Epibatidine total synthesis

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. 

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

Scheme 6.60 Total synthesis of (-)-epibatidine including a 12-catalyzed Michael addition as enantioselective key step.

The Stille coupling of 2-chloro-5-tributylstannylpyridine with an enantiopure 2-iodo-cyclohexenon (7.29.) derivative formed the basis of the total synthesis of (+)-epibatidine. The reaction is a nice example of the chemical inertness of arylstannanes and the mildness of the coupling conditions. Both the enone moiety and the chiral ally lie centre remained untouched in the process. The effective coupling required the use of a soft ligand, triphenylarsine and the addition of copper(I) iodide as co-catalyst.40... 

While Dehmlow s review details a variety of efforts Total syntheses of towards the total synthesis of epibatidine (Dehmlow, 1995) epibatidine the synthesis of this natural product is still an intriguing challenge for academic research. More than three dozen... 

Figure 3 Retrosynthetic strategies for the total synthesis of epibatidine.

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]. 

During the reaction silver(0) deposits on the sides of the reaction vessel. The sequence of events leading to the azomethine ylide is unclear. However, evidently single-electron transfer (SET) from the amine to silver takes place either prior or subsequent to fluoride-enabled silyl cleavage. This process is repeated with a second equivalent of silver fluoride resulting in the formation of 38 either in free form or more likely as its silver complex. The scope of the method was expanded to the synthesis of bicylic systems exemplified here by tropinone 42 (Scheme 2.11).19 Pandey has also extended the protocol to the synthesis of tricycloalkanes20 and applied it to a total synthesis of the poisonous frog alkaloid epibatidine.21... 

Pandey, G., Laha, J.K., and Lakshmaiah, G. 2002. Stereoselective construction of X-azabicyclo[ i.2.1]alkanes by [3+2]-cycloaddition of non-stabilized cyclic azomethine ylides synthesis of enantiopure constrained amino acids and formal total synthesis of optically active epibatidine. Tetrahedron 58, 3525-3534. 

Basic hydrolysis of the allylic azide affords the rearranged 1,2-isomer, which was an intermediate in the synthesis of (+)-conduramine E. Following a similar strategy, but starting with dr-3,6-dibenzoyloxycyclohex-l-ene, a total synthesis of the nonopioid analgesic (—)-epibatidine was developed. ... 

The enantioselective total synthesis of (-)-epibatidine was accomplished in the laboratory of D.A. Evans." The key steps in the synthetic sequence included a hetero Diels-Alder reaction and a modified Hofmann rearrangement. The primary carboxamide was subjected to lead tetraacetate in fert-butyl alcohol that brought about the rearrangement and gave the corresponding A/-Boc protected primary amine in good yield. A few more steps from this intermediate led to the completion of the total synthesis. 

A highly exo-selective asymmetric hetero Diels-Alder reaction was the key step in D.A. Evans total synthesis of (-)-epibatidine. The bicyclic cycloadduct was then subjected to a fluoride-promoted fragmentation that afforded a (f-keto ester, which was isolated exclusively as its enol tautomer. The removal of the ethoxycarbonyl functionality was achieved using the Krapcho decarboxylation. Interestingly, the presence of a metal salt was not necessary in this transformation. Simply heating the substrate in wet DMSO gave rise to the decarboxylated product in quantitative yield. 

An asymmetric total synthesis of ent-(-) roseophilin has been reported involving an inverse electron demand DA reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate <01JA8515>. The electron deficient character of the diazadiene system of 1,2,4,5-tetrazines has been used to obtain epibatidine analogs (7-azabicyclo[2,2,l]heptane derivatives) through an inverse type DA reaction <01JMC47>. 

Aggarwal and Olofsson have developed a direct asymmetric a-arylation of prochiral ketones using chiral lithium amide bases and diaryliodonium salts [881]. In a representative example, the deprotonation of cyclohexanone derivative 684 using chiral Simpkins (/ ,/ )-base followed by reaction with the pyridyl iodonium salt gave the arylated product 685 in 94% ee (Scheme 3.275). This reaction has been employed in a short total synthesis of the alkaloid (-)-epibatidine [881]. 

Hoashi Y, Yabuta T, Yuan P, Miyabe H, Takemoto Y (2006) Enantioselective Tandem Michael Reaction to Nitroalkene Catalyzed by Bifunctional Thiourea Total Synthesis of (-)-Epibatidine. Tetrahedron 62 365... 

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