Decarboxylative Nazarov Cyclization-Based Chirality Transfer for Asymmetric Synthesis of 2-Cyclopentenones

Article abstract of DOI:10.1021/acs.orglett.9b02107

Asymmetric synthesis of 2-cyclopentenones was achieved by chirality transfer based on Lewis acid catalyzed decarboxylative Nazarov cyclization of optically active cyclic enol carbonates, which are prepared by silver-catalyzed carbon dioxide incorporation into optically pure propargyl alcohols. The stereochemistry at the 4,5-positions of the 2-cyclopentenones was cleanly constructed by reflecting the stereochemistry of the starting materials. This method could be applied to various substrates to obtain the corresponding products in high yields with highly efficient chirality transfer.

Full text of DOI:10.1021/acs.orglett.9b02107

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Decarboxylative Nazarov Cyclization-Based Chirality Transfer for
Asymmetric Synthesis of 2‑Cyclopentenones
Keiichi Komatsuki, Akane Kozuma, Kodai Saito, and Tohru Yamada*
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
*
S Supporting Information
ABSTRACT: Asymmetric synthesis of 2-cyclopentenones was
achieved by chirality transfer based on Lewis acid catalyzed
decarboxylative Nazarov cyclization of optically active cyclic enol
carbonates, which are prepared by silver-catalyzed carbon dioxide
incorporation into optically pure propargyl alcohols. The stereo-
chemistry at the 4,5-positions of the 2-cyclopentenones was cleanly
constructed by reflecting the stereochemistry of the starting
materials. This method could be applied to various substrates to obtain the corresponding products in high yields with
highly efficient chirality transfer.
he cyclopentenone unit is used frequently for the
synthesis of a variety of natural products and biologically
Scheme 1. Background and Representative Concepts of the
Present Work
T
active substances because its cyclic α,β-unsaturated ketone
skeleton is a convenient electrophile for various chemical
transformations. This has led to the development of synthetic
1
methods for cyclopentenones. One representative method for
the construction of cyclopentenones is Nazarov cyclization,
which is a conrotatory 4π electrocyclization reaction promoted
by a Lewis acid and is frequently applied to stereoselective
2
syntheses.
To achieve asymmetric synthesis of cyclopentenones based
3
on Nazarov cyclization, control of torquoselectivity, which is
defined as a priority of clockwise/counterclockwise rotation in
electrocyclization reactions, must be considered because it
influences the newly generated stereochemistry. One solution
against this difficulty is a substrate control strategy using a
4
chiral auxiliary, and some methods have been reported.
However, since removal process of the chiral auxiliary is
required after the reaction, an asymmetric Nazarov cyclization
based on a different concept of substrate control needs to be
developed.
The boron Lewis acid catalyzed decarboxylative Nazarov
occur before the racemization, the stereochemistry at C(2) of
the 5-membered enol carbonate could transfer to C(4) and
C(5) of the 2-cyclopentenone. In order to facilitate this
chirality transfer, it is crucial to select coordination species
such as solvents and catalysts that could contribute to the
stabilization of cationic intermediates, and thus, establishing
stringent reaction conditions that are much more sophisticated
than needed for racemic synthesis would be key to achieve the
efficient chirality transfer (abbreviated as ct). For example,
Toste and co-workers studied asymmetric synthesis of 2-
cyclopentenones through a gold(I)-catalyzed Rautenstrauch
rearrangement. A high degree of chirality transfer was realized
cyclization of cyclic enol carbonate derivatives has been
5
reported, which are prepared through silver-catalyzed CO
2
6
fixation from propargyl alcohols. Features of this method
include: (1) the cyclopentenone is formed through stereo-
specific and regiospecific mechanisms to give a single isomer
and (2) the reaction proceeds catalytically. On the basis of
these features, the ring-closure step at C(4) and C(5) was
expected to be rapid because the decarboxylation step would
be irreversible and erosion of the geometrical integrity of
7
alkene could occur if the ring-closure step was slow.
Comparison of this method with a general Nazarov cyclization
suggests that the formation of the pentadienyl cation
intermediate A could involve loss of the chirality at C(2)
(
Scheme 1). However, if the cleavage of the C(2)−O(2) bond
Received: June 18, 2019
and the following bond formation between C(4) and C(5)
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02107
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Examination of Reaction Conditions
Scheme 2. Substrate Scope of Asymmetric Decarboxylative
Nazarov Cyclization*
,
a
b
c
time
(h)
yield
ct
entry Lewis acid
solvent/additive
1,2-DCE
1,2-DCE
(%)
(%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
NHTf2
FeCl3
2
2
2
2
12
2
2
2
12
12
12
2
80
82
85
95
90
84
68
94
92
93
92
93
82
92
90
90
14
18
20
32
41
48
66
72
80
80
79
81
86
87
64
89
Me SiOTf 1,2-DCE
3
BF ·OEt2
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
3
d
AgSbF6
AlCl3
AlMe3
Sc(OTf)3
B(C F )
6
5
3
3
3
3
3
3
3
3
0
1
2
3
4
5
6
B(C F )
1,2-DCE/MS 3 Å
1,2-DCE/MS 4 Å
1,2-DCE/MS 5 Å
benzene/MS 5 Å
mesitylene/MS 5 Å
1,2-DCE/MS 5 Å
tert-butylbenzene/MS
6
5
B(C F )
6
5
B(C F )
6
5
B(C F )
2
2
2
2
6
5
B(C F )
6
5
B(C F )
6
5
B(C F )
6
5
5
Å
e
1
7
B(C F )
tert-butylbenzene/MS
12
90
95
6
5
3
5
Å
a
Conditions: 2a (0.075 mmol), Lewis acid (10 mol %) in 1,2-
dichloroethane (2.0 mL) at 25 °C. In the case of entries using
molecular sieves (MS), 60 mg of MS was added. Yields of 3a were
b
c
calculated on the basis of (E)-1a. Isolated yields. Optical purities of
and 3 were determined by HPLC on a chiral stationary phase.
Chirality transfer was calculated using ct (%) = ee of 3a (% ee)/ee of
1
d
e
1
°
a (% ee). Using AgSbF (30 mol %). In tert-butylbenzene at −40
6
C for 12 h. DCE = 1,2-dichloroethane.
8
,9
despite the formation of a pentadienyl cation intermediate.
The present report describes Lewis acid catalyzed asymmetric
synthesis of 2-cyclopentenones based on a chirality transfer
reaction through decarboxylative Nazarov cyclization.
An initial attempt was conducted with the optically active
cyclic enol carbonate 2a, which is prepared by silver-catalyzed
10
CO2 incorporation into the optically active 1a with a
catalytic amount of an acid in 1,2-dichloroethane (Table 1). At
first, treatment of 2a with NHTf , FeCl , or TMSOTf resulted
*Conditions: starting material 2 (0.075 mmol), B(C
F ) (10 mol %),
6 5 3
and MS 5 Å (60 mg) in tert-butylbenzene (2.0 mL) at −40 °C (details
2
3
in the Supporting Information). Yields of 3 were calculated on the
in a large loss of optical purity (entries 1−3). When BF (OEt )
3
2
a
basis of the corresponding propargyl alcohols 1. Isolated yields.
and AgSbF were used, 3a was obtained in 95% or 84% yield
6
b
Optical purities of 1 and 3 were determined by HPLC on a chiral
with 32% or 41% chirality transfer (ct), respectively (entries 4
stationary phase. Chirality transfer calculated by ct (%) = ee of 3 (%
and 5). Among aluminum catalysts, the use of AlMe resulted
c
d
3
ee)/ee of 1 (% ee). At 0 °C for 12 h. In ethylbenzene at 0 °C for 12
in moderate chirality transfer (68% yield, 66% ct, entry 7). The
e
f
h. At −20 °C for 12 h. 1j (1 mmol) and B(C F ) (20 mol %) were
employed. TBS = tert-butyldimethylsilyl.
6
5 3
catalyst Sc(OTf) was better in this reaction and afforded 3a in
3
9
4% yield with 72% ct (entry 8). The most effective catalyst
was B(C F ) , which provided high yield and the highest ct
6
5 3
(
entry 9). The presence of 5 Å molecular sieves (MS) could
improvement in ct. High selectivity was obtained when an
alkyl-group-substituted benzene derivative was used as a
solvent, and ct was improved when the reaction was performed
11
shorten the reaction time (entry12). The effects of solvent
and reaction temperature were also examined for further
B
DOI: 10.1021/acs.orglett.9b02107
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Determination of Stereochemistry and
Torquoselectivity of Ring-Closure Step
Scheme 4. Derivatization of the Synthesized 2-
Cyclopentenone
determined to be (S) and (4S,5S), respectively, by single-
crystal X-ray analysis, indicating that the ring closure occurred
13
via clockwise rotation. Reflecting the stereochemistry at C(2)
in (S)-2h, the location of the two π-orbitals of C(4) and C(5)
indicates 4h, and the in-phase overlap of the π-orbitals at C(4)
with C(5) occurs smoothly through a clockwise rotation
(
compared with counterclockwise rotation), achieving stereo-
selective Nazarov cyclization.
Further transformation of the 2-cyclopentenone derivative
was explored (Scheme 4). The absolute configuration of 1m
was determined to be (R) by single-crystal X-ray structural
13
analysis of the derived epoxide 5m. Decarboxylative Nazarov
cyclization of (R)-1m proceeded to give (4S,5R)-3m in high
yield with excellent ct through the clockwise rotation. When
1
2
at lower temperatures. Optimal reaction conditions were: 10
mol % B(C F ) , MS 5 Å, t-butylbenzene solvent, −40 °C.
Substrate scope was also explored (Scheme 2). Investigation
of the effect of the R substituent showed a slight decrease in ct
when using 2b, which contained an electron-donating group
EDG), to afford 3b in 94% yield with 82% ct. Introduction of
an electron-withdrawing group (EWG) on R (2c) improved
ct to give 3c in 83% yield with 97% ct. Use of 2d and 2e
containing different alkyl groups on R furnished 3d and 3e in
0% and 88% yields with 90% and 92% ct, respectively. The
introduction of isopropyl group on R showed a positive effect
and 3f was obtained in 84%, 98% ct. Substrates 2g−2h
containing a trisubstituted olefin unit produced the corre-
sponding products 3g−3h in high yields with excellent ct
values (99% to >99% ct). An all-carbon quaternary stereo-
center with high optical purity was constructed successfully
using 2i in 97% yield with >99% ct. Substrates 2j−2o bearing
- and 8-membered cyclic olefins were converted efficiently
into the corresponding bicyclic fused-ring structures in good to
high yield with excellent ct.
To examine the torquoselectivity of the ring-closure step, the
stereochemistry of a starting material and product was
determined (Scheme 3). After various trials, the absolute
configurations of starting material 1h and product 3h were
3m was treated with lithium aluminum hydride (LiAlH ) in
6
5 3
4
THF at −70 °C, 1,2-reduction stereoselectively proceeded to
afforded 6m in 80% yield, diastereoselectively. The hydroxy-
group directed epoxidation of 6m resulted in the successful
production of 7m having contiguous quaternary stereocenters
2
(
2
13
in 90% yield. It is worth noting that, through highly
sterochemical-controlled reactions, decarboxylative Nazarov
cyclization, and other two transformations, continuous five
stereocenters were simply constructed starting from the chiral
propargyl alcohol (R)-1m having one stereogeneic center.
In summary, asymmetric synthesis of a 2-cyclopentenone
derivative based on B(C F ) -catalyzed decarboxylative Naza-
1
9
5
6
5 3
rov cyclization involving chirality transfer was achieved using
chiral cyclic carbonate, prepared by silver-catalyzed incorpo-
ration of carbon dioxide into a chiral propargyl alcohol. This
catalytic reaction was applied to various substrates to afford
chiral 2-cyclopentenones in good yields with high chirality
transfer. The stereochemical outcome, including torquoselec-
tivity, in a conrotatory ring-closure process was elucidated by
determining the stereochemistry of the starting material and
product. Further investigation of the reaction mechanism and
application of the reaction to the synthesis of more complex
molecules are underway.
7
C
DOI: 10.1021/acs.orglett.9b02107
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Rings. In Strain and Its Implications in Organic Chemistry; de Meijere,
A., Blechert, S., Eds.; Kluwer Academic: Dordrecht, 1989; pp 25−37.
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
c) Houk, K. N.; Li, Y.; Evanseck, J. D. Transition Structures of
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02107.
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Experimental procedures, analytical data for all new
compounds, NMR spectra, and HPLC charts for the
products (PDF)
Accession Codes
CCDC 1919396 and 1919399−1919401 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/
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.
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: yamada@chem.keio.ac.jp.
ORCID
Tohru Yamada: 0000-0002-4177-5019
Notes
2801. (h) Kerr, D. J.; Miletic, M.; Chaplin, J. H.; White, J. M.; Flynn,
The authors declare no competing financial interest.
B. L. Oxazolidinone-Promoted, Torquoselective Nazarov Cycliza-
tions. Org. Lett. 2012, 14, 1732−1735. (i) Flynn, B. L.; Manchala, N.;
Krenske, E. H. Opposing Auxiliary Conformations Produce the Same
Torquoselectivity in an Oxazolidinone-Directed Nazarov Cyclization.
J. Am. Chem. Soc. 2013, 135, 9156−9163. (j) Manchala, N.; Law, H.
Y. L.; Kerr, D. J.; Volpe, R.; Lepage, R. J.; White, J. M.; Krenske, E. H.;
Flynn, B. L. Multistereocenter-Containing Cyclopentanoids from
Ynamides via Oxazolidinone-Controlled Nazarov Cyclization. J. Org.
Chem. 2017, 82, 6511−6527.
ACKNOWLEDGMENTS
This work was partially supported by JSPS KAKENHI
Scientific Research (C) 18K05112].
■
[
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(10) Optically pure propargyl alcohol 1 was prepared by the
resolution of racemic compounds via HPLC on a chiral stationary
phase.
(11) The reaction time of entry 9 in Table 1 was poorly
reproducible. When this reaction was carried out in the presence of
molecular sieves, the reaction time was reproducible. As one of
possibilities, the catalytic activity of B(C F ) was influenced due to
6
5 3
formation of the B(C F ) −H O adduct. It has been reported that
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5
3
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B(C F ) forms a stable adduct with water. Danopoulos, A. A.;
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529−2530.
12) A positive effect on an efficiency for chirality transfer of alkyl
group substituted benzenes as solvent is not clear.
13) The absolute configurations of 1h, 3h, 5m, and 7m were
(
(
evidently determined by a single crystal X-ray structural analysis using
the anomalous dispersion method.
E
DOI: 10.1021/acs.orglett.9b02107
Org. Lett. XXXX, XXX, XXX−XXX