Control of four stereocenters in an organocatalytic domino double michael reaction: efficient synthesis of multisubstituted cyclopentanes

Article abstract of DOI:10.1021/ol801246m

(Chemical Equation Presented) A highly enantioselective and diastereoselective domino organocatalytic double Michael reaction which provides expedited access to multifunctionalized five-membered rings catalyzed by 9-amino-9-deoxyepiquinine (V) has been developed. Simple operational procedures, high yields (81-92%), excellent enantioselectivity (90-97% ee), diastereoselectivities (95:5->99:1 dr), and immense potential of synthetic versatility of the products render this new methodology highly appealing for asymmetric synthesis.

Full text of DOI:10.1021/ol801246m

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3425-3428
Control of Four Stereocenters in an
Organocatalytic Domino Double Michael
Reaction: Efficient Synthesis of
Multisubstituted Cyclopentanes
Bin Tan, Zugui Shi, Pei Juan Chua, and Guofu Zhong*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link,
Singapore 637371, Singapore
guofu@ntu.edu.sg
Received June 2, 2008
ABSTRACT
A highly enantioselective and diastereoselective domino organocatalytic double Michael reaction which provides expedited access to
multifunctionalized five-membered rings catalyzed by 9-amino-9-deoxyepiquinine (V) has been developed. Simple operational procedures,
high yields (81-92%), excellent enantioselectivity (90-97% ee), diastereoselectivities (95:5->99:1 dr), and immense potential of synthetic
versatility of the products render this new methodology highly appealing for asymmetric synthesis.
The asymmetric organocatalytic domino reaction has emerged
as a powerful paradigm in accelerating the development of
new methods for the synthesis of diverse chiral molecules.1
With the benefits of ease operation, ready availability, and
low toxicity of reactants and catalysts, these organocatalytic
reactions are attractive methods in modern synthetic chem-
istry and have received remarkable attention during the past
decade.2 Of the developed strategies for asymmetric tandem
reactions, Enders et al. have performed the synthesis of
substituted cyclohexenes by applying a three-component
domino reaction3a,b while Hayashi et al. described a two-
component multistep Michael-Henry sequence for the syn-
thesis of cyclohexane derivatives by using pentane-1,5-dial
and 2-substituted nitroalkenes.3e
Although several other elegant organocatalytic tandem
reactions have also been reported recently,4 the development
of new methodologies for the generation of molecules with
multiple stereogenic carbons3 including quaternary centers
in a cascade manner remains a big challenge at the forefront
of synthetic chemistry. The Michael addition reaction, being
one of the most general and versatile methods for formation
(1) For a recent review, see: (a) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Chapman, C. J.; Frost, C. G.
Synthesis 2007, 1.
(3) (a) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006,
441, 861. (b) Enders, D.; Hu¨ttl, M. R. M.; Runsink, J.; Raabe, G.; Wendt,
B. Angew. Chem., Int. Ed. 2007, 46, 467. (c) Halland, N.; Aburel, P. S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272. (d) Marigo, M.;
Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128,
5475. (e) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem.,
Int. Ed. 2007, 46, 4922. (f) Cao, C.-L.; Sun, X.-L.; Kang, Y.-B.; Tang, Y.
Org. Lett. 2007, 9, 4151.
(2) For general reviews of organocatalysis, see: (a) Dalko, P. I., Ed.
EnantioselectiVe Organocatalysis: Reactions and Experimental Procedures;
Wiley-VCH: Weinheim, 2007. (b) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005. (c) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719. (d) Gaunt, M. J.; Johansson, C. C. C.; McNally,
A.; Vo, N. T. Drug DiscoVery Today 2007, 2, 8. (e) List, B. Chem. Commun.
2006, 819.
10.1021/ol801246m CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

of C-C bonds in organic synthesis, has received much
attention in the development of enantioselective catalytic
protocols.5 Domino Michael-Michael (also called “double
Michael”) reactions have been explored and demonstrated
as a powerful tool in organic synthesis.6 Efficient asymmetric
double Michael processes have been achieved by relying on
the use of chiral auxiliaries7 and chiral precursors8 for
stereocontrol. However, the development of organocatalytic
enantioselective versions of the reactions proved to be a
challenging task, and there have been very few reports9
regarding the formation of quaternary and tertiary stereo-
centers with both excellent enantioselectivity and diastereo-
selectivity using R,ꢀ-unsaturated esters as Michael ac-
ceptors.
Figure 1. Cinchona alkaloid and derivative catalysts tested in the
domino double Michael reactions.
In conjunction with our continuing efforts in exploring new
organocatalytic domino reactions,10 we investigated the domino
double Michael reaction. Herein we wish to report the results
of an investigation that has led to a novel organocatalytic
diastereo- and enantioselective cascade double Michael reaction,
in which two C-C bonds and four contiguous stereogenic
centers (containing one adjacent quaternary and tertiary stereo-
centers) were efficiently created in a one-pot operation with an
efficient control of stereochemistry. This new catalytic meth-
odology serves as a facile approach to synthetically useful,
highly functionalized chiral cyclopentanes.11
The design of a catalytic cascade double Michael addition
reaction required the consideration of several factors. The
reactivity of the R,ꢀ-unsaturated substrates that participates
in the second conjugate addition reaction must be reactive
enough to allow the intramolecular Michael reaction. In the
meanwhile, these substrates should be less reactive than
nitroolefins. Recognition of this reactivity profile allows the
design of systems capable of undergoing efficient double
Michael addition sequences. Furthermore, a carbon nucleo-
phile should be sufficiently active to only engage in the first
Michael addition reaction. To address this concern, we
employed easily enolized acetoacetate ester to replace the
R,ꢀ-unsaturated ester.
Readily accessible cinchona alkaloid and catalyst de-
rivatives, which were developed recently in several
research groups, have been identified as efficient bifunc-
tional organocatalysts in asymmetric Michael reactions.
To probe the feasibility of the proposed Michael-Michael
cascade reacton, we started our inverstigation by reacting
nitrostyene with diethyl 5-acetylhex-2-enedioate 2 (E:Z
) 6:1) in the presence of cinchona alkaloid catalyst I (15
mol%) at the room temperature (22 °C). To our delight,
we were able to isolate the desired product in 81% yield
as a single diastereoisomer, even though it is not enan-
tiomerically pure (Table 1, entry 1). In attempts to improve
the yield and enantioselectivity, we screened several
catalysts and reaction conditions. Catalyst II proved to
be a very efficient catalyst for Michael reaction. Therefore,
we chose II as the most promising catalyst to sceen other
conditions. However, the results were not improved
significantly when the reaction was carried out in different
solvents or at different reaction temperatures (Table 1,
entries 2-5). As such, we turned our attention to screen
more catalysts (in Figure 1, III-VI) at room temperature.
Catalyst V12 was found to be an excellent candidate to
catalyze this domino reaction with the highest stereose-
lectivity (97% ee, >99:1 dr) among all the cases inves-
(4) For a review of tandem reactions, see: (a) Enders, D.; Grondal, C.;
Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. For selected
examples of tandem reactions, see: (b) Ramachary, D. B.; Chowdari, N. S.;
Barbas III, C. F. Angew. Chem., Int. Ed. 2003, 42, 4233. (c) Yamamoto,
Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962. (d)
Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637. (e) Zhong, G. Chem. Commun.
2004, 626. (f) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 9202. (g) Cabrera, S.;
Alema´n, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2008, 47, 121. (h) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007,
129, 256. (i) Dudding, T.; Hafez, A. M.; Taggi, A. E.; Wagerle, T. R.;
Lectka, T. Org. Lett. 2002, 4, 387. (j) Wang, J.; Xie, H.; Li, H.; Zu, L.;
Wang, W. Angew. Chem., Int. Ed. 2008, 47, 4177. (k) Li, H.; Zhang, Y.;
Vogel, P.; Sinay, P.; Bleriot, Y. Chem. Commun. 2007, 183. (l) Marigo,
M.; Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 15710. (m) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Co´rdova,
A. Angew. Chem., Int. Ed. 2005, 44, 1343. (n) Yang, J. W.; Hechavarria,
M.; Fonseca, T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036. (o) Huang,
Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 15051. (p) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 14986. (q) Vicario, J. L.; Reboredo, S.; Bad´ıa, D.;
Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168.
(5) For selected reviews regarding Michel addition reactions, see: (a)
Berner, O.; Tedeschi, M. L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c) Almasi, D.; Alonso,
D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299. (d) Vicario, J. L.;
Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065.
(6) Review of double Michael reactions, see: (a) Ihara, M.; Fukumoto,
K. Angew. Chem., Int. Ed. 1993, 32, 1010.
(7) Examples using chiral auxiliaries for asymmetric double Michael
reactions, see: (a) Saito, S.; Hirohara, Y.; Narahara, O.; Moriwake, T. J. Am.
Chem. Soc. 1989, 111, 4533. (b) Dixon, D. J.; Ley, S. V.; Rodriguez, F.
Angew. Chem., Int. Ed. 2006, 45, 4763.
(8) Examples using chiral precursors for asymmetric double Michael
reactions, see: (a) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A. H.
J. Am. Chem. Soc. 2000, 122, 2742. (b) Hagiwara, H.; Kobayashi, K.; Miya,
S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett. 2001, 3, 251. (c) Herzon,
S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342. (d) Baran, P. S.;
Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D.
J. Am. Chem. Soc. 2006, 128, 8678.
(9) (a) Zu, L.; Xie, H.; Wang, J.; Tang, Y.; Wang, W. Angew. Chem.,
Int. Ed. 2007, 46, 3732. (b) Li, H.; Zu, L.; Xie, H.; Wang, J.; Jiang, W.;
Wang, W. Org. Lett. 2007, 9, 1833. (c) Hoashi, Y.; Yabuta, T.; Takemoto,
Y. Tetrahedron Lett. 2004, 45, 9185. (d) Hoashi, Y.; Yabuta, T.; Yuan, P.;
Miyabe, H.; Takemoto, Y. Tetrahedron 2006, 62, 365.
(11) For reviews of the synthesis and bioactivities of cyclopentanes, see:
(a) Biaggio, F. C.; Rufino, A. R.; Zaim, M. H.; Zaim, C. Y. H.; Bueno,
M. A.; Rodrigues, A. Curr. Org. Chem. 2005, 9, 419. (b) Silva, L. F.
Tetrahedron 2002, 58, 9137. (c) Lautens, M.; Klute, W.; Tam, W. Chem.
ReV. 1996, 96, 49. (d) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95,
1293.
(10) Tan, B.; Chua, P. J.; Li, Y.; Zhong, G. Org. Lett. 2008, 10, 2437.
3426
Org. Lett., Vol. 10, No. 16, 2008

Table 1. Organocatalytic Domino Double Michael Reactions of
Ethyl 2-Acetyl-5-oxohexanoate 1a (E:Z ) 6:1) and
trans-ꢀ-Nitrostyrenea
Table 2. Domino Double Michael Reaction of Ethyl
2-Acetyl-5-oxohexanoate 1a (E:Z ) 6:1) and Nitroolefins (2)
Catalyzed by Catalyst Va
entry catalyst solvent t (h) yield (%)b
drc
ee (%)d
entry
R
3
t (h) yield(%)b
drc ee (%)d
1
2
3
I
neat
neat
6
5
8
8
24
8
72
73
91
90
88
90
87
91
91
85
86
87
82
94:6
96:4
96:4
97:3
97:3
96:4
96:4
>99:1
97:3
>99:1
97:3
23
79
82
83
83
80
95
97
95
97
90
96
96
1
2
3
Ph (2a)
4-MeC6H4 (2b)
3-MeC6H4 (2c)
4-MeOC6H4 (2d) 3d
2-MeOC6H4 (2e) 3e
4-BrC6H4 (2f)
4-ClC6H4 (2g)
2-naphthyl (2h)
1-naphthyl (2i)
3-furanyl (2j)
2-furanyl (2k)
2-thienyl (2l)
3a
3b
3c
16
24
24
30
30
16
16
24
24
24
24
18
91
89
85
83
81
92
88
84
87
86
87
91
81
>99:1
97:3
96:4
96:4
98:2
>99:1
98:2
95:5
97:3
98:2
97
95
95
94
90
95
95
95
97
97
96
96
95
II
II
II
II
III
IV
V
VI
V
V
toluene
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
toluene
Et2O
Et2O
4e
5e
6
4
5e
6
3f
7
8
9
8
7
8
9
10
11
12
3g
3h
3i
3j
3k
3l
16
16
30
36
24
16
10f
11
12e
13g
95:5
>99:1
96:4
V
V
>99:1
>99:1
13e 4- O2NC6H4 (2m) 3m 36
a Unless otherwise specified, all the reactions were carried out using 1a
(0.3 mmol, 1.0 equiv) and 2a (0.45 mmol, 1.5 equiv) with 15 mol % of
catalyst at room temperature (22 °C). b Isolated yields. c Determined by
NMR and HPLC analysis. d Determined by chiral HPLC analysis (major
isomer). e Reaction at 0 °C. f Catalyst (10 mol %) was used. g 1a (0.45
mmol, 1.5 equiv) and 2a (0.3 mmol, 1.0 equiv) were used.
a Unless otherwise specified, the reactions were carried out using 1a
(0.3 mmol, 1.0 equiv) and 2 (0.45 mmol, 1.5 equiv) in the presence of 15
mol % of V at room temperature in diethyl ether (0.4 mL) (see Supporting
Information). b Isolated yields. c Determined by NMR and HPLC analysis.
d Determined by chiral HPLC analysis (major isomer). e 20 mol % catalyst
and 2.0 equiv of 2 were used.
enantioselectivities. To our surprise, the presence of the nitro
group on the aromatic ring did not cause the enantiomeric
excess to decrease. This may be attributed to the primary
amine group in the catalyst that can selectively capture the
two nitro groups. Interestingly, the ratio (E:Z ) 10:1) of 1a
had no effect on reactivity and selectivity (Scheme 1a). The
tigated, as shown in the Table 1, entry 10. Further
optimization of the reaction conditions elucidated that
solvents played a very important role in determining the
selectivities of the reaction and yield (diethyl ether, >99:1
dr, 97% ee, 91% yield).
Having estabilizhed the optimal reaction condition, a series
of nitroolefins were reacted with unsatuated ester substrates
to investigate the generality of the domino double Michael
process by using catalyst V in diethyl ether. It was observed
that most of the reactions are completed within 36 h with
good to excellent yields (81-92%), excellent enantioselec-
tivities (90-97% ee) and diastereoselectivities (95:5->99:1
dr). We would like to highlight that a majority of the
examples (shown in Table 2) indicate that the position and
electronic property of the substituents on aromatic rings have
a very limited effect on the stereoselectivities. Regardless
of the types of substituents on the aromatic rings, be it
electron-withdrawing (Table 2, entries 6, 7, 13), -donating
(entries 2-5), neutral (entry 1, 8, 9) groups and substrates
containing a variety of substitution (para, meta, and ortho)
groups participated in this reaction efficiently. The hetero-
cyclic thienyl and furanyl groups (Table 2, entries 10-12)
also paticipated in this process, giving good yields and
Scheme 1
.
Domino Double Michael Reactions of 1a with 2a
(E:Z ) 10:1) and 1b with 2a/2o
(12) Some papers related to using this type of catalyst: see (a) 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. (b) Xie, J.-W.;
Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett.
2007, 9, 413. (c) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri,
L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (d) McCooey, S. H.; Connon,
S. J. Org. Lett. 2007, 9, 599. (e) Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.; Wang,
X.-L.; He, L. Org. Biomol. Chem. 2007, 5, 2913.
domino reaction also proceeded smoothly when 1a was
replaced by 1b, giving excellent stereoselectivities (95% ee)
as displayed in Scheme 1b. Notably, only one double Michael
adduct was obtained from the reaction of nitrodiene 2o in
95% ee value (Scheme 1c). Theoretically, both ꢀ- and δ-
Org. Lett., Vol. 10, No. 16, 2008
3427

positions of 2o can possibly be attacked due to the congruous
two double bonds. This demostrates the high regioselectivity
and enantioselectivity of this method.
According to experimental results and the dual activation
model,13 the two substrates involved in the reaction are
activaed by catalyst V as shown in Figure 2. Nitroolefins
Figure 3. X- ray crystal structure of 3g.
double Michael reaction that provides expedited access
toward highly functionalized cyclopentane derivatives. The
structure was confirmed by X-ray analysis of adduct 3g.
Simple operational procedures, high yields (81-91%), excel-
lent enantioselectivity (90-97% ee), diastereoselectivities
(95:5->99:1 dr), and immense potential of synthetic ver-
satility of the products render this new methodology highly
appealing for asymmetric synthesis. Further applications of
this methodology toward total synthesis of natural products
and pharmaceutical agents are currently under active inves-
tigation.
Figure 2. Proposed action of catalyst.
are assumed to interact with the primary amine moiety of V
via multiple H-bonds. In this case, both the nitro group and
ꢀ-ketoester group interact with multiple H-bonds so that these
two group are on the same side, thus enhancing the
electrophilic character of the reacting carbon center and
controlling stereochemistry. The carboanion (adjacent to the
nitro group) generated from the Michael addition then attacks
the double bond of R,ꢀ-unsaturated esters to afford double
Michael products (Figure 2). The stereochemistry was
established by X-ray crystallographic determination of 3g
(Figure 3) and analysis of NMR data of the products.
In summary, we have developed a novel highly enantio-
selective and diastereoselective organocatalytic domino
Acknowledgment. Research support from the Ministry
of Education in Singapore (ARC12/07, #T206B3225) and
Nanyang Technological University (URC, RG53/07 and SEP,
RG140/06) is gratefully acknowledged. We thank Dr.
Yongxin Li in NTU for the X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
decures, characterization, spectra, chiral HPLC conditions,
and X-ray crystallograpoic data (CIF file of 3g: zgf29.cif).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
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