Synthetic Studies toward the Total Synthesis of Tautomycetin

The studies culminating in the synthesis of two large subunits of tautomycetin are described. The first one, fragment C1–C12 that has an anti-1,3-dimethyl system and a terminal diene unit, was accomplished in 10 linear steps in 7.4% overall yield. The second one, fragment C13–C25 which bears the sensitive anhydride framework and the majority of the stereogenic centers, was prepared in 13 linear steps (longest sequence) in 8% overall yield. Among the key transformations used, a regioselective epoxide opening, a Pd-catalyzed addition of terminal alkyne to acceptor alkyne, a Mukaiyama aldol reaction, a Yamaguchi esterification, and a homemade mild di-esterification can be cited. The chosen strategies allowed good yields, stereoselectivity, reproducibility, and scalability for several important intermediates.