Ketosulfones hydroxysulfones

An analog of the (6S)-methylketosulfone towards Trusopt , 5,6 dihydro-(6S)-pro-pyl-4H-thieno[2,3fc]thiopyran-4-one 7,7-dioxide ( ketosulfone , Figure 13.28), the precursor to the carbonic anhydrase inhibitor L-683393 (Merck), could be reduced to the trans-hydroxysulfone 5,6 dihydro-(4S)-hydroxy-(6S)-propyl-4H-thieno[2,3F] thiopyran 7,7-dioxide by whole cells of the yeast Rhodotorula rubra MY 2169 from the Merck collection (Lorraine, 1996). Low water-solubility limited the optimum substrate concentration to 2 g L, as organic solvents added to increase solubility resulted in lower rates, which at 0.04 g (g dew)-1 h 1 were not high to start with. Diastereomeric excess ranged from 89 to 94% d.e., and decreased with increasing conversion. 

K. Lorraine, S. King, R. Greasham, and M. Chartrain, Asymmetric bioreduction of a ketosulfone to the corresponding trans-hydroxysulfone by the yeast Rhodotorula rubra MY 2169, Enzyme Microb. Technol. 1996, 39, 250-255. 

Another yeast, Rhodotorula rubra MY 2169, has been shown to reduce a ketosulfone 8 to the corresponding tram-hydroxysulfone 9 (Scheme 19.8). This hydroxysulfone is an intermediate in the drug candidate L-685,393 (10), a carbonic anhydrase inhibitor.81 Results of this biotransformation yielded gram quantities of product with a de of >96%. Studies by Zeneca discuss additional screening experiments aimed at finding microorganisms to reduce a similar ketosulfone.82... 

Another example of the industrial use of methyl ( )-p-hydroxybutyrate is Zeneca s synthesis of an intermediate for MK-0507 (trade name Trusopt Fig. 7), an antiglaucoma drug developed by Merck [65]. In this synthesis, a ketosulfone derivative is prepared from the tosylate of methyl (/ )-P-hydroxybutyrate, which is as3nnmetrically reduced to a (45,dS)-hydroxysulfone derivative, a key intermediate for MK-0507, by a microorganism. 

Figure 5 Asymmetrical reduction of a ketosulfone to the desired (45,65)-hydroxysulfone, a key intermediate in the synthesis of a drug against glaucoma [40].

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