Efficient resolution of (±)-α-cyclopropylethanol by crystallization of its inclusion complex with chiral diols

Article abstract of DOI:10.1070/MC2003v013n03ABEH001757

The two-step inclusion crystallization of the chiral diol TADDOL with α-cyclopropylethanol has been found to allow resolving the racemic alcohol to yield (R)- or (S)-enantiomer (> 98% ee).

Full text of DOI:10.1070/MC2003v013n03ABEH001757

,
2003, 13(3), 124–125
Efficient resolution of (±)-α-cyclopropylethanol by crystallization of its inclusion
complex with chiral diols
a
a
a
a
b
Maxim G. Vinogradov,* Dmitry V. Kurilov, Galina V. Chel’tsova, Vladimir A. Ferapontov and Glenn L. Heise
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: ving@ioc.ac.ru
b
Cambrex Corporation, One Meadowlands Plaza, East Rutherford, NJ 07073, USA
1
0.1070/MC2003v013n03ABEH001757
The two-step inclusion crystallization of the chiral diol TADDOL with α-cyclopropylethanol has been found to allow resolving
the racemic alcohol to yield (R)- or (S)-enantiomer (>98% ee).
α-Cyclopropylethanol (CPE) and its derivatives, first of all
R
R
esters, belong to compounds that exhibit the enhanced biological
activity. Thus, the CPE fragment is contained in a dehydrogenase
O
O
1
2
3
Ph
Ph
Ph
Ph
inhibitor, β-blockers and substances showing insecticide or
4
herbicide activity. Over the past decades, the catalytic synthesis
Ar
Ar
Ar
Ar
HO
HO
of optically active CPE by reduction of cyclopropyl methyl
5
OH HO
HO
HO
ketone in the presence of chiral metal complexes or alcohol
dehydrogenase6 has been elaborated. However, the former
,7
1a–f (TADDOL)
2
3
variant is complicated by technological requirements (H gas
pressure), and in the latter case the reaction proceeds with
2
a R = Me, Ar = Ph
b R = Et, Ar = Ph
moderate enantioselectivity (44% ee) or inadequate ketone con-
7
c R + R = (CH ) , Ar = Ph
version (46%). The latter applies to reduction of cyclopropyl
2 4
8
9
methyl ketone with chiral organoborane and alumohydride
d R + R = (CH ) , Ar = Ph
2
5
reagents as well.
e R = Me, Ar = 4-(HO)C H4
6
Here we describe a method of straightforward resolution of
(
±)-CPE via crystallization of its inclusion complexes (IC) with
f R + R =
, Ar = Ph
†
‡
chiral diols TADDOL 1. The method is convenient for pre-
parative use because it requires only two crystallization steps
for complete resolution of the racemate to give pure (R)- or
1
a,b
OH
(
S)-CPE (> 98% ee). A number of molecular complexes of
1
0–14
TADDOL with alcohols have been described earlier;
how-
ever, there were no published data regarding CPE-containing IC
and their use for resolution of CPE enantiomers.
To obtain CPE-containing IC, crystallization of chiral diols
–3 in the presence of CPE has been attempted. Table 1 demon-
2[(S,S)-(+)-1]·[(R)-(–)-CPE]
2[(R,R)-(–)-1]·[(S)-(+)-CPE]
1
strates that only three host compounds 1a, 1b and 1e proved to
form IC with CPE, the 1/CPE ratio being 2:1 in each case. Note
that the resolution degree for (±)-CPE depends on both the diol
Scheme 1
structure and the solvent nature. Thus, the one-step crystalliza-
tion of the complex 2(1a)·(CPE) from diethyl ether–hexane gave
an enantiomeric enrichment (ee) of 75%, whereas no resolution
was observed after crystallization of the same IC from benzene–
hexane. The degree of (±)-CPE resolution by complexation with
diol 1b from diethyl ether–hexane was considerably higher than
that from THF–hexane. On the other hand, inclusion crystalliza-
tion of diol 1e with CPE from ether–hexane and other solvents
proceeded nonstereoselectively.
†
α,α,α',α'-Tetraaryl-1,3-dioxolane-4,5-dimethanols.
‡
(
±)-CPE resolution procedure. (S,S)-(+)-1a (2.5 g, 5.25 mmol) and
(
±)-CPE (0.452 g, 5.25 mmol) were dissolved in diethyl ether (8 ml),
and hexane (80 ml) was added dropwise with stirring. The mixture was
left to crystallise first at room temperature, then at 0 °C and finally at
–
25 °C (for 24 h at each temperature above). The precipitated crystals of
the complex 2[(S,S)-(+)-1a]·[(R)-(–)-CPE] (2.6 g, 96% yield, 75% ee for
CPE included into IC) were crystallised repeatedly from diethyl ether
(
5 ml)–hexane (50 ml) at –25 °C for 24 h. The complex obtained (1.2 g)
was heated in vacuo (5 Torr) at gradually increased temperature from
0 to 90 °C for 1 h, CPE elevated being collected at the dry ice cooled
trap. 0.1 g of (R)-(–)-CPE has been obtained [45% with respect to
R)-(–)-CPE in the starting racemate], ee > 98%. Absolute configuration
was assigned on the basis of the optical rotation sign for the (R)-enantiomer
Table 1 Crystallization of TADDOL in the presence of (±)-CPE.a
6
TADDOL
Crystalline product
ee (%)
(
b
c
(S,S)-(+)-1a
(S,S)-(+)-1a
IC
75 (> 98) (R)
b
d
6
IC
0
of CPE {[a] –7.55 (CHCl ), 44% ee}. The residue after the thermal
D
3
b
c
(R,R)-(–)-1b
(R,R)-(–)-1b
(R,R)-(–)-1c
(R,R)-(–)-1d
IC
78 (97) (S)
decomposition of IC was pure diol 1a. Enantiomeric analysis of CPE
b
e
IC
46 (S)
was carried out by GLC (after acetylation of the alcohol by Ac O in
2
1c
—
—
0
—
—
—
the presence of pyridine) on a Biokhrom-21 instrument using 30 m ×
1d
×
0.25 mm × 0.25 µm β-DEX™ capillary column (Supelco). The carrier
b
–1
(R,R)-(–)-1e
IC
gas (He) flow rate was 1 ml min . The retention times of the com-
(
(
(
R,R)-(–)-1f
S)-(–)-2
R)-(+)-3
1f
2
3
pounds were as follows (50 °C, min): CH4 (nonretainable gas), 1.5;
(S)-CPE acetate, 15.3; (R)-CPE acetate, 18.7. Mother liquors obtained
after the first and second crystallization steps were combined and
evaporated. The residue was heated at 100 °C for 1 h to give pure chiral
diol 1a. Totally, 2.4 g (96%) of pure resolving reagent (S,S)-(+)-1a was
returned back.
Following the above procedure, analogous results were obtained for
the resolution of (±)-CPE with chiral diol 1b. The thermal decomposition
of the isolated complex 2[(R,R)-(–)-1b]·[(S)-(+)-CPE] gave (S)-(+)-CPE
aUnless otherwise noted, crystallization was carried out from a solution of
2.5 mmol of chiral diol 1–3 and 10 mmol of (±)-CPE in diethyl ether
(10 ml)–hexane (50 ml) at –15 °C for 24 h; ee refers to CPE included into
crystalline IC. Molar ratio TADDOL:CPE = 2:1. The ee values for CPE
isolated after the first and the second (in parentheses) crystallization of IC
carried out according to the procedure described. Crystallization was per-
formed from benzene (10 ml)–hexane (50 ml). Crystallization was performed
from THF (10 ml)–hexane (50 ml).
b
c
d
e
(
9
97% ee) in 43% yield with respect to (S)-CPE in the starting racemate,
5% of pure (R,R)-(–)-1b being returned back.
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124 –

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2003, 13(3), 124–125
On the basis of the results obtained (Table 1), chiral diols 1a
and 1b were taken for preparative resolution of (±)-CPE via IC
formation. Two-step inclusion crystallization of these diols with
6
7
8
9
E. Keinan, E. K. Hafeli, K. K. Seth and R. Lamed, J. Am. Chem. Soc.,
986, 108, 162.
C. W. Bradshaw, W. Hummel and C.-H. Wong, J. Org. Chem., 1992,
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M. M. Midland, J. I. McLoughlin and J. Gabriel, J. Org. Chem., 1989,
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M. G. Vinogradov, L. S. Gorshkova, G. V. Chel’tsova, V. A. Pavlov,
I. V. Razmanov, V. A. Ferapontov, O. R. Malyshev and G. L. Heise, Izv.
Akad. Nauk, Ser. Khim., 2003, 450 (Russ. Chem. Bull., Int. Ed., 2003,
52, 471).
1
5
(
±)-CPE from diethyl ether–hexane followed by thermal dis-
sociation of the IC at 60–90 °C afforded optically pure CPE
97 and > 98% ee using diols 1a and 1b, respectively). After
5
(
evaporation of mother liquors and the subseqent heating of the
residue, 95–96% of the starting diol was returned back. In
the course of isolation of optically active CPE and diols 1 no
racemization was observed. Resolution of (±)-CPE using starting
and regenerated 1 gave identical results.
10 F. Toda, S. Matsuda and K. Tanaka, Tetrahedron: Asymmetry, 1991, 2,
83.
9
1
1
1
1 F. Toda and Y. Tohi, J. Chem. Soc., Chem. Commun., 1993, 1238.
2 F. Toda and H. Takumi, Enantiomer, 1996, 1, 29.
3 M. G. Vinogradov, L. S. Gorshkova, G. V. Chel’tsova, D. V. Kurilov,
V. A. Ferapontov, O. V. Shishkin and G. L. Heise, Izv. Akad. Nauk, Ser.
Khim., 2003, in press.
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Received: 11th April 2003; Com. 03/2083
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