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T1 - Synthesis of (-)-epibatidine
This was published in the Journal of Organic Chemistry in July 1993, just 1 year after Daly had released the structure of epibatidine. The route consists of a 9 step synthesis, progressing via intermediates 2 to 10. The yields for individual steps are very high, and so overall the yield is just over 40%.
The fused ring epibatidine analogs 44 and 45 were synthesized as outlined in . 3-Pyridyne, generated by treating 4-triethylsilylpyridin-3-yl trifluoromethanesulfonate (50) with cesium fluoride in acetonitrile, was added to 7 to give 51. Catalytic hydrogenation of 51 using 10% palladium on carbon in ethyl acetate yielded 52. Treatment of 51 and 52 with hydrogen chloride in methanol provided the desired 3,4-pyridine fused ring epibatidine analogs 44 and 45, respectively. A totally different synthesis of 45 which involved sixteen steps and a very low overall yield has been reported.
List all available synthesis (4) of Epibatidine ..
Our first synthesis of epibatidine was based on a synthesis reported by Huang and Shen (see ). In this approach, the least substituted double bond of the cycloadduct 2, prepared by a method similar to that used by Huang and Shen to prepare the N-carbomethoxy analog, was selectively reduced using nickel boride to give 96% of 3. Desulfonation and concomitant reduction of 3 proceeded cleanly to give 65% of a 2:1 mixture of the endo and exo isomers 4 and 5. The endo isomer 4 was epimerized to the exo isomer 5 in 46% yield using the reported procedure of Fletcher and co-workers. Deprotection of the N-Boc epibatidine (5) with trifluoroacetic acid at room temperature gave 97% of racemic epibatidine as a white solid. Optical resolution of (±)-1 using di-p-toluoyltartaric acid gave (+)- and (−)-1a, which were converted to their hydrochloride salts.
The unique structure and biological activity of epibatidine generated considerable interest in this compound and precipitated the development of numerous routes for its synthesis from simple starting materials. A number of these syntheses have been detailed in prior reviews.– In this review, we report the synthetic methods we used to prepare epibatidine as well as a number of epibatidine analogs that were used in a structure activity relationship (SAR) study to help characterize the pharmacophores for nAChRs and hopefully lead to new pharmacotherapies for treating nicotine addiction.
Synthesis of (−)-epibatidine - RSC Advances (RSC …
AB - matrix presented The synthesis of (-)-epibatidine has been accomplished utilizing a highly exo-selective asymmetric hetero Diels-Alder reaction. The key steps employed to transform the resulting bicycle into the natural product include a fluoride-promoted fragmentation and a Hofmann rearrangement.
In this paper, we describe an expansion of our previously reported synthesis of epibatidine analogues, and five synthetic alkaloids characterized by a symmetric, 1-substituted 7-azabicyclo[2.2.1]heptane skeleton, were evaluated for their biological activity.
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Synthesis of (±)-Epibatidine and Its Analogues - The …
In a continuation of our SAR studies to identify compounds having antagonist and mixed agonist/antagonist properties, we synthesized the 3′-(substituted phenyl)deschloroepibatidine analogs 39a–j ().
Synthesis of (-)-epibatidine — Northwestern Scholars
In a preliminary study we found that 2′-fluoro-3′-phenyldeschloroepibatidine (36a) () was, to our knowledge, the first epibatidine analog reported to show nAChR antagonist properties. In order to further develop this finding, compounds 36b–k () were synthesized and evaluated.
The synthesis of (+)- and (–)-epibatidine - Journal of …
In efforts to further characterize the nAChR pharmacophore, we synthesized 3′-substituted deschloroepibatidine analogs 27a–g ().
Synthesis of Epibatidine by Andrew C. Regan (1993)
The synthesis of 39a–h is shown in . Palladium acetate catalyzed coupling of tert-butoxycarbonyl-3′-bromodeschloroepibatidine (30) with the appropriately substituted phenylboronic acid in dimethoxyethane (DME) in the presence of tri-(o-tolyl)phosphine and sodium carbonate gave the tert-butoxycarbonyl-protected 3′-(substituted phenyl)deschloroepibatdine analogs (40a–g). Reduction of the 4-nitrophenyl intermediate 40f with iron powder in hydrochloric acid gave the 4-aminophenyl compound 41. Treatment of 40a–g and 41 with trifluoroacetic acid in methylene chloride removed the protecting tert-butoxycarbonyl group and afforded the desired 3-(substituted phenyl)deschloroepibatidine analogs 39a–h.
A total synthesis of (±)-epibatidine - ScienceDirect
In 1992 Daly and co-workers reported the isolation of a new natural product, epibatidine. Future studies showed that epibatidine was an nAChR ligand with analgesic potency 200–400 times greater than that of morphine. However, its potential as a new drug was limited by its toxic side effects, probably resulting from its activity at a number of nAChR subtypes. Epibatidine’s unique structure and potent activity made it an ideal lead structure for the development of nAChR ligands with reduced side effects and better nAChR subtype selectivity. This review presents the synthetic methods we have used to synthesize a number of epibatidine agonists, antagonists, and mixed agonists/antagonists to better characterize the α4β2 nAChR pharmacophore and hopefully provide compounds that have potential for treating nicotine addiction.
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