Cyanohydrin special

The generalized procedure described here has been demonstrated with a large number of aromatic ketone substrates, including those described in Table 8.1. When the goal is the production of a particular (5)-cyanohydrin, specialized process improvements to parameters, such as the operating temperature and pH and the choice and concentration of organic solvent and cyanide donor, may further increase both the product ee and yield values. 

Cyanohydrins -> special s. acetone cyanohydrin 3-hydroxypropionitrile Cyanoketones s. a. Acylcyanides a-Cyanoketones... 

Cyanohydrins are highly toxic by inhalation or ingestion, and moderately toxic through skin absorption (21). AH a-hydroxy nitriles are potential sources of hydrogen cyanide or cyanides and must be handled with considerable caution. Contact with the skin and inhalation should be rigorously avoided. Special protective clothing should be worn and any exposure should be avoided (18,20). The area should be adequately ventilated. Immediate medical attention is essential in case of cyanohydrin poisoning. 

The second special case is addition of a very good nucleophile hydrogen cyanide and bisnllite are the most common examples, and cyanohydrins, a-cyanoamines and bisnllite addncts (a-hydroxy snlfonates) are commonly stable enough to isolate, at least for reactive carbonyl compounds. All these compounds are prone to fall apart nnder snitable conditions, regenerating the carbonyl compound. 

For the synthesis of D-glucuronic acid, methods of oxidation of suitable D-glucose derivatives have been devised during the past two decades these procedures have been comprehensively reviewed by Marsh,6 Mehltretter,7 and Heyns and Paulsen.8 For special purposes, for example, for the preparation of 6-I4C-labelled D-glucuronic acid, chain-extension reactions of 1,2-O-isopropylidene-a-D-xy/o-pen-todialdo-I,4-fiiranose by the cyanohydrin synthesis9 or by ethynyla-tion10 are used, but these frequently yield mixtures of D-glucuronic acid and L-iduronic acid. 

Since the reaction has been reviewed recently (12) only a few additional facts will be mentioned. Many optically active cyanohydrins can be prepared (33) with e.e. s of 84 to 100% by the use of the flavopnotein D-oxynitrilase adsorbed on special (34) cellulose ion-exchange resins. Although the enzyme is stable, permitting the use of a continuously operating column, naturally only one enantiomer, usually the R isomer, is produced in excess. This (reversible) enzyme-catalyzed reaction is very rapid (34). Nonenzymic catalysts, such as the cinchona alkaloids, permit either enantiomer to be prepared in excess. 

In the special case of a low, continuous flow of ammonia, this process allows the formation of substantial amounts of AA by displacement of the cyanohydrin-aminonitrile equilibrium. The cyanohydrin form can be consid-... 

This reaction, like the cyanohydrin formation we discussed at the beginning of the chapter, is an equilibrium, and is quite general for aldehydes and ketones. But, as with the cyanohydrins, the position of the equilibrium depends on the structure of the carbonyl compound. Generally, the same steric factors (pp. 138-139) mean that simple aldehydes are hydrated to some extent while simple ketones are not. However special factors can shift the equilibrium towards the hydrated form even for ketones, particularly if the carbonyl compound is reactive or unstable. 

Of special interest is the use of protected cyanohydrins in the formation of carbocyclic rings. Ring closure of an acyclic intermediate to form a five-membered ring (75-85%) has been Ascribed in the synthesis of prostaglandins (equation 17). In addition this method is applicable to the formation of cyclopropyl, cyclobutyl and cyclohexyl rings (60-70%). ... 

Special preparations. a-Trialkylsiloxy aldehydes and l-tosyloxy-2-alkanols have been synthesized using DIBALH reduction of cyanohydrin silyl ethers and epoxy tosylates, respectively. Indoles and (Z)-allylic alcohols are acquired after simple manipulations of the primary reduction products of nitriles and a-hydroxy esters, respectively. 

Many derivatives of 1,2- and 1,3-dithiols have been used as protecting groups, but those discussed are the most common. Greene and Wuts discuss other methods for protection of ketones and aldehydes, including cyanohydrins, hydrazones, oximes, oxazolidines, and imidazolidines. 9 Most of these are rather specialized and will not be discussed in this general presentation. 

Some of the fine-chemical manufacturers who supply the pharmaceutical industry now specialize in the use of enzymes for the synthesis of chiral synthons. Chiral cyanohydrins, as well as a- and /S-amino and hydroxy acids, are just a few of the products now available, often produced directly from achiral precursors. Many of the hydroxy acids, such as citric acid (5) and both enantiomers of lactic acid, are fermentation products. The synthesis of some others (Scheme 6.20) resembles the manufacture of aspartate (see... 

Benzaldehyde cyanohydrin (mandelonitrile) provides an interesting example of a chemical defense mechanism in the biological world. This substance is synthesized by millipedes (Apheloria corrugata) and stored in special glands. When a millipede is threatened, the cyanohydrin is released from the storage gland and undergoes enzyme-catalyzed reversal of cyanohydrin formation to produce HCN, which is then... 

The most common example of the addition of hydrogen cyanide to a double bond is the formation of cyanohydrins from aldehydes and ketones with this reagent. The addition of hydrogen cyanide to olefins and acetylenes is important industrially but requires special equipment and precautions. 

---