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The First Modular Route to Core‐Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)‐Catalyzed Henry Reactions
Author(s) -
Scharnagel Dagmar,
Müller Andreas,
Prause Felix,
Eck Martin,
Goller Jessica,
Milius Wolfgang,
Breuning Matthias
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201502090
Subject(s) - enantioselective synthesis , diastereomer , chemistry , acrylonitrile , sparteine , catalysis , combinatorial chemistry , copper , yield (engineering) , stereochemistry , enantiomer , organic chemistry , materials science , polymer , metallurgy , copolymer
The first modular and flexible synthesis of core‐chiral bispidines was achieved by using an “inside‐out” strategy. The key intermediate, a NBoc‐activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β‐amino acid and 2‐(acetoxymethyl)acrylonitrile in just five steps and good 48 % yield. A simple addition–reduction protocol permitted a highly endo ‐selective introduction of substituents and, thus, a fast and variable access to 2‐ endo ‐substituted and 2‐ endo , N ‐fused bi‐ and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99 % ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2‐ endo , N ‐(3,3‐dimethylpyrrolidine)‐annelated bispidine. Its performance is superior to that of the well‐known bispidines (−)‐sparteine and the (+)‐sparteine surrogate.