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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.

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.

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.

Total synthesis of SB-203207 (1) was achieved, beginning with a desymmetrical C–H insertion reaction of a diazoester bearing our recently developed chiral auxiliary. Utilizing the optically active bicyclo[3.3.0]octane ring, four stereogenic centers were efficiently constructed in sequence. Finally, mild oxidation of 27 to carboxylic acid via a cyanohydrin intermediate and hydrolysis of cyanide to carboxyamide in the presence of the labile enamide group completed an efficient total synthesis of 1.

The synthesis of a novel homochiral metal-organic catalyst for asymmetric cyanation of aldehydes is reported.

The construction of enantiomerically enriched acyclic quaternary substituted ketones via the regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of chiral nonracemic tertiary alcohols with cyanohydrin pronucleophiles is described. This approach provides an alternative method to the α-arylation and vinylation of acyclic disubstituted ketone enolates, which remains a challenging endeavor. The combination of the allylic alkylation with ring-closing metathesis facilitates the preparation of enantiomerically enriched 2,2-disubstituted naphthalene-1-ones, which have proven very difficult to prepare using a more conventional dearomatization strategy.

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.

An asymmetric Strecker-type reaction of nitrones using acetone cyanohydrin as a source of HCN has been realized. A magnesium–tartramide complex, generated from (R,R)-2,3-dihydroxy-1,4-di(pyrrolidin-1-yl)-butane-1,4-dione and MeMgBr, promoted transcyanation from the bromomagnesium salt of the cyanohydrin, in the presence of a catalytic amount of DBU, to afford the corresponding optically active (S)-α-amino nitrile derivatives. The reaction was applicable to various nitrones giving high-to-excellent enantioselectivities.

The cyanosilylation of carbonyl compounds (I) and (IV) using TmsCN (II) and triphenylphosphine supported on polystyrene as catalyst under solvent-free conditions is described.

Various aliphatic and aromatic aldehydes produce the desired cyanohydrin products with good to excellent yields.

Biquinolyl BQU catalyzes the addition of trimethylsilyl cyanide to aldehydes, ketones, and N-benzylaldimines to give the expected cyanohydrin and Strecker adducts by subsequent desilylation.

Treatment of nitrones (I) with acetone cyanhydrin (II) in the presence of BuMgCl results in transcyanation reaction to afford the corresponding α-cyanohydroxylamines (III) in good yields.

This chapter summarizes the foundations of No Barrier Theory (NBT) and the history of its development. The algorithms used in computing a rate constant (free energy of activation) by this approach are presented. The computer programs developed to assist the calculations are described. The concept of a “simple reaction dimension” is presented and justified. The calculation of each energy contribution to the corner energies is explained. Both the qualitative (which mechanism of two analogous mechanisms has the higher intrinsic barrier) and quantitative (what is the absolute free energy of activation in solution for a particular reaction by a particular mechanism) applications of NBT are illustrated. Current and past applications of NBT to families of organic reactions are reviewed: enolate formation, cyanohydrin formation, carbonyl hydration, ketene hydration, carbon dioxide hydration, Strecker reaction, aldol addition, decarboxylation, thiol addition to a carbonyl, amine addition to a carbonyl, and sulphite addition to a carbonyl. The origins of the intrinsic barrier are discussed in terms of NBT. The use of NBT as a mechanistic criterion is illustrated.

A wide variety of carbonyl compounds can be transformed to their corresponding cyanohydrins in a single step and without any catalyst using DMSO/water as reaction medium.

Chiral macrocyclic V(V) salen complexes 1a – f derived from macrocyclic ligands obtained by the reaction of 1 R ,2 R -(−) diaminocyclohexane/(1 R ,2 R )-(+)-1,2-diphenylethylenediamine with bis-aldehydes 2 and 3 were synthesized and used as efficient catalysts in asymmetric cyanation reactions. The V(V) catalysts demonstrated excellent performance (product yields and ees up to 99%) with potassium cyanide (KCN) and sodium cyanide (NaCN). The catalytic system also performed very well with a safer source of cyanide-ethyl cyanoformate to give cyanohydrin carbonates in excellent yield and ee (up to 97%). The V(V) macrocyclic salen complex 1b retained its performance at multi-gram level and was conveniently recycled for a number of times.

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 ® .

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

Aliphatic azidonitriles separated by three or four carbon atoms undergo facile cyclo additions in the presence of BF 3 OEt 2 at room temperature or lower, to give bicyclic tetrazoles. 1-Azido-(2-aryl-1,3-dioxolanyl)-glycerols afford oxabicyclic tetrazoles with trimethylsilyl cyanide (TMSCN). Aspects of these facile proximity-induced 1,3-dipolar cyclo additions are discussed with mechanistic interpretations.

ortho-Substituted electron-rich arene carboxylic acids react with cyanohydrin (II) to give nitriles with a broad spectrum concerning the product yield.

From known cyanohydrin (I) three hydroxypiperidine building blocks, (III), (IX) and (XV) are prepared and used for the synthesis of 24 title compounds, based on N-acyliminium chemistry and cross-metathesis as the key steps.

The 1,4-addition of cyclohexenone (II) to the protected cyanohydrin ether (I) and subsequent addition of formaldehyde (III) to the resulting enolate proceed stereoselectively to afford the AC-ring system (IV).

Acylation of the cyanohydrin derivative (2) of representative aldehydes with ethyl chloroformate, followed by treatment of the corresponding mixed carbonate esters (3) with lithium hexamethyldisilazide, afforded the cyanohydrin derivative (4) of α-keto esters. Cleavage of the latter (4) with 2,6-lutidine in the presence of silver nitrate led to the procurement of α-keto esters in >50% overall yield.

Sequential addition of methyllithium and acyl chlorides to O-trimethylsilyl acetyltrimethylsilane cyanohydrin affords β-acyloxy-N,N-bis(trimethylsilyl)enamines which cyclize to 2-substituted-4,5-dimethyloxazoles under thermolysis or trimethylsilyl trifluoromethanesulfonate treatment.

Cyanohydrin diethyl phosphates, readily obtained from various ketones and aldehydes by reaction with diethyl phosphorocyanidate and lithium cyanide, reacted chemoselectively with samarium(II) iodide in THF to give the corresponding nitriles in excellent yields. This method was also found applicable to α,β-unsaturated carbonyl compounds via cyano phosphates to give β,γ-unsaturated nitriles, not obtainable by standard methods, without isomerization of the double bonds

Kinetic enzymatic resolution by Candida cylindracea lipase of racemic isoserine diacetate prepared from the cyanohydrin of glyoxylate provided ( S )-isoserine in good yield and high optical purity.

A novel one-pot synthetic method was developed for the preparation of optically active cyanohydrin acetates. Racemic cyanohydrins were generated from aldehydes and acetone cyanohydrin by quinidine-catalyzed transhydrocyanation, and the resulting cyanohydrins 2a–j were then acetylated by lipase in a stereoselective manner using isopropenyl acetate as an acylating regent. A variety of aldehydes 1a–j were successfully transformed into the corresponding cyanohydrin acetates 3a–j having 47–95% e.e. without isolating the unstable cyanohydrins 2. Moreover, the reversible nature of base-catalyzed transhydrocyanation allows for in situ racemization of the unreacted cyanohydrins and concurrent kinetic resolution by lipase enabled the preparation of (S)-3b–d with 40–82% e.e. in more than 50% yield. Polymer-supported cinchona alkaloid was also used as a catalyst for this one-pot reaction and showed the comparable chemical and optical yield to that for the soluble monomeric alkaloid. The insoluble polymer and lipase w...

The completion of the total synthesis of d,l-quassin 1 is described. Key steps are a facile intramolecular acylation of a protected cyanohydrin carbanion (4 → 5), a selective deprotonation with tri...

at will. Although the capacity shown here compares more than well with, for example, a biological alternative method using the protein cellulasea [the amounts of timolol with optimal base-line separation were 18.9 and 19.9 pg/g of dry CSP, respectively (Figure 2), and in connection with the aforementioned polarimetric study of propranolol, with fair resolution but no base-line separation, 400 p g / g of dry CSP], work aimed at increasing the capacity of analogous imprinted polymers is in progress and will further increase the applicability of the technique for (semi)preparative isolation of pure enantiomers of compounds such as &blockers. However, we feel that already today the removal of contaminating small amounts of the nondesired enantiomer may be feasible on a technical scale with the described technique.

Trimethylsilyl cyanide (TMS-CN) enantioselectively reacts with aldehydes to afford the corresponding cyanohydrin trimethylsilyl ethers in good yields in the presence of a chiral tin(II) Lewis acid prepared from 1,1′-dimethylstannocene, triflic acid and (+)-cinchonine.

Routes to the four regioisomeric 2,8-dimethyl-1,7-dioxaspiro[5.5]undecanols have been developed, and in the racemic series, mercury(II)-mediated reactions of appropriate dienone, hydroxy enone, dienedione, and hydroxy dienone systems have been exploited. Most of the epimeric pairs of alcohols (i.e. axial or equatorial) in the EE, EE, or ZE spiroacetal ring systems have been characterized by detailed H, C, and correlated NMR spectroscopy and mass spectrometry. Key enantiomers of these alcohols have been obtained by elaborating chiral starting materials such as D-mannitol, L-arabinose, poly(hydroxybutyrate), and in the case of the 5-hydroxy derivative, mandelonitrile lyase mediated formation of a key chiral cyanohydrin was employed. Most of the alcohols, as their trifluoroacetates, are resolved (into enantiomers) on a Lipodex A GC column, thus facilitating their identification from natural sources. In this way, the absolute configurations of a number of 2,8-dimethyl-l,7-dioxaspiro[5.5]undecanols present in the rectal gland secretion of Bactrocera cucumis (cucumber fly) have been determined.

Isomerization of glycidic esters and nitriles to the corresponding 2-hydroxy-3-alkenoates and their nitrile derivatives occurred on treatment with triphenylsilyl perchlorate or electrogenerated acid (EG acid). The cyanohydrin moiety of the nitriles 4 was transformed to a formyl group, giving the corresponding enals on treatment with weak base.

Optically active (R)-cyanohydrins have been transformed into cyanohydrin esters of opposite configuration under Mitsunobu conditions and subsequently solvolyzed to (S)-cyanohydrins in high chemical and optical yield. The method works well for allylic and benzylic cyanohydrins. Cyanohydrins containing strongly electron donating substituents gave extensive racemization. Saturated aliphatic cyanohydrins afforded esters in which the original configuration is retained. These results are discussed in terms of the mechanism of the Mitsunobu reaction.

Three novel, 6-s-locked rigidified retinals, racemic all-E 1,5-didemethyl-8,16-methanoretinal, all-E 1,1-didemethyl-8,18-methanoretinal and all-E 8a, 18-didehydro-1, 1-didemethyl-8, 18- methanoretinal were prepared in good yield in high purity on a 100-mg scale. For the preparation of the key intermediate in the synthesis of 1,5-didemethyl-8,16-methanoretinal, reductive cyanation of an unsaturated cyanohydrin to the corresponding conjugated nitrile was accomplished using triethylsilane and trifluoroacetic acid. The three locked retinals interact with bacterioopsin to form bacteriorhodopsin with about the same rate as the native chromophore. This work proves that steric interaction of the 1,1-dimethyl group in the chromophore is an important factor in binding to bacterioopsin.

Milbemycin spiroacetal 4 was prepared from (4S,5R)-4,5-dimethylpentan-5-olide 5 and (R)-1-(benzyloxymethyl)oxirane by alkylation and stereoselective reductive decyanation of the intermediate spiroacetal cyanohydrin 7.

Optically active γ-cyanoallylic alcohols were synthesized by using asymmetric hydrocyanation of α,β-alkenyl aldehydes catalyzed by peptide-titanium complex to give α-cyanoallylic alcohols (cyanohydrins) with high optical yields followed by palladium complex catalyzed [3.3]sigmatropic chirality transfer of the corresponding acetates.

A highly stereo- and enantioselective total synthesis of sarcophytol A (1), a marine cembranoid promising as a cancer chemopreventive agent, is described. The nitrile 10 obtained Z-selectively (Z:E=>35:1) by the Horner-Emmons reaction of (E,E)-farnesal (5) with the phosphononitrile 9 in 91% yield was converted to the conjugated 2(Z),4(E)-dienal 3 in which the terminal (E)-methyl group was functionalized. Intramolecular alkylation of the cyanohydrin TMS ether of 3 provided the macrocyclic ketone 2 in 79% of overall yield from 3 without isolation of the cyclic cyanohydrin 20 as well as its TMS ether 19. Reduction of 2 with several chiral LiAlH 4 reagents afforded 1 highly enantioselectively (78-97%) yield, from which enantiomerically pure 1 (>99% ee) was readily obtained upon a single recrystallization

A synthesis of thio- and seleno-substituted 9,10-dihydro-9,10-methanoanthracene derivatives is reported. They are obtained by Wittig rearrangement from 11-thia and 11-selena-9,10-dihydro-9,10-ethanoanthracene derivatives. This rearrangement is applied to the first synthesis of a seleno-cyanohydrin (R1R2C(SeH)CN).

Alkylation of cyanohydrin 1,3-acetonides with unsaturated substitution at the 2-position is described. The stereochemistry of the products obtained from this reaction was opposite to that anticipated.

Cyanohydrins have always held a place of importance both as technical products and as reagents in organic chemistry. It is surprising, therefore, that optically active Cyanohydrins have been extensively investigated and employed for syntheses relatively recently. This can be explained by the fact that only in the past few years have enzymatic methods made chiral Cyanohydrins readily available in high optical purity. Chiral Cyanohydrins are widespread in nature in the form of the respective glycosides and serve roughly 3000 plants and many insects as antifeedants. For the preparative organic chemist, this class of compounds offers an enormous synthetic potential for making other chiral compounds accessible. In a few instances, the pharmacological principle of a drug also incorporates a chiral cyanohydrin as constitutive structural element. In the development of novel, physiologically active compounds all possible stereo-isomers must be synthesized and investigated with respect to their activity range and the pathway of their metabolic transformations and/or degradation. The development of simple synthetic procedures for such compounds, which also entail a high degree of stereoselectivity, therefore has prime importance. To this end chiral Cyanohydrins may serve as stereochemically pure starting materials. In the present review, the following topics will be addressed: enantioselective addition of hydrogen cyanide (HCN), catalysed by the enzymes (R)-and (S)-oxynitrilase, to aldehydes and Ketones yielding (R) and (S) cyanohydrins, respectivity; enantioselective addition of HCN to aldehydes catalyzed by cyclic dipeptides; enantioselective esterification of racemic ocyanohydrins and enantioselective hydrolysis of cyanohydrin esters caytalyzed by lipases and esterases, reprectively; transformation of the nitrile groups of chiral cyanohydrins to provide optically active -hydroxycarboxylic acids, aldehydes, and ketones, as well as 2-amino alcohols; sulfonylation of the OH group of chiral cyanohydrins to furnish optically active -sulfonyloxynitriles which undergo SN2 displacement of the activated OH group yielding α-azido-,α -amino, and α-fluoronitriles with inverted configuration.