Peptidomimetic organocatalysts: Efficient Michael addition of ketones onto nitroolefins with very low catalyst loading

Article abstract of DOI:10.1039/c4ra04165h

The syntheses of two novel peptidomimetic triazole-based organocatalysts that work for the asymmetric conjugate addition of cyclohexanone to nitroolefins are described. The catalysts worked with very low loading (0.5 mol%) in the absence of any additives

Full text of DOI:10.1039/c4ra04165h

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Peptidomimetic organocatalysts: efficient Michael
addition of ketones onto nitroolefins with very low
Cite this: RSC Adv., 2014, 4, 30325
catalyst loading†
a
Srivari Chandrasekhar, Chintakunta Praveen Kumar,a Togapur Pavan Kumar,a
Received 6th May 2014
Accepted 19th June 2014
*
Kothapalli Haribabu, Bharatam Jagadeesh, Jerripothula K. Lakshmib
and Prathama S. Mainkar
a
b
*
a
*
DOI: 10.1039/c4ra04165h
www.rsc.org/advances
The syntheses of two novel peptidomimetic triazole-based organo- to design and synthesize new scaffolds, which could exhibit
catalysts that work for the asymmetric conjugate addition of cyclo- improved organocatalytic properties. We conceived that the
hexanone to nitroolefins are described. The catalysts worked with very triazole ring, which is an amide bond surrogate,7 may
low loading (0.5 mol%) in the absence of any additives to provide high contribute to form a rigid backbone conformation and thus
diastereo- and enantio-selectivities.
promote selectivity. We further anticipated that the enhanced
number of nitrogen atoms would also have an inuence on the
basicity of the catalysts. An additional amino-acid appendage as
proposed by Wennemers et al.,8 would hopefully provide
hydrogen bonding. With this background, we initiated the
synthesis of pyrrolidine-linked triazole having an isoaspargine
amino acid appendage by following the synthetic strategy as
depicted in Scheme 1.
Thus, known azidopyrrolidine 1,9 was subjected to a thermal
Huisgen [3 + 2] cycloaddition in the presence of ethyl propiolate
to furnish two regioisomeric triazoles 2 and 2a in 28 : 72 ratio,
easily separable by chromatography. Both the isomers (1,5- and
1,4-disubstituted triazoles) were independently transformed to
corresponding acids 3 or 3a followed by coupling with iso-
aspargine 4, under N-(3-dimethylaminopropyl)–N0-ethyl-
carbodiimide hydrochloride (EDCI), hydroxybenzotriazole
(HOBt) conditions to realise pyrrolidine-triazoles 5 or 5a.
Hydrogenation of benzyl ester to 6 or 6a followed by treatment
with TFA furnished 7 or 7a.
Wennemers et al.8 have extensively studied organocatalysts
based on turn-inducing D-proline–L-proline dipeptide10 and
have recently reported a novel, highly efficient tripeptide orga-
nocatalyst, exhibiting a hydrogen bond with isoaspargine.
Some of the structural demands for high efficiency have been
put forth by the group. These studies suggested that 2ꢀ amine at
the N-terminus, the carboxylic acid side chain of the aspartic
acid residue and a well-dened turn conformation are crucial
for high catalytic activity and selectivity. Other groups working
in the area of organocatalysis have proposed a different set of
rules for activity, where the turn induction and/or hydrogen
bonding are not featured.11 Thus, based on these studies, it can
be inferred that organocatalysis works either by turn induction,
thereby forming a pocket, or in a second instance, without these
properties but with hydrogen bonding. The catalyst synthesized
The asymmetric organo-catalyzed aldol and Michael reactions
have co-developed in the recent past and paved way for a new
era in asymmetric synthesis.1 Major challenges in organo-
catalysis still to be addressed include the ease of access to
catalyst and its cost, substrate generality and more importantly,
catalyst loading. Many of the organocatalysts are substrate/
reaction specic, involve multiple steps for synthesis, incorpo-
rate sensitive functionalities and are difficult to recover. Thus,
the eld is wide open for further innovations. The early exam-
ples of organocatalytic asymmetric transformations utilized 20
–50 mol% of proline as the catalyst.2 At that time, the recovery of
the amino acid was not a criterion for most researchers. With
the exploration of newer synthetic scaffolds as catalysts, which
were available in smaller quantities, the recovery and recycling
of the catalyst became a priority. In addition, experimentation
with lower concentrations of catalysts were initiated to mimic
reactions in nature. Several groups,3 including ours,4 working in
the area of organocatalysis have developed catalysts, which are
required in the ratios of 1 –10 mol% for a reaction to be fruitful.
Recently, small and medium peptides have been established as
organocatalysts.5 Our work on peptidomimetics and turn-
inducing properties of the unusual b-amino acids6 inspired us
aDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad, 500007, India. E-mail: srivaric@iict.
res.in; Fax: +91-40-27160512
bCentre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad, 500007, India. E-mail: bj@iict.res.
in; Fax: +91-40-27160512
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization, NMR spectra of compounds, HPLC chromatograms, details of
NMR and DFT studies. See DOI: 10.1039/c4ra04165h
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Fig. 1 ROE-restrained minimum energy structures for catalyst 7 (1a)
and 7a (1b).
Scheme 1 Synthesis of catalysts 7 and 7a.
250 conformations and superimposed. The structures
predominantly show single conformation, which is a turn-like
compact structure. A similar process followed for the 1,4-tri-
azole catalyst 7a, also shown in the Fig. 1b, and the results
showed that 7a adopts an extended conformation, in contrast to
7 (Fig. 1).
The detailed NMR investigations followed by ROE-restrained
molecular dynamics10 established that 1,5-disubstituted
compound 7 adopts a relatively compact turn-like conformation
(Fig. 1a), whereas the other isomer (1,4-disubstituted) 7a
exhibited an extended conformation (Fig. 1b). Either of these
properties is generally required for the asymmetric organo-
catalytic properties. To have sufficient material on hand, we
have conducted experiments with ruthenium and copper cata-
lysts, which exclusively gave 1,5- or 1,4-di-substituted-1,2,3-
triazoles.12–14
It is anticipated that the observed turn structure of 1,5-tri-
azole catalyst 7 may favour its terminal isoaspargine appendage
to participate in hydrogen bonding with the nitro group of
nitrostyrene, a stabilizing factor akin to that observed for D-Pro–
L-Pro–Asp–NH2, for an improved catalytic performance of the
catalyst.12 To prove this, a reaction was carried out between
cyclohexanone (8) and nitrostyrene (9) in presence of catalyst 7
(5 mol%) and CH2Cl2 as solvent, which resulted in 10 in 55%
yield with >99% er (Table 1, entry 1). To optimise the reaction
conditions, the solvents used were water, acetonitrile, iso-
propanol and methanol (Table 1, entries 3, 5, 9 and 11). A neat
reaction was also carried out with similar results (Table 1, entry
7). Among the solvents tried, methanol was found to give the
optimal conditions of yield and selectivity. Therefore, all
subsequent reactions were carried out in methanol. As the
catalyst performed well at 5 mol%, we were interested to see the
effect of further reduction in catalyst loading.
by Wennemers et al.8 falls in the rst category, which works at a
low concentration (<1.0 mol%). Computational models have
also been put forth to generalise the essential requirements for
organocatalytic properties, particularly for Michael-type
reactions.11
Before embarking on studying the efficiency of the catalysts
synthesized, a detailed NMR investigation was taken up for both
compounds to understand the turn pattern and hydrogen-
bonding properties. Information on the preferred conformation
of 1,5-triazole catalyst has been obtained at a concentration of
approximately 5 mM in two independent structure-supporting
solvents: water (90% D2O + 10% H2O) and CD3OH, by using 1D
and 2D (1H, COSY, TOCSY, and ROESY) NMR spectroscopy
techniques. A signicant number of intra-residue H–H ROEs is
observed for 1,5-triazole catalyst 7. Specically, the observed
unambiguous ROEs (Fig. 1a) for 7: 10H–13H, 13H–(16Hi and
16Hj), 13H–17Hk, 14H–16Nhi, 10H–6Hh, 5H–6Hg, and 6Hg–
2Hb are helpful in determining the conformation (Fig. 1a). In
order to delineate low-energy structures, ROE-restrained
molecular dynamics studies have been carried out using
simulated annealing protocol (insight II). Initially the input
structures are rapidly heated from 300 K to 900 K, allowing the
structure to remain at 300 K, 600 K and 900 K for 5 ps. The
velocity-scaling temperature-controlling method was adopted
for heating, and the temperature was allowed to vary by an order
of 10 K. The velocity verlet integration method was used for
integration. Further, the structures were slowly cooled from 900
K to 300 K by allowing the structures to remain for 5 ps at 800 K,
700 K, 600 K, 500 K, 400 K and 300 K. The cycle of simulated
annealing is repeated 250 times, and the nal structures were
stored. Fieen low-energy structures were selected among the
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Table 1 Study of catalyst loading and solvent effect
Entry
Catalysta [mol%]
Solvent
Time [h]
Yieldb [%]
drc
erd
1
2
3
4
5
6
7
8
7 (5)
7a (5)
7 (5)
7a (5)
7 (5)
7a (5)
7 (5)
7a (5)
7 (5)
7a (5)
7 (5)
7a (5)
7 (2)
7a (2)
7 (1)
CH2Cl2
CH2Cl2
H2O
30
32
30
35
16
24
30
30
30
35
30
35
35
39
40
45
48
52
55
50
72
70
93
90
92
90
95
91
96
94
82
79
82
78
80
78
90 : 10
93 : 7
97 : 3
95 : 5
92 : 8
93 : 7
92 : 8
94 : 6
96 : 4
94 : 6
97 : 3
95 : 5
97 : 3
92 : 8
97 : 3
91 : 9
96 : 4
90 : 10
>99
91 : 9
99 : 1
99 : 1
96 : 4
95 : 5
97 : 3
96 : 4
97 : 3
96 : 4
97 : 3
91 : 9
97 : 3
91 : 9
97 : 3
86 : 14
98 : 2
96 : 4
H2O
CH3CN
CH3CN
—
—
9
MeOH
MeOH
iPrOH
iPrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
10
11
12
13
14
15
16
17
18
7a (1)
7 (0.5)
7a (0.5)
a
b
Reactions were performed at rt. Isolated yield aer column chromatography. c Determined by HPLC. d Determined by chiral HPLC.
At rst, catalyst loading was decreased to 2 mol% and aer Initially, the fully relaxed minimum energy structures of 1,5-
obtaining results similar to 5 mol%, the loading of catalyst was triazole catalyst 7, 1,4-triazole catalyst 7a and nitrostyrene
further reduced to 1 mol% and then to 0.5 mol% (Table 1, obtained from simulated annealing are subjected to optimiza-
entries 13, 15 and 17). To our surprise, even for 0.5 mol%, tion at B3LYP/6-31*-level DFT calculations. The optimization
catalyst loading dr and er were retained. but the yield was was initially carried out in vacuum and then in a MeOD solvent,
slightly lower (95% to 80% for 0.5 mol%). These results by adopting polarisable continuum model (PCM). These served
surprised us as the use of 0.5 mol% of catalysts is rarely as inputs (reactants) for computing transition-state structures.
reported in literature for aldol reactions and conjugate addition
of aldehydes but not for the Michael reaction of ketones to enamine to the si and re faces of nitrostyrene were rst located
nitroolens.15
in the gas phase. These transition states are labelled a-re, a-si, s-
The transition states for the addition of anti- and syn-
A very low loading of the catalyst, the striking feature re, and s-si. The noticeable charge separation in the transition
observed in this study, has prompted us to explore the scope of state is expected upon the addition of enamine to nitrostyrene.
the catalyst by studying its effect on different substrates for To obtain improved estimates of the reaction, energetic
wider application. Thus, substituted aromatic, heteroaromatic continuum solvent effects are incorporated by computing the
nitroolens were coupled with cyclohexanone, 8, using catalyst zero-point energies by using PCM with methanol as the
7, and it was observed that the outcome of these reactions was medium. The preferred transition-state structures arising from
similar to the rst reaction of nitrostyrene (Table 2, entries 1 to anti-enamine for both the catalysts are depicted in Fig. 2.
10). We next changed the ketones to thiopyranone and acetone
On the basis of the DFT results, a mechanism is proposed to
to get products in good to average yields (Table 2, entries 11 to account for the observed stereoselectivity. The free acid of 7
14). Based on these observations one can conclude that both behaves as a bifunctional catalyst. The proline ring rst reacts
electron-donating and -withdrawing groups had negligible with cyclohexanone carbonyl group to form an enamine with
effect on the stereoselectivity of the reaction. This conrms a the help of an acidic co-catalyst. Subsequently, in the compact
wider applicability of the catalyst and non-participation of the turn structure of 7, the proton of the terminal acid hydroxyl
substituents or ring structure of the nitroolen.
group interacts with the nitro group of nitrostyrene, through
Interestingly, catalyst 7a having no turn structure was only hydrogen-bonding. The transition state involving the re-face
marginally inferior to 7 (Tables 1 and 2). DFT computations at attack on the anti-enamine (Fig. 2) was lower in energy than
the B3LYP/6-31G* level provided more insights into the catalytic other possible transition states (anti-si, syn-re, and syn-si).
activities of 7 and 7a.11,12 Standard protocols for observing Whereas, in case of 7a, there is no hydrogen-bond interaction
transition states are followed, by using Gaussian 09 soware. between the acid hydroxyl group of catalyst and the nitro
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Table 2 Substrate variation for catalysts 7 and 7a
Entry
1
Product
Catalysta
Time [h]
Yieldb [%]
drc
erd
7
7a
45
50
52
50
96 : 4
95 : 5
94 : 6
94 : 6
7
7a
42
49
72
69
90 : 10
88 : 12
93 : 7
89 : 11
2
3
4
7
7a
40
46
72
68
97 : 3
93 : 7
87 : 13
84 : 16
7
7a
40
45
68
65
97 : 3
94 : 6
79 : 21
75 : 25
7
7a
48
54
64
60
94 : 6
93 : 7
96 : 4
91 : 9
5
6
7
7
7a
42
46
65
60
93 : 7
95 : 5
96 : 4
95 : 5
7
7a
40
46
71
65
95 : 5
94 : 6
91 : 9
88 : 12
7
7a
42
46
70
67
95 : 5
93 : 7
99 : 1
97 : 3
8
9
7
7a
42
49
66
60
90 : 10
81 : 19
82 : 18
68 : 32
7
7a
48
52
73
69
97 : 3
94 : 6
95 : 5
95 : 5
10
7
7a
47
53
70
66
96 : 4
95 : 5
93 : 7
89 : 11
11e
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Table 2 (Contd.)
Entry
Product
Catalysta
Time [h]
Yieldb [%]
drc
erd
7
7a
52
57
50
45
—
—
68 : 32
65 : 35
12e
13
7
7a
50
55
56
50
—
—
68 : 32
63 : 37
7
7a
50
56
53
50
—
—
69 : 31
67 : 33
14e
a
b
All reactions were performed at room temperature in MeOH with 0.5 mol% loading of catalyst 7 and 7a. Isolated yield aer column
c
d
e
chromatography. Determined by HPLC. Determined by chiral HPLC using chiral-IA column 250 ꢁ 4.6 mm. Determined by chiral HPLC
f
using Chiralpak-IC. The stereochemistry of known compounds was conrmed by comparing optical rotation values with those reported in
literature.16
group of nitrostyrene to provide an additional stabilisation
factor, thus the 7a transition states are higher in energy than 7
(Table 3).
Conclusions
In conclusion, we report the syntheses of two compounds,
which have a peptide bond surrogate triazole between a pyrro-
lidine methylene and isoaspargine, which proved to be excellent
catalysts for Michael-addition reactions. The low loading of the
catalyst, a little explored area of organocatalysis, is the highlight
of this work. Catalyst 7 appears to be following the mechanism
established for tripeptides by a turn-like conformation and
thereby an intra-molecular hydrogen bonding; 7a appears to be
in the category of proline and proline-derived catalysts, which
do not depend on turn-like conformation for activity. These
results suggest that catalysts having turn-inducing and
hydrogen-bonding properties would have slightly superior
organocatalytic activity compared with catalysts having either
one of the characters. The applications of these catalysts for
other reactions are currently being explored.
Fig. 2 Preferred transition states for 7 and 7a.
Acknowledgements
¨
C.P.K. thanks Prof. Helmut Hugel and Dr Julie Nieri of RMIT for
their suggestions. T.P.K. thanks DST New Delhi for the INSPIRE
Faculty Award (IFA12-CH-30). The authors thank CSIR and DST
for funding.
Table 3 Energies for the preferred transition states of 7 and 7a
Transition state
energy (Hartree)
Transition state
energy (Kcal molꢂ1
)
Notes and references
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