Synthesis and Photophysical Properties of Benzotriazole-Derived Unnatural α-Amino Acids.

Jonathan D. Bell,Andrew Sutherland,Christopher R. Wellaway,Timaeus E. F. Morgan,Alexander H. Harkiss,Ned Buijs

doi:10.1021/acs.joc.9b01685

Jonathan D. Bell, Andrew Sutherland + Show 4 more

Open Access

https://doi.org/10.1021/acs.joc.9b01685

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Abstract

The synthesis of a new class of benzotriazole-derived α-amino acid is described using a highly efficient nucleophilic aromatic substitution of ortho-fluoronitrobenzenes with l-3-aminoalanine and a polymer-supported nitrite reagent-mediated diazotization and cyclization of the subsequent 1,2-aryldiamines as the key steps. Further functionalization of the benzotriazole unit by preparation of halogenated analogues and Suzuki-Miyaura cross-coupling with aryl boronic acids allowed the synthesis of α-amino acids with conjugated side chains. Analysis of the photophysical properties of these α-amino acids revealed that incorporation of electron-rich substituents results in charge-transfer-based, fluorescent compounds with MegaStokes shifts.

Highlights

IntroductionNonproteinogenic α-amino acids have been deemed as highly important targets for a range of applications.[1]
For many years, nonproteinogenic α-amino acids have been deemed as highly important targets for a range of applications.[1]In synthetic chemistry, they are widely used as chiral precursors, ligands, and catalysts and are found to be components of many natural products and pharmaceutically relevant compounds.[2]
Our approach to α-amino acids bearing benzotriazole side chains is shown in Scheme 1

Summary

Introduction

Nonproteinogenic α-amino acids have been deemed as highly important targets for a range of applications.[1] In synthetic chemistry, they are widely used as chiral precursors, ligands, and catalysts and are found to be components of many natural products and pharmaceutically relevant compounds.[2] In medicinal chemistry and the life sciences, unnatural α-amino acids are commonly used as enzyme inhibitors or as probes to study biological mechanisms and protein structure and function.[3] In this regard, there have been significant efforts on the design and development of fluorescent unnatural α-amino acids as tools for a range of chemical biology applications.[4] Many important fluorescent αamino acid probes have been rapidly prepared by incorporating a chromophore within the side chain of L-3-aminoalanine.[5]. Various benzo-fused heterocycles have been attached to the side chain of L-3-

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