The First Modular Route to Core‐Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)‐Catalyzed Henry Reactions. Issue 35 (31st July 2015)

• Record Type: Journal Article
• Authors: Scharnagel, Dagmar; Müller, Andreas; Prause, Felix; Eck, Martin; Goller, Jessica; Milius, Wolfgang; Breuning, Matthias
• Is Part Of: Chemistry. Volume 21:Issue 35(2015)
• Page Start: 12488
• Page End: 12500
• Publication Date: 2015-07-31
• Subjects: asymmetric synthesis -- bispidine -- Henry reaction -- polycyclic compounds -- stereoselective catalysis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201502090
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : Bispidine construction kit : A first modular and enantioselective synthesis of core‐chiral bi‐ and tricyclic bispidines was accomplished by using a chiral NBoc‐activated bispidine lactam as the key intermediate (see scheme). A simple addition–reduction sequence permits a facile introduction of endo ‐oriented substituents and annelated rings. One of the new bispidine ligands provided up to 99 % ee in enantioselective Henry reactions.