Collective Synthesis of Schilancidilactones A, B and Schilancitrilactones A, B, C, 20-epi-Schilancitrilactone A

Article abstract of DOI:10.1002/cjoc.201800557

Schisandraceae triterpenoids are novel natural products that contain highly fused ring systems bearing multiple chiral centers surrounding. Some of them exhibit promising bioactivities, such as antitumor, anti-HIV, etc. In this article, we describe our ef

Full text of DOI:10.1002/cjoc.201800557

Accepted Article
Title: Collective Synthesis of Schilancidilactones A, B and Schilancitrilactones A, B, C,
20-epi-Schilancitrilactone A
Authors: Hengtao Wang, Liang Wang, Yihang Li , Xiunan Zhang and Pingping Tang*
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Collective Synthesis of Schilancidilactones A, B and Schilancitrilactones A,
B, C, 20-epi-Schilancitrilactone A
a
a
a
a
,a,b
Hengtao Wang, Liang Wang, Yihang Li , Xiunan Zhang and Pingping Tang*
ABSTRACT Schisandraceae triterpenoids are novel natural products that contain highly fused ring systems bearing multiple chiral centers surrounding.
Some of them exhibit promising bioactivities, such as antitumor, anti-HIV etc. In this article, we describe our efforts to the collective total synthesis of
schilancidilactones A, B, schilancitrilactones A, B, C, and 20-epi-schilancitrilactone A from common precursors. An intramolecular radical cyclization,
late-stage halogenation and AIBN-mediated or Ni-catalyzed intermolecular radical cross coupling reaction was employed as the key steps.
KEYWORDS total synthesis, radical cyclization, nickel-catalyzed cross coupling, late-stage halogenation, triterpenoids
[
4a]
Introduction
in 2011
(Figure 1). From then on, reports about the total
synthesis of molecules in this family blossomed over the last 8
years. In 2014, Li
rubriflordilactone A, in which 6π-electrocyclization/aromatization
was adopted as the key transformation to constructed the
challenging pentasubstituted arene. Anderson
accomplished the rubriflordilactone
Co-catalyzed cyclization to form the CDE rings in one step in 2015.
In the follow years, the total synthesis of propindilactone G,
Schisandraceae, containing genera Schisandra and Kadsura,
was widely distributed in Southeast Asia and North America. 29
species of this family spread over southwest part in China, and
the most famous is Schisandra chinensis, called wuweizi in
Chinese, which has been used as traditional Chinese medicine for
[4e]
group disclosed the synthesis of
[4f]
group also
featured a Pd- or
A
[1]
the treatment of asthenia and insomnia for thousands of years.
With the enormous medical value, this family of plants has
attracted many chemists’ attention. Over the last forty years,
many chemists devoted their efforts to the extraction of valuable
bioactive molecules from schisandraceae. So far, more than 200
schisandraceae nortriterpenoids were isolated, many of which
possessed fascinating bioactivities, such as antitumor,
[4h]
[4l]
[4m]
rubriflordilactone B,
lancifodilactone G
successively completed. In 2015 and 2017, we briefly reported the
19-dehydroxyl arisandilactone
acetate and schiglautone A
A
[4n,4q]
[4p]
were
[2]
[4o]
total synthesis of schilancidilactones A,
B
and
schilancitrilactones A, B, C, 20-epi-schilancitrilactone A (Figure
). In this article, we will represent a more detailed discussion.
[4g]
[
2]
antihepatitis, anti-HIV-1. Besides fascinating bioactivities, most
schisandraceae nortriterpenoids shared novel skeletons with
2
highly fused2,3,4]ring system bearing multiple vicinal
[
stereocenters.
Therefore, many research groups have made
considerable efforts towards the synthesis of schinortriterpenoids
[3,4]
during the last two decades.
.
Figure 2 Schilancidilactones A, B and schilancitrilactones A, B, C,
0-epi-schilancitrilactone A.
2
Results and Discussion
From the structural point of view, compounds 1-5 (Figure 2) all
[5,6]
share highly fused ring systems and highly oxidative state.
There are lots of chiral centers in these molecules, many of which
are adjacent to other. Thus, to complete the total synthesis of
compounds 1-5 is a challenging work. From another point of view,
these five compounds are of great similarity to each other. All
these molecules share the same 7/5/5/5-fused CDEF ring systems
and the same side lactone. The main difference of the five
compounds lies in the left part, of which schilancidilactones A, B
are open-ring system, schilancitrilactone A is 5/5-fused ring
system, schilancitrilactones B, C are 5-member ring system. Herein,
we tend to apply the same synthetic strategy to achieve these five
Figure 1 Schindilactone A, rubriflordilactone A and B, propindilactone G,
arisandilactone A, lancifodilactone G.
The breakthrough of the synthesis of schinortriterpenoids was
the complete synthesis of schindilactone A by Yang and coworkers
a
b
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin
Chemistry, Nankai University, Tianjin 300071, China
300071, China
E-mail: ptang@nankai.edu.cn
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may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800557
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molecules. We pursued to take part of these molecules into three
components, namely left fragments 6 and 7, middle fragment 8
and right fragment 9 as shown in Scheme 1. On the whole, the left
fragment 6 or 7 was sequentially connected to the middle
fragment 8 and right fragment 9, and then underwent later-stage
transformation to achieve molecules 1-5.
The alkyl bromide 10 was expected to be installed by late-stage C
3 [8]
(sp )-H bromination at the C20 (-position of the ketal) from the
lactone 12. Stannane 9 was intended to be synthesized from the
[
9]
citraconic anhydride 11 according to Benneche’s work. The
lactone 12 was expected to be synthesized from left fragment 6
and right fragment 8 by intermolecular 1, 4-addition of
[
10,11]
[12]
organozincs
or ogranolithiums
derived from 6 to form
C7-C8 bond, and the given enolate anions was going to be trapped
[
13]
by TMSCl followed by Rubottom
oxidation to install the
hydroxyl group at C9. The resulting formyl lactone underwent
intramolecular aldol reaction to obtain lactone 12. Fragments 6
and 8 could be synthesized from 1, 3-cyclohexadiene (14) and
[
9b]
(-)-carvone (13), respectively.
Scheme 3 Synthesis of left fragment 6.
The total synthesis of schilancitrilactones A and B was
commenced with the synthesis of alkyl iodide 6 (Scheme 3) from
the commercially avaliable (-)-carvone (13). Following Fukuyama’s
Scheme 1 Retrosynthetic analysis of compounds 1-5.
Total synthesis of schilancitrilactones B, C
[
14]
work,
four steps in overall 51% yield. Aldehyde 15 was reduced with
NaBH followed by deiodination with AIBN and Bu SnH to give
compound 16. Alcohol 16 was then reacted with I , Ph P and
(-)-carvone (13) was converted to the aldehyde 15 over
4
3
2
3
[
15]
imidazole to afford the left fragment 6 in 84% yield.
Scheme 2 Retrosynthetic analysis of schilancitrilactones B and C.
Based on our retrosynthetic analysis, we initially decided to
choose schilancitrilactones A and B (4, 5, Scheme 2) as first goal.
Both molecules possessed
a
challenging backbones with
stereocenters. We
5/7/5/5/5-fused ring system and
9
hypothesized that branched domain G of molecules 4 and 5 could
Scheme 4 Synthesis of middle fragment 8.
be raised by AIBN-induced radical addition-elimination reaction of
[7]
alkyl bromide 10 and right fragment 9 as shown in Scheme 2.
The total synthesis of aldehyde 8 was shown in Scheme
4.
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[
12e,f]
Starting from 1, 3-cyclehexadiene (14), we sequentially applied
the O -participated Diels-Alder reaction, thiourea-participated
25
was observed implying a new strategy to connect left
2
fragment 6 and middle fragment 8.
reduction to give the diol, which was then protected by benzoyl
chloride to afford the compound 17 in overall 79% yield. Using
asymmetric palladium catalyzed allylic alkylation developed by
Scheme 5 depicted our new strategy to schilancitrilactones B
and C based on the aldol product 25. Iodide 6 was subjected to
LDA to give the lithium enolate which reacted with aldehyde 8 to
achieve compound 25 (d.r. =17:1 at C19). Alcohol 25 underwent
[
16]
Trost and co-workers,
the compound 17 was converted to
[
21]
lactone 19 in 70% yield. Lactone 19 was treated with NaH
followed by methyl iodide to give a methylated product, which
underwent decarboxylation by treated with NaBr to afford the
lactone 20 in overall 79% yield (d.r.= 1:1 at C13). Alkylation of
lactone 20 was achieved by sequentially adding LDA and t-butyl
bromoacetate to produce a single diastereomer 21. The latter
underwent deprotection with trifluoroacetic acid and addition of
ethyl magnesium bromide followed by acidic workup to afford
tricycle 22 in 74% yield, in which an ethyl group was installed
Dess-Martin oxidation to obtain ketone 26, which in turn was
[22]
subjected to AIBN-induced radical cyclization
to give
cycloketone 27. The structure of the ketone 27 was
unambiguously confirmed by X-ray crystallographic analysis.
Disappointedly, the absolute configurations at C8, C9 and C10
were not coincident with schilancitrilactones B and C. The
unwelcomed -face selectivity of the intramolecular conjugated
addition might be affected by the (S)-configuration at C10. Thus,
we intended to convert the (S)-configuration to the corresponding
[
17]
[23]
stereoselectively into the tricyclic framework.
The absolute
(R)-configurations. However, intramolecular cyclization
of 26
configuration of tricycle 22 was determined by X-ray
crystallographic analysis. After oxidative cleaved of double bond
by ozonolysis in compound 22, the resulting dialdehyde was
directly subjected to intramolecular aldol condensation to afford
ring-closed unsaturated aldehyde 8 in overall 80% yield for two
occurred to give 2-dihydropyran 28 under basic condition as
shown in Scheme 5.
[
18]
steps.
Table 1 Conditions for assemble blocks 6 and 8
a
Entry
Conditions
Li, naphthalene, CuCN, TMSCl
Zn, CuCN, TMSCl
Yield (%)
23,0
1
2
3
4
5
23,0
Et
PdCl
Ni(acac)
2
Zn, CuI or CuCN, TMSCl
(dppf), Et Zn, CuCN, TMSCl
, Et Zn, CuCN, TMSCl
23,0
Scheme 5 Synthetic route to the compound 27.
2
2
23,0
Herein, we intended to introduce the double bond at C10 and
C19 in order to set the iodine atom above the plane. After
2
2
23,0
fac-Ir(ppy)
3
, Hantzsch ester, Bu
visible light
3
N, MeCN,
optimization, we treated alcohol 25 with CuCl
2
and EDC in toluene
6
24,0
[24] 1
under 80 °C (Scheme 6) to give the dienes 29 in 83% yield.
H
NMR analysis showed that the 1, 3-dienes 29 were a mixture of
two inseparable isomers. Fortunately, the structure of 29-b was
confirmed by X-ray crystallographic analysis. From the X-ray
structure of 29-b, the alkyl iodide chain of B ring was above to the
face of C10-C19-C9-C8 of 1, 3-diene, which might give the right
chirality at C8 during the subsequently cyclization reaction.
7
8
Zn, CuI in EtOH and water
24,48%
23,0
t-BuLi, CuCN, TMSCl
a
Yields refer to isolated product.
We then moved to assemble left fragment 6 and middle
fragment 8 (Table 1). Firstly, we intended to prepared organozincs
or organolithiums from iodide 6 in situ,
[
11a, b]
which reacted with
fragment 8 through Michael addition in the presence of copper
salt, followed by addition of TMSCl to give the silyl enol ether 23.
However, no desired product was observed (entry 1 and 2). We
[11e]
also investigated to generate organozincs with diethylzinc,
but
only ethyl-Michael additional product was observed (entry 3 to 5).
In addition, photo-redox catalyst was used, such as Ir-induced
[
19]
radical Michael reaction, and no desired product was obtained
[
20]
(
entry 6). Under Luche’s conditions [Zn, CuI, Pyridine, H
were pleased to observe two inseparable conjugated products 24
entry 7). The absolute configuration at C8 and C9 on compound
2
O], we
(
Scheme 6 Synthetic route to the compound 29.
2
4 could not be confirmed. However, the following hydroxylation
[13a]
at C9 on compound 24 was not achieved under Rubottom,
Davis,
conditions . Under condition listed in entry 8, an aldol product
[
13b]
[11d,e]
[13g]
Herein, we started to investigate the intramolecular
cyclization reaction to form the seven-membered ring. Firstly, we
MoOPH
, Blackmond’s oxidation , and Armando’s
[
13h]
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[
22]
[29, 30]
subject 1, 3-dienes 29 with AIBN, n-Bu
Scheme 7) and trace amounts of desired cylization product was
observed. Interestingly, the unexpected dimer 30 was isolated in
0% yield. The structure of dimer 30 was exactly confirmed by
3
SnH in toluene at 80 °C
reduction
to give the alcohol 12 in 73% yield.
(
4
X-ray crystallographic analysis. This reaction brought us great
confidence because the chirality at C8 was identical to natural
products. We envisioned that the dimerization could be prevented
when a mild condition was used. To our delight, cyclization
products of two isomers 31 and 31’ were obtained under the
[
25]
Luche’s
conditions in 59% total yield (d.r.=14:1 at C10). The
choice of pyridine and water as solvents was crucial to this
transformation, while no desired product was detected without
water. When ethanol or tetrahydrofuran was used instead of
pyridine, large amounts of starting material remained unreactive.
The structure of 31’ was confirmed by X-ray crystallographic
analysis and the chirality at C8 was in line with expectation.
Scheme 9 Synthetic route to the compound 12.
We decided to introduce model reactions to test the final
coupling reaction. Bromide 37 and iodide 38 were chosen as
model substrates which could be easy achieved through two
successive steps from lactone 22 as shown in Scheme 10. Lactone
2
2 underwent Pd/C-catalyzed hydrogenation to give the
[8]
compound 36 in 97% yield. Under Scholz’s condition, the
bromine atom could be successfully introduced at -position of
ketal in 82% yield (d.r.=2:1 at C20) and the mechanism of this
conversion was considered as an acid-promoted ring opening
process as shown below. Lactone 36 underwent ring opening
process to give the intermediate 36b, which undertook
isomerization to give the carboxylic acid 36c. The latter was
trapped by bromine to achieve intermediate 36d, which
subsequently underwent cyclization to obtain the final product 37.
Iodoketal 38 was also obtained in 84% yield (d.r.=2:1 at C20) when
ICl was used as an electrophile.
Scheme 7 Synthetic route to the compounds 31 and 31’.
We next moved to the installation of the hydroxyl group at C9
Scheme 8). Interestingly, the isomers 31 easily transformed to the
(
peroxide 32 just by standing the solution in CDCl under air for a
3
couple of days. However, the auto-oxidation underwent in low
yield when the reaction was carried out in large scale. Under the
[
26]
2 2 3 2
method [Pd(OAc) , t-BuOOH, K CO , O ] discovered by Corey,
peroxide 32 was gained in 70% yield. The latter was then
[
27]
subjected to NaBH
4
to achieve the reductive product 33, the
structure of which was confirmed by X-ray crystallographic
analysis. Unfortunately, the chirality at C9 was opposite to
schilancitrilactones B (4) and C (5). The -face selectivity might
resulted from the less steric hindrance of the -face. Thus, we had
to pursue other method to overcome the problem.
Scheme 10 Synthetic route to the model substrates 37 and 38.
The right fragment 9 was synthesized in 5 steps from
commercial available compound citraconic anhydride (11) as
shown in Scheme 11. Citraconic anhydride (11) underwent a
[
9]
reported four-step process to give the bromide 39 in overall 41%
yield coupled with its E-isomer 5% yield. The latter was then
subjected to [Pd(allyl)Cl] and (Bu Sn) to afford vinyl stannane 9
2 3 2
[31]
in 49% yield and no isomer was observed. It is noteworthy that
vinyl stannane 9 is not stable during the purification and low
isolated yield was observed.
Scheme 8 Synthetic route to the compound 33.
After careful investigation, we established a roundabout
approach to install the hydroxyl group at C9 as shown in Scheme 9. Scheme 11 Synthetic route to the right frament 9.
[
28]
Lactone 31 was treated with m-CPBA to give the epoxide 34 in
1% yield coupled with its isomer 34’ in 40% yield, and the former
was then underwent NaOMe-induced rearrangement to give an
ally alcohol 35, which then underwent NiCl -NaBH mediated
With model substrates 37, 38 and right fragment 9, 39 in hand,
we then moved to the model reaction. Optimized conditions were
shown in Table 2. We first tested Zn-mediated reductive coupling
5
2
4
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[
30c-i]
reactions
of bromides 37 and 39 (entry 1-5). Under Lipshutz’s
condition (entry 1), no reaction occurred. Bromide 39 was then
subjected to activate Zn firstly, followed by addition of compound
3
3
7, but only debromination of 39 occurred (entry 2-3). Bromide
7 also underwent debromination when first subjected to activate
Zn (entry 4). Under Luche’s condition, no ideal product was gained
(
entry 5 and 11). When traditional radical conditions were applied,
[7a]
no assembled products 40/40’ were detected (entry 6 and 7)
and the bromide 37 underwent debromination to give lactone 36.
Considering that toluene might be source of the proton, we then
tested different solvents without activated proton, such as
benzotrifluoride, benzene (entry 8 and 9). Disappointedly, no
desired product was detected. When Et
3
B/O
2
was applied to
[
25,30]
initiated the reaction (entry 10),
no coupling product was
Having established the suitable conditions for the late-stage
halogenation and intermolecular radical addition reaction, we
then attempted to complete the total synthesis of the natural
products as shown in Scheme 12. Alcohol 12 was subjected to ICl
to give the iodides 42 in 63% yield as a mixture of diastereomers
gained. Excitedly, when iodide 38 was used instead of bromide 37,
the coupling products 40/40’ were observed in trace yield (entry
1
2). By addition of n-Bu
and 14), the yield could be finally increased to 75% in total. We
considered the mechanism of this transformation as a •SnBu
mediated addition-elimination process as shown in table 2. The •
SnBu was generated in situ, which further reacted with iodide 37
3
SnH and 4 Å molecular sieves (entry 13
3
(
d.r.=1.5:1 at C20), and the resulted iodides 42 was then treated
with AIBN, n-Bu SnH in toluene to finish the total synthesis of
3
3
schilancitrilactones B (4) and C (5) in overall 45% yield. The
characterization data of synthetic schilancitrilactones B and C
were in accord with the natural products.
to give the intermediate 37a. Subsequently intermediate 37a
underwent 1, 6-addition with stannane 9 to afford 37b. The
following elimination occurred to achieve the product 40 and 40’
3
and regenerated •SnBu .
Table 2 Conditions for model reactions
a
Entry
1
Conditions
7, 39, Zn, TMEDA, PdCl
PTS/H
9, Zn, LiCl, TMSCl, THF; 37, TMSCH
FeCl , TMEDA
9, Zn, LiCl, TMSCl, 1, 2-dibromoethane,
THF; 37, Ni(cod) , PyBox, TMEDA
37, Zn, THF; 39, Pd(dba) , dtbpf
37, 39, CuI, Zn, i-PrOH, H
37, AIBN, Toluene, 80°C
37, AIBN, n-Bu SnH, Toluene, 80°C
37, AIBN, n-Bu SnH, Benzotrifluoride, 80°C
37, AIBN, n-Bu SnH, Benzene, 80°C
37, Et B, O , Et
37, Zn, CuI, Bu NI, i-PrOH-H
38, AIBN, Toluene, 86°C
Yield/%(40/40’)
3
2
(Amphos), 2%
0
Scheme 12 Synthetic route to schilancitrilactones B and C.
Total synthesis of schilancidilactones A, B
With the accomplishment of schilancitrilactones B and C, we
next turned our attention to the synthesis of schilancidilactones A
and B. Based on our former retrosynthetic analysis, we decided to
applied latter-stage modification to transfer key intermediate
above to achieve schilancidilactones A and B as shown in Scheme
2
O
3
2
MgCl,
2
3
0
0
3
3
2
4
5
6
7
8
9
2
0
2
O
0
1
3. These two target molecules were expected to be assembled
0
from the iodides 42 and right fragment 9 through radical-induced
coupling reaction. The iodides 42 in turn would be raised from the
acetyl lactone 43 by late-stage iodination which was going to be
synthesized from lactone 12 through methylation at C1 followed
by oxidative cleavage at C1-C10 bond of triol 44.
3
0
0
3
3
0
10
11
12
13
14
3
2
2
O
0
4
2
O, ultrasound
0
trace
38/28
41/34
38, AIBN, n-Bu
3
SnH, Toluene, 80°C
38, AIBN, n-Bu
3
SnH, 4 Å M.S., Toluene, 80°C
1
a
Yields were determined by H NMR spectroscopy with benzyl chloride as
the internal standard.
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Scheme 15 Attemption to synthesize compounds 43 and 51.
Scheme 13 Retrosynthetic analysis of schilancidilactones A and B.
Upon former investigation, we intended to introduce the
epoxy group in the early stage as shown in Scheme 16. Alcohol 47
Beyond our expectation, the installation of hydroxyl group at
C10 was not smoothly (Scheme 14). When we subjected alcohol
[33]
underwent epoxidation
2
with the VO(acac) and TBHP to give
[
32]
the epoxide 52 in 97% yield, of which the structure was
unambiguously confirmed by X-ray crystallographic analysis. The
epoxide 52 was then treated with MeMgBr followed by oxidative
cleavage with PDC to give the ketone 51. To our delight, epoxide
1
2 to KHMDS, P(OMe)
3
, O
2
,
no reaction occurred with the
recovery of starting material. Different bases (LDA, NaOMe) under
different temperature (-78 °C, 0 °C, 25 °C) were also tested, no
desired product 45 was obtained. Epoxide 34 was then converted
to intermediate 46 by rearrangement with NaOMe followed by
5
1 could be easily transformed to alcohol 43 by reductive ring
[38]
[
33]
2
opening with SmI in 60% yield. However, the desired iodide 42
epoxidation with VO(acac)
2
,
TBHP.
Disappointedly, the
was not achieved when ICl was applied as electrophilic reagent.
reduction of epoxide 46 was not achieved under many
[
34]
Careful investigation showed that the iodide 42 might formed
conditions
DIBAL-H; H
(NiCl
2
•6H
2
O, NaBH
4
; Red-Al; H
2
, Pd/C; LiAlH
4
;
1
under low temperature (-20 °C) as being monitored by H NMR
2
, PtO ). We thought the major problem was the steric
2
but being destroyed upon quenching. The more stable bromides
hindrance caused by C6 and C7.
53 could be achieved in 81% yield when alcohol 42 was treated
with PyHBr . When we applied the bromides 53 to the radical
3
coupling reaction with vinyl stannane 9, no desired products was
gained.
Scheme 14 Attemption to synthesize compound 45.
Thus, an alternative method was raised to install the hydroxyl
group at early stage as shown in Scheme 15. Lactone 31/31’ could
be easily converted to the corresponding alcohol 47 under LDA,
[
32]
P(OMe)
3
, O
2
in 77% yield with a diastereoselectivity 5.3:1. The
favorable -face selectivity might be resulted from the less steric
hindrance of -face. Alcohol 47 underwent selective methylation
[
35]
at C1 followed by PDC-mediated oxidative cleavage at C1-C10
bond to give ketene 49 in 31% yield for two steps. However, the
introduction of oxygen atom at C9 position again encountered
[
36]
problems. We attempted to apply direct hydration to install the
hydroxyl ketone 43. However, no reaction occurred when Ag O,
2
Scheme 16 Attemption to synthesize schilancidilactones A and B.
HFIP or AcOH was used as the reagents. While TfOH or TsOH was
applied, intramolecular cyclization occurred to give the ketone 50,
which might arise from acid catalyzed deprotection of acyl group
[
37]
followed by intramolecular 1, 4-addition. Epoxidation of ketene
49 was also investigated and no desired product 51 was detected.
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Table 3 Investigation of conditions for the cross coupling
a
Entry
Conditions
Yield/%(40/40’)
1
2
3
4
5
NiCl
Ni(cod)
Ni(cod)
Ni(cod)
Ni(cod)
2
, 2,2-bipyine,KOt-Bu, t-BuOH/i-BuOH
0
0
2
(10 mol%), 2,2-bipyridine, dioxane
2
(10 mol%), dppm, dioxane
(10 mol%), dppp, dioxane
28/28
0
2
2
(40 mol%), dppm, dioxane
1
40/40
a
Yields were determined by H NMR spectroscopy with benzyl chloride as
the internal standard.
Herein, a new method to connect bromides 53 and right
fragment 9 was required. As having been discussed in detail in the
Scheme 18 Retrosynthetic analysis of schilancitrilactone A.
[
4o]
previous report,
here was only a concise introduction. Inspired
Scheme 19 illustrated the construction of key intermediate 58.
Started with alcohol 57, we applied three steps procedure to the
[
39]
by Fu’s reports on the nickel catalyzed cross coupling of alkyl
halides with stannane for the formation of C-C bond, we insisted
that this strategy could be applied in our final coupling reaction.
We then systematically evaluated different solvents, ligands,
catalyst’s loadings, and temperature (see ESI of the previous
left fragment 7. Iodonation of the hydroxyl group in 57 with PPh
and I to give the iodide 58 in 62% yields, which was sequentially
3
2
[40]
treated with MeONa and HCl to give the iodoalcohol 60. The
free alcohol was then protected by TBSCl to achieve the left
fragment 7 in overall 70% yield. Upon being treated with LDA,
iodide 7 and aldehyde 8 was connected to give the alcohol 61 in
[
4o]
report for details). As being listed in Table 3, no product was
gained under Fu’s standard conditions. After careful screening
different catalysts and ligands, Ni(cod)
give the desired product in 56% total yield (entry 3). When 2,
-bipyridine or dppp was used instead of dppm, no desired
products were observed. When the catalyst’s loading increased to
0% mol, the yield could be up to 80% in total. Gratifyingly, when
2
and dppm were found to
8
8% yield (d.r.=9:1 at C19), which underwent elimination by
treating with CuCl and EDC to afford the dienes 62 in 93% yields.
2
2
Under Luche’s condition, we successfully closed the seven
member ring of the dienes 62 to give the lactone 63 in 56% yield
4
(
d.r.=7:1 at C10). Finally, hydroxyl group at C10 was then
introduced by treating with LDA , P(OMe) under oxygen
atmosphere to give the alcohol 56 in 64% yield (d.r.=2.7:1 at C10,
4% yield for 56).
bromides 53 and vinyl stannane 9 were involved, this Ni-catalyzed
reaction proceeded smoothly to give the schilancidilactones A (1)
and B (2) in 43% total yield (Scheme 17). The characterization data
of synthetic 1 and 2 were identical with those reported data of the
natural products.
3
6
Scheme 17 Synthetic route to schilancidilactones A and B.
Total synthesis of schilancitrilactone A
Having
successfully
completed
the
synthesis
of
schilancidilactones A and B, schilancitrilactones B and C, we then
turned our attention to schilancitrilactone A. The retrosynthetic
analysis was shown in Scheme 18. Schilancitrilactone A (3) was
intended to be assmbled from bromides 54 and stannane 9
through Ni-catalyzed cross coupling reaction. Bromides 54 was
expected to be synthesized by late-stage C-H bromination from
lactone 55, which in turn was going to be raised from lactone 56
through a intramolecular Dieckmann condensation. The OTBS
group on lactone 56 was going to be introduced in the stage when
we constructed the left fragment 7. The iodide 7 was going to be
connected with middle fragment 8 to form the C10-C19 bond
through the intermolecular aldol reaction followed by CuI-Zn
induced radical cyclization to give the intermediate 56, both of
which were the same to former reaction applied in the synthesis
of schilancidilactones A and B, schilancitrilactones B and C. The
Scheme 19 Synthetic route to alcohol 56.
We then shifted our attention to synthesize intermediate 55
as illustrated in Scheme 20. The alcohol 56 was sequentially
2 2
treated with VO(acac) , TBHP and Ac O to afford the acetate 65 in
[
4g]
left fragment 7 was going to be synthesized from compound 57.
7
9% yield for two steps. And the acetate was then underwent
This article is protected by copyright. All rights reserved.

intramolecular Dieckmann-type condensation and Martin’s
20-epi-schilancitrilactone A has been accomplished from a
common precursor (8). The key steps included intermolecular
radical cyclization, late-stage halogenation (Br or I), AIBN,
[
41]
elimination
to afford compound 67 in overall 39% yield.
However, our attempt to convert the lactone 67 to hydroxide 55
by reducing the C=C double bond and ring-opening of epoxide
through Pd-catalyzed hydrogenation in one pot was unachieved, nickel-catalyzed intermolecular cross coupling of alkyl halide with
n-Bu
3
SnH-induced
intermolecular
cross
coupling
or
[
42]
only double bond being reduced to give the epoxide 68. Many
conditions were tested to open the epoxide, but failed.
vinyl stannane in the late stage. In this way, the right hand
moieties present in this family of natural products were prepared
in the final step of each total synthesis. This strategy shows
promise for entry into other derivatives and analogues by way of a
common intermediate, which may facilitate the biological studies
on schisandraceae triterpenoids.
Experimental
Total synthesis of schilancitrilactone A
All reactions were carried out under an argon atmosphere
with dry solvents under anhydrous conditions, unless otherwise
noted. Tetrahydrofuran (THF), toluene and 1, 4-dioxane were
distilled immediately before use from sodium-benzophenone
2 2 3
ketyl. Methylene chloride (CH Cl ), triethylamine (Et N), N, N–
dimethylformide (DMF) were distilled from calcium hydride and
stored under an argon atmosphere. Methanol (MeOH) was
distilled from magnesium and stored under an argon atmosphere.
Reagents were purchased at the highest commercial quality and
used without further purification, unless otherwise stated.
Solvents for chromatography were used as supplied by Tianjin
Reagents chemical. Reactions were monitored by thin layer
chromatography (TLC) carried out on silica gel Huanghai HSGF254
plates using UV light as visualizing agent and aqueous
phosphomolybdic acid or basic aqueous potassium permanganate
as developing agent. 200-300 mesh silica gel purchased from
Qingdao Haiyang Chemical Co., China was used for flash column
chromatography. Semipreparative HPLC was performed on an
UltiMate 3000 liquid chromatography with a Thermo HG-C18,
21.2 mm × 15 cm column. NMR spectra were recorded on Bruker
AVANCE AV 400 (400 MHz, 101 MHz and 376 MHz) instrument
and calibrated by using residual undeuterated chloroform
(δ =7.26 ppm) and CDCl (δ =77.16 ppm) as internal references.
The following abbreviations are used to designate multiplicities:
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,
quint=quintet, br=broad. IR spectra were recorded on a Bruker
Tensor 27 instrument. High-resolution mass spectra (HRMS) were
obtained on Varian 7.0T FTMS. Circular dichroism spectra (CD)
were obtained from JASCO J-715 Spectropolarmeter. Optical
rotations were measured with an Insmark IP 120 digital
polarimeter. X-ray diffraction was realized on a Rigaku 007 Saturn
Scheme 20 Attempt to synthesize compound 55.
Herein, we intended to directly introduce the hydroxyl group
at C9 from the C=C double bond through Mukaiyama hydration
as illustrated in Scheme 21. Alcohol 56 underwent acetylation and
intramolecular Dieckmann-type condensation to give the
compound 69 in 76% yield for two steps. The lactone 69 was then
[
43]
[
41]
sequentially subjected to Martin’s sulfurane and L-selectride to
[
43]
generate the lactone 70. Under Mukaiyama hydration
condition[Co(acac) , PhSiH , O ], the tertiary hydroxyl group at
C9 was successfully installed to give alcohol 55 in 45% yield
d.r.=1.3:1 at C9, 45% yield for 55). Finally, we completed the
2
3
2
(
synthesis of schilancitrilatone A (3) and its C20-epimer (3’) by
late-stage C(sp )-H bromination and nickel-catalyzed cross
3
H
3
C
coupling reaction. The spectra and physical properties of the
schilancitrilacetone A (3) are identical with those reported of the
natural product.
7
0 instrument.
Synthesis of aldehydes 24. To a 5 mL schlenk tube was
sequentially added compound 6 (155.3 mg, 0.579 mmol, 3.00
equiv), compound 8 (45.6, 0.193 mmol, 1.00 equiv), Zn (75.8 mg,
1
.160 mmol, 6.00 equiv), CuI (73.6 mg, 0.193 mmol, 2.00 equiv),
EtOH (592 μL) and H O (319 μL). The mixture was degassed with
for 3 times and stirred for another 10 hours before filtered
2
N
2
through celite pad. The extract was evaporated and purified by
silica gel column chromatography (EA/PE = 1/4 to 1/2) to give
aldehydes 24 (35.0 mg, 0.0925 mmol, 48%) as a yellow oil.
2
5
24-major: Rf = 0.3 (silica, EA/PE = 1/2); *α+
D
= - 35.6 (c = 0.15 in
CHCl
3
); IR (film): νmax = 3501, 2960, 2926, 2870, 2855, 1769, 1462,
1
377, 1261, 1214, 1098, 1028, 937, 912, 874, 799, 756, 705, 666
−1 1
cm ; H NMR (400 MHz, CDCl
3
): δ 9.63 (d, J = 2.0 Hz, 1H), 4.29 (dd,
Scheme 21 Synthetic route to Schilancitrilactone
0-epi-Schilancitrilactone A.
A
and
J = 5.8, 2.3 Hz, 1H), 2.74 (d, J = 18.5 Hz, 1H), 2.67 – 2.46 (m, 4H),
2
2
.42 – 2.17 (m, 3H), 2.02 – 1.87 (m, 2H), 1.81 – 1.71 (m, 2H), 1.55
1.50 (m, 1H), 1.45 (s, 3H), 1.40 (t, J = 9.2 Hz, 3H), 1.27 (s, 3H),
–
1
3
Conclusions
1.26 (s, 3H), 1.07 (t, J = 7.3 Hz, 3H); C NMR (101 MHz, CDCl
3
): δ
2
4
+
01.4, 175.3, 173.9, 120.9, 87.4, 86.7, 58.6, 55.2, 49.7, 45.9, 45.7,
In
summary, the
collective
and schilancitrilactones A, B, C,
total synthesis of
5.7, 35.0, 31.6, 28.5, 28.0, 27.6, 22.1, 19.8, 7.7. HRMS (m/z): [M
schilancidilactones A,
B
+
+
H] calcd for C21
H
30
O
6
H 379.2115, found 379.2116.
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2
5
Synthesis of ketone 26. To a stirred solution of compound 25
Rf = 0.60 (silica, EA/PE = 7:3); *α+
D
3
= + 8.6 (c = 0.37 in CHCl ); IR
(
282 mg, 0.560 mmol, 1.00 equiv) in DCM (30 mL) in THF was
(film): νmax = 2971, 2927, 1768, 1669, 1458, 1375, 1237, 1164,
1118, 906, 877, 730 cm ; H NMR (400 MHz, CDCl ): δ 6.66 (d, J =
3
−
1 1
added DMP (474 mg, 1.120 mmol, 2.00 equiv) under N
2
at room
temperature. 5 hours later, TLC showed the disappearance of
starting material. The mixture was filtered through a celite pad,
evaporated, and purified by flash silica gel column
2.3 Hz, 2H), 4.56 (dd, J = 7.2, 5.4 Hz, 2H), 2.83 – 2.51 (m, 6H), 2.45
(dt, J = 18.2, 9.0 Hz, 2H), 2.36 (s, 2H), 2.26 (d, J = 14.3 Hz, 2H), 2.00
– 1.75 (m, 8H), 1.70 – 1.45 (m, 6H), 1.38 (s, 6H), 1.23 (s, 6H), 1.21
1
3
chromatography (EA/PE = 1/2 to 1/1) to give ketone 26 (197 mg， (s, 6H), 1.12 (t, J = 7.4 Hz, 6H); C NMR (101 MHz, CDCl
.392 mmol, 70%) as a white solid.; 26: m.p. unknown
3
): δ 173.2,
0
170.1, 144.4, 135.7, 121.4, 84.4, 83.9, 61.6, 50.9, 50.4, 49.5, 45.4,
2
5
+
(decomposed > 170 °C); Rf = 0.5 (silica, EA/PE = 7:3); []
D
= +
37.7, 28.2, 27.4, 27.1, 24.3, 22.3, 18.9, 7.6; HRMS (m/z): [M + Na]
+
1
1
CDCl
5.9 (c = 0.63 in CHCl
466, 1438, 1189, 1117, 912, 873, 733 cm ; H NMR (400 MHz,
): δ 6.78 (d, J = 1.5 Hz, 1H), 5.46 (d, J = 7.9 Hz, 1H), 4.04 (d, J
3
); IR (film): νmax = 2979, 1765, 1671, 1618,
calcd for C42
H
54
O10Na 741.3615, found 741.3612.
−
1 1
Synthesis of alcohol 33. To a roundbottom flask containing
compounds 31 and 31’ (38.6 mg, 0.107 mmol, 1.00 equiv) in DCM,
3
=
1
6
1
2
C
11.5 Hz, 1H), 3.08 – 2.85 (m, 4H), 2.80 – 2.42 (m, 4H), 2.09 (m,
Pd(OAc)
2
(1.2 mg, 0.005 mmol, 0.05 equiv) and K
2
CO
3
(43.0 mg,
2
at room
H), 1.93 (m, 1H), 1.71 (m, 2H), 1.53 (s, 3H), 1.31 (s, 3H), 1.09 (m,
0.120 mmol, 1.12 equiv) was added (5.00 mL) under O
1
3
H); C NMR (101 MHz, CDCl
3
): δ 189.8, 171.7, 168.8, 144.8,
temperature. 70% aqueous t-BuOOH (0.30 mL) was then added,
and stirring continued for 3 hours. The reaction mixture was
filtered and the organic solvents were removed under reduced
pressure. The crude product was purified by silica gel column
chromatography (EA/PE = 2/1 to 1/1) to give compound 32 (27.4
mg, 0.0749 mmol, 70%). To a solution of freshly prepared
compound 32 (27.4 mg, 0.0749 mmol, 1.00 equiv) in MeOH (3.00
mL) was slowly added NaBH
After 30 min later, the reaction mixture was quenched with
saturated aqueous NH Cl, and the resulted mixture was extracted
with EtOAc (3 × 15.0 mL). The combined organic extracts were
dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude product was purified by silica
gel column chromatography (EA/PE = 1/4 to 1/2) to give the
product 33 (25.5 mg, 0.0677 mmol, 90%) as a red solid. 33: m.p.
40.8, 119.9, 87.1, 83.9, 53.9, 49.5, 48.08, 46.9, 43.8, 33.0, 30.1,
+
6.3, 26.3, 21.8, 15.5, 6.2; HRMS (m/z): [M + Na] calcd for
+
21
H27IO
6
Na 525.0750, found 525.0748.
Synthesis of ketone 27. To a roundbottom flask containing
compound 26 (197 mg, 0.392 mmol, 1.00 equiv), AIBN (12.9 mg,
.0784 mmol, 0.20 equiv) was added toluene (10.0 mL) under N
n-Bu SnH (0.126 mL, 0.470 mmol, 1.20 equiv) was added, and the
0
2
.
3
4
(8.5 mg, 0.225 mmol, 3.00 equiv).
mixture was heated to reflux. After stirring for 5 hours at that
temperature, the solvent was removed under reduced pressure.
The resulted mixture was purified by silica gel column
chromatography (EA/PE = 1/5 to 1/2) to give the product 27 (103
4
mg, 0. 274mmol, 70%) as a white solid; 27: m.p. 116-117 °C; Rf =
1
0
5
1
2
–
2
4
.40 (silica, EA/PE = 7:3); H NMR (400 MHz, CDCl
3
): δ 4.64 (t, J =
.0 Hz, 1H), 3.70 (d, J = 13.4 Hz, 1H), 3.20 (dd, J = 17.3, 10.4 Hz,
H), 2.70 (dd, J = 58.4, 18.7 Hz, 4H), 2.39 (dd, J = 16.7, 5.9 Hz, 1H),
.30 – 1.94 (m, 3H), 1.90 – 1.70 (m, 4H), 1.55 – 1.40 (m, 4H), 1.40
2
5
79-80 °C; Rf = 0.25 (silica, EA/PE = 7:3); *α+
CHCl ); IR (film): νmax = 3442, 2934, 1752, 1676, 1465, 1375, 1264,
1178, 1132 910, 871, 730 cm ; H NMR (400 MHz, CDCl
(d, J = 3.3 Hz, 1H), 4.42 (dd, J = 7.2, 4.0 Hz, 1H), 2.87 (m, 2H), 2.64
D
= + 9.5 (c = 0.55 in
3
1
3
−1 1
(m, 7H), 1.10 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl
3
): δ
3
): δ 6.88
03.5, 174.2, 170.5, 119.6, 85.1, 83.8, 58.1, 57.8, 55.3, 53.5, 49.3,
5.2, 42.2, 29.3, 28.3, 26.8, 26.6, 25.9, 21.8, 19.6, 7.8; HRMS (m/z): (dd, J = 76.7, 18.0 Hz, 2H), 2.10 (m, 2H), 1.98 (m, 2H), 1.85 – 1.70
+
+
[
M + Na] calcd for C21
H
28
O
6
Na 399.1784, found 399.1782.
(m, 6H), 1.49 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H), 1.08 (t, J = 7.4 Hz,
13
Synthesis of dihydropyran 28. To a solution of lithium
3
3H); C NMR (101 MHz, CDCl ): δ 173.8, 170.3, 139.0, 136.7,
diisopropylamide (0.2 mL, c = 2.00 M in THF, 0.400 mmol, 2.00
equiv) in THF (11.5 mL) was slowly added a solution of compound
121.9, 89.2, 85.4, 81.3, 52.0, 51.1, 48.8, 48.6, 45.7, 41.5, 28.2,
+
27.0, 25.1, 24.6, 23.8, 19.1, 7.6; HRMS (m/z): [M + Na] calcd for
+
2
6 (101 mg, 0.200 mmol, 1.00 equiv) in tetrahydrofuran (15.0 mL)
at -78 °C. After stirring at that temperature for 1 h, the reaction
was quenched with saturated aqueous NH Cl. The resultant
C
21
H
28
O
6
Na 399.1784, found 399.1784.
Synthesis of iodides 38. To a stirred solution of compound 36
4
(150.0 mg, 3.65 mmol, 1.00 equiv) in THF (5.0 mL) was added ICl
(148 mg, 0.911 mmol, 1.35 equiv). Stirring continued for 20 min
before the organic solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography
mixture was extracted with EtOAc (3 × 20.0 mL) and the
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography
(silica, EA/PE/Et
3
N = 1/4/0.05) to give the diastereisomers of
(
EA/PE = 1/4 to 1/2) to give dihydropyran 28 (52.0 mg, 0.139
compounds 38 (198 mg, 0.565 mmol, 84%, 2:1) as a yellow oil.
2
5
mmol, 70%) as a colorless oil. 28: Rf = 0.47 (silica, EA/PE = 7:3);
38-Minor: Rf = 0.5 (silica, EA/PE = 1:4); *α+
D
= –8.5 (c = 0.20 in
2
5
*
α+D = + 4.0 (c = 0.60 in CHCl ); IR (film): ν = 3421, 2976, 2933,
CHCl ); IR (film): ν = 2930, 2857, 1770, 1733, 1645, 1455, 1418,
3
max
3
max
−1 1
1
768, 1629, 1466, 1270, 1249, 1140, 1104, 901, 867, 733 cm ; H
): δ 6.50 (s, 1H), 5.31 (d, J = 7.8 Hz, 1H), 4.44
dd, J = 11.2, 2.1 Hz, 1H), 4.01 – 3.82 (m, 1H), 3.11 (d, J = 17.7 Hz,
1378, 1362, 1319, 1294, 1260, 1229, 1189, 1160, 1089, 1059,
−1 1
NMR (400 MHz, CDCl
3
1019, 966, 953, 936, 864, 800, 760, 740, 700, 668, 653 cm ; H
NMR (400 MHz, CDCl ): δ 4.40 (q, J = 7.0 Hz, 1H), 4.21 (dd, J = 6.9,
(
3
H), 3.01 – 2.80 (m, 2H), 2.75 – 2.45 (m, 3H), 1.95 (dd, J = 13.0,
.8 Hz, 1H), 1.84 – 1.57 (m, 4H), 1.50 (s, 3H), 1.20 (s, 3H), 1.16 (s,
H), 1.08 (t, J = 7.3 Hz, 3H); C NMR (101 MHz, CDCl ): δ 173.5,
3
3.4 Hz, 1H), 2.82 (d, J = 19.0 Hz, 1H), 2.65 (d, J = 19.0 Hz, 1H),
2.18-2.10 (m, 1H), 2.07 (t, J = 7.0 Hz, 3H), 1.94 – 1.87 (m, 1H),
1.78-1.69 (m, 1H), 1.67-1.53 (m, 3H), 1.60 – 1.54 (m, 1H), 1.43 (s,
1
3
1
3
68.3, 156.4, 139.2, 134.2, 121.5, 103.3, 88.0, 83.2, 66.06, 50.8,
9.7, 45.5, 45.2, 33.1, 27.5, 27.1, 22.8, 21.4, 16.72, 7.4; HRMS
3
3H), 1.25-1.21 (m, 2H); C NMR (101 MHz, CDCl ): δ 173.5, 116.4,
74.6, 51.7, 50.3, 46.1, 27.4, 24.9, 24.6, 24.2, 24.1, 20.2, 19.6.
+
+
+
+
H
26
O
6
Na 397.1627, found 377.1625.
HRMS (m/z): [M + H] calcd for C13
H19IO
3
H
351.0452, found
Synthesis of dimer 30. To a roundbottom flask containing
compounds 29 (30.4 mg, 0.625 mmol, 70%) and AIBN (2.1 mg,
.0125 mmol, 0.20 equiv) was added toluene (2.0 mL), n-Bu SnH
20.1 μL, 0.075 mmol, 1.20 equiv). The mixture was heated to
0 °C and stirring continued for 5 hours at that temperature. The
solvent was evaporated. The remainder was resolved in MeCN
10.0 Ml) and washed with hexane (3 × 4 mL). MeCN was
removed under reduced pressure, the crude product was purified
by silica gel column chromatography (EA/PE = 1/2 to 1/1) to give
the product 30 (17.9 mg, 0.249 mmol, 40 %) as a colorless oil. 30:
351.0450.
Synthesis of epoxide 46. To a stirred solution of compound 34
(24.0 mg, 0.637 mmol, 1.00 equiv) in methanol (2.0 mL) was
added NaOMe (17.2 mg, 3.185 mmol, 5.00 equiv), stirring
0
(
8
3
2
continued for 0.5 h at room temperature. 2.0 mL H O was added,
and the resulted mixture was extracted with EtOAc (3 × 2.0 mL).
The combined extracts were evaporated to give the crude
product 35 (24.0 mg). The crude product 35 was used for the next
step without further purification. To a roundbottom flask
containing compound 35 (24.0 mg, 0.637 mmol, 1.00 equiv) and
(
This article is protected by copyright. All rights reserved.

+
+
VO(acac)
mL) under N
.00 equiv) was slowly added, and the mixture was stirring for 3
2
(1.7 mg, 0.0637 mmol, 0.10 equiv) was added DCM (2.0
20.0, 7.9. HRMS (m/z): [M + H] calcd for C22
found 349.2007.
H
28
O
5
H 349.2010,
2
at 0°C. TBHP (25% v/v in DCM, 735 L, 1.911 mmol,
3
Synthesis of epoxide 64. To a round–bottom flask covered
with tinfoil was added compound 56 (90.0 mg, 0.178 mmol, 1.00
equiv) and VO(acac) (13.7 mg, 0.0533 mmol, 0.30 equiv), DCM
2
(4.5 mL). A solution of TBHP (25% v/v in DCM, 0.8 mL, 2.131
mmol, 12.0 equiv) was slowly added to the reaction mixture.
hours. The solvent was evaporated and the crude product was
purified by silica gel column chromatography (EA/PE = 1/1 to 2/1)
to give the product 46 (15.0 mg, 0.382 mmol, 60% yield) as a
2
5
colorless oil. 46: Rf = 0.2 (silica, EA/PE = 1:1); *α+
D
= 41.6 (c =
0
1
6
1
1
–
.57 in CHCl
3
); IR (film): νmax = 3501, 2960, 2926, 2870, 2855, 1769, After stirring for 3.5 hours, TLC showed the disappearance of the
462, 1377, 1261, 1214, 1098, 1028, 937, 912, 874, 799, 756, 705,
starting material and the reaction mixture was evaporated under
reduced pressure. The crude product was purified by silica gel
column chromatography (EA/PE = 2/3 to 1/1) to give the product
64 (74.0 mg, 0.142 mmol, 88% yield) as a colorless oil; 64: Rf = 0.2
−
1 1
3
66 cm ; H NMR (400 MHz, CDCl ): δ 4.36 (dd, J = 6.7, 3.7 Hz,
H), 3.49 (s, 1H), 2.85 (s, 1H), 2.71 (d, J = 17.3 Hz, 1H), 2.63 (dd, J =
5.8, 8.1 Hz, 1H), 2.56 (d, J = 18.0 Hz, 1H), 2.52-2.42 (m, 1H), 2.25
2.20 (m, 1H), 2.11 (s, 1H), 2.09 (s, 1H), 1.87 – 1.67 (m, 4H), 1.52
2
5
(silica, EA/PE = 1/1); *α+
D
3
= 22.5 (c = 0.08 in CHCl ); IR (film): νmax
1
3
(
(
6
1
s, 3H), 1.42 (s, 3H), 1.26 (s, 3H), 1.08 (t, J = 7.3 Hz, 3H); C NMR
101 MHz, CDCl ): δ 173.4, 172.1, 121.4, 87.2, 86.1, 80.8, 64.0,
2.3, 52.5, 50.8, 50.5, 46.0, 45.6, 40.2, 29.2, 28.0, 25.1, 23.7, 22.4,
= 3467, 2960, 2926, 2854, 1771, 1463, 1412, 1377, 1260, 1096,
1020, 939, 800, 699 cm ; H NMR (400 MHz, CDCl ) δ 4.39 (d, J =
3
−
1 1
3
5.5 Hz, 1H), 3.62 (dd, J = 31.5, 10.6 Hz, 2H), 3.38 (s, 1H), 3.22 (s,
1H), 2.80 – 2.69 (m, 2H), 2.62 – 2.52 (m, 3H), 2.24 (dd, J = 16.0,
10.7 Hz, 1H), 1.96 – 1.80 (m, 3H), 1.76 (dd, J = 14.1, 7.2 Hz, 1H),
1.72 – 1.64 (m, 1H), 1.58 – 1.45 (m, 1H), 1.41 – 1.31 (m, 1H), 1.28
(s, 3H), 1.25 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H), 0.88 (s, 9H), 0.07 (s,
+
+
28 7
9.7, 7.6. HRMS (m/z): [M + H] calcd for C21H O H 393.1908,
found 393.1903.
Synthesis of ketene 49. To a stirred solution of compound 47
(
50.0 mg, 0.133 mmol, 1.00 equiv) in THF (2.2 mL) was slowly
1
3
added MeMgBr (3.0 M in THF, 0.1 mL, 0.300 mmol, 2.25 equiv) at
°C under the atmosphere of N . 3 hours later, the reaction
3
6H); C NMR (101 MHz, CDCl ) δ 176.3, 173.9, 120.6, 89.3, 85.5,
0
2
74.0, 68.9, 68.4, 56.9, 52.4, 50.89, 48.1, 45.7, 43.6, 33.4, 28.4,
25.9, 25.0, 22.9, 20.8, 19.6, 18.3, 7.7, -5.3, -5.4. HRMS (m/z): [M +
mixture was quenched with MeOH (1.0 mL). The resulting mixture
was carefully evaporated under reduced pressure. The remainder
was filtered with silica gel (EtOAc), and the solvent was
evaporated to give the crude products 48 (dr=1.5:1 at C1). The
crude products were purified by silica gel column
chromatography (EA/PE = 1/1) to give the products 48 (22.0 mg,
+
+
H] calcd for C27
H
42
O
8
SiH 523.2722, found 523.2723.
Synthesis of acetyl epoxide 65. To a stirred solution of
compound 64 (70.0 mg, 0.134 mmol, 1.00 equiv) in DCM (1.4 mL)
was sequentially added NEt
Ac O (75.5 μL, 0.804 mmol, 6.00 equiv) at room temperature.
After stirring for 3 hours, the reaction was quenched with
saturated aqueous NaHCO . The resulted mixture was extracted
3
(270 μL, 2.678 mmol, 20.0 equiv) and
2
0
.0561 mmol, dr=1.5:1 at C1, 42% yield). To a stirred solution of
compounds 48 (22.0 mg, 0.0561 mmol, 1.00 equiv) in DCM (4.0
mL) was slowly added PDC (63.3 mg, 0.168 mmol, 3.00 equiv).
After stirring for 3 hours, the reaction mixture was filtered
through silica gel and the residue was evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography (EA/PE = 1/4 to 2/5) to give the product 49 (16
mg, 0.425 mmol, 75% yield) as a colorless oil; 49: Rf = 0.3 (silica,
3
with DCM (3 × 3.0 mL) and the combined organic extracts were
dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude product was purified by silica
gel column chromatography (EA/PE = 1/3 to 1/2) to give the
product 65 (68.0 mg, 0.120 mmol, 90% yield) as a colorless oil; 65:
2
5
Rf = 0.3 (silica, EA/PE = 1/1); *α+
D
3
= 31.2 (c = 0.17 in CHCl ); IR
2
5
EA/PE = 1:2); *α+
2
1
D
= 2.7 (c = 0.23 in CHCl
3
); IR (film): νmax = 3397,
(film): νmax = 2958, 2927, 2855, 1777, 1746, 1463, 1376, 1260,
−
1 1
952, 2923, 2854, 1768, 1728, 1660, 1462, 1367, 1258, 1109,
1221, 1094, 1049, 1021, 935, 800, 702, 685, 663, 618 cm ; H
NMR (400 MHz, CDCl ) δ 4.39 (d, J = 5.2 Hz, 1H), 3.74 (s, 2H), 3.15
−
1 1
022, 938, 909, 800, 760, 721, 666, 611 cm ; H NMR (400 MHz,
) δ 5.96 (s, 1H), 4.40–4.34 (m, 1H), 3.74–3.66 (m, 1H), 3.13–
3
CDCl
3
(s, 1H), 2.79 – 2.67 (m, 3H), 2.64 – 2.53 (m, 2H), 2.24 (dd, J = 15.9,
10.7 Hz, 1H), 2.15 (s, 3H), 1.95 – 1.65 (m, 5H), 1.63 – 1.54 (m, 1H),
1.44 – 1.37 (m, 1H), 1.34 (s, 3H), 1.26 (s, 3H), 1.15 (t, J = 7.3 Hz,
3
2
2
1
.04 (m, 1H), 2.77 (d, J = 18.6 Hz, 1H), 2.72–2.54 (m, 3H), 2.53–
.44 (m, 1H), 2.22–2.11 (m, 1H), 2.06–1.94 (m, 4H), 1.87–1.73 (m,
H), 1.64 (s, 3H), 1.55-1.50 (m, 1H), 1.49 (s, 3H), 1.45 – 1.36 (m,
1
3
3H), 0.88 (s, 9H), 0.06 (d, J = 7.0 Hz, 6H); C NMR (101 MHz, CDCl
3
)
1
3
H), 1.29 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl
3
)
δ 173.9, 171.7, 169.5, 120.6, 89.7, 85.0, 78.0, 69.9, 67.0, 56.3,
δ 200.3, 174.0, 170.7, 165.1, 128.1, 119.9, 89.0, 84.2, 54.5, 53.8,
0.1, 46.7, 45.2, 37.7, 29.6, 29.1, 25.1, 23.7, 22.7, 22.0, 19.9, 7.9.
52.7, 50.9, 48.2, 45.6, 43.2, 33.6, 28.5, 25.9, 24.7, 23.7, 21.4, 21.2,
+
+
5
19.7, 18.3, 7.7, -5.4. HRMS (m/z): [M + H] calcd for C29
H
44
O
9
SiH
+
+
HRMS (m/z): [M + H] calcd for C22
H
30
O
6
H
391.2115, found
565.2827, found 565.2834.
91.2118.
Synthesis of ketone 50. To a solution of compound 49 (3.0 mg, (63.2 mg, 0.112 mmol, 1.00 equiv) in THF (4.0 mL) was slowly
.00768 mmol, 1.00 equiv) in H O (1.0 mL) was added TfOH (2.0 added LDA (2.0 M in THF, 1.7 mL, 0.340 mmol, 3.00 equiv) at –
L, 0.0230 mmol, 0.30 equiv). The reaction mixture was heated to 78 °C under the atmosphere of N . After stirring for 3 h, the
reaction was quenched with saturated aqueous NH Cl. The
Synthesis of alcohol 66. To a stirred solution of compound 65
2
2
4
resulting mixture was extracted with EtOAc (3 × 5.0 mL) and the
combined organic extracts were dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography
the product 50 (2.2 mg, 0.00607 mmol, 79% yield) as a white solid. (EA/PE = 1/2 to 1/1) to give the product 66 (30.1 mg, 0.0533
2
5
5
0
1
0: m.p. 65-66 °C; Rf = 0.4 (silica, EA/PE = 1:1); *α+
.17 in CHCl ); IR (film): νmax = 3459, 2958, 2923, 2852, 1767, 1728, *α+
713, 1468, 1453, 1378, 1260, 1091, 938, 863, 800 cm ; H NMR
): δ 2.88 (d, J = 18.5 Hz, 1H), 2.84 – 2.75 (m, 2H),
.59 (d, J = 18.7 Hz, 1H), 2.36 (d, J = 18.5 Hz, 1H), 2.28 (d, J = 7.8
D
= -15.0 (c =
mmol, 48% yield) as a colorless oil; 66: Rf = 0.2 (silica, EA/PE = 1:1);
2
5
3
D
= –3.8 (c = 0.10 in CHCl
2853, 1778, 1767, 1462, 1413, 1377, 1260, 1096, 1019, 800 cm ;
H NMR (400 MHz, CDCl ) δ 4.44 (d, J = 6.3 Hz, 1H), 3.69 (s, 1H),
3
3
); IR (film): νmax = 3398, 2958, 2924,
−
1
1
−1
1
(400 MHz, CDCl
3
2
3.50 – 3.41 (m, 2H), 2.97 (d, J = 17.5 Hz, 1H), 2.89 – 2.67 (m, 4H),
2.54 (d, J = 17.7 Hz, 1H), 2.44 – 2.26 (m, 3H), 1.94 – 1.83 (m, 1H),
1.83 – 1.66 (m, 3H), 1.60 – 1.55 (m, 1H), 1.36 – 1.30 (m, 1H), 1.29
– 1.24 (m, 4H), 1.22 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H), 0.87 (s, 9H),
Hz, 1H), 2.22 – 2.13 (m, 1H), 2.08 – 2.02 (m, 1H), 1.87 (ddd, J =
4.3, 11.5, 5.7 Hz, 3H), 1.79 – 1.71 (m, 2H), 1.70-1.62 (m, 3H),
.36 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H), 1.09 (t, J = 7.3 Hz, 3H;
): δ 212.0, 174.4, 120.3, 89.6, 84.2, 75.2,
6.0, 55.2, 54.7, 49.3, 47.5, 45.6, 42.5, 32.7, 29.3, 27.3, 26.4, 25.3,
1
1
13
C
1
3
NMR (101 MHz, CDCl
5
3
0.04 (s, 6H); C NMR (101 MHz, CDCl
3
) δ 173.8, 171.2, 121.6,
107.9, 92.6, 88.8, 88.7, 69.9, 68.1, 52.7, 52.3, 51.9, 50.8, 46.1,
This article is protected by copyright. All rights reserved.

4
3.6, 42.7, 32.7, 27.8, 26.4, 25.9, 23.1, 21.2, 19.3, 18.6, 7.6, 0.1, References
+
+
-
5.2, -5.4. HRMS (m/z): [M + H] calcd for C29
found 565.2828.
H
44
O
9
SiH 565.2827,
[
1] Law, Y. W. Science Press, Beijing, 1996, 30, 231173.
Synthesis of lactone 67. To a stirred solution of compound 66
26.6 mg, 0.0471 mmol, 1.00 equiv) in DCM (2.3 mL) was added
Martin’s sulfurane (57.1 mg, 0.0849 mmol, 1.80 equiv). After
stirring for 3 hours, the reaction was quenched with saturated
[2] (a) Chang, J. B.; Reiner, J.; Xie, J. X. Chem. Rev. 2005, 105, 4581. (b)
Xiao, W. L.; Li, R. T.; Huang, S. X.; Pu, J, X.; Sun, H. D. Nat. Prod. Rep.
(
2008, 25, 871. (c) Shi, Y. M.; Xiao, W. L.; Pu, J. X.; Sun, H. D. Nat.
Prod. Rep. 2015, 32, 367. (d) Li, X.; Cheong, P. H. R.; Carter, G.
Angew. Chem. Int. Ed. 2017, 56, 1704.
4
aqueous NH Cl. The resulted mixture was extracted with DCM (3
×
5.0 mL) and the combined organic extracts were dried over
[
3] Selected examples of synthetic efforts on schisandraceae
triterpenoids: (a) Tang, Y. F.; Deng, L. J.; Zhang, Y. D.; Dong, G. B.;
Chen, J. H.; Yang, Z. Org. Lett. 2005, 7, 593. (b) Tang, Y. F.; Zhang, Y.
D.; Dai, M. J.; Luo, T. P.; Deng, J. H.; Chen, J. H.; Yang, Z. Org. Lett.
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography (EA/PE = 1/3 to 1/1) to give the product 67 (21.0
mg, 0.384 mmol, 82% yield) as a colorless oil; 67: Rf = 0.3 (silica,
2
5
EA/PE = 1:1); *α+
D
3
= – 26.9 (c = 0.16 in CHCl ); IR (film): νmax =
2005, 7, 885. (c) Zhang, Y. D.; Tang, Y. F.; Luo, T. P.; Shen, J.; Chen,
2
1
4
959, 2925, 2854, 1772, 1653, 1462, 1377, 1358, 1261, 1095,
J. H.; Yang, Z. Org. Lett. 2006, 8, 107. (d) Krishnan, K. S.; Smitha, M.;
Suresh, E.; Radhakrishnan, K. V. Tetrahedron, 2006, 62, 12345. (e)
Fischer, D.; Theodorakis, E. A. Eur. J. Org. Chem. 2007, 4193. (f)
Zhang, Y. D.; Ren, W. W.; Lan, Y.; Xiao, Q.; Wang, K.; Xu, J.; Chen, J.
H.; Yang, Z. Org. Lett. 2008, 10, 665. (g) Wang, Q.; Chen, C.; Org. Lett.
2008, 10, 1223. (h) Paquette. L. A.; Lai, K. W. Org. Lett. 2008, 10,
−
1 1
021, 939, 802, 763 cm ; H NMR (400 MHz, CDCl
3
) δ 4.97 (s, 1H),
.37 (d, J = 5.3 Hz, 1H), 3.66 (d, J = 11.1 Hz, 1H), 3.53 (d, J = 11.1
Hz, 1H), 3.20 (s, 1H), 2.82 (dd, J = 10.0, 6.2 Hz, 1H), 2.77 – 2.53 (m,
4
1
1
6
9
2
H), 2.18 (dd, J = 15.7, 10.3 Hz, 1H), 2.06 – 1.93 (m, 1H), 1.93 –
.71 (m, 3H), 1.71 – 1.62 (m, 1H), 1.54 – 1.48 (m, 2H), 1.43 (s, 3H),
.24 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H), 0.86 (s, 9H), 0.05 (d, J = 2.9 Hz,
1
3
3
H); C NMR (101 MHz, CDCl ) δ 184.1, 173.9, 173.6, 120.8, 101.9,
2111. (i) Lai, K. W.; Paquette, L. A.; Org. Lett. 2008, 10, 2115. (j)
0.6, 87.6, 84.3, 69.0, 67.7, 57.5, 53.0, 50.8, 46.2, 45.6, 43.5, 34.1,
8.6, 25.8, 24.2, 22.3, 20.8, 19.5, 18.3, 7.7, -5.3, -5.4. HRMS (m/z):
Paquette. L. A.; Lai, K. W. Org. Lett. 2008, 10, 3781. (k) Cordonnier,
M. C. A.; Kan, S. B. J.; Anderson, E. A. Chem. Commun. 2008, 5818. (l)
Mehta, G.; Bhat, B. A.; Suresha Kumara, T. H. Tetrahedron Lett. 2010,
+
+
[
M + H] calcd for C29
H
42
O
8
SiH 547.2722, found 547.2730.
Synthesis of lactone 68. Preparation of solution A: Pd
CHCl (15.0 mg, mmol) and n-Bu P (7.0 L, mmol) was dissolved in
, 4-dioxane (0.5 mL), and stirring continued for 10 min.
Preparation of solution B: HCOOH (52.0 L, mmol) and DIPEA
92.0 L, mmol) were dissolved in 1, 4-dioxane (0.36 mL), and
2 3
dba
51, 4069. (m) Maity, S.; Matcha, K.; Ghosh, S. J. Org. Chem. 2010, 75,
3
3
1
4192. (n) Matcha, K.; Maity, S.; Malik, C. K.; Ghosh, S. Tetrahedron
Lett. 2010, 51, 2754. (o) Hossain, M. F.; Matcha, K.; Ghosh, S.
Tetrahedron Lett. 2011, 52, 6473. (p) Bartoli, A.; Chouraqui, G.;
Parrain, J. L. Org. Lett. 2012, 14, 122. (q) Ignatenko, V. A.; Han, Y.;
Tochtrop, G. P.; J. Org. Chem. 2013, 78, 12229. (r) Gockel, B.; Goh, S.
S.; Puttock, E. J.; Baars, H.; Chaubet, G.; Anderson, E. A. Org. Lett.
(
stirring continued for 10 min.
To a stirred solution of compound 67 (11.3 mg, 0.0207 mmol,
1

.00 equiv) in 1, 4-dioxane (0.4 mL) was sequentially added 100.0
L of solution A and 50.0 L of solution B under N .The reaction
mixture was heated to 45 °C, and stirring continued for another
0 hours. The resulted mixture was filtered, and the solvents
2
2014, 16, 4480. (s) Wang, Y.; Li, Z. L.; Lv, L. B.; Xie, Z. X. Org. Lett.
1
2016, 18, 792. (t) Grimblat, N.; Kaufman, T. S.; Sarotti, A. M. Org.
Lett. 2016, 18, 6420. (u) Wang, Y.; Zhang, Y. H.; Li, Z. L.; Yang, Z. J.;
Xie, Z. X. Org. Chem. Front. 2017, 4, 47.
were removed under reduced pressure. The crude product was
purified by silica gel column chromatography (EA/PE = 1/5 to 1/2)
to give the product 68 (6.0 mg, 0.0109 mmol, 53% yield) as a
[
4] (a) Xiao, Q.; Ren, W. W.; Chen, Z. X.; Sun, T. W.; Li, Y.; Ye, Q. D.;
Gong, J. X.; Meng, F. K.; You, L.; Liu, Y. F.; Zhao, M. Z.; Xu, L. M.; Shan,
Z. H.; Shi, Y.; Tang, Y. F.; Chen, J. H.; Yang, Z. Angew. Chem. Int. Ed.
2
5
colorless oil; 68: Rf = 0.3 (silica, EA/PE = 1/1); *α+
in CHCl ); IR (film): νmax = 2957, 2926, 2855, 1778, 1768, 1462,
453, 1377, 1259, 1209, 1168, 1101, 1064, 1032, 933, 874, 837,
D
= 7.8 (c = 0.15
3
1
8
−
1 1
2011, 50, 73730. (b) Sun, T. W.; Ren, W. W.; Xiao, Q.; Tang, Y. F.;
3
02, 760, 666 cm ; H NMR (400 MHz, CDCl ) δ 4.45 (dd, J = 11.4,
5
2
1
.9 Hz, 2H), 3.59 – 3.50 (m, 2H), 3.05 (s, 1H), 2.87 – 2.74 (m, 2H),
.70 (dd, J = 17.4, 11.9 Hz, 2H), 2.54 (d, J = 17.7, 1H), 2.44 (t, J =
0.1 Hz, 1H), 2.30 (dd, J = 16.3, 10.9 Hz, 2H), 1.92 – 1.79 (m, 2H),
.76 – 1.67 (m, 2H), 1.48-1.37 (m, 1H), 1.37 – 1.24 (m, 2H), 1.21 (d,
Zhang, Y. D.; Li, Y.; Meng, F. K.; Liu, Y, F.; Zhao, M. Z.; Xu, L. M.; Chen,
J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2321. (c) Li, Y.; Chen, Z. X.; Xiao,
Q.; Ye, Q. D.; Sun, T. W.; Meng, F. K.; Ren, W. W.; You, L.; Xu, L. M.;
Wang, Y. F.; Chen, J. H.; Yang, Z. Chem. Asian J. 2012, 7, 2334. (d)
Ren, W. W.; Chen, Z. X.; Xiao, D.; Li, Y.; Sun, T. W.; Zhang, Z. Y.; Ye,
Q. D.; Meng, F. K.; You, L.; Zhao, M. Z.; Xu, L. M.; Tang, Y. F.; Chen, J.
H.; Yang, Z. Chem. Asian J. 2012, 7, 2341. (e) Li, J.; Yang, P.; Yao, M.;
Deng, J.; Li, A. J. Am. Chem. Soc. 2014, 136, 16477. (f) Goh, S. S.;
Chaubet, G.; Gockel, B.; Cordonnier, M. A.; Baars, H.; Phillips, A. W.;
Anderson, E. A. Angew. Chem. Int. Ed. 2015, 54, 12618. (g) Wang, L.;
Wang, H. T.; Li, Y. H.; Tang, P. Angew. Chem. Int. Ed. 2015, 54, 5732.
1
1
3
J = 3.7 Hz, 3H), 1.16 – 1.09 (m, 6H), 0.87 (s, 9H), 0.04 (s, 6H);
C
3
NMR (101 MHz, CDCl ) δ 174.3, 173.8, 121.5, 92.1, 88.8, 86.8,
8
2
1.3, 69.2, 67.8, 55.0, 54.5, 52.4, 50.8, 46.0, 43.0, 35.7, 32.5, 27.8,
6.2, 25.9, 23.0, 19.3, 18.4, 17.6, 7.6, -5.2, -5.4. HRMS (m/z): [M +
+
+
H] calcd for C29
H
44
O
8
SiH 549.2878, found 549.2884.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
(
h) You, L.; Liang, X. T.; Xu, L. M.; Wang, Y. F.; Zhang, J. J.; Su, Q.; Li, Y.
H.; Zhang, B.; Yang, S. L.; Chen, J. H.; Yang, Z. J. Am. Chem. Soc. 2015,
37, 10120. (i) Xu, L. M.; You, L.; Shan, Z. H.; Yu, R. C.; Zhang B., Li, Y.
1
Acknowledgement
The authors dedicated this manuscript to 100th anniversary
of Nankai University. This work was supported by the National
Key Research and Development Program of China
H.; Shi, Y.; Chen, J. H.; Yang, Z.; Chem. Asian J. 2016, 11, 1406. (j)
Zhang, J. J.; You, L.; Wang, Y. F.; Li, Y. H.; Liang, X. T.; Zhang, B.; Yang,
S. L.; Su, Q.; Chen, J. H.; Yang, Z. Chem. Asian J. 2016, 11, 1414. (k)
Liang, X. T.; You, L.; Li, Y. H.; Yu, H. X.; Chen, J. H.; Yang, Z. Chem.
Asian J. 2016, 11, 1425. (l) Yang, P.; Yao, M.; Li, J.; Li, Y.; Li, A. Angew.
Chem. Int. Ed. 2016, 55, 6964. (m) Han, Y. X.; Jiang, Y. L.; Li, Y.; Yu, H.
X.; Tong, B. Q.; Niu, Z.; Zhou, S. J.; Liu, S.; Lan, Y.; Chen, J.-H.; Yang, Z.
(
2016YFA0602900), NFSC (21522205, 21672110) and the
Fundamental Research Funds for the Central Universities.
This article is protected by copyright. All rights reserved.

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Entry for the Table of Contents
Page No.
Collective Synthesis of Schilancidilactones
A, B and Schilancitrilactones A, B, C,
2
0-epi-Schilancitrilactone A
The collective total synthesis of schilancidilactones A, B, schilancitrilactones A, B, C, and
0-epi-schilancitrilactone A were accomplished. The key steps include intermolecular radical
2
cyclization, late-stage halogenation, intermolecular cross coupling of alkyl halide with vinyl
stannane.
Hengtao Wang, Liang Wang, Yihang Li,
Xiunan Zhang, Pingping Tang*
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