Enantioselective <i>gem</i>-Chlorofluorination of Active Methylene Compounds Using a Chiral Spiro Oxazoline Ligand

Shibatomi, Kazutaka; Narayama, Akira; Soga, Yoshinori; Muto, Tsubasa; Iwasa, Seiji

doi:10.1021/ol201007e

Cited by 88 publications

(24 citation statements)

References 25 publications

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“…However, although the desired α-chloroketone 2a was obtained in good yield, the resulting enantioselectivity was poor. We also examined the reaction with a chiral Lewis acid catalyst prepared from a spiro pyridyl monooxazoline ligand L1 and copper(II) trifluoromethanesulfonate because it is known to catalyse electrophilic halogenation of β-ketoesters with high enantioselectivity222324. However, the decarboxylative chlorination of 1a using this catalyst also proceeded with poor enantioselectivity.…”

Section: Resultsmentioning

confidence: 99%

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

et al. 2017

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Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via SN2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.

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Section: Resultsmentioning

confidence: 99%

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

et al. 2017

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“…Recently, we reported the enantioselective synthesis of α-chloro-α-fluoro-β-keto esters via the sequential chlorination–fluorination of β-keto esters with the Cu(II) complex of SPYMOX [9], a spiro chiral oxazoline ligand developed by our research group [9–12]. In that study, we succeeded in determining the absolute stereochemistry of the α-chloro-α-fluoro-β-keto ester 6 by the X-ray crystallographic analysis of its derivative 7 (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

“…Compound 8 was synthesized from 6 (94% de) according to the procedure reported in [9]. A flame-dried flask under argon was charged with 8 ( anti / syn = 10:1, 0.35 mmol) and 1,2-dichloroethane (2 mL).…”

Section: Methodsmentioning

confidence: 99%

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

Shibatomi¹,

Okimi²,

Abe³

et al. 2014

Beilstein J. Org. Chem.

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SummaryIn a previous study it was shown that the enantioselective α-fluorination of racemic α-chloroaldehydes with a chiral organocatalyst yielded the corresponding α-chloro-α-fluoroaldehydes with high enantioselectivity. It was also revealed that kinetic resolution of the starting aldehydes was involved in this asymmetric fluorination. This paper describes the determination of the absolute stereochemistry of a resulting α-chloro-α-fluoroaldehyde. Some information about the substrate scope and a possible reaction mechanism are also described which shed more light on the nature of this asymmetric fluorination reaction.

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“…[14,15] The subsequent substitution might follow a radical mechanism as delineated in Scheme 4; [16,31] however, a classical S N 2 mechanism, as proposed previously even for tertiary carbon atoms adjacent to carbonyl groups, cannot be ruled out. [32,33] Support for the intermediacy of iodinated compounds is gained from the observation that the use of molecular iodine allows for the isolation of ethyl-1-iodo-2-oxocyclohexanecarboxylate when 1 a is reacted with I 2 ; the substitution with NaN 3 then proceeds quite smoothly to produce 2 a (Scheme 4). Due to the low stability of the 2-iodo-3-oxoester intermediate at room temperature, this two-step sequence provides azide 2 a in poor overall yields, thus demonstrating the experimental advantage of the use of a high-yielding, one-pot protocol (Method B).…”

Section: Resultsmentioning

confidence: 99%

Practical Azidation of 1,3‐Dicarbonyls

Harschneck

Hummel

Kirsch

et al. 2011

Chemistry A European J

107

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An operationally simple, direct azidation of 1,3-dicarbonyl compounds has been developed. The reaction proceeds readily under ambient conditions using sodium azide and an iodine-based oxidant such as I(2) or 2-iodoxybenzoic acid (IBX)-SO(3)K/NaI. In particular, the latter method, as a new and well-balanced oxidizing agent, shows excellent functional group tolerance and substrate scope and thus allows access to a variety of tertiary 2-azido and 2,2-bisazido 1,3-dicarbonyl compounds that would be more difficult to access by using traditional methods. Because the azide-containing products easily undergo 1,3-dipolar cycloaddition with alkynes, our report represents a novel route to analogues of sensitive complex molecules.

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Enantioselective gem-Chlorofluorination of Active Methylene Compounds Using a Chiral Spiro Oxazoline Ligand

Cited by 88 publications

References 25 publications

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

Practical Azidation of 1,3‐Dicarbonyls

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