Synthesis of methylated phenylalanines via hydrogenolysis of corresponding 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acids

Abstract

A new method of synthesizing ortho‐methylated phenylalanines has been developed. Phenylalanines with at least one free ortho‐position undergo a Pictet—Spengler cyclization with formaldehyde followed by hydro‐genolytic splitting of the endocyclic benzylic C—N bond of 1,2,3,4‐tetrahydroisoquinolines and afford corresponding ortho‐methyl derivatives. Repeating this reaction sequence on the ortho‐substituted phenylalanines yielded ortho, ortho‐disubstituted derivatives, and pro‐substituted phenylalanines yielded ortho,para‐disubstituted analogs. Our modified method of cyclization preserved the configuration at the chiral center: hydrogenolysis, on the other hand, led to racemization. Incorporation of the methylated phenylalanines into position 2 of oxytocin led to, in the case of the D‐isomers, potent uterotonic inhibitors.

(L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation

“…In the subsequent step, the resulting sterically hindered dehydroamino acid was subjected to enantioselective hydrogenation in order to establish the desired C-alpha configuration [1]. An elegant synthetic route to Mmt was proposed by Majer et al [31] who conceived to obtain a regioselective monomethylation of Tyr via hydrogenolysis of tetrahydroisoquinoline-3-carboxylic acid prepared from Tyr, through a Pictet-Spengler cyclization. Unfortunately, the drastic conditions required in the reductive step led to extensive racemization leading to the obtainment of Mmt in racemic form.…”

, -Dimethylphenylalanine : A Useful Aromatic Amino Acid Surrogate for Tyr or Phe Residue in Opioid Peptides

“…The 2,6-dimethylation of the aromatic moiety in Leu-enkephalin (ENK) imparted high enzymatic stability to the peptide [ 36 ]. These findings prompted a study to modify a Phe aromatic moiety at position 3 or 4 of opioid peptides through 2,6-dimethylation because no derivatives with phenyl ring-methylated Phe incorporated into opioid peptides have been reported, only other biologically active peptides have been prepared [ 37 , 38 ]. The usefulness of incorporating the artificial aromatic amino acid, 2′,6′-dimethylphenylalanine (Dmp) ( Figure 1 ) as an aromatic amino acid surrogate in opioid peptides to develop opioid ligands specific for opioid receptors was investigated.…”