Ruthenium-Catalyzed Highly Enantioselective Synthesis of cis-3-Quinuclidinols via DKR Asymmetric Transfer Hydrogenation

Abstract

A method for the enantioselective synthesis of cis-3-quinuclidinols by Ru-catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution is described. The reaction proceeded under mild conditions using ammonium formate as the hydrogen donor, affording the products in high yields (up to 99%) with excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (95−99% ee). This protocol was applicable to gram-scale preparation with perfect enantioselectivity through simple recrystallization.

Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Carbonitriles via Dynamic Kinetic Resolution

“…Asymmetric transformations comprising DKR processes are very attractive since racemic substrates converge ideally to a diastereo- and enantiomerically pure product in this transformation. − In particular, the DKR encountered in asymmetric transfer hydrogenation (ATH) of ketones is a powerful protocol for “deracemization” of substrates, which possess a stereolabile α-carbon by converting them into alcohols with two contiguous stereogenic centers. − In 1989, Noyori and co-workers reported trailblazing work on the asymmetric hydrogenation of β-keto esters using Ru–BINAP catalysts . Since then, the utility of reductive DKR processes has been further accentuated by taking advantage of asymmetric transfer hydrogenation (ATH) with bifunctional Ru, Rh, and Ir catalysts containing chiral N -sulfonyl-1,2-diamine scaffolds. − …”

Prediction of the enantiomeric excess value for asymmetric transfer hydrogenation based on machine learning

“…The dataset we curated from the literature contained approximately 380 reactions. 1,14–34 This is not a very large dataset for ML. Currently, very popular deep learning algorithms cannot be applied in this work.…”

Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

“…In 2020, Zhang, Wang, and co-workers reported the Ru-catalyzed ATH through DKR for the enantioselective synthesis of cis-2-[(het)arylmethyl]quinuclidin-3-ols (Scheme 37). 50 After an extensive screening of the reaction parameters, the reaction proceeded in the presence of 1 mol% of (R,R)-CAT15 with HCO 2 NH 4 as the hydrogen source in i-PrOH/CH 2 Cl 2 at 50 °C for 72 h providing the corresponding cis-2-[(het)arylmethyl]quinuclidin-3-ols in 92-99% yield with diastereoselectivities up to >99:1 dr and 95 to >99% ee. The position of the substitution on the aryl ring or the electronic properties of the quinuclidin-3-ones did not have a significant influence on the reactivity and stereoselectivity of the ATH transformation.…”