Asymmetric organocatalytic efficiency of synthesized chiral β-amino alcohols in ring-opening of glycidol with phenols

Article abstract of DOI:10.1007/s10562-012-0814-4

A series of novel chiral β-amino alcohols 3-5 and 7-10 were synthesized by regioselective ring opening of epoxides and chiral amines with a straightforward method in high yields (up to 99 %). Kinetic resolution of racemic glycidol with phenols was achieved by using chiral amino alcohols as organocatalysts. Amino alcohols 5, 8 and 10 exhibited the highest enantioselectivities with p-cresol, phenol, and p-methoxyphenol by 63, 65, 58 % ee, respectively. The moderate enantioselectivities were observed with catalyst 9b towards all the nucleophiles (34-48 % ee). The ee values of the desired 3-aryloxy-1, 2-diols were determined by HPLC. This study presents an attractive tool for the synthesis of β-blockers and structurally complex molecules.

Full text of DOI:10.1007/s10562-012-0814-4

Catal Lett (2012) 142:794–802
DOI 10.1007/s10562-012-0814-4
Asymmetric Organocatalytic Efficiency of Synthesized Chiral
b-Amino Alcohols in Ring-Opening of Glycidol with Phenols
•
Tarik Aral Mehmet Karakaplan Halil Hos¸goren
•
¨
Received: 18 December 2011 / Accepted: 19 March 2012 / Published online: 11 April 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of novel chiral b-amino alcohols 3–5
and 7–10 were synthesized by regioselective ring opening
of epoxides and chiral amines with a straightforward
method in high yields (up to 99 %). Kinetic resolution of
racemic glycidol with phenols was achieved by using chiral
amino alcohols as organocatalysts. Amino alcohols 5, 8
and 10 exhibited the highest enantioselectivities with
p-cresol, phenol, and p-methoxyphenol by 63, 65, 58 % ee,
respectively. The moderate enantioselectivities were
observed with catalyst 9b towards all the nucleophiles
(34–48 % ee). The ee values of the desired 3-aryloxy-1,
2-diols were determined by HPLC. This study presents an
attractive tool for the synthesis of b-blockers and struc-
turally complex molecules.
1 Introduction
Asymmetric organocatalysis with chiral organic Bronsted
acids and bases is an important field of investigation in
modern asymmetric synthesis [1]. This approach is very
attractive due to its conceptual and experimental simplic-
ity, the absence of hazardous heavy metal salts in reaction
mixtures and extremely high efficiency of catalysis [2]. The
use of chiral Bronsted acids as catalysts for asymmetric
synthesis has recently become a particularly popular and
productive field of research [3].
Amino alcohols that include both Bronsted acid and base are
very important compounds for asymmetric synthesis. For
example, chiral b-amino alcohols have been used in many
reactions as catalysts such as asymmetric addition of organo-
zinc reagents to ketones and aldehydes [4–7], asymmetric
transfer hydrogenation [8, 9], reduction of ketones to alcohols
[10, 11]. Furthermore, the asymmetric ring opening of epoxides
by alcohol and thiol nucleophiles were also achieved with
Ti(i-OPr)4 and Sc(OTf)3 mediated amino alcohols, respectively
[12, 13]. On the other hand, amino alcohols can also serve as
catalysts in their own right, that is, without any metal ion.
Therefore, Russo and Lattanzi [14] used chiral amino alcohols
as organocatalysts in the asymmetric epoxidation of a,b-enones
up to 89 % ee. In addition, cinchonine-derived chiral quater-
nary ammonium salts and quinine have also been successfully
employed as organocatalysts in the desymmetrization of meso-
aziridines with benzenethiols [15, 16].
Keywords Epoxide ring opening ꢀ b-Amino alcohols ꢀ
Kinetic resolution ꢀ Organocatalysts ꢀ
3-Aryloxy-1,2-propanediols
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-012-0814-4) contains supplementary
material, which is available to authorized users.
T. Aral
Enantiopure 3-aryloxy-1,2-propanediols are valuable
targets for asymmetric synthesis as a result of their role as
key synthetic intermediates in a variety of pharmaceuti-
cally (such as b-blockers) important compounds [17]. In
principle, access to these building blocks may be provided
by several routes, including asymmetric reduction of
aryloxy ketone [18–20] or the ring opening of enantiopure
Department of Chemistry, Faculty of Science and Art,
University of Batman, Batman, Turkey
e-mail: tarik.aral@batman.edu.tr
¨
M. Karakaplan (&) ꢀ H. Hos¸goren
Chemistry Department, Faculty of Science, University of Dicle,
21280 Diyarbakir, Turkey
e-mail: mkkaplan@dicle.edu.tr
123

Asymmetric Organocatalytic Efficiency of Chiral b-Amino Alcohols
795
terminal epoxides with phenols [21–23]. Therefore, epox-
ides are versatile building blocks that have been exten-
sively used in the synthesis of complex organic
compounds. Their utility as valuable intermediates has
further expanded with the advent asymmetric catalytic
methods for their synthesis [24–27]. Terminal epoxides are
the most important subclass of these compounds, but no
general and practical methods were available for their
synthesis in enantiomerically pure form.
enantioselective ring opening of glycidol with phenols. The
regioselective ring opening of epoxides by amines is an
important way for the preparation of b-amino alcohols [37,
38]. Thus, chiral b-amino alcohols were synthesized in the
catalyst-free medium by regioselective ring opening of
terminal epoxides with chiral amines 2 and 6 by using
methanol as a solvent (Schemes 1,2). Chiral secondary
amines 2 and 6 were synthesized by benzylation of trans-
(1R,2R)-1,2-diaminocyclohexane obtained from classical
resolution of cis/trans mixtures of 1,2-diaminocyclohexane
and readily available (R)-cyclohexylethylamine, respec-
tively. The ring opening reaction of (R)-glycidol with
chiral amine 2 formed major regioisomeric products 3 and
4 in 33 and 35 % yields respectively. Chiral amino alcohol
5 was obtained from chiral amine 2 and regioselective ring
opening of (S)-propylene oxide in 99 % yield.
The development of new methodologies, characterized
by operational simplicity and the use of easily available
catalysts, is the main target of modern organic synthesis.
Hydrolytic kinetic resolution (HKR) developed by Jacob-
sen has emerged in recent times as a powerful tool to
synthesize both terminal epoxides and their corresponding
diols in highly enantiomerically pure form by using low
loading of recyclable chiral cobalt-based salen complexes
[28, 29]. The first phenolic kinetic resolution of terminal
epoxides provided 3-aryloxy-1,2-propanediols were repor-
ted by Jacobsen et al. [30, 31]. The use of enzymes for the
kinetic resolution of racemic substrates in order to afford
enantiopure compounds in high enantiomerically pure form
and good yields, has long been a popular strategy in syn-
thesis [32–35]. The interest in the field of organocatalysts
has increased greatly over the last few years [8]. Organo-
catalysts, by now, has definitely been maturated to a rec-
ognized third methodology, of potentially equal status to
organometallic and enzymatic catalysis. They are usually
robust, inexpensive, readily available and non-toxic.
Catalysts 7 and 8 were obtained by aminolysis reaction
of (R)-glycidol and (R)-styrene oxide with amine 6 by
yields 99 and 65 %, respectively. Surprisingly, it was
observed that selective ring opening of racemic phenyl
glycidyl ether could be achieved with chiral amine 6 to
give complete conversion to the diastereomer pair of 9a
and 9b, which was efficiently separated by column chro-
matography. Catalyst 10 was also obtained with chiral
amine 6 and two equivalent ratios of (R)-styrene oxide at a
high regioisomeric yield (69 %). The low regioselectivities
obtained in the case of compounds 8 and 10 arising from
more electrophilic character of benzylic carbon of styrene
oxide when compared with other epoxides. It was shown
that amines 2 and 6 exhibited a preference for nucleophilic
attack at terminal or achiral carbon of epoxides as a SN2
reaction to give corresponding chiral b-amino alcohols
with retention of configuration on stereogenic center as
reported previously [37, 38]. Therefore, this method pro-
vided an easy and efficient route to the corresponding
chiral b-amino alcohols without using any catalyst and
excess amounts of amine dealing with thermally sensitive
epoxides due to the side reactions.
In our previous study, it was found that chiral b-amino
alcohols effectively catalyzed the asymmetric ring opening
of glycidol with phenols [36]. To the best of our knowl-
edge, this was the first example to have been reported in
the literature. Therefore, it is still necessary to develop the
structurally simple and effective organocatalysts for the
activation of epoxides, which renders them to be more
susceptible to nucleophilic attack under milder condition.
Thus, in this study, we focused our attention on the syn-
thesis of a new series of chiral b-amino alcohols as
organocatalyst in the kinetic resolution of racemic glycidol
with phenols to provide enantiomerically enriched 3-aryl-
oxy-1,2-propanediols. Chiral b-amino alcohols 3–5, 7–10
were synthesized from chiral secondary amines 2 and 6 and
appropriate epoxides in high regioselectivities and yields
with a cost-effective and environmentally friendly process
(Schemes 1,2). Enantiomeric excess (ee) of desired
3-aryloxy-1,2-propanediols were determined by HPLC.
We have demonstrated that the chiral b-amino alcohols
are efficient enantioselective organocatalysts for kinetic
resolution of racemic glycidol with phenols [36]. However,
the enantioselectivities of amino alcohol organocatalysts
were obtained drastically different with respect to the
phenol nucleophiles. We also showed that the reaction
conditions have a strong influence on the yield and
enantioselectivity of the reaction; no significant reactions
occurred when performed at the room temperature to the
studied temperature (50 °C). The higher temperatures and
further reaction periods lead to higher yields but lower
enantioselectivities [36]. Encouraged by these observa-
tions, we aimed to practically route to synthesise of chiral
b-amino alcohols as efficient organocatalysts. Therefore,
p-methoxyphenol, p-cresol (p-methylphenol) and phenol
2 Results and Discussions
In this study, a series of novel chiral b-amino alcohols 3–5,
7–10 were synthesized and used as organocatalysts for
123

796
T. Aral et al.
Scheme 1 Reactions and
conditions: i 1 PhCHO, MeOH,
reflux, 2 h. 2 NaBH4, reflux.
ii MeOH, 40 °C. iii MeOH, rt
Ph
Ph
N
N
H
HO
OH
3
i
iii
+
Ph
Ph
OH
+
O
N
N
H2N
NH2
H
H
2
+
1
Ph
Ph
N
N
O
HO
OH
HO
OH
ii
4
Ph
Ph
N
N
OH
HO
5
H
+
O
NH2
i
N
ii
ii
OH
N
+
+
HO
O
O
OH
HO
N
H
7
8
6
OPh
ii
O
+
N
N
PhO
PhO
OH
OH
9b
9a
iii
+
N
NH2
O
HO
OH
10
Scheme 2 Reactions and conditions: i 1 MeOH, reflux, 3 h. 2 NaBH4, rt, 2 h. ii MeOH, 50 °C. iii MeOH, 70 °C
were chosen as oxygen nucleophiles due to the convenient
determination of ee values of desired 3-aryloxy-1,2-diol
adducts by HPLC. However, in general, reactions of
epoxides with oxygen nucleophiles are rather difficult, and
therefore, the epoxide ring opening with phenolic oxygen
nucleophiles is quite challenging (pKa value of Ar-
OH & 10) when compared with glycidol and ethanol. All
the reactions were performed with 10 mol % of amino
alcohol organocatalaysts in ethanol at 50 °C and the results
were summarized in Table 1.
123

Asymmetric Organocatalytic Efficiency of Chiral b-Amino Alcohols
Table 1 Catalytic asymmetric ring opening of glycidol with phenols
797
Reactions run in absolute ethanol at 55 °C for 24 h
a
Absolute configurations 9a and 9b were determined by the reaction of 6 and (S)-glycidyl phenyl ether which was found to be enantiopure form of 9a
b
c
d
Isolated yields after thin layer chromatography on silica gel
Determined by chiral HPLC analysis on Chiralcell OD column
Major enantiomer was determined according to the enantiomerically pure chromatograms of corresponding 3-aryloxydiols on HPLC
123

798
T. Aral et al.
R'''
R''
OH
R'
N
Activate electrophile
Activate nucleophile
H
O
R'
O
HO
R'
O
H
H
O
N
O
OH
OH
O
O
H
N
R'''
R''
OH
+
R''
R
R'''
R'''
R
Scheme 3 Proposed H-bonding-mediated cooperative catalysis mechanism of the reaction
Pioneering studies of Wynberg [39] and then followed
by Wang [16] proposed that the natural cinchona alkaloids
are bifunctional catalysts utilizing both the tertiary amine
and the hydroxyl group to activate and orient the nucleo-
phile and electrophile, respectively, thus achieving opti-
mum asymmetric catalysis. Prompted by these results and
our efforts for epoxide transformations, we believe that the
chiral amino alcohols, upon interaction with both a
nucleophile and electrophile through the suitable atoms of
the catalyst, may form a rigid pocket around the activated
nucleophile or electrophile, thereby allowing them to
function as efficient organic catalysts. As shown in
Scheme 3, the possible mechanism of the reaction involves
the activation of the glycidol ring followed by attack of
activated phenol by hydrogen bond formation with the
catalyst.
energetically differentiated transition state of racemic
glycidol. Catalyst 5 favoured to form the S isomers of
products with low enantioselectivities (16–32 % ee). This
may be due to the low steric hindrance of methyl substit-
uents on alcohol functional groups.
Non symmetric catalysts 7–9 were selected due to their
structurally simplicity and to employed their enantiose-
lectivity on the reaction. Catalyst 7, bearing hydroxy-
methylene substituent on the alcohol stereogenic center
exhibited low enantioselectivity (22 % ee for phenol). On
the other hand, catalyst 8 showed a good enantioselectivity
with p-methoxyphenol and phenol nucleophiles, by 51 and
65 % ee for S enantiomer of desired products, respectively.
This indicates that the phenyl group is an appropriate
substituent on the stereogenic center of alcohol for these
catalysts. Catalyst 10 was chosen to investigate the scope
and limitations of phenyl substituent on selectivity of the
reaction. The catalyst 10 showed similar stereochemical
outcomes with the catalyst 8 (Table 1). It can be stated that
the further alcohol functionality was not found to be
effective on the enantioselectivity of the reaction.
Considering the values in Table 1, it can be noted that
catalyst 3 with secondary amine unit, exhibits low con-
version and enantioselectivities (16 % ee only for
p-methoxyphenol). This is probably due to the preference
only; Lewis-base catalysed reaction to the acid catalysed
via –NH– unit of the catalyst 3. Catalyst 4 showed better
conversion and enantioselectivities than the catalysts 3 and
5 especially with p-cresol nucleophile by 63 % ee for
R enantiomer of 3-(p-methylphenoxy)-1,2-propanediol
which was found to be the highest among the other cata-
lysts. Such different stereochemical outcomes were also
obtained with a previously report [16]. This selectivity may
be explained by electronic and steric effect of methyl
substituent on p-cresol and catalyst’s characteristics. The
p-cresol is more sterically hindered than phenol, whereas
weaker nucleophile than the methoxyphenol. The appro-
priate orientation of catalyst 4 with p-cresol involving p–p
interactions between aromatic moiety of nucleophile and
benzyl substituent of amine group of catalyst leads to
Low enantioselectivity of catalyst 7 led us to prepare
catalyst 9a and 9b which bearing more sterically hindered
group on the alcohol stereogenic center. The inductive
electron withdrawing effect of phenoxy unit on the cata-
lysts 9a and 9b makes them to exhibit a good reactivity.
(R,R)-9b showed better enantioselectivities than (S,R)-9a
by an appropriate orientation of chiral substituents on the
stereogenic center of alcohol group. The selectivities of
p-methoxyphenol, p-cresol (p-methylphenol) and phenol
nucleophiles with 9b were found to be 44, 34 and 48 % ee
values of (R)-3-aryloxy-1,2-propanediols, respectively. The
substituents and configuration of alcohol group of catalysts
9a and 9b were found to be closely relevant to the ste-
reochemical outcomes of the reaction. In generally, the
123

Asymmetric Organocatalytic Efficiency of Chiral b-Amino Alcohols
799
4.2 Synthesis
configurations of obtained 3-aryloxy-1,2-propanediol
products were found to be relevant with the configuration
of employed catalysts as shown in Table 1. Steric and
electronic effects of substituent on the phenols were found
to have significant influence on the yield and the enanti-
oselectivities of 3-aryloxy-1,2-propanediols.
4.2.1 (R,R)-1,2-Diaminocyclohexane (1)
(R,R)-1,2-Diaminocyclohexane 1 was isolated from isomeric
mixture of cis- and trans-1,2-diaminocyclohexane according
to the method reported earlier [40]. (R,R)-1,2-Diaminocy-
clohexane L-tartrate: yield 39 %, [a]D20: ?11.6 (c 1, H2O)
Ref. [40] ?11.6 (c 1, H2O). (R,R)-1,2-Diaminocyclohexane:
yield 95 %, [a]2D0: -19.8 (c 1, 1 M HCl), Ref. [40] -20 (c 1,
1 M HCl).
It was shown that the catalysts could be synthesized
from readily available starting materials, usually less
expensive and applied in less-demanding reaction condi-
tions. Moreover, the absence of a transition metal makes
this type of reaction an attractive tool for the synthesis of
pharmaceuticals, such as b-blockers, in which compounds,
the presence of hazardous metallic traces are inadmissible
in the final product. In this strategy, these factors contribute
to superior atom efficiency, allowing the direct synthesis of
structurally complex molecules.
4.2.2 (R,R)-N,N0-Dibenzyl-1,2-diaminocyclohexane (2)
This compound was synthesized as a described method
[41] by using (R,R)-1,2-diaminocyclohexane 1 (1.5 g,
13.16 mmol) was dissolved in anhydrous MeOH (8.0 ml)
and heated to reflux. Benzaldehyde (2.67 ml, 26.32 mmol)
was added dropwise over a period of 2 min, and the mix-
ture was stirred at reflux temperature for 30 min. The
solution was allowed to cool to room temperature and
sodium borohydride (1.05 g, 27.60 mmol) was added
portion wise. After the vigorous effervescence had sub-
sided the mixture was heated to reflux for 15 min. The
reaction was then quenched by the addition of water (8 ml)
and the aqueous phase was extracted with DCM
(3 9 15 ml). The separated organics were dried over
potassium carbonate, filtered and the solvent evaporated to
give the diamine 2 as a waxy solid (3.86 g, 99 %). [a]2D0:
3 Conclusions
In conclusion, we have described a straightforward syn-
thesis of series chiral b-amino alcohols in high yield and
regioselectivities. b-amino alcohols were employed as an
efficient organocatalysts for the enantioselective ring
opening of glycidol with phenols, giving rise to the
3-aryloxy-1,2-propanediols in moderate yield and enanti-
oselectivities. Although the control of enantioselection of
the reaction is modest, future modifications of the system
based on mechanistic understanding may improve the ste-
reochemical performance of the catalysts.
1
-79.7 (c 2.5, CHCl3), [41] -80 (c 2.5, CHCl3); H NMR
(400 MHz, CDCl3): d (ppm) 7.50–7.20 (m, 10H), 3.98 (d,
2H, J = 13.2 Hz), 3.75 (d, 2H, J = 13.2 Hz), 2.40–2.30
(m, 2H), 2.24 (d, 2H, J = 13.2 Hz), 2.15 (bs, 2H),
1.85–1.81 (m, 2H), 1.36–0.130 (m, 2H), 1.15–1.1 (m, 2H).
13C NMR (100 MHz, CDCl3): d (ppm) 141.01, 128.38,
128.19, 126.79, 60.90, 50.89, 31.56, 25.08.
4 Experimental
4.1 Reagents and General Methods
All chemicals were of reagent grade unless otherwise
specified. (R)-cyclohexylethylamine, (R)-glycidol, (R)-sty-
rene oxide and (S)-propylene oxide were purchased from
Fluka. Silica Gel 60 (Merck, 0.040–0.063 mm) and silica
gel/TLC-cards (F254) were used for flash column chro-
matography and TLC. All reactions were carried out under
an N2 atmosphere with a dry solvent under anhydrous
conditions, unless otherwise noted. Optical rotations were
taken on a Perkin Elmer 341 model polarimeter. 1H
(400 MHz) and 13C (100 MHz) NMR spectra were recor-
ded on a Bruker AV-400 High Performance Digital
FT-NMR Spectrometer. The chemical shifts (d) and cou-
pling constants (J) are expressed in parts per million and
hertz. The elemental analyses were obtained with CARLO-
ERBA Model 1108 apparatus. Enantiomeric excesses were
determined by HPLC system (BioRad Pomp and UV
detector, Daicel Chiral Cell-OD column).
4.2.3 (2S)-3-{Benzyl[(1R,2R)-2-
(benzylamino)cyclohexyl]amino}propane-1,2-diol
(3)
(R)-glycidol (241 mg, 3.26 mmol) was added to a solution
of (R,R)-N,N0-dibenzyl-1-2-diaminocyclohexane (500 mg,
1.63 mmol) in methanol (3 ml) and stirred at room tem-
perature for 24 h. The solution was concentrated under
reduced pressure. The residue was purified by silica-gel
column chromatography (n-hexane/EtOH/TEA = 6/1/0.5),
to afford 3 (200 mg 33 %) as a colourless oil. [a]2D0: -61.5
(c 2.5, CHCl3). IR: 3326, 3031, 2933, 2858, 1452, 1380,
1
1240, 1105, 1079, 1041, 738 cm-1. H NMR (400 MHz,
CDCl3): d (ppm) 7.35–7.22 (m, 10H), 3.79–3.55 (m, 7H),
3.42-3.37 (m, 2H), 2.74–1.72 (m, 8H), 1.25–1.03 (m, 5H).
13C NMR (100 MHz, CDCl3): d (ppm) 140.10, 140.04,
123

800
T. Aral et al.
128.87, 128.44, 128.37, 128.22, 69.28, 64.44, 62.43, 56.93,
52.00, 48.98, 31.66, 25.51, 25.08, 23.52. Anal. Cald. for
C23H32N2O2: C, 74.96; H, 8.75; N, 7.60. Found: C, 74.88;
H, 8.66; N, 7.71.
CDCl3): d (ppm) 7.38–7.29 (m, 5H), 3.89 (d, 1H,
J = 13.2 Hz), 3.75 (d, 1H, J = 13.2 Hz), 2.58–2.51 (m,
1H), 1.82–1.71 (m, 6H), 1.44–1.14 (m, 4H), 1.09–1.01 (m,
5H). Anal. Cald. for C15H23N: C, 82.89; H, 10.67; N, 6.44.
Found: C, 82.80; H, 10.59; N, 6.51.
4.2.4 (2S)-3-{Benzyl[(1R,2R)-2-{benzyl[(2S)-2,3-
dihydroxypropyl]amino}cyclohexyl]amino}propane-
1,2-diol (4)
4.2.7 3-[N-Benzyl((R)-1-cyclohexylethyl)amino]-(R)-
propane-1,2-diol (7)
(R)-Glycidol (241 mg, 3.26 mmol) was added to a solution
of (R,R)-N,N0-dibenzyl-1-2-diaminocyclohexane (500 mg,
1.63 mmol) in methanol (3 ml) and stirred at room tem-
perature for 24 h. The solution was concentrated under
reduced pressure. The residue was purified by silica-gel
column chromatography (n-hexane/EtOH/TEA = 6/1/0.5),
to afford 4 (250 mg, 35 %) as a colourless oil. [a]2D0: -54.2
(c 2.5, CHCl3). IR: 3367, 3030, 2943, 2864, 1456, 1377,
To a solution of (R)-N-benzyl-1-cyclohexylethylamine 6
(1.42 g, 6.53 mmol) in methanol (5 ml) was added (S)-
glycidol (518 mg, 7.0 mmol) and stirred at 50 °C in an oil
bath equipped with contact thermometer for 24 h. The
solvent was evaporated and then excess glycidol was
removed by kugelruhr distillation apparatus to give 1.90 g
(99 %) of compound 7 as colourless oil. [a]2D0: -30.3 (c
2.5, CHCl3). IR: 3370, 3031, 2927, 2844, 1457, 1382,
1
1
1331, 1252, 1113, 1080, 1030, 914, 749, 702 cm-1. H
1079, 1029, 741 cm-1. H NMR (400 MHz, CDCl3): d
NMR (400 MHz, CDCl3): d (ppm) 7.03–7.33 (m, 10H),
3.92–3.30 (m, 10H); 2.95–2.71 (m, 4H); 2.48–2.21 (m,
4H); 1.95–1.81 (m, 4H); 1.42–1.14 (m, 6H). 13C NMR
(100 MHz, CDCl3): d (ppm) 138.25, 128.59, 128.31,
127.37, 68.96, 65.19, 58.25, 52.16, 25.63, 24.14, 22.01.
Anal. Cald. for C26H38N2O4: C, 70.56; H, 8.65; N, 6.33.
Found: C, 70.61; H, 8.69; N, 6.26.
(ppm) 7.30–7.21 (m, 5H), 3.78 (d, 1H, J = 13.6 Hz),
3.61–3.29 (m, 5H), 3.54 (d, 2H, J = 6.8 Hz), 2.44–2.36
(m, 1H), 2.18 (d, 1H, J = 12.8 Hz), 1.75–1.64 (m, 4H),
1.45–1.35 (m, 1H), 1.30–1.10 (m, 4H), 1.01 (d, 3H,
J = 6.8 Hz), 0.92–0.80 (m, 2H). 13C NMR (100 MHz,
CDCl3): d (ppm) 140.07, 129.03, 128.42, 127.18, 69.19,
64.78, 62.79, 54.95, 54.57, 41.04, 31.52, 30.53, 26.52,
26.43, 26.33, 11.56. Anal. Cald. for C18H29NO2: C, 74.18;
H, 10.03; N, 4.81. Found: C, 74.11; H, 10.09; N, 4.74.
4.2.5 (1R,2R)-N,N0-Dibenzyl-N,N0-bis(ethan-(1-(S)-
methyl)-1-ol)-trans-diaminocyclo-hexane (5)
4.2.8 2-[N-Benzyl-((R)-1-cyclohexylethyl)amino]-(S)-1-
phenylethanol (8)
(S)-1,2-Epoxypropane (118 mg, 2.0 mmol) was added to a
solution of (R,R)-N,N0-dibenzyl-1-2-diaminocylohexane 2
(250 mg, 0.82 mmol) in methanol (3 ml) and stirred at
40 °C in an oil bath equipped with contact thermometer for
24 h. The solution was concentrated under reduced pres-
sure to give product 5 (340 mg, 99 %) as a colourless oil.
IR: 3384, 3031, 2923, 2858, 1953, 1882, 1812, 1600, 1452,
(R)-Phenyl oxirane (720 mg, 6.0 mmol) was added to the
solution of (R)-N-benzyl-cyclohexylethylamine 6 (1.30 g,
5.96 mmol) in methanol (5 ml). The solution was stirred at
50 °C in an oil bath equipped with contact thermometer for
24 h. The solvent was evaporated and excess phenyl oxi-
rane was removed by kugelrohr distillation apparatus. The
crude product was purified by silica-gel column chroma-
tography (Petroleum ether/EtOAc/TEA = 8.5/1/0.5), to
afford 8 (1.3 g, 65 %) as a colourless oil. [a]2D0: -185.0 (c
2.5, CHCl3). IR: 3448, 3070, 3031, 2927, 2850, 1953,
1882, 1810, 1606, 1496, 1452, 1382, 1336, 1247, 1201,
1
1296, 1388, 1336, 1253, 1132, 1060, 964, 746 cm-1. H
NMR (400 MHz, CDCl3): d (ppm) 7.36–7.15 (m, 10H),
5.92 (bs, 2H), 3.74 (d, 2H, J = 12.8 Hz), 3.49–3.40 (m,
4H), 2.70–2.60 (m, 4H), 2.40–2.34 (m, 2H), 2.00–1.90 (m,
2H), 1.80–1.60 (m, 2H), 1.20–0.9 (m, 10H). 13C NMR
(100 MHz, CDCl3): d (ppm) 139.78, 129.61, 128.23,
127.21, 65.89, 64.31, 59.83, 56.92, 25.97, 25.03, 21.78.
Anal. Cald. for C26H38N2O2: C, 76.06; H, 9.33; N, 6.82.
Found: C, 75.98; H, 9.39; N, 6.77.
1
1066, 1035, 746 cm-1. H NMR (400 MHz, CDCl3): d
(ppm) 7.50–7.34 (m, 10H), 4.79 (dd, 1H, J1 = 3.6 Hz,
J2 = 3.2 Hz), 4.01 (d, 1H, J = 13.6 Hz), 4.00 (bs, 1H),
3.51 (d, 1H, J = 13.6), 2.76–2.57 (m, 3H), 2.37 (d, 1H,
J = 12.8 Hz), 1.87–1.77 (m, 4H), 1.60–1.45 (m, 1H),
1.45–1.25 (m, 3H), 1.12 (d, 3H, J = 6.4 Hz), 1.04–0.95
(m, 2H). 13C NMR (100 MHz, CDCl3): d (ppm) 142.45,
139.44, 129.23, 128.48, 128.26, 127.36, 127.19, 125.96,
69.18, 59.02, 57.98, 54.04, 40.73, 31.14, 30.64, 26.50,
26.41, 26.21, 10.21. Anal. Cald. for C23H31NO : C, 81.85;
H, 9.26; N, 4.15. Found: C, 81.79; H, 9.32; N, 4.09.
4.2.6 (R)-N-benzyl-cyclohexylethylamine (6)
According to the same procedure as that of 2, the product 6
was prepared starting from (R)-cyclohexylethylamine
(1 ml, 6.82 mmol), benzaldehyde (6.95 ml, 6.82 mmol)
and sodium borohydride (272 mg, 7.15 mmol) to obtain 6
(1.42 g, 96 as a colourless oil. 1H NMR (400 MHz,
123

Asymmetric Organocatalytic Efficiency of Chiral b-Amino Alcohols
801
4.2.9 2-[N-Benzyl((R)-1-cyclohexylethyl)amino]-(S)-1-
phenoxyethanol (9a) and 2-[N-Benzyl((R)-1-
cyclohexylethyl)amino]-(R)-1-phenoxyethanol (9b)
(500 mg, 3.94 mmol) in methanol (5 ml). The solution was
stirred at 70 °C in an oil bath equipped with contact ther-
mometer for 24 h. Solvent evaporated and excess (R)-sty-
rene oxide was removed by kugelrohr distillation
apparatus. The crude product was purified by silica-gel
column chromatography (Petroleum ether/EtOAc/
TEA = 8.5/1/0.5), to afford 10 (1 g, 69 %) as a colourless
oil. [a]2D0: -119.6 (c 2.5, CHCl3). IR : 3396, 3062, 3028,
2916, 2851, 2662, 2357, 2336, 1947, 1888, 1604, 1493,
Racemic glycidyl phenyl ether (1.9 g, 12.66 mmol) was
added to
a
solution of (R)-N-benzyl-1-cyclohex-
ylethylamine 6 (2.22 g, 11.75 mmol) in methanol (10 ml)
and stirred at 50 °C in an oil bath equipped with contact
thermometer for 24 h. The solvent was evaporated and then
excess glycidyl phenyl ether was removed by kugelruhr
distillation apparatus. Diastereomer pair was separated by
silica-gel column chromatography (petroleum ether/ethyl
acetate/triethyl amine = 85/10/5), to afford a higher Rf
value (0.65) of 9a (2.1 g 49 %) as a colourless oil. [a]2D0:
-76.8 (c 2.5, CHCl3). IR: 3460, 3063, 3030, 2934, 2857,
1
1447, 1373, 133151242, 1062, 966, 912, 753 cm-1. H
NMR (400 MHz, CDCl3): d (ppm) 7.45–7.32 (m, 10H),
4.76 (dd, 2H, J1 = 4.4, J2 = 4.0), 4.97 (bs, 2H), 2.69–2.61
(m, 4H), 2.52–2.45 (m, 2H), 1.88–1.75 (m, 4H), 1.43–1.26
(m, 4H), 1.00 (d, 3H, J = 6.8), 0.96(m, 2H). 13C NMR
(100 MHz, CDCl3): d (ppm) 142.72, 128.41, 127.52,
126.06, 70.96, 61.53, 58.45, 40.57, 31.03, 30.85, 26.72,
26.54, 26.38, 11.14. Anal. Cald. for C24H33NO2: C, 78.43;
H, 9.05; N, 3.81. Found: C, 78.37; H, 9.11; N, 2.71.
1
1600, 1496, 1458, 1380, 1298, 1247, 1047, 752 cm-1. H
NMR (400 MHz, CDCl3): d (ppm) 7.39–7.27 (m, 7H),
6.99–6.90 (m, 3H), 4.10–4.00 (m, 1H), 3.99–3.95 (m, 1H),
3.89–3.84 (m, 2H), 3.65 (bs, 1H), 3.40 (d, 1H,
J = 13.6 Hz), 2.70–2.47 (m, 3H), 2.24 (d, 1H,
J = 13.2 Hz), 1.77–1.65 (m, 4H), 1.50–1.30 (m, 1H),
1.30–1.11 (m, 3H), 1.06 (d, 3H, J = 6.8 Hz), 0.90–0.80
(m, 2H). 13C NMR (400 MHz, CDCl3): d (ppm) 158.83,
139.54, 129.41, 129.17, 128.50, 127.20, 120.83, 114.53,
70.40, 65.84, 59.28, 54.11, 52.36, 40.80, 31.11, 30.69,
26.52, 26.43, 26.21, 10.24. Anal. Cald. for C19H31NO: C,
78.84; H, 10.79; N, 4.84. Found: C, 78.92; H, 10.88; N,
4.90. The diastereomer 9b (2.1 g 49 %) with lower Rf
value (0.40) was also obtained as a colourless oil. [a]2D0:
-40.8 (c 2.5, CHCl3). IR : 3445, 3063, 3038, 2928, 2857,
4.2.11 General Procedure for the Ring Opening
of Glycidol
A solution of glycidol (0.66 mol), phenol or phenol deriv-
atives (0.33 mol) and catalyst (0.033 mol) was dissolved in
absolute ethanol (1 ml). The mixture was stirred at constant
temperature (50 °C) for 24 h. The solvent was evaporated
and the desired 3-aryloxy-1,2-propanediols was purified by
silica-gel TLC plate (EtOAc/n-hexane = 2/1). Ee values
were determined by HPLC analysis (Biorad pump, DaicelÒ
chiralcel OD column, UV-detector 254 nm, ethanol:
n-hexane = 1: 9, flow rate: 1 ml min-1). Retention times
for (R) and (S) of 3-(p-methoxyphenoxy)-, 3-(p-methyl-
phenoxy)- and 3-phenoxy-1,2-propanediol were found to be
8 and 10, 13 and 17 and 9 and 17 1 min, respectively.
1600, 1498, 1456, 1250, 1047, 758 cm-1 1H NMR
.
(400 MHz, CDCl3): d (ppm) 7.34–7.26 (m, 8H), 6.08–6.84
(m, 2H), 3.96–3.93 (m, 1H), 3.84–3.80 (m, 1H), 3.76–3.74
(m, 2H), 3.44 (d, 1H, J = 13.2 Hz), 2.79–2.73 (m, 1H),
2.67–2.63 (m, 1H), 2.46–2.41 (m, 1H), 2.24 (d, 1H,
J = 13.2 Hz), 1.77–1.65 (m, 4H), 1.50–1.35 (m, 1H),
1.30–1.10 (m, 3H), 1.06 (d, 3H, J = 6.4 Hz), 0.92–0.80
(m, 2H). 13C NMR (100 MHz, CDCl3): d (ppm) 158.70,
140.26, 129.39, 128.36, 127.06, 120.84, 114.41, 70.33,
67.94, 62.49, 55.02, 54.39, 41.09, 31.54, 30.56, 26.56,
26.46, 26.28, 11.24. Anal. Cald. for C19H31NO: C, 78.84;
H, 10.79; N, 4.84. Found: C, 78.94; H, 10.79; N, 4.94. In
order to the determination of absolute configurations of
diastereomers pair (R)-N-benzyl-1-cyclohexylethylamine 6
and (S)-glycidyl phenyl ether was reacted as usual manner.
The optical rotation of purified diastereomer was measured
to give 9a by [a]2D0: -76.8 (c 2.5, CHCl3).
Acknowledgments We thank the Research Project Council of Dicle
¨
University (DUBAP-08-FF-13) and the Scientific and Technological
˙
Research Council of Turkey (TUBITAK) (Project no: 110T468) for
their financial support.
References
1. Terada M, Machioka K, Sorimachi K (2006) Angew Chem Int Ed
45:2254
2. Saito S, Yamamoto H (2004) Acc Chem Res 37:570–579
3. Akiyama T (2007) Chem Rev 107:5744
4. Cobb AJ, Marson CM (2005) Tetrahedron 61:1269
´
5. Forrat VJ, Ramon DJ, Yus M (2008) Tetrahedron Asymmetry
19:537
6. Micheau JC, Buhse T, Lavabre D, Islas JR (2008) Tetrahedron
Asymmetry 19:416
4.2.10 N-(R)-1-Cyclohexylethyl-3-aza-(S,S)-1,5-diphenyl-
1,5-pentanediol (10)
7. Zhong J, Guo H, Wang M, Yin M, Wang M (2007) Tetrahedron
Asymmetry 18:734
8. Parambadath S, Singh AP (2009) Catal Today 141:161
(R)-Styrene oxide (1.04 g, 8.66 mmol) was added to
the solution of (R)-N-benzyl-1-cyclohexylethylamine (6)
123

802
T. Aral et al.
9. Xiaofeng W, Xiaohong L, Matthew MC, Ourida S, Jianliang X
(2006) J Mol Catal A 247:153
25. Jacobsen EN (1993) In Ojima I (ed) Catalytic asymmetric syn-
thesis. Wiley–VCH, New York, p 287
10. Zhou Y, Wang YW, Dou W, Zhang D, Lio WS (2009) Chirality
21:657
26. Sun J, Yuan F, Yang M, Pan Y, Zhu C (2009) Tetrahedron Lett
50:548
11. Zhang YX, Du DM, Chen X, Lu¨ SF, Hua WT (2004) Tetrahedron
Asymmetry 15:177
12. Chen YJ, Chen C (2007) Tetrahedron Asymmetry 18:1313
27. Kureshy RI, Kumar M, Agrawal S, Khan NH, Abdi SHR, Bajaj
HC (2010) Tetrahedron Asymmetry 21:451
28. Tokunaga M, Larrow JF, Kakiuchi F, Jacobsen EN (1997) Sci-
ence 277:936–938
29. Bonollo S, Lanari D, Vaccaro L (2011) Eur J Org Chem 14:2587
30. Ready JM, Jacobsen EN (1999) J Am Chem Soc 121:6086
31. Peukert S, Jacobsen EN (1999) Org Lett 1:1245
32. Groger H (2001) Adv Synth Catal 343:547
¨
13. Tschop A, Marx A, Sreekanth AR, Schneider C (2007) Eur J Org
Chem 14:2318
14. Russo A, Lattanzi A (2008) Eur J Org Chem 16:2767
15. Luo ZB, Hou XL, Dai LX (2007) Tetrahedron Asymmetry
18:443
16. Wang Z, Sun X, Ye S, Wang W, Wang B, Wu J (2008) Tetra-
hedron Asymmetry 19:964
17. Kumar P, Naidu V, Gupta P (2007) Tetrahedron 63:2745
33. Roberts SM (2001) J Chem Soc Perkin Transact 1:1475
34. Reetz MT (2001) Angew Chem Int Ed 40:284
35. Bala N, Chimni SS (2010) Tetrahedron Asymmetry 21:2879
´
¨
36. Turgut Y, Aral T, Karakaplan M, Deniz P, Hos¸goren H (2010)
Synth Commun 40:3365
37. Panchgalle SP, Gore RG, Chavan SP, Kalkote UR (2009) Tet-
rahedron Asymmetry 20:1767
38. Jonet A, Dassonville-Klimpt A, Da Nascimento S, Leger JM,
Guillon J, Sonnet P (2011) Tetrahedron Asymmetry 22:138
39. Wynberg H (1986) Top Stereochem 16:87–129
40. Mucha P, Mlostron G, Jasinski M, Linden A, Heimgartner H
(2008) Tetrahedron Asymmetry 19:1600
18. Lagos FM, Carballeira JD, Bermudez JL, Alvarez E, Jose
Sinisterra V (2004) Tetrahedron Asymmetry 15:763
19. McKerlie F, Procter DJ, Wynne G (2002) Chem Commun 6:584
20. Takahashi H, Sakuraba S, Takea H, Achiwa K (1990) J Am
Chem Soc 112:5876
21. Chen J, Shum W (1995) Tetrahedron Lett 36:2379
22. Kitaori K, Furukawa Y, Yoshimoto H, Otera J (1999) Tetrahe-
dron 55:14381
23. Zhu X, Venkatasubbaiah K, Weck M, Lones CW (2010) J Mol
Catal A 329:1
41. Tye H, Eldred C, Wills M (2001) Tetrahedron Lett 43:155
24. Johnson RA, Sharplesss KB (1993) In: Ojima I (ed) Catalytic
asymmetric synthesis. Wiley–VCH, New York, p 103
123