摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting U n iversi ty of Notti ng ham Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products. Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products.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 CB4 4WF England. 1992 Annual Subscription Price E.C. f222.00 Overseas f250.00 U.S.A. $474.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts. SG6 1 HN England. Air Freight and mailing in the U.S.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 1 1003. Second-Class postage paid at Jamaica NY 11 431 -9998. All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 1992 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 photQgraphic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge Subscription rates for 1992 E.C. f222.00 Overseas f250.00 U.S.A. US $474.00 Subscription rates for back issues are (1 987) (1 988) (1 989) (1 990) (1 991 ) U.K. f142.00 f159.00 f169.00 f177.00 f198.00 Overseas f159.00 f183.00 f194.00 f204.00 f228.00 U.S.A. US $280.00 US $342.00 US $388.00 US $398.00 US $467.00 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 CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP99209FX001

出版商:RSC    

年代:1992

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99209BX003

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

Pyrrole Pyrrolidine Piperidine Pyridine and Azepine Alkaloids A. R. Pinder Department of Chemistry University of Central Florida Orlando Florida 3287 6 USA Reviewing the literature published between July 1989 and June 1990 (Continuing the coverage of literature in Natural Product Reports 1990 Vol. 7 p. 447) 1 Pyrrole Alkaloids 2 Pyrrolidine Alkaloids 3 Piperidine Alkaloids 3.1 Bispiperidine Alkaloids 4 Pyridine Alkaloids 4.1 Azafluorene and Aza-anthracene Alkaloids 5 Azepine Alkaloids 6 References 1 Pyrrole Alkaloids OMe A new pyrrole alkaloid trikentramine has been isolated from the Senegalese sponge Trikentrion loeve. Its structure (1) has been arrived at by spectral study and X-ray diffraction analysis. The absolute configuration of the alkaloid which is dextro- rotatory remains to be sett1ed.l 0 OMe 2 Pyrrolidine Alkaloids A new alkaloidal growth inhibitor has been found in radish seedlings grown under artificial light.Infrared NMR and 0 electron-impact mass spectral studies revealed that it is E-3-methylthiomethylene-2-pyrrolidinethione (2).’. The aerial parts of Piper demeraranum contain the alkaloidal amide (3) formulated on spectral e~idence.~ A novel phenolic triamide (4) has been obtained from the bulbs of a Chinese lily Lilium regale. It forms a monoacetate and on alkaline hydrolysis affords p-coumaric and methylsuccinic acids and 1,4-diamino- (4) butane (putrescine). This behaviour along with extensive spectral study allows its f~rmuiation.~ A new imide palasimide is found in the pods of Butea monosperma an Indian plant.It has been identified as palasonine N-phenylimide (5) on spectral evidence and by spectral c~mparison.~ Interest in the chemistry of ant venoms continues. trans-2-Butyl-5-(8-nonen-1-yl)pyrrolidine (6) and trans-2-(5-hexen- 1-yl)-5-(8-nonen-1 -yl)pyrrolidine (7) have been isolated from Monomorium smithii,6 and a further five 2,5-disubstituted pyrrolidines of similar structures were found in the venom of M. indicum.’ A stereocontrolled organopalladium route to 2,5- dialkylpyrrolidines has been devised ; it is exemplified by its application to the synthesis of trans-2-n-butyl-5-n-heptylpyrro-lidine (8) the major component of M. latinode venom along with the cis-isomer (Scheme l).E Another synthesis of 2,5- dialkylpyrrolidines has been reported briefly.It uses an acyl nitronate as starting point and has been used to synthesize several ant venom component^.^ 18 NATURAL PRODUCT REPORTS 1992 n-C4Hg n-C4HgCrCH n-C7H15C=CH A H H AIBU~ n-C4Hg NHTs ~ (A) + (B) iv n-C7H15 n-C4H9vn-C7H15 n-C7H1 5 n-C4Hg& OAc OH vii viii NHTs 1 n-C4Hg --@n-C7H15 -.c ix x n-c4HgTn-C7H1 5 H OMS Reagents i DIBAL then I,; ii DIBAL; iii PdCl,(PPh,), catalytic am.; iv Pd(OAc) LiCl LiOAc benzoquinone AcOH pentane (chloroacetoxylation); v NaNHTs Cs,CO, DMF; vi NaOH MeOH H,O; vii H, PtO, MeOH; viii MsCi Et,N THF; ix K,CO, MeOH; x Na NH Scheme 1 (9) Shihunine (10) X=H (12) R' = R2 = OMe R3 = H (11) X=Br (13) R' = OMe R2R3 = OCH20 (14) R' = R2 = R3 = OMe (Piplartine) HoYo2Et -HO H COZEt H ii iii * BnOQ*-*.pmH H OH iv ).Q-..wBnO 0 v vi J Me02CGOBn -= ix M e O JG OBn = viii viioQ%mOBn - BnOQ*-=aH OBn (Bn = benzyl) (15) (+)-Conhydrine Reagents i Ref. 14 15; ii Na EtOH THF -20 "C 2h; iii PhCH,OH BF,-Et,O r.t. 15 h; iv K,CO, MeOH 0 "C 0.5 h; v Me,CuLi Et,O -5 "C 4h; vi NaH PhCH,Br DME r.t. 15 h; vii MCPBA BF -Et,O CH,Cl, r.t. 2 h then Et,N 0 "C 1.5 h; viii K,CO, MeOH 0 "C 2 h; ix HN Ph,P DEAD benzene r.t. 2 h; x; H, Pd-black MeOH then toluene 120 "C 15 h; xi LiAlH, THF,r.t. 0.5 h; xii H, 5 Oh Pd-C EtOH conc. HCl Scheme 2 NATURAL PRODUCT REPORTS 1992-A. R. PINDER 9Mel -2% LiI -Q,yh 0 1-Ph H*'* Ph Me H (16) (17) (18) Allosedamine S02Ph I ... SO,Ph I I1 I CH3 liii S02Ph I Bn V Bn H2 CI-(Bn = benzyl) (19) (-)-2,6-Lupetidine hydrochloride Reagents i Bu'Li (2.2 equiv.) THF 0 "C then HMPA .78 "C; ii qli -78 "C+r.t.; iii TsCl py 0 "C; iv BnNH, 85 "C; v Na/Hg EtOH r.t.; vi H, Pd(OH),-C MeOH r.t. then HCl Scheme 3 H (20) trans Solenopsin A (21) cis lsosolenopsinA fy"" (22) Micropine Three additional new syntheses of the spiro phthalide- pyrrolidine alkaloid shihunjne (9) have been described. Two start from phthalic anhydride and the third from phthalalde- hydic acid methyl ester.1° Vasicol an alkaloid of Peganurn harmala is to be formulated as (10) on the basis of an X-ray diffraction analysis of its 4-bromoderivative (1 3 Piperidine Alkaloids The Taiwanese creeping shrub Piper arborescens has been found to contain three cytotoxic pyridone alkaloids.All are N-cinnamoyl-A3-piperidin-2-oneq(12) (1 3) and (14). Their structures were revealed by spectral measurements ; the last proved to be identical with piplartine.12 An enantiospecific synthesis of natural (+)-conhydrine (1 5) starting from diethyl (S,S)-tartrate has been reported (Scheme 2).13 A simple steroespecific route to (f)-allosedamine (18) has been described; it involves a ring opening of the isoxazolidine (16) by conversion into its methiodide (17) and then treatment with lithium iodide. The ketone I-methyl-2-phenacylpiperidine is a by-product.16 (-)-2,6-Lupetidine (2R,6R-dimethyl-piperidine) (19) an alkaloid of Nanophyton erinaceurn has been synthesized stereoselectively from S-1,2-epoxypropane (Scheme 3)? Several new cis-and trans-2,6-dialkylpiperidineshave been isolated from ant venom from Monomoriurn delagoense.Their structures have been arrived at by spectral investigation and by synthesis from appropriate pyridines. They possess insecticidal and repellent properties.18 New syntheses of the racemic forms of solenopsin A (20) and isosolenopsin A (21) starting from 6-methyl-2-piperidone have been published. An easily separable mixture of the two was ~btained.'~. Micropine (22) is a major alkaloid of the leaves of the Philippine plant Microcos philippinensis. Its structure and configuration have been settled by careful mass and NMR spectral analysis.2o The structure and configuration earlier assigned to andrachamine (23) have been confirmed by a synthesis of its racemate using a nitrone cycloaddition reaction recently shown to be useful as a general route to trans-2,6- NATURAL PRODUCT REPORTS 1992 (on mixture) -..-I (23) And rachani ne Reagents i but-1-ene CHCl, 110 “C (only aldonitrone A reacts); ii Zn AcOH Scheme 4 (24) Lelobanonol ine Me Me dialkylpiperidines (Scheme 4). An authentic sample of the natural (-)-base was not available but the stereochemistry of the final racemic product (23) was secured by NMR spectral comparisons and by a knowledge of the steroechemical pathway of the sequence.21 The Chinese plant Lobeliu duvidii contains a new alkaloid lelobanonoline (24) formulated on spectral evidence., A synthesis of the two unnatural isomers (25) and (26) of the alkaloid tecomanine (the isotecomanines) has been described via a hydroboration-oxidation route under stereochemical The structure and configuration assigned to (-)-mearsine an alkaloid of the North Queensland plant Peripentadeniu rne~rsii,~~ has been corroborated by a stereospecific synthesis of the (+)-enantiomer (28) (Scheme 5).The starting material (-)5-methyl-2-cyclohexenone (27) was secured from (+)-pulegone by successive hydrolytic cleavage to (+)-3-methyl-cyclohexanone then brominationaehydrobromination.25 3.1 Bispiperidine Alkaloids From the leaves of Prosopis julifZora a Pakistani shrub two new alkaloids juliprosinine (29) and juliflorinine (30) have been isolated ;their structures and configurations have been deduced from spectral studies.However the molecular formula (C40H, N 0,)given for the former is not consistent with structure (29) which has one CH less. It is suggested from a comparison with (30) that the lower carbon chain in the former should be H3 aNBn H I H liii HQ iv - H H (Bn = benzyl) (28) (+)-Mearsine Reagents i BnNH .HCl metaldehyde conc. HCl MeOH reflux 16h; ii H, Pd-e (5%) MeOH;-iii NCS pentane r.t. 1 h; iv KOBut hexane r.t. 2 h Scheme 5 (CH,), rather than (CH,),.26 Haliclamines A and B are two cytotoxic alkaloids occurring in an unnamed marine sponge of the genus Huliclonu. Their structures and configurations (3 1) and (32) respectively are based on extensive NMR spectral analyse~.~’ 4 Pyridine Alkaloids Four alkaloids with antineoplastic activity have been isolated from the Okinawan marine sponge Theonella swinhoei.They NATURAL PRODUCT REPORTS 1992-A. R. PINDER H CI-H (29) Juliprosinine (?) (30) Juliflorinine NHR 14 15 (31) Haliclamine A (33) Theonelladine A (R = H) (?) (32) Haliclamine B (A14 cis) (34) Theonelladine B (R = Me) (?) NHR (35) Theonelladine C (R = H) (36) Theonelladine D (R = Me) HO Me02CflH Me02c@H \ N N (37) Plectrodorine (38) lsoplectrodorine CH(OMe) YHO HO YHo HO I ’ Oglu HO ; (39) (40) (41) Euphrosine (glu = glucose) are the theonelladines A B C and D the structures and alkaloid of this subgroup occurring in Orthocarpus luteus a configurations of which (33)-(36) have been settled by NMR shrub collected in Colorado.Its structure was inferred from and mass spectral study.28 [It should be noted that the structures spectral study and confirmed by synthesis from euphroside (33) and (34) for A and B are not consistent with the molecular (39) an iridoid of known structure by successive acetalization formulae given in the text each formula having one carbon to (40),then treatment with dilute aqueous acid followed by atom too many.] Two new monoterpene alkaloids plectro- basification with gaseous ammonia. 30 dorine (37) and isoplectrodorine (38) have been separated The previously demonstrated ability of I ,2,3-triazines to from aerial parts of Plectronia odorata a South Pacific island undergo a Diels-Alder reaction with enamines has been applied shrub.Their structures and configurations have resulted from to a synthesis of tortuosamine (42) and its N-formyl and -acetyl detailed spectral mea~urements.~~ Euphrosine (41) is another derivatives (Scheme 6).31 NATURAL PRODUCT REPORTS 1992 OMe OMe OMe OMe @OMe vi Ncqj (42) Tortuosamine Reagents i methyl acrylate Triton B; ii NaH; iii AcOH-10% H,SO,; iv pyrrolidine TSA hexane reflux; v 1,2 3-triazine CHCl, 100-1 10 "C (sealed tube) 3 h; vi Ref. 32 33 Scheme 6 OH 0g ' OMe 0-OH OH OMe (43) Orellanine (44) (45) Oxylopine (R' = OH R2 = OMe) (47) Cleistopholine (46) Ursuline (R' = OMe R2 = OH) <" 0 (48) (-)-Turkiyenine (R = H) (49) (+)-Oxoturkiyenine (RR = 0) The 13C NMR parameters of the bispyridine alkaloid orellanine (43) have been published with unambiguous assignments of signals.34 4.1 Azafluorene and Aza-anthracene Alkaloids 6,7-Dimethoxyonychine (44)is a new alkaloid isolated from the bark of Pulyalthia Zungifolia.It is formulated on spectral evidence.35 The synthesis of two other alkaloids of this group oxylopine (isoursuline) (45) and ursuline (46) as well as of cleistopholine (47) an aza-anthracene alkaloid have been described using the earlier reported36 pathway for constructing cycloalkenopyridines from oxime 0-ally1 ethers of cyclo-alkanones. As a consequence of this work the structure of oxylopine needs to be revised to 6-hydroxy-5-methoxyonychine (45) from 5-hydroxy-6-rnetho~yonychine.~~ 5 Azepine Alkaloids (-)-Turkiyenine (48)is an unusual alkaloid found in Cheli-donium majus along with a host of well-known bases.38 Its structural assignment is based on its recognition as the enantiomer of a base isolated earlier from Hypecoum pro-curnbe~s.~~ The related lactonic base (49) occurs in H.pendulum.40 6 References M. Aknin J. Miralles J.-M. Kornprobst R. Faure E.-M. Gaydou N. Boury-Esnault Y. Kato and J. Clardy Tetrahedron Lett. 1990 31 2979. M. Sakoda T. Hase and K. Hasegawa Phytochemistry 1990,29 1031. A. Maxwell and D. Rampersad J. Nat. Prod. 1989 52 891. Y. Mimaki and Y.Sashida Chem. Pharm. Bull. 1990 38 541. P. K. Guha R. Poi and A. Bhattacharyya Phytochemistry 1990 29 2017. T. H. Jones A. Laddago A. W. Don and M. S. Blum J. Nut. Prod. 1990 53,375. T. H. Jones M. S. Blum P. Escoubas and T. M. M. Ali J. Nat. Prod. 1989 52 779. NATURAL PRODUCT REPORTS 1992-A. R. PINDER 8 J.-E. Backvall H. E. Schink and Z. F. Renko J. Org. Chem. 1990 55 826. 9 M. Miyashita B. Z. E. Awen and A. Yoshikoshi Chem. Lett. 1990 239. 10 V. G. Gore M. D. Chordia and N. S. Narasimhan Tetrahedron 1990 46 2483. 11 M. V. Tekzhenetskaya B. Tashkhodzhaev M. R. Yagudaev B. T. Ibragimov and S. Y. Yunusov Chem. Nat. Compd. (Eng. Transl.) 1989 25 14. 12 C.-Y.Duh Y.-C. Wu and S.-K. Wang Phytochemistry 1990,29 2689.13 Y. Masaki T. Imaeda K. Nagata H. Oda and A. Ito Tetra-hedron Lett. 1989 30 6395. 14 Y. Masaki Y. Serizawa K. Nagata H. Oda H. Nagashima and K. Kaji Tetrahedron Lett. 1986 27 231. 15 Y. Masaki K. Nagata and K. Kaji Chem. Lett. 1983 1835. 16 A. Liguori R. Ottana G. Romeo G. Sindona and N. Uccella Chem. Ber. 1989 122 2019. 17 S. Najdi and M. J. Kurth Tetrahedron Lett. 1990 31 3279. 18 T. H. Jones M. S. Blum and H. G. Robertson J. Nat. Prod. 1990. 53 429. 19 T. Nagasaka H. Hayashi M. Kumakawa M. Sakamoto M. Mizuno and F. Hamaguchi Heterocycles 1989 29 2157. 20 A. M. Aguinaldo and R. W. Read Phytochemistry 1990 29 2309. 21 W. Carruthers P. Coggins and J. B. Weston J. Chem. Soc. Perkin Trans. I 1990 2323. 22 M.-Z. Zhang J.-C.Wang and S.-H. Zhou Phytochemistry 1990 29 1353. 23 J. L. Brayer J. P. Alazard and C. Thal Tetrahedron 1990 46 5187. See A. R. Pinder ‘Specialist Periodical Reports The Alkaloids’ Royal Society of Chemistry London 1982 12 35. 24 G. B. Robertson U. Tooptakong J. A. Lamberton Y. A. G. P. Gunawardana and I. R. C. Bick Tetrahedron Lett. 1984 25 2695. 25 J. R. Crouse and A. R. Pinder J. Nat. Prod. 1989 52 1227. 26 V. U. Ahmad A. Sultana and S. Qazi J. Nat. Prod. 1989 52 497. 27 N. Fusetani K. Yasumuro S. Matsunaga and H. Hirota Tetra-hedron Lett. 1989 30 6891. 28 J. Kobayashi T. Murayama Y. Ohizumi T. Sasaki T. Ohta and S. Nozoe Tetrahedron Lett. 1989 30 4833. 29 D. Gournelis A.-L. Skaltsounis F. Tillequin M. Koch J. Pusset and S.Labarre J. Nat. Prod. 1989 52 306. 30 C. A. Boros F. R. Stermitz and G. H. Harris J. Nat. Prod. 1990 53 72. 31 T. Okatani J. Koyama and K. Tagahara Heterocycles 1989,29 1809. 32 J. Koyama T. Sugita Y. Suzuta and H. Irie Heterocycles 1981 16 969. 33 J. Koyama T. Sugita K. Tagahara Y. Suzuta and H. Irie Heterocycles 1984 22 1973. 34 S. Rapior and A. Fruchier Anal. Quim. Ser. C 1989 85 69. 35 M. Chakrabarty and A. Patra Indian J. Chem. B 1990 29 394. 36 See A. R. Pinder ‘Specialist Periodical Reports The Alkaloids’ Royal Society of Chemistry London 1981 11 29. 37 J. Koyama T. Okatani K. Tagahara and H. Irie Heterocycles 1989 29 1649. 38 G. Kadan T. Gozler and M. Shamma J. Nat. Prod, 1990 53 531. 39 T. Gozler B. Gozler I. Weiss A. J. Freyer and M. Shamma J. Am. Chem. SOC.,1984 106 6101. 40 1. E. Mete and T. Gozler J. Nut. Prod. 1988 51 272.

ISSN:0265-0568    

DOI:10.1039/NP9920900017

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting University of Notting ham Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bio-organic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis and chemistry of the major groups of natural products -alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds. Many reviews provide details of biological activity and wider aspects of bio-organic chemistry including developments in enzymology genetics and structural spectroscopic and chromatographic methods 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 CB4 4WF England. 1993 Annual Subscription Price E.C. f242.00 Overseas f266.00 U.S.A. $532.00. Change of address and orders with payment in advance to The Royal Society of Chemistry The Distribution Centre Blackhorse Road Letchworth Herts.SG6 1 HN England. Air Freight and mailing in the U.S. by Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. US Postmaster send address changes to Natural Product Reports Publications Expediting Service Inc. 200 Meacham Avenue Elmont NY 11003. Second-Class postage paid at Jamaica NY 11431-9998.All other despatches outside the U.K. are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. Printed in the U.K. 0 The Royal Society of Chemistry 1993 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 the University Press Cambridge Subscription rates for 1993 E.C. f242.00 Overseas f266.00 U.S.A. US $532.00 Subscription rates for back issues are (1988) (1989) (1 990) (1991) (1992) U.K. f 159.00 f 169.00 f 177.00 f198.00 €222.00 Overseas f183.00 f 194.00 f204.00 f228.00 €250.00 U.S.A. US $342.00 US $388.00 US $398.00 US $467.00 US$474.00 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 CB4 4WF England

ISSN:0265-0568    

DOI:10.1039/NP99209FX025

出版商:RSC    

年代:1992

数据来源: RSC

ISSN:0265-0568    

DOI:10.1039/NP99209BX027

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

ISSN 0265-0568 NPRRDF 91-1-1-63 (1 992) Natural Product Reports A journal of current developments in bio-organic chemistry Volume 9 Indexes CONTENTS ... 111 Preliminary pages for Volume 9 1-1 Index of Authors Cited 1-35 Subject Index ISSN 0265-0568 Coden NPRRDF Natural Product Reports A journal of current developments in bio-organic chemistry Volume9 1992 The Royal Society of Chemistry Cambridge Natural Product Reports (ISSN 0265-0568) 0The Royal Society of Chemistry 1993 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 the University Press Cambridge ISSN 0265-0568 NPRRDF 9 1-596 1-1-1-63 (I 992) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 9 CONTENTS 1 Diterpenoids J. R. Hanson Reviewing the literature published during 1990 17 Pyrrole Pyrrolidine Piperidine Pyridine and Azepine Alkaloids A. R. Pinder Reviewing the literature published between July 1989 and June 1990 25 Quinoline Quinazoline and Acridone Alkaloids J. P. Michael Reviewing the literature mainly published between July 1989 and June 1990 37 Steroids Reactions and Partial Syntheses A. B. Turner Reviewing the literature published in 1989 81 Muscarine Oxazole Thiazole Imidazole and Peptide Alkaloids and Other Miscellaneous Alkaloids J.R. Lewis Reviewing the literature published between July 1989 and June 1990 103 Angucycline Group Antibiotics J. Rohr and R. Thiericke 139 The Micro biological Transformation of Diterpenoids J. R. Hanson Reviewing the literature between 1973 and June 1991 153 The Biosynthesis of Shikimate Metabolites P. M. Dewick Reviewing the literature published during 1990 183 Amaryllidaceae and Sceletium Alkaloids J. R. Lewis Reviewing the literature published during 1990 193 Natural Products and the Sesquicentenary of the Royal Society of Chemistry Some Random Comments L. Crombie 199 Intracellular Steps of Bacterial Cell Wall Peptidoglycan Biosynthesis Enzymology Antibiotics and Antibiotic Resistance T. D. H.Bugg and C. T. Walsh 217 Natural Sesquiterpenoids B. M. Fraga Reviewing the literature published during 1989 243 Clerodane Diterpenoids A. T. Merritt and S. V. Ley 289 Peroxy Natural Products D. A. Casteel Reviewing the literature to December 1990 313 Pyrrolizidine Alkaloids D. J. Robins Reviewing the literature published between July 1990 and June 1991 323 Marine Natural Products D. J. Faulkner Reviewing the literature published during 1990 365 P-Phenylethylamines and the Isoquinoline Alkaloids K. W. Bentley Reviewing the literature published between July 1990 and June 1991 393 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites Reviewing the literature published between July 1990 and June 1991 447 Biosynthesis of Polyketide Metabolites D.O’Hagan Reviewing the literature published between 1989 and mid 1991 48 1 The Sesterterpenoids J. R. Hanson Reviewing the literature published between July 1985 and October 1991 J. E. Saxton 49 1 Azetidine Pyrrole Pyrrolidine Piperidine and Pyridine Alkaloids Reviewing the literature published between July 1990 and June 1991 505 Appreciation Edward Leete 1928-1992 507 The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites Reviewing the literature published between August 1989 and December 1990 53 1 Monoterpenoids D. H. Grayson Reviewing the literature published during 1988 and 1989 557 Natural Sesquiterpenoids B. M. Fraga Reviewing the literature published during 1990 581 Steroids Reactions and Partial Synthesis J.R. Hanson Reviewing the literature published in 1990 A. R. Pinder R. B. Herbert Natural Product Reports Editorial Board Professor T. J. Simpson (Chairman) University of Bristol Dr C. Abell University of Cambridge Dr J. R. Hanson University of Sussex Dr R. B. Herbert University of Leeds Professor J. Mann University of Reading Dr D. A. Whiting University of Nottingham Natural Product Reports is a bimonthly journal of critical reviews. It aims to foster progress in the study of bio-organic chemistry by providing regular and comprehensive reviews of the relevant literature published during well-defined periods. Topics include the isolation structure biosynthesis and chemistry of the major groups of natural products -alkaloids terpenoids and steroids aliphatic aromatic and 0-heterocyclic compounds.Many reviews provide details of biological activity and wider aspects of bio-organic chemistry including developments in enzymology genetics and structural spectroscopic and chromatographic methods 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. This journal includes reviews of books relating to natural products. Volumes for review should be sent to the editorial office for which the address is The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cambridge CB4 4WF and marked for the attention of the Senior Editor Reviews.Contributors to Volume 9 Bentley K. W. 365 Bugg T. D. H. 199 Casteel D. A. 289 Grayson D. H. 531 Hanson J. R. 1 139 481 581 Herbert R. B. 507 O’Hagan D. 447 Pinder A. R. 17 491 Robins D. J. 313 Crombie L. 193 Lewis J. R. 87 183 Rohr J. 103 Dewick P. M. 153 Ley S. V. 243 Saxton J. E. 393 Faulkner D. J. 323 Merritt A. T. 243 Thiericke R. 103 Fraga B. M. 217 557 Michael J. P. 25 Turner A. B. 37 Walsh C. T. 199 Nomenclature It is the policy of’The Royal Society of Chemistry to en-courage the use of IUPAC and IUB Recommendations on nomenclature. Although many of the appropriate nomen-clature documents are included in the new edition of the IUB publication ‘Biochemical Nomenclature and Related Documents’ (published by The Biochemical Society London 1992) a selection of recent Recommendations that will be of particular interest to those who investigate the chemistry occurrence or biosynthesis of natural products includes Extension of Rules A-1.1 and A-2.5 concerning numerical terms used in organic nomenclature (Recommendations 1986) Pure Appl.Chem. 1986 58 1693-1696. [The original versions of these Rules are in ‘Nomenclature of Organic Chemistry Sections A B C D E F and H’ 1979 Edition] Nomenclature of tetrapyrroles (Recommendations 1986) Pure Appl. Chem. 1987 59 779-832. Nomenclature and symbols for folic acid and related compounds (Recommendations 1986) Pure Appl. Chem. 1987 59 833-836; Eur. J. Biochem. 1987 168 251-253. Nomenclature of prenols (Recommendations 1986) Pure Appl.Chem. 1987 59 683-689; Eur. J. Biochem. 1987 167 181-184. Nomenclature of retinoids (Recommendations 198 l) Pure Appl. Chem. 1983 55 721-726; Eur. J. Biochem. 1982 129 1-5. Nomenclature of vitamin D (Recommendations 198 I) Pure Appl. Chem. 1982 54 151 1-1516; Eur. J. Biochem. 1982 124 223-227. Nomenclature of tocopherols and related compounds (Recommendations 1981) Pure Appl. Chem. 1982 54 1507-1510; Eur. J. Biochem. 1982 123 473475. Recommendations for the presentation of thermodynamic and related data in biology (1985) Eur. J. Biochem. 1985 153 429434. ‘Enzyme Nomenclature (Recommendations 1984) ’ Supplement 1 Corrections and additions Eur. J. Biochem. 1986 157 1-26. ‘Enzyme Nomenclature 1992 ’ (Recommendations of the Nomenclature Committee of the International Union of Biochemistry on the nomenclature and classification of enzyme- catalysed reactions) Academic Press Orlando Florida 1992.Nomenclature for multienzymes (Recommendations 1989) Eur. J. Biochem. 1989 185 485436. Symbolism and terminology in enzyme kinetics (Recommendations 1981) Eur. J. Biochem. 1982 128 281-291. Symbols for specifying the conformation of polysaccharide chains (Recommendations 198l) Pure Appl. Chem. 1983 55 1269-1272; Eur. J. Biochem. 1983 131 5-7. Polysaccharide nomenclature (Recommendations 1980) Pure Appl. Chem. 1982 54 1523-1526; Eur. J. Biochem. 1982 126 439441. Abbreviated terminology of oligosaccharide chains (Recommendations 1980) Pure Appl.Chem. 1982 54 1517-1522; Eur. J. Biochem. 1982 126 433437. Nomenclature of glycoproteins glycopeptides and peptidoglycans (Recommendations 1985) Eur. J. Biochem. 1986 159 1-6. Nomenclature and symbolism for amino acids and peptides (Recommendations 1983) Pure Appl. Chem. 1984 56 595-624; Eur. J. Biochem. 1984 138 9-37 (see also Eur. J. Biochem. 1985 152 1 and the Newsletter 1985 of NC-IUB and JCBN ibid. 1985 146 pp. 238 and 239 and the Newsletter 1986 ibid. 1986 154 pp. 485 and 486). Nomenclature for incompletely specified bases in nucleic acid sequences (Recommendations 1984) Eur. J. Biochem. 1985 150 1-5 (see also Eur. J. Biochem. 1986 157 1). Abbreviations and symbols for the description of conformations of polynucleotide chains (Recommendations 1982) Pure Appl.Chem. 1983 55 1273-1280; Eur. J. Biochem. 1983 131 9-15 (see also the Newsletter 1984 of NC-IUB and JCBN Eur. J. Biochem. 1984 138 p. 7). The most recent of the lists of restriction endonucleases and their isoschizomers (updated annually) is R. J. Roberts and D. Macelis Nucl. Acids Res. 1991 19 2077-2109. Recent codes of nomenclature for organisms include ‘International Code of Nomenclature of Bacteria and Statutes of the International Committee on Systematic Bacteriology (1989 Revision)’ ed. P. H. A. Sneath V. B. D. Skerman and V. McGowan American Society for Microbiology Washington D.C. U.S.A. 1976. [Appendix 2 of this publication (Approved Lists of Bacterial Names) appeared in Znt.J. Syst. Bucteriol. 1989 39.1 ‘International Code of Botanical Nomenclature (1988)’ ed. W. Greuter H. M. Burdett W. G. Chaloner V. Demoulin R. Grolle D. L. Hawksworth D. H. Nicholson P. C. Silva F. A. Stafleu E. G. Voss and J. McNeill Koeltz Scientific Books Konigstein Federal Republic of Germany 1988. ‘International Code of Zoological Nomenclature ’. 3rd edn. ed. W. D. L. Ride C. W. Sabrosky G. Bernardi R. V. Melville J. 0. Corliss J. Forest K. H. L. Key and C. W. Wright International Trust for Zoological Nomenclature in association with the British Museum (Natural History) London U.K. and the California Press Berkeley and Los Angeles U.S.A. 1985.

ISSN:0265-0568    

DOI:10.1039/NP99209FP031

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

Steroids Reactions and Partial Syntheses A. B. Turner Chemistry Department University of Aberdeen Aberdeen A69 2UE,Scotland Reviewing the literature published in 1989 (Continuing the coverage of literature in Natural Product Reports 1991 Vol. 8 p. 17) 1 1.1 1.1.1 1.1.2 1.1.3 1.2 1.2.1 1.2.2 1.3 1.3.1 1.3.2 1.3.3 1.4 1.5 1.6 1.7 2 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3 Reactions Alcohols and Carboxylic Acids and their Derivatives Halides and Epoxides Oxidation Substitution and Reduction Esters and Ethers Opening of Epoxide Rings Unsaturated Compounds Electrophilic Addition Other Reactions of Olefinic and Aromatic Steroids Carbonyl Compounds Reduction and Dehydrogenation Other Reactions Reactions of a$-Unsaturated Carbonyl Compounds and Enols or Enolic Derivatives Compounds of Nitrogen Phosphorus Sulfur and Other He tero -elemen t s Molecular Rearrangements Remote Functionalization Reactions Photochemical Reactions Partial Synthesis Derivatives and Analogues of Cholestane Vitamins D their Derivatives and their Metabolites Cholanes Norcholanes and Dinorcholanes Pregnanes Androstanes and Oestranes Cardenolides and Bufadienolides Heterocyclic Compounds Cyclopropano-steroids Microbiological Transformations References This report follows the pattern established in previous years and covers the literature published from November 1988 to December 1989.l During this period the following topics have been reviewed methods for the elaboration of the corticoid side-chain from 17-ketosteroid~,~ progress in the synthesis of bras~inolides~.and ecdysones,4 and the applications of octafluorotoluene in derivatization of steroids for GC-MS analysis and general use in protecting group formation.6 Other reviews are mentioned in the appropriate sections. In addition the IUPAC recommendations for the nomenclature of steroids have been updated.' I Reactions 1.1 Alcohols and Carboxylic Acids and their Derivatives Halides and Epoxides 1.1.1 Oxidation Substitution and Reduction The oxidation of the (2)-5,lO-secocholestenediolmonoacetate (1) with lead tetraacetate gives the (Z)-ketone (2) in 15% yield together with products of allylic oxidation whereas similar oxidation of the (E)-isomer (3) gives the (E)-ketone(4) in 65 YO yield.In an analytical application of the periodate cleavage of the corticoid side-chain both 18-oxocortisol and its tetrahydro- metabolite are predominantly cleaved to 17-ketosteroids along with lesser amounts of y-etiolactones. The course of the C8H17 II AcO 0 (3) (4) OCH2Ph Ho-rrl 0m-I CH2Ph n + KXNH (n-C,6H33)21;IICH,CH20-C Me N' J (7) oxidative cleavage is thought to reflect an equilibrium between C-20 0x0 and cyclic hemiacetal forms in which the glycerol type side-chain of the latter becomes the precursor of a 17-ketone. Reaction of the alcohol (5) with diethylaminosulfur trifluoride (DAST) in dichloromethane at -78 "C allows the generation of an electrophilic centre on the side-chain attached to ring c leading to the 1,l lp-ethano-bridged oestradiol (6) in an overall yield of 61 %.lo Only a trace amount of the corresponding 1 1 p-fluoroethyl product is formed in keeping with the ability of DAST to activate the C-0 bond without generating a high concentration of fluoride ion.Imidazole-functionalized surfactants such as the quartenary ammonium salt (7) transfer acetyl groups from p-nitrophenyl acetate to cholesterol in vesicular coaggregates providing a 37 38 NATURAL PRODUCT REPORTS 1992 vo CBH17 M e t w o Me0 (8) R = COCHZCH2COzH (9) R = H / 0 (12) R' = R2= H (14) R' = R2 = Tos (15) R~=Tos,R2=H simple analogue of lecithin :cholesterol acyltransferase.l1 Selec-tive acetylation also occurs using the same system. Reaction of cholestan-36-01 is favoured over cholestan-3a-01 and regio- selective acetylation of the 36-alcohol is strongly favoured over that of cholestan-6,8-ol. l2 2-Propynyl ethers of steroid alcohols (with hydroxyl groups at C-3 C-17 or C-20) are prepared by treating the alcohol with 3-bromoprop- 1 -yne under various conditions of phase transfer ~ata1ysis.l~Other hydroxyl groups can be protected as methoxymethyl or tetrahydropyranyl ethers. The preparation of 1 1 a-hemisuccinylprogesterone (8) from 1 1 a-hydroxypro-gesterone (9) has been improved by using 4-dimethylamino- pyridine in boiling dioxan.14 The hapten when linked to an appropriate macromolecule is a useful solid-phase antigen for the immunoassay of progesterone.The selective acylation of hydroxyl groups of cholic acid esters by acetic anhydride with N-methylimidazole as catalyst has been investigated. l5 Product mixtures were analysed by gas chromatography. The results were of value in defining the optimum conditions for the formation of methyl diacetoxycholate an intermediate in chenodeoxycholic acid production. A series of glycosides e.g. the cholestane (lo) has been prepared by a redox process involving thionoester inter-mediates.l6 The sequence involves initial condensation of a sterol with an aldonic acid thionation of the resulting ester reductive alkylation with lithium triethylborohydride and final ring closure using a silver (I) catalyst.A new boronic acid derivative (1 1) has been devised as a fluorescence derivatization reagent for the analysis of brassino- R' (17) R' = OH R2 = CH20H (18) R' = OAc R2 = CH20Tos (1 9) R' = OTHP R2= CH~OTOS (22) R' = OH R2 = CH20Me steroids by liquid chromatography. li The cyanoisoindole reagent (1 1) is prepared directly from o-phthalaldehyde and rn-aminophenylboronic acid and derivatization of the diols is carried out in acetonitrile in the presence of pyridine at 70 "C. The resulting brassinolide boronates show excellent chromato- graphic characteristics for plant analysis providing a detection limit of 20 pg using reversed-phase HPLC. Simultaneous inversion of the configurations of the C-22 and C-23 hydroxyl groups of the 22S,23S-diol (12) cannot be effected via its ditosylate or dimesylate derivatives.18 Reaction of the diol (12) with toluene-p-sulphonyl chloride in pyridine gives the epoxide (13) the ditosylate (14) and the monotosylate (15) in yields of 50 YO,20 YOand 30 YO,respectively.Acetolysis and hydrogenolysis of the 7-methanesulphonyl- oxycyclocholestanes (1 6) have been investigated. l9 The 7p- mesylate is hydrogenolysed faster than its 7a-epimer. Acetolysis leads to elimination substitution and rearrangement with participation of the cyclopropane ring. The 7a-mesylate gives mainly the products of elimination but the 7p-epimer is much more susceptible to the neighbouring group participation reaction.The four possible stereoisomers of 16-hydroxymethyl-3-methoxyoestra- 1,3,5( lO)-trien-17-01 (17) have been converted into the 16-tosyloxymethyl- 17-acetoxyesters (1 8).20 Upon al- kaline methanolysis those derivatives having their ring D-substituents cis give the corresponding oxetane (20) whereas trans precursors give the D-seco aldehyde (21). Under similar conditions the 16-tosyloxymethyl- 17-tetrahydropyranyl ethers (19) give the 16-methoxymethyl derivatives (22). The silver(1) promoted solvolysis of the 3a-halogenated bridged ether (23) converts the halogen into an alkoxyl or hydroxyl group with retention of configuration.21 Anchimeric assistance by the ether oxygen which is antiperiplanar to the halogen atom facilitates the cleavage. Halolactones and haloesters which would produce strained transition states are inert.A study of the kinetics of dehydrobromination of 7a-bromocholesteryl benzoate in nitrobenzene confirms the op- eration of a normal salt effect in the presence of tetraethyl- NATURAL PRODUCT REPORTS 1992-A. B. TURNER C8H 17 X -O& H (23) X = Br orI (24) R’ = HI R2= SH (25) R’ = COPh R2 = SAC OR2 OMe (33) R’ = SiMePh2 R2 = SiMe2CMe3 (37) (34) R’ = SiMe2CMe3 R2 = SiMePh2 (35) R’= H R2 = SiMe2CMe3 (36) R’ = SiMe2CMe3 R2 = H ,,.OH OH HO ammonium perchlorate but indicates an abnormal salt effect with lithium perchlorate.22 This is due to the electrophilic assistance of the lithium ion in the heterolysis.7a-Thiohydroxy- cholesterol (24) is obtained from cholesteryl benzoate by allylic bromination with N-bromosuccinimide followed by conden- sation with thioacetic acid and reduction with lithium alu- minium h~dride.~~ The intermediate thioacetate (25) is separ- ated from its 7P-epimer by HPLC. The dicyanonitrocholestanes (26) are prepared by reaction of the corresponding 7a-bromo- 6-nitrocholestenes (27) with potassium cyanide in the presence of hydrogen ~hloride.’~ Treatment of the dicyanides (26) with zinc and ammonia gives the 7-carboxamides (28). 1.I .2 Esters and Ethers Alcoholysis of 3,5-cyclo-6/3-methoxycholestane(29) in the presence of methanesulphonic acid gives the ethers (30)-(32) in 65-76 Oh yield.25 Tosylation azidolysis and amination of No (26) R = H OH OAC,CI (27) (30) R = Me(CH2)15 (31) R = Me(CH2)7CH=CH(CH2)8 (32) R = HO(CH2)g (38)R = CH2CH=CMe2 (39) R= OH the alcohol (32) with dimethylnaphthalene diamine produces a highly fluorescent cholesteryl ether.Acetyl chloride efficiently converts steroidal tetrahydro-pyranyl ethers into acetates in aprotic solvents.26 Sodium azide in dimethylformamide cleaves the methyldiphenylsilyl ether bond under conditions where t-butyldimethylsilyl ethers are table.^' In this way selective cleavage of the bis-silyl ethers (33) and (34) gives the mono-silyl ethers (35) and (36) in yields of 81 YOand 88 % respectively. Evidence has been obtained from ESR studies of virtual immobility in niosomes derived from steroidal lariat ethers.’* Nitroxide radical probes show correlation times which are 300 times longer in lariat ether-derived niosomes than are observed in egg lecithin vesicles and the membranes are so rigid that the spectra are almost identical to those of frozen systems.The ester (37) undergoes a-alkylation with 4-bromo-2-methylbut-2-ene after conversion into its ester enolate with An lithium di-isopropylamide in tetrahydrof~ran.~~ 87 13 mixture of the product (38) and its C-22 epimer is obtained in 75 % yield the ratio of the stereoisomers being determined by HPLC. Treatment of the potassium enolate of the ester (37) with Davis’ oxaziridine reagent gives a 3 1 mixture of the hydroxy-ester (39) and its C-22 epimer in 70% yield. Acid- catalysed reaction of the ketoester (40) with methanol in benzene leads to the hemiacetal (41) whereas the ketol (42) is formed under basic condition^.^^ Solubilities partition coefficients and hydrolysis rate con- stants of a series of aryl carboxylic acid esters of testosterone have been determined in order to evaluate their potential as long-acting With increasing chain length the partition NATURAL PRODUCT REPORTS 1992 0 R AcO‘ HO&R CH2 (43) (44) (45) (46) AcO R C8H17 MeO’**@OH MeO’.’ HO 0 0 & R (47) (49) (50) R = OH CI Br SAC lii OH Reagents i hv aq.HMPA; ii Bu,SnH toluene 111 “C Scheme 1 coefficients increase but the rates of hydrolysis decrease apart from the benzoate which has the slowest rate.The use of diphenyl(2-pyridy1)phosphine instead of triphenylphosphine in the Mitsunobu esterification procedure facilitates isolation of the ester.32 The phosphine oxide produced is conveniently removed by extraction with dilute acid. 1.I .3 Opening of Epoxide Rings Lactonization of the epoxyester (43) under acidic conditions provides a new approach to bras~inolides.~~ The resulting P-lactone (44) which is obtained quantitatively arises by inversion of configuration at C-22. The 23s-configuration of the alcohol (44) is readily inverted by oxidation with pyridinium dichromate followed by catalytic reduction over platinum. Selective epoxidation of the A’-bond in A-homo-B 19- dinorsteroids of type (45) takes place with participation of the 3P-hydroxyl group to give transannular 9a-hydroxy-3P lop- oxides (46).34 The corresponding 3P-acetoxy compounds undergo normal epoxidation to the 9a,lOa-epoxides (47) which after hydrolysis of the ester groups also give rise to the transannular 3P 1 OP-oxides.The isomeric hydroxy-epoxides (48) and (49) are interconvertible by epoxide migration under both acidic and basic condition^.^^ A series of 4-substituted derivatives of 19-hydroxyandrost-4- ene-3,17-dione (50) have been prepared from 4P,SP-epoxy- 19- hydro~yandrostane-3,17-dione.~~ The 4-hydroxy- and 4-chloro compounds are effective inhibitors of testosterone ring A-aromatase. C-3 Radicals (51) formed by photolysis of 3P-acetoxy- NATURAL PRODUCT REPORTS 1992-A. B. TURNER 08 SCH2CH2C02H (54) (55) (58) (60) R=NMe2 (63) R = H Me CMe3 Ph OEt Me(CH2) [n = 4,7 and 161 4~,5~-epoxycholestanes or by tributyltin hydride reduction of 3P-thiocarbonyloxy derivatives (Scheme 1) give 5-cholest-3- enoxyl radicals (52) which undergo reversible cleavage of the C(5)-C( 10) bond.37 The major product is cholest-3-en-5P-01 (53) isolated in 60-75 YOyield after chromatography.Reaction of trimethylsilylimidazole with SP,lO~-epoxy-3-ketones at reflux temperature leads mainly to aromatization of ring whereas at 90 "C the predominant product is the A3-en01 silyl ether. Treatment of the epoxide (54) with 3-mercaptopropanoic acid gives the 1 la-hydroxyprogesterone hapten (55).39 The related hapten (57) is obtained by addition of the same thiol to the epoxide (56) followed by deketalization.The spiro-epoxide (58) is cleaved by ethyleneimine to give the aziridine (59) in 70 YOyield and with aqueous dimethylamine to give the tertiary amine (60) in 26% yield.40 The mechanism of. the boron trifluoride etherate-catalysed rearrangement of an acyclic trisubstituted epoxide to a ketone has been studied using the 13C-labelled desmosterol benzoates (61).41 Hydrogen migration from C-24 to C-25 leading to the 24-0x0 compound (62) the major product (60% yield) occurs with retention of configuration at C-25 whereas C-23 alkyl group migration leading to aldehyde (25 YOyield) proceeds with inversion of configuration at C-25. 1.2 Unsaturated Compounds I .2.1 Electrophilic Addition The influence of the cata1yst:substrate ratio on the P-stereospecific epoxidation of cholesteryl acetate by air in the presence of a ruthenium tetramesitylporphyrin has been A molar ratio close to 1 :25 is optimal for the (62) P~o-R-~~CH~, from a-epoxide Pro-S-13CH3 from P-epoxide @R X (67) X = H2 or 0 R = C8H17 (68) X = 0 R = HI OAc COMe preparative P-epoxidation and the catalytic system is inhibited by ethanol.The epoxidation of a wide range of cholesteryl esters (63) using this catalyst system gives P-epoxides (64) in yields of 7694Y0.~~ The A5-steroids (65) and (66) are also conveniently converted into their SP,6P-epoxides by this catalyst system. Treatment of cholesteryl acetate and its analogues with chromium(v1) acetate at low temperature also leads to 5P,6P- epoxides with a stereoselectivity of at least 90%0.*~ An alternative route to 2a,3a-diols (68) from A'-5a-steroids (67) which avoids the use of osmium tetroxide is of potential value for brassinolide synthesis.45 It makes use of a sequence involving epoxidation with 3-chloroperbenzoic acid in benzene cleavage of the oxirane ring with hydrogen iodide acetylation oxidative replacement of the iodine atom by hydroxyl and hydrolysis with alkali all without purification of intermediates.The presence of a 6-0x0 group is tolerated and yields of the diols (68) are in the range 16-69% comparable to those obtained by osmylation. NATURAL PRODUCT REPORTS 1992 CBH17 (69)R= Br (70)R=SnBu3 (72) R = H (75)R = CI (71)R=I HO 0 CBH17 (80)R = H OAc CI,OMe OH (811 (82) R = H OAc CI The bromovinyloestradiol(69) is prepared by reaction of the tributylstannane (70) with bromine in carbon tetrachl~ride.~~ Use of NHgs2Br and Na77Br in combination with thiocyanate allows the preparation of the 82Br- and 77Br-radiolabelled compounds.The vinyl bromide (69) shows similar uterine uptake and specific receptor binding properties to the cor-responding iodovinyloestradiol (7 1). Oxymercuration-demercuration of cholest-5-ene (72) gives the 6-alcohols (73) and (74)." The chlorocholestene (75) similarly gives the diol (76) and the enone (77). 1.2.2 Other Reactions of Olefinic and Aromatic Steroids Tordanone (78) a doubly-bent steroid having both rings A/B and B/C cis-fused has been prepared by stereospecific hydro- genation of the dienone (79).48 There is severe steric hindrance on the p-face where the angular methyl group at the C/D ring junction is in compression with the 7P-hydrogen of ring B.Reaction of nitroalkenes with iodotrimethylsilane provides more convenient access to ketosteroids than other methods such as reduction with hydrazine and Raney nickel (cf. Reference 103) or zinc and hydrochloric acid.49 Thus 6- nitrocholest-5-enes (80) are reduced by iodotrimethylsilane (generated in situ from chlorotrimethylsilane and sodium iodide) at -5 "Cto 6-oxocholestanes (81) in 75-85 % yield. The corresponding 5a-hydroxy compounds and their oximes are obtained as minor products. Addition of ethane- 172-dithiol to 6-nitrocholest-5-enes of type (80) in the presence of boron trifluoride etherate gives the corresponding oximes (82).50 Yields of the 22-alcohol (84) obtained by hydroboration- oxidation of the pregnene (83) are dependent upon the molar ratios of sodium borohydride and boron trifluoride f~herate.~' (83) (84) 13CNMR spectroscopy can be used to confirm the stereo- chemistry at C-5 of 3,6-dio~osteroids.~~ In particular the analysis is based upon the chemical shifts of C-7 C-9 and C-19 in both 5a-an 5P-cholestane-3,6-diones prepared from cholesterol.Reduction of (E)-2O-iodopregna-5,17(20)-diene(86) ob- tained by cyclization of the secosteroid (85) with lithium aluminium hydride in ethereal solvents yields a mixture of the E and 2 isomers of pregn-5,17(20)-diene7 (87) and (88) in the ratio of 69:31.53 When tributyltin hydride is used as the reducing agent the E:Z ratio is 60:40.The observed stereo- chemistry of the reduction points to a single electron transfer mechanism (Scheme 2). 17-Iodo- 16-enes are also readily reduced to 16-enes by these reagents. The mechanism involved in the rearrangements of allylic hydroperoxides have been investigated by means of lSO-labelling and ESR spectral Rearrangement of 5a-hydroperoxy-3~-hydroxycholest-6-ene(89) in solution under NATURAL PRODUCT REPORTS 1992-A. B. TURNER (85) (86) Jii Reagents i Bu,SnH AIBN PhH 80 "C; ii LiAIH in Et,O THF or MeOCH,CH,OMe Scheme 2 C8H 17 I 1 -'OH OH OH (89) (90) Scheme 3 AcO& 3W'0 H H 0 H (94) 1802 gives unlabelled 7cc-hydroperoxy- 3P-hydroxycholest- 5-ene (90) whereas the epimerization of this product to 7p-hydroperoxycholesterol (9 1) proceeds with incorporation of 73-83 % of 1802 into the hydroperoxyl group.The rearrange- ments involve the corresponding hydroperoxyl radical inter- mediates which have different ESR spectra and thus exist as distinct species. The former reaction exhibits a first-order dependence upon hydroperoxide concentration and half-order dependence upon the initiator tert-butyl hyponitrite. It is suggested that this reaction is a [2,3]sigmatropic rearrangement (95) whereas the latter reaction involves a dissociative mechanism (Scheme 3). Diels-Alder reaction of butadiene with the 16-dehydropreg- nenolone (92) at 1000-1500 MPa catalysed by aluminium chloride gives the adduct (93).55 Thus the combination of a Lewis acid and high pressure brings about this highly hindered cycloaddition.Similar treatment of the pentacyclic enone (94) gives the hexacyclic adduct (95). Diels-Alder addition of the 14,16-diene (96) to phenylvinyl sulphone gives three cycloadducts (97F(99) two of which NATURAL PRODUCT REPORTS. 1992 + Me0 (96) OAc (104) Scheme 5 (106) R = HI Me X = 0 P-Et a-H (Scheme 4) have been efficiently converted into 14a-hydroxymethyl- 19-norprogesterone ( Overall yields of 60 YO are attained for the six-step conversion (96)-+(100). [4+ 21Cyclo-addition of the related diene (101) with benzyl nitrosoformate (Scheme 5) gives the ring D-bridged adducts (102) and (103) which are readily converted into the 14a- and 14P-hydroxy- 17-ketones (104) and (105).57 Transformation of the adduct mixture into the 14P-alcohol simply involves heating the crude product in methanol followed by catalytic reduction of the resulting 14P-oximino enone.Reaction of oestranes of type (106) with ammonium cerium (107) (108) (IV)nitrate in aqueous acetic acid gives the usual Ba-hydroxy- 1lp-nitrates (107).58,59 These have been deoxygenated at C-9 to give 1 lp-nitrates (108) using triethylsilane and boron trifluoride etherate.58 When the oxidation is carried out in aqueous lithium chloride the corresponding chlorohydrin is formed.This is deoxygenated to the 1 1P-chloro compound. The corresponding 9a 1 1a-epoxides are formed in 2740 % yields with sodium hydroxide in ~yridine.~~ Oestrone (1 09) itself gives the mononitro- and dinitro-derivatives (1 10) and (1 1I) in yields of 37 YO and 31 YO,respectively following reaction with ammonium cerium(1v) nitrate in acetic acid.60 NATURAL PRODUCT REPORTS 1992-A. B. TURNER 0 HO R’p- R2 (109) R’ = R~ = H (110) R’ = NOp R2= H (111) R’= R2=NO2 (118) R’ = OH R2 =H (119) R’ (120) R’ (121) R’ (122) R’ (123) R’ (130) R’ OH Br = CHO R2= H (1 24) = H R2 = CHO = Br R2 =H = OMe R2= H = R2 = Br = R~ = H OR2 X (127) R’ = R2= H X= 0 (128) R’ = R2= Ac X = H2 (129) R’ = Me2CHS02 R2 = H X = 0 Selective acetylation at C-2 of the bisnoroestradiol de-rivative (1 13) with acetyl methanesulphonate occurs efficiently following the cyclization of the precursor (1 12) by this reagent.61 Prolonged treatment of a chloroform solution of the cyclo- propane (1 12) with acetyl methanesulphonate gives the ketone (114) in 85% yield.The procedure works equally well with oestrone methyl ether (1 15) which upon stirring in chloroform in the presence of six molar equivalents of acetyl methane- sulphonate gives the acetyl derivative (116) in 89% yield. Baeyer-Villiger oxidation with 3-chloroperbenzoic acid gives the acetate (I 17) in 63 YOyield and this can be converted into 2-hydroxyoestrone (1 18) with hydrogen bromide. Regioselective methods for the formylation of oestrogens have been developed.62 2-Formyloestradiol(ll9) is conveniently prepared from oestradiol by formylation of the lithio derivative of bis(met hoxymet hy1)- oestradiol with N-me thylformanilide followed by removal of the protecting groups with hydrochloric acid.4-Formyloestradiol (120) is similarly prepared by lithi- ation of the methoxymethyl ether of 4-bromo-oestradiol. Some related derivatives including 2-formyloestriol have also been obtained by this route. Reimer-Tiemann formylation of Me0 (113) R= H (114) R = COMe (115) R= H (116) R=COMe (1 17) R = OCOMe OR X (131) R=Ac X=O (132) R = H X = NNHTos oestrone and oestradiol give mixtures of 2- and 4-formyl derivatives in low yield and this method is deemed unsuitable for preparative purposes.Nucleophilic displacement of bromine from 2-bromo-oestradiol (121) occurs with sodium methoxide in the presence of copper(r) iodide and benzo- 15-crown-5- 15-crown-5 dibenzo- 18-crown-6 or 18-cr0wn-6.~~Thus 2-methoxy-oestradiol (122) is obtained in 84% yield when the bromide (121) is stirred with sodium methoxide copper(1) iodide and benzo-15-crown-5 in dimethylformamide at 105-1 10 “C. Oxy- genation of dibromo-oestradiol (123) with nitric acid in acetic acid gives the dienone (124) which is reduced to the ketol(l25) by hydrogenation over palladium.64 The ketol(l25) is converted into the 4-en-3-one (126) with perchloric acid toluene-p- sulfonic acid or Nafion-H. The corresponding 17-0x0- and 1601,17/3-dihydroxy-19-norsteroids can also be prepared by this sequence of reactions.The 6-0x0-oestradiol derivative (1 27) prepared by chromium trioxide oxidation of the diacetate (128) followed by hydrolysis with sodium hydroxide is converted into its 3-isopropanesulphonate (1 29) by phase- transfer catalysed esterification with isopropanesulfonyl chlo- ride.65 6-Dehydrooestradiol (130) has been prepared in improved yield from the 6-ketone (131) via the Shapiro elimination reaction of the tosylhydrazone (1 32).66 NATURAL PRODUCT REPORTS 1992 R OH {p OH (133) R' = H OMe NMe2 (135) R = H OMe NMe2 R2= F CI Br CaH17 CBH17 R (136) X= 0 (139) X = a-OH P-H (141) R=CHO (137) X = a-OH P-H (140) X = P-OH a-H (142) R = CH20H (138) X = P-OH a-H CH20H (144) The arylandrostanes (133) are obtained from the epoxide (134) by addition of the corresponding benzylmagnesium chlorides or bromide~.~'They undergo stereo-and regio-specific 6-endo-trig-cyclization with lithium in liquid ammonia and tetrahydrofuran to give the benzyl-bridged androstanes (135).The regioselectivity of this ring closure is in complete contrast to the course of the reaction in less hindered systems in which analogous alkenylphenyl radicals cyclize preferentially or exclusively in a 5-exo-trig fashion. 1.3 Carbonyl Compounds 1.3.1 Reduction and Dehydrogenation The 7-carbonyl groups of the trimethylcholestane (136) is stable towards various reducing agents e.g. sodium borohyd- ride in methanol lithium tri-t-butoxyaluminium hydride in tetrahydrofuran and hydrogen over platinum in the presence of perchloric acid.68 This resistance to reduction is in marked contrast to the ready reduction of 7-oxolanostane derivatives of natural 9a-configuration.The reduction is achieved with an excess of lithium aluminium hydride in boiling ether and proceeds with unusual stereochemistry reflecting the steric congestion of the 7-OX0 group in the folded conformation dictated by the unnatural 9P-configuration. The product consists of a mixture of the epoxy-7a- and -7P-alcohols (137) and (138) in the approximate ratio 2 1. The stereochemistry is confirmed by the transformation of the epoxides into the 9a,ll- ketones (1 39) and (140) under acidic conditions.The survival of the 9p,l lp-epoxide ring in the hydride reduction is probably CH2OH CHZOH 1 \'-0 (145) due to the fact that diaxial opening of the ring would require nucleophilic attack at the severely hindered a-face. The asymmetric hydrogenation of 17- and 20-ketones with chiral hydrosilane-rhodium-( +)-and (-)-DIOP complex catalysts in the presence of diphenyldihydrosilane allows different stereoselectivities in the formation of 17-alcohols but not of 20-alcohols.69 Pregna-3,5-dien-20-one gives the 20-hydroxy epimers in roughly equal amounts whereas reduction of the 17-0x0 group of oestrone and its methyl ether gives significantly different mixtures of 17-hydroxy epimers depen- ding upon the chirality of the DIOP-ligand in the rhodium catalyst.The degree of selectivity attained which is higher than in other methods is explained in terms of the preferred conformation of the a-siloxysteroid-rhodium complex inter- mediates. Reduction of the carboxaldehyde (141) with sodium boro- hydride gives the alcohol (142) which is cleaved with methyl iodide in acetonitrile to the dienones (143) and (144).'O Epoxidation of the former with 3-chloroperbenzoic acid gives the epoxide (145) whereas the latter affords both the 14a,15a- and the 14P 15P-epoxides (1 46). In studies relating to corticosteroid metabolism a series of thirty two 6-hydroxylated pregnanes have been synthesized by selective reduction of the A4-bond the 3-0x0 group and/or the 20-0x0 group of 601- and $3-hydroxy- 11 -deoxycorticosterone (147).'l The gas chromatographic retention times of the syn and anti isomers of the methoxinetrimethylsilyl ethers at C-3 are characteristic of the configuration of the hydroxyl group at C-6.NATURAL PRODUCT REPORTS 1992-A. B. TURNER OH C8H17 Br (150) R = Br (154) R=3H H (159) 1,4-Dien-3-ones (148) have been synthesized from various bile acids and esters and their reduction to bile acids of the allo-series by both catalytic and chemical methods studied. 72 Lithium-ammonia reduction is the best method for production of 3-0x0- and 3P-hydroxy-allo bile acids. Bromination of the bromocholestenone (149) with bromine and hydrogen bromide at 0 "C or N-bromosuccinimide in carbon tetrachloride gives the tribromo derivative (1 SO) which upon dehydrobromination in boiling pyridine affords the trienone (151).7'3 The chole- stadienones (152) and (153) are obtained by bromination of the enone (149) with bromine and hydrogen bromide at 30 "C.I .3.2 Other Reactions Catalytic debromination of the tribromocholestenone (150) 0 (148) R',R2 = HI OH,HC02 R3 = H,Me 0 R@ R Br (152) R=Br (153) R= H 0 0 (157) 0 (1 61 ) a-epoxide (162) P-epoxide with tritium gas yield tritium-labelled enone (154) of high specific activity. 74 A convenient one-step procedure for the synthesis of deuterium or tritium labelled norethynodrel (1 59 norethindrone (1 56) and 6-methyleneandrostenedione (I 57) makes use of water as the source of the label.75 The choice of exchange (lithium or sodium hydroxide) is crucial in controlling the rearrangement of the labile P,y-unsaturated ketone system of norethynodrel.Ansasecosteroids of type (1 58) readily available from 5,7- dienes undergo regioselective Baeyer-Villiger oxidation to form 15-membered ring lactones (1 59). 76 Similar oxidation of the 19-hydroxy-3,17-diketones(160)-(162) occurs prefer-entially at the 17-0x0 group.77 The rearranged lactone (163) is the main product from the diketone (160) using 3-chloroperbenzoic acid in chloroform. It is possibly formed via NPR 9 NATURAL PRODUCT REPORTS 1992 CBH17 0 OMgBr tiSi-0 &-""0 the 4a,5a-epoxide and a 5P-aldehyde which immediately cyclizes with the 19-hydroxyl group rather than undergoing further rearrangement.Perbenzoic acid oxidation of the oxime (164) gives the B-norsteroids (1 65) and (166) together with the epoxide (1 67).78 The formation and gas chromatographic separation of syn- and anti-isomers of methoxime- trimethylsilyl derivatives of 20-0x0- and 21-hydroxy-20-oxo-pregnaneshas been The degree of separation of the geometrical isomer is dependent upon the position of additional hydroxyl groups in the steroid nucleus. The acid (168) is obtained by the action of the bis-Grignard reagent from 1,4-dibromobutane on the oestrone silyl ether (1 69) followed by carboxylation of the resulting complex (1 70) with carbon dioxide and desilyation.80 Addition of aryl-zirconium tributoxides to the ketone (171) gives the 17-arylcarbinols (1 72)? The organozirconium reagents act as selective nucleophiles towards the 17-ketones being less basic than organo-lithium or -magnesium reagents thereby causing fewer problems with the readily enolizable ketones.Condensation of 5a-cholestan-3-one with 2-hydroxy- 1- naphthaldehyde in ethanolic hydrogen chloride to give the chiral 2,2'-spirobenz[d]chromene derivative (1 73) results in the formation of a new chiral centre at C-3 with complete diastereoselectivity.82 The direction of asymmetric induction in this reaction may be explained by steric hindrance in the final cyclization of the benz[d]chromenium salt intermediates. However since the two enantiomers can equilibrate readily via the oxonium salt under acidic conditions it is more likely that the stereochemical outcome is determined by a significant difference in energy between the two spiro forms.The determination of the 17-ketosteroid sulphates and glucuronides by HPLC has been facilitated by improvements in the efficiency of pre-labelling of the conjugates with dansyl- hydra~ine.~~ Sensitive derivatization reagents having an an- thracene nucleus as a fluorophore have been developed. 84 These also possess a carboxylic acid hydrazide or O-aralkylhydroxyl- amine as the nucleophilic centre for attack upon a carbonyl (172) Ar= O X (X = H F,Me OMe) group of the substrate. The derivatization reagents anthracene- 1- and 2-carboxylic acid hydrazides and 0-(1-,2- and 9-anthrylmethy1)hydroxylamines are readily prepared from an- thracene carboxylic acids and they react with ketones under mild conditions.The resulting hydrazides and oximes are highly responsive towards the fluorescence detector. I .3.3 Reactions of a$-Unsaturated Carbonyl Compounds and Enols or Enolic Derivatives Reduction of norethindrone (1 56) by sodium borohydride in the presence of tetra-N-methylethane- 1,2-diamine gives the tetrahydrodiols as mixtures of 3-and 5-epimers the individual isomers of which have been isolated by flash chr~matography.~~ Oxidation with pyridinium chlorochromate gives 5a-and 5P-dihydronorethindrone which have been converted into four stereoisomeric 2,2,3,4-pentadeuteriated 19-norpregn-20-yne-3,17-diols by isotopic exchange with D20-MeOD under alkaline conditions followed by reduction with sodium borodeuteride.This gives the complete set of unconjugated norethindrone metabolites and their deuteriated forms in a simple synthetic sequence. Catalytic transfer hydrogenation of testosterone with sodium hypophosphite over palladium-carbon gives a mixture of the 5a-epimers of 17P-hydroxyandrostan-3-0ne.~~ Reduction of 3~-acetoxycholest-5-en-7-one(1 74) with lithium tri-t-butoxyaluminium hydride has now been achieved stereo-selectively to give the allylic 7P-alcohol (175) in 97 YOyield.87 The metal hydride is generated in situ at -78 "C and no trace of the epimeric 7a-alcohol is formed in the crude product. The related cholate ester (176) is hydrogenated over palladium on calcium carbonate or palladium hydroxide in neutral acidic or alkaline media.88 The ketocholanate (177) is obtained in 98 YO yield by catalytic hydrogenation in propan-2-01.Conjugate addition of Grignard reagents to the 16-en-20-one (178) with rigorous exclusion of air including during the work- up allows the isolation of the expected 16a-adducts from phenylmagnesium bromide and phenoxybutylmagnesium bro- mide.89 However the introduction of trace amounts of oxygen 49 NATURAL PRODUCT REPORTS 1992-A. B. TURNER C8H17 CSH17 AcO& AcOCt?H C02Me AcO2 AcOdo AcOd before the reaction has been fully quenched leads to the formation of 17a-hydroperoxides. During hydrolysis and Oppenauer oxidation the intermediate hydroperoxide can decompose to form 16P-alkyl- 17-ketones.The structure of one Me0 such by-product (179) has been established by X-ray crys- tallography. In the same way rigorous exclusion of air until (1 83) (1 84) quenching is complete allows copper-catalysed Grignard addition to the dienone (180) to become reproducible and to give increased yields of 1,6-addition products. It is evident that enolates formed by conjugate addition of Grignard reagents to enones or dienones tend to react with oxygen faster than they / W O OMe c protonate under commonly employed reaction conditions. A Pregnane-5,16a-dicarbonitriles(1 81) have been prepared by hydrocyanation of the enone (1 82) prepared from diosgenin by a sequence involving oxidation hydrocyanation and Marker degradation.90 The 14,16-diene (1 83) formed by addition of phenyllithium to A15-oestrone methyl ether followed by trifluoroacetic acid- ClOH21 catalysed dehydration undergoes stereo- and regio-selective Diels-Alder reactions with a range of dienophile~.~~ Cycload-dition of ethynyl methyl ketone gives the ketone (184) which on treatment with sodium methoxide in methanol followed by AcO'.. (185) Ace%@ reduction with Selectride and acetylation gives (1'9-1 64 1'-acetoxyethyl)-3,15a-dimethoxy-17P-phenyl- 14a,l7a-etheno- oestra- 1,3,5( 10)-triene (1 85). 0 0 Hydroxylation of 2,4-dien-6-ones (1 86) of the spirostane and stigmastane series with silver(1) acetate in aqueous acetic acid (186) (187) containing iodine gives the diacetates (1 87) in 37-59 % yield.92 4-2 NATURAL PRODUCT REPORTS 1992 C8H17 X (191) X = OH COMe CBH17 Double hydroxylation of the enol silyl ether (188) with 3- chloroperbenzoic acid in the presence of potassium hydrogen carbonate followed by acidic work-up gives the corticosteroid (189).93 This novel one-step construction of the dihydroxy- acetone side-chain in corticoids has also been applied to the synthesis of cortisone and c~rtexolone.~~ The trio1 (190) has been prepared by oxidation of the cholestenone (174) with osmium tetroxide.95 Regioselective synthesis of eight stereo- isomeric cholestane-3P,4,5a,6- and of 3P,5a76,7-tetrol triace- tates are also described. 6-Carboxymethylene derivatives (1 9 1) of testosterone and progesterone are prepared by reaction of the palladium chloride complexes of the hormones with the sodium salts of active methylene compounds (e.g.dimethylmalonate).96 The inter- mediates (192) undergo hydrolysis and elimination upon treatment with sodium hydroxide in aqueous ethanol to give the (E)-acids (191). Regiospecific fluorination at the 6-position of the dienamine (193) with the iodoarene difluoride (194) is enhanced by the presence of N-methylviologen as an electron transfer agent.97 CHRC0,Me (192) R = C02Me S02Ph,S02Me 0 0 0 The intermediate dienolate anion (195) in the hydroxide ion catalysed isomerization of androst-5-ene-3,17-dioneto the 4- ene-3,17-dione has been observed by ultraviolet spectroscopy (Amax -256 nm).” Rate constants for the formation of the ion (195) and both its reversion to the 5-en-3-one and its convertion to the 4-en-3-one in aqueous solution have been determined as well as the pK values for the starting material and product (12.7 and 16.1 respectively).The results are discussed in relation to the mechanism of action of the enzyme 3-oxo-A5- steroid isomerase. The free (E)-and (2)-1 7(2O)-en-20-01-2 1-aldehydes (1 96) and (197) together with their acetate derivatives have been prepared from five corticosteroids by reaction with zinc acetate in acetic acid.99 The pure geometrical isomers of the enols were separated and isolated for the first time by reverse phase HPLC and show significant differences in their spectroscopic properties.Stereochemical assignments follow from unequivo- cal partial synthesis (Scheme 6). NATURAL PRODUCT REPORTS 1992-A. B. TURNER (199) (200) R’ = H CHZCO~H R2 = CH(Me)C02H 4-C6H40H C8H17 R& Rfi NOH 0 (205) R = HI CI OAC (207) 1.4 Compounds of Nitrogen Phosphorus Sulfur and Other Hetero-elements Radioiodinated benzoyl esters (198) and amides (199) of 20- hydroxy- and 20-amino-pregnenes have been prepared for evaluation as adrenal imaging agents.loo The derivatives were obtained by reaction of the alcohol or amine with 2-iodobenzoic acid in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine and labelled with radioiodine by isotope exchange with Na 1251in pivalic acid. Only the esters (208) R’ = CI R2 = CBH~~, OH OAc displayed appreciable adrenal specificity.Amino-acid conju- (210) R’ = SPh gates (200) of 3a,7a-dihydroxy-5P-cholan-24-oic acid have been prepared using the mixed anhydride method of peptide synthesis.lol The amino-acids used are alanine proline and N-(4-hydroxypheny1)glycine. Thermal rearrangement of secondary and tertiary allylic nitro compounds gives allylic alcohols in moderate to good yields.lo2 Thus heating the 6P-nitrocholest-4-ene (20 1) in tetralin gives the diol (202) in 33% yield. Reduction of 3P- chloro-6-nitrocholest-5-ene(80; R = Cl) with hydrazine hy- drate (cfReference 49) in the presence of Raney nickel gives the (209) R = CI (212) R = H CI 6-ketone (81; R = Cl) together with the azines (203) and (211) R = SPh (2O4).lo3 The dimers probably arise by condensation of the 6- ketone with hydrazine rather than by reductive coupling of the nitro compound.Oxidation of the oximes (205) with perbenzoic OMe acid gives 6P-nitrocholestanes (206) 6-ketones (8 l) and lactones (207).Io4 N-chloroazasteroids (208) and (209) are readily prepared by the action of N-chlorosuccinimide with the parent lactams. lo5 They react with thiols e.g. benzenethiol and cysteine esters to give N-thiolactams (210) and (21 1). Photolysis in methanol gives enamides (212) from the azacholestane (208) or carbinol amide methyl ethers (213) from (209). These products arise by solvent trapping or isomerization of reactive N-acylimine NATURAL PRODUCT REPORTS 1992 (214 R = C27H45 C28H43 C29H47 (21 5) (21 6) R = CH2CO2H (CH2)2C02H X=S,Se COCH~SAC intermediates suggesting possible applications in affinity labelling and enzyme inhibition.Bis-(N,N-diethy1amido)thio-and -selenophosphates of sterols (214) are obtained by phosphorylation of the sterol with tris(diethy1amino)phosphine followed by sulphurization of the resulting conjugates (215) in benzene at 2&25 OC.lo6 The seleno-compounds are prepared by selenation at 70 "C in benzene. 2 1-Thioalkanoic acid derivatives of corticosteroids (216) are obtained by nucleophilic substitution of 21-sulfonates and 21 -halo derivatives with salts of mercapto- alkanoic acids.lo7 They can also be prepared by reaction of 21-chloro- and 21-bromocorticosteroids with mercaptoalkanoic acids in dipolar aprotic solvents.The corresponding methyl and isopropyl esters have been prepared by similar methods using the esters of the mercaptoalkanoic acids or by esterifi- cation of the acids in the presence of carbodiimides.lo8 Esterification of the acids (21 6) with N-hydroxysuccinimide in the same way gives the corresponding N-hydroxysuccinimide esters.'Og When treated with ammonia or primary and secondary amines these give the corresponding amides and alcohols give the corresponding esters. Reaction of the cyclohexanopregnenone (21 7) with benzene thiol in the presence of boron trifluoride etherate gives a mixture of phenylthio derivatives (21 8)-(220).ll0 The tosylate also gives this mixture when it reacts with benzenethiol in the presence of potassium acetate.Desulfurization of these compounds with Raney nickel gives the pentacycles (221) and (222). The pregnenedione (223) reacts with a large excess of sodium azide in methanol to give a mixture of the methyl etianate (224) and the spirodithiolanone (225).'11 6a-Methyl- and D-homo- analogues of the dione (223) have been prepared and their reactions with sodium azide studied. CH MeC02H (226) R' = Me R2= H (227) R' = H R2 = Me OR AcOT CI (228) R = OCOPh OCOCMe3 A review of the synthesis of radiolabelled compounds via organometallic intermediates includes a number of methods for producing steroidal vinyl iodides from organostannanes and organomercurials. 112 1.5 Molecular Rearrangements Heating Sa-cholestan-3P-01 in cyclohexane with K10-mont- morillonite gives cholest-2-ene which undergoes backbone rearrangement to give a mixture of four isomeric sterenes (20R+20S)-(226) and -(227).Il3 Their structures have been elucidated by IH and 13C NMR spectroscopy.The same mixture is obtained when the cholestanol is replaced by 5a-cholest-2-ene but when 5a-cholest- 1-ene is used the proportion of the new sterenes (226) in the product mixture is markedly increased. Backbone- and Westphalen-rearranged products form part of the mixture obtained by the action of boron trifluoride etherate on ~tigmastane-5a-6a-epoxides.~~~ 6P-Chloro substi- tuted Westphalen diol derivatives (228) are converted into the NATURAL PRODUCT REPORTS 1992-A. B. TURNER OH HO€P 0=cP ... . CH2 (229) CaH1 7 C8H1 7 OAc OHC' (233) H 0 (239)R = H (244)R = NO2 0& diene (229) by lithium aluminium hydride.'15* 116Hydrogenation gives the diol (230) which has been oxidized to the antiandro- genic ketol (231). A two-step procedure for the degradation of Westphalen diol diacetate (232) to the keto-aldehyde (233) and 4-hydroxy-2-methylcyclohexanone has been deve1oped.l" Ozonolysis of the 9,lO-double bond followed by retro-aldol cleavage gives the des-AB cholestane (233) in 42% yield. Reaction of the unsaturated lactol (234) with iodobenzene diacetate leads to ,&fragmentation and cyclization of the initial alkoxy radical to give the spiro-anhydride (235).11* Its structure is confirmed by reduction with tributyltin hydride/AIBN or lithium aluminium hydride and conversion into spirolactones (236) and (237).HO H (234) 0%' 0 e 0 0 Me0 Attempts to introduce the alkynyl group selectively at C-17 of the dione (238) with dipotassium acetylide in tetrahydrofuran do not give the desired product (239).'19 Instead several rearranged products are obtained after preparative HPLC including the diketones (240) and (241) and the corresponding C- 17 hydroxyethynylated derivatives. Also isolated is the seco-steroid (242). This and its 17-0x0 analogue are intermedi- ates in the formation of the rearranged compounds and it is clear that suitable protection of the 4-en-3-one system of (238) is necessary to prevent retro-aldol ring-opening to the seco- steroid.Thus the target ethynyl derivative (239) is prepared via reaction of the dienol ether (243) with lithium acetylide-ethylenediamine in tetrahydrofuran followed by acid hy- NATURAL PRODUCT REPORTS 1992-A. B. TURNER CaHl7 (248) R= H (250) n= 1,2 (249) R = CI drolysis. This allows the development of practical routes to 901- hydroxypregnenes by epimerization and hydration of the ethynyl alcohol (239).12* The following three methods have been used (i) nitration of the 17P-hydroxyl group with fuming nitric acid in acetic anhydride to give (244) followed by treatment with silver nitrate to give the epimeric diol (245) (ii) trifluoroacetylation of the 17P-hydroxyl group and subsequent treatment with mercury(1r) acetate (iii) methanesulfonylation of the 17P-hydroxyl group followed by reaction with silver(1) nitrate.In none of these methods of epimerization is the 9a-hydroxyl group susceptible to rearrangement or other side reactions. Method (i) is the most efficient (90% yield overall). 9a-Hydroxypregnenes functionalized at C-21 are obtained by introducing a 17a-halogenated ethynyl group into the dione (238). Epimerization and hydration by the 17P-nitrooxy method gives 2 1-halogenated 9a-hydroxypregnenes which are conver- ted into the 21-acetate (246). Detailed kinetic and spectroscopic studies have been made of the inhibition of the dienone-phenol rearrangement of 1,4-dien- 3-ones by the introduction of an 11-0x0 group.121 It appears that the carbonyl group reduces the migrating ability of the adjacent atom C-9 allowing migration of the angular methyl group to C-1 to become the dominant pathway.The critical destabilizing interaction in the intermediate (247) could be that between the electropositive atoms C-10 and C-1 I. 1.6 Remote Functionalization Reactions Bifunctional templates have been designed to direct function- alization at two sites in the steroid nucleus. 3a-Cholestanyl esters of bipyridine carboxylic acids and of iodophenylpyridine acids can direct radical chlorination to both C-9 and C-17 with high efficiency. 122 The double functionalization is sensitive to reaction conditions and precise geometry. The process is exemplified by the photochemical chlorination of the ester (248) with three equivalents of iodobenzene dichloride in dichloromethane to give the dichloro derivative (249) in quantitative yield.H 0 (253) X = H2 (254) X = 0 A long-range intramolecular functionalization by alkoxyl radicals has been used to achieved hydroxylation of the cholestane side-chain at C-25. 123 Alkoxyl radicals generated by photolysis of hypoiodites of the cholestanes (250) abstract the hydrogen atom from the tertiary C-25 position to give the macrocycles (25 1). Reduction of the ether lactones (25 I) with sodium in liquid ammonia gives 5a-cholestane-7a,25-diol(252). 1.7 Photochemical Reactions Intramolecular aryl sensitized photoreduction of a keto group can be achieved by a novel energy relay pathway with utilizes an internal singlet-triplet The dimethylphenylsilyloxy group is appended to the 3a-position of 5a-androstan- 17-one and Sa-androstan- 1 1,17-dione to provide compounds (253) and (254) in which the silyloxy group functions as an antenna NATURAL PRODUCT REPORTS 1992-A.B. TURNER AcO AcO AcO OCOEt C8H17 chromophore for self-sensitized photoreduction. Excitation of the dimethylphenylsilyloxy group in the dione (254) in acetonitrile containing triethylamine leads to exclusive re- duction of the 17-0x0 group (57 YOyield). Direct excitation of the keto groups of this dione causes both the epimerization of ring D (i.e.at C-14 and C-17) primarily via an excited singlet state of the 17-0x0 group as well as photoreduction via the triplet state.There is no such difference in photochemistry as a function of the site of excitation for the ketone (253). In the dione (254) the 1 1-0x0 group apparently functions as a singlet- triplet switch during the transmission of excitation from the aryl group to the 17-0x0 group. The complete sequence involves aryl excitation intramolecular singlet energy transfer from the aryl group to the carbonyl group at C-11 intersystem crossing intramolecular triplet energy transfer from the 11 -ox0 to the 17-0x0 group and photoreduction by triethylamine. One advantage of this switch is that it bypasses the inefficient intersystem crossing characteristic of cyclopentanones by utilizing the readier intersystem crossing observed for cyclohex- anones.Intramolecular singlet energy transfer for the aryl antenna to the more remote 17-exo group as in (253) is much less efficient (1 1 "/O). Irradiation of the (E)-5,10-seco-ketone (255) in acetone gives the (Z)-isomer (256) the anthrasteroid (257) and the la,5a- oxetane (258) in yields of 6 YO,7 YO,and 42 YO,re~pective1y.l~~ The lP,SP-oxetane (259) is also formed. The enone (257) results from a transannular cyclization accompanied by elimination of acetic acid while the oxetanes arise by an intramolecular Paterno-Buchi reaction. Photolysis of a-0x0-oxetanes may partly depend upon stereo- electronic factors which require coplanarity of the a-cleaved oxetane bond with the singly or doubly occupied carbon p-orbital of the n,n*-carbonyl group and the zwitterionic character of the initial bond-cleaved species may also be imporfant.lz6 Models show that in the 3a,5a-epoxy-6-ketone (260) which on photolysis gives the seco-aldehyde (261) the oxetane C(5)-0 bond is in the same plane as the singly or doubly occupied p-orbital at C-6.Irradiation of testosterone propanoate in the solid state gives the dimer (262) in 10% ~ie1d.l~' The structure of the dimer is determined by the molecular packing of the crystal. Irradiation of testosterone itself in the solid state yields andros-4-ene-3,17- dione and 5a-androstane-3,17-dione, whereas that of methyl- estosterone gives the 17-methyl- 13,17-secoandrost-4-ene-3,17-dione (263).lZ8 Details of the use of hypervalent organoiodine compounds for the generation of alkoxyl radicals which can undergo intramolecular hydrogen atom abstraction to give iodohydrins and tetrahydrofurans have appeared.IZ9 The reagents are more convenient and efficient than the heavy metal derivatives usually employed. Photolysis of the 6P-alcohol (264) in the presence of iodine and iodobenzene diacetate gives the 6P,19- epoxy derivative (265) in 90 YOyield. Similarly the 20-alcohols NATURAL PRODUCT REPORTS 1992 Me H Me AcO C8H 17 &fl 0 0 0 Me0& (272)R = Me X = '7 (273)X= '7 (275) 0 0 (274)R=H X=O (277)X = 0 (276)R=Me X=O (278)R = CHzPh CH2CH=CH2 (279)R = CH*Ph (281)R = Me (282)R = H Me OMe (283)R = H Me OMe (280)R=Me CH2CHzCH2 (284)R = H (285) (286)R = Me Et (287)R = NO2 (289) 5a (288)R= H (290)5P (266) give the tetrahydrofuran derivatives (267) via the iodohydrins in 49-55 % overall yield.Irradiation of hypo- 0 iodites of ketols in the presence of mercury(I1) oxide and iodine HOJ.4J-p in benzene gives a-hydroxy e-lactones and enolic e-lactones by p-scission of the intermediate a-oxoalkoxyl radicals. 130 The 5p-'H hydroxy-6-ketone (268) gives a 1 :1 mixture of the epimeric R hydroxylactones (269) in 25 % yield together with the lactone (270) in 18 % yield. (292)R= H A key step in the nine stage synthesis of I 1-0xaoestrone (27 1) (293)5a R = NO2 NATURAL PRODUCT REPORTS 1992-A. B. TURNER 0 CaH17 (298)R’ = H R2= NO2 (300) R’ = H2 R2 = NOH (299) R’ = N02 R2 = H (301) R’ = NOH R2 = H2 0 (302) R’ = H R2 = OMe (303) R’ = NO2 R2= Br from oestrone is the dye-sensitized photooxygenation of the styrene (272) to give the seco-aldehyde (273).131 The same reaction of A9(11)-oe~tr~ne (274) gives a complex mixture from which only the endoperoxide (275) can be isolated in low yield.132 In contrast the methyl ether (276) yields the secoaldehyde (277) as the major product suggesting that the 1,2-dioxetane is a primary photooxygenation intermediate.As the electron-donating character of the substituent at C-3 decreases in the sequence (274; R = Bz > Ac > Tos) the rate constant becomes much smaller as compared with (274; R = H Me) and no photoproducts are detected. 4-Allyl- and 4-benzyl-lactams (278) give 6-substituted deriv- atives (279) upon i1-radiati0n.l~~ The 4-methyl compound (280) gives the aziridinyl ketone (281) via a-cleavage to a diradical which can reorganize to an aziridine before recombination.The aryl lactams (282) give bis-A-homo steroids (283) upon irradiation.134 Here the diradical formed by initial a-cleavage can reorganize and recombine at the ortho position of the aromatic ring. In the case of the phenyl lactam (282; R = H) the aziridine (284) is formed in small amounts. Contrasting photochemical reactions have been observed for a-nitro enones. Direct irradiation of 2a-nitrocholest-4-en-3- ones (285) in methanol or ethanol gives 2,3-secocholest-4-en-3- ones (286) by an unexpected a-cleavage of the carbonyl group whereas the 4a-nitro compound (287) suffers only loss of the nitro group to give cholestenone (288).135 The a-cleavage stems from the 2a-nitro group which directs this cleavage over other photoprocesses common to the excited a$-unsaturated car-bony1 group.Photoinduced removal of the nitro group of the 2,4-dinitrocholestanes (289) and (290) which exist in their enolic forms in ethanol gives diosphenols (291) and (292).136 On the basis of the stability to photolysis of a likely intermediate (293) obtained by nitration of 5a-cholestane-2,3-dione with butyl nitrate and potassium t-butoxide in tetrahydrofuran a pathway for the removal of the nitro group involving initial loss of the nitro group at C-4 followed by the formation of an oxaziridine is suggested. Irradiation of 16-nitro-5a-androstan- 17-one (294) which also exists largely in the enol form in ethanol gives the cyclic N-hydroxyimide (295) as the major The photolysis of A-homo-a-nitro ketones (298) and (299) gives the corresponding a-hydroxyimino ketones (300) and (301).The photochemical reaction of the methyl ethers (302) and (303) with amines and hydroxide ion have been studied in connection with their possible use as photoaffinity labels.13* 2 Partial Synthesis 2.1 Derivatives and Analogues of Cholestane Oogoniol(304) has been prepared from adrenosterone (305) in a multistep These include the 1,4-addition of the magnesium cyanocuprate (306) to the epoxide (307) to give the alcohol (308). Selective hydrogenation of the 16-ene gives the NATURAL PRODUCT REPORTS 1992 p-si'+ I I (307)+ '+ I OH -*-*- &OH HO Scheme 7 (309) (310)R=H,Br,CI stigmastene with the desired stereochemistry at C15 C17 and C, as the sole product (Scheme 7).Dehydro-oogoniol (309) has been prepared from progesterone by hydroxylation at the 1la- and 1 S,&positions using Aspergillus gigante~s.'~~ The side- chain is constructed by means of stepwise Wittig and Horner-Emmons reactions and the 7-0x0 group is then introduced by allylic oxidation. 4a-Substituted cholestanes (3 10H3 12) have been prepared as potential inhibitors of sterol 4-demethylation. lgl The key intermediate is the ketoester (3 13) obtained by regiocontrolled alkylation with methyl cyanoformate. 14a-Aminomethyl sub- stituted lanosterols e.g.(314),prepared by a complete A7 to A' (311)R1=Ac R2=H (312) (31 3) R' = H R~= CN isomerization (Scheme 8) inhibit fungal ergosterol biosyn- The 3/3,26-diol (3 15) a metabolite of 3P-hydroxy-5a-cholest-8( 14)-en- 15-one (3 16) has been prepared from dio- sgenin.lg3 It is an inhibitor of various enzymes involved in sterol biosynthesis. The synthesis of zymosterol (3 17) fecosterol (3 1 8) and related intermediates of sterol biosynthesis are described in Allylpotassium derivatives prepared from various alkenes with butyllithium-potassium tert-butoxide react with the 22- iodide (319) to give after deprotection a wide variety of and A24(28)-~tero1~. 145 These include desmosterol fucosterol 24(E)-propylidenecholesterol (320) and mutasterol (32 1).Con- NATURAL PRODUCT REPORTS 1992-A. B. TURNER C8H17 .. v-vi i iii I +I C8H17 t (314) Reagents i hv PhH; ii Ac,O pyridine (93 YO);iii LiAlH,-AlCI (82 %); iv HBr AcOH (83 YO); v MeSO,CI pyridine; vi collidine 171 "C; vii LiAIH,-AlCI (32 YOoverall v-vii); viii aq.MeOH pH 4.5 (100 Yo) Scheme 8 "'.p I HO OMe (315) R = OH (319) (317) R = 'm (316) R= H (318) R = ...+ -Et n HO trol of the regiochemistry of unsymmetrical allyl metals is achieved by addition of Li,CuCl, which allows unprecedented control in favour of the less substituted terminus of the allyl -..&Me system. This enables the synthesis of fucosterol and desmosterol in 65-69 % yield. Stigmasta-5,23(E)- and -(Z)-dien-3P-ols have been prepared by dehydration of side-chain alcohols with phosphorous oxych10ride.l~~A two-step hydroboration-dehydration procedure can be used for reversing the geometry of trisubstituted double bonds.Borane migration takes place readily in the hydroboration reaction with retention of Two other C-24 and C-25 epimeric pairs (322) are obtained configuration at C-24. The 24R and 24s epimers of the stereoselectively by ester-enolate Claisen rearrangement of acetates of 24,25-epoxycholesterol and 24,25-epoxylanosterol ketene acetals (323). 14* Configurations at C-24 and C-25 can be differentiated by 13C NMR Neither pair have been confirmed by X-ray crystallography and 13C NMR of epimers can be differentiated by 'H NMR spectroscopy. signals reassigned.NATURAL PRODUCT REPORTS 1992 I '-1 '%Oho (324)(325) 22,23-di hyd ro 0 .-.oH@o (327) (328) (329)X = H2 (330)X = CH2 0 H CH20Me OCH,OMe 0,'-I OMe (332) (333) The triol (324) isolated from the bryozoan M. truncata has been prepared from stigmasterol. 149 The related triol (325) isolated from S. gracilis has been prepared from sitoster01.~~~ The withanolide D (326) side-chain has been built up from 20-oxopregnane by a stereocontrolled synthesis. 151 Control of stereochemistry at C-20 and C-22 involves hydrogenation of the enone (327) to give the y-lactone (328) which is efficiently transformed into the 8-lactone (329). A final isomerization of the methylene lactone (330) is catalysed by rhodium(1rr) chloride. Construction of the side-chain of brassinolide and its analogues is achieved by the aldol reaction of lithiofuran with the 22-aldehyde (33 l) obtained from 3a,6a-dihydroxy-5P-cholanoic The 22R,23R-lactone (332) is a key in- termediate.The allylic alcohol (333) which featured promi- nently in the first reported synthesis of brassinolide by Fung and Siddall in 1980 is a potentially useful intermediate for the synthesis of many other sterols. An alternative route to this alcohol and therefore formally of brassinolide has been developed using selenosulfonation methodology (Scheme 9).153 The C-22 aldehyde (334) derived from stigmasterol gives the 22s-adduct (335) as the major C-22 epimer with 3-lithio-1-trimethylsilypropyne. Selenosulfonation of (335) followed by base-catalysed isomerization and selenoxide elim- ination lead to the allenic sulfone (336) as a mixture of diastereoisomers.Their separation is unnecessary as both stereoisomers can be converted into the allylic alcohol (337) via an organocuprate addition step which proceeds with high stereoselectivity affording only the required (2)-isomer (337). This indicates that the direction of addition is controlled by steric factors and that there is no complexation of the cuprate with the C-22 hydroxyl group. New routes from ergosterol to the brassinolide stereoisomers (338) and (339) are avail-able.154q155 In one of these the 7-oxalactone ring is formed by oxidation of an enol silyl ether with 3-chloroperoxybenzoic The (22R,23R)-epoxide (340) and its (22S,23S)-isomer NATURAL PRODUCT REPORTS 1992-A.B. TURNER Id4 OH OH I OMe 1.32:l (334) (335) iii 86% 1 OH SePh OH SePh '...+ 86% I I S02Ar .Mnr .Mnr v 83% i CH=C=CHSO,Ar vi t. **** ....? 52% (336) (337) 21% (333)45% 27% Reagents i LiCH,C = CSiMe,; ii BuiN+F-; iii 4-CH,C6H,SO,SePh hv;iv Et,N PhMe; v ButOOH; vi Pr;CuLi(SMe,); vii Mg MeOH Scheme 9 0 (338)R = H OH ! c (339)R = H (340)R=Ac NATURAL PRODUCT REPORTS 1992 (345) (346) R = CH=CC12 (347) R=C=CLi (348) (349) OH R OH R $C02Et HO HO 0 Hoe*- H' OH (354) R = Me Bu,(CH2)40H (355) R=H (356) R = Me (357) are obtained by oxidation of 2a,3a-diacetoxy-5a-ergost-22-en-6-one with the same peracid.156 Brassinolide analogues (34 1)-(344) without a side-chain show some brassinoid activity.15' The allene (345) is obtained stereoselectively by a route involving reaction of the alkene (346) with butyllithium to give the lithiated alkyne (347) which is treated in situ with the pregnenolone silyl ether (348). 15* The resulting propargyl alcohol (349) is reduced to the allene (345) with lithium aluminium hydride. When the pregnenolone (348) is treated with the alkyne acetal(350) in the presence of butyllithium the alkyne (351) is ~btained.'~' Reduction of this with lithium aluminium hydride gives the allene (352) and the ally1 alcohol (353). These and related compounds designed as suicide inhibitors of the C-22 hydroxylation step in ecdysone biosynthesis are found to inhibit the synthesis of ecdysone in the prothoracic glands of locusts.Side-chain homologues (354) of 20-hydroxyecdysone prepared from poststerone show relatively low receptor binding affinities. 160 Details of the method for the attachment of the 20-isocholesterol side-chain to 3P-hydroxyandrost-5-en- 17-one have appeared.161 A key step is the stereoselective methylation of the pregnenoate (355) with methyl iodide and lithium diisopropylamide to give the C-22 ester (356). Dithionite-initiated addition of perfluoroalkyl iodides to an olefinic double bond is an efficient method for the incorporation of a perfluoroalkyl group into the steroid side-chain. Starting from the cholanic acid (357) the fluorinated analogues (358) of NATURAL PRODUCT REPORTS 1992-A.B. TURNER HO& (361) R=C02H (363)R = CH2CO2H (367) R=H (368) R=OH cholesterol are prepared by this route.’62 The dimer (359) is also obtained. The fluorinated sterols are resistant to degradation by some microorganisms. (26-13C)Desmosterol and its 3-benzoate have been prepared from Et13C0,H and the cholenal (360).163 Labelled forms of various possible precursors of cholestanol in mammals e.g. cholestenones epi-cholesterol and cholest-4-en-3a- and -38- ols have been prepared.“j4 Chain extension by means of the Arndt-Eistert reaction has been employed in the conversion of the bile acid (36 1) into 5P-cholestane-3a,6P,7a,25,26-pentol (362).165 The C, bile acid (363) is then converted into the pentol (362) by standard methods.Coupling of the C, halides (364) and (365) with the sulfone (366) leads by reductive desulfonylation and deprotection to cholesta-5,7-diene-38,25-diol (367) and -la,38,25-triol (368).166 Iodine and copper(I1) acetate previously used to convert alkenes into trans-iodo acetates has now been found applicable to the synthesis of the more hindered cis-diols. Thus the 28,3/3- diol (369) is obtained in 91 % yield by reaction of 5a-cholest-2- ene with iodine and copper(I1) acetate in acetic acid followed by hydrolysis with potassium hydroxide in aqueous meth- anol.16’ Simple cycloalkenes similarly give cis-diols in good yield. The method affords several advantages over the Prevost reaction when acetic acid is used but with propionic acid the yield is markedly reduced.2.2 Vitamins D their Derivatives and their Metabolites The pioneering work on (62)-tacalciol dating back some forty years has been reviewed,168 together with studies on the synthesis of des-AB cholestane precursors of calcitriol from 2- methylcyclopent-2-en-1-one.169 OH (364)R = H,X = Br (365) R=OTHP X=I 0 (370)R = SiMe2CMe3 RO’** OR ?XR1 A RO”’ (371) R’=CHO (373) (374) (372)R1= CECH DCH~OCH~CHO Me0 RO”* (375) (376) The synthesis of the A-ring precursor (370) of calcitriol has been achieved in seven steps from ethyl acetoacetate via acyl radical cycli~ation.~’~ Other such precursors (371) and (372) have been prepared by an enantiospecific route from (R)-( -)-carvone (373).”l The route involves chromium(I1) mediated reaction of the ally1 iodide (374) with the aldehyde (375) to give the common precursor (376).The influence of substituents such NPR 9 NATURAL PRODUCT REPORTS 1992 CaH17 CaH17 OEt H2C+ I C-C-(CH2),-C-SePh II HH AcO'.' (377) (378) R = Me 4-MeC6H4 0JY AcO as ether silyl ether and cyclic acetal groups at positions 3 and 5 upon the mode and efficiency of cyclization of 6-heptenoyl radicals has been studied in connection with calcitriol syn- Thus treatment of the precursor (377) with tributyltin hydride and azobisisobutyronitrile in benzene gives 5-ethoxyhept-6-enol(35YO) and 4-ethoxycycloheptanone (27 YO) a trace of 3-ethoxy-2-methylcyclohexanone.The ready reaction of sulfonyl derivatives (378) of calciol acetate with potassium thioacetate in dimethylsulfoxide results exclusively in 19-acetylthiolation.173 Similarly the cyclopropanes (379) gives lp-thiol analogues of calciol and calcidiol. The products are the triene (380) and the cyclopropane (381). The latter gives calciol and calcitriol derivatives with acetic acid. Reduction of 1 -oxo-3,5-cyclo-calciol and -ercalciol has been Lithium aluminium hydride reduction in ether gives mainly l~-hydroxy-3,5-cyclo-calciol and -ercalciol which can be converted into lp-hydroxy-calciol and -ercalciol. The allylic alcohol (382) is obtained in three steps from calcidiol.175 The immediate precursor of the 8-hydroxy com- AcO'= (379) R = HI OH X = OS02Me(P) (381) R = HI OH X = SAc(a) 0 R! R2 (384) (385) R' = H R2 = OH R' = OH R2 = H (386) R' = H R2 = OMe R1 = OMe R2 = H o.** ,b FH2CH2 OH 05' CH2CH2N H C 0 pound (382) is the epoxide (383) which is cleaved by the lithium bromide-hexamethylphosphorous triamide complex in boiling toluene.The C-23 epimers of the major metabolite (384) of 24(R)- hydroxycalciodiol have been synthesized and their configur- ations at C-23 have been determined by X-ray analysis.176 The naturally occurring epimer of the 24-0x0 compound (384) is found to have the S configuration at C-23 by comparison of its spectral properties and HPLC behaviour with those of the synthetic isomers. The 22-hydroxy- and 22-methoxy-derivatives (385) and (386) of calcitriol are prepared from the 22-aldehyde (387).17' The 22(S)-epimers show much more potent biological activities.A major structural difference is found in their side- chain conformations which were elucidated by molecular mechanics calculations and NMR spectroscopy. A zig-zag conformation is sterically favourable for the 22(S)-isomers whereas such a conformation is energetically unfavourable for the 22(R)-isomers owing to an interaction between the 22- substituent and the 16-methylene group. The side-chain NATURAL PRODUCT REPORTS 1992-A. B. TURNER OH HO' HO" (390)R = 2H 3H (3911 (392) (393) OH I sio" -ti (394) (395) (396) (397) conformation is thought to be responsible for differences in their biological activities.Details of the thirteen-step synthesis of A9(11~-citlcitriol (388) from (S)-(+)-carvone have appeared.178 The A9(")-bond which prevents tautomerization via a [1,7]sigmatropic shift to a previtamin structure causes only modest reduction of the calcitropic effect of the vitamin. The lZ5I-labelled ester (389) of calcidiol has been prepared from the p-alanine conjugate by standard methods of peptide coupling. 179 The deuterium and tritium labelled 24(R)-hydroxycalcidiols (390) have been pre- pared via sulphur dioxide adducts.180 25-0x0-25-phosphacalciol (39I) the first phosphorus ana- logue of calciol has been prepared by coupling of the precursors (392) and (393).lS1 The cD-precursor (392) is obtained by ozonolysis of the alkene (394) to the 22-aldehyde followed by (398) rebuilding of the side-chain via Wittig reaction to the carboethoxymethylene derivative reduction and final reaction with sodium dimethyl phosphide.The phosphorus analogue has its heteroatom at position 25 with oxygen attached as in calcidiol itself. It is active with respect to intestinal calcium absorption but gives a weaker response for bone calcium --*fCHO mobilization. This contrasts with the 25-aza analogue which inhibits both of these effects acting as an antagonist via inhibition of 25-hydroxylation in the liver. Condensation of the sulfone (395) with the aldehyde (396) to give the sulphone (397) is a key step in the synthesis of la-hydroxyercalciol (398).182 Desulfonylation with sodium amal- gam gives the 22-ene which is desilylated to give the diol(398).Similar /3-hydroxysulphone intermediates are employed in the synthesis of ercalcitriol and its 24(R)-epimer from the aldehyde (399).la3 The oxidative conversion of ercalciol into the Windaus ketone has been improved and regioselective hydroxylation at (399) C-26 of the ketone is achieved via ~rganoboranes.'~~ NATURAL PRODUCT REPORTS 1992 CHO -1 4 steps AcO'** H "OAc I Ji /OAPh 0--.-'OH I H H OAOEt + OAc OAc AcO a OAc OAc iiv Ph v-ix ~ HO HO (400) Reagents i BuLi THF 0 "C (60%); ii NaOH aq.MeOH 65 "C (> 90%); iii ClCO,Et dioxane (90%); iv Me,SiOCOCF, C,H,Cl, -20 "C (40%); v NaOH aq.MeOH (> 90%); vi ButMe,SiCl DMAP CH,Cl (90%); vii H,/Pd MeOH (> 95 YO);viii Ac,O pyridine THF (83 Oh); ix CH,CN/48 YOHF ratio 95 5 (> 90 YO) Scheme 10 cholanic acids half of which are new compounds have been 2.3 Cholanes Norcholanes and Dinorcholanes prepared from 3a,7a-dihydroxy-SP-cholanicacid by standard Mosesin-4 (400) a naturally occurring shark repellant has reactions.lS7The ketone silyl acetal (405) also derived from been synthesized from cholic acid (Scheme 10).lS5 Methyl chenodeoxycholic acid is efficiently oxidized to 23(R)-and acids (406) with cholate 3-cathylate (401) is used as a model compound to study 23(S)-3a,7a,23-trihydroxy-5P-cholan-24-oic methods of attaching the galactose residue at the hindered 7a-lead(1v) acetate in dichloromethane.ls8 3a,12cc,23-Trihydroxy-position.Best results are achieved using P-galactose penta-5/3-choIan-24-oicacid (bitocholic acid) has also been prepared acetate in the presence of trimethylsilyl triflate in 1,2-by this route and the configuration at C-23 confirmed as (R). dichloroethane. The cholane analogue (402) of mosesin-4 is The influence of the hydroxyl group at C-23 on the physical obtained from the ester (40 1) by trans-esterification with properties of bile acids has been investigated. 7P-Alkylated sodium ethoxide in ethanol. Glycosylation with 2-deoxy-2-chenodeoxycholic acids are stereoselectively prepared by fluoro-a-D-glucopyranosyl bromide triacetate gives mixtures addition of Grignard reagents to 3a-hydroxy-7-oxo-S~-cholanic and P-D-gluco-acid.ls9The method is much superior to that involving oxazoline of 3,4,6-trio-O-acetyl-2-deoxy-2-fluoro-a-pyranoside derived from the alcohols (403) (404) and digi-intermediates.toxigenin.ls6 The conjugation is carried out in 1,2-The deuteriated bile acids (407)-(409) have been obtained dichloroethane in the presence of silver silicate and molecular on a preparative scale by coupling the reduction of the sieves and the P-anomers are the predominant products. triketone (410) catalysed by 7a-or 12a-hydroxy-steroids Chromatographic separation and deacetylation affords the 2-dehydrogenase to the oxidation of [1-2H]-glucose,catalysed by deoxy-2-fluoroglucosides. glucose dehydrogenase. Transfer of deuterium from glucose The complete set of eight stereoisomeric 3,6,7-trihydroxy-SP-to the bile acid is mediated by catalytic amounts of coenzyme NATURAL PRODUCT REPORTS 1992-A.B. TURNER HO -.-+co2Me AcO HO AcogoAc AcO H0‘ CO2Et OSiMe HO ?I/YCO,H HO OH I H HO”-OGC‘OEt H (407) (409) X = a-OH p-D (410) X=O 0 H OH continuously recycled in situ. Isotopic purity of 3 94% is established by ’H NMR spectrometry. The macrocycles (41 1) are prepared from cholic acid in up to 33 % overall yield.lgl The precursor amino acid is obtained by selective addition of an organomanganese reagent derived from a protected 4-bromobenzylamine to methyl 7a,l2a-diacetoxy-3-0x0-5P-cholanate. The ‘cholophane ’ structure has potential for molecular recognition and biomimetic catalysis. Polymerization of certain cyclic dienes by a free radical mechanism proceeds readily in inclusion compounds formed with deoxycholic acid.lg2 The polymers consist mainly of 1,4-linked monomer units in the cases of cyclopentadiene 1’3- cyclohexadiene and 1,3-~ycloheptadiene.1,5-Cyclooctadiene (411) R’ = R2 = H Ac PhCO and 2,Snorbornadiene did not polymerize. Details of the short and efficient degradation of the bile acid R’ = H Ac R2 = PhCH2 side-chain involving cleavage of a sulfine group have R’ = Ac R2 = H NATURAL PRODUCT REPORTS 1992 AcO'.' H (412) R = R' = R2= H (413) R = Me R'R2 = SO (414) R = Me R1R2= 0 (415) R = Me R'R2 = NOH (416) R=Me R1=S02Me R2=H OH -..-JCHO OR (421) R = CH2Ph (423) (422) R = Me appeared.lS3 The 11 -ketone (41 2) gives the 23-sulfinyl derivative (413) with thionyl chloride in pyridine followed by addition of methanol.The sulfine group can be cleaved by various oxidants to give the 23-ketone (414). This reaction also occurs with acetic anhydride-sulphuric acid and with dinitro- gen tetroxide the reaction can be stopped at the oxime (415) stage. The sulfinate (41 6) a by product in the preparation of the sulfine (413) is obtained in good yield by heating (413) with methanol and pyridine. In the original thionyl chloride reaction its formation can be suppressed by neutralizing the excess of pyridine with camphor sulfonic acid prior to the addition of methanol. Aerial oxidation in the presence of an organic base and catalytic amounts of copper(r1) salts causes degradation of the ester (414) to the 20-ketone (417) and the intermediate 22- aldehyde (41 8) can be isolated in good yield.During studies on the mechanism of this reaction the 'dimeric' cholestanyl ester (419) has been prepared in order to determine the fate of the ketone and ester groups. Cholestanol is isolated quantitatively following oxidative degradation of this ester along with the 20- ketone (417). Conversion into the aldehyde (418) is found to involve the formation of one mole each of carbon dioxide and carbon monoxide. These and other experimental observations are rationalized in terms of the cyclization of a 22-hydro-peroxide intermediate at the ester carbonyl group to give the a-keto-y-perlactone (420) or its hemiacetal derivative which collapses to the 22-aldehyde (41 8).Ozonolysis of cyclosteroid derivatives of phytosterols from the de-odourizer distillates of canola oil gives the C-22 aldehyde (421). Canola oil thus provides a convenient source of a key steroid intermediate. lS4 A stereoselective route from diosgenin to the 6-methoxycyclosteroid (422) has been de- veloped.lS5 Oxidation of the tricarbonyliron complex (423) derived from ergosterol acetate by manganese(1v) oxide or lead(rv) oxide gives the corresponding C-22 aldehyde. lg6 2.4 Pregnanes Oxidation of cholest-4-en-3-one to progesterone by the GiP \' system (catalytic Fe species and zinc dust) has been studied over the temperature range -40 to +80 OC.lg7 The optimum (424) (425) temperature is +20° at which the yield is 5 YO.Below zero the yield of progesterone diminishes and 25-hydroxycholest-4-en- 3-one accumulates with the yield reaching 7 %.This compound has been prepared from lithiocholic acid. ~-Nor-5P-cholestan- %one a major product of the oxidation is probably formed by oxidation of an intermediate diosphenol. 5P-Reduction and 14P-hydroxylation convert the planar progesterone molecule into the bent cardiac glycoside con- formation. The 5P,14P-pregnane (424) synthesized from digi- toxin exhibits cardiac glycoside-like activity. lg8 Two methods have been studied for introducing a 14P-amino function into the steroid nucleus ; (i) cyclization of a 12,13-se~o-A'~-steroid bearing a 12-methanesulphonyl group in the presence of ammonia or hydrazoic acid and boron trifluoride etherate and (ii) treatment of a A14-steroid with hydrazoic acid and a Lewis acid.lSs In both methods the 14P-azides are reduced with metal hydrides.The second method is used to prepare the cardioactive 14P-amino-5P-pregnane-3P,20/3-diol (425) from deoxycholic acid and progesterone. Conjugates of 1 la-hydroxyprogesterone (426) and (427) with adenosine triphosphate and P-nicotinamide adenine dinucleotide (NAD) have been prepared. 2oo Evaluation of the bioluminescence of these compounds indicates that conjugate (427) is the most efficient having 20 % of the bioluminescence of NAD and NADH. The monoglucosides and diglucoside of pregn-5-ene-3P,20(R)-diolhave been prepared and character- ized by HPLC and mass spectrometry.201 Dehydration of cobalt carbonyl complexes of 17a-ethynyl- 17P-hydroxyandrostenes gives pregn- 1 6-ene-20-ynes7 e.g.(428).202 Iodobenzene diacetate can be used to convert the 17- ethynyl- 17p-01~ into 2 1-hydroxypregn- 16-en-2O-ones. Aldosterone is converted via its 3-enol-3,18,21-triacetate into 6P-hydroxyaldosterone and its 6a-e~imer.~~~ These are slowly transformed into their 17a-isomers in dilute alkali. 6P-Hydroxyaldosterone and 6P-hydroxy- 17-isoaldosterone are identical to products isolated from incubations of aldosterone with liver microsomes. 18,2 1-Anhydroaldosterone (429) its 19- nor analogue (430) and the reduced compound (431) all of which may be present in acid-processed urine have been prepared by cleavage of their 20-acetal derivatives with hot NATURAL PRODUCT REPORTS 1992-A.B. TURNER 0 H\N* X“ (426) X=ATP (427) X = P-NAD R’ (432) R’ = H F R2 = Me Et Pr Bu Ph COMe (433) R’= F R2 = Me Et 0 (435) R = SH (436) R = CHzSH (437) R = CH2SMe CHzSEt CH*SPr CH2SCH2CH=CH2 CH~SCH~CECH (440) R = CH2N3 (441) R=CHO (442) R=OH mineral The 4-en-3-ones can also be prepared in good yield by direct dehydration of aldosterone and 19-noraldosterone. 21 -Substituted corticosteroids e.g. (432) containing a variety of sulfur-containing groups have been prepared and tested for vasoconstrictive activity in Replacement of the 21-hydroxy group by a lower alkylthio group enhances the activity and the 6a,9a-difluoro derivatives (433) are more potent than betamethasone- 17-valerate.The related 21 -thio compounds (434) prepared by reaction of betamethasone 17- esters with various mercapto derivatives have been evaluated as topical anti-inflammatory agents.206 The structural com- bination of a thio group at C-21 and an ester group at (2-17 enhances vasoconstrictive activity. 2.5 Androstanes and Oestranes Thiol-containing androgens have been prepared during studies on the structural features required for the inhibition of aromata~e.~~’ Analogues of androstenedione having thiol groups in either the 2a,lOp- or 19-positions cause inhibition CH 111 C (429) R = Me (431) (430) R = H (434) R’ = Me Et Pr Bu R2= H Me,Pr Ph n eodP (438) R = OS02Me (439) R= I with the oestrane (435) being the most potent suicide substrate and the androstane (436) the best inhibitor overall.Aromatase previously inactivated by these compounds can be reactivated by incubation with the disulfide reducing agent dithiothreitol suggesting that a disulfide bond may be formed during inactivation of the enzyme by these inhibitors. However the 19-thioalkyl derivatives (437) also show competitive inhibition (increasing as the size of the alkyl substituent decreases).208 These are prepared from the 19-methanesulfonates (438) via the 19-iodo-derivatives (439) the iodo group of which can readily be displaced by reactive nucleophiles (e.g.. MeS0,S and N3-)without rearrangement. The most potent aromatase inhibitor among the 19-azasteroids prepared is 19-azidoandrostenedione (440) and both this and the thioalkyl compounds are thought to act by providing a sixth ligand to the heme iron of cytochrome P-450.The reaction of the aldehyde (441) with a model complex of the peroxo intermediate by cytochrome P-450 in acetonitrile gives the lop-hydroxyoestrenedione (442) as the major This compound readily gives oestrone with acid. These and other results support a mechanism for oestrone biosynthesis which involves the lop-alcohol (442) and C-10 radical species of 19-norandrostenedione as intermediates and the peroxo rather than the oxenoid species of the cytochrome P-450/aromatase system. The effects of modifications in ring D have also been investigated.210 An oxygen atom at C-17 is not essential for NATURAL PRODUCT REPORTS 1992 OCOPh OH (443) 't viii ix vi vii 0 -0 (444) Reagents i Br, AcOH; ii CaCO, CH,CONMe, 165%; iii NaOH aq.MeOH; iv H,O, aq.MeOH; v SeO, ButOH AcOH 82 "C; vi ButMe,SiC1 imidazole DMF; vii LiAlH, THF; viii MnO, CHCl,; ix 40% aq.HF CH,CN 0 "C Scheme 11 0 OH CHOH {fi2 0 (445) (446) (447) 0 OR OAc (448) R = SiMe2Bu' (450) R'=H R2=Me (4511 (452) (449) R=Ac R' = Me R2 = H Me binding of inhibitors to aromatase suggesting that hydrogen bonding to D-ring oxygen does not play a major role in enzyme binding.Dihydrotestosterone benzoate (443) has been con- verted into la-hydroxytestosterone (444) in nine stages (Scheme 11).211 The diol (444) has previously only been obtained by microbiological hydroxylation.Spironolactone (445) has been prepared from ethisterone in six steps.212 A key step is hydroformylation of the acetal (446) with carbon monoxide and hydrogen in the presence of rhodium(I1) acetate dimer and triphenylphosphine to give the lactol (447). Androst- 1-en-3-ones (448) and (449) have been converted into the polymethylated derivatives (450).,13 Methylation of the kinetic lithium dienolate of the enone (448) gives 1,4-dimethylated derivatives whereas thiomethylation of the enone (449) via the thermodynamic dienolate or an equivalent intermediate followed by desulphurization with Raney nickel affords the 1,2-dimethyl compound (45 1). The trimethylated androstane (452) is prepared using a combination of these methods.Dehydrogenation of these 1-en-3-ones with benzene- seleninic anhydride gives the corresponding 1,4-dien-3-0nes. The androstane analogue (453) of brassinolide prepared from 17P-hydroxy-5a-androst-2-en-6-one, shows high activity in cell elongation and cell division.214 Full details have appeared of the thermolysis of 5a,8a-peroxides (454) which leads to the disecosteroids (' steroklastanes ') containing a fourteen-membered ring.215 The process could be concerted or involve fragmentation of a biradical. Depending upon the conditions thermolysis of the 17P-acetoxy derivative gives the macrocyclic diones (455) or (456) as primary products. Reaction with 3- chloroperbenzoic acid brings about epoxidation and Baeyer- Villiger oxidation to give epoxyenol lactones e.g.(457). Oestrone has been converted into 14,15-seco-oestratriene-15-ynes which are mechanism-based inhibitors of oestradiol dehydrogenase.216 The precursor (458) is prepared from oestrone in five steps in an overall yield of 40 %. The diol(459) and the ketol (460) are obtained from the ester (458). 19-Nortestosterone has been converted into 2-fluoro- 71 NATURAL PRODUCT REPORTS 1992-A. B. TURNER OAc OCOCH2CHMe2 AcOf-yp2 00 -. ,o 0 '0 AcO (453) (454) R' = OAC C8H17 OH (455) (456) R~=H,R~R~=O OAc 0 d-*R2 LP OH R1O Me0 (457) (458) R' = Ac R2 = C02Me (459) R' = HI R2 = CH(0H)CECH (460) R' = H R2 = COC=CH OH 0 vCHO Me04v OH (463) (464) (467) 0 Me CH co H (468) oestradiol which gives 2-hydroxyoestradiol upon treatment in fourteen steps.221 14P-Hydroxylation of the 15-en- 17-one with Fremy's salt in the presence of iodide Aromatization (465) with selenium dioxide and conversion of the 14p-of 19-nortestosterone by abstraction of an a-proton with hydroxy- 16-ene leads to the malonate (466) which undergoes lithium diisopropylamide in tetrahydrofuran solution followed intramolecular cyclopropane ring formation upon treatment by treatment with phenylselenyl chloride gives oestradiol in with copper(I1) and lithium chlorides in dimethylformamide at 52 % yield.218 The yield is lower when the 17P-hydroxyl group 100 "C.The cyclopropane ring is selectively opened by the is protected in the form of its tetrahydropyranyl ether.The 17- thiophenolate anion leading to the aldehyde (467) which is ketone (461) is converted into the ester (462) by successive condensed with (methoxymethy1)diphenylphosphine oxide in Wittig reactions.219 Analagous derivatives of 5a-androstane the presence of lithium diisopropylamide in tetrahydrofuran to have also been prepared. The biotinyl-6a-oestradiol conjugate give the cardenolide (464). (463) has been synthesized for use in antigen- and antibody- The 16-ketone (468) derived from thujone is converted by immobilized enzyme immunoassay techniques. 220 means of selenium reagents into the cross-conjugated dienone (469) and thence by standard reactions into the cardenolide analogue (470).222 This completes a formal synthesis of 2.6 Cardenolides and Bufadienolides digitoxigenin.A route to the dienone (469) from androstene- The cardenolide (464) is prepared from the androstenone (465) dione has also been developed. NATURAL PRODUCT REPORTS 1992 AcOdo Br (4711 (472) (475) 00 H (478) R = H Me (479) A sixteen-step synthesis of strophanthidin from 3p-a~etoxypregna-5~16-dien-20-one includes the selective reduction of the 14,16-dien-2-one (471) to the 14-en-20-one (472).223 Another key feature is a one-pot introduction of 5p-and 14p- hydroxyl groups by addition of hypobromous acid to the strophanthidin derivative (473) to give the bis-bromohydrin (474). The stereo-and regio-selectivity of the addition of hypobromous acid to the A5-bond is controlled by the 19- formyloxy group.The 2 1 adduct between diethyl-(cyanomethy1)phosphonate and strophanthin formed under protic conditions is shown to have structure (475) by 2-D NMR and NOE difference In continuation of work on the synthesis of bufadienolides from deoxycholic acid reactions of the enal (476) with 0-silylated ketene acetals have been studied. 225 Depending upon the reaction conditions both Michael adducts and [4 +2]cyclo-adducts are formed. 2.7 Heterocyclic Compounds Several new 16-azaoestrones (477) and 17-aza-~-homo-oestrones have been prepared from oestrone methyl ether.226 Among other azasteroids synthesized this year are the 8-aza-~- homo-oestrone analogues (478)227 and the 12-aza compound (479). An improved synthesis of the 2-oxa- 19-hydroxymethylchol- estenone (480) from cholesteryl acetate is achieved in nine steps and I0 % overall The 6-oxaoestrone derivatives (48 1) Br (473) (474) R' (476) (477) 0 Me0 (481) X = H2 (482) X= '7 0 OH Me0a] 044 have been converted into the orthoesters (482) by reaction with ethylene oxide in the presence of boron trifluoride etherate followed by Birch reduction.230 11-Oxaoestradiol (484) has been prepared by two routes.231 One involves aroinatization of the dienone (485) while the other more efficient route from oestrone involves photolytic chlorinative decarboxylation of a 9-oxo-9,l I -seco-1 1 -carboxylic acid and cyclization of the 9/3-hydroxy-9,l l-seco- 1 l-nor- 12-chloride derived from the degra- dation product.The cortisol analogues have also been obtained by the latter route.ll-Oxaprogestrone (486) is obtained from pregnanedione (487) in eleven A key step is photolytic cleavage of the lactols (488) in the presence of mercury(I1) oxide iodine and pyridine to give the iodoformates (489). The ring A-bridged ether 2p 19-oxaandrostenedione (490) is obtained from the 2a,19-diol (491) by a Mitsunobu etherifi- cation.233 Ring D-fused azetidines of type (492) are prepared NATURAL PRODUCT REPORTS. 1992-A. B. TURNER OAc vo I voR RO’** H (489) R = CH2CH20Me OH I Me0 H HO (493) C8H 17 R 4fP 0 N/No 0 (497) (498) vo CN .*-from the oestratrienol (493) via the 17-ethylidene derivative (494).234 Michael addition of malonitrile and related active methylene compound to 16-dehydropregnenolone acetate gives products which can be cyclized to ring D-fused pyridines (495) and thienopyridines (496).235 Ring B-fused thiazoles are obtained by treatment of 7a-bromocholestan-6-ones with thi~acetamide,~~~ and the ring B-H H (487) (488) R = CH2CH20Me 0& (492) X = 0 H OH R (499) N-N rYk ‘N H-+N’CoMe (503) (504) fused pyrazole dioxides (497) are formed by reaction of cholest- 5-en-7-one oximes with fuming nitric The Westphalen dione (498) reacts with hydrazoic acid in the presence of boron trifluoride etherate to give the tetrazole (499) and the lactam (500).238Reaction of 1601-cyanoprogesterone (501) with the same reagent combination gives the ring A-fused tetrazoles (502)-(504) in yields of 20% 15% and 22% NATURAL PRODUCT REPORTS 1992 (505) (506) R = H OMe (507)R = H Me (508) (509) (510)X= 0,S (511) R = AC (514)R = H I Me 0 0 ;;;cHc12 CI )cHc'2R2Nc;& 0 H H OH respectively.239 Ring A-fused triazines (505) and (506),240 pyrimidines (507) and (508),241and pyrazines (509) and (510),242 have also been prepared.1,3-Dipolar cycloaddition of 5,lO-secosteroids (51 1) with methylhydroxylamine takes place with elimination of acetic acid to give the ring A-bridged cholestanes (512) and (513).243 A similar cycloaddition involving the 3-alcohol (514) proceeds without elimination to give the isoxazolidine (515). The ring A-fused oxazolidinones (516) and (517) are formed from the epoxide (518) and dimethylformamide in the presence of urea.244 The ring A-fused pyranones (519) are prepared by reaction of enaminones (520) with dichloroketene at 70 "C and treatment H of the resulting unstable cycloadducts (52 1) with diazabicyclo- undecene at 20 0C.245 Dibromooestradiol (522) on treatment with copper(I1) chloride and sodium methoxide gives the [2,3]dioxane (523) as the major product and the [3,4]dioxane (524) as a minor The ring A-fused dioxanes are useful for the synthesis of various 2,4-disubstituted oestradiols.1,3-Dipolar cycloaddition of nitrile oxides to 22-enes e.g. (525) gives isoxazolines of types (526) and (527).247 These undergo dehydration of pregna-5,lO-dienes. Reaction of the alkyne (528) with the oxime (529) gives the isoxazole (530).248 Thiazoles of type (531) are obtained by Hantzsch reaction of 21-bromopregnan-20-ones.249 Thiazolidones (532) are prepared by cyclization of thiosemicarbazones of 17-ketones with NATURAL PRODUCT REPORTS 1992-A.B. TURNER (525) R = CH=CHZ (526) R = Me CHMe2 C02Et (527) (529) (528) R = CGCH (530) (531) R = NH2 NHMe NMee (532) Ph Me CH2,C02Me / (533) AcO AcO (538) (539) 0 I I1 AcO EtOZC C02Et (543) chloroacetic acid in acetic acid containing sodium acetate.250 17-Spirodithiolanones of type (533) are prepared from cortico- steroid derivatives (534) by treatment with a ten-fold excess of potassium thioacetate. 251 Their structures have been elucidated by physical methods.252 2.8 Cyclopropano-steroids Simmons-Smith methylenation of the 4-ene (533 followed by (540) R = H (542) R = CH(C02Et)Z 1 (544) acetylation gives the 4P,5~-cyclopropanoandrostane(536).253 Acetolysis of this cyclopropane gives the rearranged products (537)-(539).The 15p 16P-methyleneandrostenone (540) has been converted into the pentacyclic dione (54 1) in several steps.254 A key transformation is the ring opening-recyclization of the malonate derivative (542) to give the 7,15-ethano bridged dione (543). 24-Methylenecycloartanol (544) has been converted into an epimeric mixture of 24-methyl- 19,29-dinorlanost-9( 11)-en-3- NATURAL PRODUCT REPORTS 1992 0 (545) (546) X X H H (549) X = a-H P-OH (551)X = a-H P-OH (550)X = 0 (552)X = 0 H one (545).255 The synthesis involves acid-catalysed cleavage of the cyclopropane ring 4/3-demethylation Barton reaction dehydration of the 1 1/3-hydroxy derivative and oxidation of the 19-alcohol followed by photolysis.2.9 Microbiological Transformations Reduction of the A4-bond of testosterone and androst-4-ene- 3,17-dione by the 5a-reductase enzyme of Penicilliurn decurnbens takes place with trans stereochemistry. 256 Reduction of tes- tosterone gives 17P-hydroxy-Sa-androstan-3-oneand 5a-androstane-3,17-dione in yields of 10YOand 40 YO,respectively whereas reduction of androstenedione gives 5a-androstane- dione in yields of 50-70 %. Dehydrogenation of the dienedione (546) to 6-dehydro-oestrone using Corynebacteriurn simplex is a crucial step in the transformation of the enone (547) to the methyl ether (548) in an overall yield of 27YOz5’ Microbial side-chain cleavage of sterols is a slow process because of the poor solubility of substrates and products as well as their low transport rates to and from cells.Addition of cyclodextrins boosts the conversion of cholesterol sitosterol and cholest-4-en-3-one to androstenedione and androstadi- enedione by Mycobacteriurn spp. in a purely aqueous fer- mentation system without any appreciable influence upon cell For cholesterol /I-cyclodextrin gives the best results whereas y-cyclodextrin is the best clathrate for sitosterol and cholestenone transformation. An optimal molar ratio of 2 1 is found in all cases.This results in up to a three-fold increase in (547) (548) OH V0 (553)X= NH (555) (554) x = 0 specific side-chain cleavage activity. Under optimal conditions yields of androstadienedione are increased from 35-40 % after conversion for 175 hours in control experiments to over 80 Yo conversion during 120 hours in the presence of cyclodextrins. The transformation properties of Aspergillza ochraceus incubated with modified A-ring steroids have been Transformed yields of 11a-hydroxysteroids in the range 54-65 % are obtained independent of A-ring size for the A- norandrostanes (549) and (550) and the A-homo-androstanes (551) and (552). The 4-aza- and 4-oxa-androstanes (553) and (554) give 65-70 YOyields of 1la-hydroxy derivatives while 4- a~a-5a-pregnane-3~20-dione (555) is unexpectedly converted into the A-I la-hydroxy derivative (556) in 35 % yield.3 References I A. B. Turner Nat. Prod. Rep. 1991 8 17. 2 G. Han and G. Huang Youji Huaxue 1989 9 15. 3 W. Zhou Pure Appl. Chem. 1989 61 431. 4 T. Honda and M. Tsubuki Yuki Gosei Kagaku Kyokaishi 1990 48 43. 5 T. Kametani and M. Tsubuki Ecdysone 1989 74 ed. J. 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ISSN:0265-0568    

DOI:10.1039/NP9920900037

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

Muscarine Oxazole Thiazole Imidazole and Peptide Alkaloids and Other Miscellaneous Alkaloids J. R. Lewis Department of Chemistry University of Aberdeen Meston Walk Old Aberdeen AB9 2UE Reviewing the literature published between July 1989 and June 1990 (Continuing the coverage of literature in Natural Product Reports 1991 Vol. 8. p. 171) 1 Muscarine Oxazole Thiazole and Imidazole yielded (+)-muscarine (5; X = Cl) as outlined in Scheme 1. Alkaloids An alternative concise enantiomeric synthesis of (+)-muscarine 2 Peptide Alkaloids iodide (5; X = I) has been obtained from the easily prepared 0- 3 Miscellaneous Alkaloids (R)-benzylgl ycidol (6)where ace ty lena tion and me thylation 4 References (6+8) followed by ring closure gave the unstable 2,3-dihydrofuran (9).Hydroboration and selective oxidation gave alcohol (3) and thence to (5;X = I) Scheme 2. (4-)-Iforresthe is a novel heterocyclic oxazole isolated from the unique I Muscarine Oxazole Thiazole and lmidazole Australian plant Isotropis forrestii. This nephrotoxin (10) is the Alka lo ids causative agent for acute renal proximal tubular necrosis A total synthesis of (+)-muscarine (5; X = Cl) has been associated with animals ingesting the plant.3 achieved by a carbenoic cyclization reaction to form first a Dihydroxyaerothionin (1 1) and aerophobin (12) are two disubstituted 2,5-3(2H)-furanone with the necessary favoured brominated tyrosine related metabolites which have been 'cis' isomerism (3).l Thereafter conventional modification found in the deep water marine sponge Verongula rigid^.^ X-(5) Reagents i (COCl) trace DMF; ii CH,N,; iii Rh(OAc) 1 % weight CH,Cl,; iv H, Pd(OH),; v NaHB(OAc),; vi TsCl/py; vii Me,N; viii ion exchange Scheme 1 (5)-vii viii J--q -A---OBn OBn (3) (9) Reagents 1 LiC=CH-ethylenediamine complex Me,S04; ii BuLi HMPA MeI THF -78" to r.t.; iii CuBr (2 eq.) (CH,O) (2 eq.) diisopropylamine dioxane reflux; iv KOBut (2 eq.) MeSO, 60 "C; v dicyclohexylborane THF 25 "C then H,U NaUH EtOH; vi H, Pd(OH),X MeOH ; vii p-MeC,H,SO,Cl py CH,Cl ; viii NaH butan-2-one; (ix) excess NMeJEtOH Scheme 2 81 6-2 NATURAL PRODUCT REPORTS 1992 OMe HO qvo 0 0 In the biosynthesis of virginiamycin M1 (13; ab double bond) the dehydroproline residue is derived from R-and S-proline the 3-pro-R proton (13; ab sat.) being lost stereo- specifically in a process thought to involve hydroxylation at position 3 followed by dehydrati~n.~ The structures of three bioactive marine metabolites ob- tained from a sponge of the Mycale genus have been characterized by 2D NMR.6 Mycalolide A has structure (14; R1+R2 = 0),mycalolide B (14; R1 = H R2 = OCOCH(0Me)-CH,OMe) and mycalolide C (14; R' = H R2 = OCOCH-(0Me)Me).These oxazole macrolides are hybrids of the ulapualides and of halichondramide. * They possess potent 73 antitumour or cytotoxic activity. Much of these data has also been published in a Japanese J~urnal.~ Prototropy of chartelline A (15) one of the alkaloids found in the marine bryozoan Chartella papyracea reveals that the N5-H isomer is predominant in solution while the N7-H isomer is present in the crystalline ethyl acetate adduct.1° A patent has been taken out1' to manufacture the bioactive substance M4582 using Paecilomyces lilacinus strain M4582.This thiazole (16) has aldose reductase inhibiting activity and is offered for the treatment of cataract retinitis and nephrophy. Leinamycin is a new antitumour antibiotic produced by a micro-organism taxonomically assigned to the Streptomyces family.l2 Its unusual 1,3-dioxo- 1,2-dithiolane structure (1 7) is somewhat unstable in the normal culture medium and special precautions are necessary for its production. The Ascidiacea are the main source for polypeptides OMe HO H '"OH N 0 NMe AH0 containing oxazoline thiazol-thiazoline ring systems e.g.the didemnins (loc. cit.) patellamides8 and lissoclinamides.8 Three publications on the constituents of Lissoclinum patella have established the identities of six new cyclic peptides namely lissoclinamide 413,14 (18; R1 = CHMe, R2 =dCH,Ph ab sat. cd unsat) lissoclinamide 513314 (18; R' = CHMe, R2 =-CH,Ph ab and cd unsat) lissoclinamide 613 (18; R1 = CHMe, R2 =.rCH,Ph ab sat cd unsat) lissoclinamide 715 (18; R' = CHMe, R2 =4CH,Ph ab and cd sat) and lissoclinamide 815 (1 8; R1 = CHMe, R2 =4CH,Ph ab sat cd unsat) and patellamide D13 (19). Results from the cytotoxic examination of these peptides have enabled some suggestions to be made as to structure-activity re1ati0nships.l~ Two thiazoline rings as in lissoclinamide 7 is purported to give the best in vitro cytotoxicity (see however Natural Product Reports 1990 7 367).The structure of ulithiacyclamide B a metabolite of Lissoclinum patella has been determined to be (20; R = Ph)16 and it is closely related to that of ulithiacyclamide (20; R = CH,CHMe,).17 The mechanistic aspects of the cytocidal action of ulithiacyclamide (20 ; R = CH,CHMe,) on mouse leukaemia L1210 cells in uitro has been studied and it is found that the peptide inhibited cell growth as a self-destructive process as well as inhibiting protein synthesis. The cytotoxic mechanism still remains obscure however ; with bleomycin synergism occurs.lS In the case of ulicyclamide no protein inhibition occurred but its cytotoxicity was maintained some- what (50%) when its oxazoline ring was opened.Complete NATURAL PRODUCT REPORTS 1992-5. R. LEWIS OR EtMe iMeEt Ph 0 SMe NH2 m HN I OMe -0 *N /\ 'A Br/ Br Br fission of the cyclic peptide ring destroyed cytotoxicity however.l9 In these new series of structure-activity mea-surements using L1210 cell lines ulicyclamide is cytotoxic its precursor the linear peptide is inactive and its oxazoline precursor is three times less active.lg These results contradict the previous reports that the oxazoline ring plays an important role in cytotoxi~ity.'~ A useful compilation of the conformation and structures of cytotoxic cyclic peptides from the Ascidiaceae is given in Reference 15.Corallistine (21) is a new 'polynitrogen ' compound isolated I OMe H (29) from the sponge Corallistes fylvodesimus.20 The structure of this novel 2-methylthioimidazole was determined by X-ray crys- tallography. 1-Methylpteridine-2,4-dione (22) was also ob-tained from this sponge. The bright yellow coloured marine sponge Cluthrina clathrus contains the imidazole clathridine (23) together with a small quantity of its zinc complex (24). Both compounds being isolated from a chloroform extract of the lyophilized sponge.21 Treatment of clathridine in methylene chloride with zinc sulphate solution produced the zinc complex quantitatively. A biologically active 1,2,3-trithiane derivative (25) has been isolated from a New Zealand ascidian a 'D' species of Aplidium.22 In neutral or slightly basic media it slowly interconverts to the trans isomer (26).Both isomers are active against P388 leukaemia in mice. Two collections of a Hexadella sponge one at a depth of 40 metres (SCUBA) and one at 100-200 metres (submersible) have revealed differences in their secondary metabolite con- tent.23 The shallower sponge contained the new tyrosine derivatives hexadellin A (27) and hexadellin B (28) while the deep water variety contained topsentin B2 (29; R = OH NATURAL PRODUCT REPORTS 1992 0 Me -. . Meo*>OH Me0 H I NHR H QN H N -+ 0 ‘Br OH (33) Br H2N M e-O m CI-NHCOPh R2 = Br). A patent has been taken out on the use of topsentin analogues as antitumour and antiviral agents.’* From a sponge of the Topsentia family 4,5-dihydro-6”-deoxybromotopsentin (29; R1= H R2 = Br) was isolated and the patent covers analogues based on N-substitution and the presence or absence of bromine.Also found in another member of this Aplysinidae sponge family are Z/E mixtures of 2’-demethyl-aplysinopsin (30 ; R = H) 2’-demethyl-3’-N-methylaplysinopsin (30 ; R = Me) and their 6-bromo derivative^.'^ Photoisomerization increases the E stereoisomer content while heat reconverts to the naturally occurring ratio favouring the Z isomer (95 %). Two imidazole alkaloids pyronaamide (31)and kealiiquinone (32) have been isolated from a yellow button-like sponge of the Leucetta group.26 Two halocyamines obtained from the ascidian Halocynthia roretzi have antimicrobial properties.” The structures of halocyamine A (33) and halocyamine B (34) were determined by degradation studies and spectroscopy ; both compounds also exhibited cytotoxic activity. A bromine containing guanidine derivative named dib- romoagelaspongin has been isolated from a marine sponge of the Agelas family. Its structure was determined by X-ray crystallography to be (35) indicating its biogenetic relationship to other C,,N compounds found in the sponge families Agelasidae and Axinellidea. 28 -0Me OMe (32) H OH OH (34) OH /\ WNHCHO Meo&NHCOPh OH OR’ R3 N COCH = ~50 (39) 2 Peptide Alkaloids A review on the synthesis of naturally occurring cyclopeptides and cyclopeptolides has appeared.29 Two P-phenylethylamine derived amides have been found in Piper guayranum.Tembamide acetate (36; R = Ac) has been identified as a natural product for the first time while alatamide (37) was known previously only as a Rutaceous constit~ent.~~) Another synthesis of erbstatin’ (38) the epidermal growth factor inhibitor has been reported. This five step procedure can be applicable for making N-acylated P-amin~styrenes.~~ Three new amides belonging to the cinnamoyl series have been isolated from the stem bark of Zanthoxyfunz rubescen~.~~ Rubescenamide (39; R1 = R2 = R3 = CH, R4+R5 = CH,) rubescenamin (39; R1 = R2= CH, R3 = H R4+R5 = CH,) 85 NATURAL PRODUCT REPORTS 1992-5.R. LEWIS 0 a NH2 Me2N gNo2 NO2 .. ... 11 111 & 0 \ 0 'CI I IH OMe H OMe (43) (44) (45) iv v Reagents i 80 YO H,SO, 75 "C 30 min. ; ii PCl,/POCl, 70 "C 45 min.; iii CAN/H,O/MeCN 0 "C 15 min. ; iv 2-aza- 1,3-bis- (t-butyldimethylsily1oxy)-1,3-butadiene7 CHCl, 35 "C 8 h;v CH,I K,CO, tris[2-(2-methoxyethoxy)ethyl]amine,DMF rt 1 hr ;vi H,/Pd/C Et,N MeOH rt 20 hr Scheme 3 0 ~tachyium,~ have been isolated. Brachystamide A is N-isobutyl-15(3',4'-methylenedioxyphenyl) -2E74E-pentadecadienamide (41 ; ab sat) and brachystamide B N-isobutyl- 15(3',4'-methyl- enedioxyphenyl)-2E,4E 14E-pentadecatrienamide (41; ab unsat). Ill 7\ Because of the high potency of antibiotic FL-657C (42), 0 which completely inhibits the growth of Friend leukaemic cells a patent has been taken out on its manufacture from a strain (FERM P-7296) of Strept~myces.~~ The new aromatic alkaloid amphimedine (47) isolated from a Pacific sponge of the Aamphimedon family has been ~ynthesized.,~ This new fused ring system was assembled in six and xanthosin (39; R' +R2 = CH, R3 = H.R4= R5 = CH,) steps starting from 2,5-(MeO),C6H,NHCOCH2COC6H4N0,-o were characterized by spectroscopic methods. In another (43) through intramolecular cyclization to give the quinolone on the stem bark of the same plant two related (44) which upon chlorination and oxidative demethylation gave inve~tigation,~ amides have been obtained rubenamide is N-methyl-(3,4-(45). Diels-Alder reaction then gave the adduct (46) and an dimethoxyphenylethyl)-3,4-dimethoxycinnamamide(39 ; R1= isomer; (46) being taken through to the alkaloid (47) as R2 = R3= R4 = R5 = CH,) and rubesamide is 3,4-(dimethoxy- indicated in Scheme 3.phenylethyl)-3',4'-dimethoxycinnamamide(40). Of the four glutarimide based antibiotics isolated from In the search for potent plant insecticides two new Streptomyces hygroscopicus two are new.37 B and B are unsaturated amides from the aerial parts of Piper brachy- stereoisomers of structure (48). HO’ (49) HO,C /I) Eponemycin (49) is produced by Streptomyces liygroscopicus strain P247-71. It shows antitumour properties against B16 A Red Sea tunicate as yet unidentified contains an antimicrobial cytotoxic compound possessing a diketopip-erazine structure as well as a hydroxyimate grouping (50).The name given to this metabolite is etzionin after the biblical name for the Port of Eilat.39 Philanthoxin is a novel and potent antagonist in the glutamate receptor. It was isolated from the venom of the solitary digger wasp Philanthus triangulum and its structure (51) was also confirmed by a total synthesis.40 The novel lactone (52) produced by a Bacillus species (Y 05460M) is both an antibiotic and an anticancer agent.41 The phenyl-pepstatin derivative (53) produced by a novel Streptomyces has been shown to be more effective against NATURAL PRODUCT REPORTS 1992 Ph OH H .N * H2N 0 OH A B renin than pepstatin and may be useful in the treatment of heart congestion.42 Manufacture of the active aminopeptidases probestin (54) and prostatin (55) has been achieved by fermentation of Streptomyces azureus species MH633-2F6 and MH663-2F6 respectively.43 A new synthesis of (+)-pederine (56) the potent insect poison which includes complete stereochemical control has been published.44 Using a new and effective method for the synthesis of 1-alkoxyamides (Scheme 4) and suitable protecting groups pederine was assembled by joining parts A and B through this new procedure.In the biosynthesis of manumycin (57) the oxygens are introduced through an oxidase (oxygenase) process and the nitrogen comes from gly~ine.~~ In both manumycin (57) and asukamycin (58) the central multi-functional C,N unit which NATURAL PRODUCT REPORTS 1992-5.R. LEWIS I YMe NH=C(OMe)R2 ’ S-(N=CR2)2 + R’COCI OMe ’ OMe I R’CONH~H A R’K”R2 R2 0 Reagents i SOCl (0.52 eq.) Et,N (1.9 eq.) CH,CI, rt 10 min.; ii AcCl (2.1 eq.) py 4.2 eq. CH,Cl, r.t 20 hr; iii NaBH, EtOH 0 “C 10 min Scheme 4 \ 1 (57) Me OH H ~H=CHR’ CH=CH-CONHCHCONH serves as the starter for the short polyketide chain is formed from a C Krebs cycle and a C triophosphate pool intermediate in a new pathway quite distinct from the shikimate polyketide or pentosephosphate A patent describes the incubation of Streptomyces parvalus BSM 40722 in the presence of substituted benzoic acids to give manumycinl’ derivatives. Ring A can contain a variety of substituents all of which are monofunctional.These elastase inhibitors have potential use as pharmaceutical^.^' Two novel peptides designated Bu 2867T I-F (59; R1 = (CH,),CH, R2 = CH,) and 1-G (58; R1= (CH,),CH,, R2= CH,OH) are manufactured by cultivating Polyangium 0 NH H brachysporum strain K48 1-B 101. Both compounds possess antifungal and antitumour proper tie^.^^ An enantioselective total synthesis of (+)-(9-dihydro-periphylline (60) has been reported. The procedure relies on a new method for elaborating the thirteen membered lactam ring via an intramolecular cyclization involving an iminium intermediate. 49 The synthesis of three spermidine alkaloids (& )-inandenin-10-01 (61 ; R = H +OH) inandenin- 10-one (61 ; R = 0) and (+)-oncinotine (62) have been carried through a ring enlargement procedure [Aga-Zip Reaction (63) +(64)].From Zizyphus rugosa a new cyclopeptide alkaloid ru-NPR 9 N Me2 (68) gosanine B has been isolated together with mummularine F and sativanine H.51 This 13-membered cyclic peptide was found in the bark and its structure (65) was determined by chemical degradation and spectroscopic analysis. A chloroform extract of the stem bark of Canthium anorldianum contains a pinkish coloured crystalline compound. From spectroscopic data52 this substance (anorldianine) was characterized as a peptide alkaloid (66). A novel peptide alkaloid has been obtained from the ariel parts of Plectronia odor at^.^^ It is N-desmethylmyrianthine C (67). Sanjoin (seeds of Zizypus vulgaris var spinosus) and Daechu (fruits of Zizypus jujuba var inermis) are traditional oriental medicines used for the treatment of insomnia but other pharmacological properties have also been described for these preparations.Of the fourteen alkaloids found in Sanjoin seven were identified as cyclopeptides of which six are new.54 Sanjoinine G2 is an open chain peptide alkaloid (68) sanjoinine A is frangufoline (69; R = CH X-Y = CH=CH) sanjoinine B (69; R = H X = Y = CH=CH) sangoinine D (69; R = CH,X-Y = CH(OCH3)CH,),sanjoinineGl(69;R = CH3X-Y = CH(OH)CH,) sanjoinine GI (70; ab sat) sanjoinine G2 (70; ab unsat). In the fruit extract of Daechu five alkaloids were obtained the one belonging to the peptide group was daechucyclopide 1 (71) while the root bark extract yielded twelve alkaloids four being fourteen membered and eight thirteen membered-cyclopeptides.Table I lists these com-pounds. Traditionally Sanjoin is produced by roasting the plant material and in this investigation it was found that the effect of heat on sanjoinine A (frangufoline) produced the more sedatively active artefact sanjoininine Ah- 1. Both these com- pounds were inter-convertible and a structure determination revealed that Ah- 1 was produced by isomerization of the chiral centre * as in (69) and not by conformational isomerism of the ring. The oxygen removing substance 41047 (74) (either stereoisomer) is manufactured by growing the fungus Pseudonocardia Q-1047 in a shake culture. This compound NATURAL PRODUCT REPORTS 1992 Ph’ OH is scavenger for the superoxide anion and is suggested for use as a neoplasm inhibitor.55 In a second patent the hydroquinone is listed as the active compound and in this case two enantiomers are vaguely described.56 Antibiotic NK86-0084 (75) is produced from a Streptomyces strain (NK86-0084) this hydroquinone has antimicrobial anticancer and blood vessel formation inhibition pr0perties.j’ The structure of biphenomycin A a novel tripeptide involving a 15membered biphenyl system in solution has been determined by 2D NMR and molecular modelling.58 Quantitative NOE data normal bond angles and lengths planarity constraints and a single chirality constraint (C,,S) when fed into the DGEOM distance geometry programme59 gave after re-finement the stereochemistry as indicated (76).Isocanocarpine (77) is a new type of spermidine alkaloid obtained from the root bark of Capparis decidua60 Interest still prevails in the maytansinoids. A total synthesis of maytansine has been reported6’ while six members of this group of anticancer agents have been isolated from the moss Isothecium subdiversiforme. 62 One of these ansamitocin P-3 (78) is new and it has also been isolated in low yield from other NATURAL PRODUCT REPORTS 1992-5. R. LEWIS Table 1 Daechuine-S1 (Frangufoline) -S2 (Frangulanine) -S4 (Franganine) -S5 (new) OR' / NH R2 Daechuine-S3 (new) -S6 (new) -S7 (new) -S8-I (new) -S9 (Mucronine D) -SIO (new) -S26 (new) -S27 Nummularine B) 0 H o$/--.-($o ' '0 OMe OH R1 R2 N(Me),-Phe-(CH,),CHCH,-N(Me),-Ile-(CH,),CHCH,-N(Me),-Leu-(CH,),CHCH,-N(Me) ,-Val- (CH,),CHCH 2-R1 R2 Me N(Me),Ile-Ile-Me N(Me),-Phe-Me N(Me),-Leu-Me N(Me),-Leu-Leu-Me N(Me),-Phe-Leu-Me N(Me) ,-Thry- H N(Me) ,-Phe- Me NH(Me)Gla-Val OH OCOCHMe, 7' Me NATURAL PRODUCT REPORTS 1992 -Me 0 HOpCH2-~H-CONHCHCONHCHMe I I NMe co 0 I I co NMe CH,INCOCH(Me)NHCOCHCHz O O M e I ' Me (79) 0 o-04-CH2cHMe2 CHMe 0 I CHyHPh A1 R2 (83) members of the moss family Thuidiaceae namely Claopodium crispifohin and Anomodon attenuatus.63 Rubia cordifolia produces a neoplasm inhibitor (P388 in mice) which has been characteri~ed~~ as the macrocyclic peptide (79).The stereochemistry and structure of cleromyrine (80) a new cyclohexapeptide obtained from Clerodendrum myricoides has been elucidated by chiral chromatography of its hydrolysate together with NMR technique^.^^ It is one of the few naturally occurring homodelic cyclopeptides built exclusively of 'natural ' L amino acids. The culture broth of Metarhizinum anisophiae was monitored by bioassay and fractionated to give ten destruxins. Of these cyclodepsipeptides two namely destruxin E2 (8 1 ; R1 =A R2 = CHMe,) and the chlorohydrin destruxin CHL (81 ; R1 = CH(OH)CH2C1 R2 = CH(Me)CH,Me) are new.66 A number of cyclic peptides e.g. (82) are produced by the fermentation of Streptomyces silvensis. All show oxytocin and vasopressin antagonist Cultivation of a Nortoe ATCC 53789 fungus gives the ketodioxadiazacyclohexadecenetetrone(83 ; R1R2= 0)which upon Zn/Cu/EtOH reduction gives the unsaturated derivative (83; R'R2 = double bond).68 This latter compound is par- ticularly effective against filmentous fungi while OsO hy-droxylation of it gave the diol (83; R' = R2 = OH) which exhibited improved activity.69 :I (84) Four geodiamolides have been isolated from a marine sponge of the Pseudaxinyssa family found in Papua New Guinea.70 Geodiamolide C is (84; R' = C1 R2 = Me) D (84; R' = I R2 = H) E (84; R1= Br R2 = H) and F (84;R' = C1 R2 = H). A practical synthesis of the peptide part of this macrocycle as exemplified by jaspamide (85) has been rep~rted.~' Conventional assembly was improved by protection of the phenolic group.The complete details of the total synthesis of the immunosuppressant (-)-FIG506 (86) has now been published. As this unique 21-membered macrolactam is more effective than cyclosporin A it represents an important new advance in immunosuppressant therapy. 72 It has been evaluated against dogs and baboons with continued success. 73 Perhaps the similarity in structure has stimulated the re-evaluation of an old compound namely rapamycin as an immunosuppressive agent.74 A re-examination of a New Zealand sponge of the Mycale group produces not only mycalamide A (87; R = H) but also its methyl ether mycalamide B (87; R = Me). Both of which are potent antiviral and anti-tumour agents.75 The mycalamide molecule constitutes a feature of the onnamides.These are a biologically active group of compounds typified by onnamide A (88) and isolated from a Theonella sponge.76 It and related compounds have been patented.77 The pacidamycins are a novel group of antibiotics with NATURAL PRODUCT REPORTS 1992-5. R.LEWIS OH ROKH 0 R2R”KN R6 N R42:+ 0boH R3 C02H SMe activity against Pseudomonas aeruginosa. 78 Seven of these compounds have been obtained from the culture fluid of Streptomyces coeruleorubidus strain AB 1183F-64. Pacidamycin is (89; R1= alanyl R2= 3-indolyl) pacidamycin 2 (89; R1 = alanyl R2= Ph) pacidamycin 3 (89; R1= alanyl R2= 3-hydroxyphenyl) pacidamycin 4 (89; R1 = H R2= 3-indolyl) pacidamycin 5 (89; R1= H R2= Ph) pacidamycin 6 (89; R1= glycyl R2= 3-indolyl) and pacidamycin 7 (89; R1= glycyl R2= Ph).The mureidomycin group of antibiotics also possess antibacterial properties and are related to the pacidamycins. A patent79 has been taken out on mureidomycin Me2CH Me2N1CO-Val -N C H CO Pro-Pro-0 Me E (90 ;R = 8-hydroxy-1,2,3,4-tetrahydroiso-quinolan-3-y1) and mureidomycin F (90; R = 6-hydroxy- 1,2,3,4-tetrahydro-iso- quinolan- 3-yl). The ocean sea hare Dolabella auricularia contains the powerful cytostatic constituent dolastatin 15. It is active against P388 lymphocytes. The structure of this constituent (91) was determined by 2D NMR and high resolution MS.*OA growth inhibitory substance isolated from the sea hare Dolabella auricularia has been characterized as a new type of cyclo-depsipeptide.*l Dolastatin 13 is active against P388 leukaemia and through high field 2 dimensional NMR and tandem mass NATURAL PRODUCT REPORTS 1992 ov '"-9NL0 "u -8 CHZOH '.il OMe (94) spectrometry its structure has been reported to be (92; ab.sat.). Dolastatin 13 is also antineoplastic and it co-occurs with its dehydro derivative (92; ab. unsat.) in this sea hare.82 Dolastatin 14 a cyclodepsipeptide (93) with antineoplastic activity has been obtained from the same Indian ocean sea hare Dolabella auricularia.83 A complete spectral assignment of didemnin B (94; R = CH,CHMe,) and nordidemnin B (94; R = CHMe,) has been made. These two antitumour and antivirally active cyclic peptides were isolated from the tunicate Trididemnum solidum collected at Guadaloupe Island in the Caribbean.84 B is currently in a Phase I1 clinical trial as an anticancer agent.Echinocandin B (95; R1= linolenyl R2 = Me) is produced by several Aspergillus species it is a lipopeptide with antifungal properties. Loss of the lipid side chain leads to loss of antifungal activity e.g. (95; R' = H R2 = Me). This loss can be selectively achieved by microbial hydrolysis using Actinoplanes utahensi~.~~ Conversely addition of alternative sidechains e.g. 4-n-octylbenzoyl re-establishes activity which is superior to that of the natural product.86 Echinocandin A (95; R' =CO(CH,),CH(Me)CH,CHMeCH2Me,R2 =CH,CONH,) has been produced by an as yet unidentified mycelial micro- organi~m.~' The closely related mulundocandin (95 ; R1= CO(CH,),CH,CH(Me)CH,Me R2= H) has been pro- duced by a novel Aspergillus sydowii strain88 of Indian origin.The amatoxins are a group of bicyclic octapeptides present in the poisonous mushroom Amanita phalloides. Recent X-ray results from the crystals of several of these toxins show them to have a similar conformation (octapeptide ring) and therefore the difference in toxicity is due to changes in the nature of the substituents (96; R' to R7) located on the periphery of the ring.89 N Me 0 Tf NMe / I (95) R'COCHZCH-CO-N hCONHCHR3 I I co NH F$ax ct cH-CO NH NH co NHCO~HNHCOC'H ~~ .CH-R'' R6 A5 Puwainaphycin C obtained from the blue-green alga Anabaena BQ-16-1 elicits a strong positive iontropic effect on isolated mouse atria.This novel chlorine containing cyclic decapeptide structure (97; R = OH) was determined through 2-D NOE CH CC and CN correlation spectroscopy. A related decapeptide puwainaphycin D has structure (97; R = Me).90 An increasing number of glycopeptide compounds are being isolated from fungal sources. Interest in these molecules has been stimulated because of their pharmacological properties. Structurally they possess a triphenyl ether moiety connected to a heptapeptide giving a macro~ycle.~~ Variation mostly occurs NATURAL PRODUCT REPORTS 1992-5. R. LEWIS O-glucosam ine/glycosyl I R I HO OH CI HO CI HO OH on the periphery of this macrocycle e.g.mannose; glucose ; first examples the pseudo-aglycone retains its antibacterial glucoseamine ; aromatic chlorine substitution; variation in a~tivity.~' An Indian A ctinomycetes is reportedly used for the amide functionality etc. e.g. (98). Four new glycopeptides manufacture of three compounds all as effective as van-have been obtained from Amycolutopis orient~lis.~~.~~ and a new glycopeptide (99) of the teicoplanin type In the two c~rnycin,~~ NATURAL PRODUCT REPORTS 1992 Ho2qo :J;O q ' CI ' CI OH OH (antibiotic UK 68,597) has been produced by submerged aerobic fermentation of Actinoplanes sp. ATCC 53533.95Novel derivatives of teicoplanin can be obtained by mutation of Actinoplanes teichomycelicus using nitrosoguanidineg6 while demannosylation of teicoplanin and presumably other similar heptapeptides can be achieved through microbial hydrolysis using Norcordia orientalis." Chemical modification of gly- copeptides can also be carried out by introducing an amide functionalityg8 onto the free carboxy group using two moles of amine in DMF with (PhO),P(O)N,. A biomimetic based synthetic approach to part of the vancomycin molecule as in (99) has been achieved by oxidative macrocyclic cyclization. This investigation by the Evans group has enabled a solution to the C/D and D/E connections to be made.99 Complestatin is described as one of the best known inhibitors of haemolysis of sensitized erthyrocytes. Its isolation from the mycelium of Streptomyces lavendulae and structure deter- mination using HMBC''' shows it to possess a novel glycopeptide structure (1 00) Actinoplanes strain ATCC 33076 produces three novel CI CI ' CI ' CI OH OH antibiotics.These A-16686 factors are A'l (101; R = COCH=CHCH=CHCH,) A'2 (101 ;R = COCH=CHCH= CHCH,CHMe,) and A'3 (101 ; R = COCH=CH=CHCH CH,CHMe,). Thirteen kg of crude fermentation of product gave 150 600 and 30 mg of each antibiotic respectively."' During an investigation into the bioactive metabolites from Okinawan marine organisms two novel 24-membered macro- lides were characterized. Iejimalide A (102; R = H) and iejimalide B (102; R = Me) both of which showed powerful antileukaemic activity were obtained from Eudistoma rigida.Also present in this sponge was a potent cytotoxic /3-carboline.lo2 The complete structure i.e. the relative and absolute stereochemistry of (+)-hitachimycin (stubomycin) is both the solid state and in solution has been determined using X-ray and 2D NMR It was shown that the same conformation (103) occurred in both phases. 3 Miscellaneous Alkaloids A benzoxazine glucoside (blepharin) and benzoxazolone (104) NATURAL PRODUCT REPORTS 1992-5. R. LEWIS Me0 H( Me)=CHCH=C( Me)CH2NHCOyHNHCH0 OMe Lvs H OH OH have been obtained from Blepharis edulis this is the first time (104) has been reported from an Acanthaceae species.'04 Duchualkaloid A obtained from the fruit of the Daechin tree (Ziypus jujuba var inermis) has the interesting tricyclic structure (105).56 The active antitumour principle found in extracts of Artemisiae capilluris has been identified as the bislysyl coumarin capillarison (106).This alkaloid showed activity against tumour L-929 and KB cell lines but its alglycone was not active presumably due to its insolubility.105 Tobagolide is a new pseudopterane diterpenoid (107) isolated from the octocoral Pseudopterogorgia acerosu.lo6Treatment of this metabolite with acetic anhydride not only acetylated the hydroxy group but also displaced the NMe group by OAc with retention of configuration. Two terpene isonitriles kalihinene (108) and isokalihinol B (109) have been isolated from the marine sponge Acanthellu kZethra and from a Halielonu sponge species two macrocyclic CH,OH Me0 0 (103) H II NMe OH alkaloids haliclamine A (1 10 ;ab unsat) and haliclamine B (1 10 ; ab sat) have been obtained.All four compounds were cytotoxic and the isonitriles also showed antifungal activity.lo7 A novel tyrosine kinase inhibitor has been isolated from the culture fluid of Streptomyces graseoluvendus. lo*Lavendustin A (111) is some fifty times more active than erb~tatin.~ FAB-MS and NMR studies have been used to elucidate the structures of two metabolites produced by Actinomudura verrucosospora.logOne is the novel thioquinolone (1 12) and the other is N-acetyltyramine. The novel benzazepine alkaloid aphanorphine obtained from the fresh water blue-green alga Aphanizomenon fZos-aquae has been synthesizedllO thus establishing its absolute configuration as lR 4R (113).The Streptomyces species DO- 105 produces an antibiotic DC-105 (1 14) which is active against lymphocytic leukaemia P-388 in mice.'l' Further investigations on the antitumour antibiotic FR NATURAL PRODUCT REPORTS. 1992 OMe OMe \ N Me OHCmNR NC 60 0 900482 (1 15 R = H)171g1 have been made. Enhanced production has been obtained with a new strain of Streptomyces san-daerisis." Its triacetate FK973 (1 15 R = Ac) is metabolized in blood to a di- and mono-acetate and ultimately to the parent compound FR 900482 (1 15 RH). No improvement in activity was observed for these partially de-acetylated derivatives. 113 Synergism occurs when FR 66973 (1 15 R = lower alkanoyl) is used in conjunction with other antitumour agents.l14 In the presence of NaCl solutions of FR 66973 (1 15 R = lower alkanoyl) are stabilized somewhat.l15 Construction of the bicyclic hydroxylamine hemi-ketal ring system found in FR 900482 and related antibiotics has been described.'16 Reaction of (1 16) with NaCN in the presence of ally1 chlorocarbonate gave the protected cyanohydin (1 17; R1 = 0,R2 = NO,) which was ketalized [117; R1 = (OMe), R2 = NO,].Reduction of the nitro-ketal [117; R1 = (OMe), R2= NO,] gave the hydro- xylamine [117; R1 = (OMe) R2 = NHOH] which could be cyclized to the hydroxylamine ketal (118) thereafter intra- molecular cross coupling gave the tricyclic hydroxylamine hemiketal (1 19) ring system.Scorazanone is a 1-aza-anthraquinone (120) isolated from the dried roots of Goniothalamus scortechinii 11' while the red mutant strain of the fungus Nectria haematococca produces 2-aza-anthraquinones. The red and yellow coloured pigments found therein are bostrycoidin (121; R = OH) and 5-deoxybostrycodin (121 ; R = H).l18 A new aristolactam piperolactam C (122) has been isolated from both Piper bochimerifolium and Piper 10ngum."~ 3-Ethyl-2,5-dimethylpyrazine(123) found in the poison glands of worker ants is the main component of their trail pheromone and accounts for this behaviour in the ant Messor bouvieri. Streptomyces species (strain 9659) produces two antibiotics OProt OMe 0 0 OMe OMe both of which contain a novel phenazine ring system.121 Antibiotic WS-9659A (124; R = H) and WS-9659B (124; R = C1)12 both possess testosterone 5a-reductase inhibitor activity which suggests a use in prostate therapy.123 The new antibiotic phenazinomycin isolated from the mycelium of Streptomyces WK 2057 has widespread phar- macological activity being active against Gram positive bacteria cytotoxic to HeLa S, P388 and P388 doxorubicin resistant cells in vitro and against murine tumours in ~iv0.l~~ Its structure has been elucidated,125 showing it to have a sesquiterpene moiety attached to a phenazine ring (125).A total synthesis of the azaphenanthrene alkaloid eupolauramine (126) has been accomplished126 using an intramolecular trapping procedure involving a N-methoxy-N-acylnitrenium ion derived from (127; R = Cl) via (127; R = H).Three alkaloids have been obtained from the sea squirt Cystodites dellichiajei. 12' The structures of two of these tetracyclic antitumour active compounds have been reported as (128; R = COCH = CMe,) and (128; R = COCH,CMe,OH). A strategy to synthesize amphimedine (1 3 1) has been studied using the Diels-Alder oxazole procedure. Although this step created the tricyclic system (129) +(130) the final closure failed.128 But (131) has been synthesized by two method^.^^^*'^^ The first also employed a Diels-Alder reaction to give the tricyclic precursor (1 32) +(1 33) +(1 34) and thence to (1 3 1)12' while the started from the azafluorenone (1 35). A revised structure for 2-bromoleptoclinidinone has been proposed (136; R = Br).It is based on spectral data and on a debromination giving ascididemin (1 36 ; R = H)131 A synthesis has confirmed this assignment. Ascididemin itself has been patented presumably because of its antitumour Three lumazine derivatives have been obtained from the luminescent marine polychaete Odontosyllis unide~imdonta,'~~ NATURAL PRODUCT REPORTS. 1992-5. R. LEWIS CH,CH2 OMe OMe R~H 0 CH20H OH 0 0 0 CI 0 \ CI N\ Si Prot HN / 0 9 %NO2 O 'I\ OSiProt trivially known as the 'fireworm '. 6-Propionyllumazine (137; R1= R2= H) was accompanied by its 3-methyl derivative (137; R' = H R2 = Me) and its 1,3-dimethyl derivative (137; R1= R2 = Me). Two novel alkaloids from a sponge of the Plakortis family possess a pyrrolo-acridine ring system of a type not found previously in the marine or terrestrial kingdom.Plakinidine A (138; R1 = H R2 = Me) and plakinidine B (138; R' = R2 = Me) both showed in vitro activity against the parasite Nippostrongylus brisiIiensis.135 Diplamine is a cytotoxic polyaromatic alkaloid isolated from a tunicate of the Displosoma family. This orange coloured compound (I 39) showed activity against L1210 murine leukaemia as well as antimicrobial a~tivity.'~~ The prianosines A B C and D reported in last years reviewg1 have now been patented as antitumour while the structurally related discorhabdine D (140) has also been thus protected.140 Another pentacyclic thiazinone alkaloid has been isolated from a colonial tunicate of the Tididemnum family.lgl Shermitamine B (141; R = H) is the debromo analogue of shemitamine A (141 ; R = Br).00 0 0 (144) The sponge Reniera sarae is widely present in the Bay of Naples and it contains two homologues series of alkaloids the sarins 1 to 3 and sarins A to C together with a minor metabolite isosarin 1. Originally reported in 1986 the structures of the sarins have now been elucidated. Sarin 1 is (142; m = 6) sarin 2 (142; n = 5) and sarin 3 (142; n = 7). Sarins A B and C are also similarly related with sarin A being (143) and isosarin 1 being an enantiomer. 142 Renieramycins E (144; R = H) and F (144; R = OMe) are NATURAL PRODUCT REPORTS 1992 98 CHCH2S3Me I ND O H 0,Me HO Of$ HOfJ-&0 / \ H 10 OMe V yd OMe OH Y' (149) two very unstable alkaloids isolated from the sponge Reniera collected in Palau.143 Their stereochemistry has now been reassigned and it is the same as in the saframycins. Alkaloid pigments from the fruiting bodies of the toadstools Lactarius necator and Lactarius antroviridis have been identified as bis-dibenzonaphthyridines. Nectarone is the monomer and oxidative coupling occurs at the 4-position to give the dimer (145). 10-Deoxy-4,4-binecatorone is the other metab01ite.l~~ The polycyclic guanidine alkaloid ptilomycalin A (146) exhibits remarkable antifungal antiviral and antitumour activity. It was found in the Caribbean sponge Ptilocaulis spiculifer and in red coloured species of the Hemimycale sponge family obtained from the Red Sea.145 A novel antitumour agent BMY-28 175 has been produced by fermentation of Actinomadura verrucosospora.It is the unusual polyyne amide (147) and it has an impressive antineoplastic activity.146 The calicheamicins are another new family of antitumour antibiotics produced by Micrornonospora echinospora calichensis. Seven were isolated from a fe~mentationl~' and characterized. One of them is /I,Br (148). An Achinoplanes R-304 strain on cultivation produced four polycyclic xanthone containing alkaloids (149) where X and Y are H halogen or amino groupings.14* Maxonine is a novel indolo-pyrido-naphthyridinemolecule obtained from Simira maxonii. Its structure (150) was de-termined primarily by 2D NMR.14' Julifloricine (1 5 1) possesses significant antifungal activity NATURAL PRODUCT REPORTS 1992-J.R. 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ISSN:0265-0568    

DOI:10.1039/NP9920900081

出版商:RSC    

年代:1992

数据来源: RSC