i. mechanistic studies of a copper-catalyzed electrophilic amination of diorganozinc reagents by o

248 Pages·2009·2.35 MB·English

I. MECHANISTIC STUDIES OF A COPPER-CATALYZED
ELECTROPHILIC AMINATION OF DIORGANOZINC REAGENTS BY
O-BENZOYL N,N-DIALKYLHYDROXYLAMINES

II. DEVELOPMENT OF A 3-EXO-DIG CYCLIZATION FOR THE
PREPARATION OF VINYLIDENE CYCLOPROPANES

III. TOTAL SYNTHESIS OF (+)-POLYANTHELLIN A
Matthew James Campbell
A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill
in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the
Department of Chemistry
Chapel Hill
2009

Approved by:
Jeffrey S. Johnson
Erik J. Alexanian
Maurice S. Brookhart
Joseph L. Templeton
Cynthia K. Schauer
© 2009
Matthew James Campbell
ALL RIGHTS RESERVED
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ABSTRACT

MATTHEW JAMES CAMPBELL:
I. Mechanistic Studies of a Copper-Catalyzed Electrophilic Amination of Diorganozinc
Reagents by O-Benzoyl N,N-Dialkylhydroxylamines
II. Development of a 3-Exo-Dig Cyclization for the Preparation of Vinylidene
Cyclopropanes
III. Total Synthesis of (+)-Polyanthellin A
(Under the direction of Professor Jeffrey Scott Johnson)

I. Mechanistic Studies of a Copper-Catalyzed Electrophilic Amination of
Diorganozinc Reagents by O-Benzoyl N,N-Dialkylhydroxylamines
The mechanism of the Cu-catalyzed amination of R Zn reagents by O-benzoyl
2
N,N-dialkylhydroxylamines has been investigated. An S 2 pathway has been supported
N
because : (i) stoichiometrically generated cuprates were used to prove zinc is not essential
in the C–N bond forming step; (ii) the configuration at the reacting carbon is retained
through the reaction, ruling out a radical pathway; (iii) the endocyclic restriction test
proceeded without intramolecular amination. A Cu-catalyzed amination of Grignard
reagents was realized after experiments determined the relative rates of O-acylation,
transmetalation, and C–N bond formation were favorable. O-Mesitoyl N,N-
dialkylhydroxylamines were found to be suitable R N(+) synthons for the uncatalyzed
2
amination of Grignard reagents, including unhindered vinyl Grignard reagents.
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R'R'
BzO NR'2 cat Cu
+ R N OBz RNR'2
R Zn
2
S 2-like
N
R'MgX (slow add'n)
R 2.5-15 mol % CuCl R
N OBz 2 N R'
THF, rt
R 10-30 min R
58–95% yield
II. Development of a 3-Exo-Dig Cyclization for the Preparation of
Vinylidene Cyclopropanes
The first all-carbon 3-exo-dig cyclization was developed. These cyclizations lead
to vinylidene cyclopropanes with electron-withdrawing substituents, products that are not
available using carbene chemistry. Both cyclic and acyclic precursors can be used with
equal efficacy, although high dilution conditions were necessary to enable cyclization of
the latter. The products were amenable to a number of common derivatizations,
including halogenation, hydrogenation, and hydroboration.
R O O
1 R
Y R2 TBAF, THF Y 2 R3
R1 = H, TBS X = Cl, Br, I R
X R2 = CO2Me, CO2Et, CNY = CH2, OMe H 3
R3 = H, Me
R3 R3 yield 36-95%
III. Total Synthesis of (+)-Polyanthellin A
(+)-Polyanthellin A was synthesized in 15 linear steps from methallyl alcohol in
2% overall yield, with an average yield of 77% per step. This synthesis demonstrates the
utility of the [3+2]-cycloaddition between cyclopropanes and aldehydes in a complex
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setting. The use of the hindered catalyst, MADNTf , was essential to ensure a successful
2
cyclization, and has extended the scope of the cycloaddition to include sensitive protected
β-hydroxyaldehydes. Other key steps included a Cu-catalyzed cyclopropanation, ring-
closing metathesis, selective alkene oxidation, and an iodoetherification.
TMSO
O
CO2Me MADNTf2 O R AcO H H
TMSO (10 mol %)
+OHC O O O
H 3 equiv. 76% H H H
(+)-Polyanthellin A

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ACKNOWLEDGEMENTS

I would first like to acknowledge Professor Jeff Johnson for guiding my research
during the five years I've been here at UNC. As I matured as a chemist, he was more
than willing to let me research in my own style, but still would nudge me back on track if
I started to stray away from straightforward and simple solutions. I was able to work on
diverse projects throughout my tenure here that have opened me up a number of unrelated
areas in synthetic chemistry. For this opportunity, I am truly grateful as I realize this is
not generally true for organic students. I'm also appreciative of Jeff's ability to not pass
judgment, even when I'm arguing against reason, and for humoring the bad ideas I've
come up with over the years.
I thank Professors Erik Alexanian, Maurice Brookhart, Joseph Templeton, and
Cynthia Schauer for serving on my defense committee, and Jim Morken for serving as
my committee chair for my oral examination.
Thanks to past and present Johnson group members (Andrew Satterfield, Shanina
Sanders, Chris Tarr, Dan Schmitt, Austin Smith, Greg Boyce, Mike Slade, Jenn Carman,
and Kim Steward) for maintaining a low-key working environment that was seldom
boring, and for putting up with my eccentricities of singing and being obnoxious in
general. The group has always been relatively coherent even when fantasy football
threatens to destroy our fine social fabric. I especially extend thanks to Pat Pohlhaus,
Andrew Parsons, and Ash Berman who contributed to the projects that I've worked on at
UNC. For fine conversations about chemistry and life and for being good friends, I thank
Andrew Parsons, Steve Greszler, and Dave Nicewicz.
Mike Barrett and Matt Haley have also been along for the ride with me. My time
here (not to mention Sundays) would have been much more boring if I hadn't had met
you both. Thanks for the fond memories I'll be able to take with me from Carolina.
I'd like to thank my girlfriend, Miranda Welsh, for the love she has provided me
for the last ten years, beginning in 11th grade AP Biology. Without you, I probably
wouldn't have made it this far, and now it is your turn to finish your degree at UNC. I'm
sad I won't be together for our entire academic career, but we've made it pretty far.
Finally, I'd like to thank the rest of my family who have supported me over the
years. My parents extended patience to me when I told them everyday or so that I wanted
to live in the woods, and accepted my desire while I was out there for a little while. They
were good-natured and wise enough to financially plan for their children's educations,
and all four of us have benefited greatly from being able to pursue our educations without
the complications money brings. My brother and his wife, Anita, have enabled me to
have an immediate family in North Carolina, and my sisters, Stephanie and Kristin, have
set a scholarly example since I can remember. Thanks for letting me know high school
academics were a waste of time, which let me enjoy wood shop, zoology, and other such
pleasures.
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TABLE OF CONTENTS
LIST OF TABLES...........................................................................................................xi
LIST OF FIGURES AND SCHEMES..........................................................................xii
LIST OF ABBREVIATIONS AND SYMBOLS.........................................................xvi
CHAPTER 1 MECHANISTIC STUDIES OF A COPPER-
CATALYZED ELECTROPHILIC AMINATION
OF DIORGANOZINC REAGENTS BY
O-BENZOYL N,N-DIALKYLHYDROXYLAMINES......................1

1.1 Introduction...........................................................................................................1

1.2 Background............................................................................................................2

1.2.1 Mechanistic Studies of Uncatalyzed Electrophilic Aminations....................2

1.2.2 Mechanistic Studies of Copper-Catalyzed Electrophilic Aminations...........5

1.3 Results and Discussion..........................................................................................8

1.3.1 Amination with Stoichiometric Cuprates......................................................8

1.3.2 Amination of Stereodefined Organozinc Reagents.....................................10

1.3.3 Endocyclic Restriction Test........................................................................13

1.3.4 Development of Copper-Catalyzed and
Uncatalyzed Amination of Grignard Reagents
with O-Acyl N,N-Dialkylhydroxylamines..................................................15

1.3.5 Uncatalyzed Amination of Vinyl Grignard
Reagents with O-Mesitoyl N,N-Diethylhydroxylamine..............................21

1.4 Conclusion...........................................................................................................22

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1.5 Experimental........................................................................................................23

1.6 References...........................................................................................................57
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CHAPTER 2 DEVELOPMENT OF A 3-EXO-DIG
CYCLIZATION FOR THE PREPARATION
OF VINYLIDENE CYCLOPROPANES..........................................61

2.1 Introduction.........................................................................................................61

2.2 Background..........................................................................................................61

2.2.1 3-Exo-Dig Cyclizations...............................................................................61

2.2.2 Retrosynthesis of the Cladiellin Core.........................................................65

2.2.3 Synthetic Utility of Vinylidene Cyclopropanes..........................................68

2.3 Results and Discussion........................................................................................72

2.3.1 Attempted Synthesis via Carbene Methodology.........................................72

2.3.2 Synthesis of Cyclic Propargyl Chlorides....................................................72

2.3.3 Optimization of 3-Exo-Dig Cyclizations with Propargyl Chlorides...........74

2.3.4 Synthesis of Propargylic Iodides.................................................................76

2.3.5 Optimization of 3-Exo-Dig Cyclizations with Propargyl Iodides...............77

2.3.6 Substrate Scope with Propargylic Iodides...................................................78

2.3.7 Structural Assignment.................................................................................80

2.3.8 Stereoelectronic Considerations..................................................................81

2.3.9 Synthesis of Acyclic Propargyl Halides......................................................82

2.3.10 Reaction Development using Acyclic Propargyl Halides...........................83

2.3.11 Derivatization of Vinylidene Cyclopropanes..............................................84

2.4 Conclusion...........................................................................................................89

2.5 Experimental........................................................................................................89

2.6 References.........................................................................................................143
CHAPTER 3 TOTAL SYNTHESIS OF (+)-POLYANTHELLIN A .................147

3.1 Introduction.......................................................................................................147

3.1.2 Biogenetic Proposal and Properties of Cladiellins....................................147

3.1.3 Syntheses of Cladiellins Containing Two Oxygen Bridges......................149

3.2 Results and Discussion......................................................................................156

3.2.1 Synthesis of Model Systems ....................................................................156

3.2.2 Cycloadditions with Model Systems.........................................................158

3.2.3 Retrosynthetic Analysis of (+)-Polyanthellin A........................................161

3.2.4 Synthesis of the Allyl Cyclopropane.........................................................162

3.2.5 Synthesis of the Aldehyde Coupling Partner............................................163

3.2.6 [3+2]-Cycloaddition Optimization............................................................164

3.2.7 Failed Allylic Oxidation and Alkene Isomerization.................................170

3.2.8 Revised Retrosynthetic Analysis of (+)-Polyanthellin A..........................172

3.2.9 Revised Synthesis of the Vinyl Cyclopropane..........................................173

3.2.10 Cycloaddition and Olefin Metathesis of the Vinyl Cycloadduct..............174

3.2.11 Completion of (+)-Polyanthellin A...........................................................177

3.3 Conclusion.........................................................................................................182

3.4 Experimental......................................................................................................182

3.5 References.........................................................................................................224

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