First anti-Selective Direct Michael Addition of α-Alkoxy Ketones to Enones by Cooperative Catalysis of Samarium(III) Trifluoromethanesulfonate and Tributyltin Methoxide

Article abstract of DOI:10.1002/ejoc.201700501

A new highly anti-diastereoselective Michael addition of α-alkoxy ketones to α,β-unsaturated ketones was achieved. This method features a dual-catalyst protocol that combines samarium(III) trifluoromethanesulfonate and Bu₃SnOMe. The combination of these two catalysts effectively allowed the generation of enolate species from α-alkoxy ketones and produced Michael adducts in high yields with high anti diastereoselectivity. A variety of enones and α-alkoxy ketones were applied to this system to give the anti products. One-pot domino Michael/aldol reactions effectively afforded cyclic enones with a defined configuration.

Full text of DOI:10.1002/ejoc.201700501

A Journal of
Accepted Article
Title: First anti-Selective Direct Michael Addition of α-Alkoxyketones to
Enones by Cooperative Catalysis of Sm(OTf)3 and Bu3SnOMe
Authors: Naoto Esumi, Yoshihiro Nishimoto, and Makoto Yasuda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700501
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700501
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10.1002/ejoc.201700501
European Journal of Organic Chemistry
COMMUNICATION
First anti-Selective Direct Michael Addition of α-Alkoxyketones to
Enones by Cooperative Catalysis of Sm(OTf)3 and Bu3SnOMe
Naoto Esumi,[a] Yoshihiro Nishimoto,*[b] and Makoto Yasuda*[a]
Abstract: A new highly anti-diastereoselective Michael addition of α-
of Sm(OTf)3 and Bu3SnOMe (Scheme 1b).[8,9] In this reaction
system, control of both the geometry of generated metal enolates
and the chelated transition state via the combination of catalysts
achieved high anti-selectivity.
alkoxyketones to α,β-unsaturated ketones was achieved. This method
features
a dual-catalyst protocol that combines Sm(OTf)3 and
Bu3SnOMe. The combination of these two catalysts effectively
generates enolate species from α-alkoxyketones and produces
Michael adducts in high yields with high anti-diastereoselectivity. A
variety of enones and α-alkoxyketones were applied to this system to
give the anti-products. The one-pot domino Michael/aldol reactions
effectively afford cyclic enones with defined configuration.
Previous report : syn-selective direct Michael addition of α-oxy ketones
O
R3
O
R1
R2
O
R1
O
R2
R1
Zn complex
(ref. 6a, 6b)
+
(a)
R3
R2
O
H
O
OH
syn
O
Zn
OH
Zn
Non-chelate
R3
α-hydroxy ketones
The diastereoselective Michael addition reaction is a powerful and
versatile tool in organic synthesis.[1, 2] In particular, much effort has
been extended to develop the reaction of enolates as
nucleophiles with α,β-unsaturated carbonyl compounds, which is
one of the most useful methods for the construction of 1,5-
dicarbonyl units.[3] Especially, the ability to directly use carbonyl
compounds as nucleophiles is desired for atom- and step-
economical reactions. α-Functionalized ketones are applied to
various direct catalytic diastereoselective Michael reactions with
enones to provide functionalzed 1,5-dicarbonyl compounds. In
many cases, however, the functional groups that can be used at
the α-position of the carbonyl group has been limited to electron-
withdrawing groups because of the ease of enolization.[4]
Therefore, demands to extend the diversity of available functional
groups have increased. In particular, the application of α-
oxycarbonyl compounds such as α-hydroxy- and α-alkoxyketones
to yield 2-oxy-1,5-dicarbonyl compounds, which are important
building blocks for bioactive compounds,[5] remains a challenging
issue. Previous reports have described the syn-selective direct
catalytic 1,4-addition of α-hydroxyketones to enones catalyzed by
dinuclear Zn complexes (Scheme 1a).[6] A catalytic reaction
system that could selectively give an anti-product, however, has
never been reported.[7] Therefore, a methodology for the control
of diastereoselectivity is needed, especially for the production of
an anti-form. In the present study, we present the first highly anti-
selective direct catalytic Michael addition of α-alkoxyketones to
α,β-unsaturated ketones via the combination of a catalytic amount
This Work : anti-selective direct Michael addition of α-oxy ketones
O
R3
R1
R2
cat. Sm(OTf)3
cat. Bu3SnOMe
O
R1
O
O
SnBu3
O
+
R3
R2
(b)
RO
O
R1
R2
OR
anti
H
OR
R3
H
α-alkoxy ketones
Chelate
Scheme 1. Catalytic diastereoselective Michael additions by the α-oxy ketones
to enones.
The optimization of the reaction conditions of a Michael
addition
of
benzylideneacetone
(1a)
with
α-
methoxyacetophenone (2a) was conducted in the presence of
various types of Lewis acids and basic additives (Table 1). The
combination of Sm(OTf)3 as a Lewis acid and Bu3SnOMe as a
base[10] afforded the product 3aa in high yield and high
diastereoselectivity (88% yield, anti/syn = 93:7) (entry 1). Using
other lanthanide triflate catalysts such as La(OTf)3, Yb(OTf)3, and
Sc(OTf)3 gave the product 3aa in lower yields (entries 2–4), but
some main group metal and transition metal catalysts were not
effective (entries 5–9). The addition reaction was significantly
suppressed in the absence of either Sm(OTf)3 or Bu3SnOMe
(entries 10 and 11). When other basic additives such as an amine
or sodium alkoxide were used, the reactions resulted in only
moderate yields and moderate diastereoselectivities (entries 12–
14). These results clearly show that the combination of Sm(OTf)3
and Bu3SnOMe contributed to both high yield and high
diastereoselectivity.
[a]
[b]
N. Esumi, Prof. Dr. M. Yasuda
Department of Applied Chemistry
Graduate School of Engineering, Osaka University
2-1, Yamada-oka, Suita, Osaka, 565-0871 (Japan)
E-mail: yasuda@chem.eng.osaka-u.ac.jp
Dr. Y. Nishimoto
Table 1. Optimization of reaction conditions of the anti-selective Michael
addition.[a]
O
Frontier Research Base for Global Young Researchers Center for
Open Innovation Research and Education (COiRE)
Graduate School of Engineering, Osaka University
2-1, Yamada-oka, Suita, Osaka, 565-0871 (Japan)
E-mail: nishimoto@chem.eng.osaka-u.ac.jp
Ph
Ph
Lewis Acid (5 mol %)
base (10 mol %)
O
Ph
O
O
Ph
O
1a
+
+
Ph
Ph
MeCN, 60 °C, 24 h
O
OMe
syn-3aa
OMe
anti-3aa
OMe
2a (1 equiv)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700501
European Journal of Organic Chemistry
COMMUNICATION
O
Lewis
acid
basic
Yield
[%][b]
88(84)[d]
79
Entry
anti/syn[c]
5
1e
1f
3ea
3fa
70
80
94:6
95:5
additives
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Sm(OTf)3 Bu3SnOMe
93:7
90:10
94:6
89:11
Nd
Nd
Nd
Nd
Nd
O
La(OTf)3
Yb(OTf)3
Sc(OTf)3
In(OTf)3
Sn(OTf)2
Zn(OTf)2
AgOTf
Cu(OTf)2
none
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Sm(OTf)3
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
Bu3SnOMe
none
6[d]
42
50
<5
0
7
<5
<5
0
11
61
73
70
O
X
7
8
9
10[e]
X = H
Cl
1g
1h
1i
3ga
3ha
3ia
84
91
85
96:4
94:6
95:5
OMe
Nd
O
1j
3ja
75
93:7
85:15
75:25
78:22
83:17
O
iPr2NEt
NaOMe
NaOt-Bu
X
11[f]
12[f]
X = H
1k
1l
3ka
3la
89
87
91:9
92:8
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), Lewis acid (0.050 mmol),
basic additives (0.10 mmol), MeCN (1.0 mL), 60 °C, 24 h. [b] Determined by 1H
NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard. [c]
Determined by 1H NMR analysis of the crude products. [d] Isolated yield.
OMe
O
13[f]
14[f]
15[d,f]
16
1m
1n
1o
1p
3ma
3na
3oa
2pa
89
89
79
<5
96:4
95:5
95:5
nd
S
O
With the optimized reaction conditions in hand (Table 1, entry
1), various enones 1 were applied to the reaction of α-
methoxyacetophenone (2a), as shown in Table 2. β-Aryl
substituted enones 1a–1e furnished the corresponding products
in high yields and high anti-selectivity (entries 1–5).[11] The
sterically hindered enone 1f was also applicable to afford the
product 3fa (entry 6). Excellent yields were obtained in the
reactions of aromatic enones bearing electron-withdrawing and
electron-donating groups 1g–1i (entries 7–9). It is noteworthy that
aliphatic enone 1j was also applied to this reaction system to give
3ja in high yield and high selectivity (entry 10). Chalcone
derivatives 1k and 1l furnished the corresponding products 3ka
and 3la, respectively, in a high yield with a high level of
diastereoselectivity (entries 11 and 12). The heteroaryl-
substituted enones 1m and 1n were smoothly converted to the
corresponding Michael addition products 3ma and 3na,
respectively (entries 13 and 14). The reaction of highly conjugated
enone 1o also proceeded to provide the corresponding 1,4-
addition product 3oa (entry 15). Unfortunately, the reaction of
cyclic enone 1p resulted in a very low yield (entry 16).
O
O
O
[a] Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), Bu3SnOMe (0.10 mmol),
Sm(OTf)3 (0.050 mmol), MeCN (1.0 mL), 60 °C, 24 h. [b] Isolated products. [c]
Determined by 1H NMR analysis of the crude products. [d] Sm(OTf)3 (10 mol %)
was used. [e] THF was used instead of MeCN. [f] The reaction was performed
at 40 °C.
Next, the reactions of various α-alkoxyketones
2 with
benzylideneacetone (1a) were investigated, as shown in Table 3.
In the reactions of o-, m-, and p-methylated α-
methoxyacetophenones 2b–2d, the position of Me group on the
aryl ring of methoxyacetophenones had little effect on either yield
or diastereoselectivity (entries 1–3). Naphthyl substituted ketone
2e provided high yield and high anti-selectivity (entry 4). Although
the yield of 3af was low, aliphatic methoxyketone 2f was also
applicable to this reaction system (entry 5). The reaction of
isopropoxy ketone 2g, which has the greater steric hindrance of
an alkoxy group, afforded the corresponding product 3ag with
high diasteoselectivity, although the yield was moderate (entry 6).
Table 2. Substrate scope of enones 1.[a]
O
O
R1
O
Ph
Ph
R2
Sm(OTf)3 (5 mol %)
O
OMe
O
Bu3SnOMe (10 mol %)
anti-3
+
OMe
+
R1
O
R1
R2
Ph
MeCN, 60 ºC, 24 h
1
2a (1 equiv)
R2
syn-3
OMe
Table 3. Substrate scope of alkoxyketones 2.[a]
O
O
Ph
O
Yield
[%][b]
Entry
1
Product
anti/syn[c]
R3
Sm(OTf)3 (5 mol %)
Bu3SnOMe (10 mol %)
OR4
O
O
O
anti-3
OR4
+
+
Ph
R3
Ph
O
MeCN, 60 ºC, 24 h
X
1a
2 (1 equiv)
R3
1
2
3
4
X = H
Cl
1a
1b
1c
1d
3aa
3ba
3ca
3da
84
83
83
76
93:7
92:8
93:7
91:9
OR4
syn-3
Me
Yield
[%][b]
Entry
2
Product
anti/syn[c]
OMe
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10.1002/ejoc.201700501
European Journal of Organic Chemistry
COMMUNICATION
O
The cooperative Sm(OTf)3/Bu3SnOMe system includes two
important points that allow the realization of a selective reaction
for the anti-form, 3: 1) samarium triflate can have a higher
coordination number to give the chelated Z-form 6; and, 2) the
chelated transition state TS-anti includes highly coordinated tin
enolates, which is favorable.
OMe
1[d]
2b
2c
2d
2e
3ab
3ac
3ad
3ae
82
79
74
81
96:4
93:7
94:6
93:7
O
OMe
2
O
OMe
3
During the course of the present study, we found that a direct
Michael addition followed by heating at high temperature gave
cyclic enones (Scheme 3).[2j, 18] The reaction of enone 1a with
methoxyketone 2a was conducted under the optimized catalyst
system in propionitrile for 24 h, and then the reaction mixture was
heated to reflux (ca.115 °C) to afford a cis-isomer of cyclic enone
9ba in a 90% yield.[19, 20] Reaction using either enone 1b or α-
methoxyketone 2d also gave the corresponding cis-isomers 9ba
and 9ad, respectively, in high yields with high diastereoselectivity.
O
4[d]
OMe
O
OMe
5
6
2f
3af
24
30
94:6
92:8
O
OIPr
2g
3ag
OMe
Sm(OTf)3 (5 mol %)
Bu3SnOMe (10 mol %)
R3
R1
[a] Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), Bu3SnOMe (0.10 mmol),
Sm(OTf)3 (0.050 mmol), MeCN (1.0 mL), 60 °C, 24 h. [b] Isolated products. [c]
Determined by 1H NMR analysis of the crude products. [d] The reaction was
performed at 50 °C.
O
O
+
OMe
R3
2 (1 equiv)
R1
reflux
24 h
EtCN, 60 ºC, 24 h
1
6
O
Cl
OMe
OMe
OMe
A plausible reaction mechanism is shown in Scheme 2. First,
the transmetalation between Bu3SnOMe and Sm(OTf)3 proceeds
to give the samarium methoxide 4 and Bu3SnOTf.[12] Samarium
methoxide 4 is coordinated by alkoxyketone 2 to form the chelate
complex 5, which increases the acidity of the α-proton.[13] Then, a
proton abstraction of the methoxy group on the samarium atom
effectively affords the samarium enolate species 6 in Z-form,
because of the chelation effect. In the transmetallation between
Bu3SnOTf and 6, (Z)-tin enolate 7 is formed,[14} and the reaction
of 7 with (E)-enone 1 affords the corresponding Michael adduct 8
in anti-selectivity through the chelated transition state, TS-anti.
Ph
Ph
Ph
Ph
O
O
O
9aa
90%
cis/trans = 82/18
9ba
73%
9ad
70%
cis/trans = 83/17
cis/trans = 89/11
Scheme 3. Michael/aldol cyclization reaction of enone 1 with alkoxyketone 2.
A possible reaction mechanism is shown in Scheme 4. The
acetyl moiety of Michael adduct 3 is converted into a tin enolate
unit by Sm(OTf)3/Bu3SnOMe. Subsequently, an intramolecular
aldol reaction and a dehydration reaction proceed to give the
[15,16,17]
The syn product is suppressed by the steric repulsion
between enone 1 and R1 in TS-syn. Finally, the protonation of 8
by MeOH yields the product anti-3, and Bu3SnOMe is regenerated.
corresponding cis-isomer of a cyclic enone.
Enolization by
Sm/Sn catalysis
O
R1
O
O
R1 OSnBu3
R3
R3
Sm(OMe)(OTf)2
OMe
O
O
OMe
OMe
3
OMe
R1
R1
OMe
OMe
OMe
2
MeOH
H
5
Bu3SnO
R3
R1
HO
R3
R1
R3
R1
Δ
MeOH
Sm(OTf)2
O
Sm(OMe)(OTf)2
4
-Bu3SnOMe
-H2O
OMe
6
R1
Bu3SnOTf
Sm(OTf)3
O
O
O
9
Z-form
Scheme 4. Possible mechanism of cyclization reaction of Michael adduct 3.
In summary, we have developed the first anti-selective direct
diastereoselective Michael addition reaction of α-alkoxyketones
to enones using Bu3SnOMe/Sm(OTf)3 cooperative catalysis. This
reaction is applicable to various types of enones to afford 1,5-
dicarbonyl compounds in a high level of anti-product. Moreover,
the direct Michael addition/intramolecular aldol condensation
sequence effectively provided a variety of cyclic enones.
SnBu3
O
Bu3SnOMe
OMe
Z-form
R1
7
O
R2
O
O
SnBu3
R3
R1
R3
O
R2
O
R2
R3
OMe
anti-3
1
R1
anti/syn-conformation
determination step
MeOH
OMe
anti
8
Chelated form
R3
R3
O
R1
O
SnBu3
H
O
SnBu3
MeO
R2
anti-3
syn-3
R1
O
H
OMe
R2
H
Experimental Section
TS-anti
TS-syn
H
Scheme 2. Plausible reaction mechanism of the anti-selective Michael
addition of alkoxyketone 2 with enone 1.
Typical procedure (Table 2): To a suspended solution of Sm(OTf)3 (0.050
mmol) in acetonitrile (1.0 mL), enone 1 (1.0 mmol), α-methoxyketone 2
(1.0 mmol), and Bu3SnOMe (0.10 mmol) was added. The reaction mixture
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10.1002/ejoc.201700501
European Journal of Organic Chemistry
COMMUNICATION
was stirred for 24 h at 60 °C, and then quenched by NH4F aq (10%, 10
mL). The mixture was extracted with diethyl ether (10 mL x 3). The
collected organic layers were dried over MgSO4, and evaporation of
volatiles gave the crude product, which was analyzed by 1H NMR
spectroscopy to decide diastereomeric ratio. The crude product was
purified by column chromatography to give the product.
[5]
a) S. Bera, S. K. Das, T. Saha, G. Panda, Tetrahedron Lett. 2015, 56,
146. b) H. Nemoto, N. Matsuhashi, M. Imaizumi, M. Nagai, K. Fukumoto
J. Org. Chem. 1990, 55, 5625. c) D. Taub, R. D. Hoffsommer, H. L. Slates,
N. L. Wendler J. Am. Chem. Soc. 1958, 80, 4435. d) G. V. Pillai, A. J.
Smith, P. A. Hunt, P. B. Simpson Biochem. Pharmacol. 2004, 68, 819.
a) N. Kumagai, S. Matsunaga, M. Shibasaki, Org. Lett. 2001, 3, 4251. b)
[6]
[7]
S. Harada, N. Kumagai, T. Kinoshita, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2003, 125, 2582. c) Y.-Z. Hua, M.-M. Liu, P.-J. Huang, X.
Song, M.-C. Wang, J.-B. Chang, Chem. Eur. J. 2015, 21, 11994.
The stoichiometric amount of tin amide promoted anti-selective direct
Michael addition of α-alkoxyketones to enone. a) I. Shibata, K. Yasuda,
Y. Tanaka, M. Yasuda, A. Baba, J. Org. Chem. 1998, 63, 1334. The
stoichiometric amount of lithium diisopropylamide promoted syn-
selective direct Michael addition of α-alkoxyacetate to enone. b) S.
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Acknowledgements
This work was supported by the JSPS KAKENHI Grant Numbers
JP15H05848 (in Middle Molecular Strategy) and JP16K05719. Y.N. thanks
the Frontier Research Base for Global Young Researchers at Osaka
University, a program of MEXT. We thank Dr. Nobuko Kanehisa for
valuable advice regarding X-ray crystallography. Thanks are due to the
Analytical Instrumentation Facility, Graduate School of Engineering,
Osaka University, for assistance in obtaining the MS spectra.
[8]
[9]
Enantioselective direct Michael addition of α-alkoxyketones to
nitroalkenes was reported. a) H. Huang, E. N. Jacobsen, J. Am. Chem.
Soc. 2006, 128, 7170. catalytic cycloaddition of α-hydroxyketones with
dicyanoalkenes including anti-selective Michael addition step of α-
hydroxyketones to dicyanoalkenes was reported. b) S. Tsunoi, Y. Seo,
Y. Takano, I. Suzuki, I. Shibata Org. Biomol. Chem. 2016, 14, 1707.
Intramolecular Direct catalytic Michael addition of α-oxyketone moiety to
enone moiety a) J. christensen, Ł. Albrecht, K. A. Jørgensen, Chem.
Asian. J. 2013, 8, 648. b) Y. Liu, A. Lu, K. Hu, Y. Wang, H. Song, Z. Zhou,
C. Tang, Eur. J. Org. Chem. 2013, 4836. c) D. J. B. Antúnez, M. D.
Greenhalgh, C. Fallan, A. M. Z. Slawin, A. D. Smith, Org. Biomol. Chem.,
2016, 14, 7268.
Keywords: Michael addition • tin • samarium • methoxyketones
• diastereoselectivity
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[12] The transmetalation between Bu3SnOMe and Sm(OTf)3 smoothly
proceeded at ambient temperature and the process was observed by 13
NMR, see supporting information.
C
[13] The coordination of alkoxyketone by samarium methoxide was observed
by 13C NMR, see, supporting information.
[14] When Me3SnOMe was used instead of Bu3SnOMe, the anti-selectivity
was quite changed (75% yield, anti/syn = 77/23). This result suggested
that the tin enolate generated in situ acted as a reactive species of
Michael addition step, see supporting information.
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10.1002/ejoc.201700501
European Journal of Organic Chemistry
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Naoto Esumi,[a] Yoshihiro Nishimoto,*[b]
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First anti-Selective Direct Michael
Addition of α-Alkoxyketones to
Enones by Cooperative Catalysis of
Sm(OTf)3 and Bu3SnOMe
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A cooperative Sm/Sn-catalyzed highly anti-selective Michael reaction of α-
alkoxyketone with enone was achieved. Key to this anti-selectivity was the effective
generation of (Z)-tin enolates by the combination of Sm(OTf)3 and Bu3SnOMe and
the eight-membered chelated transition state. This reaction also provided an
efficient access to diastereoselective cyclic enones.
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