Kinetic Resolution of Unsaturated Amides in a Chlorocyclization Reaction: Concomitant Enantiomer Differentiation and Face Selective Alkene Chlorination by a Single Catalyst

Abstract

The first example of a kinetic resolution via chlorofunctionalization of olefins is reported. The enantiomers of racemic unsaturated amides were found to have different hydrogen-bonding affinities for chiral Lewis bases in numerous solvents. This interaction was exploited in developing a kinetic resolution of racemic unsaturated amides via halocyclization. The same catalyst serves to both "sense chirality" in the substrate as well as mediate a highly face-selective chlorine delivery onto the olefin functionality, resulting in stereotriad products in up to 99:1 dr and up to 98.5:1.5 er. The selectivity factors were typically greater than 50 to allow for the simultaneous synthesis of both the products and unreacted substrates in highly enantioenriched form at yields approaching 50%. The reaction employs catalytic amounts (≤0.50 mol %) of a commercially available and recyclable organocatalyst.

ChemInform Abstract: Recent Advances in Organocatalytic Kinetic Resolution for the Synthesis of Functionalized Products

“…The OCKR of unsaturated amides by chlorocyclization was performedi n2 013 by Borhan et al [35] Cinchona alkaloid derived catalysth ydroquinidine 1,4-phthalazinediyl diether [(DHQD) 2 PHAL, 61 b]w as used in discriminating the racemate of unsaturated amides 70 and effectively delivered the chloronium ion to the distinct p face of unsaturated amide (R)-70.H ighly diastereoselective chlorocyclization was observed to produce stereotriadp roducts 71 in excel-lent yields with high diastereo-and enantioselectivities (Scheme 14). Highly enantioenriched products and less-reactive unsaturated amides (S)-70 could be simultaneously obtained under this chlorocyclization reaction.…”

Recent Advances in Organocatalytic Kinetic Resolution for the Synthesis of Functionalized Products

“…The OCKR of unsaturated amides by chlorocyclization was performed in 2013 by Borhan et al . Cinchona alkaloid derived catalyst hydroquinidine 1,4‐phthalazinediyl diether [(DHQD) 2 PHAL, 61 b ] was used in discriminating the racemate of unsaturated amides 70 and effectively delivered the chloronium ion to the distinct π face of unsaturated amide ( R )‐ 70 .…”

Cinchona Alkaloids as Organocatalysts in Enantioselective Halofunctionalization of Alkenes and Alkynes

“…Kinetic resolution of racemic unsaturated amides was also realized using dimeric cinchona alkaloid catalysts in chlorocyclizations (Scheme 9). [45] Heterocycles with three contiguous stereogenic centers were prepared in high ees.…”