Ferruginine

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Ferruginine
Ferruginine v2.svg
(+)-Ferruginine
Identifiers
  • 1-(8-Methyl-8-azabicyclo[3.2.1]oct-2-en-2-yl)ethanone
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C10H15NO
Molar mass 165.236 g·mol−1
3D model (JSmol)
  • CC(=O)C1=CCC2CCC1N2C
  • InChI=1S/C10H15NO/c1-7(12)9-5-3-8-4-6-10(9)11(8)2/h5,8,10H,3-4,6H2,1-2H3
  • Key:KQIRSQYBYQBMIG-UHFFFAOYSA-N

Ferruginine is a naturally occurring tropane alkaloid isolated from rainforest tree species such as Darlingia ferruginea and Darlingia darlingiana . [1] It acts as a nicotinic acetylcholine receptor (nAchR) agonist. [2] [3] Nicotinic agonists have been studied for their possible roles in cognitive enhancement and in the treatment of neurodegenerative diseases. [4]

Contents

Ferruginine is structurally related to methylecgonidine, but it contains a keto group in place of the ester. This substitution is advantageous because, unlike an ester, the keto group cannot be hydrolyzed into a carboxylic acid, a process that commonly leads to metabolic deactivation. (+)-Ferruginine is the natural enantiomer, with a reported specific rotation of ° (CHCl3). [5]

Ferruginine has long been a target in total synthesis research, with efforts directed at both its natural (+) and unnatural (−) enantiomers. [1] The natural (+)-ferruginine [2] [6] acts as a potent agonist of the nicotinic acetylcholine receptor (nAchR). [2] [7] By contrast, the unnatural (−)-enantiomer exhibits much lower affinity for nAchR. The distinctive structural features and pharmacological properties of ferruginine and its analogues have made them attractive scaffolds for synthetic studies. [8]

Pharmacology

The natural (+)-ferruginine exhibits high affinity for the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs), with Ki values reported as low as 3.7 nM in structure-activity studies, indicating strong potency and preference for this receptor subtype. [9] In contrast, the synthetic (−)-ferruginine shows moderate affinity for α4β2 nAChRs, with Ki values in the 94–120 nM range, and a weaker affinity (about 270 nM) for the α7 subtype. [10] Both enantiomers demonstrate significantly lower affinity for α7 nAChRs, but overall, (+)-ferruginine, the natural form, is pharmacologically distinguished by its high affinity and selectivity for central α4β2 nAChRs.

Synthesis

The synthesis of ferruginine has been accomplished through a variety of strategies, reflecting its importance as a structurally complex tropane alkaloid. One of the earliest and most efficient approaches employed a tandem cyclopropanation / Cope rearrangement sequence catalyzed by dirhodium(II) tetraoctanoate (Rh2(oct)4), which afforded racemic ferruginine in yields of up to 96%. [11]

Ferruginine synthesis Ferruginine synthesis.svg
Ferruginine synthesis

A related method based on a BF3-induced rearrangement of aziridino cyclopropanes achieved comparable yields (~90%). [12] Subsequent work has expanded the synthetic toolbox to include enantioselective routes from chiral pool precursors such as L-glutamic acid, [13] catalytic asymmetric dealkoxycarbonylation strategies using pig liver esterase (PLE), [5] and intramolecular iminium ion cyclizations. [13] Other formal and total syntheses have employed strategies such as palladium-catalyzed intramolecular aminocarbonylation, [14] radical-based methodologies, [15] and total syntheses of both (–)-cocaine and (–)-ferruginine via shared intermediates. [16] Together, these diverse approaches highlight ferruginine as a longstanding challenge in synthetic organic chemistry, with catalytic systems ranging from Rh2(oct)4 to Wilkinson's catalyst finding application in key synthetic steps. [17]

The unnatural enantiomer of ferruginine (see picture) was made from natural cocaine. [5] [18] In the cited reference ( [5] ) it says (−)-ferruginine (cocaine isomer) was found to be an agonist for the nicotine acetylcholine receptor. [19] [10] [20] However there appears to be an underlying discrepancy in that according to John W. Daly, the (+)-enantiomer was 7600nM and the value for the (−)-enantiomer was 120nM. [21]

See also

References

  1. 1 2 Yin Z, He Y, Chiu P (November 2018). "Application of (4+3) cycloaddition strategies in the synthesis of natural products". Chemical Society Reviews. 47 (23): 8881–8924. doi:10.1039/c8cs00532j. PMID   30394457.
  2. 1 2 3 Daly JW (June 2005). "Nicotinic agonists, antagonists, and modulators from natural sources". Cellular and Molecular Neurobiology. 25 (3–4): 513–552. doi:10.1007/s10571-005-3968-4. PMC   11529529 . PMID   16075378.
  3. ↑ Seifert S, Stehl A, Tilotta MC, Gündisch D, Seitz G (June 2004). "Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies". Die Pharmazie. 59 (6): 427–434. PMID   15248455.
  4. ↑ Crestini A, Carbone E, Rivabene R, Ancidoni A, Rosa P, Tata AM, et al. (January 2024). "A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia". Cells. 13 (3): 237. doi: 10.3390/cells13030237 . PMC   10854606 . PMID   38334629.
  5. 1 2 3 4 Katoh T, Kakiya K, Nakai T, Nakamura S, Nishide K, Node M (October 2002). "A new divergent synthesis of (+)- and (−)-ferruginine utilizing PLE-catalyzed asymmetric dealkoxycarbonylation". Tetrahedron: Asymmetry. 13 (21): 2351–2358. doi:10.1016/S0957-4166(02)00657-2.
  6. ↑ Gohlke H, Gündisch D, Schwarz S, Seitz G, Tilotta MC, Wegge T (February 2002). "Synthesis and nicotinic binding studies on enantiopure diazine analogues of the novel (2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene UB-165". Journal of Medicinal Chemistry. 45 (5): 1064–1072. doi:10.1021/jm010936y. PMID   11855986.
  7. ↑ Seifert S, Stehl A, Tilotta MC, Gündisch D, Seitz G (June 2004). "Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies". Die Pharmazie. 59 (6): 427–434. PMID   15248455.
  8. ↑ Pollini GP, Benetti S, De Risi C, Zanirato V (June 2006). "Synthetic approaches to enantiomerically pure 8-azabicyclo[3.2.1]octane derivatives". Chemical Reviews. 106 (6): 2434–2454. doi:10.1021/cr050995+. PMID   16771455.
  9. ↑ Tilotta MC. Novel Nicotinic Acetylcholine Receptor Ligands based on Cytisine, Ferruginine, Anatoxin-a and Choline (Ph.D. thesis). Universitäts-und Landesbibliothek Bonn.
  10. 1 2 Gündisch D, Harms K, Schwarz S, Seitz G, Stubbs MT, Wegge T (October 2001). "Synthesis and evaluation of diazine containing bioisosteres of (-)-ferruginine as ligands for nicotinic acetylcholine receptors". Bioorganic & Medicinal Chemistry. 9 (10): 2683–91. doi:10.1016/s0968-0896(01)00188-2. PMID   11557356.
  11. ↑ Davies HM, Saikali E, Young WB (September 1991). "Synthesis of (.+-.)-ferruginine and (.+-.)-anhydroecgonine methyl-ester by a tandem cyclopropanation/Cope rearrangement". The Journal of Organic Chemistry. 56 (19): 5696–5700. doi:10.1021/jo00019a044.
  12. ↑ Jonsson SY, Löfström CM, Bäckvall JE (December 2000). "BF(3)-Induced rearrangement of aziridino cyclopropanes derived from 2-phenylsulfonyl 1,3-dienes. Application to the total synthesis of (+/-)-ferruginine". The Journal of Organic Chemistry. 65 (25): 8454–8457. doi:10.1021/jo001147b. PMID   11112563.
  13. 1 2 Hernández AS, Thaler A, Castells J, Rapoport H (1 January 1996). "Enantiospecific Synthesis of (+)- and (−)-Ferruginine from l -Glutamic Acid. Synthesis of Tropanes via Intramolecular Iminium Ion Cyclization". The Journal of Organic Chemistry. 61 (1): 314–323. doi:10.1021/jo9515081.
  14. ↑ Ham WH, Jung YH, Lee K, Oh CY, Lee KY (May 1997). "A formal total synthesis of (±)-ferruginine by Pd-catalyzed intramolecular aminocarbonylation". Tetrahedron Letters. 38 (18): 3247–3248. doi:10.1016/S0040-4039(97)00575-3.
  15. ↑ Piccardi R, Renaud P (October 2007). "Formal Synthesis of (+)- and (–)-Ferruginine". European Journal of Organic Chemistry. 2007 (28): 4752–4757. doi:10.1002/ejoc.200700427.
  16. ↑ Cheng G, Wang X, Zhu R, Shao C, Xu J, Hu Y (April 2011). "Total synthesis of (-)-cocaine and (-)-ferruginine". The Journal of Organic Chemistry. 76 (8): 2694–2700. doi:10.1021/jo200069m. PMID   21391709.
  17. ↑ Doyle MP, Davies H, Manning JR (15 April 2006). "Dirhodium(II) Tetraoctanoate". Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons. doi:10.1002/047084289X.rd462.pub2. ISBN   0-471-93623-5.
  18. 1 2 3 Bick I, Gillard J, Leow H (1979). "Alkaloids of Darlingia ferruginea". Australian Journal of Chemistry. 32 (11): 2537. doi:10.1071/CH9792537.
  19. ↑ Herken H, Aktories K, Hucho F (1992). "Selective Neurotoxicity". In Swanson KL, Albuquerque EX (eds.). Handbook of experimental pharmacology. Vol. 102. Springer. p. 620–621.
  20. ↑ Gündisch D, Kämpchen T, Schwarz S, Seitz G, Siegl J, Wegge T (January 2002). "Syntheses and evaluation of pyridazine and pyrimidine containing bioisosteres of (+/-)-pyrido[3.4-b]homotropane and pyrido-[3.4-b]tropane as novel nAChR ligands". Bioorganic & Medicinal Chemistry. 10 (1): 1–9. doi:10.1016/S0968-0896(01)00258-9. PMID   11738601.
  21. ↑ Daly JW (June 2005). "Nicotinic Agonists, Antagonists, and Modulators From Natural Sources". Cellular and Molecular Neurobiology. 25 (3–4): 513–552. doi:10.1007/s10571-005-3968-4. PMC   11529529 .
  22. ↑ Davies HM, Saikali E, Huby NJ, Gilliatt VJ, Matasi JJ, Sexton T, et al. (April 1994). "Synthesis of 2 beta-acyl-3 beta-aryl-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites in rat striatum and frontal cortex". Journal of Medicinal Chemistry. 37 (9): 1262–1268. doi:10.1021/jm00035a005. PMID   8176704.
  23. ↑ Davies HM, Gilliatt V, Kuhn LA, Saikali E, Ren P, Hammond PS, et al. (May 2001). "Synthesis of 2beta-acyl-3beta-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites". Journal of Medicinal Chemistry. 44 (10): 1509–1515. doi:10.1021/jm000363+. PMID   11334561.
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