An Efficient Synthesis of 4(5)-Benzyl-l-histidines Employing Catalytic Transfer Hydrogenolysis at Elevated Temperatures

Abstract

An efficient two-step synthesis of 4(5)-benzyl-l-histidine from l-histidine was developed. A Pictet–Spengler reaction between l-histidine and benzaldehyde in the presence of excess strong base yielded 4-l-phenylspinacine within one hour. Catalytic transfer hydrogenolysis in methanol at reflux using ammonium formate rapidly converted 4-l-phenylspinacine to 4(5)-benzyl-l-histidine within five minutes. No racemization of the final product 4(5)-benzyl-l-histidine was observed using the Marfey reagent. To show the utility of this method, a series of fluorinated benzylhistidines were prepared.

Key words

amino acids - benzylation - Pictet–Spengler reaction - catalytic transfer hydrogenolysis - electrophilic aromatic substitution

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