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T. Prisinzano et al. / Tetrahedron: Asymmetry 14 (2003) 3285–3289
the aid of the SHELX97 system of programs. The
full-matrix least-squares refinement on F2 used three
restraints and varied 843 parameters including atom
coordinates and anisotropic thermal parameters. H
atoms were included using a riding model [coordinate
shifts of C applied to attached H atoms, C–H dis-
solid material was washed with CH2Cl2 (150 mL). The
filtrate was evaporated under reduced pressure to
afford 4.0 g of a crude oil that was used without
further purification. A solution of the crude oil in dry
pyridine (25 mL) was cooled to 0°C and treated with
p-toluenesulfonyl chloride (5.3 g, 27.6 mmol). The
resulting mixture was stirred vigorously and allowed
to warm to room temperature overnight. The mixture
was poured in an ice (200 g), H2O (100 mL) mixture
and the resulting aqueous mixture was extracted with
Et2O (3×100 mL). The combined Et2O portion was
washed successively with 2N HCl (3×50 mL), H2O
(100 mL), and saturated NaCl (100 mL) and dried
(Na2SO4). Removal of the solvent under reduced pres-
sure afforded 7.6 g of 8 (93%) as a tan solid, mp
44–48°C (lit.17 mp 54–55°C).
,
tances set to 0.96 to 0.93 A, H angles idealized,
Uiso(H) were set to 1.2 to 1.5 Ueq(C). Final residuals
were R1=0.064 for the 6903 observed data with Fo>
4|(Fo) and 0.095 for all data. Final difference Fourier
−3
,
excursions of 0.24 and −0.27 e A . The data crystal
was twined but was resolved with the aid of the pro-
gram Gemini. The assignment as (S)-(+)-4 was on the
basis of the asymmetric synthesis. While the Flack
parameter24 indicates the (S)-configuration, the level
of uncertainty makes this indication unreliable due
both to the twinning and the weak anomalous scatter-
ing of the fluorines. Coordinates of each of the
twinned compounds have been deposited with the
Cambridge Crystallographic Data Centre (Cambridge
University Chemical Laboratory, Cambridge CB2
1EW, UK). CDCC number: 203142.
4.5. 1-(4-{2-[Bis-(4-fluorophenyl)methoxy]-ethyl}piperazin-
1-yl)-2-phenylpropan-2-ol dimaleate, ( )-4
A suspension of 1-{2-[bis-(4-fluorophenyl)-methoxy]-
ethyl}piperazine (1.1 g, 3.3 mmol), 8 (1.1 g, 3.5
mmol), Na2CO3 (1.0 g, 9.9 mmol) in absolute EtOH
(30 mL) was heated at reflux overnight. The solvent
was removed under reduced pressure to afford a crude
oil. H2O (150 mL) was added and the mixture was
extracted with CH2Cl2 (3×50 mL). The combined
CH2Cl2 portion was washed with saturated NaCl (75
mL) and dried (Na2SO4). Removal of the solvent
under reduced pressure afforded an oily residue that
was purified by flash chromatography (eluent: CHCl3/
MeOH, 19:1) to afford a pale yellow oil. The oil was
dissolved in MeOH (50 mL) and maleic acid (2.2
equiv.) was added. The precipitate was collected by
filtration and dried to afford 1.6 g (70%) of ( )-4 as a
white solid, mp 183–184°C (lit.12 mp 182–183°C).
4.2. General remarks
Optical rotations were determined on a Perkin–Elmer
341 polarimeter at 365 nM and 20°C. All melting
points were determined on a Thomas–Hoover melting
point apparatus and are uncorrected. The 1H NMR
spectra were recorded on a Varian XL-300 instrument
using CDCl3 or DMSO-d6 as solvent, l values in ppm
1
(TMS as internal standard), J (Hz) assignments of H
resonance coupling. Thin layer chromatography (TLC)
was performed on 250 mm Analtech GHLF silica gel
plates using either n-hexanes/EtOAc, 7:3 or CHCl3/
MeOH, 19:1 as eluent. Elemental analyses were per-
formed by Atlantic Microlabs, Inc., Norcross, GA.
4.6. (S)-(+)-1-(4-{2-[Bis-(4-fluorophenyl)methoxy]-ethyl}-
piperazin-1-yl)-2-phenylpropan-2-ol dimaleate, (S)-(+)-4
4.3. Methyl 2-hydroxy-2-phenylpropionate, 7
A suspension of 6 (2.0 g, 12.0 mmol), iodomethane
(1.9 g, 13.2 mmol), and K2CO3 (1.8 g, 13.2 mmol) in
acetone (30 mL) was heated at reflux overnight. The
solvent was removed under reduced pressure and H2O
(100 mL) was added to the residue. The aqueous mix-
ture was extracted with CH2Cl2 (3×50 mL). The com-
bined CH2Cl2 portion was washed with saturated
NaCl (75 mL) and dried (Na2SO4). Removal of the
solvent under reduced pressure afforded 2.2 g (97%) of
A suspension of 1-{2-[bis-(4-fluorophenyl)-methoxy]-
ethyl}piperazine (1.1 g, 3.3 mmol), (S)-821 (1.1 g, 3.5
mmol), Na2CO3 (1.0 g, 9.9 mmol) in absolute EtOH
(30 mL) was heated at reflux overnight. The solvent
was removed under reduced pressure to afford a crude
oil. H2O (150 mL) was added and the mixture was
extracted with CH2Cl2 (3×50 mL). The combined
CH2Cl2 portion was washed with saturated NaCl (75
mL) and dried (Na2SO4). Removal of the solvent
under reduced pressure afforded an oily residue that
was purified by flash chromatography (eluent: CHCl3/
MeOH, 19:1) to afford a pale yellow oil. The oil was
dissolved in MeOH (40 mL) and maleic acid (2.2
equiv.) was added. The precipitate was collected by
filtration and dried to afford 1.7 g (74%) of (S)-(+)-4
as a white solid, mp 187–188°C: 1H NMR (DMSO-
d6): l 7.1–7.5 (m, 13H); 6.1 (s, 4H); 5.5 (s, 1H); 2.4–
3.6 (m, 18H); 1.4 (s, 3H); [h]23605=+10.4 (c=0.68,
MeOH); Anal. calcd for (C28H32F2N2O2·2C4H4O4): C,
61.88; H, 5.77; N, 4.01. Found: C, 61.98; H, 5.77; N,
3.96.
1
7 as a clear oil: H NMR (CDCl3): l 7.2–7.6 (m, 5H);
3.7 (m, 4H); 1.8 (s, 3H).
4.4. 2-Phenyl-1-tosyloxy-2-propanol, 8
A solution of 7 (5.0 g, 27.7 mmol) in dry THF (50
mL) was added in a dropwise manner to a suspension
of LAH (1.2 g, 30.5 mmol) in dry THF (100 mL) at
0°C. The mixture was stirred vigorously at room tem-
perature for 2 h. The mixture was cooled to 0°C and
then cautiously treated with H2O (1.2 mL) and 10%
NaOH (1.2 mL). After warming to room temperature,
Celite was added and the mixture was filtered and the