Abstract

The intramolecular styryl Diels – Alder (ISDA) reaction is a rare and unique [4+2] cycloaddition with potential in the syntheses of polycycles. Its utility is based on the formation of two rings and one stereocenter in a single step, making it an efficient method for the construction of lignan-type natural product targets. Detailed mechanistic studies with complex esters and the application to natural product synthesis has been limited due to drawbacks including the loss of aromaticity, producing slow reactivity, a potentially problematic thermal [1,3]-hydrogen shift, and electronic mismatch related to the substituents on the aryl functional groups. In this research, we found conditions that led to the successful application of the ISDA reaction on the total synthesis of the anticancer deoxypodophyllotoxin and the antiviral agent F4-4. Deoxypodophyllotoxin was synthesized in seven steps, which is a very concise synthesis for a complex lignan. Density functional theory was used to analyze the two components of the ISDA reaction, the [4+2] cycloaddition and the [1,3]-hydrogen shift. Several pathways were analyzed, and the rate determining step was determined to be the [4+2] cycloaddition. We also found that the [1,3]-hydrogen shift is assisted by di-tert-butylhydroxytoluene and is lower in energy than the [4+2] cycloaddition.The two targets chosen for this research have important biological activities. Deoxypodophyllotoxin is known as a potent anticancer agent related to podophyllotoxin. Podophyllotoxin is a more abundant lignan which is the precursor of the FDA approved drugs etoposide and teniposide, used for the treatment of lung and testicular cancer. Other biological activities of deoxypodophyllotoxin have been found including antibacterial, antiviral, and anti-inflamatory activity. Also, it was recently discovered that F4-4 possesses antiviral activities against Herpes simplex viruses 1 (HSV-1), 2(HSV-2), and H. zoster. Since both deoxypodophyllotoxin and F4-4 are not available in large quantities from natural sources, chemical synthesis is important for continuing research and drug development of these compounds.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2019-03-01

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd11131

Keywords

Intramolecular Diels-Alder, styryl, lignan, deoxypodophyllotoxin, anticancer, antiviral

Language

english

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