A semisynthesis of 3′-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone

Article abstract of DOI:10.3762/bjoc.13.257

Spinetoram, a mixture of 3′-O-ethyl-5,6-dihydrospinosyn J (XDE-175-J, major component) and 3′-O-ethylspinosyn L (XDE-175-L, minor component), is a novel kind of green and efficient insecticide with a broad range of action against various insects. Nowadays, spinetoram is widely used in agriculture and food storage. This work reports a 7-step semisynthesis of 3′-O-ethyl-5,6-dihydrospinosyn J from spinosyn A aglycone. The C9-OH and C17-OH of the aglycone are successively connected to 3-O-ethyl-2,4-di-O-methylrhamnose and D-forosamine after selective protection and deprotection steps. Then, with 10% Pd/C as catalyst, the 5,6-double bond of the macrolide was selectively reduced to afford 3′-O-ethyl-5,6-dihydrospinosyn J. In addition, the 3-O-ethyl-2,4-di-O-methylrhamnose is synthesized from rhamnose which is available commercially, while the D-forosamine and aglycone are obtained via the hydrolysis of spinosyn A. High yields were obtained in each step, and all intermediates in the synthesis were characterized by ¹H NMR, ¹³C NMR and MS techniques. This study can be helpful for developing an efficient chemical synthesis of spinetoram, and it also offers opportunities to synthesize spinosyn analogues and rhamnose derivatives.

Full text of DOI:10.3762/bjoc.13.257

A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J
based on the spinosyn A aglycone
Kai Zhang1, Shenglan Liu1, Anjun Liu1, Hongxin Chai1, Jiarong Li*1 and Lamusi A*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2603–2609.
1School of Chemistry and Chemical Engineering, Beijing Institute of
Technology, 5 South Zhongguancun Street, Haidian District, Beijing,
China and 2Institute of Grassland Research of CAAS, No. 120
Wulanchabu East Street, Saihan District, Hohhot, China
doi:10.3762/bjoc.13.257
Received: 28 June 2017
Accepted: 16 November 2017
Published: 06 December 2017
Email:
Jiarong Li* - jrli@bit.edu.cn; Lamusi A* - alms721@163.com
Associate Editor: S. Bräse
* Corresponding author
© 2017 Zhang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
3-O-ethyl-2,4-di-O-methylrhamnose; protecting groups;
semisynthesis; spinetoram; spinosyn A
Abstract
Spinetoram, a mixture of 3'-O-ethyl-5,6-dihydrospinosyn J (XDE-175-J, major component) and 3'-O-ethylspinosyn L (XDE-175-L,
minor component), is a novel kind of green and efficient insecticide with a broad range of action against various insects.
Nowadays, spinetoram is widely used in agriculture and food storage. This work reports a 7-step semisynthesis of 3'-O-ethyl-5,6-
dihydrospinosyn J from spinosyn A aglycone. The C9–OH and C17–OH of the aglycone are successively connected to
3-O-ethyl-2,4-di-O-methylrhamnose and D-forosamine after selective protection and deprotection steps. Then, with 10% Pd/C as
catalyst, the 5,6-double bond of the macrolide was selectively reduced to afford 3'-O-ethyl-5,6-dihydrospinosyn J. In addition, the
3-O-ethyl-2,4-di-O-methylrhamnose is synthesized from rhamnose which is available commercially, while the D-forosamine and
aglycone are obtained via the hydrolysis of spinosyn A. High yields were obtained in each step, and all intermediates in the synthe-
sis were characterized by 1H NMR, 13C NMR and MS techniques. This study can be helpful for developing an efficient chemical
synthesis of spinetoram, and it also offers opportunities to synthesize spinosyn analogues and rhamnose derivatives.
Introduction
Spinosyns, a large family of secondary metabolites produced by W, Y) have been found [2-5]. There are two generations of
aerobic fermentation of Saccharopolyspora spinosa, are a new spinosyns: spinosad and spinetoram (Figure 1). Structurally,
kind of green and efficient insecticides [1]. Since the discovery spinosad and spinetoram both consist of a unique tetracyclic
of spinosyns in 1982, more than 20 species of spinosyns (named nucleus which is attached to rhamnose analogues and D-foros-
spinosyn A, B, C, D, E, F, J, K, L, M, N, O, P, Q, R, S, T, U, V, amine [6].
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Beilstein J. Org. Chem. 2017, 13, 2603–2609.
Figure 1: The structures of spinosad and spinetoram.
Spinosad was introduced by Dow AgroSciences in 1997 for the Although the structure of spinetoram is similar to that of spin-
control of insect pests in cotton under the trade name of Tracer osad, spinetoram has a broader spectrum of insecticide activity
[7]. Spinosad is a mixture of approximately 85% spinosyn A and more efficient performance in contrast with spinosad [14].
and 15% spinosyn D [8], and it can effectively control several Spinetoram has been widely applied in insect control and steril-
pests including Lepidoptera, Diptera, Thysanoptera, Coleoptera ization. Similar to spinosad, spinetoram can be rapidly degraded
and Orthoptera insects [8-11]. Importantly, it shows a great into natural components by several ways, such as photodegrada-
selectivity toward the target insects, reduced environmental tion and biodegradation [15], suggesting that spinetoram is safe
persistence and low mammalian and avian toxicity [12]. There- for the environment. In addition, spinetoram shows excellent
fore, spinosad was awarded the Presidential Green Chemistry selectivity for the target insects, while being less harmful to
Challenge Award in 1999. However, spinosad was not effec- beneficial predators, mammals and human beings [16]. There-
tive in killing certain key pests of fruit trees and nut trees. To fore, spinetoram was awarded the Presidential Green Chem-
solve this problem, Dow AgroSciences used an "artificial neural istry Challenge Award in 2008.
network (ANN)" to identify analogous molecules that might be
effective to control fruit-tree pests, and then, spinetoram was At present, spinetoram is obtained from spinosyn J and spin-
discovered [13].
osyn L by a chemical modification [13] (Scheme 1). However,
Scheme 1: Chemical modifications of spinosyn J and spinosyn L.
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Beilstein J. Org. Chem. 2017, 13, 2603–2609.
the fermentation productivity of spinosyn J and spinosyn L is Since the discovery of spinosyns, many researchers have
low, resulting in high cost. So we envisage that spinetoram can engaged in modifying the structures of spinosyns to acquire
be synthesized via a chemical method. So far, several total syn- spinosyn analogues which may have more efficient insecticidal
theses of spinosyn A have been reported [17-22], but there are activity [23-26]. This study offers a novel approach to synthe-
few studies on the chemical synthesis of 3'-O-ethyl-5,6-dihydro- size spinosyn analogues.
spinosyn J. Considering the high fermentation productivity and
Results and Discussion
low cost of spinosyn A, we designed a semi-synthesis of 3'-O-
Hydrolysis of spinosyn A and famation of
aglycone and D-forosamine
As reported [27], both aglycone and D-forosamine
are the hydrolysis products of spinosyn A (Scheme 3). The
spinosyn A aglycone and D-forosamine were prepared by a
ethyl-5,6-dihydrospinosyn J from the spinosyn A aglycone via
sequential glycosylation after suitable protection and deprotec-
tion. In this synthesis route, there are three important parts:
D-forosamine, 3-O-ethyl-2,4-di-O-methylrhamnose and agly-
cone (Scheme 2).
Scheme 2: Retrosynthetic analysis of 3'-O-ethyl-5,6-dihydrospinosyn J.
Scheme 3: Hydrolysis of spinosyn A and formation of the aglycone and D-forosamine.
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Semisynthesis of 3'-O-ethyl-5,6-dihydro-
two-step hydrolysis under different acidic conditions. In
addition, spinosyn A can be hydrolyzed under strong acidic spinosyn J
conditions to give the aglycone in one step, but The C9–OH and C17–OH groups of the aglycone have similar
the separation and purification of the aglycone and D-foros- activity, so different protection strategies are required for the
amine are complicated. Therefore, the aglycone and D-foros- hydroxy groups (Scheme 5). According to Martynow’s work
amine are obtained through a two-step hydrolysis process in our [34], C9–OH can be selectively protected by TBDMSCl in the
work.
presence of 4-DMAP in dry dichloromethane, presumably due
to the steric hindrance around C17. Then C17–O-protected
compound 6 was prepared by using TIPSOTf as protecting
reagent in the presence of 2,6-lutidine in dry dichloromethane.
Preparation of
3-O-ethyl-2,4-di-O-methylrhamnose
3-O-Ethyl-2,4-di-O-methylrhamnose was synthesized from Due to the different stabilities of the C9–OH and C17–OH of
commercial rhamnose via a multistep process (Scheme 4). the aglycone, the protecting groups of two hydroxy groups can
Rhamnose contains several hydroxy groups with similar chemi- be successively removed under different conditions.
cal activities, so regioselective protection and alkylation are
challenges. Common protecting groups of the hydroxy group at Compound 6 was hydrolyzed in the presence of HOAc to afford
1-position of rhamnose include allyl [28], methoxyphenyl [29] 7, and then the subsequent glycosidation of compound 7 with
and 1-thiorhamnoside [30]. Compared with the reaction condi- glycosyl donor 8 yielded compound 9. Compound 8 was syn-
tions of the other two protecting groups, the conditions of thesized from 4 and 2,2,2-trifluoro-N-phenylethanimidoyl chlo-
selective allyl protection are mild, and no irritant gas is pro- ride in the presence of potassium carbonate. Compound 9
duced during the reaction, so selective allyl protection was was desilylated with hydrofluoric acid at 0 °C to offer 10,
chosen to afford 1. A survey of literature [31-33] shows and then compound 10 was glycosylated with donor 11 to
that the combination of Bu2SnO and EtBr can selectively provide 12. Compound 11 was prepared from D-forosamine
ethylate the hydroxy group at 3-position of rhamnose. and trichloroacetonitrile with Cs2CO3 as catalyst. Finally, 3'-O-
The structure of 2 was also ascertained by NMR. Then ethyl-5,6-dihydrospinosyn J was obtained through the selective
compound 2 was methylated at 0 °C in the presence hydrogenation of 12 catalyzed by 10% Pd/C. During the final
of iodomethane and sodium hydride to afford 3. Finally, reduction step, as ascertained by NMR and mass spectrometry,
3-O-ethyl-2,4-di-O-methylrhamnose (4) was obtained by the only the 5,6-double bond was reduced, and the other unsatu-
deprotection of 3 with Pd(PPh3)4 as catalyst in acetic acid under rated bonds were not affected. There is a conjugation between
argon gas.
the 13,14-double bond and the carbonyl group, resulting in
greater stability of the 13,14-double bond compared to the 5,6-
The synthetic route of 3-ethoxy-2,4-di-O-methylrhamnose is double bond. Thus, the 5,6-double bond can be selectively
simple and innovative. All the reagents used in the research are reduced.
available commercially, so it is likely that 3-ethoxy-2,4-di-O-
methylrhamnose can be produced on a large scale. In addition, Conclusion
this method can also be used to synthesize the derivatives of In summary, we have developed a 7-step semisynthesis of 3'-O-
rhamnose.
ethyl-5,6-dihydrospinosyn J based on spinosyn A with high
Scheme 4: Synthesis of 3-O-ethyl-2,4-di-O-methylrhamnose (4).
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Beilstein J. Org. Chem. 2017, 13, 2603–2609.
Scheme 5: The semi-synthesis of 3'-O-ethyl-5,6-dihydrospinosyn J.
yields in each step. With this synthetic route, we achieved a on the chemical modification of spinosyns. Furthermore, this
chemoselective hydrogenation of the 5,6-double bond under synthesis provides a chemical method to synthesize spinosyn
mild conditions, which is of great significance for future studies analogues containing different substituents at C9-position and
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We thank the National Natural Science Foundation of China
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