Nickel Catalyzed Asymmetric Reductive Ring Opening of Oxabicyclic Alkenes

284 Pages·1999·13.3 MB·English

Nickel Catalyzed Asymmetric Reductive Ring Opening
of Oxabicyclic Alkenes
Tomislav Rovis
A thesis submitted in confofTI11:ty with the requirements
for the degree of Doctor of Philosophy
Graduate Department of Chernistry
University of Toronto
@ Copyright by Tomislav Rovis (1998)
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Objectives
The overall objective was to develop an lymmetnc reductive ring opening of
oxabicyclic alkenes in order to generate efli~11tiomencalley ~chedcy clohexenols and
cycloheptenols. Extension of this methodology to heterobenzonorbornadienes was also
examined.
The f m o bjective was to determine the metal. ligand and hydride source to effecr
this reaction in high enantiorneric excess. Building on prior work the investigations
focused on the use of the nickel cataiyzed hydroalumination reaction in the presence of
chiral ligands. An eariy goal was to successfully ~g open oxabicyclo[3- 2.l loctenes with
high ee, as the product cycloheptenols were potential intermediates to the naairal product
ionomyc in.
The second objective was to extend dus methodology to the
oxabenzonorbomadiene class of substrates. The product dihydronaph thalenols are
potential intermediates to a number of biologicdly important compounds . Su bsequent
reactions of dihydronaphthalenols were also examined leading to the total synthesis of the
anti depressant semaline.
The third objective was to detemine the mechanism of the nickel cataiyzed
reductive Mig opening of oxabicyclic alkenes.
iii
Nickel Catalyzed Asymrnetric Reductive Ring Opening
of Oxabicyclic Alkenes
Tomislav Rovis
Ph.D. thesis, 1998
Graduate Departmeni of Chemistry
University of Toronto
Oxabicyclo(2.2. llheptenes were shown to undergo highly enantioselective
reductive ring opening with DIBAL-H in the presence of a cataiytic amount of Ni(COD)?
and BINAP. The product cyclohexenols were produced in ee's of 81-97% and yields of
50-96%. Slow addition of DIBAL-H to the reaction was found to be crucial for high ee' S.
Oxabenzonorbomadienes could aiso be enantioselectively ring opened if the reaction was
conducted in THF. Dihydronaphthalenols were produced in ee's of 73-98% and yields of
50-88%.
Oxabicyclo[3.2. lloctenes were shown to undergo a highly enantioselective ring
opening when the reaction was conducted at >60 OC. Various cycloheptenols were
produced in yields of 83-99% and ee's of 93-99.54. Lower temperatures were found to
give significantly lower ee's and low yields.
This methodology has been applied to the total synthesis of the important anti-
depressant sertraline. The synthesis was completed in nine steps from dihydronaphthalenol
with an overall yield of 3896. The dihydronaphthalene skeleton was also found to undergo
several highiy selective reactions Ieading to polyfunctionalized tetrahydronaphthalenes.
The mechnnisrn of the asymmetric nickel catalyzed hydroalumination reaction was
examined by studying the scope of the reaction and by NMR techniques. A revesible
3 ' ~
hydronickelation followed by an ineversible hlirnination from the organonickel has been
proposed as the key step.
Acknowledgements
First and foremost, 1w ould like to thank my supervisor, Professor Mark Lautens,
for his guidance and support throughout the course of my graduate work. His enthusiasm
for chemistry and his abilities as a teacher foster an excellent environment in which to do
and lem chemistry. In addition, 1 would like to thanis Dr. Robin Cox, Professor Stewart
McLean and the late Professors Peter Yates and John Buntïng for initially stimulating my
interest and love of orgaoic chemistry. I am also deeply indebted to Professor Dave Farrar
for taking the time to teach me ligand field theory and in so doing, enflame my interest in
inorganic chemistry. Many thanks to Professor Robert Morris for helpful discussions
regarding the mechanism of the reaction and for providing facilities to make Crabtree's
catalyst, and to Professor Rob Batey for helpful discussions.
A number of people within the Lautens group deserve special recognition. Pauline
Chiu, whose project I inherited and Shihong Ma who worked on a closely related project
deserve special thanks. Yi Ren, William Tarn, Dr. Sophie Kumanovic, Dr. Alan Haughan
and Dr. Christophe Meyer are thanked for teaching me the skills of organic chemistry, and
the rest of the Lautens group, past and present, for providùig such a fantastic environment
in which to enjoy research. Specid thanks go to James Blackwell, John Colucci and Eric
Fion for sharing their love and interest in organic chemistxy. James BlackwelI, John
Colucci and Greg Hughes are thanked for proofkeading parts of this thesis. Outside the
group, Mark McGovern is thanked for his fnendship and interest in my research, and
Cameron Forde and Marcel Schlaf are thanked for helpful discussions, both organic and
inorganic.
The technical assistance of a number of people is deeply appreciated: Dr. Alex
Young for timely mass spectral analyses and GC-MS help, Dr. Alan Lough for a very
informative X-Ray structure search, Ron Legge for glassblowing, Dan Mathers, Nick
Plavac, and especially Dr. Patcicia Aroca-Oueuete and Dr. Tim B m w f or extensive NMR
training and support.
1 am deeply gratefbi to my parents for their constant support: my mother, the first
scientist 1e ver met, and my father, who taught me how to think. Voce nije pub daieko od
stabla. 1t hank my oniy sister for her support, and her continuhg interest in understanding
what exactly it is that I am studying. FinaiIy, very special thanks to my wife, Markma,
who has been by my side throughout the course of my graduate work, and provided me
with ail the love, encouragement and support anyone could ever want.
to Morimvra,
my 1%
my love
"Tkre me at lean two reasom why scientists have an obligation to explain what
science is all about. OM is naked self-interest. Much of the fwidng for science cornes
fiom the public, and the public has a rïght to know how iheir money is king spent. If w e
scientLns kreare the public excitemeni about science, drere is a good chance of k i n g
more public supporters. The other is thm it 's rremendously exciting ru communicute your
own excitement to others. "
-Car1 Sagan
Table of Contents
..
Objectives u
.. -
Abstract lll
Acknowledgements iv
Dedication vi
Table of Contents vu..*
Chiral Ligands xiv
List of Abbreviations XV
List of Tables xviii
List of Figures xix
GENERAL INTRODUCTION
8 1 CATALYZED HYDROMETALATLONS
§ 1-1 Non-asymmetric Hydrometalotions
fi 1.1.1 Hydromagnesia~on
$ 1.1.2 Hydruzircot~io n
§ 1.1.3 Hydruzincation
5 1.1.4 Hydruboration
5 1.1.5 HydrosiIyla tim
5 1.1.6 Hydro~~hmuiation
§ 1.2 Asyrnmeîtic Eydrometalations
§ 1.2.1 Asymmetric Hydroboration
9 1.2.2 Asymmetnc Hydrosilylation
5 1.2.3 Asymmetric HydroulumuuZtion
5 2 REDUCTIVE IUNG OPENING OF
OXABICYCLIC ALKENES
5 2.1 Synthetic Precedent
j 2.1.1 Use of Oxabicyclic Alkenes in Synthesis
$ 2.1.2 Nucleophilic Ring Opening of Oxabicyclic Alkenes
§ 2.1.3 Reductive Ring Openùtg of Oxabicyclic Alkenes
$ 2.2 Goak and Targets
5 2.2.1 nie Development of a Catalytic AsymmernrnHc ydrometalation
9 2.2.2 Natural Prorkcr Turgets
§ 2.3 Outline
5 3 REFERlENCES
CHAPTER I CATALYTIC ASYMMETLUC REDUCTIVE RING OPENING
OF OXABICYCLO[N.L.l]ALKENES 34
5 1.1 INTRODUCTION
5 1.1.1 Synthesis of Enantiomerically Enriched Cyclohexenols
§ 1.1.2 Synthesis of Enantionericaily Enriched Cycloheptenols
8 1.1.3 Synthesis of Enantiomerically Enriched Tetralins
5 1.2 RESULTS AND DISCUSSION
8 1.2.1 Synthesis of Substrates
$ 1.2.1.1 Preparation of Oxobicyclo[2.2. llheptenes
g 1.2.1.2 Synthesis of Oxnbicyclo[3.2.l]octenes
5 1-2.1.3 Synthesis of Oxabenzonorbonradienes
5 1.2.1.4 Synihesis of Azanorbomadienes