Peyote and Related Alkaloids XVI: Synthesis of 3,4,5-Trimethoxyphenylalanine, an Amino Acid Analog of Mescaline

Contrary to an earlier literature report, acid hydrolysis of diethyl α-acetamido-α-3,4,5-trimethoxybenzylmalonate during the synthesis of 3,4,5-trimethoxyphenylalanine has been shown to lead to a mixture of products. The major hydrolysis products were isolated and identified bynmR and mass spectrometry as 3,4,5-trimethoxyphenylalanine (34%), 4-hydroxy-3,5-dimethoxyphenylalanine (13%), 3-hydroxy-4,5-dimethoxyphenylalanine (8%), and 3,4-dihydroxy-5-methoxyphenylalanine (5%). Under basic conditions, the acetamidomalonate ester as well as its formamido analog, obtained by the condensation of trimethoxybenzyl chloride and diethyl formamidomalonate, gave low yields (5–7%) of the required trimethoxyphenylalanine. However, no phenolic side-products were formed under basic conditions. An efficient alternative synthesis of 3,4,5-trimethoxyphenylalanine has been accomplished; it involves the condensation of hydantoin with trimethoxybenzaldehyde followed by hydrogenation and basic hydrolysis of the resulting 5-(3,4,5-trimethoxybenzylidine)hydantoin. GC–mass spectrometric examination of the peyote amino acid fraction gave no evidence for the presence of trimethoxyphenylalanine and other trioxygenated phenylalanine analogs obtained during these synthetic studies.