In(OTf)3-Catalyzed Cascade Cyclization for Construction of Oxatricyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.8b03461

A highly diastereoselective cascade cyclization reaction has been developed for establishing a series of oxatricyclic compounds using Chan's diene and simple keto alkynal substrates with only 1 mol % of In(OTf)₃ as the catalyst in 82-92% yields. The potential utility of this synthetic strategy has been demonstrated in model studies for the construction the core structures of 1α,8α:4α,5α-diepoxy-4,5-dihydroosmitopsin and cortistatin A.

Full text of DOI:10.1021/acs.orglett.8b03461

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
In(OTf)3‑Catalyzed Cascade Cyclization for Construction of
Oxatricyclic Compounds
Wenli Bao,† Yezi Tao,† Jiangqun Cheng,† Junrong Huang,† Jingming Cao,† Mengxun Zhang,†
Weijian Ye,† Bo Wang,† Yang Li,† Lizhi Zhu,†,‡ and Chi-Sing Lee*,†,§,⊥
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen University Town, Xili, Shenzhen 518055, China
‡Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University,
Health Science Center, Shenzhen 518035, China
§Institute of Research and Continuing Edition (Shenzhen), Hong Kong Baptist University, Industrialization Complex Building,
Shenzhen Virtual University Park, Shenzhen 518000, China
⊥Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR
S
* Supporting Information
ABSTRACT: A highly diastereoselective cascade cyclization
reaction has been developed for establishing a series of
oxatricyclic compounds using Chan’s diene and simple keto
alkynal substrates with only 1 mol % of In(OTf)3 as the catalyst
in 82−92% yields. The potential utility of this synthetic strategy
has been demonstrated in model studies for the construction the
core structures of 1α,8α:4α,5α-diepoxy-4,5-dihydroosmitopsin
and cortistatin A.
natural products) (Figure 1) and corianlactone3 and
8-Oxabicyclo[3.2.1]octane (I) is a common structural motif
found in polycyclic natural products.1−4 When a five- or six-
1α,8α:4α,5α-diepoxy-4,5-dihydroosmitopsin (proposed struc-
ture)4 (III-bearing natural products). Cortistatin A, isolated
membered ring was fused at its C1,2-position, I became 12-
oxatricyclo[7.2.1.01,6]dodecone (II) or 11-oxatricyclo-
from the sponge Corticium simplex by Kobayashi’s group in
[6.2.1.01,5]undecane (III), respectively (Figure 1). These
2006, is particularly a promising lead for further study due to its
highly potent and selective antiproliferative activity against
human umbilical vein endothelial cells (HUVECs, IC50 = 1.8
fused ring systems appeared widely among bioactive natural
products, such as cortistatin A1 and mollfoliagein E2 (II-bearing
nM).1 Due to its unique array of structural features and
remarkable activities against HUVECs,5 this natural product has
attracted tremendous amounts of attention from the scientific
community, including six total and semisyntheses,6 five formal
syntheses,7 and more than 10 model studies for the core
synthesis.8 The 12-oxatricyclo[7.2.1.01,6]dodecone (II) fused
ring system of cortistatin A has been established by a variety of
synthetic strategies,6−8 such as cycloetherification, oxa-Michael
addition, aldol condensation, aza-Prins reaction, [4 + 3]
cycloaddition, radical cyclization, ene-yne metathesis, rearrange-
ment reaction, and oxidative and alkylative dearomatizations.
For the construction of the 11-oxatricyclo[6.2.1.01,5]undecane
(III) fused ring systems,9 different synthetic strategies, such as
[4 + 3] cycloaddition, air oxidation of furan, [3 + 2]
cycloaddition, transannular etherification, oxonium ylide
rearrangement, and radical cyclization, have been employed.
Our group is particularly interested in developing cascade
reactions for establishing 1-oxadecalin-containing natural
products, including phomactin A and cortistatin A. We have
Figure 1. Examples of natural products bearing 12-oxatricyclo-
Received: October 30, 2018
[7.2.1.01,6]dodecone (II) and 11-oxatricyclo[6.2.1.01,5]undecane (III).
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03461
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Organic Letters
Letter
a
previously reported a dual-mode Lewis-acid-mediated inter-
molecular Prins/Conia-ene cascade cyclization for construction
of the 1-oxadeclin fused ring system (Scheme 1, eq 1) and
Table 1. Cascade Cyclization of 2a and Chan’s Diene
Scheme 1. Our Previous Work (1) and Strategy of This Work
(2)
b
entry
Lewis acid (equiv), solvent
temp (°C)
time
( )-1a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
TiCl4 (1), THF
−78
−78
−78
−78 to rt
rt
10 min
10 min
30 min
18 h
5 min
20 min
1 min
1 h
1 h
5 h
5 h
1 h
e
f
TiCl4 (1), CH2Cl2
TiCl4 (1), CH2Cl2
TiCl4 (1), CH2Cl2
AuCl(PPh3)/AgSbF6, CH2Cl2
AuCl(PPh3)/AgSbF6, toluene
AuCl3 (0.01), CH3CN
ZnBr2 (1), CH2Cl2
ZnI2 (1), CH2Cl2
g
trace
58
h
43
h
60
70
75
72
85−89
91
90
90
92
c
c
rt
rt
rt to 40
rt to 40
rt to 40
rt to 110
rt to 40
rt to 40
rt to 40
rt to 40
rt to 40
Zn(OTf)2 (1), CH2Cl2
Zn(OTf)2 (1), toluene
d
InX3 (1), CH2Cl2
In(OTf)3 (1), CH2Cl2
In(OTf)3 (0.5) CH2Cl2
In(OTf)3 (0.1) CH2Cl2
In(OTf)3 (0.01) CH2Cl2
1 h
3 h
5 h
5 h
accomplished a formal synthesis of phomactin A using this
synthetic strategy.10 Herein, we report a two-component
cascade cyclization for establishing a series of oxatricyclic
compounds (1a−d) and demonstrated their potential utilities
for establishing the core structures of 1α,8α:4α,5α-diepoxy-4,5-
dihydroosmitopsin and cortistatin A.
A dual-mode Lewis acid that can induce reaction upon both σ-
and π-binding should be able to catalyze the Mukaiyama aldol
reaction between Chan’s diene11 and aldehyde 2 and the in situ
intramolecular Prins/Conia-ene cascade reaction of 3, affording
tricyclic products (1) in a single step (Scheme 1, eq 2). To
search for the appropriate conditions for this two-component
cascade cyclization reaction, cyclization precursors 2a−d were
readily prepared from commercially available alkynols 5a and 5b
(Scheme 2). PCC oxidation of 5a and 5b followed by Grignard
a
b
General procedures were followed. Isolated yield (%) of ( )-1a
c
after silica gel column chromatography. 0.03 equiv of Lewis acid was
d
e
used. X = Cl, Br, or I. Compound ( )-3a (55%) was isolated.
f
g
Compound ( )-3a (78%) was isolated. Detected by LC-MS along
h
with 89% of ( )-4a. Decomposition of substrates.
of ( )-3a. Switching the solvent to CH2Cl2 at −78 °C resulted
in a higher yield of ( )-3a (Table 1, entry 2). Surprisingly,
extending the reaction time led to a trace amount of the expected
cyclization product ( )-1a along with 89% of the Prins
cyclization intermediate ( )-4a (Table 1, entry 3). With this
encouraging result in hand, the effects of reaction temperature
were studied, and we found that the cascade reaction proceeded
smoothly at room temperature for 18 h, which afforded ( )-1a
as a single diastereomer in 58% yield (Table 1, entry 4). The
structure of ( )-1a was confirmed unambiguously by X-ray
crystallography.12 After the study using TiCl4 as the σ-Lewis
acid, several π-Lewis acids were examined. AuCl(PPh3)/AgSbF6
in CH2Cl2 resulted in rapid decomposition of the substrates
(Table 1, entry 5). Interestingly, switching the solvent to toluene
led to ( )-1a in 43% yield (Table 1, entry 6). However, several
attempts at improving the yields by changing the reaction time
and temperature failed due to the stability of the substrates
toward the Au(I) catalyst. The substrates are also found to be
highly unstable toward AuCl3 in CH3CN (Table 1, entry 7).
In our previous study, Zn(II) and In(III) were found to be
effective dual-mode Lewis acids for inducing the intermolecular
Prins/Conia-ene cascade cyclization.9 Because of this, a variety
of Zn(II) and In(III) catalysts were investigated. ZnBr2, ZnI2,
and Zn(OTf)2 in CH2Cl2 at room temperature only provided
intermediate ( )-4a. The in situ Conia-ene reaction proceeded
smoothly by increasing the reaction temperature and gave
( )-1a in 60, 70, and 75% yields (Table 1, entries 8−10).
Switching the solvent to toluene with Zn(OTf)2 gave a similar
Scheme 2. Synthesis of Cyclization Precursors 2a and 2b
addition resulted in 6a−d.12 After oxidation of the resulting
alcohol to ketones, ozonolysis of the terminal alkenes of 7a−d
afforded cyclization precursors 2a−d.
With the cyclization precursors prepared, the cascade
cyclization of 2a with Chan’s diene was studied using a variety
of Lewis acids. As shown in Table 1, using strong σ-Lewis acids,
such as TiCl4, in THF at −78 °C induced Mukaiyama aldol
reaction and gave ( )-3a as the only product (Table 1, entry 1).
However, extending the reaction time led to slow decomposition
B
DOI: 10.1021/acs.orglett.8b03461
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Organic Letters
Letter
result (Table 1, entry 11). Using the same protocol for
controlling the reaction temperature, InX3 (X = Cl, Br, I or
OTf) in CH2Cl2 gave better results than the Zn(II)-based Lewis
acids (Table 1, entries 12 and 13). In(OTf)3/CH2Cl2 was found
to be the optimal dual-mode Lewis acid for the two-component
cascade cyclization reaction, which provided 91% yield of
( )-1a in a single step. The effects of In(OTf)3 loading was then
studied (Table 1, entries 14−16). We found that the catalyst
loading of In(OTf)3 can be reduced to 1 mol % without affecting
the efficiency of the reaction (Table 1, entry 16). The optimal
condition for the cyclization only required 1 mol % of In(OTf)3
in CH2Cl2 at room temperature for 10 min and then reflux for 5
h, which gave ( )-1a as a single diastereomer in 92%.
Scheme 4. Scope of Substrates for the Cascade Cyclization
To investigate the potential utility of this synthetic strategy,
the oxatricyclic fused ring system of ( )-1a was converted to the
syn-diepoxy structure of 1α,8α:4α,5α-diepoxy-4,5-dihydroosmi-
topsin. Surprisingly, decarboxylation of ( )-1a under basic
conditions led to decomposition of the substrate. Switching the
condition to LiCl/DMSO at 150 °C afforded enone 8 in 65%
yield (Scheme 3). Epoxidation of enone 8 using H2O2/NaOH at
Scheme 5. Model Study of Cortistatin A
Scheme 3. Diastereoselective Reduction and Epoxidation of
Enone 8
exocyclic alkene, basic hydrolysis of β-keto ester ( )-14
afforded 15, which contains the ABC tricyclic core of cortistatin
A.
0 °C followed by NaBH4 reduction of ( )-9 at 0 °C afforded
( )-10 as a single diastereomer. The structure and relative
configurations of ( )-10 were confirmed unambiguously by X-
ray crystallography.12 Unfortunately, the result indicated that
epoxidation occurred in the concave face of enone 8 and gave
the undesired epoxide diastereomer. To resolve this problem,
the sequence of epoxidation and reduction was then switched.
NaBH4 reduction of enone 8 at 0 °C gave allylic alcohol ( )-11
as a single diastereomer. The relative configurations of ( )-11
were determined by NOESY.13 Hydroxyl-directed epoxidation
using m-CPBA afforded ( )-12, which was found to be a
diastereomer of ( )-10, indicating a syn-epoxy structure.
To study the scope of the substrates, cascade cyclizations of
2b−d with Chan’s diene were investigated. We found that all of
the substrates underwent the cascade reaction smoothly under
the optimized conditions and afforded 82−88% of the cyclized
products ( )-1b−d with different ring sizes as a single
diastereomer under the same reaction condition (Scheme 4).
The structure of ( )-1c was confirmed unambiguously by X-ray
crystallography, and the relative configurations of ( )-1b and
( )-1d were determined by NOESY.13
In summary, we have developed an In(OTf)3-catalyzed two-
component cascade cyclization of 2a−d with Chan’s diene and
simple keto alkynal substrates. The condition of the cascade
reaction was optimized by using 1 mol % of In(OTf)3 in CH2Cl2
and provided very good yields of a series of oxatricyclic
compounds 1a−d (82−92%) diastereoselectively in a single
operation. The utility of this reaction has been demonstrated in
model studies by converting cyclized product ( )-1a to the syn-
diepoxy structure of 1α,8α:4α,5α-diepoxy-4,5-dihydroosmitop-
sin and cyclized product ( )-1c to the ABC tricyclic core of
cortistatin A in three simple transformations. We are currently
exploring the utility of this synthetic strategy for synthesis of
natural products that contain these oxatricyclic cores, such as
cortistatin A and 1α,8α:4α,5α-diepoxy-4,5-dihydroosmitopsin.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03461.
Experimental procedures, characterization details, and 1H
and 13C NMR spectra of all new compounds (PDF)
The potential utility of this cascade cyclization reaction for the
synthesis of cortistatin A was also investigated by employing
cyclic product ( )-1c as the substrate in a model study. As
shown in Scheme 5, NaBH4 reduction of the ketone moiety of
( )-1c gave good yields of ( )-13 as a single diastereomer (the
stereochemistry was not determined). After ozonolysis of the
Accession Codes
CCDC 1868304, 1868353, and 1880206 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
C
DOI: 10.1021/acs.orglett.8b03461
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cslee-chem@hkbu.edu.hk.
ORCID
Chi-Sing Lee: 0000-0002-3564-8224
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank the National Natural Science Foundation of
China (Grant Nos. 21502002, 21572006, and 21871017), the
Natural Science Foundation of Guangdong Province, China
(Grant No. 2017A030313042), the Shenzhen Science and
Technology Innovation Committee (Grant Nos.
JCYJ20160428153421635 and JCYJ20160330095659560), Pe-
king University Shenzhen Graduate School and Hong Kong
Baptist University for their financial support. A special
acknowledgement is made to Ms. Shunan Zhao (Southern
University of Science and Technology) for the X-ray
crystallography of compounds ( )-1a and ( )-10, and Mr.
Ying Gao (Peking University Shenzhen Graduate School) for
the X-ray crystallography of ( )-1c.
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