Illuminati, D.; Trapella, C.; Zanirato, V.; Guerrini, R.; Albanese, V.; Sturaro, C.; Stragapede, S.; Malfacini, D.; Compagnin, G.; Catani, M.; Fantinati, A. (L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation. Pharmaceuticals2023, 16, 1592.
Illuminati, D.; Trapella, C.; Zanirato, V.; Guerrini, R.; Albanese, V.; Sturaro, C.; Stragapede, S.; Malfacini, D.; Compagnin, G.; Catani, M.; Fantinati, A. (L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation. Pharmaceuticals 2023, 16, 1592.
Illuminati, D.; Trapella, C.; Zanirato, V.; Guerrini, R.; Albanese, V.; Sturaro, C.; Stragapede, S.; Malfacini, D.; Compagnin, G.; Catani, M.; Fantinati, A. (L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation. Pharmaceuticals2023, 16, 1592.
Illuminati, D.; Trapella, C.; Zanirato, V.; Guerrini, R.; Albanese, V.; Sturaro, C.; Stragapede, S.; Malfacini, D.; Compagnin, G.; Catani, M.; Fantinati, A. (L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation. Pharmaceuticals 2023, 16, 1592.
Abstract
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 literature. More recently, the non-natural amino acid (L)-2-methyl tyrosine (Mmt), with steric hindrance among 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(sp2)–H activation approach, since there is a paucity of other synthetic routes in 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 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 Phe1 in the sequence of N/OFQ(1-13)-NH2 was very well tolerated in terms of pharmacological profile and bioactivity.
Chemistry and Materials Science, Organic Chemistry
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