Cyanohydrin large-scale production

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. 

R)- and ( -selective HNLs. A number of recombinant HNLs have also been expressed in E. coli, Saccharomyces cerevisiae, and Pichia pastoris. Recently, protein engineering has been successfully applied to the development of a tailor-made HNL for large-scale production of specific cyanohydrins [69,70]. 

Fig. 8 General production figure for the cyanohydrins on a large-scale.

Both recombinant (R)- and (S)-HNL have been successfully used in the synthesis of chiral cyanohydrins at the plant-scale level. Their availability on a large-scale via fermentation and their striking similarities in reaction technology and chemical behavior have been crucial for the development of robust, cost-effective processes applicable to a wide variety of substrates. Exploitation of the possibilities of HNL technology has just begun. The large number of substrates and follow-up products with applications in fine chemistry reflects the attractiveness of this transformation. 

Cyanohydrins are bifunctional molecules and therefore constitute a particularly useful class of compounds for synthetic purposes. A hydroxyl and a nitrile functional group are available for chemical and enzymatic follow-up reactions (Scheme 25.2 [7, 93-95]), resulting in hydroxy carboxylic acids [96-99], carbamates [KXl], hydroxy-amides [101], primary and secondary hydroxyamines [46,102-104], aziridines [105, 106], aminonitriles [107, 108], diamines [108], azidonitriles [108], a-fluoronitriles [109], hydroxy ketones [110], and many more. The (S)-selective H HNL and the (R)-selective PaHNL, in particular are used on large scale either for the s)mthesis of (S)-3-phenoxybenzaldehyde cyanohydrin, a precursor for p5U ethroids, a class of insecticides (R)- and (S)-mandelonitrile, which can be further converted to man-delic acids (R)-chloromandelonitrile, a precursor for an anticoagulant (R)-2-hydroxy-4-phenylbutyronitrile, which serves as intermediate for the production of angiotensin-converting enzyme inhibitors (ACEi) or (R)-2-amino-l-(2-furyl)ethanol [94]. Several HNLs are commercially available as free or immobilized enzymes. 

The major process currently operated on the commercial scale is known as the acetone cyanohydrin (23) (ACN) process [14]. This process uses readily available cheap raw materials (Scheme 2.3). Acetone is produced from propylene and hydrogen cyanide or can be obtained as a byproduct from acrylonitrile production. Acrylonitrile is manufactured via propylene ammoxidation or by catalytic ammoxidation of natural gas. Sulphuric acid is readily available but constitutes the major environmental problem of the acetone cyanohydrin process since a large excess is required to effect the hydrolysis of acetone cyanohydrin to form the methacrylamide sulphate intermediate. 

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