Highly Enantioselective Organocatalytic Hydroxyalkylation of Indoles with Ethyl Trifluoropyruvate

Török, Béla; Abid, Mohammed; London, Gábor; Esquibel, Joseph; Török, Marianna; Mhadgut, Shilpa C.; Yan, Ping; Prakash, G. K. Surya

doi:10.1002/anie.200462877

Cited by 187 publications

(29 citation statements)

References 30 publications

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“…Catalytic elaboration at the C-3 position of indoles in particular has received considerable attention. [39,40] The C-3-alkylation of indoles is a well-documented process [41][42][43] that takes advantage of the electron-rich nature of this position, which can be viewed as possessing enamine-like character. In contrast, the electron-deficient nature of the pyridine moiety, which reduces the overall nucleophilicity of the 7-azaindole system, causes inertness of the 3-position of azaindoles when compared to that of indoles.…”

Section: Introductionmentioning

confidence: 99%

Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

et al. 2006

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The AuIII‐catalyzed reactions of 7‐azaindole derivatives with α,β‐enones are described. Factors that can direct the C‐3‐ versus N‐1‐alkylation reaction on the 7‐azaindole nucleus are explored. The AuIII‐catalyzed reaction of 7‐azaindole with β‐unsubstituted α,β‐enones afforded 1‐substituted7‐azaindoles through an aza‐Michael‐type reaction. Incontrast, 6‐substituted 7‐azaindoles underwent regioselective C‐3‐alkylation through a Na[AuCl4]·2H2O‐catalyzed conjugate addition‐type reaction. Analogously, the Na[AuCl4]·2H2O‐catalyzed reaction of 7‐azaindole derivatives with β‐aryl‐substituted α,β‐enones gave 3‐substituted 7‐azaindoles in moderate‐to‐satisfactory yields. Moreover, the Na[AuCl4]·2H2O‐catalyzed reaction of 1‐substituted 7‐azaindoles with α,β‐enones allowed an easy entry to 1,3‐disubstituted 7‐azaindoles in moderate‐to‐high yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Section: Introductionmentioning

confidence: 99%

Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

et al. 2006

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“…The synthesis of the compounds has been carried out based on our earlier work using cinchonidine (CD) and cinchonine (CN) organocatalysts 20 , †. While CD provided the ( S )-products, CN resulted in the formation of the ( R )-enantiomers (Fig.…”

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confidence: 99%

Effect of chirality of small molecule organofluorine inhibitors of amyloid self-assembly on inhibitor potency

Sood

Abid

Hailemichael

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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The effect of enantiomeric trifluromethyl-indolyl-acetic acid ethyl esters on the fibrillogenesis of Alzheimer's amyloid β (Aβ) peptide is described. These compounds have been previously identified as effective inhibitors of the Aβ self-assembly in their racemic form. Thioflavin-T Fluorescence Spectroscopy and Atomic Force Microscopy were applied to assess the potency of the chiral target compounds. Both enantiomers showed significant inhibition in the in vitro assays. The potency of the enantiomeric inhibitors appeared to be very similar to each other suggesting the lack of the stereospecific binding interactions between these small molecule inhibitors and the Aβ peptide.Amyloid formation, either beneficial or harmful, is central to many life processes. Such protein deposits are associated with several human diseases, including the Alzheimer's disease. [1][2][3][4][5][6] As a possible therapeutic option, the theory of self-assembly inhibition of Alzheimer's amyloidbeta (Aβ) peptide has been widely tested and many effective inhibitors have been described, usually in two broadly defined categories: small molecule and peptide-based inhibitors. [6][7][8][9][10][11][12] Among these inhibitors there are several compounds, either natural or synthetic, that are chiral. However, the role of molecular chirality during the self-assembly is poorly understood and only sporadically investigated. There are many reasons to broaden these investigations. First, if such molecules ever reach the clinical trial phase, data regarding both enantiomers of a drug candidate are required. Aside from this practical reason, the role of chirality in the design and action of Aβ inhibitors is still unclear. The literature appears to be very limited on this issue. A recent study on amyloid type fibrils, including Aβ, reported the formation of specific amyloid suprastructures of helical chirality indicating that Aβ is sensitive to a chiral environment. 13 Regarding inhibition-related investigations similar conclusions were drawn by Chalifour et al. using peptide-based inhibitors. 14 The authors observed that peptide inhibitors assembled from the unnatural D-enantiomer of the amino acids exhibited significantly stronger potency in inhibition than that of the peptides synthesized from L-amino acids. 14 In contrast, using both enantiomers of nicotine, an alkaloid, in Aβ self-assembly and neurotoxicity inhibition Allsop et al. found that the absolute configuration did not play a significant role in determining potency. 15 The two nicotine enantiomers showed consistent activity within ∼10% range. Based on their studies the authors concluded that the effect of nicotine cannot be due to a stereospecific binding between the alkaloid and the peptide. 15 Correspondence to: Marianna Török. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of ...

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“…High enantioselectivity is commonly obtained at lower temperatures where the rate of the reactions might drop dramatically. Our success in enantioselective catalytic applications with ethyl trifluoropyruvate (ETFP) and its imine, [30,31] prompted us to further explore the use of this valuable synthon. Herein, we describe the first example of subzero temperature (-25°C) enantioselective reaction assisted with microwave irradiation.…”

Section: Introductionmentioning

confidence: 99%

Highly Enantioselective Organocatalytic Addition of Ethyl Trifluoropyruvate to Ketones with Subzero Temperature Microwave Activation

Landge

Török

2009

Catal Lett

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An enantioselective organocatalytic microwave-assisted method for the addition of ethyl trifluoropyruvate to ketones to synthesize highly enantiomerically enriched organofluorine synthons is described. Besides the high yields, diastereo-and enantioselectivities, the most important observation is that the use of microwave irradiation at subzero temperatures proved to be beneficial. The results indicate that subzero temperature microwave chemistry is a potentially intriguing tool for asymmetric synthesis.

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Highly Enantioselective Organocatalytic Hydroxyalkylation of Indoles with Ethyl Trifluoropyruvate

Cited by 187 publications

References 30 publications

Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

Gold‐Catalyzed C‐3‐Alkylation of 7‐Azaindoles Through Michael‐Type Addition to α,β‐Enones

Effect of chirality of small molecule organofluorine inhibitors of amyloid self-assembly on inhibitor potency

Highly Enantioselective Organocatalytic Addition of Ethyl Trifluoropyruvate to Ketones with Subzero Temperature Microwave Activation

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