合成路线1

Alkylation of acid (I) with allyl bromide in the presence of two equivalents of lithium diisopropylamide (LDA) in THF gave (II). Curtius rearrangement of acid (II) using diphenylphosphoryl azide (DPPA), followed by treatment of the intermediate isocyanate with benzyl alcohol afforded benzyl carbamate (III). Dihydroxylation of (III) with N-methylmorpholine-N-oxide (NMO) and a catalytic amount OsO4 provided diol (IV), which was selectively tosylated at the primary hydroxyl group with p-toluenesulfonyl chloride in the presence of dimethylaminopyridine (DMAP). Protection of secondary hydroxyl group of the resulting tosylate (V) was effected with tert-butyldimethylsilyl chloride in the presence of imidazole, affording silyl ether (VI). Then, benzyl carbamate was removed by hydrogenolysis using palladium on carbon in methanol to give free amine (VII), and further cyclization in the presence of 1,8-diazabicycloundec-7-ene (DBU) in refluxing benzene afforded azaspiro compound (VIII). This was alkylated with ethyl bromoacetate in the presence of K2CO3, followed by deprotection of the silyl ether with tetrabutylammonium fluoride to give (IX). Alcohol (IX) was then converted into azide (X) under Mitsunobu's conditions, and subsequently reduced to primary amine (XI) by catalytic hydrogenation. Hydrolysis of ester (XI) with LiOH gave acid (XII), which was cyclized by treatment with diphenylphosphoryl azide and triethylamine to give rise to the tetracyclic system (XIII). Treatment of (XIII) with iodomethane in the presence of sodium hydride provided the N-methylated compound (XIV). Condensation of (XIV) with aldehyde (XV) was performed using LDA as a base in THF at -78 C to form two separable aldol adducts (XVI), which were determined to be epimeric at the benzylic position.