Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506

Article abstract of DOI:10.1021/ja00170a024

Asymmetric syntheses of FK506 and (C₈,C₉-¹³C₂)-FK506 are reported. The latter compound was designed to facilitate an investigation of the interactions between FK506 and its receptor, the recently discovered immunophilin, FKBP. The syntheses involved the preparation of intermediates 7-9 in nonracemic form; the key coupling reactions included a Cram-selective addition of the vinyl Grignard reagent derived from bromide 9 to aldehyde 8 and the addition of the lithioanion of phosphonamide 7 to aldehyde 51, followed by thermal elimination. Dithiane 65 was then hydrolyzed, and glycolic ester 6 (or 6*) was added via an aldol reaction that allowed the introduction of ¹³C labels at C₈ and C₉. Elaboration to FK506 proceeded via a Mukaiyama lactamization reaction and a selective deprotection/oxidation sequence, the efficiency of which was critically dependent upon the order of protecting group removal.