Removal of the E-Olefin Barrier of Humulene Leading to Unnatural Terpenoid-like Skeletons

Article abstract of DOI:10.1021/acs.orglett.8b03259

An unnatural terpenoid scaffold containing a bicyclo[5.4.0]undecane moiety, as well as a salvialane skeleton based on an intramolecular C-C bond formation strategy were synthesized. Such a strategy was made possible by the removal of strained E-olefin conformations of the humulene skeleton. Some compounds were identified to show PPARα antagonist activity.

Full text of DOI:10.1021/acs.orglett.8b03259

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Removal of the E‑Olefin Barrier of Humulene Leading to Unnatural
Terpenoid-like Skeletons
Takehiro Nishimura,† Junya Kawai,‡ Yoshiteru Oshima,† and Haruhisa Kikuchi*,†
†Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
‡Mushroom Research Laboratory, Hokuto Corporation, Nagano, 381-0008, Japan
S
* Supporting Information
ABSTRACT: An unnatural terpenoid scaffold containing a
bicyclo[5.4.0]undecane moiety, as well as a salvialane skeleton
based on an intramolecular C−C bond formation strategy were
synthesized. Such a strategy was made possible by the removal
of strained E-olefin conformations of the humulene skeleton.
Some compounds were identified to show PPARα antagonist
activity.
he diversity and high three-dimensionality of natural
products have made these products useful in developing
intramolecular C−C bond formation based on the humulene
skeleton would also be a useful strategy for fabricating of
diverse natural product-like compounds.13−15 However, the
treatment of tetracyanoethylene with humulene epoxide II
affords only bicyclo[8.1.0]undecane (1) and tricyclo-
[7.2.0.02.4]undecane (2) moieties because of the highly
strained structure provided by three E-olefins, which limits
the possible reactions that may occur under nonenzymatic
conditions (Figure 1A).14 Recently, Appendino et al. have
constructed isoprenoid compounds based on zerumbone
under conditions permitting Nazarov’s reaction. In this case,
reactions began from the C6−C10 bond formation of
zerumbone because the carbonyl group at the C8 position
acted as a trigger of transannular cyclization, permitting the
breach of the E-olefin barrier (Figure 1B).16 Thus, we
attempted to overcome this barrier using a different strategy,
in which we removed the strained E-olefin conformation to
construct new ring systems. In this letter, we used humulene
epoxide II as a starting point and constructed rare and non-
natural terpenoid scaffolds by intramolecular electrophilic C−
C bond formation.
The Lewis acid-mediated ring-opening reaction of epoxides
and electrophilic olefin cyclization is a useful strategy for the
construction of terpenoid scaffolds from well-designed
precursors.17,18 Because the humulene skeleton contains
three olefins, it can be converted into various other skeletons
depending on the combination of electron-rich olefins and
nucleophilic epoxides that are used. For example, as shown in
Figure 1C, 6,7-epoxy-9,10-saturated humulene derivative 3 and
2,3-epoxy-6,7-saturated humulene derivative 5 would be
converted into unnatural terpenoid skeletons 4 and 6,
T
new drugs. However, because natural products have been
explored for a long time, it is becoming difficult to discover
structurally diverse compounds.1,2 Diversity-oriented synthesis
based on natural products is an effective strategy for
constructing chemical libraries bearing diverse structures.3−8
There have been some successful examples of the construction
of useful compound libraries based on natural products. The
“ring-distortion strategy,”5 proposed by Hergenrother et al.,
produced compounds that possess a higher molecular
complexity and diversity than those from standard screening
collections by systematically altering the core ring structures of
the natural products9,10 via chemoselective reactions that
distort the ring system. Terpenoids bearing a medium-sized
ring system are used in the biosynthesis of sesquiterpenoids.11
They are also useful precursors for constructing diverse ring
systems7,8 because these systems may be afforded by
controlling the cyclization reactions of this process. The
structural transformation of compounds containing medium-
sized rings is another effective strategy for the construction of
diverse and sp3-rich natural product-like chemical libraries that
are useful for drug discovery. Baran et al. used epoxy-
germacrenol as a core skeleton and constructed a variety of
sesquiterpenoid frameworks by acid-mediated transannular
cyclization reactions.7
Humulene is commonly found in nature in sources such as
hops, or Humulus lupulus, and contains an 11-membered ring
structure with three E-configured double bonds.12 In other
words, humulene is a suitable starting point for the
construction of a chemical library based on natural products.
We have previously constructed a humulene-derived terpenoid
alkaloid-like compound library containing diverse structures
that is useful for drug discovery via Lewis acid catalyzed
intramolecular C−O bond formation followed by a ring-
rearrangement metathesis reaction.4 On the other hand,
Received: October 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03259
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Letter
Figure 2. (A) Synthesis of unnatural terpenoid-like compounds 9−
12. (B) Predicted reaction mechanism of 9−12.
Figure 1. (A,B) Transannulation reactions based on a humulene
skeleton. (C) Our strategy for production unreported terpenoid-like
structures.
be a precursor for the unnatural terpenoid moiety 6. The
aziridination of humulene epoxide II with a rhodium catalyst
and O-(2,4-dinitrophenyl)hydroxylamine predominantly af-
forded compound 13, which was obtained with diastereomers
of 2,3- or 9,10-aziridinated products.23 Treatment with CSA in
MeOH afforded an epoxide ring-opened product without
aziridine cleavage. This was followed by the N-protection of
aziridine with a nosyl group to provide compound 14 for the
activation of the aziridine. Treatment of 14 with lanthanum-
(III) triflate afforded cyclized compounds 15−17 bearing a
bicyclo[5.3.0]decane ring system, denoted as a salvialane
skeleton,24 which was not expected from bicyclo[5.4.0]-
undecane ring system. The treatment of compounds 15 and
16 with thiophenol and potassium carbonate afforded
denosylated products 18 and 19, respectively (Figure 3A). A
possible reaction mechanism is shown in Figure 3B. At first, as
was expected and as shown in Figure 1C, a bicyclo[5.4.0]-
undecane system was constructed by the formation of a C3−
C9 bond via the similar mechanism that permitted the
formation of compounds 9−12. Wagner−Meerwein rearrange-
ment then afforded a salvialane skeleton, generating a more
stable carbocation by 1,2-alkyl shift not methyl group
migration. This rearrangement was also proposed in
Vietmeyer’s and Ohe and Uemura’s reports.13,25 To our best
knowledge, the salvialane moiety has only been reported for 15
natural products26−35 and has only been constructed in six
synthetic reports.6,13,24,36−38 Because the salvialane skeleton is
relevant in biosynthesis and is synthetically derived from a
germacrene-type precursor by a ring expansion reaction, our
approach provides a new efficient method for the selective
construction of a salvialane moiety.
respectively, which are not biosynthetically constructed in
nature.
To remove a strained E-double bond of humulene epoxide
II, hydroxyamination with the nitrogen source chloramine T
was chosen.19 The introduction of a nitrogen atom, which acts
as a hydrogen bonding donor or acceptor, is of value when
synthesizing compounds useful for drug discovery.20,21 The
hydroxyamination of humulene epoxide II afforded 6,7-epoxy-
9,10-saturated humulene derivatives 7 and 8 by the site-
selective and facial selective reaction of the C9−C10 double
bond; osmium(VIII) oxide could not approach the sterically
hindered C2−C3 olefin and C9−C10 double bond from the
opposite face of epoxide because of the strained humulene
skeleton. By the treatment of a mixture of compounds 7 and 8
with lanthanum(III) triflate, compounds 9−12 were obtained
(Figure 2A). Using Lewis acid activation, we used the
remaining olefin in the electrophilic C−C bond formation
between C2 and C7 because of the stability of the carbocation
at C3 and the fact that C7 is more electrophilic than is C6
under Lewis acidic conditions, which produced the
bicyclo[5.4.0]undecane moiety (Figure 2B). This terpenoid-
like structure is not found in nature and has not yet been
synthetically derived. These terpenoid-like compounds are
expected to show unique bioactivities. Here, we used
chloramine T as a nitrogen sourse. The tert-butyl carbamate-
or benzyl carbamate-based hydroxyamination would afford N-
Boc or N-Cbz products, which can be used as interemediates
for further deritives.22
On the other hand, aziridination has a great advantage in
terms of the introduction of nitrogen; like epoxide, this
functional group is expected to act as a nucleophile in
electrophilic cyclization. We expected that the aziridination of
the C2−C3 double bond and ring-opening of C6−C7 epoxide
would afford a 2,3-imino-6,7-saturated scaffold, which would
We synthesized unnatural terpenoid-like (9−12) and
salvialane-type compounds (15−19). To determine whether
these compounds are useful for drug discovery, we screened
the synthesized terpenoid-like compounds for peroxisome
proliferator-activated receptor α (PPARα) activity (Figure 4).
Because humulene derived compound which we previously
B
DOI: 10.1021/acs.orglett.8b03259
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Letter
associated with sustained PPARα gene expression, which
increases intracellular H2O2 and causes DNA damage and thus
leads to liver cancer.43 Therefore, a PPARα antagonist could
be used for novel cancer therapy.44 However, a limited number
of PPARα antagonists have been disclosed, such as GW647145
and MK886.46 For these reasons, compound 11 would be a
seed compound for downregulating PPARα in patients with
hepatitis and may have application in cancer therapy.
In summary, we synthesized unreported bicyclo[5.4.0]-
undecane terpenoid-like (9−12) and salvialane-type com-
pounds (15−19) by the removal of a E-configured double
bond of humulene epoxide II, allowing us to overcome the E-
barrier of the humulene skeleton. The former compound type
has never been found in nature or fabricated in previous
humulene transannulation studies. The construction of the
latter type provided a basis for the efficient formation of a
salvialane moiety. Biological screening illustrated that
bicyclo[5.4.0]undecane-containing compounds 9−12 and 16
inhibited PPARα activity, demonstrating that the most potent
compound 11 would be a seed compound in prevention of
liver cancer for the patients with hepatitis. In our previous
work, diverse ring structures were constructed by new C−O
bond formation, in contrast to the C−C bond formation
strategy explored in this study. These results support the
usefulness of a medium-sized ring containing natural products
for constructing diverse ring systems. We will expand upon our
strategy to the use of other medium sized-ring containing
natural products, such as germacrene and some macrolides, as
well as screen for various bioactivities in future studies.
Figure 3. (A) Synthesis of salvialane-type compounds 15−17. (B)
Predicted reaction mechanism for 15−17.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03259.
General experimental procedures, detailed experimental
procedures, and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hal@mail.pharm.tohoku.ac.jp
ORCID
Figure 4. Effects on PPARα activity as determined by luciferase
reporter assay using the Gal4/PPAR chimera system.47 A pGL4.35 luc
vector and pBIND-hPPARα were transfected into HepG2 cells. At 24
h after transfection, the cells were treated with each compound for 5
h. Control cells (Cont.) received the vehicle (DMSO) at a final
concentration of 0.3% in the media. Bezafibrate (Beza) was used as a
positive control. Data are expressed relative to the mean value of the
control cells. Bars indicate the standard error of three independent
experiments. The statistical significance of the differences was
determined by Dunnett’s test. *p < 0.05**p < 0.01, ***p < 0.001
vs Cont.
Haruhisa Kikuchi: 0000-0001-6938-0185
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by the Grants-in-Aid for
Scientific Research (no. 16H03279) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan; the Platform Project for Supporting in Drug Discovery
and Life Science Research (Basis for Supporting Innovative
Drug Discovery and Life Science Research (BINDS)), and
Practical Research for Innovative Cancer Control from AMED
under grant nos. JP18am0101095 and JP18am0101100, the
Shorai Foundation for Science and Technology, Kobayashi
International Scholarship Foundation, the Takeda Science
Foundation, Suzuken Memorial Foundation, and the Uehara
Memorial Foundation.
synthesized enhanced PPARα gene expression,4 we expected
compounds constructed in this work to show similar activities.
As a result, the bicyclo[5.4.0]undecane series (9−12) and 16
were found to inhibit PPARα activity. In particular, compound
11 inhibited 45% of this activity compared with a control at 30
μM. PPARα plays an important role in controlling the gene
expression of lipid metabolism.39−42 In the liver, PPARα acts
as a mediator that maintains the rates of β-oxidation and
ketogenesis during a state of fasting. On the other hand, it is
suggested that chronic hepatitis C virus infections are
C
DOI: 10.1021/acs.orglett.8b03259
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(35) He, J.-B.; Lu, Q.; Cheng, Y.-X. Helv. Chim. Acta 2015, 98,
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