Esterase-mediated synthesis of optically active GABA analogues containing a stereogenic all-carbon quaternary carbon atom

Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic β,β-dialkyl-γ-nitroesters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered substrates, such as those possessing a stereogenic quaternary carbon atom next to the reaction site. The resulting optically active γ-nitroesters gave access to optically active β,β-disubstituted γ-aminoacids as well as α,α-disubstituted succinic acids, both being biologically relevant compounds.

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Ethyl 3-methyl-3-(nitromethyl)heptanoateC11H21NO462% ee[α]D25=-0.8 (c 0.65, CHCl3)Absolute configuration: (S)Source: enzymatic resolution

Ethyl 3,5-dimethyl-3-(nitromethyl)hexanoateC11H21NO488% ee[α]D25=-1.3 (c 1.9, CHCl3)Absolute configuration: (S)Source: enzymatic resolution

Ethyl 3-benzyl-3-methyl-4-nitrobutanoateC14H19NO491% ee[α]D25=+36.0 (c 1.8, CHCl3)Configuration: (R)Source: enzymatic resolution

Ethyl 3-Methyl-1-(nitromethyl)cyclohexaneacetateC12H21NO4>99% ee[α]D25=-2.5 (c 1.8, CHCl3)Configuration: (1S,3R)Source: enzymatic resolution

Ethyl 6-(nitromethyl)bicyclo[3.2.0]hept-2-ene-6-acetateC12H17NO4>99% ee[α]D25=-18.8 (c 1.0, CHCl3)Configuration: (1R,5S,6R)Source: enzymatic resolution

3-Methyl-3-(nitromethyl)heptanoic acidC9H17NO474% ee[α]D25=+2.1 (c 0.5, CHCl3)Configuration: (R)Source: enzymatic resolution

3,5-Dimethyl-3-(nitromethyl)hexanoic acidC9H17NO475% ee[α]D25=+3.7 (c 0.35, CHCl3)Configuration: (R)Source: enzymatic resolution

3-Benzyl-3-methyl-4-nitrobutanoic acidC12H15NO471% ee[α]D25=-4.4 (c 0.5, CHCl3)Configuration: (S)Source: enzymatic resolution

3-Methyl-1-(nitromethyl)cyclohexaneacetic acidC10H17NO478% ee[α]D25=+3.2 (c 0.35, CHCl3)Configuration: (1R,3S)Source: enzymatic resolution

6-(Nitromethyl)bicyclo[3.2.0]hept-2-ene-6-acetic acidC10H13NO494% ee[α]D25=+25.1 (c 1, CHCl3)Configuration: (1S,5R,6S)Source: enzymatic resolution

2-Butyl-2-methylsuccinic acidC9H16O474% ee[α]D25=+2.2 (c 0.5, CHCl3)Configuration: (R)Source: enzymatic resolution

2-Isobutyl-2-methylsuccinic acidC9H16O488% ee[α]D25=-6.1 (c 0.25, CHCl3)Configuration: (S)Source: enzymatic resolution

2-Benzyl-2-methylsuccinic acidC12H14O491% ee[α]D25=+3.3 (c 1, MeOH)Configuration: (R)Source: enzymatic resolution

1-Carboxy-3-methylcyclohexaneacetic acidC10H16O499% ee[α]D25=-2.6 (c 0.8, CHCl3)Configuration: (1S,3R)Source: enzymatic resolution

6-Carboxybicyclo[3.2.0]hept-2-ene-6-acetic acidC10H12O4>99% ee[α]D25=-14.9 (c 0.5, CHCl3)Configuration: (1R,5S,6R)Source: enzymatic resolution

4-Butyl-4-methylpyrrolidin-2-oneC11H23NO63% ee[α]D25=+8.0 (c 1, CHCl3)Configuration: (S)Source: enzymatic resolution

4-Isobutyl-4-methylpyrrolidin-2-oneC11H23NO88% ee[α]D25=+11.4 (c 1, CHCl3)Configuration: (S)Source: enzymatic resolution

4-Benzyl-4-methylpyrrolidin-2-oneC12H15NO91% ee[α]D25=-10.0 (c 0.8, CHCl3)Configuration: (R)Source: enzymatic resolution

7-Methyl-2-azaspiro[4.5]decan-3-oneC10H17NO>99% ee[α]D25=-11.8 (c 1.15, CHCl3)Configuration: (5S,7R)Source: enzymatic resolution

Spiro[bicyclo[3.2.0]heptane-6-pyrrolidin]-5′-oneC10H13NO>99% ee[α]D25=+28.5 (c 1, CHCl3)Configuration: (1S,3′R,5S)Source: enzymatic resolution

3-(Aminomethyl)-3-methylheptanoic acid hydrochlorideC9H20ClNO263% ee[α]D25=-2.0 (c 1, H2O)Configuration: (S)Source: enzymatic resolution

3-(Aminomethyl)-3,5-dimethylhexanoic acid hydrochlorideC9H20ClNO288% ee[α]D25=-2.4 (c 1.25, MeOH);Configuration: (S)Source: enzymatic resolution

4-Amino-3-benzyl-3-methylbutanoic acid hydrochlorideC12H18ClNO291% ee[α]D25=+13.0 (c 0.5, H2O)Configuration: (R)Source: enzymatic resolution

1-(Aminomethyl)-3-methylcyclohexaneacetic acid hydrochlorideC10H16ClNO2>99% ee[α]D25=-1.5 (c 0.9, H2O)Configuration: (1S,3R)Source: enzymatic resolution

6-(Aminomethyl)bicyclo[3.2.0]heptane-6-acetic acid hydrochlorideC10H16ClNO2>99% ee[α]D25=+8.0 (c 1.5, H2O)Configuration: (1S,5S,6R)Source: enzymatic resolution