New syntheses of the macrocyclic bisbibenzyl natural products, riccardin D, riccardin C, polymorphatin A and an unnatural analogue; formal total syntheses of cavicularin and asterelin A

Abstract

This thesis describes total syntheses of many different macrocyclic bisbibenzyl natural products including riccardin D 1.1, riccardin C 1.2, asterelin A 1.4, cavicularin 1.5 and polymorphatin A 1.6 as well as an unnatural macrocyclic bisbibenzyl analogue 1.3.

The first approach developed a strategy for the total synthesis of riccardin D 1.1. The key fragments in the target are synthesised then connected using a Heck reaction. An intramolecular Wittig reaction is then used to achieve macrocyclisation.

The second approach provides access to many natural products in the macrocyclic bisbibenzyl family, including riccardin C 1.2, asterelin A 1.4 and cavicularin 1.5 as well as an unnatural analogue 1.3. We have synthesised and connected the key fragments of each target. To close the macrocyclic ring, we have demonstrated for the first time a new strategy involving an alkyllithium mediated displacement reaction to make the macrocycle via a Corey Seebach reaction. We have used the method to complete total syntheses of riccardin C 1.2 and an unnatural analogue 1.3. The work additionally constitutes formal total syntheses of asterelin A 1.4 and cavicularin 1.5.

The third approach provided a method to achieve the first total synthesis of polymorphatin A 1.6. A nickel-mediated cross-coupling reaction was used to effect macrocyclisation and install the strained biaryl linkage connecting its two distorted arenes.

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Identifiers

ORCID for David C. Harrowven: orcid.org/0000-0001-6730-3573

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