1. Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate
- Author
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Mary Ann A. Endoma-Arias, Helen E. Dela Paz, and Tomas Hudlicky
- Subjects
Ketone ,pinacol-type coupling ,Pharmaceutical Science ,Chemistry Techniques, Synthetic ,Acetates ,010402 general chemistry ,01 natural sciences ,Radical cyclization ,Medicinal chemistry ,Article ,Catalysis ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,lcsh:Organic chemistry ,enzymatic dihydroxylation ,Heck reaction ,Drug Discovery ,Physical and Theoretical Chemistry ,total synthesis ,chemistry.chemical_classification ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Total synthesis ,Stereoisomerism ,0104 chemical sciences ,10-keto-oxycodone ,CAN-mediated hydroxyazidation ,chemistry ,Chemistry (miscellaneous) ,Dihydroxylation ,Yield (chemistry) ,Molecular Medicine ,Stereoselectivity ,Azide ,Oxycodone ,aminohydroxylation - Abstract
The total synthesis of (+)-10-keto-oxycodone was attained from phenethyl acetate in a stereoselective manner. Absolute stereochemistry was established via enzymatic dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) that furnished the corresponding cis-cyclohexadienediol whose configuration corresponds to the absolute stereochemistry of the ring C of (+)-10-keto-oxycodone. Intramolecular Heck reaction was utilized to establish the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl and C-10 ketone were installed via SmI2-mediated radical cyclization, and oxidation of a benzylic alcohol (obtained from an intermediate nitrate azide), respectively. The synthesis of (+)-10-keto-oxycodone was completed in a total of 14 operations (21 steps) and an overall yield of ~2%. Experimental and spectral data are provided for key intermediates and new compounds.
- Published
- 2019
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