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Andreas Stolz - One of the best experts on this subject based on the ideXlab platform.
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Enzymatic cascade synthesis of (S)-2-hydroxycarboxylic amides and Acids: Cascade reactions employing a hydroxynitrile lyase, nitrile-converting enzymes and an amidase
Journal of Molecular Catalysis B: Enzymatic, 2015Co-Authors: Fred Van Rantwijk, Andreas StolzAbstract:Abstract Enantiomerically pure 2-hydroxycarboxylic Acids are valuable synthetic building blocks. This review summarises the development of bienzymatic cascades to convert aldehydes, via hydrocyanation and subsequent hydration or hydrolysis, into the corresponding (S)-2-hydroxycarboxylic amides and Acids. The biocatalysts comprised an (S)-specific hydroxynitrile lyase combined with a nonselective nitrile hydratase or nitrilase. The key to success was preventing racemisation of the intermediate (S)-2-hydroxynitrile while adequately protecting the nitrile-converting enzyme, either in a cross-linked enzyme aggregate (CLEA) or in resting cells. Two biocatalyst systems for the synthesis of (S)-mandelic Acid were developed: a combined crosslinked enzyme aggregate (combi-CLEA) of an (S)-hydroxynitrile lyase and a nitrilase, as well as a whole-cell Escherichia coli biocatalyst expressing both enzymes. The nitrilase formed large amounts of mandelic amide, which was remedied by including an amidase in the combi-CLEA as well as by using nitrilase variants obtained by directed mutagenesis in the whole-cell biocatalyst. Eventually, excellent results – >95% conversion of benzaldehyde into (S)-mandelic Acid with near-quantitative enantiomeric purity – were obtained with both biocatalyst systems. Directed mutagenesis of the nitrilase provided an amide-selective whole-cell biocatalyst, which produced (S)-mandelic amide in near-stoichiometric yields. (S)-2-hydroxylalkanoic carboxamides were synthesised in the presence of CLEAs of hydroxynitrile lyase and nitrile hydratase.
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The combi-CLEA approach: enzymatic cascade synthesis of enantiomerically pure (S)-mandelic Acid
Tetrahedron: Asymmetry, 2013Co-Authors: Andrzej Chmura, Sven Rustler, Monica Paravidino, Fred Van Rantwijk, Andreas Stolz, Roger A. SheldonAbstract:Abstract Enantiomerically pure ( S )-mandelic Acid was synthesised from benzaldehyde by sequential hydrocyanation and hydrolysis in a bienzymatic cascade at starting concentrations up to 0.25 M. A cross-linked enzyme aggregate (CLEA) composed of the ( S )-selective oxynitrilase from Manihot esculenta and the non-selective nitrilase from Pseudomonas fluorescens EBC 191 was employed as the biocatalyst. The nitrilase produces approx. equal amounts of ( S )-mandelic Acid and ( S )-mandelic amide from ( S )-mandelonitrile under standard conditions, but we surprisingly found that high (up to 0.5 M) concentrations of HCN induced a marked drift towards amide production. By including the amidase from Rhodococcus erythopolis in the CLEA we obtained ( S )-mandelic Acid as the sole product in 90% yield and >99% enantiomeric purity.
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Application of a Recombinant Escherichia coli Whole‐Cell Catalyst Expressing Hydroxynitrile Lyase and Nitrilase Activities in Ionic Liquids for the Production of (S)‐Mandelic Acid and (S)‐Mandeloamide
Advanced Synthesis & Catalysis, 2012Co-Authors: Stefanie Baum, Fred Van Rantwijk, Andreas StolzAbstract:The conversion of benzaldehyde and cyanide into mandelic Acid and mandeloamide by a recombinant Escherichia coli strain which simultaneously expressed an (S)-hydroxynitrile lyase (oxynitrilase) from cassava (Manihot esculenta) and an arylacetonitrilase from Pseudomonas fluorescens EBC191 was studied. Benzaldehyde exhibited a pronounced inhibitory effect on the nitrilase activity in concentrations ≥25 mM. Therefore, it was tested if two-phase systems consisting of a buffered aqueous phase and the ionic liquid 1-butyl-1-pyrrolidinium bis(trifluoromethanesulfonyl)imide (BMpl NTf2) or 1-butyl-3-methylimidazolium hexafluorophosphate (BMim PF6) could be used for the intended biotransformation. The distribution coefficients of the substrates, intermediates and products of the reaction were determined and it was found that BMpl NTf2 and BMim PF6 were highly efficient as substrate reservoirs for benzaldehyde. The recombinant E. coli strain was active in the presence of BMpl NTf2 or BMim PF6 phases and converted benzaldehyde and cyanide into mandelic Acid and mandeloamide. The two-phase systems allowed the conversion of benzaldehyde dissolved in the ionic liquids to a concentration of 700 mM with product yields (=sum of mandelic Acid and mandeloamide) of 87–100%. The cells were slightly more effective in the presence of BMpl NTf2 than in the presence of BMim PF6. In both two-phase systems benzaldehyde and cyanide were converted into (S)-mandeloamide and (S)-mandelic Acid with enantiomeric excesses ≥94%. The recombinant E. coli cells formed, in the two-phase systems with ionic liquids and increased substrate concentrations, higher relative amounts of mandeloamide than in a purely aqueous system with lower substrate concentrations.
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construction of recombinant escherichia coli catalysts which simultaneously express an s oxynitrilase and different nitrilase variants for the synthesis of s mandelic Acid and s mandelic amide from benzaldehyde and cyanide
Advanced Synthesis & Catalysis, 2009Co-Authors: Olga Sosedov, Andrzej Chmura, Fred Van Rantwijk, Josef Altenbuchner, Kathrin Matzer, Sibylle Burger, Christoph Kiziak, Stefanie Baum, Andreas StolzAbstract:Recombinant Escherichia coli strains were constructed which simultaneously expressed the genes encoding the (S)-oxynitrilase from cassava (Manihot esculenta) together with the wild-type or a mutant variant of the arylacetonitrilase from Pseudomonas fluorescens EBC191 in a single organism under the control of a rhamnose-inducible promoter. The whole cell catalysts obtained converted benzaldehyde and potassium cyanide in aqueous media at pH 5.2 mainly to (S)-mandelic Acid and/or (S)-mandelic amide and synthesized only low amounts of the corresponding (R)-enantiomers. The conversion of benzaldehyde and potassium cyanide (KCN) by a whole-cell catalyst simultaneously expressing the (S)-oxynitrilase and the wild-type nitrilase resulted in a ratio of (S)-mandelic Acid to (S)-mandelic amide of about 4:3. This could be explained by the strong nitrile hydratase activity of the wild-type nitrilase with (S)-mandelonitrile as substrate. The relative proportion of (S)-mandelic amide formed in this system was significantly increased by coexpressing the (S)-oxynitrilase with a carboxy-terminally truncated variant of the nitrilase. This whole-cell catalyst converted benzaldehyde and KCN to mandelic amide and mandelic Acid in a ratio of about 9:1. The ee of the (S)-mandelic amide formed was calculated to be > 95%.
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Simultaneous expression of an arylacetonitrilase from Pseudomonas fluorescens and a (S)-oxynitrilase from Manihot esculenta in Pichia pastoris for the synthesis of (S)-mandelic Acid
Applied Microbiology and Biotechnology, 2008Co-Authors: Sven Rustler, Hassan Motejadded, Josef Altenbuchner, Andreas StolzAbstract:The arylacetonitrilase of Pseudomonas fluorescens EBC191 catalyzes the conversion of ( S )-mandelonitrile to ( S )-mandelic Acid and ( S )-mandeloamide. This biotransformation is optimally performed under Acidic pH values because ( S )-mandelonitrile rapidly decomposes under neutral conditions. Therefore, the gene encoding the arylacetonitrilase of P. fluorescens EBC191 was integrated and expressed under the control of the AOX1 promoter in the methylotrophic yeast Pichia pastoris which was supposed to act as an Acidotolerant expression system. These recombinant strains hydrolyzed ( R , S )-mandelonitrile at pH values ≥3 to mandelic Acid and mandeloamide and were more Acidotolerant than previously constructed Escherichia coli whole cell catalysts synthesizing the same nitrilase activity. Subsequently, recombinant P. pastoris strains were constructed which simultaneously expressed the ( S )-oxynitrilase of Manihot esculenta and the arylacetonitrilase of P. fluorescens EBC191 each under the control of individual AOX1 promoters in order to obtain a whole cell catalyst for the synthesis of ( S )-mandelic Acid from benzaldehyde and cyanide. Resting cells of the recombinant strains converted under Acidic conditions benzaldehyde and cyanide initially to mandelonitrile which was immediately converted to mandelic Acid and mandeloamide. The chiral analysis of the products formed revealed a high enantiomeric excess for the ( S )-enantiomers.
José R. Pedro - One of the best experts on this subject based on the ideXlab platform.
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( S )-Mandelic Acid enolate as a chiral benzoyl anion equivalent for the enantioselective synthesis of non-symmetrically substituted benzoins
Tetrahedron, 2011Co-Authors: Gonzalo Blay, Isabel Fernández, Belen Monje, Marc Montesinos‐magraner, José R. PedroAbstract:A strategy for the enantioselective synthesis of non-symmetrically substituted benzoins from (S)-mandelic Acid and aromatic aldehydes has been developed. This strategy is based on a diastereoselective aldol reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from (S)-mandelic Acid and pivalaldehyde with aromatic aldehydes, which gives the corresponding aldols in good yields. Subsequent hydroxyl group protection as MEM ethers, basic hydrolysis of the dioxolanone ring, oxidative decarboxylation of the α-hydroxy Acid moiety, and hydroxyl group deprotection provides chiral non-symmetrically substituted benzoins with high enantiomeric excesses.
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Catalytic enantioselective addition of terminal alkynes to aromatic aldehydes using zinc-hydroxyamide complexes
Organic & biomolecular chemistry, 2009Co-Authors: Gonzalo Blay, Isabel Fernández, M. Carmen Muñoz, Luz Cardona, Alicia Marco‐aleixandre, José R. PedroAbstract:A mandelamide ligand, derived from (S)-mandelic Acid and (S)-phenylethanamine, catalyzes the addition of aryl-, alkyl- and silyl-alkynylzinc reagents to aromatic and heteroaromatic aldehydes with good yields and good to high enantioselectivities.
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Tailoring the ligand structure to the reagent in the mandelamide-Ti(IV) catalyzed enantioselective addition of dimethyl- and diethylzinc to aldehydes
Journal of Molecular Catalysis A-chemical, 2007Co-Authors: Gonzalo Blay, Isabel Fernández, Victor Hernandez‐olmos, Alicia Marco‐aleixandre, José R. PedroAbstract:Amides derived from (S)-(+)-mandelic Acid in the presence of titanium isopropoxide catalyze the enantioselective addition of dimethyl- and diethylzinc to aldehydes with good yields and ee up to 90%. Because of the modular character of the mandelamides, the structure of the ligand can be tailored to obtain the best results with each reagent. Thus, best results with dimethylzinc are obtained with N-benzyl mandelamide while N-(pyridin-2-yl) mandelamide is the best ligand for the addition of diethylzinc.
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Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic Acid enolate and α,β-enones
Tetrahedron, 2006Co-Authors: Gonzalo Blay, Isabel Fernández, Belen Monje, M. Carmen Muñoz, José R. Pedro, Carlos VilaAbstract:Abstract An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic Acid and α,β-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic Acid and pivalaldehyde with α,β-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereoselectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding α-hydroxy Acids (in hemiacetal form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me2opba complex as catalyst give chiral 2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic Acid acts as an umpoled chiral equivalent of the benzoyl anion.
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Diastereoselective Michael addition of (S)-mandelic Acid enolate to 2-arylidene-1,3-diketones: enantioselective diversity-oriented synthesis of densely substituted pyrazoles
Tetrahedron, 2006Co-Authors: Gonzalo Blay, Isabel Fernández, M. Carmen Muñoz, José R. Pedro, Eva Molina, Carlos VilaAbstract:Abstract A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, α-aryl-α-pyrazolylatrolactic Acid and α-aryl-α-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2 S ,5 S )- cis -1,3-dioxolan-4-one derived from optically active ( S )-mandelic Acid and pivalaldehyde to several 2-arylidene-1,3-diketones, which proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. The cyclocondensation of the 1,3-diketone moieties present in Michael adducts with several hydrazines leads to enantiomerically pure densely substituted pyrazoles. Subsequent basic hydrolysis of the dioxolanone moiety present in these products leads to enantiomerically pure α-aryl-α-pyrazolylatrolactic Acids. Finally, oxidative decarboxylation of these using oxygen, pivalaldehyde and the Co(III)–Me 2 opba complex as catalyst gives α-aryl-α-pyrazolylacetophenones. In this approach four points of diversity are introduced, one of them is the configuration of the ( S )-mandelic Acid, which acts as an umpoled chiral equivalent of the benzoyl anion.
Fred Van Rantwijk - One of the best experts on this subject based on the ideXlab platform.
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Enzymatic cascade synthesis of (S)-2-hydroxycarboxylic amides and Acids: Cascade reactions employing a hydroxynitrile lyase, nitrile-converting enzymes and an amidase
Journal of Molecular Catalysis B: Enzymatic, 2015Co-Authors: Fred Van Rantwijk, Andreas StolzAbstract:Abstract Enantiomerically pure 2-hydroxycarboxylic Acids are valuable synthetic building blocks. This review summarises the development of bienzymatic cascades to convert aldehydes, via hydrocyanation and subsequent hydration or hydrolysis, into the corresponding (S)-2-hydroxycarboxylic amides and Acids. The biocatalysts comprised an (S)-specific hydroxynitrile lyase combined with a nonselective nitrile hydratase or nitrilase. The key to success was preventing racemisation of the intermediate (S)-2-hydroxynitrile while adequately protecting the nitrile-converting enzyme, either in a cross-linked enzyme aggregate (CLEA) or in resting cells. Two biocatalyst systems for the synthesis of (S)-mandelic Acid were developed: a combined crosslinked enzyme aggregate (combi-CLEA) of an (S)-hydroxynitrile lyase and a nitrilase, as well as a whole-cell Escherichia coli biocatalyst expressing both enzymes. The nitrilase formed large amounts of mandelic amide, which was remedied by including an amidase in the combi-CLEA as well as by using nitrilase variants obtained by directed mutagenesis in the whole-cell biocatalyst. Eventually, excellent results – >95% conversion of benzaldehyde into (S)-mandelic Acid with near-quantitative enantiomeric purity – were obtained with both biocatalyst systems. Directed mutagenesis of the nitrilase provided an amide-selective whole-cell biocatalyst, which produced (S)-mandelic amide in near-stoichiometric yields. (S)-2-hydroxylalkanoic carboxamides were synthesised in the presence of CLEAs of hydroxynitrile lyase and nitrile hydratase.
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The combi-CLEA approach: enzymatic cascade synthesis of enantiomerically pure (S)-mandelic Acid
Tetrahedron: Asymmetry, 2013Co-Authors: Andrzej Chmura, Sven Rustler, Monica Paravidino, Fred Van Rantwijk, Andreas Stolz, Roger A. SheldonAbstract:Abstract Enantiomerically pure ( S )-mandelic Acid was synthesised from benzaldehyde by sequential hydrocyanation and hydrolysis in a bienzymatic cascade at starting concentrations up to 0.25 M. A cross-linked enzyme aggregate (CLEA) composed of the ( S )-selective oxynitrilase from Manihot esculenta and the non-selective nitrilase from Pseudomonas fluorescens EBC 191 was employed as the biocatalyst. The nitrilase produces approx. equal amounts of ( S )-mandelic Acid and ( S )-mandelic amide from ( S )-mandelonitrile under standard conditions, but we surprisingly found that high (up to 0.5 M) concentrations of HCN induced a marked drift towards amide production. By including the amidase from Rhodococcus erythopolis in the CLEA we obtained ( S )-mandelic Acid as the sole product in 90% yield and >99% enantiomeric purity.
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Application of a Recombinant Escherichia coli Whole‐Cell Catalyst Expressing Hydroxynitrile Lyase and Nitrilase Activities in Ionic Liquids for the Production of (S)‐Mandelic Acid and (S)‐Mandeloamide
Advanced Synthesis & Catalysis, 2012Co-Authors: Stefanie Baum, Fred Van Rantwijk, Andreas StolzAbstract:The conversion of benzaldehyde and cyanide into mandelic Acid and mandeloamide by a recombinant Escherichia coli strain which simultaneously expressed an (S)-hydroxynitrile lyase (oxynitrilase) from cassava (Manihot esculenta) and an arylacetonitrilase from Pseudomonas fluorescens EBC191 was studied. Benzaldehyde exhibited a pronounced inhibitory effect on the nitrilase activity in concentrations ≥25 mM. Therefore, it was tested if two-phase systems consisting of a buffered aqueous phase and the ionic liquid 1-butyl-1-pyrrolidinium bis(trifluoromethanesulfonyl)imide (BMpl NTf2) or 1-butyl-3-methylimidazolium hexafluorophosphate (BMim PF6) could be used for the intended biotransformation. The distribution coefficients of the substrates, intermediates and products of the reaction were determined and it was found that BMpl NTf2 and BMim PF6 were highly efficient as substrate reservoirs for benzaldehyde. The recombinant E. coli strain was active in the presence of BMpl NTf2 or BMim PF6 phases and converted benzaldehyde and cyanide into mandelic Acid and mandeloamide. The two-phase systems allowed the conversion of benzaldehyde dissolved in the ionic liquids to a concentration of 700 mM with product yields (=sum of mandelic Acid and mandeloamide) of 87–100%. The cells were slightly more effective in the presence of BMpl NTf2 than in the presence of BMim PF6. In both two-phase systems benzaldehyde and cyanide were converted into (S)-mandeloamide and (S)-mandelic Acid with enantiomeric excesses ≥94%. The recombinant E. coli cells formed, in the two-phase systems with ionic liquids and increased substrate concentrations, higher relative amounts of mandeloamide than in a purely aqueous system with lower substrate concentrations.
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construction of recombinant escherichia coli catalysts which simultaneously express an s oxynitrilase and different nitrilase variants for the synthesis of s mandelic Acid and s mandelic amide from benzaldehyde and cyanide
Advanced Synthesis & Catalysis, 2009Co-Authors: Olga Sosedov, Andrzej Chmura, Fred Van Rantwijk, Josef Altenbuchner, Kathrin Matzer, Sibylle Burger, Christoph Kiziak, Stefanie Baum, Andreas StolzAbstract:Recombinant Escherichia coli strains were constructed which simultaneously expressed the genes encoding the (S)-oxynitrilase from cassava (Manihot esculenta) together with the wild-type or a mutant variant of the arylacetonitrilase from Pseudomonas fluorescens EBC191 in a single organism under the control of a rhamnose-inducible promoter. The whole cell catalysts obtained converted benzaldehyde and potassium cyanide in aqueous media at pH 5.2 mainly to (S)-mandelic Acid and/or (S)-mandelic amide and synthesized only low amounts of the corresponding (R)-enantiomers. The conversion of benzaldehyde and potassium cyanide (KCN) by a whole-cell catalyst simultaneously expressing the (S)-oxynitrilase and the wild-type nitrilase resulted in a ratio of (S)-mandelic Acid to (S)-mandelic amide of about 4:3. This could be explained by the strong nitrile hydratase activity of the wild-type nitrilase with (S)-mandelonitrile as substrate. The relative proportion of (S)-mandelic amide formed in this system was significantly increased by coexpressing the (S)-oxynitrilase with a carboxy-terminally truncated variant of the nitrilase. This whole-cell catalyst converted benzaldehyde and KCN to mandelic amide and mandelic Acid in a ratio of about 9:1. The ee of the (S)-mandelic amide formed was calculated to be > 95%.
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synthesis of enantiomerically pure s mandelic Acid using an oxynitrilase nitrilase bienzymatic cascade a nitrilase surprisingly shows nitrile hydratase activity
Tetrahedron-asymmetry, 2006Co-Authors: Cesar Mateo, Andrzej Chmura, Sven Rustler, Fred Van Rantwijk, Andreas Stolz, Roger A. SheldonAbstract:Abstract Benzaldehyde was converted into enantiomerically pure ( S )-mandelic Acid by sequential HCN addition and hydrolysis in the presence of a cross-linked enzyme aggregate composed of the ( S )-selective oxynitrilase from Manihot esculenta and the non-selective recombinant nitrilase from Pseudomonas fluorescens EBC 191. Surprisingly, ( S )-mandelic amide was formed in large amounts. It was shown, in separate experiments, that the nitrilase hydrolyses ( S )-mandelonitrile into an approx. equimolar mixture of Acid and amide, whereas with the ( R )-enantiomer only 10% of amide was formed.
Gonzalo Blay - One of the best experts on this subject based on the ideXlab platform.
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Catalytic Enantioselective Addition of Me2Zn to Isatins
Catalysts, 2017Co-Authors: Carlos Vila, Gonzalo Blay, Andrés Del Campo, J. R. PedroAbstract:Chiral α-hydroxyamide L5 derived from (S)-(+)-mandelic Acid catalyzes the enantioselective addition of dimethylzinc to isatins affording the corresponding chiral 3-hydroxy-3-methyl-2-oxindoles with good yields and er up to 90:10. Furthermore, several chemical transformations were performed with the 3-hydroxy-2-oxindoles obtained.
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( S )-Mandelic Acid enolate as a chiral benzoyl anion equivalent for the enantioselective synthesis of non-symmetrically substituted benzoins
Tetrahedron, 2011Co-Authors: Gonzalo Blay, Isabel Fernández, Belen Monje, Marc Montesinos‐magraner, José R. PedroAbstract:A strategy for the enantioselective synthesis of non-symmetrically substituted benzoins from (S)-mandelic Acid and aromatic aldehydes has been developed. This strategy is based on a diastereoselective aldol reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from (S)-mandelic Acid and pivalaldehyde with aromatic aldehydes, which gives the corresponding aldols in good yields. Subsequent hydroxyl group protection as MEM ethers, basic hydrolysis of the dioxolanone ring, oxidative decarboxylation of the α-hydroxy Acid moiety, and hydroxyl group deprotection provides chiral non-symmetrically substituted benzoins with high enantiomeric excesses.
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Catalytic enantioselective addition of terminal alkynes to aromatic aldehydes using zinc-hydroxyamide complexes
Organic & biomolecular chemistry, 2009Co-Authors: Gonzalo Blay, Isabel Fernández, M. Carmen Muñoz, Luz Cardona, Alicia Marco‐aleixandre, José R. PedroAbstract:A mandelamide ligand, derived from (S)-mandelic Acid and (S)-phenylethanamine, catalyzes the addition of aryl-, alkyl- and silyl-alkynylzinc reagents to aromatic and heteroaromatic aldehydes with good yields and good to high enantioselectivities.
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Tailoring the ligand structure to the reagent in the mandelamide-Ti(IV) catalyzed enantioselective addition of dimethyl- and diethylzinc to aldehydes
Journal of Molecular Catalysis A-chemical, 2007Co-Authors: Gonzalo Blay, Isabel Fernández, Victor Hernandez‐olmos, Alicia Marco‐aleixandre, José R. PedroAbstract:Amides derived from (S)-(+)-mandelic Acid in the presence of titanium isopropoxide catalyze the enantioselective addition of dimethyl- and diethylzinc to aldehydes with good yields and ee up to 90%. Because of the modular character of the mandelamides, the structure of the ligand can be tailored to obtain the best results with each reagent. Thus, best results with dimethylzinc are obtained with N-benzyl mandelamide while N-(pyridin-2-yl) mandelamide is the best ligand for the addition of diethylzinc.
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Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic Acid enolate and α,β-enones
Tetrahedron, 2006Co-Authors: Gonzalo Blay, Isabel Fernández, Belen Monje, M. Carmen Muñoz, José R. Pedro, Carlos VilaAbstract:Abstract An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic Acid and α,β-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic Acid and pivalaldehyde with α,β-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereoselectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding α-hydroxy Acids (in hemiacetal form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me2opba complex as catalyst give chiral 2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic Acid acts as an umpoled chiral equivalent of the benzoyl anion.
Isabel Fernández - One of the best experts on this subject based on the ideXlab platform.
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( S )-Mandelic Acid enolate as a chiral benzoyl anion equivalent for the enantioselective synthesis of non-symmetrically substituted benzoins
Tetrahedron, 2011Co-Authors: Gonzalo Blay, Isabel Fernández, Belen Monje, Marc Montesinos‐magraner, José R. PedroAbstract:A strategy for the enantioselective synthesis of non-symmetrically substituted benzoins from (S)-mandelic Acid and aromatic aldehydes has been developed. This strategy is based on a diastereoselective aldol reaction of the lithium enolate of the 1,3-dioxolan-4-one derived from (S)-mandelic Acid and pivalaldehyde with aromatic aldehydes, which gives the corresponding aldols in good yields. Subsequent hydroxyl group protection as MEM ethers, basic hydrolysis of the dioxolanone ring, oxidative decarboxylation of the α-hydroxy Acid moiety, and hydroxyl group deprotection provides chiral non-symmetrically substituted benzoins with high enantiomeric excesses.
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Catalytic enantioselective addition of terminal alkynes to aromatic aldehydes using zinc-hydroxyamide complexes
Organic & biomolecular chemistry, 2009Co-Authors: Gonzalo Blay, Isabel Fernández, M. Carmen Muñoz, Luz Cardona, Alicia Marco‐aleixandre, José R. PedroAbstract:A mandelamide ligand, derived from (S)-mandelic Acid and (S)-phenylethanamine, catalyzes the addition of aryl-, alkyl- and silyl-alkynylzinc reagents to aromatic and heteroaromatic aldehydes with good yields and good to high enantioselectivities.
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Tailoring the ligand structure to the reagent in the mandelamide-Ti(IV) catalyzed enantioselective addition of dimethyl- and diethylzinc to aldehydes
Journal of Molecular Catalysis A-chemical, 2007Co-Authors: Gonzalo Blay, Isabel Fernández, Victor Hernandez‐olmos, Alicia Marco‐aleixandre, José R. PedroAbstract:Amides derived from (S)-(+)-mandelic Acid in the presence of titanium isopropoxide catalyze the enantioselective addition of dimethyl- and diethylzinc to aldehydes with good yields and ee up to 90%. Because of the modular character of the mandelamides, the structure of the ligand can be tailored to obtain the best results with each reagent. Thus, best results with dimethylzinc are obtained with N-benzyl mandelamide while N-(pyridin-2-yl) mandelamide is the best ligand for the addition of diethylzinc.
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Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic Acid enolate and α,β-enones
Tetrahedron, 2006Co-Authors: Gonzalo Blay, Isabel Fernández, Belen Monje, M. Carmen Muñoz, José R. Pedro, Carlos VilaAbstract:Abstract An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic Acid and α,β-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic Acid and pivalaldehyde with α,β-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereoselectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding α-hydroxy Acids (in hemiacetal form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me2opba complex as catalyst give chiral 2-substituted 1,4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic Acid acts as an umpoled chiral equivalent of the benzoyl anion.
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Diastereoselective Michael addition of (S)-mandelic Acid enolate to 2-arylidene-1,3-diketones: enantioselective diversity-oriented synthesis of densely substituted pyrazoles
Tetrahedron, 2006Co-Authors: Gonzalo Blay, Isabel Fernández, M. Carmen Muñoz, José R. Pedro, Eva Molina, Carlos VilaAbstract:Abstract A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, α-aryl-α-pyrazolylatrolactic Acid and α-aryl-α-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2 S ,5 S )- cis -1,3-dioxolan-4-one derived from optically active ( S )-mandelic Acid and pivalaldehyde to several 2-arylidene-1,3-diketones, which proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. The cyclocondensation of the 1,3-diketone moieties present in Michael adducts with several hydrazines leads to enantiomerically pure densely substituted pyrazoles. Subsequent basic hydrolysis of the dioxolanone moiety present in these products leads to enantiomerically pure α-aryl-α-pyrazolylatrolactic Acids. Finally, oxidative decarboxylation of these using oxygen, pivalaldehyde and the Co(III)–Me 2 opba complex as catalyst gives α-aryl-α-pyrazolylacetophenones. In this approach four points of diversity are introduced, one of them is the configuration of the ( S )-mandelic Acid, which acts as an umpoled chiral equivalent of the benzoyl anion.
