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Don M. Coltart - One of the best experts on this subject based on the ideXlab platform.
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on the mechanism of the asymmetric Aldol Addition of chiral n amino cyclic carbamate hydrazones evidence of non curtin hammett behavior
Chemistry: A European Journal, 2019Co-Authors: Md Nasir Uddin, John D. Knight, Ettore J. Rastelli, Thomas A. Albright, Chirine Soubraghaoui, Don M. ColtartAbstract:he mechanistic details of the Aldol Addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-Aldol product is formed exclusively. Under these conditions the anti- and syn-Aldolate intermediates are in equilibrium and the transformation is under thermodynamic control. The anti-Aldolate that leads to the anti-Aldol product was calculated to be 3.7 kcal mol-1 lower in energy at room temperature than that leading to the syn-Aldol product, which sufficiently accounts for the exclusive formation of the anti-Aldol product. When the reaction is conducted at -78 °C it is under kinetic control and favors formation of the syn-Aldol Addition product. In this case, it was found that a solvent separated aza-enolate anion and aldehyde form a σ-intermediate in which the lithium cation is coordinated to the aldehyde. The σ-intermediate collapses with a very small activation barrier to form the β-alkoxy hydrazone intermediate. The chiral nonracemic lithium aza-enolate discriminates between the two diastereotopic faces of the pro-chiral aldehyde, and there is no rapid direct pathway that interconverts the two diastereomeric intermediates. Consequently, the reaction does not follow the Curtin-Hammett principle and the stereochemical outcome at low temperature instead depends on the relative energies of the two σ-intermediates.
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expanding the scope of the asymmetric anti Aldol Addition of chiral n amino cyclic carbamate hydrazones
ChemInform, 2014Co-Authors: John D. Knight, Don M. ColtartAbstract:An asymmetric anti-Aldol Addition process of ketone-derived donors that is not limited by the structure of the ketone is described.
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asymmetric anti Aldol Addition of achiral ketones via chiral n amino cyclic carbamate hydrazones
ChemInform, 2013Co-Authors: John D. Knight, Don M. ColtartAbstract:The diastereoselective Aldol Addition reaction of chiral hydrazones (I) and aldehydes (II) followed by O-benzylation of the resulting Aldol adduct and subsequent removal of the chiral auxiliary affords desired O-benzylated β-hydroxyketones (V) in high overall yields.
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expanding the scope of the asymmetric anti Aldol Addition of chiral n amino cyclic carbamate hydrazones
Tetrahedron Letters, 2013Co-Authors: John D. Knight, Don M. ColtartAbstract:An asymmetric anti-Aldol Addition process of ketone-derived donors that is not limited by the structure of the ketone is described. This is achieved by merging the enantioselective α,α-bisalkylation of N-amino cyclic carbamate (ACC) hydrazones with the asymmetric anti-Aldol Addition of ACC hydrazones. The products of this process are obtained with essentially perfect stereoselectivity. Using this procedure it is possible to gain access to ketone-based anti-Aldol Addition products that are inaccessible in a controlled sense via direct Aldol methods.
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asymmetric anti Aldol Addition of achiral ketones via chiral n amino cyclic carbamate hydrazones
Chemical Communications, 2013Co-Authors: John D. Knight, Don M. ColtartAbstract:The asymmetric anti-Aldol Addition of ketone-derived donors and aldehyde acceptors is described. Asymmetric induction is achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. The transformation exhibits essentially perfect anti-diastereoselectivity and enantioselectivity, and has the unusual feature of proceeding via thermodynamic, rather than kinetic control.
Pere Clapés - One of the best experts on this subject based on the ideXlab platform.
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Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes.
Journal of the American Chemical Society, 2020Co-Authors: Roser Marín-valls, Karel Hernández, Jesús Joglar, Jordi Bujons, Teodor Parella, Michael Bolte, Pere ClapésAbstract:The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the Aldol Addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In Addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.
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model based optimization of the enzymatic Aldol Addition of propanal to formaldehyde a first step towards enzymatic synthesis of 3 hydroxybutyric acid
Chemical Engineering Research & Design, 2019Co-Authors: Morana Cesnik, Pere Clapés, Simon J. Charnock, Karel Hernández, Teodor Parella, Martina Sudar, đurđa Vasicracki, Raquel Roldan, Zvjezdana Findrik BlaževicAbstract:Abstract 3-Hydroxyisobutyric acid is an important intermediate in the biosynthesis of methacrylic acid. Its biocatalytic synthesis can be performed by Aldolase-catalyzed Aldol Addition of propanal to formaldehyde followed by an enzymatic oxidation of the resulting 3-hydroxy-2-methylpropanal to 3-hydroxyisobutyric acid. In this work, d -fructose-6-phosphate Aldolase D6Q variant was investigated as a key step for the biocatalytic preparation of 3-hydroxy-2-methylpropanal, a commercially unavailable precursor of 3-hydroxyisobutyric acid. The kinetic model of this step was developed for the purpose of reactor selection and process optimization. It was found that enzyme operational stability decay is co-dependent on the initial formaldehyde concentration. Thus, the choice of the initial conditions is crucial for a successful process set-up. It was concluded that fed-batch was the best reactor choice for this reaction due to enzyme inhibition by formaldehyde and propanal, and its operational stability decay. At the optimal process conditions, the product concentration, product yield, and volume productivity after 5.5 h were 72 g L−1, 88.5% and 313.7 g L−1 d−1, respectively. Enzymatic oxidation of 3-hydroxy-2-methylpropanal to the corresponding acid was performed as a proof of concept using an aldehyde dehydrogenase in the presence of NAD+, regenerated by water-forming NADH oxidase, and 2.5 g L−1 (24 mM) of 3-hydroxyisobutyric acid was obtained.
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engineered serine hydroxymethyltransferase from streptococcus thermophilus for the synthesis of α α dialkyl α amino acids
ChemInform, 2015Co-Authors: Karel Hernández, Jesús Joglar, Jordi Bujons, Teodor Parella, I Zelen, Giovanna Petrillo, Isabel Uson, Claudia M Wandtke, Pere ClapésAbstract:A highly diastereoselective Aldol Addition of aldehydes to serine and alanine is established.
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Aldolase catalyzed synthesis of conformationally constrained iminocyclitols preparation of polyhydroxylated benzopyrrolizidines and cyclohexapyrrolizidines
ChemInform, 2014Co-Authors: Pedro Laborda, Jesús Joglar, Teodor Parella, Francisco J Sayago, Carlos Cativiela, Pere ClapésAbstract:A straightforward chemo-enzymatic synthesis of new polyhydroxylated benzopyrrolizidines and cyclohexapyrrolizidines is developed. The two-step strategy consists of l-fuculose-1-phosphate Aldolase variant F131A-catalyzed Aldol Addition of dihydroxyacetone phosphate to rac-N-benzyloxycarbonylindoline-2-carbaldehyde as well as (2S*,3aS*,7aS*)- and (2S*,3aR*,7aR*)-N-benzyloxycarbonyloctahydroindole-2-carbaldehydes and a subsequent one-step catalytic deprotection–reductive amination.
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mathematical model for Aldol Addition catalyzed by two d fructose 6 phosphate Aldolases variants overexpressed in e coli
Journal of Biotechnology, 2013Co-Authors: Martina Sudar, Pere Clapés, Zvjezdana Findrik, đurđa Vasicracki, Carles LozanoAbstract:Abstract Two d -fructose-6-phosphate Aldolase variants namely, single variant FSA A129S and double variant FSA A129S/A165G, were used as catalysts in the Aldol Addition of dihydroxyacetone (DHA) to N -Cbz-3-aminopropanal. Mathematical model for reaction catalyzed by both enzymes, consisting of kinetic and mass balance equations, was developed. Kinetic parameters were estimated from the experimental data gathered by using the initial reaction rate method. The model was validated in the batch and continuously operated ultrafiltration membrane reactor (UFMR). The same type of kinetic model could be applied for both enzymes. The operational stability of the Aldolases was assessed by measuring enzyme activity during the experiments. FSA A129S/A165G had better operational stability in the batch reactor (half-life time 26.7 h) in comparison to FSA A129S (half-life time 5.78 h). Both variants were unstable in the continuously operated UFMR in which half-life times were 1.99 and 3.64 h for FSA A129S and FSA A129S/A165G, respectively.
Scott E. Denmark - One of the best experts on this subject based on the ideXlab platform.
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lewis base catalysis of the mukaiyama directed Aldol reaction 40 years of inspiration and advances
Angewandte Chemie, 2013Co-Authors: Gregory L Beutner, Scott E. DenmarkAbstract:: Since the landmark publications of the first directed Aldol Addition reaction in 1973, the site, diastereo-, and enantioselective Aldol reaction has been elevated to the rarefied status of being both a named and a strategy-level reaction (the Mukaiyama directed Aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed Aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed Aldol Addition reactions. The evolution of this process is chronicled from the authors' laboratories as well as in those of Professor Teruaki Mukaiyama.
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lewis base catalyzed enantioselective Aldol Addition of acetaldehyde derived silyl enol ether to aldehydes
Journal of Organic Chemistry, 2005Co-Authors: Scott E. DenmarkAbstract:Chiral phosphoramide catalyzed-enantioselective Aldol Addition of an acetaldehyde-derived trialkylsilyl enol ether to aromatic aldehydes provides protected Aldol products in good yields with good to excellent enantioselectivities. Preliminary studies show that the Aldolization intermediate (a chlorohydrin adduct) can be trapped with tert-butyl isocyanide to form an α-hydroxy lactone with good selectivity in a single-pot operation.
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lewis base catalyzed enantioselective Aldol Addition of methyl trichlorosilyl ketene acetal to ketones
Journal of Organic Chemistry, 2005Co-Authors: Scott E. Denmark, Yu Fan, Martin D EastgateAbstract:The catalytic enantioselective Addition of an acetate enolate equivalent to ketones is described. Methyl trichlorosilyl ketene acetal reacts with a wide range of ketones in the presence of pyridine N-oxide to afford the Aldol Addition products in excellent yields. Chiral 2,2‘-pyridyl bis-N-oxides bearing various substituents at the 3,3‘- and 6,6‘-positions also provide excellent yields of the Aldol products with variable enantioselectivities ranging from 94/6 er for aromatic ketones to nearly racemic for aliphatic ketones. An X-ray crystal structure of the complex between a catalyst and silicon tetrachloride (((P)-(R,R)-19·SiCl4)) has been obtained. Extensive computational analysis provides a stereochemical rationale for the observed trends in enantioselectivities.
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chiral phosphoramide catalyzed Aldol Additions of ketone enolates preparative aspects
ChemInform, 1999Co-Authors: Scott E. Denmark, Robert A Stavenger, Kentsung WongAbstract:Trichlorosilyl enolates of ketones (enoxytrichlorosilanes) were demonstrated to be highly reactive Aldol Addition reagents. Trichlorosilyl enolates of cyclohexanone (E-enolate) and propiophenone (Z-enolate) reacted readily at room temperature with a wide variety of aldehydes to afford Aldol Addition products in high yield and diastereoselectivity (E → syn, Z → anti). These reactions were shown to be highly susceptible to acceleration by catalytic quantities of chiral phosphoramides. In particular, a phosphoramide derived from (S,S)-stilbenediamine was remarkably effective not only in accelerating the reaction but also in modulating the diastereoselectivity and in providing the Aldol Addition products in good to excellent enantioselectivity. The diastereoselectivity of the unpromoted process has been interpreted as a consequence of reaction via a pentacoordinate, trigonal bipyramidal (tbp) silicon complex through a boatlike transition structure. The phosphoramide-catalyzed reactions are more complicated an...
John D. Knight - One of the best experts on this subject based on the ideXlab platform.
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on the mechanism of the asymmetric Aldol Addition of chiral n amino cyclic carbamate hydrazones evidence of non curtin hammett behavior
Chemistry: A European Journal, 2019Co-Authors: Md Nasir Uddin, John D. Knight, Ettore J. Rastelli, Thomas A. Albright, Chirine Soubraghaoui, Don M. ColtartAbstract:he mechanistic details of the Aldol Addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-Aldol product is formed exclusively. Under these conditions the anti- and syn-Aldolate intermediates are in equilibrium and the transformation is under thermodynamic control. The anti-Aldolate that leads to the anti-Aldol product was calculated to be 3.7 kcal mol-1 lower in energy at room temperature than that leading to the syn-Aldol product, which sufficiently accounts for the exclusive formation of the anti-Aldol product. When the reaction is conducted at -78 °C it is under kinetic control and favors formation of the syn-Aldol Addition product. In this case, it was found that a solvent separated aza-enolate anion and aldehyde form a σ-intermediate in which the lithium cation is coordinated to the aldehyde. The σ-intermediate collapses with a very small activation barrier to form the β-alkoxy hydrazone intermediate. The chiral nonracemic lithium aza-enolate discriminates between the two diastereotopic faces of the pro-chiral aldehyde, and there is no rapid direct pathway that interconverts the two diastereomeric intermediates. Consequently, the reaction does not follow the Curtin-Hammett principle and the stereochemical outcome at low temperature instead depends on the relative energies of the two σ-intermediates.
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expanding the scope of the asymmetric anti Aldol Addition of chiral n amino cyclic carbamate hydrazones
ChemInform, 2014Co-Authors: John D. Knight, Don M. ColtartAbstract:An asymmetric anti-Aldol Addition process of ketone-derived donors that is not limited by the structure of the ketone is described.
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asymmetric anti Aldol Addition of achiral ketones via chiral n amino cyclic carbamate hydrazones
ChemInform, 2013Co-Authors: John D. Knight, Don M. ColtartAbstract:The diastereoselective Aldol Addition reaction of chiral hydrazones (I) and aldehydes (II) followed by O-benzylation of the resulting Aldol adduct and subsequent removal of the chiral auxiliary affords desired O-benzylated β-hydroxyketones (V) in high overall yields.
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expanding the scope of the asymmetric anti Aldol Addition of chiral n amino cyclic carbamate hydrazones
Tetrahedron Letters, 2013Co-Authors: John D. Knight, Don M. ColtartAbstract:An asymmetric anti-Aldol Addition process of ketone-derived donors that is not limited by the structure of the ketone is described. This is achieved by merging the enantioselective α,α-bisalkylation of N-amino cyclic carbamate (ACC) hydrazones with the asymmetric anti-Aldol Addition of ACC hydrazones. The products of this process are obtained with essentially perfect stereoselectivity. Using this procedure it is possible to gain access to ketone-based anti-Aldol Addition products that are inaccessible in a controlled sense via direct Aldol methods.
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asymmetric anti Aldol Addition of achiral ketones via chiral n amino cyclic carbamate hydrazones
Chemical Communications, 2013Co-Authors: John D. Knight, Don M. ColtartAbstract:The asymmetric anti-Aldol Addition of ketone-derived donors and aldehyde acceptors is described. Asymmetric induction is achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. The transformation exhibits essentially perfect anti-diastereoselectivity and enantioselectivity, and has the unusual feature of proceeding via thermodynamic, rather than kinetic control.
Jesús Joglar - One of the best experts on this subject based on the ideXlab platform.
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Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes.
Journal of the American Chemical Society, 2020Co-Authors: Roser Marín-valls, Karel Hernández, Jesús Joglar, Jordi Bujons, Teodor Parella, Michael Bolte, Pere ClapésAbstract:The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the Aldol Addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In Addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.
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Biocatalytic Aldol Addition of Simple Aliphatic Nucleophiles to Hydroxyaldehydes
2018Co-Authors: Raquel Roldán, Karel Hernández, Jesús Joglar, Jordi Bujons, Teodor Parella, Marielle Lemaire, Israel Sánchez-moreno, Virgil Hélaine, Christine Guérard-hélaine, Wolf-dieter FessnerAbstract:Asymmetric Aldol Addition of simple aldehydes and ketones to electrophiles is a cornerstone reaction for the synthesis of unusual sugars and chiral building blocks. We investigated d-fructose-6-phosphate Aldolase from E. coli (FSA) D6X variants as catalysts for the Aldol Additions of ethanal and nonfunctionalized linear and cyclic aliphatic ketones as nucleophiles to nonphosphorylated hydroxyaldehydes. Thus, Addition of propanone, cyclobutanone, cyclopentanone, or ethanal to 3-hydroxypropanal or (S)- or (R)-3-hydroxybutanal catalyzed by FSA D6H and D6Q variants furnished rare deoxysugars in 8–77% isolated yields with high stereoselectivity (97:3 dr and >95% ee)
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engineered serine hydroxymethyltransferase from streptococcus thermophilus for the synthesis of α α dialkyl α amino acids
ChemInform, 2015Co-Authors: Karel Hernández, Jesús Joglar, Jordi Bujons, Teodor Parella, I Zelen, Giovanna Petrillo, Isabel Uson, Claudia M Wandtke, Pere ClapésAbstract:A highly diastereoselective Aldol Addition of aldehydes to serine and alanine is established.
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sequential biocatalytic Aldol reactions in multistep asymmetric synthesis pipecolic acid piperidine and pyrrolidine homo iminocyclitol derivatives from achiral building blocks
Advanced Synthesis & Catalysis, 2014Co-Authors: Anna Soler, Karel Hernández, Jordi Bujons, Teodor Parella, Xavier Garrabou, Mariana L Gutierrez, Eduardo Busto, Jesús JoglarAbstract:A multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine-dependent Aldolases and both D-fructose-6-phosphate Aldolase (FSA) or dihydroxyacetone phosphate (DHAP)-dependent Aldolases is presented. The methodology allowed the preparation of known and innovative imine-derived molecules with a great structural diversity from simple achiral substrates. The strategy consisted of two key Aldol Addition steps: a first Aldol Addition of glycine to dimethoxyacetaldehyde catalyzed by L- and D-glycine Aldolases and a second Aldol Addition of DHAP, dihydroxyacetone, hydroxyacetone or glycolaldehyde using FSA or DHAP-dependent Aldolases as catalysts to a conveniently transformed Aldol adduct from the first Aldol Addition. Catalytic reductive amination on the Aldol adducts rendered the polyhydroxypipecolic acid analogues, (homo)iminocyclitols and polyhydroxylated pyrrolidine iminocyclitols. The reported strategy is thus designed to create up to five new stereogenic centers in three steps, four of them being controlled in two enzymatic reactions. Moreover, it allowed the installation of diverse functionalities in the molecules. This was possible by taking the full advantage of using Aldolases in a multistep approach by virtue of their stereocomplementarity, stereoselectivity and broad substrate tolerance.
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Aldolase catalyzed synthesis of conformationally constrained iminocyclitols preparation of polyhydroxylated benzopyrrolizidines and cyclohexapyrrolizidines
ChemInform, 2014Co-Authors: Pedro Laborda, Jesús Joglar, Teodor Parella, Francisco J Sayago, Carlos Cativiela, Pere ClapésAbstract:A straightforward chemo-enzymatic synthesis of new polyhydroxylated benzopyrrolizidines and cyclohexapyrrolizidines is developed. The two-step strategy consists of l-fuculose-1-phosphate Aldolase variant F131A-catalyzed Aldol Addition of dihydroxyacetone phosphate to rac-N-benzyloxycarbonylindoline-2-carbaldehyde as well as (2S*,3aS*,7aS*)- and (2S*,3aR*,7aR*)-N-benzyloxycarbonyloctahydroindole-2-carbaldehydes and a subsequent one-step catalytic deprotection–reductive amination.