In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.
Combining the advantages of homogeneous and heterogeneous catalysis is possible by heterogenization of homogeneous transition metal complexes based on a grafting/anchoring technique. Wilkinson’s catalyst ((RhCl(PPh3)3) immobilized on common silica showed high activity and selectivity in transfer hydrogenation reactions of different carbonyl compounds in isopropanol. Reactions conducted at reflux in isopropanol afforded the corresponding carbinols in high yields in short reaction times. The heterogeneous feature of the catalyst allows easy recovery and efficient reuse in the same reaction up to 5 times without loss of catalytic activity.
The direct intramolecular stereospecific substitution of the hydroxyl group in stereogenic secondary alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five- and six-membered heterocycles in good to excellent yields and high enantiospecificity with water as the only by product. Mechanistic studies using both experiments and calculations have been performed. Rate order determination shows first-order dependences in catalyst, internal nucleophile, and electrophile concentrations, however, independence on external nucleophile and electrophile. Furthermore, phosphinic acid does not promote SN1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activations of both nucleofuge and nucleophile occur in a bridging SN2-type transition state.
We herein report a Fe(OTf)3-catalyzed stereospecific substitution of the hydroxyl (OH) group in secondary and tertiary alcohols by N-, and O-centered nucleophiles to generate synthetically precious enantioenriched pyrrolidines, tetrahydrofuran, 1,2,3,4-tetra-hydroquinolines, and chromanes. The substitution of the OH group in benzylic, allylic, and aliphatic alcohols proceed with high yields and high degree of enantiospecificity to give saturated five- and six-membered heterocyclic products and water as the only by-product. Mechanistic studies revealed that the intramolecular substitution reaction proceeds through an SN2 reaction with secondary alcohols and an SN1 reaction, comprising a tight ion pair, with tertiary alcohols giving products with inversion of configuration at the stereogenic carbon in both cases. The iron interacts with both nucleofile and nucloefuge, where the latter leads to a controlled carbon−oxygen (C–O) bond cleavage. The procedure opens up new atom efficient technique for catalytic stereospecific reactions that allow easily accessible stereogenic secondary and tertiary alcohols to be considered as substrates in substitution reactions.
Neodisaccharides consisting of two monosaccharides linked by a bridging nitrogen atom have been synthesised. Converting one of the monosaccharide coupling components into an unsaturated derivative enhances its electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated 4-alcohols gave the 4-amino pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino pseudodisaccharide as the major product along with other minor products. Derivatisation of the C=C double bond in pseudodisaccharides allowed the formation of Man(N4–6)Glc and Man(N4–6)Man neodisaccharides. The inhibitory activity of some N-linked neodisaccharides against the enzyme α-Glucosidase II is reported.
A versatile approach for the production of dispersed thiol-stabilized gold nanoparticles in the pores of siliceous mesocellular foam (MCF) is described and the thiol-stabilized gold nanoparticles were found to catalyze the cyclization of 4-pentynoic acids to lactones. The reported method is based on an electrochemical oxidation of a gold substrate generating oxidative Au(III) species which give rise to a surface-confined redox reaction yielding MCF supported Au(I)-thiolates. By reducing the MCF-S-Au(I) complex with sodium borohydride thiol-stabilized gold nanoparticles were obtained which were characterized with Transmission Electron Microscopy (TEM). The nanoparticles were found to be in the size of 1-8 nm. Inductive Coupled Plasma (ICP) analysis indicated an Au loading of 3 % (w/w) on the MCF. Further 0.5 mol% of the MCF-S-Au(0) solids were used to catalyze the cyclization reaction of 4-alkynoic acid under mild conditions with high selectivity (> 99%).
Using an indirect method, we have synthesised α-linked carbasugar analogues of galactofuranosides for the first time. Opening of a β-talo configured carbasugar 1,2-epoxide by alcohol nucleophiles under Lewis acidic conditions proceeded with very good regioselectivity to give α-talo configured C-1-substituted ethers with OH-2 free. Inversion of configuration at OH-2 by an oxidation–reduction sequence gave the α-galacto configured carbahexofuranose C-1 ethers. A carbadisaccharide corresponding to the Galf(α1→3)Manp substructure from Apodus deciduus galactomannan was synthesised to exemplify the method.
A selectively protected carbasugar analogue of β-galactofuranose was synthesised from glucose using ring-closing metathesis as the key step. The carbasugar was converted into an α-galacto configured 1,2-epoxide, which was an effective electrophile in Lewis acid catalysed coupling reactions with alcohols. The epoxide was opened with regioselective attack at C-1 to give β-galacto configured C-1 ethers. Using carbohydrates as nucleophiles, we synthesised a number of pseudodisaccharides.
A partially protected carbasugar analogue of β-galactofuranose was converted into an α-galacto configured 1,2-epoxide, which was was opened by alcohols under Lewis acid catalysis with regioselective attack at C-1 to give β-galacto configured C-1 ethers. Using OH-5 and OH-6 carbagalactofuranose derivatives as nucleophiles, we synthesised pseudodisaccharide analogues of substructures of the arabinogalactan from M. tuberculosis. The dicarba analogue of the disaccharide Galf(β1→5)Galf was found to moderately inhibit the action of GlfT2 galactofuranosyl transferase from M. tuberculosis.
Bacterial polysaccharides are comprised of a variety of monosaccharides, L-rhamnose (6-deoxy-Lmannose) being one of them. This sugar is often part of α-(1→2)- and/or α-(1→3)-linkages and wehave therefore studied the disaccharide α-L-Rhap-(1→2)-α-L-Rhap-OMe to obtain information onconformational preferences at this glycosidic linkage. The target disaccharide was synthesized with 13C site-specific labeling at C1' and at C2', i.e., in the terminal group. 2D 1H,13C-HSQC-HECADE and 1H,13C-J-HMBC NMR experiments, 1D 13C and 1H NMR spectra together with total line-shape analysis were used to extract conformationally dependent hetero- and homonuclear spin-spincoupling constants. This resulted in the determination of 2JC2',H1' , 3JC1',C1 , 3JC1',C3 , 3JC2',C2 , 2JC1',C2 ,1JC1',C2' , and 1JC1',H1' . These data together with previously determined JC,H and 1H,1H NOEs result in fourteen conformationally dependent NMR parameters that are available for analysis of glycosidiclinkage flexibility and conformational preferences. A molecular dynamics simulation of the disaccharide with explicit water molecules as solvent showed a major conformational state at ΦH =40° and ψH = –35°, consistent with experimental NMR data.
An array of NMR spectroscopy experiments have been carried out to obtain conformationallydependent 1H,13C- and 13C,13C-spin-spin coupling constants in the trisaccharide a-L-Rhap-(1®2)[a-LRhap-(1®3)]-a-L-Rhap-OMe. The trisaccharide was synthesized with 13C site-specific labeling at C2'and C2'', i.e., in the rhamnosyl groups in order to alleviate 1H spectral overlap. Using both the naturalabundance compound and the 13C-labeled sample 2D 1H,13C-J-HMBC and 1H,13C-HSQC-HECADENMR experiments, total line-shape analysis of 1H NMR spectra and 1D 13C NMR experiments wereemployed to extract 3C,H J , 2C,H J , 3C,C J , and1C,C J . The 13C site-specific labeling facilitates straightforward determination of nC,C J as the splitting of the 13C natural abundance resonances. This studyresulted in seven conformationally dependent coupling constants for the trisaccharide and illustrates theuse of 13C site-specific labeling as a valuable tool that extends the 1D and 2D NMR methods in currentuse to attain both hetero- and homonuclear spin-spin coupling constants.
Herein we report the use of Ir-N,P catalysts for the asymmetric hydrogenation of β-hydroxy silanes via an in-situ generated olefin intermediate. The reaction proceeds via an acid catalysed Peterson olefination reaction and provides hydrogenated products in excellent ee’s of up to 99% accompanied with high isolated yields under mild reaction conditions and short reaction times. Modification of the reaction conditions provides a choice to hydrogenate either an olefin or a β-hydroxy silane in a chemo-selective manner leaving the other functionality unaffected in the product.
A variety of oxazolidinone-enamides were prepared and evaluated in this reaction. High yields, (up to 99%) and excellent ee, (up to 99%) were obtained.
A series of single-site ruthenium(III) complexes (2a-d) were synthesized and characterized, and employed in the oxidation of H2O. A linear free-energy relationship study was conducted in order to establish a correlation between the electrochemical properties and the electronic parameters of the introduced substituents in complexes 2a-d.