100007-62-3

A group of tridentate Schiff bases derived from (+)-α-pinene were synthesized. The steric effects in the transition state, the importance of π-π stacking interactions as well as the electronic effects of aryl aldehydes according to Hammett constant values in the enantioselective addition of Et2Zn to aldehydes with the use of Schiff bases as chiral ligands are described. Also, a variety of aldehydes were cyanated using a catalyst prepared in situ from titanium tetraisopropoxide and chiral Schiff bases. The influence of a conjugated double-bond in the cyanation substrates on enantioselectivity was observed. The chemical structures of the chiral Schiff base-titanium alkoxide complexes are discussed based on their 1H and 13C NMR spectra. 3D models of the Zn2-complex catalyst and Ti-complex catalyst containing α-pinane-type Schiff bases based on X-ray diffraction experiments are postulated. The models presented were consistent with the reported chirality of the addition product and observed ee.

Zr(OBut)4 can serve as an effective promoter for the Meerwein-Ponndorf-Verley alkynylation of aldehydes and also facilitate MPV type cyanide transfer to aldehyde carbonyls with commercially available acetone cyanohydrin under mild conditions. Based on this finding, a new procedure for asymmetric cyanohydrin synthesis has been developed employing (4R,5R)-2,2-dimethyl-α,α,α′,α′-tetraph enyl-1,3-dioxolane-4,5-dimethanol (TADDOL, 6) as a chiral ligand. For instance, sequential treatment of CH2Cl2 solution of 6 (1 equiv.) with Zr(OBut)4 (1 equiv.) and acetone cyanohydrin (2 equiv.) at room temperature for 1 h, and subsequent reaction with 3-phenylpropanal at -40°C for 7.5 h resulted in formation of the corresponding cyanohydrin 5g [R=Ph(CH2)2] in 63% isolated yield with 85% ee. The scope and limitations of this method have been clarified with various aldehydes as substrates.

The merging of photoredox catalysis and N-heterocyclic carbene (NHC) catalysis for γ- and ?-alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ-oxidized enals with alkyl halides worked well for the synthesis γ-multisubstituted-α,β-unsaturated esters, including those with challenging vicinal all-carbon quaternary centers. The synthesis of ?-multisubstituted-α,β-γ,δ-diunsaturated esters by an unprecedented NHC-catalyzed ?-functionalization was also established.

The vanadium(V)(salalen) complex prepared in situ from the corresponding vanadium(IV) complex 4 under aerobic conditions was found to be an excellent catalyst for asymmetric transcyanation of aliphatic aldehydes with acetone cyanohydrin as the cyanide sou

Cetiedil ((±)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers of the Ca2+-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca2+-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (K(vol)) of liver cells. The enantiomers did not differ substantially in their ability to block the Ca2+-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 ± 0.2 (s.d.) times more active than the (-) form. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 ± 0.54 (s.d.) μM; (-)-cetiedil was 2.6 ± 0.8 (s.d.) times less active (IC50 of 5.2 ± 1.2 μM). Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.

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Chiral titanium reagents derived from optically active sulfoximines and Ti(O-i-Pr)4 promote the asymmetric addition of trimethysilyl cyanide to aldehydes affording cyanohydrins in high yields with good enantioselectivities (up to 91% ee). The ligand structure and the reaction conditions have been optimized. With substoichiometric amounts of the sulfoximine-titanium reagent the product is obtained in decreased yield with lower enantiomeric excess. The molecular structures of (R)-S-(2-hydroxypheny)-S-methyl sulfoximine [(R)-4a] and (R)-S-(2-hydroxyphenyl)-S-(1.1-dimethylethyl) sulioximine [(R)-4d) have been determined by X-ray diffraction analysis. Acta Chemica Scandinavica 1996.

Disclosed are alpha keto amide and alpha hydroxy amide compounds and compositions that inhibit soluble epoxide hydrolase (sEH), methods for preparing the compounds and compositions, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, pulmonary, and diabetic-related diseases.

6,6'-Bis(methylaminosulfonyl)-7,7'-dihydroxy-8,8'-biquinolyl (3) catalyzes (5-10 mol-%) the addition of trimethylsilyl cyanide to aldehydes (aryl, alkyl, and α,β-unsaturated; 42-92 % yields), ketones (aryl alkyl, dialkyl; 22-82 % yields), and N-benzylaldimines (14-78 % yields) in toluene (0 °C or room temp.) to give the expected cyanohydrin and Strecker adducts following desilylation. Among a series of closely related compounds lacking any one of their defining structural features, bis-sulfonamide 3 and its N,N'-dimethyl derivative are exceptional in catalyzing the silylcyanation of benzaldehyde in the absence of all other additives. Hammett analysis of the competitive silylcyanation of para-substituted benzaldehydes catalyzed by 3 showed a linear free-energy relationship (R2 = 0.928) with a modest positive reaction constant (ρ = +1.52). X-ray diffraction analysis of (±)-3 indicated a cisoid biaryl conformation and the existence of an intramolecular hydrogen bond between C7'-OH and C7-O. Resolution of (±)-3 was achieved by HPLC separation of its tetravalerate derivative on a chiral stationary phase. The absolute configurations of the optical isomers of 3 were assigned by correlation of the ECD spectra with those of related biquinolyls of known configuration. The silylcyanation of aldehydes catalyzed by (-)-(aR)-3 leads to cyanohydrins with a preference for the (S)-configured product with an ee of 10 %. The organocatalytic action of 3 is ascribed to hydrogen bonding and Bronsted acid catalysis effects that are dependent on its acidifying sulfonamide groups, general base capability, and interannular proximity effects made possible by the biaryl structure. Copyright

Room-temperature synthesis of enantioenriched non-protected cyanohydrins using acetone cyanohydrin as the cyanide source was achieved by V(salalen) catalyst. Aliphatic aldehydes underwent the cyanation with 89-95% ee in the presence of only 0.2-0.4 mol% catalyst. Aromatic cyanohydrins were also obtained in high enantiomeric excesses under modified conditions.

α-Aminonitriles inaccessible by traditional Strecker chemistry are obtained in redox-neutral fashion by direct amine α-cyanation/N-alkylation or alternatively, α-aminonitrile isomerization. These unprecedented transformations are catalyzed by simple carboxylic acids.

Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer, Down syndrome or early onset Alzheimer's disease.

A hydroxynitrile lyase was isolated and purified to homogeneity from seeds of Eriobotrya japonica (loquat). The final yield, of 36% with 49-fold purification, was obtained by 30-80% (NH4)2SO4 fractionation and column chromatography on DEAE-Toyopearl and Concanavalin A Sepharose 4B, which suggested the presence of a carbohydrate side chain. The purified enzyme was a monomer with a molecular mass of 72 kDa as determined by gel filtration, and 62.3 kDa as determined by SDS-gel electrophoresis. The N-terminal sequence is reported. The enzyme was a flavoprotein containing FAD as a prosthetic group, and it exhibited a Km of 161 μM and a k cat/Km of 348 s-1 mM-1 for mandelonitrile. The optimum pH and temperature were pH 5.5 and 40°C respectively. The enzyme showed excellent stability with regard to pH and temperature. Metal ions were not required for its activity, while activity was significantly inhibited by CuSO4, HgCl2, AgNO3, FeCl3, β-mercaptoethanol, iodoacetic acid, phenylmethylsulfonylfluoride, and diethylpyrocarbonate. The specificity constant (kcat/Km) of the enzyme was investigated for the first time using various aldehydes as substrates. The enzyme was active toward aromatic and aliphatic aldehydes, and showed a preference for smaller substrates over bulky one.

Several aliphatic, aromatic and heteroaromatic aldehydes have been converted into the chiral cyanohydrins using the (S) hydroxynitrile lyase from Hevea brasiliensis. The corresponding cyanohydrins were obtained in moderate to good yield and high enantiomeric excess with the exeption of phenyloxyacetaldehyde, benzyloxyacetaldehyde and the pyrrole-, pyridine- and indolealdehydes investigated. In contrast to previously reported results, cinnamaldehyde could be converted into (S)-(-)-2-hydroxy-4-phenyl-(E)-but-3- enenitrile with good selectivity by means of optimized reaction conditions.

The 1,2-addition of trialkylsilylcyanides to aldehydes and ketones produces the corresponding protected cyanohydrins in good to excellent yields when carried out at 0°C to room temperature in the presence of catalytic amounts of the nonionic strong base P(RNCH2CH2)N (R = Me, i-Pr) in THF. These catalysts are easily removed from the product by hydrolysis or column filtration through silica gel.

The present technology is directed to compounds of formula (I), compositions thereof, and methods related to inhibition of ASKI. In particular, the present compounds and compositions may be used to treat ASKl-mediated disorders and conditions, including,

A nickel/zinc-catalyzed cross-electrophile coupling of alkyl electrophiles activated by an α-cyano group and chlorosilanes is reported. Elemental zinc is the stoichiometric reductant in this reductive coupling process. By this, a C(sp3)?Si bond can be formed starting from two electrophilic reactants whereas previous methods rely on the combination of carbon nucleophiles and silicon electrophiles or vice versa.

The invention belongs to the field of, asymmetric synthesis, and discloses a method for catalyzing asymmetric cross- coupling to synthesize: an alkyne, and the L method comprises, the following steps, of A: preparing B a cuprous, salt and C a: ligand; preparing a catalyst; adding a base; reacting the compound with the compound with the compound; and reacting the compound with the compound. Of these, one of them, X is selected from the group consisting of, R halogens. 1 Optionally substituted heteroarylsulfonylcyanamide groups selected from the, group consisting, of optionally substituted, phenyl groups In-flight vehicle, R6 Trialkyl silyl groups or alkyl radicals, R2 Cycloalkyl radicals optionally substituted with an, optionally substituted alkyl, (CH radical2 )n R4 Multi,layer chain, n＝0-10,R saw blade4 A group selected, from, the group consisting of phenyl, alkenyl, aralkynyls, noonyloxy,and, noonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylsulphonylphenyl disiloxy-radicals. R3 A ligand, selected from hydrogen or any of the functional groups, is selected from the group consisting of, hydrogen and any L other functional group. The method, R disclosed by the, A invention has the, advantages of good catalytic, R ’ effect, wide application range. and high catalytic efficiency, and the, method disclosed by the, invention has the. advantages of good catalytic effect, wide application range and high catalytic efficiency. (by machine translation)

Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of more than half of pharmaceutic drugs, and inactivation of CYP3A4 can lead to adverse drug-drug interactions. The substituted imidazole compounds 5-fluoro-2-[4-[(2-phenyl-1H-imidazol-5-yl) methyl]-1-piperazinyl]pyrimidine (SCH 66712) and 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP) have been previously identified as mechanism-based inactivators (MBI) of CYP2D6. The present study shows that both SCH 66712 and EMTPP are also MBIs of CYP3A4. Inhibition of CYP3A4 by SCH 66712 and EMTPP was determined to be con-centration, time, and NADPH dependent. In addition, inactivation of CYP3A4 by SCH 66712 was shown to be unaffected by the presence of electrophile scavengers. SCH 66712 displays type I binding to CYP3A4 with a spectral binding constant (Ks) of 42.9 ± 2.9 μM. The partition ratios for SCH 66712 and EMTPP were 11 and 94, respectively. Whole protein mass spectrum analysis revealed 1:1 binding stoichiometry of SCH 66712 and EMTPP to CYP3A4 and a mass increase consistent with adduction by the inactivators without addition of oxygen. Heme adduction was not apparent. Multiple monooxygenation products with each inactivator were observed; no other products were apparent. These are the first MBIs to be shown to be potent inactivators of both CYP2D6 and CYP3A4.

Invented are novel 1 H-imidazo[4,5-c]pyridin-2-yl compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

The chiral oxazaborolidinium salts 1 and 2 are excellent catalysts for the enantioselective cyanosilylation of a wide variety of aldehydes (see Table 1) using trimethylsilyl (TMS) cyanide and triphenylphosphine oxide as the source of a new reactive cyanide donor. This donor appears to be the isocyanophosphorane Ph3P(OTMS)(N=C:) (4). The novel process described herein has several advantages: predictability of absolute configuration of cyanohydrin products from a mechanistic model (3), high yields and very good enantiomeric purity of products (≥90%), and, finally, easy and efficient recovery of the catalytic ligand. Copyright

Enzymatic kinetic resolution of a series of aromatic and aliphatic cyanohydrins in organic media has been investigated. The behavior of potential lipases, molecular sieves, acyl reagent, reaction temperature, and organic solvents on the kinetic resolution was studied. The influence of substrate structure, steric, and electronic nature and position of the aryl substituent on the enantioselectivity was discussed. Under the optimized reaction conditions, good enantioselectivity could be achieved for most of the investigated compounds. Specifically, substrates 1a, 1c, 1d, 1f, 1u could be resolved with the kinetic enantiomer ratio (E) higher than 200.

Oxovanadium(V) complex 4 was prepared from VOSO4 and tridentate Schiff base ligand, which was prepared from substituted salicylaldehyde and inexpensive (S)-valine. Asymmetric silylcyanation of the aldehydes catalyzed by catalyst 4 afforded cyanohydrins with good enantioselectivities.

Five tridentate Schiff bases have been prepared from (1R,2S,3R,4S)-3-amino- 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol and salicylaldehydes. X-ray structure investigation revealed differences in their molecular conformation, and their titanium(IV) complexes

A multistereogenic salen-Mn(iii) complex bearing an aromatic pocket and two benzylic groups as helping hands was found to be efficient in the catalysis of asymmetric cyanosilylation. The salen-Mn catalyst partially mimics the functions of biocatalysts by

α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.

Treatment of α,β-unsaturated nitriles with Mn(dpm)3 (3 mol%), PhSiH3 in isopropyl alcohol in the presence of oxygen resulted in reduction and α- and β-hydroxylation.

A novel reaction involving cyano transfer from benzophenone cyanohydrin to aldehydes and imines was realized by using dibutyltin dimethoxide as a catalyst. Various cyanohydrins and α-amino nitriles were obtained in moderate to high yields by this reaction. Ketimines also showed remarkable reactivity as cyano acceptors under conventional reaction conditions. This catalytic reaction was further applied to a three-component condensation reaction of aldehydes, aniline, and benzophenone cyanohydrin in the presence of Drierite. Copyright

N-Heterocyclic carbenes produced in situ from salts of imidazolium, benzimidazolium, pyrido[1,2-c]imidazolium, imidazolinium, thiazolium, and triazolium catalyze the addition of trimethylsilylcyanide to aldehydes to yield cyanohydrin trimethylsilyl ethers. The use of C2-symmetric imidazolidenyl carbene derived from (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium chloride led to enantioselective cyanosilylation.

Cyanosilylation of various aldehydes and ketones with TMSCN proceeded smoothly under mild conditions to give the corresponding cyanohydrin trimethylsilyl ethers in the presence of nanocrystalline magnesium oxide. The cyanohydrin trimethylsilyl ethers of aldehydes produced cyanohydrins in good to high yields on treatment with 2 N HCl. 29Si NMR spectral evidence proved that the reaction proceeds through the hypervalent silicate species by coordination to O2-/O- (Lewis basic site) of nanocrystalline magnesium oxide. Copyright Taylor & Francis Group, LLC.

(Matrix presented) In the presence of MS 4A in DMSO, cyanobenzoylation of various aldehydes with benzoyl cyanide proceeded very smoothly to give the corresponding cyanohydrin benzoates in high to excellent yields without an acid or a base. On the other hand, reaction of aldehydes with BzCN in DMSO-H2O also occurred readily to afford the corresponding free cyanohydrins exclusively.

A copper-catalyzed nucleophilic displacement of α-triflyloxy nitriles and esters with silicon nucleophiles allows for the stereospecific generation of highly enantioenriched α-silylated carboxyl compounds. The enantioselective synthesis of α-silylated nitriles is unprecedented. The catalytic system exhibits good functional group tolerance. The stereochemical course of the substitution is shown to proceed with inversion of the configuration. The new reaction is an addition to the still limited number of methods for catalytic C(sp3)-Si cross-coupling.

We report a new thiourea - Bronsted acid cooperative catalytic system for the enantioselective cyanosilylation of aldehydes with yields up to 90% and enantioselectivities up to 88%. The addition of an achiral acid was found to be crucial for high asymmetric induction. Mechanistic investigations using a combination of NMR, ESI-MS, and density functional theory computations (including solvent corrections) at the M06/6-31G(d,p) level of theory suggest that the key catalytic species results from the cooperative interaction of bifunctional thioureas and an achiral acid that form well-defined chiral hydrogen-bonding environments.

Thermodynamic and kinetic control of a chemical process is the key to access desired products and states. Changes are made when a desired product is not accessible; one may manipulate the reaction with additional reagents, catalysts and/or protecting groups. Here we report the use of carbon dioxide to accelerate cyanohydrin synthesis under neutral conditions with an insoluble cyanide source (KCN) without generating toxic HCN. Under inert atmosphere, the reaction is essentially not operative due to the unfavored equilibrium. The utility of CO2-mediated selective cyanohydrin synthesis was further showcased by broadening Kiliani–Fischer synthesis under neutral conditions. This protocol offers an easy access to a variety of polyols, cyanohydrins, linear alkylnitriles, by simply starting from alkyl- and arylaldehydes, KCN and an atmospheric pressure of CO2.

Chiral zirconium alkoxides prepared in situ from Zr(OBu(t))4, TADDOL and acetone cyanohydrin in CH2Cl2 effect the enantioselective Meerwein-Ponndorf-Verley cyanation of alde-hydes, giving optically active cyanohydrins. The

A chiral C2-symmetric NCN ligand, (5R,7R)-1,3-bis(6,6-dimethyl-5,6,7,8-tetrahydro-5,7-methanoquinolin-2-yl)benzene has been synthesized. A direct cyclometalation of this ligand with K2MCl4 (M = Pt, Pd) in dry acetic acid offered the corresponding pincer complexes, [(5R,7R)-1,3-bis(6,6-dimethyl-5,6,7,8-tetrahydro-5,7-methanoquinolin-2-yl)phenyl]platinum(II) chloride 5a and its palladium(II) analogue 5b. The Pt(II) and Pd(II) complexes 5 were characterized by NMR spectroscopy, and X-ray crystal structure analysis was done for the Pt(II) complex. The NMR data for both the complexes and X-ray crystal structural data for the chloro-Pt(II) complex indicate the existence of intramolecular C-H?Cl hydrogen bonding both in solution and in solid states. Chloride abstraction from 5a by treatment with silver triflate resulted in the corresponding triflate complex 6a, which generates the corresponding cationic aqua complex 7a in the presence of water molecules. The Pt(II) complex 6a/7a was used as asymmetric catalyst in the aldol reaction between methyl isocyanoacetate and aldehydes and also in the silylcyanation of aldehydes.

Complexes formed between lanthanide trichlorides and 2,6- bis(substituted-2-oxazolin-2-yl)pyridine (pybox) ligands are effective catalysts for the enantioselective addition of trimethylsilylcyanide (TMSCN) to a range of aldehydes.

The first method for the stereoconvergent cross-coupling of racemic α-halonitriles is described, specifically, nickel-catalyzed Negishi arylations and alkenylations that furnish an array of enantioenriched α-arylnitriles and allylic nitriles, respectively. Noteworthy features of this investigation include: the highly enantioselective synthesis of α-alkyl-α-aryl nitriles that bear secondary α-alkyl substituents; the first examples of the use of alkenylzinc reagents in stereoconvergent Negishi reactions of alkyl electrophiles; demonstration of the utility of a new family of ligands for asymmetric Negishi cross-couplings (a bidentate bis(oxazoline), rather than a tridentate pybox); in the case of arylzinc reagents, carbon-carbon bond formation at a remarkably low temperature (-78 °C), the lowest reported to date for an enantioselective cross-coupling of an alkyl electrophile; a mechanistic dichotomy between Negishi reactions of an unactivated versus an activated secondary alkyl bromide.

Cyanohydrins are versatile intermediates toward valuable organic compounds like α-hydroxy carboxylic acids, α-amino acids, and β-amino alcohols. Numerous protocols are available for synthesis of (O-protected) cyanohydrins, but all procedures invariably rely on the use of toxic cyanide sources. A novel cyanide-free synthesis of O-trityl protected cyanohydrins via a catalytic Passerini-type reaction involving aldehydes and trityl isocyanide is reported. The feasibility of a catalytic asymmetric reaction is demonstrated using chiral phosphoric acid catalysis.

The synthesis of BMPD, 1,3-bis(2-methylferrocenyl)-propane-1,3-dione, was achieved via the Claisen condensation of a homochiral ferrocenecarboxylate and an acetylferrocene derived from the same chiral formylferrocene. Several metal complexes were prepared to exemplify the complexation ability of BMPD. A BMPD-yttrium complex was found to act as a new catalyst for silylcyanation of aldehydes with remarkable efficiency. As little as 0.2 mol% of the complex catalyzed the reaction of benzaldehyde and cyanotrimethylsilane to afford the cyanohydrin in 95% yield with 87% ee.

There is provided small molecule anti-human immunodeficiency virus (anti-HIV) compounds as well as a phenotypic cell-based high throughput screening (HTS) assay for their identification.

The first method for cyanosilylation of aldehydes with trimethylsilyl cyanide in the presence of the N-heterocyclic carbene prepared from 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride and potassium tert-butoxide, as a nucleophilic catalyst, is described. Georg Thieme Verlag Stuttgart.

We describe a new efficient synthesis of the prescribed racemic drug cetiedil [(±)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethylester], Additionally, we report herein a high yielding large scale, route to its acid precursor 7, subsequently enabling large-scale synthesis of the chiral forms of cetiedil, and detailed pharmacological investigations. Additionally, we describe a novel route to α-ketocarboxylic acids, starting from readily available or easily obtainable aldehydes: The mild conditions utilised opens up its applicability for use on molecules of biological interest. Georg Thieme Verlag Stuttgart.

A one-pot chemo-enzymatic synthesis of highly enantiomerically enriched O-acetylcyanohydrins has been developed. The bimetallic (salen)titanium complex 1 is used to convert aldehydes into nonracemic (R)-O-acetylcyanohydrins with 61 to 93 % enantiomeric ex

It is well-recognized that aldimines are less reactive than aldehydes toward nucleophilic additions. In this paper, an unprecedented change in the reactivity is described: preferential reactions of aldimines over aldehydes in nucleophilic additions using

Ruthenium-catalyzed dehydrogenation of cyanohydrins under acceptorless and base-free conditions was demonstrated for the first time in the synthesis of acyl cyanide. As opposed to the thermodynamically preferred elimination of hydrogen cyanide, the dehydrogenation of cyanohydrins could be kinetically controlled with ruthenium (II) bidentate phosphine complexes. The effects of the arene, phosphine ligands and counter anions were investigated in regard to catalytic activity and selectivity. Selective dehydrogenation can occur via β-hydride elimination with the experimentally observed [(alkoxide)Ru] complex. (Figure presented.).

A monometallic bifunctional catalyst, in which only one imidazolyl moiety is directly attached at the 3-position of a binaphthol moiety, has been developed. The ligand (R)-1, which lacks C2-symmetry and flexible linkers, in combination with Ti(OiPr)4, has been demonstrated to promote the enantioselective cyanation of aldehydes with trimethylsilylcyanide (TMSCN), giving excellent enantioselectivities of up to 98 % ee and high yields of up to 99%. The use of this bifunctional catalytic system obviates the need for additives and is extremely simple as the reagents are added in one portion at the beginning of the reaction. The protocol has been found to tolerate a relatively wide range of aldehydes when 10 mol% of the (R)-1/Ti(OiPr) 4 complex is deployed in CH2Cl2 at -40°C, the conditions which proved most practical and effective. The asymmetric cyanations also proceeded with lower catalyst loadings (5 mol%, or even 2 mol%), still giving satisfactory enantiomeric excesses and yields. Interestingly, the use of freshly distilled TMSCN dried over CaH2 gave a low enantioselectivity and only a moderate yield of the adduct as compared with direct use of the commercial reagent. The results of 13C NMR spectroscopic studies implicate HCN as the actual reactive nucleophile.

A new hydroxynitrile lyase (HNL) was isolated from the seed of Japanese apricot (Prunus mume). The enzyme has similar properties with HNL isolated from other Prunus species and is FAD containing enzyme. It accepts a large number of unnatural substrates (benzaldehyde and its variant) for the addition of HCN to produce the corresponding cyanohydrins in excellent optical and chemical yields. A new HPLC based enantioselective assay technique was developed for the enzyme, which promotes the addition of KCN to benzaldehyde in a buffered solution (pH=4.5).

Chiral cyanohydrins are useful intermediates in the pharmaceutical and agricultural industries. In nature, hydroxynitrile lyases (HNLs) are a kind of elegant tool for enantioselective hydrocyanation of carbonyl compounds. However, currently available methods for demonstrating hydrocyanation are still stalled at precise, but low-throughput, GC or HPLC analyses. Herein, we report a chromogenic high-throughput screening (HTS) method that is feasible for the cyanohydrin synthesis reaction. This method was highly anti-interference and sensitive, and could be used to directly profile the substrate scope of HNLs either in cell-free extract or fermentation clear broth. This HTS method was also validated by generating new variants of PcHNL5 that presented higher catalytic efficiency and stronger acidic tolerance in variant libraries.

The right combination: A series of aromatic, heteroaromatic, aliphatic, and α,β-unsaturated aldehydes can be converted into the desired silylated cyanohydrins by reaction with (CH3)3SiCN and a catalyst system consisting of the combination of a chiral ruthenium complex and Li2CO3 (see scheme). The reaction is highly enantioselective and affords the R products with up to 98% ee within 24 h at a substrate-tocatalyst ratio of 10000:1. (Chemical Equation Presented).