Organocatalytic enantioselective conjugate addition of nitromethane to alkylidenemalonates: Asymmetric synthesis of pyrrolidine-3-carboxylic acid derivatives

Article abstract of DOI:10.1039/c3ra42014k

A highly enantioselective nitromethane addition to alkylidene malonates catalyzed by cinchona-alkaloid derived thiourea based organocatalyst has been developed that offers a new route to the synthesis of substituted pyrrolidine-3-carboxylic acid derivatives and 3-arylpyrrolidines/pyrrolidones. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra42014k

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Organocatalytic enantioselective conjugate addition
of nitromethane to alkylidenemalonates: asymmetric
synthesis of pyrrolidine-3-carboxylic acid derivatives3
Cite this: RSC Advances, 2013, 3, 10185
Received 28th February 2013,
Accepted 25th April 2013
Saumen Hajra,* Sk Mohammad Aziz and Rajat Maji
DOI: 10.1039/c3ra42014k
www.rsc.org/advances
A highly enantioselective nitromethane addition to alkylidene
malonates catalyzed by cinchona-alkaloid derived thiourea based
organocatalyst has been developed that offers a new route to the
synthesis of substituted pyrrolidine-3-carboxylic acid derivatives
and 3-arylpyrrolidines/pyrrolidones.
To the best of our knowledge, there are only two reports of
nitroalkane addition to alkylidene malonates till date. First one is
by Maruoka et al. under phase transfer condition by using a
complex N-spiro C2-symmetric chiral quaternary ammonium
catalyst.10 Very recently during our study, Chiarucci et al.
reported11 the catalytic enantioselective addition of nitroalkane
to alkylidene malonates. But surprisingly, other than only one
example for nitromethane addition to benzylidene malonate (ee
88%),10 both reports are restricted to higher nitroalkanes and
avoid the use of nitromethane. Moreover lack of C5-substitution of
the pyrrolidine3 further underscores the drawback of the existing
methodologies.
Pyrrolidine-3-carboxylic acids (PCA) and their derivatives are
important structural motifs abundant in biologically active natural
products and pharmaceuticals.1,2
A structure based search
revealed that 2,4-disubstituted- and 4-substituted PCAs 1 and 2
are more abundant than trisubstituted- and other di- or mono-
substituted isomeric PCAs (for details see ESI )3—among these,
3
In recent years, organocatalytic conjugate addition reactions
have emerged as an important weapon in the arsenal of the
synthetic organic chemist.12 For this particular study we decided
to use thiourea based organocatalysts with tethered amine
functionality as it is presumed that the unique structural feature
of the catalyst enables it to act bifunctionally via activation of
alkylidene and in situ enolate generation from nitromethane. We
commenced our screening with chiral trans-cyclohexanediamine
derived catalyst A and B for benzylidene malonate 5a (R = OEt)
under different conditions (Table 1). Initial results by using these
catalysts were promising but still unsatisfactory as these showed
moderate enantioselectivity 47% and 40%, respectively, with poor
to moderate conversions (entries 2 and 3). It was therefore decided
to turn our attention to naturally occurring chiral cinchona
the 4-aryl PCAs outnumber the 4-alkyl ones. Some notable
examples, which show promising bioactivity, are endothelin A
antagonists ABT-627 and ABT 546, MK-0489, hKN1, CCR5 etc.2
Other than PCA, 3-substituted pyrrolidines and 4-substituted-2-
pyrrolidones 3 are the third most abundant structural unit after
PCAs 1 and 2. These compounds also show high enantiospecificity
towards interaction with respective receptors. Thus development
of a concise and general divergent method for enantioselective
synthesis for these compounds is an attractive challenge to
synthetic and medicinal chemists.
Retrosynthetic analyses divulge that a-acyl-b-aryl-c-amino
butyric acid derivatives 4, an important motif found in many
natural products and pharmaceuticals,4 could be a common
precursor to such pyrrolidine based molecules which in turn can
be obtained by two different ways: conjugate addition of malonate
to nitrostyrene (route 1), or nitromethane addition to alkylidene
malonate (route 2, Scheme 1). Extensive research efforts have been
dedicated to the former strategy accompanied with excellent
success in terms of yields and stereoselectivity.5,6 General
nitromethane addition to enone,7 chalcone,8 a,b-unsaturated acid
derivatives9 are known in the literature, but addition of
nitromethane to alkylidene malonates is still a formidable
challenge.
Department of Chemistry, Indian Institute Technology Kharagpur, Kharagpur
721302, India. E-mail: shajra@chem.iitkgp.ernet.in; Fax: +91 3222 255303; Tel: +91
3222 283340
Scheme 1 Divergent retrosynthetic route of PCAs 1, 2 and 3.
RSC Adv., 2013, 3, 10185–10188 | 10185
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3
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Table 1 Screening of organocatalysts for the conjugate addition of nitro-
methane to benzylidene malonates 5aa
Table 2 Generalization of catalytic enantioselective conjugate addition of
nitromethane to alkylidene malonates 5
Entry
R
Substrate 5 Time (d) Yield (%)a ee (%)b
1
2
3
4
5
6
7
8
9
10
Ph
5a
5b
5c
5d
5e
5f
4
4
4
3
5
5
4
5
4
4
67
70
68
76
69
67
64
65
64
62
72
98
76
97
76
80
70
68
59
66
4-F-C6H4
2-F-C6H4
4-NO2-C6H4
2-Cl-C6H4
4-Cl-C6H4
2-Br-C6H4
4-Me-C6H4
5g
5h
4-OMe-C6H4 5i
5j
Entry
R9
Catalyst
Time (d)
Yield of 6a (%)b
ee (%)c
11
12
5k
5l
5
4
58
57
63
55
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
i-Pr
t-Bu
Bn
—
A
B
C
D
E
7
4
4
4
4
4
4
6
5
7
NRd
69
55
67
58
63
60
47
27
67
—
47
40
72
271
51
65
73
51
78
F
C
C
C
a
Isolated yields after column chromatography; 10–20% substrate 5
b
was recovered. Enantioselectivity was determined by HPLC using
chiral column.
10
a
Reaction condition: 5a (0.40 mmol), catalyst (10 mol%) in
nitromethane (1.0 ml) was stirred at room temperature (25 uC).
b
Isolated yields after column chromatography; 10–20% substrate 5a
c
was recovered. Enantioselectivity was determined by HPLC using
chiral column.d NR: no reaction.
found ee drops significantly (nearly 30%) in non-polar solvents like
toluene. The effects of variation of catalyst loading and
temperature were evaluated by using simplified neat condition.
With increase in temperature ee drops down sharply along with
yield. Variation of catalyst loading also has a considerable effect on
yield and selectivity: decreasing the catalyst loading to 5 mol%
resulted in a significant drop in ee, while increasing the catalyst
loading (20 mol%) raised the yield minutely keeping selectivity
same. Therefore we decided to pursue further investigations with
10 mol% catalyst loading and diethylalkylidene malonates to
maintain an ideal compromise among yield, easy accessibility,
cost and selectivity.
With these optimized conditions in hand we performed an
extensive screening of various aromatic and heterocyclic alkylidene
malonates (Table 2). All substrates underwent smooth reaction
and provided moderate to good yields in spite of incomplete
conversion. The electron withdrawing groups at para-position (p-F
and p-NO2) gave excellent enantioselectivities (ee 98% and 97%) as
well as good conversion (entries 2 and 4). o-Fluoro substrate 5b
also afforded good yield, but enantioselectivity decreased to 76%
(entry 2). p-Cl, o-Cl– and o-Br-phenyl alkylidenes 5e, 5f and 5g gave
good yields (64–69%) with high enantioselectivities (ee 80%, 76%
and 70%; entries 5–7). The enantioselectivity suffered for the
electron donating substrates, p-methyl- and p-methoxy substrates
alkaloids-derived catalysts C, D, E, F assuming that, presence of
bulky aromatic rings and other pendant functionalities may
provide more effective shielding to one enantioface leading to an
increase in enantioselectivity. Indeed we are delighted to report
better result in terms of selectivity and conversion. Cinchonine
and cinchonidine based catalysts C and D showed similar, but
opposite enantioselectivity and provided up to 72% selectivity for
5a (entries 4 and 5). Quinine based catalyst E provided lower yield
as well as selectivity (entry 6); whereas the corresponding dihydro
catalyst F proved to be better with 65% of enantioselectivity (entry
7), but lower than catalysts C and D. Modification of alcoholic
counterpart of malonates provided some interesting results-
i
t
introduction of bulkier Pr and Bu groups saw a lowering of
yields while introduction of the Bn group had no such effect. On
i
the other hand, Pr and Bn groups afforded slightly enhanced
selectivities (entries 8 and 10), while selectivity suffered on
t
modification to Bu group (entry 9).
An extensive solvent study was performed encompassing a
wide range of solvents from polar, non-polar and mixed but the
neat reaction condition turned out to be the best. Notably we
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which showed moderate diastereo- and enantioselectivity. The
method is exemplified with the efficient synthesis of 4-phenyl-
pyrrolidine-3-carboxylic acid ester. Further investigation towards a
more efficient catalyst system and more extensive applications of
this protocol is currently in progress.
Scheme 2 Nitromethane addition to benzylidene acetylacetate 7.
Acknowledgements
We thank DST, New Delhi for providing financial support.
SMA and RM thank CSIR, New Delhi, for their fellowship.
5h and 5i showed moderate ee (entries 8 and 9). This asymmetric
protocol has also been successfully applied to the heteroaromatic
substrates. Their reaction profiles are similar to electron-rich
aromatic alkylidenes, provided good yield of addition products,
but with moderate enantioselectivities (entries 10–12). The
absolute stereochemistry of the adduct 6a was determined to be
‘‘S’’ by comparing the optical rotation {[a]2D5 = +6.12 (c, 1.30,
CHCl3)} with the literature5b,6c data {[a]D25 = +7.30 (c, 1.07, CHCl3)}
and by analogy stereochemistry of other adducts 6 produced by
cinchonine mediated catalyst C was assigned.
This nitromethane addition was also explored to 2-benzylidene
acetylacetate 7, generating an additional chiral center. Under the
same reaction conditions this provided good yield of addition
products 8 with moderate diastereo- and enantioselectivity
(Scheme 2).
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10188 | RSC Adv., 2013, 3, 10185–10188
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