Enzyme‐Catalysed Synthesis of Secondary and Tertiary Amides

Abstract

Thes ynthesis of the amide bondb etween an amine andacarboxylic acid is one of the most significant reactions in industrial pharmaceutical synthesis.D espite the apparents implicityo fs ynthetic methodsf or amide bond formation, many of these are disadvantaged by their requirementf or toxic or hazardous reagents for the activation of the acid component, or poora tom economy resulting from the need for stoichiometric amountso fc oupling reagents.I nt his context, biocatalysis hase merged as an alternative catalytic method for amide bond formation, presenting the advantages of both environmentally benign reagents andc onditions and also atom economy.I nthis review we detail developments in the enzyme-catalysed preparation of secondary andt ertiary amides for the synthesis of pharmaceutical-type molecules andr eview the applications of hydrolases,s uch as lipasesa nd penicillina cylases, to these reactions.W ea lso summarise the activity of ATP-dependent enzymesf or amide bondf ormation and assess their potentialf or the preparative synthesis of amidesf rom carboxylic acids and amines in aqueous media.

Recent developments in catalytic amide bond formation

“…At the moment however, such methods lack broad scope (as might be expected of enzymatic methods), often not tolerating even secondary amines [32,33] and require activated AMP-esters which hydrolyze under the reaction conditions [34] and can require large excesses to achieve desirable yields. While recent reports have sought to address both issues, [35][36][37] such technologies can be presently of interest as complements to SPPS in the form of alternative strategies to native chemical ligation or cyclization. [38][39][40] Another alternative approach to strictly catalytic methods is the recycling of reagents and solvents.…”

The Hitchhiker's guide to biocatalysis: recent advances in the use of enzymes in organic synthesis

“…Moreover, they are catalytically versatile and can catalyse reactions such as aminolysis (the conversion of esters to amides, using amines as the nucleophile) and direct amidation of carboxylic acids. 86 An interesting recent development in reverse hydrolysis reactions, such as the formation of carboxylic esters, is the use of the acyltransferase from Mycobacterium smegmatis (MsAcT) to catalyse the synthesis of avour esters by transesterication in water. 87 MsAcT is characterised by a hydrophobic tunnel leading to the active site, where access of water is disfavoured.…”

Rapid Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents, a Method for Hexa-amidation of Biotin[6]uril

“…Acetyl phosphate 17 displayed a singlet signal at δ = −2.1 ppm in 31 P NMR, which rapidly disappeared after the addition of morpholine, both in D2O solution and in the solid state (see Supporting Information). In the 13 C NMR spectrum, carbonyl group 17 showed a doublet signal at δ = 168.1 ppm (JCP = 8.8 Hz), due to its coupling with the neighboring phosphorus. 65 Significantly lower yields of 17 were attained with K3PO4 or with TCFH as coupling reagent (Figure 2).…”