Epibatidine analogues

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

Synthesis of Different Epibatidine Analogues with Domino- and Reductive Heck Reactions... 

Abstract New epibatidine analogues were synthesized by palladium catalyzed reductive Heck and Domino-Heck reactions and regioselective results were obtained. 

Keywords Epibatidine analogues, Epipedobates tricolor, Domino Heck reaction, frog, synthesis... 

Toxic effects of epibatidine and the fact that the amount of this compound had been isolated from some 750 Ecuadorian frogs less than one milligram [4], causes the need of synthesizing new analogues which are not toxic but have the same biological properties. We, therefore become interested in synthesizing of the new epibatidine analogues. 

Heck reactions, the hydroarylation methodology, has been a key tool in the synthesis of varions epibatidine analogues, due to the ability of this approach to address regio- and stereochemistry in substituted azabicyclo ring systems [6],... 

We continued our work with the reductive Heck and Domino-Heck reactions [1, 7J of new bicyclic compound (3) by treating it with different aryl- and hetaryl-iodides, as a result a series of new epibatidine analogues were synthesized, continuously separated and purificated by column chromatography on silica gel. Treatment of 3 with iodobenzene, 2-iodothiophene, 1-iodonapthalene and 2-chloro-5-iodopy-ridine under reductive Heck conditions gave new compounds 4a-d and 5b, 5d as exo-regioisomers after chromatographic separations. The reactions with iodobenzene and 1-iodonapthalene gave only 5-exo- products. The use of trimethylsily-lacetylene under Domino-Heck conditions provided alkynic bicyclic systems 6e andf. 

New epibatidine analogues were characterized with the aid of one and two dimensional NMR techniques and IR, GC-MS spectroscopies (Fig. 38.1). All signals in the NMR spectra appeared in pairs due to the presence of rotamers that are resulted from the rotation between the unpaired electrons and benzoyl substituent on the nitrogen atom (Scheme 38.2). 

Syntheses, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2 -Substituted 5-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Epibatidine-analogues, J. Med. Chem. 

Scheme 10 A facile synthesis of the intermediates of epibatidine analogues via high-pressure IEDARs of pyrrole 31 [36]...

Several 3/3-(aryl)-2/3-(3-substituted isoxazol-5-yl)tropanes 375 were synthesized from methyl esters 374 by reaction with the dilithium salt of the appropriate ketone or aldehyde oxime (Scheme 90) <2004JME296>. The same procedure was applied to 7-ethoxycarbonyl-2-azabicyclo[2.2.1]heptanes for the synthesis of novel epibatidine analogues, such as 376 <2004JOC5328>. The reaction of a-bromoketone oximes with isocyanides and sodium carbonate led to 5-aminoisoxazole derivatives in good yields. Probably, isocyanides are involved in a [4-1-1] cycloaddition with nitrosoalkene intermediates <1997TL8027>. 

Suzuki coupling of such boronic acids with the triflate 240 of the protected ketone 239 gives bicyclic compounds such as 241 easily reduced to epibatidine analogues such as 242. 

The Baltz-Schiemann reaction is the most often used method for the synthesis of 3-fluoropyridines. This method utilizes readily accessible 3-nitropyridines as the precursors, since they can be readily reduced into amines and then used in the Baltz-Schiemann reaction. In this section, selected examples applied for the synthesis of practically important compounds are given. For example, the Baltz-Schiemann reaction was used for the synthesis of fluoro-substituted epibatidine analogue 79 (epibatidine is a high-affinity nonselective ligand for nicotinic cholinergic receptor (nAChRs)) (Scheme 6.27). 

Carroll, F.L. Liang, F. Navarro, H.A. Brieaddy, L.E. Abraham, R Damaj, M.I. Martin, B. R. Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-cxo-2-(2 -substituted 5 -pyridinyl)-7-azabicyclo [2.2.1]heptanes. Epibatidine analogues. J. Med. Chem. 44(13),2229-2237. 

In the same context, Kanfmann and coworkers [24] have applied a three-component domino Mizoroki-Heck rednctive transformation for the preparation of epibatidine analogues 29. In the presence of triphenylarsine as ligand, Pd(OAc>2, iodobenzene and trimethylsilylacetylene, 27 led to 28 diastereoselectively (Schemes 8.5 and 8.6). 

Carroll FI, Lee JR, Navarro HA, Ma W, Biieaddy LE, Abraham P, Damaj MI, Martin BR (2002) Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2, 3 -disubstituted 5 -pyiidinyl)-7-azabicyclo[2.2.1]heptanes epibatidine analogues a new positron emission tomography ligand for nicotinic receptors. J Med Chem 45(21) 4755 761... 

J.-P.G. Seerden, M.T.M. Tulp, H.W. Scheeren, C.G. Kruse, Synthesis and structure-activity data of some new epibatidine analogues, Bioorg. Med. Chem. 6 (1998) 2103-2110. 

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