A number of highly cytotoxic polyketides, including the anguinomycins,1 leptofuranins,2 leptomycin,3 and kazusamycin,4 having similar gross chemical structures have been isolated from Streptomyces strains. Recently, a structurally related polyketide, callystatin A 1, was isolated from the marine sponge, Callyspongia truncata, in the Nagasaki Prefecture.5 Callystatin A shows remarkable in vitro cytotoxicity (IC50 ) 0.01 ng/mL) against KB cells. The relative and absolute stereostructure of callystatin A was established by a combination of spectroscopic methods and chemical synthesis.5-7 The limited quantities of callystatin A available from natural sources, as well as the possibility for carrying out syntheses and structure elucidation of the related antitumor antibiotics, prompted us to pursue a total synthesis of callystatin A.8 Here we disclose the asymmetric total synthesis of (-)-callystatin A exploiting our recently developed asymmetric aldol protocol with chlorotitanium enolates of acyl oxazolidinethiones.9 Strategically, E-selective olefination10 of aldehyde 2 (Scheme 1) with the phosphorane derived from tributylphosphonium salt 3 appeared to offer the most convergent assembly of callystatin A. Aldehyde 2 representing C1 to C12 would be constructed from a similar olefination between the masked pyranone aldehyde 4 (Scheme 2) and phosphonium salt 5 (Scheme 3). The C13 to C22 propionate fragment 3 was to be constructed through consecutive asymmetric aldol additions9 employing acyl oxazolidinethione 6 (Scheme 4). The synthesis of aldehyde 4 began with S-glycidol 7 as illustrated in Scheme 2. Protection of S-glycidol as its TBDPS ether followed by copper-catalyzed epoxide opening with vinylmagnesium bromide provided the alcohol 8 in 85% overall yield. Conversion of the secondary alcohol to the isopropoxy propenyl ether provided a mixed acetal which was exposed to the Grubbs catalyst11 to effect ring-closing metathesis to dihydropyran 9 (71% overall). Removal of the TBPDS protecting group with n-Bu4-