chemical and the enzymatic Baeyer-Villiger reaction can usually be predicted by
assuming that the carbon atom best able to support a positive charge will migrate
preferentially, i. e. tert-alkyl > sec-alkyl ~ phenyl > prim-alkyl > methyl [1352].
All mechanistic studies on enzymatic Baeyer-Villiger reactions support the hypothesis that conventional and enzymatic reactions are closely related [1206, 1353]. The
oxidized flavin cofactor peroxy species (FAD-4a-OO
À , see Scheme 2.147) plays the
role of a nucleophile similar to the peracid. The strength of enzyme-catalyzed Baeyer–
Villiger reactions resides in the recognition of chirality [1354–1356], which has been
accomplished by conventional means with moderate selectivities [1357].
The enzymatic Baeyer-Villiger oxidation of ketones is catalyzed by flavindependent monooxygenases and plays an important role in the breakdown of carbon
structures containing a ketone moiety (Scheme 2.148). Early studies were
performed by using whole microbial cells, particularly in view of avoiding the
necessity for NAD(P)H-recycling [1358]. However, whole-cell Baeyer–Villiger
oxidations often suffer from low yields due to side reactions catalyzed by competing hydrolytic enzymes. Furthermore, some of the most potent strains, such as
Acinetobacter calcoaceticus, are potentially pathogenic and therefore have to be
handled with extra care (see the Appendix, Chap. 5).
39
To avoid further degradation of esters and lactones in microbial Baeyer-Villiger
reactions catalyzed by hydrolytic enzymes and to maximize product accumulation,
the following approaches are possible:
• Blocking of the hydrolytic enzymes by selective hydrolase-inhibitors such as
tetraethyl pyrophosphate (TEPP [1359]) or diethyl p-nitrophenylphosphate
(paraoxon). However, all of these inhibitors are highly toxic and have to be
handled with extreme caution.
• Development of mutant strains lacking lactone-hydrolases.
• Application of nonnatural ketones, whose lactone products are not substrates for
the hydrolytic enzymes.
• Use of isolated Baeyer-Villigerases together with NAD(P)H-recycling is nowadays the method of choice.
X
O
O
O
R 2
R 1
X
R 2
R 1
O
O
O
H
X
HO
Biochemical: X = flavin
Chemical: X = acyl-group
Criegee-intermediate
+
O
O
R
1
R 2
Scheme 2.161 Mechanism of the chemical and biochemical Baeyer-Villiger oxidation
39 Acinetobacter calcoaceticus NCIMB 9871 is a class-II pathogen.
190
2 Biocatalytic Applications
assuming that the carbon atom best able to support a positive charge will migrate
preferentially, i. e. tert-alkyl > sec-alkyl ~ phenyl > prim-alkyl > methyl [1352].
All mechanistic studies on enzymatic Baeyer-Villiger reactions support the hypothesis that conventional and enzymatic reactions are closely related [1206, 1353]. The
oxidized flavin cofactor peroxy species (FAD-4a-OO
À , see Scheme 2.147) plays the
role of a nucleophile similar to the peracid. The strength of enzyme-catalyzed Baeyer–
Villiger reactions resides in the recognition of chirality [1354–1356], which has been
accomplished by conventional means with moderate selectivities [1357].
The enzymatic Baeyer-Villiger oxidation of ketones is catalyzed by flavindependent monooxygenases and plays an important role in the breakdown of carbon
structures containing a ketone moiety (Scheme 2.148). Early studies were
performed by using whole microbial cells, particularly in view of avoiding the
necessity for NAD(P)H-recycling [1358]. However, whole-cell Baeyer–Villiger
oxidations often suffer from low yields due to side reactions catalyzed by competing hydrolytic enzymes. Furthermore, some of the most potent strains, such as
Acinetobacter calcoaceticus, are potentially pathogenic and therefore have to be
handled with extra care (see the Appendix, Chap. 5).
39
To avoid further degradation of esters and lactones in microbial Baeyer-Villiger
reactions catalyzed by hydrolytic enzymes and to maximize product accumulation,
the following approaches are possible:
• Blocking of the hydrolytic enzymes by selective hydrolase-inhibitors such as
tetraethyl pyrophosphate (TEPP [1359]) or diethyl p-nitrophenylphosphate
(paraoxon). However, all of these inhibitors are highly toxic and have to be
handled with extreme caution.
• Development of mutant strains lacking lactone-hydrolases.
• Application of nonnatural ketones, whose lactone products are not substrates for
the hydrolytic enzymes.
• Use of isolated Baeyer-Villigerases together with NAD(P)H-recycling is nowadays the method of choice.
X
O
O
O
R 2
R 1
X
R 2
R 1
O
O
O
H
X
HO
Biochemical: X = flavin
Chemical: X = acyl-group
Criegee-intermediate
+
O
O
R
1
R 2
Scheme 2.161 Mechanism of the chemical and biochemical Baeyer-Villiger oxidation
39 Acinetobacter calcoaceticus NCIMB 9871 is a class-II pathogen.
190
2 Biocatalytic Applications