Access towards enantiopure α,α-difluoromethyl alcohols by means of sulfoxides as traceless chiral auxiliaries

Batisse, Chloé; Panossian, Armen; Hanquet, Gilles; Leroux, Frédéric R.

doi:10.1039/c8cc05571h

Cited by 21 publications

(22 citation statements)

References 57 publications

(13 reference statements)

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“…Although we could not determine the absolute stereochemistry of the predominant enantiomer, it was clear from the assay that there was a significant enantiomeric ratio (4:1) of 6 which translates to a 60% enantiomeric excess (ee, see Supporting Information File 1). We note that there have been chemical methods developed for the synthesis of enantiomerically enriched aryl fluoroalkyl sulfoxides, however, this appears to be the first enzymatic approach [23–25].…”

Section: Resultsmentioning

confidence: 99%

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

Rodil¹,

Slawin²,

Al‐Maharik³

et al. 2019

Beilstein J. Org. Chem.

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We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substituent for bioactives discovery chemistry. Incubation of two aryl–SCF2CH3 ethers with the model yeast organism Cunninghamella elegans, indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more slowly to the sulfone. When the substrate was (p-OMe)PhSCF2CH3, then the resultant (demethylated) phenol sulfoxide had an enantiomeric excess of 60%, and when the substrate was the β-substituted-SCF2CH3 naphthalene, then the enantiomeric excess of the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether (p-OMe)PhOCF2CH3, which was converted to the (demethylated) phenol acetate ester during C. elegans incubation. We conclude that the aryl–S–CF2CH3 motif is metabolised in a similar manner to aryl–SCF3, a motif that is being widely explored in discovery chemistry. It is however, significantly less lipophilic than aryl-SCF3 which may offer a practical advantage in tuning overall pharmacokinetic profiles of molecules in development.

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Section: Resultsmentioning

confidence: 99%

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

Rodil¹,

Slawin²,

Al‐Maharik³

et al. 2019

Beilstein J. Org. Chem.

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“…After separation of the diastereomers of the α,α-difluoro-β-hydroxysulfoxides and removal of the chiral auxiliary, this strategy allows to access highly enantioenriched α-difluoromethyl alcohols (Scheme 1). 8 The presence of a sulfanyl, sulfinyl or sulfonyl group in α position of a carbanion is known to stabilize this anionic species. This effect has therefore been widely explored and discussed over the last decades.…”

Section: Description Of the Strategymentioning

confidence: 99%

“…In our case, the use of an enantiopure difluoromethyl sulfoxide was required to access highly enantioenriched α,α-difluoro-βhydroxysulfoxides and α-difluoromethyl alcohols (Scheme 1). 8 This strategy will be discussed in detail in this paper. We will first present the numerous trials that were carried out in the aim of synthesizing an enantiopure aryl difluoromethyl sulfoxide.…”

Section: A R T I C L E I N F O Abstractmentioning

confidence: 99%

“…In this way, the pre-activation of zinc powder is not necessary. Finally, and as previously described, 8 highly enantioenriched difluoromethyl p-tolyl sulfoxide (SS)-4a was obtained after decarboxylation of enantioenriched sulfinylester (SS)-7a, followed by recrystallisation from diethyl ether.…”

Section: Scheme 4 Preparation Of a Less Electron-deficient Sulfide Amentioning

confidence: 99%

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Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

et al. 2019

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The-CHF2 moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of difluoromethylated compounds. However, the more challenging enantioselective introduction of the difluoromethyl group has been scarcely described yet. We recently developed a new strategy, based on the use of an enantiopure difluoromethyl sulfoxide used as chiral and traceless auxiliary, for the synthesis of highly enantioenriched αdifluoromethyl alcohols. 8 The first method developed in our laboratory aims to access highly stereoenriched α,α-difluoro-β-hydroxysulfoxides through the condensation of the enantiopure difluoromethyl sulfoxide on carbonyl derivatives. It is noteworthy that highly diastereo-and enantioenriched α,α-difluoro-β-hydroxysulfoxides can also be accessed after the diastereoselective reduction of highly enantioenriched α,α-difluoro-β-ketosulfoxides. Finally, the expected difluoromethyl-substituted alcohols can be obtained after removal of the chiral auxiliary with complete retention of stereoenrichment at carbon.

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“…In particular, their biological activity is promising. They are also key intermediates for trifluoromethyl-containing sulfoximine synthesis and are excellent chiral auxiliaries [2,3,4,5]. Synthetic approaches dedicated to trifluoromethyl sulfoxides include (1) trifluoromethylation of the corresponding sulfinyl halides or sulfinic esters using TMSCF 3 [6,7,8], (2) reaction of aromatic compounds with triflinate salts [9], (3) rearrangement of aryl triflinates in the presence of AlCl 3 [10], (4) trifluoromethanesulfinilation using Langlois’ system (CF 3 SO 2 Na/POCl 3 ) [11] or with 1-(trifluoromethylsulfinyl)-pyrrolidine-2,5-dione [12].…”

Section: Introductionmentioning

confidence: 99%

General, Practical and Selective Oxidation Protocol for CF3S into CF3S(O) Group

et al. 2019

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Access towards enantiopure α,α-difluoromethyl alcohols by means of sulfoxides as traceless chiral auxiliaries

Cited by 21 publications

References 57 publications

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

General, Practical and Selective Oxidation Protocol for CF3S into CF3S(O) Group

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