Natural Product Cerbinal and Its Analogues Cyclopenta[c]pyridines

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Functional Structure/Activity Relationships

Natural Product Cerbinal and Its Analogues Cyclopenta[c]pyridines: Synthesis and Discovery as Novel Pest Control Agents Ling Li, Ji-Yong Zou, You Shengyong, Zhaoyang Deng, Yuxiu Liu, and Qingmin Wang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b03699 • Publication Date (Web): 27 Aug 2019 Downloaded from pubs.acs.org on August 27, 2019

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Journal of Agricultural and Food Chemistry

1

Natural Product Cerbinal and Its Analogues Cyclopenta[c]pyridines: Synthesis

2

and Discovery as Novel Pest Control Agents

3 4

Ling Li † , *, Jiyong Zou † , Shengyong You † , Zhaoyang Deng † , Yuxiu Liu ‡ , Qingmin

5

Wang‡, *

6 7

Institute of Applied Chemistry, Jiangxi Academy of Sciences, Nanchang, 330096,

8

†

9

China. State Key Laboratory of Elemento-Organic Chemistry, Research Institute of

10

‡

11

Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center

12

of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071,

13

China.

14 15 16 17 18 19 20 21 22 23 24 25 26 27

To whom correspondence should be addressed. For Ling Li, E-mail: [email protected]; Phone:

28

0086-791-88133587;

29

[email protected]; Phone: 0086-22-23503952; Fax: 0086-22-23503952.

Fax:

0086-791-88133587;

For

Prof.

30 1

ACS Paragon Plus Environment

Qingmin

Wang,

E-mail:


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31 32

ABSTRACT:

33

Owing to the changing needs of agriculture, the exploration of new pest control agents

34

remains as critical as ever. The analogues 3a–3v of natural product cerbinal were

35

synthesized from genipin by an efficient and practical method under additive-free

36

condition.

37

cyclopenta[c]pyridines (3a–3v) were evaluated systematically. Most of the

38

synthesized compounds exhibited higher anti-TMV activities than the lead compound

39

cerbinal. Compound 3s (2-(4-methoxyphenyl)) had the most promising inhibitory

40

activities against TMV (inactivation effect 49.0±0.8 %, curative effect 41.2±4.3 %,

41

protection effect 51.5±2.7 % at 500 μg/mL). Among the synthesized compounds, only

42

3v (2-(2-chloro-4-(trifluoromethoxy)phenyl)) reached the activity level of cerbinal

43

against Plutella xylostella. Those suggested that the cyclopenta[c]pyridines obtained

44

by modifications of cerbinal at position 2 are very significant for anti-TMV activity,

45

and yet which were exceptionally less active for the insecticidal activities.

The

antiviral

and

insecticidal

effects

of

cerbinal

and

these

46 47

KEYWORDS:

natural

product,

cerbinal,

48

anti-TMV activity, insecticidal activities

cyclopenta[c]pyridines,

synthesis,

49 50

Introduction

51

The statistics show that up to 50 % loss of global crop yields is mainly due to

52

pesticide resistance.[1] Moreover, with environmental pollution, and residual hazards

53

accumulate and many other problems appeared, some highly toxic drugs have been

54

banned. Therefore, it is a highly urgent demand to discover new and green pesticides

55

to effectively and selectively control agricultural pests. [2]

56

Natural products play an important role in the discovery and development of new

57

pesticides.

58

of weed, pathogen, and insect pests. Nowadays, they have served as inspiration for the

59

discovery and development of new pest control agents.

60

Cerbinal (Scheme 1), an aromatic cyclopenta[c]pyran natural product, was initially

[3-4]

In history, they have been important tools in controlling a wide range

2


Page 3 of 27


61

isolated from the bark of Cerbera manghas L. in 1977 by Fumiko et al.[5] It is

62

considered as a subclass of the iridoids.[6] Cerbinal was reported to show antifungal

63

activity

64

Colletotrichum lagenarium, and Puccinia species.[7] In our previous work, the iridoid

65

glycosides from gardenia jasminoides fruit[8] and genipin glycoside derivatives[9]

66

were found to have good anti-TMV and insecticidal potential. As a continuation of

67

our work, cerbinal were synthesized and evaluated for their biological activities. We

68

discovered that cerbinal displayed moderate anti-TMV activity, and good insecticidal

69

activities against Plutella xylostella.

70

Pyridines are privileged scaffolds found in numerous natural products and

71

biologically active molecules.[10-12] Therefore they are ubiquitous in agrochemicals,

72

pharmaceuticals and advanced materials.[13-15] Iridoids are monoterpenes, but they are

73

often found as intermediates in the biosynthesis of alkaloids.[6] These motivated us to

74

design and synthesize cyclopenta[c]pyridines with cerbinal as the lead compound.

75

Most of the reported strategies for them[16-20] have some limitations such as multi-step

76

reaction, high pressure, requiring the use of moisture-incompatible reagents and toxic

77

transition metal catalysts, which reduce the synthetic applicability. Therefore, an

78

efficient and practical method to access various N-substituted cyclopenta[c]pyridines

79

under additive-free conditions has been developed (Scheme 1). Sequentially, their

80

anti-TMV and insecticidal activities were systematically evaluated.

against

Bipolaris

sorokiniana,

Helminthosporium,

Pyricularia,

81 82 83

MATERIALS AND METHODS

84 85

Instruments. Melting points were determined on an X-4 binocular microscope

86

melting point apparatus and were uncorrected. 1H NMR and

87

recorded on a Bruker Ascend 400 MHz (or 500MHz) spectrometer. Chemical shift

88

values (δ) are given in ppm and downfield with tetramethylsilane as internal

89

standards. High-resolution mass spectra (HRMS) were recorded on FT-ICR MS

90

(Ionspec, 7.0 T). Analytical TLC was performed on silica gel GF 254. Column 3


13C

NMR spectra were


91

chromatographic purification was performed using silica gel or neutral alumina.

92

General Synthesis. The synthesis of cerbinal was refered to literature [21].

93

General Synthetic Procedure for the Target Compounds 3a–3v.

94

To a solution of genipin (8.00 g, 35.4 mmol) in dimethylsulfoxide (200 mL) was

95

added 2-iodoxybenzoic acid (IBX) (10.89 g, 38.9 mmol). After the resulting mixture

96

was stirred at room temperature for 3 h under argon, water (300 mL) was added. The

97

white slurry was filtered, the filtrate was extracted with ethyl acetate (4×200 mL). The

98

combined organic layers were washed with water (3×250 mL) and brine, dried with

99

anhydrous MgSO4, and concentrated under reduced pressure to afford crude 2, which

100

was purified by flash column chromatography (silica gel, petroleum ether/ethyl

101

acetate mixtures) to afford pure product 2.

102

To a solution of 2 (1.00g, 4.46mmol) in n-BuOH (60 mL) were added primary amine

103

(4.46 mmol). After the reaction mixture was heated at reflux for 5 h, the n-BuOH was

104

evaporated in vacuo. The residue was purified by neutral alumina column

105

chromatography with petroleum ether (60–90 °C)/ethyl acetate as eluent to give the

106

target compound 3.

107

Methyl 7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3a): mp: 167–169 °C; 1H

108

NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.82 (s, 1H), 9.08 (s, 1H), 8.38 (s, 1H),

109

7.87 (d, J = 3.6 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 3.94 (s, 3H). 13C NMR (100 MHz,

110

DMSO-d6) δ 183.23, 166.20, 141.94, 135.30, 132.03, 128.76, 125.67, 120.00, 114.99,

111

108.06, 52.54. HRMS (ESI) calcd for C11H10NO3 [M+H]+ 204.0655, found 204.0658.

112

Methyl 2-ethyl-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3b): mp: 191–

113

192 °C; 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 9.10 (s, 1H), 8.18 (d, J = 1.4 Hz,

114

1H), 7.92 (d, J = 3.7 Hz, 1H), 7.10 (d, J = 3.7 Hz, 1H), 4.35 (q, J = 7.3 Hz, 2H), 4.03

115

(s, 3H), 1.64 (t, J = 7.3 Hz, 3H).

116

143.96, 134.63, 133.69, 130.17, 127.12, 120.22, 116.22, 109.12, 54.42, 52.37, 17.01.

117

HRMS (ESI) calcd for C13H14NO3 [M+H]+ 232.0968, found 232.0969.

118

Methyl 2-pentyl-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3c): mp: 108–

119

110 °C; 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 9.08 (s, 1H), 8.17 (s, 1H), 7.92 (d,

120

J = 3.6 Hz, 1H), 7.11 (d, J = 3.4 Hz, 1H), 4.27 (t, J = 7.4 Hz, 2H), 4.03 (s, 3H), 2.03–

13C

NMR (100 MHz, CDCl3) δ 184.41, 166.20,

4


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13C

121

1.93 (m, 2H), 1.42–1.30 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

NMR (100 MHz,

122

CDCl3) δ 183.76, 166.15, 144.09, 135.17, 134.12, 130.81, 127.20, 120.01, 116.15,

123

109.53, 59.63, 52.42, 31.40, 28.39, 22.17, 13.81. HRMS (ESI) calcd for C16H20NO3

124

[M+H]+ 274.1438, found 274.1440

125

Methyl 2-octyl-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3d): mp: 81–

126


127

1H), 7.90 (d, J = 3.7 Hz, 1H), 7.08 (d, J = 3.7 Hz, 1H), 4.24 (t, J = 7.4 Hz, 2H), 4.02

128

(s, 3H), 1.99–1.91 (m, 2H), 1.35–1.24 (m, 10H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR

129

(100 MHz, CDCl3) δ 184.44, 166.19, 143.80, 134.48, 133.95, 130.47, 126.90, 120.24,

130

115.93, 108.93, 59.50, 52.30, 31.66, 31.63, 29.68, 28.97, 26.29, 22.53, 13.99. HRMS

131

(ESI) calcd for C19H26NO3 [M+H]+ 316.1907, found 316.1909.

132

Methyl 7-formyl-2-isopropyl-2H-cyclopenta[c]pyridine-4-carboxylate (3e): mp: 151–

133


134

1H), 7.91 (d, J = 3.7 Hz, 1H), 7.08 (d, J = 3.7 Hz, 1H), 4.61 (dt, J = 13.5, 6.8 Hz, 1H),

135

4.03 (s, 3H), 1.68 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 184.48, 166.36,

136

143.89, 134.98, 132.29, 128.31, 127.05, 120.26, 116.22, 108.93, 61.23, 52.35, 23.48.

137


138

Methyl 2-(tert-butyl)-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3f): mp:

139

198–200 °C; 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 9.43 (s, 1H), 8.49 (s, 1H),

140

7.91 (d, J = 3.5 Hz, 1H), 7.05 (d, J = 3.5 Hz, 1H), 4.04 (s, 3H), 1.81 (s, 9H). 13C NMR

141

(100 MHz, CDCl3) δ 184.01, 166.56, 144.04, 134.58, 131.16, 127.77, 127.13, 120.26,

142

115.81, 108.84, 63.86, 52.38, 30.57. HRMS (ESI) calcd for C15H18NO3 [M+H]+

143

260.1281, found 260.1283.

144

Methyl

145

yield: 40.35%; mp: 179–180 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.25

146

(s, 1H), 8.58 (s, 1H), 7.91 (d, J = 3.6 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 4.81 (t, J = 6.5

147

Hz, 2H), 3.96 (s, 3H), 3.27 (t, J = 6.5 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ

148

183.32, 165.89, 142.92, 135.41, 133.99, 132.17, 126.25, 120.41, 118.34, 115.46,

149

108.43, 53.42, 52.69, 20.03. HRMS (ESI) calcd for C14H13N2O3 [M+H]+ 257.0921,

150

found 257.0923.

2-(2-cyanoethyl)-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate

5


(3g):


151

Methyl 2-allyl-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3h): mp: 148–

152


153

1H), 7.93 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.7 Hz, 1H), 6.11–6.00 (m, 1H), 5.44 (d, J

154

= 10.2 Hz, 1H), 5.32 (d, J = 17.0 Hz, 1H), 4.87 (d, J = 5.9 Hz, 2H), 4.02 (s, 3H). 13C

155

NMR (100 MHz, CDCl3) δ 184.63, 166.15, 144.12, 134.37, 134.09, 131.25, 130.43,

156

126.90, 121.13, 120.57, 116.09, 109.16, 61.17, 52.36. HRMS (ESI) calcd for

157

C14H14NO3 [M+H]+ 244.0968, found 244.0970.

158

Methyl 7-formyl-2-(furan-2-ylmethyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3i):

159

mp: 180–182 °C; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 9.15 (s, 1H), 8.23 (s,

160

1H), 7.92 (d, J = 3.2 Hz, 1H), 7.43 (s, 1H), 7.09 (d, J = 3.1 Hz, 1H), 6.54 (d, J = 2.2

161

Hz, 1H), 6.39 (s, 1H), 5.36 (s, 2H), 4.01 (s, 3H).

162

184.62, 166.09, 147.09, 144.40, 144.24, 134.29, 133.89, 130.32, 126.88, 120.72,

163

116.10, 111.06, 110.97, 109.25, 54.93, 52.36. HRMS (ESI) calcd for C16H14NO3

164

[M+H]+ 284.0917, found 284.0921.

165

Methyl 2-benzyl-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3j): mp: 158–

166

160 °C;

167

(d, J = 3.6 Hz, 1H), 7.42–7.35 (m, 3H), 7.25–7.20 (m, 2H), 7.10 (d, J = 3.6 Hz, 1H),

168

5.41 (s, 2H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.60, 166.09, 144.15,

169

134.44, 134.35, 134.28, 130.64, 129.47, 129.28, 127.49, 126.90, 120.68, 116.20,

170

109.21, 62.55, 52.34. HRMS (ESI) calcd for C18H16NO3 [M+H]+ 294.1125, found

171

294.1128.

172

Methyl

173

(3k): mp: 190–191 °C; 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 9.17 (s, 1H), 8.60

174

(d, J = 4.3 Hz, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 3.7 Hz, 1H), 7.70 (td, J = 7.7,

175

1.7 Hz, 1H), 7.28 (dd, J = 7.5, 5.4 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 3.6

176

Hz, 1H), 5.51 (s, 2H), 4.00 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.52, 166.07,

177

153.96, 150.30, 144.18, 137.47, 134.59, 134.34, 131.30, 126.90, 123.80, 121.82,

178

120.73, 116.05, 109.25, 63.62, 52.28. HRMS (ESI) calcd for C17H15N2O3 [M+H]+

179

295.1077, found 295.1080.

180

Methyl 7-formyl-2-phenyl-2H-cyclopenta[c]pyridine-4-carboxylate (3l): mp: 224–

1H

13C

NMR (100 MHz, CDCl3) δ

NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 9.16 (s, 1H), 8.17 (s, 1H), 7.93

7-formyl-2-(pyridin-2-ylmethyl)-2H-cyclopenta[c]pyridine-4-carboxylate

6


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181


182

1H), 7.98 (d, J = 3.7 Hz, 1H), 7.62–7.49 (m, 5H), 7.18 (d, J = 3.7 Hz, 1H), 4.03 (s,

183

3H). 13C NMR (100 MHz, CDCl3) δ 184.73, 166.08, 144.84, 143.97, 133.83, 133.68,

184

130.57, 130.29, 129.54, 126.81, 124.28, 121.37, 115.98, 109.58, 52.41. HRMS (ESI)

185

calcd for C17H14NO3 [M+H]+ 280.0968, found 280.0970.

186

Methyl 2-(4-fluorophenyl)-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3m):

187

mp: 215–217 °C; 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 9.24 (s, 1H), 8.35 (s,

188

1H), 7.99 (d, J = 3.6 Hz, 1H), 7.55 (dd, J = 8.8, 4.4 Hz, 2H), 7.31 (t, J = 8.3 Hz, 2H),

189

7.18 (d, J = 3.5 Hz, 1H), 4.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.72, 165.98,

190

164.09, 161.59, 144.99, 140.12, 133.63, 130.52, 126.79, 126.33, 126.24, 121.45,

191

117.42, 117.19, 116.02, 109.75, 52.45. HRMS (ESI) calcd for C17H13FNO3 [M+H]+

192

298.0874, found 298.0876.

193

Methyl 7-formyl-2-(p-tolyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3n): mp: 209–

194

210 °C; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 9.29 (s, 1H), 8.41 (s, 1H), 7.98 (d,

195

J = 3.0 Hz, 1H), 7.41 (dd, J = 17.3, 8.1 Hz, 4H), 7.18 (d, J = 3.0 Hz, 1H), 4.04 (s, 3H),

196

2.48 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.23, 166.08, 144.75, 141.60, 139.90,

197

134.24, 133.88, 130.86, 130.77, 126.91, 124.00, 121.09, 116.00, 109.73, 52.43, 21.12.

198


199

Methyl

200

7-formyl-2-(4-(trifluoromethoxy)phenyl)-2H-cyclopenta[c]pyridine-4-carboxylate

201

(3o): mp: 170–172 °C; 1H NMR (500 MHz, CDCl3) δ 9.94 (s, 1H), 9.26 (s, 1H), 8.37

202

(d, J = 1.6 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7

203

Hz, 2H), 7.19 (d, J = 3.9 Hz, 1H), 4.04 (s, 3H).

204

184.84, 165.89, 149.67, 145.13, 142.19, 133.41, 133.27, 130.14, 126.83, 125.94,

205


206

C18H13F3NO4 [M+H]+ 364.0791, found 364.0793.

207

Methyl

208

7-formyl-2-(4-(trifluoromethyl)phenyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3p):

209

mp: 200–202 °C; 1H NMR (500 MHz, CDCl3) δ 9.95 (s, 1H), 9.30 (s, 1H), 8.40 (d, J

210

= 1.7 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz,

13C

7


NMR (100 MHz, CDCl3) δ


211

2H), 7.20 (d, J = 3.6 Hz, 1H), 4.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 183.92,

212

164.84, 145.44, 144.39, 132.29, 131.86, 130.92, 130.59, 128.79, 126.63(q), 125.96,

213

123.70, 120.93, 115.29, 109.12, 51.48. HRMS (ESI) calcd for C18H13F3NO3 [M+H]+

214

348.0842, found 348.0845.

215

Methyl 2-(4-chlorophenyl)-7-formyl-2H-cyclopenta[c]pyridine-4-carboxylate (3q):

216

mp: 249–251 °C; 1H NMR (500 MHz, CDCl3 δ 9.93 (s, 1H), 9.25 (s, 1H), 8.35 (d, J =

217

1.6 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 7.61–7.57 (m, 2H), 7.53–7.49 (m, 2H), 7.18 (d,

218

J = 3.6 Hz, 1H), 4.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.80, 165.93, 145.04,

219

142.38, 135.74, 133.45, 133.24, 130.47, 130.12, 126.84, 125.52, 121.63, 116.10,

220

109.81, 52.43. HRMS (ESI) calcd for C17H13NO3Cl [M+H]+ 314.0578, found

221

314.0581.

222

Methyl 7-formyl-2-(4-nitrophenyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3r): mp:

223

187–189 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.27 (s, 1H), 8.58 (d, J =

224

1.3 Hz, 1H), 8.49 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 3.6 Hz,

225

1H), 7.10 (d, J = 3.6 Hz, 1H), 3.97 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 183.99,

226

165.72, 148.59, 147.87, 133.76, 133.16, 131.13, 126.58, 125.82, 121.76, 115.72,

227

109.47, 52.85. HRMS (ESI) calcd for C17H13N2O3 [M+H]+ 325.0819, found

228

325.0822.

229

Methyl 7-formyl-2-(4-methoxyphenyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3s):

230


231

= 1.5 Hz, 1H), 7.97 (d, J = 3.7 Hz, 1H), 7.49–7.44 (m, 2H), 7.18 (d, J = 3.7 Hz, 1H),

232

7.10–7.06 (m, 2H), 4.04 (s, 3H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.65,

233

166.15, 160.35, 144.54, 137.15, 134.01, 133.80, 130.85, 126.75, 125.53, 121.21,

234

115.86, 115.26, 109.37, 55.80, 52.37. HRMS (ESI) calcd for C18H16NO4 [M+H]+

235

310.1074, found 310.1075.

236

Methyl 7-formyl-2-(3-methoxyphenyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3t):

237

mp: 196 °C; 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 9.29 (s, 1H), 8.40 (s, 1H),

238

7.98 (d, J = 3.3 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 7.12 (d, J =

239

7.8 Hz, 1H), 7.10–7.04 (m, 2H), 4.03 (s, 3H), 3.90 (s, 3H). 13C NMR (100 MHz,

240

CDCl3) δ 184.59, 166.04, 160.89, 145.01, 144.76, 133.86, 133.61, 131.06, 130.53, 8


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Page 9 of 27


241

126.72, 121.40, 116.36, 115.89, 115.01, 110.38, 109.59, 55.80, 52.36. HRMS (ESI)

242

calcd for C18H16NO4 [M+H]+ 310.1074, found 310.1080.

243

Methyl 7-formyl-2-(2-methoxyphenyl)-2H-cyclopenta[c]pyridine-4-carboxylate (3u):

244


245

= 1.4 Hz, 1H), 7.96 (d, J = 3.7 Hz, 1H), 7.53 (td, J = 8.1, 1.5 Hz, 1H), 7.40–7.34 (m,

246

1H), 7.18 (d, J = 3.7 Hz, 1H), 7.12 (t, J = 7.5 Hz, 2H), 4.01 (s, 3H), 3.82 (s, 3H). 13C

247

NMR (100 MHz, CDCl3) δ 184.50, 166.23, 153.35, 144.34, 135.68, 134.07, 132.55,

248

131.36, 127.26, 126.21, 121.21, 121.14, 115.34, 112.48, 109.40, 55.99, 52.24. HRMS

249

(ESI) calcd for C18H16NO4 [M+H]+ 310.1074, found 310.1079.

250

Methyl

251

2-(2-chloro-4-(trifluoromethoxy)phenyl)-7-formyl-2H-cyclopenta[c]pyridine-4-carbo

252

xylate (3v): mp: 250–251 °C; 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 9.02 (s,

253

1H), 8.16 (s, 1H), 8.01 (d, J = 3.4 Hz, 1H), 7.60–7.52 (m, 2H), 7.38 (d, J = 8.3 Hz,

254

1H), 7.23 (d, J = 3.4 Hz, 1H), 4.02 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 184.85,

255

165.74, 150.25, 145.36, 139.41, 134.23, 133.43, 132.19, 131.19, 129.41, 126.31,

256


257

C18H12ClF3N2O4 [M+H]+ 398.0401, found 398.0409.

258

Biological Assay. Each group of tests was repeated three times at 25±1 °C. Activity

259

results were given as a percentage scale of 0–100 (0: no activity; 100: total inhibited).

260

Detailed bioassay procedures for the anti-TMV[22] and insecticidal[23] activities were

261

described in literature.

262 263

RESULTS AND DISCUSSION

264

Chemistry.

265

Iridoid 2 was prepared by oxidation of genipin (1). The test reaction for the synthesis

266

of cyclopenta[c]pyridines was commenced by employing compound 2 and 25 %

267

ammonium hydroxide as model substrates under several conditions, and the results

268

are summarized in support information. The optimal reaction condition for the

269

cyclopenta[c]pyridines was 2 (1 equiv), and amine (1 equiv) in n-butyl alcohol at

270

reflux for 5 h. The structure of cyclopenta[c]pyridine was unequivocally confirmed by 9



Page 10 of 27

271

X-ray crystallographic analysis of compound 3d (Figure 1). With optimized condition

272

in hand, a wide range of alkylamines, as well as aromatic amines, were employed to

273

test the efficiency of the reaction, and the results are shown in Schemes 2.

274

With respect to the aliphatic variants, we explored linear ethyl, n-pentyl, n-octyl chain

275

as well as branched isopropyl and t-butyl groups. Interestingly, linear chain length did

276

not play significant role, as the resulting products 3b-3d were all isolated in equal

277

level yields. However, steric effects on the α-position of the primary amines could

278

impair the reactivity, because the reaction yields of the branched isopropyl and

279

tert-butyl amines were slightly lowered. 3-Aminopropanenitrile, allylamine,

280

furan-2-ylmethanamine, benzylamine and pyridin-2-ylmethanamine were tolerated by

281

our reaction conditions. These aliphatic amines furnished the corresponding

282

cyclopenta[c]pyridine 3g−3k in moderate yields within several hours of reaction time.

283

Generally, for the substituted aromatic amines, the electron-rich groups (Me, MeO)

284

gave better yields compared to electron-withdrawing groups (F, OCF3, CF3, Cl, NO2).

285

Moreover, the positional variation of the same substituents in the phenyl ring altered

286

the yields of the corresponding cyclopenta[c]pyridine products, because of

287

unfavorable steric hindrance in the case of an ortho-substituent. The yield of

288

compound 3u was lower than that of 3s and 3t. The reaction to generate compound 3v

289

was weakest.

290

Based on the control experiment outcomes (see support information) and literature

291

precedents[24-25],

292

cyclopenta[c]pyridine reaction is proposed in Scheme 3. The reaction takes place

293

through the sequence of two selectively nucleophilic additions, eliminations and one

294

oxidation cascade.

295

Phytotoxic Activity.

296

Before evaluating anti-TMV activities of cerbinal and compounds 3a−3v, we first

297

performed a blank control trial at 500 μg/mL. That is to say, the Nicotiana tabacum L.

298

was not inoculated with TMV, and only the tested compounds solution was smeared

299

on Nicotiana tabacum L. Next, they were cultured at 25 C for 72 h. It is found that

300

the Nicotiana tabacum L. grew well and there was no any phytotoxicity.

a

plausible

mechanism

for

10


additive-free,

one-pot

Page 11 of 27


301

Antiviral Activity.

302

The preliminary inhibition rates of all of the title compounds 3a−3v, including

303

cerbinal and commercial antiviral agent — ribavirin, against TMV were shown in

304

Table 1. The results suggested that all the synthesized compounds, except the

305

compounds 3g (2-cyanoethyl) and 3j (2-benzyl), had higher anti-TMV activities than

306

the parent compound cerbinal. Furthermore, compounds 3b (2-ethyl), 3d (2-octyl), 3h

307

(2-allyl), 3l (2-phenyl), 3o (2-(4-(trifluoromethoxy)phenyl)), 3r (2-(4-nitrophenyl)),

308

3s (2-(4-methoxyphenyl)), 3v (2-(2-chloro-4-(trifluoromethoxy)phenyl)) showed

309

higher inactivation effect than that of ribavirin. Especially, 3h (2-allyl), 3r

310

(2-(4-nitrophenyl)), 3s (2-(4-methoxyphenyl)) had significant activities with a higher

311

inhibition rate than ribavirin in all three test modes at a concentration of 500 μg/mL.

312

Therefore, the overall results revealed that the modifications at position 2 of the

313

cerbinal molecule would maintain or improve the anti-TMV potency of the parent

314

compound up to the level of ribavirin.

315

In N-alkyl cyclopenta[c]pyridines 3b−3k, compound 3h (2-allyl) had the highest

316

activities (inactivation effect 40.2±4.5 %, curative effect 44.9±4.0 %, protection effect

317

39.6±2.3 % at 500 μg/mL). The cyclopenta[c]pyridines containing 2-linear alkyl on

318

nitrogen (3b-3d) exhibited good anti-TMV activities, but which were no obvious

319

structure-activity relationships. However, upon increasing the size from ethyl to

320

tert-butyl (compared with 3b, 3e and 3f), a loss in inhibitory activity against TMV

321

was observed. These results suggested that steric hindrance at the α-position of the

322

primary amines would decrease the inhibitory potency against TMV. Moreover, the

323

various substituent groups on aliphatic chains (3g−3k) also affected the activity

324

against TMV, and most were exceptionally less active. Fortunately, some maintained

325

the anti-TMV activity, and compound 3h (2-allyl) had the higher activities than

326

ribavirin.

327

In N-aryl cyclopenta[c]pyridines 3l−3v, compound 3s (2-(4-methoxyphenyl))

328

exhibited the most promising inhibitory activities against TMV (inactivation effect

329

49.0±0.8 %, curative effect 41.2±4.3 %, protection effect 51.5±2.7 % at 500 μg/mL).

330

The mainly difference among 3s, 3t and 3u consisted in the replacement of methoxyl 11



Page 12 of 27

331

group in benzene ring. Compound 3s exhibited higher TMV inhibitory effects than

332

the others, which showed that the introduction of substituent group at 4-position of

333

benzene ring is favorable for antiviral activity. Among N-(4-substituent phenyl)

334

cyclopenta[c]pyridines 3m−3s, compounds 3o (2-(4-(trifluoromethoxy)phenyl)), 3r

335

(2-(4-nitrophenyl)), and 3s (2-(4-methoxyphenyl)) displayed higher antiviral activities

336

than 3l (2-phenyl). Moreover, compound 3o (2-(4-(trifluoromethoxy)phenyl))

337

displayed

338

(2-(2-chloro-4-(trifluoromethoxy)phenyl)), which further revealed that the substituent

339

at 2-position of benzene ring is unfavorable for antiviral activity.

340

The anti-TMV activities of some compounds were greatly affected by treatment

341

concentration. It was considered that those compounds might have a synergistic

342

inhibitory effect at different stages of the process of tobacco mosaic virus

343

proliferation. When the concentration was high, the compound could act on different

344

stages of the whole process to produce a significant inhibitory effect; but when the

345

concentration was low, the compound could only act at a certain stage, and the

346

inhibition effect is poor or even ineffective.

347

Insecticidal Activity.

348

The insecticidal activities of target compounds and the commercial natural insecticide

349

rotenone against Plutella xylostella and Tetranychus cinnabarinus are listed in Table

350

2. The results against P. xylostella revealed that most of the compounds were similar

351

or a bit more potent compared to the parent compound 3a, and compound 3v

352

(2-(2-chloro-4-(trifluoromethoxy)phenyl)) reached the activity level of the lead

353

compound cerbinal. In N-alkyl cyclopenta[c]pyridines 3b−3k, steric effects on the

354

α-position of the primary amines were also detrimental to the insecticidal activities

355

against the P. xylostella. However, the side chain length of amines had little effect on

356

the activity level. The N-aryl cyclopenta[c]pyridines 3l−3v, except for compound 3t,

357

had similar or higher insecticidal activities than compound 3l (2-phenyl). Among

358

them,

359

(2-(4-(trifluoromethoxy)phenyl),

360

(2-(2-chloro-4-(trifluoromethoxy)phenyl)) displayed higher antiviral activities than 3l

higher

compounds

anti-TMV

3m

activities

(2-(4-fluorophenyl)), 3s

3n

than

(2-(p-tolyl)),

(2-(4-methoxyphenyl)) 12


and

3v

3o 3v

Page 13 of 27


361

(2-phenyl). The activity data indicated that the introduction of substituents on the aryl

362

was beneficial to the enhancement of P. xylostella activity, but the electronic effect of

363

the substituents has an inconsistent effect on the insecticidal activities against P.

364

xylostella. Among these compounds, it was also observed that some of N-alkyl

365

cyclopenta[c]pyridines and N-aryl cyclopenta[c]pyridine 3n exhibited the insecticidal

366

activities against T. cinnabarinus at 600 mg/kg.

367

Conclusion

368

In

369

cyclopenta[c]pyridines were prepared and tested for their anti-TMV and insecticidal

370

activities for the first time. Firstly, a robust chemistry to construct N-substituted

371

cyclopenta[c]pyridines under additive-free condition was developed. Secondly, the

372

cyclopenta[c]pyridines obtained by modifications of cerbinal at position 2 were very

373

significant for anti-TMV activity. All the synthesized compounds, except the

374

compounds 3g (2-cyanoethyl) and 3j (2-benzyl), had higher anti-TMV activities than

375

the lead compound cerbinal. Compound 3s (2-(4-methoxyphenyl)) exhibited the most

376

promising inhibitory activities against TMV (inactivation effect 49.0±0.8 %, curative

377

effect 41.2±4.3 %, protection effect 51.5±2.7 % at 500 μg/mL). Lastly, the

378

insecticidal activities against P. xylostella revealed that cerbinal was similar with

379

rotenone.

380

(2-(2-chloro-4-(trifluoromethoxy)phenyl)) reached the activity level of rotenone.

381

Current research provides powerful support for the application of cerbinal and its

382

derivatives in plant protection.

summary,

natural

However,

product

among

cerbinal

the

and

its

synthesized

derivatives

N-substituted

compounds,

only

3v

383 384 385

ASSOCIATED CONTENT

386

Supporting Information

387

Reaction

388

Cyclopenta[c]pyridines, the spectra data of compounds 3a−3v are available free of

389

charge via the Internet at http://pubs.acs.org.

Optimization

and

Control

Experiments

390 13


for

Synthesis

of


Page 14 of 27

391

AUTHOR INFORMATION

392

Corresponding Authors

393

*(L.

394

0086-791-88133587

395

*(Q.Wang) E-mail: [email protected]. Phone: 0086-22-23503952. Fax:

396

0086-22-23503952

397

Funding

398

Financial support from the National Natural Science Foundation of China (no.

399

21562023 and 21561014), the Key Research Project of Jiangxi Province (no.

400

20171BBF60074 and 20192BBF60038) is greatly acknowledged.

401

Notes

402

The authors declare no competing financial interest.

Li)

E-mail:

[email protected];

Phone:

0086-791-88133587;

Fax:

403 404 405

REFERENCES

406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427

1. Gould, F; Brown, Z. S.; Kuzma, J. Wicked evolution: can we address the sociobiological dilemma of pesticide resistance? Science, 2018, 360, 728–732. 2. Yan, Y.; Liu, Q.; Jacobsen, S. E. Tang, Y. The impact and prospect of natural product discovery in agriculture. EMBO reports, 2018, 19, e46824. 3. Sparks, T. C.; Hahn, D. R.; Garizi, N. V. Natural products, their derivatives, mimics and synthetic equivalents: role in agrochemical discovery. Pest. Manag. Sci., 2017, 73, 700–715. 4. Lorsbach, B. A.; Sparks, T. C.; Cicchillo, R. M.; Garizi, N. V.; Hahn, D. R.; Meyer, K. G. Natural products: a strategic

lead

generation

approach

in

crop

protection

discovery.

Pest.

Manag.

Sci.,

2019,

https://doi.org/10.1002/ps.5350. 5. Fumiko, A.; Hikaru, O.; Tatsuo, Y. Studies on cerbera. ii. cerbinal and its derivatives, yellow pigments in the bark of Cerbera Manghas L. Chem. Pharm. Bull., 1977, 25, 3422–3424. 6. Tintas, M.; Bogdan, E.; Grosu, I. Cyclopenta[c]pyrans. J. Heterocyclic Chem., 2011, 48, 747–762. 7. Ohashi, H.; Tsurushima, T.; Ueno, T.; Fukami, H. Cerbinal, a pseudoazulene iridoid, as a potent antifungal compound isolated from Gardenia jasminoides Ellis, Agric. Biol. Chem., 1986, 50, 2655–2657. 8. Li, L.; Zou, J.; Xia, Q.; Cui, H.; You, S.; Liu, Y.; Wang, Q. Anti-TMV and insecticidal potential of four iridoid glycosides from gardenia jasminoides fruit. Chem. Res. Chin. Univ., 2018, 34(5), 697–699 9. Xia, Q.; Dong, J.; Li, L.; Wang, Q.; Liu, Y.; Wang, Q. Discovery of glycosylated genipin derivatives as novel antiviral, insecticidal, and fungicidal agents. J. Agric. Food Chem., 2018, 66, 6, 1341–1348. 10. Donohoe, T. J.; Jones, C. R.; Kornahrens, A. F.; Barbosa, L. C.; Walport, L. J.; Tatton, M. R.; O'Hagan, M.; Rathi A. H.; Baker, D. B. Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. J. Org. Chem., 2013, 78, 12338–12350. 11. Fu, P.; Wang, S.; Hong, K.; Li, X.; Liu, P.; Wang, Y.; Zhu, W. Cytotoxic bipyridines from the marine-derived 14


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actinomycete actinoalloteichus cyanogriseus WH1-2216-6. J. Nat. Prod., 2011, 74, 1751–1756. 12. Song, Z.; Huang, X.; Yi, W.; Zhang, W. One-pot reactions for modular synthesis of polysubstituted and fused pyridines. Org. Lett., 2016, 18, 5640–5643. 13. Chen, Y. L.; Braselton, J.; Forman, J.; Gallaschun, R. J.; Mansbach, R.; Schmidt, A. W.; Seeger, T. F.; Sprouse, J. S.; Tingley, F. D.; Winston, E.; Schulz, D. W. Synthesis and SAR of 2-aryloxy-4-alkoxy-pyridines as potent orally active corticotropin-releasing factor 1 receptor antagonists. J. Med. Chem., 2008, 51, 1377–1384. 14. Guan, A. Y.; Liu, C. L.; Sun, X. F.; Xie, Y.; Wang, M. A. Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods. Bioorg. Med. Chem., 2016, 24, 342–353. 15. Ye, H.; Chen, D.; Liu, M.; Su, S.-J.; Wang, Y.-F.; Lo, C.-C.; Lien, A.; Kido, J. Pyridine‐containing electron ‐transport materials for highly efficient blue phosphorescent OLEDs with ultralow operating voltage and reduced efficiency roll-off. Adv. Funct. Mater., 2014, 24, 3268–3275. 16. Sezer, S.; Gümrükçü, Y.; Bakırcı, I.; Ünver, M. Y.; Tanyeli, C. Stereoselective synthesis of optically active cyclopenta[c]pyridines and tetrahydropyridines. Tetrahedron: Asymmetry, 2012, 23, 662–669. 17. Beckett, J. S.; Beckett, J. D.; Hofferberth, J. E. A divergent approach to the diastereoselective synthesis of several ant-associated iridoids. Org. Lett., 2010, 12, 1408–1411. 18. Uredi, D.; Motati, D. R.; Watkins, E. B. A simple, tandem approach to the construction of pyridine derivatives under metal-free conditions: a one-step synthesis of the monoterpene natural product, (−)-actinidine. Chem. Commun., 2019, 55, 3270–3273. 19. Martin, R. E.; Lehmann, J.; Alzieu, T.; Lenz, M.; Corrales, M. A. C.; Aebi, J. D.; Märki, H. P.; Kuhn, B.; Amrein, K.; Mayweg, A. V.; Britton, R. Synthesis of annulated pyridines as inhibitors of aldosterone synthase (CYP11B2). Org. Biomol. Chem., 2016, 14, 5922–5927. 20. Yin, J.; Ye, Q.; Hao, W.; Du, S.; Gu, Y.; Zhang, W.-X.; Xi, Z. Formation of cyclopenta[c]pyridine derivatives from 2,5-disubstituted pyrroles and 1,4-dibromo-1,3-butadienes via pyrrole-ring one-carbon expansion. Org. Lett., 2017, 19, 138–141. 21. Ge, Y.; Isoe, S. An efficient synthesis of cerbinal, a 10 π aromatic iridoid. Chem. Lett., 1992, 21, 139–140. 22. Li, L.; Li, Z.; Wang, K.; Liu, Y.; Li, Y.; Wang, Q. Synthesis and antiviral, insecticidal, and fungicidal activities of gossypol derivatives containing alkylimine, oxime or hydrazine moiety. Bioorg. Med. Chem., 2016, 24 474– 483. 23. Zhao, H. P.; Liu, Y. X.; Cui, Z. P.; Beattie, D.; Gu, Y. C.; Wang, Q. M. Design, synthesis, and biological activities of arylmethylamine substituted chlorotriazine and methylthiotriazine compounds. J. Agric. Food Chem., 2011, 59, 11711−11717. 24. Frederiksen, S. M.; Stermitz, F. R. Pyridine monoterpene alkaloid formation from iridoid glycosides. a novel PMTA dimer from geniposide. J. Nat. Prod. 1996, 59, 41–46. 25. Baghdikian, B.; Ollivier, E.; Faure, R.; Debrauwer, L.; Rathelot, P.; Balansard, G. Two new pyridine monoterpene alkaloids by chemical conversion of a commercial extract of harpagophytum procumbens. J. Nat. Prod. 1999, 62, 211–213.

464 465

15



466

Scheme 1. The structure of cerbinal and the synthesis of its analogues cyclopenta[c]pyridines H

CO2Me

H

CO2Me

IBX O

467

HO

H

OH genipin (1)

DMSO

O OHC H OH 2

CO2Me

CO2Me RNH2 N R OHC Cyclopenta[c]pyridines (3)

O

n-C4H9OH

OHC Cerbinal

468 469

16


Page 16 of 27

Page 17 of 27


470

471 472 473

Figure 1. X-ray crystal structure of 3d.

17



474

Schemes 2. Synthesis of Various Cyclopenta[c]pyridines from Iridoid 2 and amines. CO2Me

CO2Me

NH

N

OHC 3a: 77.7%

OHC

N

N OHC

3f: 55.5%

OHC

3g: 55.3%

OHC

OHC

3h: 54.0%

3p: 31.9%

N F

3m: 39.8%

OHC 3n: 48.5%

CO2Me

CH3

CO2Me

N

N Cl

3q: 43.9%

OHC 3r: 27.4%

CO2Me

CO2Me

CO2Me

3j: 44.0%

CO2Me

N

OHC CF3

N OHC

CO2Me

N OCF3

3e: 52.5%

O

3i: 61.1%

OHC

OHC

OHC

CO2Me

N OHC

CO2Me

N

3d: 65.1%

N

3l:43.0%

CO2Me

3o: 26.2%

CN OHC

N 7

CO2Me

N N

3k: 44.6%

OHC

OHC

3c: 69.6%

CO2Me

CO2Me N

4

CO2Me

CO2Me

CO2Me

N

N OHC

3b: 67.2%

CO2Me

CO2Me

CO2Me

NO2

CO2Me OCH3

N

N

475 476

3s: 46.4%

OCH3

N

OCH3

N

OHC

OHC

OHC

3t: 44.7%

OHC 3u: 35.7%

Cl 3v: 24.8%

18


OCF3

Page 18 of 27

Page 19 of 27

477


Scheme 3. Possible Reaction Mechanism. H

CO2Me

H

CO2Me 5

O OHC H OH 2A

H

HN R OHC H O (A) H

H

CO2Me N

H

478 479

OHC H OH (D)

R

H

RNH2

CO2Me

HN R OHC H O (C)

CO2Me

CO2Me

[O] by air

-H2O N

2

O

1 OHC 9 H O 2C

OHC H O (B)

CO2Me

3

7

OHC H O 2B

CO2Me OH -H2O

CO2Me

4 8

6

OH

H

N

R OHC (E)

R

N OHC

R

3

480

19



481 482

Table 1. In Vivo Antiviral Activity of cerbinal and compounds 3a−3v against TMV a

(μg/mL)

Inactivation Effect (%)

Curative Effect (%)

Protection Effect (%)

500

33.5±0.2

—

—

500

45.3±2.1

37.1±3.6

40.7±3.2

100

8.2±1.0

14.6±1.4

0

500

38.9±1.7

—

—

500

43.0±0.6

29.4±4.9

35.1±3.5

100

13.1±0.3

0

6.8±2.2

3e

500

36.1±2.9

—

—

3f

500

28.8±4.8

—

—

3g

500

22.4±1.3

—

—

500

40.2±4.5

44.9±4.0

39.6±2.3

100

6.7±0.6

11.5±1.8

0

3i

500

32.7±1.9

—

—

3j

500

20.5±5.2

—

—

3k

500

35.2±0.3

—

—

500

42.8±3.7

38.1±1.4

31.9±2.9

100

6.2±1.2

0

0

3m

500

34.0±4.8

—

—

3n

500

39.7±1.4

—

—

500

44.1±2.9

32.3±4.6

41.7±1.6

100

15.2±0.6

0

12.4±0.2

3p

500

29.8±2.3

—

—

3q

500

25.1±5.5

—

—

500

47.9±3.4

42.6±2.8

46.3±4.0

100

7.5±0.2

11.8±1.2

13.7±0.6

500

49.0±0.8

41.2±4.3

51.5±2.7

100

18.0±1.5

6.4±2.4

16.9±1.0

3t

500

38.4±2.1

—

—

3u

500

31.2±0.5

—

—

500

40.9±4.0

29.7±4.6

35.8±1.7

100

0

0

7.4±0.3

500

23.1±0.5

—

—

500

39.2±0.4

37.5±2.9

38.9±1.3

100

12.6±0.8

10.9±0.3

14.2±0.9

compounds 3a 3b 3c 3d

3h

3l

3o

3r

3s

3v cerbinal ribavirin

483 484 485

Page 20 of 27

a

concentration

In order to improve work efficiency, when the inactivation effect of the tested compound was higher than that of

the commercial antiviral agent — ribavirin at 500 μg/mL, we tested the compound in curative and protection modes and at lower concentrations. 20


Page 21 of 27

486 487


Table 2 Insecticidal Activities of the Target Compounds 3a−3v against Plutella xylostella and Tetranychus cinnabarinus T. cinnabarinus

P. xylostella (%)

compound

(%)

600 mg/kg

200 mg/kg

100 mg/kg

600 mg/kg

3a

80±2

39±2

—

0

3b

100±0

61±3

—

0

3c

100±0

76±1

—

50±4

3d

92±3

77±4

—

0

3e

39±1

—

—

70±2

3f

70±2

—

—

28±3

3g

100±0

61±1

—

49±1

3h

82±3

50±2

—

0

3i

0

—

—

0

3j

29±1

—

—

60±2

3k

0

—

—

52±4

3l

60±3

—

—

0

3m

82±2

30±4

—

0

3n

100±0

63±3

—

62±3

3o

81±2

50±1

—

0

3p

72±3

—

—

0

3q

68±3

—

—

0

3r

61±1

—

—

0

3s

88±2

41±1

—

0

3t

30±4

—

—

0

3u

63±3

—

—

0

3v

100±0

100±0

72±3

0

cerbinal

100±0

100±0

57±2

0

rotenone

100±0

100±0

77±4

0

488

21



489

Page 22 of 27

TOC CO2Me O OHC Modifications at position 2

Cerbera manghas L.

H

CO2Me

H

CO2Me

H

490

HO OH genipin (1)

CO2Me R NH2

IBX O

cerbinal

O OHC H OH 2

N

additive free one step

R OHC Cyclopenta[c]pyridines (3)

22


PEST CONTROL

Page 23 of 27


Figure 1. X-ray crystal structure of 3d.



Scheme 1. The structure of cerbinal and the synthesis of its analogues cyclopenta[c]pyridines


Page 24 of 27

Page 25 of 27


Schemes 2. Synthesis of Various Cyclopenta[c]pyridines from Iridoid 2 and amines.



Scheme 3. Possible Reaction Mechanism.


Page 26 of 27

Page 27 of 27


TOC


Natural Product Cerbinal and Its Analogues Cyclopenta[c]pyridines

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