Proline-threonine dipeptide as an organocatalyst for the direct asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2009.06.018

A new proline-threonine (H-Pro-Thr-OH) dipeptide has been demonstrated as an efficient organocatalyst for a direct asymmetric aldol reaction. It was found that this new peptide-based catalyst efficiently catalyzed the reaction between an aldehyde and acetone to provide β-hydroxy ketones in good yields with good enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2009.06.018

Tetrahedron: Asymmetry 20 (2009) 1742–1745
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Tetrahedron: Asymmetry
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Proline–threonine dipeptide as an organocatalyst for the direct asymmetric
aldol reaction
*
Srivari Chandrasekhar , Kancharla Johny, Chada Raji Reddy
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new proline–threonine (H-Pro-Thr-OH) dipeptide has been demonstrated as an efficient organocatalyst
for a direct asymmetric aldol reaction. It was found that this new peptide-based catalyst efficiently cat-
alyzed the reaction between an aldehyde and acetone to provide b-hydroxy ketones in good yields with
good enantioselectivities.
Received 12 May 2009
Accepted 18 June 2009
Available online 17 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
tivity.8 Hence, herein we report prolinamide with terminal carbox-
ylic acid group (H-Pro-Thr-OH), derived from proline and
L
-Proline and several derivatives of this small amino acid have
threonine, catalyzed asymmetric direct aldol reaction of various
aldehydes with acetone (Scheme 1).
proven to be useful organocatalyst for metal-free aldol reac-
tions.1–3 For the proline-catalyzed reaction, the acidic proton of
the carboxylic acid group is crucial for the stereoselectivity and
reactivity. Based on transition state model studies most of the
proline derivatives, for example, triazoles, tetrazoles, and sulfona-
mides, developed have been holding this acidic proton.3 However,
O
OTBS
N
HN
H
OH
O
O
COOH
in simple L-prolinamide, the acidic nature of the –CONH proton is
(20 mol%)
+
CHO
R
less, therefore it is ineffective catalyst for the aldol rection.1c To
overcome this problem various prolinamide derivatives including
di- and tri-peptides have been developed.4 Particularly, prolina-
mides with a terminal hydroxyl group have received significant
interest compared to other derivatives due to the improved hydro-
gen bond donor character of the hydroxyl group. However, prolina-
mide derivatives containing a free carboxyl group (C-terminal) are
less explored for asymmetric direct aldol reactions.5 Therefore, in
continuation of our interest in organocatalysis,3a,6 we became
interested in a dipeptide prolinamide with a terminal carboxylic
acid group catalyzed asymmetric aldol reaction. For this purpose,
we chose a dipeptide derived from proline and threonine. We
envisaged that the free –OH and –COOH groups on threonine after
peptidation with proline would provide an additional push in the
catalytic aldol process. Earlier attempts were made using a pro-
line–threonine catalyst with free hydroxyl group while blocking
the carboxylic acid as an ester for aldol reaction.7 We were inter-
ested in preparing the dipeptide with silyl protection on the hydro-
xyl group while keeping free the –COOH group as in natural
proline, thus deriving the dual advantages of selectivity and reac-
R
CHCl3, rt
R = aryl or alkyl
Scheme 1. Direct asymmetric aldol reaction catalyzed by proline–threonine
dipeptide (H-Pro-Thr-OH) 1.
2. Results and discussion
The dipeptide catalyst 1 chosen for the asymmetric aldol reac-
tion was synthesized in five steps starting from proline (Scheme
2). The coupling of Cbz-protected proline9 3 with threonine benzyl
ester8a 4 was achieved under standard EDCI, HOBt coupling condi-
tions. After obtaining the dipeptide 5, the free hydroxyl group was
protected as TBS ether 6 followed by hydrogenolysis to afford the
required prolinamide-based dipeptide 1 with a terminal free car-
boxylic acid group.
Initially, the aldol reaction of 4-nitro benzaldehyde 7a with ace-
tone 8a was investigated using the above dipeptide catalyst 1
(20 mol %) at room temperature. The reaction was complete in
1 h and provided the expected product 9a in 70% yield with 75%
ee (Table 1, entry 1). To check the effect of various solvents for bet-
ter yield and selectivities, the same reaction was tested in different
solvents and the results are summarized in Table 1. Among the
* Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.018

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1742–1745
1743
OH
COOBn
COOBn
CbzCl, NaOH
0 oC, 2 h, 93%
4
NH2
HN
O
COOH
COOH
OH
5
N
H
N
EDCI, HOBt
CH2Cl2:DMF (4:1)
rt, 14 h, 92%
Cbz
N
2
3
Cbz
COOBn
COOH
HN
O
HN
Pd(OH)2/C
TBSCl, Imidazole
OTBS
OTBS
CH2Cl2:DMF (10:1)
rt, 24 h, 78%
H2, rt, 12 h
74%
N
N
O
6
1
Cbz
H
Scheme 2. Synthesis of proline–threonine dipeptide 1.
solvents screened, CHCl3 was found to be the best solvent, giving
the product in 91% yield with 82% enantiomeric excess (Table 1,
entry 9). Much improvement is not there in either the yield or
the enantioselectivity when decreasing the reaction temperature
to 0 °C (Table 1, entry 10). The enantioselectivity of this substrate
in the case of known catalyst prolinamide with free terminal hy-
droxyl group (H-Pro-Thr-OMe) was 69%.7 Encouraged by this re-
sult, we planned to expand the generality of this dipeptide
catalyst with a free terminal acid group (H-Pro-Thr-OH) 1 using
the reaction of various aldehydes with acetone.
4. Experimental
4.1. General
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica
gel of 60–120 mesh. IR spectra were recorded on a Thermo Nicolet
Nexus 670 spectrometer. Optical rotations were obtained on Perkin
Elmer digital polarimeter. 1H and 13C NMR spectra were recorded
in CDCl3 and DMSO-d6 solution on a Varian Gemini 200 and Bruc-
ker Avance 300. Chemical shifts were reported in parts per million
(PPM) with respect to internal TMS. Coupling constants (J) are
quoted in hertz. Mass spectra were obtained on an Agilent Tech-
nologies SHIMADZU GC/MS, 6510 Q-TOF LC/MS. HPLC was per-
formed on SHIMADZU HPLC using chiral pak IA and eurocel IA
columns with isopropyl alcohol and hexane as eluants.
Table 1
Effect of solvents
OH
O
catalyst 1
(20 mol%)
CHO
O
+
solvent, rt
4.1.1. (S)-Benzyl 2-((2R,3S)-1-(benzyloxy)-3-hydroxy-1-
oxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate 5
O2N
O2N
9a
7a
8a
N-Benzyloxycarbonyl-protected proline 3 (2 g, 7.9 mmol) was
dissolved in dry dichloromethane (10 mL), after which HOBt
(1.28 g, 9.48 mmol) was added and the reaction mixture was stir-
red for 15 min. The solution was cooled to 0 °C and EDCI (3.02 g,
15.8 mmol) was added. To this solution was added a solution
of benzyl ester of threonine 4 (2.55 g, 7.9 mmol) and DIEPA
(7.9 mmol, 1.10 mL) dissolved in dry dichloromethane (10 mL)
and the mixture was stirred overnight at room temperature. After
completion of the reaction (monitored by TLC), water (20 mL) was
added, and the two layers were separated. The organic layer was
washed with aq ammonium chloride (10 mL) and sodium bicar-
bonate (15 mL) simultaneously, dried over sodium sulfate, and
evaporated in vacuo. The crude product was purified by column
chromatography (EtOAc/hexanes, 30:70) to yield the pure dipep-
Entry
Solvent
Time (h)
Yielda (%)
eec (%)
1
2
3
4
5
6
7
8
Acetone
DMSO
Dioxane
DMF
Water
Acetonitrile
Methanol
Dichloromethane
Chloroform
Chloroform
1
10
10.5
1.6
10
5
70
43
40
65
35
35
50
75
91
86
75
73
61
71
31
69
61
69
82
85
2
1.5
1.3
12
9
10b
a
b
c
Isolated yields after column chromatography.
Reactions performed at 0 °C.
ee% calculated by using chiral HPLC.
tide 5 as a white solid (3.07 g, 92% yield). ½a D25
¼ ꢁ53 (c 1, CHCl3);
ꢀ
mp: 175–176 °C; IR (KBr):
m ;
3385, 3319, 2954, 1728, 1662 cmꢁ1
Accordingly, the reaction of acetone 8a (aldol donor) with a
1H NMR (DMSO-d6, 300 MHz): d 1.02 (dd, J = 37.7, 6.2 Hz, 3H),
1.68–1.88 (m, 1H), 2.06–2.16 (m, 3H), 3.43 (m, 2H), 4.14–4.24
(1H, m), 4.29–4.49 (m, 3H), 4.91–5.19 (m, 6H), 7.21–7.41 (m,
10H), 8.06 (t, J = 8.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 172.8,
172.5, 153.9, 153.8, 137.0, 136.9, 135.9, 128.3, 128.3, 128.2, 127.9,
127.7, 127.5, 127.4, 126.9, 66.3, 66.1, 65.9, 65.8, 65.9, 65.8, 65.7,
59.3, 58.8, 57.9, 57.8, 47.1, 46.5, 31.1, 29.8, 23.7, 29.8, 23.7, 22.8,
20.1, 20.0; ESIMS (m/z) 441 (M+); HRMS calcd for C24H28N2O6Na
463.1845, found 463.1841.
variety of aldehydes including aromatic and aliphatic ones was
investigated using organocatalyst 1 under optimal conditions.
The results are summarized in Table 2. All the reactions proceeded
smoothly with 20 mol % of catalyst in good yields (72–91%) with
high enantioselectivities regardless of the nature of the aldehyde.
3. Conclusions
In conclusion, we have developed a proline–threonine dipeptide
catalyst with a free terminal acid group (H-Pro-Thr-OH) for the di-
rect asymmetric aldol reaction of acetone with various aldehydes.
The yields are typically good and the enantioselectivities are high
in almost all the cases examined, including those with aromatic
and aliphatic aldehydes. The synthetic utility of this dipeptide as
an organocatalyst in organic synthesis will be explored to other
reactions.
4.1.2. (S)-Benzyl 2-((2R,3S)-1-(benzyloxy)-3-(tert-
butyldimethylsilyloxy)-1-oxobutan-2-ylcarbamoyl)pyrrolidine-
1-carboxylate 6
To dipeptide 5 (100 mg, 0.23 mmol), dissolved in dry dichloro-
methane (2 mL), was added dry dimethyl formamide dropwise un-
til the solution became clear. tert-Butyldimethylsilyl chloride

1744
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1742–1745
Table 2
Proline–threonine dipeptide 1 catalyzed aldol reaction of aldehydes with acetone
Entry
1
Aldehyde
Product
Time (h)
1.5
Yielda (%)
91
eec (%)
82
OH
O
CHO
7a
9a
O2N
O2N
OH
O
CHO
2
2
85
71
7b
9b
NO2
NO2
OH
OH
O
CHO
3
4
3
2
88
88
71
77
9c
7c
Br
Cl
Br
Cl
O
CHO
9d
7d
OH
O
O
CHO
5
2.5
86
57
9e
9f
7e
Cl
Cl
OH
CHO
6
7b
8
10
78
75
82
80
85
77
7f
F
F
OH
O
PhO
O2N
9g
CHO
PhO
O2N
12
1
7g
OH
Cl
O
CHO
9h
Cl
7h
OH
O
CHO
9
7
72
75
9i
7i
OH
O
CHO
10
5
8
74
80
65
75
9j
7j
OH
O
CHO
7k
11
9k
a
Isolated yields after column chromatography.
Reactions performed at 4 °C.
ee% calculated by using chiral HPLC.
b
c
(44.41 mg, 0.29 mmol) and imidazole (31.3 mg, 0.46 mmol) were
then added simultaneously at 0 °C. The solution was stirred for
24 h at room temperature. After completion of the reaction (mon-
itored by TLC), water (2 mL) was added, the two layers were
separated, and the aqueous layer was extracted twice with dichlo-
romethane (2 ꢂ 3 mL). The combined organic layers were dried
over sodium sulfate, concentrated, and the crude product was
purified by column chromatography (EtOAc/hexanes: 10/90) to
13C NMR (CDCl3, 75 MHz): d 172.6, 172.1, 169.9, 154.1, 153.8,
153.6, 136.8, 135.4, 128.3, 128.0, 127.9, 127.6, 127.4, 127.3,
126.9, 68.1, 66.1, 65.9, 65.8, 65.6, 59.3, 58.7, 57.5, 57.5, 47.0,
46.4, 31.0, 29.4, 25.4, 23.7, 22.7, 20.1, 19.9, 17.5, ꢁ4.5, ꢁ5.4; ESIMS:
(m/z) 555 (M+); HRMS calcd for C30H42N2O6SiNa 577.2709, found
577.2721.
4.1.3. (2R,3S)-3-(tert-Butyldimethylsilyloxy)-2-(S)-pyrrolidine-
2-carboxamido)butanoic acid 1
The TBS-protected peptide 6 (500 mg, 0.90 mmol) was dis-
solved in methanol (5 mL), after which 20% Pd(OH)2/C (50 mg)
was added and the reaction mixture was stirred for 24 h at room
temperature under a hydrogen atmosphere. The reaction mass
give the product as colorless viscous oil (98 mg, 78%). ½a D25
¼ ꢁ30:4
ꢀ
(c 1, CHCl3); IR (neat):
m
2953, 1747, 1691 cmꢁ1
;
1H NMR (CDCl3,
300 MHz): d ꢁ0.09 to 0.03 (m, 3H), 0.08 (s, 9H), 1.02 (dd, J = 37.9,
6.0 Hz, 3H), 1.72–2.17 (m, 4H), 3.40 (m, 2H), 4.27–4.58 (m,
3H), 4.90–5.17 (m, 4H), 7.26–7.41 (s, 10H), 7.73–7.85 (m, 1H);

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 20 (2009) 1742–1745
1745
was filtered through Celite, washed with methanol (2 ꢂ 3 mL),
Acknowledgment
and evaporated in vacuo. The crude product was recrystallized from
ether to obtain the dipeptide organocatalyst 1 (74% yield, 218 mg);
K.J. thanks the CSIR, New Delhi for financial assistance.
½
a 2D5
ꢀ
¼ ꢁ21:1 (c 0.5, MeOH); mp: 227–228 °C; IR (KBr, thinfilm):
m
3430, 3271, 2933, 1679, 1586, 1389 cmꢁ1 1H NMR (CD3OD,
;
References
300 MHz): d 0.07 (s, 6H), 0.74 (s, 9H), 1.01 (d, J = 6.2 Hz, 3H), 1.79–
1.96 (m, 2H), 1.94–2.07 (m, 1H), 2.30–2.24 (m, 1H), 3.07–3.24 (m,
3H), 4.07–4.11 (d, J = 2.2 Hz, 1H), 4.18–4.24 (dd, J = 8.4, 6.4 Hz,
1H), 4.32–4.40 (m, 1H). 13C NMR (CD3OD, 75 MHz): d 175.7, 175.5,
170.7, 70.7, 61.7, 61.2, 47.5, 31.1, 26.4, 26.2, 25.3, 22.0, 19.0,
ꢁ3.56, ꢁ4.37, ꢁ4.47, ꢁ5.69; ESIMS: (m/z) 331 (M+); HRMS calcd
for 331.2053 C15H31N2O4SiNa, found 331.2068.
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4.1.4. Representative procedure for the aldol reaction
To a stirred solution of catalyst 1 (20 mol %) in chloroform
(2 mL), was added acetone (4 mmol) and then stirred for 15 min.
After this time, aldehyde (1 mmol) was added and stirring was
continued for a given time (Table 2) at room temperature. After
completion of the reaction, (monitored by TLC), water was added
and extracted with dichloromethane (2 ꢂ 5 mL). The combined or-
ganic layers were dried over sodium sulfate and evaporated in va-
cuo. The crude product was purified by silicagel column
chromatography to afford the pure product.
4.1.4.1. (R)-4-(2-Fluorophenyl)-4-hydroxybutan-2-one 9f. Col-
orless oil, ½a 2D5
ꢀ
¼ þ65:9 (c 1, CHCl3); IR (neat):
m 3417, 2923,
1636, 769 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 2.19 (s, 3H),
2.83–2.89 (m, 2H), 3.69 (d, J = 3.7 Hz, 1H), 5.39–5.46 (m, 1H),
6.96–7.04 (1H, m), 7.12–7.18 (m, 1H), 7.21–7.29 (m, 1H), 7.49–
7.56 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 30.4, 50.3, 63.9,
114.8, 115.1, 124.2, 127.1, 127.2, 128.7, 128.8, 129.5, 129.7,
157.5, 160.7, 208.9; ESIMS: (m/z) 205 (M+Na+); HRMS calcd for
182.0743 C10H11FO2, found 182.0740. Enantiomeric excess: 80%,
determined by HPLC analysis using chiral pak 250 ꢂ 4.6
l, col-
umn (isopropanol/hexanes 05:95), UV 210 nm, flow rate
,
1.0 ml/min, , major isomer tR 7.39 min, tR minor isomer 8.23;
IR, 1H, 13C NMR and mass spectral data of the known products
9a and 9b,6c 9c to 9e,4f 9g,10 9h,6c 9i to 9k4f were identical with
the reported data.
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