Chiral Cyanohydrins Research Articles

A practical high through-put continuous process for the synthesis of chiral cyanohydrins.

A practical high through-put continuous process for the synthesis of chiral cyanohydrins is reported. Pretreated almond meal (or other solid raw enzyme sources) was loaded in a column to form a reactor, to which were attached a supplying system to deliver a solution of substrate and HCN in solvent on one end and a collecting-separating system on the other end. By controlling the flowing rate, optimal conditions were achieved for the hydrocyanation of various aromatic carboxaldehydes in a "micro-aqueous" medium to produce chiral cyanohydrins in high yields and high enantiomeric excess (ee) with high substrate/catalyst ratio.

Mass transfer limitation as a tool to enhance the enantiomeric excess in the enzymatic synthesis of chiral cyanohydrins

The enantioselective synthesis of cyanohydrins catalyzed by R-hydroxynitrile lyase in an aqueous-organic liquid two-phase system using, mass transfer limitation to enhance enantiomeric excess at 5°C and pH 5.5 is described. Benzaldehyde, a good substrate, and cinnamaldehyde, a notoriously difficult substrate, were used as model substrates and compared in order to establish the mass transfer limitation concept in a two-liquid phase system, where the non-enzymatic-racemic reaction competes. Enzyme concentration and phase volume ratio between organic and buffer phase were geared to one another to enhance the enantiomeric excess for each substrate. In both cases, after optimization, excellent chemical conversion (>99% on a 60 mmol scale), high throughput and high enantiomeric excess (benzaldehyde >99% and cinnamaldehyde >96%) were achieved.

Analyzing the hydrocyanation reaction: chiral HPLC and the synthesis of racemic cyanohydrins

A method to directly analyze unprotected cyanohydrins (with regard to enantiomeric purity and conversion) via chiral HPLC is described. The influence of the solvent composition on the stability of the unprotected cyanohydrins is investigated. By acidifying the solvent during HPLC analysis, hydrocyanation reactions can be directly followed in time. For many chiral cyanohydrins it is possible to determine both conversion and enantiomeric purity without prior protection of the cyanohydrin. Using a special aqueous-organic two-phase system racemic cyanohydrins can be synthesized in excellent yields.

ChemInform Abstract: Biocatalysis in the Enantioselective Formation of Chiral Cyanohydrins, Valuable Building Blocks in Organic Synthesis

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Elucidation of the mode of substrate binding to hydroxynitrile lyase from Hevea brasiliensis.

The hydroxynitrile lyase from Hevea brasiliensis (Hb-HNL) is used as a catalyst in enantiospecific syntheses of alpha-hydroxynitriles from aldehydes and methyl-ketones. The catalyzed reaction represents one of the few industrially relevant examples of enzyme mediated C-C coupling reactions. In this work, we modeled Hb-HNL substrate complexes that have as yet proven inaccessible to experimental structure determination and were able to identify two binding modes for the natural substrate acetone cyanohydrin in docking simulations. Discrimination of the two alternatives was achieved by modeling complexes with two different chiral cyanohydrins followed by an analysis of the respective relative binding energies from molecular mechanics and thermodynamic integration. Only for one of the alternative binding modes the experimentally established S-selectivity of the enzyme was correctly predicted. Our results yielded further support for an enzymatic mechanism involving the catalytic triad Ser80, His235, and Asp207 as a general acid/base. A pivotal role was ascribed to Lys236, which seems to be crucial for enzymatic activity at low pH values. In addition, the modeling calculations provided possible explanations for the observed substrate and enantioselectivity of the enzyme that rationalize available mutational data and will be the basis for future protein engineering efforts.

The Development of Materials, Mixtures and Gels for Ferroelectric Displays

Ferroelectric liquid crystals have developed from the early single component chiral systems, that brought a wealth of fundamental knowledge, to multi-component achiral host systems with optimised physical properties that have a small quantity of chiral dopant added to provide the required ferroelectricity. The research into ferroelectric liquid crystals has been intense, but the technology has not yet proved commercially viable. This paper discusses the developments in ferroelectric materials and focuses on the ferroelectric mixtures generated from ortho-difluoroterphenyl host materials and the chiral cyanohydrin dopants which have a high dielectric biaxiality and are suitable for use in τVmin devices. Such ferroelectric mixtures have been incorporated into structurally matched diacrylates and polymerised to form a gel network, and the interesting results of these systems are discussed in comparison with the conventional ferroelectric mixtures.

Synthesis of γ-Hydroxy-α,β-unsaturated Esters and Nitriles from Chiral Cyanohydrins

The Horner–Wittig reaction of cyanomethyl- and carbethoxymethyl diphenylphosphine oxides with a range of O-protected chiral α-hydroxy aldehydes is described. The α-hydroxy aldehydes were prepared with high enantiomeric purity from chiral O-protected cyanohydrins. The γ-hydroxy-α,β-unsaturated compounds formed were isolated in high enantiomeric purity and excellent yield. In all cases complete E-selectivity was observed.

Enzyme-Catalyzed Preparation and Synthetic Applications of Optically Active Cyanohydrins

Chiral cyanohydrins are widespread in nature as cyanoglycosides, serving more than two thousand plants and many insects as antifeedant. Fast release of HCN from cyanohydrins in cells is catalyzed by hydroxynitrile lyases (HNLs). The importance of HNLs in organic syntheses is the enantioselectivity of cleavage as well as formation of cyanohydrins by these biocatalysts. For the preparation of (R)-cyanohydrins from aldehydes and HCN on a preparative scale, (R)-PaHNL from bitter almonds proves to be the best catalyst. For the synthesis of (S)-cyanohydrins, the recombinant HNLs from cassava (MeHNL) and rubber tree (HbHNL) are most suitable. In organic solvents or in biphasic systems, the chemical addition of HCN to the carbonyl compounds can be suppressed, resulting in high optical yields of the obtained cyanohydrins. Stereoselective follow-up reactions of (R)- and (S)-cyanohydrins lead to other important classes of compounds with stereogenic centers. Starting from (R)-cyanohydrins, (R)-2-hydroxy carboxylic acids, (R)-2-hydroxy aldehydes, (R)-2-hydroxy ketones, (1R)-2-amino alcohols, and (1R,2S)-2-amino alcohols are easily obtainable in high optical and chemical yields by transformation of the cyano group. Analogous transformations are possible starting from (S)-cyanohydrins. Sulfonylation of the OH function in cyanohydrins allows nucleophilic substitution of the sulfonate group with complete inversion of configuration. In this way, starting, e.g., from (R)-cyanohydrins, (S)-2-azido nitriles, (S)-2-amino nitriles, (S)-2-amino acids, (S)-1,2-diamines and (S)-2-sulfanyl nitriles are obtained in high optical yields.

Synthesis and characterization of novel chiral liquid crystalline polysiloxanes

Several novel side chain liquid crystalline polysiloxanes have been prepared containing a chiral cyanohydrin moiety prepared using enantioselective synthesis. Homopolymers incorporating a side chain with the chiral group exhibited no liquid crystalline behavior. Copolymers of the side chain with the cyanohydrin group with an alkenyloxybenzoate yielded polymers exhibiting a N * phase. Increased amounts of the side chain with the cyanohydrin moiety led to a decrease in the transition temperatures of the resulting copolymers. Dielectric relaxation studies showed that all polymers exhibited 6 motion due to relaxation of the longitudinal dipole of the mesogen around its short axis. One copolymer with a large amount of the chiral unit and a long flexible spacer exhibited distinct α and 6 relaxations where the u relaxation is assigned to the motions of the dipoles perpendicular to the side chain. The fact that both are clearly seen as independent peaks rather than in a broad peak which must be deconvoluted is indicative of the fact that long, flexible spacer chains decouple the two motions from each other. The 6 process for the polymers with a small amount of the cyanohydrin side chain tended to be dominated by the non-chiral pendant group. The motion of the polymer with an increased amount of the pendant group containing the chiral moiety was dominated by the cyanohydrin side chain and the 6 relaxation was much slower (longer relaxation time) due to the bulky nature of the chiral moiety.

Intramolecular Cycloaddition Reactions of ω-Unsaturated Chiral Nitrones

The intramolecular 1,3-dipolar cycloaddition of ω-un-saturated chiral nitrones is described. Starting materials for this reaction are O-protected chiral cyanohydrins, prepared by an R-oxynitrilase catalyzed asymmetric addition of hydrogen cyanide to ω-unsaturated aldehydes. Intramolecular cycloaddition, followed by reductive opening of the isoxazolidine ring, produced five- and seven-membered ring compounds with chiral hydroxy and amine functionalities of high enantiomeric purity in excellent yield.

ChemInform Abstract: Chiral Cyanohydrin Phosphates. Part 2. Stereoselective Umpolung Reactions with Metalated P‐Chiral Cyanohydrin Phosphates‐ Enantioselective Synthesis of Tertiary Cyanohydrins.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Direct Conversion of Chiral Cyanohydrins to Chiral Nitrones by Transimination.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereoselective Umpolung Reactions with MetalatedP‐Chiral Cyanohydrin Phosphates—Enantioselective Synthesis of Tertiary Cyanohydrins

AbstractWe present the first cyanohydrin derivative4that allows diastereoselective umpolung reactions. In4the OH group of the cyanohydrin is linked with a chiral phosphate, which can be removed hydrolytically after asymmetric synthesis. Cyclization of pseudoephedrine1dwith POCl3gave2d. This was followed by addition of racemic benzaldehyde cyanohydrin3to give the key intermediate4dwith complete retention of the configuration at phosphorus. Deprotonation of4d, followed by addition of a wide variety of electrophiles afforded the crystalline products5with high diastereomeric excesses (deup to 94%). High asymmetric induction was also achieved for the reaction of4−Li+with acyl halides, α‐bromoacetates, 2‐cycloalkenones, α,β‐unsaturated esters, and γ‐bromoacetates. Lewis acid assisted hydrolysis proceeded without racemization and gave high yields of ketone cyanohydrins6. From the ring‐opened chiral auxiliary7, optically pure pseudoephedrine1was readily recovered by acid hydrolysis. Optically pure (R) and (S) ketone cyanohydrins are now accessible in a very general strategy, which circumvents the substrate limitations of enzymatic synthesis.

Direct conversion of chiral cyanohydrins to chiral nitrones by transimination

A new method for the preparation of enantiomerically pure N-benzyl nitrones is described. By using either a one-pot reduction-transimination or a one-pot Grignard addition-transimination sequence chiral O-protected α-hydroxynitriles can be converted into chiral aldo- and ketonitrones, respectively.

ChemInform Abstract: Synthesis of α‐Hydroxy‐β‐amino Acids from Chiral Cyanohydrins.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Mechanism of cyanogenesis: the crystal structure of hydroxynitrile lyase from Hevea brasiliensis

Background: Over three thousand species of plants, including important food crops such as cassava, use cyanogenesis, the liberation of HCN upon tissue damage, as a defense against predation. Detoxification of cyanogenic food crops requires disruption of the cyanogenic pathway. Hydroxynitrile lyase is one of the key enzymes in cyanogenesis, catalyzing the decomposition of an acyanohydrin to form HCN plus the corresponding aldehyde or ketone. These enzymes are also of potential utility for industrial syntheses of optically pure chiral cyanohydrins, being used to catalyze the reverse reaction. We set out to gain insight into the catalytic mechanism of this important class of enzymes by determining the three-dimensional structure of hydroxynitrile lyase from the rubber tree, Hevea brasiliensis. Results The crystal structure of the enzyme has been determined to 1.9 Å resolution. It belongs to the α/ β hydrolase superfamily, with an active site that is deeply buried within the protein and connected to the outside by a narrow tunnel. The catalytic triad is made up of Ser80, His235 and Asp207. By analogy with known mechanisms of other members of this superfamily, catalysis should involve an oxyanion hole formed by the main chain NH of Cys81 and the side chains of Cys81 and Thr11. Density attributed to a histidine molecule or ion is found in the active site. Conclusion By analogy with other α/ β hydrolases, the reaction catalyzed by hydroxynitrile lyase involves a tetrahedral hemiketal or hemiacetal intermediate formed by nucleophilic attack of Ser80 on the substrate, stabilized by the oxyanion hole. The SH group of Cys81 is probably involved in proton transfer between the HCN and the hydroxynitrile OH. This mechanism is significantly different from the corresponding uncatalyzed solution reaction.

Synthesis of α-hydroxy-β-amino acids from chiral cyanohydrins

Abstract (−)-( R , E )-2-hydroxy-3-pentenenitrile 1 , obtained by R-oxynitrilase catalyzed addition of HCN to 2-butenal, was shown to be an excellent chiral starting material for the synthesis of α-hydroxy-β-amino acids of high enantiomeric and diastereomeric purity. The synthesis of N -benzyl ( S )-isoserine 7a and (2 S ,3 S )-isoallothreonine 7b , as well as N -benzoyl (2 S ,3 S )-3-phenylisoserine 14 is reported.

Preparation of optically active cyanohydrins using the ( S)-hydroxynitrile lyase from Hevea brasiliensis

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

Synthesis and characterization of chiral smectic C liquid crystalline terpolysiloxanes

Abstract A number of tailor-made side chain liquid crystalline terpolysiloxanes, containing chiral cyanohydrin ester, phenyl pyrimidine and fluorinated phenylbenzoate as the side groups, have been synthesized for potential applications as ferroelectric liquid crystal polymers. All the polysiloxanes exhibit the mesomorphic sequence of crystal-chiral smectic C-smectic A-isotropic phases.

Biosynthesis of cyanohydrin glucosides from unnatural nitriles in intact tissue of Passiflora morifolia and Turnera angustifolia

Passiflora morifolia, which under natural conditions contains cyanohydrin glucosides linamarin, lotaustralin and epilotaustralin, converted cyclopentanecarbonitrile, 2-cyclopentenecarbonitrile and 3-methylbutaneitrile into the corresponding cyanohydrin glucosides. Turnera angustifolia, which normally produces glucosides of cyclopentenone cyanohydrin, converted cyclopentanecarbonitrile, 2-methylpropanenitrile and 2-methylbutanenitrile, but not 3-methylbutanenitrile, into the corresponding cyanohydrin glucosides. Mixtures of epimers were produced when these glucosides contained chiral cyanohydrin carbon atoms. Feeding with cyclopentanecarbonitrile resulted in formation of 1-(β- d-glucopyranosyloxy)cyclopentanecarbonitrile, a saturated analogue of deidaclin and tetraphyllin A. Neither plant utilized cyclopropanecarbonitrile as substrate. The experiments demonstrate broad substrate specificity of nitrile hydroxylases present in these plants. A novel glycoside, 2-[6-O-(β- d-xylopyranosyl )-β- d-glucopyranosyloxy]propane (isopropyl primeveroside), was isolated from P. morifolia. The compound represents a rare example of natural isopropyl glycoside; its characterization included assignment of all 1H and 13C NMR signals of the primeverosyl group using two-dimensional NMR methods. Biosynthesis of the isopropyl moiety of the primeveroside is unclear, but the formation of alcohols corresponding to natural cyanohydrins may be a previously unrecognized extension of the cyanohydrin biosynthesis pathway in higher plants.