Enantioselective Michael Addition of a Malonic Ester to a Maleic Ester Catalyzed by Lithium Binaphtholate

Article abstract of DOI:10.1055/s-0035-1562691

Lithium 3,3′-chlorobinaphtholate was found to catalyze the enantioselective Michael addition of a malonic ester to a maleic ester. High enantioselectivities (>90% ee) were observed, especially in the reactions of 2-alkylmalonic esters and maleic esters.

Full text of DOI:10.1055/s-0035-1562691

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
A
letter
Synlett
M. Sakamoto et al.
Letter
Enantioselective Michael Addition of a Malonic Ester to a Maleic
Ester Catalyzed by Lithium Binaphtholate
Cl
Midori Sakamoto
Tetsuya Kaneko
O
O
Li
Li
Yuya Orito
O
Makoto Nakajima*
O
O
O
OR3
OR3
O
Graduate School of Pharmaceutical Science, Kumamoto
University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973,
Japan
R1
R1
Cl
2
OR3
OR3
(
10 mol%)
R O
2
R O
+
nakajima@gpo.kumamoto-u.ac.jp
TBME, r.t. to 50 °C
2
O
R O
O
2
R O
O
up to 98% ee
12 samples
1
i
R
= H, Me, Et, Pr
2
3
R ,R = Me, Et, Bn
Received: 23.05.2016
Cl
Accepted after revision: 23.06.2016
Published online: 15.07.2016
DOI: 10.1055/s-0035-1562691; Art ID: st-2016-u0352-l
O
O
Li
Li
O
Abstract Lithium 3,3′-chlorobinaphtholate was found to catalyze the
enantioselective Michael addition of a malonic ester to a maleic ester.
High enantioselectivities (>90% ee) were observed, especially in the re-
actions of 2-alkylmalonic esters and maleic esters.
O
BnO
O
O
OEt
OEt
Cl
4
a
OEt
OEt
(10 mol%)
BnO
BnO
+
O
BnO
O
O
Key words asymmetric catalyst, asymmetric synthesis, enantioselec-
tivity, Michael addition, chiral catalyst, lithium binaphtholate
O
2a
1a
3aa
Scheme 1 Enantioselective Michael addition of malonate 1a to male-
ate 2a
The Michael addition is one of the most versatile tools
for forming carbon–carbon bonds. A number of catalytic
1
enantioselective Michael additions have been reported for
the preparation of biologically active compounds with chi-
ral centers using various Michael donors and acceptors. The
Michael addition of a malonic ester to a maleic ester is a
typical example of this chemical transformation, which is
described even in an early volume of the famous ‘Organic
7
butyllithium at room temperature. The reaction proceeded
smoothly to give the corresponding adduct 3aa in high
yield but with moderate enantiomeric excess. Solvent
screening (Table 1) revealed that tert-butyl methyl ether
was the best solvent for optimizing the chemical yield and
selectivity. A lower catalyst concentration improved the se-
lectivity, and higher selectivities were not observed at cata-
lyst concentrations below 0.01 mmol/mL. Lowering the
temperature did not increase the selectivity.
Among the 3,3′-disubstituted naphthols tested, 3,3′-
chlorobinaphthol gave the best enantioselectivity as a cata-
lyst precursor (Table 2). Interestingly, unsubstituted
binaphthol (4e) significantly reduced the catalytic reactivi-
ty and selectivity (Table 2, entry 5).
2
Syntheses’; however, enantioselective Michael additions to
a maleic ester have not been reported to date. We have pre-
viously reported that optically active lithium 3,3′-dichloro-
binaphtholate is an effective catalyst for the enantioselec-
tive Michael addition of α-alkyl-β-keto ester to methyl vinyl
3–6
ketone. Herein, we report the first example of the enantio-
selective Michael addition of a malonic ester to a maleic es-
ter, affording the corresponding adducts in high enantio-
selectivities.
First, we investigated the Michael addition using diben-
zyl malonate (1a) as a donor and diethyl maleate (2a) as an
acceptor (Scheme 1).
With the optimized conditions in hand, we investigated
the Michael addition of malonate to various acceptors. Di-
methyl maleate (2b) and dibenzyl maleate (2c) gave slightly
8
Previously described reaction conditions for the Michael
addition of β-keto ester to methyl vinyl ketone were ap-
lower selectivities compared with diethyl maleate (Table 3,
entries 1 and 2). N-Phenylmaleimide (2e) and chalcone
3
9
10
plied here: the donor and acceptor were added dropwise to
a diethyl ether solution of lithium 3,3′-chlorobinaphtholate
(2f) gave the adducts in good yields but with low enantio-
selectivities (Table 3, entries 3 and 4). Interestingly, fuma-
rate11 (2g), the geometric isomer of maleate, gave the ad-
(0.1 mmol/mL) prepared from 3,3′-chlorobinaphthol and n-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Synlett
M. Sakamoto et al.
Letter
Table 1 Michael Addition of 1a to 2a with 4a as a Catalyst
Table 3 Michael Addition of Various Donors and Acceptors
Entry
Solvent
Et
c (mol/L)a
Conditions
Yield (%)b ee (%)c
Entry
Donor
Acceptor
Conditions
Yield (%)a ee (%)b
1
2
3
4
5
6
2
O
0.1
r.t., 0.5 h
r.t., 0.5 h
r.t., 4 h
93
92
85
94
94
92
88
45
20
57
58
90
90
91
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
2b
2c
2e
2f
r.t., 1 h
r.t., 1 h
r.t., 2 h
r.t., 1 h
r.t., 24 h
50 °C, 1 h
r.t., 1 h
r.t., 1 h
r.t., 1 h
r.t., 1 h
94
75
69
78
83
79
94
93
92
99
85
83
18
20
–8c
4
toluene
THF
0.1
0.1
TBME
TBME
TBME
TBME
0.1
r.t., 0.5 h
r.t., 1 h
0.01
0.003
0.1
2g
2h
2a
2b
2a
2a
r.t., 1 h
7
0 °C, 3 h
90
a
85d
Catalyst concentration
Isolated yield.
Determined by chiral HPLC.
b
c
77
55
10
a
b
c
Isolated yield.
Determined by chiral HPLC.
The predominant enantiomer has the opposite absolute configuration to
Table 2 Michael Addition of 1a to 2a with Various Catalysts
that from 2a.
X
4a: X = Cl
d
The absolute configuration of 3bb was determined to be R by comparison
to literature values of the HPLC retention times [CHIRALPAK AD-H, hexane–
2-PrOH (9:1), 0.5 mL/min; 23.4 min (S), 24.3.2 min (R)].
4
4
4
4
b: X = Br
c: X = Ph
d: X = Me
e: X = H
10a
O
O
Li
Li
O
O
O
O
Cl
1
2
1
1
a: R = H, R = Bn
4
O
OEt
OEt
1
2
O
O
b: R = H, R = Me
1
BnO
BnO
OEt
OEt
(10 mol%)
2a: R = Et
O
O
1
2
t
+
BnO
1c: R = H, R = Bu
1
OR3
OR3
2b: R = Me
1
2
O
2
2 1d: R = Me,R = Me
1
R O
OR
2c: R = Bn
1
2
BnO
O
1e: R = Me, R = Bn
O
2a
R1
2d: R = BB
1
1
2
1
1
f: R = Et, R = Bn
1a
3aa
1
i
2
g: R = Pr, R = Bn
BB = p-BrC6H4CH2
1
i
2
1h: R = Pr, R = Et
Entry
Cat. X
Conditions
Yield (%)a
ee (%)b
O
O
O
1
2
3
4
4a Cl
4b Br
4c Ph
4d Me
4e H
r.t., 1 h
r.t., 1 h
r.t., 3 h
r.t., 24 h
r.t., 24 h
94
94
79
99
65
90
87
18
25
20
O
Ph
Ph
EtO
NPh
OEt
Ph
Ph
O
e
O
2g
O
2h
2
2f
5
a
Figure 1 Donors and acceptors for Michael addition
Isolated yield.
Determined by chiral HPLC.
b
duct in almost racemic form (Table 3, entry 5). These results
revealed that a cis geometry at the C–C double bond was es-
sential for obtaining a high enantioselectivity, but a ketone
with a cis geometry (1,4-diphenyl-but-2-ene-1,3-dione,
ethyl, or even isopropyl groups at the 2-position gave the
corresponding adducts 3da,ed,ea,fa,ga,hc in good yield
with a high enantioselectivity, although dibenzyl 2-isopro-
pylmalonate required 20 mol% catalyst to achieve a smooth
reaction.
12
2h) gave a very low selectivity (Table 3, entry 6).
Among the Michael donors, no alkyl ester performed
In summary, we developed an enantioselective Michael
addition of malonates to maleates, catalyzed by chiral lithi-
um binaphtholate. This is the first example of an enantiose-
lective Michael addition using maleates as the acceptors.
High enantioselectivities were observed, especially in the
reactions of 2-alkylmalonic esters as donors. Further stud-
ies designed to enhance the enantioselectivity and explore
the reaction mechanism are in progress and will be report-
ed in due course.
better than dibenzyl malonate (Table 2, entries 9 and 10).
The absolute configuration of the Michael adduct prepared
from 1b and 2b (Figure 1) was found to be R, assigned by
10a
comparison of the HPLC data to literature values; there-
fore, other Michael adducts would be expected to have the
same absolute configuration.
This Michael addition can be extended to the addition
13
of sterically congested donors (Figure 2).
2-Alkyl
malonate donors gave the adducts with a quaternary car-
bon in high enantioselectivities. Malonate with methyl,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
Synlett
M. Sakamoto et al.
Letter
Nakatsu, M.; Nakajima, M. Molecules 2011, 16, 5008.
(c) Ichibakase, T.; Nakajima, M. Org. Lett. 2011, 13, 1579.
BB = p-bromobenzyl
O
O
O
(d) Ichibakase, T.; Nakajima, M. Synthesis 2012, 44, 3145.
O
OEt
OEt
O
OBB
OBB
(e) Ichibakase, T.; Kaneko, T.; Orito, Y.; Kotani, S.; Nakajima, M.
Tetrahedron 2012, 68, 4210. (f) Kotani, S.; Kukita, K.; Tanaka, K.;
Ichibakase, T.; Nakajima, M. J. Org. Chem. 2014, 79, 4817.
(g) Osakama, K.; Nakajima, M. Org. Lett. 2016, 18, 236.
Me
Me
MeO
MeO
BnO
BnO
O
O
O
3da
3ed
(5) Selected examples of lithium binaphtholate-catalyzed asym-
metric reactions: (a) Schiffers, R.; Kagan, H. B. Synlett 1997,
rt, 1 h
rt, 1 h
92%, 93% ee
9
1%, 94% ee
1175. (b) Loog, O.; Maeorg, I. Tetrahedron: Asymmetry 1999, 10,
2411. (c) Holmes, I. P.; Kagan, H. B. Tetrahedron Lett. 2000, 41,
7453. (d) Hatano, M.; Ishihara, K. Synthesis 2010, 3785.
O
O
(
e) Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010,
O
OEt
OEt
O
OEt
OEt
Me
Et
132, 56. (f) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K.
J. Am. Chem. Soc. 2010, 132, 56.
BnO
BnO
BnO
(
6) Selected reports for the catalytic asymmetric Michael additions
using alkli metal salts of binaphthol derivatives: (a) Tamai, Y.;
Kamifuku, A.; Koshiishi, E.; Miyano, S. Chem. Lett. 1995, 957.
O
O
O
BnO
O
3ea
3fa
rt, 1 h
rt, 3 h
(b) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.;
9
3%, 98% ee
88%, 92% ee
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (c) Belokon, Y.
N.; Gugkaeva, Z. T.; Maleev, V. I.; Moskalenko, M. A.; Tsaloev, A.
T.; Khrustalev, V. N.; Hakobyan, K. V. Tetrahedron: Asymmetry
2011, 22, 167. (d) Otani, T.; Sugawara, A.; Tamai, Y. Tetrahedron
Lett. 2014, 55, 4923.
O
O
O
OEt
OEt
O
OBn
OBn
iPr
iPr
BnO
BnO
EtO
EtO
(7) Lithium salt prepared from the corresponding naphthol and
lithium hydroxide gave lesser result (68% yield, 75% ee under
the conditions given in Table 1, entry 7).
O
O
O
O
3
ga
0 ºC, 17 h, 4a: 20 mol%
1%, 95% ee
3hc
(
8) Typical Experimental Procedure for the Enantioselective
5
50 °C, 17 h
79%, 90% ee
Michael Addition Catalyzed by Lithium Binaphtholate
9
Under argon atmosphere, n-BuLi (0.10 mmol, 20 mol%) in
Figure 2 Enantioselective Michael addition of 2-alkylmalonate esters
catalyzed by 4a (10 mol%)
hexane (0.15 M, 0.67 mL) was added to the solution of (R)-Cl BI-
2
NOL (4a, 17.8 mg, 0.050 mmol, 10 mol%) in TBME at r.t. After
stirring for 1 min, dibenzyl malonate (1a, 0.13 mL, 0.5 mmol)
and diethyl maleate (2a, 0.10 mL, 0.6 mmol, 1.2 equiv) were
successively added to the reaction mixture. After stirring for 1 h,
Acknowledgment
the reaction was quenched with sat. NH Cl aq (2 mL). The
4
aqueous layer was extracted with EtOAc (20 mL), and the com-
bined organic layers were washed with brine (20 mL). After
drying over Na SO , filtration, and concentration, the crude
This study was supported in part by grants from the Naito Foundation
and the Ministry of Education, Science and Culture of Japan.
2
4
product was purified by silica gel column chromatography
(
hexane–EtOAc = 9:1, SiO 10 g) to give the adduct 3aa as a col-
Supporting Information
2
27
orless oil (214 mg, 94% yield, 90% ee). [α]
CHCl
NMR (400 MHz, CDCl
+11.5 (c 1.03,
4
35
) for 90% ee. IR (film): 3066, 3033, 1731, 1159 cm–1
.
1
H
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562691.
3
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
3
): δ = 1.15 (t, J = 7.2 Hz, 3 H, CH
2
CH
3
), 1.23
(
t, J = 7.6 Hz, 3 H, CH CH ), 2.66 (dd, J = 17.0, 5.2 Hz, 1 H, CH CO),
2
3
2
2
.79 (dd, J = 17.0, 7.6 Hz, 1 H, CH CO), 3.60–3.62 (m, 1 H), 4.04–
2
References and Notes
4.12 (m, 5 H), 5.14 (s, 2 H, CH Ph), 5.15 (s, 2 H, CH Ph), 7.28–
2
2
13
7
3
1
.37 (m, 10 H, ArH). C NMR (100 MHz, CDCl ): δ = 13.8, 14.1,
3.4, 40.4, 52.3, 60.8, 61.4, 67.4, 128.2, 128.3, 128.4 128.5,
3
(
1) Review
a) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M. Synthesis
007, 1279. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
c) Almasi, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry
for
the
enantioselective
Michael
addition:
(
2
(
34.9, 135.0, 167.3, 167.5, 171.1, 171.5 (3 C overlapped). MS–
+
FAB: m/z = 457 (M + H ), 91. HRMS: m/z calcd for C25H29O :
8
457.1862; found: 457.1868.
2
4
2
007, 18, 299. (d) Matsunaga, S. In Comprehensive Chirality; Vol.
; Carreira, E. M.; Yamamoto, H., Eds.; Elsevier: Amsterdam,
012, 243. (e) Takemoto, Y.; Stadler, M. In Comprehensive Chiral-
(
9) Recent examples of enantioselective Michael addition to
maleimide derivatives: (a) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L.
M.; Leow, D.; Soh, Y.-T.; Tan, C.-H. Adv. Synth. Catal. 2007, 349,
ity; Vol. 6; Carreira, E. M.; Yamamoto, H., Eds.; Elsevier: Amster-
dam, 2012, 243.
2454. (b) Gómez-Torres, E.; Alonso, D. A.; Gómez-Bengoa, E.;
Nájera, C. Org. Lett. 2011, 13, 6106.
(
(
2) Clarke, H. T.; Murray, T. F. Org. Synth., Coll. Vol. I 1941, 272.
3) Kotani, S.; Moritani, M.; Nakajima, M. Asian J. Org. Chem. 2015,
(
10) Selected examples of recent enantioselective Michael addition
of malonate to chalcone: (a) Evans, D. A.; Rovis, T.; Kozlowski,
M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122,
4, 616.
(
4) Lithium binaphtholate catalyzed reactions developed in our
group: (a) Tanaka, K.; Kukita, K.; Ichibakase, T.; Kotani, S.;
Nakajima, M. Chem. Commun. 2011, 47, 5614. (b) Ichibakase, T.;
9
2
134. (b) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett.
005, 7, 3195. (c) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan,
W.; Wang, W. J. Am Chem. Soc. 2006, 128, 12652. (d) Naka, H.;
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Synlett
M. Sakamoto et al.
Letter
Kanase, N.; Ueno, M.; Kondo, Y. Chem. Eur. J. 2008, 14, 5267.
e) Agostinho, M.; Kobayashi, S. J. Am Chem. Soc. 2008, 130,
430. (f) Wascholowski, V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley,
(13) Compound 3ea (Representative Product)
29
(
2
[α] –11.4 (c 1.0, CHCl ) for 98% ee. IR (ATR): 2983, 1728, 1213
D
3
cm–1. 1H NMR (400 MHz, CDCl ): δ = 1.16 (t, J = 7.2 Hz, 3 H,
3
S. V. Chem. Eur. J. 2008, 14, 6155. (g) Chen, D.; Chen, Z.; Xiao, X.;
Yang, Z.; Lin, L.; Liu, X.; Feng, X. Chem. Eur. J. 2009, 15, 6807.
CH CH ), 1.24 (t, J = 7.6 Hz, 3 H, CH CH ), 1.50 (s, 3 H, CCH ),
2
3
2
3
3
2.56 (dd, J = 16.6, 3.2 Hz, 1 H, CH CO), 2.77 (dd, J = 16.6, 10.4 Hz,
2
(h) Mase, N.; Furusawa, M.; Kitagawa, N.; Shibagaki, F.; Nishiro,
1 H, CH CO), 3.76 (dd, J = 10.4, 3.2 Hz, 1 H, CHCO), 4.03 (q, J = 7.2
2
N.; Takabe, K. Synlett 2010, 2340. (i) Mao, Z.; Jia, Y.; Li, W.;
Wang, L. J. Org. Chem. 2010, 75, 7428. (j) Yoshida, M.; Narita, M.;
Hara, S. J. Org. Chem. 2011, 76, 8513. (k) Espinosa, M.; Blay, G.;
Cardona, L.; Pedro, J. R. Chem. Eur. J. 2013, 19, 14861. (l) Tsubo,
T.; Yamada, T. Synlett 2015, 26, 1111. (m) Lippur, K.; Kaabel, S.;
Järvibg, I.; Rissanen, K.; Kanger, T. J. Org. Chem. 2015, 80, 6336.
11) See ref. 10m for the only example for the enantioselective
Michael addition to fumarate.
12) Recent examples of the enantioselective Michael addition to
diphenyl butenedione: Zari, S.; Kailas, T.; Kudrjashova, M.;
Öeren, M.; Järving, I.; Tamm, T.; Lopp, M.; Kanger, T. Beilstein J.
Org. Chem. 2012, 8, 1452.
Hz, 2 H, CH CH ), 4.10 (q, J = 7.6 Hz, 2 H, CH CH ), 5.08 (d, J =
2
3
2
3
12.4 Hz, 1 H, CH Ph), 5.12 (s, 2 H, CH Ph), 5.14 (d, J = 12.4 Hz, 1
2
2
13
H, CH Ph), 7.22–7.25 (m, 4 H, ArH), 7.30–7.32 (m, 6 H, ArH).
C
2
NMR (100 MHz, CDCl ): δ = 13.9, 14.1, 17.9, 32.9, 45.5, 55.6,
3
60.8, 61.2, 67.5, 128.1, 128.2, 128.3, 128.3, 128.5, 128.5, 135.1,
169.9, 170.1, 171.5, 171.5 (two carbons overlapped). MS–FAB:
+
(
(
m/z = 471 [M + H ], 91. HRMS: m/z calcd for C26H31O : 471.2019;
8
found: 471.2022.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D