Cytotrienin A (1) is a microbial antitumor secondary metabolite, isolated from a fermentation broth of Streptomyces sp. RK95-74 from soil. It possesses a (E, E, E)-triene within a 21-membered cyclic lactam which also contains four chiral centers, common structural features of the ansamycin-class of natural products, including the mycotrienins (or ansatrienins), trienomycins, thiazinotrienomycins, and trierixin. Cytotrienin A, with its unusual aminocyclopropane carboxylic acid side chain, exhibits potent apoptosis-inducing activity on HL-60 cells, with an ED_<50> value of 7.7nM. To facilitate elucidation of its mechanism of action, the development of a method for its total synthesis and derivatization is highly desirable. The first asymmetric total synthesis of (+)-cytotrienin A has been achieved, and its absolute stereochemistry has been determined. There are several noteworthy features to this total synthesis: A practical diastereo- and enantio-selective aldol reaction using novel catalyst 10 under solvent-free conditions, highly diastereoselective construction of the three contiguous chiral centers, a deoxygenation reaction without positional or E/Z isomerization (from 22 to 23), desulfonylation using NaBH_4 (from 30 to 31), control of the absolute configuration at C_<13> by proline-mediated α-aminoxylation (from 32 to 33), and RCM for the formation of the 21-membered macrolactam (from 43 to 44).
