Synthesis of (E,E)-Germacrane Sesquiterpene Alcohols via Enolate-Assisted 1,4-Fragmentation

An efficient method has been developed for the synthesis of (E,E)-germacrane sesquiterpene alcohols. The key step in these syntheses involves the enolate-assisted 1,4-fragmentation of properly functionalized perhydro-1-naphthalenecarboxaldehydes with 1 equiv of sodium tert-amylate as base, to give the corresponding (E,E)-germacrane aldehydes. These aldehydes are not very stable, and in situ reduction of the aldehyde function with Red-Al is required to obtain high yields of the desired germacrane alcohols. This procedure has led to the successful synthesis of 15-hydroxygermacrene B (4) and 15-hydroxyhedycaryol (35) from the mesylates 6 and 33, respectively. When KHMDS is used instead of sodium tert-amylate in the fragmentation reaction of 6, isomerization of the initially formed C(4)−C(5) E double bond cannot be avoided and results, after in situ reduction with Red-Al, in the formation of the (E,Z)-germacrane alcohol 24. The 15-hydroxy-(E,E)-germacranes are excellent starting materials for the selective synthesis of the corresponding 4,5-epoxides, which in turn can perfectly well be used in studies on the biomimetic formation of guaiane sesquiterpenes.