An optimized and practical synthesis of (−)-Ambrox from (R)-carvone

(−)-Ambrox is a benchmark ambergris odorant with extensive applications in perfumery and related industries. While we have previously reported a synthesis from ( R )-carvone, its practical utility was hampered by the use of hazardous reagents (hydrazine hydrate and tert-butyllithium) and a moderate overall yield of 26%. This work addresses these critical limitations by developing an improvement: a safe and efficient three-step sequence for installing the 2-hydroxyethyl side chain. This new protocol, employing a nucleophilic addition of an ethyl acetate enolate followed by dehydration and reduction, completely eliminates the need for explosive and pyrophoric reagents. More importantly, this strategic modification directly elevates the overall yield to 42%, representing a greater than 60% increase in efficiency. The optimized route thereby provides a safer, more productive, and operationally simpler access to (−)-Ambrox, enhancing its potential for scalable preparation.