Synthesis 1,4-addition reactions with cyanohydrin ethers

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

In 1993 Corey et al. [60] reported a new enantioselective method for synthesis of chiral cyanohydrins [61] from aldehydes and trimethylsilyl cyanide (TMSCN) by the use of a pair of synergistic chiral reagents. Reaction of cyclohexane carbaldehyde 78 and trimethylsilyl cyanide (TMSCN) 79 in the presence of 20 mol % chiral magnesium complex 80 afforded the cyanohydrin TMS ether 81 in 85 % yield with 65 % ee. This modest enantioselectivity was fiirther enhanced to 94 % ee by addition of a further 12 mol % of the bis(oxazoline) 70 (Sch. 34). 

The 1,2-addition of a cyanide ion to a carbonyl compound to form a cyanohydrin is a fundamental carbon-carbon bond-forming reaction in organic chemistry, and has frequently been at the forefront of advances in chemical transformations. In 2000, Belokon and North developed a catalytic system based on a vanadium-salen complex (Scheme 9.1). The synthesis of vanadium(iv) complex 1 was accomplished by refluxing a mixture of the corresponding Schiff base with vanadium(iv) sulfate and pyridine in ethanol under an argon atmosphere. A very low catalyst loading of 0.1 mol% was employed to convert aromatic and aliphatic aldehydes to cyanohydrin silyl ethers 3 with enantioselectivities of 68-95% after 24 h. Further investigations... 

An interesting extension of this method involves the reaction of Af-silyl oxyketene imines derived from cyanohydrins (Scheme 19) [81]. By judicious selection of the protecting group on the oxygen, highly functionalized (3-hydroxy cyanohydrins can be accessed with high levels of enantio- and diastereoselectivity. These products can then be transformed into a diversity of structural motifs (amines, aldehydes, imines, ketones) important for the synthesis of polyketide and other classes of natural products. In addition, the ethers can be easily converted to enantiomerically enriched unsymmetrical benzoins, thus revealing the synthetic equivalency of A-silyl oxyketene imines as acyl anions (Scheme 19). 

---