Asymmetric Total Synthesis of ent-Pyripyropene A

Article abstract of DOI:10.1002/chem.201500703

An asymmetric total synthesis of ent-pyripyropene A was achieved by a convergent synthetic route. We used our originally developed Ti^III-catalyzed radical cyclization to construct an AB-ring portion that consisted of a trans-decalin skeleton wi

Full text of DOI:10.1002/chem.201500703

DOI: 10.1002/chem.201500703
Full Paper
&
Natural Products
Asymmetric Total Synthesis of ent-Pyripyropene A
[a, g]
[a]
[a]
[a]
Shinichiro Fuse,*
Ayako Ikebe, Kazuya Oosumi, Tomoya Karasawa,
[a]
[b]
[c]
[c]
Keisuke Matsumura, Miho Izumikawa, Kohei Johmoto, Hidehiro Uekusa,
[
d]
[e]
[f]
Kazuo Shin-ya, Takayuki Doi, and Takashi Takahashi*
Abstract: An asymmetric total synthesis of ent-pyripyrope-
total synthesis of ent-pyripyropene A. An evaluation of the
insecticidal activity of ent-pyripyropene A against two aphid
species revealed that ent-pyripyropene A was 35–175 times
less active than naturally occurring pyripyropene A. This
result indicated that the biological target of pyripyropene A
recognizes the absolute configuration of pyripyropene A.
ne A was achieved by a convergent synthetic route. We
III
used our originally developed Ti -catalyzed radical cycliza-
tion to construct an AB-ring portion that consisted of
a trans-decalin skeleton with five contiguous stereogenic
centers. The coupling between the AB-ring and the DE-ring
portions, and a subsequent C-ring cyclization, led to the
Introduction
The isolation and structural determination of pyripyropenes A
[
1]
¯
to D and pyripyropenes E to L were reported by the Omura
[
2]
group more than two decades ago (Figure 1). Pyripyropenes
are mixed polyketide–terpenoids (meroterpenoids), and were
isolated from Aspergillus fumigatus. Bioassay results have re-
vealed that pyripyropenes A and C retain the highest degree
of inhibitory activity against cholesterol acyltransferase (ACAT)
[
1a,c]
among naturally occurring compounds.
ACAT is regarded
[a] Dr. S. Fuse, A. Ikebe, K. Oosumi, T. Karasawa, K. Matsumura
Department of Applied Chemistry, Tokyo Institute of Technology
2
-12-1, Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
[b] Dr. M. Izumikawa
Japan Biological Informatics Consortium (JBIC)
2
-4-7, Aomi, Koto-ku, Tokyo 135-0064 (Japan)
[
c] Dr. K. Johmoto, Dr. H. Uekusa
Department of Chemistry and Materials Science
Tokyo Institute of Technology
2
-12-1, Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
Figure 1. Chemical structures of pyripyropenes A to L.
[d] Dr. K. Shin-ya
National Institute of Advanced Industrial Science and Technology (AIST)
2
-4-7, Koto-ku, Tokyo 135-0064 (Japan)
as a promising target for the development of anti-hypercholes-
[
e] Prof. T. Doi
[3]
Graduate School of Pharmaceutical Sciences, Tohoku University
terolemia agents. Recently, molecular biological studies have
[4]
6
-3, Aza-Aoba, Aramaki, Aoba, Sendai 980-8578 (Japan)
revealed the presence of two isozymes, ACAT1 and ACAT2.
[
f] Prof. T. Takahashi
Yokohama College of Pharmacy, 601, Matano-cho, Totsuka-ku
Yokohama-shi, Kanagawa 245-0066 (Japan)
Selective ACAT2 inhibition is thought to be preferable for the
development of anti-atherosclerotic agents, whereas ACAT1 in-
[5]
hibition might cause detrimental effects. From this point of
view, pyripyropene A and its synthetic analogues are attractive
because pyripyropene A is known to exert highly selective in-
[g] Dr. S. Fuse
Present address: Chemical Resources Laboratory
Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku
Yokohama, 226-8503 (Japan)
[6]
hibitory activity against ACAT2.
E-mail: sfuse@res.titech.ac.jp
In 1995, the Gloer group isolated pyripyropene A from Eupe-
nicillium reticulisporum, and first reported the insecticidal activi-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500703. It contains details for synthetic
procedures, spectroscopic data, copies of H and C NMR spectra, and bio-
logical assays.
[7]
1
13
ty of pyripyropene A against the corn earworm. Ten years
later, Kim et al. assumed that ACAT inhibitors would be good
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insecticidal agents because insects essentially require sterols
for their growth and utilize a sterol-acylating enzyme that par-
ticipates in the storage and transport of sterols and in the acti-
vation and degradation of hormones. Kim et al. actually con-
firmed that ACAT inhibitors, which included pyripyropene A,
exert insecticidal activity against both the corn earworm and
reagent. This synthetic plan would allow the synthesis of either
the natural compound or its enantiomer because both enan-
tiomers of epoxy alkene 5 can be readily prepared by Sharp-
less–Katsuki asymmetric epoxidation of the corresponding al-
[15]
lylic alcohol.
A key to the total synthesis was the construction of trans-
decalin 4 by tandem radical cyclization. Pioneering work for
the construction of the 11-desoxo congener of trans-decalin 4
from farnesyl acetate by tandem radical cyclization was report-
[
8]
the mealworm. Moreover, Goto et al. recently reported that
pyripyropenes also retain potent insecticidal activity against
[
9]
aphids.
[16]
¯
The Omura–Smith group achieved the first total synthesis of
ed by the Breslow group more than 45 years ago. In 2001,
the Barrero group demonstrated the synthesis of the 11-
[
10]
pyripyropene A in a highly convergent manner.
However,
[17]
their total synthesis included several steps that cannot be
desoxo congener of 4 from an epoxy alkene by tandem radi-
[
11]
III
¯
scaled up. Therefore, the Omura–Nagamitsu group devel-
oped a practical, linear synthetic route for the total synthesis
cal cyclization using a stoichiometric amount of a Ti reagent
under conditions that were originally reported by Nugent and
[
11]
[18]
of pyripyropene A. They successfully synthesized pyripyro-
pene analogues with a simplified A-ring structure based on
Rajanbabu. At the same time, we also reported the synthesis
of a 13-desoxo-congener of 4 that was used for the synthesis
[
12]
III
their developed synthetic route. Herein, we wish to report
the convergent synthesis of ent-pyripyropene A based on our
originally developed tandem radical cyclization by using a cata-
of smenospondiol by using a stoichiometric amount of a Ti
[19]
reagent. In 2006, the Barrero group reported the radical cyc-
1
2
lization of 5 ((R =tert-butyldimethylsilyl (TBS), R =acetyl (Ac))
in the presence of a catalytic amount of Ti using trimethylsilyl
III
[13]
III
lytic amount of a Ti reagent.
[
20]
1
We were interested in the insecticidal activity of ent-pyripyr-
opene A (1) that has not yet been reported, although numer-
ous analogues of naturally occurring pyripyropene A have
been synthesized and their biological activities have been eval-
chloride (TMSCl)/2,4,6-collidine additives
to afford 4 (R =
TBS, R =Ac) in a moderate yield (41%). However, Oikawa
2
[21]
1
et al. reported that they performed the cyclization of 5 (R =
TBS, R =Ac) by using a stoichiometric amount of a Ti reagent
2
III
[
6b,d–f,14]
uated (Scheme 1).
We planned to develop a convergent
(41% yield) because Barrero’s catalytic conditions were not
[22]
suitable for providing the desired product. Since we inde-
pendently reported radical cyclization conditions using a cata-
III
lytic amount of a Ti reagent with BEt /TMSCl or BEt /2,6-lutidi-
3
3
[13]
ne·HCl additives, we planned to apply the above conditions
[23]
to the asymmetric synthesis of AB-ring 4.
Results and Discussion
Cyclization precursor 9 was prepared from farnesyl acetate (6)
in four steps, as shown in Scheme 2. Allylic oxidation of 6 af-
[24]
forded alcohol 7 as a 9:1 mixture of E/Z-isomers 7a and 7b,
which could not be separated by column chromatography.
[15]
Therefore, the Sharpless–Katsuki asymmetric epoxidation of
Scheme 1. Synthetic plan for ent-pyripyropene A (1).
synthetic route that would enable ready access to various pyri-
pyropene analogues in the future. Our synthetic plan is shown
in Scheme 1. The nucleophilic addition of DE-ring carbanion 3
to the AB-ring aldehyde 2, oxidation of the generated allylic al-
cohol to the corresponding enone, stereoselective construction
of a C-ring by oxa-Michael addition, and the following stereo-
[
10a]
selective reduction
of a ketone would lead to pyripyrope-
ne A (1). The AB-ring 2 would be synthesized from 4 by the in-
troduction of a hydroxy group at the 7-position, isomerization
of an alkene, and oxidation of the 13-OH group. The trans-dec-
alin 4 containing five contiguous stereogenic centers would be
constructed by tandem radical cyclization of the enantiomeri-
Scheme 2. Preparation of cyclization precursor 9. TBHP=tert-butyl hydroper-
oxide, DET=diethyl tartrate, MS=molecular sieve.
III
cally pure epoxy alkene 5 by using a catalytic amount of a Ti
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the mixture of the allylic alcohols 7a and 7b was carried out.
The mixture of epoxy alcohols 8a and 8b was obtained in
a high yield and in good enantiomeric excess (ee). The major
isomer 8a was isolated by careful silica-gel column chromatog-
raphy. However, minor isomer 8b could not be purely isolated
and a 1:4 mixture of 8a and 8b was obtained. Thus, we as-
III
Table 1. Examination of Ti -catalyzed tandem radical cyclization condi-
tions.
1
signed all the H NMR spectroscopic signals for both 8a and
1
8
b. From H NMR spectroscopic analysis of the crude product
of this epoxidation, we determined that the ratio of 8a and
b was 9:1. The ee was determined by chiral HPLC analysis
[a]
Entry T [8C]
Additive
Solvent
Yield [%]
8
1
2
3
4
5
6
7
RT
Et
3
3
3
3
B/TMSCl
B/TMSCl
B/TMSCl
B/TMSCl
THF
THF
15
43
after converting the isolated epoxy alcohol 8a to the corre-
sponding benzoate (for details for determination of the ee, see
the Supporting Information). We conducted a preliminary ex-
amination of the protecting groups (TBS, 4-methoxyphenyl
methyl (MPM), methoxymethyl (MOM), Ac, and benzoyl (Bz))
À20 to RT Et
À20 to RT Et
À20 to RT Et
toluene/THF=3:2 44
benzene/THF=3:2 51
RT
60
60
Et B/2,6-lutidine·HCl THF
3
45
46
Et
Et
3
B/2,6-lutidine·HCl THF
B/2,6-lutidine·HCl benzene/THF=3:2 46
1
3
for R of 5 in a key radical cyclization, and the TBS protection
afforded the best results. This observation was consistent with
[a] Isolated yield.
[19a]
our previous results in the synthesis of smenospondiol.
Therefore, the cyclization of precursor 9 with a TBS group was
prepared, as shown in Scheme 2.
The catalytic conditions were examined using a readily avail-
The influence of the stereochemistry at the 10-position on
radical cyclization was examined by using pure 9a, and a mix-
ture of 9a and 9b (9a/9b=1:4), as shown in Scheme 3. As
able mixture of 9a and 9b (9a/9b=9:1), as shown in Table 1.
In accordance with our previously developed procedure, the
[13]
additives Et B/TMSCl (entries 1–4) and Et B/2,6-lutidine·HCl
3
3
(
Table 1, entries 5–7) were examined. The combinations of
Et B/TMSCl at room temperature resulted in a low yield
3
(
entry 1), which was probably due to an undesired generation
of chlorohydrin. To suppress the undesired chlorohydrin forma-
tion, the reaction was carried out at a lower temperature
(
entry 2). As expected, the yield of 10 was improved. Solvent
effects were examined as shown in entries 2–4. As a result, the
use of a mixed solvent (benzene/THF=3:2) afforded the best
yield (51% in entry 4). Alternative additives, Et B/2,6-lutidi-
3
ne·HCl, provided the desired product (entries 5–7), but the
yields were up to 46%.
The tandem radical cyclization of the isolated epoxy alkene
9
a was carried out by using the optimized catalytic conditions
(
Table 1, entry 4), as shown in Scheme 4. The manganese
Scheme 3. Tandem radical cyclization of epoxy alkenes 9a and 9b mediated
III
by stoichiometric amounts of Ti reagent, and determination of the stereo-
chemistries of the cyclization product by X-ray crystallographic analysis of
11. TBAF=tetrabutylammonium fluoride, 2,2-DMP=2,2-dimethoxypropane.
III
Scheme 4. Ti -catalyzed tandem radical cyclization of the isolated epoxy
alkene 9a.
a result, cyclization of the pure 9a afforded the desired cycliza-
tion product 10 in a 60% yield. Surprisingly, the cyclization of
the mixture of 9a and 9b afforded a complex mixture that
contained only a trace amount of the desired cyclization prod-
uct 10. This result indicates that the isomer 9a is a suitable
cyclization precursor, while isomer 9b is not. The relative ster-
eochemistries of the cyclization products were unambiguously
determined by X-ray crystallographic analysis of 11 that was
powder, K CO , MS4A, and a solution of 9a (1.0 equiv) in ben-
2
3
zene, all were placed in a round-bottomed flask. After stirring
at room temperature for 1 h, the mixture was frozen by cool-
ing at À208C. To the frozen mixture, a supernatant of
[(Cp) TiCl] (Cp=cyclopentadienyl; 0.20 equiv) in THF that was
2
prepared in situ by mixing [(Cp) TiCl ] and Mn, was added
2
2
dropwise at À208C. Then, solutions of TMSCl in benzene and
Et B in THF were added successively at À208C. After stirring at
3
[
25]
derived from 10.
room temperature, the standard workup procedure and silica-
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gel column chromatographic separation afforded the desired
product 10 in a 60% yield.
cohol was oxidized to the corresponding aldehyde. A subse-
quent isomerization of the alkene in the presence of DBU af-
[28]
The automation of synthetic procedures improves both the
reproducibility and the reliability of the syntheses because au-
tomated synthesizers minimize the variability of the experi-
forded the desired enal 15 in a good yield.
The DE-ring portion was prepared in accordance with the
previously reported Katritzky synthesis of 6-phenyl-4-hydroxy-
[
26]
[29]
mental manipulations. We carried out the synthesis of 10 in-
2-pyrone, as shown in Scheme 6. Thus nucleophilic acyl sub-
III
cluding the key step, Ti -catalyzed radical cyclization by using
our originally developed automated synthesizer, ChemKon-
[26c]
zert
(for details of the automated synthesis of 10, see the
Supporting Information). This automation is noteworthy be-
cause the obtained compound 10 is useful for the synthesis of
numerous bioactive natural products.
The cyclization product 10 was converted to AB-ring 15, as
shown in Scheme 5. After the protection of the secondary alco-
hol with a TBS group, the hydroxy group was introduced at
the 7-position to afford allylic alcohol 12. The stereochemistry
1
of the 7b-OH group in 12 was determined by H NMR spectro-
scopic analysis (7a-H was observed as a broad singlet). The ste-
reochemistry of the 7b-OH group in 12 was inverted by the ox-
[
27]
idation–reduction sequence. In the Luche reduction, the hy-
dride attacked from the sterically less-hindered b-face to afford
the desired 7a-alcohol 13 as a major product (7a-OH/7b-OH=
8
4%:9%). The stereochemistry of the 7a-OH in 13 was con-
Scheme 6. Preparation of DE-rings 20–22. NIS=N-iodosuccinimide.
1
firmed by H NMR spectroscopic analysis (J7,8 =4.8, 11.1 Hz).
The following protection of the alcohol with a TBS group af-
forded 14. After removal of the acetyl group, the resultant al-
stitution of 17 with the carbanion generated from 2,2,6-tri-
[30]
methyl-1,3-dioxin-4-one (16) provided 18. The acyl ketene
9 was in situ generated by a retro-Diels–Alder reaction of 18
1
under heating, and the subsequent spontaneous cyclization af-
forded the desired pyridyl pyrone 20 in a good yield. We pre-
pared methylated- and iodinated-pyridylpyrones 21 and 22 as
candidates for the DE-ring portion as the coupling partner of
AB-ring 15.
Unfortunately, extensive attempts failed to generate the de-
sired anions at the 3’-position in DE-rings 20 and 21 with
tBuLi. In the case of 20, an undesired addition of tBuLi to the
[31]
pyridine ring occurred. It was difficult to suppress this unde-
sired addition by controlling either the temperature or the
quantity of tBuLi. In the case of 21, an undesired nucleophilic
acyl substitution to the pyrone ring occurred and the pyrone
ring was cleaved. These results turned our attention to gener-
ating the desired anion from alkenyl iodide 22 with a Grignard
[32]
reagent, as shown in Scheme 7. A THF solution of iPrMgCl·-
[33]
LiCl was added at À788C to a suspension of 22 in THF, and
the reaction mixture was stirred at the same temperature for
Scheme 5. Synthesis of AB-ring 15. IBX=2-iodoxybenzoic acid, DBU=1,8-di-
azabicyclo[5.4.0]undec-7-ene.
Scheme 7. Coupling between AB-ring 15 and DE-ring 22.
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20 min under an Ar atmosphere. A solution of aldehyde 15 in
THF was added dropwise to the reaction mixture at the same
temperature. After stirring at 08C for 2 h, a standard workup
procedure afforded the desired coupling product 23 in a 41%
yield with a 54% recovery of enal 15 (89% yield BRSM). Al-
though the stereochemistry of the 13-OH was not determined,
a single stereoisomer was obtained in this coupling reaction. It
should be noted that approximately 30% of DE-ring that was
used was also recovered as the desiodo compound 21. This re-
covered 21 was reusable for the coupling reaction after iodina-
tion to 22. Although the yield of the key coupling reaction was
moderate, this reaction was rather clean. Only three com-
pounds, unreacted 15, desiodo compound 21, and the desired
product 23 were observed in the crude reaction mixture.
These compounds could be readily separated by silica-gel
column chromatography.
Scheme 9. Completion of the total synthesis of ent-pyripyropene A (1).
DMAP=4-(dimethylamino)pyridine.
TBSO group did not proceed in the absence of NaI even at the
reflux temperature.
¯
In accordance with the procedure reported by the Omura–
[11]
The obtained alcohol 23 was oxidized in the presence of
Nagamitsu group, 26 was converted to ent-pyripyropene A
(1) as shown in Scheme 9. Three TBS groups were removed by
in situ generated HCl, and the acetyl groups then were intro-
[
34]
Dess–Martin periodinane (DMP)
to the corresponding
ketone 24 (Scheme 8). The following removal of the methyl
[27]
duced. The final Luche reduction afforded the desired 1 in
1
a good yield. The structure of 1 was confirmed by H NMR,
13
C NMR, IR, and HRMS spectra, as well as by specific rotation.
The observed spectra were consistent with the previously re-
ported data except for the opposite sign of its specific rota-
[10a,11]
tion.
The insecticidal activity of both ent-pyripyropene A (1) and
naturally occurring pyripyropene A was tested against two
aphid species (Megoura viciae and Myzus persicae), as shown in
Table 2 (for details of the evaluation of insecticidal activity, see
Table 2. Evaluation of insecticidal activity of ent-pyripyropene A and nat-
urally occurring pyripyropene A against two aphid species.
Entry
Compound
Aphid
ED50 [ppm]
1
2
3
4
ent-pyripyropene A
ent-pyripyropene A
pyripyropene A
Megoura viciae
Myzus persicae
Megoura viciae
Myzus persicae
666
273
4
pyripyropene A
8
Scheme 8. C-ring cyclization for the synthesis of 26.
the Supporting Information). It was interesting that ent-pyripyr-
opene A (1) retained a much weaker degree of insecticidal ac-
tivity against both aphid species compared with pyripyrope-
ne A. The observed ED50 values were 35–175 times higher than
those of pyripyropene A. This result indicates that the biologi-
cal target of pyripyropene A recognizes the absolute configura-
tion of pyripyropene A, because the enantiomeric pairs of pyri-
pyropene A had almost identical physical properties. This is
noteworthy because ent-pyripyropene A can be used as an
ideal negative control for the detection of the biological
group was carried out in accordance with the conditions es-
[
35]
tablished by Yadav using CeCl ·7H O and NaI. In this reac-
3
2
tion, both the temperature and the quantity of the reagents
were important for a good yield. Either a higher temperature
or the use of a larger amount of reagents caused the unde-
sired elimination of the TBSO group at the 7-position. An at-
tempt for a one-pot operation to obtain the cyclized product
26 from 24 resulted in the undesired elimination of the TBSO
group. Because heating conditions (MeCN, reflux) were neces-
sary for the desired C-ring cyclization, however, in the presence
of NaI, these heating conditions caused the undesired elimina-
tion of the TBSO group. For these reasons, after the removal of
the methyl group, the obtained enol 25 was roughly purified
[36]
target of pyripyropene A in the future.
Conclusion
by short-pass column chromatography. CeCl -mediated cycliza-
We achieved the asymmetric total synthesis of unnatural ent-
3
[28]
III
tion then was performed to afford the desired product 26 in
pyripyropene A (1). Our originally developed Ti -catalyzed radi-
a good yield (2 steps, 67%). The undesired elimination of the
cal cyclization conditions using Et B/TMSCl were successfully
3
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applied to the rapid construction of 10, which consisted of
a trans-decalin skeleton with five contiguous stereogenic cen-
ters. The coupling between the functionalized AB-ring 15 and
DE-ring 22 was successfully performed by a Grignard addition
reaction. A subsequent C-ring cyclization that was mediated by
Tomoda, Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1108–1115; d) M.
Ohtawa, H. Yamazaki, D. Matsuda, T. Ohshiro, L. L. Rudel, S. O¯ mura, H.
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¯
3798–3801; f) M. Ohtawa, H. Yamazaki, S. Ohte, D. Matsuda, T. Ohshiro,
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CeCl led to the first total synthesis of ent-pyripyropene A (1).
3
2
013, 23, 1285–1287.
7] H. J. Wang, J. B. Gloer, D. T. Wicklow, P. F. Dowd, Appl. Environ. Microbiol.
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An evaluation of insecticidal activity revealed that the ent-pyri-
pyropene A (1) was 35–175 times less active than naturally oc-
curring pyripyropene A. This result indicates that the biological
target of pyripyropene A recognizes the absolute configuration
of pyripyropene A.
[
[
[
1
8] Y. Kim, H. Lee, M. Rho, H. Kim, H. Song, S. Kim, WO2004/060065A1,
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biomimetic syntheses of a less functionalized congener, pyripyropene E
Experimental Section
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5
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[
11] A. Odani, K. Ishihara, M. Ohtawa, H. Tomoda, S. O¯ mura, T. Nagamitsu,
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The authors are thankful for the financial support of a Tokyo
Tech Engineering Grant for a New Assistant Professor and
Grant-in-Aid for Scientific Research on Innovative Areas “Chem-
ical Biology of Natural Products”. We also thank Dr. Juergen
Langewald and Felix Schneider, BASF SE, Limburgerhof, for car-
rying out the insecticidal activity assay.
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Keywords: insecticidal activity · meroterpenoids · natural
products · radical reactions · titanium
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Received: February 18, 2015
Published online on May 26, 2015
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www.chemeurj.org
9460
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim