Highly Enantioselective Conjugate Addition of Diethylzinc to Acyclic Enones with Fine-Tunable Phosphite−Pyridine Ligands

Abstract

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

Cu‐ and Ni‐Catalyzed Conjugated Additions of Organozincs and Organoaluminums to α,β‐Unsaturated Carbonyl Compounds

“…The conjugated addition of Et 2 Zn to chalcone under the same conditions proceeded with up to 94% ee. The synthesis of ligands bearing also a chiral biphenyl backbone such as L40c enabled the enantioselectivity to be increased to 97% [120].…”

Diastereomeric phosphite–pyridine ligands for enantioselective 1,4-conjugate additions

“…Surprisingly, sterically hindered ligand Lb did not exhibit better stereoselectivity with low catalytic activity, while its enantiopure analogue (S,S)-1b showed the best results in the same reaction. 10 As there are two diastereomeric phosphite-pyridine Cu(I) complexes, which showed different reaction rates in the reaction system, there can be no doubt that these rate differences determine the product ee under this situation. To improve the reaction conversion, which resulted from the sterically hindered ligand, more catalyst was used to accelerate the reaction.…”

“…The amides 4 were prepared according to the literature procedure. 10 The ee values were determined by HPLC with a ChiralPak-AD column. d The absolute configuration was assigned by the comparison of the specific rotation data.…”

“…1), for high enantioselective Cu(I)-catalysed 1,4-conjugate additions of Et 2 Zn to a variety of acyclic enones. 10 Encouraged by the above results, we became interested in developing the phosphite-pyridine ligands L from the racemic biphenyl backbone 2 and (S)-BI-NOL and testing their application in transition metal catalysed asymmetric reactions. Our more previous studies had shown that the matched phosphite-pyridine ligand (S,S)-3a, derived by (S)-NOBIN (NOBIN = 2-amino-2 0 -hydroxy-1,1 0 -binaphthyl) and (S)-BINOL, obtained much better result (91% ee with 92% of yield) than its diastereomer (R,S)-3b [derived by (R)-NOBIN and (S)-BINOL, 54% ee with 15% of yield] in the Cu(I)-catalysed asymmetric 1,4-conjugate addition of …”

Development of new chiral P,N ligands and their applications in enantioselective 1,4-conjugate additions of diethylzinc to chalcones

“…Although many efficient chiral copper catalytic systems have been developed for the 1,4-conjugate additions of diorganozinc to various types of enones, [4][5][6][7][8][9] only a few copper complexes coordinated with chiral P,N ligands have proven to be efficient when chalcone was used as the enone substrate. 2a,3f,9c On the basis of our latest report 10 on the Cu(I)-catalysed 1,4-conjugate addition with phosphite− pyridine ligands III (Fig. 1) derived from the electronrich chiral biphenyl backbone, 11 where the electronic property of the ligands played a very important role in obtaining high ee, compared to the phosphite−pyridine ligands II (Fig.…”