Date of Completion

6-20-2013

Embargo Period

12-16-2013

Keywords

natural products; organic; synthesis; Diels-Alder; metathesis;

Major Advisor

Dennis L. Wright

Associate Advisor

Amy Anderson

Associate Advisor

Mark Peczuh

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The presence of a heterocyclic moiety can be observed in many of today’s bioactive natural products. One of the most commonly observed is furan, an aromatic five-membered ring containing an oxygen atom. Furan is a simple compound, yet versatile enough to be used as a synthetic synthon leading to complex structures such as the antioxidant Phelligridin G and the antibacterial agent Platensimycin. In the former, it is spiro-fused to the five-membered carbocycle of the 6-5-5 tricyclic domain while in the latter it makes up the ether-bridged cycloadduct of the hydrophobic cage. Conventionally, furan can undergo cycloadditions in the presence of reactive dienophiles via the Diels-Alder reaction to form oxabicyclic synthons.

A strategy for the synthesis of the embedded spirocyclic core of phelligridin G from a 2-phenylfuran system was developed. Finding a suitable dienophile compatible with this biphenyl ring was a daunting task; however, we successfully obtained the oxabicyclo[2.2.1]heptadiene intermediate upon surveying a plethora of available dienophiles. Exposure of the strained ring system to the Grubbs’ 2nd generation ruthenium-based catalyst facilitated a domino ring-opening metathesis/ring-closing metathesis (ROM/RCM) to give a spiroannulated furan. Further evaluation showed the highly reactive tetrachlorocyclopropene was a compatible dienophile leading to the formation of spiro-fused pyran ring structures through a related metathesis approach.

Recently, we have developed a novel and expedient route towards the tetracyclic caged domain of platensimycin using an oxabicyclo[3.2.1]octadiene building block. Within our methodology a late-stage intermediate has been established from the [4+3] cycloaddition of a substituted furan with tetrabromocyclopropene along with an intramolecular γ–alkylation to form the seco-cage of this hydrophobic region. It has been postulated that structural modifications could help improve its poor pharmacokinetic profile while retaining potent bioactivity. Utilizing this furan-based route has led to the synthesis of several novel analogues that will be evaluated for their antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). We have assembled a unique derivative in which the cyclohexanone moiety has been replaced with the more constricted cyclopentanone ring. A second series of analogues synthesized have the C-ring completely removed from the caged domain and manipulation of the ketone functionality was evaluated.

Download

Share

COinS