title: Synthesis of a stereochemically diverse library of medium-sized lactams and sultams via S(N)Ar cycloetherification.
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).
authors.affiliation: Chemical Biology Platform, The Broad Institute of Harvard and MIT, Cambridge Center, Massachusetts 02142, United States.
authors.forename: Baudouin
authors.initials: B
authors.lastname: Gerard
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lowe
authors.forename: Tiffanie
authors.initials: T
authors.lastname: Murillo
authors.forename: Jingqiang
authors.initials: J
authors.lastname: Wei
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Akella
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Marcaurelle
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D055808:Drug Discovery / Q000379:methods; D007769:Lactams / Q000138:chemical synthesis*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis; D008956:Models, Chemical; D054852:Small Molecule Libraries / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: D007769:Lactams; D047028:Macrocyclic Compounds; D054852:Small Molecule Libraries