Table Of ContentSpringer Theses
Recognizing Outstanding Ph.D. Research
Robert J. Sharpe
Stereoselective
Desymmetrization
Methods in the
Assembly of Complex
Natural Molecules
Springer Theses
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Robert J. Sharpe
Stereoselective
Desymmetrization Methods
in the Assembly of Complex
Natural Molecules
Doctoral Thesis accepted by
The University of North Carolina
123
Author Supervisor
Dr. RobertJ.Sharpe Prof. Dr. Jeffrey Johnson
AdvancedResearch Chemist TheUniversity of NorthCarolina
EastmanChemical Company ChapelHill, NC
JohnsonCity,TN USA
USA
ISSN 2190-5053 ISSN 2190-5061 (electronic)
SpringerTheses
ISBN978-3-319-39024-6 ISBN978-3-319-39025-3 (eBook)
DOI 10.1007/978-3-319-39025-3
LibraryofCongressControlNumber:2016939115
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Parts of this thesis have been published in the following journal articles:
1. Sharpe, R. J.; Malinowski, J. T.; Johnson, J. S. J. Am. Chem. Soc. 2013, 135,
17990.
2. Sharpe, R. J.; Malinowski, J. T.; Sorana, F.; Luft, J. C.; Bowerman, C. J.;
DeSimone, J. M.; Johnson, J. S. Bioorg. Med. Chem. 2015, 23, 1849.
3. Sharpe, R. J.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 4968.
4. Sharpe, R. J.; Johnson, J. S. J. Org. Chem. 2015, 80, 9740.
To my wife in honor of her love, patience,
encouragement, and support during these
past four years.
I can’t wait for our next adventure together,
and I wouldn’t want to do it with anyone else
but you!
’
Supervisor s Foreword
The design and implementation of new chemical reactions is central to the
advancement of the chemical and pharmaceutical industries. Whether these pro-
cesses provide more efficient access to known compounds or entry into heretofore
underexploredstructuralmotifs,syntheticorganicchemistryremainsacriticalfacet
in the betterment of global health. These goals have remained at the core of our
researchprogramindesigningandimplementingnovel reaction methodologiesfor
rapid introduction of structural and stereochemical complexity from relatively
simple starting materials.
In pursuing these challenges, our most fruitful source for inspiration is nature
itself, which for centuries has been the source of architecturally complex and
biologically interesting small molecules. These molecular scaffolds charge the
organic chemist with extending the limits of known reaction space, and it is often
the case that endeavors in natural product synthesis lead simultaneously (and
perhapsoutofnecessity!)tonewreactiondevelopment.Eachofthetotalsynthetic
endeavors in our group have been made possible by or ultimately resulted in new
reaction development.
Oneofthemostfruitfulreactionmethodologiesinourlaboratoryinrecentyears
hasbeenthemanipulationofmolecularsymmetryelementsforrapidlyintroducing
stereochemical information that would otherwise require multiple stepwise trans-
formations. It may come as no surprise to the reader that this strategy was initially
borne out of desperation with a challenging total synthesis! When Robert Sharpe,
the author of this thesis, joined our group in 2011, we were “knee deep” in the
synthesis of the aminocyclitol natural product pactamycin. While this molecule’s
biological profile has made it an attractive target for biological investigation, the
inherent cytotoxicity of the parent structure has, to date, precluded its use in
chemotherapy.Thus,thevalueofanexpedienttotalsynthesisofpactamycin(vis-à-
vis,structure–activityrelationshipinvestigations)isobvious.However,for50years
sinceitsdiscovery,thismoleculehadremainedimpervioustototalsynthesisuntila
32-step synthesis was reported in 2011. In revising our original approach to pac-
tamycin, Robert, in cooperation with another student in our group, came upon a
ix
x Supervisor’sForeword
symmetry-breaking diketone monoreduction strategy which completed assembly
of the entire carbon skeleton of the molecule within the first three steps of the
synthesis. Additionally, the discovery of a fortuitous “stereochemical correction”
downstreaminthesynthesisultimatelyyieldedthenaturalproductin15stepsfrom
commercial starting materials. This work challenged the limits of synthetic cre-
ativityandprovidedexpedientaccesstofurtherexplorationofthebiological space
in which pactamycin participates. Robert then went on to prepare 25 unique
structural analogs of the parent structure via this synthetic route and demonstrated
its effectiveness in modifying biological activity of the parent structure.
Our studies in implementing stereoselective desymmetrization reactions then
continued with the preparation of the indole-diterpene alkaloid natural product
paspaline,theparentmemberofanowextensivefamilyofnaturalproducts.While
thesynthesisofsteroidandsteroid-likemoleculeshasbeenextensivelystudied,the
recent discovery of new molecules bearing unique deviations from the classical
steroid design has reignited investigations in this arena. In Robert’s hands, pas-
paline again served as the breeding ground for new reaction development, as a
biocatalytic enantioselective desymmetrization rapidly assembled core features
of the molecule. As the synthesis progressed, however, a second avenue for
stereoselective desymmetrization presented itself; in this iteration, an
oxime-directed symmetry-breaking C–H activation/acetoxylation delivered the
necessarystereochemicalinformationatacriticalall-carbon quaternarycenternear
the end of the synthesis. Robert’s work on this molecule continued to demonstrate
the viability of desymmetrization analysis in planning for complex molecule
synthesis.
This thesis is outstanding, not just for the quality of the science described, but
alsofordelineatingthatscienceinanarrativethateffectivelytellstheentirestoryof
each total synthesis. In each chapter, Robert describes in detail the initial results
that,whileultimatelyunfruitfulinourroutes,representqualitycontributionstothe
synthetic toolbox and guided our thinking as we arrived at the final, successful
approachineachproject.Thisthesisisthefinalproductofanincredibleamountof
hard work and sheer determination and should be inspirational to future graduate
studentsundertakingchallengingtotalsyntheses.Theworkdescribedhereinserved
as an inspiration to UNC faculty and students alike. I hope this document will
motivateyouinyourfutureendeavorstocontinuetochallengethelimitsofknown
spacetocreateknowledgethatwilllikewiseinspireanothergenerationofscientists.
February 2016 Jeffrey Johnson
Acknowledgements
My success in this program has been primarily the result of contributions and
encouragementfromsomanyothersoutsideofmyselfduringthesepastfouryears.
I would first like to thank my advisor, Jeff Johnson, for the teaching, mentorship,
patience,andsupporthehasprovidedmesinceIbeganinhisprogramin2011.Jeff,
even going back to when I was crowding your inbox with emails as a prospective
student, your kindness to me has been far more than I deserve. Because of your
researchprogram,Ifeelequippedforsuccessinanyfuturescientificendeavor,not
just because of your training in synthesis, but also for your training in effectively
communicating scientific discoveries, devising creative approaches to hard prob-
lems, and managing time effectively. I am especially grateful for your help and
referrals during my job search: one interviewer, when asked by me why I was
brought on-site for an interview, simply stated, “I have a high respect for Jeff, and
he wrote you a strong recommendation.” Thank you for taking me on four years
ago,andIamgratefultohavebeenapartofyourprogramandtohaveworkedon
some really fun projects.
I would like to thank Professors Michel Gagné, Simon Meek, Michael
Crimmins, and Maurice Brookhart for serving on my final defense committee as
wellasaspecialthank youtoSimonMeekandChrisLuftforbeingreferencesfor
job applications. Chemistry at UNC truly has an incredible support network for
solving challenging problems in science, and I am grateful for the guidance and
support you all have provided.
I am thankful for the incredible group of co-workers I have been able to work
alongside during my four years in the Johnson Lab. The current group is strong
(GuyGoodman,WillMackay,SamBartlett, MattHorwitz,KendrickSmith,Jamie
Giarusso,DesireéMatias,BlaneZavesky,SteffenGood,andJessicaGriswold),and
Ihaveverymuchenjoyedgettingtoknoweachofyou.Iamespeciallygratefulfor
all of the students I worked with directly on projects. Justin Malinowski, I really
appreciateyoushowingmetheropesinthelaboratoryandforthegreattimewehad
working on pactamycin. Federico Sorana, I had a blast making pacta derivatives
with you and getting to know more about your life and work in Italy. Steffen,
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