Ethyl α-Fluoro Silyl Enol Ether:  Stereoselective Synthesis and Its Aldol Reaction with Aldehydes and Ketones

Huang, Xiao‐Ting; Chen, Qing‐Yun

doi:10.1021/jo010820+

Cited by 23 publications

(11 citation statements)

References 11 publications

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“…Stereoselective CÀCbond formation could provide acomplementary approach for controlling fluorine-bearing stereocentres (Scheme 1). However,aldol (and related) reactions of esters of fluoroacetic acid generally exhibit poor diastereoselectivity (e.g.r eactions of lithium enolates, [8] Reformatsky reactions [9] and Mukayama aldol reactions [10] ). In any case,the reactants typically used in such aldol reactions (ethyl fluoroacetate and sodium fluoroacetate) are toxic.…”

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confidence: 99%

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

et al. 2016

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The trans‐o‐hydroxybenzylidene pyruvate aldolase‐catalysed reactions between fluoropyruvate and many (hetero)aromatic aldehydes yield aldol adducts without subsequent dehydration. Treatment of the reaction products with hydrogen peroxide yields the corresponding syn‐configured α‐fluoro β‐hydroxy carboxylic acids which have >98 % ee. The overall chemoenzymatic approach, in which fluoropyruvate serves as a fluoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.

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confidence: 99%

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

et al. 2016

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confidence: 99%

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

et al. 2016

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The trans-o-hydroxybenzylidene pyruvate aldolasecatalysed reactions between fluoropyruvate and many (hetero)aromatic aldehydes yield aldol adducts without subsequent dehydration. Treatment of the reaction products with hydrogen peroxide yields the corresponding syn-configured afluoro b-hydroxy carboxylic acids which have > 98 %ee. The overall chemoenzymatic approach,i nw hich fluoropyruvate serves as af luoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.Fluorination can profoundly affect the conformation, bioavailability,m etabolism, pharmacokinetics and pharmacodynamics of bioactive small molecules.[1] Thei ntroduction of fluorine is therefore widely used to tune biological function, and around 20 %ofleading drugs contain at least one fluorine atom [2] (10 of the top 50 drugs in 2013 by US prescription [3] ). Examples of leading fluorinated pharmaceuticals include the cholesterol-lowering drug Rosuvastatin [4] and the antidiabetic drug Sitagliptin. [4] Thec ontrolled formation of fluorine-substituted stereocentres,h owever, presents as ignificant challenge.M ost usually,t he challenge is addressed by stereoselective CÀF bond formation. Fore xample,t he fluorination of allylic silanes is often diastereoselective, [5] and organo- [6] and Pd- [7] catalysed methods enable the enantioselective a-fluorination of carbonyl compounds. Stereoselective CÀCbond formation could provide acomplementary approach for controlling fluorine-bearing stereocentres (Scheme 1). However,aldol (and related) reactions of esters of fluoroacetic acid generally exhibit poor diastereoselectivity (e.g.r eactions of lithium enolates, [8] Reformatsky reactions [9] and Mukayama aldol reactions [10]

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“…Ethyl (2S,3S)-2-fluoro-3-(4-methoxyphenyl)propanoate (2g): [39] The reaction was scaled by a factor of 100 compared to the screening reactions. Into a solution of 1g (200 mg, 0.823 mmol) in 1.67 mL methanol, was added KRED Mix N (1.91 g in 33.3 mL deionized H 2 O) and 33.3 mg ketoreductase.…”

Section: Kred Scale-up Reaction (100x)mentioning

confidence: 99%

“…After 24 h, the reaction was extracted by EtOAc (2 × 10 mL). The combined organic extract was dried with anhydrous Na 2 SO 4 and was subjected to 1 H, 13 [39] Mosher ester synthesis and analysis. An in-tube derivatization similar to that previously described was used to synthesize MPTA (α-methoxy-α-trifluoromethylphenylacetic acid) esters of the product alcohols.…”

Section: Kred Scale-up Reaction (100x)mentioning

confidence: 99%

Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

et al. 2019

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Racemic α‐fluoro‐β‐keto esters were stereoselectively transformed to α‐fluoro‐β‐hydroxy esters through dynamic reductive kinetic resolution (DYRKR) using commercially available NAD(P)H‐dependent ketoreductases. Aromatic, alkenyl, and alkyl substrates were all reduced in high optical purities and yields. For most substrates, either anti or syn diastereomers could be produced with high enantiomeric excess, depending on the enzyme employed. The enzyme reactions with ethyl α‐fluoroacetoacetate were conveniently monitored in real time by in situ 19F NMR spectroscopy. These commercially available enzymes provide convenient access to stereoisomers of α‐fluoro‐β‐hydroxy esters from easily accessible racemic substrates.

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Ethyl α-Fluoro Silyl Enol Ether: Stereoselective Synthesis and Its Aldol Reaction with Aldehydes and Ketones

Cited by 23 publications

References 11 publications

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

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