Enantioselective synthesis of (+)-brefeldin A

Abstract

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...

A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

“…The unique biological profile of brefeldin A, C, and analogues has attracted a lot of interest in the synthetic organic chemistry community. The first synthesis of the racemic brefeldin A was reported by Corey and Wollenberg in 1976 followed by around 40 total and formal syntheses . Brefeldin C was prepared for the first time by total synthesis in 1988 by Schreiber and Meyers followed by Takano, Guingant (along with aspects of the biological properties of BFA) and Tsunoda .…”

Sulfones and sulfoxides in the total synthesis of biologically active natural compounds

“…192 Syntheses of brefeldin A (130) performed predominantly with the use of sulfinyl-containing intermediates or auxiliary reagents are presented below. Solladie et al 193 A new approach to the synthesis of carbohydrates 196 and to the preparation of (+)-nonactic and 8-epi-nonactic acids, which served as the starting compounds in the synthesis of the macrolide antibiotic nonactin, 197 was developed using 2-hydroxy sulfoxides as precursors. A modification of this method involving the reaction of homochiral sulfinyl ketones with Et 2 AlCN made it possible to prepare alkylglycidic acids with ee 97% and a highly reactive hypoglycemic agent (+)-(R)-palmoxirate.…”

“…The formation of chiral centres at C(4) and C(15) in the brefeldin molecule was completely controlled by the sulfinyl group of the compound 149. The (E )-C(10)=C(11) bond in the fragment 151 was formed using the Julia olefination with the participation of the aldehyde group of the precursor 148 193. Two analogous schemes proposed by Corey (R 1 = MOM, Ar = Tol, R 2 = Me)194 and Nokami (R 1 = MEM, Ar = 4-ClC 6 H 4 , R 2 = Et)195 for the construction of the g-hydroxy-a,b-unsaturated C(4)7C(15) fragment of the brefeldin molecule are based on a simplified approach using the SPAC reaction.…”

The Structure-Activity Relationships of 2,4(1H,3H)-pyrimidinedione Derivatives as potent HIV type 1 and type 2 inhibitors

“…The 6-substituted-2,4(1H,3H)-pyrimidinedione derivatives [8-10] were prepared from the barbituric acid as previously described ( Figure 2) (Son et al, 1996). were obtained commercially, and alcohols [11d-i] were prepared by reported methods (Figure 3) (Brown et al,1950;Meinwald et al,1962;Murdock and Angier, 1962;Schmid and Wolkoff, 1967;Depres and Green, 1984;Sample and Hatch, 1984;Kohler et al, 1993;Solladi and Lohse, 1993). The appropriate tosylates or bromides were prepared (Figure 4) from the alcohols [11a-i] in Figure 3 by either tosylation with p-TsCl in pyridine (Bartellet et al, 1965) or bromination with carbon tetrabromide and triphenylphosphine in CH 2 Cl 2 (Ashton et al, 1988).…”