Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.     

Enantioselective synthesis of the carbacephem antibiotic loracarbef via Mitsunobu and Dieckmann cyclization from an unnatural amino acid

The nucleus of the carbacephem antibiotic loracarbef was synthesized in a highly efficient and enantioselective fashion from 2S,3S-2-amino-3-hydroxy-6-heptenoic acid (AHHA), which was derived from enzyme-catalyzed condensation of glycine and 4-pentenaldehyde. The bicyclic framework of this compound was established through sequential Mitsunobu reaction and aldol condensations.     

Synthesis and evaluation of new potential HIV-1 non-nucleoside reverse transcriptase inhibitors. New analogues of MKC-442 containing Michael acceptors in the C-6 position

Analogues of MKC-442 capable of undergoing Michael addition reactions were synthesised in order to investigate the activity against the HIV-1 mutant (Y181C). An improved activity was postulated on the basis of a possible covalent binding to the mercapto group of Cys181. Lithiation of the C-6 position of 1-ethoxymethyl-5-ethyl-1H-pyrimidine-2,4-dione (5) was followed by reaction with alpha,beta-unsaturated aldehydes and oxidation of the alcohols formed to give the alkenoyl analogues 1a-3a. Analogues 1b-3b containing an allyloxymethyl group in the N-1 position instead of the ethoxymethyl group could not be synthesised due to isomerisation of the allylic group during the metallation reaction. The NMR data for compounds 1a-3a showed a hindered rotation, which was more pronounced for the 6-cyclohexenylcarbonyl derivative 3a than for the propenyl derivatives 1a and 2a. Moderate activity against wild type HIV-1 was observed for the alcohol 8 and the ketones 2a-3a. However, no activity was observed against the Y181C mutant.     

Anti-HIV Active Naphthyl Analogues of HEPT and DABO

Summary.  5-Isopropyl-6-naphthyl uracil and 5-isopropyl-6-naphthyl-2-thiouracil were alkylated to give N-1-(ethoxymethyl and methylthiomethyl) uracil and S²-cyclohexyl-thiouracil, respectively. 5-Ethyl-6-naphthyl uracil and 5-ethyl-6-naphthyl-2-thiouracil afforded N-1-(ethoxymethyl, methoxy-methyl, methylthiomethyl, acetoxyethoxy methyl and hydroxyethoxy methyl) uracil and S²-((2,2- diethoxyethyl), methoxycarbonylmethyl, ethoxycarbonylpropyl, methylthiomethyl, ethoxymethyl, methyl and cyclohexyl)-thiouracil upon alkylation. Received September 25, 2001. Accepted (revised) December 3, 2001     

Small-angle neutron scattering study of structural changes in temperature sensitive microgel colloids

The structure of temperature-sensitive poly(N-isopropylacrylamide) microgels in dilute suspension was investigated by means of small-angle neutron scattering. A direct modeling expression for the scattering intensity distribution was derived which describes very well the experimental data at all temperatures over an extensive q range. The overall particle form as well as the internal structure of the microgel network is described by the model. The influence of temperature, cross-linking density, and particle size on the structure was revealed by radial density profiles and clearly showed that the segment density in the swollen state is not homogeneous, but gradually decays at the surface. The density profile reveals a box profile only when the particles are collapsed at elevated temperatures. An increase of the cross-linking density resulted in both an increase of the polymer volume fraction in the inner region of the particle and a reduction of the smearing of the surface. The polymer volume fraction inside the colloid decreased with increasing particle size. The structural changes are in good agreement with the kinetics of the emulsion copolymerization used to prepare the microgel colloids.     

Identification and Directed Development of Non‐Organic Catalysts with Apparent Pan‐Enzymatic Mimicry into Nanozymes for Efficient Prodrug Conversion

Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a narrow range of mammalian enzymes, near‐exclusively performing redox reactions. We present an unexpected discovery of non‐proteinaceous enzymes based on metals, metal oxides, 1D/2D‐materials, and non‐metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan‐glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme‐prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti‐inflammatory and antibacterial agents, as well as “nanozyme prodrug therapy” to mediate antibacterial measures.     

Fluoride-bridged {Ln(2)Cr(2)} polynuclear complexes from semi-labile mer-[CrF(3)(py)(3)] and [Ln(hfac)(3)(H(2)O)(2)

The trifluorido complex mer-[CrF(3)(py)(3)] (py = pyridine) reacts with 1 equiv. of [Ln(hfac)(3)(H(2)O)(2)] and depending on the solvent forms the tetranuclear clusters [Cr(2)Ln(2)(μ-F)(4)(μ-OH)(2)(py)(4)(hfac)(6)], 1Ln, and [Cr(2)Ln(2)(μ-F)(4)F(2)(py)(6)(hfac)(6)], 2Ln, in acetonitrile and 1,2-dichloroethane, respectively (Ln = Y, Gd, Tb, Dy, Ho, and Er; hfacH = 1,1,1,5,5,5-hexafluoroacetylacetone). Reaction with [Dy(hfac)(3)(H(2)O)(2)] in dichloromethane produces the dinuclear cluster [CrDy(μ-F)F(OH(2))(py)(3)(hfac)(4)], 3Dy. All the clusters feature fluoride bridges between the chromium(iii) and lanthanide(iii) centres. Fits of susceptibility data for 1Gd and 2Gd reveal the fluoride-mediated chromium(iii)-lanthanide(iii) exchange interactions to be 0.43(5) cm(-1) and 0.57(7) cm(-1), respectively (in the convention). Heat capacity measurements on 2Gd reveal a moderate magneto-caloric effect (MCE) reaching -ΔS(m)(T) = 11.4 J kg(-1) K(-1) for ΔB(0) = 9 T → 0 T at T = 4.1 K. Out-of-phase alternating-current susceptibility (χ') signals are observed for 1Dy, 2Dy and 2Tb, demonstrating slow relaxation of the magnetization.