Preparation of Axially Chiral Biphenyl Diphosphine Ligands and Their Application in Asymmetric Hydrogenation

Abstract

Development of efficient methods for catalytic enantioselective synthesis has been an important subject for the practical synthesis of optically active organic compounds.1) Numerous methods of enantioselective synthesis employing various catalysts such as transition metal complexes coordinated with many types of chiral ligands have been reported for more than three decades. [1][2][3][4][5][6] For the development of efficient chiral catalysts, creation of new types of ligands is a most significant strategy. Among various types of chiral ligands, diphosphines are the most effective and are widely applicable in the catalytic asymmetric hydrogenation of prochiral compounds such as olefins, ketones, and imines using transition metal (rhodium, ruthenium, iridium, etc.) complexes as catalyst. We previously proposed a novel idea, "respective control concept" for designing new chiral ligands, 7-10) and developed efficient diphosphine ligands such as (2S-cis)-4-(dicyclohexylphosphino)-2-[(diphenylphosphino)methyl]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester (BCPM) and its analogs, 8,[11][12][13] (4R-trans)-[(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)]bis[bis(4-methoxy-3,5-dimethylphenyl)phosphine] (MOD-DIOP) and its analogs, [14][15][16][17] etc. (Fig. 1) for rhodium-catalyzed asymmetric hydrogenation of some prochiral ketones (ketopantolactone, a-and bamino ketones, etc.), and olefins (itaconic acid and its derivatives, N-acyldehydroamino acids, etc.). Furthermore, we revealed that phosphines bearing electron-donating groups such as cyclohexyl groups, p-(dimethylamino)phenyl groups, and p-methoxy-m,mЈ-dimethylphenyl groups enhance not only the catalytic activity but also the enantioselectivity in the rhodium-catalyzed hydrogenations. The p-methoxym,mЈ-dimethylphenyl (abbreviated to MOD) group was found to be a useful component for developing efficient ligands on the basis of its steric effect (m-Me) as well as its electronic effect (p-MeO, m-Me).15) We also reported in preliminary communications the design and preparation of axially chiral diphosphines, [18][19][20][21] which were found to be very efficient ligands for ruthenium-catalyzed asymmetric hydrogenation of a b-keto ester or rhodium-catalyzed asymmetric hydrogenation of an a-amino ketone. In this article we describe in detail the synthesis of optically pure 3,3Ј-dimethoxy-2,2Ј,4,4Ј-tetramethyl-1,1Ј-biphenyls 8a-c bearing one or two 6,(6Ј)-dicyclohexylphosphino group(s) and/or 6,(6Ј)-diphenylphosphino group(s), and an application to rhodium-catalyzed asymmetric hydrogenation. Results and DiscussionThe synthetic route of axially dissymmetric biphenyldiphosphine ligands 8a-c bearing one or two dicyclohexylphosphino group(s) and/or one or two diphenylphosphino group(s) is described in Chart 1 (8a-c were abbreviated to BIMOP, Cy-BIMOP, and MOC-BIMOP, respectively). Iodination of 2,6-dimethylnitrobenzene (1) was carried out selectively at the 3-position by heating with iodine at 90°C for 4 d in the presence of periodic acid in acetic acid containing d...

A Modular Approach to Atropisomeric Bisphosphines of Diversified Electronic Density on Phosphorus Atoms

“…Other than the cases described in Achiwa’s work [ 55 , 56 ], our attempts to separate BIMOPO ( 9c ) enantiomers by fractional crystallization with addition of DBTA did not lead to satisfactory results. This was the case with further efforts to use chiral acids such as 2,3-di(phenylaminocarbonyl) tartaric acid [ 57 ], monodimethylamide DBTA, naproxen, mandelic acid or similar tested in a wide range of organic solvents.…”

The metabolism and excretion of 2‐methylaminoethoxycarbonyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylenedioxybiphenyl‐2′‐carboxylic acid (DDB‐S) in rats and human

“…The synthesis was performed by coupling the d 5 ‐substituted phenyl compound with the unsubstituted phenyl ring compound using the Ullmann reaction 11–13. The overall scheme for the synthesis is described in Scheme .…”

Catalytic Asymmetric Synthesis of α-Amino Acids

“…This theory was developed when bisphosphine ligand (S a )-79 was allowed to form the Rh complexes in the hydrogenation reaction of 1c, with 79c and 79d being the most efficient chiral entities. 98 The chiral polysubstituted biphenyls 80 99 and 81 100 and the 3,3′-bipyridines 82 101,102 afforded good results of the hydrogenated compounds 2 (Table 8, entries 11-16) but never gave the excellent performance of the homogeneous complex (S a )-83-[Rh] (Table 8, entry 17). 103 Even the (S a )-83-[Rh] complex anchored on a lithiated DOWEX 50W X2 resin was able to maintain a 99.9% ee in its second cycle of the hydrogenation of compound 1a (Table 8, entry 18), 103 unlike the two silica gel supported Rh complexes derived from bisphosphines (R a )-84 and (S a )-85, which induced lower enantioselections during similar transformations 104 (up to 40% ee).…”