Organometallic Scaffolding as a Practical Approach toDiversity-Oriented Synthesis: Stereo- and RegiocontrolledSequential Functionalization of Pyranylalkylidene AllylmolybdenumComplexes Public

Abstract

Organometallic enantiomeric scaffolding is a powerful and versatile tool for enantiocontrolled bond construction. Tp(CO)2allylmolybdenum complexes of pyrans and piperidines are noteworthy examples of this approach to synthesis. A streamlined procedure for the construction of the key h3(2,3,4)-5-oxopyranyl molybdenum complex was developed, facilitating scale up, and making these scaffolds more available to the synthetic community. The key scaffold was derivatized to include an alkylidene moiety that provided new opportunities for synthesis of heterocyclic skeletons and stereochemical relationships not accessible with existing methods. An unprecedented intermolecular 1,5-Michael reaction of this substrate was evaluated for its scope and mechanism, whereby the addition of alkoxide nucleophiles to neutral allyl molybdenum complexes is apparently favorable, and likely goes through an anionic molybdenum intermediate. The products of this reaction were studied for use in a novel and general sequential functionalization protocol, whereby iterative leaving group abstraction/nucleophilic addition sequences afford highly substituted pyran architectures with divergent, yet predictable regiochemical outcomes, notably those bearing 2,6-trans and 2,2,6- functionality. Other highlights include a [5+2] cycloaddition reaction to 5,6-disubstituted pyranyl complexes, and hetero Diels-Alder reaction to form spiroketals. The full utility of the method is ultimately demonstrated by the synthesis of highly functionalized enantiomerically pure pyran rings bearing functionality equipped for further manipulations.

Table of Contents

Chapter 1: Highlights of recent developments in the synthesis of 2,6-cis and 2,6-trans substituted pyrans. Introduction to organometallic scaffolding as a means of generating highly functionalized pyran architectures

Introduction:

Reductions of Hemiketals

Hetero Diels-Alder Cycloadditions

Metal-Catalyzed Cycloetherification Reactions

Ring Opening/Cyclization onto Epoxides

Prins Cyclizations and Related Reactions

Enantiomeric Scaffolding Approach to Stereocontrolled Synthesis

Results and Discussion:

Improved Synthetic routes to 5-oxopyranyl scaffold

Conclusions:

Experimental Details:

Chapter 2: Efforts toward the synthesis of non-anomeric spiroketals using pyranylalkylidene η³-allylmolybdenum complexes

Introduction:

Spiroketals and the Anomeric Effect

Synthesis of Non-Anomeric Spiroketals

Project Design

Improved Synthetic Routes to Enone Complexes

Hetero Diels-Alder Cycloadditions

Attempts to Functionalize the 2-Position of Spiroketal Complex

Conclusions:

Experimental Procedures:

Chapter 3: The intermolecular 1,5-Michael Reaction: Mechanistic studies, and efforts toward its application to spiroketal synthesis

Introduction:

Results and Discussion:

Investigating the Scope of the Intermolecular 1,5-Michael Reaction

Synthetic Applications of the Intermolecular 1,5-Michael Reaction

Rationalizing the Ionization Selectivity

Conclusions:

Experimental Details:

Chapter 4: A highly regio- and stereoselective ionization/nucleophilic addition

sequence leading to the construction of functionalized pyrans bearing stereochemical,

substituent and skeletal diversity

Introduction:

Results and Discussion:

Investigation into INA reaction of 78

Synthetic Elaboration if INA Products to Diverse and Highly Functionalized Pyrans

Second INA Sequence to Provide Trifunctionalized Pyrans

Synthetic Elaboration and Demetalation of Products

Stereo- and Regiocontrolled Synhtesis of Functionalized Pyrans of High Enantiopurity

Conclusions:

Experimental Details:

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Mot-clé	pyran organometallic chiron diversity oriented synthesis scaffolding
Committee Chair / Thesis Advisor	Liebeskind, Lanny S, Emory University
Committee Members	McDonald, Frank, Emory University Blakey, Simon, Emory University

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