165528-89-2Relevant academic research and scientific papers
A Process Chemistry Benchmark for sp2-sp3Cross Couplings
Beutner, Gregory L.,Simmons, Eric M.,Ayers, Sloan,Bemis, Christopher Y.,Goldfogel, Matthew J.,Joe, Candice L.,Marshall, Jonathan,Wisniewski, Steven R.
, p. 10380 - 10396 (2021/07/31)
As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.
Ni-catalyzed reductive homocoupling of unactivated alkyl bromides at room temperature and its synthetic application
Peng, Yu,Luo, Long,Yan, Chang-Song,Zhang, Jian-Jian,Wang, Ya-Wen
, p. 10960 - 10967 (2013/11/19)
A room-temperature Ni-catalyzed reductive approach to homocoupling of unactivated primary, secondary, and tertiary alkyl bromides is described. The catalytic system can be easily generated from air-stable and cheap materials and demonstrates broad functional group tolerance, thus allowing facile access to useful dimeric triterpene and lignan-like molecules. Moreover, the dimerization of tertiary bromide 6 efficiently establishes sterically hindered vicinal quaternary carbons (C3a and C3a′), which is a key linkage of intriguing bispyrrolo[2,3-b]indoline alkaloids, thereby enabling us to complete the total syntheses of racemic chimonanthine (9) and folicanthine (10). In addition, this dimerization method can be expanded to the highly stereoselective synthesis of bisperhydrofuro[2,3-b]furan (5a) and the dimeric spiroketal 5b, signifying the involvement of possible radical species.
