Enantioselective recognition of 1,2-amino alcohols by reversible formation of imines with resonance-assisted hydrogen bonds

Article abstract of DOI:10.1021/ol051267b

(Chemical Equation Presented) A chiral aldehyde with three H-bond donating groups (2) has been synthesized. This aldehyde binds a variety of chiral 1,2-amino alcohols in benzene with the same sense of stereoselectivity. Computational and experimental data

Full text of DOI:10.1021/ol051267b

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3525-3527
Enantioselective Recognition of
1,2-Amino Alcohols by Reversible
Formation of Imines with
Resonance-Assisted Hydrogen Bonds
Kwan Mook Kim,*,† Hyunjung Park,† Hae-Jo Kim,‡ Jik Chin,*,‡ and
Wonwoo Nam*,†
Department of Chemistry, DiVision of Nano Sciences, and Center for Biomimetic
Systems, Ewha Womans UniVersity, Seoul 120-750, South Korea, and
Department of Chemistry, 80 St. George Street, UniVersity of Toronto,
Toronto, Ontario, Canada M5S 3H6
kkmook@ewha.ac.kr; jchin@chem.utoronto.ca; wwnam@ewha.ac.kr
Received May 30, 2005
ABSTRACT
A chiral aldehyde with three H-bond donating groups (2) has been synthesized. This aldehyde binds a variety of chiral 1,2-amino alcohols in
benzene with the same sense of stereoselectivity. Computational and experimental data indicate that one imine bond, one resonance-assisted
H-bond to the imine nitrogen, and two H-bonds to the alcoholic oxygen all play an important role in the stereoselective recognition.
Chiral amino alcohols are useful as intermediates for making
a variety of biologically active molecules1 and also as ligands
for stereoselective catalysts.2 Over the years there have been
numerous publications on developing receptors for amines,
amino acids, and amino alcohols.3-5 In most of these studies,
molecular recognition is based on noncovalent interactions
such as hydrogen bonding, metal coordination, and hydro-
phobic hydrogen bonding, metal coordination, and hydro-
phobic interactions. Reversible imine formation has rarely
been explored systematically for the recognition studies.6
When compared to noncovalent interactions, imine bonds
are slower to form but have the advantage of being much
(3) (a) Bradshaw, J. S.; Izatt, R. M.; Bordunov, A. V.; Zhu, C. Y.;
Hathaway, J. K. In ComprehensiVe Supramolecular Chemistry; Gokel, G.
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G. W.; Abel, E. In ComprehensiVe Supramolecular Chemistry; Gokel, G.
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Am. Chem. Soc. 2005, 127, 5986-5987.
(5) (a) Kurta´n, T.; Vesnas, N.; Li, Y.-Q.; Huang, X.; Nakanishi, K.;
Berova, N. J. Am. Chem. Soc. 2001, 123, 5962-5973. (b) Kim, S.-G.; Kim,
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16175.
† Ewha Womans University.
‡ University of Toronto.
(1) (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis. Construc-
tion of Chiral Molecules Using Amino Acids; Wiley: New York, 1987. (b)
Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576;.
(2) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994. (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
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10.1021/ol051267b CCC: $30.25
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Published on Web 07/07/2005

stronger and structurally well defined. These are features that
are particularly desirable for developing stereoselective
receptors. We recently showed that resonance assisted
hydrogen bonds (RAHB)7 can greatly increase the rate and
equilibrium constants for imine formation.8 Furthermor,
RAHB can orient the imine and restrict its conformational
mobility. Here, we compare three stereoselective receptors
(1-3) for amino alcohols.
Table 1. Enantioselective Imine Formation (KR/KS) between 2
and Chiral Amines As Determined by H NMR
1
δ, ppm
imine C-H benzylic CH2
amines
phenethylamine
R
S
R
S
KR/KS
7.96 7.96 4.71 4.80
4.65 4.72
1.0
2-amino-1-propanol
2-amino-1-butanol
8.21 8.13 4.85 4.88
4.66 4.79
8.25 8.08 4.81 4.77
4.61 4.69
3.7
3.1
3.7
4.8
2-amino-3-phenyl-1-propanol 8.01 7.97 4.84 4.92
4.64 4.83
2-amino-2-phenylethanol
8.25 8.16 4.84 4.84
4.61 4.77
2-aminopropanol to 2. The ratio of 2a and 2b can be
measured from the imine C-H and benzylic hydrogen
signals. Integration of the two peaks shows that the ratio of
2b/2a is 1.9:1 at equilibrium. This indicates that the imine
formation constant for 2b (KR) is larger than that for 2a (KS)
by a factor of about 3.7 (1.92).10 Even if 2a is first formed
by the addition of 1 equiv of (S)-2-aminopropanol, the above
equilibrium ratio is obtained within 10 min upon addition
of 1 equiv of (R)-2-aminopropanol to 2a.
Compounds 1-3 were synthesized from (S)-2,2′-binol-3-
aldehyde9 as described in the Supporting Information. All
of the products were purified by column chromatography.
Compound 2 is freely soluble in DMSO-d6 and sparingly
soluble in CDCl3 and benzene-d6, whereas compounds 1 and
3 are freely soluble in all three solvents.
Figure 1a shows the 1H NMR spectrum for 2 in benzene-
d6 containing 5% DMSO-d6. Addition of (S)-2-aminopro-
1
panol to 2 results in a rapid decrease in the aldehyde H
Table 1 shows that 2 compares favorably with previously
reported receptors for stereoselective recognition of amino
alcohols.5 Furthermore, 2 binds all four amino alcohols with
the same sense of stereoselectivity. Insight into the origin
of stereoselectivity may be gained from molecular mechanics
computation.11 Aside from the RAHB between the phenolic
proton and the imine, the alcohol group is within hydrogen-
bonding distance of the urea group (Figure 2). In the imines
formed with (R)-amino alcohols, the imine C-H comes in
contact with the hydrogen attached to the chirality center.
In the imines formed with (S)-amino alcohols, it is the alkyl
or aryl group attached to the chirality center that comes in
contact with the imine C-H. The greater steric effect in the
(S)-imines appears to be the reason for the greater stability
of the (R)-imines. Molecular mechanics computation was
used to correctly predict the sense of stereoselectivity for
all four amino alcohols in Table 1.
NMR signal at 9.74 ppm with concomitant increase in the
imine (2a) C-H signal at 8.13 ppm (Figure 1b). Similarly,
addition of (R)-2-aminopropanol to 2 results in an increase
in the imine (2b) C-H signal at 8.21 ppm (Figure 1c). Aside
from the imine C-H signals, the benzylic CH2 signals are
also useful for distinguishing 2a and 2b. The benzylic
hydrogens are diastereotopic and appear as an AB quartet.
Figure 1d shows the 1H NMR spectrum for a mixture of 2a
and 2b formed by the addition of two equivalents of racemic
Several experimental results indicate that hydrogen bonds
play an important role in stereoselective reognition of amino
(7) (a) Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc.
2000, 122, 10405-10417. (b) Gilli, G.; Bellucci, F.; Ferretti, V.; Bertolasi,
V. J. Am. Chem. Soc. 1989, 111, 1023-1028. (c) Bertolasi, V.; Gilli, P.;
Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 1991, 113, 4917-4925.
(8) (a) Chin, J.; Mancin, F.; Thavarajah, N.; Lee, D.; Lough, A.; Chung,
D. S. J. Am. Chem. Soc. 2003, 125, 15276-15277. (b) Chin, J.; Kim, D.
C.; Kim, H.-J.; Panosyan, F. B.; Kim, K. M. Org. Lett. 2004, 6, 2591-
2593.
(9) (a) Kim, H. C.; Choi, S.; Kim, H.; Ahn, K.-H. Tetrahedron Lett.
1997, 38, 3959-3962. (b) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.;
Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 2252-2260.
(10) KR ) [2b]/([2][R]) and KS ) [2a]/([2]/[S]) where [R] and [S] are
concentrations of R- and S-2-aminopropanol, respectively. Thus, KR/KS )
([2b][S])/([2a][R]) ) ([2b]/[2a])2.
(11) Molecular mechanics computation was performed using Spartan ‘04
Windows from Wavefunction, Inc.
1
Figure 1. Partial H NMR spectra (in benzene-d6) of (a) 2, (b)
2a, (c) 2b, and (d) mixture of 2a and 2b formed from addition of
2 equiv of racemic 2-aminopropanol to 2.
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Org. Lett., Vol. 7, No. 16, 2005

Figure 3. Energy-minimized structure of the imine formed from
3 and S-2-aminopropanol.
repulsion (Figure 3). Molecular mechanics calculations show
that this has the effect of inverting the stereoselectivity. In
the imines formed with (S)-amino alcohols, the imine C-H
comes in contact with the hydrogen attached to the chirality
center (Figure 3). In the imines formed with (R)-amino
alcohols, the imine C-H comes in contact with the alkyl or
aryl group attached to the chirality center. Therefore, it is
the (S)-amino alcohols that form the more stable imines.
In summary, we have developed stereoselective receptors
for amino alcohols based on reversible imine formation.
Three-point interactions including an imine, an RAHB, and
another hydrogen bond allow us to obtain high stereoselec-
tivity as well as an understanding of the origin of the
selectivity through molecular mechanics computation. Such
understanding should be useful for developing evermore
selective receptors.
Figure 2. (a) Schematic representation showing steric repulsions
in 2a and 2b. (b) Energy-minimized structure of 2b formed from
2 and R-2-aminopropanol. Dotted lines indicate hydrogen bonds.
alcohols with 2. Compound 2 does not bind phenethylamine
with appreciable stereoselectivity (Table 1). Thus, hydrogen
bonding with the alcohol group appears to be important.
Compound 1 binds the four amino alcohols with the same
sense of stereoselectivity as compound 2. However, the
stereoselectivity of compound 1 is only about half that of
compound 2 presumably because the acetamide group in 1
has only one hydrogen bond donor whereas the urea group
in 2 has two. Urea and thiourea groups have recently been
shown to be excellent H-bond donors in chiral catalysts.12
The stereoselectivity 2 is almost completely lost in DMSO
where hydrogen bonds are much weaker than in benzene.
Acknowledgment. This work was supported by a grant
from MOST through the Creative Research Initiative Pro-
gram, the Korea Research Foundation Grant (KRF-2004-
005-C00093), and the Natural Sciences and Engineering
Research Council of Canada.
The stereoselectivity of compound 3 is about half that of
compound 2 but with the opposite sense of stereoselectivity.
Without the RAHB, the imine group is expected to rotate
away about 180° from the phenoxy oxygen due to lone pair
Supporting Information Available: Synthesis of 1-3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558-10559. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 466-468. (c) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672-12673. (d) Schreiner, P. R. Chem. Soc. ReV. 2003,
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