Aqueous reactions dipeptides

FIGURE 7.21 Synthesis of a dipeptide by reaction of an amino-acid A-carboxyanhydride (A) with an amino-acid ester in tetrahydrofuran65 and (B) with an amino acid in aqueous solution.67... 

The amide functionality plays an important role in the physical and chemical properties of proteins and peptides, especially in their ability to be involved in the photoinduced electron transfer process. Polyamides and proteins are known to take part in the biological electron transport mechanism for oxidation-reduction and photosynthesis processes. Therefore studies of the photochemistry of proteins or peptides are very important. Irradiation (at 254 nm) of the simplest dipeptide, glycylglycine, in aqueous solution affords carbon dioxide, ammonia and acetamide in relatively high yields and quantum yield (0.44)202 (equation 147). The reaction mechanism is thought to involve an electron transfer process. The isolation of intermediates such as IV-hydroxymethylacetamide and 7V-glycylglycyl-methyl acetamide confirmed the electron-transfer initiated free radical processes203 (equation 148). 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

Aqueous surfactants are another class of catalysts. Substantial rate enhancement is seen in the reaction occurring at the micellar hydrocarbon-water interface, which is ascribed to a concentration of the reactant in the micellar pseudo-phase. Chiral p-nitrophenyl esters derived from phenylalanine are hydrolyzed by a histidine-containing dipeptide at a micellar interphase, at which a very high enantiomer discrimination, kR/ks up to 30.4 at 0°C, is observed (49). As shown in Scheme 20, the enantioselectivity is expressed at the stage at which a transient, zwitter-ionic tetrahedral intermediate leading to the acylimidazole is formed,... 

This equation is not intended to imply a mechanism for peptide synthesis. The equilibrium position for this reaction in an aqueous solution favors the free amino acids rather than the peptide. Therefore, both biological and laboratory syntheses of peptides usually do not involve a simple splitting out of water. Since the dipeptide of Eq. 2-11 still contains reactive carboxyl and amino groups, other amino acid units can be joined by additional peptide linkages to form polypeptides. These range from short-chain oligomers to polymers of from 50 to several thousand amino acid units, the proteins.75-77... 

Reid DL, Armstrong DA, Rauk A, Nese C, Schuchmann MN, Westhoff U, von Sonntag C (2003) H-atom abstraction by C-centered radicals from cyclic and acyclic dipeptides. A theoretical and experimental study of reaction rates. Phys Chem Chem Phys 5 3278-3288 Roberts BP (1996) Understanding the rates of hydrogen abstraction reactions empirical, semi-em-pirical and ab initio approaches. J Chem Soc Perkin Trans 2 2719-2725 Russell GA (1973) Reactivity, selectivity, and polar effects in hydrogen atom transfer reactions. In Kochi JK (ed) Free radicals. Wiley, New York, pp 275-331 Russo-Caia C, Steenken S (2002) Photo- and radiation-chemical production of radical cations of methylbenzenes and benzyl alcohols and their reactivity in aqueous solution. Phys Chem Chem Phys 4 1478-1485... 

Upon facing the difficulty of stereochemical control in peptide alkylation events, Maruoka and coworkers envisaged that the chiral phase-transfer catalyst should play a crucial role in achieving an efficient chirality transfer, and consequently examined the alkylation of the dipeptide, Gly-L-Phe derivative 57 (Scheme 5.28) [31]. When a mixture of 57 and tetrabutylammonium bromide (TBAB, 2 mol%) in toluene was treated with a 50% KOH aqueous solution and benzyl bromide at 0°C for 4h, the corresponding benzylation product 58 was obtained in 85% yield with the diastereo-meric ratio (DL-58 LL-58) of 54 46 (8% de). In contrast, the reaction with chiral quaternary ammonium bromide (S,S)-lc under similar conditions gave rise to 58 with 55% de. The preferential formation of LL-58 in lower de in the reaction with (R,R)-lc indicated that (R,R)-lc is a mismatched catalyst for this diastereofacial differentiation of 57. Changing the 3,3 -aromatic substituent (Ar) of the catalyst 1 dramatically increased the stereoselectivity, and almost complete diastereocontrol was realized with (S,S)-lg. 

A library of vancomycin analogues has been prepared using ring closing metathesis reactions in aqueous solution (Nicolaou, K. C., Hughes, R., Cho, S. Y., Wissinger, N., Labischinski, H., Endermann, R. Chem. Eur. J. 2001, 7, 3824) a kinetic template effect was observed when the library was prepared in the presence of a dipeptide trap. 

To complete the synthesis, it is necessary only to remove the protecting groups. The BOC group is removed by treatment with aqueous acid. This reaction occurs under very mild conditions that do not also hydrolyze the ester group. Note that this dipeptide, deprotected at the N-terminal, can be reacted with another N-protected, carboxyl-activated amino acid to produce a tripeptide. These steps can be repeated to produce a tetrapeptide, and so on. 

To the resulting aqueous phase (containing the DNP-dipeptide), add 100 /d of 6 N HC1. Make sure that the pH is 1.0 by putting a small drop of the reaction on pH paper after mixing. You may notice some bubbles forming in the solution as the H+ causes the formation of carbon dioxide gas and water from the formation of... 

The five dipeptides listed below were treated as follows (a) The dipeptide was reacted exhaustively with FDNB. (b) The reaction was then acidified and extracted with ether, (c) The ether phase from this extraction was dried down, resuspended in 0.5 ml of 6 N HC1, and heated at 110°C for 12 hr. (d) 1 ml of water and 2 ml of ether were then added to the sample. For each of the dipeptides listed below, list the peptide-derived compounds that you would expect to find in the final ether phase and the final aqueous phase following the series of four treatments described above. 

Proteins are linear polymers formed by linking the a -carboxyl group of one amino acid to the a -amino group of another amino acid with a peptide bond (also called an amide bond). The formation of a dipeptide from two amino acids is accompanied by the loss of a water molecule (Figure 3.18). The equilibrium of this reaction lies on the side of hydrolysis rather than synthesis. Hence, the biosynthesis of peptide bonds requires an input of free energy. Nonetheless, peptide bonds are quite stable kinetically the lifetime of a peptide bond in aqueous solution in the absence of a catalyst approaches 1000 years. 

Dipeptide formation is also prevented by an intermediate N,0-bis(trimethylsilylation) of the amino acid with chlorotrimethylsilane (TMSCl). The silyl groups are cleaved during aqueous workup leading to Fmoc amino adds in 78-94% yields. Following the suggestion of Yadav et al. that carbamates can be produced from amino acids under neutral conditions by reaction with chloroformates in the presence of zinc dust, A/ -Fmoc amino acids were obtained rapidly (15-20 min) in high yields without detectable dipeptide contaminants. ... 

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