Direct amide bond formation

Green Catalytic Direct Amide Bond Formation... 

Scheme 17.1 Direct amide bond formation from unactivated carbojylic acids and amines.

In the last 5 years, catalytic antibodies have been generated for several reaction types, including the various types of hydrolysis, transesterification, amide bond formation, /3-elimination, cycloreversion, transacylation, redox reactions, E-Z isomerization, epoxidation, and Diels-Alder reactions. For more information on these and other recent developments, such as semi-synthetic antibodies, site-directed mutagenesis, and the bait-and-switch strategy, the reader should consult the appropriate authorities (Schultz, 1988, 1989a,b Benkovic et al., 1990 Janda et al., 1990, 1991 Janjic and Tramontano, 1990 Lerner et al., 1991). 

Due to the vast numbers and rapidity of novel developments in solid-phase synthesis over the past ten years, a number of reports currently found in the literature deal with solid-phase syntheses of lanthionine peptides. There are at least two different approaches to synthesize lanthionine peptides in which the sulfide bond links amino acid halves that are not direct neighbors within the peptide chain (Scheme 10). One obvious approach, method A, is based on the coupling of a preformed, orthogonally protected lanthionine monomer to the N-terminus of a peptide oxime resin. 48 This is then followed by acid-catalyzed cyclization and simultaneous release from the resin during amide bond formation with the C-terminal carboxy group via the peptide cyclization method on oxime resin (see Section 6.73.2.2). The alternative approach is lanthionine formation after peptide synthesis from amino acid derivatives, such as serine and cysteine (method B). 

Amide bond formation by direct condensation between an acid and an amine is not obvious and must overcome adverse thermodynamics (8). This dehydrative process can be achieved under forcing conditions such as high temperatures (160-180° C), which are usually incompatible with the presence of other functionalities. Contrary to the ester formation between an acid and an alcohol, which is an equilibrium, the acid and the amine undergo first an acido-basic reaction that yields the stable salt. Therefore, the acid must be activated by the attachment of a leaving group before being reacted with the amine (see Fig. 2). 

The main mechanistic pathways of amide bond formation by carbodiimides have been the object of intensive investigations.There is general consensus that an (9-acylisourea such as 12 is formed as the key intermediate which directly undergoes nucleophilic attack by an amino group to produce the amide or reacts with a second carboxy component to generate... 

A conceptually different approach to assemble fully unprotected peptides is to use an enzyme to attain both specificity and catalysis of the amide bond formation. This strategy has been developed using proteases, enzymes that cleave peptide backbone amide bonds. Following the principle of microscopic reversibility, any enzyme can be coerced to catalyze a reaction not only in the forward direction but also in the reverse direction. Such reverse proteolysis methods typically use substrates containing activated C-termini,... 

Amides from Carboxylic Acids Peptide Synthesis. Analogous to ester formation, reaction of equimolar amounts of a carboxylic acid and (1) in THF, DMF, or chloroform, followed by addition of an amine, allows amide bond formation. The method has been applied to peptide synthesis (eq 5). One equivalent of (1) is added to a 1M solution of an acylamino acid in THF, followed after 1 h by the desired amino acid or peptide ester. The amino acid ester hydrochloride may be used directly instead of the free amino acid ester. An aqueous solution of the amino acid salt can even be used, but yields are lower. 

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