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Synthesis of N ‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine
Author(s) -
Lehmann Anna,
Brocke Constanze,
Barker David,
Brimble Margaret A.
Publication year - 2006
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200600326
Subject(s) - chemistry , methyllycaconitine , pharmacophore , hydroxymethyl , tricyclic , stereochemistry , anthranilic acid , substituent , ring (chemistry) , organic chemistry , biochemistry , receptor , nicotinic agonist , nicotinic acetylcholine receptor
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 1 7 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 . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)