University of Zagreb, Faculty of Pharmacy and Biochemistry, Ante Kovačića 1, 10000 Zagreb, Croatia.
Department of Chemistry, LMU München, Butenandtstrasse 5-13, D-81377 München, Germany.
Org Biomol Chem. 2021 Jan 28;19(4):854-865. doi: 10.1039/d0ob02187c. Epub 2021 Jan 6.
The Hofmann-Löffler-Freytag (HLF) reaction can be successfully used to synthesize saturated heterocyclic nitrogen-containing nature-derived pharmaceuticals such as nicotine and its derivatives. In this study the rate-determining hydrogen atom transfer (HAT) step in nicotine synthesis has been analyzed using quantum chemical methods. Through quantification of substituent effects in the HAT step of the reaction on both nitrogen and carbon atoms, optimized synthetic strategies are outlined for the racemic as well as the stereoselective synthesis of nicotine. This latter process can be achieved using common nitrogen protecting groups, such as Ac, TFAc, and Boc. The said protecting groups show superior nitrogen radical activation as compared to the commonly used Tosyl group. Computational results indicate that the 1,5-HAT step is in this case likely to work even for the reaction with primary unactivated carbon centers.
霍夫曼-勒夫勒-弗雷塔格（HLF）反应可成功用于合成饱和杂环含氮天然药物，如尼古丁及其衍生物。在这项研究中，使用量子化学方法分析了尼古丁合成中速率决定的氢原子转移（HAT）步骤。通过量化反应中氮原子和碳原子上 HAT 步骤的取代基效应，为尼古丁的外消旋和立体选择性合成勾勒出了优化的合成策略。后一种方法可以使用常见的氮保护基，如 Ac、TFAc 和 Boc。与常用的甲苯磺酰基相比，这些保护基对氮自由基的活化作用更强。计算结果表明，在这种情况下，1,5-HAT 步骤甚至可能适用于与未活化的一级碳中心的反应。
