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

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.

New luminescent organoboron esters based on damnacanthal: one-pot multicomponent synthesis, optical behavior, cytotoxicity, and selectivity studies against MDA-MBA-231 breast cancer cells

“…After cooling to room temperature, the excess of solvent was evaporated, and the resulting product was filtered and washed with cold acetonitrile to afford 45 mg (0.084 mmol, 85% yield) of a yellow solid precipitate 4a. [1,3,7,2]oxazaborinin-5,10,15-trione (4b). Preparation of 4b was accomplished following the same procedure of 4a, from 1 (28 mg, 0.10 mmol), anthranilic acid (14 mg, 0.10 mmol), and 4-nitrophenylboronic acid (17 mg, 0.10 mmol).…”

“…Over the past years, the development of biogenic templates based on α-amino acids, 1 peptides, 2 sugar analogues, 3,4 DNA fragments, 5 steroids, 6 and bioactive metabolites 7 coordinated to transition metal, 8 noble metal 9 and main group elements 10–12 has gained increasing attention as they can give access to many bio-organometallic compounds with promising applications like therapeutic agents 13 and fluorescent probes. 14 Among these compounds, plant-synthesized anthraquinones are a versatile type of chemical scaffold with multiple therapeutic applications, whose planarity, rigidity, and aromaticity allow them to act as DNA intercalators.…”

Fluorescent amino acids as versatile building blocks for chemical biology

“…Another FlAA with a built-in fluorophore, benzoacridone-modified alanine, was synthesized by an Ullmann-type coupling between 3-chloro-2-naphthoic acid and aminophenylalanine, followed by cyclization of 2-aminonapthoic acid to yield green-fluorescent benzoacridone amino acid (λem.= 500-550 nm, quantum yield ~50%) 74 . Furthermore, a non-natural FlAAs have been synthesised by building aryl-substituted pyridyl, pyrazole, benzotriazole and pyrazoloquinazoline (24) heterocyclic chromophores on aspartic acid and asparagine structures (λem.= 348-460 nm) [75][76][77][78] (Figure 3b).…”

Synthesis of complex unnatural fluorine-containing amino acids

“…The synthesis of fluorinated benzotriazole amino acids was reported by Sutherland and co-workers in 2019 ( Scheme 12 ) [ 52 ], with benzo-fused amino acids being used for a variety of applications including biological probes and fluorescence imaging access [ 53 , 54 ]. Using an S N Ar approach, amine 43 was treated with 4-fluoro-3-nitrobenzotrifluoride 44 in the presence of base to give the intermediate 45 .…”

“…Reduction of the nitro group followed by triazole formation gave the protected trifluoromethyl benzotriazole amino acid 47 , which was then deprotected under acidic conditions to give the free amino acid 48 .

Scheme 12 Synthesis of benzotriazole amino acids, Sutherland and co-workers [ 52 ].

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