Highly diastereo-and enantioselective synthesis of 5-substituted 3-pyrrolidin-2-ones: Vinylogous michael addition under multifunctional catalysis

Article abstract of DOI:10.1002/anie.201008255

A direct line: A direct organocatalytic asymmetric vinylogous Michael addition of α,β-unsaturated γ-butyrolactams with α,β-unsaturated ketones has been developed (see scheme; Boc=tert-butoxycarbonyl, Trp=tryptophan, Ts=4-toluenesulfonyl). The resulting Mi

Full text of DOI:10.1002/anie.201008255

Communications
DOI: 10.1002/anie.201008255
Asymmetric Catalysis
Highly Diastereo- and Enantioselective Synthesis of 5-Substituted
3-Pyrrolidin-2-ones: Vinylogous Michael Addition under
Multifunctional Catalysis**
Huicai Huang, Zhichao Jin, Kailong Zhu, Xinmiao Liang, and Jinxing Ye*
5-Substituted 3-pyrrolidin-2-ones and their structural ana-
logues have been found as crucial fragments in a number of
complex natural and non-natural compounds,[1] such as the
lycorane-type alkaloids, the stemona family, and the large
family of indole alkaloids including haplophytine, vindoline,
and the strychnos family of alkaloids (Scheme 1). All these
Aldol, Michael, and other simple transformations of either
direct or Mukaiyama-type reactions.[3] Even more attractive
are the diastereo- or enantioenriched products that could be
further utilized as versatile building blocks towards more
functionalized pyrrolidin-2-ones.[4]
However, stereoselective transformations involving this
interesting molecule still remain rare, both in the field of
organocatalytic synthesis and organometallic catalysis, com-
pared with other important nucleophilic reagents. The
scarcity of reactions is partially due to the difficulties in the
chemoselective activation of the a, b-unsaturated vinylogous
system either as a donor or as an acceptor in chemical
reactions, and the challenges in the enantio- and diastereo-
selectivity during those processes.[5] Satisfactory results were
achieved in the recent report of Shibasaki and co-workers[5a]
in the asymmetric vinylogous Mannich and Michael reaction
of this a,b-unsaturated g-butyrolactam with N-Boc imines
and nitroolefins involving a dinuclear nickel catalytic system.
Furthermore, Chen and co-workers[5d] have presented an
asymmetric Michael addition with a,b-unsaturated aldehydes
under the well-established iminium activation using the
catalyst developed by Jørgensen and Hayashi.[6] However,
to the best of our knowledge, the vinylogous Michael
additions of this a,b-unsaturated g-butyrolactam to a,b-
unsaturated ketones has never been reported and still
represents a challenging task regarding the reactivity and
stereoselectivity of the two relatively inert reactants.[7]
Herein, we report our investigations on this transformation
under a multifunctional catalytic system, as well as some
explorations into the use of the resulting products to
demonstrate the potential utility of this strategy in the
pharmaceutical and organic synthesis fields.
Our initial investigations were carried out using a series of
catalysts (1–3) for the model reaction of benzalacetone 4a
and a,b-unsaturated g-butyrolactam 5a in CH2Cl2 at room
temperature (Table 1, entries 1–11). Experimental data
showed that the cyclohexane-1,2-diamine catalysts 1a and
1b could promote the reaction more effectively than other
types of catalysts, with conversions of up to 93% after
72 hours, but with low stereoselectivity (entries 1 and 2). The
9-amino-epiquinine 2a and its derivative 2b afforded the
products with slightly increased ee values, but still with
unsatisfactory reaction conversions or stereoselectivity
(entries 3 and 4). Then our attention turned to another type
of iminium-activation catalyst bearing a chiral 1,2-diphenyl-
ethane-1,2-diamine fragment with the hope that it would
provide an improvement in this transformation. Attractive
ee values were attained using the simple (R,R)-1,2-diphenyl-
Scheme 1. Several natural products that contain the fragments of
5-substituted 3-pyrrolidin-2-one derivatives.
molecules display marvelous biological properties including
antiviral, pesticidal, and antitumor activity, as well as other
pharmacological properties,[2] which undoubtably contribute
greatly to their importance in the field of organic chemistry
both in terms of their chemical synthesis and in the develop-
ment of synthetic methodologies.
As one of the efficient chemical precursors to 5-substi-
tuted 3-pyrrolidin-2-one derivatives, a,b-unsaturated g-butyr-
olactam has recently appeared as one of the most attractive
reactants in various chemical reactions including Mannich,
[*] H. Huang, Z. Jin, K. Zhu, Prof. Dr. X. Liang, Prof. Dr. J. Ye
Engineering Research Centre of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy
East China University of Science and Technology
130 Meilong Road, Shanghai 200237 (China)
E-mail: yejx@ecust.edu.cn
[**] This work was supported by the Innovation Program of Shanghai
Municipal Education Commission (11ZZ56), the National Natural
Science Foundation of China (20902018), the Shanghai Pujiang
Program (08J1403300), the Fundamental Research Funds for the
Central Universities, and 111 project (B07023).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008255.
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Angew. Chem. Int. Ed. 2011, 50, 3232 –3235

the reaction conversions (entries 6–11). A bulky acid partner
was crucial for the stereocontrol,[8] so a series of commercially
available bulky N-Boc amino acids were surveyed in combi-
nation with the organocatalysts. The diastereoselectivity
decreased with 3a, 3b, and 3c as catalysts in the presence of
the bulky N-Boc-l-Phe. However, bulky N-Boc amino acids
improved the diastereoselectivity significantly with catalysts
3d–3g. To our delight, both excellent enantio- and diastereo-
selectivity could be achieved using the catalytic system
consisting of 3e and N-Boc-l-Trp. Furthermore, investiga-
tions showed that the amount of acidic additives had little
effect, and the reaction could proceed well in many different
solvents to give excellent ee values and good to excellent
d.r. values.[9] Finally, the reaction conversion could be
improved to 93% with high d.r. and ee values when the
reaction was run at 358C in CHCl3 (entry 12).
With the optimized reaction conditions in hand, the scope
of this organocatalytic asymmetric vinylogous Michael addi-
tion was exploited to check the substrate generality of this
strategy (Table 2). To our great delight, this well-established
approach could be utilized for a large variety of a,b-
unsaturated ketones bearing either electron-donating
(entries 1–10) or electron-withdrawing (entries 11–18)
groups. All the Michael products could be acquired in
excellent yields with excellent enantio- and diastereoselec-
tivity. Notably, the Michael receptors could be extended to
aliphatic a,b-unsaturated ketones (entries 22–31), including
various cyclic vinyl ketones, to result in complete enantiose-
lectivity and favorable d.r. values with excellent product
yields (entries 30 and 31).
Table 1: Primary screening results.[a]
The bromide product 6r was recrystallized and the
corresponding single crystal was subjected to X-ray analysis
to determine the absolute structure.[10] On the basis of this
result and our previous work,[8] a plausible catalytic mecha-
nism involving multisite interactions was assumed to explain
the high stereoselectivity of this process (Scheme 2).
Having successfully extended this strategy to a large
variety of vinyl ketones, we then devoted our efforts to
exploring some additional transformations of the enantio-
and diastereopure Michael products, which are important
fragments in the structure of many biologically active
molecules. The malonate group can be introduced into the
5-substituted 3-pyrrolidin-2-ones under sodium hydride and
TMSCl conditions. Highly stereoselective dihydroxylation of
the 5-substituted 3-pyrrolidin-2-ones proceed well with
Entry
Cat.
Solvent
Acid additive
Conv.
[%][b]
d.r.[b]
ee
[%][c,d]
1
2
3
4
5
6
7
8
1a
1b
2a
2b
3a
3b
3c
3d
3e
3 f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3[f]
none
none
none
none
none
none
none
none
none
none
none
N-Boc-l-Trp
93
58
30
71
16
13
0
63
66
65
42
93
2:1
2:1
2:1
2.5:1
1:1.5
1:1.5
–
2:1
1:2.5
1:1
1.5:1
15:1
50(27)
0(31)
48(66)
77(72)
77(90)
20(8)
–
6(36)
21(0)
11(21)
25(11)
98
9
10
11
12
3g
3e[e]
[a] Unless noted otherwise the following reaction conditions were used:
5a (1.0 equiv, 0.10 mmol, 0.5m), 4a (1.3 equiv), catalyst (0.10 equiv),
and acid additive (0.10 equiv). [b] Determined by 1H NMR analysis of the
crude reaction mixture. [c] Determined by HPLC on a chiral stationary
phase. [d] The data in the parentheses are the ee values of the other
diastereomer. [e] 0.15 equiv of 3e was employed. [f] The reaction was
carried out at 358C. Boc=tert-butoxycarbonyl.
ethane-1,2-diamine (3a), but the conversion and diastereose-
lectivity were disappointing (entry 5). So a series of 3a
derivatives were sequentially examined to find the suitable
catalyst. However, the stereoselectivity did not even show
marginal improvements, albeit with some improvements in
Scheme 2. Proposed transition state in the vinylogous Michael reac-
tion.
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Communications
Table 2: The scope of the vinylogous Michael reaction.[a]
RuCl3·H2O and NaIO4.[5b] The transformations are summar-
ized in Scheme 3.
In summary, a direct organocatalytic asymmetric vinyl-
ogous Michael reaction of a,b-unsaturated g-butyrolactam
with a,b-unsaturated ketones has been developed. The
corresponding Michael products could be obtained with
excellent enantio- (95% to 99% ee) and diastereoselectivity
(4:1–30:1 d.r.) in excellent yields (75–90%). Moreover, those
enantiopure products could serve as important fragments in a
number of biologically active natural and non-natural com-
pounds, and might be of importance in both natural product
synthesis and pharmaceutical research because of their
potential utility towards construction of attractive molecules.
Additional investigations involving the application of this
catalytic approach are currently under way in our group and
will be reported in due course.
Entry
R1
R2
Adduct
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
6a
6b
6c
6d
6e
6 f
6g
6h
6i
86
88
86
83
83
84
75
90
88
15:1
98
98
95
98
99
99
98
99
98
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
25:1
15:1
14:1
15:1
17:1
15:1
18:1
19:1
2,3-(MeO)2C6H3
2,4-(MeO)2C6H3
10
Me
6j
82
15:1
98
Experimental Section
11
12
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
2-naphthyl
2-furanyl
2-thiopenyl
Me
nPr
nBu
pentyl
hexyl
Me
C6H5CH2CH2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bu
6k
6l
88
80
81
82
76
81
83
85
81
83
85
85
81
84
86
83
80
78
81
79
83
16:1
13:1
12:1
20:1
12:1
12:1
16:1
14:1
13:1
>30:1
>30:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
18:1
99
98
98
99
98
96
98
98
98
99
99
98
98
98
98
98
98
99
98
99
99
General procedure: a,b-Unsaturated g-butyrolactam 5a (0.5 mmol,
1.0 equiv) was added to a mixture of catalyst 3e (0.075 mmol,
0.15 equiv), N-Boc-l-Trp (0.075 mmol, 0.15 equiv), and a,b-unsatu-
rated ketones 4 (0.65 mmol, 1.3 equiv) in CHCl3 (1.0 mL) at 358C.
The reaction mixture was maintained at this temperature for 3 days
and then the solvent was removed under vacuum. The residue was
purified by chromatography on silica gel to yield the desired addition
product. The enantiomeric ratio was determined by HPLC on a chiral
stationary phase.
6m
6n
6o
6p
6q
6r
6s
6t
6u
7a
7b
7c
7d
7e
7 f
7g
7h
7i
Received: December 30, 2010
Published online: March 4, 2011
Keywords: asymmetric catalysis · ketones · Michael addition ·
.
organocatalysis · synthetic methods
Me
Me
=
C6H5CH CH
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[9] For details, see the Supporting Information.
[10] CCDC 804551 (6r) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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