From Acyclic Intramolecular-[4 + 2]- to Transannular Bis-[4 + 2]-Cycloaddition of the Macrodiolide for the Stereoselective Synthesis of the Octahydronaphthalene Core of Polyenic Macrolactam Sagamilactam.

The strategy for the synthesis of the octahydronaphthalene core of natural macrolide sagamilactam has unintentionally evolved from the acyclic intramolecular (IMDA) to the transannular (TADA) Diels-Alder reaction. Lewis acid-promoted IMDA of a protected 2,8,10-4,6,12-trihydroxy-2,8,10-decatrienal model with a diol of 4,6- relative configuration, as proposed by DP4+-based computational studies, afforded the -octahydronaphthalene diastereomer through the approach. The 26-membered macrodiolide generated, under thermal reaction conditions, the -octahydronaphthalene by a double TADA reaction along the desired orientation.