Development of a Convergent Fragment Coupling Strategy Toward Grayanane Diterpenoids: Enantioselective Synthesis of (+)-Auriculatol A

Author: Thompson, Jordan Kenji

Year: 2026

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Stoltz, Brian M.; Peters, Jonas C.; Fu, Gregory C.; Reisman, Sarah E.

Option: Chemistry

DOI: 10.7907/8sth-7196

Abstract

Total synthesis is a cornerstone of organic chemistry, serving not only as a demonstration of synthetic strategy and innovation but also as a gateway to accessing biologically active natural products that are often scarce or inaccessible from natural sources. Among such natural products, the grayanane diterpenoids represent a structurally complex and medicinally intriguing family of compounds. These molecules, first identified as the active agents in “mad honey,” have a rich history of traditional use and a modern resurgence in medicinal interest due to their activity as sodium channel modulators, carbonic anhydrase inhibitors, and potential analgesics. Grayanotoxin III, in particular, exhibits great pain-relieving properties, positioning it and its analogs as compelling targets for chemical synthesis. Despite their early isolation and full structural elucidation by the early 1960s, the grayananes remain difficult to access in the realm of total synthesis, a testament to their dense stereochemical architecture and unusual [5-7-6-5] fused tetracyclic core.

This work explores synthetic strategies toward the construction of these challenging natural products, with the aim of enabling broader access to their biological potential and deepening our understanding of chemical tools to use in their synthesis. This work introduces complex bond-forming strategies and methods development, with a particular emphasis on nickel catalysis to advance the total synthesis of grayanane diterpenoids. A convergent approach was designed to maximize efficiency at each stage, beginning with the development of a model system to rapidly evaluate γ-functionalization strategies of butenolides or masked butenolide equivalents using siloxyfuran intermediates as a polarity reversal tactic. Key advances include the synthesis of a 5,5-fused butenolide fragment and the discovery and optimization of a unique vinylogous Mukaiyama aldol reaction. Early studies on the diastereoselective 1,4-reduction of butenolides and the development of a nickel-catalyzed α-enolate arylation reaction are highlighted. Subsequent chapters explore the construction of the 3.2.1 bicycle through a range of innovative transformations, including a Snider radical cascade, palladium-catalyzed decarboxylative Tsuji-Stoltz allylation, and a nickel catalyzed intramolecular carbonyl 1,2-addition. The result of these efforts is a rapid fragment coupling strategy that enables access to the pentacyclic core of auriculatol A through the use of a nickel catalyzed α-enolate alkenylation reaction using a unique olefin-supported nickel catalyst. In addition to discovering that low-valent olefin-supported nickel catalysts are privileged for α-enolate arylation and alkenylation, an unexpected 6-membered ring-containing side product was isolated in these reactions, which could have unique mechanistic implications in the area of dehydrogenative catalysis. To follow, detailed investigations into late-stage olefin functionalization and hydrogenation ultimately culminate in the first synthesis of (+)- auriculatol A along with its epimer (+)-9-epi-auriculatol A. Collectively, these studies offer a blueprint for future synthetic approaches to the broader grayanane diterpenoid family and stand as a hallmark achievement for the synthesis of grayanane natural products containing an embedded e ring in an uncommon pentacyclic scaffold.

Files