Asymmetric bioreduction of a ketosulfone to the corresponding trans-hydroxysulfone by the yeast Rhodotorula rubra MY 2169.
A microbial screen identified the yeast Rhodotorula rubra MY 2169 as a suitable biocatalyst for the asymmetric bioreduction of a ketosulfone (5,6 dihydro-6(s)-propyl-4H-thieno[2,3b] thiopyran-4-one-7,7-dioxide) to the corresponding trans-hydroxysulfone. This synthesizer is a precursor to the carbonic anhydrase inhibitor L-685,393, a new drug candidate targeted for the treatment of ocular glaucoma. Process development studies revealed that the rate of bioreduction was sensitive to temperature, pH, solvent concentration and the physiological state of the yeast cells. The maximum specific bioreduction rate was achieved by employing cells harvested in the stationary phase of growth. The diastereomeric excess of the trans-hydroxysulfone produced was found to be only affected by the residual amount of ketosulfone present in the bioconversion medium; therefore, when close monitoring of the residual ketosulfone was implemented, the desired enantiomeric excess was achieved at harvest. When scaled up, this bioreduction process supported the production of gram quantities of highly optically pure trans-hydroxysulfone (diastereomeric excess > 96%).
Lorraine
K
K
Merck Research Laboratories, Rahway, NJ 07065, USA.
King
S
S
Greasham
R
R
Chartrain
M
M
D000438:Alcohols / Q000494:pharmacology; D019149:Bioreactors; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011714:Pyrans / Q000378:metabolism* / Q000494:pharmacology; D012248:Rhodotorula / Q000201:enzymology / Q000378:metabolism*; D013237:Stereoisomerism; D013450:Sulfones / Q000378:metabolism*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
C104005:5,6-dihydro-6(S)-propyl-4H-thieno(2,3b)thiopyran-4-one-7,7-dioxide; D000438:Alcohols; D002257:Carbonic Anhydrase Inhibitors; C104004:L 685393; D011714:Pyrans; D013450:Sulfones; D013876:Thiophenes; D010100:Oxygen; D004121:Dimethyl Sulfoxide