Cyanohydrin formation from ketone

The endo-spiro-OZT could be prepared through a reaction sequence similar to that applied for the exo-epimer, with spiro-aziridine intermediates replacing the key spiro-epoxides (Scheme 18). Cyanohydrin formation from ketones was tried under kinetic or thermodynamic conditions, and only reaction with the d-gluco derived keto sugar offered efficient stereoselectivity, while no selectivity was observed for reaction with the keto sugar obtained from protected D-fructose. The (R) -cyanohydrin was prepared in excellent yield under kinetic conditions (KCN, NaHC03, 0 °C, 10 min) a modified thermodynamic procedure was applied to produce the (S)-epimer in 85% yield (Scheme 18). 

Figure 2.11 Deng s cyanohydrin formation from ketones [181].

Table 3. (R)-Cyanohydrins by Enzymatic Formation from Ketones and Hydrocvamic Acid as well as (7 )-a-Hydroxy-a-methyl Carboxylic Acids by Hydrolysis...

S)-Selective Cyanohydrin Formation from Aromatic Ketones 259... 

The second example is the familiar one of cyanohydrin formation from a ketone. The reaction is indeed reversible but in basic solution the cyanide anion is more stable than the oxyanion in the product and the carbonyl group is very stable too. In acidic solution (at pHs less than about 12) the oxyanion will be protonated and the reaction driven over to the right. 

FIGURE 17.7 The mechanism of cyanohydrin formation from an aldehyde or a ketone. Cyanide ion is a catalyst it is consumed in the first step, and regenerated in the second. 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

The production of optically active cyanohydrins, with nitrile and alcohol functional groups that can each be readily derivatized, is an increasingly significant organic synthesis method. Hydroxynitrile lyase (HNL) enzymes have been shown to be very effective biocatalysts for the formation of these compounds from a variety of aldehyde and aliphatic ketone starting materials.Recent work has also expanded the application of HNLs to the asymmetric production of cyanohydrins from aromatic ketones. In particular, commercially available preparations of these enzymes have been utilized for high ee (5)-cyanohydrin synthesis from phenylacetones with a variety of different aromatic substitutions (Figure 8.1). 

Cyanohydrins are readily prepared from 3-ketones by exchange with acetone cyanohydrin.54 Selective cyanohydrin formation at C-3 is achieved in the presence of a 20-ketone unsubstituted at the 17- and 21-positions in dilute solution. Thus 5or-pregnane-3,20-dione (60) gives the 3-monocyanohydrin (61) in ethanol, but in neat acetone cyanohydrin the dicyanohydrin (62) is obtained.73... 

The failure with bulky ketones is largely due to steric effects. Cyanohydrin formation involves rehybridizing the sp2 carbonyl carbon to sp3, narrowing the angle between the alkyl groups from about 120° to about 109.5°, increasing their steric interference. 

Scheme 5.6 HNL-catalyzed formation of cyanohydrins from ketones and their application in synthesis.

Cyanohydrins derived from aldehydes are generally more stable than those from ketones (Ternay, 1976). Cyanohydrin formation is the first step in the well-known chain-lengthening sequence, the Kiliani-Fischer synthesis. For example, D-arabinose, an aldopentose, ultimately affords both o-glucose and D-mannose by this set of reactions (Carey, 2000b). 

A similar ring structure resulted, with no evidence of live-membered ring formation, from the treatment of methyl vinyl ketone cyanohydrin and phosphoric acid in toluene/nitromethane during 1 hour with a suspension of 2,3,6-trimethyl hydroquinone and boron trifluoride in toluene at 0-5°C, followed by reaction at ambient temperature for 13 hours to give an 81% yield of 2-cyano-2,5,7,8-tetramethyl-6-hydroxychroman (ref. 163). 

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