Probing the Synergistic Catalytic Model: A Rationally Designed Urea-Tagged Proline Catalyst for the Direct Asymmetric Aldol Reaction

Article abstract of DOI:10.1021/acs.joc.8b00962

A urea tag was incorporated at the C-4 position of proline, cis to its COOH group, in order to explore the prospect of a synergistic effect between the two functional groups in the transition state of the enamine route to the asymmetric aldol reaction. Th

Full text of DOI:10.1021/acs.joc.8b00962

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Article
Probing the Synergistic Catalytic Model: A Rationally Designed Urea-
Tagged Proline Catalyst for the Direct Asymmetric Aldol Reaction
MEETA BHATI, Kiran Kumari, and Srinivasan Easwar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00962 • Publication Date (Web): 30 May 2018
Downloaded from http://pubs.acs.org on May 30, 2018
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Probing the Synergistic Catalytic Model: A Rationally Designed UreaꢀTagged Proline
Catalyst for the Direct Asymmetric Aldol Reaction
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Meeta Bhati, Kiran Kumari and Srinivasan Easwar*
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Department of Chemistry, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, NHꢀ8,
Bandarsindri, Distt. Ajmer, Rajasthan 305817, INDIA
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eꢀmail: easwar.srinivasan@curaj.ac.in
Table of Contents Graphic
Abstract:
A urea tag was incorporated at the Cꢀ4 position of proline, cis to its COOH group, in order to explore
the prospect of a synergistic effect between the two functional groups in the transition state of the enamine
route to the asymmetric aldol reaction. The catalyst proved to be an excellent performer, delivering aldols in
high yields and with excellent enantioꢀ and diastereoselectivities using just 2 molꢀ% loading in the presence of
water; it also exhibited good levels of recyclability under aqueous conditions. The favourable results reveal the
interesting possibility of an intramolecular hostꢀguest interaction between the urea and the amino acid moieties,
exerting a beneficial effect on the catalysis. The concept could certainly offer a new direction toward more
efficient catalyst design.
Introduction
The discovery of the proline catalysed direct asymmetric aldol reaction by List, Lerner and Barbas in
2000 would certainly go down as one of the landmark achievements of the century.1 More than a decade and a
half later, proline still reigns supreme as the organocatalytic model of choice for this quintessential CꢀC bond
forming reaction, as is evident from the numerous prolineꢀderived organocatalysts that populate the available
asymmetric protocols.2 Of late, asymmetric synthesis is witnessing the rapid rise of modularly designed
organocatalysts (MDO’s) and selfꢀassembled supramolecular catalytic assemblies to leverage a synergistic
effect of two individual catalytic moieties.3 Cooperative catalysis, as this concept is termed, has also made its
mark in the classic enamine route to the aldol reaction; a host of coꢀcatalysts that include (thio)ureas,4 BINOL,5
guanidinium salts6 and Bronsted acids7,8 have been employed in combination with an amino acid – proline in
most cases – to achieve a spike in the catalytic performance. On a parallel note, over the last few years amineꢀ
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thioureas and related compounds have undoubtedly had a huge impact in the field of asymmetric bifunctional
catalysis, and their proficiency in promoting Michael addition reactions through a combination of enamine and
hydrogenꢀbonding activation has been well established.9 Therefore, amongst the coꢀcatalysts mentioned above,
the use of thioureas as a cooperative additive in the enamine route to the aldol reaction is particularly
interesting.4aꢀf Demir & coꢀworkers were the pioneers in this regard, utilizing a prolineꢀthiourea combination for
the first time in an asymmetric aldol reaction; the superior performance of their dual catalytic assembly in
comparison to the parent amino acid provided an excellent illustration of synergistic catalysis. The authors
proposed a specific hostꢀguest interaction between the proline and the thiourea that operated favourably in the
transition state to afford enhanced stereoselectivity even in an unconventional nonꢀpolar reaction medium.4a,e In
a more recent study, they also showed that the model could be made to work efficiently in the presence of water
by using a calixeraneꢀlinked thiourea as a hydrophobic coꢀcatalyst.4f The inspirational work of Demir & coꢀ
workers entailed other reports of a similar kind, employing various thioureas as coꢀcatalysts for the enamine
mediated asymmetric aldol reaction, and also sparked mechanistic studies toward understanding and
rationalizing the cooperative role of the thiourea additive.10
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Excited by the dual catalytic hostꢀguest complex theory and aspiring to extend our interest in proline
based catalysis,11 we pondered the design of a bifunctional catalyst that would have both the aforeꢀmentioned
features of host and guest implanted into a single molecular entity. Specifically, the idea was to construct a
modular catalyst bearing a free amino acid moiety and a urea/thiourea functionality in optimal proximity,
which we imagined could replicate the synergistic collaboration exhibited by two distinct molecular entities in
the earlier reports. A more organized transition state might be anticipated for the asymmetric aldol reaction as a
result of this intramolecular interaction, and enhanced activity and greater stereocontrol ought to ensue. Such a
catalyst may be envisaged simply by incorporation of a urea/thiourea tag onto the 4ꢀposition of proline as
depicted by 1 (Figure 1). The relative ‘cis’ orientation of the cooperative moiety and the COOH group in 1 was
perceived as vital for the interaction to take effect. In fact, favourable effects of appending influential groups –
such as an ionꢀtag – cis to the reaction site of a proline derived catalyst for the asymmetric aldol reaction have
been demonstrated and rationalized by Trombini & Lombardo and coꢀworkers12 and, more recently, by our
group.11a The proposed ‘cis’ urea/thioureaꢀtagged proline 1 presents itself therefore as a rational model to probe
the idea of an inherent hostꢀguest complex. Ureas/thioureas have previously been incoporated at the 4ꢀposition
as a linker to attach the proline unit to a mesoporous support13 or a cyclodextrin.14 However, the focus of these
reports, and the performance of these systems themselves, revolved around the heterogeneous appendage rather
than the linker. It would thus be interesting to study the asymmetric aldol reaction catalysed by 1a/1b in terms
of any favourable effect as an upshot of a cooperative intramolecular interaction between the two distinct
functional parts of the catalyst in the transition state. We herein present our efforts and the results obtained in
this direction.
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Figure 1. Proposed “cis” urea/thiourea tagged proline
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Results and Discussion
Our endeavours started with a straightforward synthesis of the proposed prolineꢀurea catalyst 1b,
illustrated in Scheme 1. Following a literature protocol,15 transꢀ4ꢀhydroxyꢀLꢀproline (2) was converted into the
primary amine 3, having the NH2 and COOH groups cis to each other. Treating amine 3 with phenyl isocyanate
in CH2Cl2 at room temperature afforded the catalyst precursor 4 bearing the desired urea substituent at the 4ꢀ
position of proline. Finally, hydrogenolysis of 4 under the standard conditions exposed the amino acid and
delivered the ‘cis’ ureaꢀtagged proline 1b.
Scheme 1. Synthesis of the ‘cis’ ureaꢀtagged proline catalyst 1b
Reagents and conditions: (i) PhNCO, CH2Cl2 (84%); (ii) H2, Pd/C (10%), MeOH, room temp., 4 h (90%).
The initial results obtained with the catalyst 1b in the direct asymmetric aldol reaction of
cyclohexanone (5) and pꢀnitrobenzaldehyde (6a) were quite promising. By employing just 5 molꢀ% of 1b in the
presence of 50 ꢀL (ca. 1.2 equiv.) of water, a high yield of the aldol was obtained in only 6 h with very good
diastereoselectivity and excellent enantioselectivity for the anti diastereomer (Table 1, entry 1). While the
superiority of 1b to proline itself is evident here, the result is also a significant improvement over the use of the
prolineꢀthiourea dual catalytic system, where a higher loading of the individual catalysts and a longer duration
were required to achieve a similar level of performance, albeit under different reaction conditions.4a We were
certainly delighted with the outcome since it lent weight to our assumption of an intramolecular hostꢀguest
interaction entailing a cooperative beneficial effect on the catalysis. On a further pleasing note, it was observed
that the efficiency and selectivity of the catalyst remained largely undiminished even with just a 2 molꢀ%
loading (entry 2). The result compares favourably with the use of proline based ionꢀtagged organocatalysts,
which have come to be renowned for their exceptional performance in the direct asymmetric aldol reaction over
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the past decade.11a,12a,16 A more detailed comparative study was needed at this stage to corroborate the presence
of the proposed intramolecular interaction and place our results in better perspective. A simple way to further
substantiate our theory would be to compare the performance of 1b with the corresponding ‘trans’ ureaꢀtagged
proline catalyst, in which the proposed intramolecular interaction would be sterically complicated. This
diastereomeric catalyst 1c was synthesized by gaining access to the required transꢀamine 3' using a literature
protocol, followed by a replication of the steps used for the conversion of 3 to catalyst 1b (Scheme 2). The
aldol reaction carried out using the ‘trans’ catalyst 1c was quite revealing; with a 2 molꢀ% loading and under
identical conditions employed with 1b, only a 45% yield of the aldol could be obtained, albeit accompanied by
comparable stereoselectivity values (Table 1, entry 3). The steep drop (~50%) in the yield while using the
‘trans’ ureaꢀtagged proline 1c provides a clear indication of a favourable intramolecular interaction between the
amino acid and urea moieties in the diastereomer 1b, where the cis relation between the two functional groups
orients them proximal in space for the interaction to take effect. Furthermore, to gain a better perspective of the
catalytic efficiency of 1b, comparative studies under identical reaction conditions were taken up with proline as
well as with the DemirꢀRios prolineꢀthiourea dual catalytic system,4a,b using two different thioureas – the
unsubstituted 1,3ꢀdiphenyl thiourea (I) and (3,5ꢀbistrifluoromethylphenyl)thiourea II. The use of proline
resulted in only a 9% conversion (Table 1, entry 4); the combination of proline with I / II did not prove
effective in mediating the aldol reaction either (Table 1, entries 5 & 6). This could perhaps be due to the
minimal interaction of the principal catalyst – the highly hydrophilic amino acid – with the substrates in the
presence of water, leaving no role for the secondary catalysts I / II. We therefore conducted additional
experiments with these systems in the absence of water. As expected, the conversion shot up several notches,
but yet did not match up to the efficiency of 1b, while there was also a dip in the stereochemical performance
(Table 1, entries 7 & 8). The results provide further evidence of the proposed synergistic hostꢀguest interaction
in operation in 1b; they also place added emphasis on the design of suitably derivatised prolines such as 1b to
achieve optimum results for the asymmetric aldol reaction in the presence of water. It is perhaps pertinent to
add here that thioureaꢀtagged catalyst 1a (Figure 1) could not be accessed by an analogous synthetic route; the
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Scheme 2. Synthesis of the ‘trans’ ureaꢀtagged proline catalyst 1c.
Reagents and conditions: (i) PhNCO, CH2Cl2 (86%); (ii) H2, Pd/C (10%), MeOH, room temp., 4 h (85%).
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Pdꢀcatalysed deprotection at the last step met with failure, presumably due to the presence of the sulphur.
Fortunately, the oxyꢀanalog has proven quite proficient toward exploring our hypothesis. Nonetheless, we have
taken up the synthesis of 1a by an alternative route – involving a Bocꢀ rather than Cbzꢀprotected proline. This
is currently in progress in our laboratory and the results in this regard shall be communicated in due course.
Satisfied with the comparative study, we proceeded to optimize the asymmetric aldol addition using 1b. The
critical and often intriguing role of water in organocatalysed asymmetric transformations17 was once again
exemplified by a reaction in its absence, which resulted in a drop in both efficiency and selectivity of the
catalyst (Table 1, entry 9). Further optimization showed the ideal amount of added water to be 25 or 50 ꢀL (ca.
1.2 or 2.4 eq. respectively) for the reaction on a 0.5 mmol scale (entries 10ꢀ13). Organocatalytic reactions
in/on/in the presence of water have entailed interesting discussions and mechanistic investigations.18,19 The
studies carried out by Blackmond and coꢀworkers19a to comprehend the advantages of the addition of “micro”
quantities of water in enamine catalysis are particularly pertinent here; while, the efforts of Jung and Marcus19b
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Table 1. Comparative and optimisation studies for the reaction of cyclohexanone and pꢀnitrobenzaldehyde[a]
Catalyst
[molꢀ%]
H2O
[µL]
Time
[h]
Yield
[%][b]
d.r.
anti ee
Entry
[anti/syn][c]
[%][d]
1
2
3
1b [5]
50
50
50
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8
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95
92
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96:4
98:2
96:4
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99
95
1b [2]
1c [2]
4
5
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7
LꢀPro [2]
50
50
50
0
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8
8
8
9[e]
7[e]
5[e]
58
n.d.
n.d.
n.d.
n.d.
n.d.
88
LꢀPro [2] + I[f] [2]
LꢀPro [2] + II[f] [2]
LꢀPro [2] + I [2]
n.d.
85:15
8
LꢀPro [2] + II [2]
1b [2]
0
8
8
62
78
87:13
91:9
96:4
93:7
96:4
95:5
97:3
n.d.
95
89
9
0
10
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12
13
14
15
16
1b [2]
25
8
93
97
1b [2]
100
250
500
50
8
62
99
1b [2]
24
24
8
85
98
1b [2]
91
99
1b [1]
75
98
1b [0.3]
1b [0.3]
50
24
24
7[e]
12[e]
n.d.
n.d.
10
n.d.
[a] Reactions were carried out at 25 °C on 0.5 mmol of pꢀnitrobenzaldehyde using 5 eq. of cyclohexanone. [b] Refers to isolated yields.
1
[c] Determined by H NMR of the crude reaction mixture. [d] Determined by HPLC on a chiral stationary phase (see Supporting
Information). [e] Refers to % conversion determined by 1H NMR analysis. n.d. = not determined. [f] I: 1,3ꢀdiphenyl thiourea; II: 1,3ꢀ
bis(3,5ꢀbis(trifluoromethyl)phenyl) thiourea.
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that sought to rationalize the beneficial effects of “on water” reactions employing heterogeneous aqueous
biphasic conditions must also be acknowledged. A noteworthy outcome of this study was the admirable ability
of 1b to exhibit near identical stereoselectivity even when a large quantity of water was employed – “bulk”
water conditions as it is termed – albeit with a lowered efficiency. Lastly, a reaction was attempted with just 1
molꢀ% of the catalyst was also found to work reasonably well – a 75% yield of the aldol was obtained in 8 h
with 98% ee, impressive for a proline derived catalyst in the direct asymmetric aldol reaction (entry 14). An
interesting study carried out by Rulli et al20 on kinetic versus thermodynamic control in organocatalysed
asymmetric aldol additions in aqueous medium offered considerable insight with regards to the above results
obtained using 1b. In a series of experiments, the authors observed a significant drop in the optical purity of the
aldol with increased catalyst loading over a range of 0.5 to 10 mol%, which was attributed to a switch from
kinetic to thermodynamic control for the enamine mediated reaction. Pertinently on the basis of the above
report, the admirable ee’s obtained with just a 2 mol% loading of 1b in the present case may presumably be the
outcome of a predominantly kinetically controlled reaction, giving rise to enhanced stereocontrol.
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Catalyst recyclability is often considered an important aspect in the organocatalysis domain, as the
research community strives towards ever more sustainable protocols.21 Curious to examine 1b on this platform,
we tested it in the standard reaction between 5 and 6a employing two different workꢀup methods – one
involving a direct extraction of the product from the reaction mixture, and the other involving removal of
excess cyclohexanone under reduced pressure prior to extraction of the product. The variation did not seem to
affect the performance, as the catalyst remained admirably efficient up to 5 cycles in both cases. It is worth
noting though that consistently excellent levels of diastereoselectivity and enantioselectivity were maintained
through all the recycling runs using both methods (Table 2).
Table 2. Recycling studies for the reaction of cyclohexanone (5) with pꢀnitrobenzaldehyde (6a) catalysed by 1b.[a]
Method A[b]
Method B[f]
Yield
anti ee
Yield
anti/syn
anti ee
Run
anti/syn[d]
Run
[d]
[%][c]
[%][e]
[%][c]
[%][e]
1
2
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4
5
6
7
95
91
93
90
85
66
29
96:4
96:4
96:4
96:4
96:4
93:7
91:9
98
98
98
98
97
97
97
1
2
3
4
5
6
7
8
96
93
93
91
87
65
45
20
96:4
95:5
96:4
96:4
96:4
96:4
94:6
n.d.
98
97
97
97
96
96
95
90
[a] Recycling studies were carried out on 0.5 mmol scale of the aldehyde using 5 molꢀ% of 1b, 5 eq. of 5 and 50 µL of water. [b]
Involved removal of excess cyclohexanone from the reaction mixture prior to workꢀup (for details, see Experimental Section). [c] Refers
to isolated yields. [d] Determined by 1H NMR of the crude reaction mixture. [e] Determined by HPLC on a chiral stationary phase (see
Supporting Information). [f] Excess cyclohexanone was not removed prior to the workꢀup (for details, see Experimental Section).
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Pleased with the recyclability results, we then explored the scope of the reaction with cyclohexanone as
the donor using a number of acceptor aldehydes (Table 3) and with a couple of donor ketones using pꢀ
nitrobenzaldehyde as the electrophile (Table 4). Reactions were carried out using the optimized conditions –
using a 2 molꢀ% loading of the catalyst, 50 ꢀL of water and 5 eq. of the donor ketone. Electron deficient
aldehydes resulted in excellent yields as expected, along with very good enantioꢀ and diastereoselectivities
(Table 3, entries 1ꢀ8). A swift reaction was observed with pentafluorobenzaldehyde, delivering a near
quantitative yield of the aldol with an excellent ee and exceptionally high diastereomeric ratio (entry 5). The
heteroaromatic nicotine and isoꢀnicotine aldehydes (entries 6 & 7) also participated with high efficiency,
although the ee was marginally compromised in an especially rapid reaction with the latter. The other
aldehydes employed in the study, including the electron neutral benzaldehyde and βꢀnaphthaldehyde, delivered
the corresponding aldols in moderate to good yields, accompanied by consistently high levels of
stereoselectivity (entries 9ꢀ14). Only the strongly electron donating pꢀanisaldehyde resulted in a poor yield of
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Table 3. Asymmetric aldol reactions of cyclohexanone (5) with various aldehydes catalysed by 1b in the presence of
water
Time
[h]
Yield
[%][a]
anti/
anti ee
Entry
Ar
syn[b]
[%][c]
1
2
2ꢀNO2ꢀC6H4 (7b)
3ꢀNO2ꢀC6H4 (7c)
4ꢀCNꢀC6H4 (7d)
4ꢀCF3ꢀC6H4 (7e)
C6F5 (7f)
12
12
12
15
5
94
90
95
93
99
90
95
96:4
97:3
96:4
98:2
>99:1
96:4
94:6
96
97
97
97
98
97
90
3
4
5
6[d]
7[d]
3ꢀpyridyl (7g)
4ꢀpyridyl (7h)
5
3
8
4ꢀClꢀ3ꢀNO2ꢀC6H3 (7i)
12
95
97:3
99
9[d]
4ꢀClꢀC6H4 (7j)
3ꢀClꢀC6H4 (7k)
24
24
48
30
67
55
81
52
94:6
94:6
93:7
95:5
92
94
91
96
10
11[d] 4ꢀBrꢀC6H4 (7l)
12[e] C6H5 (7m)
13
14
2ꢀNapthyl (7n)
30
30
54
60
35
92:8
93:7
94
95
95
3ꢀC6H5ꢀOꢀC6H4 (7o)
15[e] 4ꢀOMeꢀC6H4 (7p)
120
81:19
[a] Refers to isolated yields. [b] Determined by 1H NMR of the crude reaction mixture. [c] Determined by HPLC on a chiral stationary
phase (see Supporting Information). [d] 25 µL H2O was used. [e] 5 molꢀ% catalyst was used.
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Table 4. Asymmetric aldol reactions of different donors with pꢀnitrobenzaldehyde (6a) catalysed by 1b in the presence of
water
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5
6
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9
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14
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32
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50
51
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H2O
[µL]
Time
[h]
Yield
[%][a]
anti/
anti ee
Entry
R1, R2
syn[b]
[%][c]
1
2
ꢀ(CH2)3ꢀ (9a)
CH3, H (9b)
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[a] Refers to isolated yields. [b] Determined by 1H NMR of the crude reaction mixture. [c] Determined by HPLC on a chiral stationary
phase (see Supporting Information).
the aldol, nevertheless with high enantiomeric purity (entry 15). Varying the donor ketone in reactions with pꢀ
nitrobenzaldehyde worked excellently in the case of cyclopentanone, affording near quantitative yield of the
aldol with 90% ee in just 7 h (Table 4, entry 1). The reaction with the waterꢀmiscible acetone as the donor was
interesting; when the reaction was attempted without water, a 51% of the aldol was obtained in 8 h, with 59 %
ee (entry 3). However, in stark contrast, the reaction of acetone under the standard conditions that employed 50
ꢀL of water afforded the aldol with just 8% ee, albeit in 80% yield (entry 2). If one were to attempt to
rationalize these results, the higher efficiency in the latter case is presumably a consequence of the enhanced
homogeneity of the reaction provided by the more hydrophilic acetone. Unfortunately however, this would also
imply a dominant interfering presence of water in the transition state, which apparently has a detrimental effect
on the steroselectivity. On the other hand, in the reaction without water, the absence of the interfering water
molecules in the transition state evidently spikes up the stereoselectivity but simultaneously compromises the
ease of interaction of the amino acid catalyst with the substrate ketone, resulting in the observed poor
conversion. This is in complete contrast to the use of more lipophilic donors such as cyclohexanone, where the
presence of water has a beneficial effect on the catalyst performance.11a,12a,17,19 The example once again offers a
glimpse into the intriguing role that water many a time plays in organocatalytic reactions, especially so in the
enamineꢀmediated asymmetric aldol addition.
Lastly, we also attempted an enantioselective and diastereoselective desymmetrisation of 4ꢀmethyl
cyclohexanone (10) by the 1bꢀmediated aldol addition to 4ꢀnitrobenzaldehyde (6a). Rios and coꢀworkers had
earlier utlized the prolineꢀthiourea dual catalytic system to carry out this challenging reaction, which gives rise
to 4 possible diastereomeric product pairs, with excellent levels of stereoselectivity.4b We were very pleased to
find that using just 2 molꢀ% of 1b, the reaction of 10 with 6a proceeded to deliver the corresponding aldol 11 in
93% yield accompanied by excellent levels of both diastereoꢀ and enantioselectivity (Scheme 3).
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Scheme 3. Desymmetrisation of 4ꢀmethyl cyclohexanone by an aldol addition mediated by 1b
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Turning to the mechanism, we pondered a transition state illustrated by C in Figure 2 for the reaction
using 1b, based on our hypothesis and the observed results. As is typical of proline catalysed aldol additions,
the transition state may be expected to involve concomitant development of partial iminium and carboxylate
ions on the proline moiety and Hꢀbonding activation of the aldehyde. Of further significance, an intramolecular
interaction between the –COOH group and the cis urea moiety is envisioned to be in operation in the 1bꢀ
mediated reaction – similar to the supramolecular assembly proposed by Demir & coꢀworkers in the transition
state of the reaction mediated by the prolineꢀthiourea dual catalytic system – depicted by B in Figure 2.4a,e The
proposed interaction might be expected to have a stabilising effect, leading to a more organized and “tighter”
transition state, and eventuates in considerably enhanced activity and greater stereocontrol of 1b. Admittedly,
such an interaction is still a conjecture at this stage; various other factors might be at play, e.g. the presence of
water. Nevertheless, the results obtained in this study using 1b and 1c have certainly provided a favourable
indication of the possibility, and further probing – possibly with the help of computational studies – might help
shed more light on this aspect.
In summary, a urea moiety tagged onto the 4ꢀposition of proline, cis to the –COOH group, proved to be
a favourable factor in the direct asymmetric aldol reaction in the presence of water. The catalyst was quite
proficient, delivering high yields of the aldol adducts with just 2 molꢀ% loading, along with excellent levels of
enantioꢀ and diastereoselectivity. To our knowledge, the performance of the ureaꢀtagged proline is on par with
Figure 2. A: The ListꢀHouk model of the transition state of the proline catalysed aldol reaction. B: Demir & coꢀworkers’
prolineꢀthiourea hostꢀguest complex model of the transition state. C: The proposed intramolecular hostꢀguest interaction in
the transition state of the aldol reaction catalysed by ureaꢀtagged proline 1b.
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some of the best reported catalytic systems for the asymmetric aldol reaction under aqueous conditions,
particularly the popular ionꢀtagged proline derivatives; it also surpassed the deeds of conceptually similar
predecessors such as the dual catalytic supramolecular prolineꢀthiourea model. Further of note was the
exceptional ability of 1b to afford identical levels of stereoselectivity in both a micro aqueous environment as
well as under aqueous biphasic “bulk water” conditions. Lastly, it was also pleasing to observe that the catalyst
could be recycled with a good degree of success. Mechanistically, the study alludes to a nonꢀcovalent role of
the urea moiety, possibly in the genesis of an intramolecular synergistic interaction that stabilises the transition
state. Computational studies are currently being strategized in our group to gain a better understanding of the
favourable influence of the urea tag. Presently though, we believe that the commendable results achieved by
tagging a urea moiety onto proline could open up a new avenue in the design of proline derived bifunctional
catalysts that can be employed for mediating asymmetric transformations in the presence of water.
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Experimental Section
General: Chemicals and solvents were purchased from commercial suppliers or purified by standard
techniques. Merck 60 F254 preꢀcoated silica gel plates were used for thin layer chromatography (TLC) and
compounds were visualised by irradiation with UV light and/or by treatment with a solution of KMnO4
followed by heating. Column chromatography was performed using silica gel of mesh 60ꢀ120 / 100ꢀ200,
1
procured from Merck. H and 13C NMR spectra were recorded on a Brucker Avance 500 MHz NMR
spectrometer. Mass spectra were obtained using HRMSꢀESIꢀQꢀTime of Flight LCꢀMS (Synapt G2, Waters).
Chiral HPLC studies were carried out on a Shimadzu LCꢀ2010CHT HPLC system. Cyclohexanone, acetone,
benzaldehyde, pyridineꢀ3ꢀ/pyridineꢀ4ꢀcarboxaldehyde were distilled before use. Commercial samples of all the
other substrates were used without any purification.
Synthesis of dibenzyl (2S,4S)ꢀ4ꢀ(3ꢀphenylureido)pyrrolidineꢀ1,2ꢀdicarboxylate (4): To a solution of cisꢀNꢀ
cbzꢀ4ꢀaminoproline benzyl ester 3 (1.01 g, 2.85 mmol) in CH2Cl2 (5 mL), phenyl isocyanate (0.34 mL, 3.13
mmol) was added dropꢀwise and the reaction mixture was stirred for 2 h at room temperature. The solvent was
removed under vacuum and the residue was purified by column chromatography (petroleum ether / ethyl
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acetate 3:2) to give 4 as a colourless hygroscopic solid (1.13 g, 84%). [α]D = ꢀ42.33 (c = 1.5, CHCl3); H
NMR (500 MHz, CDCl3, two conformational isomers): δ 1.96ꢀ2.22 (m, 1 H), 2.23ꢀ2.60 (m, 1 H), 3.47ꢀ3.68 (m,
1 H), 3.69ꢀ3.89 (m, 1 H), 4.35ꢀ4.53 (m, 1 H), 4.55ꢀ4.65 (m, 1 H), 4.93ꢀ5.25 (m, 4 H), 5.27ꢀ5.34 (& 5.61ꢀ5.69)
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(m, 1 H), 6.39 (& 6.67) (bs, 1 H), 7.00ꢀ7.12 (m, 1 H), 7.20ꢀ7.45 (& 7.46ꢀ7.72) (m, 14 H); C NMR (125 MHz,
CDCl3, two conformational isomers): δ 36.2 (& 37.2), 48.8 (& 49.7), 53.6 (& 53.8), 57.8 (& 58.3), 67.3 (&
67.4), 67.5 (& 67.6), 120.0 (& 120.3), 123.3 (& 123.5), 127.6 (& 127.9), 128.0 (& 128.1), 128.2 (& 128.3),
128.5 (& 128.6), 128.63 (& 128.7), 129.1 (& 129.13), 132.0 (& 132.1), 135.0 (& 135.2), 136.0 (& 136.1),
138.6 (& 138.4), 154.2 (& 154.6), 155.0 (& 155.4), 173.8 (& 173.9); HRMS (ESIꢀTOF): m/z [M + H]+
calculated for C27H28N3O5: 474.2023; found: 474.2024.
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Synthesis of the ‘cis’ ureaꢀtagged proline catalyst [(2S,4S)ꢀ4ꢀ(3ꢀphenylureido)pyrrolidineꢀ2ꢀcarboxylic
acid (1b)]: To a solution of 4 (500 mg, 1.05 mmol) in MeOH (15 mL) was added 5% palladium on carbon (50
mg). The mixture was stirred for 2 h under hydrogen at room temperature and atmospheric pressure. The
reaction mixture was then filtered and washed with methanol (5 mL × 5). The combined organic layer was
concentrated in vacuo to afford the proline derivative 1b as a white hygroscopic solid (235 mg, 90%). [α]D20 = ꢀ
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103.57 (c = 2.8, MeOH); H NMR (500 MHz, D2O): δ 1.96ꢀ2.05 (m, 1 H), 2.51ꢀ2.61 (m, 1 H), 3.28 (dd, J = 5
& 12.5 Hz, 1 H), 3.45 (dd, J = 6.5 & 12.5 Hz, 1 H), 4.08 (dt, J = 1.4 & 8 Hz, 1 H), 4.26ꢀ4.35 (m, 1 H), 7.02 (t, J
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= 7.5 Hz, 1 H), 7.16 (d, J = 7.8 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 2 H); C NMR (125 MHz, D2O): δ 34.5, 49.2,
50.2, 60.0, 121.3, 124.2, 129.2, 137.7, 157.5, 173.9; HRMS (ESIꢀTOF): m/z [M + H]+ calculated for
C12H16N3O3: 250.1186; found: 250.1187.
Synthesis of dibenzyl (2S,4R)ꢀ4ꢀ(3ꢀphenylureido)pyrrolidineꢀ1,2ꢀdicarboxylate (4'): Prepared from transꢀ
NꢀCbzꢀ4ꢀaminoproline benzyl ester 3' (800 mg, 2.26 mmol) following the same procedure as described for 4
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above; colourless hygroscopic solid (920 mg, 86%). [α]D = ꢀ36.66 (c = 3, CHCl3); H NMR (500 MHz,
CDCl3, two conformational isomers): δ 2.11ꢀ2.23 (m, 1 H), 2.24ꢀ2.31 (& 2.34ꢀ2.43) (m, 1 H), 3.44 (& 3.54)
(dd, J = 3 & 11.5 Hz, 1 H), 3.81 (dd, J = 6 & 11 Hz, 1 H), 4.38ꢀ4.53 (m, 2 H), 4.90ꢀ5.20 (m, 4 H), 5.26 (&
5.30) (d, J = 7 Hz, 1 H), 6.73 (& 6.74) (bs, 1 H), 7.04ꢀ7.11 (m, 1 H), 7.20ꢀ7.38 (m, 14 H); 13C NMR (125 MHz,
CDCl3, two conformational isomers): δ 36.2 (& 37.4), 48.9 (& 49.5), 52.5 (& 52.8), 57.7 (& 58.1), 67.1 (&
67.3), 67.6, 120.3 (& 120.4), 123.7, 127.6 (& 127.7), 128.15, 128.2, 128.45, 128.5 (& 128.56), 128.6, 129.2,
135.3, 135.9 (& 136.0), 138.4, 154.6 (& 154.9), 155.0 (& 155.4), 171.6 (& 171.8); HRMS (ESIꢀTOF): m/z [M
+ Na]+ calculated for C27H27N3O5Na: 496.1843; found: 496.1843.
Synthesis of the ‘trans’ ureaꢀtagged proline catalyst [(2S,4R)ꢀ4ꢀ(3ꢀphenylureido)pyrrolidineꢀ2ꢀcarboxylic
acid (1c)]: Prepared from 4' following the same procedure as described for 1b above; white hygroscopic solid
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(158 mg, 85%). [α]D = ꢀ8.62 (c = 5.1, H2O); H NMR (500 MHz, D2O): δ 2.21ꢀ2.33 (m, 2 H), 3.23 (dd, J =
4.5 & 12 Hz, 1 H), 3.54 (dd, J = 6 & 12 Hz, 1 H), 4.18 (t, J = 8.5 Hz, 1 H), 4.29 (quintet, J = 5.5 Hz, 1 H), 7.03
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(t, J = 7.5 Hz, 1 H), 7.17 (d, J = 8 Hz, 2 H), 7.24 (t, J = 8 Hz, 2 H); C NMR (125 MHz, D2O): δ 34.5, 49.6,
50.6, 60.0, 121.5, 124.2, 129.1, 137.6, 157.7, 173.6; HRMS (ESIꢀTOF): m/z [M + H]+ calculated for
C12H16N3O3: 250.1186; found: 250.1174.
Typical Catalysis Procedure (Table 1, Entry 2):
Cyclohexanone (5, 0.26 mL, 2.5 mmol) and water (50 µL, 2.8 mmol) were added to the catalyst 1b (2.5 mg,
0.01 mmol) and the mixture was allowed to stir for 10 min at room temperature. 4ꢀNitrobenzaldehyde (6a, 75.5
mg, 0.5 mmol) was then added and the reaction mixture was allowed to stir at room temperature. After 8 h of
stirring, the reaction mixture was charged directly onto a silica gel column and eluted with petroleum ether /
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ethyl acetate (~7:3) to isolate the pure aldol product 7a (114.5 mg, 92%). The ee was determined by chiral
HPLC using a Daicel Chiralpak ADꢀH column (hexane / 2ꢀpropanol = 87.5:12.5, flow rate: 0.8 mL minꢀ1,
λ =
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254 nm); tR syn = 15.7 min, tR syn = 18.8 min, tR anti (minor) = 20.5 min, tR anti (major) = 27.1 min.
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2ꢀHydroxy(4ꢀnitrophenyl)methyl)cyclohexanꢀ1ꢀone (7a)22
Yield: 114.7 mg (92%)
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2ꢀHydroxy(2ꢀnitrophenyl)methyl)cyclohexanꢀ1ꢀone (7b)22
Yield: 117.1 mg (94%)
2ꢀHydroxy(3ꢀnitrophenyl)methyl)cyclohexanꢀ1ꢀone (7c)22
Yield: 112.2 mg (90%)
2ꢀ(Hydroxyꢀ(4ꢀcyanophenyl)methyl)cyclohexanꢀ1ꢀone (7d)23
Yield: 108.9 mg (95%)
2ꢀ(Hydroxy(4ꢀ(trifluoromethyl)phenyl)methyl)cyclohexanꢀ1ꢀone (7e)4e
Yield: 126.6 mg (93%)
2ꢀ(Hydroxy(perfluorophenyl)methyl)cyclohexanꢀ1ꢀone (7f)24
Yield: 145.7 mg (99%)
2ꢀ(Hydroxy(pyridinꢀ3ꢀyl)methyl)cyclohexanꢀ1ꢀone (7g)24
Yield: 92.4 mg (90%)
2ꢀ(Hydroxy(pyridinꢀ4ꢀyl)methyl)cyclohexanꢀ1ꢀone (7h)23
Yield: 97.5 mg (95%)
2ꢀ((4ꢀChloroꢀ3ꢀnitrophenyl)(hydroxy)methyl)cyclohexanꢀ1ꢀone (7i)25
Yield: 134.8 mg (95%)
2ꢀ((4ꢀChlorophenyl)(hydroxy)methyl)cyclohexanꢀ1ꢀone (7j)23
Yield: 79.9 mg (67%)
2ꢀ((3ꢀChlorophenyl)(hydroxy)methyl)cyclohexanꢀ1ꢀone (7k)26
Yield: 65.6 mg (55%)
2ꢀ((4ꢀBromophenyl)(hydroxy)methyl)cyclohexanꢀ1ꢀone (7l)23
Yield: 114.7 mg (81%)
2ꢀ(Hydroxy(phenyl)methyl)cyclohexanꢀ1ꢀone (7m)22
Yield: 53.1 mg (52%)
2ꢀ(Hydroxy(naphthalenꢀ2ꢀyl)methyl)cyclohexanꢀ1ꢀone (7n)23
Yield: 68.7 mg (54%)
2ꢀ(Hydroxy(3ꢀphenoxyphenyl)methyl)cyclohexanꢀ1ꢀone (7o)27
Yield: 88.9 mg (60%)
2ꢀ(Hydroxy(4ꢀmethoxyphenyl)methyl)cyclohexanꢀ1ꢀone (7p)23
Yield: 41.1 mg (35%)
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2ꢀ(Hydroxy(4ꢀnitrophenyl)methyl)cyclopentanꢀ1ꢀone (9a)23
Yield: 116.4 mg (99%)
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4ꢀHydroxyꢀ4ꢀ(4ꢀnitrophenyl)butanꢀ2ꢀone (9b)22
Yield: 83.7 mg (80%)
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2ꢀ(Hydroxy(4ꢀnitrophenyl)methyl)ꢀ4ꢀmethylcyclohexanꢀ1ꢀone (11)4b
Yield: 122.4 mg (93%)
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Typical Procedure for Catalyst Recycling Studies (Table 2)
Method A
Cyclohexanone (5, 0.26 mL, 2.5 mmol) and water (50 µL, 2.8 mmol) were added to the catalyst 1b (6.23 mg,
0.025 mmol) and the mixture was allowed to stir for 10 min at room temperature. 4ꢀNitrobenzaldehyde (6a,
75.5 mg, 0.5 mmol) was then added and the reaction mixture was allowed to stir for 6 h at room temperature.
The excess cyclohexanone was removed under reduced pressure and the reaction mixture was dried under
vacuum for 1 h. The reaction mixture was then extracted with Et2O (2 mL × 4) following which the reaction
flask was dried under vacuum for 1h. It was again charged with the reactants in identical amounts and order as
above. The crude product was purified by evaporation of the combined organic extracts and subjecting the
residue to silica gel chromatography to obtain the pure aldol 7a.
Method B
Same as Method A, except that the excess cyclohexanone was not removed prior to the extraction; the reaction
mixture was subjected directly to Et2O extraction.
Supporting Information
1
The chiral HPLC data of the aldol adducts (determination of ee), the H NMR spectra of the crude reaction
mixtures (determination of diastereomeric ratio), the 1H and 13C NMR spectra of the purified aldol adducts and
the spectral data of the catalyst and catalyst precursors are provided in the Supporting Information.
Acknowledgements
M.B. and K.K. thank UGC and CSIR respectively for a research fellowship. The authors gratefully
acknowledge funding received from UGC and CSIR, India in the form of research grants (UGC Grant Ref. No.:
F.30ꢀ97/2015(BSR); CSIR Grant Ref. No.: 02(0316)/17/EMRꢀII). The authors thank DSTꢀFIST for a research
grant to the Department of Chemistry (Grant Ref. No.: SR/FST/CSIꢀ257/2014 (C) and also thank Central
University of Rajasthan for support.
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R. L.; Joshi, N. N. Role of Additives in Chiral Amineꢀcatalyzed Direct Aldol Reaction. Synth.
Commun. 2014, 44, 352ꢀ360.
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