92 FK506及びFKBPプローブ試薬(C_8,C_9-^<13>C_2)-FK506の全合成 : FK506/FKBP複合体に関する研究(口頭発表の部)

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Asymmetric Synthesis of FK506 and (C_8, C_9-^<13>C_2)-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 synthesis involved the preparation of intermediates 7-9 in nonracemic forms. 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 43, followed by thermal elimination. Dithiane 44 was then hydrolyzed, and glycolic ester 6 (or 6^*) was added via an aldol reaction that allowed the introduction of ^<13>C labels at C_8 and C_9. 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. ^<13>C labeled FK506 (2)-FKBP drug protein complex was examined by ^<13>C NMR; the experiments did not show an enzyme bound tetrahedral intermediate, but revealed a noncovalent, fully reversible interaction of the drug with its receptor.
天然有機化合物討論会の論文
1990-09-25