A highly diastereo- and enantioselective synthesis of multisubstituted cyclopentanes with four chiral carbons by the organocatalytic domino Michael-Henry reaction

Article abstract of DOI:10.1021/ol801273x

(Chemical Equation Presented) Highly functionalized cyclopentanes with four stereogenic carbons including two quaternary stereocenters have been synthesized in excellent yields (90-95%) with complete diastereoselectivities and excellent enantioselectivities (88-96% ee) by the organocatalyzed asymmetric domino Michael-Henry reaction.

Full text of DOI:10.1021/ol801273x

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3489-3492
A Highly Diastereo- and
Enantioselective Synthesis of
Multisubstituted Cyclopentanes with
Four Chiral Carbons by the
Organocatalytic Domino Michael-Henry
Reaction
Bin Tan, Pei Juan Chua, Xiaofei Zeng, Min Lu, and Guofu Zhong*
DiVision of Chemistry & Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link,
Singapore 637371, Singapore
guofu@ntu.edu.sg
Received June 5, 2008
ABSTRACT
Highly functionalized cyclopentanes with four stereogenic carbons including two quaternary stereocenters have been synthesized in excellent
yields (90-95%) with complete diastereoselectivities and excellent enantioselectivities (88-96% ee) by the organocatalyzed asymmetric domino
Michael-Henry reaction.
The asymmetric construction of a stereogenic carbon center
with a quaternary carbon atom remains one of the most
challenging and demanding topics in the synthesis of natural
products and chiral drugs.1 The development of asymmetric
methods for the preparation of functionalized cyclopentanes
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.2
Catalytic enantioselective cascade reactions3 are seen as
possible solutions due to the rapid increase in molecular
complexity from simple and readily available starting materi-
als to afford enantioenriched compounds in a single opera-
tion. Although several elegant organocatalytic4 domino
(3) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Wasilke,
J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001.
(c) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (d) Tietze,
L. F. Chem. ReV. 1996, 96, 115. (e) Nicolaou, K. C; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
(1) For reviews on an enantioselective construction of all carbon
quaternary stereocenters, see: (a) Fuji, K. Chem. ReV. 1993, 93, 2037. (b)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (c)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591.
(2) Reviews of synthesis and bioactivities of cyclopentanes: (a) Silva,
L. F. Tetrahedron 2002, 58, 9137. (b) Trost, B. M. Angew. Chem., Int. Ed.
1986, 25, 1.
(4) For books and selected recent reviews on organocatalysis, see: (a)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418. (b) Ballini, R.; Bosica, G.;
Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105, 933. (c) Seayad, J.; List,
B. Org. Biomol. Chem. 2005, 3, 719. (d) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis;Wiley-VCH: Weinheim, Germany, 2005. (e)
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10.1021/ol801273x CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

reactions have been reported recently,5 the development of
new approaches in C-C bond formation with multiple
stereogenic centers6 in a cascade manner remains a challenge
at the forefront of synthetic chemistry.
nocatalysts in asymmetric Michael reactions,10 Henry reac-
tions,11 and tandem Michael-Henry reactions (Scheme 1, n
The Michael reaction is widely recognized as one of the
most important C-C bond formation processes in organic
chemistry as it is a versatile tool to assemble highly
functionalized carbon skeletons.7 One of the challenges of
such transformation lies in the ability of the catalyst to impart
both high enantioselectivity and diastereoselectivity during
the formation of the quaternary and tertiary stereocenters in
a sterically hindered environment. The Henry reaction is
another powerful C-C bond-forming tool that transforms
nitro alcohol (nitroaldol) products into a number of nitrogen
and oxygen-containing derivatives such as nitroalkenes,
amino alcohols, and amino acids.8 In addition to substrate-
controlled stereospecific nitroaldol reactions, the use of
organocatalysts to provide good stereoselectivities has been
developed in recent years.9 However, to the best of our
knowledge, there is no report describing the formation of
two quaternary centers in the asymmetric synthesis of
cyclopentanes as well as the possibility of using the domino
Michael-Henry reaction strategy for the synthesis of mul-
tisubstituted chiral cyclopentanes with good results. In this
paper, we disclose a facile organocatalytic enantioselective
domino Michael-Henry reaction to afford highly function-
alized cyclopentane derivatives with four stereogenic centers
(two quaternary and two tertiary stereocenters) in complete
diastereoselectivities and excellent enantioselectivities (88-
96% ee).
Scheme 1. Organocatalytic Synthesis of Cycloalkanes Using
Tandem Michael-Henry Reactions Strategy
) 1).12 These results prompted us to explore the feasibility
of employing diamine catalyst I13 to catalyze tandem
Michael-Henry reactions involving a nitroolefin and a
rationally designed carbon nucleophiles 1a to form chiral
cyclopentanes (Scheme 1, n ) 0). To our disappointment,
the enantioselectivity of the desired product was only 67%
ee (Table 1, entry 1). Despite changing the reaction condi-
tions such as catalysts, solvents, and temperature, the highest
enantiomeric excess obtained was 82% (Table 1, entries
1-4). In our bid to get better results, we turned our attention
to designed substrates. The investigation of various substrates
demonstrated that the domino Michael-Henry reaction
proceeded smoothly to afford the desired cyclopentane ring
products in high yields (92-95%, Table 1, entries 5, 7-9)
with the exception of the less reactive substrate 1c (Table 1,
entry 6). Surprisingly, only one diastereomer was obtained
in all of the cases investigated. However, varied enantiose-
lectivities were observed with different substituents on 1.
For example, higher enantiomeric excesses (75% ee) were
observed when 1a was substituted with 1d or 1e.
Readily accessible cinchona alkaloid and derivatives
catalysts which were developed recently in several research
groups have been identified as efficient bifunctional orga-
Despite many attempts, the best result achieved was only
83% ee with catalyst II. Therefore, it seemed essential to
change the organocatalysts for much higher enantioselec-
tivity. To our delight, the product was obtained in 93% yield
with 90% ee (Table 1, entry 13) when catalyst I was used.
(5) For a review of tandem reactions, see: Enders, D.; Grondal, C.; Hu¨ttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. For selected examples of
tandem reactions, see: (a) Li, H; Zhang, Y.; Vogel, P.; Sinay, P.; Bleriot,
Y Chem. Commun. 2007, 183. (b) Zhong, G.; Yu, Y. Org. Lett. 2004, 6,
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A. M.; Taggi, A. E.; Wagerle, T. R.; Lectka, T. Org. Lett. 2002, 4, 387. (e)
Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III Angew. Chem., Int.
Ed. 2003, 42, 4233. (f) Yamamoto, Y.; Momiyama, N.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 5962. (g) Marigo, M.; Schulte, T.; Franzen,
J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (h) Yang, J. W.;
Hechavarria, M.; Fonseca, T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036.
(i) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 15051. (j) Brandau, S.; Maerten, E.; Jørgensen, K. A.
J. Am. Chem. Soc. 2006, 128, 14986. (k) Vicario, J. L.; Reboredo, S.; Bad´ıa,
D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168. (l) Aroyan, C. E.;
Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256. (m) Reyes, E.; Jiang, H.;
Milelli, A.; Elsner, P.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2007, 46, 9202. (n) Cabrera, S.; Alema´n, J.; Bolze, P.; Bertelsen, S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2008, 47, 121.
(10) For developments and applications of cinchona-derived bifunctional
catalysts, see: (a) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.;
Deng, L. Acc. Chem. Res. 2004, 37, 621. (b) Ye, J.; Dixon, D. J.; Hynes,
P. S. Chem. Commun. 2005, 4481. (c) Vakulya, B.; Varga, S.; Csa´mpai,
A.; Soo´s, T. Org. Lett. 2005, 7, 1967. (d) Tillman, A. L.; Ye, J.; Dixon,
D. J. Chem. Commun. 2006, 1191. (e) Mattson, A. E.; Zuhl, A. M.;
Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932. (f)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (g)
France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka,
T. J. Am. Chem. Soc. 2005, 127, 1206. (h) Taggi, A. E.; Hafez, A. M.;
Wack, H.; Young, B.; Drury, W. J., III; Lectka, T. J. Am. Chem. Soc. 2000,
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(6) (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.;
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Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (b) Li, H.; Wang, B.;
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The results of forming chiral cyclohexanes with excellent enantioselectivities
(97 to >99% ee) and high diastereoselectivities (93:7-99:1 dr) were
reported.
(13) For some papers related to using this type of catalyst, see: (a) Xie,
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Org. Lett., Vol. 10, No. 16, 2008

Table 1. Organocatalytic Domino Michael-Henry Reactions of
Ethyl 2-Acetyl-4-oxo-4-phenylbutanoate (1a) and
trans-ꢀ-Nitrostyrenea
Table 2. Organocatalytic Domino Michael-Henry Reactions of
Ethyl 2-Acetyl-4-oxo-4-phenylbutanoate (1d) and Nitroolefins
Catalyzed by Catalyst Ia
entry
R
3
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
36
48
60
48
48
40
36
40
48
60
72
48
93
91
93
90
91
94
95
93
91
91
90
95
95
92
92
90
95
91
95
93
92
96
91
92
3-MeO-C6H4
4-MeO-C6H4
2-Me-C6H4
4-Me-C6H4
4-Br-C6H4
4-Cl-C6H4
2-thienyl
entry
1
catalyst solvent time (h) yieldb (%) eec (%)
2-furyl
10
11
12
1-naphthyl
4- O2N-C6H4
4-CF3-C6H4
3j
3k
3l
1
2
1a
1a
1a
1a
1b
1c
1d
1e
1d
1d
1d
1d
1d
1d
1d
I
Et2O
neat
toluene
toluene
neat
neat
neat
neat
toluene
toluene
toluene
toluene
toluene
Et2O
18
3
10
18
3
3
3
3
10
18
10
18
18
18
36
92
94
92
90
92
NRe
95
94
92
93
94
93
93
92
93
67
71
80
82
70
NAf
75
75
80
83
75
65
90
88
95
II
II
II
II
II
II
II
II
II
III
IV
I
3
a All the reactions were carried out using 1d (1.0 mmol, 2.0 equiv) and
2 (0.5 mmol, 1.0 equiv) in the presence of 10 mol % of I at 4 °C with
toluene (0.5 mL). b Isolated yields. c Determined by chiral HPLC analysis.
4d
5
6
7
8
9
ortho), participated in this reaction efficiently. Not only
aromatic groups but also heteroaromatic groups such as furyl
and thienyl could be successfully employed to afford the
respective cyclopentane derivatives with excellent enanti-
oselectivity (entries 8 and 9). To our surprise, the presence
of the nitro group on the aromatic ring (entry 11) did not
decrease the enantiomeric excess. This demostrates the point
that the primary amine group in the catalyst is able to capture
one of the two nitro groups selectively. Furthermore, the
domino reaction also proceeded smoothly when 1a was
replaced with either 1b or 1c, as displayed in Scheme 2.
10d
11
12
13
14
15d
I
I
toluene
a Unless otherwise specified, all the reactions were carried out using 1
(1.0 mmol, 2.0 equiv) and 2a (0.5 mmol, 1.0 equiv) with 10 mol % of
catalysts at room temperature. b Isolated yields. c Determined by chiral HPLC
analysis. d Reaction at 4 °C. e No reaction. f Not applicable.
When catalyst IV was used, the lower enantiomeric excess
indicated that the OMe group on the catalyst was critical
for stereoselectivity (Table 1, entry 12). Although the reaction
time was prolonged to 36 h, higher ee (95% ee) was afforded
when the reaction temperature was lowered to 4 °C (Table
1, entry 15). The domino Michael-Henry reaction indeed
proceeded smoothly to yield the desired cyclopentane ring
product in excellent yield (95%) and good enantioselectivity
(75% ee). With the optimized reaction conditions, we
embarked on the investigation of the generality of the domino
Michael-Henry process by using a variety of nitroalkenes.
It was observed that all of the reactions were completed
within 72 h, giving adducts in excellent yields (90-95%)
and with complete diastereoselectivities and excellent enan-
tioselectivities (88-96% ee). It appeared that the position
and the electronic property of the substituents for aromatic
rings had a very limited influence on the stereoselectivities
of the reactions (Table 2, entries 2-7). Electron-withdrawing
(entries 6, 7 and 11, 12), electron-donating (entries 2-5),
and neutral (entries 1 and 10) groups, as well as substrates
containing a variety of substitution patterns (para, meta and
Scheme 2. Organocatalytic Domino Michael-Henry Reactions
of Trisubstituted Carbon Nucleophiles (1b or 1c) to
trans-ꢀ-Nitrostyrene Catalyzed by Catalyst I
The dual activation model was proposed14 where the two
substrates involved in the reaction are activated simulta-
(14) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119.
Org. Lett., Vol. 10, No. 16, 2008
3491

Information). The stereochemistry of this domino reaction
was then established by analysis of the X-ray crystal
structures together with analysis of the NMR data.
In summary, we have described a facile organocatalytic,
enantioselective synthesis of highly functionalized chiral
cyclopentanes with four stereogenic centers (two quaternary
and two tertiary stereocenters) in excellent yields (90-95%),
enantioselectivities (88-96% ee), and complete diastereo-
selectivities by the domino Michael-Henry reaction strategy.
The domino reaction was efficiently catalyzed by readily
available catalyst I (9-amino-9-deoxyepiquinine) to give
synthetically valuable multifunctionalized chiral cyclopen-
tanes, where the organocatalytic intramolecular Henry reac-
tion of common ketones was employed for the cyclopentane
ring-closing step in excellent stereoselectivities. This domino
synthesis is quite useful in natural product synthesis since
we know that there are many types of biologically active
natural substances that bear optically active cyclopentane
derivatives. We hope that this strategy of developing a
practical and efficient domino Michael-Henry reaction can
spark further efforts into the designing of such organocata-
lytic domino reactions. This approach constitutes our future
direction aimed at expanding the scope and applications of
these powerful tandem processes.
Figure 1. Proposed action of catalyst.
neously by catalyst I as shown in the Figure 1. Nitroolefins
have been assumed to interact with the primary amine moiety
of I via multiple H-bonds, thus enhancing the electrophilic
character of the reacting carbon center. However, the enolic
form of 1 is assumed to interact with the tertiary amine group
and a subsequent deprotonation results in a highly nucleo-
philic enolate species. The carbonanion adjacent to the nitro
group then attacks the carbonyl group to afford Henry
products. The absolute configuration of 3f was determined
by X-ray crystallography (Figure 2, see the Supporting
Acknowledgment. Research support from the Ministry
of Education in Singapore (ARC12/07, No. T206B3225) and
Nanyang Technological University (URC, RG53/07 and SEP,
RG140/06) is gratefully acknowledged. We thank Dr.
Yongxin Li from Nanyang Technological University for the
X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
decures, characterization, spectra, chiral HPLC conditions,
and X-ray crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 2. X-ray crystal structure of 3f.
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Org. Lett., Vol. 10, No. 16, 2008