Bifunctional 3, 3′-Ph2-BINOL-Mg catalyzed direct asymmetric vinylogous michael addition of α, β-unsaturated γ-butyrolactam

Article abstract of DOI:10.1021/ol202713f

Bifunctional 3, 3'-Ph₂-BINOL-Mg catalyzed direct asymmetric vinylogous Michael addition of α, β-unsaturated γ-butyrolactam has been developed. The catalytic activity of this protocol was slightly affected by different types of Michael acceptors

Full text of DOI:10.1021/ol202713f

ORGANIC
LETTERS
Bifunctional 3,30-Ph2-BINOL-Mg Catalyzed
Direct Asymmetric Vinylogous Michael
Addition of r,β-Unsaturated
2011
Vol. 13, No. 24
6410–6413
γ-Butyrolactam
Li Lin,† Jinlong Zhang,† Xiaojuan Ma,† Xu Fu,† and Rui Wang*,†,‡
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, State Key
Laboratory of Applied Organic Chemistry and Institute of Biochemistry and Molecular
Biology, Lanzhou University, Lanzhou, 730000, P. R. China, and State Key Laboratory
of Chiroscience and Department of Applied Biology and Chemical Technology, The
Hong Kong Polytechnic University, Hong Kong
wangrui@lzu.edu.cn
Received October 10, 2011
ABSTRACT
Bifunctional 3,30-Ph2-BINOL-Mg catalyzed direct asymmetric vinylogous Michael addition of R,β-unsaturated γ-butyrolactam has been developed.
The catalytic activity of this protocol was slightly affected by different types of Michael acceptors, such as a variety of enones as well as
R,β-unsaturated N-acylpyrroles. The Michael products were obtained with high diastereoselectivities (up to 20:1) and excellent enantio-
selectivities (up to 98%).
Chiral γ-butyrolactams as well as γ-butyrolactones are
present in a variety of natural products as well as bioactive
compounds. These frameworks are also very important
synthetic intermediates to many organic compounds.
Among several of the synthetic protocols to the chiral
γ-butyrolactams/lactones synthesis, the most attractive
one is vinylogous addition which has always attracted
chemists’ interests.1 Although asymmetric vinylogous
Mukaiyama additions have been well established,2 the
more practical direct asymmetric vinylogous additions
were less developed until recent years. The present reports
mainly focused on the organocatalytic direct vinylogous
additions.3,4 However, these strategies seriously suffer
from not only a limited substrate scope but also low
catalytic activity. Most reactions always proceeded over
days. In contrast, organometallic catalysis has many ad-
vantages such as being more easily tunable and exhibiting
† Lanzhou University.
‡ The Hong Kong Polytechnic University.
(1) Reviews: (a) Fuson, R. C. Chem. Rev. 1935, 16, 1. (b) Casiraghi,
G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929.
ꢀ
(c) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (d) Cordova, A. Acc.
Chem. Res. 2004, 37, 102. (e) Denmark, S. E.; Heemstra, J. R.; Beutner,
G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (f) Casiraghi, G.; Zanardi,
F.; Battistini, L.; Rassu, G. Synlett 2009, 1525. (g) Cordes, M.; Leibniz,
M. K. Chemtracts Org. Chem. 2010, 23, 141. (h) Casiraghi, G.; Battistini,
L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076.
(2) Recent examples: (a) Carswell, E. L.; Snapper, M. L.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2006, 45, 7230. (b) Mai, H.; Mai, K.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 17961. (c)
Wiel, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2008, 131, 570. (d) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem.
Soc. 2008, 130, 7202. (e) Yanai, H.; Takahashi, A.; Taguchi, T. Chem.
Commun. 2010, 46, 8728. (f) Curti, C.; Battistini, L.; Ranieri, B.; Pelosi,
G.; Rassu, G.; Casiraghi, G.; Zanardi, F. J. Org. Chem. 2011, 76, 2248.
(g) Qin, T.; Johnson, R. P.; Porco, J. A. J. Am. Chem. Soc. 2011, 133,
1714.
(3) Organocatalytic direct vinylogous 1, 2-additions: (a) 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. (b) Niess, B.; Jorgensen, K. A. Chem.
Commun. 2007, 1620. (c) Ube, H.; Shimada, N.; Terada, M. Angew.
Chem., Int. Ed. 2010, 49, 1858. (d) Cui, H.-L.; Huang, J.-R.; Lei, J.;
Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 720. (e)
Yang, Y.; Zheng, K.; Zhao, J.; Shi, J.; Lin, L.; Liu, X.; Feng, X. J. Org.
Chem. 2010, 75, 5382. (f) Pansare, S. V.; Paul, E. K. Chem. Commun.
2011, 47, 1027. (g) Luo, J.; Wang, H.; Han, X.; Xu, L.-W.; Kwiatkowski,
J.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 1861.
r
10.1021/ol202713f
Published on Web 11/16/2011
2011 American Chemical Society

higher catalytic efficiency and a broader application
scope.5 B. M. Trost’s group and M. Shibasaki’s group
have reported their pioneering works on the organome-
tallic catalytic direct vinylogous additions to imines as well
as nitroolefins, respectively. Unfortunately, enones as the
more challenging substrates were not explored in these
studies, maybe due to the poor reactivity as well as
difficulty in stereocontrol. Besides Shibasaki’s dinuclear
nickel catalytic system, there were only three organocata-
lytic systems which were developed for the direct asym-
metric vinylogous Michael addition of R,β-unsaturated γ-
butyrolactams to R,β-unsaturated aldehydes4f as well as
enones4g,h (Figure 1). It must be noted that these three
organocatalysts were critically required for different
Michael acceptors due to their greatly varied activity affected
by the substituents of the carbonyl. Accordingly, a highly
efficient bifunctional catalytic system is eagerly required.
mainly focused on the 1,3-dicarbonyl compound addition8
and the activated ester-Aldol type reaction (Scheme 1).9 In
general, these processes underwent an R-deprotonation
pathway, which involved deprotonating HR of the car-
bonyl to generate the enolate or dienolate intermediate.
Alkaline earth metal catalyzed direct γ-deprotonation of
the carbonyl to generate a dienolate for related trans-
formations still remains unexplored.10 Herein, we report
a bifunctional 3,30-Ph2-BINOL-Mg catalyzed direct asym-
metric vinylogous Michael addition of R,β-unsaturated
γ-butyrolactam to a variety of enones and R,β-unsaturated
N-acylpyrrole.
Scheme 1. Alkaline Earth Metal Catalyzed Enolate Addition
Figure 1. R,β-Unsaturated carbonyls explored in title reaction.
Unlike the transition metal, the alkaline earth metal has
been well recognized for its vast abundance and being
inexpensive as well as relatively nontoxic. However, appli-
cation of these catalysts, especially the magnesium
catalyst,6 to novel transformations has been rarely
revealed.7 Although alkaline earth metal catalysis has
received growing attention very recently, these studies
Primarily, alkoxyl alkaline earth metals in combination
with various BINOL derivatives were explored in the
direct asymmetric vinylogous addition of R,β-unsaturated
γ-butyrolactone. However, these catalysts displayed very
poor catalytic activity as well as stereoselectivity, which
might be caused by the nature of the reactants and the
intermediates (Figure 2). First, the alkoxyl alkaline earth
metals were moisture and air sensitive. This led to poor
repetition either for the reaction activity or for the reaction
stereoselectivity. Second, the rotatable monochelated bond
in the generated complex A might lead to difficulty in ste-
reocontrol. While using an R,β-unsaturated γ-butyrolactam
with an N-Boc protection group, stereocontrol would be
much more favorable with the contribution of the bidentate
chelation between the intermediate and the catalyst in
complex B. Thereby, N-Boc-R,β-unsaturated γ-butyrolac-
tam 1 was exploited in the subsequent investigation.
(4) Organocatalytic direct vinylogous Michael additions: (a) Xue, D.;
Chen, Y.-C.; Wang, Q. -W.; Cun, L.-F.; Zhu, J.; Deng, J.-G. Org. Lett.
2005, 7, 5293. (b) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen, Y.-C.;
Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563. (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) Huang,
H.; Yu, F.; Jin; Li, W.; Wu, W.; Liang, X.; Ye, J. Chem. Commun. 2010,
46, 5957. (f) Feng, X.; Cui, H.-L.; Xu, S.; Wu, L.; Chen, Y.-C. Chem.;
Eur. J. 2010, 16, 10309. (g) Huang, H.; Jin, Z.; Zhu, K.; Liang, J. Ye
Angew. Chem., Int. Ed. 2011, 50, 3232. (h) Zhang, Y.; Shao, X., Y.-L.;
Xu, H.-S.; Wang, W. J. Org. Chem. 2011, 76, 1472. (i) Quintard, A.;
Lefranc, A.; Alexakis, A. Org. Lett. 2011, 13, 1540. (j) Terada, M.;
Ando, K. Org. Lett. 2011, 13, 2026.
(5) Organometallic catalyzed direct vinylogous addition: (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) Shepherd, N. E.;
Tanabe, H.; Xu, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 3666. (d) Zhou, L.; Lin, L.; Ji, J.; Xie, M.; Liu, X.; Feng, X.
Org. Lett. 2011, 13, 3056.
(6) Recent examples: (a) Crimmin, M. R.; Arrowsmith, M.; Barrett,
A. G. M.; Casely, I. J.; Hill, M. S.; Procopiou, P. A. J. Am. Chem. Soc.
2009, 131, 9670. (b) Yoshino, T.; Morimoto, H.; Lu, G.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 17082. (c) Ito, S.; Fujiwara,
Y.; Nakamura, E.; Nakamura, M. Org. Lett. 2009, 11, 4306. (d) Trost,
B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674.
(7) Recent reviews for alkaline-earth metal catalyzed CꢀC bond
formation: (a) Kazmaier, U. Angew. Chem., Int. Ed. 2009, 48, 5790.
(b) Harder, S. Chem. Rev. 2010, 110, 3852. (c) Kobayashi, S.; Yamashita,
Y. Acc. Chem. Res. 2011, 44, 58. (d) Kobayashi, S.; Mori, Y.; Fossey,
J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626.
Figure 2. Reaction intermediate of γ-butyrolactone (A) vs
γ-butyrolactam (B).
(8) Selected examples: (a) Agostinho, M.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 2430. (b) Tsubogo, T.; Yamashita, Y.; Kobayashi,
S. Angew. Chem., Int. Ed. 2009, 48, 9117. (c) Poisson, T.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 7890.
(9) Selected examples: (a) Evans, D. A.; Nelson, S. G. J. Am. Chem.
Soc. 1997, 119, 6452. (b) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. (c) Nguyen, H. V.;
Matsubara, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 5927.
Org. Lett., Vol. 13, No. 24, 2011
6411

using ether solvent due to its negative coordination with
the magnesium (entry 4). Chloride hydrocarbon solvents
were more favorable. The highest enantioselectivity (ee up
to 94%) was observed while the model reaction was carried
out in DCM (entry 7). Lowering the reaction temperature
to ꢀ40 °C caused a sharp decrease of the reaction en-
antioselectivity (only 10% ee) (entry 8). The ee value of 3a
also decreased markedly to 80% while reducing the cata-
lyst loading to 5 mol % (entry 9).
Scheme 2. Ligand Screening for the Model Additiona
Table 1. Reaction Condition Optimization of Model Reactiona
L4*-Mg
entry
(mol %)b
additivec
MgSO4
solvent
ee (%)d
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
5
Tol
73
89
84
78
90
88
94
10e
80
˚
4 A MS
Tol
˚
4 A MS
Xylene
THF
CHCl3
DCE
DCM
DCM
DCM
a The reactions were carried out with 1 (0.24 mmol, 1.2 equiv) and 2a
(0.2 mmol) in 1 mL DCM at 0 °C overnight. (a) Prepared in situ by
stirring 1:1 of L* and Bu2Mg (1 M in heptane) for 2 h in 1 mL solvent.
(b) ee value in parentheses referred to the reaction carried out in toluene.
˚
4 A MS
˚
4 A MS
˚
4 A MS
˚
4 A MS
˚
4 A MS
˚
4 A MS
Although the BINOLꢀmetal complex has been widely
used in asymmetric catalysis, applications of the typical
BINOL-Mgwere lessdisclosed.11 This type of complex can
be easily obtained by combining in situ the ligand and
Bu2Mg. Using MgSO4 as the additive, a series of BINOL
derivatives and disulfonamides was explored in the model
reaction with results summarized in Scheme 2. Generally
speaking, 3,30-substituted BINOL exhibited different cat-
alytic activities with an obvious solvent effect. The enan-
tioselectivity of the model reaction decreased sharply by
changing the 3,30-substituents of the BINOL derivatives
with either larger or smaller groups. An excellent ee (94%)
for 3a was observed under the catalysis of an L4*ꢀMg
complex. Unfortunately, disulfonamideꢀMg complexes12
did not work in controlling the stereoselectivity of the
model reaction.
a Unless otherwise noted, reactions were carried out with 1 (0.24
mmol, 1.2 equiv) and 2a (0.2 mmol) in 1 mL of solvent at 0 °C overnight
(about 8 h). b Prepared in situ by stirring 1:1 of L4* and Bu2Mg (1 M in
heptane) for 2 h in 1 mL of solvent. c 50 mg of the freshly dried MgSO4 or
4 A MS were used. d Determined by HPLC analysis. e Reaction was
˚
performed at ꢀ40 °C.
Under the optimal conditions, varieties of aryl enones
were compatible with the present protocol. The reaction
activity as well as the enantioselectivtiy was minimally
affected by either the aryl substituents of the carbonyl or
the γ-aryl substituents of the enone (Table 2). Either
electron-deficient or electron-rich γ-aryl substituted 2
could be transferred to 3 favorably with ee up to 98%
and dr up to over 20:1. With a γ-(o-substituted)-phenyl
substituent, hindered enones underwent the direct asym-
metric vinylogous Michael addition successfully to afford
products 3 with 92ꢀ95% ee, respectively (entries 2, 5, 7).
The Michael addition of γ-butyrolactam 1 to γ-(4-CN-
phenyl) substituted 2k afforded 3k with an excellent ee up
to 98% (entry 11). Either R- or β-naphthyl substituted 2
also proceeded favorably to give 3lꢀm with a high ee of
91% and 93%, respectively (entries 12ꢀ13). With p-sub-
stituted-phenyl substituents, adducts 3oꢀp were obtained
with excellent ee values of 91% and 97% (entries 15ꢀ16).
Even heteroaromatic substituted 3q was also favorably
afforded with a high yield of 81% and 94% ee (entry 17).
The relative configuration of 3 was confirmed by compar-
ison with the literature 1H NMR spectra, and the absolute
configuration of 3 was confirmed by comparison with the
literature optical rotation.4h
The solvent effect as well as additive effect was further
studied in more detail (Table 1). It was found that the
enantioselectivity of the model reaction was not well
repeated when using MgSO4 as the additive due to its
˚
moisture sensitivity. More easily handled 4 A molecular
sieve was used instead of MgSO4, and the reaction gave a
higher enantioselectivity (entry 2 vs 1). The enantioselec-
tivity of the model reaction was intensively affected by
(10) Generation of dienolate via an alkaline-earth metal catalyzed R-
deprotonation pathway was reported: (a) Yamaguchi, A.; Aoyama, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 3387. (b) Yamaguchi,
A.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 10842.
(11) (a) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.
Pure Appl. Chem. 1988, 60, 1597. (b) Bolm, C.; Beckmann, O.; Cosp, A.;
Palazzi, C. Synlett 2001, 1461. (c) Du, H.; Zhang, X.; Wang, Z.; Bao, H.;
You, T.; Ding, K. Eur. J. Org. Chem. 2008, 13, 2248. (d) Bao, H.; Wu, J.;
Li, H.; Wang, Z.; You, T.; Ding, K. Eur. J. Org. Chem. 2010, 6722. (e)
Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2009, 132, 56. (f)
Hatano, M.; Horibe, T.; Ishihara, K. Org. Lett. 2010, 12, 3502. (g)
Tsubogo, T.; Kano, Y.; Yamashita, Y.; Kobayashi, S. Chem.;Asian J.
2010, 5, 1974. (h) Hara, K.; Park, S.-Y.; Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. Chem.;Asian J. 2008, 3, 1500.
It was well recognized that either the substituent of the
carbonyl or γ-substituent of the enone significantly af-
fected the reactivity of the enone substrate, which is the
mainlimitation inthe reportedcatalytic systems. However,
we were very pleased to find that our present protocol is
(12) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452.
6412
Org. Lett., Vol. 13, No. 24, 2011

because it is too hard for the intermediate to construct a
highly selective chiral center with the aid of a γ-methyl
group of the enone that is too small. It was of great
significance to find that R,β-unsaturated N-acylpyrrole is
also a compatible substrate to the catalytic system.13 The
Michael adduct 3t was favorably afforded with a high ee of
92%. Moreover, the versatile 3t possessed far more syn-
thetic utilities due to the N-acylpyrrole being easily trans-
formed into esters, acids, and amides.
Table 2. Catalyzed Direct Asymmetric Vinylogous Michael
Addition of R,β-Unsaturated γ-Butyrolactam to Aryl Enonesa
Figure 3. Versatility of the present protocol.
In summary, we developed direct asymmetric vinylo-
gous Michael additions of R,β-unsaturated γ-butyrolac-
tams using a bifunctional 3,30-Ph2-BINOL-Mg catalyst.
The addition to a variety of enones afforded the products
with high yields (70ꢀ94%), high diastereoselectivities (up
to over 20:1), and excellent enantioselectivities (up to
98%). The stereoselectivity of the reaction was slightly
affectedbythesubstituent of the enone carbonylbuthighly
affected by its γ-substituent. We also disclosed the first
highly enantioselective direct vinylogous Michael addition
of R,β-unsaturated γ-butyrolactamstoR,β-unsaturatedN-
acylpyrroles. The versatility of the N-acylpyrrole moiety
makes this protocol a powerful tool for synthetic chemistry
as well as new drug discovery. Further investigation of the
present bifunctional catalyst in bioactive compound synthe-
sis is underway in our laboratory.
a L4*-Mg was prepared in situ by stirring L4* (10 mol %) and Bu2Mg
(10 mol %, 1 M in heptane) for 2 h in 1 mL of DCM before 1 (0.24 mmol,
1.2 equiv) and 2 (0.2 mmol) being added. Then the reaction was
performed at 0 °C overnight (about 8 h). b The absolute configuration
of 3 was confirmed by comparison with literature 1H NMR spectra and
optical rotation.4h c Isolated yield of the major diastereomer. d Deter-
mined by 1H NMR analysis of the crude product. e Determined by
HPLC analysis.
also applicable to different Michael acceptors possessing a
similar nature to enone (Figure 3). It is noteworthy that
direct asymmetric vinylogous Michael addition of 1 to an
inert aliphatic enone afforded3r witha very highee of 92%
and a moderate yield of 62%. Replacing the γ-aryl moiety
with a methyl group resulted in the enantioselectivity of the
catalytic process dramatically decreasing to a moderate
level, and only 54% ee for 3s was observed. This may be
Acknowledgment. We gratefully acknowledge financial
support from NSFC (21002043, 20932003, and 90813012)
and the National S&T Major Project of China
(2012ZX09504001-003).
(13) Selected examples: (a) Evans, D. A.; Borg, G.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2002, 41, 3188. (b) Kinoshita, T.; Okada, S.;
Park, S.-R.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2003,
42, 4680. (c) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559. (d) Mita, T.; Sasaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514. (e)
Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 13419. (f) Zhao, D.; Wang, Y.; Mao, L.; Wang, R.
Chem.;Eur. J. 2009, 15, 10983.
Supporting Information Available. Experimental pro-
cedures and spectral data for isolated products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
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