Synthesis and structure of macrocyclic bis(hydroxynaphthoic amide)s connected by an achiral or chiral diamine

Article abstract of DOI:10.1021/jo0340298

Macrocyclic bis(hydroxynaphthoic amide)s 6, connected by an achiral or chiral diamine, were synthesized by the tandem Claisen rearrangement. CD spectra, X-ray crystallographic analyses, and variable-temperature NMR measurements of the chiral bis(hydroxyna

Full text of DOI:10.1021/jo0340298

Syn th esis a n d Str u ctu r e of Ma cr ocyclic Bis(h yd r oxyn a p h th oic
a m id e)s Con n ected by a n Ach ir a l or Ch ir a l Dia m in e
Hiroaki Yoshida,† Kazuhisa Hiratani,*,‡ Tamako Ogihara,§ Yuka Kobayashi,†
Kazushi Kinbara,† and Kazuhiko Saigo*,†
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-8656, J apan, Department of Applied Chemistry, Utsunomiya University,
Youtou, Utsunomiya, Tochigi 321-8585, J apan, and Nanoarchitectonics Research Center, National
Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Ibaraki 305-8565, J apan
saigo@chiral.t.u-tokyo.ac.jp
Received J anuary 8, 2003
Macrocyclic bis(hydroxynaphthoic amide)s 6, connected by an achiral or chiral diamine, were
synthesized by the tandem Claisen rearrangement. CD spectra, X-ray crystallographic analyses,
and variable-temperature NMR measurements of the chiral bis(hydroxynaphthoic amide)s revealed
that the two hydroxynaphthalene rings in these macrocycles adopt a twisted conformation both in
solution and in the crystalline state because of the steric hindrance between the two hydroxynaph-
thalene rings and that the chirality of the twisted conformation is generated by that of the chiral
linker. Theoretical calculations revealed that the chiral linker works effectively to favor energetically
one conformer of the diastereomers, although a flipping process was possible and can be observed
to occur on the NMR time scale in variable-temperature experiments.
CHART 1
In tr od u ction
Organic compounds whose chirality arises from their
helical structures have been attracting much attention.
Many sterically crowded aromatic compounds are well-
known to adopt a helical or twisted structure.1 For
example, an alkyl-chain-connected dinaphthalene adopts
a twisted structure in the crystalline state,2 and chiral
tether-bridged dinaphthalenes have been used for the
preparation of chiral, twisted 1,1′-binaphthyl deriva-
tives.3 Macrocyclization of a dinaphthalene has also been
used to induce a helical arrangement of the naphthyl
moieties.4 Although the highly symmetrical, helical, or
twisted structures of these compounds are very fascinat-
ing in themselves as fundamental chiral skeletons, most
of the compounds lack a reactive functional group that
can be used for their transformation into useful materi-
als.
steric hindrance between two hydroxyaryl groups con-
nected by an isobutenylene unit; this linker is not long
enough to allow the two hydroxyaryl groups to become
coplanar. However, no indication of such twisted confor-
mation in solution has been obtained from the NMR and
CD spectra, probably due to the flexibility of the isobu-
tenylene unit allowing rapid conformational change at
room temperature. These observations prompted us to
During our research on the tandem Claisen rearrange-
ment,5 which is a useful method for the synthesis of
macrocyclic polyphenols and polynaphthols applicable as
hosts6 for organic guest molecules and ligands7 for metal
ions (Chart 1), it became apparent that some of the
macrocycles may adopt a twisted conformation due to the
(5) (a) Hiratani, K.; Takahashi, T.; Kasuga, K.; Sugihara, H.;
Fujiwara, K.; Ohashi, K. Tetrahedron Lett. 1995, 36, 5567-5570. (b)
Hiratani, K.; Uzawa H.; Kasuga, K.; Kambayashi H. Tetrahedron Lett.
1997, 38, 8993-8996. (c) Hiratani, K.; Kasuga, K.; Goto, M.; Uzawa,
H. J . Am. Chem. Soc. 1997, 119, 12677-12678. (d) Uzawa, H.;
Hiratani, K.; Minoura, N.; Takahashi, T. Chem. Lett. 1998, 307-308.
(e) Houjou, H.; Lee, S.-K.; Hishikawa, Y.; Nagawa, Y.; Hiratani, K.
Chem. Commun. 2000, 2197-2198. (f) Tsuzuki, S.; Houjou, H.;
Nagawa, Y.; Goto, M.; Hiratani, K. J . Am. Chem. Soc. 2001, 123, 4255-
4258.
(6) (a) Choi, W.; Hiratani, K. Chem. Lett. 1999, 807-808. (b)
Yoshida, H.; Saigo, K.; Hiratani, K. Chem. Lett. 2000, 116-117. (c)
Hiratani, K.; Goto, M.; Nagawa, Y.; Kasuga, K.; Fujiwara, K. Chem.
Lett. 2000, 1364-1365. (d) Tokuhisa, H.; Ogihara, T.; Nagawa, Y.;
Hiratani, K. J . Inclusion Phenom. Macro. Chem. 2001, 39, 347-352.
(7) Rao, M. L. N.; Houjou, H.; Hiratani, K. Chem. Commun. 2002,
420-421.
* To whom correspondence should be addressed. Fax: +81-3-5802-
3348.
† The University of Tokyo.
‡ Utsunomiya University.
§ National Institute of Advanced Industrial Science and Technology.
(1) Borchadt, A.; Hardcastle, K.; Gantzel, P.; Siegel, J . S. Tetrahe-
dron Lett. 1993, 34, 273-276.
(2) Feagins, J . P.; Abboud, K. A.; Minton, M. A.; Whitesell, J . K.;
Davis, R. E. Acta Crystallogr., Sect. C 1990, 27, 711-713.
(3) Rosini, C.; Superchi, S.; Bianko, G.; Mecca, T. Chirality 2000,
12, 256-262.
(4) Grochowski, J .; Rys, B.; Serda, P.; Wagner, U. Tetrahedron:
Asymmetry 1995, 6, 2059-2066.
10.1021/jo0340298 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/26/2003
5812
J . Org. Chem. 2003, 68, 5812-5818

Synthesis of Macrocyclic Bis(hydroxynaphthoic amide)s
SCHEME 1
TABLE 1. Con d ition s a n d Yield s of th e Cycliza tion a n d
Rea r r a n gem en t Rea ction s
fix the twisted conformation by introducing a chiral group
into the macrocyclic system in the expectation that the
chiral group would be able to control the direction of the
twist and that adjusting the ring to a suitable size would
make the transition energy for flipping of the two
hydroxyaryl groups high enough to prevent it occurring
at room temperature. This macrocyclic system has three
distinctive features: (1) the acidic hydroxy groups can
contribute to host-guest interaction and/or chelation to
metal ions, (2) the C2 symmetry of the system presents
the fascinating possibility of using the system as a chiral
ligand for a metal catalyst, because the number of
diastereomeric transition states in metal-catalyzed enan-
tioselective processes will be restricted,8 and (3) the
flexibility of the isobutenylene unit allows for dynamic
conformational change.
In this paper, we describe both the synthesis of new
macrocyclic bis(hydroxynaphthoic amide)s via the tan-
dem Claisen rearrangement and the twisted conforma-
tions they adopt, as well as the activation energies for
the flipping of these conformations.
Resu lts a n d Discu ssion
Macrocyclic bis(hydroxynaphthoic amide)s 6a -f were
synthesized from methyl 3-hydroxy-2-naphthoate (1) in
four steps as shown in Scheme 1. Compound 1 was
treated successively with sodium hydride and isobuten-
ylene dichloride (2) to give bis(aryl ether) 3. After
hydrolysis of 3, the resultant dicarboxylic acid 4 was
converted to the diacyl halide by treatment with thionyl
chloride and then allowed to react with either an achiral
or a chiral diamine under high dilution conditions. All
of the reactions proceeded very smoothly, and the mac-
rocyclic diamides 5 were obtained in acceptable yields.
The results are listed in Table 1.
Macrocyclic bis(hydroxynaphthoic amide)s 6 were ob-
tained by the tandem Claisen rearrangement of macro-
cyclic diamides 5. At first, the tandem Claisen rearrange-
ments were performed in the molten state; for those
macrocyclic diamides 5 melting rapidly at a temperature
lower than 220 °C (Table 1, entries 2, 3, 7, and 8),
rearrangement in the molten state gave 6 in satisfactory
yields, whereas the rearrangement gave only poor results
with macrocyclic diamides 5 which did not melt easily
at a temperature lower than 220 °C (Table 1, entries 1,
4, 5, and 6). For such macrocyclic diamides 5, the
rearrangements were carried out in solution in N,N-
dimethylaniline, which had previously been reported to
be a good solvent for the Claisen rearrangement.9 In
(9) Wang, J .; Gutsche, C. D. J . Am. Chem. Soc. 1998, 120, 12226-
12231.
(8) Whitesell, J . K. Chem. Rev. 1989, 89, 1581-1590.
J . Org. Chem, Vol. 68, No. 15, 2003 5813

Yoshida et al.
F IGURE 2. CD spectra of 6c-e,g in acetonitrile.
hindrance between the two hydroxynaphthalene groups.
Moreover, the fact that the CD spectrum of acyclic (R,R)-
6g, a ring-opened analogue of macrocyclic (S,S)-6b, did
not show any remarkable Cotton effect strongly supports
the conclusion that the Cotton effect of 6b results not
from the chirality of the amine moiety, but rather from
the twisted conformation of the hydroxynaphthalene
rings, and that the macrocyclic structure is essential for
this chirality to be induced (Figure 2). The Cotton effect
of (1R,2R)-1,2-cyclohexanediamine-linked (R,R)-6c was
almost the same as that of (1R,2R)-1,2-diphenylethyl-
enediamine-linked (R,R)-6b (Figure 2), indicating that
the conformation of the two hydroxynaphthalene rings
in the rearranged product 6c is very similar to the
twisted conformation of 6b in solution. Moreover, (S,S)-
6b and (S,S)-6c gave Cotton effects that were mirror
images of those of (R,R)-6b and (R,R)-6c, respectively.
These results clearly indicate that the chiral diamine
components do indeed control the direction of the twist.
(2S,3S)-2,3-Isopropylidenedioxy-1,4-butanediamine-
linked (S,S)-6e showed a Cotton effect that was clearly
weaker than those of (R,R)-6b and (R,R)-6c, even though
in this case too the Cotton effect arose from a twisted
conformation of the two hydroxynaphthalene rings, the
enlargement of the ring size (from the fifteen-membered
rings of (R,R)-6b and (R,R)-6c to the 17-membered ring
of (S,S)-6e) makes the twist of the hydroxynaphthalene
rings smaller, diminishing the Cotton effect. In contrast,
cis-1,2-cyclohexanediamine-linked 6d showed no Cotton
effect, as expected for a meso form. These CD spectral
observations indicate that the chirality arising from the
twisted conformation is induced by the chiral diamine
component of macrocyclic bis(hydroxynaphthoic amide)s
6.
F IGURE 1. CD and UV spectra of (R,R)-5b and (R,R)-6b in
acetonitrile.
general, the yields of the rearranged products were
higher when the rearrangements were carried out in the
molten state, when possible.
The CD and UV spectra of macrocyclic diamide 5b and
bis(hydroxynaphthoic amide) 6b are shown in Figure 1.
(1R,2R)-1,2-Diphenylethylenediamine-linked (R,R)-5b
showed a very weak Cotton effect centered at 220 nm,
which can be ascribed to the chirality of the 1,2-diphen-
ylethylenediamine unit. The Cotton effects of (1S,2S)-
1,2-diphenylethylenediamine-linked (S,S)-5b, (1R,2R)-
1,2-cyclohexanediamine-linked (R,R)-5c, (1S,2S)-1,2-cy-
clohexanediamine-linked (S,S)-5c, and (2S,3S)-2,3-iso-
propylidenedioxy-1,4-butanediamine-linked (S,S)-5e were
essentially the same as that of (R,R)-5b, except for
differences in the signs of the first and second Cotton
effects; the observed Cotton effect arises from the chiral
diamine components. These results indicate that there
is no contribution of the naphthalene rings to the Cotton
effects for the unrearranged macrocycles 5. On the other
hand, the rearranged product, the (1R,2R)-1,2-diphenyl-
ethylenediamine-linked bis(hydroxynaphthoic amide)
(R,R)-6b, showed a large Cotton effect centered at 250
nm. Since the UV absorption at 250 nm is caused by the
transition of the long axes of the hydroxynaphthalene
rings, this Cotton effect must be induced by the two
hydroxynaphthalene rings, i.e., by the chirality arising
from distortion of the long axes of the hydroxynaphtha-
lene rings (a twisted conformation) in solution. The
difference in CD spectral behavior between the unrear-
ranged compound 5b and the rearranged compound 6b
arises from their structural features; in the case of 5b,
the naphthalene rings are connected by a long and
flexible isobutenylenedioxo group and there are no steric
interactions inside the macrocycle, while the hydroxy-
naphthalene rings of 6b are linked by the obviously
shorter and rather rigid isobutenylene group, making the
flipping of the twisted conformation hard due to the steric
X-ray crystallographic analyses were performed for bis-
(hydroxynaphthoic amide)s (R,R)-6b, (R,R)-6c, (S,S)-6e,
and 6f. As can be seen from Figure 3, in all cases, the
two hydroxynaphthalene rings are twisted due to the
steric hindrance between them to generate a C2 axis
through the CdC bond of the isobutenylene moiety. Thus,
the isobutenylenedinaphthyl moiety becomes chiral. The
crystal of (1R,2R)-1,2-diphenylethyleneamine-linked (R,R)-
5814 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Macrocyclic Bis(hydroxynaphthoic amide)s
F IGURE 3. Crystal structures of (a) (R,R)-6b, (b) (R,R)-6c, (c) (S,S)-6e, and (d) 6f. Solvent molecules are omitted for clarity.
6b belongs to the space group P212121, indicating that it
consists of molecules of a single diastereomer and that
the absolute configuration of the twisted isobutenylene-
dinaphthyl moiety is fixed to be M because of the chirality
of the (1R,2R)-diphenylethylenediamine component. The
crystal structures of (1R,2R)-1,2-cyclohexanediamine-
linked (R,R)-6c and (2S,3S)-2,3-isopropylidenedioxy-1,4-
butanediamine-linked (S,S)-6e are very similar to that
of (R,R)-6b; the twisted conformation is fixed to be M.
These results strongly suggest that the absolute config-
uration of the isobutenylenedinaphthyl moiety in the
macrocyclic bis(hydroxynaphthoic amide)s linked with a
chiral diamine is determined by the absolute configura-
tion of the substituents on the chiral diamine component.
Even the two hydroxynaphthalene rings of achiral 2,2-
dimethyl-1,3-propanediamine-linked 6f also adopt a
twisted conformation in the crystalline state as do chiral
6b,c,e, although its crystal includes both P and M twisted
conformations.
naphthalene rings in these macrocyclic bis(hydroxynaph-
thoic amide)s connected by a chiral diamine are twisted
counterclockwise. The X-ray crystal structures of (R,R)-
6b, (R,R)-6c, and (S,S)-6e also showed that their hy-
droxynaphthalene rings takes up a counterclockwise
twisted conformation (Figure 3). These observations
indicate that the conformations of (R,R)-6b, (R,R)-6c, and
(S,S)-6e in solution and in the crystalline state are
similar to each other and that locking of the twisted
conformation is governed by the chiral diamine compo-
nent in these macrocyclic bis(hydroxynaphthoic amide)s.
Variable-temperature NMR measurements were car-
ried out for the macrocyclic bis(hydroxynaphthoic amide)s
6. The NMR spectrum of ethylenediamine-linked, 15-
membered 6a at 30 °C showed two sets of split signals
corresponding to the methylene protons of the isobuten-
ylene and ethylenediamide parts, and these signals
became broader on raising the temperature, as shown
in Figure 4. At 70 °C, the signals of the methylene
protons of the isobutenylene part fused to a singlet, and
the signals of the methylene protons of the ethylenedia-
mide part became extraordinarily broad, the signal being
hard to distinguish from the baseline. At 80 °C, the
signals of the methylene protons of the ethylenediamide
part coalesced. Upon further raising the temperature,
each of the two methylene signals reappeared as a
singlet. On the other hand, the signals of the methylene
protons of 16-membered 6f were broad singlets even at
-10 °C (Figure 5). Lowering the temperature led to
The CD exciton chilarity method10 is known to be
useful for explaining the relationship between two exci-
tons in solution. As shown in Figures 1 and 2, each of
(R,R)-6b, (R,R)-6c, and (S,S)-6e showed a negative
primary Cotton effect and a positive secondary Cotton
effect. This means that the long axes of the two hydroxy-
(10) (a) Berova, N.; Nakanishi, K. In Circular Dichroism-Principles
and Applications; Berova, N., Nakanishi, K., Woody, R. W., Eds.; Wiley-
VCH: New York, 2000; pp 337-382. (b) Harada, N.; Nakanishi, K.
Circular Dichroic Spectroscopy-Exciton Coupling in Organic Stereo-
chemistry; University Science Books: Mill Valley, CA, 1983.
J . Org. Chem, Vol. 68, No. 15, 2003 5815

Yoshida et al.
F IGURE 5. Vt NMR spectra of 6f in CD2Cl2 (300 MHz).
F IGURE 4. Vt NMR spectra of 6a in DMSO-d6 (300 MHz).
TABLE 2. Activa tion En er gies for F lip p in g
entry substrate Tc/K δνa/Hz J a/Hz ∆Gq b/kcal mol-1
splitting of the signals of two sets of methylene protons.
At -50 °C, two signals were observed for the methylene
protons of the diamide part, and the signal of the
methylene protons of the isobutenylene part split at -60
°C. Even though the X-ray crystallographic analysis of
achiral macrocyclic bis(hydroxynaphthoic amide) 6f
showed that the isobutenylenedinaphthyl moiety has a
twisted conformation, the NMR spectral change observed
for 6f indicates that fast flipping of the two naphthalene
rings takes place at room temperature in solution.
On the basis of these NMR spectral observations, the
activation energies for flipping of the twist conformations
(∆Gq) were estimated to be 16.5 kcal mol-1 for 15-
membered 6a and 10.8 kcal mol-1 for 16-membered 6f
(Table 2).11 In contrast, in the cases of chiral macrocyclic
bis(hydroxynaphthoic amide)s, 15-membered 6b and 6c
and even 17-membered 6e showed no coalescence of any
signals at a temperature of up to 180 °C.
To clarify the behavior of the NMR signals in the series
6b, 6c, and 6e, we performed theoretical calculations for
the flipping of 6b. (R,R)-6b can exist as two diastereo-
mers, (M)-(R,R)-6b and (P)-(R,R)-6b , for which the
absolute configurations of the two hydroxynaphthalene
groups are M and P, respectively. Each geometry was
optimized at the B3LYP/3-21g* level of theory, and the
structures determined are displayed in Figure 6.12 The
Tc
1
2
3
4
5
6a
343
c
c
c
223
159
135
142
65.1
58.2
16.2
16.5
16.8
15.3
16.2
16.5 ( 0.2
(R,R)-6b
(R,R)-6c
6e
6f
10.8 ( 0.2
a
The δν and
J values for the methylene protons of the
b
isobutenylene part are listed. The activation energy was calcu-
lated from the following equation: πSQR[(δν2+6J 2)/2] ) RTc
exp(-∆GqTc/RTc)/Nh.11 c No coalescence of the signals was observed
up to a temperature of 180 °C.
Cchiral center plane and the Cphenyl-Cchiral center-Namide plane
are 166.3° and -83.5° for (P)-(R,R)-6b and (M)-(R,R)-6b,
respectively, and (M)-(R,R)-6b is calculated to be 7.9 kcal
mol-1 more stable than (P)-(R,R)-6b. The calculated
structure for (M)-(R,R)-6b is very similar to actually
found for (M)-(R,R)-6b in the crystalline state. The
geometry of the 1,2-diphenyldiamine, optimized using the
same method, is quite similar to that of the chiral linker
part in (P)-(R,R)-6b. This structural information leads
us to the conclusion that lowering the strain of the
twisted conformation of the hydroxynaphthalene rings
dominates the overall stability of (M)-(R,R)-6b, even
though there is an accompanying loss in stability due to
the less favorable conformation of the chiral diamine.
calculated dihedral angles between the Camide-Namide
-
However, the absolute energy difference (7.9 kcal mol-1
)
(11) (a) Curtin, D. Y.; Carlson, C. G.; McCarty, C. G. Can. J . Chem.
1964, 42, 565-571. (b) Shvo, Y.; Taylor, E. C.; Mislow, K.; Raban, M.
J . Am. Chem. Soc. 1967, 89, 4910-4917.
(12) All theoretical calculations were performed employing Beck’s
exchange and Lee-Yang-Parr’s 3parameter correlation functionals
with 3-21g* basis sets using a Gaussian 98 package.
5816 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Macrocyclic Bis(hydroxynaphthoic amide)s
F IGURE 6. Two diastereomers of (R,R)-6b and an intermediate optimized with B3LYP/3-21g*. Dihedral angles are in degrees.
is obviously small enough to allow the existence of not
only (M)-(R,R)-6b but also (P)-(R,R)-6b under the condi-
tions of the present NMR study. A minimum energy
intermediate structure ((R,R)-6bm in ) was also found on
the flipping path. The direction of sliding of the two
hydroxynaphthalene rings governs the conformation of
the isobutenylenedinaphthyl moiety in the product. The
dihedral angles of (R,R)-6bm in corresponding to those in
(M)-(R,R)-6b and (P)-(R,R)-6b are 113.2° and -85.2°. The
energy of (R,R)-6bm in is 10.9 mol-1 higher than (M)-(R,R)-
6b and 3.0 kcal mol-1 higher than (P)-(R,R)-6b. If the
coalescence of (R,R)-6b occurs at greater than 180 °C,
then the activation barrier (∆Gq) is estimated to be
greater than 22.0 kcal/mol. However, the energy of the
intermediate (R,R)-6bm in is not that high compared to
those of (M)-(R,R)-6b and (P)-(R,R)-6b. So, the transition
states for flipping likely lie at an absolute energy level
difference of less than 22 kcal mol-1. These theoretical
calculations and considerations suggest that flipping
occurs under the conditions of the NMR spectral study,
and that the coalescence cannot be detected in a NMR
time scale. However, the equilibrium is largely shifted
toward the more stable diastereomer (M)-(R,R)-6b, since
the chiral linker makes the hydroxynaphthalene rings
of the other diastereomer (P)-(R,R)-6b highly distorted.
the absolute configuration of the substituents on the
chiral diamine component. CD spectra and variable-
temperature NMR spectra of the chiral macrocyclic bis-
(hydroxynaphthoic amide)s, and a theoretical study on
6b showed that chiral linker works effectively to favor
one diastereoisomer enegetically, although the flipping
process occurred within the NMR temperature range.
Exp er im en ta l Section
The general procedure is listed in the Supporting Informa-
tion. The melting points are uncorrected. 1H NMR (300 or 500
MHz) spectra were measured with Me4Si as an internal
standard when CDCl3 was used as solvent; otherwise, residual
protiated solvent was used as an internal standard; the δ and
J values are given in ppm and Hz, respectively. The IR spectra
are recorded in units of cm-1
.
Meth yl 2-[[2-[2-[3-(Meth oxyca r bon yl)n a p h th oxy]m eth -
yl]a llyl]oxy]-3-n a p h th oa te (3). Sodium hydride (7.2 g, 0.3
mol) and potassium iodide (100 mg) were added in succession
at rt to a solution of methyl 3-hydroxy-2-naphthoate (1) (50.5
g, 0.25 mol) in DMF (200 mL). To this yellow suspension was
added 3-chloro-2-chloromethyl-1-butene (2) (15.6 g, 0.125 mol)
at 70 °C, and the mixture was stirred for 3 h. The mixture
was concentrated under reduced pressure and then extracted
with CH2Cl2. After the usual workup, 3 was obtained as a
brownish amorphous mass (56.2 g, 0.123 mol, 98%), which was
used in the following reactions without further purification.
An analytical sample was recrystallized from hexane/diethyl
ether (10/1) to give a yellow solid: mp 98.3-98.7 °C; IR (KBr)
Con clu sion
1
1730, 1630, 1600; H NMR (300 MHz, CDCl3) δ 3.90 (6H, s),
Macrocyclic bis(hydroxynaphthoic amide)s connected
by either an achiral or a chiral diamine were synthesized.
X-ray crystal analyses revealed that the macrocylclic bis-
(hydroxynaphthoic amide)s had a twisted conformation
in the crystalline state because of the steric hindrance
between the two hydroxynaphthalene rings and that the
absolute configuration of the twist was determined by
4.93 (4H, s), 5.59 (2H, s), 7.30 (2H, s), 7.44 (2H, t, J ) 7.5),
7.51 (2H, t, J ) 7.5), 7.71 (2H, d, J ) 8.4), 7.83 (2H, d, J )
8.5), 8.34 (2H, s). Anal. Calcd for C28H24O6: C, 73.67; H, 5.30.
Found: C, 73.67; H, 5.43.
2-[[2-[2-[3-(Meth oxyca r bon yl)n a p h th oxy]m eth yl]a llyl]-
oxy]-3-n a p h th oic Acid (4). An aqueous solution (10 mL) of
sodium hydroxide (370 mg, 9.3 mmol) was added at rt to a
J . Org. Chem, Vol. 68, No. 15, 2003 5817

Yoshida et al.
solution of 3 (1.06 g, 2.32 mmol) in ethanol/THF (4/1) (20 mL).
The mixture was stirred for 4 h at 70 °C. A yellow precipitate
was obtained by adjusting the pH of the mixture to ∼3 by
adding concentrated aqueous HCl. Recrystallization of the
precipitate from THF/H2O (4/1) gave 4 as yellow needles (850
mg, 1.98 mmol, 86%): mp 221-225 °C; IR (KBr) 3000, 1680;
1H NMR (500 MHz, DMSO-d6) δ 4.90 (4H, s), 5.51 (2H, s), 7.40
(2H, t, J ) 7.6), 7.47 (2H, s), 7.53 (2H, t, J ) 7.6), 7.80 (2H, d,
J ) 8.2), 7.94 (2H, d, J ) 8.1), 8.27 (2H, s), 12.96 (2H, s). Anal.
Calcd for C26H20O6: C, 72.89; H, 4.71. Found: C, 72.73; H,
4.97.
(R,R)-N-1-P h en yleth yl 2-[[2-[2-[3-(N-1-p h en yleth ylca r -
bam oyl)n aph th oxy]m eth yl]allyl]oxy]-3-n aph th oic Am ide
((R,R)-5g). (R,R)-5g was obtained from 4 (860 mg, 2.01 mmol)
and R-R-phenylethylamine (484 mg, 3.99 mmol) as a white
solid (1.17 g, 1.84 mmol, 92%).
Syn th esis of Ma cr ocyclic Na p h th ol 6. Compound char-
acterization data for 6b-g are listed in the Supporting
Information.
Ma cr ocyclic Na p h th ol 6a . 5a (150 mg, 0.331 mmol) was
dissolved in N,N-dimethylaniline (5 mL) at 150 °C. The
solution was heated at 180 °C for 2 h to afford a yellow
precipitate. The precipitate was collected by filtration and
washed with CH2Cl2 to give 6a (30 mg, 0.066 mmol, 20%) as
a yellow powder: mp 325-326 °C; IR (KBr) 3320, 1640; 1H
NMR (300 MHz, DMSO-d6) δ 3.14 (2H, d, J ) 7.8), 3.38 (2H,
d, J ) 16.8), 3.70 (2H, d, J ) 15.6), 4.15 (2H, s), 5.43 (2H, s),
7.31 (2H, t, J ) 7.8), 7.50 (2H, t, J ) 7.7), 7.80 (2H, d, J )
8.1), 8.02 (2H, d, J ) 8.4), 8.20 (2H, s), 8.82 (2H, s), 11.35 (2H,
s). Anal. Calcd for C28H24N2O4: C, 74.32; H, 5.35; N, 6.19.
Found: C, 74.55; H, 5.46; N, 6.15.
Ma cr ocyclic Na p h th ol (R,R)-6b. (R,R)-5b (70 mg, 0.116
mmol) was melted at 220 °C by using a glass tube oven
equipped with a vacuum pump. The melt was heated at 180
°C for 1 h. Purification by PTLC (CHCl3×2) gave (R,R)-6b (43
mg, 0.071 mmol, 60%) as a yellow solid. A crystal suitable for
X-ray analysis was obtained from a CH2Cl2 solution by the
vapor diffusion method.
Syn th esis of Ma cr ocycle 5. The synthetic procedure for
5a is representative for the preparation of all the other
compounds 5. Compound characterization data for 5b-g are
listed in the Supporting Information.
Ma cr ocycle 5a . To a suspension of 4 (1.71 g, 4.00 mmol)
in benzene (40 mL) was added thionyl chloride (9.5 g, 80 mmol)
at rt. The mixture was stirred for 10 h at 60 °C to afford a
yellow solution. The solution was concentrated under reduced
pressure to give a yellow solid that was dried under vacuum
at 60 °C. After the solid had been dissolved in benzene (200
mL), triethylamine (1.6 g, 16 mmol) was added at rt. Ethyl-
enediamine (240 mg, 4.00 mmol) in benzene (200 mL) was
added dropwise over 2 h at 50 °C to this solution. After being
stirred for an additional 2 h, the mixture was concentrated
under reduced pressure and then extracted with CH2Cl2. After
the usual workup, 5a was obtained as a white solid (873 mg,
1.70 mmol, 43%): mp 209-211 °C; IR (KBr) 3400, 1640; 1H
NMR (300 MHz, CDCl3) δ 3.83 (4H, dd, J ) 2.9, 3.0), 4.88 (4H,
s), 5.78(2H, s), 7.25 (2H, s), 7.42 (2H, t, J ) 7.7), 7.53 (2H, t,
J ) 7.5), 7.72 (2H, d, J ) 8.1), 7.92 (2H, d, J ) 8.1), 8.29 (2H,
s), 8.77 (2H,s). Anal. Calcd for C28H24N2O4: C, 74.32; H, 5.35;
N, 6.19. Found: C, 74.17; H, 5.32; N, 6.12.
Ma cr ocyclic Na p h th ol (S,S)-6b. (S,S)-5b (75 mg, 0.124
mmol) was melted at 220 °C by using a glass tube oven
equipped with a vacuum pump. The melt was heated at 180
°C for 1 h. Purification by PTLC (CHCl3 × 2) gave (S,S)-6b
(60 mg, 0.099 mmol, 80%) as a yellow solid.
Ma cr ocyclic Na p h th ol (R,R)-6c. According to the proce-
dure given for the preparation of 6a , (R,R)-6c was obtained
from (R,R)-5c (150 mg, 0.296 mmol) as a yellow solid (93 mg,
0.184 mmol, 62%) after purification by PTLC (CHCl3). A crystal
Ma cr ocycle (R,R)-5b. (R,R)-5b was obtained from 4 (428
mg, 1.00 mmol) and (1R,2R)-diphenylethylenediamine (212
mg, 1.00 mmol) as a white solid (182 mg, 0.301 mmol, 30%)
after purification by PTLC (CHCl3 × 5).
suitable for X-ray analysis was obtained from
solution.
a DMSO
Ma cr ocycle (S,S)-5b. (S,S)-5b was obtained from 4 (435
mg, 1.01 mmol) and (1S,2S)-diphenylethylenediamine (214 mg,
1.01 mmol) as a white solid (234 mg, 0.387 mmol, 38%) after
purification by PTLC (CHCl3 × 5).
Ma cr ocyclic Na p h th ol (S,S)-6c. According to the proce-
dure given for the preparation of 6a , (S,S)-6c was obtained
from (S,S)-5c (116 mg, 0.228 mmol) as a yellow solid (64 mg,
0.126 mmol, 55%) after purification by PTLC (CHCl3).
Ma cr ocyclic Na p h th ol 6d . According to the procedure
given for the preparation of 6a , 6d was obtained from 5d (123
mg, 0.243 mmol) as a yellow solid (39 mg, 0.077 mmol, 32%)
after purification by PTLC (CHCl3×2). A crystal suitable for
X-ray analysis was obtained from a DMSO solution.
Ma cr ocyclic Na p h th ol (S,S)-6e. (S,S)-5e (51 mg, 0.092
mmol) was heated at 160 °C for 2 h by using a glass tube oven
equipped with a vacuum pump. Purification by PTLC (CHCl3/
ethyl acetate (2/1) × 2) gave (S,S)-6e (45 mg, 0.081 mmol, 88%)
as a yellow solid. A crystal suitable for X-ray analysis was
obtained from a DMSO solution.
Ma cr ocycle (R,R)-5c. (R,R)-5c was obtained from 4 (857
mg, 2.00 mmol) and (1R,2R)-1,2-cyclohexanediamine (228 mg,
2.00 mmol) as a white solid (300 mg, 0.592 mmol, 30%) after
purification by column chromatography (CHCl3).
Ma cr ocycle (S,S)-5c. (S,S)-5c was obtained from 4 (233
mg, 0.544 mmol) and (1S,2S)-1,2-cyclohexanediamine (62 mg,
0.543 mmol) as a white solid (95 mg, 0.189 mmol, 35%) after
purification by column chromatography (CHCl3).
Ma cr ocycle 5d . 5d was obtained from 4 (857 mg, 2.00
mmol) and cis-1,2-cyclohexanediamine (228 mg, 2.00 mmol)
as a white foam (666 mg, 1.31 mmol, 66%) after purification
by column chromatography (CHCl3).
Ma cr ocyclic Na p h th ol 6f. According to the procedure
given for the preparation of (S,S)-6e, 6f was obtained from 5f
(63 mg, 0.127 mmol) as a yellow solid (27 mg, 0.055 mmol,
43%) after purification by PTLC (CHCl3 × 3). A crystal suitable
for X-ray analysis was obtained from a CH2Cl2 solution.
(R,R)-N-1-P h en yleth yl-2-h yd r oxy-1-[2-[1-[2-h yd r oxy-3-
(N-1-p h en ylet h ylca r b a m oyl)n a p h t h yl]m et h yl]a llyl]-3-
n a p h th oic Am id e ((R,R)-6g). According to the procedure
given for the preparation of (S,S)-6e, (R,R)-6g was obtained
from (R,R)-5g (153 mg, 0.241 mmol) as a yellow solid (104 mg,
0.164 mmol, 68%) after purification by PTLC (benzene/ethyl
acetate (95/5) × 3).
Ma cr ocycle (S,S)-5e. (S,S)-5e was obtained from 4 (857
mg, 2.00 mmol) and (2S,3S)-2,3-isopropylidenedioxy-1,4-bu-
tanediamine (320 mg, 2.00 mmol), which was prepared ac-
cording to the literature methods,14-16 as a white foam (580
mg, 1.05 mmol, 52%) after purification by column chromatog-
raphy (CHCl3/ethyl acetate (4/1)).
Ma cr ocycle 5f. 5f was obtained from 4 (857 mg, 2.00 mmol)
and 2,2-dimethyl-1,3-propanediamine (204 mg, 2.00 mmol) as
a white foam (821 mg, 1.65 mmol, 83%) after purification by
column chromatography (CHCl3).
(13) Zijlstra, R. W. J .; J ager, W. F.; Lange, Ben.; Duijnen, P.;
Feringa, Ben. L.; Goto, H.; Saito, A.; Koumura, N.; Harada, N. J . Org.
Chem. 1999, 64, 1667-1674.
(14) Reduction of tartaricamide: Haines, A. H.; Morley, C.; Murrer,
B. A. J . Med. Chem. 1989, 32, 742-745.
(15) Isopropyridenation of tartaric acid: Mash, E. A.; Nelson, K. A.;
Van Deusen, S.; Hemperly, S. B. Org. Synth. 1990, 68, 92-103.
(16) Amidation of tartaric acid: Carroll, F. I. J . Org. Chem. 1966,
31, 366-368.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for (R,R)-6b, (R,R)-6c, 6d , (S,S)-6e, and 6f, compound
characterization data for 5b-g and 6b-g, and 1H NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O0340298
5818 J . Org. Chem., Vol. 68, No. 15, 2003