Various polar tripeptides as asymmetric organocatalyst in direct aldol reactions in aqueous media

Article abstract of DOI:10.1002/chir.22205

A series of tripeptide organocatalysts containing a secondary amine group and two amino acids with polar side chain units were developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. The eff

Full text of DOI:10.1002/chir.22205

CHIRALITY (2013)
Various Polar Tripeptides as Asymmetric Organocatalyst in Direct
Aldol Reactions in Aqueous Media
SAADI BAYAT,1 BIMO A. TEJO,1 ABU BAKAR SALLEH,2 EMILIA ABDMALEK,1 YAHAYA M. NORMI,2 AND
1
*
MOHD BASYARUDDIN ABDUL RAHMAN
1Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
2Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
ABSTRACT
A series of tripeptide organocatalysts containing a secondary amine group and
two amino acids with polar side chain units were developed and evaluated in the direct asymmet-
ric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. The effectiveness of
short polar peptides as asymmetric catalysts in aldol reactions to attain high yields of enantio-
and diastereoselective isomers were investigated. In a comparison, glutamic acid and histidine
produced higher % ee and yields when they were applied as the second amino acid in short tri-
meric peptides. These short polar peptides were found to be efficient organocatalysts for the
asymmetric aldol addition reaction in aqueous media. Chirality 00:000–000, 2013.
Periodicals, Inc
© 2013 Wiley
KEY WORDS: short polar peptide; Aldol reaction, asymmetric; organocatalyst
INTRODUCTION
EXPERIMENTAL SECTION
Materials and Instruments
The development of metal-free asymmetric organocatalysts
has emerged as an attractive field in organic chemistry to pro-
duce enantio- and diastereoselectivity products in the past few de-
cades.1–4 Either secondary or primary amino acids have proven to
be useful organocatalyst for direct aldol reactions.5–8 In recent
years, L-proline and derivatives have been frequently developed
for aldol and many other reactions.9–11 Proline is a privileged
catalyst able to promote various highly enantioselective transfor-
mations.12,13 However, it only provides high stereoselectivity for
the direct aldol reaction of aliphatic aldehydes with ketones.14
Aromatic aldehydes appear to be challenging substrates of the
proline catalyzed aldol reaction. Thus, the development of new
efficient organocatalysts other than amino acids for direct aldol
reactions is in great demand. The presence of both a pyrrolidine
ring and the acidic proton of carboxylic acid are crucial for
reactivity and stereoselectivity. Barbas and co-worker studies
showed that the simple L-prolinamide with the acidic nature of
the –CONH proton is less, therefore it is an ineffective catalyst
for the aldol rection.6 To overcome this problem a range of
prolinamide derivatives including di- and tri-peptides were devel-
oped to be excellent catalysts for asymmetric transformation.15–20
Synthetic peptides have the advantage of designable modularity,
are readily available, and they are made up from the same chiral
building blocks (amino acid residues) as enzymes. Hydrogen
bonding activation has been confirmed to be an extremely
powerful strategy for the construction of enantioselective
transformations.21–24 We became interested designing short
polar tripeptides with different positions to compare their
catalytic activity in aldol reactions. We envisaged that the
hydroxyl, carboxylic, and imidazol groups after peptidation
with proline would provide an additional push in the catalytic
aldol process due to creation of hydrogen bonding. For this
purpose, L-tyrosine, L-histidine, and L-glutamic acid were
chosen to synthesize short polar peptides attached to the
L-proline as a first sequence (Fig. 1). Since water is the reac-
tion media for most enzymatic reaction in living systems, our
group, with inspiration from the natural system, used the
ecofriendly solvents in aldol reactions.
All chemicals were purchased and used without further purification.
Analytical thin-layer chromatography (TLC) was performed using a
Merck 60 F254 precoated silica gel plate (0.2 mm thickness). Flash
chromatography was performed using Merck silica gel 60 (70–230
mesh). For Fourier transform infrared spectroscopy (FTIR), a Perkin
Elmer Spectrum 100 was used for identification of functional groups. Nu-
clear magnetic resonance (NMR) data were recorded on 700 and
500 MHz for 1H NMR and 100 MHz for 13C NMR (JEOL JNM ECA
and Bruker 700 MHz) spectrometer. The relative and absolute configura-
tions (dr) of the aldol reactions were determined by comparison with 1H
NMR spectroscopic analysis. Mass spectra (MS) were measured with a
spectrometer (DIMS QP5050A Shimadzu). Enantioselectivity was deter-
mined by high-performance liquid chromatography (HPLC) (Waters
1525 Binary Pump and UV-Water 2489) analysis employing a Daicel
ChiralCel OD-H and Chiralpak AD-H columns (4.6 × 250 mm). Purity of
peptide (overall, more than 95%) was measured by analytical Waters
HPLC (Binary HPLC pump 1525 and UV-Waters 2489), (RPC18, Xbridge
4.6 × 250 mm), flow rate 0.5 ml/min, 220 nm. ChemDraw Ultra 8. was used
to draw chemical structures.
Catalyst Preparation
All tripeptides (Fig. 1) were used for this work. Synthesizing and purifica-
tion of these were carried out according to the Fmoc solid-phase strategy.
Briefly, each peptide was synthesized from a Fmoc-Rink-Amide-Am-Resin
manually, using 3-fold molar excess of amino acid derivatives with HCTU/
DIPEA as the coupling reagent and double coupling cycles. At the end of syn-
thesizing, peptide was separated from cocktail by use of trifluoroacetic acid
(TFA, 92.5%), triisopropylsilane (2.5%), 1,4 dithiothritol (2.5%), and water
(2.5%). Ten ml of this mixture was used for 1 gr resin within 2 h. The peptide
was precipitated in dry diethyl ether and lyophilized. Purity of peptide (overall,
more than 95%) was measured by analytical Waters HPLC (Binary HPLC
Additional Supporting Information may be found in the online version of this
article.
Correspondence to: Mohd Basyaruddin Abdul Rahman, Department of Chem-
istry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Serdang,
Selangor, Malaysia. E-mail: basya@upm.edu.my
Received for publication 27 April 2013; Accepted 29 May 2013
DOI: 10.1002/chir.22205
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2013 Wiley Periodicals, Inc.

BAYAT ET AL.
Fig. 1. Short polar tripeptides by reverse sequence.
pump 1525 and UV-Waters 2489), (RPC18, Xbridge 4.6 × 250 mm), flow rate
0.5 ml/min, 220 nm (Scheme 1).
NMR (500MHz, CDCl3): δ (ppm) = 1.30–1.39 (m, 1H),
1.48-1.61 (m, 3H), 1.62–1.66 (td, J = 13, 3.5 Hz, 1H), 1.78–1.81
(m, 1H), 2.06-2.11 (m, 1H), 2.30-2.37 (td, J = 13.75Hz,
J = 6.9 Hz, 1H), 2.45-2.48(m, 1H), 2.54–2. 52(m, 1H), 4.82 (d,
J = 8 Hz, 1H), 7.44 (d, J = 9.15 Hz, 2H), 8.14 (d, J = 9.15Hz, 2H).
13C NMR (100 MHz, CDCl3) δ = 24.66, 27.63, 30.74, 42.65,
57.16, 74.01, 123.56, 123.52, 127.85, 128.47, 130.17, 133.73,
148.30, 214.76. DEPT90 and 135 deg show four methylene groups
(negative) and six methine groups (positive). MS (DI) = 249.
Yield: 98%. The ee of the product was determined by chiral
HPLC (ChiralCel OD-H, iPrOH/n-hexane 5/95, flow rate= 0.8
mL/min, λ = 254 nm), ): tmajor = 21.940min, tminor = 29.882
min, ee = 94%, dr= 95/5 (anti/syn).
General Procedure for the Catalytic Direct Asymmetric
Aldol Reaction
To H2O (0.6 mL) was added the corresponding catalyst (0.004 mmol,
3.0 mol%,), NMM (pH = 5–5.5), and iPrOH (0.4 mL). The reaction mixture
was stirred for 20 min followed by addition of the corresponding ketone
(0.168 mmol, 1.2 eq). Then the requisite aldehyde (0.14 mmol, 1 eq) was
added to the reaction mixture. The resulting mixture was stirred at room
temperture (RT) for 24 h. The reaction was monitored by TLC. This was
then treated with saturated ammonium chloride solution and the mixture
was extracted with ethyl acetate (3 × 2 mL). The combined organic extract
was washed with brine, dried (Na2SO4), and concentrated in vacuo. After
NMR analysis to determine diastereomeric ratio where needed, the resi-
due was purified by flash column chromatography with hexanes/ethyl ac-
etate (3:1) to afford the aldol products that were subjected to chiral HPLC
analysis to determine enantiomeric excesses.
(S)-2-((S)-(2-chlorophenyl)(hydroxyl)methyl)cyclohexanone 2a.
FT-IR (cm-1): 3437, 2940, 2864, 1696, 1438, 1030, 756; 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.51–1.81 (m, 5H), 2.04–2.1 (m,
1H), 2.29–2.35 (td, J = 13.75 Hz, J = 7 Hz 1H), 2.43–2.46 (m, 1H),
2.63-2.68 (m, 1H), 5.33 (d, J = 8 Hz, 1H), 7.20 (dd, J = 8, J = 2.3 Hz,
(R)-2-((S)-hydroxy(4-nitrophenyl)methyl)cyclohexanone 1a. FT-IR
(cm-1): 3510, 2938, 2901, 2875, 1686, 1603, 1507, 1339; 1H
Scheme 1. Solid phase synthesis of peptide 1 as a model.
Chirality DOI 10.1002/chir

TRIPEPTIDES AS ASYMMETRIC ORGANOCATALYST
determined by chiral HPLC (ChiralCel OD-H, iPrOH/n-hexane
10/90, flow rate= 1 mL/min, λ = 254 nm), tmajor = 15.172 min,
tminor = 17.852 min, ee = 81%, dr= 98:2 (anti/syn)
(R)-2-((S)-(4-chlorophenyl)(hydroxy)methyl)cyclohexanone
4a.
FT-IR (cm-1): 2828, 2663, 2552, 1678, 1418, 1284, 926; 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.25–1.27 (m, 2H), 1.52–1.55
(m, 2H), 1.56–1.60 (m, 1H), 1.60–1.63 (m, 1H), 2.07-2.08 (m,
1H), 2.31-2.37 (td, J = 13.7 Hz, J = 6.8 Hz, 1H), 2.46-2.53 (m,
Scheme 2. Aldol reaction catalyzed by peptide 1.
1H),
2.54-2.55 (m, 1H), 4.76 (d, J = 9.15 Hz, 1H), 7.25
(d, J = 9.15 Hz, 2H), 7.32 (d, J = 9.15 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ = 24.68, 27.71, 30.74, 42.65, 57.34,
74.13, 128.36, 128.52, 130.16, 133.58, 133.66, 139.43,
TABLE 1. Effect of the solvent ratio on the catalytic aldol
reaction between cyclohexanone and p-nitrobenzaldehydes
catalyzed by 1a
and 135 deg
215.37. DEPT90
demonstrate four methylene
groups (negative) and 6 methine groups (positive). MS
(DI) = 238. Yield: 96%. The ee of the product was deter-
i
mined by chiral HPLC (ChiralCel OD-H, PrOH/n-hexane
5/95, flow rate = 0.5 mL/min, λ = 254 nm): tmajor = 22.316
min, tminor = 29.783 min, ee = 86%, dr = 93:7 (anti/syn).
2-((S)-(4-(trifluoromethyl)phenyl)(hydroxy)methyl)cyclohexa-
none 5a. FT-IR (cm-1): 3065, 2828, 2663, 2552, 1678, 1418,
1
1285, 928; H NMR (500 MHz, CDCl3): δ (ppm) = 1.18–1.21
(m, 2H),
1.47–1.49 (m, 2H), 1.49-1.52 (m, 1H), 1.53–1.61
(m, 1H), 2.02- 2.04 (m, 1H), 2.28–2.32 (td, J = 5.7 Hz,
J = 13.7 Hz, 1H), 2.40-2.43 (m, 1H), 2.50-2.52 (m, 1H), 4.77
(d, J = 8 Hz, 1H), 7.37 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ = 24.70, 27.68, 30.74, 42.66,
57.24, 74.27, 122.99, 125.28, 125.32, 126.05, 127.34, 129.96,
144.93, 215.10. DEPT90 and 135 deg demonstrate four methy-
lene groups (negative) and six methine groups (positive).
MS(DI) = 272. Yield: 97%. The ee was determined by chiral
Entry
Water (ml)
iPrOH (ml)
Yieldb [%]
eec [anti](%)
1
2
3
4
5
6
7
8
9
10
0
1
70
72
77
80
85
92
93
90
82
69
65
70
73
73
76
78
81
80
72
70
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
i
HPLC (Chiral OD-H, PrOH/n-hexane 10/90, flow rate = 0.5
mL/min, λ = 254 nm): tmajor = 23.901 min, tminor = 32.114
min, ee = 70%, dr = 90 : 10 (anti/syn).
2-((S)-(4-bromophenyl)(hydroxy)methyl)cyclohexanone
6a.
FT-IR (cm-1): 2941, 2833, 2659, 2550, 1678, 1415, 1281,
925; 1H NMR (500 MHz, CDCl3): δ (ppm) = 1.25–1.32
(m, 1H), 1.49–1.69 (m, 4H), 1.71–1.85 (m, 1H), 2.06–2.10
(m, 1H), 2.31–2.39 (td, J = 13.7 Hz, J = 5.7 Hz, 1H), 2.43–2.48
(m, 1H), 2,52–2.57 (m, 1H), 4.74 (d, J = 9.2 Hz, 1H), 7.19 (d,
J = 8 Hz, 2H), 7.46 (d, J = 8 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ = 24.67, 27.69, 30.73, 42.64, 57.28, 74.18, 121.70,
127.50, 128.71, 130.14, 131.47, 139.93, 215.33. DEPT90 and
aReaction condition: p-nitrobenzaldehyde (30 mg, 0.198 mmol, 1 eq), cyclohexa-
none (23.3 mg, 0.238 mmol, 1.2 eq), NMM (pH = 5–5.5) , solvents at RT within 24 h.
bIsolated yield.
cDetermined by HPLC on CHIRALCEL OD-H column.
1H), 7.26–7.31 (m, 2H), 7.52 (dd, J = 8, J = 2.3Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ = 24.84, 27.76, 30.35, 42.66, 57.52, 70.40,
127.19, 128.19, 128.70, 129.16, 132.91, 139.00, 215.26. DEPT90
and135degdemonstratefourmethylenegroups(negative)andsix
methine groups (positive). MS(DI) = 238. Yield: 97%. The ee of
the product was determined by chiral HPLC (ChiralCel OD-H,
iPrOH/n-hexane 10/90, flow rate = 1.3 mL/min, λ = 254 nm),
tmajor = 8.670 min, tminor = 10.822 min, ee = 88%, dr = 99/1
(anti/syn).
135 deg
demonstrate four methylene groups (negative) and
six methine groups (positive). MS(DI) = 282. Yield: 96%.
The ee was determined by chiral HPLC (Chiral OD-H,
iPrOH/n-hexane 10/90, flow rate = 1 mL/min, λ = 254 nm):
tmajor = 12.366 min, tminor = 15.775 min, ee = 78%, dr = 75: 25
(anti/syn).
2-[Hydroxy-(4-cyano-phenyl)-methyl]-cyclohexanone 7a. FT-IR
(R)-2-((S)-hydroxy(2-nitrophenyl)methyl)cyclohexanone 3a. FT-IR
(cm-1): 3411, 2942, 2866, 1703, 1524, 1349; 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.53–1.75(m, 5H), 1.80–1.85 (m,
1H), 2.05–2.11 (m, 1H), 2.28–2.35 (td, J = 13.75 Hz, J = 7 Hz,
1H), 2.40–2.45 (m, 1H), 5.42 (d, J = 6.85 Hz, 1H), 7.40 (t,
J = 8 Hz, 1H), 7.61 (t, J = 6.9 Hz, 1H), 7.74 (d, J = 8 Hz, 1H), 7.82
(d, J = 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 24.96,
27.74, 31.11, 42.81, 57.27, 69.77, 124.08, 128.39, 128.97, 133.07,
136.58, 148.69, 215.02. DEPT90 and 135 deg demonstrate four
methylene groups (negative) and six methine groups (posi-
tive). MS(DI)= 249. Yield: 96%. The ee of the product was
(cm-1): 3425, 3356, 2932, 2860, 1688, 1481, 1053, 824; 1H
NMR (500 MHz, CDCl3):
1.62–1.71 (m, 3H), 1.89–1.99 (m, 2H), 2.06–2.12 (m,
1H), 2.29–2.35 (m, 1H), 4.75 (d, J = 9.15 Hz, 1H), 5.31
δ (ppm) = 1.43–1.54(m, 1H),
(d, J = 2.3 Hz, 1H) 7.41 (d, J = 8 Hz, 2H), 7.58 (d,
J = 8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 20.25,
22.24, 26.66, 38.94, 55.97, 74.43, 110.82, 118.71, 126.19,
127.17, 132.11, 148.30, 219.91. DEPT90 and 135 deg demon-
strate four methylene groups (negative) and six methine
groups (positive). MS(DI) = 229. Yield: 95%. The ee of
the product was determined by chiral HPLC (ChiralCel
Chirality DOI 10.1002/chir

BAYAT ET AL.
TABLE 2. Aldol reaction catalyzed by different short polar peptides
Entry
1
Product
Cat.
Time (h)
24
Yielda (%)
Drb (anti/syn)
91/9
Eec (%)
1
93
81
2
3
4
2
3
4
24
24
24
96
96
98
82/18
93/7
95/5
85
89
94
1a
5
6
1
2
24
24
92
95
88/12
92/8
67
74
7
3
24
95
84/16
81
(Continues)
Chirality DOI 10.1002/chir

TRIPEPTIDES AS ASYMMETRIC ORGANOCATALYST
Table 2. Continued
Entry
8
Product
Cat.
4
Time (h)
24
Yielda (%)
Drb (anti/syn)
99/1
Eec (%)
97
88
2a
9
1
2
3
4
24
24
24
24
92
93
95
96
97/3
99/1
99/1
98/2
72
74
76
81
10
11
12
3a
aIsolated yield.
bdr values were determined by 1H NMR.
cee values were determined by HPLC using a Chiral OD-H column.
OD-H, iPrOH/hexane 5/95, flow rate = 0.8 mL/min, λ =254 nm):
tmajor = 23.301 min, tminor = 32.981 min, ee = 81%, dr = 99:1
(anti/syn).
(bs, 1H), 5.10 (dd, J = 8.9, 3.7 Hz, 1H), 7.29 (m, 4H). 13C
NMR (100 MHz, CDCl3) δ = 30.74, 51.76, 69.15, 127.00,
128.65, 133.32, 141.14, 208.93. DEPT90 and 135 deg demonstrate
one methylene groups (negative) and five methine groups
(positive). The ee was determined by chiral HPLC (Chiral
AD-H, iPrOH/n-hexane 10/90, flow rate = 0.5 mL/min,
λ = 254 nm): tmajor = 28.735 min, tminor = 30.630 min, ee = 49%.
(S)-4-(2-chlorophenyl)-4-hydroxybutan-2-one
8a. 1H
NMR
(500 MHz, CDCl3): δ (ppm) = 2.20 (s, 3H), 2.67 (dd, J = 12.6,
10.3 Hz, 1H), 2.97 (dd, J= 17.2, 2.3 Hz, 1H), 4.79 (bs, 1H), 5.50
(dd, J = 12.6, 10.3 Hz, 1H), 7.45 (t, J= 8Hz, 1H), 7.56 (t, J =8 Hz,
1H), 8.10 (d, J = 8 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ = 30.57, 49.98, 66.55, 127.02, 128.44, 129.29, 130.16, 133.73,
140.00, 209.43. DEPT90 and 135 deg demonstrate one methylene
groups (negative) and five methine groups (positive). Yield:
96%. The ee was determined by chiral HPLC (Chiral AD-H,
iPrOH/n-hexane 10/90, flow rate = 1 mL/min, λ = 254 nm):
tmajor = 13.864 min, tminor = 14.719 min, ee = 45%.
(S)-4-hydroxy-4-(4-nitrophenyl)butan-2-one 10a. FT-IR (cm-1):
3430, 3068, 2922, 1700, 1414, 1281.1H NMR (500 MHz,
CDCl3): δ (ppm) = 2.18 (s, 3H), 2.81 (d, J = 5.7Hz, 2H), 3.96
(bs, 1H), 5.22 (dd, J = 6.9, 5.7 Hz, 1H), 7.49 (d, J = 8 Hz, 2H),
8.15 (d, J = 9.15 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ = 30.65, 51.45, 68.80, 123.68, 126.36, 147.21, 150.01, 208.47.
DEPT90 and 135 deg demonstrate one methylene groups (nega-
tive) and five methine groups (positive). Yield: 98%; The ee of
the product was determined by chiral HPLC (Chiral AD-H,
iPrOH/n-hexane 10/90, flow rate = 0.8 mL/min, λ = 254 nm):
tmajor = 18.147 min, tminor = 17.530 min, ee = 52%.
(S)-4-(4-chlorophenyl)-4-hydroxybutan-2-one 9a. FT-IR (cm-1):
3425, 3077, 2919, 1703, 1515, 1340. 1H NMR (500 MHz,
CDCl3): δ (ppm) = 2.17(s, 3H), 2.78 (d, J = 4.6 Hz, 2H), 3.36
Chirality DOI 10.1002/chir

BAYAT ET AL.
TABLE 3. Catalytic aldol reactions between cyclic and acyclic ketones and aromatic aldehydes catalyzed by 4
Entry
1
Product
Time (h)
Yielda [%]
Drb (anti/syn)
Eec [%]
86
24
96
93/7
4a
5a
2
3
24
24
97
96
90/10
75/25
70
78
6a
7a
4
24
95
99/1
81
5
6
24
24
96
95
—
—
45
49
8a
9a
7
8
24
24
98
97
—
—
52
45
10a
11a
9
24
30
97
60
—
56
87
12a
10
99/1
13a
11
24
65
98/2
93.7
14a, no NMM
aIsolated yield.
bdr values were determined by 1H NMR.
cee values were determined by HPLC using a Chiral OD-H and ADH columns.
Chirality DOI 10.1002/chir

TRIPEPTIDES AS ASYMMETRIC ORGANOCATALYST
Fig. 2. Proposed transition state model for the aldol reaction catalyzed by four different tri-peptides (Cat.1, 2, 3, 4).
(S)-4-(4-(trifluoromethyl)phenyl)-4-hydroxybutan-2-one 11a. FT-IR
synthesis, the peptides were separated from cocktail by use of
a mixture of TFA) (92.5%), triisopropylsilane (2.5%), 1, 4
dithiothritol (2.5%), and water (2.5%) by agitation for 2 h. Then
the catalytic properties of peptides 1–4 were evaluated using the
aldol reaction between cylohexanone and p-nitrobenzaldehyde
as a test reaction. First, the reaction optimized conditions were
screened for enantioselective aldol reaction between cyclohexa-
none (23.3 mg, 0.238 mmol, 1.2 eq), and p-nitrobenzaldehyde
(30 mg, 0.198 mmol, 1 eq) in the presence of catalyst 1 (Fig. 1)
as an asymmetric catalyst (0.004 mmol, 3.0 mol%, fw = 406
gr/mol) using iPrOH as solvent and NMM (N-
(cm-1): 3420, 3078, 2914, 1705, 1515, 1341. 1H NMR (500 MHz,
CDCl3): δ (ppm) = 2.17 (s, 3H), 2.81 (d, J = 4.55 Hz, 2H), 3.54
(bs, 1H), 5.18 (dd, J = 7.4, 3.45 Hz, 1H), 7.44 (d, J = 8 Hz, 2H),
7.57 (d, J= 9.15 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 30.65,
51.45, 68.80, 123.68, 126.36, 147.21, 150.01, 208.47.DEPT90 and
135 deg
demonstrate one methylene groups (negative) and
five methine groups (positive). Yield: 97%. The ee was de-
i
termined by chiral HPLC (Chiral AD-H, PrOH/n-hexane
10/90, flow rate = 1 mL/min, λ = 254 nm): tmajor = 11.708
min, tminor = 12.045, min, ee = 45%.
methylmorpholine) as
a pH adjustment (pH = 5–5.5)
(S)-4-hydroxy-4-(2-nitrophenyl)butan-2-one 12a. FT-IR (cm-1):
3418, 3077, 2922, 1706, 1520, 1344. 1H NMR (500 MHz, CDCl3):
δ (ppm) = 2.21 (s, 3H), 2.70 (dd, J = 17.7, 10.3 Hz, 2H), 3.7 (bs,
1H), 5.65 (dd, J = 9.15, 2.3 Hz, 1H), 7.41 (d, J = 8 Hz, 2H), 7.64 (t,
J= 8Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 7.93 (d, J = 8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ = 30.41, 51.04, 65.57, 124.41, 128.15,
128.25, 133.80, 138.37, 147.11, 208.80. DEPT90 and 135 deg demon-
strate one methylene groups (negative) and five methine groups
(positive). Yield: 97%. The ee was determined by chiral HPLC
i
(Scheme 2). In the presence of only the PrOH as solvent,
the reaction occurred with moderate yield and
enantioselectivity (Table 1, entry 1). Various additives, such
as water, amines, and carboxylic acids, have previously been
shown to get better yield and ee from proline-catalyzed aldol
reactions.25,26
With 0.1 ml water added to 0.9 ml iPrOH, the reaction
proceeded to increase gradually (Table 1, entry 2). A
i
combination of water with PrOH promoted the reaction with
high yield and good enantioselectivity (Table 1, entry 7 showed
the best result compared to the other ratio).
i
(Chiral AD-H, PrOH/n-hexane 5/95, flow rate = 0.5 mL/min,
λ = 254 nm): tmajor = 41.505 min, tminor = 43.206 min, ee = 56%.
The hypothesis of this work relies on investigating the role of
different polar amino acids as a biofunctional stereocenter with
a change in sequence to observe the capability of polar side
chains in the enhancement of enantio- and diastereoselectivity
in the aldol reactions (Fig. 1). At the beginning, the catalytic
activities of all catalysts (Fig. 1) were evaluated under our
previous optimized reaction. The results are summarized in
Table 2. Peptide 1, Pro-Tyr-Glu-NH2, provided the product with
high yield and good stereoselectivity (Table 2, entry 1). The
corresponding aldol product was produced with high yield
and the enantioselectivity increased up to 85% (Table 2, entry
2) when peptide 2, Pro-Glu-Tyr-NH2, which had the reverse
sequence of amino acid residue, was employed. To evaluate
more peptides with the polar side chain, peptides 3 and 4 were
designed and synthesized. Catalytic activity between catalysts
3 and 4 was compared by reaction of p-nitrobenzaldehyde
and cyclohexanone at the optimized condition. As seen from
Table 2 (entries 3 and 4), peptide 3 is less active compared to
4 (ee = 89% and 94%, respectively). The scope and limitations
of the direct aldol reaction of cyclohexanone with various
Chirality DOI 10.1002/chir
(S)-2-[(R)-Hydroxy(4-methoxyphenyl)methyl]cyclohexanone
13a. 1H-NMR (500 MHz, CDCl3)
δ
(ppm) = 1.13-1.21
(m, 1H), 1.43-1.61 (m, 3H), 1.65-1.71 (m, 1H), 1.87-1.90
(m, 1H), 1.94-1.97 (m, 1H), 2.24-2.34 (m, 1H), 2.51-2.56
(ddd, J = 13.7, 8.5, 4.6 Hz, 1H), 3.68 (s, 3H), 4.72 (d,
J = 9.15 Hz, 1H), 6.78 (d, J = 9.15Hz, 2H), 7.17 (d,
J = 8 Hz, 2H).
13C-NMR (125 MHz, CDCl3) δ (ppm) = 24.73, 28.52, 31.16,
42.55, 55.40, 58.51, 114.12, 128.97, 129.28, 130.37, 133.70,
160.14, 214.23. DEPT90 and 135 deg demonstrate four
methylene groups (negative) and six methine groups (posi-
tive). Yield: 60%. The ee was determined by chiral HPLC (Chi-
i
ral OD-H, PrOH/n-hexane 10/90, flow rate = 0.5 mL/min,
λ = 254 nm): tmajor = 7.418 min, tminor = 9.108 min, ee = 87%.
RESULTS AND DISCUSSION
At the beginning, four tripeptides were synthesized on solid
peptide synthesizing method (Fig. 1). Rink-Amide-Am-resin
was used to synthesize these peptides and at the end of

BAYAT ET AL.
aromatic aldehydes, catalyzed by tripeptides, were explored
NMM is an additive to adjust the pH. To further explore,
the reaction was performed between p-nitrobenzaldehyde
and cyclohexanone using Pro-His-Glu-NH2.TFA salt as cata-
lyst in the defined condition without any NMM. Although
the result demonstrated that the yield decreased
dramatically from 98% to 65%, the NMM had almost no effect
on the enantioselectivity (Table 3, entry 11).
On the basis of the experimental results, we were encouraged
to focus on the transition state. The good diastereoselectivities
and excellent enantioselectivities can be explained by the transi-
tion model (Fig. 2). As shown in Figure 2, the bifunctional
organocatalysts pyrrolidine moiety reacts with the cyclohexa-
none to form the nucleophilic enamine in the presence of an
acidic pH. The aldehyde is activated by bifurcated H-bonding
with hydroxyl, carboxyl, and imidazole groups of side chain
amino acids as well as NH of peptide backbone through hydro-
gen bond interactions.29,30
next (Table 2, entries 5–12). Benzaldehydes substituted by p-ni-
tro, o-chloro, and o-nitro afforded the corresponding anti-aldol
products with high yield and excellent stereoselectivity.
(Table 2). It is also interesting to note that both the para-
and ortho-substitutions exhibited the highest yield and
stereoselectivity when catalyst 4 was applied (Table 2, entries
4, 8, 12). This demonstrates that glutamic acid can form the
hydrogen bonding better than tyrosine and, on the other hand,
histidine as a second amino acid is the best polar amino acid to
improve either yield or stereoselectivity in comparison with
the others.
Among the four synthesized peptides (Fig. 1, 1–4), it was
found that peptide
4
exhibited the best yield and
enantioselectivity for the aldol reactions. With the optimal condi-
tions in hand, we next investigated substituent effects of the aro-
matic aldehydes on the aldol reactions in order to identify the
scope and limitations of the aldehyde substrate, as shown in
Table 3. In order to test the substrate generality of this peptide
(4) in direct aldol reaction, the reactions of various aromatic alde-
hydes with cyclic ketone (cyclohexanone) and acyclic ketone
(acetone) were studied. The results are summarized in Table 3.
We chose nitro, trifluoromethyl, cyano, and halogen substituents
as representative electron-withdrawing groups (Table 3, entries
1–9) and a methoxy substituent as an electron-donating group
on the benzene ring (Table 3, entry 10). The reactions of cyclo-
hexanone with aromatic aldehydes bearing electron-withdraw-
ing groups at the para-position proceeded smoothly to afford
the corresponding anti-aldol products in excellent yields with
high enantioselectivities (Table 3, entries 1–4, yield 95–97% and
ee 70–86%). The aldehyde substituted by a nitro group at
the para position with cyclohexanone converted into the cor-
responding anti-aldol product in excellent yield with high
enantioselectivities (Table 2, entry 4). The reaction of less re-
active p-trifluoromethylbenzaldehyde with cyclohexanone
also gave anti-aldol product in excellent yield with good %
ee (Table 3, entry 2). p-Anisaldehyde was a moderate
substrate for the aldol reaction, giving moderate yields
(60%) despite the longer reaction time; however, high
enantioselectivity was observed (Table 3, entries 10). The
highest diastereoselectivities (>99:1) were observed in the
reactions of p-cyanobenzaldehyde and p-anisaldehyde with
cyclohexanone (Table 3, entries 4, 10). The aldol reactions
were also carried out between acetone (2 eq) and aromatic al-
dehydes (1 eq) in the best condition of solvents mixture,
shown in Table 1.
CONCLUSION
In conclusion, we designed several different short polar
tripeptides and investigated their catalytic activity in the aldol
reactions. The result illustrated that histidine as a second
amino acid attached to the proline was the best polar amino
acid which produced the highest yield and stereoselectivity.
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