Please use this identifier to cite or link to this item: http://hdl.handle.net/10125/51108

Synthetic Methods Inspired by Terpenoid Natural Products

File Description Size Format  
2015-08-phd-lewis r.pdf Version for non-UH users. Copying/Printing is not permitted 20.7 MB Adobe PDF View/Open
2015-08-phd-lewis uh.pdf For UH users only 20.8 MB Adobe PDF View/Open

Item Summary

Title:Synthetic Methods Inspired by Terpenoid Natural Products
Authors:Lewis, Robert
Date Issued:Aug 2015
Publisher:[Honolulu] : [University of Hawaii at Manoa], [August 2015]
Abstract:Terpenes are a large family of natural compounds derived from linked isoprene subunits. Steroids, flavorings, fragrances, and a large number of pharmaceuticals are either terpenes or have a terpene component. The research presented in this thesis arose from approaches to terpenoids containing seven-membered rings
We attempted to directly synthesize seven-membered rings via a [5+2] cycloaddition between pentadienyl ketones and alkenes to provide cycloheptanones. This conceptual cycloaddition shared symmetry elements with the [3+2] dipolar cycloaddition and the [4+2] Diels-Alder cycloaddition. Two substrate classes expected to participate in [5+2] cycloadditions were synthesized. Unfortunately, the anticipated cycloaddition did not occur under several screened Lewis-Acidic conditions.
The natural products psiguadial A and premnalatifolin A inspired us to exploit ortho-quinone methides (o-QMs) to generate their central heptacycles. o-QMs are extremely reactive intermediates that are often difficult to control, and there are few examples of the addition of highly basic enolates to o-QMs. We reasoned that an enolate and an o-QM could both be generated by treatment of a mixture of a silyl enol ether or silyl ketene acetal and an O-silylated phenoxy benzyl halide with anhydrous fluoride, resulting in the simultaneous generation and coupling of an enolate nucleophile and electrophilic o-QM. The reactive nature of the o-QMs facilitated the formation of sterically congested carbon–carbon bonds that are otherwise difficult to generate using conventional enolate alkylation. Our protocol generates ketone or ester enolates and o-QMs in situ in a single flask, which join to give a variety of -(2-hydroxyphenyl)-carbonyl compounds in a single step. The resulting functionalized phenols are common building blocks in natural product synthesis. This method provides the foundation for construction of psiguadial A and premnalatifolin A.
During our attempts to harness aza-ortho-xylylenes in a system analogous to o-QMs, we encountered and developed a system for the functionalization of anilines. Aniline and aminophenol structures constitute a useful family of synthetic building blocks, ligands and catalyst frameworks, and are a part of many biologically-active compounds and natural products. Despite the importance of these substructures, methods that allow direct access to these classes of compounds are rare. We developed an efficient process to generate functionalized anilines utilizing metal-free conditions and easily accessable reagents. Our process displays some generality in both aniline and acitvating agent. These C–O, C–C, and C–N bond formations are facilitated by an increase in oxidation level from aniline to aniline-N-oxide, conveniently generated by treating the corresponding anilines with mCPBA. Following an O-acylation event, group transfer from nitrogen to carbon excises the weak N–O bond and gives an iminium ion, and after loss of a proton, aromaticity and electron density at nitrogen are restored. These bond formations proceed in seconds to minutes at low temperature, in an effecient and convieneient manner.
As part of our broader research program with N,N-dialkylaniline-N-oxides, we exploited an observed Polonovski-type reactivity by capturing a putative iminium ion prior to carbon atom loss. N,N-dimethylanilines containing an ortho-nucleophilic function, installed previously using our aniline functionalization, are transformed into N-methylindolines via the corresponding N,N-dimethylaniline-N-oxides.
The first terpenoid target, psiguadial A, features three fused rings in a 7-5-7 arrangement, with both seven member rings heavily substituted. This compound possesses remarkable cytotoxicity, inhibiting the growth of HepG2 cells (IC50 = 61.07 ± 1.77 nM). We envisioned joining a complex enol ether to an o-QM utilizing our coupling conditions, followed by an oxa-Michael ring-closing. We have accomplished this assembly with a model system, and are now targeting the natural product.
The second terpenoid, premnalatifolin A, displays considerable activity against the MCF-7 line of human breast cancer cells, with an (IC50 = 1.77 μM) compared to the activity of doxorubicin (IC50 = 3.67 μM). The potent activity and novel dimeric structure attracted our interest. To construct each monomer utilizing our o-QM method, we envisioned a simple retrosynthesis that disconnects the cycloheptene central ring into two halves of comparable complexity. We imagined a metathesis event sealing the cycloheptene after initial alkylation of the o-QM, where our diastereoselectivity is derived from alkylation by the less hindered face of the enolate. Initial studies of the o-QM enolate coupling to prepare models of the icetexane core are underway.
Description:Ph.D. University of Hawaii at Manoa 2015.
Includes bibliographical references.
URI:http://hdl.handle.net/10125/51108
Appears in Collections: Ph.D. - Chemistry


Please email libraryada-l@lists.hawaii.edu if you need this content in ADA-compliant format.

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