Enantioselective Inclusion of Sulfoxides
J . Org. Chem., Vol. 65, No. 1, 2000 75
P r ep a r a tion of In clu sion Com p ou n d s of Alk yl P h en yl
Su lfoxid e a n d (R,R)-1. Meth od A. (R,R)-1 (1.0 mmol) was
dissolved in 0.1 M aqueous HCl, then the pH was adjusted to
about 6.5 by the addition of 0.1 M aqueous NaOH.4a After the
addition of a racemic sulfoxide (2, 3, or 4) (2.0 mmol) to the
aqueous solution of (R,R)-1, the resulting mixture was allowed
to stand at an ambient temperature for several days. The
deposited inclusion compound was collected by filtration and
washed with water (20 mL) and CHCl3 (20 mL).
Meth od B. Crystals of (R,R)-1 are essentially insoluble in
organic solvents and water. A suspension of (R,R)-1 (1.0 mmol)
in water (2 mL) was stirred together with a racemic sulfoxide
(2, 3, or 4) (2.0 mmol) at ambient temperature for 1 day. The
formed inclusion compound was collected by filtration and
washed with water (20 mL) and CHCl3 (20 mL).
Meth od C. An agate mortar and (R,R)-1 were dried in a
desiccator. A mixture of (R,R)-1 (1.0 mmol) and a racemic
sulfoxide (2, 3, or 4) (2.0 mmol) was often grounded in an agate
mortar at ambient temperature for 30 min. To keep dry, the
mortar was stored in a desiccator when not being used. The
formed inclusion compound was washed with water (20 mL)
and CHCl3 (20 mL).
Deter m in a tion of Efficien cy, Ster eoch em istr y, a n d
En a n tiom er ic Excess in th e In clu sion . After decomposition
of the inclusion compound with diluted DCl in D2O, inclusion
efficiency was determined by NMR measurement. The in-
cluded sulfoxide was isolated by dissolution of the inclusion
compound in 0.1 M aqueous HCl (40 mL) and extraction with
CHCl3. The absolute stereochemistry of recognized sulfoxides
was determined by comparison of the optical rotation to the
value of the literature and/or by chiral shift reagents [(R)-(+)-
2,2′-dihydroxy-1,1′-binaphthyl7a ((R)-BINOL, 1 mol equiv for
the sulfoxide) and (S)-R-methoxyphenyl acetic acid7b ((S)-
MPAA, 3 mol equiv for the sulfoxide)]. Enantiomeric excess
of the sulfoxide was determined by a chiral HPLC (Daicel
Chiralcel OB).
2e: [R]25 ) +177.9 (c ) 1.1, acetone); 72% ee R by HPLC;
D
HPLC eluent, hexane/2-propanol (20:1), flow rate ) 0.6 mL/
1
min, tR(S) ) 25.7 min, tR(R) ) 28.2 min); H NMR (with (R)-
BINOL in CDCl3) δ 2.84 (s, 2.6H, R major), 2.84 (s, 0.4H, S
minor), 2.58 (s, 6H), 7.04 (d, 2H, 7.6 Hz), 7.22 (t, 1H, 7.6 Hz)
2g: [R]25D ) -87.8 (c ) 1.3, acetone); 73% ee S by NMR, 1H
NMR (with (R)-BINOL in CDCl3) δ 2.63 (s, 2.60H, R minor),
2.64 (s, 0.40H, S major), 2.31 (s, 3H), 2.39 (s, 3H), 7.08 (d, 1H,
7.8 Hz), 7.14 (d, 1H, 7.8 Hz), 7.73 (s, 1H). HPLC showed no
baseline separation (eluent, hexane/2-propanol (20:1), flow rate
) 0.5 mL/min, tR(S) ) 38.3 min, tR(R) ) 40.9 min).
2i: [R]25 ) +57.86 (c ) 0.59, acetone), 30% ee R by NMR;
D
1H NMR (with (R)-BINOL in CDCl3,) δ 2.63 (s, 1.95H R major),
2.64 (s, 1.05H, S minor), 2.33 (s, 3H), 2.36 (s, 3H), 7.01 (s, 1H),
7.23 (d, 1H, 8.0 Hz), 7.80 (d, 1H, 8.0 Hz). HPLC showed no
baseline separation (eluent, hexane/2-propanol (20:1), flow rate
) 0.5 mL/min, tR(S) ) 32.3 min, tR(R) ) 34.8 min).
2f: [R]25 ) -102.59 (c ) 0.925, acetone); 77% ee S by
D
HPLC; HPLC eluent, hexane/2-propanol (9:1), flow rate ) 0.6
1
mL/min, tR(S) ) 16.8 min, tR(R) ) 23.5 min); H NMR (with
(R)-BINOL in CDCl3) δ 2.37 (s, 6H), 2.67 (s, 0.3H, R minor),
2.68 (s, 2.7H, S major), 7.11 (s, 1H), 7.23 (s, 2H).
2h : [R]25D ) -111.33 (c )0.98, acetone); 79% ee S by HPLC;
HPLC eluent, hexane/2-propanol (9:1), flow rate ) 0.6 mL/
1
min, tR(S) ) 20.8 min, tR(R) ) 41.3 min); H NMR (with (R)-
BINOL in CDCl3, 75% ee S) δ 2.304 (s, 3H), 2.309 (s, 3H), 2.648
(s, 0.4H, R minor), 2.662(s, 2.6H, S major). Aromatic 3H could
be not identified because of the binaphthyl.
4b starting material (major/minor ) 3:1):15a 1H NMR
(CDCl3) (major, RR*,SR*) δ 1.75 (d, 3H, 7.1 Hz), 2.30 (s, 3H),
3.76 (q, 1H, 7.1 Hz), 7.08-7.44 (m, 5H), (minor, RR*,SS*) δ
1.73 (d, 3H, 7.1 Hz), 2.18 (s, 3H), 3.86 (q, 1H, 7.1 Hz), 7.08-
7.44 (m, 5H). 1H NMR (with (S)-MPAA in CDCl3) (major,
RS,SS) δ 1.72 (d, 3H, 7.1 Hz), 2.34 (s,3H), 3.93 (q, 1H, 7.1 Hz),
(major, RR,SR) 1.69 (d, 3H, 7.1 Hz), 2.35 (s, 3H), 3.95 (q, 1H,
7.1 Hz), (minor, RR,SS) 1.69 (d, 3H, 7.1 Hz), 2.24 (s,3H), 3.99
(q, 1H, 7.1 Hz), (minor, RS,SR) 1.68 (d, 3H, 7.1 Hz), 2.26 (s,
3H), 4.12 (q, 1H, 7.1 Hz). Aromatic H could be not identified
because of (S)-MPAA.
2c, 3c, 4a , and 4c were not recognized enantiomerically,
and 3d and 4e were not included at all.
2a [R]25 ) +190.5 (c ) 1.3, acetone); 92% ee R by [R];23
D
4d : [R]25 ) -55.7 (c ) 1.1, acetone), 81% ee R by NMR;
D
HPLC eluent, hexane/2-propanol (4:1), flow rate ) 0.6 mL/
1H NMR (with (S)-MPAA in CDCl3) δ 2.33 (s, 3H), 2.49 (s,
0.27H, S minor), 2.51 (s, 2.72H, R major), 3.94 (d, 0.91H J )
12.7 Hz, R major), 3.95 (d, 0.09H, J ) 12.7 Hz, S minor), 4.17
(d, 1H, J ) 12.6 Hz), 7.23 (t, 1H 7.6 Hz), 7.14 (d, 1H, 7.6 Hz),
7.06 (s, 1H), 7.04 (d, 1H, 7.6 Hz). HPLC showed no baseline
separation (eluent, hexane/2-propanol (9:1), flow rate ) 0.6 mL/
min, tR(S) ) 29.4 min, tR(R) ) 33.4 min).
1
min, tR(S) ) 11.0 min, tR (R) ) 22.8 min); H NMR (with (R)-
BINOL in CDCl3) δ 2.64 (s, 2.6H, R major), 2.65 (s, 0.4H, S
minor), 2.36 (s, 3H), 7.19-7.61 (m, 4H).
2b: [R]25 ) -120.4 (c ) 1.0, EtOH); 92% ee S by [R],6b
D
HPLC eluent, hexane/2-propanol (4:1), flow rate ) 0.6 mL/
1
min, tR(S) ) 10.7 min, tR(R) ) 15.4 min); H NMR (with (R)-
BINOL in CDCl3) δ 2.41 (s, 3H), 2.67 (s, 0.1H, R minor), 2.68
(s, 2.9H, S major), 7.45 (s, 1H). Aromatic 3H could be not
identified because of the binaphthyl group.
X-r a y An a lyses. X-ray powder diffractions were obtained
with a MAC Science MXP diffractometer using graphite-
monochromated Cu KR radiation (40 kV, 300 mA). The spectra
were measured at room temperature between 2° and 50° in
the 2θ scan mode with steps of 0.01° in 2θ and 4°/min.
Cr ysta llogr a p h ic Da ta for th e In clu sion Com p ou n d s.
To the solution of (R,R)-1 was added a methanol solution of
the guest (3a , 2b, or 4a ) directly in a vial, then the lid of the
vial was loosely closed for evaporation of the solvent. The
samples were allowed to stand for several days to form the
desirable single crystals. Data of an inclusion complex with
2d were already reported in our previous paper.4a Data
collection was performed on a Mac Science MXC18 four-circle
diffractometer with graphite-monochromated Cu KR (λ ) 1.541
78) radiation using the 2θ-ω scan technique, and the X-ray
intensities were measured up to 2θ ) 140° at 298 K. The
structures were solved by a direct method SIR 9226 and refined
by a computer program package, CRYSTAN-GM ver. 6.2.1 or
maXus ver. 1.1 from MAC Science Co. Ltd. Hydrogen atoms
are calculated in the appropriate position.
2c: [R]25 ) +21.0 (c ) 2.2, acetone); 18% ee R by [R],24
D
HPLC eluent, hexane/2-propanol (4:1), flow rate ) 0.6 mL/
1
min, tR(S) ) 11.6 min, tR(R) ) 22.9 min); H NMR (with (R)-
BINOL in CDCl3) δ 2.67 (s, 1.8H, R major), 2.68 (s, 1.2H, S
minor), 2.41 (s, 3H), 7.32 (d, 2H 8.2 Hz), 7.52 (d, 2H, 8.2 Hz).
2d : [R]25 ) -143.1 (c ) 1.4 EtOH); 74% ee S by [R],25a,b
D
HPLC eluent, hexane/2-propanol (4:1), flow rate ) 0.7 mL/
min, tR(S) ) 11.3 min, tR(R) ) 20.5 min).
3a : [R]25 ) +140.6 (c ) 1.0, acetone); 48% ee R by HPLC;
D
HPLC eluent, hexane/2-propanol (9:1), flow rate ) 0.7 mL/
1
min, tR(S) ) 18.5 min, tR(R) ) 23.6 min); H NMR (with (R)-
BINOL in CDCl3) δ 2.78 (s, 2.2H, R major), 2.79 (S, 0.8H, S
minor). Aromatic 4H could be not identified because of the
binaphthyl group.
3b: [R]25 ) -85.2 (c ) 0.87, acetone); 92% ee S by HPLC;
D
HPLC eluent, hexane/2-propanol (9:1), flow rate ) 0.7 mL/
1
min, tR(S) ) 18.3 min, tR(R) ) 27.0 min); H NMR (with (R)-
BINOL in CDCl3) δ 2.69 (s, 0.1H, R minor), 2.70 (s, 2.9H, S
major), 7.43-7.48 (m, 3H), 7.64-7.64 (m, 1H).
Th e in clu sion com p ou n d of 3a (2-ch lor op h en yl m eth yl
su lfoxid e): C23H23ClN2O4S, M ) 459.00, crystal dimensions
0.15 × 0.10 × 0.05 mm, orthorhombic, P212121, a ) 16.226(4)
Å, b ) 24.679(6) Å, c ) 5.635(2) Å, V ) 2256.5(9) Å3, Z ) 4,
(23) Dun˜ach, E.; Kagan, H. B. Nouv. J . Chim., 1985, 9, 1.
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Chem. 1995, 60, 8086.
(25) (a) Mikolajczyk, M.; Drabowicz, J . J . Am. Cem. Soc. 1978, 100,
2510. (b) Rebiere, F.; Samuel, O.; Ricard, L.; Kagan, H. B. J . Org. Chem.
1991, 56, 5991.
(26) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J . Appl. Crystallogr. 1994, 27,
435.