Asymmetric vinylogous michael reaction of α,β-unsaturated aldehyde with buteno-4-lactone

Article abstract of DOI:10.1246/cl.2011.518

The asymmetricvinylogous Michael reactions of α,β-unsaturated aldehydes with γ-butenolide(buteno-4-lactone) were efficiently catalyzed by the Jorgensen-Hayashi catalyst and LiOAc. The desired products were obtained in satisfactory yields with excellent enantioselectivities and moderate diastereoselec- tivities.

Full text of DOI:10.1246/cl.2011.518

doi:10.1246/cl.2011.518
518
Published on the web April 23, 2011
Asymmetric Vinylogous Michael Reaction
of ¡,¢-Unsaturated Aldehyde with Buteno-4-lactone
Xiaoyan Luo, Zhiqiang Zhou, Feng Yu, Xin Li, Xinmiao Liang, and Jinxing Ye*
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy,
East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China
(Received February 14, 2011; CL-110123; E-mail: yejx@ecust.edu.cn)
The asymmetric vinylogous Michael reactions of ¡,¢-
Table 1. Optimization studies
Ph
Ph
OR2
unsaturated aldehydes with £-butenolide(buteno-4-lactone) were
efficiently catalyzed by the Jørgensen-Hayashi catalyst and
LiOAc. The desired products were obtained in satisfactory yields
with excellent enantioselectivities and moderate diastereoselec-
tivities.
O
N
OR1
N
N
H
H
H
2a: R1 = H
2b: R1 = Li
3a: R2 = H
3b: R2 = TMS
1
O
O
Cat. (10 mol%)
Compounds containing a £-butyrolactone ring occur in
many natural products, which are of broad biological activities
such as antibacterial, anticancer, antivirus, and nonsteroidal
anti-inflammatory drugs.1 With the discovery of the potential
bioactivities and other uses of those compounds, the preparation
of them become a focus of attention.
Ph
+
O
O
∗
O
Solvent, Additive
∗
Ph
O
4a
5
6a
Conv.
/%b
ee
/%c
Entrya Cat Solvent Additive
drb
1d
2d
1
MeOH None
2a MeOH None
2b MeOH None
3a MeOH None
85
38
72
93
43
55
66
51
70
82
91
68
85
47
21
9
1.6:1.0
1.6:1.0 nd
0
Initially, intensive studies have been focused on the
applications of silyloxyfuran.2 Lewis acid-mediated asymmetric
Mukaiyama Aldol and Mannich reactions employing silyloxy-
furan and pyrrole have been well studied.2f,3 Furthermore,
MacMillan developed an enantioselective Mukaiyama-Michael
reaction of silyloxyfuran with aliphatic ¡,¢-unsaturated alde-
hyde affording chiral £-butenolide by MacMillan’s amine
catalyst.4 The direct reaction is highly valuable from the
standpoint of atom economy. Therefore, in recent years, the
intensive studies have been concentrated on the reactions of £-
butenolide and its derivatives.5 Moreover, Li and Wang realized
diastereo- and enantioselective organocatalytic direct Michael
addition of £-butenolide or its derivatives to chalcones.6 Our
group reported a general and direct organocatalytic asymmetric
vinylogous Michael reaction of £-butenolide with ¡,¢-unsat-
urated ketones catalyzed by a multifunctional primary amine
salt.7 Although great effort has been made for the vinylogous
reactions of ¡,¢-unsaturated system, the direct vinylogous
Michael reactions of £-butenolide to ¡,¢-unsaturated aldehyde
still remains a challenge due to the preference for 1,2-addition
over 1,4-addition. Moreover, there has been no report of the
direct vinylogous Michael reactions of £-butenolide to ¡,¢-
unsaturated aldehydes. This stimulated us to screen various
conditions to overcome the difficulties.
3d
1.7:1.0
3.0:1.0
2.2:1.0
1.9:1.0
1.9:1.0
2.1:1.0
2.4:1.0
2.4:1.0
16
4d
87
98
98
97
97
97
99
5d
3b MeOH None
6e
3b MeOH Boc-L-Phe
3b MeOH Boc-D-Phe
3b MeOH PhCOOH
3b MeOH PhCOOLi
3b MeOH LiOAc
3b MeOH LiOAc
7e
8e
9e
10e
11
12
13
14
15
16
17
18
19
20
2.5:1.0 >99
3b EtOH
3b DMF
3b H2O
LiOAc
LiOAc
LiOAc
1.9:1.0
2.1:1.0
2.2:1.0
2.2:1.0 nd
2.4:1.0 nd
2.6:1.0 nd
2.5:1.0
2.3:1.0
2.6:1.0
95
74
99
3b MeCN LiOAc
3b Toluene LiOAc
3b CHCl3 LiOAc
LiOAc
3b MeOHf LiOAc
3b MeOHg LiOAc
13
50
93
89
3b None
99
99
99
aUnless otherwise noted, all reactions were performed with
3.0 mmol of 4a, 1.0 mmol of 5, 0.10 mmol of catalyst, and
0.20 mmol additive in 1.0 mL solvent at room temperature for
b
1
c
30 h. Determined by H NMR of the crude product. Deter-
mined by chiral GC (the data are for the major isomer)
d20 mol % of organic catalyst was used and the reaction time
was 24 h. e20 mol % of organic catalyst and 20 mol % of
additive were used and the reaction time was 24 h. fThe
reaction was stirred in 0.5 mL MeOH. gThe reaction was
stirred in 2.0 mL MeOH.
In this communication, we report the direct vinylogous
Michael reactions of £-butenolide to ¡,¢-unsaturated aldehydes
with high yields, excellent enantioselectivities, and moderate
diastereoselectivities, which are catalyzed by the Jørgensen-
Hayashi catalyst.8
We initially screened the conditions of direct vinylogous
Michael reactions of £-butenolide to ¡,¢-unsaturated aldehydes.
Since £-butenolides can easily isomerize into dienolates in the
presence of a mild base, we first conducted the reaction of
cinnamaldehyde (4a) and £-butenolide (5) in the presence of
pyrrolidine. To our delight, the reaction proceeded to 85% of
conversion (Table 1, Entry 1). This indicated that the direct
vinylogous Michael reactions could be efficiently promoted by
the base. We next carried out the reaction in the presence of the
chiral organocatalysts 2 and 3. However, inferior results were
Chem. Lett. 2011, 40, 518-520
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

519
Table 2. Asymmetric vinylogous Michael reactions of
£-butenolide (5) to ¡,¢-unsaturated aldehydes 4
obtained catalyzed by 2 (Table 1, Entries 2 and 3). To our great
delight, up to 93% conversion with 87% ee and 3.0:1.0 dr were
obtained in the presence of 3a (Table 1, Entry 4). Catalyzed by
3b, excellent enantioselectivity (98%) with lower conversion
(43%) was obtained (Table 1, Entry 5). We next used catalyst 3b
in the presence of acidic and basic additives. Screening results
showed that the additives had a profound effect on the reaction
rate but both the diastereo- and enantioselectivity were not
remarkably effected (Table 1, Entries 6-10). For instance, Boc-
D-phenylglycine, Boc-L-phenylglycine, and benzoic acid were
introduced to produce the adducts with higher conversions and
similar dr and ee values (Table 1, Entries 6-8). This revealed
that acidic additive could not promote the reaction efficiently.
Gratifyingly, the reaction would become fast in the presence of
basic additive. The role of a mild base was proposed to shift the
keto-enol tautomeric equilibrium to the enolic form, which is
active for the nucleophilic reactions. With dr and ee values
maintained, lithium benzoate and lithium acetate would gave
70% and 82% conversion respectively (Table 1, Entries 9 and
10). Next, the catalyst loading was also taken into account.
Reducing the catalyst loading to 10 mol %, up to 91%
conversion with 2.5:1.0 dr and >99% ee were obtained after
prolonged time (Table 1, Entry 11). A survey of different
reaction solvents revealed that methanol was the most suitable
solvent for this procedure. Performing the reaction in ethanol
and DMF would induce a slight decrease of conversion (Table 1,
Entries 12 and 13). However, the reaction in H2O, MeCN,
toluene, and CHCl3 would become sluggish (Table 1, Entries
14-17). Interestingly, up to 50% conversion with 2.5:1.0 dr and
99% ee could still be observed when the reaction was carried out
neat (Table 1, Entry 18). In addition, the amount of solvent was
also examined. Unfortunately, this variation did not bring any
improvement in the conversion and stereoselectivity (Table 1,
Entries 19 and 20).
OH
O
O
3b (10 mol%)
NaBH4
MeOH
R
+
O
O
O
O
MeOH, LiOAc
R
R
O
O
4
5
6
7
Entrya
R
Yield/%b
drc
eed/%
1
2e
Ph
2-ClPh
4-ClPh
4-FPh
94, 7a
71, 7b
77, 7c
69, 7d
74, 7e
90, 7f
88, 7g
92, 7h
81, 7i
75, 7j
93, 7k
93, 7l
92, 7m
87, 7n
56, 6o
43, 6p
57, 6q
68, 6r
2.2:1.0
1.6:1.0
2.2:1.0
2.5:1.0
2.3:1.0
1.6:1.0
2.2:1.0
2.5:1.0
2.2:1.0
2.1:1.0
2.5:1.0
2.3:1.0
2.8:1.0
2.7:1.0
2g:1.0
98 (83)
93 (88)
95 (89)
98 (88)
96 (84)
98 (96)
98 (100)
98 (87)
97 (88)
94 (83)
96 (84)
94 (97)
98 (92)
97 (91)
94h (77h)
82h (84h)
97h (86h)
3e
4e
5e
6
7
8
9
10
11
12
13
14
15f
16f
17f
18f
4-BrPh
2-MePh
3-MePh
4-MePh
2-MeOPh
3-MeOPh
4-MeOPh
2, 3-diMeOPh
2, 4-diMeOPh
2-Naphthyl
Me
Et
Pr
i-Pr
2g:1.0
2g:1.0
2g:1.0 >99h (95h)
aUnless otherwise noted, all reactions were performed with
2.0 mmol of 4, 1.0 mmol of 5, 0.1 mmol of 3b, and 0.20 mmol
LiOAc in 1.0 mL MeOH at room temperature for 36 h.
bIsolated yield of product after column chromatography.
cDetermined by the crude 1H NMR. dDetermined by chiral
HPLC (the data in parentheses is related to the minor isomer).
e20 mol % of 3b and 30 mol % LiOAc were used. f1.0 mmol of
4 and 3.0 mmol of 5 were used. gDetermined by GC with area
percentage. hDetermined by chiral GC with area percentage
(the data in parentheses is related to the minor isomer).
Having identified the best reaction conditions, we next
explored the scope of the direct vinylogous Michael reactions of
£-butenolide to ¡,¢-unsaturated aldehydes.9 Under the opti-
mized conditions shown in Table 1, the reactions of a variety of
¡,¢-unsaturated aldehydes 4 with £-butenolide (5) were carried
out.10 Representative results are shown in Table 2. The addition
of £-butenolide to aromatic ¡,¢-unsaturated aldehydes gave
products in good to excellent yields with good to excellent
enantioselectivities and moderate diastereoselectivities (Table 2,
Entries 1-13). Especially, the major diastereomers all formed
with excellent enantioselectivities ranging from 93% to 98%.
The results also indicated that the yields afforded by electron-
donating groups were higher than those by electron-withdrawing
groups, while the position of the substituent groups on the
benzene ring have limited effect on stereoselectivity. Addition-
ally, the large 3-(2-naphthyl)acrylaldehyde was also explored
and the adduct was formed in 87% yield with 2.7:1.0 dr and
97/91% ee values (Table 2, Entry 14). Promising results were
also achieved from the addition of £-butenolide to aliphatic ¡,¢-
unsaturated aldehydes. Apart from (E)-pent-2-enal, the enantio-
selectivities of major diastereomers afforded by crotonaldehyde
and hexenal, were excellent (Table 2, Entries 15-18).
O
O
O
Ph
Ph
OTMS
O
N
H
H2O
N
Ph
Ph
Ph
Ph
N
-OH
OTMS
OTMS
O
O
H2O
O
O
Figure 1. Proposed catalytic cycle.
Comparing proton nuclear magnetic resonance (1H NMR)
spectra and optical rotation of the minor diastereomer 6r with
the literature data4a revealed that it was obtained as the (S,R)-
diastereomer. Thus, according to the mechanism of catalyst 3b
(Figure 1), the major diastereomer 6r is (S,S) absolute config-
uration.
In conclusion, an enantioselective vinylogous Michael
reactions of ¡,¢-unsaturated aldehydes with £-butenolide was
Chem. Lett. 2011, 40, 518-520
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

520
efficiently developed. This approach serves as a powerful tool
for the synthetically chiral £-butenolide skeleton. The desired
products were obtained in high yields with excellent enantio-
selectivities and moderate diastereoselectivities.
b) Y. Huang, A. M. Walji, C. H. Larsen, D. W. C.
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We thank Innovation Program of Shanghai Municipal
Education Commission (No. 11ZZ56), Shanghai Pujiang Pro-
gram (No. 08PJ1403300), National Natural Science Foundation
of China (No. 20902018), and the Fundamental Research Funds
for the Central Universities for financial support.
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General procedure for asymmetric Michael addition of ¡,¢-
unsaturated aldehyde with £-butenolide and reduction: To a
solution of £-butenolide (5) in solvent was added ¡,¢-
unsaturated aldehyde 4 and catalyst. The reaction mixture
was stirred at room temperature for the time indicated in
Table 2. Methanol was added to the mixture and then NaBH4
was introduced. The resulting solution was stirred for an
additional 1 h at rt. The crude was filtered using sintered
discs with silica gel. The filtration was evaporated under
reduced pressure to remove the solvent. The residue was
purified by silica gel chromatography to yield the desired
product.
7
8
9
3
4
Organocatalytic conjugate addition of silyloxyfuran with
¡,¢-unsaturated aldehyde: a) S. P. Brown, N. C. Goodwin,
D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 1192.
10 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 518-520
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/