Bioinspired Scalable Total Synthesis of Opioids

Abstract

As one of the largest and most representative families of natural medicines harvested from plants, the mass production of opioids legitimately occupies large farmland for the cultivation of opium poppies in the world, causing serious regulation difficulty and supply uncertainty. Due to their complex structures, chemical synthesis of opioids has been criticized infeasible for large-scale production in view of lengthy synthetic steps and low overall efficiency. Here we report a practical and scalable total synthesis of oxycodone, codeine, and related opioids by imitating the biosynthetic dearomatization arene coupling reaction, which allows efficient preparation of a key thebaine-like core on decagram scale.For the synthesis of oxycodone and codeine, less than eight continuous operations and one column chromatography purification were required throughout the synthesis in 11% and 13%

Madangamine alkaloids: Madness and tranquility

“…To simulate natural blueprints, the biogenetic hypothesis should be followed as strategic guidance instead of stringent instruction. [43,44,45] Any adjustment would be necessary to realize the key transformation and preclude side pathways. A compromised narrative ratified in the sensation of biomimetic synthesis was that practical considerations become secondary to theoretical success if the isolated yield is extremely low.…”

Concise total synthesis of opioids

“…3 The recent approval of samidorphan ( 6 ) by the FDA for the treatment of major depressive disorder 4 further reflects the value of the privileged morphinan framework in developing indispensable drugs. Owing to the pharmacological significance and challenging structures of opioids, synthetic biologists and chemists have made tremendous efforts to solve the opioid supply issue, 5–28 which remains unresolved to this day. For example, Smolke and co-workers recently achieved the first complete biosynthesis of thebaine and its derivatives in yeast.…”

“…Our laboratory disclosed a Pd-catalyzed arene coupling of bromide 13 bearing a C8-methoxy moiety, which generated the expected product 14 in 92% yield. 28 As demonstrated in the above-mentioned recent two examples, the use of blocking groups dramatically improved the yield of the coupling reaction, which, however, required tedious installation and deprotection steps, resulting in non-ideal overall efficacy. In other words, efficient dearomatization C12–C13 bond formation without using blocking groups on the aromatic rings has been highly challenging and remains unsolved in the synthesis of opioids.…”

“…8 However, this technology is far from practical application because "it would take 4400 gallons of bioengineered yeast to produce a single therapeutic dose for pain relief". 29 As regards the chemical synthesis, over 40 total syntheses of various morphinan alkaloids have been documented through the development of many creative methodologies and strategies [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] over the past 70 years. Despite the great advances, the overall efficacy of the known synthetic approaches is not ideal and not suitable for industrial scale-up production of opioids, compared to the current supply protocol through farming/isolation/semi-synthesis.…”

“…However, such a transformation constitutes a great challenge that has puzzled synthetic chemists for decades in the bio-inspired total synthesis of morphine alkaloids. 20,26,28,[31][32][33][34][35] Initially, the Barton group documented the conversion of 7 in the presence of MnO 2 or K 3 Fe(CN) 6 to yield a trace amount of 8 (≤ 0.03%). 31 In 1982, Szantay and co-workers reported the transformation of 7 to 8 with a detectable 2.7% reaction yield using Pb(OAc) 4 , 33 while in the same period, Schwartz et al prepared the tetracyclic core 10 in an increased but still low yield (27%) from the amide substrate 9.…”