Total Synthesis and Target Identification of Pestalachloride B to Facilitate Antibiotic Development Open Access

Abstract

Antibacterial natural products are proven to be valuable tools for discovering new bacterial targets and can therefore promote the development of antibiotics with novel mechanism of actions. The pestalachorides A-C were originally isolated from Pestalotiopsis adusta in 2008 and demonstrated antimicrobial activities against plant pathogens. Among them, pestalachloride B has demonstrated remarkably low toxicity against human cells while retaining promising antibacterial activity towards S. aureus and E. faecalis, with minimum inhibitory concentrations of 1.25 ug/mL and 5 ug/mL respectively. Such a discovery suggests pestalachloride B’s potential as a chemical probe for identifying a novel intracellular bacterial target. The use of affinity-based protein profiling can be facilitated by employing the inherently photoreactive benzophenone moiety. The goal of this project is to synthesize pestalachloride B and elucidate its bacterial targets. A convergent synthetic route was designed to access pestalachloride B. Different hydroxyl protecting groups were explored and MOM was found to give the highest yield during the key fragment coupling step. Optimization of a late-stage prenylation was performed. Future work aims to finish the natural product synthesis, expand upon the known biological activity of the natural product, prepare a series of alkynylated probes, and elucidate interactions with proteins using affinity-based protein profiling. 

Table of Contents

Table of Contents

Section 1: The crisis of antibacterial resistance and discovery of novel bacterial targets guided by natural products. 2

1.1 Background: The crisis of antimicrobial resistance 2

1.2 Discovery of bacterial targets guided by natural products. 3

1.3 Novel strategy for target identification: Affinity-based protein profiling 4

Section 2: Total Synthesis of Pestalachloride B 8

2.1 Isolation and Evaluation of the pestalachloride natural products 8

2.2 Retrosynthetic Analysis 9

2.3 Construction of the eastern and western fragments 11

2.3.1 Synthesis of the wester fragment (fragment A) 11

2.3.2 Synthesis of the eastern fragment (fragment B) 14

2.4 Nucleophilic addition and oxidation of the two aromatic fragments 14

2.5 Prenylation on the aromatic ring A 15

2.6 Installation of a hydroxymethyl functionality on aromatic ring A 17

Section 3: Future Directions 20

3.1 Final synthesis of pestalachloride B 20

3.2 Biological Evaluation of Pestalachloride B 20

3.3 Target Identification 21

Section 4: Discussion 22

Section 5: Supporting Information 23

5.1 General information 23

5.2 Experimental Procedures 23

5.3 Characterization Data 38

5.3.1 1H NMR Spectra 38

5.3.2 X-ray crystal structure 47

Reference 48

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Medicinal Chemistry Natural Product Total Synthesis
Committee Chair / Thesis Advisor	William Wuest, Emory University
Committee Members	Matthew Weinschenk, Emory University Mingji Dai, Emory University

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