Kinetic resolution of primary amines via enantioselective N-acylation with acyl chlorides in the presence of supramolecular cyclodextrin nanocapsules

Article abstract of DOI:10.1016/j.tet.2013.11.097

The non-enzymatic kinetic resolution of primary amines via enantioselective N-acylation with acyl chlorides was accomplished for the first time by using the selective sequestration of one enantiomer within a supramolecular cyclodextrin (CD) nanocapsule in nonpolar solvents. In addition, the first example of a crystalline structure for an inclusion complex between an acyl chloride and a CD derivative is reported.

Full text of DOI:10.1016/j.tet.2013.11.097

Tetrahedron 70 (2014) 197e203
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Kinetic resolution of primary amines via enantioselective
N-acylation with acyl chlorides in the presence of supramolecular
cyclodextrin nanocapsules
*
Haruyasu Asahara, Toshiyuki Kida, Takuya Iwamoto, Tomoaki Hinoue, Mitsuru Akashi
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 October 2013
Received in revised form 26 November 2013
Accepted 27 November 2013
Available online 4 December 2013
The non-enzymatic kinetic resolution of primary amines via enantioselective N-acylation with acyl
chlorides was accomplished for the first time by using the selective sequestration of one enantiomer
within a supramolecular cyclodextrin (CD) nanocapsule in nonpolar solvents. In addition, the first ex-
ample of a crystalline structure for an inclusion complex between an acyl chloride and a CD derivative is
reported.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclodextrin
Kinetic resolution
Supramolecular nanocapsule
Acyl chloride
Inclusion complex
1. Introduction
nonpolar solvents.6 In particular, the KR of racemic 1-(1-naphthyl)
ethylamine (1-NEA) was achieved via enantioselective N-acylation
Enantiomerically pure amines and amides are ubiquitous sub-
structures in biologically active compounds, pharmaceuticals, and
chiral catalysts.1 The kinetic resolution (KR) of a racemic amine is
one of the most useful methods to access optically pure amines.
Since the first report by Fu’s group,2 a great deal of attention has
been paid to non-enzymatic acylation processes for the KR of ra-
cemic amines.2,3 In most cases, less reactive acylation reagents and
considerably lower temperatures were needed for the KR of amines
due to their high reactivity.
Supramolecular nanocapsules formed by the self-assembly of
molecular building blocks have attracted considerable attention due
to their ability to act as reaction vessels and confinement con-
tainers.4 Recently, Gibb et al. reported the KR of constitutional iso-
mers of long-chain esters utilizing a self-assembled supramolecular
nanocapsule as a means for selective protection.5 In this system, one
isomer was selectively encapsulated into the supramolecular
nanocapsule cavity, and thus its hydrolysis was remarkably inhibi-
ted. More recently, we reported the high chiral recognition and KRof
primary amines utilizing a supramolecular chiral nanocapsule as-
with benzoic anhydride in the presence of this supramolecular
chiral nanocapsule with an enantiomeric excess of up to 91%. This
result implies that the supramolecular cyclodextrin nanocapsule
can potentially function as a powerful tool for the KR of highly re-
active chemical species including primary amines. The application
of this supramolecular chiral nanocapsule to the KR of racemic
amines with commonly used acylation reagents, such as acyl chlo-
rides, will greatly increase its synthetic utility. In general, it has been
considered that the reactivity of acyl chlorides is too high to use as
acylation reagents in KR,7 although acyl chlorides are the most
useful acylation reagents from the viewpoints of accessibility and
reactivity. Herein, we report the first example of the KR of primary
amines through enantioselective N-acylation with acyl chlorides
utilizing the selective sequestration of one enantiomer within the
supramolecular CD nanocapsule.
2. Results and discussion
2.1. The formation of inclusion complexes between 6-O-
modified CDs and primary amines
sembled by 6-O-triisopropylsilylated b-cyclodextrin (TIPS-b-CD) in
Based on our recent finding,6 (R)- and (S)-1-(1-naphthyl)ethyl-
amine [(R)- and (S)-1], (R)- and (S)-1-(2-naphthyl)ethylamine [(R)-
and (S)-2], and (R)- and (S)-1-(1-phenyl)ethylamine [(R)- and (S)-3]
* Corresponding author. Tel.: þ81 6 6879 7356; fax: þ81 6 6879 7359; e-mail
address: akashi@chem.eng.osaka-u.ac.jp (M. Akashi).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.097

198
H. Asahara et al. / Tetrahedron 70 (2014) 197e203
(Fig. 1) were chosen as primary amine substrates. 6-O-tert-Butyldi-
methylsilylated -cyclodextrin (TBDMS- -CD) and TIPS- -CD (Fig. 1)
were used as components of supramolecular CD capsules. Table 1
chloride 4a in the presence of the supramolecular TIPS-b-CD
b
b
b
nanocapsule was examined. Similar to our recent study using acid
anhydride as an acylation reagent,6 cyclohexane was chosen as the
summarizes the association constants (K) between these 6-O-sily-
solvent, in which the supramolecular TIPS-
showed high chiral recognition towards 1 (Table 1, entry 1). A
mixture of primary amines 1e3, TIPS- -CD (5.0 equiv), and trie-
thylamine (1.0 equiv) in cyclohexane was stirred for 1 h to reach
complexation equilibrium. Then benzoyl chloride 4a (0.5 equiv) was
added at 10 ꢀC, and the mixture was stirred at 10 ꢀC for 6 h. Table 2
shows the conversion of 1e3, the enantiomeric excess (ee, %) of the
resulting N-benzoyl-(R)-amines, and the s-factor (s).8 The enantio-
selective N-acylation of 1 with 4a exceeded 77% ee (Table 2, entry 1).
As expected from the lower chiral recognition capability of the su-
b-CD nanocapsule
lated
and the chiral selectivity (KS/KR). In this study, we newly determined
the association constants between TBDMS- -CD and (R)- or (S)-1 and
between TIPS- -CD and (R)- or (S)-3 by an NMR titration method.
Shifts of the H3 and H5 proton signals of TBDMS- -CD upon the ad-
dition of (R)- or (S)-1 were observed in cyclohexane-d12 (Fig. S1,
Supplementary data), suggesting the formation of a TBDMS-
CDe(R)- or (S)-1 complex. Job plots using an NMR method showed
a maximum at a [TBDMS- -CD]/[(R)- or (S)-1] molar ratio of 2:1
(Fig. S5, Supplementary data), indicating that TBDMS- -CD formed
a 2:1 complex with (R)- or (S)-1. This result demonstrates that a su-
pramolecular dimer capsuleofTBDMS- -CD incorporates these chiral
guests inside the cavity. The chiral recognition ability of the supra-
molecular TBDMS- -CD nanocapsule towards 1 was lower than that
of the supramolecular nanocapsule derived from TIPS- -CD (Table 1,
entries 2 and 4), showingthata differenceinthesubstituentsontheSi
atom between TBDMS- -CD and TIPS- -CD has large effect on the
b-CDs and the chiral amines in benzene-d6 or cyclohexane-d12,
b
b
b
b
b-
b
b
pramolecular TIPS-b-CD nanocapsule towards 2 and 3 as compared
to 1 (Table 1), the reactions of these amines with 4a proceeded with
lower enantioselectivity (Table 2, entries 2 and 3). These results
confirm that the origin of the enantioselectivity in this reaction
system should be the selective sequestration of one isomer of the
amines within the supramolecular CD nanocapsule. The 1H NMR
spectra of the products showed that no reaction occurred between
b
b
b
b
b
the free OH group of TIPS-b
-CD and 4a under these conditions.9
chiral recognition in nonpolar solvents. On the other hand, when (R)-
or (S)-3 bearing a phenyl group was used as a guest, Job plots showed
Table 2
Enantioselective N-acylation of primary amines 1, 2, and 3 with benzoyl chloride 4a
the formation of
Supplementary data), in contrast to the complexes between TIPS-
CD and other chiral guests bearing a naphthyl group with 2:1 molar
ratios. Even when the supramolecular TIPS- -CD nanocapsule was
a 1:1 complex with TIPS-b-CD (Fig. S6,
in the presence of TIPS-
b
-CD in cyclohexane at 10 ꢀCa
b-
b
used, little chiral selectivity for 3 (KS/KR¼1.0) was observed. This re-
sult indicates that the presence of the supramolecular dimer capsule
plays a crucial role for the high chiral recognition.
Entry
Primary amine
Conv.b (%)
eeb (%)
s
1
2
3
1
2
3
44
44
45
77
11
2
14
1.3
1.0
a
N-acylation of 1, 2, and 3 (1.0 mM) was carried out with benzoyl chloride 4a in
nonpolar solvents (0.6 mL) at 10 ꢀC for 12 h in the presence of TIPS-
b-CD (5.0 equiv)
and triethylamine (1.0 equiv).
b
Conversion of 1, 2, and 3 and enantiomeric excess of N-benzoyl-(R)- amines
were determined by HPLC.
A larger scale reaction of racemic amine 1 (0.1 mmol) with 4a
(0.05 mmol) proceeded with the almost same conversion and se-
lectivity (conv.¼46%, ee¼76%, s¼14) as those of the above-
mentioned micromole scale reaction (Table 2, entry 1). This result
indicates that the enantioselective N-acylation of the primary
Fig. 1. Primary amines 1e3 and 6-O-silylated CDs used in this study.
Table 1
Association constants between 6-O-silylated b
-CD and (R)- or (S)-1, 2, and 3 in nonpolar solvents at 10 or 25 ꢀC
Entry
CDs
Solvent
T (ꢀC)
Association constant
Selectivity
KR
KS
KS/KR
(R)- or (S)-1/Mꢁ2
1a
TIPS-
TIPS-
TIPS-
b
b
b
-CD
-CD
-CD
Cyclohexane-d12
Cyclohexane-d12
Benzene-d6
10
25
25
25
(1.5ꢂ0.52)ꢃ106
(4.2ꢂ0.96)ꢃ106
(1.5ꢂ0.31)ꢃ106
(1.8ꢂ0.40)ꢃ105
(6.1ꢂ2.1)ꢃ109
(1.3ꢂ0.20)ꢃ108
(1.8ꢂ0.41)ꢃ107
(1.2ꢂ0.33)ꢃ106
41ꢂ13
31ꢂ6.1
12ꢂ2.6
6.1ꢂ1.6
2a
3a
4
TBDMS-
b-CD
Cyclohexane-d12
(R)- or (S)-2/Mꢁ2
5a
TIPS-
TIPS-
b
b
-CD
-CD
Cyclohexane-d12
Cyclohexane-d12
25
25
(1.2ꢂ0.12)ꢃ107
(2.2ꢂ0.49)ꢃ102
(2.7ꢂ0.18)ꢃ107
(2.3ꢂ0.40)ꢃ102
2.3ꢂ0.21
1.0 ꢂ0.22
(R)- or (S)-3/Mꢁ1
6
a
Ref. 6.
2.2. Enantioselective N-acylation of primary amines in the
presence of supramolecular 6-O-modified CDs nanocapsules
amines with acyl chlorides in the presence of the supramolecular
TIPS- -CD nanocapsule is little affected by the reaction scale.
b
Using 1 and 4a as an amine substrate and an acylation reagent,
respectively, we examined the effect of the reaction conditions, such
as the amount of CD, the solvent type, temperature, and the CD type,
On the basis of the results mentioned in Section 2.1, the enan-
tioselective N-acylation of racemic amines 1e3 with benzoyl

H. Asahara et al. / Tetrahedron 70 (2014) 197e203
199
on the enantioselective N-acylation (Table 3). Decreasing the molar
ratio of 4a to 1 in the presence of 5.0 equiv of TIPS- -CD increased the
enantioselectivity (Table 3, entries 2e4). Inparticular, the N-acylation
of 1 with 0.1 equiv of 4a in the presence of 5.0 equiv of TIPS- -CD
proceeded with the highest enantioselectivity and s-factor (90% ee,
s¼20). A decrease in the amount of TIPS- -CD from 5.0 to 1.0 equiv
largely decreased the enantioselectivity (Table 3, entries 4 and 5),
suggesting that the presence of the dimer capsule of TIPS- -CD is
with higher enantioselectivity. On the other hand, when acetyl
chloride, which bears a less bulky methyl group, was used, the
enantioselectivity decreased (Table 4, entry 2). In the reaction of 1
with 1-naphthoyl chloride 4i, the conversion was low but with
good enantioselectivity. In sharp contrast to these cases, the re-
action of 1 with 2,4,6-trimethylbenzoyl chloride 4j did not proceed
under these conditions (Table 4, entry 10), possibly due to the large
steric bulkiness of 4j. These results clearly show that the use of acyl
chloride with an appropriately bulky substituent is required for the
N-acylation of 1 with high enantioselectivity.
b
b
b
b
essential to the high enantioselectivity. When benzene was used as
a solvent, the ee decreased to 54% (Table 3, entry 6). This decrease can
be explained by a decrease in the chiral recognition capability of the
supramolecular TIPS-
b
-CD nanocapsule towards 1 with the change in
2.3. The formation of inclusion complexes between TIPS-
CDs and acyl chlorides
b-
solvent from cyclohexane to benzene (Table 1, entries 1 and 3). An
increase in the reaction temperature to 25 ꢀC lowered the enantio-
selectivity (Table 3, entry 8), possibly due to a decrease in the chiral
selectivity of the supramolecular nanocapsule towards 1 (Table 1,
entry 2). When TBDMS-
pramolecular nanocapsule instead of TIPS-
tioselectivity was obtained (Table 3, entry 7). These results clearly
show that the key step in the enantioselective N-acylation is the se-
lective inclusion of(S)-1 over(R)-1 withinthe supramolecularcapsule
cavity. Interestingly, there was no significant difference in the enan-
tioselectivity and s-factor (s) for the enantioselective N-acylation of 1
Interestingly, it was found that TIPS-b-CD formed inclusion
complexes with adamantoyl chloride 4g, 2,4-dichlorobenzoyl
chloride 4h, and 1-naphthoyl chloride 4i in cyclohexane-d12 by
NMR studies (Fig. 2 and Figs. S3 and S4, Supplementary data). Job
plots using the NMR method (Figs. S7e9, Supplementary data)
b-CD was used as the component of the su-
b-CD, much lower enan-
showed a maximum at a [TIPS-
b-CD]/[4gei] molar ratio of 2:1 in
cyclohexane-d12, clearly indicating that TIPS-
b
-CD formed a 2:1
complex with 4gei. The association constants (K) between TIPS-b-
CD and 4gei, which were estimated from the 1H NMR spectral
in the presence of TIPS-b-CD between benzoyl chloride 4a and ben-
changes upon the addition of the acyl chlorides, were shown in
zoic anhydride (conv.¼7%, ee¼91%, s¼23; conv.¼49%, ee¼75, s¼15),6
suggesting that the supramolecular CD nanocapsule can be applied to
the KR of primary amines with not only acid anhydride, but also with
more reactive acyl chlorides.7 To the best of our knowledge, this is the
first report of the enantioselective N-acylation of a primary amine
with acyl chloride as an acylation reagent.
Table 4. TIPS-
than towards 4g and 4h in cyclohexane-d12 (Table 4, entries 7e9),
possibly due to a better spatial fit of 4i within the cavity of TIPS-
CD dimer. These results show that the supramolecular TIPS- -CD
nanocapsule incorporates 4i within the cavity more stably, result-
ing in the large inhibition of the N-acylation of 1.
b-CD showed higher inclusion capability towards 4i
b
-
b
Crystals of the inclusion complex between the TIPS-b-CD su-
pramolecular nanocapsule and 4i were obtained from the cyclo-
hexane solution. The X-ray crystalline structure showed that the 4i
Table 3
Enantioselective N-acylation of 1 with benzoyl chloride 4a in the presence and
molecule was included within the cavity of the TIPS-
a similar fashion to a TIPS-
-CDe(S)-1-(1-naphthyl)ethylamine6 or
TIPS-
-CDepyrene10 complex previously reported (Fig. 3). In-
b-CD dimer in
absence of 6-O-silylated-b
-CD in nonpolar solventsa
b
b
terestingly, both the carbonyl oxygen and chlorine atoms of the 1-
naphthoyl chloride molecule formed hydrogen bonds with the 3-
OH group of the upper and lower TIPS-
O/O and Cl/O distances are 2.68 and 3.14 A, respectively).
The CH/ interaction between the CeH group of cyclohexane
and the naphthalene ring of 4i appears to contribute somewhat to
the stabilization of the naphthalene moiety of 4i within the TIPS-
CD dimer cavity.11 These observations indicate that the combina-
tion of hydrogen bonds between 4i and TIPS- -CD and the CH/
interaction between 4i and cyclohexane inside the cavity plays
a key role in forming a stable inclusion complex between them. To
the best of our knowledge, this is the first example of a crystalline
structure for an inclusion complex between a cyclodextrin de-
rivative and an acyl chloride.12
b-CDs, respectively (the
ꢀ
Entry
CDs
4a (mM)
Solvent
Conv. (%)
eeb (%)
s
p
1
2
3
4
5
6
7
8
9
d
0.50
0.10
0.40
0.50
0.50
0.50
0.50
0.50
0.50
c-C6H12
c-C6H12
c-C6H12
c-C6H12
c-C6H12
C6H6
c-C6H12
c-C6H12
c-C6H12
47
7
d
d
20
17
14
4
TIPS-
TIPS-
TIPS-
TIPS-
TIPS-
TBDMS-
TIPS-
TIPS-
b
b
b
b
b
-CD
-CD
-CD
-CDc
-CD
90
84
77
45
54
21
66
71
b
-
33
44
47
48
48
41
40
b
p
6
2
8
9
b
-CD
b
b
-CDd
-CDe
a
N-acylation of 1 (1.0 mM) was carried out with benzoyl chloride 4a in nonpolar
solvents (0.6 mL) at 10 ꢀC for 6 h in the presence of CDs (5.0 equiv to 1) and trie-
thylamine (1.0 equiv).
b
Conversion of 1 and enantiomeric excess of (R)-5a were determined by HPLC.
TIPS-b-CD (1.0 equiv) was used.
At 25 ꢀC.
3. Conclusion
c
d
e
In conclusion, we have demonstrated that the non-enzymatic
kinetic resolution of primary amines via enantioselective N-acyla-
tion with acyl chlorides can be realized by using the selective se-
questration of one enantiomer within the supramolecular CD
nanocapsule in nonpolar solvents. In particular, the kinetic reso-
lution of racemic 1-(1-naphthyl)ethylamine via enantioselective N-
acylation with benzoyl chloride in the presence of a supramolecular
In the absence of NEt3.
We also examined the enantioselective N-acylation of 1 with
a variety of acyl chlorides 4bej in the presence of the supramo-
lecular TIPS- -CD nanocapsule (Table 4). The N-acylation of 1 was
carried out with acyl chloride (0.5 equiv) in cyclohexane at 10 ꢀC for
5 h in the presence of TIPS- -CD (5.0 equiv) and triethylamine
b
b
TIPS-b-CD nanocapsule proceeded with high enantioselectivity and
(1.0 equiv). Most of the acyl chlorides examined here afforded the
corresponding amide with moderate to good enantioselectivities.
In particular, acyl chlorides bearing a phenyl (Table 4, entry 1),
hexyl (Table 4, entry 5), cyclohexyl (Table 4, entry 6), and 1-
adamantyl group (Table 4, entry 7) gave N-acylation products
s-factor (90% ee, s¼20). Furthermore, we reported the first example
of a crystal structure for an inclusion complex between an acyl
chloride and a CD derivative. Further studies on the applications of
6-O-modified CDs as a supramolecular nanocapsule are now in
progress at our laboratory.

200
H. Asahara et al. / Tetrahedron 70 (2014) 197e203
Table 4
Enantioselective N-acylation of 1 with acyl chlorides 4aej in the presence of TIPS-b-CD and association constants (K) between TIPS-b
-CD and 4aej in cyclohexanea,b
Entry
1
Acyl chlorides
Product 5
s
Kb (Mꢁ2
w0
)
Conv.c (%)
44
eec (%)
77
5a
14
2d
3e
5a
5b
46
45
76
58
14
6
df
df
w0
df
4
5
6
5c
5d
5e
42
46
43
64
65
74
7
8
12
7
8
5f
45
41
75
75
13
12
w0
5g
(7.0ꢂ2.5)ꢃ10
(1.3ꢂ0.2)ꢃ10
9
5h
5i
50
15
70
65
12
5
10
(2.7ꢂ0.3)ꢃ106
11
5j
n.d.
d
d
df
a
N-acylation of 1 (1.0 mM) was carried out with acyl chlorides 4aej in cyclohexane (0.6 mL) at 10 ꢀC for 5 h in the presence of TIPS-
b-CD (5.0 equiv) and triethylamine
(1.0 equiv).
b
c
Determined by NMR titration in cyclohexane-d12 at 25 ꢀC.
Conversion of 1 and enantiomeric excess of (R)-5aei were determined by HPLC.
d
N-acylation of 1 (0.1 mmol) was carried out with benzoyl chloride 4a in cyclohexane (100 mL)at 10 ꢀC for 12 h in the presence of TIPS-
b-CD (5.0 equiv, 1.1 g) and
triethylamine (1.0 equiv).
e
Acid chlorides (0.6 mM) were used.
The shift of proton signals of TIPS-b-CD was not observed.
f
4. Experimental section
1.0 mM) was titrated in an NMR tube with increasing amounts of
the guest stock solution. The titration curves (changes in the
chemical shift of the host protons (Dd) against the guest/host
concentration ratio) were analyzed by a non-linear least-squares
curve fitting method to generate association constants (K) for the
4.1. Determination of association constants by NMR
spectroscopy
In the complexation of a heptakis(6-O-triisopropylsilyl)-
b
-cy-
hosteguest complexes. In the complexation of TIPS-b-CD (host)
clodextrin (TIPS-
thylsilyl)- -cyclodextrin (TBDMS-
cyclohexane-d12 at 25 ꢀC, a solution of the host molecule (600
b
-CD) host or a heptakis(6-O-tert-butyldime-
-CD) host with 1, 3, and 4gei in
L,
with 4i (guest) in cyclohexane-d12 at 25 ꢀC, the exchange of com-
plexed and uncomplexed hosts was slow on the NMR time scale.
Thus, the association constant (K) was determined by the
b
b
m

H. Asahara et al. / Tetrahedron 70 (2014) 197e203
201
4.2. Experimental procedure for Job plots
In the complexation of TIPS- -CD or TBDMS-
b
b-CD (host) with
each guest in cyclohexane-d12, Job plots were made by monitoring
the changes in the chemical shift of the host protons (Dd) in a series
of solutions with varying host/guest ratios, but with the total
concentration of the host and guest kept constant (2.0 or 0.8 mM).
The relative concentration of the host-guest complex estimated
from the Dd$[host] value was then plotted against ([host]/{[host]þ
[guest]}).
4.3. Enantioselective N-acylation of primary amines
The N-acylation of racemic 1, 2, and 3 was carried out with acyl
chlorides as acylation reagents and triethylamine as the base in
Fig. 2. 1H NMR spectral changes observed for TIPS-
b
-CD (1.0ꢃ10ꢁ3 M) upon the ad-
dition of 1-naphthoyl chloride 4i in cyclohexane-d12 at 25 ꢀC. Green circles denote
cyclohexane in the presence and absence of TIPS-b-CD. After
newly appeared signals.
a mixture of racemic 1, 2, and 3 (6.0ꢃ10ꢁ4 mmol) and 6-O-silylated
b
-CD was stirred for 1 h in cyclohexane (600 mL) to reach the
complexation equilibrium between 1, 2, and 3 and 6-O-silylated b-
CD, triethylamine (6.0ꢃ10ꢁ4 mmol), the acyl chlorides 4aej were
added at 10 ꢀC. The mixture was then stirred at 10 ꢀC for 6 h. The
resulting products were analyzed by HPLC using the chiral phase
column Diacel Chiralcel OD-H (250 mmꢃ4.6 mm i.d.) using hexane/
2-propanol¼80:20 or 95:5 as an eluent at a flow rate of 0.5 or
1.5 mL minꢁ1 using UV detection (254 nm). The HPLC charts of the
products obtained after N-acylation of 1, 2, and 3 (6.0ꢃ10ꢁ4 mmol)
with acyl chlorides 4aej (3.3ꢃ10ꢁ4 mmol) in cyclohexane (600
mL)
including triethylamine (6.0ꢃ10ꢁ4 mmol) in the absence and
presence of TIPS-
b
-CD (3.0ꢃ10ꢁ3 mmol) are shown in Figs. S18e26,
respectively.
4.4. Analytics
Fig. 3. Crystal structure of the TIPS-b-CDe4i inclusion complex. (a) Side view: TIPS-b-
CD is shown with a cylinder representation, whereas 4i and cyclohexane are shown
with space-filling representations. The hydrogen atoms in all compounds are omitted
1H and 13C NMR spectra were recorded on a JEOL NMR system
(400 MHz) in DMSO-d6 and the chemical shifts in parts per million
(ppm) refer to DMSO (dH 2.50, dC 39.52) as an internal standard. The
following abbreviations were used for chemical shift multiplicities:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet. NMR
signal assignments were based on additional 2D-NMR spectroscopy
(e.g., COSY, NOESY, HSQC, and HMBC). Infrared (IR) spectra were
obtained with a Spectrum 100FT-IR spectrometer (Perkin Elmer).
Melting points were determined on a Stanford Research Systems
MPA100 OptiMelt Automated Melting Point System and are un-
corrected. High-resolution mass spectra were obtained on a JEOL
JMS-DX303HF mass spectrometer.
for clarity. (b) Top view: TIPS-
and cyclohexane are shown with ball-and-stick representations. Colour labels: grey,
carbon in TIPS- -CD; cyan, silicon; red, oxygen; green, chloride in 4i; yellow, naph-
thalene ring and carbon in 4i; violet, cyclohexane molecules interacting with 4i; pink,
cyclohexane molecules incorporated near the C-6 position of TIPS- -CD; white dotted
line, hydrogen bonds between a carbonyl oxygen of 4i and the 3-OH group of TIPS-
CD and between the chloride of 4i and the 3-OH group of TIPS- -CD. Assuming that the
-CD nanocapsule is an ellipsoid, the cavity
b-CD is shown with a cylinder representation, whereas 4i
b
b
b-
b
cavity shape of the supramolecular TIPS-
b
volume is estimated to be 0.58 nm3 (Fig. S27).
integration of the NMR signals for complexed and uncomplexed
hosts.
4.5. Crystal structure determination
For a 2:1 hosteguest complex, the following expression can be
written:
X-ray diffraction data were collected on a Rigaku R-AXIS RAPID
diffractometer with
monochromatized Cu K
(SIR-2002) were then used to solve for the structure.13 All calcu-
a
a
2D area detector using graphite-
2 host þ guest%ðhostÞ2$ðguestÞ
ꢀ
radiation (
l¼1.54178 A). Direct methods
The association constant is given by Eq. 1
Â
Ãꢀ
lations were performed with the observed reflections [I>2s(I)]
K ¼ ðhostÞ2$ðguestÞ ½hostꢄ2½guestꢄ
(1)
using the CrystalStructure crystallographic software package,14
except for refinements, which were performed using SHELXL-
97.15 Non-hydrogen atoms were refined with anisotropic dis-
placement parameters, except for the carbon atoms of the triiso-
propylsilyl groups and cyclohexane molecules placed around the
where [host], [guest], and [(host)2$(guest)] are equilibrium
concentrations.
On the other hand, for a 1:1 hosteguest complex, the following
expression can be written:
rim of TIPS-b-CD, which were refined isotropically owing to their
high thermal parameters. About half of the triisopropylsilyl groups
were clearly disordered over two or more positions, which were
refined as disordered groups. Hydrogen atoms were placed in their
idealized positions and refined as rigid atoms with the relative
isotropic displacement parameters. Although the gaps between the
host þ guest%host$guest
The association constant is given by Eq. 2
K ¼ ½host$guestꢄ=½hostꢄ½guestꢄ
(2)
where [host], [guest], and [host$guest] are equilibrium
TIPS-b-CD supramolecular dimers in the structure must be occu-
concentrations.
pied by cyclohexane molecules, they were all of highly disordered

202
H. Asahara et al. / Tetrahedron 70 (2014) 197e203
with no possibility of refining them reasonably. To improve their
refinement, they were removed using the SQUEEZE routine
implemented in the PLATON software package.16 Crystallographic
data for the structure reported in this paper have been deposited
with the Cambridge Crystallographic Data Center as supplementary
1678.8 (C]O). HRMS (EI) m/z calcd for C19H15Cl2NO: 343.0531,
found 343.0534.
4.6.6. (ꢂ)-N-(1-(Naphthalen-1-yl)ethyl)-1-naphthamide 5i. White
powder, mp 177e178 ꢀC (from hexane/chloroform). 1H NMR
publication no.CCDC-953149 (TIPS-
b
-CDe4i inclusion complex).
(CDCl3)
d
1.86 (d, J¼6.4 Hz, 3H), 6.23 (br, 1H), 6.26 (q, J¼6.4 Hz, 1H),
Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223 336
033; e-mail: deposit@ccdc.cam.ac.uk).
7.38 (dd, J¼7.3, 7.7 Hz, 1H), 7.45e7.56 (m, 5H), 7.40e7.49 (m, 5H),
7.57e7.65 (m, 2H), 7.82e7.91 (m, 4H), 8.31e8.36 (m, 2H). 13C NMR
(CDCl3)
d 20.8, 45.3, 122.8, 123.7, 124.8, 124.9, 125.3, 125.5, 126.2,
126.6, 126.9, 127.3, 128.4, 128.7, 129.0, 130.3, 130.7, 131.4, 133.8,
4.6. Analytical data of the products
134.2, 134.6, 138.1, 168.6. IR: 1615.2 (C]O). HRMS (EI) m/z calcd for
C23H19NO: 325.1467, found 325.1464.
The spectral data for known compounds, N-benzoyl-1 (¼5a), 5b,
5c, N-benzoyl-2, and N-benzoyl-3, were found to be identical to
those described in the literature [N-benzoyl-1, 2, and 3,17 5b,18
5c19]. Compounds 5dei (racemic mixtures) described below were
synthesized for the analysis by N-acylation of rac-1 with the cor-
Acknowledgements
This work was supported by the Funding Program for Next
Generation World-Leading Researchers (GR067).
responding acyl chlorides in the absence of TIPS-b-CD.
Supplementary data
4.6.1. (ꢂ)-N-(1-(Naphthalen-1-yl)ethyl)pivalamide 5d. White pow-
der, mp 143e144 ꢀC (from hexane/chloroform). 1H NMR (CDCl3)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.097.
d
1.23 (s, 9H), 1.58 (d, J¼6.3 Hz, 3H), 3.41 (br, 1H), 5.00 (q, J¼6.3 Hz,
1H), 7.46e7.56 (m, 3H), 7.63 (d, J¼7.3 Hz, 1H), 7.76 (d, J¼8.2 Hz, 1H),
7.88 (d, J¼8.2 Hz, 1H), 8.13 (d, J¼8.6 Hz, 1H). 13C NMR (CDCl3)
d 24.8,
References and notes
27.6, 39.0, 46.8, 121.8, 123.3, 126.0, 126.1, 126.6, 127.9, 129.5, 131.1,
134.4, 168.6. IR: 1613.6 (C]O). HRMS (EI) m/z calcd for C17H21NO:
255.1623, found 255.1625.
1. For selected reviews, see: (a) North, M. J. Chem. Soc., Perkin Trans. 1 1998,
2959e2972; (b) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002,
344, 1037e1057; (c) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.;
Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788e824; (d) Enantio-
selective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, Germany,
2007; (e) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753e819; (f)
Chiral Amine Synthesis: Methods, Development and Applications; Nugent, T. C.,
Ed.; Wiley-VCH: Weinheim, Germany, 2010.
4.6.2. (ꢂ)-N-(1-(Naphthalen-1-yl)ethyl)octanamide
5e. White
powder, mp 94e95 ꢀC (from hexane/chloroform). 1H NMR (CDCl3)
d
0.83e0.88 (t, J¼6.8, Hz, 3H), 1.19e1.31 (m, 8H), 1.59e1.63 (m, 2H),
1.67 (d, J¼6.8 Hz, 3H), 2.09e2.18 (m, 2H), 5.69 (br, 1H), 5.94 (dq,
J¼6.8, 7.2 Hz, 1H), 7.43e7.56 (m, 4H), 7.80 (d, J¼8.2 Hz, 1H), 7.87 (d,
2. Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001, 40,
234e236.
J¼7.7 Hz, 1H), 8.09 (d, J¼8.2 Hz, 1H). 13C NMR (CDCl3)
d
14.2, 20.7,
3. For recent reviews, see: (a) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613e1666;
(b) Krasnov, P. V.; Gruzdev, A. D.; Levit, L. G. Eur. J. Org. Chem. 2012, 1471e1493;
For examples of non-enzymatic KR of primary amines, see: (c) Arnold, K.;
22.7, 25.9, 29.1, 29.3, 31.8, 37.0, 44.5, 122.7, 123.7, 125.3, 126.0, 126.7,
128.5, 128.9, 131.3, 134.0, 138.4, 172.1. IR: 1625.7 (C]O). HRMS (EI)
m/z calcd for C20H27NO: 297.2093, found 297.2097.
ꢁ
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J. Am. Chem. Soc. 2011, 133, 2848e2851.
4.6.3. (ꢂ)-N-(1-(Naphthalen-1-yl)ethyl)cyclohexanecarboxamide
5f. White powder, mp 161 ꢀC (from hexane/chloroform). 1H NMR
(CDCl3)
d 1.18e1.21 (m, 3H), 1.39e1.46 (m, 2H), 1.63e1.67 (m, 4H),
1.70e1.81 (m, 3H), 1.85 (d, J¼11.9 Hz, 1H), 2.03 (dd, J¼8.2, 8.2 Hz,
1 H) 5.63 (m, 1H), 5.90 (q, J¼8.6 Hz, 1H), 7.41e7.55 (m, 4H),
7.78e7.81 (m, 1H), 7.84e7.87 (m, 1H), 8.04e8.07 (m, 1H). 13C
NMR (CDCl3)
d 20.7, 25.8, 29.7, 29.9, 44.4, 45.8, 122.6, 123.8,
125.3, 126.0, 126.6, 128.5, 128.9, 131.4, 134.1, 138.5, 175.0. IR:
1625.9 (C]O)HRMS (EI) m/z calcd for C19H23NO: 281.1780, found
281.1782.
5. Liu, S.; Gan, H.; Hermann, A. T.; Rick, S. W.; Gibb, B. C. Nat. Chem. 2010, 2, 847e852.
6. Kida, T.; Iwamoto, T.; Asahara, H.; Hinoue, T.; Akashi, M. J. Am. Chem. Soc. 2013,
135, 3371e3374.
7. The kinetics of the reactions of benzoyl chloride with amines and the elec-
trophilicities of the benzoyl chloride were reported by Mayr et al., see: Nigst, T.
A.; Mayr, H. Eur. J. Org. Chem. 2013, 2155e2163.
4.6.4. (ꢂ)-(3r,5r,7r)-N-(1-(Naphthalen-1-yl)ethyl)adamantane-1-
carboxamide 5g. White powder, mp 187e188 ꢀC (from hexane/
chloroform). 1H NMR (CDCl3)
d
1.64 (d, J¼6.9 Hz, 3H), 1.63e1.73 (m,
6H), 1.82e1.83 (m, 6H), 1.99e2.11 (m, 3H), 5.78 (d, J¼7.3 Hz, 1H),
8. The s factor is defined as s¼(rate of the faster-reacting enantiomer)/(rate of the
5.91 (dq, J¼6.9, 7.3 Hz,1H), 7.43e7.55 (m, 4H), 7.79 (d, J¼8.2 Hz,1H),
slower-reacting enantiomer). Values of
s were calculated using Kagan’s
7.87 (d, J¼7.8 Hz, 1H), 8.04 (d, J¼8.2 Hz, 1H). 13C NMR (CDCl3)
d 20.8,
method. See: Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249e330.
9. Acylation of 2- or 3-OH groups of 6-O-silylated CDs with acyl chlorides needs
the heating condition and long reaction time to be performed, example see:
Zhang, P.; Ling, C.-C.; Coleman, A. W.; Parrot-Lopez, H.; Galons, H. Tetrahedron
Lett. 1991, 32, 2769e2770.
28.2, 36.6, 39.3, 40.7, 44.4, 122.6, 123.8, 125.3, 126.0, 126.6, 128.5,
128.8, 131.4, 134.1, 138.7, 176.9. IR: 1648.2 (C]O). HRMS (EI) m/z
calcd for C23H27NO: 333.2093, found 332.2095.
10. Kida, T.; Iwamoto, T.; Fujino, Y.; Tohnai, N.; Miyata, M.; Akashi, M. Org. Lett.
2011, 13, 4570e4573.
11. In the crystal structure of the TIPS-b-CDe4i inclusion complex, the CH/p in-
4.6.5. (ꢂ)-2,4-Dichloro-N-(1-(naphthalen-1-yl)ethyl)benzamide
5h. White powder, mp 153e154 ꢀC (from hexane/chloroform). 1H
teractions between three CeH groups of cyclohexanes and the naphthalene ring of
4i were observed, and the distances between these cyclohexane carbons and the
NMR (CDCl3)
d
1.69 (d, J¼6.8 Hz, 3H), 5.95e6.04 (m, 1H), 6.41 (br,
ꢀ
naphthalene ring of 4i are 3.50, 3.56, and 3.67 A, respectively. For references on CH/
1H), 7.11e7.19 (m, 1H), 7.33e7.38 (m, 1H), 7.40e7.49 (m, 5H), 7.71 (d,
J¼8.2 Hz, 1H), 7.78 (d, J¼8.2 Hz, 1H), 8.09 (d, J¼8.2 Hz, 1H). 13C NMR
p
interactions, see: (a) Takahashi, O.; Kohno, Y.; Iwasaki, S.; Saito, K.; Iwaoka, M.;
Tomoda, S.; Umezawa, Y.; Tsuboyama, S.; Nishio, M. Bull. Chem. Soc. Jpn. 2001, 74,
2421e2430; (b) Desiraju, G. R. Acc. Chem. Res. 2002, 35, 565e573; (c) Tsuzuki, S.
Annu. Rep. Prog. Chem., Sect. C: Phys. Chem. 2012, 108, 69e95.
(CDCl3)
d 20.7, 45.8, 122.9, 123.6, 125.3, 126.1, 126.7, 127.5, 128.7,
129.0, 130.1, 131.1, 131.2, 131.7, 133.6, 134.1, 136.8, 137.7, 164.6. IR:

H. Asahara et al. / Tetrahedron 70 (2014) 197e203
203
12. One example of the inclusion complex between CD and acyl chloride (valeryl
chloride) has been reported, but there is no spectroscopic evidence for the
formation of this complex, see: Glazyrin, A. E.; Syrtsev, A. N.; Kurochkina, G. I.;
14. Crystal Structure 4.0: Crystal Structure Analysis Package; Rigaku: Tokyo, Japan,
2000e2010.
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Kononov, L. O.; Grachev, M. K.; Nifantev, E. E. Russ. Chem. Bull. 2003, 52,
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