Efficient direct asymmetric vinylogous Michael addition reactions of γ-butenolides to chalcones catalyzed by vicinal primary-diamine salts

Article abstract of DOI:10.1039/b923925a

The first direct organocatalytic asymmetric vinylogous Michael addition reactions of γ-butenolides to chalcones have been developed by using chiral 1,2-diaminocyclohexane as a novel organocatalyst via a di-iminium transition state to provide syn-Michael p

Full text of DOI:10.1039/b923925a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Efficient direct asymmetric vinylogous Michael addition reactions of
c-butenolides to chalcones catalyzed by vicinal primary-diamine saltsw
Junfeng Wang, Chao Qi, Zemei Ge,* Tieming Cheng and Runtao Li*
Received (in Cambridge, UK) 16th November 2009, Accepted 3rd February 2010
First published as an Advance Article on the web 19th February 2010
DOI: 10.1039/b923925a
The first direct organocatalytic asymmetric vinylogous Michael
addition reactions of c-butenolides to chalcones have been developed
by using chiral 1,2-diaminocyclohexane as a novel organocatalyst
via a di-iminium transition state to provide syn-Michael products
with good yields, high diastereoselectivities and enantioselectivities
(up to 78% yield, >99 : 1 dr and 96% ee).
value. Depending on the hypothesis, various chiral amine
catalysts, additives and reaction conditions were screened for
the reaction of furanone 1a and chalcone 2a. As listed in
Table 1, all the secondary amine catalysts gave unsatisfactory
results for this reaction (Table 1, entries 1–4). After an
extensive survey of various organocatalysts and conditions
(see ESIw), we were delighted to find that catalyst V with
hexanedioic acid as the additive displayed unique and remark-
able reactivity in the mixture solvent of CH2Cl2–MeOH
(2 : 1) at room temperature and the corresponding product
5-substituted 2(5H)-furanone 3a was obtained in a 69% yield,
>99 : 1 dr and 96% ee (Table 1, entry 10).
g-Butenolides and their derivatives are common structural
subunits in many natural products,1 and particularly, in
compounds with biological activities.2 Therefore, the develop-
ment of methodologies for the construction of substituted
g-butenolides has attracted much attention.3 For this purpose,
reactions of 2-silyloxyfurans with various electrophiles
have emerged as effective strategies,4,5 among which the
Mukaiyama–Michael reactions of 2-silyloxyfurans with var-
ious Michael acceptors such as a,b-unsaturated carbonyl
derivatives,6a b-nitroalkyenes,6b 2-benzylidenemalononitrile,6b
are effective for the preparation of 5-substituted g-buteno-
lides.6 However, so far, only a few examples of the asymmetric
Mukaiyama–Michael addition reactions of 2-silyloxyfurans
have been reported. Moreover, these reactions were almost
catalyzed by chiral metal complexes.7–10
Application scope of the catalytic system was then examined
under the optimized reaction conditions. As shown in Table 2,
except 2(5H)-furanone 1e, this catalytic system worked well
with a wide range of butenolides and chalcones to enable the
access to a broad variety of 5-substituted 2(5H)-furanones in
good yields and excellent diastereo-/enantio-selectivities. It
appeared that the electron nature of the substituents on the
aromatic ring at the 4-position of butenolides (1) did not have
an obvious effect on both diastereoselectivities and enantio-
selectivities, though it seemed that the electron-donating
substituents led to the decrease of the yields (Table 2, entries
16 and 17). A variety of chalcones (2) were also examined, and
either electron-rich substituents or electron-deficient substitu-
ents on both aromatic rings Ar1 or Ar2 in substrates 2 all
underwent smoothly the reaction with substrates 1 in satis-
factory results, except the chalcone with an o-substituent on
Ar2 (Table 2, entry 7, 80% ee, and entry 15, 83% ee). Having
obtained the satisfactory results with catalyst V, we then used
(1R,2R)-1,2-diaminocyclohexane (VI) as the catalyst and
obtained the corresponding opposite enantiomers in the same
results as well (Table 2, entries 18–20).
Though organocatalytic asymmetric Michael addition has
been investigated extensively,11 to the best of our knowledge,
the only organocatalytic asymmetric Mukaiyama–Michael
reaction of 2-silyloxyfurans was reported by Macmillan
(Scheme 1(1)).12 More recently, Trost13 disclosed the first direct
use of butenolides in Michael reactions with nitroalkyenes
under a zinc catalyst (Scheme 1(2)), which avoided the
preformation of 2-silyloxyfurans from g-butenolides. However,
there is still no report on the direct asymmetric vinylogous
Michael addition reactions of g-butenolides catalyzed by
an organocatalyst. Herein, we disclose the first direct organo-
catalytic asymmetric vinylogous Michael addition reaction of
g-butenolides to chalcones catalyzed by vicinal primary-
diamine salts in good yields, excellent diastereoselectivities
and enatioselectivities (Scheme 1(3)).
Inspired by Macmillan’s and Trost’s work, we assumed that
if a suitable organocatalyst could be employed successfully in
the direct asymmetric Michael reaction of butenolides with
a,b-unsaturated carbonyl compounds, it would be of great
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, 38 Xueyuan Road,
Beijing, 100191, P. R. China. E-mail: Lirt@mail.bjmu.edu.cn,
Zmge@bjmu.edu.cn; Fax: +86-10-82716956; Tel: +86-10-82801504
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and characterization data for 3a–3r; CIF file
for 3k. CCDC 743805. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b923925a
Scheme 1 Asymmetric Michael addition reactions for the synthesis of
chiral 5-substituted 2(5H)-furanones.
ꢀc
This journal is The Royal Society of Chemistry 2010
2124 | Chem. Commun., 2010, 46, 2124–2126

View Article Online
Table 1 Screening of catalysts for direct Michael reactions of
g-butenolide 1a with chalcone 2a
Table
2
Organocatalyzed direct Michael addition reactions of
g-butenolides to chalcones
1
Entry
Ar1
Ar2
Yield %a dr syn : antib,c ee %b
1
2
3
4
5
6
1a 4-CH3Ph Ph
69(3a)
65(3b)
2-Thienyl 62(3c1)
>99 : 1
93 : 7
>99 : 1
>99 : 1
96 : 4
96
91
89
91
94
96
1a Ph
1a Ph
Ph
1a 4-CH3Ph 2-Thienyl 70(3d)
1a Ph 4-CH3Ph 61(3e)
1a 3-NO2Ph 2-Thienyl 36(3f)
93 : 7
7
8
9
1a Ph
1b Ph
1b Ph
2-ClPh
Ph
63(3g)
66(3h)
2-Thienyl 71(3i)
>99 : 1
98 : 2
97 : 3
>99 : 1
>99 : 1
>99 : 1
91 : 9
95 : 5
98 : 2
>99 : 1
98 : 2
1 : 1
80
95
95
91
96
96
92
91
83
93
95
À83
À91
À95
Entry Cat.a Additive
Yield (%)c drd
ee (%)d
10
11
12
13
14
15
16
17
18d
19d
20d
1b 4-CH3Ph 2-Thienyl 74(3j)
1b 4-CH3Ph Ph 75(3k1)
4-CH3Ph 69(3l)
1
2
3
4
5
6
7
8
I
II
I
III
IV
V
V
V
V
V
—
—
TEA
TEA
AcOH
AcOHb
N.R
Trace
N.R.
Trace
8
—
—
—
—
—
—
—
—
0
87
90
—
—
1b Ph
1b Ph
1b Ph
1b Ph
1c Ph
4-ClPh
3-ClPh
2-ClPh
78(3m)
78(3n)
73(3o)
—
2-Thienyl 37(3p)
35
98 : 2
98 : 2
—
1d 4-CH3Ph Ph
1e
1a Ph
1b 4-CH3Ph Ph
46(3q)
67(3r)
Hexanedioic acid 40
H
H
TfOH
—
Hexanedioic acid 69
Trace
Trace
2-Thienyl 61(3c2)
73(3k2)
95 : 5
>99 : 1
9
—
10e
>99 : 1 96
a
b
Isolated yields of the corresponding products. Enantio- and
diastereoselectivities determined by chiral-phase HPLC and/or 1H
a
b
The catalyst and additive loading was 20 mol%. The additive
c
c
NMR. Relative and absolute configuration were assigned by
single-crystal X-ray analysis and/or CD spectrum by comparison with
loading of HOAc was 40 mol%. Isolated yield of the corresponding
product. Determined by chiral-phase HPLC and/or 1H NMR. The
reaction was conducted at room temperature in the dark for 6 days;
solvent: CH2Cl2–MeOH = 2 : 1.
d
e
d
references. (1R,2R)-cyclohexane-1,2-diamine as the catalyst.
It is easy to see that the reaction showed syn-selectivities
from the X-ray crystal structure of the product 3p (Fig. 1). The
syn/anti ratio was assigned by chiral-phase HPLC data and/or
1H NMR. In comparison with the results of CD measurements
on the determination of the absolute configuration of
g-butenolides in the literatures,14 the negative n-p* Cotton effect
at about 260 nm of product 3p suggested that the product 3p
has the (S)-configuration at the g-C-atom of butenolide ring
(Table 2, entry 16).15 Based on the diimine intermediate
reported by Chin’s group,16 we proposed that chalcones were
activated by chiral 1,2-diaminocyclohexane via the di-iminium
transition state as shown in Scheme 2. The di-iminium inter-
mediate formed from catalyst (1S,2S)-cyclohexane-1,
2-diamine led to the syn- selective Michael products with the
(S)-configuration at the g-C-atom (Table 2, 3a, 3b, 3c1, 3d–3j,
3k1 and 3l–3q), which is consistent with the X-ray crystal
structure and the CD spectrum analysis.
Scheme 2 Proposed di-iminium mechanism in the Michael reactions
of g-butenolides and chalcones.
In conclusion, we have presented the first example for the
direct vinylogous Michael addition reactions of g-butenolides
to chalcones catalyzed by vicinal primary-diamine salts. In the
process, g-butenolides as substrates were employed directly in
the reactions to achieve a wide variety of 5-substituted
furanones with high diastereo- and enantioselectivies. Further
theoretical study of this reaction and a full account of the
reactions based on direct use of g-butenolides and a wide
survey of vicinal primary-diamine salts in other important
reactions will be forthcoming in our laboratory.
Fig. 1 X-Ray structure of product 3p.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2124–2126 | 2125

View Article Online
This research was supported by the funds of the National
Natural Science Foundation of China (No. 20572004), and the
Major State Basic Research Development Program (Grant
No. 2004CB719900).
6 (a) K. Narasaka and T. Mukaiyama, Chem. Lett., 1974, 1223;
(b) K. Narasaka, K. Soai, Y. Aikawa and T. Mukaiyama, Bull.
Chem. Soc. Jpn., 1976, 49, 779; (c) K. Saigo, M. Osaki and
T. Mukaiyama, Chem. Lett., 1976, 163; (d) T. Fukuyama and
L. Yang, Tetrahedron Lett., 1986, 27, 6299; (e) T. Fukuyama and
L. Yang, J. Am. Chem. Soc., 1987, 109, 7881; (f) T. Fukuyama and
L. Yang, J. Am. Chem. Soc., 1989, 111, 8303; (g) A. M. Brimble,
T. M. Brimble and J. J. Gibson, J. Chem. Soc., Perkin Trans. 1,
1989, 179; (h) A. M. Brimble, J. L. Duncalf and C. W. D. Reid,
Tetrahedron: Asymmetry, 1995, 6, 263; (i) T. Okano, S. Eguchi and
Y. Hayakawa, Tetrahedron, 2000, 56, 6219.
7 (a) G. Desimoni, P. Quadrelli and P. Righetti, Tetrahedron,
1990, 46, 2927; (b) G. Desimoni, P. Quadrelli, G. Faita,
G. Mellerio, P. Righetti and C. Zanelli, Gazz. Chim. Ital., 1992,
122, 269.
8 (a) C. Botteghi, S. Paganelli, A. Schionato, C. Boga and A. Fava,
J. Mol. Catal., 1991, 66, 7; (b) J. Christoffers, Liebigs Ann./Recl.,
1997, 1353.
Notes and references
1 For reviews encompassing major classes of butenolide-containing
natural products, see: (a) Furanocembranoid diterpenes:
A. D. Rodriguez, Tetrahedron, 1995, 51, 4571; (b) Acetogenins:
F. W. Alali, X.-X. Liu and J. L. McLaughlin, J. Nat. Prod., 1999,
62, 504; (c) C. J. Smith, D. Abbanat, V. S. Bernan, W. M. Maiese,
M. Greenstein, J. Jompa, A. Tahir and C. M. Ireland, J. Nat. Prod.,
2000, 63, 142; (d) Cardiac steroids or cardenolides: J. R. Hanson,
Nat. Prod. Rep., 2002, 19, 381; (e) R.-T. Li, Q.-B. Han, Y.-T. Zheng,
R.-R. Wang, L.-M. Yang, Y. Lu, S.-Q. Sang, Q.-T. Zheng,
Q.-S. Zhao and H.-D. Sun, Chem. Commun., 2005, 2936;
(f) A. Dalpiaz, B. Pavan, M. Scaglianti, F. Vitali, F. Bortolotti,
C. Biondi, A. Scatturin and S. Manfredini, Int. J. Pharm., 2005, 291,
171; (g) S. Antane, C. E. Caueld, W. Hu, D. Keeney, P. Labthavikul,
K. Morris, S. M. Naughton, P. J. Petersen, B. A. Rasmussen,
G. Singh and Y. Yang, Bioorg. Med. Chem. Lett., 2006, 16, 176.
2 For examples, see: (a) Y. S. Rao, Chem. Rev., 1976, 76, 625;
(b) E. Fukusaki, S. Senda, Y. Nakazono and T. Omata, Tetrahedron,
1991, 47, 6223; (c) K. Mori, Tetrahedron, 1989, 45, 3233;
(d) J. W. Wheeler, G. M. Happ, J. Araujo and J. M. Pasteels,
Tetrahedron Lett., 1972, 13, 4635; (e) R. Bloch and L. Gilbert, J. Org.
Chem., 1987, 52, 4603; (f) L. Thijs, W. P. Waanders, E. H.
M. Stokkingreef and B. Zwanenburg, Recl. Trav. Chim. Pays-Bas.,
1986, 105, 332.
3 (a) G. Casiraghi and G. Rassu, Synthesis, 1995, 607;
(b) G. Casiraghi, G. Rassu, F. Zanardi and L. Battistini, in
Advances in Asymmetric Synthesis, ed. A. Haassner, JAI Press,
Stamford, 1998, vol. 3, pp. 113–189; (c) G. Rassu, F. Zanardi,
L. Battistini and G. Casiraghi, Synlett, 1999, 1333.
4 (a) For a review on the vinylogous aldol reaction in butenolide
synthesis, see: G. Casiraghi, F. Zanardi, G. Appendino and
G. Rassu, Chem. Rev., 2000, 100, 1929; (b) For a review on the
vinylogous Michael reaction in butenolide synthesis, see:
J. Christoffers, Synlett, 2001, 723.
9 M. Sawamura, H. Hamashima and Y. Ito, Tetrahedron, 1994, 50, 4439.
10 S. Kobayashi, S. Suda, M. Yamada and T. Mukaiyama, Chem.
Lett., 1994, 97.
11 (a) J. M. Betancort and C. F. Barbas III, Org. Lett., 2001, 3, 3737;
(b) N. Halland, R. G. Hazell and K. A. Jøgensen, J. Org. Chem.,
2002, 67, 8331; (c) N. Halland, P. S. Aburel and K. A. Jøgensen,
Angew. Chem., Int. Ed., 2003, 42, 661; (d) H. Li, Y. Wang, L. Tang
and L. Deng, J. Am. Chem. Soc., 2004, 126, 9906; (e) T. Okino,
Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto, J. Am. Chem.
Soc., 2005, 127, 119; (f) J. Lu, F. Liu and T. P. Loh, Adv. Synth.
Catal., 2008, 350, 1796; (g) J. Lu, F. Liu and T. P. Loh, Adv. Synth.
Catal., 2008, 350, 1781.
12 S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am.
Chem. Soc., 2003, 125, 1192.
13 B. M. Trost and J. Hitce, J. Am. Chem. Soc., 2009, 131, 4572.
14 (a) F. Beecham, Tetrahedron Lett., 1972, 13, 1669; (b) W. Stocklin,
T. G. Waddell and T. A. Geisman, Tetrahedron, 1970, 26, 2397;
(c) G. Snatzke, Angew. Chem., Int. Ed. Engl., 1968, 7, 14;
(d) G. Snatzke, Tetrahedron, 1965, 21, 413 and 439;
(e) L. G. Yao, H. L. Liu, Y. W. Guo and E. Mollo, Helv. Chim.
Acta, 2009, 92, 1085.
15 (a) A. Gypser, C. Bulow and H. D. Scharf, Tetrahedron, 1995, 51,
1921; (b) J. Bernstein, U. Shmeuli, E. Zadock, Y. Kashman and
I. Neeman, Tetrahedron, 1974, 30, 2817.
5 For reviews on the vinylogous Mannich reaction in butenolide
synthesis, see: (a) S. K. Bur and S. F. Martin, Tetrahedron, 2001,
57, 3221; (b) S. F. Martin, Acc. Chem. Res., 2002, 35, 895.
16 H. Kim, C. Yen, P. Preston and J. Chin, Org. Lett., 2006, 8,
5239.
ꢀc
This journal is The Royal Society of Chemistry 2010
2126 | Chem. Commun., 2010, 46, 2124–2126