N-Prolinylanthranilic acid derivatives as bifunctional organocatalysts for asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tet.2011.04.033

Several N-prolinylanthranilic acid derivatives were prepared and tested as bifunctional organocatalysts in the direct asymmetric aldol reaction of cyclohexanone with p-nitrobenzaldehyde. It was found that methyl substitution ortho to the carboxylic acid i

Full text of DOI:10.1016/j.tet.2011.04.033

Tetrahedron 67 (2011) 3969e3975
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Prolinylanthranilic acid derivatives as bifunctional organocatalysts
for asymmetric aldol reactions
*
Anthony J. Pearson , Santanu Panda
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several N-prolinylanthranilic acid derivatives were prepared and tested as bifunctional organocatalysts
in the direct asymmetric aldol reaction of cyclohexanone with p-nitrobenzaldehyde. It was found that
methyl substitution ortho to the carboxylic acid improves enantioselectivity, but substitution ortho to the
anilide group does not. The catalyst derived from 2-amino-6-methylbenzoic acid was tested over a range
of direct asymmetric aldol reactions and its overall performance is equal to or better than many of the
known prolinamide catalysts in terms of yield, diastereoselectivity, and enantioselectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 February 2011
Received in revised form 7 April 2011
Accepted 11 April 2011
Available online 16 April 2011
Keywords:
Asymmetric aldol reaction
Organocatalysis
Prolinamide
Anthranilic acid
1. Introduction
great advantage to using proline is that it is inexpensive and readily
available as either enantiomer, but its solubility properties limit its
Organocatalysis is currently one of the most rapidly growing
areas of organic synthesis research, and one entire recent issue of
Chemical Reviews was devoted to this topic.1 The use of organo-
catalysts promises to allow organic reactions to proceed with high
selectivity (regio and stereo) without the intervention of organo-
metallic catalysts, some of which pose problems for use on large
scale, and their eventual disposal. Moreover, recent developments
in organocatalysis have shown that some can be used effectively in
aqueous solution,2 said to be a desirable environmentally benign
property, although this has been the subject of some debate be-
cause the water that is used for such reactions is contaminated and
cannot be discarded without scrubbing.2d This paper focuses on the
development of some new proline-derived organocatalysts for
asymmetric aldol reactions. The aldol reaction is one of the most
important CeC bond-forming reactions in organic synthesis (and
indeed in biosynthesis of many important classes of compounds).
compatibility with many aldol substrates. While proline does cat-
alyze aldol reactions in water, racemic products are usually obtai-
ned.2j In addition, proline has a pronounced tendency to form
oxazolidinones by reaction with the aldol substrates, thus poten-
tially impairing its catalytic efficiency under certain conditions.5
Consequently, modifications of this system have been of consider-
able recent interest.6
Many modified proline systems are amide derivatives of the
proline carboxylate group that incorporate auxiliary chiral moie-
ties, some of which are either expensive or require multistep syn-
thesis. Simple prolinamide catalysts (as opposed to proline itself)
rely on weak hydrogen bonding from the amide NH to activate the
aldehyde partner in the transition state.7 N-Prolinyl-2-amino-
phenol derivatives have been studied for enantioselective aldol
reactions, utilizing the additional hydrogen bonding offered by the
phenol/amide combination, but these met with modest success.8
Improved results were obtained by modification of the pyrroli-
dine ring of proline, introducing a 3-alkoxy substituent.9 Our own
The earliest example of the use of L-proline to promote asymmetric
aldol reactions is the intramolecular version published by Eder and
co-workers in 1971, and also by Hajos and Parrish in 1974 (both
groups were awarded German patents in 1971).3 More recently, List
approach is to employ the secondary amine of L-proline as the
functional catalytic unit and an anthranilic acid moiety to provide
a carboxylic acid group (structures 1e6). The resulting prolinamide
has two important hydrogen bonding units: the NH of the amide
and the OH of the carboxylic acid unit. These functionalities were
anticipated to act in concert to give an ordered enamine/aldehyde
reaction transition state, as a result of the structural rigidity of the
aromatic template, to activate the substrates and promote high
diastereoselectivity and enantioselectivity for the aldol reaction.
and co-workers introduced the use of L-proline as a catalyst for
asymmetric intermolecular aldol reactions.4 The mechanism of the
proline-catalyzed reaction, which proceeds via the formation of
a pyrrolidine enamine of the ketone nucleophile and its subsequent
reaction with the aldehyde electrophile, is well understood. The
* Corresponding author. E-mail address: ajp4@case.edu (A.J. Pearson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.033

3970
A.J. Pearson, S. Panda / Tetrahedron 67 (2011) 3969e3975
This idea is illustrated by the schematics for TS A and TS B, the
former being the accepted transition state for proline-catalyzed
aldol reactions, the latter being our proposed modification.
obtained with 12 mol % of TFA and 50 mL of water (ca. 1400 mol %
relative to p-nitrobenzaldehyde) (entry 11). While incorporation of
a methyl group ortho to the acid (catalyst 2) improves the enantio-
Me
H
N
N
H
R
H
N
H
N
NH
NH
NH
O
O
H
O
O
O
O
CO2H
TS A
CO2H
CO2H
Me
2
1
3
N
H
R
H
N
H
N
NH
H
N
O
NH
O
(R)
NH
O2N
H
N
O
CO2H
O
O
O
CO2H
H
CO2CH2Ph
NO2
6
O
4
5
TS B
R
In addition, we designed a selection of molecules that would
probe the effects of steric bias close to the functional centers of the
catalyst (2 and 3 compared with 1), whether or not the carboxylic
acid is a contributing structural component (ester 4 vs 1), and
whether catalyst activity is affected by acidity of the carboxyl group
(5 vs 1, and 6 vs 2). As far as we are aware, such anthranilamide
derivatives have not been previously investigated as aldol catalysts,
the closest reported analogs being oxazolines derived from the
carboxylate group of catalyst 1, which afforded rather modest
enantioselectivities for the aldol reactions of cyclohexanone with
a range of substituted benzaldehydes.10
selectivity, methyl substitution ortho to the anilide (catalyst 3)
lowers the enantioselectivity somewhat relative to the parent
compound 1 (entry 13 vs 15). That the carboxylic acid indeed plays
an important role in this reaction was confirmed by testing catalyst
4, for which the reaction was very sluggish and gave poorer enan-
tioselectivity (entry 14 vs 15). Thus, activation by hydrogen bonding
expected for the amide/acid combination makes a significant con-
tribution to both reaction rate and enantioselectivity. On the other
hand, increased acidity of the pendant carboxyl group, as in catalysts
5 and 6, does not improve the outcome, in terms of both conversion
and enantioselectivity (entry 16 vs 15, and 17 vs 11); the superior
performance of catalyst 6 compared with 5 again indicates the im-
portance of substitution ortho to the carboxyl group, as for catalyst
2 versus 1. Reducing the amount of catalyst gave the expected rate
reduction and a small reduction in enantioselectivity (entries 18 and
19, catalyst concentration is mol % relative to p-nitrobenzaldehyde).
Based on the results in Table 1, we chose catalyst 2 at 10 mol %
loading for further study.
2. Results and discussion
Synthesis of each catalyst requires only 2e3 steps (two steps for
the best catalyst, 2, see Eq. 1: amide coupling11 between the
anthranilic acid derivative and L-proline-N-Cbz using phosphorus
oxychloride and pyridine at ꢀ10 ꢁC afforded the Cbz-protected
prolinylanthranilic acid derivative, which was shown to be opti-
cally pure by chiral HPLC analysis; hydrogenolytic removal of the
Cbz protecting group completed the synthesis of the catalyst;
others are detailed in the Experimental section).
Table 1
Optimization of catalyst and conditions
O
CHO
O
OH
Catalyst (10 mol %)
+
DMSO/H2O/CF3CO2H
NO2
NH2
1) L-proline-NCbz,
POCl3, py
NH
H
N
NO2
Anti (major diastereomer)
ð1Þ
COOH
O
2) H2, Pd-C, EtOH
Me
COOH
Entry Catalyst TFA (mol %) Water (
m
L) Conversion (%) eec [anti] (%)
Me
1a
1
1
1
2
2
2
2
2
2
2
2
2
3
4
1
5
0
5
5
0
5
20
0
20
20
0
20
15
82
15
10
52
70
80
85
30
100
42
75
10
80
85
90
55
20
68
72
75
78
89
90
92
94
97
95
98
94
82
78
85
80
95
93
95
2
2a
3a
First, the reaction conditions were screened for enantioselective
aldol reaction between cyclohexanone and p-nitrobenzaldehyde
using DMSO as solvent (Table 1). In the presence only of catalyst 1, no
reaction occurred. Various additives, such as water, amines, and
carboxylic acids, have previously been shown to improve the yield
and ee from proline-catalyzed aldol reactions.12 With added water,
the reaction proceeded but with low conversion and poor enantio-
selectivity (entry 1). By using TFA as an acidic additive in the absence
of water, the enantioselectivity increased somewhat but the yield
was still low (entry 2). Combination of TFA and water promoted the
reaction with high yield and good enantioselectivity (entry 3; TFA
showed the best results compared to other acidic additivesdsee
later). Catalyst 2 gave higher enantioselectivity compared with
catalyst 1 under identical conditions, though the reaction was no-
ticeably slower (entries 4, 5, 6 vs 1, 2, 3, respectively; reaction time
for all entries was 72 h, so conversions, estimated from 1H NMR of
the crude product mixtures, qualitatively reflect relative rates).
Lowering the temperature improved the yield and enantiose-
lectivity (entry 7 vs 6). Varying the amount of TFA and water also
affected the yield and enantioselectivity, optimum results being
4a
5a
6a
5
5
20
20
20
20
20
50
100
50
50
50
50
50
50
50
7b
8b
10
12
20
12
12
12
12
12
12
12
12
12
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
6
2 (5%)
2 (2%)
a
Unless specified otherwise, the concentration of aldehyde is 0.13 M, and v/v of
cyclohexanone/DMSO is (1:4), the reactions were run at room temperature.
b
Unless specified otherwise, the concentration of aldehyde is 0.40 M, and v/v of
cyclohexanone/DMSO is (1:4), the reactions were run at
DMSO¼0.4 mL. Reaction time¼72 h.
4
ꢁC. Volume of
c
Enantiomeric excess was determined using CHIRALPAK AD-H column; the dr
varied between 5:1 (anti/syn) to 10:1 (anti/syn), determined by 1H NMR.

A.J. Pearson, S. Panda / Tetrahedron 67 (2011) 3969e3975
3971
DMSO as the solvent for these reactions has some limitations
with regard to optimization of selectivity because it cannot be used
(except as a co-solvent) at low temperatures, e.g., ꢀ78 ꢁC, at which
one might expect improvements in both diastereoselectivity and
enantioselectivity. While DMSO and DMF are commonly used for
aldol reactions catalyzed by proline and its derivatives, these sol-
vents are generally considered to be problematic for large scale
reactions because of inconvenient work-up and solvent removal/
recovery, and there has been some effort to develop catalysts that
can be used in THF or dichloromethane13 (in which proline has very
low solubility). Mindful of these issues, we examined the reaction
of cyclohexanone with p-nitrobenzaldehyde, using catalyst 2 in the
presence of TFA and water (per Table 1, entry 11) at 4 ꢁC, in a se-
lection of solvents typically used for this reaction with other cata-
lysts. The results (Table 2) indicate that DMSO is the best solvent for
this particular catalyst.
essentially self explanatory, confirming that TFA is much better
than other carboxylic acids, there being a qualitative correlation of
enantioselectivity with acidity of the carboxylic acid used. Aryl-
sulfonic acids give poor conversion, but again show that the
stronger acid gives better ee. The use of the much stronger acid HCl
essentially shuts down the reaction, likely due to complete con-
version of the proline residue to its ammonium salt, thereby pre-
venting formation of the requisite enamine. We suggest that these
results might reflect a pH-dependent equilibrium between various
forms of the amine/acid structure that leads to an optimum con-
centration of the most active form of the catalyst for best yield and
selectivity.
Table 3
Aldol reaction of cyclohexanone with p-nitrobenzaldehyde in DMSO using various
acid additives
Entry
Additivea
Conversionb (%)
anti/syn ratiob
eec [anti] %
1
2
3
4
5
6
7
8
9
10
TFA
100
80
85
70
70
100
50
10
15
<5
15:1
12:1
5:1
8:1
8:1
10:1
8:1
8:1
10:1
nd
98
94
88
80
78
82
58
75
52
nd
Table 2
CCl3CO2H
2,4-DNBd
HCO2H
PhCO2H
CH3CO2H
Salicylic
2,4-DNBSe
p-TsOH
HCl
Aldol reaction of cyclohexanone with p-nitrobenzaldehyde in different solvents
Entry
Solventa
Conversionb (%)
anti/syn ratiob
eec [anti] (%)
1
2
3
4
5
6
7
8
9
DMSO
DMF
100
90
20
80
90
30
20
60
40
15:1
12:1
10:1
20:1
5:1
4:1
8:1
12:1
10:1
98
93
45
73
70
20
48
55
78
CH2Cl2
THF
Neatd
MeOH
H2O
a
All reactions were run under the general conditions noted for Table 1 entry 11,
using 12 mol % of the acid additive over p-nitrobenzaldehyde.
Brine
b
Conversion and diastereomeric ratios were estimated from the 1H NMR
H2O/ketonee
spectrum of the crude product mixture.
a
c
All reactions were run under the general conditions noted for Table 1, entry 11,
but replacing DMSO with the solvent noted.
Determined by HPLC on CHIRALPAK AD-H column.
2,4-Dinitrobenzoic acid.
2,4-Dinitrobenzenesulfonic acid.
d
b
e
Conversions and diastereomeric ratios at 72 h reaction time were estimated
from the 1H NMR spectrum of the crude product mixture.
c
Determined by HPLC on CHIRALPAK AD-H column.
Cyclohexanone was used as the solvent.
A mixture of water and cyclohexanone (1:1 v/v) was used as the solvent.
d
The scope and limitations of direct aldol reaction of cyclohexa-
none with various aromatic aldehydes, catalyzed by 2, were next
explored (Table 4). Benzaldehydes substituted by p-nitro, p-tri-
fluoromethyl and o-nitro afforded the anti products with high
diastereo- and enantioselectivity (entries 1e3). The aldol reaction
of o-nitrobenzaldehyde and cyclohexanone afforded 85:1 dr, 99%
ee, and excellent yield (entry 3), which illustrates the benefits of
using a sterically hindered aldehyde, and compares very favorably
with the best catalysts reported in the literature.12d,15 Less reactive
benzaldehydes were also studied. Using p-bromo- or m-chlor-
obenzaldehyde the anti products were obtained in modest/good
yield and 95% ee (entries 4 and 5), while benzaldehyde itself
reacted with good dr, good ee but modest yield (entry 6). Pyridine
aldehydes (entries 7 and 8) are also good substrates16 affording
high ee’s. There is a marked difference in the diastereoselectivities
for 4-pyridinal versus 2-pyridinal, presumably reflecting less steric
demand in the latter as a result of the missing ortho hydrogen
compared to the 4-isomer.
We also studied the aldol reaction with various ketones using
selected reactive aromatic aldehydes (Table 5). The aldol reaction
between dihydro-2H-thiopyran-4(3H)-one (a valuable surrogate
for 3-pentanone which, after desulfurization leads to propionyl
aldol products with good selectivity12b) and substituted benzalde-
hydes gave the anti products with somewhat variable diaster-
eoselectivities, but uniformally high ee’s for the anti products. Best
results were obtained using p-trifluoromethylbenzaldehyde, which
afforded 98% ee and 30:1 dr ratio (entry 2). In the case of o-nitro-
benzaldehyde the yield and enantiomeric excess was very good but
the dr was unexpectedly modest (entry 3). At the present time this
difference in behavior of cyclohexanone versus its sulfur analog is
not understood.
e
As seen from Table 2, DMF is also a reasonable solvent for this
reaction (entry 2), but dichloromethane leads to slow reaction
(poor conversion after 72 h) and only modest enantioselectivity,
although the diastereomeric ratio is quite acceptable (entry 3).
Tetrahydrofuran as solvent (entry 4) works well in terms of con-
version and diastereoselectivity, but again the ee is low compared
to DMSO. We were unable to improve selectivity using DCM and
THF at low temperature because catalyst 2 precipitated from so-
lution upon cooling. Omission of solvent (entry 5) allows faster
conversion, but poorer diastereoselectivity and ee, while methanol
as solvent is not useful (entry 6).
The results of reaction in water are actually fairly encouraging
(entry 7), given the poor performance of proline itself under
aqueous conditions,2j and suggest that future catalyst engineering
might afford systems that perform well under these conditions (we
independently tested L-proline under aqueous conditions identical
to those used for entry 7 and observed no conversion to aldol
products after several days reaction time). A significant improve-
ment was noted when brine was used as solvent instead of water
(entry 8). With high concentration of cyclohexanone in water
(entry 9), reasonable conversion rate was observed and good ee and
diastereoselectivity were obtained. Given the superior performance
of DMSO for this reaction using catalyst 2, we elected to use this
solvent for the next set of investigations, which probed the use of
acid additives other than TFA.
In order to determine whether trifluoroacetic acid is the opti-
mum acidic additive for this reaction using catalyst 2, we tested
several alternatives that have also been shown to be effective in
prolinamide-catalyzed aldol reactions12c,14 (Table 3). The results are
With cyclopentanone as the aldol donor the reaction worked
well with all three benzaldehydes, for example, reaction with

3972
A.J. Pearson, S. Panda / Tetrahedron 67 (2011) 3969e3975
Table 4
Table 5
Direct aldol reactions of cyclohexanone with various aromatic aldehydes in the
Direct aldol reactions between selected ketones and aromatic aldehydes in the
presence of catalyst 2
presence of catalyst 2
Entry
1
Product
Yielda (%)
92
anti/syn ratiob
eec [anti] (%)
Entry
1
Product
Yielda (%)
88
anti/syn ratiob
eec [anti] (%)
O
OH
O
OH
15:1
98
5:1
94
NO2
CF
S
NO2
CF3
O
OH
O
OH
2
88
10:1
99
2
78
30:1
98
S
O
S
OH NO2
O
OH NO2
3
4
84
68
85:1
9:1
99
95
3
4
92
85
2:1
97
99
O
O
OH
OH
O
O
OH
OH
1.2:1
Br
Cl
NO2
CF3
5d
58
56
96
6:1
13:1
28:1
95
92
95
5
79
1.6:1
95
O
OH
6
O
OH NO2
6
88
65
2:1
98
96
O
O
OH
OH
O
OH
7
7d
10:1
N
O
O
O
NO2
OH NO2
8d
70
3:1
92
N
8d
52
12:1
92
O
O
O
a
Isolated yield after separation from unreacted starting materials and catalyst. All
reactions were run under the general conditions noted for Table 1, entry 11.
b
Diastereomeric ratios were estimated from the 1H NMR spectrum of the crude
OH
product mixture.
9
65
52
NA
NA
80
81
c
Determined by HPLC on CHIRALPAK AD-H column for isolated products after
separation from unreacted starting materials and catalyst.
NO2
OH NO2
d
Reaction time was 96 h.
O
10
p-nitrobenzaldehyde gave the anti product with 99% ee and good
combined yield of the two diastereomers (Table 5, entry 4). How-
ever, we observed a decrease in diastereomeric ratio going from
cyclohexanone to cyclopentanone, which is not uncommon for
prolinamide catalysts.12d,17 Interestingly, high ee’s were obtained
for the syn products from some of these reactions: entry 5 gave 95%
ee, entry 6 gave 86% ee; also, entry 3 gave 94% ee. Very few pub-
lications that describe these reactions of cyclopentanone include
ee’s for the minor syn products, but our results appear to be su-
perior to the ones that are reported.18 With the acetonide of
1,3-dihydroxyacetone as the nucleophile, an important building block
for the synthesis of carbohydrate structures,19 the anti product was
obtained with excellent ee and diastereoselectivity, but the reaction
was slower and the yield was poorer compared with other cyclic
ketones. The resulting anti-1,2-diol unit has a configuration com-
plementary to the syn-1,2-diol that is obtained by Sharpless
a
Isolated yield after separation from unreacted starting materials and catalyst. All
reactions were run under the general conditions noted for Table 1, entry 11.
b
Diastereomeric ratios were estimated from the 1H NMR spectrum of the crude
product mixture.
c
Determined by HPLC on CHIRALPAK AD-H column for isolated products after
separation from unreacted starting materials and catalyst.
d
Reaction time was 96 h.
3. Conclusions and outlook
In summary, we have developed a new very easily prepared
prolinamide derivative that is an excellent bifunctional organo-
catalyst for direct asymmetric aldol reactions. High enantiose-
lectivities were observed for the majority of aldol reactions studied,
comparing very favorably with the best catalysts reported in the
literature, many of which employ secondary chiral groups attached
to a proline unit, such as binaphthalene moieties that are expensive
or require multistep synthesis for their preparation. A catalyst with
outstanding performance over all aldol reactions is yet to be dis-
covered. For example, one recently reported13 proline-sulfonamide
asymmetric dihydroxylation of
a,b
-unsaturated ketones.20 When
acetone was employed as the aldol donor (entries 9 and 10), the ee’s
were higher than the same reactions catalyzed by proline itself
(which generally gives around 70e75% ee for the reaction with
p-nitrobenzaldehyde4), but there is clearly still room for improve-
ment with this particular reaction.

A.J. Pearson, S. Panda / Tetrahedron 67 (2011) 3969e3975
3973
25
D
derivative that typifies this problem gives very impressive selec-
tivities over a range of direct aldol reactions of cyclohexanone, but
does not perform as well for several other ketone donors (catalyst
2 affords higher ee with comparable diastereoselectivity for the
reactions shown in Table 5, entries 4 and 7).
(790 mg, 79%). [
CD3OD)
a
]
ꢀ59.2 (c 0.13, CH2Cl2); 1H NMR (400 MHz,
d
(ppm) 8.60 and 8.52 (1H, d, J¼8.0 Hz, rotamers),
8.05e7.93 (1H, td, J¼8.0, 1.2 Hz), 7.52e7.43 (1H, td, J¼8.0 Hz,
1.2 Hz), 7.43e7.00 (10H), 7.00e6.85 (1H, dd, J¼8.0 Hz, 1.2 Hz),
5.24e4.81 (4H), 4.41e4.31 (1H), 3.77e3.44 (2H), 2.33e2.14 (1H, m),
2.02 (1H, m), 1.93e1.76 (2H); 13C NMR (150 MHz, CD3OD, rotamers)
The present work offers proof-of-principle and indicates that
the proline/anthranilamide structural motif has significant poten-
tial. The anthranilic acid core represents a very convenient template
for structural modification, with a view to further improving both
the enantioselectivity and diastereoselectivity of reactions that
have proved troublesome using other catalysts, such as those of
cyclopentanone. The carboxyl group provides an obvious site for
facile attachment of structural units that can provide alternate
hydrogen bonding arrays that may or may not incorporate addi-
tional chirality. Such modifications might benefit from the known21
intramolecular hydrogen bonding in anthranilamide derivatives,
resulting in conformations that mimic a reverse turn, and might
provide structurally simple but effective binding pockets suitable
for aldol substrates. The beneficial effect of strategic methyl sub-
stitution (catalyst 2 vs 1 or 3) is also interesting from the standpoint
of structural modification to afford catalysts that have greater lipid
solubility, as one can envision the incorporation of longer and/or
branched alkyl chains that might serve to further enhance selec-
tivity while providing catalysts that can be used in common organic
solvents. These propositions will form the basis of future in-
vestigations in our laboratory, with special emphasis on ease of
preparation of catalysts from readily available inexpensive starting
materials.
d
(ppm) 172.4, 172.1, 167.9, 167.7, 155.9, 155.1, 140.7, 140.6, 136.8,
136.4, 135.9, 134.5, 134.4, 130.9, 128.6, 128.4, 128.3, 128.1, 127.9,
127.7, 127.6, 123.2, 120.1, 115.8, 115.7, 67.3, 67.1, 66.9, 62.7, 62.4, 47.6,
47.5, 47.3, 46.9, 31.3, 30.3, 24.1, 23.5; HRMS (ESIþ) calcd for
C27H26N2O5Na [MþNa]þ 481.1739, found 481.1730.
4.2.2. (S)-2-(Pyrrolidine-2-carboxamido)benzoic acid (1). To a solu-
tion of the above protected derivative of 1 (500 mg, 1.1 mmol)
dissolved in ethanol (10 mL) was added palladium 10% on carbon
wetted with 50% water (200 mg) and the mixture was stirred under
hydrogen for 10 h. The reaction was monitored by TLC. The reaction
mixture was filtered through Celite, washed with methanol
(3ꢂ5 mL) then with methanol/water (1:1) (3ꢂ5 mL). The combined
filtrate was concentrated in vacuo to afford the product (203 mg) as
25
D
white powder. Yield 79% as white solid, mp 225e227 ꢁC. [
a]
ꢀ93.2 (c 0.1, 5% TFA in CH3OH); 1H NMR (400 MHz, CD3OD)
d (ppm)
8.41 (1H, d, J¼8.4 Hz), 8.04 (1H, d, J¼7.6 Hz), 7.40 (1H, td, J¼8.4,
2.0 Hz), 7.09 (1H, td, J¼8.4, 1.2 Hz), 4.54 (1H, t, J¼7.3 Hz), 3.4 (2H),
2.53 (1H, m), 2.32e1.92 (3H); 13C NMR (150 MHz, CD3OD)
d (ppm)
172.9, 165.9, 139.5, 131.1, 123.0, 119.3, 61.5, 45.9, 29.3, 23.9; HRMS
(ESIþ) calcd for C12H14N2O3Na [MþNa]þ 257.0901, found 257.0910.
4.3. Preparation of catalyst 2
4. Experimental section
4.1. General procedures
4.3.1. (S)-2-(1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido)-6-
methylbenzoic acid. To a stirred solution of N-benzyloxycarbonyl-
L-proline (500 mg, 2.0 mmol) in pyridine (12 mL) was added
All reactions were performed with anhydrous solvents in oven
dried and argon charged glassware unless otherwise stated.
Chemicals and solvents were purchased from Aldrich and Fisher
Scientific. Analytical thin layer chromatography was carried out
using glass bedded Whatman silica gel 60 F254; 0.25 mm thickness.
Flash chromatography was carried out on silica gel 60 (200e400
mesh). 1H NMR and 13C NMR spectra were recorded on a Varian
6.1C (400 MHz) or Varian INOVA (600 MHz) spectrometer and are
internally referenced to residual solvent signals. High resolution
mass spectra were recorded by the University of Michigan Mass
spectrometry facility on a VG 70-250-S mass spectrometer manu-
factured by Micromass Corp. Specific rotations were measured on
a Perkin Elmer polarimeter model 241. High pressure liquid chro-
matography (HPLC) was performed on a Beckman HPLC with 32
Karat software using Daicel Chiralpak AD-H column (4.6 mm,
25 cm) and a guard column (4 mm,1 cm). Absolute stereochemistry
of the aldol products was confirmed by direct comparison of HPLC
phosphorus oxychloride (0.2 mL, 2.0 mmol) dropwise, maintaining
the temperature at ꢀ10 ꢁC under an argon atmosphere. The re-
action mixture was stirred for 1 h at ꢀ10 ꢁC, and 2-amino-6-methyl-
benzoic acid (302 mg, 2.0 mmol) in pyridine (2 mL) was added. The
reaction mixture was stirred for 8 h at ꢀ10 ꢁC (ꢀ5 ꢁC), then added
to ice-cooled 1 M aq HCl solution and extracted with ethyl acetate
(3ꢂ15 mL). The combined extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. Flash chromatography (hex-
anes/ethyl acetate¼1:1) afforded the pure compound as a gum
25
(627 mg, 82%). [
a
]
ꢀ88.1 (c 0.12, CH2Cl2); 1H NMR (400 MHz,
D
CD3OD)
d
(ppm) 7.95, 7.78 (1H, 2 d, J¼8.0 Hz, rotamers), 7.40e7.16
(5H), 7.12 (1H, t, J¼8.0 Hz), 7.00 (1H, d, J¼8.0 Hz), 5.18e4.90 (2H),
4.40e4.25 (1H, m), 3.70e3.40 (2H), 2.45 (3H, s), 2.30e1.80 (4H); 13C
NMR (150 MHz, CD3OD)
d (ppm, N-Cbz rotamers) 175.0, 174.0,
172.4,172.1,170.3, 155.9,155.3,138.9,138.8,137.1,136.9, 136.8, 136.5,
130.9, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.66, 127.63, 127.4,
123.2, 120.1, 67.4, 67.3, 67.02, 67.0, 62.2, 61.8, 59.4, 59.0, 46.8, 46.5,
31.2, 30.7, 30.2, 29.8, 24.1, 24.0, 23.4, 23.2, 21.2, 21.1, 19.7; HRMS
(ESIþ) calcd for C21H23N2O5 [MþH]þ 383.1607, found 383.1596.
with materials produced using
reaction.
L-proline as the catalyst for the same
4.2. Preparation of catalyst 1
4.3.2. (S)-2-Methyl-6-(pyrrolidine-2-carboxamido)benzoic acid (2). To
a solution of the above amide (450 mg, 1.17 mmol) in ethanol
(8 mL) was added palladium 10% on carbon wetted with 50% water
(90 mg) and the mixture was stirred under 1 atm hydrogen for 10 h.
The reaction mixture was filtered through Celite, and the pad was
washed with methanol (3ꢂ5 mL) then with methanol/water (1:1)
(3ꢂ5 mL). The combined filtrate was evaporated to dryness in
4.2.1. (S)-Benzyl 2-(2-(benzyloxycarbonyl)phenylcarbamoyl)pyrroli-
dine-1-carboxylate. To a stirred solution of N-benzyloxycarbonyl-
L-
proline (548.5 mg, 2.2 mmol) and benzyl anthranilate22 (500 mg,
2.2 mmol) in pyridine (12 mL) was added phosphorus oxychloride
(0.2 mL, 2.2 mmol) dropwise maintaining the temperature at
ꢀ10 ꢁC under an argon atmosphere. The reaction mixture was
stirred for 6e8 h at ꢀ10 to ꢀ5 ꢁC. The mixture was then added to
ice cooled 1 M aq HCl and extracted with ethyl acetate (3ꢂ15 mL).
The combined extract was washed with brine, dried over Na2SO4,
and concentrated in vacuo. Flash chromatography (hexanes/ethyl
acetate¼2:1) afforded the pure compound as a pale yellow gum
vacuo to afford the product as a white powder (224 mg, 77%), mp
25
195e197 ꢁC. [
a
]
ꢀ71.1 (c 0.1, 5% TFA in CH3OH); 1H NMR
D
(400 MHz, CD3OD)
d
(ppm) 7.53 (1H, d, J¼8 Hz), 7.3 (1H, t, J¼8 Hz),
7.15 (1H, d, J¼7.6 Hz), 4.46 (1H, dd, J¼8.0, 7.2 Hz), 3.45e3.25 (2H),
2.50 (1H, m), 2.43 (3H, s), 2.15e2.00 (3H); 13C NMR (150 MHz,
CD3OD)
d (ppm) 170.5, 167.2, 137.5, 134.5, 129.9, 128.3, 122.2, 60.5,

3974
A.J. Pearson, S. Panda / Tetrahedron 67 (2011) 3969e3975
46.2, 29.5, 23.8, 19.8; HRMS (ESIþ) calcd for C13H17N2O3 [MþH]þ
4.6. Preparation of catalyst 5
249.1239, found 249.1238.
4.6.1. 2-(1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxamido)-4-ni-
trobenzoic acid. Prepared as described above for the precursor to
4.4. Preparation of catalyst 3
catalyst 2, coupling
with 4-nitroanthranilic acid. Yield 78%. [
1H NMR (400 MHz, CDCl3)
(ppm) 8.38e8.12 (3H), 4.65 (1H, m),
3.72e3.42 (2H), 2.35 (1H, m), 2.22e1.82 (3H), 1.55, 1.18 (9H, 2s,
amide rotamers); 13C NMR (150 MHz, CDCl3)
(ppm, rotamers)
L-proline-Boc (instead of the Cbz derivative)
25
D
a]
ꢀ65 (c 0.13, CH2Cl2);
This compound was prepared by the two-step procedure de-
scribed for the preparation of catalyst 2, but using 2-amino-3-
methylbenzoic acid as the starting material:
d
d
165.5, 165.0, 158.6, 158.4, 154.7,153.7,153.6, 152.7,147.8,147.6, 130.7,
130.4, 122.6, 122.5, 122.3, 122.2, 121.7, 80.6, 80.5, 59.8, 59.7, 47.1,
46.8, 32.0, 31.1, 28.6, 28.5, 24.5, 23.8; HRMS (ESIþ) calcd for
C17H21N3O7 [MþH]þ 380.1452, found 380.1448.
4.4.1. (S)-2-(1-((Benzyloxy)carbonyl)pyrrolidine-2-carboxamido)-3-
methylbenzoic acid. Yield 82%. [
(400 MHz, CD3OD)
a
]
25 ꢀ70.6 (c 0.13, CH2Cl2); 1H NMR
D
d
(ppm) 7.75 (1H, dd, J¼7.6, 1.2 Hz), 7.40e7.10
(7H), 5.25 (2H), 4.46 (1H, dd, J¼7.2, 5.6 Hz), 3.69e3.61 (1H, m),
3.55e3.40 (1H, m), 2.22 (3H, m), 2.10 (3H, s), 1.85 (1H, m); 13C NMR
4.6.2. 4-Nitro-2-(pyrrolidine-2-carboxamido)benzoic acid (5). Rem-
(150 MHz, CD3OD)
d (ppm) 173.2, 169.7, 169.6, 156.8, 156.5, 137.8,
oval of the Boc protecting group was accomplished as described for
137.7, 137.6, 137.3, 136.4, 135.6, 129.5, 129.4, 129.34, 129.30, 129.0,
128.9, 128.8, 128.7, 128.6, 128.4, 128.2, 127.9, 127.2, 68.3, 68.2, 68.0,
67.9, 62.4, 62.0, 47.9, 47.5, 31.9, 31.7, 30.8, 25.2, 25.0, 24.3, 24.2, 18.8,
18.7; HRMS (ESIþ) calcd for C21H23N2O5 [MþH]þ 383.1607, found
383.1599.
25
catalyst 4. Yield 62%. [
a
]
ꢀ79 (c 0.1, 5% TFA in CH3OH); 1H NMR
D
(400 MHz, CD3OD)
d
(ppm) 9.33 (1H, d, J¼2.0 Hz), 8.30 (1H, d,
J¼8.8 Hz), 8.03e8.00 (1H, dd, J¼8.8, 2.0 Hz), 4.63 (1H, m), 3.58e3.39
(2H), 2.58 (1H, m), 2.35e2.02 (2H); 13C NMR (150 MHz, CD3OD)
d
(ppm) 169.5,168.3,160.0,159.7,159.4,151.9,141.7,133.7,123.1,118.8,
117.3, 116.4, 115.4, 62.3, 47.1, 30.1, 24.8; HRMS (ESIþ) calcd for
4.4.2. (S)-3-Methyl-2-(pyrrolidine-2-carboxamido) benzoic acid
C12H13N3O5 [MþH]þ 280.0928, found 280.0927.
25
(3). Yield 80%; mp 182e185 ꢁC. [
a
]
D
ꢀ62.6 (c 0.12, 5% TFA in
CH3OH); 1H NMR (400 MHz, CD3OD)
d
(ppm) 7.81 (1H, dd, J¼8.0,
4.7. Preparation of catalyst 6
1.6 Hz), 7.48 (1H, dd, J¼8.0, 1.6 Hz), 7.30 (1H, t, J¼8.0 Hz), 4.51 (1H,
dd, J¼6.8, 1.6 Hz), 3.46e3.31 (2H), 2.55 (1H, m), 2.38 (1H, m), 2.28
4.7.1. 2-(1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxamido)-6-ni-
trobenzoic acid. 2-(1-(tert-Butoxycarbonyl)pyrrolidine-2-carbox-
amido)-6-nitrobenzoic acid was prepared as described above for
(3H, s), 2.08 (2H); 13C NMR (150 MHz, CD3OD)
d (ppm) 169.1, 168.3,
137.6, 135.5, 135.3, 129.7, 129.1, 128.0, 61.3, 47.1, 30.3, 24.7, 18.0;
HRMS (ESIþ) calcd for C13H17N2O3 [MþH]þ 249.1239, found
249.1235.
the precursor to catalyst 2, coupling
L
-proline-Boc with 2-amino-6-
25
D
nitrobenzoic acid.23 Yield 72%. [
(400 MHz, CD3OD)
a]
ꢀ72 (c 0.15, CH2Cl2); 1H NMR
d
(ppm) 8.48, 8.42 (1H, d, J¼5.2 Hz), 7.69e7.55
4.5. Preparation of catalyst 4
(2H), 4.41e4.21 (1H, m), 3.63e3.48 (2H), 2.42e1.81 (4H), 1.58, 1.12
(9H, 2s, amide rotamers); 13C NMR (150 MHz, CD3OD)
d
(ppm)
4.5.1. (S)-tert-Butyl 2-((2-((benzyloxy)carbonyl)phenyl)carbamoyl)
pyrrolidine-1-carboxylate. (S)-tert-Butyl 2-((2-((benzyloxy)carbonyl)-
phenyl)carbamoyl)pyrrolidine-1-carboxylate was prepared as described
above for (S)-benzyl 2-(2-(benzyloxycarbonyl)phenylcarbamoyl)pyr-
174.1, 167.3, 155.7, 151.2, 138.8, 132.9, 127.1, 120.3, 120.2, 118.7, 81.8,
63.1, 62.7, 47.7, 32.1, 31.1, 28.5, 25.2, 24.5. The product was used in
the next step without further characterization.
rolidine-1-carboxylate, but using
L
-proline-Boc instead of
L
-proline-
4.7.2. 2-Nitro-6-(pyrrolidine-2-carboxamido)benzoic acid (6). Remo-
Cbz. Yield 76%. [
a
]
25 ꢀ65.5 (c 0.11, CH2Cl2); 1H NMR (400 MHz, CDCl3)
val of the Boc protecting group was accomplished as described for
D
25
d
(ppm) 11.61, 11.55 (1H, s, rotamers), 8.78 (1H, t, J¼9.2 Hz), 8.08 (1H,
catalyst 4. Yield 66%. [
a
]
ꢀ95 (c 0.1, 5% TFA in CH3OH); 1H NMR
D
t, J¼9.2 Hz), 7.45e7.33 (5H), 5.35 (2H, s), 4.45, 4.30 (1H, dd, J¼8.0,
(400 MHz, CD3OD) d (ppm) 7.75e7.72 (1H), 7.64e7.60 (1H),
3.6 Hz), 3.80e3.40 (2H), 2.35e1.85 (4H), 1.50, 1.30 (9H, 2 s, amide
7.44e7.39 (1H), 4.23 (1H), 3.24e3.02 (2H, m), 2.38e1.78 (4H, m); 13C
rotamers); 13C NMR (100 MHz, CDCl3)
d
(ppm) 172.6, 172.1, 167.8,
NMR (150 MHz, CD3OD) d (ppm) 168.9, 166.9, 149.7, 136.6, 132.0,
155.2, 154.3, 144.4, 141.4, 135.7, 134.9, 131.2, 130.9, 128.8, 128.6, 128.5,
128.4, 122.9, 122.7, 120.2, 115.4, 80.3, 77.9, 77.5, 77.2, 67.2, 66.9, 62.9,
62.3, 47.3, 46.9, 31.7, 30.7, 28.7, 28.4, 24.5, 23.9; HRMS (ESIþ) calcd for
C24H29N2O5 [MþH]þ 425.2076, found 425.2074.
131.5, 124.6, 122.4, 61.4, 47.2, 30.5, 24.7; HRMS (ESIþ) calcd for
C12H13N3O5 [MþH]þ 280.0928, found 280.0925.
4.8. General optimized procedure for the aldol reaction
4.5.2. (S)-Benzyl 2-(pyrrolidine-2-carboxamido)benzoate (4). To
To anhydrous DMSO (0.2 mL; anhydrous solvent was used to en-
sure reproducible water content throughout) was added the corre-
sponding catalyst (0.02 mmol), trifluoroacetic acid (0.024 mmol), and
a
stirred solution of the above N-Boc derivative (250 mg,
0.59 mmol) in 2 mL dichloromethane at room temperature was
added 0.14 mL trifluoroacetic acid (1.8 mmol). The resulting mix-
ture was stirred at room temperature for 18 h. The excess solvent
was rotary evaporated and the residue was added to aq sodium
bicarbonate solution, extracted with dichloromethane, and the
water (50 mL, 14 equiv relative to the aldehyde). The reaction mixture
was stirred for 5 min followed by addition of the corresponding
ketone (1 mmol). The reaction mixture was stirred for 10 min at
4 ꢁC followed by addition of a solution of the requisite aldehyde
(0.2 mmol) in 0.2 mL DMSO. The resulting mixture was stirred at 4 ꢁC
for 72 h then treated with saturated ammonium chloride solution,
and the mixture was extracted with ethyl acetate (3ꢂ2 mL). The
combined organic extract was washed with brine, dried (Na2SO4), and
concentrated in vacuo. After NMR analysis to determine conversion
and diastereomeric ratio where needed, the residue was purified by
flash column chromatography with hexanes/ethyl acetate (3:1) to
afford the aldol products that were subjected to chiral HPLC analysis
to determine enantiomeric excesses, details of which are provided in
Supplementary data.
combined extract was dried over sodium sulfate and evaporated to
25
give compound 4 (152 mg, 79%). [
NMR (400 MHz, CDCl3)
a
]
D
ꢀ48.9 (c 0.12, CH2Cl2); 1H
d
(ppm) 12.19 (1H, s), 8.78 (1H, dd, J¼8.0,
1.2 Hz), 8.07 (1H, dd, J¼8.0, 1.6 Hz), 7.53 (1H, td, J¼8.0, 1.6 Hz),
7.47e7.32 (5H), 7.07 (1H, td, J¼8.0, 1.2 Hz), 5.38 (2H, ABq,
JAB¼12.4 Hz, Dn¼13.6 Hz), 3.90 (1H, dd, J¼9.2, 4.8 Hz), 3.25 (2H, m),
2.20 (1H, m), 2.05 (1H, m), 1.75 (2H, m); 13C NMR (100 MHz, CDCl3)
d
(ppm) 174.7, 167.5, 141.0, 135.8, 134.7, 131.3, 128.9, 128.6, 128.4,
122.9, 120.8, 116.2, 67.1, 62.0, 47.5, 31.4, 26.3; HRMS (ESIþ) calcd for
C19H21N2O3 [MþH]þ 325.1552, found 325.1554.

A.J. Pearson, S. Panda / Tetrahedron 67 (2011) 3969e3975
3975
ꢁ ꢁ
11. Quelever, G.; Burlet, S.; Garino, C.; Pietrancosta, N.; Laras, Y.; Kraus, J.-L. J. Comb.
Chem. 2004, 6, 695e698.
Supplementary data
12. (a) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570e579; (b) Pihko, P. M.;
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.04.033.
Laurikainen, K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62,
ꢁ
317e328; (c) Gryko, D.; Zimnicka, M.; Lipinski, R. J. Org. Chem. 2007, 72,
964e970; (d) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734e735; (e) Da, C.-S.; Che, L.-P.;
Guo, Q.-P.; Wu, F.-C.; Ma, X.; Jia, Y.-N. J. Org. Chem. 2009, 74, 2541e2546.
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