acid gave the allenic tricyclic ketone 145.Hydrogenation of 145 in the presence of a palladium catalyst resulted not only in the stereoselective saturation of the allene grouping but also the reductive cycliz- ation of the a-(o-nitropheny1)ketone function with direct formation of ( f)-tubifolidine 142. Introduction of an ester group a to the ketone group in 145 gave a P-keto ester 146 which on hydrogenation over a palladium catalyst gave ( f)-19,2O-dihydroakuammicine 143. However when the hydro- chloride of 146 was hydrogenated briefly over a palladium catalyst a mixture of 143 and ( f)-akuammicine 138 was obtained (Scheme 23).60 Martin and his have developed an irnpres-sive new route to akuammicine which involves a brilliant 136 139 1 iii iv 137 140 Norfluorocurarine I 1 iv I H CHO C02Me I 138 Akuammicine 141 Scheme 22 Reugents i,(Z)-BrCH,CI =CHMe K,CO, MeCN; ii Ni(COD), NEt, LiCN MeCN DMF; iii ClCO,Me NaH DME 60 T;iv hv MeOH; v Me,N+ =CHCl C1-realisation of the presumed corynantheoid-akuamma re-arrangement that is the cornerstone of the theory of the biogenesis of the Strychnos alkaloids.In the initial stages deformylgeissoschizine 30 was prepared (Scheme 24) by an application of Martin's route63 to the heteroyohimbine and corynantheoid alkaloids. Reaction of 30 with tert-butyl hypochlorite gave a mixture of epimeric 7-chloroindolenines 147 which were not isolated but treated immediately with lithium hexamethyldisylazide which gave ( f)-akuammicine 138 directly in 30-35% yield.The mechanism of this novel rearrangement is not yet fully understood. One possibility is that the strong base induces the formation of a 2,16-bond via the anion from 147; the further removal of a proton from the product 148 could then set in train the formation of the very stable anilinoacrylate function with simultaneous migration of C-3 to C-7 and expulsion of the chlorine atom. This route has obvious potential for a new brief synthesis of strychnine via a C-18 hydroxy derivative 149 since this has already been converted into strychnine by Overman et a/.'7 However although the benzyl ether 150 of this alcohol was successfully obtained by this route attempts so far to remove the protecting group have not proved possible without also hydrogenating the double bond.Clearly an alternative protect- ing group is required and future progress in this promising route to strychnine will be awaited with interest. The synthesis of mossambine 151 by Kuehne and his co-worker~,~~ affords another example of the formation of a vital ring by a radical cyclization reaction an approach which was first introduced in a synthesis of vincadifformine and 134 1 44 J ii A IH I \ 142 Tubifoiidine 1 45 I iv C02Me C02Me 143 19,2O-Dihydroakuammicine 1 46 1' C02Me 138 Akuammicine Scheme 23 Reagents i ICH,C =CCH,SiMe, K,CO, MeCOEt 80 "C; ii BF,.Et,O CH,Cl,; iii H, Pd/C Na,CO, MeOH; iv LDA HMPA THF -78 "C then NCC0,Me; v HCl then H, Pd/C MeOH 100psi acetoxyacetaldehyde which gave the tetracyclic anilino-acrylate ester 154 via cyclization of the transient triene ester 155.Hydrolysis and oxidation stages then gave 156 which was the substrate for free-radical cyclization to the mixture of geometrical isomers E-157 and 2-157 from which ,5157 could be obtained pure by crystallization of chromatographically enriched fractions (Scheme 25). Alternatively a superior yield of 156 could be obtained by Swern oxidation of 158 followed by oxidation of the ketone 159 by means of tert-butyl hypochlorite and triethylamine. Yet a third route to 156 was generated by the alkylation of the tetracyclic ester 160 pre-viously prepared,65 followed by oxidation by phenylseleninic anhydride.The synthesis of mossambine 151 was then com- pleted by reduction of E-157 by ceric chloride and sodium borohydride. Some 14-epimossambine 161 was also formed which could be obtained exclusively from E-157 by reduction with L-selectride. The availability of both epimers allowed the stereochemistry at C-14 to be firmly established. Thus a NOE between the C-14 p-H and the C-21 a-H in 14-epimossambine but not in mossambine indicated that the C-14 hydroxy group in mossambine is p as in 151; and the E geometry of the double bond was confirmed by NOE coupling of the C-18 methyl group with H-15 in both isomers 151 and 161 and of H-19 with H-21 a in mossambine.Subsequently the unsatu- rated keto ester E-157 was resolved via its condensation prod- uct with (R)-(N-methylphenylsulfonimidoyl)methyllithium (Johnson's method) which gave a mixture of two diastereo- isomers 14R,SR and I4S,SR. Selective pyrolysis of the 14R,SR 162 isomer in the mixture then gave E (-)-157 which on completion of the synthesis gave natural ( -)-mossambine 151 related alkaloids (q.v.). The indoloazepine ester 152 used as starting material by Kuehne in so many of his alkaloid (Scheme 25).64 syntheses was alkylated on nitrogen by (2)-1-bromo-2-A new approach to the synthesis of the Strychnos alkaloids iodobut-2-ene and the product 153 was then reacted with has so far reached the tetracyclic amide 163.66 Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids 57 1 CI COPh I I 07% Me02C 30 147 the 2-carbonyl group over the 3-carbonyl group in r m 1 N-benzylindole-2,3-dicarboxylicanhydride 165.Reaction of ji 165 with (3-bromo-4-pyridy1)triisopropoxytitaniumgave the keto acid 166 which on decarboxylation debenzylation Wittig methylenation and reduction gave the 1 -(4-pyridyl)-l- (2-indoly1)ethane derivative 167. Replacement of the bromine in 167 by a vinyl ether substituent then gave the enol ether 168, I which on acid-catalysed cyclization gave ellipticine 164 148 (Scheme 26). The synthesis of the non-alkaloidal relatives of ellipticine 9-hydroxyellipticine and 9,ll-dihydroxyellipticine (biogenetic numbering) has been reported.68 Three ellipticine-oestradiol conjugates e.g.169 have been synthesised in an attempt to target the cytotoxicity of ellipti- cine to oestrogen-receptor cells.69 From the same laboratory comes another study in which a number of novel Nb-acyldihydroellipticine derivatives have been synthesized for R cytotoxicity studies.70 Another investigation7' has focused on 138 Akuarnrnicine R = H the synthesis of several 2-aminoethylellipticinium salts some 149 R=OH 150 R=OCH2Ph of which showed a significant increase compared to ellipticine in their ability to bind nucleic acids. Scheme 24 Reagents i SnCl, Bu'OCl; ii LiHMDS Rubiralta and his co-workers have continued their investi- gations on the use of 2-( 1,3-dithian-2-yl)indolesin alka-loid synthesis and have completed a synthesis72 of 20-2.4 Ellipticine uleine and apparicine group epidasycarpidone 170 and 20-epiuleine 171.Condensation Aside from a few approaches to synthesis there is very little of the dianion 172 with N-methyl-3-ethyl-1,2,5,6-progress to report in this subgroup. tetrahydropyridin-2-one 173 gave a mixture of epimers 174 .~ In the latest synthesis of ellipticine 164 Miki et ~1took ~ and 175; separation and reductive cyclization of 175 then gave advantage of the superior reactivity towards nucleophiles of the isomers 176 and 177 resulting from cyclization on to the C02Me C02Me 152 153 155 154 R=Ac ,/' iii 1 iv 158 R=H / v (on 158) -Qy@T ix x ; viii * \ \15 or xi N l9 (on1574 H H C02Me C02Me 161 157 E 156 159 157 Z 4.I ix x (on157E) vii iv C02Me 162 151 Mossarnbine 160 Scheme 25 Reagents i (2)-1-bromo-2-iodo-but-2-ene K2C03 NEt, MeCOMe; ii AcOCH,CHO PhMe heat; iii K,CO, MeOH H20; iv (PhSeO),O PhH heat; v TFAA DMSO NEt, CH,Cl, -70 "C; vi Bu'OCl NEt, CH,Cl,; vii (Z)-l-bromo-2-iodo-but-2-ene, THF; viii Bu,SnH AIBN PhH 85 OC; ix NaBH, CeCl, MeOH THF; x separation by crystallization from MeOH; ix L-selectride THF 0 "C 572 Natural Product Reports 1997 tive 177 by heating it in aqueous acetic acid. Finally release of the ketone grouping gave 20-epidasycarpidone 170 and replacement of the carbonyl group by a methylene group gave Q-$j-jo -Qp-i 20-epiuleine 171. CH2Ph 0 I 0 165 166 ?Et iiiv " \ vi -Q-W H H Me Me 1 68 167 Me 164 Ellipticine Scheme 26 Reagents i 3-bromo-4-pyridyltitanium triisopropoxide THF -96 "C; ii 20% HCIO,; iii AICI, PhOMe 100 "C; iv Ph,P=CH,; v H, PtO,; vi Bu,Sn(OEt)=CH, Pd(PPh,), PhMe heat; vii 10% HCl THF HOw ... Me 169 indole nitrogen and position 3 of the indole ring respectively (Scheme 27). As in the earlier studies the N,-substituted isomer 176 could be isomerized to the desired dithian deriva- 0 R2 II Me /Nvo UEt + Li+ u-U -. 173 172 174 R' = H; R2 = Et 175 R' = Et; R2 = H MeN3177 iii 176 iv v -170 20-Epidasycarpidone 171 20-Epiuleine Scheme 27 Reagents i Red-Al THF; ii H,O AcOH heat; iii (CF,CO,),IPh MeCN H,O; iv MeLi; v A1,0 2.5 Aspidospermine group The full report of the isolation of crooksidine and demethoxy- carbonyltetrahydrosecodine" reveals that the aerial parts of Haplophyton crooksii also contain cimicine and cimicidine.Four new alkaloids have been isolated from the leaves of the double flowering variety of Tabernaemontana divaricata. Voafinine 178a and N-methylvoafinine 178b prove to be the Rj 179a Voafinidine H 178a Voafinine R = H 178b NMethylvoafinine R = Me 0 0 179b Voalenine 180 Aspidospermiose 16P-hydroxy derivatives of voaphylline and N-methylvo-aphylline re~pectively,~~" while voafinidine 179a is N-methylvoaphylline-l4a 1SP-diol and voalenine 179b is the 7-hydroxyindolenine derivative of 16-oxovoaphylline. 73b Yet another new alkaloid from the leaves of Rhazya stricta aspidospermiose 180 is formulated74 as ( -)-aspidospermidine carrying a pentose unit on N,.This unusual structure as well as the absolute stereochemistry need comfirmation. The isolation of rhazinilam and the aspidofractinine derivatives kopsingine kopsaporine kopsinginine 17a-hydroxy-14,15-didehydrokopsinine,kopsinol kopsinginol and kopsinganol from the stem bark of Kopsia teoi has again been described.38 The stem extracts of Kopsia pauczjiora Hook f. from Sabah (North Borneo) have yielded two new alkaloids one of which is 12-methoxy-10-demethoxykopsidasinine 181 181 12-Methoxy-l O-demethoxykopsidasinine 'OH 'H HO 182 Kopsinitarine D Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids together with the known alkaloids kopsinine N-methoxy- carbonyl- 12-methoxy- 16,17-didehydrokopsinine,N-methoxy-carbonyl- 1 1,12-methylenedioxykopsinaline, kopsamine N-oxide N-methoxycarbonyl-11,12-dimethoxykopsinalineand N-meth- oxycarbonyl- 12-methoxykopsinaline.75 In the most recent extraction^^^ of the leaves of Kopsia teoi a further new alkaloid kopsinitarine D 182 has been isolated in addition to the kopsinitarines A-CI7 and mersingines A and B,77 reported earlier. The stem extracts of this same species have yielded k~psingine.~~ A novel ring system containing a lactone function is exem- plified in paucidactines A and B which have been found in Kopsia pauczjlora (plant part ~nspecified).~~ The structures of these alkaloids are based on an oxidised aspidofractinine system in which the C-16 ester group has formed a lactone with a hydroxy group generated at C-6.The structure of paucidactine A 183 was established by X-ray crystal structure analysis; paucidactine B 184 according to its NMR spectrum is 2 1-deoxypaucidactine A. 0 183 Paucidactine A R = OH 184 Paucidactine B R = H Recently the leaves of Kopsia pauczjlora have been to contain two further new alkaloids pauciflorines A and B which are the result of oxidative fission of the 20,21-bond in an aspidofractinine framework. Pauciflorine A has the molecular formula C24H26N208 (mass spectrum) it is a dihydroindole derivative (UV spectrum) which contains a methylenedioxy group at positions 11 and 12 an N,-methoxycarbonyl group a methyl ester function and a hydroxy group at C-16 a lactam carbonyl group and a trisubstituted double bond ('H and I3C NMR spectra).COSY and HMQC experiments revealed the presence of an isolated methylene group a CH2CH unit and a CH2CH,CH2 unit. This limits the position of the lactam carbonyl group to C-21 and allows the structure of pauci- florine A to be defined as 185. The presence of the lactam carbonyl group at C-21 accounts for the unusual deshielding of H-3a (S4.03) and is also supported by the observed 3J corre-lation between C-21 and H-6. The pattern of substitution on C-16 is consistent with a long-range W-coupling between the 3 185 Pauciflorine A 186 Pauciflorine B intramolecularly-bonded 16-hydroxy proton and H- 17p as well as the observed 3J (C-17 to 16-OH) and ,J (C-16 to 16-OH) interactions.These and other key HMBC correlations and NOE interactions serve to establish structure 185 for pauciflorine A unequivocally and a further comparison of NMR data allows the structure of pauciflorine B to be defined as the 11,12- dimethoxy analogue 186. These alkaloids are reported to inhibit 574 Natural Product Reports 1997 melanin biosynthesis in B16 melanoma cells; this represents a rare example of such activity by indole alkaloids.79 Complete assignments of the I3C and 'H resonances of obscurinervine and obscurinervinidine have been made follow- ing the use of high-field NMR techniques and computerised data analysis procedures." Reaction of 3-oxotabersonine 187 with nitrosonium tetrafluoroborate in dichloromethane at 0 "C gives a mixture of 1O-nitro-3-oxotabersonine the 16-nitroindolenine derivative 188 and the dimeric species 189 (Scheme 28).The configur- 0 0 + C02Me Me02C NO2 187 3-Oxotabersonine 188 + 0 Scheme 28 Reagent i NOBF, CH,Cl, 0 "C ation at C-16 in 188 has not been proved unequivocally but is based on the known selectivity of reactions at this position in the parent alkaloid." In a new attempt to convert vincadifformine into a com- pound containing the meloscine ring system Lewin and his co-workers82 heated the epimeric mixture of nitriles 190 190 J Br Meses \ '/ Br Me02C' 191 Et Scheme 29 Reagent i TFA heat prepared as described previo~sly,~~ with trifluoroacetic acid.The product however did not contain the meloscine ring system but was shown by X-ray crystal structure analysis to have the structure 191 and is clearly the result of a remarkable rearrangement in which carbon atoms 6 and 16 have exchanged positions via two 1,5-sigmatropic shifts (Scheme 29). This result prompted a reassessment of the rearrangement of 5-cyanovincadifformine 16-chloroindolenine 192 which had earlier46 been postulated to give the (3-carboline derivative 193. Reinterpretation of the NMR spectrum of this product which was very similar to that of of 191 led to its reformulation as the y-carboline derivative 194 (Scheme 30).82 194 Me02C I W C Et 193 Scheme 30 Reagents i rn-CPBA CH,CI,; ii (CF,CO),O CH2CI, N, 0 "C; iii 0.5 M NaOH H,O The electrochemical oxidation of vindoline using a platinum anode in the presence of trifluoroacetic acid and a graphite cathode followed by controlled potential cathodic reduction yields 10,lO'-bisvindoline 195 as the major product.83 Two minor products so far unidentified were also obtained.C02Me Hot! Me H The attempt by Lewin and co-~orkers'~ to transform vin- cadifformine into goniomitine has been taken a stage further by converting the intermediate 196 prepared as described earlier,77 into (+)-16-hydroxymethylgoniomitine 197 by a series of reductions (Scheme 31).84 However it has not yet proved possible to convert 197 into goniomitine itself.Sl-Et v v 196 197 (+)-I 6-Hydroxymethylgoniomitine Scheme 31 Reugents i LiAlH, THF heat; ii H, Pd/C; iii TiCl, MeOH H20 The second synthesis of crooksidine 198 is an enantiospecific which starts from (+)-(S)-l -benzyloxycarbonyl-l,2,3,6-tetrahydropyridin-3-01 199 obtained from the corresponding racemate by preferential lipase-catalysed esterification of its enantiomer by means of vinyl acetate. Reaction of 199 with triethyl orthoacetate followed by Johnson-Claisen rearrange-ment gave the tetrahydropyridine ester 200 which was con- verted by unexceptional means into the keto amide 201. 0 \\ iii-vi i -0. 'CH2C02Et 200 201 1 viii-x 202 (+)-( R) -De met hox yca rbo nyI-198 (+)-(R)-Crooksidine 15,16,17,20-tetrahydrosecodine Scheme 32 Reagents i lipase PS vinyl acetate CH,CI,; ii MeC(OEt), Johnson-Claisen rearrangement; iii H, PtO, EtOAc; iv LiBH, THF; v PhSSPh Bu,P py; vi 50% KOH EtOH 110 "C; vii 2-acetylindole-3-carboxylic acid DCC THF; viii LiAlH, dioxane heat; ix Na NH,; x NaBH,CN BF,.OEt,; xi Dess-Martin oxidation Reductive removal of the functional groups then afforded another synthesis of (+)-(R)-demethoxycarbonyl-15,16,17,20-tetrahydrosecodine 202 and Dess-Martin oxidation of the latter gave (+)-crooksidine 198 [a] +7.8" which is thus unequivocally shown to have the R configuration (Scheme 32).Because of the discrepancy in the recorded value [aID +27.6" for the optical rotation of natural crooksidine the above synthesis was repeated with the enantiomer of 199 which gave ( -)-(8-crooksidine [aID -7.4".The most recent synthesis of aspidospermidine 203 has been contributed by Rubiralta and co-workers,86 and involves the construction of a pyridocarbazole derivative which constitutes rings A-D of aspidospermidine; ring E was then closed in the final stages of the synthesis. In the first stage a Michael addition of the dianion from 2-( 1,3-dithian-2-yl)indole on to N-(2-benzyloxyethyl)-3-methylenepiperid-2-onegave the adduct 204 which was then reduced and cyclized to the tetracyclic dithian derivative 205. Isomerization by means of acetic acid followed by debenzylation gave the desired tetra- cyclic intermediate 206 which on tosylation and treatment with base gave the dithian derivative 207 of 1,2-didehydro-l6- oxoaspidospermidine.Removal of the dithian function by Raney nickel in ethanol then gave some ( f)-aspidospermidine 203 together with ( f)-N,-ethylaspidospermidine 208 but desulfurization with Raney nickel in dioxane gave 30% of ( f)-aspidospermidine 203 and 350/0 of ( f)-1,2-didehydroaspidospermidine 209 which could subsequently be reduced to ( f)-aspidospermidine by lithium aluminium hydride (Scheme 33).86 Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids CH2CH20CH2Ph PhCH20CH2CH2N PhCH20CH2CH2N t -Lo \T a E ji q$.-nTdEt \ sus “u PhCH20CH2CH2N ..Et 204 1 iv 205 208 U U 206 209 HH 203 Aspidospermidine Scheme 33 Reagents i BuLi THF -78 “C HMPA then EtI -78 OC; ii DIBAL; iii AcOH H20 heat; iv Me,$ BF,-Et,O CH,CI, 35 “C; v KOBu‘ TsCl THF; vi W-2 Raney nickel EtOH; vii W-2 Raney nickel dioxane heat; viii LiAIH Szantay and his co-workers’ synthesis of 19-ethoxycarbonyl- 19-demethylvincadifformine 210 proceeds via the tetracyclic ester 211 and its C-20 epimer prepared by a Kuehne-type synthesis from the tryptamine ester 212 and ethyl methyl 3-formyladipate (Scheme 34).g7 Separation of epimeric esters followed by debenzylation and cyclization gave the penta- cyclic lactam 213 which on removal of the lactam oxygen via the corresponding thiolactam gave 19-ethoxycarbonyl- 19- demethylvincadifformine 210.This synthesis also constitutes a formal synthesis of ( f)-12-demethoxy-N-acetylcylindrocarine 214 which has earlier been preparedg8 from 210.The most recent synthesis of vincadifformine 3-oxovincadifformine and tabersonine is described in yet another substantial contribution from Kuehne and his co-w~rkers,~~ who have developed a new strategy which com- bines features of the biomimetic synthesis with intramolecular free-radical cyclizations and Heck cyclizations. The synthesis of vincadifformine 215 starts with the formation of the tetra- cyclic amine 216 by a familiar Kuehne-type preparation from the indoloazepine ester 152. This intermediate consisted of an epimeric mixture in which the desired N,Se cis isomer obtained in 49% yield predominated; however it turned out that both epimers could be used in the ensuing stages. Alkyla- tion of 216 with 2,3-dibromopropene gave 217/218 and ring D was then closed by a radical cyclization in which the configur- ation of the C-20 phenylselenyl group had little if any effect.In fact vincadifformine 215 was obtained in 85% yield from 217 and in 71% yield from 218 (Scheme 35). For the synthesis of 3-oxovincadifformine 219 the phenylse- lenyl group in the intermediate 216 was replaced by a propi- onic ester residue again by a radical-induced reaction this time with acrylic ester to give the epimeric mixture 220. The final cyclization gave mainly 3-oxovincadifformine 219 epimerization occurring at C-20 in one of the epimers during this last stage. The intermediate 216a was also used in a synthesis of tabersonine 221. Alkylation of 216a by (Z)-1,3-diiodopropene followed by elimination of the phenylselenyl group gave a ring C diene 222 which was cyclized by a reductive Heck reaction with palladium acetate sodium formate triphenylphosphine and base with formation of tabersonine 221 in 43% yield (Scheme 35).89 576 Natural Product Reports I997 Other recent synthetic work includes a stereoselective multi- stage preparation” of the quebrachamine intermediate 223 i ii CH2COzEt -CH2CH2C02Me 212 I t /-NCH*Ph ... C02Me 21 1 (+ C-20 epimer) \ H C02Me C02Me 21 3 v vi HI AC C02Me 214 12-Demethoxy- 210 19-Ethoxycarbonyl-N,-acety lcylindrocarine 19-demethylvincadifformine Scheme 34 Reagents i Et02CCH2CH(CHO)CH2CH2C02Me TSOH*H,O PhMe heat; ii chromatographic separation of epimers; iii Pd/C H, AcOH; iv TsOH heat; v P,S,; vi Raney Ni; vii ref.88 - aN@Et\ \ SePh iv \ \ C02Me C02Me152 C02Me 216a P-SePh C02Me 220 216b a-SePh SePh 215 Vincadifformine 217 P-SePh vii viii 219 3-Oxovincadifformine 218 a-SePh 222 221 Tabersonine Scheme 35 Reugents i MeCH,CH(SePh)CHO PhMe heat; ii BrCH,CBr=CH, THF; iii Bu,SnH AIBN PhH 85 "C; iv Bu,SnH AIBN CH,=CHCO,Me; v TsOH PhMe heat; vi (2)-ICH=CHCH,I K,CO, THF heat; vii rn-CPBA CH,Cl, -75 "C; viii PPh, -30 "C; ix Pd(OAc),,-PPh, HCO,Na NEt, MeCN heat and an approach to andranginine which has so farg' reached the intermediate 224. Ph 0 226 Criocerine Me02c..3 1 ji ,H 223 224 Q-QN N 2271ii 2.6 Vincamine group The stems of Kopsiapauczjlora new alkaloid (+)-19-oxoeburneburnamine (+)-isoeburnamin have been shown to coamine 225 together wite and (+)-eb~rnamonine.'~ ntain a h ( -)-Q-qNN Me02C' Et 15' 231 I I HO LI 230 225 (+)-19-0xoeburnarnine It was recently reported that criocerine 226 gives a dimeric species 227 when treated with acetic acid.77 It is now revealed92 iii that when treated with a stronger acid (trifluoroacetic acid) -criocerine gives a different dimer which has the structure 228 ,H N Q-qN+ and which in dimethyl sulfoxide solution undergoes a reverse Diels-Alder ring fission with formation of the product 229.It might be expected that the dimer 227 would be an intermediate Me02CA&-J 0 in the formation of 228; however it appears that when treated H Et H with trifluoroacetic acid 227 merely suffers fission of the 228 229 oxygen bridge and dehydration with formation of 230.It is Scheme 36 Reagents i AcOH; ii TFA; iii DMSO rt Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids 577 proposed that with trifluoroacetic acid criocerine first dimerizes to the sterically crowded dimer 231 which is then further protonated on oxygen attached to C-15'; forma- tion of the oxygen to C-15' bond with loss of H-17 and further dehydration then gives the final product 228 (Scheme 36). In a synthesis of 21-epidihydroeburnamenine 232 Padwa and Semonesg3 have adopted an entirely new concept for the construction of the tetrahydro-P-carboline system. In this approach ring C is formed by an intramolecular 1,4-cycloaddition of a thiazinium betaine 233 synthesized as outlined in Scheme 37.The last stage in the ingenious 0 liv 0 H v Et 233 235 Et 232 Scheme 37 Reagents i Bu"Li; ii N-(2-iodoethyl)indole; iii Lawesson's reagent; iv C,O,; v heat at 210 "C; vi NaBH, TFA dioxane heat formation of 233 involved the reaction of its precursor 234 with carbon suboxide; spontaneous cycloaddition of 233 at 25 "C then afforded the desired 1,4-cycloadduct 235 as a single diastereoisomer in 95% yield. The synthesis of 232 was then completed by fragmentation of 235 at 210 'C with loss of COS followed by reduction. The stereo-chemistry of the ring junction in 232 was confirmed by X-ray crystallography . The synthesis of (+)-vincine (1 1-methoxyvincamine) and apovincine by adaptation of a known route to vincamine has been reported,94 both cis-and trans-desethyleburnamonine have been synthesized from the same ester intermediate,"" and the chiral vincamine intermediate 236 has been prepared95h Et 237a 236 237b from both (R)-and (9-1-ethoxycarbonyl-5-hydroxycyclopent-1-ene.New enantioselective syntheses of the intermediates 237a and 237b constitute additional formal syntheses of (+l-~incamine.~~ 2.7 Catharanthine and ibogamine group The stem bark of Panamanian Sternrnadenia obovata Benth. has been shown to contain a new alkaloid obovamine 238 together with coronaridine voacangine (19S)-heyneanine (1 9S)-voacristine and the hydroxyindolenine derivatives of 238 Obovamine these last four alkaloid^,^' and 19-epivoacristine occurs in Peschiera afini~,~~ Most of the earlier syntheses of ibogamine 239 have involved the construction of an indolylethylquinuclidine derivative and the ring system is then completed by the formation of the 2,16-bond.Grieco's new approachg8 to ibogamine is notable therefore in that it proceeds via an intermediate in which tryptamine is attached at position 2 to a polysubstituted cyclohexane derivative and the final stages consist of the formation of the Nb-21 and N,-3 bonds. The synthesis starts with the vinylogous ester acid 240 prepared from 3,5-dimethoxybenzoic acid. A Grignard reaction on 240 followed by acid hydrolysis esterification and reduction gave the allylic alcohol 241a as a mixture of epimers both of which were used in the ensuing synthesis.Prolonged reaction of 241a with N-benzyloxycarbonyltryptamine in the presence of cam- phorsulfonic acid and lithium perchlorate in ether gave the intermediate 242 which could also be obtained by reaction of the acetate 241b with N-benzyloxycarbonyltryptamineusing lithium cobalt bis-carbollide as catalyst (Scheme 38). Hydroboronation-oxidation of 242 then gave a single alcohol 243 whose stereochemistry was established by extensive NMR studies. With all 19 carbon atoms required for the ibogamine skeleton now in place attention was directed towards the closure of the Nb-21 bond via oxidation of 243 to the corresponding ketone 244. However this oxidation in the presence of an unprotected indole nitrogen proved to be non-trivial but was eventually achieved by use of the hyper- valent iodine species 245.Removal of the benzyloxycarbonyl group at elevated temperature with concomitant cyclization gave an imine which was reduced at ambient temperature to the amines 246 and 247. Again the stereochemistry of these diastereoisomers was elucidated by extensive use of NMR spectroscopy. Thermal cyclization of the amino ester 246 then gave the lactam 248 which was finally reduced to ( f)-ibogamine 239 by lithium aluminium hydride. Similar treat- ment of 247 then gave ( f)-epiibogamine 250 via the lactam 249 (Scheme 38).98 Kuehne's new approach to the vincadifformine group of alkaloids has also been applied to the synthesis of pseudo- vincadiff~rrnine.~~ Again the starting material was the indoloazepine ester 152 which was alkylated by means of 1-bromo-2-ethylprop-2-ene.Reaction of the product 251 with phenylselenylacetaldehyde,followed by thermal fragmentation and recyclization then gave the tetracyclic base 252 via a transient secodine derivative in a typical Kuehne-type syn- thesis. Free-radical cyclization of 252 by means of tributyl tin hydride and azabisisobutyronitrile finally gave a mixture of pseudovincadifformine 253 and 20-epipseudovincadifformine 254 in a combined yield of 85% (Scheme 39). Full details of the ~ynthesis'~ of desethylibophyllidine by the Barcelona group have now been publi~hed.~~ Details of the of the tacamine group of alkaloids by Lounasmaa and his co-workers have been pub- lished loo and two alkaloids of Tabernaernontana eglandulosa 578 Natural Product Reports 1997 C02Me NHZ Z = C02CH2Ph viii 245 + NHZ xi H 239 lbogamine Me02C C02Me 246 244 ix Et q)-,& QJ-G Et La$-+ 1 "Et H 250 Epi-ibogamine 249 Me02C 247 Scheme 38 Reagents i EtMgBr; ii acid hydrolysis; iii CH,N,; iv NaBH, CeCI * 6H,O MeOH; v LiC104 Et,O N-benzylcarbonyltryptamine CSA; vi N-benzyloxycarbonyltryptamine lithium cobalt bisdicarbollide CICH,CH,CI; vii B2H6; THF then H,O, base; viii 245 CH,Cl,; ix 10% PdC THF EtOH C6H,0 80 "C; then THF NaBH,CN TFA; x 220 "C Ar; xi LiAIH, THF HI %..C02Me C02Me Ho H H Et MeO2C**W"'Et 152 251 HH 255 P-OH 257 256 a-OH 3 Bisindole alkaloids Two new alkaloids ramiflorine A 258 and ramiflorine B 259 which are 10-methoxy-4',17-dihydrotchibangensines have been found in the stem bark and seeds of Aspidusperma + \ \ 0-m HI HI C02Me C02Me 253 Pseudovincadifformine 254 20-Epipseudovincacadifformine Scheme 39 Reagents i BrCH,CEt =CH, K2C03 MeCOMe; ii PhSeCH,CHO PhMe heat; iii Bu3SnH AIBN PhH (16R)-demethoxycarbonyltacamine 255 and (16S)demethoxy- 258 Ramiflorine A 17a-H carbonyltacamine 256 have been prepared for the first time 259 Ramiflorine B 17P-H simply by reduction of tacamonine with lithium aluminium hydride.Lounasmaa and his co-workers"' have also developed an improved preparation of the amino ester 257 a pivotal ramflurum from BraziL6 Matopensine and four new bis-intermediate in the synthesis of the tacamine group of strychninoid alkaloids panganensine R 260 panganensine S alkaloids.261 and an epimeric mixture of panganensines X and Y 262 Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids 260 Panganensine R 19’R 261 Panganensine S 19s 262 Panganensines X and Y have been isolated from the root bark of Tanzanian Strychnos panganen~is,~ and villalstonine has been shown to occur in the stems of Alstonia ang~stifolia.~~ Macrocarpamine 263 has been synthesised by coupling synthetic ( -)-anhydromacrosalhine methine 82 with natural (+)-pleiocarpamine 264 in acid solution (Scheme 40). lo2 Me 82 H/ H’ Me02C Me02C H H‘ H H‘ 264 (+)-Pleiocarpamine i H H ? , @--N, \ I H‘ MeO2c-ey 263 Macrocarpamine Scheme 40 Reagent i dry 0.2 M HCI THF Crooksiine and haplophytine are two of the 15 alkaloids extracted from the aerial parts of Haplophyton crooksii.lo Norpleiomutine and kopsoffine have been found in the bark of Kopsia ma~rophylla,~~ and the former of these also in the stems of Kopsia pauc80ra.~’ Three new bisindole alkaloids tenuisines A-C 265-267 have been isolated from the leaves of Kopsiu tenuis Leenh. et Steenis from Sarawak.Io3 Tenuisine A an amorphous base gives a base peak which is also the highest peak in the EIMS 580 Natural Product Reports 1997 Me02C I I Me02C 265 Tenuisine A Me02C 266 Tenuisine B R1 = OMe; R2 = H2 267 TenuisineC R1 =H; R2=0 at mlz 396 but in the FABMS gives a peak owing to MH’ at mlz 793 appropriate to a molecular formula of C,H,8N40,0.The proton NMR spectrum integrates for 24 protons indicat- ing a symmetrical dimer except that signals owing to C-12 and to a lesser extent C-18 are doubled as a consequence of the presence of amide rotamers. The 13C NMR data resemble those observed for lundurine B 268 except for the absence of a cyclopropyl unit which is replaced by a lactone function and in fact show a greater resemblance in the non-aromatic portion of the molecule to the data for lapidilectine B 269. These and C02Me C02Me 268 Lundurine B 269 Lapidilectine B other data indicate that tenuisine is a symmetrical bis-lactone in which two molecules of the hydroxy acid derived from a 10-methoxylapidilectine B have esterified each other with formation of the dimeric species 265.Tenuisine B 266 is 11,ll ‘-dimethoxytenuisine A and tenuisine C 267 is 3,3’- dioxotenuisine A. lo3 The long-range ‘H 15N couplings and I5N chemical shifts have been assigned for navelbine (5’-noranhydrovinblastine) by application of gradient-enhanced HMQC for the observation of long-range heteronuclear couplings at natural abundance. lo4 Kuehne and Bandarage’” have improved the enantioselec- tivity of an earlier synthesis46 of vinblastine by making use of a chiral auxiliary derived from ferrocene for the construction of the vital intermediate 270. In this improved approach the indoloazepine ester 152 was alkylated on Nb by 2-diphenylp hosp hinyl-( S)-a-ferrocen yle thy1 acetate 271 and the product 272 was condensed with the chiral protected aldehyde 273 under milder conditions than are normally adopted for condensations of this kind.The result of the ensuing fragmentation and recyclization by a typical Kuehne synthesis was 274 obtained as a single stereoisomer. Acetolysis of 274 then released 271 and a 7:l mixture of the tetracyclic diastereoisomers 275 and 276 which were easily QyqH + ;e)qFe@ PPh2 C02Me *" 152 271 Ii 1 C02Me 272 274 iv v/ \ v .. . C02Me C02Me 276 275 1 vi C02Me 270 Scheme 41 Reugents i NEt, EtOH heat; ii PhH heat; iii CH2Cl, MeOH NaBH (to remove excess 273);iv AcOH heat; v chromato-graphic separation; vi PhCH,Br NEt, MeCOMe K,CO separated by chromatography.This epimerization at the C/D ring junction proceeds via reversible protonation of 275 at C-16 with formation of an indole-iminium ion with destruc- tion of the asymmetry at positions 7 and 21; this is supported by the observation that equilibration of 275 in acetic acid gives the same 7:l mixture of diasteroisomers. Benzylation of 275 then gave the intermediate 270 which has previously been in the synthesis of vinblastine (Scheme 41). 4 Biogenetically related quinoline alkaloids 4.1 Cinchona group Hoffmann and his co-workers have reported a one-pot conver- sion of the Cinchona alkaloids to quinuclidine derivatives. For example the reaction of quinidine 277 with lithium aluminium hydride deactivated by isopropyl alcohol in the presence of TMEDA and oxygen results in reductive cleavage of the 4',9-bond (Rabe numbering) with formation of 6-methoxyquinoline and the quinuclidine alcohol 278 (Scheme 42).3',4'-Dihydroquinidine and 1',2',3',4'-tetrahydroquinidine 277 Quinidine Scheme 42 Reagents i LiAlH, Pr'OH TMEDA O2 were also formed in small amounts and when the reaction was conducted under argon they were the dominant prducts but the vinyl group appeared to be unaffected. Quinine behaved similarly. In a separate series of experiments from the same labora- torylo7 quinidine 277 was hydrobrominated to give an epimeric mixture of 10-bromo- 10,ll -dihydroquinidines 279 and 280 acetylation of which followed by dehydrobromination gave 2-281 and ,5282 (Scheme 43).cis-Hydroxylation of 281 gave the epimeric diols 283a and 283b which could be converted into the epoxides 284a and 284b. However in a one-pot process the alkene 2-281 was converted into the two remain- ing epoxides 285a and 28513; some 2,9-epoxides 286a and 286b were also formed. The structures of these compounds are not in doubt since the structure of 286b was confirmed by X-ray crystallography. Several chiral organometallic complexes of Cinchona alka- loids with lanthanoid salts have been prepared e.g. [(qs-C,H,)(Ph,P)(OC)RuL]+BF - where L =quinine cinchoni- dine or quinidine and [(q6-p-cymene)Cl,RuL] where L = quinine cinchonidine or cinchonine. lo* Removal of HC1 from the last two of these complexes gave the neutral complexes 287 and 288 whose structures were determined by X-ray crystallography.At least seven metabolites of quinine have been detected in human urine. lo9 These include 3-hydroxyquinine (the major metabolite) 2'-oxoquinine quinine glucuronide quinine N-oxide and 0-demethylquinine; the remaining metabolites were unidentified. The thermodynamically controlled cyclooligomerization of the hydroxy ester 289a derived from quinine gives only the cyclic trimer 290a; the hydroxy acid 289b derived from cinchonidine behaves similarly with formation of 290b (Scheme 44). lor( Since a wider distribution of oligomers would have been expected several authentic linear oligomers have been prepared"" by the sequence illustrated in Scheme 45 for the trimer 291 and cyclised under kinetic conditions.Both the linear trimer 291 and its tetrameric analogue cyclised to give moderately good yields of 290a and the cyclic tetramer respectively together with small amounts of higher oligomers. The cyclic trimer 290a prepared from 289c via 291 was identified with that obtained from the direct thermodynami- cally controlled trimerization of 289a. Hence the absence of higher oligomers in this last reaction is not due to a kinetic effect on ring formation and suggests that the cyclic trimer is a particularly stable molecule possibly the consequence of a degree of rigidity in the molecule which predisposes it to favour the cyclic trimer 290a. Molecularly imprinted polymers have been prepared by the photopolymerization of methacrylic acid and ethylene glycol dimethacrylate in the presence of Cinchona alkaloids ( -)-cinchonidine and (+)-cinchonine followed by the removal of alkaloid by exhaustive washing with acid.When the polymers were used as HPLC stationary phases the imprinting template alkaloids were most strongly retained on the polymers pre- pared in their presence and large separation factors (>31) were observed. Hence mixtures of these alkaloids could readily be separated using these polymers as chiral stationary phases. They could also be used but rather less effectively for the separation of mixtures of quinine and quinidine. 581 Saxton Recent progress in the chemistry of the rnonoterpenoid indole alkaloids OMe -ii-iv + k-'H H H V 279 280 282 Scheme 43 Reagents i 62% HBr; ii AGO DMAP; iii.seuaration of isomers; iv DBU; v. OsO, DABCO; vi chloramine-T H2S0, H20 MeCOMe; vii K2C0,,' MeOH; & Bu"Li Bu'OK THF .78 "C; ix TsCI THF 78 'C +it Me 288 A method involving the HMQC correlation of diastereoiso- meric salts with quinine has been developed for the determi- naton of chiral purity of carboxylic acids."* The asymmetric catalysis by (-)-cinchonidhe in the polyaddition of 1,3-dimercaptobenzene to prochiral bis-unsaturated ketones has been examined,lI3 as has the stereo- chemical course of aldol reactions in the presence of quat- ernary fluorides derived from Cinchona alkaloids. l4 Other asymmetric reactions in the presence of Cinchona alkaloids that have recently been reinvestigated include the hydro- genation of pyruvic esters1I5' and the hydrogenation of a-phenylcinnamic acid.l7 The remaining papers involving the Cinchona alkaloids are all concerned with the asymmetric dihydroxylation of alkenes by means of osmium tetroxide in the presence of catalysts derived from the alkaloids. New and improved catalysts for this reaction continue to be developed. Although the dihydroxylation of allylic and homoallylic alcohols and in particular their p-methoxy- 582 Natural Product Reports 1997 289a R=OMe 289b R=H li 290a R =OMe 290b R=H Scheme 44 Reagents i 5% KOMe 18-crown-6 PhMe heat remove MeOH azeotropically benzoate esters proceeds with good enantioselectivity in the presence of the bis(dihydroquinidiny1)pyridazine [(DHQD),-PYDZ] catalyst the corresponding oxidation of bis-homoallylic alcohol derivatives occurs with substantially lower facial selectivity possibly owing to diminished binding of the bis-homoallylic p-methoxybenzoate esters to the U-shaped region of the catalyst.Hence in order to overcome this 289c li ii,iii ii,iv 1 291 Scheme 45 Reagents i 2,6-dichlorobenzoyl chloride NEt, DMAP CH,Cl, rt; ii TBAF THF rt; iii 289c 2,6-dichlorobenzoyl chloride NEt, DMAP CH,Cl, rt; iv Pd(PPh3)4 morpholine THF rt deficiency Corey and his co-workers"' have designed a cata- extended to dienes e.g. derivatives of 2-hydroxymethylbuta-l9 lyst 292 which contains an additional aromatic system i.e.an 1,3-diene and 2-hydroxyethylbuta-1,3-diene.' The results show that here also excellent regio- and enantio-selectivity can be achieved. ,OMe These oxidation reactions with osmium tetroxide in the presence of potassium ferricyanide and bis-Cinchona alkaloid catalyst follow Michaelis-Menten kinetics and are consistent with Corey's transition state model 294.'* Other workers however prefer to view the reaction as proceeding via an osmaoxetane intermediate 295. 'H 292 anthracenylmethyl group close to the U-shaped hydrophobic J pocket. The results of asymmetric dihydroxylation with this catalyst show that it is superior to the bis(dihydr0quini- diny1)pyridazine catalyst particularly with terminal olefins 0 N-0 ;;;o where low enantioselectivity is usually observed.Thus oxi- dation of the homoallylic ester 293 in the presence of (DHQD),PYDZ gives 95% of the diol with 79% enantio-L purity but in the presence of the improved catalyst 29299% of R \ the R diol with 90% enantiopurity is obtained. 294 295 L = Cinchona alkaloid The two mechanisms have been discussed and subjected to a critical analysis at some length,', from which it is concluded that 293 WOMe the Corey model is favoured rather than the Sharpless model. An experimental comparison of the two mechanisms which involves measuring the I2C/I3C kinetic isotope effects at the olefinic carbon atoms for the (DHQD),PYDZ-catalysed In recent experiments the asymmetric dihydroxylation reac- osmium tetroxide oxidation of 4-nitrostyrene 5-methoxy- tion in the presence of the [DHQD],PYDZ catalyst has been styrene and ally1 p-methoxybenzoate shows that the results Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids Meom WoMe 296 accord well with a mechanism based on a [3+2] cycloaddition pathway (Corey) rather than a [2+2] cycloaddition process (Sharple~s).'~~ The mechanism of this reaction has also been discussed by Lohray et ~1.'~~ Lohray et al.have also studied the asymmetric dihydroxy- lation of dienes by osmium tetroxide in the presence of [DHQD],PYDZ immobilized via thioethanol on silica gel 296.'25The results show that the rates and yields of the reactions are comparable to those of the homogeneous reac- tion; however the enantiomeric excesses observed for the prod- ucts were lower especially in the case of the aliphatic alkenes.Petri et a1.126have also used an insoluble polymer containing a Cinchona alkaloid derivative as chiral ligand in the heterogeneous enantioselective dihydroxylation of alkenes and have concluded that the enantioselectivity is similar to that observed in the homogeneous reaction under the same reaction conditions. 4.2 Camptothecin The stems of Nothapodytes foetida from Taiwan contain two new alkaloids nothapodytines A and B which are presumably derived from camptothecin by decarboxylative fission of ring E. Nothapodytine B has the structure 297 and nothapodytine A is its 9-methoxy derivative 298'27 R I Me 297 Nothapodytine B R = H 298 Nothapodytine A R = OMe Details of the synthesis of camptothecin by Curran et aL21 have been published,'28 and an improved second generation synthesis has also been deve10ped.l~~ In this new synthesis and in contrast to the strategy adopted in the first synthesis the lactone ring was built up before the completion of rings A-D.The critical intermediate was therefore the bicyclic lactone 300 which was prepared by relatively straightforward means as outlined in Scheme 46. The same procedure was then applied for the addition of rings A-C as in the first synthesis; thus the pyridone 300 was alkylated on nitrogen by prop-2-ynyl bromide and the product 301 was reacted with phenyl iso- cyanide and hexamethylditin with irradiation which gave camptothecin 299 following two radical cyclizations and aromatization.This approach is obviously versatile and by use of appropriate prop-2-ynyl halides and substituted aryl isocyanates allows the synthesis of a wide range of camptothecin derivatives. By this means the camptothecins 302-304 and GI-147211C 305 have already been obtained irinotecan 306 has been prepared via 302 and topotecan 307 via 304. OMe OMe TMS TMS Jv OMe OMe '\ vii viii OMe OMe TMS 0 Et' OH Et' OH 0 1. 0 301 300 xii J Et-HO x" 0 299 Camptothecin R1= R2 = H 302 R1 = Et; R2 = OMe 303 R' = Et; R2 =OH 304 R' = H; R2 =OH 307 Topotecan R1= CH2NMe2; R2 = OH Scheme 46 Reagents i Bu'Li; ii Me,NCH,CH,NMeCHO; iii Bu"Li; iv I,; v MeCH=CHCH,OH Et,SiH TFA; vi Pd(OAc), K,CO, Bu,NBr; vii OsO, (DHQD),PYDZ; viii I, CaCO, ix ICl; x HI H,O or TMSI; xi HC=CCH,Br NaH LiBr DMF DME; xii PhNC Me,SnSnMe, PhH 70 "C hv In a new approach to camptothecin synthesis'30 rings A-D are constructed by the intramolecular [4+21 cycloaddition of an N-arylimidate 308 prepared and cyclized in situ as outlined in Scheme 47.This preparation of the tetracyclic nitrile 309 by this route constitutes a new formal synthesis of ( f)-lo-methoxycamptothecin. In the absence of an electron-donating group on the aromatic ring yields in this type of cycloaddition 584 Natural Product Reports 1997 Me the _I Me iii-iv Me 1. he _I 308 309 Me Scheme 47 Reagents i NCCH2CONH2 K2C03 MeCOMe heat; ii HC=CCH2Br DMF K,CO,; iii NaOH H,O DMF; iv p-MeOC6H,NH2 EtN =C =NCH,CH,CH,NMe, 1-hydroxybenzo-triazole CH,Cl,; v Me,OBF, CH,Cl, rt then MeCN heat are poor and a preferred alternative proceeds via a benzox- azinone derivative as in 310 prepared as shown in Scheme 48.Intramolecular cycloaddition of 310 followed by loss of carbon dioxide gives the intermediate 311 which has earlier been converted into ( f)-camptothecin. This new strategy has been used in a concise convergent synthesis of (9-1 0-methoxycamptothecin 312 in which the longest linear sequence involves only six stages.'31 The two essential intermediates for thls synthesis the complex acetal 310 I 305 GI-1 47211C \/ 311 Me 0QNcooyJ++o Scheme 48 Reagent i Ac,O heat Et-w Me:vH2Ph HO 0 306 lrinotecan C02Me OEt 0 A/4C02Et -Eto2cyJo 4 CN 1 ii Me0 C02H I1 00 v 4 313 NC02Me H I iv Meoj-J+&NH 314 Scheme 49 Reagents i LDA THF -78 to -20 "C; ii 5% PdK H, MeOH; iii Me,OBF, MeCN -40 to 50 "C; iv 30% HBr AcOH rt 313 and the tricyclic pyrroloquinoline derivative 314 were prepared as shown in Schemes 49 and 50 the latter involving the cycloaddition of an 0-methylarylimidate as in Scheme 47.Coupling of 313 and 314 to give the intermediate 315 was achieved by use of a water-soluble carbodiimide and hydroxy- benzotriazole. Acid-catalysed cyclization of the acetal 315 followed by DDQ oxidation completed the formation of the pyridone ring D as in 316 and the final stages included reduction of the methyl ester function in 316 by means of diisobutylaluminium hydride then reduction by sodium borohydride and finally the addition of sodium hydroxide.Acidification of the reaction mixture then gave by direct precipitation (9-10-methoxycamptothecin 312 which was thus obtained in an enantiomeric excess of 98.9% and a yield of 70% from 316. For the preparation of the clinically valuable topotecan 307 10-methoxycamptothecin 312 was 585 Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids C02Me C02Me C02Me -M mo 313 + 314 i e 0 Me0 k C02Me Et-kC02Me MOMO Et-J\CONEt2 MOMO Et-J\C02H MOMO Me0 /--OyO 315 1 ii iii 316 + iv-vii MeOy 1 0 HO 8 Ei 0 312 (S)-10-Methoxycarnptothecin Scheme 50 Reagents i EtN=C=NCH,CH,CH,NMe, 1 -hydroxy-benzotriazole NEt, THF; ii TFA H,O PhMe; iii DDQ; iv DIBAL CH,Cl,; v NaBH, MeOH; vi NaOH H,O; vii AcOH demethylated by means of hydrobromic acid and the 10-hydroxycamptothecin so obtained was subjected to a Mannich reaction with bis(dimethy1amino)methane in methyl-ene chloride; topotecan 307 was thus obtained in 91% yield and >99.5% ee.The new enantioselective synthesis of (20S)-camptothecin 299 by Ciufolini and R~schangar'~~ is a brief and efficient one in which the phosphonate 317 was first coupled with the aldehyde 318 in a Wittig condensation (Scheme 51). Michael addition of cyanoacetamide to the product 319 gave an intermediate which was cyclized and oxidised to a pyridone derivative hydrolysis and lactonization of which gave the y-lactone 320.Reduction to the diol 321 then hydrolysis and relactonization gave (209-camptothecin 299 in an overall yield of 30% in 10 stages. This is claimed to be twice as efficient as the best alternative synthesis of camptothecin currently available. Irinotecan (CPT-11 306) suffers photodegradation of ring E when it is irradiated in aqueous solution.'33 The products were tentatively identified as the y-lactone 322 the hemiacetal 323 and the pyridone derivative 324 (Scheme 52). In contrast the metabolism of irinotecan by human patients involves degradation of the terminal piperidine ring with formation of RPR 121056A 325,'34 which was synthe-sized by coupling 7-ethyl-10-hydroxycamptothecin 303 with the piperidine derivative 326,followed by hydrogenolysis and decarboxylation (Scheme 53).Reaction of camptothecin 299 with nitronium fluoroborate in acetic anhydride gives (20S)-20-O-acetylcamptothecin and 14-nitro-(20S)-20-O-acetylcamptothecin 327 but in trifluoro-acetic acid the product is 5-hydroxy-14-nitro-(20S)-camptothecin 328 (Scheme 54).'35 Numerous new derivatives of camptothecin have been prepared for purposes of pharmacological evaluation. Thus several camptothecin derivatives with a heterocyclic 586 Natural Product Reports 1997 a: Et-Go iv-vii T Z M e + MOMO NEt2 318 317 viii Et-fiCONEt;! Et-bCONEt2 MOMO MOMO 319 CN CONEt2 320 1 xi xii c-- HO 0 9 Et-299 (20s)-Carnptothecin 321 Scheme 51 Reagents i pig liver esterase DMSO H,O pH 6.8-7.4 35 "C; ii N-methyl-2-chloropyridiniumiodide Et,NH Et,N CH,Cl,; iii DIBAL THF -78 "C; iv 1,3-bis(diphenylphosphino)propane7 NaOAc MeOH DMF 105atm CO 140°C; v NBS (BzO), hv CC1,; vi MeOH H2S04 heat; vii (MeO),POCH,Li THF -78 "C; viii BuOK DME 50°C; ix H,NCOCH,CN Bu'OK DMSO; x SeO, silica gel Bu'OOH AcOH 110 T then 10% aq.H2S04,heat; xi NaBH, CeCl, EtOH 0 'C 20 min then 45 "C 30 min; xii 60% H,SO, EtOH 115 "C C N<N COO Yo HOEi 0 r 306 %Me i-'c COEt Ho Et 322 323 324 Scheme 52 Reagent i hv pH 10 0 PhCH20 AN~C02CH2Ph I Q I C02H COCl I 326 i-iii -Irinotecan \/ HO 0 HO%o \ / \/ 325 RPR 121056A Ei 0 HO ; Et 0 303 Scheme 53 Reagents i C5H5N 20 "C; ii H, Pd(OH), AcOH MeOH 15 psi; iii PhMe azeotropic distillation then HCl H20 (20S)-20- OAcetylcamptothecin Et 0 299 Camptothecin Et '0 327 14-Nitro-20-OAcetylcamptothecin \ii 328 5-Hydroxy-l4-Nitro-(20S)-Acetylcamptothecin Scheme 54 Reagents i NO,BF, Ac,O 80 "C; ii NO,BF, TFA 80 "C five-membered ring attached to C-10 via a 2-aminoethoxy side chain have been prepared by the Friedlander condensation of the tricyclic lactone 329 with appropriate o-aminoalde- hyde derivatives (Scheme 55).The derivatives containing pyrrole 330a-c and thiophene 331a,b rings were more potent than camptothecin itself against several human tumour cell lines; the furan derivatives were less active.'36 Lackey et al.137have prepared eleven 7-substituted quater- nary salts of 10,ll-methylenedioxycamptothecinand 10,ll- ethylenedioxycamptothecin via a Friedlander synthesis of the appropriate 7-chloromethyl derivative of camptothecin followed by nucleophilic displacement of the halogen with an aromatic amine.All these salts were more potent than camp- tothecin in the in vitro cleavable complex assay and all were cytotoxic against three human tumour cell lines. Two of them (332 and 333) were more effective than topotecan in delaying tumour growth in the nude mouse HT-29 xenograft model and in an extended in vivo model 333 demonstrated tumour regression. A South Korean group have preparedI3* by total synthesis a number of novel water-soluble racemic 7-(2-amino-ethy1)camptothecin derivatives all of which exhibited excellent antitumour activity against five tumour cell lines.The most potent of these was the isopropyl derivative 334. The same group have also ~ynthesized'~~ sixteen racemic 20-desethyl-20- substituted camptothecin analogues which have also been evaluated for cytotoxic activity against five tumour cell lines. n Et ,OH "Yo I 329 li BocNHcH2cH20'o Et HO 0 ii iii 1 RNHCH2CH20-\ I H Me CH20Me 330a 330b 330c CH20Me 331a 331 b 331c Scheme 55 Reagents i TsOH PhMe heat; ii HCI MeOH; iii RCOCl or RS0,CI Of these 335 was observed to exhibit activity comparable to that of camp to thecin.Finally Comins and SahaI4' have reported a short conver- gent route to ( f)-mappicine 336. 2-Fluoro-4-iodo-3-methylpyridine was first prepared from 2-fluoro-3-iodo-pyridine by the so-called halogen dance reaction and then converted into the pyridone 337 by standard reactions. Alkyla- tion of 337 by 2-bromo-3-bromomethylquinoline then gave 338 which was cyclized to mappicine ketone 339 by means of palladium acetate; reduction then gave ( f)-mappicine 336 (Scheme 56). Saxton Recent progress in the chemistry of the monoterpenoid indole alkaloids 4 N. Aimi M. Kitajima N. Oya W. Nitta H. Takayama S. Sakai I. Kostenyuk Y. Gleba S. Endress and J. Stockigt Chem. Pharm. Bull. 1996,44,1637. 5 H. Mavar-Manga J. Quetin-Leclerq G. Llabres M.-L.Belem-Pinheiro A. F. I. Da Rocha and L. Angenot Phytochemistry 1996,43,1 125. <To 0 6 M. F.S. Marques L. Kato H. F. Leitao Filho and F. de A. M. Et-HO 0 332 Et-' 333 Reis Phytochemistry 1996,41,963. 7 C. Kan-Fan J. A. Zuanazzi J.-C. Quirion and H.-P. Husson Nut. Prod. Lett. 1995,7,317. 8 H. Kohda A. Namera A. Koyama K. Yamasaki and T. Tani Chern. Pharm. Bull. 1996,44,352. 9 (a) P. T.Ky T. N. Huu and N. V. Hung Tap Chi Duoc HOC 1995,2 (Chem. Abstr. 1996 124 141 074); (b) A. Madinaveitia M. Reina G. de la Fuente and A. G. Gonzalez J. Nat. Prod 1996,59 185. 10 M. A. Mroue K. L. Euler M. A. Ghuman and M. Alam J. Nat. Prod. 1996,59,890. 11 (a)A.Madinaveitia E. Valencia J. Bermejo and A. G. Gonzalez Biochem. Syst.Ecol. 1995,23,877;(b) B. P. Korzun A. F. St. Andre and P. R. Ulshafer J. Am. Pharm. Assoc. Sci. Ed. 1957 46,720. 12 C. Kan J.-R. Deverre T. Sevenet J.-C. Quirion and H.-P. Husson Nut. Prod. Lett. 1995,7,275. 13 C. Perez Y.L. Janin and D. S.Grierson Tetrahedron 1996,52 987. 14 M. Amat S. Hadida S. Sathyanarayana and J. Bosch Tetra-7NHCHMe2 hedron Lett. 1996,37,3071. 15 H. Takayama Y. Miyabe T. Shito M. Kitajima and N. Aimi Chem. Phurm. Bull, 1996,44,2192. 16 M. Lounasmaa P. Hanhinen and S. Lipponen Heterocycles 1996,43 1365. 17 J. E.Saxton Nat. Prod. Rep. 1995,12,385. To HO c\H2 0 18 M.Lounasmaa P. Hanhinen and R. Jokela Heterocycles 1996 334 Et HO 0 CH20CH20Me 335 COEt 1iv COEt 4- 0 338 vi qLxhcr"j \ \ \ / Me \ / Me 09- H' Et 339 336 Mappicine Scheme 56 Reagents i LDA MeI; ii BuLi EtCHO; iii PCC; iv HCl H,O; v 2-bromo-3-bromomethylquinoline,BuOK; vi Pd(OAc),, Bu,NBr KOAc MeCN; vii NaBH 5 References 1 The Alkaloids ed.G. A. Cordell Academic Press New York 1996,vol. 48. 2 M. 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ISSN:0265-0568    

DOI:10.1039/NP9971400559

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

Isopentenyl diphosphate isomerase a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function. Ana C. Ramos-Valdivia,? Robert van der Heijden and Robert Verpoorte" Division of Pharmacognosy LeidenlAmsterdam Center for Drug Research Leiden University PO Box 9502 2300 RA Leiden The Netherlands E-mail VER P 00R T@LA CDR.Leidenun iv. NL 1 Introduction 2 Biosynthetic pathways leading to the formation of C,-units 3 Assay of IPP isomerase activity 4 Characterization of IPP isomerase 5 Mechanism of isomerization 6 Regulation of IPP isomerase activity 6.1 Does IPP isomerase play a regulatory role in plants? 6.2 Compartmentation 6.3 Multienzyme complexes 6.4 Metabolic pools of IPP and DMAPP 6.5 Transport of IPP and DMAPP 6.6 Regulation of IPP isomerase activity under various conditions 7 Conclusions 8 Acknowledgements 9 References 1 Introduction Isoprenoids and isoprenoid derived compounds play vital roles in all living systems e.g.in the structure of cells in electron transport in photosynthesis in cell to cell signaling in the structure of organisms and in the interactions between organ- isms. Characteristic of the isoprenoids is that they all derive from the same building block the isoprene C,-unit. The iso- prenoids can be divided into two major groups the terpenoids and the meroterpenoids. The terpenoids are by far the largest group of natural products. Terpenoids are solely derived from C,-units. The most simple are the products directly derived from one C,-unit the hemiterpenoids.Isoprene is an example of this group of natural products which is emitted in consider- able amounts from the leaves of many plants and represents about half of all hydrocarbon emission of biological origin. Two diphosphorylated C,-units dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP) can condense in a head-to-tail manner to produce geranyl diphosphate (GPP Clo) (see Fig. 1). This type of reaction can be repeated by further reaction of the product with IPP yielding farnesyl diphosphate (FPP C 5) and geranylgeranyl diphosphate (GGPP Cz0). GGPP forms the basis for a broad range of diterpenoids and is used in the biosynthesis of chlorophyll. Two molecules of GGPP can be coupled to yield phytoene (C4& the intermediate for the carotenoids.FPP is the pre- cursor of sesquiterpenoids one of the largest groups of terpenoids. Two molecules of FPP coupled head-to-head yield squalene (C,,,) the intermediate for the biosynthesis of steroids and triterpenoids. Coupling of an indefinite number of C,-units yields latex (rubber). In plants terpenoids perform a plethora of different func- tions. Steroids and triterpenes are part of cell membranes and occur in the cuticle of plants. Steroids abscisic acid and gibberellic acid derivatives act as signal compounds between cells. Mono- sesqui- di-and tri-terpenes play a role in plant ?Present address Departamento de Biotecnologia Centro de defence systems against pests and diseases.Recently a book has been published2 in which the various roles of terpenoids in plant ecology is dealt with e.g. Threlfall and Whitehead reviewed the terpenoid phytoalexins; Fischer reported on terpenoids as allelopathic compounds; and Bergstrom Pickett Rimpler and Camps discussed different aspects of plant-insect relationships. Langenheim3 has reviewed the role of terpenoids for the interactions of a plant with its environment. For the hemiterpenoid isoprene (2-methyl-buta-l,3-diene) which is emitted from the leaves of many plants a similar role as for the plant hormone ethylene has been suggested. Isoprene is formed by dephosphorylation of DMAPP in a reaction catalyzed by the enzyme isoprene synthase. Isoprene emission is strictly dependent on light and may thus be regulated by a light activated isoprene synthase or by a light regulated production of DMAPP e.g.by modulation of IPP isomerase a~tivity.~ Other highly volatile hemiterpenoids such as iso- pentenol and 3,3-dimethylallyl alcohol occur in some essential oils either in free form or as esters. Meroterpenoids are formed by the reaction of one inter- mediate of the terpenoid pathway with an intermediate from another biosynthetic pathway. In many of these reactions prenyl diphosphates and prenyltransferases are involved. Four types of prenyltransferase may be recognized with two types involved in pure terpenoid reactions catalyzing head-to-tail Acetyl-CoA 1 Acetoacetyl-CoA Prenylated (secondary) metabolites e.g.cytokinins anthraquinones HMG-COA t-1 MVA Hemiterpenes 4 1 Isoprene IPP isomerase LOPP * LOPP 1 lndole aikaloids /Fppl Sesquiterpenes GGPP Ubiquinone Plastoquinone Squalene . Prenylated proteins I 1 Diterpenes --m Triterpenes Gibberellins Chlorophyll I Saponins Prenylated proteins 1 Carotenoids Phytosterols Investigacion y Estudios Avanzados (CINVESTAV) Apdo Postal Fig. 1 Central position of IPP isomerase in the biosynthesis of 14-740 CP 07000 Mexico DF Mexico. (mero)terpenoids; see text for definition of abbreviations Ramos- Valclivia et al. Biochemistry and function of IPP isomerase a review 591 and head-to-head condensations of prenyl diphosphates. Furthermore one type is involved in the prenylation of and one type in the biosynthesis of meroterpenoids.Examples of addition of C,-units to aromatic structures are manyfold. Some of these are constitutively produced in certain plant parts e.g. the bitter acids containing three C,-groups attached to a phloroglucinol derivative are found in hop cone^.^,^ Others are formed after induction of certain secondary metabolite pathways through infection with micro- organisms e.g. prenylated isoflavones" or prenylated ptero- carpans. Different types of terpenoid derived phytoalexins have been reviewed. ' In meroterpenoids C- and 0-alkylation are commonly observed particularly in molecules with a nucleophilic site e.g. methylene groups and phenolic oxygens. l3 The involvement of a C,-unit as precursor for a certain product is sometimes not clear from the structure as the presence of the dimethylallyl unit is not always immediately obvious.In the case of furanocoumarins it is obscured by the fact that the C,-unit suffers degradative modification after insertion. Also in anthraquinones the presence of a C,-unit is not directly obvious especially since these compounds can also be formed along the polyketide pathway in which no C precursors are used. Only through the use of labelled precursors or the identification of intermediates in which the C is still present in a non-modified form can this be proven. Another major group of meroterpenoids concerns com-pounds in which the C,-unit itself is not coupled to another molecule but in which other products of the terpenoid path- way are involved.Certain types of such meroterpenoids have great biological importance as they are involved in the primary metabolism of the cell ubiquinones plastoquinones toco-pherols menaquinones phylloquinones and chlorophyll All these substances possess a quinone system (p-benzo- or 1,4 naphtho-) and are involved in electron transport in living organisms thus playing a fundamental role in oxida tion-reduc tion chains. In plant secondary metabolism the terpenoid indole alkaloids can be mentioned as a major group of compounds in which a highly oxidized C,,-moiety (the iridoid secologanin) is coupled with tryptamine to yield strictosidine. From stricto- sidine about 3000 different indole alkaloids are derived (for a review see ref.14). The cannabinoids are another example in which a C,,-moiety is coupled with the non-terpenoid precursor olivetolic acid. Thus with a relatively simple C,-building block living organisms have developed many different specific metabolic pathways serving the organism for its internal metabolism and organization and for survival in its ecosystem. In Fig. 1 isoprenoid biosynthesis from acetyl-CoA to the various long- chain prenyl diphosphates is summarized as well as the branching points leading to the individual isoprenoid com- pounds. To fulfill the specific requirements for precursors of the individual pathways regulation mechanisms are required. These mechanisms may involve processes at gene protein (enzyme) and metabolite level including compartmentation (subcellular localization) and transport.Numerous reviews have been published in the past years on isoprenoid biosynthesis. 5p27 In the present review we will focus on the enzyme IPP isomerase (EC 5.3.3.2) which catalyzes the isomerization of IPP and DMAPP the latter compound being the primer of (mero)terpenoid biosynthesis. The characteristics as well as the possible regulatory role of this enzyme in different systems in particular in plants will be discussed. 2 Biosynthetic pathways leading to the formation of C,-units Much of our understanding of isoprenoid biosynthesis in plants is based on the pioneering investigations of the bio- synthesis of sterols in yeast and mammalian liver.In these cells all isoprenoids originate from IPP which is formed from acetyl- 592 Natural Product Reports 1997 Mevalonate pathway I Non-mevalonate pathway) 0 0 AS-C~A Aoo-+ OFop Acetyl-CoA OH Pyruvate Glyceraldehyde 3-phosphate 1 uS-CoA Acetoacetyl-CoA OH I 0 OH 1-Deoxyxylulose 5-phosphate coo-HMG-COAI HO Me 0A-OH "&OH coo- I MVAI I Ho+oP coo- I1 MVAP + L Ho&opp -OPP LOPP coo-MVA PP IPP DMAPP Fig. 2 Biosynthesis of C,-isoprene units (IPP and DMAPP) according to the classical mevalonate and the alternative non-mevalonate pathway2' CoA via acetoacetyl-CoA and HMG-CoA and subsequent reduction to mevalonic acid (MVA) (Fig. 2). MVA is then phosphorylated in two steps to the mono- and the di-phosphate (MVAP and MVAPP) by the specific ATP-dependent enzymes MVA kinase (EC 2.7.1.36) and MVAP kinase (EC 2.7.4.2) respectively.MVAPP is converted by diphosphomevalonate decarboxylase (EC 4.1.1.33) to yield IPP. These enzymes have so far only been characterized in a few plant species and have not yet been given as much attention as HMG-CoA reductase. A series of reviews on the early steps in terpenoid biosynthesis have been published. ',-'8,21722726,27 The reaction catalyzed by IPP isomerase transforms the relatively unreactive IPP into a reactive molecule (DMAPP) involving the concerted addition (at C-4) and abstraction (at C-2) of protons in IPP (Fig. 3).29 The isomerase is highly stereospecific; the two methyl groups in DMAPP do not become equivalent.The isomerization is reversible but the equilibrium is towards DMAPP formation. Equilibrium con- centration ratios of 1PP:DMAPP of 1 13.3,30-33 1:3.134 and 1:335,36were reported. DMAPP itself can easily undergo a nucleophilic attack at C-1. The diphosphate which is a good leaving group will be lost in this reaction. Besides this well documented mevalonate pathway leading to IPP and isoprenoids there is evidence for other pathways as well. In pea seeds the incorporation of the branched-chain amino acids leucine and valine into squalene and P-amyrin has been reported.37 The labels from the amino acids were equally distributed over the DMAPP and IPP derived parts of these molecules. In Cinnamomum cumphora and Pelurgonium roseurn Pseudomonas sesami Rhodopseudomonas capsulata Escherichia coli and Alicyclobacillus acidoterrestri~)~'~~~~~ another com- pletely different pathway exists that leads to the formation of DMAPP and IPP and from there to hopane-type triter-pene~~?~~ and membrane sterols4' and ubiquinone-8 ,4143 This non-mevalonate pathway is thought to be more or less similar to the valine biosynthetic route,46 using glyceraldehyde 3-phosphate and pyruvate as precursors of the C,-isoprene units (Fig.2).28 The localization of the MVA biosynthetic pathway will not LCOOH I-Gb07 Glu207 IPP DMAPP Fig. 3 Mechanism of the enzyme catalyzed isomerization of IPP and DMAPP29 plants however the DMAPP derived parts of monoterpenoids showed higher incorporations than the IPP part.38 In the DMAPP parts about 65% were labelled after feeding with l4C-labe1led valine or leucine but with labelled MVA only 32% incorporation was found.This means that the C,-unit in that case might be derived from the leucine degradative pathway in combination with a reversed MVA shunt pathway (Fig. 4)., In cell cultures of Andrographis paniculata no incorporation of leucine or valine in sesquiterpenoids or phytosterols could be detected.39340 From various feeding experiments and enzyme studies in recent years it has become clear that besides the ubiquitous MVA pathway in certain microorganisms (e.g. Zymomonas mobilis Methylobacterium fujisawaense Azotobacter vinelandii 0 HO uMe -MeKSCoA Acetoacetate Acetyl-CoA \ \ 00 Me-SCoA Acetoacetyl-CoA \I 0 HO he 0 HO -SCoA HMG-COA I 0 HO Me -CH20H HO Mevalonic acid L'CH2OPP IPP t be discussed further here but this controversial topic has been dealt with extensively in several recent reviews." 18,2 In essence the two extreme hypotheses are one cytosolic site of MVA production as the source for all isoprenoid producing cell compartments or each compartment (cytosol mitochon- dria and plastids) having its own complete IPP-pathway.In Fig. 5 the possibilities for the compartmentation of MVA biosynthesis are summarized. In view of the new pathway postulated by Rohmer and co-w~rkers,~',~~ in which DMAPP is possibly formed directly from pyruvate instead of IPP via acetyl-CoA and HMG- CoA the (possible) occurrence of this pathway in plants needs some consideration for the present review.Recent studies with developing chloroplast in barley leaves have indicated that the subcellular localization of IPP syn- thesis can change during development. Immature chloro- plasts are capable of forming isoprenoids through MVA formed from CO via pyruvate and acetyl COA.~~ In iso- prenoid production in these immature plastids both pyruvate and acetate are used and are not competitive. In mature chloroplasts however the activity of this pathway is strongly reduced. Instead these chloroplasts rely on the cytosolic IPP production for which they show a much higher permeability for IPP than the immature chloroplasts.The incorpor-ation of labelled MVA into isoprenoids thus increases upon maturation of the plastids whereas the incorporation of CO Me 0 * HO hSC~A 3-Methylglutacon yl-CoA t MSC~A -MSC~A Dimethylacrylyl-CoA lsovaleryl-CoA t t uOH uCOOH Dimethylacrylate Ketoisocaproate t t DMAPP Dimethylallyl alcohol Dimethylallyl aldehyde Leucine Fig. 4 Biosynthesis of C,-isoprene units (IPP and DMAPP) in relation to the mevalonate shunt pathway and leucine degradation Ramos- Valdivia et al. Biochemistry and function of IPP isomerase a review Pyruvate Mitochondria Pyruvate Acetyl-CoA HMG-COA 1 Cytosol DMAPP Fig. 5 Subcellular compartmentation of IPP isomerase isoenzymes and their metabolic function decreases. The incorporation of MVA into sterols (cytosol as the site of biosynthesis) did not change upon maturation of the cells and was similar to the incorporation into plastidial isoprenoids in mature chloroplasts.This supports the use of the same cytosolic pool of IPP in older cells for both cytosolic and plastidial isoprenoids. Previous studies demon- strating developmental changes in plastid envelope per-meability towards acetate citrate and mevalonate5' and IPP49 reinforce the view that the subcellular localization of IPP synthesis depends on the type of tissue examined and possible changes during development of the tissue in responses to different metabolic requirements. Evidence for the presence of a complete MVA pathway in plastids or a central cytosolic IPP biosynthesis feeding the other isoprenoid producing compartments has been discussed by various authors.17,21,22,26,49,51,52 Another explanation for the contradictory results of studies with plastids might be that the non-mevalonate pathway rather than the MVA pathway is involved.Heintze et aL5' studied this possibility by feeding radioactive pyruvate and acetate to isolated immature spinach chloroplasts. [1-14C]Acetate was incorporated with a five times higher rate than [l-'4C]pyruvate. Based on these findings the authors suggested that in immature chloroplasts IPP is formed via MVA rather than via the non-mevalonate-pathway. However no evidence was given for the position of the labelled carbons in the isoprenoid molecules the results do support the presence of a complete MVA pathway but do not exclude the presence of the pyruvate pathway as well.The subcellular compartmentation of IPP synthesis was also studied in secretory cells isolated from glandular trichomes of pe~permint.~~ These cells are not photosynthetically active and contain only leucoplasts. Their experimental set-up allowed assessment of cytoplasmic and organellar metabolism in situ. Incubation with either [14C]citrate or ['4C]acetyl-CoA resulted in the accumulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) without formation of isoprenoids. Exogenous [I4C]MVA and [14C]IPP produced an abnormally high pro- portion of sesquiterpenes. The results indicated that the cyto- plasmic pathway is blocked at HMG-CoA reductase and that the IPP utilized for both rnonoterpene and sesquiterpene biosynthesis was biosynthesized exclusively in plastids.The IPP isomerase from plastids needs thus to regulate the flux of IPP towards the cytosol and sesquiterpene biosynthesis. As in the case of mature chloroplasts which export IPP a regulation 594 Natural Product Reports 1997 of the IPP flux by compartmentation (transport and induction or inhibition of IPP isomerase isoforms) may occur but in the opposite direction. Soler et ul.,53 working with purified plastids isolated from non-photosynthetic cell suspensions of Vitis vinifera presented evidence of an IPP translocator in the plastid envelope. The rather high value of its K for IPP (500~~) means a low specificity.However the lack of interference with natural substrate analogues such as DMAPP and GPP indicated a relative specifity of this translocator towards IPP. The non-mevalonate pathway might be involved in the biosynthesis of ginkgolides a group of diterpenes in Ginkgo bi10ba.~~ The incorporation pattern of I3C- and 2H-labelled precursors excluded MVA as an intermediate for these diterpenes. The IPP units used for formation of ginkgolides are the result from a decarboxylative condensation of pyruvate and a triose phosphate. On the other hand it was demonstrated that MVA was incorporated in p-sitosterol. These two independent biosynthetic pathways were strictly compartmentalized. At the C level apparently some trans- port between the compartments seemed to occur resulting in small quantities of cytosolic FPP from the MVA-P-sitosterol biosynthesic route being used by most likely plastidial GGPP synthase to couple with an IPP unit from the non-mevalonate pathway thus resulting in 'hybrid' diterpenes.Recent studies using 13C NMR spectroscopy to detect the site of labelled carbons in a molecule showed that neither MVA nor leucine were incorporated into the isoprenyl unit of chalcomoracin produced in Morus alba cell cultures. Catabolic processes via acetyl-CoA were thought to cause the scrambling of the leucine label in the skeleton of chalcomoracin. The enrichment pattern in the isoprenyl substituent after feeding labelled acetate could only be explained by passing of the acetate through the TCA-cycle.55,56 Further studies using the HMG-CoA reductase inhibitor compactin confirmed the existance of two biosynthethic pathways compactin did not affect the isoprene biosynthesis for prenylchalcones.Scrambling of labels has also been reported in the sesquiter- penoid biosynthesis in Andrographis panic~late.~~ Recently the presence of the glyceraldehyde phosphate/pyruvate pathway was identified in the biosynthesis of diterpenes in Ginkgo biloba and Salvia miltiorrhiza (cited from ref. 28). Also the diterpene taxane skeleton was found not to be of mevalonoid origin.58 3 Assay of IPP isomerase activity Both purification and characterization of an enzyme require an adequate assay for the activity. The most widely used assay of IPP isomerase is the one that was used in the first reports on this enzyme.30,31,59 A more recent protocol has been described.60 The assay is based on the acid-lability of the allylic prenyl diphosphates.These allylic compounds are readily converted into the corresponding alcohol under acidic con- ditions whereas the homoallylic IPP is stable under such conditions. Thus after the incubation of IPP isomerase with radiolabelled IPP (usually [1-'4C]IPP) the reaction is stopped by adding concentrated hydrochloric acid in methanol. The mixture is then incubated for another preset period after which the alcohols formed are extracted with a non-polar solvent such as diethyl ether toluene petroleum ether or other alkane (pentane hexane). In the extract the radioactivity is counted as a measure for the conversion of IPP in DMAPP.In the incubation mixture Mn" and/or Mg2' is added as well as various compounds which might stabilize the enzyme (ie. bovine serum albumin leupeptin 2-mercaptoethanol dithio- ethreitol etc.). Prenyltransferases and phosphatases may influence the assay. Prenyltransferases will result in the incorporation of IPP into products which will also be converted by the acid treat- ment and similarly the alkaline phosphatases will convert IPP into an extractable alcohol. Both will result in higher levels of radioactivity in the extract and thus to an overestimation of the isomerase activity. By adding KF to the incubation mix- ture the phosphatases can be inhibited. Some authors applied GC after the extraction of the alcohols; this can be used to estimate the prenyltransferase activity.The radioactivity found in the farnesol peak usually the major side product should be divided by three and then added to the amount found in the 3,3-dimethylallyl alcohol peak to correct for the prenyltrans- ferase activity. 32742*61 The combination GC-MS was used to measure the incorporation of deuterium in connection with mechanistic studies.36 Reardon and Abeles62 used the acid-labile method but instead of extraction the mixture is run over a Dowex C1-column after basification and the eluent is counted. They also used another method alkaline phosphatase treat-ment after the incubation extraction with diethyl ether after saturation with NaCl and separation by HPLC (RP HPLC with water-MeOH 8:2) followed by counting of the differ- ent alcohol-containing fractions.The alcohols dimethylallyl alcohol isopentenol farnesol and geraniol were also separated by normal phase HPLC using a silica column and 1.5% n-butanol in hexane as el~ent.~~’~~ Beyer et al.65 reported the separation of prenyl diphosphates by means of ion-pairing reversed-phase HPLC using tetra-n- butylammonium as ion-pairing agent. The isolation and quan- tification of a series of intermediates of the early steps of the biosynthesis have been reported.66 By means of ion-pair reversed-phase chromatography [C 8 column with a mobile phase of 10 mM tetra-n-butylammonium in water-methanol gradient (0-70%) pH 61 with radioactivity detection some CoA-esters HMG-CoA MVA its mono- and di-phosphate IPP DMAPP GPP FPP and GGPP could be determined.Zhang and P~ulter~~ reported the analysis and purification of DMAPP IPP GPP FPP GGPP and GFPP on a C, column in which a mobile phase (gradient 0-100% acetonitrile) containing 25 mM ammonium bicarbonate (pH 8.0) was used. This has the advantage that no residues of the mobile phase will be left after evaporation of the solvent in preparative applications. By capillary electrophoresis in com- bination with indirect laser-induced fluorescence detection IPP GPP FPP and GGPP could be separated within 6min and detected to concentrations as low as 0.5 p~.~* Until recently radiolabelled MVA and IPP were the only intermediates in terpenoid biosynthesis which were com-mercially available.Research in this field started in many cases with the synthesis of the (labelled and ‘cold’) allylic diphosphates. At present most of the intermediates are now available from a commercial source but due to the high prices synthesis remains common practice. For many years the method as first reported by Cramer and BOhm6’ has been applied for the synthesis of isoprenoid diphosphates but since purification method (purity>95%) for the yeast enzyme in connection with the cloning of the gene. They found a specific activity that was 4.6 times higher than that of Reardon and Abeles.62 The estimated molecular mass was similar (39 kDa). However from the sequence of the gene a protein of 288 amino acids with a molecular mass of 33 350 Da was calcu- lated.This points to a post-translational modification. Although several potential glycosylation sites are present in the protein various tests on a-glucoside and a-mannoside linkages were negative. In a later it was shown that the recombinant enzyme on SDS-PAGE behaved as the enzyme isolated from yeast having a much higher molecular mass (39 OOUO000) than its actual size. The K value for IPP measured for the recombinant enzyme was 43 p~. Ladeveze et ~21.~’ transformed yeast with this gene; the cells showed a tenfold increase of isomerase activity but no increase of ergosterol levels. On the other hand in a mutant yeast resistant to the ergosterol biosynthesis-inhibiting compound fenpropi- morph an increased activity (1.5 times) of IPP isomerase was observed.From these results a regulatory role of the isomerase on the flux through the ergosterol pathway is not obvious. By complementation using a disrupted yeast gene a cDNA clone from Schizosaccharomyces pombe was isolated.” S. pombe isomerase is relatively small (26.9 kD 227 amino acids) but shows a high degree of similarity with the yeast enzyme. It contained the essential Cys and Glu catalytic residues. Another source from which IPP isomerase was isolated is the mold Claviceps purpure~.~~.~~ Bruenger et al.77 purified the enzyme to near homogeneity and made a direct comparison with the enzyme from pig liver. From gel filtration and SDS-PAGE a molecular mass of 35 kDa was estimated con- siderably higher than for the mammalian enzyme (22 kDa) but similar to the yeast enzyme.A number of active site- directed irreversible inhibitors was tested on this enzyme (see late^-).^^-^^ .~~ McGrath et ~ 1 reported the isolation of the isomerase together with two different types of prenyltransferases from Penicillium cyclopium. The molecular mass as determined by gel filtration varied (20-50 kDa) depending on the culture conditions of the microorganism. Only one form of the enzyme could be detected; this should thus serve the prenyltransferase leading to isoprenoids and the prenyl-aryltransferase leading to cyclopiazonic acid. Thus the isomerase was thought not to be a rate limiting step. The purified IPP isomerase from E.coli shows a K for IPP of 5 p~; the detergent Triton X-100 has no effect on the activity.42 The enzyme requires Mn2+ or Mg2+ for activity Mn2+ is more active at lower concentrations than Mg2’ but at higher concentrations they are equally active. Interestingly the enzyme was found not to be markedly inhibited by then some more efficient procedures have been rep~rted.~’-~~ iodoacetamide (41% at 5 mM). 4 Characterization of IPP isomerase IPP isomerase has been characterized from quite a few different organisms. Studies of the enzyme are hampered by the fact that prenyltransferases such as FPP synthase usually present in considerable amounts in any protein extract obtained without subcellular fractionation will immediately convert DMAPP into higher prenyl derivatives.Some extent of purification of the isomerase is thus required but often the separation from the prenyltransferases is difficult. Moreover phosphatases interfere with determining IPP isomerase ac-tivity. Despite these experimental difficulties the yeast enzyme Banthorpe et reported data different from those .~~ presented by Shah et ~1for the isomerase purified from pig liver. The K at the optimum pH (6.3) and Mn2’ concen-tration is 2.7p~ the PI between 6.0-6.2 and the molecular weight is about 82 500 estimated by means of gel filtration. Both Mn2+ and Mg2+ can act as cofactor at levels of 2-8 mM. The former gives a threefold higher level of activity the maximum being at 2 mM. A series of prenyl diphosphates show inhibition of 50-70% of the activity at a concentration of 5 mM.ATP causes inhibition (1-5 mM) with a sigmoidal relationship between concentration and inhibitory effect. Iodoacetamide (1 mM) and iodoacetic acid (0.1 mM) N-ethylmaleimide (5 mM) and p-hydroxymercuribenzoate (0.1 mM) give complete was partially purified and characterized in the 1 950~~’~~~~~~ and inhibition. MVA (1 mM) strongly enhances the activity as well by the 1960s the mammalian enzyme had been partially puri- as thiols (5 mM) such as reduced glutathione mercaptoethanol fied.32 Some characteristics of IPP isomerase purified from and dithiothreitol. Bruenger et al.77 obtained two isoforms different sources are presented in Table 1. from pig liver one was retained on DEAE-cellulose the other The yeast enzyme was reported to be a monomer with unretained.For both of these molecular mass was estimated a molecular mass of about 40 kDa. It has a broad pH by means of gel filtration to be about 22 kDa. The retained optimum the K for IPP is 35 p~. The enzyme is inactivated form shows a PI of 6.2 with isoelectric focusing whereas the by iodoacetamide.62 Anderson et al.79 reported an improved unretained form showed values of 7.1 6.7 and 6.2. Rumos- Vuldiviu et al. Biochemistry and function of IPP isomerase a review Table 1 Characteristics of IPP isomerase (partially) purified from different sources Source MWI kDa No. of isoforms PI K,l p~ Cofactors (optimumconc./mM) pH opt. Purity(specific activity/ pmol mg -min -I) Purification method Ref.E. coli E. coli (yeast Claviceps recombinant) purpurea 39 35 5 43 5.4 Mg2+ (10) Mn2' (0.2) Mg2+ Mgz+ (0.2) Mn2+ 7.5-8.5 6-8.5 Partially >95% pure (20)Near homogeneity -(3000) (NH,),SO precip. DEAE cellulose Sephadex G50 DEAE-To yopearl Octyl sepharose IEP and (NH4),S04 precip. Blue-Trisacrvl DEAE celluiose (42) (76) (77) Claviceps purpurea 2.4 Mg2+ 5-9 90% (3.6) Sephadex G-100 DEAE-Trisacryl IEP and (NH4)2S04 precip. Butyl sepharose TSK DEAE 650s (35) DEAE 5PW Penicillium 2&50 4.5 6.7 Mn2+ Mg2+ 6.0 Partially Biogel A IEF (NH4),S04 precip. (78) Yeast 36 Mg2+(5) 5.5-9.3 Partially (6.6) Dialysis A1203 (30,31,59) Yeast 40 35 Mg2+ (NH,),PO4IEP and (NH4)3P04 precip. DEAE cellulose (62) Hydroxylapatite Gelfiltration Yeast 39 43 Mg2+ Homogeneous(12.3) FPLC Mono-Q IEP and (NH4)2S04 precip.DEAE cellulose Butyl sepharose ChromatofocusingSephacryl S-200 DEAE-5PW (79) Pig liver 60 8.2 Mg2+ (5) 4-8.3 Partially (1) (NH4)2S04Dialysis Ca-phosphate gel DEAE cellulose Pig liver Pig liver 82.5 6.0-6.2 4 2.7 Mn2+ (2) Mn2+ (2) 6.0 6.3 Partially (29) Partially (5.9) Dialysis Sephadex G-200 DEAE cellulose Sephadex G-100 CM cellulose (NH4)2S04 (NH4)2S04 DEAE cellulose Pig liver Avian liver Avian liver Bombyx mori (silkworm) Cucurbita pep0 (pumpkin) Gossypium hirsutum roots Ly copersicon (tomato) plastids 22 35 98 34 2 4 2 6.2 6.7 5.28 1.3-2.5 11.2 20 45+22 73.6 5.7 Mg2+ (0.5) (isoform I) Mn" (0.25) Mg2+ Mn2+ (0.1) (isoform 2-4) Mg2+ (1) Mg2+ Mg" (2) Mn2+ Mg2+ 6.6 7-8 7 7.4-8 8.2 Partially Partially Partially Partially Partially 95% (6.2) Partially (8.2) see Cluviceps (NH4)2S04DEAE cellulose DEAE cellulose Sephadex G-25 Hydroxyapatite Sephadex G-100 Sephadex G-200 Hydroxyapatite DEAE cellulose DEAE Sephadex A-25 Sepharose 6B Bio-Gel A DEAE cellulose (NH4)2S04 (NH4)2S04 (NH4)ZS04 (NH4)2S04 Capsicum annuum plastids Narcissus pseudonarcissus (daffodil)chromoplasts cell suspension Cinchona robusta 33.5 32+28 34 29 1 2 I I1 6 7.6 5.1 1.0 Mg2' Mn2+ (0.5) Mn2+ (0.5) Mn2+ (2) Mg2+ (1) Mg2+(4) 7-8 6-8 7.2-7.5 7.2-7.5 Homogeneity (6.2) Partially (300) Homogeneity Homogeneity Sephadex G- 100 Chromato focusing PEG precipitation SephacelAPP-SepharoseSephadex G-100 Phenyl-Superose HR5 DEAE-5PW Q-Sepharosehydroxyapatite Pheny 1-Sepharose Mono-Q 596 Natural Product Reports 1997 From avian liver homogenates four different isoforms were obtained.82 All isoforms have similar pH optima the activity is dependent on Mn" (0.5 mM for I 0.25 mM for 11-IV).The K values are respectively 1.7 1.3 1.3 and 2.5 p~for the isoforms I-IV. Mg2' only slightly increased activity. Inorganic diphos- phate and iodoacetamide inhibit activity with the effect de- creasing in the order from I-IV; isoform IV in fact not being inhibited by iodoacetamide. Efforts to isolate the isomerase from chicken or pigs liver using the same method of purifica- tion as used for the Claviceps enzyme were not successful.77 From fresh chicken livers one activity band was obtained but after 1 h at room temperature two peaks were found; proteo- lysis was thought to be involved. The major peak has a PI of 6.7.The chicken liver enzyme has a K for IPP of 11.2 p~. Recently a gene was cloned from human promyelocyte cells which had more than 50% homology with the yeast IPP isomerase gene.93 The open reading frame codes for a protein of 228 amino acids which is smaller than the yeast enzyme (see above). In particular three regions showed high homology composing less than half of the protein. These regions included the active-sites Cys139 and Glu207 of the yeast with the adjacent four amino acids on either sides of the active residues being identical. The gene was induced by the addition of a phorbol ester to the cells the gene might be involved in the regulation of ras oncogene function as ras is a prenylated protein. Koyama et a1.83 isolated IPP isomerase from silkworm (Bornbyx rnori).The molecular mass was estimated to be 35 000 by gel filtration. The enzyme shows maximum activity at pH 7-8. A K for IPP of 20 p~was determined. Activation by Mn2' is stronger than by Mg2+ particularly at lower concentrations i.e. at 2 mM both cations give about similar activity for the enzyme. Ogura et al.84 reported the first partial purification of IPP isomerase from a plant source pumpkin fruits. Two active peaks were obtained from a hydroxylapatite column. The isomerase is inhibited by inorganic diphosphate as well as a series of prenyl diphosphates at a level of 0.1 mM the corre- sponding monophosphates only show little inhibition at that The isoforms differ in sensitivity for iodoacetamide in hi bi tion .85 Evidence for the presence of a proplastidial and a mito- chondrial form of IPP isomerase in developing castor bean (Ricinus cornrnunis) endosperm was presented by Green et al.96 In the proplastidial fraction GGPP synthase activity was also found.The permeability of the mitochondria1 and proplas- tidial membranes for IPP were thought to play a regulatory role. Spurgeon et a1.87 partly purified the isomerase from tomato fruit plastids. By means of gel filtration the molecular mass was estimated to be 34 kDa and the K for IPP of 5.7~~. Mg2+ and/or Mn2' are required as cofactor the combination of the two being the most effective. Iodo- acetamide (1 mM) totally inhibits the enzyme. Moreover DMAPP and GPP inhibit the isomerase at 80 PM with 40 and 60% respectively whereas FPP has little inhibitory effect.Similar K (6 p~) and molecular mass (about 33 500) were found for the isomerase isolated from Capsicum chromo- plasts.88 A pH optimum of 7-8 was found. Under mild extraction conditions the plastidial isomerase was always found to be associated with GGPP synthase. The purified isomerase from daffodil chromoplasts showed similar characteristics as from Both Mn2' and Mg2' can act as cofactor however for the former a clear optimum at 0.5 mM was found whereas with the latter a gradual saturation of the activity is observed up to a concen- tration of 6m~. On SDS-PAGE two proteins were observed with molecular masses of about 32 and 28 kDa. Widmaier et al.86 purified a protein fraction from Gossypiurn hirsutum roots.This fraction was able to produce the four different isomers of FPP with IPP as single substrate. Accord- ing to electrophoresis this fraction consists of three proteins on gel filtration however only one single peak was obtained. It was thought to be a multienzyme complex having IPP isomerase cis-and trans-prenyltransferase activities. Only the isomerase could be obtained pure and was subsequently characterized. The molecular mass was estimated on SDS-gels to be 98 kDa a K of 73.6 PM for IPP and optimum activity at pH 7.4-8.0 in the presence of 2 mM Mg2'. Other sources in which the isomerase has been detected are orange peels (Citrus sinensis) and Pinus radiata seedlings.97 Recently a gene coding for IPP isomerase was cloned from flower-plastids of Clarkia breweri.The cDNA library was screened with a partial IpicDNA clone from Arabidopsis thaliana. The cDNA has an open reading frame of 287 codons with a calculated molecular mass of 32 970 Da. The Clarkia IPP isomerase amino acid sequence was for 90% identical with the Arabidopsis sequence and less than 50% identical with yeast IPP isomerase. A putative transit peptide was found at the N terminus which is cleaved after import into the chloro- plast. The mature protein would then be approximately 27 kDa.98 In Cinchona robustu cell cultures elicited with a homogenate of Phytophthora cinnarnorni the induced accumulation of anthraquinones is preceded by a 2.5-fold transient induction of IPP isomerase activity.This elicitor-inducible IPP isomerase activity resolved chromatographically in two is~forms.~~ The isoforms were purified and were found to be monomers of 34 and 29 kDa. The K values for IPP were 5.1 and 0.95 p~ respectively. Both isoforms are completely inhibited by the specific IPP isomerase inhibitor 2-(dimethy1amino)ethyl diphosphate (NPP). The isoform with the highest affinity for IPP preferred Mn2+ over Mg2+ as cofactor. GPP inhibited IPP isomerase in a competitive manner with a Ki of 96 PM which may be part of a feedback regulation. The two isoforms were recognized by antibodies raised against purified plastidial IPP isomerase from Capsicum annuurn (Camara et al. un-published results) suggesting substantial homology between the Cinchona and pepper enzymes.By immunodetection two IPP isomerase isoforms were observed in a crude extract from an elicited C. robusta culture while only one isoform was detected in the extract of non-treated cells. This suggests that the second inducible form is not an artefact of the purification procedure. The characteristics of the isomerase of the various pro- karyotic and eukaryotic sources show that there is a great deal of similarity (Table 1). The enzyme is not too stable but can still be isolated and purified using standard methods. Apparently different isoenzymes occur in at least two different cell compartments in plants and mammalian cells. The role of Mg2' and Mn2' as cofactor is clear but the results obtained for the enzyme from the various sources do differ considerably.The K values found are similar except for the yeast enzyme which has a higher K value of almost tenfold. 5 Mechanism of isomerization Detailed investigations of the reaction mechanism carried out with the enzyme from pig liver yeast and Claviceps have indicated that the isomerization of IPP proceeds via a carbo- cationic intermediate (or through at least a transition state with carbocationic character). The isomerization of IPP involves an electrophilic attack by H' from the aqueous medium on the re-re face of the IPP double bound (Fig. 3). This produces a transient carbocation (or intermediate with carbocation character) which is stabilized by the simultaneous stereospecific elimination of the C-2 pro-R hydrogen of IPP (the C-4 pro-S in MVA).As proton removal and proton addition occur on opposite sides of the molecule the iso- merization is considered to be a concerted mechanism process rather than a consecutive addition and elimination as it occurs in the reaction of IPP with DMAPP. The isomerization is thus a stereoselective antarafacial [1.3) allylic rearrangement in which the new methyl group is generated in the (a-position Rarnos- Valdivia et al. Biochemistry and function of IPP isomerase a review this methyl group thus carries a proton originating from the aqueous medium. 34,69,99p1'' With a recombinant yeast IPP isomerase Street et ~1.''~ studied the proton exchange in an incubation of IPP and the enzyme in D,O using NMR spectrometry.The (@-methyl protons of DMAPP rapidly disappeared in the 'H NMR spectra but also the (a-methyl protons slowly exchanged with D20 (rate of ca. 2% of the isomerization). Even the DMAPP C-2 proton decreased in intensity though at an even lower rate (ca. 0.5% of isomerization). The C-1 proton signal did not change at all. In other words the conversion does not have a complete stereospecific fidelity. However for the reaction product this is not required either. Shibuya et ~1.''~ reported an 8-10% scrambling of the 13C-label at C-2 of MVA in the biosynthesis of clavine alkaloids in Claviceps. The isomerase was thought the most likely step where this occurs. The concerted mechanism of the reaction requires that the catalytic pocket in the enzyme has two active sites which are opposed to each other and thus can interact with the opposite faces of the ally1 function in IPP (Fig.3). Lynen et ~1.~' previously postulated that a thiol and Shah et ~1.~~ group might be present in one of the active sites. The inactivation of the isomerase by iodoacetamide supports the involvement of a thiol fun~tion.~~,~~ A series of inhibitors including various alkyl diphosphates and fluoro- and amino- derivatives of IPP was reported by Reardon and Abeles.62~'00 2-(Dimethy1amino)ethyl diphosphate inactivated the yeast iso- merase (non-covalent binding) whereas the isomerization of (Z)-3-(trifluoromethyl)but-2-enyl diphosphate showed a lo6-fold slower isomerization than IPP.Based on these findings a mechanism involving a carbonium ion as intermediate was proposed. Muehlbacher and Po~lter~~~''' studied the effect of a series of inhibitors of the Claviceps IPP isomerase. These compounds were analogues of IPP and DMAPP con- taining a fluorine epoxy or ammonium group. The 3-methyl- 3,4-epoxybutyl diphosphate (EIPP) and 3-fluoromethylbut-3- enyl diphosphate (FIPP) formed stable covalently bound products with the isomerase. The 2-(dimethy1amino)ethyl diphosphate (NPP) showed a stable non-covalent binding to the isomerase. FIPP had a KI of 85n~ for the yeast isomerase and during the reaction fluoride was released stoic hiometrically .92 The pig liver enzyme was found to also catalyze the isomerization of 3-ethylbut-3-enyl diphosphate into trans-3-methylpent-3-enyl diphosphate and of the latter into the corresponding trans-3-methylpent-3-enyldiphosphate.'04 The former conversion is irreversible the latter reversible.The formation of the cis-pent-2-enyl derivative from 3-ethylbut-3- enyl diphosphate was much slower than that of the trans-pent- 3-enyl. This abnormal behaviour fits the model of two bindings sites in the enzyme being involved in the isomerization and the ethyl group hampering proper binding to one of these sites. Later the isomerization of some further homoisopentenyl diphosphates was reported.36 The gene for IPP isomerase in S. cerevisiae was recently cloned and sequenced79 and an overproducing strain of E. coli glutamate also plays a role in the catalytic pocket of the yeast IPP isomerase.6 Regulation of IPP isomerase activity IPP isomerase finds itself at a central position in terpenoid biosynthesis. Its activity is required in a large number of essential processes and it is thus expected that the activity of the enzyme is controlled by various means. Aspects of these regulatory mechanisms in particular those found in plants are discussed in this chapter. 6.1 Does IPP isomerase play a regulatory role in plants? Above we described the characteristics of IPP isomerase and also mentioned the possibility that this enzyme plays a regu- latory role in terpenoid biosynthesis. It produces the primer molecule for the isoprenoid biosynthesis as well as the pre- cursor for the biosynthesis of various meroterpenoids such as certain coumarins cytokinins isoflavonoids and anthra- quinones.Before further discussing the present knowledge on IPP isomerase in terms of a regulatory role it is probably best to first consider in which way IPP isomerase could be involved in the regulation of isoprenoid biosynthesis. In doing so we have to be aware of the fact that it might not be at all possible to describe a unifying concept for this. Between species but even within a single organism on cellular and subcellular level and even more during development of the tissue different types of regulation may occur for apparently similar pathways. In discussing this we also have to take into account the possibility that DMAPP is formed via the glyceraldehyde 3-phosphate/pyruvate pathway which may not require the intermediacy of IPP.Being the primer for the isoprenoid biosynthesis DMAPP must be present in any cell compartment where isoprenoids are biosynthesized. That means there exist two possibilities either an in situ production or a transport of DMAPP. If we take these two options as a starting point for possible regulation we come to the following possibilities (a) Transport of DMAPP which includes the two options (i) that metabolic pool(s) of DMAPP exist(s) in a cell. DMAPP may be present in one pool supplying all cellular compart- ments or in separate pools in the different compartments (which may be exchangeable). In the former case transport could regulate the channelling of the C unit into the various isoprenoid pathways but also the activity of the prenyltrans- ferases coupling DMAPP and IPP may play a role in this.In the latter case the prenyltransferases could regulate the fluxes into the different pathways provided IPP is available; and (ii) that DMAPP is made upon demand and transported to the site where it is needed. This process requires either an inducible activity of IPP isomerase or an induction of the production of IPP. (b) In situ production of DMAPP which include that the flux in the pathway is determined by either the IPP isomerase activity the production of IPP or the activity of the prenyl- containing the IPP isomerase gene (IDII) was con~tructed,~~ thus opening the way for further studies of the mechanism of the enzymatic isomerization.Replacement of cysteine (Cys 139) in the recombinant isomerase with alanine or valine by site- directed mutagenesis resulted in an inactive enzyme,29394 thus supporting the involvement of a thiol group in the isomeriz- ation. The irreversible inhibitor EIPP was found to bind to Cys139'05 via a thioether linkage. Also FIPP35 binds to this active-site n~cleophile.~~-~~ On the other hand Cys138 is not essential for activity.29 In efforts to identify a second nucleophilically active site using active site-directed irreversible inhibitors another important group was found which is involved in covalently binding of the substrate and its 3-fluoro-derivative to the enzyme. This group is the glutamate at position 207 (Glu207).The loss of activity in E207 mutants suggests that the carboxylate moiety of 598 Natural Product Reports 1997 transferases. With these possibilities in mind we will discuss below the following aspects of IPP isomerase compartmentation of enzyme activity multienzyme complexes metabolic pools transport and (other) factors affecting IPP isomerase activity. This discussion is complicated by the fact that still no consen- sus exists about the compartmentation of the isoprenoid pathway in plants. Several models have been put forward. The two opposed hypotheses are that the pathway from acetate to IPP is only present in the cytosol or that each isoprenoid producing compartment contains this complete pathway (e.g as reviewed in refs.15-18,24,26 and 27). At least it is clear that the various types of isoprenoids are produced from IPP in different cell compartments e.g. sterols triterpenes and ses- quiterpenoids in the cytoplasm and endoplasmatic reticulum; mono-and di-terpenes in certain types of plastids; carotenoids tocopherols plastoquinone and chlorophyll in chloroplasts; and ubiquinone in mitochondria. In the biosynthesis of meroterpenoids a different situation exists as DMAPP is not coupled with IPP but to another non-isoprenoid precursor. IPP is thus only utilized through the isomerase (DMAPP) and not taking part in the reaction itself as it is in the formation of the various terpenoids. 6.2 Compartmentation As discussed above there are several models for the compart- mentation of terpenoid biosynthesis differing in the fact that at any stage of the steps leading to IPP transport of inter- mediates occurs.In fact the uptake of IPP in plastids has been rep~rted.~~.~~.~~ No evidence for DMAPP transport has been reported to our knowledge. The very fact that DMAPP is the primer of the biosynthesis of all terpenoids means that in each compartment where terpenoids are produced DMAPP should be formed assuming that no transport of DMAPP occurs. As a consequence one expects an isomerase to be present in these compartments if at least no other pathway exists which leads directly to DMAPP without the intermediacy of IPP. Only few studies report the presence of more than one isomerase. Ogura et uI.*~ separated two different forms of isomerase from pumpkin fruits but the localization of these enzymes was not determined.In castor beans a mitochondrial and a proplastidial IPP isomerase have been detected.96 IPP isomerase has been isolated from various types of plastids.3437m The presence of IPP isomerase in chloroplasts chromoplasts and leucoplasts can also be concluded from the rapid incorporation of IPP into isoprenoids compounds in preparations of isolated plastids.lo6 The presence of IPP isomerase activity in plant mitochondria was further indicated by the IPP feeding studiesio7 in isolated pure and intact mitochondria from potato tubers spinach leaves and daffodil flowers which have the ability to incorporate IPP into ubiquinones. MVA Sdiphosphate the immediate bio-synthetic precursor of IPP was not accepted as substrate even when ruptured mitochondria were used.This points to the importation of IPP into the mitochondria. Also mature chloroplasts seem to be able to utilize an external cytosolic source of IPP for the biosynthesis of i~oprenoids.~~ In glundular trichomes of peppermint it was found that the cytoplasmatic mevalonic acid pathway was blocked at the level of HMG-CoA reductase and that the IPP utilized for both plastidial monoterpene and cytosolic sesquiterpene bio- synthesis is synthesized exclusively in the plastids. A con-nection of the pathways was proposed at the level of IPP (same pool) which requires translocation of IPP to the differ- ent compartments and the presence of (an isoform) of IPP isomerase in each ~ompartment.~~ In the biosynthesis of rubber the starter molecule is also DMAPP and in the latex an IPP isomerase was indeed detected.Io8 An epoxy analogue of IPP (3,4-epoxy-3-methyl-l- butyl diphosphate) inhibited rubber biosynthesis at the level of the isomerase with the prenyltransferase activity not being affected by the inhibitor.Also in rubber particles some iso- merase activity was detected with the actual prenyltransferase (a cis-l,4-prenyl transferase) responsible for the rubber also bound to these particles. A soluble trans-prenyl transferase was found in the latex but was only responsible for the formation of FPP. This FPP can act as starter molecule for rubber biosynthesis only requiring further IPP molecules.In mitochondria of rat liver and kidney cells IPP isomerase should be present as they can utilize IPP as substrate for the biosynthesis of ubiquinones. lo9 Also in mammalian mito- chondria IPP-import is required as MVA itself cannot be utilized for ubiquinone biosynthesis. Interestingly Krisans et a1.I'" recently provided evidence for the presence of the complete MVA-isoprenoid pathway including the isomerase in peroxisomes of mammalian cells. In plant cells such studies have not yet been made. These facts support the hypothesis that DMAPP is formed at subcellular level in the compartments involved in the biosynthesis of a certain type of isoprenoids. However only mitochondrial and plastidial forms have so far been reported.Although a cytosolic IPP isomerase has not yet been demon- strated in plants its occurrence cannot be excluded from the data presented by for example Ogura et dB5 and Valdi~ia.*~ In fact one expects an isomerase in the compartment where sesquiterpene and sterol biosynthesis is located. 15,16,24,26 The isomerases found in mammalian cells and microorganisms are soluble enzymes and thus could well be located in the cytosol. The localization of IPP isomerase can be seen separately from the discussion on the site of IPP biosynthesis as DMAPP can be formed from IPP imported to the compartment concerned (see ref^.'^,^^ for a review on this controversial topic). In contrast to IPP transport of DMAPP has not been reported so far. 6.3 Multienzyme complexes Srere' has comprehensively reviewed and discussed the evidence for the occurrence of sequential metabolic enzymes in complexes.Also in plants there is ample evidence that enzymes are arranged in complexes which is obviously the case for membrane-bound enzymes.* l2 Soluble enzymes can be arranged in multienzyme complexes but such complexes are difficult to detect as they are easily destroyed during extrac- tion.' l3 In the biosynthesis of isoprenoids multienzyme complexes are involved e.g. the plastidial stroma phytoene synthase complex. According to Liitzow and coworkers343' l4 this complex is not associated with the isomerase in daffodil chromoplasts. In fact the isomerisation and phytoene bio- synthesis proceed independently.However in tomatoB7 and Capsicum chromoplastsg8 the isomerase was co-purified in several steps with this complex. In the latter plant it was found that under mild extraction conditions GGPP synthase was associated with the IPP isomerase or the phytoene synthase complex in a noncovalent way. From the various efforts to purify IPP isomerase it is clear that it is hard to separate from prenyltransferases. For example Allen et ~1."~ reported the purification of FPP synthase and even upto the last steps of purification the enzyme was able to accept IPP alone as substrate i.e. iso- merase activity was present. Widmaier et aLB6reported the co-elution of a cis- and a trans-prenyltransferase together with IPP isomerase from cotton roots; they proposed that these enzymes exist as a multienzyme complex.The occurrence of multienzyme complexes are in accordance with an in situ production of DMAPP on the site of the isoprenoid biosynthesis. 6.4 Metabolic pools of IPP and DMAPP An important point in connection with the possible regulatory role of IPP isomerase is whether a metabolic pool of DMAPP exists. In such a case the IPP isomerase would not regulate the fluxes into the pathways but in the case of an IPP pool the isomerase would be the flux-controlling enzyme. Several studies point to the presence of a C,-pool. In rat levels of IPP and IPP isomerase significantly altered by changes in diet with a regulatory role for IPP isomerase in cholesterol biosynthesis being proposed.' l6 Evidence for the existence of a DMAPP pool is found in the non-equivalent labelling of the IPP and DMAPP part of various terpenoids.Examples of this have been reported by a number of authors (e.g. see refs. 117-120). In Menthapiperita' 17.' l8 the feeding of radioactively labelled MVA resulted in the preferential labelling of the IPP moieties of mono- and sesqui-terpenoids. Moreover the labelling per- centage of the sesquiterpenes was much higher than in mono- terpenes. Even with labelled CO and glucose the label was found particularly in the IPP-derived part. These pre-cursors are better incorporated into the monoterpenoids Ramos- Vuldivia et al. Biochemistry and function of IPP isomerase a review than into the sesquiterpenoids; the opposite was found for MVA.From this besides separate sites of biosynthesis of these terpenoids it was concluded that an endogenous pool of DMAPP is involved. Even separate pools for mono-and sesqui-terpenoid biosynthesis may exist in the oil glands. Other possible explanations but less likely according to the authors could be that DMAPP is derived from another pathway along with compartmentation. Similarly in Tanacetum vulgare Pelargonium graveolens and Mentha pulegium1'5,121 it was found that in monoterpenes the labels of fed IPP are not uniformly channelled into the two C,-parts of the molecule. The portion of the molecule derived from IPP is usually more heavily labelled than that derived from DMAPP. Also labelled CO, acetate MVA and DMAPP resulted in such an asymmetric labelling.Several explanations were suggested such as influence of high non-physiological levels of the fed precursors; DMAPP is derived from another pathway than IPP; or a pool of DMAPP exists. An alternative pathway via leucine was shown not to be present as this amino acid was not incorporated. Based on these results and previous reports the authors proposed that two metabolic pools exist; one being of the free intermediate and a larger one of the intermediate bound to proteins. The fed precursors are channelled through the first pool whereas the primer molecule DMAPP comes from the second bound pool. The two pools might be fed from different pathways. Efforts to detect the postulated pool of C were not successful.Allen and Banthorpe'22 studied the prenyltransferases in Pisum sativum. They studied the presence of a DMAPP pool. Incubations were made with both C-1 and C-4 l4C-labe1led IPP in the presence of an IPP isomerase inhibitor and subse- quently the formed FPP was chemically degradated. By com- paring the distribution of the labels over the fragments with the expected patterns in case of a DMAPP or GPP pool it was clearly shown that only the presence of a DMAPP pool fits the results. The size of the pool of DMAPP (or biogenetic equivalent) probably bound to protein was calculated to be about 10 nmol mg -protein. In case of a free DMAPP metabolic pool being present the high reactivity of DMAPP means that it should be compart- mentalized in such a way that it is not available for the prenyltransferases.Another possibility is that the prenyltrans- ferases are rate limiting. It is interesting to note that trihydroxy pterocarpan dimethylallyl transferase a membrane-bound enzyme in soybean probably localized in the chloroplasts envelope is inhibited strongly by IPP (Ki 7.5 PM; K for DMAPP 3.9p~)." This means that no IPP-pool can be present in the same compartment due to the fact that this enzyme is involved in the plants defence system. Kreuz and were unable to detect any of the enzymes of the MVA pathway in plastids or mitochondria from spinach leaves. They could measure the activity of these enzymes only in the endoplasmic reticulum. Based on this they concluded that the cytosol was also the source of IPP for plastidial and mitochondria1 isoprenoid biosynthesis.Banthorpe et al.61 found in several plants seasonally- dependent enzymes which converted IPP DMAPP GPP and nerol-PP into water soluble products e.g. epoxides diols and triols. Activity clearly increased in the autumn the enzymes were thought to play a role in a salvage system. Such a system might be the reason why incorporation of fed precursors sometimes result in irregular labelling of the products the salvage products also being a pool for IPP and DMAPP synthesis. 6.5 Transport of IPP and DMAPP Several studies demonstrated that intact chloroplasts and chromoplasts incubated with [1 -14C]IPP actively incorporated the labelled substrate into isoprenoid compounds (for reviews see e.g.refs. 15,17,18,26 and 123). Green et a/.96 postulated 600 Natural Product Reports 1997 that the permeability of the mitochondrial and proplastidial membranes for IPP could regulate the biosynthesis of iso- prenoids in these compartments. Assuming one site of IPP biosynthesis and based on experiments with leucoplasts from the peel of young Citrofortunella mitis Bernard-Daga~~',~ postulated that Pinus pinaster leucoplasts utilize IPP from the cytosol in monoterpene biosynthesis. In mature plastids of Vitis vinifera the import of IPP seems to be an active process.53 Heintze et al.49 reported that chloroplasts from young barley leaves efficiently produced terpenoids from CO, whereas chloroplasts from mature leaves were more permeable for IPP and did not incorporate CO as efficiently.This finding would thus be the compromise between the two opposite hypotheses plastids being capable of both in situ production of IPP and of import of IPP depending on their age. Also mitochondria from potato tubers have been shown to be permeable for IPP'07 and thus could utilize IPP from an external source. 6.6 Regulation of IPP isomerase activity under various conditions In a number of studies the fluxes through isoprenoid bio- synthetic pathways have been compared under conditions of stress wounding different light regimens etc. Although the induction of isoprenoid pathways with fungal elicitors has been extensively studied in among others POtato,2,125-129 tobac~o,~~'~~-'~~ (both forming sesquiter-penoid-phytoalexins) and Tabernaemontana (forming triter- penoid-phytoalexin~)'~~'~~~ few studies have been done on the role of the isomerase in the induction of these pathways.On the level of HMG-CoA reductase differently regulated genes were found in potato t~bers,'~~,'~~ with one gene being induced by methyl jasmonate and showing concommitant increase of steroidal alkaloid production. This gene was sup- pressed by arachidonic acid. The other HMG-CoA reductase gene was not affected by methyljasmonate but was strongly induced by arachidonic acid with a corresponding decrease of steroidal alkaloid production and increase in sesquiterpenoid- phytoalexin production. Thus two separate pathways for the C,-units for the sesquiterpenes and steroids exist in this plant whether this also includes different isoenzymes of IPP isomerase is not known.The regulation of HMG-CoA reductase activity in plants has been reviewed re~ently.~~,'~~ In tobacco it was found that IPP isomerase was strongly induced by elicitation with ~ellulase.'~~ The induction paralleled the induction of sesquiterpene cyclase GPP and FPP synthase activity. In cell cultures of Tabernaemontana divaricata elicitation results in the induction of triterpene production whereas the pathways leading to terpenoid indole alkaloids and phyto- sterols are strongly inhibited. 134 HMG-CoA reductase activity was found to be strongly increased (tenfold) but within 24 h it was back to normal 1e~els.I~~ IPP isomerase activity was increased about threefold after 24 h and remained higher than the control levels for 72 h.Also the prenyltransferase activity was increased (twofold) and remained high. In Ammi majus elicitation leads to the accumulation of furanocoumarins. 137 An umbelliferone DMAPP transferase directs the C5into this pathway. Unexpectedly the FPP and squalene synthase activities were only little affected by the elicitation but incorporation of labelled MVA in the cells into squalene was blocked. Consequently the pathway must be blocked at another earlier step. As apparently DMAPP production is available for phytoalexin biosynthesis the most likely explanation is that the pathways are compartmentalized. The umbelliferone DMAPP transferase should thus not be located in the endoplasmic reticulum as reported earlier,138 but within plastids.In these plastids a separate pathway leading to IPP should thus be activated by the elicitation. Neither labelled acetate nor MVA was incorporated into the furanocoumarins the latter supports a plastidial pathway for the production of DMAPP. The increase of IPP isomerase activity with 33% could thus be due to a plastidial isoenzyme. The site of blocking the C,-flux into squalene and sterols remains unclear the compartmentation or even the non-mevalonate pathway for DMAPP-biosynthesis for the furanocoumarins are among the points which need further attention. In C. robusta cell cultures the biosynthesis of anthra-quinones can be induced by elicitors.The accumulation of these meroterpenoids is accompanied by a transient induction of IPP isomerase activity and a transient inhibition of FPP synthase. It is observed that one isoform of IPP isomerase which was not present in untreated cells was specifically induced localization studies of the two isoforms were not performed. Both isoforms showed different affinities to the cofactors Mg2+ and Mn2+ which could play some role in the fine regulation of the enzyme acti~ity.~~’*~ El-Jack et al.139 reported that in non-plastidial carotenoid biosynthesis in Aspergillus giganteus light is an important regulatory factor. Among others IPP isomerase activity was increased by light. Also in maize etioplasts carotenoid bio- synthesis is stimulated by light through an induction of IPP isomerase a~tivity.’~’ In fact the isomerase was the only enzyme out of the five measured from the pathway starting at MVA which showed an increased activity (2.8-fold).This paralleled the increase of carotenoid accumulation the iso- merase thus being a rate-limiting enzyme in this system. An increase of the isomerase activity is not in contradiction with the model in which IPP is produced in the young developing chloroplast and a subsequent increase of IPP imported from the cytosol in mature chloroplast^.^^ In Pelargonium graveolens IPP isomerase activity was fol- lowed through the year and it showed a similar profile as geraniol and GPP synthase with a maximum during the summer months.’41 In geraniol no difference was found in incorporation rates in the two C parts.Cell cultures of a series of monoterpenoid-producing plants did not produce these compounds however IPP isomerase levels were similar to those in the intact plant.I4’ GPP and FPP synthase activities were present in these cultures at even much higher levels than in the plant. The fact that no monoterpenoids are being formed in these cell cultures may indicate that GPP synthase does not play a regulatory role in the flux through the pathway. Spurgeon et reported that both DMAPP and GPP inhibit IPP isomerase isolated from tomato plastids. The isomerases isolated from pumpkin fruits were also found to be inhibited by inorganic diphosphate and alkyl diphosphates; differences for the structure of the alkyl group seemed to be not significant for the inhibitory effect.GPP was among the compounds tested. FPP also inhibits the i~omerase.~~ These observations point to a separation in space of the isomerase and the diphosphates in the cell and/or possible feedback inhibition. 7 Conclusions IPP isomerase has been known for almost 30 years and the mechanism of the catalysis is now well understood. Con-sidering the possibilities for the regulation of isoprenoid bio- synthesis at the level of DMAPP one must conclude that DMAPP is most likely produced in situ in each compartment of isoprenoid biosynthesis as there is no evidence for DMAPP transport. In support of the in situ DMAPP production is the evidence for at least two isoforms of IPP isomerase in plants which are localized in the mitochondria and in the plastids.The levels of IPP isomerase in plastids may vary but only in case of carotenoid biosynthesis is there some evidence that the enzyme controls the flux into this pathway. Also in the cytosol (or endoplasmic reticulum) an isoform is expected to be present as the biosynthesis of sesquiterpenes triterpenes and sterols occurs in this compartment. However so far no proof for such an isoform has been reported. Only one of the isoenzymes from chromoplasts has been purified to homogeneity. The plastidial isomerase could be part of a multienzyme complex which also includes prenyltransferases. There are indications that each cellular compartment is capable of IPP production but there is still no consensus about this or whether DMAPP is formed from IPP produced in the same cell compartment or from imported IPP.There is clear evidence that IPP to a variable extent can be imported from the cytosolic compartment to plastids and mitochondria. In plastids a pool of bound DMAPP might be present but the occurrence of an alternative non-mevalonate pathway possibly leading directly to DMAPP is complicating the picture. Quite a few observations in experiments with feeding labelled precursors might be due to the occurrence of an alternative non-mevalonate C,-pathway in plastids. In fact the cooccurrence of the MVA pathway and the non-mevalonate pathway in plastids may explain some of the contradictory results such as asymmetric labelling different rates of incorporation of pyruvate and acetate in plastids a DMAPP-pool which cannot be detected and the non-incorporation of MVA in e.g.anthraquinones and furano- coumarins. The plastidial isoprenoids could thus be hybrids of two different C,-pathways. If the non-mevalonate pathway leads directly to DMAPP without the involvement of IPP the role of the isomerase would be limited to the MVA part of the pathway only. Thus despite the extensive studies on isoprenoid bio-synthesis still quite a few question marks remain concerning the channelling of the C unit its compartmentation and the possible occurrence of metabolic pools. Although the isomerase may play a regulatory role in the isoprenoid path- ways the few studies done on this enzyme concern quite different systems and in fact no studies have been done on the role of different isoenzymes for the various isoprenoid path- ways in a single system.All studies were done with rather crude enzyme extracts from either whole plant material or isolated plastids measuring total isomerase activity. This makes it difficult to interpret all the reported results in terms of a regulatory role of IPP isomerase in the various isoprenoid pathways. With the available data it is too early to come to a general model for the regulatory role of IPP isomerase in the various isoprenoid pathways. 8 Acknowledgements A.R.-V. was recipient of a fellowship of ‘Consejo Nacional de Ciencia y Tecnologia de Mexico’ (CONACYT).The research of R.v.d.H. is has been made possible by a fellowship of the Royal Netherlands Academy of Sciences. 9 References 1 F. Loreto and T. D. 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ISSN:0265-0568    

DOI:10.1039/NP9971400591

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

~ Quinoline quinazoline and acridone alkaloids Joseph P. Michael Centre for Molecular Design Department of Chemistry University of the Witwatersrand Wits 2050 South Africa Covering July 1995 to June 1996 Previous review 1997 14 11 1 Quinoline alkaloids 1.1 Occurrence 1.2 Non-terpenoid quinoline and quinolinone alkaloids from rutaceous sources 1.3 Terpenoid rutaceous quinoline alkaloids and tricyclic derivatives 1.4 Furoquinoline alkaloids from rutaceous sources 1.5 Quinoline alkaloids from microbial sources 1.6 Quinoline alkaloids from animals 2 Quinazoline alkaloids 2.1 Isolation 2.2 Structural and synthetic studies 3 Acridone alkaloids 3.1 Occurrence and structural studies 3.2 Synthesis and biological studies 4 References 1 Quinoline alkaloids 1.1 Occurrence The overwhelming majority of quinoline alkaloids are found in the Rutaceae.In Table 1 are listed new rutaceous quinoline alkaloids described in the period from July 1995 to June 1996 as well as known alkaloids isolated from new sources belong- ing to this family.'-I5 Table 2 contains a list of quinoline alkaloids and antibiotics isolated from non-rutaceous plants microbial sources and Unless otherwise stated it may be assumed that all new compounds were compre- hensively characterised with the aid of NMR and other spectroscopic techniques. A substantial survey of the alkaloids isolated from medicinal plants of New Caledonia includes a large section on quinoline and acridone alkaloids from rutaceous plant sources unique to this South Pacific island.27 1.2 Non-terpenoid quinoline and quinolinone alkaloids from rutaceous sources A surprising new twist on the 2-alkylquinolin-4-one alkaloids is provided by two new metabolites isolated from the Bolivian tree Dictyuluma peruviana.' Dictyolomides A and B 1 and 2 are unique optically active 1,2,3,4,6,11 -hexahydropyrido- [1,2-a]quinolin-6-ones that can plausibly be derived by cyclis- ation of a simpler quinolinone bearing an unsaturated chain at C-2 for example the known alkaloid 2-(nona-3,6-dienyl)- quinolin-4-one 3.A more than usually comprehensive range of 0 0 1 Dictyolomide A 2 Dictyolomide B 3 Michael Quinoline quinazoline and acridone alkaloids NMR experiments was used to deduce the gross structures of the two new alkaloids and the (2)-geometry of the alkene substituent in 1.However neither the absolute stereochemistry of the alkaloids nor the relative stereochemistry of 2 were established. Both were found to have antileishmanial activity and induced complete lysis of parasites at 100 pg ml -Two 2-arylquinolin-4-one alkaloids from the roots of the Brazilian plant Esenbeckia grandflura have proved to be more highly substituted derivatives of the well-known compound graveoline 4. The new alkaloids are 3'-methoxygraveoline 5 and 3',8-dimethoxygraveoline The 8-methoxy substituent in the latter uncommon in simple quinolin-4-ones [cf ref. 28(a)] seems to be emerging as a chemotaxonomic marker for Esenbeckia.In support of this hypothesis is the recent isolation of ( -)-lunacrinol 7 from E. hier~nimi.~ 0 R2 OMe Me 4 Graveoline R1 = R2 = H 7 Lunacrinol 5 R1 = H; R2 = OMe 6 R1=R2=OMe Glycocitridine 8 a new quinolin-2-one alkaloid isolated from the leaves of Glycusmis ~itrifolia,~ is unusual in bearing a formyl substituent at C-3. This group almost certainly arises from oxidation and cleavage of the furan ring in a furo-[2,3-b]quinoline alkaloid such as skimmianine 9 which was also isolated in this investigation. The authors have apparently not realised that spontaneous aerial oxidation of methoxylated furoquinoline alkaloids to give 3-carbaldehydes akin to glyco- citridine was demonstrated as recently as 1992.29 Both G.citrifolia5 and Tetradium gl~brifoliurn'~ also produce the new alkaloid evomeliaefolin 10 which can be envisaged as arising from glycocitridine by 'aldol' chain extension. An even more unusual alkaloid the diester-bearing quinolin-4-one 11 was isolated from the leaves of Sarcu-melicupe dugniensis a rutaceous tree from New Caledonia. ' The authors postulate a novel biogenesis for this compound which they suggest arises by oxidative cleavage of the electron- rich aromatic ring of an acridone alkaloid such as melicopidine 12. The ruthenium-catalysed reductive cyclisation of 2-nitrochalcones to give 2-arylquinolin-4-ones described in the previous report in this series,28a has now been improved by using palladium(I1) 2,4,6-trimethylbenzoate as catalyst 3,4,7,8-tetramethyl- 1,lO-phenanthroline as ligand and an atmosphere of carbon m~noxide.~' For example the nitrochalcone 13 was easily converted into a mixture of norgraveoline 14 (78%) and its 2,3-dihydro analogue (16%).Oxidation of the crude reaction mixture with 2,3-dichloro-5,6-dicyanobenzoquinone 605 Table 1 Isolation and detection of quinoline alkaloids from rutaceous plants Species Dictyoloma peruviana Esenbeckia almawillia Esenbeckia grandiyora Esenbeckia hieronimi Evodia roxburghiana Gly cosm is citr fo lia Haplophyllum perforatum Haplophyllum vulcanicum Melicope semecarpijolia (=M. confusa =Evodia merrillii) Metrodorea nigra Orixa japonica Sarcomelicope dogniensis Skimmia caureola ssp.multinervia Tetradium glabrifolium (=Evodia meliaefolia) Vepris bilocularis Zanthoxylum chalybeum Zanthoxylum dissitum Zan thoxy lurn nit idum (=Fagara nitida) Zanthoxylum regnellianum Zanthoxylum simulans Zan th oxy lum usam barense Alkaloid“ Ref. (+)-Dictyolomide Ab 1 1 (+)-Dictyolomide B’ 2 Flindersiamine 2 Maculosidine Flindersiamine 2 Kokusaginine Maculine 2-(3-Methoxy-4,5-methylenedioxyphenyl)- 1-methylquinolin-4-one’ 5 8-Methoxy-2-( 3-methoxy-4,5- methylenedioxypheny1)-1-methylquinolin-4-one’ 6 4-Methoxy-1-methylquinolin-2-one y-Fagarine 3 Flindersiamine Kokusaginine ( -)-Lunacrinol7 Maculine Skimmianine 9 Buchapine 32 4 3-Prenyl-4-prenyloxyquinolin-2-one 33 (+)-Roxiamine Ah 34 Roxiamine Bb 35 (+)-Roxiamine C’ 36 1,2-Dimethylquinolin-4-one 5 Evomeliaefolinb 10 y-Fagarhe Glycocitridine’ 8 (4-Rhoifolinic acid methyl ester (a-Rhoifolinic acid methyl ester S kimmianine Haplosamine’ 21 6 Dictamnine 40 7 Haplopine Evomerrine’ 37 8 Haplopine Platydesmine (a-Rhoifolinic acid methyl ester 9 (2)-Rhoifolinic acid methyl ester (+)-3‘-O-Acetylisopteleflorine’ 23 10 2,3-Dicarbomethoxy-1 -methylquinolin-4-one’ 11 11 Evoxine 39 12 ( -)-Evomeliaefolin’ 10 13 4-Methoxy-1-methylquinolin-2-one Robustine Haplamine 25 14 7-Methoxyflinder~ine~ 26 N-Methyl-7-prenyl~xyflindersine~ 28 7-Prenyloxyflinder~ine~ 27 (+)-N-Methylplatydesmine 15 Dictamnine 16 y-Fagarine Haplopine 4-Methoxy- 1 -methylquinolin-2-one Skimmianine Edulitine 17 y-Fagarine Isoplat ydesmine 4-Methoxy-1-methylquinolin-2-one Ribalinine Dictamnine 18 4-Methoxyquinolin-2-one 19 Simulansine’ 31 ( -)-Edulinine 15 “Only new alkaloids and new records for a given species are listed.Structures of most known alkaloids may be found in previous reviews in this series. bNew alkaloids. 606 Natural Product Reports 1997 Table 2 Isolation and detection of quinoline alkaloids from non-rutaceous plants microbial sources and animals Species Alkaloid" Ref. Archangium gephyru 4-Hydroxymethylquinoline 41 20 strain Ar T205 Quinoline-4-carbaldehydeb 42 Quinoline-4-carbaldoximeb 43 Quinoline-4-carboxylic acidb 44 Cussia grandis Kokusaginine 21 Clavelina lepadijbrmis Lepadin A 63 22 (tunicate) ( -)-Lepadin B' 64 ( -)-+padin Cb65 Eichhornia crcissipes 1,4-Dimethylquinoliniurn 23 iodideh Viridicatin Myxococcus virescens 4-Hydroxymethylquinoline 41 20 strain Mx v48 Quinoline-4-carbaldoxime' 43 Prostheceraeus villatus Lepadin A 63 22 (marine flatworm) ( -)-Lepadin B' 64 ( -)-Lepadin Ch 65 Pseudomonas cepaciu 2-(Hept-2-enyl)-3-24 strain PC-I1 methylquinolin-4-one 45 3-Methyl-2-(non-2-enyl)quinolin-4-one 46 2-Heptyl-3-methylquinolin-4-one' 47 3-Methyl-2-nonylquinolin-4-oneb 48 3-Methyl-4-pentylquinolin-4-one' 49 Streptomyces nitrosporeus ( -)-Benzastatin Ch 53 25 30643 ( -)-Benzastatin D' 54 Subcoccinella 24-punctata ( +)-N,-Quinaldyl-L-arginine 26 (Coccinellid beetle) hydrochlorideb 62 "Only new alkaloids and new records for a given species are listed.Structures of most known alkaloids may be found in previous reviews in this series. 'New alkaloids. OMe OMe Me0* Me0 0 OMe H OMe 8 Glycocitridine 9 Skimmianine OMe OH 0 0 C02Me Me0 C02Me OMe H Me 10 Evorneliaefolin 11 0 OMe Me OMe Me OMe 12 Melicopidine (DDQ) gave a quantitative yield of 14 which could easily be methylated with iodomethane in the presence of potassium carbonate to give graveoline 4 in 71% overall yield. The crude alkaloidal extract isolated from the bark of Galipea longzflora used as a traditional medicine in Bolivia for the treatment of recurrent fevers such as malaria shows Michael Quinoline quinazoline and acridone alkaloids 0 0 13 14 15 R = (CH2)2Me 18 Chimanine D 16 R = (CH2)4Me 17 R=CH=CHMe &\ / %o) Ph \ o 19 20 antiplasmodial activity in mice infected with the malaria- causing parasite Plasmodium vinckei pettai3' While all six alkaloids identified in this extract [2-propylquinoline 15 2-pentylquinoline 16 chimanines B 17 and D 18 4-methoxy-2-phenylquinoline 19 and 2-(3,4-methylenedioxyphenylethyl)-quinoline 201 proved effective when tested separately against the parasite compound 16 was especially active showing approximately the same level of activity as the well-known antimalarial compound chloroquine.1.3 Terpenoid rutaceous quinoline alkaloids and tricyclic derivatives Epigeal parts of specimens of Haplophyllum perforatum collected in Kazakhstan have yielded haplosamine 21 a new quinolin-2-one alkaloid bearing an unusually modified prenyl group at C-3.6 This trihydroxylated chain seems to be unique amongst the quinoline alkaloids.Haplosamine proved to be identical with a compound previously obtained by hydrolysing the methiodide of dubinidine 22 with aqueous ammonia.32 &+iH \ I Me 21 Haplosarnine 22 Dubinidine 0 23 R=Ac 24 R=H The stems of Orixa japonica have yielded a new dihydrofuro[2,3-b]quinolinealkaloid (+)-3'-O-acetylisoptele-florine 23.'lo The customary spectroscopic evidence for the structure was supplemented by hydrolysis of 23 with dilute alkali to give (-)-isopteleflorine 24 which though not itself a natural product has previously been ~ynthesised.~~ The absolute configuration of the alkaloid was not determined.A suite of pyrano[3,2-~]quinolinonesisolated from the leaf extract of Vepris bilocularis a forest tree of south India includes the known compound haplamine 25 and three I H H 25 Haplamine 26 R 27 R=H 28 R=Me new flindersine derivatives bearing oxygen at C-7 namely 7-methoxyflindersine 26 7-prenyloxyflindersine 27 and N-methyl-7-prenyloxyflindersine 28.14 This exclusive oxygen- ation at C-7 has previously been observed only in the African genus Oricia which like Vepris belongs to the sub-family Toddalioideae. So uncommon are the monoterpenoid quinoline alkaloids that the recent isolation of several new examples including huajiaosimuline 29 and zanthosimuline 30 from Zanthoxylum simulans [cf.ref. 28(b)] was a noteworthy event. The root bark of this plant has now yielded a further new analogue simulansine 31.l9 Spectroscopic evidence for this structure was bolstered by transformation into huajiaosimuline 29 upon oxidation with chromium trioxide. in human lymphoblastoid host cells (EC5,=0.94 mM IC5,=29.0 mM and EC50= 1.64 mM IC5,=26.9 mM respect- ively). They also showed inhibitory activity in an HIV-1 reverse transcriptase assay (IC,,= 12 and 8 mM respectively). 1.4 Furoquinoline alkaloids from rutaceous sources Three new 7-oxygenated furo[2,3-b]quinoline alkaloids roxiamines A B and C 3436 have been isolated from aerial OMe Me02C L o & H 34 (+)-Roxiamine A OMe I Me02CLorn 35 Roxiamine B OMe I HO HG-,D 36 (+)-Roxiamine C parts of the Thai plant Evodia roxb~rghiana.~ These related compounds are different from most known 7-0 ‘prenylated’ furoquinolines in having no methoxy substituent at C-8; furthermore the prenyl group has been substantially modified in all three metabolites.The geometry of the double bond in roxiamine B 35 in which the E methyl group of the prenyl unit has been oxidised and esterified was established by NOE experiments. (+)-Roxiamine A 34 is a saturated analogue of and (+)-roxiamine C 36 is effectively the hydroxy-demethoxycarbonylated analogue of 34. The S absolute con- figuration of 36 was determined from Ad values in the ‘H NMR spectra of both the (R)-and (S)-Mosher’s ester deriva- tives.Comparison of the ORD curves of 34 and 36 and further correlations involving a suite of model compounds provided good evidence that 34 also has the S configuration. 35 \ I Me 29 Huajiaosimuline R = C(=O)CHMe2 30 Zanthosimuline R = CH=CMe2 31 Simulansine R = CH(OH)CHMe2 The anti-HIV activity of extracts of Evodia roxburghiana appears to be due to the presence of buchapine 32 and 3-prenyl-4-prenyloxyquinolin-2-one33 rather than the roxiamines (see Section 1.4 be lo^).^ When isolated both compounds were shown to be active against infectious HIV-1 d-OMe HO R 37 Evomerrine R=CHO 38 Confusameline R = H OMe I OH OMe 39 Evoxine 40 Dictamnine Evomerrine 37 was obtained as colourless needles from I I the leaves of Melicope semecarpifolia (=M.confusa=Evodia merrillii) a Rutaceous tree indigenous to Taiwan and the H H Philippines.’ Like glycocitridine 8 (cf. Section 1.2) this new 32 Buchapine 33 alkaloid bears a highly unusual formyl substituent which in 608 Natural Product Reports 1997 this case is hydrogen-bonded to a phenolic OH group on an adjacent position. The location of these two substituents was substantiated by formylation of the related alkaloid con-fusameline 38 -also isolated in this study -under Reimer- Tiemann conditions with chloroform and sodium hydroxide. The mass spectrometric fragmentation pattern of evoxine 39 has been elucidated with the aid of mass-analysed ion kinetic energy (MIKE) spectrometry.'2 Dictamnine 40 is one of the compounds responsible for the strong in vitro antiplatelet aggregation activity in the bark extract of Chinese Zanthoxy-lum schinifolium coumarins constituting the remaining active constituent^.'^ 1.5 Quinoline alkaloids from microbial sources Alkaloids and antibiotics containing quinoline rings are crop- ping up with increasing frequency in non-rutaceous plants as well as in microbial sources and animals.A group of anti- fungal constituents isolated from cultures of the soil myxo- bacterium Avchangium gephyra (strain Ar T205) included four simple quinoline alkaloids 4-hydroxymethylquinoline 41 quinoline-4-carbaldehyde 42 quinoline-4-carbaldoxime 43 and / / \ / \ / doHOH \N 'N N 41 42 43 44 quinoline-4-carboxylic acid 44.20Another gliding bacterium Myxococcus virescens (strain Mx v48) also yielded small amounts of 41 and 43.Although all these compounds are comparatively well known as synthetic materials only 4-hydroxymethylquinoline 41 has previously been recorded as a natural product35 [cf. ref. 28(c)]. Labelling studies with L-[1'-'4C]tryptophan which was efficiently incorporated into both 41 and 43 indicated that the quinoline ring must be derived by indole-quinoline rearrangement a process that is well established in plant secondary metabolism. Many 2-alkylquinolin-4-one alkaloids bear the trivial names 'pseudans' because of their occurrence in bacteria of the genus Pseudomonas.In a search for natural antagonists of the soil-borne pathogen Phytophthora capsici which is responsible for 'phytophthora blight' in red peppers (Capsicum annuum) the culture broth of P. cepacia strain PC-I1 was screened by bioactivity-guided fra~tionation.~~ Reverse-phase HPLC of the active fractions yielded two known 3-methylpseudans 45 and 0 0 H H 45 n=3 47 n=l 46 n=5 48 n=3 49 n=5 46 as well as the three new analogues 4749 in the ratio 67:26:2:3:2. The E configuration of the unsaturated com-pounds was inferred from the large coupling constants (J 16.3 and 15.3 Hz respectively) apparent in their 'H NMR spectra. Of the five compounds isolated 2-(hept-2-enyl)-3- methylquinolin-4-one 45 proved to be the most active against P.capsici and other fungal plant pathogens. Furthermore when red pepper seeds were treated with this compound before planting their growth was significantly enhanced. This is the Michael Quinoline quinazoline and acridone alkaloids first report of plant growth simulation by a quinolin-4-one alkaloid. The structures of compounds 47 48 and related 2-alkylquinolin-4-ones were confirmed by the simple Conrad- Limpach condensation shown as 50+51+52.36 0 EtOJ+P2W 0 PhNHz,- Et02CKR R 50 R = H Me = 4 6 8 NI H (CH2hMe 51 I 0 H 52 The culture broth of Streptomyces nitrosporeus 30643 has yielded two new tetrahydroquinoline antibiotics ( -)-benzastatins C and D 53 and 54 which are related in structure to the comparatively well-known microbial metabolite virant- mycin 55.25 The gross structures of 53 and 54 were deduced 0 H 2 N qH + OMe 53 Benzastatin C R = CI 54 Benzastatin D R = OH 0 ..da;:;-I OMe 55 Virantmycin NH2 56 Benzastatin A with the aid of standard spectroscopic techniques.However nuclear Overhauser experiments gave ambiguous results for their relative stereochemistry because of the conformational flexibility of the piperidine ring. Nevertheless the stereo-chemistry was assigned as shown because the 1H NMR chemical shifts and coupling constants matched those reported for virantmycin rather than its diastereomer. The (9R,10R) absolute configurations were apparent from comparisons of the circular dichroism spectra of the new compounds with that of virantmycin.Benzastatin D 54 appears to be biogenetically derived by oxidative cyclisation of another simpler new metabolite benzastatin A 56. All the benzastatins proved to be free-radical scavengers which inhibited lipid peroxidation in rat liver microsomes albeit less effectively than vitamin E. However benzastatins C and D were about as potent as 609 0 0 57 (-)-Sandrarnycin vitamin E in inhibiting glutamate toxicity in N18-RE-105 hybrid cancer cells although the former proved to be cytotoxic. Since the recently published37 total synthesis of the anti- tumour antibiotic ( -)-sandramycin 57 is essentially an exer- cise in the construction of a cyclic decadepsipeptide it will not be outlined here.Of greater interest is the synthesis of the pendent 3-hydroxyquinoline-2-carboxylicacid group the benzyl ether 58 of which was prepared from 2-amino-benzaldehyde 59 and the pyruvic ester derivative 60 by a modified Friedlander synthesis (Scheme l).38 Attaching this acHo + 10Bn i-iii 2-35% NH2 N' C02Et C02H I 59 OMe 58 60 Scheme 1 Reagents i KOH EtOH reflux; ii Me] Bu,NI NaHCO, CH,Cl, 25 "C;iii LiOH*H,O THF-MeOH-H,O (3:1:1) 25 "C heteroaromatic chromophore to the cyclic depsipeptide at a comparatively late stage of the synthesis permitted access to a number of analogues which proved useful in probing the antibiotic's preferential binding to DNA in regions containing alternating A and T residues. Studies of the 1:l complex of sandramycin and d(GCATGC) revealed that the antibiotic maintains a twofold axis of symmetry when intercalating between the central two AT base pairs but that it folds such that the distance between the chromophores is 10.1 A.This is significantly different from the single rigid conformation adopted in solvents other than DMSO (determined from NMR studies) the estimated distance between the chromo- phores being 17-19 A,enough to span three DNA base pairs.Studies of the binding between calf thymus DNA and 57 or analogues bearing zero or one heteroaromatic chromophore revealed that the cyclic decadepsipeptide backbone is respon- sible for the largest share of the minor-groove binding (AGO= -6 kcal mol- ') with increments of 3.2 and 1.0 kcal mol -' respectively as each chromophore is added.San- dramycin thus ends up being about lo3 times as potent a binder as an analogue with only one chromophore and lo5 times as potent as the cyclic depsipeptide parent itself. 1.6 Quinoline alkaloids from animals The crystal structure of the monohydrate of xanthurenic acid a well-known metabolic product of kynurenin induced as a result of vitamin B deficiency has been determined.39 The authors interpret the results in favour of the zwitterionic OH 99+co2-OH H 61 When under threat ladybirds and other insects of the Coccinellidae exude hemolymph droplets from their leg joints in a process known as 'reflex bleeding'. Defensive alkaloids contained in this fluid are responsible for its powerful repel- lency towards predators.Quinoline alkaloids have not hitherto been detected in these exudates but the ladybird Subcoccinella 24-punctata has now been found to secrete (+)-N,-quinaldyl- L-arginine 62 which was isolated as the hydrochloride salt 62 (8 mg from 328 adult insects).26 Spectroscopic evidence for this structure was complemented by a simple synthesis from quinoline-2-carbonyl chloride and L-arginine. The new alkaloid proved to be a highly effective feeding deterrent to the ant species Myrmica rubra; the concentration at which 50% of ants were repelled (RD50) was 10-'M making it a more powerful antifeedant than other Coccinellid alkaloids for which deterrence has been evaluated. The carnivorous marine flatworm Prostheceraeus villatus has been found22 to sequester defensive alkaloids from its prey the tunicate (sea-squirt) Clavelina lepadz$ormis which has previously been shown to produce the decahydroquinoline alkaloid lepadin A 63.40 Specimens of both animals were collected by SCUBA off the coast of Norway at Bergen.The ,,OR b. HIH Me structure 61 with an intramolecular hydrogen bond between the protonated nitrogen atom and the carboxylate group and 63 Lepadin A R = COCH20H; X = 2H a molecule of water acting as an intermolecular hydrogen- 64 LepadinB R=H; X=2H bonding bridge between several different sites in the molecule. 65 LepadinC R=COCH20H; X=O 610 Natural Product Reports 1997 chloroform-soluble extract from 200 flatworms was purified by Me iH A, fractionation on Sephadex followed by reverse-phase HPLC to give as the trifluoroacetate salts lepadin A (0.2 mg per worm) ,C02Me % m and the new alkaloids ( -)-lepadin B 64 (0.04 mg per worm) and ( -)-lepadin C 65 (0.02 mg per worm) as well as two new pyrrolidine alkaloids all of which were thoroughly character- ised by spectroscopic methods.The alkaloidal extract from the enf-66 (-)-Pumiliotoxin C 71 72 tunicate had essentially the same composition. This appears to be the first known case of alkaloid transfer from a prey & A organism to a flatworm predator. Lepadins A and B showed \\ 111% significant in vitro cytotoxic activity towards a variety of murine and human cancer cell lines but lepadin C was inactive. The frog skin alkaloid pumiliotoxin C also known as decahydroquinoline cis-195A remains a popular target for synthesis.(+)-Pumiliotoxin C 66 the unnatural enantiomer has been formally prepared by Fukumoto and co-workers by a route in which a pivotal palladium-induced reductive cyclis- ation of enyne 67 to 68 was later followed by the regio- and stereo-specific Beckmann rearrangement of 69 to 70 in order to introduce the nitrogen atom (Scheme 2).41The conversion of BnO \ OH I 7 steps 1 IN OBn H HIZ HO-” 73 74 Gephyrotoxin m~nication~~ [cf. ref. 28(d)] has now been published in full together with related studies on the epimer 71.45This research has also been summarised in a more wide-ranging review.46 The synthesis of compound ( -)-72 by Davies and Bhala~~~ in several steps from (R)-( +)-pulegone represents a formal syn- thesis of the ( -)-alkaloid since ent-72 has previously been transformed into the unnatural (+)-pumiliotoxin C 66.48 Finally the work of Comins et af.in preparing alkaloids of the pumiliotoxin C class has been outlined in a comprehensive review on the use of 1-acylpyridinium salts as intermediates in alkaloid synthesis.49 In this regard Comins has also prepared the octahydroquinolinone 73 as part of a planned synthesis of the tricyclic amphibian alkaloid gephyrotoxin 74.50 q* H 68 ii iii 57% I $.Ho\ 2 Quinazoline alkaloids A review describing a century of progress in the chemistry of indoloquinazolines includes brief mention of the isolation and synthesis of the quinazoline alkaloids tryptanthrin 75 candidine 76 and hinckdentine A 77.51 { H MeH Q+Q HO 0 69 vi I61% Me Me :H 66 (+)-Pumiliotoxin C 70 Scheme 2 Reugenrs i (dba),Pd2*CHCI (2.5 mol%) N,N-bis (benzylidene)ethylenediamine (5 mol%) polymethylhydrosiloxane HOAc CICH,CH,Cl; ii Na NH, THF -78 ‘C then NH,CI; iii 0, MeOH -78 “C then Me$; iv 1,l’-thiocarbonyldiimidazole,DMAP CH,CI, reflux; v Bu,SnH AIBN C,H, reflux; vi NH,OH.HCI NaOAc MeOH then p-TsC1 NaOH H,O-THF ent-70 into the ( -)-alkaloid ent-66 has been described by Murahashi et af.,42while a similar conversion in the racemic series was recently described by Mehta and Pra~een~~ [cf.ref. 28(6)]. Kibayashi’s acylnitroso Diels-Alder route to ( -)-pumiliotoxin C ent-66 previously revealed in a cam-Michael Quinoline quinazoline and acridone alkaloids 0p 0 )i”\H VN 75 Tryptanthrin 76 Candidine 0 77 Hinckdentine A 2.1 Isolation Bioassay-guided fractionation of the extracts of Zanthoxylurn integrifolium fruits yielded three alkaloids that showed antiplatelet aggregation activity.52 These proved to be the known compounds rutaecarpine 78 and 1 -hydroxyrutae- carpine 79 and a new natural product 1-methoxyrutaecarpine 80.The structure of 80 was established by comparison with a 611 &b H 0 N R 78 Rutaecarpine R = H 79 1-Hydroxyrutaecarpine R = OH 80 1-Methoxyrutaecarpine R = OMe sample prepared by methylating 79 with diazomethane and further confirmed by an NOE difference experiment.In in vitro tests 1-hydroxyrutaecarpine was the strongest inhibitor of platelet aggregation induced by arachidonic acid and showed an IC, value of 1-2 mg ml -'. Rutaecarpine has also been isolated from the leaves of Tetradium glabrif~lium.~~ The vasodilatory effects of rutaecarpine and two related carbazolo- quinazoline alkaloids have been demonstrated in smooth muscle from rat thoracic aortas containing intact endothelium cells.54 Benzomalvins A-C 81-83 reported in 1994 as metabolites of a Penicillium culture,55 have previously been mentioned in this series of reviews.28eA further unstable new metabolite (+)-benzomalvin D has now been extracted from the same culture.56 On standing overnight in solution at room tempera- ture benzomalvin D was converted into benzomalvin A 81; similarly benzomalvin A interconverted with benzomalvin D.The equilibrated mixtures contained a 4:l mixture of 81 and the new metabolite 84. Separation of these compounds was possible by HPLC and storage of the solid compounds at -40 "Cretarded their equilibration. When thorough spectro- scopic analysis failed to give a clear picture of the structural differences between the two compounds a total synthesis of benzomalvin A from isatoic anhydride 85 L-phenylalanine and methyl anthranilate was undertaken (Scheme 3). -The enantio- merically pure synthetic benzomalvin A (3.7% overall yield based on isatoic anhydride) equilibrated in the same way as the natural product. Eventually variable temperature NMR revealed that the two compounds are conformational isomers -in fact atropisomers.Molecular dynamics calculations sug- gested the conformers 86 and 87 possessing equatorial and axial benzyl groups for the structures of benzomalvins A and D respectively; and these structures correlated well with the observed NMR spectra. Furthermore atropisomerism now - O i,ii 96% 0 85 0 -0 47% 81 Benzomalvin A 7'\\ 81 Benzomalvin A 86 YN,b :'s O Me 1 82 Benzomalvin B 83 Benzomalvin C pNb 0 kN / dN-7'' ~ Me \ '3 84 Benzomalvin D 87 provides a feasible rationalisation for the observed optical activity of benzomalvin B 82 which possesses no stereogenic carbon centres. The structures of fumiquinazolines A-C 88-90 metabolites of the fungus Aspergillus fumigatus separated from the gastro- intestinal tract of the marine fish Pseudolabrus japonicus were revealed in a communication in 1992,57 and described in this series of reviews shortly afterwards.2xf Full details on the structural elucidation have now been published in a paper in which the structures of four new fumiquinazolines D-G -0 Scheme 3 Reagents i L-phenylalanine NEt, H,O rt; ii HOAc reflux; iii Lawesson's reagent THF rt then flash chromatography on Si02; iv NaOH (40% aq.) MeI Bu,NHSO, toluene rt; v methyl anthranilate 135 "C 612 Natural Product Reports 1997 0 0 88 Fumiquinazoline A R1 = Me; R2 = H 90 Fumiquinazoline C 89 Fumiquinazoline B R1 = H; R2 = Me 92 Fumiquinazoline E R1 = Me; R2 = OMe H% 0 91 Fumiquinazoline D 93 Fumiquinazoline F R1 = Me; R2 = H 94 Fumiquinazoline G R1= H; R2 = Me 91-94 are also rep~rted.~' X-Ray crystallography established the structures and relative stereochemistry of fumiquinazolines C and D while the absolute configurations of these two compounds were established by the formation of L-( +)-alanine upon acidic hydrolysis.In addition the expected plethora of NMR studies and a range of chemical interconversions and degradations served to establish the relative and absolute stereostructures of the remaining metabolites as well as several interesting conformational effects. Fumiquinazolines F 93 and G 94 proved to be epimeric at C-3; basic equilibration of either yielded a 3:2 mixture of the isomers with F predominating.All the fumiquinazolines were moderately cytotoxic in the P388 lymphocytic leukaemia test system. 2.2 Structural and synthetic studies Important new crystallographic investigation^^^ on two well- known alkaloids from the Indian medicinal plant Adhatoda vasica have been used to refute a 20 year old claim6" that ( -)-vasicine has the 3R absolute configuration. The discovery came about because X-ray analysis of the hydrobromide salt of ( -)-vasicinone 95 revealed an incontrovertible 3s absolute 0 X OH 95 (-)-Vasicinone R = H; X =OH 96 (-)-Vasicine R = H 98 Vasicinolone R = X = OH 97 (+)-Vasicinol R = OH 100 Deoxyvasicinone R = X = H 99 R=OMe configuration based on analysis of the Flack parameter a and a consistent set of anomalous dispersion results.The authors' suspicions concerning the correctness of the earlier work were aroused in view of the well-established fact that (-)-vasicinone can be obtained from ( -)-vasicine by autoxidation or oxidation with hydrogen peroxide. They therefore analysed ( -)-vasicine and its dextrorotatory hydrobromide salt by Michael Quinoline quinazoline and acridone alkaloids X-ray crystallography and their anomalous dispersion studies strongly suggested that the earlier assignment of absolute configuration for (-)-vasicine should be revised to 3S,as shown in 96. The absolute structures of two other alkaloids which have previously been correlated with ( -)-vasicine (+)-vasicinol97 and vasicinolone 98 must now also be revised to 3s.A fascinating corollary to the above study was provided by analysis of the (+)-and (-)-Mosher's esters of (-)-vasicinone by NMR spectroscopy.These results did nut sup-port the revised 3s absolute configuration but this aberration was ascribed to the profound change in molecular confor- mation imparted by the heteroatoms close to the stereogenic centre which invalidates the correlation upon which the Mosher method is based. The structure of the monohydrate of 7-methoxyvasicinone 99 another alkaloid from Adhatoda vasica has been determined by X-ray crystallography but no assignment of absolute configuration was made.6' Other recent crystallo- graphic studies include those on deoxyvasicinone 100 its hydrochloride salt and a tetrachlorocobaltate salt.62 Vasicine 96 (commonly named peganine in the Russian literature) can conveniently be separated from mixtures containing related Peganum harmala quinazoline alkaloids by formation of tetra- chlorozincate salts followed by sequential precipitation and recrystallisation of the perchlorate and nitrate In a search for new therapeutic agents for the treatment of Alzheimer's disease deoxyvasicine 101 and eleven synthetic analogues have been assayed for anticholinesterase activity in the rat brain and in human red blood cells.64 The most potent inhibitor in the series 102 provides a useful new lead for further investigations.101 R=H 102 107 R = Me H 103 n=l; R=H 104 R=H 105 n=l; R=Me 106 R=Me 108 n=2; R=H 109 n=2; R=Me Reductive carbonylation of N-allyl-2-aminobenzylamine 103 with carbon monoxide and hydrogen over a rhodium catalyst yielded dihydrodeoxyvasicine 104 in 96% yield.65 The methylallyl analogue 105 yielded mixtures of the hexahydro- pyrroloquinazoline 106 and the tetrahydro derivative 107 while the homologues 108 and 109 afforded even more complex mixtures of fused quinazoline products.The fungal metabolite chrysogine has been mentioned frequently in these and the assignment of its absolute configuration has been discussed on several occasions. The first asymmetric synthesis of this alkaloid (incorrectly called chrysogenine) from (S)-(-)-lactic acid 110 and anthra- nilamide 111 (Scheme 4) has now been published.66 The synthesis supports the assignment of S absolute stereo- chemistry for the ( -)-alkaloid 112.Febrifugine 113 is a Hydrangea alkaloid that possesses antimalarial and anticoccidial properties. A new synthetic route to trans-2-alkylpiperidin-3-01s has now paved the way for a stereoselective synthesis of the racemic alkaloid (Scheme 5).67 In this route partial reduction of 1-ethoxycarbonylpiperidin-2-one114 followed by elimination and oxidation with dimethyldioxirane yielded the epoxide 115. i ii Me Me Ho , I 0 OH OAc 110 1 -iv V 80% iii OH ___) dOMe 40% 112 (-)-Chrysogine NH2 111 Scheme 4 Reugents i AcCl; ii SOCl, 0-10 'C; iii NH,OH 0-90 "C; iv py rt; v 1% aq. NaOH MeOH rt I I1 117 116 H 0 113 Febrifugine Scheme 5 Reagents i LiBHEt, THF -78 "C then HCl EtOH; ii MgSO, toluene reflux; iii dimethyldioxirane acetone 0 "C to rt; iv NaH DMF 0 "C then chloroacetone 0 "C to rt; v TMSOTf Pr',NEt CH,CI, rt; vi TiCl, CH,Cl, 0 "C; vii flash chromatography then KOH diethylene glycol H,O heat This disguised N-acyliminium ion precursor reacted with the trimethylsilyl enol ether 116 made in two steps from 4-hydroxyquinazoline 117 (probably co-existing with its keto tautomer) in the presence of titanium tetrachloride giving a 1:1 mixture of cis and trans isomers of N-ethoxycarbonylfebrifugine 118.The isomers were separated by flash chromatography after which the desired alkaloid trans-113 was formed by basic hydrolysis of the ethoxycarbonyl substituent.3 Acridone alkaloids 3.1 Occurrence and structural studies The thirteen new acridone alkaloids reported during the review period all from plants belonging to the Rutaceae are listed in Table 3 along with known alkaloids from new plant sources.1 1 14-68-73 1,3,5-Trihydroxy-2,4-diprenylacridonealkaloids hitherto found almost exclusively in the genera Atalantia and Citrus have now been isolated from the taxonomically distant plant Boszstoa transversa.68 Leaf and bark material of this previously unexplored Australian tree yielded several known acridone alkaloids of the type under discussion including N-methylatalaphylline 119 N-methylatalaphyllinine 120 and yukocitrine 121 as well as the three new compounds bosi- stidine 122 bosistine 123 and the yukocitrine derivative 124.The structures were determined with the aid of standard spectroscopic techniques but insufficient quantities were isolated to permit the absolute configuration to be established. Over the past few years this series of reviews has kept track of the phenomenal number of new acridone alkaloids isolated from Citrus plants and hybrids by the research groups of Ju-ichi and Furukawa. Much of the work on the hybrid 'Yalaha' has now been collected into a single paper that not only gives full details of the isolation of no fewer than seventy alkaloids coumarins and other compounds but also introduces another new alkaloid 1,3,5-trihydroxy-N-614 Natural Product Reports 1997 OH I I OH Me A 119 KMethylatalaphylline 120 KMethylatalaphyllinine 0 OH 0 OH II OH Me OH Me R 121 Yukocitrine 122 Bosistidine R = H 123 Bosistine R = prenyl 0 OH I1 1 y 124 methylacridone 125 -ironically one of the simplest acridones that these workers have yet reported.72 Furukawa and co-workers have also isolated two new acridones acrifoline 126 and glycofolinine 127 from Glycosmis ~itrifolia.~~ The structure of 126 was confirmed by conversion into the known alkaloid citracridone-I1 128 upon treatment with iodomethane and anhydrous potassium carbonate in acetone.The structure Table 3 Isolation and detection of acridone alkaloids Species Alkaloid“ Ref. Bosistou trunsversu ( -)-Bosistidine’ 122 68 ( -)-Bosistine’ 123 Citrusamine (+)-4-(2-Hydroxy-3-methylbut-3-enyl) yukocitrineb 124 Junosine N-Methylatalaphylline 119 N-Methylatalaphyllinine 120 Yukocitrine 121 Citrus grundiJ Citbismine-A 132 69 Citbismine-B’ 133 Citbismine-Cb 134 Citbismine-Eb 136 70 Citrus grundis f.buntun Buntanbismineh 137 71 Citrus hybrid ‘Yuluhu’ Acrignine-A 72 (C. paradisi x C. tungerinu) Acrimarine-B -C -D -E -F and -H Citpressine-I and -11 Citracridone-I -11 and -111 Citramine Citropone-C Citrusamine Citrusinine-I and -11 1,3-Dihydroxy-lO-methylacridone Gl ycocitrine-I Grandisinine 5-H ydrox ynoracronycine Mars hmine Natsucitrine-I and -11 Neoacrimarine-C Pummeline 1,3,5-Trihydroxy-10-methylacridone’ 125 Citrus parudisi Citbismine-B’ 133 69 Citbismine-Ch 134 Citbismine-D’ 135 70 Citbismine-E’ 136 Glycosmis citrijoliu Acrifolineh 126 73 Glycofolinine’ 127 Surcornelicope dogniensis 1-0xo- 1,2-dihydro- 12-11 demethyl- 12- hydroxyacronycineb 130 Vepris biloculuris Vebilocine’ 129 14 “Only new alkaloids and new records for a given species are listed.Structures of most known alkaloids may be found in previous reviews in this series. ’New alkaloids. of vebilocine 129 isolated from leaves of Vepris biloculuris was determined by standard spectroscopic methods. l4 The acronycine derivative 130 isolated from the leaves of Surcomelicope dogniensis,’ is unusual on two counts. Firstly modifications to the pyran moiety of pyrano[3,2-c]acridone alkaloids are extremely rare; oxidation to a pyran-4-one has been found only once before in the alkaloid 131 -also a metabolite from S.d~gniensis.~~ More striking however is the N-hydroxy substituent which is unprecedented amongst the acridone alkaloids. It should be borne in mind of course that even though the compound has been represented as an N-hydroxy-9-acridone this structure probably exists in equilibrium with the 9-hydroxy-N-oxide tautomer. Citbismine A 132,75 the first naturally-occurring bis-acridone dimer from the genus Citrus was described in last year’s review.28’’ Full spectroscopic and crystallographic characterisation of this compound which possesses a novel Michael Quinoline quinazoline and acridone alkaloids 0 OH @OH OH Me 125 0 OH 0 OH 126 Acrifoline R = H 127 Glycofolinine 128 Citracridone-ll R = Me 0 OH a&::““5. NI Me 0 NI R / 0 0 129 Vebilocine 130 R=OH 131 R=H 0 OH q!-h$ 0 OMe H 132 Citbismine-A 0 OH OMe k2 133 Citbismine-B R1 = Me; R2 = H 134 Citbismine-C R1 = Me; R2 = Me 136 Citbismine-E R1 = H; R2 = Me skeleton containing a C-C linkage between aromatic and dihydrofuran rings of two monomeric acridone alkaloids has now been published.69 In addition the roots of C.parudisi have been shown to contain four new analogues of citbismine A to which the names citbismines B 133,69C 134,69D 13570 and E 13670have been given. With the exception of citbismine D the alkaloids were also isolated from the roots of C. gr~ndis.~~’ 70 The structures of the new alkaloids were eluci- dated with the aid of exhaustive spectroscopic methods and NOE experiments played a major role in ascertaining the location of substituents.It should be noted that all five dimers were isolated in optically inactive form; the authors suggest alkaloids) are linked by a C-C bond between an aromatic and a dihydropyran ring. The structure was elucidated by spectro- scopic analysis of the native alkaloid and its 1-acetyl and 1,Sdiacetyl derivatives. HO 3.2 Synthesis and biological studies A high-yielding highly regioselective 2-prenylation of 33-dimethoxyacetanilide 138 with 3-methylbut- 1-en-3-01 in the presence of boron trifluoride has facilitated a simple synthesis HO of important acridone alkaloids possessing antitumour activity (Scheme 6).76After hydrolysis of the amide group of product 139 an interesting copper-catalysed N-arylation with iodo- 135 Citbismine-D nium salt 140 yielded the diarylamine 141 in 92-94% yield.Cyclisation to the acridone 142 was induced with poly- 0 OH phosphoric ester under strictly anhydrous conditions follow- ing which this intermediate was converted into glycocitrine-I1 143 acronycine 144 and des-N-methylacronycine 145 as illustrated. Heating the hydrochloride salt of acronycine 144 at 250 "C for 2.5 h has yielded dihydronorisoacronycine 146 as the major product (7.2%) together with no fewer than seven identifiable minor products all in minuscule yield.77 Heating norisoacro- nycine 147 under reflux with hydrochloric acid in methanol Me0 afforded in 15% yield a new type of dimer 148 possessing a C-C linkage between the prenyl-derived moieties.78 In last year's review the synthesis of o-quinomethanes from 137 Buntanbismine the reaction between acridone alkaloids and organolithium compounds was described.28' Similar intermediates 149 have now been obtained by treating 1-hydroxy-3-methoxy- that they may either be artifacts or formed in the plant cells by N-me thy lacridone 150 with o-li thiated N-(tert-bu t oxy- Upon further treatment with hydrochloric non-enzymatic processes.~arbony1)anilines.~~ Yet another novel skeleton is found in buntanbismine 137 a acid cyclisation of the blue intermediates occurred to give red bis-acridone alkaloid isolated from the stem bark of C.grandis quino[4,3,2-kl]acridines 151 (2542% overall yields) which In this case the two moieties (both of them known contain fused ring systems reminiscent of those found in f. b~ntan.~~ OMe OMe OMe ANA +AN I H I H OMe 0% OMe -H2NtMe 138 1 39 &'+a I iii 92-94% 140 0 OH 0 OMe Me H 143 Glycocitrine-ll vi-viiiJ 142 \ 141 vi vii. ix 144 Acronycine 1 45 Scheme 6 Reagents i 3-methylbut-1-en-3-01 BF,*Et,O (cat.) dioxane reflux; ii alkaline hydrolysis; iii 140 Cu(OAc), Pr'OH; iv PPE anhydrous conditions; v MeI; vi EtSNa DMF; vii DDQ o-CI,C,H, reflux; viii excess MeI; ix CH,N, BF,-Et,O 616 Natural Product Reports 1997 0 OH yyTk Me Me OH Me \ 146 1 47 156 Me o\ Hfl 148 Buto2c& \ \ N OMe I Me 149 R=HorOMe 0 OH a OMe I I Me Me 150 151 R=HorOMe q Me \ 152 Noracronycine 153 R = H or OMe Et02C % I OMe \ N I / 0 Me Me \ 154 155 several marine alkaloids.Noracronycine 152 underwent simi- lar reactions to yield products 153. 0-Alkylation of the same two precursors 150 and 152 with diethyl bromomalonate followed by base-induced cyclisation has yielded furo[2,3,4- Michael Quinoline quinazoline and acridone alkaloids HO OMe Me 157 Acrirnarine-F kllacridines 154 and 155 (17-1 8%).*' All compounds prepared in the latter study were weakly cytotoxic towards L1210 murine lymphocytic leukaemia cells. Twenty-five acridone alkaloids from Citrus plants have been assayed for their inhibitory effects on the activation of Epstein-Barr virus in Raji cells incubated with butyric acid as inducer and then stained with a serum containing a human cancer cell line carrying the EBV genome.81 All test samples showed weak cytotoxicity with 5-hydroxynoracronycine 156 and acrimarine-F 157 holding the greatest potential as antitumour promotors.References 1 C. Lavaud G. Massiot C. Vasquez C. Moretti M. Sauvain and L. Balderrama Phytochemistry 1995 40 317. 2 F. M. Oliveira A. E. G. Santana L. M. Conserva J. G. S. Maia and G. M. P. Guilhon Phytochemistry 1996 41 647. 3 F. delle Monache M. Trani R. A. Yunes and D. Falkenberg Fitoterapia 1995 66 474. 4 J. L. McCormick T. C. McKee J. H. Cardellina I1 and M. R Boyd J. Nat. Prod.1996 59 469. 5 T.-S. Wu F.-C. Chang and P.-L. Wu Phytochemistry 1995 39 1453. 6 K. A. Rasulova and I. A. Bessonova Chem. Nat. Compd. (Engl. Transl.) 1995 31 487 (Chem. Abstr. 1996:. 125 81 831). 7 B. Gozler D. Rentsch T. Gozler N. Unver and M. Hesse Phytochemistry 1996 42 695. 8 I.-L. Tsai S.-J. Wu T. Ishikawa H. Seki S.-T. Yan and 1.3. Chen Phytochemistry 1995 40 1561. 9 A. H. Muller P. C. Vieira M. F. das G. F. da Silva and J. B. Fernandes Phytochemistry 1995 40 1797. I 10 S. Funayama K. Murata and S. Nozoe Phytochemistry 1996 41 1231. 11 S. Mitaku A.-L. Skaltsounis F. Tillequin M. Koch J. Pusset and T. Sevenet Nat. Prod. Lett. 1995 7 219. 12 M. He H. Zhang X. He and M. Zhang Rapid Commun. Mass Spectrom. 1995 9 1 122. 13 T.-S.Wu J.-H. Yeh and P.-L. Wu Phytochemistry 1995 40 121. 14 G. Brader M. Bacher H. Greger and 0. Hofer Phytochemistry 1996 42 881. 15 A. Kato M. Moriyasu M. Ichimaru Y. Nishiyama F. D. Juma J. N. Nganga S. G. Mathenge and J. 0.Ogeto J. Nut. Prod. 1996 59 316. 16 J. Tang W. Zhu and Z. Tu Zhongcuoyuo 1995 26 563 (Chem. Abstr. 1996 124 170 992). 17 T. Ishikawa M. Seki (nPe Imai) K. Nishigaya Y. Miura H. Seki I.-S. Chen and H. Ishii Chem. Pharm. Bull. 1995 43 2014. 18 M. S. P. Arruda J. A. 0. Brito and A. C. Arrudo J. Braz. Chem. Soc. 1996 7 217 (Chem. Abstr. 1996 125 270 486). 19 1.S. Chen S.-J. Wu Y.-L. Leu I.-W. Tsai and T.3. Wu Phyto-chemistry 1996 42 217. 20 B. Bohlendorf E. Forche N. Bedorf K. Gerth H. Irschik R. Jansen B. Kunze W. Trowizsch-Kienast H.Reichenbach and G. Hofle Liebigs Ann. 1996 49. 21 E. Valencia A. Madinaveitia J. Bermejo A. G. Gonzalez and M. P. Gupta Fitoterapia 1995 66 476. 22 J. Kubanek D. E. Williams E. D. de Silva T. Allen and R. J. Anderse Tetrahedron Lett. 1995 36 6189. 23 D. Zhao and S. Zheng Fudan Xuebao Ziran Kexueban 1996 35 177 (Chem. Abstr. 1996 125 163 236). 24 S.-S. Moon P. M. Kang K. S. Park and C. H. Kim Phyto-chemistry 1996 42 365. 25 (a) W.-G. Kim J.-P. Kim C.-J. Kim K.-H. Lee and 1.-D. Yoo J. Antibiot. 1996 49 20; (b)W.-G. Kim J.-P. Kim and 1.-D. Yoo J. Antibiot. 1996 49 26. 26 S. F. Wang J. C. Braekman D. Daloze J. Pasteels P. Soetens N. V. Handjieva and P. Kalushkov Experientia 1996 52 628 27 T. Sevenet and J. Pusset in The Alkaloids.Chemistry and Pharma- cology ed. G. A. Cordell Academic Press San Diego 1996 vol. 48 ch. 1 p. Iff. 28 J. P. Michael Nat. Prod. Rep. (a) 1997 14 11; (b) 1995 12 469; (c) 1993 10 100; (d) 1997 14 15; (e) 1995 12 472; (f)1994 11 167; (g) 1995 12 82; (h) 1997 14 18; (i) 1997 15 19. 29 M. Y. Rios and G. Delgado J. Nat. Prod. 1992 55 1307. 30 R. Annunziata S. Cenini G. Palmisano and S. Tollari Synth. Commun. 1996 26 495. 31 J. C. Gantier A. Fournet M. H. Munos and R. Hocquemiller Planta Med. 1996 62 285. 32 I. A. Bessonova E. G. Mil’grom Y. V. Rashkes A. D. Vdovin and D. M. Razakova Khim. Prir. Soedin. 1993 418 (Chem. Abstr. 1995 123 286 356). 33 C. F. Neville M. F. Grundon V. N. Ramachandran and J. Reisch J. Chem. Soc.Perkin Trans. 1 1991 259. 34 1.-S. Chen Y.-C. Lin 1.-L. Tsai C.-M. Teng F.-N. KO T. Ishikawa and H. Ishii Phytochemistry 1995 39 1091. 35 W.-R. Abraham and G. Spassov Phytochemistry 1991 30 371. 36 S.-S. Moon P. M. Kang K. S. Yoon S.-J. Yun and B. B. Park Bull. Korean Chem. Soc. 1995 16 1128 (Chem. Abstr. 1996 124 86 655). 37 D. L. Boger J.-H. Chen and K. W. Saionz J. Am. Chem. Soc. 1996 118 1629. 38 D. L. Boger and J.-H. Chen J. Org. Chem. 1995 60 7369. 39 N. Okabe J. Miura and A. Shimosaki Acta Crystallogr. Sect. C 1996 52 663. 40 B. Steffan Tetrahedron 1991 47 8729. 41 M. Toyota T. Asoh and K. Fukumoto Tetrahedron Lett. 1996 37 4401. 42 S. Murahashi S. Sasao E. Saito and T. Naota J. Org. Chem. 1992 57 2521. 43 G.Mehta and M. Praveen J. Org. Chem. 1995 60 279. 44 M. Naruse S. Aoyagi and C. Kibayashi Tetrahedron Lett. 1994 35 9213. 45 M. Naruse S. Aoyagi and C. Kibayashi J Chem. Soc. Perkin Trans. I 1996 1113. 46 C. Kibayashi and S. Aoyagi Synlett 1995 873. 47 S. G. Davies and G. Bhalay Tetrahedron Asymmetry 1996 7 1595. 48 A. G. Schultz P. J. McCloskey and J. J. Court J. Am. Chem. Soc. 1987 109 6493. 49 D. L. Comins and S. P. Joseph Adv. Nitrogen Heterocycl. 1996 2 251. 50 D. L. Comins S. P. Joseph and D. D. Peters Tetrahedron Lett. 1995 36 9449. 51 A. D. Billimoria and M. P. Cava Heterocycles 1996 42 453. 52 W.-S. Sheen 1.-L. Tsai C.-M. Teng F.-N. KO and I.-S. Chen Planta Med. 1996 62 175. 53 T.-S. Wu F.-C. Chang P.-L. Wu C.-S. Kuoh and 1.-S.Chen J. Chin. Chem. Soc. 1995 42 929. 54 W.-F. Chiou J.-F. Liao and C.-F. Chen J. Nat. Prod 1996 59 374. 55 H. H. Sun C. J. Barrow D. M. Sedlock A. M. Gillum and R. Cooper J. Antibiot. 1994 47 515. 56 H. H. Sun C. J. Barrow and R. Cooper J. Nat. Prod. 1995 58 1575. 57 A. Numata C. Takahashi T. Matsushita T. Miyamoto K. Kawai Y. Usami E. Matsumura M. Inoue H. Ohishi and T. Shingu Tetrahedron Lett. 1992 33 1621. 58 C. Takahashi T. Matsushita M. Doi K. Minoura T. Shingu Y. Kumeda and A. Numata J. Chem. Soc. Perkin Trans. 1 1995 2345. 59 B. S. Joshi M. G. Newton D. W. Lee A. D. Barber and S. W. Pelletier Tetrahedron Asymmetry 1996 7 25. 60 K. Szulwesky E. Hohne S. Johne and D. Groger J. Prakt. Chem. 1976 318 463. 61 D.K. Magotra V. K. Gupta Rajnikant K. N. Goswami R. K. Thappa and S. G. Agarwal Acta Crystallogr. Sect. C 1996 52 1491. 62 K. K. Turgunov B. Tashkhodzhaev L. V. Molchanov and K. N. Aripov Chem. Nat. Compd. (Engl. Transl.) 1995 31 714 (Khim. Prir. Soedin. 1995 849; Chem. Abstr. 1996 125 86 959). 63 L. V. Molchanov V. N. Plugar’ A. L. D’yakonov and K. N. Aripov Chem. Nat. Compd. (Engl. Transl.) 1996 32 56 (Khim. Prir. Soedin. 1996 70; Chem. Abstr. 1996 125 276 269). 64 J. C. Jaen V. E. Gregor C. Lee R. Davis and M. Emmerling Bioorg. Med. Chem. Lett. 1996 6 737. 65 E. M. Campi J. Habsuda W. R. Jackson C. A. M. Jonasson and Q. J. McCubbin Aust. J. Chem. 1995 48 2023. 66 D. K. Maiti P. P. Ghoshdastidar and P. K. Bhattacharya J. Chem. Rex (S) 1996 306.67 L. E. Burgess E. K. M. Gross and J. Jurka Tetrahedron Lett. 1996 37 3255. 68 A. A. Auzi T. G. Hartley R. D. Waigh and P. G. Waterman Phytochemistry 1996 42 235. 69 Y. Takemura Y. Matsushita N. Nagareya M. Abe J. Takaya M. Ju-ichi T. Hashimoto Y. Kan S. Takaoka Y. Asakawa M. Omura C. It0 and H. Furukawa Chem. Pharm. Bull. 1995 43 1340. 70 M. Ju-ichi Y. Takemura N. Nagareya M. Omura C. Ito and H. Furukawa Heterocycles 1996 42 237. 71 T.-S. Wu S.-C. Huang and P.-L. Wu Phytochemistry 1996,42,221. 72 Y. Takemura H. Kawaguchi S. Maki M. Ju-Ichi M. Omura C. Ito and H. Furukawa Chem. Pharm. Bull. 1996 44,804. 73 T. Ono C. Ito H. Furukawa T.-S. Wu C.-S. Kuoh and K.-S. Hsu J. Nat. Prod. 1995 58 1629. 74 S. Mitaku A.-L.Skaltsounis F. Tillequin M. Koch J. Pusset and G. Chauviere Heterocycles 1987 26 2057. 75 Y. Takemura M. Ju-ichi T. Hashimoto Y. Kan S. Takaoka Y. Asakawa M. Omura C. Ito and H. Furukawa Chem. Pharm. Bull. 1994 42 1548. 76 R. C. Anand and N. Selvapalam Chem. Commun. 1996 199. 77 S. Funayama T.-Y. Pan S. Nozoe and G. A. Cordell Hetero-cycles 1996 43 1251. 78 S. Funayama T. Aoyagi K. Tadauchi T.-Y. Pan S. Nozoe and G. A. Cordell Heterocycles 1995 41 1381. 79 C. Jolivet C. Rivalle C. Hue1 and E. Bisagni J. Chem. Soc. Perkin Trans. I 1995 2333. 80 C. Jolivet C.Rivalle A. Croisy and E. Bisagni Heterocycles 1996 43 641. 81 Y. Takemura M. Ju-ichi C. Ito H. Furukawa and H. Tokuda Planta Med. 1995 61 366. 618 Natural Product Reports 1997

ISSN:0265-0568    

DOI:10.1039/NP9971400605

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

Indolizidine and quinolizidine alkaloids Joseph P. Michael Centre for Molecular Design Department of Chemistry University of the Witwatersrand Wits 2050 South Africa Covering July 1995 to June 1996 Previous review 1997 14 21 1 General reviews 2 Slaframine 3 Hydroxylated indolizidine alkaloids 3.1 Lentiginosine and related compounds 3.2 Swainsonine and related compounds 3.3 Castanospermine and related compounds 4 Alkaloids from ants and amphibians 4.1 5-Alkylindolizidine and 5,8-dialkylindolizidine alkaloids 4.2 3,5-Dialkylindolizidine alkaloids 5 A steroidal indolizidine alkaloid 6 Phenanthroindolizidine and phenanthroquinolizidine alkaloids 7 Lythraceae alkaloids 8 Alkaloid A58365B 9 Alkaloids of the lupinine-cytisine-sparteine-matrine-Orrnosiu group 9.1 Occurrence detection and analysis 9.2 Chemotaxonomy and chemical ecology 9.3 Structural and spectroscopic studies 9.4 Synthesis and other chemical studies 9.5 Enantioselective transformations mediated by ( -)-sparteine 10 Alkaloids from marine sources 11 Alkaloids from coccinellid beetles 12 References 1 General reviews The use of achiral and chiral 1-acylpyridinium salts as inter- mediates for the synthesis of alkaloids has been comprehen- sively surveyed by Comins and Joseph in a review that is liberally illustrated with examples showing how the method has been applied to the synthesis of indolizidines (e.g.amphibian metabolites Elueocarpus alkaloids) phenanthroindolizi-dines (septicine tylophorine) and quinolizidines (lupinine and epilupinine myrtine and epimyrtine porantheridine and Lythraceae alkaloids).' The achievements of Kibayashi II 0 2 3 O4 and Aoyagi in synthesising alkaloids by means of hetero Diels-Alder reactions with N-acylnitroso dienophiles have been highlighted in a short review summarising their syntheses of swainsonine and 3,5-dialkylindolizidines from frogs and ants amongst others.2 An important review by Casiraghi and co-workers describing stereoselective approaches to bioactive carbohydrates and polyhydroxylated alkaloids includes a large section on the synthesis of lentiginosine swainsonine castanospermine and some of their unnatural indolizidine and quinolizidine analogues3 2 Slaframine In a formal enantioselective synthesis of ( -)-slaframine 1 by Gallagher and co-w~rkers,~ the stereogenic centre at C-6 was introduced at an early stage when 3,3-dimethoxypyrrolidine2 was acylated with benzyloxycarbonyl (Z)-protected (9-2- aminopent-4-enoic acid 3 to give the amide 4 (Scheme 1).The indolizidine nucleus was constructed from the subsequently formed keto aldehyde 5 by a problematic intramolecular aldol condensation which was eventually achieved in low yield (3 1%) with piperidine as base. Diastereoselective reduction of the ketone group of the aldol product 6 was accomplished in 60% yield and better than 95% excess with the Corey oxazaborolidine 7. Once the desired alcohol (19-8 had been protected by silylation catalytic hydrogenation of the C=C bond not only set up the stereogenic centre at the bridgehead position with the correct absolute configuration but also cleaved the benzyloxycarbonyl protecting group.Reprotection as the tert-butoxycarbonyl (Boc) derivative 9 completed a formal synthesis of the target alkaloid since Hua et ~1.~ have previously converted 9 into ( -)-slaframine 1. Duodenal infusion of the parasympathomimetic secreta-gogue slaframine ('slobber factor') in steers showed limited effect on the digestibility of starch in the rumen and small intestine.6 Although the administration of slaframine induced hyperglycemia and hyperinsulemia in goats the effects could be blocked by prior administration of an antagonist of the M muscarinic receptor which is implicated in the regulation of pancreatic fluid secretion.' 0 0 / 1(-)-Slaframine O9 O8 Scheme 1 Reagents i 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, CH,Cl,; ii OsO (cat.) NaIO, THF-H,O; iii HCl (2 M) THF-H,O; iv piperidine THF rt 24 h then acid 1 h; v 7,CH,CI, -20 "C; vi TBDMSC1 imidazole DMF; vii H, 10% Pd-C EtOH; viii (Boc),O CH,CI Michael Indolizidine and quinolizidine alkaloids 3 Hydroxylated indolizidine alkaloids 3.1 Lentiginosine and related compounds The absolute configuration of natural lentiginosine a selective inhibitor of amyloglucosidase has been disputed for some years [cJ refs.8a and b]. In brief the levorotatory natural product ([a] -3.3') was originally assigned the all-S con- figuration shown in 10 on biogenetic grounds but later syn- theses of this enantiomer yielded a dextrorotatory product.Gurjar and co-worker~,~ who synthesised both enantiomers of the alkaloid [see ref. 8b] felt that the original assignment of the alkaloid's absolute configuration must have been wrong and that natural lentiginosine must have the all-R configuration. A new synthesis of (1 S,2S,8aS)-( +)-lentiginosine 10 from L-( +)-tartaric acid by Petrini and co-workers" (Scheme 2) apparently provided further support for Gurjar's contention. OMOM L-Tartaric -. acid OMOM OMOM OBn iv 88% OH H OMOM H ,OH 10 (+)-Lentiginosine Scheme 2 Reagents i BnO(CH,),MgBr THF reflux; ii H (1 atm) Raney Ni W2 MeOH rt; iii NH,OCOH 10% Pd-C EtOH reflux; iv Ph,P CCI, NEt, DMF rt; v conc.HCl MeOH reflux Brandi and co-workers have now offered an alternative explanation for the anomalous results. These workers also synthesised both enantiomers of the alkaloid by a route based on dipolar cycloaddition between methylenecyclopropane and nitrones 11 and ent-11 prepared from L-(+)-tartaric acid and D-( -)-tartaric acid respectively." Their synthesis of (1S,2S,8aS)-( +)-lentiginosine 10 was previously reported in a communicationI2 and highlighted in an earlier review in this series;'" their preparation of (I R,2R,8aR)-( -)-lentiginosine ent-10 followed essentially the same course. The two synthetic enantiomers were then tested for their ability to inhibit various glycosidases.While both were specific for amyloglycosidases from various sources ( -)-lentiginosine was about 35 times less potent than (+)-lentiginosine which had approximately the same activity as that reported for the natural alkaloid. Natural lentiginosine is thus almost certainly the (lS,2S,8aS)- (+) enantiomer 10. Since the optical rotations of the pure enantiomers were found to be very small the negative rotation originally reported for lentiginosine must have been due to the presence of impurities -a plausible explanation since impurities are evident in the published NMR spectrum of the natural product. Brandi's group has also reported three new synthetic analogues of lentiginosine in the period under review (lS,- 7S,8aR)-(+)-1,7-dihydroxyindolizidine l2,I3 (1 S,2S,7R,8aS)-(+)-1,2,7-trihydroxyindolizidine 13 and (lS,2S,7S,8aS)-( +)-1,2,7-trihydroxyindolizidine14.14 When tested as glycosidase inhibitors the latter two compounds were as specific as but 620 Natural Product Reports 1997 OSiPh2E3uf 2 ROSiPh2But 1 I>OSiPh2But 113-OSiPh2But ,N+ -0 -0,N+ ent-10 (-)-Lentiginosine 11 ent-1 1 c 12 13 14 less active than (+)-lentiginosine in competitively inhibiting various amyloglucosidases.All three were inactive against 2 1 other glycosidases although 13 was weakly active against bovine epididymal a-L-fucosidase. A model to rationalise the structure-activity relationship of the three compounds based on structural comparisons with known amyloglucosidase inhibitors has been proposed.3.2 Swainsonine and related compounds Batch cultures of the fungus Metarhizium anisopliae from stirred-tank reactors have been found to produce up to 40 mg 1-of ( -)-swainsonine 15 at 170 h which is more than double the rate of production in shaken-flask culture^.'^ Variables that affected the production of the alkaloid included the impeller geometry aeration strategy and culture homogeneity. A simple assay based on potent and specific inhibition of jack bean a-mannosidase has been devised for determining low concentrations of the alkaloid in M. anisopliae cultures.I6 The assay is suitable for detecting con- centrations up to 0.5 pg ml -'; because of the complex kinetics of inhibition the calibration curve rises too steeply above this level to be reliable.The new assay was used to demonstrate that the addition of L-lysine to the culture medium stimulated swainsonine production by approximately fourfold. A new synthesis of (-)-swainsonine 15 from 2,3-0-isopropylidene-D-erythronolactone 16 used iodocyclisation of the trichloroacetimidate derivative of the (2)-allylic alcohol 17 for stereoselective introduction of the nitrogen atom (Scheme 3).17 The use of iodine monobromide rather than iodine itself for the cyclisation proved to be crucial for the stereocontrolled formation of the trans-oxazoline 18 which was obtained virtually free of the cis isomer. Furthermore the reliable trans-addition of the interhalogen compound across the double bond also introduced iodine in such a way that its subsequent intramolecular S 2 displacement to give lac tone 19 also created the last stereogenic centre with the correct absolute configuration for the target alkaloid.Both rings of the indolizidine nucleus were formed simultaneously during hydrogenolysis of intermediate 20. Completion of the synthesis as shown in Scheme 3 was straightforward. The formal synthesis of ( -)-swainsonine 15 by Zhou et al. previously reported as a communication" and described in an earlier review in this series'" has now been published with full experimental details." In this synthesis the target was the swainsonine derivative 21. The preparation of the enantio- merically pure pyrrolidine 22 in four steps from the 6H-1,2- oxazine 23 by Reissig and co-workers" also completes a formal synthesis of ( -)-swainsonine since the conversion of 22 into the alkaloid has been reported previously.21 Swainsonine has been shown to inhibit a-mannosidases from various insect sources.22 It has also been used as a tool to differentiate between two distinct a-mannosidases from rat liver endoplasmic reticulum and a cytosolic a-rnanno~idase.~~ By contrast the alkaloid did not inhibit an a-mannosidase prepared from hen oviduct which suggests that this enzyme is preferentially involved in processing high mannose-type oligosa~charides.~~ Further recent examples of swainsonine's OTBDPS ' ' ( YXY OTBDPS 17 16 - - x xi vi-ix 90% 56% Nh'' 'OH Icc13 OTBDPS CCI3 19 18 xii xiii 81% xiv r 0 15 (-)-Swainsonine 20 Scheme 3 Reugents i DIBAL CH,Cl, -78 "C; ii TBDPSO(CH2),PPh,+I -,BuLi HMPA THF 0 "C; iii p-TsOH acetone rt; iv Cl,CCN DBU MeCN-CH,CI, 0 "C; v DBU IBr MeCN ca.-60 "C;vi NH,F MeOH 45 "C; vii Swern oxidation; viii NaClO, 2-methylbut-2-ene NaH,PO, Bu'OH-H,O rt; ix Ag,CO, C6H6 65-70 "C; x TFA H,O rt; xi BnO,CCl K2C03 MeOH 0 "C; xii mesitylene-2-sulfony1 chloride NEt, CH,CI, 0 "C; xiii p-TsOH Me,C(OMe), acetone rt; xiv H, 10% Pd-C K,CO, rt to reflux; xv BH * Me$ THF rt; xvi H,O, NaOH reflux; xvii aq. HCl (6 M) rt 21 22 23 use in unravelling the intricacies of glycoprotein processing abound but the methods are now sufficiently routine to warrant individual mention Recent studies on the toxicology of swainsonine appear to be limited to an investigation of tissue and serum concen- trations of the alkaloid in sheep grazing on the 'locoweed' Astragalus lentigino~us.~~ The results showed a correlation between tissue levels of the alkaloid and the dose ingested but not with the length of exposure; however the absorption metabolism and excretion of the alkaloid depended on the individual.Swainsonine forms the focus of a new review describing the anticancer activity of inhibitors of carbohydrate processing.26 This useful article describes amongst other issues the connec- tion between malignancy and processing in the carbohydrate portion of glycoproteins the role that inhibitors of carbo- hydrate processing can play in the search for antitumour agents the therapeutic advantages of swainsonine anticancer mechanisms in tumour cells and in hosts phase I clinical trials with swainsonine and considerations in the design of new carbohydrate processing inhibitors.The potential importance of swainsonine in cancer chemotherapy has been probed further in a study that demonstrated the alkaloid's ability to activate resident tissue-specific macrophages in several mouse strains.27 Dose- and time-dependent tumoricidal activity of lung and spleen macrophages was observed after systematic administration of the alkaloid. Furthermore in vivo activation Michael Indolizidine and quinolizidine alkaloids of macrophages in animals with compromised immune systems suggested that the alkaloid might be acting directly on the macrop hages.3.3 Castanospermine and related compounds The most convenient source of the important glucosidase inhibitor (+)-castanospermine 24 is the Moreton Bay chestnut Castanospermum australe whose seeds have also yielded sev- eral other polyhydroxylated alkaloids of significant therapeutic potential. Callus cultures prepared from leaf and stem explants of young specimens of C. australe or from leaves of mature trees and cultivated on a supplemented Murashige-Skoog medium have now been shown to produce 24.28The castano- spermine content of the cultures was approximately 0.004% based on fresh weight which is slightly higher than that in mature leaf extracts (0.0030/,). Developments in this area are sure to be awaited with interest. The tetrabenzylated gluconolactam 25 available in four steps from tetrabenzylglucopyranose was the starting material in a new formal synthesis of (+)-castanospermine 24 (Scheme 4).29 The novel feature of this synthesis was the construction of the indolizidine nucleus by metathesis of the dialkene 26 in the presence of the popular Grubbs catalyst 27.The formation of 28 in 70% yield is remarkable when one considers that a metathesis in which one of the participating double bonds is part of an a$-unsaturated ester is apparently unprecedented. Dihydroxylation of the newly formed C =C bond was immediately followed by conversion via cyclic sulfites into the cyclic sulfates 29 and 30 which were obtained in a ratio of 15. NOE experiments confirmed that the major isomer had the correct relative stereochemistry for the target alkaloid.Reduction of this compound with sodium boro- hydride yielded the bicyclic lactam 31 a compound that previously featured in the synthesis of the alkaloid by Miller and Chamberlin.30 Single-crystal X-ray diffraction has been used to confirm the relative and absolute structure of indolizidinone 32 a key 621 BnO OBn BnO BnO 0 0 25 26 70% phTh BnO Pcy3-R~ I-PCy3 CI' Cl vi-ix 27 (1 :5) BnO' It 0 0 29 28 0 0 30 31 24 (+)-Castanospermine Scheme 4 Reagents i H,C=CHCH,Br Bu,NI (cat.) KOH (50% aq.)-CH,CI (1:l); ii Ac,O FeCl, then NH, MeOH; iii Dess-Martin periodinane; iv Ph,P=CHCO,Me; v Grubbs reagent 27(5% w/w) toluene Ar 110 "C; vi OsO (cat.) NMO; vii SOCl, NEt,; viii RuCl (cat.) NaIO, CH,Cl,-H,O-MeCN (2:3:2); ix separation on SO2; x NaBH, MeCONMe, then H2S04 (20% aq.) Et20 wiMe2Bd HO 0 32 33 34 35 36 intermediate en route to (+)-ca~tanospermine.~' New synthetic polyhydroxyindolizidines inspired by castanospermine include three isomers of 6-deoxycastanospermine 33-35,32 and an unusual thia analogue 36.33 As the potential clinical importance of castanospermine de- rivatives grows so does the necessity for finding new methods by which the alkaloid can be selectively functionalised.Selective modification at C-8 has hitherto been elusive but has now been achieved by two research groups. Landmesser et al. successfully prepared 6,7-di-Z castanospermine in situ by acylation of (+)-castanospermine 24 with benzyl chloro- formate in pyridine at -15 "C after which conventional acylation with butyryl chloride gave a 76% yield of the ester 37.34 Hydrogenolysis followed by acidification afforded 8-butanoylcastanospermine 38 as its hydrochloride salt (78%).The approach of Tyler and co-workers was to effect temporary stannylation of castanospermine with dibutyltin oxide.35 Sub- sequent benzoylation afforded in 75% yield a 4:l mixture of the tribenzoates 39 and 40 the former providing the required entrke to the desired derivatives. As an alternative benzylation was less successful eventually giving the desired compound 41 (50%) together with a rearranged product 42 (I 5%). Attempts to transform the free hydroxy group of 39 into a better leaving group also resulted in skeletal rearrangement to analogues of 42 apparently by a mechanism involving neighbouring group participation by the bridgehead nitrogen atom.However reaction with methanesulfonyl chloride opened up a pathway 622 Natural Product Reports 1997 0 37 R=Z 39 R = BZ 38 R=H 41 R=Bn O 02CPh H PhC02 a BrieBn BnO-PhCOz' 40 42 to preferential formation of amine and amide derivatives 43 and 44 while deoxygenation via the imidazolethiocarbamate yielded 8-deoxycastanospermine 45. Use of the benzyl ether 41 ultimately yielded the 8-fluoro 46 8-methoxy 47 and 8-pivaloyloxy 48 analogues of castanospermine. Numerous other derivatives still possessing the benzoyl or benzyl protect- ing groups were also obtained as well as products 49-52 from the competitive rearrangement pathway.Interestingly none of the new polyhydroxylated indolizidines matched castano-spermine in its ability to inhibit glucosidases although 47 48 and 50 came close in their effects on lysosomal a-glucosidase. 43 R=NH2 49 R=NHAc 44 R=NHAc 50 R=F 45 R=H 51 R=OMe 46 R=F 52 R=OH 47 R=OMe 48 R=02CCMe3 Castanospermine’s ability to alter glycoprotein processing is now so well established that very few of the alkaloid’s routine uses in probing glycosidase function and activity need indi- vidual mention. One interesting finding is the ability of castanospermine 6-epi-castanospermine 53 and other poly- 53 6-epi-Castanospermine hydroxylated alkaloids to inhibit a variety of insect glyco- sidases.22*3h In these two studies the hydrolysis of carbohy- drate substrates by enzyme preparations from 22 insect species representing seven different orders was examined after the insect homogenates had been incubated with alkaloids at different concentrations.The pattern of inhibition in the insects was not surprisingly found to be quite different from that in mammals; castanospermine for example proved to be a significant inhibitor of insect (3-glucosidases but not a-glucosidases other than trehalase. It also inhibited iso-maltase in coleopterous insects of the family Tenebrionidae and maltase in the species Zophubas morio and showed an un- expected pH-dependent inhibition of maltase in aphids and the lepidopteran Heliconius melpomene.6-epi-Castanospermine 53 showed modest activity against hydrolysis of isomaltose palatinose and lactose in a few cases. A novel result is that castanospermine can also induce the production of a-glucosidases as was shown when Mucor juvanicus was cultured with the alkaloid.” The antitumour potential of castanospermine continues to receive much attention. In vivo experiments with nude mice proved that the alkaloid altered endothelial cell glycosylation prevented angiogenesis and inhibited tumour growth.38 It suppressed syncytium formation and hemolytic activity in baby hamster kidney cells infected with Newcastle disease virus but did not affect synthesis and cell surface expression of the hemagglutinin-neuraminidase glycoprotein in the viral envelope.39 This result supports the hypothesis that poor transport of the alkaloid across membrane barriers may limit its therapeutic use.Uptake and metabolism of the more readily absorbed (more lipophilic) derivative BuCast (6-0- butanoylcastanospermine) 54 has now been followed in 54 tumour cell lines and during oral administration to mice by using material labelled with I4C at C-7.40 Upon absorption into the cells or through the gastrointestinal tract 54 was rapidly converted into the parent alkaloid which is the active metabolite. Furthermore multiple dosing in mice produced additive results. These findings have clear implications for the clinical use of BuCast in for example anti-AIDS therapy for which the compound is currently undergoing clinical trials.4 Alkaloids from ants and amphibians A review of the alkaloids isolated from the skins of frogs includes a summary of the major classes of compound and their amphibian sources and speculations on the dietary origin Michael Indolizidine and quinolizidine alkaloids of some of the alkaloid^.^' The total synthesis of alkaloids of the pumiliotoxin and allopumiliotoxin classes has been reviewed by Franklin and Overman in a significant article that emphasises the imaginative new strategies and methodologies that have been devised for attaining these formidable targets.42 4.1 5-Alkylindolizidine and 5,8-dialkylindolizidine alkaloids A genuinely novel approach to the construction of the indo- lizidine ring system is to be found in a short synthesis of two 5-alkylindolizidine alkaloids by a group of Korean worker^.^' The transformation of interest is intramolecular radical attack on a P-aminoacrylate system as exemplified by the trans- formation of the (3-proline-derived pyrrolidine 55 into indolizidine 56 using tributyltin hydride as radical initiator under conditions of high dilution (Scheme 5).Not only is it H (9-Proline Et02C 55 H i OTs 57 iv 99% I Et02C/ R 60 58 (-)-lndolizidine 1679 R = Me 59 (-)-lndolizidine 209D R = Bu Scheme 5 Reagents i Bu,SnH (1.2 equiv. syringe pump 4 h) AIBN (0.1 equiv.) C,H, reflux; ii LiAIH,; iii p-TsC1 NEt, CH,CI,; iv Me,CuLi or Bu,CuLi Et,O 0 “C uncommon to make an indolizidine by forming the C-5-C-6 bond but the fact that this ring closure was achieved with complete stereocontrol is noteworthy.Product 57 was readily converted into two frog skin alkaloids ( -)-indolizidine 167B 58 and ( -)-indohidine 209D 59 as illustrated in Scheme 5. A simple extension to quinolizidine 60 (55% yield) would seem to offer opportunities for synthesis of the recently discovered frog quinolizidine alkaloids. Ahman and Somfai’s novel approach to the indolizidine skeleton by efficient aza-[2,3]-Wittig rearrangement of vinyl- aziridines was communicated in 199544 and highlighted in the previous review in this series.8d Full experimental details of their synthesis of frog alkaloid ( -)-indolizidine 209D 59 have now been published together with an extension that yields ( -)-indolizidine 209B 61 as shown in Scheme 6.45 For some years now Jefford and co-workers have been developing short efficient routes to indolizidine alkaloids based on stereoselective reduction of bicyclic pyrroles derived from amino acids.The latest extension of this methodology to 63. Hydrogenation in acetic acid with 10% palladium on OH OTBDMS carbon proceeded with complete hydrogenolysis of the ketone I i group and yielded indolizidine 64 as a single stereoisomer ,fo i-iii ,f iv-vii (75%). However when hydrogenation was conducted over ~ :N-H -rhodium on alumina in ethanol containing only a trace of acid 80% 39% hydrogenolysis was prevented and indolizidinol 65 was viii 97% (CH2)4Me 61 (-)-lndolizidine 2098 Scheme 6 Reagents i NaN, NH,CI MeOCH,CH,OH-H,O reflux; ii TBDMSCI DMAP NEt, CH,CI, rt; iii PPh, toluene reflux; iv BrCH,CO,Bu' 18-crown-6 K2C03,THF rt; v Bu,NF-3H20 THF rt; vi (COCI), DMSO NEt, CH,CI, -78 "C; vii Ph,P=CHMe THF rt; viii LDA THF -78 "C; ix H (1 atmj 5% Pd-C EtOH rt; x LiAlH, THF 0 "C to rt; xi Ph,P=CHCO,Et CH2Cl, -78 "C to rt; xii H (4kg cm-') 10% Pd-C EtOH rt; xiii Me,A1 (1 M in hexanej C,H, rt to reflux; xiv LiAIH, THF reflux the synthesis of frog alkaloids (Scheme 7)46 started conven- tionally with diethyl L-glutamate hydrochloride 62 but rapidly reached a critical juncture with reduction of the keto pyrrole obtained.Both products proved to be valuable intermediates for further transformations.The first for instance was readily transformed via aldehyde 66 into ( -)-indolizidine 209D 59 as shown and into a tunicate alkaloid (see Section 10). Indo- lizidinol 65 was transformed in seven steps into 67 thus completing a formal synthesis4' of ( -)-indolizidine 209B 61. Much of this work has been summarised in a published conference report.4g Takahata and Momose have frequently exploited stereo- selective electrophile-mediated heterocyclisations of Z-protected alkenylamines as the first step in the synthesis of various alkaloids. In a new development on this theme they have shown that urethane 68 readily available from L-norvaline underwent smooth intramolecular amidomercur- ation with mercuric trifluoroacetate. Subsequent oxidation of the organomercury intermediate gave the cis disubstituted hydroxymethylpiperidine 69 (5 1%) accompanied by a small amount of the trans isomer (13%) (Scheme 8).49 Conventional transformations led to the chain-extended piperidine 70 and thence to indolizidinone 71 which was readily reduced with lithium aluminium hydride to give (+)-indolizidine 167B ent-58.This is one of the few reported approaches to this alkaloid in which the construction of the six-membered ring precedes that of the five-membered ring. A similar reaction sequence commencing with D-norvaline yielded ent-70 which was transformed in four steps and 68% yield into the acetal72. This completed a formal synthesis5' of the frog alkaloid ( -)-indolizidine 223AB 73. 4.2 3,5-Dialkylindolizidine alkaloids Takahata et a/.found that in contrast with the work cited above oxymercuration of the urethane 74 yielded a 2,5-trans disubstituted pyrrolidine a preference that placed a projected 0 OHH ii -0 92% (+5% 89%64) C02Et C02Et 62 63 65 iii 75% v viii vii 47% 1 1 &) :&) vi vii (CH2kMe 59 (-)-lndolizidine 209D (CH2)4Me 61 (-)-lndolizidine 209B CHO V 98% &)C02Et 66 64 xii 75% - OHCb x xi 51% - I (CH2)4Me 67 Scheme 7 Reagents i 2,5-dimethoxytetrahydrofuran,H,O-ClCH,CH,CI 80 "C; ii BBr, CH,Cl, 5 "C to rt; iii H (55 psi) 10% Pd-C AcOH rt; iv H (55 psi) 5% Rh-AI20, EtOH-AcOH (99:1) rt; v DIBAL Et,O -70 "C then MeOH -70 "C to reflux; vi Ph,P=CHBu THF -78 T; vii H (40 psi) PtO, EtOAc rt; viii Ph,P=CHPr THF -78 "C; ix Jones oxidation; x Ph,P=CHOMe THF -78 "C; xi HCl(6 M) Et,O rt; xii NaBH, EtOH 624 Natural Product Reports 1997 68 69 iii iv 80% I 71 70 vii 79% I ent-58 (+)-lndolizidine167B Scheme 8 Reagenrs i Hg(OCOCF,), MeNO, rt then NaHCO (as.) KBr; ii O, NaBH, DMF rt; iii (COCl), DMSO NEt, CH,Cl, -78°C; iv (EtO),POCH,CO,Et NaH THF 0°C; v H (1 atm), Pd(OH), EtOH rt; vi Me,Al (1 M in hexane) CH,CI, rt to reflux; vii LiAIH, Et,O rt to reflux ent-70 72 73 (-)-lndolizidine 223AB synthesis of the ant venom alkaloid (3S,5S,8aR)-( +)-3-butyl-5-(pent-4-enyl)indolizidine75 in je~pardy.~’ However they circumvented the problem by performing a Sharpless asymmetric dihydroxylation on 74 with AD-mix$ as reagent.Although this reaction afforded a diastereomeric mixture of alcohols 76 manipulation of the mixture as shown in Scheme 9 yielded the readily separable hydroxymethyl-pyrrolidine 77 and its cis isomer 78 in a ratio of 1:4. Straight- forward transformations performed on the latter then led to indolizidinone 79. The unsaturated chain at C-5 was introduced by the completely stereoselective reaction of a-aminonitrile 80 with pentylmagnesium bromide thereby completing the first total synthesis of the target alkaloid 75. The innovative approach to indolizidines by Lee et al. described in Section 4.1 has been adapted to yield 33-dialkylindolizidine alkaloids by using iterative radical cyclis- ati~n.~~ Starting with Z-protected D-glutamic acid 81 which was transformed in eight steps into the P-aminoacrylate 82 these workers demonstrated that cyclisation of 82 to a 1:2 mixture of the piperidine derivatives 83 and 84 could be achieved with tributyltin hydride under conditions of high dilution (Scheme 10).The major isomer 84 was then converted in five steps into the next radical precursor 85 which under similar conditions afforded some deselenenylated piperidines (40%) together with the indolizidine 86 as an inseparable mixture of isomers (57%). However the dithiolane derivatives of the desired bicyclic compounds were separable. These were reduced with Raney nickel to yield the Pharaoh ant trail pheromone (+)-monomorine I 87 and the frog alkaloid (+)-indolizidine 195B 88 respectively.ZNH 98% (CH2)3Me 76 ii-vi 69% (1:4) I vii-ix 59% I x-xiii 58% Et02C (CH2)3Me xiv 83% H H xv-xvii 0-a 0 I I1 (ICH2)W CN (ICH2)3Me 80 79 xviii 36% from 79 I %-.J 75 -‘-Scheme 9 Reagents i AD-mix-P Bu‘OH-H,O (1 :I); ii TBDMSC1 imidazole DMF; iii MsCI NEt,; iv H, Pd(OH), MeOH; v HCl (1%); vi ZC1 NaOH; vii Jones oxidation acetone; viii CH,N,; ix AgO,CPh MeOH; x LiBHEt,; xi (COCl), DMSO NEt, CH,Cl,; xii (EtO),POCH,CO,Et NaH THF 0 “C; xiii H, Pd(OH),; xiv Me,Al; xv DIBAL; xvi HCIO (60% aq.); xvii KCN; xviii H,C =CH(CH,),MgBr Lhommet and co-workers previously reported53 that the reductive cyclisation of keto-pyrrolidine 89 to ( -)-indolizidine 195B ent-88 with hydrogen and a palladium catalyst was completely stereoselective.A more recent communication has shown that this reduction in fact gives both ent-88 (86%) and the epimer ( -)-90 (140/0) which is also a known amphibian alkal~id.’~ Interestingly enough reduction of the analogous keto pyrrolidine 91 under the same conditions proceeded with reversed stereoselectivity and indolizidine 92 was isolated in better than 90% yield. Solladie and Chu have shown that reductive alkylation of the unsaturated keto piperidine 93 with hydrogen and palladium on charcoal gave a separable mixture of (+)-monomorine I 87 (26%) and (+)-indolizidine 195B 88 (46%).” Finally a new synthesis of l-benzyl-5-butylpyrrolidin-2-one 94 by treatment of the sulfone 95 with butylmagnesium chloride in the presence of zinc bromide constitutes a formal synthesis of monomorine I (cj ref.57). 5 A steroidal indolizidine alkaloid An atypical steroidal alkaloid ( -)-96 isolated from the bulbs of Fritillaria rnaxirnowiczii a member of a genus used in China and south-east Asia for its antitussive properties contains a uniquely substituted indolizidine nucleus.58 This structural component can be viewed as the product of ring D cleavage between C-15 and C-16 in a more typical steroidal Michael Indo liz idin e and quinoliz idine alkalo ids SePh C02Et 81 82 83 84 5 steps 76% I H 88 (+)-lndolizidine 195B Scheme 10 Reagents i Bu,SnH (1.3 equiv. syringe pump 5 h) AIBN (0.1 equiv.) C,H, reflux; ii Bu,SnH (2.7 equiv. syringe pump 6 h) AIBN (0.1 equiv.) C,H, reflux; iii HSCH,CH,SH BF,*OEt, CH,CI, rt; Raney Ni EtOH rt H ent-88 (-)-lndolizidine 1958 90 R = (CH2)sMe 92 R=C02Me HO OH OH I OH 89 R = (CHhMe 91 R=C02Me 93 94 R = (CH2)3Me 95 R=SO*Ph of both the native metabolite and its aglycone which was obtained by incubating 96 with hesperidinase.The structures of the sugar units were corroborated by GC analysis. 6 Phenanthroindolizidine and phenanthroquinolizidine alkaloids Plants of the family Asclepiadaceae which serve as natural hosts for danaid butterflies also appear to contain phyto- chemicals that stimulate egg-laying. Methanolic extracts from the Japanese asclepiadaceous plant Tylophora tanakae were found to evoke a strong oviposition response in the butterfly Ideopsis sirnilis; the egg-laying females reacted by '.. . rapidly drumming the surface of the substrate with their forelegs curling the abdomen and bringing the ovipositor in contact with the underside of the substrate and finally laying an egg . . .'.59 The major chemical constituents of the extract phenanthroindolizidine alkaloids were isolated in a parallel study,60 which was reported in last year's review.8e By careful fractionation and bioassay the two principal stimulants were isolated and subsequently identified as (+)-isotylocrebrine 98 and ( -)-7-demethyltylophorine 99. Interestingly these OMe MeOv OMe OH 98 (+)-lsotylocrebrine 99 (-)-7-Demethyltylophorine OMe 96 alkaloid precursor such as solanidine 97. Compound 96 is thus effectively the first representative of a new class of steroidal alkaloids and the indolizidine ring is the result more of chance Me0 than design.The structure was deduced from the NMR spectra 100 (-)-Cryptopleurine 626 Natural Product Reports 1997 - 76% 64% OSiMe3 I BnO 102 103 rI I iii-v 67% BnO -P 67% 0 Me0 Me0 101 (-)-Julandine Me0 Scheme I1 Reagents i BF,.Et,O CH,Cl, rt; ii BH, THF rt to reflux; iii 4-methoxyphenylacetyl chloride NaOH (as. 5%) CH,Cl, 0 "C; iv K,CO, MeOH-H,O reflux; v PDC CH,Cl, 4 8,molecular sieves rt; vi KOH (aq. 5%) EtOH reflux; vii LiAlH,-AlC1 (3:1) THF 0 "C to rt compounds were inactive when tested on their own but turned out to be highly active oviposition stimulants in combination.Whether other alkaloids in the mixture contribute to the synergistic function remains to be determined. The first enantioselective synthesis of (R)-(-)-crypto-pleurine 100 by Kibayashi and co-workers was communi- cated in 19956' and described in last year's review.8' The full paper on this research62 also includes the total synthesis of (R)-(-)-julandine 101 the seco analogue of cryptopleurine (Scheme 11). The key to enantioselectivity once again was highly diastereoselective (>99% de) Lewis acid-catalysed con- densation between silyl enol ether 102 and the acyliminium ion formed from the proline-derived lactam 103. The rest of the sequence was completed as illustrated. This synthesis permits the absolute configuration of natural (+)-julandine to be assigned as 9aS i.e.ent-101. 7 Lythraceae alkaloids A minor alkaloid named demethylvertine isolated from Heimia montana in 1986 was first mentioned in the literature in 1990,63 although at the time it was not certain which methyl group of vertine 104 was missing. The matter has now been settled satisfactorily in favour of structure 105 and the equivo- cal 'demethylvertine' should now be replaced by the unam- biguous name 1 O-epi-lyf~line.~~ The resolution of the problem was achieved by means of extensive NMR experiments in conjunction with molecular dynamics calculations. These cal- culation established the preferred conformation of 105 and hence allowed correlation of theoretical interatomic distances with observed NOE effects.In the calculated conformation the two aromatic rings form part of a right-handed helix which agrees with the absolute stereochemistry previously determined for lythridine 106 by X-ray and ORD-CD measurements. The methods employed in this paper were also applied to lyfoline 107 the structure of which has long been assumed but never unambiguously confirmed until now. 8 Alkaloid A58365B A new synthesis65 of the alkaloid A58365B 114 which is a metabolic product of Streptomyces chrornofuscus NRRL 15098 has an enyne radical cyclisation as its centrepiece Michael Indolizidine and quinolizidine alkaloids OMe OMe 104 Vertine R=Me 106 Lythridine 105 10-epi-Lyfoline R = H OMe 107 Lyfoline (Scheme 12). Condensation of the complex carboxylic acid 108 with the methyl ester of E-hydroxynorleucine 109 yielded a separable mixture of the two amide diastereoisomers llOa and llOb in a ratio of 3:2.The structures of these isomers were not elucidated and each was taken separately through the reaction sequence. After oxidation and cyclisation to the piperideine derivatives 11 la and lllb cyclisation was initiated by heating with tin hydride reagents. Interestingly triphenyltin hydride was the reagent of choice for the major isomer of 111 which -significantly or not -exists as two rotamers at room tempera- ture while tributyltin hydride was more successful with the minor isomer of 111 which is a single rotamer. In the event the hard-to-purify reaction products 112a and 112b were protodemetallated with trifluoroacetic acid to yield alkenes 113a and 113b.Both diastereoisomers could be converted as illustrated into the target alkaloid 114 which is an inhibitor of angiotensin-converting enzyme. - $3C02H + I 65% (3:2) C02Me 0 108 109 0 llOa,b ii iii 5740% I -0 112a,b llla,b vii 0 OH OH - 63% (2steps) ____) 67% 0 H02C H02C 114 A583658 Scheme 12 Reagents i l-hydroxybenzotriazole N-methylmorpholine DMF 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide rt; ii PCC 4 8 molecular sieves CH,Cl, rt; iii TFA 4 8 molecular sieves CH,Cl, rt; iv Ph,SnH AIBN toluene reflux; v Bu,SnH AIBN toluene reflux; vi TFA THF rt; vii 0, CH,CI, -78 "C then Ph,P -78 "C to rt; viii NEt, THF 60 "C; ix (Bu,Sn),O C,H, reflux 9 Alkaloids of the lupinine-eytisine-sparteine-matrint+ Ormosia group 9.1 Occurrence detection and analysis Only three new lupin alkaloids appear to have been reported during the period covered by this review.These are listed in Table 1 along with known alkaloids detected in or isolated from new SOU~C~S.~~~~ Dore et al. analysed chromatographic data for 87 quino-lizidine alkaloids from 97 chromatograms by means of statisti- cal methods in order to assess multidimensional relationships between structure physicochemical properties and chromato- graphic beha~iour.'~ This work forms part of a continuing study designed to devise methods for optimising chromato- graphic separations and to find empirical rules governing the choice of adsorbents and eluents.9.2 Chemotaxonomy and chemical ecology An intriguing study by van Wyk and Verdoorn points out for the first time just how important it may be to specify optical rotation when reporting the presence of sparteine and lupanine in plants." A previous analysis of the genus Podalyria" has shown two distinct groups of species one accumulating hydroxylated lupanines and their esters and the other accu- mulating lupanine and derived a-pyridone alkaloids [cf ref. 8v)]. A closer examination of members of the former group (P. cuneifolia P. sericea) has now revealed that they produce the stereochemically complementary alkaloids ( -)-sparteine 115 and (+)-lupanine 116 while members of the latter group (P. argentea P. calyptrata P.canescens P. cordata P. glauca) yield the less common ( -)-lupanine ent-116. Although the existence of two independent biosynthetic pathways leading to ester vs. a-pyridone alkaloids has been mooted before it would now appear that the enzymes involved in alkaloid esterification may be enantiomer-specific and recognise only compounds biogenetically derived from ( -)-sparteine. It is worth noting that almost all a-pyridone alkaloids have an absolute config- uration that correlates with (+)-sparteine and ( -)-lupanine 628 Natural Product Reports 1997 H P . . R0 115 (-)-Sparteine 116 (+)-Lupanine R = H 118 R =OH 0 117 (-)-Anagyrine 0 119 Cytisine R=H 120 R=Me and even when they bear additional hydroxy groups it is extremely rare to find these groups esterified.The case for the importance of optical rotation measurements in clarifying biosynthetic and chemotaxonomic issues is cogent and it will be interesting to see whether future workers pay more attention to this often overlooked experimental detail. Studies on the alkaloidal constituents of Genista Zobelii and G. salzmanii have suggested that these two morphologically similar taxa should be regarded as synonymo~s.~~ More inter- estingly statistically analysed alkaloidal variations in indi- vidual plants seemed to correlate with their geographical origin rather than any taxonomic difference; sparteine-rich specimens came from Corsica Elba and Sardinia lupanine-rich plants originated in Liguria while plants from Provence had a very low alkaloid content.A distinctive group of Lupinus species from arid areas of North America and Canada (L. jlavoculatus L. kingii L. odoratus L. pusillus L. shockleyi) is characterised by the presence of alkaloids of the sparteine and lupanine types and the absence of ester alkaloid^.'^ Unusually anagyrine 117 is the major seed alkaloid in all but L. kingii where Table 1 Isolation and detection of alkaloids of the lupininexytisine-sparteine-matrine-Ormosia group" Species A1 kaloid Ref. Species Alkaloid Ref. Chamaecytisus austriacus (+)-13-Hydroxylupanine 118 66 Plagiocarpus axillaris Epibaptifoline 75 ( -)-a-Isosparteine (continued) Epilupinine ( -)-Sparteine 115 N-Formylcytisine (+)-Lupanine 116 4P-H ydrox ylupinine ( -j-17-Oxosparteine Hydroxysparteines (two Chamaecytisus proliferus' Sparteine 67 position uncertain) Chamuecytisus supinus 4-H ydrox ylupanine 66 14-H ydrox ysparteine Cuscuta chilensis Ma trine 68 a-Isolupanine (holoparasite on N-Methylcytisine 120 a-I sosparteine Sophora macrocurpa) Sophoranol P-Isosparteine Genista lobelii s.1.N-Acetylcytisine 69 Lupanine Anagyrine 117 Lupinine Baptifoline Lusitanine Cytisine 119 N-Methylcytisine 5,6-Dehydrolupanine 124 17-Oxosparteine Epibaptifoline Rhombifoline N-Formylcytisine Sparteine a-Isolupanine Poecilanthe spp.' N-Acetylcytisine 76 Lupanine Aceylepilupinine N-Methylcytisine 11-Allylcytisine Rhombifoline Anagyrine Sparteine Aph yllidine Gonocytisus angulatus Anagyrine 70 71 Aphylline 126 and G.dirmilensis Cytisine Baptifoline N-Formylcytisine Camoensidine Lupanine Cytisine N-Methylcytisine 5,6-Dehydrolupanine Rhombifoline Lupinus albus cv. BAC (+)-Sparteine ent-115 72 Dihydrolusitanined 121 Lupinus pusillus group" N-Acetylcytisine 73 Epibaptifoline Anagyrine Epilupinine Angustifoline 117 N-Formylcytisine Baptifoline 40-H ydroxyepilupinine Cytisine Lupanine 5,6-Dehydrolupanine Lusitanine I l1I2-Dehydrosparteine N-Methylcytisine Epibaptifoline Rhombifoline Epilupinine Tashiromine N-Formylcytisine Thermopsine 13a-Hydroxylupanine Tinctorine a-Isolupanine Retama (=Lygosj spp! N-Acetylcytisine 77 a-Isosparteine 11-Allylcytisine P-Isosparteine Anagyrine Lupanine Aphy lline Lupinine Baptifoline Lusitanine N-Carbomethoxycytisine N-Methylcytisine C ytisine 17-Oxolupanine Dehydrobaptifoline (tentative) 17-Oxosparteine Dehydrocytisines A and B Rhombifoline 5,6-Dehydrolupanine Sparteine Dehydroretamine" (tentative) Lygos raetam var.( -)-6a-Hydroxylupanine" 123 74 Dehydrosparteines (two posi- sarcocarpu tion uncertain) Plagiocarpus axillaris N-Acetylcytisine 75 11,12-Dehydrosparteine 11-Allylcytisine Epilupinine Anagyrine N-Formylcytisine Baptifoline 12a-H ydroxylupanine Cytisine a-Isolupanine 5,6-Dehydrolupanine a-Isosparteine Dehydrosparteine (position a-Isosparteine uncertain) Lupanine 1 1,12-Dehydrosparteine N-Me t h ylcytisine "Only new alkaloids and new records for a given species are listed. Structures of most known alkaloids may be found in previous reviews in this series.'Chamaecytisus proliferus spp. prollferus var. calderae ssp. proliferus var. canariae ssp. proliferus var. hierrensis ssp. proliferus var. palmensis ssp. proliferus var. prollferus ssp. angustifolius ssp. meridionalis. "Lupinus jhoculatus L. kingii L. pusillus ssp. pusillus L. pusillus ssp. rubens L. shockleyi. dNew alkaloids. 'Poecilanthe amazonica P. efusa P. falcata P. grandflora P. hostmannii P. itapuana P. ovalifolia P. purvijlora P. subcostata P. ulei. 'Retama (=Lygos) raetam R. sphaerocarpa R. monospermu. Michael Indolizidine and quinolizidine alkaloids 629 Table 1 Continued Species Alkaloid Ref. Plagiocarpus uxillaris 17-Oxoretamine 77 (continued) 17-Oxosparteine Retamine 122 Rhombifoline Sparteine Templetonia bilobu N-Acetylcytisine 78 Anagyrine Angustifoline Bapti foline Cytisine 5,6-Dehydrolupanine Epi baptifoline Epilupinine N-Formylcyt isine 13a-hydroxylupanine 118 and lupanine dominated; most other members of the tribe Genisteae accumulate cytisine 119 or N-methylcytisine 120 in the seeds.Furthermore different dis- tinctive combinations of major and minor alkaloids in the five species suggest that alkaloidal patterns in Lupinus may be diagnostically useful even at the species level. The place of the monotypic Australian genus Plagiocarpus in the tribe Brongniartieae appears to be confirmed by the co- occurrence of lupinine and a-pyridone alkaloids which is a characteristic of other Australian members of the tribe.75 The presence of several different hydroxysparteines suggests a close link between P.axillaris and some members of the genus Templetonia especially T. incana. However the previously unexplored species T. biloba unlike other Templetonia species contains no alkaloids of the ormosanine class a finding that corroborates morphological evidence that the species has been misplaced in this The unusual combination of a-pyridone alkaloids and comparatively rare tetrahydro-cytisine derivatives in T. biloba leaves its phylogenetic status uncertain. The taxonomic position of the tropical South American genus Poecilanthe in the tribe Dalbergieae is by no means certain. However a study of the alkaloidal constituents of all ten known Poecilanthe species -the first such study on the genus -has revealed a relationship with the Sophoreae or Brongniartieae rather than the Dalbergieae.76 With limited amounts of plant material available an unusually large number of apparently new alkaloids still remain unidentified.However good mass spectrometric evidence was obtained for dihydrolusitanine 121 a hitherto unknown natural product. .NHCOMe 121 122 Retamine The use of capillary GLC-MS has permitted the identifi- cation of some 28 quinolizidine alkaloids in Mediterranean plants of the genus Retama (Lygos)-substantially more than in any previous These included retamine 122 which is otherwise rather uncommon in the Leguminosae and a new alkaloid tentatively identified as a dehydroretamine.Alkaloidal patterns were very similar in the three species studied; in fact there was greater variation in the alkaloid content of different Species Alkaloid Ref. ~ ~~ ~ Templetoniu bilobu N-Formyltetrahydrocytisine 78 (continued) 13-Hydroxylupanine a-Isolupanine 0-Isosparteine Lupanine Lupinine N-Meth ylangustifoline N-Methylcytisine N-Methyltetrahydrocytisine Rhombifoline Sparteine Tetrah ydrocytisine Tetrahydrorhombifoline plant organs than in the three species. Sparteine and retamine were the major components of roots and stems while bio- genetically more advanced a-pyridone alkaloids such as cyti- sine 119 dominated in flowers and seeds. The authors suggest that selective transport of a-pyridone alkaloids in the phloem is responsible for the observed distribution patterns.An important study on the transfer of alkaloids between Lupinus albus and Cuscuta reflexa has produced several startling results that appear to overturn some long-held beliefs.82 By determining the net flow of alkaloids in control plants and in the host-parasite system the authors concluded that alkaloids are transported mainly in the xylem rather than in the phloem sap. This conclusion in turn conflicts with the view that quinolizidine alkaloid synthesis in lupins must be restricted to leaf chloro- plasts; the new model proposes that the main site of alkaloid synthesis is the roots. However the parasite still seems to obtain over 95% of its alkaloids from the phloem which implies an efficient xylem-phloem transfer mechanism.While parasitism resulted in retarded catabolic processes in the host and an approximate halving in the host’s alkaloid levels the total alkaloid levels in the host-parasite pair rose by about 1.3-fold suggesting both a massive shift in nitrogen metabolism towards alkaloids and the enormous sink potential of Cuscuta for nitro- genous compounds. Cuscuta can apparently survive when quinolizidine alkaloids constitute its sole source of nitrogen which indicates substantial catabolic degradation of alkaloids. 9.3 Structural and spectroscopic studies ( -)-6a-Hydroxylupanine 123 is a new alkaloid isolated from the aerial parts of Lygos raetam var. ~arcocarpa.~~ Structural elucidation was by means of spectroscopic techniques while the relative stereochemistry of the OH group was suggested by NOE correlations between OH H-lOa and H-8a.The final confirmation of structure including the assignment of the (7R,9R,1 1 R) absolute configuration was made by dehydration of 123 with trifluoroacetic acid to give the known compound (+)-5,6-dehydrolupanine 124. The new alkaloid is a plausible biosynthetic intermediate between lupanine and 5,6-dehydrolupanine and also thus likely to be implicated in the biosynthesis of a-pyridone alkaloids. c> qy-g N N H 0 0 123 124 (+)-5,6-Dehydrolupanine 630 Natural Product Reports 1997 From time to time some doubts have been expressed about OH the structure of (+)-retamhe. When this compound was recently isolated from L.raetam var. sarcocarpa the authors took the opportunity to confirm its structure by means of a thorough spectroscopic and X-ray crystallographic The results confirmed that the alkaloid indeed has the relative configuration of 12a-hydroxysparteine 122 with rings A and B in chair conformations ring C in a boat conformation a trans ring junction between rings C and D and the OH group axial. The X-ray structural analysis of sparteine derivatives and their protonated salts frequently reported in these pages has now been reviewed and the factors causing conformational and configurational changes of the molecular skeleton have been evaluated.84 Other crystallographic analyses reported during the review period are for 2-cyan0-2-phenylsparteine~~ and 2-cyano-2-methylsparteine perchlorate.86 The equilibrium between two different solution confor-mations of 13-oxolupanine (2,13-dioxo- 11 a-sparteine) 125 has been determined with the aid of 'H NMR spectro~copy.~~ iii,iv 83% I 1 129 128 vi 80-90°/0 t CHO /OH H H As expected the major conformational change occurs in ring C for which the fraction of chair conformer is unusually high (44%; compare 10% in lupanine).This may reflect decreased destabilisation as ring D is flattened by the additional carbonyl mo H II 0 0 125 126 Aphylline eA 0 H' 127 (-)-Angustifoline group. Aphylline 126 appears to have an even greater equi- librium concentration of ring C chair conformer although the precise amount was not calculated.88 This publication also contains reliable 'H and 13Cchemical shift data interpreted in terms of structural properties and substituent effects for eleven natural and unnatural sparteine derivatives.Gradient-selected HMBC spectra have been used to elucidate the full range of H-I3C coupling constants for angustifoline 127.89 9.4 Synthesis and other chemical studies A single-electron transfer from the a-silylpiperidine 128 photochemically induced in the presence of 1,4-dicyano-naphthalene as electron acceptor was used to prepare the quinolizidine 129 which without further purification was cleaved by ozonolysis to give the aldehyde 130 in 90% overall yield (Scheme 13).90 This product was readily reduced to ( f)-epilupinine rac-131 which was further purified via its benzoate.Complementary intramolecular Schmidt rearrangements on the norbornanone-derived azido ketones 132 and 133 took place stereospecifically to yield the tricyclic lactams 134 and 135 in yields of 82% and 9240 respectively." Similarly the azido dione 136 gave product 137; but attempted Schmidt reaction on the tricyclic precursor 138 only yielded the corresponding aldehyde 139 thereby frustrating a rather straightforward synthetic approach to sparteine. New synthetic derivatives of cytisine 119 include the phosphonates 140 prepared in 78-90% yields from the parent alkaloid the corresponding aldehyde and dimethyl phosphite;"* the 12-cyanomethyl compound 141 made by treating cytisine with gly~olonitrile;~~ and the glycine deri- Michael Indolizidine and quinolizidine alkaloids 130 131 Epilupinine Scheme 13 Reagents i TFA CH,Cl, 0 'C; ii I(CH,),C =CCH,OH K,CO, MeCN reflux; iii H (35 psi) Pd-CaCO, MeOH rt; iv PPh, CC1,-CH2Cl (4:l) K,CO, reflux; v hv 1,4-dicyanonaphthaIene Pr'OH K,CO, rt; vi 0, MeOH-CH,Cl, -78 "C then Me,S; vii NaBH, EtOH reflux; viii PhCOC1 NEt, THF rt; ix NaOH LO) MeOH rt Xk .3 j 132 X=2H 133 N3 134 X=2H 135 138 R=CH2N3 137 X=O 139 R=CHO vative 142.94The lupinine derivative 143 was prepared from the parent alkaloid and maleic anh~dride,~' while ( f)-1-hydroxymethylindolizidin-8-01144 is a new synthetic com- pound with a skeleton isomeric to that found in tashiromine 145.96 9.5 Enantioselective transformations mediated by ( -)-sparteine A veritable explosion in the number of publications dealing with enantioselective transformations arising from the use of ( -)-sparteine-alkyllithium complexes makes individual men- tion of each article impractical.Over 50 publications during the review period address topics such as enantioselective deprotonation enantioselective addition to multiple bonds and asymmetric polymerisation. A selection of these articles is highlighted below. A published conference paper by Hoppe and co-workers gives further examples of heteroatom-directed lithiation of chiral alkylcarbamates such as 146 from which pro-S protons 631 R 0 0 140 R = Pri Ph pMeOC6H4 141 142 143 144 145 146 147 a to the oxygen are preferentially abstracted by the ( -)-sparteine-sec-butyllithium complex.97 Some of this work has been published separately.'" 98 More recently Hoppe and co-workers showed that when a stereogenic centre is present P to oxygen the ratio of diastereoisomers formed is independent of the electrophile used in trapping the lithiated intermediate a trend supported by semiempirical PM3 calculations on the transition state formed during depr~tonation.~~ As a result of this double stereodifferentiation the ( -)-sparteine-sec-butyllithium deprotonation leads to efficient kinetic resolution of racemic alkylcarbamates.Hoppe has also demonstrated regioselective and enantioselective titanation and stannylation of the lithiated intermediates formed from 0-crotylcarbamates such as 147,'" while other workers have exploited enantio- selective deprotonation of 0-crotylcarbamates in partial or total syntheses of natural products."" '02 Important contributions on the enantioselective deprotona- tion of carbamates with alkyllithium compounds continue to come from the research group of Beak and co-workers who have recently shown that out of about 20 chiral nitrogen- donor ligands studied (-)-sparteine is still by far the best promotor of enantioselective deprotonation a to the nitrogen atom of N-Boc-pyrrolidine 148 outstripping the related alka- loid ( -)-isosparteine 149 in enantioselectivity and rate of conversion.'03 Kinetic investigations with isopropyllithium support the notion that a pre-lithiation complex -perhaps having a structure such as that shown in 150 -is rapidly formed in an equilibrium process as the predominant species in solution prior to the rate-determining enantioselective depro- tonation.'04 Synthetic uses of ( -)-sparteine complexes of a-lithiated N-Boc-N-benzylamines have been described both by Beak'05 '06 and by others.'07 Schlosser and Limat have made the significant observa- tion that when N-Boc-N-methylbenzylamine is treated with ( -)-sparteine-sec-butyllithium the initially formed lithiated intermediate racemised instantaneously.'O8 After a while the original homochirality was restored as the chiral ligand intercepted one component from the rapidly equilibrating organometallic antipodes. Most remarkably subsequent reaction with electrophiles proceeded with either retention or 148 149 a-lsosparteine 150 inversion of configuration depending on the solvent used; inversion predominated when solvents with good coordinating properties were used.A dynamic equilibrium between the organolithium-( -)-sparteine contact species 151 and the solvent-coordinated ion pair 152 was proposed to rationalise 151 the observations. The synthetic potential of this new work is enormous since sparteine methodology has hitherto been limited by the availability of only the ( -)-enantiomer of the alkaloid. Other uses of ( -)-sparteine-alkyllithium complexes in enan- tioselective deprotonations have met with variable success. The preparation and reaction of P-lithiated N-methylamides (i.e. homoenolate ions) gave highly enantioenriched products (ee mostly >800/),'09 but a P-arylsulfanyl substituent affected the enantioselectivity adversely (ee <47%). 'lo Directed ortho metallations of N,N-dialkylarylamides followed by reaction with electrophiles led to 2-alkylnaphthalene-1-carboxamide atropisomers (ee ca. 50%)'' ' and chiral 2-substituted ferrocene-1-carboxamides (ee >8 l%).' l2 Reactions at the benzylic position of N-(2-ethylphenyl)pivalamide were highly enantioselective (ee mostly 77790%) when the anion was generated at -25 "C and cooled to -78 "C prior to the addition of electrophiles; enantioenriched trimethylstannyl products could in turn be lithiodestannylated with ( -)-sparteine-sec-butyllithium and treated with electrophiles to give products that were enantiomers of those prepared by the 'warrrxool' protocol.'' Excellent enantioselectivities were observed in the deprotonation and electrophilic substitution of indenes (>95%)' l4 and aryldimethylphosphine-borane complexes (ee >79%),' l5 and in the desymmetrisation of meso epoxides derived from medium-sized cycloalkenes' l6 or norbornene' l7 by deprotonation and rearrangement (for example the conversion of 153 into 154).By contrast the enantioselectivity in sparteine-mediated a-silylation of an a-lithiated diphenylphosphine oxide' '' was negligible while a 77Se NMR study showed modest stereochemical bias in ( -)-sparteine-a-phenylselanylalkyllithium complexes.'l9 632 Natural Product Reports 1997 HrOH 153 154 Enantioselective nucleophilic additions mediated by ( sparteine are relatively uncommon.New examples include asymmetric carbolithiation of cinnamyl alcohols and related compounds with n-butyllithium in non-polar solvents (ee <84Y0),'~' the addition of n-butyllithium to N-metallated benzaldimines to yield (R)-a-butylbenzylamine (ee <740/0) 12' and the addition of organolithium compounds to prochiral arene-tricarbonylchromium complexes (ee 3654%). The enantioselective ring-opening of a meso-oxetane with lithium diphenylphosphide provides a rare example of a (-)-sparteine-mediated nucleophilic substitution.'23 Low asym- metric induction by ( -)-sparteine has been observed in the synthesis of a p-lactam by the CuI-induced addition of phenyl- acetylene to C,N-diphenylnitrone (ee 210/0)'~~ and in the addition of phenylmagnesium bromide to a 2-thiazolylnitrone (ee 31450/;,).'25A 'combinatorial' investigation of the effect of chiral ligands and metal salts on the generation and intra- molecular trapping of a carbene from an a-diazo ester included ( -)-sparteine amongst the array of reagents.'26 10 Alkaloids from marine sources The Indonesian sponge Clathria basilana is the source of a unique tetrahydroquinolizinium alkaloid clathyrimine A 155 155 Clathyrimine A R = C02H 156 Clathyrimine B R = H the structure of which was elucidated mainly on the basis of NMR spectroscopy.12' Clathyrimine A proved unstable in solution and underwent partial decarboxylation to a com- pound named clathyrimine B 156 during the NMR studies.The reaction could be driven to completion merely on heating at 40 "C in deuteriated chloroform. A Japanese sponge Halichondria okadai produces a novel spiroquinolizidine macrolide 157 to which the name halichlo- rine has been given.'28 The structural relationship between this compound and two other new metabolites pinnaic acid 158 and tauro-pinnaic acid 159 from the Okinawan bivalve Pinna rn~ricata,'~~ is striking. The structure and relative config- uration of the new macrolide ([a] +240.7" cO.54 MeOH) were determined after detailed analysis of coupling constants H ro I rsJi "Me HO CI OH CI OH 157 Halichlorine 158 Pinnaic acid R = OH 159 Tauro-pinnaic acid R = NHCH2CH2S03H Michael Indo lizidine and quino lizidine alkaloids and NOE effects in the NMR spectrum.Halichlorine 157 inhibited the induction of VCAM-1 (vascular cell adhesion molecule-1) with an IC, of 7 pg ml- ' and thus may be a useful lead in the search for drugs for treating atherosclerosis coronary heart diseases and angina amongst others. Piclavines Al-A4 recently discovered antimicrobial con-stituents of the tunicate (sea-squirt) Clavelina picta were originally assigned the structures 16&163 on the basis of IR *(CH&Me 160 161 H H spectra.8h.I3O Jefford and co-workers have now adapted the methodology described in Section 4.1 in order to synthesise ( -)-piclavine 161.46,48 Starting with the previously described indolizidine carbaldehyde 66 (see Scheme 7) they employed several straightforward transformations to accomplish the first reported synthesis of a piclavine as shown in Scheme 14.As it CHO bOMe 66 ii 100% J H H i=/(CH2)5Me \CHO 161 (-)-Piclavine A4 Scheme 14 Reagents i Ph,P=CHOMe THF -78 "C; ii HCI (6 M) Et,O rt; iii Ph,P=CH(CH,),Me THF -78 "C turned out the NMR spectra obtained revealed that isomer 161 was identical with piclavine A4 not piclavine A2. The data obtained allowed the tentative structures of piclavines Al-A4 to be reassigned as 162 163 160 and 161 respectively. Two recently described quinolizidine alkaloids from Clavelina picta clavepictines A 164 and B 165 have also been synthesised for the first time.13' Commencing with the enantio- pure piperidinone 166 Momose and co-workers used an Eschenmoser sulfide contraction to introduce a functionalised carbon chain at the ring position adjacent to nitrogen (Scheme 15).Reduction of the resulting vinylogous urethane 167 with sodium cyanoborohydride in acidic medium pro- duced mainly the 2,6-trans diastereoisomer 168 (1 1 1). Further chain extension eventually yielded the unsaturated sulfone 169 which underwent spontaneous and completely stereoselective 633 166 1 67 168 7steps 31% I vii-xii MOMO" 62% ':;$-S02Ph 'SOZPh 171 H MOMO" 165 (+)-Clavepictine B 164 (-)-Clavepictine A Scheme 15 Reagents i Ac20 pyridine; ii Lawesson's reagent THF reflux; iii BrCH,CO,Me; iv PPh, NEt, MeCN reflux; v NaBH,CN TFA 0 "C; vi 10% Cd-Pb THF-NH,OAC (aq.1 M) rt 48 h; vii HCl (lo%) EtOH reflux; viii TBDPSCI imidazole DMF 80 "C; ix MOMCl Pr',NEt CHCl, reflux; x HF (40%) pyridine THF; xi I, PPh, imidazole C,H,; xii Bu,SnH AIBN toluene reflux; xiii BuLi trans-non-2-ena1 -80 "C to -50 T;xiv 5% Na-Hg Na,HPO, MeOH rt; xv conc. HCl MeOH reflux cyclisation to give the quinolizidine 170 on removal of the Troc protecting group on nitrogen with a mixed cadmium-lead &@J0 Q0 reductant. The assignment of the stereochemistry of 170 initially made on the basis of NMR spectra was confirmed by an X-ray diffraction analysis which also indicated the (3R,4S,6S,10s) absolute configuration that is preserved in the target alkaloids. A noteworthy step in completing the synthesis of ( -)-clavepictine A 164 and (+)-clavepictine B 165 was the Julia coupling of sulfone 171 with trans-non-2-enal which ensured the requisite E,E geometry in the decadienyl side chain.11 Alkaloids from coccinellid beetles Two reviews on the defensive chemicals produced by coccinel- lid (ladybird) beetles were published in the period covered by the present report. In their article Daloze and co-workers (the discoverers of many of the beetle alkaloids) have described the insects' defensive mechanisms summarised the structures of the 34 alkaloids -many of them 9b-azaphenalenes -identified to date discussed the chemotaxonomic implications of these structures and reviewed the few biosynthetic data currently available.132 Their review also includes information on the toxicity and repellency of the alkaloids their mode of release and alkaloidal variations during the insects' life cycles.The review by King and Mein~ald'~~ concentrates on describing the isolation and structure of coccinellid alkaloids and briefly covers biosynthesis bioactivity and other chemical defence mechanisms. A new 'dimeric' alkaloid chilocorine B 172 has recently been isolated from the coccinellid Chilocorus cacti,'34 bringing the number of 'dimeric' ladybird alkaloids discovered to date to three. 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ISSN:0265-0568    

DOI:10.1039/NP9971400619

出版商:RSC    

年代:1997

数据来源: RSC

摘要:

~~ Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids David O'Hagan Department of Chemistry University of Durham Science Laboratories South Road Durham UK DHI 3LE Covering 1994 to 1996 with selected references from 1993 Previous review 1994 11 581 Pyrrole alkaloids Pyrrolidine alkaloids Pyridine alkaloids Pyridone and hydropyridone alkaloids Piperidine alkaloids Spiropiperidine alkaloids Azepine alkaloids Tropane and related alkaloids References 1 Pyrrole alkaloids The pyrrole funebral 3 is a component of the secondary metabolite cocktail2 of Quararibea funebris a tree of medicinal and religious significance to the New World Aztec civilisation. Funebral 3 has been prepared3 from the amine 1 also a component of the cocktail by a Paal-Knorr type synthesis of this bis-a,&unsaturated diketone 2 as illustrated in Scheme 1.i Ti(OPri) ii Os04.Hi04 iii NaBH3CN 0 3 Scheme 1 The success of this reaction relied on titanium(1v) isopropoxide as a catalyst. Other titanium salts generated more acidic side products which promoted pyrrol polymerisations. Oxidative cleavage of the resultant Paal-Knorr product generated a dialdehyde and partial reduction afforded compound 3. Stevensine 4 and hymenin 5 are structurally related alkaloids which were isolated from the marine sponge Pesduxayniass-nacahterlla4.* and they are clearly related biosynthetically to pyrroloazepine6 6 a metabolite of the Mediterranean sponge Phakellia falabellata. Stevensine 4 has been converted7 into hymenin 5 by the sequence shown in Scheme 2.Rigidin 7 identified' from a marine tunicate Eudistoma cf. rigida is a potent inhibitor of the calmodulin-activated brain phospho- diesterase. However its mode of action is uncertain. Due to the lack of available natural product for further study rigidin 7 has been the subject of a total synthesis.' The compound was prepared in nine steps and 26% overall yield from 6-chlorouracil. The marine alkaloids polycistrin-A 8 and H H2NQ Br 0 5 Scheme 2 H %H 6 0 OH Br Br 8 R=H 9 R=Me -B 9 have been isolated" from a Polycitor sp. (Ascidiaceae). Steglich and co-workers have executed an elegant synthesis' of polycistrin-A 8 as shown in Scheme 3 which may represent a biomimetic route to the alkaloid.Oxidative dimerisation of 3-(4-methoxyphenyl)pyruvic acid 10 in the presence of ammonia gave the pyrrole dicarboxylic acid 11 and then oxidative decarboxylation generated the maleimide 12. Conversion to the corresponding maleic anhydride was con- venient for bromination and deprotection and the target 0'Hagan Pyrrole p y rrolidine p yr idine piperidine azepine Uind tropane alkaloids 0 0 Meo&D Me0 &co2H 17 OMe 10 J H H %OMe / OMe H02c*co2H Oe0 19 QQ=Qy8 Scheme 4 Me0 OMe Me0 OMe 11 12 Scheme 3 H H Q-j-&J N H H 13 14 alkaloid 8 was prepared by treatment with tyramine. Support- ing evidence for the biomimetic hypothesis comes from the co-occurrence of structurally related alkaloids 13 and 14 fo~nd'~,'~ in the slime mould Lycogala epidendrum.Clearly by the same analysis 14 is a biosynthetic precursor to 13. 2 Pyrrolidine alkaloids Norhygrine 15 and two new polyhydroxylated sterols have been isolatedI4 from Nierembergia hippomanica a toxic plant native to Argentina. Surprisingly this is the first time that norhygrine 15 the N-demethylated analogue of hygrine has been isolated from a plant source. The novel hygroline based alkaloid 16 has been i~olated'~ from the leaves of the Chilean HO QJ H 15 16 plant Schizanthus integrifolius Phil. Ruspoline 19 one of three pyrrolidine alkaloids of Ruspoliia hypercrateriforrnis has been synthesisedI6 as shown in Scheme 4.The key step involved a photo-Fries type rearrangement of 17 to 18 and then reduc- tion gave racemic ruspoline 19. The defense alkaloids of the Mexican bean beetle Epilachna varivestis have been re-analysed17 and two previously unreported pyrrolidines 20 and 21 were identified in the cocktail. The absolute configuration of these pyrrolidines has been assignedI8 the 2S,12'R configur- ation as illustrated after the synthesis of the unnatural stereo- isomers of the pyrrolidines and 'H NMR analysis of the 638 Natural Product Reports 1997 n 20 R=H 21 R = CH2CH20H diamide generated after treatment with (5")-Mosher's acid chloride. The pyrrolidines 22-27 have been isolated" from the poison glands of female Leptothoracini (Myrmicinae) ants. These compounds are variously N-alkylated and possess a C-3 methyl (or for 25 a hydroxymethyl) group.The structures of all of the compounds were established after the synthesis of reference compounds although stereochemical issues were not addressed. The N-alkyl moieties of the pyrrolidines 22-27 / / / /-OH / dd (2 d S OH \ ai i b 22 23 24 25 26 27 clearly derive from decarboxylated amino acids. Irniine 31 and bgugaine 32 are alkaloids of the Moroccan tuber Arisarum vulgare.20Scheme 5 summarises a synthesis to these alkaloids2' in a stereoselective manner after treatment of the appro- priate y-keto acid with (R)-phenylglycinol 28 to form the oxazololactams 29 and 30 in homochiral form. Reductive extrusion of 2-phenylethanol followed by N-methylation as illustrated in Scheme 5 generated each of the alkaloids in ~98% ee.These compounds inhibited the growth of selected gram positive bacteria and yeasts at pg m- concentrations. Plakoridine A 33 a novel tyramine-containing alkaloid has been isolated22 from the Okinawan sponge Plakortis sp. Other fully functionalised pyrrolidines have been isolated23 from branches of Broussonetia kazinoki a deciduous tree of the Pacific rim. Broussonetine-C 34 and -D 35 were shown to be P-galactosidase and P-mannosidase inhibitors. 3 Pyridine alkaloids Niphatesine C 38 is a pyridine alkaloid isolated24 from the Okinawan marine sponge Niphates sp. It belongs to a large group of 3-alkylpyridine metabolites which display anti-microbial and cytostatic activities.The absolute configuration HOW U 29 R=Ph 30 R = (CH2)4Me ’H H;T HO 0 OAc Me i Me 02( Me 31 R=Ph 32 R = (CH2)4Me Scheme 5 resultant keto thiophene 37 was sequentially reduced and functional group manipulation allowed the introduction of the primary amine and completion of the synthesis of 38. Four new cytotoxic sesquiterpene pyridine alkaloids emarginatinine 39 and emarginatines C 40 D 41 and E 42 have been isolated26 from the Taiwanese plant Maytenus emarginata OH 33 which extends the family from emarginatines A 43 and B 44. The structurally related alkaloids celahinine A 45 celhin A 46 and the already known emarginatine A 43 were isolated27from another Taiwanese plant Celastrus hindsii. These compounds OAc R2 / R3 H- - 0 Me of niphatesine C 38 has been established as S after a stereo-Me+H n specific synthesis25 from the known thiophene 36 and 5-(3-pyridy1)pentanoyl chloride as illustrated in Scheme 6.The ““-Wo 0 Pd = Q“‘ Q 36 OBZ = c=o c=o 0 0 0 I OAc display potent cytotoxicity activity against various human 37 carcinoma cell lines. An elegant chemo-enzymatic strategy for the synthesis of a series of pyridine monoterpene alkaloids (PMTA) from iridoid glycosides has been described.28PMTAs often co-occur with iridoid glycosides. For example 47 and 48 are found together in Castilleja rhexifolia plants.29 Their probable biosynthetic relationship is forcefully demonstrated by the observation that when 49 is treated with a P-glucosidase in 10% ammonium acetate solution then pyridine 50 is Scheme 6 generated albeit in low yield as shown in Scheme 7.The O’Hagan Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids 639 C02Me C02Me "o\ I "o\ I 47 48 P-Glucosidase NH~OAC 49 50 Scheme 7 mechanism of the process is discussed in a preliminary way and some ideas are presented in the paper by Frederiksen and Stermitz.28 In the previous review' of this series the isolation and structural elucidation of epibatidine 51 by Daly in 1992 was alluded to. Since then there has been an extraordinary interest in the synthesis of this compound stimulated by its potent analgesic properties lack of availability and its unusual and attractive structure.Five total syntheses were published in 1993,30-34 six in 1994,3540 two in 199541,42 and five in 1996.4347 No more please! It is beyond the scope of this review to summarise all of the various syntheses of epibatidine 51 however some highlights are presented here. A review of the 1993-1994 syntheses has been published.48 Broka3' is credited with the first total synthesis however the most direct of the early syntheses are those of Huang and Shen31 and Clayton and Rega~~,~~ although these give rise only to racemic material. The route of Huang and Shen31 shown in Scheme 8 involved a Diels-Alder cycloaddition between an N-protected pyrrole and the phenylsulfonylacetylene 52 and generated a 2:l mixture of 51 and epi-epibatidine.However later method^^',^^ have 51 0 0 + -A-kz" t 52 1 0 Me0K 51 epi-51 -2 1 Scheme 8 shown that the epimer can be epimerised to 51 by treatment with KOBut. The route of Clayton and Regan34 shown in Scheme 9 is attractive in that it is short and generates the correct diastereoisomer directly. The key step involves the palladium mediated coupling of 2-chloro-5-iodopyridine and the N-protected 7-azabicyclo[2.2. llheptene 53. Successful coupling albeit in moderated yield (35%) generated 54 which 0 0 53 54 51 Scheme 9 was deprotected to give epibatidine 51. Several enantiomeric syntheses of 51 have been executed. The routes of C~rey~~ and Fletcher32339 and their co-workers involved resolutions of intermediates and the latter st~dy~~,~~ established the natu- ral product as ( -)-epibatidine with the 1R,2R,4S absolute configuration as shown in structure 51.Remarkably each enantiomer shows a similar level of biological activity. The first asymmetric synthesis of ( -)-51 was reported by Trost and Cook49 in 1996 and is shown in Scheme 10. Desymmetrysation 0 55 TMSN3 (dba)3 Pd.CHCl3 I I OBz N3 HNBoc 56 >95%ee 57 I I i 0(yBr HNBoc HNBoc 51 Scheme 10 of the meso ester 56 was achieved by a palladium cross coupling reaction mediated by the ligand 55 to displace a benzyloxy group for an azide in a highly stereoselective manner. Reduction to the amine and protection generated 57. The conversion to ( -)-epibatidine 51 is then relatively straightforward.4 Pyridone and hydropyridone alkaloids The pyridone alkaloid cerpegin 60 is a metabolite5' of the Indian plant Ceropgia juncea. This plant has had a profile in folklore medicine with extracts of the plant exhibiting tranquilising and local anesthetic activities. In order to test the individual biological activity of cerpegin 60 it has been syn- thesi~ed,~'.~~ in the four step sequence shown in Scheme 11. The key step involved a Michael reaction between phenylthio- acetonitrile and the butenolide 58. Oxidation of the thioether and elimination generated nitrile 59 which was reduced and cyclised to give 60. The alkaloid piplaroxide 61 has been identified53 in extracts from leaves of the shrub Piper 640 Natural Product Reports 1997 Q S-CN -+ 58 I 60 59 Scheme 11 OMe MR e o k N p o 00 61 R=H 62 R = OMe tuberculatum and a related compound 62 has been isolated54 from Piper verrucosum.These alkaloids are among a group of analogues which confer ant-repellant properties to the leaves and in general these plants are ignored by leaf cutting ants. Adalinine 64 is a novel reduced pyridone alkaloid which has recently been isolated55 as a defense alkaloid from the ladybird beetles Adalia bipunctata and Adalia decempunctata. When the ladybirds are molested they emit droplets of a repellant yellow fluid. Adalinine 64 co-occurs in this fluid with the homotro- pane alkaloid 63 and a reasonable mechanism can be drawn as shown in Scheme 12 which suggests that adalinine 64 is H roT "";----\ 63 64 Scheme 12 derived from 63 in vivo.The biosynthetic origin of the homotropane skeleton 63 is unknown but it is relatively wide spread and occurs for example among the alkaloids of the Mexican bean beetle Epilachna varivestis. l7 Several formal total syntheses of the cytotoxic marine alkaloid amphimedine 65 isolated59 from a sponge of the Amphimedon sp. are 0 65 reported.5c58 These syntheses developed new routes to inter- mediates from a much earlier total synthesis by Prager et a1.60 5 Piperidine alkaloids Piperdarine 66 has been identified6' for the first time in chloroform extracts of Piper tuberculatum and co-occurs with the related piperidine amide alkaloids 67 and 68 as well as the 0 0 68 hydropyridones 61 and 62 discussed above.( -)-Coniine 71 has been synthesised by Comins and co-workers62 in a stereo- selective manner as shown in Scheme 13. The route starts by OMe 0 C02R* C02R' 69 R* = (-)-8-Phenylmenthyl i H i-r 71 Scheme 13 treatment of the chiral pyridinium salt 69 with an aliphatic Grignard reagent to generate 70 as the predominant dia- stereoisomer. This in due course gave ( -)-coniine 71 in homo- chiral form. The same general strategy63 was applied to a synthesis of solenposin-A 73 a 2,6-disubstituted piperidine. The second alkyl group in this case was introduced by direct deprotonation and alkylation of the monosubstituted piperi- dine 72 as shown in Scheme 14.The piperidine (+)-sedridine 77 an alkaloid of Serum acre has been ~ynthesised~~ in a stereoselective manner as summarised in Scheme 15. The key 641 O'Hagan Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids OMe COpR* Boc H 69 72 73 Scheme 14 Q -0 74 + -%;,,:. WHH M e -0I ,-. 'pTol 0 'pTol 'Me 76 77 Me 75 Scheme 15 asymmetric step involved the cycloaddition of nitrone 74 and the homochiral sulfoxide 75 to generate the isoxazolidine 76. Reductive cleavage of 76 followed by reductive removal of the pendant auxiliary generated 77 in enantiomerically pure form. By a similar synthetic strategy the absolute configuration of (+)-8-ethylnorlobelol-I 78 has been reassigned6' as 2S,8S.u HH 78 PMBN &C02Me I Ts 79 I ' OH PMBN &C02Me Ts I ?\,,o 0 HN Me I IH Ts H 80 77 Scheme 16 (+)-Sedridine 77 has also been prepared66 by the route out- lined in Scheme 16. The key asymmetric step involved an (R)-(BINAP)RuCI mediated reduction of ketone 79. The piperidine ring system was generated by heterocyclisation of the 1,3-cyclic sulfate 80. Comins and Hong have explored67 the reaction of metal enolates with the chiral pyridinium salt 81 and using this methodology have executed a stereoselective synthesis of (-)-sedamine 83. The route is summarised in 642 Natural Product Reports 1997 OMe 0-Zn 0 81 82 83 R" = (-) trans-2-(a-Cum y1)cyclohexanol (TCC ) Scheme 17 Scheme 17 where the first and key step involved treatment of 81 with the zinc enolate of phenyl methyl ketone to generate 82 (90% de).The piperidine alkaloid 85 was isolated68 from the Strepto-myces sp. S20846 and has been given the rather bland code SS20846A 85. Its structure has attracted attention and it has been the subject of a total ~ynthesis,~' as summarised in Scheme 18. The key step involved cycloaddition of the 84 II 0 JJ PMP OH OH 85 Scheme 18 p-methoxyaniline imine of the homochiral iron-tricarbonyl aldehyde 84 with the Danishefsky diene. Subsequent manipu- lations allowed access to 85. On the basis of this synthesis the absolute configuration of SS20846A 85 is assigned 2S,4S as shown in Scheme 18.The pseudodistomins A 86 and B 87 were isolated7' from the Okinawan tunicate Pseudodistomo kanoko and are apparently the first piperidine alkaloids identified from a marine source. Total synthesis of 86 and 8771has established that the double bond geometry and location were incorrectly assigned in the first place. This was further confirmed after degradation A H 86 4 H 87 \\\ H 88 analysis of fresh compound from a source.72 The consensus structures for 86 and 87 are now as shown. A third member of this family pseudodistomins C 88 has been isolated73 from the )I same tunicate and intriguingly the stereochemistry at C-4 and + H~NOAC+ +CgHigCHO C-5 of the piperidine ring of 88 is opposite to that of 86 and 87. MeOH I Confirmation of this observation was made by total synthesis74 of 88.A general and very straightforward method has been developed75 for the synthesis of 2,6-disubstituted piperidines. Reaction of an a$-unsaturated ketone an aldehyde and an amine (including ammonia) affords the 2,6-dialkyl-3-oxo skeleton e.g. 89 in Scheme 19. The stereoselective reduction cis>>trans 90 of the ketone with sodium borohydride gave the racemate 89 of piperidine 241D 90 the (+)-enantiomer of which is a Scheme 19 Dendronatid frog alkaloid. A biosynthetic on pinidine 92 in Ponderosa pine (Pinus ponderosa) seeds has demon- strated that racemic ~is-[lO-'~C]pinidinone 91 is efficiently Q..A-Q..x incorporated into pinidine 92. A series of other alkaloids are co-produced with pinidine in the germinating seeds and the conversions indicated in Scheme 20 represent their tentative biosynthetic relationships.( -)-Pinidine 92 has been syn-117 the~ised~~ by an asymmetric enolisation of the bicyclic ketone 93 followed by Simmons-Smith cyclopropanation of the resultant silylenol ether 94 to generate 95 as the predominant product with the methyl group em as illustrated in Scheme 21. 91 I3C label Oxidative cleavage of the cyclopropane then generated the I (E) double bond with a relatively straightforward series of n subsequent conversions to make ( -)-pinidine 92. Oppolzer re~iewed~~.~~ the methods he had developed for the synthesis of piperidine and pyrrolidine alkaloids (Scheme H 92 22) by the asymmetric synthesis of nitrones 96 and their stereoselective reduction.The general strategy is illustrated by Scheme 20 the synthesis'" of (-)-phidine 92 in Scheme 23 where the N-acylated chiral sultam 97 undergoes an electrophilic Go GOTMs-NaH a-hydroxyamination with 1-chloro- 1 -nitrosocyclohexane 98 TMSCI ~ to generate nitrone 99 as a single stereoisomer. Stereo-N selective reduction and subsequent transformation provide an I homochiral N I ' elegant route to ( -)-pinidine 92. The 2,6-dialkyl piperidines Ts base Ts Ts H >Me solenopsin A 73 B 103 and C 104 are alkaloids of the fire 93 94 95 ant SoZenopsis invicta and they have been prepared" in enantiomerically pure form from the 1,5-diols 100 101 and 102 respectively as summarised in Scheme 24.The stereo- chemistry of andrachamine 105 an alkaloid of the shrub Andrachne aspera from Karachi,82 has been reassignedg3 as shown after a synthesis. It is a meso compound and the new 92 assignment has corrected the absolute configuration at C-6 Ts Scheme 21 and C-8. (-)-Pinidine n H (-)-Allosedamine /' (-)-Coniine R r 2 I' N 0 0-H (-)-Solenopsine-A v-.dNk (-)-2-Heptylpyrrolidine H (-)-Soienopsis fugax venom Scheme 22 O'Hagan Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids 643 COSEt bo I OH 97 0 107 1 n n n 0 OH 0 0- 92 99 Scheme 23 OH OMS OMS R BnNH21 105 (+)-Himbacin 108 is a 2,6-disubstituted piperidine alkaloid which was isolated from the Australian pine Galbulimima baccata and displays potent muscarinic antagonist activity.It has been the subject of two total synthese~.~~~~~ The firsts4 was a 20 step synthesis. The key framework assembly step involved an intramolecular Diels-Alder cycloaddition to generate the tricyclic fused ring system as shown in Scheme 25. The final step involved methylation of 108 to generate (+)-himbeline 109 a related alkaloid. The second synthesiss5 (Scheme 26) also involved an intramolecular Diels-Alder cycloaddition. Ester 110 contains the latent carbon framework and the functional groups of himbacin 108. The cycloaddition followed by base epimerisation delivered 111 as a single stereoisomer which was then manipulated through to the target alkaloid 108.The first total synthesis of iso-6-cassine 112 has been executed86 and a total synthesis of micropine 116 an alkaloid isolated from the leaves of Microcos philippinensis has been rep~rted.'~ This latter synthesis relied on a Grignard addition to the aldehyde 113 as shown in Scheme 27. Poor diastereo- selectivity in this reaction was circumvented by oxidation and a stereoselective reduction of the resultant ketone to alcohol 114 with Zn(BH,),. Mercury(I1)-catalysed cyclisation of 114 generated the piperidine 115 which was then taken through to 116. Piperidine ring cyclisation was not stereoselective and thus the correct acetonide protected diastereoisomer had to be separated. A total synthesis" of ( -)-sedacryptine 120 has allowed the absolute stereochemistry of the alkaloid to be assigned as shown.The route summarised in Scheme 28 involved an elegant double intramolecular conjugate addition 644 Natural Product Reports 1997 do 0 108 R=H 109 R=Me Scheme 25 H' OBOc H' pB0 -108 0 110 111 Scheme 26 {.. N H1. 0 112 OH CHO i RMgBr ii Swern iii Zn(BH& B$J 113 114 I Boc 115 116 Scheme 27 I 0 I S02Ph 117 O\pNNMeOH Ph 120 S02Ph 32% 118 + TBso$N~o FPh S02Ph 45% 119 Scheme 28 1 H30’ of the key intermediate 117 to generate 118 and 119. Stereo-OH HO isomer 118 was then taken through to ( -)-sedacryptine 120. Polyhydroxylated piperidines (aza sugars) are potent and HO specific inhibitors of glycosidase enzymes.For example H (+)-nojirimycin 121 is the analogue of D-glucose 122 and (-)-121 i RedAl ii Ac20 Pyr H HO.. HO (-)-123 Scheme 29 (+)-121 122 0 H 126 127 ‘OhoH OH HO& Ho H HO (+)-123 124 ( -)-mannojirimycin 123 is the analogue of D-mannose 124 where NH replaces the ring oxygen in each case. Both of these aza sugars have attracted considerable synthetic interest. Dondoni et a1.89have developed methodology which uses the thiazole ketone 125 as a key intermediate to the aza sugars. Scheme 29 illustrates a route to the unnatural enantiomer of nojirimycin ( -)-121 and by controlling the facial selectivity of reduction of ketone 125 the route was used to prepare the unnatural enantiomer of mannojirimycin ( -)-123.The natu- ral products mannonolactam 126 and deoxymannojirimycin 127 compounds which are a-mannosidase inhibitors have also been the subject of total ~yntheses,~~ in racemic form. Two recent syntheses” .92 of (+)-galactostatin 130 the D-galactose aza sugar analogue have been reported. The first,” sum-marised in Scheme 30 used the readily available natural polyhydroxylated cyclohexane L-quebrachitol 128 as a start- i OH 128 4-0 OMe 4-0 ing material. Nitrogen was introduced by stereo- and regio- OH selective epoxide ring opening with azide and a regioselective Baeyer-Villiger oxidation was used to cleave the cyclohexane ring system. Dondoni and Perroneg2 have applied the thiazole methodology discussed above in their route to (+)-galactostatin 130.In this case the fully protected thiazole intermediate 131 was selectively deprotected to generate alde- hyde 132 and then SO was used to release the galactostatin 1 29 Scheme 30 HHO o k H 130 o H O’Hagan Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids 645 131 132 OH OH HO.,I/COH HO,,&OH 130 129 Scheme 31 bisulfite adduct 129 also a known natural product.93 This compound was readily converted to (+)-galactostatin 130 as shown in Scheme 31. The alkaloids ( -)-magellanine 136 and (+)-megallaninone 137 were isolated in the mid to late 1970s from various species of the club moss Lycopodium. A number of years elapsed and then two total synthese~~~?~' of these alkaloids were communi- cated within two months of each other.The first was by Overmann and co-~orkers~~ in 1993 and is outlined in Scheme 32. The key step involved a Prins-pinacol rearrangement of acetal 133 to generate the fused tetracyclic ring system 134. Et& - \\-(OMe OMe 133 -H -H gH OMe OMe H H OH I EA@io2Et - S II tt OMOM OMOM O& OMOM t- . 'OH 'H 'H MeN MeN 136 137 Scheme 33 PhOCOCI,TiCI4 mo a. Pri2NEt * Q 134 'f" \ Me & OH A0 H H H 136 137 Scheme 32 Oxidative cleavage of the olefin followed by double reductive amination furnished 135 with the requisite piperidinium ring The second synthesis by Paquette and co-w~rkers~~,~~ is sum- marised in Scheme 33.A strategic and elegant double Michael reaction set the necessary carbon framework for further elbo- ration. Sandham and Meyers have developed97 an alternative approach illustrated in Scheme 34 to the Lycopodium alkaloid framework. Activation of the pyridine 138 to intramolecular 646 Natural Product Reports 1997 138 I Ph02C 139 nucleophilic attack gave 139. Subsequent manipulation afforded 140 which possesses the desired alkaloid skeleton. 6 Spiropiperidine alkaloids The spiropiperidines represent a small but structurally inter- esting class of alkaloids many of which occur in nature as racemates. ( -)-Nitramhe 143 (+)-isonitramine 144 and ( -)-sibirine 145 have however been isolated as homochiral H H compounds from various Nitrariu plants and this has stimu- lated several enantioselective syntheses'T2 of these compounds.For example,98 in Scheme 35 the P-hydroxy ester 141 was 0.1P u .,Si n,Si< OH 0 Li-0 0 N O,*'OEt 142hBr * 141 N-Si' OH 0 (-)-143 142 &/" (+)-144 R = H (+)-145 R = Me Scheme 35 alkylated with the protected amine 142 in a stereoselective manner which set the spiro-centre and framework for further elaboration to ( -)-143 (+)-144 and (+)-145. These three spiropiperidines have also been prepared99 by an alternative asymmetric route. The general strategy is shown for ( -)-144 and ( -)-145 in Scheme 36. The synthesis starts with a radical 1 46 1 47 1 I t OH 04 $3 (-)-144 R = H (-)-145 R = Me Scheme 36 cyclisation of the homochiral bromo acetal 146 to generate the spiro-centre in 147.Nucleophilic attack of the resultant hemi- acetal by 1,3-dithiane introduced a further carbon atom into the framework and subsequent manipulation allowed ( -)-sibirine 145 to be prepared via ( -)-isonitramine 144. 148 &-HH -;? H+ Cyclohexane ring inversion 1 HN 1 149 Scheme 37 strated experimentally. ''I The achiral bis-imine 148 was syn- thesised and heating of this compound in buffered aqueous solution generated nitraramine 149 as the sole isomer. A sequence of events rationalising this observation is shown in Scheme 37. The authors highlight that nitraramine 149 is isolated as a racemate and suggest a similar biosynthetic pathway with a nonenzymatic cyclisation of 148 to 149 oper-ating in vivo.The isomer 1-epinitraramine 150 was recently isolated'02 from Natruriu billardieri. 150 7 Azepine alkaloids The bengamides are a series of capralactams isolated from a Fijian Choristid sponge and they continue to be the focus of synthetic efforts. The synthetic challenge lies in the proper execution of the stereocontrolled construction of their side chains. Bengamide B 151 has been the subject of a lengthy total ~ynthesis''~from the natural product L-quebrachitol and two syntheses of (+)-bengamide E 154 have been reported. The end of Mukai and co-workers route'04~'05 to (+)-bengamide E OH OMe 0 &;-Nitraramine 149 isolated"' from Nitrariu schoberi is a struc- OH OH 0 turally more complex alkaloid than the spiropiperidines ( -)-143 (+)-144 and ( -)-145.A biosynthetic hypothesis for nitraramine 149 has been proposed and elegantly demon- 151 O'Hagan Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids }-ow;e OBn 152 II 0 1HzN-cY 153 I 154 Scheme 38 154 is shown in Scheme 38 where the acetyleneic p-lactone 152 has been assembled. Treatment of 152 with (S)-2-amino- caprolactam 153 followed by stereoselective reduction of the acetylene generated 154. Marshall and Luke have pre- paredlo6 (+)-bengamide E 154 from the y-lactone intermediate 155 shown in Scheme 39 followed by ring opening with (S)-2-aminocaprolactam 156."OMe 156 .1 OH OMe -* 154 --..-.-.-'-lr"$r MOM0 OBn 0 Scheme 39 8 Tropane and related alkaloids Asymmetric deprotonation of tropinone 157 with chiral lithium amide bases has proved to be a particularly effect- ive strategy for the enantioselective synthesis of a range of tropane alkaloids. For example 159 en?-darlingine 160 and (+)-enhydroecgonine 161 are among a range of alkaloids which have been preparedIo7 by acylation or aldol conden- sation of the chiral enolate 158 (95% ee) of tropinone 157 with appropriate electrophiles (Scheme 40). When the chiral enolate 158 is treated in the presence of ethyl chloroformate then ring opening of the tropane framework to 162 is the predomi- nant reaction'" as illustrated in Scheme 41.This strategy allows new entries into tropane targets and the potential of the methodology is demonstrated by the synthesis of ( -)-7~-acetoxy-3a-tigloyloxytropane164 via 7P-acetoxy-tropinone 163 summarised in Scheme 42. (+)-Ferruginine 168 has been synthe~ised''~ by the [6n:+2n:] cycloaddition of the azepine chromium tricarbonyl complex 165 and the homochi- 648 Natural Product Reports 1997 Q- 157 158 159 161 (+)-Anhydroecgonine 160 ent-Darlingine Scheme 40 OLi 0 0 II MeN I 158 ROAO 162 Scheme 41 0 OAc 0 I -g 162 - - MeNQ OAOR 0 AcO 163 Scheme 42 C02Me )*R* I 165 166 167 >98% de Ti(ONO& 1 Me 0 OMe 168 Scheme 43 ral acrylate 166 as shown in Scheme 43.Ring contraction of the product 167 (98% de) and further straightforward manipu- lations delivered (+)-ferruginine 168. rnetu-Hydroxycocaine 169 and rneta-hydroxybenzoylecgonine170 both metabolites of cocaine have been prepared"' in a straightforward manner for toxicology studies as much of the effect of the alkaloid is attributed to such metabolites. The polyhydroxylated nortropane alkaloids typified by the calystegines A 171 B 172 and B 173 have relatively recently come to the fore."' They are natural products from Solonaceae plants (including potato leaves and tubers) and are somewhat unusual in that they contain an animal 0 169 R=Me 170 R=H 171 172 173 H:*o*oH HO-OH 174 functionality. These alkaloids possess P-glucosidase and P-galactosidase activities similar to the aza sugars such as nojirimycin 121.Another member of the family 3-0-p-D-glucopyranosyl(ca1ystegineB,) 174 which possesses the calys- tegine B aglycone 172 has recently been isolated''2 from Nicandra physalodes and calystegine B 173 has been ident- ified"' in the seeds of the Australian weir vine Ipomoea sp. co-occurring with indolizidine alkaloids. A total synthesis' l4 of (-)-calystegine A 171 has been executed and the two key intermediates 175 and 176 are shown in Scheme 44. The HNZ HNZ 175 176 i HP. Pd(OH)2 ii H30+ iii NaOH NH HO I " 171 Scheme 44 pseudosymmetric alcohol 176 was generated in high optical purity by lipase mediated acetylation of the meso diol.Two total syntheses"5,'16 of calystegine B 173 have been reported. The first"' prepared both enantiomers from D-glucose as a starting material. The second' l6 involved the cycloaddition of the protected diene 177 with benzyl 2-nitrosoacetate 178 to introduce an N and 0 functionality in 179 with the desired syn stereochemistry. Further straightforward transformations generated 173 as shown in Scheme 45. ( -)-(9-Physoperuvine 182 is a tropine aminal alkaloid isolated from Physalis peruviana. It has been elegantly pre- pared' l7 by desymmetrisation of olefin 180 after treatment with a chiral rhodium(r) BINAP catalyst to generate the protected hydroxy ketone 181. Conversion of the hydroxy group to an amine and ring closure to the aminal gener- ated (-)-(a-physoperuvine 182 as shown in Scheme 46.A racemic synthesis of physoperuvine 182 has also been BnO' Ph' OBn 177 178 179 I 0 NH Hfi-Bn3J2 TBSO Ho OH BnO HNZ 173 J Scheme 45 OTBDMS OTBDMS OTBDMS 0-3 OTBDMS 0181 180 OTBDMS 11 MeNBz P-0 1 82 0 Scheme 46 reported' which took advantage of a nitroso cycloaddition with cyclohepta- 1,3-diene to generate 183. Reduction and cyclisation led then to the natural product as shown in Scheme 47. 0 ills HNR t -:1) 182 HNMe Scheme 47 Anatoxin-a 184 is a neurotoxin secreted by the cyanobacte- rium AnabaenaJEos-aquae.The structure of anatoxin-a 184 was reported in 1977'19 and its potent biological activity and interesting 9-azabicyclo[4.2.llnonane ring system have ren-dered it an attractive synthetic target. There has been much synthetic activity focused on this alkaloid since its isolation and an excellent and comprehensive review'20 covering all the literature throughout 1995 has recently been published. Two conflicting on the biosynthesis of anatoxin-a 649 O'Hagan Pyrrole pyrrolidine pyridine piperidine azepine and tropane alkaloids HN 0 184 3 x COz /I H02C I H 184 185 Scheme 48 184 have been reported. In the first121 the incorporations of ~-[U-'~C]arginine and [1,4-'4C]putrescine ~-[U-'~C]ornithine into anatoxin-a in Anabaena JEos-aquae appeared consistent with classic tropane alkaloid assembly. 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ISSN:0265-0568    

DOI:10.1039/NP9971400637

出版商:RSC    

年代:1997

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Pyrrolizidine alkaloids J. Richard Liddell I2 Merryweather Estate Ringwood Hampshire UK BH24 I UL Covering July 1995 to June 1996 Previous review 1996 13 187 Synthesis of necines Synthesis of necic acids Alkaloids of the Asteraceae (Compositae) Alkaloids of the Boraginaceae Alkaloids of the Ranunculaceae Alkaloids from animals General studies Pharmacological and biological studies References 1 Synthesis of necines The use of chiral dirhodium(I1) carboxamidates for the highly diastereoselective and regioselective synthesis of (-)-heliotridane 6 has been demonstrated by Doyle and Kalinin (Scheme I).' Pyrrolidinone 1 was converted via 2 to 1 2 v/ Me / H Me t-+ 0 0 6 4 5 Scheme 1 Reagents i TsCI NEt,; ii Me,CuLi; iii LiAIH,; iv succinimidyl diazoacetate NEt,; v Rh2(4S-MACIM),; vi LiAlH, then isolation and recrystallisation of picrate 1-(2-diazoacetyl)-5-ethylpyrrolidin-2-one3.The key reaction is the cyclisation in the presence of catalytic amounts of dirhodium(I1) tetrakis[methyl 1-acetylimidazolidin-2-one-(4S)-carboxylate] Rh2(4S-MACIM), of 1-(2-diazoacety1)-5- ethylpyrrolidin-2-one 3 to give the pyrrolizidinone 4 in high yield and 92% diastereomeric excess. The use of non- chiral catalysts resulted in markedly lower yields and the formation of 5 as the major product. Finally heliotridane 6 was obtained from 4 by reduction. Using a similar approach the pyrrolidine methyl ether 7 was converted into (1S,8S)-1-hydroxypyrrolizidin-3-one 8. Pyrrolam A 14 previously isolated from Streptomyes olivaceus,2 has been synthesised using samarium diiodide mediated cyclisation as the key step (Scheme 2).3 Prolinol Liddell Pyrrolizidine alkaloids -n..p N O..COOH H H 9 10 Iii Iiv 1 Ph Scheme 2 Reagents i LiAlH,; ii 3-phenylpropiolic acid 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide NEt,; iii NBS Ph,P; iv HMPA 0.1 M SmI, THF 0 "C; v 0, Me,S; vi Tf,O Pr',NEt; vii Pd(Ph3P), LiCl Bu,SnH 10 obtained from D-proline 9 was condensed with 3-phenylpropiolic acid in the presence of 1-ethyl-3-(3-dimethyl-aminopropy1)carbodiimide to give alkyne 11 which on bromination afforded the key bromide 12.Intramolecular ring closure of 12 in the presence of samarium diiodide under optimised conditions provided 13 in high yield.Lactam 13 was converted into pyrrolam A 14 by ozonolysis trifluoro- methanesulfonylation of the enol form of the resultant diketone and finally reductive removal of the introduced trifluoromethanesulfonate group. A stereocontrolled synthesis of (+)-hastanecine 20 has been reported by Pilli and Russowsky which involved the reaction of a chiral boron enolate with an N-acyliminium ion (Scheme 3>. The racemic succinimide 15 was stereoselectively reduced and acetylated to yield 16. In situ formation of the required N-acyliminium ion from 16 and reaction with the boron enolate of 17 provided (-)-18 as a single stereoisomer. This on removal of the chiral auxiliary silylation and reduc- tion gave 19 which was cyclised and then deprotected to give (+)-hastanecine 20.Li and Marks have demonstrated the use of organo-samarium reagents to catalyse highly regiospecific bicyclis- ations of amino dialkenes amino dialkynes and amino enynes to produce pyrrolizidines (and indolizidines) in good to excel- lent yield.5 For example substrates 21 and 23 were converted into 22 and 24 respectively. A possible pathway for the catalytic process has been proposed. A route to the construction of bridged pyrrolizidines such as stemofoline 25 has been reported by Kercher and Livinghouse (Scheme 4).6The amine 26 was converted into the imine 27 which in the presence of titanium tetrachloride underwent a sequential stereoselective allylsilane-imine cyclisation-lactamisation to provide pyrrolizidinone 28 as a single diastereomer.Treatment of 28 with Lawesson's reagent followed by triethyloxonium tetrafluoroborate effected a second desilylationxyclisation and gave the bridged tricyclic pyrrolizidine 29 in excellent overall yield. n /SiMe2 TBDMSO Acq 01 6h iPh 18 Ph 'Ph 19 viii ix /OH 20 Scheme 3 Reagents i NaBH, EtOH -23 "C; ii aq. HC1; iii Ac,O; iv Bu",BOTf Pr',NEt CH,Cl, 0 "C; v LiBH, THF; vi TBDMSiOTf 2,6-lutidine CH,Cl,; vii BH,-Me,& THF; viii H, Pd(OH), EtOAc then Ph,P NEt, CH,CN; ix HF CH,CN 21 22 23 24 0 25 The use of a-amino acids as precursors for pyrrolidine and pyrrolizidine synthesis has been developed further by Chiacchio et al.' Initial approaches to the key aldehyde 31 from L-proline resulted in a racemic mixture but a modified approach from ester 30 gave homochiral material (Scheme 5).Treatment of 31 with N-methylhydroxylamine gave nitrone 32 which spontaneously cyclised to (+)-33. This on reduction gave either pyrrolizidinone 34 or pyrrolizidine 35 depending on the reagents used. Replacing proline by a non-cyclic amino acid also provided access to the analogous pyrrolidine compounds. Murray and co-workers have reported further details of their work on N-acyl anion cyclisations,' Using their meth- odology amide 36 was cyclised reduced and the resultant epimeric mixture of pyrrolizidinones reacted with methane- 26 27 1 ii wg--og---iii iv Me2Si 29 28 Scheme 4 Reagents i THF 4 8,mol.sieve ethyl levulinate 12 h rt; ii TiCl (1 equiv.) CH,Cl, -78 "C to rt; then aq. KHCO, inverse addition; iii Lawesson's reagent (0.55 equiv.) Pr',NEt (0.25 equiv.) toluene rt; iv Et,O+BF,- CH,CN 0 "C to rt Me W O M e -i HO 0 30 32 Me Me Me ,./ Scheme 5 Reagents i cinnamoyl chloride NEt, CH,Cl,; ii DIBAL toluene -78 "C; iii MeNHOH-HCl NEt, EtOH reflux; iv Zn AcOH 70 "C; v LiAlH iv v i H 0 39 Scheme 6 Reagents 1 LHMDS over 0.5 h THF -78 "C 2.5 h; ii NaBH, EtOH 24 h; iii MsCl NEt, CH,CI, 0 "C 2 h rt 3 h; iv DBU CHCl, rt 2.5 h; v H, Pd/C EtOH rt sulfonyl chloride to give 37 and 38 in 3:l ratio and 98.9% ee (Scheme 6). Separation of the major isomer treatment with diazabicyclo[5.4.0]undecene(DBU) and then catalytic hydro- genation afforded (2R,8S)-2-methylpyrrolizidin-3-one39.Using a cycloaddition strategy platynecine 45 has been synthesised in four steps by Correia et al. (Scheme 7)." The [2+2]cycloaddition reaction of ene carbamate 40 with ketene 41 (prepared in situ from 4-chlorobutyryl chloride) gave 42 as a 2:1 mixture of endo:exo isomers. Baeyer-Villiger oxidation of the isomers provided the y-lactones 43a,b again in a 2:l endo:exo ratio. On hydrogenolysis of the mixed lactones 43a gave the hydrochloride salt of the azatricyclic lactone 44 while 43b led to decomposition products. Reduction of 44 afforded 654 Natural Product Reports 1997 HH HH 0 $ Z CI 40 41 42 1 ii I CI 43a 43b 45 Scheme 7 Reagents i hexane reflux; ii MCPBA NaHCO, CH,Cl,; iii Pd(OH), H (20 psi) MeOH; iv LiAlH, THF reflux platynecine 45 in 20% overall yield.Using the same method- ology with a different ketene the authors also prepared the indolizidine 46. HO (OH IH a 46 Both enantiomers of dihydroxyheliotridane 55 and ( -)-platynecine 45 have been synthesised by Hashimura and co-workers." The key steps in the syntheses were the intra- molecular 1,3-dipolar cycloaddition reactions of the azo-methine ylides 48 and 49 generated from aziridine esters 47a,b in which the stereochemistry of the products 50 and 2,3-epi-50 (9:l ratio) or 51 and 2,3-epi-51 (3:l ratio) was controlled by the transition state conformations (Scheme 8). Partial reduction of 50 followed by a Horner-Emmons reaction gave bicyclic ester 52 stereoselectively which was then trans- formed to the tricyclic lactam 53 (Scheme 9).Deprotection of 53 followed by iodination elimination and hydrolysis provided the ketone 54 which was then acetylated subjected T I H OBn 'H BC02Et n 50 52 iii-v1 H H vi-ix- O 54 I x xi (-)-55 (+)-55 Scheme 9 Reagents i DIBAL-H THF -40°C; ii. (EtO),P(O)-CH,CO,Et NaH THF; iii H, Pd(OH),; iv LiOH aq. THF; v (PhO),P(O)N, NEt, DMF; vi EtSH BF,-OEt, CH,Cl,; vii I, Ph,P imidazole; viii DBU THF; ix 1% HCI; x Ac,O NEt, DMAP then urea-H,O, (CF,CO),O; xi LiAlH to Baeyer-Villiger oxidation and finally reduced to give ( -)-dihydroxyheliotridane 55. Using a generally similar approach the inseparable 3 1 mixture of 51 and 2,3-epi-51was elaborated into (+)-dihydroheliotridane 55 and ( -)-platynecine 45 respectively.A new route to the Geissman-Waiss lactone 60 a key intermediate in many pyrrolizidine alkaloid syntheses has been reported.I2 Dihydrofuran 56 was converted into the protected amine 57 and then cyclised by amido-mercuration followed by chloridation to provide 58 (Scheme 10). Removal of the mercury by iodination elimination to afford the enol ether 59 and finally hydration of the enol and oxidation of the resulting lactol afforded the Geissman-Waiss lactone 60 in 40% overall yield from 56. 2 Synthesis of necic acids Honda and co-workers have synthesised crobarbatic acid 67 and lactone 69 used in the synthesis of integerrinecic acid lactone 70.13 Starting from the cyclopentanone 61 the key intermediates 62 and 63 were synthesised in four steps (Scheme 1 1).Samarium diiodide-promoted cleavage of the major isomer 62 gave 64 in high yield. Removal of the H H '-/.B*oBn +*0 HO Bn 48 Bn 0 H 49 47a n=l 47b n=O 1 t HH H H HH H a:;;'^""" qroBn IH IH OBn + + cXFoBn IH Bn 0 Bn 0 Bn 0 Bn 0 50 2,3-epi-50 51 2,3-epi-51 Scheme 8 Reagents i diphenyl ether 260 "C ca. 5 min Liddell Pyrrolizidine alkaloids H H H (+)-fbcitronellol 71 using procedures established earlier l4 was converted into 73 subjected to Katsuki-Sharpless epoxi-dation and the alcohol oxidised via the aldehyde to the acid 56 57 ClHg Boc 58 vi-viii I Boc Boc 60 59 Scheme 10 Reagents i LiN,; ii LiAlH,; iii (Bu'O),C,O,; iv Hg(CF,COO),; v NaCl; vi I, CH,Cl,; vii NaI DMF 100 "C; viii Bu'OK THF; ix H,O H'; x TPAP i-iv -7 4--L$ -COOMe COOMe O ACOOH Ao&ZO&OH 0' 67 66 65 Scheme 11 Reagents i conc.HCl Bu,N+Br- MeCN rt; ii K,CO, MeI DMF rt; iii MeLi THF -78 "C; iv Et,SiOTf 2,6-lutidine CH,CI, rt; v SmI, THF-HMPA rt; vi Bu,N+F -,THF rt; vii 0, EtOH -78 'C then NaBH,; viii o-nitrophenyl selenocyanate Bu,P THF rt; ix MCPBA CH,Cl, 0 "C; x RuCI, NaIO, CH,CN-CC1,- H2O protecting group lactonisation ozonolysis and reduction afforded the alcohol 65 from which was obtained the alkene 66 and on oxidation (+)-crobarbatic acid 67. Similarly key intermediate 63 was converted into alkene 68 (Scheme 12). ,0SiEt3 YCOOMe 68 63 I i-iii 0~cooH=oQ& 69 70 Scheme 12 Reagents i DIBAL-H THF -78 "C; ii BuLi 2-trimethylsilyl-1,3-dithiane, THF -15 "C; iii PTSA CH,Cl, rt This on reduction ring expansion and oxidation provided lactone 69 which had previously been converted into integerrinecic acid lactone 70 by White et all4 Both 'cis' and 'trans' nemorensic acids 80 and 81 have been synthesised from citronellol and the stereochemistry of nemo- rensine 82 revised." The allylic alcohol 72 obtained from 656 Natural Product Reports 1997 74 (Scheme 13).Selective reduction of the epoxide protection I I SOHI Ref. 9 OH i ii OH ~ OMe 71 72 73 I vi-ix 1iii-v1PocooH \ 75 x-xii +OM 74 C02Me 1 I xiv xiv C02H C02H 80 81 Scheme 13 Reagents i PhSeC1 MeOH NaHCO,; ii H,O,; iii Ti(OPr'), ( -)-DITP Bu'OOH; iv (COCI), DMSO NEt,; v NaClO, NaH,PO, Me,C=CHMe; vi LiAlH, THF; vii CH,N,; viii TBDMSiOTf NEt,; ix 0, CH,CI, Me,S; x MeMgBr Et,O -78 "C; xi (COCI), DMSO NEt,; xii (EtO),P(O)CH,CO,Et KH THF; xiii Bu",N+F -,THF; xiv LiOH THF of the resultant alcohol and the acid functionalities followed by ozonolysis provided 75.A carefully controlled Grignard reaction followed by Swern oxidation and a Wadsworth- Emmons reaction afforded a 5.6:l mixture of the esters 76 and 77. After separation by chromatography 77 on deprotec-tion cyclised to a 4.5:l mixture of 78 and 79 which on hydrolysis provided the acids 80 and 81 respectively the stereochemistries of which were confirmed by NMR NOE experiments.Acid 80 was shown to be identical to the acid obtained from the hydrolysis of nemorensine 82 and this was confirmed by X-ray crystallographic analysis of nemorensine. A crobarbatine derivative 86 has been synthesised by Chou and Fang.I6 The available ketene dithioacetal 8317,l8 was protected as the benzyl ether converted into the activated carbonylimidazole 84 and then reacted with (+)-retronecine regioselectively to give 85 as a diastereomeric mixture (Scheme 14). Brief exposure to acid and cyclisation afforded a 1:l mixture of macrocycles 86 and 87. A correction for an editorial error in a reaction scheme given in an earlier review" has been published.20 eeo r' 82 i-iii -U 83 84 1 iv & 85 I v vi 86 87 Scheme 14 Reagents i NaH PhCH2Br THF reflux 4h; ii Bu'OK (8 equiv.) H20 (2 equiv.) THF 26 "C 30 min then HCI; iii CDI (1.1 equiv.) THF 26 "C 4 h; iv NaH (0.2 equiv.) retronecine THF 26"C 2h then aq.NH,Cl; v HCI CH,C12 26"C 30min; vi CF,COOAg (6 equiv.) DMAP (12 equiv.) THF reflux 40 h 3 Alkaloids of the Asteraceae (Compositae) The pyrrolizidine alkaloids isolated from species in the 1.21-31 Asteraceae are listed in Table The new alkaloids 88 89 OA&O N+ \ I 0-88 89 6-J r fi O&OAC 0 COOH \ and 91 are indicated with an asterisk. Mulgediifoline 88 and oxyretroisosenine 89 are 13-membered macrocycles and their absolute stereochemistries were determined unambiguously along with those of cis-nemorensic acid 90 and retroisosenine.7-Angelyl-9-acetylretronecine 91 is the only new acyclic diester. Benn and co-workers have isolated the methylene pyrrolizidine 92 and its N-oxide from Senecio schweinf~rthii.~~ This is the second reported occurrence of methylene pyrrolizi- dines from Senecio species. A summary has been given of the alkaloids previously isolated from six Senecio species growing in Turkey. In all nineteen alkaloids were identified.28 Gas chromatographic analysis of teas and drug preparations of coltsfoot (Tussilago farfara) have shown the presence of the toxic alkaloids senecionine and senkirkine. Also present were the non-toxic alkaloids tussilagine and isot~ssilagine.~~ An analysis of the alkaloid content of flowers of Senecio vulgaris subjected to water and nutrient deficiencies revealed little change in the amounts of alkaloids present in the flowers.Under favorable growing conditions however the plants produced a greater number of flowers and were therefore potentially more 4 Alkaloids of the Boraginaceae Investigation of Echium humile has shown it to contain numerous alkaloids eight of which were positively identified.33 Three of these are new namely pycnanthine 93 echihumiline 94 and its N-oxide and one is the tetrahydroisoquinoline alkaloid carnegine 95 which has not previously been reported from the Boraginaceae. Helibracteatinine 96 and helibrac- teatine 97 are new and have been isolated from Heliotropium HO -/ OH 0 -N-93 94 MeO-N' 95 96 97 98 bra~teatum.~~ Their structures were determined by chemical and spectroscopic methods.The same group has also reported another new alkaloid heliscabine 98 which was obtained from Heliotropium scabrum along with the known retr~necine.~' Heliotropium arborescens which is used medicinally in South America and Europe has been shown to contain the toxic alkaloids indicine and its 3'-a~etate.~~ These findings highlight once again the doubtful safety of many medicinally used plants. A new study of Cynoglossum creticum has revealed a different distribution of alkaloids to those found previo~sly.~'-~~ In all 13 alkaloids were detected of which COOH the major ones were 3'-acetylrinderine 3'-acetylechinatine 90 91 92 3'-acetylheliosupine and heliosupine.Investigation of Liddell Pyrrolizidine alkaloids Table 1 Pyrrolizidine alkaloids in the Asteraceae Species Pyrrolizidine alkaloids Ref. Senecio mulgedifolius *Mulgediifoline 88 *isoretroisosenine 89 retroisosenine bulgarsenine 21 S. triangularis Hook *7-Angelyl-9-acetylretronecine 91 7-angelylretronecine 9-angelylretronecine 22 7-angel yl-9-senecio ylretronecine S. pseudaureus Rydb. Retrorsine senecionine 22 S. streptanthifolius Greene Retrorsine senecionine 22 (=S. cymbalorioides Nutt.) S. jacalensis Senecionine platyphylline 23 S. callosus Rosmarinine 23 S. schweinfurthii 0.Hoffm. 7 P-Hydroxy- 1-methylene-8a-pyrrolizidine N-oxide 7 P-hydroxy- 1-methylene-8a-pyrrolizidine 24 S. linifolius Rosmarinine rosmarinine-2-acetate 25 S.pterophorus Rosmarinine isorosmarinine senecionine seneciphylline acetylseneciphylline spartioidine 25 acetylspartioidine S. chrysocoma 7-Angelylhastanecine 9-angelylhastanecine 9-angelylplatynecine neosarracine sarracine 26,27 7P-angelyl-1-methylene-8a-pyrrolizidine 7a-angely l-1-methylene-8a-pyrrolizidine a-angelyl-1-methylene-8a-pyrrolizidine N-oxide S. ayuuticus spp. erratcus Retronecine retrorsine riddelline seneciphylline 28 S. integrifolius spp. aucherii Aucherine integerrimine retronecine retrorsine senecionine seneciphylline senkirkine 28 S. othonnae Othonnine platyphylline retronecine retrorsine riddelline 28 S. pseudo-orientalis Jacoline platyphylline,retronecine retrorsine riddelline 28 S. racemosus 9-Angelylplatynecine dihydroretrorsine racemocine racemodine racernonine racemozine sarracine 28 senecioracenine S.vernalis Integerrimine retronecine retrorsine riddelline senecionine seneciphylline senkirkine 28 Eupatorium portoricense Urban Amabiline echinatine 12-0-acetylechinatine 29 Adenostyles alliariae Seneciphylline N-oxide 30 A. glabra Seneciphylline N-oxide 30 Tussilugo farfara Senecionine senkirkine tussilagine isotussilagine 31 *New alkaloids. Adenocarpus complicatus growing in Turkey found decortica- and use by insect^,^' alkaloids used in insect defense and sexual sine and norloline in the pods and seeds4' The biosynthesis of comm~nications,~~ and the multi-level complexity of alkaloid pyrrolizidines in Cynoglossum ofinale has been found to occur usage.53 in both the roots and shoots of the plant.Site differences in alkaloid production were observed as was the transportation of alkaloids from shoots to roots and from old leaves to 7 General studies shoot^.^' A study of the structural stabilities of retronecine and heliot- ridine using ab initio semi-empirical and molecular mechanical methods has been carried out and the results compared with 5 Alkaloids of the Ranunculaceae The known alkaloids senecionine and integerrimine have earlier data from X-ray crystal structure and 'H NMR In both molecules the exo conformers were the been isolated from Trollius laxus. This is the first report of most stable conformations and the theoretical results are pyrrolizidines in this genus.42 generally in good agreement with the physical data.The stereochemistries of pyrrolizidines 99 and 100 synthesised 6 Alkaloids from animals The distribution of autogenous and host-derived chemical defenses in a number of species of Oreina leaf beetles has been C02Et analysed. Variations both within and between species was & found to be diet dependent.43 Alkaloids isolated from Senecio Me RMe vulgaris have been shown to act as feeding deterrents for the larvae of the cotton leafworm Spodoptera littorali~.~~ The CN alkaloids present in 38 genera of Ithomiinae butterfies have 99 100 Ph been investigated by Trigo and co-worker~.~~ The same group has also published a more detailed report on the alkaloid acquisition and use pattern in three species of Ithomiin~e.~~ have been determined by X-ray crystallo-The role of the alkaloids present in the male sex pheromones of previ~usly,~~ The feeding graph^.^^ Analysis of the surface chemicals on the leaves of Idea leuconoe butterflies has been in~estigated.~~ behavior of loggerhead shrikes Lanius ludovicianus appears to four Senecio species failed to detect any alkaloids although a be unaffected by pyrrolizidines present in their prey.48 The number of amino acids were identified the proportions of A highly sensitive and specific large scale poisoning of pigs and poultry in South Australia in which differed ~ignificantly.~~ 1993 has been shown to have been due to contamination of method for the determination of retrorsine senecionine and The physiologi- integerrimine has been developed,58 and Cooper et al.have feed by seed from Heliotropium eur~paeum.~~ cal properties role and dietary sources of alkaloids found in reported the use of high speed counter-current chroma-frogs has been re~iewed,~' and a number of reviews dealing tography for the preparative separation of pyrrolizidines. 59 with various aspects of pyrrolizidine plant-insect interactions Editorial errors in some of the tables of a recent 'H NMR have been published. These include an overview of pyrrolizi- review6' have now been corrected.61 A general alkaloid review dine biosynthesis by plants and the subsequent sequestration (in Russian) has been published,62 and a mechanistic view of 658 Natural Product Reports 1997 the diversity and variability of secondary plant metabolism with particular reference to the pyrrolizidines has been presented.8 Pharmacological and biological studies Interest in the toxicology of pyrrolizidines remains high and two analytical techniques have been reported. These are a gas chromatographic method for the measurement of the hydrolysis rates of pyrrolizidines by guinea pig carboxyleste- rase GPH1,64 and a simple procedure for determining the aqueous half-lives of pyrrolic metabolite^.^^ Huxtable's group have continued to study the metabolic processes responsible for pyrrolizidine toxicity. Thus in isolated perfused liver monocrotaline has been shown to produce a 30-fold increase in the release of free and conjugated glutathione into the bile,66 and the mechanism whereby monocrotaline activates an increase in glutathione synthesis has been identified.67 High hepatic glutathione levels and lowered taurine levels have been observed on the administration of retrorsine.68 Differences in the metabolism of the alkaloids retrorsine senecionine trichodesmine and monocrotaline have been quantified and compared and the results used to account for the relative toxicities of the alkaloids.6' Administration of taurine has been shown to reduce the toxicity of monocrotaline but guanidinoethane sulfate (the amidino analog of taurine) was not benefi~ial.~' Based on physicochemical and metabolic studies the greater lethality and neurotoxicity of tricho-desmine 101 compared to monocrotaline 102 has been 101 102 attributed to trichodesmine being more lipophilic and more sterically hindered specifically at C-14.7' The characteristics of DNA-protein cross-links induced by pyrrolizidines have been investigated and the cross-linking potency of the alkaloids found to coincide with their known 73 The geno- toxic activity of a number of alkaloids from Senecio species has also been determined.74 A number of reviews have appeared 7 U.Chiacchio F. Casuscelli A. Corsaro V. Librando A. Rescifina R. Romeo and G. Romeo Tetrahedron 1995,51,5689. 8 A. Murray G. R. Proctor and P. J. Murray Tetrahedron 1996,52 3757. 9 J. R. Liddell Nut. Prod. Rep. 1996 13 187 and ref. 5 therein. 10 C. R.D.Correia A. R. de Faria and E. S. Carvalho Tetrahedron Lett. 1995,36,5109.11 K. Hashimura S. Tomita K. Hiroya and K. Ogasawara J. Chem. SOC. Chem. Commun. 1995 2291. 12 C. Paolucci F. Venturelli and A. Fava Tetrahedron Lett. 1995,36 8127. 3 T. Honda F. Ishikawa and S. Yamane J. Chem. SOC. Perkin Trans. 1 1996 1125. 4 J. D. White J. C. Amedio Jr. S. Gut S. Ohira and L. R. Jayasinghe J. Org. Chem. 1992 57 2270. 5 M. P. Dillon N. C. Lee F. Stappenbeck and J. D. White J. Chem. SOC.,Chem. Commun. 1995,1645. 6 W.-C. Chou and J.-M. Fang J. Org. Chem. 1996 61 1473. 7 J.-M. Fang Pure & Appl. Chem. 1996 68 581. 8 J.-M. Fang and B.-C. Hong J. Org. Chem. 1987,52,3162. 9 D. J. Robins Nut. Prod. Rep. 1993 10 487. 20 D. J. Robins Nut. Prod. Rep. 1994,11 121. 21 A. 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ISSN:0265-0568    

DOI:10.1039/NP9971400653

出版商:RSC    

年代:1997

数据来源: RSC