The efficient synthesis of an Fmoc-Gly-Ile phosphinic pseudodipeptide was desired as an eventual building block for construction of matrix metalloproteinase inhibitors. A Michael-type addition reaction of bis(trimethylsilyl) phosphonite with the appropriate acrylate generated the pseudodipeptide bond. Additional of adamantyl (Ad) protection by our prior route (reaction of in situ generated phosphinic acid chloride with the sodium salt of adamantanol) was surprisingly inefficient. Adamantyl protection was achieved in high yield by refluxing the phosphinic acid, Ag₂O, and 1-AdBr in chloroform. Subsequently a concise one-pot three-step reaction comprising a double deprotection of the N- and C-termini under catalytic hydrogenation conditions followed by selective protection of the N-terminus with an Fmoc group yielded Fmoc-NHCH₂PO(OAd)CH₂CH(2-butyl)CO₂H in 41 % overall yield. These results indicate that, as the diversity of phosphinic pseudodipeptides is increased to create selective matrix metalloproteinase inhibitors, different synthetic pathways may be required for efficient building block preparation.

中文翻译：

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Fmoc-Gly-Ile 膦假二肽的合成：用于构建基质金属蛋白酶抑制剂构建块的残留特异性条件。

Fmoc-Gly-Ile 次膦酸假二肽的有效合成被期望作为构建基质金属蛋白酶抑制剂的最终构件。双（三甲基甲硅烷基）亚膦酸酯与合适的丙烯酸酯的迈克尔型加成反应产生了假二肽键。通过我们先前的途径（原位生成的次膦酰氯与金刚烷醇的钠盐的反应）额外的金刚烷基 (Ad) 保护是非常低效的。通过回流次膦酸 Ag ₂以高收率实现金刚烷基保护O 和 1-AdBr 的氯仿溶液。随后进行简洁的一锅三步反应，包括在催化氢化条件下对 N 端和 C 端进行双重脱保护，然后用 Fmoc 基团选择性保护 N 端，生成 Fmoc-NHCH ₂ PO(OAd)CH ₂ CH(2-丁基)CO ₂ H，总产率为41%。这些结果表明，随着次膦酸假二肽的多样性增加以产生选择性基质金属蛋白酶抑制剂，可能需要不同的合成途径来进行有效的构建块制备。