合成路线1

12) Reaction of N-substituted-pyrrole derivatives with activated dienophiles. Retrosynthetic analysis revealed that the [4+2] cycloaddition reaction between pyrrole and dienophiles should be a general method for the synthesis of the 7-azanorborane ring system. Unfortunately, pyrrole is not a good diene for the Diels-Alder reactions. Pyrrole and its derivatives readily undergo Michael addition upon treatment with dienophiles, and the resulting 7-aza[2.2.1]bicycloheptenes are thermodynamically unstable. In order to stablize the resultant products and accelerate the cycloaddition reaction, N-protected pyrroles with a decreased aromaticity of the pyrrole ring are usually used as diene components and acetylene equivalents are used as dienophiles. In 1993 Shen et al. first reported a 4-step synthesis of racemic epibatidine. A Diels-Alder reaction of N-carbomethoxypyrrole (XLV) and phenylsulfonyl(6-chloro-3-pyridyl)acetylene (XLVI) afforded the adduct (XLVII) in 70% yield. Desulfonation and concomitant reduction of conjugated double bond with sodium amalgam resulted in a mixture of 1:2 ratio of exo-(XLVIII) to endo-(XLVIII).