Enantioselective Synthesis of α-Methyl-β-cyclopropyldihydrocinnamates
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- 作者：Melodie Christensen ; Andrew Nolting ; Michael Shevlin ; Mark Weisel ; Peter E. Maligres ; Joshua Lee ; Robert K. Orr ; Christopher W. Plummer ; Matthew T. Tudge ; Louis-Charles Campeau ; Rebecca T. Ruck
- 刊名：Journal of Organic Chemistry
- 出版年：2016
- 出版时间：February 5, 2016
- 年：2016
- 卷：81
- 期：3
- 页码：824-830
- 全文大小：426K
- ISSN：1520-6904
文摘
α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki–Miyaura cross-coupling conditions affording (Z)-α-methyl-β-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.