1,4-Addition copper-catalyzed asymmetric

Tlie constrLiction of carbocydic cotnpoutidi by ring-annulation procedures frequently plays a prominent role in total syntliesis. Tlie tolerance of various functional groups in tlie zinc reagents employed in copper-catalyzed asymmetric 1,4-additions fornis tlie basis for tliree novd catalytic enantioselective annulation metliods discussed bete. 

In 1993, Alexakis et al. reported the first copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexenone using phosphorous ligand 28 (32% ee).36 An important breakthrough was achieved by Feringa et al. with chiral phosphoramidite (S,R,R)-29 (Figure 1), which showed excellent selectivity (over 98% ee) for the addition of 2-cyclohexenone.37 Since then, efficient protocols for the conversion of both cyclic and acyclic enones, as well as lactones and nitroalkenes, have been developed featuring excellent stereocontrol. 

The use of TADDOL-based ligands offers an important alternative for copper-catalyzed asymmetric 1,4-additions. TADDOLs (a, a, a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol compounds), introduced by Seebach, are among the most successful currently known ligands in asymmetric catalysis. Seebach also developed the first copper-catalyzed 1,4-addition of a Grignard reagent using a TADDOL derivative as a chiral ligand (see Scheme 7.2) [17]. We have reported TADDOL-based... 

Acyclic Enones as Substrates Compared to cyclic enones, acyclic enones are generally more challenging substrates for the copper-catalyzed asymmetric 1,4-addition reactions. Several ligands have been reported that can achieve high ee when p-aryl acyclic enones are used as substrates in the 1,4-addition of diethyl-zinc (Figure 3.5). ° ... 

However, very few catalyst systems reported to date are highly effective for both p- aryl and p-alkyl acyclic enone substrates in the copper-catalyzed asymmetric 1,4-addition. Ligand 27, developed by Hoveyda, shows high enantioselectivity in the 1,4-addition of dialkylzinc reagents to various acyclic enones (Figure 3.6). " ... 

Ligand 4, which is highly effective for the 1,4-addition of diethylzinc to 2-cyclohexen-l-one, shows relatively wide scope with respect to the p-substituent in the copper-catalyzed asymmetric 1,4-addition of diethylzinc to acyclic nitroalkenes... 

As recent examples of copper-catalyzed asymmetric conjugate addition of organo-zinc reagents (a) Mizutani, H. ... 

Soai [8], Bolm [9], Feringa [10], and Alexakis [11] have reported nickel-or copper-catalyzed asymmetric conjugate addition of diethylzinc, with chiral amino alcohols or a chiral trivalent phosphorus compound (Scheme 8D.2). 

A new class of phosphaferrocene-oxazoline ligands has been disclosed by Fu and co-workers30 and applied to the copper-catalyzed asymmetric conjugate addition of diethylzinc to acyclic enones with good enantioselectivity. The substitution pattern on the phosphoryl ring as well as on the oxazoline was shown to have an enormous impact on the selectivity. Ligands 26 and 27, which share the same absolute configuration in the oxazoline, provide the (5)-l,4-adduct preferentially. This observation led to the conclusion that the stereochemistry at the oxazoline, and not the planar... 

Hawner C, Li K, Cirriez V, Alexakis A (2008) Copper-catalyzed asymmetric conjugate addition of aryl aluminum reagents to trisubstituted enones construction of aryl-substituted quaternary centers. Angew Chem Int Ed 47 8211-8214... 

The coordination of NHC ligands greatly enhances the copper-catalyzed asymmetric addition of diethylzinc to cyclohexenone [45]. Employing imi-dazolinylidene ligands with chiral centers in the heterocycle, the alkylation of a-enones [46,47] was systematically studied by the groups of Mangeney and Alexakis [10,48-50]. A summary of the results obtained is presented in Table 1. 

Table 1-3. Representative recent copper-catalyzed asymmetric 1,4-additions.

Another example of a domino allylation reaction was published by Cook and Jarugumili [169]. Fe2(CO)g in combination with PPhj has been identified as a low-cost and environmentally benign catalyst system for the allylation of zinc enolates 158 generated in situ from copper-catalyzed asymmetric conjugate addition reactions. This catalyst system provides the allylated products 159 in modest to good yields at room temperature with unprecedented diastereoselectivity in cyclic enone systems (Scheme 12.74). 

A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphi-noylimines has been developed for the synthesis of chiral a,a,a-trifluoromethyl-amides (249). Ketimines (250), generated in situ from the corresponding hemiaminals, led to the chiral amides in high yields and excellent enantiocontrol (Scheme 101). ... 

The addition of aryl groups to C=N bonds can be achieved using cooper-catalyzed asymmetric reactions with organometallic reagents. The addition of alkylzinc and related reactions is quite common in literature [47] whereas copper-catalyzed asymmetric arylation of imines is somewhat harder to find. We wish to report some successful examples of this type of catalysts. 

Feringa BL, Badorrey R, Pena D, Harutyunyan SR, Minnaard AJ (2004) Copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic enones. Proc Natl Acad Sci U S A 101 5834-5838... 

Tissot M, Li H, Alexakis A (2014) Copper-catalyzed asymmetric conjugate addition and allylic substitution of organometallic reagents to extended multiple-bond systems. In Alexakis A, Krause N, Woodward S (eds) Copper catalyzed asymmetric synthesis. Wiley-VCH, Weinheim, pp 69-84... 

Li, K., Alexakis, A. (2005). Copper catalyzed asymmetric conjugate addition-bromination of a, 3-unsaturated ketones. A highly efficient one-pot reaction for the synthesis of chiral a-bromo-p-aUcylketones. Tetrahedron Letters, 46, 5823 -5826. 

The copper-catalyzed asymmetric hydrophosphonylation of ketimines has been reported (Scheme 4.120) [198]. Shibasaki used a readily available copper precursor in combination with a resolved bisphosphine to promote the addition reaction. For most of the examples, the authors selected ketimines that incorporated a small alkyl group on one side of the ketamine and an aromatic group on the other side. This substrate design may have contributed to the selectivity of the overall reaction [192,193]. When they moved to substrates that reduced the steric bulk around the ketamine, the selectivity was reduced as well. The reactions occurred at mild conditions (room temperature) with a very low catalyst loading (0.5%). Due to the availability of the precursors, low catalyst loading, high conversions, high selectivity, and mild conditions, this is a very attractive catalyst system for the hydrophosphonylation of ketimines. 

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