Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education & Research (NIPER) S.A.S. Nagar, Sahibzada Ajit Singh Nagar, Mohali, 160062, India.
Chem Rec. 2023 Nov;23(11):e202300207. doi: 10.1002/tcr.202300207. Epub 2023 Aug 11.
Our current unhealthy lifestyle and the exponential surge in the population getting affected by a variety of diseases have made pharmaceuticals or drugs an imperative part of life, making the development of innovative strategies for drug discovery or the introduction of refined, cost-effective and modern technologies for the synthesis of clinically used drugs, a need of the hour. Ever since their discovery, free radicals and radical cations or anions as reactive intermediates have captivated the chemists, resulting in an exceptional utilization of these moieties throughout the field of chemical synthesis, owing to their unprecedented and widespread reactivity. Sticking with the idea of not judging the book by its cover, despite the conventional thought process of radicals being unstable and difficult to control entities, scientists and academicians around the globe have done an appreciable amount of work utilizing both persistent as well as transient radicals for a variety of organic transformations, exemplifying them with the synthesis of significant biologically active pharmaceutical ingredients. This review truly accounts for the organic radical transformations including radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling with metal-complexes and radical cations coupling with nucleophiles, that offers fascinating and unconventional approaches towards the construction of intricate structural frameworks of marketed APIs with high atom- and step-economy; complementing the otherwise employed traditional methods. This tutorial review presents a comprehensive package of diverse methods utilized for radical generation, featuring their reactivity to form critical bonds in pharmaceutical total synthesis or in building key starting materials or intermediates of their synthetic journey, acknowledging their excellence, downsides and underlying mechanisms, which are otherwise poorly highlighted in the literature. Despite great achievements over the past few decades in this area, many challenges and obstacles are yet to be unraveled to shorten the distance between the academics and the industry, which are all discussed in summary and outlook.
我们当前不健康的生活方式和各种疾病影响人群的指数级增长，使得制药或药物成为生活中必不可少的一部分，因此，开发创新的药物发现策略或引入精细、具有成本效益和现代的技术来合成临床使用的药物，是当下的需求。自从自由基和自由基阳离子或阴离子作为反应中间体被发现以来，化学家们一直对它们着迷，这导致在整个化学合成领域中，这些部分得到了异常的利用，因为它们具有前所未有的广泛反应性。尽管传统的思维认为自由基是不稳定且难以控制的实体，但我们不应该以貌取人，全球的科学家和学者们在利用持久性和瞬态自由基进行各种有机转化方面做了大量的工作，并用它们来合成具有重要生物活性的药物成分来证明这一点。这篇综述真正涵盖了有机自由基转化，包括自由基加成、自由基级联环化、自由基/自由基交叉偶联、与金属配合物的偶联以及自由基阳离子与亲核试剂的偶联，为构建具有高原子经济性和步骤经济性的已上市 API 的复杂结构框架提供了引人入胜和非常规的方法；补充了其他传统方法。这篇综述提供了一套全面的用于自由基生成的方法，介绍了它们的反应性，以形成药物全合成中的关键键，或构建其合成过程中的关键起始材料或中间体，承认它们的卓越性、缺点和潜在机制，这些在文献中往往没有得到很好的强调。尽管在过去几十年中，在这一领域取得了巨大的成就，但仍有许多挑战和障碍需要克服，以缩短学术界和工业界之间的距离，这些都在总结和展望中进行了讨论。
