PROJECT SUMMARY The grayanane diterpenoids are a class of structurally complex natural products that have compelling biological activity but are challenging to synthesize de novo in the laboratory. The unique structural features of the grayananes isolated from nature have inspired numerous studies in pharmacological laboratories, ultimately leading to diverse bioactivity being uncovered. In one recent notable example, several grayananes were identified as potent carbonic anhydrase inhibitors (CAIs). Several FDA-approved drugs that target various human diseases are CAIs, with some being included as entries in the World Health Organization's List of Essential Medicines. Additionally, grayanane natural products have also shown anti-HIV, anti-microbial, and immunomodulatory activity. These biological results point toward opportunities to develop grayanane-based therapeutic agents that span diverse disease areas. However, to accomplish these studies, the development of convergent total synthesis routes that allow organic chemists to rapidly synthesize structural derivatives is necessary. Perhaps reflective of their stereochemical complexity and tricyclic fused [5-7-6] carbocyclic skeleton, reports of completed total syntheses of grayanane targets are rare. Moreover, the majority of completed syntheses focus on building each ring one at a time, preventing the rapid synthesis of synthetic congeners to probe further into biological activity and mechanisms of action. We envisioned a general convergent route toward the assembly of the central seven-membered ring by uniting the two rapidly-prepared perimeter rings through two sequential coupling reactions. In this proposal, we apply this strategy to the first total synthesis of a recently isolated grayanane natural product, Auriculatol A. In the first key step, we propose a chemoselective α-arylation reaction between a silyl enolate on the five-membered ring unit and the triflate group of a 1-bromo-2-triflyl arene. Then, a second intramolecular coupling reaction between the remaining aryl bromide and an epoxide to establish the central cycloheptane ring is proposed. In total, this proposal aims to establish an expedient route to synthesize the challenging core of Auriculatol A, as well as provide a template for synthesizing structural derivatives. The successful development of this strategy would facilitate further studies into the biological mechanism of action of the grayananes, as well as potentially uncover new, diverse bioactivity.