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UBC Theses and Dissertations
Synthesis and applications of alkyl and aryl vinyl sulfides and sidearm-substituted bisoxazolines Bichler, Paul
Abstract
The presence of sulfur in numerous blockbuster drugs, natural products and other medicinally active molecules necessitates the development of efficient methods for the synthesis of carbon-sulfur bonds. Transition metal approaches towards the construction of CS bonds have largely aided in the synthesis of aryl thioethers and related functionalities. However, few examples of catalytic processes demonstrate a tolerance for less reactive aliphatic thiols, leading to a widespread belief of an incompatibility of these substrates in catalytic C-S bond formation. To this end, our group has demonstrated the first examples of rhodium-catalyzed alkyne hydrothiolation processes for the synthesis of alkyl vinyl sulfides. The work detailed in this thesis encompasses the use of Wilkinson’s catalyst in alkyne hydrothiolation for the selective formation of E-linear alkyl and aryl vinyl sulfides. The substrate scope of this process is quite general, tolerating a variety of useful functional groups capable of undergoing further elaboration. Interestingly, alkyne substrates with adjacent heteroatoms undergo a reversal of regioselectivity, often favouring the branched regioisomer relative to the expected E-linear vinyl sulfide. The use of our catalytic alkyne hydrothiolation methodology was applied to the synthesis of a promising cancer chemotherapeutic agent, ON 01910.Na, which shows broad-spectrum activity towards a large number of cancer cell lines. Additionally, the reactivity of aryl and vinyl sulfides was evaluated within the context of vinylogous thioesters capable of undergoing electrocyclizations. The development of a Sonogashira cross-coupling thio-Michael addition sequence allowed for the synthesis of a variety of heteroaromatic substituted vinylogous thioesters. The treatment of these substrates with excess triflic acid proved optimal in facilitating cyclization to thiaindanone-type products, a motif found in molecules with application towards the treatment of neurologic diseases. The observation of interesting skeletal rearrangements suggests a competition between the expected Nazarov cyclization and an intramolecular Friedel-Crafts acylation. Lastly, a series of sidearm-substituted bisoxazolines were synthesized and a preliminary investigation of their coordination chemistry is reported. The application of these complexes towards a variety of asymmetric transformations, including the Nazarov cyclization, is currently ongoing.
Item Metadata
Title |
Synthesis and applications of alkyl and aryl vinyl sulfides and sidearm-substituted bisoxazolines
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2012
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Description |
The presence of sulfur in numerous blockbuster drugs, natural products and other
medicinally active molecules necessitates the development of efficient methods for the
synthesis of carbon-sulfur bonds. Transition metal approaches towards the construction of CS
bonds have largely aided in the synthesis of aryl thioethers and related functionalities.
However, few examples of catalytic processes demonstrate a tolerance for less reactive
aliphatic thiols, leading to a widespread belief of an incompatibility of these substrates in
catalytic C-S bond formation.
To this end, our group has demonstrated the first examples of rhodium-catalyzed
alkyne hydrothiolation processes for the synthesis of alkyl vinyl sulfides. The work detailed
in this thesis encompasses the use of Wilkinson’s catalyst in alkyne hydrothiolation for the
selective formation of E-linear alkyl and aryl vinyl sulfides. The substrate scope of this
process is quite general, tolerating a variety of useful functional groups capable of
undergoing further elaboration. Interestingly, alkyne substrates with adjacent heteroatoms
undergo a reversal of regioselectivity, often favouring the branched regioisomer relative to
the expected E-linear vinyl sulfide. The use of our catalytic alkyne hydrothiolation
methodology was applied to the synthesis of a promising cancer chemotherapeutic agent, ON
01910.Na, which shows broad-spectrum activity towards a large number of cancer cell lines.
Additionally, the reactivity of aryl and vinyl sulfides was evaluated within the context
of vinylogous thioesters capable of undergoing electrocyclizations. The development of a
Sonogashira cross-coupling thio-Michael addition sequence allowed for the synthesis of a
variety of heteroaromatic substituted vinylogous thioesters. The treatment of these substrates
with excess triflic acid proved optimal in facilitating cyclization to thiaindanone-type
products, a motif found in molecules with application towards the treatment of neurologic
diseases. The observation of interesting skeletal rearrangements suggests a competition
between the expected Nazarov cyclization and an intramolecular Friedel-Crafts acylation.
Lastly, a series of sidearm-substituted bisoxazolines were synthesized and a
preliminary investigation of their coordination chemistry is reported. The application of these
complexes towards a variety of asymmetric transformations, including the Nazarov
cyclization, is currently ongoing.
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Genre | |
Type | |
Language |
eng
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Date Available |
2013-08-31
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0062322
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2012-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International