Synthesis of a stereochemically diverse library of medium-sized lactams and sultams via S(N)Ar cycloetherification
Baudouin Gerard1, Jeremy R Duvall, Jason T Lowe
1Chemical Biology Platform, The Broad Institute of Harvard and MIT, Cambridge Center, Massachusetts 02142, United States.
Abstract:
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 S(N)Ar 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).
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