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Article

Enantioselective Michael/Hemiketalization Cascade Reactions between Hydroxymaleimides and 2-Hydroxynitrostyrenes for the Construction of Chiral Chroman-Fused Pyrrolidinediones

by
Dong-Hua Xie
,
Cheng Niu
and
Da-Ming Du
*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5 Zhongguancun South Street, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(16), 5081; https://doi.org/10.3390/molecules27165081
Submission received: 20 July 2022 / Revised: 8 August 2022 / Accepted: 9 August 2022 / Published: 10 August 2022
(This article belongs to the Special Issue Recent Advances of Catalytic Asymmetric Synthesis)
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Abstract

:
In this paper, the organocatalytic asymmetric Michael addition/hemiketalization cascade reactions between hydroxymaleimides and 2-hydroxynitrostyrenes were developed, which provided a new protocol for building a chiral ring-fused chroman skeleton. This squaramide-catalyzed cascade reaction provided chiral chroman-fused pyrrolidinediones with three contiguous stereocenters in good to high yields (up to 88%), with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 96% ee) at −16 °C. Moreover, a scale-up synthesis was also carried out, and a possible reaction mechanism was proposed.

Graphical Abstract

1. Introduction

The development of pharmaceutical science is inseparable from the discovery of lead compounds, primarily derived from natural products and analogues with biological activity. Ring-fused chroman skeletons are widely present in many natural products and analogues with bioactivity [1,2,3,4,5,6,7,8,9,10,11] (Figure 1). For example, myrtucommulone E, isolated from the Mediterranean folk herb Myrtucommulone, has α-glucosidase inhibitory activity [1]; rhodomyrtone, isolated from the leaves of myrtle, a small Indonesian shrub, has antibacterial activity [2]; miroestrol, isolated from the root of kudzu, a Thai herb, has estrogenic activity [3]; rhododaurichromanic acid A, isolated from the shoots and leaves of azalea from northern China and eastern Siberia, has anti-HIV activity [4] and so on. In addition to specific actions in the field of biomedicine, the ring-fused chroman skeleton also shows particular potential in the area of modern pesticide development. For example, greveichromenol, isolated from geronniang, the traditional herbal medicine of the Dai ethnic group, showed antitobacco mosaic virus activity, providing a lead compound for the development of antitobacco mosaic virus pesticide [5]. Therefore, the construction of the chroman skeleton has received great attention from organic and medicinal chemists. In recent years, a large number of synthetic strategies of chroman derivatives have been consistently reported [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26].
2-Hydroxynitrostyrene plays an essential role in these reactions in the construction of chiral chroman derivatives. For example, in 2013, Zhu’s group reported a new asymmetric oxa-Michael/Michael cascade reaction for the construction of enantiomerically enriched indolinone spiro-fused chromans; this protocol offered excellent stereo control under mild conditions [27] (Scheme 1a). In 2018, Xu’s group developed an asymmetric catalytic method for the synthesis of polysubstituted chromans through an oxa-Michael-nitro-Michael reaction, and the squaramide-catalyzed domino reaction of 2-hydroxynitrostyrenes with trans-β-nitroolefins produced chiral chromans with excellent enantioselectivities, diastereoselectivities and yields [28] (Scheme 1b). At the same time, because of the importance of the 2,5-pyrrolidinedione framework in biomedicine [29,30], Wang’s group synthesized chiral chroman-fused pyrrolidinediones for the first time in excellent yields with excellent stereoselectivities using organocatalytic enantioselective [4+2] cyclization reaction [31] (Scheme 1c). Inspired by their work and continuing with our project with organocatalyzed domino or cascade reactions for the synthesis of bioactive heterocycles, we intend to synthesize chiral chroman-fused pyrrolidinediones using 2-hydroxynitrostyrenes as substrates to consolidate and develop this research result (Scheme 1d).

2. Results and Discussion

2.1. Optimization of Reaction Conditions

Initially, we started our study with hydroxymaleimide 1a (3-ethyl-4-hydroxy-1-phenyl-1H-pyrrole-2,5-dione) and 2-hydroxynitrostyrene 2a as model substrates. We first tested the feasibility of the model reaction in the presence of 10 mol% cinchona-derived squaramide bifunctional catalyst C1 (Figure 2) in dichloromethane (DCM) at room temperature. Under these conditions, the desired product 3aa was obtained in high yield (82%) with excellent diastereoselectivity (>20:1 dr), although with moderate enantioselectivity (53% ee). Encouraged by this important result and inspired by our previous work [32,33], we tried to reduce the reaction temperature to −16 °C to improve the enantioselectivity. Luckily, the results improved to 80% yield, >20:1 dr, and 87% ee. Furthermore, we tried to screen several catalysts, reaction solvent, and catalyst loading to further improve the outcome and enantioselectivity. The results are outlined in Table 1.
Temperature is a vital factor to affect the stereoselectivity in asymmetric organic reaction, so we evaluated reaction temperature at first. Unexpectedly, a lower temperature can lead to higher yield and enantioselectivity. To avoid the contingency of the case, we took another catalyst C2 to confirm this. We can easily find that a lower temperature is better for reaction from entries 1–4. Given the temperature conditions, we evaluated several catalysts (Table 1, entries 2, 4–12) next; the cinchona-derived bifunctional thiourea catalyst C9 had the best yield, while the enantioselectivity was ordinary and the diastereoselectivity was not good enough (entry 11, 90% yield, −69% ee, 16:1 dr). The cinchona-derived squaramide catalyst C6 has almost the best yield, as well as diastereoselectivity, but enantioselectivity is so low that we do not consider it (entry 8, 89% yield, 59% ee, >20:1 dr). In terms of enantioselectivity, cinchona-derived squaramide catalysts are better, compared to the diaminocyclohexane-derived squaramide catalyst C10 (entry 12, 81% yield, 59% ee, 9:1 dr). When taking into account entry 2 (80% yield, 87% ee, >20:1 dr) and entry 4 (83% yield, 73% ee, >20:1 dr), we easily find that the cinchona-derived squaramide catalyst C1 is superior to the cinchona-derived thiourea catalyst C2. Taking into account entry 2 (80% yield, 87% ee, >20:1 dr) and entry 5 (88% yield, 96% ee, >20:1 dr), we can easily find that the quinine-derived squaramide catalyst C3 is superior to the cinchonidine-derived squaramide catalyst C1. Eventually, we chose the quinine-derived squaramide catalyst C3 (entry 5, 88% yield, 96% ee, >20:1 dr) as the best catalyst in this reaction.
After a preliminary screening of the catalysts, a survey of the solvent effect using C3 as the organocatalyst concluded that dichloromethane (DCM) was still the best solvent among 1,2-dichloroethane (DCE), chloroform, toluene, acetonitrile, tetrahydrofuran (THF). Some solvents, such as 1,4-dioxane, will freeze at −16 °C; we do not consider these (Table 1, entries 13–17). It seems unexpected that when the reaction was carried out in THF, only trace products was detected by TLC. In general, THF will have an effect on stereoselectivity owing to compete hydrogen bond formation with catalyst, but the great influence on product yield may have other reason. We finally discovered that hydroxymaleimide 1a, one of the substrates, cannot dissolve well in THF, which could shed light on this phenomenon.
Afterwards, we further investigated the reaction with 5 and 2.5 mol% catalyst loading, respectively (Table 1, entries 18 and 19), and no improvements were obtained. Therefore, the optimal reaction conditions for this Michael/hemiketalization cascade reaction were to use a catalyst loading of 10 mol% of squaramide C3 in DCM at −16 °C for 24 h.

2.2. Substrate Scope

With the optimized conditions in hand, we then began to investigate the substrate scope and limitation of this reaction, and the results are summarized in Scheme 2.
Firstly, we examined the tolerance of various hydroxymaleimides 1 under the optimized conditions. Various hydroxymaleimides with electron withdrawing and electron donating substituents at the 4-position on the benzene ring participated in the reaction easily, and the corresponding products 3ba–3ha could be generated in high yields (79–88%) with excellent stereoselectivities (up to >20:1 dr and up to >99% ee), except products 3da and 3fa, whose diastereoselectivity was 4:1 and 5:1, respectively. There is no clear rule of the influence of substituents on stereoselectivity. The effect of substituents on stereoselectivity cannot be explained by the electronic effect, because the enantioselectivity and diastereoselectivity are affected by many factors. Afterwards, the cascade process gave the desired products 3ia–3na with high stereoselectivity and good yield, even with the substituents at the 3-position or 3,5-position on the benzene ring. Unfortunately, substrate 1o substituted with phenyl did not work with 2a; no other addition was observed. The starting materials were recovered unaltered, probably because of the steric hindrance and the phenyl delocalization of the negative charge, so that the intramolecular Michael addition step cannot occur. Furthermore, we tested some substituents at different positions on 2-hydroxynitrostyrenes; most of them showed excellent results, including 3ab–3ae and 3ag (up to >20:1 dr, 92% ee). However, when the substituent is a nitro group, such as 2f, the reaction cannot work well, probably due to the strong electron-withdrawing effect of the nitro group, which lowers the nucleophilic reactivity of the corresponding phenoxy anion. The nitro group in 2f can block the catalyst by hydrogen bonding, and this may also hinder the reaction from proceeding.
We also tried to lower the temperature to increase the stereo control of the reaction. One can take 3ca as an example. When the reaction was carried out at −30 °C, the trace product was detected even after 72 h; when the reaction was carried out at −20 °C, the yield decreased to 78% and the diastereoselectivity remained at 10:1 dr.
To expand the synthetic application and the substrate scope, we also tried other types of Michael accepter, such as (E)-3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one, (E)-methyl 4-(2-hydroxyphenyl)-2-oxobut-3-enoate, and 2-benzylidenemalononitrile, but the corresponding reaction results were not satisfactory, no new products were observed when these Michael acceptors reacted with 1a, and the starting materials were recovered unchanged.

2.3. Scaled-Up Synthesis

To prove the synthetic value of this cascade reaction, a scaled reaction of 1a and 2a with amplification ten times was carried out under standard conditions. As shown in Scheme 3, the desired product 3aa was obtained in slightly reduced yield (85%), with maintained diastereoselectivity and slightly lower enantioselectivity (>20:1 dr, 94% ee). This result shows that this asymmetric catalytic strategy has broad prospects for mass production.

2.4. X-ray Diffraction Analysis

A single crystal of 3ca was obtained from the slow evaporation from the mixed solvents of methanol and dichloromethane. The absolute configuration of product 3ca was unambiguously determined by single-crystal X-ray diffraction analysis as (3aS,9S,9aR) (Figure 3) [34] (See Supplementary Materials). The absolute configurations of the other products were assigned by analogy.

2.5. Controlled Reactions and Plausible Mechanism

For a better understanding of the mechanism of this cascade reaction, we designed three controlled reactions (Scheme 4). When hydroxymaleimide 1b and β-nitrostyrene 2h were used under the optimized conditions, the corresponding Michael addition product 4 was obtained with a yield of 20%. This result indicated that 1a is a suitable Michael donor to trigger the first Michael addition step of the Michael/hemiketalization cascade reaction. When the OH group in hydroxymaleimide 1a was protected with the acetyl group, as in substrate 1q, no reaction was observed when 1q reacted with 2-hydroxynitrostyrene 2a. Meanwhile, N-phenylmaleimide 1r also could not react with 2a. The last two control experiments indicated that the OH group in hydroxymaleimides is essential, and the hemiketalization reaction was the second step of the cascade reaction, instead of the oxa-Michael reaction as the first step.
Based on these experimental results and previous work [33], we proposed a plausible mechanism based on the absolute configuration of 3aa (Scheme 5). In the first step of Michael addition, the squaramide catalyst C3 initially promotes the formation of transition state A, and catalyst C3 works in a double activation model. 2-Hydroxynitrostyrene 2a is oriented and activated by the squaramide moiety through double hydrogen bonding and the OH group in 1a is deprotoned by the tertiary amine unit to form enolate, which is oriented by another hydrogen bond. 2-Hydroxynitrostyrene 2a is attacked by the enolate of 1a from the Si-face. In the second step of the hemiketalization reaction, the OH group in 2-hydroxynitrostyrene 2a is deprotoned by the tertiary amine unit in squaramide, and the newly formed carbonyl group in 1a is attacked by the deprotonated phenolic hydroxyl of 2a from the Si-face via transition state B, leading to the formation of (3aS,9S,9aR)-configured 3aa and regenerates the bifunctional catalyst C3 after a protonation process.

3. Conclusions

In conclusion, we have successfully developed novel Michael addition/hemiketalization cascade reactions between hydroxymaleimides and 2-hydroxynitrostyrenes to synthesize chiral ring-fused chromans. Under mild conditions, a range of structurally diverse chiral chroman-fused pyrrolidinediones, containing hemiketals, were obtained in good to high yields with excellent stereoselectivities. Additionally, the potential utility of this methodology has been demonstrated by scaling-up synthesis. This cascade synthetic strategy is bound to be a powerful tool for medicinal chemistry studies.

4. Materials and Methods

4.1. General Information

Commercially available compounds were used without further purification. Solvents were dried according to standard procedures. Column chromatography was performed with silica gel (200–300 mesh). The melting points were determined with an XT-4 melting point apparatus and were not corrected. 1H NMR spectra were measured with a Bruker Ascend 400 MHz spectrometer (Karlsurhe, Germany) and the chemical shifts were reported in δ (ppm) relative to tetramethylsilane (TMS) as the internal standard. 13C NMR spectra were measured at 100 MHz with a 400 MHz spectrometer, and the chemical shifts were reported in ppm relative to tetramethylsilane and referenced to the solvent peak (CDCl3, δC = 77.00 ppm; CD3OD, δC = 49.05 ppm; acetone-d6, δC = 30.83 ppm). High-resolution mass spectra were measured with an Agilent 6520 Accurate-Mass Q-TOF MS system (Beijing, China), equipped with an electrospray ionization (ESI) source. Optical rotations were measured with a Krüss P8000 polarimeter (Beijing, China) at the indicated concentration with units of g/100 mL. Enantiomeric excesses were determined by chiral HPLC analysis, using an Agilent 1200 LC instrument (Beijing, China) with a Daicel Chiralpak IA, IB, IC, or AD-H column.

4.2. Materials

Materials 1a–1p were prepared according to the literature reported by Wang et al. [35] and 2a–2g were prepared according to the literature [36]. The chiral organocatalysts were prepared following the procedures reported [37,38,39,40].

4.3. Procedure for the Asymmetric Synthesis of Compounds 3

In a small dried bottle, 1 (0.10 mmol), 2 (0.12 mmol), chiral organocatalyst C3 (6.0 mg, 0.01 mmol, 10 mol%) and DCM (1.0 mL) were added. The mixture was stirred at −16 °C for 24 h. After completion of the reaction, the residue was purified by flash column chromatography on silica gel to obtain the pure products 3 as solids. Racemates were prepared following a similar procedure with Et3N (20 mol%).
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno [2,3-c]pyrrole-1,3(2H,3aH)-dione (3aa). From 1a (21.6 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 33.6 mg (88% yield) compound 3aa as a white solid, m.p. 215–218 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 32.9 min (major), tR = 35.3 min (minor); 96% ee. [α]D25 = +10.8 (c = 1.68, CH2Cl2). 1H NMR (400 MHz, CDCl3): 7.38–7.36 (m, 3H, ArH), 7.29 (dd, J1 = 1.2 Hz, J2 = 7.8 Hz, 1H, ArH), 7.18 (m, J1 = 1.2 Hz, J2 = 7.4 Hz, 1H, ArH), 7.06 (td, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H, ArH), 6.99 (d, J = 8.0 Hz, 1H, ArH), 6.90–6.87 (m, 2H, ArH), 4.85–4.71 (m, 3H, CH2 + OH), 4.24 (dd, J1 = 4.4 Hz, J2 = 10.8 Hz, 1H, CH), 2.20–2.01 (m, 2H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 174.1, 171.9, 150.6, 130.5, 130.3, 129.6, 129.4, 129.3, 125.9, 124.5, 124.1, 118.0, 98.1, 74.4, 55.0, 39.7, 24.8, 9.4 ppm. HRMS (ESI): m/z calcd. for C20H19N2O6 [M + H]+ 383.1238, found 383.1233.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-2-(4-methoxyphenyl)-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ba). From 1b (24.6 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 33.0 mg (80% yield) compound 3ba as a white solid, m.p. 184–186 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 20.0 min (minor), tR = 22.0 min (major); 86% ee. [α]D25 = +80.9 (c = 1.65, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.12 (s, 1H, OH), 7.32 (td, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H, ArH), 7.14 (dd, J1 = 1.8 Hz, J2 = 7.4 Hz, 1H, ArH), 7.08–7.04 (m, 1H, ArH), 7.00 (d, J = 8.0 Hz, 1H, ArH), 6.95–6.92 (m, 2H, ArH), 6.82–6.78 (m, 2H, ArH), 5.22 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.79 (dd, J1 = 11.6 Hz, J2 = 12.8 Hz, 1H, CH), 4.16 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 3.79 (s, 3H, CH3), 2.30–2.21 (m, 1H, CH2), 2.13–2.07 (m, 1H, CH2), 1.11 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.4, 173.4, 161.8, 153.2, 132.1, 131.3, 129.4, 126.7, 125.6, 125.5, 119.7, 116.2, 101.0, 76.5, 56.84, 56.79, 41.7, 26.3, 10.7 ppm. HRMS (ESI): m/z calcd. for C21H21N2O7 [M + H]+ 413.1343, found 413.1331.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-9-(nitromethyl)-2-(p-tolyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ca). From 1c (23.0 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 32.6 mg (82% yield) compound 3ca as a white solid, m.p. 183–185 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 94:6, flow rate 1.0 mL/min, detection at 254 nm): tR = 22.8 min (minor), tR = 25.0 min (major); 90% ee. [α]D25 = +58.6 (c = 1.63, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.12, 2.80 (s, 1H, OH), 7.33 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H, ArH), 7.21 (d, J = 8.4 Hz, 2H, ArH), 7.14 (dd, 1H, J1 = 1.6 Hz, J2 = 7.2 Hz, ArH), 7.06 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.02–6.99 (m, 1H, ArH), 6.78 (d, J = 8.0 Hz, 2H, ArH), 5.22 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.79 (dd, J1 = 11.4 Hz, J2 = 12.6 Hz, 1H, CH), 4.17 (dd, J1 = 4.2 Hz, J2 = 11.4 Hz, 1H, CH2), 2.32 (s, 3H, CH3), 2.29–2.21 (m, 1H, CH2), 2.15–2.08 (m, 1H, CH2), 1.11 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.2, 173.3, 153.2, 140.9, 132.1, 131.5, 131.4, 130.4, 128.0, 126.7, 125.7, 119.7, 101.1, 76.5, 56.8, 41.7, 26.3, 22.1, 10.7 ppm. HRMS (ESI): m/z calcd. for C21H21N2O6 [M + H]+ 397.1394, found 397.1385.
(3aS,9S,9aR)-9a-Ethyl-2-(4-fluorophenyl)-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3da). From 1d (23.5 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 32.9 mg (82% yield) compound 3da as a white solid, m.p. 205–206 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 17.0 min (major), tR = 19.2 min (minor); 88% ee. [α]D25 = +84.8 (c = 1.65, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.28, 2.93 (s, 1H, OH), 7.33 (td, J1 = 7.6 Hz, J2 = 1.7 Hz, 1H, ArH), 7.23–7.18 (m, 2H, ArH), 7.15 (dd, J1 = 1.8 Hz, J2 = 7.4 Hz, 1H, ArH), 7.07 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.02–6.95 (m, 3H, ArH), 5.23 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.80 (dd, J1 = 11.6 Hz, J2 = 12.8 Hz, 1H, CH), 4.18 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.93 (s, OH), 2.29–2.22 (m, 1H, CH2), 2.17–2.09 (m, 1H, CH2), 1.12 (t, J = 7.6 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, methanol-d4): δ 176.3, 173.1, 163.9 (d, 1JC-F = 246.3 Hz), 152.8, 131.4, 130.7, 129.6 (d, 3JC-F = 9.0 Hz), 128.3 (d, 4JC-F = 3.3 Hz), 126.2, 124.9, 119.1, 117.2 (d, 2JC-F = 23.3 Hz), 100.5, 75.6, 55.5, 41.4, 25.8, 9.8 ppm. HRMS (ESI): m/z calcd. for C20H18FN2O6 [M + H]+ 401.1143, found 401.1140.
(3aS,9S,9aR)-2-(4-Chlorophenyl)-9a-ethyl-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ea). From 1e (25.0 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 33.4 mg (80% yield) compound 3ea as a white solid, m.p. 196–197 °C. HPLC (Daicel Chiralpak IB, n-hexane/ethyl acetate = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 9.0 min (minor), tR = 11.2 min (major); 96% ee. [α]D25 = +31.7 (c = 1.67, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.22 (s, 1H, OH), 7.49–7.45 (m, 2H, ArH), 7.32 (td, J1 = 7.8 Hz, J2 = 1.6 Hz, 1H, ArH), 7.15 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.07 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 7.01–6.96 (m, 3H, ArH), 5.23 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.83–4.77 (dd, J1 = 11.6 Hz, J2 = 12.8 Hz, 1H, CH), 4.19 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.30–2.22 (m, 1H, CH2), 2.17–2.10 (m, 1H, CH2), 1.12 (t, J = 7.6 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): δ 176.0, 172.9, 153.1, 136.1, 132.2, 131.7, 131.4, 131.2, 129.8, 126.6, 125.7, 119.7, 101.1, 76.4, 56.9, 41.4, 26.2, 10.5 ppm. HRMS (ESI): m/z calcd. for C20H18ClN2O6 [M + H]+ 417.0848, found 417.0849.
(3aS,9S,9aR)-2-(4-Bromophenyl)-9a-ethyl-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3fa). From 1f (29.4 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 36.4 mg (79% yield) compound 3fa as a white solid, m.p. 209–211 °C. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 9.3 min (minor), tR = 12.1 min (major); 86% ee. [α]D25 = +100.7 (c = 1.82, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.22 (s, 1H, OH), 7.63–7.60 (m, 2H, ArH), 7.32 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H, ArH), 7.15 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H, ArH), 7.07 (dd, J1 = 0.8 Hz, J2 = 7.6 Hz, 1H, ArH), 7.00 (d, J = 8.0 Hz, 1H, ArH), 6.93–6.90 (m, 2H, ArH), 5.23 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.83–4.77 (dd, J1 = 11.6 Hz, J2 = 12.8, 1H, CH), 4.19 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.31–2.22 (m, 1H, CH2), 2.17–2.08 (m, 1H, CH2), 1.11 (t, J = 7.6 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 175.9, 172.8, 153.1, 134.2, 132.14, 132.12, 131.3, 130.0, 126.5, 125.7, 124.1, 119.7, 101.0, 76.4, 56.9, 41.4, 26.2, 10.5 ppm. HRMS (ESI): m/z calcd. for C20H1879BrN2O6 [M + H]+ 461.0343, found 461.0341; calcd. for C20H1881BrN2O6 [M + H]+ 463.0323, found 463.0323.
(3aS,9S,9aR)-9a-Ethyl-2-(4-ethylphenyl)-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ga). From 1g (24.4 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 36.2 mg (88% yield) compound 3ga as a white solid, m.p. 189–190 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 13.5 min (minor), tR = 15.1 min (major); >99% ee. [α]D25 = +43.1 (c = 1.81, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 7.33 (td, J1 = 7.6 Hz, J1 = 1.6 Hz, 1H, ArH), 7.25 (d, J = 8.8 Hz, 2H, ArH), 7.14 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.06 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.00 (d, J = 8.0 Hz, 1H, ArH), 6.80 (d, J = 8.4 Hz, 1H, ArH), 5.22 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.80 (t, J = 12.2 Hz, 1H, CH), 4.16 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.91 (s, 1H, OH), 2.63 (q, J = 7.6 Hz, 2H, CH2), 2.31–2.22 (m, 1H, CH2), 2.15–2.08 (m, 1H, CH), 1.18 (t, J = 7.6 Hz, 3H, CH3), 1.11 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.3, 173.3, 153.2, 147.2, 132.1, 131.3, 130.6, 130.3, 128.1, 126.7, 125.6, 119.7, 101.0, 76.4, 56.9, 41.7, 30.0, 26.3, 16.8, 10.7 ppm. HRMS (ESI): m/z calcd. for C22H23N2O6 [M + H]+ 411.1551, found 411.1544.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-2-(4-isopropylphenyl)-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ha). From 1h (26.0 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 35.7 mg (84% yield) compound 3ha as a white solid, m.p. 192–193 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 19.8 min (minor), tR = 23.0 min (major); 70% ee. [α]D25 = +9.3 (c = 1.79, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.24 (s, OH), 7.34–7.27 (m, 3H, ArH), 7.14 (d, J = 7.6 Hz, 1H, ArH), 7.06 (t, J = 7.2 Hz, 1H, ArH), 7.00 (d, J = 8.0 Hz, 1H, ArH), 6.82 (d, J = 7.2 Hz, 2H, ArH), 5.22 (dd, J1 = 3.2 Hz, J2 = 12.8 Hz, 1H, CH2), 4.81 (t, J = 12.2 Hz, 1H, CH), 4.17 (dd, J1 = 3.2 Hz, J2 = 11.6 Hz, 1H, CH2), 3.07 (d, J = 10.4 Hz, 1H, CH), 2.94–2.86 (m, 1H, CH), 2.30–2.22 (m, 1H, CH2), 2.15–2.08 (m, 1H, CH2), 1.196 (d, J = 6.8 Hz, 3H, CH3), 1.192 (d, J = 6.8 Hz, 3H, CH3), 1.11 (t, J = 6.8 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.3, 173.2, 153.2, 151.7, 132.0, 131.3, 130.6, 128.9, 128.0, 126.7, 125.6, 119.6, 101.0, 76.4, 56.8, 41.7, 35.5, 26.3, 25.0, 10.7 ppm. HRMS (ESI): m/z calcd. for C23H25N2O6 [M + H]+ 425.1707, found 425.1699.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-9-(nitromethyl)-2-(m-tolyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ia). From 1i (23.0 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 35.3 mg (89% yield) compound 3ia as a white solid, m.p. 203–204 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 12.2 min (major), tR = 14.3 min (minor); 80% ee. [α]D25 = +6.0 (c = 1.77, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.14 (s, 1H, OH), 7.33 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H, ArH), 7.28 (t, J = 7.8 Hz, 1H, ArH), 7.21 (d, J = 7.6 Hz, 1H, ArH), 7.14 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.07 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.00 (d, J = 8.0 Hz, 1H, ArH), 6.73 (s, 1H, ArH), 6.66 (d, J = 8.0 Hz, 1H, ArH), 5.22 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.83–4.78 (m, 1H, CH), 4.17 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.28 (s, 3H, CH3), 2.26–2.22 (m, 1H, CH2), 2.16–2.09 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3), ppm. 13C NMR (100 MHz, acetone-d6): 176.2, 173.2, 153.2, 141.0, 133.0, 132.1, 131.5, 131.4, 130.8, 128.7, 126.7, 125.7, 125.3, 119.7, 101.1, 76.5, 56.8, 41.7, 26.3, 22.1, 10.7 ppm. HRMS (ESI): m/z calcd. for C21H21N2O6 [M + H]+ 397.1394, found 397.1390.
(3aS,9S,9aR)-2-(3-Chlorophenyl)-9a-ethyl-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ja). From 1j (25.1 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 33.4 mg (80% yield) compound 3ja as a white solid, m.p. 185–187 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 30.1 min (major), tR = 33.5 min (minor); 79% ee. [α]D25 = +51.2 (c = 1.67, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 7.46–7.45 (m, 2H, ArH), 7.34 (td, J1 = 7.8 Hz, J2 = 1.6 Hz, 1H, ArH), 7.16 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.08 (t, J = 7.0 Hz, 1H, ArH), 7.03–7.01 (m, 1H, ArH), 6.92–6.89 (m, 1H, ArH), 5.23 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.80 (t, J = 12.2 Hz, 1H, CH), 4.20 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.97 (s, 1H, OH), 2.32–2.22 (m, 1H, CH2), 2.18–2.11 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 175.8, 172.7, 153.1, 135.8, 134.1, 132.5, 132.1, 131.3, 131.0, 128.1, 126.8, 126.5, 125.7, 119.7, 101.0, 76.4, 56.9, 41.3, 26.0, 10.5 ppm. HRMS (ESI): m/z calcd. for C20H18ClN2O6 [M + H]+ 417.0848, found 417.0844.
(3aS,9S,9aR)-2-(3-Bromophenyl)-9a-ethyl-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ka). From 1k (29.4 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:9) as eluent to obtain 35.5 mg (77% yield) compound 3ka as a white solid, m.p. 197–198 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 97:3, flow rate 1.0 mL/min, detection at 254 nm): tR = 18.6 min (major), tR = 23.2 min (minor); 80% ee. [α]D25 = +136.0 (c = 1.78, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.34, 3.08 (s, 1H, OH), 7.60–7.57 (m, 1H, ArH), 7.38 (t, J = 8.0 Hz, 1H, ArH), 7.33 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H, ArH), 7.18–7.15 (m, 2H, ArH), 7.07 (t, J = 7.4 Hz, 1H, ArH), 7.02 (d, J = 8.0 Hz, 1H, ArH), 6.95 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 5.23 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 2H, CH2), 4.81 (t, J = 12.2 Hz, 1H, CH), 4.20 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.32–2.23 (m, 1H, CH2), 2.18–2.09 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 175.8, 172.7, 153.0, 134.2, 133.9, 132.7, 132.1, 131.3, 130.9, 127.2, 126.5, 125.7, 123.5, 119.7, 101.0, 76.3, 56.9, 41.3, 26.0, 10.5 ppm. HRMS (ESI): m/z calcd. for C20H1879BrN2O6 [M + H]+ 461.0343, found 461.0329; calcd. for C20H1881BrN2O6 [M + H]+ 463.0323, found 463.0315.
(3aS,9S,9aR)-9a-ethyl-3a-hydroxy-2-(3-methoxyphenyl)-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3la). From 1l (24.6 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:9) as eluent to obtain 35.1 mg (85% yield) compound 3la as a white solid, m.p. 191–192 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 22.3 min (minor), tR = 23.1 min (major); 89% ee. [α]D25 = +47.4 (c = 1.76, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.25, 2.99 (s, 1H, OH), 7.36–7.29 (m, 2H, ArH), 7.15 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.07 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 7.02 (d, J = 8.0 Hz, 1H, ArH), 6.98–6.95 (m, 1H, ArH), 6.48–6.46 (m, 1H, ArH), 6.38 (t, J = 2.2 Hz, 1H, ArH), 5.22 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.80 (dd, J1 = 11.6 Hz, J2 = 12.8 Hz, 1H, CH), 4.18 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 3.73 (s, 1H, CH3), 2.30–2.22 (m, 1H, CH2), 2.15–2.08 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.1, 173.0, 162.0, 153.2, 134.0, 132.1, 131.8, 131.4, 126.8, 125.7, 120.3, 119.7, 116.1, 114.3, 101.0, 76.4, 56.9, 56.8, 41.7, 26.2, 10.6 ppm. HRMS (ESI): m/z calcd. for C21H21N2O7 [M + H]+ 413.1343, found 413.1339.
(3aS,9S,9aR)-2-(3,5-Dimethylphenyl)-9a-ethyl-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ma). From 1m (24.6 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:7) as eluent to obtain 34.9 mg (85% yield) compound 3ma as a white solid, m.p. 176–178 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm): tR = 17.7 min (minor), tR = 19.8 min (major); 82% ee. [α]D25 = +16.7 (c = 1.75, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.13 (s, 1H, OH), 7.33 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H, ArH), 7.14 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.07 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.00 (d, J = 8.4 Hz, 2H, ArH), 6.48 (s, 2H, ArH), 5.21 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.79 (t, J = 12.0 Hz, 1H, CH), 4.17 (dd, J1 = 4.2 Hz, J2 = 11.4 Hz, 1H, CH2), 2.28–2.24 (m, 1H, CH2), 2.22 (s, 6H, CH3), 2.15–2.07 (m, 1H, CH2), 1.11 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.2, 173.3, 153.2, 140.7, 133.0, 132.3, 132.0, 131.3, 126.6, 125.8, 125.6, 119.7, 101.0, 76.5, 56.8, 41.7, 26.3, 22.0, 10.6 ppm. HRMS (ESI): m/z calcd. for C22H23N2O6 [M + H]+ 411.1551, found 411.1550.
(3aS,9S,9aR)-2-(3,5-dimethoxyphenyl)-9a-ethyl-3a-hydroxy-9-(nitromethyl)-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3na). From 1n (27.6 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 39.4 mg (89% yield) compound 3na as a white solid, m.p. 180–181 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 12.9 min (minor), tR = 16.4 min (major); 73% ee. [α]D25 = +89.3 (c = 1.97, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.23, 2.99 (s, 1H, OH), 7.34 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H, ArH), 7.16 (dd, J1 = 1.6 Hz, J2 = 7.2 Hz, 1H, ArH), 7.10–7.06 (m, 1H, ArH), 7.02 (d, J = 8.0 Hz, 2H, ArH), 6.51 (t, J = 2.2 Hz, 1H, ArH), 5.97 (d, J = 2.0 Hz, 2H, ArH), 5.21 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.81 (t, J = 12.2 Hz, 1H, CH), 4.18 (dd, J1 = 4.2 Hz, J2 = 11.4 Hz, 1H, CH2), 3.71 (s, 6H, CH3), 2.29–2.20 (m, 1H, CH2), 2.14–2.06 (m, 1H, CH2), 1.11 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.0, 173.0, 163.0, 153.2, 134.5, 132.0, 131.4, 126.9, 125.7, 119.8, 106.7, 102.2, 101.1, 101.0, 76.3, 56.9, 41.9, 26.1, 10.6 ppm. HRMS (ESI): m/z calcd. for C22H23N2O8 [M + H]+ 443.1449, found 443.1448
(3aS,9S,9aR)-9a-Benzyl-3a-hydroxy-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3qa). From 1q (28.0 mg, 0.10 mmol) and 2a (19.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:10) as eluent to obtain 39.2 mg (88% yield) compound 3qa as a white solid, m.p. 210–211 °C. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 8.3 min (major), tR = 9.3 min (minor); 46% ee. [α]D25 = +69.9 (c = 1.96, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 7.41–7.39 (m, 1H, ArH), 7.34–7.21 (m, 7H, ArH), 7.17 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H, ArH), 7.06 (td, J1 = 7.4 Hz, J2 = 0.8 Hz, 1H, ArH), 6.98 (d, J = 8.4 Hz, 2H, ArH), 6.19–6.16 (m, 2H, ArH), 5.43 (dd, J1 = 4.4 Hz, J2 = 12.8 Hz, 1H, CH2), 4.94 (t, J = 12.2 Hz, 1H, CH), 4.34 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 3.84 (d, J = 13.2 Hz, 1H, CH2), 3.26 (d, J = 13.2 Hz, 1H, CH2), 2.93 (s, 1H, OH) ppm. 13C NMR (100 MHz, acetone-d6): 174.8, 172.4, 153.1, 136.9, 132.7, 132.6, 132.1, 131.4, 130.7, 130.6, 130.3, 129.4, 128.1, 126.6, 125.5, 119.5, 100.6, 76.4, 58.6, 43.3, 39.1 ppm. HRMS (ESI): m/z calcd. for C25H21N2O6 [M + H]+ 445.1394, found 445.1393.
(3aS,9S,9aR)-5-Ethoxy-9a-ethyl-3a-hydroxy-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ab). From 1a (21.6 mg, 0.10 mmol) and 2b (25.0 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:8) as eluent to obtain 35.9 mg (84% yield) compound 3ab as a white solid, m.p. 186–187 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 88:12, flow rate 1.0 mL/min, detection at 254 nm): tR = 17.1 min (major), tR = 20.2 min (minor); 80% ee. [α]D25 = +26.6 (c = 1.80, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 7.44–7.39 (m, 3H, ArH), 7.01–6.90 (m, 4H, ArH), 6.69 (dd, J1 = 2.0 Hz, J2 = 6.8 Hz, 1H, ArH), 5.21 (dd, J1 = 4.4 Hz, J2 = 12.6 Hz, 1H, CH2), 4.81 (t, J = 12.0 Hz, 1H, CH), 4.14 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 4.08–4.00 (m, 2H, CH2), 2.92 (s, 1H, OH), 2.29–2.24 (m, 1H, CH2), 2.14–2.07 (m, 1H, CH2), 1.30 (t, J = 6.8 Hz, 3H, CH3), 1.11 (t, J = 7.6 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.0, 173.0, 150.8, 142.4, 133.1, 131.0, 130.8, 128.2, 128.1, 125.6, 122.7, 116.3, 101.0, 76.3, 66.4, 56.9, 42.0, 26.2, 16.1, 10.7 ppm. HRMS (ESI): m/z calcd. for C22H23N2O7 [M + H]+ 427.1500, found 427.1494.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-6-methyl-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ac). From 1a (21.6 mg, 0.10 mmol) and 2c (17.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:9) as eluent to obtain 34.1 mg (86% yield) compound 3ac as a white solid, m.p. 183–185 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 10.1 min (minor), tR = 11.1 min (major); 89% ee. [α]D25 = +1.05 (c = 1.71, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.21, 2.96 (s, 1H, OH), 7.45–7.39 (m, 3H, ArH), 7.00 (d, J = 7.6 Hz, 1H, ArH), 6.93 (dd, J1 = 1.8 Hz, J2 = 8.2 Hz, 2H, ArH), 6.87 (d, J = 7.6 Hz, 1H, ArH), 6.83 (s, 1H, ArH), 5.19 (dd, J1 = 4.4 Hz, J2 = 12.4 Hz, 1H, CH2), 4.77 (t, J = 12.2 Hz, 1H, CH), 4.14 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 2.28 (s, 3H, CH3), 2.25–2.20 (m, 1H, CH2), 2.14–2.07 (m, 1H, CH2), 1.11 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.2, 173.2, 153.0, 142.4, 133.1, 131.0, 130.8, 128.2, 126.3, 123.4, 120.0, 100.9, 76.6, 56.8, 41.2, 28.5, 26.3, 22.1, 10.6 ppm. HRMS (ESI): m/z calcd. for C21H21N2O6 [M + H]+ 397.1394 found 397.1388.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-7-methyl-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ad). From 1a (21.6 mg, 0.10 mmol) and 2d (17.8 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate/petroleum ether (1:9) as eluent to obtain 34.5 mg (87% yield) compound 3ad as a white solid, m.p. 188–189 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 15.8 min (major), tR = 17.6 min (minor); 86% ee. [α]D25 = +82.7 (c = 1.73, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 7.45–7.39 (m, 3H, ArH), 7.13 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H, ArH), 6.94–6.88 (m, 4H, ArH), 5.21 (dd, J1 = 4.4 Hz, J2 = 12.4 Hz, 1H, CH2), 4.78 (dd, J1 = 11.4 Hz, J2 = 12.6 Hz, 1H, CH), 4.12 (dd, J1 = 4.4 Hz, J2 = 11.2 Hz, 1H, CH2), 2.29–2.21 (m, 1H, CH2), 3.84, 2.96 (s, 1H, OH), 2.24 (s, 3H, CH3), 2.15–2.08 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.2, 173.3, 150.9, 135.1, 133.1, 132.5, 131.5, 131.0, 130.8, 128.2, 126.4, 119.4, 100.9, 76.5, 56.8, 41.7, 26.3, 21.6, 10.6 ppm. HRMS (ESI): m/z calcd. for C21H21N2O6 [M + H]+ 397.1394, found 397.1384.
(3aS,9S,9aR)-9a-Ethyl-3a-hydroxy-7-methoxy-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ae). From 1a (21.6 mg, 0.10 mmol) and 2e (21.4 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate: petroleum ether (1:9) as eluent to obtain 34.7 mg (84% yield) compound 3ae as a white solid, m.p. 197–198 °C. HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 12.4 min (minor), tR = 14.0 min (major); 92% ee. [α]D25 = +54.7 (c = 1.74, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 8.17, 2.92 (s, 1H, OH), 7.45–7.39 (m, 3H, ArH), 6.96–6.92 (m, 3H, ArH), 6.88 (dd, J1 = 3.2 Hz, J2 = 8.8 Hz, 1H, ArH), 6.71 (d, J = 3.2 Hz, 1H, ArH), 5.22 (dd, J1 = 4.6 Hz, J2 = 13.0 Hz, 1H, CH2), 4.84–4.78 (dd, J1 = 11.6 Hz, J2 = 12.8 Hz, 1H, CH), 4.13 (dd, J1 = 4.4 Hz, J2 = 11.6 Hz, 1H, CH2), 3.73 (s, 3H, CH3), 2.30–2.20 (m, 1H, CH2), 2.14–2.08 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 176.2, 173.3, 157.7, 146.6, 133.1, 131.0, 130.8, 128.3, 127.9, 120.5, 117.1, 116.2, 101.0, 76.3, 56.92, 56.85, 42.2, 26.2, 10.7 ppm. HRMS (ESI): m/z calcd. for C21H21N2O7 [M + H]+ 413.1343, found 413.1345.
(3aS,9S,9aR)-7-Chloro-9a-ethyl-3a-hydroxy-9-(nitromethyl)-2-phenyl-9,9a-dihydrochromeno[2,3-c]pyrrole-1,3(2H,3aH)-dione (3ag). From 1a (21.6 mg, 0.10 mmol) and 2g (20.0 mg, 0.12 mmol), purified by silica gel (200–300 mesh) column chromatography using ethyl acetate: petroleum ether (1:9) as eluent to obtain 37.1 mg (89% yield) compound 3ag as a white solid, m.p. 208–210 °C. HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 11.0 min (major), tR = 12.5 min (minor); 90% ee. [α]D25 = +34.1 (c = 1.86, CH2Cl2). 1H NMR (400 MHz, acetone-d6): 7.47–7.41 (m, 3H, ArH), 7.36 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H, ArH), 7.22 (d, J = 2.4 Hz, 1H, ArH), 7.06 (d, J = 8.8 Hz, 1H, ArH), 6.98 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H, ArH), 5.26 (dd, J1 = 4.4 Hz, J2 = 13.2 Hz, 1H, CH2), 4.81 (t, J = 12.2 Hz, 1H, CH), 4.20 (dd, J1 = 4.4 Hz, J2 = 11.2 Hz, 1H, CH2), 2.93 (s, 1H, OH), 2.32–2.23 (m, 1H, CH2), 2.18–2.09 (m, 1H, CH2), 1.12 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 175.9, 172.8, 152.0, 132.9, 132.1, 131.1, 131.0, 130.0, 128.6, 128.2, 121.5, 101.3, 101.2, 76.0, 56.6, 41.1, 26.3, 10.6 ppm. HRMS (ESI): m/z calcd. for C20H18ClN2O6 [M + H]+ 417.0848, found 417.0840.

4.4. Procedure for the Scaled-Up Synthesis of Compound 3aa

In a dried bottle, 1a (0.216 g, 1.0 mmol), 2a (0.368 g, 1.2 mmol), chiral organocatalyst C3 (60.0 mg, 0.1 mmol, 10 mol%) and DCM (10.0 mL) were added. The mixture was stirred at −16 °C for 24 h. After completion of the reaction, the residue was purified by flash column chromatography on silica gel to obtain the pure product 3aa (0.496 g, 85% yield).

4.5. Procedure for the Synthesis of Compound 4

In a dried bottle, hydroxymaleimide 1b (43.2 mg, 0.20 mmol), β-nitrostyrene 2h (30.4 mg, 0.24 mmol), chiral organocatalyst C3 (12.0 mg, 0.02 mmol, 10 mol%) and DCM (2.0 mL) were added. The mixture was stirred at −16 °C for 24 h. After completion of the reaction, the residue was purified by flash column chromatography on silica gel to afford the pure product 4 (15.1 mg, 20% yield, 2:1 dr) as a white solid, m.p. 182–191 °C. 1H NMR (400 MHz, acetone-d6): 7.40–7.34 (m, 3H, ArH), 7.22–7.17 (m, 2H, ArH), 7.09–7.04 (m, 2.7H, ArH), 6.96 (d, J = 8.8 Hz, 0.66 H, ArH), 6.73 (d, J = 8.8 Hz, 0.66 H, ArH), 5.48–5.41 (m, 1H, CH2), 5.36–5.18 (m, 1H, CH2), 4.22 (dd, J1 = 11.4 Hz, J2 = 4.0 Hz, 1H, CH), 3.85 (s, 2H, OCH3), 3.82 (s, 1H, O CH3), 2.37–2.14 (m, 2H, CH2), 1.10–1.05 (m, 3H, CH3) ppm. 13C NMR (100 MHz, acetone-d6): 200.4, 198.3, 175.9, 174.9, 162.22, 162.17, 160.6, 160.3, 136.3, 135.9, 131.21, 131.18, 131.0, 130.9, 130.7, 130.5, 129.41, 129.38, 125.0, 124.9, 116.3, 116.1, 76.5, 76.0, 59.2, 59.0, 56.95, 56.91, 49.3, 48.4, 27.2, 27.0, 10.2, 9.6 ppm. HRMS (ESI): m/z calcd. for C21H21N2O6 [M + H]+ 397.1394, found 397.1419.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27165081/s1, Spectroscopic data (1H and 13C NMR), X-ray single-crystal data and chiral HPLC chromatograms for all new compounds 3.

Author Contributions

D.-H.X. performed the experiments, acquired and analyzed the original data, and wrote the preliminary manuscript. C.N. reviewed and edited the manuscript. D.-M.D. designed the research plan, supervised the experiments, modified all figures and schemes, analyzed and checked all the data, and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank the Analysis and Testing Center of Beijing Institute of Technology for the measurement of NMR and mass spectrometry.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3 are available from the authors.

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Molecules 27 05081 g001 550
Figure 1. Representative examples of natural products and biologically active compounds with a ring-fused chroman skeleton.
Figure 1. Representative examples of natural products and biologically active compounds with a ring-fused chroman skeleton.
Molecules 27 05081 g001
Molecules 27 05081 sch001 550
Scheme 1. Previous reports and our work. ((a) oxa-Michael/Michael cascade reaction [27]; (b) oxa-Michael/nitro-Michael reaction [28]; (c) [4+2] cyclization reaction, [31]; (d) our research plan.).
Scheme 1. Previous reports and our work. ((a) oxa-Michael/Michael cascade reaction [27]; (b) oxa-Michael/nitro-Michael reaction [28]; (c) [4+2] cyclization reaction, [31]; (d) our research plan.).
Molecules 27 05081 sch001
Molecules 27 05081 g002 550
Figure 2. Organocatalysts selected.
Figure 2. Organocatalysts selected.
Molecules 27 05081 g002
Molecules 27 05081 sch002 550
Scheme 2. Substrate scope for chroman-fused pyrrolidinediones 3. The reactions were carried out with 1 (0.10 mmol), 2 (0.12 mmol), and catalyst C3 (10 mol%) in DCM (1.0 mL) at −16 °C for 24 h. The yields were isolated after column chromatography. The dr values were determined by 1H NMR and the ee values were determined by HPLC analysis.
Scheme 2. Substrate scope for chroman-fused pyrrolidinediones 3. The reactions were carried out with 1 (0.10 mmol), 2 (0.12 mmol), and catalyst C3 (10 mol%) in DCM (1.0 mL) at −16 °C for 24 h. The yields were isolated after column chromatography. The dr values were determined by 1H NMR and the ee values were determined by HPLC analysis.
Molecules 27 05081 sch002
Molecules 27 05081 sch003 550
Scheme 3. Scaled-up synthesis of 3aa.
Scheme 3. Scaled-up synthesis of 3aa.
Molecules 27 05081 sch003
Molecules 27 05081 g003 550
Figure 3. X-ray crystal structure of 3ca.
Figure 3. X-ray crystal structure of 3ca.
Molecules 27 05081 g003
Molecules 27 05081 sch004 550
Scheme 4. Controlled reactions to explore the mechanism.
Scheme 4. Controlled reactions to explore the mechanism.
Molecules 27 05081 sch004
Molecules 27 05081 sch005 550
Scheme 5. Proposed reaction mechanism.
Scheme 5. Proposed reaction mechanism.
Molecules 27 05081 sch005
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 27 05081 i001
EntrySolventCatalystTemperate
(°C)		Yield b (%)dr cee d (%)
1CH2Cl2C1rt82>20:153
2CH2Cl2C1−1680>20:187
3CH2Cl2C2rt85>20:155
4CH2Cl2C2−1683>20:173
5CH2Cl2C3−1688>20:196
6CH2Cl2C4−1679>20:177
7CH2Cl2C5−1677>20:195
8CH2Cl2C6−1689>20:159
9CH2Cl2C7−1682>20:181
10CH2Cl2C8−1678>20:173
11CH2Cl2C9−169016:1−69
12CH2Cl2C10−16819:159
13DCEC3−1687>20:193
14TolueneC3−1680>20:185
15MeCNC3−1689>20:179
16CHCl3C3−1683>20:187
17THFC3−16trace––
18 eCH2Cl2C3−1686>20:195
19 fCH2Cl2C3−1680>20:189
a Unless otherwise specified, the reactions were carried out with 1a (0.10 mmol), 2a (0.12 mmol) and catalyst (10 mol%) in solvent (1.0 mL) for 24 h. b Isolated yield after column chromatography purification. c Determined by 1H NMR analysis. d The enantiomeric excess (ee) was determined by HPLC analysis. e 5 mol% catalyst was used. f 2.5 mol% catalyst was used.
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Xie, D.-H.; Niu, C.; Du, D.-M. Enantioselective Michael/Hemiketalization Cascade Reactions between Hydroxymaleimides and 2-Hydroxynitrostyrenes for the Construction of Chiral Chroman-Fused Pyrrolidinediones. Molecules 2022, 27, 5081. https://doi.org/10.3390/molecules27165081

AMA Style

Xie D-H, Niu C, Du D-M. Enantioselective Michael/Hemiketalization Cascade Reactions between Hydroxymaleimides and 2-Hydroxynitrostyrenes for the Construction of Chiral Chroman-Fused Pyrrolidinediones. Molecules. 2022; 27(16):5081. https://doi.org/10.3390/molecules27165081

Chicago/Turabian Style

Xie, Dong-Hua, Cheng Niu, and Da-Ming Du. 2022. "Enantioselective Michael/Hemiketalization Cascade Reactions between Hydroxymaleimides and 2-Hydroxynitrostyrenes for the Construction of Chiral Chroman-Fused Pyrrolidinediones" Molecules 27, no. 16: 5081. https://doi.org/10.3390/molecules27165081

APA Style

Xie, D. -H., Niu, C., & Du, D. -M. (2022). Enantioselective Michael/Hemiketalization Cascade Reactions between Hydroxymaleimides and 2-Hydroxynitrostyrenes for the Construction of Chiral Chroman-Fused Pyrrolidinediones. Molecules, 27(16), 5081. https://doi.org/10.3390/molecules27165081

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