# Asymmetric de Novo Synthesis of a Cardenolide: The Total Synthesis of Sarmentogenin

> **NIH NIH F31** · DARTMOUTH COLLEGE · 2024 · $48,974

## Abstract

Applicant: Andrea Bucknam
Project Summary/Abstract
Natural product synthesis contributes significantly to the identification and development of
potential therapeutics. Retrosynthetic analysis of a natural product target demands innovation at
all levels of study, giving rise to the design of novel reaction technology and creative application
of established reactivity to provide access to structures with pharmaceutical potential.
Tetracyclic triterpenoid natural products present a challenging landscape for synthetic organic
chemists to explore novel chemical transformations. More than one hundred FDA-approved
drugs are tetracyclic triterpenoids. Cardenolides are a class of tetracyclic triterpenoid natural
products with many members having demonstrated medically-relevant biological activity, but
further investigation of their pharmaceutical potential is hindered by limited access to natural
sources and a lack of reported approaches to synthesis of the cardenolide carbon framework.
The research project proposed herein would report a solution to key challenges to cardenolide
synthesis—C10 and C13 quaternary centers, C14 tertiary alcohol, and C17 substitution (steroid
numbering)—thus establishing an asymmetric de novo synthesis of a cardenolide natural
product, sarmentogenin. A novel oxidative dearomatization/Wagner-Meerwein rearrangement,
in which a 1,2-methyl shift from C9 to C10 would establish the quaternary center at C10 and
oxidation in the C-ring. This synthesis would be an application of a recently reported
methodology from the Micalizio group to install C17 substitution, a historically significant
challenge to completing the total synthesis of cardenolide natural products. The long-term
success of the project proposed herein would be a report of a cardenolide total synthesis,
paving the way for future investigations of pharmaceutically-relevant cardenolide bioactivity. The
fellowship award would support continued graduate research and training in the Micalizio
laboratory at Dartmouth College. The Micalizio group has a well-established program for
developing novel reaction technology to concisely synthesize complex natural product targets.
The research supported by the award would take place in an established organic synthesis
laboratory with all necessary equipment for the preparation, purification, and characterization of
organic compounds.

## Key facts

- **NIH application ID:** 10825062
- **Project number:** 1F31AT012724-01
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Andrea Rachel Bucknam
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-24 → 2026-07-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825062

## Citation

> US National Institutes of Health, RePORTER application 10825062, Asymmetric de Novo Synthesis of a Cardenolide: The Total Synthesis of Sarmentogenin (1F31AT012724-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10825062. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*