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

Natalia Mateu,Andrew Madin,David R Spring,Leen Kalash,Sarah L Kidd,Hannah F Sore,Andreas Bender

doi:10.1002/chem.201803143

Natalia Mateu, Andrew Madin + Show 5 more

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https://doi.org/10.1002/chem.201803143

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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.

Highlights

N-containing quaternary stereocenters are important motifs in medicinal chemistry and are present in significant essential medicines including the antihypertensive methyldopa (Aldomet®) and the anaesthetic ketamine (Ketalar®) (Figure 1, a-b).[1]
Allyl-containing cyclic quaternary amino esters have been used for the diversity-oriented synthesis (DOS) of small molecule collections.[21],[22] structurally diverse, sp3-rich and complex libraries are still underrepresented in probe and drug discovery screening collections
Synthesis of the DOS library To validate our hypothesis, we initially selected the racemic methyl propargylglycine 1 (R = Me) as a model substrate to perform the reagent-based DOS outlined in this work (Scheme 1)

Summary

Introduction

N-containing quaternary stereocenters are important motifs in medicinal chemistry and are present in significant essential medicines including the antihypertensive methyldopa (Aldomet®) and the anaesthetic ketamine (Ketalar®) (Figure 1, a-b).[1]. Despite all the advances made in the field of asymmetric catalysis to generate α-branched amino-containing compounds,[16,17,18,19] the majority of the reported reactions are based on simple scaffolds with restricted structural diversity and there has been a limited exploration into the construction of such motifs into more complex molecules. Some examples in the literature have validated this strategy by the target-oriented synthesis (TOS) of biologically active small molecules.[20] More recently, allyl-containing cyclic quaternary amino esters have been used for the diversity-oriented synthesis (DOS) of small molecule collections.[21],[22] structurally diverse, sp3-rich and complex libraries are still underrepresented in probe and drug discovery screening collections.

Results

Conclusion