co2000218_si_003.xls (1.57 MB)

Synthesis of a Stereochemically Diverse Library of Medium-Sized Lactams and Sultams via SNAr Cycloetherification

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posted on 11.07.2011, 00:00 by Baudouin Gerard, Jeremy R. Duvall, Jason T. Lowe, Tiffanie Murillo, Jingqiang Wei, Lakshmi B. Akella, Lisa A. Marcaurelle
We have implemented an aldol-based “build/couple/pair” (B/C/P) strategy for the synthesis of stereochemically diverse 8-membered lactam and sultam scaffolds via SNAr cycloetherification. Each scaffold contains two handles, an amine and aryl bromide, for solid-phase diversification via N-capping and Pd-mediated cross coupling. A sparse matrix design strategy that achieves the dual objective of controlling physicochemical properties and selecting diverse library members was implemented. The production of two 8000-membered libraries is discussed including a full analysis of library purity and property distribution. Library diversity was evaluated in comparison to the Molecular Library Small Molecule Repository (MLSMR) through the use of a multifusion similarity (MFS) map and principal component analysis (PCA).