Creation of a Chiral All-Carbon Quaternary Center Induced by CF3 and CH3 Substituents via Cu-Catalyzed Asymmetric Conjugate Addition

Cu-catalyzed asymmetric construction of a chiral quaternary center bearing CH3 and CF3 groups was achieved with high to excellent enantioselectivity using our originally developed ligands. The asymmetric conjugate addition of Me3Al to β-CF3-substituted enones and unsaturated ketoesters proceeded efficiently. The use of unsaturated ketoesters gives optically active furanones in high yields with high enantioselectivities. The perfluoroalkyl-substituted enone does not seem to be favorable in the present reaction.

T he creation of fluorine-and fluorocarbon-bearing chiral carbons has recently attracted much attention in the area of pharmaceutical chemistry. 1There have been promising studies on the enantioselective introduction of fluorine atoms and a trifluoromethyl group (CF 3 ), since natural products contain various C−H-and C−CH 3 -substituted achiral or chiral centers.Although the introduction of H and F at the same carbon atom has been reported extensively, there have been several reports on the introduction of the CH 3 group and the CF 3 group at the same carbon atom (Figure 1).While several biologically active compounds have fluorine-and fluorocarbonbearing chiral carbons, to our knowledge there have been rare examples on the enantioselective construction of CH 3 and CF 3 group-induced all-carbon quaternary centers (Figure 2). 2,3For the preparation of a quaternary carbon bearing CH 3 and CF 3 groups, several approaches are available including nucleophilic methylation and electrophilic methylation (Figure 3).There have been a several examples of nucleophilic, electrophilic, and radical trifluoromethylations, which are not reactive enough for the construction of a chiral quaternary carbon. 4Therefore, the addition reaction to CF 3 -substituted compounds seems to be a favorable approach. 5Herein, we report a novel example of the enantioselective catalytic construction of a CH 3 -and CF 3substituted chiral quaternary carbon via the conjugate addition of a CH 3 -nucleophile to a CF 3 -substituted activated olefin. 6 To achieve the present strategy, we examined our previously developed multinuclear catalysts for the enantioselective conjugate addition of organoaluminum reagents to β-CF 3substituted α,β-unsaturated ketones (Table 1). 7The use of monophosphine ligand BmP (10 mol %) with CuCl 2 •2H 2 O (5 mol %) for the conjugate addition of Me 3 Al (3 equiv) to 1a in THF at 0 °C to rt gave the desired product 2a in good yield, but the enantioselectivity was moderate (entry 1).The use of bisphosphine BP (5 mol %) instead of BmP gave the product 2a in good yield, but the enantioselectivity was poor (entry 2).Finally, the use of SP as a ligand gave product 2a in moderate yield, but the enantioselectivity was high (entry 3).Therefore, we selected SP as a suitable ligand in the present reaction (Figure 4).The use of Cu(OAc) 2 (5 mol %) instead of CuCl 2 • 2H 2 O with SP (5 mol %) for the conjugate addition of Me 3 Al (3 equiv) to 1a in THF at 0 °C to rt gave the product 2a in improved yield, 85%, but the enantioselectivity dramatically decreased (entry 4).The use of CuI or Cu(BF 4 ) 2 •6H 2 O as a Cu-source gave moderate results (entries 5 and 6).To our delight, the use of Cu(NO 3 ) 2 •3H 2 O as a Cu-source showed high catalytic activity and enantioselectivity (entry 7).
The products are given in Figure 5.The reaction gave the para-substituted products 2b, 2c, 2d, and 2e in high yield with high enantioselectivity; electron-donating (-OMe in 2d) and electron-withdrawing (-F in 2e) groups are compatible with the reaction conditions.In contrast, the starting material was almost completely recovered for the ortho-tolyl derivative 1f.The heteroaromatic derivatives 2g and 2h were obtained with high enantioselectivity, albeit in moderate yield.The relatively bulky 2-naphthyl group is compatible with the reaction, and product 2i was obtained in moderate yield with high enantioselectivity.
Unsaturated ketoesters were used for the synthesis of furanone derivatives via conjugate addition and subsequent intramolecular cyclization.7a We have already reported the use of simple unsaturated ketoesters for the one-pot synthesis of furanones, which are promising synthetic intermediates in biologically active molecules.The optimized reaction conditions were applied to several unsaturated ketoesters (Figure 6; see the Supporting Information for screening of conditions).The products 4b−e were obtained in high yield with high enantioselectivity.The Br-substituted 4e gave a fine crystal, which showed an R enantiomer by X-ray crystallographic analysis.The cyclohexylcarbonyl derivative 4f was obtained in moderate yield with high ee, but the acetyl derivative 4g was not detected due to the high volatility.The use of Et 3 Al instead of Me 3 Al retarded the reaction and gave the desired product 4h in moderate yield with good ee along with the generation of unidentified byproducts.The acyclic products 5a and 5g, not furanones, were obtained when the reaction was conducted below 0 °C (eq 1).The reaction of 3a under low temperature  The ee was determined by chiral HPLC analysis.The sign of optical rotation of the major enantiomer is given in parentheses.gave the acyclic product 5a in 66% yield with 92% ee and gave 4a in 9% yield with 94% ee.The acyclic product 5g derived from 3g was obtained at −20 °C in a good yield with moderate enantioselectivity.
Other fluoroalkyl group was examined to understand the influence of the fluorine atom on the reactivity (eq 2).The reactivity of pentafluoroethyl-substituted enone 6 under the optimized conditions was very low, and only a trace amount of product was observed (not isolated).The present result indicates that the strong electron-withdrawing effect of a perfluoroalkyl substituent might not be suitable for use in the present Cu-catalysis, since a generated Cu I -π-complex would be a key intermediate for the insertion of a C−C double bond to a Cu−Me bond. 8,9The weak donating ability of a strongly electron-deficient olefin to a Cu-center might be disfavored in promoting the reaction via a π-complex for oxidative addition.There might be other factors of fluorine atoms retarding the reaction.We postulate a plausible stereoselectivity as shown in Figure 7.The reaction of CuX and Me 3 Al gives a CuMecomplex and Me 2 Al−X, where the Me 2 Al−X assisted con struction of the CuMe-enone complex promotes the methylation.The X-ray diffraction analysis of furanone 4e indicates that the present stereoselectivity is the same as that in the reaction using typical trisubstituted enones in the presence of the same catalyst system. 7Based on the ESI-TOF-MS analyses of Cu-complexes derived from SP (see, the Supporting Information), 7d,e Al-linked SP-Cu-complex is one of the possible structures for the effective stereoselectivity of conjugate addition (Figure 8).The result of the reaction using enone 1f (R 1 = Ph, R 2 = o-tolyl) indicates that the steric hindrance around the carbonyl group of s-cis or s-trans enone might prevent the effective coordination to a Cu-center.The decrease of enantioselectivity using enone 3g (R 1 = Me, R 2 = CO 2 Et) for 5g might be attributed to the smaller steric repulsion in the s-trans enone.There might be π−π interaction between an enone and a Cu-complex for higher enantioselectivity.To elucidate the effect of olefinic geometry, (Z)-1a and (Z)-3a was used in the present reaction (eq 3).The opposite major enantiomer of 2a and 4a was observed as compared to that derived from (E)-1a and (E)-3a.Thus, the olefinic geometry of enones affects the stereoselectivity dramatically, as described in the transition state model.We previously reported that the Cu-catalyzed conjugate addition of Me 3 Al to enones and unsaturated ketoersters in the presence of SP as a ligand shows the same stereoselectivity.7a,d We consider that the same stereoselectivity works on the present conjugate addition to CF 3 -substituted enones 1 and unsaturated ketoesters 3 under the same catalyst system (see, the Supporting Information).
In conclusion, this report describes the highly enantioselective construction of CH 3 -and CF 3 -substituted chiral allcarbon quaternary carbon.A variety of enones possessing a CF 3 group at the C−C double bond are tolerable under the reaction conditions and give the desired products in high enantioselectivity.The tandem conjugate addition/cyclization gives furanone derivatives in high yield with high enantioselectivity.The results of this study may encourage other researchers to develop methods for the construction of allcarbon chiral quaternary centers bearing CH 3 and CF 3 groups.

Figure 2 .
Figure 2. Examples of compounds bearing a CH 3 -and CF 3substituted chiral center.

Figure 5 .
Figure 5. Examples of compounds bearing CH 3 -and CF 3 -substituted chiral centers.The reaction of enones (0.25 mmol) and Me 3 Al (3 equiv) was carried out in the presence of Cu(NO 3 ) 2 •3H 2 O (5 mol %) and SP (5 mol %) in THF at 0 °C to rt. a NMR yield is given in parentheses.b 1c (1 mmol) was used.

Figure 8 .
Figure 8. Postulated working model of the Cu complex with SP.