Dynamic resolution is a more elegant approach [77–82] This comprises a
classic resolution with an additional feature, i.e., the resolution is carried out
using conditions under which the substrate enantiomers are in a rapid equilibrium
(racemizing). Thus, as the well-accepted substrate-enantiomer is depleted by the
enzyme, the equilibrium is constantly adjusted by racemization of the poorly
accepted counterpart. To indicate the nonstatic character of such processes, the
term ‘dynamic resolution’ has been coined [83, 84].
5
In this case, several reactions occur simultaneously and their relative rates
determine the stereochemical outcome of the whole process (Fig. 2.9):
• The enzyme should display high specificity for the enantiomeric substrates A/B
(k A » k B or k B » k A ).
• Spontaneous hydrolysis (k spont ) should be a minimum since it would yield
racemic product.
• Racemization of the substrate should occur at an equal or higher rate compared
to the biocatalytic reaction in order to provide a sufficient amount of the ‘wellfitting’ substrate enantiomer from the ‘poor-fitting’ counterpart (k rac
Sub
! k A or
k B , resp.).
• Racemization of the product (k rac
Prod
) should be minimal.
Although the above-mentioned criteria are difficult to meet experimentally, the
benefits are impressive. Examples of this type of biotransformation have increased
recently [85–91]; several examples are given in subsequent chapters.
The kinetics of a dynamic resolution is outlined in the following example
[78, 92]. Figure 2.9 shows the e.e. S and e.e. P plotted for an enantiomeric ratio
of E ~ 10. In a classic resolution process, the product is formed in ~83% e.e. at
the very beginning of the reaction, but this value rapidly decreases when the
reaction is run towards ~50% conversion as indicated by the symbol ‘
*
’. In a
dynamic process, this depletion does not occur, because the enzyme always
encounters racemic substrate throughout the reaction since the ‘well-fitting’ enantiomer is not depleted but constantly restored from the ‘poor-fitting’ counterpart via
racemization. Thus, e.e. P remains constant throughout the reaction as indicated by
the dashed arrow.
The e.e. P of dynamic processes is related to the enantioselectivity (E value)
through the following formulas [93]:
e:e: P ¼
E À 1
ð
Þ
E þ 1
ð
Þ
E ¼
1 þ e:e: P
ð
Þ
1 À e:e: P
ð
Þ
In the case where the racemization (k rac
Sub
) is limited, the dynamic resolution
gradually turns into a classic kinetic resolution pattern. Figure 2.9 shows the extent
of the depletion of e.e. P depending on the conversion for several ratios of k rac
Sub /k A
(E ~ 10). As can be expected, e.e. P decreases only slightly during the early stage of
the reaction because the fast-reacting enantiomer is sufficiently available during
5 Dynamic resolution is a type of second-order asymmetric transformation [79, 83]
48
2 Biocatalytic Applications
classic resolution with an additional feature, i.e., the resolution is carried out
using conditions under which the substrate enantiomers are in a rapid equilibrium
(racemizing). Thus, as the well-accepted substrate-enantiomer is depleted by the
enzyme, the equilibrium is constantly adjusted by racemization of the poorly
accepted counterpart. To indicate the nonstatic character of such processes, the
term ‘dynamic resolution’ has been coined [83, 84].
5
In this case, several reactions occur simultaneously and their relative rates
determine the stereochemical outcome of the whole process (Fig. 2.9):
• The enzyme should display high specificity for the enantiomeric substrates A/B
(k A » k B or k B » k A ).
• Spontaneous hydrolysis (k spont ) should be a minimum since it would yield
racemic product.
• Racemization of the substrate should occur at an equal or higher rate compared
to the biocatalytic reaction in order to provide a sufficient amount of the ‘wellfitting’ substrate enantiomer from the ‘poor-fitting’ counterpart (k rac
Sub
! k A or
k B , resp.).
• Racemization of the product (k rac
Prod
) should be minimal.
Although the above-mentioned criteria are difficult to meet experimentally, the
benefits are impressive. Examples of this type of biotransformation have increased
recently [85–91]; several examples are given in subsequent chapters.
The kinetics of a dynamic resolution is outlined in the following example
[78, 92]. Figure 2.9 shows the e.e. S and e.e. P plotted for an enantiomeric ratio
of E ~ 10. In a classic resolution process, the product is formed in ~83% e.e. at
the very beginning of the reaction, but this value rapidly decreases when the
reaction is run towards ~50% conversion as indicated by the symbol ‘
*
’. In a
dynamic process, this depletion does not occur, because the enzyme always
encounters racemic substrate throughout the reaction since the ‘well-fitting’ enantiomer is not depleted but constantly restored from the ‘poor-fitting’ counterpart via
racemization. Thus, e.e. P remains constant throughout the reaction as indicated by
the dashed arrow.
The e.e. P of dynamic processes is related to the enantioselectivity (E value)
through the following formulas [93]:
e:e: P ¼
E À 1
ð
Þ
E þ 1
ð
Þ
E ¼
1 þ e:e: P
ð
Þ
1 À e:e: P
ð
Þ
In the case where the racemization (k rac
Sub
) is limited, the dynamic resolution
gradually turns into a classic kinetic resolution pattern. Figure 2.9 shows the extent
of the depletion of e.e. P depending on the conversion for several ratios of k rac
Sub /k A
(E ~ 10). As can be expected, e.e. P decreases only slightly during the early stage of
the reaction because the fast-reacting enantiomer is sufficiently available during
5 Dynamic resolution is a type of second-order asymmetric transformation [79, 83]
48
2 Biocatalytic Applications