Synthesis of spinosyn analogues for modern crop protection

Article abstract of DOI:10.1002/ejoc.201200600

New spinosyn analogues 3 with an arene group as ring A and containing a L-rhamnose moiety have been prepared. The key step in the synthesis of 3 is a Pd-catalyzed twofold Heck reaction of glycosylated bromoarene 4, containing an iodovinyl side chain and a

Full text of DOI:10.1002/ejoc.201200600

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FULL PAPER
DOI: 10.1002/ejoc.201200600
Synthesis of Spinosyn Analogues for Modern Crop Protection
Lutz F. Tietze,*[a] Nina Schützenmeister,[a] Alexander Grube,[a] Timo Scheffer,[a]
Mohammad Merajuddin Baag,[a] Markus Granitzka,[b] and Dietmar Stalke[b]
Dedicated to Professor Theophil Eicher on the occasion of his 80th birthday
Keywords: Total synthesis / Natural products / Macrolactones / Heck reaction / Cyclization / Spinosyns / Insecticides /
Crop protection
New spinosyn analogues 3 with an arene group as ring A
and containing a -rhamnose moiety have been prepared.
The key step in the synthesis of 3 is a Pd-catalyzed twofold
Heck reaction of glycosylated bromoarene 4, containing an
iodovinyl side chain and a tri-O-methyl-L-rhamnose moiety
with the cyclopentene-annulated macrolactone 5. Com-
pounds 3 may be of interest as new insecticides.
L
using Saccharopolyspora spinosa (Figure 1). The spinosyns
have a tetracyclic backbone, which contains a 12-membered
Introduction
Spinosyns represent a family of natural products produced macrocyclic lactone and two sugar moieties. Spinosyn D
by the soil organisms Saccharopolyspora spinosa[1] and Sac- (1b) differs from spinosyn A (1a) by an additional methyl
charopolyspora pogona[2] with a strong insecticidal activity.[3] group at the B-ring. A recent highly successful development
They are used for crop protection and have been commer- is the generation of semisynthetic spinetoram (2) containing
cialized since 1997 as Spinosad, an 85:15 mixture of spino- 3Ј-O-ethyl-5,6-dihydrospinosyn J as the major component
syn A (1a) and D (1b), which is produced by fermentation (Figure 1).[4]
Figure 1. Naturally occurring spinosyns 1, spinetoram 2 and spinosyn analogues 3a and 3b.
[a] Institute of Organic und Biomolecular Chemistry of the Georg
The mode of action of these insecticides is unique though
August University Göttingen,
not fully understood. The compounds kill target insects due
to exhaustion of the firing capability of the neurons. So
far they seem to target the nicotinic acetylcholine receptor
(nAChR) subunit Dα6[5] and to interact with the γ-amino
butyric acid (GABA) receptor. Spinosad is highly selective
relative to other insecticides and thus, is non-toxic to mam-
mals and has little to no effect on non-target insects and
Tammannstraße 2, 37077 Göttingen, Germany
Fax: +49-551-399476
E-mail: ltietze@gwdg.de
Homepage: http://www.tietze.chemie.uni-goettingen.de/
[b] Institute of Inorganic Chemistry of the Georg August
University Göttingen,
Tammannstraße 4, 37077 Göttingen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200600.
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fish.[3c,6] This selectivity, combined with an excellent envi- methyl-l-rhamnose 6, and bromobenzaldehyde 7 whereas
ronmental profile, makes spinosad an important crop pro- macrolactone 5 could be generated from 1,2-cis-disubsti-
tecting agent.
tuted cyclopentene 8 and hexane derivative 9 (Scheme 1).
Due to the recent development of resistance to the spino- The cis-orientation of the two substituents in 8, and finally
syns by target insects new spinosyn analogues are highly in the macrolactone 5, is necessary to allow facially selective
desirable.[7] Although little is known about structure– addition anti to the substituents in the first Heck reaction
activity relationships (SAR) for the spinosyns, the existing and a Pd-H-syn elimination in the second Heck reaction.
data show that an additional double bond between C-7 and We have used 8 as a racemic mixture in this approach to
C-11 has no negative effects on the biological activity. In- allow the preparation of diastereomers, although it can also
stead, a slight increase in the insecticidal activity has been be employed as an enantiopure compound.[10]
noted with the addition of this functionality.[8] Based on
The alcohol moiety in rac-8 was oxidized with Dess–
this finding we have designed new spinosyn analogues with Martin periodinane (DMP) in CH2Cl2 in 92% yield. Re-
reduced complexity. Our work is focused on the synthesis sulting aldehyde rac-10 was then used in an Evans aldol
of compounds containing a double bond between C-7 and reaction[11] with the boron-enolate of oxazolidinone 11
C-11 as part of an aromatic ring A instead of the cyclopen- using NEt3 as base. The reaction was highly stereoselective
tane moiety observed with the natural spinosyns. In this and furnished expected enantiopure diastereomers 12 and
way we can circumvent the issue of introducing and con- 13 as an almost 1:1 mixture; these products could not be
trolling three stereogenic centers. We have recently reported separated by chromatography at this stage (Scheme 2).
on a convergent synthesis of a spinosyn analogue devoid Employing the same route to enantiopure cyclopentene 8,
of any sugar moieties.[9] Here we describe the synthesis of stereoisomer 12 was formed in the Evans aldol reaction in
analogues 3 containing a tri-O-methyl-l-rhamnose moiety 83% yield.
using a twofold Heck reaction and glycosylated bromoarene
4 containing an iodovinyl side chain and cyclopentene-
annulated macrolactone 5 (Scheme 1). This route is highly
flexible and allows the synthesis of analogues with different
constitutions and stereochemistry, which are envisioned to
be useful in carrying out SAR studies.
Scheme 2. Synthesis of 12 and 13: a) 1.50 equiv. DMP, room temp.,
30 min, CH2Cl2, 92%; b) 1.20 equiv. 11, 1.30 equiv. nBu2BOTf (1 m
in CH2Cl2), 1.50 equiv. NEt3, 0 °C, 1 h, then addition of rac-10 at
–78 °C, maintain temperature for 1 h, then warm to 0 °C over
course of 4 h, 92%.
Subsequent reductive removal of the Evans auxiliary in
12/13 with LiBH4 and EtOH led directly to diastereomeric
diols 14 and 15 as an almost 1:1-mixture. Unlike 12/13,
diols 14 and 15 could now easily be separated by column
chromatography on silica gel (Scheme 3). Both hydroxy
groups in 14 and 15 were then protected as TBS ethers
using TBSOTf and 1,6-lutidine in CH2Cl2 to give 16 and
Scheme 1. Retrosynthesis of spinosyn analogue 3a.
18. Selective removal of the primary TBS group with HF/
pyridine in THF/pyridine afforded enantiopure primary
alcohols 17 and 19 in 97% and 90% yield, respectively
(Scheme 3).
Results and Discussion
For confirmation of the proposed structure of these com-
The retrosynthetic analysis of spinosyn analogue 3a sug- pounds, enantiopure 12 was treated with TBSOTf and imid-
gests the application of two Heck reactions involving 4 and azole at 60 °C to give corresponding TBS ether 20 in 82%
5. Aryl bromide 4 could be envisioned to arise from tri-O- yield, for which crystals could be obtained allowing for
2
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Synthesis of Spinosyn Analogues for Modern Crop Protection
raphy on silica gel. Removal of small amounts of the corre-
sponding Wurtz product formed in the reaction was pos-
sible by RP chromatography.
The preferred formation of diastereomers 24 and 27 can
be explained by applying the Felkin–Anh model.[13]
Acetylation of the mixture of 24 and 25 using an excess
of Ac2O and NEt3 and catalytic amounts of DMAP in
CH2Cl2 afforded diastereomeric mixture 26 in 83% yield
based on aldehyde 21. As described for 24/25, the same
transformation was applied to alcohol 27 to give acetate 29
in 66% based on aldehyde 22 (Scheme 4).
Scheme 3. Synthesis of alcohols 17 and 19 a) 1.10 equiv. EtOH,
1.10 equiv. LiBH4, Et2O, –20 °C, 90 min, 45% (14) and 49% (15);
b) 8.0 equiv. 2,6-lutidine, 4.0 equiv. TBSOTf, CH2Cl2, –10 °C,
40 min, 95% (16); c) HF·pyr, pyr/THF, 1:2, 0 °CǞroom temp., 8 h,
94% (17); d) 6.0 equiv. 2,6-lutidine, 3.0 equiv. TBSOTf, CH2Cl2,
–10 °C, 45 min, 97% (18); e) HF·pyr, pyr/THF, 1:2, 0 °CǞroom
temp., 14 h, 90% (19).
crystal structure determination (Figure 2). In this way the
absolute configuration of all stereogenic centers of 20 as
well as those of 17 and 19 could be unambiguously as-
signed.
Scheme 4. a) 3.0 equiv. DMP, CH2Cl2, 4 h, quant.; b) 1.30 equiv.
23, THF, LiCl, –78 °C; c) 8.0 equiv. NEt3, 5.0 equiv. Ac2O,
20.0 mol-% DMAP, CH2Cl2, room temp., 4 h, 83% (based on 21);
d) 3.0 equiv. DMP, CH2Cl2, 4 h, 83%; e) 1.30 equiv. 23, THF, LiCl,
–78 °C; f) 8.0 equiv. NEt3, 5.0 equiv. Ac2O, 20.0 mol-% DMAP,
CH2Cl2, room temp., 4 h, 66% (based on 22).
Cleavage of the MEM ether in 26 with TMSI,[14] gener-
ated in situ, afforded compounds 30 in 64% (86% brsm)
and cleavage of the tert-butyl ester with TMSOTf and 2,6-
lutidine in THF led to acids 31 in 95% yield. Macrolacton-
ization following Yamaguchi’s procedure[15] using 2,4,6-tri-
chlorobenzoyl chloride (TCBzCl) gave a mixture of macro-
lactones 32 and 33 in 45% and 12% yield, respectively,
which could be separated by column chromatography on
silica gel (Scheme 5).
Figure 2. Structure of 20 determined by crystallography. Aniso-
tropic displacement parameters are depicted at the 50% probability
level. All hydrogen atoms except 3-H and 7-H, to illustrate the con-
figuration at C-3 and C-7, respectively, are omitted for clarity. The
disorder of the tBu group is also omitted for clarity (see Supporting
Information).
Alcohols 17 and 19 were oxidized with DMP in CH2Cl2
to give aldehydes 21 and 22, respectively which were inde-
pendently used in a Grignard reactions with enantiopure
23. Grignard reactions were carried out in THF with and
without LiCl[12] as additive. The reaction of 21 at –78 °C in
the presence of LiCl led to a 1.8:1 mixture of 24 and 25 in
favor of the desired (3ЈЈS)-diastereomer 24. Alcohols 24 and
25 could not be separated by chromatography at this stage;
each product also contained small amounts of the Wurtz-
coupled byproduct. Without the addition of LiCl the reac-
tion was much slower and the reaction temperature had to
be raised to –60 °C leading to large amounts of the Wurtz
product. Unexpectedly, the ratio of the diastereomers thus
generated was almost the same as was the case at –78 °C
with a 24/25 ratio of 1.6:1. The Grignard reaction of alde-
hyde 22 with 23 in the presence of LiCl at –78 °C yielded
two diastereomers 27 and 28 in a 2.4:1 ratio in favor of 27,
Scheme 5. a) 2.2 equiv. TMSCl, 2.20 equiv. NaI (in three portions),
CH3CN/CH2Cl2 (4:1), –45 °C, 4 h, 64% (86% brsm); b) 14.0 equiv.
2,6-lutidine, 7.0 equiv. TMSOTf, THF, room temp., 1.5 h, 95%;
c) 6.0 equiv. NEt3, 4.0 equiv. TCBzCl, THF, room temp., 1.5 h,
then slow addition (syringe pump) to 10.0 equiv. DMAP, toluene,
which could be separated from 28 by column chromatog- 60 °C, 165 min, 45% (32) and 12% (33).
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The MEM ether cleavage of acetate 27 with in TMSI, lutidine in THF furnished acid 35 in 96% yield and subse-
generated in situ, led to secondary alcohol 34 in 65% yield. quent macrolactonization afforded macrolactone 36 in 96%
Hydrolysis of the tert-butyl ester with TMSOTf and 2,6- yield (Scheme 6).
Macrolactones 32 and 36 were subsequently used in the
twofold Heck reaction. For the first, intermolecular, step
Pd(OAc)2, TBACl[16] (Scheme 7) and an inorganic base in
DMF were employed. The second, intramolecular, Heck
coupling exploited Herrmann–Beller catalyst 43 and the
base
n-Bu4NOAc
in
DMF/CH3CN/H2O
(5:5:1)
(Scheme 8).[17]
Scheme 6. a) 2.40 equiv. TMSCl, 2.40 equiv. NaI (in three por-
tions), CH3CN/CH2Cl2 (3.5:1), –45 °C, 5 h, 65% (84% brsm);
b) 14.0 equiv. 2,6-lutidine, 7.0 equiv. TMSOTf, THF, room temp.,
4.3 h, 96%; c) 6.0 equiv. NEt3, 4.0 equiv. TCBzCl, THF, room
temp., 1.5 h, then slow addition (syringe pump) to 10.0 equiv.
DMAP, toluene, 60 °C, 165 min, 96%.
Scheme 8. Intramolecular Heck reaction of 37 and 40 respectively.
Initial Heck reaction of 32 and 36 gave desired products
37 and 40 in 26% and 33% yield, respectively (Table 1). In
addition, regioisomers 39 and 42 as well as E-isomers 38
and 41 were obtained. The corresponding E-isomers of 39
and 42 were not found. The overall yields for these transfor-
mations were very high nearing 100% (Scheme 7). One
drawback to this approach however, was that considerable
amounts of the E-isomers were formed, which cannot be
used in the second Heck reaction.
The second Heck reaction using Z-isomers 37 and 40,
respectively led to desired tetracyclic products 44 and 45 in
over 90% yield. Subsequent cleavage of the TBS ether with
HF·pyr at 60 °C followed by removal of the acetyl-protect-
ing group with K2CO3 in MeOH at 0 °C yielded spinosyn
analogues 3a and 3b in high yields (Scheme 9).
Scheme 7. Intermolecular Heck reaction.
Table 1. Summary of Intermolecular Heck reaction results.[a]
Entry
SM
Catalyst loading Base
Reaction temp.
Time (d)
Products and yields (%)
1
2
3
4
32
32
32
36
10 mol-%
3 mol-%
3 mol-%
3 mol-%
NaOAc[b]
NaOAc
Na2CO3
NaOAc
room temp.
0 °C
room temp.
0 °C
2
7
2
8
37 (20)
38 (45)
38 (63)
38 (54)
41 (58)
39 (11)
39 (11)
39 (20)
42 (Ͻ5)
37 (26)
37 (9)
40 (33)
[a] Conditions: Starting material: 31 and 36, respectively; base (1.0 equiv.), Pd(OAc)2, TBACl (0.3 equiv.), DMF. [b] 0.7 equiv.
4
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Synthesis of Spinosyn Analogues for Modern Crop Protection
crystals.[18] An appropriate crystal was selected using a polarized
microscope, mounted on the tip of a MITEGEN©MicroMount,
fixed to a goniometer head and shock-cooled by the crystal cooling
device.
The data for 20 were collected from a shock-cooled crystal at
100(2) K on a BRUKER TXS-Mo rotating anode (used Mo-Kα
radiation, λ = 71.073 pm) with mirror optics and APEX II detector
with a D8 goniometer. The data of 20 were integrated with
SAINT[19] and an empirical absorption correction (SADABS)[20]
was applied. The structure was solved by direct methods
(SHELXS-97) and refined by full-matrix least-squares methods
against F2 (SHELXL-97)[21] implemented in the SHEXLE GUI.[22]
All non-hydrogen-atoms were refined with anisotropic displace-
ment parameters. The hydrogen atoms were refined isotropically
on calculated positions using a riding model with their Uiso values
constrained to equal to 1.5 times the Ueq of their pivot atoms for
terminal sp3 carbon atoms and 1.2 times for all other carbon atoms.
Disordered moieties were refined using geometric and anisotropic
displacement parameter restraints.
Scheme 9. Synthesis of 3a and 3b: a) HF·pyr, pyr/THF, 1:3, 60 °C,
16 h, 96%; b) 1.0 equiv. K2CO3, MeOH, 0 °C (2.5 h)Ǟroom temp.
(4 h), 66% (82% brsm); c) HF·pyr, pyr/THF, 1:3, 60 °C, 15.5 h,
96%; d) 1.0 equiv. K2CO3, MeOH, 0 °C (80 min)Ǟroom temp.
(4 h), 81% (89% brsm).
The CCDC number, crystal data and experimental details for the
X-ray measurements are also listed in the Supporting Information
CCDC-879948 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Conclusions
We have reported on the synthesis of spinosyn A ana-
logues 3a and 3b containing a tri-O-methyl-l-rhamnose
moiety using a twofold Heck reaction sequence to construct
the tetracyclic backbone. Further reactions employed to
generate 3a and 3b include a stereoselective Evans-aldol re-
action, a Grignard addition and Yamaguchi macrolactoni-
zation. The aim of this work is to prepare new spinosyns
that enable improved pest management by circumventing
mechanisms of spinosyn resistance.
Compound 37: A solution of the vinylic iodide 4 (64.5 mg,
126 μmol, 1.0 equiv.) and cyclopentene derivative 32 (171 mg,
377 μmol, 3.0 equiv.) in abs. DMF (3 mL) was degassed and
Pd(OAc)2 (847 μg, 3.77 μmol, 3 mol-%), NaOAc (31.3 mg,
377 μmol, 3.0 equiv.) and TBACl (34.9 mg, 126 μmol, 1.0 equiv.)
were added at room temp., the reaction mixture was cooled to 0 °C
and stirred under exclusion of light at 0 °C for 7 d. The mixture
was then diluted with Et2O (30 mL) and water (20 mL) was added.
The layers were separated and the aqueous layer was extracted with
Et2O (2ϫ30 mL). The combined organic layer were washed with
brine (20 mL), dried with MgSO4, filtered and the solvent was re-
moved in vacuo. Purification of the residue by column chromatog-
raphy on silica gel (PE/Et2O, 2:1ǞPE/AcOEt, 1:1) gave the pure
product 37 (27.5 mg, 32.8 μmol, 26%) as a light brown oil. In ad-
dition, a mixture of 37 and 39 [11.9 mg, 14.2 μmol, 11%, ca. 2:1
(37/39)] as well as 38 (66.0 mg, 78.8 μmol, 63%) were obtained.
Experimental Section
General Methods: All reactions were performed under argon atmo-
sphere. THF and diethyl ether were dried and distilled prior usage
by usual laboratory methods. All other solvents were used from
commercial sources and stored over molecular sieves. All reagents
were obtained from commercial sources and were used without fur-
ther purification. Thin-layer-chromatography (TLC) was per-
formed on precoated silica gel 60 F254 plates (Merck) and silica gel
60 (0.063–0.200 mm, Merck) was used for column chromatography.
Phosphomolybdic acid in methanol or vanillin in methanolic sulf-
uric acid were used as staining reagents. UV spectra were taken in
CH3CN or MeOH with a Perkin–Elmer Lambda 2 spectrometer
or a JASCO V-630. IR spectra were recorded as KBr pellets or as
film between NaCl plates with a Bruker IFS 25 spectrometer or
Analytical Data of 37: Rf = 0.32 (PE/AcOEt, 3:1). [α]2D0 = –108.0 (c
= 0.7 , in CHCl3). UV (MeCN): λmax (lgε) = 198.5 (4.398), 215.0
(4.365), 286.0 (3.100) nm. IR (film): ν = 2932, 1729, 1566, 1463,
˜
1373, 1247, 1198, 1104, 1049, 1009, 902, 866, 837, 807, 774, 732,
703, 664 cm–1. 1H NMR (600 MHz, CDCl3): δ = –0.15, –0.09 (2ϫs,
2ϫ3 H, SiCH3), 0.62 [s, 9 H, SiC(CH3)3], 0.81–0.89 (m, 6 H, 7-
CH2CH3, 12-CH3), 1.24 (d, J = 9.6 Hz, 3 H, 6ЈЈЈ-H3), 1.04–1.13
(m, 1 H), 1.17–1.31 (m, 1 H), 1.43–1.70 (m, 5 H), 1.73–1.82 (m,
2 H) (8-H2, 9-H2, 10-H2, 12-H, 7-CH2CH3), 1.99 [s, 3 H, OC(O)
CH3], 2.37 (mc, 1 H, 3a-H), 2.48 (d, J = 18.0 Hz, 1 H, 4-HA), 2.94
(dd, J = 18.6, 12.6 Hz, 1 H, 4-HB), 3.16 (t, J = 9.6 Hz, 1 H, 4ЈЈЈ-
H), 3.20 (mc, 1 H, 3-H), 3.29 (mc, 1 H, 13a-H), 3.35 (d, J = 10.8 Hz,
1 H, 13-H), 3.51, 3.52, 3.53 (3ϫs, 3 ϫ3 H, 3ϫOCH3), 3.55–3.60
(m, 1 H, 5ЈЈЈ-H), 3.63 (dd, J = 9.0, 3.0 Hz, 1 H, 3ЈЈЈ-H), 3.68 (mc,
1 H, 2ЈЈЈ-H), 4.95 (mc, 1 H, 7-H), 5.29 (mc, 1 H, 11-H), 5.40 (t, J
= 10.8 Hz, 1 H, 1Ј-H), 5.45 (d, J = 1.2 Hz, 1 H, 1ЈЈЈ-H), 5.53–5.57
(m, 1 H), 5.65–5.68 (m, 1 H) (1-H, 2-H), 6.43 (d, J = 10.8 Hz, 1 H,
2Ј-H), 6.79 (d, J = 3.0 Hz, 1 H, 6ЈЈ-H), 6.86 (dd, J = 9.0 Hz, 2.4 Hz,
1 H, 4ЈЈ-H), 7.41 (d, J = 8.4 Hz, 1 H, 3ЈЈ-H) ppm. 13C NMR
(151 MHz, CDCl3): δ = –4.5, –1.3 (2ϫSiCH3), 9.6, 10.0 (C-7-
CH2CH3, C-12-CH3), 17.8 (C-6ЈЈЈ), 18.0 [SiC(CH3)3], 21.1 [OC(O)-
1
neat (ATR) with a JASCO FT/IR-4100. H- and 13C-spectra were
recorded with UNITY 300 (300 MHz), MERCURY-Vx
(300 MHz), VNMRS-300 (300 MHz) and INOVA-600 (600 MHz)
Varian spectrometers. Chemical shifts are reported in ppm with the
solvent as internal standard.
The following abbreviations are used: MTBE (methyl tert-butyl
ether), PE (petroleum ether b.p. 40–60 °C), s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), b (broad) and combinations
thereof.
Single-crystal structural analysis: Single crystals were selected from
a flask that was stored at –18 °C for two weeks and covered with
perfluorated polyether oil on a microscope slide, which was cooled
with a nitrogen gas flow using the XTEMP2 to avoid melting of the
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L. F. Tietze et al.
CH3], 19.8, 28.0, 30.6, 30.8 (C-8, C-9, C-10, C-7-CH2CH3), 26.3 Et2O (2ϫ90 mL). The combined organic layers were washed with
FULL PAPER
[SiC(CH3)3], 34.2 (C-4), 38.3 (C-12), 44.1 (C-3a), 47.2 (C-13a), 50.7
(C-3), 57.8, 59.2, 60.9 (3ϫOCH3), 68.6 (C-5ЈЈЈ), 71.9 (C-11), 76.2
brine (50 mL), dried with MgSO4, filtered and the solvent was re-
moved in vacuo. Purification of the residue by column chromatog-
(C-7), 77.1 (C-2ЈЈЈ), 77.3 (C-13), 80.7 (C-3ЈЈЈ), 81.8 (C-4ЈЈЈ), 95.0 raphy on silica gel (PE/AcOEt, 5:1ǞPE/AcOEt, 4:1) gave 40
(C-1ЈЈЈ), 115.3 (C-4ЈЈ), 116.0 (C-2ЈЈ), 119.3 (C-6ЈЈ), 130.6 (C-2Ј), (102 mg, 122 μmol, 33%) as a white foam. In addition, 36 (341 mg,
133.1 (C-3ЈЈ), 134.5, 135.8 (C-1, C-2), 136.7 (C-1Ј), 138.9 (C-1ЈЈ), 753 μmol) and 41 (179 mg, 214 μmol, 58%) were obtained.
155.2 (C-5ЈЈ), 170.7, 173.2 [C-5, OC(O)CH3] ppm. MS (DCI): m/z
Analytical Data of 40: Rf = 0.37 (PE/AcOEt, 3:1). [α]2D0 = +55.5 (c
(%) = 856.5 (100) [M + NH4]+. HRMS (ESI) m/z: calcd. for
= 0.8 , in CHCl3). UV (MeCN): λmax (lgε) = 213.0 (4.360), 286.5
C42H65BrO10Si: 854.38686 [M + NH4]+, found 854.38665
(3.115) nm: IR (film): ν = 2931, 2856, 1731, 1564, 1462, 1382, 1292,
˜
[M + NH4]+.
1247, 1104, 1048, 1032, 1010, 953, 908, 871, 835, 812, 773, 737,
671 cm–1. 1H NMR (600 MHz, CDCl3): δ = –0.23, –0.03 (2ϫs,
2ϫ3 H, 2ϫSiCH3), 0.79 [s, 9 H, SiC(CH3)3], 0.83 (t, J = 7.4 Hz,
3 H, 7-CH2CH3), 0.86 (d, J = 6.7 Hz, 3 H, 12-CH3), 1.23 (d, J =
6.1 Hz, 3 H, 6ЈЈЈ-H3), 1.19–1.29 (m, 2 H), 1.44–1.66 (m, 5 H), 1.76
(mc, 2 H) (8-H2, 9-H2, 10-H2, 12-H, 7-CH2CH3), 1.97 [s, 3 H,
OC(O)CH3], 2.24 (dd, J = 16.5, 13.0 Hz, 1 H, 4-HA), 2.52 (dd, J =
16.5, 3.6 Hz, 1 H, 4-HB), 2.58 (mc, 1 H, 3a-H), 2.94 (mc, 1 H, 13a-
H), 3.15 (t, J = 9.5 Hz, 1 H, 4ЈЈЈ-H), 3.23 (mc, 1 H, 3-H), 3.49–3.57
(m, 1 H, 5ЈЈЈ-H), 3.51, 3.52, 3.53 (3ϫs, 3 ϫ3 H, 3ϫOCH3), 3.60
(dd, J = 9.5, 3.2 Hz, 1 H, 3ЈЈЈ-H), 3.68 (dd, J = 3.2, 1.4 Hz, 1 H,
2ЈЈЈ-H), 3.84 (d, J = 1.9 Hz, 1 H, 13-H), 4.72 (dd, J = 11.2, 5.0 Hz,
1 H, 7-H), 4.95–5.06 (m, 1 H, 11-H), 5.43 (d, J = 1.4 Hz, 1 H, 1ЈЈЈ-
H), 5.51 (t, J = 10.8 Hz, 1 H, 1Ј-H), 5.59 (d, J = 5.8 Hz, 1 H), 5.80
(mc, 1 H) (1-H, 2-H), 6.45 (d, J = 11.2 Hz, 1 H, 2Ј-H), 6.84 (d, J
= 3.0 Hz, 1 H, 6ЈЈ-H), 6.87 (dd, J = 8.9 Hz, 3.0 Hz, 1 H, 4ЈЈ-H),
7.44 (d, J = 8.9 Hz, 1 H, 3ЈЈ-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = –3.2, –3.1 (2ϫSiCH3), 9.2 (C-12-CH3), 10.0 (C-7-
CH2CH3), 17.9 (C-6ЈЈЈ), 18.5 [SiC(CH3)3], 18.7 (C-9), 21.1 [OC(O)-
CH3], 26.2 [SiC(CH3)3], 28.6, 31.1, 32.0 (C-8, C-10, C-7-CH2CH3),
34.2 (C-4), 43.4 (C-12), 45.4 (C-3a), 49.6 (C-3), 53.0 (C-13a), 58.1,
59.5, 61.0 (3ϫOCH3), 68.2 (C-13), 68.8 (C-5ЈЈЈ), 74.7 (C-7), 77.3
(C-2ЈЈЈ), 77.4 (C-11), 81.0 (C-3ЈЈЈ), 82.0 (C-4ЈЈЈ), 95.3 (C-1ЈЈЈ), 116.1
(C-2ЈЈ), 116.3 (C-4ЈЈ), 118.5 (C-6ЈЈ), 130.3 (C-2Ј), 132.7, 134.4 (C-
1, C-2), 133.4 (C-3ЈЈ), 136.2 (C-1Ј), 138.7 (C-1ЈЈ), 155.3 (C-5ЈЈ),
170.6, 173.6 [C-5, OC(O)CH3] ppm. MS (DCI): m/z (%) = 854.4
(6) [M + NH4]+. HRMS (ESI) m/z: calcd. for C42H65BrO10Si:
854.38686 [M + NH4]+, found 854.38677 [M + NH4]+.
Compound 44: A solution of 37 (63.8 mg, 76.1 μmol, 1.0 equiv.) and
nBu4NOAc (45.9 mg, 152.3 μmol, 2.0 equiv.) in DMF/CH3CN/
H2O (5 mL, 5:5:1) was degassed and Pd-catalyst 43 (5.0 mg,
5.33 μmol, 7.0 mol-%) was added at room temp. The mixture was
stirred for 5 min at room temp. and warmed to 125 °C for 1.75 h.
The mixture was cooled to room temp., diluted with Et2O (15 mL)
and washed with water (15 mL). The aqueous layer was extracted
with Et2O (2ϫ15 mL), the combined organic layers were washed
with brine (15 mL), dried with MgSO4, filtered and the solvent was
removed in vacuo. Purification of the residue by column
chromatography on silica gel (PE/AcOEt, 5:1) gave the tetracycle
44 (54.0 mg, 71.3 μmol, 94%) as a colourless oil.
Rf = 0.27 (PE/AcOEt, 3:1). [α]2D0 = –169.6 (c = 1.14 , in CHCl3).
UV (MeCN): λmax (lgε) = 227.0 (4.431), 265.0 (3.768), 275.0
(3.695), 299.0 (3.247) nm. IR (film): ν = 2930, 1732, 1603, 1573,
˜
1498, 1463, 1376, 1249, 1103, 1020, 871, 836, 775, 737, 704,
665 cm–1. 1H NMR (600 MHz, CDCl3): δ = –4.78, –4.25 (2ϫs,
2ϫ3 H, 2ϫSiCH3), 0.79 (d, J = 6.6 Hz, 3 H, 2ЈЈ-CH3), 0.81 [s,
9 H, SiC(CH3)3], 0.81 (t, J = 7.2 Hz, 3 H, 9ЈЈ-H3), 1.23 (d, J =
6.0 Hz, 3 H, 6ЈЈЈ-H3), 1.20–1.32 (m, 2 H), 1.46–1.66 (m, 4 H), 1.70–
1.77 (m, 1 H), 1.93–2.00 (m, 1 H) (4ЈЈ-H2, 5ЈЈ-H2, 6ЈЈ-H2, 8ЈЈ-H2),
1.82 (mc, 1 H, 2ЈЈ-H), 1.97 [s, 3 H, OC(O)CH3], 2.63 (dd, J = 16.2,
8.4 Hz, 1 H, 2-HA), 2.69 (dd, J = 16.2, 2.4 Hz, 1 H, 2-HB), 3.03–
3.09 (m, 1 H, 3aЈ-H), 3.16 (t, J = 9.6 Hz, 1 H, 4ЈЈЈ-H), 3.19–3.25
(m, 1 H, 3Ј-H), 3.52, 3.53, 3.54 (3ϫs, 3 ϫ3 H, 3ϫOCH3), 3.61–
3.66 (m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 3.71 (dd, J = 3.0, 1.8 Hz, 1 H, 2ЈЈЈ-
H), 4.02 (d, J = 9.0 Hz, 1 H, 9bЈ-H), 4.28 (d, J = 3.0 Hz, 1 H, 1ЈЈ-
H), 4.75 (mc, 1 H, 7ЈЈ-H), 5.01–5.10 (m, 1 H, 3ЈЈ-H), 5.48 (d, J =
1.8 Hz, 1 H, 1ЈЈЈ-H), 5.55 (s, 1 H, 1Ј-H), 5.80 (dd, J = 9.6, 3.0 Hz,
1 H, 4Ј-H), 6.24 (dd, J = 9.6, 1.8 Hz, 1 H, 5Ј-H), 6.68 (d, J =
3.0 Hz, 1 H, 6Ј-H), 6.83 (dd, J = 8.4, 3.0 Hz, 1 H, 8Ј-H), 7.00 (d, J
= 8.4 Hz, 1 H, 9Ј-H) ppm. 13C NMR (126 MHz, CDCl3): δ = –4.8,
–4.3 (2ϫSiCH3), 9.7 (C-9ЈЈ), 10.8 (C-2ЈЈ-CH3), 17.8 (C-6ЈЈЈ), 18.3
[SiC(CH3)3], 19.9 (C-5ЈЈ), 21.1 [OC(O)CH3], 25.9 [SiC(CH3)3], 27.7,
30.4, 31.1 (C-4ЈЈ, C-6ЈЈ, C-8ЈЈ), 39.9 (C-2), 43.8 (C-9bЈ, C-2ЈЈ), 47.5
(C-3Ј), 50.1 (C-3Ј), 57.8, 59.2, 60.9 (3ϫOCH3), 68.5 (C-5ЈЈЈ), 72.9
(C-1ЈЈ), 74.8 (C-3ЈЈ), 77.3 (C-2ЈЈЈ), 77.6 (C-7ЈЈ), 80.9 (C-3ЈЈЈ), 82.0
(C-4ЈЈЈ), 95.2 (C-1ЈЈЈ), 114.7 (C-6Ј), 114.9 (C-8Ј), 126.1 (C-5Ј), 128.2
(C-9Ј*), 128.7 (C-9Ј), 131.1 (C-4Ј), 133.1 (C-5Ј*), 133.4 (C-1Ј),
146.5 (C-2Ј), 155.0 (C-7Ј), 170.4, 171.5 [C-1, OC(O)CH3] ppm. MS
(DCI): m/z (%) = 774.4 (100) [M + NH4]+. HRMS (ESI) m/z: calcd.
for C42H64O10Si: 779.41610 [M + Na]+, found 779.41571 [M +
Na]+.
Analytical Data of 41: Rf = 0.29 (PE/AcOEt, 3:1). [α]2D0 = +117.3
(c = 1.0 , in CHCl3). UV (MeCN): λmax (lgε) = 219.5 (4.447), 254.5
(4.230), 299.0 (3.411) nm. IR (film): ν = 2933, 2856, 1732, 1564,
˜
1462, 1382, 1300, 1245, 1121, 1105, 1033, 1009, 980, 871, 836, 811,
1
773, 670 cm–1. H NMR (600 MHz, CDCl3): δ = 0.04, 0.09 (2ϫs,
2ϫ3 H, SiCH3), 0.83 (t, J = 7.5 Hz, 3 H, 7-CH2CH3), 0.86 [s, 9 H,
SiC(CH3)3], 0.90 (d, J = 6.8 Hz, 3 H, 12-CH3), 1.23 (d, J = 6.5 Hz,
3 H, 6ЈЈЈ-H3), 1.20–1.33 (m, 2 H), 1.46–1.54 (m, 3 H), 1.60–1.71 (m,
2 H), 1.74–1.87 (m, 2 H) (8-H2, 9-H2, 10-H2, 12-H, 7-CH2CH3),
1.99 [s, 3 H, OC(O)CH3], 2.51–2.59 (m, 1 H, 4-HA), 2.60–2.69 (m,
2 H, 3a-H, 4-HB), 2.99–3.04 (m, 1 H, 13a-H), 3.12 (mc, 1 H, 3-
H), 3.17 (t, J = 9.6 Hz, 1 H, 4ЈЈЈ-H), 3.54, 3.54, 3.54 (3ϫs, 9 H,
3ϫOCH3), 3.58 (mc, 1 H, 5ЈЈЈ-H), 3.63 (dd, J = 9.6, 3.4 Hz, 1 H,
3ЈЈЈ-H), 3.73 (dd, J = 2.8, 1.9 Hz, 1 H, 2ЈЈЈ-H), 3.97 (d, J = 2.5 Hz,
1 H, 13-H), 4.79 (dd, J = 11.2, 5.3 Hz, 1 H, 7-H), 5.02–5.09 (m,
1 H, 11-H), 5.49 (d, J = 1.9 Hz, 1 H, 1ЈЈЈ-H), 5.61 (d, J = 5.6 Hz,
1 H), 5.82 (mc, 1 H) (1-H, 2-H), 5.99 (dd, J = 15.6, 9.0 Hz, 1 H,
1Ј-H), 6.65 (d, J = 15.6 Hz, 1 H, 2Ј-H), 6.81 (dd, J = 8.7, 2.8 Hz,
1 H, 4ЈЈ-H), 7.20 (d, J = 2.8 Hz, 1 H, 6ЈЈ-H), 7.40 (d, J = 8.7 Hz,
1 H, 3ЈЈ-H) ppm. 13C NMR (126 MHz, CDCl3): δ = –3.1, –2.9
(2ϫSiCH3), 9.2 (C-12-CH3), 10.0 (C-7-CH2CH3), 17.9 (C-6ЈЈЈ),
18.6 (C-9), 18.7 [SiC(CH3)3], 21.1 [OC(O)CH3], 26.2 [SiC(CH3)3],
28.6, 31.1, 32.0 (C-8, C-10, C-7-CH2CH3), 34.5 (C-4), 43.3 (C-12),
44.7 (C-3a), 52.9 (C-13a), 55.1 (C-3), 58.0, 59.4, 61.1 (3ϫOCH3),
68.4 (C-13), 68.8 (C-5ЈЈЈ), 74.7 (C-7), 77.2 (C-2ЈЈЈ), 77.6 (C-11),
80.9 (C-3ЈЈЈ), 82.0 (C-4ЈЈЈ), 95.3 (C-1ЈЈ), 114.8 (C-6ЈЈ), 115.7 (C-
Compound 40: A solution of vinylic iodide 4 (190 mg, 370 μmol,
1.0 equiv.) and cyclopentene derivative 36 (502 mg, 1.10 mmol,
3.0 equiv.) in abs. DMF (10 mL) was degassed and Pd(OAc)2
(2.49 mg, 11.1 μmol, 3.0 mol-%), NaOAc (91.1 mg, 1.10 mmol,
3.0 equiv.) and TBACl (103 mg, 370 μmol, 1.0 equiv.) were added
at room temp., the reaction mixture was cooled to 0 °C and stirred
under the exclusion of light at 0 °C for 8 d. Then the mixture was
diluted with Et2O (90 mL) and washed with water (50 mL). The
layers were separated and the aqueous layer was extracted with
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20600
/KAP1
Date: 04-09-12 15:44:57
Pages: 10
Synthesis of Spinosyn Analogues for Modern Crop Protection
2ЈЈ), 116.7 (C-4ЈЈ), 129.2 (C-2Ј), 132.6, 134.3 (C-1, C-2), 133.6 (C- H2, 8ЈЈ-H2, OH), 2.02 [s, 3 H, OC(O)CH3], 2.05–2.12 (m, 1 H, 2ЈЈ-
3ЈЈ), 136.1 (C-1Ј), 137.9 (C-1ЈЈ), 155.7 (C-5ЈЈ), 170.6, 173.6 [C-5,
OC(O)CH3] ppm. MS (DCI): m/z (%) = 854.4 (5) [M + NH4]+.
HRMS (ESI) m/z: calcd. for C42H65BrO10Si: 854.38686 [M +
NH4]+, found 854.38693 [M + NH4]+.
H), 2.59 (dd, J = 15.0, 5.4 Hz, 1 H, 2-HA), 2.81 (dd, J = 15.0,
4.0 Hz, 1 H, 2-HB), 3.11–3.19 (m, 2 H, 3Ј-H, 4ЈЈЈ-H), 3.39–3.46 (m,
1 H, 3aЈ-H), 3.51, 3.53, 3.54 (3ϫs, 9 H, 3 ϫOCH3), 3.59–3.67 (m,
2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 3.70 (m, 1 H, 2ЈЈЈ-H), 4.15 (d, J = 9.6 Hz, 1 H,
9bЈ-H), 4.25 (s, 1 H, 1ЈЈ-H), 4.72 (mc, 1 H, 7ЈЈ-H), 4.94 (mc, 1 H,
3ЈЈ-H), 5.47 (s, 1 H, 1ЈЈЈ-H), 5.69 (s, 1 H, 1Ј-H), 5.83 (dd, J = 9.6,
3.6 Hz, 1 H, 4Ј-H), 6.23 (d, J = 9.6 Hz, 1 H, 5Ј-H), 6.69 (d, J =
2.4 Hz, 1 H, 6Ј-H), 6.83 (dd, J = 8.4, 2.4 Hz, 1 H, 8Ј-H), 7.00 (d, J
= 8.4 Hz, 1 H, 9Ј-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 9.6
(C-9ЈЈ), 10.5 (C-2ЈЈ-CH3), 17.8 (C-6ЈЈЈ), 20.0 (C-5ЈЈ), 21.1 [OC(O)-
CH3], 27.9, 30.3, 31.8 (C-4ЈЈ, C-6ЈЈ, C-8ЈЈ), 37.5 (C-2), 38.2 (C-2ЈЈ),
43.9 (C-3aЈ), 44.2 (C-9bЈ), 51.5 (C-3Ј), 57.9, 59.2, 60.9 (3ϫOCH3),
68.5 (C-5ЈЈЈ), 69.1 (C-1ЈЈ), 75.9 (C-3ЈЈ), 77.3 (C-2ЈЈЈ), 77.5 (C-7ЈЈ),
80.8 (C-3ЈЈЈ), 82.0 (C-4ЈЈЈ), 95.2 (C-1ЈЈЈ), 114.7 (C-6Ј), 115.1 (C-8Ј),
125.6 (C-5Ј), 128.4 (C-9aЈ*), 128.6 (C-9Ј), 131.0 (C-4Ј), 132.1 (C-
1Ј), 133.0 (C-5aЈ*), 145.5 (C-2Ј), 155.1 (C-7Ј), 170.8, 172.2 [C-1,
OC(O)CH3] ppm. MS (DCI): m/z (%) = 660.4 (8) [M + NH4]+,
642.4 (100) [M]+. HRMS (ESI) m/z: calcd. for C36H50O10:
665.32962 [M + Na]+, found 665.32967 [M + NH4]+.
Compound 45: A solution of 40 (163 mg, 195 μmol, 1.0 equiv.) and
nBu4NOAc (118 mg, 390 μmol, 2.0 equiv.) in DMF/CH3CN/H2O
(12 mL, 5:5:1) was degassed and Pd-catalyst 43 (12.8 mg,
13.6 μmol, 7.0 mol-%) was added at room temp. The mixture was
stirred for 5 min at room temp. and warmed to 125 °C for 1.3 h.
Then, the mixture was cooled to room temp., diluted with Et2O
(35 mL) and washed with water (35 mL). The aqueous layer was
extracted with Et2O (2ϫ35 mL), the combined organic layers were
washed with brine (30 mL), dried with MgSO4, filtered and the
solvent was removed in vacuo. Purification of the residue by col-
umn chromatography on silica gel (PE/AcOEt, 3:1Ǟ2.5:1) gave
tetracycle 45 (133 mg, 176 μmol, 90%) as a colourless oil.
Rf = 0.25 (PE/AcOEt, 3:1). [α]2D0 = +11.3 (c = 1.0 , in CHCl3). UV
(MeCN): λmax (lgε) = 222.0 (4.480), 265.0 (3.815), 299.0 (3.278),
274.5 (3.741), 309.0 (3.193) nm. IR (film): ν = 2933, 1728, 1603,
˜
Spinosyn Analogue 3a: To a solution of acetate 46 (45.9 mg,
71.4 μmol, 1.0 equiv.) in abs. MeOH (4.5 mL) was added at 0 °C
K2CO3 (9.87 mg, 71.4 μmol, 1.0 equiv.), and the mixture was
stirred for 2.5 h at 0 °C and 4.0 h at room temp. The reaction was
quenched with sat. NH4Cl-sol. (5 mL) and H2O (20 mL) and the
mixture extracted with CH2Cl2 (3ϫ25 mL). The combined organic
layers were dried with MgSO4, filtered and the solvent was removed
in vacuo. Purification of the residue by column chromatography on
silica gel (PE/AcOEt, 1:1) yielded diol 3a (28.4 mg, 44.3 μmol, 66%
1498, 1463, 1369, 1250, 1104, 1048, 1017, 961, 874, 837, 775 cm–1.
1H NMR (600 MHz, CDCl3): δ = –0.13, 0.00 (2ϫsbr, 2ϫ3 H,
2ϫSiCH3), 0.67–0.94 [m, 15 H, SiC(CH3)3, 9ЈЈ-H3, 2ЈЈ-CH3], 1.23
(d, J = 6.4 Hz, 3 H, 6ЈЈЈ-H3), 1.02–1.15 (m, 1 H), 1.16–1.32 (m,
1 H), 1.47–1.86 (m, 7 H) (2ЈЈ-H, 4ЈЈ-H2, 5ЈЈ-H2, 6ЈЈ-H2, 8ЈЈ-H2),
1.98 [s, 3 H, OC(O)CH3], 2.57 (sbr, 1 H), 2.72–3.02 (m, 3 H, 2-H2,
3Ј-H, 3aЈ-H), 3.16 (t, J = 9.4 Hz, 1 H, 4ЈЈЈ-H), 3.52, 3.54, 3.54
(3ϫs, 3 ϫ3 H, 3ϫOCH3), 3.61–3.67 (m, 1 H, 5ЈЈЈ-H), 3.64 (dd, J
= 9.2, 3.1 Hz, 1 H, 3ЈЈЈ-H), 3.71 (dd, J = 3.3, 2.1 Hz, 1 H, 2ЈЈЈ-H),
4.07 (sbr, 1 H, 9bЈ-H), 4.22 (sbr, 1 H, 1ЈЈ-H), 4.92 (sbr, 1 H), 5.01 (sbr,
1 H) (3ЈЈ-H, 7ЈЈ-H), 5.49 (d, J = 1.4 Hz, 1 H, 1ЈЈЈ-H), 5.72 (sbr, 1 H,
1Ј-H), 5.90 (sbr, 1 H, 4Ј-H), 6.26 (d, J = 9.4 Hz, 1 H, 5Ј-H), 6.71
(d, J = 2.6 Hz, 1 H, 6Ј-H), 6.81 (dd, J = 8.5, 3.0 Hz, 1 H, 8Ј-H),
7.01 (d, J = 8.5 Hz, 1 H, 9Ј-H) ppm. 13C NMR (126 MHz, CDCl3):
δ = –5.1, –4.4 (2ϫSiCH3), 9.1 (C-2ЈЈ-CH3), 10.0 (C-9ЈЈ), 17.8 (C-
6ЈЈЈ), 18.2 [SiC(CH3)3], 18.8 (C-5ЈЈ), 21.2 [OC(O)CH3], 25.8
[SiC(CH3)3], 28.2, 29.7, 31.1, 31.4 (C-2ЈЈ, C-4ЈЈ, C-6ЈЈ, C-8ЈЈ), 37.3,
37.9, 43.8, 50.4 (C-2, C-3Ј, C-3aЈ, C-9bЈ), 57.9, 59.2, 60.9
(3ϫOCH3), 68.5 (C-5ЈЈЈ), 73.4, 73.6 (C-1ЈЈ, C-3ЈЈ), 77.4 (C-2ЈЈЈ),
77.5 (C-7ЈЈ), 80.9 (C-3ЈЈЈ), 82.1 (C-4ЈЈЈ), 95.2 (C-1ЈЈЈ), 114.4 (C-6Ј),
115.5 (C-8Ј), 126.2, 129.7, 131.4 (C-1Ј, C-4Ј, C-5Ј), 128.5 (C-9Ј),
129.0, 132.9 (C-2Ј, C-5aЈ, C-9aЈ), 154.8 (C-7Ј), 170.6, 173.4 [C-1,
OC(O)CH3] ppm. MS (DCI): m/z (%) = 774.4 (100) [M + NH4]+.
HRMS (ESI) m/z: calcd. for C42H64O10Si: 774.46070 [M + NH4]+,
found 774.46058 [M + NH4]+.
1
yield, 86% brsm) as a white solid. Rf = 0.16 (PE/AcOEt, 1:1); H
NMR (600 MHz, CDCl3): δ = 0.83–0.90 (m, 6 H, 9ЈЈ-H3, C-2ЈЈ-
H3), 1.23 (d, J = 6.3 Hz, 3 H, 6ЈЈЈ-H3), 1.20–1.38 (m, 1 H), 1.45–
1.54 (m, 1 H), 1.55–1.74 (m, 5 H), 1.86 (mc, 2 H), (2ЈЈ-H, 4ЈЈ-H2,
5ЈЈ-H2, 6ЈЈ-H2, 8ЈЈ-H2), 1.98 (sbr, 1 H, 1ЈЈ-OH), 2.36 (sbr, 1 H, 3ЈЈ-
OH), 2.48 (dd, J = 17.0, 9.3 Hz, 1 H, 2-HA), 2.73 (dd, J = 17.0,
3.0 Hz, 1 H, 2-HB), 3.02–3.08 (m, 1 H, 3Ј-H), 3.12–3.17 (m, 1 H,
3aЈ-H), 3.16 (t, J = 9.6 Hz, 1 H, 4ЈЈЈ-H), 3.51, 3.53, 3.54 (3ϫs, 9 H,
3ϫOCH3), 3.60–3.66 (m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 3.69–3.72 (m, 1 H,
2ЈЈЈ-H), 3.90 (mc, 1 H, 3ЈЈ-H), 4.12 (d, J = 9.6 Hz, 1 H, 9bЈ-H),
4.28 (mc, 1 H, 7ЈЈ-H), 4.37 (sbr, 1 H, 1ЈЈ-H), 5.47 (d, J = 1.5 Hz,
1 H, 1ЈЈЈ-H), 5.79 (sbr, 1 H, 1Ј-H), 5.83 (dd, J = 10.0, 4.1 Hz, 1 H,
4Ј-H), 6.24 (d, J = 10.0 Hz, 1 H, 5Ј-H), 6.69 (d, J = 2.6 Hz, 1 H,
6Ј-H), 6.84 (dd, J = 8.1, 2.6 Hz, 1 H, 8Ј-H), 7.03 (d, J = 8.6 Hz,
1 H, 9Ј-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 4.8, 10.4 (C-
9ЈЈ, C-2ЈЈ-CH3), 17.8 (C-6ЈЈЈ), 20.0, 27.0, 28.8, 32.1 (C-4ЈЈ, C-5ЈЈ,
C-6ЈЈ, C-8ЈЈ), 36.5 (C-2ЈЈ), 38.4 (C-2ЈЈ), 43.8 (C-9bЈ), 44.9 (C-3aЈ),
51.1 (C-3Ј), 57.9, 59.2, 60.9 (3ϫOCH3), 68.5 (C-5ЈЈЈ), 74.6 (C-1ЈЈ),
74.8 (C-3ЈЈ), 77.3 (C-2ЈЈЈ), 80.9 (C-3ЈЈЈ), 81.0 (C-7ЈЈ), 82.0 (C-4ЈЈЈ),
95.2 (C-1ЈЈЈ), 114.7 (C-6Ј), 115.3 (C-8Ј), 125.9 (C-5Ј), 128.6, 128.6
(C-9Ј, C-9aЈ*), 130.3, 130.4 (C-1Ј, C-4Ј), 132.9 (C-5aЈ*), 147.2 (C-
2Ј), 155.1 (C-7Ј), 171.9 (C-1) ppm. MS (DCI): m/z (%) = 618.4
(100) [M + NH4]+. HRMS (ESI) m/z: calcd. for C34H48O9
623.31905 [M + Na]+, found 623.31924 [M + Na]+.
Compound 46: To a solution of TBS-protected alcohol 44 (42.0 mg,
55.5 μmol, 1.0 equiv.) in abs. pyridine (2.0 mL) was added at 0 °C
HF·pyridine (0.65 mL). The reaction mixture was warmed to 60 °C
and stirred for 16 h. Afterwards, the reaction was cooled to room
temp., washed with 2 m HCl solution. (2ϫ10 mL), sat. NaHCO3
solution. (10 mL) and brine (10 mL). The organic layer was dried
with MgSO4, filtered and the solvent was removed in vacuo. Purifi-
cation of the residue by column chromatography on silica gel (PE/
AcOEt, 1:1) yielded alcohol 46 (28.5 mg, 44.3 μmol, 80%) as a
white solid.
Compound 47: To a solution of TBS-protected alcohol 45 (126 mg,
166 μmol, 1.0 equiv.) in abs. pyridine (5.9 mL) was added at 0 °C
HF·pyridine (1.96 mL). The reaction mixture was warmed to 60 °C
and stirred for 15.5 h. Afterwards it was cooled to room temp.,
washed with 2 m HCl solution. (2ϫ25 mL), sat. NaHCO3 solution.
Rf = 0.30 (PE/AcOEt, 1:1). [α]2D0 = –158.7 (c = 0.75 , in CHCl3).
UV (MeCN): λmax(lgε) = 226.0 (4.432), 257.0 (3.714), 265.0 (3.789),
274.5 (3.686), 298.5 (3.259) nm. IR (film): ν = 2929, 1730, 1602, (25 mL) and brine (25 mL). The organic layer was dried with
˜
1499, 1463, 1375, 1249, 1103, 1016, 874 cm–1. 1H NMR (600 MHz,
CDCl3): δ = 0.85 (t, J = 7.2 Hz, 3 H, 9ЈЈ-H3), 0.90 (d, J = 6.6 Hz,
MgSO4, filtered and the solvent was removed in vacuo. Purification
of the residue by column chromatography on silica gel (PE/AcOEt,
3 H, 2ЈЈ-CH3), 1.23 (d, J = 6.0 Hz, 3 H, 6ЈЈЈ-H3), 1.15–1.41 (m, 1:1Ǟ2:3) yielded alcohol 47 (103 mg, 160 μmol, 96%) as a light
2 H), 1.47–1.72 (m, 6 H), 1.77–1.86 (m, 1 H), (4ЈЈ-H2, 5ЈЈ-H2, 6ЈЈ-
brown solid. Rf = 0.37 (PE/AcOEt, 1:1). [α]2D0 = +56.8 (c = 0.5 , in
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FULL PAPER
CHCl3). UV (MeCN): λmax (lgε) = 222.5 (4.428), 225.5 (4.428),
256.5 (3.739), 264.5 (3.806), 274.5 (3.705), 299.5 (3.282) nm. IR
calcd. for C34H48O9 623.31905 [M + Na]+, found 623.31926
[M + Na]+.
(film): ν = 2928, 1725, 1603, 1499, 1463, 1370, 1248, 1138, 1102,
˜
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures for all new compounds as well as copies
of the 1H and 13C NMR spectra of the key intermediates and final
products as well as the X-ray crystal structure.
1
1047, 1015, 874, 801, 663 cm–1. H NMR (600 MHz, CDCl3): δ =
0.66 (d, J = 6.8 Hz, 3 H, 2ЈЈ-CH3), 0.85 (t, J = 7.5 Hz, 3 H, 9ЈЈ-
H3), 1.24 (d, J = 6.2 Hz, 3 H, 6ЈЈЈ-H3), 1.16–1.29 (m, 1 H), 1.34–
1.43 (m, 1 H), 1.44–1.60 (m, 4 H), 1.78–1.90 (m, 4 H) (2ЈЈ-H, 4ЈЈ-
H2, 5ЈЈ-H2, 6ЈЈ-H2, 8ЈЈ-H2, OH), 1.99 [s, 3 H, OC(O)CH3], 2.49 (dd,
J = 14.1, 9.0 Hz, 1 H, 2-HA), 2.67 (d, J = 14.1 Hz, 1 H, 2-HB),
2.88–2.96 (m, 2 H, 3Ј-H, 3aЈ-H), 3.16 (t, J = 9.3 Hz, 1 H, 4ЈЈЈ-H),
3.52, 3.53, 3.54 (3ϫs, 9 H, 3 ϫOCH3), 3.60–3.67 (m, 2 H, 3ЈЈЈ-H,
5ЈЈЈ-H), 3.71 (sbr, 1 H, 2ЈЈЈ-H), 4.02 (d, J = 9.5 Hz, 1 H, 9bЈ-H),
4.43 (sbr, 1 H, 1ЈЈ-H), 4.87–5.00 (m, 2 H, 3ЈЈ-H, 7ЈЈ-H), 5.48 (sbr,
1 H, 1ЈЈЈ-H), 5.76 (sbr, 1 H, 1Ј-H), 5.88 (dd, J = 9.8, 3.7 Hz, 1 H,
4Ј-H), 6.29 (d, J = 9.8 Hz, 1 H, 5Ј-H), 6.72 (d, J = 2.5 Hz, 1 H, 6Ј-
H), 6.82 (dd, J = 8.2, 2.5 Hz, 1 H, 8Ј-H), 7.02 (d, J = 8.2 Hz, 1 H,
9Ј-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 7.9 (C-2ЈЈ-CH3), 9.9
(C-9ЈЈ), 17.8 (C-6ЈЈЈ), 18.4 (C-5ЈЈ), 21.1 [OC(O)CH3], 28.2, 31.3,
32.8 (C-4ЈЈ, C-6ЈЈ, C-8ЈЈ), 36.5 (C-2ЈЈ), 39.5 (C-2), 43.7 (C-9bЈ),
47.2, 50.7 (C-3Ј, C-3aЈ), 57.9, 59.2, 60.9 (3ϫOCH3), 68.5 (C-5ЈЈЈ),
70.6 (C-1ЈЈ), 75.5 (C-7ЈЈ), 77.2, 77.3 (C-3ЈЈ, C-2ЈЈЈ), 80.9 (C-3ЈЈЈ),
82.0 (C-4ЈЈЈ), 95.2 (C-1ЈЈЈ), 114.4 (C-6Ј), 115.5 (C-8Ј), 126.5 (C-5Ј),
128.5 (C-9Ј), 128.6 (C-9aЈ*), 129.1 (C-1Ј), 129.8 (C-4Ј), 132.9 (C-
5aЈ*), 148.0 (C-2Ј), 155.1 (C-7Ј), 171.0, 174.1 [C-1, OC(O)-
CH3] ppm. MS (DCI): m/z (%) = 660.5 (100) [M + NH4]+. HRMS
(ESI) m/z: calcd. for C36H50O10 665.32962 [M + Na]+, found
665.32954 [M + Na]+.
Acknowledgments
N. S. thanks the Konrad-Adenauer-Foundation for a doctoral fel-
lowship and M. M. B. the Humboldt-Foundation for a postdoc-
toral fellowship. Generous support by the Deutsche Forschungsge-
meinschaft (DFG) and the Fonds der Chemischen Industrie is
gratefully acknowledged. M. G. and D. S. thank the DNRF-funded
Center for Materials Crystallography (CMC) for funding.
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Spinosyn Analogue 3b: To a solution of acetate 47 (71.3 mg,
110 μmol, 1.0 equiv.) in abs. MeOH (7.0 mL) was added at 0 °C
K2CO3 (15.3 mg, 110 μmol, 1.0 equiv.), and the mixture was stirred
for 80 min at 0 °C and 4.0 h at room temp. The reaction was
quenched with sat. NH4Cl-sol. (5 mL) and H2O (15 mL) and the
mixture extracted with CH2Cl2 (3ϫ15 mL). The combined organic
layers were dried with MgSO4, filtered and the solvent was removed
in vacuo. Purification of the residue by column chromatography on
silica gel (PE/AcOEt, 1:1) yielded diol 3a (53.5 mg, 89.1 μmol, 81%
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V. L. Salgado, J. J. Sheets, G. B. Watson, A. L. Schmidt, Pestic.
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yield, 90% brsm) as a white solid. Rf = 0.12 (PE/AcOEt, 1:1). [α]
20
= +51.7 (c = 0.6, in CHCl3). UV (MeCN): λmax (lgε) = 222.0
D
(4.450), 257.0 (3.726), 264.5 (3.801), 274.5 (3.727), 299.5 (3.264),
309.0 (3.184) nm. IR (film): ν = 3474, 2934, 1721, 1603, 1498, 1462,
˜
1
1365, 1252, 1101, 1048, 1015, 875, 800 cm–1. H NMR (600 MHz,
CDCl3): δ = 0.60 (d, J = 7.1 Hz, 3 H, 2ЈЈ-CH3), 0.84 (t, J = 7.3 Hz,
3 H, 9ЈЈ-H3), 1.24 (d, J = 6.4 Hz, 3 H, 6ЈЈЈ-H3), 1.06–1.14 (m, 1 H),
1.38–1.74 (m, 7 H), 1.75–1.84 (m, 1 H) (2ЈЈ-H, 4ЈЈ-H2, 5ЈЈ-H2, 6ЈЈ-
H2, 8ЈЈ-H2), 1.89–2.04 (m, 1 H, OH), 2.21–2.32 (m, 1 H, OH), 2.46
(dd, J = 14.2, 9.3 Hz, 1 H, 2-HA), 2.59 (d, J = 14.2 Hz, 1 H, 2-HB),
2.76–2.82 (m, 1 H, 3aЈ-H), 2.82–2.87 (m, 1 H, 3Ј-H), 3.17 (t, J =
9.5 Hz, 1 H, 4ЈЈЈ-H), 3.52, 3.54, 3.54 (3ϫs, 9 H, 3 ϫOCH3), 3.62–
3.68 (m, 2 H, 3ЈЈЈ-H, 5ЈЈЈ-H), 3.70–3.73 (m, 1 H, 2ЈЈЈ-H), 3.94–4.00
(m, 2 H, 9bЈ-H, 3ЈЈ-H), 4.56 (sbr, 1 H, 1ЈЈ-H), 4.90 (mc, 1 H, 7ЈЈ-H),
5.49 (d, J = 1.7 Hz, 1 H, 1ЈЈЈ-H), 5.99 (sbr, 1 H, 1Ј-H), 6.03 (dd, J
= 9.8, 4.9 Hz, 1 H, 4Ј-H), 6.35 (d, J = 9.8 Hz, 1 H, 5Ј-H), 6.75 (d,
J = 2.4 Hz, 1 H, 6Ј-H), 6.81 (dd, J = 8.3, 2.4 Hz, 1 H, 8Ј-H), 7.02
(d, J = 8.3 Hz, 1 H, 9Ј-H) ppm. 13C NMR (126 MHz, CDCl3): δ =
4.5 (C-2ЈЈ-CH3), 9.9 (C-9ЈЈ), 17.8 (C-6ЈЈЈ), 19.4 (C-5ЈЈ), 28.3, 31.9,
33.5 (C-4ЈЈ, C-6ЈЈ, C-8ЈЈ), 35.6 (C-2ЈЈ), 37.9 (C-2), 43.0 (C-9bЈ), 47.3
(C-3aЈ), 50.4 (C-3Ј), 57.8, 59.1, 60.9 (3ϫOCH3), 68.5 (C-5ЈЈЈ), 74.1
(C-3ЈЈ), 74.6 (C-1ЈЈ), 77.3 (C-2ЈЈЈ), 78.0 (C-7ЈЈ), 80.8 (C-3ЈЈЈ), 82.0
(C-4ЈЈЈ), 95.2 (C-1ЈЈЈ), 114.3 (C-6Ј), 115.7 (C-8Ј), 127.4 (C-5Ј), 127.5
(C-1Ј), 128.2 (C-9Ј), 128.6 (C-4Ј), 129.0 (C-9aЈ*), 133.1 (C-5aЈ*),
148.4 (C-2Ј), 154.9 (C-7Ј), 174.2 (C-1) ppm. MS (DCI): m/z (%) =
618.6 (100) [M + NH4]+, 600.6 (2) [M + H]+. HRMS (ESI) m/z:
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8
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Synthesis of Spinosyn Analogues for Modern Crop Protection
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Received: May 7, 2012
Published Online: ᭿
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L. F. Tietze et al.
FULL PAPER
Total Synthesis
The natural spinosyns A and D are highly
potent insecticides, but there is a great de-
mand for analogues to overcome resistance.
L. F. Tietze,* N. Schützenmeister,
A. Grube, T. Scheffer, M. M. Baag,
M. Granitzka, D. Stalke ................. 1–10
Synthesis of Spinosyn Analogues for
Modern Crop Protection
Keywords: Total synthesis / Natural prod-
ucts / Macrolactones / Heck reaction /
Cyclization / Spinosyns / Insecticides /
Crop protection
10
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