Mu-Wang Chen

Biomimetic Asymmetric Hydrogenation: In Situ Regenerable Hantzsch Esters for Asymmetric Hydrogenation of Benzoxazinones

A catalytic amount of Hantzsch ester that could be regenerated in situ by Ru complexes under hydrogen gas has been employed in the biomimetic asymmetric hydrogenation of benzoxazinones with up to 99% ee in the presence of chiral phosphoric acid. The use of hydrogen gas as a reductant for the regeneration of Hantzsch esters makes this hydrogenation an ideal atom economic process.

Dehydration triggered asymmetric hydrogenation of 3-(α-hydroxyalkyl)indoles

Highly enantioselective hydrogenation of 3-(α-hydroxyalkyl)indoles promoted by a Bronsted acid for dehydration to form a vinylogous iminium intermediate in situ was developed with Pd(OCOCF3)2/(R)-H8-BINAP as catalyst with up to 97% ee. This methodology provides an efficient and rapid access to chiral 2,3-disubstituted indolines.

Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies

An efficient palladium-catalyzed asymmetric hydrogenation of a variety of unprotected indoles has been developed that gives up to 98% ee using a strong Brønsted acid as the activator. This methodology was applied in the facile synthesis of biologically active products containing a chiral indoline skeleton. The mechanism of Pd-catalyzed asymmetric hydrogenation was investigated as well. Isotope-labeling reactions and ESI-HRMS proved that an iminium salt formed by protonation of the C═C bond of indoles was the significant intermediate in this reaction. The important proposed active catalytic Pd-H species was observed with (1)H NMR spectroscopy. It was found that proton exchange between the Pd-H active species and solvent trifluoroethanol (TFE) did not occur, although this proton exchange had been previously observed between metal hydrides and alcoholic solvents. Density functional theory calculations were also carried out to give further insight into the mechanism of Pd-catalyzed asymmetric hydrogenation of indoles. This combination of experimental and theoretical studies suggests that Pd-catalyzed hydrogenation goes through a stepwise outer-sphere and ionic hydrogenation mechanism. The activation of hydrogen gas is a heterolytic process assisted by trifluoroacetate of Pd complex via a six-membered-ring transition state. The reaction proceeds well in polar solvent TFE owing to its ability to stabilize the ionic intermediates in the Pd-H generation step. The strong Brønsted acid activator can remarkably decrease the energy barrier for both Pd-H generation and hydrogenation. The high enantioselectivity arises from a hydrogen-bonding interaction between N-H of the iminium salt and oxygen of the coordinated trifluoroacetate in the eight-membered-ring transition state for hydride transfer, while the active chiral Pd complex is a typical bifunctional catalyst, effecting both the hydrogenation and hydrogen-bonding interaction between the iminium salt and the coordinated trifluoroacetate of Pd complex. Notably, the Pd-catalyzed asymmetric hydrogenation is relatively tolerant to oxygen, acid, and water.

Iridium‐Catalyzed Asymmetric Hydrogenation of Pyridinium Salts

As one of the most straightforward and powerful approaches for the preparation of optically active compounds, asymmetric hydrogenation has been successfully used for different types of aromatic compounds, including quinolines, isoquinolines, quinoxalines, indoles, pyrroles, furans, imidazoles, and aromatic carbocyclic ring, with excellent enantioselectivities. Despite these advances, direct hydrogenation of simple pyridines is still a challenge. The inherent problems are apparent: First, substrates and corresponding products that possess strong coordination ability might cause the deactivation of catalysts. Second, pyridines have a stabilizing aromatic structure that might impede the reduction. Therefore, only limited examples of hydrogenation of specific pyridine derivatives bearing powerful electron-withdrawing substituent at the 2or 3-position have been previously described. In 2000, Studer et al. reported the first homogeneous rhodium-catalyzed asymmetric hydrogenation of pyridines, but only poor enantioselectivity was obtained. Zhang and co-workers described an efficient three-step rhodium-catalyzed asymmetric hydrogenation of nicotinates. Subsequently, the group of Rueping documented the first enantioselective organocatalytic transfer hydrogenation of 3-cyanoor carbonyl-substituted pyridines using Hantzsch esters as hydrogen sources, and our group also employed [{Ir(cod)Cl}2]/(S)-MeO-biphep/I2 catalyst system for asymmetric hydrogenation of specific pyridines with excellent enantioselectivities. Additionally, an elegant asymmetric hydrogenation of activated pyridines, that is, N-iminopyridinium ylides, was developed by Charette et al. As chiral piperidines are important building blocks for the synthesis of biologically active molecules and natural products, the development of an efficient strategy for the highly challenging hydrogenation of the simple pyridines is still of great significance. Iminium salts generally exhibit higher activity than the corresponding imines in hydrogenation, therefore we envisioned that the activation of simple pyridines as the corresponding N-benzyl-pyridinium bromides would effectively eliminate coordination ability of the substrate and thus the reactivity could be greatly enhanced. Moreover, the stoichiometric amount of hydrogen bromide generated in situ would effectively inhibit the coordination ability of the desired product through the formation of its piperidine hydrogen bromide salt (Scheme 1). Also, the benzyl protecting groups could be conveniently removed by hydrogenolysis. Herein, we disclose the iridium-catalyzed asymmetric hydrogenation of 2-substituted pyridinium salts with excellent enantioselectivity.

Enantioselective Iridium-Catalyzed Hydrogenation of 1-and 3-Substituted Isoquinolinium Salts

Chiral 1,2,3,4-tetrahydroisoquinolines are ubiquitous structural motifs in many natural alkaloids and biologically active compounds. Among the various catalytic methods developed for the construction of chiral tetrahydroisoquinolines during the past decades, asymmetric hydrogenation of isoquinolines unquestionably serves as one of the most straightforward and powerful methods. So far, significant progress on the asymmetric hydrogenation of aromatic compounds has been implemented successfully for substrates such as quinolines, quinoxalines, indoles, pyrroles, pyridines, furans, imidazoles, thiophenes and aromatic carbocyclic rings. However, the development of the enantioselective hydrogenation of isoquinolines has met with limited success, probably owing to lower reactivity and strong coordination to the catalyst. In 2006, our group reported the first iridium-catalyzed asymmetric hydrogenation of isoquinolines, which were activated by chloroformates, with moderate enantioselectivity and yield. Very recently, an enantioselective hydrogenation of 3,4-disubstituted isoquinolines employing catalyst activation was successfully described, nevertheless, this strategy is not suitable for 1substituted isoquinolines. Moreover, there is no report on the asymmetric hydrogenation of 3-substituted isoquinolines heretofore. Therefore, the development of a general and efficient strategy for asymmetric hydrogenation of 1and 3substituted isoquinolines is still a very valuable and challenging area of chemical research. Recently, our group successfully documented the iridiumcatalyzed asymmetric hydrogenation of simple pyridinium salts, which were formed by using benzyl bromide and possess higher reactivity than the corresponding pyridines. As part of our ongoing efforts to promote the development of asymmetric hydrogenation of heteroaromatic compounds, and considering the similar structure of pyridine to isoquinoline, we envisioned that activating isoquinoline as the N-benzyl isoquinolinium salt would effectively improve the reactivity to facilitate hydrogenation (Scheme 1). Herein, we report the iridium-catalyzed asymmetric hydrogenation of 1and 3-substituted isoquinolinium salts with up to 96 % ee, as well as the application of the method to the synthesis of the chiral drug (+)-solifenacin. To begin the study, N-benzyl-1-phenyl isoquinolinium bromide (1; Ar = Ph) was chosen as a model substrate for the iridium-catalyzed asymmetric hydrogenation (Table 1). The reaction occurred smoothly in CH2Cl2 to give the desired product with moderate enantioselectivity and yield (entry 1). Further assessment of solvent revealed that the transformation was very sensitive to the reaction medium. The protic polar solvents displayed lower reactivity and enantioselectivity (entries 4 and 5). Gratifyingly, the mixed solvent system of THF/CH2Cl2 (1:1) gave the best result in terms of enantioselectivity and yield (entry 7). Subsequently, exploration of various commercially available bisphosphine ligands showed that (Rax,S,S)-C3*-TunePhos was the best ligand with respect to the yield and enantioselectivity (entry 13), whereas (R)-Binap gave lower enantioselectivity despite with high reactivity. Replacement of the bromide counterion by the trifluoromethanesulfonate anion resulted in no reactivity. In particular, when the CO2iPr group was introduced at the 2position of the benzyl group [1; Ar = 2-(iPrCO2)C6H4], the enantioselectivity was increased slightly, possibly because of its steric bulk and/or interaction with the iridium atom (entry 13 versus 16). With the optimized reaction conditions in hand, we turned our attention to investigate the scope of 1-substituted isoquinolinium salts, and the results are summarized in Table 2. It is noteworthy that various 1-substituted isoquinolinium salts proved to be good substrates under the standard reaction conditions. The transformation proceeded with excellent enantioselectivity and yield regardless of the Scheme 1. General strategy for asymmetric hydrogenation of 1and 3substituted isoquinolines. BCDMH= 1-bromo-3-chloro-5,5-dimethylhydantoin.

An Enantioselective Approach to 2,3-Disubstituted Indolines through Consecutive Brønsted Acid/Pd-Complex-Promoted Tandem Reactions

Tandem reactions and consecutive catalysis (or relay catalysis) have been receiving considerable attention in organic synthesis due to their abilities of constructing multiple new chemical bonds to build complex chiral molecules in a single operation. Transition-metal-catalyzed asymmetric hydrogenation is one of the most widely used and reliable catalytic methods for preparation of chiral molecules. The combination of Brønsted acid/transition-metal-catalyzed tandem reactions involving asymmetric hydrogenation as key step remains rare, although Krische and co-workers reported the C C bond formation with metal hydride as the catalytic species. Chiral 2,3-disubstituted indolines are significant building blocks in biologically active natural products and pharmaceutically active compounds. Generally, these compounds are synthesized from either dynamic resolution or multiplestep reactions. The most straightforward and atom economic means towards chiral indolines may be the asymmetric hydrogenation of substituted indole derivatives. Recently, some significant progress has been achieved by us and other groups for the highly enantioselective hydrogenation of substituted indoles using chiral Pd, Rh, Ru, and Ir complexes as catalysts. Very recently, we developed a facile approach to chiral 2,3-disubstituted indolines through dehydration-triggered asymmetric hydrogenation of 3-(a-hydroxyalkyl)indoles. Despite these contributions, the tedious procedure for the preparation of the substrates limits its synthetic applications. So, the search for a rapid, simple, and divergent method for synthesizing chiral 2,3-disubstituted indolines is still highly desirable. Considering reductive alkylation (Friedel–Crafts/dehydration/reduction) of 2-substituted indoles and aldehydes can rapidly lead to 2,3-disubstituted indoles, we envisioned that combination of reductive alkylation of 2-substituted indoles and asymmetric hydrogenation of 2,3-disubstituted indoles can lead to a rapid and divergent approach to chiral 2,3-disubstituted indolines (Scheme 1). Herein, we describe the enantioselective access to chiral 2,3-disubstituted indolines through consecutive Brønsted acid/Pd-complex-

Enantioselective Pd-catalyzed hydrogenation of fluorinated imines: facile access to chiral fluorinated amines.

An enantioselective hydrogenation of simple fluorinated imines has been developed using Pd(OCOCF(3))(2)/(R)-Cl-MeO-BIPHEP as a catalyst, and up to 94% ee was achieved. This method provides an efficient route to enantioenriched fluorinated amines.

Highly effective and diastereoselective synthesis of axially chiral bis-sulfoxide ligands via oxidative aryl coupling.

A series of axially chiral bis-sulfoxide ligands have been efficiently synthesized via oxidative coupling with high diastereoselectivities. The axial chirality is well controlled by the tert-butylsulfinyl or the p-tolylsulfinyl group. These axially chiral bis-sulfoxides proved to be remarkably efficient ligands for the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to 2-cyclohexenone with 99% ee.

C–H Oxidation/Michael Addition/Cyclization Cascade for Enantioselective Synthesis of Functionalized 2-Amino-4H-chromenes

A streamlined method for the enantioselective synthesis of 2-amino-4H-chromenes from readily available 2-alkyl-substituted phenols and active methylene compounds bearing a cyano group with up to 97% ee is presented. This reaction is a cascade procedure including manganese dioxide mediated C-H oxidation for the generation of o-quinone methides and bifunctional squaramide-catalyzed Michael addition/cyclization.

4,5-Dihydropyrrolo(1,2‑a)quinoxalines: A Tunable and Regenerable Biomimetic Hydrogen Source

A series of tunable and regenerable biomimetic hydrogen sources, 4,5-dihydropyrrolo[1,2-a]quinoxalines, have been synthesized and applied in biomimetic asymmetric hydrogenation of 3-aryl-2H-benzo[b][1,4]oxazines and 1-alkyl-3-aryl-quinoxalin-2(1H)-ones, providing the chiral amines with up to 92% and 89% ee, respectively.