A new cyclohexyl-based chiral auxiliary: application in the total synthesis of (+)-linalool oxide

Abstract

Seven different racemic cyclohexyl-based chiral auxiliaries (2.4-2.10) were synthesised in moderate to good yields (38-85%) by nucleophilic opening of cyclohexene oxide using carbanions. The racemic cyclohexyl-based chiral auxiliaries were coupled with the 6-methyl-2- methylenehept-5-enoyl chloride (2.20) to form the dienes esters 2.38-2.44. The chiral auxiliarydiene ester adducts 2.38-2.44 were subjected to a comparative study in the permanganatemediated oxidative cyclisation. The best result was obtained by using (±)-trans-2-trityl-1- cyclohexanol ((±)-2.10 (±)-TTC)), resulting in high diastereoselectivity (dr = 97:3) in the resulting THF diols 2.51a/b. The other auxiliaries synthesised gave only moderate to no diastereoinduction. Different methods were used to resolve the racemic auxiliary (±)-TTC including enzymatic resolution and classical resolution. A successful classical resolution was achieved and the enantiomer (–)-TTC was obtained in excellent yield and enantiopurity (99 % ee). The stereochemistry of the obtained enantiomer was defined as (1S,2R) from the X-ray structure of its Mosher ester derivative 2.76. (–)-TTC was used in the total synthesis of (+)-linalool oxide (1.247) which was achieved in 9 steps and 13% overall yield. Finally, nucleophilic additions to ?-keto esters containing (±)-TTC were investigated and the preliminary results are described

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ORCID for Richard C.D. Brown: orcid.org/0000-0003-0156-7087

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