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• 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]

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]

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]

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]

Abstract: In this article we describe a new accessible methodology for the synthesis of isobenzofuran-1(3H)-ones. In this process we exploited an effective, economic, useful and environmentally benign K2CO3 catalyzed, solvent-free one-pot tandem aldol-lactonization reaction between active methylene compounds and methyl 2-carboxy benzaldehyde. A particularly simple work-up and purification procedure are additional advantages addressed to a general green chemistry approach to this important class of heterocyclic compounds. [Copyright &y& Elsevier]

Abstract: Highly diastereocontrolled synthesis of alkaloids, (−)-241D and (−)-isosolenopsin was achieved in 7.7% and 5.3% yields, respectively, using a Barbier-type allylation of a chiral imine and d-proline catalyzed aldol addition reaction of a β-amino aldehyde with acetone as the key steps. The synthesis involves a nine-step sequence using (S)-valinate imine in a Barbier-type allylation for the first time. [Copyright &y& Elsevier]

Abstract: The direct aldol addition of malonates to aromatic, hetero-aromatic and unsaturated aldehydes leading to β-hydroxymalonates is described. The stability of these products, the trimethyl silyl protection of the hydroxyl group as well as the role of both SiCl4 and i-Pr2EtN in attaining the final products are also discussed. [Copyright &y& Elsevier]

Abstract: 3-Methyl-2H-furo[2,3-c]pyran-2-ones 1 and 2, a unique and remarkable seed germination stimulant, and its analogue were synthesized using direct and regioselective Ti-crossed aldol addition between dihydro-2H-pyran-3(4H)-ones and methyl pyruvate as the key step, followed by furanone formation. [Copyright &y& Elsevier]

Abstract: 2-Keto-3-deoxy-6-phosphogluconate (KDPG) and 2-keto-3-deoxy-6-phosphogalactonate (KDPGal) aldolases catalyze an identical reaction differing in substrate specificity in only the configuration of a single stereocenter. However, the proteins show little sequence homology at the amino acid level. Here we investigate the determinants of substrate selectivity of these enzymes. The Escherichia coli KDPGal aldolase gene, cloned into a T7 expression vector and overexpressed in E. coli, catalyzes retro-aldol cleavage of the natural substrate, KDPGal, with values of k cat/K M and k cat of 1.9×104 M−1 s−1 and 4s−1, respectively. In the synthetic direction, KDPGal aldolase efficiently catalyzes an aldol addition using a limited number of aldehyde substrates, including d-glyceraldehyde-3-phosphate (natural substrate), d-glyceraldehyde, glycolaldehyde, and 2-pyridinecarboxaldehyde. A preparative scale reaction between 2-pyridinecarboxaldehyde and pyruvate catalyzed by KDPGal aldolase produced the aldol adduct of the R stereochemistry in >99.7% ee, a result complementary to that observed using the related KDPG aldolase. The native crystal structure has been solved to a resolution of 2.4Å and displays the same (α/β)8 topology, as KDPG aldolase. We have also determined a 2.1Å structure of a Schiff base complex between the enzyme and its substrate. This model predicts that a single amino acid change, T161 in KDPG aldolase to V154 in KDPGal aldolase, plays an important role in determining the stereochemical course of enzyme catalysis and this prediction was borne out by site-directed mutagenesis studies. However, additional changes in the enzyme sequence are required to prepare an enzyme with both high catalytic efficiency and altered stereochemistry. [Copyright &y& Elsevier]

Abstract: The stereochemical course in the addition of lithiated benzylcyanide and propionitrile to aromatic Schiff bases, as well as of the subsequent alkylation reaction has been investigated. The stereochemical ratios in the condensation reaction are proved to result from the intermediacy of a prochiral carbanionic intermediate, produced by a fast proton shift in the initially formed azanion. Subsequent one-pot alkylation reaction with a variety of electrophiles leads in high to moderate yields to diastereoselective formation of a second carbon–carbon bond at the same carbon center. Diastereoselectivity in alkylation, which varies from outstanding to high and poor is rationalized in terms of open-chain, product-like or reactant-like transition state models. [Copyright &y& Elsevier]

Vapor-phase synthesis of 3-pentanone from 1-propanol over CeO2–Fe2O3 catalysts was investigated, and the reaction pathway was discussed in comparison with the reactions of propanal and n-propyl propionate over the CeO2–Fe2O3. 1-Propanol was preferentially converted into 3-pentanone over the CeO2–Fe2O3 catalysts at 450 °C, and propanal, 3-hydroxy-2-methylpentanal, and n-propyl propionate were observed as by-products. The addition of Fe2O3 to CeO2 enhances the ability of CeO2 for the catalytic dehydrogenation of 1-propanol to propanal without losing the ability for the dimerization of propanal. The turnover frequency (TOF) based on a basic site varies with Fe content. Both the selectivity–conversion curves and similarity in the TOF between the reactants of 1-propanol at 450 °C and propanal at 400 °C suggest that propanal is an initial intermediate converting into the final product, 3-pentanone. The formation of 3-pentanone from 1-propanol over the CeO2–Fe2O3 proceeds via aldol addition of propanal into 3-hydroxy-2-methylpentanal, followed by the decomposition into 3-pentanone, while n-propyl propionate is formed as a mere by-product. [Copyright &y& Elsevier]

An efficient TiCl4–Bu3N—(cat. TMSCl)-promoted aldol addition between ketones and ketones or aldehydes was performed. This environmentally benign method is advantageous from a green chemical viewpoint with regard to yield, substrates variation, reagent availability, and simple procedures. This method was applied to a short step formal synthesis of (R)-muscone, a natural macrocyclic musk. [Copyright &y& Elsevier]

X-Ray structure analysis of a titanium(IV) isopropoxide/mandelic acid complex provides an insight into the mechanism of this novel direct enantioselective aldol addition. The catalytic cycle mediated by the titanium(IV) alkoxide/mandelic acid complex is presented. [Copyright &y& Elsevier]