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84 Stereochemistry

1. Separation by crystallization (Pasteur’s first method, achiral stationary phase. After separation the chiral aux-
1848) iliary is removed (e.g., by hydrolysis in the case of an
2. Separation by formation and separation of ester).
diastereomers (Pasteur’s second method, 1853): To understand the third method, “asymmetric transfor-
(a) separation by crystallization, (b) separation by mation,” we must first take up “racemization,” i.e., the
chromatography conversion of one of the enantiomers into a racemate. This
3. Asymmetric transformation (a) of diastereomers, apparently counterproductive process is actually useful:
(b) of enantiomers In resolution the undesired enantiomer is produced as an
4. Kinetic resolution: (a) chemical, (b) enzymatic equimolar by-product. Racemization of that enantiomer
(Pasteur, 1858) allows one to start the resolution process over. Actually,
5. Separation by chromatography on chiral stationary racemization involves converting one enantiomer into the
phases opposite one, but since enantiomers have the same free
6. Enantioselective synthesis energy, the equilibrium constant between them is unity,
7. Synthesis from enantiomerically pure precursors i.e., the product of equilibration is the racemate. However,
(sometimes called enantiospecific synthesis) racemization, to be feasible, requires a chemical pathway.

8. Miscellaneous methods For example, a chiral ketone, RR CHCOR may be racem-

ized by base via the resonance-stabilized achiral enolate

−
Pasteur’s method of manually separating enantiomor- anion RR C COR ⇔ RR C CR O .
−

phous crystals of enantiomers is obviously not practical; If such equilibration occurs concomitant with reso-
it is also not general. Racemic mixtures can lead to three lution, it is sometimes possible to convert the race-
different kinds of crystals: conglomerates, racemic com- mate entirely into one of the enantiomers. This process,
pounds, and racemic solid solutions. Compounds (where called “crystallization-induced asymmetric transforma-
the unit cell, the smallest unit of a crystal, contains equal tion,” may be observed during crystallization of diastere-
numbers of enantiomeric molecules) are unsuitable for omers when the stereoisomers to be resolved can simul-
Pasteurian resolution, as are racemic solid solutions. Only taneously be equilibrated. An example is phenylglycine,
when the enantiomers crystallize in discrete crystals (i.e., C 6 H 5 CH(NH 2 )CO 2 H, required as the (−) isomer in man-
as a macroscopic mixture called a “conglomerate”) can ufacture of the antibiotic ampicillin. Equilibration of the
the two types of crystals be separated even in principle. enantiomers is effected by adding benzaldehyde to the
But only ca. 10% of racemic mixtures (ca. 20% in the racemic material (resulting in reversible formation of a
case of salts) crystallize as conglomerates. When they do, Schiff base which is readily racemized) and precipitation
separation can be achieved by a modification of Pasteur’s of the desired (−) acid as its salt with (+)-tartaric acid.
technique (called the “method of entrainment”) involv- The (+) isomer is concomitantly reconverted to the race-
ing alternate seeding with one enantiomer, separating the mate; in the end, nearly the entire amino acid crystallizes
additional crystalline material formed, replenishing the as the (+)-tartrate of the (−) acid.
solution with racemate, then seeding with the opposite Kinetic resolution has already been discussed. Purely
enantiomer, thereby inducing crystallization of the second chemical approaches (exemplified by the resolution of chi-
enantiomer. Large quantities of enantiomers, for exam- ral allylic alcohols, e.g., C 6 H 11 CHOHCH CHCH 3 , with
ple, of glutamic acid, have been separated in this manner Sharpless’ reagent, which contains isopropyl tartrate as
commercially. the chiral constituent) are currently rare; enzymatic meth-
Pasteur’ssecondmethod,formationofdiastereomersby ods (e.g., hydrolysis of esters of chiral alcohols catalyzed
reaction of a racemate with an optically active auxiliary by lipase enzymes) are more common since enzymes are
or “adjuvant” (“resolving agent”), is much more common. frequently highly selective for one enantiomer over the
Common resolving agents are naturally occurring chiral other and the effectiveness of kinetic resolution depends
acids [such as (−)-malic acid, HO 2 CCHOHCH 2 CO 2 H] on the degree of selectivity.
for chiral bases, and naturally occurring chiral bases, such While ordinary chromatography does not separate
as (−)-quinine, for chiral acids. The salts formed are of- enantiomers (though it can lead to separation of diastere-
ten crystalline and can be separated by fractional crys- omers), enantiomers can be separated by chromatography
tallization. After separation, the resolved acid or base is employing a chiral stationary phase enriched in a single
liberated by treatment of the salt with mineral acid or enantiomer. In that case, the interactions between the two
base, respectively. Alternatively, covalent diastereomers enantiomers of the analyte and the chiral stationary phase
may be formed [e.g., by esterification of a racemic acid are diastereomeric in nature and therefore often differ in
with (−)-menthol (2-isopropyl-5-methylcyclohexanol)] strength, the stronger interaction leading to longer reten-
and separated by some type of chromatography on an tion time.