Asymmetric Synthesis of Indolines by Catalytic Enantioselective Reduction of 3<i>H</i>-Indoles

Rueping, Magnus; Brinkmann, Claus; Antonchick, Andrey P.; Atodiresei, Iuliana

doi:10.1021/ol1019234

Cited by 118 publications

(43 citation statements)

References 58 publications

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“…Our computations predict that remote sterics exert little stereocontrolling effect; this correlation is consistent with the reduction of all known cyclic imines involving Hantzsch esters, in which proximal sterics dictate the level of stereoinduction. An optimal catalyst for such a reaction has large proximal sterics, some examples where this general trend is observed are given in Table 3 25, 26, 27, 28. The catalyst entries 6 and 7 (Table 2) present similar proximal steric environments but yet the enantioselectivities are very different.…”

Section: Resultsmentioning

confidence: 85%

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

Reid

Goodman

2017

Chemistry A European J

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Choosing the optimal catalyst for a new transformation is challenging because the ideal molecular requirements of the catalyst for one reaction do not always simply translate to another. Large groups at the 3,3′ positions of the binaphthol rings are important for efficient stereoinduction but if they are too large this can lead to unusual or poor results. By applying a quantitative steric assessment of the substituents at the 3,3′ positions of the binaphthol ring, we have systematically studied the effect of modulating this group on enantioselectivity for a wide range of reactions involving imines, and verified this analysis using ONIOM calculations. We have shown that in most reactions, the stereochemical outcome depends on both proximal and remote sterics. Summarising detailed calculations into a simple qualitative model identifies and explains the steric features required for high selectivity. This model is consistent with seventy seven papers reporting reactions (over 1000 transformations in total), and provides a straightforward decision tree for selecting the best catalyst.

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Section: Resultsmentioning

confidence: 85%

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

Reid

Goodman

2017

Chemistry A European J

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“…[7] In contrast, Rueping et al presented the chiral Brønsted acid catalyzed transfer hydrogenation of 3H-indoles with Hantzsch dihydropyridine as the hydrogen source. [8] Nevertheless, to the best of our knowledge, there is no successful precedent on the direct asymmetric reduction of 1H-indoles to access chiral indolines under metal-free conditions despite the fantastic progress of organocatalysis over the past decade. [9] Recently we discovered a highly diastereoselective intramolecular direct imino-ene reaction of indoles tethered to an olefinic side chain at C3, in which a Lewis acid promoted enamine-imine isomerization of the indole through C3 protonation was key to its success.…”

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confidence: 99%

Direct Asymmetric Hydrosilylation of Indoles: Combined Lewis Base and Brønsted Acid Activation

et al. 2011

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In light of their occurrence in a broad spectrum of natural alkaloids and several important pharmaceutically active compounds, [1] such as those outlined in Scheme 1, enantioenriched indolines have triggered increasing attention in both the synthetic and medicinal chemistry communities. [2] While a variety of protocols, including traditional enzymatic or non-enzymatic kinetic resolutions, [3] and organicmolecule-or metal-mediated asymmetric transformations [4] have been described, the direct asymmetric reduction of prochiral indole precursors would be one of the most straightforward ways to make chiral indolines.[5] Thus, a few transition metal/chiral phosphine complexes, including Rh, Ru, and Ir, have been applied by the groups of Kuwano, Feringa, Pfaltz, and others to the asymmetric hydrogenation of indoles, but the methods usually suffer from a limited substrate scope and relatively harsh reaction conditions.[6] A noteworthy breakthrough was made by Zhou, Zhang, and coworkers who reported an elegant palladium-catalyzed enantioselective hydrogenation of unprotected indoles activated by Brønsted acids. [7] In contrast, Rueping et al. presented the chiral Brønsted acid catalyzed transfer hydrogenation of 3H-indoles with Hantzsch dihydropyridine as the hydrogen source.[8] Nevertheless, to the best of our knowledge, there is no successful precedent on the direct asymmetric reduction of 1H-indoles to access chiral indolines under metal-free conditions despite the fantastic progress of organocatalysis over the past decade.[9]Recently we discovered a highly diastereoselective intramolecular direct imino-ene reaction of indoles tethered to an olefinic side chain at C3, in which a Lewis acid promoted enamine-imine isomerization of the indole through C3 protonation was key to its success.[10] We also recognized that, for unprotected indoles, a similar C3 protonation would occur in the presence of suitable Brønsted acids, which would destroy the aromaticity of indoles and result in the formation of electrophilic indolenium ions.[11] We envisioned that the asymmetric reduction of indoles might be realized by utilizing a chiral organocatalytic system that is compatible with a Brønsted acid activation process. Herein we report our endeavors on the first direct enantioselective hydrosilylation of prochiral 1H-indoles by combined Brønsted acid/Lewis base activation (Scheme 2). [12] The initial investigation in the direct hydrosilylation of 2-methylindole (2 a) with excess HSiCl 3 was conducted by employing N,N-dimethylformamide (1 a; DMF) as the Lewis base catalyst at 0 8C. One equivalent of H 2 O was added to react with HSiCl 3 to generate a strong Brønsted acid, HCl. [13] The reaction was quite inspiring, and the desired indoline product 3 a was cleanly obtained in high yield after 24 hours Scheme 1. Representative chiral indoline derivatives.Scheme 2. Proposed direct asymmetric hydrosilylation of indoles through both Lewis base and Brønsted acid activations.

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“…The reaction proved to be general and the products were obtained in high yields (54-99%) (70-99% ee) (Figure 22.17) [43]. In addition, lowering the catalyst loading from 1 to 0.1 mol.% resulted in a lower conversion without any significant detrimental influence on the selectivity.…”

Section: Asymmetric Brønsted Acid Catalyzed Hydrogenation Of Indolesmentioning

confidence: 87%

“…Despite their utility, only a few catalytic systems have been reported for the reduction of these cyclic imines and they are restricted to alkyl-substituted derivates, particularly methyl-and ethyl-substituted ones [45]. Considering the success of the organocatalytic enantioselective transfer hydrogenation of imines [11a-c], quinolines [33,34], and indoles [43], it became apparent that the bio-inspired strategy could be applicable to the transfer hydrogenation of the whole set of imine containing heterocycles (Figure 22.18). Analogous to the previously reported procedure, it was anticipated that the chiral Brønsted acid would activate the substrates through catalytic protonation, thus enabling hydride transfer from the dihydropyridine to occur (Scheme 22.19).…”

Section: Asymmetric Brønsted Acid Catalyzed Hydrogenation Of Benzoxazmentioning

confidence: 99%

Bio‐Inspired Transfer Hydrogenations

Rueping

Schoepke

Atodiresei

et al. 2011

Biomimetic Organic Synthesis

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IntroductionThe demand for chiral molecules, particularly those with hydrogen as part of the stereogenic center, has increased in recent years, and intensive research has been carried out in both industry and academia to develop efficient methods for synthesizing such compounds [1]. In this context, significant attention has been devoted to the asymmetric hydrogenation of unsaturated compounds, for example, olefins, carbonyls, and imines, which is recognized as one of the most important and convenient routes to the corresponding optically active products [2]. So far, most of the enantioselective reductions rely on biological processes or transition metal catalyzed high-pressure hydrogenations, hydrosilylations, and transfer hydrogenations. Beside their high substrate specificity, the enzymatic processes sometimes suffer from undesired by-products, poor catalyst stability under the operational conditions, substrate and/or product inhibition, and problems with catalyst recovery. Likewise, despite the high reactivity and selectivity exhibited by the organometallic complexes employed in the metal-catalyzed processes, most of these protocols suffer from a limited number of substrates and difficulties with catalyst separation and recycling. Hence, an alternative approach to these chiral compounds would be of great value. Nature's Reductions: Dehydrogenases as a Role ModelEnzymes are catalysts that evolve in Nature and one of their characteristics is high selectivity. During biochemical transformations, enzymes are assisted by non-proteinogenic molecules called co-factors. For instance, nicotinamide adenine dinucleotide (NADH), one of the essential co-factors in Nature, serves as a hydride source for various biological reductions. The synthesis of the amino acid glutamate by the glutamate dehydrogenase (GDH) catalyzed reductive amination of 2-ketoglutarate represents one example (Equation 22.1). The reaction is reversible Biomimetic Organic Synthesis, First Edition. Edited by Erwan Poupon and Bastien Nay.

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Asymmetric Synthesis of Indolines by Catalytic Enantioselective Reduction of 3H-Indoles

Cited by 118 publications

References 58 publications

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

Direct Asymmetric Hydrosilylation of Indoles: Combined Lewis Base and Brønsted Acid Activation

Bio‐Inspired Transfer Hydrogenations

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