Synthesis of a stereochemically diverse library of medium-sized lactams and sultams via S(N)Ar cycloetherification

ACS Comb Sci. 2011 Jul 11;13(4):365-74. doi: 10.1021/co2000218. Epub 2011 Apr 28.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Combinatorial Chemistry Techniques / methods*
  • Drug Discovery / methods
  • Lactams / chemical synthesis*
  • Macrocyclic Compounds / chemical synthesis
  • Models, Chemical
  • Small Molecule Libraries / chemical synthesis*
  • Stereoisomerism

Substances

  • Lactams
  • Macrocyclic Compounds
  • Small Molecule Libraries