Abstract
In this paper we describe the chemoenzymatic synthesis of enantiopure l-2-arylthiazol-4-yl alanines starting from their racemic N-acetyl derivatives; by combining the lipase-catalysed dynamic kinetic resolution of oxazol-5(4H)-ones with a chemical and an enzymatic enantioselective hydrolytic step affording the desired products in good yields (74%–78%) and high enantiopurities (ee > 99%). The developed procedure exploits the utility of the single-walled carbon nanotubes-bound diethylaminoethanol as mild and efficient racemisation agent for the dynamic kinetic resolution of the corresponding oxazolones.
Highlights
Optically-active α-amino acids bearing heterocyclic side chains are of great utility in various fields, individually, but especially incorporated in more complex structures, such as peptides and proteins, for the creation of new peptide-based pharmaceutical drug candidates [1,2]
In order to alleviate the selectivity decrease caused by the racemisation agent, we describe the use of single-walled carbon nanotubes (SWCNT)-bound diethylaminoethanol in the lipase-catalysed dynamic kinetic resolution of the arylthiazole-based oxazolones
The synthesis of racemic 2-arylthiazol-4-yl alanines rac-6a–d and their derivatives rac-3-5a–d is depicted in Scheme 2. 2-Aryl-4-chloromethylthiazoles 1a–d were synthesized through the Hantzsch condensation of the corresponding thioamides with 1,3-dichloroacetone [17]
Summary
Optically-active α-amino acids bearing heterocyclic side chains are of great utility in various fields, individually, but especially incorporated in more complex structures, such as peptides and proteins, for the creation of new peptide-based pharmaceutical drug candidates [1,2]. The thiazole core frequently appears in many natural peptides, such as the Bleomycin family (anti-cancer glycopeptide antibiotics) [3], Nocathiacins [4], Aeruginazoles [5], and Thiazomycins [6] (a new class of cyclic thiopeptide antibiotics). The biological potential of this heterocyclic ring system is exploited for the design of new thiazole-bearing biologically active compounds, many of them being introduced in therapy. Enantiopure L-α-2-arylthiazole-4-yl alanines constitute chiral synthons with potential applications in drug design, especially when an extended conjugation is beneficial for interaction with pharmacological receptors. Lipases are often used as biocatalysts for the stereoselective production of variously functionalized optically-active products, due to their ability to transform a wide range of unnatural substrates in a regio- and stereoselective manner, in hydrolysis, and in alcoholysis, aminolysis, or hydrazinolysis reactions using esters, lactones, or lactames as substrates [7]
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