Methodological advances permit the stereocontrolled construction of diverse fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a

作者：Wright Peter M; Myers Andrew G^*

来源：Tetrahedron, 2011, 67(51): 9853-9869.

DOI：10.1016/j.tet.2011.09.143

• Tetracycline
• Enone synthesis
• Michael-Claisen cyclization
• Quaternary center
• Cyclopropane ring-opening

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 beta-substituted AB enones and o-toluate ester anion D-ring precursors. Novel and versatile beta-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 beta-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a beta-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.

• 出版日期2011-12-23