Enantioselective Friedel–Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids

Borkin, Dmitry; Landge, Shainaz M.; Török, Béla

doi:10.1002/chir.20982

Cited by 28 publications

(19 citation statements)

References 42 publications

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“…In some cases, we used our own earlier methods, [18–20] in the case of the remaining products literature analogies were applied. [21] A few selected chiral compounds were also synthesized by a cinchona alkaloid-catalyzed hydroxy-alkylation, [20, 22] to confirm the effect of inhibitor stereochemistry on the anti-aggregation potency, especially since in our earlier report only the anti-fibril effect was described. [17] …”

Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships of Organofluorine Inhibitors of β‐Amyloid Self‐Assembly

et al. 2012

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A broad group of structurally diverse small organofluorine inhibitors have been synthesized and evaluated in the self-assembly of amyloid β. The major goal was to generate a diverse library of compounds with the same functional group and observe general structural features that characterize the oligomer and fibril inhibitors, and ultimately find lead structures for further, focused inhibitor design. The common structural motifs in these compounds were the CF3-C-OH or CF3-C-NH groups that were proposed to be a binding unit in our earlier studies. A broad range of potential small molecule inhibitors were synthesized by adding different carbocyclic and heteroaromatic rings with an array of substituents, overall 106 molecules. The compounds were tested by standard methods, such as thioflavine T-fluorescence spectroscopy for following fibril formation, biotinyl-Aβ(1–42) single-site streptavidin-based assay for observing oligomer formation and atomic force microscopy for morphological studies. These assays yielded a number of structures that showed significant inhibition against either fibril or oligomer formation. A detailed analysis on the structure activity relationship of anti-fibril and -oligomer properties is provided. In addition, these data present further experimental evidence for the distinct nature of the fibril vs oligomer formation and that the interaction of the Aβ peptide with chiral small molecules is not stereospecific in nature.

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Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships of Organofluorine Inhibitors of β‐Amyloid Self‐Assembly

et al. 2012

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“…39,40 The N-substituted product can be obtained under kinetic control using a strong base or metal mediated reactions. 25 However, our recent mechanistic and DFT investigations showed that the outcome of this hydroxyalkylation reaction is highly dependent on the choice of the reaction conditions, especially the selection of the solvent.…”

Section: Resultsmentioning

confidence: 99%

Environmentally benign, microwave-assisted chemoselective N-hydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal

Schäfer¹,

Ellstrom²,

Sood³

et al. 2017

Arkivoc

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Dedicated to Prof. Kenneth Laali on the occasion of his 65 th birthday and life-long contributions to chemistryReceived 07-31-2017 Accepted 10-27-2017 Published on line 11-05-2017 AbstractThe chemoselective microwave-activated N-hydroxyalkylation of indoles using trifluoroacetaldehyde methylhemiacetal as the alkylating agent under mild conditions is described. The chemoselectivity of this reaction is determined by the solvent used. In dimethyl sulfoxide, the reaction occurs without the use of a strong base or a metal catalyst. This approach can be applied to a variety of different substituted indoles to obtain the corresponding N-alkylated products with high selectivity. The product 2,2,2-trifluoro-1-(1-H-indol-1-yl)ethanols combine two moieties of frequent pharmacological interest: the indole core and a CF 3 -group containing a hydroxyalkyl substituent.

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“…3‐Substituted‐2‐phenylindoles have been recognized as privileged structures in medicinal chemistry with a broad biological activity profile for G protein‐coupled receptor modulation . The available synthetic methods for the installation of the stereogenic, (trifluoromethyl)hydroxymethyl group at position 3 of indoles are presently limited to a radical cross‐dehydrogenative coupling and an enantioselective Friedel–Crafts reaction of indoles with trifluoroacetaldehyde, catalyzed by cinchona alkaloids . The latter approach, however, provides only very low enantioselectivities.…”

Section: Methodsmentioning

confidence: 99%

Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands

Brüning

Nagae

Käch

et al. 2019

Chemistry A European J

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The asymmetric hydrogenation of 2,2,2‐trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well‐defined chloride‐bridged dinuclear rhodium(III) complex bearing Josiphos‐type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2‐trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2‐phenyl‐3‐(haloacetyl)‐indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.

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Enantioselective Friedel–Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids

Cited by 28 publications

References 42 publications

Structure–Activity Relationships of Organofluorine Inhibitors of β‐Amyloid Self‐Assembly

Structure–Activity Relationships of Organofluorine Inhibitors of β‐Amyloid Self‐Assembly

Environmentally benign, microwave-assisted chemoselective N-hydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal

Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands

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