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318 Pages·2015·12.23 MB·English

New meta-Terphenyl-Derived Primary Amines in
Asymmetric Catalysis
Citation
Witten, Michael R. 2015. New meta-Terphenyl-Derived Primary Amines in Asymmetric Catalysis.
Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467173
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New meta-Terphenyl-Derived Primary Amines in Asymmetric Catalysis

A dissertation presented
by
Michael R. Witten

to

The Department of Chemistry and Chemical Biology

in partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
in the subject of
Chemistry

Harvard University
Cambridge, Massachusetts
January 2015
© 2015 – Michael R. Witten
All rights reserved.
Dissertation Advisor: Professor Eric N. Jacobsen Michael R. Witten

New meta-Terphenyl-Derived Primary Amines in Asymmetric Catalysis

Abstract

In this dissertation, two distinct asymmetric reaction types are described: [5 + 2] pyrylium
cycloadditions and aldehyde α-functionalizations. Both reactions are mediated by simple, organic
primary amine catalysts bearing bulky meta-terphenyl moieties. The main text of this thesis is
divided into five chapters outlining the relevant background and the original research.
Chapter 1 provides a thorough historical overview of [5 + 2] oxidopyrylium cycloadditions
and related asymmetric [3 + 2] cycloadditions. Early discoveries of intermolecular and
intramolecular processes, asymmetric precedents, and pertinent frontier molecular orbital
considerations are examined. The application of these transformations to the synthesis of natural
products and bioactive compounds is also discussed.
In Chapter 2, a new method for effecting catalytic enantioselective intramolecular [5 + 2]
cycloadditions based on oxidopyrylium intermediates is presented. The development and
employment of a dual catalyst system—consisting of a chiral m-terphenyl-containing primary
aminothiourea and a second achiral thiourea—are described. Experimental evidence points to a
new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium
ion pair that undergoes subsequent cycloaddition with high enantioselectivity.
Chapter 3 details the successful expansion of the enantioselective [5 + 2] methodology to
intermolecular reactions. Highly enantioselective intermolecular [5 + 2] cycloadditions of
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pyrylium ion intermediates with electron-rich alkenes are promoted by the same dual catalyst
system as in Chapter 2. The observed enantioselectivity is highly dependent on the substitution
pattern of the 5π component, and the basis for this effect is analyzed in detail using experimental
and computational evidence. The resultant 8-oxabicyclo[3.2.1]octane derivatives possess a
scaffold common in natural products and medicinally active compounds and are also versatile
chiral building blocks for further manipulations. Several stereoselective complexity-generating
transformations of the 8-oxabicyclooctane products are described.
In Chapter 4, we transition into a literature survey of catalytic asymmetric α-
functionalizations of α-branched aldehydes. First, the challenges associated with the efficient
functionalization of such substrates, relative to their unbranched counterparts, are detailed. This
introduction is followed by a comprehensive overview of catalytic, enantioselective α-
heterofunctionalizations: aminations, oxygenations, sulfenylations, and fluorinations. Advantages
and drawbacks to previously described methods are analyzed in detail.
Chapter 5 recounts our own contributions to this area. A new chiral m-terphenyl-containing
primary amine catalyst for the asymmetric α-hydroxylation and α-fluorination of α-branched
aldehydes is reported. The products of the title transformations are isolated in high yields and
exceptional enantioselectivities within short reaction times. Both processes can be performed at
high concentrations and on gram scale. The remarkable similarity between the procedures,
combined with computational evidence, implies a possible general catalytic mechanism for α-
functionalizations. Promising initial results for α-amination and α-chlorination support this
hypothesis.
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Table of Contents
Abstract iii
Table of Contents v
Acknowledgments ix
List of Abbreviations and Symbols xv
Chapter 1. An Overview of [5 + 2] Cycloadditions of Oxidopyrylium Dipoles and Related
Ylides 1

1.1 Introduction 1
1.2 Oxidopyrylium Generation from Acetoxypyranones 2
1.2.1 Intermolecular Oxidopyrylium Cycloadditions from Acetoxypyranones 3
1.2.2 Intramolecular Oxidopyrylium Cycloadditions from Acetoxypyranones 7
1.3 Oxidopyrylium Generation from Alternate Starting Materials 8
1.3.1 Epoxyindanones as Oxidopyrylium Precursors 8
1.3.2 β-Hydroxy-γ-pyrones as Oxidopyrylium Precursors 11
1.4 Asymmetric Access to the 8-Oxabicyclo[3.2.1]octane Core 15
1.4.1 Diastereoselective [5 + 2] Oxidopyrylium Cycloadditions 16
1.4.2 Catalytic Enantioselective [3 + 2] Carbonyl Ylide Cycloadditions 19
1.4.3 Catalytic Enantioselective [5 + 2] Benzopyrylium Cycloadditions 24
1.5 [5 + 2] Oxidopyrylium Cycloadditions in Total Syntheses 25
1.6 Outlook 33
Chapter 2. Hydrogen-Bonding and Primary Amine Catalysis in Enantioselective [5 + 2]
Pyrylium Cycloadditions 34

2.1 Introduction 34
2.2 Reaction Development 38
v
2.3 Substrate Scope 40
2.4 Mechanistic Studies 43
2.4.1 Catalyst Structure‒Activity Study 43
2.4.2 An FMO Analysis to Support an Aminopyrylium Intermediate 46
2.4.3 Rationalization of Stereoselectivity by DFT Calculations 49
2.5 Conclusions and Outlook 51
2.6 Experimental Details 52
2.6.1 General Information 52
2.6.2 Synthesis and Characterization of Catalysts 53
2.6.3 Synthesis and Characterization of Substrates 55
2.6.4 Procedures for Cycloadditions and Characterization of Products 79
2.6.5 Computational Procedures and Results 87
2.6.6 Frontier Molecular Orbital Methods 95
2.6.7 Additional Optimization Studies 96
2.6.8 Results with Sub-Optimal and Unreactive Substrates 97
2.6.9 Crystallographic Information 99
Chapter 3. Expansion of Catalytic Asymmetric [5 + 2] Cycloadditions to Intermolecular
Reactions 105

3.1 Introduction 105
3.1.1 The Catalytic Asymmetric [5 + 2] Pyrylium Cycloaddition 107
3.1.2 Asymmetric Intermolecular [5 + 2] Pyrylium Cycloadditions 108
3.2 Reaction Development 111
3.3 Substrate Scope 116
3.4 An Asymmetric Total Synthesis of (‒)-Descurainin 118
vi
3.5 Mechanistic Studies 119
3.6 Derivatization of Cycloadducts 122
3.7 Conclusions and Outlook 125
3.8 Experimental Details 125
3.8.1 General Information 125
3.8.2 Synthesis and Characterization of Substrates 126
3.8.3 Procedures for Cycloadditions and Characterization of Products 140
3.8.4 Synthesis and Characterization of Product Derivatives 148
3.8.5 Computational Procedures and Results 159
3.8.6 Additional Optimization Studies 168
3.8.7 Results with Sub-Optimal and Unreactive Substrates 171
3.8.8 Crystallographic Information 172
Chapter 4. An Overview of Amine-Catalyzed α-Functionalizations of Branched Aldehydes
175

4.1 Introduction 175
4.2 α-Amination Reactions 180
4.3 α-Oxygenation Reactions 186
4.4 α-Sulfenylation Reactions 190
4.5 α-Fluorination Reactions 191
4.6 Outlook 195
Chapter 5. A New Primary Amine Catalyst for Efficient Asymmetric α-Functionalizations
of Branched Aldehydes 197

5.1 Introduction 197
5.1.1 α-Oxygenation Reactions 199
vii
5.1.2 α-Fluorination Reactions 201
5.1.3 α-Functionalization Reactions from the Jacobsen Lab 202
5.2 Reaction Development 203
5.2.1 An N-Sulfonyloxaziridine Hydroxylating Reagent 203
5.2.2 Condition Optimization 205
5.3 Regarding Benzamide Catalysts 208
5.4 Substrate Scope 212
5.5 Mechanistic Studies 217
5.5.1 A DFT Model for Enantioinduction 217
5.5.2 Investigation of Other α-Functionalizations 219
5.6 Conclusions and Outlook 223
5.7 Experimental Details 223
5.7.1 General Information 223
5.7.2 Synthesis and Characterization of Catalyst 38 224
5.7.3 Synthesis and Characterization of Substrates 227
5.7.4 Procedures for α-Functionalizations and Characterization of Products 239
5.7.5 Computational Procedures and Results 270
5.7.6 Additional Optimization Studies 277
5.7.7 Results with Additional Substrates 288
5.7.8 Crystallographic Information 289
viii
Acknowledgments
There are several people without whom this thesis (and by extension my own career) would
not have been possible. Foremost among them is my advisor. Eric Jacobsen has managed to
cultivate a group that shares his own enthusiasm for science and zeal for diligent research. His
intellectual curiosity has served as an inspiration and his attitude towards advising has afforded
me the freedom to develop as an independent researcher. Although we have not always seen eye-
to-eye (usually due to my own dimwittedness), I cannot imagine having had a more enjoyable
graduate school experience and consider myself truly fortunate to join his chemical family tree—
even if I am the figurative beech bark disease.
I must also express my gratitude towards Professors Andrew Myers and Tobias Ritter who
have served on my graduate advising committee for the entirety of my five years in the Jacobsen
group. Their advice and encouragement during committee meetings, especially in response to my
independent research proposal, have been invaluable. Their feedback has been instrumental in my
development as both a scientist and a public speaker. I must also give recognition to Professor Dan
Kahne for providing additional feedback on my research proposal.
Throughout the entire ordeal of navigating graduate school, Nicole Minotti has kept the
ship on course. Although graduate students typically have a reputation for working ridiculously
long hours (hey, at least the pay is awful!), Nicole has often worked even longer and harder at
making sure the Jacobsen group remains afloat. Remarkably, she always does so with a smile on
her face. The minutes before entering Eric’s office prior to committee meetings could have been
some of the most grueling in all of graduate school, but Nicole’s jokes and words of encouragement
always kept me levelheaded prior to jumping into the shark tank.
Before I even fully grasped what chemistry was, I had the dual influences of two excellent
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