Scalable Synthesis of a Chiral Selenium π-Acid Catalyst and Its Use in Enantioselective Iminolactonization of β,γ-Unsaturated Amides

Article abstract of DOI:10.1055/s-0039-1690109

Chiral selenium π-acid catalysis has for a long time been lagging behind other areas of asymmetric catalysis due to a lack of highly enantioselective catalysts. In this regard, we recently developed the first chiral selenium π-acid catalyst which performs the oxidative cyclization of β,γ-unsaturated carboxylic acids with high enantioselectivities. We report herein our improved synthesis of this chiral selenium catalyst, which allows access to a large quantity of the catalyst as the diselenide. In addition, the catalyst is tested in the oxidative cyclization of N -methoxy β,γ-unsaturated amides to give iminolactones with high enantioselectivities.

Full text of DOI:10.1055/s-0039-1690109

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
cluster
A
en
Synlett
Y. Otsuka et al.
Cluster
Scalable Synthesis of a Chiral Selenium -Acid Catalyst and Its Use
in Enantioselective Iminolactonization of ,-Unsaturated Amides
Yuta Otsukaa,b
2
Se
O
OTBS
Yuto Shimazakic
MeO
MeO
Hitoshi Nagaokac
Keiji Maruoka*1,c,d
6 steps
Takuya Hashimoto*a,b,c
(R,R)-6
0
0
0
0-
0
0
0
2-6
9
6
3-4
3
2
2
a
O
(R,R)-6 (5 mol%)
OMe
Department of Chemistry, Graduate School of Science, Chiba
University, 1-33, Yayoi, Inage, Chiba, 263-8522, Japan
takuya.hash@chiba-u.jp
Chiba Iodine Resource Innovation Center, 1-33, Yayoi, Inage,
Chiba, 263-8522, Japan
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto, 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
NFSI (1.05 equiv)
O
R
OMe
R
N
N
CaCO3 (3 equiv)
toluene
b
c
H
21–81% yield
1–98% ee
2 examples
R = aliphatic, aromatic
5
1
d
School of Chemical Engineering and Light Industry, Guang-
dong University of Technology, Panyu District, Guangzhou,
510006,
P. R. of China
Published as part of the Cluster Organosulfur and Organoselenium Compounds in Catalysis
Received: 13.05.2019
Accepted after revision: 18.06.2019
Published online: 28.06.2019
While asymmetric selenium -acid catalysis has been
known for decades, the obtained enantioselectivities re-
main modest in most cases.10 Our contribution to this area
was the development of the first chiral selenium -acid cat-
alyst that promoted highly enantioselective oxidative cy-
clizations of ,-unsaturated carboxylic acids with a broad
substrate scope (Scheme 1).11 In continuation of this study
and to expand its utility, we were prompted to improve the
catalyst synthesis procedure. There are two major bottle-
necks in our initial synthesis: One is the difficulty to obtain
a large quantity of the key chiral indanol scaffold, resulting
from the use of column chromatography to separate the en-
antiomers as chiral-auxiliary-linked diastereomers; the
second is the handling of the precatalyst 5, as this com-
pound is a viscous oil rendering its weighing laborious.
DOI: 10.1055/s-0039-1690109; Art ID: st-2019-w0268-c
Abstract Chiral selenium -acid catalysis has for a long time been lag-
ging behind other areas of asymmetric catalysis due to a lack of highly
enantioselective catalysts. In this regard, we recently developed the
first chiral selenium -acid catalyst which performs the oxidative cy-
clization of ,-unsaturated carboxylic acids with high enantioselectivi-
ties. We report herein our improved synthesis of this chiral selenium
catalyst, which allows access to a large quantity of the catalyst as the
diselenide. In addition, the catalyst is tested in the oxidative cyclization
of N-methoxy ,-unsaturated amides to give iminolactones with high
enantioselectivities.
Key words selenium, diselenide, asymmetric catalysis, oxidative cy-
clization, iminolactones
Previous study
PMB
In the pursuit of ideal asymmetric catalysis, which has
continued for more than half a century, a myriad of chiral
metal and organocatalysts have been created and their util-
ities have been verified in highly enantioselective transfor-
Se
OTBS
MeO
(S)-5
2
mations. A broad range of accessible elements from the pe-
OH
(10 mol%)
O
R
O
R
riodic table have been used for this purpose. However,
when it comes to selenium, its use in asymmetric catalysis
has been underdeveloped despite its well-known abilities
O
NFSI
additive, toluene
0 °C to r.t., 2–12 h
up to 97% ee
1
3
Scheme 1 Our previous work on chiral electrophilic selenium catalysis
to catalyze a variety of unique transformations. The major
catalytic properties of organoselenium compounds are
4
Lewis base catalysis, -acid (electrophilic selenium) catal-
We report herein a scalable synthesis of a new chiral
diselenide precatalyst as a crystalline solid for our selenium
-acid catalysis. This diselenide can be synthesized from a
commercial source in 6 steps with minimal column chro-
matography. With this chiral diselenide in hand, we also ex-
5
6
ysis, and -hole catalysis. Among these, Lewis base cataly-
sis is most successful in asymmetric catalysis, and there are
a couple of chiral catalysts which achieve high levels of en-
7–9
antioselectivity.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
Y. Otsuka et al.
Cluster
amined the oxidative cyclizations of N-methoxy ,-unsat-
urated amides, which were found to give iminolactones
with high enantioselectivities.
verted it into diselenide (R,R)-6, which is an easy-to-handle,
orange crystalline solid, by using [bis(trifluoroacetoxy)io-
do]benzene (PIFA) as the oxidant.
The synthesis of the enantiopure indanol scaffold (R)-2
started from commercially available 6-methoxy-1-inda-
none (1) on 100 mmol scale (Scheme 2). Dimethylation and
reduction of 1 were conducted in one pot in awareness of
PMBSe
OH
OH
i) nBuLi (2.5 equiv)
Et2O, r.t., 6 h
MeO
MeO
ii) PMBSeCN (1.5 equiv)
THF, 0 °C, 30 min
12
pot economy, providing (rac)-2 in quantitative yield with-
out purification. N-Boc-L-Phe was then attached to (rac)-2
as a chiral auxiliary for the resolution of the enantiomers.
While the two diastereomers (R,S)-3 and (S,S)-3 were sepa-
(R)-2
(R)-4 64%
PMBSe
OTBS
TBSCl (3 equiv)
imidazole (4 equiv)
viscous oil,
precatalyst used
in our previous work
MeO
11
rable by column chromatography, this was impractical on
large scale. Accordingly, we took advantage of the solubility
difference of these two diastereomers. By suspending the
mixture of diastereomers in hexane, one isomer (S,S)-3
could be selectively washed out from the solid material
DMF, r.t., 20 h
(R)-5 89%
Se
2
OTBS
crystalline solid, a
new easy-to-handle
precatalyst
PIFA (0.5 equiv)
13
MeO
with modest purity. From the remaining solid, the other
isomer (R,S)-3 was collected in good yield and high purity.
After hydrolysis of the auxiliary, indanol (R)-2 was obtained
CH2Cl2, r.t., 20 min
14
(R,R)-6 86%
with >99% ee. It should be noted that all the steps shown
in Scheme 2 are free of column chromatography for facili-
tating scale-up.
Scheme 3 Scalable synthesis of chiral diselenide (R,R)-6
As the first synthetic application of diselenide (R,R)-6,
we focused on oxidative cyclizations of ,-unsaturated am-
ides, which would give either N- or O-cyclized products.
i) MeI (2.4 equiv)
O
OH
NaOtBu (2.4 equiv))
15,16
MeO
MeO
THF, –10 °C to r.t., 2 h
Among several N-substituents examined (e.g., Ts, Cbz, Ac),
the N-methoxy group was the only productive substituent,
giving the O-cyclized iminolactones 8 in good yields and
high enantioselectivities with a range of aliphatic sub-
strates 7 (Scheme 4).17 No N-cyclized -lactam was ob-
served in these cases. The lower reactivity of 7g is presum-
ably due to the acetylene moiety which competitively inter-
acts with the selenium -acid. CaCO3 was needed to
sequester HF, which is generated during the reaction and
ii) aq NH4Cl (0.5 equiv)
NaBH4 (1.5 equiv)
(
rac)-2 >99%
1
0
°C to r.t., 2 h
O
N-Boc-L-Phe (1.2 equiv)
WSC·HCl (1.5 equiv)
DMAP (10 mol%)
(
S) Bn
O
trituration
in hexane
MeO
NHBoc
THF, r.t., overnight
(
R,S)- and (S,S)-3
degrades the catalyst. In the absence of CaCO , the products
3
O
18,19
were obtained with slightly lower enantioselectivities.
Bn
O
OH
aq NaOH
MeOH
(R,R)-6 (5 mol%)
NFSI (1.05 equiv)
MeO
MeO
O
OMe
NHBoc
O
R
OMe
R
N
60 °C, 4 h
N
CaCO3 (3 equiv)
toluene, r.t., 2 h
H
(
R,S)-3, 32%
(R)-2 >99%, >99% ee
7
8
Scheme 2 Scalable synthesis of a chiral indanol scaffold
Ph
With a multigram quantity of (R)-2 in hand, we turned
our attention to attachment of the selenium moiety to this
chiral scaffold (Scheme 3). As for the lithiation of (R)-2, n-
BuLi could be used by running the reaction in diethyl ether
at room temperature, eliminating the need for t-BuLi as
8a
8b
8c
53%, 98% ee
73%, 97% ee
75%, 96% ee
TIPS
BnO
PhthN
MeO2C
11
used in our previous study. Addition of p-methoxybenzyl
selenocyanate to lithiated (R)-2 gave the desired selenide
(
R)-4 in good yield. The alcohol moiety was then protected
8d
6%, 97% ee
8e
74%, 96% ee
8f
8g
33%, 96% ee
7
81%, 96% ee
with TBSCl to give precatalyst (R)-5 as a viscous oil. To
change the properties of this precatalyst, we further con-
Scheme 4 Substrate scope with aliphatic substrates
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D

C
Synlett
Y. Otsuka et al.
Cluster
This chiral diselenide catalyst was also applicable to
substrates 9 possessing aromatic substituents (Scheme 5).
In comparison with the cyclization of ,-unsaturated car-
Funding Information
T.H. thanks the Japan Society for the Promotion of Science (KAKENHI
Grant Numbers JP16H01021 and JP18H04256 in Precisely Designed
Catalysts with Customized Scaffolding, and JP19H02710). K.M. thanks
the Japan Society for the Promotion of Science (KAKENHI Grant Num-
11
boxylic acids, the reactions of aromatic substrates 9a–c
gave the products 10a–c with higher enantioselectivities by
running the reactions at 10 °C. Attachment of an electron-
donating methoxy group (9d and 9e) led to lower enanti-
oselectivities, presumably due to partial racemization
during the course of the reaction. The low to modest yields
in these examples were due to the formation of nitrile 11 as
bers JP26220803 and JP17H06450).
J
a
p
a
n
S
o
c
i
ety forth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
6
H
0
1
0
2
1)J
a
p
a
n
S
o
c
i
ety forth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
8
H
0
4
2
5
6)J
a
p
a
n
S
o
c
i
ety forth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
9
H
0
2
7
1
0)J
a
p
a
n
S
o
c
i
ety
f
orth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
2
6
2
2
0
8
0
3)J
a
p
a
n
S
o
c
i
ety forth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
7
H
0
6
4
5
0)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690109.
20
the major byproduct.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
porit
ng Inform ati
o
n
(
R,R)-6 (5 mol%)
O
NFSI (1.05 equiv)
References and Notes
Ar
OMe
Ar
N
O
N
CaCO3 (3 equiv)
toluene
H
(1) New address: Graduate School of Pharmaceutical Sciences,
Kyoto University, Sakyo, Kyoto, 606-8501, Japan.
OMe
9
10 °C, 20–24 h
10
(2) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Ed.; Springer: Berlin, 1999.
Me
Br
(3) Wirth, T. Organoselenium Chemistry: Synthesis and Reactions;
Wiley-VCH: Weinheim, 2012.
(
4) Ortgies, S.; Breder, A. ACS Catal. 2017, 7, 5828.
1
0a
10b
50%, 95% ee
10c
32%, 90% ee
(5) Lewis Base Catalysis in Organic Synthesis; Vedejs, E.; Denmark, S.
E., Ed.; Wiley-VCH: Weinheim, 2016.
6
1%, 93% ee
(
6) (a) He, X.; Wang, X.; Tse, Y.-L.; Ke, Z.; Yeung, Y.-Y. Angew. Chem.
Int. Ed. 2018, 57, 12869. (b) Benz, S.; Mareda, J.; Besnard, C.;
Sakai, N.; Matile, S. Chem. Sci. 2017, 8, 8164. (c) Wonner, P.;
Vogel, L.; Düser, M.; Gomes, L.; Kniep, F.; Mallick, B.; Werz, D. B.;
Huber, S. M. Angew. Chem. Int. Ed. 2017, 56, 12009.
MeO
O
Ar
CN
MeO
10d
10e
34%, 51% ee
11
(7) (a) Tao, Z.; Robb, K. A.; Zhao, K.; Denmark, S. E. J. Am. Chem. Soc.
21%, 81% ee
2018, 140, 3569. (b) Denmark, S. E.; Chi, H. M. J. Org. Chem.
2017, 82, 3826. (c) Denmark, S. E.; Kornfilt, D. J. P. J. Org. Chem.
2017, 82, 3192. (d) Denmark, S. E.; Rossi, S.; Webster, M. P.;
Scheme 5 Substrate scope with substrates possessing aromatic sub-
stituents
Wang, H. J. Am. Chem. Soc. 2014, 136, 13016. (e) Denmark, S. E.;
Chi, H. M. J. Am. Chem. Soc. 2014, 136, 8915. (f) Denmark, S. E.;
Chi, H. M. J. Am. Chem. Soc. 2014, 136, 3655. (g) Denmark, S. E.;
Hartmann, E.; Kornfilt, D. J. P.; Wang, H. Nat. Chem. 2014, 6,
The absolute configurations of compounds 8e and 10a
were determined as (S)-8e and (R)-10a by X-ray crystallo-
21,22
graphic analysis (Figure 1).
ometries were assigned as Z.
Their C=N double bond ge-
1056. (h) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am. Chem.
Soc. 2011, 133, 15308.
(
8) (a) See, J. Y.; Yang, H.; Zhao, Y.; Wong, M. W.; Ke, Z.; Yeung, Y.-Y.
ACS Catal. 2018, 8, 850. (b) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2013, 135, 1232.
(
9) (a) Qin, T.; Jiang, Q.; Ji, J.; Luo, J.; Zhao, X. Org. Biomol. Chem.
8e =
10a =
2019, 17, 1763. (b) Liu, X.; Liang, Y.; Ji, J.; Luo, J.; Zhao, X. J. Am.
Chem. Soc. 2018, 140, 4782. (c) Luo, J.; Cao, Q.; Cao, X.; Zhao, X.
Nat. Commun. 2018, 9, 527. (d) Luo, J.; Liu, Y.; Zhao, X. Org. Lett.
2
017, 19, 3434.
(10) (a) Fujita, K.; Iwaoka, M.; Tomoda, S. Chem. Lett. 1994, 923.
b) Fukuzawa, S.-i.; Takahashi, K.; Kato, H.; Yamazaki, H. J. Org.
Figure 1 X-ray crystal structures of iminolactones 8e and 10a
(
Chem. 1997, 62, 7711. (c) Wirth, T.; Häuptli, S.; Leuenberger, M.
Tetrahedron: Asymmetry 1998, 9, 547. (d) Tiecco, M.; Testaferri,
L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A.
Tetrahedron: Asymmetry 2000, 11, 4645. (e) Tiecco, M.;
Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;
Temperini, A. Chem. Eur. J. 2002, 8, 1118. (f) Browne, D. M.;
Niyomura, O.; Wirth, T. Org. Lett. 2007, 9, 3169. (g) Krätzschmar,
F.; Ortgies, S.; Willing, R. Y. N.; Breder, A. Catalysts 2019, 9, 153.
11) Kawamata, Y.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
In conclusion, we have demonstrated herein that our
chiral selenium -acid catalyst (R,R)-6 has become available
in large quantity, as an orange crystalline solid, by the use
of an improved synthetic procedure. This diselenide was ap-
plied to the oxidative cyclization of N-methoxy ,-unsatu-
rated amides to give the corresponding iminolactones with
high enantioselectivities. Further research on the use of this
diselenide and its analogues will be reported in due course.
(
(
2016, 138, 5206.
12) Hayashi, Y. Chem. Sci. 2016, 7, 866.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D

D
Synlett
Y. Otsuka et al.
Cluster
(13) The filtrate containing (S,S)-3 and a lesser amount of (R,S)-3 was
(19) (R,Z)-5-Benzylfuran-2(5H)-one O-Methyl Oxime (8a)
hydrolyzed to give (S)-2 with modest ee. This material can be
converted into enantiomerically pure (S)-2 by following the
same procedure using N-Boc-D-Phe.
Prepared according to the general procedure with 7a (0.10
mmol, 20.5 mg) to give 8a in 73% yield (73 mol, 14.8 mg) and
1
97% ee as a colorless oil. [] 18 °C = –204 (c 1.6, CHCl ); H NMR
D
3
(
14) Hashimoto, T.; Shimazaki, Y.; Omatsu, Y.; Maruoka, K. Angew.
Chem. Int. Ed. 2018, 57, 7200.
(396 MHz, CDCl ):  = 7.19–7.34 (m, 5 H), 6.56 (dd, J = 6.0, 1.9
3
Hz, 1 H), 6.09 (dd, J = 6.0, 1.9 Hz, 1 H), 5.39–5.44 (m, 1 H), 3.87
(s, 3 H), 3.26 (dd, J = 13.5, 5.6 Hz, 1 H), 2.89 (dd, J = 13.5, 8.2 Hz,
(15) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1987, 52,
13
2018.
1 H); C NMR (100 MHz, CDCl ):  = 160.62, 141.59, 135.34,
3
(
(
16) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y. J. Org. Chem. 2016, 81, 545.
17) (a) Kuriyama, M.; Yamamoto, K.; Ishimaru, K.; Fujimura, N.;
Minato, D.; Onomura, O. Heterocycles 2018, 97, 744. (b) Arai, T.;
Watanabe, O.; Yabe, S.; Yamanaka, M. Angew. Chem. Int. Ed.
129.37, 128.67, 127.03, 121.21, 89.42, 62.49, 40.72; HRMS (ESI):
+
m/z [M
+
Na] calcd for C12H13NNaO2: 226.0838; found:
226.0823; HPLC: Daicel CHIRALPAK IC-3, hexane/iPrOH = 5:1,
flow rate = 1.0 mL/min, t = 10.8 min (major), 14.9 min (minor).
R
2
015, 54, 1276.
(20) (a) Lourie, L. F.; Serguchev, Y. A.; Bentya, A. V.; Ponomarenko,
M. V.; Rusanov, E. B.; Vovk, M. V.; Fokin, A. A.; Ignat’ev, N. V.
J. Fluorine Chem. 2015, 179, 42. (b) Trabulsi, H.; Guillot, R.;
Rousseau, G. Eur. J. Org. Chem. 2010, 5884.
(
18) Enantioselective Iminolactonization; General Procedure
A flask containing CaCO (0.30 mmol, 30.0 mg) was flame-dried
under vacuum and filled with an argon atmosphere. Catalyst
3
(

R,R)-6 (5 mol, 3.8 mg), dry toluene (0.50 mL), substrate 7 (100
mol) and NFSI (105 mol, 33.1 mg) were added successively to
(21) Product 8a was derivatized into (R)-5-benzylfuran-2(5H)-one
and its optical rotation was compared with that reported in the
literature. See the Supporting Information for details.
this flask at room temperature. After stirring for 2 h at room
temperature, the reaction was quenched by adding Et N (300
(22) CCDC 1912360 (8e) and CCDC 1912361 (10a) contain the sup-
plementary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
3

mol, 41.8 L), and diluted with CH Cl (ca. 0.5 mL). This sus-
2 2
pension was directly loaded onto silica gel for purification by
column chromatography, eluting with hexane/acetone (3% to
30% gradient) to give the corresponding iminolactone 8.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D