Ferruginine
Chemical compounds
From Wikipedia, the free encyclopedia
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 | |
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| Formula | C10H15NO |
| Molar mass | 165.236 g·mol−1 |
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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]
![{\displaystyle [\alpha ]_{D}^{19}=+37}](http://wikimedia.org/api/rest_v1/media/math/render/svg/6a8bee3110aaf0bdd1e614133960e944ff02af82)
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]
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]