Efficient total synthesis of didemnins A and B

Article abstract of DOI:10.1021/ja00184a041

Didemnins A and B (1 and 2), cytotoxic cyclic peptides from a Caribbean tunicate Trididemnum solidum, have been efficiently prepared by a convergent scheme from two key eastern and western fragments. Efficient routes to derivatives of the constituents of didemnis were explored. Benzyl (2RS,4S)-[O-(tert-butyldimethylsilyl)hydroxyisovaleryl]propionate (Hip derivative) was prepared from 2-hydroxyisovaleric acid by use of C-acylation of Meldrum's acid with diethyl phosphorocyanidate as a key step. Derivatives of (3S,4R,5S)-isostatine (Ist) were prepared from Boc-(R)-alloisoleucine. Methylation of Boc-(R)-Leu-OH and Z-(S)-Tyr-OH respectively afforded the corresponding N-methyl and N,O-dimethyl derivatives. The key eastern fragment, (2RS,4S)-Hip-(S)-Leu-(S)-Pro-OBzl (3), was prepared stepwise from (S)-Pro-OBzl, while Boc-(R)-MeLeu-(S)-Thr[Z-(S)-MeTyr(Me)]-(3S,4R,5S)-Ist(TBDMS)-OH (4), the key western fragment for didemnin A (1), was prepared from Ist derivatives. Coupling of 3 with 4 and cyclization, followed by deprotection, afforded didemnin A (1), which was converted to didemnin B (2).