Enantioselectivity, copper-catalyzed

Table 12.1. Enantioselective Copper-Catalyzed Allylic Oxidation of Cyclohexene...

Using the results of an earlier study concerning enantioselective copper-catalyzed intramolecular C—H insertion of metal carbenoids,109 an interesting system for optimizing the proper combination of ligand, transition metal, and solvent for the reaction of the diazo compound (75) was devised (see Scheme 19).110 The reaction parameters were varied systematically on a standard 96-well microtiter/filtration plate. A total of five different ligands, seven metal precursors, and four solvents were tested in an iterative optimization mode. Standard HPLC was used to monitor stereoselectivity following DDQ-induced oxidation. This type of catalyst search led to the... 

Q.-L. Zhou, A. Pfaltz, Chiral Mercaptoaryl-oxazolines as Ligands in Enantioselective Copper-Catalyzed 1,4-Additions of Grignard Reagents to Enones, Tetrahedron, 1994, 50, 4467-4478. 

It may be concluded from the different examples shown here that the enantioselective copper-catalyzed allylic substitution reaction needs further improvement. High enantioselectivities can be obtained if chirality is present in the leaving group of the substrate, but with external chiral ligands, enantioselectivities in excess of 90% ee have only been obtained in one system, limited to the introduction of the sterically hindered neopentyl group. 

The use of vinyl epoxides as substrates in enantioselective copper-catalyzed reactions, on the other hand, has met with more success. An interesting chiral ligand effect on Cu(OTf)2-catalyzed reactions between cyclic vinyloxiranes and dialkylzinc reagents was noted by Feringa et al. [51]. The 2,2 -binaphthyl phosphorus amidite ligands 32 and 43 (Fig. 8.5), which have been successfully used in copper-catalyzed enantioselective conjugate additions to enones [37], allowed kinetic resolution of racemic cyclic vinyloxiranes (Scheme 8.26). 

For enantioselective copper catalyzed addition of organozinc reagents to imines, see [97-116]. Enantioselective Ni-catalyzed alkyne, imine, triethylborane 3-component coupling has been reported, but modest selectivities (51-89% ee) are observed. For this method, vinylation is accompanied by ethyl transfer [149]... 

SCHEME 3. Enantioselective copper-catalyzed addition of butylmagnesium chloride to 2-cyclo-hexenone... 

TABLE 1. Enantioselective copper-catalyzed conjugate addition of Giignard reagents to 2-cyclohexenone ... 

FIGURE 4. Chiral NHC ligands for the enantioselective copper-catalyzed conjugate addition of Grignard reagents... 

Compared to the enantioselective allylic alkylation using soft nucleophiles, the reaction with Grignard reagents has received much less attention. The first enantioselective copper-catalyzed allylic alkylation with alkylmagnesium reagents was reported in 1995 by the groups of Backvall, van Koten and coworkers (Scheme 13). ... 

Finally, the best enantioselectivity with this system was obtained by using cop-per(II) acetate, with propionic acid as additive, and by conducting the reaction at lower temperatures (70 %, 57 % ee) [20]. Later, the use of an azanorbornane add, which was a bicyclic analog of proline, resulted in better activity and enantioselectivity (65 % ee) [21], In the same year, Pfaltz reported the use of chiral bisoxazoline 3 in the enantioselective copper-catalyzed acyloxylation reaction (Scheme 3) [22], Although long reaction times were required, the enantioselectivity achieved with... 

Figure 2. Pyridine derivatives for the enantioselective copper-catalyzed allylic oxidation.

Vuagnoux-d Augustin M, KeMi S, Alexakis A (2007) Enantioselective copper-catalyzed conjugate addition to 2- or 3-substituted cyclopent-2-en-l-ones construction of stereogenic quaternary carbon centers. Synlett 2057-2060... 

Scheme 3 Enantioselective copper-catalyzed 1,4-conjugate addition...

Several other groups developed alternative BINOL-derived phosphoramidite ligands for highly enantioselective copper-catalyzed Michael additions. Whereas Waldmann et al. included a bicyclic bispidine in... 

Very similar ligands were used by Hoveyda et < /.298,298a,298b for the enantioselective copper-catalyzed SN2 -substitution of allyl phosphates, allowing the highly enantioselective formation of tertiary und quarternary... 

The peptidic phosphine ligands that had been introduced by Hoveyda and co-workers271 for enantioselective copper-catalyzed Michael additions (see Section 9.12.2.2.1) were also employed successfully in silver-catalyzed asymmetric Mannich reactions.3 Thus, the aryl-substituted imines 372 reacted with various silyl enol ethers in the presence of stoichiometric amounts of isopropanol, as well as catalytic amounts of silver acetate and ligand 373 to... 

An enantioselective copper catalyzed addition of alkynes to enamines was reported... 

Enantioselective C-H insertion is clearly the domain of chiral dinuclear rhodium catalysts (see Chap. 16.2). Only very few examples of enantioselective copper-catalyzed reactions of this type have been reported. As a possible approach to the mitomycine ring system, Sulikowski has studied the cyclization of diazo esters 28 quite extensively using various chiral transition metal catalysts... 

Mercaptoaryl-1,3-oxazolines 3.52 (X = SH) have recently been recommended as ligands in enantioselective copper-catalyzed 1,4-addition of orga-nomagnesium reagents to a-cyclenones [969], although interesting selectivities are only observed with 2-cycloheptenone. 

An interesting enantioselective copper-catalyzed coupling of pyrroles 261 with isatins 260 was reported for the synthesis of 3-substituted-3-hydroxy-2-oxindoles 262. This reaction proceeds in moderate to high yield with high ee (140L3192). 

Enantioselective copper-catalyzed desymmetrization of meso cyclic allylic bisdiethyl-phosphates has alsobeen conducted with dialkylzinc reagents. Piarulli and Gennari initially showed that the copper(l) complex of a chiral Schiff base catalyzed tlie enantioselective desymmetrization of 4-cyclopentene-l,3-bis(diethylphosphate) with diethyzinc (Equation 20.75). Piarulli, Gennari, and Feringa then improved upon the enantioselectivities... 

The scope of enantioselective, copper-catalyzed allylic substitution reactions is not limited to so-called hard carbon nucleophiles and achiral acyclic linear electrophiles. A recent report from Ito, Sawamura, and co-workers showed that a diboron reagent can serve as a pronucleophile for enantioselective, copper-catalyzed boronation of (Z)-aUylic carbonates (Equation 20.85). The corresponding chiral allylboronates were isolated in good yields with high enantioselectivities. 

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