Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Matthias Brewer

Abstract

The Brewer research group has a longstanding interest in both methodology development and natural products total synthesis. More specifically, we are interested in discovering and developing unknown reactivities of highly unstable cationic intermediates, most recently vinyl diazonium salts and vinyl cations generated by the Lewis acid-mediated dehydroxylation of β-hydroxy-α-diazocarbonyl compounds. My work on developing the known reactivities of these types of compounds falls into both of the aforementioned subdisciplines of organic synthesis. The total synthesis of natural products is often regarded as an ambitious testing ground for newly developed methodologies. Based on a metal-free, annulative ring expansion/C-H insertion reaction of vinyl cations developed by our group in 2017, I designed and have been working through the total synthesis of the fusicoccane natural product Anadensin. The vinyl cation C-H insertion reaction will be the key step in forming the 5-8-5 tricyclic fusicoccane skeleton. Progress towards the synthesis of the C-H insertion precursor and the synthetic difficulties encountered therein are presented.

Vinyl diazonium salts derived from Lewis acid-mediated dehydroxylation of β-hydroxy-α-diazocarbonyls are the immediate progenitors to vinyl cations via loss of N2, but at low temperature or in the presence of milder Lewis acids these intermediates have significant enough lifetime in solution to undergo other types of reactions. It was found that the β position of these intermediates is highly electrophilic, which lead to the discovery and development of a new Mukaiyama-Michael type reaction using these diazonium salts as electrophiles and enoxysilanes as nucleophiles. This new reaction was demonstrated to be general and that a catalytic amount of Zn(OTf)2 could be used to promote the reaction. The 2-diazo-1,5-dicarbonyl products were formed in yields up to 99% and diastereomeric ratios of up to >20:1, and most importantly retain the diazo group for further manipulation. This diazo-retentive conjugate addition was unprecedented at the time of publication.

2-diazo-1,5-dicarbonyls are well-known for their ability to form carbonyl ylides under Rh(II) catalysis. These reactive dipoles can be used to form highly functionalized tetrahydrofuran products via 1,3-dipolar cycloaddition. Using the products from the conjugate addition reaction (vide supra), we were able to form a variety of complex tetrahydrofurans which contained up to 6 stereogenic centers, installed over only two synthetic steps.

Language

en

Number of Pages

301 p.

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