Organocatalytic enantioselective cascade michael-aldol condensation reactions: Efficient assembly of densely functionalized chiral cyclopentenes

Article abstract of DOI:10.1002/anie.200703163

(Chemical Equation Presented) A cascade of possibility: A novel and highly enantioselective cascade Michael-aldol condensation reaction of α,β-unsaturated aldehydes with dimethyl malonate aldehyde has been developed. The process, efficiently catalyzed by a simple chiral diphenylprolinol TES ether, serves as a powerful approach to the preparation of highly functionalized chiral cyclopentenes with the formation of two new C-C bonds. TES = triethylsilyl.

Full text of DOI:10.1002/anie.200703163

Communications
DOI: 10.1002/anie.200703163
Organocatalysis
Organocatalytic Enantioselective Cascade Michael–Aldol
Condensation Reactions: Efficient Assembly of Densely
Functionalized Chiral Cyclopentenes**
Jian Wang, Hao Li, Hexin Xie, Liansuo Zu, Xu Shen, and Wei Wang*
The development of asymmetric methods for the preparation
of functionalized cyclopentenes has been of long-standing
interest to organic chemists. As a result of their broad
applications in organic synthesis they are widely distributed in
a vast array of bioactive molecules.[1,2] In the past, significant
advances have been made in this area by using transition-
metal-mediated [3+2] and [4+1] cycloaddition reactions.[1]
Furthermore, stereospecific ring opening of chiral cyclopro-
panes,[3] ring-closing metathesis of chiral dienes,[4] and organ-
ometallic-catalyzed Nazarov cyclizations[5] have also been
described. Herein, we report a novel strategy for the
preparation of chiral cyclopentenes through an organocata-
lytic, highly enantioselective cascade Michael–aldol conden-
sation reaction. Significantly, the cascade sequence enables
quick construction of heavily functionalized cyclopentenes
chiral diarylprolinol silyl ethers to catalyze asymmetric
cascade Michael–aldol condensation processes by using
heteroatoms S, O, or N as nucleophiles for the formation of
[9–12]
À
À
new C X and C C bonds (Scheme 1),
we sought to
À
extend the concept for the construction of multiple C C
bonds in a one-pot transformation. The development of such
processes has been a challenging task, and only few examples
have been recently described.[9c,d,10f,j,k]
À
with the generation of two new C C bonds with high
enantioselectively (91–97% ee) from readily available start-
ing materials under mild reaction conditions.
À
C C bond-forming reactions are considered the most
important processes in organic synthesis. Developing novel
Scheme 1. Cascade organocatalytic enantioselective conjugate addi-
tion–aldol condensation reactions involving the formation of sequen-
À
cascade reactions that achieve the formation of multiple C C
bonds in one operation is a particularly attractive strategy for
the efficient construction of complex molecular architectures.
The formation of more than one bond adds an environ-
mentally friendly aspect owing to the elimination of time-
consuming and costly purification procedures and protection/
deprotection steps.[6–8] Having established the capacity of
À
À
tial C X and C C bonds. NP=nitrogen-protected form, TMS=tri-
methylsilyl, TES= triethylsilyl.
Motivation for this study was influenced by the lack of
catalytic asymmetric approaches to the Michael–aldol con-
densation process involving the production of multiple new
À
C C bonds. Development of such a catalytic cascade process
[*] Dr. J. Wang, H. Li, H. Xie, L. Zu, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico
requires a stable and electron-rich carbon species as nucle-
ophile for the initial Michael addition to an a,b-unsaturated
aldehyde 1 (Scheme 2). On the other hand, the carbon
nucleophilic species should be compatible with an electro-
philic aldehyde functionality in one chemical entity 2, which
serves as a latent electrophile for the subsequent aldol
reaction.
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax: (+1)505-277-2609
E-mail: wwang@unm.edu
Prof. Dr. X. Shen, Prof. Dr. W. Wang
Department of Pharmacology, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica
Chinese Academy of Sciences
An even more challenging issue is that the two aldehyde
groups in the respective a,b-unsaturated aldehyde 1 and
nucleophilic aldehyde 2 could compete with the catalyst chiral
diarylprolinol silyl ethers I–III (Scheme 3). Undesired reac-
tion of 2 with the catalyst to produce an iminium C or
enamine D could significantly complicate the cascade process.
Potentially the iminium C could undergo reversible intra-
molecular cyclopropanation and thus slow down the desired
cascade process. Moreover, the enamine D could participate
in the Michael reaction with iminium A. We envisioned that
these problems could be minimized by the use of bulky and
readily enolizable malonates and the sterically hindered
Shanghai 201203 (China)
Prof. Dr. X. Shen
School of Pharmacy
East China University of Science & Technology
Shanghai 200237 (China)
[**] Financial support of this research by the University of New Mexico,
ACS-PRF, NSF (CHE 0704015), and NIH-INBRE program (P20
RR016480) is gratefully acknowledged. Thanks are expressed to Dr.
Elieen N. Duesler for performing X-ray analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 1: Organocatalytic enantioselective cascade Michael–aldol con-
densation reaction of 1a with 2.[a]
Entry
Cat.
Additive
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
I
none
none
18
18
36
48
18
12
12
48
74
73
54
33
78
78
88
<5
89
91
88
69
91
90
II
II
II
II
II
II
III
PhCO2H (0.1 equiv)
TEA (0.1 equiv)
NaOAc (0.1 equiv)
NaOAc (0.5 equiv)
NaOAc (0.5 equiv)
none
7[d]
8
92
n.d.[e]
[a] Unless specified, see the Experimental Section for reaction condi-
tions. [b] Yields of isolated products. [c] Determined by HPLC on a chiral
stationary phase (ChiralpakAS-H). [d] In Cl(CH2)2Cl. [e] Not determined.
Scheme 2. Cascade organocatalytic enantioselective conjugate addi-
tion–aldol condensation reactions involving the formation of two new
À
C C bonds.
result (Table 1, entry 6). To further determine the scope of the
cascade process, examination of the reaction medium led to
the selection of Cl(CH2)2Cl (Table 1, entry 7). The increased
reaction yield with Cl(CH2)2Cl is probably due to the
increased solubility of the base, which thereby favorably
facilitates the enolization of the malonate moiety in 2.
After the optimal conditions had been established, the
generality of the cascade Michael–aldol condensation pro-
cesses was explored. The organocatalytic enantioselective
cascade reactions serve as an efficient route for the prepara-
tion of highly functionalized cyclopentenes (Table 2). Signifi-
cantly, the new stereogenic center is created in high enantio-
selectivity (91–97% ee) in the one-pot procedure. Moreover,
the process affords the formation of a new quaternary carbon
Scheme 3. Possible undesired reactions of catalysts I–III withmalonate
aldehydes 2.
Table 2: Catalyst II promoted cascade Michael–aldol condensation
reactions of trans-a,b-unsaturated aldehydes 1 with 2.[a]
organocatalysts I–III. Accordingly, compound 2 with a
nucleophilic malonate and an electrophilic aldehyde was
designed for the cascade Michael–aldol condensation process
(Schemes 2 and 3).
Entry
R
Product
t [h]
Yield [%][b]
ee [%][c]
Validation of the proposed cascade Michael–aldol con-
densation process started by evaluating a model reaction
between trans-4-nitro cinnamaldehyde (1a) with dimethyl 2-
oxoethylmalonate (2) in the presence of 10 mol% I in CH2Cl2
(Table 1). The cascade Michael–aldol condensation process
proceeded smoothly to afford desired product 3a in 74%
yield and 89% ee (Table 1, entry 1). No side products were
detected. Encouraged by this, we surveyed pyrrolinol ethers II
and III for the reaction under the same reaction conditions.
While II afforded comparable results with a slightly higher
ee value (Table 1, entry 2), no reaction occurred for the more
sterically bulky catalyst III (Table 1, entry 8). Screening
additives including acid (Table 1, entry 3) and bases
(Table 1, entries 4–7) revealed that they had an effect on
the process, and the use of 0.5 equiv NaOAc gave the best
1
2
3
4
5
6
7
8
4-NO2C6H4
4-FC6H4
4-CF3C6H4
4-CNC6H4
2-NO2C6H4
2-ClC6H4
2-MeOC6H4
4-MeOC6H4
3-MeO-4-AcOC6H3
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
12
24
18
36
14
24
48
48
48
24
36
88
73
75
63
85
82
78
80
78
81
89
92
93[d]
93
94
94
95
97
96
95
93
91
9
10
11
3j
3k
2-furanyl
[a] Unless specified, see the Experimental Section for reaction condi-
tions. [b] Yields of isolated products. [c] Determined by HPLC on a chiral
stationary phase (ChiralpakAS-H, or ChiralcelOD-H or OJ-H). [d] Deter-
=
mined after conversion into the corresponding enone with Ph3P COPh.
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Communications
center, and significant structural variation of a,b-unsaturated
Keywords: aldehydes · cascade reactions · cyclopentenes ·
Michael–aldol reaction · organocatalysis
.
aldehydes can be tolerated. The electronic nature of the
aromatic rings of a,b-unsaturated aldehydes 1 has limited
influence on the stereochemical outcome. It demonstrates
that the electron-withdrawing (Table 2, entries 1–6), electron-
donating (Table 2, entries 7 and 8), combined electron-with-
drawing and -donating (Table 2, entry 9), neutral (Table 2,
entry 10), and heteroaromatic (Table 2, entry 11) systems can
participate in the reactions. Probing the steric effect on the
enantioselectivity of the cascade processes indicates that such
impact is also minimal (Table 2, entries 5–7). Finally, less
reactive aliphatic enals were used, and almost no reaction
occurs. The absolute configuration of product 3 f was deter-
mined by X-ray crystal structural analysis (Figure 1).[13]
[1] Reviews of synthesis and bioactivities of cyclopentenes: a) F. C.
Biaggio, A. R. Rufino, M. H. Zaim, C. Y. H. Zaim, M. A. Bueno,
A. Rodrigues, Curr. Org. Chem. 2005, 9, 419; b) G. Helmchen,
M. Ernst, G. Paradies, Pure Appl. Chem. 2004, 76, 495; c) L. F.
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1.
[2] For selected examples of cyclopentenes synthesis, see: a) M.
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J. Org. Chem. 1993, 58, 2345.
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719; b) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151;
c) J. Pietruszka, Chem. Rev. 2003, 103, 1051; d) W. A. Donald-
son, Tetrahedron 2001, 57, 8589.
[4] For reviews, see: a) J. C. Conrad, D. E. Fogg, Curr. Org. Chem.
2006, 10, 185; b) S. F. Martin, Pure Appl. Chem. 2005, 77, 1207;
c) M. E. Maier, Angew. Chem. 2000, 112, 2153; Angew. Chem.
Int. Ed. 2000, 39, 2073; d) R. H. Grubbs, S. J. Miller, G. C. Fu,
Acc. Chem. Res. 1995, 28, 446.
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61, 7577; b) K. L. Habermas, S. E. Demark, T. K. Jones, Org.
React. 1994, 45, 1; c) C. Santelli-Rouvier, M. Santelli, Synthesis
1983, 429.
[6] For recent reviews of cascade reactions, see: a) K. C. Nicolaou,
D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292;
Angew. Chem. Int. Ed. 2006, 45, 7134; b) H. Guo, J. Ma, Angew.
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Pellissier, Tetrahedron 2006, 62, 2143; d) L. F. Tietze, N. Rack-
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Figure 1. X-ray crystal structure of 3 f. Thermal ellipsoids are drawn at
the 20% probability level.
In conclusion, we have described a novel organocatalytic,
enantioselective cascade Michael–aldol condensation reac-
tion. The process is efficiently catalyzed by readily available
(S)-diphenylprolinol triethylsilyl ether to give synthetically
useful, highly functionalized chiral cyclopentenes. The sig-
nificance of the methodology is highlighted by its correlation
to the protocols for the preparation of cyclohexenes, devel-
oped by the Enders[10f] and Hayashi groups.[10j] In principle,
the strategy described can also be extended to the preparation
of six-membered ring systems. This approach constitutes our
future direction aimed at expanding the scope of the powerful
cascade processes.
[7] Recent reviews of organocatalysis, see: a) A. Berkessel, H.
Groger, Asymmetric Organocatalysis: From Biomimetic Con-
cepts to Applications in Asymmetric Synthesis, Wiley, Weinheim,
2005; b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248;
Angew. Chem. Int. Ed. 2004, 43, 5138.
Experimental Section
General procedure (Table 2, entry 1): A mixture of 1a (21 mg,
0.12 mmol), 2 (17 mg, 0.1 mmol), NaOAc (5 mg, 0.05 mmol), and the
catalyst II (3.4 mg, 0.01 mmol) in Cl(CH2)2Cl (0.5 mL) was stirred at
room temperature for 12 h. The mixture was purified by silica gel
column chromatography, eluted by hexane/EtOAc (20:1 to 2:1) to
give the desired product in 88% yield, 92% ee as determined by
HPLC on a chiral stationary phase (ChiralpakAS-H column, 70:30
[8] For a review of organocatalytic cascade reactions, see: D.
Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119,
1590; Angew. Chem. Int. Ed. 2007, 46, 1570.
[9] Recently, our group has reported catalytic, asymmetric cascade
reactions; for selected examples, see: a) W. Wang, H. Li, J. Wang,
L.-S. Zu, J. Am. Chem. Soc. 2006, 128, 10354; b) L.-S. Zu, J.
Wang, H. Li, H.-X. Xie, W. Jiang, W. Wang, J. Am. Chem. Soc.
2007, 129, 1036; c) L.-S. Zu, H. Li, H.-X. Xie, J. Wang, W. Jiang,
Y. Tang, W. Wang, Angew. Chem. 2007, 119, 3806; Angew. Chem.
Int. Ed. 2007, 46, 3732; d) H.-X. Xie, L.-S. Zu, H. Li, J. Wang; W.
Wang, J. Am. Chem. Soc. 2007, 129, 10886; W. Wang, J. Am.
Chem. Soc. 2007, 129, 10886; e) R. Rios, H. Sunden, I. Ibrahem,
G.-L. Zhao, L. Eriksson, A. Córdova, Tetrahedron Lett. 2006, 47,
hexanes/iPrOH at 0.5 mLminÀ1, l = 254 nm); tminor = 37.5 min, tmajor
=
,
52.9 min; [a]D23 (major) = À194.4 degcm3 gÀ1 dmÀ1 (c = 1.3 gcmÀ3
CHCl3).
Received: July 15, 2007
Published online: October 19, 2007
9052 www.angewandte.org
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Angew. Chem. Int. Ed. 2007, 46, 9050 –9053
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8547; f) H. SundØn, I. Ibrahem, G.-L. Zhao, L. Eriksson, A.
Córdova, Chem. Eur. J. 2007, 13, 574.
Carrillo, Angew. Chem. 2007, 119, 5260; Angew. Chem. Int. Ed.
2007, 46, 5168.
[10] For selected examples of organocatalytic cascade reactions, see:
a) B. D. Ramachary, N. S. Chowdari, C. F. Barbas III, Angew.
Chem. 2003, 115, 4365; Angew. Chem. Int. Ed. 2003, 42, 4233;
b) Y. Yamamoto, N. Momiyama, H. Yamamoto, J. Am. Chem.
Soc. 2004, 126, 5962; c) Y. Huang, M. C. Walji, H. Larsen,
D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 15051; d) J. W.
Yang, M. T. H. Fonseca, B. List, J. Am. Chem. Soc. 2005, 127,
15036; e) M. Marigo, T. Schulte, J. Franzen, K. A. Jørgensen, J.
Am. Chem. Soc. 2005, 127, 15710; f) D. Enders, M. R. M. Huttl,
C. Grondal, G. Raabe, Nature 2006, 441, 861; g) M. Marigo, S.
Bertelsen, A. Landa, K. A. Jørgensen, J. Am. Chem. Soc. 2006,
128, 5475; h) C. E. Aroyan, S. J. Miller, J. Am. Chem. Soc. 2007,
129, 256; i) B. Wang, F. Wu, Y. Wang, X. Liu, L. Deng, J. Am.
Chem. Soc. 2007, 129, 768; j) Y. Hayashi, T. Okano, S. Aratake,
D. Hazelard, Angew. Chem. 2007, 119, 5010; Angew. Chem. Int.
Ed. 2007, 46, 4922; k) J. L. Vicario, S. Reboredo, D. Badía, L.
[11] For a review of reactions catalyzed by chiral pyrrolinol ethers,
see: C. Palomo, A. Mielgo, Angew. Chem. 2006, 118, 8042;
Angew. Chem. Int. Ed. 2006, 45, 7876.
[12] For leading studies of reactions catalyzed by chiral pyrrolinol
ethers, see: a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A.
Jørgensen, Angew. Chem. 2005, 117, 804; Angew. Chem. Int. Ed.
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Angew. Chem. 2005, 117, 4284; Angew. Chem. Int. Ed. 2005, 44,
4212; c) Y. Chi, S. H. Gellman, J. Am. Chem. Soc. 2006, 128,
6804.
[13] The structure of the compound derived from molecule 3 f was
determined by X-ray crystal analysis. CCDC-652571 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif..
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