Guohua Hou

Enantioselective Hydrogenation of N-H Imines

N-H ketoimines 3a-3v are readily prepared in high yield via organometallic addition to nitriles and isolated as corresponding bench-stable hydrochloride salts. Homogeneous asymmetric hydrogenation of unprotected N-H ketoimines 3a-3v using Ir-(S,S)-f-binaphane as catalyst provides chiral amines 4a-4v in 90-95% yield with enantioselectivities up to 95% ee.

Iridium−Monodentate Phosphoramidite-Catalyzed Asymmetric Hydrogenation of Substituted Benzophenone N−H Imines

Homogeneous asymmetric hydrogenation of unprotected benzophenone N-H imines 1a-r using Ir-(S)-N-benzyl-N-methyl-MonoPhos as a catalyst provides chiral amines 2a-r in 80-96% yield with enantioselectivities up to 98% ee (18 examples) for ortho-substituted substrates.

Highly efficient and highly enantioselective asymmetric hydrogenation of ketones with TunesPhos/1,2-diamine-ruthenium(II) complexes.

The TunePhos/diamine-Ru(II) complex combined with t-BuOK in 2-propanol effectively catalyzes enantioselective hydrogenation of a wide range of simple ketones including aromatic, heteroaromatic, alpha,beta-unsaturated, and cyclopropyl ketones, affording high reactivity (up to 1,000,000 TON) and excellent enantioselectivities (>99% ee for 13 examples).

Electron‐Donating and Rigid P‐Stereogenic Bisphospholane Ligands for Highly Enantioselective Rhodium‐Catalyzed Asymmetric Hydrogenations

Development of chiral phosphorus ligands has drawn intensive interest owing to their significant role in transition-metalcatalyzed asymmetric reactions. Catalytic asymmetric hydrogenation has been widely used as a practical and efficient method in the synthesis of chiral molecules. Although excellent enantioselectivities have been obtained by using benchmark ligands such as dipamp (1,2-ethanediylbis[(2-methoxyphenyl)phenylphosphane]), binap (2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl), DuPhos (1,2bis(phospholano)benzene derivatives), and more recently TangPhos 1 and DuanPhos 2 (Figure 1), it is still highly desirable to develop ligands that can be prepared easily and have high enantioselectivity, reactivity, and with broad substrate scope for asymmetric hydrogenation. Herein, we report a new highly electron-donating and conformationally rigid P-stereogenic bisphospholane ligand 3 (named ZhangPhos; Figure 1) where both enantiomers can be synthesized conveniently. High enantioselectivities and reactivities have been achieved at room and elevated temperature in rhodiumcatalyzed hydrogenation of various functionalized alkene derivatives. Since the discovery of the landmark ligand dipamp, more attention has been paid to P-stereogenic phosphorus ligands because the chiral environment induced by the ligands is close to the transition metal centers. For example, BisP* (1,2bis(alkylmethylphosphino)ethane), miniphos (1,2-bis(alkylmethylphosphino)methane), and trichickenfootphos (tertbutylmethylphosphino-di-tert-butylphosphinomethane) provide excellent enantioselectivities in asymmetric hydrogenation, especially for the challenging tetra-substituted olefins. However, the development of P-stereogenic ligands is still limited owing to difficulty with synthesizing them. Our research group has ever reported a P-stereogenic ligand 1, TangPhos, which is one of the most efficient ligands for asymmetric hydrogenation. More recently, many other groups found that TangPhos exhibited the highest enantioselectivities for diverse transition-metal-catalyzed asymmetric reactions such as arylcyanation and alkylation of imidazoles at high temperatures. However, only one enantiomer of TangPhos (1S,1S’,2R,2R’-1) is readily available owing to the requisition of chiral induction from ( )-sparteine. Later on, we introduced another P-stereogenic phosphorus ligand 2, DuanPhos, with both enantiomers being available. But the synthesis of DuanPhos requires resolution in the final step and its electron-donating ability is not as strong as that of TangPhos. The wide applications of TangPhos and DuanPhos encourage us to develop a more synthetically practical and conformationally rigid P-stereogenic bisphospholane scaffold 3, ZhangPhos. The two five-membered phospholane rings in the backbone of 3 are believed to restrict the conformational flexibility and lead to high enantioslectivity. It is envisioned that the electron-rich bis(trialkylphosphane) structure contributes to the high reactivity. In addition to the excellent enantioselective induction, the two chiral cyclohexane rings on the backbone are expected to further benefit the electron-donating ability and conformational rigidity of 3. Ligand 3 was synthesized in a straightforward manner in five steps from a commercially available chiral source, (1S,2S)-1,2-cyclohexanedicarboxylic acid (4), which was reduced to chiral diol 5 quantitatively (Scheme 1; see the Figure 1. Structure of the three P-stereogenic phosphorus ligands.

Efficient Synthesis of Chiral β‐Arylisopropylamines by Using Catalytic Asymmetric Hydrogenation

Transition metal catalyzed asymmetric hydrogenation of enamides[1] is a powerful method to prepare chiral amines, which are important building blocks in organic synthesis.[2] With the development of many effective chiral ligands,[1] a variety of prochiral enamides such as 1,[3] 2,[3a,c,d,e,g] 3,[4] and 4,[5] have been hydrogenated in excellent enantioselectivities (Figure 1). However, asymmetric hydrogenation of 5 was rarely studied. To our knowledge, the only result was reported to give moderate enantioselectivity (50% ee) for the hydrogenation of 5a (Ar = Ph) with a Rh/DIPAMP complex.[6] In this paper, we prepared a series of enamides of both (Z)-5 and (E)-5 and tested them in Rh-catalyzed asymmetric hydrogenation with several chiral ligands. Excellent ee’s (up to 99% ee) have been achieved for those (Z)-configured enamide with Rh/TangPhos catalytic system. Figure 1 Prochiral enamide substrates for asymmetric hydrogenation. A number of methods for the preparation of enamides have been reported, including rearrangement reactions,[6, 7] reduction of nitro alkenes[8] or ketoximes,[9] acylation of imines,[10] and direct condensation of ketone and amide.[11] Recently, a Merck group has developed an efficient Pd-catalyzed amidation reaction leading to a diverse array of enamides.[12] Under optimized condition, good selectivity for (Z)-enamide such as 6 was achieved (Scheme 1). To gain quick access to the desired substrates 5a-5i, we chose the direct condensation method due to its operational simplicity. As shown in Table 1, both isomers of 5 can be separated from the concentrated reaction mixture via flash column chromatography; in most cases, more of (Z)-enamide was obtained than the corresponding (E)-isomer. Although the moderate yields remain to be optimized, we found the present method is well suited for quick synthesis of both (Z)-5 and (E)-5 from inexpensive starting materials at laboratory scale. In addition, a diaryl enamide 5i was prepared in acceptable yield (entry 9, Table 1), which complements Pd-catalyzed amidation for this bulky substrate.[12b] Scheme 1 Pd-catalyzed amidation for the synthesis of (Z)-enamide 6.[12] Table 1 Preparation of (Z)- and (E)-5 via direct condensation of 7 with acetamide.[a] With the synthesis of a set of enamides 5, we compared Rh-catalyzed asymmetric hydrogenation of (Z)-5a and (E)-5a with four widely used chiral ligands, including TangPhos (L1),[13a] DuanPhos (L2),[13b] Et-DuPhos (L3),[13c] and Binapine (L4).[13d] Notably, under the same reaction condition each ligand showed a striking difference in enantio-differentiating ability toward the two isomers (Table 2). For (Z)-5a, excellent ee’s were obtained by the use of all ligands except L4, with TangPhos giving the best result. Change of solvent had little effect on enantioselectivity. In contrast, much lower ee’s were observed for (E)-configured 5a in EtOAc, albeit with the same sense of product chirality as from (Z)-5a. Change of solvent gave no improvement of enantioselectivity. Therefore, unlike asymmetric hydrogenation of isomeric mixture of β-substituted α-aryl enamides 2,[3a,c,d,e,g] the configuration of double bond in 5 has a dramatic influence on enantioselectivity.[14] To achieve excellent enantioselectivity with current ligands, (Z)-configured substrates need to be used. Table 2 Rh-catalyzed asymmetric hydrogenation of (Z)-5a and (E)-5a with different ligands.[a] We further tested other substrates (Z)-5b-5i with Rh/TangPhos catalytic system under the optimized condition. As shown in Table 3, all substrates gave excellent ee’s. Substitution pattern on the phenyl ring generally has no appreciable effect on enantioselectivity (entries 2–4). Even hindered enamides (Z)-5h and (Z)-5i were hydrogenated with excellent results (entries 8, 9). At reduced catalyst loading (TON = 1000), (Z)-5a was still converted to 8a with almost unchanged ee (entry 10). Hence current hydrogenation route is a practical way for the preparation of various amines in this category (Figure 2).[15] For example, deacylation of the chiral product 8a leads directly to (S)-Amphetamine 9, which is a useful stimulant with strong biological and physiological effects.[16] Further modification will result in Selegiline 10 for the treatment of Alzheimer’s disease.[17] Asymmetric hydrogenation of (Z)-5c will also provide a practical access to important chiral drugs such as Formoterol 11[18] and Tamsulosin 12.[19] Figure 2 Chiral drugs bearing β-aryl isopropylamine fragment. Table 3 Asymmetric hydrogenation of (Z)-5 with Rh/TangPhos catalytic system.[a] In this communication, we showed that β-aryl isopropylamines, an important class of chiral compounds with valuable pharmaceutical applications, can be prepared via highly efficient asymmetric hydrogenation. Excellent enantioselecitivity was obtained for (Z)-enamides, which were easily prepared via acid-catalyzed condensation of β-aryl ketone with acetamide. Alternatively, these substrates can be synthesized via Pd-catalyed amidation that exhibits better preference for the formation of (Z)-configured substrates.[12] Expansion of this methodology to other structurally relevant enamides is currently in progress and will be reported in a due course.

Highly Efficient Iridium-Catalyzed Asymmetric Hydrogenation of Unprotected β-Enamine Esters

A highly efficient and enantioselective hydrogenation of unprotected β-enamine esters catalyzed by Ir-(S,S)-f-Binaphane complex has been developed. This methodology provides straightforward access to free β-amino acids in high yields with excellent enantioselectivities up to 97% ee and high reactivities (TON > 5000).

Developing chiral phosphorus ligands for asymmetric hydrogenations

Chiral rigid and electron-donating phosphocyclic phosphine ligands and modular atropisomeric biaryl phosphine ligands were designed and synthesized. The performance of these chiral ligands in the asymmetric hydrogenations of prochiral dehydroamino acid derivatives, enamides, imines, keto esters, and ketones has been demonstrated to be excellent.

Highly Efficient RhI-Catalyzed Asymmetric Hydrogenation of β-Amino Acrylonitriles

Enantiomerically pure b-amino nitriles and their derivatives are important intermediates in organic synthesis and pharmaceutical chemistry. The nitrile group is one of the most versatile functional groups in organic chemistry and can be readily transformed into a variety of valuable functionalities, including carboxyl; aldehyde; and amino groups, and, hence, b-amino nitriles enable facile approaches to b-amino acids, aldehydes, and 1,3-diamines. Therefore, the synthesis of b-amino nitriles has attracted much attention in recent decades. The early preparation of b-amino nitriles started from b-amino alcohols and involves a reaction with toxic cyanic reagents. Some recent progress includes addition reactions of alkyl nitriles to imines catalyzed by Cu, Pd, Ru, or Lewis base complexes, with good yields. An alternative approach to b-amino nitriles is the ring-opening of aziridines with trimethylsilyl cyanide (TMSCN). To the best of our knowledge, there are few reports of the direct preparation of chiral b-amino nitriles by asymmetric hydrogenation of the corresponding b-amino acrylonitriles. This is mainly due to the electronic structure of nitriles, which prefer the end-on coordination of metal ions, making the conjugated double bond unsuitable for hydrogenation reactions. Another challenge in the direct hydrogenation of b-amino acrylonitriles is achieving chemoselectivity between the olefinic double bond and the nitrile group. Asymmetric hydrogenation catalyzed by transition metals has proved to be a highly efficient method for the synthesis of chiral amines. A number of chiral phosphine ligands have been developed that improve the chemoand enantioselectivity of the hydrogenation reaction. We envisioned that the electron-donating, rigid, chiral ligands, such as TangPhos, DuanPhos, and Binapine (shown here), developed in