Ketones microbial reduction

The chiral intermediate (S)-l-(2 -bromo-4 -fluorophenyl) ethanol was prepared by the enantioselective microbial reduction of 2-bromo-4-fiuoroacetophenone [lObj. Organisms from genus Candida, Hansmula, Pichia, Rhodotcnda, Saccharomyces, Sphingomonas, and baker s yeast reduced the ketone to the corresponding alcohol in... 

Recently, XAD was used as material to control the stereochemical course of microbial reductions [19], In the presence of XAD, simple aliphatic and aromatic ketones were reduced to the corresponding (S)-alcohols in excellent enantioselec-tivity while low enantioselectivities were observed in the absence of the polymer (Figure 8.23). 

Hydroxy esters have been obtained successfully with baker s yeast (Sac-charomyces cerevisidae), and this has shown a wide scope of application. The facial selectivity in the reduction of both isolated ketones and //-keto esters can be reliably determined by using Prelog s rule,8 which predicts that the hydrogen addition by the yeast will occur from the front face (Scheme 8-2). Anti-Prelog microbial reduction of a-ketones with Geotrichum sp. 38 (G38) has been introduced by Gu et al.9... 

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... 

Microbial reduction of prochiral cyclopentane- and cyclohexane-1,3-diones was extensively studied during the 1960 s in connection with steroid total synthesis. Kieslich, Djerassi, and their coworkers reported the reduction of 2,2-dimethylcyclohexane-l,3-dione with Kloeokera magna ATCC 20109, and obtained (S)-3-hydroxy-2,2-dimethylcyclohexanone. We found that the reduction of the 1,3-diketone can also be effected with conventional baker s yeast, and secured the hydroxy ketone of 98-99% ee as determined by an HPLC analysis of the corresponding (S)-a-methoxy-a-trifluoromethylphenylacetate (MTPA ester).(S)-3-Hydroxy-2,2-dimethy1cyc1ohexanone has been proved to be a versatile chiral non-racemic building block in terpene synthesis as shown in Figure 1. 

Microbial reduction of ketones is a useful method for the preparation of optically active secondary alcohols. Recently, both enantiomers of secondary alcohols were prepared by reduction of the corresponding ketones with a single microbe.Thus, reduction of aromatic ketones with Geotrichum candidum IFO 5767 afforded the corresponding 5-alcohols in an excellent ee when Amberlite XAD-7, a hydro-phobic polymer, was added to the reaction system the same microbe afforded... 

Table 3.2 Microbial reduction of ketones using G. candidum IFO 5767 using the procedure in Section 3.2.2.

Figure 6 Preparation of chiral synthon for P-3-receptor agonist microbial reduction of ketone (6) to chiral alcohol (7).

The microbial reduction of 4-benzyloxy-3-methanesulfonylamino-2 -bromoace-tophenone (6) to the corresponding (A)-alcohol (7) was demonstrated by S. paucimobilis SC 16113 (Fig. 6). Among cultures evaluated, Hansenula anamola SC 13833, H. anamola SC 16142, Rhodococcus rhodochrous ATCC 14347, and S. paucimobilis SC 16113, gave desired alcohol (7) in >96% e.e. and >15% reaction yield. S. paucimobilis SC 16113, in the initial screening, catalyzed the efficient conversion of ketone (6) to the desired chiral alcohol (7) in 58% reaction yield and >99.5% e.e. 

Table 4 Semipreparative Batches for Microbial Reduction of Ketone (6)...

One of the key Intermediates in Corey s total synthesis of prostaglandins is the lactone (35) whose optically active form was obtained by resolution of (+) 36. Upon analysis of the sequence of reactions from cy-clopentadiene to 35 one would readily visualize the possibility of carrying out microbial resolution of various Intermediates along the synthetic pathway. One such resolution has been accomplished by microbial reduction of the (+) ketone 37 with Saccharomyces drosophylarum to yield the (+) exo and (-) endo alcohols (38 and 39). These were separated by chromatography and were oxidized to the optically active ketones (37).63 One of these was converted to 36. 4... 

The acyclic portion of brefeldin A was elaborated by means of a microbial reduction (Eq. 1.6). Thus acetylenic ketone 181 was reduced with baker s yeast (Saccharomyces cerevisiae) to afford the (5)-( -I- )-alcohol 244 in 56% yield and >99% ee. Completion of the synthesis of 161 from intermediates 231 and 244 was then achieved as previously outlined. ... 

Scheme 10.4 Prelog s rule to predict the stereochemistry of the microbial reduction of a ketone.

It might be mentioned in passing that a recent study (80) on microbial reduction of ( )-60 with Rhodotorula rubra offered a convenient method for its optical resolution in that the microbe preferentially reduced the (- )-( )-enantiomer and left (+)-(R)-ketone intact with 58% optical purity. 

The opposite enantiomer selectivity towards these cage-shaped C2 ketones was demonstrated in oxidation-reduction mediated by horse liver alcohol dehydrogenase (HLADH) (170). Incubation of racemic C2 ketones with HLADH in a phosphate buffer (pH 7.0) containing coenzyme NADH afforded a mixture of the alcohols corresponding to the M C2 ketone and the recovered P C2 ketones, both with much higher optical purities than that found in the microbial reduction. In the oxidative direction (with NAD coenzyme), HLADH was found to preferentially catalyze oxidation of the alcohols corresponding to the M C2 ketone with excellent selectivity. 

Ketones with useful heteroatomic functional groups containing nitrogen 199 2121, oxygen[163, 213 2171, phosphorus12181 and sulfur11 4, 18+1 219-2271 have been reduced by biocatalysts. For example, an intermediate in the synthesis of p-lactam antibiotics was obtained by microbial reduction of a P-keto ester as shown in Fig. 5-39(a)(1991, while yeast reduction of a p-keto dithioester afforded an easily separable mixture of p-hydroxy-dithioesters, the major component of which was converted enantiose-lectively into a sex attractant of the pine saw-fly as shown in Fig. 15-39(b)12191. 

Bulky ketones such as diaryl ketones can be also reduced by biocatalysts. For example, a rice plant growth regulator, (S )-N-isonicotinoyl-2-amino-5-chlorobenzhy-drol, was prepared by microbial reduction of 2-amino-5-chlorobenzophenone with Rhodosporidium toruloides followed by isonicotinoylation as shown in Fig. 15-42(a)1243). A phosphodiesterase 4 inhibitor was also prepared by microbial reduction of a diaryl ketone 9 with Rhodotorula pilimanae, which was found by the screening of 310 microbial strains [Fig. 15-42(b)][244. ... 

With strains of Saccharomyces the (25,35)-isomer is produced predominantly, accompanied by some of the (2/J,3,S )-isomer. Similar to ft-keto esters, the formation of the undcsired isomer can be decreased by the addition of an a,/i-unsaturatcd carbonyl compound, e.g.. methyl vinyl ketone, or an allylic alcohol. These additives probably act as inhibitors for the enzyme which produces the (2/ ,35)-isomer202 203. More recently, the microbial reduction of a variety of simple 2,2-disubstituted cyclic 1,3-diketones of various ring size has been investigated204 205 206. In most cases one of the substituents in the 2-position is methyl. The configuration of the hydroxy group in the reduced product is always S, and the enantiomeric excess is often high (Table 7). 

Further examples of microbial reductions of methyl ketones employ Beauveria sulfurescens and other fungi instead of yeasts47 49. Along with the saturated ketones, small amounts of saturated alcohols are also obtained. It is interesting to note that the saturated alcohols do not have the same configuration as the ketones. It seems therefore, that the saturated alcohol arises from reduction of the a,/f-unsaturated alcohol. The size of the /(-substituent R2 seems critical since no reaction occurs when R2 = butyl or pentyl. Whenever a reaction did occur excellent yields were obtained (see Table) and the products were optically pure. 

In addition, the linear approach was represented by sequential dithiane coupling [21] of the epoxides for the necessary fragments to either side of the ketone function at C21. Another approach uses microbial reduction (baker s yeast) to set the stereocenter at C25 before elaboration of that fragment into a methyl acetylenic ketone [89]. This acetylenic ketone was condensed with the aldehyde partner representing Cl5-19 to give the aldol adduct which was cyclized in acid to afford a precursor similar to those obtained from acetylide addition to lactone B 3. Yet another linear assembly pathway involves the alkylation of the portion containing C23-27 of 22,23-dihydroavermectin B to the dianion of 2,4-pentanedione followed by another condensation to 3-be-nzyloxypropanal [108]. Subsequent acidic cyclization and standard chemistry provided the thermodynamic spiroketal. 

Enzymic Asymmetric Carbonyl Reductions. Microbial reduction of ketones continues to result in the highest optical yields of chiral... 

Diastereoselective Reduction of Ketones by Baker s Yeast. Asymmetric microbial reduction of oc-substituted ketones leads to the formation of diastereomeilc syn-and anh -products. Because the chiral center on the a-position of the ketone is stereochemically labile, rapid in-situ racemization of the substrate enantiomers occurs via enolization ° - leading to dynamic resolution [67, 895, 896]. Thus, the ratio between the diastereomeric syn- and anti-products is not 1 1, but is determined by the selectivities of the enzymes involved in the reduction process [897]. Under optimal conditions it can even be as high as 100 0 [898]. 

Synthesis of BMY-14802 (228) commenced from pyrimidine derivative 243 which reacted with piperazine 244 to give derivative 245 (Scheme 58) [215, 216]. Reduction of the compound 245 followed by deprotection gave amine 246, which was alkylated with chloride 247 and then subjected to acidic hydrolysis to form ketone 248. Reduction of 248 allowed BMY-14802 (228) to be obtained. Pure enantiomers of 228 were also obtained. To achieve this, the following methods were used resolution of 228 with using reaction with a-phenylethyl isocyanate [217] or lipase-catalyzed acetylation or hydrolysis [218], alkylation of 245 with enantiopure alcohols 249 [219] and microbial reduction [305] or Ru-catalyzed enantioselective hydrogenation [220] of 248. 

Kawai, Y, Saitou, K., Hida, K., Dao, D.H., and Ohno, A. (1996) Stereochemical control in microbial reduction. XXVlll. Asymmetric reduction of a, 3-unsaturated ketones with bakers yeast. Bull. Chem. 

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