Organocatalytic domino reactions: Synthesis of densely functionalized cyclohexene derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.04.049

A highly enantioselective domino reaction of α,β-unsaturated aldehydes and 4-acetyl-5-oxohexanal catalyzed by a chiral secondary amine catalyst has been developed, providing an efficient synthetic approach for the synthesis of densely functionalized chiral cyclohexene derivatives with high yields (up to 96%) and enantioselectivities (up to 97% ee) under mild conditions.

Full text of DOI:10.1016/j.tetlet.2014.04.049

Tetrahedron Letters 55 (2014) 3344–3347
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic domino reactions: synthesis of densely
functionalized cyclohexene derivatives
b,
Bo Bi a,b, Yuyang Ding a,b, Qinxin Lou b, Wenhui Hu b, Albert S. C. Chan c, Hongrui Song a, , Junling Zhao
⇑
⇑
a School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
b Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China
c Hong Kong Baptist University, Kowloon Tong, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective domino reaction of
a,b-unsaturated aldehydes and 4-acetyl-5-oxohexanal
Received 7 March 2014
Revised 8 April 2014
Accepted 15 April 2014
Available online 23 April 2014
catalyzed by a chiral secondary amine catalyst has been developed, providing an efficient synthetic
approach for the synthesis of densely functionalized chiral cyclohexene derivatives with high yields
(up to 96%) and enantioselectivities (up to 97% ee) under mild conditions.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalytic
Enantioselectivity
Domino reaction
Cyclohexenes
Chiral cyclohexenes are common structural motifs of many nat-
ural products and biologically important molecules,1 and the syn-
thesis of structurally versatile cyclohexene frameworks has long
been of interest to the chemical community. Asymmetric Diels–
Alder cycloadditions2 are one of the most common methods
employed to prepare various substituted chiral cyclohexenes;
however, the starting materials are limited to active dienes and
dienophiles. Organocatalytic domino reactions,3 which combine
domino reactions4 and organocatalysis,5 have proven to be an effi-
cient method for the synthesis of complex molecules. Chiral sec-
ondary amines play an important role in this area, as they form
iminium6 and enamine7 intermediates with active carbonyl com-
pounds that can then react with nucleophiles and electrophiles,
respectively, to generate at least two new bonds and, in some
cases, several chiral centers.8 Organocatalytic domino reactions
have been successfully used for the synthesis of chiral cyclohex-
enes with high stereoselectivities. The most impressive example
was reported by Enders et al.,9 who developed a triple cascade
using an enamine–iminium–enamine activation strategy for the
synthesis of cyclohexenes to generate three new bonds and four
chiral centers in just one operation.9a–e There are two steps in this
protocol: first, the generation of an intermediate capable of both
nucleophilic and electrophilic attack; this compound then reacts
with an a,b-unsaturated aldehyde in an iminium–enamine manner
by catalysis with a chiral secondary amine to produce the cycliza-
tion products. Jørgensen and coworkers8a,b,f–h,o employed a similar
strategy for the synthesis of cyclohexene-carbaldehyde deriva-
tives10 with
a,b-unsaturated aldehydes and activated methylene
compounds as the starting materials. To better manipulate this
process for the synthesis of diversified cyclohexenes, we have
explored the reaction of 4-acetyl-5-oxohexanal (3) and a,b-unsat-
urated aldehydes (2) with prolinol ether as a catalyst. Herein, we
present our preliminary results on the synthesis of heavily func-
tionalized chiral cyclohexenes.
4-Acetyl-5-oxohexanal (3) is a very simple compound, but it has
two nucleophilic sites and three electrophilic groups (Scheme 1).
The C@O groups of both the aldehyde and the ketones are good
electrophilic groups, and the 1,3-diketone scaffold enolizes read-
ily8k,11 to provide an active nucleophile. The aldehyde reacts with
secondary amine 1 to generate an enamine,12 which is also a
well-known nucleophilic reagent. Thus, the two species compete
with each other to react with the iminium ion produced from the
a,b-unsaturated aldehyde in the presence of catalyst 1, which gen-
erates two different intermediates which finally provide final prod-
ucts 4 and 5, respectively.
To begin our investigation, cinnamaldehyde (2) and 4-acetyl-5-
oxohexanal (3) were reacted in the presence of (S)-diphenyl-pro-
linol-TMS ether (1b, 20 mol %) in dichloromethane at 20 °C. To
our delight, the reaction was finished in 20 h to give 4 as the only
product in 86% yield and 92% ee (Table 1, entry 1); product 5 was
not detected. The addition of benzoic acid (20 mol %) significantly
⇑
Corresponding authors. Tel.: +86 13019394507; fax: +86 2423986443 (H.S.);
tel.: +86 2032093736; fax: +86 2032015299 (J.Z.).
E-mail addresses: hongruisong@163.com (H. Song), zhao_junling@gibh.ac.cn
(J. Zhao).
http://dx.doi.org/10.1016/j.tetlet.2014.04.049
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

B. Bi et al. / Tetrahedron Letters 55 (2014) 3344–3347
3345
reaction. In general, the solvent substantially affects the yield and
has little influence on the enantioselectivity of the cyclization.
When THF, dioxane, and DMF (entries 5, 10, and 12) were used,
only traces of the product were detected by TLC, and high enanti-
oselectivities were obtained when EA, chloroform, toluene, and
ether were employed (entries 3, 4, 6, and 11). The best result
was achieved in chloroform, which afforded 4a in 76% yield and
96% ee (entry 3).
With these results in hand, we tested other prolinol silyl ether
catalysts (Table 1). A hydroxy group in the catalyst suppressed
the reaction; for example, when prolinols were employed, only
traces of the product were detected by TLC (entries 15, 17). How-
ever, it was noteworthy that when catalyst 1c was used, the reac-
tion was completed in 8 h to give 4a in 92% yield and 95% ee (entry
16). When 1e was employed, the yield was moderate, but the
enantioselectivity still reached 93% ee (entry 18).
electrophilic attack
O
O
O
electrophilic attack
MeOC
MeOC
O
-H+
base
N
H
3
+
1
O
O
N
MeOC
N
O
MeOC
nucleophilic attack
nucleophilic attack
With the optimal reaction conditions determined, we studied the
R
iminium
reaction of 3 with various substituted
a,b-unsaturated aldehyde
substrates 2 to explore the generality of this reaction, and the results
are summarized in Table 2. 13 In general, moderate to high yields and
high enantioselectivities were achieved with
hydes bearing different aryl substituents. The electronic nature of
the aromatic ring of the ,b-unsaturated aldehyde has little influ-
ence on both the yield and enantioselectivity of product 4. Elec-
tron-donating (entries 2–3, 13, 17), electron-withdrawing (entries
5–12), and 1-naphthyl (entry 16) aromatic enals react smoothly
with 3; substrates with ortho-substituted aromatic rings required
prolonged reaction times and afforded the product in low yields,
most likely due to the steric hindrance (entries 13–15).
a,b-unsaturated alde-
R
OHC
R
OHC
CHO
a
COMe
COMe
4
COMe
5
Scheme 1. Possible domino reactions of 3.
The absolute configuration of the newly created carbon center
in 4 was (R), as determined by a single crystal X-ray crystallo-
graphic analysis of 4o (Fig. 1).
reduced the reaction time to 8 h with a 90% yield without decreas-
ing the enantioselectivity (Table 1, entry 2). Encouraged by this
promising result, we then studied the effect of the solvent on this
Table 1
Optimization of the reaction conditionsa
Ar
N
H
Ar
OR
OHC
Ph
20 mol% 1
20 mol% PhCO2H
MeOC
CHO
CHO
Ph
+
1a
: Ar=Ph, R=H
solvent rt 20h
COMe
1b: Ar=Ph, R=TMS
1c: Ar=Ph, R=TES
MeOC COMe
2a
3
4a
1d
: Ar=3,5-(CF3)2C6H3, R=H
1e: Ar=3,5-(CF3)2C6H3, R=TMS
Entry
Solvent
Cat.
Yieldb (%)
eec (%)
1d
2e
3
4
5
6
7
8
9
10
11
12
13
14
15
16e
17
18
DCM
DCM
Et2O
CHCl3
THF
Toluene
MeCN
MeOH
ClCH2CH2Cl
Dioxane
EA
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
1e
86
90
64
76
Trace
74
65
25
76
Trace
30
Trace
53
50
Trace
92
92
92
95
96
—
95
91
90
94
—
95
—
95
95
—
DMF
MTBE
o-Xylene
CHCl3
CHCl3
CHCl3
CHCl3
95
—
93
Trace
55
a
Unless stated otherwise, the reaction was carried out with 2a (0.1 mmol), 3 (0.12 mmol), catalyst (0.02 mmol), and benzoic acid (0.02 mmol) in 0.4 mL of solvent at 20 °C
for 20 h. The mixture was then purified directly by silica gel chromatography.
b
Isolated yield.
c
Determined by HPLC analysis with a chiralpak OD-H column.
Without benzoic acid.
Reaction time is 8 h.
d
e

3346
B. Bi et al. / Tetrahedron Letters 55 (2014) 3344–3347
Table 2
OHC
OHC
R
Organocatalyzed domino reaction of
a
,b-unsaturated aldehydes (2a–q) and 4-acetyl-
5-oxohexanal (3)a
R
COMe
COMe
OHC
R
N
H
1b
20 mol%
2
MeOC
CHO
CHO
20 mol% PhCO2H
4
1
+
R
dehydration
COMe
CHCl3
MeOC COMe
2a-q
N
3
4a-q
OH
N
R
Entry
Ar
Ph
Product
Time (h)
Yieldb (%)
eec (%)
iminium
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
20
20
16
12
20
20
20
16
20
24
24
12
48
48
24
36
24
76
96
93
88
84
82
92
75
82
80
72
91
59
56
49
65
69
96
91
92
91
94
95
97
92
95
94
96
96
91
86
96
90
92
4-MeOC6H4
4-MeC6H4
4-t-ButylC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-FC6H4
4-CF3C6H4
4-NO2C6H4
3-BrC6H4
3-NO2C6H4
2-MeOC6H4
2-MeC6H4
2-ClC6H4
MeOC COMe
CHO
B
O
N
R
MeOC
COMe
aldol reaction
3
enamine
Michael addition
MeOC
COMe
A
Scheme 2. Proposed catalytic cycle of the domino reaction.
1-Naphthyl
Piperonyl
good yield and high enantioselectivity under mild reaction condi-
tions. Further applications of this protocol toward the synthesis
of structurally diverse cyclohexene derivatives are in progress.
a
Unless stated otherwise, the reaction was carried out with 2a (0.1 mmol), 3
(0.12 mmol), catalyst (0.02 mmol), and benzoic acid (0.02 mmol) in 0.4 mL of sol-
vent at 20 °C. The mixture was then purified directly by silica gel chromatography.
b
Acknowledgements
Isolated yield.
c
Determined by HPLC analysis with a chiralpak OD-H column.
We thank the National Natural Science Foundation of China
(Grant 21102145) and the Guangdong Pearl River Nova Program
(Grant 2012J2200014) for financial support. Professor Zhongyuan
Zhou is gratefully acknowledged for X-ray structure determination.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
04.049.
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A plausible catalytic cycle for the reaction of
a,b-unsaturated
aldehydes (2) and 4-acetyl-5-oxohexanal (3) is depicted in
Scheme 2. In the first step, the secondary amine catalyst 1 reacts
with 2 to form an iminium ion, which undergoes Michael addi-
tion11 with 3 to give intermediate A. In the second step, the result-
ing enamine A undergoes an intramolecular aldol reaction to
generate B; subsequent hydrolysis and elimination of water give
cyclohexene product 4 and regenerate catalyst 1 for the next cata-
lytic cycle.
In conclusion, we developed a secondary amine-catalyzed
enantioselective domino reaction of
a,b-unsaturated aldehydes 2
and 4-acetyl-5-oxohexanal (3). A series of densely functionalized
optically active cyclohexene derivatives 4 were synthesized in

B. Bi et al. / Tetrahedron Letters 55 (2014) 3344–3347
3347
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13. Typical procedure for the domino reaction of
a,b-unsaturated aldehydes and 4-
acetyl-5-oxohexanal: To a solution of ,b-unsaturated aldehyde 2a (0.1 mmol)
a
and 4-acetyl-5-oxohexanal (3, 0.12 mmol) in 0.4 mL of chloroform, catalyst 1b
(0.02 mmol) and benzoic acid (0.02 mmol) were added. The mixture was
stirred at room temperature for 20 h, and the crude product was purified
directly by column chromatography on silica gel (hexane/ethyl acetate = 2:1)
to afford the corresponding product 4a as a white solid in 76% yield and 96% ee.
9. (a) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (b)
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