Role of Electronic Asymmetry in the Design of New Ligands: The Asymmetric Hydrocyanation Reaction

The concepts of C2 symmetry and catalyst-substrate steric interactions have played an important role in the design and understanding of asymmetric catalysts and stereoselective reagents.1,2 The C2 symmetry element often simplifies the synthesis of the reagents and serves to reduce the number of competing diastereomeric intermediates in reactions involving their use.3,4 Most often, the models5 which adequately predict the stereochemical outcome of these reactions are based on the spatial orientation of groups within the disymmetric environment of the auxiliary or catalyst. Such steric-based, heuristic models are used not only to rationalize results but also to design more effective catalysts.6 Even so, examples of the electronic tuning of asymmetric catalysts are appearing in the literature with increasing frequency.7-12 Furthermore, in several cases, good enantioselectivities were obtained using chiral ligands without C2 symmetry.7,10-12 The underlying reasons for the dependence of enantioselectivity on ligand electronics are only poorly understood. Nonetheless, the mechanistic and structural information that has become available in these cases suggests that a rationale based on steric effects alone does not adequately explain the stereochemical outcome. For reactions under the Curtin-Hammett regime, stereoelectronics may well play a determining role in the relative transition-state energies involved in the enantioselective step(s).13-15 Thus, a transition metal complex with a bidentate ligand in which the two ligating atoms are electronically different could impart stereoelectronic control in the formation of a specific product, resulting in enhanced selectivity.14 Indeed such effects may be responsible for the high enantioselectivity observed in a number of asymmetric reactions wherein different chelating atoms are used.11,12 Unfortunately, a clear delineation of the steric and electronic effects is not possible in many of these systems. Ligands specifically designed to probe pure electronic asymmetry gave only moderate improvements over the more symmetric analogs.19 To the best of our knowledge such ligands have not been tested in asymmetric carbon-carbon bond-forming reactions. Here we report on the use of an electronically unsymmetrical bis-3,4diarylphosphinite ligand derived from an R-D-fructofuranoside (3) to achieve the highest enantioselectivity (R/S: 97.5/2.5) ever recorded for the asymmetric hydrocyanation reaction. In addition, the concept is further illustrated with the use of one of the simplest C2-symmetric systems, viz., a bis-phosphinite derived from (S,S)-tartranil (6). Vinylarenes react with HCN in the presence of Ni(0) complexes of vicinal diarylphosphinites to give exclusively the branched nitriles, which are potential intermediates for the synthesis of arylpropionic acids (eq 1). The enantioselectivity depends on the phosphorus substituents, and we have previously shown that electron-withdrawing substituents on phosphorus in a D-glucose-derived phosphinite system gave high ee’s (∼91%) for this reaction,10a,c in which the major product is the S-