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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.

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 .

Hydroxynitrile lyase from the white rabbit's foot fern Davallia tyermanii (DtHNL) catalyzes the enantioselective synthesis of α-cyanohydrins, key building blocks for pharmaceutical and agrochemical industries. An efficient and competitive process necessitates the availability and robustness of the biocatalyst. Herein, the recombinant production of DtHNL1 in Komagataella phaffii is described, yielding approximately 900,000 U/L. DtHNL1 constitutes approximately 80% of the total protein content. The crude enzyme was immobilized. Cross-linked enzyme aggregates (CLEAs) resulted in significant enhancement of the biocatalyst stability under acidic conditions (activity retained after 168 h at pH 2.4). The DtHNL1-CLEA was employed for (R)-mandelonitrile synthesis (99% conv., 98% ee) in a biphasic system, and evaluated for the synthesis of (R)-hydroxypivaldehyde cyanohydrin, at reaction conditions which immediately inactivate non-immobilized DtHNL1. The results show DtHNL1-CLEA to be a stable biocatalyst for the synthesis of enantiomerically pure cyanohydrins under acidic conditions.

Reactions of pyrazine-2,3-dicarboxylic acid (H2pzdc), cobalt nitrate and lanthanide (Ln) oxide under hydrothermal conditions result in four new 3d-4f heterometal coordination polymers, namely, [Ln2Co(pzdc)4(H2O)6]·2H2O [Ln = La (1), Pr (2), Eu (3) and Gd (4)]. All compounds were characterized by elemental analysis, infrared spectroscopy, thermal gravimetric analysis, and X-ray diffraction. The compounds exhibit a three-dimensional (3D) brick-like structure with rectangular-shaped nano-scale channels along a axis direction, made up of wave-like layers containing [Ln(pzdc)]+ units, which are connected by one-dimensional (1D) chain of [Co(pzdc)2]2–. The catalytic properties of compounds 1 and 3 were investigated in the synthesis of cyanohydrins at room temperature under solventless conditions. They showed similar catalytic activities with very high conversions of benzaldehyde and high selectivity towards cyanohydrin. The control experiment without addition of the coordination polymers only reached 16 % conversion. Other aldehydes could also be converted totally under shorter reaction times also with very high selectivities for the corresponding cyanohydrins. Compound 1 could also be recycled in another catalytic cycle.

A hydroxynitrile lyase from the passion fruit Passiflora edulis (PeHNL) was isolated from the leaves and showed high stability in biphasic co-organic solvent systems for cyanohydrin synthesis. Cyanohydrins are important building blocks for the production of fine chemicals and pharmaceuticals. Thus, to enhance production yields of PeHNL for industrial applications, we cloned and expressed recombinant PeHNL in Escherichia coli BL21(DE3) and Pichia pastoris GS115 cells without a signal peptide sequence. The aim of this study is to determine the effect of N-glycosylation on enzyme stability and catalytic properties in microbial expression systems. PeHNL from leaves (PeHNL-N) and that expressed in P. pastoris (PeHNL-P) were glycosylated, whereas that expressed in E. coli (PeHNL-E) was not. The enzymes PeHNL-N and PeHNL-P showed much better thermostability, pH stability, and organic solvent tolerance than the deglycosylated enzyme PeHNL-E and the deglycosylated mutant N105Q from P. pastoris (PeHNL-P-N105Q). The glycosylated PeHNL-P also efficiently performed transcyanation of (R)-mandelonitrile with a 98 % enantiomeric excess in a biphasic system with diisopropyl ether. These data demonstrate the efficacy of these methods for improving enzyme expression and stability for industrial application through N-glycosylation.

Cyanohydrins are versatile compounds with high applicability in organic synthesis; they are used as starting materials for the synthesis of other chemical targets with high industrial added value. Lipase-mediated kinetic resolution reactions are a promising route for the synthesis of optically active cyanohydrins. These reactions can be carried out through the acylation of cyanohydrins or the deacylation of cyanohydrin esters, with different biocatalysts and under different reaction conditions. Unfortunately, depending on the substrate structure, long reaction times can be required to achieve suitable enantiomeric excesses. In this context, we present a high-throughput protocol for the production of optically active cyanohydrins in continuous-flow mode. The products were obtained with moderate to good enantioselectivity (E values from 8 up to >200) and with productivity values from 2.4 to 8.7 times higher in continuous-flow mode than in batch mode. Moreover, the reaction times were reduced from hours in batch mode to minutes in continuous-flow mode.

The absolute stereochemistry of cyanohydrins, derived from ketones and aldehydes, is obtained routinely, in a microscale and derivatization-free manner, upon their complexation with Zn-MAPOL, a zincated porphyrin host with a binding pocket comprised of a biphenol core. The host-guest complex leads to observable exciton-coupled circular dichroism (ECCD), the sign of which is easily correlated to the absolute stereochemistry of the bound cyanohydrin. A working model, based on the ECCD signal of cyanohydrins with known configuration, is proposed.

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Hydroxynitrile lyases (HNLs) catalyse the reversible cleavage of cyanohydrins to carbonyl compounds and HCN. The recent discovery of bacterial HNLs with a cupin fold gave rise to a new promising class of these enzymes. They are interesting candidates for the synthesis of cyanohydrins on an industrial scale owing to their high expression levels in Escherichia coli. The activity and enantioselectivity of the manganese-dependent HNL from Granulicella tundricola (GtHNL) were significantly improved by site-saturation mutagenesis of active site amino acids. The combination of beneficial mutations resulted in a variant with 490-fold higher specific activity in comparison to the wild-type enzyme. More importantly, GtHNL-A40H/V42T/Q110H is a highly competitive alternative for the synthesis of chiral cyanohydrins, such as 2-chlorobenzaldehyde cyanohydrin, (R)-2-hydroxy-4-phenylbutyronitrile, and (R)-2-hydroxy-4-phenyl-3-butene nitrile, which serve as intermediates for the synthesis of pharmaceuticals.

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.

Hydroxynitrile lyases (hnls) catalyze the conversion of chiral cyanohydrins to hydrocyanic acid (hcn) and aldehyde or ketone. hydroxynitrile lyase from arabidopsis thaliana (athnl) is the first r-selective hnl enzyme containing an /-hydrolases fold. in this article, the catalytic mechanism of athnl was theoretically studied by using qm/mm approach based on the recently obtained crystal structure in 2012. two computational models were constructed, and two possible reaction pathways were considered. in path a, the calculation results indicate that the proton transfer from the hydroxyl group of cyanohydrin occurs firstly, and then the cleavage of c1-c2 bond and the rotation of the generated cyanide ion (cn-) follow, afterwards, cn- abstracts a proton from his236 via ser81. the c1-c2 bond cleavage and the protonation of cn- correspond to comparable free energy barriers (12.1 vs. 12.2 kcal mol(-1)), suggesting that both of the two processes contribute a lot to rate-limiting. in path b, the deprotonation of the hydroxyl group of cyanohydrin and the cleavage of c1-c2 bond take place in a concerted manner, which corresponds to the highest free energy barrier of 13.2 kcal mol(-1). the free energy barriers of path a and b are very similar and basically agree well with the experimental value of hbhnl, a similar enzyme of athnl. therefore, both of the two pathways are possible. in the reaction, the catalytic triad (his236, ser81, and asp208) acts as the general acid/base, and the generated cn- is stabilized by the hydroxyl group of ser81 and the main-chain nh-groups of ala13 and phe82. proteins 2015; 83:66-77. (c) 2014 wiley periodicals, inc.

This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling.The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-Lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen complex with a tertiary amine as a catalytic system in the enantioselective synthesis of O-acylated cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step.The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of O-acylated and O-formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved.

An efficient method for the synthesis of 2-aminoindolizines by the 5-exo-dig cyclization of 2-alkyl-1-(1-cyanoalkyl)pyridinium salts has been developed. These substrates were prepared by N-alkylation of 2-alkylpyridines with readily available cyanohydrin triflates. The method allows the introduction of various substituents at the 1-, 3-, 6-, 7-, and 8-positions and leaves no undesired acceptor groups in the products.

Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into β-adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.

The cyano-rich borate anion [B(tceg)2]– (tceg = tetracyanoethylene glycolate) has been synthesized in a two-step reaction from Na[B(OMe)4] with two equivalents of the cyanohydrin analogue Me3SiOC2(CN)4OSiMe3. The structures of the starting materials, an isolated intermediate Na2[B2(OMe)2(tceg)3], and Na[B(tceg)2] are discussed. Thermal studies of WCC[B(tceg)2] [WCC = 1-ethyl-3-methylimidazolium (EMIm), 1-butyl-3-methylimidazolium (BMIm), 1-octyl-3-methylimidazolium (OMIm), Me4N, Et4N, and Bu4N], synthesized by salt metathesis, showed that the compounds with EMIm, BMIm, OMIm, and Bu4N have ionic liquid properties. The synthesis, structure, and analytical results of Me3SiOC(CN)3 are discussed as well as the results of its conversion with Na[B(OMe)4].

Chiral keto nitriles (β-cyano ketones) have been prepared by a facile and efficient asymmetric conjugate hydrocyanation of poorly active chalcone-type enones with benzophenone cyanohydrin. Using in situ generated 5–10 mol-% of sodium (S)-6,6′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diyl phosphate as catalyst and 5–10 mol-% of 2-tert-butylphenol as an additive, high yields and excellent enantioselectivities were obtained within 2 h in toluene at 80 °C. The development of catalysts, optimization of the reaction parameters, and substrate scope are reported. On the basis of the experimental results, HCN is shown to be the real cyanide source and a mechanism is proposed to explain the origin of the enantioselectivity with the chiral-anion-modified nucleophile HCN.

A new bifunctional titanium/Schiff base catalyst was developed for the enantioselective cyanoformylation of aldehydes with ethyl cyanoformate. The reaction proceeded smoothly with a mild reaction condition to afford the cyanohydrin ethyl carbonates in high yields (up to 96%) and good enantioselectivities (up to 85% enantiomeric excess). Copyright © 2013 John Wiley & Sons, Ltd.

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.

The N-alkylation of pyridines with cyanohydrin triflates or α-halonitriles furnishes 1-(1-cyanoalkyl)pyridinium salts that can react with nitroolefins under basic conditions to furnish polysubstituted indolizines. Overall, the indolizine core can be constructed from a pyridine, two aldehydes, and a nitroalkane, and no undesired functional groups remain in the products. When bromoacetonitrile was used for the N-alkylation, indolizine-3-carbonitriles were obtained instead. The pyridine component may be replaced by other azines, giving rise to related heterocyclic systems.

Enantioselective reactions of simple ketones, α,α- and β,β-dialkoxy ketones, and α-alkoxy ketones with trimethylsilyl cyanide catalyzed by the bimetallic systems of amino acid/BINAP/ruthenium(II) complexes and lithium phenoxide have been studied [BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]. The Ru(PhGly)2(BINAP)-lithium phenoxide system showed high enantioselectivity for the reaction of acetophenone derivatives to afford the cyanated products in up to 90% ee [PhGly=phenylglycinate]. For the cyanosilylation of dialkoxy ketones and α-alkoxy ketones, the Ru(t-Leu)2(BINAP)-lithium phenoxide system exhibited the best catalyst performance to produce the cyanohydrin derivatives in up to 99% ee and 98% ee, respectively [t-Leu=tert-leucinate]. The excellent catalytic activity resulted in complete conversion in the reaction with a substrate-to-catalyst molar ratio (S/C) of 10,000 in the best cases.

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

A three-step, one-pot synthesis and diastereoresolution sequence is described in anhydrous toluene starting from methyl α-D-2,3,4-tri-O-acetylgalacto- (1a), -manno- (1b) and -glucopyranosides (1c). The reaction sequence, including consecutive transformations through the aldehyde [PhI(OAc)2, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)] and cyanohydrin [basic resin or (R)-oxynitrilase] into the (6R)-cyanohydrin ester (lipase) is shown to proceed in a one-pot cascade, except that the basic resin (when used) should be removed before the addition of the enzymatic acylation reagents. We have shown that the effective transformation of 1a (75 % reaction yield) through labile intermediates gives the stable (6R)-cyanohydrin butanoate (85 % de). Further diastereomeric purification by chromatography is possible, although the product is already of high diastereopurity. (6R)-Cyanohydrin esters are obtained through acylation with Burkholderia cepacia lipase. The (6S)-ester (de 99 %) is produced by Candida rugosa lipase when the sequence is started from 1c whereas the other sugar derivatives are less suited to the reaction with lipase.

Asteroids and their fragments have impacted the Earth for the last 4.5 Gyr. Carbonaceous meteorites are known to contain a wealth of indigenous organic molecules, including amino acids, which suggests that these meteorites could have been an important source of prebiotic organic material during the origins of life on Earth and possibly elsewhere. We report the detection of extraterrestrial amino acids in thermally altered type 3 CV and CO carbonaceous chondrites and ureilites recovered from Antarctica. The amino acid concentrations of the thirteen Antarctic meteorites ranged from 300 to 3200 parts-per-billion (ppb), generally much less abundant than in amino acid-rich CI, CM, and CR carbonaceous chondrites that experienced much lower temperature aqueous alteration on their parent bodies. In contrast to low-temperature aqueously altered meteorites that show complete structural diversity in amino acids formed predominantly by Strecker- cyanohydrin synthesis, the thermally altered meteorites studied here are dominated by small, straight- chain, amine terminal (n-x-amino) amino acids that are not consistent with Strecker formation. The carbon isotopic ratios of two extraterrestrial n-x-amino acids measured in one of the CV chondrites (d 13 C approximately )25&) are consistent with 13 C-depletions observed previously in hydrocarbons produced by Fischer-Tropsch type reactions. The predominance of n-x -amino acid isomers in thermally altered meteorites hints at cosmochemical mechanisms for the preferential formation and preservation of a small subset of the possible amino acids.

The (R)-selective hydroxynitrile lyase from Arabidopsis thaliana (AtHNL) is a promising biocatalyst for the synthesis of a broad range of chiral cyanohydrins. However, the enantiomeric excess of the reaction is strongly compromised by a non-catalyzed side reaction resulting in racemic cyanohydrins besides the chiral product obtained by enzymatic catalysis. This reaction is influenced by the pH value, the temperature and the water content of the reaction medium. In aqueous media this side reaction can be suppressed at low pH (4―5) and by lowering the temperature. However both approaches are not possible with AtHNL, since the enzyme is rapidly inactivated below pH 5.4, which prevents its use in aqueous media or two-phasic aqueous-organic reaction systems. Alternatively the side reaction can be suppressed by lowering the water concentration in the reaction system as far as possible. This approach was successfully tested for AtHNL using buffer-saturated methyl tert-butyl ether (MTBE) as a reaction medium for the hydrocyanation of aromatic, heteroaromatic and aliphatic aldehydes. Here we compare the activity and stability of AtHNL immobilized on celite (celite-AtHNL) and in solgel (solgel-AtHNL) relative to the precipitated enzyme, which was directly used in the organic solvent. Surprisingly, AtHNL was activated (up to 10-fold) upon solgel immobilization, an effect that was up to now only described for solgel-immobilized lipases. In contrast to lipases, AtHNL is not stabilized by the solgel. Best results were obtained with AtHNL adsorbed on celite, which is an easy and efficient way of immobilization and shows good recyclability (> 5 cycles), storability (τ 1/2 = 71 days, 4°C) and excellent catalytic properties upon adjustment of a relative water content of 26% water per g celite-AtHNL as determined by thermogravimetry.

This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling.The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-Lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen complex with a tertiary amine as a catalytic system in the enantioselective synthesis of O-acylated cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step.The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of O-acylated and O-formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved.

New bifunctional N-oxide salen―Ti IV complexes and a pyrrolidine salen―Ti IV complex in combination with achiral N-oxide were developed and applied to the asymmetric addition of trimethylsilyl cyanide to aldehydes. Notably, both enantiomers of trimethylsilyl ethers of cyanohydrins could be easily prepared by modifying the catalysts employed in this reaction, which are based on the same chiral diamine collar derived from L-tartaric acid. The products were obtained generally with moderate to good enantiomeric excesses and excellent yields by using relatively low catalyst loadings and only 1.05 equivalents of trimethylsilylcyanide (TMSCN).

A novel copper-catalyzed cyanation of aryl and heteroaryl bromides using acetone cyanohydrin has been developed.

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 ® .

Fully acetylated D- and L-α-mannosylacetaldehydes have been prepared and used as substrates to produce the corresponding cyanohydrins or cyanohydrin acetates with (2S) or (2R) configuration, respectively, at the cyanohydrin moiety. The (R)-oxynitrilase-catalysed synthesis and lipase-catalysed diastereomeric kinetic and dynamic kinetic resolutions were investigated. Sequential catalysis with almond meal [an economic source of (R)-oxynitrilase] and Burkholderia cepacia lipase was shown to be a straightforward method that yielded the four diastereomeric target cyanohydrins, the absolute configurations of which were confirmed by 1 H NMR analysis.

The absolute stereochemistry of ketone cyanohydrins can be easily determined by preparing a single MPA derivative. The comparison of two NMR spectra at different temperatures allows the assignment by just paying attention to the evolution of the cyanohydrin chemical shifts. The special case of α-aryl-substituted cyanohydrins is also described.

A concise and efficient asymmetric process for the total synthesis of (20S)-7-ethyl-10-hydroxycamptothecin (=SN-38; 1f), an active metabolic form of the prodrug irinotecan, is described. This approach features the enantioselective cyanosilylation of indolizinone 4 into the corresponding cyanohydrin 5, mediated by a bifunctional thiourea-based cinchona alkaloid under mild conditions, and I2-catalyzed Friedlander condensation of the tricyclic lactone 6 and 2-amino-5-hydroxy propiophenone (=1-(2-amino-5-hydroxyphenyl)propan-1-one).

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

The asymmetric addition of trimethylsilyl cyanide to aldehydes can be catalysed by Lewis acids and/or Lewis bases, which activate the aldehyde and trimethylsilyl cyanide, respectively. It is not always apparent from the structure of the catalyst whether Lewis acid or Lewis base catalysis predominates. To investigate this in the context of using salen complexes of titanium, vanadium and aluminium as catalysts, a Hammett analysis of asymmetric cyanohydrin synthesis was undertaken. When Lewis acid catalysis is dominant, a significantly positive reaction constant is observed, whereas reactions dominated by Lewis base catalysis give much smaller reaction constants. [{Ti(salen)O}(2)] was found to show the highest degree of Lewis acid catalysis, whereas two [VO(salen)X] (X=EtOSO(3) or NCS) complexes both displayed lower degrees of Lewis acid catalysis. In the case of reactions catalysed by [{Al(salen)}(2)O] and triphenylphosphine oxide, a non-linear Hammett plot was observed, which is indicative of a change in mechanism with increasing Lewis base catalysis as the carbonyl compound becomes more electron-deficient. These results suggested that the aluminium complex/triphenylphosphine oxide catalyst system should also catalyse the asymmetric addition of trimethylsilyl cyanide to ketones and this was found to be the case.

The asymmetric reaction of α-keto esters and (CH 3 ) 3 SiCN, catalyzed by a combined system of [Ru{(S)-phgly) 2 {(S)-binap}] and C 6 H 5 OLi with a substrate-to-catalyst molar ratio (S/C) of 1000 at -60 °C, affords silylated cyanohydrins in up to 99 % ee. Cyanosilylation smoothly proceeds with an S/C of 10,000 at ―50 °C. The use of Xyl-Binap instead of Binap as a ligand provides better enantioselectivity in some cases. A series of aromatic, hetero-aromatic, aliphatic, and α,β-unsaturated keto esters are converted into the desired products.

Potassium 4-benzylpiperidinedithiocarbamate was found to be an efficient organocatalyst for facile addition of trimethylsilyl cyanide to a wide variety of aldehydes and ketones to afford corresponding cyanohydrin trimethylsilyl ethers in high to quantitative yields. The reaction proceeded smoothly by employing 2.0 mol% PBPDC loading under mild conditions at room temperature within a very short reaction time. Copyright © 2009 John Wiley & Sons, Ltd.

Acetyl cyanide adds to alkyl benzoylformates and to 2-oxoalkanoates to yield enantioenriched acylated cyanohydrins in one step in the presence of a catalytic amount of a chiral base. The reaction i ...

In the presence of small amount (0.2–1.0 mol%) of a titanium complex catalyst prepared from a partially hydrolyzed titanium alkoxide and an optically active tridentate Schiff base ligand, the enantioselective silylcyanation of aldehydes and ketones proceeded in a short reaction time at room temperature to afford the corresponding optically active cyanohydrin derivatives in excellent chemical yield with high enantiomeric excess (86–97% ee). The results indicate that partially hydrolyzed titanium alkoxides are a promising titanium source for the preparation of efficient catalysts for asymmetric synthesis.

Catalyze this! Detailed study of the mechanism of asymmetric cyanohydrin synthesis catalyzed by VO(salen)X complexes (see figure) led to the development of VO(salen)NCS, as the most active vanadium-based catalyst yet developed for this reaction.The mechanism by which oxovanadium(V)(salen) complexes(1) VO(salen)X catalyze the asymmetric addition of trimethylsilyl cyanide to benzaldehyde has been studied. The reaction kinetics indicated that the structure of the counterion (X) had a significant influence on the rate, but not on the enantioselectivity of the reaction. The less coordinating the counterion, the lower the catalytic activity; a trend that was confirmed by a Hammett analysis. Variable temperature kinetics allowed the enthalpies and entropies of activation to be determined for some catalysts, and showed that, for others, the overall reaction order changes from second order to zero order as the temperature is reduced. The order with respect to the catalyst was determined for nine of the VO(salen)X complexes and showed that the less active catalysts were active predominantly as mononuclear species whilst the more active catalysts were active predominantly as dinuclear species. Mass spectrometry confirmed the formation of dinuclear species in situ from all of the VO(salen)X complexes and indicated that the dinuclear complexes contained one vanadium(V) and one vanadium(IV) ion. The latter conclusion was supported by cyclic voltammetry of the complexes, by fluorescence measurements and by the fact that catalyst deactivation occurs when reactions are carried out under an inert atmosphere. Based on this evidence, it has been deduced that the catalysis involves two catalytic cycles: one for catalysis by mononuclear VO(salen)X species and the other for catalysis by dinuclear species. The catalytic cycle involving dinuclear species involves activation of both the cyanide and aldehyde, whereas the catalytic cycle involving mononuclear species activates only the aldehyde, thus explaining the higher catalytic activity observed for catalysts which are predominantly active as dinuclear complexes. Based on these mechanistic results, two new VO(salen)X complexes (X=F and NCS) were predicted to form highly active catalysts for asymmetric cyanohydrin synthesis. VO(salen)NCS was indeed found to be the most active catalyst of this type and catalyzed the asymmetric addition of trimethylsilyl cyanide to thirteen aldehydes. In each case, high yields and enantioselectivities were obtained after a reaction time of two hours at room temperature using just 0.1 mol % of the catalyst.

Recyclable polymeric 1 and dimeric 2 chiral Mn(III) salen complexes catalyzed enantioselective cyanosilylation of various ketones in the presence of triphenylphosphine oxide as an additive proceeded smoothly at room temperature, providing excellent yields (up to 98%) and enantiomeric excess (up to 86%) of respective cyanohydrin trimethylsilyl ether. For most of the substrates, the Catalyst 1 showed slightly better reactivity and enantioselecitivity than the Catalyst 2 nevertheless both the catalysts were easily recovered and reused four times with the retention of their efficiency. Chirality, 2009. © 2008 Wiley-Liss, Inc.

An immobilized form of the hydroxynitrile lyase from Linum usitatissimum (LuHNL) as cross-linked enzyme aggregate (CLEA) with high specific activity (303.5 U/g) and recovery (33%) was developed. Molecular imprinting using 2-butanone as additive in the immobilization process improved the synthetic activity of the biocatalyst. LuCLEA could be partially recycled for the synthesis of (R)-2-butanone cyanohydrin on a preparative scale over two batches. The enantioenriched cyanohydrin obtained was further hydrolyzed to give (R)-2-hydroxy-2-methylbutyric acid in 85% yield (from 2-butanone) and 87% ee.

Screening for stereoselective cyanohydrin synthesis in 96-well plates was employed in the development of an efficient, pH-stable hydroxynitrile lyase for the conversion of sterically hindered aliphatic aldehydes. Site-saturation mutagenesis (SSM) resulted in a powerful catalyst for the stereoselective conversion of hydroxypivalaldehyde and pivalaldehyde to their corresponding (R)-cyanohydrins (ee >97%) which are used as chiral building blocks (e.g., for pantothenic acid production). Furthermore, redesigning the PaHNL5 gene and improving its expression by Pichia pastoris with the help of a new P AOX1 promoter variant and the helper protein PDI (protein disulfide isomerase) led to elevated amounts of today's most efficient biocatalyst for vitamin B 5 synthesis.

Highly enantioselective cyanoformylation of aldehydes catalyzed by VV chiral salen complex by using ethyl cyanoformate as a source of cyanide was accomplished in the presence of several cocatalysts. Excellent yields and ee values for the resulting cyanohydrin carbonates were achieved when imidazole was used as a cocatalyst at –20 °C. The ee value of the cyanohydrin carbonate of 2-naphthaldehyde was further improved to >99 % by recrystallization. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The overcoming of thermodynamic limitations in the synthesis of optically active ketone cyanohydrins by using organic solvent-free systems has been investigated. Therefore, substrates with known unfavorable results within hydroxynitrile lyase-catalyzed reactions were selected for the determination of limitations and bottlenecks in ketone cyanohydrin synthesis. The highly (S)-selective hydroxynitrile lyase from Manihot esculenta (MeHNL) has been chosen for the conversion of acetophenone and the corresponding derivatives, which are substrates that exhibit only low grades of conversion also with several other hydroxynitrile lyases. With organic solvent-free systems under optimized reaction conditions conversions up to 78 % with>99.0 ee (S) were obtained. Finally, 5 mL of (S)-acetophenone cyanohydrin with an enantiomeric excess of 98.5 % ee (S) were synthesized.

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.

Aluminum phthalocyanine (AlPc) in the presence of Ph3PO acts as a highly effective catalyst for cyanosilylation of various aldehydes to the corresponding cyanohydrin trimethylsilyl ethers. The reaction proceeds smoothly with 5 mol% catalyst loading at room temperature, giving up to 96% yield. Copyright © 2007 John Wiley & Sons, Ltd.