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Synthesis of Cyclobutane-Containing Natural Products using Macrocyclic 1,4-Diketones as Templates for Diastereoselective Transformations and Strained Carbon-Carbon Bond Formation, and the Development of Novel Non-Phosphate Carbohydrate-Based Inhibitors of the IspH-Enzyme in Isoprene Synthesis




Barnes, Timothy

Type of Degree

PhD Dissertation


Chemistry and Biochemistry

Restriction Status


Restriction Type

Auburn University Users

Date Available



Chapter 1: Macrocyclic control as a tool for diastereoselective transformation has been an area of research dating back to Still’s total synthesis of periplanone B. The exact source of this control is not always well understood, but often offers profound diastereomeric control in comparison to similar acyclic homologs. This chapter aims to discuss historically relevant transformations aided by a macrocyclic structure, and then our investigation of diastereoselective enolate alkylations on macrocyclic 1,4-diketones. This structural motif, when embedded with the framework of [n.4]metacyclophanes, has been found to be a powerful tool for diastereoselective transformations en route toward complex molecule synthesis. Chapter 2: Cyclobutane containing natural products are a challenging class of molecules for chemical synthesis and approaches towards construction of this motif has been dominated by the [2+2] cycloaddition. Undoubtably, this is the most economical route towards their synthesis, but introduction of suitable olefin partners for cycloaddition is not always possible. Herein, we have utilized a transannular McMurry reaction of various functionalized macrocyclic 1,4-diketones for the synthesis of cyclobutane containing lignans and their analogs. This method is the only method for synthesis of cyclobutane lignans that is not reliant on the [2+2] cycloaddition strategy. Chapter 3: The classical approach towards inhibitors of enzymes found in isoprene synthesis has focused on the use of highly charged phosphate-based inhibitors. These inhibitors generally mimic one or several structural nuances of key substrates from the enzymatic pathway. These inhibitors often require the use of transport enzymes. Herein, a series of non-phosphate carbohydrate-based inhibitors have been synthesized and effectiveness evaluated.