Naphthyl groups in chiral recognition: Structures of salts and esters of 2-methoxy-2-naphthylpropanoic acids

Article abstract of DOI:10.1002/asia.201200345

The crystal structures of salt 8, which was prepared from (R)-2-methoxy-2-(2-naphthyl)propanoic acid ((R)-MβNP acid, (R)-2) and (R)-1-phenylethylamine ((R)-PEA, (R)-6), and salt 9, which was prepared from (R)-2-methoxy-2-(1-naphthyl)propanoic acid ((R)-MαNP acid, (R)-1) and (R)-1-(p-tolyl)ethylamine ((R)-TEA, (R)-7), were determined by X-ray crystallography. The MβNP and MαNP anions formed ion-pairs with the PEA and TEA cations, respectively, through a methoxy-group-assisted salt bridge and aromatic CH...π interactions. The networks of salt bridges formed 2₁ columns in both salts. Finally, (S)-(2E,6E)-(1-²H ₁)farnesol ((S)-13) was prepared from the reaction of (2E,6E)-farnesal (11) with deuterated (R)-BINAL-H (i.e., (R)-BINAL-D). The enantiomeric excess of compound (S)-13 was determined by NMR analysis of (S)-MαNP ester 14. The solution-state structures of MαNP esters that were prepared from primary alcohols were also elucidated. Princess and the PEA: The crystal structures of the MαNP and MβNP salts were determined by X-ray crystallography. The 1-naphthyl group of the MαNP anion and the 2-naphthyl group of the MβNP anion acted as a C-H donor and -acceptor, respectively. Copyright

Full text of DOI:10.1002/asia.201200345

DOI: 10.1002/asia.201200345
Naphthyl Groups in Chiral Recognition: Structures of Salts and Esters of 2-
Methoxy-2-naphthylpropanoic Acids
Akio Ichikawa,*[a] Hiroshi Ono,[b] and Yuji Mikata[c]
Abstract: The crystal structures of salt
8, which was prepared from (R)-2-me-
formed ion-pairs with the PEA and
TEA cations, respectively, through
a methoxy-group-assisted salt bridge
and aromatic CH···p interactions. The
networks of salt bridges formed 21 col-
umns in both salts. Finally, (S)-(2E,6E)-
(1-2H1)farnesol ((S)-13) was prepared
from the reaction of (2E,6E)-farnesal
(11) with deuterated (R)-BINAL-H
(i.e., (R)-BINAL-D. The enantiomeric
excess of compound (S)-13 was deter-
mined by NMR analysis of (S)-MaNP
ester 14. The solution-state structures
of MaNP esters that were prepared
from primary alcohols were also eluci-
dated.
thoxy-2-(2-naphthyl)propanoic
acid
((R)-MbNP acid, (R)-2) and (R)-1-phe-
nylethylamine ((R)-PEA, (R)-6), and
salt 9, which was prepared from (R)-2-
methoxy-2-(1-naphthyl)propanoic acid
((R)-MaNP acid, (R)-1) and (R)-1-(p-
tolyl)ethylamine ((R)-TEA, (R)-7),
were determined by X-ray crystallogra-
phy. The MbNP and MaNP anions
Keywords: chirality
·
conforma-
tional analysis · crystal engineering ·
molecular recognition · pi interac-
tions
Introduction
Recent studies have shown a high degree of crystallinity
in acids 1–3 and their derivatives.[3,4,10,14–16] Therefore, these
compounds are expected to be useful in the preparation of
crystalline diastereomeric salts.
In 2003, it was estimated that more than half of the chiral
pharmaceuticals on the market were produced by the crys-
2-Aryl-2-methoxypropanoic acids 1–3 possess unracemizable
chiral centers and polycyclic aromatic groups (Figure 1).[1,2]
Therefore, these acids are attractive for the development of
new methods for the preparation and structural elucidation
of single-enantiomers.[1–13] We have previously reported the
synthesis of acids 1–3[10,12,13] and applied them as agents for
the enantioresolution of biofunctional molecules.[6–8] Acids
1–3 exhibited powerful chiral-resolving ability in the HPLC
separation of their diastereomeric esters and amides. Acids
1 and 3 exhibited large shielding effects during the acquisi-
tion of NMR spectra. Acids 1 and 3 showed similar chiral-
resolving ability,[8] which was superior to that of 3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoic acid (MTPA, 4).[7]
However, many properties of acid 2 have not yet been fully
clarified.
[a] Dr. A. Ichikawa
Division of Insect Sciences
National Institute of Agrobiological Sciences
Tsukuba, Ibaraki 305-8634 (Japan)
Fax : (+81)29-838-6028
E-mail: ichikawa@affrc.go.jp
[b] Dr. H. Ono
Analytical Science Division
National Food Research Institute
Tsukuba, Ibaraki 305-8642 (Japan)
[c] Dr. Y. Mikata
KYOUSEI Science Center for Life and Nature
Nara Womenꢀs University
Nara, Nara 630-8506 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200345.
Figure 1. Structures of chiral resolving agents and their derivatives.
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
&
&
&
These are not the final page numbers! ÞÞ

FULL PAPER
tallization of diastereomeric salts.[17] The use of diastereo-
meric-salt formation to separate enantiomers[18–21] does not
require heavy metals and removes impurities. This method
has been used with mandelic acid (5) as a chiral resolving
agent for the preparation of single enantiomers that contain
amino group.[22,23] Crystal engineering[24–27] of these salts is
also important for elucidating stereochemistry because X-
ray crystallography is the most reliable method aside from
synthesis.
In 1978, Goto et al. prepared acids (R)-(ꢀ)-1 and (R)-
(ꢀ)-2 by the formation of diastereomeric salts with (R)-6.[28]
Recently, we determined the crystal structures of diastereo-
meric MaNP salts (R)-1·(R)-6 and (S)-1·(R)-6 (Fig-
ure 2a,b).[14] The mechanism for chiral recognition in these
ysis of the less-soluble MbNP salt (8), which consisted of
(R)-2 and (R)-6 (Figure 2c). However, the conformational
features of the MbNP anion differed significantly from
those of the MaNP anion. In addition, the crystal structure
of salt 9, which was prepared from (R)-1 and (R)-7, was elu-
cidated by X-ray crystallography (Figure 2d). The distance
between the 1-naphthyl- and p-tolyl groups in salt 9 was
shorter than the distance between the 1-naphthyl- and
phenyl groups in salt (R)-1·(R)-6. This result suggests that
crystalline MaNP salts are useful for identifying substituent
effects on aromatic CH···p interactions. The crystal packing
of salts 8 and 9 were also elucidated.
Many molecules contain multiple CH groups and p orbi-
tals; moreover, interactions between these groups are impor-
tant in supramolecular chemistry, in determining the stereo-
selectivity of reactions, and in the specificity of biomacro-
molecules.[29–31] Individual CH···p interactions are weak but
become significant when multiple interactions act coopera-
tively. Furthermore, it has been reported that CH···p inter-
actions function even in relatively remote positions.[32] The
T-shaped interactions of aromatic groups are known as aro-
matic CH···p interactions.[21,29–31]
Recently, Suzuki et al. reported that CH···p interactions,
a hydrogen bond, and van der Waals interactions are impor-
tant for the binding of juvenile hormones to their carrier
protein.[33] Therefore, understanding the properties of weak
interactions in crystalline salts is valuable for the rational
design of agrochemicals.
In 2009, Mayoral et al. characterized an insect farnesol de-
hydrogenase (AaSDR-1), which oxidizes (2E,6E)-farnesol
(10) into (2E,6E)-farnesal (11, Scheme 1), a biosynthetic in-
termediate of juvenile hormone in the corpora allata of
mosquito Aedes aegypti.[34] They noted that AaSDR-1 is
a rate-limiting enzyme in juvenile hormone biosynthesis.
Yeast alcohol dehydrogenase converts (S)-(1-2H1)ethanol
into (1-2H)acetoaldehyde in the presence of nicotinamide
adenine dinucleotide (NAD+), a coenzyme.[35] However, to
the best of our knowledge, the stereoselectivity of AaSDR-
1 and its orthologues have not yet been identified.
Figure 2. Crystal structures of MaNP and MbNP salts. [a] See refer-
ence [14].
In 1984, Noyori et al. reported the preparation of (R)-13
from (2E,6E)-(1-2H)farnesal (12) by using binaphthol-modi-
fied lithium aluminum hydride agent (R)-BINAL-H (see the
Supporting Information, Scheme 2).[36,37]
MaNP salts was as follows: 1) The MaNP anion and the
PEA cation formed a closest ion-pair through bifurcated hy-
drogen bonds,[4] that is, a methoxy-group-assisted salt bridge
(Figure 3). 2) The aromatic CH···p interactions[29–31] between
the 1-naphthyl group of the (R)-MaNP anion and the
phenyl group of the (R)-PEA
Recently, the development of deuterium-containing phar-
maceuticals has become important.[38–40] Because the C D
ꢀ
ꢀ
bond is stronger than the C H bond, the pharmacological
or metabolic profiles of deuterated pharmaceuticals differ
from those of their protonated analogues.[40]
cation stabilized the ion-pair to
form the less-soluble salt (R)-
1·(R)-6 (Figure 2a). The aro-
matic groups of the more-solu-
ble salt, (S)-1·(R)-6, did not
overlap (Figure 2b).
The methoxy-group-assisted
salt bridge was also evident in
the X-ray crystallographic anal-
A single enantiomer of compound 13 would allow the
clarification and determination of the stereoselectivity and
rate-limiting step of farnesol dehydrogenase. This fact
prompted us to prepare compound (S)-13 from compound
11 by using deuterated (R)-BINAL-H (i.e., (R)-BINAL-D),
which was prepared from lithium aluminum deuteride
(LiAlD4, Scheme 1). The enantiomeric excess of compound
Figure 3. Structure of the me-
1
(S)-13 was determined by analysis of the H NMR spectrum
of (S)-MaNP ester 14. The assignment of prochiral methyl-
thoxy-group-assisted
bridge.
salt
&
&
&2
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Naphthyl Groups in Chiral Recognition
cell. This result is the first struc-
tural elucidation of a crystalline
MbNP salt.
A
methoxy-group-assisted
salt bridge (Figure 3), a structur-
al motif that has previously
been observed in crystalline
MaNP salts,[14] was also ob-
served in salt 8. The interatomic
distances between ammonium
hydrogen atom H1A and car-
boxylate oxygen atom O1 (d1)
or methoxy oxygen atom O3
(d2) were 1.85 ꢂ and 2.58 ꢂ, re-
spectively (Table 2). The intera-
tomic angles N1-H1A···O1 and
N1-H1A···O3 were 1718 and
1168, respectively; that is, the
H1A atom was inclined toward
the O1 atom. This result sug-
gested that the salt bridge and
Scheme 1. Preparation of (S)-(2E,6E)-(1-2H1)farnesol and related compounds.
ene signals at the 1-position in
ester 15, which was prepared
from compounds 10 and (S)-1,
was made by comparison with
the H NMR spectrum of ester
14. The conformation of the
MaNP ester that was prepared
from the primary alcohol was
the first to be elucidated
(Figure 4).
Table 1. X-ray crystallographic data for salts 8 and 9.
Compound
8
9
chemical formula
Mw
crystal system
space group
Z
C22H25NO3
351.44
monoclinic
P21
C23H27NO3
365.47
monoclinic
C2
1
2
4
Figure 4. Conformation of (S)-
MaNP ester that was prepared
from a primary alcohol.
a [ꢂ]
b [ꢂ]
c [ꢂ]
12.042(5)
6.570(3)
12.267(5)
96.696(6)
963.9(7)
1.211
23.437(3)
6.7299(4)
21.582(3)
141.392(3)
2124.1(4)
1.143
0.749
55.0
123
8391
4818
0.0208
244
0.0554
0.1597
1.173
b [8]
V [ꢂ3]
In addition to conventional chiral resolving agents, 2-aryl-
2-methoxypropanoic acids 1–3 are suitable for stereochemi-
cal studies of biofunctional molecules, agrochemicals, and
pharmaceuticals. Herein, we demonstrate the versatility of
acids 1 and 2 and provide new methods for the preparation
of single enantiomers through the crystal engineering of
salts, reductive deuteration, and the structural elucidation of
a-deuterated primary terpene alcohols. These methods are
applicable to studies in insect endocrinology and to research
and development in the agrochemical and pharmaceutical
industries.
Dcalculated
m [cmꢀ1
]
0.799
2qmax [8]
54.9
T [K]
123
total reflns
unique reflns
Rint
parameters
final R1 (I>2q(I))[a]
wR2 (all data)[b]
GOF
7545
4225
0.0252
235
0.0519
0.1356
1.103
Flack parameter
ꢀ1.1(14)
0.9(13)
2
2
[a] R1=(Sj jFojꢀjFcj j)/
(SjFoj). [b] wR2={[Sw
U
ACHTUNGTRENNUNG .
(Fo )2]}1/2
Results and Discussion
the NH+···O hydrogen bond were the major and minor com-
ponents, respectively.[41] Notably, the 2-naphthyl group in
Crystal Conformation of MbNP Salt 8
Salt 8[28] was prepared from compounds rac-2 and (R)-6 in
MeOH and CHCl3 as less-soluble needle-like crystals. Re-
crystallization from a “greener” solution of EtOH and water
yielded thicker crystals of salt 8, which were analyzed by X-
ray crystallography (Table 1 and Figure 5 show the crystallo-
graphic data and ORTEP, respectively). Salt 8 crystallized in
the monoclinic space group P21 with two ion-pairs per unit
salt 8 acted as a C H acceptor, whereas the 1-naphthyl
ꢀ
ꢀ
group of the MaNP anion acted as a C H donor (Figure 2).
Aromatic hydrogen atom H18 of the phenyl group was on
the naphthyl plane (d5 =2.7 ꢂ). Furthermore, hydrogen
atom H15, which was on the chiral center of the PEA
cation, was almost on the naphthyl plane so that the bulky
methyl group of the PEA cation was orientated in the oppo-
site direction. These results suggest that chiral recognition
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
3
&
&
&
These are not the final page numbers! ÞÞ

Akio Ichikawa et al.
FULL PAPER
by using methoxy-group-assisted salt bridges and CH···p in-
teractions are common in crystalline salts that are prepared
from 2-aryl-2-methoxypropanoic acids.
The conformational properties of the MbNP anion dif-
fered significantly from those of
the MaNP anions. The methyl
group that was attached to the
chiral center was almost per-
pendicular to the naphthyl
plane, with a C3-C2-C6-C5 di-
hedral angle of ꢀ94.6(3)8
(Figure 6, Table 2). Short dis-
tances were observed between
aromatic hydrogen atom H7
Figure 6. Conformation of the
MbNP anion in the single crys-
tal.
and carboxylate oxygen atom
O2 (d3 =2.48 ꢂ) and between
Figure 5. ORTEP of salt 8. Ellipsoids set at 50% probability.
atom H5 and methoxy oxygen
Table 2. Dihedral angles, interatomic distances, and interatomic angles in
atom O3 (d4 =2.33 ꢂ), thus sug-
crystalline salt 8.[a]
gesting the presence of CH···O
hydrogen bonds.[4,25,29,30] The interatomic C7-H7···O2 and
C5-H5···O3 angles were 1258 and 1018, respectively. As in
the case of the MaNP anions, the three oxygen atoms of the
MbNP anion were almost in the same plane, with a O1-C1-
C2-O3 dihedral angle of +26.4(3)8. In contrast, the methyl
group of the methoxy moiety was not in the MbNP plane,
with a C4-O3-C2-C1 dihedral angle of +67.2(3)8.
Crystallization is a kinetically controlled process.[24] There-
fore, it is not clear whether this MbNP anion is the major
conformer in solution. However, it is probable that the 2-
naphthyl group affords the MbNP moiety with altered con-
formational properties.[12] Sekiguchi et al. reported the crys-
tal structure of an MbNP amide, in which the methyl group
was in the naphthyl plane.[3] Also, note that aromatic hydro-
gen atoms H5 and H7 of the MbNP anion were almost
equivalent about the bond between ipso-carbon atom C6
and chiral center C2 (Figure 6). Ohba et al. reported a flip-
ped conformation of the 2-hydroxymethyl-2-(2-naphthyl)-
propanoate derivative.[42]
The crystalline salts that were prepared from acids 1 or 2
suggested moderate flexibility of the PEA cations. The N1-
C15-C17-C22 dihedral angle in salt 8 was +53.1(3)8. The
equivalent dihedral angle in the other PEA cations varied
somewhat: (R)-1·(R)-6 +55.8(2)8,[14] (S)-1·(R)-6 +28.9(2)8.[14]
A statistical study suggested that the majority of PEA cat-
ions were in a narrow angular region, with an average value
of +59.758.[43]
Dihedral angle [8]
O1-C1-C2-O3
C4-O3-C2-C1
C3-C2-C6-C5
N1-C15-C17-C22
+26.4(3)
+67.2(3)
ꢀ94.6(3)
+53.1(3)
Interatomic distance [ꢂ]
H1A···O1 (d1)
H1A···O3 (d2)
H7···O2 (d3)
H5···O3 (d4)
H18···p (d5)
1.85
2.58
2.48
2.33
2.7
The conformational difference between the MaNP and
MbNP anions is important for the preparation of crystalline
diastereomeric salts from a wide variety of amines.
Interatomic angle [8]
Crystal Packing of MbNP Salt 8
N1-H1A···O1
N1-H1A···O3
C7-H7···O2
C5-H5···O3
171
116
125
101
Figure 7a shows the crystal packing of salt 8, as viewed
along the a axis. The closest ion-pairs, which consisted of the
MbNP anion and the PEA cation, formed 21 columns with
strong interactions between the carboxylate and ammonium
groups (i.e., salt bridges[14,25,41], Figure 7b). In addition to
[a] 8: (R)-MbNP acid·(R)-PEA salt. Van der Waals radii [ꢂ]: C 1.70,
H 1.20, O 1.52; half-thickness of the aromatic ring: 1.77.
&
&
&4
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Naphthyl Groups in Chiral Recognition
naphthyl groups. The distances between aromatic hydrogen
atoms H11 and H12 and the neighboring 2-naphthyl group
were both 2.9 ꢂ (Figure 7d); the interplanar angle between
the 2-naphthyl groups was 478 (Figure 7a).
Figure 8 shows the crystal packing of salt 8, as viewed
along the c axis. In addition to the interactions noted above,
two other heteroaromatic CH···p interactions were ob-
Figure 8. Crystal packing of salt 8 as viewed along the c axis.
served: 1) The intermolecular distance between atom H9
and its neighboring phenyl group was 2.9 ꢂ; and 2) the inter-
molecular distance between atom H20 and its neighboring
2-naphthyl group was 3.0 ꢂ.
Figure 7. Crystal packing of salt 8 as viewed along the a axis. The packing
Saigo and Sakai developed the “space-filler” con-
cept,[19,20,22] which states that, if the molecular length of the
resolving agent is identical to—or slightly longer than—that
of the racemic substance, then enantioresolution is likely to
be successful. If a gap exists between the lengths of the re-
solving agent and the substrate, it can be compensated for
by a protic solvent, such as water or MeOH.[19,20] In this
case, the 2-naphthyl- and phenyl groups of salt 8 assembled
to fill the gap (see the Supporting Information, Figure 14).
These results suggested that the aromatic CH···p interac-
tions are important for chiral recognition and for the forma-
tion of the crystal structure.
in c) and d) was rotated for clarity of the intermolecular interactions.
the methoxy-group-assisted salt bridge, other salt bridges
were observed between the MbNP anion and their neighbor-
ing PEA cations. The interatomic distance between ammo-
nium hydrogen atom H1B and its neighboring carboxylate
oxygen atom (O1) was 1.88 ꢂ, whilst the interatomic dis-
tance between ammonium hydrogen atom H1C and its
neighboring carboxylate oxygen atom (O2) was 1.93 ꢂ. It is
certain that these salt bridges were the strongest intermolec-
ular interactions in the crystal. Furthermore, the interatomic
distance between aromatic hydrogen atom H22 of the
phenyl group and its neighboring carboxylate oxygen atom
(O2) was 2.58 ꢂ, thus suggesting the presence of a CH···O
hydrogen bond.
Aromatic CH···p and CH···p interactions were also ob-
served between the PEA cations (Figure 7c). The distance
between aromatic hydrogen atom H19 and its neighboring
phenyl group was 2.9 ꢂ. The distance between hydrogen
atom H16C of the methyl group and its neighboring phenyl
group was 2.8 ꢂ.
As shown in Figure 7d, the CH···O hydrogen bond bound
the MbNP anions. The interatomic distance between hydro-
gen atom H4A of the methoxy group and its neighboring
carboxylate oxygen atom (O2) was 2.59 ꢂ.
The core moiety of the column that was formed by the
network of salt bridges was covered with 2-naphthyl- and
phenyl groups. The columns were bound together by inter-
actions between these aromatic groups.[19,44] The homo-aro-
matic CH···p interactions were observed between the 2-
Crystal Conformation of MaNP Salt 9
Salt 9 was prepared from compounds (R)-1 and (R)-7 and
was recrystallized in a solution of MeOH and CHCl3
(Table 1 and Figure 9 show the crystallographic data and
ORTEP, respectively). Salt 9 crystallized in the monoclinic
space group C2 with four ion-pairs per unit cell.
The crystal conformation of salt 9 was similar to that of
MaNP salt (R)-1·(R)-6 (Figure 2a,d). The closest ion-pair of
the MaNP anion and the TEA cation was formed through
a methoxy-group-assisted salt bridge. The interatomic dis-
tances between ammonium hydrogen atom H1A and car-
boxylate oxygen atom O1 (d1) or methoxy oxygen atom O3
(d2) were 2.03 ꢂ and 2.16 ꢂ, respectively (Table 3). Aromat-
ic CH···p interactions were observed between aromatic hy-
drogen atoms H11 and H12 and the p-tolyl group (d5 =
2.6 ꢂ, d6 =3.1 ꢂ), that is, the 1-naphthyl group of the MaNP
ꢀ
anion acted as a C H donor. The methyl group at the chiral
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
5
&
&
&
These are not the final page numbers! ÞÞ

Akio Ichikawa et al.
FULL PAPER
Table 3. Dihedral angles, interatomic distances, and interatomic angles of
crystalline salt 9.[a]
Figure 9. ORTEP of salt 9. Ellipsoids set at 50% probability.
center of the TEA cation was orientated in the opposite di-
rection to that of the MaNP anion.
The carboxylate and methoxy groups formed the MaNP
plane with O1-C1-C2-O3 and C4-O3-C2-C1 dihedral angles
of ꢀ27.4(4)8 and ꢀ177.7(2)8, respectively. The methyl group
of the MaNP moiety was in the 1-naphthyl plane, with a C3-
C2-C5-C6 dihedral angle of ꢀ6.3(3)8. The distances between
aromatic hydrogen atom H12 and oxygen atoms O1 (d3) or
O3 (d4) were 2.79 and 2.51 ꢂ, respectively. These conforma-
tional properties are typical of the MaNP moiety.[4,5,13] How-
ever, this conformational analysis of crystalline salt 9 con-
tributed to the NMR analysis of MaNP esters that were pre-
pared from farnesols. The N1-C15-C17-C22 dihedral angle
was +45.9(5)8 in the TEA cation.
The crystalline MaNP salt represented a new molecular
balance[45] and provided an opportunity to observe substitu-
ent effects on the intermolecular aromatic CH···p interac-
tions by using X-ray crystallography. However, the influence
of other intermolecular interactions could not be ignored.
Substitution of the face component by a methyl group re-
portedly stabilizes the aromatic CH···p interactions.[46] In
fact, the intermolecular distances between the 1-naphthyl-
and p-tolyl groups were shorter than those between the 1-
naphthyl- and phenyl groups in salt (R)-1·(R)-6[14] (Table 4):
In salt 9, the interatomic distance between the C11 and C19
atoms (dL)=3.68 ꢂ and the interatomic distance between
the C12 and C18 atoms (dM)=3.72 ꢂ; in salt (R)-1·(R)-6,[14]
dL =3.71 ꢂ and dM =3.79 ꢂ. These results suggest that crys-
talline MaNP salts can be used to clarify and evaluate the
effect of the substituent on aromatic CH···p interactions.
Dihedral angle [8]
O1-C1-C2-O3
C4-O3-C2-C1
C3-C2-C5-C6
N1-C15-C17-C22
ꢀ27.4(4)
ꢀ177.7(2)
ꢀ6.3(3)
+45.9(5)
Interatomic distance [ꢂ]
H1A···O1 (d1)
H1A···O3 (d2)
H12···O1 (d3)
H12···O3 (d4)
H11···p (d5)
2.03
2.16
2.79
2.51
2.6
H12···p (d6)
3.1
Interatomic angle [8]
N1-H1A···O1
N1-H1A···O3
C12-H12···O1
C12-H12···O3
149
133
144
115
[a] 9: (R)-MaNP acid·(R)-TEA salt. Van der Waals radii [ꢂ]: C 1.70,
H 1.20, O 1.52; half-thickness of aromatic ring: 1.77.
bridges (Figure 10b). In addition to the methoxy-group-as-
sisted salt bridge, two other salt bridges were observed in
the column. The interatomic distance between ammonium
hydrogen atom H1B and its neighboring carboxylate oxygen
atom (O1) was 1.95 ꢂ, whilst the interatomic distance be-
tween ammonium hydrogen atom H1C and its neighboring
carboxylate oxygen atom (O2) was 1.99 ꢂ. It is certain that
these salt bridges were the strongest intermolecular interac-
tions in the crystal of salt 9, as in the crystal of salt 8. Fur-
thermore, intermolecular CH···O interactions were also ob-
served in the columns. The interatomic distance between hy-
drogen atom H16A of the p-tolyl group and its neighboring
Crystal Packing of MaNP Salt 9
The crystal packing of salt 9, as viewed along the a axis, was
similar to that of MaNP salt (R)-1·(R)-6 (Figure 10a).[14]
The closest ion-pairs, which consisted of the MaNP anion
and the TEA cation, formed 21 columns through strong salt
&
&
&6
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Naphthyl Groups in Chiral Recognition
Table 4. Interatomic distances between the 1-naphthyl- and phenyl
groups in crystalline MaNP salts.
the methyl- and 1-naphthyl groups, where the distance be-
tween methyl hydrogen atom H16C and its neighboring p-
tolyl group was 2.7 ꢂ (Figure 10c).
Homoaromatic CH···p interactions were observed be-
tween the 1-naphthyl groups. The distances between aromat-
ic hydrogen atoms H9 and H10 and their neighboring 1-
naphthyl group were 2.5 ꢂ and 3.0 ꢂ, respectively (Fig-
ure 10d), whilst the interplanar angle between the 1-naph-
thyl groups of the MaNP moieties was 588 (Figure 10a).
This angle was larger than that between the 2-naphthyl
groups of the MbNP moieties in salt 8. A perpendicular ge-
ometry (i.e., 908) has been reported to maximize the effi-
ciency of aromatic CH···p interactions.[47]
Compound
X
dL[a] [ꢂ]
dM[b] [ꢂ]
9
H3C
H
3.68
3.71
3.72
3.79
(R)-1·(R)-6[c]
Carbon atoms C11 and C12 were slightly offset from the phenyl planes;
[a] dL is the interatomic distance between the C11 and C19 atoms; [b] dM
is the interatomic distance between the C12 and C18 atoms; [c] for the
crystalline structure of salt (R)-1·(R)-6, see reference [14].
As shown in Figure 11, the crystal packing of salt 9, as
viewed along the c axis, was significantly different to that of
salt (R)-1·(R)-6.[14] To avoid overlap between the bulky p-
Figure 11. Crystal packing of salt 9 as viewed along the c axis.
tolyl- and 1-naphthyl groups, each of the stacking sheets was
offset by half a unit. A heteroaromatic CH···p interaction
was observed between the 1-naphthyl- and p-tolyl groups,
with a distance between aromatic hydrogen atom H7 and its
neighboring p-tolyl group of 2.7 ꢂ.
As viewed along the b axis, the six aromatic groups
formed an oval motif[25] so as to bind the 21 columns togeth-
er (see the Supporting Information, Figure 15).
Crystal engineering by using acids 1–3 may be important
in the development of agrochemicals and pharmaceuticals
as a means of assessing the benefits and potential risks of
each enantiomer.
Figure 10. Crystal packing of salt 9 as viewed along the a axis. The pack-
ing in d) was rotated for clarity of the intermolecular interactions.
MaNP Esters of Farnesol and (1-2H1)Farnesol
AHCTUNGTREG(NNNU 2E,6E)-Farnesal (11) was prepared from (2E,6E)-farnesol
oxygen atom (O1) was 2.57 ꢂ, whilst the interatomic dis-
tance between hydrogen atom H22 of the p-tolyl group and
its neighboring oxygen atom (O2) was 2.46 ꢂ (Figure 10b).
As described previously,[14] the MaNP anions formed
stacks that were stabilized by CH···p interactions between
the methoxy- and 1-naphthyl groups, where the distance be-
tween methoxy hydrogen atom H4C and its neighboring 1-
naphthyl group was 2.7 ꢂ (Figure 10d). The TEA cations
formed similar stacks through CH···p interactions between
(10) by using activated manganese(IV) oxide (MnO2) in n-
hexane (Scheme 1). The reductive deuteration of compound
11 was performed with deuterated (R)-BINAL-H[36,37] (i.e.,
(R)-BINAL-D), which was prepared from the reaction of
LiAlD4, EtOH, and (R)-1,1’-binaphthol, to yield compound
(S)-13 in 56% yield and 83% ee (ee value determined by
1H NMR analysis of the (S)-MaNP esters, ½aꢁ2D9 =+0.54, c=
3.0, cyclopentane; cf. compound (R)-13,[37] 88% ee, ½aꢁD
=
24
ꢀ0.80, c=4.0, cyclopentane). Noyori et al. explained this
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
7
&
&
&
These are not the final page numbers! ÞÞ

Akio Ichikawa et al.
FULL PAPER
stereoselectivity by using chair-like transition state 16, in
which the n/p-type electronic repulsion between the axial
oxygen atom and the unsaturated moiety is smaller.[36]
Previously, the enantiomeric excess and absolute configu-
ration of the a-deuterated primary alcohols were deter-
mined by 1H NMR analysis of their (ꢀ)-camphanic acid
Acylation of compounds (S)-13 and 10 with compound
(S)-1 by using 1-ethyl-3-(3-dimethylaminopropyl)carbodii-
mide hydrochloride (EDC·HCl) and 4-dimethylaminopyri-
dine (DMAP) afforded esters 14 and 15, respectively. The
NMR signals of ester 14 and 15 were assigned based on
analysis of their COSY, NOESY, HSQC, and HMBC spec-
esters with EuACTHNGUTERNNUG
(dpm)3.[50] The prochiral methylene signals of
MaNP ester 15 were well-separated without the need for an
NMR shift reagent (Figure 12b). Therefore, acid 1 can be
used to investigate the stereochemistry of a-deuterated pri-
mary alcohols.
Mixtures of the cis/trans isomers of compound 11 under-
went reductive deuteration with (R)-BINAL-D. After acyla-
tion of the a-deuterated primary alcohols with compound
(S)-1, ester 17 (Figure 13) was isolated by using preparative
1
tra (800 MHz, CDCl3). Figure 12 shows the H NMR signals
Figure 13. Structure of ester 17.
1
HPLC in two steps, along with ester 14. H NMR analysis of
esters 14 and 17 elucidated that they were formed in 28%
and 31% de, respectively (see the Supporting Information,
Figure 16). The E/Z configuration at the 6-position of farne-
sol had little influence on the stereoselectivity of the reduc-
tive-deuteration reaction.
Yamakawa et al. reported that CH···p interactions are im-
portant for asymmetric hydrogen transfer in solution.[51]
A
better understanding of CH···p and, therefore, aromatic
CH···p interactions is crucial for understanding the stereose-
lectivity of reactions.
Figure 12. Region of the 1H NMR spectra of esters 14 and 15 (800 MHz,
CDCl3); expansion of the signals at the 1-positions of the farnesol moiet-
ies. * The minor doublet at 4.60 ppm (8.3%) is due to the (Ralcohol,Sacid)-
diastereomer.
Conclusions
of the methylene protons at the 1-positions of esters 14 and
15. The proton at the 1-position of ester 14 (d=4.52 ppm,
91.7%) was shifted upfield compared to that of the minor
(Ralcohol,Sacid)-diastereomer (d=4.60 ppm, 8.3%; Figure 12a).
It has been reported that the a-D atom of the CHD group
perturbs the chemical shift of the remaining H atom by
about d=0.02 ppm upfield of the signal of the parent CH2
hydrogen atoms.[48] Therefore, the chemical shifts of the pro-
S and pro-R hydrogen atoms (HS and HR) at the 1-position
of ester 15 were assigned to the peaks at d=4.62 ppm and
d=4.54 ppm, respectively (Figure 12b), that is, the 1-naph-
thyl group of the MaNP moiety shielded the HR atom of
ester 15. The conformation of the MaNP moiety has already
been clarified (Figure 2 and Table 3).[4,5,13] These results sug-
gested that the carbonyl group of ester 15 was located be-
tween the hydrogen atoms of the methylene group at the 1-
position (Figure 4). Nicolaou et al. observed similar confor-
mations in the crystal structures of esters that were prepared
from halogen-containing primary alcohols.[49]
MbNP salt 8 and MaNP salt 9 formed methoxy-group-as-
sisted salt bridges in crystals. The conformation of the
MbNP anion was significantly different from that of the
MaNP anion. The methyl group was perpendicular to the
naphthyl plane in the MbNP anion and the 2-naphthy group
ꢀ
acted as a C H acceptor. Conversely, the methyl group was
in the naphthyl plane in the MaNP anion and the 1-naph-
ꢀ
thyl group acted as a C H donor. In both salts, the methyl
groups at the chiral centers of the ammonium cations were
in the opposite direction of the carboxylate anions. The net-
works of strong salt bridges bound the carboxylate and am-
monium groups to form the 21 columns. Acids 1 and 2 can
be used to effectively extend the range of crystallizable
amines in the preparation of salts. The distance between 1-
naphthyl- and p-tolyl groups was shorter than the corre-
sponding distance between 1-naphthyl- and phenyl groups.
This suggested that the crystalline MaNP salts can be used
to clarify the properties of the aromatic CH···p interactions.
(S)-13 was prepared by reductive deuteration with the
&
&
&8
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Naphthyl Groups in Chiral Recognition
solution was allowed to stand at RT to give colorless crystals of salt 9
(28.9 mg, 79 mmol) in 61% yield.
BINOL-modified
agent,
originally
developed
by
Noyori.[36,37] The prochiral methylene protons at the 1-posi-
tion of MaNP ester 15 were unambiguously assigned by
comparing with that of deuterated ester 14. In addition, the
conformational model of the MaNP ester prepared from
primary alcohol was elucidated. This demonstrates the utili-
ty of the MaNP method in determining the stereochemistry
of primary terpene alcohols containing a deuterium atom at
the 1-position. 2-Aryl-2 methoxypropanoic acids showed po-
tential for use in the development of single-enantiomer bio-
functional molecules, agrochemicals, and pharmaceuticals.
(R)-1-(p-Tolyl)ethylammonium (R)-2-methoxy-2-(1-naphthyl)propanoate
(9)
M.p. 1578C; elemental analysis calcd (%) for C23H27NO3: C 75.59, H 7.45,
N 3.83; found: C 75.15, H 7.65, N 3.80.
Preparation of (2E,6E)-farnesal (11)
A mixture of (2E,6E)-farnesol 10 (24.9 mg, 112 mmol, Sigma–Aldrich, St.
Louis, Missouri, USA) and activated MnO2 (519.0 mg, 5.97 mmol,
Sigma–Aldrich) was stirred in dry n-hexane for 3 h at 08C. The mixture
was directly purified by column chromatography on silica gel (Supelco,
Discovery DSC-Si SPE tube, 2 g, Sigma–Aldrich). The column was
eluted with n-hexane/CH2Cl2. The eluent was concentrated in vacuo to
give aldehyde 11 (20.0 mg, 90.8 mmol) in 81% yield. Aldehyde 11 was
kept in n-hexane under an argon atmosphere at ꢀ308C and used in the
next reaction without characterization.
Experimental Section
General
Preparation of (S)-(2E,6E)-(1-2H1)farnesol ((S)-13)
NMR spectroscopy was performed on Bruker Avance 800 and Avance
500 spectrometers (Bruker BioSpin, Rheinstetten, Germany) that were
Noyori et al. originally reported the preparation of compound (R)-13
(88% ee) from (2E,6E)-(1-2H)farnesal (12) with (R)-BINAL-H at
ꢀ1008C in 91% yield.[36,37] This reaction was modified as follows: A solu-
tion of (R)-BINAL-D was prepared from the reaction of LiAlD4
(2.2 mL, 1.0 molLꢀ1 in THF, uncorrected value, Sigma–Aldrich), a solu-
tion of EtOH (140 mL, 2.4 mmol) in THF (2 mL), and a solution of (R)-
binaphthol (626.7 mg, 2.19 mmol, Tokyo Kasei, Tokyo, Japan) in THF
(4 mL). Subsequently, the solution of (R)-BINAL-D was used directly in
equipped with cryoprobes. 13C NMR spectra were obtained with H com-
1
posite pulse decoupling. IR spectra were recorded on an FTIR-8200 spec-
trophotometer (Shimadzu, Kyoto, Japan) with a KBr cell. MS data were
obtained on an Apex 70e ESI-FTICR MS instrument (Bruker Daltonics,
Bremen, Germany) in positive-ion mode. HPLC was performed on
LC10AT VP systems (Shimadzu) that were equipped with a UV or a pho-
todiode array detector.
A Kusano C.I.G. pre-packed Si-5 column
(100 mmꢃ22 mm I.D., Kusano, Tokyo, Japan) and a capcell pak C18
AG120 column (250 mmꢃ20 mm I.D., Shiseido, Tokyo, Japan) were used
for preparative HPLC.
the reductive deuteration of
a solution of aldehyde 11 (155.6 mg,
706 mmol) in THF (1 mL) to afford compound (S)-13[52] (88.5 mg,
396 mmol, 83% ee (see below)) in 56% yield. The reaction time was 2 h
and the reaction temperature was ꢀ728C (dry-ice/EtOH bath). Com-
pound (S)-13 was purified by column chromatography on silica gel (n-
hexane/CH2Cl2, 2:1 to 1:1).
X-ray crystallography
Single crystals of salts
8 (0.400 mmꢃ0.100 mm ꢃ0.100 mm) and 9
(0.200 mmꢃ0.100 mmꢃ0.050 mm) were covered by paraffin oil and
mounted onto a glass fiber. All data were collected at 123 K on a Rigaku
Mercury CCD detector with monochromatic MoKa radiation, operating
at 50 kV/40 mA. Data were processed on a PC by using CrystalClear
Software (Rigaku, Tokyo, Japan). Structures were solved by using direct
methods and refined by full-matrix least-squares methods on F2
(SHELXL-97).
(S)-(2E,6E)-(1-2H1)Farnesol ((S)-13)
½aꢁ2D9 =+0.54 (c=3.0, cyclopentane); 1H NMR (800 MHz, CDCl3, 258C,
TMS): d=5.42 (brd, J=7 Hz, 1H), 5.11 (tsext, J=7, 1 Hz, 1H), 5.09
(tsept, J=7, 1 Hz, 1H), 4.13 (m, 1H), 2.12 (brq, J=7 Hz, 2H), 2.06 (brq,
J=7 Hz, 2H), 2.04 (brt, J=7 Hz, 2H), 1.98 (brt, J=7 Hz, 2H), 1.69
(brd, J=1 Hz, 3H), 1.68 (brd, J=1 Hz, 3H), 1.60 (brs, 3H), 1.60 (brs,
3H), 1.12 ppm (brd, J=5 Hz, 1H; this coupling constant suggested free
rotation of the primary hydroxy group[53]); 13C NMR (201 MHz, CDCl3,
258C, TMS): d=139.94, 135.38, 131.36, 124.32, 123.78, 123.27, 59.09 (t,
J=22 Hz), 39.70, 39.55, 26.72, 26.30, 25.70, 17.70, 16.29, 16.01 ppm; IR
(KBr, CHCl3): n˜ =3612, 3448, 3009, 2968, 2918, 2856, 1665, 1448, 1383,
CCDC 871215 (salt 8) and CCDC 871216 (salt 9) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1107, 986, 934, 891, 837 cmꢀ1
; HRMS (ESI-FTICR): m/z calcd for
Preparation of salt 8
C15H25ODNa+: 246.1939 [M+Na]+; found: 246.1939.
A mixture of compounds rac-2 (77.5 mg, 337 mmol) and (R)-6 (41.3 mg,
341 mmol) was dissolved in MeOH/CHCl3 (1:1, v/v, 6 mL). The solution
was partially concentrated under vacuum in a water bath at 458C. The
solution was allowed to stand in a refrigerator. After removal of the
mother liquor from the mixture, the crystals were washed with cold
EtOH (about 0.5 mL) to afford crude salt 8[28] (52.8 mg, 150 mmol) in
45% yield. The same recrystallization procedure was then repeated twice
at RT to give needle-like crystals. Finally, salt 8 was recrystallized from
EtOH/water (19:1, v/v) to give colorless crystals that were used for X-ray
crystallography.
Preparation of ester 14
Ester 14 (9.5 mg, 22 mmol) was prepared from compounds (S)-13 (4.9 mg,
22 mmol) and (S)-1 (34.7 mg, 151 mmol) with EDC·HCl (119.8 mg,
625 mmol), DMAP (99.2 mg, 812 mmol), and CH2Cl2 (0.4 mL) in 99%
yield. The reaction time was 18 h. The crude product was purified by
HPLC on a pre-packed Si-5 column (n-hexane/EtOAc). For details, see
references [6,8].
(S)-(2E,6E)-3,7,11-TrimethylACHTUNGTRNEUNG
(1-2H1)-2,6,10-dodecatrienyl (S)-2-methoxy-2-
(1-naphthyl)propanoate (14)
(R)-1-Phenylethylammonium (R)-2-methoxy-2-(2-naphthyl)propanoate
1H NMR (800 MHz, CDCl3, 258C, CHCl3; see the Supporting Informa-
tion): d=8.37 (m, 1H), 7.84 (m, 1H), 7.83 (brd, J=8 Hz, 1H), 7.60 (dd,
J=7 and 1 Hz, 1H), 7.47 (m, 1H), 7.46 (m, 1H), 7.45 (dd, J=8 and 7 Hz,
1H), 5.13 (brd, J=7 Hz, 1H), 5.07 (tsept, J=7 and 1 Hz, 1H), 5.02
(tsext, J=7 and 1 Hz, 1H), 4.60 (brd, J=7 Hz, 0.083H; (Ralcohol,Sacid)-dia-
stereomer), 4.52 (brd, J=7 Hz, 0.917H), 3.09 (s, 3H), 2.04 (brq, J=7 Hz,
2H), 1.98 (s, 3H), 1.96 (m, 2H), 1.95 (brt, J=7 Hz, 2H), 1.89 (br t, J=
7 Hz, 2H), 1.67 (brd, J=1 Hz, 3H), 1.59 (brs, 3H), 1.55 (br s, 3H),
1.47 ppm (brs, 3H); 13C NMR (201 MHz, CDCl3, 258C, TMS; see the
(8)
M.p. 1348C; elemental analysis calcd (%) for C22H25NO3: C 75.19, H 7.17,
N 3.99; found: C 75.06, H 7.15, N 3.87.
Preparation of salt 9
A mixture of compounds (R)-1 (30.0 mg, 130 mmol) and (R)-7 (24.4 mg,
180 mmol) was dissolved in MeOH/CHCl3 (2:1, v/v, 3 mL). The solution
was partially concentrated under vacuum in a water bath at 458C. The
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
9
&
&
&
These are not the final page numbers! ÞÞ

Akio Ichikawa et al.
FULL PAPER
Supporting Information): d=174.06, 142.91, 135.34, 135.27, 134.11,
131.33, 131.32, 129.42, 128.66, 126.34, 125.63, 125.63, 125.28, 124.67,
124.31, 123.65, 117.63, 81.64, 61.96 (t, J=22 Hz), 50.97, 39.67, 39.36,
26.71, 26.12, 25.70, 21.89, 17.70, 16.34, 15.98 ppm; IR (KBr, CHCl3): n˜ =
3011, 2934, 2855, 1732, 1508, 1456, 1339, 1258, 1136 cmꢀ1; HRMS (ESI-
FTICR): m/z calcd for C29H37O3DNa+: 458.2776 [M+Na]+; found:
458.2776.
(201 MHz, CDCl3, 258C, CDCl3, see the Supporting Information): d=
174.09, 142.83, 135.45, 135.14, 134.04, 131.60, 131.27, 129.43, 128.63,
126.34, 125.65, 125.63, 125.21, 124.65, 124.39, 124.22, 117.60, 81.55, 61.95
(t, J=22 Hz), 50.92, 39.62, 31.90, 26.53, 25.89, 25.74, 23.35, 21.82, 17.64,
16.28 ppm; IR (KBr, CHCl3): n˜ =2932, 2855, 1734, 1456, 1375, 1259,
1136 cmꢀ1; HRMS (ESI-FTICR): m/z calcd for C29H37O3DNa+: 458.2776
[M+Na]+; found: 458.2778.
Preparation of ester 15
Ester 15 (33.9 mg, 78 mmol) was prepared from the reaction of com-
pounds (2E,6E)-farnesol 10 (42.3 mg, 190 mmol) and (S)-1 (24.3 mg,
106 mmol) with EDC·HCl (92.7 mg, 484 mmol), DMAP (96.4 mg,
789 mmol), and CH2Cl2 (0.5 mL) in 74% yield. The reaction time was
67 h. See above for details.
Acknowledgements
The authors are grateful to Ms. I. Maeda (NFRI) for measurement of the
NMR spectra.
ACHTUNGTRENNUNG(2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrienyl (S)-2-methoxy-2-(1-
naphthyl)propanoate (15)
[1] N. Harada, Chirality 2008, 20, 691–723.
½aꢁ2D7 =+11.2 (c=0.339, EtOH); 1H NMR (800 MHz, CDCl3, 258C, TMS;
see the Supporting Information): d=8.37 (m, 1H), 7.84 (m, 1H), 7.83
(brd, J=8 Hz, 1H), 7.61 (dd, J=7 and 1 Hz, 1H), 7.46 (m, 1H), 7.46 (m,
1H), 7.45 (dd, J=8 and 7 Hz, 1H), 5.14 (tsext, J=7 and 1 Hz, 1H), 5.08
(tsept, J=7 and 1 Hz, 1H), 5.02 (tsext, J=7 and 1 Hz, 1H), 4.62 (brdd,
J=12 and 7 Hz, 1H), 4.54 (brdd, J=12 and 7 Hz, 1H), 3.09 (s, 3H), 2.04
(brq, J=7 Hz, 2H), 1.99 (s, 3H), 1.96 (m, 2H), 1.95 (brt, J=7 Hz, 2H),
1.89 (brt, J=7 Hz, 2H), 1.68 (brd, J=1 Hz, 3H), 1.60 (brs, 3H), 1.56
(brs, 3H), 1.47 ppm (brs, 3H); 13C NMR (201 MHz, CDCl3, 258C, TMS;
see the Supporting Information): d=174.10, 142.85, 135.32, 135.16,
134.06, 131.34, 131.29, 129.44, 128.65, 126.35, 125.66, 125.64, 125.24,
124.67, 124.28, 123.62, 117.64, 81.57, 62.26, 50.94, 39.66, 39.34, 26.67,
26.08, 25.72, 21.83, 17.70, 16.33, 15.97 ppm; IR (KBr, CHCl3): n˜ =3011,
2934, 2856, 1732, 1452, 1377, 1259, 1134, 937 cmꢀ1; HRMS (ESI-FTICR):
m/z calcd for C29H38O3Na+: 457.2713 [M+Na]+; found: 457.2715.
[2] A. Ichikawa, H. Ono in Stereochemistry Research Trends (Ed.:
M. A. Horvat, J. H. Golob), Nova, New York, 2008, pp. 51–88.
[3] S. Sekiguchi, J. Naito, H. Taji, Y. Kasai, A. Sugio, S. Kuwahara, M.
Watanabe, N. Harada, Chirality 2008, 20, 251–264.
[4] S. Kuwahara, J. Naito, Y. Yamamoto, Y. Kasai, T. Fujita, K. Noro,
K. Shimanuki, M. Akagi, M. Watanabe, T. Matsumoto, M. Wata-
nabe, A. Ichikawa, N. Harada, Eur. J. Org. Chem. 2007, 1827–1840.
[5] Y. Kasai, A. Sugio, S. Sekiguchi, S. Kuwahara, T. Matsumoto, M.
Watanabe, A. Ichikawa, N. Harada, Eur. J. Org. Chem. 2007, 1811–
1826.
[6] A. Ichikawa, H. Ono, Biosci. Biotechnol. Biochem. 2008, 72, 2418–
2422.
[7] A. Ichikawa, H. Ono, J. Chromatogr. A 2006, 1117, 38–46.
[8] A. Ichikawa, H. Ono, Tetrahedron: Asymmetry 2005, 16, 2559–2568.
[9] A. Ichikawa, H. Ono, N. Harada, Chirality 2004, 16, 559–567.
[10] A. Ichikawa, H. Ono, N. Harada, Tetrahedron: Asymmetry 2003, 14,
1593–1597.
Preparation of ester 17
[11] A. Ichikawa, H. Ono, S. Hiradate, M. Watanabe, N. Harada, Tetra-
hedron: Asymmetry 2002, 13, 1167–1172.
(R)-BINAL-D was prepared from LiAlD4 (2.2 mL, 1.0 molLꢀ1 in THF),
EtOH (2.2 mL, 1 molLꢀ1 in THF), and (R)-binaphthol (621 mg,
2.17 mmol). (1-2H1)Farnesol (mixture of E/Z isomers, 38.2 mg, 171 mmol)
was obtained from the reaction of farnesal (mixture of E/Z isomers,
168.7 mg, 766 mmol, Sigma–Aldrich) in THF (1 mL) with the solution of
(R)-BINAL-D in 22% yield. The reaction time was 2 h and the reaction
temperature was ꢀ728C. For details, see references [36,37].
[12] A. Ichikawa, S. Hiradate, A. Sugio, S. Kuwahara, M. Watanabe, N.
Harada, Tetrahedron: Asymmetry 2000, 11, 2669–2675.
[13] A. Ichikawa, S. Hiradate, A. Sugio, S. Kuwahara, M. Watanabe, N.
Harada, Tetrahedron: Asymmetry 1999, 10, 4075–4078.
[14] A. Ichikawa, H. Ono, T. Echigo, Y. Mikata, CrystEngComm 2011,
13, 4536–4548.
Then, (1-2H1)farnesol (mixture of E/Z isomers, 19 mg, 85 mmol) was acy-
lated with compound (S)-1 (49.6 mg, 215 mmol) by using EDC·HCl
(85.1 mg, 444 mmol), DMAP (88.6 mg, 725 mmol), and CH2Cl2 (0.5 mL) to
give a crude mixture of MaNP esters (44.9 mg). The reaction time was
19 h. Considering the retention time of ester 15, the crude products were
purified by preparative HPLC (pre-packed Si-5 column, n-hexane/EtOAc
91:9, flow rate: 3 mLminꢀ1, UV detection: 315 nm) to give a mixture of
esters 14 and 17 (61:39, 27.2 mg, 62 mmol). Finally, esters 14 and 17 (1 mg
of each) were obtained by reversed-phase preparative HPLC (capcell
pak C18 AG120 column, MeCN/water 94:6, flow rate: 4 mLminꢀ1, UV
detection: 280 nm). The retention times of esters 14 and 17 were
38.89 min and 37.58 min, respectively. 1H NMR analysis elucidated that
esters 14 and 17 were formed in 28% and 31% de, respectively. The ste-
reochemistry of ester 17 and the (Ralcohol,Sacid)-diastereomer were deter-
mined from the 1H NMR chemical shifts in the 1-positions (d=4.52 ppm
and 4.60 ppm, respectively).
[15] A. Ichikawa, H. Ono, Y. Mikata, CrystEngComm 2010, 12, 2261–
2268.
[16] A. Ichikawa, H. Ono, Y. Mikata, Tetrahedron: Asymmetry 2008, 19,
2693–2698.
[17] A. M. Rouhi, Chem. Eng. News 2003, 81, 45–55.
[18] J. Jacques, A. Collet, S. H. Wilen in Enantiomers, Racemates, and
Resolutions, Krieger Pub. Co., Florida, 1994.
[19] K. Saigo, K. Sakai, J. Synth. Org. Chem. Jpn. 2011, 69, 499–505 (in
Japanese with English summary).
[20] K. Saigo, J. Synth. Org. Chem. Jpn. 2006, 64, 1240–1250 (in Japanese
with English summary).
[21] Y. Kobayashi, K. Saigo, J. Am. Chem. Soc. 2005, 127, 15054–15060.
[22] K. Sakai, Chemistry & Chemical Industry 2004, 57, 507–511 (in Jap-
anese).
[23] K. Sakai, R. Sakurai, A. Yuzawa, Y. Kobayashi, K. Saigo, Tetrahe-
dron: Asymmetry 2003, 14, 1631–1636.
[24] G. R. Desiraju, Chem. Asian J. 2006, 1, 231–244.
[25] G. R. Desiraju, Acc. Chem. Res. 2002, 35, 565–573.
[26] G. R. Desiraju, Angew. Chem. 1995, 107, 2541–2558; Angew. Chem.
Int. Ed. Engl. 1995, 34, 2311–2327.
[27] M. Miyata, N. Tohnai, I. Hisaki, Acc. Chem. Res. 2007, 40, 694–702.
[28] J. Goto, M. Hasegawa, S. Nakamura, K. Shimada, T. Nambara, J.
Chromatogr. 1978, 152, 413–419.
[29] M. Nishio in Introduction to Intermolecular Forces in Organic
Chemistry, Kodansha, Tokyo, 2008 (in Japanese).
[30] O. Takahashi, Y. Kohno, M. Nishio, Chem. Rev. 2010, 110, 6049–
6076.
(S)-(2E,6Z)-3,7,11-TrimethylACHTUNGTRNEUNG
(1-2H1)-2,6,10-dodecatrienyl (S)-2-methoxy-2-
(1-naphthyl)propanoate (17)
1H NMR (800 MHz, CDCl3, 258C, CHCl3, see the Supporting Informa-
tion): d=8.36 (m, 1H), 7.84 (m, 1H), 7.83 (brd, J=8 Hz, 1H), 7.61 (dd,
J=7 and 1 Hz, 1H), 7.47 (m, 1H), 7.46 (m, 1H), 7.45 (m, 1H), 5.13 (brd,
J=7 Hz, 1H), 5.09 (tsept, J=7 and 1 Hz, 1H), 5.02 (brt, J=7 Hz, 1H),
4.60 (brd, J=7 Hz, 0.344H; (Ralcohol,Sacid)-diastereomer), 4.52 (brd, J=
7 Hz, 0.656H), 3.09 (s, 3H), 2.02 (brq, J=7 Hz, 2H), 1.99 (m, 2H), 1.98
(s, 3H), 1.96 (m, 2H), 1.88 (brt, J=7 Hz, 2H), 1.68 (brd, J=1 Hz, 3H),
1.66 (brq, J=1 Hz, 3H), 1.59 (brs, 3H), 1.47 ppm (brs, 3H); 13C NMR
&
&
&10
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Naphthyl Groups in Chiral Recognition
[31] K. Kobayashi, N. Hayashi in Solid-phase organic chemistry, Kagaku-
dojin, Kyoto, 2009 (in Japanese).
[32] S. Tsuzuki, K. Honda, T. Uchimaru, M. Mikami, K. Tanabe, J. Am.
Chem. Soc. 2000, 122, 3746–3753.
[33] R. Suzuki, Z. Fujimoto, T. Shiotsuki, W. Tsuchiya, M. Momma, A.
Tase, M. Miyazawa, T. Yamazaki, Sci. Rep. 2011, 1, 133,
DOI:10.1038/srep00133.
[44] Q. He, S. Rohani, J. Zhu, H. Gomaa, Chirality 2012, 24, 119–128.
[45] W. R. Carroll, C. Zhao, M. D. Smith, P. J. Pellechia, K. D. Shimizu,
Org. Lett. 2011, 13, 4320–4323.
[46] M. O. Sinnokrot, C. D. Sherrill, J. Am. Chem. Soc. 2004, 126, 7690–
7697.
[47] K. Kinbara, Y. Harada, K. Saigo, J. Chem. Soc. Perkin Trans. 2 2000,
1339–1347.
[34] J. G. Mayoral, M. Nouzova, A. Navare, F. G. Noriega, Proc. Natl.
Acad. Sci. USA 2009, 106, 21091–21096.
[48] V. Jonnalagadda, K. Toth, J. P. Richard, J. Am. Chem. Soc. 2012,
134, 6568–6570.
[35] H. S. H. Yuan, R. C. Stevens, R. Bau, H. S. Mosher, T. F. Koetzle,
Proc. Natl. Acad. Sci. USA 1994, 91, 12872–12876.
[36] R. Noyori, I. Tomino, Y. Tanimoto, M. Nishizawa, J. Am. Chem.
Soc. 1984, 106, 6709–6716.
[49] K. C. Nicolaou, N. L. Simmons, Y. Ying, P. M. Heretsch, J. S. Chen,
J. Am. Chem. Soc. 2011, 133, 8134–8137.
[50] H. Gerlach, B. Zagalak, J. Chem. Soc. Chem. Commun. 1973, 274–
275.
[37] R. Noyori, I. Tomino, M. Yamada, M. Nishizawa, J. Am. Chem. Soc.
1984, 106, 6717–6725.
[38] A. T. Yarnell, Chem. Eng. News 2009, 87, 36–39.
[39] K. Sanderson, Nature 2009, 458, 269.
[51] M. Yamakawa, I. Yamada, R. Noyori, Angew. Chem. 2001, 113,
2900–2903; Angew. Chem. Int. Ed. 2001, 40, 2818–2821.
[52] J. A. Digits, H.-J. Pyun, R. M. Coates, P. J. Casey, J. Biol. Chem.
2002, 277, 41086–41093.
[40] K. C. Buteau, J. High Tech. L. 2009, 10, 22–74.
[41] T. Steiner, Angew. Chem. 2002, 114, 50–80; Angew. Chem. Int. Ed.
2002, 41, 48–76.
[42] S. Ohba, T. Tsutsumi, Y. Terao, K. Miyamoto, H. Ohta, Acta Crystal-
logr. Sect. E 2005, 61, o1283–o1285.
[53] E. Pretsch, T. Clerc, J. Seibl, W. Simon; translated into Japanese by
K. Nakanishi, M. Kajiwara, K. Tsutsumi in Tables of Spectral Data
for Structure Determination of Organic Compounds, Kodansha,
Tokyo, 1982, p. 119.
Received: April 16, 2012
[43] P. G. Karamertzanis, S. L. Price, J. Phys. Chem. B 2005, 109, 17134–
17150.
Revised: May 11, 2012
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
11
&
&
&
These are not the final page numbers! ÞÞ

FULL PAPER
Crystal Engineering
Akio Ichikawa,* Hiroshi Ono,
Yuji Mikata
&&&& — &&&&
Naphthyl Groups in Chiral Recogni-
tion: Structures of Salts and Esters of
2-Methoxy-2-naphthylpropanoic Acids
Princess and the PEA: The crystal
structures of the MaNP and MbNP
salts were determined by X-ray crystal-
lography. The 1-naphthyl group of the
MaNP anion and the 2-naphthyl group
ꢀ
of the MbNP anion acted as a C H
donor and -acceptor, respectively.
&
&
&12
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!