Subscribe to RSS
DOI: 10.1055/a-2595-1691
Development of Novel Bioactive Alkaloids Based on Specific Reactions of the 4,5-Epoxymorphinan Framework
This work was partly supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15K16553, 17K13259, 19K05710, 20H04763, and 24K08610 to N.K.; 16H05098 and 20H03361 to H.N.), the Japan Agency for Medical Research and Development (AMED), Moonshot Program (JP21zf0127005), and TORAY Industries, Inc. The International Institute For Integrative Sleep Medicine (IIIS) is also supported by the World Premier International Research Center Initiative (WPI), Japan.
Abstract
Morphinan alkaloids, such as morphine, codeine, heroin, and thebaine, are referred to as opioids and are pharmacologically important compounds. They are widely known to exhibit diverse pharmacological effects by acting on μ-, δ-, and κ-opioid receptors (MOR, DOR, and KOR). Naltrexone, a commercially available 4,5-epoxymorphinan alkaloid, is a drug primarily used to manage alcohol and opioid dependence. From a pharmacological perspective, naltrexone is classified as an MOR antagonist. On the other hand, from an organic chemistry perspective, naltrexone contains a wealth of functional groups and possesses four consecutive asymmetric centers within a single molecule, giving rise to its unique chemical reactivity. While this reactivity may not be universally applicable, gaining a clear understanding of it is crucial for researchers working on the organic chemistry of morphinan alkaloids. In this account, we provide a comprehensive overview of our research findings over the past decade, with a particular focus on the specific reactions of the 4,5-epoxymorphinan framework. We hope this account will be useful for both organic synthetic and medicinal chemists.
1 Introduction
2 Influence of the E-Ring in the 4,5-Epoxymorphinane Framework
2.1 Reaction of the C6 Ketone with a Stabilized Sulfur Ylide
2.2 Reaction of the C14 Hydroxy Group with Thionyl Chloride
2.3 Reaction of the C14 Hydroxy Group with Acetic Anhydride
2.4 Reaction of 14-Aminonaltrexone with Acetic Anhydride
2.5 Baeyer–Villiger-Type Oxidation of the 4,5-Epoxymorphinan
2.6 Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan
2.7 Unique Rearrangement of Morphinan Into Arylmorphan
3 Synthesis of Bioactive Compounds Based on 4,5-Epoxymorphinan
3.1 Synthesis of (–)-Galanthamine
3.2 Synthesis of (–)-Homogalanthamine
4 Summary
Key words
morphinan - 4,5-epoxymorphinan - bioactive alkaloids - rearrangement - substrate-specific reaction - naltrexonePublication History
Received: 31 March 2025
Accepted after revision: 25 April 2025
Accepted Manuscript online:
25 April 2025
Article published online:
17 June 2025
© 2025. Thieme. All rights reserved
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
References
- 1 Kutsumura N, Nagase H. J. Synth. Org. Chem. Jpn. 2018; 76: 914
- 2a Kuhn B, Mohr P, Stahl M. J. Med. Chem. 2010; 53: 2601
- 2b Zhang D.-W, Zhao X, Hou J.-L, Li Z.-T. Chem. Rev. 2012; 112: 5271
- 2c Giordanetto F, Tyrchan C, Ulander J. ACS Med. Chem. Lett. 2017; 8: 139
- 2d Appavoo SD, Huh S, Diaz DB, Yudin AK. Chem. Rev. 2019; 119: 9724
- 2e Zhao J, Varzhel N, Hokimoto Y, Nakamura T. Chem. Eur. J. 2025; 31: e202500424
- 2f Nakamura T, Kuwabara M, Zhang H, Okazawa K, Boero M, Shigeta Y, Nabeshima T. J. Org. Chem. 2025; 90: 3603
- 3a Nagase H, Kawai K. J. Synth. Org. Chem. Jpn. 1989; 47: 374
- 3b Nagase H, Abe A, Portoghese PS. J. Org. Chem. 1989; 54: 4120
- 4 Nagase H, Watanabe A, Nemoto T, Yamamoto N, Osa Y, Sato N, Yoza K, Kai T. Tetrahedron Lett. 2007; 48: 2547
- 5 Ananthan A, Saini SK, Dersch CM, Xu H, McGlinchey N, Giuvelis D, Bilsky EJ, Rothman RB. J. Med. Chem. 2012; 55: 8350
- 6 Koolpe GA, Nelson WL, Gioannini TL, Angel L, Appelmans N, Simon EJ. J. Med. Chem. 1985; 28: 949
- 7 Ida Y, Nemoto T, Hirayama S, Fujii H, Osa Y, Imai M, Nakamura T, Kanemasa T, Kato A, Nagase H. Bioorg. Med. Chem. 2012; 20: 949
- 8 Osa Y, Ida Y, Yano Y, Furuhata K, Nagase H. Heterocycles 2006; 69: 271
- 9 Nagase H, Yamamoto N, Nemoto T, Yoza K, Kamiya K, Hirono S, Momen S, Izumimoto N, Hasebe K, Mochizuki H, Fujii H. J. Org. Chem. 2008; 73: 8093
- 10a Nagase H, Akiyama J, Nakajima R, Hirayama S, Nemoto T, Gouda H, Hirono S, Fujii H. Bioorg. Med. Chem. Lett. 2012; 22: 2775
- 10b Nagase H, Nakajima R, Yamamoto N, Hirayama S, Iwai T, Nemoto T, Gouda H, Hirono S, Fujii H. Bioorg. Med. Chem. Lett. 2014; 24: 2851
- 10c Nakajima R, Yamamoto N, Hirayama S, Iwai T, Saitoh A, Nagumo Y, Fujii H, Nagase H. Bioorg. Med. Chem. 2015; 23: 6271
- 11 Kutsumura N, Okada T, Imaide S, Fujii H, Nagase H. Synthesis 2018; 50: 4263
- 12a Maeda K, Ohrui S, Tokuda A, Nagumo Y, Yamamoto N, Tanimura R, Saitoh T, Kutsumura N, Nagase H. Org. Lett. 2023; 25: 3407
- 12b Maeda K, Sugai T, Tokuda A, Kajino K, Saitoh T, Nagase H, Kutsumura N. Bioorg. Med. Chem. Lett. 2024; 99: 129611
- 13 Fujii H, Imaide S, Watanabe A, Nemoto T, Nagase H. Tetrahedron Lett. 2008; 49: 6293
- 14 Wang TH, Wang JX, Huang TZ. Chem. Ber. 1990; 123: 2141
- 15 Prantz K, Mulzer J. Chem. Rev. 2010; 110: 3741
- 16 Yamamoto N, Fujii H, Imaide S, Hirayama S, Nemoto T, Inokoshi J, Tomoda H, Nagase H. J. Org. Chem. 2011; 76: 2257
- 17 Fujii H, Narita M, Mizoguchi H, Murachi M, Tanaka T, Kawai K, Tseng LF, Nagase H. Bioorg. Med. Chem. 2004; 12: 4133
- 18 Hino T, Kutsumura N, Saitoh T, Yamamoto N, Nagumo Y, Mogi Y, Watanabe Y, Nagase H. Tetrahedron Lett. 2021; 63: 152714
- 19a Funk RL, Munger JD. Jr. J. Org. Chem. 1985; 50: 707
- 19b Funk RL, Abelman MM, Munger JD. Jr. Tetrahedron 1986; 42: 2831
- 19c Funk RL, Stallman JB, Wos JA. J. Am. Chem. Soc. 1993; 115: 8847
- 20 Portoghese PS, Sultana M, Nagase H, Takemori AE. Eur. J. Pharmacol. 1992; 218: 195
- 21a Miyata Y, Fujii H, Osa Y, Kobayashi S, Takeuchi T, Nagase H. Bioorg. Med. Chem. 2011; 21: 4710
- 21b Miyata Y, Fujii H, Uenohara Y, Kobayashi S, Takeuchi T, Nagase H. Bioorg. Med. Chem. Lett. 2012; 22: 5174
- 21c Kutsumura N, Koyama Y, Saitoh T, Yamamoto N, Nagumo Y, Miyata Y, Hokari R, Ishiyama A, Iwatsuki M, Otoguro K, Ōmura S, Nagase H. Molecules 2020; 25: 1112
- 22a Kutsumura N, Nakajima R, Koyama Y, Miyata Y, Saitoh T, Yamamoto N, Iwata S, Fujii H, Nagase H. Bioorg. Med. Chem. Lett. 2015; 25: 4890
- 22b Kutsumura N, Koyama Y, Nagumo Y, Nakajima R, Miyata Y, Yamamoto N, Saitoh T, Yoshida N, Iwata S, Nagase H. Bioorg. Med. Chem. 2017; 25: 4375
- 23 Kutsumura N, Koyama Y, Suzuki Y, Tominaga K, Yamamoto N, Saitoh T, Nagumo Y, Nagase H. Org. Lett. 2018; 20: 1559
- 24 Yata M, Kutsumura N, Nagumo Y, Yamamoto N, Saitoh T, Ishikawa Y, Irukayama-Tomobe Y, Yanagisawa M, Nagase H. Heterocycles 2019; 99: 134
- 25a Hayashida K, Hirayama S, Iwai T, Watanabe Y, Takahashi T, Sakai J, Nakata E, Yamakawa T, Fujii H, Nagase H. Bioorg. Med. Chem. Lett. 2017; 27: 2742
- 25b Watanabe Y, Hayashida K, Saito D, Takahashi T, Sakai J, Nakata E, Kanda T, Iwai T, Hirayama S, Fujii H, Yamakawa T, Nagase H. Bioorg. Med. Chem. Lett. 2017; 27: 3495
- 25c Saitoh A, Tominaga H, Ogawa Y, Irukayama-Tomobe Y, Yamada M, Yanagisawa M, Nagase H. Pharmacol. Rep. 2018; 70: 350
- 25d Yamada D, Yanagisawa S, Yoshizawa K, Yanagita S, Oka J, Nagase H, Saitoh A. Neuropharmacology 2019; 160: 107792
- 26a Nagase H, Yamamoto N, Yata M, Ohrui S, Okada T, Saitoh T, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ishikawa Y, Ogawa Y, Hirayama S, Kuroda D, Watanabe Y, Gouda H, Yanagisawa M. J. Med. Chem. 2017; 60: 1018
- 26b Yamamoto N, Ohrui S, Okada T, Yata M, Saitoh T, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Watanabe Y, Hayakawa D, Gouda H, Yanagisawa M, Nagase H. Bioorg. Med. Chem. Lett. 2017; 27: 4176
- 26c Ohrui S, Yamamoto N, Saitoh T, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Watanabe Y, Hayakawa D, Gouda H, Yanagisawa M, Nagase H. Bioorg. Med. Chem. Lett. 2018; 28: 774
- 26d Yamamoto N, Ohrui S, Okada T, Saitoh T, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Watanabe Y, Hayakawa D, Gouda H, Yanagisawa M, Nagase H. Bioorg. Med. Chem. 2019; 27: 1747
- 26e Saitoh T, Seki K, Nakajima R, Yamamoto N, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Tanimura R, Yanagisawa M, Nagase H. Bioorg. Med. Chem. Lett. 2019; 29: 2655
- 26f Saitoh T, Seki K, Nakajima R, Yamamoto N, Kutsumura N, Nagumo Y, Irukayama-Tomibe Y, Ogawa Y, Ishikawa Y, Yanagisawa M, Nagase H. Bioorg. Med. Chem. Lett. 2020; 30: 126893
- 26g Nagumo Y, Katoh K, Iio K, Saitoh T, Kutsumura N, Yamamoto N, Ishikawa Y, Irukayama-Tomobe Y, Ogawa Y, Baba T, Tanimura R, Yanagisawa M, Nagase H. Bioorg. Med. Chem. Lett. 2020; 30: 127360
- 26h Katoh K, Yamamoto N, Ishikawa Y, Irukayama-Tomobe Y, Tanimura R, Saitoh T, Nagumo Y, Kutsumura N, Yanagisawa M, Nagase H. Bioorg. Med. Chem. Lett. 2022; 59: 128527
- 26i Katoh K, Kutsumura N, Yamamoto N, Nagumo Y, Saitoh T, Ishikawa Y, Irukayama-Tomobe Y, Tanimura R, Yanagisawa M, Nagase R. Bioorg. Med. Chem. Lett. 2022; 59: 128550
- 27 Iio K, Kutsumura N, Nagumo Y, Saitoh T, Tokuda A, Hashimoto K, Yamamoto N, Kise R, Inoue A, Mizoguchi H, Nagase H. Bioorg. Med. Chem. Lett. 2022; 56: 128485
- 28 Yamamoto N, Okada T, Harada Y, Kutsumura N, Imaide T, Saitoh H, Fujii H, Nagase H. Tetrahedron 2017; 73: 5751
- 29a Pereira EF. R, Reinhardt-Maelicke S, Scharattenholz A, Maelicke A, Albuquerque EX. J. Pharmacol. Exp. Ther. 1993; 265: 1474
- 29b Sramek JJ, Frackiewicz EJ, Cutler NR. Expert Opin. Invest. Drugs 2000; 9: 2393
- 29c Lilienfeld S. CNS Drug Rev. 2002; 8: 159
- 29d Heinrich M, Teoh HL. J. Ethnopharmacol. 2004; 92: 147
- 30 Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, Ganorkar R, VanAlstine MA, Guo C, Cohen DJ, Bidlack JM. Bioorg. Med. Chem. Lett. 2009; 19: 2289
- 31a Furrow ME, Myers AG. J. Am. Chem. Soc. 2004; 126: 5436
- 31b Wu H, Thatcher LN, Bernard D, Parrish DA, Deschamps JR, Rice KC, MacKerell AD. Jr, Coop A. Org. Lett. 2005; 7: 2531
- 32 Trost BM, Tang W, Toste FD. J. Am. Chem. Soc. 2005; 127: 14785
- 33 Nagase H, Nemoto T, Matsubara A, Saito M, Yamamoto N, Osa Y, Hirayama S, Nakajima M, Nakao K, Mochizuki H, Fujii H. Bioorg. Med. Chem. Lett. 2010; 20: 6302