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Efficient Synthesis of the Azabicyclo[3.3.1]nonane Ring System in the Alkaloid Methyllycaconitine Using Bis(alkoxymethyl)alkylamines as Aminoalkylating Agents in a Double Mannich Reaction
Author(s) -
Brimble Margaret A.,
Brocke Constanze
Publication year - 2005
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.200500003
Subject(s) - chemistry , methyllycaconitine , mannich reaction , nonane , alkaloid , ring (chemistry) , stereochemistry , bicyclic molecule , synthon , organic chemistry , combinatorial chemistry , catalysis , biochemistry , receptor , nicotinic agonist , nicotinic acetylcholine receptor
Abstract The double Mannich reaction of cyclic β‐keto esters with bis(alkoxymethyl)alkylamines provides an efficient and versatile method for the construction of azabicyclo[3.3.1]nonanes and azabicyclo[3.2.1]octanes. The optimum conditions for efficient reaction involve use of the activator trichloromethylsilane in acetonitrile as solvent at ambient temperature. The utility of this synthetic method is further demonstrated by the facile synthesis of several AE ring analogues 39 , 42 of the alkaloid methyllycaconitine by appendage of the key N ‐(methylsuccininimido)anthranilate pharmacophore to the N ‐(3‐phenylpropyl)‐substituted double Mannich adducts 18 , 27 . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)