Process-Scale Total Synthesis of Nature-Identical (−)-(S,S)-7-Hydroxycalamenal in High Enantiomeric Purity through Catalytic Enantioselective Hydrogenation

A process-scale stereoselective synthesis of nature-identical (−)-(S,S)-7-hydroxycalamenal (=(−)-(5S,8S)-5,6,7,8-tetrahydro-3-hydroxy-5-methyl-8-(1-methylethyl)naphthalene-2-carbaldehyde; (−)-1a) in 96% enantiomeric excess (ee) with the aid of chiral Ru complexes has been developed. The key step was the enantioselective hydrogenation of easily accessible 2-(4-methoxyphenyl)-3-methylbut-2-enoic acid (10) to (+)-11 in a 86% ee (Scheme 5 and Table 1). A substantial increase in optical purity (96% ee) was achieved by induced crystallization of the intermediate (+)-3,4-dihydro-4-(1-methylethyl)-7-methoxy-2H-naphthalen-1-one ((+)-3). Computational conformation analysis carried out on the analog (−)-9 rationalized the high diastereoselectivity achieved in the catalytic hydrogenation of the CC bond.