A chiral ketone for enantioselective recognition of 1,2-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.07.037

A novel auxillary chiral ketone has been designed, synthesized, and used to enantioselectively recognize 1,2-amino alcohols. This work proves that the keto group can serve as a chiral recognition center by imine formation supported by resonance assisted h

Full text of DOI:10.1016/j.tetlet.2007.07.037

Tetrahedron Letters 48 (2007) 6582–6585
A chiral ketone for enantioselective recognition
of 1,2-amino alcohols
Raju Nandhakumar, Yong-En Guo, Hyunjung Park, Lijun Tang, Wonwoo Nam
and Kwan Mook Kim*
Department of Chemistry and Division of Nano Sciences, Ewha Womans University, Seoul 120-750, South Korea
Received 2 June 2007; accepted 3 July 2007
Available online 2 August 2007
Abstract—A novel auxillary chiral ketone has been designed, synthesized, and used to enantioselectively recognize 1,2-amino alco-
hols. This work proves that the keto group can serve as a chiral recognition center by imine formation supported by resonance
assisted hydrogen bonding (RAHB).
Ó 2007 Elsevier Ltd. All rights reserved.
The development of synthetic molecular receptors as
chiral hosts capable of exhibiting enantiomeric differen-
tiation towards racemic guests has become an important
and rapidly growing field of chemistry. Recent work has
led to the design and synthesis of chiral hosts for alka-
loids,1 peptides,2 amino acids,3 amino alcohols4–6 and
other neutral guests.7 In particular, chiral discrimination
of amino alcohols by molecular receptors needs much
attention because of their importance as vital intermedi-
ates for establishing a wide spectrum of biologically
active molecules8 and also as ligands for stereoselective
catalysts.9
experience a different steric hindrance around the imine
bond as shown in Scheme 1. Hence, the imine formation
constants KR and KS are ideally not the same.10a Herein,
we report the synthesis of 1 and its stereoselective recog-
nition property.
Receptor 1 was conveniently synthesized from (S)-2,20-
binol via ortho lithiation through a five step protocol
(Scheme 2).13 The reaction of (S)-2,20-binol 2 with
sodium hydride and chloromethylmethylether in
dimethyl-formamide yielded the MOM protected binol
3. Ortho lithiation of compound 3 and subsequent
Many molecular recognition studies are based on non-
covalent interactions such as hydrogen bonding, metal
coordination, etc. Our recent works10 proved that an
aldehyde can be a good stereoselective recognition cen-
ter for 1,2-amino alcohols via reversible imine formation
with resonance assisted hydrogen bonding.11 Although
keto compound acetone was known to racemize amino
acids,12 no keto compound has been studied as a recep-
tor for chiral recognition through imine formation. In
interest of the above, we designed a novel chiral keto
receptor 1 for the stereoselective recognition of 1,2-ami-
no alcohols. Receptor 1, after the imine formation, 1a
and 1b with (S)- and (R)-2-aminopropanol, respectively,
CH3
H
H
O
N
H
N
H
O
O
H
N
S
-2-aminopropanol
KS
O
1a
O
H
H
N
H
O
O
N
O
H
CH3
H
1
O
N
H
H
N
KR
H
N
O
O
R
-2-aminopropanol
O
Keywords: Chiral ketone; Enantioselective recognition; 1,2-Amino
alcohols; Imine bond.
1b
*
Corresponding author. Tel.: +82 2 3277 4083; fax: +82 2 3277
3419; e-mail: kkmook@ewha.ac.kr
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.037

R. Nandhakumar et al. / Tetrahedron Letters 48 (2007) 6582–6585
6583
OH
H
H
OH
a
c
b
OH
OH
OMOM
OMOM
OMOM
OMOM
OMOM
OMOM
+
3
4a
4b
2
H
N
H
N
Br
O
O
O
H
H
N
O
7
H
N
d
OH
OH
OMOM
OMOM
O
O
b
a
O
c
e
f
d
e
6
1
5
Scheme 2. Reagents and conditions: (a) NaH/DMF, MOMCl, rt, 2 h, 98%; (b) n-Bu–Li, C6H5CHO, THF, ꢀ78 °C, 3 h, 70%; (c) PCC, CH2Cl2, 4 h,
74%; (d) conc. HCl, EtOH, reflux, 2 h, (Quant.); (e) NaH, DMF, rt, 5 h, 33%.
treatment with benzaldehyde afforded epimers 4a and 4b
with considerable stereoselectivity. Oxidation of both
epimers using pyridinium chlorochromate (PCC) in
methylene chloride followed by deprotection with an
acid provided the keto binol 6. Finally, ketone 6 and
phenylurylbenzyl bromide12a were reacted in the pres-
ence of sodium hydride in dimethyl-formamide silica
gel column chromatography afforded the designed
receptor 1 in moderate yield. Compound 1 is freely sol-
uble in solvents such as DMSO, CHCl3, benzene, etc.
the imine over a period of 24 h. This can be clearly noted
by the downfield chemical shift of Hd (doublet) in recep-
tor 1 from 6.60 ppm to 6.65 ppm. Similarly, there is a
significant chemical shift from 6.60 ppm to 6.53 ppm
by the addition of (R)-2-aminopropanol to 1. Besides,
Hd proton chemical shifts, the benzylic CH2 signals
exhibit prominent splitting pattern thereby providing
some vital informations for distinguishing 1a and 1b.
The benzylic hydrogens are diastereotopic and appear
1
as an AB quartet. Figure 1d shows the H NMR spec-
trum for a mixture of 1a and 1b formed by the addition
of two equivalents of racemic 2-aminopropanol to 1.
The ratio of 1a and 1b are obtained from the signals
of the benzylic hydrogen and Hd. Integration of the
two peaks provides the ratio of 1a/1b is 1.5:1 at equilibi-
rium. This indicates that the imine formation constant
for 1b (KR) is larger than that for 1a (KS) by a factor
of about 2.25 (1.52).14
Figure 1 shows the partial 1H NMR spectra of the recep-
tor 1 and the imines formed. Figure 1a indicates the H
NMR spectrum for 1 in benzene-d6. Addition of (S)-2-
aminopropanol to 1 results in a steady formation of
1
Table 1 lists the values of KR/KS for four amino alco-
hols, which shows that the keto binol receptor 1 com-
pares favourably with previously reported receptors
for enantioselective recognition of 1,2-amino alcohols.
The origin of the stereoselectivity of 1 is the steric hin-
drance around imine bond as shown in Scheme 1. More
steric energy is assumed in the imine of (S)-aminopropa-
nol (1a) due to the repulsion between phenyl ring and
methyl group than in the imine of (R)-aminopropanol
(1b) where repulsion between phenyl ring and proton
is less. The molecular mechanics computation15 corrob-
orates the same sense of stereoselectivity for all four
amino alcohols in Table 1.
The stereoselectivity KR/KS, depends on the degree of
the difference of steric energies around imine bonds
between 1a and 1b. This will be maximized in the condi-
tion that the whole imine complex is rigid by hydrogen
bonds (resonance assisted hydrogen bond between imine
nitrogen and phenolic –OH, and the hydrogen bond be-
tween uryl –NH and alcoholic –OH). Experiments with
1
Figure 1. Partial H NMR spectra (benzene-d6) of (a) 1, (b) 1a, (c) 1b
and (d) mixture of 1a and 1b formed from addition of 2 equiv of
racemic 2-aminopropanol to 1.

6584
R. Nandhakumar et al. / Tetrahedron Letters 48 (2007) 6582–6585
Table 1. Enantioselective imine formation (KR/KS) between 1 and
chiral amines as determined by 1H NMR
References and notes
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Amines
d, ppm
Benzylic
KR/KS
Hd
CH2
R
S
R
S
Methylbenzylamine
2-Amino-1-propanol
2-Amino-1-butanol
6.72 6.72 4.79 4.80 1.0
4.85 4.87
6.53 6.65 4.79 4.91 2.3
4.54 4.82
6.57 6.66 4.90 4.97 2.4
4.65 4.84
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H. J. Am. Chem. Soc. 1994, 116, 4240.
2-Amino-3-phenyl-1-propanol 6.58 6.69 4.98 5.06 2.3
4.67 4.94
2-Amino-2-phenylethanol
6.55 6.70 4.93 4.98 2.1
4.58 4.89
4. (a) Wang, Q.; Chen, X.; Tao, L.; Wang, L.; Xiao, D.; Yu,
X.; Pu, L. J. Org. Chem. 2006, 72, 97; (b) Bradshaw, J. S.;
Izatt, R. M.; Bordunov, A. V.; Zhu, C. Y.; Hathaway, J.
K. In Comprehensive Supramolecular Chemistry; Gokel,
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5986.
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6. (a) Kurtan, T.; Vesnas, N.; Li, Y.-Q.; Huang, X.;
Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2001, 123,
5962; (b) Kim, S.-G.; Kim, K.-H.; Kim, Y. K.; Shin, S. K.;
Ahn, K. H. J. Am. Chem. Soc. 2003, 125, 13819.
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Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1991, 30, 858;
(b) Webb, T. H.; Suh, H.; Wilcox, C. S. J. Am. Chem. Soc.
1991, 113, 8554; (c) Murakami, Y.; Hayashida, O.; Nagai,
Y. J. Am. Chem. Soc. 1994, 116, 2611.
8. (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis.
Construction of Chiral Molecules Using Amino Acids;
Wiley: New York, 1987; (b) Bergmeier, S. C. Tetrahedron
2000, 56, 2561.
Figure 2. Energy minimized structures of 1a and 1b calculated by semi
empirical computation.
methylbenzylamine for imine formation, compound 1
does not bind with noticeable stereoselectivity explain-
ing that the hydrogen bonds perform an important role
in stereoselective recognition of amino alcohols. The
complete loss of stereoselectivity of the receptor 1 in
DMSO is also explicable by the hydrogen bond effect.
9. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1994; (b) Helmchen, G.;
Pfaltz, A. Acc. Chem. Res. 2000, 33, 336; (c) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
10. (a) Kim, K. M.; Park, H.; Kim, H. J.; Chin, J.; Nam, W.
Org. Lett. 2005, 7, 3525; (b) Chin, J.; Kim, D. C.; Kim,
H.-J.; Panosyan, F. B.; Kim, K. M. Org. Lett. 2004, 6,
2591.
The energy differences between 1a and 1b were calcu-
lated to be ꢁ3 kcal/mol by molecular mechanics compu-
tation and to be ꢁ0.3 kcal/mol by semi empirical
computation using the Spartan program. The semi
empirical calculation better corresponds to the experi-
mental results in Table 1. The energy minimized struc-
tures of 1a and 1b are shown in Figure 2.
11. (a) Feuister, E. K.; Glass, T. E. J. Am. Chem. Soc. 2003,
125, 16174; (b) Chin, J.; Mancin, F.; Thavarajah, N.; Lee,
D.; Lough, A.; Chung, D. S. J. Am. Chem. Soc. 2003, 125,
15276; (c) Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J.
Am. Chem. Soc. 2000, 122, 10405; (d) Gilli, G.; Bellucci,
F.; Ferretti, V.; Bertolasi, V. J. Am. Chem. Soc. 1989, 111,
1023; (e) Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G. J.
Am. Chem. Soc. 1991, 113, 4917.
In conclusion, we have developed a novel keto receptor
recognizing the chirality in amino alcohols, whose origin
is supported through the semi empirical computation.
This work proves that the keto group can serve as a chi-
ral recognition center by imine formation and it extends
the scope of chiral ketones which were viewed mainly as
asymmetric catalyst in epoxidation.16
12. (a) Brian, P. C.; Richard, W. J. Am. Chem. Soc. 2005, 126,
4514; (b) Ana, R.; Juan, C.; Tina, L. A.; John, P. R. J. Am.
Chem. Soc. 2001, 123, 7949.
13. Data for compound 4a and 4b: Compound 4a: mp: 185 °C.
1H NMR (DMSO-d6, 250 MHz) d 8.17 (s, 1H), 8.05 (d,
1H), 7.94 (t, 2H), 7.68 (d, 1H), 7.21–7.44 (m, 10H), 7.05 (d,
1H), 6.80 (d, 1H), 6.25 (d, 1H, –CH), 6.05 (d, 1H, –OH),
5.19 (dd, 2H, –O–CH2–OCH3), 4.75 (dd, 2H, –O–CH2–
OCH3), 3.13 (s, 3H, –O–CH2–OCH3) 2.86 (s, 3H, –O–
CH2–OCH3). Anal. Calcd for C31H28O5: C, 77.48; H, 5.87.
Acknowledgements
This research was supported by the Ministry of Science
and Technology of Korea, through NRL and SRC pro-
gram of MOST/KOSEF at Ewha Womans University
(Grant: R11-2005-008-000000) and by the Korea
Research Foundation Grant (KRF-2004-005-C00093).
1
Found: C, 77.55; H, 5.98. Compound 4b: mp: 156 °C. H

R. Nandhakumar et al. / Tetrahedron Letters 48 (2007) 6582–6585
6585
NMR (DMSO-d6, 250 MHz) d 8.17 (s, 1H), 8.07 (d, 1H),
7.97 (t, 2H), 7.59 (d, 1H), 7.20–7.44 (m, 10H), 6.96–7.02
(m, 2H), 6.20 (d, 1H, –CH), 6.03 (d, 1H, –OH), 4.96–5.11
(dd, 2H, –O–CH2–OCH3), 4.27–4.48 (dd, 2H, –O–CH2–
OCH3), 2.98 (s, 3H, –O–CH2–OCH3), 2.69 (s, 3H, –O–
CH2–OCH3). Anal. Calcd for C31H28O5: C, 77.48; H, 5.87.
Found: C, 77.63; H, 6.02.
132.633, 130.787, 130.370, 130.247, 129.703, 129.336,
128.654, 128.381, 127.046, 126.706, 124.826, 124.662,
124.608, 123.501, 120.966, 117.817, 115.276, 113.915.
Anal. Calcd for C27H18O3: C, 83.06; H, 4.65. Found: C,
83.23; H, 4.81.
Data for compound 1: mp: 108 °C. 1H NMR (C6D6,
250 MHz) d 8.08 (s, 1H), 7.94 (d, 1H), 7.82 (d, 2H), 6.96–
7.61 (m, 20H), 6.84 (d, 1H), 6.60 (d, 2H), 4.61–4.82 (dd,
2H, –O–CH2). 13C NMR (CDCl3, 63 MHz), 201.933,
154.058, 153.753, 153.296, 138.409, 138.292,138.025,
137.800, 137.315, 136.417, 133.673, 132.740, 130.267,
129.895, 129.849, 129.477, 128.938, 128.573, 128.311,
126.950, 126.893, 125.127, 124.814, 124.206, 124.031,
123.280, 121.736, 121.598, 119.971, 119.354, 118.831,
118.484, 118.127, 115.252. HRMS [EI] Calcd for
C41H30N2O4: 614.2206. Found: 614.2210.
1
Data for compound 5 and 6: Compound 5: mp: 94 °C. H
NMR (CDCl3, 250 MHz) d 8.17 (s, 1H), 8.10 (d, 2H), 7.98
(d, 1H), 7.87 (d, 2H), 7.08–7.68 (m, 8H), 7.09 (d, 2H), 5.22
(s, 2H, –O–CH2–OCH3), 4.32–4.45 (dd, 2H, –O–CH2–
OCH3), 3.34 (s, 3H, –O–CH2–OCH3), 3.12 (s, 3H, –O–
CH2–OCH3). 13C NMR (CDCl3, 63 MHz) 196.200,
152.912, 150.741, 137.684, 134.926, 134.202, 133.887,
133.244, 130.240, 130.188, 130.044, 129.879, 129.599,
128.713, 128.344, 127.991, 127.611, 126.795, 126.575,
126.031, 125.671, 125.421, 124.174, 119.714, 116.287,
99.628, 94.842, 56.435, 56.045. Anal. Calcd for
C31H26O5: C, 77.81; H, 5.48. Found: C, 77.72; H, 5.32.
Compound 6: mp: 132 °C. 1H NMR (CDCl3, 250 MHz) d
11.57 (s, 1H, –OH), 8.43 (s, 1H), 6.85–7.98 (m, 15H), 5.06
(s, 1H, –OH). 13C NMR (CDCl3, 63 MHz) 201.787,
155.920, 151.484, 138.094, 137.763, 137.443, 133.478,
14. KR = [1b]/([1][R]) and KS = [1a]/([1][S]) where [R] and [S]
are concentrations of R- and S-2-aminopropanol, respec-
tively. Hence, KR/KS = ([1b] [S])/([1a][R]) = ([1b]/[1a])2
when [1]0 = [R]0 = [S]0.
15. Molecular mechanics computation was performed using
Spartan’04 Windows from Wavefunction, Inc.
16. Yang, D. Acc. Chem. Res. 2004, 37, 497.