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Organometallic Enantiomeric Scaffolds in the Synthesis of Alkaloids: I. Homo-SN2´-like Reaction/Annulative Demetallation and the Application in the Synthesis of (+)-Isofebrifugine II. Uncatalyzed Electrophilic C-C Bond Forming Reactions of Pyranyl and Pyridinyl Molybdenum Complexes

Chen, Wenyong (2010)
Dissertation (236 pages)
Committee Chair / Thesis Adviser: Liebeskind, Lanny S
Committee Members: Liotta, Dennis C ; Blakey, Simon
Research Fields: Chemistry, Organic
Keywords: organometallic; enantiomeric scaffold; synthesis of alkaloids
Program: Laney Graduate School, Chemistry
Permanent url: http://pid.emory.edu/ark:/25593/8k0ks

Abstract


Chapter One A novel homo-SN2'-like reaction between neutral TpMo(CO)2(5-acyloxy-
η3-pyranyl) and TpMo(CO)2(5-acyloxy-η3-pyridinyl) scaffolds and a variety of
stabilized carbonanion nucleophiles provided a powerful methodology to construct C-C
bonds stereoselectively. Moreover, it proceeded through an interesting anionic
mechanism and preliminary mechanistic study was reported. Based on the Mo complex
produced in the reaction, a mechanistically related annulative demetallation was
developed to furnish the framework of 2,7-dioxabicyclo[4.3.0]nonane and 2-aza-7-
oxabicyclo[4.3.0]nonane in good to excellent yields. In order to demonstrate the power of
this new reaction sequence, (+)-isofebrifugine was synthesized in a concise route by
employing the homo-SN2'-like-annulative demetallation sequence.
Chapter Two Neutral TpMo(CO)2(5-trifluoroacetate-η3-pyranyl) and TpMo(CO)2(5-
trifluoroacetate-η3-pyridinyl) scaffolds underwent an uncatalyzed Friedel-Crafts-like
reaction with a variety of electron-rich arenes and olefins to form substitution products in
high yields. A preliminary study of the mechanism showed that TpMo(CO)2(5-
trifluoroacetate-η3-pyranyl) in DMSO rapidly rearranged to TpMo(CO)2(2-
trifluoroacetate-η3-pyranyl) complex first, which then reacted with indole derivatives. By
contrast, TpMo(CO)2(5-trifluoroacetate-η3-pyranyl) in acetonitrile or chloroform reacted
with electron-rich arenes and olefins without the initial rearrangement. And, silyl enol
ethers and allylsilanes could only react with the unrearranged TpMo(CO)2(5-
trifluoroacetate-η3-pyranyl) complex. Further annulative demetallation proved to be
successful with a series of substrates to form oxygen heterocycles and carbocycles in 5 or
6 membered rings in a mild condition. This methodology has been successfully utilized to
access the tetracyclic structure of vindoline in a model system.
Chapter Three A short, practical route to a versatile 5-oxo-4-methyl-(η-2,3,4)-
allylmolybdenum pyranyl and 5-oxo-4-methyl-(η-2,3,4)-allylmolybdenum pyridinyl
scaffold has been developed using the Achmatowicz rearrangement. Further
transformation through reduction and dehydration enabled a rapid access to Δ5-4-methyl-
(η-2,3,4)-allylmolybdenum pyridinyl scaffold.

Table of Contents

Contents
Chapter One The Development of Homo-SN2´-like Reaction/Annulative Demetallation
and the Application in the Synthesis of (+)-Isofebrifugine ................................................ 1
Background..................................................................................................................... 2
Palladium catalyzed allylic substitution ...................................................................... 2
Molybdenum catalyzed asymmetric allylic substitution ............................................. 5
Iridium catalyzed asymmetric allylic substitution..................................................... 10
Introduction ................................................................................................................... 16
Results and Discussion .................................................................................................. 17
Initial studies and project design ............................................................................... 17
Homo-SN2´-like reaction ........................................................................................... 21
Mechanistic consideration ......................................................................................... 31
An important side reation: ring opening.................................................................... 35
Demetallation............................................................................................................. 37
Total synthesis of (+)-isofebrifugine ......................................................................... 44
Conclusion..................................................................................................................... 54
References ..................................................................................................................... 55
Experimental Section..................................................................................................... 56
Chapter Two Uncatalyzed Electrophilic C-C Bond Forming Reactions of Pyranyl and
Pyridinyl Molybdenum Complexes. A synthetic Tactic for the Enantioselective
Construction of Indole Alkaloids.................................................................................... 102
Background.................................................................................................................. 103
Stoichiometric transition metal mediated electrophilic reactions............................ 103
Cobalt Complex....................................................................................................... 103
Iron Complex........................................................................................................... 105
Molybdenum complex............................................................................................. 108
Introduction ................................................................................................................. 111
Results and discussion................................................................................................. 113
Study in the typical Homo-SN2´-like reaction condition......................................... 113
Preparation of new substrate and discovery of an uncatalyed Friedel-Crafts reaction
................................................................................................................................ 115
Mechanistic consideration ....................................................................................... 117
Uncatalyed Friedel-Crafts reaction in pyridinyl molybdenum scaffold.................. 121
Studies on various indole derivatives..............................................................125

Uncatalyzed Friedel-Crafts reaction with electron-rich olefins .............................. 130
Demetallation........................................................................................................... 134
Application to the synthesis of natural products ..................................................... 138
Conclusion................................................................................................................... 142
References ................................................................................................................... 143
Experimental Section................................................................................................... 145
Chapter Three Synthesis of 4-Methyl Substituted Pyranyl and Pyridinyl Scaffold..... 193
Background.................................................................................................................. 194
Introduction ................................................................................................................. 196
Results and discussion................................................................................................. 197
Synthesis of 4-methoxy scaffold 3.2 ....................................................................... 197
The first route to scaffold 3.1 .................................................................................. 198
Synthesis of the oxygen scaffold 3.14 ..................................................................... 200
Synthesis of the scaffold 3.17.................................................................................. 202
Synthesis of the scaffold 3.1.................................................................................... 203
Study on the [5+2] reaction of scaffold 3.1............................................................. 206
Conclusion................................................................................................................... 207
References ................................................................................................................... 208
Experimental Section................................................................................................... 209

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