Enantiopure cyclic O-substituted phenylphosphonothioic acid: Synthesis and chirality-recognition ability

Article abstract of DOI:10.1002/chir.20702

As a new acidic selector (resolving agent), we synthesized an enantiopure O-alkyl phenylphosphonothioic acid with a seven-membered ring ((R)-5), which was designed on the basis of the results for the enantioseparation of 1-arylethylamine derivatives with acyclic O-ethyl phenylphosphonothioic acid (I). The phosphonothioic acid (R)-5 showed unique chirality-recognition ability in the enantioseparation of 1-naphthylethylamine derivatives, aliphatic secondary amines, and amino alcohols; the ability was complementary to that of I. The X-ray crystallographic analyses of the less- and more-soluble diastereomeric salts showed that hydrogen-bonding networks in the salt crystals are 2₁-column-type with a single exception which is cluster-type. In the cases of the 2₁-column-type crystals, stability of the crystals is firstly governed by hydrogen bonds to form a 2₁-column and secondly determined by intra-columnar T-shaped CH/π interaction(s), intra-columnar hydrogen bond(s), inter-columnar van der Waals interaction and/or inter-columnar T-shaped CH/π interaction(s). In contrast, the cluster-type salt crystal is stabilized by the assistance of inter-cluster T-shaped CH/π and van der Waals interactions. To realize still more numbers of intra- and inter-columnar and -cluster T-shaped CH/π interactions, the seven-membered ring of (R)-5 plays a considerable role. Copyright

Full text of DOI:10.1002/chir.20702

CHIRALITY 23:438–448 (2011)
Enantiopure Cyclic O-Substituted Phenylphosphonothioic Acid:
Synthesis and Chirality-Recognition Ability
*
NIGEL RIBEIRO, YUKA KOBAYASHI, JIN MAEDA, AND KAZUHIKO SAIGO
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, 113-8656 Japan
ABSTRACT
As a new acidic selector (resolving agent), we synthesized an enantio-
pure O-alkyl phenylphosphonothioic acid with a seven-membered ring ((R)-5), which
was designed on the basis of the results for the enantioseparation of 1-arylethylamine
derivatives with acyclic O-ethyl phenylphosphonothioic acid (I). The phosphonothioic
acid (R)-5 showed unique chirality-recognition ability in the enantioseparation of 1-naph-
thylethylamine derivatives, aliphatic secondary amines, and amino alcohols; the ability
was complementary to that of I. The X-ray crystallographic analyses of the less- and
more-soluble diastereomeric salts showed that hydrogen-bonding networks in the salt
crystals are 21-column-type with a single exception which is cluster-type. In the cases of
the 21-column-type crystals, stability of the crystals is firstly governed by hydrogen
bonds to form a 21-column and secondly determined by intra-columnar T-shaped CH/p
interaction(s), intra-columnar hydrogen bond(s), inter-columnar van der Waals interac-
tion and/or inter-columnar T-shaped CH/p interaction(s). In contrast, the cluster-type
salt crystal is stabilized by the assistance of inter-cluster T-shaped CH/p and van der
Waals interactions. To realize still more numbers of intra- and inter-columnar and -clus-
ter T-shaped CH/p interactions, the seven-membered ring of (R)-5 plays a considerable
C
VV
role. Chirality 23:438–448, 2011.
2009 Wiley-Liss, Inc.
KEY WORDS: chirality-recognition; diastereomeric salt; hydrogen-bonding network;
hydrogen bond; T-shaped CH/p interaction; van der Waals interaction;
globular cluster; infinite 21-column; X-ray crystallographic analysis
INTRODUCTION
cations and the phosphonothioate anions. One is a globu-
lar hydrogen-bonding network consisting of four ammo-
nium cations and four phosphonothioate anions (cluster),
and the other is an infinite columnar hydrogen-bonding
network having a two-fold screw axis in the center (21-col-
umn).6,7 The two types of diastereomeric salts showed dif-
ferent tendency from each other with regard to the enan-
tiomeric excess (ee) of the amine incorporated in the salt7;
high ee (>95%) was achieved when a cluster-type salt
once deposited as a less-soluble diastereomeric salt, while
ee varied from 0 to 99%, as was observed in the enantiose-
paration of racemates with usual resolving agents, when a
21-column-type salt was formed as a less-soluble salt. The
precise comparison of the X-ray crystal structures of the
Enantioseparation of racemates through the diastereo-
meric salt formation with a selector (resolving agent) is
one of the most attractive methods for obtaining enantio-
pure compounds not only in a laboratory-scale but also in
an industry-scale owing to the recyclability of the resolving
agent and the simplicity and scalability of the procedure.1,2
However, a long and exhausting effort is usually required
in selecting a suitable resolving agent. Therefore, the elu-
cidation of chirality-recognition mechanism for diastereo-
meric salt crystallization and the development of widely ap-
plicable, new resolving agents designed on the basis of
the mechanism have been highly desired to shorten time
for seeking an effective resolving agent and to expand the
scope of the diastereomeric salt formation method.
In the course of our continuous study on the rational
design of new resolving agents and on their chirality-rec-
ognition ability/mechanism,3–5 we have found that O-sub-
stituted aryl/alkylphosphonothioic acids, in particular O-
ethyl phenylphosphonothioic acid (I), have an excellent
chirality-recognition ability for racemic 1-arylethylamine
derivatives.6–10 The X-ray crystallographic analyses of the
less- and more-soluble diastereomeric salt crystals
revealed that there are two distinct categories for hydro-
This work is Dedicated to Professor Domenico Misiti on the occasion of
his 75th birthday.
Contract grant sponsor: Grant-in-Aid for Scientific Research from the Min-
istry of Education, Science, Sports and Culture of Japan; Contract grant
numbers: 18.06738, 19350064
*Correspondence to: Kazuhiko Saigo, Department of Chemistry and Bio-
technology, Graduate School of Engineering, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
E-mail: saigo@chiral.t.u-tokyo.ac.jp
Received for publication 13 September 2008; Accepted 16 December 2008
DOI: 10.1002/chir.20702
Published online 19 February 2009 in Wiley Online Library
gen-bonding networks formed between the ammonium (wileyonlinelibrary.com).
C
VV
2009 Wiley-Liss, Inc.

CYCLIC O-SUBSTITUTED PHOSPHONOTHIOIC ACID
439
two types to each other indicated that the structural differ- 13C NMR (75 MHz, CDCl3) d 36.9 (CH3), 128.2 (aromatic
ence resulted in the difference of the torsion angle y CH x 2), 131.3 (aromatic CH), 131.9 (aromatic CH 3 2),
between the aromatic plane and ester group in the O-alkyl 132.9 (aromatic CH); 31P NMR (121 MHz, CDCl3) d 82.6;
phenylphosphonothioate anions;10 the y values in the clus- EI-MS (70 eV) m/z (%) 228 (6) [M]1, 196 (23) [M – S]1,
ter-type crystals were 31–368 (338 in average), whereas 152 (85) [C8H11NP]1, 109 (100).
those in the 21-column-type crystals were 50–658 (608 in
average). Moreover, the X-ray analyses suggested that the
smaller y values in cluster-type crystals might arise from
steric repulsion between the alkyl group in the O-alkyl
N,N,N0,N0-Tetramethyl-(2-(3-tert-
butyl(dimethyl)siloxypropyl)phenylphosphonothioic
Diamide (3)
phenylphosphonothioic acids and the substituent(s) of the
To a solution of the diamide 2 (5.4 g, 23.6 mmol) in dry
amines. These results prompted us to synthesize an O- diethyl ether (55 ml) was dropwise added a solution of
alkyl phenylphosphonothioic acid with less flexibility and butyllithium (1.6 M, 15.5 ml) at room temperature. After
to apply it as a new resolving agent.
the reaction mixture was stirred at room temperature for
In this article, we report the synthesis and chirality-rec- 16 h, a solution of 3-bromopropoxy(tert-butyl)dimethylsi-
ognition ability of an enantiopure cyclic O-substituted lane (8.38 g, 33.11 mmol) in dry diethyl ether (20 ml) was
phosphonothioic acid.
dropwise added to the reaction mixture, and the resultant
mixture was refluxed for 7 h. After distilled water (20 ml)
was added to the reaction mixture, the aqueous phase was
extracted with CH2Cl2 (2 3 20 ml). The combined organic
layers were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel with hexane/EtOAc (93:7, v/v) as an eluant to
afford 3 (6.2 g, 65%) as a colorless oil. Rf 5 0.35 (hexane/
EtOAc 5 93:7, v/v); IR (neat) m 3056, 2927, 2885, 2856,
EXPERIMENTAL SECTION
General Information
All reactions were carried out under argon atmosphere.
THF and diethyl ether were distilled from Na/benzophe-
none before use. Butyllithium in hexane (1.6 M) was pur-
chased from Kanto Chemicals and used as received. Thin
layer chromatography (TLC) was performed on glass
plates coated with silica gel 60 F254 (Merck). Column
chromatography was carried out using silica gel 60 (Kanto
1
2801, 1470, 1254, 1187, 1101, 982, 837, 776, 719 cm21; H
NMR (300 MHz, CDCl3) d 0.08 (6H, s, Si(CH3)2), 0.92
(9H, s, C(CH3)3), 1.88–1.97 (2H, m, CH2), 2.70 (12H, d, J
5 10.5 Hz, N(CH3)2), 3.10 (2H, t, J 5 8.1 Hz, CH2), 3.72
(2H, t, J 5 6.3 Hz, CH2), 7.20-7.51 (4H, m, aromatic CH);
13C NMR (75 MHz, CDCl3) d 25.1 (Si(CH3)2), 18.5
(SiC(CH3)3), 26.2 (SiC(CH3)3), 29.8 (CH2), 34.3 (CH2),
37.6 (N(CH3)2), 63.3 (CH2OSi), 125.3 (aromatic CH), 131.3
(aromatic CH), 131.3 (aromatic CH), 131.4 (aromatic CH),
132.7 (C(CH2)3OTBDMS), 146.8 (CPS(NMe2)2); 31P NMR
(121 MHz, CDCl3) d 77.5; EI-MS (70 eV) m/z (%) 368 (9)
[M – S]1, 343 (62) [M – C4H9]1, 210 (12) [C11H19N2P]1,
166 (67) [C9H13NP]1, 147 (48), 119 (30), 73 (100).
Chemicals, 63–210 mesh). H, 31P, and 13C NMR spectra
1
were recorded on a Varian Mercury 300 equipment operat-
ing at 300, 121, and 75 MHz, respectively. Chemical shifts
are reported in ppm relative to the singlet at 0 ppm of tet-
ramethylsilane for 1H NMR spectra, the center line of a tri-
plet at 77.16 ppm of CDCl3 for 13C NMR, and 0 ppm of 85%
H3PO4 for 31P NMR, respectively. Significant 1H NMR
data are listed in the following order; chemical shift (d),
number of protons, multiplicity (s, singlet; d, doublet; m,
multiplet), coupling constant J in Hz. HPLC analyses were
performed on Daicel Chiracel columns. IR spectra were
recorded on a JASCO model FT/IR-480 plus.
Cyclic Phosphonothioic Acid Methyl Ester (4)
N,N,N0,N0-Tetramethylphenylphosphonothioic
Diamide (2)
To a solution of the pendant-attached diamide 3 (8.88 g,
22.16 mmol) in dry methanol (90 ml) was added 4 M HCl
To a solution of freshly distilled phenylphosphonothioic in dioxane (55 ml, 220 mmol) under vigorous stirring. Af-
dichloride (1) (10.55 g, 50 mmol) in dry THF (40 ml), ter the mixture was stirred for 3 h at room temperature,
cooled with an ice bath, was gradually added a 2 M solu- the volatiles were removed under reduced pressure, and
tion of dimethylamine in THF (100 ml, 200 mmol) to form then distilled water (50 ml) was added to the mixture. The
white precipitates. The reaction mixture was stirred at 08C aqueous phase was extracted with CH2Cl2 (2 3 40 ml).
for 45 min and then at room temperature for 3 h. Distilled The combined organic layers were dried over MgSO4, fil-
water (100 ml) was added to quench the reaction, and the tered, and concentrated under reduced pressure. The
aqueous phase was extracted with CH2Cl2 (2 3 100 ml). crude product was purified by column chromatography on
The combined extracts were dried over MgSO4, filtered, silica gel with hexane/EtOAc (9:1, v/v) as eluant to give 4
and concentrated under reduced pressure. The crude (4.22 g, 83%) as a white crystal. Rf 5 0.37 (hexane/EtOAc
product thus obtained was purified by column chromatog- 5 9:1, v/v); mp 60–658C; IR (KBr) m 3049, 2942, 2923,
raphy on silica gel with hexane/EtOAc (95:5, v/v) as an 1440, 1046, 1015, 948, 823, 792, 766, 713, 641, 529 cm21
;
eluant to give 2 (10.76 g, 94%) as a white crystal. Rf 5 0.47 1H NMR (300 MHz, CDCl3) d 1.90–2.12 (2H, m, CH2),
(hexane/EtOAc 5 9:1, v/v); IR (KBr) m 3072, 3051, 2992, 2.98–3.04 (1H, m, PhCH2), 3.33–3.41 (1H, m, PhCH2), 3.87
2940, 2871, 2833, 2799, 1475, 1455, 1434, 1282, 1257, 1182, (3H, d, J 5 13.8 Hz, CH3), 4.14–4.29 (1H, m, CH2OP),
1
1152, 1105, 1052, 980, 953, 737, 716 cm21; H NMR (300 4.41–4.54 (1H, m, CH2OP), 7.19 (1H, t, J 5 6.3 Hz, aro-
MHz, CDCl3) d 2.60 (12H, d, J 5 12.6 Hz, CH3), 7.43–7.47 matic CH), 7.27–7.32 (1H, m, aromatic CH), 7.37–7.42
(3H, m, aromatic CH), 7.91–7.98 (2H, m, aromatic CH); (1H, m, aromatic CH), 7.80–7.88 (1H, m, aromatic CH);
Chirality DOI 10.1002/chir

440
RIBEIRO ET AL.
13C NMR (75 MHz, CDCl3) d 29.2 (CH2), 33.4 (PhCH2), amount rac-5 used). The enantiomeric excess of (R)-5
52.5 (CH3), 68.4 (CH2OP), 126.5 (aromatic CH), 130.5 (aro- thus obtained was determined to be >99% by an HPLC
matic CH), 131.9 (aromatic CH), 132.3 (aromatic CH), analysis (Daicel Chiralcel OJ-RH; eluant, HClO4 (pH 2)/
132.9 (C(CH2)3), 142.0 (CPS); 31P NMR (121 MHz, CH3CN 5 85:15, v/v; flow rate, 0.5 ml/min; t1 (Rp isomer)
CDCl3) d 90.5; EI-MS (70 eV) m/z (%) 228 (95) [M]1, 213 5 19.6 min, t2 (Sp isomer) 5 22.7 min). [a]18 5 1518 (c
D
(72) [M 2 CH3]1, 195 (60), 181 (80) [C9H10O2P]1, 163 1.02 , CHCl3); mp 119–1218C; IR (KBr) m 3000, 1440, 1010,
1
(49), 149 (43), 133 (36), 115 (90), 63 (100).
939, 792, 758, 697, 622 cm21. The H, 13C, and 31P NMR
were the same as those of rac-5. HRMS (ESI) m/z calcd.
for C9H12O2PS ([M - H]1), 215.0296; found, 215.0305.
Racemic Cyclic Phosphonothioic Acid (rac-5)
The cyclic phosphonothioate 4 (3.63 g, 15.93 mmol)
and sodium 2-propanethiolate (3.44 g, 35.04 mmol) were
dissolved in dry THF (100 ml), and the solution was
refluxed for 6 h. After the volatiles were removed under
reduced pressure, the remaining crude product was dis-
solved in CH2Cl2 (200 ml) and washed with 3 M KOH (2
3 100 ml). The combined aqueous phases were diluted
with distilled water (50 ml) and acidified to pH 1 with con-
centrated HCl. The aqueous phase was extracted with
CH2Cl2 (2 3 50 ml), and the combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure to give crude rac-5 (3.41 g) as an yellow
solid. After dicyclohexylamine (3.2 ml, 16 mmol) was
added to the crude solid, the resulting salt was once
recrystallized from EtOH/hexane (1:1, v/v; 40 ml) to give
the chemically pure salt. Treatment of the salt with 3 M
KOH (50 ml), followed by acidification with concentrated
HCl until pH 1 and extraction with CH2Cl2 (3 3 30 ml),
afforded pure rac-5 (2.96 g, 86%) as a white solid. Mp 136–
1378C; IR (KBr) m 2895, 1440, 1011, 947, 793, 758, 700, 625
General Procedure for the Enantioseparation by (R)-5
To a solution of racemic 6, 7 or 8 (1 mmol) in a solvent
(see Table 2) was added an equimolar amount of (R)-5, and
the suspension was heated up to dissolve the salt. The mix-
ture was slowly cooled down to room temperature and stood
overnight at the temperature. The crystalline salt deposited
was collected by filtration and washed with a small amount
of the solvent used. The yield was calculated on the basis of
a half amount of the racemic amine. To determine the enan-
tiomeric excess of the amine incorporated in the salt, a small
amount of the salt crystals was dissolved in about 1 ml of 1
M KOH, and the mixture was extracted with CH2Cl2 (2 ml).
After the volatiles were removed under reduce pressure, the
enantiomeric excess of the amine was determined by a
HPLC analysis. In the cases of the aliphatic amines and
amino alcohols, they were acylated with 3,5-dinitrobenzoyl
chloride and benzoyl chloride, respectively, and then purified
by preparative TLC, prior a HPLC analysis.
X-ray Crystallographic Analysis
cm21 1H NMR (300 MHz, CDCl3/CD3OD) d 1.88–2.10
;
X-Ray crystallographic data were corrected on
Rigaku/MSC Mercury diffractometer with graphite mono-
chromated Mo Ka radiation (Table 1).
a
(2H, m, CH2), 2.95–3.02 (1H, m, PhCH2), 3.47 (1H, t, J 5
12.3Hz, PhCH2), 4.17–4.32 (1H, m, CH2OP), 4.49–4.62
(1H, m, CH2OP), 7.15–7.19 (1H, m, aromatic CH), 7.25–
7.31 (1H, m, aromatic CH), 7.35–7.39 (1H, m, aromatic
CH), 7.83–7.91 (1H, m, aromatic CH); 13C NMR (75 MHz,
RESULTS AND DISCUSSION
Design and Synthesis of an Enantiopure Cyclic O-
Substituted Phenylphosphonothioic Acid (5)
CDCl3/CD4OD)
d 29.1 (CH2), 33.4 (PhCH2), 68.1
(CH2OP), 126.0 (CH aromatic), 130.1 (CH aromatic), 130.6
(CH aromatic), 131.5 (CH aromatic), 135.6 (C(CH2)3),
141.7 (CPS); 31P NMR (121 MHz, CDCl3/CD4OD) d 82.6;
At first, we considered that cyclic O-substituted phenyl-
EI-MS (70 eV) m/z (%) 215 (18) [M 1 H]1, 214 (11) phosphonothioic acids are possible candidates to prevent
[M]1, 199 (61), 179 (36), 163 (48), 115(57), 91 (28).
the easy change of the torsion angle y between the aro-
matic plane and ester group. Then, we performed calcula-
tions at a B3LYP/CC-PVDZ level for several cyclic O-sub-
Enantiopure Cyclic Phosphonothioic Acid ((R)-5)
To a solution of rac-5 (15.1 g, 70.55 mmol) in a mixture stituted phenylphosphonothioic acids in the gas phase. As
of H2O/EtOH (1:1, v/v; 450 ml) was added (1R, 2S)-2- a result, among the phosphonothioic acids examined, the
amino-1,2-diphenylethanol (ADPE; 15.0 g, 70.55 mmol). cyclic phosphonothioic acid 5 with a seven-membered
The mixture was stood overnight, and the deposit was col- ring was found to be a reasonable candidate; its torsion
lected by filtration using a membrane filter (T050A047A, angle y was estimated to be 338 in the gas phase (Fig. 1).
Advantec). The deposit was recrystallized from H2O/
EtOH (1:1, v/v; 450 ml), and the crystal was collected
using the membrane filter to afford white crystals. The
second recrystallization from H2O/EtOH (1:1, v/v; 200
ml) gave the diastereopure (R)-5ꢀADPE salt. The salt was
treated with 5 M KOH (400 ml), and the mixture was
washed with CH2Cl2 (3 3 100 ml). Then, concentrated
HCl was added to the aqueous phase until pH 1. The free
acid liberated was extracted with CH2Cl2 (3 3 100 ml),
and the combined organic layers were dried over MgSO4,
filtered, and concentrated to dryness under reduced pres-
sure to give (R)-5 (3.30 g, 44% on the basis of a half
Fig. 1. Structures of O-substituted phenylphosphonothioic acids.
Chirality DOI 10.1002/chir

CYCLIC O-SUBSTITUTED PHOSPHONOTHIOIC ACID
441
TABLE 1. Crystal structure information
(R)-5ꢀ(S)-
7aꢀEtOAc
(R)-5ꢀ(1S,2R)-
8aꢀH2O
Compound
(R)-5ꢀ(R)-7a
(R)-5ꢀ(S)-7e
(R)-5ꢀ(R)-7e
(R)-5ꢀ(S)-8b
(R)-5ꢀ(R)-8b
Formula
C25H32NO4PS C21H24NO2PS C115H26NO2PS C15H26NO2PS CI7H22NO3PS C17H22NO3PS C23H28NO4PS
Formula weight
Crystal system
Space group
473.56
385.46
Monoclinic
P21
315.41
Monoclinic
P21
11.092(8)
6.854(4)
12.074(8)
90.000(2)
111.037(3)
90.000(2)
856.74
315.41
351.40
351.40
Monoclinic
P21
445.51
Triclinic
P1
Orthorhombic
P212121
17.2604(14)
22.1910(19)
22.5213(18)
90
Orthorhombic Orthorhombic
P212121
7.083(3)
11.145(5)
22.449(10)
90
90
90
1772.12
4
1.182
P212121
8.7456(9)
8.8976(9)
22.3775(19)
90
90
90
1741.3
4
1.34
˚
a (A)
12.234(9)
6.813(5)
13.063(9)
90.000(3)
117.204(3)
90.000(3)
968.366
2
9.106(3)
12.495(4)
23.351(7)
90.0000(13)
93.8036(14)
90.0000(13)
2651.01
6
12.092(5)
13.885(6)
14.269(7)
83.198(15)
89.407(16)
77.206(14)
2319.49
4
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
90
90
8626.23
16
1.187
3
˚
V (A )
Z
2
Dc (g/cm3)
1.373
1.223
1.321
1.224
R
Rw
0.0545
0.1222
700941
0.0414
0.1229
700942
0.0958
0.2468
700944
0.031
0.0830
700945
0.0649
0.1762
700947
0.039
0.1097
700948
0.0692
0.1641
700946
Number CCDCa
aThe crystallographic data of the compounds were deposited at the Cambridge Crystallographic Data Center; the data can be obtained free of charge via
www.ccdc.cam.ac.uk.
Scheme 1 shows the route for the synthesis of enantio- followed by hydrolysis, gave the racemic free acid rac-5 in
pure 5 started from commercially available materials. The 86% yield. Finally, the enantioseparation of rac-5 was suc-
phosphonothioic dichloride 1 was converted to the phenyl- cessfully achieved by using (1R, 2S)-2-amino-1,2-diphenyl-
phosphonothioic diamide 2 in 94% yield. After complete ethanol (ADPE) as a resolving agent in EtOH/H2O. Upon
orthometallation of 2 with butyllithium, the intermediate recrystallized twice, we obtained the enantiopure cyclic
was allowed to react with 3-bromopropoxy(tert-butyl)di- phosphonothioic acid (R)-5 in 44% yield (based on a half
methylsilane, (which was synthesized from commercially amount of the racemic acid used).
available 3-bromo-1-propanol and tert-butyl(chloro)di-
methylsilane), to afford the alkylated product 3 in 65%
yield.11 Upon exposing with methanol and anhydrous HCl
Chirality-Recognition Ability
in dioxane, the intermediate 3 was cleanly converted to
The cyclic phosphonothioic acid (R)-5 showed unique
the desired cyclic product 4 in good yield (83%). Selective chirality-recognition ability. The results are summarized in
demethylation by the action of sodium 2-propanethiolate, Table 2.
Scheme 1. Synthesis of the enantiopure cyclic thiophosphonic acid (R)-5.
Chirality DOI 10.1002/chir

442
RIBEIRO ET AL.
TABLE 2. Chirality-recognition ability of (R)-5
Entry
Amine
Solvent (ml)a
Yieldb (%)
eec (%)
Efficiencyd
1
2
3
4
5
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
8g
8h
8i
ether/hexane 5 1/2
hexane/EtOAc 5 1.5/1
hexane/EtOAc 5 4/1
EtOAc 5 19
hexane/EtOAc 5 1/1
EtOAc 5 20
EtOAc 5 1
EtOAc 5 0.5
EtOAc/EtOH 5 4/1.2
EtOAc 5 5
hexane/EtOAc 5 2/1
hexane/EtOAc 5 0.4/0.65
EtOH/H2O 5 2.5/2.5
hexane/acetone 5 2/0.2
EtOAc 5 20
NCe
NCe
NCe
63
72
79
71
74
90
64
77
96
61
80
77
74
79
67
–
–
–
–
–
–
20 (R)
0.12
0.19
0.05
0.38
0.65
0.30
0.58
0.37
0.65
0.60
0.57
0.47
0.26
0.59
0.55
0.73
0.53
0.35
0.07
28 (NDf)
6 (R)
6
7g
8g
9h
10
11
12h
13
14
15
16
17
18
19
20
21
22
54 (S)
88 (S)
34 (S)
91 (R)
48 (S)
68 (R)
99 (1S,2R)
71 (S)
61 (R)
EtOAc 5 4
EtOAc 5 2
EtOAc 5 5
35 (S)
75 (S)
82 (S)
hexane/EtOAc 5 0.5/2.4
EtOAc/EtOH 5 1.8/0.2
EtOAc/EtOH 5 1.8/1
ether 5 4
83
56
94
93
88 (NDf)
95 (NDf)
38 (1S,2R)
8 (NDf)
8j
aThe amount of the solvent(s) was adjusted so as to control the yield of the salt to be as close as possible to a range of 60–95%. The amount is normal-
ized for a 1 mmol-scale. Crystallization was performed at room temperature.
bYield of the crystallized diastereomeric salt based on a half amount of the racemic amine used.
cEnantiomeric excess (ee) of the liberated amine, which was determined by a HPLC analysis.
dEfficiency is the product of the yield and the ee.
eNot crystallized.
fNot determined.
gCrystallized at 2208C.
hCrystallized at 4ꢁC.
The chirality-recognition ability of (R)-5 for the 1-phe- the cyclic phosphonothioic acid (R)-5 showed a chirality-
nylethylamine derivatives 6a–f was poor in the diastereo- recognition ability a little worse than did the acyclic phos-
meric salt formation; the resolution efficiencies (RE 5 the phonothioic acid I for 2-amino alcohols with a small sub-
yield x the ee of the amine incorporated) were very low or stituent at the 2-position such as 2-amino-1-butanol (8c)7
the corresponding salt did not crystallize at all (entries 1– (RE: 0.47 by (R)-5 vs. 0.74 by I), (R)-5 could recognize
6). In contrast, (R)-5 showed a good chirality-recognition the chirality of 2-amino alcohols with a large substituent at
ability for 1-naphthylethylamine derivatives 7a,b (entries 7 the 2-position such as erythro-2-amino-1,2-diphenylethanol
and 8). Worth noting is that the chirality-recognition ability (8a) and 2-amino-3-methyl-1-butanol (8g), which could not
of (R)-5 for 1-arylethylamines is quite different from that recognize well with I7 (RE: 0.60 by (R)-5 vs. 0.17 by I and
of the acyclic phosphonothioic acid I; the acid I showed a 0.73 by (R)-5 vs. 0.25 by I, respectively). Thus, (R)-5 was
moderate/excellent chirality-recogniton ability to 1-phenyl- found to show a wide chirality-recognition ability for 2-
ethylamine derivatives, while it poorly recognized the chir- amino alcohols with a large substituent at the 2-position.
ality of 1-naphthylethylamine derivatives or the corre-
These results indicate that the cyclic phosphonothioic
sponding salt did not crystallized.7 This unique ability of acid (R)-5 and the acyclic phosphonothioic acid I have a
(R)-5 is most likely attributable to the bulkiness and/or ri- chirality-recognition ability complementary to each other
gidity of the seven-membered ring in (R)-5, although the for a wide variety of racemic amines and amino alcohols.
structural characteristic might result in mismatch in mo- The complementarity might arise from the difference in
lecular size between (R)-5 and the 1-phenylethylamine the flexibility of the O-alkyl group.
derivatives.3
Structural Characteristics of the Diastereomeric Salt
Prompted by the peculiar chirality-recognition ability of
(R)-5, we next examined other possible substrates for
Crystals
enantioseparation. As a result, the chirality of the aliphatic
To elucidate the origin of the chirality-recognition ability
amines 7 could be recognized by (R)-5 at a moderate/ shown by the cyclic phosphonothioic acid (R)-5, we per-
excellent level (entries 9–12). Moreover, the chirality-rec- formed X-ray crystallographic analyses of the salts of (R)-5
ognition ability of (R)-5 for the 2-amino alcohols 8 was with the amines. Single crystals suitable for X-ray analyses
also moderate/excellent except for 8j having a particular could be obtained in the cases of the less-soluble diaster-
substituent with fluorine atoms (entries 13–21). Although eomeric salts with 1-(1-naphthyl)ethylamine (7a), 2-pentyl-
Chirality DOI 10.1002/chir

CYCLIC O-SUBSTITUTED PHOSPHONOTHIOIC ACID
443
alize a greater number of CH/p interactions.13 In a similar
manner, the seven-membered ring of (R)-5 is rigid as a
substituent of a phosphonothioic acid in crystals, so that
the torsion angle y would be enlarged to avoid steric repul-
sion and/or to realize a greater number of CH/p interac-
tions in the diastereomeric salt crystals.
TABLE 3. Hydrogen-bonding network and torsion angle h of
(R)-5 molecules in crystals
Hydrogen-bonding
Entry
Amine
network pattern
Angles y (8)
Less-soluble
salt
Crystal Structure of the Less- and More-Soluble Salts of the
Cyclic Phosphonothioic Acid ( R)-5 with 4-Methyl-2-
pentylamine (7e)
1
2
3
4
5
6
(S)-7a
(R)-7d
(S)-7e
(1S,2R)-8a
(S)-8b
(S)-8f
cluster
column
column
column
column
column
55.1, 50.2, 53.3, 51.3
53.1
52.4
47.3, 51.8
54.0
In the less-soluble (R)-5ꢀ(S)-7e salt crystal (Fig. 2a and
2b), there exists a 21-columnar hydrogen-bonding net-
work, which is composed of hydrogen bonds between the
phosphonothioate anions and the ammonium cations. The
49.9
More-soluble
salt
˚
distances of the hydrogen bonds are 2.785 and 2.824 A for
7
8
9
(R)-7a
(R)-7e
(R)-8b
column
column
column
51.0
32.5
48.6, 51.9, 57.3
the ammonium nitrogen atom-the phosphonothioate oxy-
˚
gen atoms and 3.352 A for the ammonium nitrogen atom-
the phosphonothioate sulfur atom. The molecules of (S)-
7e are located parallel to the hydrogen-bonding network
amine (7d), 4-methyl-2-pentylamine (7e), erythro-2-amino- and perpendicular to (R)-5 molecules. The crystal is stabi-
1,2-diphenylethanol (8a), 2-amino-2-phenylethanol (8b), lized by very effective p/p interaction between the phenyl-
and 2-amino-4-methyl-1-pentanol (8f). Moreover, we could ene groups of (R)-5 molecules; the distance between the
˚
fortunately prepare the single crystals of three more-solu- phenylene planes is 3.396 A.
ble diastereomeric salts with the amines 7a, 7e, and 8b,
The more-soluble (R)-5ꢀ(R)-7e salt is also a 21-column-
although it is generally very difficult to obtain more-solu- type crystal formed by hydrogen bonds between the phos-
ble diastereomeric salt crystals suitable for X-ray crystallo- phonothioate anions and the ammonium cations (Fig. 2c
graphic analyses due to their poor crystallinity. As a result, and 2d). The distances of the hydrogen bonds are 2.775
we could solve the crystal structures of three types of less- and 2.859 A for the ammonium nitrogen atom-the phos-
and more-soluble salt pairs for the amines 7a, 7e, and 8b phonothioate oxygen atoms and 3.383 A for the ammo-
˚
˚
(1-naphthylethylamine-type, 2-alkylamine-type and amino nium nitrogen atom-the phosphonothioate sulfur atom.
alcohol-type, respectively).
Between the methylene hydrogen atom in a (R)-5 mole-
cule and the phenylene group of the neighbored (R)-5
molecule, inter-columnar T-shaped CH/p interaction is
Pattern of Hydrogen-Bonding Networks and
Torsion Angles
˚
observed (3.474 A), which makes the conformation of the
The hydrogen-bonding network pattern and torsion seven-membered ring in (R)-5 unfavorably boat-like.
angle(s) y of the salt crystals are listed in Table 3. Con-
From the viewpoints of intermolecular interaction and
trary to our expectation, most of hydrogen-bonding net- molecular conformation in the crystals, the (R)-5ꢀ(S)-7e
works in these salt crystals are 21-column-type except for salt crystal is reasonably more stable than the (R)-5ꢀ(R)-
the less-soluble (R)-5ꢀ(S)-7a salt crystal, of which the net- 7e salt crystal: (1) Although both crystals are similarly sta-
work is cluster-type. Moreover, the torsion angles y bilized by intra-columnar hydrogen-bonding interactions,
between the phenylene plane and ester group of the cyclic the inter-columnar p/p interaction in the (R)-5ꢀ(S)-7e salt
phosphonothioic acid (R)-5 in these salt crystals are also crystal is more effective than the inter-columnar CH/p
disappointedly far (47.3–57.38) from the y value predicted interaction in (R)-5ꢀ(R)-7e salt crystal for the packing of
for (R)-5 in the gas phase (338), except for that the more- the columns. (2) The conformation of (R)-5 in the (R)-
soluble (R)-5ꢀ(R)-7e salt crystal (32.58). As a result, no 5ꢀ(S)-7e salt crystal must be more stable than that in the
correlation between the hydrogen-bonding pattern and the (R)-5ꢀ(R)-7e salt crystal (chair-like vs. boat-like). The sta-
y value was observed. The torsion angles y seem to be bility difference is also supported by their melting points;
strongly determined by the conformation of the seven- the melting points of the (R)-5ꢀ(S)-7e and (R)-5ꢀ(R)-7e
membered ring in the cyclic phosphonothioic acid (R)-5. salt crystals are 145.5–1478C and 131–1348C, respectively,
Namely, the conformation in the (R)-5ꢀ(R)-7e salt crystal indicating that (R)-5ꢀ(S)-7e is more stable than (R)-5ꢀ(R)-
with a small y value is boat-like, while those are chair-like 7e. The difference in stability should affect the difference
in the other crystals with a large y value.
Recently, we have found a few examples of cluster-type was generally observed in diastereomeric salts.
in solubility between (R)-5ꢀ(S)-7e and (R)-5ꢀ(R)-7e, as
diastereomeric salt crystals with a y value larger than 508,
Crystal Structure of the Less- and More-Soluble Salts of the
when we used O-ethyl arylphosphonothioic acids having a
naphthyl8 or 4-chlorophenyl12 group bigger than a phenyl
Cyclic Phosphonothioic Acid ( R)-5 with
1-(1-Naphthyl)ethylamine (7a)
group as the aryl group. These results would suggest that
there exists steric repulsion around the hydrogen-bonding
The crystal of the less-soluble diastereomeric salt of (R)-
network in the formation of a cluster and the torsion angle 5 with 7a is an assembly of a cluster composing of four
y is enlarged to minimize the steric repulsion and/or to re- (R)-5 molecules and four (S)-7a molecules, which
Chirality DOI 10.1002/chir

444
RIBEIRO ET AL.
includes ethyl acetate used for crystallization in a ratio of polar solvent; even from ethanol, the growth of crystal was
very fast upon cooling the solution to room temperature to
1:1:1 ((R)-5ꢀ(S)-7aꢀAcOEt) (Figs. 3a and 3b). Hydrogen
give large crystals. This apparently contradictory observa-
tion can be explained as follows: The nucleation of the (R)-
5ꢀ(R)-7a crystal with an infinite 21-column-type structure
might be inhibited in a rather non-polar solvent such as
ethyl acetate, because for the nucleation of such a 21-col-
umn-type crystal, the solvation of the polar phosphono-
thioate anion and ammonium cation is highly required. In
contrast, the non-polar solvent can solvate the cluster con-
sisting of four (R)-5 molecules and four (S)-7a molecules
because the surface of the cluster is rather non-polar to
allow the crystallization of the clusters by cooperatively
using a number of CH/p interactions between the clusters.
bonds exist between the phosphonothioate anions and the
ammonium cations. The distances of the hydrogen bonds
are different from each other so that the symmetry of the
closed hydrogen-bonding network is low; the distances
˚
are in a range of 2.704–2.816 A for the ammonium nitro-
gen atom-the phosphonothioate oxygen atoms and in a
˚
range of 3.287–3.490 A for the ammonium nitrogen atom-
the phosphonothioate sulfur atom. This low symmetry is
most likely due to the steric repulsion between (R)-5 and
(S)-7a. In addition to the hydrogen bonds, many T-shaped
CH/p interactions are observed; there exist two CH/p inter-
actions between the (CH)s of the phenylene groups in (R)-
5 molecules and the p planes of the naphthyl groups of (S)-
Crystal Structure of the Less-Soluble Salt of the Cyclic
Phosphonothioic Acid ( R)-5 with Erythro-2-amino-1,2-
diphenylethanol (8a)
˚
7a molecules (3.443 and 3.609 A) in the cluster, and ten
kinds of CH/p interactions between the clusters (the distan-
˚
ces range from 3.572 to 3.904 A). These CH/p interactions,
The crystal structure of the less-soluble salt including
water ((R)-5ꢀ(1S, 2R)-8aꢀH2O) is shown in Figure 4. In
the crystal, there exists a 21-columnar hydrogen-bonding
network, which is also composed of hydrogen bonds
between the phosphonothioate anions and the ammonium
cations; the distances of the hydrogen bonds are in a
especially the inter-cluster interactions, largely enhance the
cohesion of the clusters, for which the naphthyl group of
(S)-7a plays a very important role to increase the number
of interactions.5,8,14 In the cluster there are large voids aris-
ing from the naphthyl groups, which stuck out of the spheri-
cal surface of the cluster. However, the voids are filled up
by ethyl acetate molecules to keep the crystal from destabi-
lization. As a result, the inter-cluster CH/p interactions by
the naphthyl groups of (S)-7a molecules cooperatively con-
tribute to the stabilization of the crystal.
˚
range of 2.650–2.722 A for the ammonium nitrogen atom-
the phosphonothioate oxygen atoms and in a range of
˚
3.202–3.283 A for the ammonium nitrogen atom-the phos-
phonothioate sulfur atom. Other than these hydrogen
bonds, the hydroxy hydrogen atom of (1S, 2R)-8a also
interacts with the sulfur atom. Moreover, water molecules
participate to the hydrogen-bonding network as a hydro-
gen-donor and a hydrogen-acceptor to form hydrogen
bonds with two ammonium cations, a phosphonothioate
anion, and a sulfur atom. Worth noting is that these addi-
tional hydrogen bonds are considerably short to strongly
reinforce the columnar hydrogen-bonding network. Two
different arrangement of (R)-5 molecules were found in
the crystal; (R)-5 molecules alternatively locate parallel
and perpendicular to the hydrogen-bonding network. Inter-
estingly, a (R)-5 molecule perpendicularly placed forms
two T-shaped CH/p interactions with the phenylene and
methylene groups of (R)-5 molecules placed in a parallel
The corresponding more-soluble (R)-5ꢀ(R)-7a salt crys-
tal (Figs. 3c and 3d) is of a 21-column formed by hydrogen
bonds between the phosphonothioate anions and the am-
monium cations. The distances of the hydrogen bonds are
˚
2.811 and 2.812 A for the ammonium nitrogen atom-the
˚
phosphonothioate oxygen atoms and 3.318 A for the am-
monium nitrogen atom-the phosphonothioate sulfur atom.
There exist two T-shaped CH/p interactions between (R)-
7a molecules to stabilize the crystal; intra-columnar CH/p
interaction between the methyl group of a (R)-7a molecule
˚
and the naphthyl group of the stacked (R)-7a (3.431 A),
and inter-columnar CH/p interaction between the CH of
the naphthyl group in a (R)-7a molecule and the p plane
of the naphthyl group of a (R)-7a molecule in the neigh-
˚
manner (3.571 and 3.506 A). These T-shaped CH/p inter-
˚
bored column (3.519 A).
actions are very efficient to stabilize the crystal with a co-
lumnar structure. In contrast to the strong interactions in
the column, there is no interaction between the columns
other than van der Waals interaction. However, the surface
of the column is considerably smooth to make the van der
Waals interaction effective. Indeed, the microscopic obser-
vation showed that the present crystal is a thin needle-type
crystal; this is a coherent characteristic of crystals con-
structed by strong intra-columnar interactions, such as
hydrogen bonds, CH/p interaction, and p/p interaction,
with effective inter-columnar van der Waals interaction.3–5
Although the crystal structure of the corresponding more-
soluble salt is not solved at present, the solubility of the
(R)-5ꢀ(1S,2R)-8aꢀH2O salt would considerably lower
owing to the strong hydrogen bonds and T-shaped CH/p
interactions in the column as well as the effective van der
Waals interaction between the columns. As a result, the
Upon due consideration about the crystal structures of
the cluster-type (R)-5ꢀ(S)-7a and 21-column-type (R)-5ꢀ(R)-
7a salts, it is surprising that (R)-5ꢀ(S)-7a was the less-solu-
ble diastereomeric salt; the (R)-5ꢀ(S)-7a crystal is lower
than the (R)-5ꢀ(R)-7a crystal in the symmetry of hydrogen-
bonding network and affords large voids in the crystal,
which are fortunately filled by solvent molecules. These
facts suggest that the (R)-5ꢀ(S)-7a crystal might be less sta-
ble than the (R)-5ꢀ(R)-7a crystal. Actually, the (R)-5ꢀ(S)-7a
crystal has a melting point (182–1848C) obviously lower
than that of the (R)-5ꢀ(R)-7a crystal (190–1928C). More-
over, in the preparation of the single crystal of (R)-5ꢀ(R)-7a
from a mixture of enantiopure (R)-5 and enantiopure (R)-
7a, we found that the mixture was insoluble even in boiling
ethyl acetate. We could indeed obtain the single crystal of
(R)-5ꢀ(R)-7a by using hot ethanol, which is a much more
Chirality DOI 10.1002/chir

CYCLIC O-SUBSTITUTED PHOSPHONOTHIOIC ACID
445
Figure 2. (See legend on the following page.)
Figure 3. (See legend on the following page.)
Chirality DOI 10.1002/chir

Fig. 4. Crystal structure of the less-soluble (R)-5ꢂ(1S,2R)-8aꢂH2O salt. (a) Top and (b) side views. Circle indicates a column, and hydrogen bonds
and CH/p interactions are shown by dotted lines and arrows, respectively. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Fig. 5. Crystal structures of the salts of (R)-5 with 8b. (a) Top and (b) side views of the less-soluble (R)-5ꢂ(S)-8b salt crystal. Circles indicate col-
umns, and hydrogen bonds and CH/p interactions are shown by dotted lines and arrows, respectively. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
Fig. 2. Crystal structures of the salts of (R)-5 with 7e. (a) Top and (b) side views of the less-soluble (R)-5ꢂ(S)-7e salt crystal. Circle indicates a col-
umn, and hydrogen bonds and p/p interactions are shown by dotted lines and arrows, respectively. (c) Top and (d) side views of the more-soluble (R)-
5ꢂ(R)-7e salt crystal. Circle indicates a column, and hydrogen bonds and CH/p interactions are shown by dotted lines and arrows, respectively. [Color
figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 3. Crystal structures of the salts of (R)-5 with 7a. (a) Top view and (b) globular molecular cluster of the less-soluble (R)-5ꢂ(S)-7a salt with ethyl
acetate. Circles indicate a globular molecular cluster and included solvent (ethyl acetate) molecules, and hydrogen bonds and CH/p interactions are
shown by dotted lines and arrows, respectively. (c) Top and (d) side views of the more-soluble (R)-5ꢂ(R)-7a salt crystal. Circle indicates a column, and
hydrogen bonds and CH/p interactions are shown by dotted lines and arrows, respectively. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]

CYCLIC O-SUBSTITUTED PHOSPHONOTHIOIC ACID
447
TABLE 4. Hydrogen-bonding interactions for specified
atoms in the (R)-5ꢀ(R)-8b salt crystal
difference in solubility between the less- and more-soluble
salts become large enough to achieve the very high ee of
8a incorporated in the salt (Table 2, entry 13).
Type of atom
in one of the folds
Interaction
in fold A
Interaction
in fold B
Interaction
in fold C
Crystal Structure of the Less- and More-Soluble Salts of the
Cyclic Phosphonothioic Acid ( R)-5 with 2-Amino-2-
phenylethanol (8b)
N1
O2
S
S ; O2; OH
N1 ; OH
N1
S ; O2 ; OH
2 N1
2 O2 ; OH
N1 ; OH
OH
N1
In the less-soluble (R)-5ꢀ(S)-8b salt crystal (Figs. 5a
and 5b), there exists a 21-column formed by hydrogen
bonds between the phosphonothioate anions and the am-
monium cations, and by a hydrogen bond between the
hydroxy hydrogen atom of a (S)-8b molecule and the sul-
OH
N
1 ; O2
N1 ; S
N1 ; O2
fur atom of a (R)-5 molecule. The distances of the hydro- because the hydrogen-bonding network of the (R)-5ꢀ(S)-
˚
gen bonds are 2.877 and 2.874 A for the ammonium nitro- 8b salt crystal is C2 symmetric while that of (R)-5ꢀ(R)-8b
˚
gen atom-the phosphonothioate oxygen atoms, 3.212 A for salt crystal has obviously disadvantageous pseudo three-
the ammonium nitrogen atom-the phosphonothioate sulfur fold screw axis. The melting points of the less- and more-
˚
atom, and 3.262 A for the hydroxy hydrogen atom-the soluble salts (188–1908C and 167.5–168.58C, respectively)
phosphonothioate sulfur atom. One intra-columnar T- strongly support the deduction.
˚
shaped CH/p interaction (3.788 A) is found between the
Thus, most of hydrogen-bonding networks in the less-
methylene hydrogen atom of a (S)-8b molecule and the and more-soluble diastereomeric salt crystals are column-
phenylene ring of the neighbored (R)-5 molecule, and two type; an exception is the less-soluble (R)-5ꢀ(S)-7a salt
weak inter-columnar CH/p interactions (1) between the crystal, of which the network is cluster-type. The columnar
methylene hydrogen atoms of a (R)-5 molecule and the salt crystals are stabilized by hydrogen bonds to form an
˚
phenylene ring of a (R)-5 molecule (3.900 A) and (2) infinite 21-column, intra-columnar T-shaped CH/p interac-
between the methylene hydrogen atom and the phenyl tion(s) and/or hydrogen bond(s) to reinforce the column,
ring of a (S)-8b molecule in the neighbored column (3.938 and van der Waals interaction and/or inter-columnar T-
˚
A) to make the crystal packing highly stable.
shaped CH/p interaction(s) to tightly bind the columns.
The crystal structure of the more-soluble (R)-5ꢀ(R)-8b Because the hydrogen bonds forming a 21-column are
salt (Fig. 5c and 5d) is also column-type with a pseudo obviously stronger than the other intermolecular interac-
three-fold axis. Table 4 shows atoms, which contribute to tions, the hydrogen bonds firstly govern the stability of
the formation of the hydrogen-bonding interactions in the crystals, and the difference in stability between the
each fold. The ammonium nitrogen atom, phosphono- less- and more-soluble salt crystals is secondly determined
thioate oxygen and sulfur atoms, and hydroxyl hydrogen by the other interactions, as observed for diastereomeric
and oxygen atoms are not equivalent. Five intra-columnar salt crystals prepared in our previous studies.3–5 In con-
T-shaped CH/p interactions are observed between the trast, the cluster-type salt crystal is formed upon closely
methylene hydrogen atoms in (R)-5 molecules and the packing the clusters by the assistance of inter-cluster T-
˚
phenyl rings in (R)-8b molecules (3.336 and 3.652 A), shaped CH/p and van der Waals interactions. To actualize
between the methyne hydrogen atoms of (R)-8b mole- still more numbers of intra- and inter-columnar and -clus-
cules and the phenylene rings of (R)-5 molecules (3.585 ter T-shaped CH/p interactions, the seven-membered ring
˚
and 3.677 A), and between the aromatic CH of a (R)-8b of (R)-5 plays an important role.
molecule and the phenylene ring of a (R)-5 molecule
In the case of the less-soluble (R)-5ꢀ(S)-7e, there exists
˚
˚
(3.777 A); the CH-p distance of 3.336 A observed here is p/p interaction to stabilize the crystal, which would arise
rarely short. Moreover, other than the intra-columnar from flexible and quite less interactive alkyl chain of (S)-
interactions, there exist seven inter-columnar T-shaped 7e. Worth noting is that such interaction is rarely
CH/p interactions, although they are rather weak.
observed in diastereomeric salt crystals and that the con-
Totally twelve T-shaped CH/p interactions stabilize the formation of the seven-membered ring in (R)-5 gives great
more-soluble (R)-5ꢀ(R)-8b salt crystal, while only four influence to the stability of the salt crystal.
interactions contribute to the stabilization of the less-solu-
ble (R)-5ꢀ(S)-8b salt crystal. However, hydrogen-bond
interaction is the most important among intermolecular
CONCLUSIONS
interactions in a crystal, because hydrogen-bond interac-
The enantiopure cyclic phosphonothioic acid (R)-5 was
tion is fairly stronger than the others. Therefore, even if easily synthesized from commercially available phenyl-
there are CH/p interactions in a diastereomeric salt crys- phosphonothioic dichloride in good overall yield. A study
tal fewer than those in the other diastereomeric salt crys- on the chirality-recognition ability of (R)-5 showed moder-
tal, the difference in stability/symmetry between the co- ate/excellent performance in the enentioseparation of 1-
lumnar hydrogen-bonding networks of the two diastereo- naphthylethylamine derivatives, aliphatic amines, and b-
meric salt crystals is a predominant factor for the amino alcohols. The X-ray crystallographic analyses of the
determination of the stability/solubility difference between less- and more-soluble salts revealed that there were sev-
the diastereomeric salts. Thus, the (R)-5ꢀ(S)-8b salt crys- eral chirality-recognition modes, depending on the type of
tal might be more stable than the (R)-5ꢀ(R)-8b salt crystal, target amino compounds, which would bring important
Chirality DOI 10.1002/chir

448
RIBEIRO ET AL.
thylamine derivatives with enantiopure O-ethyl phenylphosphono-
thioic acid. Org Lett 2004;6:4227–4230.
insight on the origin of the chirality-recognition ability of
enantiopure thiophosphonic acids.
7. Kobayashi Y, Morisawa F, Saigo K. Enantiopure O-substituted phenyl-
phosphonothioic acids: chiral recognition ability during salt crystalliza-
tion and chiral recognition mechanism. J Org Chem 2006;71:606–615.
ACKNOWLEDGMENTS
8. Kobayashi Y, Maeda J, Saigo K. Synthesis and chiral recognition abil-
ity of O-ethyl (2-naphthyl)phosphonothioic acid. Tetrahedron: Asym-
metry 2006;17:1617–1621.
N.R. acknowledges the Japan Society for the Promotion
of Science (JSPS) for a Postdoctoral Fellowship for
Foreign Researchers.
9. Kobayashi Y, Maeda J, Morisawa F, Saigo K. Synthesis and chiral rec-
ognition ability of O-phenyl ethylphosphonothioic acid with a confor-
mationally flexible phenoxy group for CH/p interaction. Tetrahedron:
Asymmetry 2006;17:967–974.
LITERATURE CITED
1. Jacques J, Collet A, Wilen SH. Enantiomers, racemates and resolu-
tions. Malaber, FL: Krieger Publishing Company; 1994.
10. Kobayashi Y, Handa H, Maeda J, Saigo K. Factors determining the
pattern of a hydrogen-bonding network in the diastereomeric salts of
1-arylethylamines with enantiopure P-chiral acids. Chirality 2008;20:
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Chirality DOI 10.1002/chir