Highly enantioselective Michael-cyclization cascade promoted by synergistic asymmetric aminocatalysis and Lewis acid catalysis

Article abstract of DOI:10.1016/j.tetlet.2010.01.096

The novel dual cooperative asymmetric aminocatalysis and Lewis acid catalysis has been successfully developed for promoting cascade Michael-cyclization reaction with high enantio-, regio- and chemo-selectivity. The simple and practical process affords a one-pot approach to synthetically useful cyclopentenes.

Full text of DOI:10.1016/j.tetlet.2010.01.096

Tetrahedron Letters 51 (2010) 1742–1744
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective Michael-cyclization cascade promoted
by synergistic asymmetric aminocatalysis and Lewis acid catalysis
a,
Chenguang Yu a,b, Yinan Zhang a, Shilei Zhang a, Jing He b, , Wei Wang
*
*
a Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA
b State Key Laboratory of Chemical Resources Engineering, Beijing University of Chemical Technology, Beijing 100029, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel dual cooperative asymmetric aminocatalysis and Lewis acid catalysis has been successfully
developed for promoting cascade Michael-cyclization reaction with high enantio-, regio- and chemo-selec-
tivity. The simple and practical process affords a one-pot approach to synthetically useful cyclopentenes.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 January 2010
Revised 23 January 2010
Accepted 25 January 2010
Available online 4 February 2010
Keywords:
Cascade
Michael
Organocatalysis
Pd catalysis
Cascade Michael-Michael reaction (Eqn. 1)12
Cascade reactions are unrivaled in their power to rapidly
construct complex molecular frameworks with high synthetic
efficiency and atom economy.1 While asymmetric cascade organ-
ocatalysis has received considerable attention recently,2,3 particu-
larly chiral second amines—the most widely used catalytic
systems,4 it is realized that in these cases, only the ‘classical’ elec-
trophilic partners such as appendant aldehydes, ketones, enones,
EtO2C
10 mol% I
CHO
O
O
MeO2C
H
+
OEt
EtOH, rt
up to 95% yield
99% ee
R
CO2Me
cat.
MeO2C CO2Me
R
1
2
Ph
Ph
OTMS
Ph
Ph
OTMS
MeO2C
Second
Michael
dr > 20:1
N
H
I
Ph
Ph
a,b-unsaturated esters, and alkyl halides can be employed for trap-
ping nucleophilic enamine. Clearly, an important direction with
goal of expanding the scope of the powerful synthetic strategy
should go beyond the current territory.
N
OTMS
N
CO2Et
O
First Michael
R
OEt
Given the great success of Lewis acid catalysis and aminocatal-
ysis, we question whether it might be possible to merge the two
catalytic systems5 for developing new enantioselective cascade
processes. However, to our knowledge, no asymmetric protocols
using the strategy have been reported.6,7 Herein we describe the
development of the first combined aminocatalysis and Lewis acid
catalysis in an asymmetric Michael-cyclization cascade to afford
highly enantioenriched (89–99% ee) versatile cyclopentenes.8,9
R
CO2Me
CO2Me
CO2Me
New cascade Michael-cyclization reaction in this work (Eqn. 2)
O
CHO
CHO
R
H
+
MeO2C
R
1
R
MeO2C CO2Me MeO2C CO2Me
In the past decade, Lewis acid complexes with
p-bonds (termed
CO2Me
exo 4
‘p
-acids’ or ‘
p
-ligands’)10 such as alkynes11 have been demonstrated
Ph
endo 5
3
cyclization
Ph
N
to be valuable electrophiles in organic transformations. We envision
H
I
OTMS
Ph
Ph
OTMS
Mn+
that incorporation of the moiety instead of a classic electrophilic
partner a
,b-unsaturated ester (e.g., 2, Scheme 1, Eq. 1)12 into a nucle-
Ph
Ph
N
N
ophilic malonate generates a new bifunctional dimethyl propargyl-
malonate 3 (Eq. 2). The newly designed substance can potentially
endo
R
Michael
OTMS
MeO2C
exo
6
R
CO2Me
MeO2C CO2Me
* Corresponding authors. Tel.: +86 10 6442 5385 (J.H.); +1 505 277 0756; fax: +1
505 277 2609 (W.W.).
E-mail addresses: jinghe@263.net.cn (J. He), wwang@unm.edu (W. Wang).
Scheme 1. Enantioselective cascade reactions.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.096

C. Yu et al. / Tetrahedron Letters 51 (2010) 1742–1744
1743
engage in a new binary catalytic asymmetric Michael-cyclization
process to create synthetically useful chiral cyclopentenes in one-
pot operation. In the proposed cascade, chiral amine I activates an
enal 1 to form an iminium, which is subject to the Michael addition
to form an enamine 6. Activation of the alkyne by a Lewis acid en-
ables an intramolecular cyclization. Such corporative catalysis
may improve the reaction efficiency (yields and/or enantioselectiv-
ity). The working hypothesis looks simple on paper. However, the
implementation of the strategy faces significant barriers. The pri-
mary and most obvious issue is the compatibility of a chiral amine
base and a Lewis acid in one-pot and their interference may affect
the enantioselectivity significantly. Second, in the subsequent cycli-
zation reaction, possible exo- and endo- enamine attack of the Lewis
on the reaction yield (entries 10 and 11). Reducing the amount of
PdCl2 led to improvement. We decided to select the use of
10 mol % PdCl2 to probe the scope of the cascade reaction due to
much shorter reaction time (entry 10).
The binary catalytic system promoted asymmetric Michael-
cyclization reaction serve as a viable approach to the chiral cyclo-
pentenes with significant structural variation (Table 2). The facile
production of the cyclopentene products is especially noteworthy
given that one quaternary carbon and one stereogenic center are
created in the one-pot operation. It appears that the electronic
nature has little influence on both reaction yield and enantioselec-
tivity. The aromatic ring bearing electron-neutral (entry 1), -with-
drawing (entries 2–6), and -donating (entries 7–9) groups and a
combination of electron-withdrawing and -donating substituents
(entry 10) can be readily accommodated. Furthermore, heteroaro-
matic furanyl enal can effectively participate in the process as well
(entries 11). Finally, we also found that the steric effect on the
cascade process is limited too (entries 2, 5, and 9). It is also realized
the limitation of the cascade reaction. When aliphatic pent-2-enal
was employed, no desired Michael-cyclization product was ob-
tained. 2-Ethyl-3-methyl benzaldehyde was isolated, in addition
to other unidentified products. It was believed that the substituted
benzaldehyde product was formed through a possible [4+2] pro-
cess.13 The absolute configuration of the products compounds is
determined by single X-ray crystal structure analysis from a deriv-
ative 7 from 4b (Fig. 1).14
The preliminary mechanistic studies show that the synergistic
effect of the two catalysts contributes to the high reaction yields
and high enantioselectivity. In the absence of PdCl2, only the Mi-
chael reaction occurred with poor ee (67%) and in a very low yield
(17%) under the same reaction conditions and at the same reaction
time (36 h) (Scheme 2, Eq. 3 vs Table 2, entry 1). The absence of
catalyst I resulted in no reaction. Finally, the Michael adduct 8
can be efficiently transformed into the cyclic product 4a in the
presence of catalyst I and PdCl2 (Eq. 4). In a control, without I,
the cyclization reaction did not occur, indicative of an enamine
involved.
acid activated triple bond (e.g., p-acid) could result in multiple prod-
ucts 4 and 5. It is conceived that the steric and kinetic effects favor
the 5-exo-dig process.
Initial validation of the hypothesis was carried out with a reac-
tion between cinnamaldehyde 1a and dimethyl propargylmalonate
3 in CH2Cl2 at rt in the presence of organocatalyst I (20 mol %) and
a Lewis acid (20 mol %) (Table 1). Mixed but encouraging results
were produced. The reaction proceeded cleanly with only the for-
mation of highly regio-selective conjugated cyclopentene aldehyde
4a with excellent ees (95–99%) albeit very low yields (6–13%) due
to slow conversion when PdCl2 (entry 1), Pd(OAc)2 (entry 2), ZnCl2
(entry 3), and AgOTf (entry 7) were employed. This finding indi-
cates that these soft acids have a limited effect on the chiral amine
initiated asymmetric conjugate addition reaction. Moreover, the
cascade process is highly chemo- and regio-selective. No reaction
occurred for other screened metal complexes including Au(I) and
Au(III) (entries 5 and 6). We chose PdCl2 as Lewis acid for further
optimization of reaction conditions, mainly aimed at improving
reaction yields since it co-catalyzed the reaction more efficiently.
The dramatic improvement in yield arose from the addition of acid
additives without sacrificing the enantioselectivity (entries 8–10).
Notably, the reaction yield (63%) was improved dramatically with
PhCO2H (entry 9). Screening of reaction solvents revealed that
CH2Cl2 was the choice of the cascade process (see Supplementary
data for details). Tuning the ratio of I and PdCl2 had an impact
In conclusion, we have developed an unprecedented asymmet-
ric Michael-cyclization protocol for one-pot preparation of highly
enantioenriched cyclopentenes under mild reaction conditions. A
catalytic strategy features the combination of widely used aminoc-
atalysis and Lewis acid catalysis to achieve high enantioselectivity
and high yields in a cooperative manner for the first time. Further
Table 1
Exploration of combined aminocatalysis and Lewis acid catalysis in asymmetric
Michael-cyclization cascadea
CHO
I (20 mol%)
MeO2C
CO2Me
Lewis acid (20 mol%)
Ph
+
CHO
Table 2
Ph
additive (20 mol%)
Scope of I and PdCl2 promoted cascade Michael-cyclization reactionsa
CH2Cl2, rt
MeO2C CO2Me
1a
3
4a
O
CHO
MeO2C
+
CO2Me
I (20 mol%)
PdCl2 (10 mol%)
Entry
Lewis acid
Additive
t (h)
Yieldb (%)
eec (%)
H
PhCO2H
(20 mol%)
CH2Cl2, rt
R
MeO2C CO2Me
4
1
2
3
4
5
6
7
8
9
PdCl2
Pd(OAc)2
ZnCl2
None
None
None
None
None
None
None
TEA
24
24
40
24
50
50
40
58
48
36
96
13
6
13
0
0
0
11
2
63
81
80
95
95
97
—
—
—
99
—
99
95
99
R
1
3
CuOTfÁ½Tol
Entry
R
t (h)
Yieldb (%)
eec (%)
AuCl
AuCl3
AgOTf
PdCl2
1
2
3
Ph, 4a
36
96
108
36
36
60
36
72
60
60
81
64
63
83
77
86
91
61
76
73
65
95
95
97
99
99
93
99
92
99
97
89
4-BrC6H4, 4b
3-FC6H4, 4c
2-FC6H4, 4d
2-NO2C6H4, 4e
4-NO2C6H4, 4f
4-MeC6H4, 4g
4-MeOC6H4, 4h
2-MeOC6H4, 4i
4d
5d
6
PdCl2
PhCO2H
PhCO2H
PhCO2H
d
10
11
PdCl2
e
PdCl2
7
8
9
10
11
a
Unless stated otherwise, the reaction was carried out with 1a (0.1 mmol) and 3
(0.1 mmol) in the presence of 20 mol % organocatalyst I, 20 mol % PdCl2 and addi-
tive (0.2 equiv) in CH2Cl2 (0.5 mL) was added a and the resulting solution was
stirred for specified time at rt. The reaction mixture was directly purified by silica
gel chromatography without work-up.
4-Ac-3-MeO-C6H4, 4j
furanyl, 4k
108
b
a
b
c
Isolated yield.
Determined by HPLC analysis (Chiralpak IC).
10 mol % PdCl2 used.
1 mol % PdCl2 used.
Unless specified, see footnote a in Table 1 and Supplementary data.
Isolated yield.
Determined by HPLC analysis (Chiralpak IC).
30 mol % I used in 0.25 mL of CH2Cl2.
c
d
e
d

1744
C. Yu et al. / Tetrahedron Letters 51 (2010) 1742–1744
Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354; (c) Pellissier, H. Tetrahedron 2006,
62, 2143; (d) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006.
2. For reviews of organocatalytic cascade reactions, see: (a) Enders, D.; Grondal,
C.; Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (b) Yu, X.; Wang, W.
Org. Biomol. Chem. 2008, 6, 2037; Recent selected examples, see: (c) Bencivenni,
G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200; (d) Zhu, D.; Lu, M.; Dai, L.;
Zhong, G. Angew. Chem., Int. Ed. 2009, 48, 6205; (e) Rueping, M.; Antonchick, A.
P. Angew. Chem., Int. Ed. 2008, 47, 10090; (f) Enders, D.; Wang, C.; Bats, J. W.
Angew. Chem., Int. Ed. 2008, 47, 7539; (g) Zhu, D.; Lu, M.; Chua, P. J.; Tan, B.;
Wang, F.; Yang, Y.; Zhong, G. Org. Lett. 2008, 10, 4585; (h) Dodda, R.; Goldman, J.
J.; Mandal, T.; Zhao, C.-G.; Broker, G. A.; Tiekink, E. R. T. Adv. Synth. Catal. 2008,
350, 537; (i) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int. Ed.
2008, 47, 4012; (j) de Figueiredo, R. M.; Froelich, R.; Christmann, M. Angew.
Chem., Int. Ed. 2008, 47, 1450; (k) Vo, N. T.; Pace, R. D.; O’Hara, M. F.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 404; (l) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard,
D. Angew. Chem., Int. Ed. 2007, 46, 4922; (m) Zhou, J.; List, B. J. Am. Chem. Soc.
2007, 129, 7498; (n) Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew.
Chem., Int. Ed. 2007, 46, 5168; (o) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 47, 1101; (p) Biddle, M. M.; Lin, M.; Scheidt, K.
A. J. Am. Chem. Soc. 2007, 129, 3830; (q) Rios, R.; Vesely, J.; Sundun, H.; Zhao, G.;
Dziedzic, P.; Cordova, A. Adv. Synth. Catal. 2007, 349, 1028; (r) Enders, D.; Hüttl,
M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (s) Huang, Y.; Walji, M.
C.; Larsen, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051; (t) Yang, J.
W.; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc. 2005, 127, 15036; (u) Yamamoto,
Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962; (v)
Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III Angew. Chem., Int. Ed. 2003,
42, 4233.
3. Selected examples from our laboratory: (a) Wang, W.; Li, H.; Wang, J.; Zu, L.-S. J.
Am. Chem. Soc. 2006, 128, 10354; (b) Li, H.; Wang, J.; E-Nunu, T.; Zu, L.-S.; Jiang,
W.; Wei, S.-H.; Wang, W. Chem. Commun. 2007, 507; (c) Li, H.; Wang, J.; Li, H.;
Zu, L.-S.; Xie, H.-X.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833; (d)
Zu, L.-S.; Wang, J.; Li, H.; Xie, H.-X.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007,
129, 1036; (e) Xie, H.-X.; Zu, L.-S.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 129, 10886; (f) Wang, J.; Li, H.; Xie, H.-X.; Zu, L.-S.; Shen, X.; Wang, W.
Angew. Chem., Int. Ed. 2007, 46, 9050; (g) Wang, J.; Xie, H.-X.; Li, H.; Zu, L.-S.;
Wang, W. Angew. Chem., Int. Ed. 2008, 47, 4177; (h) Zu, L.-S.; Zhang, S.-L.; Xie,
H.-X.; Wang, W. Org. Lett. 2009, 11, 1627.
Figure 1. X-ray crystallographic structure 7.
4. For selected recent reviews of aminocatalysis, see: (a) Notz, W.; Tanaka, F.;
Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580; (b) Erkkila, A.; Majander, I.; Pihko,
P. M. Chem. Rev. 2007, 107, 5416; (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
List, B. Chem. Rev. 2007, 107, 5471; (d) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (e) Bertelsen, S.; Jørgensen, K.
A. Chem. Soc. Rev. 2009, 38, 2178.
5. For reviews of dual catalysis, see: (a) Duschek, A.; Kirsch, F. S. Angew. Chem., Int.
Ed. 2008, 47, 5703; (b) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem.
2006, 4, 393; (c) Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566.
6. Examples of non-asymmetric versions, see: (a) Ibrahem, I.; Córdova, A. Angew.
Chem., Int. Ed. 2006, 45, 1952; (b) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959; (c)
Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10,
1025; (d) Wang, H.-F.; Yang, F.; Xu, P.-F.; Dixon, D. J. Chem. Commun. 2009,
3916; (e) Yang, T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem. Commun. 2008,
2923; Asymmetric version: (f) Bihelovic, F.; Matovic, R.; Vulovic, B.; Saicic, R. N.
Org. Lett. 2007, 9, 5063; (g) Chercheja, S.; Eilbracht, P. Adv. Synth. Catal. 2007,
349, 1897.
7. Selected examples of the use of combined chiral phosphoric acids or phase
transfer catalysts and Lewis acids in dual asymmetric catalysis, see: (a)
Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003,
42, 2054; (b) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448;
(c) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496; (d)
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336; (e) Reuping, M.;
Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed. 2007, 46, 6903; (f)
Klussmann, M. Angew. Chem., Int. Ed. 2009, 48, 7124; (g) Han, Z.-Y.; Xiao, H.;
Chen, X.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182; (h) Cai, Q.; Zhao, Z.-A.;
You, S.-L. Angew. Chem., Int. Ed. 2009, 48, 7428.
O
MeO2C
CO2Me
MeO2C CO2Me
CHO Eqn. 3
I (20 mol%)
+
H
PhCO2H
8
(20 mol%)
CH2Cl2, 36 h, rt
Ph
Ph
1a
3
17% yield and 67% ee
CHO
MeO2C CO2Me
CHO
I (20 mol%)
PdCl2 (10 mol%)
Ph
Eqn. 4
PhCO2H
(20 mol%)
MeO2C CO2Me
Ph
8
4a
CH2Cl2, 12 h, rt
67% ee
87% yield and 86% ee
Scheme 2.
investigation of this powerful and general approach aimed at
expanding the scope of asymmetric cascade catalysis and the
mechanism of the cascade process is under way in our laboratory.
Acknowledgments
The financial support of the work by the NSF (CHE-0704015)
and the Chinese Scholarship Council (C. Yu) is gratefully acknowl-
edged. Thanks are expressed to Dr. Elieen N. Duesler for perform-
ing X-ray analysis. The Bruker X8 X-ray diffractometer was
purchased via an NSF CRIF:MU award to the University of New
Mexico, CHE-0443580.
8.
A related non-cascade method was reported recently: Belot, S.; Vogt, K.
A.; Besnard, C.; Krause, N.; Alexakis, A. Angew. Chem., Int. Ed. 2009, 48,
8923.
9. During the preparation of the manuscript, a similar study was reported: Zhao,
G.-L.; Ullah, F.; Deiana, L.; Lin, S.; Zhang, Q.; Sun, J.; Ibrahem, I.; Dziedzic, P.;
Córdova, A. Chem. Eur. J. 2010. doi:10.1002/chem.200902818.
10. For details of the discussion regarding ‘p-acids’, see reviews: (a) Fürstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410; (b) Hashmi, A. S. K. Chem.
Rev. 2007, 107, 3180; (c) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem.
Commun. 2009, 5075.
Supplementary data
11. For reviews, see: (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348,
2271; (b) Widenhoefer, R. A.; Han, X. Q. Eur. J. Org. Chem. 2006, 48, 4555; (c)
Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.096.
12. We have developed organocatalytic enantioselective Michael-Michael cascade
reactions of enals with malonate
a,b-unsaturated esters: Zu, L.-S.; Li, H.; Xie,
H.-X.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46,
3732.
References and notes
13. Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8, 2217.
14. CCDC 749905 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge via www.ccdc.cam.ac.uk.
1. For general recent reviews of cascade reactions, see: (a) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134; (b) Guo, H.;