Asymmetric Synthesis of Rupestonic Acid and Pechueloic Acid

Article abstract of DOI:10.1021/acs.orglett.7b03459

In this report, the originally proposed rupestonic acid (5) and pechueloic acid (3) were efficiently synthesized. The chiral lactone 13, recycled from the degradation of saponin glycosides, was utilized to prepare the key chiral fragment 11. During the exploration of this convergent assembly strategy, the ring-closing metathesis (RCM), SmI₂-prompted intermolecular addition, and [2,3]-Wittig rearrangement proved to be effective transformations for the synthesis of subunits.

Full text of DOI:10.1021/acs.orglett.7b03459

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of Rupestonic Acid and Pechueloic Acid
Pan Han,† Zhu Zhou,† Chang-Mei Si,*,† Xian-Yi Sha,† Zheng-Yi Gu,*,‡ Bang-Guo Wei,*,†
and Guo-Qiang Lin†
†Institutes of Biomedical Sciences and School of Pharmacy, Fudan University, 220 Handan Road, Shanghai 200433, China
‡Xinjiang Institute of Materia Medica, Lane 140, South Xinhua Road, Urumqi, Xinjiang 830004, China
S
* Supporting Information
ABSTRACT: In this report, the originally proposed rupes-
tonic acid (5) and pechueloic acid (3) were efficiently
synthesized. The chiral lactone 13, recycled from the
degradation of saponin glycosides, was utilized to prepare
the key chiral fragment 11. During the exploration of this
convergent assembly strategy, the ring-closing metathesis
(RCM), SmI2-prompted intermolecular addition, and [2,3]-Wittig rearrangement proved to be effective transformations for
the synthesis of subunits.
atural sesquiterpenes are a promising class of compounds
for drug discovery due to their interesting biological
method to these important chemical series is still challenging
(Figure 1).
N
activities.1 Guaianes and guaianolides in this family have attracted
Structurally, the absolute configuration of rupestonic acid (5)
was first proposed as (5S,8S,8aS) form4 and was later revised to
(5S,8R,8aR).7 Surprisingly, the originally proposed structure
(5S,8S,8aS)-5 is still being used in scientific publications without
any explanation.8,9 Due to its remarkable bioactivities, especially
against influenza viruses, rupestonic acid (5) and the scarce
pechueloic acid (3) attracted considerable attention in structural
modifications and activity evaluations.8,9 A few groups reported
their total syntheses; for example, optically pure pechueloic acid
(3) was first synthesized from (+)-dihydrocarvone by Pedro,10
significant attention in recent years. As shown in Figure 1,
and the racemate was prepared by Depres
́
in 2009.8e
(+)-Achalensolide (4) was asymmetrically synthesized by
Mukai and co-workers using a Rh(I)-catalyzed Pauson−
Khand-type reaction as the key step to construct the
bicyclo[5.3.0]decane skeleton.11 The above synthetic routes
applied excellent chemical transformations except imperfect
Figure 1. Several structures of guaianes and guaianolides.
stereochemistry control for some chiral centers. In 2009, Depres
́
and co-workers reported a synthetic method to ( )-rupestonic
acid (5).8e However, the 1H and 13C NMR spectroscopic data of
synthetic rac-5 were not identical to those reported in the original
literature for the rupestonic acid (5) isolation4 or to the later
revised (5S,8R,8aR) form. As a continuation of our interest in
developing divergent syntheses of natural products,12 we decided
to confirm the absolute structure of natural rupestonic acid (5)
through an asymmetric method. We herein present an
asymmetric approach to synthesizing the original rupestonic
acid (5) and pechueloic acid (3) using the recovered material 13
from industrial waste.13
xerantholide2a (1) was first isolated in 1977 from Pechuel-
Loeschea leibnitziane, and the absolute configuration was
confirmed in 1982.2b From the same plant, another natural
product (+)-methyl pechueloate2c (2) was subsequently isolated
in 1982. Later, pechueloic acid (3) and its methyl ester (2), as
well as achalensolide (4), were isolated in 1987 from Decachaeta
scabrella.2c,3 In 1988, rupestonic acid (5), as the main active
ingredient, was isolated from Artemisia rupestris L,4 a well-known
traditional Chinese medicinal plant (Yizhihao in Chinese) in
Xinjiang. Rupestonic acid demonstrated potential use in
detoxification, antihypersusceptibility, antibacterial, antitumor,
antivirus as well as liver protection.5 In addition, rupestonic acid
is chosen as the “marker compound” for the chemical evaluation
or standardization of A. rupestris L. Although many interesting
approaches to such [5,7]-skeletons have been reported in recent
years,6 it is difficult to apply them in asymmetric synthesis of
these natural products. Therefore, an efficient asymmetric
Our retrosynthetic analysis of the originally proposed
rupestonic acid (5) is outlined in Figure 2, with high
stereocontrol of each chiral center as our focus in constructing
Received: November 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03459
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
give a mixture of two inseparable alcohols 17 in 64% combined
yield. Notably, this new chiral center from Grignard addition
would be eliminated at a later stage, therefore the diastereomeric
mixture was used in the following steps. Protection (TBSCl) and
debenzylation (Pd/C, H2) gave the primary alcohol, which could
be oxidized to the corresponding aldehyde 11 in 77% overall
yield.
As shown in Scheme 2, chiral iodide 10 was conveniently
prepared through a key [2,3]-Wittig rearrangement.17 The
Scheme 2. Preparation of Chiral Iodide 10
Figure 2. Our strategy to access rupestonic acid (5).
this target molecule. The key intermediate 6 could be obtained
through intramolecular aldol condensation.14 As for the
formation of the seven-membered ring 7, we proposed to use a
ring-closing metathesis (RCM)15 reaction from compound 8.
One terminal olefin was formed through Peterson olefination,16
and the other key chiral center was generated using [2,3]-Wittig
rearrangement.17 The key intermediate 9 could be obtained
through SmI2-promoted coupling of iodide 10 and aldehyde
11.18 Moreover, the concept of “from nature to nature” was
applied in our asymmetric synthesis of chiral fragment 11,
specifically that the intermediate 11 could be prepared from
industrial waste 13.13
The chiral lactone 13, recycled from the degradation of
saponin glycosides,13 was easily converted to the key chiral acid
14 in 41% overall yield12e,f (Scheme 1). After the introduction of
chiral auxililary oxazolidinone,19 the subsequent allylation gave
15 in 63% yield with high diastereoselectivity (dr > 98:2).
Reduction (NaBH4) of 15 and the following protection
produced ether 16 in 61% yield. Dihydroxylation (K2OsO4,
NMO)20 of 16 and subsequent cleavage (NaIO4) gave crude
aldehyde, which was treated with ethylmagnesium bromide to
conversion of chiral aldehyde 19 to the desired chiral iodide 10
was achieved according to the following synthetic sequence:
Wittig reaction gave olefin 20 with 88:12 selectivity (Z/E), and
the pure Z isomer was obtained in 62% yield. Reduction
(DIBAL-H) and subsequent etherification (BrCH2COOMe)
gave ether 21 in 90% overall yield. The following key step, [2,3]-
Wittig rearrangement of 21, was accomplished by treatment with
lithium bis(trimethylsilyl)amide (LiHMDS), smoothly produc-
ing the desired chiral product 12 with high diastereoselectivity
(dr > 99:1) in 67% yield. Reduction (LiAlH4) of 12 and
subsequent cleavage (NaIO4) gave crude aldehyde, which was
directly reduced with sodium borohydride (NaBH4) to give
alcohol 22 in 81% overall yield. Finally, iodination (Ph3P/I2,
imidazole) of 22 resulted in the desired chiral iodide 10 in 78%
yield.
Next, we turned our attention to the preparation of diene 8
(Scheme 3). Different conditions were surveyed for the coupling
of iodide 10 and aldehyde 11 (see Supporting Information).
When the reaction was conducted using SmI217 in the presence
of hexamethylphosphoric triamide (HMPA) at −50 °C to room
temperature overnight, the desired adduct (3R)-9 was obtained
in 52% yield. Again, this new chiral center from SmI2-promoted
Scheme 1. Preparation of Aldehyde 11
Scheme 3. Preparation of Terminal Olefin (5R)-8
B
DOI: 10.1021/acs.orglett.7b03459
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
addition would be eliminated at a later stage, therefore the
diastereomeric mixture was used in the following steps. After the
protection (TBSOTf) of alcohol (3R)-9, selective release of the
primary hydroxyl group was achieved with HF/Pyridine to give
(6R)-23 in 55% yield. Oxidation of alcohol (6R)-23 with
tetrapropylammonium perruthenate (TPAP) in the presence of
NMO gave an aldehyde, which underwent Peterson olefination
to afford the desired diene (5R)-8 in 75% yield.
With the diene (5R)-8 in hand, the initial attempt of ring-
closing metathesis (RCM)15 reaction failed when Grubbs
second-generation catalyst was used, most likely due to the
steric hindrance. Thus, deprotection (TBAF) of (5R)-8 and
subsequent oxidation (TPAP) were conducted to give diketone
(8R)-24 in 71% overall yield (Scheme 4). Fortunately, the
Moreover, in analytical reversed-phase HPLC (see the SI),
synthetic (5S,8S,8aS)-5 showed a different retention time from
the isolated natural product. By comparison of the respective
NMR data of synthetic (5S,8S,8aS)-5 with the natural product,
the perceptible differences in the signals of the C-5 position
suggested that the stereochemistry assigned to C-5 position
might be incorrect.
To confirm our hypothesis, we synthesized a diastereomeric
compound, pechueloic acid (3) (Scheme 5). The (S,S)-10 was
Scheme 5. Preparation of Pechueloic Acid 3
Scheme 4. Preparation of Proposed Rupestonic Acid 5
prepared from the (R)-2,2-dimethyl-1,3-dioxolane-4-carbalde-
hyde. Following the similar synthetic sequence described above,
pechueloic acid (3) was obtained and the stereochemistry was
confirmed by X-ray crystallography (see the SI).
To our delight, the optical rotations [[α]D24 = +115.0 (c 0.814,
EtOH)] and the NMR data of synthetic pechueloic acid (3) (see
SI) were in excellent agreement with those reported for isolated
33c and the originally proposed natural rupestonic acid 5.4 As
mentioned previously, the synthetic rupestonic acid (5) showed
a different retention time compared to authentic rupestonic acid
in analytical reversed phase HPLC (see the SI). However,
synthetic pechueloic acid (3) and the authentic rupestonic acid
displayed an identical retention time, and coeluted under two
different HPLC conditions. Therefore, we conclude that the
absolute structure of natural rupestonic acid isolated from the
traditional Chinese medicinal plant (Yizhihao in Chinese) in
Xinjiang in 19884 is the same as the pechueloic acid (3) isolated
from Decachaeta scabrella in 1987.3c
In summary, the first asymmetric approach to rupestonic acid
(5) and pechueloic acid (3) has been accomplished using our
previously proposed “from nature to nature” strategy. It is worth
mentioning that this convergent assembly process provided an
efficient approach to synthesize both (5R,8S,8aS)-5 and
pechueloic acid (3). Peterson olefination, SmI2 prompted
intermolecular addition and [2,3]-Wittig rearrangement offered
an effective method for the synthesis of subunits to rupestonic
acid. Moreover, the absolute stereochemistry of natural
rupestonic acid (5) is the same as that of the pechueloic acid (3).
subsequent ring closure using Grubbs second-generation catalyst
successfully afforded the seven membered (2S,3S,6R)-7 in 99%
yield. Upon the reduction of carbon−carbon double bond in
(2S,3S,6R)-7 by hydrogenation (Pd/C, H2) in 73% yield, the
intramolecular aldol condensation of the resulting (2S,3S,6S)- 25
was achieved by treatment with t-BuOK to afford the desired
bicyclic skeleton (5S,8S,8aS)-6 in 77% yield.
Deprotection (80% AcOH) and subsequent selective
protection of the primary hydroxy group with TBSCl afforded
(5S,8S,8aS)-26 in 78% yield. Oxidation of (5S,8S,8aS)-26 with
TPAP afforded ketone (5S,8S,8aS)-27 in 79% yield, which was
converted to the olefin product using standard Wittig condition
(NaHMDS, Ph3PCH3Br) in 73% yield. Upon cleavage of O-TBS
protection group, the resulting alcohol was subjected to
sequential Jones oxidation, Pinnic oxidation, affording proposed
rupestonic acid [(5S,8S,8aS)-5][[α]D23 = +49.6 (c 0.357, EtOH),
lit.4 [α]D26 = +150 (c 0.176, EtOH)] in 47% isolated yield. The
stereochemistry of synthetic (5S,8S,8aS)-5 was confirmed by X-
ray crystallography (see the SI).
To our surprise, the analytical data of optical rotation and
NMR spectra generated from synthetic (5S,8S,8aS)-5 were
substantially different from those reported for rupestonic acid.4
C
DOI: 10.1021/acs.orglett.7b03459
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Haire, L. F.; Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.;
Hay, A. J.; Gamblin, S. J.; Skehel, J. J. Nature 2006, 443, 45.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03459.
■
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graphic data for this paper. These data can be obtained free of
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data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sicm@fudan.edu.cn.
*E-mail: zhengyi087@126.com.
*E-mail: bgwei1974@fudan.edu.cn.
ORCID
Bang-Guo Wei: 0000-0003-3470-6741
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21772027, 21472022 to B.-G.W., 21702032 to C.-M.S.) for
financial support. We thank the National Natural Science
Foundation of China and Xinjiang Joint Foundation
(U1303224 to Z.-Y.G.) for financial support. We thank Prof.
Wei-Sheng Tian (SIOC) for providing the lactone 13. We thank
Dr. Han-Qing Dong (Arvinas, Inc.) for helpful suggestions. We
also thank Prof. Haji Akber Aisa (XTIPC.CAS) for providing
isolated rupestonic acid.
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