Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment.
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 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-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.
Barker
David
D
School of Chemistry, University of Sydney, Camperdown, NSW, Australia.
Brimble
Margaret A
MA
McLeod
Malcolm D
MD
Savage
G Paul
GP
D000157:Aconitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D001372:Aza Compounds / Q000138:chemical synthesis*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D003500:Cyclization; D031882:Delphinium / Q000737:chemistry*; D015394:Molecular Structure
D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; C054634:methyllycaconitine; D000157:Aconitine