Synthesis of ABE tricyclic analogues of methyllycaconitine using a Wacker oxidation–aldol strategy to append the B ring to the AE fragment

Abstract

The synthesis of ABE tricyclic analogues 18 of the alkaloid methyllycaconitine 1 is described. The analogues contain the key pharmacophore reputed to be responsible for the biological activity of methyllycaconitine 1, namely, a homocholine motif formed from a tertiary N-ethylamine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester side chain. The 3-azabicyclo[3.3.1]nonane ring system 10 was assembled via a double Mannich reaction of ethyl 3-(but-3′-enyl)-2-oxocyclohexane-1-carboxylate 9 with ethylamine and formaldehyde. Attempts to append a B ring to this AE ring system via McMurray coupling of dialdehyde 5 were hampered by the inability to effect conversion of the C-9 ketone 10 to vinyl ether 6. Wittig methylenation of ketone 10 afforded diene 7, however, subsequent attempts to effect double hydroboration–oxidation of diene 7 failed to realise diol 11enroute to the key dialdehyde precursor 5 required for the McMurray coupling. Wacker oxidation of the homoallyl group of 10 afforded methyl ketone 12 which underwent intramolecular aldol condensation to form enone 13. After selective reduction of the ketone and methylation, the resultant methyl ethers 15 underwent reduction of the ester sidechain affording neopentyl substituted alcohols 16. Finally, the 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester sidechain was appended by treatment of alcohols 16 with N-(trifluoroacetyl)anthranilic acid followed by fusion of the resultant anthranilates 17 with methylsuccinic anhydride.