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. Author manuscript; available in PMC: 2014 Nov 15.
Published in final edited form as: J Org Chem. 2013 Nov 7;78(22):10.1021/jo401969g. doi: 10.1021/jo401969g

Metal-free [3+2+1]/[2+2+1] Biscyclization: Stereospecific Construction with Concomitant Functionalization of Indolizin-5(1H)-one

Tuan-Jie Li †, Zhong-Qiu Liu †, Hong-Mei Yin †, Chang-Sheng Yao †, Bo Jiang †, Xiang-Shan Wang †, Shu-Jiang Tu †,✉, Xiu-Ling Li, Guigen Li ‡,§,✉
PMCID: PMC3876276  NIHMSID: NIHMS538862  PMID: 24168348

Abstract

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A metal-free [3+2+1]/[2+2+1] biscyclization strategy has been developed for the stereospecific construction with concomitant derivation of biologically significant indolizin-5(1H)-ones from simple and commercial starting materials. The transformations are notable because they can yield five new sigma bonds and six stereocenters including a quaternary carbon center in a single operation.

INTRODUCTION

Azabicyclic ring systems are widely distributed in numerous natural products and synthetic compounds and exhibit a broad range of biological activities and pharmacological properties.1 Among these systems, indolizin-5(1H)-one as an azabicyclic framework is well-represented, and this bicyclic core is frequently found in a number of biologically active natural alkaloids (Figure 1).2 Moreover, indolizin-5(1H)-one derivatives would serve as cytotoxicity agents,3 inhibitors of α-thrombin,4 oligopeptidase inhibitors,5 dipeptide mimetics,6 integrin antagonists,7 and inhibitors of aldosterone synthase.8 Indolizin-5(1H)-ones have also been attractive synthetic targets because of their unique structures and powerful biological activities. Therefore, some research groups have devoted many efforts on the syntheses of these important products.9

Figure 1.

Figure 1

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Representatives of natural products containing an indolizin-5(1H)-one core

In the meanwhile, indolizin-5(1H)-one bicyclic scaffolds have been proven to be key building block for the total synthesis of various indolizidine alkaloids.10 Several approaches to bicyclic motifs have been developed, including the Schmidt reaction,11 ring-closing metathesis reaction,12 metal-catalyzed cycloaddition,13 and Rh-catalyzed cyclization.14 However, most of these approaches suffer from several noticeable drawbacks, such as the use of costly and toxic metal catalysts, multi-step procedures,15 inaccessible substrates, and lack of effective derivation from the target skeleton. Thus, the development of metal-free strategies for the assembly and concomitant derivation of indolizin-5(1H)-ones from readily available starting materials with the aim of discovering new potentially interesting bioactive azabicyclic compounds would be a significant contribution to biomedical community.

In fact, creating molecular diversity and complexity from common and readily available reactants and forming various single and double bonds and rings in a single operation continue to be challenging in organic synthesis.16 Multicomponent domino reactions (MDRs) have emerged as useful tools for this purpose; such reactions present many advantages over their classical counterparts, including high atom efficiency, minimizing time-consuming isolation of steps, and required high purity of precursors, etc.17 Over the past few years, our group18 and others19 have developed various MDRs that can offer easy access to highly functionalized nitrogen-containing compounds of chemical and pharmaceutical interest. We recently discovered a novel ABC2 type MDR20 to give tricyclic pyrro[1,2-a]quinoline core of gephyrotoxin, an alkaloid isolated from the tropical frog Dendrobates histrionicus.21 Considering the open-ring reaction of 4-hydroxy-2H-chrome-2-one treated with amine,22 we hypothesized that the reactions of 4-hydroxy-2H-chromen-2-one, 3-aryl-1-(pyridin-2-yl)prop-2-en-1-one and pyridin-2-ylmethanamine or pyrazin-2-ylmethanamine will not only provide an efficient construction of bicyclic indolizin-5(1H)-one scaffolds, the parent core of Sessilifollamide J isolated from Stemona sessilifolia,2h but also provide a facile method of deriving this framework through simultaneous introduction of pyridine and pyrazine rings with biological importance.23

RESULTS AND DISCUSSION

According to the analysis described above, we began our investigation of this multi-component domino reaction by first reacting 3-(4-chlorophenyl)-1-(pyridin-2-yl)prop-2-en-1-one (1a), 4-hydroxy-2H-chromen-2-one (2a), and (pyridin-2-yl)methanamine (3a) to determine optimal conditions (Table 1). The catalyst-free model reaction was carried out at room temperature by using DMF as a solvent under inert gas protection. The desired compound 4a was obtained after chromatographic separation in 55 % yield, and its structure was confirmed by 1H NMR, 13C NMR, and HRMS (Table 1, entry 1). We then examined the solvent effect of chemical yield. Compared with DMF, EtOH, CH3CN, CH2Cl2, and THF, the use of anhydrous MeOH as a solvent provided optimal yield (Table 1, entry 3). To optimize the reaction conditions further, the optimal reaction temperature was determined. Results revealed that 35 °C is the optimal reaction temperature for the bicyclization reaction with highest yield of 79 % (Table 1, entry 8).

Table 1.

Optimization of conditions for the model reaction

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Entry Solvent T / °C Time / h Yield / %a
1 DMF 25 16 55
2 EtOH 25 20 36
3 MeOH 25 18 64
4 CH3CN 25 20 31
5 CH2Cl2 25 20 26
6 THF 25 20 NR
7 MeOH 30 18 73
8 MeOH 35 16 79
9 MeOH 45 16 70
10 MeOH 50 16 61
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a

Isolated yields

We next explored the scope of present multicomponent domino reactions under the above optimized conditions (Table 2). A range of 3-aryl-1-(pyridin-2-yl)prop-2-en-1-ones were smoothly converted into their corresponding products in good yields (Table 2, entries 2–7). When 3-aryl-1-(pyrazin-2-yl)prop-2-en-1-ones were used, the corresponding indolizin-5(1H)-ones were obtained (Table 2, entries 8–10). We then replaced pyridin-2-ylmethanamine (3a) with pyrazin-2-ylmethanamine for examination, and the target compounds (Table 2, entries 11, 12) were formed in good yields of 80 % and 78 %, respectively. The use of either 4-hydroxy-6-methyl-2H-chromen-2-one or 6-bromo-4-hydroxy-2H-chromen-2-one in place of 4-hydroxy-2H-chromen-2-one (2a) also smoothly afforded the corresponding products under the same conditions (Table 2, entries 13–18). As shown in Table 2, for 3-aryl-1-(pyridin-2-yl)prop-2-en-1-ones and 4-hydroxy-2H-chromen-2-one, the electronic properties of both electron-donating groups and electron-withdrawing groups in the aryl substituent exerted very limited influence on the reactivity of reactants.

Table 2.

Synthetic results of products 4

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Entry 4 Ar R X/Z Yield / % b
1 4a 4-ClC6H4 H CH/CH 79
2 4b 2-ClC6H4 H CH/CH 76
3 4c 4-CH3C6H4 H CH/CH 81
4 4d 4-CH3OC6H4 H CH/CH 78
5 4e 3,4-(CH3O)2C6H3 H CH/CH 79
6 4f 2,4-Cl2C6H3 H CH/CH 80
7 4g 2,3-(CH3O)2C6H3 H CH/CH 75
8 4h 4-BrC6H4 H CH/N 77
9 4i 4-ClC6H4 H CH/N 74
10 4j 2,3-(CH3O)2C6H3 H CH/N 82
11 4k 4-ClC6H4 H N/CH 80
12 4l 2,3-(CH3O)2C6H3 H N/CH 78
13 4m 4-ClC6H4 Br CH/CH 82
14 4n 4-FC6H4 Br CH/CH 76
15 4o 4-CH3C6H4 Br CH/CH 83
16 4p 4-CH3OC6H4 Br CH/CH 81
17 4q 4-ClC6H4 CH3 CH/CH 79
18 4r 4-CH3OC6H4 CH3 CH/CH 77
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b

Isolated yields

To confirm the stereochemistry of the indolizin-5(1H)-ones 4, the relative stereo-configuration of a single crystal of 4a was established by X-ray diffractional analysis. As shown in the crystal structure of 4a (Figure S1 in Supporting Information), six stereocenters in the molecular structure and two aryl groups in anti-configuration have been successfully formed.

According to the experimental outcomes, a mechanism hypothesis for this domino reaction is proposed as shown in Scheme 1. The first step of the mechanism is believed to be intermolecular Michael-addition between 4-hydroxy-2H-chromen-2-one (2) and 3-aryl-1-heteroarylprop-2-en-1-one (1) to generate intermediate 5. Next, the intermediate 6 is formed by intermolecular nucleophilic addition of intermediate 5 to 3, followed by an intramolecular nucleophilic addition to afford intermediate 7. Intermediate 8 was formed via a ring-opening of 7 followed by dehydration to give intermediate 9. The following step would involve intramolecular 1,4-addition or the one-step [3+2] cycloaddition to give trhe final product.

Scheme 1.

Scheme 1

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Proposed mechanism for the synthesis of 4

CONCLUSION

We have developed a metal-free [3+2+1]/[2+2+1] biscyclization strategy for the synthesis of indolizidin-5(1H)-one bicyclic scaffolds. This methodology yields indolizidin-5(1H)-ones with different substituent groups from readily accessible commercial starting materials under one-pot multi-component systems. The transformations are notable because they can yield five new sigma bonds and six stereocenters including a quaternary carbon center.

EXPERIMENTAL SECTION

General information

All reactions were carried out in an nitrogen atmosphere and solvents were dried according to established procedures. Thin layer chromatography was performed on silica gel GF254 plates. Silica gel (300–400 mesh) was used for column chromatography. Melting points are uncorrected. 1H NMR spectra were measured on 400 MHz and 13C NMR spectra were recorded on 100 MHz in CDCl3. IR spectra are reported in cm−1. HRMS were performed on TOF mass spectrometer with an ESI source. The X-ray single-crystal diffraction was performed on CCD area detector.

General procedure for synthesis of 4

A mixture of 3-aryl-1-(pyridin-2-yl)prop-2-en-1-ones or 3-aryl-1-(pyrazin-2-yl)prop-2-en-1-ones (1) (2.0 mmol) prepared according to the literature methods,24 4-hydroxy-2H-chromen-2-one or 4-hydroxy-6-methyl-2H-chromen-2-one or 6-bromo-4-hydroxy-2H-chromen-2-one (2) (1.0 mmol) and 2-(aminomethyl)pyridine or pyrazin-2-ylmethanamine (3) (1.0 mmol) was dissolved in 5 mL anhydrous methanol in a 25-mL 3-mouth flask, stirred with nitrogen incoming, heated to 35 °C progressively. The mixtures were stirred for a certain time (monitored by TLC). Then the solvent was removed in vacuum, and the residue was separated by column chromatography on silica gel (petroleum ether/ethyl acetate 4:1 v/v) to afford the producrts 4.

2,7-Bis(4-chlorophenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hexahydroin dolizin-5(1H)-one (4a)

White solid (583 mg, 79% yield): m.p. 278–280 °C; IR (KBr): 3049, 1696, 1671, 1585, 1492, 1435, 1348, 1232, 1160, 1091, 1033, 1012, 993, 955, 867, 776, 751, 688, 607, 571 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.90 (s, 1H), 9.51 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.70–8.68 (m, 1H), 8.23 (d, J = 4.8 Hz, 1H), 8.02 (td, J = 8.0, 2.0 Hz, 1H), 7.77–7.71 (m, 2H), 7.50–7.42 (m, 2H), 7.35–7.23 (m, 3H), 7.19–7.15 (m, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 6.91–6.89 (m, 3H), 6.83–6.75 (m, 2H), 6.38 (d, J = 8.4 Hz, 2H), 5.62 (d, J = 12.8 Hz, 1H), 5.18 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.21–4.13 (m, 2H), 3.42 (dd, J = 14.4, 3.2 Hz, 1H), 3.28 (dd, J = 14.4, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 200.6, 196.9, 168.8, 162.7, 160.3, 157.7, 154.2, 149.3, 148.7, 148.3, 141.5, 137.3, 136.9, 136.3, 136.2, 135.4, 133.2, 132.0, 129.7, 129.5, 128.8, 128.7, 128.4, 127.3, 124.0, 123.3, 122.9, 122.7, 122.3, 120.2, 118.9, 118.6, 74.4, 69.4, 61.5, 53.1, 50.1, 44.4, 39.6; HRMS (ESI) m/z: Calcd. for C43H32Cl2N4O4 [M+Na]+ 761.1698, found: 761.1707.

2,7-Bis(2-chlorophenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hexahydroin dolizin-5(1H)-one (4b)

White solid (561 mg, 76% yield): m.p. 249–250 °C; IR (KBr): 3031, 1681, 1644, 1587, 1541, 1474, 1438, 1403, 1346, 1288, 1236, 1198, 1159, 1101, 1036, 995, 956, 886, 783, 749, 564 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.96 (s, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.60–8.59 (m, 2H), 8.26 (d, J = 4.0 Hz, 1H), 7.93–7.88 (m, 2H), 7.77 (td, J = 7.6, 1.6 Hz, 1H), 7.56–7.53 (m, 1H), 7.46 (td, J = 7.6, 1.6 Hz, 2H), 7.37 (ddd, J = 6.0, 4.8, 0.8 Hz, 1H), 7.32–7.27 (m, 2H), 7.21–7.10 (m, 5H), 7.07–6.98 (m, 4H), 6.79 (d, J= 7.6 Hz, 1H), 6.69–6.50 (m, 1H), 5.72 (d, J = 12.8 Hz, 1H), 5.46 (d, J = 9.6 Hz, 1H), 4.94 (dd, J = 10.8 Hz, 1H), 4.69 (dd, J = 12.4, 10.8 Hz, 1H), 3.76 (td, J = 10.8, 3.6 Hz, 1H), 2.99–2.88 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 202.3, 196.2, 168.2, 162.9, 158.9, 157.9, 155.5, 149.2, 148.1, 147.1, 138.9, 136.8, 136.6, 136.0, 135.9, 133.7, 131.5, 130.2, 130.0, 128.2, 127.9, 127.3, 127.0, 126.7, 125.8, 123.3, 122.6, 122.6, 122.4, 120.3, 118.7, 118.0, 74.3, 60.6, 56.0, 44.2, 36.9; HRMS (ESI) m/z: Calcd. for C43H32Cl2N4O4 [M+Na]+ 761.1698, found: 761.1726.

6-(2-Hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)-2,7-dip-tolylhexahydroindolizin-5(1 H)-one (4c)

White solid (565 mg, 81% yield): m.p. > 300 °C; IR (KBr): 3011, 1694, 1667, 1589, 1515, 1405, 1341, 1157, 1034, 994, 953, 884, 856, 747, 666 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.97 (s, 1H), 9.54 (d, J = 7.2 Hz, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 8.03–7.99 (m, 1H), 7.70 (s, 2H), 7.43–7.29 (m, 4H), 7.23–7.13 (m, 2H), 6.98–6.94 (m, 4H), 6.88–6.86 (m, 1H), 6.79–6.72 (m, 4H), 6.33 (d, J = 6.4 Hz, 2H), 5.66 (d, J = 12.8 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 4.55 (d, J = 11.2 Hz, 1H), 4.16–4.12 (m, 2H), 3.43 (d, J = 12.0 Hz, 1H), 3.33–3.26 (m, 1H), 2.18 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 201.1, 197.2, 169.2, 162.59, 160.7, 158.2, 154.4, 149.1, 149.1, 148.6, 148.2, 140.2, 137.0, 136.8, 136.6, 136.0, 135.9, 135.7, 135.6, 133.9, 133.8, 129.9, 129.2, 128.9, 128.1, 127.2, 127.0, 124.0, 123.3, 122.6, 122.4, 122.3, 120.4, 118.8, 118.4, 74.5, 69.6, 61.6, 53.4, 50.4, 44.8, 40.0, 21.0, 20.8; HRMS (ESI) m/z: Calcd. for C45H38N4O4 [M+Na]+ 721.2791, found: 721.2814.

6-(2-Hydroxybenzoyl)-2,7-bis(4-methoxyphenyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hexahydro indolizin-5(1H)-one (4d)

White solid (569 mg, 78% yield): m.p. 272–273 °C; IR (KBr): 3010, 1669, 1637, 1587, 1514, 1436, 1344, 1251, 1179, 1158, 1032, 827, 744, 622 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.98 (s, 1H), 9.54 (d, J = 7.6 Hz, 1H), 8.72 (d, J = 3.6 Hz, 1H), 8.68 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 3.6 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.73–7.68 (m, 2H), 7.46–7.34 (m, 2H), 7.35–7.27 (m, 2H), 7.23–7.22 (m, 1H), 7.15–7.12 (m, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.80–6.74 (m, 2H), 6.66 (d, J = 8.4 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 6.37 (d, J = 8.8 Hz, 2H), 5.63 (d, J =13.2 Hz, 1H), 5.18 (d, J = 10.8 Hz, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.18–4.07 (m, 2H), 3.66 (s, 3H), 3.60 (s, 3H), 3.46–3.41 (m, 1H), 3.31–3.25 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 201.2, 197.3, 169.1, 162.6, 160.7, 158.7, 158.3, 157.8, 154.4, 149.2, 148.6, 148.2, 137.1, 136.70, 136.1, 136.0, 135.2, 129.9, 129.2, 128.8, 128.3, 127.0, 124.0, 123.3, 122.7, 122.5, 122.3, 120.4, 118.8, 118.4, 113.9, 113.6, 74.4, 69.6, 61.7, 55.1, 55.1, 53.513, 50.1, 44.8, 39.7; HRMS (ESI) m/z: Calcd. for C45H38N4O6 [M+Na]+ 753.2689, found: 753.2720.

2,7-Bis(3,4-dimethoxyphenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hexahy droindolizin-5(1H)-one (4e)

White solid (624 mg, 79% yield): m.p. 242–243 °C; IR (KBr): 3049, 1696, 1672, 1586, 1518, 1491, 1451, 1435, 1404, 1438, 1269, 1159, 1091, 1031, 1072, 933, 886, 867, 853, 824, 786, 750, 662 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.00 (s, 1H), 9.55 (d, J = 8.0 Hz, 1H), 8.74–8.70 (m, 2H), 8.30 (d, J = 4.0 Hz, 1H), 8.03 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 4.0 Hz, 2H), 7.49–7.42 (m, 2H), 7.32–7.28 (m, 2H), 7.25–7.22 (m, 1H), 7.17–7.14 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.81–6.68 (m, 3H), 6.64 (d, J = 8.0 Hz, 1H), 6.49 (s, 1H), 6.42 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 6.04 (d, J = 8.0 Hz, 1H), 5.68 (d, J = 12.8 Hz, 1H), 5.18 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.18–4.07 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 3.54 (s, 3H), 3.54–3.50 (m, 1H), 3.36–3.29 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 201.2, 197.3, 169.0, 162.66, 160.86, 158.28, 154.37, 149.20, 148.59, 148.47, 148.22, 148.03, 147.31, 137.11, 136.79, 136.2, 136.0, 135.6, 129.6, 129.3, 127.1, 124.3, 123.6, 122.6, 122.5, 122.4, 120.4, 119.7, 119.4, 118.8, 118.5, 111.6, 111.2, 110.9, 110.8, 74.3, 69.6, 61.4, 55.7, 50.4, 44.5, 40.4; HRMS (ESI) m/z: Calcd. for C47H42N4O8 [M+Na]+ 813.2900, found: 813.2907.

2,7-Bis(2,4-dichlorophenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hexahydr oindolizin-5(1H)-one (4f)

White solid (645 mg, 80% yield): m.p. 246–247 °C; IR (KBr): 3057, 1680, 1647, 1587, 1474, 1438, 1406, 1345, 1313, 1281, 1251, 1233, 1197, 1160, 1106, 1046, 995, 954, 884, 863, 780, 746, 727, 688, 662, 619 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.89 (s, 1H), 8.81 (s, 1H), 8.59 (s, 2H), 8.27 (s, 1H), 7.94–7.91 (m, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.52–7.47 (m, 1H), 7.41–7.30 (m, 3H), 7.20–7.03 (m, 8H), 6.82 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 8.0 Hz, 1H), 5.66 (d, J = 11.6 Hz, 1H), 5.45–5.38 (m, 1H), 4.91 (d, J = 10.8 Hz, 1H), 4.65 (t, J = 12.0 Hz, 1H), 3.77–3.72 (m, 1H), 2.93–2.77 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 201.8, 196.0, 167.9, 162.9, 158.6, 157.5, 155.3, 149.2, 148.1, 147.1, 137.5, 136.9, 136.8, 136.2, 136.1, 134.5, 134.4, 133.3, 131.5, 130.0, 129.8, 128.7, 127.7, 127.4, 126.8, 125.7, 123.4, 122.8, 122.6, 122.5, 120.2, 119.0, 118.2, 74.2, 55.6, 44.1, 36.3, 31.0; HRMS (ESI) m/z: Calcd. for C43H30Cl4N4O4 [M+Na]+ 831.0889, found: 831.0906.

2,7-Bis(2,3-dimethoxyphenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hexahy droindolizin-5(1H)-one (4g)

White solid (593 mg, 75% yield): m.p. 264–266 °C; IR (KBr): 3049, 1670, 1632, 1585, 1478, 1434, 1399, 1338, 1264, 1223, 1160, 1089, 1067, 995, 872, 779, 746, 667, 617, 520 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.98 (s, 1H), 9.69 (d, J = 8.0 Hz, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.14 (s, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.65 (s, 2H), 7.50–7.26 (m, 4H), 7.18–7.11 (m, 2H), 6.87–6.78 (m, 5H), 6.68–6.67 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.46–6.42 (m, 1H), 5.83 (d, J = 12.8 Hz, 1H), 5.36 (d, J = 11.2 Hz, 1H), 5.23 (d, J = 7.2 Hz, 1H), 4.70–4.66 (m, 2H), 4.47 (t, J = 12.0 Hz, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.52 (s, 3H), 3.31 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 201.1, 197.4, 169.2, 162.6, 161.0, 158.7, 154.4, 152.7, 152.6, 149.1, 148.6, 148.5, 148.1, 146.7, 136.9, 136.5, 136.0, 135.9, 130.2, 130.0, 126.9, 123.7, 123.4, 123.3, 122.4, 122.4, 122.1, 121.2, 118.8, 118.4, 117.3, 111.6, 110.2, 74.4, 68.6, 60.8, 60.6, 60.5, 55.6, 55.5, 46.1, 44.4, 32.5, 32.5; HRMS (ESI) m/z: Calcd. for C47H42N4O8 [M+Na]+ 813.2900, found: 813.2929.

2,7-Bis(4-bromophenyl)-6-(2-hydroxybenzoyl)-8a-(pyrazin-2-yl)-1-(pyrazine-2-carbonyl)-3-(pyridin-2-yl)hexahydroindolizin-5(1H)-one (4h)

White solid (637 mg, 77% yield): m.p. > 300 °C; IR (KBr): 3046, 1697, 1632, 1591, 1574, 1488, 1437, 1395, 1338, 1302, 1245, 1206, 1157, 1073, 1055, 1010, 962, 859, 802, 748, 633, 610 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.82 (s, 1H), 10.00 (s, 1H), 9.13 (s, 1H), 8.74 (s, 1H), 8.66–8.62 (m, 3H), 8.33 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.37–7.26 (m, 5H), 7.16 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 3H), 6.75 (t, J = 8.0 Hz, 1H), 5.32–5.26 (m, 2H), 4.71 (d, J = 10.4 Hz, 1H), 4.21 (t, J = 12.0 Hz, 1H), 3.12–3.08 (m, 1H), 2.88–2.83 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 201.5, 195.5, 167.4, 163.0, 156.8, 154.0, 149.6, 149.0, 147.8, 147.6, 144.8, 144.2, 142.9, 141.8, 140.4, 137.1, 136.4, 136.3, 132.1, 131.9, 131.8, 129.8, 128.3, 124.7, 123.0, 121.5, 121.3, 120.1, 119.1, 118.3, 72.6, 70.5, 61.5, 57.0, 48.6, 43.9, 39.5; HRMS (ESI) m/z: Calcd. for C41H30Br2N6O4 [M+Na]+ 853.0572, found: 853.0567.

2,7-Bis(4-chlorophenyl)-6-(2-hydroxybenzoyl)-8a-(pyrazin-2-yl)-1-(pyrazine-2-carbonyl)-3-(pyridin-2-yl)hexahydroindolizin-5(1H)-one (4i)

White solid (548 mg, 74% yield): m.p. 293–294 °C; IR (KBr): 3050, 1699, 1633, 1591, 1573, 1492, 1439, 1400, 1338, 1302, 1248, 1207, 1156, 1092, 1054, 962, 902, 880, 858, 824, 750, 716, 680, 665, 616 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.82 (s, 1H), 10.00 (s, 1H), 9.13 (d, J = 1.2 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.67–8.61 (m, 3H), 8.34 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.18–7.12 (m, 5H), 7.07 (d, J = 8.0 Hz, 3H), 6.89 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 7.6 Hz, 1H), 5.33–5.27 (m, 2H), 4.71 (d, J = 10.0 Hz, 1H), 4.25–4.19 (m, 1H), 3.15–3.09 (m, 1H), 2.90–2.81 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 201.5, 195.5, 167.4, 163.0, 156.8, 154.1, 149.6, 149.0, 147.8, 147.7, 144.8, 144.2, 142.8, 141.8, 139.9, 137.1, 136.2, 135.9, 133.3, 133.2, 131.8, 129.4, 129.2, 129.0, 128.0, 124.7, 122.9, 120.1, 119.1, 118.3, 72.6, 70.6, 61.6, 57.1, 48.5, 44.0, 39.4; HRMS (ESI) m/z: Calcd. for C41H30Cl2N6O4 [M+Na]+ 763.1603, found: 763.1626.

2,7-Bis(2,3-dimethoxyphenyl)-6-(2-hydroxybenzoyl)-8a-(pyrazin-2-yl)-1-(pyrazine-2-carbony l)-3-(pyridin-2-yl)hexahydroindolizin-5(1H)-one (4j)

White solid (650 mg, 82% yield): m.p. 228–229 °C; IR (KBr): 3044, 1698, 1587, 1480, 1387, 1270, 1158, 1090, 1016, 957, 891, 877, 861, 834, 817, 794, 742, 670, 666, 650, 625, 605 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.93 (s, 1H), 10.15 (s, 1H), 9.11 (s, 1H), 8.65 (s, 2H), 8.59 (s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.11–7.10 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.92–6.84 (m, 3H), 6.79–6.65 (m, 5H), 5.48 (d, J = 12.8 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 5.01(d, J = 10.4 Hz, 1H), 4.52 (t, J = 11.2 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.51–3.48 (m, 1H), 3.45 (s, 3H), 3.33 (s, 3H), 2.81 (t, J = 13.2 Hz, 1H), 2.70 (d, J = 10.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 202.3, 195.9, 168.0, 162.9, 158.1, 154.7, 152.8, 152.8, 149.5, 149.5, 148.4, 148.0, 147.2, 146.8, 144.8, 143.6, 142.7, 141.5, 136.6, 136.0, 134.5, 131.8, 130.8, 124.3, 123.8, 123.8, 122.5, 120.8, 120.3, 118.9, 118.8, 118.0, 111.6, 111.3, 73.0, 70.0, 61.1, 60.5, 60.3, 55.6, 55.0, 44.6, 44.5, 34.4; HRMS (ESI) m/z: Calcd. for C45H40N6O8 [M+Na]+ 815.2805, found: 815.2816.

2,7-Bis(4-chlorophenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3-(pyrazin-2-yl)-8a-(pyridin-2-yl) hexahydroindolizin-5(1H)-one (4k)

White solid (591 mg, 80% yield): m.p. > 300 °C; IR (KBr): 3048, 1667, 1584, 1527, 1592, 1447, 1435, 1342, 1291, 1260, 1234, 1158, 1092, 1034, 1014, 909, 882, 824, 788, 696, 663, 647, 618, 572, 522 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.82 (s, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.62–8.60 (m, 2H), 8.39 (d, J = 2.4 Hz, 1H), 8.21–8.18 (m, 2H), 7.90 (td, J = 8.0, 1.6 Hz, 1H), 7.69–7.65 (m, 2H), 7.38–7.35 (m, 1H), 7.28–7.24 (m, 1H), 7.19– 7.17 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.72–6.68 (m, 1H), 6.33 (d, J = 8.4 Hz, 2H), 5.57 (d, J = 12.8 Hz, 1H), 5.21 (d, J = 11.2 Hz, 1H), 4.20 (d, J = 10.8 Hz, 1H), 4.22–4.10 (m, 2H), 3.36–3.23 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.5, 195.5, 168.0, 161.7, 159.0, 153.0, 152.6, 147.7, 147.5, 144.5, 142.9, 142.8, 140.1, 136.2, 135.9, 135.5, 133.5, 132.9, 131.2, 128.4, 128.4, 128.1, 127.6, 127.4, 126.4, 122.0, 121.5, 121.3, 119.0, 117.9, 117.7, 73.3, 66.0, 60.6, 51.9, 49.0, 43.2, 38.8; HRMS (ESI) m/z: Calcd. for C42H31Cl2N5O4 [M+Na]+ 762.1651, found: 762.1630.

2,7-Bis(2,3-dimethoxyphenyl)-6-(2-hydroxybenzoyl)-1-picolinoyl-3-(pyrazin-2-yl)-8a-(pyridi n-2-yl)hexahydroindolizin-5(1H)-one (4l)

White solid (617 mg, 78% yield): m.p. 290–291 °C; IR (KBr): 2936, 1691, 1627, 1584, 1480, 1444, 1409, 1366, 1335, 1307, 1287, 1263, 1220, 1161, 1089, 1063, 1038, 997, 966, 945, 907, 860, 825, 795, 749, 683, 618 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.00 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.57 (d, J = 4.0 Hz, 2H), 8.37 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 4.0 Hz, 1H), 8.26 (s, 1H), 7.94–7.89 (m, 2H), 7.75 (td, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.37–7.34 (m, 1H), 7.31–7.26 (m, 1H), 7.21 (dd, J = 7.2, 4.8 Hz, 1H), 6.90–6.84 (m, 3H), 6.77 (d, J = 8.4 Hz, 1H), 6.72–6.62 (m, 4H), 5.69 (d, J = 12.8 Hz, 1H), 5.40 (d, J = 10.8 Hz, 1H), 4.99 (d, J = 10.8 Hz, 1H), 4.40 (dd, J = 12.4, 11.2 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.56 (s, 3H), 3.50 – 3.43 (m, 1H), 3.35 (s, 3H), 2.94 – 2.85 (m, 2H); 13C NMR (100 MHz, CDCl3) : δ 202.9, 196.5, 168.7, 162.8, 159.3, 155.6, 154.7, 152.8, 148.3, 148.1, 147.1, 147.0, 145.2, 143.9, 143.2, 136.7, 136.5, 135.8, 135.0, 131.8, 130.5, 126.6, 125.4, 124.2, 124.0, 122.6, 122.4, 120.6, 120.4, 119.4, 118.8, 117.9, 111.6, 111.3, 74.4, 67.6, 60.5, 60.3, 60.2, 55.6, 56.0, 55.4, 44.4, 44.2, 35.0; HRMS (ESI) m/z: Calcd. for C46H41N5O8 [M+Na]+ 814.2853, found: 814.2825.

6-(5-Bromo-2-hydroxybenzoyl)-2,7-bis(4-chlorophenyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hex ahydroindolizin-5(1H)-one (4m)

White solid (669 mg, 82% yield): m.p. 287–289 °C; IR (KBr): 3049, 1671, 1587, 1570, 1493, 1468, 1435, 1412, 1346, 1287, 1174, 1093, 1048, 1014, 899, 857, 826, 779, 747, 697, 626 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.64 (s, 1H), 9.81 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.0 Hz, 1H), 8.68 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 4.0 Hz, 1H), 8.11–8.07 (m, 1H), 7.76–7.70 (m, 2H), 7.54–7.38 (m, 4H), 7.30–7.26 (m, 1H), 7.22–7.19 (m, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 6.37 (d, J = 8.4 Hz, 2H), 5.62 (d, J = 13.2 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.15–4.07 (m, 2H), 3.44 (dd, J = 14.4, 3.2 Hz, 1H), 3.32–3.24 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.4, 196.8, 168.3, 161.2, 160.3, 157.3, 154.0, 149.7, 148.6, 148.4, 141.5, 138.7, 137.5, 136.8, 136.2, 135.1, 133.2, 132.5, 132.1, 129.5, 128.8, 128.6, 128.4, 127.3, 123.3, 123.3, 123.0, 122.7, 122.2, 121.3, 120.5, 110.6, 74.3, 69.0, 61.5, 53.6, 50.4, 44.5, 39.0; HRMS (ESI) m/z: Calcd. for C43H31BrCl2N4O4 [M+Na]+ 839.0803, found: 839.0764.

6-(5-Bromo-2-hydroxybenzoyl)-2,7-bis(4-fluorophenyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hex ahydroindolizin-5(1H)-one (4n)

White solid (596 mg, 76% yield): m.p. 247–248 °C; IR (KBr): 3046, 1670, 1585, 1510, 1348, 1231, 995, 831, 787, 745, 626 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.67 (s, 1H), 9.82 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.69 (d, J = 4.0 Hz, 1H), 8.28 (d, J = 4.0 Hz, 1H), 8.09 (t, J = 4.0 Hz, 1H), 7.76–7.71 (m, 2H), 7.54–7.37 (m, 4H), 7.30–7.26 (m, 1H), 7.20 (dd, J = 7.2, 5.2 Hz, 1H), 7.09 (dd, J = 8.4, 5.2 Hz, 2H), 6.87–6.79 (m, 3H), 6.72–6.64 (m, 3H), 6.43–6.40 (m, 2H), 5.63 (d, J = 12.8 Hz, 1H), 5.17 (d, J = 10.8 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.15–4.07 (m, 2H), 3.45 (dd, J = 7.2, 5.2 Hz, 1H), 3.31–3.25 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.6, 196.9, 168.4, 161.3, 160.4, 157.5, 154.1, 149.7, 148.7, 148.4, 138.7, 137.5, 136.9, 136.2, 132.6, 132.4, 132.3, 129.8, 129.7, 128.9, 128.8, 127.3, 123.4, 123.3, 123.0, 122.7, 122.3, 121.4, 120.5, 115.7, 115.4, 115.3, 115.0, 110.6, 74.3, 69.2, 61.6, 53.9, 50.4, 44.7, 39.0; HRMS (ESI) m/z: Calcd. for C43H31BrF2N4O4 [M+Na]+ 807.1394, found: 807.1395.

6-(5-Bromo-2-hydroxybenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)-2,7-dip-tolylhexahydroind olizin-5(1H)-one (4o)

White solid (644 mg, 83% yield): m.p. 275–276 °C; IR (KBr): 3012, 1696, 1669, 1587, 1570, 1515, 1468, 1435, 1404, 1344, 1287, 1175, 1046, 995, 890, 819, 780, 747, 713, 689, 627 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.73 (s, 1H), 9.84 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 4.0 Hz, 1H), 8.09 (t, J = 8.0 Hz, 1H), 7.74–7.68 (m, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.47–7.36 (m, 3H), 7.28–7.26 (m, 1H), 7.17 (dd, J = 7.2, 5.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.79 (t, J = 8.0 Hz, 3H), 6.69 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 8.0 Hz, 2H), 5.68 (d, J = 12.8 Hz, 1H), 5.21 (d, J = 11.2 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.13–4.03 (m, 2H), 3.46 (dd, J = 14.4, 3.2 Hz, 1H), 3.33–3.26 (m, 1H), 2.20 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 200.0, 197.3, 168.9, 161.4, 160.9, 158.0, 154.5, 149.8, 148.9, 148.6, 140.4, 138.6, 137.5, 137.1, 136.9, 136.3, 136.0, 133.8, 132.9, 129.5, 129.2, 128.3, 127.4, 127.3, 123.6, 123.5, 123.0, 122.7, 122.5, 121.8, 120.6, 110.7, 74.7, 69.4, 61.8, 54.0, 51.0, 45.1, 39.6, 21.2, 21.0; HRMS (ESI) m/z: Calcd. for C45H37BrN4O4 [M+Na]+ 799.1896, found: 799.1864.

6-(5-Bromo-2-hydroxybenzoyl)-2,7-bis(4-methoxyphenyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)h exahydroindolizin-5(1H)-one (4p)

White solid (654 mg, 81% yield): m.p. 169–170 °C; IR (KBr): 3047, 1670, 1612, 1586, 1513, 1486, 1435, 1401, 1343, 1290, 1177, 1114, 1032, 995, 882, 828, 780, 746, 716, 688, 672, 618 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.75 (s, 1H), 9.85 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 4.0 Hz, 1H), 8.68 (d, J = 4.0 Hz, 1H), 8.31 (d, J = 4.0 Hz, 1H), 8.10 (t, J = 8.0 Hz, 1H), 7.74–7.68 (m, 2H), 7.58 (d, J = 4.0 Hz, 1H), 7.48–7.45 (m, 1H), 7.42–7.36 (m, 2H), 7.30–7.26 (m, 1H), 7.18 (dd, J = 6.8, 4.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.69 (dd, J = 8.8, 1.6 Hz, 3H), 6.51 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 8.8 Hz, 2H), 5.65 (d, J = 13.2 Hz, 1H), 5.21 (d, J = 10.8 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.13–4.02 (m, 2H), 3.68 (s, 3H), 3.63 (s, 3H), 3.49–3.44 (m, 1H), 3.33–3.26 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 199.88, 197.18, 168.65, 161.23, 160.72, 158.71, 157.86, 157.83, 154.24, 149.58, 148.66, 148.37, 138.46, 137.37, 136.70, 136.06, 135.25, 132.65, 129.24, 128.58, 128.31, 127.09, 123.43, 123.28, 122.84, 122.51, 122.25, 121.56, 120.37, 113.96, 113.62, 110.52, 74.38, 69.19, 61.72, 55.07, 55.05, 54.03, 50.43, 44.93, 39.09. HRMS (ESI) m/z: Calcd. for C45H37BrN4O6 [M+Na]+ 831.1794, found: 831.1755.

2,7-Bis(4-chlorophenyl)-6-(2-hydroxy-5-methylbenzoyl)-1-picolinoyl-3,8a-di(pyridin-2-yl)hex ahydroindolizin-5(1H)-one (4q)

White solid (594 mg, 79% yield): m.p. 254–255 °C; IR (KBr): 3050, 1695, 1667, 1588, 1491, 1435, 1411, 1338, 1293, 1247, 1171, 1091, 1051, 1013, 825, 779, 748, 698, 670, 620 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.64 (s, 1H), 9.71 (d, J = 7.6 Hz, 1H), 8.75 (d, J = 4.0 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 3.6 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.76–7.71(m, 2H), 7.51–7.42 (m, 2H), 7.28–7.25 (m, 1H), 7.20–7.17 (m, 1H), 7.15–7.12 (m, 4H), 7.06 (d, J = 8.4 Hz, 2H), 6.93–6.88 (m, 3H), 6.72 (d, J = 9.2 Hz, 1H), 6.40 (d, J = 8.0 Hz, 2H), 5.64 (d, J = 12.8 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.19–4.13 (m, 2H), 3.45 (dd, J = 14.4, 2.8 Hz, 1H), 3.32–3.25 (m, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 200.0, 196.9, 168.9, 160.5, 160.4, 157.8, 154.1, 149.3, 148.7, 148.4, 141.7, 137.3, 137.1, 136.9, 136.3, 135.3, 133.2, 131.9, 129.8, 129.5, 128.8, 128.7, 128.4, 127.7, 127.3, 124.0, 123.3, 122.9, 122.7, 122.3, 119.7, 118.2, 74.4, 69.3, 61.5, 53.3, 50.4, 44.5, 39.2, 20.7; HRMS (ESI) m/z: Calcd. for C44H34Cl2N4O4 [M+Na]+ 775.1855, found: 775.1826.

6-(2-Hydroxy-5-methylbenzoyl)-2,7-bis(4-methoxyphenyl)-1-picolinoyl-3,8a-di(pyridin-2-yl) hexahydroindolizin-5(1H)-one (4r)

White solid (573 mg, 77% yield): m.p. 172–173 °C; IR (KBr): 2927, 1672, 1612, 1587, 1514, 1436, 1399, 1342, 1251, 1177, 1091, 1032, 995, 828, 780, 746, 688, 671, 618 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.72 (s, 1H), 9.74 (d, J = 8.0 Hz, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.68 (d, J = 4.0 Hz, 1H), 8.28 (d, J = 4.0 Hz, 1H), 8.03 (t, J = 4.0 Hz, 1H), 7.73–7.68 (m, 2H), 7.48–7.44 (m, 1H), 7.42–7.39 (m, 1H), 7.26–7.24 (m, 1H), 7.17–7.11 (m, 3H), 7.04 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 4.0 Hz, 1H), 6.71– 6.67 (m, 3H), 6.48 (d, J = 8.0 Hz, 2H), 6.38 (d, J = 8.0 Hz, 2H), 5.65 (d, J = 12.0 Hz, 1H), 5.20 (d, J = 8.0 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.16–4.07 (m, 2H), 3.67 (s, 3H), 3.62 (s, 3H), 3.46 (dd, J = 14.8, 3.2 Hz, 1H), 3.31–3.25 (m, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 200.6, 197.3, 169.3, 160.9, 160.4, 158.7, 158.3, 157.8, 154.3, 149.1, 148.7, 148.3, 137.0, 137.0, 136.7, 136.1, 135.4, 129.9, 129.2, 128.7, 128.3, 127.6, 127.1, 123.9, 123.4, 122.7, 122.5, 122.3, 119.9, 118.1, 114.0, 113.6, 74.4, 69.4, 61.7, 55.1, 55.0, 53.7, 50.3, 44.9, 39.2, 20.7; HRMS (ESI) m/z: Calcd. for C46H40N4O6 [M+Na]+ 767.2846, found: 767.2870.

Supplementary Material

1_si_002
2_si_001

ACKNOWLEDGMENTS

We thank the financial support from the NSFC (Nos. 21242014, 21272095 and 21271091), the Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Science and Technology Support Program (No. BE2011045), Natural Science Foundation of Xuzhou City (XM12B074), Robert A. Welch Foundation (D-1361) and NIH (4R33DA031860).

Footnotes

ASSOCIATED CONTENT

Supporting Information

Copy of 1H and 13C NMR spectra for all products. X-ray CIF files for 4a. This material is available free of charge via the Internet at http://pubs.acs.org.

Contributor Information

Shu-Jiang Tu, Email: laotu@jsnu.edu.cn.

Guigen Li, Email: guigen.li@ttu.edu.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1_si_002
NIHMS538862-supplement-1_si_002.cif (21.7KB, cif)
2_si_001
NIHMS538862-supplement-2_si_001.pdf (4.2MB, pdf)

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