Asymmetric vinylogous Michael reaction of α,β-unsaturated ketones with γ-butenolide under multifunctional catalysis

Article abstract of DOI:10.1039/c0cc01054e

A general and direct organocatalytic asymmetric vinylogous Michael reaction of γ-butenolide with α,β-unsaturated ketones was investigated with a multifunctional primary amine salt as catalyst. The reaction enables straightforward access toward synthetically versatile γ-substituted butenolides from simple 2(5H)-furanone with satisfactory yields, diastereo- and enantioselectivities (up to 30:1 dr and 95-99% ee).

Full text of DOI:10.1039/c0cc01054e

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Asymmetric vinylogous Michael reaction of a,b-unsaturated ketones with
c-butenolide under multifunctional catalysisw
Huicai Huang, Feng Yu, Zhichao Jin, Wenjun Li, Wenbin Wu, Xinmiao Liang* and
Jinxing Ye*
Received 21st April 2010, Accepted 7th June 2010
DOI: 10.1039/c0cc01054e
A general and direct organocatalytic asymmetric vinylogous
Michael reaction of c-butenolide with a,b-unsaturated ketones
was investigated with a multifunctional primary amine salt as
catalyst. The reaction enables straightforward access toward
synthetically versatile c-substituted butenolides from simple
2(5H)-furanone with satisfactory yields, diastereo- and enantio-
selectivities (up to 30 : 1 dr and 95–99% ee).
Table 1 Direct organocatalytic asymmetric vinylogous Michael
reaction with g-butenolidea
Conversion
(%)b
ee
As one of the most powerful and useful carbon–carbon bond-
forming reactions, the asymmetric Michael reaction enables
access to a variety of optically active adducts combining
abundant and various donors and acceptors. A variant of
the reaction with a vinylogous nucleophile, known as the
vinylogous Michael reaction, has attracted much interest.1,2
It provides efficient access to functionalized g-butenolides,
which are ubiquitous building blocks for many natural
products. Since g-butenolides can easily isomerize into
dienolates in the presence of a mild base, we envisioned that
an asymmetric vinylogous Michael reaction could be achieved
with 2(5H)-furanone with a chiral organocatalyst. Recently, a
few excellent examples of catalytic asymmetric Mannich,
aldol, Michael and allylation reactions have been reported
with 2(5H)-furanone and related compounds as direct nucleo-
philes.3 While this manuscript was in preparation, Li and
Entry
Catalyst
Solvent
drc
(%)d
1
2
1
2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
Toluene
THF
MeOH
DCE
EtOAc
MeCN
Et2O
Dioxane
n-
Hexane
84
85
90
96
95
93
95
94
97
79
86
68
90
87
91
93
98
92
94
93
97
95
91
99
2.8 : 1
2.8 : 1
3.5 : 1
2.8 : 1
4.8 : 1
7 : 1
11 : 1
15 : 1
10 : 1
1 : 2.4
15 : 1
15 : 1
12 : 1
11 : 1
13 : 1
13 : 1
9 : 1
65
88
39
38
75
85
95
98
97
47
97
96
97
96
97
96
92
77
97
96
95
96
96
95
3
3a
3a
3a
3a
3a
3b
3c
3d
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
4e
5f
6g
7h
8h
9h
10h
11i
12j
13k
14l
15h
16h
17h
18h
19h
20h
21h
22h
23h
24h
2 : 1
co-workers reported
a catalytic asymmetric vinylogous
11 : 1
11 : 1
8 : 1
10 : 1
15 : 1
9 : 1
Michael addition of substituted g-butenolides to chalcones
catalyzed by vicinal primary-diamine salts.4 But the substrate
scope was limited to 3,4-diarylfuran-2(5H)-one and chalcones.
For the simple 2(5H)-furanone, only 83% enantioselectivity
and no diastereoselectivity were obtained. Herein we describe
our efforts to address this reaction with much improved scope
and efficiency, where a primary amine organocatalyst promoted
the direct catalytic asymmetric vinylogous Michael reaction of
simple 2(5H)-furanone with a,b-unsaturated ketones with high
diastero- and enantioselectivities.5z
a
All reactions were carried out using 1.0 equiv. of 4 (0.10 mmol,
b
0.5 M), 2.0 equiv. of 5a and 0.10 equiv. of catalyst. Conversion was
determined by GC. Diastereoselectivity was determined by 1H NMR
c
d
of the crude reaction mixture. Enantiomeric excess of the major
e
diastereoisomer, determined by chiral HPLC. With 10 mol% of
f
g
CH3CO2H. With 10 mol% of CCl3CO2H. With 10 mol% of
h
PhCO2H. With 10 mol% of N-Boc-L-Phe (N-Boc-L-phenylalanine).
Catalyst 1 developed in our group for the Michael reaction
of a,b-unsaturated ketones was first examined in the reaction
of benzalacetone and 2(5H)-furanone.6 The reaction proceeded
smoothly with 65% ee and 2.8 : 1 dr (Table 1, entry 1). Using
9-amino (9-deoxy) epiquinine as catalyst in the absence or
i
j
With 20 mol% of N-Boc-L-Phe. With 30 mol% of N-Boc-L-Phe.
k
l
With 10 mol% of N-Boc-D-Phe. With 10 mol% of N-Boc-L-Phg
(N-Boc-L-phenylglycine).
presence of acidic additives, the reaction proceeded with 88%
ee and 2.8 : 1 diastereoselectivity (Table 1, entry 2). Based on
molecular modeling and conformational analysis of the
iminium intermediate of the catalyst and benzalacetone, we
hypothesized that a triamine might be a potential catalyst
scaffold,7 where a primary amine plays a role in activating the
a,b-unsaturated ketone through an iminium mechanism,8 and
the secondary amine and hydrogen bond donor motif would
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, China.
E-mail: liangxm@ecust.edu.cn, yejx@ecust.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products.
CCDC 774478. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc01054e
ꢀc
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be beneficial to the reactivity and chiral assembly of 2(5H)-
Table 2 Organocatalytic asymmetric vinylogous Michael reaction of
various a,b-unsaturated ketonesa
furanone.
Yieldb
Adduct (%)
ee
Entry R1
R2
drc
(%)d
1
2
3
4
5
6
7
8
Ph
Me 6a
Me 6b
Me 6c
Me 6d
Me 6e
Me 6f
Me 6g
Me 6h
Me 6i
Me 6j
Me 6k
Me 6l
Me 6m
Me 6n
84
80
75
79
78
81
75
78
85
73
84
83
85
86
15 : 1
10 : 1
15 : 1
15 : 1
11 : 1
10 : 1
10 : 1
8 : 1
13 : 1
19 : 1
10 : 1
19 : 1
19 : 1
11 : 1
98
97
96
98
95
97
97
95
98
97
96
97
96
97
As such we designed another new type of catalyst 3 derived
from L-amino acid and (1R,2R)-1,2-diphenyl-1,2-ethanediamine,
which had a primary amine, a vicinal secondary amine and a
terminal hydrogen bond donor sulfonamide (catalysts 3a–3d).
The three functional groups constitute a chiral spatial pocket,
which is responsible for both diastereo- and enantioselectivity.
With catalyst 3a, the reactivity and diastereoselectivity
remained, while the enantioselectivity decreased (39% ee,
entry 3). Screening found that the acidic additive had a
profound effect both on the diastereoselectivity and enantio-
selectivity. Acetic acid produced similar results (entry 4).
Trichloroacetic acid and benzoic acid as additives improved
diastereo- and enantioselectivities (entries 5–6). Bulky
N-Boc-L-Phe (N-Boc-L-phenylalanine) gave excellent results
with 11 : 1 dr and 95% ee (entry 7). Screening of catalysts
3a–3d revealed that 3b from L-valine gave the highest diastereo-
and enantioselectivities (entries 7–10). On increasing the
amount of the bulky acidic additive, the reactivities decreased,
while the stereoselectivities remained. (entries 7, 11–12). With
other bulky acidic additives, N-Boc-D-Phe and N-Boc-L-Phg
(N-Boc-L-phenylglycine), the reaction produced the desired
chiral adducts only with slightly low diastereoselectivities
(entries 13–14). This indicated that the chirality of the
N-protected amino acid did not have a profound effect on
the stereoselectivity of the reaction. Good to excellent stereo-
selectivities and conversions were observed in all the solvents
screened except methanol (entries 15–24).
o-FC6H4
m-FC6H4
p-FC6H4
o-ClC6H4
m-ClC6H4
m-BrC6H4
p-BrC6H4
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
m-MeC6H4
p-MeC6H4
2,3-
9
10
11
12
13
14
(MeO)2C6H4
2,4-
15
Me 6o
85
11 : 1
13 : 1
>30 : 1 97
15 : 1
7 : 1
>20 : 1 98
>20 : 1 96
>20 : 1 97
>20 : 1 97
7 : 1
19 : 1
2 : 1
7 : 1
98
98
(MeO)2C6H4
2-Naphthyl
2-Furanyl
2-Thiophenyl
Ph
16
17
18
19
20
21
22
23
24
25
26e
27e
Me 6p
Me 6q
Me 6r
86
79
83
79
75
74
82
78
65
76
51
67
98
97
Ph
6s
Pr
Bu
Me 6t
Me 6u
Me 6v
Me 6w
Bu 6x
Me 6y
Pen (pentyl)
Hex (hexyl)
Me
PhCH2CH2
–(CH2)2–
–(CH2)4–
99
97
97
97
7a
7b
a
All reactions were carried out using 1.0 equiv. of 4 (0.50 mmol,
0.5 M), 2.0 equiv. of 5, 0.10 equiv. of catalyst 3b and N-Boc-L-Phe in
b
CHCl3. Isolated yield. Diastereoselectivity was determined by
c
1H NMR of the crude reaction mixture. Enantiomeric excess of
d
e
the major diastereoisomer, determined by chiral HPLC. With
20 mol% catalyst.
With these optimized conditions, the reactions of a variety
of enones with g-butenolide using 3b were examined (Table 2).
The reaction of benzalacetone with either an electron-
withdrawing or electron-donating substituent—halogen,
methoxy, methyl—at an ortho-, meta- or para-position
afforded the desired products in high yield with high diastereo-
and enantioselectivity (entries 2–15). The reactions between
heteroaryl enones and g-butenolide were quite successful
(entries 17–18). It should be noted that chalcone was also
applicable, affording the vinylogous product with 88 : 12 d.r.
and 97% ee. Alkyl substituted enones were suitable substrates
for the direct Michael reaction (entries 20–23). The reaction of
2-octen-4-one gave excellent enantioselectivity (99%) and
good diastereoselectivity (7 : 1). With cyclic Michael acceptors,
excellent enantioselectivity was observed using 20 mol% of
catalyst 3b with moderate to good yield and diastereo-
selectivity (entries 26–27).
in Fig. 1. The enone formed an iminium salt with the primary
amine of the catalyst, and the secondary amine and sulfonamide
motifs may direct the g-attack of the dienolate of 2(5H)-
furanone toward one enantioface of the double bond. The G
substituent and C anion simultaneously block the other
enantioface of the double bond, which would also favor high
enantioselectivity. TS B has less steric repulsion between the
dienolate moiety and the C anion than TS A, leading to high
diastereoselectivity. This hypothesis was supported by the
excellent diastereo- and enantioselectivities when large G
substituents (Bn, i-Pr, i-Bu vs. Ph) and bulky C anion motiꢁfs
(N-Boc-L-Phe, N-Boc-D-Phe, N-Boc-L-Phg anion vs. PhCO2
,
CH3CO2ꢁ) were present.
In summary, a general and direct organocatalytic asymmetric
vinylogous Michael reaction of g-butenolide with a,b-unsaturated
ketones was developed. The reaction enables straightforward
access toward synthetically versatile g-substituted butenolides
from simple 2(5H)-furanone with satisfactory yields, diastereo-
and enantioselectivities (2 : 1 - 30 : 1 dr and 95–99% ee).
Crystals of bromide product 6h were obtained for an X-ray
analysis, which established the anti stereochemical outcome
and the absolute configuration.9 A proposed transition state
model that accounts for the observed stereoselectivity is given
ꢀc
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Crystal structure determination of compound 6h: C14H13BrO3,
0.308 mm),
T = 293(2) K, l(Mo-Ka) = 0.71073 A, orthorhombic, space
M
=
309.15;
a
block crystal (0.425
ꢂ
0.340
ꢂ
group: P212121,
a = 6.5631(11) A, b = 7.7659(12) A, c =
27.286(4) A, V = 1390.7(4) A3, 8391 total reflections, 3168 unique,
Rint = 0.0517, R1 = 0.0414 (I > 2s), wR2 = 0.0838, Flack parameter:
0.036(12).
1 For the reactions of silyloxy furan, see
a recent review:
(a) G. Casiraghi, F. Zanardi, L. Battistini and G. Rassu, Synlett,
2009, 1525. Selected examples: (b) H. Kitajima, K. Ito and
T. Katsuki, Tetrahedron, 1997, 53, 17015; (c) H. Kitajama
and T. Katsuki, Synlett, 1997, 568; (d) H. Nishikori, K. Ito and
T. Katsuki, Tetrahedron: Asymmetry, 1998, 9, 1165;
(e) G. Desimoni, G. Faita, S. Filippone, M. Mella,
M. G. Zamponi and M. Zema, Tetrahedron, 2001, 57, 10203;
(f) S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am.
Chem. Soc., 2003, 125, 1192; (g) Y. Huang, A. M. Walji,
C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 15051; (h) H. Yang and S. Kim, Synlett, 2008, 555; (i) H. Suga,
H. Takemoto and A. Kakehi, Heterocycles, 2007, 71, 361.
2 For the reactions of a,a-dicyanoalkene, see
a recent review:
(a) H.-L. Cui and Y.-C. Chen, Chem. Commun., 2009, 4479. Selected
examples: (b) D. Xue, Y.-C. Chen, Q.-W. Wang, L.-F. Cun, J. Zhu
and J.-G. Deng, Org. Lett., 2005, 7, 5293; (c) T. B. Poulsen,
C. Alemparte and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127,
11614; (d) J.-W. Xie, L. Yue, D. Xue, X.-L. Ma, Y.-C. Chen, Y. Wu,
J. Zhu and J.-G. Deng, Chem. Commun., 2006, 1563; (e) J.-W. Xie,
W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu,
J. Zhu and J.-G. Deng, Angew. Chem., Int. Ed., 2007, 46, 389;
(f) J. Aleman, C. B. Jacobsen, K. Frisch, J. Overgaard and
K. A. Jørgensen, Chem. Commun., 2008, 632.
3 (a) A. Yamaguchi, S. Matsunaga and M. Shibasaki, Org. Lett.,
2008, 10, 2319; (b) B. M. Trost and J. Hitce, J. Am. Chem.
Soc., 2009, 131, 4572; (c) H. Ube, N. Shimada and M. Terada,
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H. Tanabe, Y. Xu, S. Matsunaga and M. Shibasaki, J. Am. Chem.
Soc., 2010, 132, 3666; (e) H.-L. Cui, J.-R. Huang, J. Lei,
Z.-F. Wang, S. Chen, L. Wu and Y.-C. Chen, Org. Lett., 2010,
12, 720.
4 J. Wang, C. Qi, Z. Ge, T. Cheng and R. Li, Chem. Commun., 2010,
46, 2124.
5 The asymmetric Michael reaction of chalcones and 2(5H)-furanone
was catalyzed by Takemoto’s bifunctional catalyst. Y. Zhang,
C. Yu, Y. Ji and W. Wang, Chem.–Asian J., 2010, DOI: 10.1002/
asia.201000014.
Fig. 1 X-Ray crystal structure of 6h and proposed transition state in
the vinylogous Michael reaction.
6 (a) P. Li, Y. Wang, X. Liang and J. Ye, Chem. Commun., 2008,
3302; (b) P. Li, S. Wen, F. Yu, Q. Liu, W. Li, Y. Wang, X. Liang
and J. Ye, Org. Lett., 2009, 11, 753.
Expansion of the scope of this catalytic chemistry is currently
underway.
7 (a) K. Ishihara and K. Nakano, J. Am. Chem. Soc., 2005, 127,
10504; (b) K. Ishihara and K. Nakano, J. Am. Chem. Soc., 2007,
129, 8930.
We thank the Shanghai Pujiang Program (08PJ1403300),
National Natural Science Foundation of China (20902018),
the Fundamental Research Funds for the Central Universities
and 111 project (B07023) for financial support.
8 For primary amine catalyzed Michael reactions of unsaturated
ketones through iminium mechanism, see the review:
(a) G. Bartoli and P. Melchiorre, Synlett, 2008, 1759. Selected
examples: (b) Y.-C. Chen, Synlett, 2008, 1919; (c) L.-W. Xu,
J. Luo and Y. Lu, Chem. Commun., 2009, 1807; (d) H. Kim,
C. Yen, P. Preston and J. Chin, Org. Lett., 2006, 8, 5239;
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P. Melchiorre, Org. Lett., 2007, 9, 1403; (f) X. Lu and L. Deng,
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X. Wang and B. List, Angew. Chem., Int. Ed., 2008, 47, 8112.
9 The absolute and relative configurations of 6h were determined by
X-ray crystallographic analysis.
Notes and references
z General procedure for asymmetric Michael addition: to a solution of
a,b-unsaturated ketone 5 (1.0 mmol, 2.0 equiv.) in CHCl3 (1.0 mL)
was added catalyst 3b (0.05 mmol, 0.1 equiv.) and N-Boc-L-Phe
(0.05 mmol, 0.1 equiv.) followed by 2(5H)-furanone (0.5 mmol,
1.0 equiv.) The reaction mixture was stirred at 50 1C for 3 days and
then the solvent was removed under vacuum. The residue was purified
by silica gel chromatography to yield the desired addition product.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 5957–5959 | 5959