Asymmetric Hydrogenation of α-Substituted Acrylic Acids Catalyzed by a Ruthenocenyl Phosphino-oxazoline–Ruthenium Complex

Abstract

Asymmetric hydrogenation of various α-substituted acrylic acids was carried out using RuPHOX-Ru as a chiral catalyst under 5 bar H2, affording the corresponding chiral α-substituted propanic acids in up to 99% yield and 99.9% ee. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 5000 S/C), and the resulting product (97%, 99.3% ee) can be used as a key intermediate to construct bioactive chiral molecules. The asymmetric protocol was successfully applied to an asymmetric synthesis of dihydroartemisinic acid, a key intermediate required for the industrial synthesis of the antimalarial drug artemisinin.

Recent Advances in the Synthesis of Ibuprofen and Naproxen

“…Asymmetric hydrogenation is a valuable methodology for chiral medicine synthesis [ 98 , 99 , 100 ]. For NSAID synthesis, the chiral ferrocene-ruthenium complex was reported to be promising, as shown in Scheme 27 in 2016 [ 101 ]. This reduction process was developed for NSAID synthesis and other chiral propionic acid skeletons, such as artemisinin.…”

Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines

“…8, 139.2, 137.7, 134.0, 130.6, 129.4, 128.6, 128.5, 126.7. 2-(2-Chlorophenyl)acrylic Acid. 28 CAS RN [1225777-50-3]. White solid, 23% yield (for two steps, 0.70 g).…”

The Synthesis of Chiral α‐Aryl α‐Hydroxy Carboxylic Acids via RuPHOX‐Ru Catalyzed Asymmetric Hydrogenation

“…This complex has been employed as a chiral catalyst for the asymmetric hydrogenations of simple ketones and β ‐amino ketones, providing the corresponding products in up to 99% yield and 99.9% ee –. Very recently, an efficient and mild RuPHOX−Ru catalyzed asymmetric hydrogenation of α‐substituted acrylic acids was developed in up to 99% yield and 99.9% ee, and was applied in the synthesis of dihydroartemisinic acid (DHAA), a key intermediate used for the synthesis of the antimalarial drug artemisinin (Qinghaosu) (Scheme ) . Encouraged by these promising results, we herein report the RuPHOX−Ru catalyzed asymmetric hydrogenation of α‐aryl keto acids for the direct synthesis of chiral α‐aryl α‐hydroxy carboxylic acids (Scheme ).…”