Alkylation of peptides

ALKYLATION OF PEPTIDE BONDS TO DECREASE AGGREGATION 2-HYDROXYBENZYL PROTECTORS... 

JF Reichwein, RMJ Liscamp. Site-specific V-alkylation of peptides on the solid phase. Tetrahedron Lett 39, 1243, 1998. 

Scheme 5. The oNBS-protecting group enables the N-alkylation of peptides such as 21. It can also be used as temporary N-protecting group in solid-phase peptide synthesis (DMA = A/.N-dimethylaceta-mide MTBD, 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene).

D. Seebach, Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures, Angew. Chem. Int. Ed. Engl 1988, 27, 1624-1654. 

Boc-Ala-(Et)Leu-OMe, Site-Specific N-Alkylation of Peptides on Solid Phase Using 2-Nitrophenyl-sulfonyl Protection Typical Procedure f ... 

Table 12. Asymmetric induction in the photo-alkylation of peptide (66)...

If the Claisen rearrangement is carried out with peptide allylic esters, the transfer of an allylic side chain to the a-position of the C terminal amino acid results in a modification of the peptide chain. This concept is comparable to the alkylations of peptide enolates described by Seebach et al. [93]. If it is possible to carry out the rearrangement not only with amino acids but also with peptide esters, the question arises if it is possible to transfer the chiral information from the peptide chain to the new chiral center formed during the rearrangement process, prohahly via some peptide metal enolate complexes. 

Seebach, D. Structure and reactivity of lithium enolates. From pinacolone to selective C-alkylations of peptides. Difficulties and opportunities afforded by complex structures. Angew. Chem., Int. Ed. Engl. 1988, 27,1624-1654. 

For pioneering work on the alkylation of peptidic enolates, see (a) Seebach, D. (1988) Angew. Chem., 100, 1685-1715 Angew. Chem., Int Ed. Engl, 27, 1624-1654j (b) Seebach, D., Beck, A.K., and Studer, A. (1995) in Modern Synthetic Methods, vol. 7 (eds B. Ernst and C. Leumann), Helvetica Chimica Acta/VCH, Basel/Weinheim, pp. 1-178 and references therein (c) For a personal review entitled How we drifted into peptide chemistry and where we have arrived at, see Seebach, D., Kimmerlin, T, Sebesta, R., Campo, M.A., and Beck, A.K. (2004) Tetrahedron, 60, 7455-7506. 

The development and use in peptide synthesis of the 1-adamantyloxymethyl protecting group for N -histidine 28 was reported <9 CS(P1)2139>. A procedure for the regiospecific alkylation of histidine and histamine at N-l(t) via the corresponding tetrahydro oximidazo[l,5-c]pyrimidines 29 was also developed <96T5363>. 

Bolton, J. L. Turnipseed, S. B. Thompson, J. A. Influence of quinone methide reactivity on the alkylation of thiol and amino groups in proteins studies utilizing amino acid and peptide models. Chem.-Biol. Interact. 1997, 107, 185-200. 

K. Mizutani, T. Electronic and structural requirements for metabolic activation of butylated hydroxytoluene analogs to their quinone methides, intermediates responsible for lung toxicity in mice. Biol. Pharm. Bull. 1997, 20, 571-573. (c) McCracken, P. G. Bolton, J. L. Thatcher, G. R. J. Covalent modification of proteins and peptides by the quinone methide from 2-rm-butyl-4,6-dimethylphenol selectivity and reactivity with respect to competitive hydration. J. Org. Chem. 1997, 62, 1820-1825. (d) Reed, M. Thompson, D. C. Immunochemical visualization and identification of rat liver proteins adducted by 2,6-di- m-butyl-4-methylphenol (BHT). Chem. Res. Toxicol. 1997, 10, 1109-1117. (e) Lewis, M. A. Yoerg, D. G. Bolton, J. L. Thompson, J. Alkylation of 2 -deoxynucleosides and DNA by quinone methides derived from 2,6-di- m-butyl-4-methylphenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

A group of peptide derivatives such as peptide arginals and boronic acid peptide derivatives belong to another class of reversible thrombin inhibitors. One such inhibitor is PPACK (D-Phe-Pro-Arg chloromethyl ketone), which functions as a powerful irreversible thrombin inhibitor by alkylating the histidine residue at the catalytic site of thrombin (58). It, however, is unstable in neutral solution, as it undergoes cyclization and inactivation. However, the D-methyl derivative of D-Phe-Pro-Arg-H (D-Mephe-Pro-Arg-H) called efegatran, with a molecular mass of 515 Da, is a stable selective reversible inhibitor of thrombin with a K. of approximately 100 nM. The basic amino terminus in this compound is responsible for promoting the specificity toward thrombin (63). 

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