Total synthesis of FK-506. Part 2: Completion of the synthesis

Article abstract of DOI:10.1016/S0040-4020(97)00866-1

The C15-C16 bond of FK-506 was formed via sulfone anion coupling followed by chelation controlled reduction of the C15 ketone. Efficient methylation of the C15-OH was accomplished by a combination of Me₃OBF₄-4A molecular sieves in the presence of Proton Sponge. A procedure was developed to avoid epimerization at the C2 position of the pipecolinate section during alkaline hydrolysis. A reductive fragmentation of the C21-C24 [6,6]-spiroketal iodide using active Zn/Aggraphite delivered the α'-allyl aldol section. The C9-C10 [5,6]-spiroketal acetonide was de-blocked via a novel β-elimination, using a combination of LiHMDS-Mg(HMDS)₂ in HMPA-DME (I:]), to afford an enediol acetal, which was oxidized with dimethyl dioxirane to generate the C8-C10 a, P diketoanlide acetal function. Final desilylations completed the total synthesis of FK-506.