Enantioselective synthesis of bridgehead hydroxyl bicyclo[2.2.2]octane derivatives via asymmetric allylindation

A recent new strategy for the transformation of mono-dioxolane protected 1,3-cyclohexadione into bridgehead hydroxyl bicyclo[2.2.2]octane derivatives, based on allylindation followed by ozonolysis and intramolecular aldol addition, was modified to include asymmetric allylindation. This enabled the first enantioselective synthesis of (1R,4R,6S)-endo-4-(tert-butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-one and (1S,4S,6R)-endo-4-(tert-butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-one in high enantiomeric excess. Issues concerning the non-reproducibility of the asymmetric allylindation were also addressed.

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(+)-(7S)-7-Allyl-1,4-dioxaspiro[4.5]decane-7-olC11H18O3Ee = 78%[α]D22=+19.8 (c 1.66, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (7S)

(−)-7-(2-Methyl-allyl)-1,4-dioxaspiro[4.5]decane-7-olC12H20O3Ee = 71%[α]D22=-13.9 (c 0.90, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: not determined

(−)-7-Allyl-1,4-dithiaspiro[4.5]decane-7-olC11H18OS2Ee = 54%[α]D22=-10.8 (c 1.30, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: not determined

(−)-7-(2-Methyl-allyl)-1,4-dithiaspiro[4.5]decane-7-olC12H20OS2Ee = 23%[α]D22=-2.7 (c 1.08, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: not determined

(−)-1-Allyl-3,3-dimethyl-cyclohexanolC11H20OEe = 37%[α]D22=-0.3 (c 1.13, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: not determined

(+)-3,3-Dimethyl-1-(2-methyl-allyl)-cyclohexanolC12H22OEe = 38%[α]D22=+1.4 (c 1.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: not determined

(−)-(7R)-(7-Allyl-1,4-dioxaspiro[4.5]dec-7-yloxy)-tert-butyl-dimethyl silaneC17H32O3SiEe = 79%[α]D22=-0.5 (c 1.11, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (7R)

(+)-(7S)-(7-Allyl-1,4-dioxaspiro[4.5]dec-7-yloxy)-tert-butyl-dimethyl-silaneC17H32O3SiEe = 78%[α]D22=+0.5 (4.09, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (7S)

(+)-(3R)-3-Allyl-3-(tert-butyl-dimethyl-silyloxy)-cyclohexanoneC15H28O2SiEe = 79%[α]D22=+7.6 (c 1.30, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (3R)

(+)-(1R,4R,6S)-exo-4-(tert-Butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-oneC14H26O3SiEe = 79%[α]D22=+12.6 (c 1.09, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,4R,6S)

(+)-(1S,4S,6R)-endo-4-(tert-Butyl-dimethyl-silyloxy)-6-hydroxy-bicyclo[2.2.2]octan-2-oneC14H26O3SiEe = >98%[α]D22=+10.1 (c 1.01, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,4S,6R)