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.
Highlights
Interest in the preparation of 10-keto opiates and related derivatives such as the10-hydroxy-morphinans was aimed at pursuing κ-selective analgesics [1]
Of the three types of opioid receptors (μ, δ, κ), the κ-opioid receptor has been especially interesting because its activation produces analgesia with minimal physical dependence [2]
Among the efforts directed toward the preparation of the afore-mentioned 10-keto opiates are those aimed at the preparation of
Summary
Interest in the preparation of 10-keto opiates and related derivatives such as the. 10-hydroxy-morphinans was aimed at pursuing κ-selective analgesics [1]. 10-keto, 10α-, 10β-hydroxy-TRK-820 [4], 10-keto-naltrexone, 10-keto-oxymorphone, 10-keto-oxycodone (Figure 1) [5], 10-keto-naloxone, and 10-keto-naloxone 3-methyl ether [6] from the corresponding opiates These preparations are all conducted from natural morphinans by semi-syntheses. Even the most efficient academic synthesis, published by Rice [28], may not be amenable for scale-up in the industrial preparation of morphinans. A de novo preparation of oxycodone and related medicinal opiate-derived agents for medicinal use could alleviate the negative oxycodone and related medicinal opiate-derived agents for medicinal use could alleviate the negative impacts of any future unfavorable events that may limit the supply of natural sources—such as climate impacts of any future unfavorable events that may limit the supply of natural sources—such as or political changes in the opium-producing areas.
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