摘要:

A synthetic approach to the pseudopterosins Simon Gill," Philip Kocienski,*" Andrew Kohler," Alessandro Pontirolia and Liu Qunb a Department of Chemistiy, The University, Southampton, UK SO1 7 1BJ Department of Chemistry, Northeast Normal University, Changchun 130024, Peoples Republic of China Three Lewis acid catalysed reactions used in a synthesis of the tricyclic core of the marine anti-inflammatory pseudopterosins are reported; the reductive cleavage of an oxirane with inversion, the cyclisation of an a-hydroxy ketenedithioacetal to an arene, and a stereoselective annulation using an allylic sulfone as the electrophile. Pseudopterosins A-D la-d were the first members of a family of diterpene pentose glycosides isolated from the Caribbean sea whip Pseudopterogorgia elisabethae.Their potent anti-inflammatory and analgesic activities were the spur for the total syntheses of the glycoside,24 the aglycone,5,6 and advanced fragments of pseudopterosins A and E.7-13We now report a highly stereoselective synthesis of the tricyclic derivative 2 whose enantiomer had previously been converted to pseudo- pterosin A la.6 The absolute configuration of 2 corresponds to the tricyclic core of pseudopterosins K le and L If which have yet to be synthesised.14 The synthesis began (Scheme 1) with a highly stereoselective hydroxy group directed epoxidationl5 of (1S,2S,SR)-neoisopu-legol3 which is readily available from commercial (lR,2S,5R)-isopulegol.16 The oxirane 4 was cleaved with clean inversion of configuration by reduction with NaBH3CN in the presence of BF3.0Et2 to give the diol 5 as a single diastereoisomer in 79% yield.17 Selective protection of the primary hydroxy group (84%) followed by Swern oxidation returned the ketone 7 which was then converted to the a-oxoketenedithioacetal 8 by a one- pot, four step procedure involving reaction of the lithium enolate derived from 7 with CS2 followed by a second enolisation and trapping of the intermediate ketene dithiolate with 1,3-dibromopropane (71 % overall). A critical step in the synthesis was the conversion of a-oxoketenedithioacetal 8 to the aromatic ring in intermediate 10-a reaction which is based on the work of Dieter, Ila and Junjappa. 18.19 Thus, addition of methallylmagnesium chloride to the ketone 8 followed by treatment of the crude alcohol 9 with BF,.OEt, in MeOH-THF gave methoxyarene 10 in 63% overall yield for the two steps. The structure of the ketenedithioacetal was critical to the success of the reaction since similar treatment of the dithioacetal derivative 13 under identical conditions returned the methylthioarene 14 (Scheme 2) in 84% yield.20To complete the synthesis, the alcohol 10 was converted to its tosylate 11which was then added to the lithium derivative of A 6 3 H OTBS@; 9 x 163% (2 steps) I YMe \-xii91% H OR 10R=H xi Elo A ii 9 OR 4 -5R=H iii 84% -+ 6R=TBS iv 188% I v-viii t--71% OTBS OTBS 8 7 I YMe I ?Me xiii H@ \~Hp\ 79% Ph02S IT12 2 H'qH R1 R2 R3 Ala H H H Kle R=H Blb Ac H H L If R=Ac Clc H Ac H Dld H H Ac 2 + 16.8 (C 0.57, CHC13)11 R=Ts [a]~ Scheme 1 Reagents and conditions: i, VO(a~ac)~, ButOOH, PhH, room temp.; ii, NaBH3CN, BF3-OEt2, THF; iii, TBSCl, imidazole, DMF, room temp.; iv, Swem oxidation; v, LHMDS, DMPU, THF, -78 "C; vi, CS2, -78+0 "C; vii, LHMDS, -78 "C; viii, Br(CH2)3Br, -78 "C+room temp.; ix, methallylmagnesium chloride, THF, 0 "C; x, BF3-OEt2, MeOH-THF, -40 "C-+room temp.; xi, TsC1, DMAP, NEt3, 0 "C-+room temp.; xii, Me2C = CH-CH(Li)S02Ph, THF, -78 oC-+room temp.; xiii, EtAlC12, THF, -78 "C-+room temp.OTBS OH 13 14 Scheme 2 Reagents and conditions: i, methallyl magnesium chloride; ii, BF3.0Et,, THF-MeOH, 84% Chem. Commun., 1996 1743 3-methylbut-2-enyl sulfone to afford the alkylation product 12 as a mixture (ca.1 : 1) of diastereoisomers in 91% yield. Treatment of the mixture of sulfones 12 with EtAlC12 in THF at -78 "C returned the tricycle 2 as a mixture of diastereoisomers (10 : 1) in favour of the desired stereochemistry.21 The structure and stereochemistry of pure diastereoisomer 2 obtained by simple crystallisation from 2-PrOH (mp 95-96 "C) was confirmed by comparison with NMR spectra kindly provided by Dr Stuart McCombie of the Schering-Plough Research Institute. In conclusion we have accomplished a concise and efficient synthesis of the enantiomerically pure tricyclic core of the pseudopterosins starting from cheap and readily available starting materials.Since (lR,2R,5S)-neoisopulegol(ent-3) is available from commercial (S)-citronellal, both enantiomeric series of the pseudopterosin aglycones are available by our route. A noteworthy feature of our synthesis is the trans- formation of a-oxoketenedithioacetal 8 to methoxyarene 10 -a transformation which hitherto has been limited to the production of methylthioarenes as in 1L14. We thank Glaxo-Wellcome for a CASE studentship (S. G.), the Collegio Ghislieri di Pavia and the Universiti di Pavia for a scholarship (A. P.) and the British Council for a fellowship (L. Q.). We also thank Dr David Harrowven for helpful discussions. References 1 S. A. Look, W. Fenical, G. K. Matsumoto and J.Clardy, J.Org. Chem., 1986,51, 5140. 2 C. A. Broka, S. Chan and B. Peterson, J. Org. Chem., 1988, 53, 1584. 3 E. J. Corey and P. Carpino, J.Am. Chem. SOC., 1989,111,5472. 4 E. J. Corey and P. Carpino, Tetrahedron Lett., 1990,31, 3857. 5 S. W. McCombie, B. Cox, S.-I. Lin, A.K. Ganguly and A. T. McPhail, Tetrahedron Lett., 1991, 32, 2083. 6 S. W. McCombie, B. Cox and A. K. Ganguly, Tetrahedron Lett., 1991, 32, 2087. 7 A. K. Ganguly, S. W. McCombie, B. Cox, S. Lin and A. T. McPhail, Pure Appl. Chem., 1990,62, 1289. 8 A. P. Kozikowski and J. P. Wu, Synlett, 1991, 465. 9 S. W. McCombie, C. Ortiz, B. Coz and A. K. Ganguly, Synlett, 1993, 541. 10 M. E. Jung and C. S. Siedem, J.Am. Chem. SOC., 1993,115,3822. 11 D. C. Harrowven, S.T. Dennison and P. Howes, Tetrahedron Lett., 1994,35,4243. 12 H. G. Schmalz, A. Majdalani, T. Geller, J. Hollander and J. W. Bats, Tetrahedron Lett., 1995,36, 4777. 13 L. Eklund, I. Sarvary and T. Frejd, J.Chem. SOC.,Perkin Trans. I, 1996. 303. 14 V. Roussis, Z. Wu, W. Fenical, S. A. Strobel, G. D. Van Duyne and J. Clardy, J. Org. Chem., 1990, 55,4916. 15 K. B. Sharpless and R. C. Michaelson, J. Am. Chem. SOC., 1973, 95, 6136. 16 D. Friedrich and F. Bohlmann, Tetrahedron, 1988,44, 1369. 17 R. 0.Hutchins, I. M. Taffer and W. Burgoyne, J.Urg. Chem., 1981,46, 5214. 18 R. K. Dieter, Tetrahedron, 1986, 42, 3029. 19 H. Junjappa, H. Ila and C. V. Asokan, Tetrahedron, 1990, 46,5423. 20 R. K. Dieter and Y. J. Lin, Tetrahedron Lett., 1985, 26, 39. 21 B. M. Trost and M. Reza Ghadiri, J. Am. Chem. SOC., 1986, 109, 1098. Received, 26th April 1996; Corn. 6102930B 1744 Chem. Commun., 1996

ISSN:1359-7345    

DOI:10.1039/CC9960001743

出版商:RSC    

年代:1996

数据来源: RSC