Alkylation of Schiff Base-Activated Peptides

A variety of alkyl halides can be employed as an electrophile in this alkylation, as summarized in Table 5.8 (entries 1-5). The efficiency of the transmission of stereochemical information was not affected by the side-chain structure of the pre-existing amino acid residues, as demonstrated in the phase-transfer benzylation 

Peptide modification is an essential, yet flexible, synthetic concept for the efficient target screening and optimization of lead structures in the application of naturally occurring peptides as pharmaceuticals. The introduction of side chains directly to a peptide backbone represents a powerful method for the preparation of unnatural peptides [44]. 

It was envisaged that chiral PTC should play a crucial role in achieving an efficient chirality transfer hence, an examination was conducted of the alkylation of the dipeptide, Gly-L-Phe derivative 47 (Table 11.5). When a mixture of 47 and tetrabutylammonium bromide (TBAB 2mol%) in toluene was treated with 50% KOH aqueous solution and benzyl bromide at 0°C for 4h, the corresponding benzylation product 48 was obtained in 85% yield with the diastereomeric ratio (DL-48 LL-48) of 54 46 (8% diastereomeric excess (de)) (entry 1). In contrast, the reaction with chiral quaternary ammonium bromide (S,S)-9g possessing a 3,5-bis(3,5-di-tert-butylphenyl)phenyl group under similar conditions reahzed almost complete diastereocontrol (entries 4—6) [45]. 

Chiral PTC with S,S)- [or (R,R)-[ 9g can be successfully extended to the stereoselective N-terminal alkylation of LL-, DL-49 and DDL-50, and the corresponding protected tri- or tetra-peptide was obtained in high yield with excellent 

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