Abstract
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 (5R)-5-hydroxy-l-lysine (1). Finally, opening 15 with 7 using sodium 2-ethyl hexanoate (Na-EH) gave 8, which on deprotection yielded LAF389.
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