Applications of Werner Complexes as Chiral Solvating Agents and Catalysts in Enantioselective Synthesis

Abstract

When NMR spectra of chiral racemic organic molecules containing a Lewis basic functional group are recorded in the presence of air and water stable salts of the cobalt(III) trication [Co((S,S)-NH2CHArCHArNH2)3]3+ ((S,S)-23+ for Ar = Ph), separate signals are usually observed for the enantiomers (28 diverse examples, >12 functional groups). Several chiral molecules can be simultaneously analyzed, and enantiotopic groups in prochiral molecules differentiated (16 examples). Particularly effective are the mixed bis(halide)/tetraarylborate salts Λ-(S,S)-23+ 2X–BArf– (X = Cl, I; BArf = B(3,5-C6H3(CF3)2)4), which are applied in CD2Cl2 or CDCl3 at 1-100 mol% (avg 34 and 14 mol%). Job plots establish 1:1 binding for Λ-(S,S)-23+ 2Cl–BArf– and 1-phenylethyl acetate or 1-phenyl¬ethanol, and ca. 1:2 binding with DMSO (CD2Cl2). Selected binding constants are determined, which range from 7.60-2.73 M–1 for the enantiomers of 1-phenylethanol to 28.1-22.6 M–1 for the enantiomers of 1-phenylethyl acetate. The NH moieties of the C2 faces of the trication are believed to hydrogen bond to the Lewis basic functional groups, as seen in the crystal structure of a hexakis(DMSO) solvate of -(S,S)-23+ 3I–. These salts rank with the most broadly applicable chirality sensing agents discovered to date.

The chiral enantiopure cobalt(III) complex -(S,S)-23+ 2Cl–B(C6F5)4– is an effective catalyst, together with pyridine (10 mol% each), for enantioselective additions of substituted cyanoacetate esters NCCH(R)CO2R' to acetylenic esters R"CCCO2R"'. In the resulting adducts, which feature quaternary carbon stereocenters, NC(R'O2C)C¬(R)CR"C=CHCO2R"', C=C isomers in which the CO2R"' moiety is trans to the new carbon-carbon bond dominate (avg. ratio 98:2). These are obtained in 70-98% ee (avg. 86%; data for optimum R' and R"'), as determined by 1H NMR with the chiral solvating agent Λ-(S,S)-23+ 2I–BArf–. NMR experiments show that the cyanoacetate and acetylenic esters and pyridine can hydrogen bond to certain NH groups of the catalyst. Rates are zero order in the cyanoacetate and acetylenic esters as well as the catalyst, and implications are discussed.

Exploratory studies were conducted with three additional reactions. First, the reaction of methyl 2-oxocyclopentanecarboxylate with N-fluorobenzenesulfonimide in the presence of Λ-(S,S)-23+ 2Cl–BArf– (10 mol%) gave the monofluorinated product methyl 1-fluoro-2-oxocyclopentanecarboxylate in >99% yield and 79% ee. Second, the Neber reaction of 3-((tosyloxy)imino)butanoate catalyzed by 10 mol% Λ-(S,S)-23+ 2Cl–BArf– in the presence of 2.0 equiv of Et3N gave 3-methyl-2H-azirine-2-carboxylate in >99% yield and 97% ee. Third, intramolecular hydride transfer and cyclization of dimethyl 2-(2-(dialkylamino)benzylidene)malonate gave tetrahydroquinoline products in 50% to >99% yields and 0-82% ee using 10 mol% of the catalyst Λ-[Co((S,S)-NH2CHArCHArNH2)3]3+ 2Cl–BArf– (Λ-(S,S)-3b3+ 2Cl–BArf– for Ar = 1-naphthyl) at 50-80 ℃. Extension of these promising results to other substrates will be studied and communicated in the future.

When the complex Λ-(S,S)-23+ 3Cl– was treated with AgF, a new salt Λ-(S,S)-23+ 3F– was obtained in 98% yield. This could be used as the catalyst in the trifluoromethylation of aromatic aldehydes to give trimethylsilyl-1-aryl-2,2,2-trifluoroethanols in 20-70% isolated yields and 54-99% ee. Extension to other aldehydes gave low yields and ee values. The chloride anions in Λ-(S,S)-23+ 2Cl–BArf– was exchanged in situ with anions of the enantiomers of proline to generate the catalyst Λ-(S,S)-23+ 2(proline)–BArf–. The catalyst was used in the addition of acetone to trans-β-nitrostyrene to give the adduct 5-nitro-4-phenylpentan-2-one in 90% yield and 58% ee. Without the proline anions or the cation Λ-(S,S)-23+, lower ee values were obtained.