Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

Eliglustat (Cerdelga (R), Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the S(N)i and the S(N)1 mechanisms, leading to the retention of stereochemistry.

Automated summary

The total synthesis of eliglustat, an approved drug for non-neurological Gaucher disease, starting from 1,4-benzodioxan-6-carbaldehyde is described. The synthesis involves Sharpless asymmetric dihydroxylation and diastereoselective amination steps, with chlorosulfonyl isocyanate as a key reactant.