Study of asymmetric aldol and Mannich reactions catalyzed by proline-thiourea host-guest complexes in nonpolar solvents

Article abstract of DOI:10.1016/j.tetasy.2013.03.014

A proline-thiourea host-guest complex has been described as a good catalyst for asymmetric reactions such as aldol and Mannich reactions. High stereoselectivities were obtained under optimal conditions. Thiourea was observed to have an important effect on the reactivity and selectivity, even in an unconventional nonpolar reaction medium and without the need to utilize low temperatures. This proline-thiourea host-guest system has the ability to participate in a hydrogen bonding network.

Full text of DOI:10.1016/j.tetasy.2013.03.014

Tetrahedron: Asymmetry 24 (2013) 515–525
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Study of asymmetric aldol and Mannich reactions catalyzed
by proline–thiourea host–guest complexes in nonpolar solvents
Ayhan Sıtkı Demir a,z, Sinan Basceken a,b,
⇑
a Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b Department of Chemistry, Hitit University, 19030 Corum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 February 2013
Accepted 13 March 2013
A proline–thiourea host–guest complex has been described as a good catalyst for asymmetric reactions
such as aldol and Mannich reactions. High stereoselectivities were obtained under optimal conditions.
Thiourea was observed to have an important effect on the reactivity and selectivity, even in an unconven-
tional nonpolar reaction medium and without the need to utilize low temperatures. This proline–thio-
urea host–guest system has the ability to participate in a hydrogen bonding network.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
chiral molecules with additional functionality, which are much
more precious than the proline itself.5
Asymmetric catalysis with proline was first realized in the
Hajos–Parrish–Eder–Sauer–Wiechert reaction, an enantiogroup
differentiating aldol cyclization.1 The field of enamine catalysis
was effectively developed by Barbas, Lerner, and List;1 they
showed that small organic molecules, such as proline, could cata-
lyze some chemical reactions as well as larger organic molecules
(enzymes) by using similar mechanisms. The works of McMillan
et al.2 on iminium catalysis, urea derivatives from Jacobsen3 and
others have provided interesting contributions in this field of
organocatalysis.
Although proline is a relatively good catalyst, it is not without
some potential drawbacks, such as (1) low solubility, which thus
limits reactivity in typical organic solvents; (2) potential side reac-
tions and established parasitic equilibria with substrates;4 and (3)
low selectivities with planar, aromatic aldehydes in direct organo-
catalytic reactions. Therefore, a considerable effort has been direc-
ted toward the development of proline analogs in order to improve
the reactivity, selectivity, and scope. Considering the practical syn-
thetic issues, the carboxylic acid moiety of the proline has been tar-
geted as a site for modifications, in which the reactivity and
selectivity of proline were enhanced in custom-made catalysis,
even though the identification of a good catalyst in turn required
the synthesis of various analogues of a proposed catalyst design
in order to identify the optimal one. Moreover, the improved cata-
lyst was usually obtained through modification of proline with
The basic catalyst system for developing catalysts is modular in
nature, and offers an opportunity for structural diversity. However,
our main interest lies in using these catalysts in combination with
a library of achiral thiourea additives in order to multiply the num-
ber of new catalysts available by means of complementary hydro-
gen bonding interactions. Thioureas are readily available, and the
use of amine and isothiocyanates allows for a range of these addi-
tives to be readily synthesized.6 For our proof of concept studies, a
relatively small library was generated, and the discussion herein
focuses on the catalysts generated from proline and other amino
acids and achiral thiourea derivatives.
2. Results and discussion
Herein we report the synthesis of two types of bipyridine de-
rived achiral thioureas and their application as co-catalysts (guest)
in the proline (host) catalyzed asymmetric aldol and Mannich
reactions.
2.1. Synthesis of bipyridine derived achiral thioureas
The preparation of bipyridine derived thiourea 5 was per-
formed from commercially available 4,40-dimethyl-2,20-bipyridine
1, according to the seven-step route illustrated in Scheme 1.7 This
procedure involves the oxidation of the methyl groups to carbox-
ylic acids with potassium permanganate. The subsequent esterifi-
cation with methanol, reduction of the ester to the alcohol with
sodium borohydride, substitution with hydrobromic acid, reaction
with phthalimide potassium salt, and then reaction with hydra-
zine monohydrate gave 4,40-bis(aminomethyl)-2,20-bipyridine 4.7
⇑
Corresponding author. Tel.: +90 (0)364 227 7000; fax: +90 (0)364 227 7005.
E-mail address: sinanbasceken@hitit.edu.tr (S. Basceken).
Deceased on Professor Dr. Ayhan Sıtkı Demir (1950–2012).
As
a
result, 1,10-([2,20-bipyridine]-4,40-diylbis(methylene))bis
z
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.014

516
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
N
N
OH
N
N
Br
Br
N
N
i, ii, iii
iv
OH
2
3
1
v, vi
CF3
NCS
S
N
N
NH2
F3C
N
H
N
H
F3C
CF3
N
CHCl3, 6 h, rt
85%
NH2
N
H
N
H
N
CF3
4
5
S
CF3
Scheme 1. Synthesis of novel thioureas. Reagents and conditions:7 (i) KMnO4, H2SO4,
phthalimide potassium salt, DMF; (vi) H2NNH2.H2O, EtOH, , 98%.
D, 24 h, 50%; (ii) MeOH, H2SO4, D, 98%; (iii) EtOH, NaBH4, D, 97%; (iv) HBr, D, 60%; (v)
D
(3-(3,5-bis(triflu-oromethyl)phenyl)-thiourea) 5 was obtained by
reaction of 3,5-bis(trifluoromethyl)phenyl isothiocyanate with
4,40-bis(aminomethyl)-2,20-bipyridine 4 in chloroform.
In order to elucidate the structural changes upon binding be-
tween host and guest, we examined the hydrogen bond interac-
tions of bipyridine derived thiourea (guest) 7 with proline (host)
NCS
H
N
H
N
CF3
NH2
N
S
N
F3C
CF3
CF3
CF3
S
N
N
acetone, 48 h, rt
70%
F3C
N
H
N
H
H2N
7
6
1,10-([2,20-Bipyridine]-4,40-diyl)bis(3-(3,5-bis(trifluoromet-hyl)
phenyl)thiourea) 7 was prepared by the reaction of 3,5-bis(trifluo-
romethyl)phenyl isothiocyanate with commercially available 4,40-
diamino-2,20-bipyridine 6 in acetone, according to the step shown
in Scheme 1.
in solution. Some information about the nature of the proline–thio-
urea species was obtained from the 1H NMR experiments (Fig. 2),
with spectra being recorded in acetone-d6. The results of these
experiments showed that following the addition of proline in the
mixture, the N–H proton of the thiourea underwent a downfield
shift (Dd = 0.24 ppm) and decreased in intensity due to the domi-
2.2. Direct asymmetric aldol reaction
nant interactions (Fig. 2), that are present in the formation of a
hydrogen bonding network, as shown in Figure 2.
The first amine-catalyzed, direct asymmetric intermolecular al-
dol reaction was developed by List et al. in 2000.8 Proline catalyzed
direct aldol reactions have been shown experimentally and com-
putationally to proceed through enamine intermediates, in which
the transition state (TS)-A is highly stabilized by hydrogen bond
donation from a carboxylic acid moiety as can be seen in Figure 1.8
The data collected thus far indicated that a specific proline–
thiourea interaction may operate to afford an enantioselective
reaction. Exactly which intermediates and transition states oper-
ate, or whether an alternative transition state is involved, is cur-
rently under investigation in our laboratory. The possibility of
fine-tuning similar proline–thiourea interactions also presents a
possible strategy for asymmetric catalyst development.8
In order to optimize the asymmetric catalyst, the role of suitable
additives or co-catalysts can be crucial in enhancing the reactivity
and stereoselectivity of the catalytic system. For example, it has
been shown that the addition of a small amount of water often
accelerates the reaction rate and increases the enantioselectivity
of proline-catalyzed aldol reactions.8 Recently, Shan et al. have
shown that using chiral diols as additives can improve the enanti-
oselectivity of proline catalyzed aldol reactions, probably through
their involvement in the transition state, via the formation of a
hydrogen bonding network.8
A
B
F3C
Host
δ+
N
δ+
O
δ-
O
δ-
N
HN
HN
CF3
H
H
O
O
O
O
S
R
R
H
H
N
As a testing ground for the new approach we decided to study
the enantioselective aldol reaction of ketones to aldehydes. This
was done with the idea of developing a simple catalytic solution
Figure 1. (A) The List–Houk model of (S)-proline catalyzed intermolecular aldol
reactions,8 (B) The possible interaction of the bipyridine derived thiourea moiety 7
with (S)-proline in the transition state.

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
517
N
O
H
and
(c) (d)
H
O
(b)
H
H
H
H
N
H
N
N
N
CF3
CF3
(a)
N
S
H
N
H
N
N
S
CF3
H
CF3
CF3
H
CF3
H
CF3
S
N
N
S
S
N
CF3
H
F3C
N
N
CF3
F3C
N
N
S
N
H
H
H
H
H
H
F3C
N
N
O
O
O
O
H
H
H
H
H
H
H
N
N
H
H
(a)
H
(b)
(c)
(d)
11.0
ppm
10.0
9.0
8.0
7.0
(a) Thiourea
(b) Host-Guest (1:1)
(c) Host-Guest (3/2:1)
(d) Host-Guest (2:1)
Figure 2. 1H NMR (400 MHz) spectra of thiourea 7 with (S)-proline in acetone-d6 at 300 K.
for the enantioselective aldol reaction by using small organic
molecules (amino acids). We found that the possible host–guest
complex of proline–thiourea (TS)-B, can catalyze direct enantiose-
lective aldol reactions in nonpolar solvents (hexane) with high dia-
stereo- and enantioselectivities better than proline (Table 1, entries
3–4). These results clearly demonstrate the benefit of bipyridine
derived thioureas on the reactivity and selectivity, even in an
unconventional nonpolar reaction medium without the need to
utilize low temperatures. The sense of stereoselection is the same
as that with proline as the sole catalyst. In addition, the compara-
tive experiments using pyridine, 2,6-dimethyl-pyridine, and bipyr-
idine as additives did not provide product 10a (Table 1, entries 5–
7). These results clearly demonstrate that the hydrogen bonding
effect of proline–thiourea, not the basicity of pyridine moiety,
plays the most important role in nonpolar solvents.
We assumed that the asymmetric aldol reaction occurs via an
enamine mechanism (Fig. 3). In analogy to the mechanism pub-
lished by List et al.8 we proposed that the enamine with a bipyri-
dine thiourea moiety in the backbone attacks the carbonyl group
of the aldehyde acceptor with high enantiofacial selectivity, which
is imposed by a highly organized tricyclic hydrogen bonded frame-
work resembling a metal-free Zimmerman-Traxler type transition
state.8
This mechanism reflects our observation that both NH groups of
the thiourea moiety and the acidic proton of the proline are re-
quired to catalyze this reaction. The host–guest complex of pro-

518
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
Table 1
Enantioselective direct aldol reaction with p-nitrobenzaldehyde 9a and cyclohexanone 8 by using various catalysts in hexanea
OH
O
O
O
(R)
(S)
H
catalyst
+
hexane, rt
O2N
O2N
anti-10a
9a
8
Entry
1
Guest
Catalyst loading (mol %)
Yield (%)
drb (anti:syn)
eec (%)
46
S
I
20
40
55:45
N
N
H
N
H
CF3
S
2
20
60
75:25
79
II
N
N
N
CF3
H
H
CF3
S
F3C
N
H
N
H
N
5
3
10
75
74:26
92
N
H
H
F3C
N
N
S
CF3
H
H
F3C
N
N
S
N
N
CF3
CF3
4
10
90
90:10
99
7
S
F3C
N
N
H
N
H
5
6
20
20
0
0
—
—
—
—
N
N
7
20
0
—
—
N
a
The reactions were conducted with (S)-proline (20 mol %), thiourea or pyridine derivatives (10–20 mol %), cyclohexanone (16 equiv), p-nitrobenzaldehyde (0.125 mmol)
and hexane (2 mL) at room temperature for 24 h.
b
Determined by chiral HPLC analysis of the mixture of anti/syn product.
Determined by a chiral HPLC column.
c
line–thiourea may facilitate each individual step of the mechanism
(Fig. 3), including the nucleophilic attack of the amino group (a),
the dehydration of the carbinol amine intermediate (b), the car-
bon–carbon bond forming step (c), and both steps of the hydrolysis
of the iminium–aldol intermediate (d and e).8 Typically, anti-dia-
stereoselectivity is observed in the proline–thiourea catalyzed al-
dol reaction, although other possible mechanisms cannot be
ruled out at this stage.
We began the investigations with donor ketone cyclohexanone
8 and acceptor aldehyde p-nitrobenzaldehyde 9a under proline
catalysis and pyridine derived thioureas (Table 1, entries 1–2) as
the additive in a nonpolar solvent. After the first results of the aldol
reaction (46% ee, Table 1, entry 1), we started to develop multi-
functional thioureas with bipyridine moieties to examine several
functionalities for further modification and applied them to enan-
tioselective aldol reactions. Among them, four functionalized thio-
ureas showed high ee and yields as shown in Table 1. The catalyst
combinations of proline and the synthesized bipyridine bridged
bis-thioureas (Table 1, entries 3–4) showed better catalytic activi-
ties and stereoselectivities than those of the co-catalysts with a
single thiourea moiety (Table 1, entries 1–2). Although the exact
mechanism is not clear, the possible cooperation of the two thio-
urea moieties may account for this advantage. The selected thio-
urea 7 (Table 1, entry 4) was the optimum choice.

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
519
O
-H2O
N
N
HN
O
O
O
a
b
H
+
H
H
O
HO
O
O
L*
L*
L*
RCHO
c
OH
OH
R
+H2O
d
R
N
O
N
H
N
R
O
O
O
H
OH
O
+
O
H
O
L*
L*
e
re-facial attack
si-enamine + re-aldehyde
OH
O
TS-B
HN
O
R
H
H
H
N
N
O
CF3
L*
L*
=
anti
N
S
CF3
Figure 3. Proposed mechanism of aldol reaction.
Table 2
Solvent screening for the enantioselective aldol reaction with 9a and 8a
O
O
OH
O
(R)
catalyst
(S)
H
+
solvent, rt
O2N
O2N
9a
8
anti-10a
Entry
Solvent
Catalyst (%) proline/thiourea (host/guest)
Yield (%)
drb (anti /syn)
eec (%)
1
2
Hexane
Toluene
Benzene
Hexane
Hexane
20:10
20:10
20:10
20:10
20:10
90
85
76
70
64
90/10
63/37
72/28
71/29
64/36
99
91
92
60
56
3
4d
5e
a
The reactions were conducted with (S)-proline (20 mol %), 7 (10 mol %), cyclohexanone (16 equiv), p-nitrobenzaldehyde (0.125 mmol), and solvent (2 mL) at room
temperature for 24 h.
b
Determined by chiral HPLC analysis of the mixture of the anti/syn product.
Determined by chiral HPLC with AD-H column.
(S)-tert-Leucine was used as the catalyst.
(S)-Tryptophan was used as the catalyst.
c
d
e
Table 3
The enantioselective direct aldol reaction with various aldehydes and cyclohexanone
The cooperation of the proline host and bipyridine derived thio-
urea guest 7 was screened using hexane, toluene, and benzene as
nonpolar solvents, both the efficiency and selectivity were remark-
ably enhanced as shown in Table 2. Hexane was the most favorable
solvent and the best diastereo- and enantioselectivity was ob-
tained as shown in Table 2, entry 1 (up to 90/10 dr and >99% ee)
and high isolated yield (90%). When the aldol reaction was carried
out without solvent it also furnished the product in high diastereo-
and enantioselectivities (90% ee) but in much lower yield (<25%).
For demonstrating the modularity of the host–guest system,
two other representative amino acids namely (S)-tert-leucine and
(S)-tryptophane are also screened as catalysts and good yields
(<70%) and stereoselectivities (up to 71/29 dr and <60% ee) were
obtained under unoptimized conditions with the same stereo-
chemical preference as proline. Proline, however, turned out to
be the most efficient and practical catalyst for this reaction.9 In
fact, both the pyrrolidine ring and the carboxylate were found to
be essential for effective catalysis to occur (Fig. 1).1 This catalytic
system was then applied to various aldehydes as summarized in
Table 3. The anti-aldol products were obtained as the major prod-
uct in good to excellent yields (62–90%) with high diastereoselec-
tivity and excellent enantioselectivity as can be seen in Table 3,
8a
OH
O
O
O
catalyst
Ar
+
Ar
H
hexane, rt
9a-h
anti-10a-i
8
Entry
Aldehyde (Ar)
Yield (%)
drb (anti/syn)
eec (%)
(Conf.)d
1
2
3
4
5
6
7
8
9e
4-NO2Ph
3-NO2Ph
4-BrPh
4-CF3Ph
4-CNPh
2-MeOPh
4-FPh
90
70
67
75
88
73
65
62
82
90/10
87/13
91/9
91/9
94/6
99
91
98
98
92
96
95
95
99
(2R,10S)
(2R,10S)
(2R,10S)
(2R,10S)
(2R,10S)
(2R,10S)
(2R,10S)
(2R,10S)
(2R,10S)
99/1
85/15
84/16
43/57
Ph
4-NO2Ph
a
The reactions were conducted with (S)-proline (20 mol %), 7 (10 mol %), cyclo-
hexanone (16 equiv), aldehyde (0.125 mmol), and hexane (2 mL) at room temper-
ature for 24 h.
b
Determined by chiral HPLC analysis of the mixture of anti/syn product.
Determined by a chiral HPLC column.
By comparison of their specific rotations with those reported for anti-10a-i.
Cyclopentanone was used.
c
d
e

520
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
entries 1–8. The reactions with aldehydes bearing high
electron-withdrawing groups proceeded smoothly to afford the al-
dol adducts in 24 h (Table 3, entries 1–5 and 7), with a good level of
diastereoselectivity. For the neutral and electron-rich aromatic
aldehydes (Table 3, entries 6 and 8), the reactions commonly re-
quired a longer time (48 h or 72 h).
Concerning the anti/syn and absolute configuration, the same
preference as proline is obtained. The modular catalysts can be ap-
plied to aldol type C–C bond forming reactions in high conversion,
high diastereo- and enantioselectivity.
B
Host
H3CO
a
A
O
N
H
CF3
O
N
N
H
O
N
H2PMP
H
H
O
N
H
N
R
H
N
R'
S
R
CF3
R'
Figure 4. (A) The List model of the TS of the Mannich reaction, (B) The possible
interaction of the bipyridine derived thiourea 7 with (S)-proline in the TS.
2.3. Asymmetric Mannich reactions
The Mannich reaction is a highly useful transformation for the
construction of nitrogenous molecules.10 In this transformation,
three components, namely two carbonyl compounds and an amine,
react to form a b-amino-carbonyl compound. List et al. found the
first proline-catalyzed Mannich reaction; that proline catalyzed
the direct asymmetric three component Mannich reaction of ke-
tones with aldehydes and p-anisidine with high ee’s and dr’s,11
with opposite enantiofacial selectivity compared to the proline-
catalyzed aldol reaction. Consequently, the major product had
the opposite absolute configuration at the stereogenic center bear-
ing the heteroatom. The diastereoselectivity was also inverted with
syn-products in the Mannich and anti-products in the aldol
reaction.
In our initial experiment, we found that the possible proline–
thiourea host–guest system (TS)-B (Fig. 4), can catalyze the asym-
metric Mannich reaction of p-nitrobenzaldehyde 9a, p-anisidine
11, and acetone in benzene and toluene to give the expected b-
amino-carbonyl compound 12a in 45% yield. The corresponding al-
dol product 13 was formed as well under those conditions but in
much lower yield (<21%) as shown in Table 4. Among the nonpolar
solvents used, the best results were obtained in toluene as can be
seen in Table 4, entry 2. Most importantly, high enantioselectivity
was observed in the Mannich products (91% ee) and the absolute
configuration was found to be (S).
By using aliphatic aldehydes instead of p-nitro-benzaldehyde
9a under the same reaction condition only the Mannich product
was obtained. This reaction then carried out with various aliphatic
aldehydes 14a–c and the Mannich products 15a–c was obtained in
high ee’s as summarized in Table 5.
We were particularly fascinated by the prospect of replacing the
aldehyde with imines. The aldimine from p-nitrobenzaldehyde 9a
and p-anisidine 11, with acetone in nonpolar solvents such as ben-
zene, and toluene with 20 mol % of the proline–thiourea host–
guest catalyst furnished only the Mannich product. Toluene was
the most favorable solvent and showed the highest effectivity con-
cerning of yield and ee’s (91% ee) in Table 6, entry 1. We found that
with 20 mol% of catalyst and hexane as a nonpolar solvent the
Mannich product is not formed. Under similar conditions, the Man-
nich reaction without thiourea gives, after 6 h, a product which
was isolated and HPLC analysis showed 20% ee; then adding bipyr-
idine derived thiourea 7 in the reaction mixture increased the ee in
48 h to 91%.
Other ketones can readily be used in proline–thiourea catalyzed
Mannich reactions with excellent results as summarized in Table 6.
Reacting two different ketones (2-butanone, and hydroxyacetone,
each 20 vol %) with the aldimine in toluene furnished the desired
products in good yields and with excellent ee’s (95–99%).
Table 4
Solvent screening of the asymmetric three component Mannich reactionsa
OMe
O
HN
O
H2N
12a
O
NO2
catalyst
H
+
+
+
solvent, rt
OMe
O
OH
NO2
11
9a
13
NO2
Entry
Solvent
Catalyst (%) proline/thiourea (host/guest)
Yield (%)
eeb (%)
(Conf.)c
1
2
Hexane
Toluene
Benzene
Toluene
20:20
20:20
20:20
20:20
n.d
65
62
50
n.d
91
88
—
(S)
(S)
—
3
4d
n.d
a
The reactions were conducted with (S)-proline (20 mol %), 7 (20 mol %), acetone (50 lL), p-anisidine (0.063 mmol), aldehyde (0.063 mmol), and solvent (2 mL) at room
temperature for 48 h.
b
Determined by chiral HPLC with an AD column.
By comparison of their specific rotations with those reported.
(S)-tert-Leucine was used as the catalyst.
c
d

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
521
Table 5
Additionally, in the case of 2-butanone 16b and hydroxyacetone
16c excellent diastereoselectivities were observed. High regiose-
lectivities generally favoring products resulting from the higher
substituted side of the ketone were found with oxygenated ke-
tones, while butanone furnished a 2.5:1 regioisomeric mixture
which could not be isolated. The chemoselectivity in these reac-
tions was also high, and essentially no aldol product was formed
in all three cases. Under similar conditions using (S)-tert-leucine
furnished product in 24% ee.
In order to explain the observed stereoselectivities, it was pro-
posed that the reaction follows an enamine mechanism and in-
volves a transition state (TS)-A11 and B similar to the earlier
proposed transition state for the corresponding aldol reaction as
can be seen in Figure 1.
The proposed mechanism of the proline–thiourea catalyzed
Mannich reaction is depicted in Figure 5. Accordingly, the nucleo-
philic attack of the proline (a), the dehydration of the carbinol
amine to give an enamine (b), the carbon–carbon bond forming be-
tween imine and enamine in the transition state (c), and then reac-
tion to give, after hydrolysis, the enantiomerically enriched
Mannich product (d and e). This mechanism is similar to the one
we proposed for the proline-catalyzed aldol reaction (Fig. 3) with
the only difference being that the aldehyde is first converted into
an imine before reacting with the presumed proline enamine.11
Typically, Mannich products are formed via si-face attack on an
imine. Accordingly, in the Mannich transition state we assume (E)-
configurations of both the proline enamine and the imine.11 The si-
face of the imine is selectively attacked by the enamine to allow for
Three components Mannich reactions with various aliphatic aldehydes (PMP = p-
Methoxyphenyl)a
OMe
OMe
15a-c
O
O
7
10 mol%
10 mol% (S)-proline
H
R
+
+
O
HN
toluene, rt
14a-c
(R)
R
NH2
Entry Aldehyde (R)
Product
Yield
(%)
eeb
(%)
(Conf.)c
PMP
O
O
O
HN
HN
HN
1
2
(CH3)2CHCH2–
CH3(CH2)3–
90 81
88 81
(R)
(R)
PMP
PMP
3
(CH3)2CH–
85 90
(S)
a
The reactions were conducted with (S)-proline (10 mol %), 7 (10 mol %), acetone
lL), p-anisidine (0.063 mmol), aldehyde (0.063 mmol), and toluene (2 mL) at
(20
room temperature for 24 h.
b
Determined by chiral HPLC with an OD-H column.
By comparison of their specific rotations with those reported.
c
Table 6
Two component Mannich reactionsa
OMe
MeO
O
HN
O
catalyst
N
+
toluene, rt
H
R
R
NO2
16a-c
NO2
12a-d
Entry
1
Ketone (R)
–H
Product
Yield (%)
eeb (%)
(Conf.)c
PMP
O
HN
65
70
91
(S)
(S)
NO2
PMP
O
HN
(S)
(S)
2d
–CH3
95
(3S,4S)
NO2
PMP
O
HN
99
97
(S)
(S)
NO2
PMP
O
HN
(S)
3
–OH
62
(3S,4R)
(R)
OH
NO2
a
b
c
The reactions were conducted with (S)-proline (20 mol %), 7 (20 mol %), ketone (50–100
Determined by chiral HPLC with AD or AD-H column.
By comparison of their specific rotations with those reported in the literature.
Two inseparable regioisomeric products.
lL), aldimine (0.0625 mmol), and toluene (2 mL) at room temperature for 48 h.
d

522
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
R1 = -H, -CH3, -OH
O
R1
-H2O
N
N
HN
R1
O
O
O
R1
H
a
b
+
H
H
O
HO
O
O
L*
L*
L*
NAr
RCHO
+
ArNH2
-H2O
c
R
H
H
Ar
Ar
NH
NH
R
+H2O
d
Ar
R
R1
R
N
N
H
N
O
O
R1
N
O
R1
H
OH
O
O
O
L*
L*
e
si-facial attack
si-enamine + si-imine
TS-B
Ar
R
NH
O
HN
+
O
H
R1
syn
O
L*
Fig. 5. Proposed mechanism of the Mannich reaction.
protonation of its lone pair and compensation of negative charge
formation. Attack of the imine re-face would result in unfavorable
steric interactions between the pyrrolidine and the aromatic ring
(Fig. 4, arrow a). Moreover, if substituted ketone donors are used
excellent syn-selectivity was typically observed11 (Table 6, entries
2 and 3).
200 lL, 16 equiv) was added, in which the resulting mixture was
stirred for 15 min at ambient temperature followed by the addition
of aldehyde (0.125 mmol) wherein stirring was continued for 24 h
(TLC monitoring). The reaction mixture was then treated with sat-
urated aqueous ammonium chloride solution and the whole mix-
ture was extracted with ethyl acetate. The organic layer was
washed with brine, dried, and concentrated to give a crude residue,
which was purified with column chromatography over silica gel
using hexane–ethyl acetate as an eluent to afford pure product.
Diastereoselectivity was determined by 1H NMR analysis of the
crude aldol product. The enantiomeric excess (ee) of products
was determined by chiral-phase HPLC analysis. The absolute con-
figuration of the aldol products was determined by comparing
the values with those previously reported in the literature.12
3. Conclusion
The scope, optimization, and application of the proline–thiourea
complex catalyzed asymmetric two and three component Mannich
reactions have been described herein. The development of this
reaction constitutes a major advancement over prior asymmetric
Mannich reaction technologies. Exceptionally high enantio-, dia-
stereo-, regio-, and chemoselectivities have been obtained. The
reactions are operationally simple and use an inexpensive modular
and nontoxic catalyst that is available in both enantiomeric forms
in a nonpolar medium.
In summary, the synthesis of novel achiral bipyridine derived
thioureas and their application as co-catalysts in the proline cata-
lyzed asymmetric aldol and Mannich reactions were described. The
proline–thiourea system demonstrated excellent reactivity, diaste-
reoselectivity, and enantio-selectivity in nonpolar solvents. Thio-
ureas may be synthesized easily in good yields, and to the best of
our knowledge this is the first report of organocatalysis by these
host–guest complexes. The success of this catalyst design will open
up new perspectives in asymmetric organocatalysis. More detailed
studies regarding the mechanism and synthetic applications of this
catalyst on enantioselective organocatalytic reactions are currently
under investigation.
4.2. General procedure for the asymmetric Mannich reaction
The mixture of (S)-proline (0.0125 mmol, 1.4 mg, 10 mol%),
thiourea 7 (0.0125 mmol, 9.1 mg, 10 mol%), and 2 mL toluene
was placed in a screw capped vial, then aldimine (0.0625 mmol,
16 mg) was added, in which the resulting mixture was stirred for
30 min at ambient temperature followed by addition of 50–
100 lL ketone (acetone, 2-butanone, hydroxyacetone) wherein
stirring was continued for 48 h (TLC monitoring). The reactions
were worked up by adding phosphate-buffered saline (PBS) solu-
tion (pH 7.4), extracting with ethyl acetate, drying the organic
layer with Na2SO4, purifying the crude product by column chroma-
tography over silica gel using hexane-ethyl acetate as an eluent to
afford pure product. The enantiomeric excess of products was
determined by chiral-phase HPLC analysis. The absolute configura-
tions of products were determined by comparing the values with
those previously reported in the literature.11,13
4. Experimental
4.3. Thioureas I and II are known compounds14
4.1. General procedure for the asymmetric aldol reaction
1-Phenyl-3-(pyridin-2-yl)thiourea I and 1-(3,5-bis(tri-fluorom-
ethyl)phenyl)-3-(pyridin-2-yl)thiourea II were prepared according
to literature methods.14
The mixture of (S)-proline (0.025 mmol, 2.8 mg, 20 mol %), thio-
urea 7 (0.0125 mmol, 9.1 mg, 10 mol %), and 2 mL hexane was
placed in a screw capped vial, then cyclohexanone (2 mmol,

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
523
4.3.1. 1-Phenyl-3-(pyridin-2-yl)thiourea I
122.9, 118.8, 117.3, 114.2 (d, Ar-C); IR (ITR) mmax (cmꢀ1): 3202,
3035, 3004, 2917, 2851, 1590, 1575, 1527, 1382, 1275, 1133; m/z
(ESI-TOF) 729 (60, MH+), 757 (30), 759 (18), 500 (100), 360
(60%); HRMS (ESI-TOF): MH+, found 729.0762. C28H16F12N6S2 re-
quires 729.0764.
1H NMR (CDCl3): d 13.7 (s, 1H), 9.6 (s, 1H), 8.1 (s, 1H), 7.6 (m,
3H), 7.3 (m, 2H), 7.1 (m, 1H), 6.9 (m, 2H); 13C NMR (CDCl3): d
178.8 (s, C@S), 153.4 (s, pyridine-C-2), 145.6, 139.0 (d, Ar-C),
138.7 (s, ArC-NHR), 128.8, 126.3, 125.1, 118.3, 112.7 (d, Ar-C).
4.6. (2R,10S)-2-[Hydroxy-(4-nitrophenyl)methyl]cyclohex-an-1-
4.3.2. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-(pyridin-2-yl)-thiou-
rea II
one 10a:12
1H NMR (CDCl3): d 14.2 (s, 1H), 9.0 (s, 1H), 8.2 (m, 3H), 7.7 (m,
2H), 7.1 (m, 1H), 6.8 (d, J = 8.3 Hz, 1H); 13C NMR (CDCl3): d 179.2 (s,
C@S), 152.8 (s, pyridine-C-2), 145.8 (d, Ar-C), 140.2 (s, ArC-NHR),
139.5 (d, Ar-C), 132.1, 131.8 (s, ArC-CF3), 124.5 (d, Ar-C), 124.4 (s,
C-F), 118.9, 112.5 (d, Ar-C).
Following the general procedure, compound 10a was obtained
as a slightly yellow solid, 90%, in a maximum of 99% ee. Rf = 0.4
(EtOAc/hexanes 1:2 v/v); The enantiomeric purity was determined
by HPLC on AD-H, hexanes/i-PrOH = 90:10, flow rate = 0.5 mL/min,
UV = 254 nm, anti/syn = 90/10, syn-10a tR = 36.2 min (major) and
tR = 42.5 min (minor), anti-10a tR = 62.1 min (major). 1H NMR
(CDCl3): d 8.21 (2H, d, J = 8.7 Hz), 7.51 (2H, d, J = 8.7 Hz), 4.90
(1H, d, J = 8.3 Hz), 4.09 (1H, s), 2.63–2.58 (1H, m), 2.53–2.47 (1H,
m), 2.41–2.33 (1H, m), 2.15–2.08 (1H, m), 1.85-1.36 (6H, m). 13C
NMR (CDCl3): d 214.7 (s, C@O), 148.4, 147.6, 127.9, 123.6, 74.0,
57.2, 42.7, 30.8, 27.6, 24.7.
4.4. 1,10-([2,20-Bipyridine]-4,40-diylbis(methylene))bis(3-(3,5-
bis(trifluoromethyl)phenyl)thiourea) 5
4,40-Dicarboxy-2,20-bipyridine (not shown), 4,40-dimethoxy-
carboyl-2,20-bipyridine (not shown), 4,40-bis(hydroxymethyl)-
2,20-bipyridine 2, 4,40-bis(bromomethyl)-2,20-bipyridine 3, and
4,40-bis(aminomethyl)-2,20-bipyridine 4 were prepared according
to literature methods.7
4.7. (2R,10S)-2-[Hydroxy-(3-nitrophenyl)methyl]cyclohex-an-1-
one 10b12
To a solution of 4,40-bis(aminomethyl)-2,20-bipyridine 4 (50 mg,
0.23 mmol) in dried chloroform (2 mL) was added dropwise 3,5-
Following the general procedure, compound 10b was obtained
as a slightly yellow solid, 70%, in a maximum of 91% ee. Rf = 0.4
(EtOAc/hexanes 1:2 v/v); The enantiomeric purity was determined
by HPLC on AD-H, hexanes/i-PrOH = 95/5, flow rate = 1.0 mL/min,
UV = 254 nm, anti/syn = 87/13, syn-10b tR = 26.5 min (major) and
tR = 29.7 min (minor), anti-10b tR = 33.5 min (major) and
tR = 43.3 min. 1H NMR (CDCl3): d 8.21 (1H, s), 8.15 (1H, d,
J = 8.2 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.53 (1H, t, J = 7.8 Hz), 4.90
(1H, d, J = 8.4 Hz), 4.17 (1H, s), 2.67–2.61 (1H, m), 2.52–2.48 (1H,
m), 2.42–2.34 (1H, m), 2.13–2.10 (1H, m), 1.83 (1H, d,
J = 12.8 Hz), 1.73–1.53 (3H, m), 1.44–1.34 (1H, m). 13C NMR
(CDCl3): d 214.8 (s, C@O), 148.2, 143.3, 133.2, 129.2, 122.8, 122,
74, 57.1, 42.6, 30.7, 27.6, 24.6.
bis(trifluoromethyl)phenyl isothiocyanate (150 lL, 0.86 mmol).
The reaction mixture was stirred at room temperature and sud-
denly a precipitate formed. The suspension was then stirred for
6 h and added on dried hexane (15 mL). The resulting precipitate
was filtered off, washed with dry hexane, and dried to give the
compound
1,10-([2,20-bipyridine]-4,40-diylbis(methylene))bis(3-
(3,5-bis(trifluoromethyl)phenyl-)thiourea) 5 (149 mg, 85%) as a
slightly yellow solid; [Found: C, 47.43; H, 2.62; N, 11.0; S, 8.46.
C30H20F12N6S2 requires C, 47.62; H, 2.66; N, 11.11; S, 8.48%]; mp
225–228 °C; 1H NMR (CD3COCD3): d 9.8 (br s, 2H), 8.6 (app d,
J = 5.0 Hz, 2H), 8.5 (app s, 2H), 8.4 (app d, J = 4.8 Hz, 4H), 7.7 (app
s, 2H), 7.4 (app dd, J = 1.5, 5.0 Hz, 2H) , 5.07 (app d, J = 4.8 Hz,
4H); 13C NMR (CD3COCD3): d 183.2 (s, C@S), 156.9 (s, bipyridine-
C-2, bipyridine-C-20), 150.1 (d, bipyridine-C-6, bipyridine-C-60),
149.7 (s, bipyridine-C-4, bipyridine-C-40), 142.8 (s, ArC-NHR),
132.2, 131.9 (s, ArC-CF3), 128.4 (d, Ar-C), 125.7 (s, C-F), 123.8,
123.5, 123.0, 120.2, 117.8 (d, Ar-C), 47.6 (t, Ar-CH2R); IR (ITR) mmax
(cmꢀ1): 3238, 3105, 3034, 2917, 2851, 1598, 1573, 1527, 1382,
1273, 1174, 1132; m/z (ESI-TOF) 757 (100, MH+), 758 (40), 759
(18), 487 (30%); HRMS (ESI-TOF): MH+, found 757.1052.
4.8. (2R,10S)-2-[Hydroxy-(4-bromophenyl)methyl]cyclo-hexan-
1-one 10c12
Following the general procedure, compound 10c was obtained
as a yellow solid, 67%, in a maximum of 98% ee. Rf = 0.4 (EtOAc/
hexanes 1:2 v/v); The enantiomeric purity was determined by
HPLC on AD-H, hexanes/i-PrOH = 95/5, flow rate = 1.0 mL/min,
C30H20F12N6S2 requires 757.1078.
UV = 220 nm,
anti/syn = 91/9,
syn-10c
tR = 17.8 min
and
tR = 21.1 min, anti-10c tR = 27.9 min (minor) and tR = 32.5 min (ma-
jor). 1H NMR (CDCl3): d 7.47 (2H, d, J = 8.4 Hz), 7.19 (2H, d,
J = 8.3 Hz), 4.75 (1H, dd, J = 8.7, 2.6 Hz), 4.01 (1H, d, J = 2.7 Hz),
2.58-2.31 (3H, m), 2.11–2.06 (1H, m), 1.81–1.51 (3H, m), 1.34–
1.23 (1H, m). 13C NMR (CDCl3): d 215.2 (s, C@O), 140.1, 131.5,
128.6, 121.7, 74.2, 57.3, 42.7, 30.8, 27.7, 24.7.
4.5. 1,10-([2,20-Bipyridine]-4,40-diyl)bis(3-(3,5-bis(trifluoro-
methyl)phenyl)thiourea) 7
To a suspension of the commercially available 4,40-diamino-
2,20-bipyridine 6 (250 mg, 1.34 mmol) in acetone (50 mL) was
added dropwise 3,5-bis(trifluoromethyl)phenyl isothiocyanate
4.9. (2R,10S)-2-[Hydroxy-(4-(trifluoromethyl)phenyl)methyl]-
(500 lL, 2.7 mmol). The reaction mixture was stirred at room tem-
cyclohexan-1-one 10d12
perature for 48 h, until a clear solution was formed. After evapora-
tion of the excess acetone, the resulting product was purified by
chromatography on silica gel. The crude product 1,10-([2,20-bipyri-
dine]-4,40-diyl)bis(3-(3,5-bis-(trifluoromethyl)phenyl)thio-urea) 7
was obtained as a slightly green solid (689 mg, 70%); [Found: C,
46.10; H, 2.19; N, 11.51; S, 8.77. C28H16F12N6S2 requires C, 46.16;
H, 2.21; N, 11.53; S, 8.80%]; mp 124–126 °C; 1H NMR (CD3COCD3):
d 10.1 (br s, 2H), 8.6 (app d, J = 2.0 Hz, 2H), 8.5 (app d, J = 5.5 Hz,
2H), 8.3 (app s, 4H), 7.9 (app dd, J = 2.0, 5.5 Hz, 2H), 7.8 (app s,
2H); 13C NMR (CD3COCD3): d 181.1 (s, C@S), 150.7 (s, bipyridine-
C-4, bipyridine-C-40), 142.2 (s, ArC-NHR), 132.7 (d, bipyridine-C-6,
bipyridine-C-60), 132.3, 131.9 (s, ArC-CF3), 125.7 (s, C-F), 124.9,
Following the general procedure, compound 10d was obtained
as a slightly yellow solid, 75%, in a maximum of 98% ee. Rf = 0.4
(EtOAc/hexanes 1:2 v/v); The enantiomeric purity was determined
by HPLC on OD-H, hexanes/i-PrOH = 95/5, flow rate = 1.0 mL/min,
UV = 220 nm, anti/syn = 91/9, syn-10d tR = 8.7 min and tR = 9.5 min,
anti-10d tR = 11.2 min (major) and tR = 14.7 min (minor). 1H NMR
(CDCl3): d 7.60 (2H, d, J = 8.1 Hz), 7.44 (2H, d, J = 8.1 Hz), 4.85
(1H, dd, J = 8.6, 2.8 Hz), 4.09 (1H, d, J = 3.0 Hz), 2.63–2.57 (1H, m),
2.50–2.47 (1H, m), 2.40–2.32 (1H, m), 2.12–2.07 (1H, m), 1.82–
1.79 (1H, m), 1.71–1.49 (2H, m), 1.38–1.29 (1H, m). 13C NMR

524
A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
(CDCl3): d 215.1 (s, C@O), 145.0, 127.4, 126.1, 125.3, 74.2, 57.3,
42.7, 30.7, 27.7, 24.7.
J = 2.8 Hz), 2.65–2.58 (1H, m), 2.50–2.44 (1H, m), 2.39–2.31 (1H, m),
2.09–2.04 (1H, m), 1.79-1.48 (3H, m), 1.34–1.26 (1H, m). 13C NMR
(CDCl3): d 213.1 (s, C@O), 138.6, 126, 125.5, 124.7, 72.3, 55.1, 40.2,
28.5, 25.4, 22.3.
4.10. (2R,10S)-2-[Hydroxy-(4-cyanophenyl)methyl]cyclo-hexan-
1-one 10e12
4.14. (2R,10S)-2-[Hydroxy-(4-nitrophenyl)methyl]cyclo-pentan-
1-one 10i12
Following the general procedure, compound 10e was obtained
as a white solid, 88%, in a maximum of 92% ee. Rf = 0.3 (EtOAc/hex-
anes 1:2 v/v); The enantiomeric purity was determined by HPLC on
Following the general procedure, compound 10i was obtained
as a white solid, 82%, in a maximum of 99% ee. Rf = 0.4 (EtOAc/hex-
anes 1:2 v/v); The enantiomeric purity was determined by HPLC on
AD-H, hexanes/i-PrOH = 90/10, flow rate = 0.5 mL/min, UV
=
220 nm, anti/syn = 94/6, syn-10e tR = 41.3 min (minor) and
tR = 34.9 min (major), anti-10e tR = 59.5 min (major) and
tR = 47.3 min. 1H NMR (CDCl3): d 7.65 (2H, d, J = 8.3 Hz), 7.45 (2H,
d, J = 8.2 Hz), 4.85 (1H, dd, J = 8.4, 2.8 Hz), 4.06 (1H, d, J = 3.1 Hz),
2.61–2.46 (2H, m), 2.40–2.32 (1H, m), 2.14–2.08 (1H, m), 1.85–
1.80 (1H, m), 1.68–1.54 (2H, m), 1.40-1.33 (1H, m). 13C NMR
(CDCl3): d 214.8 (s, C@O), 146.4, 132.2, 127.8, 111.7, 74.2, 57.1,
42.7, 30.7, 27.7, 24.7.
AD-H,
hexanes/i-PrOH = 95/5,
flow
rate = 0.5 mL/min,
UV = 254 nm, anti/syn = 43/57, syn-10i tR = 48.4 min (major) and
tR = 67.2 min (minor), anti-10i tR = 88.1 min (major). 1H NMR
(CDCl3):
d 8.19–8.17 (2H, dd, J = 6.2, 3.2 Hz), 7.53 (2H, d,
J = 8.4 Hz), 5.42 (1H, s), 4.88 (1H, d, J = 8.8 Hz), 2.49–1.55 (6H, m).
13C NMR (CDCl3): d 219.5 (s, C@O), 150.2, 148.6, 147.2, 127.4,
126.4, 123.7, 123.6, 74.4, 70.5, 56.1, 55.1, 38.9, 38.6, 26.8, 22.4,
20.4, 20.3.
4.11. (2R,10S)-2-[Hydroxy-(2-methoxyphenyl)methyl]cyclo-
4.15. (S)-4-(4-Nitrophenyl)-4-(4-methoxy-phenylamino)-butan-
hexan-1-one 10f12
2-one 12a11,13
Following the general procedure, compound 10f was obtained
as a slightly yellow solid, 73%, in a maximum of 96% ee. Rf = 0.4
(EtOAc/hexanes 1:2 v/v); The enantiomeric purity was determined
by HPLC on OD-H, hexanes/i-PrOH = 95/5, flow rate = 0.5 mL/min,
UV = 280 nm, anti/syn = 99/1, anti-10f tR = 26.2 min (major) and
tR = 36.7 min (minor). 1H NMR (CDCl3): d 7.34 (1H, dd, J = 7.6,
1.7 Hz), 7.19–7.15 (1H, dd, J = 7.5, 1.7 Hz), 6.92–6.89 (1H, t,
J = 7.5 Hz), 6.79–6.78 (1H, d, J = 8.1 Hz), 5.20–5.17 (1H, dd, J = 8.5,
2.5 Hz), 3.78 (1H, d, J = 3.5 Hz), 3.73 (3H, s), 2.69–2.62 (1H, m),
2.42–2.36 (2H, m), 2.31–2.22 (1H, m), 2.00–1.94 (1H, m),
1.73–1.35 (3H, m). 13C NMR (CDCl3): d 214.5 (s, C@O), 155.7,
128.6, 127.6, 126.7, 119.9, 109.5, 67.6, 56.3, 54.4, 41.5, 29.5, 26.9,
23.7.
Following the general procedure, compound 12a was obtained as
yellow oil, 65%, in 91% ee. The enantiomeric purity was determined
by HPLC on AD, hexanes/i-PrOH = 50/50, flow rate = 0.5 mL/min,
UV = 280 nm, tR(R) = 15.7 min and tR(S) = 18.6 min. 1H NMR
(CDCl3): d 8.17 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 6.69 (2H,
d, J = 8.9 Hz), 6.46 (2H, d, J = 8.9 Hz), 4.85 (1H, t, J = 6.4 Hz), 4.24
(1H, br), 3.69 (3H, s), 2.94 (2H, d, J = 6.4 Hz), 2.15 (3H, s). 13C NMR
(CDCl3): d 206.1 (s, C@O), 152.8, 150.7, 147.2, 140.1, 127.4, 124.1,
115.4, 114.8, 55.6, 54.6, 50.7, 30.7.
4.16. (3S,4S)-4-(4-Methoxy-phenylamino)-3-methyl-4-(4-nitro-
phenyl)-butan-2-one 12b and (S)-1-(4-methoxy-phenylamino)-
1-(4-nitro-phenyl)-pentan-3-one 12c11,13
Following the general procedure, compound 12b and 12c were
obtained as slightly yellow oil, 70%, in 95% ee and 99% ee, respec-
tively. The enantiomeric purity was determined by HPLC on AD,
hexanes/i-PrOH = 85/15, flow rate = 1.0 mL/min, UV = 280 nm,
tR(3R,4R-12b) = 17.4 min, tR(3S,4S-12b) = 20.1 min and tR(S-
12c) = 28.6 min. 1H NMR (CDCl3): d 8.18 (2H, d, J = 8.7 Hz), 7.52
(2H, d, J = 8.7 Hz), 6.67 (2H, d, J = 8.9 Hz), 6.40 (2H, d, J = 8.9 Hz),
4.86 (1H, t, J = 6.6 Hz), 4.76 (1H, d, J = 5.1 Hz), 3.68 (3H, s), 3.02
(1H, m), 2.91 (2H, d, J = 6.2 Hz), 2.43-2.37 (2H, m), 2.17 (3H, s),
1.09 (3H, d, J = 7.1 Hz), 1.01 (3H, t, J = 7.2 Hz). 13C NMR (CDCl3): d
209.7, 208.9 (s, C@O), 152.8, 152.7, 150.8, 149.4, 147.3, 140.2,
127.9, 127.4, 124.0, 123.9, 115.4, 115, 114.8, 59.2, 55.7, 54.9,
52.5, 49.4, 36.9, 29.4, 10.9, 7.5.
4.12. (2R,10S)-2-[Hydroxy-(4-fluorophenyl)methyl]cyclo-hexan-
1-one 10g12
Following the general procedure, compound 10g was obtained
as a slightly yellow solid, 65%, in a maximum of 95% ee. Rf = 0.6
(EtOAc/hexanes 1:2 v/v); The enantiomeric purity was determined
by HPLC on AD-H, hexanes/i-PrOH = 95/5, flow rate = 1.0 mL/min,
UV = 220 nm, anti/syn = 85/15, syn-10g tR = 12.5 min and
tR = 14.8 min, anti-10g tR = 23.1 min (major) and tR = 20.5 min
(minor). 1H NMR (CDCl3): d 7.23–7.20 (2H, dd, J = 8.0, 5.7 Hz),
6.98-6.93 (2H, t, J = 8.6 Hz), 4.70 (1H, d, J = 8.6 Hz), 3.96 (1H, s),
2.53–2.39 (2H, m), 2.32–2.24 (1H, m), 2.04–1.99 (1H, m), 1.73–
1.45 (2H, m), 1.25–1.18 (1H, m). 13C NMR (CDCl3): d 215.4 (s,
C@O), 163.6, 161.2, 136.8, 128.7, 115.3, 74.1, 57.5, 42.6, 30.8,
27.7, 24.7.
4.17. (3S,4R)-3-Hydroxy-4-(4-methoxy-phenylamino)-4-(4-
nitrophenyl)-butan-2-one 12d11,13
4.13. (2R,10S)-2-[Hydroxy-(phenyl)methyl]cyclohexan-1-one
Following the general procedure, compound 12d was obtained
as slightly yellow foam, 62%, in 97% ee. The enantiomeric purity
was determined by HPLC on AD-H, hexanes/i-PrOH = 85/15, flow
rate = 1.0 mL/min, UV = 254 nm, anti/syn = 3/97; tR(3S,4R) =
38.9 min (major) and tR(3R,4S) = 44.4 min (minor). 1H NMR
(CDCl3): d 8.17 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.7 Hz), 6.68
(2H, d, J = 9.0 Hz), 6.45 (2H, d, J = 9.0 Hz), 5.02 (1H, d, J = 2.2 Hz),
4.43 (1H, d, J = 2.3 Hz), 4.25 (1H, s), 3.67 (3H, s), 2.37 (3H, s). 13C
NMR (CDCl3): d 206.5 (s, C@O), 152.9, 147.4, 139.2, 128.2, 123.8,
115.2, 115, 80.0, 58.8, 55.6, 24.9.
10h12
Following the general procedure, compound 10h was obtained as
a white solid, 62%, in a maximum of 95% ee. Rf = 0.4 (EtOAc/hexanes
1:2 v/v); The enantiomeric purity was determined by HPLC on AS-H,
hexanes/i-PrOH = 90/10, flow rate = 0.5 mL/min, UV = 220 nm, anti/
syn = 84/16, syn-10h tR = 20.7 min and tR = 22.9 min, anti-10h
tR = 26.3 min (major) and tR = 24.8 min (minor). 1H NMR (CDCl3): d
7.36–7.26 (5H, m), 4.80–4.77 (1H, dd, J = 8.8, 2.7 Hz), 4.00 (1H, d,

A. S. Demir, S. Basceken / Tetrahedron: Asymmetry 24 (2013) 515–525
525
4.18. (R)-4-(4-Methoxy-phenylamino)-6-methyl-heptan-2-one
is gratefully acknowledged. Thanks are also due to Professor Metin
Balci for editorial assistance.
15a11,13
Following the general procedure, compound 15a was obtained
as oil, 90%, in 81% ee. The enantiomeric purity was determined
by HPLC on OD-H, hexanes/i-PrOH = 90/10, flow rate = 1.0 mL/
min, UV = 254 nm, tR(S) = 6.2 min (minor) and tR(R) = 10.0 min
(major). 1H NMR (CDCl3): d 6.77 (2H, d, J = 8.2 Hz), 6.57 (2H, d,
J = 8.7 Hz), 3.83–3.77 (1H, m), 3.74 (3H, s), 3.35 (1H, br), 2.67–
2.63 (1H, dd, J = 16.3, 4.9 Hz), 2.58–5.52 (1H, dd, J = 16.3, 6.4 Hz),
2.13 (3H, s), 1.78–1.71 (1H, m), 1.51–1.44 (1H, m), 1.34–1.29
(1H, m), 0.93 (3H, d, J = 6.8 Hz), 0.91 (3H, d, J = 6.6 Hz). 13C NMR
(CDCl3): d 208.4 (s, C=O), 152.2, 141.4, 115.0, 114.9, 55.8, 49.2,
48.1, 44.8, 31.0, 25.1, 23.0, 22.3.
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4.19. (R)-4-(4-Methoxy-phenylamino)-octan-2-one 15b11,13
Following the general procedure, compound 15b was obtained
as oil, 88%, in 81% ee. The enantiomeric purity was determined
by HPLC on OD-H, hexanes/i-PrOH = 90/10, flow rate = 1.0 mL/
min, UV = 254 nm, tR(S) = 6.7 min (minor) and tR(R) = 10.1 min
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J = 8.9 Hz), 3.74 (3H, s), 3.74 (1H, m), 2.65 (1H, dd, J = 16.3,
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4.20. (S)-4-(4-Methoxy-phenylamino)-5-methyl-hexan-2-one
15c11,13
Following the general procedure, compound 15c was obtained
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Acknowledgements
Financial support from the Scientific and Technological
Research Council of Turkey (TÜBITAK), the Turkish Academy of
Sciences (TÜBA), and the Middle East Technical University (METU)
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