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

Abstract

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.

1. Introduction

The Michael addition of α,β-unsaturated compounds is an atom-economic carbon-carbon bond-forming reaction in organic synthesis, and the development of the enantioselective catalytic approach for this transformation, has attracted intensive attention [1,2,3,4]. Among the often-used acceptors, unactivated α,β-unsaturated enones always exhibit relatively sluggish reactivity and emerge as a class of historically challenging substrates for metal- and organocatalytic approaches [5,6,7,8,9,10,11]. In this context, the elegantly-designed chiral primary amines, especially those based on cinchona alkaloids, provide a particularly efficient LUMO-lowering (LUMO: lowest unoccupied molecular orbital) activation mode through the formation of iminium ions with these unsaturated enones [12,13,14]. Therefore, a broad range of conjugate additions of α,β-unsaturated enones with various different nucleophiles have been successfully established with constantly high enantiocontrol [15,16,17,18,19]. However, the asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds [20,21,22,23,24,25,26,27], except for 4-hydroxycoumarin and its analogues [7,28,29,30,31,32,33,34,35,36], to α,β-unsaturated enones, especially chalcones, generally draws less attention in comparison with other type of donors [37,38,39], albeit the adducts of such a conjugate addition reaction are versatile precursors to construct several classes of compounds possessing enormous bioactivities [40,41]. Liu and Feng have successfully developed an efficient Michael addition between dimedone and cinnamones employing the unmodified chiral diphenylethylenediamine (DPEN) [37]. In contrast, only moderate enantioselectivity was obtained for the Michael addition of dimedone to unfunctionalized chalcone according to Singh’s protocol [38]. Consequently, the development of the enantioselective Michael addition of cyclic β-diones to α,β-unsaturated enone is still highly sought.

Based on our continuous interest in asymmetric Michael reactions involving α,β-unsaturated enones [42,43,44,45], herein we would like to further extend the scope of donor to cyclic β-diones [20,21,22,23,46,47,48,49]. Dimedone and its analogues smoothly react with a variety of α,β-unsaturated enones, furnishing the corresponding adducts in good yields and high levels of optical purities. The synthetic potential of the desired Michael adduct is demonstrated by the easy formation of enantioenriched 4H-pyran and 2,3-dihydrofuran.

2. 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. Optimization of reaction conditions for the Michael addition of dimedone 1a to cinnamone 2a. ^a

Entry	Cat.	Acid	Solvent	Time (h)	Yield (%) b	ee (%) c
1	3a	TsOH	toluene	48	60	66
2	3a	TFA	toluene	48	65	75
3	3a	AcOH	toluene	48	82	85
4	3a	BA	toluene	24	89	90
5	3a	ONBA	toluene	36	91	90
6	3a	PNBA	toluene	36	96	89
7	3a	OFBA	toluene	24	96	88
8	3a	p-MeOC6H4CO2H	toluene	36	91	87
9	3a	SA	toluene	24	99	90
10	3b	SA	toluene	96	89	−82
11	3c	SA	toluene	36	89	−82
12	3a	SA	PhCF3	24	96	85
13	3a	SA	DCM	24	55	83
14	3a	SA	EtOH	24	99	69
15	3a	SA	THF	24	99	94
16 d	3a	SA	THF	24	99	94
17 d,e	3a	SA	THF	96	99	97

^a Unless otherwise noted, the reaction was performed with 0.1 mmol of 1a, 0.15 mmol of 2a, 20 mol % of 3a, and 40 mol % of acid in 1 mL of solvent at room temperature (r.t.). TsOH = p-toluenesulfonic acid, TFA = trifluoroacetic acid, BA = benzoic acid, ONBA = o-nitrobenzoic acid, PNBA = p-nitrobenzoic acid, OFBA = o-fluorobenzoic acid, DCM = dichloromethane. ^b Isolated yield after flash chromatography on silica gel. ^c Determined by HPLC analysis on a chiral stationary phase (Chiralcel AD-H). ^d 0.12 mmol of 2a was employed. ^e Carried out at 0 °C.

, 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, 12–14). 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. Substrate scope of the Michael addition of cyclic β-diones to cinnamones and its analogues. ^a

Entry	1	R2	R3	2	4	Yield (%) b	ee (%) c
1	1a	Ph	Me	2a	4aa	99 (95) d	97 (94) d
2	1a	o-ClC6H4	Me	2b	4ab	87	91
3	1a	m-ClC6H4	Me	2c	4ac	99	96
4	1a	p-ClC6H4	Me	2d	4ad	99	97 (S) e
5	1a	p-FC6H4	Me	2e	4ae	96	96
6	1a	p-BrC6H4	Me	2f	4af	99	97
7	1a	p-MeC6H4	Me	2g	4ag	95	97
8	1a	p-MeOC6H4	Me	2h	4ah	89	97
9	1a	1-naphthyl	Me	2i	4ai	89	96
10	1a	2-naphthyl	Me	2j	4aj	98	98
11	1a	2-furanyl	Me	2k	4ak	78	95
12	1a	2-thiophenyl	Me	2l	4al	97	91
13	1a	Me	Me	2m	4am	69	91
14	1a	n-Bu	Me	2n	4an	75	94
15	1a	-C3H6-		2o	4ao	91	98
16	1a	Ph	Et	2p	4ap	63	98
17	1b	Ph	Me	2a	4ba	71	94
18	1b	p-ClC6H4	Me	2d	4bd	78	95
19	1b	p-BrC6H4	Me	2f	4bf	67	96

^a Unless otherwise noted, the reaction was performed with 0.1 mmol of 1a, 0.12 mmol of 2a, 20 mol% of 3a, and 40 mol % of salicylic acid in 1 mL of THF at 0 °C for 96 h. ^b Isolated yield after flash chromatography on silica gel. ^c Determined by HPLC analysis on a chiral stationary phase. ^d Data within parentheses is that performed on an one-mmole scale. ^e Configuration of 4ad.

, 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 17–19), 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.

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. Substrate scope of the Michael addition of cyclic β-diones to chalcones. ^a

Entry	1	R2	Ar1	5	6	Yield (%) b	ee (%) c
1	1a	Ph	Ph	5a	6aa	95 (99) d	93 (91) d (R) e
2	1a	p-ClC6H4	Ph	5b	6ab	99	94
3	1a	p-MeC6H4	Ph	5c	6ac	96	93
4 f	1a	2-thiophenyl	Ph	5d	6ad	95	91
5 f	1a	2-naphthyl	Ph	5e	6ae	68	91
6	1a	Ph	p-ClC6H4	5f	6af	98	87
7	1a	Ph	p-MeC6H4	5g	6ag	99	95
8	1a	Ph	2-thiophenyl	5h	6ah	99	97
9 f	1b	Ph	Ph	5a	6ba	93	91
10 g	1a	n-Pr	Ph	5i	6ai	93	52

^a Unless otherwise noted, the Michael addition was performed with 0.1 mmol of 1, 0.12 mmol of 5, and 20 mol % of 7 in 1 mL of chloroform at rt for 120 h. ^b Isolated yield after flash chromatography on silica gel. ^c Determined by HPLC analysis on a chiral stationary phase. ^d Data within parentheses is that performed on a one-mmole scale. ^e Configuration of 6aa. ^f Performed with 168 h. ^g Performed with 72 h.

, 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-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].

3. Materials and Methods

3.1. General Remarks

¹H- and ¹³C-NMR spectra were recorded on Varian 400 MHz spectrometers. Chemical shifts (δ) are reported in ppm downfield from CDCl₃ (δ = 7.26 ppm) for ¹H-NMR and relative to the central CDCl₃ resonance (δ = 77.0 ppm) for ¹³C-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.

3.2. General Procedure for the Asymmetric Michael Reaction of Cinnamones

9-Amino-epi-quinine 3a (6.5 mg, 0.02 mmol), α,β-unsaturated enones (0.12 mmol), dimedone (14.0 mg, 0.1 mmol), and salicylic acid (4.9 mg, 0.04 mmol) were dissolved in THF (1 mL) without stirring. Once the solution was cooled down to 0 °C, the reaction mixture was stirred for 96 h. After the solvent was removed in vacuo, the residue was purified by flash chromatography on silica gel (EtOAc/petroleum ether) to afford the desired 3,4-dihydropyran.

2-Hydroxy-2,7,7-trimethyl-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4aa) [37]. Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.30–7.23 (m, 2H), 7.19–7.12 (m, 3H), 4.03 (br s, 0.6H), 3.84 (t, J = 8.4 Hz, 0.6H), 3.31 (br s, 0.4H), 3.16–3.12 (m, 0.4H), 2.50–2.15 (m, 6H), 1.48 (s, 1.7H), 1.46 (s, 1.3H), 1.19 (s, 1.7H), 1.16 (s, 1.3H), 1.11 (s, 1.7H), 1.07 (s, 1.3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.3, 196.9, 169.6, 168.6, 144.9, 142.9, 128.8, 128.2, 127.8, 127.7, 126.9, 126.8, 126.5, 125.7, 113.0, 110.5, 99.8, 99.2, 50.6, 50.5, 42.9, 42.8, 42.7, 40.5, 33.9, 32.8, 31.9, 31.4, 29.5, 28.6, 28.3, 27.8, 27.4, 27.1; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 4.820 min, t_major = 7.627 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −4.2° (c = 0.028, EtOH).

4-(2-Chlorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ab) [60]. Colorless oil; 87% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.36–7.29 (m, 1H), 7.10–7.05 (m, 3H), 4.36–4.24 (m, 1H), 3.83 (br s, 0.5H), 3.43 (br s, 0.5H), 2.49–2.11 (m, 6H), 1.49 (s, 1.4H), 1.48 (s, 1.6H), 1.18 (s, 1.6H), 1.16 (s, 1.4H), 1.09 (s, 1.6H), 1.07 (s, 1.4H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.7, 196.5, 169.7, 140.5, 133.6, 129.9, 129.5, 127.8, 127.6, 126.9, 126.7, 126.6, 112.6, 110.4, 99.7, 98.1, 50.7, 50.6, 42.9, 42.8, 37.7, 31.9, 31.5, 29.4, 28.9, 28.2, 27.9, 27.6, 27.3; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (90/10), 1.0 mL/min, UV 254 nm, t_minor = 7.703 min, t_major = 9.353 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −32.8° (c = 0.021, EtOH).

4-(3-chlorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ac) [37]. Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.19–7.09 (m, 3H), 7.02 (t, J = 7.8 Hz, 1H), 4.34 (br s, 0.5H), 3.89 (t, J = 4.8 Hz, 0.5H), 3.82–3.77 (m, 1H), 2.48–2.09 (m, 6H), 1.44 (s, 3H), 1.18 (s, 1.3H), 1.15 (s, 1.7H), 1.09 (s, 1.3H), 1.07 (s, 1.7H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.3, 197.0, 169.9, 169.1, 147.3, 145.9, 134.2, 133.9, 129.6, 129.5, 129.1, 127.9, 127.5, 127.1, 126.4, 125.9, 125.27, 125.25, 112.6, 110.3, 99.6, 98.1, 50.6, 50.5, 42.9, 42.8, 42.5, 40.5, 33.9, 33.3, 31.9, 31.5, 29.9, 29.5, 28.6, 28.3, 27.8, 27.4, 26.9; 96% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.267 min, t_major = 7.583 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +5.5° (c = 0.039, EtOH).

4-(4-Chlorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ad) [37]. Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.23 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.95 (d, J = 4.4 Hz, 0.5H), 3.81 (d, J = 8.6 Hz, 0.5H), 3.16–3.09 (m, 0.5H), 2.95 (br s, 0.4H), 2.49–2.17 (m, 6H), 1.53 (s, 1.5H), 1.50 (s, 1.5H), 1.18 (s, 1.5H), 1.15 (s, 1.5H), 1.10 (s, 1.4H), 1.08 (s, 1.6H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.9, 196.6, 169.3, 168.3, 143.5, 141.9, 132.1, 131.3, 129.1, 128.8, 128.49, 128.47, 128.3, 127.9, 112.9, 110.5, 99.5, 97.9, 50.74, 50.72, 42.9, 42.8, 42.5, 40.3, 33.6, 32.6, 32.0, 31.5, 29.5, 28.7, 28.3, 28.1, 27.5, 27.4; 97% ee was determined by HPLC on OD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.493 min, t_major = 8.417 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +13.8° (c = 0.039, EtOH), [α]_D²° = +10.5° (c = 0.039, DCM).

4-(4-Fluorophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ae) [37]. Colorless oil; 96% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.13 (t, J = 6.4 Hz, 1H), 7.08 (t, J = 6.4 Hz, 1H), 6.94 (t, J = 9.4 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H), 3.94 (br s, 0.5H), 3.82 (dd, J = 9.8, 8.2 Hz, 0.5H), 3.51–3.27 (m, 1H), 2.48–2.11 (m, 6H), 1.47 (s, 3H), 1.78 (s, 1.4H), 1.14 (s, 1.6H), 1.09 (s, 1.4H), 1.07 (s, 1.6H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.2, 196.9, 169.5, 168.6, 161.2 (d, J¹_C-F = 243.3 Hz), 160.9 (d, J¹_C-F = 241.8 Hz), 140.6 (d, J⁴_C-F = 3.2 Hz), 139.0 (d, J⁴_C-F = 3.3 Hz), 129.2, 129.1, 128.5 (d, J³_C-F = 7.8 Hz), 128.2 (d, J³_C-F = 7.8 Hz), 115.4 (d, J²_C-F = 21.1 Hz), 115.0 (d, J²_C-F = 21.2 Hz), 114.6, 114.4, 113.0, 110.7, 99.6, 98.1, 60.4, 50.7, 50.6, 42.9, 42.8, 42.7, 40.6, 33.4, 32.6, 31.9, 31.4, 29.5, 28.6, 28.3, 27.9, 27.3, 27.0, 20.9, 14.1; 96% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.043 min, t_major = 9.330 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −5.4° (c = 0.041, EtOH).

4-(4-Bromophenyl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4af) [37]. Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.37 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 3.90 (t, J = 5.4 Hz, 0.5H), 3.72 (pseudo triple, J = 5.4 Hz, 0.6H), 3.50 (br s, 0.5H), 3.19 (br s, 0.4H), 2.48–2.07 (m, 6H), 1.49 (s, 1.6H), 1.48 (s, 1.4H), 1.17 (s, 1.4H), 1.14 (s, 1.6H), 1.09 (s, 1.4H), 1.07 (s, 1.6H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.0, 196.7, 169.4, 168.4, 144.1, 142.6, 131.6, 131.4, 130.9, 129.6, 128.9, 128.7, 120.0, 119.4, 112.8, 110.4, 99.5, 97.9, 50.7, 50.6, 42.9, 42.8, 42.4, 40.3, 33.7, 32.8, 31.9, 31.5, 29.5, 28.7, 28.3, 28.1, 27.4, 27.3; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.720 min, t_major = 10.570 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +13.9° (c = 0.010, EtOH).

2-Hydroxy-2,7,7-trimethyl-4-(p-tolyl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ag) [60]. Colorless oil; 95% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.16–7.01 (m, 4H), 3.99 (br s, 0.6H), 3.80 (pseudo triple, J = 8.8 Hz, 0.6H), 3.33 (pseudo double, J = 9.6 Hz, 0.8H), 2.50–2.13 (m, 9H), 1.47 (s, 3H), 1.19 (s, 1.7H), 1.15 (s, 1.3H), 1.10 (s, 1.7H), 1.07(s, 1.3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.1, 196.7, 169.2, 169.1, 141.8, 139.6, 136.2, 135.1, 129.8, 129.0, 128.7, 127.5, 126.8, 126.7, 113.3, 110.5, 99.7, 98.1, 50.7, 42.9, 42.8, 42.7, 40.3, 33.6, 31.9, 31.5, 29.5, 28.8, 28.3, 27.9, 27.4, 27.3, 21.0, 20.9; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.313 min, t_major = 7.733 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +6.2° (c = 0.041, EtOH).

2-Hydroxy-4-(4-methoxyphenyl)-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ah) [37]. Colorless oil; 89% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.10 (d, J = 8.8 Hz, 1.1H), 7.05 (d, J = 8.8 Hz, 0.9H), 6.82 (d, J = 7.6 Hz, 1.1H), 6.79 (d, J = 8.4 Hz, 0.9H), 3.99 (br s, 0.6H), 3.80 (pseudo triple, J = 8.8 Hz, 0.6H), 3.75 (s, 3H), 3.59 (br s, 0.4H), 3.31 (br s, 0.6H), 2.49–2.11 (m, 6H), 1.47 (s, 1.7H), 1.46 (s, 1.3H), 1.19 (s, 1.7H), 1.15 (s, 1.3H), 1.10 (s, 1.7H), 1.07 (s, 1.3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.0, 196.7, 169.1, 167.9, 158.2, 157.6, 136.8, 134.4, 128.7, 127.9, 127.8, 114.5, 113.8, 113.4, 113.3, 110.6, 99.7, 88.1, 55.2, 55.1, 50.8, 42.9, 42.8, 42.7, 40.1, 33.2, 31.9, 31.49, 31.47, 29.5, 28.8, 28.3, 27.9, 27.5; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 6.353 min, t_major = 12.270 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +6.5° (c = 0.030, EtOH).

2-Hydroxy-2,7,7-trimethyl-4-(naphthalen-1-yl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ai). Colorless oil; 89% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 8.18 (d, J = 8.0 Hz, 0.3H), 8.13 (d, J = 8.4 Hz, 0.7H), 7.90 (d, J = 8.0 Hz, 0.7H), 7.85 (d, J = 7.6 Hz, 0.3H), 7.74 (d, J = 8.4 Hz, 0.7H), 7.68 (d, J = 8.0 Hz, 0.3H), 7.65–7.54 (m, 2.5H), 7.34 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 5.6 Hz, 0.5H), 4.82 (d, J = 6.8 Hz, 0.8H), 4.70 (br s, 0.5H), 3.39 (br s, 0.8H), 2.63–2.23 (m, 6H), 1.47 (s, 3H), 1.27 (s, 2H), 1.24 (s, 1H), 1.17 (s, 2H), 1.12 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.9, 196.7, 169.7, 138.6, 134.7, 130.8, 129.3, 128.9, 127.9, 126.2, 125.8, 125.4, 125.3, 125.2, 123.3, 122.5, 118.8, 117.1, 110.2, 99.5, 98.3, 50.8, 50.7, 43.1, 42.9, 37.9, 32.1, 31.5, 29.4, 29.2, 28.0, 27.9, 27.83, 27.80; ESI-HRMS calcd. for C₂₂H₂₄O₃ + H⁺ 337.1804, found 337.1798; 96% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 4.927 min, t_major = 6.790 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −88.9° (c = 0.045, EtOH).

2-Hydroxy-2,7,7-trimethyl-4-(naphthalen-2-yl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4aj) [37]. Colorless oil; 98% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.81–7.69 (m, 3H), 7.59 (s, 0.5H), 7.55 (s, 0.5H), 7.44–7.35 (m, 2.5H), 7.27–7.26 (m, 0.5H), 4.19 (br s, 0.5H), 4.01 (pseudo triple, J = 8.6 Hz, 0.5H), 3.29–3.17 (m, 1H), 2.57–2.17 (m, 6H), 1.49 (s, 3H), 1.26 (s, 2H), 1.19 (s, 1H), 1.13 (s, 1.6H), 1.09 (s, 1.4H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.2, 196.9, 169.7, 168.6, 142.3, 140.5, 133.6, 133.5, 132.3, 132.1, 128.8, 127.9, 127.7, 127.53, 127.52, 127.4, 126.1, 125.7, 125.65, 125.57, 125.52, 125.4, 124.9, 124.8, 113.0, 110.4, 99.8, 98.2, 50.7, 50.6, 42.9, 42.8, 42.5, 40.0, 34.1, 32.9, 32.0, 31.5, 29.9, 29.5, 28.7, 28.4, 27.9, 27.5, 27.2; 98% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 7.073 min, t_major = 13.053 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +60.2° (c = 0.051, EtOH).

4-(Furan-2-yl)-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ak) [37]. Colorless oil; 78% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.36 (s, 0.6H), 7.29 (s, 0.4H), 6.28 (dd, J = 3.0, 1.8 Hz, 1H), 6.02 (d, J = 3.2 Hz, 0.7H), 5.95 (d, J = 2.0 Hz, 0.3H), 4.15 (d, J = 6.8 Hz, 1H ), 4.04 (br s, 1H), 2.55–2.22 (m, 6H), 1.55 (s, 2.2 H), 1.41 (s, 0.8H), 1.17 (s, 3H), 1.11 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.7, 168.9, 155.5, 141.9, 140.3, 110.6, 110.3, 108.4, 106.0, 105.3, 98.3, 50.7, 42.8, 35.9, 32.0, 28.6, 28.2, 27.9, 26.1; 95% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.327 min, t_major = 6.257 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −12.9° (c = 0.015, EtOH).

2-Hydroxy-2,7,7-trimethyl-4-(thiophen-2-yl)-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4al). Brown oil; 97% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.17 (d, J = 4.8 Hz, 0.6H), 7.06 (d, J = 4.8 Hz, 0.6H), 6.89–6.87 (m, 1H), 6.81 (s, 1H), 4.32 (d, J = 5.6 Hz, 0.6H), 4.23 (pseudo triple, J = 8.0 Hz, 0.4H), 3.53 (br s, 1H), 2.51-2.11 (m, 6H), 1.52 (s, 2H), 1.46 (s, 1H), 1.19 (s, 2H), 1.16 (s, 1H), 1.10 (s, 2H), 1.07 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.8, 196.7, 169.1, 168.1, 148.7, 147.2, 127.0, 126.4, 124.6, 124.2, 123.8, 123.7, 123.2, 122.4, 112.9, 110.7, 99.4, 98.4, 50.6, 42.8, 42.7, 39.9, 31.9, 31.4, 29.4, 29.3, 28.5, 28.4, 27.7, 27.66, 27.61, 27.3; ESI-HRMS calcd. for C₁₆H₂₀O₃S + H⁺ 293.1211, found 293.1206; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.850 min, t_major = 7.423 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −18.9° (c = 0.047, EtOH).

2-Hydroxy-2,4,7,7-tetramethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4am). Colorless oil; 69% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 3.66–3.35 (m, 1H), 2.77–2.66 (m, 1H), 2.29–2.06 (m, 6H), 1.55 (s, 1.4H), 1.50 (s, 1.6H), 1.23 (d, J = 7.6 Hz, 2H), 1.21 (d, J = 7.6 Hz, 1H), 1.05 (s, 3H), 1.02 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 213.5, 198.5, 197.9, 170.7, 166.7, 166.5, 117.1, 114.9, 114.3, 99.1, 97.8, 51.3, 51.2, 51.1, 49.2, 43.2, 42.8, 42.7, 41.5, 39.2, 31.9, 31.4, 29.8, 29.2, 28.4, 28.1, 28.0, 27.2, 26.9, 24.3, 22.9, 22.1, 19.7, 19.4, 18.5; ESI-HRMS calcd. for C₁₃H₂₀O₃ + H⁺ 225.1491, found 225.1485; 91% ee was determined by HPLC on IC column, hexane/i-propanol (95/5), 1.0 mL/min, UV 254 nm, t_minor = 49.740 min, t_major = 77.910 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −5.5° (c = 0.017, EtOH).

4-Butyl-2-hydroxy-2,7,7-trimethyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4an). Colorless oil; 75% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 3.19–3.10 (m, 1H), 2.93–2.87 (m, 0.5H), 2.64 (s, 0.3H), 2.59 (s, 0.3H), 2.30–2.09 (m, 6H), 2.01–1.89 (m, 1H), 1.79–1.73 (m, 1H), 1.65–1.45 (m, 3H), 1.35–1.19 (m, 4H), 1.06–1.02 (m, 6H), 0.89–0.81 (m, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 213.8, 198.6, 197.8, 171.5, 167.1, 166.7, 115.7, 114.2, 113.9, 99.3, 97.9, 51.4, 51.3, 51.2, 48.3, 43.2, 42.9, 42.8, 38.2, 35.1, 32.1, 31.8, 31.7, 31.3, 30.9, 30.5, 29.8, 29.7, 29.4, 29.3, 28.5, 28.3, 28.2, 28.1, 28.0, 27.9, 27.1, 26.8, 22.8, 22.7, 22.4, 14.1, 14.0; ESI-HRMS calcd. for C₁₆H₂₆O₃ + H⁺ 267.1960, found 267.1964; 94% ee was determined by HPLC on IC column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 4.440 min, t_major = 8.093 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −13.0° (c = 0.034, EtOH).

2-Hydroxy-9,9-dimethyl-2,3,4,5,6,8,9,10-octahydro-7H-2,6-methanobenzo[b]oxocin-7-one (4ao) [37]. White solid; 91% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 4.46 (s, 1H ), 3.15 (s, 1H), 2.29 (s, 2H), 2.19 (s, 2H), 2.02 (d, J = 12.8 Hz, 1H), 1.93 (d, J = 12.4 Hz, 1H), 1.74 (d, J = 15.2 Hz, 1H), 1.16 (dd, J = 13.0, 3.8 Hz, 1H), 1.59 (d, J = 11.2 Hz, 2H), 1.45–1.33 (m, 2H), 1.04 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.7, 171.2, 112.3, 101.3, 50.3, 42.0, 38.7, 36.2, 32.3, 28.5, 28.4, 28.2, 26.9, 19.2; 98% ee was determined by HPLC on IC column, hexane/i-propanol (90/10), 1.0 mL/min, UV 254 nm, t_major = 12.987 min, t_minor = 14.423 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +4.7° (c = 0.023, EtOH).

2-Ethyl-2-hydroxy-7,7-dimethyl-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ap) [37]. Colorless oil; 63% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.24–7.16 (m, 2.5H), 7.12 (d, J = 7.6 Hz, 1H), 7.09–7.06 (m, 1.5H), 3.99 (br s, 0.5H), 3.76 (pseudo triple, J = 9.0 Hz, 0.5H), 3.15–3.00 (m, 1H), 2.44–2.09 (m, 6H), 1.69–1.63 (m, 2H), 1.13 (s, 1.6H), 1.09 (s, 1.4H), 1.04 (s, 1.6H), 1.00 (s, 1.4H), 0.89 (0.86) (t, J = 7.6 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 196.9, 196.5, 169.3, 168.0, 145.1, 142.9, 129.0, 128.3, 126.9, 126.7, 125.8, 113.3, 110.4, 101.3, 99.7, 50.8, 42.9, 42.8, 40.3, 38.0, 33.9, 33.6, 33.2, 32.0, 31.9, 31.5, 29.5, 28.9, 28.3, 27.5, 7.3, 7.2; 98% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.247 min, t_major = 11.667 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −5.4° (c = 0.018, EtOH).

2-Hydroxy-2-methyl-4-phenyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4ba) [60]. White solid; 71% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.28 (t, J = 7.2 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.19–7.12 (m, 3H), 4.02 (br s, 0.5H), 3.84 (pseudo triple, J = 8.8 Hz, 0.5H), 3.36–3.31(m, 0.5H), 2.63–2.45 (m, 2H), 2.42–2.30 (m, 2H), 2.27–2.15 (m, 2H), 2.11–1.95 (m, 2H), 1.47 (s, 1.5H), 1.45 (s, 1.5H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.2, 196.9, 171.1, 170.1, 144.8, 142.7, 128.9, 128.3, 127.9, 127.7, 126.79, 126.77, 126.6, 125.8, 114.4, 111.6, 99.6, 97.9, 42.8, 40.4, 36.9, 33.9, 32.5, 29.3, 29.2, 27.9, 27.2, 20.8, 20.2; 94% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 5.343 min, t_major = 6.693 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −8.2° (c = 0.019, EtOH).

4-(4-chlorophenyl)-2-hydroxy-2-methyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4bd): White solid; 78% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.25 (d, J = 7.2 Hz, 0.6H), 7.21 (d, J = 8.8 Hz, 1.5H), 7.11 (d, J = 8.8 Hz, 0.6H), 7.07 (d, J = 7.6 Hz, 1.4H), 3.95 (pseudo triple, J = 4.8 Hz, 0.5H), 3.82 (pseudo triple, J = 9.0 Hz, 0.5H), 3.33 (br s, 0.5H), 3.05 (br s, 0.5H), 2.61–2.33 (m, 4H), 2.26–2.17 (m, 2H), 2.07–1.97 (m, 2H), 1.51 (s, 1.6H), 1.49 (s, 1.4H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.2, 196.8, 171.2, 170.2, 143.4, 141.8, 132.0, 131.2, 128.8, 128.4, 128.3, 128.2, 114.2, 111.6, 99.4, 97.8, 42.5, 40.3, 36.9, 33.5, 32.6, 29.3, 29.2, 28.1, 27.2, 20.7, 20.2; ESI-HRMS calcd. for C₁₆H₁₇ClO₃ + H⁺ 293.0944, found 293.0937; 95% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 6.397 min, t_major = 8.430 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −11.9° (c = 0.007, EtOH).

4-(4-Bromophenyl)-2-hydroxy-2-methyl-2,3,4,6,7,8-hexahydro-5H-chromen-5-one (4bf). White solid; 67% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.38 (d, J = 8.8 Hz, 0.8H), 7.36 (d, J = 8.8 Hz, 1.2H), 7.05 (d, J = 10.0 Hz, 0.8H), 7.03 (d, J = 8.8 Hz, 1.2H), 3.93 (pseudo triple, J = 5.0 Hz, 0.5H), 3.81 (pseudo triple, J = 9.2 Hz, 0.5H), 3.23 (br s, 0.5H), 2.99 (br s, 0.5H), 2.61–2.33 (m, 4H), 2.28–2.17 (m, 2H), 2.07–1.97 (m, 2H), 1.52 (s, 1.6H), 1.49 (s, 1.4H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.2, 196.8, 171.2, 170.2, 143.9, 142.4, 131.7, 131.4, 130.9, 129.6, 128.8, 128.6, 120.1, 119.4, 114.2, 111.6, 99.4, 97.8, 42.5, 40.3, 36.9, 36.8, 33.6, 32.7, 29.3, 29.2, 28.1, 27.2, 20.7, 20.2; ESI-HRMS calcd. for C₁₆H₁₇BrO₃ + H⁺ 337.0439, found 337.0438; 96% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 6.780 min, t_major = 8.967 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −8.5° (c = 0.008, EtOH).

3.3. Procedure for the Asymmetric Michael Reaction of Chalcones

Dimedone 1a (14.0 mg, 0.1 mmol), chalcone 5a (25.0 mg, 0.12 mmol), and quinine-based squaramide 7 (12.5 mg, 0.02 mmol) were dissolved in chloroform (1.0 mL). After stirring at room temperature for 120 h, triethylamine (41.7 μL, 0.3 mmol) was added in one portion. Subsequently, acetyl chloride (14.2 μL, 0.2 mmol) was added dropwise. Once the reaction completed (1 h), the crude product was purified over silica gel by column chromatography (EtOAc/petroleum ether) to afford 6aa (37.1 mg, 95 % yield) as a colorless oil.

5,5-Dimethyl-3-oxo-2-(3-oxo-1,3-diphenylpropyl)cyclohex-1-en-1-yl acetate (6aa) [38,53]. ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.96 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.28–7.22 (m, 4H), 7.15 (t, J = 6.6 Hz, 1H), 4.79 (t, J = 7.4 Hz, 1H), 3.82 (ABX, J_AB = 17.2 Hz, J_AX = 8.0 Hz, 1H), 3.75 (ABX, J_AB = 17.2, J_BX = 6.8 Hz, 1H), 2.53 (AB, J_AB = 18.0 Hz, 1H), 2.42 (AB, J_AB = 17.2 Hz, 1H), 2.24 (s, 2H), 2.15 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.7, 198.6, 167.3, 163.9, 142.0, 136.8, 132.9, 128.9, 128.5, 128.2, 128.1, 127.4, 126.1, 116.4, 51.7, 42.7, 40.8, 35.7, 32.5, 28.1, 27.9, 20.9; 93% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 7.467 min, t_major = 10.760 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +41.5° (c = 0.032, CHCl₃).

2-(1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)-5,5-dimethyl-3-oxocyclohex-1-en-1-yl acetate (6ab). Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.95 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.24–7.17 (m, 4H), 4.74 (t, J = 7.2 Hz, 1H), 3.79 (ABX, J_AB = 17.6 Hz, J_AX = 7.2 Hz, 1H), 3.72 (ABX, J_AB = 17.8 Hz, J_BX = 7.8 Hz, 1H), 2.53 (AB, J_AB = 18.0 Hz, 1H), 2.42 (AB, J_AB = 17.6 Hz, 1H), 2.24 (s, 2H), 2.20 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.8, 198.3, 167.4, 164.0, 140.5, 136.7, 133.1, 131.9, 128.9, 128.7, 128.6, 128.3, 128.1, 51.7, 42.7, 40.6, 35.3, 32.6, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C₂₅H₂₆ClO₄ + H⁺ 425.1514, found 425.1514; 94% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 6.560 min, t_major = 11.080 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +79.6° (c = 0.019, EtOH).

5,5-Dimethyl-3-oxo-2-(3-oxo-3-phenyl-1-(p-tolyl)propyl)cyclohex-1-en-1-yl acetate (6ac). Colorless oil; 96% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.96 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 4.74 (t, J = 7.4 Hz, 1H), 3.82 (ABX, J_AB = 17.2 Hz, J_AX = 8.0 Hz, 1H), 3.73 (ABX, J_AB = 17.2 Hz, J_BX = 6.8 Hz, 1H), 2.53 (AB, J_AB = 17.6 Hz, 1H), 2.43 (AB, J_AB = 17.6 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 2H), 2.17 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.9, 198.8, 167.5, 163.8, 138.9, 136.9, 135.7, 132.9, 129.1, 128.9, 128.5, 128.1, 127.4, 51.8 42.8, 40.9, 35.5, 32.6, 28.0, 27.9, 20.9; ESI-HRMS calcd. for C₂₆H₂₉O₄ + H⁺ 405.2060, found 405.2061; 93% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 6.467 min, t_major = 13.007 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +70.1° (c = 0.018, EtOH).

5,5-Dimethyl-3-oxo-2-(3-oxo-3-phenyl-1-(thiophen-2-yl)propyl)cyclohex-1-en-1-yl acetate (6ad). Colorless oil; 95% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.72–7.67 (m, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.20–7.16 (m, 4H), 7.10–7.09 (m, 1H), 7.05–7.00 (m, 1H), 4.71 (t, J = 7.4 Hz, 1H), 3.72 (ABX, J_AB = 16.2 Hz, J_AX = 8.4 Hz, 1H), 3.57 (ABX, J_AB = 16.4 Hz, J_BX = 6.4 Hz, 1H), 2.45 (AB, J_AB = 18.0 Hz, 1H), 2.36 (AB, J_AB = 17.6 Hz, 1H), 2.16 (s, 2H), 2.12 (s, 3H), 0.93 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.8, 191.7, 167.4, 164.1, 144.3, 141.8, 133.7, 132.1, 128.7, 128.2, 128.0, 127.4, 126.2, 51.7, 42.7, 41.3, 36.0, 32.6, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C₂₃H₂₅O₄S + H⁺ 397.1468, found 397.1468; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 6.903 min, t_major = 10.567 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +29.6° (c = 0.016, EtOH).

5,5-Dimethyl-2-(1-(naphthalen-2-yl)-3-oxo-3-phenylpropyl)-3-oxocyclohex-1-en-1-yl acetate (6ae). Colorless oil; 68% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 8.00 (d, J = 8.0 Hz, 2H), 7.78–7.73 (m, 4H), 7.56 (t, J =7.4 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.43–7.39 (m, 3H), 4.97 (t, J = 7.2 Hz, 1H), 3.94 (ABX, J_AB = 17.6 Hz, J_AX = 8.4 Hz, 1H), 3.88 (ABX, J_AB = 17.0 Hz, J_BX = 7.0 Hz, 1H), 2.56 (AB, J_AB = 18.0 Hz, 1H), 2.43 (AB, J_AB = 18.0 Hz, 1H), 2.28 (AB, J_AB = 16.8 Hz, 1H), 2.24 (AB, J_AB = 17.6 Hz, 1H), 2.15 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.8, 198.6, 167.4, 164.1, 139.5, 136.9, 133.3, 133.0, 132.0, 128.8, 128.5, 128.1, 127.9, 127.7, 127.5, 126.5, 125.8, 125.6, 125.3, 51.7, 42.8, 40.8, 35.9, 32.6, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C₂₉H₂₉O₄ + H⁺ 441.2060, found 441.2061; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 7.943 min, t_major = 11.667 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +79.7° (c = 0.011, EtOH).

2-(3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl)-5,5-dimethyl-3-oxocyclohex-1-en-1-yl acetate (6af). White solid; 98% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃₎ δ (ppm) 7.90 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.26–7.23 (m, 4H), 7.20–7.23 (m, 1H), 4.77 (t, J = 7.4 Hz, 1H), 3.82 (ABX, J_AB = 17.2 Hz, J_AX = 8.0 Hz, 1H), 3.70 (ABX, J_AB = 17.2 Hz, J_BX = 6.8 Hz, 1H), 2.54 (AB, J_AB = 17.6 Hz, 1H), 2.42 (AB, J_AB = 18.0 Hz, 1H), 2.24 (s, 2H), 2.17 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.9, 197.5, 167.3, 164.0, 141.8, 139.3, 135.1, 129.5, 128.75, 128.72, 128.2, 127.4, 126.2, 51.7, 42.7, 40.7, 35.8, 32.5, 27.8, 20.9; ESI-HRMS calcd. for C₂₅H₂₆ClO₄ + H⁺ 425.1514, found 425.1514; 87% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 9.913 min, t_major = 15.547 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +57.9° (c = 0.016, EtOH).

5,5-Dimethyl-3-oxo-2-(3-oxo-1-phenyl-3-(p-tolyl)propyl)cyclohex-1-en-1-yl acetate (6ag). Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.87 (d, J = 8.0 Hz, 2H), 7.29–7.23 (m, 6H), 7.19–7.11 (m, 1H), 4.79 (t, J = 7.4 Hz, 1H), 3.79 (ABX, J_AB = 16.4 Hz, J_AX = 7.6 Hz, 1H), 3.73 (ABX, J_AB = 16.8 Hz, J_BX = 6.8 Hz, 1H), 2.53 (AB, J_AB = 18.0 Hz, 1H), 2.42 (AB, J_AB = 17.6 Hz, 1H), 2.40 (s, 3H), 2.25 (s, 2H), 2.17 (s, 3H), 1.03 (s, 3H), 1.01 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.8, 198.3, 167.4, 163.8, 143.7, 142.1, 134.4, 129.1, 129.0, 128.2, 128.1, 127.5, 126.1, 51.7, 42.7, 40.6, 35.7, 32.6, 27.9, 21.6, 20.9; ESI-HRMS calcd. for C₂₆H₂₉O₄ + H⁺ 405.2060, found 405.2061; 95% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 9.573 min, t_major = 13.540 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +77.1° (c = 0.018, EtOH)

5,5-Dimethyl-3-oxo-2-(3-oxo-1-phenyl-3-(thiophen-2-yl)propyl)cyclohex-1-en-1-yl acetate (6ah). Colorless oil; 99% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.88 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 7.03–6.97 (m, 1H), 6.83–6.74 (m, 2H), 4.97 (t, J = 7.0 Hz, 1H), 3.82 (ABX, J_AB = 17.4 Hz, J_AX = 7.8 Hz, 1H), 3.70 (ABX, J_AB = 17.6 Hz, J_BX = 6.4 Hz, 1H), 2.49 (AB, J_AB = 18.0 Hz, 1H), 2.38 (AB, J_AB = 17.6 Hz, 1H), 2.19 (s, 2H), 2.15 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.4, 198.0, 167.3, 164.1, 145.7, 136.6, 133.0, 128.5, 128.2, 128.1, 126.4, 124.1, 123.3, 51.6, 42.6, 42.3, 32.6, 31.5, 27.9, 27.8, 20.9; ESI-HRMS calcd. for C₂₃H₂₅O₄S + H⁺ 397.1468, found 397.1469; 97% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 7.623 min, t_major = 9.193 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +102.9° (c = 0.019, EtOH)

3-Oxo-2-(3-oxo-1,3-diphenylpropyl)cyclohex-1-en-1-yl acetate (6ba). Colorless oil; 93% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.97 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.44 (t, J =7.4 Hz, 2H), 7.29–7.23 (m, 4H), 7.16 (t, J = 6.6 Hz, 1H), 4.80 (t, J = 7.2 Hz, 1H), 3.81 (ABX, J_AB = 17.8 Hz, J_AX = 6.6 Hz, 1H), 3.75 (ABX, J_AB = 17.6 Hz, J_BX = 7.6 Hz, 1H), 2.65 (dt, J = 18.0, 6.4 Hz, 1H), 2.53 (dt, J = 18.0, 5.9 Hz, 1H), 2.37 (t, J = 6.4 Hz, 2H), 2.17 (s, 3H), 1.98–1.89 (m, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 198.8, 198.7, 167.3, 165.6, 142.0, 136.8, 132.9, 130.1, 128.5, 128.1, 128.0, 127.5, 126.1, 40.8, 37.9, 35.7, 29.0, 20.9, 20.7; ESI-HRMS calcd. for C₂₃H₂₃O₄ + H⁺ 363.1591, found 363.1591; 91% ee was determined by HPLC on AD-H column, hexane/i-propanol (70/30), 1.0 mL/min, UV 254 nm, t_minor = 7.667 min, t_major = 10.660 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +92.4° (c = 0.016, EtOH).

3-Oxo-2-(3-oxo-1,3-diphenylpropyl)cyclopent-1-en-1-yl acetate (6ca). Colorless oil; 31% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.94 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.0 Hz, 2H), 7.36–7.34 (m, 2H), 7.26 (t, J = 6.8 Hz, 2H), 7.18 (t, J = 7.0 Hz, 1H), 4.49 (t, J = 7.2 Hz, 1H), 4.06 (ABX, J_AB = 17.6 Hz, J_BX = 8.8 Hz, 1H), 3.56 (ABX, J_AB = 17.6 Hz, J_BX = 6.0 Hz, 1H), 2.93–2.79 (m, 2H), 2.47–2.38 (m, 2H), 2.21 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 205.3, 198.3, 176.7, 166.5, 141.9, 136.8, 133.1, 129.9, 128.6, 128.5, 128.0, 127.8, 126.7, 40.8, 35.8, 34.7, 26.9, 21.1; ESI-HRMS calcd. for C₂₂H₂₂O₄ + H⁺ 349.1440, found 349.1437; 57% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 8.787 min, t_major = 12.983 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +29.0° (c = 0.014, EtOH).

5,5-Dimethyl-3-oxo-2-(1-oxo-1-phenylhexan-3-yl)cyclohex-1-en-1-yl acetate (6ai). Colorless oil; 93% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.91 (d, J = 7.2 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 3.32 (ABX, J_AB = 16.4 Hz, J_BX = 6.8 Hz, 1H), 3.23 (ABX, J_AB = 16.0 Hz, J_BX = 6.4 Hz, 1H), 2.46 (AB, J_AB = 18.0 Hz, 1H), 2.41 (AB, J_AB = 18.0 Hz, 1H), 2.27 (AB, J_AB = 15.6 Hz, 1H), 2.21 (AB, J_AB = 15.2 Hz, 1H), 2.20 (s, 3H), 1.77–1.68 (m, 2H), 1.54–1.47 (m, 1H), 1.21–1.16 (m, 2H), 1.06 (s, 3H), 0.99 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 199.7, 199.4, 167.7, 163.8, 137.2, 132.8, 128.6, 128.4, 128.1, 52.1, 42.7, 42.0, 35.0, 32.4, 31.6, 28.0, 27.9, 21.1, 20.9, 13.9; ESI-HRMS calcd. for C₂₂H₂₉O₄ + H⁺ 357.2066, found 357.2064; 52% ee was determined by HPLC on IC column, hexane/i-propanol (99/1), 1.0 mL/min, UV 254 nm, t_major = 39.457 min, t_minor = 42.963 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = +4.75° (c = 0.022, EtOH).

3.4. Preparation of 4H-Pyran via Dehydrating

Thionyl chloride (7.3 μL, 11.9 mg, 0.1 mmol) was added dropwise to a solution of 4a (28.6 mg, 0.1 mmol, 97% ee) and pyridine (14.1 μL, 15.8 mg, 0.2 mmol) in DCM (1.0 mL) at rt. After the reaction completed, the solvent was removed under reduced pressure. The residue was subjected to silica gel flash chromatography (EtOAc/petroleum ether) to provide 8 (19.3 mg, 72% yield) as a white solid.

2,7,7-Trimethyl-4-phenyl-4,6,7,8-tetrahydro-5H-chromen-5-one (8): ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.29–7.24 (m, 4H), 7.17–7.13 (m, 1H), 4.90 (d, J = 4.8 Hz, 2H), 4.28 (d, J = 4.0 Hz, 1H), 2.39 (s, 2H), 2.22 (AB, J_AB = 16.0 Hz, 1H), 2.16 (AB, J_AB = 16.4 Hz, 1H), 1.88 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 197.3, 164.7, 145.8, 145.6, 128.2, 127.8, 126.2, 112.2, 104.5, 50.8, 41.4, 35.2, 31.9, 29.1, 27.6, 18.6; ESI-HRMS calcd. for C₁₈H₂₀O₂ + H⁺ 269.1542, found 269.1541; 98% ee was determined by HPLC on OD-H column, hexane/i-propanol (90/10), 1.0 mL/min, UV 254 nm, t_minor = 5.880 min, t_major = 8.550 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −182.7° (c = 0.024, EtOH).

3.5. 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 H₂O (1 mL) was treated with Bu₄NI (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 Na₂S₂O₃ (25 mL) and extracted by dichloromethane (25 mL × 3). The organic layer was dried over Na₂SO₄ 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.

2-Benzoyl-6,6-dimethyl-3-phenyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one (9) [61]. White solid; 61% yield purified by flash column chromatography; ¹H-NMR (400 MHz, CDCl₃) δ (ppm) 7.82 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.36 (t, J =7.2 Hz, 2H), 7.30–7.28 (m, 1H), 7.25–7.23 (m, 2H), 5.89 (d, J = 4.8 Hz, 1H), 4.40 (d, J = 4.0 Hz, 1H), 2.63 (ABX, J_AB = 18.0 Hz, J_AX = 1.6 Hz, 1H), 2.53 (AB, J_AB = 17.6 Hz, 1H), 2.25 (AB, J_AB = 16.4 Hz, 1H), 2.18 (AB, J_AB = 16.4 Hz, 1H), 1.17 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ (ppm) 193.5, 192.8, 176.3, 141.2, 134.1, 133.1, 129.0, 128.89, 128.86, 127.6, 127.3, 115.1, 91.8, 51.1, 48.9, 37.6, 34.3, 29.0, 28.3; 93% ee was determined by HPLC on AD-H column, hexane/i-propanol (80/20), 1.0 mL/min, UV 254 nm, t_minor = 10.843 min, t_major = 15.107 min; ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ = −44.6° (c = 0.021, EtOH).

4. 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.