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our needs, this material is also important for a variety of other reasons, includ-
ing the use of dihalide derivatives for stereochemical substitution[2] and
organometallic chemistry studies.[3] Similar diastereomerically pure reagents
are also very important as synthons for stereoselective synthesis. Although
there are several previously published methods for the preparation of this
compound,[4–6] none of them is either efficient or facile for obtaining diaste-
reomerically pure cis-2,4-pentanediol. Of the many methods available for
obtaining a mixture of cis- and trans-2,4-pentanediols, the most useful appears
to be the reduction of commercially available 2,4-pentanedione with NaBH4
in methanol, as described by Pritchard and Vollmer.[2] It is the further isolation
of pure cis-diol from this mixture, which is the focus of this report.
Separation of the cis-isomer from the racemic trans-2,4-pentanediols
has been accomplished in the past by preparation and separation of cyclic
derivatives of the diols. For example, Pritchard and Vollmer[2] made cyclic
sulfite esters from the diols, but fractional distillation to separate the diaster-
eomers proved very difficult due to their similar boiling points. Gordillo and
Hernandez[6] reported the use of cyclic phosphorochloridites to obtain diols
with 98% diastereomeric purity, but only in unacceptable low yield (23%).
We reasoned that an asymmetric and sterically hindered carbonyl compound
would selectively react with the cis-diol to form a six-membered cyclic acetal.
The acetal should form preferentially from the cis-diol, leading to a product
with the two terminal methyl groups situated in equatorial positions of a chair
conformation, whereas in the trans-diols one of the methyl groups would be
forced to reside in an axial orientation. Diaxial nonbonded interactions thus ther-
modynamically disfavor the formation of acetal from the trans-diol. Indeed,
using hexane as a relatively low boiling solvent, we were delighted to discover
that the acetal formed by allowing the diol mixture to react with a limiting
amount of acetophenone yielded essentially a single product, determined to be
the predicted result of selective acetal formation with the cis-diol. The acetals
formed from the trans-diols would complicate the isolation procedure, but by
limiting the amount of acetophenone used it is possible to form selectively the
cis-acetal, leaving the trans-diols unreacted. The latter, which are more water
soluble, are simply removed from the reaction mixture by washing with water.
Therein lies the beauty of this method.
Conveniently, the cis-acetal is a solid at room temperature (m.p. 63.5–
648C[7]) that readily crystallizes. Surprisingly, this acetal exists predominantly
as the conformer with the axial phenyl group, identified by Bailey et al.,[8]
favored over the equatorial phenyl conformer by 2.55 kcal/mol (Fig. 1).
Because the desired thermodynamic product of this reaction is a solid and
can be readily isolated and purified, the facility of this method becomes
obvious. Acetal 1 was then simply cleaved by catalytic hydrogenation, which
forms volatile ethylbenzene as a by-product, thus preventing equilibrium
Bonner, Lisa
