Sodium Enolate Derived Reactions of N-Boc and N-benzyl-2-(S)-Pyroglutamates with Electrophiles: Synthesis of 4-Substituted and 2-Substituted Pyroglutamates

Background: 4-substituted pyroglutamates have found use in the synthesis of ACE inhibitors e.g. Fosinopril, conformationally constrained peptides as well as bioactive natural products. Such versatile applications associated with 4-substituted Pyroglutamates encouraged researchers to study the Lienolate derived alkylation of pyroglutamate with electrophiles. Though several reports are available on Li-enolate derived reactions of pyroglutamates with electrophiles, but sodium-enolate derived reactions of pyroglutamate with electrophiles have not been investigated, and that prompted us to study the behaviour of sodium enolate derived reactions of N-protected pyroglutamates with electrophiles. Results and Discussion: Herein we have reported our studies on the sodium enolate derived reactions of N-protected pyroglutamate with electrophiles, where N-Boc-(2S)-menthyl pyroglutamate on reaction with various electrophiles in the presence of Sodium hydride afforded 4-substituted pyroglutamates while under similar conditions N-benzyl-(2S)-menthyl pyroglutamate afforded exclusively 2-substituted pyroglutamates. Conclusion:We have successfully accomplished sodium enolate derived alkylation/aldol reaction on NBoc- (2S)-menthyl and N-Benzyl-(2S)-menthyl pyroglutamate with an objective to synthesize 4– substituted pyroglutamates as well as 2-substituted pyroglutamates. These 4-substituted pyroglutamates and 2-substituted pyroglutamates have potential to serve as intermediate for the synthesis of bioactive natural products, ACE inhibitors and conformationally restricted peptide analogs.