Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Vertex Pharmaceuticals (Europe) Ltd., 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire, OX14 4RW, UK.
Nat Commun. 2019 Jan 3;10(1):21. doi: 10.1038/s41467-018-07871-x.
The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. Cu-catalyzed allylic desymmetrizations enable the enantioselective formation of carbon-carbon bonds, but these transformations are limited in substrate scope and by the use of highly reactive premade organometallic reagents at cryogenic temperatures. Here we show that diverse meso-bisphosphates in combination with alkylzirconium nucleophiles undergo highly regio-, diastereo- and enantio-selective Cu-catalyzed desymmetrization reactions. In addition, C-symmetric chiral bisphosphates undergo stereospecific reactions and a racemic substrate undergoes a Cu-catalyzed kinetic resolution. The reaction tolerates functional groups incompatible with many common organometallic reagents and provides access to a broad range of functionalized carbo- and hetero-cyclic structures. The products bear up to three contiguous stereogenic centers, including quaternary centers and spirocyclic ring systems. We anticipate that the method will be a useful complement to existing catalytic enantioselective reactions.
meso-化合物的非对称化是一种有用的合成方法，许多天然产物合成中的策略应用都证明了这一点。Cu 催化的烯丙基非对称化能够实现对映选择性地形成碳-碳键，但这些转化受到反应底物范围的限制，并且需要在低温下使用高反应性的预制有机金属试剂。在这里，我们展示了各种 meso-双磷酸酯与烷基锆亲核试剂结合，可以进行高度区域、立体和对映选择性的 Cu 催化非对称化反应。此外，C 对称手性双磷酸酯可以进行立体特异性反应，外消旋底物可以进行 Cu 催化的动力学拆分。该反应可以容忍与许多常见有机金属试剂不兼容的官能团，并提供了广泛的功能化碳和杂环结构的途径。产物带有多达三个连续的立体中心，包括季碳原子和螺环系统。我们预计该方法将成为现有催化对映选择性反应的有益补充。
