Diastereodivergent and Enantioselective [4+2] Annulations of γ-Butenolides with Cyclic 1-Azadienes.

An asymmetric annulation reaction of γ-butenolides and cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif has been studied, proceeding in a tandem Michael addition-aza-Michael addition sequence. Endo-type cycloadducts bearing fused tetracyclic skeletons were isolated in fair yields and with high enantioselectivity (up to >99% ee) under the catalysis of modified cinchona alkaloid (DHQD)2PHAL. Besides, exo-type diastereomers could be produced using β-isocupreidine (β-ICD) as the catalyst, though with moderate enantioselectivity.

1. Introduction

γ-Butenolides represent an important class of heterocycles, which widely exist in a large number of natural products and pharmaceutically useful molecules [1,2]. In addition, the γ-butenolides act as competent direct vinylogous nucleophiles in addition reactions for the construction of an array of structurally diverse architectures [3,4,5,6], even for preparing more challenging molecules with quaternary carbon centers by using γ-substituted butenolides [7,8,9,10,11,12,13]. In contrast to abundant γ-regioselective vinylogous addition reactions, to the best of our knowledge, no examples have been reported to utilize the γ-butenolides as the reactants towards tandem reactions in consideration of the potential reactivity of both γ- and β-positions [14]. Recently, our group reported a direct asymmetric allylic alkylation of γ-butenolides with MBH carbonates to access γ,γ-disubstituted butenolides that could allow sequential aza-Michael addition to deliver interesting bicyclic piperidine derivatives [15]. These results inspired us to explore domino or tandem Michael addition-aza-Michael addition to construct a variety of polycyclic skeletons.

On the other hand, our group recently developed a series of asymmetric reactions involving cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif [16,17,18,19]. They are stable materials, and readily available from diverse saccharins and aldehydes. Importantly, they exhibit high electrophilicity, and can perform as either 2π or 4π partners in Diels-Alder cycloaddition reactions with HOMO-activated enamine species. Therefore, the good reactivity of such 1-azadienes in cycloaddition reactions suggests that they could be applied as potential reactants in the [4+2] reaction with the in situ generated dienolates from the γ-butenolides, either in a concerted or stepwise manner [15]. Here, we would like to report the asymmetric assembly of 3-vinyl-1,2-benzoisothiazole-1,1-dioxides and γ-butenolides to furnish chiral tetracyclic molecules with high structural and functional complexity.

2. Results and Discussion

2.1. The Cycloaddition Reaction of Cyclic 1-Azadienes and γ-Butenolides

2.1.1. Catalyst Screenings for the Cycloaddition Reaction

The initial reaction of styryl-substituted cyclic imine 2a and commercially available α-angelica lactone 3a was examined in DCM at 20 °C by applying bifunctional tertiary amine-thiourea 1a as the catalyst [20]. Unfortunately, the reaction was complicated, and both β,γ-regioselective endo-cycloadduct 4a and exo-cycloadduct 5a were produced in poor yields. In addition, the α-regioselective Michael addition product 6 could also be detected, albeit in much lower yield. Moreover, the enantioselectivity was very disappointing for both diastereomers (Table 1, entry 1). β-isocupreidine (β-ICD) 1b exhibited excellent exo-diastereoselectivity but with moderate enantioselectivity (entry 2) [21]. Poorer results were obtained in the presence of α-isocupreine (α-IC) 1c (entry 3) [22]. Subsequently, a number of modified cinchona alkaloids 1d–1h were investigated (entries 4–8) [23]. To our gratification, (DHQD)2PHAL 1g provided much better diastereoselectivity, and the enantioselectivity for the major endo-cycloadduct 4a was also good, though the yield was only fair; nevertheless, the ee value of the corresponding exo-product was very poor (entry 7).

Table 1

Initial catalyst screening studies on [4+2] cycloaddition of 3-styryl-1,2-benzoisothiazole-1,1-dioxide 2a and α-angelica lactone 3a a.

Entry	Cat	t (h)	Yield (%) b 4a/5a	dr c	ee (%) d 4a/5a
1	1a	24	18/18	1:1	30/10
2	1b	24	-/36	1:19	-/55
3	1c	48	11/44	1:4	21/36
4	1d	48	55/18	3:1	−45/18
5	1e	48	37/9	4:1	−85/19
6	1f	24	55/23	2:1	10/−35
7	1g	24	48/5	9:1	82/7
8	1h	24	67/13	5:1	62/−16

a Reactions were performed with 2a (0.025 mmol), 3a (0.05 mmol), 1 (10 mol %) in DCM (0.25 mL) at 20 °C. b Determined by crude 1H-NMR analysis using mesitylene as the internal standard. c By crude 1H-NMR analysis. d By chiral HPLC analysis. (DHQ)2PYR 1d: hydroquinine-2,5-diphenyl-4,6-pyrimidinediyl diether; (DHQ)2PHAL 1e: hydroquinine 1,4-phthalazinediyl diether; (DHQ)2AQN 1f: hydroquinine (anthrax-quinone-1,4-diyl) diether; (DHQD)2PHAL 1g: hydroquinidine 1,4-phthalazinediyl diether; (DHQD)2PYR 1h: hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether.

2.1.2. Studies on Endo-Cycloaddition Reaction Catalyzed by (DHQD)2PHAL 1g

In order to further improve the data of endo-cycloadduct 4a by the catalysis of (DHQD)2PHAL 1g, more reaction parameters were investigated. The results are summarized in Table 2. At first, a few solvents were explored at 20 °C (Table 2, entries 1–4), and better diastereoselectivity and excellent enantioselectivity could be obtained in PhCF3 (entry 4). The enantioselectivity was decreased at lower or higher reaction temperature (entries 5 and 6). In addition, the yield could not be improved by increasing the catalyst loadings (entry 7) or reaction concentration (entry 8), or by adding 1-azadiene 3a in portions (entry 9). It should be pointed out that significant amounts of α-regioselective Michael adduct 6 (about 20%) was observed in all the tested reactions, which might account for the fair yield of endo-cycloadduct 4a.

Table 2

Reaction condition screenings catalyzed by (DHQD)2PHAL 1g a.

Entry	Solvent	T (°C)	t (h)	Yield (%) b	dr c	ee (%) d
1	DCM	20	24	48	9:1	82)
2	CH3CN	20	48	54	5:1	73
3	PhCH3	20	48	32	9:1	96
4	PhCF3	20	48	44	11:1	95
5	PhCF3	0	48	28	11:1	90
6	PhCF3	50	48	51	7:1	80
7 e	PhCF3	20	48	44	11:1	95
8 f	PhCF3	20	48	44	11:1	95
9 g	PhCF3	20	48	44	11:1	95

a Unless noted otherwise, reactions were performed with 2a (0.025 mmol), 3a (0.05 mmol), 1g (10 mol %) in solvent (0.25 mL). b Determined by crude 1H-NMR analysis using mesitylene as the internal standard. c By crude 1H-NMR analysis. d By chiral HPLC analysis. e With 20 mol % of 1g. f In 0.125 mL solvent. g 2a was added in three portions.

2.1.3. Substrate Scope of Endo-Cycloaddition Reaction Catalyzed by (DHQD)2PHAL 1g

With the optimized conditions in hand, we then explored a variety of cyclic 1-azadienes 2 and γ-butenolides 3 under the catalysis of (DHQD)2PHAL 1g in PhCF3 at 20 °C. The results are summarized in Table 3. At first, a variety of cyclic 1-azadienes bearing electron-withdrawing or -donating groups on the aryl ring were tested in reactions with α-angelica lactone 3a (Table 3, entries 1–6). In general, the substrates could be effectively consumed, but the reactions were not clean since some side products were always observed. The desired endo-type [4+2] cycloadducts 4 could be smoothly isolated in fair to moderate yields, while high to excellent ee values were generally obtained. In addition, outstanding enantioselectivity was also attained for the cyclic 1-azadienes bearing heteroaryl groups, though the yields were still unsatisfactory (entries 7 and 8). In addition, substitutions on the isothiazole ring had marginal effect on the yields and ee values (entries 9 and 10). On the other hand, other γ-butenolides were further explored in reactions with 1-azadiene 2a. The similar excellent enantioselectivity along with a fair yield was gained for γ-phenyl-substituted butenolide (entry 11), while the simple 2-butenolide showed poor reactivity, and a moderate ee value was produced (entry 12).

Table 3

Substrate scope of endo-cycloaddition reaction a.

Entry	R	R1	R2	t (h)	Yield (%) b	ee (%) c
1	Ph	H	CH3	48	4a, 44	95
2	4-Me-C6H4	H	CH3	36	4b, 32	96
3	2-MeO-C6H4	H	CH3	36	4c, 43	94
4	3-MeO-C6H4	H	CH3	32	4d, 34	>99
5	3,5-(MeO)2-C6H3	H	CH3	36	4e, 31	94
4	2-F-C6H4	H	CH3	35	4f, 30	89
5	3-Br-C6H4	H	CH3	32	4g, 57	87
6	4-Br-C6H4	H	CH3	35	4h, 42	>99
7	2-Furyl	H	CH3	36	4i, 29	92
8	2-Thienyl	H	CH3	48	4j, 40	>99
9	Ph	6-Cl	CH3	36	4k, 31	97
10	Ph	6-tBu	CH3	40	4l, 46	98
11	Ph	H	Ph	36	4m, 31	94
12	Ph	H	H	120	4n, 30	79

a Reactions were performed with 2 (0.3 mmol), 3 (0.6 mmol), and catalyst 1g (10 mol %) in PhCF3 (3 mL) at 20 °C. b Isolated pure endo-product. c Determined by chiral HPLC analysis.

Moreover, 4-styryl-1,2,3-benzoxathiazine-2,2-dioxides 7 could also be assembled with α-angelica lactone 3a under the same catalytic conditions, and the corresponding cycloadducts 8 were isolated in excellent enantioselectivity and with modest yields (Scheme 1).

Scheme 1

More exploration with other cyclic 1-azadienes.

2.1.4. More Studies on the Exo-Type Cycloaddition Reaction Catalyzed by β-ICD 1b

As mentioned above, β-ICD 1b-catalyzed reaction of 1-azadiene 2a and α-angelica lactone 3a dominantly gave exo-type cycloadduct 5a in DCM, thus we explored more reaction conditions with β-ICD 1b. The results are summarized in Table 4. The similar data were obtained in 1,2-dichloroethane (DCE, Table 4, entry 2), but both diastereo- and enantioselectivity were decreased when other solvents were used (entries 3–6). In addition, changing other types of parameters, such as reaction temperature (entry 7), catalyst loadings (entry 8), and substrate ratio (entry 9), failed to improve the yield and enantioselectivity. As the γ-regioselective vinylogous Michael addition intermediate also was detected in the reaction mixture, tetramethylguanidine (TMG) was added to facilitate the intramolecular aza-Michael addition after the disappearance of substrate 2a. Pleasingly, better yield for exo-5a could be obtained without diminishing the stereoselectivity (entry 10). Therefore, the exo-cycloadduct seems to be greatly favored by using less hindered Brønsted base as the promoter. Although moderate ee value was obtained, the optical purity of exo-cycloadduct 5a could be improved to 90% ee after a single recrystallization (entry 10, data in parentheses).

Table 4

Screening studies on the exo-cycloaddition reaction catalyzed by β-ICD 1b a.

Entry	Solvent	T (°C)	Yield (%) b	dr c	ee (%) d
1	DCM	20	36	>19:1	55
2	DCE	20	34	>19:1	55
3	PhCH3	20	30	7:1	44
4	PhCF3	20	35	3:1	30
5	Dioxane	20	33	4:1	55
6	CH3CN	20	33	3:1	56
7 e	DCM	10	37	>19:1	56
8 f	DCM	20	38	>19:1	55
9 g	DCM	20	37	>19:1	55
10 h	DCM	20	60 (44)	>19:1	55 (90)

a Unless noted otherwise, evaluation reactions were performed with 2a (0.025 mmol), 3a (0.05 mmol), and 1b (10 mol %) in solvent (0.25 mL) for 48 h. b Determined by 1H-NMR analysis using mesitylene as the internal standard. c By crude 1H-NMR analysis. d Determined by chiral HPLC analysis. e With 20 mol % of 1b. f Three equiv of 3a was used. g TMG was added after 2a was consumed. h Data in parentheses referred to those after recrystallization.

Consequently, a few cyclic imine 2 were further tested in reactions with α-angelica lactone 3a under the above optimized conditions. As summarized in Table 5, all the reactions exhibited exclusive exo-diastereoselectivity, and the similar moderate enantioselectivity along with fair to modest yields was obtained (Table 5, entries 1–6). Simple 2-butenolide showed good reactivity, delivering the product 5g in moderate yield and ee value (entry 7).

Table 5

Substrate scope of exo-type cycloadditions catalyzed by 1b a.

Entry	R	R1	R2	Yield (%) b	ee (%) c
1	Ph	H	CH3	5a, 60	55
2	4-Me-C6H4	H	CH3	5b, 61	63
3	4-Br-C6H4	H	CH3	5c, 47	56
4	2-Thienyl	H	CH3	5d, 34	63
5	1-Naphthyl	H	CH3	5e, 44	66
6	Ph	6-Cl	CH3	5f, 37	55
7	Ph	H	H	5g, 58	54

a Reactions were performed with 2 (0.3 mmol), 3 (0.6 mmol), and 1b (10 mol %), in DCM (3 mL) at 20 °C for 24 h. b Isolated pure exo-product 5. c By chiral HPLC analysis.

2.2. Absolute Configuration of Endo-4a and Exo-5a

In order to determine the absolute configuration of the cycloadducts, single crystals suitable for X-ray crystallographic analysis were obtained from product 4a and 5a, respectively. Over 99% ees could be obtained after recrystallization from 4a (95% ee) and 5a (55% ee) in a mixture of ethyl acetate, isopropanol and petroleum ether. Thus, the absolute configuration of 4a and 5a could be unambiguously assigned, as outlined in Figure 1 [24], and more crystal data and structures refinement for 4a and 5a could be found in the supplementary materials.

Figure 1

X-ray crystal structures of the cycloadducts 4a and 5a.

2.3. Derivation of the Cycloaddition Product

The unsaturated cyclic enamide group of 4a could be reduced by Et2O.BF3 and Et3SiH [25], delivering the corresponding product 9 in a good yield and with a moderate diastereoselectivity (Scheme 2).

Scheme 2

Reduction of cycloaddition product.

3. Experimental Section

3.1. General Methods

NMR data were obtained for 1H at 600 MHz and for 13C at 151 MHz. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl3 solution. ESI HRMS was recorded on a Waters SYNAPT G2. In each case, enantiomeric ratio was determined by HPLC analysis on a chiral column in comparison with authentic racemate, using a Daicel Chiralcel OD-H Column (250 × 4.6 mm), Chiralcel IA Column (250 × 4.6 mm), Chiralcel IC Column (250 × 4.6 mm), Chiralcel IE Column (250 × 4.6 mm), Chiralcel IF Column (250 × 4.6 mm), or Chiralcel AS-H Column (250 × 4.6 mm). UV detection was monitored at 210 nm or 285 nm. Optical rotation was examined in CH2Cl2 solution at 25 °C. Column chromatography was performed on silica gel (400 mesh) eluting with ethyl acetate and petroleum ether or DCM. TLC was performed on glass-backed silica plates. UV light and I2 were used to visualize products. All chemicals including α-angelica lactone 2a were used without purification as commercially available unless otherwise noted, and the other butenolides were prepared according to the literatures [15]. α,β-Unsaturated imines 2 and 7 were prepared according to the literature procedures [16]. The tertiary amines 1b and 1c were also synthesized according to the literature procedures [21,22], and others were commercial available.

3.2. Experimental Procedures

3.2.1. General Procedure for the Preparation of Endo-Cycloadduct 4 or 8

The reaction was carried out with cyclic 1-azadiene 2 or 7 (0.3 mmol) and butenolide 3 (0.6 mmol) in benzotrifluoride (3.0 mL) in the presence of tertiary amine catalyst 1g (23.4 mg, 0.03 mmol) at 20 °C. After accomplishment, the solution was concentrated and the residue was purified by flash chromatography on silica gel (DCM/ethyl acetate = 150:1) to afford the chiral product 4 or 8.

3.2.2. General Procedure for the Preparation of Exo-Cycloadduct 5

3-Vinyl-1,2-benzoisothiazole-1,1-dioxide 2 (0.3 mmol) and butenolide 3 (0.6 mmol) were dissolved in DCM (2.0 mL). Then tertiary amine catalyst 1b (9.3 mg, 0.03 mmol) was added. The solution was stirred at 20 °C for 24 h. After the disappearance of 2, TMG (3.8 μL, 0.03 mmol) was added and the mixture was stirred for another 12 h. Then the solution was concentrated and the residue was purified by flash chromatography on silica gel (DCM/ethyl acetate = 150:1) to afford the chiral product 5.

3.2.3. General Procedure for the Preparation of 9

To a solution of 4a (37 mg, 0.10 mmol) in DCM (1 mL) was added Et2O·BF3 (100 μL, 1 mmol) and Et3SiH (130 μL, 1 mmol). The solution was stirred at room temperature for 4 h. Purification by column chromatography on silica gel (eluting with DCM/EA = 150:1) to give 9 as a white solid.

(3aS,4R,11aS)-3a-Methyl-4-phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4a) was obtained in 44% yield; the enantiomeric excess was determined to be 95% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 23.48 min, tminor = 38.66 min. = 71.0 (c = 0.4 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.85 (d, J = 7.8 Hz, 1H), 7.72–7.67 (m, 2H), 7.63–7.59 (m, 1H), 7.35–7.29 (m, 5H), 5.81 (d, J = 4.7 Hz, 1H), 4.55 (t, J = 6.3 Hz, 1H), 3.82 (d, J = 4.7 Hz, 1H), 2.98 (dd, J = 6.1, 5.2 Hz, 2H), 1.61 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.71, 136.38, 133.51, 132.42, 131.07, 130.51, 128.94, 128.44, 128.09, 121.28, 101.14, 83.58, 54.95, 47.71, 36.26, 26.78; ESI HRMS: calcd. for C20H17NO4S + Na+ 390.0776, found 390.0775.

(3aS,4R,11aS)-3a-Methyl-4-(p-tolyl)-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridine-2(11aH)-one 10,10-dioxide (4b) was obtained in 32% yield; the enantiomeric excess was determined to be 96% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 26.39 min, tminor = 40.71 min. = 136.5 (c = 0.8 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.86 (d, J = 7.8 Hz, 1H), 7.74–7.67 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 5.81 (d, J = 4.8 Hz, 1H), 4.55 (t, J = 6.5 Hz, 1H), 3.80 (d, J = 4.7 Hz, 1H), 2.97 (d, J = 6.3 Hz, 2H), 2.34 (s, 3H), 1.62 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.75, 137.88, 133.49, 133.19, 132.39, 130.93, 130.45, 130.36, 129.14, 128.97, 121.27, 101.29, 83.57, 54.87, 47.33, 36.32, 26.87, 21.07; ESI HRMS: calcd. for C21H19NO4S + Na+ 404.0932, found 404.0929.

(3aS,4R,11aS)-4-(2-Methoxyphenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4c) was obtained in 43% yield; the enantiomeric excess was determined to be 94% by HPLC analysis on Daicel Chiralcel IA column (10% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 33.00 min, tmajor = 41.11 min. = 19.8 (c = 0.44 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.85 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.4 Hz, 2H), 7.61 (d, J = 6.6 Hz, 1H), 7.34–7.27 (m, 2H), 6.95 (dd, J = 14.1, 7.7 Hz, 2H), 5.71 (d, J = 4.2 Hz, 1H), 4.60–4.55 (m, 1H), 4.47 (s, 1H), 3.89 (s, 3H), 3.12 (dd, J = 18.1, 5.2 Hz, 1H), 3.01 (dd, J = 18.1, 7.1 Hz, 1H), 1.60 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.87, 157.77, 133.38, 132.39, 130.71, 130.24, 129.29, 129.16, 125.54, 121.17, 120.67, 110.74, 84.44, 55.63, 55.27, 35.93, 26.23; ESI HRMS: calcd. for C21H19NO5S + Na+ 420.0882, found 420.0880.

(3aS,4R,11aS)-4-(3-Methoxyphenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4d) was obtained in 34% yield; the enantiomeric excess was determined to be >99% by HPLC analysis on Daicel Chiralcel IA column (10% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 42.73 min, tmajor = 50.51 min. = 89.9 (c = 0.96 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.86 (d, J = 7.9 Hz, 1H), 7.74–7.67 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 3.8 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.91–6.84 (m, 2H), 5.80 (d, J = 4.6 Hz, 1H), 4.56 (t, J = 6.2 Hz, 1H), 3.81 (s, 1H), 3.80 (s, 3H), 3.06 (dd, J = 18.1, 5.3 Hz, 1H), 2.98 (dd, J = 18.1, 7.1 Hz, 1H), 1.62 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.69, 159.51, 137.96, 133.47, 132.46, 131.02, 130.48, 129.36, 128.93, 122.87, 121.27, 116.68, 113.11, 101.10, 83.54, 55.00, 47.66, 36.15, 26.77; ESI HRMS: calcd. for C21H19NO5S + Na+ 420.0882, found 420.0883.

(3aS,4R,11aS)-4-(3,5-Dimethoxyphenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4e) was obtained in 31% yield; the enantiomeric excess was determined to be 94% by HPLC analysis on Daicel Chiralcel IA column (10% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 47.47 min, tmajor = 51.77 min. = 116.4 (c = 0.28 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.85 (d, J = 7.8 Hz, 1H), 7.72–7.67 (m, 2H), 7.62 (d, J = 7.3 Hz, 1H), 6.49 (d, J = 1.9 Hz, 2H), 6.42 (s, 1H), 5.79 (d, J = 4.6 Hz, 1H), 4.58–4.54 (m, 1H), 3.78 (s, 6H), 3.75 (d, J = 4.5 Hz, 1H), 3.11 (dd, J = 18.1, 5.2 Hz, 1H), 2.98 (dd, J = 18.1, 7.1 Hz, 1H), 1.62 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.73 (s), 160.60 (s), 138.75 (s), 133.46 (s), 130.96 (s), 130.48 (s), 128.92 (s), 121.27 (d, J = 11.3 Hz), 108.96 (s), 101.09 (s), 99.55 (s), 83.53 (s), 55.41 (s), 55.08 (s), 47.78 (s), 36.03 (s), 26.70 (s) ppm; ESI HRMS: calcd. for C21H21NO6S + Na+ 450.0987, found 450.0984.

(3aS,4R,11aS)-4-(2-Fluorophenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4f) was obtained in 30% yield; the enantiomeric excess was determined to be 89% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 20.02 min, tminor = 33.58 min. = 91.3 (c = 0.88 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.85 (d, J = 7.8 Hz, 1H), 7.69 (q, J = 7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.32 (dd, J = 13.7, 6.9 Hz, 1H), 7.13 (dt, J = 18.2, 8.2 Hz, 2H), 5.68 (d, J = 4.1 Hz, 1H), 4.62–4.57 (m, 1H), 4.28 (d, J = 3.9 Hz, 1H), 3.16 (dd, J = 18.2, 4.5 Hz, 1H), 3.05 (dd, J = 18.2, 6.9 Hz, 1H), 1.62 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.58, 162.01, 160.37, 133.53, 132.43, 131.48, 131.38, 130.56, 129.93, 128.85 124.33, 124.19, 124.10, 121.25, 115.51, 115.36, 100.38, 83.84, 55.16, 39.58, 35.97, 26.08; ESI HRMS: calcd. for C20H16FNO4S + Na+ 408.0682, found 408.0678.

(3aS,4R,11aS)-4-(3-Bromophenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4g) was obtained in 57% yield; the enantiomeric excess was determined to be 87% by HPLC analysis on Daicel Chiralcel IA column (20% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 22.19 min, tminor = 29.23 min. = 72.8 (c = 0.88 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.86 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 8.1 Hz, 2H), 7.66–7.61 (m, 1H), 7.51–7.46 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.73 (d, J = 4.2 Hz, 1H), 4.57 (dd, J = 6.6, 4.6 Hz, 1H), 3.78 (d, J = 4.2 Hz, 1H), 3.13 (dd, J = 18.2, 4.4 Hz, 1H), 3.04 (dd, J = 18.2, 6.8 Hz, 1H), 1.60 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.51, 139.05, 133.56, 133.28, 132.50, 131.38 , 131.26, 130.64, 129.96, 129.21, 128.78, 122.50, 121.30, 100.45, 83.41, 55.14, 47.34 , 36.11, 26.33; ESI HRMS: calcd. for C20H16BrNO4S + Na+ 467.9881, found 467.9882.

(3aS,4R,11aS)-4-(4-Bromophenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4h) was obtained in 42% yield; the enantiomeric excess was determined to be >99% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 21.91 min, tminor = 77.19 min. = 100.4 (c = 0.52 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.85 (d, J = 7.8 Hz, 1H), 7.74–7.67 (m, 2H), 7.63 (dd, J = 10.5, 4.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 5.74 (d, J = 4.4 Hz, 1H), 4.56 (s, 1H), 3.79 (d, J = 4.3 Hz, 1H), 3.02 (t, J = 6.4 Hz, 2H), 1.59 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.51, 135.60, 133.57, 132.47, 132.11, 131.60, 131.36, 130.65, 128.77, 122.26, 121.29, 100.54, 83.38, 55.05, 47.14, 36.19, 26.50; ESI HRMS: calcd. for C20H16BrNO4S + Na+ 467.9881, found 467.9885.

(3aS,4R,11aS)-4-(Furan-2-yl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e] pyridin-2(11aH)-one 10,10- dioxide (4i) was obtained in 29% yield; the enantiomeric excess was determined to be 92% by HPLC analysis on Daicel Chiralcel IA column (20% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 42.11 min, tminor = 58.68 min. = 5.8 (c = 0.12 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.87 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.73–7.69 (m, 1H), 7.64 (dd, J = 11.1, 4.0 Hz, 1H), 7.41 (d, J = 1.0 Hz, 1H), 6.35 (dd, J = 3.1, 1.9 Hz, 1H), 6.28 (d, J = 3.2 Hz, 1H), 5.81 (d, J = 5.7 Hz, 1H), 4.53 (t, J = 8.1 Hz, 1H), 3.97 (d, J = 5.7 Hz, 1H), 2.97 (dd, J = 18.0, 8.2 Hz, 1H), 2.83 (dd, J = 18.0, 8.1 Hz, 1H), 1.69 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.21, 149.97, 142.95, 133.52, 132.33, 130.88, 130.72, 128.72, 121.43, 121.33, 110.75, 110.47, 97.16, 82.67, 53.88, 41.71, 35.48, 27.14; ESI HRMS: calcd. for C18H15NO5S + Na+ 380.0569, found 380.0567.

(3aS,4S,11aS)-3a-Methyl-4-(thiophen-2-yl)-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4j) was obtained in 40% yield; the enantiomeric excess was determined to be >99% by HPLC analysis on Daicel Chiralcel IA column(10% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 49.55 min, tminor = 68.53 min. = 70.5 (c = 0.4 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.87 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 5.1 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 7.01–6.99 (m, 1H), 5.93 (d, J = 5.3 Hz, 1H), 4.54 (t, J = 7.7 Hz, 1H), 4.13 (d, J = 5.5 Hz, 1H), 2.94 (dd, J = 17.9, 7.9 Hz, 1H), 2.79 (dd, J = 17.9, 7.3 Hz, 1H), 1.68 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.58, 138.90, 133.56, 132.48, 130.88, 130.76, 128.99, 128.64, 127.22, 126.27, 121.41, 100.21, 82.85, 54.36, 42.84, 36.03, 27.08; ESI HRMS: calcd. for C18H15NO4S2 + Na+ 396.0340, found 396.0338.

(3aS,4R,11aS)-8-Chloro-3a-methyl-4-phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4k) was obtained in 31% yield; and the enantiomeric excess was determined to be 97% by HPLC analysis on Daicel Chiralcel ID column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285nm, tmajor = 16.55 min, tminor = 21.63 min. = 120.5 (c = 0.8 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.83 (s, 1H), 7.65 (s, 2H), 7.38–7.31 (m, 5H), 5.80 (d, J = 4.5 Hz, 1H), 4.58–4.53 (m, 1H), 3.82 (d, J = 4.5 Hz, 1H), 3.01 (dd, J = 11.9, 6.1 Hz, 2H), 1.61 (s, 3H) ppm; 13C-NMR (151 MHz, CDCl3) δ: 172.51, 136.71, 136.23, 133.94, 133.63, 130.46, 130.30, 128.49, 128.17, 127.32, 122.53, 121.41, 101.97, 83.45, 55.14, 47.68, 36.16, 26.58; ESI HRMS: calcd. for C20H16ClNO4S + Na+ 424.0386, found 424.0384.

(3aS,4R,11aS)-8-(tert-Butyl)-3a-methyl-4-phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4l) was obtained in 46% yield; the enantiomeric excess was determined to be 98% by HPLC analysis on Daicel Chiralcel IF column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 9.39 min, tminor = 10.78 min. = 78.5 (c = 0.6 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.85 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.36–7.31 (m, 5H), 5.77 (d, J = 4.8 Hz, 1H), 4.55 (s, 1H), 3.83 (d, J = 4.7 Hz, 1H), 2.96 (d, J = 6.6 Hz, 2H), 1.62 (s, 3H), 1.38 (s, 9H); 13C-NMR (151 MHz, CDCl3) δ: 172.74, 155.05, 136.44, 132.40, 131.32, 131.12, 130.53, 128.40, 128.05, 126.35, 120.98, 117.56, 100.32, 83.65, 54.94, 47.75, 36.30, 35.56, 31.07, 26.95; ESI HRMS: calcd. for C24H25NO4S + Na+ 446.1402, found 446.1400.

(3aR,4R,11aS)-3a,4-Diphenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4m) was obtained in 31% yield; and the enantiomeric excess was determined to be 94% by HPLC analysis on Daicel Chiralcel IF column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 10.98 min, tminor = 12.35 min. = 22.8 (c = 0.36 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.87 (d, J = 7.9 Hz, 1H), 7.75–7.69 (m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.38–7.33 (m, 3H), 7.25–7.22 (m, 3H), 7.18 (t, J = 7.4 Hz, 2H), 6.93 (d, J = 7.3 Hz, 2H), 5.84 (d, J = 3.1 Hz, 1H), 5.03 (d, J = 3.8 Hz, 1H), 4.12 (d, J = 2.8 Hz, 1H), 3.39 (dd, J = 17.6, 1.4 Hz, 1H), 2.65 (dd, J = 17.6, 5.0 Hz, 1H); 13C-NMR (151 MHz, CDCl3) δ: 172.97, 139.70, 136.24, 133.54, 132.50, 131.09, 130.38, 130.23, 129.03, 128.85, 128.78, 127.89, 127.67, 125.25, 121.21, 101.61, 86.25, 56.43, 49.05, 35.65; ESI HRMS: calcd. for C25H19NO4S + Na+ 452.0932, found 452.0930.

(4R,11aS)-4-Phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (4n) was obtained in 30% yield; the enantiomeric excess was determined to be 79% by HPLC analysis on Daicel Chiralcel IC column(40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 20.60 min, tmajor = 35.62 min. = −12.8 (c = 0.4 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.84 (d, J = 7.9 Hz, 1H), 7.71 (dd, J = 17.3, 7.6 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.37 (td, J = 14.1, 7.1 Hz, 5H), 5.75 (d, J = 2.4 Hz, 1H), 4.95 (t, J = 4.0 Hz, 1H), 4.81 (s, 1H), 4.10 (d, J = 3.6 Hz, 1H), 3.46 (d, J = 17.5 Hz, 1H), 2.86 (dd, J = 17.5, 5.1 Hz, 1H); 13C-NMR (151 MHz, CDCl3) δ: 172.99, 137.45, 133.51, 132.25, 131.72, 130.48, 129.19, 129.05, 128.72, 127.95, 121.17, 99.76, 78.12, 51.24, 40.94, 36.76; ESI HRMS: calcd. for C19H15NO4S + Na+ 376.0619, found 376.0616.

(3aS,4S,11aS)-3a-Methyl-4-phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e] pyridine-2(11aH)-one 10,10-dioxide (5a) was obtained in 60% yield; the enantiomeric excess was determined to be 55% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 20.97 min, tminor = 28.28 min. = −27.6 (c = 0.84 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.87 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.35 (t, J = 7.1 Hz, 1H), 7.28 (d, J = 7.2 Hz, 2H), 5.80 (d, J = 3.1 Hz, 1H), 4.55 (t, J = 8.1 Hz, 1H), 3.93 (d, J = 2.9 Hz, 1H), 3.25 (dd, J = 17.7, 7.4 Hz, 1H), 3.04 (dd, J = 17.7, 8.9 Hz, 1H), 1.19 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.4, 137.4, 133.5, 132.2, 130.5, 129.9, 129.4, 128.7, 128.0, 127.96, 121.3, 99.5, 82.9, 53.3, 46.2, 36.5, 21.8; ESI HRMS: calcd. for C20H17NO4S + Na+ 390.0776, found 390.0775.

(3aS,4S,11aS)-3a-Methyl-4-(p-tolyl)-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e] pyridin-2(11aH)-one 10,10-dioxide (5b) was obtained in 61% yield; the enantiomeric excess was determined to be 63% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 21.40 min, tminor = 30.40 min. = 73.4 (c = 0.80 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.86 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 5.78 (d, J = 3.1 Hz, 1H), 4.53 (t, J = 8.1 Hz, 1H), 3.88 (d, J = 3.1 Hz, 1H), 3.22 (dd, J = 17.7, 7.4 Hz, 1H), 3.02 (ddd, J = 17.7, 8.6, 2.7 Hz, 1H), 2.36 (s, 3H), 1.18 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.46, 137.72, 134.33, 133.89, 132.17, 130.47, 129.80, 129.36, 129.28, 128.71, 121.35, 121.28, 99.87, 82.97, 53.27, 45.76, 36.46, 21.93, 21.05; ESI HRMS: calcd. for C21H19NO4S + Na+ 404.0932, found 404.0929.

(3aS,4S,11aS)-4-(4-Bromophenyl)-3a-methyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (5c) was obtained in 47% yield; the enantiomeric excess was determined to be 56% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 23.11 min, tminor = 36.52 min. = 21.3 (c = 1.60 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.88 (d, J = 7.8 Hz, 1H), 7.76–7.70 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 5.72 (d, J = 3.0 Hz, 1H), 4.57–4.49 (m, 1H), 3.89 (d, J = 2.9 Hz, 1H), 3.25 (dd, J = 17.8, 7.6 Hz, 1H), 2.99 (dd, J = 17.8, 9.2 Hz, 1H), 1.18 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.11, 136.36, 133.53, 132.23, 131.82, 131.06, 130.69, 130.28, 128.45, 122.14, 121.38, 98.53, 82.40, 53.27, 45.75, 36.36, 21.81; ESI HRMS: calcd. for C20H16BrNO4S + Na+ 467.9881, found 467.9883.

(3aS,4R,11aS)-3a-Methyl-4-(thiophen-2-yl)-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (5d) was obtained in 34% yield; the enantiomeric excess was determined to be 63% by HPLC analysis on Daicel Chiralcel IA column (10% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 57.94 min, tmajor = 73.67 min. = 32.0 (c = 0.92 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.86 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.30 (dd, J = 4.8, 1.0 Hz, 1H), 7.07–7.03 (m, 2H), 5.84 (d, J = 3.2 Hz, 1H), 4.57 (dd, J = 8.5, 7.8 Hz, 1H), 4.22 (d, J = 3.0 Hz, 1H), 3.24 (dd, J = 17.8, 7.5 Hz, 1H), 3.00 (dd, J = 17.8, 8.9 Hz, 1H), 1.27 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.14, 139.78, 133.52, 132.29, 130.69, 129.99, 128.47, 127.18, 121.41, 98.83, 82.82, 53.22, 41.82, 36.48, 21.82; ESI HRMS: calcd. for C18H15NO4S2 + Na+ 396.0340, found 396.0338.

(3aS,4S,11aS)-3a-Methyl-4-(naphthalen-1-yl)-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (5e) was obtained in 44% yield; the enantiomeric excess was determined to be 66% by HPLC analysis on Daicel Chiralcel IF column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 20.51 min, tminor = 34.12 min. = 23.5 (c = 1.04 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 8.15 (d, J = 8.5 Hz, 1H), 7.93–7.88 (m, 2H), 7.85 (d, J = 8.1 Hz, 1H), 7.74–7.67 (m, 2H), 7.63 (dd, J = 15.3, 7.7 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 5.81 (d, J = 2.9 Hz, 1H), 4.93 (s, 1H), 4.60 (t, J = 6.8 Hz, 1H), 3.29 (dd, J = 22.4, 6.8 Hz, 2H), 1.22 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.56, 134.84, 133.97, 133.50, 132.21, 130.46, 129.93, 129.02, 128.89, 128.76, 127.39, 126.85, 126.11, 125.13, 123.34, 121.31, 101.64, 84.32, 53.78, 40.23, 36.23, 22.80; ESI HRMS: calcd. for C24H19NO4S + Na+ 440.0932, found 440.0928.

(3aS,4S,11aS)-8-Chloro-3a-methyl-4-phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (5f) was obtained in 37% yield; the enantiomeric excess was determined to be 55% by HPLC analysis on Daicel Chiralcel ID column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 17.39 min, tmajor = 22.99 min. = 35.9 (c = 1.16 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.84 (d, J = 1.1 Hz, 1H), 7.69–7.63 (m, 2H), 7.42–7.33 (m, 3H), 7.28–7.24 (m, 2H), 5.80 (d, J = 3.3 Hz, 1H), 4.53 (t, J = 8.0 Hz, 1H), 3.91 (d, J = 3.0 Hz, 1H), 3.23 (dd, J = 17.8, 7.4 Hz, 1H), 3.04 (dd, J = 17.7, 8.6 Hz, 1H), 1.19 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.16, 137.19, 136.75, 133.89, 133.40, 129.38, 129.18, 128.74, 128.05, 127.06, 122.61, 121.48, 100.35, 82.74, 53.40, 46.18, 36.39, 22.04; ESI HRMS: calcd. for C20H16ClNO4S + Na+ 424.0386, found 424.0384.

(4S,11aS)-4-Phenyl-3a,4-dihydro-1H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2(11aH)-one 10,10-dioxide (5g) was obtained in 58% yield; the enantiomeric excess was determined to be 54% by HPLC analysis on Daicel Chiralcel IE column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 29.40 min, tmajor = 51.53 min. = −17.5 (c = 0.72 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.86 (d, J = 7.9 Hz, 1H), 7.70 (dt, J = 15.9, 7.7 Hz, 2H), 7.62 (dd, J = 10.8, 3.9 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.25 (d, J = 7.3 Hz, 2H), 5.74 (d, J = 4.3 Hz, 1H), 4.70 (t, J = 4.1 Hz, 1H), 4.64 (dd, J = 8.3, 5.1 Hz, 1H), 4.01 (t, J = 3.9 Hz, 1H), 3.42 (dd, J = 17.5, 3.1 Hz, 1H), 2.93 (dd, J = 17.6, 5.5 Hz, 1H); 13C-NMR (151 MHz, CDCl3) δ: 172.86, 139.35, 133.56, 132.26, 130.95, 130.54, 129.30, 129.02, 128.13, 121.24, 99.18, 80.44, 48.17, 41.21, 36.38; ESI HRMS: calcd. for C19H15NO4S + Na+ 376.0619, found 376.0617.

3-(2-(1,1-Dioxidobenzo[d]isothiazol-3-yl)-1-phenylethyl)-5-methylfuran-2(3H)-one (6). 1H-NMR (600 MHz, CDCl3) δ: 7.86 (t, J = 8.5 Hz, 1H), 7.71 (s, 2H), 7.64 (dd, J = 6.7, 4.5 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.9 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 6.21 (d, J = 6.5 Hz, 1H), 4.05 (t, J = 7.1 Hz, 1H), 3.77 (dd, J = 12.8, 7.7 Hz, 1H), 3.07 (dd, J = 18.5, 3.6 Hz, 1H), 2.21–2.17 (m, 1H), 2.11 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 167.35, 137.45, 134.02, 130.99, 129.44, 129.31, 128.26, 128.02, 127.92, 121.75, 106.73, 45.03, 42.37, 39.43, 30.29. ESI LRMS: calcd. for C20H17NO4S + H+ 368.1, found 368.

(3aS,12R,12aS)-12a-Methyl-12-phenyl-3,3a,12,12a-tetrahydro-2H-benzo[e]furo[2',3':5,6]pyrido [1,2-c][1,2,3]oxathiazin-2-one 5,5-dioxide (8a) was obtained in 56% yield; the enantiomeric excess was determined to be 92% by HPLC analysis on Daicel Chiralcel IA column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 5.40 min, tminor = 8.00 min. = − 2.7 (c = 1.2 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.60 (d, J = 7.9 Hz, 1H), 7.44–7.36 (m, 6H), 7.26 (dd, J = 8.9, 6.4 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.24 (d, J = 3.9 Hz, 1H), 4.68 (dd, J = 8.5, 1.7 Hz, 1H), 3.58 (d, J = 3.9 Hz, 1H), 3.14 (dd, J = 19.3, 8.5 Hz, 1H), 2.80 (dd, J = 19.3, 1.7 Hz, 1H), 1.40 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 173.19, 148.77, 136.83, 133.29, 131.14, 130.07, 128.69, 127.95, 126.46, 124.19, 119.52, 117.65, 115.56, 92.17, 62.29, 49.41, 34.60, 25.14; ESI HRMS: calcd. for C20H17NO5S + Na+ 406.0725, found 406.0723.

(3aS,12R,12aS)-8-Bromo-12a-methyl-12-phenyl-3,3a,12,12a-tetrahydro-2H-benzo[e]furo[2ʹ,3ʹ:5,6] pyrido[1,2-c][1,2,3]oxathiazin-2-one 5,5-dioxide (8b) was obtained in 45% yield; the enantiomeric excess was determined to be >99% by HPLC analysis on Daicel Chiralcel IA column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 6.28 min, tminor = 8.00 min. = 6.4 (c = 1.6 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.46 (d, J = 8.6 Hz, 1H), 7.42–7.35 (m, 6H), 7.32 (d, J = 1.5 Hz, 1H), 6.24 (d, J = 3.9 Hz, 1H), 4.67 (dd, J = 8.4, 1.4 Hz, 1H), 3.55 (d, J = 3.9 Hz, 1H), 3.14 (dd, J = 19.3, 8.5 Hz, 1H), 2.76 (dd, J = 19.3, 1.5 Hz, 1H), 1.39 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 172.98, 148.76, 136.60, 132.56, 130.01, 129.80, 128.74, 128.04, 125.23, 124.08, 122.81, 116.69, 116.30, 92.02, 62.36, 49.43, 34.60, 25.06; ESI HRMS: calcd. for C20H16BrNO5S + Na+ 483.9830, found 483.9827.

(3aS,4R,5aS,11aS)-3a-Methyl-4-phenyl-1,3a,4,5,5a,11a-hexahydro-2H-benzo[4,5]isothiazolo[2,3-a]furo[2,3-e]pyridin-2-one 10,10-dioxide (9) was obtained in 86% yield; the diastereomer ratio was determined to be 4:1 by 1H-NMR analysis and the enantiomeric excess was determined to be 93% by HPLC analysis on Daicel Chiralcel IA column (20% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 210 nm, tmajor = 17.07 min, tminor = 25.06; = −32.5 (c = 0.36 M CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ: 7.80 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.39–7.31 (m, 6H), 4.34 (d, J = 11.3 Hz, 1H), 4.19 (d, J = 4.7 Hz, 1H), 3.79 (d, J = 18.0 Hz, 1H), 2.98 (ddd, J = 16.6, 15.5, 4.3 Hz, 2H), 2.47–2.42 (m, 1H), 2.30–2.22 (m, 1H), 1.34 (s, 3H); 13C-NMR (151 MHz, CDCl3) δ: 173.56, 138.32, 136.22, 135.09, 133.30, 129.68, 129.52, 128.53, 127.86, 122.46, 121.25, 83.36, 59.21, 58.31, 50.52, 34.65, 31.04, 23.49; ESI HRMS: calcd. for C20H19NO4S + Na+ 392.0932, found 392.0930.

4. Conclusions

We have investigated the asymmetric and β,γ-regioselective [4+2] annulation reactions of γ-butenolides and cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif. These reactions occurred in a cascade Michael addition-aza-Michael addition sequence to give complex fused tetracyclic architectures. Diastereodivergent cycloadducts could be produced by employing different Brønsted base catalysts. Endo-type cycloadducts were obtained in high enantioselectivity (up to >99% ee) under the catalysis of modified cinchona alkaloid (DHQD)2PHAL. On the other hand, exo-type diastereomers could be produced catalyzed by β-isocupreidine (β-ICD) followed by TMG-promoted cyclization process, though with moderate enantioselectivity. The potential application of such natural product-like compounds in biological studies is in exploration.