Reduction microorganism screening

Other biocatalysts were also used to perform the dynamic kinetic resolution through reduction. For example, Thermoanaerobium brockii reduced the aldehyde with a moderate enantioselectivity [30b,c], and Candida humicola was found, as a result of screening from 107 microorganisms, to give the (Jl)-alcohol with 98.2% ee when ester group was methyl [30dj. 

Microbial reduction has been recognized for decades as a laboratory method of preparing alcohols from ketones with exquisite enantioselectivity. The baker s yeast system represents one of the better known examples of biocatalysis, taught on many undergraduate chemistry courses. Numerous other microorganisms also produce the ADH enzymes (KREDs) responsible for asymmetric ketone reduction, and so suitable biocatalysts have traditionally been identified by extensive microbial screening. Homann et have... 

Streptomyces punipalus converted thaicarpine (94) to hemandalinol (400), whose structure was proven by synthesis by reduction (H2/Pt-HOAc or excess NaBH4) of the alkaloid hemandaline (256). It was also shown that 256 is converted to 400 by S. punipalus, and therefore inferred that 256 is an intermediate in the overall transformation of 94. Of 22 microorganisms that were screened, 5 were shown to give metabolites from thalicarpine, but only S. punipalus was investigated in detail (237). The above microbial transformations have been reviewed (258). 

Scientists at Merck have reported a number of biocatalytic routes derived from screening various microorganisms targeted to produce key intermediates that are then combined with chemical reactions to prepare the target molecule. The biocatalytic step was often carried out by necessity as a result of poor chemical yield, low optical purity, or both. 6-Bromo-P-tetralone (2) was reduced to (S)-6-bromo-P-tetralol (3) by the yeast Trichosporon capitatum MY 1890 (Scheme 19.6).79 The tetralol 3 is a key intermediate for the synthesis of MK-0499 (4), a potassium channel blocker. The (S)-P-tetralol 3 was produced in gram quantities with an ee of >99% to support further development of MK-0499. Baker s yeast was tested for its ability to carry out this reduction but showed insignificant product formation. 

The reactions shown here illustrate the versatility of yeast, bacterial, and fungal reductions. In all these cases, screening studies were usually conducted first followed by refinement of the bioreduction using the best microorganism. Other examples where reductions are used to produce pharmaceutical intermediates can be found in a review by Patel.107... 

In an alternate process, enantioselective microbial reduction of 6-oxobus-pirone (19, Fig. 18.6) to either (R)- and (.S )-6-hydroxybuspirone was described. About 150 microorganisms were screened for the enantioselective reduction of 19. Rhizopus stolonifer SC 13898, Rhizopus stolonifer SC 16199, Neuros-pora crassa SC 13816, Mucor racemosus SC 16198, and Pseudomonas putida SC 13817 gave >50% reaction yields and >95% ee s of (,S )-6-hydroxybuspi-rone. The yeast strains Hansenula polymorpha SC 13845 and Candida maltosa SC 16112 gave (R)-6-hydroxybuspirone in >60% reaction yield and >97% ee (Patel et aL, 2005). 

Screening of Microorganisms Producing Optically Active 1,3-BDO from 4-Hydroxy-2-butanone (4H2B) by Asymmetric Reduction... 

Tab. 1 Screening of microorganisms producing optically active 1,3-BDO from 4H2B by asymmetric reduction.

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