of crystalls could not be obtained. Separation of the diaster-
eomers syn-(3R,5S)-1 and anti-(3S,5S)-1 by column chro-
matography is ineffective as a result of marked coelution,
and the same holds for the cyclic derivatives syn-(3R,5S)-2
and anti-(3S,5S)-2.6
On deprotecting a syn/anti mixture of acetonide 2 with a
catalytic amount of diluted aqueous hydrochloric acid in
dichloromethane solution, we observed that the anti diaste-
reomer hydrolyses much faster than the syn diastereomer.
Premature quenching of the acid catalyst with aqueous
sodium bicarbonate solution resulted in a mixture of the diols
syn-(3R,5S)-1 and anti-(3S,5S)-1 and highly enriched syn-
acetonide syn-(3R,5S)-2 (Scheme 1). Because of the great
diastereomer-differentiating hydrolysis as described above.
At 20 °C and a substrate concentration of 0.2 mol L-1, the
hydrolysis is slow enough to be conveniently monitored by
means of gas chromatography.7 In a representative example,8
a noncrystallizing mother liqour residue, consisting mainly
of dihydroxy esters syn-(3R,5S)-1 and anti-(3S,5S)-1 in a
diastereomeric ratio syn/anti (drs:a) of 9:1, gave acetonide
syn-(3R,5S)-2 with drs:a ) 221:1. The unreacted acetonide
syn-(3R,5S)-2 was isolated by flash chromatography, which
removed the other polar impurities originating from the
preceding synthesis steps as well (67% isolated yield; 75%
based on the syn diastereomer present in the starting
material). Apart from the minute content of remaining anti
diasteremoer (<0.5%), the product syn-(3R,5S)-2 was pure
according to NMR and GC-MS analysis. Remarkably, the
acid-sensitive tert-butyl ester group is not significantly
affected under these conditions.
Scheme 1a
This workup procedure was successfully applied to benz-
yloxy-substituted â,δ-dihydroxy ester syn-(3R,5S)-39 as well
(Scheme 2). Treating a diastereomeric mixture of this
Scheme 2a
a (a) (1) 2,2-Dimethoxypropane, cat. CSA, acetone, 20 °C, 2 h;
(2) 2 N HCl (5 mol %), CH2Cl2, 20 °C, 3 h; (b) flash chromatog-
raphy, 77% isolated yield (88% based on the syn diastereomer
present in the starting material).
a (a)2 N HCl (5 mol %), CH2Cl2, 20 °C, 4 h; (b) flash
chromatography (isolated yields shown).
compound as described above led to an increase of the
diastereomeric ratio syn/anti from 7.3:1 to more than 400:1
(GC-MS analysis). Acetonide syn-(3R,5S)-4 was obtained
in a 77% yield after flash chromatography (88% yield with
regard to the amount of syn diastereomer present in the
starting material).
To confirm the general applicability of this method, we
investigated the hydrolysis of two other 1,3-diol-acetonides.
For that purpose, diastereomeric mixtures of the racemic
differences in polarity, the diastereomeric diols 1 can be
easily removed from the corresponding acetonides 2 by flash
chromatography. Thus, the diastereomer-differentiating ac-
etonide hydrolysis turns the difficult syn/anti diastereomer
separation into a separation of nonstereoisomeric compounds,
which show great differences in their physical properties and
can therefore be readily separated.
On the basis of these observations, we developed a workup
procedure for the mother liquor residues of the large-scale
synthesis of dihydroxy ester syn-(3R,5S)-1. To this end, the
residues are treated with excess 2,2-dimethoxypropane in the
presence of camphor sulfonic acid to generate the acetonides
syn-(3R,5S)-2 and anti-(3S,5S)-2. The crude product, obtained
by merely evaporating the volatiles, is subjected to the
acetonides syn/anti-5 (drs:a ) 1.2:1) and syn/anti-6 (drs:a
)
(7) At higher concentrations (>0.3 mol L-1) the reaction is impracticably
slow, whereas at a lower concentrations (<0.1 mol L-1) the reaction is too
fast to be reasonably monitored by GC.
(8) To a solution of â,δ-dihydroxy ester syn-(3R,5S)-1 [34.5 g, mother
liquor residue, chemical purity ∼85% (1H NMR), ee > 99.5%, drs:a ) 9:1]
in acetone/2,2-dimethoxypropane (210 mL, 50:50 v/v) was added camphor
sulfonic acid (0.5 g, 2.2 mmol). The solution was stirred at room temperature
for 2 h and then concentrated in vacuo. The oily residue was dissolved in
dichloromethane (0.7 L), and hydrochloric acid (2 mol L-1, 3.2 mL, 6.4
mmol) was added. After vigorously stirring at 20 °C for 3 h, the solution
was washed with saturated aqueous NaHCO3 solution and water, dried over
MgSO4, and evaporated in vacuo. Flash chromatography of the residue (ethyl
acetate/isohexane 10:90 v/v, 10 cm Ø column, 0.38 kg SiO2) gave acetonide
syn-(3R,5S)-2 as a weakly yellow oil: yield 23.2 g (67%); drs:a 221:1 [GC-
(4) (a) Thottathil, J. K.; Pendri, Y.; Li, W. S.; Kronenthal, D. R. U.S.
Patent 5,278,313, 1994; Chem. Abstr. 1994, 120, 217700. (b) Kizaki, N.;
Yamada, Y.; Yasohara, Y.; Nishiyama, Y.; Miyazaki, M.; Mitsuda, M.;
Kondo, T.; Ueyama, N.; Inoue, K. Eur. Patent Application 1,024,139, 2000;
Chem. Abstr. 2000, 132, 166230.
(5) Diastereomeric ratio (drs:a) syn-(3R,5S)-1:anti-(3S,5S)-1 )5:1 up to
9:1, ee > 99.5%.
1
(6) For the sake of clarity, the relative configuration of the acetonides
2, 4, 5, and 6 is expressed by adopting the syn/anti descriptors of the
underlying 1,3-diols instead of using the cis/trans nomenclature.
MS, HP-5MS column (Hewlett-Packard), 120 °C]. H and 13C NMR data
of this compound are described elsewhere.3b
(9) Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014-1017.
620
Org. Lett., Vol. 4, No. 4, 2002