Organocatalytic direct asymmetric vinylogous Michael reaction of an α,β-unsaturated γ-butyrolactam with enones

Article abstract of DOI:10.1021/jo102223v

An organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to enones has been achieved with a simple bifunctional thiourea-tertiary amine catalyst, affording the γ-substituted butyrolactam products with high diaster

Full text of DOI:10.1021/jo102223v

pubs.acs.org/joc
significant progress has been made in vinylogous aldol,2
Organocatalytic Direct Asymmetric Vinylogous
Michael Reaction of an r,β-Unsaturated
γ-Butyrolactam with Enones
Mannich,3 and Michael4 reactions by employing masked
dienol ethers, the direct approaches are still highly valuable
from the standpoint of atom economy. Accordingly, this
issue has attracted much research interest recently.5,6
Chiral γ-butyrolactams are ubiquitous building blocks for
many natural products.7 Despite their synthetic utility, R,β-
unsaturated γ-butyrolactams have not been well explored in
the direct catalytic asymmetric reactions.8 Very recently,
Shibasaki and co-workers9 pioneered the research on direct
catalytic asymmetric vinylogous Mannich and Michael reac-
tions of R,β-unsaturated γ-butyrolactams by using a chiral
dinuclear nickel complex. Chen and co-workers10 reported
the first organocatalytic conjugate addition reaction of R,β-
unsaturated γ-butyrolactams to R,β-unsaturated aldehydes
via iminium catalysis. Herein, we disclose an efficient con-
jugate addition of R,β-unsaturated γ-butyrolactams to en-
ones catalyzed by a bifunctional alkaloid-derived thiourea
organocatalyst, which affords the desired products in up
to >40:1 dr and 94-99% ee.
Yong Zhang, Yong-Liang Shao, Hai-Sen Xu, and
Wei Wang*
State Key Laboratory of Applied Organic Chemistry, College
of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, Gansu 730000, P. R. China
wang_wei@lzu.edu.cn
Received November 15, 2010
Chiral cinchona alkaloids and amine thioureas have pre-
viously been utilized as effective bifunctional organocatalysts
for the conjugate addition of various carbon nucleophiles
to R,β-unsaturated carbonyls via acid-base cooperative
activation.11 Accordingly, our initial investigation began with
screening this type of organocatalysts (I-VI, Figure 1). As
(4) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192 and references therein.
(5) (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) Cui,
H.-L.; Huang, J.-R.; Lei, J.; Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org.
Lett. 2010, 12, 720. (d) Wang, J.; Qi, C.; Ge, Z.; Cheng, T.; Li, R. Chem.
Commun. 2010, 46, 2124. (e) Zhang, Y.; Yu, C.; Ji, Y.; Wang, W. Chem. Asian
J. 2010, 5, 1303. (f) Huang, H.; Yu, F.; Jin, Z.; Li, W.; Wu, W.; Liang, X.; Ye,
J. Chem. Commun. 2010, 46, 5957. (g) Ube, H.; Shimada, N.; Terada, M.
Angew. Chem., Int. Ed. 2010, 49, 1858. (h) Yang, Y.; Zheng, K; Zhao, J. N.;
Shi, J.; Lin, L. L.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2010, 75, 5382.
(6) For the reactions of R,R-dicyanoalkene, see a recent review: (a) Cui,
H.-L.; Chen, Y.-C. Chem. Commun. 2009, 4479. Selected examples: (b) Xue,
D.; Chen, Y.-C.; Wang, Q.-W.; Cun, L.-F.; Zhu, J.; Deng, J.-G. Org. Lett.
2005, 7, 5293. (c) Poulsen, T. B.; Alemparte, C.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 11614. (d) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.;
Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563.
(e) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu,
Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389. (f) Liu, T.-Y.;
Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. J. Am. Chem.
Soc. 2007, 129, 1878. (g) Aleman, J.; Jacobsen, C. B.; Frisch, K.; Overgaard,
J.; Jørgensen, K. A. Chem. Commun. 2008, 632.
An organocatalytic asymmetric direct vinylogous Michael
addition of R,β-unsaturated γ-butyrolactam to enones has
been achieved with a simple bifunctional thiourea-tertiary
amine catalyst, affording the γ-substituted butyrolactam
products with high diastereo- and enantioselectivity
(up to >40:1 dr and 94-99% ee).
Catalytic asymmetric vinylogous reactions have been
demonstrated as effective protocols for carbon-carbon
bond formation at the γ-position, which enables access to a
diverse array of chiral γ-functionalized products from the
combination of various donors and acceptors.1 Although
(7) Reviews: (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (b) Pyne,
S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.;
Tang, M. Synlett 2004, 2670. (c) Cheng, Y.; Huang, Z.-T.; Wang, M. X. Curr.
Org. Chem. 2004, 8, 325.
(1) Review: Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G. Synlett
2009, 1525.
(8) For racemic direct-type vinylogous reactions of R,β-unsaturated
γ-butyrolactam and related donors, see: (a) Sartori, A.; Curti, C.; Battistini,
L.; Burreddu, P.; Rassu, G.; Pelosi, G.; Casiraghi, G.; Zanardi, F. Tetra-
hedron 2008, 64, 11697. (b) Curti, C.; Sartori, A.; Battistini, L.; Rassu, G.;
Burreddu, P.; Zanardi, F.; Casiraghi, G. J. Org. Chem. 2008, 73, 5446.
(9) Shepherd, N. E.; Tanabe, H.; Xu, Y.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2010, 132, 3666.
(2) Reviews: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929. (b) Denmark, S. E.; Heemstra, J. R., Jr.;
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (c) Kalesse, M. Top.
Curr. Chem. 2005, 244, 43. Selected examples: (d) Sedelmeier, J.; Hammerer,
T.; Bolm, C. Org. Lett. 2008, 10, 917. (e) Zhu, N.; Ma, B.-C.; Zhang, Y.;
Wang, W. Adv. Synth. Catal. 2010, 352, 1291. (f) Singh, R. P.; Foxman,
B. M.; Deng, L. J. Am. Chem. Soc. 2010, 132, 9558.
(10) Feng, X.; Cui, H.-L.; Xu, S.; Wu, L.; Chen, Y.-C. Chem.;Eur. J.
2010, 16, 10309.
(3) Reviews: (a) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221. (b)
Martin, S. F. Acc. Chem. Res. 2002, 35, 895. Selected examples: (c) Carswell,
E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2006, 45, 7230.
(d) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008,
350, 399. (e) Mandai, H.; Mandai, K.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2008, 130, 17961. (f) Sickert, M.; Abels, F.; Lang, M.; Sieler, J.;
Birkemeyer, C.; Schneider, C. Chem.;Eur. J. 2010, 16, 2806.
(11) Reviews: (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) Akiyama, T.
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1472 J. Org. Chem. 2011, 76, 1472–1474
Published on Web 01/18/2011
DOI: 10.1021/jo102223v
r
2011 American Chemical Society

Zhang et al.
JOCNote
TABLE 2. Enantioselective Direct Vinylogous Michael Reaction of
r,β-Unsaturated γ-Butyrolactam 1 with Chalcones 2 Catalyzed by VIa
time yieldb
eed
(%)
entry
R, Ar, 2
(h)
(%)
drc
1
2
3
4
5
6
7
8
Ph, Ph, 2a
72
48
48
72
48
72
60
60
48
84
84
84
60
60
60
90
90
92
86
89
83
93
88
90
78
81
73
95
88
83
>30:1
25:1
15:1
18:1
20:1
>25:1
>30:1
15:1
>40:1
16:1
98
95
98
97
96
97
96
97
94
96
96
95
96
98
98
Ph, 4-NO2C6H4, 2b
Ph, 4-CNC6H4, 2c
Ph, 4-FC6H4, 2d
Ph, 4-CF3C6H4, 2e
Ph, 4-ClC6H4, 2f
Ph, 2-ClC6H4, 2g
Ph, 3-ClC6H4, 2h
Ph, 2,4-Cl2C6H4, 2i
Ph, 4-CH3OC6H4, 2j
Ph, 4-CH3C6H4, 2k
4-CH3OC6H4, Ph, 2l
4-BrC6H4, Ph, 2m
4-CH3OC6H4, 4-CNC6H4, 2n
4-CH3OC6H4, 4-NO2C6H4,
2o
FIGURE 1. Organocatalysts for screening.
9
10
11
12
13
14
15
>25:1
>30:1
>25:1
15:1
TABLE 1. Selected Studies of the Direct Vinylogous Michael Reaction
of r,β-Unsaturated γ-Butyrolactam 1 with Chalcone 2aa
10:1
16
17
18
19
2-BrC6H4, 4-CNC6H4, 2p
thienyl, thienyl, 2q
CH3, Ph
48
84
84
84
93
78
trace
trace
>20:1
15:1
nde
98
99
nd
nd
t-Bu, Ph
nd
aUnless otherwise noted, the reaction was performed with 2.0 equiv of
1 (0.1 mmol, 0.5 M), 1.0 equiv of 2, and 0.1 equiv of catalyst in 0.2 mL of
CHCl3 at 50 °C. bIsolated yield after purification by column chroma-
tography. cDetermined by 1H NMR analysis of crude mixture. dDeter-
mined by HPLC analysis using Daicel chiral IC or OD-H column. eNot
determined.
yieldb
(%)
eed
(%)
entry
catalyst
solvent
time
drc
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VI
VI
VI
VI
VI
VI
VI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3CN
THF
10 d
10 d
10 d
10 d
10 d
10 d
10 d
10 d
10 d
10 d
10 d
60 h
72 h
30
45
trace
68
75
75
65
45
74
85
70
90
90
15:1
12:1
42
44
nd
94
97
98
97
94
94
99
98
97
98
nde
10:1
eoselectivity, and 98%ee after10 days atambienttemperature
(entry 6) in CH2Cl2.
>30:1
>30:1
18:1
12:1
10:1
>30:1
>30:1
15:1
The influence of different solvents on the reaction catalyzed
by VI was therefore investigated (Table 1, entries 6-11).
CHCl3 proved to be the best reaction medium (entry 10),
which further enhanced the yield to 85% and the ee value to
99% and maintained the dr value as >30:1. Reaction tem-
perature and catalyst loading had a dramatic influence on the
efficiency of the process. Elevation of the reaction tempera-
ture from ambient temperature (entry 10) to 50 °C (entry 12)
significantly shortened the reaction time from 10 days to
60 h and improved the yield from 85% to 90%, while the
diastereo- and enantioselectivities were slightly decreased
from >30:1 dr to 15:1 dr and from 99% ee to 97% ee, respec-
tively. When the catalyst loading was lowered to 10 mol %,
the diastereo- and enantioselectivities were further improved
to>30:1 dr and 98% ee, with a slightly extended reaction
time of 72 h (entry 13).
Applying the conditions described in Table 1, entry 13 as
the optimal compromise between reactivity and stereoselec-
tivity, the generality of this protocol was demonstrated by
evaluating a variety of enones (Table 2). The enone sub-
strates with either an electron-withdrawing or electron-do-
nating group at the ortho-, meta-, or para-position of Ar and
R were examined. High diastereo- and enantioselectivities
(from 10:1 to >40:1 dr and from 94 to 99% ee) were achieved
for these enone substrates (Table 2, entries 1-16). A hetero-
cyclic system (thiophene as an example) was also applicable,
9
10
11
12f
13g
CHCl3
Cl(CH2)2Cl
CHCl3
CHCl3
>30:1
aUnless otherwise noted, the reaction was performed with 0.2 mmol
of 1, 0.1 mmol of 2a, and 20 mol % of catalyst in 0.2 mL solvent.
bIsolated yield after purification by column chromatography. Deter-
c
1
d
mined by H NMR analysis of crude mixture. Determined by HPLC
analysis using Daicel chiral IC column. eNot determined. fThe reaction
was carried out at 50 °C. gThe reaction was carried out at 50 °C, and 10
mol % of catalyst was used.
shown in Table 1, the catalytic activity and enantioselectivity
varied significantly when different catalysts were applied. In
the presence of catalysts I-III (Table 1, entries 1-3), poor
reactivities and diastereo- and enantioselectivities were ob-
served for the reaction of R,β-unsaturated γ-butyrolactam 1
with chalcone 2a. In contrast, amine thioureas IV-VI showed
promising results (entries 4-6). The cinchona alkaloid-based
thiourea catalysts12 proved to be more effective: the catalyst
VI gave the addition product with 75% yield, >30:1 diaster-
(12) For the original report on the application of cinchona alkaloid-based
thiourea catalysts for the activation of chalcones, see: Vakulya, B.; Varga, S.;
ꢀ
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
ꢀ
J. Org. Chem. Vol. 76, No. 5, 2011 1473

Zhang et al.
JOCNote
FIGURE 3. Proposed transition states for conjugate addition of
R,β-unsaturated γ- butyrolactam to enones catalyzed by VI.
FIGURE 2. X-ray crystallographic structure of 3q0.
access to synthetically versatile γ-substituted butyrolactams
in up to >40:1 dr and 94-99% ee. Further studies of R,β-
unsaturated γ-butyrolactam as versatile nucleophile in orga-
nocatalytic asymmetric reactions, and its applications in
natural product synthesis are currently underway in our
laboratory.
affording the vinylogous product with 15:1 dr and 99% ee
(entry 17). However, when R was an aliphatic moiety (e.g.,
CH3 or t-Bu), the reaction did not occur, presumably owing to
the low reactivity of the enone substrate (entries 18 and 19).
The absolute configuration of the reaction products was
derived from the single crystal structure of 3q0 (Figure 2). We
failed to obtain a single crystal of product 3q, although nu-
merous conditions for the crystal growth were attempted.
However, we found that the chiral center of C5 in 3q was
epimerized under basic conditions, such as in the presence of
DBU,13 and the diastereoisomer 3q0 could be easily isolated
from 3q (scheme in Figure 2). Fortunately, we were able to
obtain a single crystal of 3q0 by slow evaporation of a mixture
of ethyl acetate and hexane. The X-ray structural analysis
(Figure 2) indicates that the absolute configuration of 3q0 is
(5S,6R), and therefore the absolute configuration of the
adduct 3q could be concluded as (5R,6R).14
Experimental Section
Genaral Procedure for Direct Catalytic Asymmetric Vinylo-
gous Michael Reaction of r,β-Unsaturated γ-Butyrolactam. To a
solution of chalcone 2a (0.1 mmol, 1.0 equiv) in CHCl3 (0.2 mL)
was added catalyst VI (0.01 mmol, 0.1 equiv) followed by R,β-
unsaturated γ-butyrolactam 1 (0.2 mmol, 2.0 equiv). The reac-
tion mixture was stirred at 50 °C until the consumption of 2a, the
progress of which was monitored by TLC analysis. The solvent
was then removed under vacuum. The residue was purified by
silica gel chromatography (hexane/AcOEt=4/1 to 2/1 as eluent)
to afford the desired addition product 3a (90% yield). [R]20
=
D
þ109 (c 1.0, CHCl3); 98% ee, determined by HPLC analysis
using Daicel chiral IC column, EtOH flow rate: 0.3 mL/min,
detection at 254 nm, tR (minor) = 19.43 min, tR (major) = 21.91
min; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz, 2H),
7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.34 (q, J = 7.2
Hz, 2H), 7.27 (dd, J = 13.3, 6.8 Hz, 3H), 7.04 (dd, J = 6.1, 1.7
Hz, 1H), 6.19 (d, J = 6.1 Hz, 1H), 4.87-4.84 (m, 1H), 4.60-4.54
(m, 1H), 3.28 (dd, J = 17.2, 9.7 Hz, 1H), 3.04 (dd, J = 17.2, 4.6
Hz, 1H), 1.64 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 197.2,
169.2, 149.2, 147.8, 139.2, 136.7, 133.2, 128.9, 128.6, 128.0,
127.9, 127.8, 127.4, 83.6, 66.8, 40.8, 35.1, 28.2; ESI-HRMS
calcd for [C24H25NO4 þ Na] 414.1676, found 414.1668.
Two possible routes for the formation of C-C bond could
therefore be envisioned, representing two distinct activation
models for the interaction of tertiary amine/thiourea organo-
catalyst with the electrophile and the nucleophile (Figure 3).
ꢀ
According to the mechanistic studies by Papai and co-
workers15 for conjugate additions, the transition state B should
be more favorable to explain the stereoselective outcome. The
carbonyl group of the chalcone was activated by the N-H
proton of ammonium through hydrogen bond, while the
thiourea coordinated to γ-butyrolactam. Therefore, the de-
sired product (5R,6R)-3q could be obtained by the si-face
attack of the activated enone (pathway B in Figure 3).
In conclusion, we have developed an organocatalytic
enantioselective direct vinylogous Michael reaction of R,β-
unsaturated γ-butyrolactam with enones by using a cinchona
alkaloid-based thiourea. This method enables efficient
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20972064), the
111 project, and the Key Grant Project of Chinese Ministry
of Education (No. 309028) is gratefully acknowledged. We
also thank Prof. Chun-An Fan and anonymous referees for
valuable comments and suggestions.
(13) Gheorghe, A.; Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71, 2173.
(14) As shown in Figure 2, the ee values of isolated 3q0 (40% yield) and
recovered 3q (55% yield) were both kept as 99% after epimerization,
indicating that only the chiral center of C5 in 3q was epimerised in the
presence of DBU. See Supporting Information for characterization details.
Supporting Information Available: Full characterization for
the new compounds, crystallographic data of compound 3q0 in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
ꢀ
(15) Hamza, A.; Schubert, G.; Soos, T.; Papai, I. J. Am. Chem. Soc. 2006,
128, 13151.
1474 J. Org. Chem. Vol. 76, No. 5, 2011