Macrocyclic Ring Closure of OH‐assisted Prins Reaction. A new and efficient synthesis of (R,S)‐muscone

Abstract

AbstractA new strategy for the synthesis of muscone (1) using the OH‐assisted Prins reaction for macrocyclic ring closure has been developed. The monoacetal 4 of (Z,E)‐4,8‐dodecadienedial (3), easily obtainable from (Z,E,E)‐1,5,9‐cyclododecatriene (2), is treated with methallylmagnesium chloride, and the resulting C16‐precursor 5 is subjected to acid‐catalyzed cyclization in dilute (⩽1%) solutions. This results in formation of the bicyclic dihydropyran derivatives 6 which directly yield muscone (1) on heating with a noble metal catalyst saturated with hydrogen. The five‐step pathway proceeds with readily available starting materials in conventional steps and excellent overall yield (∼40%). This new principle of macrocyclic ring formation has also been used successfully for the preparation of 3‐methylcyclotridecanone (34) and should be generally applicable for other suitable ring systems.