Abstract:A new type of phosphite-pyridine (P,N) ligand derived from (S)-NOBIN and (S)-BINOL was employed in Cu(I)-catalyzed conjugate addition of diethylzinc to chalcones. The new P,N ligands were highly efficient in the copper-catalyzed enantioselective 1,4-conjugate additions of diethylzinc to acyclic enones, and up to 97% ee was achieved.Design and synthesis of chiral ligands play a very important role in the development of highly enantioselective asymmetric reactions.1 Tunable and easily synthetic ligands are often desired for achieving high enantioselectivities because of strong substrate dependence in most cases. In fact, subtle changes in conformational, steric, and/or electronic properties of the chiral ligands can often lead to dramatic variation of the reactivity and enantioselectivity. The transition-metal-catalyzed 1,4-addition of organozinc reagents to conjugate enones is one of the most important methods of carbon-carbon bond formation.1,2 In the past decade, great effort has been made to develop efficient chiral ligands for enantioselective catalytic conjugate additions.3,4 The chiral P,N ligand-copper complexes have been proven to be efficient catalysts for 1,4-conjugate addition.5 Among the P,N ligands, Zhang's phosphine-pyridine ligand (Figure 1) showed the best enantioselectivities in the Cu(I)-catalyzed 1,4-conjugate additions of diethylzinc to chalcones; 5f however, the synthetic route was relatively long [six steps from chiral 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN 1, 6 Scheme 1)], relatively lower chemical activity was observed, and electronic and steric properties were relatively difficult to adjust. We are particularly interested in exploring some new efficient chiral P,N ligands, which were easily synthesized and could be finely tuned, for asymmetric diethylzinc addition to acyclic enones. Therefore, we have designed and developed a new type of phosphite-pyridine ligand 4 by tethering a pyridine amido component and a phosphite component with a single chiral NOBIN.Synthesis of the phosphite-pyridine ligands 4 can be accomplished from NOBIN in two steps (Scheme 1). Amidation of NOBIN with 2-picolinic acid in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) 7 as the condensation reagent proceeded smoothly to afford the amides 2 in high yields. (6) For using NOBIN derivatives in asymmetric catalysis, see: (a) Vsykocil, S.; Jaracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7738. (b) Vsykocil, S.; Jaracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P.

Abstract:A new series of fine-tunable phosphite-pyridine (P,N) ligands derived from (S)-2-amino-2′-hydroxy-6,6′-dimethyl-1,1′-biphenyl and (S)-2-amino-2′-hydroxy-4,4′,6,6′-tetramethyl-1,1′-biphenyl was employed in Cu(I)-catalyzed conjugate addition of diethylzinc to acyclic enones. Excellent enantioselectivities (up to 98% ee) and highly catalytic activities were achieved for a variety of acyclic enones.The 1,4-addition of organometallic reagents to conjugate enones is one of the most important methods for carbon-carbon bond formation. Figure 1). In our previous paper, we developed chiral phosphitepyridine ligands derived from (S)-2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) and (S)-2,2′-dihydroxy-1,1′-binaphthyl (BINOL) for Cu(I)-catalyzed Et 2 Zn addition to chalcones.10a High enantioselectivities and yields are obtained for a set of chalcones except for some electronrich substrates such as 4′-methyl and 4′-methoxy chalcones. The substrate limitation could probably be ascribed to the electron-deficiency of chiral phosphitepyridine ligands at the NOBIN moiety, which implied that the limitation could be improved by an electron-rich and electronic tunable ligand. In this paper, we synthesize a new series of phosphite-pyridine ligands L1-4, derived from relatively electron-rich biphenyl backbones, for Cu(I)-catalyzed Et 2 Zn additions to acyclic enones in order to overcome the substrate limitation and verify the subtle alternating effects of electronic property of the chiral ligands. The new phosphite-pyridine ligands L1-4 can be conveniently synthesized from our newly developed chiral biphenyl backbones 3 12 in two steps (Scheme 1). 10aOur previous studies showed that toluene is an appropriate solvent for the Cu(I)-catalyzed enantioselective conjugate additions of Et 2 Zn to chalcones (1).10a Thus L1 and chalcone were chosen to optimize the reaction conditions. The conjugate addition of Et 2 Zn to chalcone was

No abstract