Solid state properties of 1,2-epoxy-3-(2-methoxyphenyloxy)-propane - Valuable intermediate in non-racemic drug synthesis

Article abstract of DOI:10.1016/j.tetasy.2005.09.013

Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 undergoes spontaneous resolution upon crystallization. This fact is confirmed by coincidence of the IR spectra of racemic and scalemic crystalline samples of 1, by thermal analysis (single eutectic V-shape binary melting phase diagram), and X-ray analysis (space group P2₁2₁2₁, Z = 4). Racemic 1 could be resolved into (S)-(+)- and (R)-(-)-1 by a preferential crystallization procedure.

Full text of DOI:10.1016/j.tetasy.2005.09.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3361–3366
Solid state properties of 1,2-epoxy-3-(2-methoxyphenyloxy)-
propane—valuable intermediate in non-racemic drug synthesis
Alexander A. Bredikhin,* Elena I. Strunskaya, Dmitry V. Zakharychev,
Dmitry B. Krivolapov, Igor A. Litvinov and Zemfira A. Bredikhina
A.E. Arbuzov Institute of Organic & Physical Chemistry, Russian Academy of Sciences, Arbuzov st., 8, Kazan 420088,
Russian Federation
Received 6 July 2005; accepted 29 September 2005
Available online 20 October 2005
Abstract—Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 undergoes spontaneous resolution upon crystallization. This fact
is confirmed by coincidence of the IR spectra of racemic and scalemic crystalline samples of 1, by thermal analysis (single eutectic V-
shape binary melting phase diagram), and X-ray analysis (space group P212121, Z = 4). Racemic 1 could be resolved into (S)-(+)-
and (R)-(ꢀ)-1 by a preferential crystallization procedure.
Ó 2005 Elsevier Ltd. All rights reserved.
O
1.Introduction
O
O
*
Chiral epoxides are versatile buildingblocks for modern
enantioselective synthesis due to their regio- and stereo-
1
H
N
CH3
chemically controlled reactivity with a broad range of
nucleophiles.1 Amongthese, aryl glycidyl ethers have
been widely used for the production of non-racemic
drugs with b-adrenergic activities.1a,2
OH
O
N
H
N
OH
O
O
O
*
O
N
H3C
*
2
3
Moprolol
1,2-Epoxy-3-(2-methoxyphenyloxy)-propane, glycidyl
ether 1 has an obvious structural similarity with, and
can be used as an intermediate in the synthesis of the
b-adrenoblocker moprolol 2, antianginal remedy ranol-
azine 3, anxiolytic mephenoxalone 4, expectorant guai-
fenesin 5, and skeletal muscle relaxant methocarbamol
6. For the whole of the family of b-adrenoblockers, it
has been shown that the (S)-enantiomers are eutomer
components of the racemic drug, whereas the (R)-enan-
tiomers (distomers) usually display other (often unde-
sirable) activity.3 There is evidence that in the case of
methocarbamol 6 one enantiomer is more active
in vivo than the other or the racemate.4 From the
standpoint of the modern tendency to replace racemic
drugs by enantiopure version it is desirable to have a
precise knowledge about the properties of scalemic 1,
and to outline the direct access to both its enantiomeric
forms.
Ranolazine
O
OH
OH
O
O
O
O
O
O
NH2
O
OH
O
NH
*
*
*
O
4
6
5
Mephenoxalone
Methocarbamol
Guaifenesin
A number of different approaches have been developed
for obtainingscalemic aryl lgycidyl ethers including
syntheses from chiral natural products or nucleophilic
substitution of activated enantioenriched epoxypro-
panes. For the present, a wide assortment of kinetic res-
olutions of racemic aryl glycidyl ethers exists, assisted by
catalysts of synthetic or biological nature. Most of the
existingapproaches can be illustrated by the preparation
of enantioenriched epoxide 1. For the first time both
enantiomers of this compound were obtained with low
to moderate yield duringmultistep synthesis from natu-
ral D-mannitol.5 Some years later (R)-1 was resynthe-
sized from the same startingmaterial, whereas ( S)-1
*
Correspondingauthor. Tel.: +7 8432 727392; fax: +7 8432 731872;
e-mail: baa@iopc.knc.ru
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.013

3362
A. A. Bredikhin et al. / Tetrahedron: Asymmetry 16 (2005) 3361–3366
was obtained from (R)-epichlorohydrin via nucleophilic
reaction with guaiacol.6 Enantioenriched (S)-1 was pre-
pared from the correspondingscalemic 1-chloro-3-(2-
methoxyphenyloxy)-propane-2-ol, which was in its turn
obtained through lipase catalyzed hydrolysis of the
chlorohydrin esters.7 Racemic 1 was kinetically resolved
duringenantioselective ringopeningof epoxide with
trimethylsilylazide or isopropylamine in the presence
of b-cyclodextrin; (R)-enantiomer with ee 59–90% was
recovered.8 Recently (R)-1 was obtained by partial enan-
tioselective hydrolysis of rac-1 in the presence of the
Jacobsen (salen)-Co(III) chiral catalyst.9
form should be identical for conglomerate formation
and different for racemic compounds. Figure 1 shows
almost complete coincidence of the two spectra.
This is a good diagnostic for racemic conglomerate
formation for the compounds with the pronounced
H-bondinggroups, but for the compounds possessing
no classical H-donors (such as 1), the similarity of the
IR spectra must be treated with caution.12
2.2. Thermochemical investigations
This part of the work deals with binary mixtures of (R)-
and (S)-1 usingdifferential scanningcalorimetry as a
research method. A (solid + liquid) diagram of the
meltingtemperature against composition was obtained
for this system. Thermodynamic data on binary mix-
tures of enantiomers are useful, for instance for checking
the purity (includingenantiomeric purity) of chiral com-
pounds, and for obtaininginformation concerninga
particular technique to be used for achievingenantio-
meric resolution and/or enrichment.
The reports by Schneider et al. and Kamal et al.7,8
contain no experimental details about the epoxides
obtained, and there are some discrepancies amongchar-
acteristics of non-racemic epoxides 1 mentioned in other
5
sources. Accordingto Nelson et al. the mp values for
both enantiomers are equal to 56–57 °C. Caroon
et al.6 reports the values of mp 52–54 °C and [a]D =
ꢀ11.7 (c 0.995, MeOH) for (R)-1 (ee 98 1%, NMR);
and mp 43–47 °C and [a]D = +13.6 (c 0.997, MeOH)
for (S)-1 (ee 98 1%, NMR). Bredikhin et al.9 report
20
the value ½aŠ ¼ ꢀ11:9 (c 0.87, EtOH) for liquid (R)-1
The temperature data were determined accordingto the
method of Ho¨hne et al.,13 followingthe procedure
described by Gallis et al.14 The solidus values corre-
spond to the extrapolated peak onset temperatures TE.
The determination of the liquidus points TL requires a
correction for the shift of the peak temperature due to
the heatingof the sample and due to the distortions of
the peak shape, usingthe correct angle c. The angle is
obtained from a meltingexperiment usinga pure stan-
dard substance (doubly sublimed naphthalene in our
case) at the respective heatingrate; the slope of the lin-
ear front section of the curve determines c. For a pure
(chemically and enantiomerically) component, the
extrapolated peak onset temperature and the corrected
peak temperature almost coincide (Fig. 2a); and in all
cases corrected values have been used (Fig. 2a and b).
D
(ee 89%, NMR).
2.Results and discussion
Here we present the results of our IR, thermochemical,
and X-ray investigations revealing the conglomerate nat-
ure of chiral epoxide 1. The crystallization of a chiral
substance as a racemic conglomerate makes it possible
to resolve it without resortingto enantiopure chiral
reagents and/or auxiliaries. We have found that rac-1 is
capable on spontaneous resolution upon crystallization
and can be resolved by the entrainment technique.10,11
2.1. IR spectroscopy
To investigate the type of crystallization we compared
the IR spectra of racemic and highly enantiomerically
enriched crystalline samples of 1 in KBr pellets, since
the IR spectra of the optically active and the racemic
For the right evaluation of the binary phase diagram the
correct information concerningan enantiomeric compo-
sition [mole fraction of each enantiomer, nR and nS,
(nR + nS) = 1] of the samples investigated is of primary
importance. We have used for this purpose the value
of optical purity [ai]/[amax] = op ꢁ ee = j(nR ꢀ nS)j/
a
b
d
a
γ
T
TE
L
c
b
γ
TL
55
60
Temperature, oC
65
35
40
45
Temperature, oC
500
1000
1500
2000
2500
3000
ν, cm-1
Figure 2. Thermal curves for 1,2-epoxy-3-(2-methoxyphenyloxy)-pro-
pane 1 [(a), (S)-(+)-, op ꢁ 100%; (b), (S)-(+)-, op ꢁ 99.0%; (c), rac-, as
obtained after recrystallization; (d), rac-, after grinding].
Figure 1. IR spectra of the crystalline 1,2-epoxy-3-(2-methoxyphenyl-
oxy)-propane 1 [(a), (S)-(+); (b), racemic].

A. A. Bredikhin et al. / Tetrahedron: Asymmetry 16 (2005) 3361–3366
3363
Table 1. D.s.c. measured meltingpoint and enthalpy of fusion of racemic (low index R) and (S)-(+) (low index A) 1,2-epoxy-3-(2-meth-
oxyphenyloxy)-propane 1
T0Af (°C)
T0Rf (°C)
DHfA (J molꢀ1
)
DHfR (J molꢀ1
)
DSml (J Kꢀ1 molꢀ1
)
DG0 (J molꢀ1
)
58.8
37.6
25,400
21,300
4.79
ꢀ165
(nR + nS). The closer is the value [amax] used in the cal-
culations to the value of the specific rotation for enan-
tiopure sample, the better is equivalence between the
optical purity and the enantiomeric excess. We believe
One other circumstance is worthy of notice. Whereas the
endothermic event for routinely prepared polycrystalline
sample of highly enantioenriched epoxide 1 is depicted
by smooth unimodal curve (Fig. 2a), analogous events
for the similar racemic samples are depicted by remark-
able polymodal comb-shaped curves (Fig. 2c). For the
carefully ground samples the heating curve changes its
shape to a relatively broad unimodal one (Fig. 2d).
that enantiopure samples of (S)-1 are characterized
20
by the values ½aŠ ¼ þ13:0 Æ 0:1 (c 0.61, EtOH) or
D
20
½aŠ ¼ þ16:0 Æ 0:1 (c 1.02, MeOH). The following
D
reasons were taken into account to establish enantio-
meric purity of such a sample. (1) The value of specific
rotation was constant after several consecutive crystalli-
zations. Runningahead, it can be mentioned that for
conglomerate forming substances (only) this is a solid
evidence for the enantiomeric purity. (2) The 31P
NMR control of the enantiomeric purity of this sample
with the use of our developed derivatizingphosphorus
reagent based upon bis-N,N0-dimethylamide of natural
tartaric acid9,15 reveals no traces of the second enantio-
mer. (3) The d.s.c. heatingcurve for this sample has vir-
tually ideal shape (Fig. 2a), with a base line and a linear
front part of the curve constitutes a nearly perfect angle.
We believe that these peculiarities of the racemic sample
heating curves are diagnostic indicators for a conglom-
erate formingsubstances. The thermally induced event
for such a substance is not a proper melting. The process
begins from the formation of a limited amount of a
liquid (eutectic) phase promoted by microscopic con-
taminations followed by the dissolution of scalemic crys-
tals in racemic melt. As the entrapped crystals dissolve
in this portion of a melt, the endothermic process ceases.
The expansion of liquid zones through the sample is
restrained by surface tension, so it is realized as intermit-
tent advance. If the sample consists of the rather coarse
individual crystals, this succession of distinct events of
near complete dissolution of the solid in the one part
of the sample and stepwise growth of the liquid drops
encapsulatingnew portions of crystals leadingto new
endothermic events would generate a comb-shaped ther-
mal curve. If the sample consists of the thin-grinded
crystals, these consequences will lead to smooth but
rather broad thermal curve as compared with the curve
for enantiopure sample of the same mass.
In an effort to test this criterion we demonstrate another
20
curve for the sample with op ꢁ 0.99 {½aŠ ¼ þ12:9 (c
0.6, EtOH)} (Fig. 2b); one can see dramatiDcally changed
front, which is evidence of enantiomeric impurities.
The results obtained for the temperature and the enthal-
py of fusion of the pure enantiomer and the pure race-
mate are presented in Table 1. From the d.s.c. data
the meltingtemperature against composition diagram
was drawn and is depicted in Figure 3.
Experimental points in Figure 3 form an obvious single
eutectic V-shape curve typical to a racemic conglomer-
ate.10 Figure 3 presents also the theoretical liquidus
curve (dashed line) deduced for conglomerate from the
Schro¨der–Van Laar equation lnðnÞ ¼ ðDHfA=RÞð1=TAf ꢀ
1=Tf Þ. Both experimental and theoretical sets corre-
late quite well. The calculated10,16 entropy of mixing
for enantiomeric 1 in the liquid state is equal to
4.79 J Kꢀ1 molꢀ1, which is slightly less but close to
the ideal value of 5.77 J Kꢀ1 molꢀ1 (Rln2) for
conglomerates.
2.3. X-ray investigations
The X-ray studies of single crystals picked up from a
racemic sample of 1 revealed that all crystals belongto
the ÔchiralÕ space group P212121, Z = 4. This fact implies
that epoxide 1 crystallizes as a racemic conglomerate,
and homochiral molecules only are present in the single
crystal elementary cell. The geometry of 1 is depicted in
Figure 4. Structural parameters (bond lengths and
angles) of 1 have normal values, usually observed in sim-
ilar compounds. The methoxyphenyl fragment of the
molecule is planar, the oxypropyl fragment also has
nearly planar trans-conformation with the torsions
C(1A)O(2)C(3)C(2) = 172.1(3) and O(2)C(3)C(2)C(1) =
156.5(5)°.
60
50
40
30
Analysis of the intermolecular interactions in the homo-
chiral crystal of 1 showed no pronounced p–p interac-
tions between benzene rings. Dihedral angles between
the planes of the neighboring benzene rings are about
84.7°. Two short intermolecular contacts were observed
between hydrogen atoms of methyl and methylene
groups and the center of gravity [Cg(2)] of the neighbor-
ingextramolecular benzene rin:g C(4)–H(4B) ꢂ ꢂ ꢂCg(2)
0.0
0.2
0.4
0.6
0.8
1.0
Mole fraction of (S)-enantiomer
˚
[x ꢀ 1,y,z], the distance Hꢂ ꢂ ꢂCg(2) 2.69 A, the angle
Figure 3. Experimental (circles) and calculated (dashed lines) melting
point phase diagram of 1.
C(4)–H(4B)ꢂ ꢂ ꢂCg(2) 152°, and C(3)–H(3B)ꢂ ꢂ ꢂCg(2)

3364
A. A. Bredikhin et al. / Tetrahedron: Asymmetry 16 (2005) 3361–3366
tion of preferential crystallization, it can be insufficient
to ensure a practical entrainment effect under some cir-
cumstances.17 So we tried to realize the experimental
resolution of racemic 1 through entrainment procedure,
havingin mind to demonstrate the effect of entrainment
first of all, and makingno effort to achieve an optimum
condition for the process. We employed rectified ethanol
as the solvent.
A supersaturated solution of rac-1 includinga small
excess of (R)-(ꢀ)-1 was prepared by heating, and then
cooled to 10 °C. A small number of seeds of (R)-(ꢀ)-1
were added and the stirred solution was allowed to crys-
tallize for 30 min. The weight of (R)-(ꢀ)-1 obtained after
filtration was more than the common weight of initial
excess of (R)-enantiomer and seed added, although the
op of the precipitate was only 83%. To the mother
liquor, rac-1 was added in order that the quantity of 1
in the solution could be recovered. The mixture was
heated until the solid was completely dissolved and then
cooled to 10 °C. After the solution had been seeded with
(S)-(+)-1 and stirred for 30 min, the precipitated
(S)-(+)-1 was collected in a similar manner.
Figure 4. Geometry of the molecule
numberingscheme.
1 in crystal, and atomic
The current degree of resolution is low as yet, but it cer-
tainly might be improved by a future detailed examina-
tion of the resolution conditions.
3.Conclusion
To the best of our knowledge the glycidyl ether 1 is only
a third conglomerate forming representative among the
broad class of epoxides. The two others are glycidyl 3-
nitrobenzenesulfonate18 and (2RS, 3SR)-3-(4-methoxy-
phenyl)glycidic acid 4-chloro-3-methylphenyl ester.19
The last compound resolved by entrainment procedure
was already used in the synthesis of single enantiomer
coronary vasodilator diltiazem. We believe that more
intent search for conglomerates within this highly reac-
tive class of chemicals would lead to more intent practi-
cal use of the unappreciated potential of spontaneous
resolution phenomenon.
Figure 5. Packingdiagram of crystal 1. View along OZ axis.
4.Experimental
4.1. General
˚
[1/2 + x,1/2 ꢀ y,1 ꢀ z], Hꢂ ꢂ ꢂCg(2) 3.19 A, C(3)–
H(3B)ꢂ ꢂ ꢂCg(2) 155°. Another type of week intermolecu-
lar interactions, the hydrogen bond C(1)–H(1A)ꢂ ꢂ ꢂO(3)0
[1/2 + x,1/2 ꢀ y,2 ꢀ z] characterized by the distances
C(1)–H(1A) 0.97, H(1A)ꢂ ꢂ ꢂO(3)0 2.58, C(1)ꢂ ꢂ ꢂO(3)0
The NMR spectra were recorded on a Bruker MSL-400
1
(400.13 MHz for H; 100.6 MHz for 13C) spectrometer
in CDCl3 with TMS or the signals of the solvent as
the internal standard. The IR spectra of the polycrystal-
line samples of rac-1 and (R)- or (S)-1 in KBr pellets
were recorded on an Bruker IFS-66v Fourier-transform
spectrometer. Optical rotations were measured on a
Perkin–Elmer model 341 polarimeter (concentration c
is given as g/100 mL). Melting points for general pur-
poses were determined usinga Boe¨tius apparatus and
are uncorrected.
0
˚
3.347(7) A, and angle C(1)–H(1A)ꢂ ꢂ ꢂO(3) 136° have
been observed. The general hydrogen bond motif is zig-
zagchains along OX axis. As a whole crystalline epoxide
1 has a lamellar type of the packing( Fig. 5).
2.4. Resolution of the glycidyl ether 1 by preferential
crystallization
The above mentioned material created a solid evidence
that 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 crys-
tallizes as a racemic conglomerate. Although a stable
conglomerate is a necessary condition for the applica-
The meltingcurves of the samples of 1,2-epoxy-3-
(2-methoxyphenyloxy)-propane were measured on a
Setaram DSC-111 differential scanningcalorimeter in

A. A. Bredikhin et al. / Tetrahedron: Asymmetry 16 (2005) 3361–3366
3365
stainless steel cells with the rate of heatingof
30 min at 5–6 °C, (S)-1 {0.12 gafter dryi;ng
20
filtDration.
1 °C minꢀ1. Mass of the samples amounted to approxi-
mately 2.5 mg. Temperature scale and heat flux were cal-
ibrated against the data for a-corundum (sapphire),
phenol, and naphthalene. Experimental DSC curves
½aŠ ¼ þ11:1 (c 1.1, EtOH), op 83%} was collected by
A high degree of enantiomeric purity of collected 1,2-
epoxy-3-(2-methoxyphenyloxy)-propanes canbeachieved
14
were treated accordingto Gallis et al.
by slow crystallization from ethanol. Thus crop of crude
20
4.2. Synthesis
(R)-1 {200 mg; ½aŠ ¼ ꢀ11:1 (c 1.07, EtOH)} was dis-
solved in 0.7 ml oDf ethanol at 50–60 °C. The solution
was cooled to 7 °C and left standingat this temperature
Racemic epichlorohydrin and guaiacol were commer-
cially available. (R)- and (S)-epichlorohydrin were pre-
pared accordingto Jacobsen method without
modifications.20 Racemic 1,2-epoxy-3-(2-methoxyphen-
yloxy)-propane rac-1 was prepared from racemic epi-
chlorohydrin and guaiacol by known procedure,21 bp
88–90 °C at 0.05 mmHg, mp 38–40 °C (colorless needles
from ethanol) [lit.21 bp 120 °C/0.9 mmHg; lit.22 mp
overnight; 155 mg of enantiomerically pure (R)-1
20
D
{½aŠ ¼ ꢀ13:1 (c 1.22, EtOH)} was collected by filtration.
4.4. X-ray analysis
4.4.1. X-ray crystallography of 1. C10H12O3,
M = 180.21, orthorhombic, space group P212121, a =
1
3
˚
˚
36 °C (light petroleum)]; H NMR (400 MHz, CDCl3)
5.068(2), b = 18.169(7), c = 10.128(7) A, V = 932.5(8) A ,
Z = 4, qcalcd = 1.28 Mgm ꢀ3. Cell parameters and inten-
sities of 2751 independent reflections were measured on
an Enraf-Nonius CAD-4 diffractometer in the x/2h-scan
mode, h 6 64.8°, usingCu K a radiation (graphite mono-
d = 6.97–6.86 (m, 4H–Ar), 4.23 (dd, 2J = 11.44, 3J =
3.27, 1H, CH2), 4.02 (dd, 2J = 11.44, 3J = 5.45, 1H,
CH2), 3.85 (s, 3H, CH3), 3.39–3.36 (m, 1H, CH),
2
3
2
2.87 (dd, J = 4.63, J = 4.36, 1H, CH2), 2.72 (dd, J =
4.91, 3J = 2.72, 1H, CH2). 13C NMR (100.6 MHz,
CDCl3) d = 149.93, 148.25, 122.11, 121.01, 114.70,
112.33, 70.45, 55.99, 50.29, 44.88 [lit.23,21].
˚
chromator, k 1.54184 A). The stability of crystals and
experimental conditions were checked every 2 h using
three control reflections, while the orientation was mon-
itored every 200 reflections by centeringtwo standards.
Linear decay correction of intensities of reflections was
applied, because 74% decay of intensity control reflec-
tions were observed. Absorption corrections were not
applied (lCu 7.41 cmꢀ1). Corrections for Lorentz and
polarization effects were applied. The structure was
solved by direct method usingthe SIR program24 and
refined by the full matrix least-squares using SHELXL97
program.25 All non-hydrogen atoms were refined aniso-
tropically. The hydrogen atoms were solved from differ-
ence Fourier maps and its contribution on structural
factors was included with fixed positional and thermal
parameters in the last cycles. The absolute crystal struc-
ture and absolute molecule configuration were deter-
mined by the Flack parameter (absolute structure
parameter 0.0035(15)). The final residuals were R =
0.057, Rw = 0.112, goodness-of-fit on F2 = 0.945 on
1331 observed reflections with F2 P 2r.
4.2.1. (S)-1,2-Epoxy-3-(2-methoxyphenyloxy)-propane.
(S)-1 used as seed was obtained from the (R)-epichloro-
20
D
hydrin {6.33 g, 0.07 mol; ½aŠ ¼ ꢀ24:4 (c 1.7, MeOH),
op 70%} and guaiacol (2.80 g, 0.025 mol) as described
for racemic compound.21 The configuration of the
product is inverted as against the configuration of the
startingepichlorohydrin. The crude ( S)-1 was crystal-
lized four times from EtOH to give colorless needles
20
D
{1.43 g(35%); mp 59–60 °C; ½aŠ ¼ þ13:0 (c 0.61,
20
EtOH), ½aŠ ¼ þ16:0 (c 1.02, MeOH), ee > 99%}; [lit.5
D
20
D
mp 56–57 °C]; {lit.6 mp 43–47 °C, ½aŠ ¼ þ13:6 (c
0.997, MeOH) (ee 98 1%, NMR)}.
4.2.2. (R)-1,2-Epoxy-3-(2-methoxyphenyloxy)-propane.
(R)-1 used as seed was synthesized analogously from
the (S)-epichlorohydrin. The colorless needles; mp
20
D
59–60 °C (EtOH), ½aŠ ¼ ꢀ12:9 (c 0.53, EtOH) {lit.6
mp 52–54 °C, [a]D = ꢀ11.7 (c 0.995, MeOH) (ee
98 1%, NMR)}.
Cell parameters, data collection, and data reduction
were performed on Alpha Station 200 computer using
MolEN program.26
4.3. Resolution of racemic 1,2-epoxy-3-(2-methoxy-
phenyloxy)-propane 1 by preferential crystallization
(entrainment)
Atomic coordinates, bond lengths, bond angles, and
thermal parameters have been deposited at the Cam-
bridge Crystallographic Data Centre (CCDC). These
data can be obtained free of charge via www.ccdc.
cam.uk/conts/retrieving.html (or from the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336 033; or deposit@ccdc.cam.ac.uk). Any request
to the CCDC for data should quote the full literature
citation and CCDC reference number CCDC 275429.
Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane
20
D
rac-1 (1.9 g) and (R)-1 {0.15 g, ½aŠ ¼ ꢀ12:7 (c 0.94,
EtOH)} were dissolved in 20 ml of ethanol at 30 °C.
The solution of this specially prepared sample
(op ꢁ 7%) was cooled to 10 °C and seeded with finely-
pulverized (R)-1 (13 mg). After stirring the mixture for
30 min at 5–6 °C, precipitated (R)-1 was collected by
20
filtration {0.22 gafter dryin;g
½aŠ ¼ ꢀ11:1 (c 1.1,
EtOH), op 83%}. The extra portioDn of rac-1 (0.22 g)
was then dissolved in the mother liquor at 30 °C; the
Acknowledgment
resultingsolution was cooled to 10 °C. After addition
The authors thank the Russian Fund of Basic Research
for financial support (grant nos. 03-03-33084, 04-03-
32156).
20
D
of (S)-1 {13 mg, ½aŠ ¼ þ13:0 (c 0.61, EtOH)} as seed
crystals to the solution, and stirringthe mixture for

3366
A. A. Bredikhin et al. / Tetrahedron: Asymmetry 16 (2005) 3361–3366
13. Ho¨hne, G. W. H.; Cammenga, H. K.; Eysel, W.; Gmelin,
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