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Modular Synthesis of Polyketide Natural Products: Synthesis of the C9-C27 Degradation Product of Aflastatin A and Total Synthesis of Fostriecin

Robles-Resendiz, Omar (2009)
Dissertation (169 pages)
Committee Chair / Thesis Adviser: McDonald, Frank
Committee Members: Liebeskind, Lanny S ; Gallivan, Justin
Research Fields: Chemistry, Organic
Keywords: Total Synthesis; Natural Products; Polyketides; Anticancer; Antifungal; Asymmetric Synthesis
Program: Laney Graduate School, Chemistry
Permanent url: http://pid.emory.edu/ark:/25593/4sqmc

Abstract

Modular Synthesis of Polyketide Natural Products:
Synthesis of the C9-C27 Degradation Product of Aflastatin A
and Total Synthesis of Fostriecin

By
Omar Robles-Resendiz
Modular approaches for the synthesis of polyketide natural products were applied
to the synthesis of the C9-C27 degradation product of aflastatin A and the total
synthesis of fostriecin. The synthesis of the C9-C27 degradation product of
aflastatin A featured the cross-coupling of alkynes with epoxides as the key
reaction for the union of structurally complex and stereochemically rich
polypropionates. For the total synthesis of fostriecin, sequential palladium-
catalyzed Negishi cross-coupling reactions were used for the rapid access of an
advanced intermediate in gram scale. Then, regio- and stereoselective Sharpless
asymmetric dihydroxylation reaction was applied to introduce the C8 and C9
chiral centers at a late stage, providing a concise route to this type of natural
products.

Table of Contents

Table of Contents
Chapter 1, Introduction to Polyketide Natural Products…………………………….1
1.1 Introduction and Background…………………….………………………..1
1.2 Biosynthesis of Polyketides………………………………………………..4
1.3 Synthetic Approaches to Polyketides….………………………………….7
1.3.1 Aldol Reactions in Polyketide Synthesis……………………….8
1.3.2 Allylation and Crotylation Reactions in Polyketide Synthesis..9
1.3.3 Cycloaddition Reactions in Polyketide Synthesis……………11
1.3.4 Strategies to Link Large Polyketide Fragments……………...12

Chapter 2, Synthesis of the C9-C27 Degradation Product of Aflastatin A……….15
2.1 Introduction and Background…………………………………………….15
2.2 Synthetic Strategy…………………………………………………………21
2.3 Results and Discussion…………………………………………………..23
2.3.1 Initial approach to the synthesis of Module 14……………….23
2.3.2 Synthesis of Module 14………………………………………...26
2.3.3 Synthesis of Module 15a..……………………………………...29
2.3.4 Synthesis of Module 16………………………………………...30
2.3.5 Cross-Coupling of Modules 15a and 16……………………..30
2.3.6 Cross-Coupling of Modules 14 and 46……………………….32
2.3.7 Completion of the Synthesis of 13…………………………….34

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