Asymmetric de Novo Synthesis of a Cardenolide: The Total Synthesis of Sarmentogenin
Project Number1F31AT012724-01
Contact PI/Project LeaderBUCKNAM, ANDREA RACHEL
Awardee OrganizationDARTMOUTH COLLEGE
Description
Abstract Text
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.
Public Health Relevance Statement
Applicant: Andrea Bucknam
Project Narrative
Medicinal chemistry programs continue to be fueled by rapid access to classes of natural
products with demonstrated pharmaceutically-relevant biological activity, and molecularly
flexible total synthesis programs expand access to enantiomerically enriched natural products
and natural product-like compounds to broaden the investigation of their potential as
therapeutics. There are greater than 100 FDA-approved drugs which are tetracyclic triterpenoid
natural products, and yet some classes of tetracyclic triterpenoids–including cardenolides–have
yet to be investigated deeply as drug candidates despite their structural relatedness to in-use
pharmaceutical agents. The research proposed herein is an asymmetric de novo synthesis of
sarmentogenin, a cardenolide natural product utilizing a novel oxidative
dearomatization/Wagner-Meerwein rearrangement to establish a key quaternary center and
oxidation pattern characteristic of the cardenolide carbon framework in a stereospecific manner.
National Center for Complementary and Integrative Health
CFDA Code
213
DUNS Number
041027822
UEI
EB8ASJBCFER9
Project Start Date
24-July-2024
Project End Date
23-July-2026
Budget Start Date
24-July-2024
Budget End Date
23-July-2025
Project Funding Information for 2024
Total Funding
$48,974
Direct Costs
$48,974
Indirect Costs
Year
Funding IC
FY Total Cost by IC
2024
National Center for Complementary and Integrative Health
$48,974
Year
Funding IC
FY Total Cost by IC
Sub Projects
No Sub Projects information available for 1F31AT012724-01
Publications
Publications are associated with projects, but cannot be identified with any particular year of the project or fiscal year of funding. This is due to the continuous and cumulative nature of knowledge generation across the life of a project and the sometimes long and variable publishing timeline. Similarly, for multi-component projects, publications are associated with the parent core project and not with individual sub-projects.
No Publications available for 1F31AT012724-01
Patents
No Patents information available for 1F31AT012724-01
Outcomes
The Project Outcomes shown here are displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed are those of the PI and do not necessarily reflect the views of the National Institutes of Health. NIH has not endorsed the content below.
No Outcomes available for 1F31AT012724-01
Clinical Studies
No Clinical Studies information available for 1F31AT012724-01
News and More
Related News Releases
No news release information available for 1F31AT012724-01
History
No Historical information available for 1F31AT012724-01
Similar Projects
No Similar Projects information available for 1F31AT012724-01