Total Synthesis of the Polyene-Polyol Macrolide RK-397, Featuring Cross-Couplings of Alkynylepoxide Modules

The total synthesis of the natural product RK-397 is based on a new synthetic strategy for
assembling polyacetate structures, by efficient cross-coupling of nucleophilic terminal alkyne modules with
electrophilic epoxides bearing another alkyne at the opposite terminus. The natural product is constructed
from four principal modules:  a polyene precursor for carbons 3−9, and three alkyne-terminated modules
for carbons 10−16, 17−22, and 23−33. Each module is prepared with control of all stereochemical elements,
and the alkynyl alcohols obtained from alkyne−epoxide couplings are converted into 1,3-diols by a sequence
of hydroxyl-directed hydrosilylation, C−Si bond oxidation, and stereoselective ketone reduction with induction
from the β-hydroxyl group. The highly convergent nature of our synthetic pathway and the flexibility of the
modular synthesis strategy for virtually any stereoisomer can provide access to other members of the
polyene-polyol macrolides, including stereoisomers of RK-397.