Total synthesis of (-)-colombiasin A and (-)-elisapterosin B and the discovery of new thermal cyclobutenone rearrangements

Abstract

This thesis concerns the total synthesis of the natural products (-)-colombiasin A and (-)-elisapterosin B, isolated from the Caribbean sea whip, Pseudopterogorgia elisabethae. These marine diterpenes have displayed interesting biological activity, with both being potent inhibitors of Mycobacterium tuberculosis H37Rv. Indeed, (-)-elisapterosin B has also shown strong antiplasmodial activity against Plasmodium falciparum, the parasite responsible for the most severe forms of malaria.

The fascinating molecular architecture of (-)-colombiasin A and (-)-elisapterosin B has made them attractive and challenging targets for the synthetic organic chemist. Previous synthetic approaches to both natural products are reviewed in Chapter 1.

Our own total synthesis of (-)-colombiasin A and (-)-elisapterosin B is described in Chapter 2. A key feature of our approach is the use of a Moore rearrangement to set up intramolecular [4 + 2] and [5 + 2] cycloaddition to assemble the tetracyclic carbon skeletons.

Studies towards ‘second generation’ syntheses of (-)-colombiasin A and (-)-elisapterosin B (Chapter 3), unearth a new thermal rearrangement of vinylcyclobutenones leading to spirocycles. Further investigation reveals four new rearrangements of cyclobutenones that can be used to access a variety of carbocyclic ring systems (Chapter 4). Work on the regioselectivity of carbanion addition to a cyclobutendione, and studies towards (+)-elisabethin A are also described (Chapter 5).

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