Methodological Advances Permit the Stereocontrolled Construction of Diverse Fully Synthetic Tetracyclines Containing an All-Carbon Quaternary Center at Position C5a

摘要

Here we describe chemical innovations that enable the preparation of fully synthetic tetracyclines containing an all-carbon quaternary, stereogenic center at position C5a, a structurally novel class of compounds in this important family of therapeutic agents. In the key transformation and an important extension of the powerful Michael–Claisen cyclization (AB plus D) approach to the construction of fully synthetic tetracyclines, we show that the six-membered C ring comprising a C5a quaternary carbon center can be assembled by highly stereocontrolled coupling reactions of β-substituted AB enones and o-toluate ester anion D-ring precursors. Novel and versatile β-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone >1 (the key precursor to fully synthetic tetracyclines) into a diverse range of β-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a β-methyl ester-substituted AB enone. A C5a-C11a-bridged cyclopropane tetracycline precursor was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. Two compounds prepared from the bridged cyclopropane intermediate served as (further) diversifiable branch-points, allowing maximally expedient synthesis of C5a-substituted tetracyclines by final-step diversification.