Readily Prepared Chiral P,N Ligands and Their Applications in Cu-Catalyzed Enantioselective Conjugate Additions

Abstract

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.

Nonlinear effects in the enantioselective 1,4-conjugate addition of diethylzinc to chalcone

“…of ligand 1a provided very high activity (92% yield) and enantioselectivity (91% ee) under the same reaction conditions. 9 These results demonstrated that the efficient catalytic species was an ML 2 -type complex: one metal coordinated with two chiral ligands. Thus, the positive nonlinear effect could be explained by Kagan's ML 2 model system.…”

“…7,8f,j,k We recently reported a new type of bidentate phosphite-pyridine (P,N) ligand and obtained high enantioselectivities in Cu(I)-catalyzed 1,4-conjugate addition of Et 2 Zn to chalcones by using 1 mol% [Cu(CH 3 CN) 4 ]BF 4 and 2.5 mol% ligand 1a. 9 Herein, we report the study of the relationship between ligand enantiopurity, tuned by mixing 1a and 1b and the product ee to obtain more information on the active catalytic species (Fig. 1).…”

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 or cyclohexenone, catalyzed by [Cu(MeCN) 4 ]BF 4 in toluene, yielded the corresponding products in 97% and 56% ee, respectively [118]. A high asymmetric induction was observed with a related ligand L40b, which was a mixture of two diastereoisomers, bearing racemic biphenyl and chiral binaphthyl frameworks [119].…”

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

“…It is noteworthy that both ligands (S,S)-3a and (R,S)-3b afforded the products with the same absolute configuration. 11 Therefore, we envisioned that the strategy could obtain high stereoselectivity in Cu(I)-catalysed 1,4-conjugate addition of Et 2 Zn to acyclic enones. 12,13 Moreover, the low efficient resolution of biphenyl backbones 2 14 also drove us to develop a convenient and efficient ligands with a new strategy.…”