14 Biological Chemistry Part (iv) Alkaloids By D. G. BUCKLEY Chemistry Department Queen Mary College Mile End Road London El 4NS 1 Introduction In the three years since alkaloids were last reviewed in Annual Reports a great deal of new work has been published and for a comprehensive survey the reader is referred to Volumes 5 and 6 of the Specialist Periodical Reports on the Alkaloids which cover the period July 1973 to June 1975.’#* Biosynthetic aspects are also treated in the companion on biosynthesis and these include a tabular survey of all tracer incorporations into alkaloids reported during 1973 and 1974. The period covered for this short review is 1974-1976 inclusive. 2 Pyridine and Piperidine Alkaloids The details of the isolation and structural elucidation of the macrocyclic spermidine alkaloid oncinotine (l),and the structurally related bases neo-oncinotine and iso-oncinotine have been published.’ The synthesis of (k)-oncinotine (1) was reported subsequently,6 the key step being the formation of the macrocyclic lactam by treatment of the appropriate amino-acid chloride precursor with triethylamine at high dilution.‘The Alkaloids’ ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1975 Vol. 5. 2 ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Chemical Society London 1976 Vol. 6. 3 ‘Biosynthesis’ ed. T. A. Geissman (Specialist Periodical Reports) The Chemical Society London 1975 VOl. 3. ‘Biosynthesis’ ed. J. D. Bu’Lock (Specialist Periodical Reports) The Chemical Society London 1976 VOl.4. A. Guggisberg M. M. Badawi M. Hesse and M. Schmid Helv. Chim.Acta 1974 57,414. F. Schneider K. Bernauer A. Guggisberg P. Van den Broek M. Hesse and H. Schmid Helv. Chim. Acta 1974 57 434. 397 398 D. G.Buckley Several new examples of spiropiperdine alkaloids have been isolated and they are related structurally to histrionicotoxin (2) and dihydrohistrionicotoxin (3) differing from these bases only in the nature of the 2-C and 7-C4 ~ide-chains.~ These alkaloids are of value in studies of ion conductance in electrogenic membranes; the nature of the side-chain is important in connection with cholinolytic activity or antagonism to the transport of sodium and potassium ions through such mem- brane~.~ Several stereocontrolled syntheses of (*)-perhydrohistrionicotoxin (4)'-'' and the naturally occurring (*)-octahydrohistrionicotoxin (5)8,9 have been described.cis (2) R' = R2= CH=CHCGCH (3) R' =CH2CH=C=CH2; R2=CH=CHCrCH (4) R' = R2=n-C4H9 (5) R' = R2=CH2CH2CH=CH2 C labelling has been used in studies of alkaloid biosynthesis with notable success recently and a good exampie is the structural and biosynthetic investigations on tenellin (6). First 13Cn.m.r. was used in conjunction with biosynthetic labelling of tenellin to provide valuable insight into the structure of this metabolite of Beauvaria species.' ' Second feeding experiments with putative precursors singly labelled with 13C led to the conclusion12 about the origins of the carbon skeleton shown in Scheme 1; C-15 and C-16 arise from methionine.Of note is the fact that C-1 of phenylalanine appears at C-4 of tenellin and C-2 at C-6. Incorporation of [1,2-'3C2]acetate gave tenellin with the expected satellite resonances due to I3C-l3C spin-spin coupling from which the intact two-carbon acetate-derived units could be discerned (see Scheme 1). Scheme1 7 T. Tokuyama K. Uenoyama G. Brown D. W. Daly and B. Witkop Helv. Chim. Acta 1974,57,2597. 8 M. Aratani L. V. Dunkerton T. Fukuyama Y. Kishi H. Kakoi S. Sugiara and S. Inone J. Org. Chem. 1975,40,2009. 9 T. Fukuyama L. V. Dunkerton M. Aratani and Y. Kishi J. Org. Chem. 1975,40 2009. 10 E. J. Corey J. F. Amett and G. N. Widiger J. Amer. Chem.Soc. 1975 97,430. A. G. McInnes D. G. Smith C.-K. Wat L. C. Vining and J. L. C. Wright J.C.S. Chem. Comm. 1974 281. 12 A. G. McInnes D. G. Smith J. A. Walter L. C. Vining and J. L. C. Wright J.C.S. Chem. Comm. 1974 282. Biological Chemistry -Part (iv) Alkaloids The general biosynthetic routes to the tobacco alkaloids nicotine (7) nornicotine (8) and anabasine (9) are fairly well established although the biosynthesis of the closely related bases anatabine (10) and a$-dipyridyl (1 1) has been investigated only re~ent1y.I~ The results suggest that (10) and (11)arise from precursors derived from nicotinic acid only and the authors suggest that dimerization of a dihyd- ropyridine takes place with subsequent elaboration to anatabine (10) and a$-dipyridyl (11)(Scheme 2).(7) R=Me (8) R=H 1 3 @-Phenethylamines and Isoquinoline Alkaloids Rubesamide (12) a p -phenethylamine derivative of cyclopropanecarboxylic acid has been isolated from the root bark of the Ghanaian tree Fuguru rubescens; the assigned structure (12) was confirmed by synthe~is.’~ (12) Another novel structure is possessed by macrostomine (13) an alkaloid from Pupaver macrostomum.” The structure was assigned on the basis of spectroscopic l3 E. Leete and S.A. Slattery J. Amer. Chem. SOC., 1976 98 6326. l4 B. A. Dadson and A. Minta J.C.S. Perkin I 1976 146. l5 V. A. Mnatsakanyan V. Preininger V. Simanek A. Klasek L. Dolejs and F. Santavy Tetrahedron Letters 1974 851. 400 D.G.Buckley (13) analysis and the (S)-configuration was deduced from comparison of its Cotton effect with those of (S)-(-)-nicotine and (S)-(-)-brevicolline.Further attention has been given to the electro-oxidative preparation of mor-phinandien~nes.'~*~' It has been proposed that at low potentials the amine func- tionality anchimerically assists the coupling (Scheme 3).l6 Cathodic cyclization of 1-OMe OMe "'"a \ \ Me0 Me0 / OMe OMe Ie 'OMe 'OMe Me0 Me0 MC 'Me Me0 OMe OMe Scheme3 (0-iodobenzyl)isoquinoliniummethiodides e.g. (14),has been reported to yield the corresponding aporphines e.g. (15) in high yield after catalytic hydrogenation. This sequence represents one of the most efficient direct routes to aporphines to date.18 16 L.L. Miller F. R. Stermitz J. Y.Becker and V. Ramachandran,J. Amer. Chem. SOC. 1975,97,2922. 17 T. Kametani K. Shishido and S. Takano J. Heterocyclic Chem. 1975,12 305. 18 R. Gottlieb and J. L. Neameyer J. Amer. Chem. SOC.,1976,97 7108. Biological Chemistry -Part (iv) Alkaloids (14) (15) The tricyclic base (-)-(16)? a key intermediate in the synthesis of various ipecacuanha alkaloids has been synthesized from (+)-(17)? the ethyl ester of cincholoipin (Scheme 4).l9 . .. y: '-C0,Et k '-C0,Et vii (16) Reagents:i 3,4-dimethoxyphenacyI chloride K,CO, benzene; ii NaBH, EtOH; iii Hg(OAc), edta 1 % aq. HOAc; iv Pd/C H2 EtOH 70% aq. HCIO,; v IN-NaOH EtOH 20°C; vi 10% HCI boiling; vii EtOH HCl 25 "C; viii POC13 toluene; ix PtO, H, EtOH.Scheme4 The cryptostyline alkaloids e.g. (-)-cryptostyline-I (1S) are the first isoquinoline alkaloids to be isolated from natural sources with an aryl group at C-1 which makes i9 T. Fujii and S. Yoshifuji Tetrahedron Letters 1975 73 1. 402 D. G.Buckley them a group of bases of some biosynthetic interest. The skeleton apart from the aryl substituent arises from a p-phenethylamine in the normal way,2o and the c& unit seems to be derived from an aromatic aldehyde derived by way of dopamine.21 The pathway so far delineated is broadly similar to the one deduced in detail for the cactus alkaloids.22 In spite of extensive and fruitful studies on the biosynthesis of benzylisoquinoline alkaloids research rather than speculation on the nature of the molecule which condenses with dopamine to give the benzylisoquinoline skeleton had remained neglected until recently.Evidence has now been provided for the pathway shown in Scheme 5; the pathway illustrated represents the conclusions of studies using Papaver orientale seedlings and latex23 and P. sornniferiurn Not only was norlandanosoline (22) labelled by [1-I4C,2-3H]dopamine (without change in isotope ratio) but also the previously unknown amino-acid (20),23 which was isolated when inactive material was used as carrier. Further evidence implicating (20) as an intermediate in isoquinoline biosynthesis comes from the efficient incorporation of labelled (20) into (22),23 and from the specific incorporation of labelled (20) into morphine (23).24 Oxidative decarboxylation of (20) affords (21) which was found to act as a precursor for morphine.24 These observations amongst suggest that the amino-acid (20) and the imine (21) are intermediates in the biosynthesis of the benzylisoquinoline bases.Amongst the alkaloids produced by Stephania japonica Miers are the biosyntheti- cally intriguing bases hasubanonine (24) and protostephanine (25). Attempts to understand how these bases are formed in vivo have long been frustrated although some progress has now been made.25 [2-14C]-Labelled tyrosine dopa tyramine and dopamine were incorporated into both alkaloids without randomization of label. The detailed results show (i) that both alkaloids are constructed from two C6-C2 units for which tyrosine is the source and (ii) that only one unit i.e.the one which generates ring cwith its attached ethanamine residue is labelled by [2-'4C]tyramine [2-14C]dopamine and [2-14C]dopa. The extent to which this latter p-phenethylamine unit is hydroxylated and methylated before combination with the other C6-C2 unit was examined by feeding the phenethylamines (26)-(29) to S. japonica. The bases (26) and (27) but not (28) and (29) acted as precursors for hasubanonine (24) and protostephanine (25) from which it is clear that it is the phenethylamine (27) which is involved in coupling with the other c&2 unit. These results give sets of possible isoquinoline and bisphenethylamine precursors the roles of which in hasubanonine and protostephanine biosynthesis have yet to be exp- 10red.~~ A new generally applicable synthesis of the proaporphine alkaloid (*)-glaziovine (30) involves a straightforward approach to the amine (31) which is then diazotized to give the o-amino-oxide (32) under alkaline conditions; a fast photo-cyclization 2o S.Agurell I. Granelli K. Leander B. Liining and J. Rosenblom Acta Chem. Scand. 1974 B28,239. 21 S. Agurell I. Granelli K. Leander and J. Rosenblom Acta Chem. Scand. 1974 B28,1175. 22 For reviews see J. Lundstrom Acta Pharm. Suecica 1971,8,275;R. B. Herbert in 'The Alkaloids' ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1971 Vol. 1,p. 16; 1973 Vol. 3 p. 16. 23 M. L. Wilson and C. J. Coscia J. Amer. Chem. SOC.,1975 97 431. 24 A. R. Battersby R. C. F. Jones and R.Kazlauskas Tetrahedron Letters 1975 1873. 25 A. R. Battersby R.C. F. Jones R. Kazlauskas C. Poupat C. W. Thornber S. Ruchirawat and J. Staunton J.C.S. Chem Comm. 1974,773. Biological Chemistry -Part (iv1Alkaloids HO Tyrosine R =H Dopa R = OH H02C OH OH (20) OH (19) / Ho / 0@NMe HO / Scheme5 (26) R=H (28) R'=H; R2=Me (27) R=Me (29) R' = Me; R2= H 404 D. G.Buckley Me0 / MeomNMe HO NH2 CH2 0 0 H°FMe OH M-0e o w M e N' CH2 OH OH (32) ensues on irradiation of the intermediate (32) to give the proaporphine (*)-(30) in 45% yield [from (3 1)].26 Recently reported" studies on the biosynthesis of (-)-ophiocarpine (33) demon-strated that hydroxylation of the (-)-tetrahydroberberine cf.(39 occurs as the final step and furthermore that it proceeds with retention of configuration i.e. that stereospecific removal of the pro-R-hydrogen atom occurs to give (-)-(33). The highly stereoselective transannular cyclization of the trans-dibenzazacine (34) and its [13-3H] derivative was shown to provide an efficient route for the synthesis of the (*)-[13w3H]-and (*)-[ 13p-3H]-tetrahydroberberines,(35) and (36) respectively. (33) R' =H; R2= OH (34) (35) R' =3H;R2 = 'H (36) R' = 'H; R2= 3H The first known in vim conversion of berberine (37) into the phthalideiso- quinoline alkaloids (*)-a-hydrastine (38) and (*)-P-hydrastine is accomplished by an efficient route which may emulate in part the biogenetic process.28 The key to 26 C.Casagrande and L. Canonica J.C.S. Perkin I 1975,1647. 27 P.W. Jeffs and J. D. Scharver J. Amer. Chem. SOC.,1976,98,4301. 28 J. L.Moniot and M. Shamma J. Amer. Chem. SOC.,1976,98,6714. Biological Chemistry-Part (iv) Alkaloids 405 the conversion was the isolation of a novel oxidation dimer designated oxybis- berberine from the ferricyanide oxidation of (37).** This dimer was cleaved in methanolic hydrogen chloride to give (37) and 8-methoxyberberinephenolbetaine (39). Compound (39) may be regarded as a masked ester and hydrolysis gave a secondary amino-ester which was methylated with methyl iodide and the product was immediately reduced to give a 1:2 mixture of (&)-a-hydrastine (38)and (*)-P-hydrastine in high overall yield.'OMe (37) R'=R~=H;X=CI (38) (39) R' =OMe; R2 = 0-;no X- 4 Erythrina Alkaloids The Erythrina alkaloids are known to arise from the benzylisoquinoline (S)-N-norprotosinomenine (40) via the dibenzanonine (41) and erysodienone (42).29 t- NH Me0 Hod i OH OMe (41) OMe Recent have shown that only (-)-erysodienone which has the (5s)-chirality of the natural alkaloids is a precursor for erythraline (43) and a-and P-erythroidine (46). The conversion of (S)-N-norprotosinomenine (40)into (5s)-erysodienone (42),involves formally at least an inversion of chirality. However the chirality of (40) may well be lost in viuo for it was found that the biosynthetic intermediate (41) prepared by chemical reduction from chiral erysodienone (42) underwent very rapid racemization at room temperature.Further experiments have established the aromatic Erythrinu alkaloids as pre- cursors of the lactonic bases (46);satisfactory incorporations of the bases (42),(44) and (45) have been demonstrated to occur without ~crarnbling.~' 29 D. H. R. Barton C. J. Potter and D. A. Widdowson J.C.S. Perkin I 1974,346; R. B. Herbert in ref. 2 p. 25. 30 D. H. R Barton R. D. Bracko C. J. Potter and D. A. Widdowson J.C.S. Perkin I 1974,2278. 406 D. G. Buckley Me0 0 Me0 (42) (43) R1-R2 = CH2 (44) R1 = H; R2= Me (45) R'=R~=H 5 Terpenoid Indole Alkaloids A technique which must be certainly now be regarded as established in its applicabil- ity to the complex indole alkaloids is 13Cn.m.r.spectros~opy;~~ indeed a recent revision of the structure of vindolinine from (47) to (48)32would have been difficult (47) Incorrect Structure (48)Vindolinine to achieve simply by any chemical or other spectroscopic methods. Because it has been found that the 13C chemical shifts for carbons in typical indole alkaloid environments have reliably characteristic values a selection of data from those so far available on typical alkaloids derivatives and simple model compounds has been collected recently in a convenient form.31 An interesting example of asymmetric induction has been used in a new biogenetic-type synthesis of (-)-tetrahydroharman and (-)-(49) from L-try~tophan;~~ the synthesis of (-)-(49) is outlined in Scheme 6.Apparently the Pictet-Spengler closure is stereospecific and affords the 1,3-cis-isomer (50); removal of the unwanted carboxyl derivative is achieved in good yield and without epimerization at C-1 by NaBH reduction of an a-aminonitrile. This synthetic approach may well find application in other areas. The synthesis of ellipticine (51)continues to attract considerable attention owing to the reported anti-neoplastic activity of the alkaloid and much new work has been Scheme 7 illustrates one of the new approaches35 which together with a variant reported simultaneously involves the formation of the C-7-C-19 or possibly the C-19-C-20 bond. 31 J. A. Joule in ref. 1 pp. 184-191. See also A. Ahond A.-M. Bui P. Potier E. W. Hagaman and E. Wenkert J. Org. Chem.1976,41 1878. 32 A. Ahond M.-M. Janot N. Langlois G. Lukacs P. Potier P. Rasoanaivo M. Sangare N. Neuss M. Plat J. Le Men E. W. Hagaman and E. Wenkert J. Amer. Chem. SOC.,1974,96,633. 33 H. Akimoto K. Okamura M. Yui T. Shiroiri M. Kuramoto Y. Kikugawa and S. Yamada Chem. and Pharm. Bull (Japan) 1974 22 2614. 34 J. E. Saxton in ref. 2 pp. 229-231. 35 R. Besselikvre C. Thal H. P. Husson and P. Potier J.C.S. Chem. Comm. 1975 90. Biological Chemistry-Part (iv) Alkaloids 407 o-PCONH~ %ONH* \ I 1 NH,,HCI i \ I I N N-H H H' (-)-(49) Reagents i CI(CHJ,CHO H,O-MeOH; ii POCL,-C,H,N-DMF; iii NaBH, EtOH-C,H,N. Scheme6 Me Me / rl Me Me Ellipticine (51) Reagents i MeI; ii NaBH,; iii KOBul-DMSO; iv MeCH &Me,OAc AcOH; v Pd-C decalin.Scheme7 408 D. G.Buckley Two new iboga alkaloids ibophyllidine (52) and iboxyphylline (53) have been isolated from Tabernanthe iboga and T. Subsessilis and have been shown to be members of a new iboga sub-gr~up.~~ A consideration of chemical and spectro- scopic data led to their structural assignments and the structure of (53) was confirmed by X-ray analysis. This new sub-group may possibly arise as shown in Scheme 8.36After construction of the normal iboga skeleton enzymic oxidation to the cation radical (54) could then lead to cleavage of the C-20-C-21 bond to give (54a). Further oxidation would lead to (54b) which could either undergo a Mannich ring-closure to yield the precursor of (53) or suffer hydrolysis to (54c) which could then be elaborated to give (52).*I8 19 22 17 15 19 22 17 A Corynanthe-Iboga type Strichnos type (54) H \ \ N 0 OMe (52) Ibophyllidine (53) Iboxyphylline Scheme8 Macrolidine (55) from the heartwood of Adina rubescens is a new glycosidic indole alkaloid in which the terminal primary alcohol function in a 5-carboxyisovincoside derivative has formed a novel macrocyclic lactone ring with the 36 F. Khuong-Hua M. Cesario J. Guilhem and R. Goutarel Tetrahedron 1976 32 2539. Biological Chemistry -Part (iv)Alkaloids retained tryptophan carboxy-group.37 The structure was deduced from the spectra of macrolidine and its tetra-acyl derivatives and was confirmed by reaction of macrolidine tetra-acetate with methanolic sodium methoxide followed by re-acetylation which gave the known methyl 3a,5a-tetrahydrodesoxycordifoline penta-acetate (56).H H' H (55) (56) The intriguing tryptophan derivative trichotomine (57),isolated38 from the fruit of Clerodendron trichotornurn is a novel type of blue pigment. Chemical and spectros- copic evidence led to the structure (57)38* which was confirmed 38b by an X-ray analysis of the NN'-di-p-bromobenzoyl derivative. Interestingly although there must be extensive conjugation throughout the system the two indole rings are not in the same plane but at a dihedral angle of 38.6".Natural trichotomine has been synthesized (Scheme 9)" starting with L-tryptophan methyl ester and succinic H 0 HO,C (57) Trichotomine Reagents i succinic anhydride-PhH-heat; ii CH,N,; iii 200 "C; iv P,O,-PhH-heat; v -90 OC-0,-Bu"0H; vi 1N-KOH-MeOH-Et,O.Scheme9 37 R. T. Brown and A. A. Charalambides J.C.S. Chem. Comrn. 1974,553. 38 (a)S. Iwadare Y. Shizuri K. Sasaki and Y. Hirata Tetrahedron Letters 1974 1051; (6)K. Sasaki S. Iwadare and Y. Hirata ibid. p. 1055; (c)S.Iwadare Y. Shizuri K. Yamada and Y. Hirata ibid.,p. 1177. 410 D. G.Buckky anhydride components which may well also represent the biosynthetic precursors of the pigment. Cyclization to (58) was followed by a remarkably easy oxidative dimerization to the diester which was readily hydrolyzed to the pigment itself. 6 Terpenoid Bases The total synthesis of napelline (59) has now been completed by the Wiesner The recent work 39a,b describes the synthesis of the racemate (60) from the pentacyclic intermediate (6l) and the conversion of lucidusculine (62) into the identical but optically active derivative (60).Using this optically active intermediate (60) as a relay the synthesis of napelline was completed. OH 0 (59) Napelline ?H The total synthesis of talatisamine (63) has been accomplished by way of the atisine-type intermediate (64);a key step is the rearrangement of an atisine skeleton cf. (64) to a lycoctonine skeleton cf. (63).40This type of rearrangement has been proposed for the biogenesis of alkaloids possessing the lycoctonine skeleton and Johnson and O~erton~~ have previously reported studies and Ayer and De~hpande~~ of this process. The synthesis is summarised as (64)+(74)in seq~ence.~' A new diterpene alkaloid delphisine has been isolate from the seeds of Delphinium staphisagra.Chemical and spectroscopic studies indicated it to be a member of the aconitine-type alkaloids and an X-ray crystallographic study of delphisine hydrochloride revealed its structure to be (75).43 This definitive study has 39 (a)K. Wiesner Pak-tsun Ho and C. S. J. Tsai Canad. J. Chem. 1974,52,2353;(b)K. Wiesner Pak-tsun Ho C. S. J. Tsai and Yin-Kuen Lam ibid. p. 2355; (c) S. W. Pelletier and S. W. Page in ref. 1 pp. 235-238. 40 K. Wiesner T. Y. R. Tsai K. Huber and S. E. Bolton J. Amer. Chem. Soc. 1974,96 4990. 41 J. P. Johnston and K. H. Overton J.C.S. Perkin I 1972 1490. 42 W. A. Ayer and P. D. Deshpande Canad. J. Chem.1973,51,77. 43 S. W. Pelletier W. H. De Camp S. D. LajSik Z. Djarmati and A. H. Kapadi J. Amer. Chem. Soc. 1974 96 7815; ibid. 1976 98 2617. Biological Chemistry-Part (iv)Alkaloids 41 1 Ac (64) R'=O R2=R3=H Talatisamine (63) R =H (65) R1 =0,R2=OZCPh R3=H (72) R=Ac (66) R'=<O] R2=OH R3=H (67) R'=<"-J R~R~=O 0 0 rMe ____--/OMe #I I, M&z] \. .'OR CH20Me 07, Ac--N (70) R'R~=< R~=O 0 0 ,L* H (71) R'R~=< 7, CH,OMe R~=H~ 0 (68) R =H (73) R1R2=0,R3=H2 (69) R=Ts (74) R' =H R2=OH R3=H2 enabled the question of the structures of neoline chasmanine and homochasmanine to be clarified since these three alkaloids have been chemically correlated with delphi~ine.~~ Wiesner and co-w~rkers~~ had originally assigned structure (76) to neoline.However in a subsequent correlation with chasmanine which had been assigned structure (77) on the basis of a reported correlation with br~wniine,~~ Marion and co-workers assigned structure (78) to ne01ine.~~ New work has now demon-~trated~~*~~*~~ that neoline has structure (76) and that the structures of chasmanine and homochasmanine must now be revised to (79) and (go) respectively. A 13Cn.m.r. study of the bases chasmanine (79) neoline (76) delphisine (75) amongst supports the assignment of the la-groups in structures (75) (76) (79) and (80). The recent X-ray crystallographic studies on delphi~ine~~ and chas- manine" also define the absolute stereochemistries of these alkaloids to be as shown.44 S. W. Pelletier Z. Djarmati and S. LajSiC J. Amer. Chem. SOC.,1974,% 7815. 45 K. Wiesner H. W. Brewer D. L. Simmons D. R. Babin F. Bickelhaupt J. Kallos and T. Bogri Tetrahedron Letters 1960 17. 46 0.E. Edwards L. Fonzes and L. Marion Canad. J. Chem. 1966,44 583. 47 L. Marion J. P. Boca and J. Kallos Tetrahedron Suppl. 1966 8 Pt. 1 p. 101. 48 S. W. Pelletier and S. W. Page in ref. 2 pp. 258-259. 49 S. W. Pelletier and Z. Djarmati J. Amer. Chem. SOC.,1976,98 2626. so S. W. Pelletier W H. De Camp and Z. Djarmati J.C.S. Chem. Cumm. 1976 253. 412 D. G.Buckley TMe OMe Delphisine (75) R' = Ha R2 = R3= Ac (77) R=Me Neoline (76) R'=R 2 =R3=H (78) R=H Chasmanine (79) R' = Me; R2 = R3= H Homochasmanine (80) R' =R2= Me; R3 = H From the above it is clear that the previously reported correlation of chasmanine with br~wniine~~ must be in error.7 Tropane Alkaloids An impressively efficient new route to the synthesis of tropane derivatives has been reported re~ently.~~'~~ This involves as a key stage the promotion of C-C bond formation by means of transition-metal carbonyl~.'~ The most useful synthetic route to arise from this work involves the reaction of aaa'a'-tetrabromoacetone and N-methoxycarbonylpyrrole with di-iron enneacarbonyl which gives finally the mixture of adducts (81)and (82) which were readily separated (Scheme 10). Under MeO,C Br2CHCOCHBr2 R3 H (81) R' =H. R2 =R3=Br (82) R'=R 3 =Br; R2=H Scheme 10 appropriate conditions (H2-Pd/C-EtOH) the double bond could be hydrogenated and the bromine atoms removed simultaneously from the mixed adducts (81) and (82) to give the ketone (83).Reduction of (83) with an excess of di-isobutylaluminium hydride at -78 "C then gave a separable mixture of tropine (84) and pseudotropine (85). It is noteworthy that this last stage unlike most chemical methods of reduction affords predominantly the desired a,-alcohol. A potentially more important use of the adducts (81) and (82) consists of the removal of the bromine atoms without hydrogenation of the double bond by means s1 R. Noyori S. Makino Y. Baba and Y. Hagakawa Tetrahedron Letters 1974 1049. 52 R. Noyori Y. Baba and Y. Hayakawa J. Amer. Chem. SOC.,1974,% 3336. s3 J.E. Saxton in ref. 1 pp. 74-75. Biological Chemistry -Part (iv) Alkaloids of Zn-Cu in methanol to give the unsaturated ketone (86). Reduction of (86) with di-isobutylaluminium hydride then affords the alcohols (87) and (88)(in proportion 93 :7) the former of which is a vital intermediate in the synthesis of alkaloids such as scopine (89) and teloidine (90).52 MeO,C MeO,C N N (84) R' = OH; R2=H (85) R' = H; R2= OH Me\ HOH 0 A H R' OH OH (87) R' = OH; R2 =H (88) R' = H R~=OH (89) 8 Miscellaneous Alkaloids Early investigations of the biosynthesis of the unusual heterocyclic acid (91) were without significant issue.54 An attractive mechanism for ring-closure of methionine (92) was envisaged," but experimental proof was lacking.43 MeS-CH2-CH2 I HN-Lco,H H2N-$H-F02H (91) (92) Methionine A specific incorporation of [1-I4C 4-3H]methionine [as (92)] into azetidine-2- carboxylic acid (91) without change in isotope ratio showed that the oxidation level at C-4 was unaffected in the biotransformation of (92) into (91) thus excluding as intermediates aspartic+ -semialdehyde (93) and aspartic acid (94).56 Conflicting evidence on the relative levels of incorporation of homoserine (95) and methionine has been ~btained,~~*~~ although the differences are quite small. However when a relatively large amount of inactive homoserine was fed together with labelled methionine incorporation of the latter decrea~ed.~~ It seems likely therefore that homoserine (95) is a biosynthetic intermediate.More significantly [l-14C 2-3H]methionine [as (92)] was incoporated with almost complete tritium loss and so methionine and S-adenosylmethionine cannot be the ultimate precursors of (9 1)? Further 2,4-diaminobutyric acid (96) has been found 54 R. B. Herbert in ref. 1,pp. 50-51. 55 E.Leete J. Amer. Chem. SOC. 1964,86,3162. 56 E.Leete G. E. Davis C. R. Hutchinson,K. W. Woo and M. R. Chedekel,Phytochemistry 1974,13,427. 57 M.-L. Sung and L. Fowden Phytochemistry 1971.10 1523. 414 D.G.Buckley R-CH2 I H2N-CH-CO2H (93) R=CHO (94) R=COZH (95) R=CH20H (96) R = CH2NH2 to be a better precursor for (91) than methionine.” The loss of tritium originally present at C-2 of methionine can be accounted for if 4-amino-2-ketobutyric acid is an intermediate derivable from (96).Ring-closure of the amino-ketone would give azetine-2-carboxylic acid (97) which in turn would generate azetidine-2-carboxylic acid (91) on reducti~n.~~’~~ N-I_LCO,H (97) The structures of the azaphenalene alkaloids of Poranthera corymbosa poran-therine (98) porantheridine poranthericine (99) and 0-acetylporanthericine (1 00) (99) R=H (100) R=Ac are now firmly established and the structure of a new base porantheriline (101) has been determined. 58*59 (ax) AcO*-w A remarkably successful total synthesis of the tetracyclic alkaloid (It)-porantherine (98) by Corey and Balanson6’ (Scheme 11) was planned by means of computer-assisted retrosynthetic analysis.The 6-amino-undeca-2,lO-dionederiva-tive (102),efficiently prepared in four stages from 5-chloropentan-2-one ethylene acetal was cyclized to the A2-piperideine (103) (ring A). Ring B was formed by acid-catalyzed addition to the enamine. Removal of the N-methyl group and J8 S. R. Johns J. A. Lamberton A. A. Siournis and J. Suares Austral. J. Chem. 1975 27 2025. 59 M. F. Grundon in ref. 2 pp. 100-101. 6o E. J. Corey and R. D. Balanson J. Amer. Chem. SOC.,1974,96,65 16. Biological Chemistry -Part (iv) Alkaloids 3 2 Me B t-~ v-vii o> Me B iii iv Me B 0 Reagents:i 10% aq. HCI; ii TsOH-MeCO,C(Me) CH,-PhH reflux; iii Cr0,-py; iv Os0,-HIO,; TsOH-(CH20H),; vi 110 "C-OH-EtOH; vii 10% aq. HCI; vin 110 "C-TsOH-PhMe; ix NaBH,; x SOC1,-py.Scheme 11 oxidation of the terminal double bond resulted in cyclization of an amino-aldehyde to give ring C cf. (104). Intramolecular addition to the enamine function then furnished the tetracyclic ketone (105) which was converted readily into (*)-porantherine (98).