Dipeptide synthesis from amino acids

A second application of the use of Lewis acid catalysis in the Julia coupling can be found in the synthesis of trans-Biiktnt isosteres of dipeptides (478 Scheme 62). Initially, attempts to couple aldehydes derived from amino acids (473) resulted in poor overall yield of the alkene. This difficulty was solved by reversing the substituents, and introducing the amino acid portion as the anion of sulfone (476) to the chiral aldehyde (477). The dianion of the sulfone was formed and to it were added 2 equiv. of aldehyde and 1 equiv. of diisobutylaluminum methoxide. The resulting p-hydroxy sulfone was t en on to the reductive elimination step to produce the desired ( )-alkene (478), in 74% overall yield. 

Proteins are polymers made of amino aeids. The stepwise synthesis of a protein molecule involves the joining of individual amino acids. Consider the formation of the dipeptide (a two-amino-acid unit) alanylglycine from alanine and glycine. This reaction represents the first step in the synthesis of a protein molecule ... 

On the other hand, the esters of the polypeptides are of the greatest importance and they are prepared by the action of alcoholic hydrochloric acid. Hydrolysis of the polypeptide does not occur if prolonged heating be avoided, nor does hydrolysis occur when the esters are saponified by dilute cold caustic alkali. The esters have served in particular for the further synthesis of polypeptides and for the isolation of dipeptides from mixtures on treatment with alcoholic ammonia, the dipeptide esters are converted into their diketopiperazines. They are not soluble in petroleum ether and they are soluble with difficulty in ether, and they thus differ from amino acid esters. Chloroform dissolves them, and in this solvent their combination with acid chlorides has been generally effected. 

As weU as in edible-oil processing, the use of organic solvents is also relevant in the synthesis of amino adds and their derivatives. In producing dipeptides such as L-aspartyl-L-phenylalanine methyl ester, better known as aspartame, from amino acids and derivatives via enzymatic processes in organic solvents such as butyl acetate and 2-methyl-2-butanol, unreacted amino acids should be recycled after the synthesis to make the process more efficient. Reddy et al. tested several commercial membranes and found a polyamide-polyphenylene sulfone composite to be promising for this appHcation. However, further research is stiU needed here to apply other membrane materials, which are more resistant towards solvents like butyl acetate [33]. 

Organisms do not use single amino acids as biocatalysts, but rather macromolecules comprised of them - enzymes - with nearly perfect selectivities in the functions they perform. But already the combination of just two amino acids to a dipeptide often creates a much better catalyst for the synthesis of caibohydiates under aqueous conditions (45, 46). Alanine for example catalyses the formation of erythrose with 7% ee (44) and the dipeptide L-Ala-L-Ala with 33% ee (46). How exactly peptides evolved under prebiotic conditions is another topic of debate as peptide formation from amino acids in water is thermodynamically not favored, requiring special conditions and activations (47). 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

OS 26] [R 4] [P 18] For dipeptide formation from the pentafluorophenyl ester of Boc-D-alanine and (S)-a-methylbenzylamine an extent of racemization of 5.6% was found [86]. This experiment also served to demonstrate monitoring of the racemization of an a-amino acid used in peptide synthesis. 

In an attempt to identify new, biocompatible diphenols for the synthesis of polyiminocarbonates and polycarbonates, we considered derivatives of tyrosine dipeptide as potential monomers. Our experimental rationale was based on the assumption that a diphenol derived from natural amino acids may be less toxic than many of the industrial diphenols. After protection of the amino and carboxylic acid groups, we expected the dipeptide to be chemically equivalent to conventional diphenols. In preliminary studies (14) this hypothesis was confirmed by the successful preparation of poly(Z-Tyr-Tyr-Et iminocarbonate) from the protected tyrosine dipeptide Z-Tyr-Tyr-Et (Figure 3). Unfortunately, poly (Z-Tyr-Tyr-Et iminocarbonate) was an insoluble, nonprocessible material for which no practical applications could be identified. This result illustrated the difficulty of balancing the requirement for biocompatibility with the need to obtain a material with suitable "engineering" properties. 

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

The variety of prebiotic organic reactions seems to be almost unlimited. Strasdeit et al. (2002) from the University of Hohenheim (Germany) reported the synthesis of zinc and calcium complexes of the amino acids valine and isovaline. They assume that these could have had a certain significance on the mineral-rich primeval Earth on heating to 593 K under nitrogen, valine was converted to the corresponding cyclic dipeptide. 

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