Wu Qing-Feng, Shen Peng-Xiang, He Jian, Wang Xiao-Bing, Zhang Forrest, Shao Qian, Zhu Ru-Yi, Mapelli Claudio, Qiao Jennifer X, Poss Michael A, Yu Jin-Quan
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA.
Science. 2017 Feb 3;355(6324):499-503. doi: 10.1126/science.aal5175.
The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.
原料化学品异丁酸的酶促β-C-H羟基化反应已实现了多种聚酮化合物的不对称合成。异丁酸衍生底物的类似过渡金属催化对映选择性β-C-H官能化反应，应为从这种丰富的C-4骨架构建具有对映体富集α-手性中心的有用结构单元提供一种通用方法。然而，有机金属催化剂对普遍存在的异丙基进行去对称化仍然是一个未解决的挑战。在此，我们报道了手性单保护氨基甲基恶唑啉配体的设计，该配体能够通过钯插入前手性甲基之一的C(sp)-H键实现异丙基的去对称化。我们详细介绍了异丁酸/2-氨基异丁酸衍生物的对映选择性β-芳基化、-烯基化和-炔基化反应，这些反应可作为构建α-手性中心的平台。
