Lipase-catalyzed kinetic resolution of α-hydroxymethylcycloalkanones with a quaternary carbon center. Chemoenzymatic synthesis of chiral pseudoiridolactones

The resolution of α-alkyl-α-hydroxymethylcyclopentanones 1 and cyclohexanones 3 has been efficiently achieved by using lipase-catalyzed transesterification reactions with vinyl acetate as the acylating agent. The enantiomeric selectivities were dependent on both the ring size of the cycloalkanone and the bulk of the carbon group located at the stereogenic quaternary center. The resolved α-alkyl-α-hydroxymethylcyclopentanones 1 were used as enantiopure (or enantioenriched) precursors for the synthesis of the optically active pseudoiridolactones 6–7.

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2-Hydroxymethyl-2,4,4-trimethylcyclopentanoneC9H16O2Ee = 99%[α]D20=-79.1 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (S)

2-Hydroxymethyl-2-methylcyclopentanoneC7H12O2Ee = 82%[α]D20=-50.4 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (S)

2-Benzyl-2-hydroxymethylcyclopentanoneC13H16O2Ee = 99%[α]D20=+81.4 (c 1.0, CHCl3)Source of chirality: enzymatic transesterification

2-Allyl-2-hydroxymethylcyclopentanoneC9H14O2Ee = 98%[α]D20=+38.0 (c 1.1, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (R)

2-Butyl-2-hydroxymethylcyclopentanoneC10H18O2Ee = 99%[α]D20=+11.0 (c 1.0, CHCl3)Source of chirality: enzymatic transesterification

2-Hydroxymethyl-2-methylcyclohexanoneC8H14O2Ee = 82%[α]D20=+67.0 (c 1.01, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (S)

2-Benzyl-2-hydroxymethylcyclohexanoneC14H18O2Ee = 98%[α]D20=+41.0 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (R)

2-Acetoxymethyl-2,4,4-trimethylcyclopentanoneC11H18O3Ee = 99%[α]D20=+58.7 (c 1.1, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (R)

2-Acetoxymethyl-2-methylcyclopentanoneC9H14O3Ee = 99%[α]D20=+87.8 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (R)

2-Acetoxymethyl-2-benzylcyclopentanoneC15H18O3Ee = 99%[α]D20=-17.0 (c 1.1, CHCl3)Source of chirality: enzymatic transesterification

2-Acetoxymethyl-2-allylcyclopentanoneC11H16O3Ee = 99%[α]D20=-19.0 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (S)

2-Acetoxymethyl-2-butylcyclopentanoneC12H20O3Ee = 98%[α]D20=-12.5 (c 1.0, CHCl3)Source of chirality: enzymatic transesterification

2-Acetoxymethyl-2-methylcyclohexanoneC10H16O3Ee = 98%[α]D20=-18.0 (c 1.1, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (R)

2-Acetoxymethyl-2-benzylcyclohexanoneC16H20O3Ee = 98%[α]D20=-19.0 (c 1.1, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (S)

6,6,7a-Trimethyl-5,6,7,7a-tetrahydro-cyclopenta[c]pyran-3(1H)-oneC11H16O2Ee = 99%[α]D20=+208.9 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (7aR)

7a-Methyl-5,6,7,7a-tetrahydro-cyclopenta[c]pyran-3(1H)-oneC9H12O2Ee = 82%[α]D20=+184.4 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (7aR)

7a-Benzyl-5,6,7,7a-tetrahydro-cyclopenta[c]pyran-3(1H)-oneC15H16O2Ee = 99%[α]D20=+52.4 (c 1.0, CHCl3)Source of chirality: enzymatic transesterification

7a-Allyl-5,6,7,7a-tetrahydro-cyclopenta[c]pyran-3(1H)-oneC11H14O2Ee = 98%[α]D20=+83.4 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (7aS)

7a-Buyl-5,6,7,7a-tetrahydro-cyclopenta[c]pyran-3(1H)-oneC12H18O2Ee = 99%[α]D20=+101.0 (c 0.9, CHCl3)Source of chirality: enzymatic transesterification

6,6,7a-Trimethylhexahydrocyclopenta[c]pyran-3(1H)-oneC11H18O2Ee = 99%[α]D20=+82.0 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (7aR)

7a-Methylhexahydrocyclopenta[c]pyran-3(1H)-oneC9H14O2Ee = 82%[α]D20=+28.6 (c 1.1, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (7aR)

7a-Benzylhexahydrocyclopenta[c]pyran-3(1H)-oneC15H18O2Ee = 99%[α]D20=-34.0 (c 1.1, CHCl3)Source of chirality: enzymatic transesterification

7a-Allylhexahydrocyclopenta[c]pyran-3(1H)-oneC11H16O2Ee = 98%[α]D20=-27.0 (c 1.0, CHCl3)Source of chirality: enzymatic transesterificationConfiguration: (7aS)

7a-Butylhexahydrocyclopenta[c]pyran-3(1H)-oneC12H20O2Ee = 99%[α]D20=+26.4 (c 1.0, CHCl3)Source of chirality: enzymatic transesterification