A new and efficient chemoenzymatic route to both enantiomers of α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones

A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones starting from α-hydroxy cyclic enones is described. Protection of 1,2-diketones, manganese(III) acetate-mediated acetoxylation followed by enzyme-mediated hydrolysis of α′-acetoxy enones gives acetoxy enones 3a–d and hydroxy enones 4a–d with high enantiomeric excesses (up to 99%) and good yields. The transesterification of rac-4b in the presence of DMAP afforded (+)-4b and (−)-3b in high enantiomeric excesses (91–94%) and good chemical yields.

Figure optionsDownload as PowerPoint slide

(−)-3-Methoxy-4-methyl-2-oxocyclohex-3-enyl acetateC10H14O4Ee = 97%[α]D25=-140 (c 0.5, CHCl3)Source of chirality: enzymatic resolution

(+)-3-Methoxy-4,6,6-trimethyl-2-oxocyclohex-3-enyl acetateC12H18O4Ee = 76%[α]D25=-39.5 (c 0.6, CHCl3)Source of chirality: enzymatic resolution

(+)-6-Hydroxy-2-methoxy-3-methylcyclohex-2-en-1-oneC8H12O3Ee = 90%[α]D25=+81.6 (c 0.2, CHCl3)Source of chirality: enzymatic resolution

(+)-6-Hydroxy-2-methoxy-3,5,5-trimethylcyclohex-2-en-1-oneC10H16O3Ee = 99%[α]D25=+111 (c 0.3, CHCl3)Source of chirality: enzymatic resolution

(+)-3-Methoxy-4-methyl-2-oxocyclopent-3-enyl acetateC9H12O4Ee = 87%[α]D25=+10.6 (c 0.8, CHCl3)Source of chirality: enzymatic resolution

(+)-4-Ethyl-3-methoxy-2-oxocyclopent-3-enyl acetateC10H14O4Ee = 93%[α]D20=+32.1 (c 1, CHCl3)Source of chirality: enzymatic resolution

(−)-5-Hydroxy-3-methyl-2-methoxy-2-cyclopentene-1-oneC7H10O3Ee = 96%[α]D20=-9.6 (c 0.8, CHCl3)Source of chirality: enzymatic resolution

(+)-3-Ethyl-5-hydroxy-2-methoxy-2-cyclopentene-1-oneC8H12O3Ee = 95%[α]D20=+15.2 (c 0.8, CHCl3)Source of chirality: enzymatic resolution