Utilization of a Michael Addition-Dipolar Cycloaddition Cascade Involving 2,3- bis(Phenylsulfonyl)butadiene for Alkaloid Synthesis Público

Abstract

The azaspirocyclic nucleus is a structural motif found in a wide variety of medicinally relevant natural products. A unique and operationally-simple approach to the construction of this structural subunit was developed and makes use of readily available oxime substrates and a disubstituted diene. The reaction platform represents facile entry into complex azacyclic structures, permitting rapid generation of a variety of 2,2-disubstituted piperidine derivatives.

Approaches to several natural product alkaloid targets are presented utilizing the tandem Michael Addition-Dipolar Cycloaddition Cascade. The key element of each synthesis consisted of a conjugate addition of an oxime to one of the termini of 2,3-bis(phenylsulfonyl)butadiene, followed by a proton transfer to give a nitrone intermediate. This nitrone immediately cyclizes across the tethered p-bond providing unique azaoxabicyclo[2.2.1]heptanes with diastereospecificity. The N-O bond in these systems was readily cleaved under reductive conditions to furnish functionalizable 4-piperidone subunits. Depending on the nature of the starting oxime, 4-piperidone core structures were generated which allowed for the total syntheses of ()-cylindricine C, ()-7,8-epi-perhydrohistrionicotoxin, and ()-yohimbenone. Formal syntheses of ()-desamyl-perhydrohistrionicotoxin and ()-emetine were reached through this reaction manifold, as well as an approach to halichlorine. The method's tractability is underscored by its versatility, operational ease, and its ability to employ readily available oxime inputs. A previously unreported ring-oxidation mechanism involving N-alkyl-4-piperidones is also described, as well as a novel [4+2]-cycloaddition involving an oxofuran derivative.

Table of Contents

I. INTRODUCTION

II. RESULTS AND DISCUSSION

Chapter 1. Part 1. Application to the Total Synthesis of (±)-Cylindricine C.

Introduction

Results and Discussion

First Generation Cylindricine Approach.

Epoxidation-Reduction Sequence.

Second Generation Cylindricine Approach.

Studies Dealing With the Oxidation of N-Alkyl-4-piperidones.

Final Approach to (±)-Cylindricine C

Part 2. Application of the Method toward Perhydrohistrionicotoxin (PHTx)

Part 3. Application of the Method to a Formal Syntehsis of (±)-Emetine

Part 4. Application of the Method to the Synthesis of (±)-Yohimbenone

Part 5. Use of the Cascade Method for an Approach to Halichlorine and Pinnaic Acid

Chapter 2. Studies Directed Toward an Oxofuran Diels-Alder Approach to the Morphine Skeleton

III. EXPERIMENTAL SECTION

IV. X-RAY DATA

REFERENCES

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palabra Clave	emetine oxime cylindricine perhydrohistrionicotoxin alkaloid pinnaic acid total synthesis morphine chemistry dipolar cycloaddition yohimbenone natural product synthesis halichlorine piperidine synthesis furan Diels-Alder
Committee Chair / Thesis Advisor	Padwa, Albert, Emory University
Committee Members	McDonald, Frank, Emory University Blakey, Simon, Emory University

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