Isocyanurates with planar chirality: Design, optical resolution, and isomerization

Article abstract of DOI:10.1002/chir.22093

Designs and syntheses of isocyanurates (1-3) are described on the basis of a novel concept that two enantiotopic faces of C_s-symmetric, prochiral planar molecules are differentiated with a location of groups at the top or bottom of the planar skeleton using a rigid linker. Such isocyanurates are atropisomeric. The planar-chiral structures of and _anti (anti-conformer of) were confirmed by single-crystal X-ray analyses, and the space groups were P1 (for) and P2₁/c (for _anti), resulting that the crystals were racemates. Optical resolutions of 1-3 were successfully accomplished by using chiral high-performance liquid chromatography technique in combination with circular dichroism, absorption, and nuclear magnetic resonance spectroscopies and mass spectrometry. Furthermore, the rotational barriers (ΔGs) related to isomerizations of 1-3 were estimated to be 27.2 (for at 50 °C), 27.6 (for _anti at 50 °C), and 40.6 (for _syn at 150 °C) kcal/mol. The ΔGs of and were higher than that of and, in particular, that of was highest among them. This result indicates that an introduction of bulky substituents and an intramolecular bridging are effective for inhibitions of the isomerizations. Copyright

Full text of DOI:10.1002/chir.22093

CHIRALITY (2012)
Isocyanurates with Planar Chirality: Design, Optical Resolution,
and Isomerization
*
HIDETOSHI GOTO, MASANAO SUDOH, KEIKO KAWAMOTO, HIROSHI SUGIMOTO, AND SHOHEI INOUE
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
ABSTRACT
Designs and syntheses of isocyanurates (1–3) are described on the basis of a novel
concept that two enantiotopic faces of Cs-symmetric, prochiral planar molecules are differentiated
with a location of groups at the top or bottom of the planar skeleton using a rigid linker. Such isocya-
nurates are atropisomeric. The planar-chiral structures of 1 and 2anti (anti-conformer of 2) were con-
firmed by single-crystal X-ray analyses, and the space groups were P1 (for 1) and P21/c (for 2anti),
resulting that the crystals were racemates. Optical resolutions of 1–3 were successfully accom-
plished by using chiral high-performance liquid chromatography technique in combination with
circular dichroism, absorption, and nuclear magnetic resonance spectroscopies and mass spectrom-
etry. Furthermore, the rotational barriers (DG{s) related to isomerizations of 1–3 were estimated to
be 27.2 (for 1 at 50 ꢀC), 27.6 (for 2anti at 50 ꢀC), and >40.6 (for 3syn at 150 ꢀC) kcal/mol. The DG{s of
2 and 3 were higher than that of 1 and, in particular, that of 3 was highest among them. This result
indicates that an introduction of bulky substituents and an intramolecular bridging are effective for
inhibitions of the isomerizations. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: planar chirality; isocyanurate; atropisomerism; chiral resolution; racemization;
isomerization; thermodynamics; kinetics
INTRODUCTION
chiral metallocenes and p-arene complexes are representatives
(Fig. 1C).10–14,20–31 Bridging between P and Q with two
flexible linkers (L1s) generates cyclic molecules such as
cyclophanes1–9,15–19 and strapped porphyrins,50–56 which is
also one of the most widely used strategy (Fig. 1D). Herein,
if a single rigid linker (L2) is employed instead of the L1s,
the planar-chiral structure might be retained, which is our
concept (Fig. 1E) (see footnote1). As the prochiral planar
skeletons (Ps) in Figure 1D and E rotate around the bonds
between P and L1 or L2, the planar-chiral compounds are
Planar-chiral molecules have been developed from the aspect
of not only unique three-dimensional structures1–14 but also
potential applications to auxiliaries and catalysts for asymmetric
syntheses,15–31 catalysts for stereospecific polymerizations,32,33
and chiral sensors.34,35 Our previous interests were focused on
chiral porphyrins36–62 having topological chiralities to provide
model compounds of chiral porphinoids being abundant in
living systems.63–73 In particular, planar-chiral porphy-
rins41,42,44,50–52 were found to work as effective chiral cata-
lysts for asymmetric oxidations and as effective selectors
for biomolecules. Among such planar-chiral porphyrins, we
have paid attention to topological, chiral structures of
strapped (or fly-over) porphyrins adopting cyclophane-type
structures composed of planar porphyrin rings and flexible
straps via covalent linkages.50–56 Most recently, we designed
planar-chiral metal complexes on the basis of our novel
concept: planar structures built up of metal species and two
metal-coordinating moieties via coordination bond may be
employed as alternatives of planar porphyrin rings.74 In fact,
fly-over-type metal complexes consisting of square-planar-
coordinated metals and achiral flexible tetradentate ligands
were synthesized, and the optical resolutions of the racemic
complexes were subsequently accomplished.74
In general, such planar-chiral molecules have been developed
on the basis of design concepts as follows (Fig. 1). Achiral planar
skeletons (D1h-symmetry) are desymmetrized by attachment
of substituent or functional groups to form prochiral planar
skeletons (P) (Cs-symmetry) with enantiotopic planes; the
orientations of the planes are indicated by arrow (Fig. 1A).
As functional groups (Q) are located at the top or bottom of
the prochiral planar skeletons (P) through covalent or coordina-
tion bonding, the molecules are planar-chiral (C1-symmetric)
(Fig. 1B). Metal (Q)-coordination perpendicular to the
enantiotopic plane of P is one of the most widely used strategy;
© 2012 Wiley Periodicals, Inc.
*Correspondence to: Hiroshi Sugimoto, Department of Industrial Chemistry,
Faculty of Engineering, Tokyo University of Science, 12-1 Ichigaya-funaga-
wara, Shinjuku, Tokyo 162-0826, Japan. E-mail: hrssgmt@rs.kagu.tus.ac.jp
Received for publication 13 April 2012; Accepted 06 June 2012
DOI: 10.1002/chir.22093
Published online in Wiley Online Library
(wileyonlinelibrary.com).
1Both models of two compounds as shown in Figure 1D and E have two
topological chiralities. One is planar chirality generated as the achiral
desymmetrized planes (Ps) are marked from out-of-plane, substituent or
functional groups (Q and L1 or L2). The other is axial chirality generated
as the bonds between the planes (Ps) and the groups (L1 or L2) are
focused on. During such chiralities, we have paid attention on the planar
chirality in this report. This is due to two following points. First, the differ-
ence between our planar-chiral concept and axially chiral aromatic
systems such as 1,1-binaphthol is the existence of the phenyl (Q) group
connected to the phenylene (L2) group. The bulky Q group covers the
top or bottom of the isocyanurate (P) platform by the steric repulsion
between the phenyl and isocyanurate rings. Secondly, our motivation is
to develop analogs of planar-chiral porphinoids and to utilize the isocyanu-
rate skeletons as the platform of the functional materials. In fact, in our
laboratory, metalloporphyrins have frequently been employed not only
as chiral catalysts for asymmetric syntheses and chiral selectors for
biomolecules36–62 but also as catalysts for precision macromolecular
syntheses (polymethacrylates, polyesters, polyethers, polycarbonates,
and so on).118 In addition, we employed an isocyanurate skeleton as the
platform for distinguishing enantiomers of guest molecules as described
in the following sections. The isocyanurates had flexible amino acid units
with central chirality.96

GOTO ET AL.
because the isocyanurate framework is a rigid six-membered
ring and has three O atoms with electron-donating properties
and three N atoms to which a variety of functional groups is
connected. Optically active isocyanurates having three flexi-
ble amino acid units were previously reported to distinguish
between enantiomers of guest molecules.96 In this study, a
planar-chiral isocyanurate [1-(biphenyl-2-yl)-3-phenyl-1,3,
5-triazinane-2,4,6-trione (1)] bearing phenyl and 20-biphenyl
groups at two N atoms of the isocyanurate backbone was
designed (Fig. 3). Although the synthesis and optical resolu-
tion of 1 ahead of 1,3-bis(biphenyl-2-yl)-1,3,5-triazinane-2,4,
6-trione (2) and O,O0-(hexane-1,6-diyl)-1-(3-oxybiphenyl-2-yl)-
3-(2-oxyphenyl)-1,3,5-triazinane-2,4,6-trione (3) were accom-
plished, racemization of 1 proceeded at ambient temperature.
Our ideas to suppress the atropisomerization of 1 were to
introduce a bulky substituent (for 2) and to intramolecularly
bridge (for 3). Racemization of 2 was slower than that of 1,
and no racemization of 3 was observed. The details will be
described hereinafter.
Fig. 1. Designs of planar-chiral molecules based on achiral planar
skeletons. The planar skeletons (D1h-symmetry) are desymmetrized by
attachment of substituent or functional groups to form prochiral planar
skeletons (P) (Cs-symmetry) with enantiotopic planes; the orientations of the
planes are indicated by arrow (A). Planar-chiral molecules are generated by
introduction of Q at the top or bottom of the enantiotopic plane of P through
linkages or interactions (B). Chiral metal complexes using coordination bondings
(C), chiral molecules using flexible covalent linkages (D), and planar-chiral mole-
cules using rigid covalent linkages based on our concept (E).
MATERIALS AND METHODS
Materials
Dimethyl cyanocarbonimidodithioate, 2-phenylaniline, bromobenzene,
BBr3 (1M in CH2Cl2), and 1,6-dibromohexane were purchased from Tokyo
Chemical Industry (Tokyo, Japan). Isocyanatobenzene and 1-isocyanato-2-
methoxybenzene were purchased from (Sigma-Aldrich (St. Louis, MO,
USA). Trifluoroacetic acid was purchased from Wako Pure Chemical In-
dustries (Osaka, Japan). Triethylamine (Et3N) and 1,4-dioxane were dried
with CaH2 and then distilled over sodium benzophenone ketyl under
nitrogen. Acetonitrile and CH2Cl2 were dried with CaH2 and then distilled
over CaH2 under nitrogen. Isocyanatobenzene, 2-isocyanato-1,10-biphenyl,
1-isocyanato-2-methoxybenzene, 1,6-dibromohexane, and bromobenzene
were distilled under reduced pressure. Dimethyl cyanocarbonimidodithioate
was recrystallized from toluene. Other reagents were used without puri-
fication. Compound 797 and ethyl N-carbonylcarbamate98 were synthe-
sized by the literatures’ methods.
isomerized (Fig. 2A and B). Because the atropisomerizations
of the cyclophanes are prevented by bulky groups (Rs) intro-
duced to P, the inhibition of the isomerizations of the concep-
tual, planar-chiral molecules might be accomplished in the
similar way as well. Furthermore, the arrangement of two R
units at equally neighboring positions of the bond between
P and L2 induces an orthogonal conformation of L2–Q against
P (Fig. 2B). Cyclic N-phenylimides adopt the orthogonal con-
formation due to steric repulsion between the ortho H atoms
of the phenyl group and the O atoms (Fig. 2C).75–77
We have focused our interests on isocyanurate78–95 for the
purpose of the synthesis and utility of novel enzyme models
Instruments
Hydrogen and carbon nuclear magnetic resonance (1H and 13C NMR)
measurements were performed at 400 and 100 MHz with CDCl3 or
DMSO-d6 as the solvents at 30 ꢀC on a Bruker BioSpin DPX-400 spectrom-
eter (Billerica, MA, USA). They were referenced using tetramethylsilane
(TMS; d 0.00) or the solvent residual signal as an internal standard. The
chemical shift values are expressed as d values (ppm), and the couple con-
stants values (J) are in Hertz (Hz). The following abbreviations were used
for signal multiplicities: s, singlet; d, doublet; t, triplet; dd, double-doublet;
dt, double-triplet; m, multiplet; and br, broad. Infrared (IR) spectra were
recorded using a JASCO FT/IR-4100 spectrometer (Hachioji, Japan).
Electron spray ionization mass spectra were measured using a Bruker
Daltonics microTOF-NR focus mass spectrometer. Absorption measure-
ments were performed on a JASCO V-550 spectrometer. Circular dichroism
(CD) measurements were carried out with a JASCO J-725 spectropolari-
meter. Optical rotations were measured using a Horiba SEPA-200 polarim-
eter (Kyoto, Japan). Melting points were measured using a MEL-TEMP II
melting point apparatus (Laboratory Devices, Holliston, MA, USA).
Elemental analyses were performed by using a Perkin-Elmer 2400II
Fig. 2. Atropisomerization mechanisms of cyclophanes (A) and our con-
ceptual planar-chiral molecules (B) and models of planar-chiral molecules
bearing bulky groups (R) for inhibition of atropisomerization. (C) Conforma-
tion of N-phenyl-substituted cyclic imides.
Fig. 3. Design concept and structures of planar-chiral isocyanurates (1–3).
Chirality DOI 10.1002/chir

PLANAR-CHIRAL ISOCYANURATES
CHN analyzer (Waltham, MA, USA). High-performance liquid chromatog-
been deposited with the Cambridge Crystallographic Data Centre
(CCDC-857457). Copies of the data can be obtained, free of charge, on appli-
cation to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, United
Kingdom (Fax: 44-1223-336033 or E-mail: deposit@ccdc.cam.ac.uk).
raphy (HPLC) experiments for estimations of enantiomeric excesses were
carried out on a Hitachi instrument (L-7610 degasser, L-6000 pump,
L-7400 UV detector, and D-2500 integrator) (Tokyo, Japan) with a
SumichiralW OA-4600 [25 ꢁ 0.46 (i.d.) cm, 5 mm particle; Sumika Chemical
Analysis Service, Tokyo, Japan]. HPLC experiments for separations and
isolations of stereoisomers were performed on a Hitachi instrument
(L-7110 pump, L-7250 autosampler, L-4000 H UV detector, L-5200 fraction
collector, and D-2500 integrator) with a SumichiralW OA-4600 [25ꢁ 2 (i.d.)
cm, 5 mm particle]. Single crystal X-ray analyses were conducted using a
Bruker AXS SMART X-ray diffractometer equipped with a CCD area direc-
tor and Mo-Ka radiation (l = 0.71073 Å).
Synthesis of Isocyanurate 2
1-[1,5-Bis(biphenyl-2-yl)-4-(methylthio)-6-oxo-5,6-dihydro-1,3,5-
triazin-2(1H)-ylidene]-3-phenylurea (6)99. After Et3N (8.5 ml, 60 mmol)
was added to a white suspension of 4 (13.0 g, 48.4 mmol) in acetonitrile
(170 ml under nitrogen), the mixture was heated at 40 ꢀC for 30 min.
2-Isocyanato-1,10-biphenyl (17.6 ml, 102 mmol) was dropwise added to
the suspension at 60 ꢀC over 10 min. The white suspension became a
colorless clear solution during the dropwise addition. When heated at
60 ꢀC for approximately 1 h, the mixture gradually changed to a white
suspension powder. After heating the suspension at 60 ꢀC for 24 h,
the precipitate was collected by suction filtration and washed with
acetonitrile to afford 6 as a white powder. The filtrate was concen-
trated under high vacuum to leave a crude product as a white powder.
The crude product was purified by silica gel chromatography with
CHCl3/acetone (15/1, v/v) and subsequent recrystallization from
CHCl3/hexane twice to obtain 6 as a white powder (total yield: 16.0 g,
24.3 mmol, 50.1%). mp: 172.7–175.2 ꢀC (dec). 1H NMR (CDCl3): d 2.29
(s, 3H, CH3), 6.29 (s, 1H, NH), 6.91 (d, J = 7.6 Hz, 1H, Ar–H), 6.95
(dd, J = 7.6 and 1.6Hz, 1 H, Ar–H), 6.99–7.18 (m, 6H, Ar–H), 7.22
(dd, J = 7.6 and 1.6 Hz, 1H, Ar–H), 7.26–7.35 (m, 4H, Ar–H), 7.36–7.48
(m, 12H, Ar–H), 7.55 (dt, J = 7.6 and 1.2 Hz, 1H, Ar–H), 8.05 (br, 1H,
Ar–H). 13C NMR (CDCl3): d 15.46, 123.84, 124.62, 127.17, 127.77,
128.15, 128.20, 128.26, 128.46, 128.55, 128.59, 128.72, 128.83, 128.87,
128.98, 129.17, 129.23, 129.51, 129.66, 129.90, 130.31, 130.43, 130.83,
131.02, 131.71, 132.04, 132.23, 132.86, 134.70, 138.13, 138.53, 139.13,
140.03, 142.61, 146.53, 149.54, 160.18, 167.08. IR (KBr, cmꢂ1): 3394
(nN-H), 1734 (nCO), 1693 (nCO), 1638 (nN-H), 1505 (nCN).
Synthesis of Isocyanurate 1
Methyl N-(biphenyl-2-yl)-N0-cyanoimidothiocarbamate (4)99
. A
solution of dimethyl cyanocarbonimidodithioate (73.1 g, 500 mmol)
purified by recrystallization and 2-phenylaniline (84.6 g, 500 mmol) in
ethanol (500 ml) was heated under reflux. The color of the solution grad-
ually changed from slight yellow to brown during heating. After being
heated for 11 days, the mixture was cooled to room temperature. The
mixture was concentrated under high vacuum to leave a crude product
as a white powder. The product was purified by recrystallization from
ethanol to afford 4 as a slightly yellow needle crystal (27.6 g, 103 mmol,
20.6%). mp: 166.8–168.5 ꢀC. 1H NMR (CDCl3): d 2.31 (s, 3H, CH3), 7.34
(d, J = 6.4 Hz, 2H, Ar–H), 7.37–7.45 (m, 5H, Ar–H), 7.48 (t, J = 6.4 Hz, 2H,
Ar–H), 7.66 (br, 1H, NH). 13C NMR (CDCl3): d 14.56, 114.51, 127.15,
128.41, 128.57, 129.03, 129.09, 130.95, 132.98, 137.48. IR (KBr, cmꢂ1):
3198 (nN-H), 2170 (nCꢃN), 1524 (nCN).
1-[5-(Biphenyl-2-yl)-4-(methylthio)-6-oxo-1-phenyl-5,6-dihydro-
1,3,5-triazin-2(1H)-ylidene]-3-phenylurea (5)99. After Et3N (1.14 ml,
8.36 mmol) was added to a white suspension of 4 (2.14 g, 8.00 mmol) in
acetonitrile (24 ml under nitrogen), the mixture was heated at 60 ꢀC for
30 min. Isocyanatobenzene (1.74 ml, 16.0 mmol) was dropwise added to
the suspension at 60 ꢀC over 10 min. The white suspension became a
slightly yellow solution during the dropwise addition. After being stirred
at 60 ꢀC for 4 h, the reaction mixture was cooled to room temperature.
The mixture was concentrated under high vacuum to leave a crude
product as a yellow powder. The product was purified by recrystallization
from CHCl3/hexane twice to afford 5 as a white powder (3.90 g, 7.72 mmol,
96.5%). mp: 215.3–217.1 ꢀC. 1H NMR (CDCl3): d 2.38 (s, 3H, CH3), 6.78
(s, 1H, NH), 7.01 (t, J=7.2Hz, 1H, Ar–H), 7.13 (d, J= 7.2 Hz, 2H, Ar–H),
7.25 (t, J = 7.2 Hz, 2H, Ar–H), 7.31–7.48 (m, 12H, Ar–H), 7.50 (dt, J = 7.6
and 1.2 Hz, 1H, Ar–H), 7.59 (dt, J = 7.6 and 1.2 Hz, 1H, Ar–H). 13C NMR
(CDCl3): d 15.56, 119.35, 123.39, 128.34, 128.44, 128.57, 128.66, 128.92,
128.95, 129.04, 129.55, 129.87, 131.17, 131.68, 131.70, 135.13, 137.79,
138.75, 142.14, 149.10, 167.63. IR (KBr, cmꢂ1): 3407 (nN-H), 1731
(nCO), 1682 (nCO), 1636 (nC-N), 1511 (nCN).
1,3-Bis(biphenyl-2-yl)-1,3,5-triazinane-2,4,6-trione (2)99
. After 6
(16.0 g, 24.3 mmol) was dissolved in 1,4-dioxane (320 ml) under reflux,
an HCl aqueous solution (2 M, 450 ml, 900 mmol) was added to the solu-
tion. After being heated under reflux for 2.5 h, the mixture was cooled to
room temperature. The mixture was concentrated under high vacuum to
leave a crude product as a yellow solid. The product was purified by silica
gel chromatography with CHCl3/acetone (15/1, v/v) and subsequent
recrystallization from benzene twice to afford 2 as a white solid (total
yield: 2.52 g, 5.88 mmol, 24.2%). mp: 224.8–226.1 ꢀC. 1H NMR (CDCl3):
d 6.91 (dd, J = 7.6 and 1.2 Hz, 2H, Ar–H), 7.22–7.29 (m, 6H, Ar–H),
7.37–7.46 (m, 10H, Ar–H), 7.49 (dt, J = 7.6 and 1.6 Hz, 2H, Ar–H), 7.63
(br, 1H, NH). 13C NMR (CDCl3): d 128.10, 128.38, 128.48, 128.55,
128.89, 130.10, 130.94, 130.96, 138.31, 141.51, 147.59, 148.88. IR
(KBr, cmꢂ1): 3209 (nN-H), 1727 (nCO), 1698 (nCO). HRMS–ESI (m/z):
[M ꢂ H]ꢂcalcd for C27H18N3O3, 432.1348; found, 432.1346. Anal. Calcd
for C27H19N3O3ꢄ0.1H2O: C, 74.50; H, 4.45; N, 9.65. Found: C, 74.40;
H, 4.25; N, 9.64. Crystallographic data for the structure of 2anti have
been deposited with the Cambridge Crystallographic Data Centre
(CCDC-857458). Copies of the data can be obtained, free of charge, on appli-
cation to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, United
Kingdom (Fax: 44-1223-336033 or E-mail: deposit@ccdc.cam.ac.uk).
1-(Biphenyl-2-yl)-3-phenyl-1,3,5-triazinane-2,4,6-trione (1)99
.
When an HCl aqueous solution (2 M, 50 ml, 100 mmol) was added to a
solution of 5 (1.77 g, 3.50 mmol) in 1,4-dioxane (35 ml), the mixture
gradually became turbid. During heating of the white suspension, the
suspension gradually changed to the colorless clear solution. After being
heated under reflux for 90 min, the reaction mixture was cooled to room
temperature and further stored in a refrigerator (~ 5 ꢀC) for 10 days to
leave a crude product as a white powder. The product was purified by
recrystallization from CHCl3/hexane twice to afford 1 as a white powder
(0.843 g, 2.36 mmol, 67.6%). mp: 212.0–212.5 ꢀC. 1H NMR (CDCl3): d 6.98
(br, 2H, Ar–H), 7.26–7.32 (m, 2H, Ar–H), 7.37 (dd, J = 7.6 and 1.6 Hz, 1H,
Ar–H), 7.39–7.47 (m, 7H, Ar–H), 7.49 (dt, J = 8.0 and 2.0 Hz, 1H, Ar–H),
7.54 (dt, J = 7.2 and 1.6 Hz, 1H, Ar–H), 8.37 (br, 1H, NH). 13C NMR
(CDCl3/CD3OD = 9/1, v/v): d 127.91, 128.20, 128.27, 128.39, 128.66,
129.09, 129.28, 129.35, 129.86, 130.79, 131.16, 133.02, 138.28, 141.33,
148.41, 148.58, 149.37 135.13, 137.79, 138.75, 142.14, 149.10, 167.63. IR
(KBr, cmꢂ1): 3212 (nN-H), 1718 (nCO), 1693 (nCO). HRMS–ESI (m/z):
[M ꢂ H]ꢂcalcd for C21H14N3O3, 356.1035; found, 356.1039. Anal. Calcd
for C21H15N3O3ꢄ0.2H2O: C, 69.88; H, 4.30; N, 11.64. Found: C, 69.81;
H, 3.99; N, 11.64. Crystallographic data for the structure of 1 have
Synthesis of Isocyanurate 3
1-Methoxy-6-phenylaniline (8). NaOH (2.23 g, 55.8 mmol, pellet)
was added to a solution of N-(3-methoxybiphenyl-2-yl)acetamide (7)97
(2.71 g, 11.2 mmol) in ethanol (100 ml). After being heated under reflux
for 8 days, the reaction mixture was cooled to room temperature. The
mixture was concentrated under high vacuum to leave a residue as a
viscous brown liquid. A solution of the residue in CHCl3 was washed
with water, dried over Na2SO4, and concentrated by rotary evaporator
to leave a crude product as a viscous brown liquid. The product was
purified by silica gel chromatography with hexane/ethyl acetate (1/1, v/v)
1
to afford 8 as a brown liquid (1.98 g, 9.94 mmol, 88.7%). H NMR (CDCl3):
d 3.82 (s, 3H, OCH3), 4.28 (br, 2H, NH2), 6.64–7.47 (m, 8H, Ar–H).
MS–ESI (m/z): 201.10 [M + Na]+.
Chirality DOI 10.1002/chir

GOTO ET AL.
1-(3-Methoxybiphenyl-2-yl)-3-(2-methoxyphenyl)urea (9).
120.39, 122.23, 123.35, 123.66, 125.61, 126.98, 127.63, 127.95, 128.06,
128.77, 128.88, 129.00, 139.61, 142.09, 149.38, 155.78, 156.17. IR
(KBr, cmꢂ1): 3323 (nN-H), 1650 (nCO), 1549 (nN-H), 1242 (nC-O-C).
MS–ESI (m/z): 425.18 [M + Na]+.
1-Isocyanato-2-methoxybenzene (1.2 ml, 9.5 mmol) was dropwise added to
a mixture of 8 (1.90 g, 9.54 mmol) and Et3N (0.3 ml, 2.2 mmol) in 1,4-dioxane
(30 ml) at room temperature over 10 min under nitrogen. During stirring of
the mixture at 35 ꢀC, the color of the solution gradually changed from slight
yellow to brown. After stirring the mixture for 4.5 h, the conversion of 8 was
approximately 30%. 1-Isocyanato-2-methoxybenzene (4.0 ml, 30 mmol) was
further added to the mixture. After being stirred at 35 ꢀC for further 4 h,
the mixture was cooled to room temperature. Ethanol was added to
the mixture to quench an excess amount of the isocyanate. The mixture
was concentrated under high vacuum to leave a crude product as a dark
brown viscous oil. The product was purified by silica gel chroma-
tography with CHCl3/methanol (10/1, v/v) to afford 9 as a white
powder (1.34 g, 3.68 mmol, 38.5%). mp: 166.2–167.5 ꢀC. 1H NMR
(DMSO-d6): d 3.81 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 6.80 (dt, J = 7.6
and 1.6 Hz, 1H, Ar–H), 6.86 (dt, J = 7.6 and 1.6 Hz, 1H, Ar–H), 6.92
(dd, J = 8.0 and 1.6 Hz, 1H, Ar–H), 6.95 (dd, J = 8.0 and 1.6 Hz, 1H,
Ar–H), 7.07 (dd, J = 8.0 and 1.2 Hz, 1H, Ar–H), 7.25–7.34 (m, 2H, Ar–H),
7.34–7.42 (m, 4H, Ar–H), 7.97 (dd, J = 8.0 and 1.6 Hz, 1H, Ar–H), 8.02
(br, 1H, NH), 8.10 (s, 1H, NH). 13C NMR (CDCl3): d 55.71, 56.06, 110.04,
110.80, 119.24, 121.27, 122.33, 122.95, 123.57, 127.65, 128.00, 128.51,
128.67, 129.05, 138.83, 140.88, 147.90, 154.22, 155.27. IR (KBr, cmꢂ1):
3320 (nN-H), 1649 (nCO), 1543 (nN-H), 1256 (nC-O-C). MS–ESI (m/z): 349.14
[M + H]+.
O,O0-(Hexane-1,6-diyl)-1-(3-oxybiphenyl-2-yl)-3-(2-oxyphenyl)-1,3,5-
triazinane-2,4,6-trione (3)100,101
.
Ethyl N-carbonylcarbamate98
(1.35 ml, 1.31 mmol) was added to a suspension of 11 (0.533 g, 1.33 mmol)
in dry bromobenzene (60 ml) at room temperature under nitrogen.
During heating of the mixture under reflux, the suspension became a
slightly brown solution during heating. After being heated under reflux
for 24 h, the mixture was cooled to room temperature. The mixture
was concentrated under high vacuum to leave a crude product as a
slightly brown viscous liquid. The product was purified by silica gel
chromatography with CHCl3/acetone (30/1 to 10/1, v/v) and subsequent
reprecipitation with CHCl3/hexane to afford 3 as a white solid (0.152 g,
0.322 mmol, 24.2%). mp: 286.4–288.2 ꢀC. 1H NMR (CDCl3): d 1.47–1.67
(m, 4H, CH2), 1.71 (br, 2H, CH2), 1.81 (br, 2H, CH2), 3.90 (dt, J = 9.2
and 1.6 Hz, 1H, OCH2), 3.99 (dt, J = 9.2 and 1.6 Hz, 1H, OCH2), 4.19
(m, 2H, OCH2), 6.91 (dd, J= 8.0 and 2.0 Hz, 1H, Ar–H), 6.97 (d, J= 7.2Hz,
1H, Ar–H), 6.98 (dd, J = 8.0 and 1.6 Hz, 1H, Ar–H), 7.01 (t, J= 8.0Hz,
2H, Ar–H), 7.26–7.40 (m, 6H, Ar–H), 7.43 (t, J = 8.0 Hz, 1H, Ar–H), 8.21
(s, 1H, NH). 13C NMR (CDCl3): d 27.72, 27.84, 29.07, 29.19, 69.08, 70.04,
112.65, 113.67, 120.61, 121.21, 122.40, 122.50, 127.99, 128.33, 128.37, 129.69,
130.75, 131.16, 138.30, 143.10, 147.70, 147.81, 148.54, 154.78, 154.96. IR
(KBr, cmꢂ1): 3225 (nN-H), 1723 (nCO), 1700 (nCO), 1291 (nC-O-C). HRMS–ESI
(m/z): [M ꢂ H]ꢂcalcd for C27H24N3O5, 470.1716; found, 470.1708. Anal.
Calcd for C27H25N3O5ꢄ0.4H2O: C, 67.74; H, 5.43; N, 8.78. Found: C, 67.71;
H, 5.23; N, 8.74.
1-(3-Hydroxybiphenyl-2-yl)-3-(2-hydroxyphenyl)urea (10). BBr3
(1 M in CH2Cl2, 50 ml, 50 mmol) was dropwise added to a solution of 9
(1.20 g, 3.29 mmol) in CH2Cl2 (300 ml) at 0 ꢀC over 4 h under nitrogen.
During stirring of the solution at room temperature, the color of the
solution gradually changed from colorless to gray. After being stirred
for 18 h, the mixture was carefully poured into water (200 ml) to quench
an excess amount of BBr3. During quenching, a large amount of a white
powder appeared in the mixture. The precipitate was collected by
suction filtration, washed with water, and dried in vacuo to afford 10
as a white powder (1.04 g, 3.25 mmol, 98.7%). mp: 152.6–154.5 ꢀC
(dec.). 1H NMR (DMSO-d6): d 6.68 (dt, J = 7.2 and 1.6 Hz, 1H, Ar–H),
6.74 (dt, J = 7.6 and 1.6 Hz, 1H, Ar–H), 6.77 (dd, J = 8.0 and 1.6 Hz, 1H,
Ar–H), 6.78 (dd, J = 8.0 and 1.6 Hz, 1H, Ar–H), 6.90 (dd, J = 8.0 and
1.6Hz, 1H, Ar–H), 7.14 (t, J = 8.0 Hz, 1H, Ar–H), 7.27–7.34 (m, 1H, Ar–H),
7.39 (d, J = 8.0 Hz, 4H, Ar–H), 7.86 (dd, J = 8.0 and 1.6 Hz, 1H, Ar–H), 8.12
(br, 2H, NH) 9.44 (br, 1H, OH), 9.75 (s, 1H, OH). 13C NMR (DMSO-d6):
d 114.58, 115.64, 118.60, 119.08, 120.79, 121.55, 122.96, 126.84, 126.90,
128.10, 128.71, 139.77, 140.22, 145.50, 153.56, 154.46. IR (KBr, cmꢂ1):
3467 (nO-H), 3288 (nN-H), 1627 (nCO), 1559 (nN-H), 1102 (nC-OH). MS–ESI
(m/z): 343.12 [M+ Na]+.
Optical Resolutions
A typical procedure for optical resolutions of 1–3 is described as follows.
A stock solution (0.5 mg/ml) of 1 in a mixture of hexane/ethanol (9/1, v/v)
including mesitylene (t0 = 8.9 min) as a standard was prepared. A 1.5 ml
aliquot of the 1 solution was injected into an HPLC system [eluent,
hexane/ethanol/trifluoroacetic acid (90/10/0.5, v/v/v); flow speed:
6.5 ml/min] with a SumichiralW OA-4600 [25 ꢁ 2 (i.d.) cm] to collect
fractions. The solvents of the fractions were removed under reduced
pressure at low temperature (less than 20 ꢀC). The same operations
were repeatedly carried out 10 times to give enantiometically pure 1a
(the first eluent) and 1b (the second eluent) as white powders. The
optical purities of the collected fractions were estimated to be more than
98% ee by the HPLC analyses.
Optical resolutions of 2 and 3 were also carried out under the same
conditions except for initial concentrations of stock solutions [1.0 (for 2)
and 0.5 (for 3) mg/ml]. Both chromatograms showed three peaks
(10.9, 13.0, 19.6 min for 2 and 17.9, 19.6, 22.0 min for 3), so all three
components (2a, 2b, 2c for 2 and 3a, 3b, 3c for 3) were fractionated.
To measure optical rotations of the isolated stereoisomers of 1–3, each
stock solution of the isocyanurates in THF [10 mg/3 ml (= 0.333 g/dl)]
was prepared by using measuring flasks. Each stock solution was
transferred to a 1.0 cm quartz cell by a pipet (approximately 2 ml). Optical
rotation measurements of the isomers were performed at ambient tempera-
ture (27–29 ꢀC); 1a [(ꢂ)-1]: [a]2D9ꢂ116 (c 0.333, THF) (aꢂ0.0384), 1b [(+)-1]:
[a]D29 + 120 (c 0.333, THF) (a + 0.0399), 2a [(ꢂ)-2anti]: [a]D28ꢂ141 (c 0.333,
THF) (aꢂ0.0468), 2b [(+)-2anti]: [a]2D7 + 146 (c 0.333, THF) (a + 0.0485), 3a
[(ꢂ)-3syn]: [a]2D9ꢂ126 (c 0.333, THF) (aꢂ0.0420), 3b [(+)-3syn]: [a]2D9 + 127
(c 0.333, THF) (a + 0.0424).
O,O0-(Hexane-1,6-diyl)-1-(3-oxybiphenyl-2-yl)-3-(2-oxyphenyl)
urea (11). 1,6-Dibromohexane (0.50 ml, 3.3 mmol) was added to a
suspension of 10 (1.05 g, 3.27 mmol) and K2CO3 (3.0 g, 22 mmol) in
acetonitrile (1.5 l) at 0 ꢀC under nitrogen, and the mixture was then
stirred at room temperature. After stirring the mixture for 7 days, the
conversion of 10 was approximately 30%. After the mixture was stirred
at 35 ꢀC for further 14 days, the conversion of 10 was over 90%. The color
of the supernatant gradually changed from colorless to yellow during
stirring. After cooled to room temperature, the mixture was concentrated
under high vacuum to leave a yellow solid. After the solid was dissolved
in a mixture of CHCl3/water, the organic solution was collected by a
separating funnel, washed with water, and dried over Na2SO4 to leave a
crude product as a slightly yellow solid. The product was purified by silica
gel chromatography with CHCl3/ethyl acetate (9/1, v/v) to afford 11 as
a white solid (0.623 g, 1.55 mmol, 47.4%). mp: 219.7–223.4 ꢀC (dec.). 1H
NMR (DMSO-d6): d 1.57 (br, 2H, CH2), 1.67 (br, 6H, CH2), 3.96
(br, 2H, OCH2), 4.15 (br, 2H, OCH2), 6.85 (dt, J = 7.6 and 1.6 Hz, 1H,
Ar–H), 6.96 (dd, J = 7.6 and 1.2 Hz, 1H, Ar–H), 6.98 (dd, J = 8.0 and
1.6 Hz, 1H, Ar–H), 7.00 (dt, J = 8.0 and 1.6Hz, 1H, Ar–H), 7.07 (dd, J = 7.2
and 1.2 Hz, 1H, Ar–H), 7.29 (d, J = 8.0 Hz, 1H, Ar–H), 7.34 (dt, J = 8.0 and
1.2Hz, 2H, Ar–H), 7.43 (t, J = 7.6 Hz, 2H, Ar–H), 7.51 (dd, J = 8.0 and
1.2Hz, 1H, Ar–H), 7.69 (br, 1H, NH), 7.85 (br, 1H, NH). 13C NMR
(DMSO-d6): d 26.53, 27.58, 28.59, 29.48, 69.56, 70.77, 113.20, 113.40,
Absorption and Circular Dichroism Measurements
To measure absorption and CD spectra of the isolated stereoisomers of
1–3, each stock solution of the isocyanurates in THF [6.3 mg/100 ml
(0.18 mM for 1 s, 0.14 mM for 2 s, 0.13 mM for 3 s)] was prepared by us-
ing measuring flasks. Each stock solution was transferred to a 0.1-cm
quartz cell by a pipet (approximately 0.5 ml). Absorption and CD spectra
of the stereoisomers of the isocyanurates were measured at the ranges of
200–600 (for absorption) and 210–350 (for CD) nm at room temperature
(25–27 ꢀC).
Chirality DOI 10.1002/chir

PLANAR-CHIRAL ISOCYANURATES
Isomerization Investigations
A typical procedure for the investigations of the isomerizations of the
isolated stereoisomers of the isocyanurates is described as follows. The
solution (0.5 mg/ml) of 1a in a mixture of hexane/ethanol (9/1, v/v)
was prepared and then kept at 50 ꢀC for a predetermined amount of
time. At each predetermined time, a 100 ml aliquot of the solution was
injected into the chiral HPLC system to estimate a stereoisomeric
population of 1. The stereoisomeric populations were plotted versus
time, and then, an initial rate constant (kT) of isomerization was calcu-
lated. Furthermore, the isomerization barrier (DG{) of 1 was calculated
by using kT and Eyring equation: DG{T = ꢂRT ln(kTh/kkBT), where R
is the universal gas constant (8.31441 J K/mol), T the absolute tem-
perature (K), kT the kinetic rate constant, h the Plank’s constant
(6.626176 ꢁ 10ꢂ34 Js), k the transition factor (k =0.5), and kB the Boltzmann
constant (1.380662 ꢁ 10ꢂ23 J/K).102–105
The isomerization investigations of 2 and 3 were also carried out under
the same conditions except for initial concentrations of stock solutions
(1.0 (for 2) and 0.5 (for 3) mg/ml).
RESULT AND DISCUSSION
Synthesis and Characterization of 1
Fig. 4. (A) Ball-and-stick drawing of 1 with thermal ellipsoids at 50%
probability. Each one of the independent molecules is shown here. H atoms
are partially omitted for clarity. (B) Steric illustration of 1 with denotation of
benzene and heterocyclic rings, dihedral angles, spatial distance, and angle:
Ph1, Ph2, Ph3 for three benzene rings; Isc for isocyanurate ring; f, w, c
for three dihedral angles; d for spatial distance between carbon of Ph3
and hydrogen at ortho position of Ph1; for angle of C-H(Ph1)ꢄꢄꢄC(Ph3).
The synthesis of 1 was performed at three steps according
to a method employed for a synthesis of an isocyanurate
having two phenyl groups at two N atoms (Scheme 1).99
2-Phenylaniline as a starting material was reacted with
dimethyl cyanocarbonimidodithioate under an equimolar
condition in ethanol to afford methyl N-(biphenyl-2-yl)-N0-
cyanoimidothiocarbamate (4). A condensation of 4 with two
equivalents of isocyanatobenzene in acetonitrile containing Et3N
formed a corresponding triazine derivative, 1-[5-(biphenyl-
2-yl)-4-(methylthio)-6-oxo-1-phenyl-5,6-dihydro-1,3,5-triazin-2
(1H)-ylidene]-3-phenylurea (5). 5 was hydrolyzed under an
acidic condition with aqueous HCl to obtain 1.
For the purpose of investigating whether 1 forms a chiral
conformation as expected, the characterization of 1 was
carried out by using single crystal X-ray crystallography.
Single crystals of 1 suitable for X-ray crystallographic
analysis were obtained from the solution of 1 in a mixture
of hexane/CHCl3. The ball-and-stick drawing and packing of
the crystal structure of 1 are drawn in Figs. 4 and S1 in the
Supporting Information, respectively. The selected dihedral
angles and lengths are summarized in Table 1. As three phe-
nyl and one isocyanurate rings of 1 are denoted as Ph1
(for the N-phenyl group), Ph2 (for the phenylene group in
TABLE 1. Selected structural data of 1
Distance
(Å)
Angle
(ꢀ)
Dihedral angle (ꢀ)
f
w
c
d
θ
(Isc–Ph1)
(Isc–Ph2)
(Ph2–Ph3)
(H1PhꢄꢄꢄC3Ph
)
(C-H1PhꢄꢄꢄC3Ph
)
94.1
95.7
74.9
80.3
77.2
82.0
74.5
61.7
56.4
3.28
3.32
3.10
137.3
148.8
177.0
Mean 88.3 Mean 79.8 Mean 64.2
Mean 3.23
N-(biphenyl-2-yl) one), Ph3 (for the phenyl group in N-(biphenyl-
2-yl) one), and Isc (for the isocyanurate skeleton), vide infra,
three dihedral angles between two rings, a shortest spatial
distance between C atoms of Ph3 and an H atom at ortho
position of Ph1, an angle with the hydrogen as the center
of C–HꢄꢄꢄC are represented as f(Isc–Ph1), w(Isc–Ph2),
c(Ph2–Ph3), d(HP1hꢄꢄꢄCP3h), (C–H1PhꢄꢄꢄCP3h) (Fig. 4B). 1 was
crystallized in a triclinic system with a space group of P1.
Six independent molecules, which are pR- and pS-forms of
three different conformers, were found in the dissymmetric
unit. The two phenyl groups (Ph1 and Ph2) covalently
bonded to the imide N atoms were orthogonally distorted
to the isocynanurate planes in the ranges of 74.9–95.7ꢀ for
f and 77.2–81.9ꢀ for w because of steric repulsions between
the phenyl rings and the oxygens on the isocyanurate ring.
These values were comparable with torsion angles (60–80ꢀ)
between benzene rings and heterocyclic rings of N,N0,
N00-triphenylisocyanurates in crystal.76,77 The dihedral
angles (c) between Ph2 and Ph3 were 56.4–74.5ꢀ which are
larger than those (~ 50ꢀ) between two benzene rings of
ortho-terphenyl in crystal.106–108 Furthermore, the spatial
distances (ds) between the carbons of Ph3s and the hydrogens
Chirality DOI 10.1002/chir
Scheme 1. Synthesis of 1.

GOTO ET AL.
at ortho positions of Ph1s were 3.10–3.32 Å, being longer than
those between hydrogens and aromatic rings in molecular
structures formed by C-Hꢄꢄꢄp-arene interactions.109–111 These
results suggest that 1 expectedly adopts a chiral conforma-
tion (C1, centrosymmetric) stabilized by steric repulsion as
the major driving force and CH–p interaction as the minor
one in crystal. However, any crystals consisted of 1:1 mixtures
of the antipodes.
Optical Resolution and Isomerization of 1
The optical resolution of 1 was carried out by using HPLC
with SumichiralW OA-4600 as a chiral column [eluent: hexane/
ethanol/trifluoroacetic acid (90/10/0.5, v/v/v)] (Fig. 5). A
chromatogram of 1 showed two peaks with comparable peak
areas in 27.9 and 29.6 min (t0 = 8.9 min for mesitylene as a
standard material). Thus, 1 was fractionated to afford the
components corresponding to the two peaks. Absorption
(Fig. 6, bottom), 1H NMR, and MS spectra of the component
of the first fraction separated by chiral HPLC were identical
with those of the second fraction. On the other hand, a CD
spectrum of the component of the first fraction (1a) exhib-
ited a negative Cotton effect at 230 nm, whereas that of the
second fraction (1b) showed a positive Cotton effect. These
CD patterns were completely mirror images in the range of
210–280 nm (Fig. 6, top). Furthermore, the optical rotations,
[a]Ds, of 1a and 1b were estimated to be ꢂ116 and +120,
respectively. These results indicate that the two components
(1a and 1b) are a pair of enantiomers of 1 [1a = (ꢂ)-1 and
1b = (+)-1].
Fig. 6. Circular dichroism and absorption spectra of stereoisomers of 1
(solid line, 1a; dashed line, 1b) in THF at room temperature (25–27 ꢀC).
[1] = 0.18 mM.
proceeded under the condition. The ratios of the 1b area to
the area of all peaks, that is [area of 1b] / [[area of 1a] + [area
of 1b]], were plotted with time in Figure 7. The first-order
kinetic constant (k323) and the half-life period [t1/2(323)] of
racemization at 50 ꢀC (black circles) were estimated to be
2.86 ꢁ 10ꢂ6 secꢂ1 and 33.7 h (1.40 day), respectively. In addition,
the Gibbs’ free-energy change (DG{323) of the rotational barrier
around the C-N bond between biphenyl and isocyanurate
rings was calculated as 27.2 kcal/mol using the Eyring
equation.102–105 The racemization behaviors of 1 at 30 (blue
circles) and 70 (red circles) ꢀC were also pursued in the similar
manner: k303 =1.00ꢁ 10ꢂ7 secꢂ1, t1/2(303) = 960 h (40.0 days),
DG{303 = 27.5 kcal/mol, k343 =5.52ꢁ 10ꢂ6 secꢂ1, t1/2(343) = 17.4 h
(0.73 day), DG{343 = 28.4 kcal/mol. Herein, because the racemiza-
tion rate at 70 ꢀC was relatively fast, the plot data over 0–10 h
were used. The DG{s calculated with the kTs at 30 and 70ꢀC
was similar to that at 50 ꢀC (see footnote2). Racemization of 1
is considered to arise from the rotation around the C-N bond
between the biphenyl group and the isocyanurate ring at
30–70 ꢀC (Scheme 2).
To investigate a thermal stability of 1 in solution, the
change of the chromatogram of 1 was periodically monitored
by chiral HPLC after the solutions of 1b (98.5% ee) in
hexane/ethanol (9/1, v/v) was kept at 50 ꢀC for a predetermined
amount of time. The peak of the chromatogram for 1b grad-
ually became lower over time, whereas that for 1a became
higher (Fig. 7). No other peaks were observed during incu-
1
bation of the solution. Furthermore, the H NMR spectra
of the solutions before and after incubation were completely
identical. These results suggest that racemization of 1
Designs and Syntheses of 2 and 3
For the purpose of developing more stable isocyanurates
with planar chirality than 1, the rotation of the C-N bond must
be restricted. Two strategies were worked out: (1) introduction
of a bulky substituent at ortho position of Ph1 and (2) intramo-
lecular bridging between two benzene rings (Ph1 and Ph2)
adjacent to the isocyanurate ring of 1 (Scheme 3A and D).
In the first strategy, although a clockwise rotation of the
20-biphenyl group of the anti-form around the C-N bond
induces the formation of the syn-form, an anti-clockwise rota-
tion may be prevented by steric repulsion between Ph3 and
the bulky group located at ortho positions of Ph1. Herein,
clockwise rotation is denoted as a rotation of the 20-biphenyl
group into the right side as shown in Scheme 3A. Another
phenyl group as the bulky group was attached at the ortho
position of Ph1 of 1 to design 2 with two biphenyl groups
(Fig. 3). This is because 2 adopts three structures [two
2The kinetic parameters (DH{ and DS{) of 1 with the racemization rates at
30, 50, and 70 ꢀC were calculated to be 20.3 kcal/mol and ꢂ23 cal/
(molꢄK), respectively. Furthermore, the racemization barrier at 25 ꢀC
was estimated to be 27.2 kcal/mol with these values.
Fig. 5. Chromatographic resolution of stereoisomers of 1 on SumichiralW
OA-4600. Column: 25 ꢁ 0.46 (i.d.) cm. Eluent: hexane/ethanol/trifluoroacetic
acid (90/10/0.5, v/v/v). Flow rate: 0.35 ml/min.
Chirality DOI 10.1002/chir

PLANAR-CHIRAL ISOCYANURATES
The phenolic 10 was mixed with 1,6-dibromohexane under very
low concentration (<1 mM) condition to yield a cyclic urea 11. A
condensation of 11 with ethyl N-carbonylcarbamate98 caused a
production of 3 with the intramolecular bridging unit.100,101
Single crystals of 2 were obtained from a solution of 2 in hot
ethanol. The ball-and-stick drawing and packing of the crystal
structure of 2 are drawn in Figs. 8 and S2 in the Supporting
Information, respectively. The anti-conformer of 2 (2anti) was
crystallized in a monoclinic system with a space group of
P21/c. Two phenyl groups in the biphenyl groups of 2 lay above
and below the isocyanurate ring. Two independent molecules
were pR- and pS-forms of 2anti in a unit cell. In contrast with
the torsion angles for 2anti (f = 78.5 and 90.8ꢀ, c = 53.7 and
106.4ꢀ) similar to those for 1, the spatial distances for 2anti
(d = 3.96 and 4.76 Å) were longer than those for 1. On the other
hand, the syn-conformer of 3 (3syn) was crystallized, of which
the strap unit blocks one face of the isocyanurate plane for
3syn (see footnote4). These structures were the same as those
expected. Any crystals consisted of 1:1 mixtures of the antipodes.
Fig. 7. Racemization behaviors of 1 at 30 (triangle), 50 (circle), and 70 ꢀC
(square) in hexane/ethanol (9/1, v/v). The enantiomeric ratio of 1b means
the ratio of the area of 1b to that of all peaks [[area of 1b] / [[area
of 1a] +[area of 1b]]]. The solid lines are calculated from plot data over 0–25
(for 30 and 50ꢀC) or 0–10 h (for 70 ꢀC) at each temperature using the first-order
rate equation. The broken lines are extrapolated from plot data over 0–10h
at 70 ꢀC.
Optical Resolutions and Isomerizations of 2 and 3
Optical resolutions of 2 and 3 were carried out by chiral
HPLC under the almost same condition as that of 1 (Fig. 9).
The chromatogram of 2 showed three peaks in 19.8 (first),
21.9 (second), and 28.5 (third) min; the areas of two peaks (first
and second) were comparable, whereas the area of the third
peak was smaller than others. Absorption (Fig. 10, bottom), 1H
NMR, and MS spectra of the component assignable to the first
fraction (2a) collected by using chiral HPLC were identical with
those of the second fraction (2b). On the other hand, a CD spec-
trum of 2a exhibited a negative Cotton effect at 230 nm, whereas
that of 2b showed a positive Cotton effect (Fig. 10). These CD
patterns were completely mirror images. On the contrary, the
component assignable to the third fraction (2c) was CD-silent.
In addition, although the MS spectrum of 2c was identical with
that of 2a, the absorption and NMR spectra of 2c were different
from those of 2a. Furthermore, the optical rotations of 2a and
2b were estimated to be ꢂ141 and +146, respectively. These
results suggest that 2a and 2b are a pair of enantiomers of the
anti-conformers of 2 [2a = (ꢂ)-2anti and 2b= (+)-2anti], and 2c
is the syn-conformer (meso-isomer) [2c= 2syn] (see footnote5).
3 was also separated into three components [first fraction,
3a (26.7 min); second fraction, 3b (28.5 min); third fraction,
3c (30.9 min)] by using chiral HPLC; the peak areas derived
from 3a and 3b were comparable, whereas the area of 3c
was smaller than others. Absorption (lmax = 277 nm, Fig. 10,
Scheme 2. Pathway of racemization of 1 at first step.
anti-forms and one syn-form (meso-form)], whereas isocya-
nurates with other substituents instead of the phenyl group
form four structures (two anti-forms and two syn-forms).
The anti-form of 2 is denoted as a stereoisomer of 2 with
two phenyl groups being spatially distant from each other.
The second is frequently utilized to gain representative chiral
cyclophanes with planar chiralities. Even if the 20-biphenyl
group of isocyanurates intramolecularly bridged with a
short spacer rotates around the C-N bond clockwise or
anti-clockwise, the spacer may collide with the isocyanurate
plane to inhibit the isomerization. Hexylene-1,6-dioxy group
as the intramolecular bridge was employed, where the chain
length was considered to be enough to restrict the rotation
of the C-N bond of 3 based on molecular minimizations.
The anti-form of 3 is denoted as a stereoisomer of 3 with
two ethereal O atoms being spatially distant from each other.
2 was synthesized similarly to 1 (Scheme 4), whereas a
different synthetic route for 3 was employed (Scheme 5)
(see footnote3). For the synthesis of 3, an amide 7 obtained
according to the literature97 was converted into the
corresponding aniline 8 under an alkaline condition. The
aniline 8 was reacted with 2-methoxyphenyl isocyanurate
to afford the corresponding urea 9. Two methoxy groups
(O-CH3) of 9 were converted into boronate groups (O-BBr2)
with boron tribromide (BBr3), and then, the boronate groups
were hydrolyzed with H2O to generate a phenolic urea 10.
1
bottom), H NMR, and MS spectra of 3a were identical with
those of 3b. On the other hand, 3a and 3b exhibited CD
spectra with negative and positive Cotton effects at 220 nm,
respectively (Fig. 10), of which patterns were mirror images.
In contrast, 3c was CD-silent. Furthermore, although the MS
spectrum of 3c was identical with that of 3a, the absorption
(lmax = 292 nm) and NMR spectra of 3c were different from
43 was confirmed to form a chiral syn-form, although the quality of the
crystal is not good.
5To investigate which of 2syn and 2anti is more stable, the geometry optimi-
zations of 2syn and 2anti were performed using the DMol3 module as imple-
mented in the Materials Studio software (version 5.0; Accerlys Inc. (San
Diego, CA, USA)) (Figure S3 in the Supporting Information). The differen-
tial energy of 2syn against 2anti was+ 2.7kcal/mol, indicating 2anti is more
stable than 2syn. The value of the differential energy is consistent with the free
energy (+ 1.9 kcal/mol) from the equilibrium constant based on the peak
areas of three stereoisomers of 2 [[area of 2anti] : [area of 2syn]=96 : 4, 298K].
3Before a synthetic route of 3 as described in Scheme 5 was chosen, we
carried out an alkylation of an isocyanurate bearing a phenolic hydroxy
group according to the same method as those of 1 and 2. When the
isocyanurate was reacted with 1-bromohexane under basic condition,
the alkylation at both phenolic oxygen and isocyanuric N atoms were
observed. This result indicated that the synthetic route of 1 and 2 was
unsuitable for the preparation of 3.
Chirality DOI 10.1002/chir

GOTO ET AL.
Scheme 3. Pathways to inhibit isomerizations of isocyanurates with bulky group (A–C) and intramolecular bridge (D–F).
Scheme 4. Synthesis of 2.
Scheme 5. Synthesis of 3.
those of 3a. Furthermore, the optical rotations of 3a and 3b
To investigate isomerizations of 2 and 3 in solution,
solutions of the isolated enantiomers 2a (>99% ee) and
3a (>99% ee) in hexane/ethanol (9/1, v/v) were kept at
50 and 150 ꢀC, respectively, and then analyzed by the chi-
ral HPLC. Whereas the peak area of 2a decreased gradu-
ally, the peak area derived from 2c gradually increased,
followed by a slower increase of that derived from 2b
(Fig. S4). The kinetic parameters (k323, t1/2(323), and
were estimated to be ꢂ126 and +127, respectively. These
results indicate that 3a and 3b are a pair of enantiomers of
the syn-conformers of 3 [3a = (ꢂ)-3anti and 3b = (+)-3syn],
and 3c is a racemic mixture of the anti-conformers
[3c = (ꢅ)-3anti] (see footnote6).
6To investigate which of 3syn and 3anti is more stable, the geometry opti-
mizations of 3syn and 3anti were performed in the same manner as those
of 2 (Fig. S3 in the Supporting Information). The differential energy of
3anti against 3syn was + 31.3 kcal/mol, indicating 3syn afforded by recrys-
DG{323) of 2 were estimated to be 1.35 ꢁ 10ꢂ6 secꢂ1
,
71.5 h (2.98 days), and 27.6 kcal/mol, respectively. On the
other hand, even when the solution of 3a was kept at
tallization is more stable than 3anti
Chirality DOI 10.1002/chir
.

PLANAR-CHIRAL ISOCYANURATES
150 ꢀC for 6 days in a sealed tube, no decrease of the peak
area of 3a was observed. If a small amount (0.5 mol%) of
3a isomerized under that condition, k423, t1/2(423), and
DG4{23 of 3 were calculated to be <1.0 ꢁ 10ꢂ8 secꢂ1, >1.0
104 h (400 days), and >40.6 kcal/mol, respectively. The
lower isomerization rates of 2 and 3 than that of 1 and,
in particular, the lowest rate of 3 among them were pre-
dictable results (Scheme 6), indicating that the introduc-
tion of bulky substitutes and the intramolecular bridging
are effective for inhibition of isomerization.
Fig. 8. Ball-and-stick drawing of 2anti with thermal ellipsoids at 50% prob-
ability. Each one of the independent molecules is shown here. H atoms are
partially omitted for clarity. (B) Steric illustration of 2anti with denotation of
benzene and heterocyclic rings, dihedral angles, spatial distance, and angle:
Ph1, Ph2, Ph3, Ph4 for four benzene rings; Isc for isocyanurate ring; f, w
for two dihedral angles; d for spatial distance between carbon of Ph2
and hydrogen at ortho position of Ph3; for angle of C-H(Ph3)ꢄꢄꢄC(Ph2).
CONCLUSIONS
The present study demonstrated a novel design of planar-
chiral molecules consisting of rigid backbones such as isocya-
nurates. This concept is based on differentiating enantiotopic
faces of Cs-symmetric rigid backbones by a perpendicular
array of substituents directly connected to the backbones.
Optical resolutions of the designed isocyanurates were
accomplished by means of a common chiral HPLC technique.
Furthermore, isomerization of the isocyanurates derived from
rotational behavior around Cbiphenyl-N bond was efficiently
inhibited by introducing bulky groups or by intramolecular
bridging. This result encourages designs of planar-chiral
Fig. 9. Chromatographic resolutions of stereoisomers of 2 and 3 on
SumichiralW OA-4600. Column: 25ꢁ 0.46 (i.d.) cm. Eluent: hexane/ethanol/
trifluoroacetic acid (90/10/0.5, v/v/v). Flow rate: 0.35ml/min.
Scheme 6. Pathways of isomerizations of 2 and 3 at first steps.
Fig. 10. Circular dichroism and absorption spectra of stereoisomers of 2 (left) and 3 (right) (solid lines, 2a and 3a; dashed lines, 2b and 3b; dotted lines,
2c and 3c) in THF at room temperature (25–27 ꢀC). [2] = 0.14 mM, [3] = 0.13 mM.
Chirality DOI 10.1002/chir

GOTO ET AL.
molecules based on not only isocyanurates78–95 but also
C3-symmetric molecules such as mesitylene112–117 for asym-
metric syntheses and molecular recognitions. Investigations
on absolute configurations of the isocyanurates are under
investigation in our laboratory.
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Chirality DOI 10.1002/chir