The acyl azide method

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

The acyl-azide method of coupling (Figure 2.13) has been available for about a century, but it is not attractive for routine use because it involves four distinct steps that include two stable intermediates that require purification. In addition, aminolysis of the azide is slow. The first step involves preparation of the ester (see Section 3.17), which can be methyl, ethyl, or benzyl. The ester is converted to the hydrazide by reaction in alcohol with excess hydrazine at ambient or higher... 

Acyl azides (see Section 2.13) The acyl-azide method of coupling is unique for two reasons. First, it is the only case in which the immediate precursor of the activated form of the peptide is not the parent acid. The starting material is the peptide ester that is obtained from the amino acid ester by usual chain assembly (Figure 2.25, path A). Second, it is the only method that just about guarantees production of a peptide that is enantiomerically pure, provided scrupulous attention is paid to details of procedure. There is no danger for loss of chirality during conversion of the ester to the hydrazide and then the azide, but care must be taken to avoid contact of... 

Z-Glu(OtBu)-Ala-Glu(OtBu)-OPcp [(from EtOAc) yield 78% mp 132-133 C [a]o -13.2 (c 2, CHCI3)] and Z-Glu(OtBu)-Ala-OPcp [(from MeOH) yield 64% mp 171-172 C mp 173-174 C after three crystallizations, [a]o —18.5 (c 1.33, CHCI3)] were prepared from the acid and HOPcp using DCC according to Section 3.2.1.1.3.The protected tripeptide ester had the same specific rotation as that prepared by coupling the protected dipeptide hydrazide and the amino add ester by the acyl azide method. The two esters prepared by direct esterification were demonstrated by indirect optical rotation measurements to be >99.6 and 98% enantiomerically pure, respectively. 

Crystalline adduct 25 (2.4 mmol) obtained from DCC (1 mmol) and HOPfp (3 mol) was added to a soln or suspension of R OCO-Xaa -Xaa -OH (2 mmol) in EtOAc (4-5 mL) while stirring. After 10 min, the temperature was brought to 0°C and stirring was continued for 10 min. The mixture was filtered, the solvent was removed, the residue was triturated in hexane, and the crystals were collected. The products were recrystallized (hexane or EtOAc/hexane). The products were enantiomerically pure based on analysis for isoleucine/alloisoleucine after hydrolysis and comparison of the specific rotation of a model peptide prepared by the acyl azide method. 

Acidic Supports. Three methods will be considered for enzyme immobilizations onto carboxylic acid-containing supports. All result in the formation of amide bonds to the primary amines of lysine residues on the protein, but the selectivity for lysine varies with the method used. In the acyl azide method,8 the carboxylic acid group is sequentially converted to its methyl ester, acyl hydrazide and acyl azide (Eq. 4.10) ... 

Bunsen. Later, Curtius worked with Hermann Kolbe at Leipzig University and received his Ph.D in 1882 therein. During these studies he performed the first chemical synthesis of a protected peptide (Bz-Gly-Gly-OH), and in 1902 developed the acyl azide method. Together with EmU Fischer, he pioneered peptide synthesis. 

H. Petite, I. Rault, A. Hue, P. Menasche, D. Herbage, Use of the acyl azide method for cross-linking collagen-rich tissues such as pericardium. Journal of Biomedical Materials Research 24 (2) (1990) 179-187. 

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