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Dihydroxyacetone phosphate (DHAP)-dependent aldolases catalyze the aldol addition of DHAP to a variety of aldehydes and generate compounds with two stereocenters. This reaction is useful to synthesize chiral acyclic nucleosides, which constitute a well-known class of antiviral drugs currently used. In such compounds, the chirality of the aliphatic chain, which mimics the open pentose residue, is crucial for activity. In this work, three DHAP-dependent aldolases: fructose-1,6-biphosphate aldolase from rabbit muscle, rhanmulose-1-phosphate aldolase from Thermotoga maritima, and fuculose-1-phosphate aldolase from Escherichia coli, were used as biocatalysts. Aldehyde derivatives of thymine and cytosine were used as acceptor substrates, generating new acyclic nucleoside analogues containing two new stereocenters with conversion yields between 70% and 90%. Moreover, structural analyses by molecular docking were carried out to gain insights into the diasteromeric excess observed.

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We synthesized six new camphor-derived homochiral thioureas 1-6, from commercially available (1R)-(-)-camphorquinone. These new compounds 1-6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:ß stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:ß. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for ß glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.

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This study shows the EDTA-resistant, Ca2+ and Cu2+-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) compound in reptiles sera determined by spectrophotometry UV/Vis and chiral chromatography. Samples of ten reptile species were incubated with aliquot of 100 or 400 µM HDCP in presence of 100 or 300 µM Cu2+, or 2.5 mM Ca2+ or 5 mM EDTA at 37 °C for 30-60 min. The results shown an activator effect of Cu2+ on HDCP hydrolysis in freshwater turtles sera (Trachemys scripta, Chelydra serpentina and Macrochelys temminckii) because the levels of 2,5-dichlorophenol (DCP; product hydrolysis) were similar (∼37 µM DCP) to chicken serum (positive control group). The marine turtles (Chelonia mydas and Eretmochelys imbricata) and crocodiles (Crocodylusacutus and Crocodylus moreletii) showed ∼50% less HDCPase activity (13-17 µM DCP) compared to the HDCPase activity of the freshwater turtle species. Terrestrial reptile species (snakes and lizards) showed around 25% of activity (7-13 µM DCP) with both copper concentrations. These Cu2+-dependent hydrolysis were stereospecific to R(+)-HDCP (p˂0.05) in the three freshwater turtle species that showed similar hydrolysis to the chicken serum. However, the Ca2+ did not show a significant activating effect on the HDCPase activity (1-8 µM DCP) in any reptile serum. Their hydrolysis levels were very similar to those of EDTA-resistant activity. The present study demonstrates a Cu2+-dependent A-esterase (HDCPase) activity in turtles and points serum albumin as the cuproprotein responsible for this activity, reinforcing its N-terminal sequence (DAEH) as a catalytic center.

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This work presents the study of a series of electrocyclic reactions with the main aim of obtaining new insights into the reaction process along IRCs. The energy variation of the different reaction paths as well as the different transition states have been calculated. These trends are according to the experimental data. The natural bond orbitals have been obtained and the second order perturbational theory analysis has been carried out to determine the main charge transfers due to delocalization. Bond reactivity indexes have been used to describe the reactivity mechanism in a local way. These reactivity indexes are also based on NBOs and this has made it possible to connect the results of the indexes with the previous analysis. To determine quantitatively the bond structure, we used the quantum theory of atoms in molecules and we have hereby completed the information obtained from the NBO analysis. Finally, we used the Hirshfeld population analysis as an approximation to understand how the load density changes in the different reaction pathways, and we have connected these variations with the information obtained from the bond structure. The results has found that the reaction path with the lowest energy barrier Transition State Inward Conrotatory (TSIC) or Transition State Outward Conrotatory (TSOC) is determined by two magnitudes: the charge donations by delocalisation of the substituents (which we obtained from the Second Order Perturbational Theory Analysis of the NBOs) and in the case that these donations were very similar, the non-covalent interactions dominated (which we studied by means of the interaction energies of the Hirshfeld charges). Additionality, the most important factor influencing the lower energy reaction path was the interaction of lone pairs of the substituents with the σ∗(C-C) bond that is broken at the opening of the cycle. The alignment of these lone pairs with the C-C bond favours charge donation between them and, as can be seen in the discussion, this alignment varies depending on whether the structure is TSIC and TSOC.

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In this study, the novel bifunctional homochiral thiourea-L-prolinamides 1-4, tertiary amino-L-prolinamide 5, and bis-L-prolinamides 6 and 7 were prepared from enantiomerically pure (11R,12R)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene 8 and (11S,12S)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene ent-8. Highly enantioselective and diastereoselective aldolic intermolecular reactions (up to 95% enantiomeric excess, 93:7 anti/syn) between aliphatic ketones (20 equiv) and a range of aromatic aldehydes (1 equiv) were successfully carried out in the presence of water (10 equiv) and monochloroacetic acid (10 mol%), solvent-free conditions, at room temperature over 24 h using organocatalysts 1-7 (5 mol%). Stereoselective induction using density functional theory-based methods was consistent with the experimental data.

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The use of the solvent engineering has been applied for controlling the resolution of lipase-catalyzed synthesis of ß-aminoacids via Michael addition reactions. The strategy consisted of the thermodynamic control of products at equilibrium using the lipase CalB as a catalyst. The enzymatic chemo- and enantioselective synthesis of (R)-(-)-N-benzyl-3-(benzylamino)butanamide is reported, showing the influence of the solvent on the chemoselectivity of the aza-Michael addition and the subsequent kinetic resolution of the Michael adduct; both processes are catalyzed by CalB and both are influenced by the nature of the solvent medium. This approach allowed us to propose a novel one-pot strategy for the enzymatic synthesis of enantiomerically enriched ß-aminoesters and ß-aminoacids.

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A novel ynamide preactivation strategy enables the use of otherwise incompatible reagents and allows preparation of α,ß-disubstituted enamides with high regio- and stereoselectivity. Mechanistic analysis reveals the intermediacy of a triflate-bound intermediate as a solution-stable, effective keteniminium reservoir, whilst still allowing subsequent addition of organometallic reagents.

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Avian species contain low levels of enzymes that hydrolyze organophosphorus compounds (OPs), and chickens are used as a model of OPs delayed neurotoxicity. For both reasons, we studied the ability of chicken tissue for OP detoxication. A significant activating effect of Cu2+ on the hydrolysis of O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) was observed in hen plasma and the microsomal fractions of the liver, brain, and mainly in hen serum, by spectrophotometric and chiral chromatography methods. The concentration of 1 mM of Cu2+ or Zn2+ showed 200% and 168% activation, respectively, in hen plasma compared with the Ca2+-dependent hydrolysis, whereas these cations had an inhibitory effect on soluble liver and brain fractions. An increase of 1.5 to 19.5 fold in HDCP hydrolyzing activity was obtained for the 30-250 µM Cu2+ range when using chicken serum instead of hen plasma. This Cu2+-dependent hydrolysis in chicken serum was stereoselective for the R-(+)-HDCP isomer, which proved the opposite to the Ca2+-dependent stereoselective hydrolysis of the S-(-)-HDCP isomer reported in rat and rabbit serum. The level of copper needed to exert this effect should be further evaluated for its suitability for potential therapeutic and biotechnological applications.

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For the planning of an organic synthesis route, the disconnection approach guided by retrosynthetic analysis of possible intermediates and the chemical reactions involved, back to ready available starting materials, is well established. In contrast, such concepts just get developed for biocatalytic routes. In this Review we highlight functional group interconversions catalyzed by enzymes. The article is organized rather by chemical bonds formed-exemplified for C-N, C-O- and C-C-bonds-and not by enzyme classes, covering a broad range of reactions to incorporate the desired functionality in the target molecule. Furthermore, the successful use of biocatalysts, also in combination with chemical steps, is exemplified for the synthesis of various drugs and advanced pharmaceutical intermediates such as Crispine A, Sitagliptin and Atorvastatin. This Review also provides some basic guidelines to choose the most appropriate enzyme for a targeted reaction keeping in mind aspects like commercial availability, cofactor-requirement, solvent tolerance, use of isolated enzymes or whole cell recombinant microorganisms aiming to assist organic chemists in the use of enzymes for synthetic applications.

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The 2-N,N-dibenzylamino glucopyranosyl trichloroacetimidate donor was synthesized and an extensive investigation of its glycosyl donor properties was conducted. Coupling studies incorporated a variety of glycosyl promoters and a range of acceptor alcohols representing different reactivities and protecting group patterns. Various reaction temperatures, solvents and glycosylation protocols were also examined. Exclusive ß-stereoselectivity was obtained in moderate to good yields with eight novel glycosides being produced, by probable neighbouring group participation via the formation of an aziridinium ion intermediate. Plausible reaction mechanisms were proposed based on the results obtained.

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Stereoselectivity in the C-glycosidation of lactones derived from D-fucose by following Kishi's method, which involves the addition of a nucleophile onto a carbohydrate-derived lactone and subsequent reduction of the lactol, was found to be reliant on the nature of the C2 and C3 protective groups. Lactones bearing TBDMS protecting groups selectively afford 1,3-trans products (α anomer), in which the stereoselective outcome is in apparent concordance with Woerpel's model. On the other hand, their benzylated congeners produce the 1,3-cis products (ß anomer) as the major diastereoisomers. The latter results suggest an abnormal behavior during the stereoselective nucleophilic substitution at the anomeric position of the benzylated lactones.

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