Synthesis of Structurally Diverse N‐Substituted Quaternary‐Carbon‐Containing Small Molecules from α,α‐Disubstituted Propargyl Amino Esters

Abstract

N‐containing quaternary stereocenters represent important motifs in medicinal chemistry. However, due to their inherently sterically hindered nature, they remain underrepresented in small molecule screening collections. As such, the development of synthetic routes to generate small molecules that incorporate this particular feature are highly desirable. Herein, we describe the diversity‐oriented synthesis (DOS) of a diverse collection of structurally distinct small molecules featuring this three‐dimensional (3D) motif. The subsequent derivatisation and the stereoselective synthesis exemplified the versatility of this strategy for drug discovery and library enrichment. Chemoinformatic analysis revealed the enhanced sp3 character of the target library and demonstrated that it represents an attractive collection of biologically diverse small molecules with high scaffold diversity.

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

“…4). Specically, in line with the structural data, it was thought that these investigations could include modication of the benzene ring through substitution (20)(21)(22)(23)(24)(25)(26)(27)(28), variation in the bridging heterocycle (29,30), derivatisation of the pyrrolidinone heterocycle via a-alkylation or ketone modication (31,32) and nally modication of the quaternary substituent R 1 (33).…”

“…1). 27 This included novel hits for challenging protein targets with no previously reported small molecule binders. Secondly, we highlight how molecules of this origin allow for analogues to be accessed in a synthetically efficient manner, including complex quaternary centre-containing compounds, in three to six steps from cheap (<£3 per gram) and readily available starting materials.…”

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

“…(B) Hassan et al ( 2018 ) DOS fragment library based on twisted amides. (C) Mateu et al ( 2018 ) DOS fragment library based on α,α-disubstituted amino esters. (D) Foley et al ( 2017 ) synthesis of scaffolds distantly related to natural products.…”

“…The most recent and final example of synthetic efforts within this field by Mateu et al ( 2018 ) report the use of α,α-disubstituted amino esters for the DOS of fragments incorporating a N -substituted quaternary carbon, an important and underrepresented motif within screening collections (Figure 2C ). Using a single building block, 40 structurally diverse molecules based on 27 molecular frameworks were constructed in a synthetically efficient manner using an average of only three synthetic steps to access the entire library.…”

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment‐Based Drug Discovery

“…DOS is focused on using short and divergent synthetic sequences from simple starting materials to generate structurally complex and diverse scaffolds . DOS would provide the ideal strategy to expand fragment libraries into three‐dimensional chemical space, and this challenge has been taken up across industry and academia …”