Skip navigation
Please use this identifier to cite or link to this item:
Title: The Evolution of a Strategy for the Total Synthesis of Hirsutellone B
Authors: Reber, Keith Paul
Advisors: Sorensen, Erik J
Contributors: Chemistry Department
Keywords: acylketene
natural product
total synthesis
Subjects: Organic chemistry
Issue Date: 2012
Publisher: Princeton, NJ : Princeton University
Abstract: The hirsutellone family of natural products consists of six bioactive polyketides that were isolated from an insect pathogenic fungus in 2005. The intriguing polycyclic structures of the hirsutellones feature a strained 12 or 13-membered paracyclophane aryl ether and a trans-fused decahydrofluorene ring system with seven contiguous stereocenters. The degree of structural complexity exhibited by these natural products combined with their reported antitubercular activity make the hirsutellones attractive targets for total synthesis. Our original strategy towards hirsutellone B was inspired by the proposed biosynthetic hypothesis and featured a cascade of cyclizations. Although we synthesized a model system to test the key hetero-Michael / SNi' / IMDA cascade, we were unable to form the desired cyclophane-containing product. An alternative approach to hirsutellone B featured a key dioxinone intermediate that would enable a tandem intramolecular acylketene trapping / IMDA cascade. Our initial model system incorporated solvolytic capture of the acylketene intermediate to rapidly produce the decahydrofluorene core of hirsutellone B. We were later able to achieve the full tandem reaction sequence, forming three rings, three bonds, and four contiguous stereocenters in a single step. The advanced macrolactam and macrolactone intermediates produced via this sequence possess most key features of the hirsutellone framework, including the challenging cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were unsuccessful due to competing O-alkylation.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

Files in This Item:
File Description SizeFormat 
Reber_princeton_0181D_10306.pdf20.93 MBAdobe PDFView/Download

Items in Dataspace are protected by copyright, with all rights reserved, unless otherwise indicated.