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In this work, we report a new method for obtaining racemic β-hydroxyesters by reduction of β-ketoesters. The use of glycerol as a reactional medium in selective reduction of β-ketoesters into the corresponding alcohols was shown to be a viable and more efficient alternative compared with the conventional methodology, taking into account green chemistry prerogatives.

The stereoselective addition of ethyl acetate enolate to the C═N bond of N - tert -butylsulfinylimines has been investigated in depth. A significant effect of the LHMDS amount and the N -sulfinylimine nature on the stereoselectivity of the process was observed. Conditions were found where sulfinylimines of differently substituted salicylaldehydes derivatives, ethyl acetate, and LHMDS afforded the corresponding addition products as a single diastereomer in good yields. The developed protocol was successfully applied to the first stereoselective synthesis of differently substituted 4-amino-3,4-dihydrocoumarin derivatives. Computational models confirmed the prominent role of the ortho aryl substituent in the stereoselectivity of the process. A significant and selective cytotoxic activity against Glioblastoma Multiforme (GBM) cancer line has been determined for the noncyclic hydroxy ester derivative. [Display omitted] • The first enantioselective synthesis of 4-amino-3,4-dihydrocoumarins is reported. • The new compounds show selective anticancer activity against GBM cells. • Chiral hydroxy esters derivatives exhibited good performance for the treatment of GBM in vivo. [ABSTRACT FROM AUTHOR]

Abstract: N-Heterocyclic carbenes have been employed as highly efficient organocatalysts to mediate silyl-Reformatsky type reaction. In the presence of only 0.5 mol% nucleophilic carbene 1, various aldehydes coupled with α-trimethylsilylethylacetate very smoothly in DMF at room temperature to provide the corresponding β-hydroxyesters in moderate to high yields. α-Trimethylsilylketone and α-trimethylsilylamide can also undergo the addition reaction to give β-hydroxyketone and β-hydroxyamide in moderate yields. [Copyright &y& Elsevier]

Abstract: Methyl (S)-β-hydroxybutyrate, the important chiral building block for organic synthesis was produced in high yield from the methoxycarbonylation of (S)-propylene oxide ((S)-PO) using a catalytic system consisting of dicobalt octacarbonyl [Co2(CO)8] and pyrazole. The effects of different additives, temperature and CO pressure were investigated. The reaction was greatly influenced by the variation of temperature, both the conversion of (S)-PO and the selectivity of methyl (S)-β-hydroxybutyrate decreased with increasing temperature (above 80°C). Nevertheless, the enantiomeric excess (ee) of methyl (S)-β-hydroxybutyrate is independent of the parameter of reaction temperature, no racemization reaction takes place even the reaction temperature reaches 150°C. A possible process for the formation of ethers and diethers was presented. The reaction has a bright future in an industrial scale. [Copyright &y& Elsevier]

• Enantioselectivities up to 99 % ee for sterically hindered α-substituted β-hydroxyesters • Type and configuration of the α-substituent influence the resolution on the β-carbinol • Long reaction times during acylation lead to the formation of hemiacetals Enantiomerically pure α-substituted β-hydroxyesters are important chiral building blocks for ligands, auxiliaries and β-lactam antibiotics. A two-step chemo-enzymatic procedure using lipase as biocatalyst is an efficient way to synthesize such products. To date, the methods described are limited to molecules that do not contain a chiral center adjacent to the racemic carbinol, and furthermore, they are limited to acylation. Here, we investigated the deracemization of diastereomerically pure syn - and anti -α-substituted β-hydroxyesters containing two stereo centers, using experimental methods under neat conditions and classical molecule dynamics (MD) simulation. A screening of free and immobilized commercial lipases identified immobilized lipase B from Candida antarctica (Novozyme 435) as the most appropriate biocatalyst for sterically demanding α-substituted β-hydroxyesters. Using Novozyme 435, reaction conditions were optimized and hydroxyesters (3S) or (3R) were achieved with enantiomeric excesses up to ≥99% ee and maximum overall yields of 80%. The absolute configuration of the enantiomers was eventually determined by 1H-NMR spectroscopy after derivatization with Mosher's reagent (α-methoxy-α-trifluoromethylphenylacetic acid = MTPA). [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACT This study presents the bioreduction of six β-ketoesters by whole cells of Kluyveromyces marxianus and molecular investigation of a series of 13 β-ketoesters by hologram quantitative structure-activity relationship (HQSAR) in order to relate with conversion and enantiomeric excess of β-stereogenic-hydroxyesters obtained by the same methodology. Four of these were obtained as (R)-configuration and two (S)-configuration, among them four compounds exhibited >99% enantiomeric excess. The β-ketoesters series LUMO maps showed that the β-carbon of the ketoester scaffold are exposed to undergo nucleophilic attack, suggesting a more favorable β-carbon side to enzymatic reduction based on adopted molecular conformation at the reaction moment. The HQSAR method was performed on the β-ketoesters derivatives separating them into those provided predominantly (R)- or (S)-β-hydroxyesters. The HQSAR models for both (R)- and (S)-configuration showed high predictive capacity. The HQSAR contribution maps suggest the importance of β-ketoesters scaffold as well as the substituents attached therein to asymmetric reduction, showing a possible influence of the ester group carbonyl position on the molecular conformation in the enzyme catalytic site, exposing a β-carbon side to the bioconversion to (S)- and (R)-enantiomers.