Cyanohydrin Formation Research Articles

Organocatalytic stereoselective cyanosilylation of small ketones

Enzymatic stereoselectivity has typically been unrivalled by most chemical catalysts, especially in the conversion of small substrates. According to the ‘lock-and-key theory’1,2, enzymes have confined active sites to accommodate their specific reacting substrates, a feature that is typically absent from chemical catalysts. An interesting case in this context is the formation of cyanohydrins from ketones and HCN, as this reaction can be catalysed by various classes of catalysts, including biological, inorganic and organic ones3–7. We now report the development of broadly applicable confined organocatalysts for the highly enantioselective cyanosilylation of aromatic and aliphatic ketones, including the challenging 2-butanone. The selectivity (98:2 enantiomeric ratio (e.r.)) obtained towards its pharmaceutically relevant product is unmatched by any other catalyst class, including engineered biocatalysts. Our results indicate that confined chemical catalysts can be designed that are as selective as enzymes in converting small, unbiased substrates, while still providing a broad scope.

Formal Total Synthesis of Salvinorin A.

The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was prepared from a Wieland‐Miescher ketone using a known γ‐hydroxylation, reduction of the enone double bond, cyanohydrin formation, and elimination, yielding an unsaturated nitrile. A two‐step reduction led to the required allyl alcohol. The subsequent Johnson‐Claisen rearrangement provided a mixture of two diastereomeric 1,4‐unsaturated esters in a ratio of around 2.6 : 1. The major isomer could be converted to a key intermediate of the Hagiwara synthesis of salvinorin A.

An Efficient Probe of Cyclometallated Phosphorescent Iridium Complex for Selective Detection of Cyanide.

A cyclometallated phosphorescent iridium-based probe to detect CN– was prepared through a cyanide alcoholize reaction based on the C^N type main ligand and N^N type ancillary ligand (2-phenyl pyridine and 1,10-phenanthroline-5-carboxaldehyde, respectively). The efficient probe exhibited good sensitivity in response to CN– in an CH3CN and H2O (95/5) mixture within a 1.23 μM detection limit. The response of PL is directly in line with the concentration of CN– from 0 to 2.0 equiv. The PL investigation of other reactive anions proved the great selectivity to CN–. Additionally, upon adding 1.0 equiv. of cyanide, the formation of cyanohydrin was correctly elucidated in 1H NMR, FT-IR, and mass spectra studies. The conspicuous results indicate that the iridium complex has the potential possibility of application in other biosystems related to CN–.

Cyanohydrin formation of quinone appended benzaldehyde as a tool for selective colorimetric detection of cyanide in aqueous solution in a wide pH range.

A Novel chemosensor R possessing napthoquinone substituted benzaldehyde has been successfully designed, synthesized and characterized using NMR and mass spectral techniques. The receptor exhibits striking colour change from pale yellow to intense green with sodium cyanide in DMF-H2O (80-20% v/v) in a wide range of pH (3-12). Based on the results of spectral (UV-Vis, fluorescence and NMR), electrochemical and kinetic studies a plausible mechanism has been proposed for the cyanide detection process. The mechanism of sensing of cyanide by R is through the formation of cyanohydrin in acidic, neutral and basic solutions, which is the novelty of the receptor. The pseudo-first-order rate constants for the formation of cyanohydrin are found to be 2.9 × 10-3, 3.9 × 10-3 and 4.6 × 10-3 min-1 at pH values 5, 7 and 10, respectively in DMF-H2O (80-20% v/v) medium, supporting the ability of R to form cyanohydrin with equal ease in different pH values. The results of Job's continuous variation method indicates a 1:2 (R:CN-) stoichiometry for the interaction. The only minor drawback with the receptor is the time taken to impart visible colour change with cyanide ion, which is not instantaneous.

Kinetic Resolution of Acylsilane Cyanohydrins via Organocatalytic Cycloetherification.

An asymmetric cyanation of acylsilanes involving the in-situ formation of chiral acylsilane cyanohydrins followed by their kinetic resolution via organocatalytic cycloetherification is described. The highly enantio- and diastereoselective cycloetherification was crucial for achieving a high efficiency in the kinetic resolution. Consequently, acylsilane cyanohydrins containing a tetrasubstituted chiral carbon atom bearing silyl, cyano, and hydroxy groups were obtained in an enantioenriched form. This protocol therefore offers an efficient catalytic approach to optically active acylsilane cyanohydrins, which exhibit potential as chiral building blocks for the synthesis of pharmaceutically relevant chiral organosilanes.

Lanthanide Complexes that Respond to Changes in Cyanide Concentration in Water.

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.

Lanthanide Complexes that Respond to Changes in Cyanide Concentration in Water

AbstractCyanide 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.

A Highly Selective Chemosensor for Cyanide Derived from a Formyl-Functionalized Phosphorescent Iridium(III) Complex.

A new phosphorescent iridium(III) complex, bis[2',6'-difluorophenyl-4-formylpyridinato-N,C4']iridium(III) (picolinate) (IrC), was synthesized, fully characterized by various spectroscopic techniques, and utilized for the detection of CN(-) on the basis of the widely known hypothesis of the formation of cyanohydrins. The solid-state structure of the developed IrC was authenticated by single-crystal X-ray diffraction. Notably, the iridium(III) complex exhibits intense red phosphorescence in the solid state at 298 K (ΦPL = 0.16) and faint emission in acetonitrile solution (ΦPL = 0.02). The cyanide anion binding properties with IrC in pure and aqueous acetonitrile solutions were systematically investigated using two different channels: i.e., by means of UV-vis absorption and photoluminescence. The addition of 2.0 equiv of cyanide to a solution of the iridium(III) complex in acetonitrile (c = 20 μM) visibly changes the color from orange to yellow. On the other hand, the PL intensity of IrC at 480 nm was dramatically enhanced ∼5.36 × 10(2)-fold within 100 s along with a strong signature of a blue shift of the emission by ∼155 nm with a detection limit of 2.16 × 10(-8) M. The cyanohydrin formation mechanism is further supported by results of a (1)H NMR titration of IrC with CN(-). As an integral part of this work, phosphorescent test strips have been constructed by impregnating Whatman filter paper with IrC for the trace detection of CN(-) in the contact mode, exhibiting a detection limit at the nanogram level (∼265 ng/mL). Finally, density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations were performed to understand the electronic structure and the corresponding transitions involved in the designed phosphorescent iridium(III) complex probe and its cyanide adduct.

Fluorogenic and chromogenic heterocyclic thiourea: Selective recognition of cyanide ion via nucleophilic addition reaction and real sample analysis

A sequence of new heterocylic ring connected thiourea receptors (R1–R4) with anthraquinone or phenazine signaling unit were synthesized and employed for the selective recognition of CN− ion in 25% aqueous DMSO medium. Structure of R3 was confirmed by single crystal X-ray diffraction analysis. In the presence of CN− ion, quick colorimetric response was noticed from orange to purple for R1–R2 and light yellow to orange for R3–R4. CN− ion interaction with R1–R4 was further explored by spectroscopic titration such as UV–vis and fluorescence. The formation of cyanohydrins was realized by 1H NMR spectroscopic titration. β-Correction spectroscopic technique has been employed to find out the real absorbance of the cyanide complexes of R1–R4. Visual detection of CN− ion present in the cassava flour and the quantification of CN− ion content in water samples were demonstrated by R1–R4.

Chemoenzymatic flow cascade for the synthesis of protected mandelonitrile derivatives.

A chemoenzymatic two-step cascade process, with both steps having incompatible reaction conditions, was successfully performed in continuous flow. The chemoenzymatic aqueous formation of cyanohydrins was integrated with a subsequent organic phase protection step in a single flow process utilising a membrane-based phase separation module. The wider applicability of our setup was demonstrated with the synthesis of nine protected cyanohydrin derivatives, all obtained in good yields and high to excellent enantioselectivity.

Organocatalysed Cyanations of Carbonyl Compounds

One of the most important carbon-carbon bond forming reactions in organic synthesis is the cyanation of carbonyl compounds. The resulting cyanohydrins are key building blocks for many other important compounds, namely, α- hydroxy acids, α-hydroxy ketones, primary and secondary β-hydroxy amines, α-hydroxy esters and α-amino acids, which are essential in areas such as fine chemistry, agrochemicals and pharmaceuticals. Cyanohydrin synthesis can be catalyzed by enzymes, metal complexes, inorganic and organic componds. The initial synthetic methods have been extensively explored however the organocatalyzed reaction has been referred to in more limited extent. In this paper we will review the cyanation of aldehydes and ketones in the presence of organocatalysts, addressing both the formation of racemic and nonracemic cyanohydrins. Keywords: Aldehydes, asymmetric, benzaldehyde, cyanation, cyanohydrin, ethylcyanoformate, ketones, organocatalysts, trimethylsilylcyanide, trimethylsilylcyanohydrins

Synthesis of β-amino-α.-ketoamides

β-Amino-α-ketoamides 1 are a class of compounds exhibiting biological activity as reversible covalent enzyme inhibitors. The representative examples are clinically approved drugs for the treatment of hepatitis C virus Boceprevir 2 and Telaprevir 3. β-Amino-α- ketoamide substructure is also found in a number of natural products, many of which display a remarkable biological activity. The methods for the synthesis of β-amino-α-ketoamide can be classified based on the key steps of the synthetic routes: from unsaturated amide involving epoxydation followed by a regioselective azidolysis; from esters involving aminohydroxylation; from adehydes via Passerini reaction, cyanohydrin formation, addition of the masked acylcyanide (MAC) reagent or orthothioester; from imines via addition of dithiolane derived from oxoacetic acid, addition of isoxazolyl-4-triflates or via azetidinone formation; from acids via acylation of (cyanomethylene) triphenylphosphorane (the Wasserman procedure), via acylfurane formation or via Dakin-West reaction; from nitroalkanes via Henry reaction. In this review, the information from the scientific literature published within the period from 1990 till 2014 for the synthesis of β-amino-α-ketoamides is covered and systematized according to the above mentioned key steps. Keywords: Azetidinones, cyanohydrins, dakin-west reaction, epoxides, MAC reagent, orthothioesters, henry reaction, passerini reaction, protease inhibitors, wasserman procedure, β-Amino-α-ketoamides.

ChemInform Abstract: One‐Step Preparation of O‐(α‐Bromoacyl) Cyanohydrins by Minor Enantiomer Recycling: Synthesis of 4‐Amino‐2(5H)‐furanones.

AbstractCoupling of cyanides of type (I) with various aldehydes using a one‐step recycling procedure allows formation of (α‐bromoacyl) cyanohydrins in good yields with high diastereoselectivity.

Mini-Review: Recent Developments in Hydroxynitrile Lyases for Industrial Biotechnology

Hydroxynitrile lyases (HNLs) catalyze the cleavage as well as the formation of cyanohydrins. The latter reaction is valuable for the stereoselective C-C bond formation by condensation of HCN with carbonyl compounds. The resulting cyanohydrins serve as versatile building blocks for a broad range of chemical and enzymatic follow-up reactions. A significant number of (R)- and (S)-selective HNLs are known today and the number is still increasing. HNLs not only exhibit varying substrate scope but also differ in sequence and structure. Tailor-made enzymes for large-scale manufacturing of cyanohydrins with improved yield and enantiomeric excess are very interesting targets, which is reflected in a solid number of patents. This review will complement and extend our recent review with a strong focus on applications of HNLs for the synthesis of highly functionalized, chiral compounds with newest literature, recent and current patent literature.

Accelerated stability and bioassay of a new oral α-ketoglutarate formulation for treating cyanide poisoning

Context: Due to several limitations of existing cyanide antidotes, α-ketoglutarate (α-KG) has been proposed as a promising treatment for cyanide.Objective: This study reports the accelerated stability and bioassay of a new oral α-KG formulation.Materials and methods: Amber-colored PVDF bottles containing 100 ml of 10% α-KG in 70% sorbitol, preservative (sodium methyl paraben and sodium propyl paraben), sweetener (sodium saccharine), flavor (American ice-cream soda and peppermint) and color (tartrazine), at pH 7.0–8.0 were stored in stability chamber (40 ± 2 °C and 75 ± 5% humidity) for 6 months in a GMP compliant facility. Various physical (pH, color, evaporation, extractable volume and clarity), chemical (identification and quantification of active ingredient) and microbiological (total aerobic count) analyses, together with protection studies were carried periodically in mice. Acute toxicity of the formulation and bioavailability of α-KG were assessed in rats at the beginning of the experiment.Results: No physical changes and microbiological growth were observed in the formulation. After 6 months, α-KG content in the formulation diminished by ∼24% but its protective efficacy against cyanide remained at 5.9-fold. Protection was further characterized spectrophotometrically by disappearance of α-KG spectrum in the presence of cyanide, confirming cyanohydrin formation. Oral LD50 of α-KG formulation in rats was >7.0 g/kg body weight, and did not produce any acute toxicity of clinical significance. Also, an appreciable amount of α-KG was measured in blood.Conclusion: As per the guidelines of International Conference on Harmonization, the new α-KG formulation exhibited satisfactory stability, bioefficacy and safety as cyanide antidote.

Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine, nisoxetine, and duloxetine

The asymmetric synthesis of two well-known anti-depressant drugs, fluoxetine and duloxetine has been accomplished in a chemoenzymatic manner. The main highlight of the synthesis is the enantioselective cyanohydrin formation by a plant (R)-HNL (hydroxynitrile lyase). The enantiopure cyanohydrins are then synthetically manipulated into the above two drug molecules and two of their structural analogues, atomoxetine and nisoxetine.

Synthesis of aldehydic ribonucleotide and amino acid precursors by photoredox chemistry.

Synthesis of aldehydic ribonucleotide and amino acid precursors by photoredox chemistry.

Total Synthesis of Nominal Gobienine A

The lichen-derived glycoconjugate gobienine A is structurally more complex than most glycolipids isolated from higher plants by virtue of the all-cis substituted γ-lactone substructure embedded into its macrocyclic frame. A concise entry into this very epimerization-prone and hence challenging structural motif is presented, which relies on an enantioselective cyanohydrin formation, an intramolecular Blaise reaction, a palladium-catalyzed alkoxycarbonylation, and a diastereoselective hydrogenation of the tetrasubstituted alkene in the resulting butenolide. This strategy, in combination with ring-closing olefin metathesis for the formation of the macrocyclic perimeter, allowed the proposed structure of gobienine A (1) to be formed in high overall yield. The recorded spectral data show that the structure originally attributed to gobienine A is incorrect and that it is not the epimerization-prone ester site on the butanolide ring that is the locus of misassignment; rather, the discrepancy must be more profound.

A simple separation method for (S)-hydroxynitrile lyase from cassava and its application in asymmetric cyanohydrination

Using an acetone precipitation method, crude (S)-hydroxynitrile lyase [(S)-MeHNL] was separated from Munihot esculenta (cassava) leaves, and used directly as biocatalyst to catalyze asymmetric cyanohydrination and produce cyanohydrins with enantiomeric purities (⩾90% ee) significantly greater than those previously reported. The use of a water/i-Pr2O system with an enzyme, NaCN, and appropriate amounts of acetic acid is crucial in improving the stereoselectivity of cyanohydrin formation by minimizing the non-enzymatic reaction and the racemization of the chiral products. The proposed isolation method for crude (S)-MeHNL has a high value because of its simplicity, and low cost as well as the high activity of the crude (S)-MeHNL.

Hydroxynitrile lyases with α/β-hydrolase fold: two enzymes with almost identical 3D structures but opposite enantioselectivities and different reaction mechanisms.

Hydroxynitrile lyases (HNLs) catalyze the cleavage of cyanohydrins to yield hydrocyanic acid (HCN) and the respective carbonyl compound and are key enzymes in the process of cyanogenesis in plants. In organic syntheses, HNLs are used as biocatalysts for the formation of enantiopure cyanohydrins. We determined the structure of the recently identified, R-selective HNL from Arabidopsis thaliana (AtHNL) at a crystallographic resolution of 2.5 Å. The structure exhibits an α/β-hydrolase fold, very similar to the homologous, but S-selective, HNL from Hevea brasiliensis (HbHNL). The similarities also extend to the active sites of these enzymes, with a Ser-His-Asp catalytic triad present in all three cases. In order to elucidate the mode of substrate binding and to understand the unexpected opposite enantioselectivity of AtHNL, complexes of the enzyme with both (R)- and (S)-mandelonitrile were modeled using molecular docking simulations. Compared to the complex of HbHNL with (S)-mandelonitrile, the calculations produced an approximate mirror image binding mode of the substrate with the phenyl rings located at very similar positions, but with the cyano groups pointing in opposite directions. A catalytic mechanism for AtHNL is proposed, in which His236 from the catalytic triad acts as a general base and the emerging negative charge on the cyano group is stabilized by main-chain amide groups and an α-helix dipole very similar to α/β-hydrolases. This mechanistic proposal is additionally supported by mutagenesis studies.