Six-step total syntheses of (−)-galanthamine and (−)-N-norgalanthamine
Nan Hu A B , Yu-Tao He
A B , Ping Lan A B , Martin G. Banwell A B C * and Lorenzo V. White A B *
+ Author Affiliations
- Author Affiliations
A Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong, 510632, China.
B College of Pharmacy, Jinan University, Guangzhou, 510632, China.
C Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, 524023 China.
* Correspondence to: mgbanwell@jnu.edu.cn, Lorenzo.white1312@gmail.com
Handling Editor: Martyn Coles
Australian Journal of Chemistry 75(12) 974-982 https://doi.org/10.1071/CH22183
Submitted: 21 August 2022 Accepted: 23 September 2022 Published: 16 December 2022
© 2022 The Author(s) (or their employer(s)). Published by CSIRO Publishing.
Abstract
The Amaryllidaceae alkaloid (−)-galanthamine (1) is a reversible, competitive acetylcholinesterase inhibitor deployed clinically to treat the dementia associated with Alzheimer’s disease. Here, we describe a six-step synthesis of this natural product from simple, readily accessible starting materials. Enantioselective 1,2-reduction, Mitsunobu coupling, Heck cyclization and diastereoselective allylic oxidation reactions are used in our approach, which provides the shortest synthetic route to compound 1 reported to date. A simple modification to the closing stages of the sequence allows equally facile access to (−)-N-norgalanthamine (2), a compound with a range of distinctive biological properties. The concise and operationally simple synthetic protocols reported here could obviate the need to manipulate naturally sourced galanthamine in the pursuit of analogues required for pharmacological studies.
Keywords: acetylcholinesterase, allylic oxidation, Alzheimer’s disease, galanthamine, Heck reaction, Mitsunobu coupling, N-norgalanthamine, total synthesis.
References
[1] NF Proskurnina, LY Areshknina, J Chem Gen USSR 1947, 17, 1216.(Chem. Abstr. 1948, 42, 1595h)[2] NF Proskurnina, AP Yakovieva, J Chem Gen USSR 1952, 22, 1899.(Chem. Abstr. 1953, 47, 6959c)
[3] For an informative history on the development of galanthamine as a clinical agent, see: HAM Mucke, The case of galantamine: repurposing and late blooming of a cholinergic drug. Future Sci OA 2015, 1, FSO73.
| The case of galantamine: repurposing and late blooming of a cholinergic drug.Crossref | GoogleScholarGoogle Scholar |
[4] RL Irwin, HJ Smith, Cholinesterase inhibition by galanthamine and lycoramine. Biochem Pharmacol 1960, 3, 147.
| Cholinesterase inhibition by galanthamine and lycoramine.Crossref | GoogleScholarGoogle Scholar |
[5] (a) See, for example, L Marco, M do Carmo Carreiras, Galanthamine, a natural product for the treatment of Alzheimers disease. Recent Pat CNS Drug Discov 2006, 1, 105.
| Galanthamine, a natural product for the treatment of Alzheimers disease.Crossref | GoogleScholarGoogle Scholar |
(b) J Contelles, M do Carmo Carreiras, C Rodriguez, M Villarroya, AG Garcia, Synthesis and pharmacology of galantamine. Chem Rev 2006, 106, 116.
| Synthesis and pharmacology of galantamine.Crossref | GoogleScholarGoogle Scholar |
(c) G Marucci, M Buccioni, D Dal Ben, C Lambertucci, R Volpini, F Amenta, Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 2021, 190, 108532.
| Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease.Crossref | GoogleScholarGoogle Scholar |
[6] S See, for example, Berkov, L Georgieva, V Kondakova, A Atanassov, F Viladomat, J Bastida, C Codina, Plant sources of galanthamine: phytochemical and biotechnological aspects. Biotechnol Biotechnol Equip 2009, 23, 1170.
| Plant sources of galanthamine: phytochemical and biotechnological aspects.Crossref | GoogleScholarGoogle Scholar |
[7] B Küenburg, L Czollner, J Fröhlich, U Jordis, Development of a pilot scale process for the anti-Alzheimer drug (−)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion. Org Process Res Dev 1999, 3, 425.
| Development of a pilot scale process for the anti-Alzheimer drug (−)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion.Crossref | GoogleScholarGoogle Scholar |
[8] (a) DHR Barton, GW Kirby, The synthesis of galanthamine. Proc Chem Soc 1960, 392.
| The synthesis of galanthamine.Crossref | GoogleScholarGoogle Scholar |
(b) DHR Barton, GW Kirby, Phenol oxidation and biosynthesis. Part V. The synthesis of galanthamine. J Chem Soc 1962, 806.
| Phenol oxidation and biosynthesis. Part V. The synthesis of galanthamine.Crossref | GoogleScholarGoogle Scholar |
[9] U Rinner, C Dank, T Hudlicky, Galanthamine. Targets Heterocycl Syst 2016, 20, 283.
| Galanthamine.Crossref | GoogleScholarGoogle Scholar |
[10] (a) Y Feng, Z-X Yu, Formal synthesis of (±)-galanthamine and (±)-lycoramine using Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-ene–vinylcyclopropane and CO. J Org Chem 2015, 80, 1952.
| Formal synthesis of (±)-galanthamine and (±)-lycoramine using Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-ene–vinylcyclopropane and CO.Crossref | GoogleScholarGoogle Scholar |
(b) C-H Liu, Z-X Yu, Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO: reaction development and application to the formal synthesis of (−)-galanthamine. Org Biomol Chem 2016, 14, 5945.
| Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO: reaction development and application to the formal synthesis of (−)-galanthamine.Crossref | GoogleScholarGoogle Scholar |
(c) D Dong, B Zhou, J Ren, L Lu, G Lu, P Hu, B-B Zeng, Short and efficient synthesis of Guillou's Galanthamine intermediate. Tetrahedron 2017, 73, 4719.
| Short and efficient synthesis of Guillou's Galanthamine intermediate.Crossref | GoogleScholarGoogle Scholar |
(d) N Yamamoto, T Okada, Y Harada, N Kutsumura, S Imaide, T Saitoh, H Fujii, H Nagase, The application of a specific morphinan template to the synthesis of galanthamine. Tetrahedron 2017, 73, 5751.
| The application of a specific morphinan template to the synthesis of galanthamine.Crossref | GoogleScholarGoogle Scholar |
(e) Q Zhang, F-M Zhang, C-S Zhang, S-Z Liu, J-M Tain, S-H Wang, X-M Zhang, Y-Q Tu, Catalytic asymmetric total syntheses of (−)-galanthamine and (−)-lycoramine. J Org Chem 2019, 84, 12664.
| Catalytic asymmetric total syntheses of (−)-galanthamine and (−)-lycoramine.Crossref | GoogleScholarGoogle Scholar |
(f) IR Miller, NJ McLean, GAI Moustafa, V Ajavakom, SC Kemp, RK Bellingham, NP Camp, RCD Brown, Transition-metal-mediated chemo- and stereoselective total synthesis of (−)-galanthamine. J Org Chem 2022, 87, 1325.
| Transition-metal-mediated chemo- and stereoselective total synthesis of (−)-galanthamine.Crossref | GoogleScholarGoogle Scholar |
(g) S Majumder, A Yada, S Pal, A Khatua, A Bisai, Asymmetric total syntheses of (−)-lycoramine, (−)-lycoraminone, (−)-narwedine, and (−)-galanthamine. J Org Chem 2022, 87, 7786.
| Asymmetric total syntheses of (−)-lycoramine, (−)-lycoraminone, (−)-narwedine, and (−)-galanthamine.Crossref | GoogleScholarGoogle Scholar |
(h) Z Xiong, F Weidlich, C Sanchez, T Wirth, Biomimetic total synthesis of (−)-galanthamine via intramolecular anodic aryl–phenol coupling. Org Biomol Chem 2022, 20, 4123. and references cited therein
| Biomimetic total synthesis of (−)-galanthamine via intramolecular anodic aryl–phenol coupling.Crossref | GoogleScholarGoogle Scholar |
[11] (a) MG Banwell, X Ma, OP Karunaratne, AC Wills, A first generation chemoenzymatic synthesis of (+)-galanthamine. Aust J Chem 2010, 63, 1437.
| A first generation chemoenzymatic synthesis of (+)-galanthamine.Crossref | GoogleScholarGoogle Scholar |
(b) P Lan, CJ Jackson, MG Banwell, AC Willis, Access to pyridyl-substituted 1,3,5-triazines from 4H-pyrido[1,3]oxazin-4-ones via a cyclocondensation process. J Org Chem 2014, 79, 6579.
| Access to pyridyl-substituted 1,3,5-triazines from 4H-pyrido[1,3]oxazin-4-ones via a cyclocondensation process.Crossref | GoogleScholarGoogle Scholar |
(c) J Nugent, E Matoušová, MG Banwell, A total synthesis of galanthamine involving de novo construction of the aromatic C-ring. Eur J Org Chem 2015, 3771.
| A total synthesis of galanthamine involving de novo construction of the aromatic C-ring.Crossref | GoogleScholarGoogle Scholar |
(d) J Nugent, MG Banwell, An eleven-step synthesis of galanthamine from commercially available materials. Eur J Org Chem 2016, 2016, 5862.
| An eleven-step synthesis of galanthamine from commercially available materials.Crossref | GoogleScholarGoogle Scholar |
(e) JN Buckler, ES Taher, NJ Fraser, AC Willis, PD Carr, CJ Jackson, MG Banwell, The synthesis of certain derivatives and analogues of (−)- and (+)-galanthamine and an assessment of their capacities to inhibit acetylcholine esterase. J Org Chem 2017, 82, 7869.
| The synthesis of certain derivatives and analogues of (−)- and (+)-galanthamine and an assessment of their capacities to inhibit acetylcholine esterase.Crossref | GoogleScholarGoogle Scholar |
(f) Also, see: MG Banwell, J Buckler, CJ Jackson, P Lan, X Ma, E Matoušová, J Nugent, Chapter 2 ‐ Devising New Syntheses of the Alkaloid Galanthamine, a Potent and Clinically Deployed Inhibitor of Acetylcholine Esterase. In Harmata M, editor. Strategies and Tactics in Organic Synthesis. Academic Press 2015, 11, 29.
| Chapter 2 ‐ Devising New Syntheses of the Alkaloid Galanthamine, a Potent and Clinically Deployed Inhibitor of Acetylcholine Esterase. In Harmata M, editor. Strategies and Tactics in Organic Synthesis. Academic PressCrossref | GoogleScholarGoogle Scholar |
[12] (a) S Kobayashi, H Ishikawa, M Kihara, T Shing, S Uyeo, Isolation of N-demethylgalanthamine from the bulbs of Crinum asiaticum L. var. japanicum Baker (Amaryllidaceae). Chem Pharm Bull 1976, 24, 2553.
| Isolation of N-demethylgalanthamine from the bulbs of Crinum asiaticum L. var. japanicum Baker (Amaryllidaceae).Crossref | GoogleScholarGoogle Scholar |
(b) J Bastida, F Viladomat, S Bergoñon, JM Fernandez, C Codina, M Rubiralta, J-C Quirion, Alkaloids from Narcissus leonensis. Phytochemistry 1993, 34, 1656.
| Alkaloids from Narcissus leonensis.Crossref | GoogleScholarGoogle Scholar |
(c) H-S Yoon, J-I Kang, SM Kim, A Ko, Y-S Koh, J-W Hyun, S-P Yoon, MJ Ahn, YH Kim, J-H Kang, E-S Yoo, H-K Kang, Norgalanthamine stimulates proliferation of dermal papilla cells via anagen-activating signaling pathways. Biol Pharm Bull 2019, 42, 139.and references cited there-in.
| Norgalanthamine stimulates proliferation of dermal papilla cells via anagen-activating signaling pathways.Crossref | GoogleScholarGoogle Scholar |
[13] S Eagon, C Delieto, WJ McDonald, D Haddenham, J Saavedra, J Kim, B Singaram, Mild and expedient asymmetric reductions of α,β-unsaturated alkenyl and alkynyl ketones by TarB-NO2 and mechanistic investigations of ketone reduction. J Org Chem 2010, 75, 7717.
| Mild and expedient asymmetric reductions of α,β-unsaturated alkenyl and alkynyl ketones by TarB-NO2 and mechanistic investigations of ketone reduction.Crossref | GoogleScholarGoogle Scholar |
[14] S Chanthamath, DT Nguyen, K Shibatomi, S Iwasa, Highly enantioselective synthesis of cyclopropylamine derivatives via Ru(II)-pheox-catalyzed direct asymmetric cyclopropanation of vinylcarbamates. Org Lett 2013, 15, 772.
| Highly enantioselective synthesis of cyclopropylamine derivatives via Ru(II)-pheox-catalyzed direct asymmetric cyclopropanation of vinylcarbamates.Crossref | GoogleScholarGoogle Scholar |
[15] (a) CR Johnson, MP Braun, A two-step, three-component synthesis of PGE1: utilization of .alpha.-iodo enones in Pd(0)-catalyzed cross-couplings of organoboranes. J Am Chem Soc 1993, 115, 11014.
| A two-step, three-component synthesis of PGE1: utilization of .alpha.-iodo enones in Pd(0)-catalyzed cross-couplings of organoboranes.Crossref | GoogleScholarGoogle Scholar |
(b) AB Dounay, PG Humphreys, LE Overman, AD Wrobleski, Total synthesis of the Strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck−iminium ion cyclization. J Am Chem Soc 2008, 130, 5368.
| Total synthesis of the Strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck−iminium ion cyclization.Crossref | GoogleScholarGoogle Scholar |
[16] (a) S Fletcher, The Mitsunobu reaction in the 21st Century. Org Chem Front 2015, 2, 739.
| The Mitsunobu reaction in the 21st Century.Crossref | GoogleScholarGoogle Scholar |
(b) For a closely related process, see: LV White, N Hu, Y-T He, MG Banwell, P Lan, Expeditious access to morphinans by chemical synthesis. Angew Chem Int Ed 2022, 134, e202203186.
| Expeditious access to morphinans by chemical synthesis.Crossref | GoogleScholarGoogle Scholar |
[17] KM Markovich, V Tantishaiyakul, A Hamada, DD Miller, KJ Romstedt, G Shams, Y Shin, PF Fraundorfer, K Doyle, DR Feller, Synthesis of halogenated trimetoquinol derivatives and evaluation of their .beta.-agonist and thromboxane A2 (TXA2) antagonist activities. J Med Chem 1992, 35, 466.
| Synthesis of halogenated trimetoquinol derivatives and evaluation of their .beta.-agonist and thromboxane A2 (TXA2) antagonist activities.Crossref | GoogleScholarGoogle Scholar |
[18] PJ Parsons, MD Charles, DM Harvey, LR Sumoreeah, A Shell, G Spoors, AL Gill, S Smith, A general approach to the galanthamine ring system. Tetrahedron Lett 2001, 42, 2209.
| A general approach to the galanthamine ring system.Crossref | GoogleScholarGoogle Scholar |
[19] H Fujioka, Y Sawama, N Kotoku, T Ohnaka, T Okitsu, N Murata, O Kubo, R Li, Y Kita, Concise asymmetric total synthesis of scyphostatin, a potent inhibitor of neutral sphingomyelinase. Chem Eur J 2007, 13, 10225.
| Concise asymmetric total synthesis of scyphostatin, a potent inhibitor of neutral sphingomyelinase.Crossref | GoogleScholarGoogle Scholar |
[20] BM Trost, W Tang, An efficient enantioselective synthesis of (−)-galanthamine. Angew Chem Int Ed 2002, 41, 2795.
| An efficient enantioselective synthesis of (−)-galanthamine.Crossref | GoogleScholarGoogle Scholar |
[21] LV White, MG Banwell, Conversion of the enzymatically derived (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol into enantiomerically pure compounds embodying the pentacyclic framework of vindoline. J Org Chem 2016, 81, 1617.
| Conversion of the enzymatically derived (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol into enantiomerically pure compounds embodying the pentacyclic framework of vindoline.Crossref | GoogleScholarGoogle Scholar |
[22] The use of intermediate 10 in this way represents an example of divergent total synthesis, see: L Li, Z Chen, X Zhang, Y Jia, Divergent strategy in natural product total synthesis. Chem Rev 2018, 118, 3752.
| Divergent strategy in natural product total synthesis.Crossref | GoogleScholarGoogle Scholar |
[23] A Mary, DZ Renko, C Guillou, C Thal, Selective N-demethylation of galanthamine to norgalanthamine via a non classical Polonovski reaction. Tetrahedron Lett 1997, 38, 5151.
| Selective N-demethylation of galanthamine to norgalanthamine via a non classical Polonovski reaction.Crossref | GoogleScholarGoogle Scholar |
[24] (a) See, for example, C Guillou, A Mary, DZ Renko, E Gras, C Thal, Potent acetylcholinesterase inhibitors: design, synthesis and structure–activity relationships of alkylene linked bis-galanthamine and galanthamine–galanthaminium salts. Bioorg Med Chem Lett 2000, 10, 637.
| Potent acetylcholinesterase inhibitors: design, synthesis and structure–activity relationships of alkylene linked bis-galanthamine and galanthamine–galanthaminium salts.Crossref | GoogleScholarGoogle Scholar |
(b) I Philipova, G Stavrakov, V Dimitrov, N Vassilev, Galantamine derivatives: Synthesis, NMR study, DFT calculations and application in asymmetric catalysis. J Mol Struct 2020, 1219, 128568.
| Galantamine derivatives: Synthesis, NMR study, DFT calculations and application in asymmetric catalysis.Crossref | GoogleScholarGoogle Scholar |
[25] See, for example, H Kimura, T Kawai, Y Hamashima, H Kawashima, K Miura, Y Nakaya, M Hirasawa, K Arimitsu, T Kajimoto, Y Ohmomo, M Ono, M Node, H Saji, Synthesis and evaluation of (−)- and (+)-[11C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging. Bioorg Med Chem 2014, 22, 285.See, for example,
| Synthesis and evaluation of (−)- and (+)-[11C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging.Crossref | GoogleScholarGoogle Scholar |
[26] (a) AS Hernández, JC Hodges, Solid-supported tert-alkoxycarbonylation reagents for anchoring of amines during solid phase organic synthesis. J Org Chem 1997, 62, 3153.
| Solid-supported tert-alkoxycarbonylation reagents for anchoring of amines during solid phase organic synthesis.Crossref | GoogleScholarGoogle Scholar |
(b) CY Ho, MJ Kukla, Carbamate linkers as latent N-methylamines in solid phase synthesis. Tetrahedron Lett 1997, 38, 2799.
| Carbamate linkers as latent N-methylamines in solid phase synthesis.Crossref | GoogleScholarGoogle Scholar |
[27] WC Still, M Kahn, A Mitra, Rapid chromatographic technique for preparative separations with moderate resolution. J Org Chem 1978, 43, 2923.
| Rapid chromatographic technique for preparative separations with moderate resolution.Crossref | GoogleScholarGoogle Scholar |
[28] Armarego WLF, Chai CLL. Purification of Laboratory Chemicals, 5th edn. Amsterdam: Elsevier Science; 2003.
[29] G Xu, J Wu, L Li, Y Lu, C Li, Total synthesis of (−)-daphnezomines A and B. J Am Chem Soc 2020, 142, 15240.
| Total synthesis of (−)-daphnezomines A and B.Crossref | GoogleScholarGoogle Scholar |
[30] AF Kassir, SS Ragab, TAM Nguyen, F Charnay-Pouget, R Guillot, M-C Scherrmann, T Boddaert, DJ Aitken, Synthetic access to all four stereoisomers of oxetin. J Org Chem 2016, 81, 9983.
| Synthetic access to all four stereoisomers of oxetin.Crossref | GoogleScholarGoogle Scholar |
[31] Purchased from Bide Pharmaceutical Company, China (Catalogue No.: BD8903‐0‐0.1g). CAS: 357‐70‐0, Purity: 99.23%, Batch: BGV593. While the provenance of this sample could not be determined with certainty, at the present time most suppliers of galanthamine in China obtain their marketed samples from plant sources.
[32] For a previous X-ray analysis of this compound, see: R Roques, JC Rossi, JP Declercq, G Germain, Structure du chlorhydrate de norgalanthamine. Acta Crystallogr B Struct Crystallogr Cryst Chem 1980, B36, 1589.
| Structure du chlorhydrate de norgalanthamine.Crossref | GoogleScholarGoogle Scholar |
[33] OV Dolomanov, LJ Bourhis, RJ Gildea, JAK Howard, H Puschmann, OLEX2: a complete structure solution, refinement and analysis program. J Appl Crystallogr 2009, 42, 339.
| OLEX2: a complete structure solution, refinement and analysis program.Crossref | GoogleScholarGoogle Scholar |
[34] GM Sheldrick, SHELXT - Integrated space-group and crystal-structure determination. Acta Crystallogr A Found Adv 2015, A71, 3.
| SHELXT - Integrated space-group and crystal-structure determination.Crossref | GoogleScholarGoogle Scholar |
[35] GM Sheldrick, Crystal structure refinement with SHELXL. Acta Crystallogr C Struct Chem 2015, C71, 3.
| Crystal structure refinement with SHELXL.Crossref | GoogleScholarGoogle Scholar |
