The clerodane ring system: Investigating the viability of a direct Diels-Alder approach

Abstract

Clerodane natural products 1 are a prolific family of biologically active diterpenes numbering over a thousand. This series of natural products has received comparatively little synthetic attention.2 For example, only 4 total syntheses of clerodanes containing the spiro-γ-lactone moiety, a structural feature found in a large number of all clerodane natural products isolated so far, have been reported (i.e. teucvin 1,312-epi-teucvin 2,3 teuscorolide 3,4montanin A44) (Fig. 1). Considering this apparent lack of synthetic attention and the potential biological properties the clerodane systems offer5 the authors have independently pursued total syntheses in this area, with Ley achieving the total synthesis of ajugarin 56 and Williams exploring an ambitious 6π-electrocyclisation as a general route.7 During these pursuits both groups postulated that access to the spiro-γ-lactone sub-class might be more successful through the direct application of a Diels–Alder (DA) reaction on densely functionalised systems. Although Diels–Alder approaches to these molecules have been utilised previously2–6,8 they were applied in the early stages of the various synthetic strategies. We, however, proposed a late stage DA reaction in which most of the required functionality is delivered from a very advanced intermediate.