Unique ring expansion of a 6-3 bicyclic ring system forming a functionalized 7-membered ring accelerated by nitrogen functional groups

Article abstract of DOI:10.1016/j.tetlet.2017.06.061

The treatment of (2-hydroxy-5-oxobicyclo [4.1.0] hept-3-en-3-yl) carbamic acid esters and (2-hydroxy-5-oxobicyclo [4.1.0] hept-3-en-3-yl) benzamide with TMSCl gave 7-membered ring compounds in good yields. The structure of the substituent at the C3 position of the cyclohexene ring is crucial for this ring expansion. The reaction mechanism is thought to involve the formation of a norcaradiene (bicyclo [4.1.0] hept-2,4-diene) structure and subsequent electrocyclic reaction.

Full text of DOI:10.1016/j.tetlet.2017.06.061

Accepted Manuscript
Unique ring expansion of a 6-3 bicyclic ring system forming a functionalized
7-membered ring accelerated by nitrogen functional groups
Eiko Yasui, Rio Ootsuki, Kan Takayama, Shinji Nagumo
PII:
S0040-4039(17)30799-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.061
TETL 49053
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 May 2017
17 June 2017
20 June 2017
Please cite this article as: Yasui, E., Ootsuki, R., Takayama, K., Nagumo, S., Unique ring expansion of a 6-3 bicyclic
ring system forming a functionalized 7-membered ring accelerated by nitrogen functional groups, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.061
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Unique ring expansion of a 6-3 bicyclic ring
system forming a functionalized 7-membered
ring accelerated by nitrogen functional
groups
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Eiko Yasui*, Rio Ootsuki, Kan Takayama, and Shinji Nagumo*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Unique ring expansion of a 6-3 bicyclic ring system forming a functionalized
7
-membered ring accelerated by nitrogen functional groups
a, b*
b
b
Eiko Yasui , Rio Ootsuki , Kan Takayama , and Shinji Nagumo
a, b*
a
Department of Chemistry and Life Science, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan
Department of Applied Chemistry, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan
b
ARTICLE INFO
ABSTRACT
Article history:
Received
The treatment of (2-hydroxy-5-oxobicyclo [4.1.0] hept-3-en-3-yl) carbamic acid esters and
(2-hydroxy-5-oxobicyclo [4.1.0] hept-3-en-3-yl) benzamide with TMSCl gave 7-membered ring
compounds in good yields. The structure of the substituent at the C3 position of the cyclohexene
ring is crucial for this ring expansion. The reaction mechanism is thought to involve the
Received in revised form
Accepted
Available online
formation of a norcaradiene (bicyclo [4.1.0] hept-2,4-diene) structure and subsequent
electrocyclic reaction.
Keywords:
2
009 Elsevier Ltd. All rights reserved.
7
-membered ring
cyclopropane ring expansion
trimethylsilyl chloride
norcaradiene
electrocyclic reaction
Cyclopropane rings easily undergo several types of ring
openings under appropriate conditions to afford acyclic or
different cyclic molecules and are therefore widely applied in
1-4
organic synthesis as useful building blocks. The ring system
has also been found in natural products isolated from various
5-8
living species. Their ring opening frequently correlate with
biochemical mechanisms for defense against natural enemies and
9
-11
adaptation to the habitat environment.
Furthermore, many
have potential antibacterial and antitumor activities due to the
inherent ring strain. For example, duocarmycin (4) is known to
undergo alkylation by an adenine residue in DNA through ring
1
2-14
opening
epoxyquinomycin (DHMEQ, 6) is a well known and potent
NF-κB inhibitor developed by Umezawa and co-workers (Fig.
of
the
cyclopropane.
Dehydroxymethyl
-
1
5-16
2
).
The biological activity is closely related to coupling with a
Cys residue in NF-κB, concomitant with ring opening of the
epoxide. We previously synthesized a DHMEQ analogue 7
containing a cyclopropane ring with an interest in the biological
1
7
activity based on opening the small-sized ring. Unfortunately,
analogue 7 did not inhibit NF-κB activity contrary to our
expectation, but a unique ring expansion attributed to the nature
of the cyclopropane ring was observed during the course of the
synthetic study. This report describes the ring expansion of a 6-3
bicyclic ring system forming a seven-membered ring accelerated
by attendant carbamate or amide functional groups.
Figure 1. Compounds possessing a cyclopropane ring
8
7
a and its bicyclic derivative 9 (Table 1, entry 1). Treatment of
a with TBSCl and sodium hydride (NaH) in THF generated
cyclic carbamate 9 as the major product (Entry 2). The
combination of TBSOTf and 2,6-lutidine in CH Cl was less
What led us to discover this novel ring expansion was an
attempt at protecting the hydroxyl group of synthetic
2
2
suitable for the ring expansion reaction (Entry 3). In order to
reveal the essential conditions for ring expansion, bases and silyl
reagents were used separately. Treatment of 7a with only Et N or
intermediate 7a with
tert-butyldimethylsilyl chloride (TBSCl) and triethylamine
Et N) to a solution of 7a in THF did not result in the formation
of silylated compound 11, but rather 7-membered cyclic diketone
a
TBS group. Addition of
3
2
,6-lutidine resulted in no reaction (Entries 4 and 5). On the other
(
3
2 2
hand, TBSCl alone caused the ring expansion of 7a in CH Cl to
afford 8a in 51% yield (Entry 6). Furthermore, the reaction

2
1
did not induce ring expansion (Entry 5). On the other hand,
8
proceeded more smoothly to generate 8a in quantitative yield
upon changing the solvent to THF (Entry 7). Since TBSCl
behaves like a Lewis acid in this reaction, we examined typical
treatment of 16, which is a positional isomer of 7a for the
carbamate substituent, under the same conditions resulted in the
formation of epimeric alcohol 17 (Scheme 2).
Lewis acids such as BF
with TMSOTf in CH Cl
carbamate 9 along with 10 despite longer reaction times (Entry
). BF •OEt resulted in formation of the seven-membered
3
2
•OEt and TMSOTf. Treatment of 7a
2
2
resulted in the formation of cyclic
a,b
Scheme 1. Synthesis of substrates 7a-d
8
3
2
products 8a and 9 (Entry 9). Reagent size seemed to affect the
reaction rate; the reaction proceeded more quickly with the use of
TMSCl than with the use of TBSCl. Notably, 7a was converted
to 8a within one hour upon treatment of 5 equivalents of TMSCl
(
Entry 10).
a
Table 1. Ring expansion of 7a under various conditions
a
Reagents and conditions: see, ESI.
Isolated yield.
b
a
Table 2. Ring expansion of 7a-e under the optimized conditions
a
Reagents and conditions: 7a (0.1 mmol), reagents (5 equiv.),
solvent (0.1 M), room temperature (unless otherwise noted).
b
Isolated yield.
a
Reagents and conditions: see ESI.
Isolated yield.
With the optimized conditions in hand, substituents on the
cyclohexenone ring were examined for their effect on ring
expansion (Table 2). The synthetic route towards substrates 7a-d
is shown in Scheme 1. 2,5-Dimethoxyaniline was protected with
each protecting group and oxidized with diacetoxyiodobenzene to
give dienones 12a-c. Treatment of dienones 12a-c with
trimethylsulfoxonium iodide in the presence of NaH resulted in
selective cyclopropanation to generate 13a-c. Deacetalization of
b
c
SM recovered in quantitative yield.
SM recovered in 46% yield.
d
a
Scheme 2. Reaction of a positional isomer of 7a with TMSCl
1
3a-c with PPTS afforded the diketones 14a-c in good yields.
®
Finally, reduction of 14a-c with L-selectride proceeded
stereoselectively to give 7a-c with a cis-configuration. To
synthesize benzyl (Bn) derivative 7d, diketone 14a was protected
with the benzyl group, the allyloxycarbonyl (Alloc) group of
compound 15 was then removed with Pd(0) and stereoselective
®
reduction with L-selectride gave 7d. Compound 7e was
1
8
synthesized following the reported procedure. When the
nitrogen atom was protected with an allyloxycarbonyl (Alloc)
group or a t-butoxycarbonyl (Boc) group, ring expansion
smoothly occurred to afford 7-membered ring compounds in
good yields (Entries 1 and 2). An amide such as the benzoyl (Bz)
group also worked well (Entry 3). On the other hand, the benzyl
a
Reagents and conditions: 16 (0.09 mmol), TMSCl (5 equiv.),
THF (0.1 M), 0 °C, 18 h.
Isolated yield
b
(Bn) group did not give a 7-membered ring compound (Entry 4).
We also examined the substrate with no amine substituent, but it

3
Cleavage of the cyclopropane ring conjugated with a carbonyl
group seems at first sight to occur in conjunction with a
esters and (2-hydroxy-5-oxobicyclo [4.1.0] hept-3-en-3-yl)
benzamide generating 7-membered ring compounds. Due to the
acceleration by the attendant nitrogen, the reaction proceeded
readily under mild conditions. Further mechanistic exploration
and application of this reaction are now underway.
1
7
4
,2-hydride shift (Scheme 3). However, the negative results of
d-e remind us of another potential pathway as shown in Scheme
. TMSCl coordinates with the carbonyl oxygen of 7a-c to form
an iminium ion A with the assistance of the electron-releasing
nitrogen at the C3 position. Subsequent deprotonation of ion A,
derived from 7a-c, results in the formation of enamide B with a
Acknowledgments
19
norcaradiene skeleton, which is thus converted into 8 through
and subsequent keto-enol
This study was supported in part by a grant from the Strategic
Research Foundation Grant-aided Project for Private Universities
from the Ministry of Education, Culture, Sport, Science, and
Technology, Japan (MEXT), 2014-2018 (S1411005).
20
an electrocyclic reaction
tautomerization. On the other hand, 7d should be converted to
imine D, which does not undergo any further transformation.
This can be rationalized by considering that sec-enamine-imine
tautomerism typically favors the formation of an imine. In the
case of compound 16 (Scheme 2), TMSCl coordinated with the
hydroxyl group and dehydroxylation occurred via electron
donation by the nitrogen atom. The addition of water would
proceed from the opposite side of the cyclopropane ring.
References and notes
1. Jiao, L.; Yu, Z.-X. J. Org. Chem. 2013, 78, 6842.
2. Cavitt, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43,
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04.
Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem. Int. Ed.
014, 53, 5504.
Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
3
4
.
.
2
Scheme 3. Ring expansion through a 1,2-hydride shift
5. Rӧmpp Encyclopedia Natural Products; Steglich, W., Fugmann,
B., Lang-Fugmann, S., Eds.; Georg Thieme Verlag: Stuttgart,
Germany, 2000.
6
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Seto, H.; Sasaki, T.; Yonehara, H.; Takahashi, S.; Takeuchi, M.;
Kuwano, H.; Arai, M. J. Antibiot. 1984, 37, 1076.
Staudinger, H.; Ruzicka, L. Helv. Chim. Acta 1924, 7, 177.
Anchel, M.; Hervey, A.; Robbins, W. J. Proc. Natl. Acad. Sci.
U.S.A. 1950, 36, 300.
7
8
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.
9
1
1
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0. Salaün, J. Top. Curr. Chem. 2000, 207, 1.
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nd
Drug Action, 2 ed.; Elsevier: London, 2004.
Scheme 4. Plausible reaction mechanism for the ring expansion
reaction
1
1
2. Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41,
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917.
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1
1
1
4. Boger, D. L.; Garbaccio, R. M.; Bioorg. Med. Chem. 1997, 5, 576.
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1
0, 865.
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1
1
1
7. Yasui, E.; Takayama, K.; Nakago T.; Takeda, N.; Imamura, Y.;
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8. Normal silylation of 7e with TBSCl was reported in the presence
of base. Arthurs, C. L.; Morris, G. A.; Piacenti, M.; Pritchard, R.
G.; Stratford, I. J.; Tatic, T.; Whitehead, R. C.; Williams, K. F.;
Wind, N. S. Tetrahedron 2010, 66, 9049-9060.
1
2
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Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at http://
In conclusion, we have found a ring expansion reaction of
2-hydroxy-5-oxobicyclo [4.1.0] hept-3-en-3-yl) carbamic acid
(

4
Highlights
(1) Functionalized 7-membered ring was easily
synthesized under mild conditions in good yields.
(
(
2) To synthesize the 7-membered ring, ring
expansion occurred with trimethylsilyl chloride
(
TMSCl), which is easy to handle.
3) During the ring expansion step, the nitrogen
atom triggered the reaction.