Waste Minimized Multistep Preparation in Flow of β-Amino Acids Starting from α,β-Unsaturated Carboxylic Acids

Abstract

An efficient protocol for the synthesis of βamino acids starting from easily accessible α,β-unsaturated carboxylic acids based on the combination of two heterogeneous catalytic systems is reported. This multistep approach is based on the direct β-azidation of α,β-unsaturated carboxylic acids and subsequent azido group reduction performed in flow conditions. It has been demonstrated that the catalysts can be easily recovered and reused conserving its complete efficiency. The green metrics calculations proved the high environmental efficiency of the protocol characterized by very low waste production.

Chiral Integrated Catalysts Composed of Bifunctional Thiourea and Arylboronic Acid: Asymmetric Aza-Michael Addition of α,β-Unsaturated Carboxylic Acids

“…As expected, all integrated catalysts, except sulfonamide 6c, afforded the desired β-benzyloxyamino acid 2a as a single product; in addition, the nature of the hydrogen-bond-donor moiety was observed to substantially affect the yield. Among catalysts 6a-e, thiourea 6e bearing a 3,5-bis(trifluoromethyl) phenyl group gave the best results in terms of yield and enantioselectivity (entries [1][2][3][4][5]. Regarding the achiral N-substituent of the thiourea moiety, catalysts 6g and i bearing phenyl and 4-nitrophenyl groups, respectively, exhibited higher enanti- 15% (0% ee) 6% (c) 4c and 5:…”

“…Off-white solid (313 mg, 51%); mp 108. 5 α,β-Unsaturated carboxylic acids 1h, j, and 1r-t were generally prepared by following the general procedure as indicated below.…”

“…The catalytic asymmetric aza-Michael addition of α,β-unsaturated carboxylic acid derivatives has been extensively investigated as a powerful protocol for the synthesis of optically active β-amino acids, [1][2][3][4] which are frequently encountered as important structural components in biologically active natural products and pharmaceuticals. 5) However, simple α,β-unsaturated esters and amides have only been used in a limited number of successful studies because of their inherent low reactivity as Michael acceptors. 6,7) Instead, a variety of activated ester/amide surrogates possessing greater reactivity and rigidity, which enables them to interact with appropriate catalysts, have been developed for the Michael addition.…”

Definition of green synthetic tools based on safer reaction media, heterogeneous catalysis, and flow technology

“…It has been developed and applied under SolFC to promote the direct β-azidation of α,β-unsaturated carboxylic acid, without protection/deprotection steps of the acid functionality, for the preparation of β-azido and β-aminoacids [94,95].…”

Stereoselective synthesis towards unnatural proline based amino acids

“…2,4 β-Amino acids are another class of compounds that are equally important precursors leading to more complex products with biological and pharmacological activities. 13,14 Moreover β-amino acids are precursors of β-lactams, the most important class of antibiotics. They are known to also control the conformational properties of peptides based on β-amino acids that enhance the stability towards proteases.…”