Asymmetric Total Synthesis of (-)-Spirochensilide A

Article abstract of DOI:10.1021/jacs.0c02522

An asymmetric total synthesis of (-)-spirochensilide A has been achieved for the first time. The synthesis features a semipinacol rearrangement reaction to stereoselectively construct the two-vicinal quaternary chiral centers at C8 and C10, a tungsten-med

Full text of DOI:10.1021/jacs.0c02522

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Communication
Asymmetric Total Synthesis of (-)-Spirochensilide A
Xin-Ting Liang, Jia-Hua Chen, and Zhen Yang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02522 • Publication Date (Web): 14 Apr 2020
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Journal of the American Chemical Society
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Asymmetric Total Synthesis of (-)-Spirochensilide A
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Xin-Ting Liang,† Jia-Hua Chen,*,† and Zhen Yang*,†,‡,§
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†
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for
Molecular Science, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China;
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‡
State Key Laboratory of Chemical Oncogenomics and Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Shenzhen 518055, China
§ Shenzhen Wan Laboratory, Shenzhen, 518055, China.
Supporting Information Placeholder
bearing both quaternary chiral centers and spirocycles can impose
conformational constraints to reduce the conformational entropy
penalty upon binding to a protein target in a favorable geometry.8
Herein, we report our effort on the development of an approach
for the asymmetric total synthesis of spirochensilide A (1). The
synthesis features a semi-pinacol rearrangement and a tungsten-
mediated cyclopropene-based Pauson–Khand (PK) reaction as key
steps.
Figure 1 illustrates our retrosynthetic analysis. We envisioned
that the anomeric spiroketal of 1 could be derived from furyl alcohol
A via an intramolecular oxidative cyclization.9 A was expected to
be constructed from ketones B and C via a furyl acetaldehyde Aldol
condensation10 as a key step. To construct the cyclopentenone
bearing an all-carbon quaternary chiral center in intermediate B, we
intended to employ the PK reaction11 of enyne D because this
reaction has been successfully applied in our total synthesis of the
nontriterpenoid propindilactone G.12 Enyne D was expected to be
derived from aldehyde E with a pair of vicinal quaternary chiral
centers at C8 and C10, which was envisioned to be derived from
epoxide F through a semi-pinacol rearrangement.13 F could be
prepared via a sequential Pd-catalyzed Sonogashira reaction and
epoxidation from vinyl halide G, which in turn could be prepared
via a biomimetic cyclization of the functionalized isoprenoid
polyene H.14
ABSTRACT: An asymmetric total synthesis of (-)-spirochensilide
A has been achieved for the first time. The synthesis features a semi-
pinacol rearrangement reaction to stereoselectively construct the
two-vicinal quaternary chiral centers at C8 and C10, a tungsten-
mediated cyclopropene-based Pauson–Khand reaction to install the
C13 quaternary chiral center, and a furan-based oxidative
cyclization to stereoselectively form the spiroketal motif.
Spirochensilide A (1, Figure 1)1 is a member of an emerging and
biologically important class of natural products with a unique
spirocyclic core,2 and has been isolated by Gao and co-workers from
Abies chensiensis, which is an endemic Chinese plant.3 The crude
extracts and metabolites of the Abies species have been found to
possess various bioactivities, including anti-tumor, anti-microbial,
anti-ulcerogenic, anti-inflammatory, anti-hypertensive, anti-tussive,
and central nervous system activities.4 Biologically, 1 showed a
moderate inhibitory effect on the NO production with 30%
inhibition at the concentration of 12.5 μg/mL, indicating 1 could be
a useful probe for study of inflammatory diseases.5
Me
Me
Me
Me
O
Me8
13 17
Me
OH
C
H
Me
D
Me
TBS
P2O
O
F
E
D
O
O
A10
Me
B
O
H
furyl acetaldehyde
Aldol condensation
HO
Me
H
Scheme 1. Diastereoselective synthesis of enyne 8a
oxidative
cyclization
Me Me
P1O
A
H
1
Me
Me
spirochensilide A (
)
b) Pd(PPh3)2Cl2
H
TMS
alkylation
CuI, DIPA
TMS
H
Me
Me
H
Me
Me
P2O
a) TiCl4
CH2Br2
Br
CHO
Me
9
C 13
Me
R
(93%)
10
P2O
8
10
Me
8
5
3
Me
R
4
90%
c) TBSCl
(95%)
A10
B
O
HO
TBSO
Me
H
Me
H
Me
Me Me
O
P1O
P1O
Me
P1O
PK reaction
H
4
H
H
3
Lewis acid
TMS
D
B
E
Me Me
2
(97% ee)
Me Me
Me Me
d) mCPBA, then BF3·Et2O (65%)
O
Me
+
semi-pinacol
rearrangement
Me
9
10
O
8
R
Me
O
C-O
clevage
TBSO
H
TBS
O
H
Me
Me
Me
C
5
H
P1O
Sonogashira
reaction
Me
e) CeCl3
TBSO
H
F
9CHO
Me Me
Me
BrMg
Me
H
7
H
TMS
f) K2CO3
8
10
Me
Me
X
g) TBSOTf
(76%, 3 steps)
TBSO
TBSO
H
10
H
Me
Me
Me Me
Me
3
5
P1O
8
6
H
Me
O
Me
Me
H
G
(X = halide)
aReagents and conditions: (a) TiCl4 (0.4 equiv.), CH2Br2 (epoxide 2 was 0.2
o
M in CH2Br2), -35 C, 1 h, 90%; (b) Pd(PPh3)2Cl2 (0.05 equiv.), CuI (0.03
Figure 1. Retrosynthetic analysis of spirochensilide A (1).
equiv.), DIPA (5.0 equiv.), HC≡CTMS (3.0 equiv.), THF, 50 oC, 16 h, 93%;
The structure of 1 was determined on the basis of NMR
spectroscopic data and single-crystal X-ray diffraction analysis. The
structure contains two pairs of vicinal all-carbon quaternary chiral
centers6 (C8/C10 and C13/17), an unusual spiro[4.5]ring system
(BC ring), and an anomeric spiroketal (EF ring).7 Natural products
(c) TBSCl (1.3 equiv.), imidazole (2.5 equiv.), DMF, rt, 15 h, 95%; (d)
o
o
mCPBA (2.0 equiv.), DCM, -30 C to 0 C; then BF3·Et2O (0.05 equiv.),
DCM, 0 oC, 1 h, 65%, 2 steps; (e) CeCl3 (1.5 equiv.), Grignard reagent 7 (1.5
o
equiv.), THF, 0 C, 30 min; (f) K2CO3 (5.0 equiv.), MeOH, rt, 16 h; (g)
TBSOTf (1.5 equiv.), Et3N (3.0 equiv.), DCM, -78 oC to rt, 3 h, 76%, 3 steps.
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Our synthesis began by exploring the chemistry for an
increase its reactivity in PK reactions, and their defined chiral
environment can influence the diastereoselective outcome of the PK
reaction.27 Since the three-membered ring can be cleaved under mild
conditions, we identified an alternative pathway to install the CD
ring system into the target molecule 1.
1
2
3
4
5
6
7
8
enantioselective preparation of enyne 8 (Scheme 1). We rationed
that a Lewis acid-induced cyclization15 of polyenoid 2 could
enantioselectively afford halogenated decalin16 3 bearing three
stereogenic centers at C3, C5, and C10 via a concerted cyclization
process.17 The selectivity results from the chair-like transition state
achieved via a sequence of biomimetic epoxide-initiated cationic
cyclization and nucleophilic bromination reaction.
Experimentally, we found that vinyl bromide 3 could be obtained
in 90% yield when acetylenic epoxide 218 of 97% ee was treated
with TiCl4 (0.4 equiv.) in CH2Br2 at -35 oC for 1 h (Scheme 1),19 and
unlike the previously reported protocols,20 the current reaction could
be carried out on 50 g scale.
Scheme 3. Synthesis of cyclopentenones 15a and 15ba
H
a) CeCl3
TESO
Me
CHO
Me
TMS
TMS
13
Li
TMS
H
(75%)
b) TESOTf, Et3N
then MeOH, K2CO3
(98%)
TBSO
H
Me
TBSO
9
Me
H
Me
Me
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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44
45
46
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48
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60
14
or (d) Ni(COD)2/bipy, CO
c) W(CO)3(MeCN)3 EtOH, HMPA, CO
We next turned our attention to map out an effective
stereoselective synthesis of aldehyde 6, which bears two vicinal
quaternary chiral centers at C8 and C10. To this end, 3 was
converted into alkyne 4 in an 88% overall yield by a sequence of
conventional Sonogashira and silylation reactions. After
epoxidation of 4 with mCPBA, the resultant epoxide, formed as a
single diastereoisomer, could undergo the proposed semi-pinacol
rearrangement via treatment with BF3·Et2O (0.05 equiv.)21 to afford
6 in 65% yield. The reaction of 6 with Grignard reagent 7 in the
15a 15b
: = 1:4)
(84%,
15a 15b
(61%,
:
= 1:1)
or (e) Mo(CO)3(DMF)3
15a 15b
:
(70%,
= 1:2)
TMS
H
TMS
O
H
13 17
13 17
TESO
TESO
O
+
Me
Me
15b
15a
TBSO
TBSO
H
Me
H
Me
Me
Me
22
presence of CeCl3 followed by a silylation afforded 8 in 76%
overall yield.
Scheme 2. Pauson-Khand reaction of enyne 8a
17
Me
Me
H
O
17
Me
H
Me
H
12
17
15
13
12
14
8
13
TBSO
Me
O
13
TBSO
15b
15a
ORTEP of
ORTEP of
19
O
14
15
Me
aReagents and conditions: (a) CeCl3 (1.3 equiv.), lithium reagent 13 (1.3
Cl
TBSO
OTBS
equiv.), pentane:Et2O = 3:2, -98 oC to -60 oC, 2.5 h, 75%; (b) TESOTf (1.2
TBSO
H
TBSO
H
Me Me
H
Me Me
o
o
9
12
equiv.), Et3N (3.0 equiv.), DCM, -78 C to 0 C, 2 h; then MeOH, K2CO3
(10.0 equiv.), rt, 24 h, 98%; (c) W(CO)3(MeCN)3 (1.5 equiv.), EtOH:HMPA
= 20:1, CO (1.0 atm), rt to 80 oC, 61% (15a:15b = 1:1); (d) Ni(COD)2 (1.1
equiv.), 2,2'-bipyridine (1.2 equiv.), toluene, CO (1.0 atm), rt, 84%, 15a:15b
=1:4; (e) Mo(CO)3(DMF)3 (1.5 equiv.), toluene, 60 oC, 30 min, 70%,
15a:15b = 1:2.
Me Me
11
PK reaction
various
conditions
X
c) [Rh(CO)2Cl]2, CO
65 oC, DCE (67%)
Me
b) [Rh(CO)2Cl]2, CO
160 oC, nBu2O (33%)
Me
H
H
TBSO
Me
TBSO
17
12
15
12
17
13
13
19
a) nBuLi, NCS
(87%)
Me
H
Cl
8
14
14
15
With these chemistries in mind, we then applied this strategy for
the synthesis of 15a. To this end, we have developed a
diastereoselective approach for the synthesis enyne 14 via the
reaction of aldehyde 6 with lithium reagent 1328 (see SI for details)
in the presence of CeCl3 at -98 oC. The resultant secondary alcohol
was protected as its TES ether followed by removal of TMS to
afford 14 in 73% overall yield in two steps (Scheme 3). However,
the annulation of enyne 14, under both the conventional PK reaction
(Co2(CO)8) and PK-type reactions (with other metal complexes
derived from Rh, Pd, Ir, or Ru), failed to afford 15a. To further
explore the PK reactions with other types of metal catalysts, such as
W(CO)3(MeCN)3,29 Ni(COD)2/bipy,30 and Mo(CO)3(DMF)3,31 we
fortunately found out that when W(CO)3(MeCN)3 was used as the
catalyst, 15a was isolated in ca. 30% yield, together with its
diastereoisomer 15b in 30% yield. Other catalysts, such as
Ni(COD)2/bipy or Mo(CO)3(DMF)3, could also provide 15a and
15b, but in favor of 15b, although the overall yields were higher
(Scheme 3). We also attempted to improve the yield by systematic
investigation of the W(CO)3(MeCN)3-catalyzed PK reaction for the
formation of 15a; no better results were obtained (see SI for details).
To complete the total synthesis of 1 (Scheme 4). Initially, we
attempted to carry out the reductive cyclopropane ring-opening
reaction by treatment of 15a with SmI2 or nBu3SnH. However, under
such reaction conditions, 15a was converted to 16 through 16a,
presumably because the orbitals of the double bond in 15a
overlapped better with its carbonyl group than orbitals of its
cyclopropane motif. To achieve the regioselective cyclopropane
opening, 15a underwent a selective desilylation to remove its TMS
TBSO
TBSO
H
H
Me Me
Me Me
10
8
aReagents and conditions: (a) BuLi (1.2 equiv.), NCS (1.2 equiv.), THF, -
n
o
n
78 C to rt, 87%; (b) [Rh(CO)2Cl]2 (0.5 equiv.), CO (1.0 atm), Bu2O, 160
oC, 48 h, 33%; (c) [Rh(CO)2Cl]2 (0.5 equiv.), CO (1.0 atm), DCE, 65 oC, 48
h, 67%.
We then turned our attention to the synthesis of the
cyclopentenone motif in 9 by the proposed PK reaction (Scheme 2).
Initially, we attempted various Co-mediated PK reactions of 8;
however, desired product 9 was not observed (see SI for details). We
attributed this failure to the low reactivity of enyne 8, and its steric
rigidity. Since enynes bearing a chloride as a σ-electron-
withdrawing group could promote polarization and thereby reduce
the activation barrier of the Rh-catalyzed PK reaction,23 we prepared
chloroenyne 10. However, under different optimized conditions, 11
or 12 was obtained in 33% or 67% yield, respectively. The formation
of 11 indicated the expected carbonylative annulation reaction had
indeed proceeded and provided the desired C13 quaternary center,
but the resultant product underwent a further Rh-catalyzed
carbonylative C–H insertion24 to afford 11. While the formation of
12 could be a result of a double bond isomerization followed by a
PK reaction. The structures of 11 and 12 were confirmed by X-ray
crystallographic analysis (see SI for details).
In 2005, Fox and co-workers reported a cyclopropene-based, Co-
mediated PK reaction25 for the stereoselective synthesis of
structurally diverse cyclopropane-based cyclopentenones. We also
considered the fact that the inherent strain of cyclopropene26 can
via treatment with BuOK,32 and the resultant cyclopropane then
participated in a Pd/C-catalyzed regioselective hydrogenation to
t
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afford ketone 17. 17 was then subjected to a Li/NH3-mediated
To regioselectively install the trans-double bond between C17-
C20, 18 was reacted with nBu2BOTf/DIPEA, and the resultant
enolate participated in an enol-borane-mediated aldol reaction34
with TBS-stabilized furyl acetaldehyde 19 to afford 20 as a sole
isomer in 97% yield. The observed excellent diastereoselectivity
should be attributed to the formation of the chair-like transition state
TS-A35 in the presence of bulky DIPEA,36 and the structure of 20
was confirmed by X-ray crystallographic analysis of its ester
derivative (see SI for details). Thus, further reaction of 20 with 2-
fluoro-1-methylpyridin-1-ium tosylate37 followed by a neutral
Al2O3-mediated syn-elimination afforded enone 21 in 75% yield.
The trans-configurated C17-C20 double bond in 21 was confirmed
by 2D-NMR analysis.
1
2
3
4
5
6
7
8
regioselective reductive ring-opening reaction followed by aprotic-
quenching33 with dichloroethane (DCE) to afford 18 bearing the
trans-fused bicyclic CD ring with the desired C13 stereogenic center
in 76% yield over three steps.
Scheme 4. Synthesis of spirochensilide A 1a
30
30
TMS
OM
H
13
H
13
- Smll or
nBu3Sn
17
17
TESO
Me
TMS
TESO
-
Me
OH
M = Smlll or SnnBu3
TBSO
9
TBSO
H
H
16a
16
Me
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
or nBu3SnH (44%)
a) SmI2 (77%)
To diastereoselectively generate the allylic alcohol in 23, enone
21 underwent a cuprate-mediated 1,4-addition via treatment with
Me2CuLi, and the resultant ketone was methylated (MeI/KH) to give
ketone 22 bearing the desired C17 and C20 stereogenic centers (see
SI for a DFT experiment to account for the diastereoselectivity).
Thus, further treatment of 22 with LDA followed by reaction with
PhSeCl gave a selenide, which was then selectively oxidized with
m-CPBA and reduced with DIBAL to afford 23 in 66% yield over
three steps.
30
30
H
TMS
H
17
b) tBuOK, tBuOH (95%)
13
13
17
TESO
TESO
O
O
c) Pd/C
Me
Me
H
H2 (balloon pressure)
EtOH, EtOAc
TBSO
TBSO
H
H
Me
Me
Me
Me
17
Me
15a
TBS
d) Li-NH3, then DCE
(80%, 2 steps)
HO
e) nBu2BOTf, DIPEA
O
20
Me30
Me
Me
then
H
H
17
H
19
C 13
17
TESO
Me
To complete the total synthesis, 23 bearing a TBS group38 was
first oxidized by singlet oxygen (generated by irradiation of oxygen
with tungsten lamp in the presence of methylene blue), and the
resultant 4-oxo-2-alkenoic acid intermediate39 was then treated with
ClCH2CO2H in MeCN to afford 24 in 88% yield. Selective
desilylation of 24 with TBAF·3H2O followed by DMP-oxidation of
the newly generated secondary alcohol afford a C9-ketone, which
was further subjected to a desilylation with HF to afford 1 in 87%
yield over three steps. The structure of synthetic spirochensilide A
was confirmed by single-crystal X-ray diffraction, and its NMR and
optical rotation data were in agreement with those reported in the
literature. More than 150 mg of 1 was made in our first round of
synthesis.
In summary, the total synthesis of (-)-spirochensilide A (1) has
been accomplished for the first time in 22 steps from epoxide 2, with
a total yield up to 2.2%. The keys to the success of the synthesis
were the use of 1) a semi-pinacol rearrangement of epoxide 2 to
stereoselectively generate the chiral aldehyde 6; 2) a rarely-
investigated tungsten-mediated cyclopropene-based PK reaction to
form 15a, bearing the spiro-bicyclic core of 1; and 3) singlet
oxygen-mediated oxidative cyclization of furyl alcohol 23 to form
the anomeric spiroketal motif of 1. The developed chemistry paves
the way to the stereoselective construction of this unprecedented
triterpenoid scaffold, which bears two spirocyclic systems and up to
four all-carbon quaternary chiral centers.
OHC
TESO
TBS
D
O
O
O
H
Me
15
(97%)
H
H
B
RO
19
TBSO
TBSO
H
H
Me
Me
Furyl
R
Me
Me
18
20
B
Me
O
O
f)
R
OTs
F
N
TS-A
Me
Me
O
then neutral Al2O3
(75%)
Me
TBS
20
Me
NOESY
H
O
Me
O
TBS
3.57 (dd)
3.47 (dd)
17
g) Me2CuLi
(86%)
TESO
22
1.26
(s)
2.06 (m)
12
Me
20
30
17
Me
H
H
TESO
Me
h) KH, MeI
22
(81%)
TBSO
H
Me
O
i) LDA, PhSeCl
Me
Me
(46%, 77% brsm)
j) mCPBA (87%)
k) DIBAL (98%)
H
21
TBSO
H
Me Me
Me
Me
Me
l) MB, O2, hv
Me
H
2.5 min
O
O
H
Me
O
Me
TBS
TESO
TESO
then
ClCH2CO2H
(88%)
9
O
OH
Me
H
Me
Me
Me
23
3
24
TBSO
TBSO
H
H
Me
Me
Me Me
m) TBAF·3H2O (97%)
n) DMP (95%)
o) aq. HF (94%)
Me
Me
O
O
9
Me
O
O
Me
H
Me
3
HO
H
1
1
ORTEP of
spirochensilide A (
)
Me
Me
ASSOCIATED CONTENT
Supporting Information
aReagents and conditions: (a) SmI2 (2.0 equiv.), THF:HMPA = 10:1, rt, 30
min, 77%; or nBu3SnH (5.0 equiv.), AIBN (0.5 equiv.), PhH, 80 oC, 6 h, 44%;
(b) tBuOK (7.5 equiv.), tBuOH, 85 oC, 4 d, 95%; (c) 5% Pd/C (0.2 wt., type
87L), H2 (balloon), EtOH:EA = 1:1, rt, 12 h; (d) Li-NH3, THF, -78 C, 15
min; then quenched with DCE, 80%, 2 steps; (e) Bu2BOTf (2.0 equiv.),
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and compound characterizations (PDF);
X-ray diffraction of compound 11 (CIF), 12 (CIF), 15a (CIF), 15b
(CIF), 20 ester derivative (CIF), spirochensilide A (CIF).
o
n
DIPEA (2.5 equiv.), DCM, -78 oC, then furyl acetaldehyde 19 (4.0 equiv.), -
78 oC to -50 oC, 1.5 h, 97%; (f) 2-fluoro-1-methylpyridin-1-ium tosylate (3.0
equiv.), Et3N (10 equiv.), DCM, rt, 12 h; then neutral Al2O3, rt, 1 h, 75%; (g)
Me2CuLi (2.0 equiv.), Et2O, -78 oC to -30 oC, 5 h, 86%; (h) KH (1.5 equiv.),
MeI (4.0 equiv.), THF, rt to -78 oC, 81%; (i) LDA (1.2 equiv.), THF, -78 oC
AUTHOR INFORMATION
o
o
to 0 C; then PhSeCl (1.3 equiv.), -98 C, 15 min, 46% (77% brsm); (j) m-
Corresponding Author
CPBA (1.05 equiv.), Et3N (3.5 equiv.), DCM, -78 oC to rt, 87%; (k) DIBAL
*E-mail: zyang@pku.edu.cn; E-mail: jhchen@pku.edu.cn
o
o
(2.0 equiv.), DCM, -78 C to -10 C, 3 h, 98%; (l) methylene blue (MB)
(10-4 M), O2 (bubble), DCM, hv (tungsten lamp), 0 oC, 2.5 min; then
ClCH2CO2H, H2O, MeCN, rt, 1 h, 88%; (m) TBAF·3H2O (3.0 equiv.), THF,
rt, 15 min, 97%; (n) DMP (2.0 equiv.), NaHCO3 (20 equiv.), pyridine (15
equiv.), DCM, rt, 20 min, 95%; (o) aq. 48%~51% HF, DCM:MeCN = 1:4,
rt, 4 h, 94%.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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(13) For a review, see: Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Semipinacol
This work is supported by National Science Foundation of China
(Grand No. 21772004, 21632002, and 21871012. We thank Dr. Jie
Su and Mr. Yuan-He Li from Peking University for the X-ray
crystallographic detection and analysis. This paper is dedicated to
Professor Henry N. C. Wong on the occasion of his 70th birthday.
Rearrangement in Natural Product Synthesis. Chem. Rev. 2011, 111,
7523.
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2
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Cyclization of Squalene and Oxidosqualene to Sterols and Triterpenes.
Chem. Rev. 1993, 93, 2189. (b) Yoder, R. A.; Johnston, J. N. A Case
Study in Biomimetic Total Synthesis:ꢀ Polyolefin Carbocyclizations to
Terpenes and Steroids. Chem. Rev. 2005, 105, 4730.
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