Sterically-Directed Regioselective Preparation of Orthogonally-Protected 4-Benzyl-L-histidine for Peptide Synthesis

A synthesis of 4-benzyl-Nπ-Boc-Nα-Fmoc-L-histidine was developed. 4-Phenylspinacine from Pictet-Spengler cyclocondensation of L-histidine and benzaldehyde was esterified and regioselectively Nπ-Boc protected. Catalytic transfer hydrogenolysis followed by saponification gave 4-benzyl-Nπ-Boc-L-histidine which was further Nα-protected to provide the desired amino acid in 5 steps and 40% overall yield.