Evaluation of mono- and dipeptides as organocatalysts for enantioselective aldol reaction

Article abstract of DOI:10.1016/j.tet.2014.04.016

Catalytic activities of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA)-based mono- and dipeptides and their l-proline analogs in asymmetric aldol reaction were investigated. THIQA-based dipeptides showed better enantioselectivity than proli

Full text of DOI:10.1016/j.tet.2014.04.016

Tetrahedron 70 (2014) 3707e3713
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Evaluation of mono- and dipeptides as organocatalysts
for enantioselective aldol reaction
*
Cigdem Yolacan , Murat Emrah Mavis, Feray Aydogan
Department of Chemistry, Yildiz Technical University, Davutpasa Campus, Esenler, 34010 Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalytic activities of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA)-based mono- and
Received 27 January 2014
Received in revised form 21 March 2014
Accepted 7 April 2014
dipeptides and their L-proline analogs in asymmetric aldol reaction were investigated. THIQA-based
dipeptides showed better enantioselectivity than proline analogs, whereas proline-based dipeptides gave
higher yield in the aldol reaction of cyclohexanone with several aldehydes in dichloromethane at ꢀ10 ꢁ
C
Available online 13 April 2014
in the presence of benzoic acid.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Tetrahydroisoquinoline-3-carboxylic acid
Proline
Organocatalysis
Asymmetric synthesis
1. Introduction
and the amide NH proton to form a hydrogen bond, which is nec-
essary for the enantioselectivity.18 This derivatisation also improves
the solubility of the catalyst in organic solvents, which is the im-
portant drawback of proline19 and allows the structural modifica-
tions, therefore improves the catalyst properties by varying the
stereo and electronic effects of the terminal amide to affect the
ability of hydrogen bonding formation between the catalysts and
substrates.20
Asymmetric carbonecarbon bond formation reactions catalyzed
by chiral organic molecules have become an important area in or-
ganic synthesis. The aldol reaction is the most important one of
these type of reactions in modern organic synthesis as a key step in
natural product synthesis and for rapid access to polyoxygenated
compounds. This useful reaction facilitates the construction of
larger complex molecules with new stereogenic centers from
smaller ones.1 Since the first example of a nonmetallic small-
molecule catalyst for direct intermolecular asymmetric aldol re-
actions by List et al.,2 many new nonmetallic organocatalysts have
been developed dramatically for this reaction.3e7 Organocatalysts
have several advantages over transition-metal catalysts and en-
zymes. They are usually robust, inexpensive, readily available, and
non-toxic. Because of their robustness they often do not require
demanding reaction conditions like inert gas atmosphere and an-
hydrous solvent.8e11 Especially, proline amide derivatives have
attracted special interest from researchers as organocatalysts be-
cause of their high enantioselective activities.12e17 These de-
rivatives have the proline ring to form an enamine intermediate
Although many proline7,21e25 and some hydroxyproline26,27
mono- and diamides have been synthesized and investigated for
their catalytic activity in asymmetric aldol reactions, as far as we
know, other ring systems such as tetrahydroisoquinoline have not
been investigated for this asymmetric transformation. Thus,
we decided to investigate the catalytic activity of new mono- and
dipeptides derived from (3S)-1,2,3,4-tetrahydroisoquinolin-
3-carboxylic acid (THIQA) in the asymmetric direct aldol reaction.
2. Results and discussion
THIQA-derived mono- and dipeptides are known well in the
literature for their biological activities,28e33 but, as far as we know,
they have not been used as catalysts for aldol reaction. New THIQA-
based mono- (4) and dipeptides (8a,b) (Fig. 1) were prepared by the
amidation reaction of THIQA (1), which was easily prepared start-
ing from commercially available
leucine methyl ester and/or (S)-2-amino-3-phenyl-1-propanol. The
L L-tert-
-phenylalanine,32 with
* Corresponding author. Tel.: þ90 212 383 42 13; fax: þ90 212 383 41 06; e-mail
address: cigdemyolacan@hotmail.com (C. Yolacan).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.016

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C. Yolacan et al. / Tetrahedron 70 (2014) 3707e3713
(Scheme 2) to compare their catalytic activities with catalysts 4 and
8a,b. All of the compounds, except compound 12,35 were unknown
in the literature. The structures of the compounds were determined
by their spectroscopic data.
O
O
The aldol reactions of 4-nitrobenzaldehyde and cyclohexanone
in tetrahydrofuran (THF) at different temperatures in the presence
of benzoic acid were used to evaluate the catalysts. Although cat-
alysts 8a and 8b showed similar diastereoselectivities, reactions
with the catalyst 8a gave the best enantioselectivity based on the
anti isomer, whereas the best yields were obtained with the
proline-based catalyst 16a as shown in Table 1. Besides THF, other
solvents were screened with catalysts 8a and 16a. The results are
given in Table 2. The enantioselectivity was not improved consid-
erably by the tested solvents but the yield was 80% in DCM at
ꢀ10 ꢁC with catalyst 8a. However, the yield was higher with the
proline-based dipeptide 16a than the THIQA analog 8a under this
conditions. This may be because of difficulty in the formation of the
enamine intermediate. Higher enantioselectivity of 8a may be at-
tributed to the more stable transition state of the THIQA-dipeptide
(Scheme 3). The dipeptide structure of the catalyst contributes to
the activation of the aldehyde via co-catalyst.
N
H
N
H
HN
NH
OH
OH
NH
4
12
O
O
O
O
H
N
N
H
O
N
H
HN
NH
O
O
O
O
O
O
16a
8a
O
H
N
N
H
HN
N
H
NH
NH
OH
16b
8b
OH
With this promising result, different acid additives were in-
vestigated with the same amount of catalyst (10 mol %) in DCM at
ꢀ10 ꢁC. Benzoic acid gave the best enantioselectivity and yield
among the tested acids (Table 3).
Finally, the aldol reactions of different aliphatic ketones with
aromatic aldehydes were investigated under the optimized condi-
tions with catalyst 8a (Table 4). The aldol products are known in the
literature, and their spectroscopic data are in agreement with the
literature data.36e38
Fig. 1. Proline- and THIQA-based mono- and dipeptides.
synthetic pathway of catalyst 4 and 8a,b outlined in Scheme 1, in-
cluded protection of THIQA, amidation with -tert-leucine methyl
L
ester, hydrolysis of the ester group, a second amidation, and
deprotection of the Boc group by modified literature pro-
cedures.33,34 The proline based mono- (12) and dipeptides (16a,b)
(Fig. 1) were also synthesized by a similar synthetic pathway
O
O
TFA
N
H
N
H
dry CH2Cl2
NH
OH
N
OH
0 oC
rt
Boc
4 (80%)
3 (63%)
H2N
HOBt, DCC
dry THF
Ph
OH
0 oC
rt
O
O
O
O
N
HCl.H2N
1M NaOH
O
OH
O
OH
N
+
(Boc)2O
H
NH
N
O
1,4-dioxane
HOBt, DCC, Et3N
dry THF
Boc
Boc
0 oC
rt
5 (64%)
1
2 (80%)
0 oC
rt
2N NaOH
MeOH
0 oC
rt
O
O
H
N
O
H
OH
RNH2
TFA
N
N
H
R
N
H
N
H
R
N
O
N
O
HOBt,DCC, Et3N
dry THF
dry CH2Cl2
NH
8a (82%)
8b (77%)
O
Boc
Boc
0 oC
rt
7a (61%)
0 oC
rt
6 (93%)
7b (66%)
R
7a and 8a
7b and 8b
O
O
OH
Scheme 1. Synthesis of catalysts 4 and 8a,b.

C. Yolacan et al. / Tetrahedron 70 (2014) 3707e3713
3709
O
O
TFA
N
N
dry CH2Cl2
0 oC
H
H
N
OH
NH
OH
rt
Boc
12 (76%)
11 (68%)
HOBt, DCC
dry THF
H2N
Ph
OH
0 oC
rt
O
O
O
O
HCl.H2N
10% NaOH
O
OH
O
OH
N
+
(Boc)2O
H
NH
N
N
O
THF/H2O (2/1)
HOBt, DCC, Et3N
dry THF
Boc
10 (89%)
Boc
0 oC
rt
9
13 (58%)
0 oC
rt
2N NaOH
MeOH
0 oC
rt
O
O
O
H
H
N
OH
RNH2
N
R
TFA
N
H
R
N
H
N
H
N
O
N
O
NH
O
dry CH2Cl2
0 oC
HOBt,DCC, Et3N
dry THF
0 oC
Boc
Boc
14 (91%)
rt
16a (83%)
16b (78%)
15a (63%)
15b (65%)
rt
R
15a and 16a
15b and 16b
O
O
OH
Scheme 2. Synthesis of catalysts 12 and 16a,b.
Table 2
Solvent effect on the aldol reaction with catalysts 8a and 16a
Table 1
Screening of organocatalysts for the aldol reaction
H
O
O
OH
O
catalyst 8a or 16a
H
O
(10 mol%)
O
O
OH
+
catalyst (10 mol%)
THF, Benzoic acid
NO2
solvent, Benzoic acid
+
NO2
NO2
Catalyst Solvent
Temperature Reaction Yielda drb
eec (%)
(anti/syn) (anti)
NO2
(ꢁC)
time (h)
(%)
Catalyst
Temperature
(ꢁC)
Reaction
time (h)
Yielda
(%)
drb
(anti/syn)
eec (%)
(anti)
8a
16a
8a
16a
8a
8a
16a
8a
8a
16a
8a
16a
8a
16a
8a
8a
16a
8a
16a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene rt
Toluene rt
Toluene
Toluene
rt
rt
0
0
24
24
48
48
72
72
72
96
24
24
48
48
72
72
96
24
24
48
48
66
97
31
97
80
15
97
69
58
98
49
94
49
98
50
76
85
71
94
57:43
59:41
68:32
59:41
75:25
68:32
67:33
81:19
63:37
53:47
80:20
68:32
77:23
75:25
84/16
66/34
55:45
80:20
76:24
85
36
84
35
90
71d
75
85
84
25
90
73
88
78
90
78
36
82
64
8a
rt
rt
rt
rt
rt
rt
0
0
0
0
0
0
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
24
24
24
24
24
24
48
48
48
48
48
48
72
72
72
72
72
72
65
98
71
90
53
86
62
98
58
94
68
80
68
97
43
90
49
70
80:20
63:37
80:20
74:26
57:43
77:23
77:23
60:40
84:16
82:18
77:23
79:21
83:17
68:32
84:16
80:20
74:26
76:24
87
49
75
68
65
74
88
56
82
73
81
69
86
62
77
65
68
81
16a
8b
16b
4
12
8a
16a
8b
16b
4
12
8a
ꢀ10
ꢀ10
ꢀ10
ꢀ20
0
0
Toluene ꢀ10
Toluene ꢀ10
Toluene ꢀ20
16a
8b
16b
4
H2O
H2O
H2O
H2O
rt
rt
0
0
12
a
Combined yields of isolated diastereomers.
Determined by 1H NMR of crude product.
Determined by chiral-phase HPLC analysis of the anti product.
a
b
c
Combined yields of isolated diastereomers.
Determined by 1H NMR of crude product.
Determined by chiral-phase HPLC analysis of the anti product.
b
c
d
Without benzoic acid.

3710
C. Yolacan et al. / Tetrahedron 70 (2014) 3707e3713
determined by chiral HPLC analysis of anti products by using the
O
methods from the literature.36e38
N
O
O
N
3. Conclusion
R1
H
H
N
R
O
H
R
In conclusion, the catalytic activity of new chiral THIQA-based
mono- and dipeptides in direct aldol reaction of cyclohexanone
was investigated and compared with those of L-proline mono- and
dipeptide analogs for the first time. It was shown that the enan-
tioselectivity of THIQA-based dipeptide was better than the proline
analog. These type organocatalysts may have potential to be a new
class of catalysts for asymmetric aldol reaction.
O
H
O
O
Ar
Scheme 3. Proposed transition state.
Table 3
The effect of acid additives
4. Experimental
H
O
4.1. General information
O
OH
O
catalyst 8a (10 mol%)
+
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.
NMR spectra were recorded on Varian Unity Inova 500 MHz
spectrometer and Bruker Avance III 500 MHz spectrometer.
CH2Cl2, -10 oC
co-catalyst (10 mol%)
NO2
NO2
Acid co-catalyst
(10 mol %)
Reaction
time (h)
Yielda (%)
drb
(anti/syn)
eec (%)
(anti)
Chemical shifts
d are reported in parts per million (ppm) with
d
72
72
72
72
72
15
80
56
67
65
68:32
75:25
82:18
80:20
83:17
71
90
87
86
76
TMS as internal standard and the solvents are CDCl3 and CD3OD.
Column chromatography was conducted on silica gel 60
(40e63 mM). TLC was carried out on aluminum sheets precoated
Benzoic acid
TFA
Acetic acid
Tartaric acid
with silica gel 60F254 (Merck). LC/MS spectra were obtained on
a Finnigan LC/MS instrument. Elemental analysis were carried out
on Thermo Flash EA 1112 series apparatus. Optical rotations were
measured with Bellingham Stanley ADP-410 Polarimeter. Chiral
HPLC analysis were performed with Shimadzu HPLC (Daicel
Chiralpak AD and AD-H columns) equipped with SPD-20A de-
tector and isopropanol/n-hexane mixtures as the eluent. The
a
Combined yields of isolated diastereomers.
Determined by 1H NMR of crude product.
Determined by chiral-phase HPLC analysis of the anti product.
b
c
Table 4
The aldol reactions with various aldehydes
protection of THIQA39,40 and
L
-proline41,42 was carried out
H
O
O
according to the literature procedure.
O
OH
catalyst 8a (10 mol%)
R
R
+
4.2. Synthesis of the catalysts
R'
R'
CH2Cl2, -10 oC, 72 h
Benzoic acid
R
R
4.2.1. General procedure for amidation reactions. At 0 ꢁC and with
O
Yielda
drb
eec (%)
stirring, to the solution of N-Boc-THIQA (2) or -N-Boc-proline (10)
L
ArCHO
R
(0.92 mmol) in dry THF (10 mL), HOBt (1.0 mmol) was added, and
stirred for 10 min, then DCC (1.0 mmol) was added (mixture A). In
another reaction flask, to the suspension of L-tert-leucine methyl
(%)
(anti/syn)
(anti)
R'
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclopentanone
Acetone
Ethyl methyl ketone
2-Nitrobenzaldehyde
3-Nitrobenzaldehyde
4-Cyanobenzaldehyde
4-Bromobenzaldehyde
4-Chlorobenzaldehyde
Benzaldehyde
4-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Nitrobenzaldehyde
67
81
63
nr
nr
nr
80
71
74
34e
98:2
87:13
84:16
d
89
87
83
d
ester hydrochloride (1.02 mmol) in dry THF (5 mL), triethylamine
(0.5 mL) was added and stirred at room temperature for 1 h
(mixture B). The reaction mixtures A and B were combined (in the
case of (S)-2-amino-3-phenyl-1-propanol, the amino alcohol
(1.02 mmol) was added directly to the mixture A). The reaction
mixture was stirred at room temperature for 24 h, and the reaction
was monitored by TLC. The formed precipitate of DCU was re-
moved 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 NaHCO3 (30 mLꢂ3), 5% aqueous solution of KHSO4 (30 mLꢂ3),
and brine (30 mLꢂ3), and dried with anhydrous Na2SO4. After
filtration, the filtrate was evaporated under vacuum to give the
crude products, which were purified by column chromatography
on silica gel.
d
d
d
d
75:25
28:72
d
90
50d
83
50
70:30
a
Combined yields of isolated diastereomers.
Determined by 1H NMR of crude product.
Determined by chiral-phase HPLC analysis of the anti product.
syn isomer.
b
c
d
e
Based on the 4-hydroxy-3-methyl-4-(4-nitrophenyl)butan-2-one regioisomer.
While electron poor nitrobenzaldehydes and cyanobenzalde-
hyde gave good enantioselectivity, benzaldehyde, chlor-
obenzaldehyde, and bromobenzaldehyde did not gave any reaction
under these optimized conditions. Different ketones such as
cyclopentanone, acetone, and ethyl methyl ketone were also in-
vestigated for their aldol reactions with 4-nitrobenzaldehyde under
the same conditions. Among these ketones, especially, acetone
showed good enantioselectivity, while the other ketones gave good
diastereoselectivities. Diastereomeric ratios were determined from
the 1H NMR of the crude products and enantiomeric excesses were
4.2.2. General procedure for deprotection of Boc group. To the so-
lution of N-Boc-protected compounds (3, 7a, b, 11, 15a, b)
(1.0 mmol) in dry CH2Cl2 (15 mL) at 0 ꢁC, trifluoroacetic acid
(27.0 mmol) was added dropwise over 5 min while stirring. The
reaction mixture was stirred at 0 ꢁC for 1 h and at room tempera-
ture for 2 h then 2 M K2CO3 was added to adjust to basic pH. The

C. Yolacan et al. / Tetrahedron 70 (2014) 3707e3713
3711
organic phase was washed with water, dried over MgSO4, filtrated,
and evaporated to give the pure compounds.
61%, mp 155e157 ꢁC; [
a
]
D
20 ꢀ24.8 (c 1.0, CHCl3). Found: C, 64.91; H,
8.42; N, 8.07. C28H43N3O6 requires C, 64.97; H, 8.37; N, 8.12%; 1H
NMR (500 MHz, CDCl3)
d 0.46 (s, 9H), 0.86 (s, 9H), 1.37 (s, 9H),
4.2.3. General procedure for hydrolysis of ester group. At 0 ꢁC to the
solution of compound 5 or 13 (1.0 mmol) in methanol (5 mL), 2 N
aqueous NaOH was added to adjust the pH to 11. The reaction
mixture was stirred at 0 ꢁC for 3 h, and at room temperature for
24 h, then adjusted to pH 2 with aqueous solution of KHSO4. The
solution was evaporated under vacuum to remove methanol, and
extracted with ethyl acetate (30 mLꢂ3). The combined ethyl acetate
was successively washed with brine (20 mLꢂ2) and dried with
anhydrous Na2SO4. After filtration, the filtrate was evaporated to
provide compounds 6 and 14, which were used without any further
purification.
2.97e3.00 (m,1H), 3.28 (br d,1H, J¼15.0 Hz), 3.62 (s, 3H), 4.02e4.08
(m,1H), 4.27 (d,1H, J¼8.5 Hz), 4.35e4.62 (m, 3H), 6.20e6.25 (m,1H,
NH rotamers), 6.45 and 6.61 (br s, 1H, NH, rotamers), 7.11 (br s, 4H);
13C NMR (125 MHz, CDCl3)
d
24.8, 25.7, 27.4, 31.0, 33.3, 33.6, 44.3,
50.7, 55.1, 58.9, 59.5, 80.2, 124.6, 125.1, 126.2, 127.5, 132.4, 132.6,
153.9, 168.7, 170.0, 170.5; IR (ATR)
3309, 1740, 1701, 1652 cmꢀ1
n
.
4.2.9. (S)-tert-Butyl 3-(((S)-1-hydroxy-3-phenylpropan-2-
y l c a r b a m o y l ) - 2 , 2 - d i m e t h y l p r o p y l c a r b a m o y l ) - 3 , 4 -
dihydroisoquinoline-2(1H)-carboxylate (7b). White solid, yield 66%,
mp 118e119 ꢁC; [
a
]
20 ꢀ20.0 (c 1.0, CHCl3). Found: C, 68.76; H, 7.82;
D
N, 8.06. C30H41N3O5 requires C, 68.81; H, 7.89; N, 8.02%; 1H NMR
4.2.4. (S)-tert-Butyl 3-((S)-1-hydroxy-3-phenylpropan-2-
(500 MHz, CDCl3) d 0.57 (s, 9H), 1.55 (s, 9H), 2.77e2.83 (m, 2H), 3.10
ylcarbamoyl)-3,4-dihydro-isoquinoline-2(1H)-carboxylate
(dd, 1H, J¼15.0, 6.5 Hz), 3.27 (br s, 1H), 3.49e3.66 (m, 2H),
3.73e3.76 (m, 1H), 3.99e4.22 (br s, 1H), 4.39e4.45 (m, 1H),
4.63e4.74 (m, 2H), 6.22 and 6.41 (br s, 1H, NH, rotamers), 6.48 and
6.56 (br s, 1H, NH, rotamers), 7.19e7.25 (m, 9H); 13C NMR (125 MHz,
20
(3). White solid, yield 63%, mp 142e143 ꢁC; [
a
]
ꢀ29.7 (c 1.0,
D
CHCl3). Found: C, 70.35; H, 7.26; N, 6.85. C24H30N2O4 requires C,
70.22; H, 7.37; N, 6.82%; 1H NMR (500 MHz, CDCl3)
d
1.44 (s, 9H),
1.80 (br s, 1H), 2.58e2.70 (m, 2H), 3.02e3.27 (m, 2H), 3.45e3.49
(m, 1H), 3.53e3.62 (m, 1H), 4.00 (br s, 1H), 4.07e4.34 (m, 1H),
4.45e4.49 (m, 1H), 4.57e4.75 (m, 1H), 6.03 (br s, 1H), 6.98 (br s, 2H),
CDCl3)
125.9, 126.4, 126.6, 127.1, 128.1, 128.5, 129.2, 133.6, 133.8, 138.0,
155.8, 169.6, 171.8; IR (ATR)
3351, 3264, 1674, 1662, 1631 cmꢀ1
d 26.3, 28.3, 31.4, 33.1, 36.8, 45.5, 52.9, 56.4, 62.0, 63.4, 81.8,
n
.
7.05e7.24 (m, 7H); 13C NMR (125 MHz, CDCl3)
d
27.9, 28.6, 36.8,
44.6, 52.2, 52.9, 64.3, 81.4, 126.4, 126.8, 127.3, 127.8, 128.4, 128.8,
129.4, 133.6, 137.1, 137.3, 155.8, 172.5; IR (ATR) 3380, 3302, 1662,
1654, 1644 cmꢀ1
4.2.10. (S)-Methyl 2-((S)-3,3-dimethyl-2-((S)-1,2,3,4-
n
tetrahydroisoquinoline-3-carboxamido)butanamido)-3,3-
20
.
dimethylbutanoate (8a). White solid, yield 82%, mp 76e78 ꢁC; [
ꢀ20.3 (c 2.3; CH2Cl2); Found: C, 66.18; H, 8.39; N, 10.11.
a]
D
4.2.5. (3S)-1,2,3,4-Tetrahydro-N-((S)-1-hydroxy-3-phenylpropan-2-
C
23H35N3O4 requires C, 66.16; H, 8.45; N, 10.06%; 1H NMR
yl)isoquinoline-3-carboxamide (4). White solid, yield 80%, mp
(500 MHz, CDCl3) d 0.87 (s, 9H), 0.89 (s, 9H), 1.88 (br s, 1H),
125e126 ꢁC; [
a]
20 ꢀ78.5 (c 0.56, MeOH); Found: C, 73.59; H, 7.17; N,
2.78e2.83 (m, 1H), 3.14 (dd, 1H, J¼16.2, 6.0 Hz), 3.57e3.61 (m, 1H),
3.65 (s, 3H), 3.90e3.99 (m, 2H), 4.24 (d, 1H, J¼9.5 Hz), 4.30 (d, 1H,
J¼9.5 Hz), 6.39 (br d,1H, J¼8.5 Hz), 6.98e7.01 (m,1H), 7.06e7.10 (m,
D
8.96. C19H22N2O2 requires C, 73.52; H, 7.14; N, 9.03%; 1H NMR
(500 MHz, CDCl3) d 2.05 (br s, 1H), 2.53e2.58 (m, 1H), 2.71e2.76 (m,
1H), 2.85e2.89 (m, 1H), 3.05e3.09 (m, 1H), 3.42e3.46 (m, 1H),
3.54e3.58 (m, 1H), 3.65e3.71 (m, 2H), 3.81e3.84 (br d, 1H,
J¼17.0 Hz), 4.12 (br s, 1H), 6.94 (br s, 1H), 7.06e7.09 (m, 3H),
7.12e7.14 (m, 3H), 7.18e7.22 (m, 2H), 7.41 (br s, 1H); 13C NMR
3H), 7.89 (br d, 1H, J¼9.5 Hz); 13C NMR (125 MHz, CDCl3)
d 25.4,
25.5, 30.2, 33.4, 33.6, 45.7, 50.7, 55.0, 59.2, 59.3, 124.6, 125.3, 125.7,
127.8, 133.1, 134.7, 169.4, 170.6, 172.0; ESI(ꢀ)-MS: m/z 418.3 (Mþ1);
IR (ATR)
n .
3311, 1740, 1642 cmꢀ1
(125 MHz, CDCl3)
125.6, 127.5, 127.6, 128.0, 128.1, 133.2, 135.0, 136.5, 173.0; ESI(ꢀ)-MS:
m/z¼311.1(Mþ1); IR (ATR)
3309, 3282, 3193, 1649 cmꢀ1
d 29.6, 36.0, 46.1, 51.8, 55.2, 63.9, 124.4, 125.2,
4.2.11. (S)-N-((S)-1-((S)-1-Hydroxy-3-phenylpropan-2-
n
.
ylcarbamoyl)-2,2-dimethylpropyl)-1,2,3,4-tetrahydroisoquinoline-3-
20
carboxamide (8b). White solid, yield 77%, mp 186e188 ꢁC; [
ꢀ43.4 (c 0.7, MeOH). Found: C, 70.93; H, 7.81; N, 9.96.
a]
D
4.2.6. (S)-tert-Butyl 3-((S)-1-(methoxycarbonyl)-2,2-
dimethylpropylcarbamoyl)-3,4-dihydro-isoquinoline-2(1H)-carboxyl-
C
25H33N3O3 requires C, 70.89; H, 7.85; N, 9.92%; 1H NMR (500 MHz,
20
ate (5). Colorless viscous oil, yield 64%; [
a]
ꢀ9.5 (c 1.27, CHCl3).
CD3OD) d 0.90 (s, 9H), 2.58e2.62 (m, 1H), 2.81e2.87 (m, 2H), 3.07
D
Found: C, 65.26; H, 8.06; N, 6.87. C22H32N2O5 requires C, 65.32; H,
(dd, 1H, J¼16.5, 4.5 Hz), 3.43 (br d, 2H, J¼5.5 Hz), 4.02 (dd, 1H,
J¼12.2, 5.0 Hz), 4.05e4.09 (m, 1H), 4.18 (br s, 1H), 4.25 (br s, 2H),
7.03e7.08 (br s, 1H), 7.11e7.22 (m, 9H); 13C NMR (125 MHz, CD3OD)
7.97; N, 6.93%; 1H NMR (500 MHz, CDCl3)
d
0.58 (s, 9H), 1.39 (s, 9H),
2.98e3.01 (m, 1H), 3.23e3.26 (m, 1H), 3.59 (s, 3H), 4.18 (d, 1H,
J¼9.5 Hz), 4.34e4.85 (m, 3H), 6.15 and 6.64 (br s, 1H, NH rotamers),
d
27.1, 31.2, 35.2, 37.9, 45.5, 54.0, 56.4, 62.6, 64.4, 127.2, 127.6, 128.5,
129.1, 129.3, 129.4, 129.9, 130.4, 132.0, 139.9, 169.5, 171.6; ESI(ꢀ)-MS:
m/z 424.3 (Mþ1); IR (ATR)
3420, 3260, 1671, 1636 cmꢀ1
7.08e7.12 (m, 4H); 13C NMR (125 MHz, CDCl3)
d 24.9, 27.2, 31.2, 33.3,
43.8, 50.6, 55.7, 58.6, 80.3, 125.2, 126.0, 126.7, 127.0, 132.8, 154.0,
n
.
169.2, 169.7, 170.3; IR (ATR)
n
3345, 1737, 1682 cmꢀ1
.
4.2.12. (S)-tert-Butyl 2-((S)-1-hydroxy-3-phenylpropan-2-
4 . 2 . 7 . ( S ) - [ ( { ( S ) - 2 - [ t e r t - B u t o x y c a r b o n y l ] - 1, 2 , 3 , 4 -
tetrahydroisoquinolin-3-yl}carbonyl)amino]-3,3-dimethylbutanoic
ylcarbamoyl)pyrrolidine-1-carboxylate (11). White solid, yield 68%,
mp 152e154 ꢁC; [
a
]
D
20 ꢀ84.0 (c 1.0, CHCl3). Found: C, 65.53; H, 8.07;
acid (6). Colorless oil, yield 93%; [
a
]
20 ꢀ10.0 (c 0.6, CHCl3); Found:
N, 8.09. C19H28N2O4 requires C, 65.49; H, 8.10; N, 8.04%; 1H NMR
D
C, 64.63; H, 7.81; N, 7.09. C21H30N2O5 requires C, 64.59; H, 7.74; N,
(500 MHz, CDCl3) d 1.46 (s, 9H), 1.63e1.77 (m, 2H), 1.95e2.17
7.17%; 1H NMR (500 MHz, CDCl3)
d
0.55 (s, 9H), 1.43 (s, 9H),
(m, 2H), 2.76e2.97 (m, 2H), 3.27e3.37 (m, 2H), 3.55e3.70 (m, 2H),
4.16e4.21 (br s, 2H), 6.23 and 6.67 (br s, 1H, NH rotamers),
7.12e7.23 (m, 3H), 7.28e7.31 (m, 2H); 13C NMR (125 MHz, CDCl3)
3.02e3.11 (m, 1H), 3.29e3.36 (m, 1H), 4.24 (d, 1H, J¼9.5 Hz),
4.38e4.85 (m, 3H), 6.26 and 6.63 (br s, 1H, NH rotamers), 7.20 (br s,
4H); 13C NMR (125 MHz, CDCl3)
d
24.9, 27.2, 31.2, 33.3, 43.8, 55.8,
58.6, 80.6, 125.2, 126.1, 126.8, 127.0, 132.7, 154.2, 170.6, 170.7, 173.8;
IR (ATR)
3420, 1729, 1702, 1675 cmꢀ1
d
23.2, 27.3, 28.6, 35.9, 46.0, 51.7, 59.5, 64.1, 79.7, 125.7, 127.5, 128.0,
136.6, 171.4, 172.3; IR (ATR)
n
3363, 3333, 1670, 1648 cmꢀ1
.
n
.
4.2.13. (2S)-N-((S)-1-Hydroxy-3-phenylpropan-2-yl)pyrrolidine-2-
20
4.2.8. (S)-tert-Butyl 3-((S)-1-((S)-1-methoxy-3,3-dimethyl-1-
oxobutan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamoyl)-3,4-
dihydroisoquinoline-2-(1H)-carboxylate (7a). White solid, yield
carboxamide (12). White solid, yield 76%, mp 102e104 ꢁC; [
a]
D
ꢀ30.0 (c 0.4, MeOH); [lit.35 yield 82%, mp 104.4e105.9 ꢁC; [
] ꢀ63.0
a
(c 0.5, EtOH)]; 1H NMR (500 MHz, CD3OD)
d 1.87e1.94 (m, 3H),

3712
C. Yolacan et al. / Tetrahedron 70 (2014) 3707e3713
20
2.23e2.33 (m,1H), 2.64e2.69 (m,1H), 2.80e2.84 (m,1H), 3.14e3.20
(m, 1H), 3.24e3.29 (m, 1H), 3.41e3.44 (m, 1H), 3.47e3.50 (m, 1H),
(16b). White solid, yield 78%, mp 174e176 ꢁC; [
MeOH). Found: C, 66.41; H, 8.68; N, 11.67. C20H31N3O3 requires C,
66.45; H, 8.64; N, 11.62%; 1H NMR (500 MHz, CD3OD)
0.89 (s, 9H),
a
]
ꢀ49.2 (c 0.65,
D
4.00e4.05 (m, 2H), 7.07e7.09 (m, 1H), 7.13e7.18 (m, 4H); IR (ATR)
n
d
3503, 3251, 1656 cmꢀ1
.
1.62e1.69 (m, 1H), 1.80e1.96 (m, 2H), 2.18e2.26 (m, 1H), 2.56e2.60
(m, 1H), 2.81e2.85 (m, 1H), 3.19e3.22 (m, 1H), 3.27e3.32 (m, 1H),
3.42 (d, 2H, J¼5.5 Hz), 4.06e4.09 (m, 1H), 4.13 (s, 1H), 4.18e4.21 (m,
1H), 7.03e7.06 (m, 1H), 7.13 (br d, 4H, J¼4.5 Hz), 7.92 (br d, 1H,
4.2.14. (S)-tert-Butyl 2-((S)-1-(methoxycarbonyl)-2,2-
dimethylpropylcarbamoyl)pyrrolidine-1-carboxylate
(13). Yellow
oil, yield 58%; [
a
]
20 ꢀ71.0 (c 1.52, CHCl3). Found: C, 59.71; H, 8.87; N,
J¼9.0 Hz); 13C NMR (125 MHz, CD3OD)
d 25.0, 27.1, 31.2, 35.1, 37.9,
D
8.14. C17H30N2O5 requires C, 59.63; H, 8.83; N, 8.18%; 1H NMR
47.5, 53.9, 60.8, 62.9, 64.4, 127.1, 129.2, 130.4, 139.9, 169.3, 171.6;
(500 MHz, CDCl3)
d
0.96 (s, 9H), 1.48 (s, 9H), 1.80e1.88 (m, 2H),
ESI(ꢀ)-MS: m/z¼362.2 (Mþ1); IR (ATR)
n 3416, 3285, 1669,
2.16e2.20 (m, 1H), 2.36e2.42 (m, 1H), 3.31e3.49 (m, 2H), 3.71
1644 cmꢀ1
.
(s, 3H), 4.25e4.46 (m, 2H), 7.65 (br s, 1H); 13C NMR (125 MHz,
CDCl3)
170.6, 172.1; IR (ATR)
d
23.9, 25.4, 27.3, 28.9, 33.3, 45.9, 50.6, 57.4, 58.6, 80.5, 170.1,
3333, 1740, 1686 cmꢀ1
4.2.20. General procedure for aldol reaction. The catalyst 8a
(0.1 mmol) and benzoic acid (0.1 mmol) were dissolved in CH2Cl2,
and the solution was stirred at ꢀ10 ꢁC for 30 min. Then, aldehyde
(1.0 mmol) and ketone (10.0 mmol) were added and the reaction
mixture was stirred at ꢀ10 ꢁC for 72 h. After the evaporation of
solvent, the crude products were purified by column chromatog-
raphy using EtOAc/hexane. The enantioselectivity was determined
by chiral HPLC with a Chiralpack AD or AD-H column (UV detection
set at 254 nm, i-PrOH/hexane as eluent).
n
.
4.2.15. (2S)-2-({[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]car-
bonyl}amino)-3,3-dimethylbutanoic acid (14). Yellow oil, yield 91%;
20
[
C
a
]
ꢀ60.0 (c 0.5, CHCl3). Found: C, 58.59; H, 8.65; N, 8.50.
D
16H28N2O5 requires C, 58.52; H, 8.59; N, 8.53%; 1H NMR (500 MHz,
CDCl3) 1.00 (s, 9H), 1.47 (s, 9H), 1.90 (br s, 2H), 2.16e2.20 (m, 2H),
2.35e2.38 (m, 2H), 3.33e3.50 (m, 1H), 4.28e4.45 (m, 1H), 6.68 and
7.65 (br s, 1H, NH rotamers); 13C NMR (125 MHz, CDCl3)
23.6, 25.5,
27.3, 30.0, 33.3, 46.0, 58.6, 62.6, 79.6, 170.8, 171.5, 173.5; IR (ATR)
3322, 1724, 1662 cmꢀ1
d
d
n
Acknowledgements
.
We thank Yildiz Technical University Scientific Research Foun-
dation (2011-01-02-KAP-02) for financial support.
4.2.16. (S)-tert-Butyl 2-((S)-1-((S)-1-methoxy-3,3-dimethyl-1-
oxobutan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamoyl)pyr-
rolidine-1-carboxylate (15a). White solid, yield 63%, mp 88e89 ꢁC;
References and notes
20
[
C
a
]
ꢀ52.9 (c 1.0, CHCl3). Found: C, 60.68; H, 8.98; N, 9.26.
D
23H41N3O6 requires C, 60.64; H, 9.07; N, 9.22%; 1H NMR (500 MHz,
CDCl3) 0.86 (s, 18H), 1.46 (s, 9H), 1.90 (br s, 2H), 2.15e2.18 (m, 1H),
1. Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541.
2. List, B.; Lemer, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395.
3. Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431.
4. Vishnumaya, M. R.; Singh, V. K. J. Org. Chem. 2009, 74, 4289.
5. Ma, X.; Da, C. S.; Yi, L.; Jia, Y. N.; Guo, Q. P.; Che, L. P.; Wu, F. C.; Wang, J. R.; Li, W.
P. Tetrahedron: Asymmetry 2009, 20, 1419.
6. Bellis, E.; Kokotos, G. Tetrahedron 2005, 61, 8669.
7. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249.
8. Seayed, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
d
2.28e2.35 (m, 1H), 3.33e3.49 (m, 2H), 3.71 (s, 3H), 4.14e4.17
(m, 1H), 4.26e4.35 (m, 1H), 4.40 (d, 1H, J¼8.5 Hz), 6.22 and 6.36
(br s, 1H, NH, rotamers), 6.80 and 7.59 (br s, 1H, NH rotamers); 13
C
NMR (125 MHz, CDCl3)
51.6, 59.9, 60.2, 66.7, 80.5, 155.8, 170.1, 171.7, 172.5; IR (ATR)
3297, 1742, 1701, 1643 cmꢀ1
d
26.1, 26.7, 27.0, 27.9, 30.2, 32.4, 33.0, 46.4,
n
3349,
.
9. Pellisier, H. Tetrahedron 2007, 63, 9267.
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11. Aleman, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774.
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ii, 340.
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20. Chen, F.; Huang, S.; Zhang, H.; Liu, F.; Peng, Y. Tetrahedron 2008, 64, 9585.
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4.2.17. (S)-tert-Butyl 2-((S)-1-((S)-1-hydroxy-3-phenylpropan-2-
ylcarbamoyl)-2,2-dimethylpropylcarbamoyl)pyrrolidine-1-
20
carboxylate (15b). White solid, yield 65%, mp 178e179 ꢁC; [
a]
D
ꢀ81.5 (c 1.0, CHCl3). Found: C, 65.11; H, 8.57; N, 9.04.
25H39N3O5 requires C, 65.05; H, 8.52; N, 9.10%; 1H NMR (500 MHz,
CDCl3) 0.92 (s, 9H), 1.50 (s, 9H), 1.89e1.93 (m, 2H), 2.10e2.18
C
d
(m, 2H), 2.81e2.91 (m, 2H), 3.39e3.54 (m, 3H), 3.61e3.70 (m, 1H),
3.98e4.14 (m, 1H), 4.25 (br s, 2H), 6.65 (br d, 1H, J¼8.0 Hz),
6.89e6.96 (m, 1H), 7.18e7.26 (m, 5H); 13C NMR (125 MHz, CDCl3)
d
26.7, 27.1, 28.3, 31.9, 32.7, 37.1, 47.3, 52.9, 60.8, 62.6, 63.7, 81.4,
126.3, 128.4, 129.2, 138.1, 155.9, 169.9, 172.3; IR (ATR) 3371, 3335,
1678, 1641 cmꢀ1
n
.
4.2.18. (S)-Methyl 2-((S)-3,3-dimethyl-2-((S)-pyrrolidine-2-
carboxamido)butanamido)-3,3-dimethylbutanoate (16a). Colorless
25. Thorat, P. B.; Goswami, S. V.; Khade, B. C.; Bhusare, S. R. Tetrahedron Lett. 2012,
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a
]
20 ꢀ42.9 (c 2.3, CH2Cl2). Found: C, 60.87; H, 9.31;
53, 6083.
D
26. Zhang, T.; Zhang, Y.; Li, Z.; Song, Z.; Liu, H.; Tao, J. Chin. J. Chem. 2013, 31, 247.
27. Subba Reddy, B. V.; Bhavani, K.; Raju, A.; Yadav, J. S. Tetrahedron: Asymmetry
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N, 11.83. C18H33N3O4 requires C, 60.82; H, 9.36; N, 11.82%; 1H NMR
(500 MHz, CDCl3)
d 0.95 (s, 9H), 0.99 (s, 9H), 1.25 (br s, 1H),
28. Cavalli, A.; Lizzi, F.; Bongarzone, S.; Brun, R.; Krauth-Siegel, R. L.; Bolognesi, M.
1.70e1.77 (m, 2H), 1.90e1.96 (m, 1H), 2.13e2.22 (m, 1H), 2.96e3.01
(m, 1H), 3.04e3.09 (m, 1H), 3.72 (s, 3H), 3.82e3.85 (m, 1H),
4.31e4.33 (d, 1H, J¼9.0 Hz), 4.35e4.37 (d, 1H, J¼8.5 Hz), 6.67 (br d,
1H, J¼8.5 Hz), 8.33 (br d, 1H, J¼8.5 Hz); 13C NMR (125 MHz, CDCl3)
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d
26.1, 26.5, 26.6, 30.9, 34.3, 34.6, 47.2, 51.7, 60.0, 60.3, 60.4, 170.5,
171.7, 174.5; ESI(ꢀ)-MS: m/z¼356.2 (Mþ1); IR (ATR)
n 3312, 1741,
1645 cmꢀ1
.
33. Cheng, S.; Zhang, X.; Wang, W.; Zhao, M.; Zheng, M.; Chang, H. W.; Wu, J.; Peng,
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4.2.19. (2S)-N-((S)-1-((S)-1-Hydroxy-3-phenylpropan-2-
ylcarbamoyl)-2,2-dimethyl-propyl)pyrrolidine-2-carboxamide

C. Yolacan et al. / Tetrahedron 70 (2014) 3707e3713
3713
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