A dramatic switch of enantioselectivity in asymmetric Heck reaction by benzylic substituents of ligands

Abstract

Intense efforts have been devoted to the preparation of both enantiomers of chiral compounds due to their potential unique properties and applications in organic, medicinal, biological, and pharmaceutical chemistry. One strategy in obtaining both enantiomers involves modification of substituents of the ligands in metal-catalyzed asymmetric synthesis. In this work, Wu and coworkers demonstrated that the variation of groups at the benzylic position of P,N ligands 1 and 2 had great influence on the stereoselectivity of Pd-catalyzed Heck reactions. (Chemical Equation Presented) Ligands 1 and 2 were synthesized as shown in Schemes 1 and 2, respectively. These ligands were used in an asymmetric intermolecular Heck reaction of 2,3-dihydrofuran 11 with aryl triflates 12a-e and cyclohexenyl triflate 12f (Eq. 1). (Chemical Equation Presented) The results (Table 1) showed that these ligands are apparently more active in the Heck reaction than other ligands previously reported. Interestingly, (R)-enantiomer 13 was obtained when ligands 1a-c were used (Table 1, entries 1-3, 6, 8, 12, 14), whereas (S)-13 was produced by using ligands 2a-b (Table 1, entries 4, 5, 7, 9, 11, 13, 15 ). Thus, simple replacement of hydrogens with dimethyl groups at the benzylic position reverses the enantioselectivity. This result was verified when Heck reactions of 15 (Eq. 2) were performed. As expected, ligand 1b produced (R)-16 while ligand 2a afforded the (S)-16 enantiomers. (Chemical Equation Presented) (Table Presented) Density functional theory (DFT) studies were carried out on the asymmetric insertion step of the Heck reaction (Scheme 3). The data (Table 2) indicate that for complex CP2, the cis mode is more stable than the trans mode. Nevertheless, the trans mode of the transition states (TS1) is more stable with both ligands 1a and 2a. The greater reactivity of the trans mode is due to the trans effect which activates the Pd-Ph bond. Calculations also indicate that the syn conformation is more stable than the anti in both CP2 and in TS1 with ligand 1a. In contrast, the two methyl groups on 2a favor the anti conformation of CP2 and TS1. These predictions were clearly confirmed by the crystal structures of Pd complexes of ligands 1a and 2a (Fig. 1). Because of the unsymmetrical environment (Chemical Equation Presented) effected by the phenyl groups on P, trans-syn-Si and trans-anti-Re are the more favored transition structures. Since trans-syn-Si is more favored when the ligand is 1a, the (R)-enantiomer was the major product with 1a. However, trans-anti-Re is more stable for 2a; thus the (S)-product was favored when the ligand was 2a. © 2010 Data Trace Publishing Company.