Modifications at C21 of the Tetracycle

Most of the spinosyns produced by Saccharopolyspora spinosa have an ethyl group at position C21 on the tetracycle.12,22 The C21 position was difficult to access synthetically so other approaches were taken to provide access to this region of the molecule. Modification of the starter unit for the PKS pathway provided a means to incorporate new substituents at position C21, including n-propyl, isopropyl, cyclopropyl, cyclobutyl, etc. (see Table 5.1).24 Some of these modifications at the C21 position (n-propyl, cyclobutyl) provided activity against lepidopterous pests such as Heliothis virescens (tobacco budworm) and Spodoptera exigua (beet armyworm) that was similar, or superior to, the naturally occurring spinosyns from Saccharopolyspora spinosa (see Table 5.1). Some of these same modifications also significantly increased toxicity to aphids and whiteflies (see Table 5.1).24

The 21-butenyl spinosyns produced by Saccharopolyspora pogona provided an opportunity to further understanding of the structure-activity relationships (SAR) within the spinosyns. Like the PKS-based C21 modifications, presence of a but-1-enyl moiety at C21 of the tetracycle (see Table 5.1; structures 5.18 and 5.19) imparts activity against Heliothis virescens larvae that is equal to C21-ethyl

Table 5.1 Effect of modifications of the C21 position of the spinosyn tetra-cycle on insecticidal activity.

Structure

number

R21

Ri

R6

r3-

5,6a

TBWnb

'TBWtc

BAWod

BAWte

CAf

SWF

5.1

ethylh

Me

H

Me

D

0.31

0.03

0.079

0.63

18-55

5-23

5.2

ethyl'

Me

Me

Me

D

0.8

-

-

-

65

1.7

5.7

methyl7

Me

H

Me

D

4.6

-

-

-

> 50

3.9

5.8

ethyl

Me

H

Et

D

0.03

-

0.012

0.039

8.1

5.3

5.9

ethyl

Me

H

Et

S

0.05

-

-

0.04

15

-

5.10

vinyl

H

H

Et

D

0.2

-

-

-

-

-

5.11

vinyl

Me

H

Et

D

0.5

-

0.018

-

-

-

5.12

n-propyl

Me

H

Me

D

0.16

0.025

-

0.031

27

-

5.13

isopropyl

Me

H

Me

D

-

0.02

-

0.123

-

-

5.14

cyclopropyl

Me

H

Me

D

-

0.125

-

e1

«46

> 50

5.15

cyclobutyl

Me

H

Me

D

-

0.013

-

>1

«3

55

5.16

cyclobutyl

Me

Me

Me

D

-

0.016

-

0.39

15

13.5

5.17

cyclobutyl

Me

H

Me

S

-

0.02

-

0.13

1.7

0.7

5.18

but-1-enyl

Me

H

Me

D

0.29

-

-

0.035

5-11

2

5.19

but-1-enyl

Me

Me

Me

D

0.3

-

-

-

2

-

5.20

but-1-enyl

Me

H

Et

D

-

-

-

0.004

0.95

1.65

5.21

hex-1-enyl

Me

H

Et

D

-

-

<0.012

-

15.2

-

5.22

oct-1-enyl

Me

H

Et

D

-

-

0.022

-

26

-

5.23

styryl

Me

H

Et

D

-

-

0.013

-

16.9

-

(Data in table adapted from ref. 9, 12, 14, 24 and 25). a5,6 bond: S = single bond, D = double bond.

bTBWn = tobacco budworm (Heliothis virescens) neonate drench bioassay (LC50 ppm).

cTBWt = tobacco budworm (Heliothis virescens) topical bioassay (LD50 mg larva-1).

dBAWo = beet armyworm (Spodoptera exigua) oral (diet) bioassay (LC50 mg cm-2).

eBAWt = beet armyworm (Spodoptera exigua) topical bioassay (LD50 mg larva-1).

fCA = cotton aphid (Aphis gossypii) on plant bioassay (LC50 ppm).

gSWF = sweet potato whitefly (Bemisia tabaci) on plant bioassay (LC50 ppm).

hSpinosyn A.

iSpinosyn D.

jSpinosyn E.

(Data in table adapted from ref. 9, 12, 14, 24 and 25). a5,6 bond: S = single bond, D = double bond.

bTBWn = tobacco budworm (Heliothis virescens) neonate drench bioassay (LC50 ppm).

cTBWt = tobacco budworm (Heliothis virescens) topical bioassay (LD50 mg larva-1).

dBAWo = beet armyworm (Spodoptera exigua) oral (diet) bioassay (LC50 mg cm-2).

eBAWt = beet armyworm (Spodoptera exigua) topical bioassay (LD50 mg larva-1).

fCA = cotton aphid (Aphis gossypii) on plant bioassay (LC50 ppm).

gSWF = sweet potato whitefly (Bemisia tabaci) on plant bioassay (LC50 ppm).

hSpinosyn A.

iSpinosyn D.

jSpinosyn E.

homologs such as spinosyn A and improved activity against Spodoptera exigua larvae (see Table 5.1).3 Activity against Aphis gossypii (cotton aphid) and, to a lesser extent, Bemisia tabaci (sweetpotato whitefly) is also improved (see

Table 5.1).3 The C21-but-1-enyl spinosyns also enabled further synthetic modifications of the C21 position by means of cross-metathesis reactions.25 The resulting spinosyn analogs had position C21 substituted with a variety of moieties including monounsaturated 2-, 6- and 8-carbon chains and styrene. These substitutions had little effect on activity (see Table 5.1).25

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