Chiral cyanohydrin

Nucleophilic substitutions of 0-activated 2-hydroxy carboxylic acids and esters, respectively, are well established, but little is known about the analogous reactions of activated cyanohydrins. Chiral 2-sulfonyloxynitriles, accessible from non-racemic cyanohydrins, have a relatively high configurational stability. They react with nucleophiles under very mild conditions under inversion of configuration (Scheme 8). ° ... 

Baeza, A., Casa, J., Najera, C., Sansano, J.M. and Saa, J.M., Enantioselective synthesis of O-methoxycarbonyl cyanohydrins chiral building blocks generated by bifunctional catalysis with BINOLAM-AICI. Eur. J. Org. Chem., 2006, 1949. 

Chien, L.-C., Shenouda, I. G., Saupe, A., and Jakli, A., Side-chain liquid crystalline polysiloxanes containing a cyanohydrin chiral center, Uq. Cryst., 15, 497 (1993). 

L C. Qiicn, I. G. Sbenouda, A. Saupe, and A. Jokli. Side-chain liquid crystaUine polysi-kixanes containing a cyanohydrin chiral oenter, Uq Crysmis 33 497 (1993). 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

TMSCN, (—)-DIPT [diisopropyl L-tartrate], Ti(/-PrO)4, CH2CI2, 0°, 6 h, rt, 12 h, 95% yield. These conditions afford chiral cyanohydrins. ... 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

The procedure is modified for the reaction of preformed cyanohydrins with chiral amines39. I11 a further variation, Schiff bases of aliphatic aldehydes with optically active 1-arylalkyl-amines are transformed with liquid hydrogen cyanide to the corresponding a-aminonitrilcs, which, after acid hydrolysis, give the /V-aryUilkylamino acids. Hydrogenation then yields the a-amino acids40 41. 

The addition of HCN to aldehydes or ketones produces cyanohydrins. This is an equilibrium reaction. For aldehydes and aliphatic ketones the equilibrium lies to the right therefore the reaction is quite feasible, except with sterically hindered ketones such as diisopropyl ketone. However, ketones ArCOR give poor yields, and the reaction cannot be carried out with ArCOAr since the equilibrium lies too far to the left. With aromatic aldehydes the benzoin condensation (16-54) competes. With oc,p-unsaturated aldehydes and ketones, 1,4 addition competes (15-33). Ketones of low reactivity, such as ArCOR, can be converted to cyanohydrins by treatment with diethylaluminum cyanide (Et2AlCN see OS VI, 307) or, indirectly, with cyanotrimethylsilane (MesSiCN) in the presence of a Lewis acid or base, followed by hydrolysis of the resulting O-trimethylsilyl cyanohydrin (52). The use of chiral additives in this latter reaction leads to cyanohydrins with good asymmetric... 

The hydroxynitrile lyase (HNL)-catalyzed addition of HCN to aldehydes is the most important synthesis of non-racemic cyanohydrins. Since now not only (f )-PaHNL from almonds is available in unlimited amounts, but the recombinant (S)-HNLs from cassava (MeHNL) and rubber tree (HbHNL) are also available in giga units, the large-scale productions of non-racemic cyanohydrins have become possible. The synthetic potential of chiral cyanohydrins for the stereoselective preparation of biologically active compounds has been developed during the last 15 years. 

In Table 2, the properties and characteristics of the five HNLs presently applied in the enzyme-catalyzed large-scale preparation of chiral cyanohydrins are summarized. ... 

Although considerable progress has been made in metal-catalyzed syntheses of non-racemic cyanohydrins in recent years, the HNL-catalyzed preparation of chiral cyanohydrins is by far the most important method especially for large-scale processes, due to the easy access of R)- and (5 )-HNLs and the high optical and chemical yields of the cyanohydrins obtained. ... 

OPTIMIZED REACTION CONDITIONS FOR THE HNL-CATALYZED FORMATION OF CHIRAL CYANOHYDRINS... 

For practical applications of HNLs as catalysts for the preparation of chiral cyanohydrins, three objectives have been achieved first, to get high enantioselec-tivity it is decisive to suppress the non-enzymatic addition of HCN to the substrate ... 

SYNTHETIC POTENTIAL OE CHIRAL CYANOHYDRINS IN STEREOSELECTIVE SYNTHESIS... 

Another important class of pharmaceuticals which is prepared from chiral 2-hydroxy acids is the angiotensin-converting enzyme (ACE) inhibitors. (R)-3-phenylpropionaldehyde cyanohydrin is transformed into the corresponding 2-hydroxy ester which after activation by sulfonylafion reacts with dipetides to give, under inversion of configuration, ACE inhibitors known as prils (Scheme 6). ... 

Amino alcohols, which have a broad spectrum of biological activities, can be categorized as adrenahne-like with one chiral center at C-1 or as ephedrine-like with two chiral centers at C-1 and C-2 (Scheme 7). Although a variety of methods have been developed for the stereoselective preparation of 1,2-amino alcohols, " in most cases it is easier and more efficient to prepare these important compounds stereoselectively starting from chiral cyanohydrins (Scheme... 

Stereoselective substitution of the hydroxyl group in chiral cyanohydrins... 

Although considerable progress has been made in metal-catalyzed preparations of non-racemic cyanohydrins, the HNL-catalyzed reaction is still the most important method for the synthesis of chiral cyanohydrins, especially for large-scale reactions. The usefulness of HNLs as catalysts for the stereoselective addition of HCN to carbonyl compounds has increased substantially because (7 )-PaHNL... 

Similar reactions were undertaken by Choi et al. in the presence of a new family of A -sulfonylated p-amino alcohols possessing two stereocentres as the chiral ligands. In using the chiral sulfonylated p-amino alcohol ligand depicted in Scheme 10.41, the asymmetric addition of McsSiCN to a wide range of aldehydes afforded the corresponding cyanohydrins in both excellent yields and enantioselectivities of up to 96% ee. 

The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring opening of the resulting (3-diketone. The relative configuration of the chiral centers is unaffected by subsequent transformations, so the overall sequence is stereoselective. Another key step in this synthesis is Step D, which corresponds to the transformation 10-IIa => 10-la in the retrosynthesis. A protected cyanohydrin was used as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and the C(l)-C(2) double bond. 

Hydroxynitrile lyases (HNLs or oxynitrilases) catalyze C—C bond-forming reactions between an aldehyde or ketone and cyanide to form enantiopure cyanohydrins (Figure 1.15), which are versatile building blocks for the chiral synthesis of amino acids, hydroxy ketones, hydroxy acids, amines and so on [68], Screening of natural sources has led to the discovery of both... 

Because of the instability of cyanohydrins, the characterization of cyanohydrins mostly should be hydroxyl protected. In 2001, Gerrits et al. [26] investigated the influence of solvent composition on the stability of unprotected cyanohydrins and then described a method to analyze unprotected cyanohydrins (with regard to enantiomeric purity and conversion) via chiral high-performance liquid chromatography (HPLC). Hernandez et al. [27] and the groups... 

Cyanohydrins have considerable synthetic potential as chiral building blocks, especially in a wide range of pharmaceutical and agrochemical applications. The remarkable properties of the HNLs can be exploited in catalyzing stereoselective synthesis of cyanohydrins. Especially... 

Gerrits, P.J., Zumbragel F. and Marcus, J. (2001) Analyzing the hydrocyanation reaction chiral HPLC and the synthesis of racemic cyanohydrins. Tetrahedron, 57, 8691-8698. 

Ognyanov, V.I., Datcheva, V.K. and Kyler, K.S. (1991) Preparation of chiral cyanohydrins by an oxynitrilase-mediated transcyanation. Journal of the American Chemical Society, 113, 6992-6996. 

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