Asymmetric Hydrogenation of β-Aryloxy/Alkoxy Cinnamic Nitriles and Esters

Abstract

A highly efficient and enantioselective hydrogenation of β-aryloxy/alkoxy cinnamic nitriles and esters under mild conditions has been realized by using a rhodium catalyst with a chiral f-spiroPhos ligand. The method provides efficient access to the asymmetric synthesis of a variety of chiral β-oxy-functionalized nitriles and esters with excellent enantioselectivities (up to 99.9% ee) and high turnover numbers (TON of up to 50000). This methodology has also been successfully applied to the concise and practical synthesis of the chiral pharmaceutical nisoxetine.

Synthesis of Enantioenriched β-Aryl-β-aryloxy Esters via Sequential Photoisomerization and Enantioselective Hydrogenation

“…Enantioenriched β-aryl-β-aryloxy esters are valuable synthons for preparing pharmaceutically relevant compounds and natural products. − The asymmetric hydrogenation of β-aryl-β-aryloxy-α,β-unsaturated esters ( A ) is a straightforward and atom-economical approach to these synthons (Scheme a). − A few examples of the asymmetric hydrogenation of Α and related carboxylic acids are known; − however, they employ expensive and noncommercially available catalysts that are tedious to prepare . In addition, high hydrogen pressure (30–80 atm) is required for the reaction, and the elimination of the aryloxy group from A can be a major side reaction. , …”

“…Another major limitation is the inability to readily access a pure Z- or E-isomer of Α , which is required to achieve high enantioselectivity in asymmetric hydrogenation . Although the unsaturated esters can be readily prepared as a mixture of Z- and E-isomers (less than 5:1 ratio), , the isolation of pure isomers requires crystallization or semipreparative high-performance liquid chromatography (HPLC) purification, resulting in a moderate to low yield (Scheme a). ,, …”

“…Having identified a method to access the E-isomer of β-aryl-β-aryloxy-α,β-unsaturated carboxylic esters in high yield and with high purity, we focused on identifying a practical condition for the enantioselective hydrogenation. In pioneering work, Hou and coworkers reported the enantioselective hydrogenation of β-aryloxy cinnamic esters . Although the reduced products were obtained in high yield with high enantioselectivity, 1.1 mol % of an expensive ligand, ( R , R )-f-SpiroPhos, was required.…”

“…14 Although the unsaturated esters can be readily prepared as a mixture of Z-and E-isomers (less than 5:1 ratio), 15,16 the isolation of pure isomers requires crystallization or semipreparative highperformance liquid chromatography (HPLC) purification, resulting in a moderate to low yield (Scheme 1a). 9,10,17 A method to selectively prepare Z-and E-Α will provide access to the starting material for the asymmetric hydrogenation in high yields. We were particularly interested in avoiding acidic or basic conditions because aryloxy elimination from A is observed under acidic conditions, and several functional groups may not be tolerated under basic conditions.…”

“…In pioneering work, Hou and coworkers reported the enantioselective hydrogenation of β-aryloxy cinnamic esters. 9 Although the reduced products were obtained in high yield with high enantioselectivity, 1.1 mol % of an expensive ligand, (R,R)-f-SpiroPhos, was required. In addition, the reported conditions were not convenient for large-scale operations because of the requirement of 30−80 atm hydrogen pressure.…”