Ferruginine

A divergent synthesis of tropane alkaloid ferruginine was reported by Node and coworkers [59]. The P-ketoester intermediate was prepared by a novel PLE-catalyzed asymmetric dealkoxycarbonylation (hydrolysis followed by a decarboxylation) of a symmetric tropinone-type diester (Figure 6.12). Dimethyl sulfoxide was added to the phosphate buffer pH 8 (1 9) to reduce the activity of PLE and prevent over-deal-koxycarbonylation leading to tropinone. 

Cleavage of 5-(3-phenyl-hexahydro-pyrrolo[2,l- ]oxazol-5-yl)-pent-3-en-2-one 195, when conducted in methanol with HC1 gas, produced compounds 196 and 197 in an 80/20 ratio, or after treatment with sulfuric acid in methanol at 60 °C afforded 198 as a single isomer (Scheme 26). Compound 198 was used for the total synthesis of the potent neurotoxic (-F)-ferruginine <1997JOC6704>. 

An enantiospecific synthesis of the potent anti-Alzheimer s agent (-t-)-ferruginine 1 and two enantiospecific syntheses of the potent anti-Alzheimer s agent anatoxin-a 2 were submitted essentially simultaneously earlier this year. In each case, the starting material used was the inexpensive pyroglutamic acid 3, and in each case the synthesis depended on Ru-catalyzed alkyne-alkene metathesis. 

Until recently, anatoxin-a was the only naturally occmring alkaloid possessing the 9-azabicy-clo[4.2.1]nonane ring skeleton, in contrast with the many examples of the similar 8-azabicy-clo[3.2.1]octane ring systems found in the diverse and widely distributed atropine alkaloids (i.e., ferruginine and cocaine). As a result of the combination of its biological potency and its rare structure,... 

In fact, the enantiospecific syntheses of the two potent anti-Alzheimer s agents like (+)-ferruginine (Aggarwal et al. 2004), a tropane ring system, and two enantiospecific syntheses of the anatoxin-a, were submitted essentially simultaneously at the beginning of 2004 (Mori et al. 2004 Brermeman and... 

A pyridazine-containing bioisostere of (-)-ferruginine was obtained via the coupling of triflate 159 with 4-(tributylstannyl)pyridazine (156) [71]. Several reaction conditions were tried to optimize the yield of this reaction. The best results were obtained using 10 mol% Pd(PhCN)2Cl2, 20 mol% Ph. As. and 20 mol% Cul in combination with three equivalents of LiCI in V-mcthyl pyr roll done. Removal of the carbamate group of 160 finally afforded the bioisostere of (-)-ferruginine (161). 

Ferrugine, 3a-benzyloxy-2a-hydroxybenzyltropane, darlingine, ferruginine, 2-methylbellendine... 

Ring contraction. The process is required to synthesize (+)-ferruginine based on a route starting from a chromium-promoted [6+2]photocycloaddition of azepines. The proper bridged heterobicyclic system evolves from a TTN oxidation. 

Davies has reported the synthesis of enantiomerically enriched tropanes 42 by the rhodium(II) octanaote catalyzed reaction of various N-Boc pyrroles 40 with vinyldiazomethanes 41 bearing chiral auxiliaries <97JOC1095, 97AA107>. This overall 3+4 annulation occurs by a tandem cyclopropanatlon/Cope rearrangement and was applied by the author to the synthesis of (-)-anhydroecgonine methyl ester and (-)-ferruginine. 

The synthetic utility of this chemistry was highlighted by short syntheses of various biologically interesting tropanes (Scheme 36). T vo natural products, ferruginine (98) and anhydroecgonine methyl ester (99), have been prepared by selectively hydrogenating the appropriate [3+4] aimulation product followed by ]V-deprotection and iV-methylation. A number of 4P-aryl-3p-propanoyl tropanes, such... 

Backvall and co-workers used the Blum reaction in the total synthesis of ferruginine (23)." Epoxide 21 was opened with sodium azide and the resultant azido-alcohol was reduced and cyclized with triphenylphosphine in good yield to give aziridine 22. Intermediate 22 was eventually processed to ferruginine (23). 

Recently, Ham and co-workers exploited the intramolecular aminocarbonylation in the synthesis of the tropane alkaloids rac-ferruginineand rac-anatoxin (Scheme 30). In the synthesis of rac-ferruginine the precursor for the aminocarbonylation is easily prepared in three steps from 4-cycIoheptenone. 

Numerous other alkaloids from natural origin are known ligands at nAChRs, such as the tropane alkaloid ferruginine (and several synthetic derivatives) [146,148,149], although there are limited data on their therapeutic potential in neurodegenerative diseases. Other alkaloids include the quinolizidine alkaloid C54isine (36) (occurs in... 

Giindisch D, Harms K, Schwarz S, Seitz G, Stubbs MT, Wegge T (2001) Synthesis and evaluation of diazine containing bioisosteres of (—)-ferruginine as ligands for nicotinic acetylcholine receptors. Bioorg Med Chem 9 2683-2691... 

Other nucleophiles can also be used to attack the T -alkene palladium complexes. For instance, a nitrogen nucleophile was used in a transannular reaction to give a known precursor 6.103 to ferruginine (Scheme 6.34).5i The a a-stereochemistry in the nucleophilic attack is translated into the trans disposition of the nitrogen and ester groups in the product. 

V.K. A arwal, C.I. Astle, M. Rogers-Evans, A concise asymmetric route to the bridged bicyclic tro-pane alkaloid ferruginine using enyne ring-dosing metathesis, Org. Lett. 6 (9) (2004) 1469-1471. 

ThaUium(ni) has been used in the ring contraction of seven-membered ring substrates, such as 52. This rearrangement is diastereoselective and was used in the synthesis of (+)-ferruginine 54 (Scheme 18.14) and P-cedrene. ... 

---