Page 207 - Cascade biocatalysis

8.3 Applications of DKR to Acyl Compounds 183

role of the substituents on the acidity of this proton. This topic will be extensively
discussed in the following paragraph.
Reading through the Zwanenburg’s review, it becomes evident that, except for
enzymatic catalysis, in all cases harsh conditions prevail as the most common
reaction environment. High temperature, high concentration of strong acids or
bases, anhydrous solvents, and an inert atmosphere are often required. Obviously,
such characteristics are in general incompatible with the use of enzymes for
KR, because these are usually associated with much milder reaction conditions.
Consequently, it is instrumental to focus on those cases that can be identified
among the many examples from the literature, where substrate engineering or the
discovery of new catalysts permit to efficiently racemize the targets under conditions
not too distant from a physiological environment and, hence, compatible with the
more common biocatalysts. Since enzymatic racemization is quite an attractive
opportunity that has been often analyzed and reviewed in recent years [32–34], it
will be omitted from the present discussion.

8.3
Applications of DKR to Acyl Compounds

8.3.1
Base-Catalyzed Racemization

The racemization at the α-carbon of acyclic compounds in most of the cases occurs
through a base-catalyzed enolization, where an achiral enolate is formed as an
intermediate. Consequently, it is of great importance to study and understand both
the kinetic and thermodynamic acidity of the α-proton under reasonable reaction
conditions.
In particular, a lot of work has been performed on this subject by Richard
and coworkers [35, 36], who could establish a clever and reliable method for
measuring the pK at the α-position in aqueous conditions of a representative array
a
of substrates, even if the enolate concentration is too low to be measured directly.
This is often the case when the most common aqueous buffers are used.
1
By carrying out some clever deuterium exchange monitored by H NMR spec-
troscopy, and making some reasonable assumptions on the expected mechanism

k 1 k −d
B + H C BH C C + BH
k −1 k d
+
k p [BD ]
k tx
k −1 ′
BD C D C

Scheme 8.2 Proposed mechanism of base-catalyzed enolization and proton exchange.