Development of a Directed Ketal Hydrogenation for the Synthesis of a Key Intermediate of Lanabecestat

A new route to a key ether intermediate in the synthesis of Lanabecestat is described. A directed hydrogenation approach was investigated as an alternative to the previous route, which used a borane reduction of a diketone giving a selectivity of 80:20. Directed hydrogenation of an enol ether intermediate gave a selectivity of >99:1 for the desired ether but the enol ether was problematic to synthesize and isolate. The ketal was investigated as an alternative substrate and found to give the same high selectivity, avoiding the issues of enol ether synthesis. Mechanistic studies indicate that this reaction proceeds via the enol ether.