Bicyclo[2.2.2]octane-derived chiral ligands—synthesis and application of BODOLs in the asymmetric reduction of acetophenone with catecholborane

An improved synthetic route to the bicyclo[2.2.2]octane-2,6-diol ligands (2,6-BODOLs) allowed an increased structural variation of the ligand side-arm. The addition of aromatic or vinylic Grignard reagents to hydroxyketone 1 was highly selective and ligands 3f–3l were isolated in 84–97% yield. The addition of alkyl Grignard reagents containing β-hydrogens resulted in lower yields (13–71%) due to competing ketone reduction. A number of 2,5-BODOLs were synthesized using a similar methodology. The ligands, together with Ti(OiPr)4, were tested in the asymmetric reduction of acetophenone with catecholborane (up to 98% ee). 1-Naphthyl-BODOL 3i was employed as an allylboration reagent to benzaldehyde together with Sc(OTf)3, resulting in (1S)-1-phenyl-3-buten-1-ol in 80% ee.

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(1R,2R,4S,6S)-2-Methyl-bicyclo[2.2.2]octane-2,6-diolC9H16O2Ee = >99%[α]D = +39 (c 0.50, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-Ethyl-bicyclo[2.2.2]octane-2,6-diolC10H18O2Ee = >99%[α]D = +45.2 (c 1.00, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-Butyl-bicyclo[2.2.2]octane-2,6-diolC12H22O2Ee = >99%[α]D = +40 (c 0.60, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2S,4S,6S)-2-Isopropyl-bicyclo[2.2.2]octane-2,6-diolC11H20O2Ee = >99%[α]D = +63.7 (c 1.00, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S,4S,6S)

(1R,2S,4S,6S)-2-Cyclohexyl-bicyclo[2.2.2]octane-2,6-diolC14H24O2Ee = >99%[α]D = +64 (c 0.70, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S,4S,6S)

(1R,2R,4S,6S)-2-Vinylbicyclo[2.2.2]octane-2,6-diolC10H16O2Ee = >99%[α]D = +76 (c 0.56, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-Phenyl-bicyclo[2.2.2]octane-2,6-diolC14H18O2Ee = >99%[α]D = +69.9 (c 1.36, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(4-Biphenyl)-bicyclo[2.2.2]octane-2,6-diolC20H22O2Ee = >99%[α]D = +42 (c 0.70, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(Naphthalen-1-yl)-bicyclo[2.2.2]octane-2,6-diolC18H20O2Ee = >99%[α]D = +25.6 (c 2.30, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(Naphthalen-2-yl)-bicyclo[2.2.2]octane-2,6-diolC18H20O2Ee = >99%[α]D = +50 (c 0.50, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-o-Tolylbicyclo[2.2.2]octane-2,6-diolC15H20O2Ee = >99%[α]D = +41.0 (c 2.30, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(2-Ethylphenyl)bicyclo[2.2.2]octane-2,6-diolC16H22O2Ee = >99%[α]D = +34.1 (c 2.60, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(2-Methoxyphenyl)-bicyclo[2.2.2]octane-2,6-diolC15H20O3Ee = >99%[α]D = +50.0 (c 0.70, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(2-Methoxyphenyl)-1-methylbicyclo[2.2.2]octane-2,6-diolC16H22O3Ee = >99%[α]D = +62.3 (c 0.69, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1R,2R,4S,6S)-2-(2-Methoxyphenyl)-4-methylbicyclo[2.2.2]octane-2,6-diolC16H22O3Ee = >99%[α]D = +45.2 (c 0.51, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,4S,6S)

(1S,2S,4S,5S)-2-Phenylbicyclo[2.2.2]octane-2,5-diolC14H18O2Ee = >99%[α]D = −111 (c 0.55, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4S,5S)

(1S,2S,4S,5S)-2-(2-Methoxyphenyl)bicyclo[2.2.2]octane-2,5-diolC15H20O3Ee = >99%[α]D = −59 (c 0.52, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4S,5S)

(1S,2S,4S,5S)-2-(Naphthalen-1-yl)bicyclo[2.2.2]octane-2,5-diolC18H20O2Ee = >99%[α]D = −74 (c 0.50, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4S,5S)

(1S,4S,5S)-5-Hydroxy-5- phenylbicyclo[2.2.2]octan-2-oneC14H16O2Ee = >99%[α]D = −20 (c 0.30, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,4S,5S)

(1S,4S,5S)-5-Hydroxy-5-(naphthalen-1-yl)bicyclo[2.2.2]octan-2-oneC18H18O2Ee = >99%[α]D = −22 (c 0.51, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,4S,5S)

(1S,4S,5S)-5-Hydroxy-5-(2-methoxyphenyl)bicyclo[2.2.2]octan-2-oneC15H18O3Ee = >99%[α]D = −4.9 (c 0.50, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,4S,5S)

(1S,2S,4S,5S)-2,5-Diphenylbicyclo[2.2.2]octane-2,5-diol (7a)C20H22O2Ee = >99%[α]D = −87 (c 0.40, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4S,5S)

(1S,2S,4S,5S)-2,5-Di(naphthalen-1-yl)bicyclo[2.2.2]octane-2,5-diolC28H26O2Ee = >99%[α]D = −110 (c 0.45, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4S,5S)

(1S,2S,4S,5S)-2,5-Bis(2-methoxyphenyl)bicyclo[2.2.2]octane-2,5-diolC22H26O4Ee = >99%[α]D = −24 (c 0.32, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2S,4S,5S)

(1R,2S,4R,5S)-2,5-Diphenylbicyclo[2.2.2]oct-7-ene-2,5-diolC20H20O2Ee = >99%[α]D = +74 (c 0.50, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S,4R,5S)

(1S,2R,4S,5R)-2,5-Di(naphthalen-1-yl)bicyclo[2.2.2]oct-7-ene-2,5-diolC28H24O2Ee = >99%[α]D = +13.7 (c 1.53, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R)

(1S,2R,4S,5R)-2,5-Bis(2-methoxyphenyl)bicyclo[2.2.2]oct-7-ene-2,5-diolC22H24O4Ee = >99%[α]D = −147 (c 0.23, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,2R,4S,5R)

(1R,2S,4R,5S)-2-(Naphthalen-1-yl)bicyclo[2.2.2]oct-7-ene-2,5-diolC18H18O2Ee = >99%[α]D = −44 (c 0.45, tBuOMe)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S,4R,5S)

(1S,4S)-2,5-Di(naphthalen-1-yl)bicyclo[2.2.2]octa-2,5-dieneC28H22Ee = >99%[α]D = −198 (c 1.05, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,4S)