Enantioselective direct vinylogous michael addition of functionalized furanones to nitroalkenes catalyzed by an axially chiral guanidine base

Article abstract of DOI:10.1021/ol200415u

The highly syn-diastereo- and enantioselective direct vinylogous Michael addition ofα-thio substituted furanones with conjugate nitroalkenes was demonstrated using an axially chiral guanidine base catalyst. The method provides facile access to enantioenriched α,γ-functionalized butenolides that can be further manipulated, thereby rendering them useful synthetic intermediates. 2011 American Chemical Society.

Full text of DOI:10.1021/ol200415u

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2026–2029
Enantioselective Direct Vinylogous
Michael Addition of Functionalized
Furanones to Nitroalkenes Catalyzed by
an Axially Chiral Guanidine Base
Masahiro Terada** and Kenichi Ando
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku,
Sendai 980-8578, Japan
mterada@m.tohoku.ac.jp
Received February 15, 2011
ABSTRACT
The highly syn-diastereo- and enantioselective direct vinylogous Michael addition of R-thio substituted furanones with conjugate nitroalkenes
was demonstrated using an axially chiral guanidine base catalyst. The method provides facile access to enantioenriched R,γ-functionalized
butenolides that can be further manipulated, thereby rendering them useful synthetic intermediates.
The modification of furanone derivatives at the γ-posi-
tion, namely via vinylogous reactions, represents an
attractive approach for the preparation of functionalized
γ-butenolides,1 which are commonly encountered motifs
in natural products and biologically relevant molecules.
Enantioselective catalysis of the direct vinylogous reaction
of γ-butenolides and related compounds as pronucleo-
philes has received much attention because this method
provides efficient access to optically active functionalized
γ-butenolides in an atom economical manner.1,2 Recently,
Shibasaki,3 and Trost4 independently reported the chiral
(1) For reviews of vinylogous reactions, see: (a) Casiraghi, G.;
Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929.
(b) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221. (c) Denmark,
S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005,
44, 4682. (d) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G. Synlett
2009, 1525.
(2) For selected examples of enantioselective vinylogous Michael
addition of 2-silyloxyfuranes as a preformed nucleophile. For chiral
metal catalysis, see: (a) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron
1997, 53, 17015. (b) Kitajima, H.; Ito, K.; Katsuki, T. Synlett 1997, 568.
(c) Nishikori, H.; Ito, K.; Katsuki, T. Tetrahedron: Asymmetry 1998, 9,
1165. (d) Desimoni, G.; Faita, G.; Filippone, S.; Mella, M.; Zamponi,
M. G.; Zema, M. Tetrahedron 2001, 57, 10203. (e) Suga, H.; Kitamura,
T.; Kakehi, A.; Baba, T. Chem. Commun 2004, 1414. (f) Robichaud, J.;
Tremblay, F. Org. Lett. 2006, 8, 597. (g) Yang, H.; Kim, S. Synlett 2008,
555. For organocatalysis, see: (h) Brown, S. P.; Goodwin, N. C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. (i) Huang,
Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 15051. (j) Simmons, B.; Walji, A. M.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2009, 48, 4349.
(3) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10,
2319.
(4) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572.
(5) For allylic alkylation, see: (a) Cui, H.-L.; Huang, J.-R.; Lei, J.;
Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 720. For
vinylogous Michael reactions, see: (b) Zhang, Y.; Yu, C.; Ji, Y.; Wang,
W. Chem.;Asian J. 2010, 5, 1303. (c) Wang, J.; Qi, C.; Ge, Z.; Cheng,
T.; Li, R. Chem. Commun. 2010, 46, 2124. (d) Huang, H.; Yu, F.; Jin, Z.;
Li, W.; Wu, W.; Liang, X.; Ye, J. Chem. Commun. 2010, 46, 5957. For
vinylogous aldol reactions, see: (e) Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.;
Lin., L.; Liu, X.; Feng, X. J. Org. Chem. 2010, 75, 5382.
r
10.1021/ol200415u
Published on Web 03/18/2011
2011 American Chemical Society

furanones such as R-thio substituted furanones 2, we
discovered and herein disclose a direct vinylogous Michael
addition10,11 of 2 to conjugate nitroalkenes 3 catalyzed by
axially chiral guanidine base 1 that yields densely functio-
nalized γ-butenolides 4 with high diastereo- and enantios-
electivities (Scheme 1).
Scheme 1. Direct Vinylogous Michael Addition of R-Thio
Substituted Furanones 2 to Conjugate Nitroalkenes 3 Catalyzed
by Axially Chiral Guanidine Base 1
In our previous studies, furanone 2a possessing a phe-
nylthio group at the R-position was found to function as an
efficient vinylogous pronucleophile in the vinylogous aldol
reaction of benzaldehyde, providing the corresponding
product in nearly optically pure form.7 We therefore began
our investigation with the reaction of furanone 2a with β-
nitrostyrene 3a. The catalytic reaction using 5 mol % of
guanidine 1 proceeded smoothly in THF at -40 °C to
afford the vinylogous product 4aa in good yield with high
syn-diastereoselectivity (Table 1, entry 1); however the
enantioselectivity was disappointing (43% ee). We there-
fore modified the substituent introduced at the sulfur atom
of 2 to improve the enantioselectivity (entries 2 and 3). To
our delight, introduction of an aliphatic group in place of
the phenyl substituent on the sulfur atom led to an increase
in enantioselectivity with retention of the high syn-diaster-
eoselectivity, but the chemical yields were markedly de-
pendent on the aliphatic substituents employed. The
sterically demanding tert-butyl group exhibited a benefi-
cial effect on both the chemical yield and the stereoselec-
tivity (entry 3). Further screening of ethereal solvents
revealed that chemical yields were also markedly affected
by the solvent employed (entries 4-7). The use of an
acyclic mono ether resulted in a significant decrease
in the chemical yield accompanied by considerable
formation of byproduct 5, which resulted from over-
reaction of 4ca with 3a (entries 4-6). Acetone was also
found to be inefficient for the present transformation
(entry 8).7,12 THF was most effective at facilitating the
desired reaction, and the use of 2 equiv of furanone 2a
suppressed the unfavorable overreaction, giving rise
to 4ca in good yield with high diastereo- and enantio-
selectivity (entry 9).
metal complex-catalyzed direct vinylogous Mannich and
Michael reactions of 2(5H)-furanone, respectively. Their
pioneering studies stimulated intensive interest in the
development of enantioselective direct functionalization
of furanones5 and related compounds6 at the γ-position,
and several excellent approaches have been accomplished
using chiral metal catalysis6a and organocatalysis.5,6b
Meanwhile, we have also developed a highly diastereo-
and enantioselective direct vinylogous aldol reaction of
(di)halofuranone derivatives with aromatic aldehydes
using axially chiralguanidine 1 asa base catalyst.7,8 During
this investigation, we demonstrated that R-thio substituted
furanone 2 served as an efficient vinylogous nucleophile.7,9
This vinylogous reaction of 2 enables the enantioselective
preparation of γ-butenolide derivatives adorned with mul-
tiple functional handles that can be further manipulated,
thereby rendering them useful synthetic intermediates. In
our ongoing studies of the utility of highly functionalized
(10) For recent reviews of organocatalytic conjugate (Michael) addi-
ꢀ
tions, see: (a) Almas-i, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701.
(11) For selected recent examples of enantioselective direct vinylo-
gous conjugate (Michael) additions using organocatalysts. For alkyli-
dene dicyanides, see: (a) Xue, D.; Chen, Y.-C.; Wang, Q.-W.; Cun, L.-F.;
Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293. (b) Poulsen, T. B.; Bell, M.;
Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63. (c) Xie, J.-W.; Yue, L.;
Xue, D.; Ma, X.-L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem.
Commun. 2006, 1563. (d) Jiang, L.; Zheng, H.-T.; Liu, T.-Y.; Yue, L.;
(6) For a vinylogous Mannich reaction or Michael addition of R,β-
unsaturated γ-butyrolactam, see: (a) Shepherd, N. E.; Tanabe, H.; Xu,
Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 3666. (b)
Feng, X.; Cui, H.-L.; Xu, S.; Wu, L.; Chen, Y.-C. Chem.;Eur. J. 2010,
16, 10309.
(7) Ube, H.; Shimada, N.; Terada, M. Angew. Chem., Int. Ed. 2010,
49, 1858.
ꢀ
Chen, Y.-C. Tetrahedron 2007, 63, 5123. (e) Aleman, J.; Jacobsen, C. B.;
Frisch, K.; Overgaard, J.; Jørgensen, K. A. Chem. Commun. 2008, 632.
(f) Lu, J.; Liu, F.; Loh, T.-P. Adv. Synth. Catal. 2008, 350, 1781. (g) Lu,
J.; Zhou, W.-J.; Liu, F.; Loh, T.-P. Adv. Synth. Catal. 2008, 350, 1796.
(h) Lu, J.; Liu, F.; Zhou, W.-J.; Loh, T.-P. Tetrahedron Lett. 2008, 49,
5389. For enals, see: (i) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao,
J.-H. Org. Lett. 2006, 8, 2217. (j) Bench, B. J.; Liu, C.; Evett, C. R.;
Watanabe, C. M. H. J. Org. Chem. 2006, 71, 9458.
(12) In the direct vinylogous aldol reaction catalyzed by 1, acetone
was found to be an efficient solvent with respect to diastereo- and
enantioselectivities. See ref 7.
(8) For axially chiral guanidines as enantioselective catalysts, see: (a)
Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454. (b)
Terada, M.; Ikehara, T.; Ube, H. J. Am. Chem. Soc. 2007, 129, 14112. (c)
Terada, M.; Nakano, M. Heterocycles 2008, 76, 1049. (d) Terada, M.;
Nii, H. Chem.;Eur. J. 2011, 17, 1760. Also see:(e) Terada, M.; Nakano,
M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. (f) Terada, M.;
Tsushima, D.; Nakano, M. Adv. Synth. Catal. 2009, 351, 2817. (g)
Nakano, M.; Terada, M. Synlett 2009, 1670. (h) Ube, H.; Terada, M.
Bioorg. Med. Chem. Lett. 2009, 19, 3895. (i) Terada, M. J. Synth. Org.
Chem. Jpn. 2010, 67, 1159.
(9) For vinylogous aldol reaction of 3-(phenylthio)furan-2(5H)-one
(2a) with aldehydes, see: Shirai, K.; Kumamoto, T.; Watanabe, M.;
Kurihara, H. JP Patent 60 06678 [85 06678]; Chem. Abstr. 1985, 102,
220732e.
(13) CCDC 811041 (4cc) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Org. Lett., Vol. 13, No. 8, 2011
2027

Table 1. Enantioselective Direct Vinylogous Michael Addition
of 2 to β-Nitrostyrene 3a Catalyzed by Guanidine 1a
Table 2. Enantioselective Direct Vinylogous Michael Addition
of 2c to a Variety of Nitroalkenes 3 Catalyzed by Guanidine 1a
entry
3
4
t (h) yieldb (%) syn/antic eed (%)
1
2
3
4
5
6
7
8
9
3b: 4-MeOC6H4- 4cb 40
77
65
63
60
73
62
75
93
61f
98:2
98:2
98:2
99:1
97:3
97:3
98:2
97:3
98:2
88
94
93
94
82
91
88
82
86
3c: 4-BrC6H4-
3d: 4-ClC6H4-
3e: 3-BrC6H4-
4cce 16
4cd 16
4ce 40
3f: 2-MeOC6H4- 4cf
3g: 2-BrC6H4- 4cg 40
3h: thiophen-2-yl 4ch 40
40
t
yieldb
(%)
eed
(%)
entry
2
solvent
(h)
syn/antic
3i: isobutyl
4ci
4cj
48
48
3j: cyclohexyl
1
2
3
4
5
6
7
8
9
2a
2b
2c
2c
2c
2c
2c
2c
2ch
THF
2
20
20
48
36
20
32
24
16
78
90:10
90:10
98:2
43
91
94
88
82
92
82
80
94
THF
7
a Unless otherwise noted, all reactions were carried out using 0.01
mmol of (R)-1 (5 mol %), 0.40 mmol of 2c (2.0 equiv), and 0.20 mmol of 3
in 4.0 mL of THF at -40 °C. b Isolated yield. c Diastereomeric ratio was
THF
72
Et2O
18
90:10
78:22
90:10
95:5
TBMEe
CPMEf
DMEg
acetone
THF
26
determined by H NMR analysis. d Enantiomeric excess for the major
1
32
syn-isomer was determined by chiral stationary phase column
(Chiralpak AS-H) HPLC analysis. e The absolute stereochemistries of
4cc were unambiguously determined to be 5S,10R by X-ray crystal-
lographic analysis.13 f 3j was recovered in 34%.
67
25
81(76)i
67:33
98:2
a Unless otherwise noted, all reactions were carried out using 0.01
mmol of (R)-1 (5 mol %), 0.30 mmol of 2 (1.5 equiv), and 0.20 mmol of
3a in 4.0 mL of the indicated solvent at -40 °C. b NMR yield.
c Diastereomeric ratio was determined by 1H NMR analysis. d Enantio-
meric excess was determined by chiral stationary phase column
(Chiralpak AS-H) HPLC analysis for the major syn-isomers. e TBME:
tert-Butyl methyl ether. f CPME: Cyclopentyl methyl ether. g DME: 1,2-
Dimethoxyethane. h 0.40 mmol of 2c (2.0 equiv) was employed. i Isolated
yield after purification by gel permeation column chromatography.
As illustrated in Scheme 2, vinylogous product 4ca was
readily transformed to β,γ-disubstituted butenolide 6 via
standard chemical transformations. When treated with an
organocuprate, 4ca underwent a Michael addition to yield 7,
which was subsequently oxidized to the sulfoxide followed by
Scheme 2. Derivatization of Vinylogous Michael Product 4ca to
β,γ-Disubstituted Butenolide 6
With the optimal reaction conditions in hand, we further
investigated the scope of the direct vinylogous Michael
addition of 2c to nitroalkenes 3. As shown in Table 2, a
variety of nitroalkenes 3 can be utilized in the present
vinylogous reaction, affording the corresponding products
4 in moderate to good yields. Although introduction of
electron-donating groups or ortho-substituents on the aro-
matic ring of the β-nitrostyrene derivatives retarded the
reaction considerably and led to a slight reduction of
enantioselectivities (entries 1, 5, and 6), excellent syn-
diastereoselectivities were achieved irrespective of the elec-
tronic properties and steric demand of the aromatic ring.
Nitroalkene 3h possessing a heteroaromatic ring also
served as a good Michael acceptor (entry 7). It is note-
worthy that aliphatic substituted nitroalkenes, 3i and 3j,
were also suitable substrates in the present catalytic reac-
tion (entries 8 and 9), affording the syn-diastereomer
exclusively with fairly good enantioselectivities, although
a prolonged reaction time was required.
elimination under thermal conditions to provide 6 in an
acceptable yield without considerable loss of stereoisomeric
purities.
In conclusion, we have demonstrated that R-tert-
butylthio substituted furanones can be utilized as effi-
cient vinylogous pronucleophiles in the direct vinylogous
Michael addition to conjugate nitroalkenes using an
Finally, we demonstrated the potential of the present
catalytic reaction through further elaboration of γ-butenolide
product 4 by utilization of their multiple functionalities.
2028
Org. Lett., Vol. 13, No. 8, 2011

axially chiral guanidine base catalyst. The method en-
ables facile access to densely functionalized γ-buteno-
lides in a highly syn-diastereo- and enantioselective
manner. The synthetic potential of the present catalytic
enantioselective reaction has also been demonstrated by
further manipulation of R,γ-functionalized γ-buteno-
lides by taking advantage of their multiple functional-
ities. Further studies of direct vinylogous transforma-
tions via activation of R-thio substituted furanones
by chiral guanidine catalysts are underway in our
laboratory.
Acknowledgment. This work was supported by JSPS
for a Grant-in-Aid for Scientific Research (Grant No.
20245021). We also acknowledge Profs. T. Iwamoto and
S. Ishida (Graduate School ofScience, Tohoku University)
for X-ray crystal structure determination of vinylogous
Michael addition product syn-4cc.
Supporting Information Available. Experimental pro-
cedures, spectral data of products, and determination of
stereochemistry of products. This material is available
free of charge via Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
2029