Ruthenium‐Catalyzed Asymmetric Hydrogenation of 3‐Oxoglutaric Acid Derivatives: A Study of Unconventional Solvent and Substituent Effects

Abstract

A series of 3-oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)-SunPhos]Cl (SunPhos = (2,2,2',2'-tetramethyl-[4,4'-bibenzo[d][1,3]dioxole]-5,5'-diyl)bis(diphenylphosphine)). Unlike simple β-keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH(2)Cl(2), acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5-tricarbonyl substrates in the tested solvents. The C-2 and C-4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20% in EtOH or THF to 90% in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent.

A Decennary Journey towards the Efficient Asymmetric Hydrogenation of Highly Functionalized Ketones

“…For most examples in Table , higher ee values were observed in THF than in EtOH. To further explore the solvent effects, some other uncommon solvents were also tested 59. Overall, acetone was found to be an even better solvent than THF, especially for 48e and 48j .…”

“…Studies on various substituted 3‐oxo‐glutaric acid derivatives revealed an incredible substitution and solvent effect (Scheme ) 59. Even with the same skeleton ( 48n – r ), different substituents had inexplicable influences on the reactivity and enantioselectivity.…”

“…These closed‐ring enol forms are difficult to coordinate to ruthenium until the ring is broken. For the hydrogenation of 46a to 47a in THF, a catalytic amount of H 2 SO 4 facilitated full conversion 59. We proposed that the enol form of 46a was shifted to its keto form when the pH increased.…”

“…In THF, the heteroatoms may assist in the shift of ring enols ( C ) to form β‐hydroxy enones ( B ). We also proposed that the hydrogenation of these substrates might proceed through their enol forms, that is, the C=C bonds in B 59. Currently, we are searching for a more conclusive depiction of the hydrogenation pathway.…”