Total synthesis of cryptophycin-24 (Arenastatin A) amenable to structural modifications in the C16 side chain

Two efficient protocols for the synthesis of tert-butyl (5S,6R,2E,7E)-5-[(t ert-butyldimethylsily oxy]-6-methyl-8-phenyl-2,7-octadienoate, a major comp onent of the cryptophycins, are reported. The first utilized the Noyori red uction and Frater alkylation of methyl 5-benzyloxy-3-oxopentanoate to set t wo stereogenic centers, which became the C16 hydroxyl and C1' methyl oft-he cryptophycins. The second approach started from 3-p-methoxybenzyloxypropan al and a crotyl borane reagent derived from (-)-alpha -pinene to set both s tereocenters in a single step and provided the dephenyl analogue, tert-buty l(5S,6R,2E)-5-[(tert-butyldimethylsilyl)oxy]-6 -methyl-2,7 -octadienoate, i n five steps. This compound was readily converted to the 8-phenyl compound via Heck coupling. The silanyloxy esters were efficiently deprotected and c oupled to the C2-C10 amino acid fragment to provide desepoxyarenastatin A a nd its dephenyl analogue. The terminal olefin of the latter was further ela borated via Heck coupling. Epoxidation provided cryptophycin-24 (arenastati n A).