A new enantioselective synthesis of (+)-brefeldin A is described. The five chiral centers are created by the following methodology: asymmetric Diels-Alder reaction to prepare the cyclopentanone 13, stereocontrolled reduction of the carbonyl in the ketone 14, stereocontrolled creation of the chiral centers C-4 and (2-15 by a chiral sulfoxide group.(+)-Brefeldin A, first isolated in 1958 from Penecillium decumbensl has been shown to have both antifungal and antiviral activitye2 More recently, it has been shown that the antiviral activity of the molecule is due to inhibition of the intracellular transport of secretory proteins.3 The finding that brefeldin A specifically blocks the movement of proteins from the endoplasmic reticulum to the Golgi apparatus4 has made this molecule a powerful tool for biochemical investigati~n.~The complete structure of (+)-brefeldin A was established in 1971 by X-ray analysis.s Five years later, Corey and Wollenberg reported the first synthesis of racemic brefeldin A.' The first enantioselective synthesis was reported in 1979.8 In the years since Corey's initial report, there have been numerous partial: formal,1° and totalll syntheses described.We report in this paper an enantioselective total synthesis of (+)-brefeldin A following the retrosynthetic (1) Singleton, V. L.; Bohonos, N.; Ulletrup, A. J. Nature 1958, 181, 1072. (2) (a) Betina, V.; Drobnica,L.; Nemec, P.; Zenanova,M. J. J. Antibiot. Ser. A. 1964,17,93. (b) Betina, V.; Betinova, M.; Kutkova, M. Arch. Mikrobiol. 1966,55,1. (c) Tamura, G.; Ando, K.; Suzuki, S.; Takatauki, A.; Arina, K. J. Antibiot. 1968,21, 160. (d) Takatauki, A.; Yamaguchi, I.;Tamura,G.;Miaato,T.;Arina,K.J.Antibiot. 1969,22,442. (e)Hayashi, T.; Takatauki, A.; Tamura, G. Scheme I with a complete control of the stereochemistry of the five chiral centers. Synthesis of the Chiral Hydroxy Sulfone (+)-(55)-2. (+)-Methyl (55' 1-5-[(tert-butyldimethylsily1)oxyl hexanoate (3) was already prepared in the synthesis of zearalenone that we recently reported.12 The chiral hydroxyl group was created by asymmetric reduction of a 8-keto sulfoxide.Reduction of the ester group of 3 with LiAla, followed by bromination and reaction with sodium sulfinate, afforded the sulfone 2 in 71% overall yield (Scheme 11).Synthesis of the Cyclopentanone (-)-(3&4R)-13. The cyclopentanone 13 was prepared using an asymmetric Diels-Alder reaction. Yamamotols has previously shown that the addition of (-)-menthyl fumarate to butadiene in the presence of a Lewis acid, diisobutylaluminum chloride, at low temperature, afforded (S,S)-dimenthyl cyclohex-4-ene-1,2-dicarboxylate in 56% yield and 95% de. We repeated this experiment using (+)-dimenthy1 fumarate [obtained from unnatural (+)-menthol] and diethylaluminum chloride as Lewis acid and we got the adduct 7 in the R,R configuration in 98% yield and a de higher than 90% (about 5% of the S,S isomer was detected by lSC NMR). After reduction of the two esters (Scheme 111), the two hydroxyl groups were protected (benzaldehyde acetonide 9) and DIBAL reduct...