Enantioselective Michael Addition of Cyclic β-Diones to α,β-Unsaturated Enones Catalyzed by Quinine-Based Organocatalysts

An enantioselective (52–98% ee) Michael addition between cyclic β-diones and α,β-unsaturated enones was established in the presence of quinine-based primary amine or squaramide. A variety of cinnamones were smoothly converted into the desired 3,4-dihydropyrans in moderate to high yields (63–99%). Chalcones were also suitable acceptors and gave rise to the expected adducts in satisfactory yields (31–99%). The resulting adducts readily underwent further modification to form fused 4H-pyran or 2,3-dihydrofuran.


Results and Discussion
We were pleased to find that the Michael addition of dimedone 1a to cinnamone 2a proceeded smoothly in the presence of 9-amino(9-deoxy)-epi-quinine 3a (Figure 1) in combination with a series of different acid co-catalysts. It was documented that the acid co-catalyst had a great influence on the yield and enantioinduction [16]. The aromatic carboxylic acids displayed superior catalytic effect compared with sulfonic acid and aliphatic acids ( Table 1, entries 4-9 vs. entries 1-3). The desired 3,4-dihydropyran 4a was generated with good to excellent enantioselectivities (87-90% ee) in the presence of various aromatic acids. In contrast, salicylic acid (SA) afforded an optimal yield (99%) and a superior enantioselectivity (90% ee) (entry 9 vs. entries 4-8) [50]. Having identified salicylic acid as the preferential acid co-catalyst, we turned our attention to evaluate the effect of other primary amines 3b and 3c ( Figure 1) derived from naturally occurring cinchona alkaloids [51]. Both 3b and 3c delivered the expected 3,4-dihydropyran 4a possessing opposite configurations to the adduct afforded by 3a (entries 10 and 11). Moreover, these two pseudo-enantiomers displayed poorer catalytic activities and enantioselectivities compared with 9-amino(9-deoxy)-epi-quinine 3a (entries 10 and 11 vs. entry 9). Subsequently, we examined the effect of the solvent with a combination of 3a and salicylic acid. Tetrahydrofuran (THF) emerged as the favorable one in terms of reactivity and enantioselectivity (entry 15 vs. entries 9,[12][13][14]. Notably, the model process proceeded equally smoothly when the amount of cinnamone was decreased to 1.2 equivalents (entry 16 vs. entry 15). Reducing the reaction temperature (0 °C) led to a slightly higher enantioselectivity (97% ee) (entry 17).  With the optimal reaction conditions in hand, various cinnamones 2 were treated with dimedone 1a to determine the scope and generality of this Michael addition. As presented in Table 2, the electronic property exerted marginal impact on this asymmetric process. The electron-deficient cinnamones 2c-2f generally provided the corresponding 3,4-dihydropyrans in slightly higher chemical yields, in contrast with the electron-rich acceptors 2g and 2h ( Table 2, entries 3-6 vs. entries 7 and 8). Meanwhile, all these enones gave rise to the desired adducts with excellent enantioselectivities (96-97% ee) irrespective of electronic nature (entries [3][4][5][6][7][8]. On the other hand, the steric hindrance slightly impaired the reactivity of this conjugate addition reaction. In this context, the ortho-substituted enone 2b afforded somewhat poorer conversion (87% yield) in comparison with other electron-poor cinnamones 2c-2f (96-99% yield) (entry 2 vs. entries 3-6). Gratifyingly, 2i and 2j, both possessing a bulky naphthyl group at the β-site, were also compatible with this catalytic system (entries 9 and 10). The resulting adducts 4ai and 4aj were formed in excellent yields and with high levels of enantioselectivities. The heteroaromatic enones 2k and 2l were all suitable partners for this Michael reaction (entries 11 and 12). The alkyl-substituted enones 2m and 2n were found to react relatively slowly with dimedone, however, synthetically useful yields and satisfactory enantiocontrol were still obtained (entries 13 and 14). Remarkably, cyclic enone 2o was also a competent acceptor, furnishing the bridged-ring compound 4ao in 91% yield and 98% ee (entry 15) [37]. The ketone substituent (R2) could also be varied from methyl group to ethyl group. Although relatively poorer conversion was detected, excellent enantioselectivity was maintained for this sterically more hindered acceptor (entry 16). It seemed to be an effect of increased steric bulk on the ketone, retarding the acceptor to approach the catalyst, thereby slowing down the reaction rate. On the other hand, the unsubstituted cyclic β-dione, 1,3-cyclohexanedione, was also tolerated by this catalytic system. Acceptable yields (67-78%) and high degrees of enantiomeric excesses (94-96% ee) were successfully achieved (entries [17][18][19], despite its relatively lower reactivity in contrast with dimedone [20,52]. Notably, a one mmole-scale Michael addition of cinnamone 2a and dimedone 1a was performed under optimal reaction conditions. Excellent chemical yield (95%) and enantiopurity (94% ee) were both obtained (entry 1).  With the optimal reaction conditions in hand, various cinnamones 2 were treated with dimedone 1a to determine the scope and generality of this Michael addition. As presented in Table 2, the electronic property exerted marginal impact on this asymmetric process. The electron-deficient cinnamones 2c-2f generally provided the corresponding 3,4-dihydropyrans in slightly higher chemical yields, in contrast with the electron-rich acceptors 2g and 2h ( Table 2, entries 3-6 vs. entries 7 and 8). Meanwhile, all these enones gave rise to the desired adducts with excellent enantioselectivities (96-97% ee) irrespective of electronic nature (entries 3-8). On the other hand, the steric hindrance slightly impaired the reactivity of this conjugate addition reaction. In this context, the ortho-substituted enone 2b afforded somewhat poorer conversion (87% yield) in comparison with other electron-poor cinnamones 2c-2f (96-99% yield) (entry 2 vs. entries 3-6). Gratifyingly, 2i and 2j, both possessing a bulky naphthyl group at the β-site, were also compatible with this catalytic system (entries 9 and 10). The resulting adducts 4ai and 4aj were formed in excellent yields and with high levels of enantioselectivities. The heteroaromatic enones 2k and 2l were all suitable partners for this Michael reaction (entries 11 and 12). The alkyl-substituted enones 2m and 2n were found to react relatively slowly with dimedone, however, synthetically useful yields and satisfactory enantiocontrol were still obtained (entries 13 and 14). Remarkably, cyclic enone 2o was also a competent acceptor, furnishing the bridged-ring compound 4ao in 91% yield and 98% ee (entry 15) [37]. The ketone substituent (R 2 ) could also be varied from methyl group to ethyl group. Although relatively poorer conversion was detected, excellent enantioselectivity was maintained for this sterically more hindered acceptor (entry 16). It seemed to be an effect of increased steric bulk on the ketone, retarding the acceptor to approach the catalyst, thereby slowing down the reaction rate. On the other hand, the unsubstituted cyclic β-dione, 1,3-cyclohexanedione, was also tolerated by this catalytic system. Acceptable yields (67-78%) and high degrees of enantiomeric excesses (94-96% ee) were successfully achieved (entries [17][18][19], despite its relatively lower reactivity in contrast with dimedone [20,52]. Notably, a one mmole-scale Michael addition of cinnamone 2a and dimedone 1a was performed under optimal reaction conditions. Excellent chemical yield (95%) and enantiopurity (94% ee) were both obtained (entry 1).  With the optimal reaction conditions in hand, various cinnamones 2 were treated with dimedone 1a to determine the scope and generality of this Michael addition. As presented in Table 2, the electronic property exerted marginal impact on this asymmetric process. The electron-deficient cinnamones 2c-2f generally provided the corresponding 3,4-dihydropyrans in slightly higher chemical yields, in contrast with the electron-rich acceptors 2g and 2h ( Table 2, entries 3-6 vs. entries 7 and 8). Meanwhile, all these enones gave rise to the desired adducts with excellent enantioselectivities (96-97% ee) irrespective of electronic nature (entries 3-8). On the other hand, the steric hindrance slightly impaired the reactivity of this conjugate addition reaction. In this context, the ortho-substituted enone 2b afforded somewhat poorer conversion (87% yield) in comparison with other electron-poor cinnamones 2c-2f (96-99% yield) (entry 2 vs. entries 3-6). Gratifyingly, 2i and 2j, both possessing a bulky naphthyl group at the β-site, were also compatible with this catalytic system (entries 9 and 10). The resulting adducts 4ai and 4aj were formed in excellent yields and with high levels of enantioselectivities. The heteroaromatic enones 2k and 2l were all suitable partners for this Michael reaction (entries 11 and 12). The alkyl-substituted enones 2m and 2n were found to react relatively slowly with dimedone, however, synthetically useful yields and satisfactory enantiocontrol were still obtained (entries 13 and 14). Remarkably, cyclic enone 2o was also a competent acceptor, furnishing the bridged-ring compound 4ao in 91% yield and 98% ee (entry 15) [37]. The ketone substituent (R2) could also be varied from methyl group to ethyl group. Although relatively poorer conversion was detected, excellent enantioselectivity was maintained for this sterically more hindered acceptor (entry 16). It seemed to be an effect of increased steric bulk on the ketone, retarding the acceptor to approach the catalyst, thereby slowing down the reaction rate. On the other hand, the unsubstituted cyclic β-dione, 1,3-cyclohexanedione, was also tolerated by this catalytic system. Acceptable yields (67-78%) and high degrees of enantiomeric excesses (94-96% ee) were successfully achieved (entries [17][18][19], despite its relatively lower reactivity in contrast with dimedone [20,52]. Notably, a one mmole-scale Michael addition of cinnamone 2a and dimedone 1a was performed under optimal reaction conditions. Excellent chemical yield (95%) and enantiopurity (94% ee) were both obtained (entry 1).  Having identified cinnamones as the suitable acceptors, we successively turned our attention to chalcone (Scheme 1), a class of challenging substrates for iminium ion activation [16]. Different than cinnamones, the bulky benzene group might retard the later annulation process, therefore only the initial Michael adduct was accessed. Considering the unstability of the Michael adduct due to aerobic oxidation [53], a subsequent acetylation was conducted after the initial conjugate addition in a one-pot manner. To our disappointment, the titled process allowed access to the final acetyl derivative 6aa in fairly low yield (<20%), even when the initial Michael addition was performed at room temperature. Having identified cinnamones as the suitable acceptors, we successively turned our attention to chalcone (Scheme 1), a class of challenging substrates for iminium ion activation [16]. Different than cinnamones, the bulky benzene group might retard the later annulation process, therefore only the initial Michael adduct was accessed. Considering the unstability of the Michael adduct due to aerobic oxidation [53], a subsequent acetylation was conducted after the initial conjugate addition in a one-pot manner. To our disappointment, the titled process allowed access to the final acetyl derivative 6aa in fairly low yield (<20%), even when the initial Michael addition was performed at room temperature. Fortunately, we finally found that the Michael addition of chalcone worked properly in the presence of squaramide 7 derived from quinine (see supporting material) [54,55]. As outlined in Table 3, this Michael addition was independent of the electronic nature of the substituents on the aromatic rings. Both the electron-rich acceptors 5b and 5f and the electron-deficient acceptors 5c and 5g generated the expected adducts in satisfactory yields and excellent optical purities (Table 3, entries 2 and 6 vs. entries 3 and 7). Moreover, the steric hindrance exerted influence on this Michael addition to a certain extent. The enone 5e possessing a naphthyl group afforded relatively lower isolated yield (68%) even after a prolonged reaction time, albeit accompanied by outstanding enantioselectivity (entry 5). Heteroaromatic chalcones 5d and 5h were also favorable partners, giving rise to the final acetyl derivatives with high levels of enantiopurities (entries 4 and 8). Except for dimedone, 1,3cyclohexanedione 1b was a competent donor as well, albeit a longer reaction time was required in order to achieve complete conversion (entry 9). In contrast with Singh's precedent study (72% ee for 6aa) [38], our protocol efficiently improved the enantioselectivity and displayed a wide substrate generality for this Michael addition of cyclic β-dione to chalcone [56]. Moreover, a one mmole-scale Michael addition of chalcone 5a with dimedone 1a proceeded smoothly as well. The expected acetyl derivate 6aa was formed in an almost quantitative yield and with satisfactory enantioselectivity (entry 1). The alkyl-substituted enone 5i was also a suitable acceptor, albeit unsatisfactory enantioselectivity was obtained for the resulting Michael adduct (entry 10). Fortunately, we finally found that the Michael addition of chalcone worked properly in the presence of squaramide 7 derived from quinine (see supporting material) [54,55]. As outlined in Table 3, this Michael addition was independent of the electronic nature of the substituents on the aromatic rings. Both the electron-rich acceptors 5b and 5f and the electron-deficient acceptors 5c and 5g generated the expected adducts in satisfactory yields and excellent optical purities (Table 3, entries 2 and 6 vs. entries 3 and 7). Moreover, the steric hindrance exerted influence on this Michael addition to a certain extent. The enone 5e possessing a naphthyl group afforded relatively lower isolated yield (68%) even after a prolonged reaction time, albeit accompanied by outstanding enantioselectivity (entry 5). Heteroaromatic chalcones 5d and 5h were also favorable partners, giving rise to the final acetyl derivatives with high levels of enantiopurities (entries 4 and 8). Except for dimedone, 1,3-cyclohexanedione 1b was a competent donor as well, albeit a longer reaction time was required in order to achieve complete conversion (entry 9). In contrast with Singh's precedent study (72% ee for 6aa) [38], our protocol efficiently improved the enantioselectivity and displayed a wide substrate generality for this Michael addition of cyclic β-dione to chalcone [56].
Moreover, a one mmole-scale Michael addition of chalcone 5a with dimedone 1a proceeded smoothly as well. The expected acetyl derivate 6aa was formed in an almost quantitative yield and with satisfactory enantioselectivity (entry 1). The alkyl-substituted enone 5i was also a suitable acceptor, albeit unsatisfactory enantioselectivity was obtained for the resulting Michael adduct (entry 10).  The five-membered cyclic dione, 1,3-cyclopentadione 1c, was also tolerated by our catalytic protocol (Scheme 2). However, it proved to be an inferior donor in terms of reactivity and enantioselectivity, in contrast with the six-membered cyclic dione. The related acetyl derivative 6ca was obtained in an unsatisfactory yield and with moderate optical purity. To demonstrate the synthetic potential of this Michael reaction, product modification was performed on the Michael adducts. 3,4-Dihydropyran 4aa readily underwent a dehydrating procedure to afford 4H-pyran 8 without the loss of optical purity (Scheme 3a) [20]. The Michael adduct of chalcone could be utilized for the facile preparation of the biologically interesting 2,3-dihydrofuran 9 via a successive stereoselective oxidative cyclization process (Scheme 3b) [57]. The fused 2,3- The five-membered cyclic dione, 1,3-cyclopentadione 1c, was also tolerated by our catalytic protocol (Scheme 2). However, it proved to be an inferior donor in terms of reactivity and enantioselectivity, in contrast with the six-membered cyclic dione. The related acetyl derivative 6ca was obtained in an unsatisfactory yield and with moderate optical purity.  The five-membered cyclic dione, 1,3-cyclopentadione 1c, was also tolerated by our catalytic protocol (Scheme 2). However, it proved to be an inferior donor in terms of reactivity and enantioselectivity, in contrast with the six-membered cyclic dione. The related acetyl derivative 6ca was obtained in an unsatisfactory yield and with moderate optical purity. To demonstrate the synthetic potential of this Michael reaction, product modification was performed on the Michael adducts. 3,4-Dihydropyran 4aa readily underwent a dehydrating procedure to afford 4H-pyran 8 without the loss of optical purity (Scheme 3a) [20]. The Michael adduct of chalcone could be utilized for the facile preparation of the biologically interesting 2,3-dihydrofuran 9 via a successive stereoselective oxidative cyclization process (Scheme 3b) [57]. The fused 2,3- To demonstrate the synthetic potential of this Michael reaction, product modification was performed on the Michael adducts. 3,4-Dihydropyran 4aa readily underwent a dehydrating procedure to afford 4H-pyran 8 without the loss of optical purity (Scheme 3a) [20]. The Michael adduct of chalcone could be utilized for the facile preparation of the biologically interesting 2,3-dihydrofuran 9 via a successive stereoselective oxidative cyclization process (Scheme 3b) [57]. The fused 2,3-dihydrofuran 9 was obtained as a single trans-diastereomer in a synthetically useful yield and with excellent enantioselectivity. The absolute configuration of the Michael adduct 4ad ( Table 2, entry 4) was determined to be S via comparison of the optical rotation value and HPLC traces with that of the previous literature reports [37]. On the other hand, the absolute configuration of 6aa (Table 3, entry 1) was established as R by the analysis of the optical rotation value with Singh's protocol [38]. To account for the observed stereochemical outcome of these Michael reactions, the corresponding transition state models were proposed and described in Scheme 4. The primary amine motif of 9-amino(9-deoxy)epi-quinine 3a was engaged in iminium formation with the carbonyl group of benzalacetone 1a. Meanwhile, dimedone was deprotonated by the tertiary amine moiety of aminocatalyst 3a and orientated via hydrogen-bonding, thereby leading to a favorable attack toward the si-face of cinnamon 1a. As a result, the desired S-configured product 4a was obtained. On the other hand, chalcone 5a was efficiently activated via hydrogen-bonding interactions between the NH moiety of the squaramide 7 and the carbonyl group of chalcone. Furthermore, the re-face approach of dimedone was induced by the tertiary amine of the squaramide 7 and led to the formation of the major stereoisomer with the R configuration [58].  The absolute configuration of the Michael adduct 4ad (Table 2, entry 4) was determined to be S via comparison of the optical rotation value and HPLC traces with that of the previous literature reports [37]. On the other hand, the absolute configuration of 6aa (Table 3, entry 1) was established as R by the analysis of the optical rotation value with Singh's protocol [38]. To account for the observed stereochemical outcome of these Michael reactions, the corresponding transition state models were proposed and described in Scheme 4. The primary amine motif of 9-amino(9-deoxy)-epi-quinine 3a was engaged in iminium formation with the carbonyl group of benzalacetone 1a. Meanwhile, dimedone was deprotonated by the tertiary amine moiety of aminocatalyst 3a and orientated via hydrogen-bonding, thereby leading to a favorable attack toward the si-face of cinnamon 1a. As a result, the desired S-configured product 4a was obtained. On the other hand, chalcone 5a was efficiently activated via hydrogen-bonding interactions between the NH moiety of the squaramide 7 and the carbonyl group of chalcone. Furthermore, the re-face approach of dimedone was induced by the tertiary amine of the squaramide 7 and led to the formation of the major stereoisomer with the R configuration [58]. The absolute configuration of the Michael adduct 4ad ( Table 2, entry 4) was determined to be S via comparison of the optical rotation value and HPLC traces with that of the previous literature reports [37]. On the other hand, the absolute configuration of 6aa (Table 3, entry 1) was established as R by the analysis of the optical rotation value with Singh's protocol [38]. To account for the observed stereochemical outcome of these Michael reactions, the corresponding transition state models were proposed and described in Scheme 4. The primary amine motif of 9-amino(9-deoxy)epi-quinine 3a was engaged in iminium formation with the carbonyl group of benzalacetone 1a. Meanwhile, dimedone was deprotonated by the tertiary amine moiety of aminocatalyst 3a and orientated via hydrogen-bonding, thereby leading to a favorable attack toward the si-face of cinnamon 1a. As a result, the desired S-configured product 4a was obtained. On the other hand, chalcone 5a was efficiently activated via hydrogen-bonding interactions between the NH moiety of the squaramide 7 and the carbonyl group of chalcone. Furthermore, the re-face approach of dimedone was induced by the tertiary amine of the squaramide 7 and led to the formation of the major stereoisomer with the R configuration [58].

General Remarks
1 H-and 13 C-NMR spectra were recorded on Varian 400 MHz spectrometers. Chemical shifts (δ) are reported in ppm downfield from CDCl 3 (δ = 7.26 ppm) for 1 H-NMR and relative to the central CDCl 3 resonance (δ = 77.0 ppm) for 13 C-NMR spectroscopy. Coupling constants (J) are given in Hz. ESI-HRMS spectrometry was performed with a Bruker Daltonics LCQDECA ion trap mass spectrometer. Enantiomeric excess was determined by HPLC analysis on Chiralpak AD-H, OD-H, and IC columns in comparison with the authentic racemates. Optical rotation data were recorded on a Rudolph Autopol I automatic polarimeter. Commercial grade solvents were dried and purified by standard procedures as specified in reference [59]. THF (AR grade) was used as received. All other reagents were purchased from commercial sources and were used without further purification.

Preparation of Fused Dihydrofuran via Stereoselective Oxidative Cyclization
After the initial Michael addition between 5a (49.9 mg, 0.24 mmol) and 1a (28.0 mg, 0.2 mmol) was completed, the corresponding adduct was purified via flash column chromatography. Subsequently, the mixture of PhIO (66 mg, 0.3 mmol) and Michael adduct (69.6 mg, 0.2 mmol) in H 2 O (1 mL) was treated with Bu 4 NI (111 mg, 0.3 mmol). The reaction mixture was warmed up to 30 • C and allowed to stir for 16 h. The reaction was followed by TLC until completion. The reaction mixture was successively quenched with saturated Na 2 S 2 O 3 (25 mL) and extracted by dichloromethane (25 mL × 3). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether) to furnish 2,3-dihydrobenzofuran 9 in 61% yield as a colorless oil.

Conclusions
In summary, we have successfully developed an enantioselective Michael addition of cyclic β-diones to α,β-unsaturated enones in the presence of quinine-based primary amine or squaramide. These asymmetric processes displayed especially broad substrate generalities, and various cinnamones and chalcones furnished the desired adducts in good to high yields. Although chalcones proved to be a class of challenging acceptors in the precedent study [38], good reactivities and excellent enantiopurities were achieved in the case of their Michael addition with cyclic β-diones via our protocol.
Supplementary Materials: The supplementary materials are available online.