Utilization of a Michael Addition-Dipolar Cycloaddition Cascade Involving 2,3- bis(Phenylsulfonyl)butadiene for Alkaloid Synthesis Público
Flick, Andrew C (2008)
Published
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
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