Rethinking amide bond synthesis.
ABSTRACT One of the most important reactions in organic chemistry--amide bond formation--is often overlooked as a contemporary challenge because of the widespread occurrence of amides in modern pharmaceuticals and biologically active compounds. But existing methods are reaching their inherent limits, and concerns about their waste and expense are becoming sharper. Novel chemical approaches to amide formation are therefore being developed. Here we review and summarize a new generation of amide-forming reactions that may contribute to solving these problems. We also consider their potential application to current synthetic challenges, including the development of catalytic amide formation, the synthesis of therapeutic peptides and the preparation of modified peptides and proteins.
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ABSTRACT: Despite the amide formation reaction being one of the key cornerstone reactions in organic chemistry, the direct amide formation is both little used and little explored. Acceptance of the feasibility and general applicability of the reaction depends upon the ability of researchers to bring it into the mainstream by development of: (1) an understanding of the mechanism of the reaction; and (2) the design of catalysts which promote the reaction on a wide range of substrates and under ambient conditions. From the earliest report of the direct amide formation in the 19th century, there have been relatively few reports of mechanistic studies, though it is clear that there is not a simple relationship between ease of direct amide formation and the pK(a) of the carboxylic acid and amine, or whether salt ammonium carboxylate formation is important. Consequently, direct amide formation has historically been run under higher temperature conditions. However, more recently, stoichiometric and catalytic boron compounds have been developed that considerably reduce the reaction temperatures under which direct amide formation will proceed. Limited attempts at mechanistic studies point to the formation of acyloxyborate or boronate species acting essentially as mixed anhydrides, though the exact order of these systems remains to be categorically determined.Chemical Communications 03/2010; 46(11):1813-23. · 6.38 Impact Factor
Article: Dehydrative condensation catalyses[show abstract] [hide abstract]
ABSTRACT: This report focuses on the catalytic dehydrative condensation reactions of carboxylic acids and phosphoric acids with alcohols and amines to give esters and amides without the activation of acids with stoichiometric condensing agents.Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slideTetrahedron. 01/2009; 65(6):1085-1109.
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ABSTRACT: Traditionally, in the pharma sciences, there has been an unstated but operative bifurcation into small molecules and biologics. Small molecules were seen to be, at the discovery level, in the province of chemistry, based on targets provided through biology. By contrast, "biologics" were seen to arise solely from the province of biology exploiting its accessible replicative mechanisms. Our laboratory has been dedicated to the proposition that explosive advances in chemical synthesis have been such as to render so called "biologics" as being accessible to chemical synthesis. In this article, we focus particularly on the area of glycopeptides. Chemical synthesis, in principle, offers an advantage, in that it can lead to homogeneous glycopeptides characterized by a single glycoform of the glycosidic domain mounted at a particular amino acid in the polypeptide domain. In support of this defining goal, a variety of new methods have been developed. The key problem addressed is that of ligation. In this article, we review how insights available from mechanistic organic chemistry have been used to create an imposing framework for the synthesis of structures which would, in an earlier day, have been seen to be strictly in the realm of chemically inaccessible "biologics".Biopolymers 01/2010; 94(4):373-84. · 2.88 Impact Factor