Chemoenzymatic preparation of functionalized bicyclo[3.2.1]octenone and practical utilization

A practical route for the synthesis of both enantiomers of a functionalized bicyclo[3.2.1]octenone, which is potentially useful as a versatile chiral building block, has been developed from 1,4-cyclohexanedione monoethylene acetal by employing proline-catalyzed diastereoselective intramolecular aldolization and lipase-mediated kinetic resolution as the key steps. The synthetic utility of the bicyclo[3.2.1]octenone has been demonstrated by the conversion into a chiral bicyclo[5.3.0]decane, which should serve as the key intermediate for the synthesis of the pseudoguaianolide class of antitumor sesquiterpenes.

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(1S,2S,5R,7R)-Butyric acid 7-methoxymethoxybicyclo[3.2.1]oct-3-en-2-yl esterC14H22O4Ee = 99%[α]D27=+57.8 (c 1.00, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1S,2S,5R,7R)

(1S,2R,5S,7S)-7-Methoxymethoxybicyclo[3.2.1]oct-3-en-2-olC10H16O3Ee = 99%[α]D29=+78.1 (c 0.15, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1S,2R,5S,7S)

(1R,5S,7S)-7-Methoxymethoxybicyclo[3.2.1]oct-3-en-2-oneC10H14O3Ee = 99%[α]D30=+212.7 (c 0.24, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,5S,7S)

(1R,2S,4S,5R,6R)-4-Benzyloxy-6-methoxymethoxy-2-methylbicyclo[3.2.1]octaneC18H26O3Ee = 99%[α]D23=-87.6 (c 0.5, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,2S,4S,5R,6R)

(1R,2S,4S,5S,6R)-4-Benzyloxy-2-methylbicyclo[3.2.1]octan-6-olC16H22O2Ee = 99%[α]D27=+24.7 (c 1.2, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,2S,4S,5S,6R)

(1R,2S,4S,5R)-4-Benzyloxy-2-methylbicyclo[3.2.1]octan-6-oneC16H20O2Ee = 99%[α]D23=+140.1 (c 2.0, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,2S,4S,5R)

(1S,2S,4S,5R,7S)-4-Benzyloxy-2,7-dimethylbicyclo[3.2.1]octan-6-oneC17H22O2Ee = 99%[α]D23=+121.9 (c 0.7, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1S,2S,4S,5R,7S)

(1S,2S,4S,5R,7S)-7-Allyl-4-benzyloxy-2,7-dimethylbicyclo[3.2.1]octan-6-oneC20H26O2Ee = 99%[α]D26=+74.5 (c 0.7, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,2S,4S,5R,7S)

(1R,2S,4S,5R,7S)-7-Allyl-4-hydroxy-2,7-dimethylbicyclo[3.2.1]octan-6-oneC13H20O2Ee = 99%[α]D31=-32.2 (c 0.4, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,2S,4S,5R,7S)

(1R,4S,5S,6S)-6-Allyl-4,6-dimethylbicyclo[3.2.1]octane-2,7-dioneC13H18O2Ee = 99%[α]D31=-201.5 (c 0.8, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (1R,4S,5S,6S)

(S)-Methyl 3-{(1S,2S)-2-Allyl-2-methyl-3-oxocyclopentyl}butanoateC14H22O3Ee = 99%[α]D31=-101.5 (c 1.3, CHCl3)Source of chirality: chiral resolutionAbsolute configuration: (S,1R,2S)