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

The enormous influence in terms of bioactivity, affinity, and selectivity represented by the replacement of (L)-2,6-dimethyl tyrosine (Dmt) instead of Phenylalanine (Phe) into Nociceptin/orphanin (N/OFQ) neuropeptide analogues has been well documented in the literature. More recently, the non-natural amino acid (L)-2-methyl tyrosine (Mmt), with steric hindrance included between Tyr and Dmt, has been studied because of the modulation of steric effects in opioid peptide chains. Here, we report a new synthetic strategy to obtain Mmt based on the well-known Pd-catalyzed ortho-C(sp(2))-H activation approach, because there is a paucity of other synthetic routes in the literature to achieve it. The aim of this work was to force only the mono-ortho-methylation process over the double ortho-methylation one. In this regard, we are pleased to report that the introduction of the dibenzylamine moiety on a Tyr aromatic nucleus is a convenient and traceless solution to achieve such a goal. Interestingly, our method provided the aimed Mmt either as N-Boc or N-Fmoc derivatives ready to be inserted into peptide chains through solid-phase peptide synthesis (SPPS). Importantly, the introduction of Mmt in place of Phe(1) in the sequence of N/OFQ(1-13)-NH2 was very well tolerated in terms of pharmacological profile and bioactivity.

Automated summary

The replacement of (L)-2,6-dimethyl tyrosine (Dmt) with Phenylalanine (Phe) can have a significant impact on bioactivity, affinity, and selectivity. Recent research has explored the use of a non-natural amino acid, (L)-2-methyl tyrosine (Mmt), to modulate steric effects in opioid peptide chains. This study presents a new synthetic strategy to obtain Mmt using a well-known Pd-catalyzed ortho-C(sp(2))-H activation approach. The introduction of the dibenzylamine moiety on a Tyr aromatic nucleus allows for convenient and traceless mono-ortho-methylation. The substitution of Phe(1) with Mmt in the sequence of Nociceptin/orphanin (N/OFQ) neuropeptide analogues is well tolerated in terms of pharmacological profile and bioactivity.