Direct asymmetric aldol addition-isomerization of α,β- unsaturated γ-butyrolactam with aryl α-ketoesters: Synthesis of MBH-type products

Article abstract of DOI:10.1039/c3cc40717a

A highly efficient direct asymmetric aldol addition-isomerization reaction at the α-position of α,β-unsaturated γ-butyrolactam and aryl α-ketoesters by using a bifunctional thiourea catalyst was achieved. Morita-Baylis-Hillman type adducts containing a quaternary stereocenter can be obtained in high yields and with excellent enantioselectivities (up to 99% ee). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc40717a

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Direct asymmetric aldol addition–isomerization of
a,b-unsaturated c-butyrolactam with aryl a-ketoesters:
synthesis of MBH-type products†
Cite this: Chem. Commun., 2013,
49, 3300
Received 28th January 2013,
Accepted 5th March 2013
Jinlong Zhang, Xihong Liu, Xiaojuan Ma and Rui Wang*
DOI: 10.1039/c3cc40717a
www.rsc.org/chemcomm
A highly efficient direct asymmetric aldol addition–isomerization
reaction at the a-position of a,b-unsaturated c-butyrolactam and aryl
a-ketoesters by using a bifunctional thiourea catalyst was achieved.
Morita–Baylis–Hillman type adducts containing a quaternary stereo-
center can be obtained in high yields and with excellent enantio-
selectivities (up to 99% ee).
Scheme 1 The aldol addition–isomerization at the a-position of a,b-unsatu-
rated g-butyrolactam.
Nitrogen-containing heterocycles are present in a variety of complex
natural and non-natural compounds.1 Many of these molecules
display marvelous biological properties and pharmacological
properties, which undoubtedly contribute greatly to their importance
in the field of organic chemistry. Recently, a,b-unsaturated
g-butyrolactam has appeared as one of the efficient chemical
precursors to a diverse array of attractive nitrogen heterocyclic ring
systems in various chemical reactions.2 Among the established
strategies, the catalytic direct vinylogous reactions that could be
utilized as effective protocols for carbon–carbon bond formation are
more attractive.3 And, significant progress has also been made in
asymmetric direct vinylogous Mannich and Michael reactions.4
These processes underwent a g-deprotonation pathway to generate
the dienolate intermediate and reaction at the g-position of the
activated dienolate and carbon electrophiles. Here we report a
direct asymmetric aldol addition5,6–isomerization reaction at the
a-position of the activated dienolate generated from a,b-unsaturated
g-butyrolactam and aryl a-ketoesters7 catalyzed by a bifunctional
thiourea catalyst8 for the synthesis of Morita–Baylis–Hillman
(MBH)9 type products (Scheme 1).
Preliminary results were achieved in the report of Zhou and
co-workers in the asymmetric MBH reaction of isatins and acrolein
involving alkaloid catalyst systems, which was also the first time that
the ketone has been used as the electrophile.14a Furthermore,
enantioselective MBH reactions with isatins and activated alkenes
have been well developed, using cinchona, phosphinothiourea or
phosphine–squaramide as the chiral catalyst.14 To the best of our
knowledge, the MBH reaction of aryl a-ketoesters and activated
alkenes has rarely been reported and its enantioselective versions
still represent a challenging task regarding the low reactivity and
steric hinderance.15 In view of this limitation, an alternative
approach is needed to obtain chiral MBH-type products. The
present study provides a convenient approach to MBH-type
products containing a quaternary stereocenter16 through a
direct aldol addition–isomerization sequence, providing useful
b-hydrogen esters containing a butyrolactam, which are ubiquitous
building blocks for many natural products.17
Our initial investigations were carried out using a series of
quinine and cyclohexanediamine derived catalysts 1a–1h
(Fig. 1) for the model reaction of ethyl phenylglyoxylate 3a
and a,b-unsaturated g-butyrolactam 2a. As summarized in
Table 1, excellent enantioselectivity could be attained in CH2Cl2
at 30 1C in the presence of various thiourea and quinine
derivatives. The product yield of the reaction was, however,
found to be critically dependent on the structure of the cata-
lysts. Reactions with thioureas 1a–1d or quinine 1e afforded 4a
in higher yields than thiourea 1a and quinine derivatives 1f–1h.
The nitrogen Lewis base of the thiourea catalysts and the
hydroxy group of the quinine derivatives played significant
Although the catalytic asymmetric MBH reaction has been
extensively studied by employing either chiral amines10 or phos-
phines11 as the catalysts, the electrophiles employed in the MBH
reactions are mostly aldehydes and imines, and the use of ketones
as electrophiles is very limited.12 Recently, isatin derivatives have
emerged as new electrophilic components for MBH reactions.13
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of
Basic Medical Sciences, State Key Laboratory of Applied Organic Chemistry and
Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou,
730000, China. E-mail: wangrui@lzu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 921456. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc40717a
c
3300 Chem. Commun., 2013, 49, 3300--3302
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catalyst system. Subsequently, various derivatives obtained
from aryl a-ketoesters were involved. The position of the
substituent on the aromatic ring of the aryl a-ketoester had
very little effect on the enantioselectivity. The electron-donating
substituents at different positions afforded the products in
greater than 99% ee and good yield (except for the sterically
hindered ethyl 2-methylphenylglyoxylate, which provided the
product in a moderate yield, 4f–4j). Moreover, electron-
withdrawing substituents also provided the products in high
enantioselectivities and good yields (Table 2, 4k–4p). In
addition, ethyl 2-naphthylglyoxylate afforded the product with
high enantioselectivity and moderate yield (Table 2, 4q).
At the end of the reactivity assessment of aryl a-ketoesters,
we evaluated the reactivity of b,g-unsaturated a-ketoester 3r in
the reaction with a,b-unsaturated g-butyrolactam (Scheme 2). It
is noteworthy that the process underwent direct vinylogous
Fig. 1 The structures of screened organocatalysts.
roles in the direct aldol addition–isomerization reaction. Then
the reaction solvents were examined with thiourea 1b.18 As
expected, the use of polar solvents (THF, CH3OH and MeCN),
which reduced the activity of the catalyst, resulted in poor
yields of 4a (Table 1, entries 9–11). In contrast, 1b in solvents
(CH2Cl2, toluene) efficiently promoted the reaction, affording
4a in moderate yields and with excellent enantioselectivities
(Table 1, entries 2 and 12). Next, the effects of the temperature
were investigated (Table 1, entries 2, 13 and 14). Either at lower
(0 1C) or higher temperature (reflux), a decreased yield was
observed due to the low catalyst activity and side reactions.
When the catalyst loading was reduced to 10 mol% and
5 mol%, the same excellent enantioselectivity was obtained,
but more reaction time was needed for completion of the
reaction (Table 1, entries 15 and 16). 1b at a 15 mol% loading
was selected for further studies in terms of efficiency.
Table 2 Substrate scope for the catalytic direct asymmetric aldol addition–
isomerizationa
With the optimal reaction conditions established, the
substrate scope of this bifunctional thiourea catalyzed direct
aldol addition–isomerization reaction was extended (Table 2).
The reactions with diethyl benzoylphosphinate, benzil and
trifluorophenylethanone could afford the products with no
enantioselectivities (Table 2, 4b–4d). When tert-butyl phenylglyoxy-
late was used as a reaction substrate, good yield and moderate
enantioselectivity were achieved (Table 2, 4e). The results showed
that ethyl arylglyoxylates were the best substrates for the present
Table 1 Screening of the reaction conditions
Entrya
L (mol%)
Solvent
T (1C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a (15)
1b (15)
1c (15)
1d (15)
1e (15)
1f (15)
1g (15)
1h (15)
1b (15)
1b (15)
1b (15)
1b (15)
1b (15)
1b (15)
1b (10)
1b (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3OH
CH3CN
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
30
30
30
30
30
30
30
30
30
30
30
30
0
31
78
46
61
65
16
17
20
44
65
20
82
40
71
60
52
99
99
97
95
97
97
97
95
97
94
96
98
99
98
99
99
a
Reactions were carried out with 1b (0.03 mmol, 15 mol%), a-keto-
esters 3 (0.3 mmol, 1.5 eq.) and 2a (0.2 mmol, 1.0 eq.) in CH2Cl2 (0.4 ml)
at 30 1C. Isolated yields were obtained for all the compounds and ee
values determined by chiral HPLC.
9
10
11
12
13
14
15
16
Reflux
30
30
a
Reactions were carried out with 2a (0.1 mmol) and 3a (0.15 mmol,
b
c
Scheme 2 The direct vinylogous Michael addition reaction of a,b-unsaturated
g-butyrolactam to b,g-unsaturated a-ketoester 3r.
1.5 eq.). Isolated yield. The enantiomeric excess was determined by
HPLC analysis of the isolated product.
c
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In summary, we have developed a simple bifunctional
thiourea catalyzed direct asymmetric aldol addition–isomerization
reaction of a,b-unsaturated g-butyrolactam and aryl a-ketoesters,
affording a series of chiral b-hydrogen esters. This method
represents the first construction of optically active MBH-type
products containing a quaternary chiral carbon center.
We are grateful for the grants from the National Natural
Science Foundation of China (No. 91213302, 20932003 and
21272102), the Key National S&T Program ‘‘Major New Drug
Development’’ of the Ministry of Science and Technology of
China (2012ZX09504001-003) and the Program for Changjiang
Scholars and Innovative Research Team in University (PCSIRT:
IRT1137).
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c
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3302 Chem. Commun., 2013, 49, 3300--3302