Synthesis of Oxa-Bridged Medium-Sized Carbocyclic Rings via Prins Cyclization

Article abstract of DOI:10.1021/acs.orglett.9b00491

Herein, we report a new method for the synthesis of oxa-bridged carbocyclic units based on intramolecular Prins reaction of dioxinones. Our new synthetic approach is flexible and practical and has been successfully applied to the preparation of highly fun

Full text of DOI:10.1021/acs.orglett.9b00491

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Oxa-Bridged Medium-Sized Carbocyclic Rings via Prins
Cyclization
Min-Shou Wang, Zheng Wang, Wen Chen, Xiaodong Yang,* and Hongbin Zhang*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, State Key Laboratory for
Conservation and Utilization of Bio-Resources in Yunnan, School of Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China
*
S Supporting Information
ABSTRACT: Herein, we report a new method for the
synthesis of oxa-bridged carbocyclic units based on intra-
molecular Prins reaction of dioxinones. Our new synthetic
approach is flexible and practical and has been successfully
applied to the preparation of highly functionalized seven-,
eight-, and nine-membered carbocycles. The potential utility
of this approach has also been demonstrated in a model study
toward construction of the 7,8-fused ring system presented in neoabyssomicin D.
5
n nature, there are a large number of natural products
containing oxa-bridged bicyclic (OBB) structure units.
activity. Due to their unique structures as well as their
1
I
biological importance, these oxa-bridged medium-sized carbo-
Among them, the seven- and eight-membered ring derivatives
are especially attractive due to their existence in a number of
highly bioactive natural products. In Figure 1, some
cycles have attracted considerable attention from the synthetic
6
community. To date, numerous methodologies, such as gold-
2
7
catalyzed alkyne cycloisomerization reactions, Lewis acid
8
mediated intramolecular cross-cycloadditions, photoinduced
9
10
cyclizations, 1,3-dipolar cycloadditions, [5 + 2] dipolar
1
1,6c
cycloaddition of oxidopyrylium ylides,
thesis (RCM), Prins-type cyclizations, and [4 + 3]
ring-closing meta-
1
2
13
14
cycloadditions have been developed for the synthesis of
OBB ring systems. Despite the above-mentioned methods,
practical and flexible strategies (i.e., short steps, cheap
commercially available starting materials and reagents, easy-
to-handle reaction conditions, gram-scale procedure, and
stereoselectivity) leading to the synthesis of seven-, eight-,
6
a,14e
and nine-membered rings are still in great demand.
In this
paper, we report a Lewis-acid-mediated Prins cyclization
approach for constructing medium-sized carbocycles bearing
oxa-bridged bicyclic structural units.
In 1991, Molander’s group reported an elegant vinylogous
6i,15
aldol-addition/Prins-cyclization annulative approach
to-
ward the synthesis of oxa-bridged seven- and eight-membered
ring systems via the reaction of a β-dicarbony1-l,3-dianionic
equivalent, normally bis(trimethylsilyl) enol ether, with 1,4- or
1
1
,5-dielectrophiles under the catalysis of Lewis acids (Scheme
, eq 1). The asymmetric version for the synthesis of seven-
Figure 1. Representative natural products bearing seven-, eight-, and
nine-membered OBB rings.
and eight-membered rings based on this annulation was also
developed by using chiral substrates (Scheme 1, eq 2).
Recently, we initiated a research program toward the synthesis
of neoabyssomicin D. A practical method for the construction
of the oxa-bridged bicyclic ring system is required. We noticed
that the volatile and unstable dicarbonyl compounds were
representative compounds are illustrated, such as englerin A
(
(
1), which exhibits potent and selective inhibitory activity
3
GI < 20 nm) against renal cell carcinoma; cortistatin A (2),
5
0
which inhibits the proliferation of human umbilical vein
endothelial cells (HUVECs, IC50 = 1.8 nM); and
4
Received: February 6, 2019
toxicodenane C (7), which exhibits antidiabetic nephropathy
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00491
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Approaches toward Medium-Sized
Rings
orientation of the hydroxyl group through formation of a
semiketal intermediate.
Having established the procedure based on intramolecular
Prins reaction, we next turned our attention to extending the
general utility of this process toward the synthesis of other
medium-sized ring systems. Due to the unfavorable entropic
and enthalpic factors, synthesis of eight- and nine-membered
6
rings is challenging. To our delight, a number of polycyclic
compounds containing eight-membered rings could be
synthesized under the optimal reaction conditions (Scheme
3
). The substrates bearing cyclopentane, cyclohexane, cyclo-
Scheme 3. Synthesis of 7/8/9-Membered Oxa-Bridged
Rings
1
6
difficult to handle. Inspired by Molander’s work and
Scheidt’s recent application of β-hydroxy dioxinones in the
17
synthesis of tetrahydropyran-4-ones (Scheme 1, eq 3), we
proposed an oxidative-cleavage/Prins-cyclization approach
toward the synthesis of highly functional oxa-bridged seven-,
eight-, and nine-membered rings aiming for the core structures
indicated in Figure 1. We envisioned that an olefin substrate
bearing a dioxinone moiety would be much easier to handle,
after oxidative cleavage of the double bond, and an
intramolecular Prins reaction would provide the desired
products. Our synthetic methodology is outlined in Scheme
1
(eq 4).
To test the intramolecular Prins reaction, we used amide 9
as starting material for initial studies. Reaction of amide 9 with
benzyl magnesium chloride afforded ketone 10 in 90% yield
(Scheme 2). Next we conducted the vinylogous addition
Scheme 2. Initial Studies toward Medium-Sized Ring
Synthesis
18
according to our previously established reaction conditions.
Alcohol 11 was obtained in 87% yield. This two-step
procedure quickly set the stage for the proposed oxidative
cleavage and Prins cyclization. Ozonolysis of the double bond
provided the semiketal, which presumably formed an oxonium
ion upon treatment with BF ·Et O, and finally cyclization gave
heptane, and cyclooctane (16−18, 21−26) also worked well
and afforded the corresponding tetracyclic products in 56−
78% yields (two steps). Notably, the seven−eight fused (24)
and eight−eight fused (23) ring systems could be constructed,
and even nine-membered carbocycles (Scheme 3, 25 and 26)
were obtained by this methodology. The angular carbome-
3
2
the desired oxa-bridged compound 12 in a two-step operation
67% yield). The stereochemistry was totally controlled by the
(
B
DOI: 10.1021/acs.orglett.9b00491
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thoxy (or carboethoxy) containing substrates also provided the
desired products in good yields (16, 21, 22, 25, and 26).
Having demonstrated the versatility of intramolecular
dioxinone Prins reaction in the synthesis of the medium-
sized ring system, we next examined the diastereoselectivity of
this methodology through gram-scale asymmetric synthesis of
the 5,8-fused and 5,9-fused bicyclic rings. Treatment of β-
ketoester 27, obtained in 2 steps from (−)-pulgone, with 4-
bromo-1-butene and 5-bromo-1-pentene afforded olefins 28a
and 28b (Scheme 4). Ketones 29a and 29b were obtained
an oxidative-cleavage/Prins-cyclization procedure. This annu-
lation approach is flexible and enables entry to a number of
highly functionalized fused carbocycles. Reactions in this new
methodology are easy to handle and highly diastereoselective
and can be carried out in gram scales. Finally, the utility of this
approach has also been demonstrated in a model study toward
rapid construction of the core skeleton of neoabyssomicin D.
Our new process would be applicable for the synthesis of
natural products containing oxa-bridged bicyclic seven-, eight-,
and nine-membered rings.
1
9
ASSOCIATED CONTENT
Supporting Information
Scheme 4. Asymmetric Synthesis of 5/8- and 5/9-Fused
Carbocycles from Chiral Starting Material
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00491.
Experimental procedures, characterization data, and
spectra of all key intermediates (PDF)
Accession Codes
CCDC 1895118−1895120 and 1895122−1895123 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
20
under Krapcho conditions. After reaction with dioxinone-
derived lithium dienolate, alcohols 30a and 30b were obtained
both in 65% yields, respectively. The diastereoselectivities in
the vinylogous addition step were excellent, with the desired
product being isolated as the major products. Ozonolysis of
*E-mail: zhanghb@ynu.edu.cn.
*E-mail: xdyang@ynu.edu.cn.
ORCID
Hongbin Zhang: 0000-0002-2516-2634
Author Contributions
3
0a and 30b followed by treatment of the crude aldehydes
with BF ·Et O afforded the desired carbocycles in good yields
3
2
(
Scheme 4).
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Finally, we conducted a model study to construct the 7,8-
fused ring system presented in neoabyssomicin D. Starting
from ketone 32, the vinylogous addition provided 33 in 60%
yield. After ozonolysis and treatment with BF ·Et O, the
Notes
3
2
The authors declare no competing financial interest.
desired 7,8-fused ring product was obtained in 64% yield
(
Scheme 5).
ACKNOWLEDGMENTS
In conclusion, we have developed a practical and
■
This work was supported by grants from the Natural Science
Foundation of China (21572197 and U1702286), the Program
for Changjiang Scholars and Innovative Research Team in
University (IRT17R94), and Yun-Ling Scholars of Yunnan
Province and Donglu Scholars of YNU.
straightforward method for the synthesis of medium-sized
OBB rings presented in a number of natural products based on
Scheme 5. Model Study toward Neoabyssomicin D
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DOI: 10.1021/acs.orglett.9b00491
Org. Lett. XXXX, XXX, XXX−XXX