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I. Organometallic Enantiomeric Scaffolding: Total Synthesis of (-)-Adaline and (-)-Adalinine Using a Key 5-Oxo-Pyridinyl Molybdenum Scaffold and Featuring a Semipinacol Rearrangment/1,5-"Michael-like" Sequence.

II. Exchange Reactions of 1-Alkoxy and 1-Sulfonyloxy 3-Allyl Molybdenum Complexes

Coombs, Thomas Charles (2008)
Dissertation (371 pages)
Committee Chair / Thesis Adviser: Liebeskind, Lanny S
Committee Members: MacBeth, Cora ; Menger, Fred M
Research Fields: Chemistry, Organic
Keywords: Exchange; Aza-Achmatowicz; Homotropane; Quaternary; 1,5-Michael-like; Adalinine; Adaline; Semipinacol; Scaffold; Chiron; Organometallic
Program: Laney Graduate School, Chemistry
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A short, practical route to a versatile 5-oxo-(-2,3,4)-allylmolybdenum pyridinyl scaffold has been developed using the aza-Achmatowicz rearrangement. This route features a one-pot rearrangement/metalation protocol, eliminating the need for purification of sensitive intermediates, and enabling the easy synthesis of multi-gram quantities of the scaffold in a timely manner. The protocol has been extended to chiral non-racemic substrates, providing improved access to both enantiomers of this complex in high enantiomeric excesses. A new variant of the semipinacol rearrangement was investigated utilizing allylic alcohols available in three steps from 5-oxo-(-2,3,4)-allylmolybdenum pyranyl and pyridinyl organometallic enantiomeric scaffolds. The protic acid-induced semipinacol rearrangement itself occured with complete diastereoselectivity under mild conditions and required a full equivalent of HCl. Off-ring stereocenters were efficiently generated using electrophilic halogen sources to initiate the rearrangement. The major diastereomer in each case resulted from addition to the alkene syn to the TpMo(CO)2 fragment, suggesting participation of the metal in this rearrangment. Solvent choice was especially important in these reactions to achieve synthetically-useful diastereoselectivities at the off-ring site. Asymmetric syntheses of (-)-adaline and (-)-adalinine were carried out using the enantiomerically-enriched 5-oxo-(-2,3,4)-allylmolybdenum pyridinyl complex. The synthesis of (-)-adalinine highlighted the utility of the semipinacol rearrangement for the stereocontrolled construction of quaternary centers, and also employed an oxidative demetalation protocol previously developed by the Liebeskind group to install the lactam carbonyl found in the natural product. The synthesis of (-)-adaline showcased the power of coupling the semipinacol rearrangement and 1,5-Michael-like reaction to access quaternary center-bearing bicyclic compounds. A family of related 1-alkoxy and 1-sulfonyloxy-3-allylmolybdenum complexes were shown to undergo a series of exchange reactions with external amines and alcohol nucleophiles. Alkoxy complexes reacted directly with amines, but required the participation of a Lewis acid catalyst to undergo substitution with alcohols. Sulfonyloxy complexes reacted directly with both amines and alcohols in the absence of any catalyst. In all cases, optically-active starting materials racemized when subjected to exchange conditions, suggesting that this family of reactions proceeds via carbene intermediates. Additionally, 5-oxo-pyranyl complex 1.6 was found to undergo rapid ring-opening amination reactions with both primary and secondary amines, suffering only small loss in enantiomeric purity.

Table of Contents

Chapter One. Development of an Improved Route to a Key 5-Oxo-Pyridinyl Organometallic Enantiomeric Scaffold


Development of Organometallic Enantiomeric Scaffolds

The Aza-Achmatowicz Reaction: Background and Application

Results and Discussion

Experimental Section

General Methods

Chapter Two. Semipinacol Rearrangement of TpMo(CO)2-Based Allylic Alcohols



Results and Discussion

Experimental Section

Crystal Structure Analyses

Chapter Three. Total Synthesis of (-)-Adaline and (-)-Adalinine


Early Work on Homotropanes: Pseudopelletierine

Isolation and Biosynthetic Studies: (+)-Euphococcinine, (-)-Adaline, and (-)-Adalinine

Racemic Approaches to Adaline and Euphococcinine

Asymmetric Syntheses of (-)-Adaline and (+)-Euphococcinine

Racemic Approaches to Adalinine

Asymmetric Syntheses of (-)-Adaline


Results and Discussion

Synthesis of Common Intermediate

Synthesis of (-)-Adaline

Model 1,5-Michael Study

Continuing Towards (-)-Adaline

Synthesis of (-)-Adalinine

Experimental Section

Crystal Structure Analysis

Chapter Four. Novel Substitutions of 1-Alkoxy- and 1-Sulfonyloxy-η3-Allylmolybdenum Complexes: Mechanism, Scope, and Limitations


Results and Discussion

Substrate Synthesis

Direct Exchange of Alkoxy Substitutents with Amines

Lewis Acid-Catalyzed Exchange of Alkoxy Substituents with Alcohols

Direct Exchange of Sulfonate Esters with Amines and Alcohols

Accessing Chiral, Non-racemic Complexes

Exchange Reactions with Chiral, Non-racemic Substrates

Mechanistic Rationale

Ring-opening Amination of TpMo(CO)2 5-Oxo-pyranyl Complex

Experimental Section

Crystal Structure Analyses


application/pdf Dissertation/Thesis 371 pages (6.4 MB) [Access copy of Dissertation/Thesis]
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