Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment

Abstract

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo-[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1- ly)benzoate ester. The synthesis of the ABE tricyclic analogues of MLA1 began with selective allylation at C-3 of 3 to produce allyl β-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5. The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2.5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13,14, 25 and 26, to the anthranilate esters 16,17, 27 and 28 using N-(trifluoroacetyl)-anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18,19,29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.