Formal total synthesis of (±)-fragranol via template catalyzed 4- exo cyclization

Abstract

A novel approach to the synthesis of (±)-fragranol is described that relies on a radical 4- exo cyclization. This key step is catalyzed by a cationic titanocene complex with a pending amide ligand. In this manner the radical and its acceptor are bound to the titanocene center in a two-point mode. By this interaction the 4- exo cyclization that is not supported by gem-dialkyl substitution is rendered thermodynamically and kinetically favorable. Moreover, the crucial intermediates and transition structures become highly ordered. This results in a good diastereoselectivity of cyclobutane formation. From the key-intermediate, the formal total synthesis of the natural product can be completed in a few steps.