Asymmetric baker’s yeast reductions of bridgehead-substituted bicyclo[2.2.2]octane-2,6-dione derivatives followed by conversion into catalytically active BODOLs for the diethylzinc addition to benzaldehyde

4-Substituted bicyclo[2.2.2]octane-2,6-diones have been synthesized and tested as substrates in the enantioselective reduction with baker’s yeast to give the corresponding hydroxy ketones. It was found that the derivative bearing a TIPSO group at the 4-position was not reduced at all while that with a TBDMSO group gave 87% yield and 46% ee. Other 4-oxy functionalized derivatives were reduced with varying yields (36–87%) and ees (10–82%). The best result was obtained for the 4-Oallyl derivative (80% yield, 82% ee). The hydroxy ketones carrying the benzyloxy and allyloxy groups at the 4-position were converted into the corresponding BODOLs, which were tested as catalysts in the diethylzinc addition to benzaldehyde. In this reaction the ees were 90% and 89%, respectively, which showed that BODOLs substituted at the 4-position are essentially as good catalysts in this reaction as those bearing a hydrogen.

Synthesis of bridgehead 4-substituted bicyclo[2.2.2]octan-2,6-dione derivatives is described and evaluated as substrate for asymmetric reduction with baker’s yeast. Two of the obtained optically active hydroxy ketones were further transformed into novel BODOLs (R = OBn and Oallyl) which were used as ligands in the diethylzinc addition to benzaldehyde.Figure optionsDownload as PowerPoint slide

(1R,4R,6S)-4-(tert-Butyldimethyl-silanyloxy)-6-endo-hydroxy-bicyclo[2.2.2]octan-2-oneC14H26O3SiEe = 46%[α]D20=-8 (c 1.7, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (1R,4R,6S)

(1R,4R,6S)-4-Acetoxy-6-endo-hydroxy-bicyclo[2.2.2]octan-2-oneC10H14O4Ee = 10%[α]D20=+2 (c 1.0, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (1R,4R,6S)

(1R,4R,6S)-4-Benzyloxy-6-endo-hydroxy-bicyclo[2.2.2]octan-2-oneC15H18O3Ee = 99%[α]D20=-23 (c 1.0, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (1R,4R,6S)

(1R,4R,6S)-4-(4-Bromobenzyloxy)-6-endo-hydroxy-bicyclo[2.2.2]octan-2-oneC15H17BrO3Ee = 56%[α]D20=-5 (c 1.0, CH2Cl2)Source of chirality: asymmetric reductionAbsolute configuration: (1R,4R,6S)

(1R,4R,6S)-6-endo-Hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-bicyclo[2.2.2]octan-2-oneC14H26O4SiEe = 68%[α]D20=-10 (c 1.5, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (1R,4R,6S)

(1R,4R,6S)-4-Allyloxy-6-endo-hydroxy-bicyclo[2.2.2]octan-2-oneC11H16O3Ee = 82%[α]D20=-3.3 (c 1.0, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (1R,4R,6S)

(1R,2R,4R,6S)-4-(Benzyloxy)-2-(2-methoxyphenyl)-bicyclo[2.2.2]octane-2,6-diolC22H26O4Ee = 96%[α]D20=+3 (c 1.0, CH2Cl2)Source of chirality: asymmetric reductionAbsolute configuration: (1R,2R,4R,6S)

(1R,2R,4R,6S)-4-(Allyloxy)-2-(2-methoxyphenyl)-bicyclo[2.2.2]octane-2,6-diolC18H24O4Ee = 82%[α]D20=+9 (c 1.0, CH2Cl2)Source of chirality: asymmetric reductionAbsolute configuration: (1R,2R,4R,6S)