Organocatalytic asymmetric tandem Michael-Henry reactions: A highly stereoselective synthesis of multifunctionalized cyclohexanes with two quaternary stereocenters

Article abstract of DOI:10.1021/ol8007183

(Chemical Equation Presented) A novel organocatalytic asymmetric tandem Michael-Henry reaction catalyzed by 9-amino-9-deoxyepiquinine (VI) has been developed. The reaction was efficiently catalyzed by catalyst VI to give highly functionalized cyclohexanes with four stereogenic carbons including two quaternary stereocenters in excellent enantioselectivities (97 to >99% ee) and high diastereoselectivities (93:7-99:1 dr). Thus, the first organocatalytic asymmetric Henry reaction of common ketones as acceptors is shown.

Full text of DOI:10.1021/ol8007183

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2437-2440
Organocatalytic Asymmetric Tandem
Michael-Henry Reactions: A Highly
Stereoselective Synthesis of
Multifunctionalized Cyclohexanes with
Two Quaternary Stereocenters
Bin Tan, Pei Juan Chua, Yongxin Li, and Guofu Zhong*
DiVision of Chemistry & Biological Chemistry, School of Physical and Mathamatical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
guofu@ntu.edu.sg
Received March 31, 2008
ABSTRACT
A novel organocatalytic asymmetric tandem Michael-Henry reaction catalyzed by 9-amino-9-deoxyepiquinine (VI) has been developed. The
reaction was efficiently catalyzed by catalyst VI to give highly functionalized cyclohexanes with four stereogenic carbons including two quaternary
stereocenters in excellent enantioselectivities (97 to >99% ee) and high diastereoselectivities (93:7-99:1 dr). Thus, the first organocatalytic
asymmetric Henry reaction of common ketones as acceptors is shown.
The asymmetric construction of a quaternary carbon atom
represents one of the most challenging and demanding topics
in the synthesis of natural products and chiral drugs.1 The
development of efficient methods to access complex mol-
ecules with multiple stereogenic centers also continues to
be a substantial challenge in both academic research and
industrial applications.2 One approach toward these chal-
lenges is the use of catalytic enantioselective cascade
reactions,3 which have emerged as powerful tools to give a
rapid increase in molecular complexity from simple and
readily available starting materials, thus producing enan-
tioenriched complex compounds in a single operation. Of
the developed strategies for asymmetric tandem reactions,
organocatalysis provided an efficient protocol.4 The syntheses
of substituted cyclohexenes by applying a three-component
(3) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Ramo´n, D. J.; Yus,
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Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (c) Christoffers,
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Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688.
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Lelais, D. W.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (b)
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10.1021/ol8007183 CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

domino reaction5a,b and by a two-component multistep
Michael-Henry sequence using pentane-1,5-dial and 2-sub-
stituted nitroalkenes5e have been described. Although several
other elegant organocatalytic tandem reactions have also been
reported recently,6 the development of new methods for the
generation of molecules with multiple stereogenic carbons5
including quaternary centers in a cascade manner remains a
big challenge at the forefront of synthetic chemistry.
The Michael addition reaction provides an important tool
for the construction of highly functionalized carbon skel-
etons.7 In principle, the stereocontrolled conjugate addition
of a trisubstituted carbon nucleophile to a prochiral Michael
acceptor could provide a one-step construction of such highly
congested motifs from simple precursors. However, this
requires the catalyst to impart both high enantioselectivity
and diastereoselectivity in a sterically demanding intermo-
lecular C-C bond formation that simultaneously creates both
the quaternary and tertiary stereocenters. This task has proven
to be a formidable challenge. Up to date, there were only a
few literatures that reported the 1,4-adducts containing one
adjacent quaternary and tertiary stereocenters in both excel-
lent enantioselectivity and diastereoselectivity in the field of
organocatalysis8 and still no report that is related to the
formation of two quaternary centers.
to the best of our knowledge, there is no report describing
the possibility of common ketones used as acceptors with
good results. In this paper, we disclose a novel facile
organocatalyzed enantioselective tandem Michael-Henry
reaction that generates multifunctionalized cyclohexane
derivatives with four stereogenic centers including two
quaternary stereocenters in excellent enantioselectivities (97
to >99% ee) and diastereoselectivities (up to 99:1 dr).
Readily accessible cinchona alkaloid and derivative cata-
lysts, which were developed recently in several research
groups, have been identified as efficient bifunctional orga-
nocatalysts in asymmetric Michael reactions10 and Henry
reactions.11 These results prompted us to explore the feasibil-
ity of employing thiourea catalyst I (Figure 1) to catalyze
The Henry reaction also represents a powerful C-C bond-
forming tool, and the resulting nitro alcohol products can
be transformed into a number of nitrogen and oxygen-
containing derivatives such as nitroalkenes, amino alcohols
and amino acids.9 In addition to substrate-controlled Henry
reactions, organocatalytic systems that provide good stereo-
selectivity have been developed in recent years. However,
Figure 1. Cinchona alkaloid and derivative catalysts tested in the
tandem Michael-Henry reaction.
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the tandem Michael-Henry reactions involving a nitroolefin
and carbon nucleophiles 1a containing three carbonyl groups.
To our great delight, the tandem Michael-Henry reaction
proceeded smoothly to yield the desired cyclohexane product
in high yield (85%) and good enantioselctivity (80% ee) and
diastereoselctivity (92:8 dr, Table 1, entry 1). To improve
the results, different conditions were investigated. However,
the results did not change significantly when the reaction
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M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. For selected examples of
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2438
Org. Lett., Vol. 10, No. 12, 2008

Table 1. Organocatalytic Tandem Michael-Henry Reactions of
Ethyl 2-Acetyl-5-oxohexanoate 1a and trans-ꢀ-Nitrostyrenea
Table 2. Tandem Michael-Henry Reaction of Diketo Ester 1a
and Nitroolefin (2) Catalyzed by Catalyst VIa
entry cat. solvent time (h) yieldb (%)
drc
eed (%)
entry
R
3
time (h) yieldb (%)
dr
eec (%)
1
I
I
I
neat
toluene
neat
neat
neat
neat
neat
neat
toluene
toluene
Et2O
Et2O
3
8
8
3
3
10
18
10
24
18
16
16
85
88
86
95
94
92
90
92
88
92
93
93
92:8
93:7
93:7
85:15
82:18
78:22
95:5
95:5
97:3
98:2
98:2
98:2
80
78
77
26
23
65
92
92
>99
>99
>99
>99
1
2
3
4
5
6
7
8
9
Ph
3a
16
24
24
24
30
20
24
24
24
24
93
91
89
90
88
90
87
91
94
91
98:2
95:5
96:4
95:5
93:7
99:1
93:7
96:4
98:2
95:5
>99
98
98
99
>99
97
97
97
97
98
2
4-MeO-C6H4 3b
3e
4
4-Me-C6H4
3-Me- C6H4
4-Br- C6H4
2-Br- C6H4
4-Cl- C6H4
2-Cl- C6H4
3c
3d
3e
3f
3g
3h
II
III
IV
V
VI
VI
VI
VI
VI
5
6
7
8
9
2-O2N- C6H4 3i
4-CF3- C6H4 3j
10f
11f
12f,g
10
a All of the reactions were carried out using 1a (0.4 mmol, 1.0 equiv)
and 2 (0.6 mmol, 1.5 equiv) in the presence of 15 mol % of VI at room
temperature in diethyl ether (0.4 mL). b Isolated yields. c Determined by
chiral HPLC analysis (major isomer).
a Unless otherwise specified, all of the reactions were carried out using
1a (0.6 mmol, 1.5 equiv) and 2a (0.4 mmol, 1.0 equiv) with 10 mol % of
catalyst at room temperature (23 °C). b Isolated yields. c Determined by
crude NMR. d Determined by chiral HPLC analysis (major isomer).
e Reaction at 4 °C. f 15 mol % of catalyst was used. g 1a (0.4 mmol, 1.0
equiv) and 2a (0.6 mmol, 1.5 equiv) were used.
9 and 10) or electron-donating (entries 2-4), neutral groups
(entry 1) and substrates containing a variety of substitution
patterns (para, meta, and ortho) participated in this reaction
efficiently. The reactions proceeded to afford highly enan-
tioselective adducts. 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. Notably, only one Michael-Henry adduct
was obtained from the reaction of nitrodiene 2k in 97% ee
(Scheme 1). Theoretically, both ꢀ- and δ-positions of 2k are
was carried out in solvent or when the reaction temperature
was decreased (Table 1, entries 2 and 3). As such, we turned
our attention to revolutionizing catalysts. After screening the
catalysts II-VI in Figure 1 at room temperature (23 °C)
under neat conditions, V and VI were found to be excellent
candidates to catalyze this tandem reaction with the highest
stereoselectivity (92% ee, 95:5 dr) among all the tested cases,
as shown in the Table 1. Catalyst VI12 was then chosen as
catalyst due to the higher yield obtained and its easy
synthesis. Further optimization of the reaction conditions
revealed that solvents played a very important role in
determining the selectivities of the reaction (in toluene or
diethyl ether, > 99% ee, 98:2 dr) (Table 1, entries 9-11).
With the optimized reaction conditions at hand, we
expanded the scope of the tandem Michael-Henry process
by using a variety of nitroolefins in diethyl ether at room
temperature. It was discovered that most of the reactions are
completed within 24 h with good to excellent yields (85%
- 94%), with excellent enantioselectivities (97% to > 99%
ee) and diastereoselectivities (93:7-98:2 dr). It appeared that
the position and the electronic property of the substituents
on aromatic rings have a very limited effect on the stereo-
selectivities. Regardless of the types of substituents on the
aromatic rings, be it electron-withdrawing (Table 2, entries
Scheme 1
.
Tandem Michael-Henry Reactions of 1a with 2k
and 1b/1c with 2a
(12) For 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.
possibly attacked due to the congruous two double bonds,
showing the great regioselectivity and enantioselectivity of
Org. Lett., Vol. 10, No. 12, 2008
2439

this method. Furthermore, the tandem reaction also proceeded
smoothly when 1a was replaced by either 1b or 1c, giving
excellent stereoselectivities (99% ee) as displayed in
Scheme 1.
In summary, we have developed a novel organocatalytic
tandem Michael-Henry reaction. The reaction was efficiently
catalyzed by readily available 9-amino-9-deoxyepiquinine
(VI) to give synthetically useful, highly functionalized chiral
cyclohexanes with four stereogenic centers containing two
quaternary stereocenters in good to excellent yields (85-94%),
excellent enantioselectivities (97% to >99% ee) and high
diastereoselectivities (93:7-99:1 dr). We presented the first
highly enantioselective Michael addition of R-substituted
ꢀ-ketoesters to nitroolefins catalyzed by VI and, in particular,
the first organocatalytic Henry reaction of common ketones
used as acceptors with excellent results. We hope that this
strategy of developing a practical and efficient tandem
Michael-Henry reaction can spark more efforts into the
designing of such organocatalytic reactions. This approach
constitutes our future direction aimed at expanding the scope
and applications of these powerful tandem processes.
According to the dual activation model,8e the two sub-
strates involved in the reaction are activated simultaneously
by catalyst VI as shown in Figure 2. Nitroolefins are assumed
Acknowledgment. This paper is dedicated to Professor
R. A. Lerner on the occasion of his 70th birthday. This work
is financially supported by the grant from the Ministry of
Education, Singapore (ARC12/07, no. T206B3225) and the
School of Physical and Mathematical Sciences, Nanyang
Technological University.
Figure 2. Proposed action of catalyst.
to interact with the primary amine moiety of VI via multiple
H-bonds, thus enhancing the electrophilic character of the
reacting carbon center. The carboanion (adjacent to the nitro
group) generated from the Michael addition then attacks the
si-face of the carbonyl group to afford Henry products
(Figure 2). The stereochemistry was established by X-ray
crystallographic determination of 3f (CCDC 670273) and
analysis of NMR data of the products.
Supporting Information Available: Experimental pro-
cedures, characterization, spectra, chiral HPLC conditions,
and X-ray crystallographic data (CIF file of 3f: CCDC
670273). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL8007183
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Org. Lett., Vol. 10, No. 12, 2008