Chiral primary-secondary diamines catalyzed michael-aldol-dehydration reaction between benzoylacetates and α,β-unsaturated ketones: Highly enantioselective synthesis of functioned chiral cyclohexenonfs

Article abstract of DOI:10.1002/chem.200901541

"Chemical Equation Presented" A highly enantioselective organocatalytic tandem Michael-aldol-dehydration reaction that provides an expedited access to highly functionalized chiral cyclohexenone derivatives (such as that depicted) by using a simple diamine

Full text of DOI:10.1002/chem.200901541

COMMUNICATION
DOI: 10.1002/chem.200901541
Chiral Primary–Secondary Diamines Catalyzed Michael–Aldol–Dehydration
Reaction between Benzoylacetates and a,b-Unsaturated Ketones: Highly
Enantioselective Synthesis of Functionalized Chiral Cyclohexenones
Ying-Quan Yang,[a] Zhuo Chai,[b] Hai-Feng Wang,[b] Xing-Kuan Chen,[b] Hai-Feng Cui,[b]
Chang-Wu Zheng,[b] Hua Xiao,[a] Peng Li,[b] and Gang Zhao*[a, b]
Functionalized chiral cyclohexenones are an important
class of scaffolds found in numerous naturally occurring and
synthetic molecules possessing a broad spectrum of biologi-
cal activities.[1] Several methodologies have been utilized to
access this kind of compounds, including kinetic resolution
of racemic substituted cyclohexenones by catalytic asymmet-
ric reactions[2] and various multistep synthesis.[3] Neverthe-
less, these systems more or less suffer from several draw-
backs such as only half of the starting material could be
used in kinetic resolution to obtain products with the de-
sired configuration and low efficiency for multi-step synthe-
sis.
Recently, the application of organocatalysis to this field
has afforded a valuable alternative access to these useful
compounds, which usually features readily available starting
materials, good atom- and step-economy, mild reaction con-
ditions and high stereo-/enantioselectivities.[4–8] List et al. re-
alized a highly enantioselective desymmetrizing intramolec-
ular aldol reaction of 4-substituted-2,6-heptanediones to
enantiomerically enriched 5-substituted-3-methyl-2-cyclo-
hexene-1-ones using a quinine-derived primary catalyst.[5]
Using a,b-unsaturated aldehydes as the Michael acceptors,
Jørgensen et al.[6] and Hayashi et al.[7] have successfully uti-
lized diarylprolinol silyl ether as the organocatalyst and vari-
ous nucleophilic donors to prepare different chiral cyclohex-
enones with excellent enantioselectivities. On the other
hand, a,b-unsaturated ketones as the Michael acceptors
have received less attention probably due to their reduced
reactivities compared with enals. Using a phenylalanine-de-
rived imidazolidine catalyst, Jørgensen et al.[8] were among
the first to visualize a highly enantio- and diastereoselective
Michael–aldol reaction of ketoesters and enones to provide
functionalized chiral cyclohexanes, which after dehydration
in the presence of an acid could be converted to chiral cy-
clohexenones. However, long reaction times were generally
required (95–240 h). Chen et al.[9] also applied Cinchona al-
kaloid-derived primary amine catalysts to catalyze the Mi-
chael addition of dicyanoalkenes to enones; the products
could be converted to chiral cyclohexenones in high enantio-
selectivities in one step. In the view of these results, there is
still room for the development of organocatalysts for the
highly enantioselective synthesis of functionalized chiral cy-
clohexenones.
Recently, we have developed a novel readily available pri-
mary–secondary diamine catalyst system for the Michael ad-
ditions of malonates to enones with excellent yields and
enantioselectivities.[10] We disclosed herein that a similar cat-
alyst system could also efficiently catalyze the Michael–
aldol–dehydration reaction between benzoylacetates and
a,b-unsaturated ketones to provide functionalized chiral cy-
clohexenones in excellent enantioselectivities.
[a] Dr. Y.-Q. Yang, Dr. H. Xiao, Prof. Dr. G. Zhao
Department of Chemistry, University of Science and Technology of
China
Hefei, Anhui 230026 (China)
Initially, the reaction of ethyl benzoylacetate 1a with ben-
zylideneacetone 2a was selected as a model reaction for the
catalyst evaluation (Table 1). In the presence of 20 mol% of
catalyst 3a (Figure 1) and 20 mol% of additive TFA, the re-
action was completed within 72 h to provide the desired
products in 90% yield with moderate diastereoselectivity
and excellent enantioselectivities for both diastereoisomers
(Table 1, entry 1). However, neither elongating the alkyl
chain of the second amine moiety in 3a nor increasing its
Fax : (+86)21-64166128
E-mail: zhaog@mail.sioc.ac.cn
[b] Dr. Z. Chai, Dr. H.-F. Wang, M. X.-K. Chen, Dr. H.-F. Cui,
Dr. C.-W. Zheng, Dr. P. Li, Prof. Dr. G. Zhao
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai institute of organic chemistry
Chinese Academy of Sciences, 345 Lingling Lu
Shanghai, 200032 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901541.
Chem. Eur. J. 2009, 15, 13295 – 13298
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13295

Table 2. Screening of acid additive for the Michael–aldol–dehydration re-
action between ethyl benzoylacetate 1a and benzylideneacetone 2a.[a]
Entry
Additive
Yield [%][b]
d.r.[c]
ee [%][d]
1
none
0
–
–
2
3
4
5
6
7
HOAc
TsOH
d-CSA
CF3SO3H
l-N-Boc phenylglycine
d-N-Boc phenylglycine
d,l-N-Boc phenylglycine
d-N-Boc phenylglycine
trace
trace
trace
90
93
91
–
–
–
–
–
–
Figure 1. Structures of the catalysts studied.
77:23
75:25
77:23
72:28
73:27
98/96
97/95
99/99
96/91
98/94
steric hindrance could improve the results (Table 1, en-
tries 2–7).
8
86
65
Of note is the key role the acid additive played in this
transformation: the reaction did not proceed in the absence
9[e]
[a] Reaction conditions: 2a (1.0 equiv), 1a (2.0 equiv), 3a (20 mol%),
CHCl3 (2.0 mL). [b] Yield of the isolated product after column chroma-
tography. [c] Determined by 1H NMR analysis; major isomer: trans.
[d] The ee value was determined by chiral HPLC . [e] CH2Cl2 was used as
solvent. d-CSA: d-camphor sulfonic acid.
Table 1. Screening of catalysts for the Michael–aldol–dehydration reac-
tion between ethyl benzoylacetate 1a and benzylideneacetone 2a.[a]
Heterocyclic furan enone 2k also performed well to give the
desired product albeit with a decrease in the yield (Table 3,
entry 11). Good results were also obtained when the aliphat-
ic enone 2l was used (Table 3, entry 12).
Similarly, no significant difference in chemical yield and
enantioselectivity was observed for other benzoylacetates
1b–e bearing different ester moieties while a slight better
diastereoselectivity was obtained with 1d bearing a bulky
tert-butyl group (Table 4, entries 1–4). The effective system
could also be extended to the aliphatic substrate (Table 4,
entry 5).
Entry
Catalyst 3
Additive
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3 f
3g
TFA
TFA
TFA
TFA
TFA
TFA
TFA
90
89
93
96
89
92
89
77:23
78.22
74:26
70:30
73:27
67:33
74:26
95/95
90/89
90/89
90/89
94/91
95/95
93/94
[a] Reaction conditions: 2a (1.0 equiv), 1a (2.0 equiv), 3 (20 mol%),
CHCl3 (2.0 mL). The relative configuration of 4aa was determined by
NOE experiments. For details of the reaction process, please see the Sup-
porting Information [b] Yield of the isolated product after column chro-
matography. [c] Determined by 1H NMR analysis; major isomer: trans.
[d] The ee value was determined by chiral HPLC.
Table 3. Enantioselective Michael–aldol–dehydration reaction between
ethyl benzoylacetate 1a and enones 2 catalyzed by the 3a/d-N-Boc phe-
nylglycine combination.[a]
of additives (Table 2, entry 1) and only trace product was
obtained when HOAc, TsOH and d-CSA[11] were used as
the additives (Table 2, entries 2–4). Finally, d-N-Boc-phenyl-
glycine turned out to be the additive of choice, which pro-
vided the desired product in 91% yield and 99% ee for
both diastereoisomers, albeit without improvement in the
diastereoselectivity (Table 2, entry 7). Less satisfactory re-
sults were obtained using the racemic d,l-N-Boc-phenylgly-
cine as an additive (Table 2, entry 8).[12]
Entry
R2
Product
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
Ph, 2a
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
91
85
84
76
82
79
78
77
81
87
55
98
77:23
77:23
77:23
76:24
71:29
71:29
74:26
81:19
78:22
62:38
80:20
78:22
99/99
2-naphthyl, 2b
4-FC6H4, 2c
4-ClC6H4, 2d
3-ClC6H4, 2e
2-ClC6H4, 2 f
4-BrC6H4, 2g
4-MeC6H4, 2h
4-MeOC6H4, 2i
4-NO2C6H4, 2j
2-furyl, 2k
99/>99
>99/99
99/>99
>99/>99
>99/>99
99/>99
99/99
99/99
99/99
>99/>99
99/99
With the optimized reaction conditions at hand, the scope
of the tandem Michael–aldol–dehydration reaction between
ethyl benzoylacetate 1a and enones
2 was explored
9
(Table 3). Overall, all examined substrates could provide the
desired products in moderate to excellent yields and 99% ee
for both diastereoisomers. For enones 2a–j with different
substituted benzene rings, while only negligible difference
was observed in chemical yields and enantioselectivities,
slightly higher d.r. values were obtained for substrates bear-
ing electron-donating substituents (Table 3, entry 8 and 9).
10
11
12
4aj
4ak
4al
nPr, 2l
[a] Reaction conditions: 2 (1.0 equiv), 1a (2.0 equiv), 3a/d-N-Boc-phenyl-
glycine (20 mol%), CHCl3 (2.0 mL). [b] Yield of the isolated product
after column chromatography. [c] Determined by 1H NMR analysis;
major isomer: trans. [d] The ee value was determined by chiral HPLC.
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Chem. Eur. J. 2009, 15, 13295 – 13298

Highly Enantioselective Synthesis of Cyclohexenones
COMMUNICATION
Table 4. Enantioselective Michael–aldol–dehydration reaction between
benzoylacetates 1 and enones 2a catalyzed by the 3a/d-N-Boc phenylgly-
cine combination.[a]
Scheme 1. Conversion of 4aa to 3,5-disubstituted cyclohexenone 5.
rently underway on further application of the catalyst
system to other related reactions as well as a more detailed
mechanistic understanding of the reaction.
Entry
R1
Product
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
Me, 1b
allyl, 1c
tBu, 1d
Bn, 1e
1 f
4ba
4ca
4da
4ea
4 fa
85
73
71
90
65
73:27
77:23
85:15
66:34
75:25
99/>99
99/99
>99/99
>99/>99
97/98
Experimental Section
[a] Reaction conditions: 2a (1.0 equiv), 1 (2.0 equiv), 3a/d-N-Boc-phenyl-
glycine (20 mol%), CHCl3 (2.0 mL). [b] Yield of the isolated product
after column chromatography. [c] Determined by 1H NMR analysis;
major isomer: trans. [d] The ee value was determined by chiral HPLC.
General: Unless otherwise indicated, all compounds and reagents were
purchased from commercial suppliers and used without further purifica-
tion. Proton nuclear magnetic resonance spectra are recorded at
300 MHz. All chemical shifts (d) are given in ppm. NMR spectra were re-
corded on Varian EM-360 A, Varian EM90 or Bruker AMX-300 NMR
spectrometer. IR spectra were recorded on a Perkin–Elmer 983G instru-
ment. MS or HRMS was recorded on a HP-5989 A spectrometer. Melting
points were determined on a Mettler-Toledo FP62 melting point appara-
tus and are uncorrected. HPLC analysis was carried out on WATERS
equipment. Catalysts 3a–d,[10] 3e,[15] 3 f,[16] and 3g[17] were prepared from
known procedure.
As shown in Scheme 1, the absolute configuration of 4aa
was determined by conversion to the known compound 5
via a simple decarboxylation reaction while maintaining the
stereochemical integrity at C-5. Of note is that 5 has previ-
ously been procured via multistep synthesis.[13] Thus, the
present method may be one of the most convenient ways to
this kind of chiral 3,5-substituted cyclohexenones.
The proposed mechanism for the Michael–aldol–dehydra-
tion reaction is outlined in Scheme 2. In the first step, a,b-
unsaturated ketone 2 is activated by the formation of imini-
um ion with catalyst 3a. The Re face of the enone in this in-
termediate is shielded by the bulky group of the chiral cata-
lyst allowing the benzoylace-
General procedure for the Michael–aldol–dehydration reaction: To a
mixture of enone 2 (0.25 mmol), catalyst 3 (0.05 mmol) and d-N-Boc
phenylglycine (0.05 mmol) in CHCl3 (2.0 mL) was added benzoylacetate
(1; 0.5 mmol) at ambient temperature. After stirring for 72 h, the reaction
mixture was quenched with 1m aqueous HCl solution and extracted with
EtOAc. The combined organic layer was dried over Na2SO4, filtered, and
concentrated to afford the desired product 4 after flash column chroma-
tography on silica gel (petroleum ether/Et2O).
Further details are available in the Supporting Information.
tate 1 to attack the Si face of
the enone 2. Next, the generat-
ed chiral enamine intermediate
performs an intramolecular
aldol addition to form the cy-
clohexane ring 6. After dehy-
dration, chiral cyclohexenones
4 were obtained. Since the con-
centration of the intermediate
6 is very low at all stages of
the reaction, the detection of
the intermediate does not rule
out alternative mechanisms
such as Mannich–Knoevena-
gel-type mechanism.[14]
In summary, we have devel-
oped a novel highly enantiose-
lective organocatalytic tandem
Michael–aldol–dehydration re-
action that provides an expe-
dited access to highly function-
alized chiral cyclohexenone de-
rivatives by using
a simple
amine catalyst. Efforts are cur-
Scheme 2. Proposed reaction mechanism for the Michael–aldol–dehydration reaction.
Chem. Eur. J. 2009, 15, 13295 – 13298
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Keywords: aldol reaction · asymmetric catalysis · enones ·
Michael reaction · organocatalysis
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Received: June 6, 2009
Revised: August 10, 2009
Published online: November 11, 2009
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