Enantioselective inclusion of amide guests into a chiral N,N′-ditrityl amino amide host to compensate the loss of hydrogen bonds broken by installation of trityl groups

Article abstract of DOI:10.1016/j.tetlet.2012.12.029

A new crystalline N,N′-ditrityl amino amide host included several amide guests in the host cavity to form inclusion crystals. Although the installation of trityl groups into (S)-2-aminopropanamide broke its inherent hydrogen bonds of amide groups, inclusion of guest amides compensated the loss of hydrogen bonds. X-ray crystallography showed that these inclusion cavities and host-guest interactions such as hydrogen bonds, van der Waals interaction, and CH?O interactions play important roles for highly enantioselective inclusion. The enantiomeric inclusion was 67% ee (S-form) for N-phenyl 2-methylbutanamide, 82% ee (S-form) for N-phenyl 2-chlorobutanamide, and 83% ee (S-form) for N-phenyl 2-bromobutanamide.

Full text of DOI:10.1016/j.tetlet.2012.12.029

Tetrahedron Letters 54 (2013) 707–710
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Tetrahedron Letters
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Enantioselective inclusion of amide guests into a chiral N,N0-ditrityl amino
amide host to compensate the loss of hydrogen bonds broken by installation
of trityl groups
⇑
Ken Megumi, Shohei Yokota, Shoji Matsumoto, Motohiro Akazome
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
A new crystalline N,N0-ditrityl amino amide host included several amide guests in the host cavity to form
inclusion crystals. Although the installation of trityl groups into (S)-2-aminopropanamide broke its inher-
ent hydrogen bonds of amide groups, inclusion of guest amides compensated the loss of hydrogen bonds.
X-ray crystallography showed that these inclusion cavities and host–guest interactions such as hydrogen
bonds, van der Waals interaction, and CHꢀ ꢀ ꢀO interactions play important roles for highly enantioselec-
tive inclusion. The enantiomeric inclusion was 67% ee (S-form) for N-phenyl 2-methylbutanamide, 82%
ee (S-form) for N-phenyl 2-chlorobutanamide, and 83% ee (S-form) for N-phenyl 2-bromobutanamide.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 15 September 2012
Revised 5 December 2012
Accepted 10 December 2012
Available online 19 December 2012
Keywords:
Trityl group
Amino amide
Hydrogen bonds
X-ray crystal structures
Inclusion crystals can be used for the enantiomeric separation
of organic compounds because a racemic mixture of a guest com-
pound is optically resolved when a chiral host includes one enan-
tiomer of the guest compound selectively. The design of such host
molecules is consequently an area of great interest in host–guest
chemistry.1
tion group that is stable under basic conditions and is easily re-
moved under acidic conditions.7 Crystalline host 1, an alanine
derivative, was easily prepared from commercially available (S)-
2-aminopropanamide by N-tritylation of the amide group8 and
the amino group9 (see Supplementary data).
Here we report that N,N0-ditrityl (S)-2-aminopropanamide crys-
tals included several amides and did so with high
enantioselectivity.
Hart demonstrated early in the development of host molecules
that N,N0-ditritylureas and related compounds acted as wheel-and-
axle type hosts to form inclusion crystals with many kinds of or-
ganic guest molecules.2 Recent crystal engineering research has
shown that the trityl group’s large size and its ability to promote
crystallinity3 make it a valuable component of inclusion crystals.4,5
Figure 1 illustrates our host design based on compensation of
hydrogen bonds broken by trityl groups. N-Methyl acetamide has
hydrogen bond donor (H–N) and acceptor (CO) groups that form
one-dimensional hydrogen-bonding network,6 and the hydrogen
bonds between them will be broken by installed bulky trityl
groups. At the same time, the trityl groups make cavities in which
guest molecules are captured. When a guest is suitable to compen-
sate the loss of the inherent hydrogen bonds, the hydrogen bonds
due to host–guest interaction will result in the formation of new
inclusion crystals. To demonstrate how this concept can be used
for enantiomeric separation, we focus on the following N,N0-ditrityl
amino amide: crystalline N,N0-ditrityl (S)-2-aminopropanamide
(1). In organic synthesis, the trityl group is a well-known protec-
Crystallization of 1 from ethanol yielded good-quality single
crystals belonging to space group P1. In each asymmetric unit cell
of the crystals were two molecules of 1. As expected, two bulky tri-
tyl groups broke the inherent one-dimensional hydrogen-bonding
network of the central amide groups. Between the carbonyl oxygen
of one host 1 and an amino group hydrogen of another host 1, how-
ever, there was a hydrogen bond whose Nꢀ ꢀ ꢀO (Hꢀ ꢀ ꢀO) distance and
angle (N–Hꢀ ꢀ ꢀO) were 3.344(4) Å (2.54 Å) and 165.0° (Fig. 2). This
hydrogen bond was thought to be very weak because it was longer
than any of the other hydrogen bonds in the inclusion crystals
(vide infra). We therefore thought that we could make inclusion
crystals by forming stronger hydrogen bonds between host 1 and
amide guests.
To obtain preliminary results for inclusion, we tried with a mi-
cro-scale crystallization of 1 (5.2 lmol) with a guest (1.2 equiv for
achiral guests or 2.5 equiv for chiral guests) from ethanol solution
(1 mL). Inclusion crystals of 1 with several amides (2–7) were
obtained (Scheme 1).
Although esters such as phenyl acetate and methyl benzoate did
not yield inclusion crystals, N-methyl benzamide (2) and N-phenyl
⇑
Corresponding author. Tel.: +81 43 290 3388; fax: +81 43 290 3401.
E-mail address: akazome@faculty.chiba-u.jp (M. Akazome).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.029

708
K. Megumi et al. / Tetrahedron Letters 54 (2013) 707–710
Inclusion crystals
O
Me
Ph
N
O
N
O
Ph
Ph
R2
Crystal.
EtOH
R1
N
H
R2
Ph
Ph
R1
N
H
H
H
Ph
Me
Ph
N
O
N
Ph
Ph
2: R1 = Ph, R2 = Me
3: R1 = Me, R2 = Ph
4: R1 = Ph, R2 = 2-Butyl
5: R1 = 2-Butyl, R2 = Ph
1
Ph
Ph
H
H
Ph
6: R1 = 1-Chloropropyl, R2 = Ph
7: R1 = 1-Bromopropyl, R2 = Ph
Scheme 1. Crystallization of 1 with amides (2–7) to prepare inclusion crystals.
Figure 1. A host designed to capture an amide guest to compensating the loss of
hydrogen bonds broken by trityl groups.
acetamide (3) yielded inclusion crystals in space group P212121.
Figure 3 shows that the crystal structures of 1ꢀ2 and 1ꢀ3 were quite
similar to each other. Both 2 and 3 settled in the host cavities,
Figure 3. Crystal structures of 1ꢀ2 and 1ꢀ3. For clarity, hydrogen atoms other than
those of the amino and amide groups were omitted and hydrogen bonds are shown
as solid lines.
which were formed mainly by several of phenyl groups of two tri-
tyl groups. Amide protons of the guests 2 and 3 hydrogen-bonded
to the carbonyl oxygen atoms of host 1, and these Nꢀ ꢀ ꢀO (Hꢀ ꢀ ꢀO)
distances and angles (N–Hꢀ ꢀ ꢀO)—2.782(6) Å (1.99 Å) and 150° for
1ꢀ2 and 2.819(3) Å (1.96 Å) and 164° for 1ꢀ3—were within the typ-
ical range of hydrogen-bond distances (mean Nꢀ ꢀ ꢀO 2.85 Å).10 The
carbonyl oxygen atoms of these guests, however, were in contact
not with the amide group hydrogen of the host but with the amino
group hydrogen of the host. These Nꢀ ꢀ ꢀO (Hꢀ ꢀ ꢀO) distances and an-
gles were 3.112(6) Å (2.25 Å) and 164° for 1ꢀ2 and 2.980(3) Å
(2.14 Å) and 160° for 1ꢀ3, and these values are within the sum of
the van der Waals radii of hydrogen and oxygen atoms
[2.72 Å = 1.20 Å (H) + 1.52 (O)].11 Thus the guests compensated
the loss of hydrogen bonds broken by the installation of trityl
groups, and the result was that the one-dimensional hydrogen-
bonding network was reconstructed.
Since the host 1 is a chiral compound, we examined its ability to
discriminate between the enantiomers in racemic mixtures of
amides (4–7). We used the 2-butyl group for this because the small
asymmetric group is ubiquitous. Both N-2-butyl benzamide (4) and
N-phenyl 2-methylbutanamide (5) yielded inclusion crystals (
Fig. 4), and in those crystals, the position of the 2-butyl group
and phenyl group in the cavity of 1ꢀ4 was opposite that of these
groups in the cavity of 1ꢀ5. More important, single-crystal analysis
of the 2-butyl group in 1ꢀ4 revealed that the inclusion crystal was a
disordered structure in which the 2-butyl group was included at
the ratio of 57(R):43(S) [total 14% ee (R)], which meant the cavity
included both enantiomers of 4 in the crystal. In fact, enantiomeric
excess of recovered N-2-butyl benzamide from the bulk sample of
inclusion crystals was confirmed as 10% ee (R) by a chiral HPLC
Figure 2. Crystal structure of 1. For clarity, hydrogen atoms other than those of the
amino and amide groups are omitted and hydrogen bonds are shown as dotted
lines.

K. Megumi et al. / Tetrahedron Letters 54 (2013) 707–710
709
The enantiomeric excesses of recovered amides from bulk samples
(not a crystal) were 67% ee for 5, 82% ee for 6, and 83% ee for 7,
whose predominate enantiomers were S-form. At this stage, we
could not explain the reason for the inconsistency of the enantio-
meric excesses between the bulk sample and a single crystal. Fig-
ure 6 shows that these crystals were isostructural in that the
space group (C2) was the same for each crystal, and the maximum
difference in their unit cell parameters was only 0.7% (a: 0.4%, b:
0.4%, c: 0.2%, b: 0.3%, and V: 0.7%). As seen in crystals 1ꢀ2 and
1ꢀ3, major host–guest interactions were two kinds of hydrogen
bonds between 1 and the guests. One is a hydrogen bond between
an amide hydrogen of the guest and a carbonyl group of 1, and for
this bond the Nꢀ ꢀ ꢀO (Hꢀ ꢀ ꢀO) distances and angles (N–Hꢀ ꢀ ꢀO) are
2.939(2) Å (2.07 Å) and 169° for 1ꢀ5, 2.904(2) Å (2.03 Å) and 173°
for 1ꢀ6, and 2.893(8) Å (2.02 Å) and 173° for 1ꢀ7. The other is a
hydrogen bond between an amino group of 1 and a carbonyl group
of the guest, and for this bond the Nꢀ ꢀ ꢀO (Hꢀ ꢀ ꢀO) distances and an-
gles (N–Hꢀ ꢀ ꢀO) are 3.074(2) Å (2.27 Å) and 167° for 1ꢀ5, 3.072(2) Å
(2.22 Å) and 171° for 1ꢀ6, and 3.101(8) Å (2.33 Å) and 162° for 1ꢀ7.
As also seen in Figures 4 and 5, these two kinds of hydrogen bonds
restore the original one-dimensional hydrogen-bonding network
by compensating the loss of inherent hydrogen bonds that were
broken by the installation of trityl group.
Figure 4. Crystal structures of 1ꢀ4 and 1ꢀ5. For clarity, hydrogen atoms other than
those of the amino and amide groups are omitted and hydrogen bonds are shown as
solid lines. (a) 2-Butyl groups of (R)-4 and (S)-4 colored in red and green,
respectively (site occupancy: R 57%, S 43%). (b) 1ꢀ5. Only the S-form was observed.
To find out why S-amides (5, 6, and 7) were predominately in-
cluded against their R-forms, we inspected additional host–guest
interactions in the cavity. As seen in Figure 6, we found that the
analysis. In contrast, single-crystal X-ray analysis revealed that
only the S-form of 5 was settled in the cavity of 1. This shows that
the inclusion of
enantioselectivity.
5 in the cavity of 1 occurred with high
a-hydrogen atoms of 6 and 7 were close to the carbonyl oxygen
of 1. The Hꢀ ꢀ ꢀO distances are 2.84 Å for 1ꢀ5, 2.75 Å for 1ꢀ6, and
2.71 Å for 1ꢀ7 and suggested C–Hꢀ ꢀ ꢀO interactions.12 Obviously,
the Hꢀ ꢀ ꢀO distances of 1ꢀ7 and 1ꢀ6 are shorter than that of 1ꢀ5. In
1ꢀ5, the distance is greater than the sum of the van der Waals radii
[2.72 Å = 1.20 Å (H) + 1.52 (O)].11 Since Cl and Br have large elec-
Why does the cavity in 1ꢀ4 accommodate this disorder while
the cavity in 1ꢀ5 does not? We found the two crystals have differ-
ent space groups (P212121 for 1ꢀ4 and C2 for 1ꢀ5), which means that
their crystal packing motifs are quite different. As seen in Figure 5,
the specific recognition site for the 2-butyl group was formed by
phenyl group of the neighbor trityl moiety in the adjacent one-
dimensional hydrogen-bonded host–guest column. The differently
oriented phenyl groups colored in yellow in 1ꢀ4 did not control the
preferable enantiomer of 4 in the cavity, but the phenyl groups in
1ꢀ5 encountered the 2-butyl group of 5 at a tilt angle suitable to
discriminate the S-form.
The crystal structure of 1ꢀ5 prompted us to examine the enan-
tiomeric separation of not only 5 but also 6 and 7 because amides
5–7 are same-shaped molecules whose substituent volumes of Cl,
CH3, and Br are respectively 11.62, 13.67, and 14.40 cm3/mol.11
The enantiomeric separation of amides 5–7 was performed by
crystallization from an ethanol solution containing 1 (0.1 mmol,
57 mg) and the amide (2.2 equiv). The scale of this crystallization
was about 20-fold greater than that of preliminary crystallization.
tronegativity, the more acidic
a-hydrogen atoms of 6 and 7 are
preferable hydrogen donors in a weak but important C–Hꢀ ꢀ ꢀO
interaction. This preferable electrostatic interaction would be the
reason why S-form of amides 6 and 7 was advantageously settled
in the cavity of 1 as compared to their R-form. Mesecar and Kosh-
land pointed out the importance of the four-location model in the
enzyme–substrate recognition,13 and Miyata0s group applied this
model to explain the chiral discrimination of inclusion crystals.14
As seen in Figure 7, the four-location model can also explain the
high enantioselectivity for 6 and 7. Although the positions of three
groups of atoms in 2-halobutanamides—(1) carbonyl groups, (2)
ethyl groups, and (3) the methyl group or halogen on the asym-
metric carbon—are controlled by the hydrogen bond and the phe-
nyl group shown in Figure 5b, this control is not enough to provide
high enantioselectivity. For high performance of enantiomeric rec-
Figure 5. Crystal structures of adjacent columns in 1ꢀ4 and 1ꢀ5. The yellow phenyl groups are in contact with 2-butyl groups. (a) 2-Butyl groups of (R)-4 and (S)-4 colored red
and green, respectively (site occupancy: R 57%, S 43%). (b) 1ꢀ5.

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K. Megumi et al. / Tetrahedron Letters 54 (2013) 707–710
Figure 6. Crystal structures of inclusion cavities. For clarity, hydrogen atoms on carbon atoms other than
a-hydrogens and the methyl group hydrogens of 5 are omitted.
Hydrogen bonds and C–Hꢀ ꢀ ꢀO interactions are shown as solid lines and dotted lines, respectively. (a) 1ꢀ5. (b) 1ꢀ6. (c) 1ꢀ7.
data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK. Fax:
+44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2012.12.029.
References and notes
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P. M.; Wu, W.; Fenlon, E. E.; Kim, S.; Zimmerman, S. C. Bioorg. Med. Chem. Lett.
1996, 4, 1107–1112.
Figure 7. Four-location model for the recognition site of 1ꢀ5–1ꢀ7 (X = CH3, Cl, and
Br).
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ognition in the cavity, an additional C–Hꢀ ꢀ ꢀO interaction [labeled
(4) in Fig. 7] is important. The acidic a-hydrogen of 2-halobutana-
mides is small but acts as a preferable hydrogen bonding donor di-
rected to a carbonyl oxygen of 1. Thus, highly enatioselective
inclusion of 6 and 7 would be rationalized by the four-location
model.
In conclusion, we demonstrated enantiomeric separation using
a chiral N,N0-ditrityl amino amide host. We elucidated the struc-
ture of inclusion crystals and host–guest interactions based on
four-location model. We showed that a weak C–Hꢀ ꢀ ꢀO interaction
is important for high enantioselectivity of N-phenyl 2-halobutana-
mides. The development of new amino-acid-based chiral hosts
with trityl groups is under investigation.
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Supplementary data
14. (a) Kato, K.; Aoki, Y.; Sugahara, M.; Tohnai, N.; Sada, K.; Miyata, M. Chirality
2003, 15, 53–59; (b) Kato, K.; Aburaya, K.; Miyake, Y.; Sada, K.; Tohnai, N.;
Miyata, M. Chem. Commun. 2003, 2872–2873.
Crystallographic data for the structures in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication numbers CCDC 900257-900262. These