Jacobsen-type enantioselective hydrolysis of aryl glycidyl ethers. 31P NMR analysis of the enantiomeric composition of oxiranes

Article abstract of DOI:10.1023/B:RUCB.0000024851.29744.21

The enantioselective partial hydrolysis of a number of racemic aryl glycidyl ethers in the presence of chiral Co(salen)-catalyst was studied. The enantiomeric composition of the isolated (R)-aryl glycidyl ethers was analyzed by ³¹P NMR using optically active substituted 2-chloro-1,3,2- dioxaphospholanes. A synthesis of β-adrenoblocking agents (S)-toliprolol and (S)-moprolol based on the simultaneously obtained (S)-3-aryloxypropane-1,2- diols was proposed.

Full text of DOI:10.1023/B:RUCB.0000024851.29744.21

Russian Chemical Bulletin, International Edition, Vol. 53, No. 1, pp. 213—218, January, 2004
213
Jacobsenꢀtype enantioselective hydrolysis of aryl glycidyl ethers.
31P NMR analysis of the enantiomeric composition of oxiranes
A. A. Bredikhin,ꢀ E. I. Strunskaya, V. G. Novikova, N. M. Azancheev, D. R. Sharafutdinova, and Z. A. Bredikhina
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7(843 2) 73 2253. Eꢀmail: baa@iopc.knc.ru
The enantioselective partial hydrolysis of a number of racemic aryl glycidyl ethers in the
presence of chiral Co(salen)ꢀcatalyst was studied. The enantiomeric composition of the isoꢀ
lated (R)ꢀaryl glycidyl ethers was analyzed by 31P NMR using optically active substituted
2ꢀchloroꢀ1,3,2ꢀdioxaphospholanes. A synthesis of βꢀadrenoblocking agents (S)ꢀtoliprolol and
(S)ꢀmoprolol based on the simultaneously obtained (S)ꢀ3ꢀaryloxypropaneꢀ1,2ꢀdiols was proꢀ
posed.
Key words: enantioselective hydrolysis, chiral Co(salen)ꢀcatalyst, aryl glycidyl ethers, enanꢀ
tiomeric purity, 31P NMR, 3ꢀaryloxypropaneꢀ1,2ꢀdiols, toliprolol, moprolol.
Among various approaches to nonracemic compounds,
of special value are those permitting the preparation of
broad ranges of target compounds within a single experiꢀ
mental strategy. An example of such approach is enantioꢀ
selective hydrolysis of terminal epoxides in the presence
of chiral CoIII (salen) complexes (Scheme 1), which was
recently proposed by Jacobsen.1
enantiomer with the opposite configuration of the chiral
center. The overall stereochemical outcome of the reacꢀ
tion (i.e., predominant configurations of the diol and the
epoxide) depends on the configuration of the chiral
catalyst.
Both nonracemic products 2 and 3 obtained by the
Jacobsen reaction are of considerable interest. For exꢀ
ample, aryl glycidyl ethers are valuable intermediates in
the synthesis of βꢀadrenoblocking agents of the 1ꢀalkylꢀ
aminoꢀ3ꢀaryloxypropanꢀ2ꢀol class.2 Aryloxypropanediols
3 themselves exhibit a clearꢀcut biological activity; at least
three of these compounds, mephenesin (Ar = 2ꢀMeC6H4),
guaifenesin (Ar = 2ꢀMeОC6H4), and chlorphenesin
(Ar = 4ꢀClC6H4) are registered pharmaceuticals.3
Recently, we found that some compounds of this class,
in particular, mephenesin and guaifenesin, undergo sponꢀ
taneous resolution of enantiomers upon crystallization.4
This phenomenon is of interest from the practical standꢀ
point, because it can underlie the development of effiꢀ
cient methods for largeꢀscale production of nonracemic
compounds.5 The theoretical aspects of spontaneous resoꢀ
lution, a boundary phenomenon between the chemistry
of enantioselective processes and supramolecular chemꢀ
istry, are equally important.6 To extend the studies along
this line and to develop new ways of preparing nonracemic
biologically active compounds, we needed a broad range
of nonracemic aryloxypropanediols 3.
Scheme 1
Previously, scalemic aryloxypropanediols have been
prepared from enantiopure natural feedstock7 or by parꢀ
tial alkaline hydrolysis of racemic esters by means of
enzymes8 or living microbes.9 The method used most
widely is catalytic regioselective addition of phenols to
If racemic aryl glycidyl ethers 2 are used as substrates,
this reaction gives scalemic 3ꢀaryloxypropaneꢀ1,2ꢀdiols
(3) and unreacted aryl glycidyl ethers enriched in the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 203—208, January, 2004.
1066ꢀ5285/04/5301ꢀ0213 © 2004 Plenum Publishing Corporation

214
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Bredikhin et al.
scalemic glycidols.10,11 Partial enantioselective hydrolysis
of racemic aryl glycidyl ethers according to Jacobsen
has substantial advantages over all known methods, as
it uses readily available racemic starting compounds
and the procedure is simpler and better reproducible than
those used in biotechnology. In an original study,1с this
method was used to prepare scalemic 3ꢀphenyloxyꢀ and
3ꢀ(1ꢀnaphthyl)oxypropaneꢀ1,2ꢀdiols from the correꢀ
sponding racemic ethers 2.
In this study, we carried out partial hydrolysis
of aryl glycidyl ethers 2a—k in the presence of
(S,S)ꢀN,N´ꢀbis(3,5ꢀdiꢀtertꢀbutylsalicylidene)cyclohexꢀ
aneꢀ1,2ꢀdiaminocobalt(III) ((S,S)ꢀ1) (Scheme 2).
Table 1. Yields and physicochemical characteristics of (R)ꢀaryl
glycidyl ethers 2
20
Comꢀ
pound
Yield
(%)
B.p.
/°C (Torr)
–[α]D
ee
(%)
2a
40
69—70 (0.05) 14.8 (c 7.38, CHCl3)a >89
(92)b
53
70—73 (0.05) 18.0 (c 1.91, MeOH)c >80
2b
2c
2d
2e
2f
2g
2h
2i
50
50
41
38
48
50
47
45
46
68
65—68 (0.05) 17.7 (c 0.89, EtOH)
65—70 (0.05) 17.3 (c 0.88, EtOH)
90 (0.1) 11.9 (c 0.87, EtOH)
71
89
79—80 (0.05) 10.0 (c 0.93, EtOH) >94
90—94 (0.1) 11.3 (c 1.36, МеOH)d 80
75—77 (0.05) 19.1 (c 1.91, EtOH)
76—80 (0.05) 19.7 (c 1.45, EtOH)
90—94 (0.1) 18.2 (c 0.37, EtOH)
82—85 (0.05) 12.6 (c 1.25, EtOH)
89
91
63
29
2j
2k
Scheme 2
20
a Lit. data1с for (S)ꢀ2a, [α]D +5.2 (c 7.5, CHCl3).
b Determined by polarimetry.
20
c Lit. data15 for (S)ꢀ2c, [α]D +13.2 (c 1.4, MeOH).
d Lit. data:16 [α]D25 –10.2 (c 1.29, MеOH) (25 °C).
lyst (S,S)ꢀ1 was synthesized by published procedures.1c,13
The catalyst configuration was chosen deliberately for the
preparation of diols (S)ꢀ3, because (S)ꢀenantiomers act
as eutomers both in the series of compounds 3 and in the
series of βꢀadrenoblocking agents that can be obtained
from 3.14 The yields, the enantiomeric purity, and some
characteristics of the isolated products are summarized in
Tables 1, 2. The specific rotation values of the diols we
obtained were always measured after a single recrystalliꢀ
zation from CCl4. The optical purity might increase due
to partial enrichment in one enantiomer. Although the
reaction conditions were not optimized for each case, the
data of Tables 1 and 2 show satisfactory results as regards
R = H (a), 2ꢀMe (b), 3ꢀMe (c), 4ꢀMe (d), 2ꢀMeO (e), 3ꢀMeO (f),
4ꢀMeO (g), 2ꢀCl (h), 3ꢀCl (i), 4ꢀCl (j), 2ꢀ(CH2CH=CH2) (k)
The starting compounds were prepared by the reacꢀ
tions of the corresponding sodium phenoxides with raceꢀ
mic epichlorohydrin by a known procedure.12 The cataꢀ
Table 2. Yields, physicochemical characteristics, and optical purity (ee) of (S)ꢀ3ꢀaryloxypropaneꢀ1,2ꢀdiols 3
20
Comꢀ
pound
Yield
(%)
M.p./°C
[α]D
ee (%)
experiment published data
experiment
published data
experimenta published data
3a
3b
40
23
64—65
91.5—92.5 90.9—92.9 10c –19.3 (c 1.15,
62.5—64.5 10c +10.1 (c 1.0, EtOH)
–10.8 (c 1.0, EtOH)b,8a
–19.3 (c 0.9,
88.8
>99
95 8а
>99 8а
hexane—PriOH, 4 : 1) hexane—PriOH, 4 : 1)8a
3c
3d
3e
3f
3g
3h
42
40
34
40
46
48
59—60
64—65
98—99
40—43
78—79
86—88
60—62 4
64—65 4
+9.2 (c 0.94, EtOH)
+8.4 (c 1.01, EtOH)
+9.3 (c 1.0, EtOH)8a
–9.2 (c 1.0, EtOH)b,8a
+12.9 (c 1.2, EtOH)17
+10.4 (c 1.0, EtOH)8a
+7.9 (c 1.0, EtOH)8a
–13.4 (c 1.0,
97.9
88.5
>99
82.9
88.7
90.8
>99 8a
97 8a
99 17
98 8а
96 8а
99 8а
96.8—99.1 10c +12.9 (c 0.96, EtOH)
—
79—80 4
91.8 10b
+8.8 (c 1.18, EtOH)
+7.3 (c 1.28, EtOH)
–12.3 (c 1.3,
hexane—EtOH, 4 : 1)
+12.1 (c 1.15, EtOH)
hexane—EtOH, 4 : 1)8a
+12.7 (c 1.0, EtOH)8a
–10.2 (c 1.0, MeOH)b,10c
–2.1 (c 2.8, EtOH)11
3i
3j
3k
49
39
20
74—74.5
80—81
50—51
74—76 4
94.3
91.4
>90
>99 8а
99.4 10c
>90 11
83.5—84.5 10c +9.4 (c 1.37, MeOH)
47—49 11
–2.1 (c 2.18, EtOH)
a Determined by polarimetry.
b For the (R)ꢀenantiomer.

Jacobsenꢀtype enantioselective hydrolysis
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
215
both the chemical yields and the enantiomeric purity of
the products. The method used to determine the latter
characteristics deserves special consideration.
signals are not resolved, i.e., the DDCS is close to zero.
A similar situation is observed in the spectrum of the
reaction mixture of reagent 4 and oxirane 2а. Meanwhile,
the reaction mixture obtained from chiral reagent 5 and
racꢀ2d exhibits a pair of signals with equal intensities for
the diastereomeric phosphites corresponding to the major
regioisomer (δР 139.90 and 139.69), which are suitable for
integration. Therefore, we used amide 5 for the quantitaꢀ
tive analysis of the aryl glycidyl ethers 2 we obtained.
Thus, in the simplified form (with the minor regioisomer
being neglected), the chemical meaning of the method
we propose can be represented by Scheme 3.
The optical purity checked using published data on
the specific rotations of appropriate prototypes served as a
measure of enantiomeric purity of diols 3a—k. Unfortuꢀ
nately, such data for glycidyl ethers 2 are virtually missꢀ
ing. However, even when they are available (for comꢀ
pounds 2а,с,g), only in the case of 2а, can they be comꢀ
pared with the enantiomeric excess determined by an inꢀ
dependent method.1c
Previously, we demonstrated the possibility of deterꢀ
mining the enantiomeric composition of terminal epoxides
using their reactions with enantiopure cyclic chlorides of
phosphorus acids.18 These reactions give two regioisomeric
adducts, one usually predominating. In the case of aryl
glycidyl ethers, the predominant product is the soꢀcalled
βꢀadduct in which the P atom is linked to the chiral
center of the starting epoxide through the O atom. The
configuration and the enantiomeric composition of the
adduct remain the same as in the epoxide. If the P atom in
the starting acid chloride occurs in a chiral environment
(it is not necessary and even undesirable that this atom
itself is the chirality center), the βꢀadduct is formed as a
mixture of two diastereomers, whose 31Р NMR chemical
shifts differ by a ∆δ value called diastereomeric dispersion
of chemical shift (DDCS). The ratio of the signals of the
adduct diastereomers reflects the ratio of enantiomers in
the epoxide under interest. Thus, if the organophosphoꢀ
rus reagent has a high degree of enantiomeric purity (reꢀ
garded as enantiopure), then the enantiomeric excess of
the substrate can be described by the following formula
Scheme 3
ee = (I1 – I2)/(I1 + I2),
where I1 and I2 are the integral intensities of the signals of
individual diastereomers.
Figure 1 shows fragments of the 31Р NMR spectrum of
the reaction mixtures obtained by reactions of racemic
(rac) (a) and scalemic (scal) (b) glycidyl ethers 2h with
reagent 5. It can be seen that one of the two signals (which
are identical for racꢀ2h) markedly decreases in the case of
scalꢀ2h. Besides mere illustration, this Figure should demꢀ
onstrate that adequate analysis, especially of substrates
with high enantiomeric purities, requires preliminary reꢀ
cording of the spectrum for the racemic substrate. Otherꢀ
wise, the signal of the minor diastereomer (corresponding
to the minor enantiomer of the initial substrate) may be
either lost among the noise, or another signal (for exꢀ
ample, that for the regioisomeric αꢀadduct with δР 142.09
in the case of epoxide 2h) may be misidentified as being
due to this product.
Both the quality and the mere possibility of analysis of
the enantiomeric composition of the substrate is dictated
by the DDCS, which depends, first of all, on the nature of
the phosphorus reagent. Practically, cyclic chlorides 4 19
and 5,20 derived from diethyl ester or bisꢀN,N´ꢀdiꢀ
methylamide of natural tartaric acid are most readily availꢀ
able in an enantiopure form.
Table 3 gives the chemical shifts characterizing the
individual diastereomeric phosphites shown in Scheme 3,
the relative integral intensities, and the DDCS between
their signals. It can be seen from Table 3 that the ∆δ values
The choice of the reagent for analysis was due to the
fact that the reaction of chiral reagent 4 with racemic
epoxide 2d gives regioisomeric adducts whose 31Р NMR

216
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Bredikhin et al.
resorting to published data and by a known 31Р NMR
procedure. The values are in good agreement with each
other.
As noted above, scalemic aryl glycidyl ethers are exꢀ
tensively used in organic synthesis. We believe that
aryloxypropanediols, having become readily available,
would be equally popular. Apart from the evident use as
final products (recall that 3b,e,j are pharmaceuticals3),
noteworthy are the prospects of transforming them into
cyclic sulfites 6 with subsequent opening of the epoxideꢀ
like heterocycle by nucleophiles. If primary amines are
used as the nucleophiles, βꢀadrenoblocking agents will be
formed as the products. A few examples of this approach
have been reported.21,11
To summarize our study, consider examples of synꢀ
thesis, according to Scheme 4, of the (S)ꢀisomers of two
registered drugs, toliprolol22a (7a) and moprolol22b (7b),
whose (S)ꢀisomer has its own name levotensin. Both
nonracemic βꢀadrenoblocking agents were prepared in
yields of >80% and with satisfactory enantiomeric purities.
a
b
Scheme 4
142
141
140
δ
Fig. 1. 31Р NMR spectra of the reaction mixtures obtained from
racemic (a) and scalemic (b) glycidyl ethers 2h and compound 5.
for oxiranes 2а—k vary in the range of 0.10—0.76 ppm.
Actually, too small DDCS values result in an overestiꢀ
mated integral intensity of the minor signal (integrated
against the background of the major one) and, as a conseꢀ
quence, to an underestimated enantiomeric excess. This
is reflected by the characters ">" placed ahead of the
enantiomeric excess values calculated from the integral
intensities and listed in Table 1. For phenylglycidyl ether
2a, the enantiomeric compositions determined by two
independent methods are given, namely, by polarimetry
Table 3. Chemical shifts (δ ), relative integral intensities (I ),
and diastereomic dispersion of chemical shift (∆δ) for diaꢀ
stereomic phosphites formed from oxiranes 2a—k (see Scheme 3)
Р
R = 3ꢀMe (3c, 6a, 7a), 2ꢀOMe (3e, 6b, 7b)
Thus, the strategy proposed for the transition from
racemic aryl glycidyl ethers to a broad range of nonracemic
compounds including βꢀadrenoblocking agents and the
proposed 31Р NMR method for the analysis of the enanꢀ
tiomeric purity of the resulting epoxides using organoꢀ
phosphorus derivatizing reagents are quite operative.
Substrate
δ
(I )
∆δ
Р
2a
2b
2c
2d
2e
2f
2g
2h
2i
140.28 (0.06), 140.08 (1.00)
140.94 (0.31), 140.30 (1.00)
140.60 (0.11), 140.50 (1.00)
139.84 (1.00), 139.60 (0.17)
140.43 (1.00), 140.09 (0.06)
140.74 (0.03), 140.55 (1.00)
140.30 (1.00), 140.06 (0.11)
140.53 (0.06), 140.90 (1.00)
141.80 (0.05), 141.60 (1.00)
140.20 (0.23), 140.00 (1.00)
141.06 (0.55), 140.30 (1.00)
0.20
0.64
0.10
0.24
0.34
0.19
0.24
0.63
0.20
0.20
0.76
Experimental
NMR spectra were recorded on Bruker WMꢀ250 (250.1 (1H)
and 62.9 MHz (13C)) and Bruker MSLꢀ400 (100.6 MHz (31P))
spectrometers relative to the internal (Me4Si (1H and 13C)) or
2j
2k
external (H3PO4 (
31P)) standards in CDCl3. Optical rotation

Jacobsenꢀtype enantioselective hydrolysis
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
217
was measured on a Perkin—Elmer 341 polarimeter. Mass specꢀ
tra were run on a MAТꢀ212 mass spectrometer (resolution 1000,
voltage 60 V, emission current 0.1 mA, direct sample introducꢀ
tion into the ion source with a gradual temperature rise). The
purity grade of the products was estimated by GC/MS using a
Varian 3700 chromatograph. Recording conditions: a 50ꢀm long
SE 54 column; injector temperature 240 °C; initial temperature
of the column 100 °C; heating rate 6 °C•min–1; final temperaꢀ
ture of the column 240 °C.
was dried with Na2SO4. After removal of the solvent in vacuo,
the residue was dissolved in 30 mL of Et2O and gaseous HCl was
passed through the resulting solution to give 0.76 g (85.4%)
of (2S)ꢀ1ꢀisopropylaminoꢀ3ꢀ(3ꢀmethylphenoxy)propanꢀ2ꢀol
hydrochloride (7a•HCl), m.p. 118—119 °C (from a 1 : 1
Et2O—EtOH mixture), [α]D20 –24.5 (c 1.06, EtOH) (cf. Ref. 23:
m.p. 119 °C, [α]D20 –27.4 (c 1.01, EtOH)).
(4R)ꢀ4ꢀ[(2ꢀMethoxyphenoxy)methyl]ꢀ1,3,2ꢀdioxathiolanꢀ2ꢀ
one (6b) was prepared from diol 3e (1.4 g, 7.69 mmol) similarly
to 6a in a quantitative yield, equal to 1.72 g (oil), as a mixture of
cisꢀ and transꢀisomers. 1H NMR, δ: 3.85 (s, 3 H, OMe);
3.99—4.19 (m, 1.14 H, CH2OAr (trans)); 4.25—4.46 (m, 0.86 H,
CH2OAr (cis)); 4.53—4.59, 4.68—4.71, 4.79—4.85 (all m,
totally 2 H, CH2OS (cis, trans)); 4.90—4.95 (m, 0.43 H,
CHOS (cis)); 5.23—5.32 (m, 0.57 H, CHOS (trans)); 6.89—7.05
(m, 4 H, Ar). 13C NMR, δ: 56.2 (CH3); 68.8 (CH2OS (cis));
69.0 (CH2OS (trans)); 70.2 (CH2OAr (trans)); 70.9 (CH2OAr
(cis)); 78.1 (CHOS (trans)); 80.2 (CHOS (cis)); 112.8, 112.8,
116.4, 116.6, 112.2, 121.2, 123.2, 123.4 (CH, Ar); 147.7
(iꢀC, Ar); 150.4 (iꢀC, Ar); 150.5 (iꢀC, Ar).
Complex (S,S)ꢀ1 was prepared from (S,S)ꢀN,N´ꢀbis(3,5ꢀdiꢀ
tertꢀbutylsalicylidene)cyclohexaneꢀ1,2ꢀdiaminocobalt(II).1c The
20
latter was synthesized by a known procedure,13 [α]D +1150
(c 0.02, CH2Cl2) (cf. Ref. 13, for (R,R)ꢀ1: [α]D20 –1100 (c 0.01,
CH2Cl2)). The purity was additionally checked by mass specꢀ
trometry. Substituted aryl glycidyl ethers 2 were prepared from
epichlorohydrion and aromatic alcohols.12
Kinetic hydrolytic resolution of epoxides 2 (general proceꢀ
dure). A mixture of oxirane 2 (30 mmol), complex (S,S)ꢀ1 (0.1 g,
0.15 mmol), and water (0.27 mL, 15 mmol) in 0.5 mL (or 3 mL
for 2e—g) of THF was stirred for 4—30 h (for 2e,k, 80 h). The
reaction was monitored by GC/MS. The unreacted oxirane was
evaporated in vacuo. The residue was dissolved in hot water and
the catalyst was separated by repeated extraction of the aqueous
phase with light petroleum. The solid residue formed after reꢀ
moval of water in vacuo was purified by a single recrystallization
from CCl4. Characteristics of the reaction products are summaꢀ
rized in Tables 1 and 2. The catalyst isolated from the solution in
light petroleum can be reused.
Analysis of the enantiomeric composition of oxiranes 2a—k
(general procedure). Pyridine (0.12 g, 1.52 mmol) was added at
5—10 °C in a dry nitrogen atmosphere to 2.0 mL of a THF
solution containing (4R,5R)ꢀbis(N,Nꢀdimethylaminocarbonyl)ꢀ
2ꢀchloroꢀ1,3,2ꢀdioxaphospholane (5) (0.13 g, 0.48 mmol) obꢀ
tained by a known procedure.20 The reaction mixture was kept
for 10 min, and the required oxirane 2 (0.44 mmol) in 0.3 mL of
THF was added at the same temperature. The solution was kept
for at least 1 h, filtered, and concentrated in vacuo. Several
drops of C6D6 were added and the solution was placed in a tube
for recording 31Р NMR spectrum. The spectral data are given in
Table 3.
(4R)ꢀ4ꢀ[(3ꢀMethylphenoxy)methyl]ꢀ1,3,2ꢀdioxathiolanꢀ2ꢀ
one (6a) was prepared by the reaction of diol 3c (0.77 g,
4.64 mmol) with SOCl2 (0.55 g, 4.64 mmol) in 3 mL of CH2Cl2
similarly to the previously described procedure11 as a mixture of
cisꢀ and transꢀisomers (yield 0.96 g (quantitative), oil). 1H NMR,
δ: 2.32 (s, 3 H, Me); 3.84—4.00 (m, 1.2 H, CH2OAr (trans));
4.19—4.71 (m, 2.8 H, CH2OAr (cis), CH2OS (cis, trans));
4.79—4.90 (m, 0.4 H, CHOS (cis)); 5.06—5.15 (m, 0.6 H,
CHOS (trans)); 6.58—7.29 (m, 4 H, Ar). 13C NMR, δ: 21.2
(CH3 (trans)); 21.6 (CH3 (cis)); 66.3 (CH2OS (trans)); 67.9
(CH2OS (cis)); 68.6 (CH2O (trans)); 69.2 (CH2O (cis)); 78.0
(CHOS (trans)); 80.0 (CHOS (cis)); 111.5, 111.8, 115.5, 115.6,
122.5, 122.9, 129.3, 129.7 (CH, Ar); 139.5 (C—Me (trans));
140.1 (C—Me (cis)); 157.8 (iꢀC (trans)); 158.1 (iꢀC (cis)).
(2S)ꢀ1ꢀIsopropylaminoꢀ3ꢀ(3ꢀmethylphenoxy)propanꢀ2ꢀol
(7a). A solution of dioxathiolane 6a (0.78 g, 3.67 mmol) and
PriNH2 (7.0 g) in 25 mL of DMF was kept for 45 h at 60—70 °C.
After the reaction, excess amine and DMF were removed
in vacuo, 30 mL of a 1 M solution of NaOH was added, the
mixture was extracted with AcOEt (3×30 mL), and the extract
(2S)ꢀ1ꢀIsopropylaminoꢀ3ꢀ(2ꢀmethoxyphenoxy)propanꢀ2ꢀol
(7b) was prepared from dioxathiolane 6b (1.08 g, 4.45 mmol) by
a procedure similar to that reported for aminopropanol 7a in a
yield of 1.13 g (87.6%), m.p. 75—80 °C (cf. Ref. 22b: m.p.
78—80 °C). (2S)ꢀ1ꢀIsopropylaminoꢀ3ꢀ(2ꢀmethoxyphenoxy)proꢀ
panꢀ2ꢀol hydrochloride was prepared by passing gaseous HCl
through a solution of 7b base in Et2O (30 mL). Yield 7b•HCl
0.95 g (82.1%), m.p. 124—125 °C (from a mixture Et2O—EtOH,
20
3 : 1), [α]D –16.5 (c 5.00, EtOH) (cf. Ref. 22b: m.p.
20
121—123 °C, [α]D –16.3 (c 5.00, EtOH)).
This work was supported by the Russian Foundation
for Basic Research (Project No. 03ꢀ03ꢀ33084).
References
1. (a) M. Tokunaga, J. F. Larrow, F. Kakiuchi, and E. N.
Jacobsen, Science, 1997, 277, 936; (b) E. N. Jacobsen, Acc.
Chem. Res., 2000, 33, 421; (c) S. E. Shaus, B. D. Brandes,
J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould,
M. E. Furrow, and E. N. Jacobsen, J. Am. Chem. Soc., 2002,
124, 1307.
2. Pharmaceutical Manufacturing Encyclopedia, Ed. M. Sitting,
Noyes Publications, Park Ridge, 1988, 1, 2.
3. The Merck Index, 12th ed., Ed. S. Budavari, Merck and Co.,
Inc., Whitehouse Station, 1996, 5895; 4582; 2230.
4. A. A. Bredikhin, Z. A. Bredikhina, S. N. Lazarev, and D. V.
Savel´ev, Mendeleev Commun., 2003, 104.
5. J. Jaques, A. Collet, and S. H. Wilen, Enantiomers, Raceꢀ
mates, and Resolutions, Krieger Publishing Co., Malabar
(FL), 1994, 447.
6. L. PerezꢀGarcia and D. B. Amabilino, Chem. Soc. Rev.,
2002, 31, 342.
7. W. L. Nelson, J. E. Wennerstrom, and S. R. Sankar, J. Org.
Chem., 1977, 42, 1006.
8. (a) F. Theil, J. Weidner, S. Ballschuh, A. Kunath, and
H. Schick, J. Org. Chem., 1994, 59, 388; (b) L. Salazar, J. L.
Bermudes, C. Ramirez, E. F. Llama, and J. V. Sinisterra,
Tetrahedron Asymmetry, 1999, 10, 3507.

218
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Bredikhin et al.
9. G. Egri, A. Kolbert, J. Balint, E. Fogassy, L. Novak, and
L. Poppe, Tetrahedron Asymmetry, 1998, 9, 271.
10. (a) J. M. Klunder, S. Y. Ko, and K. B. Sharpless, J. Org.
Chem., 1986, 51, 3710; (b) J. Chen and W. Shum, Tetraꢀ
hedron Lett., 1995, 36, 2379; (c) K. Kitaori, Y. Furukawa,
H. Yoshimoto, and J. Otera, Tetrahedron, 1999, 55, 14381.
11. Z. A. Bredikhina, D. V. Savel'ev, and A. A. Bredikhin,
Zh. Org. Khim., 2002, 38, 233 [Russ. J. Org. Chem., 2002, 38
(Engl. Transl.)].
16. L. He, H.ꢀS. Byun, and R. Bittman, J. Org. Chem., 1998,
63, 5696.
17. Z.ꢀM. Wong, X.ꢀL. Zhang, and K. B. Sharpless, Tetrahedron
Lett., 1993, 34, 2267.
18. Z. A. Bredikhina, V. G. Novikova, N. M. Azancheev, and
A. A. Bredikhin, Zh. Obshch. Khim., 2002, 72, 1288 [Russ.
J. Gen. Chem., 2002, 72 (Engl. Transl.)].
19. J.ꢀM. Brunel, O. Pardigon, M. Maffei, and G. Buono, Tetraꢀ
hedron Asymmetry, 1992, 3, 1243.
12. C. C. Price and L. R. Becker, J. Polym. Sci., Part Aꢀ1,
1969, 7, 575.
13. Y.ꢀJ. Hu, X.ꢀD. Huang, Z.ꢀJ. Yao, and Y.ꢀL. Wu, J. Org.
Chem., 1998, 63, 2456.
14. E. Souri, M. Sharifzadeh, H. Farsam, and N. Gharavi,
J. Pharm. Pharmacol., 1999, 51, 853; A. Barret and V. A.
Cullum, Br. J. Pharmacol., 1968, 34, 43; J. Nakano,
M. Mimura, M. Hayashida, M. Fujii, K. Kimura, and
T. Naranishi, Chem. Pharm. Bull., 1988, 36, 1399.
15. Beilst., V, 17(3), 15.
20. A. A. Bredikhin, E. I. Strunskaya, N. M. Azancheev, and
Z. A. Bredikhina, Izv. Akad. Nauk, Ser. Khim., 1998, 172
[Russ. Chem. Bull., 1998, 47, 174 (Engl. Transl.)].
21. P. H. J. Carlsen and K. Aase, Acta Chem. Scand., 1993,
47, 737.
22. The Merck Index, 12th ed., Ed. S. Budavari, Merck and Co.,
Inc., Whitehouse Station, 1996, (a) 9653; (b) 6345.
23. R. Howe and B. S. Rao, J. Med. Chem., 1968, 11, 1118.
Received June 17, 2003