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The Enantioselective Total Synthesis of Bisquinolizidine Alkaloids: A Modular “Inside‐Out” Approach
Author(s) -
Scharnagel Dagmar,
Goller Jessica,
Deibl Nicklas,
Milius Wolfgang,
Breuning Matthias
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201712852
Subject(s) - enantioselective synthesis , desymmetrization , enantiomer , total synthesis , chemistry , stereochemistry , nonane , substituent , enamine , modular design , organic chemistry , computer science , catalysis , operating system
Bisquinolizidine alkaloids are characterized by a chiral bispidine core (3,7‐diazabicyclo[3.3.1]nonane) to which combinations of an α,N‐fused 2‐pyridone, an endo‐ or exo‐α,N‐annulated piperidin(on)e, and an exo‐allyl substituent are attached. We developed a modular “inside‐out” approach that permits access to most members of this class. Its applicability was proven in the asymmetric synthesis of 21 natural bisquinolizidine alkaloids, among them more than ten first enantioselective total syntheses. Key steps are the first successful preparation of both enantiomers of C 2 ‐symmetric 2,6‐dioxobispidine by desymmetrization of a 2,4,6,8‐tetraoxo precursor, the construction of the α,N‐fused 2‐pyridone by using an enamine‐bromoacrylic acid strategy, and the installation of endo‐ or, optionally, exo‐annulated piperidin(on)es.