Chemoselectivity Control in the Asymmetric Hydrogenation of γ‐ and δ‐Keto Esters into Hydroxy Esters or Diols

Abstract

The asymmetric hydrogenation of aromatic γ- and δ-keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3-AMIQ-Ru complex was studied. Under the optimized conditions (8 atm H , Ru complex/t-C H OK=1:3.5, 25 °C) the γ- and δ-hydroxy esters (including γ-lactones) were obtained quantitatively with 97-99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H , [t-C H OK]=50 mm, 40 °C), the 1,4- and 1,5-diols were obtained predominantly with 95-99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β- and ϵ-keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ-ϵ-diketo diester into a trihydroxy ester.

Synthesis of Enantiopure γ‐Lactones via a RuPHOX‐Ru Catalyzed Asymmetric Hydrogenation of γ‐Keto Acids

“…The enantiopure g-lactone motif is also found in important precursors for the synthesis of many enantiopure drugs. [11][12][13][14] In 1990, Noyori and co-workers developed an asymmetric hydrogenation of g-keto esters by using the BINAPÀRu catalyst, providing high enantioselectivity for substrates bearing alkyl groups (Scheme 1, up). [5] Many methodologies have been reported for the synthesis of enantiopure g-lactones, including asymmetric oxidation, [6] hydroboration, [7] hydrosilylation, [8] transfer hydrogenation, [9] and enzyme catalysis, [10] etc.…”

“…[11][12][13][14] In 1990, Noyori and co-workers developed an asymmetric hydrogenation of g-keto esters by using the BINAPÀRu catalyst, providing high enantioselectivity for substrates bearing alkyl groups (Scheme 1, up). [14] The mixed products were then subjected to a further lactonization with t-BuOK as a base to deliver terminal enantiopure g-lactones. Adopting a similar catalytic system to that mentioned above (except using RuCl 3 as a metal salt), the Vinogradov group were able to promote the reaction using a somewhat lower H 2 pressure (60 atm) but high reaction temperature (60 8C).…”

“…Generally, asymmetric hydrogenation is undoubtedly an efficient pathway for the construction of enantiopure g-lactones because of its high efficiency, environmental friendliness, and low economic cost (Scheme 1). [11][12][13][14] In 1990, Noyori and co-workers developed an asymmetric hydrogenation of g-keto esters by using the BINAPÀRu catalyst, providing high enantioselectivity for substrates bearing alkyl groups (Scheme 1, up). [12] However, harsh reaction conditions (100 atm) and a long reaction time (110 h) were needed to ensure the completion of the reaction.…”

“…Just recently, Ohkuma and co-workers disclosed a P,NÀRu-complex catalyzed asymmetric hydrogenation of g-keto esters, with the corresponding g-hydroxy esters as the main products (including g-lactones) being obtained in high yields and excellent enantioselectivities (Scheme 1, middle). [14] The mixed products were then subjected to a further lactonization with t-BuOK as a base to deliver terminal enantiopure g-lactones. By using gketo esters as substrates, harsh reaction conditions and/or an additional cyclization is generally needed for the synthesis of enantiopure g-lactones.…”

“…(R)-5-(o-Tolyl)dihydrofuran-2(3H)-one (2 b)[14] : Colorless oil (50.2 mg, 95%) 1. (R)-5-(o-Tolyl)dihydrofuran-2(3H)-one (2 b)[14] : Colorless oil (50.2 mg, 95%) 1.…”