An Expedient Synthesis of LAF389, a Bengamide B Analogue

An optimized, convergent, safe synthesis of LAF389 ( 9 ), an anti-cancer agent analogous to bengamide B, is described. Starting from α- d -glucoheptonic ( d -glycero- d -gulo-heptonic acid) γ-lactone ( 10 ), the lactone 15 was constructed in five steps. Major improvements were made in the preparation of the aldehyde precursor 14 and subsequent olefination to yield 15 via a modified Julia protocol. This olefination was significantly improved by using TMSCl as an additive. The second fragment of the drug substance, ε-caprolactam 7, was obtained in two one-pot operations from (5 R )-5-hydroxy- l -lysine ( 1 ). Finally, opening 15 with 7 using sodium 2-ethyl hexanoate (Na-EH) gave 8, which on deprotection yielded LAF389.