,
2003, 13(3), 125–126
Efficient resolution of rac-2,3-O-isopropylideneglycerol by enantioselective
inclusion crystallization with the chiral diol CYTOL
a
a
a
b
Maxim G. Vinogradov,* Dmitry V. Kurilov, Vladimir A. Ferapontov and Glenn L. Heise
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
b
Cambrex Corporation, One Meadowlands Plaza, East Rutherford, NJ 07073, USA
1
0.1070/MC2003v013n03ABEH001804
The efficient resolution of rac-2,3-O-isopropylideneglycerol (IPG) using enantioselective two-step inclusion crystallization with
the chiral diol CYTOL has been performed.
The chiral C synthons (R)- and (S)-2,3-O-isopropylideneglycerols
3
1
(
IPG) are used for the syntheses of various biologically active
compounds such as lipids,
2
–4
5
6,7
antibiotics and β-blockers.
Optically active IPG is often obtained from natural sources:
8
9
10
O
O
D-mannitol, L-ascorbic acid and L-serine or by the resolution
of racemic IPG. IPG enantiomers are resolved using either a
classic approach (via diastereomeric salts) or enzymatic methods.
O
O
Ph
Ph
Ph
Ph
OH
rac-IPG
However, in the former case, the chemical modification of IPG
OH HO
CYTOL
for example, by phthalic anhydride11(a) or its analogues
11(b)
) is
(
required, whereas in the latter case enantioselectivity of the IPG
resolution is insufficiently high for preparative goals (as a rule,
1
2–14
no more than 65% ee).
The resolution of rac-IPG by inclusion crystallization was
reported.15 Using chiral 2,3-O-cyclohexylidene-1,1,4,4-tetra-
phenylthreitol (CYTOL) as a host compound and toluene–
hexane as a solvent, (S)-(+)-IPG was obtained in 38% yield.
In this work, based on a latter approach, an efficient two-
stage resolution of rac-IPG has been performed by applying, at
the first stage, inclusion crystallization in a suspension of a
(S,S)-(+)-CYTOL·(R)-(–)-IPG
(R,R)-(–)-CYTOL·(S)-(+)-IPG
∆
∆
(R)-(–)-IPG
(S)-(+)-IPG
Scheme 1
our surprise, in both cases, enrichment by the (S)-enantiomer
of IPG took place regardless of CYTOL configuration, both
crystalline ICs being of identical stoichiometric composition
(CYTOL/IPG = 1:1). To our knowledge, it is the first example
of inclusion complexation when both enantiomers of the resolving
agent are capable of giving IC enriched in the same enantiomer
of the substrate. At the same time, for the combination of
(S)-(+)-IPG–(R,R)-(–)-CYTOL, the yield of IC and enantiomeric
enrichment degree of the applied substrate is higher than that
for the combination (S)-(+)-IPG–(S,S)-(+)-CYTOL (Table 1,
entries 5 and 6). This result could be foreseen because in the
case of the resolution of rac-IPG (R,R)-(–)-CYTOL gives IC
preferably with (S)-IPG and, on the contrary, (S,S)-(+)-CYTOL
forms IC selectively with (R)-IPG. This preference is stable as
two series of 10 repeated experiments each performed with
(S,S)- and (R,R)-CYTOL (Table 1, entries 3 and 4, respectively)
gave the same stereochemical results in each series.
The ability of (R,R)- and (S,S)-CYTOL to give IC containing
the same prevailing enantiomer of IPG allows one to explain the
dependence of the IPG resolution stereoselectivity on the starting
molar ratio IPG/CYTOL (Table 1). In the case when the rac-
IPG/CYTOL ratio is 2:1 [or 1:1 with respect to the (R)-enantio-
mer of rac-IPG], a considerable excess of (S)-IPG is formed
while crystallization of the (R)-containing IC proceeds. Due to
that, probability of crystallization of the unwanted (S)-containing
IC increases (cf. entry 6) thus decreasing the inclusion com-
plexation stereoselectivity. At the same time, a four-fold or
higher excess of rac-IPG in the starting mixture prevents con-
siderable change of the IPG enantiomeric composition compared
with rac-IPG in the course of stereoselective inclusion crystal-
lization.
resolving agent. For the resolution, a suspension of (R,R)- or
†
(S,S)-CYTOL in hexane was used.
We found that the efficiency of the IPG inclusion crystal-
lization rises with increasing the IPG/CYTOL molar ratio in the
starting mixture, reaching 85–86% ee at the ratio IPG/CYTOL = 4
(
Table 1, entries 1–4), the enantioselectivity remaining the same
with a further increase of this ratio up to 10. To achieve higher
optical purity of IPG included into IC, two approaches are, in
principle, possible: the recrystallization of IC or the binding of
the minor enantiomer of IPG into IC with CYTOL of the
opposite configuration.
To select the preferable variant of further enrichment of chiral
IPG (Stage 2), the inclusion crystallization of IPG containing
8
0% (S)-enantiomer was carried out using both (R,R)- and
(S,S)-CYTOL as resolving agents (Table 1, entries 5 and 6). To
†
Resolution procedure for rac-IPG. rac-IPG (10 mmol, 1.32 g) was
added to a suspension of (S,S)-(+)-CYTOL (2.5 mmol, 1.27 g) in hexane
50 ml), and the mixture was stirred for 24 h at room temperature. The
(
obtained IC was filtered off, washed with cold hexane (5 ml) and dried at
room temperature in vacuo (1–2 Torr). 1.33 g of IC was isolated. Then,
it was recrystallised from diethyl ether (15 ml)–hexane (75 ml) at –18 °C
for 24 h to give 0.94 g (71%) of the inclusion complex. It was dried in
vacuo at room temperature. To liberate IPG from IC, the latter was
heated at 80–90 °C in vacuo condensing the liberated IPG in a trap
cooled by dry ice. 0.198 g (60% with respect to the starting reagents) of
(
R)-IPG (97% ee, GLC) has been isolated. [a] –11.05 (c 1, MeOH).
D
Crystalline residues obtained after thermodissociation of IC and after
evaporation of the mother liquid (after the recrystallization of IC) were
united and dried in vacuo at 100 °C for 1 h. 1.16 g (92%) of pure
(S,S)-(+)-CYTOL was isolated.
Enantiomeric composition of IPG was dermined for its acetate obtained
As it follows from data presented in Table 2, the (S,S)-
CYTOL·(R)-IPG complex remains unchanged after heating in
vacuo at 50 °C for 0.5 h, whereas its heating at 80 °C results
in loss of the IPG completely for the same period of time. In
the latter case, the crystalline residue was found to be pure
S,S)-CYTOL, which can be used again for the resolution of
rac-IPG.
Based on the above results (Tables 1 and 2), the preparative
by acetylation of the alcohol with Ac O in CH Cl in the presence of
2
2
2
pyridine. Analysis was carried out by GLC on a Biokhrom-21 instrument
using a 30 m × 0.25 mm × 0.25 µm quartz capillary column (Supelco). The
carrier gas (He) pressure before the column was 10 atm; the gas flow rate
–1
was 1 ml min , the column temperature was 105 °C; the detector and
evaporator temperatures were 170 °C; the nonretainable gas used was CH4.
(
The retention times of the compounds were the following (min): CH , 1.8;
4
(R)-(–)-IPG acetate, 14.7; (S)-(+)-IPG acetate, 15.4.
–
125 –
Vinogradov, Maxim G.
