Highly enantioselective aldol reactions using N-arylprolinamides with enhanced acidity and double H-bonding potential

Article abstract of DOI:10.1016/j.tetlet.2009.12.014

We have designed and synthesized N-arylprolinamides 7-10 with a potential to involve in the binding of electrophilic aldehydes via two N-H?O hydrogen bonds for application in organocatalytic aldol reactions. The catalyst 10 is shown to afford aldol produc

Full text of DOI:10.1016/j.tetlet.2009.12.014

Tetrahedron Letters 51 (2010) 912–916
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective aldol reactions using N-arylprolinamides
with enhanced acidity and double H-bonding potential
*
*
Satyajit Saha , Jarugu Narasimha Moorthy
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have designed and synthesized N-arylprolinamides 7–10 with a potential to involve in the binding of
electrophilic aldehydes via two N–HÁ Á ÁO hydrogen bonds for application in organocatalytic aldol reac-
tions. The catalyst 10 is shown to afford aldol products in excellent isolated yields with very high diaste-
reo- and enantioselectivites. In addition to enhanced acidity and double hydrogen bonding, the stacking
interactions of the p-toluenesulfonyl ring in 10 with the electrophilic aldehyde are proposed to stabilize
the transition state.
Received 12 November 2009
Revised 2 December 2009
Accepted 4 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
There is a surge of interest in developing organocatalysts for
enantioselective organic reactions at the present time due to the
advantage associated with obviating the use of scarce and hazard-
ous transition metals.1 Aldol reaction constitutes one of the tre-
mendously explored reactions in the realm of organocatalysis in
general; continued interest in this reaction owes its origin to (i)
the importance of 1,3-dioxygenated aldol products that can be
structurally further elaborated, (ii) significance associated with
C–C bond formation, and (iii) creation of two contiguous chiral
centers with the possibility of regulation of both diastereo- and
enantioselectivity.2 List et al. showed during the initial years of
the ascendency of organocatalysis that very abundant and natu-
bonding in the transition state. In continuation of these studies,
we were inspired to design simple and improved catalysts that fea-
ture two sites for hydrogen bonding of the electrophilic aldehydes.
Herein, we report that N-(o-aminophenyl)prolinamide can be func-
tionalized conveniently to afford a novel set of organocatalysts
with graded H-bonding potential and with/without aryl rings that
may further augment stabilization of the transition state. Of the
four catalysts, that is, 7–10, the tosyl-functionalized prolinamide
10 is shown to afford aldols with remarkable diastereo- as well
as enantioselectivity.
The synthetic routes for all catalysts 7–10 are shown in Scheme
1.9 The catalysts 7, 9, and 1010 were synthesized by DCC-mediated
coupling of N-Boc-protected proline with N-acetyl-, N-mesyl-, and
N-tosyl-protected 1,2-diaminobenzene, followed by deprotection
using TFA. For catalyst 8, Boc-protected N-(2-aminophenyl)-proli-
namide was reacted with triflic anhydride in the presence of trieth-
ylamine to yield Boc-protected derivative, which was subsequently
deprotected by treatment with TFA.
To identify the experimental conditions at which the prolina-
mides 7–10 yield best results, catalyst 10 with tosyl moiety
(20 mol %) was typically employed, and the stereocontrol in the al-
dol reaction of cyclohexanone with p-nitrobenzaldehyde as a rep-
resentative reaction was examined under varied solvent conditions
with and without an additive. All the experiments were uniformly
conducted at 3 1 °C on 0.3–0.4 mmol of p-nitrobenzaldehyde. As
shown in Table 1, best results were observed with DMF as the sol-
vent and with TFA (10 mol %) as an additive; it is noteworthy that
under identical conditions, change of the additive from TFA to cam-
phor sulfonic acid (CSA)/p-toluene sulfonic acid (PTSA)/3,5-dinitro-
benzoic acid (DNBA) led to longer reaction time and/or relatively
poor enantiodiscrimination, cf. Table 1; for example, the reaction
went to completion in 20 h with TFA as an additive, and the reac-
rally occurring (L)-proline regulates enantioselectivity in aldol
reactions, albeit moderately.3 A variety of catalysts with diverse
functional features have since been designed4 and explored for ste-
reoregulation in aldol reactions; these include catalysts with rein-
forced chirality,5 enhanced amide acidity,6 and double hydrogen-
bonding potential7 as shown for some catalysts in Chart 1. A fact
that appears to emerge compellingly as applied to aldol reactions
is that the enhanced acidity of the amide hydrogen contributes
to better enantiodiscrimination.6 We recently showed that (
L)-N-
perfluorophenylprolinamide 6 catalyzes the reaction between
cyclohexanone and a variety of electrophilic aldehydes leading to
aldols in excess of 90% yield and with >95% enantioselectivity.8
The fantastic performance of 6 was attributed, in addition to the
enhanced NH acidity, to the tendency of the perfluorophenyl ring
to lie orthogonally with respect to the amide group, which facili-
tates stronger binding of the electrophilic aldehyde via hydrogen
* Tel.: +91 512 2597438; fax: +91 512 2597436 (J.N.M).
E-mail address: moorthy@iitk.ac.in (J.N. Moorthy).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.014

S. Saha, J. N. Moorthy / Tetrahedron Letters 51 (2010) 912–916
913
O
HN
HO
O
O
O
S
O
N
H
N
H
CH3
N
H
HN
HN
HO
1
2
3
O
F
F
F
F
O
Ph
O
O
N
H
HN
F
N
H
HN
NH HN
Ph
Ph
HO
NH
HN
5
4
6
O
O
O
O
N
H
N
H
N
N
H
HN
HN
HN
HN
HN
H
HN
HN
HN
8
7
10
9
Ts
Tf
Ms
Ac
Chart 1.
COOH
COOH
1)
N
Boc
1)
N
Boc
DCC/DCM
oC to rt 12h
DCC/DCM
p-TsCl, Et3N
DCM
AcCl, Et3N
DCM
HN
NHAc
NH
HN
NHTs
NH
0
oC to rt 12h
TFA/DCM
0
oC to rt
3h
2)
NH2
0
oC to rt
3h
O
0
TFA/DCM
O
2)
AcHN
H2N
NHTs
7
10
COOH
N
Boc
1)
H2N
COOH
Boc
DCC/DCM
oC to rt 12h
NH2
N
DCC/DCM
0
Tf O, Et N
MsCl, Et3N
1)
3
2 DCM
oC to rt 12h
HN
NHMs
DCM
oC to rt
3h
HN
NHTf
0
oC to rt
3h
0
2)
TFA/DCM
O
O
NH
NH
MsHN
NH2
H2N
NH
0
8
9
O
2) TFA/DCM
N
Boc
Scheme 1. Synthetic routes for the preparation of the catalysts 7–10.
tion durations were as long as ca. 60 h with CSA and PTSA. Thus,
the experimental conditions involving the use of DMF, 20 mol %
catalyst, and 10 mol % TFA as an additive were deemed ideal for
enantioselective aldol reactions of ketones with a variety of elec-
trophilic aldehydes. Similar conditions were employed to gauge
the effectiveness of the catalysts 7–9. As shown in Table 2, the to-
syl-prolinamide catalyst 10 was found to be best in terms of reac-
tion durations as well as diastereo- and enantiodiscrimination.
Based on the screening results described above, we employed
the catalyst 10 for enantioselective aldol reactions of a variety of
cyclic as well as acyclic ketones with differently substituted elec-
trophilic benzaldehydes, cf. Table 3. All the aldol reactions were
conducted on 10–15 mmol of the aldehyde at 3 1 °C by employ-
ing 20 mol % tosyl-prolinamide 10 in DMF containing 10 mol %
TFA as an additive.10 The results of the enantioselective aldol reac-
tions are shown in Table 3. As can be seen, cyclohexanone under-
goes aldol reaction with diverse aromatic aldehydes to afford
aldols with a very high anti diastereoselectivity (95–98%). Further,
one obtains the anti aldols with enantiomeric excess higher than
97% (entries 1–10, Table 3). The reaction of cyclopentanone with
p-nitrobenzaldehyde and m-nitrobenzaldehyde leads to aldols
with rather attenuated diastereo- and enantioselectivities (entries
11 and 12). Further, there is a stereochemical reversion in the
sense that the major aldol product corresponds to the one with
syn stereochemistry as revealed by the chemical shifts for the diag-
nostic methine protons of syn and anti diastereomers in the 1H
NMR spectra.5d,8 A similar trend is observed for the reaction of acy-
clic ketone, viz., acetone, with m- and p-nitrobenzaldehydes (en-
tries 13 and 14). The aldols were obtained in 90% optical purity;
the stereochemistry shown in Table 1 was established by compar-
ing their optical rotations and HPLC profiles with those reported in
the literature.5d,8

914
S. Saha, J. N. Moorthy / Tetrahedron Letters 51 (2010) 912–916
Table 1
O
The screening of catalysts 10 for enantioselective aldol reaction between p-
nitrobenzaldehyde and cyclohexanone in various solvents with different additivesa
N
N
H
N
O
CHO
O
OH
O
H
S
catalyst 10
O
O
solvent
additive
O2N
H
NO2
CH3
Scheme 2. Proposed transition state structure for enantioselective aldol reaction
catalyzed by the catalyst 10.
Overall, the observed results are comparable to or even better
than those reported for a variety of organocatalysts.11 What is
more remarkable is the fact that the reactions go to completion
in relatively short durations (ca. 6–12 h) for activated electrophilic
aldehydes. Given that the structural features render the catalyst 10
rather easily accessible synthetically, the observed high diastereo-
and enantioselectivities are indeed remarkable for such simple cat-
alysts.12 Further, the derivatization of proline improves the solubil-
ity to permit application of such catalysts in common organic
solvents as well. Incidentally, the catalyst 10 was earlier synthe-
sized by Fu et al.,13 but was found to mediate the aldol reaction be-
tween o-nitrobenzaldehyde and acetone, in the absence of any
additive, to afford the corresponding aldol in negligible enantio-
meric excess. The better performance of catalyst 10 over analogous
acetyl/mesyl/triflyl derivatives (7–9) should be attributed to some
role of the toluenesulfonyl ring. If acidity were the sole factor, one
should expect the triflic amide catalyst 9 to be equally effective.
We believe that the toluenesulfonyl ring in catalyst 10 may involve
in the transition state stabilization to account for its subtle yet
superior functioning in the stereocontrol of aldol reactions.
Scheme 2 shows our proposed transition state structure, in which
the stacking interaction involving the toluenesulfonyl ring is pre-
sumed to stabilize the transition state.
a
The reactions in all solvents were run on 0.3–0.4 mmol of p-nitrobenzaldehyde
at 3 1 °C under identical conditions by employing 20 mol% of the catalyst 10.
b
Based on p-nitrobenzaldehyde.
From 400 MHz 1H NMR spectroscopy.
c
d
Based on chiral HPLC analyses for the major anti diastereomer.
Table 2
Screening of catalysts 7–10 in direct enantioselective aldol reaction between p-
nitrobenzaldehyde and cyclohexanonea
CHO
O
OH
O
catalyst
solvent
additive
O2N
NO2
In conclusion, we have shown that N-arylprolinamides can be
readily modified to include features that permit double hydrogen
bonding with tunable acidity. It is shown that the catalysts based
on N-(2-aminophenyl)prolinamide perform remarkably well in the
stereoregulation of aldol reactions of cyclic ketones with arylalde-
hydes. The aldols are shown to be formed with high diastereo as well
as enantioselectivities (>96%). The superior performance of the to-
syl-derived catalyst 10 is attributed, in addition to enhanced acidity,
a
The reactions were run on 0.4 mmol of p-nitrobenzaldehyde at 3 1 °C under
identical conditions by employing 20 mol % of the catalyst.
b
Based on p-nitrobenzaldehyde.
From 400 MHz 1H NMR spectroscopy.
c
d
Based on chiral HPLC analyses for the major anti diastereomer.
Table 3
Results of enantioselective Aldol reactions with catalyst 10a
Entry
Product
Time (h)
20
Yieldb (%)
94
anti:sync
eed (%)
>98
O
OH
1
97:3
O2N
O
OH
OH
2
3
20
20
92
86
98:2
98:2
>98
>99
NO2
NO2
O

S. Saha, J. N. Moorthy / Tetrahedron Letters 51 (2010) 912–916
915
Table 3 (continued)
Entry
Product
Time (h)
84
Yieldb (%)
anti:sync
eed (%)
OH
O
4
74
95:5
98
Cl
OH
O
5
6
7
8
50
84
50
22
50
47
84
78
96:4
95:5
97:3
95:5
>98
97
Br
OH
O
F
OH
O
>99
97
F3C
OH
O
NC
OH
O
9
6
6
88
82
98:2
97:3
>97
98
N
OH
O
10
N
OH
O
11
36
82
30:70
84
NO2
OH
OH
O
12
13
36
12
80
80
30:70
85
90
O2N
O
CH3
—
O2N
OH
O
CH3
14
12
78
—
90
NO2
a
All reactions were run on a 0.5–0.7 mmol scale at 3 1 °C with 20 mol % of the catalyst and 10 mol % of TFA in DMF (0.8–1.5 mL) containing TFA (10 mol %).
Based on aldehyde.
b
c
Ratios of diastereomers were calculated based on integrations in the 1H NMR spectrum of the crude reaction mixture in each case.
d
The ee values were calculated from HPLC profiles of the silica gel column-purified enantiomeric mixture of the anti diastereomer. The values reported are for the major
anti diastereomer.
to the participation of the toluenesulfonyl ring in the stabilization of
the transition state via stacking interactions. We are currently
exploring how double hydrogen bonding based on the design dem-
onstrated herein may augment enantioselective organocatalytic
processes accomplished by bifunctional proline-derived catalysts.
Acknowledgments
J.N.M. is thankful to the Department of Science and Technology
(DST), India, for funding through Ramanna fellowship. S.S. is grate-
ful to CSIR, India, for a senior research fellowship.

916
S. Saha, J. N. Moorthy / Tetrahedron Letters 51 (2010) 912–916
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