Rhodium(I)-Catalyzed Enantioselective Cyclization of Enynes through Site-Selective C(sp 3)-H Bond Activation Triggered by Formation of Rhodacycle

Article abstract of DOI:10.1055/a-1469-7408

Rhodium(I)-catalyzed enantioselective cyclization of enynes through C(sp ³)-H bond activation was investigated. It was found that the cyclization of enynes having a tert -butyl moiety on the alkene afforded a spirocyclic compound (up to 92% ee), while the cyclization of enynes having an isopropyl or an ethyl group on the alkene gave a cyclic diene (up to 98% ee). Furthermore, an intermolecular competition reaction using a deuterium-labeled substrate revealed that C(sp ³)-H bond activation was one of the key steps, having a high energy barrier, in this cyclization.

Full text of DOI:10.1055/a-1469-7408

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–H
special topic
A
Bond Activation – in Honor of Prof. Shinji
Y. Oonishi et al.
Special Topic
Synthesis
Rhodium(I)-Catalyzed Enantioselective Cyclization of Enynes
through Site-Selective C(sp3)–H Bond Activation Triggered by
Formation of Rhodacycle
Yoshihiro Oonishi*
Shunki Sakamoto
Shuya Agata
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0
-0
0
0
2
-
0
3
2
3
-
8
6
4
2
R1
R2 = R3 = Me
R1
9 examples
up to 88% yield
up to 92% ee
H
X
*
Yoshihiro Sato*
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0
0
0
-
0
0
0
3
-
2
5
4
0
-
5
5
2
5
R1
H
*
Rhlll-Ln
*
RhI-Ln
X
*
X
Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan
oonishi@pharm.hokudai.ac.jp
H
R2
R3
R1
R2 R3
X = O, NR
C–H activation
4 examples
31–61% yield
up to 98% ee
H
biyo@pharm.hokudai.ac.jp
X
*
R2 = H, R3 = Me
or
R2 = R3 = H
(R = Ts, Bn, 2-naphthyl)
Published as part of the Special Topic
Bond Activation – in Honor of Prof. Shinji Murai
R3
YFeaMocsauhilCilthoyboiroiroyronefoisOSP@spahopotainoh@nriamdsprhihnamiacg.rehAmuout.kihtcuhoadoklaruSiscd.aiacei.n.japcce.jsp, Hokkaido University, Sapporo 060-0812, Japan
Received: 11.03.2021
Accepted after revision: 30.03.2021
Published online: 30.03.2021
formed stereoselectively. If a C(sp3)–H bond activation oc-
curs by rhodacycle ii, spirocyclic compound 4 would be
formed in a stereoselective manner (Scheme 1, eq. 3). Here-
in, we report a Rh(I)-catalyzed enantioselective cyclization
of enynes5 through a C(sp3)–H bond activation.6,7
Initially, the reaction of 3a with {Rh[(R)-BINAP]}BF4 (10
mol%) was carried out in ClCH2CH2Cl at reflux (Scheme 2).
As a result, the cyclization proceeded through a C(sp3)–H
DOI: 10.1055/a-1469-7408; Art ID: ss-2021-f0125-st
Abstract Rhodium(I)-catalyzed enantioselective cyclization of
enynes through C(sp3)–H bond activation was investigated. It was
found that the cyclization of enynes having a tert-butyl moiety on the
alkene afforded a spirocyclic compound (up to 92% ee), while the cy-
clization of enynes having an isopropyl or an ethyl group on the alkene
gave a cyclic diene (up to 98% ee). Furthermore, an intermolecular
competition reaction using a deuterium-labeled substrate revealed that
C(sp3)–H bond activation was one of the key steps, having a high ener-
gy barrier, in this cyclization.
R
R
R
H
H
H
M
M
M
(1)
DG
DG
DG
Key words rhodium, enantioselective cyclization, C(sp3)–H bond acti-
vation, alkene, alkyne, enyne
Previous work
R
R
R
RhI
H
H
Transition-metal-catalyzed aliphatic C(sp3)–H bond ac-
tivations have emerged as one of the most powerful and
straightforward strategies for the functionalization of sim-
ple molecules in synthetic organic chemistry.1 In general,
site-selective C(sp3)–H bond activations need the assistance
of directing groups (DG) containing a nitrogen or oxygen
atom at the appropriate position in the substrates (Scheme
1, eq. 1).1 On the other hand, we reported a Rh(I)-catalyzed
cyclization of the substrate without directing groups
through a site-selective C(sp3)–H bond activation (Scheme
1, eq. 2).2–4 In this reaction, the rhodacycle i is initially
formed through oxidative cycloaddition of the alkyne and
the external C=C bond of the allene moiety of substrate 1 to
a Rh(I) complex. By the formation of rhodacycle i, a C(sp3)–
H bond on the tert-butyl moiety could be close to the Rh(III)
center, causing C(sp3)–H bond activation to produce the cy-
clic compound 2. That is, the rhodacycle i acts as a directing
group to lead to the site-selective C(sp3)–H bond activa-
tions. In this context, we speculated that if the enyne 3 hav-
ing an 1,1-disubstituted alkene instead of allenyne 1 react-
ed with the chiral Rh(I) complex, the rhodacycle ii would be
RhIII
(2)
H
RhI
•
i
1
2
This work
R1
R1
R1
R2
RhI
H
H
RhIII
(3)
R2
*
*
H
R2
RhI
3
ii
4
Scheme 1 Transition-metal-catalyzed C(sp3)–H bond activation
10 mol% [Rh(cod)2]BF4
10 mol% (R)-BINAP
H
H
TsN
TsN
TsN
+
*
*
ClCH2CH2Cl
reflux, 5 h
H
3a
4a
5a
11% yield
58% yield
65% ee
72% ee
Scheme 2 Rh(I)-catalyzed enantioselective cyclization of enyne 3a
through C(sp3)–H bond activation
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Oonishi et al.
Special Topic
Synthesis
bond activation, giving the expected cyclic compound 4a in
11% yield along with its isomer 5a in 58% yield, and their
ees showed 72% and 65%, respectively.8–10
Encouraged by this result, the cyclization of 3a was test-
ed using various ligands (Table 1). When (R)-tolBINAP was
used as a ligand, the total yield of 4a and 5a was improved
to 90% and their ees showed 85% and 81%, respectively (en-
try 2). The reaction of 3a using (R)-H8-BINAP afforded both
4a and 5a in 88% yield even though their ees were slightly
decreased (entry 3). On the other hand, segphos-type li-
gands were not effective for this cyclization (entries 4 and
5).11
Biographical Sketches
Yoshihiro Sato received his
master’s degree of Pharmaceu-
tical Sciences from Hokkaido
University in 1990, and joined
the faculty of Pharmaceutical
Sciences, Hokkaido University
as a Research Associate. He re-
ceived his Ph.D. in 1993 from
Hokkaido University under the
supervision of Professors Ma-
sakatsu Shibasaki and Miwako
Mori, then was promoted to an
Assistant Professor. After post-
doctoral research at Stanford
University (Prof. P. A. Wender’s
group) from 1997 to 1998, he
became a Lecturer at Hokkaido
University in 1999 and an Asso-
ciate Professor in 2001. In 2004,
he was promoted to Full Profes-
sor of Hokkaido University. His
research interests lie in organo-
metallic chemistry directed to-
wards
organic
synthesis,
including development of new
reaction and utilization of CO2
as a C1 unit.
Yoshihiro Oonishi received
his Ph.D. in 2005 from Hokkaido
University (Japan) under the su-
pervision of Prof. Yoshihiro Sato.
In 2005, he joined the Faculty of
Pharmaceutical Sciences of
Hokkaido University as a Re-
search Associate and then be-
came an Assistant Professor in
2007. In 2012–2013, he had the
Nolan and then returned to
Hokkaido University to continue
his research. Since 2016, he has
been an associate professor at
Hokkaido University.
opportunity
to
study
at
University of St Andrews (UK) as
a postdoctoral fellow under the
supervision of Prof. Steven. P.
Shunki Sakamoto received
his master’s degree in 2016
from Hokkaido University (Ja-
pan) under the direction of Prof.
Yoshihiro Sato. Since 2016, he
has been working in Shionogi
& Co., Ltd.
Shuya Agata was born in
1998. He studied organic chem-
istry at Hokkaido University (Ja-
pan) and joined Prof. Sato’s
group in 2020 as an undergrad-
uate student.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

C
Y. Oonishi et al.
Special Topic
Synthesis
Table 1 Cyclization Using Various Ligandsa
R
O
X
O
10 mol% [Rh(cod)2]BF4
10 mol% (R)-tolBINAP
R
X
10 mol% [Rh(cod)2]BF4
*
ClCH2CH2Cl
65 °C or reflux
10 mol% (R)-ligand
+
4a
5a
3a
ClCH2CH2Cl
3
4
reflux
CO2Me
O
Entry Ligand
Time
(h)
Yield (%)
4a/5a
Ratio
4a/5a
ee (%)
4a/5a
TSN
RN
*
*
1
2
3
4
5
(R)-BINAP
5
5
69
90
88
61
28
1/5.3
1/1.6
1/5.2
1/1.3
2.1/1
72/65
85/81
77/74
87/72
80/N.D.b
4b: 52%, 26% ee (16 h)
4c (R = Ts): 70%, 92% ee (4 h)
4d (R = Bn): 84%, 22% ee (14 h)
4e (R = 2-naphthyl): 63%, 30% ee (3 h)
(R)-tolBINAP
(R)-H8-BINAP
1
R
O
R
O
(R)-SEGPHOS
9
O
(R)-DTBM-SEGPHOS
19
TSN
*
*
a Reaction conditions: [Rh(cod)2]BF4 (0.016 mmol), ligand (0.016 mmol), 3a
(0.16 mmol), and solvent (1.6 mL).
4f (R = nBu): 77%, 78% ee (14 h)
4g (R = iPr): 88%, 15% ee (14 h)
4h (R = Me): 62%, 40% ee (16 h)
4i (R = nBu): 51%, 69% ee (3 h)
b N.D.: Not determined.
Scheme 3 Rh(I)-catalyzed cyclization through C(sp3)–H bond activa-
tion of various substrates
On the basis of the results shown in Table 1, we selected
the conditions in entry 2 using (R)-tolBINAP as a ligand and
investigated other substrates that were designed to avoid
isomerization of the olefin in the product (Scheme 3). The
cyclization of 3b having an ester moiety on the alkyne gave
the desired cyclic compound 4b in 52% yield as a single iso-
mer, but the enantioselectivity was low. When the enyne 3c
having a sulfonimide moiety was employed in this reaction,
the spirocyclic compound 4c was obtained in 70% yield with
high enantioselectivity (92% ee). However, the enantio-
selectivity was dramatically affected by both protecting
groups at the nitrogen atom and substituents on the alkyne
in the substrate. That is, the protecting group was changed
from a tosyl group to a benzyl or a 2-naphthyl group, re-
sulting in a decrease in the ee of the product. In addition,
the cyclization of 3f having a n-butyl group on the alkyne
afforded 4f in good yield, while the reaction of 3g having an
isopropyl group on the alkyne gave 4g with low ee. Further-
more, this cyclization is applicable to the construction of 5-
membered lactones, and 4h and 4i were obtained in good
yields, albeit with moderate ees.
10 mol% [Rh(cod)2]BF4
10 mol% (R)-tolBINAP
TsN
TsN
TsN
*
ClCH2CH2Cl
reflux, 1 h
3j
6j
4j
not obtained
61%, 98% ee
O
O
10 mol% [Rh(cod)2]BF4
10 mol% (R)-tolBINAP
TsN
TsN
*
ClCH2CH2Cl
reflux, 14 h
3k
6k
31%, 75% ee
10 mol% [Rh(cod)2]BF4
10 mol% (R)-tolBINAP
MeO2C
MeO2C
*
MeO2C
ClCH2CH2Cl
reflux, 3 h
MeO2C
3l
6l
61%, 41% ee
Next, enyne 3j having an isopropyl group instead of a
tert-butyl group on the alkene moiety was subjected to the
same reaction conditions (Scheme 4). Surprisingly, it was
found that the cyclic diene 6j instead of the expected spiro-
cyclic compound 4j was produced in a good yield with a
high ee. The cyclization of 3k and 3l also afforded the cyclic
dienes 6k and 6l, although their ees were moderate. The re-
action of enyne 3m having an ethyl group gave the cyclic
compound 6m in 31% yield with 3% ee.
A possible reaction mechanism for the formation of 4
and 6 from 3 is depicted in Scheme 5. Initially, stereoselec-
tive oxidative cyclization of alkyne and alkene in substrate
3 to the Rh(I) complex would occur to provide the rhodacy-
cle iii. By virtue of the formation of rhodacycle iii, a C(sp3)–
H bond on the methyl part in the tert-butyl, isopropyl, or
ethyl group in the substrate could be close to the cationic
Rh(III) center, which would cause -bond metathesis such
10 mol% [Rh(cod)2]BF4
10 mol% (R)-tolBINAP
MeO2C
MeO2C
MeO2C
*
MeO2C
ClCH2CH2Cl
reflux, 3 h
3m
6m
31%, 3% ee
Scheme 4 Cyclization of enyne having an isopropyl or an ethyl moiety
in the alkene
as transition state iv to afford the rhodacycle v.12 In the case
of a substrate having a tert-butyl moiety (R2 = R3 = Me) on
the alkene, reductive elimination from v occurs to give the
spirocyclic compound 4 along with regeneration of the
Rh(I) complex. On the other hand, in the case of a substrate
having an isopropyl (R2 = H, R3 = Me) or an ethyl (R2 = R3 =
H) moiety on the alkene, -hydride elimination from v oc-
curs more easily than reductive elimination of 4, followed
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

D
Y. Oonishi et al.
Special Topic
Synthesis
R2 = R3 = CH3
R1
R1
R1
O
X
O
X
O
O
X
*
RhI Ln
R1
H
*
RhI Ln
H
*
RhIII Ln
H
X
*
RhIII Ln
*
*
*
H
H
R2
σ-bond
reductive
elimination
oxidative
cycloaddition
Me
Me
R2
R2
R3
R3
H
R3
metathesis
H
iii
H
v
3
4
R1
‡
R2 = H, R3 = Me
or
R2 = R3 = H
O
X
β-hydride
elimination
RhIII Ln
*
*
H
H
R2
R1
R1
*
RhI Ln
R3
O
O
X
H
H
H
H
iv
X
RhIII Ln
*
*
*
reductive
elimination
R3
H
R3
vi
6
Scheme 5 Possible reaction course
by reductive elimination from vi to give the cyclic diene 6
along with regeneration of the Rh(I) complex.
In conclusion, we have succeeded in the development of
Rh(I)-catalyzed enantioselective cyclization of enyne
through C(sp3)–H bond activation. It was found that the cy-
clization of enyne having a tert-butyl moiety on the alkene
afforded a spirocyclic compound (up to 92% ee), while the
cyclization of enyne having an isopropyl or an ethyl moiety
on the alkene gave a cyclic diene (up to 98% ee). Further-
more, the results of an experiment using a deuterium-
labeled substrate support our proposed mechanism depict-
ed in Scheme 5.
To gain an insight into the reaction mechanism, we in-
vestigated the reaction of 3c-d9 having a deuterium-labeled
tert-butyl moiety (Scheme 6). The reaction of 3c-d9 under
the same conditions as those in the above-mentioned reac-
tion of 3c (shown in Scheme 3) gave the corresponding cy-
clic compound 4c-d9 in 72% yield with 84% ee (Scheme 6,
eq. 1), which is completely consistent with the mechanism
shown in Scheme 5. Next, we performed a kinetic isotope
competition experiment using an equimolar mixture of al-
lenyne 3c and 3c-d9 (Scheme 6, eq. 2). The reaction of a
mixture of 3c and 3c-d9 (3c/3c-d9 = 1:1) with [Rh(cod)2]BF4
(10 mol%) and (R)-tolBINAP (10 mol%) at 65 °C was carried
out and quenched at an early stage (1 h). As a result, it was
found that the reaction gave a mixture of 4c and 4c-d9 in
12% yield in a ratio of 4c/4c-d9 = 64.2:35.8, by which the KIE
of this reaction was calculated to be approximately 1.8. The
experimental KIE value is not high as to conclude that
cleavage of the C(sp3)–H bond activation is the rate-deter-
mining step, however, is enough to consider that this step,
having a relatively high energy barrier, is crucial in this cy-
clization.13
All manipulations were performed under an argon atmosphere, un-
less stated otherwise. DCE was distilled under an argon atmosphere
from CaH2. All other solvents and reagents were purified when neces-
sary by standard procedures. Column chromatography was per-
formed on silica gel 60 N (spherical, neutral; Kanto Kagaku, 45–50
m), or silica gel 60 N (spherical, neutral; Kanto Kagaku, 63–210 m)
with the indicated solvent as eluent. IR spectra were obtained on a
JASCO FT/IR 460Plus spectrophotometer. 1H NMR spectra were re-
corded on JEOL ECX400P (400 MHz), JEOL ECS400 (400 MHz), and
JEOL ECA500 (500 MHz) NMR spectrometer. Chemical shifts are re-
ported in ppm from the solvent as the internal standard (CDCl3:  =
7.26). Data are reported as follows: chemical shift, multiplicity (stan-
dard abbreviations), coupling constants (Hz), and integration. 13C
NMR spectra were recorded on JEOL ECX400P (100 MHz), JEOL
ECS400 (100 MHz), and JEOL ECA500 (125 MHz) NMR spectrometer.
Chemical shifts are reported in ppm from the solvent as the internal
standard (CDCl3:  = 77.00). Mass spectra were obtained on JEOL JMS-
T100LP and JMS-T100GCV and JEOL JMS-FAB mate mass spectrome-
ter, and Thermo Scientific Exactive mass spectrometer. Optical rota-
tions were measured on a JASCO P-1030 digital polarimeter at the so-
dium D line (589 nm). Chiral HPLC analyses were carried out using a
JASCO PU-980 and using indicated chiral column.
O
O
10 mol% [Rh(cod)2]BF4
D
10 mol% (R)-tolBINAP
TsN
TsN
*
(1)
ClCH2CH2Cl
65 °C, 14 h
CD3
D3C CD3
3c-d9
D3C
D3C
D
D
4c-d9
72%, 84% ee
(D-content >95%)
O
O
O
O
10 mol% [Rh(cod)2]BF4
D
10 mol% (R)-tolBINAP
Detailed syntheses of all enyne substrates are described in the Sup-
porting Information.
TsN
TsN
TsN
TsN
*
+
+
(2)
*
ClCH2CH2Cl
CD3
D3C
D3C
D
65 °C, 1 h
D
D3C CD3
Cyclization of Enynes Using [Rh(ligand)]BF4; General Procedure
4c
3c
3c-d9
4c-d9
4c + 4c-d9: 12%
4c : 4c-d9 = 64.2 : 35.8
kH/kD = 1.8
A solution of [Rh(cod)2]BF4 (0.0160 mmol, 10 mol% to a substrate) and
ligand (0.0160 mmol, 10 mol% to an enyne substrate) in degassed
(freeze–pump-–thaw cycle was conducted) DCE (0.62 mL: 0.026 M to
Rh) was stirred under H2 atmosphere at r.t. for 1 h. Then the reaction
mixture was degassed, and the reaction vessel was flushed with
Scheme 6 Mechanistic studies
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

E
Y. Oonishi et al.
Special Topic
Synthesis
argon gas. To the mixture was added a solution of the enyne substrate
(0.160 mmol) in degassed DCE (0.98 mL) and the mixture was stirred
at 65 °C or reflux until the substrate disappeared on TLC. After remov-
al of the solvent, the residue was purified by column chromatography
on silica gel to give product.
1H NMR (500 MHz, CDCl3):  = 7.71 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.5
Hz, 2 H), 5.80 (t, J = 2.5 Hz, 1 H), 4.32 (dd, J = 18.0, 2.5 Hz, 1 H), 4.01
(dd, J = 18.0, 2.5 Hz, 1 H), 3.92 (d, J = 10.0 Hz, 1 H), 3.69 (s, 3 H), 2.46
(d, J = 10.0 Hz, 1 H), 2.41 (s, 3 H), 1.88 (m, 2 H), 1.67 (m, 2 H), 1.24 (s, 3
H), 0.92 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 166.2, 162.4, 143.7, 132.0, 129.7,
128.0, 112.0, 54.8, 53.6, 52.6, 51.4, 42.6, 30.5, 25.4, 24.9, 22.4, 21.5.
(Z)-8-Ethylidene-1,1-dimethyl-6-tosyl-6-azaspiro[3.4]octane (4a)
and 8-Ethyl-1,1-dimethyl-6-tosyl-6-azaspiro[3.4]oct-7-ene (5a)
HRMS (EI): m/z [M]+ calcd for C19H25NO4S: 363.1504; found:
According to the general procedure for cyclization, the crude product,
which was prepared from 3a (51.2 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.8 mg, 0.0160 mmol) in
DCE (1.60 mL) at reflux for 5 h, was purified by column chromatogra-
phy on silica gel (benzene) to give 4a (17.9 mg, 35% yield, 85% ee) and
5a (28.1 mg, 55% yield, 81% ee) as a colorless oil.
363.1498.
(Z)-8-Ethylidene-1,1-dimethyl-6-tosyl-6-azaspiro[3.4]octan-7-one
(4c)
According to the general procedure for cyclization, the crude product,
which was prepared from 3c (53.5 mg, 0.161 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.6 mg, 0.0156 mmol) in
DCE (1.60 mL) at 65 °C for 14 h, was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc 4:1) to give 4c (37.7 mg, 70% yield,
92% ee) as a white solid; mp 108–111 °C; []D23 –14.2 (c 1.04, CHCl3).
4a
[]D20 +13.5 (c 0.90, CHCl3).
HPLC (DAICEL CHIRALPAK AS-H): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 19.7 (major), 24.6 (minor) min.
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 256 nm; tR = 11.4 (minor), 15.3 (major) min.
IR (neat): 3019, 2924, 1597, 1463, 1215, 759 cm–1
.
IR (neat): 3024, 2925, 1822, 1363, 1170 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.70 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 5.36 (m, 1 H), 3.86 (d, J = 9.2 Hz, 1 H), 3.80 (m, 1 H), 3.57 (m,
1 H), 2.48 (d, J = 9.2 Hz, 1 H), 2.42 (s, 3 H), 1.86 (m, 1 H), 1.73 (m, 1 H),
1.59 (m, 5 H), 1.12 (s, 3 H), 0.86 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 6.15 (q, J = 7.2 Hz, 1 H), 4.34 (d, J = 10.0 Hz, 1 H), 3.35 (d, J =
10.0 Hz, 1 H), 2.43 (s, 3 H), 2.18 (d, J = 7.2 Hz, 3 H), 2.06 (m, 1 H), 1.81
(m, 1 H), 1.68 (m, 2 H), 1.23 (m, 3 H), 0.78 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 143.4, 139.5, 132.7, 129.6, 127.8,
13C NMR (125 MHz, CDCl3):  = 166.5, 144.9, 137.3, 135.5, 133.8,
129.6, 128.0, 52.1, 48.8, 41.9, 30.6, 25.2, 24.8, 24.6, 21.7, 13.7.
116.5, 54.8, 52.9, 49.8, 41.0, 30.5, 25.4, 24.7, 22.5, 21.5, 14.2.
HRMS (EI): m/z [M]+ calcd for C18H25NO2S: 319.1606; found:
HRMS (ESI): m/z [M + Na]+ calcd for C18H23O3NSNa: 356.1291; found:
319.1600.
356.1286.
5a
[]D20 –4.61 (c 1.05, CHCl3).
(Z)-6-Benzyl-8-ethylidene-1,1-dimethyl-6-azaspiro[3.4]octan-7-
one (4d)
HPLC (DAICEL CHIRALPAK AS-H): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 27.5 (minor), 30.8 (major) min.
According to the general procedure for cyclization, the crude product,
which was prepared from 3d (46.2 mg, 0.171 mmol), [Rh(cod)2]BF4
(6.7 mg, 0.0165 mmol), and (R)-tolBINAP (10.6 mg, 0.0155 mmol) in
DCE (1.60 mL) at reflux for 14 h, was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc 4:1) to give 4d (38.6 mg, 84%
yield, 22% ee) as a colorless oil; []D20 –6.16 (c 0.79, CHCl3).
IR (neat): 3023, 2925, 1731, 1345, 1163 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.63 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 8.0
Hz, 2 H), 6.07 (t, J = 1.8 Hz, 1 H), 3.77 (d, J = 11.3 Hz, 1 H), 2.95 (d, J =
11.3 Hz, 1 H), 2.41 (s, 3 H), 2.22 (m, 2 H), 1.88 (m, 1 H), 1.69 (m, 2 H),
1.43 (m, 1 H), 1.10 (t, J = 7.2 Hz, 3 H), 0.95 (s, 3 H), 0.59 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 143.8, 133.9, 132.7, 129.8, 128.0,
124.2, 56.4, 56.2, 42.2, 31.9, 27.1, 27.0, 24.5, 21.8, 20.3, 12.6.
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 9.9 (minor), 11.7 (major) min.
IR (neat): 2967, 1682, 1656 cm–1
.
HRMS (EI): m/z [M]+ calcd for C18H25NO2S: 319.1606; found:
319.1600.
1H NMR (400 MHz, CDCl3):  = 7.31 (m, 5 H), 6.06 (q, J = 8.8 Hz, 1 H),
4.69 (d, J = 15.2 Hz, 1 H), 4.26 (d, J = 15.2 Hz, 1 H), 3.49 (d, J = 10.0 Hz,
1 H ), 2.92 (d, J = 10.0 Hz, 1 H), 2.33 (d, J = 8.8 Hz, 3 H), 2.01 (m, 1 H),
1.81 (m, 1 H), 1.61 (m, 2 H), 0.91 (s, 3 H), 0.88 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 169.0, 136.7, 135.7, 131.3, 128.5,
128.4, 127.5, 52.1, 48.6, 46.3, 41.8, 31.0, 25.4, 25.3, 25.1, 13.2.
Methyl (Z)-2-(1,1-Dimethyl-6-tosyl-6-azaspiro[3.4]octan-8-
ylidene)acetate (4b)
According to the general procedure for cyclization, the crude product,
which was prepared from 3b (58.3 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.6 mg, 0.0160 mmol), and (R)-tolBINAP (10.0 mg, 0.0160 mmol) in
DCE (1.60 mL) at 65 °C for 16 h, was purified by column chromatogra-
phy on silica gel (hexane/EtOAc 4:1) to give 4b (30.2 mg, 52% yield,
26% ee) as a colorless oil; []D20 +28.5 (c 1.21, CHCl3).
HRMS (EI): m/z [M]+ calcd for C18H23NO: 269.1780 found: 269.1782.
(Z)-8-Ethylidene-1,1-dimethyl-6-(naphthalen-2-ylmethyl)-6-
azaspiro[3.4]octan-7-one (4e)
According to the general procedure for cyclization, the crude product,
which was prepared from 3e (51.1 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.8 mg, 0.0167 mmol), and (R)-tolBINAP (10.9 mg, 0.0161 mmol) in
DCE (1.60 mL) at reflux for 3 h, was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc 4:1) to give 4e (32.2 mg, 63% yield,
30% ee) as a colorless oil; []D20 +0.77 (c 0.82, CHCl3).
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (95:5), 1.0
mL/min,  = 256 nm; tR = 8.3 (major), 9.9 (minor) min.
IR (neat): 2954, 2255, 1710, 1355, 1164, 909, 733 cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

F
Y. Oonishi et al.
Special Topic
Synthesis
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 10.5 (minor), 12.9 (major) min.
(Z)-8-Ethylidene-1,1-dimethyl-6-oxaspiro[3.4]octan-7-one (4h)
According to the general procedure for cyclization, the crude product,
which was prepared from 3h (29.0 mg, 0.161 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.8 mg, 0.0159 mmol) in
DCE (1.60 mL) at 65 °C for 16 h, was purified by column chromatogra-
phy on silica gel (benzene) to give 4h (18.0 mg, 62% yield, 40% ee) as a
colorless oil; []D20 –141.7 (c 0.72, CHCl3).
IR (neat): 2952, 2860, 1684, 1660 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.82 (m, 3 H), 7.69 (s, 1 H), 7.48 (m, 2
H), 7.36 (d, J = 1.2 Hz, 1 H), 6.06 (q, J = 7.6 Hz, 1 H), 4.84 (d, J = 14.8 Hz,
1 H), 4.39 (d, J = 14.8 Hz, 1 H), 3.49 (d, J = 6.4 Hz, 1 H), 2.91 (d, J = 6.4
Hz, 1 H), 2.34 (d, J = 7.6 Hz, 3 H), 2.01 (m, 1 H), 1.77 (m, 1 H), 1.56 (m,
2 H), 0.91 (s, 3 H), 0.84 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 169.1, 135.6, 134.2, 133.2, 132.8,
131.4, 128.4, 127.7, 127.6, 127.0, 126.3, 126.2, 125.9, 52.2, 48.6, 46.4,
41.8, 30.9, 25.5, 25.3, 25.1, 13.3.
HPLC (DAICEL CHIRALPAK OJ-H): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 5.4 (major), 6.7 (minor) min.
IR (neat): 2959, 2925, 1755 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.31 (q, J = 7.2 Hz, 1 H), 4.63 (d, J = 9.6
Hz, 1 H), 3.83 (d, J = 9.6 Hz, 1 H), 2.26 (d, J = 7.2 Hz, 3 H), 2.06 (m, 1 H),
1.87 (m, 1 H), 1.66 (t, J = 7.6 Hz, 2 H), 1.15 (s, 3 H), 0.92 (s, 3 H).
HRMS (EI): m/z [M]+ calcd for C22H25NO: 319.1936; found: 319.1926.
(Z)-1,1-Dimethyl-8-pentylidene-6-tosyl-6-azaspiro[3.4]octan-7-
13C NMR (100 MHz, CDCl3):  = 170.6, 138.0, 130.2, 72.4, 51.3, 41.5,
one (4f)
30.6, 25.2, 25.1, 24.4, 13.9.
HRMS (EI): m/z [M]+ calcd for C11H16O2: 180.1150; found: 180.1145.
According to the general procedure for cyclization, the crude product,
which was prepared from 3f (60.0 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.7 mg, 0.0165 mmol), and (R)-tolBINAP (10.8 mg, 0.0159 mmol) in
DCE (1.60 mL) at reflux for 14 h, was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc 4:1) to give 4f (46.1 mg, 77%
yield, 78% ee) as a colorless oil; []D20 –49.9 (c 1.32, CHCl3).
(Z)-1,1-Dimethyl-8-pentylidene-6-oxaspiro[3.4]octan-7-one (4i)
According to the general procedure for cyclization, the crude product,
which was prepared from 3i (35.1 mg, 0.158 mmol), [Rh(cod)2]BF4
(6.7 mg, 0.0165 mmol), and (R)-tolBINAP (10.9 mg, 0.0161 mmol) in
DCE (1.60 mL) at 65 °C for 3 h, was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc 9:1) to give 4i (17.9 mg, 51% yield,
69% ee) as a colorless oil; []D20 –51.7 (c 1.08, CHCl3).
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 7.3 (minor), 8.6 (major) min.
IR (neat): 2924, 1724, 1462, 1364 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4
Hz, 2 H), 6.03 (t, J = 8.0 Hz, 1 H), 4.33 (d, J = 10.0 Hz, 1 H), 3.33 (d, J =
10.0 Hz, 1 H), 2.78 (m, 1 H), 2.58 (m, 1 H), 2.42 (s, 3 H), 2.05 (m, 1 H),
1.78 (m, 1 H), 1.69 (m, 1 H), 1.60 (m, 1 H), 1.33 (m, 4 H), 1.09 (s, 3 H),
0.87 (t, J = 7.2 Hz, 3 H), 0.79 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.4, 144.8, 143.1, 135.5, 132.7,
129.6, 128.0, 52.1, 48.7, 41.8, 31.6, 30.6, 27.0, 25.2, 24.8, 24.5, 22.4,
21.6, 13.9.
HPLC (DAICEL CHIRALPAK OD-H): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 3.7 (minor), 4.2 (major) min.
IR (neat): 2952, 2927, 1754, 1462, 1363, 1114 cm–1
.
1H NMR (500 MHz, CDCl3):  = 6.21 (t, J = 7.5 Hz, 1 H), 4.62 (d, J = 9.0
Hz, 1 H), 3.83 (d, J = 9.0 Hz, 1 H), 2.84 (m, 1 H), 2.72 (m, 1 H), 2.07 (m,
1 H), 1.86 (m, 1 H), 1.66 (t, J = 7.0 Hz, 2 H), 1.49 (tt, J = 7.0, 7.0 Hz, 2 H),
1.40 (qt, J = 7.0, 7.0 Hz, 2 H), 1.15 (s, 3 H), 0.93 (t, J = 7.0 Hz, 3 H), 0.92
(s, 3 H).
13C NMR (125 MHz, CDCl3):  =170.7, 143.9, 129.4, 72.6, 51.5, 41.7,
31.8, 30.9, 27.5, 25.5, 25.4, 24.6, 22.7, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C21H29O3NSNa: 398.1760; found:
398.1760.
HRMS (EI): m/z [M]+ calcd for C14H22O2: 222.1620; found: 222.1614.
(Z)-1,1-Dimethyl-8-(2-methylpropylidene)-6-tosyl-6-
azaspiro[3.4]octan-7-one (4g)
(Z)-4-Ethylidene-3-methyl-3-(prop-1-en-2-yl)-1-tosylpyrrolidine
According to the general procedure for cyclization, the crude product,
which was prepared from 3g (56.9 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.7 mg, 0.0165 mmol), and (R)-tolBINAP (10.8 mg, 0.0159 mmol) in
DCE (1.60 mL) at reflux for 14 h, was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc 4:1) to give 4g (50.0 mg, 88%
yield, 15% ee) as a colorless oil; []D20 –13.8 (c 1.02, CHCl3).
(6j)
According to the general procedure for cyclization, the crude product,
which was prepared from 3j (48.9 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.6 mg, 0.0156 mmol) in
DCE (1.60 mL) at reflux for 1 h, was purified by column chromatogra-
phy on silica gel (benzene) to give 6j (29.8 mg, 61% yield, 98% ee) as a
colorless oil; []D20 –3.20 (c 0.91, CHCl3).
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 6.6 (minor), 7.7 (major) min.
HPLC (DAICEL CHIRALPAK AS-H): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 19.9 (minor), 23.4 (major) min.
IR (neat): 3025, 2960, 2864, 1721, 1362, 1169 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.92 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0
Hz, 2 H), 5.82 (d, J = 10.0 Hz, 1 H), 4.33 (d, J = 10.0 Hz, 1 H) , 3.71 (m, 1
H), 3.32 (d, J = 10.0 Hz, 1 H), 2.41 (s, 3 H), 2.03 (m, 1 H), 1.80 (m, 1 H),
1.67 (m, 1 H), 1.60 (m, 1 H), 1.08 (s, 3 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.93
(d, J = 6.5 Hz, 3 H), 0.78 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.2, 149.6, 144.9, 135.4, 130.7,
129.6, 128.0, 52.1, 48.4, 41.8, 30.5, 26.0, 25.1, 24.8, 24.3, 22.8, 22.7,
21.7.
IR (neat): 3019, 1216, 762 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.71 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0
Hz, 2 H), 5.17 (m, 1 H), 4.84 (s, 1 H), 4.81 (s, 1 H), 3.82 (m, 2 H), 3.46
(d, J = 9.0 Hz, 1 H), 2.84 (d, J = 9.0 Hz, 1 H), 2.43 (s, 3 H), 1.62 (s, 3 H),
1.55 (dd, J = 7.0, 2.0 Hz, 3 H), 1.16 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 146.9, 143.5, 141.7, 133.0, 129.6,
127.7, 117.1, 112.3, 58.0, 50.7, 49.6, 23.9, 21.5, 19.4, 14.4.
HRMS (EI): m/z [M]+ calcd for C17H23NO2S: 305.1450; found:
305.1450.
HRMS (ESI): m/z [M + Na]+ calcd for C20H27O3NSNa: 384.1604; found:
384.1598.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

G
Y. Oonishi et al.
Special Topic
Synthesis
(Z)-3-Ethylidene-4-methyl-4-(prop-1-en-2-yl)-1-tosylpyrrolidin-
(Z)-8-(Ethylidene-1-d)-1,1-bis(methyl-d3)-6-tosyl-6-
2-one (6k)
azaspiro[3.4]octan-7-one-2,2-d2 (4c-d9)
According to the general procedure for cyclization, the crude product,
which was prepared from 3k (51.1 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.6 mg, 0.0156 mmol) in
DCE (1.60 mL) at reflux for 1 h, was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc 15:1) to give 6k (15.6 mg, 31% yield,
75% ee) as a colorless oil; []D20 –6.60 (c 1.34, CHCl3).
According to the general procedure for cyclization, the crude product,
which was prepared from 3c-d9 (55.0 mg, 0.161 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.6 mg, 0.0156 mmol) in
DCE (1.60 mL) at 65 °C for 14 h, was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc 4:1) to give 4c-d9 (39.5 mg, 72%
20
yield, 84% ee) as a white solid; mp 103–107 °C; []D –29.6 (c 1.62,
CHCl3).
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 225 nm; tR = 11.0 (minor), 11.9 (major) min.
HPLC (DAICEL CHIRALPAK IA-3): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 256 nm; tR = 11.4 (minor), 15.3 (major) min.
IR (neat): 2925, 2854, 1719, 1460, 1376 cm–1
.
IR (neat): 2925, 2219, 1721, 1363, 1170 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.94 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.5
Hz, 2 H), 5.95 (q, J = 7.0 Hz, 1 H), 4.87 (t, J = 2.0 Hz, 2 H), 3.88 (d, J = 9.5
Hz, 1 H), 3.49 (d, J = 9.5 Hz, 1 H), 2.43 (s, 3 H), 2.12 (d, J = 7.0 Hz, 3 H),
1.63 (s, 3 H), 1.28 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.93 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 4.31 (d, J = 10.0 Hz, 1 H), 3.34 (d, J = 10.0 Hz, 1 H), 2.42 (s, 3
H), 2.16 (s, 3 H), 2.03 (d, J = 12.0 Hz, 1 H), 1.80 (d, J = 12.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 166.0, 146.6, 145.0, 138.6, 136.1,
135.4, 129.6, 128.1, 113.2, 54.8, 45.3, 25.7, 21.7, 19.3, 13.7.
HRMS (EI): m/z [M]+ calcd for C17H21NO3S: 319.1242; found:
319.1247.
13C NMR (125 MHz, CDCl3):  = 166.3, 144.5, 136.6 (t, J = 21 Hz), 135.3,
133.5, 129.3, 127.7, 51.8, 48.5, 41.0, 29.4 (m), 24.1, 24.0 (m), 24.0 (m),
21.4, 13.4.
HRMS (EI): m/z [M]+ calcd for C18H14D9NO3S: 342.1964; found:
342.1953.
(E)-Dimethyl-4-ethylidene-3-methyl-3-(prop-1-en-2-yl)cyclopen-
tane-1,1-dicarboxylate (6l)
Conflict of Interest
According to the general procedure for cyclization, the crude product,
which was prepared from 3l (42.6 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.5 mg, 0.0160 mmol), and (R)-tolBINAP (10.6 mg, 0.0156 mmol) in
DCE (1.60 mL) at reflux for 1 h, was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc 15:1) to give 6l (26.0 mg, 61% yield,
41% ee) as a colorless oil; []D20 –6.32 (c 1.41, CHCl3).
The authors declare no conflict of interest.
Funding Information
This work was financially supported by Grants-in-Aid for Scientific
Research (B) (No. 20H03360) and Grants-in-Aid for Scientific Re-
search (C) (No. 20K06960) from JSPS. The Nagase Science Technology
Foundation (for YS) and the Akiyama Life Science Foundation (for YO)
HPLC (DAICEL CHIRALPAK OJ-H): n-hexane/2-propanol (99:1), 1.0
mL/min,  = 207 nm; tR = 9.8 (major), 12.0 (minor) min.
IR (neat): 2954, 1737, 1435, 1255 cm–1
.
1H NMR (500 MHz, CDCl3):  = 5.17 (m, 1 H), 4.69 (s, 2 H), 3.71 (s, 6 H),
3.06 (d, J = 17.0 Hz, 1 H), 2.97 (d, J = 17.0 Hz, 1 H), 2.73 (d, J = 14.0 Hz,
1 H), 2.08 (d, J = 14.0 Hz, 1 H), 1.68 (s, 3 H), 1.63 (d, J = 4.0 Hz, 3 H),
1.16 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.9, 172.2, 149.5, 145.2, 117.2,
111.5, 57.8, 52.8, 52.5, 51.5, 45.0, 37.1, 26.0, 19.1, 14.4.
are also acknowledged for financial support.Japa
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Acknowledgment
We thank Takasago International Corporation for a gift of (R)-tol-
BINAP, (R)-tolBINAP, (R)-H8-BINAP, (R)-SEGPHOS, and (R)-DTBM-SEG-
PHOS.
HRMS (EI): m/z [M]+ calcd for C15H22O4: 266.1518; found: 266.1513.
Dimethyl (E)-4-Ethylidene-3-methyl-3-vinylcyclopentane-1,1-di-
carboxylate (6m)
Supporting Information
According to the general procedure for cyclization, the crude product,
which was prepared from 3m (40.4 mg, 0.160 mmol), [Rh(cod)2]BF4
(6.7 mg, 0.0165 mmol mmol), and (R)-tolBINAP (10.7 mg, 0.0160
mmol) in DCE (1.60 mL) at reflux for 4 h, was purified by column
chromatography on silica gel (n-hexane/EtOAc 15:1) to give 6m (12.5
mg, 31% yield, 3% ee) as a colorless oil; []D20 +0.93 (c 0.98, CHCl3).
Supporting information for this article is available online at
https://doi.org/10.1055/a-1469-7408. Su
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ortingInformationS
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References
HPLC (DAICEL CHIRALPAK OJ + OJ-H): n-hexane/2-propanol (99:1),
1.0 mL/min,  = 225 nm; tR = 29.4 (minor), 32.1 (major) min.
(1) For selected recent reviews, see: (a) Gutekunst, W. R.; Baran, P.
S. Chem. Soc. Rev. 2011, 40, 1976. (b) McMurray, L. F.; O’Hara, L.;
Gaunt, M. Chem. Soc. Rev. 2011, 40, 1885. (c) Wencel-Delord, J.;
Glorius, F. Nat. Chem. 2013, 5, 369. (d) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960. (e) Hartwig,
J. F. J. Am. Chem. Soc. 2016, 138, 2. (f) Davies, H. M. L.; Morton, D.
J. J. Org. Chem. 2016, 81, 343. (g) Saint-Denis, T. G.; Zhu, R.-Y.;
Chen, G.; Wu, Q.-F.; Yu, J.-Q. cience 2018, 359, 747.
IR (neat): 2955, 1736, 1435, 1262 cm–1
.
1H NMR (500 MHz, CDCl3):  = 5.72 (dd, J = 18.0, 11.0 Hz, 1 H), 5.19
(m, 1 H), 4.89 (m, 2 H), 3.70 (d, J = 18.0 Hz, 6 H), 3.06 (d, J = 17.0 Hz, 1
H), 2.99 (d, J = 17.0 Hz, 1 H), 2.52 (d, J = 17.0 Hz, 1 H), 2.24 (d, J = 17.0
Hz, 1 H), 1.64 (d, J = 5.6 Hz, 3 H), 1.16 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.8, 172.2, 145.7, 144.8, 117.2,
111.5, 57.9, 52.8, 52.7, 48.5, 46.9, 36.9, 26.0, 14.5.
(2) Oonishi, Y.; Kitano, Y.; Sato, Y. Angew. Chem. Int. Ed. 2012, 51,
7305.
HRMS (EI): m/z [M]+ calcd for C14H20O4: 252.1361; found: 252.1356.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H

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Y. Oonishi et al.
Special Topic
Synthesis
(3) For an example of Rh(I)-catalyzed cyclization through C(sp3)–H
bond activation triggered by formation of rhodacycle, see:
Mukai, C.; Ohta, Y.; Oura, Y.; Kawaguchi, Y.; Inagaki, F. J. Am.
Chem. Soc. 2012, 134, 19580 .
Y.; Yokoe, T.; Hosotani, A.; Sato, Y. Angew. Chem. Int. Ed. 2014,
53, 1135. (c) Oonishi, Y.; Hato, Y.; Sato, Y. Adv. Synth. Catal.
2015, 357, 3033. (d) Oonishi, Y.; Hato, Y.; Sato, Y. Adv. Synth.
Catal. 2016, 358, 2273. (e) Hato, Y.; Oonishi, Y.; Yamamoto, Y.;
Nakajima, K.; Sato, Y. J. Org. Chem. 2016, 81, 7847.
(4) For selected examples of Rh(I)-catalyzed cyclization through
C(sp2)–H bond activation triggered by formation of rhodacycle,
see: (a) Tanaka, K.; Otake, Y.; Wada, A.; Noguchi, K.; Hirano, M.
Org. Lett. 2007, 9, 2203. (b) Tsuchikama, K.; Kuwata, Y.; Tahara,
Y.; Yoshinami, Y.; Shibata, T. Org. Lett. 2007, 9, 3097. (c) Tanaka,
K.; Otake, Y.; Sagae, H.; Noguchi, K.; Hirano, M. Angew. Chem.
Int. Ed. 2008, 47, 1312. (d) Kawaguchi, Y.; Yasuda, S.; Kaneko, A.;
Oura, Y.; Mukai, C. Angew. Chem. Int. Ed. 2014, 53, 7608.
(e) Kawaguchi, Y.; Yasuda, S.; Mukai, C. Angew. Chem. Int. Ed.
2016, 55, 10473. (f) Kawaguchi, Y.; Yasuda, S.; Mukai, C. J. Org.
Chem. 2017, 82, 7666.
(7) For our recent study on Rh(I)-catalyzed asymmetric cyclization
of enyne through O–H bond activation, which was triggered by
the formation of the rhodacycle, see: Oonishi, Y.; Masusaki, S.;
Sakamoto, S.; Sato, Y. Angew. Chem. Int. Ed. 2019, 58, 8736.
(8) The geometry of alkene in the cyclic compound 4a was deter-
mined by NOESY. The absolute configuration of 4a and 5a was
not determined.
(9) Compound 4a was subjected to the standard reaction condi-
tions, giving 5a in 80% yield (Scheme 7).
(5) For selected examples of Rh(I)-catalyzed enantioselective
cycloisomerization of enynes through oxidative cyclization, see:
(a) Cao, P.; Wang, B.; Zhang, X.-M. J. Am. Chem. Soc. 2000, 122,
6490. (b) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
8198. (c) Mikami, K.; Yusa, Y.; Hatano, M.; Wakabayashi, K.;
Aikawa, K. Tetrahedron 2004, 60, 4475. (d) Nicolaou, K. C.; Li, A.;
Ellery, S. P.; Edmonds, D. J. Angew. Chem. Int. Ed. 2009, 48, 6293.
(e) Masutomi, K.; Noguchi, K.; Tanaka, K. J. Am. Chem. Soc. 2014,
136, 7627. (f) Deng, X.; Ni, S.-F.; Han, Z.-Y.; Guan, Y.-Q.; Lv, H.;
Dang, L.; Zhang, X.-M. Angew. Chem. Int. Ed. 2016, 55, 6295. For
an example of Rh(I)-catalyzed enantioselective Pauson–Khand-
Type reaction of enynes through oxidative cyclization, see:
(g) Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122,
6771. For selected examples of Rh(I)-catalyzed enantioselective
[2+2+2] cycloaddition of enynes through oxidative cyclization,
see: (h) Shibata, T.; Arai, Y.; Tahara, Y. Org. Lett. 2005, 7, 4955.
(i) Evans, P. A.; Lai, K. W.; Sawyer, J. R. J. Am. Chem. Soc. 2005,
127, 12466. (j) Shibata, T.; Tahara, Y. J. Am. Chem. Soc. 2006, 128,
11766. (k) Shibata, T.; Tahara, Y.; Tamura, K.; Endo, K. J. Am.
Chem. Soc. 2008, 130, 3451. (l) Ishida, M.; Shibata, Y.; Noguchi,
K.; Tanaka, K. Chem. Eur. J. 2011, 17, 12578. (m) Suda, T.;
Noguchi, K.; Tanaka, K. Angew. Chem. Int. Ed. 2011, 50, 4475.
(n) Masutomi, K.; Sakiyama, N.; Noguchi, K.; Tanaka, K. Angew.
Chem. Int. Ed. 2012, 51, 13031. (o) Yoshizaki, S.; Nakamura, Y.;
Masutomi, K.; Yoshida, T.; Noguchi, K.; Shibata, Y.; Tanaka, K.
Org. Lett. 2016, 18, 388. (p) Masutomi, K.; Sugiyama, H.; Uekusa,
H.; Shibata, Y.; Tanaka, K. Angew. Chem. Int. Ed. 2016, 55, 15373.
(q) Ueda, H.; Masutomi, K.; Shibata, Y.; Tanaka, K. Org. Lett.
2017, 19, 2913. (r) See also ref. 4c
10 mol% [Rh(cod)2]BF4
10 mol% (R)-tolBINAP
H
H
TsN
TsN
*
*
ClCH2CH2Cl
reflux, 8 h
4a
5a
80% yield
Scheme 7 Isomerization of 4a to 5a
(10) For selected examples of the cyclizations with the formation of
4-membered carbocyclic compound through C(sp3)–H bond
activation, see: (a) Chaumontet, M.; Piccardi, R.; Audic, N.;
Hitce, J.; Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc.
2008, 130, 15157. (b) Rousseaux, S.; Davi, M.; Sofack-Kreutzer,
J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O.
J. Am. Chem. Soc. 2010, 132, 10706. (c) Kefalidis, C. E.; Davi, M.;
Holstein, P. M.; Clot, E.; Baudoin, O. J. Org. Chem. 2014, 79,
11903.
(11) The effect of the counter anion (X) of a cationic Rh(I) complex
on the reactivity was investigated using a [Rh(cod)2]X (X = ClO4,
PF6, SbF6, and BArF4). However, these anions showed almost the
same reactivity as those using BF4 in this cyclization.
(12) Huang studied the mechanism for Rh(I)-catalyzed cyclization of
allenyne through C(sp3)–H bond activation (ref. 2) by means of
DFT calculation. According to this work, the cyclization pro-
ceeded through metal-assisted -bond metathesis like rhoda-
cycle iv, see: Huang, G. Org. Lett. 2015, 17, 1994.
(13) For recent reviews, see: (a) Gómez-Gallego, M.; Sierra, M. A.
Chem. Rev. 2011, 111, 4857. (b) Simmons, E. M.; Hartwig, J. F.
Angew. Chem. Int. Ed. 2012, 51, 3066.
(6) For our recent studies on Rh(I)-catalyzed cyclization through
oxidative addition of two C–C multiple bonds, see: (a) Oonishi,
Y.; Kitano, Y.; Sato, Y. Tetrahedron 2013, 69, 7713. (b) Oonishi,
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–H