Novel Biphenol Phosphoramidite Ligands for the Enantioselective Copper-Catalyzed Conjugate Addition of Dialkyl zincs

Abstract

Phosphoramidite ligands, based on a chiral amine and atropoisomerically flexible biphenols, induce high enantioselectivities (ee's up to 98%) in the copper-catalyzed conjugate addition of dialkyl zinc reagents to a variety of Michael acceptors.There have been many efforts in the field of asymmetric conjugate addition through copper-catalysis. 1 Among the various ways to introduce the chiral information, we demonstrated that trivalent phosphorous ligands were particularly efficient. 2 Later on, we introduced the use of diorganozinc reagents as primary organometallics, 3 and since this first report, in 1993, 3 this combination of a chiral phosphorus ligand and dialkyl zincs has found widespread use, 4-8 although the reaction could be also promoted by non-phosphorus ligands. 9 Typically, cyclohexenone has served as representative Michael acceptor (Scheme 1) with most often Cu(OTf) 2 as copper source (catalyst loading 0.5-2%), in toluene or CH 2 Cl 2 as solvent. Scheme 1Among the many ligands, which have been shown to be efficient, the ones based on a modular concept are of prime importance. Thus, a TADDOL or binaphthol moiety forms a ring with the phosphorus atom, whereas a chiral alcohol or amine is fixed on the exocyclic position ( Figure 1). This combination of two chiral moieties around the phosphorus atom allows for the formation of two diastereomeric ligands. The experimental results show that only one diastereomeric combination affords high enantioselectivities (the matched series) whereas the other one (the mismatched series) does not.For example, ligand L1 affords 96% ee for the conjugate addition of diethylzinc onto cyclohexenone (Scheme 1), whereas the mismatched ligand L1' affords a racemic product. 4d,4e Similarly, ligand L2 affords 98% ee 5 (75% for the mismatched L2') and ligand L3 52% ee 6 (9% for the mismatched L3') for the same reaction. Both mismatched ligands afforded, however, the opposite enantiomer, showing that the binaphthol unit is imposing the absolute stereochemistry of the conjugate adduct. Such behavior of diastereomeric ligands is not unknown and some examples have been reported. 10In the course of our studies to find new ligands, we prepared an equimolecular mixture of ligands L2 and L2', starting from racemic binaphthol. When the reaction was performed using this mixture (Scheme 2), ethyl cyclohexanone was obtained in quantitative yield and with an ee of 66%, corresponding to the enantiomer given by L2! Thus, although each ligand should afford an opposite enantiomer, the matched ligand L2 is largely more efficient and overcomes the mismatched L2'. 11

One-pot multi-substrate enantioselective conjugate addition of diethylzinc to nitroalkenes

“…14,15 Phosphoramidite F, which contains the atropisomeric bisphenol moiety, 29 reported by Alexakis, 30 gives even higher enantioselectivities for almost all products, leading to 77% for 4c. For 4b 71% ee is obtained, whereas only moderate ees have been reported until now for this substrate.…”

New biphenol-based, fine-tunable monodentate phosphoramidite ligands for catalytic asymmetric transformations

“…Other new ligands 6f-6k were synthesized from the enantiopure biphenols, amines, and PCl 3 as described (6). Fig.…”

Highly Enantioselective Copper‐Catalyzed Allylic Alkylation with Phosphoramidite Ligands

“…A few other monodentate ligands 14 ± 18 [27,28] with N,N-bis(1-phenylethyl)amine attached to different backbones were subsequently screened ( Table 2, entries 11 ± 15). The three ligands with a BINOL-type backbone gave similar results to the former ligands.…”