合成路线1

The key to the total synthesis of epibatidine is to construct the 7-azabicyclo[2.2.1]heptane system. A number of papers about the syntheses of racemic epibatidine and both of its enantiomers have been published. The different methodologies for the construction of this novel ring system can be classified into four categories. 1) Intramolecular nucleophilic ring closure of 1-amino-4-substituted-cyclohexane derivatives. Broka reported the first total synthesis of (±)-epibatidine in 1993. The preparation of ketoaldehyde (III) was achieved as a single isomer by reaction of enal (II) with 2-(trimethylsilyloxy)-1,3-butadiene. (III) was converted into aminomesylate (IV) in 15 steps, which was heated in CHCl3 to give the mesylate salt of (I) in excellent yield. Starting from 6-chloronicotinaldehyde, epibatidine was obtained via a reaction sequence of 17 steps in an overall yield of 6%. Broka's work confirmed the correctness of the structure proposed by Daly et al.