Amide bond formation - beyond the myth of coupling reagents.pdfVIP

CRITICAL REVIEW /csr | Chemical Society Reviews Amide bond formation: beyond the myth of coupling reagents Eric Valeur*w and Mark Bradley* Received 23rd June 2008 First published as an Advance Article on the web 4th December 2008 DOI: 10.1039/b701677h Amide bond formation is a fundamentally important reaction in organic synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of ‘‘acronym’’ based reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction 179 references . Introduction substrates. For this reason, it is usually necessary to ?rst activate the carboxylic acid, a process that usually takes place Amide bonds play a major role in the elaboration and by converting the –OH of the acid into a good leaving group composition of biological systems, representing for example prior to treatment with the amine Scheme 1 . Enzymatic the main chemical bonds that link amino acid building blocks catalysis has also been investigated for the mild synthesis of together to give proteins. Amide bonds are not limited to amides and the organic chemist may ?nd some of these biological systems and are indeed present in a huge array of methods useful as an alternative to traditional methods.6,7 molecules, including major marketed drugs. For example, In order to activate carboxylic acids, one can use so-called Atorvastatin 1, the top selling drug worldwide since 2003, coupling reagents, which act as stand-alone reagents to blocks the production of cholesterol and contains an amide generate compounds such as acid chlorides, mixed anhydrides, bond Fig. 1 ,1 as do Lisinopri