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A squaramide moiety introduced at the C‐4 position of proline produced an organocatalyst that promoted the direct asymmetric aldol addition in the presence of water. A variety of aldol adducts, majorly from the reaction cyclohexanone with aldehydes, were obtained in yields generally in the range of 53–99 %, accompanied by 71–99 % ee and 83 : 17 to >99 : 1 diastereomeric ratios. An asymmetric desymmetrization of 4‐alkyl cyclohexanones was also achieved using the transformation. [ABSTRACT FROM AUTHOR]

The title compound (1) was obtained within a project to synthesize analogs of the antiepileptic drug stiripentol. Compound 1 was synthesized by aldol addition of the lithium enolate of 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one (2) to 3,3-dimethylbutan-2-one (3), followed by the dehydration of the resulting β-hydroxy-ketone under acid processing. The structure of 1 was established by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. [ABSTRACT FROM AUTHOR]

The title compound (1) was obtained within a project to synthesize analogs of the antiepileptic drug stiripentol. Compound 1 was synthesized by aldol addition of the lithium enolate of 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one (2) to 3,3-dimethylbutan-2-one (3), followed by the dehydration of the resulting β-hydroxy-ketone under acid processing. The structure of 1 was established by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry.

Monovalent group 13 diyls are versatile reagents in oxidative addition reactions. We report here [1,4]-cycloaddition reactions of β-diketiminate-substituted diyls LM (M = Al, Ga, In, Tl; L = HC[C(Me)NDipp]2, Dipp = 2,6-iPr2C6H3) with various 1,2-diketones to give 5-metalla-spiro[4.5]heterodecenes 1, 4–6, and 8–10, respectively. In contrast, the reaction of LTl with acenaphthenequinone gave the [2,3]-cycloaddition product 7, with Tl remaining in the +1 oxidation state. Compound 1 also reacted with a second equivalent of butanedione as well as with benzaldehyde in aldol-type addition reactions to the corresponding α,β-hydroxyketones 2 and 3, while a reductive activation of a benzene ring was observed in the reaction of benzil with two equivalents of LAl to give the 1,4-aluminacyclohex-2,4-dien 12. In addition, the reaction of L’BCl2 (L = HC[C(Me)NC6F5]2) with one equivalent of benzil in the presence of KC8 gave the corresponding 5-bora-spiro[4.5]heterodecene 13, whereas the hydroboration reaction of butanedione with L’BH2 (14), which was obtained from the reaction of L’BCl2 with L-selectride, failed to give the saturated 5-bora-spiro[4.5]heterodecane.

Monovalent group 13 diyls are versatile reagents in oxidative addition reactions. We report here [1,4]-cycloaddition reactions of β-diketiminate-substituted diyls LM (M = Al, Ga, In, Tl; L = HC[C(Me)NDipp]2, Dipp = 2,6-iPr2C6H3) with various 1,2-diketones to give 5-metalla-spiro[4.5]heterodecenes 1, 4–6, and 8–10, respectively. In contrast, the reaction of LTl with acenaphthenequinone gave the [2,3]-cycloaddition product 7, with Tl remaining in the +1 oxidation state. Compound 1 also reacted with a second equivalent of butanedione as well as with benzaldehyde in aldol-type addition reactions to the corresponding α,β-hydroxyketones 2 and 3, while a reductive activation of a benzene ring was observed in the reaction of benzil with two equivalents of LAl to give the 1,4-aluminacyclohex-2,4-dien 12. In addition, the reaction of L'BCl2 (L = HC[C(Me)NC6F5]2) with one equivalent of benzil in the presence of KC8 gave the corresponding 5-bora-spiro[4.5]heterodecene 13, whereas the hydroboration reaction of butanedione with L'BH2 (14), which was obtained from the reaction of L'BCl2 with L-selectride, failed to give the saturated 5-bora-spiro[4.5]heterodecane. [ABSTRACT FROM AUTHOR]

This review summarizes examples for the application of vicinal ketoesters such as α-ketoesters, mesoxalic esters, and α,β-diketoesters as key intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the stabilization of reactive conformations by chelation or dipole control.

Studies on the preparation, structures, and properties of heterometallic complexes are currently of great interest because of their emergent synergistic properties. Although both rare earth and aluminum oxo clusters have been developed, only a few heterometallic compounds combine the two clusters. In this study, using “ligand-controlled partial hydrolysis”, we synthesize three hat-shaped cationic Al9Ln7 (Ln = Ce, Pr, Nd) clusters comprising tetrameric cubane units. Their unique vertex-to-edge-sharing arrangements have not been reported in either rare earth or aluminum oxo clusters. Apart from single-crystal X-ray diffraction, these compounds were characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, thermogravimetric analysis, and energy dispersive spectroscopy. Al9Ln7 clusters could serve as efficient catalysts for aldol condensation reactions between acetone and p-nitrobenzaldehyde under mild conditions, with an excellent yield of 86% by AlOC-129Ce.

Aldol addition of acyclic and cyclic ketones to 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones afforded the corresponding 1-substituted 1-hydroxy-4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-ones. The short-time reduction of 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones with sodium tetra-hydridoborate gave 1-hydroxy-4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-ones. [ABSTRACT FROM AUTHOR]

A mild and green methodology for the regiodivergent functionalization of isoquinoline‐1,3(2H,4H)‐diones under aerobic conditions was developed. Under a catalytic amount of base, heteroatom nucleophiles went through an imide opening/ring contraction sequence to give the thermodynamic controlled product; while carbon based nucleophiles led to kinetic controlled aldol type product. Moreover, the aldol type product was transformed into the benzo[c]phenanthridine core structures under transition metal free condition, which provides an environmental benign access to this framework. [ABSTRACT FROM AUTHOR]

A four‐component one‐pot transformation involving the Passerini reaction, an aldol addition, and a transesterification has been elaborated, providing an access to a library of densely functionalized tartaric acid derivatives. Two modifications of the process have been explored. In the first modification, carboxylic acids and isocyanides were treated with an excess of ethyl glyoxalate leading to the incorporation of two ethyl glyoxalate residues in the resulting post‐Passerini products. The second modification involved the initial reaction of a carboxylic acid, an aryl glyoxal and an isocyanide to form the Passerini adduct. This was followed by the in situ addition of ethyl glyoxalate to produce the second type of post‐Passerini products through aldol addition and transesterification. [ABSTRACT FROM AUTHOR]

Quaternary stereocenters are privileged structural motifs, widely distributed in natural products and in pharmaceutically active compounds. Asymmetric methods for the efficient construction of these prominent frameworks are rapidly increasing. Biocatalysis represents an alternative to the existing methods of using hazardous metals and chemicals. Enzymes discussed in this mini‐review involve thiamine‐bisphosphate (ThDP)‐dependent lyases, aldolases and hydroxynitrile lyases. The chiral products, (α‐alkyl‐α‐hydroxy ketones, α‐alkyl‐α‐hydroxy‐β‐diketones, β‐hydroxy ketones, ketone cyanohydrins) obtained by these enzymes, are valuable intermediates suitable for further transformations affording a variety of multi‐functionalized useful building blocks bearing a tetrasubstituted stereocenter, such as amino alcohols, diols, α‐hydroxy carboxylic acids, β‐hydroxy‐α‐amino acids to cite only a few. [ABSTRACT FROM AUTHOR]

• First successfully optimized enzymatic aldol addition of propanal to formaldehyde. • Model-based enzymatic process optimization and reactor selection. • Synthesis of commercially unavailable 3-hydroxy-2-methylpropanal. • Industrially relevant volume productivity, product concentration and yield obtained. • Proof-of-concept synthesis of methacrylic acid precursor; 3-hydroxyisobutyrate. 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. [ABSTRACT FROM AUTHOR]

Abstract N -Acetylneuraminic acid aldolase (NeuAcA) (EC 4.1.3.3) is a pyruvate-dependent class I aldolase that catalyzes the reversible aldol cleavage of N -acetylneuraminic acid to form N -acetyl-D-mannosamine and pyruvate. The synthetic activity of this enzyme has been applied to the preparation of many sialic acid analogues. In this report, we demonstrate the ability of NeuAcA from Clostridium perfringens to use 2-oxoethyl substituted nucleobases as unusual acceptor substrates to perform aldol additions. In this way, novel acyclic nucleoside analogues bearing a further derivatizable 4-hydroxy-2-oxo butyrate skeleton were prepared in good yields. Graphical abstract Unlabelled Image Highlights • N -Acetylneuraminic acid aldolase was used to prepare acyclic nucleoside analogues. • 2-Oxoethyl substituted nucleobases were successfully used as acceptor substrates. • The enzyme tolerates both donor and acceptor substrate excess. • Our studies showed that products are stabilized by intramolecular hydrogen bonding. • The new products bear a further derivatizable 4-hydroxy-2-oxo butyrate skeleton. [ABSTRACT FROM AUTHOR]

A copper-catalyzed cascade reaction of α,β-unsaturated esters with keto esters is reported. It features a copper-catalyzed reductive aldolization followed by a lactonization. This method provides a facile approach to prepare γ-carboxymethyl-γ-lactones and δ-carboxymethyl-δ-lactones under mild reaction conditions.

Combinations of rate measurements as functions of reactant pressures, in situ infrared spectroscopy, comparisons of kinetic isotope effects, and rate inhibition effects provide experimental evidence that aldol condensation of acetaldehyde proceeds by kinetically relevant nucleophilic attack of a reactive enolate upon an acetaldehyde molecule over anatase TiO 2 . Steady-state turnover rates of aldol condensation measured as a function of the pressures of C 2 H 4 O, C 2 H 5 OH, H 2 O, and H 2 between 503 K and 537 K show that rates reflect a second order dependence on C 2 H 4 O pressure and an inverse second order dependence on the C 2 H 5 OH pressure at the lowest C 2 H 4 O-to-C 2 H 5 OH ratios. Infrared spectra obtained in situ show that the exposed cationic Ti-atoms that facilitate aldol addition on TiO 2 surfaces are saturated with C 2 H 5 OH∗ species and C 2 H 4 O∗ coverages are much smaller. In addition, aldol rates increase when C 2 D 4 O replaces C 2 H 4 O as a reactant, which likely reflects an inverse, secondary isotope effect caused by rehybridization of C-atoms at the transition state that forms a C C bond between two reactive intermediates derived from acetaldehyde. These results suggest that the kinetically relevant step is a bimolecular surface reaction, specifically the nucleophilic attack of an enolate onto a vicinal C 2 H 4 O∗ species. This conclusion is consistent also with aldol condensation rates that decrease with an inverse second order dependence on pyridine (C 5 H 5 N) pressure, because C 5 H 5 N displaces C 2 H 4 O from the two Lewis acid sites involved in the kinetically relevant step (confirmed by in situ FTIR). Comparisons to recent reports on the mechanism of this reaction on anatase TiO 2 indicate that the presence of high coverages of C 2 H 5 OH∗ causes nucleophilic attack to become the kinetically relevant step by significantly reducing the number of enolate-acetaldehyde reactant pairs upon the surface. [ABSTRACT FROM AUTHOR]

Abstract: Under neutral conditions, spontaneous mirror symmetry breaking has been occasionally reported for aldol reactions starting from achiral reagents and conditions. Chiral induction might be interpreted in terms of autocatalysis exerted by chiral mono‐aldol or bis‐aldol products as source of initial enantiomeric excesses, which may account for such experimental observations. We describe here a thorough Density Functional Theory (DFT) study on this complex and otherwise difficult problem, which provides some insights into this phenomenon. The picture adds further rationale to an in‐depth analysis by Moyano et al, who showed the isolation and characterization of bis‐aldol adducts and their participation in a complex network of reversible steps. However, the lack of enantiodiscrimination (ees vanish rapidly in solution) suggests, according to the present results, a weak association in complexes formed by the catalysts and substrates. The latter would also be consistent with almost flat transition states having similar heights for competitive catalyst‐bound transition structures (actually, we were unable to locate them at the level explored). Overall, neither autocatalysis as once conjectured nor mutual inhibition of enantiomers appears to be operating mechanisms. Asymmetric amplification in early stages harnessing unavoidable enantiomeric imbalances in reaction mixtures of chiral products represents a plausible interpretation. [ABSTRACT FROM AUTHOR]

Lagunamide C is a depsipeptide natural product with low nM cytotoxicity towards numerous cancer cell lines. Synthetically, it is disconnected to a pentapeptide backbone and polyketide unit that possesses four stereogenic centers, of which two of centers are in question (C38 & 40). Our model system highlights a high-selective aldol addition via a Crimmin’s auxiliary setting the C40 ester linkage, and a non-facially selective cyclopropanation with subsequent ring opening for the installation of the C38 methyl center. [ABSTRACT FROM AUTHOR]

Abstract: An aldolisation protocol for methyl vinyl ketone has been developed using an arginine mediated reaction in water. The reaction brought out an interesting contrast to the reactivity of methyl vinyl ketone with two different amino acids proline and arginine under nearly identical conditions. The aldolisation was only moderately effective with aromatic aldehydes as acceptors, but proved quite efficient when isatins were used. The latter underwent a rapid aldol addition with methyl vinyl ketone at room temperature under aqueous conditions to provide an expedient access to the corresponding 3‐substituted‐3‐hydroxyindolin‐2‐ones in good yields. These adducts were further transformed in ways characteristic to the β‐unsubstituted activated olefin moiety. The method also helped access a spirooxindole pyranone in reasonable yield. [ABSTRACT FROM AUTHOR]

The aldol addition of acyldiazomethane with aromatic aldehydes, vinyl aldehyde and aliphatic aldehydes was carried out efficiently in the presence of MgI2 etherate and iPr2EtN (DIPEA) using untreated reagent-grade CH2Cl2 under atmospheric conditions in good to excellent yields. Iodide counterion and a non-coordinating reaction media (i.e. CH2Cl2) are among the critical factors for the unique reactivity of this reaction system. [ABSTRACT FROM AUTHOR]

Calix[4]pyrrole (1), calix[2]m-benzo[4]pyrrole (2), 10α,20β- and 10α,20α- bis(4-nitrophenyl)-calix[4]pyrroles 3 and 4, respectively, were found to exhibit various organocatalytic activities in the diastereoselective vinylogous addition reaction of 2-trimethylsilyloxyfuran (TMSOF, 7) to aldehydes. The γ-hydroxybutenolide products are obtained in fairly good yields and with moderate diastereoselectivity. The structures of the catalysts, as well as the reaction conditions, strongly influence the efficiency of the reaction.

A stereoselective synthesis of the title compounds was developed. Hexane- and amine-free THF solutions of α-lithiated lithium arylacetates ('arylacetic acid dianions') were aldol-added to 3-arylpropynals. This gave 2,5-diaryl-3-hydroxypent-4-ynoic acids with up to a 72:28 preference for the anti-diastereomer (27 examples + 1 exception). When treated with Ag2CO3 (1-20 mol%) in DMF at room temperature for 2.5 days, the respective mixtures underwent regio- and stereoselective lactonizations followed by an in situ dehydration. Thereby 3-aryl-5-(arylmethylidene)butenolides were obtained with a Z-configuration of the oxygenated C=C bond. Their overall yields ranged from 46% to 83% (1 exception: 28%). Three 3-aryl-5-(arylmethylidene) butenolides contained a C-Br and/or a C-I bond. They allowed a subsequent Pd-catalyzed C-C coupling, which furnished follow-up butenolides. [ABSTRACT FROM AUTHOR]

A heterogeneous supramolecular catalytic system for multicomponent aldol-‘click’ reactions is reported. The copper(I) metallohydrogel functionalized with a phenyltriazole fragment was able to catalyze the multicomponent reaction between phenylacetylene, p-nitrobenzaldehyde, and an azide containing a ketone moiety, obtaining the corresponding aldol products in good yields. A possible mechanistic pathway responsible for this unexpected catalytic behavior has been proposed. [ABSTRACT FROM AUTHOR]

A novel copper-catalyzed domino reaction of α,β-unsaturated dicarboxylate (itaconate, fumarate) with carbonyl (ketone or aldehyde) and diethyl zinc was achieved in high yield, wherein diethyl zinc has been employed as an alkyl Michael donor. In the case of maleate, diethyl zinc acts as a reducing reagent that provides a hydride for Michael addition, and thus affords the corresponding lactones following the conjugate reduction-induced domino reaction. [ABSTRACT FROM AUTHOR]

An efficient rhodium(II)-catalyzed three-component reaction of 3-diazooxindoles, indoles and formalin was reported. With this transformation, a series of 3-(hydroxymethyl)-3-indol-3′-yloxindoles were easily afforded in good to excellent yields. The resulted 3-(hydroxymethyl)-3-indol-3′-yloxindole could be easily converted to the key intermediate for the total synthesis of gliocladin C. [ABSTRACT FROM AUTHOR]

A heterogeneous supramolecular catalytic system for multicomponent aldol-‘click’ reactions is reported. The copper(I) metallohydrogel functionalized with a phenyltriazole fragment was able to catalyze the multicomponent reaction between phenylacetylene, p-nitrobenzaldehyde, and an azide containing a ketone moiety, obtaining the corresponding aldol products in good yields. A possible mechanistic pathway responsible for this unexpected catalytic behavior has been proposed.

β-Carboalkoxy-γ-lactams were synthesized in high yields via copper-catalyzed three-component reactions of α,β-unsaturated dicarboxylate esters, aldimines, and a silane. The reaction proceeds in a tandem manner via conjugate reduction, Mannich reaction, and a subsequent lactamization. The method is attractive with regard to the flexible combination of easily available reactants, the mild conditions, and the high yields. It provides a concise synthetic route to functionalized lactams with a β-ester group. [ABSTRACT FROM AUTHOR]

Abstract: The kodaistatins A and C (5a,b) inhibit a step in glucose-metabolism at ∼100 nM concentrations. This makes them potential ‘leads’ in the therapy of diabetes. We elucidated the (S)-configuration of the side-chain stereocenter of kodaistatin A by ozonolysis/reduction. The 13C NMR shifts of kodaistatin A model cis-11 suggest that the diol moiety in the dihydroxycyclopentanone core of kodaistatin is trans-configured. This model was prepared from the Feringa lactone (21) and (S)-2-methylbutanal (27) in 23 steps (14 steps in the longest linear sequence). We employed the same strategy for the simplified kodaistatin A model iso-cis-12, which resulted from the same substrates in 11 steps (6 steps in the longest linear sequence). The cyclopentenone cores of both targets stemmed from a C4+C1 approach. The C4 components were masked ‘tartaric ketones’ (16a,b) and a masked ‘tartaric aldehyde’ (18), respectively. The C1 components were the lithium-derivatives of the side-chain bearing phosphonates 19 and 22, respectively. The desired acylation/deprotonation/Horner–Wadsworth–Emmons tandem reaction succeeded in a single operation with the ‘tartaric aldehyde’ 18 but required partly or exclusively additional operations when we incorporated the ‘tartaric ketones’ 16a or 16b, respectively. The ‘tartaric ketones’ 16a,b contained an α-siloxyethyl substituent. It is noteworthy that it had to be introduced by adding the benzyltrimethylammonium enolate of lactone 18 to acetaldehyde because the lithium enolate of this lactone fragmented by an acetone-releasing β-elimination. [Copyright &y& Elsevier]

Abstract: The catalytic enantioselective decarboxylative aldol addition reaction of isatins with β-ketoacids promoted by chiral bifunctional organocatalysts have been developed, allowing facile synthesis of the corresponding chiral 3-hydroxy-3-phenacyloxindole derivatives with excellent enantioselectivity (up to 97% ee). [Copyright &y& Elsevier]

Highlights: [•] Aldol addition catalyzed by two aldolases was carried out in microreactor. [•] Three co-solvents were evaluated: ethyl acetate, acetonitrile and dimethylformamide. [•] High enzyme concentration results in higher conversion at lower residence time. [•] Enzyme inactivation occurs in microreactor and increases with residence time. [Copyright &y& Elsevier]

Copper hydride-catalyzed conjugate reduction-intermolecular aldol addition domino reactions were realized using α, β-unsaturated carboxylates as hydride acceptors and a silane as the reducing reagent. High diastereoselectivities were achieved with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene as the ligand and tert-butyl acrylate as the hydride acceptor. [ABSTRACT FROM AUTHOR]

This review summarizes examples for the application of vicinal ketoesters such as α-ketoesters, mesoxalic esters, and α,β-diketoesters as key intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the stabilization of reactive conformations by chelation or dipole control., (Copyright © 2022, Beller and Koert.)

Intramolecular conjugate reduction-aldol addition reactions of β′-oxoalkyl α, β-unsaturated carboxylates were performed in the presence of copper catalysts generated in situ from copper salts, phosphine ligands and silanes. Moderate to good yields and high diastereoselectivities were obtained in 15 min to 3 h using bis[(2-diphenylphosphino)phenyl] ether as the ligand. [ABSTRACT FROM AUTHOR]