Chinese Chemical Letters  2018, Vol. 29 Issue (6): 995-997   PDF    
Semisynthesis of new ethers from furyl-ring-based acylation derivatives of fraxinellone as insecticidal agents against Mythimna separata Walker in vivo
Ruige Yanga,1, Yong Guoa,1, Yuanyuan Zhanga, Hui Xua,b    
a Research Institute of Pesticidal Design & Synthesis, and Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A & F University, Yangling 712100, China;
b College of Plant Protection, Northwest A & F University, Yangling 712100, China
Abstract: Fraxinellone, a naturally occurring degraded limonoid, is mainly isolated from Dictamnus dasycarpus and Melia azedarach. In continuation of our program aimed at the discovery of plant natural products-based insecticidal agents, twenty-two new ethers from furyl-ring-based acylation derivatives were prepared by structural modifications of fraxinellone. Their insecticidal activity was evaluated against the pre-thirdinstar larvae of Mythimna separata Walker in vivo. Among them, compounds 5e and 5j exhibited more potent insecticidal activity than toosendanin with the final mortality rates greater than 60%. Their structure-activity relationships were also discussed.
Key words: Fraxinellone     Ethers     Furyl ring     Insecticidal activity     Mythimna separata Walker    

Mythimna separata Walker is a worldwide agricultural insect pest. After destroying crop of one field, they quickly move to another crop, especially their intermittent and severe outbreaks could result in complete crop loss [1, 2]. Meanwhile many chemical pesticides were extensively applied, however, insect resistance, negative impacts on human health and ecological disturbances also emerged [3-7]. Thus, to effectively control insect pests in the crop protection, new promising alternatives are needed to be explored urgently. For pesticides produced from plant secondary metabolites may cause less or slower emerging resistance and lower environmental pollution [8-12], recently, discovery and development of new insecticidal agents directly from plant secondary metabolites, or using them as the lead compounds for further structural modifications have gained much attention in the agricultural field [13-23].

Fraxinellone (1, Fig. 1), a naturally occurring degraded limonoid, is mainly isolated from Meliaceae and Rutaceae plants, such as Dictamnus albus, Dictamnus dasycarpus, and Melia azedarach [24]. Besides exhibiting a variety of interesting medicinal properties [25-28], compound 1 and its derivatives also displayed the interesting insecticidal activity [29-34]. More recently, we have investigated halogenation/acylation of the furyl-ring (C-ring) of compound 1 with different chlorination/bromination (N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) and 1, 3-dichloro- 5, 5-dimethylhydantoin (DCDMH)) and acylation reagents (Fig. 1), and some derivatives displayed the promising insecticidal activity against Mythimna separata Walker [35]. When compound 1 reacted with acetyl or chloroacetyl chloride (1.1 equiv.), two isomers, 2'- acylfraxinellones (, Fig. 1) and 5'-acylfraxinellones (, Fig. 1), were produced [35]. Additionally, in our previous reports, we found that some ether derivatives of 2-chloropodophyllotoxin or 2- α/β-bromopodophyllotoxin exhibited more potent insecticidal activity than their precursor and toosendanin (Fig. 2) [36, 37]. Based upon the above interesting results, and in continuation of our program aimed at the discovery and development of naturalproduct-based insecticidal agents, consequently, we prepared a series of new ethers from furyl-ring-based acylation derivatives of fraxinellone (4 and 5, Fig. 1) by introduction of the aryloxy groups into 5'/2'-chloroacetylfraxinellones (2 and 3, Fig. 1), as insecticidal agents against M. separata in vivo.

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Fig. 1. Chemical structures of halogenation/acylation products and target compounds (4 and 5)

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Fig. 2. The chemical structure of toosendanin

As shown in Scheme 1, two intermediates, 5'-chloroacetylfraxinellone (2) and 2'-chloroacetylfraxinellone (3), were firstly prepared by reaction of compound 1 (isolated from D. dasycarpus as a white solid [32]) with 1.1 equiv. of chloroacetyl chloride in the presence of AlCl3 [35]. Then, a series of C-ring-based acylation derivatives of fraxinellone (4a-k and 5a-k) were smoothly obtained by reaction of the corresponding phenols ROH with 2 and 3, respectively. Their structures were well characterized by 1H NMR, HRMS, IR, optical rotation and mp (Supporting information).

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Scheme 1. Synthesis of C-ring-based acylation derivatives of fraxinellone (4a-k and 5a-k)

In addition, the insecticidal activity of compounds 1-3, 4a-k and 5a-k against the pre-third-instar larvae of M. separata on leaves was treated with a concentration of 1 mg/mL [34]. Toosendanin, isolated from Melia azedarach, was used as the positive control, and leaves treated with acetone alone were used as a blank control group. The symptoms of M. separata treated by these tested compounds were also observed in the same way as in our previous papers [32-35]. As depicted in Table 1, among all derivatives, compounds 4d, 4e, 5d-f, 5h, and 5j exhibited pronounced insecticidal activity when compared with toosendanin. Especially compounds 5e and 5j showed the most potent insecticidal activity with the final mortality rates (FMRs) of 60.7% and 64.3%, respectively, whereas the FMRs of compound 1 and toosendanin were 42.9% and 46.4%, respectively. Introduction of 4-nitrophenyloxy or 4-chlorophenyloxy group on 2 and 3 all led to more promising compounds (4d and 4e vs. 2; 5d and 5e vs. 3). When the chlorine atom of 2 was substituted by the aryloxy groups to give 4a-k, only compounds 4d (FMR: 50.0%) and 4e (FMR: 57.1%) exhibited more potent insecticidal activity than 2 (FMR: 46.4%). In contrast, when the chlorine atom of 3 was substituted by the aryloxy groups to give 5a-k, ten compounds 5a, 5c-k exhibited higher insecticidal activity than 3 (FMR: 35.7%), and the FMRs of 5a, 5c-k were 42.9%, 39.3%, 50.0%, 60.7%, 50.0%, 42.9%, 50.0%, 46.4%, 64.3%, and 46.4%, respectively. Interestingly, to compounds 4e, 4g and 5e, 5g, the position of the chlorine atom on the phenyl ring was very important for their insecticidal activity. For instance, the FMRs of 4e and 5e (all containing a chlorine atom at the C-4 position) were 57.1%, and 60.7%, respectively; whereas the FMRs of 4g and 5g (all containing a chlorine atom at the C-2 position) were only 35.7%, and 42.9%, respectively.

Table 1
Insecticidal activity of compounds 1–3, 4a–k and 5a–k against the pre-third-instar larvae of M. separata on leaves treated with a concentration of 1 mg/mL.

In conclusion, a series of new ethers from furyl-ring-based acylation derivatives of fraxinellone were semisynthesized as insecticidal agents. Their in vivo insecticidal activity against the pre-third-instar larvae of M. separata was evaluated. Especially two compounds 5e and 5j displayed more potent insecticidal activity than toosendanin with the FMRs greater than 60%. This will lay the foundation for further structural modifications of fraxinellone as pesticidal agents for agriculture.

Acknowledgments

The present work was supported by the National Natural Science Foundation of China (No. 31672071), and Special Funds of Central Colleges Basic Scientific Research Operating Expenses (No. 2452015096).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.cclet.2017.10.018.

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