Development of C₂-Symmetric Chiral Diphosphine Ligands for Highly Enantioselective Hydrogenation Assisted by Ion Pairing

Abstract

A new series of C 2-symmetrical chiral ferrocene-based diphosphino-ethane ligands termed as f-DPE were developed. Assisted by the ion pairing interaction with the ligand, a wide scope of 2-substituted acrylic acids was hydrogenated to obtain chiral propanoic acids with high yields and enantioselectivities. The well-known anti-inflammatory drugs ibuprofen, naproxen, and flurbiprofen could be synthesized efficiently. In addition, the synthetic utilities of the current method were demonstrated by gram-scale experiments.

Plus‐Size DiPAMP Hybrids for Advanced Rhodium(I)‐Catalyzed Hydrogenation: The 2RBigFUS Model

“…But in some cases, this trend is reversed [25] . Subsequently, functional tertiary amine‐integrated ligands at the side‐chain, primed in close proximity to the metal center, were developed [3a,d,21,26] . Some ligands were tailor‐made with an added H‐bonding ability.…”

P-Stereogenic Phosphorus Ligands in Asymmetric Catalysis

“…Ferrocene-based C 2 -symmetric bisphosphorus ligands (L30, L31, L32, TriFer, f-DPE, L68, and L69) exhibit characteristic activity in asymmetric catalysis. 165,177,218,220 L30, L31, L32, and L68 are effective for the Pd-catalyzed asymmetric allylic substitution reactions, whereas TriFer and f-DPE show high performance in the Rh-catalyzed asymmetric hydrogenation of α-substituted cinnamic acids owing to the ion-pairing interaction between the dimethylamino group of the ligands and the carboxy group of the substrates. P-Stereogenic PNP tridentate ligands, L52, 194 L53, 195 L61, 207 L62, 208 and Heng-PNP, 211 can be served as efficient chiral ligands for the Ru-, Fe-, and Ir-catalyzed asymmetric hydrogenation of ketones.…”

“…The C 2 -symmetric P-stereogenic bisphosphorus ligands reported from 2001 to 2023 are shown in Figure , in the order of their publication years. ,− ,,,− A tetraphosphine ligand L41 and a C 3 -symmetric triphosphine ligand MT-Siliphos are also included in this figure as exceptions. All of these ligands possess unique structural and electronic properties, arising from the two different substituents on the phosphorus atoms and the ligand backbones, and exhibit their characteristic reactivities and stereoselectivities in various transition-metal-catalyzed asymmetric reactions.…”

“…Significant advances have been made in the Rh-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids and their derivatives with no directing groups or with weakly coordinative groups such as alkoxy group. The ligands used in these asymmetric hydrogenations are Trifer, ChenPhos, ,, WudaPhos, t -Bu-WudaPhos, SPO-Wudaphos, , and f-DPE, all of which are ferrocene-based P-stereogenic phosphorus ligands with C-centered and planar chirality, bearing the dimethylamino group (Figure ). Schemes , , , , , , and , present representative asymmetric hydrogenation reactions using these chiral ligands, providing many pharmaceutically valuable α-substituted carboxylic acids in high efficiency.…”

“…The ligands used in these asymmetric hydrogenations are Trifer, ChenPhos, ,, WudaPhos, t -Bu-WudaPhos, SPO-Wudaphos, , and f-DPE, all of which are ferrocene-based P-stereogenic phosphorus ligands with C-centered and planar chirality, bearing the dimethylamino group (Figure ). Schemes , , , , , , and , present representative asymmetric hydrogenation reactions using these chiral ligands, providing many pharmaceutically valuable α-substituted carboxylic acids in high efficiency. It is suggested that the attractive noncovalent ion-pair interaction between the dimethylamino group of the ligand and the carboxy unit of the substrate plays one of the pivotal roles both in facilitating the hydrogenation and inducing high enantioselectivity.…”