Abstract:
The synthesis of several ABE tricyclic analogues 5, 31 and 32 of the alkaloid methyllycaconitine (1) is reported. The analogues contain two key pharmacophores: a tertiary N-(3-phenylpropyl) substituent attached to a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)benzoate ester. Double Mannich reaction of the cyclic β-keto esters 6 and 17 with the bis(aminol) ether 7 using methyltrichlorosilane as an activating agent provided an efficient method for the construction of the 3-azabicyclo[3.3.1]nonanes 8 and 18. Ring-closing metathesis of the derived dienes 11, 19, and 20 afforded the tricyclic ethers 12, 21, and 22, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form the ABE tricyclic analogues 13, 23, and 24. Conversion of the alcohol 13 to the anthranilate ester 14 using N-(trifluoroacetyl)anthranilic acid followed by fusion with methylsuccinic anhydride afforded the analogue 5 containing the key N-(methylsuccinimido)anthranilate pharmacophore. In the case of the alcohols 23 and 24 the 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)benzoate ester pharmacophore was appended by direct esterification with unsaturated acid 28 followed by hydrogenation to the ABE tricyclic compounds 33 and 34.