Bioinspired Scalable Total Synthesis of Opioids
2021; Chinese Chemical Society; Volume: 3; Issue: 9 Linguagem: Inglês
10.31635/ccschem.021.202100923
ISSN2096-5745
AutoresXiaohan Zhou, Wenfei Li, Ruijie Zhou, Xiaoqing Wu, Yuan Huang, Wenlong Hou, Chunxin Li, Yifan Zhang, Wei Nie, Yu Wang, Hao Song, Xiaoyu Liu, Zhibing Zheng, Fei Xie, Song Li, Wu Zhong, Yong Qin,
Tópico(s)Innovative Microfluidic and Catalytic Techniques Innovation
ResumoOpen AccessCCS ChemistryCOMMUNICATION1 Sep 2021Bioinspired Scalable Total Synthesis of Opioids Xiaohan Zhou†, Wenfei Li†, Ruijie Zhou†, Xiaoqing Wu, Yuan Huang, Wenlong Hou, Chunxin Li, Yifan Zhang, Wei Nie, Yu Wang, Hao Song, Xiao-Yu Liu, Zhibing Zheng, Fei Xie, Song Li, Wu Zhong and Yong Qin Xiaohan Zhou† Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Wenfei Li† Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Ruijie Zhou† Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Xiaoqing Wu Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Yuan Huang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Wenlong Hou Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Chunxin Li Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Yifan Zhang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Wei Nie Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Yu Wang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Hao Song Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Xiao-Yu Liu Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 , Zhibing Zheng National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850 , Fei Xie National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850 , Song Li National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850 , Wu Zhong *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850 and Yong Qin *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041 https://doi.org/10.31635/ccschem.021.202100923 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail As one of the largest and most representative families of natural medicines harvested from plants, the mass production of opioids legitimately occupies large, worldwide farmland cultivation of opium poppies, causing severe regulation limitations and supply uncertainty. Due to their complex structures, the chemical synthesis of opioids has been criticized as infeasible for large-scale production in view of lengthy synthetic steps and overall low 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 allowed efficient preparation of a key thebaine-like core on a decagram scale. For the synthesis of oxycodone and codeine, less than eight continuous operations and one column chromatography purification were required throughout the process, resulting in overall 11% and 13% yields, respectively. Our current synthetic approach has demonstrated potential application in the industrial manufacturing of opioids. Download figure Download PowerPoint Introduction Opioids belong to an important group of small molecules that have a long history of medicinal applications ever since morphine was first isolated from nature in 1806.1 Some of the most used opioids in the clinic include the naturally occurring morphine ( 1, Figure 1, analgesic) and codeine ( 2, antitussive), as well as semisynthetic oxycodone ( 3, analgesic), oxymorphone ( 4, analgesic), naloxone ( 5, opioid antagonist), naltrexone ( 6, opioid antagonist), and nalbuphine ( 7, mixed agonist–antagonist).2 Besides the relative abundance of codeine and morphine in opium poppies, the current supply of important semisynthetic opioids with a 14-hydroxyl group (e.g., 3– 7) relies on a sequence of processes involving the farming of opium poppies, isolation of thebaine ( 8), and chemical transformations of natural product 8 into advanced derivatives, including 3– 7. More than the annual 400-ton global consumption of opium alkaloids and their derivatives requires an estimated 100,000-hectare land area for legitimately cultivated opium poppy.1 Such an unavoidable labor-intensive way of opioid production not only suffers from regulating difficulty but also takes up large amounts of arable land, leading to severe soil erosion.3 Here comes the issue that has long plagued the community and society: Do we really have to plant opium poppies for medical usage? Figure 1 | Chemical structures of selected natural morphine alkaloids and semisynthetic opioids. Download figure Download PowerPoint Efforts made by scientists aiming to solve the problem of opioid supply are tremendous. First, gene engineering techniques have been utilized to improve thebaine ( 8) yield in poppy species.4 Despite certain advances, the natural abundance of 8 in cultivated poppy straw is still nonideal (about 4%)5 and highly dependent on planting conditions. Second, synthetic biologists have recently achieved the complete biosynthesis of thebaine and derivatives in yeast, which, however, is far from practical application.6 Moreover, synthetic chemists have developed over 30 total syntheses of morphine and congeners,7–22 but none of these de novo approaches, especially those to oxycodone ( 3)18–22 and related derivatives 4– 7, are cost-competitive, considering the current farming/isolation/semisynthetic protocol for obtaining natural opioid products. An important solution to the practical synthesis of opioids would be to mimic the methods employed by Mother Nature: Biogenetically, l-tyrosine ( 9, Scheme 1a) first undergoes several transformations, including a key Mannich reaction to yield (R)-reticuline ( 10).23 Subsequent enzyme-promoted intramolecular oxidative coupling of phenols generates the morphinan scaffold (i.e., salutaridine, 11). Further elaborations lead to thebaine, a common intermediate to morphine and synthetic opioids. One of the most critical steps in the above-mentioned biosynthesis of morphine alkaloids that formed their core structures is oxidative phenol coupling.23 Organic chemists have sought to imitate this transformation in the laboratory over several decades.22,24–28 Selected results from some of these reports are outlined in Scheme 1b. In 1963, Barton's group24,25 first described the conversion of 10 into 11 using MnO2 or K3Fe(CN)6 with a very low yield (≤0.03%). In the 1980s, Szantay et al.26 and Vanderlaan and Schwartz28 prepared the morphinan cores 11 and 13 with 2.7% and 27% yields through an oxidative coupling 10 and 12, respectively. Recently, Opatz and co-workers22 achieved an electrochemical coupling of 14 with significantly improved efficacy (69% isolated yield of 15). Despite this critical advancement, this electrochemical coupling requires a low reaction concentration (0.01 M), and a 1 L reaction could only give 3.28 g of product 15,22 which largely limits its industrial application. Herein, we report a scalable total synthesis of oxycodone, codeine, and several other opioids by harnessing a highly efficient bioinspired Pd-catalyzed arene coupling process. Scheme 1 | Biosynthesis and the state of the art of bioinspired chemical synthesis of morphine alkaloids. (a) Biosynthetic pathway of morphine and congeners that relies on a key oxidative phenol coupling. (b) Literature methods for the assembly of the morphinan framework through biogenetically inspired arene couplings. (c) Retrosynthetic analysis of oxycodone (3) and codeine (2) in this study. Download figure Download PowerPoint Results and Discussion Illustrated in Scheme 1c is our retrosynthetic analysis of two representative opioids, oxycodone ( 3) and codeine ( 2). Both 2 and 3 could be traced back to a common intermediate 16 bearing a thebaine-like core structure through functionality manipulations, including the installation of a requisite C14 tertiary hydroxyl group in 3. Compound 16 could arise through dihydrofuran formation from dienone 17. We envisioned constructing the morphinan backbone 17 using transition-metal-catalyzed dearomatization coupling of the phenol 18.29,30 Deliberate design of substrate 18 possessing a methoxy group at C8 and a bromine atom at C12 would prevent the formation of undesired regioisomers at various positions of the two benzene rings (as normally generated in previous protocols24–28) and secure the regiospecific C12–C13 bond formation in the key bioinspired coupling reaction. The vital stereogenic center in 18 could be established via asymmetric hydrogenation of imine 19.31,32 In turn, 19 was accessible through a Bischler–Napieralski cyclization of amide 20, which could be prepared from known amine 2133 and acid 22.34 Our successful synthetic approach to opioids 1– 7 is shown in Scheme 2, which commenced with the preparation of amide 20. Based on modified procedures, the known primary amine 2133 and carboxylic acid 2234 were first synthesized readily and efficiently on hectogram scales from commercially available materials in 3 and 4 steps, respectively (see Supporting Information). Condensation of 21 and 22 in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and triethylamine provided amide 20 with 93% yield. The pure material was obtained readily by filtration through a silica gel pad after work-up. Compound 20 was subjected to protection of the free hydroxyl group (PMBCl) and ensuing Bischler–Napieralski reaction (Tf2O, 2-fluoropyridine), affording cyclized imine 19. We next explored the asymmetric hydrogenation of 19 to generate the key stereogenic center at C9.35–38 After extensive investigations (see Supporting Information Tables S1 and S2), [Ir(cod)Cl]2 (2.5 mol %) and (R)-BINAP (BINAP = ([1,1′-binaphthalene]-2,2′-diyl)bis(diphenylphosphane)) (5.0 mol %) were found to be an optimal combination of metal and ligand to afford excellent enantioselectivity (94% ee) of this asymmetric hydrogenation reaction. Subsequently, the installation of different substituent groups at the N-atom and removing the tert-butyldimethylsilyl (TBS) group delivered phenols 18a– 18d, respectively. At this point, filtration of the crude materials through a silica gel pad generated the corresponding pure products (i.e., 18a– 18d) in four steps with 51–71% overall yields from amide 20. Scheme 2 | Total synthesis of oxycodone (3) and codeine (2), as well as related opioids morphine (1), oxymorphone (4), naloxone (5), naltrexone (6), and nalbuphine (7). Reagents and conditions: (a) TBTU, Et3N, CH2Cl2, 0 °C to RT, 93%. (b) K2CO3, PMBCl, MeCN, 40 °C. (c) Tf2O, 2-fluoropyridine, CH2Cl2, −30 °C. (d) [Ir(cod)Cl]2 (2.5 mol %), (R)-BINAP (5.0 mol %), triethylethanaminium iodide (TEAI), CHCl3, H2 (500 psi), 0 °C; then pyridine, ClCO2Me; or Et3N, TsCl; or Et3N, (Boc)2O; or (HCHO)n, MeOH/THF (1∶1), then NaBH4, RT. (e) KF, HBr, 50 °C, MeCN/H2O (20∶1), 67% (for 18b with N-Ts, over four steps from 20). (e') tetra-n-butylammonium fluoride (TBAF), HOAc, THF, RT, 61% (for 18a with N-CO2Me, over four steps from 20), 71% (for 18c with N-Boc, over four steps from 20), 51% (for 18d with N-Me, over four steps from 20). (f) Pd(PPhtBu2)2Cl2, tBuOK, DME, 85 °C, 87%. (g) HOAc, 90 °C, 85%. (h) NaBH4, MeOH/CH2Cl2 (1∶1), 0 °C. (i) dimethylformamide dimethyl acetal, 1,4-dioxane, 60 °C. (j) tetraphenylporphyrin (TPP), O2, blue LED, CH2Cl2, RT. (k) Pd/C, HCO2H, iPrOH/H2O, H2 (10 atm), RT, 54% (over four steps from 23). (l) LiAlH4, DME, 40 °C. (m) (HCHO)n, MeOH, RT, then NaBH4, RT. (n) PdCl2, H2 (20 atm), MeOH, 30 °C, 62% (over three steps from 25). (o) IBX, DMSO, RT. (p) TsOH, THF, 60 °C, 92% (over two steps from 26). (q) Pd/C, H2 (10 atm), MeOH, 30 °C, 84%. (r) LiAlH4, DME, RT. (s) (HCHO)n, MeOH, RT, then NaBH4, RT. (t) PdCl2, H2 (20 atm.), MeOH, RT. (u) IBX, DMSO, RT, 61% (over four steps from 28). (v) TsOH, THF, 50 °C. (w) NaBH4, MeOH, 0 °C, 74% (over two steps from 29). THF, tetrahydrofuran; LED, light-emitting diode; DMSO, dimethyl sulfoxide; RT, room temperature. Download figure Download PowerPoint The next stage of the synthesis was focused on exploring the key arene coupling reaction inspired by the biosynthesis of morphine alkaloids.23 Initially, compound 18a possessing an N-methoxycarbonyl group, was selected as the reaction substrate for the Pd-catalyzed dearomatization reaction (Table 1). Several phosphorus ligands were investigated for the intramolecular arene coupling39–41 of 18a in the presence of [Pd(cinnamyl)Cl]2 (5 mol %) and K2CO3 (2.0 equiv) in 1,2-dimethoxyethane (DME) at reflux temperature. Most ligands resulted in the recovery of the starting material 18a or formation of debromo byproduct; only a few ligands were capable of furnishing the desired coupling product 17a (Table 1). Specifically, the use of L1 (RuPhos, entry 1), L2 (SPhos, entry 2), L3 (XPhos, entry 3), L4 (QPhos, entry 4), L5 (entry 5), L6 [1,1′-bis(di-tert-butylphosphino)ferrocene (DTBPF), entry 6], and L7 (entry 7) provided 17a in low to moderate yields (7–50%). To our delight, the coupling reaction occurred with significantly improved conversion (96%) of 18a and yielded (71%, entry 8) of 17a, employing a simple phosphorus ligand L8 (di-tert-butylphenylphosphine). We next examined the effect of reaction substrates and found that an electron-withdrawing group at the N-atom was crucial to the generation of the corresponding products 17a– 17c (entries 8–10), whereas an N-methyl group (i.e., 18d, entry 11) suppressed the reaction completely. This could be due to the strong binding affinity of electron-rich alkylamine to the palladium catalyst. Superior efficiency (72% yield, along with 16% starting material recovered, entry 9) was observed employing 18b, compared with that of 18a. A survey of different palladium catalysts (see Supporting Information Table S5) revealed that the commercially available Pd-complex containing PPhtBu2 (without the addition of external ligand) afforded improved results (79% yield with 18a, entry 12; 85% yield with 18b, entry 13). Furthermore, bases with potassium cation proved essential in maintaining the reaction yields (entries 13–16), and the use of tBuOK allowed for an 89% isolated yield of 17b with a complete conversion of 18b (entry 17). Reducing the loading of tBuOK from 2.0 to 1.4 equiv minimized the formation of debromo byproduct (see Supporting Information), leading to a higher yield (92%, entry 18). With these optimum conditions in hand, we scaled up the reaction on a 50 g scale (entry 19), which facilely provided the desired 17b with 87% yield after simple filtration of the crude product over a silica gel pad. Table 1 | Select Conditions for the Arene Coupling Reaction Optimizationa c Substrate [Pd] Ligand Base (equiv.) Conversion (%)b Yield (%)c 1 18a [Pd(cinnamyl)Cl]2 L1 K2CO3 (2.0) 31 18 2 18a [Pd(cinnamyl)Cl]2 L2 K2CO3 (2.0) 54 29 3 18a [Pd(cinnamyl)Cl]2 L3 K2CO3 (2.0) 42 24 4 18a [Pd(cinnamyl)Cl]2 L4 K2CO3 (2.0) 79 43 5 18a [Pd(cinnamyl)Cl]2 L5 K2CO3 (2.0) 57 14 6 18a [Pd(cinnamyl)Cl]2 L6 K2CO3 (2.0) 73 50 7 18a [Pd(cinnamyl)Cl]2 L7 K2CO3 (2.0) 68 7 8 18a [Pd(cinnamyl)Cl]2 L8 K2CO3 (2.0) 96 71 9 18b [Pd(cinnamyl)Cl]2 L8 K2CO3 (2.0) 84 72 10 18c [Pd(cinnamyl)Cl]2 L8 K2CO3 (2.0) 66 31 11 18d [Pd(cinnamyl)Cl]2 L8 K2CO3 (2.0) 99.9% ee after recrystallization with ethanol. Moreover, opiate-derived pharmaceutical agents (–)-oxymorphone ( 4), (–)-naloxone ( 5), (–)-naltrexone ( 6), and (–)-nalbuphine ( 7) were prepared from 3 according to literature methods (see Supporting Information).45–47 In contrast, total synthesis of morphine ( 1) and codeine ( 2) was implemented starting from intermediate 23 (Scheme 2). Specifically, after converting 23 into dienol ether 16 (vide supra), directly subjecting the latter to column chromatography on silica gel resulted in the generation of enone 28 (70% yield from phenol 23) through keto-enol tautomerization and alkene migration. Based on a similar sequence as that used in approaching 3, intermediate 28 was further converted into 29 with 61% yield over four steps, which ensured the transformation of N-Ts into N-Me group and reduction of the C7–C8 alkene. Elimination of the methoxy group at C8 in 29, followed by diastereoselective reduction of the carbonyl group in the resultant enone, provided (–)-codeine ( 2) with 74% yield (two steps from 29) and >99.9% ee after recrystallization of its phosphate which was usually used as the active pharmaceutical ingredients. In addition, O-demethylation of 2 gave rise to (–)-morphine ( 1) following a literature method.48 Conclusion We have developed a highly suitable and robust synthetic approach to the thebaine-like core 16 on decagram scale, which resulted in the collective and asymmetric synthesis of (–)-oxycodone ( 3, 17 steps, 11% overall yield), (–)-codeine ( 2, 15 steps, 13% overall yield), and related pharmaceutically essential opioids 1 and 4– 7 from known compounds 21 and 22. The synthesis featured two key strategies, viz, an Ir-catalyzed asymmetric hydrogenation of imine and a Pd-catalyzed intramolecular dearomatization coupling reaction. In particular, the latter transformation, to date, represents the most efficient biomimetic dearomatization arene coupling reaction among various precedents that have been documented to access the morphinan framework. Notably, the whole synthetic route required less than eight operations, among which only one column chromatography operation was necessary. Besides, most intermediates were purified through simple (re)crystallization or filtration through a silica gel pad. To the best of our knowledge, our current synthesis of opioids represents the most efficient synthesis concerning the reaction steps, operation simplification, scale-up capabilities, and overall improved yields. Collectively, this work is not only a showcase of highly efficient synthesis of opioid natural medicines, the cost of which is comparable to the current farming/isolation/semisynthesis approach, but it also provides an important opportunity to innovate the industrial manufacturing of opioids. Supporting Information Supporting Information is available and includes experimental procedures and Tables S1–S10. Conflict of Interest There is no conflict of interest to report. Funding Information Manipulations of all the controlled substances according to Narcotics and Psychotropic Drugs Regulations in China were conducted in an authorized laboratory at National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology. Financial support was provided by the National Natural Science Foundation of China (grant nos. 21991114, 21921002, and 21732005) and Drug Innovation Major Project (grant no. 2018ZX09711003). References 1. Narcotic Drugs: Estimated World Requirements for 2020—Statistics for 2018; International Narcotics Control Board: Vienna, Austria, 2019. Google Scholar 2. King S. J.; Reid C.; Forbes K.; Hanks G.A Systematic Review of Oxycodone in the Management of Cancer Pain.Palliat. Med.2011, 25, 454–470. Google Scholar 3. Bradsher K.Shake-Up on Opium Island.New York Times; 2014. www.nytimes.com/2014/07/20/business/international/tasmania-big-supplier-to-drug-companies-faceschanges.html (accessed July 20, 2014). Google Scholar 4. Millgate A. G.; Pogson B. J.; Wilson I. W.; Kutchan T. M.; Zenk M. H.; Gerlach W. L.; Fist A. J.; Larkin P. J.Morphine-Pathway Block in Top1 Poppies.Nature2004, 431, 413–414. Google Scholar 5. Fist A. J.Papaver Somniferum with High Concentration of Thebaine. U.S. Pat. Appl. 20090227796A1, 2009. Google Scholar 6. Galanie S.; Thodey K.; Trenchard I. J.; Interrante M. F.; Smolke C. D.Complete Biosynthesis of Opioids in Yeast.Science2005, 349, 1095–1100. Google Scholar 7. Rinner U.; Hudlicky T.Synthesis of Morphine Alkaloids and Derivatives.Top. Curr. Chem.2012, 309, 33–66. Google Scholar 8. Koizumi H.; Yokoshima S.; Fukuyama T.Total Synthesis of (−)-Morphine.Chem. Asian J.2010, 5, 2192–2198. Google Scholar 9. Erhard T.; Ehrlich G.; Metz P.A Total Synthesis of (±)-Codeine by 1,3-Dipolar Cycloaddition.Angew. Chem. Int. Ed.2011, 50, 3892–3894. Google Scholar 10. Geffe M.; Opatz T.Enantioselective Synthesis of (−)-Dihydrocodeine and Formal Synthesis of (−)-Thebaine, (−)-Codeine, and (−)-Morphine from a Deprotonated α-Aminonitrile.Org. Lett.2014, 16, 5282–5285. Google Scholar 11. Endoma-Arias M. A. A.; Hudlicky J. R.; Simionescu R.; Hudlicky T.Chemoenzymatic Formal Total Synthesis of Ent-Codeine and Other Morphinans via Nitrone Cycloadditions and/or Radical Cyclizations. Comparison of Strategies for Control of C-9/C-14 Stereogenic Centers.Adv. Synth. Catal.2014, 356, 333–339. Google Scholar 12. Varghese V.; Hudlicky T.Short Chemoenzymatic Total Synthesis of Ent-Hydromorphone: An Oxidative Dearomatization/Intramolecular [4+2] Cycloaddition/Amination Sequence.Angew. Chem. Int. Ed.2014, 53, 4355–4358. Google Scholar 13. Li Q.; Zhang H.Total Synthesis of Codeine.Chem. Eur. J.2015, 21, 16379–16382. Google Scholar 14. Chu S.; Münster N.; Balan T.; Smith M. D.A Cascade Strategy Enables a Total Synthesis of (±)-Morphine.Angew. Chem. Int. Ed.2016, 55, 14306–14309. Google Scholar 15. Lipp A.; Ferenc D.; Gütz C.; Geffe M.; Vierengel N.; Schollmeyer D.; Schäfer H. J.; Waldvogel S. R.; Opatz T.A Regio- and Diastereoselective Anodic Aryl–Aryl Coupling in the Biomimetic Total Synthesis of (−)-Thebaine.Angew. Chem. Int. Ed.2018, 57, 11055–11059. Google Scholar 16. Sun D.; Pedersen B.; Ellman J. A.Asymmetric Synthesis of (−)-Naltrexone.Chem. Sci.2019, 10, 535–541. Google Scholar 17. Zhang Q.; Zhang F.-M.; Zhang C.-S.; Liu S.-Z.; Tian J.-M.; Wang S.-H.; Zhang X.-M.; Tu Y.-Q.Enantioselective Synthesis of Cis-Hydrobenzofurans Bearing All-Carbon Quaternary Stereocenters and Application to Total Synthesis of (−)-Morphine.Nat. Commun.2019, 10, 2507. Google Scholar 18. Kimishima A.; Umihara H.; Mizoguchi A.; Yokoshima S.; Fukuyama T.Synthesis of (−)-Oxycodone.Org. Lett.2014, 16, 6244–6247. Google Scholar 19. Park K.; Chen D. Y.-K.A Desymmetrization-Based Approach to Morphinans: Application in the Total Synthesis of Oxycodone.Chem. Commun.2018, 54, 13018–13021. Google Scholar 20. Endoma-Arias M. A.; Makarova M.; Paz H.; Hudlicky T.Chemoenzymatic Total Synthesis of (+)-Oxycodone from Phenethyl Acetate.Synthesis2019, 51, 225–232. Google Scholar 21. Makarova M.; Endoma-Arias M. A.; Paz H.; Simionescu R.; Hudlicky T.Chemoenzymatic Total Synthesis of Ent-Oxycodone: Second-, Third-, and Fourth-Generation Strategies.J. Am. Chem. Soc.2019, 141, 10883–10904. Google Scholar 22. Lipp A.; Selt M.; Ferenc D.; Schollmeyer D.; Waldvogel S. R.; Opatz T.Total Synthesis of (−)-Oxycodone via Anodic Aryl–Aryl Coupling.Org. Lett.2019, 21, 1828–1831. Google Scholar 23. Kirby G. W.Biosynthesis of the Morphine Alkaloids.Science1967, 155, 170–173. Google Scholar 24. Barton D. H. R.; Kirby G. W.; Steglich W.; Thomas G. M.The Biosynthesis of Alkaloids.Proc. Chem. Soc.1963, 189–200. Google Scholar 25. Barton D. H. R.; Bhakuni D. S.; James R.; Kirby G. W.Phenol Oxidation and Biosynthesis. Part XII. Stereochemical Studies Related to the Biosynthesis of the Morphine Alkaloids.J. Chem. Soc. C1967, 128–132. Google Scholar 26. Szantay C.; Barczai B. M.; Pechy P.; Blasko G.; Dornyei G.Studies Aimed at the Synthesis of Morphine. 3. Synthesis of (±)-Salutaridine via Phenolic Oxidative Coupling of (±)-Reticuline.J. Org. Chem.1982, 47, 594–596. Google Scholar 27. White J. D.; Caravatti G.; Kline T. B.; Edstrom E.; Rice K. C.; Brossi A.Biomimetic Total Synthesis of (−)-Codeine.Tetrahedron1983, 39, 2393–2397. Google Scholar 28. Vanderlaan D. G.; Schwartz M. A.Synthesis and Oxidative Coupling of (±)-3-Oxoreticuline.J. Org. Chem.1985, 50, 743–747. Google Scholar 29. Bedford R. B.Dearomatization via Transition-Metal-Catalyzed Cross-Coupling Reactions. In Asymmetric Dearomatization Reactions; You S.-L., Ed.; Wiley-VCH: Weinheim, Germany, 2016. Google Scholar 30. Wu W.-T.; Zhang L.; You S.-L.Catalytic Asymmetric Dearomatization (CADA) Reactions of Phenol and Aniline Derivatives.Chem. Soc. Rev.2016, 45, 1570–1580. Google Scholar 31. Xie J.-H.; Zhu S.-F.; Zhou Q.-L.Transition Metal-Catalyzed Enantioselective Hydrogenation of Enamines and Imines.Chem. Rev.2011, 111, 1713–1760. Google Scholar 32. Tang P.; Wang H.; Zhang W.; Chen F.-E.Asymmetric Catalytic Hydrogenation of Imines and Enamines in Natural Product Synthesis.Green Synth. Catal.2020, 1, 26–41. Google Scholar 33. Arencibia J. M.; Brindani N.; Franco-Ulloa S.; Nigro M.; Kuriappan J. A.; Ottonello G.; Bertozzi S. M.; Summa M.; Girotto S.; Bertorelli R.; Armirotti A.; De-Vivo M.Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity.J. Med. Chem.2020, 63, 3508–3521. Google Scholar 34. Al-Hassan G.; Frenzel U.; Görler K.; Soicke H.Versuche zur Photochemischen Synthese von Bulbocapnin.Arch. Pharm. (Weinheim)1988, 321, 149–152. Google Scholar 35. Wang W.-B.; Lu S.-M.; Yang P.-Y.; Han X.-W.; Zhou Y.-G.Highly Enantioselective Iridium-Catalyzed Hydrogenation of Heteroaromatic Compounds, Quinolines.J. Am. Chem. Soc.2003, 125, 10536–10537. Google Scholar 36. Chang M.; Li W.; Zhang X.A Highly Efficient and Enantioselective Access to Tetrahydroisoquinoline Alkaloids: Asymmetric Hydrogenation with an Iridium Catalyst.Angew. Chem. Int. Ed.2011, 50, 10679–10681. Google Scholar 37. Xie J.-H.; Yan P.-C.; Zhang Q.-Q.; Yuan K.-X.; Zhou Q.-L.Asymmetric Hydrogenation of Cyclic Imines Catalyzed by Chiral Spiro Iridium Phosphoramidite Complexes for Enantioselective Synthesis of Tetrahydroisoquinolines.ACS Catal.2012, 2, 561–564. Google Scholar 38. Ji Y.; Shi L.; Chen M.-W.; Feng G.-S.; Zhou Y.-G.Concise Redox Deracemization of Secondary and Tertiary Amines with a Tetrahydroisoquinoline Core via a Nonenzymatic Process.J. Am. Chem. Soc.2015, 137, 10496–10499. Google Scholar 39. Xu R.-Q.; Gu Q.; Wu W.-T.; Zhao Z.-A.; You S.-L.Construction of Erythrinane Skeleton via Pd(0)-Catalyzed Intramolecular Dearomatization of Para-Aminophenols.J. Am. Chem. Soc.2014, 136, 15469–15472. Google Scholar 40. Du K.; Guo P.; Chen Y.; Cao Z.; Wang Z.; Tang W.Enantioselective Palladium-Catalyzed Dearomative Cyclization for the Efficient Synthesis of Terpenes and Steroids.Angew. Chem. Int. Ed.2015, 54, 3033–3037. Google Scholar 41. Mu X.; Yu H.; Peng H.; Xiong W.; Wu T.; Tang W.Construction of Various Bridged Polycyclic Skeletons by Palladium-Catalyzed Dearomatization.Angew. Chem. Int. Ed.2020, 59, 8143–8147. Google Scholar 42. López D.; Quiňoá E.; Riguera R.Photooxidation of Thebaine. A Route to 14-Hydroxymorphinones and Hydrodibenzofuran Analogs of Methadone.Tetrahedron Lett.1994, 35, 5727–5730. Google Scholar 43. Machara A.; Werner L.; Leisch H.; Carroll R. J.; Adams D. R.; Haque D. M.; Cox D. P.; Hudlicky T.Synthesis of Naltrexone and (R)-Methylnaltrexone from Oripavine via Direct Oxidation of Its Quaternary Salts.Synlett2015, 26, 2101–2108. Google Scholar 44. Umihara H.; Yokoshima S.; Inoue M.; Fukuyama T.Total Synthesis of (−)-Morphine.Chem. Eur. J.2017, 23, 6993–6995. Google Scholar 45. Hudlicky T.Recent Advances in Process Development for Opiate-Derived Pharmaceutical Agents.Can. J. Chem.2015, 93, 492–501. Google Scholar 46. Iijima I.; Minamikawa J.; Jacobson A. E.; Brossi A.; Rice K. C.Studies in the (+)-Morphinan Series. 5. Synthesis and Biological Properties of (+)-Naloxone.J. Med. Chem.1978, 21, 398–400. Google Scholar 47. Werner L.; Wernerova M.; Machara A.; Endoma-Arias M. A.; Duchek J.; Adams D. R.; Cox D. P.; Hudlicky T.Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides Mediated by the Burgess Reagent: Direct Synthesis of Naltrexone, Naloxone, and Other Antagonists from Oxymorphone.Adv. Synth. Catal.2012, 354, 2706–2712. Google Scholar 48. Rice K. C.A Rapid, High-Yield Conversion of Codeine to Morphine.J. Med. Chem.1977, 20, 164–165. Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentVolume 3Issue 9Page: 1376-1383Supporting Information Copyright & Permissions© 2021 Chinese Chemical SocietyKeywordsopioidmorphineoxycodonecodeinedearomatizationnatural producttotal synthesis Downloaded 2,942 times PDF DownloadLoading ...
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