Rapid Synthesis of Boc-2鈥?6鈥?dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics

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• 作者：Aaron M. Bender ; Nicholas W. Griggs ; Chao Gao ; Tyler J. Trask ; John R. Traynor ; Henry I. Mosberg
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：6
• 期：12
• 页码：1199-1203
• 全文大小：339K
• ISSN：1948-5875

文摘

The unnatural amino acid 2鈥?6鈥?dimethyl-an class="smallcaps">lan>-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2鈥?6鈥?dimethyl-an class="smallcaps">lan>-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon鈥揷arbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr¹ replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).