合成路线1

The synthesis of (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one, a key chiral intermediate for the asymmetric synthesis of (-)-epibatidine has been described: The reaction of (+)-camphorsultam (I) first with triphosgene and DIEA, and then with NH2OH gives the (+)-hydroxamic acid (II), which is oxidized with tetraethylammonium periodate in CH2Cl2 to yield the acylnitroso compound (III). The asymmetric hetero Diels-Alder cycloaddition of (III) with 2-(tert-butyldimethylsilyloxy)-1,3-cyclohexadiene (IV) affords the (1S,4R)-cycloadduct (V), which is cleaved with Mo(CO)6 providing the (+)-6-amino-2-cyclohexenone (VI) as s single diastereomer. Reduction of the carbonyl group of (VI) with NaBH4 and CeCl3 in methanol gives a 9:1 mixture of cis:trans-diastereomers, from which the major (+)-cis-diastereomer (VII) is isolated by chromatography. Elimination of the chiral auxiliary with KOH in MeOH gives the chiral (-)-oxazolidinone (VIII), which is tosylated with TsCl and NaH in THF yielding the (-)-N-tosyloxazolidinone (IX). Bromination of (IX) with Br2 in DME affords a 80:20 mixture of diastereomeric bromohydrins, from which the desired (-)-diastereo-mer (X) is isolated by column chromatography. Reductive debromination of (X) with Bu3SnH and AIBN in hot toluene followed by hydrolysis of the oxazolidinone ring by treatment with LiOH in MeOH, yields the (+)-aminocyclohexanediol (XI). The cyclization of (XI) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF affords the chiral (-)-7-azabicyclo[2.2.1]heptanol (XII) which is finally oxidized with oxalyl chloride and TEA in DMSO to provide the target chiral intermediate (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one.