Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1

摘要

Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (>1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the >AB and >CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an >ABCD aldehyde; introduction of the C(44)–C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the >EF subunit; and final fragment union via Wittig coupling of the >ABCD and >EF subunits to form the C(28)–C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (>1), maintain both the first-generation strategy for the >ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the >EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the >E- and >F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the >F-ring side chain, in conjunction with two independent tactics to access the >F-ring pyran. The first >F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the >EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second >F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (>1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.