Analgesic alkaloid epibatidine

The analgesic alkaloid epibatidine (57) continues to receive much synthetic interest <96JOC4600, 96T11053, 96TL7845> and Tmdell has devised a novel approach to the synthesis of this alkaloid, the key step of which utilizes a [4 + 2] cycloaddition of methyl 3-bromopropiolate with A -Boc-pyrrole (55) to afford the 7-azabicyclo[2.2.1]heptane skeleton 56 characteristic of this alkaloid <96JOC7189>. 

An alkaloid, epibatidin (173), has been isolated from skin of the Ecuadorian frog Epipedobates tricolor which exhibited a 200-fold potency compared with morphine as an analgesic in the Straub-tail test. Extracts from 750 frogs provided only 1 mg of the Straub-tail alkaloid. The researchers had to wait for a decade until more sensitive instruments... 

These compounds can then be readily converted into 7-azabicyclo[2.2.1]heptan-2-ones of type 1090 (Scheme 212), which have been shown to be useful precursors for the synthesis of the novel alkaloid epibatidine <1996JOC7189>. Epibatidine has been found to be 200-400 times more potent than morphine as an analgesic, and more importantly should prove to be useful for the preparation of its analogs with reduced toxicity. The approach with phenyl 1,2-propadienyl sulfone 1091 (R = S02Ph, R = H) proved to be more efficient and high yielding than the ester sequence and provided azabicycle 1090 in 19% overall yield (four steps). 

To extend this methodology, Diels-Alder reactions of several (Z)-4-arylidene (heteroarylidene)-2-phenyl-5(47/)-oxazolones with butadiene, 2,3-dimethylbuta-diene, cyclopentadiene and Danishefsky s diene have been studied. This work demonstrated that the products depended on the nature of the aromatic ring and the diene used. " An interesting application of this methodology is the synthesis of racemic epibatidine 729, a new alkaloid with a 7-azabicyclo[2.2.1]heptane skeleton that has proven to be a very potent analgesic. Preparation of 729 began with the Diels-Alder adduct 726 obtained from (Z)-4-[5 -(2 -chloropyridyhnethylene)]-2-... 

Daly, J.W. GarrafTo, H.M. Spande, T.F. Decker, M.W. Sullivan, J.P. Williams, M. (2000) Alkaloids from frog skin the discovery of epibatidine and the potoitial for developing novel non-opioid analgesics. Nat. Prod. Rep., 17, 131-5. 

A Diels-Alder reaction of N-(carbomethoxy)pyrrole and phenylsulfonyl 6-chloro-3-pyridyI acetylene was used similarly in a total synthesis of epibatidine, an alkaloid heralded for its high analgesic potency [536]. 

This technique has been applied to the synthesis of epibatidine, an alkaloid which exhibits nonopiod analgesic activity 200-500 times greater than that of morphine. Boc-protected 2,5-bis(trimethylsilyl)pyrrolidine has been chosen as the precursor of the azomethine ylid and cis- and rra .v-ethyl-(6-chloro-3-piperidyl )-2-propenoates as the dipolarophiles.448,449... 

Several note vorthy halogenated terrestrial alkaloids are known, with epibatidine (104) at the top of the list [88]. This apparent frog Epipedobates tricolor) metabolite has powerful analgesic activity [89] and an intensive search is underway for a clinically useful drug [90]. A few chlorinated plant alkaloids have also been discovered. Romucosine F (lOS) is present in Annora purpurea, a South American bushy tree [91], and the closely related romucosine B (106) is found in the stems of RolUnia mucosa [92]. The furoquinoline alkaloid chlorodesnkolbisine (107) was isolated from the African folk medicine plant Teclea nobilis [93]. The authors of this latter study provide convincing evidence that 107 is not an isolation artifact (e.g. from the corresponding epoxide with HCl). 

Epibatidine, an alkaloid discovered in 1974, has attracted considerable interest because it appears to be the first compound exhibiting analgesic activity as a selective and potent nicotinic receptor agonist. Campillo et al.207 performed a theoretical study on the conformational profile of epibatidine and its protonated form (Figure 24) using molecular mechanics, semi-empirical and ab... 

Epibatidine, exo-2-(6-chloro-3-pyridile-7-azabicyclo[2.2. 1]heptane, the structure of which is shown below, is an alkaloid extracted from the skin of the Ecuadorian frog, Epipedobates tricolor. This alkaloid has been reported to possess potent, non-opioid, analgesic properties. In order to investigate the physiological properties in more detail Watt et al. [2], synthesized Ae material and also developed an analytical procedure for identifying and measuring the enantiomers present in the natural product. 

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