Thioester Enolate Research Articles

Decarboxylative Organocatalyzed Addition Reactions of Fluoroacetate Surrogates for the Synthesis of Fluorinated Oxindoles.

Fluorinated malonic acid half thioesters (F-MAHTs) were used as thioester enolate equivalents in organocatalyzed addition reactions to isatins. The products from a range of different N-protected and nonprotected isatins were obtained under mild reaction conditions in high yields and enantioselectivities. The unique reactivity of the thioester moiety enabled diverse derivatization and allowed for the straightforward access to a fluorinated analogue of the anticancer agent (S)-YK-4-279, a therapeutically active compound against Ewing's sarcoma.

Editorial

Editorial

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to MTMs that proceeds through nucleophilic ring‐opening of Meldrum's acid derivatives followed by O‐alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34 – 92% and allows for variations of the oxo‐ and thioester moieties as well as the substituent at the C(α) position.

ChemInform Abstract: Stereoselective Synthesis of Indolines via Organocatalytic Thioester Enolate Addition Reactions.

AbstractThe synthesis of indolines (VIII) involves enantioselective addition of monothiomalonate (II) to nitrostyrenes and intramolecular Buchwald—Hartwig coupling reaction as the key steps.

Fluorovinyl Thioethers as Putative Steric and Electronic Thioester Enolate Mimetics: Chemoselective HF Addition to Acetylene Thioethers

Fluorovinyl thioethers are presented as a putative biomimetic surrogate for the enol/ate of a thioester. A method is explored for the preparation of fluorovinyl thioethers by treatment of acetylene thioethers with pyridinium (poly)-hydrogen fluoride. Titration with pyridine is important for the selectivity of the reaction. Without titration the corresponding gem-difluoroethyl thioethers are generated. With titration the hydrofluorination reaction can be stopped at an intermediate stage to recover the fluorovinyl thioether, which is a relatively stable functionality to purification and manipulation. Preliminary density functional theory calculations indicate that the fluorovinyl thioether motif shares a comparable steric and electronic profile to a thioester enol. A fluorovinyl thioether representing the terminus of the pantothenoyl chain of acetyl-CoA is prepared as a relevant biomimetic example.

Stereoselective synthesis of indolines via organocatalytic thioester enolate addition reactions.

A straightforward stereoselective synthesis route to indolin-3-yl acetates has been developed using organocatalytic addition reactions of monothiomalonates to ortho-bromo nitrostyrenes as the key step. The addition products of this highly stereoselective one-pot addition-deprotection-decarboxylation sequence were easily further converted to the target indolin-3-yl acetates, via an intramolecular Buchwald-Hartwig coupling reaction. The route provided indolin-3-yl acetates bearing tertiary and exocyclic quarternary stereogenic centers in excellent stereoselectivities and overall yields of 34-83%.

Organocatalytic stereoselective synthesis of acyclic γ-nitrothioesters with all-carbon quaternary stereogenic centers.

A method for the stereoselective synthesis of acyclic thioesters bearing adjacent quaternary and tertiary stereogenic centers under mild organocatalytic conditions was developed. α-Substituted monothiomalonates (MTMs) were used as thioester enolate equivalents. They reacted cleanly with nitroolefins in the presence of 1-6 mol % of cinchona alkaloid urea derivatives, and provided access to γ-nitrothioesters with quaternary stereocenters in high yields and diastereo- and enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access to other compounds with quaternary stereogenic centers, such as γ-nitroaldehydes and γ-butyrolactams.

ChemInform Abstract: Mono Thiomalonates as Thioester Enolate Equivalents—Enantioselective 1,4‐Addition Reactions to Nitroolefins under Mild Conditions.

AbstractCinchona alkaloid derived thiourea CIN is a highly enantioselective organocatalyst for the title reaction of monothiomalonate (I) bearing an acid labile Pmb ester and an acid stable p‐methoxyphenyl thioester group.

Mono thiomalonates as thioester enolate equivalents—enantioselective 1,4-addition reactions to nitroolefins under mild conditions

Mono thiomalonates (MTMs) are introduced as thioester enolate equivalents. Asymmetric organocatalyzed conjugate addition reactions to nitroolefins proceed under mild conditions to afford synthetically useful γ-nitrothioesters with excellent yields and enantioselectivities.

Overcoming the Limitations of the Morita−Baylis−Hillman Reaction: A Rapid and General Synthesis of α-Alkenyl-β′-hydroxy Thioesters

Acryloyl chlorides, aldehydes, and PhSLi undergo a direct aldol cascade sequence in the presence of MgBr2 x OEt2 via in situ derived thioester enolates, which is followed by oxidative elimination to give alpha-alkenyl-beta'-hydroxy thioesters. Overall, the procedure is rapid, efficient, and generally applicable, even to beta-substituted acryloyl chlorides, thus providing an alternative to the Morita-Baylis-Hillman reaction with substantially greater synthetic scope and utility.

ChemInform Abstract: A Facile and Efficient anti‐Selective Four‐Component Direct Aldol Addition via Chemoselective Thioester Enolate Formation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Facile and Efficient Anti-Selective Four-Component Direct Aldol Addition via Chemoselective Thioester Enolate Formation

A facile and efficient four-component anti-selective direct aldol addition of thioester enolates has been developed that is fully compatible with enolizable aldehydes and able to be conducted using untreated reagent-grade CH2Cl2 open to the air. The thioester enolates are generated in situ via an acylation/conjugate addition sequence using commercially available PhSLi and acryloyl chloride, thus avoiding prior enolate formation while maintaining complete chemoselectivity. The organosulfur products are convertible into various polyketide-based structures.

Divergent function in the crotonase superfamily: an anhydride intermediate in the reaction catalyzed by 3-hydroxyisobutyryl-CoA hydrolase.

3-Hydroxyisobutyryl-CoA hydrolase (HICH), a member of the enoyl-CoA (crotonase) superfamily, catalyzes the hydrolysis of 3-hydroxyisobutyryl-CoA to 3-hydroxyisobutyrate. Like other members of the superfamily, the sequence of HICH contains conserved sequences for an oxyanion hole that stabilizes anionic intermediates. In contrast to most members of the superfamily, the reaction catalyzed by HICH does not proceed via formation of a thioester enolate anion; instead, evidence based on substrate deuterium isotope effects, the reactivity of substrate analogues that cannot form thioester enolate anions, single-turnover experiments in H218O, and the kinetic phenotypes of site-directed mutants provide evidence for a mechanism involving the formation of an anhydride intermediate involving Glu143 in the active site. In the reactions catalyzed by many members of the superfamily, homologues of Glu143 abstract the alpha proton of the thioester substrate to generate the thioester enolate anion intermediate. Presumably, one or more of the anionic tetrahedral intermediates on the HICH reaction coordinate are stabilized by the oxyanion hole. Thus, we conclude that the conserved oxyanion hole in this superfamily can be used to stabilize a variety of anionic intermediates.

Thioester Enolate Stabilization in the Acyl-CoA Dehydrogenases: The Effect of 5-Deaza-flavin Substitution

The redox-inactive thioester analog 3-thia-octanoyl-CoA blocks transfer of a hydride equivalent to the flavin prosthetic group of the medium-chain acyl-CoA dehydrogenase with the accumulation of a stable enolate intermediate not encountered with normal substrates. Substitution of the normal flavin with 5-deaza-FAD would thus be expected to lead to enolate formation with both normal and 3-thia-substrate analogs, because reduction of the 5-deaza-enzyme is thermodynamically highly unfavorable. However, spectrophotometric titrations show that neither ligand forms significant enolate species with the 5-deaza-FAD enzyme. Similarly, the substituted dehydrogenase catalyzes undetectable α-proton exchange with octanoyl-CoA and ca. 1% of the corresponding rate with 3-thia-octanoyl-CoA when compared to the native enzyme. This inability to stabilize enolate species is not simply due to impaired binding of CoA-thioester analogs, because binding of a range of ligands is weakened by only 2- to 10-fold with the 5-deaza-enzyme. 4-Thia-trans-2-enoyl-CoA product is polarized normally on binding to the substituted protein, showing that this critical aspect of catalysis is apparently normal. These data, together with studies with CoA-persulfide and acetoacetyl- and p-nitrophenylacetyl-CoA, suggest that 5-deaza-FAD substitution exerts subtle, unanticipated, effects on the reductive half-reaction of the medium-chain acyl-CoA dehydrogenase. The involvement of charge–transfer interactions in the acidification of weakly acidic acyl-CoA thioesters is discussed.

Modeling Enzyme Reaction Intermediates and Transition States: Citrate Synthase

To investigate the roles of catalytic residues and the nature of the nucleophilic intermediate in citrate synthase, calculations have been carried out on models of the first stage of the reaction with ab initio (MP2/6-31+G(d)//6-31+G(d)) and semiempirical (AM1 and PM3) methods. The first stage of the reaction involves deprotonation of acetyl-CoA, with Asp-375 identified as the likely base. The resulting intermediate is believed to be stabilized by a hydrogen bond from a neutral histidine side chain (His-274), which has been suggested to be a “short, strong” or “low-barrier” hydrogen bond. Such bonds have been suggested to have exceptionally high energies and to stabilize many enzyme reaction intermediates. Transition state and stable hydrogen bonded complex geometries have been fully optimized for models of proton transfer between Asp-375 and acetyl-CoA and between the enolate of acetyl-CoA and His-274. The results support the proposal that Asp-375 is the base in the reaction and show that stabilization of the thioester enolate at the active site is required if it is to exist as a reaction intermediate. The effective basicities of methylimidazolate (representing His-274) and the thioester enolate in the hydrogen bonded complex are calculated to be clearly different. The enolate−methylimidazole complex (with the proton localized on methylimidazole) is found to be significantly lower in energy than the enol complex (in which the hydrogen bonded proton is transferred from methylimidazole), which is not stable. Unless the pKa for deprotonation of neutral His-274 is lowered by conditions in the active site, it appears that the hydrogen bond with the enolate will not be of the low-barrier type. The highly favorable energy of the interaction between the thioester enolate and methylimidazole, as well as calculations on a larger model including all three components, indicate that a normal hydrogen bond with His-274 can make an important contribution to stabilization of the enolate intermediate.

A model of the condensation step in the citrate synthase reaction

Calculations have been performed on the nucleophilic addition of simple molecules representing a thioester enolate and enol to acetone, as models for the addition step in the Claisen-type condensation reaction of acetyl-CoA and oxaloacetate catalysed by the enzyme citrate synthase. The structures of the transition state and addition product for the enolate model have been optimized at the semi-empirical (AM1, PM3 and MNDO) and ab initio ( RHF/6–31+ G( d) and MP2/6–31+ G( d)) levels. The relative energies of the transition state and addition product given by AM1 are reasonably close to the best ab initio result. The results are compared with AM1 results for addition of the enol form of the thioester model, which has been proposed as an alternative possibility for the nucleophile in the enzyme reaction. The barrier to the addition reaction for the enol model is considerably larger, due to the expected poorer nucleophilicity of the neutral enol form. It appears that the barrier for enol addition, unless significantly lowered by the enzyme, is inconsistent with the observed rate of reaction. In agreement with studies of the enolization of acetyl-CoA in citrate synthase, the enolate of acetyl-CoA appears to be a more likely nucleophilic intermediate than the enol. This conclusion may also be relevant for other enzymic Claisen condensation reactions in that efficient reaction may require stabilization of the thioester enolate to maintain a high degree of enolate character in the reactive intermediate.

ChemInform Abstract: Recent Advances in Stereoselective Aldol Reactions of Ester and Thioester Enolates

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Highly Enantioselective Protonation of Thiol Ester Enolates

Impressive enantiomer excesses of 99% were achieved in the protonation of thioester enolate 2, prepared from racemic 1, with the chiral proton sources (−)- and (+)-N-isopropylephedrine ((−)-3 and (+)-3). This large-scale procedure allows access to many enantiopure terpenoids.

Recent advances in Stereoselective Aldol Reactions of ester and thioester enolates

The aldol addition is the classical method for the construction of carbon chains with oxygen functionality in 1,3-distance. Depending on whether an α-substituted or an α-unsubstituted enolate is allowed to react with an aldehyde, two or one stereogenic centers are created. A large number of stereoselective variants developed in recent years enable to obtain nonracemic β-hydroxy-carbonyl compounds. This article reports on aldol additions of carboxylic esters and thioesters which deliver nonracemic β-hydroxycarboxylic acids in a stereoselective manner. In this context, the report emphasizes on aldol additions with triphenylglycol derived acetates and propionates.

ChemInform Abstract: A Novel Method for the Stereoselective Synthesis of β‐Aminoacid Derivatives via Tin(II) Carboxylic Thioester Enolates.

AbstractThe ketene (I) reacts with the tin mercaptide (II) to yield the thiolester enolate (III), which couples with the imines (IV) in the presence of tin triflate (V), giving the isomeric adducts (VI) and (VII).