Chemistry:Ferruginine

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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]

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 [α]D19=+37° (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

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. ↑ 1.0 1.1 "Application of (4+3) cycloaddition strategies in the synthesis of natural products". Chemical Society Reviews 47 (23): 8881–8924. November 2018. doi:10.1039/c8cs00532j. PMID 30394457. 
  2. ↑ 2.0 2.1 2.2 "Nicotinic agonists, antagonists, and modulators from natural sources". Cellular and Molecular Neurobiology 25 (3–4): 513–552. June 2005. doi:10.1007/s10571-005-3968-4. PMID 16075378. 
  3. ↑ "Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies". Die Pharmazie 59 (6): 427–434. June 2004. PMID 15248455. 
  4. ↑ "A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia". Cells 13 (3): 237. January 2024. doi:10.3390/cells13030237. PMID 38334629. 
  5. ↑ 5.0 5.1 5.2 5.3 "A new divergent synthesis of (+)- and (−)-ferruginine utilizing PLE-catalyzed asymmetric dealkoxycarbonylation". Tetrahedron: Asymmetry 13 (21): 2351–2358. October 2002. doi:10.1016/S0957-4166(02)00657-2. 
  6. ↑ "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. February 2002. doi:10.1021/jm010936y. PMID 11855986. 
  7. ↑ "Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies". Die Pharmazie 59 (6): 427–434. June 2004. PMID 15248455. 
  8. ↑ "Synthetic approaches to enantiomerically pure 8-azabicyclo[3.2.1]octane derivatives". Chemical Reviews 106 (6): 2434–2454. June 2006. 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. ↑ 10.0 10.1 "Synthesis and evaluation of diazine containing bioisosteres of (-)-ferruginine as ligands for nicotinic acetylcholine receptors". Bioorganic & Medicinal Chemistry 9 (10): 2683–91. October 2001. doi:10.1016/s0968-0896(01)00188-2. PMID 11557356. 
  11. ↑ "Synthesis of (.+-.)-ferruginine and (.+-.)-anhydroecgonine methyl-ester by a tandem cyclopropanation/Cope rearrangement". The Journal of Organic Chemistry 56 (19): 5696–5700. September 1991. doi:10.1021/jo00019a044. 
  12. ↑ "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. December 2000. doi:10.1021/jo001147b. PMID 11112563. 
  13. ↑ 13.0 13.1 "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. 1 January 1996. doi:10.1021/jo9515081. 
  14. ↑ "A formal total synthesis of (±)-ferruginine by Pd-catalyzed intramolecular aminocarbonylation". Tetrahedron Letters 38 (18): 3247–3248. May 1997. doi:10.1016/S0040-4039(97)00575-3. 
  15. ↑ "Formal Synthesis of (+)- and (–)-Ferruginine". European Journal of Organic Chemistry 2007 (28): 4752–4757. October 2007. doi:10.1002/ejoc.200700427. 
  16. ↑ "Total synthesis of (-)-cocaine and (-)-ferruginine". The Journal of Organic Chemistry 76 (8): 2694–2700. April 2011. doi:10.1021/jo200069m. PMID 21391709. 
  17. ↑ "Dirhodium(II) Tetraoctanoate". Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons. 15 April 2006. doi:10.1002/047084289X.rd462.pub2. ISBN 0-471-93623-5. https://onlinelibrary.wiley.com/doi/10.1002/047084289X.rd462.pub2. 
  18. ↑ 18.0 18.1 18.2 "Alkaloids of Darlingia ferruginea". Australian Journal of Chemistry 32 (11): 2537. 1979. doi:10.1071/CH9792537. 
  19. ↑ "Selective Neurotoxicity". Handbook of experimental pharmacology. 102. Springer. 1992. p. 620–621. 
  20. ↑ "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. January 2002. doi:10.1016/S0968-0896(01)00258-9. PMID 11738601. 
  21. ↑ "Nicotinic Agonists, Antagonists, and Modulators From Natural Sources". Cellular and Molecular Neurobiology 25 (3–4): 513–552. June 2005. doi:10.1007/s10571-005-3968-4. 
  22. ↑ "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. April 1994. doi:10.1021/jm00035a005. PMID 8176704. 
  23. ↑ "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. May 2001. doi:10.1021/jm000363+. PMID 11334561. 



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