Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

Abstract

A flexible approach, applicable on a gram scale, to chiral 2-endo-substituted 9-oxabispidines was developed. The key intermediate, a cis-configured 6-aminomethylmorpholine-2-carbonitrile, was prepared from (R)-3-aminopropane-1,2-diol and 2-chloroacrylonitrile. The 2-endo substituent was introduced by Grignard addition, cyclization, and exo-selective reduction, thus furnishing the enantiomerically pure bi- and tricyclic 9-oxabispidines in 19-59 % yield. The CuCl(2) complex of the tricyclic 9-oxabispidine, which carries an 2-endo,N-anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S-configured beta-nitro alcohols in 91-98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9-oxabispidines delivered the enantiocomplementary R-configured products in 33-57 % ee. The respective transition states were discussed.

The First Modular Route to Core‐Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)‐Catalyzed Henry Reactions

“…This distortion, which is caused by the dimethylpyrrolidine moiety of the chiral bispidine 10 b , clearly shows the strong interactions of the annelated ring with the coordination sites at the copper atom and, in consequence, its stereo‐directing effect. Similar tiltings were observed in the crystal structures of [( 2 )CuCl 2 ]24 and [( 5 )CuCl 2 ]31 and appear to be characteristic for copper(II) complexes chirally modified by tricyclic bispidines…”

“…It should be noted that the bispidines 5 and 9 , although they gave insufficient results in deprotonation reactions, induced promising enantioselectivities in several other asymmetric transformations 30. 31, 34…”

Chiral 1,1′-binaphthylazepine derived amino alcohol catalyzed asymmetric Henry reaction

“…Amongst them, the copper-containing system is particularly promising due to its ambifunctional character, 14 resulting in high catalytic activity and excellent enantioselectivity especially when in combination with chiral ligands such as bisoxazolines, [15][16][17][18][19][20][21] (À)-sparteine, 22 bisimidazolines, 23,24 diamines, [25][26][27][28][29][30][31][32][33] sulfonyldiamines, [34][35][36] aminopyridines, 37,38 salen [39][40][41][42][43][44][45] and N,N 0 -dioxides, 46 etc.…”

Unexpected activity of novel 9-oxabispidine zinc complexes in lactide polymerization

“…As the chiral diamine we choose the newly developed tricyclic 9-oxabispidine 6 (Scheme 2), which is accessible in a few steps from the imide 4 or from the cyanomorpholine 5 [14][15][16][17]. The high potential of 6 in asymmetric synthesis was recently shown in the Pd II -catalyzed kinetic resolution of secondary alcohols giving selectivity factors of up to 19 and in enan- tioselective nitro aldol reactions providing up to 98% ee [14,15]. Herein, we report on the synthesis and characterization of the first zinc complexes of the tricyclic 9-oxabispidine 6 and on their activity in the ROP of D,L-lactide (1).…”

“…The molecular weight and polydispersity of 3 were determined by gel permeation chromatography [21], the tacticity and the probScheme 2. The tricyclic 9-oxabispidine 6 and the precursors 4 and 5 [14,15]. (1) catalyzed by guanidine-derived zinc complexes of type 2 [12,13].…”