Synthetic Investigations Into the Diterpenoids Larikaempferic Methyl Ester and (-)-Hardwickiic Acid Open Access

Abstract

For the sake of accessing the skeletons of diterpenoid molecules for therapeutic purposes, disclosed within are the syntheses of larikaempferic methyl ester and (-)-hardwickiic acid—both of which represent the first formal synthetic efforts towards these two molecules. Larikaempferic methyl ester, bearing a unique (6,5,7) tricyclic core fashioned with an oxa-bridge and (6,5) trans-hydrindane core, was accessed through a biomimetic synthetic pathway leveraging a key oxidative cleavage of an abietic acid derivative to reach a (6,10) diketone proposed to be core to the compound’s biosynthesis. From here, a transannular aldol addition cleanly afforded our desired tricyclic core, also providing a hydroxyl- handle from which the oxa-bridge could be established through a downstream oxa-Michael addition, representing the completion of larikaempferic methyl ester in 9 steps. (-)-Hardwickiic acid is a clerodane-type diterpenoid recently found to possess potent antinociceptive properties but lacking computational investigations into its mechanism of action. To produce a suite of analogs for SAR studies and mechanistic elucidation, we have proposed a 13-step, modular synthetic approach to the clerodane scaffold aiming to replace its furan system with other aryl moieties. This work highlights the use of contemporary Ni(II)-mediated decarboxylative cross-coupling of redox-active esters and boronic acids, realizing the key Csp3-Csp2 bond formation necessary for developing an analog suite for biological testing. With 8 steps successfully confirmed to work, future studies will be performed to successfully complete the total synthesis of (-)-hardwickiic acid.

Table of Contents

Chapter 1: Larikaempferic Methyl Ester

1.1. Introduction to Larikaempferic Ester

1.2. A Solid Foundation; A Single Question

Chapter 2: (-)-Hardwickiic Acid

2.1. An Introduction to (-)-Hardwickiic Acid

2.2 Synthetic Studies toward (-)-Hardwickiic Acid

2.3. Concluding Thoughts and Future Directions

Supporting Information

I. General Information

II. Supporting Information for Larikaempferic Methyl Ester

III. Spectral Data for Larikaempferic Methyl Ester

IV. Supporting Information for (-)-Hardwickiic Acid

V. Spectral Data for (-)-Hardwickiic Acid

References

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic Chemistry, Biochemistry
Keyword	Medicinal Chemistry Total Synthesis Diterpenoids Decarboxylative Cross Coupling Natural Products
Committee Chair / Thesis Advisor	Mingji Dai, Emory University
Committee Members	Matthew Weinschenk, Emory University Richard Himes, Emory University

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