Theses Doctoral

Strategies for the Synthesis of Sesquiterpene Natural Products

Eagan, James

Chapter 1. Ring-Opening Knoevenagel Strategy for the Synthesis of Alpha-Carboalkoxy Cyclopentenones and Their Use in the Diels-Alder Cycloaddition.
The Diels-Alder reaction has enabled the synthesis of hundreds of natural products efficiently and with high levels of stereocontrol. Despite over eight decades of development, this reaction is incapable of forming hydrindane ring junctions from alphahydro beta-alkyl cyclopentenones. As such, we used alpha-carboalkoxy cyclopentenones as synergistic dienophiles, but exposed a lack of synthetic tools for assembling strained bicyclic cyclopentenones. We addressed this paucity by developing a ring-opening Knoevenagel reaction for synthesizing these synergistic dienophiles with varying degrees of substitution. The 6 step protecting group free total synthesis of a structurally similar natural product merrekentrone D was achieved to demonstrate the utility of the new method. In addition, the Diels-Alder cycloaddition with these molecules with the Danishefsky-Kitahara diene were studied. The variability of the ring-opening Knoevenagel reaction also led to the development of a decarboxylative Diels-Alder cycloaddition which is degenerate with the alpha-hydro beta-alkyl cyclopentenone Diels- Alder reaction. The hydrindane structures are referred to as iso-Hajos-Parrish ketones which we subsequently demonstrate as powerful building blocks for natural product total synthesis.
Chapter 2. Synthetic Studies Towards the Shizukaol Family of Oligomeric Sesquiterpene Natural Products
The shizukaol family of oligomeric natural products are one of three oligomeric sesquiterpene families. Three different generations of synthetic strategies towards the unstable and dimeric precursor lindenatriene were studied. The use of the iso-Hajos-Parrish ketone enabled a 10 step, protecting group free, total synthesis of the intermediate. In addition the formation of unnatural dimers was achieved as well as several unexpected results which led to the generalization of our strategy to other natural product families.
Chapter 3. Iso-Hajos-Parrish Ketones: Common Intermediates for Sesquiterpene Total Syntheses
The three step synthesis of the cyclopropane substituted iso-Hajos-Parrish ketone enabled rapid access to other sesquiterpene families. Through reductase phases the total synthesis of sarcandralactone was achieved in 10 steps without the use of any protecting groups. Studies were also conducted towards achieving the trans-hydrindane ring as a synthetic equivalent to a trans-Diels-Alder paradigm, which was not realized. Additionally, cyclopropane opening of the iso-Hajos-Parrish ketone led to highly oxidized eudesmane skeletons. Our attempts to hydrogenate these molecules in the reductase phase inspired a 6 step total synthesis of des-methyl pinguisone with a strikingly different sesquiterpene framework. Finally, an analysis of redox conservation in total synthesis and the generality of this chemistry to the total synthesis of sesquiterpene natural products will be presented.


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More About This Work

Academic Units
Thesis Advisors
Snyder, Scott A.
Ph.D., Columbia University
Published Here
August 7, 2014