Reduction of peptides

Note For optimal reduction of peptides, the following steps should be performed at room temperature. 

Cline DJ, et al. New water-soluble phosphines as reductants of peptide and protein disulfide bonds reactivity and membrane permeability. Biochemistry 2004 43 15195. 

Support-bound 1,2-diamines can be readily converted into imidazolidinones by treatment with carbonyl diimidazole [128,129]. The required diamines have been prepared on cross-linked polystyrene by reduction of peptides bound to MBHA resin with borane. Similarly, bicyclic imidazolines have been prepared from triamines and thiocarbonyl diimidazole (Entry 10, Table 14.3). Dehydration of polystyrene-bound monoacyl ethylene-1,2-diamines yields 4,5-dihydroimidazoles (cyclic amidines, Entry 5, Table 13.18). Several groups have reported the synthesis of 2-aminoimidazol-4-ones from resin-bound amino acid derivatives (e.g., Entry 6, Table 15.11). Most of these compounds are, however, unstable, and slowly decompose if dissolved in DMSO (Jesper Lau, private communication). 

Peptides can be chemically transformed on insoluble supports to yield other types of oligomer. These transformations include N-alkylation and reduction. N-Alkylation of polystyrene-bound peptides enables the preparation of peptide mimetics with improved enzymatic stability [270], Polyamines have been prepared by exhaustive reduction of peptides with borane [271] (see Section 10.1.6). N-Alkylated polyamines can be prepared on solid phase by reduction of the corresponding N-alkylated peptides [272]. 

Scheme 1 Reduction of Peptide Esters to Peptide Aldehydes with Diisobutylaluminum Hydride...

Peptide aldehydes 1 can be synthesized effectively by the oxidation of peptide alcohols 15, which are readily available without racemization by reduction of peptide esters 9 with sodium borohydride-lithium chloride (Scheme 5). The peptide alcohols 15 can be readily oxidized to afford enantiomerically pure aldehydes using Parikh-Doering or Dess-Martin reagents. This route is less popular than the previously described reductive methods due to (1) the sensitivity of the aldehydes to further oxidation, (2) racemization under the reaction conditions, and (3) instability of the products under the reaction conditions. 

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

Methyl 4-(4 -nitrobenzamido) benzoate added in 2 portions to a gently boiling mixture of phenylhydrazine and anisole, the flame removed when gas is beginning to evolve, and, after 2 hrs., allowed to cool —>-methyl 4-(4 -aminobenzamido)benzoate. Y 93%. — Phenylhydrazine is particularly suitable for the reduction of peptide-type compounds, for which it is a good solvent. It attacks neither the acid amide nor the ester bond. Since its oxidation products, Ng, H20, and benzene, are volatile at the reaction temp., the isolation of the reduction products is facilitated. (F. e. s. H. Bredereck and H. von Sehuh, Chem. B. 81, 215 (1948).)... 

Reduction can be achieved selectively under mild conditions by using esters more electronegative than methyl esters such as trifluoroethyl esters. E. s. S. Taka-hashi and L. A. Cohen, J. Org. Chem. 55, 1505 (1970) reduction of peptide esters in aq. medium s. O. Yonemitsu, T. Hamada, and Y. Kanaoka, Chem. Pharm. Bull. I7y 2075 (1969). 

Peptide aldehydes have been synthesized both by oxidation of peptide alcohols and by reduction of peptide acids. Both routes are restricted to peptides that do not contain other functional groups sensitive to the reducing and oxidizing reagents, and the oxidative route at least, subjects the whole peptide to a reaction which sometimes gives only poor yields. To provide increased flexibility of synthesis of peptide aldehydes, I have explored another synthetic route, which involves the preparation from a-amino alcohols of suitably protected a-amino aldehydes, the coupling of the protected aldehydes to preformed peptides, and the subsequent removal of protection from the aldehyde group. This type of synthesis has... 

Reduction. Raney Nickel treatment of thioacetals is a standard method for carbony 1-to-methylene reduction." In the presence of Triethylamine, (1) reduces azides to primary amines (eq 14). Under the acidic conditions employed for thioacetal formation, this reduction does not occur (eq 8). " Reduction of peptidic disulfides to dithiols can be conveniendy accomplished with (1). ... 

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