Formal total synthesis of (±)-Merrilactone A and studies towards anislactones A/B

Abstract

Merrilactone A (1) and the epimeric anislactones A (2) and B (3) are sesquiterpene natural products that were first isolated from the dried pericarps of Illicium merrillianum (Fukuyama in 2000) and Illicium anisatum (Kouno in 1990), respectively. Merrilactone A (1) was identified as a potent nonpeptidal neurotrophic factor that strongly promotes neurite outgrowth in the culture of foetal rat cortical neurons and is a potential small molecule lead for the treatment of neurodegenerative disorders. Merrilactone A (1) together with 2 and 3, are highly complex cage-like structures that have established themselves as challenging and attractive targets in natural product synthesis. Presented in this research is a regiodivergent approach to both sets of natural products via the first known application of the defining transformation, an intramolecular tandem cyano-aldol cyclisation. We demonstrated an efficient route to the cyano-aldol product 303, which acted as the common intermediate to either natural product by orthogonal lactonisation sequences. This culminated in the successful synthesis of known intermediate 320, which represents the formal total synthesis of 1, and advanced tetracyclic intermediate 309, that is the full carbon skeleton of 2 and 3.