Total Synthesis of (-)-Spinosyn A via Carbonylative Macrolactonization

Article abstract of DOI:10.1021/jacs.6b07585

Spinosyn A (1), a complex natural product featuring a unique 5,6,5,12-fused tetracyclic core structure, is the major component of spinosad, an organic insecticide and an FDA-approved agent used worldwide. Herein, we report an efficient total synthesis of (-)-spinosyn A with 15 steps in the longest linear sequence and 23 steps total from readily available compounds 14 and 23. The synthetic approach features several important catalytic transformations including a chiral amine-catalyzed intramolecular Diels-Alder reaction to afford 22 in excellent diastereoselectivity, a one-step gold-catalyzed propargylic acetate rearrangement to convert 28 to α-iodoenone 31, an unprecedented palladium-catalyzed carbonylative Heck macrolactonization to form the 5,12-fused macrolactone in one step, and a gold-catalyzed Yu glycosylation to install the challenging β-forosamine. This total synthesis is highly convergent and modular, thus offering opportunities to synthesize spinosyn analogues in order to address the emerging cross-resistance problems.

Full text of DOI:10.1021/jacs.6b07585

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Communication
Total Synthesis of (-)-Spinosyn A via Carbonylative Macrolactonization
Yu Bai, Xingyu Shen, Yong Li, and Mingji Dai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07585 • Publication Date (Web): 10 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 2016
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Journal of the American Chemical Society
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Total Synthesis of (−)-Spinosyn A via Carbonyla-
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Yu Bai, Xingyu Shen, Yong Li, and Mingji Dai*
Department of Chemistry and Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
Supporting Information Placeholder
nontrivial as well. So far, three total syntheses of spinosyn A
have been reported from the groups of Evans (31 steps in the
longest linear sequence (LLS), 37 steps total),4 Paquette (35
steps LLS, 44 steps total),5 and Roush (23 steps LLS, 29 steps
total).6 One chemoenzymatic synthesis has been reported by
Liu and co-workers.7 This chemoenzymatic synthesis requires
23 steps (LLS) and 35 total steps including one enzymatic
step. Currently, most of the analog exploration relies on semi-
synthesis and focuses on modifications of the tri-O-methyl-L-
rhamnose moiety.8 Structural modification of the tetracyclic
core is important but highly challenging and an efficient and
modular synthetic approach toward spinosyns is needed for
this purpose. Herein, we report such a total synthesis of (−)-
spinosyn A with 15 steps in the longest linear sequence and 23
steps total from readily available compounds 14 and 23.
β-glycosidic bond
ABSTRACT: Spinosyn A (1), a complex natural product
featuring a unique 5,6,5,12-fused tetracyclic core structure, is
the major component of spinosad, an organic insecticide and
an FDA-approved agent used worldwide. Herein, we report an
efficient total synthesis of (−)-spinosyn A with 15 steps in the
longest linear sequence and 23 steps total from readily availa-
ble compounds 14 and 23. The synthetic approach features
several important catalytic transformations including a chrial
amine-catalyzed intramolecular Diels-Alder reaction to afford
22 in excellent diastereoselectivity, a one-step gold-catalyzed
propargylic acetate rearrangement to convert 28 to α-
iodoenone 31, an unprecedented palladium-catalyzed car-
bonylative Heck macrolactonization to form the 5,12-fused
macrolactone in one step, and a gold-catalyzed Yu glycosyla-
tion to install the challenging β-forosamine. This total synthe-
sis is highly convergent and modular, thus offering opportuni-
ties to synthesize spinosyn analogs to address the emerging
cross-resistance problems.
OMe
Me
Me2N
O
O
O
OMe
OMe
Me
Me
H
H
O
5/6/5/12-fused tetracyclic ring system
β-glycosidic forosamine
O
O
organic insecticide (Spinosad)
H
H
FDA approved use for human head lice
cross-resistance developed
O
Me
R
3 prior total syntheses: 23-35 steps (LLS)
1 chemoenzymatic synthesis
SAR study limited to the carbohydrate parts
This work: 15 steps (LLS) from 14 and 23;
highly convergent and modular
Spinosyn A (1, R = H)
Spinosyn D (2, R = Me)
Spinosyn A (1, Figure 1) is the major component of spi-
nosad, an important organic and natural insecticide that is
widely used around the world in agriculture.1 Spinosad is also
an FDA-approved agent for treating human head lice. Spi-
nosyns A and D were produced by Saccharopolyspora spinosa
in a roughly 17:3 ratio and were demonstrated to have novel
mode of actions.2 They primarily target the insect nicotinic
acetylcholine receptors (nAChRs) of the nervous system. They
also function as γ-aminobutyric acid (GABA) neurotransmitter
agonists. The overall effects make the insect hyperexcited,
which ultimately leads to death. More importantly, in addition
to spinosad’s high efficacy and broad insect pest spectrum, it
has very low mammalian toxicity as well as an excellent envi-
ronment profile. Unfortunately, cross-resistance has been ob-
served for spinosad recently, which puts the usage life of this
important insecticide at risk.3 Thus, developing the next gen-
eration of spinosad insecticides becomes important and urgent.
So far, the current biosynthesis approach is effective for pro-
ducing spinosyns in large scale, but cannot be adapted to make
a large number of analogs with structural variations at differ-
ent sites to target the emerging cross-resistance.
glycosylation
PO
PO
O
Me
H
H
OP
H
H
OP
Pd, CO
Me
OH
I
O
O
Me
H
H
H
O
Me
4
palladium-catalyzed
3
carbonylative Heck macrolactonization
Evans Aldol
PO
Br
1,2-addition
Me Br
OAc
OP
OP
H
H
Me
6
Au(I), NIS
OP
Me
OP
O
H
Me
H
H
OP
H
IMDA
5
gold-catalyzed
propargylic acetate rearrangement
H
7
Figure 1. Spinosyn A and retrosynthetic analysis.
Our group9 has an ongoing interest in developing novel
catalytic carbonylative reactions10 to streamline the synthesis
of complex bioactive natural products with carbon monoxide
as a one carbon linchpin. After carefully examining the struc-
tural features of the spinosyns, we envisioned the possibility of
developing an unprecedented palladium-catalyzed carbonyla-
Structurally, spinosyn A and D consist of a unique 5,6,5,12-
fused tetracyclic ring system attached with two carbohydrates:
D-forosamine and tri-O-methyl-L-rhamnose. In addition to the
synthetic challenges posed by the tetracyclic core, stereoselec-
tive installation of the β-D-forosamine, a 2-deoxy sugar, is
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Journal of the American Chemical Society
Page 2 of 5
tive Heck macrolactonization to construct the spinosyn A
aglycone (3) from (Z)-α-iodoenone 4. Such a carbonylative
Heck macrolactonization, while challenging, would signifi-
cantly improve the synthetic efficiency and enable unique
bond scission of the carbocycle and macrolactone moieties.
Stereoselective synthesis of α-iodoenone 4 is not a simple
task. The commonly used Wittig-type olefination is not suita-
ble because of low stereoselectivity and the issues associated
with the accessibility and stability of the corresponding α-
iodo-ylide reagent.11 Iodination of the corresponding acyclic
enone is problematic as well.12 Inspired by the recent discover-
ies of Zhang13 and Shi14 for the stereoselective rearrangement
of propargylic acetates to Z or E α-iodoenones by using differ-
ent gold(I) catalysts, we envisioned propargylic acetate 5 as
the precursor of 4. Compound 5 could be assembled by 1,2-
addition of an acetylide derived from dibromide 6 to aldehyde
7 followed by in situ acetate formation. This bond disconnec-
tion is critical and strategic because it would cut compound 5
into two relatively simple pieces with about equal complexity.
Compound 6 could be readily synthesized with an Evans aldol
reaction to construct the two contiguous carbon centers. Com-
pound 7 could be assembled with an intramolecular Diels-
Alder (IMDA) reaction.
tion before it undergoes the macrolactonization with the teth-
ered remote alcohol? Second, will the six-membered ring fa-
cilitate the carbonylative-Heck macrolactonization via
1
2
3
4
5
6
7
8
a
Thorpe-Ingold type effect to improve the reaction yield?
Third, with the Thorpe-Ingold type effect, will 1,6-enyne cy-
cloisomerization become a problem since the terminal olefin
and the alkyne are getting closer in comparison to the case of
8? Fourth, what is the stereochemical outcome of the newly
generated carbon center? With these questions in mind, sub-
strate 11 was subjected to the gold-catalyzed rearrangement
conditions. The reaction turned out to be quite complex and α-
iodoenone 12 was produced in trace amount. We then found
that addition of 10% of AgNTf2 to the reaction system is bene-
ficial and 12 was obtained in 61% yield, indicating some silver
effect in this transformation.17 More importantly, the car-
bonylative Heck-macrolactonization was much more effective
and product 13 was produced in 58% yield with 3:1 diastere-
oselectivity favoring the desired stereochemical outcome.
About 10% of the regular Heck reaction product was obtained
as well. These results indicate the critical role of the six-
membered ring in facilitating the carbonylative Heck-
macrolactonization process.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
37
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b. MeI, CaCO3
MeCN/H2O, 45 ο
77%
OTBDPS
OTBDPS
OH
a. H-G II, toluene
C
CO2Me
OAc
O
I.
then TBDPSCl
imidazole, rt
S
S
c. CHI3, CrCl2
THF, rt
S
S
Pd(OAc)2 (10%)
PPh3 (20%)
PPh3AuNTf2
(5%)
I
O
O
OMe
O
OMe
80% (E/Z = 5/1)
76%
I
Et4NCl, xylene
110 οC
CO (balloon)
14
NIS (1.5 eq.)
acetone/H2O
OH
15
16
(800/1), -15 ο
84 %
C
O
O
9
OTBS
10
8
26 %
OTBDPS
SeCN
NO2
OTBDPS
d. Pd2dba3 (5%), CuTc
[Ph2PO2][NBu4]
O
OAc
PPh3AuNTf2
(5%)
O
II.
H
H
Pd(OAc)2 (10%)
H
e. PBu3, THF, rt
DMF, rt
AgNTf2 (10%)
PPh3 (20%)
O
OMe
Bu3Sn
O
OMe
HO
18
I
83%
Et4NCl, toluene
OH
NIS (1.5 eq.)
acetone/H2O
H
ArSe
90 ο
C
17
87%
O
O
(800/1), -15 ο
C
CO (balloon)
OH
19
OTBS 11
13
12
61 %
58 % (dr. 3:1)
Me
O
Me
Me
Me
OTBDPS
N
Scheme 1. Model studies.
O
f. DIBAL-H
CH2Cl2, -78 ο
85%
N
h.
H
H
OTBDPS
H
C
H
Ph
21 (20%)
So far, there have been no reports of palladium-catalyzed
carbonylative-Heck macrolactonization. Even for the sporadi-
cally reported intramolecular carbonylative Heck reactions,15
issues such as over cabonylation or no carbonylation are po-
tential problems. In the proposed gold-catalyzed propargylic
acetate rearrangement, there is a 1,6-enyne structural motif in
substrate 5 and a potential enyne cycloisomerization16 may
compete with the desired rearrangement. Under these circum-
stances, model studies were conducted (Scheme 1). We first
prepared propargylic acetate 8 with a 1,6-enyne moiety. To
our delight, using Zhang’s protocol,13 the gold-catalyzed rear-
rangement in the presence of NIS provided α-iodoenone 9 in
excellent yield and stereoselectivity without any detection of
the corresponding cycloisomerization byproduct. The TBS-
protecting group was removed as a bonus. We then explored
the feasibility of using carbonylative-Heck macrolactonization
to build the 5,12-fused macrolide. After extensive investiga-
tions, we were able to obtain desired product 10 in 26% yield
with a catalytic amount of Pd(OAc)2/PPh3 under balloon pres-
sure of CO. While the yield was not yet optimal, this result
demonstrates the feasibility and efficacy of using a carbonyla-
tive-Heck macrolactonization to build the 5,12-fused macro-
lide ring system. Encouraged by this simple model study, we
prepared model substrate 11 to investigate four things. First,
will the internal double bond of the six-membered carbocycle
intercept the acyl-palladium species via a 5-exo-trig cycliza-
g. MnO2
CH2Cl2, rt
O
H
2% H2O in MeCN
-20 ο
80%
H
C
ArSe
20
SeAr
22
81%
Scheme 2. Synthesis of 22.
We then embarked on the total synthesis. We planned to use
a chiral amine-catalyzed IMDA reaction developed by the
MacMillan group to control the relative stereochemistry of the
trans 5,6-fused ring system,18 since the substrate-controlled
cases tend to give low stereoselectivity. Among the substrates
reported in MacMillan’s work, a conjugated triene substrate
was shown to be ineffective, therefore we decided to introduce
the terminal olefin after the IMDA reaction and designed 20 as
the IMDA precursor (Scheme 2). This choice also gives us an
opportunity to release the double bond at later stage if it gets
involved in the gold-catalyzed rearrangement process. The
synthesis of 20 started with known compound 14,19 which can
be prepared via a one-pot reaction from commercial starting
materials (see the Supporting Information). Cross-metathesis
with the Hoveyda-Grubbs second generation catalyst followed
by TBDPS-protection gave 15 in 76% yield. Removal of the
thioketal group followed by Takai olefination provided vinyl-
iodide 16 with good E/Z selectivity. Stille cross-coupling20 of
16 with 17 afforded 18 in excellent yield, which was then ad-
vanced to the IMDA precursor 20 via a sequence of selenide
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Journal of the American Chemical Society
formation, DIBAL-H reduction, and MnO2 oxidation. The Instead enyne cycloisomerization product 30 was produced in
1
2
3
4
5
6
7
8
IMDA reaction took place smoothly with a 20% loading of
catalyst 21 and product 22 was produced in 80% yield as a
single diastereomer. Notably, the IMDA reaction is sluggish
and not selective in the absence of the chiral amine catalyst
even at elevated temperatures.
28% yield with 59% of 29 recycled. The structure of 30 was
tentatively assigned based on NMR studies. We then decided
to explore the gold-catalyzed rearrangement with 28 directly
and only a trace amount of desired product was obtained using
the conditions established in the model studies. Notably, both
the selenide and the secondary TBS-ether were found to be not
stable under the rearrangement conditions, which further com-
plicated the reaction process. However, we also saw an oppor-
tunity of realizing the rearrangement, oxidative selenide elimi-
nation, and TBS removal in just one step. After extensive reac-
tion condition optimizations, we learned that the ratio of
AgNTf2 and NIS is critical. When the amount of AgNTf2 is
less than the amount of NIS, the reaction was in general com-
plex and the desired product was produced in very low yield.
The amount of water is critical as well.13a Eventually, desired
product 31 was obtained in 58% yield with 3.0 equiv. of
AgNTf2 and 2.5 equiv. of NIS. Carbonylative Heck macrolac-
tonization of substrate 31 required 3 atm of carbon monoxide
and higher pressure was not beneficial and even showed inhib-
itory effect. At last, product 32 was produced in 43% yield as
a single diastereomer. The carbonylative Heck macrolactoni-
zation reaction built both the five-membered ring and the
twelve-membered macrolactone in one step. Overall, a highly
convergent and modular sequence was developed to convert
22 and 27 to tetracyclic intermediate 32 in only 3 steps!
We then prepared dibromide 27 (Scheme 3). The synthesis
is quite straightforward and started from known compound 23,
which can be prepared in three steps from cheap 1,5-
pentanediol or one step from the more expensive 5-OTBS
pentanal via an Evans aldol reaction.21 After switching the
Evans chiral auxiliary to a Weinreb amide and protecting the
secondary alcohol as PMB-ether, the TBS group was removed
to give 24. Oxidation of 24 to an aldehyde followed by an
asymmetric 1,2-addition afforded 26, which was then convert-
ed to 27 via a sequence of TBS-protection, DIBAL-H reduc-
tion, and dibromide formation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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48
49
50
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59
60
a. MeONHMe, AlMe3
CH2Cl2, -20 οC to rt
74%
d. PyrSO3, DIPEA
CH2Cl2/DMSO, rt
70%
OH
O
PMBO
O
O
OMe
N
N
O
Me
Bn
Me Me
b. PMBBr, NaH
Ph
Me
25 (6%)
NBu2
e.
THF/DMF, 0 ο
86%
C
OTBS
HO
OH
c. TBAF, THF, rt
Et2Zn, hexane/toluene
0 οC, 77%
24
23
63%
f. TBSOTf, 2,6-lutidine
PMBO
PMBO
O
CH2Cl2, 0 ο
93%
C
Br
OMe
N
Me Br
OTBS
Me Me
g. DIBAL-H, CH2Cl2, -78 ο
C
With the tetracyclic core structure assembled, the final
stage was to install the two carbohydrate moieties. Installation
of the α-tri-O-methyl-L-rhamnose proceeded smoothly. After
removal of the TBDPS-protecting group with HF/pyridine,
Schmidt glycosylation gave 34 in 65% yield in two steps. The
85%
Me
Me
h. Ph3P, CBr4, THF, -20 ο
C
OH
27
91%
26
Scheme 3. Synthesis of 27.
OAc
H
OAc
H
OPMB
AcO
OPMB
OTBDPS
c.PPh3AuNTf2 (5%)
AgNTf2 (10%)
H
OTBDPS
H
PMBO
H
H
OTBDPS
22
a. nBuLi
b. mCPBA
+
Me
THF, 0 ο
83%
C
Me
NIS (1.5 eq.)
then Ac2O
DMAP
pyridine, THF
-78 οC to rt
27
H
Me
Me
H
H
H
Me
acetone/H2O (800/1)
OTBS
SeAr
-15 ο
C
OTBS
OTBS
28
Me
30
29
28%
d. PPh3AuNTf2 (50%)
AgNTf2 (3.0 eq.), NIS (2.5 eq.)
acetone/H2O (800/1), -15 οC
71%
(59% of 29 recycled)
OMe
Me
58%
PMBO
PMBO
O
OMe
OMe
PMBO
O
I
Me
Me
f. HF/pyridine
THF, 0 οC to rt
e. Pd(OAc)2 (10%)
PPh3 (20%)
H
H
H
H
H
H
OTBDPS
OTBDPS
O
O
Me
OH
O
O
Et4NCl, toluene, 90 οC
O
g. TMSOTf, 33 (2.0 eq.)
CH2Cl2, -30 ο
C
CO (3 atm)
Me
H
H
H
H
O
H
O
Me
Me
65% (2 steps)
43%
34
32
31
OMe
Me
O
OMe
OMe
OMe
OMe
Me
Me
O
O
Cl3C
HO
Me2N
O
O
33
OMe
OMe
O
OMe
OMe
Me
Me
i. PPh3AuCl (2.0 eq.)
AgOTf (2.0 eq.)
Me
NH
H
H
H
H
O
h. DDQ, pH = 7 buffer
O
O
36 (2 eq.), PhCl, 50 ο
71% (β/α = 1:1)
C
O
O
CH2Cl2, 0 ο
C
O
36
Me2N
Me
H
H
O
H
H
O
91%
O
Me
Me
O
35
Spinosyn A (1)
O
Scheme 4. Total synthesis of (−)-spinosyn A.
With both 22 and 27 in hand, we used the Corey-Fuchs pro-
tocol to unite them and the resulting alkoxide was converted to
acetate 28 in situ (Scheme 4). Compound 28 was obtained as a
mixture of diastereomers in 71% yield from a 1:1 ratio of 22
and 27. While this 1,2-addition was not stereoselective, the
newly generated stereocenter will be eliminated at later stage,
so the effect is not permanent. mCPBA oxidative elimination
converted 28 to 29 with a terminal olefin. To our surprise,
despite the success of the two model substrates, rearrangement
of 29 to the corresponding α-iodoenone did not take place.
spectra data of 34 matches with those reported in the Roush
synthesis.6 Oxidative removal of the PMB-protecting group
gave the pseudoaglycon 35 in 91% yield. The last hurdle in
our synthesis was to introduce the β-D-forosamine. The diffi-
culty involved in a direct glycosylation with a D-foroamine
derived donor has been experienced by the previous pioneers
and no methods have been reported to stereoselectively intro-
duce the β-linkage. The Evans group used a silver zeolite cata-
lyzed glycosylation of the pseudoaglycon 35 with a N-Fmoc
protected glycosyl bromide donor to give a 69% yield of a 1:6
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(3) (a) Su, T.; Cheng, M. L. J. Med. Entomol. 2014, 51, 428. (b)
mixture of β/α-glycosides, but favoring the undesired α-
isomer.4 The Paquette group used AgOTf-catalyzed glycosyla-
tion with a glycosyl sulfide donor to give the glycosylation
product in 17% yield as a 2:3 mixture of β/α-glycosides, again
favoring the undesired isomer.5 The Roush group used a 2-
acetate glycosyl imidate donor to circumvent the stereoselec-
tivity issue, but it requires 11 steps to synthesize this donor
and another 5 steps to convert the glycosylated product to spi-
nosyn A. Recently, Yu and co-workers reported a gold-
catalyzed glycosylation, which favors β-selectivity.22 We de-
cided to investigate the Yu glycosylation in our synthesis by
using donor 36. To our delight, after finely tuning the reaction
conditions, the glycosylation product was obtained in 71%
yield along with 15% of recycled pseudoaglycon 35. While the
β/α-selectivity is only 1:1, it is still so far the most effective
way of direct glycosylation with a D-foroamine derived donor.
The β/α-glycoside isomers were separated by preparative TLC
to complete the total synthesis of (−)-spinosyn A, the spectra
data of which match with the ones of the natural product.
1
2
3
4
5
6
7
8
Rehan, A.; Freed, S. Crop Prot. 2014, 56, 10. (c) Khan, H. A. A.;
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Overall, we have developed an efficient and modular total
synthesis of (−)-spinosyn A with 15 steps in the longest linear
sequence and 23 steps total from readily available compounds
14 and 23. The synthetic approach features an organocatalyzed
IMDA reaction to build the trans 5,6-fused ring in excellent
diastereoselectivity, a one-step gold-catalyzed23 propargylic
acetate rearrangement, selenide elimination, and TBS-removal
to convert 28 to α-iodoenone 31, an unprecedented palladium-
catalyzed carbonylative Heck macrolactonization to form the
5,12-fused macrolactone, and a Yu glycosylation to install the
challenging β-forosamine. This total synthesis is highly con-
vergent and flexible, thus providing new avenues to access
spinosyn analogs to address the cross-resistance problems.
ASSOCIATED CONTENT
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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K.; Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen, J. L. Shi, X. J.
Am. Chem. Soc. 2012, 134, 9012.
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Chem. Soc. 2005, 127, 11616. (b) Lambert, T. H.; Danishefsky, S. J.
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vado, C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun.
2008, 25, 2873.
AUTHOR INFORMATION
Corresponding Author
mjdai@purdue.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank NSF (CAREER 1553820) and the ACS Petroleum Re-
search Foundation (PRF# 54896-DNI1) for financial support and
the NIH P30CA023168 for supporting shared NMR resources to
Purdue Center for Cancer Research. We also thank Dow AgroSci-
ences for sharing D-forosamine and natural sample of (−)-
spinosyn A. This paper is dedicated to Professor Samuel J. Dan-
ishefsky and Professor Stuart Schreiber on the occasion of their
80th and 60th birthdays, respectively.
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Lett. 2015, 17, 1493.
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Y.; Yu, B. Chem. Eur. J. 2015, 21, 8771. For selected applications in
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OAc
H
PMBO
O
OPMB
H
H
H
OTBDPS
OTBDPS
Br
H
1. nBuLi
+
Me Br
OTBS
Ac2O
Me
OTBS
Au-catalyzed propargylic 2. Au(I), Ag(I)
H
H
Me
Me
SeAr
SeAr
organocatalyzed
IMDA
acetate rearrangement
NIS
7
8
9
Au-catalyzed
Yu glycosylation
OMe
Me
O
PMBO
O
I
Me2N
O
O
OMe
OMe
Me
Me
3. Pd(II)
H
H
OTBDPS
H
H
O
Me
CO
O
O
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Me
H
OH
H
H
O
Me
Pd-catalyzed carbonylative
Heck Macrolactonization
CO (one carbon linchpin)
(-)-Spinosyn A
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