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Article

Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3′-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction

by
Bing Lin
1,†,
Gen Zhou
1,†,
Yi Gong
1,
Qi-Di Wei
1,
Min-Yi Tian
1,
Xiong-Li Liu
1,*,
Ting-Ting Feng
1,
Ying Zhou
1,* and
Wei-Cheng Yuan
2
1
Guizhou Medicine Edicine Edible Plant Resources Research and Development Center, College of Pharmacy, Guizhou University, Guiyang 550025, China
2
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
*
Authors to whom correspondence should be addressed.
†
These two authors contributed equally to this work.
Molecules 2017, 22(4), 645; https://doi.org/10.3390/molecules22040645
Submission received: 23 March 2017 / Revised: 11 April 2017 / Accepted: 13 April 2017 / Published: 17 April 2017
(This article belongs to the Collection Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

:
Described herein is the development of a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition of dienones 2 with azomethine ylides (thermally generated in situfrom isatins and proline or thioproline or sarcosine). Products bearing four or three consecutive stereocenters consist of two oxindole moieties and a pyrrolidinyl core, including vicinal spiroquaternary stereocenters fused in one ring structure were smoothly obtained in high yields (up to 93% yield) with good diastereoselectivity (up to >20:1). Another valuable application of this method was for the design of new hybrid architectures for biological screening through the adequate fusion of these sub-units of turmerone and 3,3′-pyrrolidinyl-dispirooxindole, generating drug-like molecules.

Graphical Abstract

1. Introduction

The close correlation between the specificity of biological activity and the complex, well-defined three-dimensionalshape of natural molecules has provided the impetus to develop novel strategies to stereoselectively access challenging target structures inherent in natural products or bioactive molecules [1,2,3,4,5]. Especially, 3,3′-pyrrolidinyl-dispirooxindoles have emerged as interesting targets owing to their complex polycyclic architecture. Some biologically active 3,3′-pyrrolidinyl-dispirooxindoles exhibit prominent bioactivities such as anticancer [6], antifungal [7], and antimicrobial [8] activities (Figure 1). Stereoselective construction of spirooxindoles is one of the most challenging tasks in catalytic organic reactions [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. Generally, isatin and its derivatives have been employed as starting materials in 1,3-dipolar cycloaddition reactions yielding the spirooxindole core [39,40,41,42,43,44,45,46,47,48,49] due to the facile preparation of the corresponding azomethine ylides in the presence of α-amino acids [50,51,52,53,54,55,56], and a variety of 1,3-dipolarophiles such as α,β-unsaturated ketones [57,58,59] arylidenemalonodinitriles [60], α,β-unsaturated lactones [61] nitrostyrenes [62], acrylamides [63] and various other electron-deficient alkenes [45,64,65] have been documented. In view of their unique structural features and inspiring biological activities, the development of novel methods for the synthesis of 3,3′-pyrrolidinyl-dispirooxindoles is desirable (Figure 1).
On the other hand, the sesquiterpenes turmerone I [66,67,68,69], (S)-ar-turmerone II [66,67,68,69] and turmerone derivatives III–V [66,67,68,69] isolated from rhizomes of Curcuma longa [66,67,68,69] are reported to exhibit cytotoxic, anti-inflammatory, anti-cancer and anti-venom activity [66,67,68,69] (Figure 1). However, a close review of the literature data revealed that this biologically important turmerone scaffold has not yet been widely studied, particularly those turmerone motifs fused with other biological scaffolds.
In this context, we have been recently attracted by these 3,3′-pyrrolidinyl-dispirooxindoles due to their potential pharmaceutical applications. As a continuing effort to develop new methodology for the construction of complex dispirooxindoles (Scheme 1a) [70,71,72], we report herein a facile construction of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition reaction of dienones 2 with azomethine ylides (thermally generated in situ from isatins and proline or thioproline or sarcosine) (Scheme 1b).

2. Results and Discussion

In our initial endeavor, the dienone 2a was prepared via a Knoevenagel condensation reaction of mesityl oxide with N-methylisatin [68]. The three-component 1,3-dipolar cycloaddition reaction of N-methylisatin 1a, dienone 2a and proline was investigated to substantiate the feasibility of the strategy under various reaction conditions, as shown in Table 1. We were pleased to find that the reaction led to the desired product 3aa in moderate to good yields and dr values in different solvents (e.g., CH3CN, DCE, EtOAc, EtOH, THF, H2O and toluene). Finally, EtOH was found to be the best choice among all the solvents with respect to the stereoselectivity and yield (Table 1, entries 1–7). The reaction also occurs at 40 °C but extended reaction time (48 h) is required and isolated yield of product 3aa is lower (52%) (Table 1, entry 8). Increasing the amount of EtOH from 6.0 mL to 10.0 mL had a positive effect on both the dr value and yield of 3aa albeit with shortened reaction time, probably because it increased solubility of the substrates 1a, 2a, proline and product 3aa in this reaction system (Table 1, entry 9). Decreasing the amount of proline led to the desired product 3aa in the relatively lower yield (72%), along with some starting materials remained (Table 1, entry 11). Thus, the optimal reaction conditions we established were: isatin 1a (0.6 mmol), dienone 2a (0.4 mmol), proline (0.8 mmol) in 10.0 mL of EtOH at reflux for 3 h.
With the optimized reaction conditions in hands, we next turned our interest to the reaction scope, and the results were summarized in Table 2, Table 3 and Table 4. Proline was first used as a standard substrate to probe the reactivity of different isatins 1 and dienones 2 in this reaction. All of the reactions proceeded smoothly under the optimal conditions, producing the desired products 3 in moderate to good yields with good diastereoselectivities (Table 2, compounds 3aa–3le). Interestingly, electron-rich (Table 2, compounds 3da, 3ha, 3ka and 3dd) and electron-poor (Table 2, compounds 3ea, 3fa, 3ga, 3ia, 3ja, 3la, 3fd, 3if and 3le) substituents on the benzomoiety of isatins 1 were totally tolerated under the conditions. In addition, significant structural variation in the benzomoiety of dienones 2 could be accommodated in this reaction, producing the desired products 3 in moderate to good yields, regardless of the electronic nature of the substituents (Table 2, compounds 3ab–3le).
The generality of the reaction was further demonstrated by using a thioproline as a standard substrate (Table 3). Significant structural variation in the benzo-moiety of isatins 1 could be accommodated in this reaction, producing the desired products 4 in moderate to good yields with excellent diastereoselectivities (Table 3, products 4aa–4ma). In addition, comparing the results reported in Table 2 and Table 3, a trend becomes evident: the yields for the reaction with proline as the substrate are higher than those obtained with thioproline, indicating that proline is more reactive than thioproline in this reaction. On the other hand, the stereoselectivities recorded with thioproline are very high regardless of the employed substrates.
To further substantiate generality of the reaction, sarcosine was also used as a substrate to probe the reactivity of different isatins 1 under the optimal conditions (Table 4, products 5aa–5oc). It was found that, regardless of electron-donating substituents 1d, 1m and 1p or electron-withdrawing substituents 1e–1g, 1i, 1j and 1n–1o on the aromatic ring of isatins 1 (Table 4, entries 1–13), the corresponding products 5 could be successfully obtained in good yields with excellent diastereoselectivities.
All the targets piropyrrolidine oxindoles 3–5 were characterized by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry, and their structures were further confirmed by X-ray crystallographic studies of single crystals of 3aa, 3ba and 5ba [73] (Figure 2).
In view of the above data and the previously disclosed similar systems in the literature [10], we tentatively propose a working model as shown in Scheme 2. The reactions of isatins (1) and proline, thioproline or sarcosine led to the azomethine ylides (A) via a decarboxylation process. The ylides (A) formed could be added to the dipolarophile dienones 2 from the less hindered side thus to give the expected cycloaddition products 3–5 (Scheme 2).
According to the reaction mechanism as shown in scheme 2, if l- or d-proline was used in this cycloaddition, the racemic products would be obtained. The regiochemical outcome of the cycloaddition was further confirmed by single crystal X-ray structures of the cycloadducts 3aa, 3ba and 5ba. The significance and the high efficacy of the current protocol were demonstrated by a gram-scale synthesis of 3aa. The 1,3-dipolar cycloaddition reaction between 1a, 2a and proline proceeded cleanly on a 4.0 mmol scale (0.96 g of 2a) in 100 mL EtOH at reflux for 5 h. As outlined in Scheme 3, the corresponding adduct 3aa was obtained smoothly in 85% yield, which was similar to that observed in the previous investigation (entry 9, Table 1).
Subsequently, to further demonstrate the potential activities of these synthesized turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles, following the literature precedent by Mosmann and coworkers [74,75] with minor modification (Alley et al.) [74,75], we evaluated in vitro anticancer (human leukemia cells K562) activities of the newly synthesized 10 compounds 3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia, 5ba, 5oa and 5pa by the MTT-based assay using the commercially available broad-spectrum anticancer drug of cisplatin as a positive control, and their IC50 concentration were depicted in Table 5. The results demonstrated that the newly synthesized 10 compounds 3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia, 5ba, 5oa and 5pa showed considerable cytotoxicities to the cell lines K562, and showed equipotent potent than the positive control of cisplatin. The results also indicated that synthesized turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles may be useful leads for further biological screenings.

3. Experimental Section

3.1. General

The 1H- and 13C-NMRspectra were recorded on Bruker Avance DMX 400 MHz or 500 M NMR spectrometers in CDCl3 using TMS as internal standard. Chemical shifts were reported as δ values (ppm). High-resolution mass spectra (HRMS-ESI) were obtained on a MicroTM Q-TOF Mass Spectrometer. Melting points were uncorrected and recorded on an Electothermal 9100 digital melting point apparatus. Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography using silica gel GF254 plates. Column chromatography was performed on silica gel (300–400 mesh).

3.2. General Experimental Procedures for the Synthesis of Compounds 3–5

A solution of isatins 1 (0.6 mmol), dienones 2 (0.4 mmol) and proline, thioproline or sarcosine (0.8 mmol) in the 10.0 mL of EtOH at reflux for 3 h. After completion of the reaction, as indicated by TLC, the removal of solvent and purification by flash column chromatography (hexane/EtOAc = 5:1~3:1) were carried out to furnish the corresponding products 3–5.

3.3. Characterization Data of Compounds 3–5

Molecules 22 00645 i005
3aa: Light orange solid, m.p. 176.5–177.8 °C; yield 89%, 20:1 dr; 1H-NMR (CDCl3) δ: 1.43 (s, 3H), 1.61 (s, 3H), 2.05–2.10 (m, 2H), 2.21–2.29 (m, 2H), 2.47–2.53 (m, 1H), 2.66–2.71 (m, 1H), 2.88 (s, 3H), 3.18 (s, 3H), 4.58–4.63 (m, 2H), 5.75 (s, 1H), 6.39–6.41 (m, 1H), 6.51–6.56 (m, 2H), 6.60 (d, J = 8.0 Hz, 1H), 7.03–7.13 (m, 2H), 7.20–7.25 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H); 13C-NMR (CDCl3) δ: 20.0, 26.0, 26.2, 27.1, 30.9, 31.3, 47.3, 59.0, 65.0, 67.2, 107.4, 121.6, 122.3, 123.1, 125.1, 125.5, 127.4, 128.8, 129.2, 143.3, 143.8, 154.4, 172.9, 177.1, 196.9; HRMS (ESI-TOF) m/z: Calcd. for C28H29N3NaO3 [M + Na]+: 478.2107; Found: 478.2109.
Molecules 22 00645 i006
3ba: Light orange solid, m.p. 112.2–113.6 °C; yield 83%, 12:1 dr; 1H-NMR (CDCl3) δ: 1.40 (s, 3H), 1.57 (s, 3H), 2.02–2.08 (m, 2H), 2.19–2.26 (m, 2H), 2.50–2.55 (m, 1H), 2.66–2.69 (m, 1H), 2.87 (s, 3 H), 4.57–4.63 (m, 2H), 4.76 (d, J = 12.4 Hz, 1H), 4.94 (d, J = 12.4 Hz, 1H), 5.74 (s, 1H), 6.34–6.37 (m, 1H), 6.41–6.44 (m, 1H), 6.50 (d, J = 6.0 Hz, 1H), 6.83–6.87 (m, 1H), 7.05–7.08 (m, 1H), 7.15–7.19 (m, 2H), 7.23–7.26 (m, 2H), 7.30–7.32 (m, 2H), 7.73 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 20.0, 26.2, 27.0, 30.8, 31.4, 44.0, 47.3, 59.1, 65.0, 67.0, 107.4, 108.6, 122.2, 123.1, 127.3, 127.4, 127.5, 128.6, 135.9, 143.0, 143.3, 154.4, 172.9, 177.0, 196.9; HRMS (ESI-TOF) m/z: Calcd. for C34H33N3NaO3 [M + Na]+: 554.2420; Found: 554.2423.
Molecules 22 00645 i007
3ca: Light orange solid, m.p. 117.2–118.6 °C; yield 61%, 12:1 dr; 1H-NMR (CDCl3) δ: 1.47 (s, 3H), 1.64 (s, 3H), 2.08–2.16 (m, 2H), 2.24–2.31 (m, 2H), 2.66–2.71 (m, 1H), 2.82–2.85 (m, 1H), 2.96 (s, 3H), 4.66–4.68 (m, 2H), 5.80 (s, 1H), 6.49–6.51 (m, 1H), 6.56–6.63 (m, 3H), 6.99–7.03 (m, 1H), 7.14–7.17 (m, 1H), 7.24–7.28 (m, 1H), 7.38–7.41 (m, 1H), 7.52–7.54 (m, 4H), 7.83 (d, J = 5.6 Hz, 1H); 13C-NMR (CDCl3) δ: 20.0, 26.2, 27.0, 30.8, 31.2, 47.4, 58.9, 65.1, 67.5, 107.4, 108.6, 121.8, 123.1, 125.7, 126.9, 127.4, 128.0, 128.9, 129.5, 143.4, 143.6, 154.3, 172.9, 176.7, 196.9; HRMS (ESI-TOF) m/z: Calcd. for C33H31N3NaO3 [M + Na]+: 540.2263; Found: 540.2265.
Molecules 22 00645 i008
3da: Light orange solid, m.p. 185.4–186.8 °C; yield 72%, 13:1 dr; 1H-NMR (CDCl3) δ: 1.45 (s, 3H), 1.63 (s, 3H), 2.05–2.11 (m, 2H), 2.23–2.33 (m, 2H), 2.46 (s, 3H), 2.48–2.53 (m, 1H), 2.69–2.72 (m, 1H), 2.93 (s, 3H), 3.49 (s, 3H), 4.58–4.65 (m, 2H), 5.76 (s, 1H), 6.36 (d, J = 5.6 Hz, 1H), 6.41–6.44 (m, 1H), 6.56 (d, J = 6.4 Hz, 1H), 6.80 (d, J = 6.0 Hz, 1H), 7.10–7.13 (m, 1H), 7.21–7.24 (m, 1H), 7.77 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 19.2, 20.0, 26.3, 27.1, 29.5, 30.8, 31.2, 47.3, 59.2, 64.9, 67.4, 107.4, 118.7, 121.3, 122.2, 123.1, 123.6, 127.5, 128.8, 133.0, 141.5, 143.3, 154.2, 173.0, 177.8, 197.0; HRMS (ESI-TOF) m/z: Calcd. for C29H31N3NaO3 [M + Na]+: 492.2263; Found: 492.2265.
Molecules 22 00645 i009
3ea: Light orange solid, m.p. 106.8–108.5 °C; yield 92%, 20:1 dr; 1H-NMR (CDCl3) δ: 1.42 (s, 3H), 1.60 (s, 3H), 2.06–2.08 (m, 2H), 2.22–2.25 (m, 2 H), 2.46–2.49 (m, 1H), 2.65–2.68 (m, 1H), 2.93 (s, 3H), 3.56 (s, 3H), 4.56–4.59 (m, 2H), 5.72 (s, 1H), 6.39–6.43 (m, 2H), 6.55 (d, J = 8.0 Hz, 1H), 6.95–6.98 (m, 1H), 7.07–7.11 (m, 1H), 7.18–7.25 (m, 1H), 7.72–7.74 (m, 1H); 13C-NMR (CDCl3) δ: 20.1, 26.4, 27.2, 29.6, 30.9, 31.4, 47.4, 59.2, 65.1, 67.4, 107.7, 114.7, 122.2, 122.4, 123.1, 124.2, 126.2, 127.5, 128.1, 129.1, 131.6, 139.7, 143.4, 154.7, 172.8, 177.5, 196.7; HRMS (ESI-TOF) m/z: Calcd. for C28H28ClN3NaO3 [M + Na]+: 512.1717; Found: 512.1717.
Molecules 22 00645 i010
3fa: Light orange solid, m.p. 204.3–206.5 °C; yield 82%, 10:1 dr; 1H-NMR (CDCl3, 500 MHz) δ: 1.40 (s, 3H), 1.57 (s, 3H), 2.02–2.06 (m, 2H), 2.17–2.24 (m, 2H), 2.41–2.47 (m, 1H), 2.63–2.67 (m, 1H), 2.86 (s, 3H), 3.12 (s, 3H), 4.50–4.57 (m, 2H), 5.70 (s, 1H), 6.09–6.12 (m, 1H), 6.46–6.49 (m, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.69–6.73 (m, 1H), 7.07–7.10 (m, 1H), 7.18–7.22 (m, 1H), 7.70 (d, J = 7.0 Hz, 1H); 13C-NMR (CDCl3, 125 MHz) δ: 20.0, 26.1, 26.2, 27.1, 30.8, 31.2, 47.3, 59.0, 65.1, 67.1, 107.6, 107.7, 113.7 (d, JCF = 25.0 Hz), 115.3 (d, JCF = 23.8 Hz), 122.4, 123.0, 126.1, 127.1, 127.2, 129.2, 139.7, 143.2, 154.6, 158.3 (d, JCF = 238.8 Hz), 172.6, 176.8, 196.6; HRMS (ESI-TOF) m/z: Calcd. for C28H28FN3NaO3 [M + Na]+: 496.2012; Found: 496.2015.
Molecules 22 00645 i011
3ga: Light orange solid, m.p. 243.3–245.5 °C; yield 85%, 19:1 dr; 1H-NMR (CDCl3) δ: 1.48 (s, 3H), 1.64 (s, 3H), 2.08–2.12 (m, 2H), 2.23–2.29 (m, 2H), 2.48–2.53 (m, 1H), 2.72–2.75 (m, 1H), 2.93 (s, 3H), 3.18 (s, 3H), 4.58–4.61 (m, 2H), 5.77 (s, 1H), 6.49–6.51 (m, 2H), 6.62 (d, J = 6.4 Hz, 1H), 7.16–7.21 (m, 2H), 7.27–7.31 (m, 1H), 7.76 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 20.0, 26.1, 26.2, 27.1, 30.8, 31.3, 47.3, 58.9, 65.2, 67.2, 107.7, 108.7, 114.3, 122.4, 122.9, 127.2, 128.8, 129.2, 131.9, 142.7, 143.2, 154.6, 172.6, 176.5, 196.6; HRMS (ESI-TOF) m/z: Calcd. for C28H28BrN3NaO3 [M + Na]+: 556.1212; Found: 556.1214.
Molecules 22 00645 i012
3ha: Light orange solid, m.p. 204.4–205.6 °C; yield 90%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.41 (s, 3H), 1.57 (s, 3H), 1.80 (s, 3H), 2.03–2.08 (m, 2H), 2.18–2.29 (m, 2H), 2.51–2.56 (m, 1H), 2.66–2.70 (m, 1H), 2.87 (s, 3H), 4.56–4.63 (m, 2H), 4.75 (d, J = 12.8 Hz, 1H), 4.91 (d, J = 12.4 Hz, 1H), 5.74 (s, 1H), 6.12 (s, 1H), 6.23 (d, J = 6.4 Hz, 1H), 6.49 (d, J = 6.0 Hz, 1H), 6.64 (d, J = 6.0 Hz, 1H), 7.06–7.09 (m, 1H), 7.15–7.19 (m, 2H), 7.22–7.26 (m, 2H), 7.30 (d, J = 5.6 Hz, 2H), 7.73 (d, J = 5.6 Hz, 1H); 13C-NMR (CDCl3) δ: 20.0, 20.7, 26.2, 27.0, 30.8, 31.4, 44.1, 47.4, 59.1, 65.2, 67.0, 107.4, 108.2, 122.1, 123.1, 126.5, 127.3, 127.4, 127.5, 128.5, 128.7, 129.2, 130.9, 136.1, 154.3, 173.0, 176.8, 197.0; HRMS (ESI-TOF) m/z: Calcd. for C35H35N3NaO3 [M + Na]+: 568.2576; Found: 568.2575.
Molecules 22 00645 i013
3ia: Light orange solid, m.p. 161.1–162.8 °C; yield 88%, 12:1 dr; 1H-NMR (CDCl3) δ: 1.47 (s, 3H), 1.64 (s, 3H), 2.08–2.15 (m, 2H), 2.24–2.29 (m, 2H), 2.53–2.59 (m, 1H), 2.73–2.77 (m, 1H), 2.95 (s, 3H), 4.61–4.65 (m, 2H), 4.81 (d, J = 15.6 Hz, 1H), 4.97 (d, J = 15.6 Hz, 1H), 5.79 (s, 1H), 6.30–6.35 (m, 2H), 6.59–6.62 (m, 1H), 6.85–6.88 (m, 1H), 7.13–7.17 (m, 1H), 7.22–7.35 (m, 6H), 7.75–7.77 (m, 1H); 13C-NMR (CDCl3) δ: 20.2, 26.3, 27.2, 30.9, 31.5, 44.3, 47.4, 59.2, 65.3, 67.1, 107.9, 109.6, 123.1, 126.2, 127.1, 127.2, 127.3, 127.6, 127.7, 128.8, 129.1, 129.3, 135.6, 154.8, 172.8, 176.7, 196.7; HRMS (ESI-TOF) m/z: Calcd. for C34H32ClN3NaO3 [M + Na]+: 588.2030; Found: 588.2032.
Molecules 22 00645 i014
3ja: Light orange solid, m.p. 180.2–182.1 °C; yield 88%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.47 (s, 3H), 1.63 (s, 3H), 2.09–2.14 (m, 2H), 2.25–2.29 (m, 2H), 2.54–2.58 (m, 1H), 2.72–2.79 (m, 1H), 2.95 (s, 3H), 4.60–4.62 (m, 2H), 4.79 (d, J = 15.6 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 5.78 (s, 1H), 6.26 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.59–6.62 (m, 1H), 6.99–7.02 (m, 1H), 7.13–7.17 (m, 1H), 7.23–7.34 (m, 6H), 7.73–7.76 (m, 1H); 13C-NMR (CDCl3) δ: 20.2, 26.3, 27.2, 30.9, 31.5, 44.2, 47.4, 59.1, 65.3, 67.2, 107.9, 110.1, 104.6, 122.5, 123.1, 127.3, 127.6, 127.7, 128.8, 129.0, 129.3, 135.6, 154.8, 172.8, 176.6, 196.7; HRMS (ESI-TOF) m/z: Calcd. for C34H32BrN3NaO3 [M + Na]+: 632.1525; Found: 632.1528.
Molecules 22 00645 i015
3ka: Light orange solid, m.p. 124.3–126.5 °C; yield 80%, 8:1 dr; 1H-NMR (CDCl3) δ: 1.24–1.27 (m, 3H), 1.47 (s, 3H), 1.62 (s, 3H), 1.92 (s, 3H), 2.09–2.13 (m, 2H), 2.25–2.28 (m, 2H), 2.52–2.56 (m, 1H), 2.69–2.73 (m, 1H), 2.90 (s, 3H), 3.63–3.67 (m, 1H), 3.80–3.85 (m, 1H), 4.61–4.65 (m, 2H), 5.78 (s, 1H), 6.20 (s, 1H), 6.51–6.57 (m, 2H), 6.84–6.87 (m, 1H), 7.13–7.16 (m, 1H), 7.23–7.27 (m, 1H), 7.78 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 12.4, 19.9, 20.7, 26.1, 27.0, 30.8, 31.3, 34.5, 47.3, 58.9, 65.2, 67.1, 107.0, 107.3, 122.0, 123.1, 126.6, 127.3, 128.7, 129.2, 130.6, 140.3, 143.3, 154.1, 172.8, 176.3, 197.1; HRMS (ESI-TOF) m/z: Calcd. for C30H33N3NaO3 [M + Na]+: 506.2420; Found: 506.2423.
Molecules 22 00645 i016
3la: Light orange solid, m.p. 206.6–207.3 °C; yield 71%, 8:1 dr; 1H-NMR (CDCl3) δ: 1.23–1.27 (m, 3H), 1.47 (s, 3H), 1.64 (s, 3H), 2.08–2.13 (m, 2H), 2.22–2.28 (m, 2H), 2.48–2.54 (m, 1H), 2.70–2.75 (m, 1H), 2.93 (s, 3H), 3.62–3.68 (m, 1H), 3.80–3.86 (m, 1H), 4.58–4.62 (m, 2H), 5.77 (s, 1H), 6.37 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.03–7.05 (m, 1H), 7.14–7.18 (m, 1H), 7.26–7.30 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H); 13C-NMR (CDCl3) δ: 12.3, 20.0, 26.1, 27.0, 30.8, 31.3, 34.7, 47.2, 58.9, 65.1, 67.0, 107.6, 108.2, 122.3, 123.0, 126.2, 126.7, 127.2, 128.9, 129.1, 141.3, 143.2, 154.5, 172.5, 176.1, 196.6; HRMS (ESI-TOF) m/z: Calcd. for C29H30ClN3NaO3 [M + Na]+: 526.1873; Found: 526.1876.
Molecules 22 00645 i017
3ab: Light orange solid, m.p. 188.3–190.5 °C; yield 71%, 15:1 dr; 1H-NMR (CDCl3) δ: 1.50 (s, 3H), 1.64 (s, 3H), 2.11–2.18 (m, 2H), 2.25–2.36 (m, 2H), 2.40 (s, 3H), 2.54–2.61 (m, 1H), 2.75–2.79 (m, 1H), 3.17 (s, 3H), 4.14 (d, J = 16.0 Hz, 1H), 4.63–4.71 (m, 2H), 5.20 (d, J = 16.0 Hz, 1H), 5.82 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 6.34–6.40 (m, 3H), 6.59–6.63 (m, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 7.01–7.05 (m, 2H), 7.08–7.12 (m, 1H), 7.19–7.23 (m, 1H), 7.60 (s, 1H); 13C-NMR (CDCl3) δ: 20.0, 21.4, 26.0, 27.1, 30.9, 31.4, 43.1, 47.5, 58.7, 65.5, 67.3, 77.8, 107.5, 108.3, 121.7, 123.1, 125.7, 125.8, 126.9, 127.9, 128.5, 129.1, 129.3, 131.7, 135.0, 154.1, 172.9, 177.0, 197.2; HRMS (ESI-TOF) m/z: Calcd. for C35H35N3NaO3 [M + Na]+: 568.2576; Found: 568.2576.
Molecules 22 00645 i018
3ac: Light orange solid, m.p. 97.3–99.1 °C; yield 68%, 9:1 dr; 1H-NMR (CDCl3) δ: 1.58 (s, 3H), 1.67 (s, 3H), 2.08–2.15 (m, 2H), 2.22–2.34 (m, 2H), 2.45–2.52 (m, 1H), 2.69–2.73 (m, 1H), 2.88 (s, 3H), 3.17 (s, 3H), 4.43–4.49 (m, 1H), 4.65 (d, J = 8.8 Hz, 1H), 5.79 (s, 1H), 6.43–6.46 (m, 2H), 6.58–6.63 (m, 2H), 7.07–7.11 (m, 1H), 7.36–7.38 (m, 1H), 7.87 (s, 1H); 13C-NMR (CDCl3) δ: 20.4, 26.2, 26.4, 27.4, 30.9, 31.6, 47.4, 59.3, 65.2, 67.1, 107.6, 109.0, 115.0, 121.9, 122.9, 124.8, 125.5, 129.5, 130.0, 131.7, 142.7, 143.9, 155.2, 172.5, 176.9; HRMS (ESI-TOF) m/z: Calcd. for C28H28BrN3NaO3 [M + Na]+: 556.1212; Found: 556.1215.
Molecules 22 00645 i019
3dd: Light orange solid, m.p. 165.3–166.6 °C; yield 89%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.46 (s, 3H), 1.63 (s, 3H), 2.08–2.16 (m, 2H), 2.23–2.31 (m, 1H), 2.33–2.38 (m, 1H), 2.44 (s, 3H), 2.51–2.58 (m, 1H), 2.71–2.76 (m, 1H), 3.42 (s, 3H), 4.14 (d, J = 16.0 Hz, 1H), 4.63–4.69 (m, 2H), 5.25 (d, J = 16.4 Hz, 1H), 5.81 (s, 1H), 6.28–6.31 (m, 2H), 6.36 (d, J = 7.6 Hz, 2H), 6.42–6.46 (m, 1H), 6.90–6.93 (m, 1H), 7.01–7.11 (m, 5H), 7.74–7.76 (m, 1H); 13C-NMR (CDCl3) δ: 19.3, 20.1, 27.2, 29.6, 31.0, 31.5, 43.2, 47.6, 58.8, 65.5, 67.5, 108.5, 119.1, 121.6, 122.3, 123.2, 123.8, 125.8, 127.1, 127.5, 128.6, 128.9, 135.1, 154.4, 173.1, 177.9, 197.2; HRMS (ESI-TOF) m/z: Calcd. for C35H35N3NaO3 [M + Na]+: 568.2576; Found: 568.2577.
Molecules 22 00645 i020
3fd: Light orange solid, m.p. 204.3–205.8 °C; yield 93%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.50 (s, 3H), 1.64 (s, 3H), 2.09–2.16 (m, 2H), 2.23–2.35 (m, 2H), 2.50–2.57 (m, 1H), 2.72–2.76 (m, 1H), 3.13 (s, 3H), 4.20 (d, J = 16.0 Hz, 1H), 4.59–4.69 (m, 2H), 5.14 (d, J = 16.0 Hz, 1H), 5.82 (s, 1H), 6.07–6.10 (m, 1H), 6.36–6.38 (m, 1H), 6.46 (d, J = 7.2 Hz, 2H), 6.53–6.56 (m, 1H), 6.84–6.89 (m, 1H), 7.03–7.15 (m, 5H), 7.73–7.76 (m, 1H); 13C-NMR (CDCl3) δ: 20.2, 26.3, 27.2, 31.0, 31.5, 43.3, 47.6, 58.8, 65.6, 67.2, 77.9, 107.8, 107.9, 108.9, 114.0 (d, JCF = 26.0 Hz), 115.5 (d, JCF = 24.0 Hz), 122.5, 123.1, 126.1, 126.4, 127.2, 127.3, 128.7, 129.3, 135.1, 140.0, 142.5, 155.0, 158.6 (d, JCF = 239.0 Hz), 172.8, 176.8, 196.8; HRMS (ESI-TOF) m/z: Calcd. for C34H32FN3NaO3 [M + Na]+: 572.2325; Found: 572.2327.
Molecules 22 00645 i021
3if: Light orange solid, m.p. 177.3–178.9 °C; yield 67%, 10:1 dr; 1H-NMR (CDCl3) δ: 1.67 (s, 3H), 1.71 (s, 3H), 2.11–2.23 (m, 2H), 2.28–2.41 (m, 2H), 2.55–2.62 (m, 1H), 2.78–2.83 (m, 1H), 4.27 (d, J = 16.0 Hz, 1H), 4.49–4.56 (m, 1H), 4.75–4.80 (m, 2H), 4.93 (d, J = 15.6 Hz, 1H), 5.17 (d, J = 16.0 Hz, 1H), 5.89 (s, 1H), 6.31–6.36 (m, 3H), 6.41 (d, J = 8.0 Hz, 2H), 6.95–7.00 (m, 3H), 7.06–7.15 (m, 5H), 7.23–7.25 (m, 2H), 7.72 (s, 1H); 13C-NMR (CDCl3) δ: 20.6, 27.5, 30.9, 31.8, 43.5, 44.3, 47.5, 59.1, 65.7, 67.0, 109.9, 110.0, 122.7, 126.0, 127.1, 127.3, 127.4, 127.5, 127.6, 127.9, 128.7, 128.8, 134.5, 135.1, 156.0, 172.4, 176.5, 196.3; HRMS (ESI-TOF) m/z: Calcd. for C40H35Cl2N3NaO3 [M + Na]+: 698.1953; Found: 698.1954.
Molecules 22 00645 i022
3le: Light orange solid, m.p. 148.3–150.5 °C; yield 84%, 14:1 dr; 1H-NMR (CDCl3) δ: 0.73–0.77 (m, 3H), 1.20–1.24 (m, 3H), 1.63–1.65 (m, 6H), 2.02–2.15 (m, 2H), 2.21–2.32 (m, 2H), 2.44–2.51 (m, 1H), 2.70–2.74 (m, 1H), 3.27–3.32 (m, 1H), 3.51–3.60 (m, 2H), 3.81–3.87 (m, 1H), 4.46–4.52 (m, 1H), 4.59 (d, J = 7.6 Hz, 1H), 5.80 (s, 1H), 6.23 (s, 1H), 6.50–6.53 (m, 2H), 7.01–7.03 (m, 1H), 7.23–7.25 (m, 1H), 7.67 (d, J = 1.6 Hz, 1H); 13C-NMR (CDCl3) δ: 12.1, 12.4, 20.5, 27.4, 30.9, 31.7, 34.7, 34.8, 47.4, 58.4, 65.6, 67.1, 108.3, 108.6, 122.8, 126.1, 126.9, 127.4, 127.5, 128.9, 129.1, 141.1, 141.4, 155.9, 171.6, 175.9, 196.3; HRMS (ESI-TOF) m/z: Calcd. for C30H31Cl2N3NaO3 [M + Na]+: 574.1640; Found: 574.1638.
Molecules 22 00645 i023
4aa: Light orange solid, m.p. 198.2–200.1 °C; yield 72%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.56 (s, 3H), 1.58 (s, 3H), 2.89 (s, 3H), 2.94 (s, 3H), 2.95–2.98 (m, 1H), 3.35–3.39 (m, 1H), 3.63 (d, J = 6.4 Hz, 1H), 3.84 (d, J = 7.2 Hz, 1H), 3.91 (d, J = 7.2 Hz, 1H), 5.26–5.31 (m, 1H), 5.52 (s, 1H), 6.61 (d, J = 6.4 Hz, 1H), 6.67 (d, J = 6.0 Hz, 1H), 7.01–7.04 (m, 1H), 7.09–7.13 (m, 1H), 7.19–7.22 (m, 1H), 7.30–7.33 (m, 1H), 7.62–7.64 (m, 1H), 7.73–7.74 (m, 1H); 13C-NMR (CDCl3) δ: 20.3, 26.2, 26.4, 27.1, 36.1, 50.4, 62.0, 65.9, 67.6, 76.4, 107.3, 107.8, 121.5, 122.0, 122.9, 123.2, 124.7, 128.5, 128.7, 129.0, 130.0, 142.4, 143.5, 156.1, 173.8, 174.2; HRMS (ESI-TOF) m/z: Calcd. for C27H27N3NaO3S [M + Na]+: 496.1671; Found: 496.1673.
Molecules 22 00645 i024
4da: Light orange solid, m.p. 174.4–176.8 °C; yield 87%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.54 (s, 3H), 1.61 (s, 3H), 2.42 (s, 3H), 2.90–2.93 (m, 1H), 2.94 (s, 3H), 3.30–3.34 (m, 1H), 3.62 (d, J = 6.0 Hz, 1H), 3.80 (d, J = 7.2 Hz, 1H), 3.84 (d, J = 6.0 Hz, 1H), 5.26–5.30 (m, 1H), 5.48 (s, 1H), 6.61 (d, J = 6.0 Hz, 1H), 6.96–7.03 (m, 3H), 7.18–7.21 (m, 1H), 7.55–7.56 (m, 2H); 13C-NMR (CDCl3) δ: 19.3, 20.4, 26.5, 27.2, 29.6, 35.7, 49.4, 61.5, 66.4, 67.6, 75.4, 107.2, 119.1, 121.4, 121.9, 123.0, 126.3, 128.4, 128.9, 133.9, 141.4, 142.6, 156.0, 174.7, 195.1; HRMS (ESI-TOF) m/z: Calcd. for C28H29N3NaO3S [M + Na]+: 510.1827; Found: 510.1829.
Molecules 22 00645 i025
4ea: Light orange solid, m.p. 196.8–198.7 °C; yield 71%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.55 (s, 3H), 1.59 (s, 3H), 2.90–2.94 (m, 1H), 2.96 (s, 3H), 3.23 (s, 3H), 3.32–3.35 (m, 1H), 3.57 (d, J = 6.4 Hz, 1H), 3.77 (d, J = 7.2 Hz, 1H), 3.87 (d, J = 6.4 Hz, 1H), 5.23–5.27 (m, 1H), 5.48 (s, 1H), 6.64 (d, J = 6.4 Hz, 1H), 6.99–7.04 (m, 2H), 7.20–7.24 (m, 2H), 7.55–7.57 (m, 1H), 7.62–7.64 (m, 1H); 13C-NMR (CDCl3) δ: 20.4, 26.5, 27.1, 29.6, 35.8, 49.6, 61.6, 66.4, 67.6, 75.6, 107.4, 115.1, 122.0, 122.2, 122.8, 128.4, 129.2, 132.3, 139.4, 142.4, 156.4, 174.1, 174.2, 194.6; HRMS (ESI-TOF) m/z: Calcd. for C27H26ClN3NaO3S [M + Na]+: 530.1281; Found: 530.1280.
Molecules 22 00645 i026
4fa: Light orange solid, m.p. 182.3–184.5 °C; yield 74%, >20:1 dr; 1H-NMR (CDCl3, 500 MHz) δ: 1.57–1.58 (m, 6H), 2.88 (s, 3H), 2.88–2.95 (m, 1H), 2.97 (s, 3H), 3.35–3.38 (m, 1H), 3.59 (d, J = 8.5 Hz, 1H), 3.77 (d, J = 9.0 Hz, 1H), 3.91 (d, J = 8.5 Hz, 1H), 5.24–5.28 (m, 1H), 5.52 (s, 1H), 6.58–6.64 (m, 2H), 7.01–7.05 (m, 2H), 7.20–7.23 (m, 1H), 7.54–7.56 (m, 1H), 7.62 (d, J = 7.5 Hz, 1H); 13C-NMR (CDCl3, 125 MHz) δ: 20.3, 26.4, 26.5, 27.1, 36.1, 50.4, 62.0, 65.8, 67.6, 76.4, 107.4, 108.0, 116.1 (d, JCF = 23.8 Hz), 117.1 (d, JCF = 26.3 Hz), 122.0, 122.7, 124.4, 128.5, 129.1, 139.4, 142.4, 156.4, 158.2 (d, JCF = 240.0 Hz), 173.6, 173.9, 194.5; HRMS (ESI-TOF) m/z: Calcd. for C27H26FN3NaO3S [M + Na]+: 514.1577; Found: 514.1580.
Molecules 22 00645 i027
4ma: Light orange solid, m.p. 198.3–199.7 °C; yield 79%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.55 (s, 3H), 1.60 (s, 3H), 2.40 (s, 3H), 2.85 (s, 3H), 2.94 (s, 3H), 2.95–2.97 (m, 1H), 3.33–3.37 (m, 1H), 3.63 (d, J = 6.4 Hz, 1H), 3.82 (d, J = 7.2 Hz, 1H), 3.87 (d, J = 6.4 Hz, 1H), 5.27–5.31 (m, 1H), 5.52 (s, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 6.98–7.02 (m, 1H), 7.08–7.10 (m, 1H), 7.17–7.21 (m, 1H), 7.58–7.60 (m, 1H); 13C-NMR (CDCl3) δ: 20.3, 21.2, 26.1, 26.4, 27.1, 35.9, 50.0, 61.7, 66.0, 67.6, 76.3, 107.2, 107.4, 121.9, 122.9, 123.1, 128.4, 128.9, 129.3, 130.1, 130.9, 141.2, 142.5, 156.0, 173.7, 174.5, 195.0; HRMS (ESI-TOF) m/z: Calcd. for C28H29N3NaO3S [M + Na]+: 510.1827; Found: 510.1827.
Molecules 22 00645 i028
4ag: Light orange solid, m.p. 211.3–211.8 °C; yield 70%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.48 (s, 3H), 1.49 (s, 3H), 2.27 (s, 3H), 2.83 (s, 3H), 2.84 (s, 3H), 2.87–2.91 (m, 1H), 3.29–3.33 (m, 1H), 3.57 (d, J = 7.2 Hz, 1H), 3.74 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 6.4 Hz, 1H), 5.19–5.23 (m, 1H), 5.44 (s, 1H), 6.43 (d, J = 6.4 Hz, 1H), 6.61 (d, J = 6.4 Hz, 1H), 6.92 (d, J = 6.4 Hz, 1H), 7.02–7.05 (m, 1H), 7.23–7.26 (m, 1H), 7.38 (s, 1H), 7.67 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 20.2, 21.2, 26.2, 26.5, 27.1, 36.2, 50.7, 62.1, 65.8, 67.6, 76.5, 107.0, 107.8, 121.4, 122.9, 123.2, 128.9, 129.0, 129.3, 129.9, 131.3, 140.1, 143.4, 155.7, 173.8, 174.0, 195.0; HRMS (ESI-TOF) m/z: Calcd. for C28H29N3NaO3S [M + Na]+: 510.1827; Found: 510.1827.
Molecules 22 00645 i029
4mh: Light orange solid, m.p. 203.8–205.4 °C; yield 93%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.52 (s, 3H), 1.61 (s, 3H), 2.33 (s, 3H), 2.82 (s, 3H), 2.87 (s, 3H), 2.88–2.91 (m, 1H), 3.27–3.30 (m, 1H), 3.55 (d, J = 6.4 Hz, 1H), 3.74 (d, J = 6.8 Hz, 1H), 3.80 (d, J = 6.4 Hz, 1H), 5.14–5.19 (m, 1H), 5.47 (s, 1H), 6.46–6.50 (m, 2H), 7.03–7.05 (m, 1H), 7.09–7.11 (m, 1H), 7.42 (s, 1H), 7.53 (s, 1H); 13C-NMR (CDCl3) δ: 20.5, 21.2, 26.2, 26.5, 27.2, 35.9, 50.0, 61.7, 65.8, 67.5, 76.0, 107.5, 108.1, 122.7, 127.4, 128.6, 128.8, 129.3, 130.3, 131.0, 141.1, 141.2, 156.7, 173.3, 174.0, 194.5; HRMS (ESI-TOF) m/z: Calcd. for C28H28ClN3NaO3S [M + Na]+: 544.1438; Found: 544.1435.
Molecules 22 00645 i030
4ng: Light orange solid, m.p. 214.2–215.6 °C; yield 72%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.49 (s, 3H), 2.27 (s, 3H), 2.82 (s, 3H), 2.87 (s, 3H), 2.88–2.91 (m, 1H), 3.29–3.32 (m, 1H), 3.50 (d, J = 7.2 Hz, 1H), 3.68 (d, J = 7.2 Hz, 1H), 3.85 (d, J = 7.2 Hz, 1H), 5.15–5.20 (m, 1H), 5.45 (s, 1H), 6.44 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 6.93–6.94 (m, 1H), 7.20–7.23 (m, 1H), 7.36 (s, 1H), 7.70 (s, 1H); 13C-NMR (CDCl3) δ: 20.3, 21.2, 26.3, 26.5, 27.1, 36.3, 50.9, 62.0, 65.7, 67.7, 76.4, 107.1, 108.5, 122.8, 124.4, 129.1, 129.4, 129.5, 129.8, 131.4, 140.1, 141.9, 156.0, 173.5, 173.7, 194.7; HRMS (ESI-TOF) m/z: Calcd. for C28H28ClN3NaO3S [M + Na]+: 544.1438; Found: 544.1439.
Molecules 22 00645 i031
4nh: Light orange solid, m.p. 189.7–190.8 °C; yield 90%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.54 (s, 3H), 1.59 (s, 3H), 2.85 (s, 3H), 2.88–2.91 (m, 4H), 3.29–3.32 (m, 1H), 3.49 (d, J = 7.2 Hz, 1H), 3.70 (d, J = 7.2 Hz, 1H), 3.84 (d, J = 7.2 Hz, 1H), 5.10–5.15 (m, 1H), 5.49 (s, 1H), 6.49 (d, J = 6.4 Hz, 1H), 6.55 (d, J = 6.8 Hz, 1H), 7.12–7.14 (m, 1H), 7.22–7.24 (m, 1H), 7.56 (s, 1H), 7.66 (s, 1H); 13C-NMR (CDCl3) δ: 20.5, 26.4, 26.6, 27.2, 36.3, 50.7, 62.0, 65.5, 67.5, 76.1, 108.2, 108.7, 122.6, 124.4, 127.2, 128.8, 129.1, 129.3, 130.0, 141.0, 141.9, 157.0, 173.0, 173.4, 194.0; HRMS (ESI-TOF) m/z: Calcd. for C27H25Cl2N3NaO3S [M + Na]+: 564.0891; Found: 564.0890.
Molecules 22 00645 i032
5aa: Light orange solid, m.p. 201.1–202.9 °C; yield 82%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.49 (s, 3H), 1.80 (s, 3H), 2.19 (s, 3H), 2.84 (s, 3H), 2.98 (s, 3H), 3.38–3.42 (m, 1H), 4.01–4.05 (m, 1H), 4.51–4.54 (m, 1H), 5.39 (s, 1H), 6.55 (d, J = 6.4 Hz, 2H), 6.87–6.91 (m, 1H), 7.01–7.04 (m, 1H), 7.11–7.14 (m, 1H), 7.21–7.24 (m, 1H), 7.28–7.31 (m, 1H), 7.47 (d, J = 6.4 Hz, 1H); 13C-NMR (CDCl3) δ: 20.5, 25.3, 26.3, 27.1, 35.3, 52.9, 55.8, 61.8, 78.6, 107.1, 107.5, 121.7, 122.1, 123.9, 124.8, 126.2, 127.8, 128.6, 129.5, 143.2, 144.1, 155.3, 173.8, 176.9, 195.6; HRMS (ESI-TOF) m/z: Calcd. for C26H27N3NaO3 [M + Na]+: 452.1950; Found: 452.1953.
Molecules 22 00645 i033
5ba: Light orange solid, m.p. 203.7–204.9 °C; yield 87%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.48 (s, 3H), 1.81 (s, 3H), 2.23 (s, 3H), 2.99 (s, 3H), 3.40–3.44 (m, 1H), 4.06–4.10 (m, 1H), 4.36 (d, J = 12.8 Hz, 1H), 4.53–4.57 (m, 1H), 4.84 (d, J = 12.4 Hz, 1H), 5.38 (s, 1H), 6.38 (d, J = 6.0 Hz, 1H), 6.61 (d, J = 6.4 Hz, 1H), 6.74 (d, J = 5.2 Hz, 2H), 6.84–6.87 (m, 1H), 6.98–7.01 (m, 1H), 7.07–7.20 (m, 5H), 7.33–7.35 (m, 1H), 7.51–7.53 (m, 1H); 13C-NMR (CDCl3) δ: 20.5, 26.3, 27.1, 35.3, 42.9, 53.0, 55.9, 61.8, 78.4, 107.2, 108.7, 122.2, 123.8, 126.7, 127.1, 128.3, 128.4, 128.6, 143.4, 155.3, 173.7, 177.1, 195.7; HRMS (ESI-TOF) m/z: Calcd. for C32H31N3NaO3 [M + Na]+: 528.2263; Found: 528.2265.
Molecules 22 00645 i034
5ca: Light orange solid, m.p. 191.4–193.2 °C; yield 72%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.49 (s, 3H), 1.86 (s, 3H), 2.36 (s, 3H), 3.00 (s, 3 H), 3.46–3.50 (m, 1H), 4.03–4.06 (m, 1H), 4.57–4.61 (m, 1H), 5.41 (s, 1H), 6.41 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 6.4 Hz, 1H), 6.83–6.89 (m, 3H), 7.02–7.05 (m, 1H), 7.09–7.13 (m, 1H), 7.15–7.21 (m, 2H), 7.28–7.33 (m, 1H), 7.36–7.39 (m, 2H), 7.53–7.54 (m, 1H); 13C-NMR (CDCl3) δ: 20.6, 26.3, 27.2, 35.3, 53.4, 55.4, 62.3, 78.8, 107.3, 108.7, 124.0, 126.3, 126.7, 128.0, 128.7, 129.3, 129.5, 143.5, 144.4, 155.3, 173.4, 177.5, 195.6; HRMS (ESI-TOF) m/z: Calcd. for C31H29N3NaO3 [M + Na]+: 514.2107; Found: 514.2109.
Molecules 22 00645 i035
5da: Light orange solid, m.p. 145.1–147.8 °C; yield 86%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.49 (s, 3H), 1.82 (s, 3H), 2.19 (s, 3H), 2.34 (s, 3H), 2.97 (s, 3H), 3.09 (s, 3H), 3.37–3.42 (m, 1H), 3.98–4.03 (m, 1H), 4.49–4.54 (m, 1H), 5.37 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.86–6.94 (m, 3H), 7.12–7.15 (m, 1H), 7.25–7.32 (m, 2H); 13C-NMR (CDCl3) δ: 19.0, 20.5, 26.3, 27.1, 28.7, 35.3, 52.9, 55.6, 62.0, 77.9, 107.1, 118.8, 121.6, 121.8, 123.9, 124.0, 127.7, 128.5, 133.3, 141.8, 143.2, 155.2, 174.5, 177.0, 195.7; HRMS (ESI-TOF) m/z: Calcd. for C27H29N3NaO3 [M + Na]+: 466.2107; Found: 466.2105.
Molecules 22 00645 i036
5ea: Light orange solid, m.p. 181.3–183.7 °C; yield 83%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.49 (s, 3H), 1.82 (s, 3H), 2.19 (s, 3H), 2.98 (s, 3H), 3.19 (s, 3H), 3.38–3.42 (m, 1H), 3.97–4.02 (m, 1H), 4.49–4.53 (m, 1H), 5.35 (s, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.88–6.95 (m, 2H), 7.13–7.18 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H); 13C-NMR (CDCl3) δ: 20.6, 26.3, 27.2, 28.7, 35.2, 53.0, 55.6, 62.1, 78.1, 107.3, 114.8, 121.9, 122.7, 123.8, 124.8, 128.8, 131.9, 139.9, 143.1, 155.6, 174.1, 176.8, 195.4; HRMS (ESI-TOF) m/z: Calcd. for C26H26ClN3NaO3 [M + Na]+: 486.1560; Found: 486.1560.
Molecules 22 00645 i037
5fa: Light orange solid, m.p. 187.7–189.3 °C; yield 71%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.50 (s, 3H), 1.81 (s, 3H), 2.20 (s, 3H), 2.84 (s, 3H), 3.02 (s, 3H), 3.36–3.40 (m, 1H), 3.98–4.01 (m, 1H), 4.49–4.53 (m, 1H), 5.38 (s, 1H), 6.47–6.49 (m, 1H), 6.58 (d, J = 7.5 Hz, 1H), 6.88–6.95 (m, 2H), 7.13–7.16 (m, 1H), 7.27–7.30 (m, 2H); 13C-NMR (CDCl3) δ: 20.6, 25.5, 26.4, 27.2, 35.3, 52.9, 55.8, 61.8, 78.6, 107.3, 107.9, 108.0, 114.4 (d, JCF = 26.3 Hz), 115.8 (d, JCF = 23.8 Hz), 121.9, 123.8, 124.5, 125.9, 127.9, 128.9, 140.1, 143.2, 155.6, 158.8 (d, JCF = 238.8 Hz), 173.6, 176.7, 195.4; HRMS (ESI-TOF) m/z: Calcd. for C26H26FN3NaO3 [M + Na]+: 470.1856; Found: 470.1859.
Molecules 22 00645 i038
5ga: Light orange solid, m.p. 203.3–205.8 °C; yield 81%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.48 (s, 3H), 1.64 (s, 3H), 2.07–2.11 (m, 2H), 2.23–2.29 (m, 2H), 2.48-2.53 (m, 1H), 2.72–2.75 (m, 1H), 2.93 (s, 3H), 3.18 (s, 3H), 4.58–4.63 (m, 2H), 5.77 (s, 1H), 6.49–6.51 (m, 2H), 6.62 (d, J = 6.4 Hz, 1H), 7.16–7.21 (m, 2H), 7.27–7.31 (m, 1H), 7.76 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 20.0, 26.1, 26.2, 27.1, 30.8, 31.3, 47.3, 58.9, 65.2, 67.2, 107.7, 108.7, 114.3, 122.4, 122.9, 127.2, 128.8, 129.2, 131.9, 142.7, 143.2, 154.6, 172.6, 176.5, 196.6; HRMS (ESI-TOF) m/z: Calcd. for C26H26BrN3NaO3 [M + Na]+: 530.1055; Found: 530.1057.
Molecules 22 00645 i039
5ia: Light orange solid, m.p. 174.7–175.9 °C; yield 71%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.50 (s, 3H), 1.81 (s, 3H), 2.24 (s, 3H), 3.04 (s, 3H), 3.39–3.44 (m, 1H), 4.04–4.08 (m, 1H), 4.36 (d, J = 16.0 Hz, 1H), 4.50–4.55 (m, 1H), 4.82 (d, J = 16.0 Hz, 1H), 5.38 (s, 1H), 6.30 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 6.4 Hz, 2H), 6.85–6.89 (m, 1H), 7.05–7.07 (m, 1H), 7.11–7.22 (m, 4H), 7.31 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H); 13C-NMR (CDCl3) δ: 20.6, 26.4, 27.1, 35.3, 43.1, 53.0, 55.8, 61.8, 78.3, 107.3, 109.6, 122.2, 123.8, 126.7, 126.9, 127.3, 128.6, 128.8, 129.4, 141.8, 143.4, 155.7, 173.2, 176.8, 195.4; HRMS (ESI-TOF) m/z: Calcd. for C32H30ClN3NaO3 [M + Na]+: 562.1873; Found: 562.1875.
Molecules 22 00645 i040
5ja: Light orange solid, m.p. 151.3–153.9 °C; yield 88%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.50 (s, 3H), 1.82 (s, 3H), 2.24 (s, 3H), 3.04 (s, 3H), 3.40–3.43 (m, 1H), 4.03–4.07 (m, 1H), 4.36 (d, J = 12.8 Hz, 1H), 4.50–4.54 (m, 1H), 4.81 (d, J = 12.8 Hz, 1H), 5.38 (s, 1H), 6.24 (d, J = 6.8 Hz, 1H), 6.64 (d, J = 6.4 Hz, 1H), 6.71 (d, J = 5.6 Hz, 2H), 6.85–6.88 (m, 1H), 7.12–7.22 (m, 5H), 7.28–7.31 (m, 1H), 7.66 (s, 1H); 13C-NMR (CDCl3) δ: 20.6, 26.4, 27.2, 35.4, 43.1, 53.1, 55.7, 61.9, 78.4, 107.4, 110.2, 115.2, 122.3, 123.9, 124.7, 126.4, 126.7, 127.4, 128.3, 128.6, 128.8, 129.6, 132.4, 134.9, 142.4, 143.4, 155.7, 173.1, 176.9, 195.4; HRMS (ESI-TOF) m/z: Calcd. for C32H30BrN3NaO3 [M + Na]+: 606.1368; Found: 606.1369.
Molecules 22 00645 i041
5ma: Light orange solid, m.p. 188.2–189.6 °C; yield 89%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.50 (s, 3H), 1.81 (s, 3H), 2.19 (s, 3H), 2.34 (s, 3H), 2.82 (s, 3H), 2.98 (s, 3H), 3.37–3.41 (m, 1H), 4.01–4.04 (m, 1H), 4.49–4.53 (m, 1H), 5.40 (s, 1H), 6.43 (d, J = 6.4 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.86–6.90 (m, 1H), 7.01–7.02 (m, 1H), 7.11–7.14 (m, 1H), 7.28–7.30 (m, 2H); 13C-NMR (CDCl3) δ: 20.5, 21.0, 25.3, 26.2, 27.1, 35.3, 52.9, 55.6, 61.8, 78.6, 107.1, 107.2, 121.7, 123.9, 126.8, 127.8, 128.5, 129.7, 131.5, 141.6, 143.1, 155.2, 173.6, 177.0, 195.6; HRMS (ESI-TOF) m/z: Calcd. for C27H29N3NaO3 [M + Na]+: 466.2107; Found: 466.2108.
Molecules 22 00645 i042
5na: Light orange solid, m.p. 170.2–171.7 °C; yield 93%, >20:1 dr; 1H-NMR (CDCl3) δ: 0.83–0.86 (m, 3H), 1.49 (s, 3H), 1.83 (s, 3H), 2.19 (s, 3H), 2.98 (s, 3H), 3.23–3.30 (m, 1H), 3.38–3.42 (m, 1H), 3.54–3.61 (m, 1H), 4.01–4.05 (m, 1H), 4.52–4.55 (m, 1H), 5.38 (s, 1H), 6.55–6.58 (m, 2H), 6.86–6.89 (m, 1H), 6.99–7.03 (m, 1H), 7.11–7.14 (m, 1H), 7.19–7.23 (m, 1H), 7.29–7.30 (m, 1H), 7.48–7.50 (m, 1H); 13C-NMR (CDCl3) δ: 12.2, 20.5, 26.2, 27.1, 33.7, 35.2, 53.0, 55.6, 61.8, 78.2, 107.1, 107.5, 121.7, 121.8, 123.9, 124.7, 126.4, 127.9, 128.5, 129.4, 143.1, 143.2, 155.2, 173.3, 177.2, 195.7; HRMS (ESI-TOF) m/z: Calcd. for C27H29N3NaO3 [M + Na]+: 466.2107; Found: 466.2107.
Molecules 22 00645 i043
5oa: Light orange solid, m.p. 181.1–182.5 °C; yield 77%, >20:1 dr; 1H-NMR (CDCl3, 500 MHz) δ: 1.49 (s, 3H), 1.75 (s, 3H), 2.21 (s, 3H), 2.98 (s, 3H), 3.37–3.41 (m, 1H), 4.05–4.09 (m, 1H), 4.49–4.53 (m, 1H), 4.67 (d, J = 15.5 Hz, 1H), 4.80 (d, J = 15.5 Hz, 1H), 5.37 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.85–6.99 (m, 5H), 7.13–7.20 (m, 4H), 7.33 (d, J = 7.5 Hz, 2H); 13C-NMR (CDCl3, 125 MHz) δ: 20.5, 26.4, 27.1, 35.3, 44.7, 52.7, 56.0, 61.9, 78.4, 107.2, 117.7 (d, JCF = 18.8 Hz), 122.2, 122.6, 123.6, 124.7, 127.1, 128.3 (d, JCF = 16.3 Hz), 128.8, 136.8, 143.2, 146.8 (d, JCF = 242.5 Hz), 155.6, 173.3, 176.5, 195.4; HRMS (ESI-TOF) m/z: Calcd. for C32H30FN3NaO3 [M + Na]+: 546.2169; Found: 546.2172.
Molecules 22 00645 i044
5pa: Light orange solid, m.p. 131.3–132.8 °C; yield 77%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.48 (s, 3H), 1.78 (s, 3H), 2.02 (s, 3H), 2.25 (s, 3H), 3.03 (s, 3H), 3.40–3.44 (m, 1H), 4.06–4.10 (m, 1H), 4.51–4.54 (m, 1H), 4.70 (d, J = 13.6 Hz, 1H), 5.03 (d, J = 13.6 Hz, 1H), 5.38 (s, 1H), 6.62–6.66 (m, 3H), 6.79–6.82 (m, 1H), 6.88–6.95 (m, 2H), 7.11–7.19 (m, 4H), 7.27 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 6.0 Hz, 1H); 13C-NMR (CDCl3) δ: 18.6, 20.5, 26.3, 27.1, 35.3, 44.2, 52.9, 55.9, 61.9, 77.6, 107.1, 118.9, 122.1, 122.2, 123.8, 124.5, 125.3, 126.6, 128.4, 128.5, 128.6, 133.6, 137.4, 155.2, 174.5, 177.2, 195.7; HRMS (ESI-TOF) m/z: Calcd. for C33H33N3NaO3 [M + Na]+: 542.2420; Found: 542.2423.
Molecules 22 00645 i045
5ai: Light orange solid, m.p. 138.0–139.8 °C; yield 87%, 19:1 dr; 1H-NMR (CDCl3) δ: 0.81–0.83 (m, 3H), 1.38 (s, 3H), 1.74 (s, 3H), 2.14 (s, 3H), 2.16 (s, 3H), 2.74 (s, 3H), 3.27–3.34 (m, 2H), 3.61–3.66 (m, 1H), 3.91–3.95 (m, 1H), 4.45–4.49 (m, 1H), 5.27 (s, 1H), 6.37 (d, J = 6.4 Hz, 1H), 6.45 (d, J = 6.4 Hz, 1H), 6.83 (d, J = 6.4 Hz, 1H), 6.91–6.95 (m, 1H), 7.04 (s, 1H), 7.11–7.14 (m, 1H), 7.41–7.43 (m, 1H); 13C-NMR (CDCl3) δ: 12.2, 20.5, 20.9, 25.1, 27.1, 34.5, 35.4, 53.2, 55.9, 61.7, 78.7, 106.9, 107.3, 122.1, 134.0, 125.2, 126.6, 128.6, 128.8, 129.4, 130.8, 140.0, 144.2, 154.8, 174.1, 176.6, 195.9; HRMS (ESI-TOF) m/z: Calcd. for C28H31N3NaO3 [M + Na]+: 480.2263; Found: 480.2265.
Molecules 22 00645 i046
5aj: Light orange solid, m.p. 214.5–215.1 °C; yield 75%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.47 (s, 3H), 1.71 (s, 3H), 2.11 (s, 3H), 2.30 (s, 3H), 2.77 (s, 3H), 3.18 (s, 3H), 3.28–3.32 (m, 1H), 3.96–3.99 (m, 1H), 4.41–4.44 (m, 1H), 5.36 (s, 1H), 6.52 (d, J = 6.4 Hz, 1H), 6.69–6.72 (m, 1H), 6.78 (d, J = 5.6 Hz, 1H), 6.96–6.99 (m, 1H), 7.11 (d, J = 5.6 Hz, 1H), 7.16–7.21 (m, 1H), 7.38–7.40 (m, 1H); 13C-NMR (CDCl3) δ: 19.1, 20.5, 25.5, 27.2, 29.8, 35.4, 52.7, 56.1, 61.4, 78.8, 107.6, 118.3, 121.5, 122.0, 123.9, 125.9, 126.3, 129.4, 132.4, 140.9, 144.0, 155.0, 173.7, 177.4, 195.7; HRMS (ESI-TOF) m/z: Calcd. for C27H29N3NaO3 [M + Na]+: 466.2107; Found: 466.2109.
Molecules 22 00645 i047
5dh: Light orange solid, m.p. 185.8–187.2 °C; yield 93%, 12:1 dr; 1H-NMR (CDCl3) δ: 1.47 (s, 3H), 1.82 (s, 3H), 2.11 (s, 3H), 2.29 (s, 3H), 2.89 (s, 3H), 3.07 (s, 3H), 3.32–3.36 (m, 1H), 3.87–3.91 (m, 1H), 4.40–4.43 (m, 1H), 5.35 (s, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.81–6.84 (m, 1H), 6.87 (d, J = 6.4 Hz, 1H), 7.04–7.06 (m, 1H), 7.20–7.22 (m, 2H); 13C-NMR (CDCl3) δ: 19.0, 20.6, 26.4, 27.2, 28.8, 35.2, 52.9, 55.6, 61.9, 77.8, 108.0, 119.0, 122.0, 123.8, 124.0, 127.1, 128.0, 128.5, 133.5, 141.8, 142.0, 156.0, 174.4, 176.7, 195.3; HRMS (ESI-TOF) m/z: Calcd. for C27H28ClN3NaO3 [M + Na]+: 500.1717; Found: 500.1719.
Molecules 22 00645 i048
5nb: Light orange solid, m.p. 200.2–201.8 °C; yield 79%, 20:1 dr; 1H-NMR (CDCl3) δ: 1.34 (s, 3H), 1.72 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.75 (s, 3H), 3.32–3.35 (m, 1H), 3.95–3.99 (m, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.45–4.49 (m, 1H), 4.95 (d, J = 12.4 Hz, 1H), 5.24 (d, J = 14.0 Hz, 1H), 6.24 (d, J = 6.4 Hz, 1H), 6.43 (d, J = 6.4 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 6.80 (d, J = 2.8 Hz, 2H), 7.03 (s, 1H), 7.11–7.13 (m, 3H), 7.15–7.17 (m, 1H), 7.49 (s, 1H); 13C-NMR (CDCl3) δ: 20.5, 21.0, 25.4, 27.1, 35.4, 43.8, 53.2, 56.5, 61.8, 78.5, 108.1, 108.4, 123.8, 126.3, 126.8, 127.4, 128.1, 128.5, 128.6, 129.0, 129.4, 131.4, 135.5, 140.3, 155.3, 173.7, 177.0, 195.5; HRMS (ESI-TOF) m/z: Calcd. for C33H32ClN3NaO3 [M + Na]+: 576.2030; Found: 576.2032.
Molecules 22 00645 i049
5oc: Light orange solid, m.p. 195.3–196.9 °C; yield 75%, >20:1 dr; 1H-NMR (CDCl3) δ: 1.47 (s, 3H), 1.84 (s, 3H), 2.15 (s, 3H), 2.95 (s, 3H), 3.34–3.37 (m, 1H), 3.91–3.94 (m, 1H), 4.29 (d, J = 12.4 Hz, 1H), 4.41–4.45 (m, 1H), 4.83 (d, J = 12.8 Hz, 1H), 5.34 (s, 1H), 6.26–6.29 (m, 1H), 6.45 (d, J = 6.4 Hz, 1H), 6.72–6.76 (m, 3H), 7.11–7.13 (m, 3H), 7.20–7.22 (m, 1H), 7.26–7.28 (m, 1H), 7.41 (s, 1H); 13C-NMR (CDCl3, 100 MHz) δ: 20.8, 26.5, 27.3, 35.3, 43.3, 53.0, 55.9, 61.6, 78.3, 108.8, 109.3, 109.4, 114.6 (d, JCF = 26.3 Hz), 115.1, 116.1 (d, JCF = 23.8 Hz), 123.6, 126.8, 126.9, 127.5, 128.7, 131.4, 131.7, 135.1, 142.6, 156.6, 158.0, 158.9 (d, JCF = 240.0 Hz), 173.2, 176.5, 195.0; HRMS (ESI-TOF) m/z: Calcd. for C32H29BrFN3NaO3 [M + Na]+: 624.1274; Found: 624.1275.
All the NMR spectra of compounds 3–5 see Supplementary Materials.

3.4. Cytotoxicity Assay

The human cancer cell lines, K562 was purchased from Chinese Academy of Sciences, Kunming Cell Bank. All the cells were cultured in RPMI-1640 medium (GIBICO, Sigma-Aldrich Company, St. Louis, MO, USA), supplemented with 10% fetal bovine serum (Hyclone, Sigma-Aldrich Company) and penicillin-streptomycin (100 U/mL, respectively) in 5% CO2 at 37 °C. The cytotoxicity assay was performed according to the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method in 96-well microplates. Briefly, 5000 cells were seeded into each well of 96-well cell culture plates and allowed to grow for 24 h before drug addition. Each tumor cell line was exposed to the test compound at the concentrations of 6.25, 12.5, 25, 50, and 100 μmol·L−1 in triplicates for 48 h, comparable to Cisplatin (Aladdin, Shanghai, China). Then the MTT reagent was added to reaction with the cancer cells for 4 h. At least, measure the OD value at 490 wavelengths. IC50 of all the compounds were calculated by IBM SPSS Statistics (version 19).

4. Conclusions

In conclusion, we have developed a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition event, reacting dienones 2 with azomethine ylides (thermally generated in situ from isatins and proline or thioproline or sarcosine). Products bearing four or three consecutive stereocenters consist of two oxindole moieties and a pyrrolidinyl core, including vicinal spiroquaternary stereocenters. These structures were smoothly obtained in high yields (up to 93% yield) with good diastereoselectivity (up to >20:1). Another valuable feature of this method was its possible application in the design of new hybrid architectures for biological screenings through the adequate fusion of these sub-units of turmerone and 3,3′-pyrrolidinyl-dispirooxindole, generating drug-like molecules.

Supplementary Materials

Supplementary materials are available online.

Acknowledgments

We are grateful for the financial support from the National Natural Science Foundations of China (No. 81560563, No. 81660576 and No. 81603390); Excellent creative talents of science and technology support plan in Guizhou Province colleges and universities ([(2015)491] Qian Jiao He KY Zi); Guizhou Chinese medicine and pharmaceutical engineering professional degree graduate student workstation (JYSZ [2014]002); Science and technology major project of Guizhou province (Qian Ke He J Zhong Da Zi ([2015]6009-5) and Major project of the graduate student education teaching reform (Qian Jiao Yan He JG Zi)[2016]06.

Author Contributions

B.L. and Y.Z. conceived and designed the experiments; G.Z. and Y.G. performed experiments; Q.D.W. and M.Y.T. analyzed data; W.C.Y. and T.T.F. contributed reagents/materials/analysis tools; X.L.L. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 3–5 are available from the authors.
Molecules 22 00645 g001 550
Figure 1. Design of turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles as a hybrid of these two motifs.
Figure 1. Design of turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles as a hybrid of these two motifs.
Molecules 22 00645 g001
Molecules 22 00645 sch001 550
Scheme 1. Construction of dispirooxindoles via 1,3-dipolar cycloaddition reaction [73].
Scheme 1. Construction of dispirooxindoles via 1,3-dipolar cycloaddition reaction [73].
Molecules 22 00645 sch001
Molecules 22 00645 g002 550
Figure 2. X-ray crystallographic structures of 3aa, 3ba and 5ba.
Figure 2. X-ray crystallographic structures of 3aa, 3ba and 5ba.
Molecules 22 00645 g002
Molecules 22 00645 sch002 550
Scheme 2. Plausible mechanism of the cycloaddition reaction providing 3,3′-pyrrolidinyl-dispirooxindoles 3–5.
Scheme 2. Plausible mechanism of the cycloaddition reaction providing 3,3′-pyrrolidinyl-dispirooxindoles 3–5.
Molecules 22 00645 sch002
Molecules 22 00645 sch003 550
Scheme 3. The 1,3-dipolar cycloaddition reaction on a gram scale.
Scheme 3. The 1,3-dipolar cycloaddition reaction on a gram scale.
Molecules 22 00645 sch003
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 22 00645 i001
Entry aSolventT (°C)Time (h)Yield b (%)Dr c
1toluene8056710:1
2DCEreflux56115:1
3EtOAcreflux54812:1
4EtOHreflux58318:1
5THFreflux57116:1
6H2O8053911:1
7CH3CNreflux58219:1
8EtOH40485217:1
9 dEtOHreflux38920:1
10 eEtOHreflux55716:1
11 fEtOHreflux37219:1
a Unless otherwise noted, reactions were carried out with 0.6 mmol of 1a, 0.4 mmol of 2a, 0.8 mmol of proline in 6.0 mL of solvent; b Isolated yield after flash chromatography; c Determined by 1H-NMR analysis of the crude products; d The reaction was carried out in 10.0 mL of EtOH; e The reaction was carried out in 3.0 mL of EtOH; f The reaction was carried out using 0.5 mmol of proline.
Table
Table 2. Synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 3 a,b.
Table 2. Synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 3 a,b.
Molecules 22 00645 i002
a Unless otherwise noted, reactions were carried out with 0.6 mmol of 1, 0.4 mmol of 2, 0.8 mmol of proline in 10.0 mL of EtOH at reflux for 3 h; b Isolated yield after flash chromatography; c Determined by 1H-NMR analysis of the crude products.
Table
Table 3. Synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 4 a,b.
Table 3. Synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 4 a,b.
Molecules 22 00645 i003
a Unless otherwise noted, reactions were carried out with 0.6 mmol of 1, 0.4 mmol of 2, 0.8 mmol of thioproline in 10.0 mL of EtOH at reflux for 3 h; b Isolated yield after flash chromatography; c Determined by 1H-NMR analysis of the crude products.
Table
Table 4. Synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 5 a,b.
Table 4. Synthesis of 3,3′-pyrrolidinyl-dispirooxindoles 5 a,b.
Molecules 22 00645 i004
a Unless otherwise noted, reactions were carried out with 0.6 mmol of 1, 0.4 mmol of 2a, 0.8 mmol of sarcosine in the 10.0 mL of EtOH at reflux for 3 h; b Isolated yield after flash chromatography; c Determined by 1H-NMR analysis of the crude products.
Table
Table 5. Cytotoxicity of the nine compounds 3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia, 5ba, 5oa and 5pa on human leukemia cells K562 a.
Table 5. Cytotoxicity of the nine compounds 3le, 3fa, 3la, 3ia, 3fd, 4da, 5ia, 5ba, 5oa and 5pa on human leukemia cells K562 a.
Compound3le3fa3la3ia3fd4da5ia5ba5oa5paCisplatin
K562 IC50 (μM)43.551.333.877.862.338.549.479.022.327.621.3
a The IC50 concentration represents the concentration which results in a 50% decrease in cell growth after two days of incubation. The given values are mean values of three experiments.

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MDPI and ACS Style

Lin, B.; Zhou, G.; Gong, Y.; Wei, Q.-D.; Tian, M.-Y.; Liu, X.-L.; Feng, T.-T.; Zhou, Y.; Yuan, W.-C. Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3′-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction. Molecules 2017, 22, 645. https://doi.org/10.3390/molecules22040645

AMA Style

Lin B, Zhou G, Gong Y, Wei Q-D, Tian M-Y, Liu X-L, Feng T-T, Zhou Y, Yuan W-C. Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3′-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction. Molecules. 2017; 22(4):645. https://doi.org/10.3390/molecules22040645

Chicago/Turabian Style

Lin, Bing, Gen Zhou, Yi Gong, Qi-Di Wei, Min-Yi Tian, Xiong-Li Liu, Ting-Ting Feng, Ying Zhou, and Wei-Cheng Yuan. 2017. "Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3′-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction" Molecules 22, no. 4: 645. https://doi.org/10.3390/molecules22040645

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