TOTAL SYNTHESIS OF FK-506 .2. COMPLETION OF THE SYNTHESIS

The C15-C16 bond of FK-506 was formed via sulfone anion coupling follo wed by chelation controlled reduction of the C15 ketone. Efficient met hylation of the CIS-OH was accomplished by a combination of Me3OBF4-4 Angstrom molecular sieves in the presence of Proton Sponge((R)). A pro cedure was developed to avoid epimerization al the C2 position of the pipecolinate section during alkaline hydrolysis. A reductive fragmenta tion of the C21-C24 [6,6]-spiroketal iodide using active Zn/Ag-graphit e delivered the alpha'-allyl aldol section. The C9-C10 [5,6]-spiroketa l acetonide was de-blocked via a novel beta-elimination, using a combi nation of LiHMDS-Mg(HMDS)(2) in HMPA-DME (1:1), to afford an enediol a cetal, which was oxidized with dimethyl dioxirane to generate the C8-C 10 alpha, beta- diketoamide acetal function. Final desilylations compl eted the total synthesis of FK-506. (C) 1997 Elsevier Science Ltd.