Scalable Total Synthesis of (-)-Vinigrol

Article abstract of DOI:10.1021/jacs.9b00621

Vinigrol is a structurally and stereochemically complex natural product that displays various potent pharmacological activities, including the capability to modulate TNF-α. A new and efficient synthetic route toward this natural product has been developed to complete the asymmetric synthesis of (-)-vinigrol and provide over 600 mg of material, manifesting the power of macrocyclic stereocontrol and transannular Diels-Alder reaction.

Full text of DOI:10.1021/jacs.9b00621

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Communication
Scalable Total Synthesis of (-)-Vinigrol
Xuerong Yu, Lianghong Xiao, Zechun Wang, and Tuoping Luo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00621 • Publication Date (Web): 15 Feb 2019
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Scalable Total Synthesis of (−)-Vinigrol
†
†
†
,†,‡
Xuerong Yu, Lianghong Xiao, Zechun Wang, Tuoping Luo*
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†Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National
Laboratory for Molecular Science (BNLMS), College of Chemistry and Molecular Engineering, Peking University, Beijing
‡
1
00871, China, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking
University, Beijing 100871, China
Supporting Information Placeholder
ABSTRACT: Vinigrol is a structurally and stereochemically
complex natural product that displays various potent
pharmacological activities, including the capability to modulate
TNF-α. A new and efficient synthetic route towards this natural
product has been developed to complete the asymmetric synthesis
of (−)-vinigrol and provide over 600 mg material, manifesting the
power of macrocyclic stereocontrol and transannular Diels-Alder
reaction.
redox
manipulations
transannular DA /
decarboxylation
H
H4aH 5
HO
H
4
9
HO
HO
O
1
2
8
9
5
4
8a
3
3
8
OH
1
1
2
8
a
H
MeO
H OH
OH
12
(
–)-Vinigrol (1)
2
4
First isolated from a fungal strain in Japan by Hashimoto and co-
1
: epimerization
H
4a
workers, vinigrol (1, Fig. 1) occupies a special position in natural
5
9
H
5
12
1
8
product small molecules. Among the structurally diverse
8
terpenoids, vinigrol is the only one that is characterized by the 6-
9
O
8a
1
6
-8 tricyclic ring system with the axial four-carbon tether bridging
2: hydroboration/
Zweifel reaction
3: 1,4-addition/
O
12
O
the densely decorated cis-decalin core. This natural product
lactonization
3
2
displays potent antihypertensive and platelet aggregation-
O
CO2Me
MeO2C
2
3
3
inhibiting properties, and has been reported as an antagonist for
3
tumor necrosis factor α (TNF-α), which intrigues us the most.
Numerous research efforts have been oriented towards the
chemical synthesis of vinigrol since its discovery in 1987, which
5
E
9
Li
8
5
9
O
12
4
have been reviewed. However, to date there are only three routes
O
8
5
CO Me
12
to accomplish this molecule (Fig. S1). The first and most efficient
2
OMe
4
4
synthesis of racemic vinigrol was reported by Baran group in 2009,
which promptly constructed the vinigrol skeleton by Diels–Alder
reactions and the Grob fragmentation, while the endgame
MeO C
2
5
[B]
H
5a
functionalization took another 12 steps. Afterwards, the approach
Figure 1. Retrosynthetic analysis of (−)-vinigrol (1).
reported by Barriault and co-workers used a Claisen rearrangement
and a type II intramolecular Diels-Alder reaction to forge the
vinigrol carbocyclic core, but again another 12 steps were needed
In contrast to previous tactics, we envisioned that the three
hydroxyl groups in vinigrol could be derived from redox
manipulation of diene 2, a highly strained intermediate with the
bridgehead alkene. The disconnection using inverse-electron-
demand transannular Diels-Alder reaction followed by in situ
extrusion of CO traced back to electron-deficient α-pyrone 3. In
2
order to achieve a highly efficient approach, we were intrigued by
the possibility of synthesizing 3 from substituted cyclodec-5-enone
5
b
to afford the target molecule. Based on this approach, Kaliappan
group completed an enantioselective formal synthesis by
5d
intercepting the vinigrol carbocyclic core. Another remarkable
6
achievement was reported by Njardarson and co-workers, which
creatively
carried
out
a
sequence
of
oxidative
dearomatization/IMDA reaction, cascade Heck cyclization, and
fragmentation to construct the 6-6-8 tricyclic ring system, but
5
c
another 14 steps were required to finish vinigrol. Therefore, the
challenges of chemical synthesis of vinigrol reside in not only the
4
, the enantiomer of which had been prepared by both Wu group
and Mehta group starting from (R)-(−)-carvone and (R)-(+)-
limonene, respectively (Fig. S2). Therefore, the other key strategic
prominent and complex molecular framework but also
8
7
continuous stereogenic centers with unique substitution patterns.
Herein, we wish to report a new strategy that provides a simple
solution to both problems, leading to a scalable synthesis of (−)-
vinigrol to facilitate the mechanism-of-action studies of this natural
product.
disconnections involved: (1) epimerization of C8 stereogenic
center (vinigrol numbering, throughout); (2) hydroboration of C5-
C9 olefin followed by Zweifel reaction; and (3) constructing the
α-pyrone motif via the condensation of dimethyl
methoxymethylenemalonate 5 with an appropriate ketone. Given
8
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the strong transannular (C8-C9) and A(1,3) interactions (C8-C12)
were achieved concomitantly to give diol 20 in quantitative yield.
In comparison, treatment of 19 with SmI only reduced the
peroxide to give diol 26, as confirmed by X-ray crystallography
1
2
3
4
5
6
7
8
9
1
1
1
1
1
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in 3, we envisioned the first task to be executed lastly. In the second
task, even though the hydroboration of the C5-C9 E-olefin would
secure the trans relationship of C5 vinyl and C9 hydrogen after the
Zweifel reaction, the absolute stereochemistry would be subjected
2
(Fig. 2).
1
0
to the cyclodecene macrocyclic stereocontrol. The third task
seemed straightforward but significant amount of experimental
exploration was anticipated, which would fine-tune the
transformation sequence to address the subtlety of stereocontrol
and minimize the use of protecting groups.
We commenced our work by preparing enantiopure 7 from (S)-
1
1
0
1
2
3
4
5
6
7
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0
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9
0
(−)-limonene (6) (Scheme 1). In comparison to the reported
7
protocols (Fig. S2), we carried out further optimizations to scale
up the preparation of (+)-4. It was therefore discovered that the
addition of the organocerium reagent to the ketone in 7 robustly
afforded alcohol 8 in 84% isolation yield on a decagram scale,
whereas the epimer was obtained in 11% yield and could be
converted to a equilibrated mixture containing 8 (see SI for
1
2
details). Regarding to the subsequent oxy-Cope rearrangement, it
was necessary to quench the enolate intermediate at −78 °C by
MeOH to afford cyclodecenones 4 and 9 in excellent yield, with a
1
ratio of 3.4:1 as determined by H-NMR (Table S1). However,
given
4 and 9 were hardly separable by routine flash
chromatography on silica gels, they were subjected to LiAlH
4
reduction to furnish a pair of separable diastereomeric alcohols, 10
and 11. Pure 4 and 9 were obtained by oxidation of 10 and 11,
respectively; the minor product, 11, could therefore be recycled to
4
via oxidation and epimerization (see SI).
It was noteworthy that the X-ray diffraction of ketone 4 revealed
a chair-chair-chair conformation, whereas alcohol 10 adopted a
boat-chair-boat conformation that shielded the Si face of C5-C9
olefin (Fig. 2). To our delight, hydroboration of 10 followed by the
formation of pinacol boronate afforded 12 as the major product
(hydroboration from the Si face), while 13 (hydroboration from the
Re face) turned out to be the minor one. Their structures were
determined by the X-ray diffraction of corresponding diols 23 and
Figure 2. ORTEP of (−)-vinigrol (1), synthetic intermediates and
related derivatives.
2
4 obtained by H
selectivity was under control by the Curtin−Hammett principle or
2 2
O oxidation (Fig. 2). Whether the observed
1
3
1
4
the hydroxyl-directed hydroboration, which could also depend on
the reagents and reaction conditions employed, invites further
investigations (see Fig. S3 and discussion in SI for details). After
extensive optimizations (see Table S2 and discussion in SI for
details), the best result was obtained by applying a one-pot
2
procedure: reaction of 10 with (+)-IpcBH was followed by
1
5
treatment with acetaldehyde to remove (−)-α-pinene, and the
resulting diethylboronic ester underwent transesterification with
excess pinacol, affording 12 in 71% isolated yield on 5-gram scale.
Subsequently, the Zweifel olefination reaction of 12 provided 14
in 92% yield, though excess vinyllithium was employed providing
the alcohol was not protected. Oxidation of 14 afforded ketone 15
in excellent yield, setting the stage for the installation of the α-
9
pyrone. Using the method developed by Boger’s group,
cyclodecanone 15 was smoothly converted to α-pyrone 16. By
heating 16 in the presence of DBU in toluene at 100 °C for 24 h, 92%
of 16 could be epimerized to 3; this pair of epimers were readily
separated. Subjecting 3 to the microwave irradiation at 200 °C in
1
,2-dichlorobenzene led to the desired product, 2, and the major
side products were identified to be 17 and 18; the mechanism for
the formation of them was proposed (Fig. S4). The confirmation of
the strained tricyclic skeleton of 2 was achieved by obtaining the
X-ray crystallography of the DIBAL reduction product, alcohol 25
(
Fig. 2). The mixture of 2, 17 and 18 could be used directly in the
next step on the gram-scale reaction, in which highly facial-
1
2
selective cycloaddition of O across the diene of 2 afforded 19 (87%
yield) and 17/18 were completely recovered. Reductive cleavage of
the resultant peroxide linkage and hydrogenation of the olefin in 19
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Scheme 1. Synthesis of (−)-Vinigrol (1)a
Table S1
MgBr
R2
8
a) CeCl3
b
) KH, 18-C-6
then MeOH
O
ref. 11
THF, –78 °C
R1
O
43% (5 steps)
84%
[18 g scale]
OH
(–)-8
97% (dr = 3.4:1)
[10 g scale]
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
1
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0
1
2
3
4
5
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9
0
1
2
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0
1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
(
S)-(–)-Limonene (6) [50 g scale]
(–)-7
(
(
+)-4: R = Me, R = H (X-ray)
1
2
+)-9: R = H, R = Me
c) LiAlH4 75% [10 g scale]
Table S2
(
pin)B
e)
Li
then I2
H
O
H
d) (+)-IpcBH then
OH
H
2
H
f) DMP
CH CHO, pinacol
OH
3
5
OH
9
95%
92%
71%
(+)-15
(+)-14
(+)-12
[5 g scale]
(+)-10 (X-ray)
separated
/ recycled
g) LDA, 5
h) DBU
+ 17% (+)-13
+ 22% (+)-11
67% (2 steps)
40 °C
H
H
i) DBU, toluene
00 °C, 24 h
j) o-DCB,
mW, 200 °C
8
8
8
O
1
O
O
+
% (+)-17
4% (–)-18
O
O
O
MeO
92%
52%
(74% brsm)
8
CO Me
MeO C
(99% brsm) MeO C
O
(–)-3
2
2
2
(+)-16
(–)-3
H
(–)-2
1
k) O , 0 °C 87%
2
H
H
H
H
H
Table S3
H
H
4
4
m) Burgess
l) H , Pd/C
O
O
HO
HO
HO
2
HO
MeO C
n) DIBAL-H
reagent
2
MeOH
3
3
MeO C
3
2
HO
MeO C
2
2
H
2
H
H
99%
88%
60%
75% brsm)
(
,4
(
(
+)-22a: 3
6
1
(+)-21a: 3,4
(–)-21b: 
(–)-19
H
6
1
(–)-20
=
–)-22b: 2
,3
=
2,3
H
HO
1
H
o) O
H
O
2
OH
(
pin)B
then PMe3
(
–)-Vinigrol (1) (X-ray)
MeO
H
57%
CO Me
2
+
10% (–)-22b
(+)-11
(+)-13
(+)-17
(–)-18
aAll reactions were carried out on a gram-scale if not specified. Reagents and conditions: a) CeCl
bromide (2.0 equiv), THF, −78 °C, 81%; b) KH (1.2 equiv), 18-C-6 (1.2 equiv), then MeOH, −78 °C, 97% (dr = 3.4:1); c) LiAlH
equiv), rt; 10, 75%; 11, 22%; d) (+)-IpcBH (2.4 equiv), THF, 0 °C, then CH CHO (20 equiv); pinacol (4.0 equiv), DCM, 40 °C; 12, 71%;
3, 17%; e) Tetravinyltin (2.5 equiv), n-BuLi (5.0 equiv), rt to −78 °C, 2 h, −40 °C, 0.5 h, THF/Et O, then I (5.1 equiv), −78 °C, then
(2.0 equiv), Isopropenylmagnesium
(2.2
3
4
2
3
1
2
2
NaOMe (7.0 equiv), −78 °C to rt, 92%; f) DMP (2.0 equiv), Pyridine (6.0 equiv), DCM, rt, 95%; g) LDA (1.1 equiv), 5 (1.2 equiv), THF,
−78 °C; h) DBU (4.0 equiv), toluene, 40 °C, 67% (2 steps); i) DBU (1.0 equiv), toluene, 100 °C, 92%, 99% brsm; j) o-DCB, mW, 200 °C;
3
, 52%, 74% brsm; 17, 8%; 18, 4%; k) TPP (0.01 equiv), air (1 atm), CHCl
atm), MeOH, rt, 99%; m) Burgess reagent (1.1 equiv), toluene/DCM, −40 to 40 °C, 60%, 75% brsm; n) DIBAL-H (3.0 equiv), DCM, −78 °C,
8%; o) TPP (0.01 equiv), O (1 atm), CDCl , rt; 1, 57%; 22b, 10%. IpcBH , monoisopinocampheylborane; DMP, Dess-Martin periodinane;
LDA, lithium diisopropylamide; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; o-DCB, 1,2-dichlorobenzene; TPP, meso-tetraphenylporphin.
3 2
, 0 °C, 87%; l) Pd/C (0.25 equiv), NaOAc (0.3 equiv), H (1
8
2
3
2
The rigid and strained skeleton of 20 allowed for the selective
elimination of the C3 hydroxyl group, delivering 21 in 60% yield
were then subjected to the singlet oxygen ene reaction. We took
advantage of the solvent deuterium isotope effect to improve the
3
,4
2,3
16
with 6:1 selectivity for ∆ unsaturation (21a) over ∆ (21b). By
varying the elimination conditions, different ratios of 21a and 21b
could be obtained, with one extreme affording only 21b (Table S3).
DIBAL reduction of 21 afforded diols 22a/b in high yield, which
efficiency of the last step, completing (−)-vinigrol (1) on a gram
scale reaction (57% isolation yield), whereas 22b was not oxidized
and recovered after the reaction. All of the analytic data for the
synthesized sample of 1 were consistent with those reported in the
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literature (Table S4).1,5 Besides 1, 4, 10, 23, 24, 25 and 26, the
structures of 11, 17 and 18 were also determined by the X-ray
diffraction of corresponding derivatives (see SI).
(1) Uchida, I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto, M.; Tada,
T.; Koda, S.; Morimto, Y. The structure of vinigrol, a novel diterpenoid
with antihypertensive and platelet aggregation-inhibitory activities. J. Org.
Chem. 1987, 52, 5292−5293.
1
2
3
4
5
6
7
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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6
In summary, we have developed a concise and scalable synthesis
to accomplish (−)-vinigrol. Each step of this route has been
optimized and validated on a gram-scale reaction whereas all the
reagents shown in Scheme 1 were commercially available. But the
synthetic approach is not without flaw. Even if the efficiency of our
approach in terms of the overall steps is high (20 steps from S-
limonene), the overall yield (1.4%) is lower than that of Baran’s for
racemic vinigrol (2.7%). If (+)-vinigrol is required, (R)-(+)-
limonene would be needed. Nonetheless, our new strategy enabled
the execution of carefully orchestrated transformations to construct
such a strained framework and uniquely substituted stereogenic
centers without the use of protecting groups. The investigation of
the biological activities of (−)-vinigrol are ongoing, which will be
reported in due course together with the evolution of our synthetic
strategies.
(
2) (a) Ando, T.; Tsurumi, Y.; Ohata, N.; Uchida, I.; Yoshida, K.;
Okuhara, M. Vinigrol, a novel antihypertensive and platelet aggregation
inhibitory agent produced by a fungus, Vigaria nigra I. Taxonomy,
fermentation, isolation, physicochemical and biological properties. J.
Antibiot. 1988, 41, 25−30. (b) Ando, T.; Yoshida, K.; Okuhara, M. Vinigrol,
a novel antihypertensive and platelet aggregation inhibitory agent produced
by a fungus, Vigaria nigra II. Pharmacological characteristics. J. Antibiot.
1
988, 41, 31−35.
3) Norris, D. B.; Depledge, P.; Jackson, A. P. Tumor necrosis factor
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a
(
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9
0
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9
0
1
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4
5
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7
8
9
0
antagonist. PCT Int. Appl. WO 91/07953, 1991.
(4) (a) Tessier, G.; Barriault, L. The conquest of vinigrol. Creativity,
frustrations, and hope. Org. Prep. Proced. Int. 2007, 37, 313−353. (b)
Huters, A. D.; Garg, N. K. Synthetic studies inspired by vinigrol. Chem. -
Eur. J. 2010, 16, 8586−8595. (c) Lu, J.-Y.; Hall, D. G. Fragmentation
enables complexity in the first total synthesis of vinigrol. Angew. Chem.,
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approaches and syntheses of vinigrol, a unique diterpenoid. Tetrahedron
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015, 71, 3775−3793. (e) Betkekar, V. V.; Kaliappan, K. P. Strategic
innovations for the synthesis of vinigrol. Tetrahedron Lett. 2018, 59,
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5) (a) Maimone, T. J.; Shi, J.; Ashida, S.; Baran, P. S. Total synthesis of
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
2
(
vinigrol. J. Am. Chem. Soc. 2009, 131, 17066−17067. (b) Poulin, J.; Grise-
Bard, C. M.; Barriault, L. A formal synthesis of vinigrol. Angew. Chem.,
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Experimental procedures and spectral data for all new
compounds (PDF)
8
X-ray crystallographic data for (−)-1 (CIF)
X-ray crystallographic data for (+)-4 (CIF)
X-ray crystallographic data for (+)-10 (CIF)
X-ray crystallographic data for (+)-23 (CIF)
X-ray crystallographic data for (+)-24 (CIF)
X-ray crystallographic data for (−)-25 (CIF)
X-ray crystallographic data for (−)-26 (CIF)
X-ray crystallographic data for (−)-S4 (CIF)
X-ray crystallographic data for (+)-S5 (CIF)
X-ray crystallographic data for (+)-S6 (CIF)
X-ray crystallographic data for (−)-S7 (CIF)
1
AUTHOR INFORMATION
Corresponding Author
4
551−4554.
10) Still, W. C.; Galynker, I. Chemical consequences of conformation
*tuopingluo@pku.edu.cn
(
in macrocyclic compounds: an effective approach to remote asymmetric
induction. Tetrahedron 1981, 37, 3981−3996.
Notes
(11) Mehta, G.; Acharyulu, P. V. R. Terpenes to terpenes. Stereo- and
The authors declare the following competing financial interest(s):
T. L., Y. X. and L. X. are inventors on patent application
ZL201811276421.1 submitted by Peking University that covers the
synthesis of (−)-vinigrol and related analogs.
enantio-selective synthesis of (+)-α-elemene and a short route to a versatile
diquinane chiron. J. Chem. Soc., Chem. Commun. 1994, 2759−2760.
(12) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. Reactions of carbonyl compounds with Grignard reagents in the
presence of cerium chloride. J. Am. Chem. Soc. 1989, 111, 4392−4398. (b)
Evans, D. A.; Andrews, G. C. Allylic sulfoxides: useful intermediates in
organic synthesis. Acc. Chem. Res. 1974, 7, 147−155.
ACKNOWLEDGMENT
This work was supported by generous start-up funds from the
National “Young 1000 Talents Plan” Program, College of
Chemistry and Molecular Engineering, Peking University and
Peking-Tsinghua Center for Life Sciences, the National Science
Foundation of China (Grant No. 21472003, 31521004, 21673011
and 21822101) and Ministry of Science and Technology (Grant No.
(13) Seeman, J. I. Effect of conformational change on reactivity in
organic chemistry. Evaluations, applications, and extensions of Curtin-
Hammett Winstein-Holness kinetics. Chem. Rev. 1983, 83, 83−134.
(
14) Rarig, R.-A. F.; Scheideman, M.; Vedejs, E. Oxygen-directed
intramolecular hydroboration. J. Am. Chem. Soc. 2008, 130, 9182−9183.
15) (a) Brown, H. C.; Mandal, A. K.; Yoon, N. M.; Singaram, B.;
(
Schwier, J. R.; Jadhav, P. K. Organoboranes. 27. Exploration of synthetic
procedures for the preparation of monoisopinocampheylborane. J. Org.
Chem. 1982, 47, 5069-5074. (b) Brown, H. C.; Jadhav, P. K.; Mandal, A.
K. Hydroboration. 62. Monoisopinocampheylborane; an excellent chiral
hydroborating agent for trans-disubstituted and trisubstituted alkenes.
2
017YFA0104000). We thank Dr. Fuling Yin, Dr. Jie Su, Dr.
Nengdong Wang, Prof. Wenxiong Zhang (Peking University) and
Dr. Xiang Hao (ICCAS) for their help in analyzing the X-ray
crystallography data, Dr. Yanlong Jiang (Peking University) for
helpful discussions and support from the High-performance
Computing Platform of Peking University.
Evidence for
a strong steric dependence in such asymmetric
hydroborations. J. Org. Chem. 1982, 47, 5074−5083. (c) Meyer, D.;
Renaud, P. Enantioselective hydroazidation of trisubstituted non-activated
alkenes. Angew. Chem., Int. Ed. 2017, 56, 10858−10861.
(16) Ogilby, P. R.; Foote, C. S. Chemistry of singlet oxygen. 34.
REFERENCES
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Unexpected solvent deuterium isotope effects on the lifetime of singlet
1
g
molecular oxygen ( ∆ ). J. Am. Chem. Soc. 1981, 103, 1219−1221.
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•
Anionic oxy-Cope Rearrangement
• Hydroboration / Zweifel Reaction
•
Transannular IMDA
Li
MgBr O
MeO C
CO Me
2
2
OH
H OH
OH
O O
OMe
15 steps
[gram scale]
(–)-Vinigrol
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