Total syntheses of bupleurynol and its analog

Article abstract of DOI:10.1016/j.cclet.2016.11.032

An efficient route to the natural products bupleurynol and its analog (RB-2), isolated from Bupleuri Radix, was established based on versatile intermediate (15). In this synthetic route, Sonogashira and Cadiot–Chodkiewicz coupling as well as Julia–Kociens

Full text of DOI:10.1016/j.cclet.2016.11.032

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Chinese Chemical Letters xxx (2016) xxx–xxx
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Chinese Chemical Letters
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Original article
Total syntheses of bupleurynol and its analog
Kai-Qing Maa, , Yan-Hong Miaoa,d, Xiao-Xia Gaoa, Jian-Bin Chaoc, Xiang Zhangb,
Q1
*
Xue-Mei Qina
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a
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China
Department of Chemistry, University of Louisville, Louisville, KY 40208, USA
Scientific Instrument Center, Shanxi University, Taiyuan 030006, China
College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China
b
c
d
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient route to the natural products bupleurynol and its analog (RB-2), isolated from Bupleuri Radix,
was established based on versatile intermediate (15). In this synthetic route, Sonogashira and Cadiot–
Chodkiewicz coupling as well as Julia–Kocienski olefination are utilized as key steps. The highly efficient
synthetic route provides opportunities to explore the biological behavior of bupleurynol and RB-2.
© 2016 Kai-Qing Ma. Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of
Medical Sciences. Published by Elsevier B.V. All rights reserved.
Received 13 September 2016
Received in revised form 7 November 2016
Accepted 16 November 2016
Available online xxx
Keywords:
Polyacetylenes
Natural product
Bupleurynol
Total synthesis
Julia–Kocienski olefination
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1. Introduction
and lack of versatility for synthesizing other polyacetylene natural
products. Hence, it remains as a challenge to develop a versatile
and efficient strategy for the total syntheses of bupleurynol and its
analogs. Herein, we reported a highly versatile route for the total
syntheses of bupleurynol and RB-2 from a common intermediate.
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Polyacetylenes are a family of structurally diverse natural
products [1], which show interesting biological activity, such as
antitumor [2], antibacterial [3], anti-obesity [4], antidiabetic effect
[5], cytoprotection [6], immunosuppressive activity [7,8] and anti-
inflammatory effects [9]. Recently, 1,3-diyne-type polyacetylenes
have attracted broad attention from both chemists and biologists
[10,11]. Bupleurynol (1) and its analog (RB-2) (2) are natural
products that were first isolated from the Bupleurum longiradiatum
in 1987 [12] and 1999 [13], respectively (Fig. 1). We also isolated
bupleurynol (1), RB-2 (2) and their isomers from Bupleuri Radix
(Chaihu in Chinese) [14]. Our study further demonstrated that
these natural products could increase the level of monoamines
such as 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in
mice. Due to their low abundance in nature and exploring the
relationship between the structural motifs and the interesting
biological activities of bupleurynol (1) and RB-2 (2), a versatile and
efficient route to synthesize them is required.
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2. Results and discussion
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Our retrosynthetic analysis for RB-2 is depicted in Scheme 1.
According to the previously reported method, RB-2 could be
prepared from the terminal alkyne 3 and the enyne fragment 4
through the Cadiot–Chodkiewicz reaction [17]. The terminal
alkyne 3 might be derived from the conjugated aldehyde 5
through a Corey–Fuchs reaction, while the enyne fragment 4 could
be prepared from the methyl propionate 6 by a Sonogashira cross-
coupling and bromination.
Our synthesis began with the preparation of the cis alkenyl
iodide 7, which was obtained in 89% yield by heating methyl
propiolate 6 and lithium iodide in acetic acid [18] (Scheme 2). The
alkenyl iodide 7 was treated with ethynyltrimethylsilane in a
Sonogashira cross-coupling reaction to give the enyne product 8 in
96% yield without isomerization. Compound 8 was converted to
allyl alcohol 9 using diisobutylaluminum hydride at ꢀ78 ꢁC in 92%
yield [19].
The first synthesis of bupleurynol was completed by the Organ
and Antunes [15]. Ghasemi et al. further developed a single
operation to synthesize bupleurynol using queued cross-coupling
reactions [16]. However, these strategies suffered from low yields
Initially, the trimethyl chlorosilane (TMS) protecting group was
removed using potassium carbonate to make the terminal alkyne,
which included the free alcohol group. However, the allyl alcohol is
* Corresponding author.
E-mail address: makaiqing@sxu.edu.cn (K.-Q. Ma).
http://dx.doi.org/10.1016/j.cclet.2016.11.032
1001-8417/© 2016 Kai-Qing Ma. Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights
reserved.
Please cite this article in press as: K.-Q. Ma, et al., Total syntheses of bupleurynol and its analog, Chin. Chem. Lett. (2016), http://dx.doi.org/
10.1016/j.cclet.2016.11.032

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K.-Q. Ma et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Table 1
Conversion of aldehyde 5 to the terminal alkyne 3.
Fig. 1. The structures of bupleuryol and RB-2.
Entry
Conditions
Yield
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3
CBr4, PPh3, DCM, then n-BuLi, THF, ꢀ78 ꢁ
C
Decomposition
Bromoalkene formed
C Decomposition
BrCH2PPh3Br, t-BuOK,
Ohira–Bestmann reagent, NaOMe, MeOH, 0 ꢁ
Scheme 1. Retrosynthetic analysis of RB-2 (2).
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extremely volatile and unstable. Therefore, it was protected with
tert-butyl(chloro)diphenylsilane (TBDPS) group, which was fol-
lowed by the removal of TMS to give the compound 11 [20]. The
bromoacetylene 12 was eventually obtained by the treatment of 11
with N-bromosuccinimide (NBS) in the presence of a catalytic
amount of AgNO3 [21] and the absence of light.
With the requisite protection version of right fragment in hand,
we developed a concise route to synthesize the (3E, 5E)-deca-3,5-
dien-1-yne 3 fragment from the commercially available aldehyde
5. However, the expected homologation product turned out to be
more difficult to prepare. As summarized in Table 1, treatment of
compound 5 via the Corey–Fuchs reaction gave only a trace
amount of desired product [22]. Treatment of the aldehyde 5 with
(bromomethyl)triphenylphosphonium bromide in the presence of
potassium tert-butoxide afforded the bromo alkene compound
[23]. The alkyne 3 was also detected based on the NMR of the crude
product using the dimethyl-(1-diazo-2-oxopropyl) phosphonate
(the Bestmann–Ohira reagent) [24], but the further purification of
the alkyne turned out to be impractical due to the instability of
compound 3.
Scheme 3. The synthesis of the olefination reaction precursor 15 and the Wittig
reaction.
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Compound 13 is commercial available. Using copper iodide as the
catalyst [25], coupling compound 12 with 13 under Cadiot–
Chodkiewicz conditions provided the diyne intermediate 14 with
67% yield (Scheme 3). The free alcohol 14 was easily transformed
into the key intermediate 15 in the presence of the Dess–Martin
reagent which paved the way for the chain elongation through
olefination [26]. With the main intermediate 15 in hand, we next
focused on the olefination reaction to assemble the trans double
bond. We first examined the feasibility of constructing the trans
double bond under Wittig reaction conditions using commercially
available pentyltriphenylphosphonium bromide [27]. Unfortu-
nately, we obtained only the cis double bond rather than the trans
double bond.
In our previous study [28], the one-pot Julia–Kocienski (J–K)
olefination with a proper substrate pair proved be a powerful tool
to prepare the trans conjugated double bond. Thus, the sulfide 18
was obtained in good yield upon the treatment of the primary
alcohol 17 through a Mitsunobu thioetherification. The sulfide 18
underwent a molybdenum-catalyzed oxidation and smoothly
afforded the sulfone 19 that could be the substrate for the J–K
In view of these results, a new approach was developed to
synthesize the natural product, by coupling (E)-pent-2-en-4-yn-
1-ol 13 and fragment 12 to form the C10–C11 double bond.
Scheme 2. The synthesis of intermediate 12.
Please cite this article in press as: K.-Q. Ma, et al., Total syntheses of bupleurynol and its analog, Chin. Chem. Lett. (2016), http://dx.doi.org/
10.1016/j.cclet.2016.11.032

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Scheme 4. Total synthesis of RB-2 (2) and bupleurynol (1).
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olefination (Scheme 4). Delightfully, the coupling of 15 and 19
through one-pot J–K olefination furnished the desired (E/E/Z)-
triene substrate 21 in a good yield with excellent E/Z-selectivity
(10:1) using the Barbier-type J–K protocol. Remarkably, the
diyne and the cis double bond were stable even under strongly
basic conditions. Finally, the removal of the TBDPS group with
triethylamine trihydrofluoride successfully yielded the natural
product RB-2 (2) in 92% yield. The general applicability of
this strategy was further demonstrated in the synthesis of
bupleurynol 1.
research project supported by Shanxi Scholarship Council of China
(No. 2015-020) and science and technology innovation project of
Shanxi Province (2016115).
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2016.11.032.
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References
Spectroscopic characterization (1H NMR, 13C NMR and high-
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natural products [12,13]. The spectral data of RB-2 and bupleurynol
1 are presented in the Supporting information. Consistent with the
report for the natural isolate, a slow isomerization to the (Z/E/Z)
isomer in neat form was observed in bupleurynol.
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