合成路线1

In an alternative method to intermediate (XI), dehydration of caronic acid (XLV) by heating with Ac2O and H2SO4 in toluene at 190 °C produces caronic anhydride (XLVI) , which is then condensed with benzylamine in tert-butyl methyl ether at 170-180 °C to yield the bicyclic imide (XLVII). Subsequent reduction of imide (XLVII) with LiAlH4 in refluxing THF followed by debenzylation of the obtained pyrrolidine derivative (XLVIII) by catalytic hydrogenation over Pd/C in AcOH furnishes 6,6-dimethyl-3-azabicyclo[3.1.0]hexane (XLIX) .
Alternatively, caronic anhydride (XLVI) is reacted with NH4OH in H2O at 155 °C or THF at 180 °C to give 6,6-dimethyl-3-azabicyclo[3.1.0]-hexane-2,4-dione (L), which can also be prepared by debenzylation of intermediate (XLVII) with H2 in the presence of Pd/C or Pt/C. Reduction of imide (L) with LiAlH4 in refluxing THF then yields the bicyclic amine (XLIX). This secondary amine is converted to the corresponding imine (LII) by chlorination with NaClO in methyl tertbutyl ether, followed by treatment of the intermediate chloramine (LI) with NaOH in the presence of Bu4NOH or NBC in MeOH , or alternatively by direct oxidation of amine (XLIX) with K2S2O8 in the presence of AgNO3 and NaOH in acetonitrile. Addition of sodium bisulfite to the imine (LII) produces the racemic sulfonate (LIII), which upon cyanation with NaCN yields the α-amino nitrile (LIV). After methanolysis of nitrile (LIV) with HCl in MeOH/MTBE, resolution of the racemic amino ester employing di-p-toluoyl-D-tartaric acid in MeOH affords intermediate (XI) .