Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
J Am Chem Soc. 2021 Nov 17;143(45):19078-19090. doi: 10.1021/jacs.1c08399. Epub 2021 Nov 4.
We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura crosscouplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 / and 93:7 / observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the crosscoupling.
我们报告了一种通过镍催化的烯醇对甲苯磺酸盐和硼酸酯的 Suzuki-Miyaura 交叉偶联反应来对映选择性地制备四取代烯烃的方法。通过巧妙选择配体和反应条件，可以从烯醇对甲苯磺酸盐起始物料的非对映异构体混合物中选择性地获得任一非对映异构体产物。类似的方案也可以从非对映异构体纯的烯醇对甲苯磺酸盐中发散式合成每个产物异构体。值得注意的是，通过对配体库的化学空间分析，对单膦配体进行高通量优化，以确保对各种配体进行了多样化的筛选。对结果的立体电子分析提供了对该转化中反应性和选择性配体要求的深入了解。然后，通过对各种四取代烯烃的立体选择性合成对优化的催化体系的合成实用性进行了探究，观察到高达 94%的产率和高达 99:1 / 和 93:7 / 的非对映选择性比。此外，详细的计算分析和实验性机理研究提供了对影响交叉偶联选择性的基础异构化过程本质的关键见解。
