Total Synthesis of Larikaempferic Acid Methyl Ester Restricted; Files Only

Abstract

Presented here is the comprehensive total synthesis of larikaempferic acid methyl ester, an abietane diterpene that was initially isolated in 1999 from the leaves of Larix kaempferi by Reiko Tanaka. Renowned for its anti-tumor properties and complex structural attributes, including an oxabicyclo[3.2.1]octane bridge system, a trans-hydrindane ring system, and six stereocenters, larikaempferic acid methyl ester stands as a compelling target for synthetic pursuits.

The initial segment of this study delves deeply into the strategic application of transannular aldol reactions in synthesizing diverse natural products. It also highlights the pivotal role and methodologies developed by research groups to facilitate the formation of oxabicyclic ring systems within total synthesis endeavors. Both aspects represent significant contributions to the construction of intricate molecular architectures, underscoring their importance in the realm of synthetic organic chemistry.

In the subsequent section, we outline our endeavors toward the total synthesis of larikaempferic acid methyl ester through the skeletal rearrangement of abietic acid. This synthetic route involves a chelation control transannular aldol addition, leading to the establishment of the trans-hydrindane ring system and two new stereocenters, along with an oxa-Michael addition to construct the oxabicyclo[3.2.1]octane bridge system.

Table of Contents

LIST OF TABLES. iv

LIST OF FIGURES. v

LIST OF SCHEMES. vi

CHAPTER 1. TRANSANNULAR ALDOL AND OXA-BRIDGE SYNTHETIC STRATEGIES. 1

1.1 Transannular Aldol Reaction. 1

1.2 Application of Transannular Aldol Reactions in Total Synthesis. 9

1.3 Oxabicyclo[3.2.1]Octane Bridge Systems in Natural Products. 20

1.4 Cortistatin Natural Products. 21

1.5 Cortistatin A – Oxabridge Synthesis. 22

1.6 Englerin Natural Products. 26

1.7 Englerin A – Oxabridge Synthesis. 27

1.8 Platensimycin Natural Products. 34

1.9 Platensimycin Oxabridge Synthetic Strategy. 35

1.10 Miscellaneous Oxabridge Synthetic Strategies. 42

1.11 Conclusion. 44

CHAPTER 2. TOTAL SYNTHESIS OF LARIKAEMPFERIC ACID METHYL ESTER.. 45

2.1 Larikaempferic Acid Isolation and Biosynthetic Pathway. 47

2.2 Results and Discussion. 50

2.2.1 Possible Challenges in Our Synthetic Approach. 51

2.2.2 Forward Synthesis. 53

2.3 Conclusion. 69

2.4 Completed Synthesis. 70

2.5 Experimental Data. 71

REFERENCES. 99

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Mot-clé	Total Synthesis, Chelation Control, Organic Synthesis, Skeletal Rearrangement
Committee Chair / Thesis Advisor	Mingji Dai, Emory University
Committee Members	Huw Davies, Emory University Frank McDonald, Emory University

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