Synthesis analogues of milbemycin and their bioactivity evaluation
Jin Hao Zhao a, Ming Hua Ji a,b, Xu Hui Xu a, Jing Li Cheng a, Guo Nian Zhu a,*
a College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310029, China
b Zhejiang NHU Ltd., Shaoxing 312500, China
Received 12 April 2010
Abstract
Eight new 13-O-aminocarbonylivermectin aglycones and 40-O-aminocarbonylivermectin monosaccharide were synthesized
from ivermectin aglycone and ivermectin monosaccharide by the selective protection of C5-OH group. Their bioactivities were
evaluated against spider mites (Tetranychus cinnabarinus), aphid (Aphis fabae) and orlental armyworm (Mythimma sepatara).
1
Their structures were confirmed by H NMR, MS.
# 2010 Guo Nian Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 13-O-Aminocarbonylivermectin aglycone; 40-O-Aminocarbonylivermectin monosaccharide; Synthesis; Insecticidal and acaricidal
activities
Recently, macrocyclic lactones play a great role in the pharmaceutical and pesticides [1,2]. Milbemycin, a 16-
membered macrocyclic lactone produced by Streptomyces hygroscopius, are potent miticidal, insecticidal and
anthelmintic compounds [3]. Milbemycin were both environmentally friendly and having efficient and wide biological
activity features. The high intrinsic potency, remarkable biological activity and unique molecular architecture have
attracted the attention of research groups concerning with chemical modification. Generally modification of
milbemycin C13-position group includes: alkylation, acylation, amination and sulfonylation, etc. [4–8]. However,
there have been no reports on N-substituted-13-O-aminocarbonylmilbemycin. Worth noting that, milbemycin and
acylivermectin aglycone have similar structure (Scheme 1). In order to explore this void field, eight novel analogues of
milbemycin have been synthesized (Scheme 2) from 5-O-TBDMS-ivermectin aglycone and 5-O-TBDMS-ivermectin
monosaccharide. Their bioactivity data against spider mites (Tetranychus cinnabarinus), aphid (Aphis fabae) and
orlental armyworm (Mythimma sepatara) were obtained herein for the first time.
As shown in Scheme 2, the key intermediates 2 and 20 were formed by selective protective reaction of C5-OH group
with tert-butyl dimethyl chlorosilane in 82.3% and 83.6% yields, respectively [9,10]. Compounds 1 and 10 were
obtained in the literature method [11,12].
The typical process of synthesis of novel analogues of milbemycin 4a–4d0 was shown as following: the key
intermediate (2, 0.351 g, 0.5 mmol) and triethylamine (0.051 g, 0.5 mmol) were dissolved in dry dichloromethane
(20 mL). And substituted isocyanate (R-NCO) (0.8 mmol) was added dropwise to the mixture at 0–5 8C. The mixture
was stirred at 20–25 8C for 8 h, and quenched with 1% aqueous HCl. The organic layer was washed to neutral with
* Corresponding author.
1001-8417/$ – see front matter # 2010 Guo Nian Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.