Asymmetric direct vinylogous aldol reaction of unactivated γ-butenolide to aldehydes

Article abstract of DOI:10.1021/jo100946d

(Figure presented) The asymmetric direct vinylogous aldol reaction of unactivated γ-butenolide with aldehydes has been developed, giving the corresponding 5-(1′-hydroxy)butenolide derivatives in high yields (up to 93%) and enantioselectivities (up to 83%

Full text of DOI:10.1021/jo100946d

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also not atom-economic, which limited its use. The VA reac-
Asymmetric Direct Vinylogous Aldol Reaction of
Unactivated γ-Butenolide to Aldehydes
tion of γ-butenolides5,6 could overcome such shortcoming
and directly afford hydroxyl-γ-butenolides (Scheme 1, eq 2).
However, γ-butenolides were infrequently investigated owing
to their low reactivity. Most recently, Terada et al. reported
the enantioselective VA reaction of aldehydes.6e Halo sub-
stituent(s) of 2(5H)-furanone were used to improve nucleo-
philicity at the γ-position and prevent the reaction at the
R-position. When nonsubstituted furanone was used, the
reaction only provided complex mixtures. To the best of our
knowledge, the enantioselective direct VA reaction of unacti-
vated γ-butenolides has not yet been reported. Herein, we
wish to describe the asymmetric VA reaction of γ-buteno-
lides catalyzed by a quinine-derived thiourea organocatalyst,
affording the corresponding products in up to 93% yield,
85:15 anti/syn, and 83% ee.
Yang Yang, Ke Zheng, Jiannan Zhao, Jian Shi, Lili Lin,
Xiaohua Liu, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry
of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China
xmfeng@scu.edu.cn
Received May 14, 2010
Chiral bifuctional thioureas7 are a type of organocatalysts
that combine a basic nitrogen with a readily tunable hydrogen-
bonding group, which have emerged as powerful tools for
asymmetric construction of chiral molecules. Accordingly,
our initial investigation began with screening chiral diamine
derived thioureas 1a-d (Figure 1). In the presence of 1a, the
reaction of γ-butenolide 2 and benzaldehyde 3a in Et2O at
30 °C afforded only a trace amount of 4a (Table 1, entry 1).
Then we synthesized thiourea 1b from cyclohexane diamine,
which promoted the reaction with 30% yield, 63:37 anti/syn,
and 76% ee of the anti product (Table 1, entry 2).8 How-
ever, when 1c, possessing two bulky ethyl groups at the
The asymmetric direct vinylogous aldol reaction of un-
activated γ-butenolide with aldehydes has been deve-
loped, giving the corresponding 5-(10-hydroxy)butenolide
derivatives in high yields (up to 93%) and enantioselec-
tivities (up to 83% ee) under mild conditions.
(4) For a review on the vinylogous aldol reaction in butenolide synthesis,
see: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000,
100, 1929. For recent examples of enantioselective catalyzed aldol reactions
ꢀ
of 2-silyloxyfurans, see: (a) Szlosek, M.; Figadere, B. Angew. Chem., Int. Ed.
2000, 39, 1799. (b) Matsuoka, Y.; Irie, R.; Katsuki, T. Chem. Lett. 2003, 32,
584. (c) Onitsuka, S.; Matsuoka, Y.; Irie, R.; Katsuki, T. Chem. Lett. 2003,
32, 974. (d) Palombi, L.; Acocella, M. R.; Celenta, N.; Massa, A.; Villano, R.;
Scettri, A. Tetrahedron: Asymmetry 2006, 17, 3300. (e) Nagao, H.; Yamane,
Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 8. (f) Sedelmeier, J.; Hammerer, T.;
Bolm, C. Org. Lett. 2008, 10, 917. (g) Frings, M.; Atodiresei, I.; Wang, Y.;
Runsink, J.; Raabe, G.; Bolm, C. Chem.;Eur. J. 2010, 16, 4577. (h) Zhu, N.;
Ma, B.; Zhang, Y.; Wang, W. Adv. Synth. Catal. 2010, 352, 1291.
(5) For direct use of γ-butenolides in racemic aldol reactions, see:
(a) Pohmakotr, M.; Tuchinda, P.; Premkaisorn, P.; Reutrakul, V. Tetra-
hedron 1998, 54, 11297. (b) Saito, S.; Shiozawa, M.; Yamamoto, H. Angew.
Chem., Int. Ed. 1999, 38, 1769. (c) Bella, M.; Piancatelli, G.; Squarcia, A.
Tetrahedron 2001, 57, 4429. (d) Sarma, K. D.; Zhang, J.; Curran, T. T. J. Org.
Chem. 2007, 72, 3311.
(6) For direct catalytic asymmetric vinylogous reactions of γ-butenolides,
see: (a) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10,
2319. (b) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572. (c) Zhang,
Y.; Yu, C.; Ji, Y.; Wang, W. Chem. Asian J. 2010, 5, 1303. (d) Wang, J.; Qi, C.; Ge,
Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 46, 2124. (e) Ube, H.; Shimada, N.;
Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858. (f) Cui, H.; Huang, J.; Lei, J.;
Wang, Z.; Chen, S.; Wu, L.; Chen, Y. Org. Lett. 2010, 12, 720. For direct catalytic
asymmetric vinylogous reaction of R,β-unsaturated γ-butyrolactams, see:
(g) Shepherd, N. E.; Tanabe, H.; Xu, Y.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 3666.
The 5-(10-hydroxy)-γ-butenolide subunits are frequently
found in biologically active natural products, such as
Nafuredin-γ1 and Lembertellols A and B.2 Many protocols
have been developed successfully for the formation of this
linchpin.3 Thus the synthesis of such compounds has at-
tracted significant attention. Recently, catalytic vinylogous
aldol (VA) reactions were described to be one of the most
efficient methods for the construction of 5-membered fur-
anone derivatives.4 2-Silyoxyfuran, which was synthesized
from γ-butenolides, was the general nucleophilic reagent in
the reactions (Scheme 1, eq 1). But it was hard to store and
(1) (a) Nagamitsu, T.; Takano, D.; Shiomi, K.; Ui, H.; Yamaguchi, Y.;
Masuma, R.; Harigaya, Y.; Kuwajima, I.; Oh mura, S. Tetrahedron Lett. 2003,
44, 6441. (b) Nagamitsu, T.; Takano, D.; Seki, M.; Arima, S.; Ohtawa, M.;
Shiomi, K.; Harigaya, Y.; Oh mura, S. Tetrahedron 2008, 64, 8117.
(2) (a) Murakami, T.; Takahashi, Y.; Fukushi, E.; Kawabata, J.;
Hashimoto, M.; Okuno, T.; Harada, Y. J. Am. Chem. Soc. 2004, 126,
9214. (b) Murakami, T.; Morikawa, Y.; Hashimoto, M.; Okuno, T.; Harada,
Y. Org. Lett. 2004, 6, 157. (c) Nomiya, M.; Murakami, T.; Takada, N.;
Okuno, T.; Harada, Y.; Hashimoto, M. J. Org. Chem. 2008, 73, 5039.
(3) For selected examples of total synthesis of furanaone derivatives, see:
(a) Kumar, P.; Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843. (b)
Ahmed, Md. M.; Cui, H.; O0Doherty, G. A. J. Org. Chem. 2006, 71, 6686. (c)
Matsuura, D.; Takabe, K.; Yoda, H. Tetrahedron Lett. 2006, 47, 1371. (d)
Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Synlett 2007, 18, 2891.
(7) For recent reviews of bifunctional amine-thiourea mediated catalysis,
see: (a) Tian, S.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc.
Chem. Res. 2004, 37, 621. (b) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4299. (c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
(d) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418. (e) Marcelli, T.; van
Maarseveen, J.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496.
(f) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (g) Connon,
S. J. Chem. Commun. 2008, 2499. (h) Akiyama, T. Chem. Rev. 2007, 107,
5744.
(8) Absolute configurations were determined by conversion to known
compound. See the Supporting Information for details.
5382 J. Org. Chem. 2010, 75, 5382–5384
Published on Web 06/30/2010
DOI: 10.1021/jo100946d
r
2010 American Chemical Society

Yang et al.
JOCNote
TABLE 2. Substrate Scope for the Catalytic Enantioselective VA
Reaction of γ-Butenolide 2 to Aldehydes 3a
entry
R
t (h) yield (%)b drc (anti/syn) ee of anti (%)c,d
1
2
3
4
5
6
7
8
9
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
2-FC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
50
48
40
40
40
52
48
52
87 (4a)
90 (4b)
83 (4c)
83 (4d)
80 (4e)
76 (4f)
91 (4g)
75 (4h)
93 (4i)
89 (4j)
73 (4k)
91 (4l)
82 (4m)
40 (4n)
85:15
84:16
81:19
82:18
85:15
81:19
81:19
82:18
82:18
79:21
83:17
85:15
79:21
80:20
82 (43)
82 (18)
81 (27)
79 (13)
82 (36)
82 (46)
83 (4)
81 (20)
81 (60)
79 (22)
78 (15)
81 (7)
2-MeOC6H4 52
10 3-MeOC6H4 52
11 4-MeOC6H4 72
12 2-thienyl
13 2-naphthyl
14 c-hexyl
48
48
48
FIGURE 1. Thiourea catalysts evaluated.
79 (4)
78 (17)
SCHEME 1. Asymmetric VA Reactions for the Synthesis of
Chiral Hydroxyl-γ-butenolides
aAll reactions were carried out with 1i (10 mol %), 2(5H)-furanone 2
(0.4 mmol), and aldehyde 3 (0.1 mmol) in Et2O (0.5 mL) at 30 °C for
b
c
40-72 h. Isolated yield. Determined by chiral HPLC analysis. Rela-
tive configurations of the product were assigned according to ref 4a.
dThe results in parentheses are ee of syn products.
amine moiety, was used, the reaction rate decreased dramati-
cally (Table 1, entry 3 vs 2). It seemed that the steric hindrance
at tertiary nitrogen hampered the deprotonation of γ-buteno-
lide to generate the active dienolate. The electron-withdrawing
trifluoromethyl group at the thiourea moiety could enhance
the acidity of the hydrogen bond donor, and catalyst 1d
promoted the reaction with improved yield and enantio-
selectivity (50% yield, 81% ee, 80:20 anti/syn; Table 1, entry 4
vs 2). To further improve the results of the reaction, several
chiral cinchona-alkaloid-derived thioureas were investi-
gated. The results suggested that thiourea 1h was superior
to the other three ones 1e-g in both yields and enantioselec-
tivities (Table 1, entry 8 vs entries 5-7). With regards to the
thiourea moiety, compound 1i, which has a bulky 3,5-bis-
(trifluoromethyl)phenyl group attached, gave a promising ee
value of 82% (Table 1, entry 9 vs 8).
To improve the outcomes, other reaction conditions were
explored. The solvent was found to be an important para-
meter on reactivity and enantioselectivity. The ether solvents
such as THF, PhOMe, and t-BuOMe gave either low yield or
poor enantioselectivity (Table 1, entries 10-12 vs entry 9).
The screening of other solvents showed that Et2O was the
best solvent for the VA reaction (Table 1, entry 9 vs entries
13-16). By increasing the amount of γ-butenolide 2 to 4
equiv and prolonging the reaction time to 50 h a 87% yield
was obtained with the selectivities maintained (Table 1, entry
17 vs 9). Therefore, the optimal reaction conditions were
identified as 0.1 mmol of benzaldehyde, 10 mol % of 1i, and
0.4 mmol of 2(5H)-furanone in 0.5 mL of Et2O at 30 °C.
Notably, the product with opposite configuration was also
obtained in 75% yield with 81% ee and 80:20 dr by using
catalyst 1d under the optimal condition (Table 1, entry 18)
(see the Supporting Information).
TABLE 1. Optimization of the Reaction Conditionsa
entry cat.
solvent
1a Et2O
1b Et2O
yield (%)b drc (anti/syn) ee of anti (%)c,d
1
2
trace
30
63:37
-76 (-35)
3
4
5
1c Et2O
1d Et2O
1e Et2O
trace
50
26
80:20
80:20
85:15
85:15
83:17
85:15
87:13
81:19
89:11
76:24
83:17
76:24
-81 (-60)
-71 (-18)
-76 (-39)
70 (35)
76 (7)
82 (54)
77 (80)
74 (53)
83 (65)
64 (32)
6
7
8
9
10
11
12
13
14
15
16
17e
18f
1f
Et2O
10
18
41
62
15
44
38
31
40
75
trace
87
75
1g Et2O
1h Et2O
1i
1i
1i
1i
1i
1i
1i
1i
1i
Et2O
THF
PhOMe
t-BuOMe
CH2Cl2
CHCl3
toluene
MeCN
Et2O
75 (36)
71 (10)
85:15
80:20
82 (43)
-81 (-60)
1d Et2O
aUnless otherwise noted, all reactions were carried out with 1 (10 mol
%), 2(5H)-furanone 2 (0.2 mmol), and benzaldehyde 3a (0.1 mmol) in
solvent (0.5 mL) at 30 °C for 40 h. bIsolated yield. cDetermined by chiral
HPLC analysis. Relative configurations of the product were assigned
according to ref 4a. dThe results in parentheses are ee of syn products.
With the optimized conditions in hand, substrate scope was
investigated and the results were summarized in Table 2. High
enantioselectivities and good diastereoseletivities were obtained
eReaction was performed with 0.4 mmol of 2 for 50 h. Reaction was
performed with 0.4 mmol of 2 for 70 h.
f
J. Org. Chem. Vol. 75, No. 15, 2010 5383

Yang et al.
JOCNote
SCHEME 2. Proposed Transition State for VA Reaction
Catalyzed by 1i and 1d
could be produced by the Re-face attack to the activated
aldehyde, as well as (5S,10R)-4a by the Si-face attack for
catalyst 1d.
In conclusion, we have developed the first enantioselective
direct aldol reaction of unactivated γ-butenolide with alde-
hydes, using a cinchona alkaloid-based thiourea. Various
aldehydes were converted into the corresponding products in
high yields (up to 93%) and enantioseletivities (up to 83% ee)
under mild conditions. This contribution provides a simple,
practical, and atom-economy synthetic strategy for direct
formation of 5-(10-hydroxy)-γ-butenolides, which are the
linchpin for further transformations. Further efforts are
devoted to the study of γ-butenolides as direct starting
materials in asymmetric reactions and its applications in
natural product synthesis.
Experimental Section
General Procedure for the Catalytic Enantioselective VA
Reaction between Aldehyde 3b and 2(5H)-Furanone 2. Aldehyde
3b (11 μL, 0.1 mmol) and catalyst 1i (5.9 mg, 0.01 mmol) were
stirred in Et2O (0.5 mL) for 20 min at ambient temperature, and
the 2(5H)-furanone 2 (28 μL, 0.4 mmol) was added. The mixture
was stirred at 30 °C for 48 h. After that, the reaction mixture was
purified directly by flash chromatography to give the desired
product 4b: 90% yield; 82% ee, 84:16 dr (determined by HPLC
analysis with a Chiral AD-H column, hexane/2-propanol 95: 5,
1.0 mL/min, UV = 210 nm; t1 = 24.2 min, t2 = 27.4 min, t3 =
31.6 min, t4 = 33.0 min); [R]25D þ94.3 (c 0.212, in CH2Cl2); 1H
NMR (400 MHz, CDCl3) δ 7.40-7.34 (m, 3H), 7.18 (dd, J = 8.0,
4.0 Hz, 1H, syn), 7.13-7.06 (m, 2H, anti, syn), 6.19 (dd, J = 6.0,
2.0 Hz, 1H, anti), 6.18 (dd, J = 6.0, 2.0 Hz, 1H, syn), 5.16-5.14
(m, 2H, syn, anti), 5.05 (m, 1H, anti), 4.74 (dd, J = 9.6, 3.2 Hz, 1H,
syn), 2.85 (d, J = 3.2 Hz, 1H, syn), 2.63 (d, J = 3.6 Hz, 1H, anti)
ppm; 13C NMR δ (100 MHz, CDCl3) δ 152.60, 134.01, 127.84 (d,
J = 5.3 Hz), 123.38, 115.83, 115.69, 86.26, 72.68; HRMS (ESI)
calcd for C11H9FO3 [M þ NH4þ] 226.0874, found 226.0872.
with a series of aromatic aldehydes (78-83% ee, up to 85:15 dr;
Table 2, entries 1-13). Substrates with electron-withdrawing
groups exhibited higher reactivity than those with electron-
donating groups. Moreover, the position of the substituents at
aromatic ring had no obvious effect on the enantioselectivity
(78-83% ee; Table 2, entries 2-11). Furthermore, the hetero-
aromatic aldehyde could be smoothly converted to the desired
product in 91% yield with 81% ee (Table 2, entry 12), while the
condensed-ring aldehyde also succeeded with 82% yield and
79% ee (Table 2, entry 13). Significantly, the aliphatic aldehyde
3n gave the corresponding product in 40% yield with 78% ee
(Table 2, entry 14).
On the basis of the absolute configurations of (5R,10S)-4a
catalyzed by 1i and (5S,10R)-4a8 catalyzed by 1d, two transi-
tion state models for the reaction of 2 and 3a have been
proposed (Scheme 2). The aldehyde 3a was activated by the
thiourea moiety through double hydrogen bonding formed
from the interaction between the NH group of 1i or 1d and
the carbonyl group of 3a,9-11 while the basic nitrogen in the
catalyst may deprotonate γ-butenolide 2 to generate dieno-
late. Then, for catalyst 1i, the desired product (5R,10S)-4a
Acknowledgment. We appreciate the financial support
from the National Natural Science Foundation of China
(Nos. 20732003 and 20902060), PCSIRT (No. IRT0846),
and the National Basic Research Program of China (973
Program No. 2010CB833300). We also thank Sichuan Uni-
versity Analytical & Testing Center for NMR analysis.
Supporting Information Available: Experimental proce-
dures and spectral and analytical data for the products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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5384 J. Org. Chem. Vol. 75, No. 15, 2010