Build/Couple/Pair Strategy for the Synthesis of Stereochemically Diverse Macrolactams via Head-to-Tail Cyclization

Abstract

A build/couple/pair (B/C/P) strategy was employed to generate a library of 7936 stereochemically diverse 12-membered macrolactams. All 8 stereoisomers of a common linear amine precursor were elaborated to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds were further diversified via capping of two amine functionalities on SynPhase Lanterns. Reagents used for solid-phase diversification were selected using a sparse matrix design strategy with the aim of maximizing coverage of chemical space while adhering to a preset range of physiochemical properties.

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

“…To discover novel small-molecule modulators of canonical autophagy, we performed a HTS of 59,541 stereochemically and skeletally diverse compounds derived from diversityoriented synthesis (DOS). These molecules are enriched for sp 3 -hybridized atoms relative to conventional commercial libraries (24)(25)(26), resulting in topographically rich 3D structures. The primary HTS measured autophagosome number in HeLa cells stably expressing GFP-LC3 (Fig.…”

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

“…A further diversity-oriented approach to synthesize macrocyclic structures with natural product-like complexity using efficient, high-throughput synthesis was developed by researchers at the Broad Institute. 21,22 A 7936-membered library (individual compounds) consisting of all eight possible stereoisomers of the general formula 6 (Figure 8.6) was synthesized using solid-phase methodology on SynPhase lanterns. Simple chiral and achiral building blocks were systematically assembled using a build/couple/pair (B/C/P) strategy to obtain a maximally diverse set of macrocyclic compounds with natural product-like complexity.…”

“…Simple chiral and achiral building blocks were systematically assembled using a build/couple/pair (B/C/P) strategy to obtain a maximally diverse set of macrocyclic compounds with natural product-like complexity. 22 This strategy was successfully applied for the synthesis of ML238 (7; Figure 8.6), a sub-nanomolar inhibitor of malaria parasite asexual blood-stage growth 23 (blood-stage malaria Dd2, GI 50 ¼ 0.54 nM).…”

Synthesis of cyclic 1,3-diols as scaffolds for spatially directed libraries

“…One is to use chiral natural product templates, which more often than not are generated from naturally occurring sources. 3 For fully synthetic libraries constructed under the rubric of diversity-oriented synthesis, the use of chiral building blocks is a hallmark of strategies such as “build/couple/pair”, 4 “click/click/cyclize”, 5 and by systematically varying the configuration and hybridization of a key stereocenter. 6 …”