Sharpless Asymmetric Dihydroxylation of 5-Aryl-2-vinylfurans: Application to the Synthesis of the Spiroketal Moiety of Papulacandin D Devan Balachari and George A. O’Doherty* Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455 odoherty@chem.umn.edu Received February 8, 2000 ABSTRACT Using the Sharpless catalytic asymmetric dihydroxylation reaction on 5-aryl-2-vinylfurans, diols are produced in high enantioexcess. The resulting diols can be efficiently transformed into the spiroketal ring precursor of the antifungal compound papulacandin D. Stereoselective reduction of this precursor followed by a diastereoselective dihydroxylation completes the synthesis of a mannopyranoside isomer of a papulacandin derivative. The papulacandins are a group of naturally occurring glycolipid-antifungal agents isolated from the fermentation broths of Papularia spherosperma 1 and Dictyochaeta sim- plex. 2 The papulacandins inhibit 1,3--glucan synthase which is essential for cell wall construction in fungal cells but not human cells. 3 Members of the papulacandin family exhibit potent in vitro activity against Candida albicans and related microorganisms. They are also found to be effective against P. carinii pneumonia, a most prevalent opportunistic infec- tion that is a frequent cause of death in AIDS patients. 4 The high degree of selective toxicity and the fascinating molecular structure have stimulated a significant amount of both biological 5 and synthetic research by a number of research groups. 6 So far, only one member of the papulacandins has succumbed to total synthesis, that being by the efforts of the Barrett group. 7 In the context of a research program aimed at the synthesis of the papulacandins and analogues, we have been looking for an easy entry into the spiroketal moiety of compound 1. (1) Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiot. 1977, 30, 289. (2) (a) Van Middlesworth, F.; Omstead, M. N.; Schmatz, D.; Bartizal, K.; Fromtling, R.; Bills, G.; Nollstadt, K.; Honeycutt, S.; Zweerink, M.; Garrity, G.; Wilson, K. J. Antibiot, 1991, 44, 45. (b) Jabri, E. D. R.; Quigley, M.; Alders, M.; Hrmova, M.; Taft, C. S.; Phelps, P.; Selitrennikoff, C. P. Curr. Microbiol. 1989, 19, 153. (c) Bartizal, K.; Abruzzo, G.; Trainor, C.; Krupa, D.; Nollstadt, K.; Schmatz, D.; Schwartz, R.; Hammond, M.; Balkovec, J.; Van Middlesworth, F. L. Antimicrob. Agent Chemother. 1992, 36, 1648. (3) (a) Baguley, B. C.; Rommele, G.; Gruner, J.; Wehrli, W. Eur. J. Biochem. 1979, 97, 345. (b) Perez, P.; Varona, R.; Garcia-Acha, I.; Duran, A. FEBS Lett. 1981, 129, 249. (c) Varona, R.; Perez, P.; Duran, A. FEMS Microbiol. Lett. 1983, 20, 243. (d) Rommele, G.; Traxler, P.; Wehrli, W. J. Antibiot. 1983, 36, 1539. (4) (a) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz, R. E.; Fromtling, R. A.; Nollstadt, K. H.; Van Middlesworth, F. L.; Wilson, K. E.; Turner, M. J. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 5950. (b) Kovacs, J.; Masur, H. J. Infect. Dis. 1988, 158, 254. (5) (a) Kaneto, R.; Chiba. H.; Agematu, H.; Shibamoto, N.; Yoshioka, T.; Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 247. (b) Chiba, H.; Kaneto, R.; Agematu, H.; Shibamoto, N.; Yoshioka, T.; Nishida, H.; Okamoto, R. J. Antibiot. 1993, 46, 356-358. (c) Aoki, M.; Andoh, T.; Ueki, T.; Masuyoshi, S.; Sugawara, K.; Oki, T. J. Antibiot. 1993, 46, 952. (d) Okada, H.; Nagashima, M.; Suzuki, H.; Nakajima, S.; Kojiri, K.; Suda, H. J. Antibiot. 1996, 49, 103. (e) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J. J. Antibiot. 1980, 33, 967. (6) For other approaches to the papulacandin ring system, see: (a) Danishefsky, S.; Philips, G.; Ciufolini, M. Carbohydr. Res. 1987, 171, 317. (b) Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163. (c) Friesen, R. W. Sturino, C. F. J. Org. Chem. 1990, 55, 5808. (d) Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994, 72, 1262. (e) Friesen, R. W.; Daljeet, A. K. Tetrahedron Lett. 1990, 31, 6133. (f) Dubois, E.; Beau, J.- M. Tetrahedron Lett. 1990, 31, 5165. (g) Dubois, E.; Beau, J.-M. Carbohydr. Res. 1992, 223, 157. (h) Rosenblum, S.; Bihovsky, M. J. Am. Chem. Soc. 1990, 112, 2746. (i) Czernecki, S.; Perlat, M. C. J. Org. Chem. 1991, 56, 6289. (j) Barrett, A. G. M.; Dhanak, D.; Lebold, S. A.; Pena, M.; Pilipauskas, D. Pest. Sci, 1991, 31, 581. (k) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117, 6605. ORGANIC LETTERS 2000 Vol. 2, No. 6 863-866 10.1021/ol0000253 CCC: $19.00 © 2000 American Chemical Society Published on Web 03/02/2000