Amino resin chemistry alkylation

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

To overcome the chain fragmentation of sensitive peptides that contain /V-alkyl amino acids caused by acids as described vide supra, the following measures are recommended (1) in solution synthesis the exploitation of protecting groups removed by acids should be minimized (e.g., apply Fmoc chemistry, use acid-labile side-chain protection as little as possible) (2) if the peptides must be subjected to acid use low temperatures (—20 °C) for the shortest time possible (monitor the reaction by HPLC ) (3) in SPPS if the peptide does not contain functionalized side chains, prepare the peptide by Fmoc chemistry on Trt resin and remove the peptide from the resin with HFIP (see Section 10.1.1.2.2). If the peptides have functionalized side chains see point (1). 

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

The SM reactions are eompatible with the solid-phase synthesis what is applied in the combinatorial chemistry [95,97]. The arylboronic acids can be immobilized on the polystyrene eontaining diethanolamine-moieties by forming boronate esters XXV. A wide variety of thus bounded arylboronic acids bearing a bromomethyl, carboxylic, amino or aldehyde-group have been converted by N- or O-alkylation, amidation, reductive alkylation and some other reactions, to amines, esters, amides, ureas, etc [96]. The resulting arylboronic acid can be regenerated from the resin by simple... 

Besides the alkylation reactions in polyamine synthesis, the reductive am-ination approach found broad entry in solid phase chemistry in the backbone amide hnker (BAL) strategy [202] (Scheme 2). Thereby, amino acids are bound to a linker via imine reduction bearing a secondary amine, which can be further acylated to obtain peptides with a variety of C-terminal function-ahties. Besides the effective synthesis of C-modified peptides, this also opens access to amide formation in peptides if C- and N-terminal residues are de-protected, commonly leading to cychc peptides [ 177]. Cleavage from the resin... 

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