Diketopiperazines racemization

In fact, the use of acyl chlorides in peptide synthesis is rare because of the potenlial for unwanted side-reactions, including racemization and dimerization to form by-products known as diketopiperazines. We will represent our activated acid as RCOX, where X is some other good leaving group such as a phenol. 

His early work on the proteins mainly involved the isolation, characterization, and identification of individual members. Then he turned to the question of their structure, and from a study of the racemization of synthetic diketopiperazines, came to the conclusion that the structure of the giant molecules of proteins could be explained (in terms of Emil Fischer s polypeptide chains) by the classical theories of valency, without the neces-... 

The racemic tryptophan derivative 207 was condensed with optically pure proline derivatives following the BOP-Cl protocol. For the synthesis of notoamides C (213) and D (215), proline ethyl ester was used as coupling partner (Scheme 41), whereas the synthesis of stephacidin A (225) and notoamide B (227) employed hydroxyproline ethyl ester 219 (Scheme 43). Towards notoamides C (213) and D (215), the diaste-reomeric diketopiperazines 210 and 211 had to be separated by chromatography. The Fmoc can be replaced by a Boc protecting group and BOP-Cl by HATU [172]. 

The number of isomers of diketopiperazines containing two molecules of different amino acids is greater than when the two amino acids in the molecule are the same. It can be calculated from the number of asymmetric carbon atoms in the molecule just as in the open chain compounds thus alanyl-leucine anhydride can exist in four optically active forms and two racemic forms —... 

If almost racemic diketopiperazine is used imder these conditions, after all, an enantiomeric excess of 81 % can stiU be achieved. However, in case the reaction is carried out in the absence of the diketopiperazine, no transformation is observed. The active catalytic species isprobably an adduct of the diketopiperazine and the cyanohydrin, being a more powerful catalyst than the diketopiperazine alone. 

Danishefsky s diene and imines to produce l,2-dialkyl-2,3-dihydro-4-pyridinones in high yields. Chiral non-racemic 2,5-diketopiperazine diene undergoes intermolecular hetero-Diels-Alder cycloaddition reactions with both c-rich and e-deficient alkene dienophiles, leading to bicyclo[2.2.2]diazaoctane structures. The regiochemical, stereoelectronic, and reactivity preferences of the diketopiperazine cycloadditions were investigated. ... 

Figure 1 summarizes the linkers used for peptide synthesis by the Multipin method. Most carboxylic acids are prepared on the 4-(hydroxymethyl)-phenoxyacetic acid handle 1 (40). To avoid diketopiperazine formation during the synthesis of peptides containing a C-terminal Pro residue, the sterically hindered linker 2 is used (41). To minimize the risk of racemization dining linker derivatization. Asp and Glu are linked via their side-chain functionality, as shown in 3. Similarly, Asn and Gin are prepared by coupling Fmoc-Asp-OrBu and Fmoc-Glu-OiBu, respectively, to the Rink linker 4 (42). 

The relative ease with which diketopiperazines are racemized by alkali was already noticed by Fischer, who also pointed out that some loss of optical activity may even occur under the conditions under which the anhydride is produced. Thus n-alanyl-n-alanine ester is converted to the active anhydride by treatment with alcoholic ammonia with only slight racemization however, the preparation of this anhydride from Ii-alanine ester by heating involves appreciable loss of optical activity... 

In a similar manner resonance affects greatly the rate of racemization by reducing the energy required for ionization. This point is discussed with reference to a-phenylamino acids and particularly with regard to amide resonance in acylamino acids, peptides, diketopiperazines and hydantoins. The literature on the racemization of proteins by alkali is also reviewed. The racemization which is observed during acylation of amino acids is also discussed, and it is pointed out that apart from oxazolone formation, mixed anhydrides may also occur as intermediates and be partly responsible for the racemization observed. 

---