The unnatural amino acid 2′,6′-dimethyl-l-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′,6′-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon–carbon 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).

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Boc-2',6'-二甲基-l-酪氨酸及其衍生物的快速合成及与阿片类肽模拟物的结合

非天然氨基酸 2',6'-二甲基-l-酪氨酸已广泛用于合成阿片类药物配体的开发。在 N 末端具有这种残基的阿片样物质通常在一种或多种阿片样物质受体类型上表现出优异的效力，但该化合物的可用性受到其成本和合成困难的阻碍。我们在此报告了一个简短的三步合成 Boc-2',6'-二甲基-l-酪氨酸 ( 3a )，利用微波辅助 Negishi 偶联进行关键的碳-碳键形成步骤，并将这种化学方法用于其他非天然酪氨酸衍生物的方便合成。这些衍生物中的三个（3c，3d，3f）以前没有被检查为 Tyr¹阿片类药物配体中的替代物。我们描述了使用我们之前报道的四氢喹啉 (THQ) 支架将这些酪氨酸衍生物掺入到一系列阿片类肽模拟物中，以及每种类似物对三种阿片受体亚型的结合和相对功效：mu (MOR)、delta (DOR) ) 和 kappa (KOR)。