Insect Control: Biological and Synthetic Agents - Index of

236 6: The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance
ultimately led to the isolation more than 20 new
spinosyns from S. spinosa (see Section 6.2.1), and
an expanding number from S. pogona (Hahn et al.,
2002; Lewer et al., 2003). At the same time, running
in parallel with the spinosyn isolation program, was
a long-standing effort aimed at the preparation of
semisynthetic derivatives/analogs of the spinosyns,
termed spinosoids. In light of the excellent activity
against lepidopterans and the desire for greater utility,
the spinosoid synthesis program had two goals.
The first was to increase activity against lepidopterans,
typically using H. virescens larvae as an
indicator species. The second goal was, if possible,
to expand the spectrum of this unique chemistry. To
date, the total number of spinosyns and spinosoids
resulting from this long-standing and continuing
effort easily exceeds 1000 molecules, the vast majority
being spinosoids.
Chemistry around the spinosyns has been focused
on modifications to various functionalities in the
spinosyn structure, which has been both limited by
and facilitated by the novel chemical nature of these
molecules. These modifications can loosely be
grouped into:
. modifications of the tetracycle,
. modification/replacement of the forosamine
sugar, and
. modification/replacement of the tri-O-methyl
rhamnose sugar.
Due to limited quantities of starting material, initial
modifications to the spinosyn structure were limited
to relatively simple or straightforward modifications,
most often associated with a reduced level of
activity. Later modifications did ultimately succeed
in devising spinosoids that were more active than
the naturally occurring spinosyns (Sparks et al.,
2000a, 2001; Crouse et al., 2001).
6.7.1. Modifications of the Tetracycle
The tetracycle of spinosad is a rather rigid structure,
the shape of which is influenced, in part, by the
conjugated 13,14 double bond. Hydration of the
13,14 double bond (compounds 71 and 72) alters
the three-dimensional shape of the tetracycle, which
is associated with a reduction in activity (Crouse
and Sparks, 1998; Crouse et al., 1999) (Table 3).
The 13,14-a-dihydro (compound 71) results in less
of a conformational change and hence less of a
distortion than the corresponding 13,14-b-dihydro
(compound 72), which is reflected in the better
activity of the a-analog (Table 3). Not surprisingly,
reduction of both the 5,6 and 13,14 double bonds
(compounds 69 and 70) reduces activity against
H. virescens larvae (Crouse et al., 1999) and is
neutral to negative for stable flies (Kirst et al.,
2002a) and mites (Table 3). In contrast, a reduction
of only the 5,6 double bond (compound 70) has little
effect on the three-dimensional shape or on activity
towards H. virescens larvae, but reduces activity to
stable flies, and is associated with an increase in
activity against aphids and mites (Crouse et al.,
2001) (Table 3). Likewise, the 5,6-b-epoxy analog
of spinosyn A is about as active against H. virescens
larvae as spinosyn A, while the 5,6-a-epoxy analog
(compound 74) is much less active (Table 3). Both
5,6-epoxides are slightly less effective against stable
fly adults compared to spinosyn A, while the 5,6-bepoxy
analog is, just like the 5,6-dihydro derivative
(compound 74), more active against mites (Table 3).
Thus, for larvae of H. virescens and stable fly
adults, alteration of the 5,6 double bond provides
no improvement in activity, while some interesting
increases in activity are noted for T. urticae (Table 3).
In general, for H. virescens larvae, any modification
to the internal structure of the tetracycle reduces
activity (Crouse et al., 1999), with the exception of
the addition of extra unsaturation at the 7–11-position
of spinosyn D (compound 73), which is about as
active as spinosyn A (Table 3). Many other synthetic
modifications have been made to the tetracycle
(Crouse and Sparks, 1998; Crouse et al., 1999) but
none has provided a significant overall improvement
in biological activity.
Where chemical synthesis has been unable to thus
far succeed, mother nature, and the genetic manipulation
thereof, have been able, in part, to fill the gap.
Extension of the alkyl group at C21 to n-propyl
(compound 30), produced through alteration of polyketidesyntase
(PKS) modules (Burns et al., 2003),
provides a slight improvement in activity over spinosyn
A against H. virescens larvae and aphids
(Table 3). Further extension of the C21 position to
21-butenyl (compound 31), the primary factor produced
by S. pogona (Lewer et al., 2003), provides
activity against H. virescens equivalent to spinosyn
A. However, for Aphis gossypii, activity is further
improved over C21-n-propyl (compound 30) (Table
3). Unfortuantely, as with the other modifications
that have improved intrinsic aphid and mite activity,
the physical properties of the spinosyns thus far discovered
generally preclude the effective plant mobility
and residuality necessary for effective control of
aphids or mites in the field (Crouse et al., 2001).
6.7.2. Modification or Replacement of the
Forosamine Sugar
As described above (see Section 6.7.1) for
the spinosyns, removal of a methyl group from the
forosamine nitrogen tends to be a fairly neutral