Proline-based reduced dipeptides as recyclable and highly enantioselective organocatalysts for asymmetric Michael addition

Article abstract of DOI:10.1039/c1ob05679d

A series of novel proline-based reduced dipeptides was developed and evaluated for a direct Michael addition of ketones and aldehydes to nitroalkenes. Excellent yields (up to 95%), diastereoselectivities (up to 98% dr) and enantioselectivities (up to 98%

Full text of DOI:10.1039/c1ob05679d

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Proline-based reduced dipeptides as recyclable and highly enantioselective
organocatalysts for asymmetric Michael addition†
Xiaohui Cao, Ge Wang, Richeng Zhang, Yingying Wei, Wei Wang, Huichao Sun and Ligong Chen*
Received 30th April 2011, Accepted 20th July 2011
DOI: 10.1039/c1ob05679d
A series of novel proline-based reduced dipeptides was devel-
oped and evaluated for a direct Michael addition of ketones
and aldehydes to nitroalkenes. Excellent yields (up to 95%),
diastereoselectivities (up to 98% dr) and enantioselectivities
(up to 98% ee) were achieved in the presence of 5 mol% catalyst
without any additional additives at room temperature.
Organocatalytic, asymmetric carbon–carbon and carbon–
heteroatom bond-forming reactions have been extensively inves-
tigated in recent years.1 The conjugate Michael addition reaction
represents one of the most elegant and attractive ways to introduce
chirality into Michael acceptors through asymmetric carbon–
carbon bond formation.2 Furthermore, the asymmetric conjugate
addition of a carbon nucleophile to nitro alkenes is of fundamental
importance, since it affords a useful synthetic method for chiral
nitro alkanes that contain at least two vicinal stereogenic centers
in a single step. Proline3 and its pyrrolidine-based derivatives have
been investigated and have been shown to be effective asymmetric
catalysts for the Michael addition of aldehydes and ketones
to nitroolefins.4 However, these organocatalysts still have some
drawbacks in that a high catalyst loading (10–30 mol%) is generally
required and they are hard to recover. These problems limit the
widespread application of the catalysts. A catalyst that overcomes
these limitations would be advantageous.
In the organocatalyst field, peptides always have had an
important status.5,6 A series of proline-based dipeptides were
evaluated for catalyzing the Michael addition by List in 20037 and
Tsogoeva in 2009.8 These peptides catalyzed reactions with high
Fig. 1 The design of the new catalysts.
yields (65%–91%), but only showed moderate enantioselectivity
their amine analogue11–13 (81%–99% ee). These results indicate that
the carbonyl group has a negative impact on enantioselectivity.
Inspired by this, we designed a series of proline-based reduced
dipeptides by removing the carbonyl groups from previously
reported dipeptides7,8 (Fig. 1). From another point of view, the
newly designed catalysts which contain a carboxyl group should be
more water-soluble than the diamine catalyst. This thus provides
an easy method to recover the catalysts by capitalizing on their
solubility characteristics.14
(56–68% ee).8 It is well known that even subtle changes in a
catalyst’s structure can often have a considerable influence on
its performance. In this paper, a series of highly enantioselective
and recoverable organocatalysts that were produced by subtle
modifications of previously reported peptides is presented.
In our recent studies, a few proline amides9–11 (Fig. 1, 1–3) were
investigated as organocatalysts for the model Michael addition
reaction of cyclohexanone 12 to nitrostyrene 13. They showed
lower enantioselection (26%–31% ee, Table 1, entry 1–3) than
As shown in Scheme 1, the proline-based reduced dipeptides
were readily prepared from N-Boc-L-prolinol (8) in four steps.
First 8 was oxidized to aldehyde 9 with pyridinium chlorochromate
(PCC) and then the formyl group was transformed to the
corresponding amine by reductive amination with an amino-acid
methyl ester. After removal of the methyl ester and successively
School of Chemical Engineering and Technology, Tianjin University, Tian-
jin, P.R. China. E-mail: lgchen@tju.edu.cn; Fax: (+86)-22-27406314;
Tel: (+86)-22-27406314
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05679d
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Table 1 Michael addition of cyclohexanone to trans-b-nitrostyrene
time of 168 h (Table 1, entry 9). Unfortunately, when the loading
of catalyst 5 and 6 were reduced to 5 mol%, only trace amounts
of the product were observed after 72 h (Table 1, entries 10 and
11). Interestingly, the diastereoisomer 4b and the catalyst 7 having
no chiral center at d-carbon atom also provided a high yield and
similar enantioselectivity (Table 1, entry 5, 12). This means the
most important stereoselector is the 2 position of the pyrrolidine
ring. On the other hand, the reduced dipeptides which contain the
carboxyl group can catalyze the reaction without any additive,
so their reaction system is simpler than the diamine catalysts
where an acidic additive is generally required to achieve good
yield and enantioseleciton.11,12,15 This advantage should make it
more convenient to recover the catalyst.
Mol
Entrya Cat. (%) Solvent Additive Time (h) yieldb syn/antic ee(syn)d
1
2
3
4
5
6
7
8
1
2
3
20
20
20
DMSO TFA
DMSO TFA
DMSO TFA
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
48
48
48
48
48
48
48
64
168
72
72
48
87% 95 : 5
86% 93 : 7
90% 98 : 2
92% 99 : 1
89% 99 : 1
91% 99 : 1
90% 99 : 1
90% 99 : 1
27% 98 : 2
trace n.d.
trace n.d.
85% 97 : 3
26%
31%
33%
98%
98%
97%
96%
98%
93%
n.d.
n.d.
94%
4a 15
Next, the addition of cyclohexanone to trans-b-nitrostyrene was
used as a model reaction to examine the recyclability of catalyst
4a (at 15 mol%). After the reaction was completed, the reaction
mixture was concentrated and the residue was diluted with ethyl
acetate to precipitate the catalyst, which was then easily recovered
by filtration. The first time the catalyst was recovered, it was
4b 15
5
6
4a
4a
5
6
7
15
15
5
1
5
5
15
9
10
11
12
MeOH
MeOH
1
characterized by HNMR to confirm that the structure did not
a 5 eq ketone used. b Yields of isolated product after column chro-
matography. c Determined by 1HNMR analysis of the crude product.
d Enantioselectivities were determined for syn-product by chiral-phase
HPLC analysis (Daicel Chiralpak AS-H).
change after the reaction. The catalyst was then used for the next
run of the reaction. As Table 2 shows, catalyst 4a could be reused
for at least 6 times without a significant loss of stereoselectivity (ee
> 96%) although the catalytic activity decreased gradually.
The scope of the Michael reactions using catalyst 4a on
MeOH was examined with a variety of carbonyl compounds and
nitroolefins (Table 3).
deprotecting the N-Boc group, the target organocatalysts were
obtained with 30–40% overall yield.
As demonstrated in Table 3, catalyst 4a can be applied to
several different Michael reactions to produce a variety of carbonyl
compounds and nitroolefins in MeOH. Cyclohexanone efficiently
underwent Michael reactions with different aryl-substituted ni-
troolefins to give Michael adducts 14a–h in high yields with
excellent enantio- (94–98% ee) and diastereo-selectivities (syn/anti
ratio up to 99/1). The results in Table 3 also show that the nature
of the substituents on the aryl groups only slightly influences the
yields and enantioselectivities. For nitroolefins with electron-rich
groups (methyl and methoxy), the reaction proceeded smoothly
to afford Michael adducts 14b–c in excellent enantio- (98–99% ee)
and diastereoselectivities (syn/anti 99/1) (Table 3, entries 2–3). For
nitroolefins with electron-deficient groups, the Michael adducts
14d–h were also obtained in high yields (87–96%) with excellent
With the organocatalysts in hand, their catalytic performance
was then examined for the model reaction of cyclohexanone 12 to
nitrostyrene 13. Representative results are summarized in Table 1.
As the results of Table 1 show, the modified organocatalysts
require lower catalysts loadings (15 mol%, Table 1, entries 4, 6
and 7) than their peptide analogues (30 mol%)7,8 to promote the
reaction and they provide much better diastereo- and enantiose-
lectivities (syn : anti 99 : 1, ee 96%–98%) than the corresponding
peptides (syn : anti 95 : 5, ee 61%–68%).7,8 These encouraging
results indicate that the strategy for modification of the peptides is
effective. The loading of catalyst 4a can be reduced to 5 mol% with
similar results but a longer reaction time is needed (Table 1, entry
8). When the loading was further reduced to 1 mol%, the yield and
enantioselectivity were decreased even with a prolonged reaction
Scheme 1 Synthesis of proline-based reduced dipeptides.
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Table 2 Recycling studies of 4a catalyzed Michael addition of cyclohex-
anone to trans-nitrostyrenea
2-butanone took place at the more substituted sites and gave the
thermodynamic controlled product 14n with lower yield (67%) and
better enantioselectivity (74%) (Table 3, entry 14) than 14m. Fur-
thermore, the 3-pentanone gave product 14l with moderate yield
(75%) and excellent enantioselectivity (94% ee) (Table 3, entry 12).
Although the a,a¢-disubstituted aldehyde iso-butyraldehyde gave
product 14p with moderate enantioselectivities (62% ee) (Table 3,
entry 16), the linear aldehydes n-butyraldehyde and propanal are
also suitable Michael donors with high diastereoselectivity as well
as good enantioselectivity (87%–90% ee) (Table 3, entries 16,17).
These results indicate that catalyst 4a should be broadly applicable
to the synthesis of g-nitro carbonyl compounds.
Cycleb
Time (h)
Yield (%)c
ee (%)d
syn : antie
1
2
3
4
5
6
12
12
16
20
24
24
93
91
88
84
80
75
98%
97%
96%
97%
97%
98%
99 : 1
99 : 1
99 : 1
98 : 2
99 : 1
97 : 3
To account for the stereochemical outcome of the Michael
reaction, a plausible transition-state model is proposed in Fig. 2.
a The reaction was conducted with 20 mmol of 12 and 100 mmol of 11
in 2 mL of solvent at room temperature. b The first recovered catalyst
was characterized by 1HNMR. c Yields of isolated products. d Determined
by1H NMR. e Determined by Chiral HPLC.
enantio- (95–99% ee) and diastereoselectivities (syn/anti ratio up
to 99/1) (Table 3, entries 4–8). The dihydro-2H-pyran-4(3H)-
one and dihydro-2H-thiopyran-4(3H)-one also showed to be an
efficient Michael donor with high yield(89–91%) and excellent
enantioselectivities. (96–97% ee) (Table 3, entries 9,10). However,
the cyclopentanone gave product 14k with moderate diastereose-
lectivities (58% ee, Table 3, entry 11). The acyclic ketone donor,
acetone has been tested under similar conditions. The reaction
of acetone with trans-b-nitrostyrene 13 resulted in product 14m
with good yield (94%) but moderate enantioselectivity (51% ee)
(Table 3, entry 12). With the increase of the length of side chain of
the ketone, the enantioselectivity of the Michael addition process
was improved (Table 3, entry 14, 15). The unsymmetrical ketone,
Fig. 2 A possible transition state.
Table 3 Michael reactions of ketones to nitroolefinsa
Entry
R1
R2, R3
R4
Product
Yield (%)b
syn : antic
ee (%)d
1
2
3
4
5
6
7
8
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2CH2OCH2)-
-(CH2CH2SCH2)-
-(CH2)3-
Et
Ph
14a
14b
14c
14d
14e
14f
14g
14h
14i
91%
90%
80%
91%
87%
92%
93%
90%
91%
89%
78%
75%
94%
67%
90%
87%
79%
99 : 1
98 : 2
99 : 1
97 : 3
96 : 4
99 : 1
99 : 1
98 : 2
99 : 1
98 : 2
80 : 20
98 : 2
—
98%
98%
97%
96%
97%
98%
95%
97%
97%
96%
58%
94%
51%
74%
90%
87%
62%
4-Me-Ph
4-OMe-Ph
4-Cl-Ph
2-Cl-Ph
2,4-Cl-Ph
4-NO2-Ph
2-NO2-Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14
15
16
17
14j
14k
14l
14m
14n
14o
14p
14q
Me, H
H, H
Me, H
Et, H
Me, H
Me, Me
Me
Me
H
H
Ph
Ph
Ph
Ph
93 : 7
97 : 3
95 : 5
—
H
a Unless otherwise noted, the reaction was conducted with 5 mmol of 13 and 25 mmol of 12 in 1 mL of solvent at room temperature. b Yields of isolated
products. c Determined by 1HNMR, d Determined by Chiral HPLC.
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As shown in TS, the secondary amine of the pyrrolidine ring
activates the ketone through the formation of an enamine inter-
mediate. The hydrogen bond donor, amine and carboxyl group,
direct the nitrostyrene to attack the re-face of the enamine.
In summary, a new family of organocatalysts which can be used
to promote highly efficient asymmetric Michael addition reactions
of ketones and aldehydes to nitroolefins has been developed by
modifying previously reported peptides. Among these, catalyst
4a is the best. The main advantages of this catalyst are ease of
synthesis and low loading (5 mol%) for high stereoselectivities (ee
up to 98%, syn/anti up to 99/1) at room temperature. Moreover,
the catalyst can be easily recovered and reused. These advantages
make 4a a potential catalyst for industrial applications.
(k) B. Ni, Q. Zhang and A. D. Headley, Tetrahedron: Asymmetry, 2007,
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Kalikhevich, Eur. J. Org. Chem., 2004, 4014; (b) S. B. Tsogoeva and
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8 M. Freund, S. Schenker and S. B. Tsogoeva, Org. Biomol. Chem., 2009,
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9 Catalyst 1 was prepared according to: Asami and Masatoshi, Bull.
Chem. Soc. Jpn., 1990, 63, 721.
10 Catalyst 2 was prepared according to: S. S. Chimni and D. Mahajan,
Tetrahedron: Asymmetry, 2006, 17, 2108.
11 Catalyst 3 was prepared according to: S. V. Pansare and K. Pandya, J.
Am. Chem. Soc., 2006, 128, 9624.
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Acknowledgements
We are grateful to Prof. Wan and his group for their support in
our research.
Notes and references
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3 (a) B. List, P. Pojarliev and H. J. Martin, Org. Lett., 2001, 3, 2423; (b) J.
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13 A. P. Carley, S. Dixon and J. D. Kilburn, Syntheis, 2009, 2509.
14 For some selected recyclable organocatalysts examples: using ionic
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`
15 Barbas has reported that the addition of Brønsted acids can promote
the formation of enamines, see: N. Mase, F. Tanaka and C. F. Barbas
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6490 | Org. Biomol. Chem., 2011, 9, 6487–6490
This journal is
The Royal Society of Chemistry 2011
©