Zhi-Shi Ye

Dihydrophenanthridine: A New and Easily Regenerable NAD(P)H Model for Biomimetic Asymmetric Hydrogenation

A new and easily regenerable NAD(P)H model 9,10-dihydrophenanthridine (DHPD) has been designed for biomimetic asymmetric hydrogenation of imines and aromatic compounds. This reaction features the use of hydrogen gas as terminal reductant for the regeneration of the DHPD under the mild condition. Therefore, the substrate scope is not limited in benzoxazinones; the biomimetic asymmetric hydrogenation of benzoxazines, quinoxalines, and quinolines also gives excellent activities and enantioselectivities. Meanwhile, an unexpected reversal of enantioselectivity was observed between the reactions promoted by the different NAD(P)H models, which is ascribed to the different hydride transfer pathway.

Highly Enantioselective Partial Hydrogenation of Simple Pyrroles: A Facile Access to Chiral 1-Pyrrolines

A highly enantioselective Pd-catalyzed partial hydrogenation of simple 2,5-disubstituted pyrroles with a Brønsted acid as an activator has been successfully developed, providing chiral 2,5-disubstituted 1-pyrrolines with up to 92% ee.

Rhodium-Catalyzed ortho-Benzoxylation of sp2 C−H Bond

A rhodium-catalyzed ortho-benzoxylation of the sp(2) C-H bond by carboxylic acids is described. The procedure tolerates carbomethoxy, formyl, bromo, chloro, and nitro groups, providing the benzoxylated products in moderate to good yields. Importantly, no external oxidant was required for the transformation.

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 Iridium-Catalyzed Hydrogenation of 3,4-Disubstituted Isoquinolines†

The past decade has witnessed rapid progress in the field of asymmetric hydrogenation of aromatic compounds, a transformation, which is regarded as one of the most straightforward means for accessing enantiopure cyclic compounds. Extensive research has significantly expanded the substrate scope of this reaction, and substrates such as quinolines, quinoxalines, indoles, furans, pyrroles, pyridines, imidazoles, and aromatic carbocycles can now be transformed through asymmetric hydrogenation. Despite achievements made, the asymmetric hydrogenation of isoquinoline still remains an important unmet challenge. Hydrogenation reactions involving this substrate have been plagued by catalyst deactivation owing to the strong coordinating ability of the substrate and the product. So far, only one example of an enantioselective hydrogenation of isoquinoline has been reported by our research group. N-protected 1-substituted 1,2-dihydroisoquinolines were obtained in moderate yield and enantioselectivity in the presence of stoichiometric amounts of chloroformate as the substrate activator (Scheme 1). However, several obvious limitations remain, such as the need for a stoichiometric amount of activating reagent and inorganic base, and that current methods only lead to products containing one stereogenic center, which is usually the C1 position. Given the prevalence of the chiral 1,2,3,4-tetrahydroisoquinoline motif in natural alkaloids and pharmaceutical molecules, the development of an efficient method for the direct hydrogenation of isoquinolines is highly desirable. Herein, we describe a highly efficient direct enantioselective iridium-catalyzed hydrogenation of 3,4-disubstituted isoquinolines. Recent results from our research group and that of others 12] have demonstrated that iodine can significantly improve the performance of an iridium catalyst in asymmetric hydrogenation. We wanted to investigate whether isoquinoline could be amenable to asymmetric hydrogenation catalyzed by an iodine-activated iridium complex. Initially, ethyl 3-methylisoquinoline-4-carboxylate 1a was chosen as model substrate. Upon exposure to 500 psi H2 in the presence of a chiral iridium complex, which is generated in situ from [Ir(cod)Cl]2/(R)-synphos and iodine at 50 8C, isoquinoline 1a underwent enantioselective hydrogenation to afford product 2a with full conversion, excellent diastereoselectivity (d.r.>20:1) and moderate enantioselectivity (59 % ee ; Table 1, entry 2); when iodine was omitted, only the 1,2hydrogenation product was observed (Table 1, entry 1). Encouraged by this promising result, we initially investigated the effect of the identity of the solvent on the substrate conversion and enantioselectivity. The substrate conversion was, in most solvents, uniformly good, whereas the ee value of 2a exhibited a dramatic dependence upon the solvent identity (Table 1, entries 2–5). The use of toluene as the solvent was the most beneficial in terms of the enantioselectivity of the hydrogenation (80% ee, Table 1, entry 6). Next, the effect of the nature of the additive was investigated using various halogen sources (Table 1, entries 6–10). Each additive promoted this transformation, thus leading to full conversion of substrate and similar enantioselectivity. Among these additives, the use of 1-bromo-3-chloro-5,5-dimethyl-hydantoin (BCDMH) led to the isolation of product with slightly superior ee value (83 % ee ; Table 1, entry 10). The effect of the nature of the ligand on the reaction was then investigated by employing BCDMH as the halogen source in combination with iridium catalysts that were generated from [Ir(cod)Cl]2 and a diverse array of commercially available ligands (Table 1, entries 10–13). Disappointingly, no ligand gave a better result than the ligand used in the initial screening of reaction conditions (L1). Dynamic kinetic resolution (DKR), which is a powerful tool for accessing enantioenriched compounds, has been successfully applied in asymmetric hydrogenation. In our previous research on asymmetric hydrogenation of 2,3-disubstituted quinolines and indoles, an interesting DKR phenomenon was also observed. 4h] For the asymmetric hydrogenation of 3,4-disubstituted isoquinolines, a dynamic kinetic resolution process was involved (see below). In Scheme 1. Asymmetric hydrogenation of isoquinoline.

Efficient Synthesis of β-CF3/SCF3-Substituted Carbonyls via Copper-Catalyzed Electrophilic Ring-Opening Cross-Coupling of Cyclopropanols

The first copper-catalyzed ring-opening electrophilic trifluoromethylation and trifluoromethylthiolation of cyclopropanols to form Csp3-CF3 and Csp3-SCF3 bonds have been realized. These transformations are efficient for the synthesis of β-CF3- and β-SCF3-substituted carbonyl compounds that are otherwise challenging to access. The reaction conditions are mild and tolerate a wide range of functional groups. Application to a concise synthesis of LY2409021, a glucagon receptor antagonist that is used in clinical trials for type 2 diabetes mellitus, is reported as well.

Copper-Catalyzed Cyclopropanol Ring Opening Csp3–Csp3 Cross-Couplings with (Fluoro)Alkyl Halides

Novel and general copper-catalyzed cyclopropanol ring opening cross-coupling reactions with difluoroalkyl bromides, perfluoroalkyl iodides, monofluoroalkyl bromides, and 2-bromo-2-alkylesters to synthesize various β-(fluoro)alkylated ketones are reported. The reactions feature mild conditions and excellent functional group compatibility and can be scaled up to gram scale. Preliminary mechanistic studies suggest the involvement of radical intermediates. The difluoroalkyl-alkyl cross-coupling products can also be readily converted to more valuable and diverse gem-difluoro-containing compounds by taking advantage of the carbonyl group resulting from cyclopropanol ring opening.

Rhodium‐Catalyzed Cascade Reaction: Aryl Addition/Intramolecular Esterification to Access 3‐Aryl and 3‐Alkenyl Phthalides

Phthalides (isobenzofuranone), a family of five-membered lactones in plants, are important building blocks in a large number of biologically active compounds. 3-Arylphthalides, for example, are useful intermediates for the synthesis of triand tetracyclic natural products such as anthracycline antibiotics. Approaches have been developed for the synthesis of these organic skeletons. The tandem carbonylation of benzylic alcohol and ortho-halo benzylic alcohol with subsequent cyclization to access phthalides have been reported by Cowell and Stille, and Larock and Fellows, respectively. In 2006, Chan and Scheidt described the NHC-catalyzed (NHC = N-heterocyclic carbene) intramolecular hydroacylation of 2-benzoylbenzaldehyde to afford phthalides in moderate yield. Lin and co-workers reported the catalytic enantioselective synthesis of chiral phthalides by efficient reductive cyclization of 2-acylarylcarboxylates. However, the development of a simple and efficient method to access 3arylphthalide still remains a highly desirable goal in synthetic chemistry. The transition metal catalyzed functionalization of the aldehyde C H bond is a straightforward and atom-economical way to construct complex organic molecules. In 2009, Onomura and co-workers reported a palladium-catalyzed arylation of methyl 2-formylbenzoate with organoboronic acids for the efficient synthesis of 3-arylphthalides. Recently, Dong and co-workers demonstrated an elegant example of rhodium-catalyzed intramolecular ketone hydroacylation. Subsequently, Dong and co-workers reported an atom-economical approach to phthalides by enantioselective C H functionalization. We envisioned a fundamentally different approach to lactonization based on this methodology (Scheme 1). Herein, we report a novel and facile strategy to obtain phthalide starting from commercially available phthalaldehyde and arylboronic acids based on the well-developed rhodium-catalyzed addition of arylboronic acids to aldehydes. We initiated our investigation by examining the reaction of phthalaldehyde and phenylboronic acid (Table 1). During the survey of rhodium sources, to our delight, phthalide was produced in 43 % yield in the presence of [{Rh(cod)Cl}2], dppb, and K2CO3 in THF (entry 3, Table 1). The influence of bases was investigated, and K2CO3 gave the best outcome (entries 3–6, Table 1). When we replaced THF with ClCH2CH2Cl, the yield dramatically increased to 83% (entry 10, Table 1). In addition to dppb, we compared the effects of several phosphino ligands, such as dppp, dppe, dppf, P(1-nap)3 and PPh3. Of these, dppb and P(1-nap)3 showed the