Synthesis of novel spinosyn a analogues by Pd-mediated transformations

Article abstract of DOI:10.1002/chem.200700464

The concept of modern crop protection demands for a continuous supply of new or modified established pesticides to avoid the development of serious resistances. Recent reports on the insecticidal spinosyns 1 and 2 show that also this class of pest managing agents is increasingly exposed to the formation of resistances. The synthesis of new derivatives is therefore highly desirable. We describe in this paper a convergent approach towards novel enantiopure spinosyn A analogues of type 3, which is based on investigations of structure-activity relationships and employs a twofold Heck reaction as key step for the preparation of the tricyclic backbone assembly.

Full text of DOI:10.1002/chem.200700464

FULL PAPER
DOI: 10.1002/chem.200700464
Synthesis of Novel Spinosyn A Analogues by Pd-Mediated Transformations
Lutz F. Tietze,* Gordon Brasche, Alexander Grube, Niels Bçhnke, and
Christian Stadler[a]
Dedicated to Professor Herbert Mayr on the occasion of his 60th birthday
Abstract: The concept of modern crop
protection demands for a continuous
supply of new or modified established
pesticides to avoid the development of
serious resistances. Recent reports on
the insecticidal spinosyns 1 and 2 show
that also this class of pest managing
agents is increasingly exposed to the
formation of resistances. The synthesis
of new derivatives is therefore highly
desirable. We describe in this paper a
convergent approach towards novel
enantiopure spinosyn Aanalogues of
type 3, which is based on investigations
of structure–activity relationships and
employs a twofold Heck reaction as
key step for the preparation of the tri-
cyclic backbone assembly.
Keywords: insecticides
·
natural
products · palladium · spinosyns ·
total synthesis
Introduction
The spinosyns represent a group of over 20 chemically relat-
ed metabolites which were extracted from fermentation
broths of the soil organism Saccharopolyspora spinosa.[1,2]
The two mainly produced compounds spinosyn A( 1) and D
(2) are almost identical in structure except for an additional
methyl group at the macrocyclic core of spinosyn D
(Figure 1). The natural products show strong insecticidal ac-
tivity and are marketed under the name Spinosad for the
protection of several important crops;[3] commercial fermen-
tation-derived formulations contain a spinosyn Ato spino-
syn D ratio of approximately 85:15. Both, the structure and
the mode of action of these novel insecticides are unique so
far. Spinosad kills susceptible species relatively fast by caus-
ing rapid excitation of the insect nervous system probably
effected through the interaction of the drug with the g-
amino butyric acid (GABA) receptor and the nicotinacetyl-
choline (NACh) receptor.[2a,4] In addition, the agent acts
Figure 1. Naturally occurring spinosyns and novel spinosyn analogue 3.
highly selectively and as such it has only little to no effect
on a broad range of non-target insects as well as mammals.[5]
These features coupled with an excellent environmental pro-
file have made spinosyn-based insecticides a worldwide de-
manded tool for the management of insect pests in agricul-
ture. However, since first signs of resistance in Thailand and
Hawaii have occurred,[6] new analogues of the compound
have to be developed for a conscientious resistance manage-
ment. The so far known total syntheses of spinosyns[7] are
rather complex and would not allow to access completely
new derivatives. Herein, we report on a convergent strategy
for the synthesis of new structurally simplified spinosyn A
analogues such as 3 in which the aliphatic five-membered
ring Ahas been replaced by a benzene moiety. Compound 3
holds many options for further manipulations and utilizes an
elegant twofold Heck reaction as key step for the B–C ring
assembly. Moreover, it was also our intention to prepare
diastereomers of 3 by changing the relative configuration at
the annulated tricycle in relation to the stereogenic center at
the macrocycle since so far structure–activity relationship in-
[a] Prof. Dr. L. F. Tietze, Dr. G. Brasche, Dipl.-Chem. A. Grube,
Dipl.-Chem. N. Bçhnke, Dr. C. Stadler
Institut für Organische und Biomolekulare Chemie
der Georg-August-Universität Gçttingen
Tammannstraße 2, 37077 Gçttingen (Germany)
Fax : (+49)-551-399476
E-mail: ltietze@gwdg.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author: The experimen-
tal procedures for the synthesis of compounds 65 and 70 starting from
44.
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8543

vestigation addressing this point have not been performed.
Apart of this work has already been published as a commu-
nication.[8]
The decision to replace the cyclopentane moiety in 1 and
2 by a benzene ring was made in consideration of investiga-
tions on structure–activity relationships.[2] It has been shown
that the incorporation of an additional double bond between
C-7 and C-8 in the Aring of spinosyn D ( 2) does not affect
the biological activity; in case of the 7,11-dehydro derivative
the insecticidal property was even slightly improved. Not
Our approach towards 3 started with the preparation of
the aromatic fragment 7. It was envisaged to synthesize sev-
eral suitable compounds differing in the residue “PG” at-
tached to the phenol moiety, since we expected that this
might have some influence on the course of the Heck reac-
tions.
We started from commercially available 3-methoxybenzal-
dehyde (9) (Scheme 2). Bromination of 9 with equimolar
amounts of bromine in CH2Cl2 at RT gave 10 in 83% yield
regioselectively. The iodovinyl side chain was introduced
through a Wittig reaction of 10 with the triphenylphosphoni-
um salt 13.[11] The desired cis-alkene 11 was isolated in 73%
yield. The subsequent treatment of 11 with BBr3 to cleave
the methoxy ether and Ac2O in pyridine in the presence of
DMAP to protect the phenol function led to the acetoxy de-
rivative 12 in nearly quantitative yield.
ꢀ
tolerated was a further C C double bond between C-4 and
C-12. This led to an inactive indenyl system (aromatic ring
B). In view of these results we assume that the cis fusion of
rings B and C is a crucial structural element which should
not be modified, whereas the idea of a planar linkage be-
tween Aand B ring would be an excellent starting point for
the synthesis of novel and active spinosyn analogues.
Results and Discussion
According to the retrosynthesis depicted in Scheme 1, we
first focussed on the assembly of the tricyclic intermediate 4.
The straightforward synthesis of such cis-annulated ring sys-
tems can easily be achieved by a twofold Heck reaction
strategy, which was developed in our group within the total
synthesis of estradiol and recently also used for the prepara-
tion of the contraceptive desogestrel.[9] In the present case
we decided to employ the bromobenzene 7 bearing an iodo-
vinyl side chain and the cis-1,2-disubstituted cyclopentene 8
as starting materials. The cis orientation of the two substitu-
ents in 8 is of particular importance, since with a trans-deriv-
ative the second Heck reaction cannot take place due to a
missing hydrogen atom in syn position for the terminating
elimination of a “H-Pd-X” species.[10] The setup of the mac-
rocyclic portion in 3 was divided into three main stages; first
addition of C-3 fragment 5 to the aldehyde moiety of 4 by
an Evans aldol reaction, then Grignard coupling of the elon-
gated intermediate with the C-6 building block 6, and finally
a macrolactonization.
Scheme 2. Synthesis of the aromatic building blocks 11 and 12:
a) 1.0 equiv Br2, CH2Cl2, RT, 16 h, 83%; b) 1.25 equiv [Ph3PCH2I]+Iꢀ
(13), 1.25 equiv KHMDS in toluene, THF, RT, 20 min, addition of 10 in
THF at ꢀ788C, 45 min, RT, 45 min, 73%; c) 1.5 equiv BBr3, CH2Cl2, 08C,
4 h, quant.; d) 5 mol% DMAP, pyridine/Ac2O 2:1, RT, 75 min, 99%.
In contrast to the bromination of 9 reaction of 14 with
bromine led to a mixture of the desired 2-bromo compound
15 and the regioisomer bearing the bromo atom in 4-posi-
tion in a 3:1 ratio. However, recrystallization allowed to get
pure 15 in 50% yield (Scheme 3). Using TMSOTf in di-
chloromethane 15 could be coupled in a high yield of 70%
with O-trimethyl rhamnopyranosyl trichloroacetimidate (17)
to give the sugar-protected phenol 18. The acetimidate 17
was obtained from trichloroacetonitrile and O-trimethyl
rhamnose (16).[12] Subsequent
Wittig olefination of 18 fur-
nished the aromatic building
block 19 in 61% yield.
The necessary cyclopentene
8 was prepared by two differ-
ent methods. Afirst approach
to racemic 8 resorted to the lit-
erature known bicycle 20,
which is easily accessible in
large quantities (Scheme 4).[13]
Treatment of 20 with Zn
powder in conc. HOAc fur-
nished the dechlorinated com-
pound 21, which was then
transformed into the lactone
Scheme 1. Retrosynthesis of the spinosyn Aanalogue 3.
23 via a domino reduction/
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Novel Spinosyn AAnalogues
FULL PAPER
Scheme 3. Synthesis of the aromatic building block 19: a) 1.0 equiv Br2, CH2Cl2, 08C to RT, 17 h, 50%; b) 20 equiv CCl3CN, 1.5 equiv DBU, CH2Cl2, 08C,
10 min, then RT, 15 min, 91%; c) 1.5 equiv 15, 10 mol% TMSOTf, MS 4 Š, CH2Cl2, 08C, 75 min, 70%, d) 1.5 equiv [Ph3PCH2I]+Iꢀ (13), 1.75 equiv
KHMDS in toluene, THF, RT, 20 min, addition of 18 in THF at ꢀ788C, 60 min, RT, 45 min, 61%.
Scheme 4. Synthesis of rac-23: a) 4.0 equiv Zn powder, conc. HOAc, 08C
to RT, 1 h, 81%; b) 3.0 equiv NaBH4, MeOH, 08C, 45 min, 78%.
Scheme 5. Synthesis of (+)-23 and (ꢀ)-23.
retro-aldol addition/reduction/lactonization sequence[14]
using NaBH4 in MeOH. The intermediate aldehyde 22 can
be isolated but is highly sensitive and easily isomerizes
under basic conditions to give the useless 1,2-trans-disubsti-
tuted cyclopentene derivative.
An alternative second route allowed the enantioselective
synthesis of both enantiomers of the lactone 23 starting
from meso compounds 24 and 25, respectively (Scheme 5).
Thus, enzymatic acetylation of diol 25 with pancreatin and
vinyl acetate afforded (ꢀ)-26[15] in 72% yield and 99% ee,
and enzymatic deacetylation of 24 with novozym 435 gave
(+)-26[16] in 96% yield with an identical ee of 99%. These
compounds can be transformed in four steps into both enan-
tiopure lactones.[17,18] However,
MeOH. In case of the tBu ester derivative sodium salt 27
was suspended in a CH2Cl2/tBuOH 1:1 mixture and NH4Cl
as well as freshly distilled isourea 28[19] were added to fur-
nish 29 in 77% yield over two steps. In the following the pri-
mary hydroxy functionality was protected as TBS ether to
give 30 in 93% yield.
Methyl ester 33 was also prepared from sodium salt 27.
However, the primary hydroxy functionality had to be pro-
tected first since the corresponding hydroxy methyl ester re-
cyclizes to lactone 23 under acidic or basic conditions. Treat-
ment of 27 with 3.5 equiv TBSCl and imidazole in DMF
gave the bissilylated compound 31, which could be easily
as a drawback this route does
not allow to prepare 23 easily
in very large quantities.
Attempts to use lactone 23
in the Heck coupling with the
aromatic building blocks 11,
12, and 19 led only to poor re-
sults. Presumably the bicycle is
not flexible enough to enter
into the desired reaction.
Therefore, we decided to con-
vert 23 into more flexible cy-
Scheme 6. Synthesis of 30 and 33: 30: a) 1.8 equiv NaOH, MeOH, reflux, 6 h; b) 10.5 equiv 28, 6.0 equiv
NH4Cl, CH2Cl2/tBuOH 1:1, 08C to RT, 19 h, 77% (two steps); c) 1.15 equiv TBSCl, 1.6 equiv imidazole, DMF,
RT, 2 h, 93%; 33: d) 2.0 equiv NaOH, MeOH, reflux, 5 h; e) 3.5 equiv TBSCl, 4.0 equiv imidazole, DMF, RT,
2 h; f) 3.5 equiv N,N’-carbonyldiimidazole, THF, 508C, 1.5 h, then addition of NaOMe in MeOH at 08C,
15 min, RT, 88% (three steps).
clopentenes as 30 and 33
(Scheme 6). Opening of the
lactone moiety was achieved
with NaOH in refluxing
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L. F. Tietze et al.
transformed into acid 32 by adding H2O to the reaction mix-
ture. Activation of the acid moiety with N,N’-carbonyldiimi-
dazole and subsequent addition of NaOMe dissolved in
MeOH gave the methyl ester 33 in a very good yield of
88% over three steps.
33 were used in a racemic form, 38–41 were obtained as in-
separable diastereomeric mixtures.
It should be noted, that a drop in yield is observed when
the Heck reactions are performed with almost equimolar
amounts of the vinyl iodides and the cyclopentene deriva-
tives (entries 2 and 6). Here, the homocoupling of 11 and 12
becomes an important reaction path. Fortunately, using an
excess of the valuable cyclopentene building blocks, the sur-
plus could be re-isolated and again used for the Heck cou-
plings.
Successful Heck reactions were carried out with the aro-
matic substrates 11, 12 and 19 and cyclopentenes 30 and 33
using 5 mol% Pd(OAc)2, 1.0 equiv TBACl, and an inorganic
A
base in DMF (Table 1). Similar conditions had been used by
Larock et al. for intermolecular Heck couplings of cycloal-
kenes with aryl and alkenyl halides and triflates, respective-
ly.[20]
The preferred formation of 34, 36, 38 and 40 needs some
ꢀ
comments since in these compounds the C C-bond forma-
tion has taken place at the
more hindered position of the
double bond in 30 and 33, re-
Table 1. Results of the intermolecular Heck reactions.[a]
spectively.
We
therefore
assume that the insertion of
the primarily formed Pd–vinyl
species into the double bond
of 30 and 33 is reversible and
the product ratio is controlled
by the Pd–hydride elimination
step, which should be favored
via TS1 compared with TS2
Entry
Vinyl-I
Cyclopentene
Reaction conditions[b]
Yield
(Scheme 7). Thus, to avoid an
base
t
T
A
B
unfavorable syn-coplanar ori-
entation of the silyloxymethyl
and the acetate group in TS2,
the Pd and the cis-b-hydrogen
are forced to take a syn-clinal
orientation, which is less favor-
able for the elimination. The
facial selectivity is controlled
by the two stereogenic centers
in 30 and 33 respectively, in-
ducing an attack exclusively
from the b-face. Thus, diaste-
1
2[c]
3
11
11
12
12
12
12
19
19
19
19
2.5 equiv 33
1.35 equiv 33
2.5 equiv 30
2.5 equiv 30
2.5 equiv 30
3.0 equiv NaOAc
3.6 equiv NaOAc
3.0 equiv NaOAc
3.0 equiv NaOAc
3.0 equiv NaOAc
3.0 equiv NaOAc
1.5 equiv NaOAc
2.0 equiv Na2CO3
2.0 equiv NaOAc
2.0 equiv Na2CO3
2 d
20 h
19 h
6 d
6 d
7 d
2 d
3 d
3 d
2 d
RT
RT
RT
ꢀ158C
ꢀ258C
ꢀ108C
RT
RT
RT
RT
37% (34)
28% [38%][d] (34)
37% (36)
20% (35)
n.d.
23% (37)
28% (37)
25% (37)
n.d.
16% (39)
18% (39)
16% (41)
15% (41)
4
5
46% (36)
51% (36)
6[e]
7[g]
8
1.2 equiv 30
40%
[51%][f] (36)
A
3.0 equiv rac-33
3.0 equiv rac-33
3.0 equiv rac-30
3.0 equiv rac-30
39% (38)
42% (38)
42% (40)
41% (40)
9
10
[a] rham = a-O-trimethyl rhamnopyranosyl. [b] 5 mol% Pd
scale). [c] 6 mol% Pd(OAc)2, 1.2 equiv TBACl were used (7.38 mmol scale). [d] Yield based on re-isolated 33.
[e] 10 mol% Pd(OAc)2 (9.35 mmol scale). [f] Yield based on re-isolated 30. [g] Three drops water added;
(OAc)2, 1.0 equiv TBACl, DMF (0.25–0.35 mmol
ACHTREUNG
ACHTREUNG
n.d.=not determined.
reomers of the products were
not found.
As expected, distinct differences in reactivity were ob-
served between the three vinyl iodides. Thus, reaction of the
methoxy derivative 11 with methyl ester 33 furnished the
desired coupling product 34 in 37% yield along with its re-
gioisomer 35 in 20% yield (entry 1). In addition, the corre-
sponding coupling products with a (E)-configured styrene
double bond as well as a homocoupling product of 11 were
also formed in a combined amount of up to 25%. All efforts
to supress the formation of these side products failed. To
our delight, much better results were obtained with the ace-
toxy derivative 12 and cyclopentene 30 (entries 3–6). Due to
its lower electron density compared to 11, compound 12 is
more reactive[10] and allowed a cleaner and more selective
conversion at lower temperature. The best isolated yield for
36 was 51% after a reaction time of 6 d at ꢀ258C (entry 5).
Although the rhamnose derivative 19 showed a lower reac-
tivity than 12, it provided useable yields of 42% and an
even better selectivity of 2.8:1 (entries 7–10). When 30 and
For the intramolecular Heck reactions of 34, 38, 40 and 42
to give 44–47 we used palladacycle 43[21] and nBu4NOAc as
base in a DMF/MeCN/H2O 5:5:1 solvent mixture at 120–
1308C (Table 2). In all attempts excellent yields in the range
of 84–90% were obtained. Merely the labile acetate group
in 36 had to be removed first with NaHCO3 in MeOH, oth-
erwise only poor results for the Heck reaction were ob-
tained. The important cis orientation of the hydrogens at
Scheme 7. Transition structures for the intermolecular Heck reaction.
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Novel Spinosyn AAnalogues
FULL PAPER
Table 2. Results of the intramolecular Heck reactions.[a]
closed six-membered transition
state.[24] Moreover, the oxazoli-
dinone induces a Si attack at
the chiral aldehyde to give the
(S,S)-configuration
at
the
newly formed stereogenic cen-
ters.[24]
Both aldol adducts 50 and
51 were transformed into the
corresponding aldehydes 53
Entry
Precursor
Reaction conditions[c]
Product
Yield
and
55,
respectively
43
t
T
(Scheme 9). First, the secon-
dary alcohol moiety in 50 and
51, respectively was protected
as TBS ether using TBSOTf
and a base; for 50 a yield of
90% and for 51 a yield of 85%
was obtained. The silyl protect-
ed compounds were then ex-
1
2
3
4
34
38
40
42
4 mol%
5 mol%
5 mol%
7 mol%
4 h
1258C
1258C
1208C
1308C
44
45
46
47
90%
85%
84%
90%
0.5 h
1.5 h
3.5 h
[a] rham = a-O-trimethyl rhamnopyranosyl. [b] 2.0 equiv NaHCO3, MeOH, RT, 7 h, 99%. [c] 43, 2.0 equiv
nBu4NOAc, DMF/MeCN/H2O 5:5:1.
the newly formed ring system was verified in each case by
NOESY NMR experiments.
When compounds 38 and 40 were used as diastereomeric
mixtures compounds 45 and 46 were obtained as inseparable
diastereomeric mixtures as well.
posed to LiOH·H2O in a THF/aqueous H2O2 solvent mix-
ture at ꢀ108C to remove the Evans auxiliary.[25] The crude
acids thus obtained were dissolved in THF, treated with
N,N’-carbonyldiimidazole to activate the acid functionality
and then reduced by successive addition of H2O and
NaBH4.[26] Interestingly, the yields of the resulting alcohols
52 and 54 (Scheme 9) with 53 and 72% yield, respectively,
were quite different. In the case of the formation of 52 the
necessary basic conditions for the cleavage of the auxiliary
led also to a hydrolysis of the methyl ester moiety to give
the corresponding diacid. However, if one avoids complete
transformation, 52 could be obtained in a yield of 76%
based on recovered 50. Finally, oxidation of the primary al-
cohols 52 and 54 with DMP in CH2Cl2 furnished the alde-
hydes 53 and 55. Both compounds were supposed to be suit-
able reaction partners in the Grignard coupling with the C-6
fragment.
For the elaboration of the further steps towards the novel
spinosyn analogues we first focused on the methyl ester de-
rivative 44 containing a methoxy group at the aromatic ring
system (Scheme 8). Cleavage of the TBS ether in 44 with
pTsOH·H2O in MeOH and subsequent oxidation of the pri-
mary alcohol with Dess–Martin periodinane (DMP) in
CH2Cl2 led to aldehyde 48, which was then used for an
Evans aldol addition[22] with the boron enolate of the (S)-
phenyl alanine derived oxazolidinone 49.[23] The reaction
was highly stereoselective and furnished only one diastereo-
mer when the enantiopure aldehyde was employed. If rac-48
was used, the two enantiopure diastereomers 50 and 51
were formed in an almost 1:1 ratio in 89% yield. They could
be easily separated by column chromatography. As for the
stereochemistry, it can be assumed that the syn orientation
of the methyl and the hydroxy substituent arises from a
Aldehyde 56, readily available from 1,4-butanediol via
mono-TIPS protection[27] and subsequent Swern oxida-
tion,[28] was used as substrate for the synthesis of the C-6
fragment 60 (Scheme 10). The necessary enantioselective in-
Scheme 8. Synthesis of 50 and 51: a) 10 mol% pTsOH·H2O, MeOH, 08C, 3 h, quant.; b) 1.75 equiv DMP, CH2Cl2, 08C, 2 h, 89%; c) 1.25 equiv 49,
1.45 equiv NEt3, 1.3 equiv nBu2BOTf, CH2Cl2, 08C, 1 h, then addition of rac-48 at ꢀ758C, keep temperature for 1 h, then warm up to ꢀ308C over 2 h,
50: 45%, 51: 44%.
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L. F. Tietze et al.
Scheme 10. Synthesis of C-6 fragment 60: a) 10 mol% 57, 2.0 equiv Ti-
(OiPr)4, toluene, 508C, 30 min, then addition of 1.8 equiv ZnEt2 at
ꢀ658C, 20 min, then addition of 56 at ꢀ208C, 68 h, 96%, 98% ee;
b) 1.75 equiv MEMCl, 2.0 equiv DIPEA, CH2Cl2, RT, 5 h, 85%;
c) 2.0 equiv TBAF·3H2O, THF, 08C, 1 h, RT, 2 h, quant.; d) 1.5 equiv
NBS, 1.2 equiv PPh3, THF, ꢀ158C, 20 min, 85%; e) 5.0 equiv Mg turn-
ings, 2 mol% Br2, THF, RT, 30 min, ꢁ50%.
Scheme 9. Synthesis of aldehydes 53 and 55: 53: a) 4.0 equiv TBSOTf,
8.0 equiv DMAP, CH2Cl2, RT, 18 h, 90%; b) 25 equiv LiOH·H2O, THF/
aqueous H2O2, ꢀ108C, 10 d; c) 6.0 equiv N,N’-carbonyldiimidazole, THF,
RT, 2.5 h, then addition of H2O and 9.0 equiv NaBH4, 08C, 1 h, 53%
[76% brsm] (two steps); d) 1.5 equiv DMP, CH2Cl2, 08C, 3.5 h, 94%; 55:
e) 1.5 equiv TBSOTf, 2.0 equiv 2,6-lutidine, CH2Cl2, ꢀ108C, 2.5 h, 85%;
f) 25 equiv LiOH·H2O, THF/aqueous H2O2, ꢀ108C, 6 d; g) 6.0 equiv
N,N’-carbonyldiimidazole, THF, 08C, 1 h, RT, 1.5 h, then addition of H2O
and 6.5 equiv NaBH4, 08C, 45 min, 72% (two steps); h) 1.5 equiv DMP,
CH2Cl2, RT, 1.5 h, 90%.
uct, which was isolated in 42% yield over two steps, was the
desired compound 62 bearing the S configuration at C-3’’.
The stereochemical orientation was carefully determined
through NOESY NMR experiments carried out on com-
pound 65, and is furthermore in accordance with related
chemical transformations[33] as well as the fact that the
major compound is likely to be formed via a Felkin–Anh
transition state.[34]
troduction of an ethyl group was performed according to
Knochel et al.[29] by using a defined mixture of ZnEt2, Ti-
As minor compound lactone 63 was isolated in 29%
yield. This compound probably arises via an interesting
Grignard coupling/TBS migration/lactonization sequence.
Compound 63 was not used for further transformations.
Cleavage of the MEM ether in 62 with in situ generated
TMSI[35] followed by cleavage of the methyl ester moiety
with LiOH·H2O at 408C gave the corresponding hydroxy
acid, which was converted without purification directly into
A
sired compound 58 was isolated in 96% yield with 98% ee.
The addition step was followed by a simple protection–de-
protection procedure to give 59 in 85% yield over two steps.
For the conversion of the primary alcohol moiety in 59 into
a bromide we used the Appel procedure with NBS and PPh3
to give 60 in 85% yield,[31]
from which the corresponding
Grignard reagent 61 could be
easily generated with bromine-
activated Mg turnings. The
concentration of the corre-
sponding Grignard solution
was determined by the method
of Paquette et al.[32]
Addition of Grignard re-
agent 61 to a solution of alde-
hyde 53 in THF at ꢀ358C fur-
nished an inseparable mixture
of two coupling products
(Scheme 11). However, after
treatment with excess PivCl,
NEt3 and DMAP in CH2Cl2 to
Scheme 11. Synthesis of the novel spinosyn analogue 65: a) 1.15 equiv 61, THF, ꢀ358C, 1 h; b) 2”(5.0 equiv
PivCl, 10 equiv NEt3, 1.0 equiv DMAP), CH2Cl2, reflux, 22 h, 62: 42% (two steps), 63: 29%; c) 4.0 equiv
TMSCl, 4.0 equiv NaI, MeCN, ꢀ358C, 4.5 h; 81%; d) 10 equiv LiOH·H2O, THF/H2O 4:1, 408C, 33 h;
e) 4.0 equiv TCBzCl, 6.0 equiv NEt3, THF, RT, 1.5 h, then slow addition to 10 equiv DMAP, toluene, 758C,
5.5 h, 74% (two steps); f) HF·pyridine/pyridine 1:3, 608C, 14 h, 91%; g) 1.5 equiv DMP, CH2Cl2, RT, 20 min,
86%.
convert the newly formed sec-
ondary alcohol moiety into a
pivaloyl ester, the two com-
pounds could be separated and
characterized. The main prod-
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Novel Spinosyn AAnalogues
FULL PAPER
lactone 64 using Yamaguchiꢁs 2,4,6-trichlorobenzoyl chlorid
(TCBzCl) method.[36] The tetracyclic compound 64 was thus
obtained in a very good yield of 60% over three steps. Fi-
nally, the TBS group in 64 was removed with HF·pyridine
and the necessary enone moiety was prepared by DMP oxi-
dation to give compound 65 in 78% yield over two steps,
the first novel spinosyn analogue of type 3.
Applying the same strategy as described above, aldehyde
55 could be transformed into the novel spinosyn analogues
69 and 70 (Schemes 12 and 13). Grignard coupling of 55
with 61 led to a mixture of epimeric alcohols in a 1.5:1 ratio
Scheme 13. Synthesis of the spinosyn analogues 69 and 70: 69: a) HF·pyr-
idine/pyridine 1:3, 608C, 14 h, 92%; b) 1.5 equiv DMP, CH2Cl2, RT,
20 min, 80%; 70: c) HF·pyridine/pyridine 1:3, 608C, 14 h, 72%;
d) 1.5 equiv DMP, CH2Cl2, RT, 20 min, 87%.
in
a
combined yield of 66% (1H NMR: (3’’-S):
(3’’-R)
A
ꢁ1.5:1); the partial formation of a d-lactone as described
for the reacion of 53 (Scheme 11) was not observed. The
separation of the two epimers at this stage was not possible,
but could be accomplished after the formation of the macro-
cycle. Subsequent treatment of the Grignard coupling prod-
ucts with PivCl and DMAP in pyridine afforded a mixture
of pivaloyl esters 66 in 94% combined yield. The MEM
ethers were cleaved to give the hydroxy acids which were
transformed into the macrolactones 67 and 68 with 47 and
26% yield after separation by column chromatography on
silica gel over three steps using the TCBzCl method.
Both lactones 67 and 68 were then treated with HF·pyri-
dine to cleave the TBS ether, and subsequently oxidized
with DMP to afford the novel spinosyn analogues 69 and 70,
respectively (Scheme 13). The two transformations were
again performed in very good yields of 72–92%. The stereo-
chemical configuration on C-3’’ could be again unambigu-
ously confirmed through NOESY NMR spectroscopy.
hydroxyl moiety was protected as TIPS ether using TIPS-
A
tionality was set free with pTsOH·H2O in MeOH, and final-
ly oxidized with DMP to give 71 in a very good overall yield
of 83%.
Subsequent Evans aldol addition of aldehyde rac-71 with
the boron enolate of enantiopure oxazolidinone 49 furnish-
ed cleanly two separable enantiopure coupling products 72
and 73 in a combined yield of 82%. As expected, when
enantiopure 71 was put to reaction with 49 solely compound
72 was isolated in a very good yield of 89%.
For the following transformations towards the spinosyn
analogues only isomer 72 was used, since we had already
shown for compound 51 that the other diastereomer of the
aldol reaction can be also converted into spinosyn analogues
of type 3 (cp. Scheme 12 and 13).
As depicted in Scheme 15, the secondary alcohol moiety
in 72 was protected as TBS ether in a yield of 84%, and
then the imide functionality directly converted into a pri-
mary alcohol with LiBH4/EtOH in Et2O. The yield of 63%
is not only higher than the 53% obtained for 52 (cp.
Scheme 9), but more important the here applied one-step
reductive procedure is much
After successful preparation of the spinosyn analogues 65,
69 and 70 containing a methoxy group at the aromatic ring
system, we focussed on the preparation of spinosyn ana-
logues with a free phenolic hydroxy group to allow the in-
troduction of different sugar moieties at a later stage.
Compound 47 was converted into aldehyde 71 via a
simple three-step procedure (Scheme 14). The free phenolic
more convenient than the two-
step auxiliary cleavage/acid ac-
tivation–reduction procedure
used in case of 50. This clearly
shows the advantage of using
72 with
a
tert-butyl ester
moiety as substrate which is
much more stable under basic
conditions compared to the
methyl ester in 50. Finally,
DMP oxidation led to alde-
hyde 74 in 91% yield, which
could be coupled afterwards
with 61 in a Grignard reaction.
Much to our delight, after
treatment with PivCl in pyri-
dine we isolated the desired
compound 75 with 3’’-(S) con-
figuration in a good yield of
Scheme 12. Synthesis of the macrolactones 67 and 68: a) 1.35 equiv 61, THF, ꢀ788C, 2 h, 66%; b) 10 equiv
PivCl, 2.0 equiv DMAP, pyridine, 608C, 14 h, 94%; c) 4.0 equiv TMSCl, 4.0 equiv NaI, MeCN, ꢀ358C, 9.5 h,
88%; d) 10 equiv LiOH·H2O, THF/H2O 6:1, RT, 2 d; e) 4.0 equiv TCBzCl, 6.0 equiv NEt3, THF, RT, 1 h, then
slow addition to 10 equiv DMAP, toluene, 758C, 4.5 h, 67: 53% (two steps), 68: 30% (two steps).
Chem. Eur. J. 2007, 13, 8543 – 8563
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8549

L. F. Tietze et al.
Scheme 14. Synthesis of 72 and 73: a) 1.5 equiv TIPSOTf, 3.0 equiv DMAP, CH2Cl2, 08C, 30 min, 96%; b) 10 mol% pTsOH·H2O, MeOH, 08C, 4 h, 95 %;
c) 1.75 equiv DMP, CH2Cl2, 08C, 2.5 h, 91%; d) 1.25 equiv 49, 1.45 equiv NEt3, 1.3 equiv nBu2BOTf, CH2Cl2, 08C, 1 h, then addition of rac-71 at ꢀ758C,
keep temp. for 1.5 h, then warm up to ꢀ308C over 2 h, 72: 39%, 73: 43%.
what lower than 74% ob-
served for 64 (cp. Scheme 11).
We assume that the TIPS pro-
tection group is partially
cleaved under the reaction
conditions and the nucleophilic
free phenol then enters into
side reactions.
HF·pyridine was used at
608C to cleave the TBS as well
as the TIPS ether in 77 and 79,
respectively in a clean reaction
with 88 and 91% yield, respec-
tively (Scheme 16). In case of
77 we also conducted the reac-
tion at 08C and observed the
exclusive formation of the
TIPS deprotected compound
after 30 min.
Scheme 15. Synthesis of 75 and 76: a) 5.0 equiv TBSOTf, 10 equiv DMAP, CH2Cl2, RT, 20 h, 84%; b) 10 equiv
LiBH4, 20 equiv EtOH, Et2O, RT, 45 min, then addition of the TBS protected 72, RT, 15 min, 63%;
c) 1.75 equiv DMP, CH2Cl2, 08C, 2 h, 91%; d) 1.25 equiv 61, THF, ꢀ358C, 1.5 h; e) 75: 10 equiv PivCl,
1.0 equiv DMAP, pyridine, 608C, 14 h, 63% (two steps); 76: PivCl/pyridine 1:10, DMAP, 608C, 17 h, 15%
(two steps).
Problems occurred as the
hydroxy phenols were treated
63% over two steps, the diastereomer 76, having the
3’’-(R) configuration was formed in only 15%. This consti-
tutes an unexpected fairly good ꢁ4:1 ratio for the Grignard
addition. Moreover, here we were able to isolate the diaste-
reomer 76 and to use it for the transformation into a diaste-
reomeric spinosyn analogue again due to the greater stabili-
ty of the tert-butyl ester moiety under basic conditions com-
pared with the methyl ester group in 53, from which the lac-
tone 63 was formed under identical conditions. The absolute
stereochemistry at C-3’’ was again assigned through NOESY
NMR experiments.
Both compounds 75 and 76 were then subjected to in situ
generated TMSI to cleave the MEM ether; for 75 a yield of
84% and for 76 a yield of 71% was obtained. Treatment of
these products with excess TMSOTf in the presence of NEt3
followed by acidic work-up led to the corresponding hy-
droxy acids, which were set in as crude materials in the sub-
sequent Yamaguchi macrolactonization. The isolated yields
of 50% for 77 and 64% for 79 were acceptable, but some-
with DMP in CH2Cl2 to build up the enone moieties; only
decomposed starting material was detected already after a
few seconds. However, the use of SO3·pyridine and DIPEA
in DMSO, which is known as Parikh–Doering oxidation,[37]
gave in the case of 80 an acceptable result of 67% yield. On
the other hand, the reaction of the epimer led to a complex
mixture of products. The oxidized product 78 was here ob-
tained in a pure form after acetylation of the phenol moiety
in only 34% yield over two steps. The different behavior of
the two epimers is somehow astounding and one must
assume that the formed enone moiety in 80 is less sensitive
to the oxidizing agent compared to 78.
Conclusions
Using the strategy outlined in Scheme 1 several enantiopure
novel spinosyn analogues of type 3 with an aromatic ring A
instead of a cyclopentene moiety as in the insecticides spino-
8550
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Chem. Eur. J. 2007, 13, 8543 – 8563

Novel Spinosyn AAnalogues
FULL PAPER
25 spectrometer. 1H and 13C NMR spectra were recorded with Mercury-
200, VXR-200, Unity-300, Inova-500, Unity Inova-600 (Varian) or AMX
300 (Bruker) spectrometer. Chemical shifts are reported in ppm with tet-
ramethylsilane (TMS) as internal standard. Multiplicities of 13C NMR
peaks were determined with the APT pulse sequence. Mass spectra were
messured with a Finnigan MAT 95, TSQ 7000 or LCQ instrument. Ele-
mental analysis: Mikroanalytisches Labor, Institut für Organische und
Biomolekulare Chemie, Georg-August-Universität Gçttingen.
The following abbreviations are used: MTBE (methyl tert-butyl ether),
PE (petroleum ether b.p. 40–608C) s (singlet), d (dublet), t (triplet), q
(quartet), m (multiplet), m (centered multiplet), b (broad) and combina-
tions thereof.
2-Bromo-5-methoxybenzaldehyde (10): Bromine (9.40 mL, 29.4 g,
184 mmol) was added dropwise at 08C to a solution of 3-methoxy-benzal-
dehyde (9) (25.0 g, 184 mmol) in CH2Cl2 (350 mL) and after warming to
room temperature the mixture stirred for 16 h. Then, 5% aqueous
Na2S2O3 was added until decolorisation of the mixture and thereupon sat.
aqueous NaHCO3 until ceasing of gas evolution. The organic phase was
separated, dried over Na2SO4 and the solvent removed under reduced
pressure. Recrystallization of the crude product from PE gave aldehyde
10 (33.0 g, 153 mmol, 83%) as light yellow needles. Rf =0.06 (PE/Et2O
200:1); m.p. 738C ; 1H NMR (200 MHz, CDCl3): d=3.85 (s, 3H; Ar-
OCH3), 7.04 (dd, J=8.8, 3.2 Hz, 1H; 4-H), 7.42 (d, J=3.2 Hz, 1H; 6-H),
7.53 (d, J=8.6 Hz, 1H; 3-H), 10.32 ppm (s, 1H; CHO); 13C NMR
(50 MHz, CDCl3): d=55.70 (Ar-OCH3), 112.59, 117.96, 123.11, 133.90,
134.53 (C-1, C-2, C-3, C-4, C-6), 159.20 (C-5), 191.76 ppm (CHO); IR
(KBr): n˜ =2876, 1677, 1599, 1571, 1475 cmꢀ1; UV/Vis (MeCN): lmax (lg
e)=224.0 (4.307), 252.5 (3.814), 328.5 nm (3.386); MS (70 eV, EI): m/z
(%): 213.9 (100) [M]+.
Scheme 16. Synthesis of the spinosyn analogues 78 and 80: 78:
a) 4.0 equiv TMSCl, 4.0 equiv NaI, MeCN/CH2Cl2 4:1, ꢀ358C, 1.5 h,
84%; b) 25 equiv TMSOTf, 30 equiv NEt3, THF, RT, 1 h; c) 4.0 equiv
TCBzCl, 6.0 equiv NEt3, THF, RT, 1.5 h, then slow addition to 10 equiv
DMAP, toluene, 758C, 5 h, 50% (two steps); d) HF·pyridine/pyridine 1:3,
608C, 14 h, 88%; e) 6.0 equiv SO3·pyridine, 10 equiv DIPEA, DMSO,
RT, 1 h; f) 5.0 equiv Ac2O, 10 equiv NEt3, 0.5 equiv DMAP, CH2Cl2, 08C,
30 min, 34% (two steps); 80: g) 4.0 equiv TMSCl, 4.0 equiv NaI, MeCN/
CH2Cl2 4:1, ꢀ358C, 2 h, 71%; h) 25 equiv TMSOTf, 30 equiv NEt3, THF,
RT, 40 min; i) 4.0 equiv TCBzCl, 6.0 equiv NEt3, THF, RT, 1 h, then slow
addition to 10 equiv DMAP, toluene, 608C, 3 h, 64% (two steps);
j) HF·pyridine/pyridine 1:3, 608C, 14 h, 91%; k) 6.0 equiv SO3·pyridine,
10 equiv DIPEA, DMSO, RT, 1 h, 67%.
(Z)-2-(2-Iodovinyl)-4-methoxybromobenzene (11): KHMDS (93.0 mL,
46.5 mmol, c ꢁ0.5m in toluene) was added dropwise at room tempera-
ture to a suspension of iodomethyltriphenylphosphonium iodide (24.7 g,
46.5 mmol) in THF (200 mL). The mixture stirred for further 20 min and
was then cooled to ꢀ788C, whereupon a solution of aldehyde 10 (8.00 g,
37.2 mmol) in THF (20 mL) was added dropwise. After stirring for
45 min at ꢀ788C and further 45 min at room temperature the reaction
was quenched by addition of sat. aqueous NH4Cl (400 mL). The organic
phase was separated and the aqueous phase extracted with Et2O (2”
200 mL). The combined organic extracts were dried over Na2SO4 and the
solvent was removed under reduced pressure. Column chromatography
(n-pentane) gave iodide 11 (9.15 g, 27.0 mmol, 73%) as a yellow oil. Rf =
0.45 (n-pentane/Et2O 100:1); 1H NMR (200 MHz, CDCl3): d=3.84 (s,
3H; Ar-OCH3), 6.73 (d, J=8.6 Hz, 1H; 2’-H), 6.78 (dd, J=8.8, 3.0 Hz,
1H; 5-H), 7.24 (d, J=3.0 Hz, 1H; 3-H), 7.32 (d, J=8.2 Hz, 1H; 6-H),
7.47 ppm (d, J=8.8 Hz, 1H; 1’-H); 13C NMR (50 MHz, CDCl3): d=55.61
(Ar-OCH3), 83.44 (C-2’), 113.82, 115.16, 115.98 (C-1, C-3, C-5), 133.23,
137.98, 138.83 (C-2, C-6, C-1’), 158.28 ppm (C-4); IR (NaCl): n˜ =2933,
1462, 1294, 1238 cmꢀ1; UV/Vis (MeCN): lmax (lg e)=190.5 nm (4.500);
MS (70 eV, EI): m/z (%): 339.8 (82) [M]+, 258.9 (22) [MꢀBr]+, 210.9
(100) [MꢀI]+, 132.0 (80) [MꢀBrꢀI]+.
(Z)-4-Acetoxy-2-(2-iodovinyl)bromobenzene (12): BBr3 (14.2 mL,
14.2 mmol, c ꢁ1m in CH2Cl2) was added to a solution of methyl ether 11
(3.20 g, 9.44 mmol) in CH2Cl2 (20 mL) at 08C. After stirring at 08C for
4 h sat. aqueous NH4Cl (20 mL) and H2O (10 mL) were added. The or-
ganic phase was separated and the aqueous phase extracted with CH2Cl2
(2”20 mL). The combined organic phases were dried over MgSO4 and
the solvent was removed under reduced pressure. The crude phenol
(3.08 g, 9.44 mmol, quant.) was dissolved in pyridine (16 mL) at 08C and
DMAP (58 mg, 0.47 mmol) and Ac2O (8 mL) were added. After stirring
for 75 min at room temperature the solvent was removed under reduced
pressure and the crude product purified by column chromatography
(n-pentane/Et2O 7:1) to give 12 (3.44 g, 9.37 mmol, 99%) as a light
yellow solid. Rf =0.58 (n-pentane/Et2O 5:1); m.p. 738C; 1H NMR
(200 MHz, CDCl3): d=2.32 (s, 3H; OC(O)CH3), 6.78 (d, J=8.7 Hz, 1H;
2’-H), 6.98 (dd, J=8.7, 2.4 Hz, 1H; 5-H), 7.30 (d, J=8.7 Hz, 1H; 6-H),
7.40 (d, J=2.7 Hz, 1H; 3-H), 7.59 ppm (d, J=8.7 Hz, 1H; 1’-H);
13C NMR (50 MHz, CDCl3): d = 21.07 (OC(O)CH3), 84.43 (C-2’), 119.85
(C-1), 122.87, 123.32, 133.04 (C-3, C-5, C-6), 138.23 (C-1’), 138.63 (C-2),
syn Aand D have been synthesized. The key reaction in all
syntheses was a double Heck reaction which allowed a rapid
access to the tricyclic core with the needed cis orientation of
the 6,5-ring system and the trans orientation for the remain-
ing stereogenic center in the tricyclic core. In addition, the
two double bonds formed in this reaction correspond to the
wanted position in the desired spinosyn analogues. The mac-
rocyclic system was assembled via an Evans aldol addition,
a Grignard coupling and a macrolactonization. Moreover,
we were able to prepare analogues with different configura-
tions at several stereogenic centers to allow investigations of
the structure–activity relationship.
Experimental Section
General methods: All reactions were performed under argon in flame-
dried flasks. THF and Et2O were dried and distilled prior to use by usual
laboratory methods, all other solvents were used from commercial sour-
ces and stored over molecular sieves. All reagents obtained from com-
mercial sources were used without further purification. Thin-layer chro-
matography (TLC) was performed on precoated silica gel SIL G/UV254
plates (Macherey-Nagel GmbH & Co. KG) and silica gel 60 (0.032–
0.063 mm, Merck) was used for column chromatography. Phosphomolyb-
dic acid in methanol (PMA) or vanillin in methanolic sulfuric acid were
used as staining reagents for TLC. UV spectra were taken in CH3CN or
MeOH with a Perkin–Elmer Lambda 2 spectrometer. IR spectra were re-
corded as KBr pellets or as films between NaCl plates with a Bruker IFS
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8551

L. F. Tietze et al.
149.28 (C-4), 169.05 ppm (OC(O)CH3); IR (KBr): n˜ =3353, 1759, 1591,
1457, 1368, 1202 cmꢀ1; UV/Vis (MeCN): lmax (lg e)=198.5 nm (4.405);
MS (70 eV, EI): m/z (%): 367.9 (22) [M]+; HRMS (ESI): m/z: calcd for
C10H8BrINaO2: 388.86446; found: 388.86452 [M+Na]+, 383.90918
[M+NH4]+; elemental analysis calcd for C10H8BrIO2 (366.98): C 32.73, H
2.20; found: C 32.73, H 2.09.
mixture was stirred for 5 min before cooling to ꢀ788C. Then, a solution
of aldehyde 18 (2.29 g, 5.88 mmol) in THF (45 mL) was added dropwise
and the resulting mixture stirred for 1 h at ꢀ788C and for 45 min at room
temperature. After addition of saturated NH4Cl solution (400 mL) the
layers were separated and the aqueous layer was extracted with Et2O
(3”200 mL). The combined organic phases were washed with brine,
dried over MgSO4 and concentrated in vacuum. Purification by column
chromatography (n-pentane/MTBE 10:1 ! 6:1) afforded vinyl iodide 19
(1.84 g, 3.59 mmol, 61%) as a light brown solid. Rf =0.18 (n-pentane/
MTBE 4:1); 1H NMR (300 MHz, CDCl3): d=1.27 (d, J=6.3 Hz, 3H;
6’’-CH3), 3.23 (dd, J=9.4, 9.4 Hz, 1H; 4’’-H), 3.58, 3.62, (2”s, 9H; 3”
OCH3), 3.62–3.69 (m, 2H; 3’’-H, 5’’-H), 3.78 (dd, J=3.0, 1.8 Hz, 1H; 2’’-
H), 5.55 (d, J=1.8 Hz, 1H; 1’’-H), 6.75 (d, J=8.7 Hz, 1H; 2’-H), 6.93
(dd, J=8.7, 3.0 Hz, 1H; 5-H), 7.30 (d, J=8.7 Hz, 1H; 6-H), 7.39 (d, J=
3.0 Hz, 1H; 3-H), 7.49 ppm (d, J=8.7 Hz, 1H; 1’-H); 13C NMR (50 MHz,
CDCl3): d=17.86 (C-6’’), 57.95, 59.34, 60.99 (3”OCH3), 68.77 (C-5’’),
77.13, 80.81, 81.92 (C-2’’, C-3’’, C-4’’), 83.89 (C-2’), 95.43 (C-1’’), 115.54
(C-1), 117.89, 118.00, 133.37 (C-3, C-5, C-6), 138.43 (C-2), 138.70 (C-1’),
2-Bromo-5-hydroxybenzaldehyde (15): Bromine (6.54 g, 2.10 mL,
40.9 mmol) was added dropwise at 08C with stirring to a suspension of 3-
hydroxybenzaldehyde (14) (5.00 g, 40.9 mmol) in CH2Cl2 (100 mL) and
stirring was continued at room temperature for 17 h. 5% aqueous
Na2S2O3 solution (20 mL), 1m HCl (10 mL), H2O (30 mL) and CH2Cl2
(100 mL) were added and the organic layer separated. After drying over
MgSO4 and removal of the solvent under reduced pressure a brown solid
was obtained which was recrystallized from diethyl ether to give 15
(4.12 g, 20.5 mmol, 50%) as light brown needles. Rf =0.48 (n-pentane/
Et2O 1:1); 1H NMR (200 MHz, CDCl3): d=5.23 (s, 1H; OH), 7.00 (dd,
J=8.6, 3.2 Hz, 1H; 4-H), 7.39 (d, J=3.2 Hz, 1H; 6-H), 7.52 (d, J=
8.6 Hz, 1H; 3-H), 10.30 ppm (s, 1H; CHO); 13C NMR (50 MHz,
[D6]DMSO): d=114.30 (C-2), 115.64, 123.42, 134.68 (C-3, C-4, C-6),
133.64 (C-1), 157.31 (C-5), 191.52 ppm (CHO); IR (KBr): n˜ =3331, 1684,
1595, 1440 cmꢀ1; UV/Vis (CH3CN): lmax (lg e)=223.0 (4.314), 253.5
(3.864), 329.5 nm (3.459); MS (EI): m/z (%): 200.0 (100) [M]+, 171.0 (17)
[MꢀCHO]+.
155.09 ppm (C-4); IR (KBr): n˜ =2976, 2930, 2826, 1563, 1460, 1104 cmꢀ1
;
UV/Vis (CH3CN): lmax (lg e)=199.5 nm (4.397); MS (DCI): m/z (%):
532.2 (10) [M+NH4]+; elemental analysis calcd (%) for C17H22BrIO5
(513.16): C 39.79, H 4.32; found: C 40.02, H 4.63.
rac-(1R,5R,6R/S)-7-Oxo-bicyclo
A
acid
methyl ester (rac-21): Zn dust (51.1 g, 781 mmol) was added in portions
at 08C to a solution of the bicyclic rac-20 (39.2 g, 195 mmol) in glacial
acetic acid (380 mL). The reaction mixture was stirred at room tempera-
ture for 1 h and subsequently filtrated. Water (08C, 1400 mL) was added
and the resulting mixture extracted with Et2O (4”200 mL). The com-
bined organic layers were neutralized with saturated aqueous NaHCO3
solution/solid NaHCO3. Drying over MgSO4, removal of the solvent
under reduced pressure and distillation of the residue (56–608C, 0.02–
0.03 mbar) gave compound rac-21 (23.8 g, 143 mmol, 81%) as a colorless
oil. Rf =0.49 (n-pentane/Et2O 2:1); 1H NMR (200 MHz, CDCl3, diaste-
reomeric mixture): d=2.40–2.85 (m, 2H; 2-H2), 3.65–3.94 (m, 5H; 1-H,
5-H, CO2CH3), 4.06–4.25, 4.38–4.45 (m, 1H; 6-H), 5.80–6.04 ppm (m,
2H; 3-H, 4-H); 13C NMR (50 MHz, CDCl3, diastereomeric mixture): d=
34.42, 35.22 (C-2), 40.77, 41.17, 51.89, 52.45, 60.11, 62.65, 66.97, 71.26 (C-
1, C-5, C-6, CO2CH3), 129.79, 130.73, 133.45, 134.32 (C-3, C-4), 165.86,
167.20 (CO2CH3), 203.87, 204.16 ppm (C-7); IR (NaCl): n˜ =2955, 2922,
2855, 1789, 1730 cmꢀ1; MS (DCI): m/z (%): 350.3 (1) [2M+NH4]+, 184.1
(100) [M+NH4]+.
O-(2,3,4-Tri-O-methyl)-a-l-rhamnopyranosyltrichloroacetimidate
(17):
DBU (2.21 g, 2.17 mL, 14.5 mmol) was added dropwise at 08C to a solu-
tion of 16 (2.00 g, 9.70 mmol) and trichloroacetonitrile (28.0 g, 19.4 mL,
194 mmol) in CH2Cl2 (180 mL). After stirring at room temperature for
15 min the solvent was removed under reduced pressure and the ob-
tained residue dried under vacuum for 30 min. Quick column chromatog-
raphy over neutral aluminum oxide (n-pentane/ethyl acetate 5:1) yielded
compound 17 (3.08 g, 8.78 mmol, 91%) as a yellow liquid. Rf =0.28
(n-pentane/ethyl acetate 5:1); 1H NMR (300 MHz, CDCl3): d=1.31 (d,
J=6.3 Hz, 3H; 6-CH3), 3.21 (dd, J=9.3, 9.3 Hz, 1H; 4-H), 3.50, 3.54,
3.56 (3”s, 9H, 3”OCH3), 3.50–3.56 (m, 1H; 3-H), 3.73 (dd, J=3.0,
1.8 Hz, 1H; 2-H), 3.77 (dq, J=9.3, 6.3 Hz, 1H; 5-H), 6.29 (d, J=1.8 Hz,
1H; 1-H), 8.58 ppm (s, 1H; NH).
2-Bromo-5-(2,3,4-tri-O-methyl-a-l-rhamnopyranosyl)benzaldehyde (18):
Amixture of activated molecular sieves (4 Š, 24 h vacuum, 200 8C,
60.0 g) and aldehyde 15 (2.64 g, 13.2 mmol) in CH2Cl2 (400 mL) was
stirred at room temperature for 1.5 h and after cooling to 08C, a solution
of trichloroacetimidate 17 (3.08 g, 8.78 mmol) in CH2Cl2 (15 mL) and
rac-(4aR,7aR)-4,4a,7,7a-Tetrahydro-1H-cyclopenta[c]pyran-3-one (rac-
23): NaBH4 (1.04 g, 27.5 mmol) was added in one portion at 08C to a
stirred solution of rac-21 (1.52 g, 9.15 mmol) in MeOH (30 mL), stirring
was continued for 45 min at 08C and the solvent was removed under re-
duced pressure. The residue was taken up in Et2O (30 mL), followed by
addition of saturated NaCl solution (20 mL) and 2m HCl solution
(20 mL). The layers were separated and the aqueous phase was extracted
with Et2O (3”20 mL). The combined organic layers were dried over
MgSO4 and the solvent was removed in vacuum. Purification of the resi-
due by column chromatography (n-pentane/MTBE 2:1) afforded lactone
23 (980 mg, 7.09 mmol, 78%) as a white solid. Rf =0.13 (n-pentane/
MTBE 2:1); 1H NMR (200 MHz, CDCl3): d=2.21–2.37 (m, 1H; 7-HA),
2.35 (dd, J=15.0, 6.6 Hz, 1H; 4-HA), 2.61–2.90 (m, 2H; 7-HB, 7a-H), 2.73
(dd, J=15.0, 7.0 Hz, 1H; 4-HB), 3.24–3.43 (m, 1H; 4a-H), 4.04 (dd, J=
11.2, 6.6 Hz, 1H; 1-HA), 4.30 (dd, J=11.2, 4.6 Hz, 1H; 1-HB), 5.56 (m,
1H; 5-H or 6-H), 5.76 ppm (m, 1H; 5-H or 6-H); 13C NMR (50 MHz,
CDCl3): d=33.80 (C-7), 33.90 (C-7a), 36.16 (C-4), 41.86 (C-4a), 70.26 (C-
1), 130.88, 131.80 (C-5, C-6), 173.29 ppm (C-3); IR (KBr): n˜ =3059, 2914,
2855, 1746 cmꢀ1; UV/Vis (CH3CN): no absorption; MS (DCI): m/z (%):
173.2 (3) [M+NH3+NH4]+, 156.2 (100) [M+NH4]+, 139.1 (7) [M+H]+;
elemental analysis calcd (%) for C8H10O2 (138.16): C 69.54, H 7.30;
found: C 69.32, H 7.01.
subsequently
a solution of TMSOTf (195 mg, 158 mL, 877 mmol) in
CH2Cl2 (15 mL) were added, the latter dropwise. The reaction mixture
was stirred at 08C for 75 min, treated with triethylamine (0.5 mL) and
left to warm to room temperature. The molecular sieves were filtered off,
washed thoroughly with CH2Cl2 and the combined filtrates were concen-
trated under reduced pressure. Column filtration over neutral aluminum-
oxide (n-pentane/ethyl acetate 8:1) and subsequent column chromatogra-
phy on silica gel (n-pentane/MTBE 15:1 ! 2:1) gave glycoside 18
(2.39 g, 6.15 mmol, 70%) as a colorless oil. Rf =0.16 (n-pentane/MTBE
3:1); 1H NMR (300 MHz, CDCl3, 9:1 anomeric mixture (a/b), a de-
scribed): d=1.25 (d, J=6.0 Hz, 3H; 6’-CH3), 3.20 (dd, J=9.4, 9.4 Hz,
1H; 4’-H), 3.57, (s, 9H; 3”OCH3), 3.54–3.67 (m, 2H; 3’-H, 5’-H), 3.76
(dd, J=3.3, 2.1 Hz, 1H; 2’-H), 5.57 (d, J=2.1 Hz, 1H; 1’-H), 7.19 (dd,
J=8.7, 3.3 Hz, 1H; 4-H), 7.56 (d, J=8.7 Hz, 1H; 3-H), 7.61 (d, J=
3.3 Hz, 1H; 6-H), 10.30 ppm (s, 1H; CHO); 13C NMR (50 MHz, CDCl3,
a described): d=17.79 (C-6’), 58.01, 59.35, 60.99 (3”OCH3), 69.00 (C-5’),
77.00, 80.74, 81.76 (C-2’, C-3’, C-4’), 95.34 (C-1’), 116.93, 123.72, 134.74
(C-3, C-4, C-6), 119.13 (C-2), 134.19 (C-1), 155.87 (C-5), 191.39 ppm
(CHO); IR (NaCl): n˜ =2934, 2830, 1694, 1590, 1469 cmꢀ1
; UV/Vis
(CH3CN): lmax (lg e)=222.0 (4.293), 251.0 (3.795), 320.5 nm (3.318); MS
(DCI): m/z (%): 796.5 (1) [2M+NH4]+, 406.3 (5) [M+NH4]+; HRMS
(ESI): m/z: calcd for C16H21BrNaO6: 411.04137; found: 411.04137
[M+Na]+.
N,N’-Diisopropyl-O-tert-butylisourea (28): CuCl (359 mg, 3.63 mmol,
(Z)-2-(2-Iodoethenyl)-4-(2,3,4-tri-O-methyl-a-l-rhamnopyranosyl)bromo-
benzene (19): KHMDS (15.6 mL, 10.3 mmol, 0.66m in toluene) was
added dropwise at room temperature to a suspension of the Wittig salt
[Ph3PCH2I]+ Iꢀ (13) (4.68 g, 8.82 mmol) in THF (90 mL). The reaction
1 mol%) was added to a solution of N,N’-diisopropylcarbodiimide
(56.8 mL, 45.8 g, 363 mmol) in tBuOH (39.7 mL, 417 mmol). The reaction
mixture was stirred for 14 h at room temperature and subsequently dis-
tilled under reduced pressure (618C, 13.3 mbar). The title compound 28
8552
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8543 – 8563

Novel Spinosyn AAnalogues
FULL PAPER
(58.9 g, 294 mmol, 81%) was obtained as a colorless oil. Note: Com-
pound 28 tends to rearrange to the more stable urea derivative and
to a solution of 23 (300 mg, 2.17 mmol) in methanol (5 mL) and the re-
sulting mixture was stirred under reflux for 5 h. The solvent was removed
under reduced pressure and the residue dried under vacuum for 20 h.
DMF (5 mL) and imidazole (591 mg, 8.68 mmol) were added to the car-
boxylate and the resulting solution was cooled to 08C. Asolution of
TBSCl (1.15 g, 7.60 mmol) in DMF (3 mL) was added, the cooling bath
removed and the reaction mixture stirred for 2 h at room temperature.
After addition of H2O (6 mL) the mixture was stirred for further 2 h at
room temperature. The reaction was quenched by adding water (20 mL)
and 1m HCl until the pH-value reached 3–4. The aqueous layer was ex-
tracted with Et2O (4”20 mL), the extracts were combined, dried over
MgSO4 and concentrated in vacuum. The obtained free acid was suspend-
ed in THF (10 mL), treated at 08C with N,N’-carbonyldiimidazole
(1.23 g, 7.60 mmol) and after increase of the reaction temperature to
508C the mixture was stirred for 1.5 h (gas evolution). After cooling to
08C NaOMe (1 mL, 5.4m in MeOH) was added dropwise and the cooling
bath removed. After 15 min water (30 mL) was added and the resulting
mixture extracted with Et2O (3”20 mL). The combined organic phases
were dried over MgSO4 and concentrated under reduced pressure. Purifi-
cation by column chromatography (n-pentane/ethyl acetate 60:1) gave
the title compound 33 (545 mg, 1.92 mmol, 88%) as a colorless oil. Rf =
0.45 (n-pentane/ethyl acetate 40:1); [a]2D0 =ꢀ69.88 (c=1.0 in CHCl3);
1
therefore storage, even at ꢀ308C is limited. H NMR (200 MHz, CDCl3):
d=0.97–1.19 (m, 12H; 2”CH
A
ACHTREUNG
2.99–3.35 (m 1H; NHCH
A
ACHTREUNG
rac-(1S,5R)-2-[(5-Hydroxymethyl)cyclopent-2-enyl]acetic acid tert-butyl
ester (29): NaOH (1.05 g, 26.3 mmol) was added to a solution of 23
(2.02 g, 14.6 mmol) in methanol (22 mL) and the resulting mixture was
stirred under reflux for 6 h. After the reaction mixture had cooled to
room temperature the solvent was removed under reduced pressure and
the residue dried under vacuum for 20 h. After powdering, 27 was sus-
pended in a solvent mixture of CH2Cl2/tBuOH 1:1 (70 mL) and cooled to
08C. After addition of NH4Cl (2.34 g, 43.80 mmol), 28 (10.2 g,
51.1 mmol) was added dropwise and the mixture stirred for 15 min at
08C and 2 h at room temperature. After cooling to 08C, NH4Cl (1.17 g,
21.9 mmol) and 28 (10.2 g, 51.1 mmol) were added and the mixture was
stirred for 15 min at 08C and 2 h at room temperature. After a third addi-
tion of NH4Cl (1.17 g, 21.9 mmol) and 28 (10.2 g, 51.1 mmol) at 08C the
mixture was stirred for 15 h at room temperature. H2O (150 mL) was
added, the phases were separated and the water phase was extracted
with CH2Cl2 (3”70 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuum. The water phase was acidified with
2m HCl (until pH ꢁ1), stirred for 20 min at room temperature and ex-
tracted with CH2Cl2 (2”50 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuum. Purification by column chro-
matography (PE/ethyl acetate 4:1) of the combined residues gave 29
(2.40 g, 11.3 mmol, 77%) as a colorless oil. In addition 23 (230 mg,
1.66 mmol, 11%) could be reisolated as a pale yellow solid. Rf =0.32
(n-pentane/Et2O 1:1); [a]2D0 =+76.88 (c=1.0 in CHCl3) (Note: the optical
rotation value corresponds to the (1S,5R)-enantiomer); 1H NMR
1H NMR (300 MHz, CDCl3): d=0.04 (s, 6H; Si
(CH3)3)), 2.04–2.16 (m, 1H; 4’-HB), 2.18 (dd, J=15.3, 9.9 Hz, 1H; 2-HB),
(CH3)2), 0.88 (s, 9H; Si(C-
AHCTREUNG
2.28–2.41 (m, 1H; 4’-HA), 2.51 (sext, J=7.4 Hz, 1H; 5’-H), 2.60 (dd, J=
15.2, 5.8 Hz, 1H; 2-HA), 3.14 (m, 1H; 1’-H), 3.58 (dd, J=10.2, 6.4 Hz,
1H; 5’-CH2-OTBS-HA), 3.61 (dd, J=10.2, 7.4 Hz, 1H; 5’-CH2-OTBS-
HB), 3.67 (s, 3H; CO2CH3), 5.71 ppm (m, 2H, 2’-H, 3’-H); 13C NMR
(50 MHz, CDCl3): d=ꢀ5.44, ꢀ5.40 (Si
C
(CH3)3)), 25.87
AHCTREUNG
(CO2CH3), 63.14 (C-5’-CH2-OTBS), 130.36, 133.91 (C-2’, C-3’),
173.87 ppm (C-1); IR (NaCl): n˜ =2954, 2930, 2857, 1742, 1255 cmꢀ1; MS
(DCI): m/z (%): 302.1 (8) [M+NH4]+, 285.0 (100) [M+H]+; HRMS
(ESI): m/z: calcd for C15H28NaO3Si: 307.16999; found: 307.16991
[M+Na]+; elemental analysis calcd (%) for C15H28O3Si (284.47): C 63.33,
H 9.92; found: C 62.99, H 9.65.
(300 MHz, CDCl3): d=1.46 (s, 9H; CO2(C(CH3)3)), 2.11–2.23 (m, 1H; 4’-
G
HB), 2.16 (dd, J=15.9, 6.9 Hz, 1H; 2-HB), 2.24 (t, J=5.7 Hz, 1H; OH),
2.32–2.44 (m, 1H; 4’-HA), 2.41 (dd, J=16.1, 8.0 Hz, 1H; 2-HA), 2.56 (m,
1H; 5’-H), 3.14 (m, 1H; 1’-H), 3.52–3.71 (m, 2H; 5’-CH2-OTBS),
5.72 ppm (m, 2H; 2’-H, 3’-H); 13C NMR (75 MHz, CDCl3): d=28.01
(CO2(C
A
General procedure for the intermolecular Heck reactions: Adegassed,
light-protected solution of vinyl iodide (1.0 equiv) and cyclopentene de-
rivative (2.5–3.0 equiv) in DMF (10 mL per mmol vinyl iodide) was treat-
(C-5’-CH2-OTBS), 80.65 (CO2(C(CH3)3)), 130.05, 134.31 (C-2’, C-3’),
A
173.30 ppm (C-1); IR (NaCl): n˜ =3429, 2978, 2930, 1729, 1152 cmꢀ1; MS
(DCI): m/z (%): 230.2 (28) [M+NH4]+, 213.2 (30) [M+H]+; HRMS
(ESI): m/z: calcd for C12H20NaO3: 235.13047; found: 235.13044 [M+Na]+.
ed with Pd(OAc)2 (5 mol%), base (2.0–3.0 equiv) and TBACl under an
H
argon atmosphere and the resulting mixture was stirred (1–6 d) at differ-
ent temperatures (ꢀ258C to room temperature). The reaction mixture
was taken up in Et2O (100 mL per mmol), washed with water (100 mL
per mmol), and the aqueous phase then extracted with Et2O (2”100 mL
per mmol). The combined organic extracts were washed with saturated
NaCl solution, dried over Na2SO4, filtered and the solvent removed
under reduced pressure. Purification of the crude product was carried out
by preparative thin-layer chromatography.
rac- and (1S,5R)-2-[(5-tert-Butyldimethylsilyloxymethyl)cyclopent-2-
enyl]acetic acid tert-butyl ester (30): Imidazole (2.17 g, 31.9 mmol) was
added at room temperature to
a solution of alcohol 29 (4.23 g,
19.9 mmol) in DMF (30 mL). After cooling to 08C a solution of TBSCl
(3.45 g, 22.9 mmol) in DMF (10 mL) was added dropwise. The cooling
bath was removed and the reaction mixture stirred for 2 h at room tem-
perature. After addition of water (250 mL) and Et2O (150 mL) the organ-
ic layer was separated and the water phase was extracted with Et2O (2”
100 mL). The combined organic layers were dried over MgSO4 and con-
centrated in vacuum. Purification by column chromatography (n-pen-
tane/Et2O 50:1) gave the title compound 30 (6.08 g, 18.6 mmol, 93%) as
a colorless oil. Rf =0.20 (n-pentane/Et2O 100:1); [a]2D0 =+76.08 (c=1.0 in
rac- and (1R,2R,5R)-(Z)-2-{2-[2-(2-Bromo-5-methoxyphenyl)vinyl]-5-
(tert-butyldimethylsilyloxymethyl)cyclopent-3-enyl}]acetic acid methyl
ester (34): Vinyl iodide 11 (102 mg, 300 mmol) and cyclopentene 33
(213 mg, 750 mmol) were treated with Pd(OAc)2 (3.4 mg, 15 mmol,
R
5 mol%), NaOAc (74 mg, 900 mmol) and TBACl (83 mg, 300 mmol) for
2 d at room temperature. After preparative thin-layer chromatography
(PE/ethyl acetate 30:1) compound 34 (54 mg, 111 mmol, 37%) was ob-
tained as a yellow oil. Moreover regioisomer 35 (31 mg, 63 mmol, 20%)
and not converted olefin 33 (132 mg, 464 mmol) were isolated. Rf =0.21
(PE/ethyl acetate 50:1); [a]2D0 =+137.28 (c=1.0 in CHCl3); 1H NMR
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.03 (s, 6H; Si
9H; Si(C(CH3)3)), 1.44 (s, 9H; CO2(C(CH3)3)), 2.07 (dd, J=15.0, 9.8 Hz,
A
A
ACHTREUNG
1H; 2-HB), 2.06–2.17 (m, 1H; 4’-HB), 2.29–2.41 (m, 1H; 4’-HA), 2.47 (dd,
J=15.0, 6.2 Hz, 1H; 2-HA), 2.44–2.54 (m, 1H; 5’-H), 3.04–3.16 (m, 1H;
1’-H), 3.54 (dd, J=10.1, 7.3 Hz, 1H; 5’-CH2-OTBS-HB), 3.62 (dd, J=10.1,
7.1 Hz, 1H; 5’-CH2-OTBS-HA), 5.71 ppm (m, 2H; 2’-H, 3’-H); 13C NMR
(300 MHz, CDCl3): d=ꢀ0.08 (s, 3H) and ꢀ0.06 (s, 3H) (Si
C
(50 MHz, CDCl3): d=ꢀ5.41, ꢀ5.37 (Si
(Si(C(CH3)3)), 28.09 (CO2(C(CH3)3)), 34.70, 35.92 (C-2, C-4’), 42.64,
42.70 (C-1’, C-5’), 63.19 (C-5’-CH2-OTBS), 80.03 (CO2(C(CH3)3)), 130.11,
134.01 (C-2’, C-3’), 172.75 ppm (C-1); IR (NaCl): n˜ =2930, 2858, 1732,
A
N
AHCTREUNG
A
ACHTREUNG
H), 3.25–3.39 (m, 1H; 2’-H), 3.50 (m, 2H; 5’-CH2-OTBS), 3.65 (s, 3H;
CO2CH3), 3.77 (s, 3H; Ar-OCH3), 5.51 (t, J=10.8 Hz, 1H; 1’’-H), 5.64–
5.69 (m, 1H) and 5.70–5.76 (m, 1H) (3’-H, 4’-H), 6.46 (d, J=11.4 Hz,
1H; 2’’-H), 6.67 (dd, J=8.7, 3.0 Hz, 1H; 4’’’-H), 6.75 (d, J=3.0 Hz, 1H;
6’’’-H), 7.43 ppm (d, J=8.7 Hz, 1H; 3’’’-H); 13C NMR (50 MHz, CDCl3):
AHCTREUNG
1473 cmꢀ1 MS (DCI): m/z (%): 344.4 (2) [M+NH4]+, 327.3 (100)
;
[M+H]+; HRMS (ESI): m/z: calcd for C18H34NaO3Si: 349.21694; found:
349.21709 [M+Na]+; elemental analysis calcd (%) for C18H34O3Si
(326.55): C 66.21, H 10.49; found: C 65.90, H 10.75.
d=ꢀ5.70, ꢀ5.60 (Si
C
G
G
rac- and (1S,5R)-2-[(5-tert-Butyldimethylsilyloxymethyl)cyclopent-2-
enyl]acetic acid methyl ester (33): NaOH (174 mg, 4.34 mmol) was added
Chem. Eur. J. 2007, 13, 8543 – 8563
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8553

L. F. Tietze et al.
136.19 (C-1’’), 138.43 (C-1’’’), 158.43 (C-5’’’), 174.04 ppm (C-1); IR
(NaCl): n˜ =3006, 2954, 2897, 1738, 1591 cmꢀ1; UV/Vis (MeCN): lmax (lg
e)=291.5 nm (3.291); MS (DCI): m/z (%): 514.1 (19) [M+NH4]+, 497.1
(100) [M+H]+; HRMS (ESI): m/z: calcd for C24H36BrO4Si: 495.15608;
found: 495.15600 [M+H]+; elemental analysis calcd (%) for
C24H35BrO4Si (495.52): C 58.17, H 7.12; found: C 58.48, H 7.21.
170.65 ppm (C-1, OC(O)CH3); IR (NaCl): n˜ =2955, 2930, 2857, 1773,
1732 cmꢀ1; UV/Vis (MeCN): lmax (lg e)=196.5 (4.389), 212.5 nm (4.397);
MS (ESI): m/z (%): 587.2 (100) [M+Na]+; HRMS (ESI): m/z: calcd for
C28H41BrNaO5Si: 587.17988; found: 587.17971 [M+Na]+, 582.22432
[M+NH4]+, 565.19782 [M+H]+.
(1S,2S,5S)- and (1R,2R,5R)-{2-(Z)-(2-[2-Bromo-5-(2,3,4-tri-O-methyl-a-
rac- and (3S,5R)-(Z)-2-{3-[2-(2-Bromo-5-methoxyphenyl)vinyl]-5-(tert-
butyldimethylsilyloxymethyl)cyclopent-1-enyl}acetic acid methyl ester
(35): Rf =0.15 (PE/ethyl acetate 50:1); 1H NMR (300 MHz, CDCl3): d=
l-rhamnopyranosyl)phenyl}vinyl)-5-tert-butyldimethylsilyloxymethylcy-
clopent-3-enyl]acetic acid methyl ester (38): Vinyl iodide 19 (51.3 mg,
100 mmol) and cyclopentene 33 (85.3 mg, 300 mmol) were treated with Pd-
0.00 (s, 6H; Si
A
(CH3)3)), 1.79–2.02 (m, 2H; 4’-
A
H), 2.91 (m, 1H; 5’-H), 3.08–3.26 (m, 2H; 2-H), 3.51–3.71 (m, 3H; 3’-H,
5’-CH2-OTBS), 3.69 (s, 3H; CO2CH3), 3.78 (s, 3H; Ar-OCH3), 5.47 (s,
1H; 2’-H), 5.60 (t, J=10.8 Hz, 1H; 1’’-H), 6.36 (d, J=11.4 Hz, 1H; 2’’-
H), 6.67 (dd, J=8.7, 3.1 Hz, 1H; 4’’’-H), 6.80 (d, J=3.0 Hz, 1H; 6’’’-H),
7.44 ppm (d, J=9.0 Hz, 1H; 3’’’-H); 13C NMR (50 MHz, CDCl3): d=
TBACl (28 mg, 100 mmol) for 3 d at room temperature. After preparative
thin-layer chromatography (n-pentane/ethyl acetate 5:1) compound 38
(28.0 mg, 41.8 mmol, 42%, ꢁ1.8:1 ratio of diastereomers) was obtained as
a colorless oil. Moreover the regioisomer 39 (12.0 mg, 17.9 mmol, 18%,
ꢁ1.8:1 ratio of diastereomers) was isolated. Rf =0.42 (n-pentane/ethyl
1
ꢀ5.53 (Si
C
(CH3)3)), 25.81 (Si(C
(CH3)3)), 35.43 (C-2,
acetate 3:1); H NMR (300 MHz, CDCl3): d=ꢀ0.07, ꢀ0.05 (2”s, 6H; Si-
A
N
6’’’’-CH3), 2.36–2.54 (m, 3H; 2-H2, 1’-H), 2.82–2.91 (m, 1H; 5’-H), 3.18,
3.19 (2”dd, J=9.6, 9.3 Hz, 1H; 4’’’’-H), 3.22–3.33 (m, 1H; 2’-H), 3.50 (m,
2H; 1’’’’’-H2), 3.54–3.70 (m, 2H; 3’’’’-H, 5’’’’-H) 3.55, 3.56, 3.57, 3.57, 3.59
(5”s, 9H; 3”OCH3), 3.64, 3.64 (2”s, 3H; CO2CH3), 3.72–3.77 (m, 1H;
2’’’’-H), 5.47, 5.51 (2”d, J=1.8 Hz, 1H; 1’’’’-H), 5.52 (dd, J=11.4,
10.5 Hz, 1H; 1’’-H), 5.66–5.78 (m, 2H; 3’-H, 4’-H), 6.43 (d, J=11.4 Hz,
1H; 2’’-H), 6.86 (dd, J=8.4, 2.7 Hz, 1H; 4’’’-H), 6.89 (d, J=2.7 Hz, 1H;
6’’’-H), 7.45 ppm (d, J=8.4 Hz, 1H; 3’’’-H); 13C NMR (75 MHz, CDCl3):
1464, 1162, 836 cmꢀ1
291.5 nm (3.399); MS (DCI): m/z (%): 514.1 (94) [M+NH4]+, 497.0 (100)
[M+H]+.
rac- and (1S,2S,5S)-(Z)-2-{2-[2-(5-Acetoxy-2-bromophenyl)vinyl]-5-(tert-
butyldimethylsilyloxymethyl)cyclopent-3-enyl}acetic acid tert-butyl ester
(36): Vinyl iodide 12 (37 mg, 100 mmol) and cyclopentene 30 (82 mg,
d=ꢀ5.67, ꢀ5.55, ꢀ5.52 (Si
A
N
ACHTREUNG
250 mmol) were treated with Pd(OAc)2 (1.1 mg, 5 mmol, 5 mol%),
H
1’), 48.77, 48.80 (C-5’), 49.34 (C-2’), 51.44, 51.55 (CO2CH3), 57.92, 57.94,
57.96, 59.25, 60.94, 60.95 (3”OCH3), 62.36, 62.38 (C-1’’’’’), 68.65, 68.68
(C-5’’’’), 77.14, 77.19 (C-2’’’’), 80.75, 80.78 (C-3’’’’), 81.87, 81.91 (C-4’’’’),
95.06, 95.37 (C-1’’’’), 115.97, 116.07 (C-2’’’), 116.10, 116.62 (C-4’’’), 118.29,
118.58 (C-6’’’), 129.82 (C-2’’), 133.08, 133.21 (C-3’’’), 133.45, 133.52,
134.41, 134.52 (C-3’, C-4’), 136.23, 136.36 (C-1’’), 138.66, 138.74 (C-1’’’),
155.16, 155.29 (C-5’’’), 173.93, 173.99 ppm (C-1); IR (NaCl): n˜ =2929,
2856, 1738, 1463 cmꢀ1; UV/Vis (CH3CN): lmax (lg e)=199.5 (2.416), 214.5
(2.410), 287.5 nm (1.207); MS (DCI): m/z (%): 688.7 (100) [M+NH4]+;
elemental analysis calcd (%) for C32H49BrO8Si (669.72): C 57.39, H 7.37;
found: C 57.12, H 7.06.
NaOAc (25 mg, 300 mmol) and TBACl (28 mg, 100 mmol) for 6 d at
ꢀ258C. After preparative thin-layer chromatography (n-pentane/ethyl
acetate 10:1) compound 36 (29 mg, 51 mmol, 51%) was obtained as
yellow oil. Moreover regioisomer 37 (14 mg, 25 mmol, 25%) and not con-
verted olefin 30 (48 mg, 146 mmol) were isolated. Rf =0.57 (n-pentane/
ethyl acetate 10:1); [a]2D0 =ꢀ113.88 (c=1.0 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=ꢀ0.06 (s, 3H) and ꢀ0.04 (s, 3H) (Si
ACHTREUNG
(s, 9H; Si(C(CH3)3)), 1.42 (s, 9H; CO2(C
A
ACHTREUNG
OC(O)CH3), 2.30–2.50 (m, 3H; 2-H, 1’-H), 2.81–2.90 (m, 1H; 5’-H),
3.25–3.37 (m, 1H; 2’-H), 3.54 (d, J=4.5 Hz, 2H; 5’-CH2-OTBS), 5.51 (t,
J=11.0 Hz, 1H; 1’’-H), 5.62–5.68 (m, 1H) and 5.74–5.81 (m, 1H) (3’-H,
4’-H), 6.45 (d, J=11.4 Hz, 1H; 2’’-H), 6.88 (dd, J=8.6, 2.6 Hz, 1H;
4’’’-H), 6.97 (d, J=2.7 Hz, 1H; 6’’’-H), 7.54 ppm (d, J=8.4 Hz, 1H; 3’’’-
A
nopyranosyl)phenyl]vinyl)-5-tert-butyldimethylsilyloxymethylcyclopent-1-
enyl}acetic acid methyl ester (39): Rf =0.39 (n-pentane/ethyl acetate 3:1);
H); 13C NMR (50 MHz, CDCl3): d=ꢀ5.68, ꢀ5.56 (Si
ACHTREUNG
(CH3)3)), 21.12 (OC(O)CH3), 25.74 (Si(C
(CH3)3)), 28.04 (CO2(C
N
1H NMR (300 MHz, CDCl3): d=ꢀ0.01, 0.00, 0.00 (3”s, 6H; Si
N
34.58 (C-2), 44.65 (C-1’), 48.74 (C-5’), 49.39 (C-2’), 62.45 (C-5’-CH2-
OTBS), 80.08 (CO2(C(CH3)3)), 120.39 (C-2’’’), 121.57 (C-4’’’), 123.49 (C-
N
C
1.77–1.99 (m, 2H; 4’-H2), 2.84–2.99 (m, 1H; 5’-H), 3.14–3.23 (m, 3H; 2-
H2, 4’’’’-H), 3.52–3.70 (m, 5H, 3’-H; 3’’’’-H, 5’’’’-H, 1’’’’’-H2), 3.55, 3.56,
3.57 (3”s, 9H; 3”OCH3), 3.69 (s, 3H; CO2CH3), 3.73–3.78 (m, 1H;
2’’’’-H), 5.43–5.52 (m, 1H; 2’-H), 5.48 (d, J=1.8 Hz, 1H; 1’’’’-H), 5.58 (dd,
J=11.4, 10.5 Hz, 1H; 1’’-H), 6.32 (d, J=11.4 Hz, 1H; 2’’-H), 6.80–6.90
(m, 1H; 4’’’-H), 6.94, 6.97 (2”d, J=2.7 Hz, 1H; 6’’’-H), 7.45 ppm (d, J=
8.7 Hz, 1H; 3’’’-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.58, ꢀ5.50, (Si-
6’’’), 129.16 (C-2’’), 133.15 (C-3’’’), 133.95, 134.09 (C-3’, C-4’), 136.95 (C-
1’’), 138.69 (C-1’’’), 149.35 (C-5’’’), 168.95, 172.87 ppm (C-1, OC(O)CH3);
IR (NaCl): n˜ =2955, 2929, 2857, 1774, 1728 cmꢀ1; UV/Vis (MeCN): lmax
(lg e)=194.5 (4.397), 213.0 nm (4.352); MS (DCI): m/z (%): 584.3 (42)
[M+NH4]+, 567.3 (100) [M+H]+; HRMS (ESI): m/z: calcd for
C28H41BrNaO5Si: 587.17988; found: 587.17989 [M+Na]+, 582.22455
[M+NH4]+, 565.19795 [M+H]+; elemental analysis calcd (%) for
C28H41BrO5Si (565.61): C 59.43, H 7.31; found: C 59.60, H 7.23.
A
G
N
35.08, 35.15, 35.44 (C-2, C-4’), 42.59, 48.91, 49.02 (C-3’, C-5’), 51.72
(CO2CH3), 57.94, 59.28, 59.31, 60.95 (3”OCH3), 65.46, 65.56 (C-1’’’’’),
68.64, 68.74 (C-5’’’’), 77.11, 77.17 (C-2’’’’), 80.78 (C-3’’’’), 81.88 (C-4’’’’),
95.28, 95.33 (C-1’’’’), 116.12, 116.17 (C-2’’’), 116.28, 116.38 (C-4’’’), 118.26,
118.38 (C-6’’’), 127.23 (C-2’’), 132.02, 132.13, 133.08, 133.11 (C-2’, C-3’’’),
137.33, 137.43 (C-1’’), 138.57, 139.25 (C-1’, C-1’’’), 155.10, 155.16 (C-5’’’),
171.81 ppm (C-1); IR (NaCl): n˜ =2931, 2856, 1742, 1464 cmꢀ1; UV/Vis
(CH3CN): lmax (lg e)=215.0 (4.399), 287.5 nm (3.237); MS (DCI): m/z
(%): 688.7 (100) [M+NH4]+, 671.7 (4) [M+H]+; HRMS (ESI): m/z:
calcd for C32H53BrNO8Si: 686.27183; found: 686.27189 [M+NH4]+.
rac- and (3S,5R)-(Z)-2-{3-[2-(5-Acetoxy-2-bromophenyl)vinyl]-5-(tert-bu-
tyldimethylsilyloxymethyl)cyclopent-1-enyl}acetic acid tert-butyl ester
(37): Rf =0.53 (n-pentane/ethyl acetate 10:1); [a]2D0 =+101.88 (c=1.0 in
1
CHCl3); H NMR (300 MHz, CDCl3): d=ꢀ0.01 (s, 6H, Si
ACHTREUNG
9H; Si(C
A
ACHTREUNG
1.94 (m, 1H; 4’-HA), 2.27 (s, 3H; OC(O)CH3), 2.82–2.93 (m, 1H; 5’-H),
2.95–3.12 (m, 2H; 2-H), 3.48 (dd, J=9.8, 6.2 Hz, 1H; 5’-CH2-OTBS-HB),
3.56 (dd, J=9.9, 5.7 Hz, 1H; 5’-CH2-OTBS-HA), 3.50–3.66 (m, 1H; 3’-H),
5.42 (s, 1H; 2’-H), 5.59 (t, J=11.0 Hz, 1H; 1’’-H), 6.31 (d, J=11.4 Hz,
1H; 2’’-H), 6.85 (dd, J=8.7, 2.7 Hz, 1H; 4’’’-H), 6.97 (d, J=2.7 Hz, 1H;
6’’’-H), 7.53 ppm (d, J=8.7 Hz, 1H; 3’’’-H); 13C NMR (50 MHz, CDCl3):
A
l-rhamnopyranosyl)phenyl]vinyl)-5-tert-butyldimethylsilyloxymethylcy-
clopent-3-enyl]acetic acid tert-butyl ester (40): Vinyl iodide 19 (51.3 mg,
100 mmol) and cyclopentene 30 (98.0 mg, 300 mmol) were treated with Pd-
d=ꢀ5.47 (Si
(Si(C(CH3)3)), 28.06 (CO2(C
3’), 49.26 (C-5’), 65.28 (C-5’-CH2-OTBS), 80.50 (CO2(C
A
N
A
ACHTREUNG
U
A
(C-2’’’), 121.49 (C-4’’’), 123.50 (C-6’’’), 126.69 (C-2’’), 131.50 (C-2’), 133.15
(C-3’’’), 138.07 (C-1’’), 138.71, 139.83 (C-1’, C-1’’’), 149.30 (C-5’’’), 169.01,
TBACl (28 mg, 100 mmol) for 3 d at room temperature. After preparative
thin-layer chromatography (n-pentane/ethyl acetate 6:1) compound 40
8554
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8543 – 8563

Novel Spinosyn AAnalogues
FULL PAPER
(30.0 mg, 42.1 mmol, 42%) and the regioisomer 41 (11.5 mg, 16.2 mmol,
16%) were obtained as colorless oils. Rf =0.53 (n-pentane/ethyl acetate
3:1); 1H NMR (300 MHz, CDCl3): d=0.00, 0.01, 0.02 (3”s, 6H; Si-
(d, J=11.4 Hz, 1H; 2’’-H), 6.63 (dd, J=8.7, 3.0 Hz, 1H; 4’’’-H), 6.75 (d,
J=3.0 Hz, 1H; 6’’’-H), 7.38 ppm (d, J=8.7 Hz, 1H; 3’’’-H); 13C NMR
(50 MHz, CDCl3): d=ꢀ5.67, ꢀ5.57 (Si
(Si(C(CH3)3)), 28.07 (CO2(C(CH3)3)), 35.03 (C-2), 44.46 (C-1’), 48.97 (C-
5’), 49.55 (C-2’), 62.39 (C-5’-CH2-OTBS), 80.62 (CO2(C(CH3)3)), 114.04
A
N
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
H2; 1’-H), 2.88–2.98 (m, 1H; 5’-H), 3.35 (dd, J=9.3, 9.3 Hz, 1H; 4’’’’-H),
3.27–3.38 (m, 1H; 2’-H), 3.58–3.76 (m, 4H; 3’’’’-H, 5’’’’-H, 1’’’’’-H2), 3.61,
3.62, 3.63, 3.64 (4”s, 9H; 3”OCH3), 3.79–3.84 (m, 1H; 2’’’’-H), 5.54, 5.57
(2”d, J=1.8 Hz, 1H; 1’’’’-H), 5.60 (dd, J=11.4, 11.4 Hz, 1H; 1’’-H),
5.73–5.87 (m, 2H; 3’-H, 4’-H), 6.50 (d, J=11.4 Hz, 1H; 2’’-H), 6.89–7.00
(m, 2H; 4’’’-H, 6’’’-H), 7.51 ppm (d, J=8.7 Hz, 1H; 3’’’-H); 13C NMR
(75 MHz, CDCl3, ꢁ2.1:1 ratio of diastereomers): d=ꢀ5.67, ꢀ5.25, (Si-
(C-2’’’), 115.80, 117.49, 129.78, 133.20, 133.33, 134.56, 136.28 (C-3’, C-4’,
C-1’’, C-2’’, C-3’’’, C-4’’’, C-6’’’), 138.45 (C-1’’’), 154.77 (C-5’’’), 173.63 ppm
(C-1); IR (KBr): n˜ =3374, 2954, 2929, 2893, 2856, 1698 cmꢀ1; UV/Vis
(MeCN): lmax (lg e)=200.5 (4.318), 213.0 (4.307), 291.5 nm (3.246); MS
(ESI): m/z (%): 1071.6 (30), 1070.6 (55), 1068.7 (100), 1066.7 (46)
[2M+Na]+, 547.1 (62), 545.1 (60) [M+Na]+, 524.9 (16), 522.9 (16)
[M+H]+; HRMS (ESI): m/z: calcd for C26H39BrNaO4Si: 545.16932;
found: 545.16920 [M+Na]+, 523.18729 [M+H]+; elemental analysis calcd
(%) for C26H39BrO4Si (523.58): C 59.64, H 7.51; found: C 59.95, H 7.10.
A
(CH3)3)), 25.71, 25.77
G
ACHTREUNG
48.58, 48.67 (C-5’), 49.51, 49.56 (C-2’), 57.89, 57.95, 59.25, 60.93 (3”
OCH3), 62.46, 62.51 (C-1’’’’’), 68.63 (C-5’’’’), 77.12, 77.18 (C-2’’’’), 80.00
General procedure for the intramolecular Heck reactions: Astirred de-
gassed mixture of the corresponding aryl bromide, palladacycle 43 (4–
7 mol%) and nBu4NOAc (2.0 equiv) in DMF/MeCN/H2O 5:5:1 (25 mL
pro mmol) was heated at different temperatures (120–1308C) for 0.5–
7.5 h under an argon atmosphere and the exclusion of light. After cooling
to room temperature Et2O (150 mL per mmol) and water (250 mL per
mmol) were added, then the organic phase was separated and the aque-
ous phase extracted with Et2O (2”150 mL per mmol). The combined or-
ganic extracts were dried over MgSO4, filtered and the solvent removed
under reduced pressure. Purification of the crude products was carried
out by column chromatography.
(CO2(C(CH3)3)), 80.73, 80.77 (C-3’’’’), 81.85, 81.89 (C-4’’’’), 95.11, 95.31
A
(C-1’’’’), 115.92, 116.50 (C-4’’’), 116.02, 116.06 (C-2’’’), 118.26, 118.69 (C-
6’’’), 129.65, 129.68 (C-2’’), 133.03, 133.14 (C-3’’’), 133.71, 134.30, 134.34
(C-3’, C-4’), 136.38, 136.57 (C-1’’), 138.68, 138.73 (C-1’’’), 155.15, 155.22
(C-5’’’), 172.81, 173.89 ppm (C-1); IR (NaCl): n˜ =2930, 2857, 1729,
1463 cmꢀ1; UV/Vis (CH3CN): lmax (lg e)=199.5 (4.412), 214.5 (4.395),
286.5 nm (3.127); MS (DCI): m/z (%): 730.5 (100) [M+NH4]+, 713.6 (36)
[M+H]+; HRMS (ESI): m/z: calcd for C35H56BrO8Si: 711.29223; found:
711.29225 [M+H]+, 728.31839 [M+NH4]+, 733.27398 [M+Na]+,
749.24796 [M+K]+.
rac- and (3R,3aR,9bR)-2-[2-(tert-Butyldimethylsilyloxymethyl)-7-me-
thoxy-3a,9b-dihydro-3H-cyclopenta[a]naphthalen-3-yl]acetic acid methyl
ester (44): Compound 34 (2.10 g, 4.24 mol) was treated with palladacycle
43 (159 mg, 170 mmol, 4 mol%) and nBu4NOAc (1.61 g, 8.48 mmol) for
4 h at 1258C. Purification by column chromatography (n-pentane/ethyl
acetate 30:1) gave compound 44 (1.58 g, 3.81 mol, 90%) as a yellow oil.
Rf =0.22 (n-pentane/ethyl acetate 30:1); [a]2D0 =+147.28 (c=1.0 in
(3S,5R)- and (3R,5S)-{3-(Z)-(2-[2-Bromo-5-(2,3,4-tri-O-methyl-a-l-rham-
nopyranosyl)phenyl]vinyl)-5-tert-butyldimethylsilyloxymethylcyclopent-1-
enyl}acetic acid tert-butyl ester (41): Rf =0.48 (PE/ethyl acetate 50:1);
1H NMR (300 MHz, CDCl3): d=0.00, 0.01 (2”s, 6H; Si
ACHTREUNG
9H; Si(C
CO2(C
ACHTREUNG
ACHTREUNG
(m, 2H; 2-H2), 3.18 (dd, J=9.3, 9.3 Hz, 1H; 4’’’’-H), 3.48–3.69 (m, 5H;
3’-H, 3’’’’-H, 5’’’’-H, 1’’’’’-H2), 3.55, 3.56, 3.57 (3”s, 9H; 3”OCH3), 3.73–
3.78 (m, 1H; 2’’’’-H), 5.45, 5.49 (2”m, 2H; 2’-H, 1’’’’-H), 5.59 (dd, J=
11.4, 11.4 Hz, 1H; 1’’-H), 6.31 (d, J=11.4 Hz, 1H; 2’’-H), 6.81–6.89 (m,
1H; 4’’’-H), 6.95, 6.99 (2”d, J=3.0 Hz, 1H; 6’’’-H), 7.45 ppm (d, J=
8.7 Hz, 1H; 3’’’-H); 13C NMR (75 MHz, CDCl3 ꢁ2.1:1 ratio of diastereo-
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.02 (s, 6H; Si
9H; Si(C(CH3)3)), 2.39 (dd, J=15.6, 9.8 Hz, 1H; 2-HB), 2.72 (dd, J=15.6,
(CH3)2), 0.88 (s,
AHCTREUNG
4.3 Hz, 1H; 2-HA), 2.98–3.14 (m, 2H; 3’-H, 3a’-H), 3.70 (s, 3H;
CO2CH3), 3.77 (s, 3H; Ar-OCH3), 4.05 (m, 1H; 9b’-H), 4.19 (m, 2H; 5’-
CH2-OTBS), 5.46 (s, 1H; 1’-H), 5.73 (dd, J=9.8, 3.2 Hz, 1H; 4’-H), 6.24
(dd, J=9.8, 2.2 Hz, 1H; 5’-H), 6.54 (d, J=2.6 Hz, 1H; 6’-H), 6.69 (dd,
J=8.3, 2.6 Hz, 1H; 8’-H), 7.03 ppm (d, J=8.3 Hz, 1H; 9’-H); 13C NMR
mers): d=ꢀ5.48, (Si
25.83 (Si(C(CH3)3)), 28.04 (CO2(C
4’), 42.55, 48.97, 49.08 (C-3’, C-5’), 57.91, 59.25, 59.27, 60.92 (3”OCH3),
65.31, 65.42 (C-1’’’’’), 68.61 (C-5’’’’), 77.15 (C-2’’’’), 80.43 (CO2(C(CH3)3)),
A
N
A
ACHTREUNG
(75 MHz, CDCl3): d=ꢀ5.40 (Si
N
N
AHCTREUNG
AHCTREUNG
(CO2CH3), 55.23 (Ar-OCH3), 61.09 (C-5’-CH2-OTBS), 112.09 (C-6’),
112.64 (C-8’), 125.60 (C-5’), 126.75 (C-9a’*), 128.73 (C-9’), 129.45 (C-1’),
131.68 (C-4’), 132.92 (C-5a’*), 144.12 (C-2’), 158.24 (C-7’), 173.25 ppm
(C-1); IR (NaCl): n˜ =2953, 2930, 2856, 1738, 1604 cmꢀ1; UV/Vis (MeCN):
lmax (lg e)=228.5 (4.477), 264.5 (3.726), 273.5 (3.651), 302.0 (3.377),
312.0 nm (3.324); MS (DCI): m/z (%): 423.5 (20) [M+NH4]+, 415.4 (100)
[M+H]+; HRMS (ESI): m/z: calcd for C24H34O4Si: 414.2226; found:
414.2226 [M]+; elemental analysis calcd (%) for C24H34O4Si (414.61): C
69.52, H 8.27; found: C 69.69, H 8.03.
80.76 (C-3’’’’), 81.86 (C-4’’’’), 95.25, 95.30 (C-1’’’’), 116.11, 116.17 (C-2’’’),
116.22, 116.32 (C-4’’’), 118.26, 118.40 (C-6’’’), 127.08 (C-2’’), 131.63,
131.71, 133.05, 133.08 (C-2’, C-3’’’), 137.53, 137.63 (C-1’’), 138.59, 139.73,
139.76 (C-1’, C-1’’’), 155.09, 155.15 (C-5’’’), 170.61, 170.63 ppm (C-1); IR
(NaCl): n˜ =2930, 2857, 1732, 1464 cmꢀ1; UV/Vis (CH3CN): lmax (lg e)=
215.0 (4.417), 280.5 nm (3.296); MS (DCI): m/z (%): 730.5 (100)
[M+NH4]+, 713.5 (10) [M+H]+; HRMS (ESI): m/z: calcd for
C35H59BrNO8Si: 728.31878; found: 728.31860 [M+NH4]+, 733.27419
[M+Na]+.
(3S,3aS,9bS)- and (3R,3aR,9bR)-[2-tert-Butyldimethylsilyloxymethyl-7-
(2,3,4-tri-O-methyl-a-l-rhamnopyranosyl)-3a,9b-dihydro-3H-cyclopen-
ta[a]naphthalen-3-yl]acetic acid methyl ester (45): Compound 38
(60.0 mg, 89.6 mmol) was treated with palladacycle 43 (4.20 mg,
4.48 mmol, 5 mol%) and nBu4NOAc (54.0 mg, 179 mmol) for 0.5 h at
1258C. Purification by column chromatography (n-pentane/ethyl acetate
10:1) gave 45 (45.0 mg, 76.4 mmol, 85%, ꢁ1.8:1 ratio of diastereomers)
rac- and (1S,2S,5S)-(Z)-2-{2-[2-(2-Bromo-5-hydroxyphenyl)vinyl]-5-(tert-
butyldimethylsilyloxymethyl)cyclopent-3-enyl}acetic acid tert-butyl ester
(42): NaHCO3 (1.49 g, 17.7 mmol) was added in one portion at room
temperature to
a solution of acetyl protected phenol 36 (5.00 g,
8.84 mmol) in MeOH (100 mL). After stirring for 7 h at room tempera-
ture the reaction was quenched by adding CH2Cl2 (200 mL) and saturat-
ed aqueous NH4Cl solution (200 mL). The organic phase was separated
and the aqueous phase extracted with CH2Cl2 (2”150 mL). The com-
bined organic layers were dried over MgSO4 and concentrated in
vacuum. Purification of the residue by column chromatography (n-pen-
tane/ethyl acetate 10:1) afforded the free phenol (4.60 g, 8.79 mmol,
99%) as a white solid. Rf =0.30 (n-pentane/ethyl acetate 10:1); m.p.
848C (n-pentane/ethyl acetate); [a]2D0 =ꢀ98.28 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=ꢀ0.06 (s, 3H) and ꢀ0.04 (s, 3H) (Si-
as
(600 MHz, CDCl3): d=0.00 (s, 6H; Si
a
yellow oil. Rf =0.39 (n-pentane/ethyl acetate 3:1); 1H NMR
A
N
1.24 (d, J=6.6 Hz, 3H; 6’’-CH3), 2.39 (dd, J=15.6, 10.2 Hz, 1H; 2-HA),
2.69 (dd, J=15.6, 4.8 Hz, 1H; 2-HB), 3.01 (m, 1H; 3’-H), 3.07 (m, 1H;
3a’-H), 3.16 (dd, J=9.3, 9.3 Hz, 1H; 4’’-H), 3.52, 3.54, 3.55 (3”s, 9H; 3”
OCH3), 3.62–3.66 (m, 2H; 3’’-H, 5’’-H), 3.68 (s, 3H; CO2CH3), 3.70–3.72
(m, 1H; 2’’-H), 4.04 (m, 1H; 9b’-H), 4.17 (m, 2H; 1’’’-H2), 5.45 (m, 1H;
1’-H), 5.48 (m, 1H; 1’’-H), 5.72 (dd, J=10.2, 3.0 Hz, 1H; 4’-H), 6.21 (dd,
J=10.2, 1.8 Hz, 1H; 5’-H), 6.68, 6.69 (2”d, J=3.0 Hz, 1H; 6’-H), 6.82,
6.83 (2”dd, J=8.4, 3.0 Hz, 1H; 8’-H), 7.01 ppm (d, J=8.4 Hz, 1H; 9’-H);
A
G
N
(m, 3H; 2-H, 1’-H), 2.81–2.91 (m, 1H; 5’-H), 3.31–3.41 (m, 1H; 2’-H),
3.49–3.60 (m, 2H; 5’-CH2-OTBS), 5.50 (t, J=11.0 Hz, 1H; 1’’-H), 5.61–
5.67 (m, 1H) and 5.74–5.81 (m, 1H) (3’-H, 4’-H), 6.14 (s, 1H; OH), 6.42
13C NMR (75 MHz, CDCl3): d=ꢀ5.42, ꢀ5.41 (Si
A
Chem. Eur. J. 2007, 13, 8543 – 8563
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8555

L. F. Tietze et al.
18.29 (Si(C
A
(CH3)3)), 37.68 (C-2), 44.22 (C-9b’), 44.70
and then cooled to ꢀ658C. ZnEt2 (90.5 mL, 90.5 mmol,
c
ꢁ1m in
(C-3a’), 50.40 (C-3’), 51.62 (CO2CH3), 57.84, 59.14, 60.93 (3”OCH3),
61.06 (C-1’’’), 68.45 (C-5’’), 77.28 (C-2’’), 80.80 (C-3’’), 82.01 (C-4’’), 95.07,
95.11 (C-1’’), 114.46, 114.52 (C-6’), 114.90, 115.07 (C-8’), 125.41 (C-5’),
128.33, 128.35, 133.04, 133.06, 144.29 (C-2’, C-5a’, C-9a’), 128.78, 128.82
(C-9’), 129.23 (C-1’), 131.73 (C-4’), 155.07, 155.09 (C-7’), 173.20 ppm (C-
1); IR (NaCl): n˜ =2931, 2856, 1738, 1499 cmꢀ1; UV/Vis (CH3CN): lmax (lg
e)=226.0 (4.498), 265.0 (3.806), 274.0 (3.731), 298.0 (3.292), 308.5 nm
(3.216); MS (DCI): m/z (%): 606.7 (100) [M+NH4]+, 589.6 (67) [M+H]+
; elemental analysis calcd (%) for C32H48O8Si (588.80): C 65.28, H 8.22;
found: C 65.02, H 7.95.
n-hexane) was added and the mixture stirred for 20 min after which the
temperature was raised to ꢀ308C. Then a solution of 4-triisopropylsily-
loxybutanal (56) (12.3 g, 50.3 mmol) in toluene (6 mL) was slowly added
dropwise whereupon the mixture was warmed to ꢀ208C and stirred for
68 h at this temperature. The reaction was quenched by addition of sat.
aqueous NH4Cl (25 mL) and diluted with Et2O (135 mL) and 2m HCl
(300 mL) after warming up to room temperature. The organic phase was
separated and the aqueous phase extracted with Et2O (3”130 mL). The
combined organic extracts were washed thoroughly with sat. aqueous
NaHCO3, dried over MgSO4 and concentrated under reduced pressure
(temperature of water bath: <308C). Column chromatography (n-pen-
tane/Et2O 5:1) gave alcohol 58 (13.3 g, 48.5 mmol, 96%) as a colorless
oil. Rf =0.38 (n-pentane/Et2O 3:1); [a]2D0 =+4.08 (c=1.0 in CHCl3);
1H NMR (200 MHz, CDCl3): d=0.91 (t, J=7.4 Hz, 3H; 6-H), 0.98–1.14
(3S,3aS,9bS)- and (3R,3aR,9bR)-[2-tert-Butyldimethylsilyloxymethyl-7-
(2,3,4-tri-O-methyl-a-l-rhamnopyranosyl)-3a,9b-dihydro-3H-cyclopen-
ta[a]naphthalen-3-yl]acetic acid tert-butyl ester (46): Compound 40
(58.1 mg, 81.7 mmol) was treated with palladacycle 43 (3.83 mg,
4.09 mmol, 5 mol%) and nBu4NOAc (49.3 mg, 163 mmol) for 1.5 h at
1208C. Purification by thin layer chromatography (n-pentane/ethyl ace-
tate 6:1) gave 46 (43.2 mg, 68.5 mmol, 84%, ꢁ2:1 ratio of diastereomers)
(m, 21H; Si(CH
3-, 5-H), 2.62 (brs, 1H; OH), 3.52 (m, 1H; 4-H), 3.71 ppm (m, 2H; 1-H);
13C NMR (50 MHz, CDCl3): d=10.01 (C-6), 11.90 (Si(CH
(CH3)2)3), 17.95
(Si(CH(CH3)2)3), 29.30, 30.11, 34.14 (C-2, C-3, C-5), 63.77 (C-1),
(CH3)2)3), 1.36–1.52 (m, 3H) and 1.57–1.70 (m, 3H) (2-,
AHCTREUNG
a
colorless oil. Rf =0.08 (n-pentane/ethyl acetate 10:1); 1H NMR
AHCTREUNG
as
(300 MHz, CDCl3): d=ꢀ0.01 (s, 6H; Si(C
(CH3)3)), 1.23 (d, J=6.0 Hz, 3H; 6’’-CH3), 1.44 (s, 9H; CO2(C
72.89ppm (C-4); IR (NaCl): n˜ =3361, 2943, 2892, 2867, 1464, 1105 cmꢀ1
;
AHCTREUNG
MS (DCI): m/z (%): 566.6 (2) [2M+NH4]+, 549.5 (2) [2M+H]+, 292.3
(43) [M+NH4]+, 275.3 (100) [M+H]+; GC: (ꢀ)-enantiomer: tR =
A
ACHTREUNG
2.26 (dd, J=15.6, 9.8 Hz, 1H; 2-HA), 2.57 (dd, J=15.6, 4.5 Hz, 1H; 2-
HB), 2.92–3.01 (m, 1H; 3’-H), 3.05–3.12 (m, 1H; 3a’-H), 3.16 (dd, J=9.3,
9.3 Hz, 1H; 4’’-H), 3.52, 3.53, 3.54 (3”s, 9H; 3”OCH3), 3.61–3.67 (m,
2H; 3’’-H, 5’’-H), 3.69–3.72 (m, 1H; 2’’-H), 4.04 (m, 1H; 9b’-H), 4.17 (m,
2H; 1’’’-H2), 5.41 (m, 1H; 1’-H), 5.48 (d, J=1.5 Hz, 1H; 1’’-H), 5.72 (dd,
J=9.9, 3.0 Hz, 1H; 4’-H), 6.21 (dd, J=9.9, 2.1 Hz, 1H; 5’-H), 6.66–6.70
(m, 1H; 6’-H), 6.79–6.86 (m, 1H; 8’-H), 7.01 ppm (d, J=8.4 Hz, 1H; 9’-
23.70 min, (+)-enantiomer: tR =24.36 min at
98% ee.
Tiso =1208C, p=80 kPa,
(4S)-4-(2-Methoxy-ethoxymethoxy)-hexanol (59): (iPr)2NEt (6.4 mL,
4.70 g, 36.4 mmol) was added dropwise at room temperature to a solution
of alcohol 58 (5.00 g, 18.2 mmol) in CH2Cl2 (50 mL) and stirring was con-
tinued for 5 min, then MEMCl (3.6 mL, 3.97 g, 31.9 mmol) was added
dropwise at 08C whereupon stirring was continued for 10 min at 08C and
5 h at room temperature. The reaction was quenched by addition of sat.
aqueous NH4Cl (50 mL), the phases were separated and the aqueous
phase was extracted with CH2Cl2 (2”50 mL). The combined organic ex-
tracts were dried over MgSO4 and concentrated under reduced pressure.
Purification of the residue by column chromatography (n-pentane/ethyl
acetate 30:1) gave the silyl- and MEM-protected diol (5.58 g, 15.4 mmol,
H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.42, ꢀ5.39 (Si
ACHTREUNG
6’’), 18.30 (Si(C
(CH3)3)), 25.87 (Si(C
(CH3)3)), 28.09 (CO2(C
ACHTREUNG
39.21 (C-2), 44.25 (C-9b’), 44.51 (C-3a’), 50.52 (C-3’), 57.84, 59.14, 60.92
(3”OCH3), 61.05 (C-1’’’), 68.44 (C-5’’), 77.28 (C-2’’), 80.49 (CO2(C-
(CH3)3)), 80.80 (C-3’’), 82.02 (C-4’’), 95.07 (C-1’’), 114.41, 114.51 (C-6’),
114.85, 115.06 (C-8’), 125.31 (C-5’), 128.45, 133.08, 133.11, 144.55 (C-2’,
C-5a’, C-9a’), 128.71 (C-1’), 128.81, 128.86 (C-9’), 132.07 (C-4’), 155.05,
155.07 (C-7’), 172.03 ppm (C-1); IR (NaCl): n˜ =2931, 2856, 1728,
1499 cmꢀ1; UV/Vis (CH3CN): lmax (lg e)=226.5 (4.484), 265.0 (3.787),
274.0 (3.712), 298.0 (3.264), 308.5 nm (3.185); MS (DCI): m/z (%): 648.6
(34) [M+NH4]+, 631.6 (100) [M+H]+; elemental analysis calcd (%) for
C35H54O8Si (630.88): C 66.63, H 8.63; found: C 66.50, H 8.34.
85%) as a colorless oil. Rf =0.54 (n-pentane/ethyl acetate 10:1); [a]D20
+4.58 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.90 (t, J=
7.5 Hz, 3H; 6-H), 1.00–1.16 (m, 21H; Si(CH(CH3)2)3), 1.47–1.68 (m, 6H;
=
AHCTREUNG
2-, 3-, 5-H), 3.39 (s, 3H; MEM-OCH3), 3.52–3.61 (m, 3H) and 3.66–3.76
(m, 4H) (1-, 4-H, MEM-OCH2CH2O), 4.76 ppm (s, 2H; MEM-OCH2O);
13C NMR (50 MHz, CDCl3): d=9.46 (C-6), 11.94 (Si(CH
ACHTREUNG
rac- and (3R,3aR,9bR)-2-[2-(tert-Butyldimethylsilyloxymethyl)-7-hy-
droxy-3a,9b-dihydro-3H-cyclopenta[a]naphthalen-3-yl]acetic acid tert-
butyl ester (47): Compound 42 (4.55 g, 8.69 mmol) was treated with palla-
dacycle 43 (572 mg, 610 mmol, 7 mol%) and nBu4NOAc (3.31 g,
17.4 mmol) for 3.5 h at 1208C. Purification by column chromatography
(n-pentane/Et2O 5:1) gave 47 (3.45 g, 7.79 mmol, 90%) as a yellow oil.
Rf =0.23 (n-pentane/ethyl acetate 10:1); [a]2D0 =ꢀ126.28 (c=1.0 in
(Si(CH
ACHTREUNG
;
MS (DCI): m/z (%): 743.0 (3) [2M+NH4]+, 380.6 (100) [M+NH4]+,
363.5 (42) [M+H]+; HRMS (ESI): m/z: calcd for C19H42NaO4Si:
385.27446; found: 385.27439 [M+Na]+, 380.31899 [M+NH4]+; elemental
analysis calcd for C19H42O4Si (363.62): C 62.93, H 11.67; found: C 62.72,
H 11.61.
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.03 (s, 6H; Si
ACHTREUNG
9H; Si(C
A
ACHTREUNG
1H; 2-HB), 2.61 (dd, J=15.2, 4.4 Hz, 1H; 2-HA), 2.94–3.04 (m, 1H; 3’-H),
3.09 (m, 1H; 3a’-H), 4.02 (m, 1H; 9b’-H), 4.20 (s, 2H; 5’-CH2-OTBS),
5.38–5.45 (m, 2H; 1’-H, OH), 5.71 (dd, J=9.8, 3.2 Hz, 1H; 4’-H), 6.18
(dd, J=9.8, 2.0 Hz, 1H; 5’-H), 6.46 (d, J=2.7 Hz, 1H; 6’-H), 6.62 (dd,
J=8.1, 2.7 Hz, 1H; 8’-H), 6.95 ppm (d, J=8.1 Hz, 1H; 9’-H); 13C NMR
To a solution of the above described diol (2.63 g, 7.25 mmol) in THF
(40 mL) was added at 08C TBAF·3H2O (4.57 g, 14.50 mmol) and the
mixture stirred for 1 h at 08C and for 2 h at room temperature. After ad-
dition of silica gel (25 g) the solvent was removed under reduced pressure
followed by column chromatography (Et2O) to give alcohol 59 (1.49 g,
7.22 mmol, quant.) as a colorless oil. Rf =0.33 (Et2O); [a]2D0 =+20.78 (c=
(75 MHz, CDCl3): d=ꢀ5.39, ꢀ5.36 (Si
(Si(C(CH3)3)), 28.09 (CO2(C(CH3)3)), 39.25 (C-2), 44.19, 44.56 (C-3a’, C-
9b’), 50.46 (C-3’), 61.09 (C-5’-CH2-OTBS), 80.74 (CO2(C(CH3)3)), 113.47,
A
G
1
A
N
1.0 in CHCl3); H NMR (300 MHz, CDCl3): d=0.90 (t, J=7.5 Hz, 3H; 6-
T
H), 1.47–1.71 (m, 6H; 2-, 3-, 5-H), 2.17 (brs, 1H; OH), 3.40 (s, 3H;
MEM-OCH3), 3.52–3.83 (m, 7H; 1-, 4-H, MEM-OCH2CH2O), 4.76 ppm
(s, 2H; MEM-OCH2O); 13C NMR (50 MHz, CDCl3): d=9.47 (C-6),
26.68, 28.27, 30.04 (C-2, C-3, C-5), 58.96 (MEM-OCH3), 62.86, 67.05,
71.79 (C-1, MEM-OCH2CH2O), 78.53 (C-4), 94.38 ppm (MEM-OCH2O);
IR (NaCl): n˜ =3427, 2937, 2879, 1456, 1045 cmꢀ1; MS (DCI): m/z (%):
224.3 (44) [M+NH4]+, 207.3 (12) [M+H]+ HRMS (ESI): m/z: calcd for
C10H22NaO4: 229.14103; found: 229.14087 [M+Na]+; elemental analysis
calcd for C10H22O4 (206.28): C 58.23, H 10.75; found: C 58.04, H 10.52.
113.96 (C-6’, C-8’), 125.36 (C-5’), 126.66 (C-9a’*), 128.93 (C-9’), 129.13
(C-1’), 131.94 (C-4’), 133.12 (C-5a’*), 144.19 (C-2’), 154.26 (C-7’),
172.44 ppm (C-1); IR (NaCl): n˜ =3392, 2955, 2930, 2885, 1727, 1698 cmꢀ1
;
UV/Vis (MeCN): lmax (lg e)=227.5 (4.425), 256.5 (3.656), 265.0 (3.735),
275.0 (3.668), 303.0 (3.368), 313.0 nm (3.307); MS (ESI): m/z (%): 467.1
(8), 466.2 (30), 465.2 (100) [M+Na]+; HRMS (ESI): m/z: calcd for
C26H39O4Si: 443.26121; found: 443.26129 [M+H]+.
(4S)-Triisopropylsilyloxyhexan-4-ol (58): Ti
was added at room temperature to a solution of (1R,2R)-trans-N,N’-bis-
(trifluormethylsulfonyl)-1,2-cyclohexanediamine (57) (1.90 g, 5.03 mmol,
10 mol%) in toluene (50 mL) and the mixture heated to 508C for 30 min
(OiPr)4 (29.6 mL, 101 mmol)
(4S)-1-Bromo-4-(2-methoxy-ethoxymethoxy)-hexane (60): NBS (1.42 g,
8.00 mmol) and PPh3 (1.68 g, 6.40 mmol) were added at ꢀ158C to a solu-
tion of alcohol 59 (1.10 g, 5.33 mmol) in THF (15 mL) and the mixture
ACHTREUNG
8556
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8543 – 8563

Novel Spinosyn AAnalogues
FULL PAPER
stirred for 20 min at ꢀ158C. Brine (25 mL) and Et2O (20 mL) were
added, the organic phase was separated and the aqueous phase extracted
with Et2O (2”20 mL). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. Purification of the resi-
due by column chromatography (n-pentane/Et2O 4:1) gave bromide 60
(1.22 g, 4.51 mmol, 85%) as a light yellow oil. Rf =0.34 (n-pentane/Et2O
3:1); [a]2D0 =+11.38 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
0.91 (t, J=7.5 Hz, 3H; 6-H), 1.44–1.78 (m, 4H) and 1.81–2.07 (m, 2H)
(2-, 3-, 5-H), 3.40 (s, 3H; MEM-OCH3), 3.43 (t, J=6.8 Hz, 2H; 1-H),
3.56 (m, 3H) and 3.72 (m, 2H) (4-H, MEM-OCH2CH2O), 4.75 ppm (m,
2H; MEM-OCH2O); 13C NMR (50 MHz, CDCl3): d=9.40 (C-6), 26.67,
28.52, 32.14, 33.98 (C-1, C-2, C-3, C-5), 59.00 (MEM-OCH3), 67.01, 71.70
(MEM-OCH2CH2O), 77.56 (C-4), 94.21 ppm (MEM-OCH2O); IR
(NaCl): n˜ =2963, 2934, 2879, 1458, 1042 cmꢀ1; MS (ESI): m/z (%): 293.2
(100) [M+Na]+; HRMS (ESI): m/z: calcd for C10H21BrNaO3: 291.05663;
found: 291.05661 [M+Na]+; elemental analysis calcd for C10H21BrO3
(269.18): C 44.62, H 7.86; found: C 44.49, H 7.63.
were added and the organic phase was separated. The aqueous layer was
extracted with CH2Cl2 (2”100 mL) and the combined organic phases
were dried over MgSO4 and concentrated under reduced pressure.
Column chromatography of the residue (n-pentane/Et2O 4:1) gave the
primary alcohol (3.35 g, 6.91 mmol, 95%) as a colorless oil. Rf =0.12 (n-
pentane/Et2O 5:1); [a]2D0 =ꢀ178.48 (c=1.0 in CHCl3, (3S,3aS,9bS)-enan-
tiomer); 1H NMR (300 MHz, CDCl3): d=1.09 (d, J=6.6 Hz, 18H;
Si(CH
G
G
AHCTREUNG
2.55 (dd, J=15.5, 5.8 Hz, 1H; 2-HA), 2.99–3.14 (m, 2H; 3’-, 3a’-H), 4.04
(m, 1H; 9b’-H), 4.17 (s, 2H; 5’-CH2-OH), 5.53 (s, 1H; 1’-H), 5.73 (dd, J=
10.0, 3.5 Hz, 1H; 4’-H), 6.22 (dd, J=9.9, 2.1 Hz, 1H; 5’-H), 6.51 (d, J=
2.4 Hz, 1H; 6’-H), 6.66 (dd, J=8.1, 2.4 Hz, 1H; 8’-H), 6.94 ppm (d, J=
8.4 Hz, 1H; 9’-H); 13C NMR (75 MHz, CDCl3): d=12.63 (Si(CH-
A
G
A
AHCTREUNG
9a’*), 128.57 (C-9’), 130.61, 131.05 (C-1’, C-4’), 132.67 (C-5a’*), 144.51 (C-
2’), 154.61 (C-7’), 172.48 ppm (C-1); IR (NaCl): n˜ =3400, 2962, 2944,
2867, 1728, 1499, 1150 cmꢀ1; UV/Vis (MeCN): lmax (lg e) = 229.0 (4.510),
256.0 (3.740), 265.5 (3.765), 275.5 (3.688), 300.5 (3.305), 310.0 nm (3.260);
MS (ESI): m/z (%): 994.2 (7), 993.2 (27), 992.2 (55), 991.2 (100)
[2M+Na]+, 509.2 (5), 508.2 (17), 507.2 (45) [M+Na]+; HRMS (ESI):
m/z: calcd for C29H44NaO4Si: 507.29011; found: 507.29012 [M+Na]+,
502.33475 [M+NH4]+, 485.30821 [M+H]+; elemental analysis calcd for
C29H44O4Si (484.74): C 71.85, H 9.15; found: C 71.65, H 9.02.
(4S)-4-(2-Methoxyethoxymethoxy)hexyl magnesium bromide (61): Bro-
mine (9 mL, 28 mg, 178 mmol, 2 mol%) was added dropwise to vacuum
dried magnesium turnings (1.08 g, 44.6 mmol) under argon at room tem-
perature. The heterogeneous mixture was stirred thoroughly for 30 min
and the excess bromine was removed under vacuum. Bromide 60 (2.40 g,
8.92 mmol) was added dropwise as a solution in THF (4 mL) and the
mixture was carefully heated with a heat gun (40–508C) until the reaction
started. The mixture was stirred for further 30 min at room temperature
and the concentration of the Grignard solution was determined by titra-
tion.[32] For this purpose menthol (51 mg, 326 mmol) and 1,10-phenanthro-
line (2–3 granules) were dissolved in THF (1 mL) at room temperature
under argon. The Grignard solution (1.15 mL) was added dropwise until
enduring burgundy coloring of the mixture. The concentration of the
The primary alcohol (3.30 g, 6.81 mmol) was dissolved in CH2Cl2
(100 mL) at 08C and DMP (5.05 g, 11.9 mmol) was added in one portion.
After stirring for 2.5 h at 08C the reaction was quenched by simultaneous
E
addition of 1m aqueous Na2S2O3 (50 mL) and sat. aqueous NaHCO3
(50 mL). The cloudy mixture was stirred at 08C for clearance (ca. 5 min).
The organic phase was then separated and the aqueous phase was ex-
tracted with CH2Cl2 (2”50 mL). The combined organic phases were
dried over MgSO4 and concentrated under reduced pressure. Purification
of the residue by column chromatography (n-pentane/Et2O 10:1) gave al-
dehyde rac-71 (3.00 g, 6.21 mmol, 91%) as a light yellow oil. Rf =0.20
(n-pentane/Et2O 10:1); [a]2D0 =ꢀ133.68 (c=1.0 in CHCl3, (3S,3aS,9bS)-en-
antiomer); 1H NMR (300 MHz, CDCl3): d=1.10 (d, J=6.6 Hz, 18H;
Grignard solution could be calculated according to the equation:
nðmentholÞ
c=VðGrignard-Sol:Þ
=
312:165mmmoLl ~0.3 molLꢀ1
rac- and (3S,3aS,9bS)-2-(2-Formyl-7-triisopropylsilyloxy-3a,9b-dihydro-
3H-cyclopenta[a]naphthalen-3-yl)acetic acid tert-butyl ester (rac-71):
DMAP (2.81 g, 23.0 mmol) was added at room temperature to a solution
of phenol rac-47 (3.40 g, 7.68 mmol) in CH2Cl2 (60 mL). After 5 min stir-
ring at this temperature the mixture was cooled to 08C and a solution of
TIPSOTf (3.1 mL, 3.53 g, 11.5 mmol) in CH2Cl2 (7 mL) was added drop-
wise. The mixture was stirred for further 30 min at 08C after which H2O
(50 mL) was added. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (2”30 mL). The combined organic ex-
tracts were dried over MgSO4 and concentrated under reduced pressure.
Purification of the residue by column chromatography (n-pentane/Et2O
50:1) gave the TIPS-protected phenol (4.40 g, 7.35 mmol, 96%) as a col-
orless oil. Rf =0.12 (n-pentane/Et2O 100:1); [a]2D0 =ꢀ112.88 (c=1.0 in
Si(CH
G
G
AHCTREUNG
1H; 2-HA), 3.25 (m, 1H; 3a’-H), 3.36 (m, 1H; 3’-H), 4.29 (m, 1H; 9b’-H),
5.72 (dd, J=9.9, 3.0 Hz, 1H; 4’-H), 6.23 (dd, J=9.9, 2.4 Hz, 1H; 5’-H),
6.55 (d, J=2.7 Hz, 1H; 6’-H), 6.61 (d, J=2.1 Hz, 1H; 1’-H), 6.71 (dd, J=
8.0, 2.6 Hz, 1H; 8’-H), 7.02 ppm (d, J=8.4 Hz, 1H; 9’-H); 13C NMR
(75 MHz, CDCl3): d=12.62 (Si(CH
28.11 (CO2(C(CH3)3)), 38.33 (C-2), 44.18, 45.90 (C-3a’, C-9b’), 47.23 (C-
3’), 80.71 (CO2(C(CH3)3)), 118.43, 118.87 (C-6’, C-8’), 123.79 (C-9a’*),
A
N
AHCTREUNG
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.02 (s, 6H; Si
9H; Si(C(CH3)3)), 1.09 (d, J=6.6 Hz, 18H; Si(CH(CH3)2)3), 1.16–1.31
(m, 3H; Si(CH(CH3)2)3), 1.47 (s, 9H; CO2(C(CH3)3)), 2.28 (dd, J=15.5,
A
AHCTREUNG
A
ACHTREUNG
125.72 (C-5’), 128.75 (C-9’), 130.97 (C-4’), 133.28 (C-5a’*), 146.33 (C-2’),
155.30 (C-7’), 155.96 (C-1’), 171.34 (C-1), 189.49 ppm (C-5’-CHO); IR
(NaCl): n˜ =2962, 2945, 2893, 2867, 1729, 1682 cmꢀ1; UV/Vis (MeCN):
lmax (lg e) = 233.0 (4.619), 286.5 (3.470), 310.0 (3.273), 338.0 (2.805),
357.0 nm (2.808); MS (ESI): m/z (%): 989.1 (25), 988.1 (56), 987.1 (91)
[2M+Na]+, 506.2 (33), 505.2 (100) [M+Na]+; HRMS (ESI): m/z: calcd
for C29H42NaO4Si: 505.27446; found: 505.27457 [M+Na]+, 500.31913
[M+NH4]+, 483.29259 [M+H]+; elemental analysis calcd for C29H42O4Si
(482.73): C 72.15, H 8.77; found: C 71.93, H 8.53.
A
ACHTREUNG
10.0 Hz, 1H; 2-HB), 2.60 (dd, J=15.5, 4.4 Hz, 1H; 2-HA), 2.94–3.04 (m,
1H; 3’-H), 3.11 (m, 1H; 3a’-H), 4.04 (m, 1H; 9b’-H), 4.20 (s, 2H; 5’-CH2-
OTBS), 5.42 (s, 1H; 1’-H), 5.70 (dd, J=9.8, 3.2 Hz, 1H; 4’-H), 6.20 (dd,
J=9.8, 2.3 Hz, 1H; 5’-H), 6.51 (d, J=2.4 Hz, 1H; 6’-H), 6.66 (dd, J=8.0,
2.3 Hz, 1H; 8’-H), 6.95 ppm (d, J=8.1 Hz, 1H; 9’-H); 13C NMR
(75 MHz, CDCl3): d=ꢀ5.40, ꢀ5.37 (Si
17.93 (Si(CH(CH3)2)3), 18.31 (Si(C(CH3)3)), 25.88 (Si(C
(CO2(C(CH3)3)), 39.25 (C-2), 44.29, 44.61 (C-3a’, C-9b’), 50.54 (C-3’),
61.12 (C-5’-CH2-OTBS), 80.44 (CO2(C(CH3)3)), 118.01, 118.49 (C-6’, C-
A
N
A
N
ACHTREUNG
ACHTREUNG
(3’S,3a’S,9b’S,1’’S,2’’S,4’’’S)-2-{2-[3-(4-Benzyl-2-oxo-oxazolidin-3-yl)-1-hy-
droxy-2-methyl-3-oxo-propyl]-7-triisopropylsilyloxy-3a,9b-dihydro-3H-cy-
clopenta[a]naphthalen-3-yl}-acetic acid-tert-butyl ester (72) and
(3’R,3a’R,9b’R,1’’S,2’’S,4’’’S)-2-{2-[3-(4-benzyl-2-oxo-oxazolidin-3-yl)-1-
hydroxy-2-methyl-3-oxo-propyl]-7-triisopropylsilyloxy-3a,9b-dihydro-3H-
cyclopenta[a]naphthalen-3-yl}acetic acid-tert-butyl ester (73): To a solu-
AHCTREUNG
8’), 125.57 (C-5’), 127.08 (C-9a’*), 128.61 (C-9’), 129.20 (C-1’), 131.55 (C-
4’), 132.85 (C-5a’*), 144.21 (C-2’), 154.48 (C-7’), 172.11 ppm (C-1); IR
(NaCl): n˜ =2947, 2930, 2893, 2867, 1730 cmꢀ1; UV/Vis (MeCN): lmax (lg
e)
= 229.0 (4.512), 258.0 (3.713), 266.0 (3.785), 275.5 (3.711), 299.5
(3.316), 310.0 nm (3.264); MS (ESI): m/z (%): 623.3 (16), 622.3 (46),
621.3 (100) [M+Na]+; HRMS (ESI): m/z: calcd for C35H59O4Si2:
599.39464; found: 599.39460 [M+H]+; elemental analysis calcd for
C35H58O4Si2 (599.00): C 70.18, H 9.76; found: C 70.37, H 9.58.
tion
of
(4S)-3-propionyl-4-benzyl-2-oxazolidinone
(49)
(1.78 g,
7.64 mmol) in CH2Cl2 (20 mL) was added dropwise with stirring at 08C
NEt3 (1.23 mL, 897 mg, 8.86 mmol) and nBu2BOTf from a fresh, new
batch (7.94 mL, 7.94 mmol, c ꢁ1.0m in CH2Cl2). Stirring was continued
for 1 h at 08C and after cooling down to ꢀ758C within 1 h a solution of
rac-71 (2.95 g, 6.11 mmol) in CH2Cl2 (6 mL) was slowly added and the
stirring continued for 1 h at this temperature, 1 h at ꢀ508C, 0.5 h at
To a solution of the TBS-protected alcohol (4.35 g, 7.26 mmol) in MeOH
(100 mL) was added at 08C pTsOH·H2O (138 mg, 726 mmol). After stir-
ring for 4 h at this temperature CH2Cl2 (100 mL) and H2O (150 mL)
Chem. Eur. J. 2007, 13, 8543 – 8563
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8557

L. F. Tietze et al.
ꢀ408C, and 0.5 h at ꢀ308C. Then the reaction was quenched by addition
of MeOH (5 mL) and aqueous 30% H2O2 in methanol (5 mL, 1:1). The
solution was stirred for further 5 min at ꢀ308C and then warmed to
room temperature. After addition of H2O (30 mL) the phases were sepa-
rated and the aqueous phase extracted with CH2Cl2 (2”20 mL). The
combined organic phases were dried over MgSO4 and concentrated
under reduced pressure. Purification of the residue by column chroma-
tography (n-pentane/Et2O 3:1 ! 1:1) gave the diastereomeric aldol ad-
ducts 72 (1.72 g, 2.40 mmol, 39%) and 73 (1.88 g, 2.63 mmol, 43%) as
light yellow foams. Analysis for 72: Rf =0.35 (n-pentane/Et2O 2:1);
[a]2D0 =ꢀ59.78 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.06
with CH2Cl2 (2”20 mL). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. Column chromatogra-
phy (n-pentane/Et2O 20:1 ! 10:1) of the residue gave the TBS-protected
alcohol (1.45 g, 1.75 mmol, 84%) as a white foam. Rf =0.43 (n-pentane/
1
Et2O 5:1); [a]2D0 =ꢀ62.38 (c=1.0 in CHCl3); H NMR (300 MHz, CDCl3):
d=0.00 (s, 3H) and 0.09 (s, 3H) (Si
N
N
1.05 (d, J=6.0 Hz, 18H; Si(CH
ACHTREUNG
A
ACHTREUNG
2.17 (dd, J=15.3, 11.4 Hz, 1H; 2-HB), 2.71 (dd, J=13.5, 9.6 Hz, 1H;
4’’’-CH2-Ph-HB), 2.98–3.17 (m, 4H; 2-HA, 3’-, 3a’-H, 4’’’-CH2-Ph-HA),
3.93–4.26 (m, 5H; 9b’-, 2’’-, 4’’’-, 5’’’-H), 4.64 (d, J=8.7 Hz, 1H; 1’’-H),
5.36 (d, J=1.5 Hz, 1H; 1’-H), 5.66 (dd, J=9.6, 2.7 Hz, 1H; 4’-H), 6.06
(dd, J=9.6, 1.8 Hz, 1H; 5’-H), 6.41 (d, J=2.4 Hz, 1H; 6’-H), 6.64 (dd,
J=8.1, 2.4 Hz, 1H; 8’-H), 6.94 (d, J=7.8 Hz, 1H; 9’-H), 7.10–7.16 (m,
2H) and 7.22–7.34 ppm (m, 3H) (EA-Ph-H); 13C NMR (150 MHz,
(d, J=6.9 Hz, 18H; Si(CH
E
(CH3)2)3),
1.30 (d, J=6.9 Hz, 3H; 2’’-CH3), 1.47 (s, 9H; CO2(C
AHCTREUNG
J=14.9, 8.3 Hz, 1H; 2-HB), 2.66–2.79 (m, 2H; 2-HA, 4’’’-CH2-Ph-HB),
3.03–3.24 (m, 3H; 3’-, 3a’-H, 4’’’-CH2-Ph-HA), 3.20 (d, J=3.9 Hz, 1H;
OH), 3.89–4.16 (m, 4H; 9b’-, 2’’-, 5’’’-H), 4.32–4.43 (m, 1H; 4’’’-H), 4.64
(m, 1H; 1’’-H), 5.45 (s, 1H; 1’-H), 5.71 (dd, J=9.8, 3.2 Hz, 1H; 4’-H),
6.15 (dd, J=9.8, 2.0 Hz, 1H; 5’-H), 6.46 (d, J=2.4 Hz, 1H; 6’-H), 6.63
(dd, J=8.3, 2.5 Hz, 1H; 8’-H), 6.92 (d, J=8.1 Hz, 1H; 9’-H), 7.10–7.17
(m, 2H) and 7.24–7.35 ppm (m, 3H) (EA-Ph-H); 13C NMR (75 MHz,
CDCl3): d=ꢀ5.03, ꢀ4.05 (Si
CH3), 17.83 (Si(CH(CH3)2)3), 18.09 (Si(C
28.08 (CO2(C(CH3)3)), 37.55 (C-4’’’-CH2-Ph), 40.33 (C-2), 42.99 (C-2’’),
43.92 (C-9b’), 45.30 (C-3a’), 49.41 (C-3’), 55.15 (C-4’’’), 65.78 (C-5’’’),
73.00 (C-1’’), 80.22 (CO2(C(CH3)3)), 117.60 (C-6’), 118.54 (C-8’), 125.06
A
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
AHCTREUNG
CDCl3): d=12.60 (Si(CH
(CH3)2)3), 28.09 (CO2(C(CH3)3)), 37.63 (C-4’’’-CH2-Ph), 39.50 (C-2),
42.12, 44.35 (C-9b’, C-2’’), 44.69, 50.00 (C-3’, C-3a’), 54.98 (C-4’’’), 65.93
(C-5’’’), 71.10 (C-1’’), 81.01 (CO2(C(CH3)3)), 117.82 (C-6’), 118.54 (C-8’),
A
(C-5’), 126.56 (C-9a’*), 127.21, 128.80 (EA-Ph-CH), 128.91 (C-9’), 129.36
(EA-Ph-CH), 132.23 (C-4’), 133.34 (C-1’), 132.65, 135.09 (C-5a’*, EA-Ph-
C), 144.43 (C-2’), 152.76, 154.57 (C-7’, C-2’’’), 171.99, 174.76 ppm (C-1, C-
3’’); IR (KBr): n˜ =2949, 2893, 2866, 1786 cmꢀ1; UV/Vis (MeCN): lmax (lg
A
ACHTREUNG
125.52 (C-5’), 126.47 (C-9a’*), 127.33, 128.80 (EA-Ph-CH), 128.89 (C-9’),
129.37 (EA-Ph-CH), 131.38 (C-4’), 132.00 (C-1’), 132.74, 134.98 (C-5a’*,
EA-Ph-C), 144.35 (C-2’), 152.92, 154.67 (C-7’, C-2’’’), 172.84, 175.87 pppm
(C-1, C-3’’); IR (KBr): n˜ =3501, 2982, 2963, 2944, 2867, 1784 cmꢀ1; UV/
Vis (MeCN): lmax (lg e) = 209.5 (4.519), 229.0 (4.488), 257.5 (3.692),
266.0 (3.739), 276.0 (3.653), 300.5 (3.269), 310.0 nm (3.219); MS (ESI):
m/z (%): 1457.2 (6), 1456.2 (18), 1455.2 (40), 1454.3 (78), 1453.3 (100)
[2M+Na]+, 740.3 (8), 739.3 (29), 738.3 (60) [M+Na]+; HRMS (ESI):
m/z: calcd for C42H57NaO7Si: 738.37965; found: 738.37935 [M+Na]+,
found: 733.42403 [M+NH4]+.
e) = 209.5 (4.515), 229.5 (4.495), 257.5 (3.689), 266.5 (3.731), 276.0
(3.642), 300.5 (3.262), 310.5 nm (3.212); MS (ESI): m/z (%): 1685.3 (14),
1684.3 (28), 1683.4 (61), 1682.4 (100), 1681.4 (87) [2M+Na]+, 854.4 (7),
853.4 (18), 852.4 (32) [M+Na]+; HRMS (ESI): m/z: calcd for
C48H75N2O7Si2: 847.51073; found: 847.510981 [M+NH4]+.
EtOH (1.33 mL, 1.05 g, 22.8 mmol) was added dropwise to a solution of
LiBH4 (5.70 mL, 11.4 mmol, c ꢁ2.0m in THF) in Et2O (20 mL) at room
temperature. The mixture stirred for 45 min with an open gas outlet
whereupon a solution of the Evans-aldol adduct 72 (950 mg, 1.14 mmol)
in Et2O (5 mL) was added rapidly. After stirring for 15 min at room tem-
perature the mixture was cooled to 08C, 1m aqueous NaOH (10 mL) was
added and the mixture stirred for further 10 min. The phases were sepa-
rated and the aqueous phase was extracted with Et2O (2”10 mL). The
combined organic phases were dried over MgSO4 and concentrated
under reduced pressure. Column chromatography (n-pentane/Et2O 3:1)
gave the primary alcohol (470 mg, 715 mmol, 63%) as a colorless oil. Rf =
0.44 (n-pentane/Et2O 2:1); [a]2D0 =ꢀ158.28 (c=1.0 in CHCl3); 1H NMR
Analysis for 73: Rf =0.15 (n-pentane/Et2O 2:1); [a]2D0 =+143.58 (c=1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.08 (d, J=6.9 Hz, 18H;
Si(CH
ACHTREUNG
Si(CH
A
ACHTREUNG
1H; 2-HB), 2.61 (dd, J=15.8, 4.6 Hz, 1H; 2-HB), 2.77 (dd, J=13.4,
9.4 Hz, 1H; 4’’’-CH2-Ph-HB), 2.85–2.94 (m, 1H; 3’-H), 3.07–3.17 (m, 2H;
3a’-H, OH), 3.21 (dd, J=13.4, 3.2 Hz, 1H; 4’’’-CH2-Ph-HA), 3.93 (dq, J=
6.9, 3.5 Hz, 1H; 2’’-H), 4.00–4.16 (m, 3H; 9b’-, 5’’’-H), 4.54–4.63 (m, 2H;
1’’-, 4’’’-H), 5.60 (s, 1H; 1’-H), 5.68 (dd, J=9.5, 3.2 Hz, 1H; 4’-H), 6.20
(dd, J=9.8, 2.0 Hz, 1H; 5’-H), 6.48 (d, J=2.7 Hz, 1H; 6’-H), 6.65 (dd,
J=8.3, 2.6 Hz, 1H; 8’-H), 6.95 (d, J=8.1 Hz, 1H; 9’-H), 7.14–7.21 (m,
2H) and 7.23–7.37 ppm (m, 3H) (EA-Ph-H); 13C NMR (75 MHz,
(300 MHz, CDCl3): d=ꢀ0.09 (s, 3H) and 0.03 (s, 3H) (Si
9H; Si(C(CH3)3)), 0.89 (d, J=6.9 Hz, 3H; 2’’-CH3), 1.09 (d, J=7.2 Hz,
18H; Si(CH(CH3)2)3), 1.14–1.32 (m, 3H; Si(CH(CH3)2)3), 1.46 (s, 9H;
CO2(C(CH3)3)), 1.75–1.94 (m, 2H; 2’’-H, OH), 2.23 (dd, J=16.1, 11.2 Hz,
A
AHCTREUNG
A
ACHTREUNG
AHCTREUNG
1H; 2-HB), 2.85 (dd, J=16.1, 3.4 Hz, 1H; 2-HA), 3.01–3.12 (m, 2H; 3’-,
3a’-H), 3.35–3.58 (m, 2H; 3’’-H), 4.04 (d, J=8.4 Hz, 1H; 9b’-H), 4.26 (d,
J=6.0 Hz, 1H; 1’’-H), 5.38 (s, 1H; 1’-H), 5.67 (dd, J=9.6, 2.7 Hz, 1H; 4’-
H), 6.20 (dd, J=9.9, 2.1 Hz, 1H; 5’-H), 6.50 (d, J=2.1 Hz, 1H; 6’-H),
6.65 (dd, J=8.1, 2.7 Hz, 1H; 8’-H), 6.95 ppm (d, J=8.1 Hz, 1H; 9’-H);
CDCl3): d=10.40 (C-2’’-CH3), 12.61 (Si(CH
(CH3)2)3), 28.07 (CO2(C(CH3)3)), 37.69 (C-4’’’-CH2-Ph), 38.92 (C-2), 41.07
(C-2’’), 44.39 (C-3a’), 44.53 (C-9b’), 51.07 (C-3’), 55.15 (C-4’’’), 66.13 (C-
5’’’), 69.25 (C-1’’), 80.72 (CO2(C(CH3)3)), 117.91 (C-6’), 118.54 (C-8’),
(CH3)2)3), 17.91 (Si(CH-
A
ACHTREUNG
AHCTREUNG
125.74 (C-5’), 126.66 (C-9a’*), 127.37 (EA-Ph-CH), 128.73 (C-9’), 128.92,
129.37 (EA-Ph-CH), 131.06 (C-1’), 131.46 (C-4’), 132.80, 135.00 (C-5a’*,
EA-Ph-C), 144.42 (C-2’), 152.82, 154.64 (C-7’, C-2’’’), 172.06, 176.79 ppm
(C-1, C-3’’); IR (KBr): n˜ =3512, 2964, 2944, 2892, 2867, 1782 cmꢀ1; UV/
Vis (MeCN): lmax (lg e) = 212.0 (4.570), 229.0 (4.550), 257.0 (3.756),
265.5 (3.782), 275.5 (3.691), 300.0 (3.313), 310.0 nm (3.265); MS (ESI): m/
z (%): 1456.1 (9), 1455.1 (27), 1454.1 (49), 1453.0 (61) [2M+Na]+, 740.3
(17), 739.4 (48), 738.3 (100) [M+Na]+; HRMS (ESI): m/z: calcd for
C42H61N2O7Si: 733.42426; found: 733.42421 [M+NH4]+, 716.39759
[M+H]+.
13C NMR (75 MHz, CDCl3): d=ꢀ5.21, ꢀ4.14 (Si
ACHTREUNG
CH3), 12.61 (Si(CH
(CH3)2)3), 17.91 (Si(CH
(CH3)2)3), 18.06 (Si(C
ACHTREUNG
25.87 (Si(C
44.01 (C-9b’), 45.35 (C-3a’), 50.47 (C-3’), 65.64 (C-3’’), 73.82 (C-1’’), 80.46
(CO2(C(CH3)3)), 118.10 (C-6’), 118.53 (C-8’), 125.85 (C-5’), 126.62 (C-
A
N
AHCTREUNG
9a’*), 128.63 (C-9’), 131.72 (C-4’), 132.91 (C-5a’*), 133.44 (C-1’), 145.11
(C-2’), 154.62 (C-7’), 172.21 ppm (C-1); IR (NaCl): n˜ =3432, 2947, 2930,
2892, 2867, 1730 cmꢀ1; UV/Vis (MeCN): lmax (lg e) = 229.5 (4.504), 257.5
(3.694), 266.0 (3.759), 276.0 (3.682), 300.0 (3.301), 310.0 nm (3.248); MS
(ESI): m/z (%): 1339.1 (6), 1338.2 (15), 1337.2 (36), 1336.2 (74), 1335.2
(69) [2M+Na]+, 681.3 (16), 680.4 (45), 679.4 (100) [M+Na]+; HRMS
(ESI): m/z: calcd for C38H68NO5Si2: 674.46305; found: 674.46297
[M+NH4]+.
(3’S,3a’S,9b’S,1’’S,2’’S)-2-{2-[1-(tert-Butyldimethylsilyloxy)-2-methyl-3-
oxo-propyl]-7-triisopropylsilyloxy-3a,9b-dihydro-3H-cyclopenta[a]naph-
thalen-3-yl}acetic acid-tert-butyl ester (74): Asolution of alcohol 72
(1.50 g, 2.09 mmol) and DMAP (2.55 g, 20.9 mmol) in CH2Cl2 (30 mL)
was stirred at room temperature for 5 min and then a solution of
TBSOTf (2.38 mL, 2.76 g, 10.5 mmol) in CH2Cl2 (4 mL) was added drop-
wise at 08C. Stirring was continued for 10 min at 08C and for 20 h at
room temperature. The reaction was quenched by addition of H2O
(40 mL), the phases were separated and the aqueous phase was extracted
The primary alcohol (65 mg, 99 mmol) was dissolved in CH2Cl2 (3 mL) at
08C and DMP (73 mg, 173 mmol) was added in one portion. The mixture
was stirred for 2 h at this temperature, and then quenched by simulta-
A
(2 mL). The cloudy mixture was stirred at 08C for clearance (ca. 5 min)
and then diluted with H2O (5 mL) and CH2Cl2 (5 mL). The organic phase
8558
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8543 – 8563

Novel Spinosyn AAnalogues
FULL PAPER
was separated and the aqueous phase extracted with CH2Cl2 (2”5 mL).
The combined organic extracts were dried over MgSO4 and concentrated
under reduced pressure. Column chromatography of the residue (n-pen-
tane/Et2O 10:1) gave aldehyde 74 (59 mg, 90 mmol, 91%) as a yellow oil.
Rf =0.52 (n-pentane/Et2O 5:1); [a]2D0 =ꢀ102.58 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=ꢀ0.09 (s, 3H) and 0.01 (s, 3H) (Si-
The secondary alcohol (430 mg, 509 mmol) was dissolved in pyridine
(5 mL) at room temperature and PivCl (626 mL, 614 mg, 5.09 mmol) and
DMAP (62 mg, 509 mmol) were added. The temperature was raised to
608C and the mixture stirred for 14 h. After that the mixture was cooled
to room temperature and diluted with Et2O (20 mL). The solution was
washed with 2m HCl (3”10 mL), sat. aqueous NaHCO3 (2”10 mL) and
brine (10 mL). The organic phase was dried over MgSO4 and concentrat-
ed under reduced pressure. Purification of the residue by column chro-
matography (n-pentane/Et2O 5:1) gave the pivaloate 75 (433 mg,
A
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
466 mmol, 92%) as a colorless oil. Rf =0.57 (n-pentane/Et2O 2:1); [a]D20
=
(m, 1H; 2’’-H), 2.75 (dd, J=15.8, 3.8 Hz, 1H; 2-HA), 3.02 (m, 1H; 3’-H),
3.09 (m, 1H; 3a’-H), 4.04 (d, J=8.7 Hz, 1H; 9b’-H), 4.59 (d, J=5.4 Hz,
1H; 1’’-H), 5.43 (s, 1H; 1’-H), 5.62 (dd, J=9.5, 2.9 Hz, 1H; 4’-H), 6.20
(dd, J=9.6, 2.1 Hz, 1H; 5’-H), 6.50 (d, J=2.4 Hz, 1H; 6’-H), 6.66 (dd,
J=8.1, 2.7 Hz, 1H; 8’-H), 6.94 (d, J=8.4 Hz, 1H; 9’-H), 9.69 ppm (d, J=
1.5 Hz, 1H; 3’’-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.21, ꢀ4.18 (Si-
ꢀ100.88 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=ꢀ0.07 (s,
3H) and 0.02 (s, 3H) (Si
N
N
3H; 9’’-H), 0.96 (d, J=6.6 Hz, 3H; 2’’-CH3), 1.04 (s, 9H; OC(O)C-
(CH3)3), 1.09 (d, J=6.9 Hz, 18H; Si(CH(CH3)2)3), 1.46 (s, 9H; CO2(C-
(CH3)3)), 1.24–1.35 (m, 5H) and 1.38–1.68 (m, 6H) (4’’-, 5’’-, 6’’-, 8’’-H,
Si(CH(CH3)2)3), 1.84 (m, 1H; 2’’-H), 2.20 (dd, J=15.6, 11.7 Hz, 1H; 2-
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
A
G
A
HB), 2.86 (dd, J=15.9, 3.3 Hz, 1H; 2-HA), 2.95 (m, 1H; 3’-H), 3.06 (m,
1H; 3a’-H), 3.39 (s, 3H; MEM-OCH3), 3.50 (m, 1H; 7’’-H), 3.56 (t, J=
4.8 Hz, 2H) and 3.66–3.78 (m, 2H) (MEM-OCH2CH2O), 4.00 (d, J=
8.1 Hz, 1H; 9b’-H), 4.15 (d, J=7.8 Hz, 1H; 1’’-H), 4.61 (m, 1H; 3’’-H),
4.74 (m, 2H; MEM-OCH2O), 5.30 (s, 1H; 1’-H), 5.59 (dd, J=9.8, 2.9 Hz,
1H; 4’-H), 6.24 (dd, J=9.8, 2.3 Hz, 1H; 5’-H), 6.53 (d, J=2.7 Hz, 1H; 6’-
H), 6.63 (dd, J=8.3, 2.6 Hz, 1H; 8’-H), 6.92 ppm (d, J=8.1 Hz, 1H; 9’-
N
G
ACHTREUNG
ACHTREUNG
126.23 (C-9a’*), 128.63 (C-9’), 131.33 (C-4’), 132.96 (C-5a’*), 134.36 (C-
1’), 144.05 (C-2’), 154.72 (C-7’), 171.85 (C-1), 204.13 ppm (C-3’’); IR
(NaCl): n˜ =2947, 2892, 2866, 1728 cmꢀ1; UV/Vis (MeCN): lmax (lg e) =
229.5 (4.513), 257.0 (3.714), 266.0 (3.758), 276.0 (3.679), 299.5 (3.309),
310.0 (3.260), 346.0 nm (2.057); MS (ESI): m/z (%): 677.3 (100)
[M+Na]+; HRMS (ESI): m/z: calcd for C38H66NO5Si2: 672.44740; found:
672.44699 [M+NH4]+.
H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.08, ꢀ3.73 (Si
ACHTREUNG
9.88 (C-2’’-CH3), 12.62 (Si(CH
A
ACHTREUNG
(Si(C
28.12 (CO2(C
(OC(O)C
A
(CH3)3)), 27.19 (OC(O)C
ACHTREUNG
(3’S,3a’S,9b’S,1’’S,2’’R,3’’S,7’’S)-2-{2-[1-(tert-Butyldimethylsilyloxy)-7-(2-
methoxy-ethoxymethoxy)-2-methyl-3-pivaloyloxynonyl]-7-triisopropylsi-
lyloxy-3a,9b-dihydro-3H-cyclopenta[a]naphthalen-3-yl}acetic acid tert-
butyl ester (75): To a solution of aldehyde 74 (505 mg, 771 mmol) in THF
(10 mL) was added dropwise at ꢀ358C a solution of the Grignard com-
pound 61 (3.21 mL, 964 mmol, c ꢁ0.3m) and the mixture stirred for 1.5 h.
The reaction was quenched by addition of buffer pH 7 (5 mL) at ꢀ358C
and the mixture was allowed to warm up to room temperature. Et2O
(10 mL) and H2O (10 mL) were added and a formed precipitate was dis-
solved by addition of 2m HCl (1 mL). The organic phase was separated
and the aqueous phase extracted with Et2O (2”10 mL). The combined
organic extracts were dried over MgSO4 and concentrated under reduced
pressure. Column chromatography of the residue (n-pentane/Et2O 3:1 !
2:1) gave the secondary alcohol (448 mg, 530 mmol, 69%) as a light
yellow solid as well as a mixture of the C-3’’-epimer and the Wurtz-cou-
pling product (140 mg) which could not be separated by chromatography.
Rf =0.35 (n-pentane/Et2O 2:1); [a]2D0 =ꢀ86.78 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=ꢀ0.11 (s, 3H) and 0.04 (s, 3H) (Si-
AHCTREUNG
(MEM-OCH2O), 118.09 (C-6’), 118.23 (C-8’), 126.35 (C-5’), 126.39 (C-
9a’*), 128.46 (C-9’), 131.18 (C-4’), 133.20 (C-5a’*), 134.65 (C-1’), 144.16
(C-2’), 154.58 (C-7’), 172.20, 176.81 ppm (C-1, OC(O)C(CH3)3); IR
E
(NaCl): n˜ =2959, 2934, 2868, 1730, 1156, 1041 cmꢀ1; UV/Vis (MeCN):
lmax (lg e) = 229.5 (4.493), 257.5 (3.704), 265.5 (3.772), 276.0 (3.668),
300.5 (3.287), 310.0 nm (3.236); MS (ESI): m/z (%): 949.7 (12), 948.7
(31), 947.7 (71), 946.7 (100) [M+NH4]+; HRMS (ESI): m/z: calcd for
C53H96NO9Si2: 946.66181; found: 946.66189 [M+NH4]+.
(3’S,3a’S,9b’S,1’’S,2’’R,3’’R,7’’S)-2-{2-[1-(tert-Butyldimethylsilyloxy)-7-(2-
methoxyethoxymethoxy)-2-methyl-3-pivaloyloxynonyl]-7-triisopropylsilyl-
oxy-3a,9b-dihydro-3H-cyclopenta[a]naphthalen-3-yl}acetic acid tert-butyl
ester (76): To a stirred solution of the C-3’’-epimeric alcohol and the
Wurtz-coupling product from the reaction of aldehyde 74 with the
Grignard-reagent 61 (140 mg) in pyridine (3 mL) were added at room
temperature PivCl (0.30 mL, 294 mg, 2.44 mmol) and DMAP (30 mg,
246 mmol) and stirring was continued at 608C for 17 h. Then the mixture
was cooled to room temperature, diluted with Et2O (15 mL), washed
with 2m HCl (3”10 mL), sat. aqueous NaHCO3 (2”10 mL) and brine
(10 mL), dried over MgSO4 and concentrated under reduced pressure.
Column chromatography of the residue (n-pentane/Et2O 5:1) gave piva-
loate 76 (107 mg, 115 mmol, 15% over two steps) as a colorless oil. Rf =
0.57 (n-pentane/Et2O 2:1); [a]2D0 =ꢀ104.08 (c=1.0 in CHCl3); 1H NMR
G
ACHTREUNG
G
ACHTREUNG
ACHTREUNG
3.5 Hz, 1H; 2-HA), 2.95 (m, 1H; 3’-H), 3.07 (m, 1H; 3a’-H), 3.35 (s, 3H;
MEM-OCH3), 3.46–3.62 (m, 4H) and 3.66–3.79 (m, 2H) (3’’-, 7’’-H,
MEM-OCH2CH2O), 4.05 (d, J=9.0 Hz, 1H; 9b’-H), 4.29 (d, J=6.6 Hz,
1H; 1’’-H), 4.74 (m, 2H; MEM-OCH2O), 5.42 (s, 1H; 1’-H), 5.63 (dd, J=
9.8, 2.9 Hz, 1H; 4’-H), 6.19 (dd, J=9.8, 2.3 Hz, 1H; 5’-H), 6.50 (d, J=
2.7 Hz, 1H; 6’-H), 6.65 (dd, J=8.1, 2.4 Hz, 1H; 8’-H), 6.95 ppm (d, J=
8.1 Hz, 1H; 9’-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.13, ꢀ3.89 (Si-
(300 MHz, CDCl3): d=ꢀ0.09 (s, 3H) and 0.01 (s, 3H) (Si
J=7.5 Hz, 3H; 9’’-H), 0.85 (s, 9H; Si(C(CH3)3)), 0.92 (d, J=6.9 Hz, 3H;
2’’-CH3), 1.08 (d, J=6.9 Hz, 18H; Si(CH(CH3)2)3), 1.20 (s, 9H; OC(O)C-
(CH3)3), 1.16–1.44 (m, 11H; 4’’-, 5’’-, 6’’-, 8’’-H, Si(CH(CH3)2)3), 1.47 (s,
9H; CO2(C(CH3)3)), 1.99 (m, 1H; 2’’-H), 2.18 (dd, J=15.3, 12.3 Hz, 1H;
A
AHCTREUNG
AHCTREUNG
A
ACHTREUNG
G
ACHTREUNG
AHCTREUNG
N
G
ACHTREUNG
2-HB), 2.88 (dd, J=15.6, 3.3 Hz, 1H; 2-HA), 3.11 (m, 1H; 3a’-H), 3.27–
3.42 (m, 2H; 3’-, 7’’-H), 3.38 (s, 3H; MEM-OCH3), 3.53 (t, J=4.6 Hz,
2H) and 3.61–3.74 (m, 2H) (MEM-OCH2CH2O), 3.98–4.95 (m, 2H; 9b’-,
1’’-H), 4.63–4.71 (m, 3H; 3’’-H, MEM-OCH2O), 5.32 (s, 1H; 1’-H), 5.84
(dd, J=9.8, 2.6 Hz, 1H; 4’-H), 6.18 (dd, J=9.9, 2.4 Hz, 1H; 5’-H), 6.47
(d, J=2.1 Hz, 1H; 6’-H), 6.63 (dd, J=8.1, 2.4 Hz, 1H; 8’-H), 6.94 ppm
(d, J=8.4 Hz, 1H; 9’-H); 13C NMR (75 MHz, CDCl3): d=ꢀ5.12, ꢀ3.76
ACHTREUNG
41.89 (C-2’’), 44.08 (C-9b’), 45.20 (C-3a’), 50.39 (C-3’), 59.01 (MEM-
OCH3), 66.94, 71.80 (MEM-OCH2CH2O), 72.46 (C-3’’), 75.48 (C-1’’),
78.65 (C-7’’), 80.47 (CO2(C(CH3)3)), 94.32 (MEM-OCH2O), 118.10 (C-6’),
118.54 (C-8’), 125.87 (C-5’), 126.54 (C-9a’*), 128.68 (C-9’), 131.71 (C-4’),
132.86 (C-5a’*), 133.98 (C-1’), 144.88 (C-2’), 154.62 (C-7’), 172.17 ppm
(C-1); IR (KBr): n˜ =3479, 2937, 2890, 2867, 1729, 1043 cmꢀ1; UV/Vis
(MeCN): lmax (lg e) = 229.5 (4.472), 257.5 (3.678), 265.5 (3.747), 276.0
(3.645), 300.5 (3.274), 310.0 nm (3.221); MS (ESI): m/z (%): 870.4 (7),
869.4 (24), 868.5 (53), 867.5 (100) [M+Na]+; HRMS (ESI): m/z: calcd for
C48H88NO8Si2: 862.60430; found: 862.60419 [M+NH4]+.
A
(Si
(Si(CH
27.25 (OC(O)C
C-6’’, C-8’’), 38.80 (OC(O)C
9b’), 45.11 (C-3a’), 49.63 (C-3’), 58.99 (MEM-OCH3), 66.84, 71.77 (MEM-
A
ACHTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
Chem. Eur. J. 2007, 13, 8543 – 8563
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8559

L. F. Tietze et al.
OCH2CH2O), 72.96 (C-1’’), 74.14 (C-3’’), 78.15 (C-7’’), 80.32 (CO2(C-
(CH3)3)), 94.24 (MEM-OCH2O), 118.01 (C-6’), 118.22 (C-8’), 125.59 (C-
ACHTREUNG
ACHTREUNG
5’), 126.56 (C-9a’*), 128.62 (C-9’), 132.45 (C-4’), 133.19 (C-5a’*), 133.83
(C-1’), 144.86 (C-2’), 154.62 (C-7’), 172.12, 177.21 ppm (C-1, OC(O)C-
(CH3)3); IR (NaCl): n˜ =2960, 2935, 2868, 1726, 1156, 1044 cmꢀ1; UV/Vis
(MeCN): lmax (lg e) = 229.5 (4.493), 257.5 (3.708), 265.5 (3.773), 276.0
(3.670), 300.0 (3.288), 310.0 nm (3.235); MS (ESI): m/z (%): 948.7 (20),
947.7 (55), 946.7 (100) [M+NH4]+; HRMS (ESI): m/z: calcd for
C53H96NO9Si2: 946.66181; found: 946.66221 [M+NH4]+.
(3’S,3a’S,9b’S,1’’S,2’’R,3’’S,7’’S)-2-{2-[1-(tert-Butyldimethylsilyloxy)-7-hy-
droxy-2-methyl-3-pivaloyloxy-nonyl]-7-triisopropylsilyloxy-3a,9b-dihydro-
3H-cyclopenta[a]naphthalen-3-yl}acetic acid-(1,7)-lactone (77): To
a
(3’S,3a’S,9b’S,2’’R,3’’S,7’’S)-2-[2-(7-Hydroxy-2-methyl-1-oxo-3-pivaloyloxy-
stirred solution of MEM-ether 75 (391 mg, 421 mmol) in MeCN (15 mL),
NaI (252 mg, 1.68 mmol) and CH2Cl2 (4 mL) were added and the mixture
was cooled to ꢀ358C. TMSCl (215 mL, 183 mg, 1.68 mmol) was added
and stirring was continued for 1.5 h. The reaction was quenched by addi-
tion of sat. aqueous Na2S2O3 (10 mL) and warmed to room temperature.
After addition of brine (15 mL) the mixture was extracted with Et2O (3”
20 mL). The combined organic extracts were dried over MgSO4 and con-
centrated under reduced pressure. Column chromatography of the resi-
due (n-pentane/Et2O 5:1) gave the free C-7’’-alcohol (298 mg, 354 mmol,
84%) as a white foam. Rf =0.19 (n-pentane/Et2O 5:1); [a]2D0 =ꢀ107.08
(c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=ꢀ0.05 (s, 3H) and
nonyl)-7-acetoxy-3a,9b-dihydro-3H-cyclopenta[a]naphthalen-3-yl]acetic
acid-(1,7)-lactone (78): HF·pyridine (0.3 mL) was slowly added to a
stirred solution of the TIPS-protected phenol 77 (8 mg, 10 mmol) in pyri-
dine (0.9 mL) in a polyethylene vessel at 08C, and stirring was continued
for 30 min after which ethyl acetate (5 mL) was added. The mixture was
washed with 2m HCl (2”5 mL) and brine (2”5 mL). The organic phase
was dried over MgSO4 and concentrated under reduced pressure.
Column chromatography of the residue (n-pentane/Et2O 2:1) gave the
free phenol (6 mg, 10 mmol, 93%) as a red oil. Rf =0.57 (n-pentane/Et2O
1
1:1); H NMR (300 MHz, CDCl3): d=ꢀ0.06 (s, 3H) and 0.06 (s, 3H) (Si-
A
N
0.03 (s, 3H) (Si
9’’-H, 2’’-CH3), 1.04 (s, 9H; OC(O)C
Si(CH(CH3)2)3), 1.46 (s, 9H; CO2(C(CH3)3)), 1.15–1.72 (m, 12H; 4’’-, 5’’-,
6’’-, 8’’-H, Si(CH(CH3)2)3, OH), 1.88 (m, 1H; 2’’-H), 2.21 (dd, J=15.9,
G
(CH3)3)), 0.89–1.01 (m, 6H;
(s, 9H; OC(O)C(CH3)3), 1.24–1.93 (m, 10H; 2’’-, 4’’-, 5’’-, 6’’-, 8’’-H, 1’’-
A
AHCTREUNG
OH), 2.65–2.84 (m, 2H; 2-H), 2.92–3.03 (m, 1H) and 3.23–3.35 (m, 1H)
(3’-, 3a’-H), 3.99 (d, J=9.3 Hz, 1H; 9b’-H), 4.29 (d, J=5.1 Hz, 1H; 1’’-
H), 4.79–4.96 (m, 2H; 3’’-, 7’’-H), 5.52 (brs, 1H; Ar-OH), 5.69 (s, 1H; 1’-
H), 5.84 (dd, J=9.6, 3.9 Hz, 1H; 4’-H), 6.24 (dd, J=9.8, 1.1 Hz, 1H; 5’-
H), 6.32 (d, J=2.1 Hz, 1H; 6’-H), 6.63 (dd, J=8.3, 2.5 Hz, 1H; 8’-H),
6.92 ppm (d, J=8.4 Hz, 1H; 9’-H); MS (ESI): m/z (%): 629.4 (44), 628.4
(100) [M+NH4]+; HRMS (ESI): m/z: calcd for C36H58NO6Si: 628.40279;
found: 628.40271 [M+NH4]+.
A
ACHTREUNG
ACHTREUNG
11.4 Hz, 1H; 2-HB), 2.90 (dd, J=15.6, 2.7 Hz, 1H; 2-HA), 2.96–3.08 (m,
2H; 3’-, 3a’-H), 3.42–3.52 (m, 1H; 7’’-H), 4.00 (d, J=8.1 Hz, 1H; 9b’-H),
4.15 (d, J=8.4 Hz, 1H; 1’’-H), 4.61 (dt, J=6.6, 3.3 Hz, 1H; 3’’-H), 5.33
(d, J=0.9 Hz, 1H; 1’-H), 5.62 (dd, J=9.6, 2.7 Hz, 1H; 4’-H), 6.25 (dd,
J=9.5, 2.0 Hz, 1H; 5’-H), 6.53 (d, J=2.1 Hz, 1H; 6’-H), 6.63 (dd, J=8.0,
2.5 Hz, 1H; 8’-H), 6.92 ppm (d, J=8.1 Hz, 1H; 9’-H); 13C NMR
The TBS-protected allylic alcohol (91 mg, 119 mmol) was dissolved in pyr-
idine (2 mL) in a polyethylene vessel and the solution was cooled to 08C.
HF·pyridine (0.5 mL) was added slowly and the temperature was raised
to 608C. After stirring for 14 h at this temperature the mixture was
cooled to room temperature and diluted with ethyl acetate (15 mL). The
mixture was washed with 2m HCl (2”10 mL) and brine (2”10 mL). The
organic phase was dried over MgSO4 and concentrated under reduced
pressure. Column chromatography of the residue (n-pentane/Et2O 1:2)
gave the free allylic alcohol (52 mg, 105 mmol, 88%) as a white foam.
Rf =0.14 (n-pentane/Et2O 1:1); [a]2D0 =ꢀ154.38 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.86 (t, J=7.3 Hz, 3H; 9’’-H), 0.91 (d,
(75 MHz, CDCl3): d=ꢀ5.08, ꢀ3.73 (Si
CH3), 12.63 (Si(CH(CH3)2)3), 17.93 (Si(CH
21.29 (C-5’’), 25.95 (Si(C(CH3)3)), 27.17 (OC(O)C
(CH3)3)), 30.10, 31.64, 36.57 (C-4’’, C-6’’, C-8’’), 38.74 (OC(O)C
39.95 (C-2’’), 40.15 (C-2), 44.15 (C-9b’), 45.35 (C-3a’), 49.74 (C-3’), 73.00
(C-7’’), 73.27 (C-1’’), 73.50 (C-3’’), 80.49 (CO2(C(CH3)3)), 118.08 (C-6’),
ACHTREUNG
A
G
ACHTREUNG
U
ACHTREUNG
G
ACHTREUNG
AHCTREUNG
118.29 (C-8’), 126.37 (C-5’), 126.42 (C-9a’*), 128.48 (C-9’), 130.98 (C-4’),
133.16 (C-5a’*), 134.86 (C-1’), 144.03 (C-2’), 154.56 (C-7’), 172.55,
176.89 ppm (C-1, OC(O)C(CH3)3); IR (KBr): n˜ =2959, 2932, 2868, 1730,
U
1157 cmꢀ1; UV/Vis (MeCN): lmax (lg e) = 229.5 (4.521), 258.5 (3.713),
266.0 (3.780), 276.0 (3.705), 300.0 (3.319), 310.0 nm (3.268); MS (ESI):
m/z (%): 860.6 (23), 859.6 (61), 858.6 (100) [M+NH4]+; HRMS (ESI):
m/z: calcd for C49H88NO7Si2: 858.60938; found: 858.60933 [M+NH4]+.
J=6.9 Hz, 3H; 2’’-CH3), 1.20 (s, 9H; OC(O)C(CH3)3), 1.15–1.36 (m, 1H)
A
and 1.43–1.95 (m, 8H) (4’’-, 5’’-, 6’’-, 8’’-H, OH), 2.12 (m, 1H; 2’’-H), 2.62
(dd, J=14.9, 5.6 Hz, 1H; 2-HB), 2.82 (dd, J=15.2, 4.1 Hz, 1H; 2-HA),
3.15 (m, 1H; 3’-H), 3.40 (m, 1H; 3a’-H), 4.12 (d, J=9.9 Hz, 1H; 9b’-H),
4.29 (s, 1H; 1’’-H), 4.75 (m, 1H; 7’’-H), 4.85–4.95 (m, 1H; 3’’-H), 5.74 (s,
1H; 1’-H), 5.81 (dd, J=9.6, 3.6 Hz, 1H; 4’-H), 6.10–6.22 (brs, 1H; OH),
6.17 (dd, J=9.8, 1.4 Hz, 1H; 5’-H), 6.43 (d, J=2.4 Hz, 1H; 6’-H), 6.59
(dd, J=8.3, 2.5 Hz, 1H; 8’-H), 6.90 ppm (d, J=8.1 Hz, 1H; 9’-H);
13C NMR (75 MHz, CDCl3): d = 9.64 (C-9’’), 10.40 (C-2’’-CH3), 19.76 (C-
NEt3 (1.33 mL, 971 mg, 9.60 mmol) and TMSOTf (1.45 mL, 1.78 g,
8.00 mmol) were added at room temperature to a solution of the above
tert-butyl ester (269 mg, 320 mmol) in THF (6 mL). After stirring for 1 h
at this temperature the reaction was quenched by addition of ethyl ace-
tate (15 mL) and 1m HCl (10 mL). The organic phase was separated and
washed thoroughly with 1m HCl (10 mL) and brine (2”15 mL), dried
over MgSO4 and concentrated under reduced pressure. The residue was
taken up in THF (3 mL), cooled to 08C and NEt3 (266 mL, 194 mg,
1.92 mmol) and TCBzCl (200 mL, 312 mg, 1.28 mmol) were added drop-
wise. The cooling bath was removed and the mixture stirred for 1.5 h at
room temperature after which toluene (8 mL) was added. The solution of
the activated acid was added dropwise over a period of 4 h to a solution
of DMAP (391 mg, 3.20 mmol) in toluene (250 mL) at 758C by a syringe
pump and stirring was continued for an additional hour. The reaction
mixture was then washed at +208C with 1m aqueous NaH2PO4 (2”
200 mL) and brine (200 mL), dried over MgSO4 and concentrated under
reduced pressure. Column chromatography of the residue (n-pentane/
Et2O 30:1) gave lactone 77 (122 mg, 159 mmol, 50%) as a white foam.
Rf =0.19 (n-pentane/Et2O 30:1); [a]2D0 =ꢀ151.08 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=ꢀ0.17 (s, 3H) and 0.01 (s, 3H) (Si-
5’’), 27.17 (OC(O)C
ACHTREUNG
(C-2), 38.21 (C-2’’), 38.94 (OC(O)C
AHCTREUNG
(C-3’), 69.24 (C-1’’), 75.81 (C-3’’), 77.55 (C-7’’), 113.67 (C-6’), 114.29 (C-
8’), 125.74 (C-5’), 126.30 (C-9a’*), 128.60 (C-9’), 130.60 (C-4’), 132.57 (C-
1’), 132.86 (C-5a’*), 145.08 (C-2’), 154.46 (C-7’), 172.56, 178.37 ppm (C-1,
OC(O)C(CH3)3); IR (KBr): n˜ =3430, 2970, 2937, 2877, 1723, 1703,
A
1167 cmꢀ1; UV/Vis (MeCN): lmax (lg e) = 228.0 (4.416), 256.5 (3.664),
265.0 (3.753), 275.5 (3.689), 304.0 (3.384), 313.0 nm (3.328); MS (ESI):
m/z (%): 514.3 (100) [M+NH4]+; HRMS (ESI): m/z: calcd for
C30H40NaO6: 519.27171; found: 519.27175 [M+Na]+, 514.31628
[M+NH4]+.
The allylic alcohol (41 mg, 83 mmol) was dissolved in DMSO (1 mL) at
room temperature and (iPr)2NEt (145 mL, 107 mg, 830 mmol) and a solu-
tion of SO3·pyridine (79 mg, 498 mmol) in DMSO (0.5 mL) were added.
The mixture was stirred for 1 h at room temperature, was then diluted
with Et2O (15 mL) and washed with sat. aqueous NH4Cl (10 mL) and
A
ACHTREUNG
AHCTREUNG
9H; OC(O)C
ACHTREUNG
8560
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8543 – 8563

Novel Spinosyn AAnalogues
FULL PAPER
brine (10 mL). The organic phase was dried over MgSO4 and concentrat-
ed under reduced pressure. Column chromatography of the residue (n-
pentane/Et2O 2:1) gave the corresponding enone as a mixture with two
other compounds.
(3.660), 266.5 (3.716), 276.0 (3.644), 300.0 (3.267), 310.0 nm (3.215); MS
(ESI): m/z (%): 860.6 (21), 859.6 (63), 858.6 (100) [M+NH4]+; HRMS
(ESI):
m/z: calcd for C49H88NO7Si2: 858.60938; found: 858.60930 [M+NH4]+.
The mixture was taken up in CH2Cl2 (2 mL), the solution was cooled to
08C and NEt3 (115 mL, 84 mg, 830 mmol), Ac2O (39 mL, 42 mg, 415 mmol)
and DMAP (5 mg, 41 mmol) were added. After stirring for 30 min at
room temperature the reaction was quenched by addition of CH2Cl2
(5 mL) and H2O (10 mL). The organic phase was separated and the aque-
ous phase was extracted with CH2Cl2 (2”5 mL). The combined organic
extracts were dried over MgSO4 and concentrated under reduced pres-
sure. Purification of the residue by preparative thin-layer chromatogra-
phy (n-pentane/Et2O 3:1) gave acetylated phenol 78 (15 mg, 28 mmol,
34% over two steps) as a white foam. Rf =0.22 (n-pentane/Et2O 3:1);
[a]2D0 =ꢀ109.88 (c=0.5 in CHCl3); 1H NMR (600 MHz, CDCl3): d=0.83
(t, J=7.5 Hz, 3H; 9’’-H), 1.07 (d, J=6.6 Hz, 3H; 2’’-CH3), 1.20 (s, 9H;
The tert-butyl ester (50 mg, 59 mmol) was dissolved in THF (1.5 mL) and
NEt3 (245 mL, 179 mg, 1.77 mmol) and TMSOTf (267 mL, 329 mg,
1.48 mmol) were added at room temperature. After stirring for 1 h at this
temperature the reaction was quenched by addition of ethyl acetate
(15 mL) and 1m HCl (10 mL). The organic phase was separated and
washed again thoroughly with 1m HCl (10 mL) and brine (2”10 mL),
dried over MgSO4 and concentrated under reduced pressure.
The residue was taken up in THF (1 mL), cooled to 08C and NEt3
(49 mL, 36 mg, 354 mmol) and TCBzCl (37 mL, 58 mg, 236 mmol) were
added dropwise. The cooling bath was removed and the mixture stirred
for 1 h at room temperature after which toluene (9 mL) was added. The
solution of the activated acid was added dropwise over a period of 2 h to
a solution of DMAP (72 mg, 590 mmol) in toluene (50 mL) at 608C using
a syringe pump and stirring was continued for an additional hour. The re-
action mixture was then washed at +208C with 1m aqueous NaH2PO4
(2”50 mL) and brine (50 mL), dried over MgSO4 and concentrated
under reduced pressure. Column chromatography of the residue (n-pen-
tane/Et2O 20:1) gave the lactone 79 (29 mg, 38 mmol, 64%) as a white
foam. Rf =0.14 (n-pentane/Et2O 30:1); [a]2D0 =ꢀ68.68 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=ꢀ0.15 (s, 3H) and ꢀ0.10 (s, 3H) (Si-
OC(O)C(CH3)3), 1.13–1.34 (m, 2H) and 1.44–1.77 (m, 6H) (4’’-, 5’’-, 6’’-,
G
8’’-H), 2.28 (s, 3H; OC(O)CH3), 2.61 (dd, J=13.8, 3.0 Hz, 1H; 2-HB),
2.96 (dd, J=13.2, 5.4 Hz, 1H; 2-HA), 3.36 (m, 1H; 3’-H), 3.45 (m, 1H;
2’’-H), 3.72 (m, 1H; 3a’-H), 4.64 (m, 1H; 9b’-H), 4.68 (m, 1H; 7’’-H),
5.00 (dt, J=10.2, 3.8 Hz, 1H; 3’’-H), 5.72 (dd, J=9.6, 3.0 Hz, 1H; 4’-H),
6.23 (dd, J=9.6, 1.8 Hz, 1H; 5’-H), 6.68 (d, J=1.8 Hz, 1H; 1’-H), 6.73 (d,
J=2.4 Hz, 1H; 6’-H), 6.89 (dd, J=7.8, 2.4 Hz, 1H; 8’-H), 7.19 ppm (d,
J=7.8 Hz, 1H; 9’-H); 13C NMR (75 MHz, CDCl3): d = 9.27 (C-9’’), 16.26
(C-2’’-CH3), 19.86 (C-5’’), 21.07 (OC(O)CH3), 27.16 (OC(O)C
27.91, 30.34, 32.69 (C-4’’, C-6’’, C-8’’), 37.61 (C-2), 38.93 (OC(O)C-
(CH3)3), 43.22 (C-3a’), 44.23 (C-2’’), 46.81 (C-9b’), 50.39 (C-3’), 75.49 (C-
A
A
ACHTREUNG
AHCTREUNG
ACHTREUNG
AHCTREUNG
3’’), 77.19 (C-7’’), 119.79 (C-6’), 120.41 (C-8’), 124.50 (C-5’), 128.85 (C-9’),
129.67 (C-9a’*), 131.76 (C-4’), 133.44 (C-5a’*), 143.49 (C-2’), 149.32 (C-
1’), 149.55 (C-7’), 169.55, 172.88, 177.63 (C-1, OC(O)CH3, OC(O)C-
AHCTREUNG
2.95–3.04 (m, 1H; 3’-H), 3.45–3.56 (m, 1H; 3a’-H), 3.85 (d, J=10.5 Hz,
1H; 1’’-H), 4.33 (d, J=10.5 Hz, 1H; 9b’-H), 4.95 (m, 1H) and 5.06 (m,
1H) (3’’-, 7’’-H), 5.81 (dd, J=9.8, 4.1 Hz, 1H; 4’-H), 6.18 (dd, J=9.8,
0.8 Hz, 1H; 5’-H), 6.29 (s, 1H; 1’-H), 6.48 (d, J=2.4 Hz, 1H; 6’-H), 6.66
(dd, J=8.3, 2.5 Hz, 1H; 8’-H), 7.06 ppm (d, J=8.1 Hz, 1H; 9’-H);
A
1212 cmꢀ1; UV/Vis (MeCN): lmax (lg e) = 225.0 nm (4.358); MS (ESI):
m/z (%): 559.3 (25) [M+Na]+, 555.3 (34), 554.3 (100) [M+NH4]+, 538.3
(19), 537.3 (54) [M+H]+; HRMS (ESI): m/z: calcd for C32H44NO7:
554.31123; found: 554.31128 [M+NH4]+, 537.28476 [M+H]+.
13C NMR (75 MHz, CDCl3): d=ꢀ3.62, ꢀ3.57 (Si
ACHTREUNG
11.24 (C-2’’-CH3), 12.64 (Si(CH
(CH3)2)3), 17.96 (Si(CH
ACHTREUNG
(3’S,3a’S,9b’S,1’’S,2’’R,3’’R,7’’S)-2-{2-[1-(tert-Butyldimethylsilyloxy)-7-hy-
(Si(C
(Si(C(CH3)3)), 27.23 (OC(O)C
(CH3)3), 40.28 (C-2’’), 41.54 (C-3a’), 44.12 (C-9b’), 52.18 (C-3’), 69.87 (C-
1’’), 72.65, 76.19 (C-3’’, C-7’’), 117.86 (C-6’), 118.66 (C-8’), 125.60 (C-5’),
127.20 (C-9a’*), 128.89 (C-9’), 130.11 (C-4’), 132.76 (C-5a’*), 134.44 (C-
1’), 141.41 (C-2’), 154.12 (C-7’), 171.33, 177.89 ppm (C-1, OC(O)C-
ACHTREUNG
droxy-2-methyl-3-pivaloyloxynonyl]-7-triisopropylsilyloxy-3a,9b-dihydro-
N
A
ACHTREUNG
3H-cyclopenta[a]naphthalen-3-yl}acetic acid-(1,7)-lactone (79): NaI
(61 mg, 408 mmol) and CH2Cl2 (2 mL) were added at room temperature
to a stirred solution of MEM-ether 76 (95 mg, 102 mmol) in MeCN
(8 mL). The reaction mixture was cooled and at ꢀ358C TMSCl (52 mL,
44 mg, 408 mmol) was added and stirring was continued for 2 h. The reac-
tion was quenched by addition of sat. aqueous Na2S2O3 (5 mL) and the
mixture warmed to room temperature. After addition of brine (10 mL)
the mixture was extracted with Et2O (3”10 mL). The combined organic
extracts were dried over MgSO4 and concentrated under reduced pres-
sure. Column chromatography of the residue (n-pentane/Et2O 5:1) gave
the free C-7’’-alcohol (61 mg, 73 mmol, 71%) as a white foam. Rf =0.20
(n-pentane/Et2O 5:1); [a]2D0 =ꢀ106.88 (c=1.0 in CHCl3); 1H NMR
AHCTREUNG
A
(MeCN): lmax (lg e) = 229.0 (4.510), 258.0 (3.692), 266.5 (3.750), 276.5
(3.681), 300.0 (3.308), 310.5 nm (3.247); MS (ESI): m/z (%): 1552.0 (8),
1551.0 (7) [2M+NH4]+, 786.5 (21), 785.5 (55), 784.5 (100) [M+NH4]+;
HRMS (ESI): m/z: calcd for C45H78NO6Si2: 784.53622; found: 784.53660
[M+NH4]+.
(3’S,3a’S,9b’S,2’’R,3’’R,7’’S)-2-[2-(7-Hydroxy-2-methyl-1-oxo-3-pivaloyl-
oxy-nonyl)-7-hydroxy-3a,9b-dihydro-3H-cyclopenta[a]naphthalen-3-yl]-
acetic acid-(1,7)-lactone (80): The double silyl protected tetracycle 79
(25 mg, 33 mmol) was dissolved in pyridine (1.2 mL) in a polyethylene
vessel and the mixture was cooled to 08C. HF·pyridine (0.4 mL) was
slowly added dropwise. The cooling bath was removed and the mixture
was heated to 608C for 14 h. After cooling to room temperature the mix-
ture was diluted with ethyl acetate (5 mL) and washed with 2m HCl (2”
5 mL) and brine (2”5 mL). The organic phase was dried over MgSO4
and concentrated under reduced pressure. Purification of the residue by
column chromatography (n-pentane/Et2O 1:1) gave the free alcohol
(15 mg, 30 mmol, 91%) as a colorless oil. Rf =0.15 (n-pentane/Et2O 1:1);
1H NMR (300 MHz, CDCl3): d=0.86 (t, J=7.4 Hz, 3H; 9’’-H), 1.04 (d,
(300 MHz, CDCl3): d=ꢀ0.07 (s, 3H) and 0.01 (s, 3H) (Si
9H; Si(C(CH3)3)), 0.82–0.89 (m, 3H; 9’’-H), 0.92 (d, J=7.2 Hz, 3H; 2’’-
CH3), 1.08 (d, J=6.9 Hz, 18H; Si(CH(CH3)2)3), 1.20 (s, 9H; OC(O)C-
(CH3)3), 1.47 (s, 9H; CO2(C(CH3)3)), 1.01–1.55 (m, 12H; 4’’-, 5’’-, 6’’-, 8’’-
H, Si(CH(CH3)2)3, OH), 2.03 (m, 1H; 2’’-H), 2.18 (dd, J=15.5, 12.1 Hz,
(CH3)2), 0.86 (s,
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
ACHTREUNG
1H; 2-HB), 2.92 (dd, J=15.8, 3.2 Hz, 1H; 2-HA), 3.13 (m, 1H; 3a’-H),
3.23–3.40 (m, 2H; 3’-, 7’’-H), 3.98–4.06 (m, 2H; 9b’-, 1’’-H), 4.67 (m, 1H;
3’’-H), 5.31 (s, 1H; 1’-H), 5.86 (dd, J=9.9, 2.7 Hz, 1H; 4’-H), 6.20 (dd,
J=9.9, 2.4 Hz, 1H; 5’-H), 6.48 (d, J=2.4 Hz, 1H; 6’-H), 6.64 (dd, J=8.1,
2.4 Hz, 1H; 8’-H), 6.95 ppm (d, J=8.1 Hz, 1H; 9’-H); 13C NMR
(75 MHz, CDCl3): d=ꢀ5.11, ꢀ3.73 (Si
CH3), 12.60 (Si(CH(CH3)2)3), 17.91 (Si(CH
21.26 (C-5’’), 25.90 (Si(C(CH3)3)), 27.25 (OC(O)C
(CH3)3)), 28.29, 29.99, 36.31 (C-4’’, C-6’’, C-8’’), 38.83 (OC(O)C
40.48 (C-2), 40.69 (C-2’’), 44.15 (C-9b’), 45.11 (C-3a’), 49.46 (C-3’), 73.16
(C-7’’), 73.34 (C-1’’), 73.93 (C-3’’), 80.32 (CO2(C(CH3)3)), 117.93 (C-6’),
ACHTREUNG
A
N
ACHTREUNG
J=6.9 Hz, 3H; 2’’-CH3), 1.22 (s, 9H; OC(O)C(CH3)3), 1.41–1.86 (m, 8H;
U
A
ACHTREUNG
4’’-, 5’’-, 6’’-, 8’’-H), 2.22 (m, 1H; 2’’-H), 2.62 (dd, J=13.7, 4.0 Hz, 1H; 2-
HB), 2.73 (dd, J=13.8, 4.5 Hz„ 1H; 2-HA), 3.07–3.15 (m, 1H; 3’-H*),
3.39–3.49 (m, 1H; 3a’-H*), 3.74 (d, J=10.5 Hz, 1H; 1’’-H), 4.29 (d, J=
10.2 Hz, 1H; 9b’-H), 4.99 (m, 1H) and 5.10 (m, 1H) (3’’-, 7’’-H), 5.80 (dd,
J=9.6, 3.9 Hz, 1H; 4’-H), 6.19 (dd, J=9.9, 1.5 Hz, 1H; 5’-H), 6.26 (s,
1H; 1’-H), 6.44 (d, J=2.7 Hz, 1H; 6’-H), 6.50 (dd, J=8.1, 2.7 Hz, 1H; 8’-
H), 7.00 ppm (d, J=8.1 Hz, 1H; 9’-H); MS (ESI): m/z (%): 520.3 (6),
A
ACHTREUNG
AHCTREUNG
118.30 (C-8’), 125.47 (C-5’), 126.63 (C-9a’*), 128.70 (C-9’), 132.63 (C-4’),
133.21 (C-5a’*), 134.07 (C-1’), 144.76 (C-2’), 154.62 (C-7’), 172.16,
177.35 ppm (C-1, OC(O)C
C
Chem. Eur. J. 2007, 13, 8543 – 8563
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8561

L. F. Tietze et al.
519.3 (18) [M+Na]+, 515.3 (11), 514.3 (32) [M+NH4]+; HRMS (ESI):
m/z: calcd for C30H40NaO6: 519.27171; found: 519.27152 [M+Na]+,
514.31624 [M+NH4]+.
e) C. F. Wyss, H. P. Young, J. Shukla, R. M. Roe, Crop Prot. 2003,
22, 307–314; f) J. K. Moulton, D. A. Pepper, T. J. Dennehy, Pest
Manage. Sci. 2000, 56, 842–848.
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2562; d) D. A. Evans, W. C. Black, J. Am. Chem. Soc. 1993, 115,
4497–4513.
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5018.
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8971–8977; b) L. F. Tietze, T. Nçbel, M. Spescha, Angew. Chem.
1996, 108, 2385–2386; Angew. Chem. Int. Ed. Engl. 1996, 35, 2259–
2261; For more recent applications, see: c) L. F. Tietze, L. P. Lücke,
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Krimmelbein, Chem. Eur. J. 2007, 13, DOI: 10.1002/
chem.200700182.
The allylic alcohol (12 mg, 24 mmol) was dissolved in DMSO (0.5 mL) at
room temperature and (iPr)2NEt (42 mL, 31 mg, 140 mmol) and a solution
of SO3·pyridine (23 mg, 144 mmol) in DMSO (0.2 mL) were added. The
mixture was stirred for 1 h at room temperature, was then diluted with
Et2O (10 mL) and washed with sat. aqueous NH4Cl (10 mL) and brine
(10 mL). The organic phase was dried over MgSO4 and concentrated
under reduced pressure. Purification of the residue by preparative thin-
layer chromatography (n-pentane/Et2O 1:1) gave the enone 80 (8 mg,
16 mmol, 67%) as a light yellow foam. Rf =0.36 (n-pentane/Et2O 1:1);
[a]2D0 =ꢀ110.28 (c=0.5 in CHCl3); 1H NMR (600 MHz, CDCl3): d=0.77
(t, J=7.2 Hz, 3H; 9’’-H), 0.93 (d, J=6.6 Hz, 3H; 2’’-CH3), 1.17 (s, 9H;
OC(O)C(CH3)3), 1.13–1.26 (m, 1H) and 1.32–1.78 (m, 7H) (4’’-, 5’’-, 6’’-,
N
8’’-H), 2.50 (dd, J=13.8, 3.6 Hz, 1H; 2-HB), 2.94 (dd, J=13.8, 4.8 Hz,
1H; 2-HA), 3.23 (m, 1H; 3’-H), 3.47 (m, 1H; 3a’-H), 3.56 (m, 1H; 2’’-H),
4.48 (m, 1H; 9b’-H), 4.88 (m, 1H; 7’’-H), 5.23 (dd, J=10.5, 3.9 Hz, 1H;
3’’-H), 5.66 (brs, 1H; OH), 5.71 (dd, J=9.6, 3.6 Hz, 1H; 4’-H), 6.12 (dd,
J=10.2, 1.8 Hz, 1H; 5’-H), 6.42 (d, J=3.0 Hz, 1H; 6’-H), 6.58 (dd, J=
7.8, 2.4 Hz, 1H; 8’-H), 7.03 (d, J=8.4 Hz, 1H; 9’-H), 7.17 ppm (s, 1H; 1’-
H); 13C NMR (150 MHz, CDCl3): d = 7.28 (C-2’’-CH3), 10.15 (C-9’’),
19.02 (C-5’’), 25.04, 25.83, 27.41 (C-4’’, C-6’’, C-8’’), 27.13 (OC(O)C-
A
N
[10] For a detailed discussion of the Heck reaction mechanism, see: I. P.
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46.24 (C-9b’), 50.49 (C-3’), 73.33 (C-3’’), 76.14 (C-7’’), 113.75 (C-6’),
114.52 (C-8’), 124.35 (C-9a’*), 125.17 (C-5’), 129.20 (C-9’), 130.57 (C-4’),
133.08 (C-5a’*), 141.71 (C-2’), 150.22 (C-1’), 154.71 (C-7’), 172.25, 178.86
(C-1, OC(O)C(CH3)3), 198.41 ppm (C-1’’); IR (KBr): n˜ =3428, 2969,
A
2935, 2875, 1724, 1161 cmꢀ1; UV/Vis (MeCN): lmax (lg e) = 230.0 (4.377),
302.0 nm (3.364); MS (ESI): m/z (%): 517.3 (41) [M+Na]+, 513.3 (22),
512.3 (70) [M+NH4]+, 495.3 (43) [M+H]+; HRMS (ESI): m/z: calcd for
C30H42NO6: 512.30066; found: 512.30051 [M+NH4]+, 495.27411 [M+H]+.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. We are also indebted to the BASF
AG, the Bayer AG, the Degussa AG and the Wacker Chemie AG for
generous gifts of chemicals.
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Novel Spinosyn AAnalogues
FULL PAPER
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Received: February 2, 2007
Published online: July 25, 2007
Chem. Eur. J. 2007, 13, 8543 – 8563
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8563