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The conversion of an aldehyde into a nitrile can be efficiently performed using O-phenylhydroxylamine hydrochloride in buffered aqueous solutions. The reported method is specifically optimized for aqueous-soluble substrates including carbohydrates. Several reducing sugars including monosaccharides, disaccharides, and silyl-protected saccharides were transformed into cyanohydrins in high yields. The reaction conditions are also suitable for the formation of nitriles from various types of hydrophobic aldehyde substrates. Furthermore, cyanide can be eliminated from cyanohydrins, analogous to the Wohl degradation, by utilizing a readily-removed weakly basic resin as a promoter.

Background: Halogenated corticosteroids are widely used in medicine, and the global need of these steroidal APIs is estimated to be 40 – 70 tons, annually. Vietnam currently imports the pharmaceutical compounds up to 90%, in particular 100% of steroidal drugs. Currently, industrial production is based on the chemical syntheses of corticosteroids from either 16- dehydropregnenolone acetate (obtained from diosgenin) or androstenedione (obtained from phytosterol). The development of shorter synthetic schemes and more economically feasible technologies is of great significance. Introduction of 1(2)-double bond at the final stages of the corticosteroids synthesis results inpoor yield. 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione (tetraene acetate) is a key intermediate in the synthesis of highly active halogenated corticosteroids such as dexamethasone and other halogenated corticosteroids. 21-acetoxypregna-1,4,9(11),16- tetraene-3,20-dione is a key intermediate in the synthesis of dexamethasone from the readily available and cheap 9α-hydroxyandrost-4-ene-3,17-dione. Objective: The purpose of this study was the development of an efficient and shorter procedure for the synthesis of 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, which is a product of a bio-oxidative degradation of the side chain of phytosterols. Methods: Pregnane side chain was constructed using cyanohydrin method. For 1(2)- dehydrogenation, selene dioxide was applied for the introduction of Δ1(2)-double bond. Other stages of the synthesis were epimerization, Stork’s iodination procedure and dehydration. Result: 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione was prepared from 9α- hydroxyandrostenedione in yield more than 46%. Conclusion: An efficient and practically feasible procedure for the synthesis of 21-acetoxypregna- 1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, a key intermediate for the synthesis of 9-haloidated corticoids, has been developed. The procedure can be applied for the production of value-added 9-haloidated corticoids.

Metabolism of bardoxolone methyl (BARD-Me), an oleanolic acid derivative, and its epoxide metabolite was studied in different in vitro systems. BARD-Me also undergoes glutathione (GSH)-adduct formation via direct nucleophilic attack at the β-carbon of the α,β-unsaturated ketone substituent on the A-ring. The presence of an electron withdrawing nitrile residue on the α-carbon increases the α,β-unsaturated ketone’s susceptibility to nucleophilic attack by thiols. This allows BARD-Me to generate reversible adducts with the thiol groups of Cysteine residues in target proteins without the potential toxic liabilities of irreversible covalent adduct formation. However, BARD-Me epoxide can also react with thiols irreversibly. Therefore, the epoxide was synthesized and its metabolic fate studied in vitro. BARD-Me epoxide was found to undergo two novel metabolic biotransformations; epoxide reduction and oxidative elimination of nitrile moiety. Both metabolic pathways proceed via nucleophilic attack of the thiol group of GSH at each of the two carbon atoms of the epoxide as evidenced by the formation of two β-hydroxy sulfide regioisomers. Oxidative elimination of nitrile moiety proceeds via nucleophilic attack of the thiol group of GSH at the epoxide carbon atom that is β to the cyano group to give a cyanohydrin metabolite, which spontaneously decomposes to release cyanide and the corresponding ketone. Nucleophilic attack of the thiol group of GSH at the epoxide carbon atom that is α to the cyano group, results in the formation of the GSH mono-adduct that undergoes intermolecular reduction with another GSH molecule, followed by elimination of oxidized GSH (GS-SG) and the formation of an enolate intermediate. Upon protonation, the enolate intermediate gives rise to hydroxylated BARD-Me, which is readily converted back to BARD-Me through the elimination of water. The chemical reactivity of the epoxide metabolite and the liberation of cyanide is of significant toxicological interest for the potential utility of BARD-Me as a therapeutic agent.

Potential toxicity of cyanogenic glycosides arises from enzymatic degradation to produce hydrogen cyanide. Information on the metabolism of cyanogenic glycosides is available from in vitro, animal and human studies. In the absence of β-glucosidase enzymes from the source plant material, two processes appear to contribute to the production of cyanide from cyanogenic glycosides; the proportion of the glycoside dose that reaches the large intestine, where most of the bacterial hydrolysis occurs, and the rate of hydrolysis of cyanogenic glycosides to cyanohydrin and cyanide. Some cyanogenic glycosides, such as prunasin, are actively absorbed in the jejunum by utilising the epithelial sodium-dependent monosaccharide transporter (SGLT1). The rate of cyanide production from cyanogenic glycosides due to bacterial β-glycosidase activity depends on; the sugar moiety in the molecule and the stability of the intermediate cyanohydrin following hydrolysis by bacterial β-glucosidase. Cyanogenic glycosides with a gentiobiose sugar, amygdalin, linustatin, and neolinustatin, undergo a two stage hydrolysis, with gentiobiose initially being hydrolysed to glucose to form prunasin, linamarin and lotaustralin, respectively. While the overall impact of these metabolic factors is difficult to predict, the toxicity of cyanogenic glycosides will be less than the toxicity suggested by their theoretical hydrocyanic acid equivalents.

The leaves of Nandina domestica Thunb. exhibited high hydroxynitrile lyase (HNL) activity in (R)-mandelonitrile synthesis. The specific activity of young leaves was significantly higher than that of mature leaves. We isolated two HNLs with molecular mass of 24.9 kDa (NdHNL-S) and 28.0 kDa (NdHNL-L) from the young leaves. Both NdHNLs were composed of two identical subunits, without FAD and carbohydrates. We purified NdHNL-L and revealed its enzymatic properties. The whole deduced amino acid sequence of NdHNL-L was not homologous to any other HNLs, and the specific activity for mandelonitrile synthesis by NdHNL-L was higher than that by other plant HNLs. The enzyme catalyzed enantioselective synthesis of (R)-cyanohydrins, exhibited high activity at pH 4.0, and high stability in the pH range of 3.5–8.0 and below 55°C. Thus, NdHNL-L is a novel HNL with novel amino acid sequence and has a potential for the efficient production of (R)-cyanohydrins. Leaves of Nandina domestica Thunb. showing high R-hydroxynitrile lyase (HNL) activity.

Carbon dioxide is an intrinsically stable molecule. Therefore, its activation requires extra energy input in the form of reactive reagents and/or activated catalysts and, often, harsh reaction conditions. Reported here is a direct carboxylation reaction of aromatic aldehydes with carbon dioxide to afford α-keto acids as added-value products. In situ generation of a reactive cyanohydrin was the key to the successful carboxylation reaction under operationally mild reaction conditions (25-40 °C, 1 atm CO2 ). The resulting α-keto acids served as a platform for α-amino acid synthesis by reductive amination reactions, illustrating the chemical synthesis of essential bioactive molecules from carbon dioxide.

A chemodosimteric reagent (1) for the efficient detection of cyanide species (CN- and/or HCN) in aq. medium as well as under physiological conditions has been described. Selective reaction of the cyanide species with this reagent in the presence of all common interfering anions, amino acids and glutathione (GSH) led to the generation of the corresponding cyanohydrin derivative. The formation of the cyanohydrin derivative of the probe is associated with a visually detectable change in solution fluorescence in aq. buffer medium with 1.9 mu M NaCN, the threshold limit set by WHO for the safe drinking water and this makes this fluorogenic sensor an ideal candidate for in-field applications. An apparent switch on the luminescence response, ultralow detection limit, low response time, cell membrane permeability and insignificant toxicity are key features of a probe molecule, which gives it a distinct edge over previously reported chemodosimetric reagents for the detection of cyanide species (CN- or HCN) in an aqueous environment. This methodology could be used for developing a generalized and efficient fluorescence-based assay for crucial enzymes like beta-glucosidase and hydroxynitrile lyase. Furthermore, spectrally-resolved fluorescence microscopy measurements on single-cells revealed that this sensor molecule could also be used for imaging the cellular uptake of cyanide species from aq. solution contaminated with NaCN. Our results confirmed that statistical analysis of integrated intensity and transition energy obtained from the emission spectra collected over various microscopic sub-cellular regions can potentially be used to discriminate the effects of local cellular environments and that due to cyanide detection.

Cyanide ions are shown to interact with lanthanide complexes of phenacylDO3A derivatives in aqueous solution, giving rise to changes in the luminescence and NMR spectra. These changes are the consequence of cyanohydrin formation, which is favored by the coordination of the phenacyl carbonyl group to the lanthanide center. These complexes display minimal affinity for fluoride and can detect cyanide at concentrations less than 1 μm. By contrast, lanthanide complexes with DOTAM derivatives display no affinity for cyanide in water, but respond to changes in fluoride concentration.

The identity of the major product of Ru-catalysed alkene metathesis of two polyene substrates has been determined using density functional theory (DFT) NMR prediction, a1H–1H Total Correlated Spectroscopy (TOCSY) NMR experiment and ultimately by single-crystal X-ray crystallography. The substrates were designed as those that would potentially allow expedient access to thetrans-decalin skeleton of the natural product (−)-euonyminol, but the product was found to be a bis-cyclopentenyl-β-cyanohydrin [1-(1-hydroxycyclopent-3-en-1-yl)cyclopent-3-ene-1-carbonitrile, C11H13NO] rather than thetrans-2,3,6,7-dehydrodecalin-β-cyanohydrin.

Determination of exposure to cyanide can be accomplished by direct cyanide analysis or indirectly by analysis of cyanide detoxification products, such as thiocyanate and 2-amino-2-thiazoline-4-carboxylic acid. A potentially important marker and detoxification product of cyanide exposure, α-ketoglutarate cyanohydrin (α-KgCN), is produced by the reaction of cyanide and α-ketoglutarate. Therefore, an ultra high-performance liquid chromatography tandem mass spectrometry method to determine α-KgCN in plasma was developed. Swine plasma was spiked with α-KgCN and α-KgCN-d4 (internal standard) and proteins were precipitated with 1% formic acid in acetonitrile. After centrifugation, the supernatant was dried, reconstituted, separated by reversed phase high performance liquid chromatography and analyzed by tandem mass spectrometry. The method produced a dynamic range of 0.3-50μM and a detection limit of 200nM for α-KgCN. Furthermore, the method produced a %RSD of less than 13% for all intra- and inter-assay analyses. The stability of α-KgCN was poor for most storage conditions tested, except for -80°C, which produced stable concentrations of α-KgCN for the 30days tested. The validated method was tested by analysis of α-KgCN in the plasma of cyanide-exposed swine. α-KgCN was not detected pre-exposure, but was detected in all post-exposure plasma samples tested. To our knowledge, this method is the first reported analytical method for detecting α-KgCN in any matrix.

A facile synthetic route is described to cyanogenic glycosides (R)-prunasin, linamarin and (S)-heterodendrin from O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)trichloroace- timidate and the corresponding α-hydroxyamides by a 3-step reaction of glycosylation, cyanohydrin formation by dehydration of carboxamides, and deprotection.

A highly regio- and stereospecific rhodium-catalyzed allylic alkylation of tertiary allylic carbonates with alkenyl cyanohydrin pronucleophiles is described. This protocol offers a fundamentally novel approach toward the synthesis of acyclic quaternary-substituted α,β-unsaturated ketones and thereby provides a new cross-coupling strategy for target directed synthesis. A particularly attractive feature with this process is the ability to directly couple di-, tri- and tetrasubstituted alkenyl cyanohydrin pronucleophiles to prepare the corresponding α,β-unsaturated ketone derivatives in a highly selective manner. Additionally, the chemoselective 1,4-reduction of the enone products provides rapid access to acyclic enantiomerically enriched α,α′-dialkyl-substituted ketones, which are challenging motifs to prepare using conventional enolate alkylation.

A convenient one-pot, two-step procedure for the synthesis of ketone cyanohydrin esters in aqueous media is reported using N -acylbenzotriazoles as the acylating agents. In saturated aqueous sodium bicarbonate containing a catalytic amount of tetrabutylammonium bromide, the reaction of ketones with potassium cyanide and N -acylbenzotriazoles proceeded readily at room temperature to provide the corresponding O -acyl cyanohydrin derivatives in good to excellent yields.

This report describes the total and facile synthesis of 3′-C-cyano & 3′-C-cyano-3′-deoxy pyrimidine pyranonucleosides. Reaction of 3-keto glucoside 1 with sodium cyanide gave the desired precursor 3-C-cyano-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (2). Hydrolysis followed by acetylation led to the 1,2,3,4,6-penta-O-acetyl-3-C-cyano-D-glucopyranose (4). Compound 4 was condensed with silylated 5-fluorouracil, uracil, thymine and N4-benzoylcytosine, respectively and deacetylated to afford the target 1-(3′-C-cyano-β-D-glucopyranosyl)nucleosides 6a–d. Routine deoxygenation at position 3′ of cyanohydrin 2, followed by hydrolysis and acetylation led to the 3-C-cyano-3-deoxy-1,2,4,6-tetra-O-acetyl-D-allopyranose (10). Coupling of sugar 10 with silylated pyrimidines and subsequent deacetylation yielded the target 1-(3′-C-cyano-3′-deoxy-β-D-allopyranosyl)nucleosides 12a–d. The new analogues were evaluated for their antiviral and cytostatic activities. It was found that 6a was endowed with a pronounced anti-proliferative activity that was only 2- to 8-fold less potent than that shown for the parental base 5-fluorouracil. None of the compounds showed activity against a broad panel of DNA and RNA viruses., Graphical abstract Synthesis of 3′-C-cyano-β-D-glucopyranosyl 6a–d & 3′-C-cyano-3′-deoxy-β-D-allopyranosyl nucleosides 12a–d, is reported. Derivative 6a was highly cytostatic against a panel of tumor cell lines at an IC50 between 1.9 and 32 μM. Highlights ► A stereoselective synthesis of 3'-C-branched chain nucleosides was accomplished. ► 3'-C-branched chain nucleosides was prepared and chemically characterized. ► The novel compounds were evaluated for their antitumor and antiviral activity. ► The 5-fluorouracil derivative, proved to be highly cytostatic.

The lactic acid content of gari, was determined by pH titration to be about 10 g lactic acid/kg gari. As the size of the gari particles increased from 400 to >1000 μm their total cyanide content increased from 5 to 21 ppm. The acetone cyanohydrin content of gari samples exposed to ambient laboratory conditions of temperature and relative humidity gradually decreased by 58% in 38 weeks whereas linamarin in cassava flour is 100% stable for 6 months. Cyanogens could not be removed from wet gari samples at 30 or 50 °C and were only slowly removed by repeated heating at 100 °C and rewetting. By mixing equal weights of gari (pH 4.1) and low cyanide cassava flour (pH 6.5), wetting and heating at 50 °C for 5 h, the cyanide content was reduced by about one half. Wetting a gari/flour (1:1) sample with 1.5 times its weight of water and standing in a 1 cm thick layer in the sun for 4 h reduced the cyanide content by about one half. This treated mixture may be cooked to prepare stiff porridge with lowered cyanide content, and may help reduce tropical ataxic neuropathy in West Africa.

The cyanohydrin substrates react with titanacyclopropanes, obtained in situ from Grignard reagents and Ti(OiPr)4, to produce 1,4-diketones.

The sensitivity of the normal picrate method for determination of total cyanide in cassava was increased tenfold using a small 1 cm 2 picrate paper, eluted using 0.5 mL instead of 5 mL of water as in the normal method. The absorbance was measured in a 2 mm cuvette in the spectrophotometer. The sensitive method was calibrated against the normal picrate method. The total cyanide content in mg HCN equivalents/kg sample = ppm, is calculated from the absorbance (A) by the equation ppm = A × 45.7 which is applicable from 0.1 to 50 ppm. A new method to determine acetone cyanohydrin was developed based on irreversible denaturation of linamarase in 0.1 M HCl at 30 °C for 1 h. Five gari samples from Mozambique gave a mean total cyanide content of 12 ppm (range 6–15 ppm) and mean acetone cyanohydrin content of 11 ppm (range 5–14 ppm). Acetone cyanohydrin liberates cyanide quantitatively in the human intestine.

Overexpression and production of the high concentration of hydroxynitrile lyase from cassava (Manihot esculenta (MeHNL, EC 4.1.2.39)) were investigated. Hydroxynitrile lyase is a useful enzyme for the production of optically active cyanohydrin compounds. The production of MeHNL was increased by changing the rare codons of the original sequence of cassava MeHNL. However, most of the produced MeHNL was in the insoluble form. In order to increase the solubility of MeHNL, the effects of the cultivation temperature were investigated. When the cultivation temperature was reduced, the cell yield and the ratio of soluble MeHNL increased significantly. The enzyme activity and yield at low-temperature cultures (17 degrees C) were 850 times higher than those obtained at the optimum growth temperature of 37 degrees C. The rate of MeHNL production in the present study was calculated as 3,000 unit/h. Low-temperature cultivation was very effective in improving the productivity of the active form of MeHNL. Unlike the temperature-shift method, low-temperature cultivation has more potential for the large-scale production of MeHNL for the optically active cyanohydrin production.

The application of hydroxynitrile lyases (HNLs) as catalysts for the stereoselective condensation of HCN with carbonyl compounds has been reported as early as 1908. This enzymatic C-C bond coupling reaction furnishes enantiopure cyanohydrins which serve as versatile bifunctional building blocks for chemical synthesis. Screening of natural sources led to the discovery of both (R)- and (S)-selective HNLs, and several distinctly different classes of these enzymes with substantial differences concerning sequence, structure, and mechanism have been found. Especially during the last two centuries, HNLs have been developed into valuable biocatalysts, which can be produced in recombinant form by overexpression in microbial hosts, resulting in the implementation of industrial processes utilizing these enzymes. Recently, protein engineering in combination with in silico methods gave rise to the development of a tailor-made HNL for large-scale manufacturing of a specific target cyanohydrin.

Reactions of readily available and stable 1-(α-alkoxyalkyl)benzotriazoles type 9a,b and 10a–d with a variety of silyl enol ethers 11 or 1,3-dicarbonyl compounds 13 give the expected ketones 12a–l (60–92%), β-keto esters 14a,b (62–67%), and malonates 14c,d (79–88%) in which a tetrahydrofuran or tetrahydropyran moiety has been introduced at the α position. 1-(Benzotriazol-1-yl)alkyl esters 7 are converted by cyanide anion into cyanohydrin esters 15a–i (55–98%).

A novel bifunctional asymmetric catalyst containing N-oxide and titanium(IV) was developed and applied to the asymmetric cyanosilylation of aldehydes. Optically active trimethylsilyl cyanohydrin ethers were obtained up to 99% yield and 80% ee in the presence of 5 mol % catalyst loading at −78 °C. Based on the experimental results, the catalytic cycle was proposed as a pathway in which Lewis acid and Lewis base activated aldehyde and trimethylsilylcyanide (TMSCN), respectively.

Enantiomerically enriched cyanohydrin O-phosphates, prepared by enantioselective cyanophosphorylation of α,β-unsaturated aldehydes, react regioselectively at the γ-position with organocuprates derived from alkyl Grignard reagents and CuCN to afford chiral γ-alkyl-substituted α,β-unsaturated nitriles. The configuration of the new C–C double bond is mainly (E) when the reaction is performed at –78 °C and (Z) when it is carried out at higher temperatures (0 °C). A high level of transfer of the chirality in the new stereocentre, corresponding to a stereospecific anti attack onto the cyanophosphate, is observed. Enantiomerically enriched (E)-γ-alkylated α,β-unsaturated esters are prepared after subsequent methanolysis in a three-step sequence from the corresponding α,β-unsaturated aldehydes. In addition, the synthesis of (R)-4-methylnonan-1-ol, also known as the sex pheromone of the yellow mealworm Tenebrio molitor L, and its (S) enantiomer have been carried out in a four-step route from (E)-oct-2-enal. This work has been supported by the DGES of the Spanish Ministerio de Educación y Ciencia (MEC) (CTQ2004-00808/BQU), the Generalitat Valenciana (CTIOIB/2002/320, GRUPOS03/134 and GV05/144) and the University of Alicante.

Hydroxynitrile lyases (Hnls) are important biocatalysts for the synthesis of optically pure cyanohydrins, which are used as precursors and building blocks for a wide range of high price fine chemicals. Although two Hnl enzymes, from the tropical rubber tree Hevea brasiliensis and from the almond tree Prunus amygdalus, are already used for large scale industrial applications, the enzymes still need to be improved and adapted to the special demands of industrial processes. In many cases directed evolution has been the method of choice to improve enzymes, which are applied as industrial biocatalysts. The screening procedure is the most crucial point in every directed evolution experiment. Herein, we describe the successful development of a novel screening assay for Hnls and its application in high-throughput screening of Escherichia coli mutant libraries. The new assay allows rapid screening of mutant libraries and facilitates the discovery of improved enzyme variants. Hnls catalyze the cleavage of cyanohydrins to hydrocyanic acid and the corresponding aldehyde or ketone. The enzyme assay is based on the detection of hydrocyanic acid produced, making it an all-purpose screening assay, without restriction to any kind of substrate. The gaseous HCN liberated within the Hnl reaction is detected by a visible colorimetric reaction. The facile, highly sensitive and reproducible screening method was validated by identifying new enzyme variants with novel substrate specificities.

Aluminum complexes of the chiral (R)- or (S)-3,3'-bis(diethylaminomethyl)-1,1'-bi-2,2'-naphthol (BINOLAM) ligand behave as efficient catalysts for the enantioselective cyanation-O-functionalization of aldehydes, thereby leading to enantiomerically enriched O-silyl, O-methoxycarbonyl, or O-phosphate derivatives of cyanohydrins. The enantioenriched cyanohydrin-O-phosphates are useful for the synthesis of several enantioenriched compounds such as α-hydroxy esters, β-amino alcohols, and γ-substituted α,β-unsaturated nitriles. Natural products such as (-)-aegeline and (-)-tembamide have been prepared in this manner.

The addition of TMSCN to ketones catalyzed by dispersed NbF5 gave corresponding cyanohydrin trimethylsilylethers with excellent yield (>90%). Cyano transfer occurs within 30 min at room temperature in the presence of 1 mol% of NbF5 under solvent-free conditions. These conditions are extremely mild, simple, and tolerate various functional groups. Copyright © 2007 John Wiley & Sons, Ltd.

Simple and mild reaction conditions, low levels of catalyst loading, high yields and shorter reaction times compared to existing methods are the advantages of this methodology.

The synthetic utility of N -heterocyclic carbenes was demonstrated by the trialkylsilylcyanation of aldehydes, ketones and imines. In the presence of a catalytic amount of 3a , the reactions with Me 3 SiCN proceeded smoothly to give the corresponding cyanohydrin trimethylsilyl ethers or amino nitrile derivatives in good to excellent yields.

A variety of cyanohydrin THP ethers were readily prepared from carbonyl compounds with trimethylsilyl cyanide and tetrahydropyran-2-yl acetate under the influence of a catalytic amount of iron(III) triflate in a convenient one-pot procedure. This method was also effective to prepare O-protected cyanohydrins by various acetal-type protective groups.

1,1,3,3-Tetramethylguanidine acts as a highly effective catalyst for cyanosilylation of various ketones and aldehydes to the corresponding cyanohydrin trimethylsilyl ethers in up to 99% yield. The reaction proceeds smoothly with 0.1 mol % catalyst loading at 25 °C under solvent-free conditions.

A highly enantioselective cyano-phosphorylation of aldehydes catalyzed by a YLi 3 tris(binaphthoxide) complex YLB 1 is described. The slow addition of diethyl cyanophosphonate 4 to aldehydes 5 in the presence of YLB 1 (10 mol %), H 2 O (30 mol %), tris(2,6-dimethoxyphenyl)phosphine oxide 3a (10 mol %), and BuLi (10 mol %) afforded cyanohydrin O -phosphates 6 in up to 98% yield and 97% ee. Mechanistic studies revealed that the addition of cyanide to aldehydes is irreversible and determines the enantioselectivity. The reaction mechanism is also discussed in detail.

Trimethylsilyl cyanide asymmetrically adds to various ketones by catalysis of 1 /triphenylphosphine oxide. This is a double activation where 1 acts as Lewis acid and Ph3PO Lewis base. Various ketones were subjected to the enantioselective addition so as to give up to 92% ee and >90% yield.

β-Amino-α-ferrocenyl alcohols [FcC(OH)(R)CH2NH2] (R = Me, Et, nPr, iPr, Ph, p-MeOC6H4, o-ClC6H4, m-ClC6H4, p-ClC6H4, Fc; Fc = C5H4FeC5H5) were prepared by the reduction of cyanohydrin trimethylsilyl ethers of acylferrocenes with lithium aluminum hydride. All new compounds were characterised by elemental analysis, IR and 1H NMR spectroscopies. The X-ray crystal structure of β-amino-α,α-diferrocenylethanol shows that it has a polymeric chain structure with hydrogen bonding interactions between the OH proton and the N of NH2.

This paper reports the straightforward enantioselective synthesis of (+)-ancistrofuran starting from a readily available enantiopure building block. A stereofacial directed diastereoselective addition of an organocerate for the installation of the required stereogenic center served as the key step. In addition, the efficient conversion of an intermediate hydroxy aldehyde to the one-carbon homologated cyanide was developed. The sequence was achieved by the mild formation of a cyanohydrin and the subsequent one-pot two-step Barton–McCombie double deoxygenation of the hydroxyl groups.

The cleavage of mandelonitrile catalysed by hydroxynitrile lyases (HNL) from Prunus amygdalus (PaHNL) and Manihot esculenta (MeHNL) proceeded more rapidly in monophasic aqueous media containing 1-propyl-3-methylimidazolium tetrafluoroborate [C4MIm][BF4] than in media containing acetonitrile or THF. Both HNLs were much more thermostable in [C4MIm][BF4] than in acetonitrile or THF. The addition of each of the four ionic liquids 1-butyl-, 1-pentyl- and 1-hexyl-3-methylimidazolium tetrafluoroborates at 2–6% (v/v in the aqueous phase) increased both the enzyme activity and the product e.e. in the PaHNL-catalysed transcyanation in an aqueous/DIPE biphasic system. However, MeHNL was inactivated by the ionic liquids, as indicated by the decreased reaction rate, substrate conversion and product e.e.

Substituted 3-amino-oxazolidin-2,4-diones have been prepared by reacting cyanohydrins or alpha-hydroxyesters subsequently with 1,1'-carbonyldiimidazole and 1,1-disubstituted hydrazines followed by acidic hydrolysis in case of the intermediate 3-amino-4-imino-oxazolidin-2-ones. Conventional and microwave-assisted syntheses of N',N'-disubstituted alpha-hydroxyhydrazides have been accomplished by reacting substituted 3-amino-oxazolidin-2,4-diones with catalytic amounts of sodium methoxide in methanol.

Various aldehydes undergo enantioselective silylcyanation with (CH3)3SiCN trimethylsilylcyanation (TMSCN) employing chiral Mn(salen) and achiral POPh3 as the catalysts. This is the double activation where Mn(salen) plays the role of Lewis acid and POPh3 Lewis base. Numerous aldehydes are subject to the enantioselective addition of TMSCN at 0°C. Hydrolysis of the adduct gave cyanohydrin with up to 96% yield and 62% ee.

The BINOL–salen compound ( S )- 5c in combination with Ti(O i Pr) 4 is found to catalyze the addition of TMSCN to aldehydes to form chiral cyanohydrins with very good enantioselectivity (75–85% ee). The reactions are carried out in one-pot at room temperature without the need to isolate the chiral Lewis acid catalyst.

The development of a new chiral aluminum catalyst is reported. This catalyst has been applied efficiently to the asymmetric cyanosilylation of aldehydes.

In continuing studies aimed at understanding the prebiotic origin of RNA, we recently demonstrated a Kiliani–Fischer-type synthesis of simple sugars from hydrogen cyanide 1 using photoredox cycling of cyanocuprates (Scheme 1).1 Scheme 1 Photoredox systems chemistry of hydrogen cyanide 1, with 1 also acting as the ultimate reductant. The photoredox cycle oxidizes 1 to cyanogen 2 and generates associated reducing power in the form of protons and hydrated electrons, which reduce further 1 to formaldehyde imine 3. Hydrolysis of 3 to formaldehyde 4 is then followed by addition of 1 to give glycolonitrile 5. Iteration of this process results in the sequential production of glycolaldehyde 6, its cyanohydrin 7, and glyceraldehyde 8. Sugars 6 and 8 are required by our recent synthesis of pyrimidine ribonucleotides as starting materials,2 but there is a catch. The concurrent hydrolysis of cyanogen 2 produces cyanate 9, which irreversibly traps the sugars 6 and 8 as cyclic adducts. We wondered if the free sugars could be obtained by a variant of the process in which something other than 1 served as the ultimate reductant in the system, and report herein our findings with hydrogen sulfide (H2S, 10) fulfilling that role. Although our previous Kiliani–Fischer-type synthesis started with hydrogen cyanide 1 and proceeded through glycolonitrile 5, compound 5 itself is probably a more plausible starting point for the synthesis. This is because 1 produced in the atmosphere, (for example through impact shock3), would have been rained into bodies of ground water along with formaldehyde 4 (produced in the upper atmosphere by photoreduction of CO24) with which it would have reacted to give 5. Accordingly, in this work we initially explored the copper-catalyzed photoreduction of 5 with 10 in aqueous solution (containing 10 % D2O to allow direct analysis by NMR spectroscopy). As phosphate is a reagent in a later stage of our ribonucleotide synthesis,2 we incorporated it into the system from the outset wherein it functioned as a pH buffer. Mixing of this solution with solid copper(I) cyanide (10 mol % with respect to 5) resulted in the formation of a fine black powdery precipitate, and a stirred suspension of this powder in the solution was irradiated at 254 nm in a quartz cuvette. Samples were withdrawn over time and analyzed by 1H NMR (with HOD suppression), or, if [13C2]-labeled 5 was used, 13C NMR spectroscopy. After 2 h of irradiation, NMR analysis (Figure 1 and Supporting Information) showed that efficient reductive conversion of glycolonitrile 5 to glycolaldehyde 6 had taken place (with 6 being detected as its hydrate 6(h) in 42 % yield in solution). However, other reduction products, namely acetonitrile 11 and acetaldehyde 12,5 were also present (as confirmed by sample spiking) that we had not observed in our earlier work. Furthermore, some cyanide had been abstracted from 5 and converted into thiocyanate 13,6 leaving formaldehyde 4 present in the form of its hydrate 4(h) and hydrogen sulfide addition product 14. The most obvious pathway to acetaldehyde 12 appeared to be deoxygenation7 of glycolaldehyde 6 (Scheme 2), and to investigate this we irradiated a system comprising copper(I) cyanide and a solution of 6, sodium phosphate, and 10. Conversion into 12 occurred, but was inefficient unless we additionally included thiocyanate 13 in the system. This suggests that 13 in some way enables more efficient redox cycling, and we note in this regard that copper(I) thiocyanate is a p-type semiconductor.8 Figure 1 13C NMR spectrum of the products of irradiation (2 h, pH 7) of a system made by mixing a solution of [13C2]-labeled glycolonitrile 5 (10 mm), hydrogen sulfide 10 (30 mm), and sodium phosphate (33 mm) with ... Scheme 2 Photoredox systems chemistry of glycolonitrile 5, with hydrogen sulfide 10 as the ultimate reductant. Although the formation of glycolaldehyde 6 is important in the context of ribonucleotide abiogenesis, the formation of acetaldehyde 12 alongside 6 and formaldehyde 4 is particularly noteworthy in the context of amino acid abiogenesis as these aldehydes are the Strecker precursors of alanine, serine, and glycine.9 Thus hints of a linked origin of ribonucleotides and amino acids began to emerge. Addition of hydrogen cyanide 1 and ammonia to such a system would convert the aldehydes into the corresponding cyanohydrins and aminonitrile Strecker intermediates. Among other things, the ratio of cyanohydrin to aminonitrile would depend on the parent aldehyde and the amount of added ammonia. Although we are ultimately most interested in mixed systems, we have first explored simpler variants in which ammonia is either absent, or in excess. In the absence of added ammonia, cyanohydrins 7 and 15 produced by rain-in of hydrogen cyanide 1 into the system have the potential to be further reduced in a second stage of photoredox chemistry (Scheme 2). We had considered the formation of 7 in this way, and envisaged its subsequent reduction as a way of producing glyceraldehyde 8 in the same system as glycolaldehyde 6, but at a later juncture. However, we had not previously considered the formation and reduction of acetaldehyde cyanohydrin 15. We thus prepared separate samples of 7 and 15 from the parent aldehydes and hydrogen cyanide 1, and subjected them to the photoreduction conditions (Supporting Information). After 2 h of irradiation of a system containing glycolaldehyde cyanohydrin 7, glyceraldehyde 8 was obtained in 17 % yield. The corresponding system based on acetaldehyde cyanohydrin 15 furnished lactaldehyde 16, which is the Strecker precursor of (allo-)threonine, in 19 % yield. In the presence of added ammonia, the cyanohydrins produced by rain-in of hydrogen cyanide 1 would be expected to undergo slow conversion to aminonitriles. Addition of 1 and excess ammonia to the system after 4 h of first-stage reduction resulted in the smooth conversion of the aldehydes 4, 12, and 6 into the corresponding aminonitriles 17, 18, and 19 over a period of days to weeks (Supporting Information). A second rain-in of hydrogen cyanide 1 after the second-stage reduction would convert some of the glyceraldehyde 8 and lactaldehyde 16 into the cyanohydrins 20 and 21 and thence to aminonitriles if sufficient ammonia were still in the system, or if more was added. In support of this, when we added 1 and ammonia to the (second-stage) photoreduction products of acetaldehyde cyanohydrin 15, lactaldehyde 16 was smoothly converted via cyanohydrin 21 to (allo-)threonine Strecker intermediate aminonitrile 22 (Supporting Information). If the first-stage reduction were to proceed to completion, all of the glycolaldehyde 6 needed to make ribonucleotides and serine (via 7 and 19) would instead be converted into acetaldehyde 12. We found that 12 was the major product after 6 h irradiation thus 2–4 h would seem to be synthetically most productive from a systems perspective. Not knowing the UV light intensity on the early earth means that we cannot convert our experimental irradiation times into real time spans, but diurnal cycling and/or weather effects mean that illumination periods corresponding to 2–4 of our hours are plausible. Addition of hydrogen cyanide 1 is needed to make cyanohydrins for the second-stage reduction as well as for aminonitrile synthesis. If the rain-in of 1 occurred during a dark period and was accompanied by the addition of cyanamide, with which glycolaldehyde 6 also reacts (to make a key ribonucleotide intermediate), then second-stage reduction of the cyanohydrins 7 and 15 giving 8 and 16 should leave this ribonucleotide intermediate and any aminonitriles unchanged (the nitrile carbon atoms of aminonitriles endure less electron-withdrawal than those of cyanohydrins, and are thus considerably less susceptible to reduction). Subsequent addition of 1 and ammonia (or equilibration with that reversibly contained in other aminonitriles) would then additionally generate the aminonitrile 22. Thus the abiogenesis of the simple sugars required to make RNA appears to be closely related to the abiogenesis of at least four of the proteinogenic amino acids of extant biology. This relationship suggests that the systems described herein have a real etiological relevance, and this has prompted us to consider geochemical scenarios that could provide appropriate conditions and starting materials. As well as being concentrated by trapping through reaction with formaldehyde 4, cyanide can also be concentrated through complexation to ferrous ions giving ferrocyanide.10 Thermal decomposition of ferrocyanide gives different products depending on the counter cation.11, 12 Sodium and potassium ferrocyanide give the corresponding alkali metal cyanide salts MCN,11 magnesium ferrocyanide gives magnesium nitride Mg3N2,12 and calcium ferrocyanide gives calcium cyanamide CaCN2.12 Rehydration of the residue remaining after strong heating of mixed ferrocyanide salts can thus give solutions containing cyanide, ammonia, and cyanamide, which are all needed for the chemistry described herein or for later stages of ribonucleotide synthesis.2 The reductant hydrogen sulfide 10 and the copper(I) cyanide based catalyst could be produced by dissolution of a copper sulfide mineral in cyanide solution,13 additional 10 being produced by similar dissolution of ferrous sulfide.14 At this stage we do not attempt to describe a more detailed scenario other than to point out that the RNA and amino acid syntheses could take place in one mixed system or in several closely related systems which then become mixed. Finally, we note that the chemistry we describe, utilizing the reducing power of hydrogen sulfide 10 to generate multiple (proto)biomolecules ultimately from C1 feedstock(s), is reminiscent of the general scenario put forward by Wachtershauser.15

The enantioselective synthesis of the initially proposed structure of usneoidone has been completed according to a convergent strategy in which the key steps were an enantioselective Michael addition involving chiral imines to set up the C12 quaternary center, and the final assembly of the chiral pyran moiety with the aromatic subunit through a cyanohydrin anion alkylation step. The obtained product displays spectroscopic data that significantly differ from the reported values. A putative revised structure in which the pyran ring is opened is proposed for usneoidones. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Three approaches to biotin (1), i.e., the Cyanohydrin method and the Strecker methods I and II, have been investigated with L-cysteine as a starting material and the last one was found to be so efficient to be applied to a multi-kilogram-scale preparation. α-Amino aldehyde 46, which was readily derived from L-cysteine, was subjected to the Strecker reaction to afford syn-α-amino nitrile 47 with high diastereoselectivity and in high yield. The compound 47 was converted to amide 48 in high yield by applying Katritzky's protocol. Novel S, N-carbonyl migration of 48 and subsequent hydrolysis enabled clean conversion to 37 that is a precursor to a key intermediate 38 for 1. The Fukuyama coupling reaction of 38 with a zinc reagent by the use of our modified procedure employing heterogeneous Pearlman's catalyst allowed efficient installation of the 4-carboxybutyl chain. Short steps, high yield, and ease of operation of the present approach would permit the hitherto most efficient access to 1.

Tertiary cyanohydrin trimethylsilyl ethers were synthesized in excellent chemical yields by using salen-Al complex (0.25 mol%) and N-oxide (0.5 mol%) without solvent at ambient temperature. The relationship between the ligand structure and catalyst efficiency is discussed. Preliminary mechanistic studies were carried out, and transition states were proposed accounting for the action of the double-activation catalysts.

A novel chiral sulfoxide-containing ligand for the catalytic addition of trimethylsilylcyanide to aldehydes is reported. The sulfoxide moiety was found to be vital for reactivity.

Optically active 2-trimethylsilyl-2-hydroxyl-ethylcyanide was prepared by enzymatic enantioselective transcyanation of acetyltrimethylsilane with acetone cyanohydrin in a biphasic system at 35 °C and pH 5. (R)-Oxynitrilase from apple seed meal was the best among all the enzymes explored and diisopropyl ether was the most suitable organic phase. Acetyltrimethylsilane was a better substrate of the enzyme than its carbon analogue. The substrate conversion and product enantiomeric excess of 2-trimethylsilyl-2-hydroxyl-ethylcyanide were >99% and >99%, respectively.

Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97 : 3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of beta(3)-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to beta-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.

(S)-Oxybutynin, an important drug acting as muscarinic receptor antagonist, was practically synthesized using catalytic enantioselective cyanosilylation of cyclohexyl phenyl ketone (6a) as a key step. Cyanohydrin 7a with 94% ee was obtained with 1 mol% of Gd-5 catalyst. The key α-hydroxy carboxylic acid 8 was synthesized from 7a in an enantiomerically pure form without column chromatography. Other cycloalkyl phenyl ketones, except cyclopentyl phenyl ketone (6e-H) gave products with high enantioselectivity. The enantioselectivity of the reaction of 6e was dramatically improved using α-deuterium substituted 6e-D. The dramatic deuterium effect provides an important insight into the competitive reaction pathway.

Exposure to cyanide from gari, a popular cassava food in West Africa, is implicated in the causation of ataxic polyneuropathy and amblyopia, but this has been questioned because cyanide was not detected in gari in a study. This study was carried out to determine if gari is a source of exposure to cyanide. Gari (150 g) containing cyanohydrin, from which 128 micromol of cyanide ions could be released, was dissolved in 500 ml of cold water for each of the 12 healthy subjects to drink. Concentrations of cyanide in plasma and erythrocytes were determined at baseline and following the meal at 30 min, 1 h, hourly for 4 h and two hourly for 12 h. The mean concentrations of cyanide in the plasma were 6 micromol/l (95% CI 2-10) at baseline, 12 micromol/l (95% CI 6-17) at peak and 6 micromol/l (95% CI 2-10) on return to baseline. The mean amount of cyanide absorbed into the plasma was 13 micromol (S.D. 12), while the transit time of absorbed cyanide was 7.3 h (S.D. 2.1). This study shows that exposure to cyanide follows consumption of gari, but the amount of cyanide absorbed into the plasma from a single meal is small and unlikely to cause acute intoxication. The long transit time of absorbed cyanide in the plasma suggests that frequent intake of gari could cause cyanide to accumulate in the plasma.

Nineteen species of Passiflora (Passifloraceae) were examined for the presence of cyanogenic glycosides. Passibiflorin, a bisglycoside containing the 6-deoxy-β- d -gulopyranosyl residue, was isolated from P. apetala , P. biflora , P. cuneata , P. indecora , P. murucuja and P. perfoliata . In some cases this glycoside co-occurs with simple β- d -glucopyranosides: tetraphyllin A, deidaclin, tetraphyllin B, volkenin, epivolkenin and taraktophyllin. P. citrina contains passicapsin, a rare glycoside with the 2,6-dideoxy-β- d - xylo -hexopyranosyl moiety, while P. herbertiana contains tetraphyllin A, deidaclin, epivolkenin and taraktophyllin, P. discophora tetraphyllin B and volkenin, and P. × violacea tetraphyllin B sulfate. The remaining species were noncyanogenic. The glycosides were identified by 1 H and 13 C NMR spectroscopy following isolation by reversed-phase preparative HPLC. From P. guatemalensis , a new glucoside named passiguatemalin was isolated and identified as a 1-(β- d -glucopyranosyloxy)-2,3-dihydroxycyclopentane-1-carbonitrile. An isomeric glycoside was prepared by catalytic hydrogenation of gynocardin. α-Hydroxyamides corresponding to the cyanogenic glycosides were isolated from several Passiflora species. These α-hydroxyamides, presumably formed during processing of the plant material, behave as cyanogenic compounds when treated with commercial Helix pomatia crude enzyme preparation. Thus, the enzyme preparation appears to contain an amide dehydratase, which converts α-hydroxyamides to cyanohydrins that liberate cyanide; this finding is of interest in connection with analysis of plant tissues and extracts using Helix pomatia enzymes.

Three new compounds, hydnohainanic acid (1), and hydnohainanin A (2) and B (3) were isolated from the fruits of Hydnocarpus hainanensis (Achariaceae). Their structures were determined by spectroscopic analysis, including 2D NMR, and MS. Compounds 1-3 were evaluated for their cytotoxic activity against the KB cell line. Compound 1 had a moderate cytotoxicity with an IC50 value of 32.5 μg/mL, while the two remaining compounds did not exhibit inhibition, even at a concentration of 128 μg/mL.