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Biogenetic Syntheses of Kopsijasminilam and Deoxykopsijasminilam Martin E. Kuehne,* Yun-Long Li, and Chang-Qing Wei Department of Chemistry, University of Vermont, Burlington, Vermont 05405
[email protected] Received March 18, 2000
The hexacyclic ketoester 7, derived from cyclization of racemic minovincine (6), was reduced to two C-19 epimeric alcohols 8 and 9. Stereoelectronically controlled fragmentations of corresponding O-sulfonyl derivatives provided, respectively, the hexacyclic enamine 14 and, after oxidation of the olefin 16, the pentacyclic lactam 17 with a brigehead double bond. Formation of a carbamate, introduction of a second double bond at C-16, and conjugate reductive hydroxylation at C-20, or hydrogenation, gave the title products. Kopsijasminilam (1) and deoxykopsijasminilam (2) are two nonbasic indoline alkaloids (Figure 1) isolated in Thailand from Kopsia jasminiflora.1 Their unprecedented structural skeleton is shared by 14,15-dehydrokopsijasminilam (3),1 and by the pauciflorines A and B (4, and 5),2 which contain the additional unusual feature of a bridgehead double bond. In continuation of our longstanding efforts in biomimetic syntheses of indole and indoline alkaloids,3 our approach to syntheses of these pentacyclic lactams was based on a cyclization of the biogenetically presumed precursor minovincine (6) and a subsequent ring fragmentation. While the generation of pentacyclic alkaloids of the minovincine (6) type from a ∆-20,21-secodine precursor has been biosynthetically established,4 and synthetically mimicked,3 extension of such endeavors to the eventual formation of kopsijasminilam (1) or pauciflorine (4, 5) type structures was still in the realm of biogenetic speculation. In this context, the presence of a C-19 oxygen function in minovincine (6) suggested not only the option of cyclization to a pleiocarpine type hexacyclic intermediate,5 but also the use of this functionality for a following ring fragmentation, to yield the ∆-19,20 bridgehead double bond of the pauciflorines. Thus, the acid-mediated cyclization of racemic minovincine (6, 19-oxovincadifformine, Scheme 1),6 an alkaloid that we had obtained previously by three alternative synthetic routes,7,8 provided a hexacyclic ketone 7. This (1) Ruangrungsi, N.; Likhitwitayawuid, K.; Jongbunprasert, V.; Ponglux, D.; Aimi, N.; Ogata, K.; Yasuoka, M.; Haginiwa, J.; Sakai, S. Tetrahedron Lett. 1987, 28, 3679. (2) Kam, T.-S.; Yoganathan, K.; Koyano, T.; Komiyama, K. Tetrahedron Lett. 1996, 37, 5765. (3) For pertinent reviews of our syntheses see (a) Overmann, L. E.; Sworin, M. Alkaloids: Chemical and Biological Perspectives; John Wiley & Sons: New York, 1985; Vol. 3, p 275. (b) Kuehne, M. E.; Marko, I. The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic Press: New York, 1990; Vol. 37, p 77. (c) Bornmann, W. G.; Kuehne, M. E. J. Org. Chem. 1992, 57, 1752. (4) (a) Qureshi, A. A.; Scott, A. I. J. Chem. Soc. 1968, 948. (b) Scott, A. I.; Reichardt, P. B.; Slaytor, M. B.; Sweeney, J. G. Bio-Org. Chem. 1971, 1, 157. (c) Kutney, J. P.; Beck, J. F.; Eggers, N. J.; Hanssen, H. W.; Sood, R. S.; Westcott, N. D. J. Am. Chem. Soc. 1971, 93, 7322. (5) (a) Guggisberg, A.; Gorman, A. A.; Bycroft, B. W.; Schmid, H. Helv. Chim. Acta 1969, 52, 76. (b) Schnoes, H. K.; Biemann, K. J. Am. Chem. Soc. 1964, 86, 5693. (6) Langlois, N.; Andriamialisoa, R. Z. J. Org. Chem. 1979, 44, 2468. (7) Kuehne, M. E.; Earley, W. G. Tetrahedron 1983, 39, 3707.
Figure 1. Structures and biogenetic pathways to the C-21 oxolactams kopsijasminilam and the pauciflorines.
compound was envisioned as the key precursor for a fragmentation reaction that would give the pentacyclic skeleton of the target lactams, and include the remarkable bridgehead double bond of the pauciflorines.9 Reduction of the hexacyclic ketone 7 with sodium borohydride led to a 1.3:1 mixture of two epimeric alcohols, 8 and 9. A reduction with NaBH4/CeCl3 gave a 2:1 mixture of alcohols 8, 9, and Super Hydride at -78 °C gave a 15:1 ratio, while DIBALH at -78 °C provided the opposite 1:4 ratio of these products. The alcohols could be separated and their stereochemistry defined by an NOE spectrum of epimer 9, which showed correlations of the hydrogens adjacent to the tert-amine (C-21) and (8) Kuehne, M. E.; Earley, W. G. Tetrahedron 1983, 39, 3715. (9) For an initial report of this fragmentation, see Kuehne, M. E.; Li, Y.-L. Org. Lett. 1999, 1, 1749. Such a fragmentation was also independently postulated by Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Lynch, V. Tetrahedron Lett. 1999, 40, 5135.
10.1021/jo000398h CCC: $19.00 © 2000 American Chemical Society Published on Web 09/07/2000
Biogenetic Syntheses of Kopsijasminilam Scheme 1a
a (a) HCl-MeOH, reflux, 44% (85% based on recovered 6); (b) DIBALH, THF, -78 °C, 8:9 ) 1:4, 72%; Super Hydride, THF, -78 °C, 8:9 ) 15:1, 85%; (c) ClCO2Me, Na2CO3, CH2Cl2, rt, 84%; (d) NaBH4, CeCl3, MeOH, 88%; (e) MsCl, TEA, DMAP, CH2Cl2, 91%; (f) MsCl, TEA, CH2Cl2, 91%; (g) ClCO2Me, Na2CO3, CH2Cl2, rt, 86%; (h) TEA, EtOH, H2O, 60 °C, 83%; (i) Ts2O, pyridine, rt, 89%; (j) NaCN, EtOH-H2O, reflux, 89%; (k) tBuOK, THF, O2, rt, 90%; (l) Swern oxidation, 70%.
the hydroxyl (C-19) groups, as well as a C-21 to C-9 hydrogen correlation. Furthermore, IR absorption at 1718 cm-1 distinguished the hydrogen bonded ester 9 from its epimer 8, which gave a normal ester absorption at 1730 cm-1. Alternatively, prior derivatization of the secondary amine 7 as its methyl carbamate 10 (a functionality found in all of the lactam alkaloids 1-5) and subsequent reduction with sodium borohydride and ceric chloride, led only to the alcohol 11, corresponding to the amino alcohol 8. On the other hand, reduction of the ketone 10 with L-Selectride yielded only the hydroxy epimer of 11, but here the reduction was very slow and the product yield poor (∼25%). Assignment of the relative stereochemistry of the hydroxyl groups in the alcohols 8 and 11 vs 9 was also based on the results of subsequent ring fragmentations. Formation of an O-mesylate 12 from the alcohol 8, followed by carbamate formation, provided a derivative 13, which matched the product of mesylation of the
J. Org. Chem., Vol. 65, No. 20, 2000 6435
alcohol 11. It might be noted here that because of steric constraints, the usual preferential derivatization of an amine over an alcohol was not seen and amino Omesylate or O-acetate derivatives were formed from alcohols 8 or 9, even with a 3-fold excess of mesylation or acylation agent. When the mesylate 13 was warmed with triethylamine in aqueous alcohol or heated with sodium acetate in DMF, methanesulfonic acid was eliminated. The product 14 displayed, in addition to the expected downfield 13C NMR signals for the two carbonyl substituents and two substituted aromatic carbons, two additional signals for a tetrasubstituted double bond (and no vinyl H signals in the 1H NMR spectrum). Formation of the hexacyclic enamine 14 is in accord with an anti-periplanar bond migration (C-17 to C-19), with loss of the C-19 mesylate and C-21H substituents. NOE correlations of the C-16 β-H with C-5 and C-6 β-H’s established the relative stereochemistry of the product 14. A reaction of the amino alcohol 9 with tosyl anhydride in pyridine gave the sulfonamide tosylate 15. Since elimination of its tosylate function was expected to lead to the stereoelectronically favored desired ring fragmentation and formation of a hydrolytically sensitive imonium salt, the reaction was carried out in the presence of cyanide. The resulting nitrile 16 was obtained in 89% yield. Oxidation of this R-aminonitrile with potassium tert-butoxide and oxygen then furnished (through a cyanohydrin) the pentacyclic lactam 17 in 90% yield. Under these conditions, the C-16 carbon bearing the ester substituent was not hydroxylated. Our hope of simultaneous introduction of hydroxyl groups adjacent to the nitrile and ester functions, by enolate formation with LDA and reaction with oxygen, led only to destruction of the nitrile 16. The N-tosyl substituent of the fragmentation product 17 could be removed with sodium amalgam and NaH2PO4, or with sodium naphthalenide (Scheme 2). It was also lost in variable yields on formation of the ester enolate with LDA and subsequent aqueous workup; perhaps assisted by bridging to the ester enolate oxygen (see below). Synthesis of a pauciflorine without aryl oxygen substituents now seemed only two simple steps away from the product pentacyclic amine 18. Formation of a carbamate from the amine 18 did not occurr as easily as the derivatization of the amine 7 (methyl chlorocarbonate and K2CO3) but required a reaction with triphosgene, followed by treatment with methanol. At 0 °C the cyclic ketene acetal-acylal 19 was obtained, while addition of methanol at room temperature led to the ortho ester 20. Its reaction with sodium methoxide in refluxing methanol provided the carbamate ester 21 and its epimer 22, which was most directly obtained from the ketene acetal-acylal 19 with sodium methoxide. To introduce a hydroxyl group at C-16, adjacent to the ester function, generation of an enolate with potassium hexamethyldisilazide at -78 °C, or with LDA, or with potassium hydride, and its reaction with molecular oxygen was attempted. Invariably, this led to recovery of the carbamate ester 22. However, a reaction of the lithiium enolate with 2-(phenylsulfonyl)-3-phenyloxaziridine10 provided the diene ester 23 in 86% yield. Genera(10) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org. Chem. 1984, 49, 3241.
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J. Org. Chem., Vol. 65, No. 20, 2000 Scheme 2a
Kuehne et al.
Biogenetically, cyclization of minovincine may be linked to introduction of the C-16 hydroxyl function of the pauciflorines through generation of a 16-R-hydroxyimine, or its more reactive N-carbamate derivative, thus leading to a pleiocarpine (24) with C-16 and C-19 hydroxyl substituents (i.e., 25, Figure 1). A mimic of such an oxidative cyclization is conceivable, with avoidance of rearrangement to vincamine-type products, by formation of an initial Nb-oxide. However, methodology would have to be developed to divert a favored C-16-β-hydroxylation to the required R-hydroxylation of minovincine (6). While the C-20 to C-21 bond fragmentation was successful, one can also consider an alternative biogenetic derivation of such products from a pleiocarpine type precursor (Figure 1), which might entail successive oxidations at Nb, rather than use of a C-19 hydroxyl derivative, followed by cleavage of the C-20 to C-21 bond with generation of a C-20 carbocation 26, that could then provide a C-20 alcohol, i.e., kopsijasminilam (1) or a ∆-19,20 double bond, i.e., the pauciflorines (4, 5). Biosynthetic studies of these alternatives with labeled synthetic precursors should prove interesting.
Experimental Section
a (a) Na naphthalenide, DME, -78 °C, 95%; (b) triphosgen, pyridine, CH2Cl2, 0 °C; MeOH, pyridine, 0 °C, 91%; (c) triphosgen, pyridine, CH2Cl2, 0 °C; MeOH, pyridine, rt, 94%; (d) PPTS, MeOH, rt, 3 d,
