Development of a Kilogram-Scale Process for the Enantioselective Synthesis of 3-Isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOS-Catalyzed Asymmetric Hayashi Addition Enabled by 1,3-Diol Additives,Organic Process Research & Development

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Development of a Kilogram-Scale Process for the Enantioselective Synthesis of 3-Isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOS-Catalyzed Asymmetric Hayashi Addition Enabled by 1,3-Diol Additives
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-09-05 00:00:00 , DOI: 10.1021/acs.oprd.7b00253
Eric M. Simmons ₁ , Boguslaw Mudryk ₁ , Andrew G. Lee ₁ , Yuping Qiu ₁ , Thomas M. Razler ₁ , Yi Hsiao ₁

Affiliation

The development of a scalable process for the Rh-catalyzed asymmetric 1,4-addition of (isopropenyl)pinacolboronate to 2-cyclohexen-1-one is reported. High-throughput ligand screening and initial optimization studies identified DTBM-SEGPHOS as an effective ligand along with a heptane/MeOH mixed solvent system. An inhibitory effect of the pinacol byproduct was identified, which could be mitigated by the addition of a 1,3-diol such as neopentyl glycol (npg). This process was demonstrated on 1 kg scale with 0.6 mol % Rh, producing (S)-1 in 82% yield and 99.6% ee, and was successfully scaled up at a vendor on 100 kg scale.

中文翻译：

通过Rh / DTBM-SEGPHOS催化的1,3-二酚添加剂不对称Hayashi加成对映选择性合成3-异丙烯基-环己-1-酮的千克规模工艺的开发

据报道，Rh催化的（异丙烯基）频哪硼烷酸酯向2-环己烯-1-酮不对称的1,4-加成反应的可扩展方法得到了发展。高通量配体筛选和初步优化研究表明，DTBM-SEGPHOS与庚烷/ MeOH混合溶剂系统一起是一种有效的配体。确认了频哪醇副产物的抑制作用，可以通过添加1,3-二醇（例如新戊二醇（npg））来减轻。在1千克规模，0.6摩尔％Rh的条件下证明了该过程，以82％的收率和99.6％ee的产率生产（S）-1，并在供应商的100千克规模上成功扩大规模。

更新日期：2017-09-06

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