# A Convergent Approach to the Synthesis of Auriculatol A

> **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2021 · $65,610

## Abstract

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.

## Key facts

- **NIH application ID:** 10148521
- **Project number:** 1F32GM139396-01A1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Conner Micheal Farley
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,610
- **Award type:** 1
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148521

## Citation

> US National Institutes of Health, RePORTER application 10148521, A Convergent Approach to the Synthesis of Auriculatol A (1F32GM139396-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10148521. Licensed CC0.

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