New and effective proline-based catalysts for asymmetric aldol reaction in water

Article abstract of DOI:10.1080/00397911.2016.1252988

New proline diamide organocatalysts with Pro-Phe peptide bonds were synthesized and their catalytic activities in asymmetric direct aldol reactions of aliphatic ketones with aromatic aldehydes were investigated. Catalyst 6a showed good enantioselectivity

Full text of DOI:10.1080/00397911.2016.1252988

New and Effective Proline Based Catalysts for Asymmetric Aldol Reaction in Water
1
1
1
Tugba Yorulmaz , Feray Aydogan , Cigdem Yolacan
1
Department of Chemistry, Yildiz Technical University, Esenler, Istanbul, Turkey
Corresponding author Cigdem Yolacan E-mail: cigdemyolacan@hotmail.com
Abstract
New proline diamide organocatalysts with Pro-Phe peptide bond were synthesized and
their catalytic activities in asymmetric direct aldol reactions of aliphatic ketones with
aromatic aldehydes were investigated. Especially, catalyst 6a showed good
o
enantioselectivity at 0 C in the presence of p-nitrobenzoic acid as co-catalyst in water.
Graphical Abstract
KEYWORDS: Aldol reaction; Proline diamide; Organocatalysis; Water medium
INTRODUCTİON
Organocatalysts are non-metal small organic compounds which have carbon, nitrogen,
[
1,2]
hydrogen, sulfur and phosphorus.
Because of their advantages such as non-toxicity,
reduction in hazardous chemical waste, saving cost, time and energy, non-inert reaction
[
3]
conditions and easy to use , these pure compounds have attracted researcher’s attention
for asymmetric version of various reactions. Diversity and applications of asymmetric
organocatalysts have been increased last decades. Proline keeps its popularity among the
1

[
4]
asymmetric organocatalysts since the first report by List. Proline has important
properties expected from an asymmetric organocatayst, for example it is easily available
in two enantiomeric form and cheap natural compound. But, proline have some
disadvantages such as insolubility in most organic solvents, some side reactions, and low
[
5]
selectivity with aromatic aldehydes. To overcome these disadvantages and to
accomplish high enantiopurity; some bifunctional proline derivatives have been designed
[
6–20]
and investigated for various reactions.
The most important one of the reactions used
proline derivatives as catalyst is aldol condensation which provides effective route to β-
hydroxy carbonyl compounds which are important precursors of biologically active
[
21-23]
natural and synthetic compounds.
prepared and used for direct asymmetric aldol reaction successfully.
organic solvents as reaction medium is an obvious disadvantage of most of these proline
Several diamide derivatives of proline have been
[
24-29]
But, using of
[
30, 31]
derivatives from the environmental aspect.
So, the development of new asymmetric
organocatalysts which are effective in water is also important contribution to green
[
32-35]
chemistry.
But as far as we know, there are only few examples for the asymmetric
[
36-43]
direct aldol reactions in water in the literature.
In this study, we have designed,
synthesized and investigated a new kind of proline based diamide asymmetric
organocatalysts (Figure 1) for direct asymmetric aldol condensation. According to
computational and experimental studies in the literature, double H-bonds interactions
with carbonyl oxygen provide more electrophile activation and rigidity in transition state
rather than single H-bonds. These interactions can increase the strength and
directionality, induce the enantioselectivity and contribute the effectiveness of catalyst.
[
15,20,44,45]
It was expected that diamide structures would show better H-bonding activity
2

than monoamide compounds due to two amide NH group. Besides, bulky groups were
also chosen on amide moieties for steric interaction to improve the stereoselectivity.
These new proline based diamide compounds are very effective organocatalysts with
high enantioselectivity in water.
RESULTS AND DİSCUSSİON
The proline based diamide organocatalysts (6a-f) (Figure 1) were prepared by simple
amidation reactions of L-proline. More detailed and as outlined in Scheme 1, after
protection of L-proline, amidation with L-phenylalanine methyl ester, hydrolysis of ester
group, second amidation with different amines and deprotection of Boc group according
[
46]
1
13
to literature procedure,
catalysts 6a-f were successfully prepared and H NMR, C
NMR, FTIR, LC-MS (QTOF) data were used to confirm the structure.
The catalytic activities of organocatalysts were investigated on the aldol reaction of 4-
nitrobenzaldehyde with cyclohexanone as a model reaction. To compare the catalytic
activities of new diamide derivatives, the model reaction was carried out under different
reaction conditions in the presence of benzoic acid co-catalyst. The reactions were
o
investigated at room temperature or 0 C with some typical solvents such as water,
dichloromethane (DCM), THF/water or without any solvent. Promising results were
obtained from the catalysts 6a, b, d and f in water as shown in Table 1. Generally,
benzoic acid, p-nitrobenzoic acid, TFA, acetic acid, tartaric acid have been investigated
as co-catayst for this reaction via an enamine mechanism, while benzoic acid and p-
[
17, 19, 28, 46]
nitrobenzoic acid have been found to be more effective ones in the literatures.
3

So, p-nitrobenzoic acid was also used as a co-catalyst. As one can see from the Table 2,
considering the yield, enantioselectivity and diastereoselectivity, catalyst 6a gave the best
results (99% yield, 92% ee and 93:7 dr) and was chosen for further evaluation. This high
activity may be due to the strong H-bond formation between amide N-H protons of
catalyst and aldehyde (Figure 2).
To broaden the substrates of the reaction, different aliphatic ketones and aromatic
aldehydes were furtherly studied in the presence of the optimal catalyst 6a (Table 3). The
aldol products are known in the literature, and their structure are in agreement with the
[
38, 39]
literature data.
The diastereomeric ratios and enantiomeric excesses were
[30, 47, 48]
determined by chiral HPLC analysis of products by using literature methods.
CONCLUSİON
As a result, we have designed and developed a new kind of proline based diamide
organocatalysts and successfully used in the direct asymmetric aldol reaction of aliphatic
ketones and aromatic aldehydes in water. Those new catalysts showed excellent catalytic
activity (up to 99% yield), enantioselectivity (up to 95% ee) and good diasereoselectivity
(up to 97:3). Especially, catalyst 6a, a proline based tripeptide, as the most effective
organocatalyst, gave the best results when different aliphatic ketones and aromatic
aldehydes with electron withdrawing groups were used.
EXPERİMENTAL
4

All reagents were of commercial quality and reagent quality solvents were used without
further purification. IR spectra were determined on a Perkin Elmer, Spectrum One FT-IR
spectrometer and Bruker Tensor 27 spectrometer. NMR spectra were recorded on Varian-
4
00 MHz High Resolution NMR spectrometer and Bruker Avance III 500 MHz
spectrometer. Chemical shifts δ are reported in ppm with TMS as internal standart and
the solvents are CDCl , CD OCD and CD OD. Column chromatography was conducted
3
3
3
3
on silica gel 60 (40–63 μM). TLC was carried out on aluminum sheets precoated with
silica gel 60F254 (Merck). LC-MS (QTOF) spectra were obtained on Agilent G6530B
model TOF/Q-TOF Mass Spectrometer. Optical rotations were measured with
Bellingham Stanley ADP-410 Polarimeter. Chiral HPLC analysis were performed with
Shimadzu HPLC (Daicel Chiralpak AD columns) equipped with SPD-20A detector and
[
49, 50]
isopropanol-n-hexane mixtures as the eluent. The protection of L-proline
and
[
51]
[51]
synthesis of compound 2 and 3 were carried out according to the literature
procedure. Spectroscopic data of these compounds were in accordance with their
structures.
Synthesis Of The Catalysts
General Procedure For Amidation Reactions
o
At 0 C and with stirring, to the solution of L-N-Boc-proline (2) (0.92 mmol) in dry THF,
HOBt (1.0 mmol) was added, and stirred for 10 min, then DCC (in the case of tyrosine
o
methyl ester, DIC) (1.0 mmol) was added. The mixture was stirred at 0 C for 1 h, and the
amine or aminoalcohol (1.02 mmol) was added (in the case of amino acid ester
hydrochloride, to the suspension of amino acid ester hydrochloride in dry THF,
5

triethylamine (0.5 mL) was added and stirred at room temperature for 1 h, and this
solution was added to the first mixture). The reaction mixture was stirred at room
temperature for 24 h, and the reaction was monitored by TLC. The formed precipitate
was removed by filtration, and the filtrate was evaporated under vacuum. The residue
was dissolved in 50 mL of ethyl acetate, the formed solution was washed successively
with saturated aqueous solution of NaHCO (30 ml x 3), 5% aqueous solution of KHSO
3
4
(30 ml x 3) and saturated aqueous solution of NaCl (30 ml x 3), and dried with anhydrous
Na SO . After filtration, the filtrate was evaporated under vacuum to give the crude
2
4
products which were purified by column chromatograpy on silica gel.
(S)-tert-Butyl 2-(((S)-1-(((S)-1-methoxy-4-methyl-1-oxopentan-2-yl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidin-1-carboxylate (5a). White solid, yield 68%, mp
o
20
1
17-118 C; [α]D -58.6 (c= 1.2, CHCl ). 1H NMR (500 MHz, CDCl ) δ 0.81 (d, J=6.5
3 3
Hz, 3H), 0.83 (d, J=5.5 Hz, 3H),1.31 and 1.36 (s, 9H, rotamers), 1.44-1.54 (m, 3H), 1.64-
.67 (m, 1H), 1.75-2.06 (m, 3H), 3.00-3.39 (m, 4H), 3.63 (s, 3H), 4.11-4.16 (m, 1H) 4.45
and 4.49 (m, 1H), 4.58-4.62 (m, 1H), 6.22, 6.56 and 6.68 (brs, 2H, rotamers), 7.10-7.18
m, 3H), 7.21-7.23 (m, 2H); 13C NMR (125 MHz, CDCl ) δ 20.7, 21.7, 23.3, 23.5, 27.2,
1
(
3
2
1
7.9, 36.0, 39.9, 46.2, 49.8, 51.2, 52.3, 59.5, 79.6, 126.0, 127.5, 128.2, 135.4, 154.5,
+
69.5, 170.7, 171.7; LC-MS (ESI-QTOF) m/z [M+H] , found 490.2900. C H N O
2
6
39
3
6
requires 490.2917; IR (Atr) ν 3377, 3278, 3073, 3031, 2975, 2953, 2931, 2873, 1739,
-1
1
679, 1645, 1523 cm .
General Procedure For Deprotection Of Boc Group
6

To the solution of N-Boc-protected compounds (5 a-f) (1.0 mmol) in dry CH Cl (15
2
2
o
mL) at 0 C, trifluoroacetic acid (27.0 mmol) was added dropwise over 5 min while
o
stirring. The reaction mixture was stirred at 0 C for 1 h and at room temperature for 2 h
then 2M K CO was added to adjust basic pH. The organic phase was washed with water,
2
3
dried over MgSO , filtrated and evaporated to give the pure compounds.
4
(S)-Methyl 4-methyl-2-((S)-3-phenyl-2-((S)-pyrrolidin-2-carboxyamido)-propanamido)
o
20
pentanoate (6a). White solid, yield 68%, mp 153-154 C; [α]D -58.8 (c= 1.0, CHCl ). 1H
3
NMR (500 MHz, CD OD) δ 0.93 (d, J= 6.5 Hz, 3H), 0.97 (d, J= 6.0 Hz, 3H), 1.47-1.58
3
(m, 2H), 1.60-1.66 (m, 3H), 1.67-1.72 (m, 1H), 1.98-2.06 (m, 1H), 2.75-2.80 (m, 1H),
2
4
.85-2.93 (m, 2H), 3.20 (dd, J= 13.75, 5.0 Hz, 1H), 3.59-3.62 (m, 1H), 3.72 (m, 3H),
.48-4.51 (m, 1H), 4.69-4.72 (m, 1H), 7.20-7.29 (m, 5H); 13C NMR (125 MHz, CD OD)
3
δ 21.8, 23.3, 25.9, 26.9, 31.8, 39.2, 41.4, 47.9, 52.1, 52.7, 54.9, 61.4, 127.8, 129.4, 130.4,
+
1
38.1, 173.6, 174.3, 177.3; LC-MS (ESI-QTOF) m/z [M+H] , found 390.2376.
C H N O requires 390.2393; IR (Atr) ν 3321, 3223, 3062, 3027, 2955, 2866, 1738,
21
31
3
4
-1
1
688, 1646, 1520 cm .
General Procedure For Aldol Reaction
The catalyst 6a (0.1 mmol) and p-nitrobenzoic acid (0.1 mmol) were stirred in water at 0
o
C for 10 min. Then, aldehyde (1.0 mmol) and ketone (10.0 mmol) were added and the
o
reaction mixture was stirred at 0 C until the reaction completed. After evaporation of
water, the crude products were purified by column chromatography eluted by
7

EtOAc/hexane. The enantioselectivity was determined by chiral HPLC with a Chiralpack
AD column (UV detection set at 254 nm, i-PrOH/n-hexane as eluent).
ACKNOWLEDGEMENTS
We thank Yildiz Technical University Scientific Research Foundation (2013-01-02-
KAP02) for financial support.
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[
1
1
1

Table 1. Screening of organocatalysts for the aldol reaction with benzoic acid co-catalyst
a
a
b
Catalyst Solvent
Temperature
Reaction
time (h)
72
dr
ee (%) Yield
o
(
C)
(anti/syn) (anti)
(%)
19
92
81
95
88
42
85
93
93
60
97
97
63
99
89
99
98
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
a
a
a
a
b
b
b
b
c
c
c
d
d
d
d
d
CH Cl
rt
rt
0
rt
70:30
63:37
74:26
54:46
53:47
59:41
62:38
82:18
79:21
72:28
61:39
66:34
69:31
67:33
84:16
52:48
77:23
39
84
88
67
75
56
80
67
76
55
60
62
60
80
89
83
80
2
2
H O
2
48
H O
2
24
none
48
THF:H O (1:2) rt
48
2
CH Cl
rt
rt
rt
72
2
2
H O
2
48
none
24
THF:H O (1:2) rt
72
2
CH Cl
rt
rt
rt
rt
rt
0
72
2
2
H O
2
24
none
24
CH Cl
72
2
2
H O
2
24
H O
2
24
none
rt
24
THF:H O (1:2) rt
48
2
1
2

6
6
6
6
6
6
e
e
e
f
CH Cl
rt
0
72
24
24
72
24
24
48
68:32
69:31
67:33
76:24
95:5
44
57
63
57
77
63
72
65
90
54
51
90
97
57
2
2
H O
2
none
rt
rt
rt
rt
CH Cl
2
2
f
H O
2
f
none
68:32
77:23
6
f
THF/H O (1:2) Rt
2
a
Determined by chiral-phase HPLC analysis.
Combined yields of isolated diastereomers.
b
1
3

Table 2. Screening of organocatalysts for the aldol reaction with p-nitrobenzoic acid co-
catalyst
a
a
b
Catalyst Solvent Temperature
Reaction
dr
ee (%)
Yield
(%)
71
o
(
C)
time (h)
24
(anti/syn)
80:20
93:7
(anti)
86
6
6
6
6
6
6
6
6
6
a
a
a
b
d
d
d
d
f
H O
rt
0
rt
rt
rt
0
rt
0
rt
0
2
H O
2
48
92
99
none
24
74:26
86:14
89:11
80:20
55:45
93:7
70
97
H O
2
24
84
92
H O
2
24
83
98
H O
2
72
88
96
none
none
48
82
76
48
86
95
H O
2
24
82:18
95:5
75
95
6
f
H O
2
24
85
99
a
Determined by chiral-phase HPLC analysis.
Combined yields of isolated diastereomers.
b
1
4

Table 3. The aldol reactions of 6a with different aldehydes
a
a
b
Ketone
Aldehyde
Reaction dr
ee (%) Yield
time (h)
48
(anti/syn) (anti)
(%)
97
98
99
91
98
94
98
55
Cyclohexanone 2-Nitrobenzaldehyde
Cyclohexanone 3-Nitrobenzaldehyde
Cyclohexanone 4-Nitrobenzaldehyde
Cyclohexanone 4-Cyanobenzaldehyde
Cyclohexanone 4-Bromobenzaldehyde
97:3
82:18
93:7
79:21
96:4
80:20
32:68
-
93
92
92
87
95
89
65
81
48
48
24
48
Cyclohexanone 4-(Trifluoromethyl)benzaldehyde 48
c
Cyclopentanone 4-Nitrobenzaldehyde
48
48
Acetone
4-Nitrobenzaldehyde
a
Determined by chiral-phase HPLC analysis.
Combined yields of isolated diastereomers.
syn isomer
b
c
1
5

Scheme 1. The synthetic route of organocatalysts
1
6

Figure 1. The structures of diamide organocatalysts (6a-f)
1
7

Figure 2. Proposed transition state
1
8