Nickel catalyzed formation of 1,2-cis-2-amino sugars to access important biomolecules

428 Pages·2017·15.15 MB·English

University of Iowa
Iowa Research Online
Theses and Dissertations
Summer 2015
Nickel catalyzed formation of 1,2-cis-2-amino
sugars to access important biomolecules
Matthew S. McConnell
University of Iowa
Copyright 2015 Matthew S. McConnell
This dissertation is available at Iowa Research Online: https://ir.uiowa.edu/etd/1881
Recommended Citation
McConnell, Matthew S.. "Nickel catalyzed formation of 1,2-cis-2-amino sugars to access important biomolecules." PhD (Doctor of
Philosophy) thesis, University of Iowa, 2015.
https://doi.org/10.17077/etd.82eyeifn
Follow this and additional works at:https://ir.uiowa.edu/etd
Part of theChemistry Commons
NICKEL CATALYZED FORMATION OF 1,2-CIS-2-AMINO SUGARS TO ACCESS
IMPORTANT BIOMOLECULES
by
Matthew McConnell
A thesis submitted in partial fulfillment
of the requirements for the Doctor of
Philosophy degree in Chemistry
in the Graduate College of

The University of Iowa
August 2015
Thesis Supervisor: Associate Professor Hien M. Nguyen
Graduate College
The University of Iowa
Iowa City, Iowa
CERTIFICATE OF APPROVAL
_______________________
PH.D. THESIS
_______________
This is to certify that the Ph.D. thesis of
Matthew McConnell
has been approved by the Examining Committee
for the thesis requirement for the Doctor of Philosophy
degree in Chemistry at the August 2015 graduation.
Thesis Committee: ___________________________________
Hien M. Nguyen, Thesis Supervisor
___________________________________
Daniel Quinn
___________________________________
Leonard R. MacGillivray
___________________________________
Scott Shaw
___________________________________
Horacio Olivo
For my Mom, Dad, and Sister
For all your love, encouragement and support
Finally, I get to join the club

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Research is to see what everybody else has seen, and to think what nobody else has
thought.

Albert Szent-Gyorgyi

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ACKNOWLEDGEMENTS

So many people have contributed to bringing this work to fruition. First and
foremost, none of this would have been possible without the care and guidance of my
advisor, Professor Hien M. Nguyen. He has been an incredible advisor and for which I
will forever be grateful. I would also like to render my sincere thanks for your
confidence in me even when I didn’t have it in myself. I have learned much from you
over the years.
To my committee members, Professor Quinn, Professor MacGillivray, Professor
Shaw and Professor Olivo, thank you for your advice, guidance and discussions.
Both past and present members of the Nguyen group need to be recognized. I
would like to thank Dr. Enoch Mensah, Dr. Ravi Loka, and Dr. Fei Yu, whom I had the
privilege to work with during the various stages of my graduate career. I learned a lot
from them, and were very instrumental to my development as a scientist. They are
friends as well as colleagues. My gratitude is also extended to Mathew McKay and
Jeffery Arnold. You did not only share a lab with me for many years, but were also great
friends. I owe a lot to you for the support over the years, and could not ask for better
labmates. I would also like to express my sincere thanks to the rest of the members of
our research group, as well as Prof. Ned Bowden and Prof. Jon Houtman for their
numerous help in diverse ways in helping bring this work to fruition.
Lastly, I would like to thank my late Mom and Dad. Your love, guidance,
encouragements, and support brought me to this far, and shaped the man I am today. I
love you guys. To my sister, Nisha, thank you for your support. For my angel, Rebekah,
you’ve always been there for me and I truly appreciate it. I love you all.

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SCHOLARLY ABSTRACT

The stereoselective formation of 1,2-cis-2-amino glycosides remains a
challenging obstacle for researchers seeking to study glycan function in nature. A variety
of techniques to form α-linked C(2)-aminoglycosides are examined herein. The most
prominent of these techniques is the nickel catalyzed stereoselective coupling of C(2)-N-
benzylidine protected trichloroacetimidates to form 1,2-cis-2-amino sugars. This
protocol demonstrates excellent α-selectivity and is applicable to a large structural
variety of C(2)-aminoglycosyl donors and acceptors.
We also describe the effectiveness of the cationic nickel(II) species, Ni(4-F-
PhCN) OTf , at catalyzing formation of 1,2-cis-2-amino glycosidic bonds between C(2)-
4 2
N-substituted benzylidene trihaloacetimidate donors and myo-inositol acceptors under
mild conditions, allowing rapid access to pseudosaccharides of glycosylphosphatidyl
inositol (GPI) anchors and mycothiol (MSH) in good yield and with excellent α-
selectivity (α:β = 10:1 – >20:1). In stark contrast, employing conventional Lewis acids,
TMSOTf and BF .OEt , to activate trichloroacetimidate donors provided the desired
3 2
pseudodisaccharides as a 1:1 mixture of α- and β-isomers. Additionally, the facile
synthesis of both C(1)- and C(6)-hydroxyl myo-inositols bearing differentiated protecting
groups from a common and easily attainable intermediate allows access to a wide variety
of GPI anchor and MSH pseudosaccharides.
The highly α-selective and scalable synthesis of the Fmoc-protected GalNAc-
threonine amino acid and T antigen in large quantities is also described. The
N
challenging 1,2-cis-2-amino glycosidic bond is addressed through a coupling of threonine
residues with C(2)-N-ortho-(trifluoromethyl)benzylidenamino trihaloacetimidates
mediated by Ni(4-F-PhCN) (OTf) . The desired 1,2-cis-2-amino glycoside was obtained
4 2
in large quantities with α-only selectivity and subsequently transformed into the Fmoc-
protected GalNAc-threonine and T antigen.
N
v
With the establishment of 1,2-cis-selective synthesis of heparan disaccharides, we
sought to develop multivalent inhibitors of heparanase. A model study of protein/glycan
interactions, in which various macromolecular architectures were examined, was
developed using Concanavalin A as the model protein. Preparations of the highly-
ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary
glycopolymers of α-mannose and β-glucose were achieved via ring opening metathesis
polymerization. Isothermal titration calorimetry measurements of these synthetic
glycopolymers with Concanavalin A, which has been reported to bind strongly to α-
mannose unit, revealed that heterofunctional diantennary architectures bearing both α-
mannose and non-binding β-glucose residues, glucose units, enhanced binding affinity.
Despite the presence of non-binding β-glucose unit on the polymer chain, a highly-
ordered heterofunctional diantennary glycopolymer (K = 16.1 x 106 M-1) can effectively
a
bind to Concanavalin A comparably to the homofunctional diantennary mannose
glycopolymer (K = 30 x 106 M-1). The monoantennary mannose glycopolymer (K =
a a
7.94 x 106 M-1) does not bind to ConA as strongly as the heterofunctional diantennary
glycopolymer.

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PUBLIC ABSTRACT

The stereoselective formation of 1,2-cis-2-amino glycosides remains a
challenging obstacle for researchers seeking to study glycan function in nature. A variety
of techniques to form α-linked C(2)-aminoglycosides are examined herein. The most
prominent of these techniques is the nickel catalyzed stereoselective coupling of C(2)-N-
benzylidine protected trichloroacetimidates to form 1,2-cis-2-amino sugars. This
protocol demonstrates excellent α-selectivity and is applicable to a large structural
variety of C(2)-aminoglycosyl donors and acceptors.
The application of the nickel catalyzed stereoselective coupling of C(2)-N-
benzylidine protected trichloroacetimidates toward the synthesis of pseudosaccharides of
glycosylphosphatidyl inositol (GPI) anchors and mycothiol (MSH) in good yield and
with excellent α-selectivity was also examined. In stark contrast, employing
conventional Lewis acids to activate trichloroacetimidate donors provided the desired
pseudodisaccharides with poor α-selectivity. Additionally, the facile synthesis of both
C(1)- and C(6)-hydroxyl myo-inositols bearing differentiated protecting groups from a
common and easily attainable intermediate allows access to a wide variety of GPI anchor
and MSH pseudosaccharides.
The highly α-selective and scalable synthesis of the Fmoc-protected GalNAc-
threonine amino acid and TN antigen in large quantities is also described. The
challenging 1,2-cis-2-amino glycosidic bond is addressed through a coupling of threonine
residues with C(2)-N-ortho-(trifluoromethyl)benzylidenamino trihaloacetimidates
mediated by Ni(4-F-PhCN) (OTf) . The desired 1,2-cis-2-amino glycoside was obtained
4 2
in large quantities with α-only selectivity and subsequently transformed into the Fmoc-
protected GalNAc-threonine and T antigen.
N
With the establishment of 1,2-cis-selective synthesis of heparan disaccharides, we
sought to develop multivalent inhibitors of heparanase. A model study of protein/glycan
vii
interactions, in which various macromolecular architectures were examined, was
developed using Concanavalin A as the model protein. Preparations of the highly-
ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary
glycopolymers of α-mannose and β-glucose were achieved via ring opening metathesis
polymerization. Isothermal titration calorimetry measurements of these synthetic
glycopolymers with Concanavalin A, which has been reported to bind strongly to α-
mannose unit, revealed that heterofunctional diantennary architectures bearing both α-
mannose and non-binding β-glucose residues, glucose units, enhanced binding affinity.

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