Asymmetric Total Synthesis of (-)-Vinigrol

Article abstract of DOI:10.1021/jacs.9b08983

A new strategy was developed for the asymmetric total synthesis of (-)-vinigrol. The strategy involved a linear sequence of 15 steps from 3-methyl-butanal (14 steps from chloro-dihydrocarvone) and did not need protecting groups. The synthetically challenging 1,5-butanodecahydronaphthalene core was constructed efficiently via a type II intramolecular [5+2] cycloaddition, followed by a unique ring-contraction cascade.

Full text of DOI:10.1021/jacs.9b08983

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Asymmetric Total Synthesis of (-)-Vinigrol
Long Min, Xiaohong Lin, and Chuang-Chuang Li
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Asymmetric Total Synthesis of (−)-Vinigrol
†
†
,†
Long Min, Xiaohong Lin, and Chuang-Chuang Li*
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†Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China
Supporting Information Placeholder
work was a landmark achievement in vinigrol synthesis. In 2012,
ABSTRACT: A new strategy was developed for the
asymmetric total synthesis of (−)-vinigrol. The strategy
involved a linear sequence of 15 steps from 3-methyl-butanal
Barriault and co-workers reported an elegant formal synthesis of
()-vinigrol that involved a notable type II intramolecular Diels–
7
a
Alder reaction. In 2013, Njardarson and co-workers reported
another elegant total synthesis of ()-vinigrol, with remarkable
oxidative dearomatization and intramolecular Diels–Alder
(
14 steps from chloro-dihydrocarvone) and did not need
protecting groups. The synthetically challenging
,5-butanodecahydronaphthalene core was constructed
8
reactions as the key steps. Very recently, Luo and co-workers
reported the first asymmetric total synthesis of (−)-vinigrol via a
well-designed transannular Diels–Alder reaction as the key step.
In all of these noteworthy achievements the Diels–Alder reaction
was a crucial element in the synthetic strategy of vinigrol.
However, the development of a new strategy for the synthesis of 1
and its analogues is still desirable. Herein, we wish to describe the
asymmetric total synthesis of (−)-vinigrol using a type II
intramolecular [5+2] cycloaddition as a new strategy.
1
efficiently via a type II intramolecular [5+2] cycloaddition,
followed by a unique ring-contraction cascade.
9
(
−)-Vinigrol (1, Fig. 1), a unique, compact and biologically
significant diterpene, was isolated by Hashimoto and co-workers
1
a
in 1987 from the fungal strain Virgaria nigra F-5408.
Structurally, (−)-vinigrol has an unprecedented and highly rigid
,5-butanodecahydronaphthalene core with eight contiguous
1
stereocenters. Notably, the strained bicyclo[5.3.1]undecane ring
Scheme 1 shows the bond disconnections in (−)-vinigrol that
led to the concise strategy used in our synthetic program. It was
envisioned that (−)-1 could be generated from the tricyclic core 2
through a series of functional group transformations. Compound 2,
which has a 1,5-butanodecahydronaphthalene core, would be
system in 1 is an unusual bridged framework that is also present
2
in the well-known terpene taxol. Vinigrol synthesis is therefore a
formidable challenge. Vinigrol displays a number of promising
1
biological activities, e.g., it inhibits human platelet aggregation
1
b
(
(
IC50 = 52 nM) and is an antagonist of tumor necrosis factor
TNF-α).
synthesized from
3
or its derivative by ring-contraction
1d
10
reactions. In turn, the bridged framework 3 with a strained
11
bridgehead double bond
throughout) could be synthesized diastereoselectively from 4 by a
type II intramolecular [5+2] cycloaddition.
at C4–C4a (vinigrol numbering
1
2,13
Compound 4 can
be derived from 5 through an Achmatowicz reaction. Lastly,
compound 5 can be prepared from readily available bromide 6
and commercially available chloro-dihydrocarvone (7) as the
14
chiral pool via several simple functional group transformations.
Scheme 1. Retrosynthetic analysis of (−)-vinigrol (1)
Figure 1. Structural features of (−)-vinigrol (1).
A combination of the complex structure and impressive
pharmacological properties of vinigrol has prompted significant
interest from the synthetic community for more than three
3
,4,5
decades.
In 2009, Baran and co-workers completed the first
and most efficient total synthesis of ()-vinigrol, with Diels–
6
Alder reactions and Grob fragmentation as the key steps. This
The synthesis began with an asymmetric preparation of
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compound 5 (Scheme 2). The starting material 7 was treated with
bridged skeletons such as 3. However, the presence of the
additional C9–C18 double bond in the bicyclo[5.4.1]dodecane or
bicyclo[5.3.1]undecane ring system of 3 (highlighted in red in
Scheme 2), which has not previously been reported, increases the
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5
6
LiHMDS and 2-chloroacetyl chloride (8) in THF, followed by
reduction of the resulting furanone with DIBAL to give furan 9 in
1
5
an overall yield of 40% (20 g scale). The bromide 6 was
1
2
produced on a large scale by organocatalytic enantioselective
strain in the molecule. To the best of our knowledge, there are
no reports in the literature to date pertaining to intramolecular
[5+2] cycloaddition reactions (a) of aliphatic ring-fused
oxidopyrylium ylides such as 4b or (b) to construct

‑hydroxymethylation of 3-methyl-butanal,15c followed by Wittig
olefination and brominating. Treatment of chloride 9 with a
Grignard reagent formed from bromide 6 in the presence of CuI in
1
2,13
THF gave compound 10 in 94% yield (30
g
scale).
eight-membered ring systems in natural product synthesis.
Hydroxymethylation at the α position of the furan ring in 10 with
n-BuLi and formaldehyde provided 5 in 82% yield (20 g scale).
Oxidative rearrangement of 15 with VO(acac) and TBHP in
2
DCM gave 4 in 92% yield (10 g scale), which was the precursor
for the type II intramolecular [5+2] cycloaddition.
Furthermore, the formation of a C8a quaternary stereogenic
bridgehead carbon center in a bridged ring system in 3 makes this
reaction particularly challenging.
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After extensive experimentation (Scheme 2), we found that
compound 4a with a trifluoroethoxyl group at C8a was a good
and stable precursor of the oxidopyrylium ylide 4b for the type II
intramolecular [5+2] cycloaddition. Compound 4a was prepared
Scheme 2. Asymmetric Synthesis of 3
1
2b
from 4 with Boc anhydride in the presence of DMAP, followed
by trifluoroethoxylation with 2,2,2-trifluoroethanol (TFE) in the
1
6
presence of AgSbF
6
in one pot (85% yield, 9 g scale). Under
optimized conditions (see the Supporting Information (SI) for
details), the type II intramolecular [5+2] cycloaddition of 4a was
realized using a catalytic amount of hydroquinidine (0.2 equiv.) as
a base with heating, giving the [6–8–7] tricyclic core-containing 3
in 40% yield (1 g scale). This was confirmed by X-ray
crystallography. To the best of our knowledge, this work
represents the first reported example of the use of
a
trifluoroethoxyl leaving group to generate the oxidopyrylium
1
3
ylide in a [5+2] cycloaddition. This route provided facile access
to a total of 10 g of 3 (see SI for details), which highlights the
robust nature of the chemistry. It is worth noting that our type II
intramolecular [5+2] cycloaddition enabled efficient construction
of the taxol-like bicyclo[5.3.1]undecane framework in 3.
Furthermore, this reaction enabled the concise, diastereoselective,
and direct installation of the C8a oxyl and C8 methyl groups,
which has previously proved to be a difficult task because of their
3x,4f,6,7a,8a
cis orientation.
With compound 3 in hand, we investigated our proposed
synthesis of the 1,5-butanodecahydronaphthalene skeleton of
vinigrol by a ring-contraction reaction (Scheme 3). We initially
1
7
tried a Wolff rearrangement to obtain 11c. It was expected that
selective cleavage of the C3–O bond and installation of a diazo
group at C3 would give the precursor 11b for the Wolff
rearrangement. Although a wide variety of conditions were
12c
screened (i.e., SmI
2
, Li/NH
3
, Na/NH
3
, and Li/EtNH
2
), none of
these reactions afforded any of the desired product 11a by
selective cleavage of the C3–O bond. Extensive experimentation
suggested that diketone 13 would be a good precursor for the
1
7e
preparation of the α-keto diazo compound.
chemoselective hydrogenation of the C9–C18 olefin in 3 with
Wilkinson’s catalyst employing 1000 psi of H in PhMe, followed
by diastereoselective hydroboration–oxidation of the enone with
BH •THF in a one-pot sequence, gave diol 12 in an overall yield
of 71% (1.2 g scale). Subsequent treatment of 12 with
-iodoxybenzoic acid (IBX, 2.0 equiv) in DMSO at 80 °C gave
the unexpected product 14 (30%), certain amount of
Therefore,
2
3
2
a
mono-ketone product S4 (see SI, 30%), the surprising
ring-contraction product 15 (10%), and some unidentified
byproducts. However, none of the expected 13 was isolated. We
reasoned that formation of the 1,5-butanodecahydronaphthalene
core 15 probably occurred via the following pathway (Scheme 4).
In the presence of IBX in DMSO at 80 °C, diketone 13, produced
from 12, was spontaneously oxidized to C4a-hydroxyl diketone
1
4. Intramolecular attack of the C4a-hydroxyl group in 14 on the
1
8
less hindered carbonyl group would yield oxetanone 14a, which
could undergo rearrangement of the C3 to the C4-carbonyl group
to give unstable -lactone 14b, which can be isolated and whose
structure was determined by 2D-NMR, MS and IR (see SI for
details). Subsequent spontaneous decarboxylation of the
The key step of the type II intramolecular [5+2] cycloaddition
1
2a
reaction was developed by our group in 2014. The reaction
involves the oxidopyrylium ylide and a simple alkene such as 4b.
It enables the efficient, diastereoselective, and direct construction
of various highly functionalized and synthetically challenging
1
9
-lactone
gave enol 14c, which underwent keto–enol
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tautomerization to generate the desired product 15
use of this reaction in total synthesis, and a mechanistic study, are
currently underway in our laboratory.
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6
7
8
9
diastereoselectively. We further optimized the reaction conditions
and finally identified the following optimum protocol. When 12
was treated with IBX (5.0 equiv.) in DMSO at 80 °C for 2 h,
Next, treatment of 15 with SmI
afforded compound 2 in 85% yield. The ketone 2 was treated with
LiHDMS and Mander’s reagent (methyl cyanoformate) in Et O,
2 2
(2.2 equiv.) in THF/H O
followed by quenching with NaHCO
3
/Na
2
S
2
O
3
in one pot, 15 was
2
obtained in 72% isolated yield (600 mg scale). Under the similar
conditions, the isolated 14 or 14b reacted further to give 15 in
good yield, respectively.
followed by phenylselenylation with PhSeBr and spontaneous
elimination to give enone-ester 16 in 60% yield (77% yield
21
based on recovered starting material). This was confirmed by
2
2
X-ray crystallography. Then, we tried to reduce the ketone and
ester groups of 16 diastereoselectively and chemoselectively in
one step, to obtain (−)-1. However, it was found that this was a
very challenging task after extensive experimentation.
Interestingly, treatment of 16 with DIBAL in the presence of
LDA in THF gave C4-epi-vinigrol 17 (5%) and compound 18
Scheme 3. Asymmetric Total Synthesis of (−)-Vinigrol
1
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(
63%) (see SI for more details). Finally, a slightly modified
9
,23
version of a previous procedure
for the singlet oxygen–ene
reaction of 18 was used, completing the asymmetric total
synthesis of (–)-1 in 60% yield.
Scheme 4. Proposed pathway from 13 to 15
In summary, we have achieved the concise asymmetric total
2
4
synthesis of (−)-vinigrol (1) via a linear sequence of 15 steps
from 3-methyl-butanal (14 steps from chloro-dihydrocarvone),
2
5
without the need for protecting groups.
Notably, the
synthetically challenging 1,5-butanodecahydronaphthalene core
of (−)-1 was synthesized efficiently via a type II intramolecular
[5+2] cycloaddition of a new precursor, 4a, using a catalytic
amount of base, followed by unique IBX-induced
a
decarboxylative ring-contraction cascade. To the best of our
knowledge, this work represents the first example of an
intramolecular [5+2] cycloaddition to construct eight-membered
ring systems in natural product synthesis. Furthermore, the eight
contiguous stereocenters, including the challenging C8a oxyl and
C8 methyl groups in a cis orientation, were constructed simply
and diastereoselectively. This new strategy will enable the diverse
synthesis of vinigrol analogues from various analogues of 6 or 7
to facilitate further biological research, which is underway and
will be reported in due course.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedure, and
1
13
H NMR and C NMR spectra, as well as X-ray data information
are available free of charge via the Internet at http://pubs.acs.org.
It is worth noting that there are few reports in the literature
pertaining to this direct ring-contraction reaction of cyclic
AUTHOR INFORMATION
20
1
-hydroxyl-2,3-diones, which could also be precursors for
Corresponding Author
synthesis of α-keto diazo compounds for the Wolff
ccli@sustech.edu.cn
1
7e
rearrangement.
This mild reaction could be an alternative
method for ring contraction in some cases. Further studies of the
ORCID
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Chuang-Chuang Li: 0000-0003-4344-0498
Exploratory studies aimed at a synthesis of vinigrol. 3. Evaluation of a
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of vinigrol. Synthesis of the octalin ring. J. Org. Chem. 2005, 70,
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(
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
8
841−8853. (r) Grisꢀ, C. M.; Tessier, G.; Barriault, L. Synthesis of the
This paper is dedicated to the memory of Professor Gilbert Stork
for his great contribution to the organic chemistry. This work was
supported by the Natural Science Foundation of China (Grant nos.
tricyclic core of vinigrol via an intramolecular Diels−Alder reaction. Org.
Lett. 2007, 9, 1545−1548. (s) Souweha, M. S.; Enright, G. D.; Fallis, A. G.
Vinigrol:ꢁ a compact, diene-transmissive Diels−Alder strategy to the
tricyclic core. Org. Lett. 2007, 9, 5163−5166. (t) Maimone, T. J.; Voica,
A.-F.; Baran, P. S. A concise approach to vinigrol. Angew. Chem., Int. Ed.
2008, 47, 3054–3056. (u) Morton, J. G. M.; Kwon, L. D.; Freeman, J. D.;
Njardarson, J. T. Thieme chemistry journal awardees − where are they
now? Efforts towards the total synthesis of vinigrol. Synlett 2009, 23−27.
2
1402083, 21502087 and 21522204) and the Shenzhen Science
and Technology Innovation Committee (Grant nos.
JCYJ20170412152454807 and JSGG20160301103446375). We
would also like to thank Prof. N. Burns at Stanford, Prof. T.
Maimone at Berkeley, Prof. T. Luo and Dr. X. Yu at Peking for
helpful discussions.
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2 2
21)It is worth to mention that a separate oxidation state with H O was
(
not required. This was also found in Maimone’s dissertation of Baran
group, see ref. 4f.
(22)Owing to the small size of the crystal, the intensity of reflections at
high 2theta is too weak to be collected. Thus, its absolute configuration
was not determined.
(23)CD CN was used instead of CDCl3 because it was found that
3
vinigrol was slightly decomposed in CDCl in our case. We also found
3
that the temperature had a great influence on the yield of this reaction.
When the reaction occurred at room temperature (about 30 °C ) in
Shenzhen, the yield is less than 10%.
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Supporting Information for more details
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