Unsaturated aldehydes Bakers’ yeast reduction

Very few enzyme-catalysed reactions involving the reduction of alkenes have achieved any degree of recognition in synthetic organic chemistry. Indeed the only transformation of note involves the reduction of a, (3-unsaturated aldehydes and ketones. For example, bakers yeast reduction of (Z)-2-bromo-3-phenylprop-2-enal yields (S)-2-bromo-3-phenylpropanol in practically quantitative yield (99 % ee) when a resin is employed to control substrate concen-tration[50]. Similarly (Z)-3-bromo-4-phenylbut-3-en-2-one yields 2(5), 3(,S)-3-bromo-4-phenylbutan-2-ol (80% yield, >95% ee)[51]. Carbon-carbon double bond reductases can be isolated one such enzyme from bakers yeast catalyses the reduction of enones of the type Ar—CH = C(CH3)—COCH3 to the corresponding (S)-ketones in almost quantitative yields and very high enantiomeric excesses[52]. 

Figure 1.18 Bakers yeast reduction of unsaturated aldehydes.

The enantioselective synthesis in Scheme 13.22 is based on stereoselective reduction of an a, (3-unsaturated aldehyde generated from (—)-(.V)-limonene (Step A). The reduction was done by Baker s yeast and was completely enantioselective. The diastereoselectivity was not complete, generating an 80 20 mixture, but the diastere-omeric alcohols were purified at this stage. After oxidation to the aldehyde, the remainder of the side chain was introduced by a Grignard addition. The ester function... 

Asymmetric reduction of a,/l-unsaturated aldehydes with transition metal catalysts has not yet proven ready for widespread industrial application. One area, namely the chiral reduction of enals to yield chiral alcohols using bakers yeast has been... 

The latter material has been used in the synthesis of asymmetrically labelled L-homoserine in a study on the mechanism of the enzymatic formation of L-threonine (9). However, we soon realized that under the experimental conditions used, the reduction of the carbonyl carbon and the saturation of the double bond are only two of the synthetic manifestations that are possible using an a-B-unsaturated aldehyde (10). Since then, we have been exploring this area and it now appears that a -unsaturated aldehydes can be reduced by baker s yeast to yield the synthetically useful chiral products indicated in Scheme 1 in a manner that depends upon the fermentation conditions and the nature of the a and Ysubstituents. 

Brerma, E Fronza, G., Fuganti, C., Gatti, F.G., Manffedi, A., Parmeggiani, F and Ronchia, P. (2012) On the stereochemistry of the baker s yeast-mediated reduction of regioisomeric unsaturated aldehydes examples of enantioselectivity switch promoted by substrate-engineering./. Mol. Catal. B, 84, 94-101. 

Scheme 32 outlines a high yielding approach to the enantiopure appetite suppressant drug 77. The reduction of the unsaturated aldehyde 74 was reported to occur with modest enantioselectivity in normal fermenting conditions with baker s yeast [155]. When the biotransformation is performed at very low substrate concentration, the e.e. can be raised to more than 90%, suggesting that incomplete enantioselectivity is due to the action of enzymes operating on the same substrate with opposite stereochemical preference [115]. However, an efficient transformation can be performed if the substrate concentration is controlled with the addition of absorbing hydrophobic resins. At 5 g/L 97% recovery and 98% e.e. was obtained. The halohydrin 75 obtained was transformed into the epoxide 76 and finally into the enantiopure 2-/ -benzylmorpholine 77, the more active enantiomer with appetite suppressant activity [26]. 

Saceharomyces cerevisiae (baker s yeast) is able to reduce the carbon - carbon double bonds to a,/S-unsaturated primary alcohols and aldehydes (see Section 2.5.1.3.1.2.), to a,/ -unsaturated ketones (see Section 2.5.1.3.1.3.) and to unsaturated a-keto acids (see Section 2.5.1.3.1.4.). On the other hand, only a few examples are known for the reduction of alkenic compounds that are substituted differently. 

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