Highly Enantioselective Chlorination of β-Keto Esters and Subsequent S<sub>N</sub>2 Displacement of Tertiary Chlorides: A Flexible Method for the Construction of Quaternary Stereogenic Centers

Shibatomi, Kazutaka; Soga, Yoshinori; Narayama, Akira; Fujisawa, Ikuhide; Iwasa, Seiji

doi:10.1021/ja304806j

Cited by 136 publications

(69 citation statements)

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“…We recently revealed that the S N 2 reaction of α-chloro-β-ketoesters proceeds smoothly to give the corresponding α-heteroatom-substituted-β-ketoesters with retained enantiopurity, despite the reaction taking place at a tertiary carbon atom2324. Encouraged by this result, we examined the nucleophilic substitution of α-chloroketone 2a (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…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%

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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: 93%

Section: Resultsmentioning

confidence: 99%

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

et al. 2017

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“…Methyl (S)-2-Chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (7a) 11,15,24) Enantiomeric excess was determined by HPLC with ChiralPak AD-H column (hexane-2-propanol=95 : 5), flow rate=0.7 mL/min; λ=254 nm; t major =14.4 min, t minor =15.4 min.…”

Section: Experimental General Methods and Materialsmentioning

confidence: 99%

“…Several research groups have reported on the asymmetric chlorination of β-keto esters using metal catalysts. [6][7][8][9][10][11][12][13][14][15][16][17] Organocatalysis, meanwhile, has received considerable attention in the area of organic synthesis because, in comparison to reactions involving metal catalysts, it is an environmentally benign method. Synthetic methods for producing α-chlorinated compounds from β-keto esters using organocatalysts have also been developed.…”

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Asymmetric Chlorination of β-Keto Esters Using Diaminomethylenemalononitrile Organocatalyst

Sakai

Hirashima

Nakashima

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Diaminomethylenemalononitrile organocatalysts promote the asymmetric chlorination of simple cyclic β-keto esters such as methyl, ethyl, and benzyl esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid. This affords the corresponding chiral α-chlorinated carbonyl products in excellent yields with high enantioselectivities.Key words organocatalyst; asymmetric chlorination; β-keto ester Chiral α-chlorinated carbonyl compounds are valuable building blocks in the production of various biologically active compounds. [1][2][3][4][5] To synthesize enantiomerically enriched α-chlorinated carbonyl compounds, direct chlorination of carbonyl compounds using a chlorine source, such as N-chlorosuccinimide (NCS), is a reliable method. Several research groups have reported on the asymmetric chlorination of β-keto esters using metal catalysts.6-17) Organocatalysis, meanwhile, has received considerable attention in the area of organic synthesis because, in comparison to reactions involving metal catalysts, it is an environmentally benign method. Synthetic methods for producing α-chlorinated compounds from β-keto esters using organocatalysts have also been developed. [18][19][20][21][22][23][24] Although chiral α-chlorinated β-keto esters are valuable synthetic intermediates, their preparation using organocatalysts and NCS with high enantioselectivity (>80% enantiomeric excess (ee)) has rarely been reported upon.19-21) Several methods for the synthesis of chiral α-chlorinated β-keto esters require high catalyst loading (>5 mol%), a complex chlorine source, and bulky ester units such as the t-butyl and adamantyl groups. The highly stereoselective (>80% ee) α-chlorination of simple esters of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid, such as methyl, ethyl, and benzyl esters (6a-c), is very rare.12,18) Among the various chlorine sources, NCS is one of the best reagents because of its simple structure and low cost. The α-chlorination of a simple cyclic β-keto ester with NCS, in the presence of an organocatalyst (ca. 1 mol%), is therefore highly desirable, and it is one of the most challenging research topics.Recently, we reported on some asymmetric reactions using organocatalysts bearing diaminomethylenemalononitrile (DMM) or diaminomethyleneindenedione (DMI) motifs. [25][26][27][28][29][30][31][32] In order to further demonstrate the value of DMM organocatalysts, we attempted to apply them to the asymmetric α-chlorination of simple cyclic β-keto esters. Results and DiscussionWe examined organocatalysts 1-5 (Fig. 1) for an enantioselective α-chlorination of β-keto ester 6a, as shown in Table 1. DMM organocatalysts 1-3 with tertiary or secondary amine groups provided the desired product 7a in excellent yields with low enantioselectivities (entries 1-3). Organocatalyst 4, which bears a chiral primary amine group, accelerates the α-chlorination of 6a and gives 7a with good enantioselectivity

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“…Chirale hypervalente Iodverbindungen und verschiedene Reaktionsbedingungen wurden in der Synthese von 2 i untersucht (Tabelle 4). [38] Die absolute Konfiguration der Reaktionsprodukte wurde mit bekannten Verbindungen verglichen, [39] und in jedem Fall wurde die R-Konfiguration der Stereozentren bestätigt. Die hçchste Se-Schema 2.…”

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Flexible stereoselektive Funktionalisierung von Ketonen durch Umpolung mit hypervalenten Iodreagentien

Mizar

Wirth

2014

Angewandte Chemie

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Die Funktionalisierung von Carbonylverbindungen in der a-Position hat aufgrund der biologischen Bedeutung der Produkte große Aufmerksamkeit als Syntheseweg erhalten. Durch Polaritätsumkehr ("Umpolung") zeigen wir, dass Sauerstoff-, Stickstoff-und sogar Kohlenstoffnukleophile nach Anknüpfung an Enolether in Additionsreaktionen eingesetzt werden kçnnen. Unsere Resultate erçffnen die Mçglichkeit neuer Retrosynthesen und einer raschen Erzeugung von vorher nur in vielstufigen Synthesen zugänglichen Strukturen. Schema 1. Nukleophile Addition an Enolates mittels Umpolung. E + = Elektrophil, Nu À = Nukleophil, I III = Iod(III)-Reagens; Y, Z = Substituenten. ] Dieses Projekt wurde von der EU unterstützt (Marie-Curie-Stipendium für P.M.; DIALMEC, No. 298642). Wir danken der School of Chemistry, Cardiff University und der EPSRC National Mass Spectrometry Facility, Swansea.Hintergrundinformationen zu diesem Beitrag (eine Beschreibung aller Synthesemethoden einschließlich spektroskopischer und analytischer Daten) sind im WWW unter http://dx.

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Highly Enantioselective Chlorination of β-Keto Esters and Subsequent S_N2 Displacement of Tertiary Chlorides: A Flexible Method for the Construction of Quaternary Stereogenic Centers

Cited by 136 publications

References 46 publications

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Asymmetric Chlorination of β-Keto Esters Using Diaminomethylenemalononitrile Organocatalyst

Flexible stereoselektive Funktionalisierung von Ketonen durch Umpolung mit hypervalenten Iodreagentien

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Highly Enantioselective Chlorination of β-Keto Esters and Subsequent SN2 Displacement of Tertiary Chlorides: A Flexible Method for the Construction of Quaternary Stereogenic Centers

Cited by 136 publications

References 46 publications

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Enantioselective decarboxylative chlorination of β-ketocarboxylic acids

Asymmetric Chlorination of β-Keto Esters Using Diaminomethylenemalononitrile Organocatalyst

Flexible stereoselektive Funktionalisierung von Ketonen durch Umpolung mit hypervalenten Iodreagentien

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Product

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Highly Enantioselective Chlorination of β-Keto Esters and Subsequent S_N2 Displacement of Tertiary Chlorides: A Flexible Method for the Construction of Quaternary Stereogenic Centers