Total Synthesis and Biological Evaluation of a C(10)/C(12)-Phenylene-Bridged Analog of Epothilone D

摘要

The total synthesis of compound 8,a conformationally constrained analog of epothilone D (2),has been achieved through a convergent strategy based on three key fragments comprising C(1)-C(6) (26),C(7)-C(12) (16),and C(13)-O(16) (19) of the macrocyclic framework.Construction of the C(12)-C(13) bond involved Pd°-mediated S-alkyl Suzuki coupling between aryl bromide 16 and olefin 19,and proceeded in excellent yield,while formation of the C(6)-C(7) bond through aldol reaction was somewhat less efficient.Surprisingly,macrolactonization was rather low-yielding and gave protected 8 only in 39% yield.Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B,the compound was devoid of any significant antiproliferative activity.