How to prepare aldehydes from carboxylic acids with enzymes
Priv . -Doz . Dr Margit Winkler of ACIB and TU Graz reviews the ways to make one of the key final products in the flavours and fragrances sector
Figure 1 - Enzymatic reduction of carboxylic acid to aldehyde
Aldehydes are reactive compounds and can undergo chemical transformations to numerous other functional groups . The aldehyde is therefore an invaluable chemical handle to make all sorts of products . 1 As final products , aldehydes find application in the flavour and fragrance sector , because they are often volatile , with characteristic olfactory properties . The most abundant aldehydes from biomass are furfural from cellulose , 4-hydroxymethylfurfural ( HMF ) from hemicellulose and aromatic aldehydes like vanillin and syringaldehyde from lignin , as well as short- , medium- , and long-chain aldehydes from oil and fat derived poly-unsaturated fatty acids ( PUFAs ). Carboxylic acids are much more stable and abundant in biomass than aldehydes . In contrast with aldehydes , which have cytotoxic effects on living organisms , they accumulate and can be produced in higher amounts . 2 Volatile organic acids are , for example , accessible by anaerobic fermentation from organic wastes and all sorts of fatty acids are available from fats and oils , including waste streams from edible oil production . Such carboxylic acids are a stable pool of aldehyde precursors . Carboxylic acid reductases ( CARs ) catalyse the single-step reduction of a carboxylic acid to an aldehyde ( Figure 1 ). CARs are very relaxed regarding the structural features of the acid they reduce and can convert aliphatic , aromatic , heteroaromatic , and arylaliphatic mono- and di-carboxylates . Halogen- , hydroxy- , methyl- , methoxy- and amino-substitutions are tolerated well , as long as they are two carbon atoms or more distant to the carboxylic acid moiety . 3 Due to their broad product scope , CARs hold great promise as a tool for platform chemical synthesis . Acid activation is accomplished directly in the CAR enzyme by ATP , while NADPH serves as the reductant ( Figure 1 ). Both co-factors are required in stoichiometric amounts . CARs can be used as isolated enzymes . In this case , co-factor supply can be accomplished by catalytic amounts of
ATP and NADPH and their recycling in vitro ( Figure 2 ). Well-established oxidoreductase recycling systems are available for the nicotinamide cofactor NADPH ( e . g . glucose dehydrogenase with glucose ). ATP recycling with kinase enzymes at the expense of polyphosphate is a focus of research in both academia and industry , with new , more efficient kinases becoming increasingly available . 4 , 5 The in vitro aldehyde synthesis strategy has been shown to be successful , for instance for the preparation of 4-methoxy-benzyaldehyde and N-carbobenzoxylated 4-formyl piperidine on a gram scale ( Figure 2 ). 5 , 6 When all of the enzymes involved are provided in purified form , aldehyde is the sole product and the selectivity of CARs can be fully exploited ( Figure 3 ). 4 A very convenient simultaneous purification and immobilisation strategy is the use of the widely applied polyhistidine tag on enzymes , including CARs . This tag can bind to
50 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981