Explorations in
Polyene Chemistry
A thesis submitted for the degree of
Doctor of Philosophy
of The Australian National UniversitySamuel Lawrie Drew
I
Declaration
This thesis is a report of the scientific investigations undertaken by myself during the period of February 2012 to August 2015 in the Research School of Chemistry of the Australian National University, under the supervision of Professor Michael S. Sherburn. Except where specific acknowledgements of others are made, all of the material contained within is my own work. The material presented has not been submitted for any other degree and is less than 100,000 words in length.
Samuel L. Drew
III
In loving memory of Julie Ann Fletcher
V
Acknowledgements
As scientists, we strive to learn more about the disciplines we love, to discover new things, and to overcome unsolved problems. But no matter how much time you invest, or determination you have, you can only achieve such goals with the help of others. This work would not have been possible without the influence, support, and inspiration of so many people.
To Mick, I thank you for all of your support and guidance over the past four years. You have taught me the importance of creativity: that there is little point in trying something if you know it is going to work.
To Andy, I thank you for being an excellent mentor, and for training me in the lab at the beginning of my candidature. You have been an inspiration to work with.
The Research School of Chemistry has been a fantastic environment to work in. I thank past and present Sherburn group members, in particular, Chris, Mike, Josh and Emily for being great housemates and for putting up with me for three years. Thanks to Nick Green for being a great role model and to Susan for being a great friend outside of the laboratory. I am very grateful for the assistance of the RSC technical staff, in particular, Tony Herlt, Chris Blake, and Anitha Jeyasingham. I must also thank the Rickards family for their very generous financial support in the form of the Rodney Rickards Scholarship.
The past four years have had their challenges outside of the lab: the loss of an amazing Aunt, which this work is dedicated to, and Mum’s recent battle with breast cancer. Thank you to all of the people who have helped support our family during these trying times, when I couldn’t always be there, in particular, Sarah, Karen, Kay, Alison, Baubre, and Uncle John.
To my brother, Jonathan, and Dad, Michael, thank you so much for all of your support. To Meng Yao, the love of my life, you are an amazing, caring person. Thank you for bringing happiness back into my life and for making me a better person.
VII
Publications and Presentations
This thesis is submitted in publication format.The following list details the publications and presentations that have resulted from the author’s research during his candidature for the Degree of Doctor of Philosophy:
Publications
1. Samuel L. Drew, Andrew L. Lawrence, and Michael S. Sherburn. Total Synthesis of Kingianins A, D, and F. Angew. Chem. Int. Ed. 2013, 52, 4221.
2. Samuel L. Drew, Andrew L. Lawrence, and Michael S. Sherburn. Unified Total Synthesis of the Natural Products Endiandric Acid A, Kingianic Acid E, and Kingianins A, D, and F. Chem. Sci. 2015, 6, 3886.
3. Christopher G. Newton, Samuel L. Drew, Andrew L. Lawrence, Anthony C. Willis, Michael N. Paddon-Row and Michael S. Sherburn. Pseudopterosin Synthesis from a Chiral Cross-conjugated Hydrocarbon Through a Series of Cycloadditions. Nat. Chem. 2015, 7, 82.
Presentations
1. “On the Synthesis and Biosynthesis of Kingianin A”. Student lecture at the RACI Natural Products Group Symposium, University of Sydney, Australia, 2012.
2. “A Radical Biomimetic Synthesis of Kingianin Natural Products”. Student lecture at the ARC Free Radical Spring Carnival, University of Wollongong, Australia, 2012.
3. “Divergent Total Synthesis of Endiandric Acid A, Kingianic Acid E, and Kingianins A, D, and F.” Invited lecture at Bristol-Myers Squibb, New Haven, CT, USA, 2014.
IX
Abbreviations
% percentage yield Δ heat
°C degree/s Celsius
µ micro
δ chemical shift
ν absorption maxima (IR)
aq. aqueous Ar aryl or argon BHT 2,6-‐di-‐tert-‐butyl-‐4-‐ methylphenol
bp. boiling point br broad Bu butyl
calcd calculated cm-‐1 wave number
COSY correlated spectroscopy 1D one dimensional 2D two dimensional d doublet/s DA Diels–Alder DBU 1,8-‐
diazabicyclo[5.4.0]undec-‐7-‐ene
DFT density functional theory
d.r. diastereomeric ratio DMDO dimethyldioxirane DMF dimethylformamide DMSO dimethylsulfoxide dppe 1,2-‐
bis(diphenylphosphino)ethane dppf [1,1'-‐
(diphenylphosphino)ferrocene] dppp 1,3-‐
bis(diphenylphosphino)propane
EDG electron donating group
ee enantiomeric excess EI electron impact Et ethyl
ESI electrospray ionization EWG electron withdrawing group g gram(s)
h hour/s
HMBC heteronuclear multiple bond coherence
HOMO highest occupied molecular orbital
HPLC high pressure liquid chromatography
HRMS high resolution mass spectrometry
HSQC heteronuclear single quantum coherence
Hz Hertz
i-‐Pr isopropyl IR infrared
J coupling constant kbar kilobar
L litre/s lit. literature
LUMO lowest unoccupied molecular orbital
m multiplet or metre/s
m-‐CPBA m-‐chloroperbenzoic acid mM millimolar
M molar
M+ molecular ion
Me methyl mg milligram/s MHz megahertz min minute mol mole
mol equiv molar equivalent/s mp. melting point MS mass spectroscopy
X
NBS N-‐bromosuccinimide
n-‐Bu n-‐butyl
n-‐hex n-‐hexyl
NMO 4-‐methylmorpholine N-‐ oxide
NMR nuclear magnetic resonance nOe nuclear overhauser effect NOESY nuclear overhauser and exchange spectroscopy
p-‐TsOH para-‐toluenesulfonic acid Ph phenyl
ppm parts per million q quartet
Rf retention factor
rt room temperature sat. saturated
SM starting material t time
t-‐Bu tert-‐butyl
Tf triflouromethanesulfonate THF tetrahydrofuran
XI
Abstract
Conjugated polyenes are an important class of organic molecules that have found applications in chemistry, medicine, and materials science. The ability of
!-bond rich polyenes to rapidly generate structural complexity through domino pericyclic reactions renders them powerful reagents for synthesis. This thesis, which is submitted in publication format, describes the application of through-conjugated and cross-conjugated polyenes in step-economic natural product synthesis. The first synthesis of a family of all-(Z)-polyene hydrocarbons is also presented.
Chapter One details the first synthesis of natural products to feature (Z,Z,Z,Z)-tetraenes in domino 8!-6! electrocyclizations. The ten-step synthesis centred on the unprecedented four-fold cis-selective partial reduction of a conjugated tetrayne. Our studies suggest that the kingianins form in nature through redox-catalyzed formal Diels–Alder dimerizations rather than thermal concerted [4+2]-cycloadditions.
Chapter Two presents the first unified strategy for the synthesis of structurally distinct kingianin, endiandric acid, and kingianic acid natural products. Five natural products were prepared from a common tetrayne intermediate. The point of divergence involved the unconventional terminal alkylation of a conjugated tetrayne. Evidence for redox-catalysis in the biosynthesis of kingianic acid E was also obtained.
Chapter Three describes an unprecedented synthesis of unsubstituted all-(Z)-polyene hydrocarbons. The synthetic campaign allowed the structure and reactivity of all-(Z)-polyenes higher than octatetraene to be examined for the first time.
Finally, Chapter Four outlines the shortest synthesis of a pseudopterosin natural product reported to date. The tricyclic framework was forged using a triple Diels–Alder reaction sequence of an axially chiral cross-conjugated 1,1-divinylallene.
XIII
Table of Contents
Declaration ... I
Acknowledgements ... V
Publications and Presentations ... VII
Abbreviations ... IX
Abstract ... XI
Chapter One: Total Synthesis of Kingianins A, D, and F ... 1
Prelude ... 3
Chapter Two: Unified Total Synthesis of the Natural Products Endiandric Acid A, Kingianic Acid E, and Kingianins A, D, and F ... 53
Prelude ... 55
Chapter Three: All-‐(Z)-‐Polyenes ... 103
Prelude ... 105
Chapter Four: Pseudopterosin Synthesis from a Chiral Cross-‐Conjugated Hydrocarbon Through a Series of Cycloadditions ... 167
Prelude ... 169
1
Chapter One
3
Total Synthesis of Kingianins A, D, and F
Prelude
The following manuscript, published in the leading chemistry journal Angewandte Chemie, details our first generation synthesis of kingianin natural products. Permission has been granted via RightsLink from John Wiley and Sons for reproduction in this thesis (licence number 3687941494903). All of the experimental work published in this paper is my own. The other authors are Dr Andrew Lawrence and Professor Michael Sherburn. The project was conceived by Dr Lawrence and Professor Sherburn, and evolved through contributions of all authors. As of 15th August 2015, the paper has been cited 17 times, and has
been highlighted in Chemistry World (Docherty, P. Totally Synthetic, 2013, May 1) and Chemistry in Australia (A Positively Radical Synthesis. Chemistry in Australia, 2013, July 11.)
The kingianins are an intriguing family of natural products that contain a structurally complex pentacyclic framework. Biosynthetically, the kingianins formulate as the product of a Diels–Alder dimerization reaction of a bicyclo[4.2.0]octadiene precursor. All previous syntheses of
Scheme 1: Our synthetic plan for the synthesis of kingianin natural products.
H H CONHEt H H H H H H O O EtHNOC O O
(±)-kingianin A CONHEt O O Z Z Z Z Z Z CONHEt O
O E E
H H CONHEt O O H H CONHEt O O bicyclo[4.2.0]octadiene
thermal Diels−Alder dimerization?
well precedented: Nicolaou, Baldwin,
Trauner, Parker, Moses thermal 8π-6π
electrocyclization
is the (Z,Z,Z,Z)-tetraene a biosynthetic precursor? thermal 8π-6π
electrocyclization CONHEt O O four-fold cis-selective partial reduction? Goals:
1. Scalable tetrayne synthesis
4
bicyclo[4.2.0]octadiene natural products had used (E,Z,Z,E)-tetraenes in thermally allowed 8!-6! electrocyclization cascades (Scheme 1). At the outset of this work, no bicyclo[4.2.0]octadiene natural products had been prepared using (Z,Z,Z,Z)-tetraenes. We elected to target the kingianins for two reasons: 1) to determine whether (Z,Z,Z,Z)-tetraenes are plausible biosynthetic precursors to bicyclo[4.2.0]octadiene natural products, and 2) to ascertain whether the kingianins form in nature through a concerted thermal Diels–Alder dimerization.
An unprecedented four-fold cis-selective partial reduction of a conjugated tetrayne generated the requisite (Z,Z,Z,Z)-tetraene in succinct fashion. Heating the all-(Z)-tetraene at 100 oC triggered a domino 8!-6! electrocyclization, which
53
Chapter Two
Unified Total Synthesis of the Natural
Products Endiandric Acid A, Kingianic
55 Unified Total Synthesis of the Natural Products Endiandric Acid A, Kingianic Acid E, and Kingianins A, D, and F.
Prelude
The following manuscript, published in the premier Royal Society journal Chemical Science, outlines a unified strategy for the synthesis of natural products of the Endiandra genus.
Permission has been granted from the Royal Society of Chemistry for reproduction in this thesis. All of the experimental work published in this paper is my own. The other authors are Dr Andrew Lawrence and Professor Michael Sherburn. The project was conceived, designed, and evolved through input of all authors. S. L. Drew wrote the first draft of the manuscript. As of 15th
August, the paper has been cited once - a highlight in Synfacts (2015, 11, 794).
103
Chapter Three
105 All-(Z)-Polyenes
Prelude
The following manuscript outlines the first synthesis and study of the all-(Z)-polyene family of fundamental hydrocarbons. The manuscript has been formatted for submission to Angewandte Chemie, but at the time of printing this thesis, has not been submitted. All of the experimental work presented in this paper is my own. The other authors are Dr Anthony C. Willis (X-ray crystallographer) and Professor Michael S. Sherburn. The project was conceived and evolved in collaboration with Professor Sherburn. S. L. Drew wrote the first draft of the manuscript.
When we commenced work on the kingianins, only one other (Z,Z,Z,Z)-tetraene synthesis had been documented in the literature. No syntheses of higher conjugated all-(Z)-polyenes had been reported, nor had any systematic study of the structure and reactivity of the parent all-(Z)-polyene hydrocarbons been described. This gap in our understanding of fundamental polyene chemistry inspired us to complete a total synthesis of the all-(Z)-polyene hydrocarbons.
167
Chapter Four
Pseudopterosin Synthesis from a
Chiral Cross-Conjugated Hydrocarbon
169 Pseudopterosin Synthesis from a Chiral Cross-Conjugated Hydrocarbon Through a Series of Cycloadditions
Prelude
The following manuscript, published in the journal Nature Chemistry, outlines a step-economic synthesis of a pseudopterosin natural product. The synthesis features a triple Diels–Alder reaction sequence of a chiral cross-conjugated hydrocarbon. Permission has been granted from the Nature Publishing Group via RightsLink for reproduction in this thesis. The other authors are Dr Christopher G. Newton, Dr Andrew L. Lawrence, Dr Anthony C. Willis (X-ray crystallographer), Professor Michael N. Paddon-Row (Computational Studies), and Professor Michael S. Sherburn. The project was conceived and designed through collaboration of C. G. Newton, S. L. Drew, A. L. Lawrence, and M. S. Sherburn. PhD students C. G. Newton and S. L. Drew carried out the synthetic experiments.
Specific contributions of S. L. Drew:
One-pot synthesis of ketone 9 from crotonaldehyde Enantioselective reduction of ketone 9 to alcohol 10
Assisted C. G. Newton with the optimization of steps 10 to 16 and 17 to 18
Developed the one-pot DIBAL-H reduction-olefination of ester 18
Assisted C. G. Newton with the optimization of step 20 to 21
Kinetic α-hydroxylation of ketone 21 to 22
Synthesis of pseudopterosin (–)-G–J aglycone from alcohol 22
Determination of the absolute stereochemistry of our synthetic sample of pseudopterosin (–)-G–J aglycone
A. C. Willis solved the single crystal X-ray structure of nitroadduct 20. M. N. Paddon-Row carried out a computational study on the first Diels–Alder reaction (conversion of 6→ 16). As of 15th August, the paper has been cited six
170
The first two chapters detailed step-economic syntheses of complex natural products that were achieved using through-conjugated (Z,Z,Z,Z)-tetraenes in 8!-6! electrocyclization-Diels–Alder reactions (Scheme 2 a). This theme of step-economic synthesis – enabled through the use of conjugated polyenes – continues in Chapter Four, although the focus transitions from through-conjugated polyenic systems to cross-through-conjugated polyenes (Scheme 2 b).
Scheme 2: a) Eight step synthesis of endiandric acid A using a through-conjugated (Z,Z,Z,Z)-tetraene to rapidly build structural complexity b) Diene-transmissive Diels–Alder reactivity of cross-conjugated 1,1-divinylallene.
1,1-Divinylallene, first synthesized by Sherburn and co-workers in 2011, is a π -bond rich cross-conjugated hydrocarbon that can react in a diene-transmissive triple Diels–Alder reaction sequence to rapidly construct tricyclic frameworks (Scheme 1 b). The following manuscript details an extension of this research and reports the first application of a substituted 1,1-divinylallene in natural product synthesis. The tricyclic (–)-pseudopterosin G–J aglycone natural product was accessed in just 10 steps from chiral pool starting materials, or in 11 steps via an enantioselective route, through the deployment of an axially chiral substituted 1,1-divinylallene in a sequence of three Diels–Alder reactions.
Z Z
Z Z
through-conjugated polyene OTBS Ph H H H Ph H H H
CO2H
(±)-endiandric acid A
2 steps a)
4 C-C bonds 4 new rings
via domino 8π-6π
electrocyclization-IMDA reaction
8 steps in total!
b)
Diels−
Alder DielsAlder−
•
Diels−
Alder
1,1-divinylallene cross-conjugated polyene
6 C-C bonds 3 new rings
