Synthesis and evaluation of (S)-proline-containing dipeptidic organocatalysts bound to MBHA resin in asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2015.09.062

The effectiveness of MBHA-bound dipeptidic organocatalysts 1a-d in the asymmetric aldol reaction between cyclohexanone and several aldehydes was evaluated. Under the optimum reaction conditions, which involved the use of Br?nsted acid and water as additiv

Full text of DOI:10.1016/j.tetlet.2015.09.062

Accepted Manuscript
Synthesis and evaluation of (S)-proline-containing dipeptidic organocatalysts
bound to MBHA resin in asymmetric aldol reactions
Elizabeth Machuca, Giovanna Granados, Bruno Hinojosa, Eusebio Juaristi
PII:
S0040-4039(15)30105-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.062
TETL 46734
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
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7 September 2015
16 September 2015
Please cite this article as: Machuca, E., Granados, G., Hinojosa, B., Juaristi, E., Synthesis and evaluation of (S)-
proline-containing dipeptidic organocatalysts bound to MBHA resin in asymmetric aldol reactions, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.062
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Synthesis and evaluation of (S)-proline-containing
dipeptidic organocatalysts bound to MBHA
resin in asymmetric aldol reactions.
Elizabeth Machuca, Giovanna Granados, Bruno Hinojosa,
Eusebio Juaristi*
Departamento de Química, Centro de Investigación
y de Estudios Avanzados, Instituto Politécnico Nacional,
Apartado Postal 14-740, 07000 México D.F., Mexico.

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis and evaluation of (S)-proline-containing dipeptidic organocatalysts bound
to MBHA resin in asymmetric aldol reactions.
Elizabeth Machuca, Giovanna Granados, Bruno Hinojosa, Eusebio Juaristi*
Departamento de Química, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Apartado Postal 14-740, 07000 México D.F., México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The effectiveness of MBHA-bound dipeptidic organocatalysts 1a-d in the asymmetric aldol
reaction between cyclohexanone and several aldehydes was evaluated. Under the optimum
reaction conditions, which involved the use of Brønsted acid and water as additives, it was found
that the presence of one glycine or one β-alanine residue in 1b and 1c resulted in improved
stereoselectivity relative to 1a. Supported organocatalyst 1d bound to the resin by a five
methylene spacer was also effective as catalyst. Representative organocatalyst 1c was re-used as
catalyst in five consecutive cycles in the asymmetric aldol reaction maintaining its effectiveness,
although some loss in yield and stereoselectivity was observed.
Available online
Keywords:
Asymmetric organocatalysis
Dipeptide
Aldol reaction
Green chemistry
2015 Elsevier Ltd. All rights reserved
.
1. Introduction
Results and discussion.
In recent years, synthetic chemists have drawn inspiration
from Nature when developing catalytic chemical reactions. A
notable example is the enormous advancement that has been
achieved in the area of asymmetric organocatalysis, inspired in
large measure by the mechanism of action of type I and type II
aldolases.1,2 In this regard, (S)-proline and derivatives have
proved to be particularly successful as a most simple enzymic
mimics, and have become indeed privileged chiral
organocatalysts.3
Organocatalysts 1a-d (Scheme 1) were manually synthesized
according to solid-phase peptide synthesis methodology, and
using Fmoc as protecting group, and then supported on MBHA
(4-methylbenzhydrylamine) resin.7
Recently, our research group has been involved in the design
and evaluation of (S)-proline-containing dipeptides as potential
organocatalysts.4 In this context, we became interested in the
preparation and use of derivatives that would be fixed to a resin
in order to improve the reaction conditions, and to allow reuse of
the catalyst, fulfilling one requirement of sustainable
chemistry.5,6
Scheme 1.Organocatalysts 1a-d anchored to MBHA (4-
methylbenzhydrylamine) resin studied in this work.
The present study examined the catalytic activity of four (S)-
proline-containing dipeptidic organocatalysts bound to MBHA
resin in asymmetric aldol reactions. In particular, this study
evaluated the effectiveness of the asymmetric catalyst when
varying the length of the linking connector (spacer) to the resin.
One goal of this analysis was to determine whether the spatial
position of the catalysts in the resin plays a relevant role in their
activity.
Organocatalysts 1a-d were evaluated in the asymmetric aldol
reaction between cyclohexanone and 4-nitrobenzaldehyde (Table
1). With 1a and after 24 hours of reaction, the aldol product
(2S,1'R)-4 was obtained in 92% yield, an anti:syn diastereomeric
ratio of 74:26, and enantiomer ratio of 77:23 for the major aldol
product (2S,1'R)-4 (Entry 1 in Table 1). By contrast, reaction
with organocatalyst-1b afforded the aldol product in only 27%
___________________________________________________________________________
*
Corresponding author. Tel.: +52 55 5747 3722; fax: +52 55 57473897.
E-mail addresses: juaristi@relaq.mx, ejuarist@cinvestav.mx (E. Juaristi).

2
Tetrahedron
yield, and low stereoselectivity (68:32 dr and 53:47 er. Entry 2
in Table 1). The low yield is probably the consequence of lack of
homogeneity of the system during the reaction. Results with
organocatalysts 1c and 1d are also included in Table 1. Both the
diastereomeric ratio and enantiomeric ratio are slightly lower
with 1c and 1d, relative to 1a.
Table 2.Optimization of the reaction conditions with
organocatalyst 1a, in the presence of water and Brønsted acid as
additives.
Table 1.Preliminary evaluation of the behavior of
organocatalysts 1a-d in the asymmetric aldol reaction between
cyclohexanone and 4-nitrobenzaldehyde.
Entry 2:H2O
Brønsted acid
Yield
(%)b
dr
erd
(anti:syn)c
1
2
3
4
5
-----
1.5:1
1:1
------
----
---
92
99
99
98
99
74:26
86:14
80:20
88:12
72:28
77:23
75:25
78:22
78:22
75:25
Entry
Cat.
1a
Yield (%)b
dr (anti:syn)c
74:26
erd
1
2
3
4
92
27
88
99
77:23
53:47
67:33
67:33
1:1.5
---
---
1b
1c
68:32
PhCO2H
(10 mol%)
PhCO2H
(5mol%)
PhCO2H
68:32
6
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
99
99
99
99
99
99
99
99
99
85:15
89:11
91:9
81:19
81:19
83:17
78:22
80:20
78:22
78:22
78:22
77:23
1d
68:32
7
aReaction conditions: cyclohexanone 2 (0.5 mL), 4-nitrobenzaldehyde 3 (0.20
mmol), Catalyst 1a-d (10mol %), 24 h. b Isolated yield. c Determined by 1H
NMR of the crude product. dDetermined by chiral HPLC.
(10 mol%)
PhCO2H
8
(20 mol%)
PhCO2H
(30mol%)
PhCO2H
(40mol%)
4-NO2-PhCO2H
(20mol%)
2-HO-PhCO2H
(20mol%)
(D)-mandelic
acid(20mol%)
(L)-mandelic
acid (20mol%)
9
85:15
86:14
87:13
85:15
87:13
90:10
For reaction optimization, the aldol reaction that was
catalyzed by dipeptide 1a was used as model (Table 2).8,9 In
particular, seeking to improve the diastereomeric and
enantiomeric ratios, we explored the effect of additives such as
water and Brønsted acids. Indeed, with different amount of water
present in the reaction system, both the reaction yield and
diastereoselectivity increased significantly. The best ratio of
cyclohexanone and H2O turned out to be 1:1.5 (99% yield, 83:17
anti:syn dr, 85:15 er. Entry 4 in Table 2).
10
11
12
13
14
In addition, we evaluated several Brønsted acids as additives,
a strategy that has proved useful to improve the enantioselectivity
of organocatalyzed reactions.10 When 10 mol% of benzoic acid
under neat conditions in the absence of water was added, the
reaction was substantially improved both in yield (the reaction
was essentially quantitative) and in time, requiring only 6 h
instead of 24 h (compare entries 1 and 5, Table 2).
aReaction conditions: cyclohexanone 2 (0.5 mL), 4-nitrobenzaldehyde 3 (0.20
b
mmol), Catalyst 1a (10mol %), H2O (0.75 mL), PhCO2H (20 mol %), 6 h.
Isolated yield. c Determined by 1H NMR of the crude product. dDetermined by
chiral HPLC.
To evaluate the potential synergistic effect of water and
Brønsted acid additives, we examined the effect of including
different amounts of benzoic acid in addition to a 1:1.5 mixture
of cyclohexanone and water. As it turned out, with 20 mol% of
benzoic acid in the presence of 1.5 mL of water, the degree of
stereoselectivity was improved substantially, obtaining the
adduct (2S,1'R)-4 in 91:9 dranti:syn and 83:17 enantiomeric ratio
(Entry 8 in Table 2). These results could not be improved further
with substituted benzoic acids (cf. entries 11 and 12 in Table 2)
or even with chiral organic acids as additives (cf. entries 13 and
14 in Table 2).
Subsequently, we determined the optimum amount of 1a
necessary to catalyze the desired reaction, finding that10 mol% is
the amount of organocatalyst that affords the best results (Entry 5
in Table 3).

3
Table 3.Evaluation of the amount of catalyst required for
efficient catalysis.
Regarding the ability to reuse the anchored organocatalysts, it
was confirmed that 1c can be reused at least 5 times, although
some loss in yield and stereoselectivity was observed (Table 5).
In this context, the organocatalyst can be recovered by simply
washing the resin with DCM before its reuse.
Table 5.Recycling organocatalyst 1c in the asymmetric aldol
reaction.
Entry
Amount
resine
1 %
Yield (%)b dr (anti:syn)c
erd (%)
-----
1
2
3
4
5
6
7
-----
53
91
98
99
99
99
-----
92:8
O
OH
O
O
1c
+
H
+
syn isomer
PhCO2H 20 mol%
72:28
78:22
72:28
83:17
75:25
80:20
NO2
NO2
anti isomer
3 %
90:10
92:8
4
2
3
5 %
Entry
Cycle
Yield (%)b
dr (anti:syn)c
94:6
erd (%)
89:11
84:16
80:20
83:17
96:4
10 %
20 %
30 %
91:9
84:16
87:13
1
2
3
4
5
1
2
3
4
5
97
93
60
63
75
76:24
86:14
aReaction conditions: cyclohexanone 2 (0.5 mL), 4-nitrobenzaldehyde 3 (0.20
84:16
b
mmol), Catalyst 1a (10mol %), H2O (0.75 mL), PhCO2H (20 mol %), 6 h.
Isolated yield. c Determined by 1H NMR of the crude product. dDetermined by
chiral HPLC.
84:16
aReaction conditions: cyclohexanone 2 (0.5 mL), 4-nitrobenzaldehyde 3 (0.20
b
Finally, we re-examined organocatalysts 1a-d under the
optimized reaction conditions, achieving the best results in the
aldol reaction organocatalyzed by dipeptide 1c. Thus, with 10
mol% of catalyst, 20 mol% of benzoic acid, and 1:1.5
cyclohexanone: water ratio, after 6 hours of reaction the desired
product (2S,1'R)-4a was obtained in 99% yield, 94:6 dr, and
89:11 er (Entry 3 in Table 4).
mmol), Catalyst 1c (10mol %), H2O (0.75 mL), PhCO2H (20 mol %), 6 h.
Isolated yield. c Determined by 1H NMR of the crude product. dDetermined by
chiral HPLC.
By contrast, organocatalysts 1a-d were not effective with less
electrophilic aldehydes. This behavior apparently has been
observed previously with other peptidic organocatalysts.11
Under the optimized reaction conditions, the observed
stereoselectivity was rather similar with all four organocatalysts.
Thus, the catalytic activity of the anchored organocatalysts is
little influenced by the length of the connector to the resin. As the
resin is a complex network of polymers, the different chains of
the spacer are apparently not differentiated in the space occupied
by the catalyst.
2. Conclusion
We carried out the synthesis of various (S)-containing
dipeptidic organocatalysts bound to MBHA resin and evaluated
their efficiency in the asymmetric aldol reactions between
cyclohexanone and 4-nitrobenzaldehyde. Spacers with different
chain size; i. e., with varying number of methylene units linking
the organocatalyst to the resin, were employed. Best results were
obtained with supported dipeptide 1c.
Table 4.Effect between the spacer in the resin organocatalysts
1a-d.
The supported organocatalysts can be reused, representing a
promising strategy for implementing the principles of green
chemistry.
Acknowledgments
The authors are indebted to Conacyt-México for financial support
via grant 130826. We are also grateful to Conacyt-México for a
doctoral fellowship to E. M. (No. 245138).
Entry
Cat.
1a
Yield (%)b
dr (anti:syn)c
91:9
erd (%)
83:17
88:12
89:11
86:14
1
2
3
4
99
72
97
99
1b
1c
93:7
94:6
References and Notes
1d
91:9
aReaction conditions: cyclohexanone 2 (0.5 mL), 4-nitrobenzaldehyde 3 (0.20
mmol), Catalyst 1a-d (10mol %), H2O (0.75 mL), PhCO2H (20 mol %), 6 h. b
Isolated yield. c Determined by 1H NMR of the crude product. dDetermined by
chiral HPLC.
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4
Tetrahedron
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7. The dipeptides were manually synthesized on MBHA resin (for 1a
0.43 mmoles, for 1b 0.29 mmoles, for 1c 0.27 mmoles, and for 1d
0.22 mmoles) with 0.63 mmol/gloading on T-bags reactors and
using Fmoc chemistry. In parallel, a second series was synthesized
on Rink-MBHA resin (0.74 mmol/g) using the same reaction
conditions. Syntheses were carried out only with (S)-amino acids
protected with N-α-fluorenylmetoxycarbonyl group (Fmoc). The
resins were solvated by successive washing steps with DCM (3 x