Total Synthesis of (+)-Anhydrohavellockate and the Tetracyclic Core of Cembranoid Natural Products

Abstract

Polycyclic cembranoid and norcembranoid natural products are congested, highly oxygenated natural products found in multiple marine sponges, and as of today, their synthesis remains a significant challenge for organic chemists. As well as being of great interest to biologists and medicinal chemists for their interesting medicinal applications, these natural products can certainly pique curiosity for the curious synthetic chemist seeking a challenge. In that optic, havellockate, one of the most complex members of this family of natural products, was chosen for the target of this research thesis.

We herein report a highly efficient enantioselective gram-scale synthesis of the tetracyclic core of (+)-havellockate as well as the total synthesis of (+)-anhydrohavellockate. The chemistry developed in this thesis can also be applied to the divergent synthesis of other higher order cembranoid and norcembranoid natural products such as mandapamate, confertdiate, dissectolide and plumarellide. Stemming off of the Barriault laboratory's expertise in gold catalysis, an initial racemic model substrate was targeted, seeking to construct a simplified version of the tetracyclic core of these natural products. The initial hypothesis was to build a linear fragment that would react multiple times with itself in a stereocontrolled manner upon treatment with an AuI catalyst. During the assembly of this linear fragment, the desired tetracyclic core target could be isolated, a serendipitous discovery that skyrocketed the efficiency of this synthesis.

Upon this discovery, an enantioselective synthesis of this tetracyclic structure was initiated, and after much optimisation, the enantiopure polycyclic structure could be accessed in a stereocontrolled manner. A linear substrate was assembled, and when exposed to Sonogashira cross-coupling conditions, a spectacular reaction cascade was observed. This cascade was thoroughly studied and underwent five chemical transformations in a single pot, which generated the tetracyclic core of the natural product havellockate in a single operation. This chemistry was developed to be applied on gram-scale and furnished plenty of material for the required late-stage transformations.

The last two transformations required to access the natural product, however, proved challenging, and multiple strategies were explored. Multiple protocols for the required penultimate alkene isomerisation were developed and ultimately succeeded, yielding the product (+)-anhydrohavellockate in 11 steps in the longest linear sequence from commercially-available TMS acetylene. The installation of the last oxygen atom, however, resisted all of our efforts, so far.

In total, this work sums of five years of efforts, where we studied a spectacular reaction cascade that stereoselectively constructed the tetracyclic core of the natural product (+)-havellockate through 5 distinctive steps that were carefully choreographed by clever chemical design and rationale. This work effectively achieved the enantioselective total synthesis of (+)-anhydrohavellockate in 11 steps from commercial reagents.