Epibatidine, synthesis

Table 4.15 Summary of reaction metrics and synthesis tree parameters for epibatidine synthesis plans ...

Scheme 4.15 Carroll (-)-epibatidine synthesis plan (1995). (a) Heat (78%) (b) EtOH, 2[Ni(OAc)2 4H2OI, 4NaBH4, then 4HCI, 4H2O (96%) (c) 5Na, 4MeOH (65%) (d) heat, KOfBu, fBuOH (46%) (e) CH2CI2, CF3COOH (cat.), then H2O (97%).

The last few stages of Corey s epibatidine synthesis are shown here. Give mechanisms for the first two reactions and suggest a reagent for the last step. 

Barlocco, D., Cignarella, G., Tondi, D., Vianello, P., Villa, S., Bartolini, A., Ghelardini, C., Galeotti, N., Anderson, D.J., Kuntzweiler, T.A., Colombo, D., Toma, L., 1998. Mono- and disubstituted 3,8-diazabi-cyclo[3.2.1]octane derivatives as analgesic stracturally related to epibatidine synthesis, activity and modeling. J. Med. Chem. 41,674-681. 

Synthesis and structure-activity data of some new epibatidine analogues [70]... 

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>. 

Figure 4.40 Synthesis map showing starting materials used for the synthesis of (-)-epibatidine. 

Figure 4.41 Synthesis trees for synthesis of (—)-epibatidine by the Carroll method (a) direct synthesis (b) includes epimerization recycling step (see Scheme 4.1 5).

Kosngi, H., Abe, M., Hatsuda, R., Uda, H., Kato, M. (1997) A Study of Asymmetric Protonation with Chiral fi-Hydroxy Sulfoxides. Asymmetric Synthesis of (—)-Epibatidine. Chemical Communications, 1857-1858. 

Fletcher, S.R., Baker, R., Chambers, M.S. et al. (1994) Total Synthesis and Determination of the Absolnte Confignration of Epibatidine. Journal of Organic Chemistry, 59, 1771-1778. 

Zhang, C. TrndeU, M.L. (1996) A Short and Efficient Total Synthesis of ( )-Epibatidine. Journal of Organic Chemistry, 61, 7189-7191. 

Aoyagi, S., Tanaka, R., Naruse, M., Kibayashi, C. (1998) Total Synthesis of (—)-Epibatidine Using an Asymmetric Diels-Alder Reaction with a Chiral N-Acylnitroso DienophUe. Journal of Organic Chemistry, 63, 8397-8406. 

Aggarwal, V.K. Olofsson, B. (2005) Enantioselective a-Arylation of Cyclohexanones with Diaryl lodoninm Salts Application to the Synthesis of (—)-Epibatidine. Angewandte Chemie International Edition, 44, 5516-5519. 

Pandey, G., Bagul, T.D., Sahoo, A.K. (1998) [3 -E 2] Cycloaddition of Non stabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analognes. Journal of Organic Chemistry, 63, 760-768. 

Szantay, C., Kardos-Balogh, Z., Moldvai, I., Szantay, C. Jr., Temesvari-Major, E., Blasko, G. (1996) A Practical Enantioselective Synthesis of Epibatidine. Tetrahedron, 52, 11053-11062. 

Huang, D.F. Shen, T.Y. (1993) A Versatile Total Synthesis of Epibatidine and Analogs. Tetrahedron Letters, 34,4477-4480. 

Hoashi, Y., Yabuta, T., Takemoto, Y. (2004) Bifunctional Thiourea-Catalyzed Enantioselective Double Michael Reaction of y,5-Unsaturated fS-Ketoesterto Nitroalkene Asymmetric Synthesis of (—)-Epibatidine. Tetrahedron Letters, 45, 9185-9188. 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

The intramolecular Michael addition is used as a key step for synthesis of epibatidine (Scheme 4.26).177 Epibatidine is an analgesic, operating by a nonopioid mechanism, it is several hundred times more potent than morphine. 

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