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Chiral indolines are ubiquitous structural motifs in naturally occurring alkaloids and many biological active molecules. 1 Some catalytic methods have been developed to obtain such molecules on the basis of the kinetic resolution. 2 Asymmetric hydrogenation of indoles is the most straight and powerful approach to make chiral indolines in terms of simplicity and atom efficiency. Despite the progress achieved in asymmetric hydrogenation of indoles and other heteroaromatic compounds in the past decade, 3 efficient hydrogenation of simple unprotected indoles remains a great challenge in organic synthesis. Kuwano and Ito developed the first highly effective hydrogenation of a series of N-protected indoles by application of a Rh or Ru complex. 4a-d Feringa and co-workers reported Rh-catalyzed hydrogenation of 2-substituted N-protected indoles with moderate enantioselectivity. 4e Very recently, the Pfaltz group revealed Ir/N,P-catalyzed hydrogenation of N-protected indoles with high ee but low reactivity. 4f To the best of our knowledge, no report on asymmetric hydrogenation of unprotected indoles has appeared despite the operational simplicity. 5 Herein, we describe a new strategy for highly enantioselective Pd-catalyzed hydrogenation of unprotected indoles with a Brønsted acid as the activator with up to 96% ee.For the asymmetric hydrogenation of aromatics, the main challenge is the low reactivity. 3 Recently, our group developed two kinds of substrate activation strategies for the asymmetric hydrogenation of six-membered heteroaromatics with a Brønsted acid and chloroformate as activators, respectively. 6 Another breakthrough in hydrogenation of imines is through formation of iminium by addition of a Brønsted acid. 7 We envision that in searching hydrogenation of five-membered heteroaromatic unprotected indoles, development of a new activation strategy is highly desirable. Considering that the simple unprotected indoles can react with a strong Brønsted acid to form the iminium salt by protonation of the carbon-carbon double bond, 8 and the aromaticity of indole is destroyed, the in situ formed iminium salts would be prone to be hydrogenated (Scheme 1).Initially, 2-methylindole was selected as a model substrate for optimization of the conditions. Recently, chiral palladium complexes have been successfully applied to asymmetric hydrogenation of activated imines by us 9 and other groups, 10 due to similarity between iminium salt and activated imine, and thus Pd(OCOCF 3 ) 2 /(R)-SegPhos was used as the catalyst. In a control experiment, without the addition of a Brønsted acid, the reaction did not occur. When the stoichiometric amount of trifluoroacetic acid was added, the reaction proceeded smoothly to give the expected 2a with full conversion and 8% ee. Screening of different acids found that L-camphorsulfonic acid (L-CSA) gave the best result (Table 1, entry 1). 11,12 Solvent experiments showed that mixture solvent DCM/TFE was the best choice (entry 8, 85% ee). Subsequently, various commercially available chiral b...

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Extensive effort has been devoted to engineering flavin-dependent halogenases (FDHs) with improved stability, expanded substrate scope, and altered regioselectivity. Here we show that variants of rebeccamycin halogenase (RebH) catalyze enantioselective desymmetrization of methylenedianilines via halogenation of these substrates distal to their pro-stereogenic center. Structure-guided engineering was used to increase the conversion and selectivity of these reactions, and the synthetic utility of the halogenated products was shown via conversion of to a chiral α-substituted indole. These results constitute the first reported examples of asymmetric catalysis by FDHs.

Triazole‐phosphine‐copper complexes (TAP−Cu) have been synthesized and applied as tunable and efficient catalysts for the selective synthesis of fluoro‐substituted 2‐aryl‐1H‐benzo[d]imidazole and 1‐benzyl‐2‐aryl‐1H‐benzo[d]imidazole derivatives from simple alcohols in only one step. TAP−Cu exhibited excellent and tunable catalytic activity for both dehydrogenation and borrowing hydrogen reactions with more than 80 examples being demonstrated for the first time. It was observed that the ligand played a critical role in catalyst activity. Mechanistic studies and deuterium labeling experiments indicated that the reactions proceeded by an initial and reversible alcohol dehydrogenation resulting in a copper hydride intermediate. This was also supported by the direct observation of a diagnostic copper hydride signal by solid‐state infrared spectroscopy. The TAP−Cu‐H complex showed absorptions at 912 cm−1 that could be assigned to copper−hydride stretches. Furthermore, the direct trapping of an intermediate bisimine was also successfully performed.magnified image

A convergent asymmetric disproportionation of dihydroquinoxalines for the synthesis of chiral tetrahydroquinoxalines using a metal/Brønsted acid relay catalysis system has been developed. The use of hydrogen gas as the reductant makes the convergent disproportionation an ideal atom-economical process. A dramatic reversal of enantioselectivity was observed in the reduction of quinoxalines because of the different steric demands in the 1,2- and 1,4-hydride transfer pathways.

The enantioselective hydrogenation of 2-benzylquinolines and 2-functionalized and 2,3-disubstituted quinolines was developed by using the [Ir(COD)Cl](2)/bisphosphine/I(2) system with up to 96% ee. Moreover, mechanistic studies revealed the hydrogenation mechanism of quinoline involves a 1,4-hydride addition, isomerization, and 1,2-hydride addition, and the catalytic active species may be a Ir(III) complex with chloride and iodide.

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.T he asymmetric hydrogenation of aromatic compounds offers straightforward access to chiral molecules with cyclic skeletons and has received much attention over the past decades. 1 Some bicyclic heteroaromatic substrates have been successfully hydrogenated because of their relatively low aromaticity (quinolines, isoquinolines, quinoxalines, indoles, and benzofurans). 2À6 This process is much more difficult for single-ring heteroaromatic compounds, although hitherto, special activated pyridines 7 and furans 6 have been successfully hydrogenated, and a single elegant example of asymmetric hydrogenation of N-Boc-protected pyrroles using a chiral Ru catalyst was reported by Kuwano and coworkers. 8 To the best of our knowledge, no report on the asymmetric hydrogenation of simple pyrroles has appeared, despite its potential usefulness. 9 Thus, the exploration of a new strategy for hydrogenation of simple pyrroles is urgently needed and of great significance.Very recently, we disclosed the Brønsted acid-activated asymmetric hydrogenation of simple indoles 5h,i using a homogeneous palladium catalyst. 10,11 As part of our ongoing effort to develop new strategies for asymmetric hydrogenation of heteroaromatic compounds and considering the similarity of pyrroles and indoles, we envisioned that electron-enriched pyrroles could be protonated in the presence of strong Brønsted acids, which would destroy their aromaticity thus be suitable for facilitating hydrogenation. Herein we report the results of our preliminary investigation of asymmetric hydrogenation of simple 2,5-disubstituted pyrroles, wherein partially hydrogenated 1-pyrrolines were obtained with up to 92% ee.Initially, 2-methyl-5-phenylpyrrole (1a) was selected as a model substrate for optimization of the reaction conditions. Pd(OCOCF 3 ) 2 /(R)-BINAP was employed as the catalyst with ethylsulfonic acid (EtSO 3 H) as the activator. When the reaction was carried out at 60°C, it proceeded smoothly, affording the unexpected product 5-methyl-2-phenyl-1-pyrroline (2a) in 70% yield with 71% ee; no pyrrolidine was detected in the reaction mixture (Table 1, entry 1). It is noteworthy that this is the first example of asymmetric hydrogenation of a pyrrole to obtain a