Organocatalytic domino Michael/cyclization reaction: efficient synthesis of multi-functionalized tetracyclic spirooxindoles with multiple stereocenters

Abstract

The asymmetric domino reaction of various 3-nitro-2H-chromene derivatives 2 to 3-isothiocyanato oxindole 3 with moderate to good enantioselectivities, employing readily available bifunctional thiourea 1d as the organocatalyst, was described. A series of chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c] pyrrole-1,3′-indoline] derivatives with four vicinal chiral carbon centers including two quaternary stereocenters were successfully prepared. Notably, the products 5 could be cleanly converted to the compounds 4 in ethanol under mild conditions.

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Introduction

Spirocyclic compounds are recognized as important precursors for easy access to a variety of cyclic products by rearrangement reaction due to their steric strain associated with the quaternary carbon.¹ Development of novel synthetic methods for the construction of new spirocyclic compounds represents a major challenge in synthetic organic and medicinal chemistry.² Recently, the highly functionalized spirocyclic oxindoles have drawn tremendous interest of researchers³ in the area of synthetic organic chemistry as well as medicinal chemistry worldwide because they occur in many natural products and have been reported to have various types of bioactivity.⁴ Due to their significant and varied biological activities design and development of novel methods for the construction of functionalized spirooxindoles have drawn remarkable interest from the synthetic, organic as well as medicinal chemists.⁵ Recently, 3-isothiocyanato oxindoles emerged as the most attractive reactants in organocatalytic cascade Aldol/cyclization reactions,⁶ Michael/cyclization reactions,⁷ Manich/cyclization reactions⁸ and [3 + 2] cyclization⁹ for the synthesis of the highly functionalized spirocyclic oxindoles. From the literature we realized that benzopyran scaffolds exhibit a wide range of biological activities such as anti-cancer, diuretic, anticoagulant, and anti-anaphylactic activity.^10–12 Recently, chiral multi-functionalized tetracyclic benzopyran derivatives have been prepared from 3-nitro-2H-chromenes in our group (eqn (1), Scheme 1).¹³ To the best of our knowledge there is no method reported for the asymmetric synthesis of chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c]pyrrole-1,3′-indoline] derivatives from the cascade reaction of 3-isothiocyanato oxindoles and 3-nitro-2H-chromenes. In continuation of our efforts towards the development of functionalized heterocycles using domino reactions, we envisioned that chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c]pyrrole-1,3′-indoline] derivatives with four vicinal chiral carbon centers including two quaternary stereocenters could be synthesized by domino reaction of 3-isothiocyanato oxindoles and 3-nitro-2H-chromenes in the presence of organocatalyst (eqn (2) and Scheme 1).

Scheme 1 General strategy for the synthesis of tetracyclic spirooxindoles.

Results and discussion

Organocatalytic asymmetric reactions have been used as a powerful tool for the synthesis of enantiopure molecules with multiple stereocenters by employing either a single catalyst or a combination of catalysts under mild, environmentally benign conditions over the past decades.¹⁴ To evaluate this hypothesis, 3-nitro-2H-chromene 2a and 3-isothiocyanato oxindole 3a were first applied. A few representative results are shown in Table 1. To our surprise, the domino reaction was completed within one minute when the reaction was carried out in the presence of the organocatalysts (Scheme 2) in DCM at −50 °C, while the diastereoselectivity was poor. To our delight, the chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c]pyrrole-1,3′-indoline] derivatives 4aa and 5aa were easily isolated by column chromatography. Both cinchona alkaloids and bifunctional thioureas have appeared to be efficient organocatalysts in asymmetric transformations since the basic tertiary nitrogen of cinchona alkaloids could activate nucleophiles by deprotonation, whereas the secondary hydroxyl group or thiourea moiety would serve as hydrogen-bonding donor in the activation of electrophiles such as α,β-unsaturated carbonyl compounds or nitroalkenes. As such, quinine 1a and cinchonine 1b were firstly screened, high yields were obtained while the ees were poor to moderate (Table 1, entries 1 and 2). Similar results were obtained when the domino reaction was catalyzed by 1c (Table 1, entry 3). Subsequently, the bifunctional thioureas 1d–1h which have appeared to be efficient organocatalysts for asymmetric additions,¹⁵ exhibited a higher catalytic activity when the domino reaction was carried out at −50 °C within one minute (Table 1, entries 4–8). To our surprise, organocatalyst 1d, derived from quinine, was proved to be superior to 1e in this domino reaction, and products were obtained with up to 78% ee (Table 1, entry 4). High yields were obtained when the domino reaction was catalyzed by other thiourea-tertiary amines 1f–1h while the enantioselectivities were somewhat low. The effect of catalyst loading on reaction efficiency has been evaluated (Table 1, entries 9–11). While 10 mol % of thiourea-tertiary amine 1d was routinely employed in this investigation, it appears that catalyst loadings as low as 5 mol % provide better enantioselectivity (Table 1, entry 10).

Table 1 Catalyst screening^a

Entry	Cat.	Time	Yield^b %/ee^c (4aa)	Yield^b %/ee^c (5aa)
a Reaction conditions: 0.24 mmol of 2a, 0.10 mmol of 3a, 10 mol% of cat in 1 mL DCM at −50 °C for 1 min.b Isolated yield.c Determined by chiral HPLC analysis.d 1 mol% of 1d was added.e 5 mol% 1d of was added.f 15 mol% of 1d was added.
1	1a	1 min	48/61	39/-32
2	1b	1 min	45/30	36/05
3	1c	1 min	57/37	37/04
4	1d	1 min	49/-78	43/72
5	1e	1 min	47/75	39/60
6	1f	1 min	52/70	40/50
7	1g	1 min	53/-36	36/13
8	1h	1 min	47/60	41/10
9^d	1d	1 min	40/76	31/69
10^e	1d	1 min	49/80	43/70
11^f	1d	1 min	51/78	43/72

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Scheme 2 Organocatalysts 1a–1h.

Subsequently, we investigated the effects of solvent on the reactivity, and most commonly used solvents are compatible with our asymmetric conditions and afforded high yields (total yields: 80–95%) with varied enantioselectivities (Table 2, entries 1–9). The reaction in a polar solvent such as THF, ethanol and ether, afforded the desired products with somewhat lower enantioselectivities (entries 3–5). After solvents were screened, chloroform turned out to be optimal to give the products in higher enantioselectivities and yields (Table 2, entry 6). In the hope of higher enantioselectivities, we decreased the reaction concentration from 1.0 to 0.5 M. As a result, a better enantiomeric excess was achieved (entry 7) within one minute. The ee was decreased when the temperature was elevated, as well as when the concentration was reduced to 0.25 M (entries 8–9). Based on the above screening, the optimal reaction conditions: 0.24 equiv of 2 and 1.0 equiv of 3a in chloroform with 5 mol% of catalyst 1d at −50 °C were established.

Table 2 Optimization of reaction conditions^a

Entry	Solvent	Yield^b/ee^c (4aa)	Yield^b/ee^c (5aa)
a Reaction conditions: 0.24 mmol of 2a, 0.10 mmol of 3a, 5 mol% of 1d in 1 mL Solvent at −50 °C.b Isolated yield.c Determined by chiral HPLC analysis.d 0.24 mmol of 2a, 0.10 mmol of 3a, in 2 mL CHCl3.e 4 mL CHCl3.f −60 °C.
1	DCM	49/80	43/70
2	Toluene	48/65	42/48
3	THF	48/50	44/20
4	Ether	43/65	37/61
5	Ethanol	45/70	39/60
6	CHCl3	52/79	43/74
7^d	CHCl3	49/81	44/77
8^e	CHCl3	50/80	45/70
9^f	CHCl3	46/82	42/70

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To test the substrate scope of domino reaction, the reaction of various 3-nitro-2H-chromene derivatives 2 with 3-isothiocyanato oxindole 3 was studied under the optimized conditions using 5 mol% of bifunctional thiourea 1d as the catalyst. The results are summarized in Table 3. As shown in Table 3, the domino reaction of various 3-nitro-2H-chromene derivatives 2 with 3-isothiocyanato oxindole 3 all gave high yields and good enantioselectivities of the desired products. Good enantioselectivities were obtained in the domino reaction of α,α-dicyanoolefins with electron-withdrawing substituent on Ar ring of 3-nitro-2H-chromene derivatives (Table 3, entries 2, 3, 5, 6). In addition, an electron-donating substituent on Ar ring of 3-nitro-2H-chromene derivatives tended to increase the reactivity and enantioselectivity (Table 3, entries 7 and 8). 3-Nitro-2H-chromene derivative 2d with electron withdrawing substituents on the ortho position afford multi-functionalized tetracyclic spiro[chromeno[3,4-c]pyrrole-1,3′-indoline] derivative with slightly inferior enantioselectivity (Table 3, entry 4). However, it should be noted that 3-nitro-2H-chromene with a furanyl show no reactivity in this system, and it remains to be explored. Gratifyingly, the reaction of 3-nitro-2H-chromene derivatives 3 with electron withdrawing substituent or electron-donating group on the R¹ group afford the desired products with a slight effect on enantioselectivities (Table 3, entries 7–11), and the enantioselectivities were up to 84%. Further exploration of the substrate scope was focused on 3-isothiocyanato oxindole 3 bearing various substituents. Replace the substituent methyl with ethyl, 3-isothiocyanato oxindole 3b showed good reactivity; excellent yields were obtained with high enantioselectivities (Table 3, entries 14–18).

Table 3 The substrate scope of domino reaction^a

Entry	R^1	Ar	2	R^2	3	Yield^b/ee^c%	4	Yield^b/ee^c%	5
a Otherwise noted, reactions performed with 0.2 mmol of 2, 0.1 mmol of 3, 20 mol% of 1e in 1 mL DCM at 10 °C under N2 for 36 h.b Isolated yield and yield based on 3.c Determined by the chiral HPLC analysis.
1	H	Ph	2a	Me	3a	49/81	4aa	44/77	5aa
2	H	p-BrC6H4	2b	Me	3a	43/82	4ab	52/80	5ab
3	H	m-BrC6H4	2c	Me	3a	56/81	4ac	42/80	5ac
4	H	o-BrC6H4	2d	Me	3a	43/67	4ad	45/70	5ad
5	H	p-ClC6H4	2e	Me	3a	49/80	4ae	47/71	5ae
6	H	p-FC6H4	2f	Me	3a	47/82	4af	46/80	5af
7	H	p-CH3C6H4	2j	Me	3a	49/83	4ag	40/85	5aj
8	H	p-OCH3C6H4	2k	Me	3a	39/83	4ah	60/81	5ak
9	5-Br	Ph	2l	Me	3a	53/83	4ai	41/51	5al
10	5-Cl	Ph	2m	Me	3a	51/84	4aj	40/51	5am
11	5-Cl	p-CH3C6H4	2n	Me	3a	49/82	4ak	37/66	5an
12	5-CH3	Ph	2o	Me	3a	40/74	4al	47/86	5ao
13	4-OCH3	Ph	2p	Me	3a	45/72	4am	38/76	5ap
14	H	Ph	2a	Et	3b	54/82	4ba	42/80	5ba
15	H	p-BrC6H4	2b	Et	3b	46/83	4bb	50/84	5bb
16	H	p-FC6H4	2f	Et	3b	46/82	4bf	47/82	5bf
17	H	p-CH3C6H4	2j	Et	3b	45/83	4bj	48/82	5bj
18	H	p-OCH3C6H4	2k	Et	3b	44/84	4bk	43/82	5bk

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Interestingly, the product 5ac could be cleanly converted to the compound 4ac in ethanol with quantitative yield under base conditions for six days, and better ee was obtained (Scheme 3).

Scheme 3 Selective transformation of domino reaction product.

To determine the absolute configuration of chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c] pyrrole-1,3′-indoline] derivatives, single crystal suitable for X-ray crystallographic analysis was fortunately obtained from enantiopure 4ca and 5ac that bear a bromine atom. As shown in Fig. 1, it composes of (C1R, C2S, C3S, C4S for 4ca; C1S, C2S, C3S, C4S for 5ca) configuration.

Fig. 1 The X-ray diffraction analysis of compounds 4ac and 5ac.

According to the above experimental results and previously reported dual activation model,^13b both the substrates involved in the transition state are activated by bifunctional thiourea 1d as proposed in Fig. 2. The Michael acceptor is assumed to be activated and oriented by the hydrogen bonds of the bifunctional thiourea, while the tertiary amine of the catalyst would provide suitable basicity to enhance the nucleophilicity of the 3-isothiocyanato oxindole. The well-defined orientation facilitates the Re attack on the activated 3-nitro-2H-chromene derivative, which favors the formation of the C2S stereocenter. Subsequent intramolecular cyclization through the attack the isothiocyanato group afforded the major C3S configured product.

Fig. 2 Proposed transition states.

Conclusions

In conclusion, we have successfully demonstrated the domino reaction of various 3-nitro-2H-chromene derivatives 2 to 3-isothiocyanato oxindole 3 with moderate to good enantioselectivities, employing readily available bifunctional thiourea 1d as the organocatalyst, which shows to be more effective catalyst than the ditrifluoromethylated one. After simple synthetic transformations, chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c]pyrrole-1,3′-indoline] derivatives with four vicinal chiral carbon centers including two quaternary stereocenters were successfully prepared. Notably, the products 5 could be cleanly converted to the compounds 4 in DCM under mild conditions. Further application of this reaction to other substrates and to the preparation of biologically relevant compound are currently underway.

Experimental section

General methods

Column chromatography was performed using silica gel (200–300 mesh) eluting with ethyl acetate and petroleum ether. ¹H NMR and ¹³C NMR spectra were recorded on Bruker DRX 400 spectrometer at room temperature in CDCl₃ as solvent. Chemical shifts for protons are reported using residual CHCl₃ as internal reference (=7.26 ppm). Carbon spectra were referenced to the shift of the ¹³C signal of CDCl₃ (=77.0 ppm). Coupling constants (J) are given in Hz. IR spectra were recorded using a Perkin-Elmer 1600 Series FTIR. ESI-HRMS spectrometer was measured with a Finnigan LCQ^DECA ion trap mass spectrometer. Optical rotations were measured at 589 nm at 25 °C in a 1 dm cell and specific rotations are given in 10⁻¹ deg cm² g⁻¹. Enantiomeric excess were determined by HPLC analysis using Daicel Chiralpak AD column (4.6 mm* 250 mm, 5 μm) Commercial grade solvents were dried and purified by standard procedures as specified in Purification of Laboratory Chemicals, 4th Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997).

General procedure for the synthesis of chiral multi-functionalized tetracyclic spiro[chromeno[3,4-c]pyrrole-,3′-indoline] derivatives

A mixture of 2a (25.3 mg, 0.10 mmol), 3a (20.4 mg, 0.10 mmol) and 5 mol% of 1d was stirred in CHCl₃ (1 mL) at −50 °C for 1 minute, then flash chromatography on silica gel (20% ethyl acetate/petroleum ether) gave product 4aa and 5aa as yellow solid.

4aa. Yellow solid, mp 204.8–206.1 °C; 22.4 mg, yield 49%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.57–7.49 (m, 3H), 7.41–7.34 (m, 3H), 7.30–7.24 (m, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.74 (t, J = 7.5 Hz, 1H), 6.44 (s, 1H), 6.28 (d, J = 7.8 Hz, 1H), 5.05 (s, 1H), 2.99 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.9, 172.7, 154.4, 143.5, 133.6, 131.9, 129.7, 129.6, 128.9, 127.0, 126.9, 126.3, 124.7, 124.5, 122.2, 118.1, 115.8, 109.4, 97.2, 79.7, 71.6, 53.0, 26.7.ESI-HRMS: calcd. for C₂₅H₁₉N₃O₄S + Na 480.0988, found 480.0983; [α]²⁰_D = −155.3 (c 0.47, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), −81% ee, t_minor = 6.61 min, t_major = 15.71 min.

5aa. Yellow solid, mp 188.4–190.2 °C; 20.1 mg, yield 44%; ¹H NMR (600 MHz, CDCl₃) δ 8.75 (s, 1H), 7.26–7.23 (m, 2H), 7.18–7.15 (m, 4H), 7.02–6.97 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.78–6.70 (m, 2H), 6.64–6.59 (m, 1H), 6.39 (dd, J = 18.5, 6.7 Hz, 3H), 5.46 (s, 1H), 3.30 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.1, 174.8, 152.4, 143.6, 133.5, 131.1, 129.6, 129.4, 129.3, 128.9, 128.1, 126.4, 123.7, 123.2, 122.6, 120.5, 118.8, 108.9, 98.4, 81.6, 72.8, 47.3, 27.3.ESI-HRMS: calcd. for C₂₅H₁₉N₃O₄S + Na 480.0988, found 480.0989; [α]²⁰_D = −103.8 (c 0.35, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), 77% ee, t_major = 5.87 min, t_minor = 10.61 min.

4ab. Yellow solid, mp 208.2–209.6 °C; 23.0 mg, yield 43%;¹H NMR (600 MHz, CDCl₃) δ 8.72 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 11.4, 4.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.42 (s, 1H), 6.27 (d, J = 7.7 Hz, 1H), 5.07 (s, 1H), 2.99 (s, 1H). ¹³C NMR (150 MHz, CDCl₃) δ 192.8, 172.7, 165.6, 154.3, 143.5, 132.8, 132.1, 131.5, 130.1, 129.8, 126.8, 126.4, 124.8, 124.5, 123.1, 122.5, 118.1, 115.6, 109.5, 97.3, 79.2, 71.7, 53.0, 26.8. ESI-HRMS: calcd. for C₂₅H₁₈BrN₃O₄S + Na 560.0079, found 560.0074; [α]²⁰_D = −125.6 (c 0.39, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −82% ee, t_minor = 5.28 min, t_major = 11.24 min.

5ab. Yellow solid, mp 198.5–200 °C; 27.8 mg, yield 52%;¹H NMR (600 MHz, DMSO) δ 11.68 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.28 (dd, J = 7.5, 4.8 Hz, 3H), 7.09 (d, J = 7.8 Hz, 1H), 7.05–7.02 (m, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.66 (dd, J = 11.5, 4.3 Hz, 1H), 6.60 (d, J = 7.4 Hz, 2H), 6.08 (s, 1H), 5.42 (s, 1H), 3.29 (s, 3H). ¹³C NMR (150 MHz, DMSO) δ 193.0, 174.3, 152.2, 144.2, 133.4, 131.8, 131.1, 131.0, 129.9, 129.8, 126.1, 124.4, 123.2, 123.0, 120.1, 118.1, 109.7, 99.2, 80.0, 73.2, 55.3, 47.7, 27.4. [α]²⁰_D = −87.7 (c 0.22, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 80% ee, t_major = 5.09 min, t_minor = 9.81 min.

4ac. Yellow solid, mp 154.4–155.3 °C; 29.9 mg, yield 56%;¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 7.73 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.55–7.45 (m, 3H), 7.31–7.13 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.42 (s, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.09 (s, 1H), 3.01 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 192.7, 172.7, 154.2, 143.5, 135.9, 132.7, 132.1, 131.9, 129.8, 128.5, 128.3, 126.8, 126.4, 124.8, 124.5, 122.5, 121.0, 118.1, 115.6, 109.5, 97.3, 78.8, 71.7, 53.0, 26.8. ESI-HRMS: calcd. for C₂₅H₁₈BrN₃O₄S + Na 560.0079, found 560.0058; [α]²⁰_D = −251.9 (c 0.35, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), −81% ee, t_minor = 6.34 min, t_major = 7.56 min.

5ac. Yellow solid, mp 216.2–218.1 °C; 22.5 mg, yield 42%;¹H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 7.56–7.53 (m, 2H), 7.28 (ddd, J = 18.8, 14.2, 7.8 Hz, 3H), 7.07 (dd, J = 18.6, 7.6 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.68 (t, J = 7.0 Hz, 2H), 6.62 (d, J = 7.3 Hz, 1H), 6.04 (s, 1H), 5.40 (s, 1H), 3.29 (s, 3H). ¹³C NMR (100 MHz, DMSO) δ 192.8, 174.3, 152.2, 147.4, 144.2, 136.5, 132.5, 131.0, 130.0, 129.8, 128.6, 126.2, 124.4, 123.2, 123.1, 121.1, 119.8, 118.0, 109.7, 99.1, 79.7, 73.1, 55.3, 47.8, 27.4. [α]²⁰_D = −37.9 (c 0.29, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), 80% ee, t_major = 5.40 min, t_minor = 7.25 min.

4ad. Yellow solid, mp 196.3–198.1 °C; 23.0 mg, yield 43%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (s, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.54–7.51 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.26–7.23 (m, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.99–6.96 (m, 2H), 6.95 (s, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.36 (d, J = 7.7 Hz, 1H), 4.93 (s, 1H), 3.04 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.0, 172.1, 153.9, 143.7, 134.0, 132.3, 132.0, 130.6, 129.7, 126.9, 126.7, 126.1, 124.6, 122.4, 118.3, 116.5, 109.3, 96.3, 77.9, 71.5, 26.7. ESI-HRMS: calcd. for C₂₅H₁₈BrN₃O₄S + Na 560.0079, found 560.0047; [α]²⁰_D = −122.0 (c 0.19, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), −67% ee, t_minor = 8.58 min, t_major = 10.10 min.

5ad. Yellow solid, mp 118.6–119.7 °C; 24.1 mg, yield 45%; ¹H NMR (600 MHz, DMSO) δ 11.75 (s, 1H), 7.67 (dd, J = 8.0, 1.0 Hz, 1H), 7.24 (td, J = 7.8, 1.0 Hz, 1H), 7.19 (td, J = 7.8, 1.5 Hz, 1H), 7.07 (dd, J = 18.2, 7.9 Hz, 2H), 7.00–6.92 (m, 2H), 6.91 (s, 1H), 6.67 (t, J = 7.2 Hz, 2H), 6.63 (d, J = 6.6 Hz, 1H), 6.57 (dd, J = 11.6, 4.2 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 5.69 (s, 1H), 3.26 (s, 3H). ¹³C NMR (150 MHz, DMSO) δ 193.8, 174.1, 151.5, 143.9, 133.8, 133.2, 131.5, 130.9, 130.1, 129.7, 129.3, 127.4, 126.0, 125.4, 124.8, 123.4, 122.8, 118.2, 109.5, 100.0, 79.8, 73.8, 55.4, 49.0, 46.3, 27.3. [α]²⁰_D = −48.0 (c 0.25, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 70% ee, t_major = 14.60 min, t_minor = 22.57 min.

4ae. Yellow solid, mp 174.3–175.8 °C; 20.1 mg, yield 49%; ¹H NMR (600 MHz, CDCl₃) δ 8.61 (d, J = 18.1 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.56–7.44 (m, 3H), 7.37–7.27 (m, 3H), 7.17 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 12.7 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.08 (s, 1H), 3.01 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.8, 172.7, 154.4, 143.5, 134.8, 132.2, 132.1, 131.2, 129.8, 127.2, 126.8, 126.4, 124.8, 124.5, 122.5, 118.2, 115.6, 109.5, 97.3, 97.3, 79.1, 71.7, 53.0, 26.7. ESI-HRMS: calcd. for C₂₅H₁₈ClN₃O₄S + Na 514.0059, found 514.0589; [α]²⁰_D = −100.0 (c 0.14, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −80% ee, t_minor = 5.17 min, t_major = 10.49 min.

5ae. Yellow solid, mp 119.5–121.2 °C; 23.1 mg, yield 47%; ¹H NMR (600 MHz, DMSO) δ 11.63 (s, 1H), 7.29 (s, 4H), 7.23 (td, J = 7.7, 1.0 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 7.00–6.96 (m, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.70 (td, J = 7.6, 0.6 Hz, 1H), 6.63–6.58 (m, 1H), 6.54 (d, J = 7.7 Hz, 2H), 6.04 (s, 1H), 5.37 (s, 1H), 3.23 (s, 3H). ¹³C NMR (150 MHz, DMSO) δ 193.0, 174.3, 152.2, 144.2, 134.3, 133.0, 131.5, 131.0, 129.9, 129.7, 128.1, 126.1, 124.4, 123.1, 123.0, 120.2, 118.1, 109.7, 99.2, 79.9, 73.2, 47.6, 27.4. [α]²⁰_D = −164.3 (c 0.14, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 71% ee, t_major = 4.97 min, t_minor = 8.80 min.

4af. Yellow solid, mp 177.3–178.9 °C; 21.8 mg, yield 47%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.55–7.52 (m, 3H), 7.30 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 8.6 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.82–6.70 (m, 1H), 6.43 (d, J = 11.1 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.06 (s, 1H), 3.01 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.0, 172.7, 163.9, 162.3, 154.4, 143.5, 132.1, 131.6, 131.6, 129.8, 129.5, 126.9, 126.3, 124.8, 124.5, 122.4, 118.2, 115.6, 114.1, 113.9, 109.5, 97.2, 79.2, 71.7, 53.1, 26.7. ESI-HRMS: calcd. for C₂₅H₁₈FN₃O₄S + Na 498.0894, found 498.0871; [α]²⁰_D = −223.9 (c 0.22, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), −82% ee, t_minor = 6.33 min, t_major = 15.26 min.

5af. Yellow solid, mp 184.3–185.6 °C; 21.8 mg, yield 46%; ¹H NMR (600 MHz, CDCl₃) δ 8.77 (s, 1H), 7.26 (dd, J = 9.4, 6.0 Hz, 1H), 7.17 (dd, J = 8.7, 5.2 Hz, 2H), 7.01 (dd, J = 11.2, 4.2 Hz, 1H), 6.89–6.83 (m, 3H), 6.79–6.72 (m, 2H), 6.64 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 6.30 (s, 1H), 5.42 (s, 1H), 3.30 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 194.8, 174.7, 164.0, 162.3, 152.3, 143.6, 131.2, 130.9, 130.8, 129.7, 129.5, 129.3, 126.4, 123.6, 123.3, 122.8, 120.1, 118.8, 115.2, 115.1, 109.0, 98.3, 80.8, 72.7, 47.4, 31.6. [α]²⁰_D = −57.3 (c 0.23, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), 80% ee, t_major = 5.95 min, t_minor = 11.33 min.

4ag. Yellow solid, mp 144.7–145.9 °C; 23.1 mg, yield 49%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 14.4, 4.6 Hz, 3H), 6.98–6.97 (m, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.73 (td, J = 7.7, 1.0 Hz, 1H), 6.39 (s, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.03 (s, 1H), 2.99 (s, 3H), 2.37 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.1, 172.8, 154.5, 143.6, 138.8, 131.9, 130.7, 129.7, 129.6, 127.9, 127.1, 126.3, 124.7, 124.5, 122.2, 118.2, 115.9, 109.4, 97.2, 79.8, 71.6, 53.0, 26.7, 21.5. ESI-HRMS: calcd. for C₂₆H₂₁N₃O₄S + Na 494.1145, found 494.1117; [α]²⁰_D = −119.1 (c 0.23, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −83% ee, t_minor = 6.96 min, t_major = 11.49 min.

5ag. Yellow solid, mp 166.1–167.4 °C; 18.8 mg, yield 40%; ¹H NMR (600 MHz, CDCl₃) δ 8.66 (s, 1H), 7.26–7.23 (m, 1H), 7.03 (dd, J = 8.3, 1.8 Hz, 2H), 6.99 (td, J = 8.2, 1.5 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.77–6.73 (m, 1H), 6.72 (td, J = 7.6, 0.8 Hz, 1H), 6.61 (td, J = 7.6, 1.1 Hz, 1H), 6.37 (dt, J = 6.6, 2.3 Hz, 3H), 5.47 (s, 1H), 3.30 (s, 3H), 2.23 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.3, 174.7, 152.4, 143.5, 139.3, 131.0, 130.4, 129.5, 129.3, 128.8, 128.7, 126.4, 123.6, 123.1, 122.5, 120.6, 118.8, 108.8, 98.4, 81.5, 72.6, 47.1, 27.2, 21.1. [α]²⁰_D = −316.2 (c 0.12, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 85% ee, t_major = 4.56 min, t_minor = 9.23 min.

4ah. Yellow solid, mp 182.4–183.5 °C; 18.9 mg, yield 39%; ¹H NMR (600 MHz, CDCl₃) δ 8.49 (s, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.52 (td, J = 7.8, 1.0 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.17–7.14 (m, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.75–6.72 (m, 1H), 6.38 (s, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.02 (s, 1H), 3.82 (s, 3H), 2.99 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.2, 172.8, 160.0, 154.5, 143.6, 132.0, 131.0, 129.7, 127.0, 126.3, 125.8, 124.7, 124.5, 122.2, 118.2, 115.8, 112.5, 109.4, 97.1, 79.6, 71.6, 55.3, 53.1, 26.7. ESI-HRMS: calcd. for C₂₆H₂₁N₃O₅S + Na 510.1049, found 510.1055; [α]²⁰_D = −90.6 (c 0.18, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −83% ee, t_minor = 6.99 min, t_major = 16.59 min.

5ah. Yellow solid, mp 166.3–167.5 °C; 29.2 mg, yield 60%; ¹H NMR (600 MHz, CDCl₃) δ 8.70 (s, 1H), 7.26–7.23 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 7.00 (t, J = 7.7 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.65–6.60 (m, 3H), 6.36 (d, J = 8.5 Hz, 3H), 5.46 (s, 1H), 3.69 (s, 3H), 3.28 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.3, 174.7, 160.1, 152.5, 143.6, 131.1, 130.3, 129.6, 129.5, 126.5, 125.6, 123.7, 123.2, 122.5, 120.7, 118.9, 113.5, 108.9, 98.5, 81.4, 72.7, 55.2, 47.1, 27.2. [α]²⁰_D = −187.5 (c 0.11, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 81% ee, t_major = 4.91 min, t_minor = 10.33 min.

4ai. Yellow solid, mp 208.4–209.5 °C; 28.4 mg, yield 53%; ¹H NMR (600 MHz, CDCl₃) δ 8.42 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.1 Hz, 2H), 7.40–7.34 (m, 3H), 7.31 (t, J = 7.5 Hz, 1H), 7.27 (dd, J = 8.8, 2.3 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 6.39 (s, 1H), 4.98 (s, 1H), 3.04 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.4, 172.6, 153.6, 143.4, 133.2, 132.7, 132.3, 129.7, 129.2, 129.0, 127.1, 126.6, 125.0, 124.5, 120.0, 118.2, 114.3, 109.5, 96.5, 80.1, 71.5, 31.7, 26.8. ESI-HRMS: calcd. for C₂₅H₁₈BrN₃O₄S + Na 560.0079, found 560.0034; [α]²⁰_D = −171.4 (c 0.16, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −83% ee, t_minor = 5.16 min, t_major = 18.83 min.

5ai. Yellow solid, mp 189.1–190.7 °C; 21.9 mg, yield 41%; ¹H NMR (600 MHz, CDCl₃) δ 8.83 (s, 1H), 7.33–7.30 (m, 1H), 7.28–7.24 (m, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.16–7.12 (m, 2H), 7.11–7.09 (m, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.65 (dd, J = 8.6, 4.3 Hz, 1H), 6.41 (dd, J = 9.6, 4.3 Hz, 2H), 6.37 (t, J = 6.5 Hz, 1H), 5.38 (s, 1H), 3.29 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 194.8, 174.6, 151.6, 143.5, 133.1, 132.5, 132.3, 131.6, 129.6, 128.8, 128.3, 126.3, 123.3, 123.1, 122.4, 120.5, 114.6, 109.2, 97.7, 81.5, 72.7, 46.8.[α]²⁰_D = −82.2 (c 0.24, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 51% ee, t_major = 5.60 min, t_minor = 10.99 min.

4aj. Yellow solid, mp 200.4–201.2 °C; 25.0 mg, yield 51%; ¹H NMR (600 MHz, CDCl₃) δ 8.40 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.1 Hz, 2H), 7.42–7.34 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.18–7.11 (m, 1H), 6.97 (dd, J = 21.8, 8.3 Hz, 2H), 6.40 (s, 1H), 6.26 (d, J = 2.3 Hz, 1H), 4.99 (s, 1H), 3.05 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.4, 172.6, 153.1, 143.4, 133.2, 132.3, 129.8, 129.7, 129.2, 128.0, 127.1, 127.1, 126.6, 126.0, 125.0, 124.5, 119.6, 117.6, 109.6, 100.0, 96.6, 80.1, 71.4, 52.7, 26.8. ESI-HRMS: calcd. for C₂₅H₁₈ClN₃O₄S + Na 514.0599, found 514.0552; [α]²⁰_D = −114.9 (c 0.16, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −84% ee, t_minor = 5.17 min, t_major = 18.67 min.

5aj. Yellow solid, mp 178.7–180.1 °C; 19.6 mg, yield 40%; ¹H NMR (600 MHz, CDCl₃) δ 8.80 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.14 (d, J = 7.5 Hz, 2H), 7.02–6.93 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.71–6.49 (m, 1H), 6.43–6.37 (m, 2H), 6.29 (d, J = 2.3 Hz, 1H), 5.39 (s, 1H), 3.30 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 194.8, 174.6, 151.1, 143.5, 133.1, 131.6, 129.7, 129.6, 129.2, 128.8, 128.3, 127.4, 126.3, 123.3, 123.2, 122.0, 120.1, 109.2, 97.8, 81.6, 72.6, 46.9, 27.3. [α]²⁰_D = −191.5 (c 0.16, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 51% ee, t_major = 5.68 min, t_minor = 10.67 min.

4ak. Yellow solid, mp 192.3–193.7 °C; 24.7 mg, yield 49%; ¹H NMR (600 MHz, CDCl₃) δ 8.42 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.20–7.11 (m, 3H), 6.99 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.35 (s, 1H), 6.26 (d, J = 2.1 Hz, 1H), 4.97 (s, 1H), 3.04 (s, 3H), 2.38 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.5, 172.6, 153.1, 143.5, 139.1, 132.3, 130.2, 129.8, 129.5, 128.0, 127.0, 125.9, 124.9, 124.5, 119.6, 117.7, 109.5, 96.5, 80.1, 71.4, 52.6, 26.8, 21.5. ESI-HRMS: calcd. for C₂₆H₂₀ClN₃O₄S + Na 528.0755, found 528.0717; [α]²⁰_D = −75.0 (c 0.13, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −82% ee, t_minor = 7.71 min, t _major = 17.79 min.

5ak. Yellow solid, mp 174.3–175.1 °C; 18.7 mg, yield 37%; ¹H NMR (600 MHz, CDCl₃) δ 8.84 (s, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 8.3 Hz, 2H), 7.00–6.96 (m, 2H), 6.96 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.40 (s, 1H), 6.36 (d, J = 7.4 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.41 (s, 1H), 3.31 (s, 3H), 2.24 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.0, 174.6, 151.1, 143.5, 139.6, 131.5, 130.1, 129.6, 129.3, 129.0, 128.7, 127.3, 126.3, 123.2, 122.3, 120.2, 109.2, 97.9, 81.6, 72.6, 46.8, 27.3, 21.2. [α]²⁰_D = −80.0 (c 0.15, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 66% ee, t_major = 5.14 min, t_minor = 12.27 min.

4al. Yellow solid, mp 176.2–177.1 °C; 18.8 mg, yield 40%; ¹H NMR (600 MHz, DMSO) δ 11.56 (s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.40–7.32 (m, 6H), 7.22 (d, J = 7.9 Hz, 1H), 7.04–6.99 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.36 (s, 1H), 6.03 (s, 1H), 5.05 (s, 1H), 2.99 (s, 3H), 1.99 (s, 3H). ¹³C NMR (150 MHz, DMSO) δ 192.1, 173.1, 151.8, 143.9, 134.4, 131.9, 131.6, 130.4, 129.8, 129.1, 127.9, 127.3, 126.7, 125.2, 124.6, 117.4, 116.9, 109.9, 97.4, 79.7, 72.1, 51.7, 26.9, 21.2. ESI-HRMS: calcd. for C₂₆H₂₁N₃O₄S + Na 494.1145, found 494.1114; [α]²⁰_D = −179.2 (c 0.24, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −74% ee, t_minor = 4.56 min, t_major = 17.89 min.

5al. Yellow solid, mp 190.1–191.6 °C; 22.1 mg, yield 47%; ¹H NMR (600 MHz, CDCl₃) δ 8.74 (s, 1H), 7.29–7.22 (m, 2H), 7.19–7.12 (m, 4H), 6.85 (d, J = 7.8 Hz, 1H), 6.79 (dd, J = 8.3, 1.4 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.40 (s, 1H), 6.32 (d, J = 7.4 Hz, 1H), 6.07 (s, 1H), 5.39 (s, 1H), 3.29 (s, 3H), 1.92 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.5, 174.8, 150.2, 143.6, 133.7, 131.9, 131.1, 130.2, 130.1, 129.3, 128.9, 128.2, 126.6, 123.6, 122.9, 119.9, 118.4, 108.8, 98.3, 81.5, 72.8, 47.0, 27.2, 21.1. [α]²⁰_D = −54.5 (c 0.15, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 86% ee, t_major = 4.53 min, t_minor = 12.58 min.

4am. Yellow solid, mp 148.3–149.6 °C; 21.9 mg, yield 45%; ¹H NMR (600 MHz, CDCl₃) δ 8.52 (s, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.57 (d, J = 6.7 Hz, 2H), 7.53 (dd, J = 15.1, 7.4 Hz, 1H), 7.44–7.34 (m, 3H), 7.31–7.26 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 7.0 Hz, 1H), 6.35 (dd, J = 8.7, 2.5 Hz, 1H), 6.18 (d, J = 8.7 Hz, 1H), 4.99 (s, 1H), 3.71 (s, 3H), 3.02 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.2, 172.9, 160.5, 155.5, 143.5, 133.6, 131.9, 129.8, 129.0, 127.0, 124.7, 124.5, 110.2, 109.4, 107.5, 102.1, 97.1, 79.8, 71.8, 55.3, 53.2, 26.7. ESI-HRMS: calcd. for C₂₆H₂₁N₃O₅S + Na 510.1049, found 510.1056; [α]²⁰_D = −101.5 (c 0.22, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), −72% ee, t_minor = 6.79 min, t_major = 10.83 min.

5am. Yellow solid, mp 138.3–139.7 °C; 18.5 mg, yield 38%; ¹H NMR (600 MHz, CDCl₃) δ 8.62 (s, 1H), 7.29–7.24 (m, 3H), 7.18–7.16 (m, 3H), 6.84–6.83 (m, 1H), 6.78 (td, J = 7.6, 0.7 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 6.37–6.34 (m, 1H), 6.31 (t, J = 2.4 Hz, 1H), 6.27–6.18 (m, 2H), 5.37 (s, 1H), 3.62 (s, 3H), 3.27 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.2, 174.8, 160.5, 153.6, 143.7, 133.5, 131.2, 130.3, 129.5, 128.9, 128.2, 126.8, 123.6, 123.2, 112.0, 109.7, 108.9, 103.3, 98.3, 81.6, 72.8, 55.4, 46.9, 27.2. [α]²⁰_D = −105.0 (c 0.13, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (35% 2-propanol/hexane, 1.0 mL min⁻¹), 76% ee, t_major = 5.04 min, t_minor = 7.99 min.

4ba. Yellow solid, mp 162.1–163.6 °C; 25.4 mg, yield 54%; ¹H NMR (600 MHz, CDCl₃) δ 8.45 (br, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 6.9 Hz, 2H), 7.44 (dd, J = 15.2, 7.5 Hz, 1H), 7.29 (ddd, J = 15.9, 7.7, 2.4 Hz, 3H), 7.20 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.42 (s, 1H), 6.23 (d, J = 7.7 Hz, 1H), 4.97 (s, 1H), 3.54 (dt, J = 14.4, 7.4 Hz, 1H), 3.27–3.18 (m, 1H), 0.63–0.61 (m, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.1, 172.8, 154.5, 143.4, 133.6, 132.0, 129.8, 129.8, 129.0, 127.0, 126.6, 124.8, 124.5, 122.2, 118.2, 115.6, 109.6, 96.9, 79.8, 71.4, 53.4, 42.5, 20.7, 11.4. ESI-HRMS: calcd. for C₂₆H₂₁N₃O₄S + Na 494.1145, found 494.1141; [α]²⁰_D = −86.5 (c 0.17, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (30% 2-propanol/hexane, 1.0 mL min⁻¹), −82% ee, t_minor = 5.63 min, t_major = 11.55 min.

5ba. Yellow solid, mp 130.5–131.6 °C; 19.8 mg, yield 42%; ¹H NMR (600 MHz, CDCl₃) δ 8.59 (s, 1H), 7.23 (t, J = 7.8 Hz, 2H), 7.20–7.14 (m, 4H), 7.00 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.62 (t, J = 7.4 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 6.39 (t, J = 7.0 Hz, 2H), 5.48 (d, J = 3.9 Hz, 1H), 3.83 (dt, J = 14.4, 7.4 Hz, 1H), 3.70–3.64 (m, 1H), 1.06 (t, J = 7.4 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.2, 174.6, 152.5, 143.1, 133.6, 131.1, 129.6, 129.4, 129.2, 128.9, 128.2, 127.0, 126.6, 123.8, 123.0, 122.6, 120.6, 118.9, 109.2, 100.0, 98.5, 81.7, 79.8, 72.6, 47.5, 42.5. [α]²⁰_D = −71.4 (c 0.14, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (30% 2-propanol/hexane, 1.0 mL min⁻¹), 80% ee, t_major = 4.99 min, t_minor = 5.94 min.

4bb. Yellow solid, mp 164.4–165.1 °C; 25.2 mg, yield 46%; ¹H NMR (600 MHz, CDCl₃) δ 8.56 (s, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.55–7.43 (m, 5H), 7.29 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 6.97 (dd, J = 19.4, 8.0 Hz, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.48 (s, 1H), 6.30 (d, J = 7.7 Hz, 1H), 5.07 (s, 1H), 3.62 (dt, J = 14.5, 7.4 Hz, 1H), 3.34–3.27 (m, 1H), 0.71 (t, J = 7.4 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 192.8, 172.7, 154.3, 143.2, 132.8, 132.1, 131.5, 130.2, 129.8, 126.8, 126.7, 124.7, 124.6, 123.2, 122.5, 118.1, 115.4, 109.7, 97.0, 79.1, 71.6, 42.5, 31.7, 11.4. [α]²⁰_D = −175.0 (c 0.12, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (30% 2-propanol/hexane, 1.0 mL min⁻¹), −83% ee, t_minor = 5.91 min, t_major = 12.47 min.

5bb. Yellow solid, mp 180.5–181.9 °C; 27.4 mg, yield 50%; ¹H NMR (600 MHz, CDCl₃) δ 8.76 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.24 (t, J = 7.7 Hz, 1H), 7.07 (t, J = 7.4 Hz, 2H), 7.02 (dd, J = 11.3, 4.2 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.47 (t, J = 8.7 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.41 (s, 1H), 3.82 (dt, J = 14.4, 7.3 Hz, 1H), 3.71–3.64 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 194.5, 174.5, 152.2, 143.0, 132.5, 131.2, 131.1, 130.5, 130.0, 129.7, 129.0, 126.4, 123.7, 123.6, 123.0, 122.8, 120.0, 118.7, 109.2, 98.1, 80.8, 72.58 42.5, 31.6, 11.5. [α]²⁰_D = −55.6 (c 0.41, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (30% 2-propanol/hexane, 1.0 mL min⁻¹), 84% ee, t_major = 5.20 min, t_minor = 7.23 min.

4bf. Yellow solid, mp 182.3–183.8 °C; 22.5 mg, yield 46%; ¹H NMR (600 MHz, CDCl₃) δ 8.71 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.50–7.41 (m, 3H), 7.23–7.17 (m, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.96 (dd, J = 12.1, 5.0 Hz, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.66 (dd, J = 10.8, 4.2 Hz, 1H), 6.41 (d, J = 9.1 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.97 (s, 1H), 3.54 (dt, 14.0, 7.0 Hz, 1H), 3.23 (dt, J = 13.9, 6.9 Hz, 1H), 0.62 (t, J = 7.3 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.0, 172.7, 171.2, 162.3, 154.4, 143.2, 132.0, 131.6, 131.6, 129.8, 126.7, 124.7, 124.5, 122.4, 118.1, 115.4, 114.0, 113.9, 109.6, 97.0, 79.1, 71.6, 60.5, 42.5, 11.4. [α]²⁰_D = −142.4 (c 0.19, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (20% 2-propanol/hexane, 1.0 mL min⁻¹), −82% ee, t_minor = 7.78 min, t_major = 19.81 min.

5bf. Yellow solid, mp 172.3–173.1 °C; 30.0 mg, yield 47%; ¹H NMR (600 MHz, CDCl₃) δ 8.85 (s, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.11 (dd, J = 8.6, 5.3 Hz, 2H), 6.94 (t, J = 7.7 Hz, 1H), 6.79 (dd, J = 17.4, 8.5 Hz, 3H), 6.70 (d, J = 8.2 Hz, 1H), 6.68–6.63 (m, 1H), 6.56 (t, J = 7.5 Hz, 1H), 6.38 (d, J = 7.3 Hz, 1H), 6.32 (d, J = 7.7 Hz, 1H), 6.23 (d, J = 3.1 Hz, 1H), 5.35 (s, 1H), 3.74 (dt, J = 14.3, 7.3 Hz, 1H), 3.64–3.57 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 194.7, 174.6, 164.0, 162.3, 152.4, 143.1, 131.1, 130.9, 130.8, 129.7, 129.1, 126.5, 123.1, 122.8, 120.2, 118.8, 115.2, 115.1, 109.2, 98.3, 80.8, 72.6, 42.5, 20.8, 11.5. [α]²⁰_D = −189.5 (c 0.19, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (20% 2-propanol/hexane, 1.0 mL min⁻¹), 82% ee, t_major = 6.50 min, t_minor = 9.12 min.

4bj. Yellow solid, mp 134.7–135.4 °C; 21.8 mg, yield 45%; ¹H NMR (600 MHz, CDCl₃) δ 8.49 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.27 (dd, J = 12.7, 5.1 Hz, 1H), 7.16 (dd, J = 11.1, 8.4 Hz, 3H), 6.98 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.73 (t, J = 7.5 Hz, 1H), 6.44 (s, 1H), 6.31 (d, J = 7.7 Hz, 1H), 5.02 (s, 1H), 3.61 (dt, J = 14.5, 7.4 Hz, 1H), 3.29 (dt, J = 14.1, 7.1 Hz, 1H), 2.38 (s, 3H), 0.70 (t, J = 7.4 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.1, 172.7, 154.5, 143.3, 138.8, 131.9, 130.7, 129.7, 129.6, 127.9, 127.0, 126.6, 124.7, 124.5, 122.2, 118.1, 115.7, 109.6, 79.7, 42.4, 21.5, 20.7, 11.4. [α]²⁰_D = −86.7 (c 0.15, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (30% 2-propanol/hexane, 1.0 mL min⁻¹), −83% ee, t_minor = 8.08 min, t_major = 12.57 min.

5bj. Yellow solid, mp 164.7–165.1 °C; 23.3 mg, yield 48%; ¹H NMR (600 MHz, CDCl₃) δ 8.78 (s, 1H), 7.25–7.20 (m, 1H), 7.03 (d, J = 7.8 Hz, 2H), 7.01–6.94 (m, 3H), 6.84 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.39–6.33 (m, 2H), 5.45 (s, 1H), 3.82 (dt, J = 14.3, 7.3 Hz, 1H), 3.69–3.63 (m, 1H), 2.23 (s, 3H), 1.05 (q, J = 7.3 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.3, 174.6, 152.5, 143.1, 139.3, 131.0, 129.6, 129.2, 128.9, 128.8, 126.6, 123.8, 123.0, 122.5, 118.9, 109.1, 81.6, 72.6, 42.5, 21.2, 20.8, 11.5. [α]²⁰_D = −113.8 (c 0.19, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (30% 2-propanol/hexane, 1.0 mL min⁻¹), 82% ee, t_major = 4.62 min, t_minor = 6.47 min.

4bk. Yellow solid, mp 162.1–163.6 °C; 20.0 mg, yield 44%; ¹H NMR (600 MHz, CDCl₃) δ 8.45 (s, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 8.4 Hz, 2H), 7.29 (dd, J = 10.2, 4.9 Hz, 1H), 7.18–7.13 (m, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.87 (dd, J = 8.8, 5.5 Hz, 2H), 6.73 (t, J = 8.0 Hz, 1H), 6.46–6.42 (m, 1H), 6.31 (d, J = 7.7 Hz, 1H), 5.02 (s, 1H), 3.83 (s, 3H), 3.65–3.59 (m, 1H), 3.30 (ddd, J = 14.1, 8.0, 6.2 Hz, 1H), 0.70 (t, J = 7.4 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 193.2, 172.7, 160.0, 154.5, 143.3, 131.9, 131.0, 130.3, 129.7, 127.0, 126.6, 125.8, 124.8, 124.5, 122.1, 118.1, 113.6, 112.5, 109.6, 79.5, 71.5, 55.2, 42.5, 22.7, 11.4. [α]²⁰_D = −100.0 (c 0.11, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), −84% ee, t_minor = 11.35 min, t_major = 24.91 min.

5bk. Yellow solid, mp 210.3–211.3 °C; 21.5 mg, yield 43%; ¹H NMR (600 MHz, CDCl₃) δ 8.72 (s, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.67–6.60 (m, 3H), 6.41–6.32 (m, 3H), 5.47 (d, J = 5.4 Hz, 1H), 3.81 (dt, J = 14.6, 7.3 Hz, 1H), 3.74–3.62 (m, 4H), 1.04 (t, J = 7.3 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 195.3, 174.5, 160.1, 152.5, 143.1, 131.0, 130.3, 129.6, 129.3, 126.7, 125.6, 123.7, 123.0, 122.5, 119.0, 113.5, 109.1, 98.5, 81.4, 72.6, 42.4, 20.8, 11.5. [α]²⁰_D = −32.7 (c 0.18, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), 82% ee, t_major = 5.58 min, t_minor = 9.72 min.

4bc/5bc. Yellow solid, 51.9 mg, yield 85%; dr = 1 : 1. ¹H NMR (600 MHz, DMSO) δ 11.80 (s, 1H), 11.68 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.15 (t, J = 7.9 Hz, 1H), 6.96–6.92 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.67 (t, J = 8.1 Hz, 2H), 6.61 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 7.1 Hz, 1H), 6.45 (dd, J = 7.6, 0.8 Hz, 1H), 6.43 (s, 1H), 6.37 (d, J = 7.0 Hz, 1H), 6.13 (d, J = 7.4 Hz, 1H), 5.40 (s, 1H), 5.08 (s, 1H), 4.98 (d, J = 15.7 Hz, 1H), 4.91 (d, J = 15.7 Hz, 1H). ¹³C NMR (150 MHz, DMSO) δ 193.2, 174.5, 153.7, 143.1, 136.0, 133.7, 131.9, 131.0, 130.9, 129.8, 129.1, 128.2, 128.1, 127.4, 126.3, 124.8, 124.6, 123.2, 123.1, 120.3, 118.1, 110.7, 99.3, 96.8, 80.1, 51.5, 44.0. [α]²⁰_D = − 42.9(c 0.19, CHCl₃); the enantiomeric ratio was determined by HPLC on Chiralpak AD column (25% 2-propanol/hexane, 1.0 mL min⁻¹), −65% ee, t_minor = 7.52 min, t_major = 12.58 min; 50% ee, t_major = 6.18 min, t_minor = 8.85 min.

Crystal data for 4ac (ESI†). C₂₅H₁₈BrN₃O₄S (536.39), Triclinic, space group P1̄, a = 9.0285(3), b = 9.3506(3), c = 14.1171(5) Å, V = 1109.38(6) ų, Z = 10, specimen 0.237 × 0.143 × 0.124 mm³, T = 296(2) K, SIEMENS P4 diffractometer, absorption coefficient 1.987 mm⁻¹, reflections collected 38 048, independent reflections 5164 [R(int) = 0.0398], refinement by Full-matrix least-squares on F², data/restraints/parameters 5164/0/308, goodness-of-fit on F² = 1.022, final R indices [I > 2(I)] R₁ = 0.0418, wR₂ = 0.0954, R indices (all data) R₁ = 0.0600, wR₂ = 0.1048, largest diff. peak and hole 0.989 and −0.734 e Å⁻³.

Crystal data for 5ac (ESI†). C₂₅H₁₈BrN₃O₄S(536.39), Orthorhombic, space group P2(1)2(1)2(1), a = 7.8034(10), b = 9.5210(13), c = 30.485(4) Å, V = 2264.9(5) ų, Z = 21, specimen 0.243 × 0.162 × 0.148 mm³, T = 296(2) K, SIEMENS P4 diffractometer, absorption coefficient 1.946 mm⁻¹, reflections collected 11 290, independent reflections 4963 [R(int) = 0.0245], refinement by Full-matrix least-squares on F², data/restraints/parameters 4963/0/307, goodness-of-fit on F² = 1.004, final R indices [I > 2(I)] R₁ = 0.0372, wR₂ = 0.0798, R indices (all data) R₁ = 0.0588, wR₂ = 0.0736, largest diff. peak and hole 0.463 and −0.478 e Å⁻³.

Acknowledgements

We are grateful for the financial support by the Program for the National Natural Science Foundation of China (21272214).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1001582 and 1001583. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra07860h

‡ These authors contributed equally to this work.

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