Practical Diastereoselective Synthesis and Scale-up Study of (+)-2-((1R,2R,3R,5S)-2-Amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol: A Key Intermediate of the Novel Prostaglandin D₂Receptor Antagonist S-5751

A new synthetic process was developed for (+)-2-((1 R,2 R,3 R,5 S )-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol, a key intermediate of S-5751. Diastereoselective alkylation of (+)-nopinone with ethyl bromoacetate, formation of O -methyl oxime, and diastereoselective reduction with NaBH 4 −AlCl 3 could be safely carried out. Stereochemistry of the (1 R,2 R,3 R,5 S )-6,6-dimethylbicyclo[3.1.1]heptane ring was discussed to achieve high diastereoselectivity on these reactions. For the scale-up, detailed consideration was given to the safety of the NaBH 4 −AlCl 3 reduction.