Baeyer–Villiger monooxygenase-catalyzed kinetic resolution of racemic α-alkyl benzyl ketones: enzymatic synthesis of α-alkyl benzylketones and α-alkyl benzylesters

The application of three BVMOs for the enantioselective oxidation of 3-phenylbutan-2-ones with different substituents in the aromatic moiety is described. By choosing the appropriate biocatalyst and substrate combination, chiral ketones and esters can be obtained with excellent enantiopurities. This methodology could also be applied to the resolution of racemic α-alkyl benzylketones with longer alkyl chains as well as with two substituted α-substituted benzylacetones. A kinetic analysis revealed that the BVMOs studied effectively convert all tested compounds showing that the enzymes are tolerant towards the substrate structure while being highly enantioselective. These properties render BVMOs as valuable biocatalysts for the preparation of compounds with high interest in organic synthesis.

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(R) 3-(4-Ethylphenyl)butan-2-oneC12H16OEe = 36% (GC, Restek RTβDEXse)[α]D25=-12.8 (c 0.80, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (R)

(S)-1-(4-Ethylphenyl)ethyl acetateC12H16O2Ee = 86% (GC, Restek RTβDEXse)[α]D25=+35.9 (c 0.74, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (S)

(R)-1-(3-Methylphenyl)butan-2-oneC11H14OEe = 42% (GC, CP-Chiralsil DEX CB)[α]D25=-21.8 (c 1.18, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (R)

(R)-1-(3-Methoxyphenyl)butan-2-oneC11H14O2Ee = 71% (GC, Restek RTβDEXse)[α]D25=-31.6 (c 1.40, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (R)

(R)-1-(3-Chlorophenyl)butan-2-oneC10H11ClOEe = 27% (GC, Restek RTβDEXse)[α]D25=-12.0 (c 0.98, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (R)

(S)-1-(3-Chlorophenyl)ethyl acetateC10H11ClO2Ee = 92% (GC, Restek RTβDEXse)[α]D25=+67.8 (c 0.78, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (S)

(R)-4-Phenylheptan-3-oneC13H18OEe = 29% (Calculated)[α]D25=-10.8 (c 1.12, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (R)

(S)-1-Phenylbutyl propionateC13H18O2Ee = 96% (GC, Hydrodex-β-TBOAc)[α]D25=+35.8 (c 0.91, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (S)

(S)-1-Phenylpentyl propionateC14H20O2Ee = 95% (GC, Hydrodex-β-TBOAc)[α]D25=+21.2 (c 0.58, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (S)

(R)-4-Phenylhept-6-en-3-oneC13H16OEe = 38% (calculated)[α]D25=-7.2 (c 0.85, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (R)

(S)-4-Phenylbut-1-enyl propionateC13H16O2Ee = 77% (GC, Hydrodex-β-TBOAc)[α]D25=+16.9 (c 0.65, CHCl3)Source of chirality: enzymatic oxidationAbsolute configuration: (S)