The stereoselective total synthesis of unnatural (+)-oxy­codone from phenethyl acetate is described. Absolute stereochemistry was established via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadienediol­ whose configuration provides for the absolute stereo­chemistry of the ring C of (+)-oxycodone. Intramolecular Heck cyclization was employed to establish the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl was installed via SmI2-mediated radical cyclization. The synthesis of (+)-oxy­codone was completed in a total of 13 steps and an overall yield of 1.5%. Experimental and spectral data are provided for all new compounds.

An improved preparation of buprenorphine via palladium-catalyzed N-demethylation/acylation is reported. Three routes were investigated and compared in overall yield. The first involved Ndemethylation/acylation of an advanced intermediate obtained from thebaine followed by hydrolysis of the N-acetamide and alkylation with cyclopropylmethyl bromide and/or reduction of the N-acetyl group with the Schwartz reagent followed by N-alkylation. The second route employed cyclopropylcarboxylic acid anhydride in the N-demethylation/acylation protocol and subsequent reduction of the cyclopropylcarbox-A C H T U N G T R E N N U N G amide by either lithium aluminum hydride or under hydrosilylation conditions. Both of these routes originated in thebaine and therefore required O-demethylation as a final step. The third route employed an N-demethylation/acylation sequence starting from oripavine rather than thebaine, thus avoiding the Odemethylation. The routes are compared for overall efficiency and experimental and spectral data are provided for all new compounds.

Whole-cell fermentation of o-halo methyl benzoates provided new cis-dihydrodiol metabolites.

Four distinct approaches to ent-oxycodone were designed and accomplished. All rely on the same starting material, the diene diol derived from phenethyl acetate by the whole-cell fermentation with E. coli JM109 (pDTG601A), a strain that overexpresses toluene dioxygenase. The key step in the first-generation approach involves the construction of the C-9/C-14 bond by a SmI2-mediated cyclization of a keto aldehyde. The second-generation design relies on the use of the Henry reaction to accomplish this task. In both of these syntheses, Parker’s cyclization was employed to construct the D-ring. The third-generation synthesis provides an improvement over the second in that the nitrogen atom at C-9 is introduced by azidation of the C-9/C-10 olefin, followed by reduction and lactam formation between the C-9 amine and the Fukuyama-type lactone. Finally, the fourth generation takes advantage of the keto–nitrone reductive coupling to generate the C-9/C-14 linkage. The four generations of the total syntheses of ent-oxycodone were accomplished in 13, 18, 16, and 11 operations (19, 23, 24, and 18 steps), respectively. Experimental and spectral data are provided for all new compounds.

The N‐oxide of O‐acyloxymorphone, when treated with the Burgess reagent, provides the corresponding oxazolidine in a one‐pot sequence and in excellent yield. The oxazolidine derived from oxymorphone, temporarily protected at O‐3 and C‐6, reacts with Grignard reagents to provide directly N‐allyl, N‐cyclopropylmethyl, and N‐cyclobutylmethyl derivatives that are further converted to the title compounds, namely naltrexone, naloxone, nalbuphone, and nalbuphine in excellent yields. Each of these medicinal agents is obtained from the oxazolidine in a one‐pot sequence. Complete spectral and experimental data are provided for all compounds.