Katalytische asymmetrische Fluorierungen

Brunet, Vincent A.; O’Hagan, David

doi:10.1002/ange.200704700

Cited by 59 publications

(6 citation statements)

References 34 publications

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“…For example, saturated afluoroesters or acids can be obtained after a simple hydrogenation step, with the chiral center staying untouched [Eqs. (2) and (3)]. The optical rotation of 33 is comparable to the literature value.…”

supporting

confidence: 80%

“…[1] Thus, the development of catalytic enantioselective CÀF bond-formation processes has become an important area in organic synthesis. [2] In particular, the stereocontrolled fluorination at the a position of a carbonyl group has been intensively explored. [3,4] Since the first report by Hintermann and Togni in 2000, [3a] a range of catalytic enantioselective a fluorination of carbonyl compounds have been developed.…”

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confidence: 99%

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Enantioselective Synthesis of β,γ‐Unsaturated α‐Fluoroesters Catalyzed by N‐Heterocyclic Carbenes

et al. 2012

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Chiral organofluorine compounds have attracted increasing attention because of their valuable applications in pharmaceutical, agrochemical, and materials industries.[1] Thus, the development of catalytic enantioselective CÀF bond-formation processes has become an important area in organic synthesis. [2] In particular, the stereocontrolled fluorination at the a position of a carbonyl group has been intensively explored. [3,4] Since the first report by Hintermann and Togni in 2000, [3a] a range of catalytic enantioselective a fluorination of carbonyl compounds have been developed. [3,4] Despite the significant progress, there remains a great need for further development of useful enantioselective fluorination processes. For example, organocatalyzed asymmetric fluorination for the synthesis of simple a-fluoroesters remains unknown. Herein, we report the first enantioselective fluorination reaction catalyzed by N-heterocyclic carbenes (NHCs).NHCs are well-known for their unique capability in reversing the polarity of aldehydes.[5] For example, in the presence of an NHC catalyst, the carbonyl carbon atoms of simple aldehydes (acyl anion equivalents), the a position of aldehydes with a leaving group at this position (enolates), and the b position of enals (homoenolates) can be rendered nucleophilic.[5] Very recently, Chi and co-workers have also demonstrated the generation of dienolates in which the g position is nucleophilic.[6] Thus, a range of new NHCcatalyzed bond-forming processes for functionalization at the a, b, and g positions of carbonyl carbon atoms of aldehydes have been developed with different electrophiles. However, NHC-catalyzed enantioselective carbonÀhalogen bond formation, a family of important processes with paramount utility, has not been realized. [7] In this work, we targeted the challenging fluorination.Previously, we have reported an NHC-catalyzed redox reaction of alkynals that bear a leaving group in g position for the synthesis of allenoates through a key cumulative allenolate intermediate. [8] In continuation of our effort, we hypothesized that enals that bear a leaving group in g position would provide access to an NHC-bound dienolate (Scheme 1), which is expected to subsequently react with an electrophilic fluorinating reagent and a nucleophile to afford a fluorinated product. We also expected that a chiral NHC would induce enantioselective CÀF bond formation. However, during executing the hypothesized reaction, several challenges may be encountered: 1) There might be a regioselectivity issue, because both the a and g positions are nucleophilic. 2) The mono-fluorinated product is quite easily deprotonated for a second fluorination, thereby invoking competing difluorination. 3) Instead of CÀF bond formation, the dienolate can undergo protonation at the a or g position to afford a nonfluorinated product. 4) It is not trivial to control the facial selectivity, given the extremely high reactivity of electrophilic fluorine and the small size of the fluorine atom. 5) The typical basic conditio...

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confidence: 99%

Enantioselective Synthesis of β,γ‐Unsaturated α‐Fluoroesters Catalyzed by N‐Heterocyclic Carbenes

et al. 2012

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“…[2] Thus, there is a strong demand to increase synthetic capabilities to construct building blocks containing a monofluoromethyl group, particularly enantiopure ones. [3] Alcohols bearing b,g-dimethyl groups are important structural features in a large number of biologically active natu-ral products and drugs. [4] For instance, (+)-pinnatoxin A (Scheme 1) was reported to be an activator of calcium channels.…”

Section: Introductionmentioning

confidence: 99%

Highly Enantio‐ and Diastereoselective Synthesis of β‐Methyl‐γ‐monofluoromethyl‐Substituted Alcohols

Yang

Wei

Pan

et al. 2011

Chemistry A European J

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Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.

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mentioning

confidence: 99%

Enantioselective Synthesis of β,γ‐Unsaturated α‐Fluoroesters Catalyzed by N‐Heterocyclic Carbenes

et al. 2012

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Chiral organofluorine compounds have attracted increasing attention because of their valuable applications in pharmaceutical, agrochemical, and materials industries. [1] Thus, the development of catalytic enantioselective CÀF bond-formation processes has become an important area in organic synthesis. [2] In particular, the stereocontrolled fluorination at the a position of a carbonyl group has been intensively explored. [3,4] Since the first report by Hintermann and Togni in 2000, [3a] a range of catalytic enantioselective a fluorination of carbonyl compounds have been developed. [3,4] Despite the significant progress, there remains a great need for further development of useful enantioselective fluorination processes. For example, organocatalyzed asymmetric fluorination for the synthesis of simple a-fluoroesters remains unknown. Herein, we report the first enantioselective fluorination reaction catalyzed by N-heterocyclic carbenes (NHCs).NHCs are well-known for their unique capability in reversing the polarity of aldehydes. [5] For example, in the presence of an NHC catalyst, the carbonyl carbon atoms of simple aldehydes (acyl anion equivalents), the a position of aldehydes with a leaving group at this position (enolates), and the b position of enals (homoenolates) can be rendered nucleophilic. [5] Very recently, Chi and co-workers have also demonstrated the generation of dienolates in which the g position is nucleophilic. [6] Thus, a range of new NHCcatalyzed bond-forming processes for functionalization at the a, b, and g positions of carbonyl carbon atoms of aldehydes have been developed with different electrophiles. However, NHC-catalyzed enantioselective carbonÀhalogen bond formation, a family of important processes with paramount utility, has not been realized. [7] In this work, we targeted the challenging fluorination.Previously, we have reported an NHC-catalyzed redox reaction of alkynals that bear a leaving group in g position for the synthesis of allenoates through a key cumulative allenolate intermediate. [8] In continuation of our effort, we hypothesized that enals that bear a leaving group in g position would provide access to an NHC-bound dienolate (Scheme 1), which is expected to subsequently react with an electrophilic fluorinating reagent and a nucleophile to afford a fluorinated product. We also expected that a chiral NHC would induce enantioselective CÀF bond formation. However, during executing the hypothesized reaction, several challenges may be encountered: 1) There might be a regioselectivity issue, because both the a and g positions are nucleophilic. 2) The mono-fluorinated product is quite easily deprotonated for a second fluorination, thereby invoking competing difluorination. 3) Instead of CÀF bond formation, the dienolate can undergo protonation at the a or g position to afford a nonfluorinated product. 4) It is not trivial to control the facial selectivity, given the extremely high reactivity of electrophilic fluorine and the small size of the fluorine atom. 5) The typical basic con...

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Katalytische asymmetrische Fluorierungen

Cited by 59 publications

References 34 publications

Enantioselective Synthesis of β,γ‐Unsaturated α‐Fluoroesters Catalyzed by N‐Heterocyclic Carbenes

Enantioselective Synthesis of β,γ‐Unsaturated α‐Fluoroesters Catalyzed by N‐Heterocyclic Carbenes

Highly Enantio‐ and Diastereoselective Synthesis of β‐Methyl‐γ‐monofluoromethyl‐Substituted Alcohols

Enantioselective Synthesis of β,γ‐Unsaturated α‐Fluoroesters Catalyzed by N‐Heterocyclic Carbenes

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