Amide and peptide formation

As for secondary alcohols, less attention has been paid to the stoichiometric non-en2ymatic KR of amines than the corresponding enzymatic processes. 

An alkaloid of the delphinine type 28 has been obtained in high enantiomeric excess by resolution of the racemate, through reaction with n-camphor sulfonyl chloride 29 in pyridine. The reaction stopped when 50% of the secondary amine was consumed, indicating an excellent stereoselectivity [47]. 

Another clear-cut resolution was described for racemic l-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydrocarboline 30 through reaction with Boc-L-Ala 31 and DCC. The (S) enantiomer reacted much faster than the (R) and left the untouched (R)-30 in high enantiomeric purity [48]. 

Atkinson et al. used diastereomeric, enantiopure 3-diacylaminoquinazoline-4(3H)-ones (DAQs) for resolution of 2-methylpiperidine [49]. The N-N bond is an 

Indeed, reaction of DAQ 32a (1 equiv) with 2-methylpiperidine (2 equiv) gave the unreacted amine (47% and 91% ee after extraction and work-up). The benzoylamide reaction product was formed with 95% ee. 

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Coupling Reagents in the Synthesis of Amides and Peptides, Formation of Active Esters... 

Coordinated a-amino amides can be formed by the nucleophilic addition of amines to coordinated a-amino esters (see Chapter 7.4). This reaction forms the basis of attempts to use suitable metal coordination to promote peptide synthesis. Again, studies have been carried out using coordination of several metals and an interesting early example is amide formation on an amino acid imine complex of magnesium (equation 75).355 However, cobalt(III) complexes, because of their high kinetic stability, have received most serious investigation. These studies have been closely associated with those previously described for the hydrolysis of esters, amides and peptides. Whereas hydrolysis is observed when reactions are carried out in water, reactions in dimethyl-formamide or dimethyl sulfoxide result in peptide bond formation. These comparative results are illustrated in Scheme 91.356-358 The key intermediate (126) has also been reacted with dipeptide... 

Alkali has long been used on proteins for such processes as the retting of wool and curing of collagen, but more recently it has received interest from the food industry. Alkali can cause many changes such as the hydrolysis of susceptible amide and peptide bonds, racemization of amino acids, splitting of disulfide bonds, beta elimination, and formation of cross-linked products such as lysinoalanine and lanthionine. 

This chapter does not cover cyclic amides and peptides, since their number would enormously expand this text. They are reviewed only if they serve as reaction intermediates during synthesis of cyclic amines. In addition, metal ions complexation will be presented in required minimum, for example, if it serves for template formation during ring synthesis or as a main topic in some application. In this chapter, most of the sections deal with the literature data for all cycle types, except Section 14.11.6, which focuses mainly on chemistry of cyclen and cyclam and their analogs and derivatives. In Section 14.11.8, we give only a brief overview of the utilizations and provide a reader with reviews where more detailed information may be found. 

Cyanuric chloride has been used for the preparation of acyl chlorides, amides, and peptides. Conversion of cyanuric chloride into 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT, 6) leads to a reagent that upon reaction with carboxylic acids produces the highly reactive 2-acyloxy-4,6-dimethoxy-l,3,5-triazines.P l The resulting active ester is a powerful acylating agent for alcohols and amines. The activation is performed in presence of a base, preferentially NMM, which leads to intermediate formation of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 7)P l (Scheme 5). This addition product is readily prepared from the commercially available CDMT (6) and NMM in THF and can be stored as solid compound in the cold.P P l It offers the advantage that it can be used in a one-... 

A further displacement of practical utility is that of halogen in phosphonic and phos-phinic chlorides by carboxylate ions (with silver or thallium salts, for example) to give mixed anhydrides, e.g. 581 and 582. Such anhydride formation provides a system particularly reactive at the carbonyl group towards nucleophiles, and thus preliminary activation of the carboxyl group by the diphenylphosphinoyl group becomes useful in amide or peptide formation ... 

Later, Venkataraman and Wagle <1979TL3037> reported the use of TCT as a useful reagent for the conversion of carboxylic acids into chlorides, esters, amides, and peptides the authors proposed the formation of the acyl chloride as shown in Scheme 44. 

The base hydrolysis of the carbonyl bonded amides and peptides display a first order dependence on the hydroxide ion concentration up to a pH of ca. 10, but then become independent of the hydroxide ion concentration due to the formation of the unreactive deprotonated amide (pK = 11 to 12). Some typical kinetic data for these reactions are summarised in Table 7.6. The p2-Co(trien) complexes have the configuration shown in (7.12). Similar studies have been carried out with complexes of the general type trans-[Co(dien)X(peptideOR)] (7.13). Typical kinetic results... 

FIGURE 5.1 Peptide formation is the creation of an amide bond between the carboxyl group of one amino acid and the amino group of another amino acid. Rj and R9 represent the R groups of two different amino acids. 

Each functional group of an amino acid exhibits all of its characteristic chemical reactions. For carboxylic acid groups, these reactions include the formation of esters, amides, and acid anhydrides for amino groups, acylation, amidation, and esterification and for —OH and —SH groups, oxidation and esterification. The most important reaction of amino acids is the formation of a peptide bond (shaded blue). 

Many enzymes have absolute specificity for a substrate and will not attack the molecules with common structural features. The enzyme aspartase, found in many plants and bacteria, is such an enzyme [57], It catalyzes the formation of L-aspartate by reversible addition of ammonia to the double bond of fumaric acid. Aspartase, however, does not take part in the addition of ammonia to any other unsaturated acid requiring specific optical and geometrical characteristics. At the other end of the spectrum are enzymes which do not have specificity for a given substrate and act on many molecules with similar structural characteristics. A good example is the enzyme chymotrypsin, which catalyzes hydrolysis of many different peptides or polypeptides as well as amides and esters. 

The templated syntheses of amide-based rotaxanes discussed until now have made use of the threading-followed-by-capping method. However there are also examples in which the clipping approach has been employed. Leigh, for example, has used a five-component clipping method to prepare [2]rotaxanes. Isophthalamide and peptide-based threads were shown to template the formation of benzylic amide macrocycles about them in non-polar solvents [69, 70]. When the peptide-based threads (49) contain bulky stoppers at their ends, the [2]rotaxanes (50) can be prepared in high yields (see Scheme 24) [71]. 

J Honzl, J Rudinger. Amino acids and peptides. XXXIII. Nitrosyl chloride and butyl nitrite as reagents in peptide synthesis by the azide method suppression of amide formation. Coll Czech Chem Commun 26, 2333, 1961. 

S-T Chen, S-H Wu, K-T Wang. A simple method for amide formation from protected amino acids and peptides. Synthesis 37-38, 1989. 

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