Chiral guanidine-catalyzed asymmetric direct vinylogous Michael reaction of α,β-unsaturated γ-butyrolactams with alkylidene malonates

Article abstract of DOI:10.1039/c2cc31470c

The asymmetric direct vinylogous Michael reaction of α,β- unsaturated γ-butyrolactams with alkylidene malonates has been developed. Various 5-substituted 3-pyrrolidin-2-ones were obtained in high yields (up to 93%) with excellent stereoselectivities (up to 94% ee, 95:5 dr), using a novel bifunctional C₁-symmetric guanidine organocatalyst embodied a secondary amine subunit. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31470c

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COMMUNICATION
Chiral guanidine-catalyzed asymmetric direct vinylogous Michael
reaction of a,b-unsaturated c-butyrolactams with alkylidene malonateswz
Yang Yang, Shunxi Dong, Xiaohua Liu,* Lili Lin and Xiaoming Feng*
Received 28th February 2012, Accepted 21st March 2012
DOI: 10.1039/c2cc31470c
The asymmetric direct vinylogous Michael reaction of a,b-
unsaturated c-butyrolactams with alkylidene malonates has been
developed. Various 5-substituted 3-pyrrolidin-2-ones were obtained
in high yields (up to 93%) with excellent stereoselectivities (up to
94% ee, 95 : 5 dr), using a novel bifunctional C1-symmetric
guanidine organocatalyst embodied a secondary amine subunit.
Fig. 1 Chiral organocatalyst evaluated.
Chiral butyrolactams are common and crucial fragments in
natural products and biologically active compounds,1 such as
(+)-lactacystin1d and haplophytine.1e Owing to their synthetic
significance, various methods for the preparation of optically active
5-substituted butyrolactam derivatives have been established.2
In recent years, a,b-unsaturated g-butyrolactams3 and 2-siloxy-
pyrrole4 have been employed as donors for the construction of
5-substituted 3-pyrrolidin-2-one derivatives. Considering atom-
economy, it is no doubt that direct vinylogous addition of
a,b-unsaturated g-butyrolactams is worthy of development.5
The Shibasaki group have employed their dinuclear nickel
catalytic system for the efficient vinylogous Mannich reaction and
Michael reaction of nitroolefins.5a Later, asymmetric vinylogous
Michael (VM) reactions with a,b-unsaturated aldehydes5b and
enones5c–e were well developed. However, the direct organocatalytic
asymmetric VM reaction of activated olefins has not yet been
reported. Herein, we describe our efforts devoted to the
asymmetric VM reaction between a,b-unsaturated g-butyrolactams
and alkylidene malonates by the use of a new bifunctional chiral
guanidine–amine organocatalyst.
Initially, the reaction between a,b-unsaturated g-butyrolactam 4
and diethyl benzylidenemalonate 5a was carried out in the presence
of chiral guanidine catalyst 1 at 30 1C in toluene (Fig. 1). To our
disappointment, the desired product 6a was afforded in only a
trace amount even after 4 days (Table 1, entry 1). Therefore,
organocatalysts with multisite activation functional groups
were designed, which could promote the reaction via acid–base
cooperative activation. C2-Symmetric bisguanidine catalysts,
previously used in the catalytic asymmetric reactions,7b,c
afforded complex mixtures. Interestingly, the untargeted
guanidine–secondary amine 2, obtained in the preparation of
the corresponding bisguanidine catalyst, was found to be
efficient for the reaction. The desired product 6a was generated
in 82% yield, 90% ee and 95 : 5 dr (Table 1, entry 2). It seemed
Table 1 Optimization of the reaction conditionsa
Recently, we have successfully developed a new type of
chiral guanidines and bisguanidines6 derived from a-amino
acids as efficient bifunctional organocatalysts.7 Inspired by prior
work, we hypothesized that guanidine moieties might be favorable
to the deprotonation of a,b-unsaturated g-butyrolactams, and
then might activate the generated dienolate to perform the VM
reaction smoothly.
Entry
Cat.
Solvent
t/h
Yieldb (%)
drc
eec (%)
1
2
3
4
5
6
7
8
1
2
3
2
2
2
2
2
2
2
PhMe
PhMe
PhMe
THF
CH2Cl2
AcOEt
CH3CN
PhCF3
PhCF3
PhCF3
96
36
96
36
96
36
96
24
24
18
Trace
82
0
72
16
70
32
82
82
82
—
95 : 5
—
95 : 5
95 : 5
94 : 6
77 : 23
90 : 10
95 : 5
95 : 5
—
90
—
91
86
85
82
93
94
94
Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China. E-mail: liuxh@scu.edu.cn,
xmfeng@scu.edu.cn; Fax: +86-28-85418249; Tel: +86-28-85418249
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available. CCDC
869057 (7i). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc31470c
9d
10d,e
a
Unless otherwise noted, all reactions were carried out with 1–3
(10 mol%), 4 (0.05 mmol) and 5a (0.1 mmol) in solvent (0.5 mL)
b
c
at 30 1C. Isolated yield. Determined by chiral HPLC analysis.
10 mg of 4 A molecular sieves. 5 mol% of 2 in 0.25 mL of PhCF3.
d
e
c
5040 Chem. Commun., 2012, 48, 5040–5042
This journal is The Royal Society of Chemistry 2012

that the secondary amine moiety was crucial for the occurrence
of the process. Then catalyst 3, the precursor of the guanidine
catalyst 2, was evaluated. However, it failed to promote the
reaction at all (Table 1, entry 3 vs. 2). These results suggested
that guanidine and secondary amino group of the catalyst 2
worked cooperatively. Next, screening of solvent revealed that
the best one was PhCF3 in reactivity and enantioselectivity
(82% yield with 93% ee; Table 1, entry 8 vs. 4–7). The
diastereoselectivity was increased to 95 : 5 when 4 A molecular
sieves (MS) were added (Table 1, entry 9 vs. 8). To our delight,
the catalyst loading could be decreased from 10 mol% to
5 mol% without decreasing the yield and stereoselectivity of
the reaction (Table 1, entry 10 vs. 9). Therefore, the optimal
reaction conditions were established using 5 mol% of 2 and 4 A
MS as additives in PhCF3 at 30 1C.
Scheme 1 Determination of the absolute configuration of the
product.
Under the optimized conditions, the ester group of benzyl-
idenemalonate was first evaluated. Similar results on the
yields, diastereo- and enantioselectivities were obtained with
dimethyl-, diethyl-, or dibenzyl benzylidenemalonate (Table 2,
entries 1–3). Then a series of diethyl alkylidene malonates was
investigated, giving the corresponding products with excellent
enantioselectivities (up to 94% ee). As shown in Table 2,
alkylidene malonates with either an electron-withdrawing or
Scheme 2 Comparative experiment.
an electron-donating substituent on the aromatic ring in the
R1 group could be converted to the corresponding 5-substituted
3-pyrrolidin-2-ones in high yields, excellent ee values, and
diastereoselectivities (up to 93% yield, 89–94% ee; Table 2,
entries 4–16). It was notable that the system demonstrated good
tolerance to fused-ring and hetero-aromatic substrates (Table 2,
entries 17–19). However, the cinnamonic substrate 5t showed
lower stereoselectivities (78% ee and 81 : 19 dr; Table 2, entry 20).
Additionally, the cyclohexylmethylene malonate 5u was also a
suitable substrate for the direct vinylogous Michael reaction with
70% yield and 90% ee (Table 2, entry 21). The absolute
configuration of the product 6i was concluded as (5R, 10S) by
X-ray crystallography of 7i (Scheme 1).8
Table 2 Substrate scope for the catalytic asymmetric VM reaction of
a,b-unsaturated g-butyrolactam 4 to alkylidene malonates 5a
Entry R1
R2
Et
t/h Yieldb (%)
drc
eec (%)
To further investigate the role of the secondary amino group
in the catalyst 2, a comparative experiment was carried out
with N-Me protected guanidine–tertiary amine derivative 9
(Scheme 2). Under the optimized conditions, both the reactivity
and stereoselectivity decreased sharply, and the product 6a was
obtained only in 15% yield and 71% ee in 18 hours. It showed that
the proton of the secondary amino group played a vital role in the
direct vinylogous Michael reactions. Based on the experiments and
our previous work,7 the possible activation model of the reaction
was proposed6h,9 as shown in Scheme 3. The basic guanidine in the
catalyst could accelerate g-deprotonation of a,b-unsaturated
g-butyrolactam 4 to generate dienolate. The N-Boc protection
group of 4 was favorable to the contribution of the dual hydrogen
bonding between the formed intermediate and the guanidine
moiety as well as the amide on the same side of the catalyst 2.
Meanwhile, the alkylidene malonate 5 was activated through a
1
2
Ph
Ph
18
6a, 82 (86)d 95 : 5
94 (93)d
93
91
94
93
Me 18
6b, 85
6c, 83
6d, 78
6e, 75
6f, 80
6g, 85
6h, 85
6i, 86
6j, 76
6k, 82
6l, 93
6m, 72
95 : 5
95 : 5
95 : 5
95 : 5
94 : 6
95 : 5
94 : 6
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
3
Ph
Bn
Et
Et
Et
Et
Et
Et
Et
Et
18
12
12
12
12
12
12
18
18
18
24
4
5
6
7
8
9
10
11
12
13
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
90
92
93
93e
93
93
93
93
3-MeOC6H4 Et
4-MeOC6H4 Et
14
Et
36
6n, 64
90 : 10 91
15
16
17
18
19
4-PhC6H4
3-PhOC6H4
2-Thienyl
3-Thienyl
2-Naphthyl
Et
Et
Et
Et
Et
18
18
18
18
18
6o, 83
6p, 89
6q, 72
6r, 70
6s, 82
95 : 5
95 : 5
95 : 5
93 : 7
93 : 7
90
89
90
91
91
20
Et
Et
12
18
6t, 75
6u, 70
81 : 19 78
95 : 5 90
21
c-Hexyl
a
Unless otherwise noted, all reactions were carried out with 2 (5 mol%),
4 (0.05 mmol), 5 (0.1 mmol) and 10 mg of 4 A MS in PhCF3 (0.25 mL) at
b
c
d
30 1C. Isolated yield. Determined by chiral HPLC analysis. The
data in parentheses are results when the reaction was carried out with
2 (5 mol%), 4 (0.5 mmol), 5 (1.0 mmol) and 100 mg of 4 A MS in PhCF3
e
(2.5 mL) at 30 1C for 18 hours. The absolute configuration of 6i has
been determined by X-ray crystallographic analysis after conversion to 7i.
Scheme 3 Proposed activation model for asymmetric VM reaction
catalyzed by 2.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5040–5042 5041

2 (a) D. M. Iula and R. E. Gawley, J. Org. Chem., 2000, 65, 6196;
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P. Burreddu, G. Rassu, G. Pelosi, G. Casiraghi and F. Zanardi,
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H.-J. Chen, W. J. Flosi, D. J. Grampovnik, C. M. Yeung, L. L. Klein
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(e) L. Lin, J. Zhang, X. Ma, X. Fu and R. Wang, Org. Lett., 2011,
13, 6410.
6 For reviews on chiral guanidine catalysts, see: (a) T. Ishikawa and
T. Isobe, Chem.–Eur. J., 2002, 8, 552; (b) D. Leow and C.-H. Tan,
Chem.–Asian J., 2009, 4, 488. For selected examples, see:
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Scheme 4 Transformations of the corresponding Michael products.
network of hydrogen bonds of NH groups of both the secondary
amine and amide on the other side of the catalyst. Therefore, the
desired product could be obtained by the Re-face attack of the
activated alkylidene malonate 5.
The highly enantiomerically enriched compounds 6 obtained by
this method can be easily converted into 5-substituted pyrrolidin-
2-ones, which are important intermediate skeletons in many
natural drug molecular structures.1a–c For example, the optically
pure 5-substituted pyrrolidin-2-one 8a, containing two adjacent
chiral centers, was easily obtained by two steps from the product
6a (Scheme 4).
In conclusion, we have developed a novel guanidine combining
with secondary amine as a highly efficient bifunctional catalyst in
asymmetric direct vinylogous Michael reaction of a,b-unsaturated
g-butyrolactams with alkylidene malonates. High yields (up to
93%) and excellent selectivities (up to 94% ee, 95 : 5 dr) were
generally obtained for a range of substrates using 5 mol% catalyst
loading under mild reaction conditions. A possible catalytic model
was proposed to explain the observed high enantioselectivities.
The successful application of C1-symmetric guanidine–amine
organocatalysts helps to design a new kind of catalysts.
Further studies on the mechanism of the reaction and the
application of this catalyst are underway.
We appreciate the National Natural Science Foundation of
China (No. 21021001 and 21072133), the Ministry of Education
of China (NCET-11-0345), and the Basic Research Program of
China (973 Program: 2010CB833300) for financial support.
Notes and references
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(e) K. C. Nicolaou, S. M. Dalby and U. Majumder, J. Am. Chem.
Soc., 2008, 130, 14942.
8 CCDC 869057 (7i)w.
9 (a) H. Ube, N. Shimada and M. Terada, Angew. Chem., Int. Ed.,
2010, 49, 1858; (b) X. Fu and C.-H. Tan, Chem. Commun., 2011,
47, 8210 and references therein.
c
5042 Chem. Commun., 2012, 48, 5040–5042
This journal is The Royal Society of Chemistry 2012