A desymmetrization-based approach to morphinans: application in the total synthesis of oxycodone

Abstract

Here we report a total synthesis of the pharmacologically significant morphinan alkaloid, oxycodone.

Interpol review of controlled substances 2016–2019

“…Oxycodone: 2016 evaluation of the susceptibility to tampering of biphasic immediate-release oxycodone/acetaminophen tablets compared with IR OC/APAP tablets [ 350 ]; evaluation of trends of diversion, abuse and street price of OxyContin to assess the durability of the initial reduction in abuse of abuse deterrent formulations [ 351 ]; 2017 Long-term efficacy and safety of oxycodone-naloxone prolonged-release formulation (up to 180/90 mg daily) [ 352 ]; design and evaluation of an extended-release matrix tablet formulation (oxycodone); the combination of hypromellose acetate succinate and hydroxypropylcellulose [ 353 ]; abuse potential of Oxycodone DETERx (R) (Xtampza (R) ER) [ 354 ]; development and characterization of a mucoadhesive sublingual formulation (oxycodone film) [ 355 ]; evaluation of a newly-developed oxycodone prolonged-release tablet [ 356 ]; 2018 Roxybond - abuse-deterrent formulation of immediate-release Oxycodone [ 357 ]; study of the introduction of an abuse-deterrent version of OxyContin in 2010 [ 358 ]; trends and uptake of new formulations of controlled-release oxycodone in Canada [ 359 ]; abuse-deterrent formulations of Oxycodone hydrochloride immediate-release analgesic for managing severe pain [ 360 ]; evaluation of the impact of OxyContin reformulation [ 361 ]; effect of a potentially tamper-resistant oxycodone formulation on opioid use and harm [ 362 ]; evaluation of the safety, tolerability, and analgesic efficacy of Oxycodone DETERx extended-release (ER) and abuse-deterrent capsules (Xtampza (R) ER) [ 363 ]; total synthesis of the pharmacologically significant morphinan alkaloid, oxycodone [ 364 ]; abuse potential of the new opioid analgesic Molecule NKTR-181 compared with Oxycodone [ 365 ]; 2019 synthesis of (−)-Oxycodone via anodic aryl-aryl coupling [ 366 ].…”

Anodic Oxidation as an Enabling Tool for the Synthesis of Natural Products

“…Based on pioneering work by Miller, [98][99][100] an intramolecular aryl-aryl coupling also served as the key step for the construction of the characteristic morphinan skeleton in the total synthesis of (-)-oxycodone [101][102][103][104][105][106] published by Opatz, Schäfer and Waldvogel. 102 The trioxygenated laudanosine derivative 41 was electrolyzed under constant current conditions, furnishing morphinandienone 42 in 69% yield (Scheme 9).…”

“…In 2010, Nishiyama and co-workers successfully dimerized phenol 101 under constant current conditions, thereby generating diaryl ether 102 in 60% yield (Scheme 19). Subsequent cathodic reduction and saponification provided intermediate 103 which, upon condensation with dimethoxytyramine (104) followed by Bischler-Napieralski reaction 163 and hydrogenation, provided O-methylthalibrine (105). The same electrochemical technique for the dimerization of phenols into diaryl ethers was utilized in the total synthesis of verbenachalcone 164 and isodityrosine, 165 a natural product which also represents an important substructure in biologically relevant cyclic peptides.…”

Bioinspired Scalable Total Synthesis of Opioids

“…Second, synthetic biologists have recently achieved the complete biosynthesis of thebaine and derivatives in yeast, which, however, is far from practical application. Moreover, synthetic chemists have developed over 30 total syntheses of morphine and congeners, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] but none of these de novo approaches, especially those to oxycodone (3) [18][19][20][21][22] and related derivatives 4-7, are competitive in cost with the current farming/isolation/semisynthesis protocol. An important solution to the practical synthesis of opioids would be to mimic the methods employed by the Mother Nature.…”