Protecting-Group-Free Syntheses of ent-Kaurane Diterpenoids: [3+2+1] Cycloaddition/Cycloalkenylation Approach

Article abstract of DOI:10.1021/jacs.9b13722

The Yu's Rh-catalyzed [3+2+1] cycloaddition followed by a Pd-mediated 5-endo cycloalkenylation is shown to be a general and powerful approach for efficient construction of the tetracyclic core structure of ent-kaurane diterpenoids. The utility of this strategy was further demonstrated by concise and protecting-group-free total syntheses of ent-1α-hydroxykauran-12-one, 12-oxo-9,11-dehydrokaurene, and 12α-hydroxy-9,11-dehydrokaurene.

Full text of DOI:10.1021/jacs.9b13722

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Protecting-group-free syntheses of ent-kaurane diterpenoids:
3+2+1] cycloaddition/cycloalkenylation approach
[
Jin Wang, Benke Hong, Dachao Hu, Yuichiro Kadonaga, Ruyao Tang, and Xiaoguang Lei
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13722 • Publication Date (Web): 22 Jan 2020
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Protecting-group-free syntheses of ent-kaurane diterpenoids: [3+2+1]
cycloaddition/cycloalkenylation approach
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Jin Wang, Benke Hong,†,‡, Dachao Hu, Yuichiro Kadonaga, Ruyao Tang, and Xiaoguang
†
,‡,
†,‡
†,‡
†,‡
*,†,‡,§
Lei
†Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engi-
neering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871,
China
‡Department of Chemical Biology, Synthetic and Functional Biomolecules Center, Peking University, Beijing 100871,
China
§Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Supporting Information Placeholder
that the ent-kaurane diterpenoids possess many promising
ABSTRACT: The Rh-catalyzed [3+2+1] cycloaddition fol-
lowed by a Pd-mediated 5-endo cycloalkenylation is shown to
be a general and powerful approach for efficient construction
of tetracyclic core structure of ent-kaurane diterpenoids. The
utility of this strategy was further demonstrated by concise
and protecting-group-free total syntheses of ent-1α-
hydroxykauran-12-one, 12-oxo-9,11-dehydrokaurene and
biological activities such as anticancer, antifungal and antivi-
1
ral activities. Their intriguing structures as well as potential
biological activities have attracted tremendous attention from
the synthetic community, culminated in numerous elegant
3
-5
syntheses of their core structures and target molecules.
Most of the reported methods required multistep reactions to
construct the tetracyclic ent-kaurene skeleton, especially the
1
2α-hydroxy-9,11-dehydrokaurene.
3
[3.2.1] bicyclic moiety.
Herein, we report a concise and general synthetic approach
to assemble the ent-kaurane diterpenoids skeleton. As
demonstrated in Scheme 1, we envisaged that the [3.2.1] bi-
cyclic motif of the tetracyclic skeleton of ent-kauranoids can
be accessed from 7 via a palladium-mediated cycloalkenyla-
tion. The 6/6/6 tricyclic ring system of enone 7 could be effi-
ciently accessed using the Rh-catalyzed [3 + 2 + 1] cycloaddi-
tion of 1-yne-vinylcyclopropane (VCP) precursor 8 and CO
The ent-kaurane diterpenoids are a unique family of tetra-
cyclic natural products and more than 1000 members have
been isolated to date from different plants species, especially
1
from Isodon genus. These natural products including ent-
2
a
2b
kaurene (1), ent-1α-hydroxykauran-12-one (2), steviol
2c
(
1
3), 12β-hydroxy-1α,6α-diacetoxy-ent-kaura-9(11),16-dien-
5-one (4),2d adenanthin (5), oridonin (6), feature a bicy-
6
2e
2f
developed by Yu’s group. Using this two-step sequence, ent-
kauranoid skeleton bearing different functional groups could
clo[3.2.1]octene ring system with different oxidation state at
the key tetracyclic skeleton (Scheme 1). It has been found
be
constructed
efficiently
from
various
1-yne-
vinylcyclopropane (VCP) precursors. If successful, this strate-
gy could not only enable the total synthesis of ent-kaurane
diterpenoids but also facilitate the efficient preparation of
diverse natural product analogues for further biological study.
The key precursor 8 might be derived from the commercially
available enone 9 via Michael addition and alkynylation.
To explore the feasibility of the proposed Rh-catalyzed
[3+2+1] cycloaddition/Pd-mediated alkenylation sequence,
8
a was chosen as a model substrate, which was accessed from
7
commercial enone 9 through Michael addition and alkynyla-
tion in 2 steps. To our delight, the key Rh(I)-catalyzed [3+2+1]
8
cycloaddition of 8a and CO occurred smoothly with 10 mol%
rhodium dimer catalyst under 0.2 atm CO atmosphere at 80 °C.
The reaction afforded 7a in 49% combined yield with a dia-
stereomeric ratio of about 2.1:1 (Table 1, entry 1). Single-
crystal X-ray diffraction analysis confirmed the desired stere-
ochemistry of the major product (see Supporting Information).
A brief screening of solvents indicated that toluene gave the
best diastereomeric ratio (Table 1, entries 1, 3, 4). Subsequent
screenings revealed that higher CO pressure facilitated the
Scheme 1. Representative ent-kauranoids and retro-
synthetic analysis of the core tetracyclic skeleton
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Table 1. Optimization of Rh-catalyzed [3+2+1] cy-
Pd(OAc) in dioxane at 23 C, the alkenylation occurred effi-
Page 2 of 6
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cloaddition
a
ciently to give 14a in 75% isolated yield. The structure of 14a
was unambiguously determined by X-ray crystallographic
analysis (see Supporting Information). An attempt to conduct
the reaction under catalytic amount of Pd(OAc)
found to be unsuccessful (Table 2, entry 7). Additionally, con-
trol experiment showed Pd(OAc) is essential for the for-
2
under O was
2
2
mation of 16 (Table 2, entry 8). The structure of 16 was as-
signed by two-dimensional NMR spectroscopy and further
confirmed by single-crystal X-ray diffraction analysis of the
TIPS deprotection product 16’ (see Supporting Information).
To the best of our knowledge, this is the first example of a Pd-
mediated oxidative cyclization of a 5-vinyl silyl enol ether to
generate the [3.2.1] ring system.
With the optimized protocol in hand, we began to explore
the substrate scope of this [3+2+1] cycloaddi-
tion/cycloalkenylation approach (Scheme 2). We first tested
different 1-yne-vinylcyclopropane (VCP) precursors (Scheme
2b). The oxidation state of C-1 did not affect the reaction effi-
ciency of the [3+2+1] cycloaddition (7b). Various vinylcyclo-
propanes with different substitutions at vinyl group were
converted into the corresponding products in moderate yields
with acceptable diastereomeric ratio (7c-7f). Substrate 7g
with two free hydroxyl groups was also compatible, which
showed this transformation could be applied to the synthesis
of highly oxidized skeletons. However, the substrate scope
studies also revealed neither electron withdrawing group nor
amino group were tolerated for this reaction (7h, 7i).
0
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9
0
o
b
c
entry
CO(atm)
solvent
toluene
toluene
dioxane
DCE
T ( C)
Yield (d.r. )
49% (2.1:1)
47% (1.9:1)
51% (1.2:1)
25% (1.1:1)
42% (5.0:1)
28% (10.7:1)
52% (2.2:1)
52% (5.8:1)
1
0.2
0.2
0.2
0.2
1
80
80
80
80
80
60
100
80
2d
3
4
5
toluene
toluene
toluene
toluene
6
1
7
8e
1
1
aUnless state otherwise, the reactions were performed with
a (0.055 mmol) and 10 mol% [Rh(CO)
under a balloon of CO for 18 h. Isolated combined yields.
Determined by H-NMR analysis. [Rh(COD)
. e20 mol% [Rh(CO)
instead of [Rh(CO) Cl] Cl]
stead of 10 m% [Rh(CO) Cl]
8
2
Cl] in solvent (1 mL)
2
b
Next, the scope of the Pd-mediated cycloalkenylation wa-
salso studied (Scheme 2c). To our delight, ent-kaurane skelet-
c
1
d
2
Cl]
2
2
was used
was used in-
2
2
2
Table 2. Optimization of Pd-mediated cycloalkenyla-
2
2
a
tion
formation of the desired diastereomer (Table 1, entry 5) while
changing temperature did not improve the reaction (Table 1,
entries 6,7). Upon increasing the catalyst loading, 7a was
generated in 52% combined yield with a diastereomeric ratio
of 5.8:1. It is noteworthy that two rings, three carbon-carbon
bonds and one quaternary stereogenic center were created in
a single operation by this remarkable [3+2+1] cycloaddition.
With 7a in hand, we then further tested the Pd-mediated
cycloalkenylation (Table 2). Although this transformation has
been well established for 5-allyl silyl enol ether precursor
we anticipated that it might be more challenging for 7:
to the best of our knowledge, there were no reported exam-
ples of transition metal-mediated 5-endo oxidative cyclization
for 5-vinyl silyl enol ether precursors. Indeed, commonly
used TMS and TBS silyl enol ether only led to the removal of
9
,10,4j
s,
conversionb
1
1
en
try
Pd
T
(oC)
solvent
source
14a
15
16
8%
0%
0%
33%
13%
9%
0%
0%
silyl group in the presence of Pd(OAc) . Therefore, the more
2
1
2
3
Pd(OAc)
2
50
50
50
50
50
23
23
50
DMSO
DMSO
24% 65%
11% 89%
stable TIPS enol ether 13 was prepared by deprotonation
with DBU and trapping with TIPSOTf. Pleasingly, the direct
subjection of 13 to stoichiometric Pd(OAc)
PdCl
2
o
2
in DMSO at 50 C
Pd(TFA)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
-
2
2
2
2
2
DMSO
0%
63%
furnished tetracycle 14a, albeit in poor yield (Table 2, entry 1).
After careful analysis, we found the byproducts of the reaction
were mainly Saegusa oxidation product 15 along with trace
intramolecular Diels-Alder product 16. In an effort to further
improve the yield, a thorough survey of reaction parameters
was conducted. There was no significant improvement with
various palladium sources (Table 2, entries 2, 3). Upon switch-
ing the solvent to dioxane, the conversion was improved to
4
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
42% 12%
50% 23%
5c
6c
7d
8
79%
0%
7%
0%
0%
0%
4
4
2% due to the inhibition of Saegusa oxidation (Table 2, entry
). Further improvement was achieved by increasing the
Reaction conditions: 7a (6.7 μmol), DBU (2 equiv), TIPSOTf
(1.8 equiv), CH
2
Cl
2
b
(0.3 mL), 3 h then Pd salt (1 equiv), solvent
1
c
equivalents of Pd(OAc)
2
to accelerate the alkenylation process
(0.3 mL), 16 h. Determined by HNMR analysis. 5 equiv
d
while decreasing the reaction temperature to reduce the
Diels-Alder product (entries 5, 6). Fortunately, upon treat-
ment of 7a with DBU and TIPSOTf followed by 5 equivalents
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
was used instead of 1 equiv Pd(OAc)
was used under a balloon of O
2
. 0.2 equiv
2
instead of 1 equiv
.
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Scheme 2. Evaluation of the substrate scope
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3
4
5
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7
8
9
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0
on with different oxidation state on the A ring and C-17 could
be generated in high yields (14a-c). Interestingly, we ob-
served that reaction of the diastereomer of 7a smoothly af-
forded the ent-beyerene skeleton (14d). These results showed
that our 2-step sequence could be applied to generate diverse
ent-kaurane natural product-like skeletons.
dehydration to isomerize the C15-C16 double bond to pro-
vide terminal alkene 17 in 43% yield. Reduction of 17 with
o
NaBH
4
in MeOH at -78 C led to the formation of two isomers
18 and 19 in 32% and 60% yield respectively. Unfortunately,
hydrogenation of the terminal double bond in 19 only provid-
ed the undesired C16 stereochemistry, due to the steric acces-
1
3
With this efficient route to ent-kaurane skeletons in hand,
we turned our attention to the synthetic utility of our strategy.
ent-1α-Hydroxykauran-12-one (2) was isolated from New
Zealand Liverworts Paraschistochila pinnatifolia in 1997 and
sibility of the β face. To overcome the substrate-controlled
selectivity, hydroxyl directed reduction was investigated.
Face-selective 1,2-reduction of 19 with NaBH
4
and CeCl af-
3
forded C12 β-OH 20 as a single diastereomer in 89% yield.
Alcohol 20 could also be obtained via one-pot reduction from
17 in 62% yield (See Supporting Information). After extensive
condition screenings (see Supporting Information), we were
pleased to find that the selective hydroxyl directed reduction
2b
showed anticancer activity. This natural product could be
readily prepared from 14a, which was synthesized in a 4-step
synthetic route (Michael addition, alkynylation, [3+2+1] cy-
cloaddition and cycloalkenylation) (Scheme 3). Obviously, the
primary challenge of the synthesis is the selective reduction of
the C15-C16 double bond to give the desired C16 stero-
chemistry. Indeed, initial attempts to reduce (hydrogenation)
of 20 was achieved with Raney Ni and H to afford the desired
2
1
4
C16 stereochemistry. Subsequent selective oxidation of the
allylic alcohol delivered enone 21 in 75% yield. The structure
of 21 was determined by two-dimensional NMR spectroscopy
and further confirmed by single-crystal X-ray diffraction anal-
ysis. Finally, reduction of 21 using Birch conditions
4
m
or isomerize (Schenck ene reaction) the trisubstituted dou-
ble bond all failed (see Supporting Information). Alternatively,
12
14a was subjected to Mukaiyama hydration
and
Scheme 3. Concise total syntheses of ent-kaurane diterpenoids and structure revision
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Page 4 of 6
(
Li/ NH
3
, EtOH) enabled the first total synthesis of ent-1α-
tional Natural Science Foundation of China (21625201,
21961142010, 91853202, 21661140001 and 21521003); the
National Key Research and Development Program of China
(2017YFA0505200); and the Beijing Outstanding Young Sci-
entist Program (BJJWZYJH01201910001001) is grateful
acknowledged.
1
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9
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hydroxykauran-12-one (2) in 10 steps from commercially
available enone 9.
Moreover, Barton–McCombie deoxygenation5o of 18 deliv-
ered 12-oxo-9,11-dehydrokaurene (22), an ent-kaurene iso-
lated from Vellozia caputardeae. Luche reduction of 22 fur-
nished the reported structure of 12β-hydroxy-9,11-
dehydrokaurene 23. Unfortunately, the proton NMR data of
our synthetic sample 23 did not match with the reported data
for the natural product. Careful analysis of the NMR data
showed significant difference on the chemical shift of H-12
1
5
15
REFERENCES
(
1) (a) García, P. A.; De Oliveira, A. B.; Batista, R. Occurrence, Biological
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(
Δδ = 0.41 ppm), suggesting the stereochemistry of 12-OH in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
natural product might be α configuration. To our delight,
treatment of 23 with 2M HCl at 50 C gave a mixture of unre-
acted 23 and the desired 12α-hydroxy-9,11-dehydrokaurene
2
o
4 (1:5, 70% isolated yield for 24). 24 exhibited the same
(2) (a) Quitt, P.; Mosettig, E.; Cambie, R. C.; Rutledge, P. S.; Briggs, L.H.
Optical Rotatory Dispersion Studies. The complete absolute
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proton NMR data compared with the previously reported data
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confirmed by single-crystal X-ray diffraction analysis. There-
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dehydrokaurenene for 24. Additionally, re-subjecting 24 to
the same acidic conditions provided the same mixture of 23
and 24 (1:5), which clearly indicated a carbocation intermedi-
ate was involved in the stereochemistry inversion.
In conclusion, we have developed a convergent and concise
approach for assembling the core structure of ent-kaurane
diterpenoids. The key elements of our strategy include im-
plementation of a rhodium-catalyzed [3+2+1] cycloaddition to
furnish the B ring and C ring in one step as well as a palladi-
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construct the key [3.2.1] ring system. This synthetic strategy
has enabled the first protecting-group free total syntheses of
(
b) Lorimer, S. D.; Perry, N. B.; Burgess, E. J.; Foster, L. M. 1-
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ent-1α-hydroxykauran-12-one
(2)
and
12-oxo-9,11-
dehydrokaurene (22) in 10 and 8 steps from enone 9, respec-
tively. Total synthesis and structure revision of 12α-hydroxy-
9,11-dehydrokaurene (24) have also been achieved in 10
steps from enone 9. The present strategy should be applicable
for assembling other ent-kaurane diterpenoids by fine tuning
the [3+2+1] cycloaddition precursor. These investigations are
currently ongoing in our laboratory and will be disclosed in
due course.
(
c) Du, M.; Lei, X. Advanced in the synthesis of kaurane diterpenoids.
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R. A. The total synthesis of dl-kaurene. J. Org. Chem. 1962, 27, 3741-
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kaurene and (±)-atisirene. J. Org. Chem. 1966, 31, 2530-2536. (c) Mori,
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and erythroxydiol A: rearrangements in bicyclooctane compounds.
Tetrahedron 1972, 28, 3217-3226. (d) Ziegler, F. E.; Kloek, J. A. The
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Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.XXXXXXX.
Experimental procedures, product characterization data (PDF)
(
CIF)
AUTHOR INFORMATION
Corresponding Author
xglei@pku.edu.cn
Author Contributions
⁋
These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Prof. Zhi-Xiang Yu for helpful discussion and sugges-
tion on the rhodium-catalyzed [3+2+1] cycloaddition, Dr. Hiu-
chun Lam for proofreading the manuscript. We also thank
Prof. Jie Su for the assistance with X-ray analysis and Prof.
Jiang Zhou for HRMS analysis. Financial support from the Na-
A and (−)-longikaurin E. J. Am. Chem. Soc. 2013, 135, 11764−11767. (k)
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gent route to ent-kaurane diterpenoids: total synthesis of
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