Dipeptides diastereomers

Based on chiral functional monomers such as (15), MICSPs can be prepared using a racemic template. Thus, using racemic A-(3,5-dinitrobenzoyl)-a-methylbenzy-lamine (16) as template, a polymer capable of racemic resolution of the template was obtained [67]. Another chiral monomer based on L-valine (17), was used to prepare MIPS for the separation of dipeptide diastereomers [68]. In these cases the configu-... 

The successful separation of dipeptide diastereomers has been reported by Wieland and Bende (14), Taschner et al. (15), and Pravada et al. (16) either as the free peptides or as the N-protected methyl esters. Hubert and Dellacherie (5) separated diastereomeric p-nitrophenyl (Np) esters of N-protected di- and tripeptides starting from pure L-methionine and DL-alanine, they synthesized Np-S-L-Met-DL-Ala-O-Np and Np-S-L-Met-L-Met-DL-Ala-O-Np. The separation was achieved on silica gel F254 precoated (Merck) plates. TLC separation of diastereomeric dipeptides has been well documented by Arendt et al. (17) and Lepri et al. (18). 

Funasaki, N., Hada, S., and Neya, S., Conformational effects in reversed-phase liquid chromatographic separation of diastereomers of cyclic dipeptides, Anal. Chem., 65, 1861, 1993. 

By quenching the aminolysis reaction at various times and examining the diastereomer ratios in the unreacted Co(III)-ester and Co(III)-dipeptide products it has been possible to build up complete concentration-stereochemistry-time profiles for several couplings. One such example is given in Fig. 7, and kinetic analysis of these data allows the rate constants for epimerization (ku k2) and aminolysis (k3, ki) to be found. Some results obtained in this way are listed in Table X. 

These data show that while the A-S (A-R) diastereomer undergoes aminolysis some 10-20 times faster than A-S (A-R), the final optical outcome in the dipeptide product also depends on the relative rates of epimerization. Thus, to take two extreme examples, the reaction of A-[Co(en)2((S)-AlaOMe)]3+ with 0.12 M (S)-PheOMe has 4(obs)/ kjobs) = 1.7, whereas that for the A-[Co(en)2((S)-LeuOMe)]3+ with 0.12 M (S)-AlaOMe has 4(obs)/ 2(obs) = 1550. The former results in —3% A-R-S impurity, while the latter coupling gives an optically pure product. 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

In order to prove the importance of the rigid structure, as in the pipera-zinediones, these authors have carried out similar hydrogenation under identical conditions with the corresponding linear dipeptide derivatives. The ratio of the two diastereomers in the product was 49 51 (77JA8346)... 

To avoid the production of diastereomers during reductive alkylation of Pro residues, the corresponding dipeptide should be first synthesized and the central amide bond subsequently selectively reduced with diborane (see Section 10.7.1.2.1). 

Direct reduction of a peptide bond with diborane 59 or a thioamide bond with several reductive procedures 60 is an alternative route for the production of a reduced peptide bond in a peptide. In some cases the reductive amination does not give satisfactory results. As described earlier, preparation of Boc-Pher )[CH2N]Pro-OH by reductive amination yields two diastereomers (Scheme ll). 57 In this case treatment of Boc-Phe-Pro-OBzl by diborane yielded the reduced pseudodipeptide Boc-Pher )[CH2N]Pro-OBzl without epimerization (Scheme 12). However, in some cases diborane is not entirely selective for the amide bond and can reduce ester functions when they are present. Another procedure is to prepare endothiopeptides directly from protected dipeptides 61-66 followed by their selective reduction. 60 ... 

Aspartame is a diastereomeric dipeptide ester, with the two asymmetric carbons ( ) being derived from (Z)-amino acids. The other three diastereomers of aspartame (the D.D-, D,L- and L,D- diastereomers) are not sweet. The three dimensional structure of aspartame in the zwitterionic form can be depicted in the following stereoscopic figure ... 

Table 8-1. Structures of LAP inhibitors, phosphinate dipeptide analogues, designed using LUDI. Experimental and predicted activities are presented for each compounds. a Value corresponding to the mixture of two diastereomers (1 1). Binding affinity for the mixture of four diastereomers. Value corresponding to the racemic mixture. Predicted binding affinity for one isomer which preferentially interacts with the protein...

Conjunction of the newly created asymmetric center with an existing one offers applications e.g., high stereoselectivity for production of all diastereomers of chiral dipeptides are achieved by means of asymmetric hydrogenation of dehydrodipeptides that have the proper choice of chiral ligands . 

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