Hooper Annie R, Burns Alexander S
Rodger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States.
Discovery Chemistry, Janssen Research & Development L.L.C., San Diego, California 92121, United States.
ACS Med Chem Lett. 2022 Apr 14;13(5):833-840. doi: 10.1021/acsmedchemlett.2c00075. eCollection 2022 May 12.
Acrylamides are privileged electrophiles used in targeted covalent therapies, often installed at the end of a synthetic sequence due to their reactive nature. Herein, we report several diene-acrylamide adducts with a range of thermal stabilities toward retro-Diels-Alder deprotection of the acrylamide, enabling this masked functionality to be introduced early in a synthetic route and deprotected in a specific temperature range. Through kinetic studies, we identify solvent and structural trends that impact the stability of trimethylsilyl cyclopentadiene (TMS-CP) acrylamide adducts. TMS-CP protected acrylamides were installed on several amine-containing drugs, whose acrylamides were thermally unveiled ( = 160 °C, time ≤ 1 h) in moderate to high yields. We also showcase the potential utility of this protection strategy by improving the yield of a base-promoted SAr reaction when the acrylamide is masked.
丙烯酰胺是用于靶向共价疗法的特殊亲电试剂，由于其反应活性，通常在合成序列的末尾引入。在此，我们报道了几种二烯 - 丙烯酰胺加合物，它们对丙烯酰胺的逆狄尔斯 - 阿尔德脱保护具有一系列热稳定性，使得这种被保护的官能团能够在合成路线的早期引入，并在特定温度范围内脱保护。通过动力学研究，我们确定了影响三甲基硅基环戊二烯（TMS - CP）丙烯酰胺加合物稳定性的溶剂和结构趋势。TMS - CP保护的丙烯酰胺被安装在几种含胺药物上，其丙烯酰胺在160°C、时间≤1小时的条件下以中等到高产率热解蔽。我们还通过在丙烯酰胺被掩蔽时提高碱促进的SAr反应的产率，展示了这种保护策略的潜在实用性。
