Tandem reaction sequences on a zirconocene template

The novel research work described in this thesis covers three areas of organozirconium chemistry.The first area concerns the synthesis of rigid core structures containing the cis-bicyclo[3.3.0]oct-2-ene skeleton. Zirconocene mediated co-cyclisation of 1,6-enynes provides unsaturated 5-membered zirconacycles which are homologated to 6-membered zirconacycles by insertion of 1,1-dihalo-1-lithio species (dihalogenocarbenoids). Further rearrangement to a novel zirconium-alkenylidene complex driven by acetylides provided a powerful method for a rapid construction of novel bicyclic compounds with the potential for functionalization at multiple sites. Such obtained analogues provided an attractive template for structure-activity studies with respect to investigating the biological function of the human orphan nuclear receptors: LRH-1 and SF-1. Equivalent tandem insertion of 1,1-dihalo-1-lithio species and lithium acetylides into saturated zirconacycles resulted in the synthesis of novel bicyclo[3.3.0]octanes, though in many cases limited by a ?-H elimination process.In the second area is presented research work relating to acyclic organozirconocene systems. Insertion of allenyl and propargyl carbenoids into organochlorozirconocenes and bisalkyl/-alkynyl zirconocenes led to 1,2-zirconate rearrangement with expulsion of the corresponding leaving group. Lewis acid promoted insertion of aldehydes and ketones into the resulting allenyl/propargyl zirconocene intermediate gave after hydrolysis a series of propargylic alcohols. Insertion of carbenoids derived from chiral propargyl tosylates into organochlorozirconocenes and further 1,2-metallate rearrangement gave the final alcohols as enantiomerically enriched products.The third area was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo[4.3.0]nonane unit with four contiguous stereocentres. Zirconocene mediated co-cyclisation of the appropriate precursor provided four possible diastereoisomers. It was proved that thermodynamic equilibration of the zirconacycle gives the desired bicyclic product as a major isomer. Although the target molecule was not realised, thorough work on Zr-based total synthesis of mucosin has been achieved and a viable route for successful completion of the synthesis has also been proposed

The first total synthesis of (+)-mucosin

The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core

Tandem reaction sequences on a zirconocene template

The novel research work described in this thesis covers three areas of organozirconium chemistry. The first area concerns the synthesis of rigid core structures containing the cis-bicyclo[3.3.0]oct-2-ene skeleton. Zirconocene mediated co-cyclisation of 1,6-enynes provides unsaturated 5-membered zirconacycles which are homologated to 6-membered zirconacycles by insertion of 1,1-dihalo-1-lithio species (dihalogenocarbenoids). Further rearrangement to a novel zirconium-alkenylidene complex driven by acetylides provided a powerful method for a rapid construction of novel bicyclic compounds with the potential for functionalization at multiple sites. Such obtained analogues provided an attractive template for structure-activity studies with respect to investigating the biological function of the human orphan nuclear receptors: LRH-1 and SF-1. Equivalent tandem insertion of 1,1-dihalo-1-lithio species and lithium acetylides into saturated zirconacycles resulted in the synthesis of novel bicyclo[3.3.0]octanes, though in many cases limited by a β-H elimination process. In the second area is presented research work relating to acyclic organozirconocene systems. Insertion of allenyl and propargyl carbenoids into organochlorozirconocenes and bisalkyl/-alkynyl zirconocenes led to 1,2-zirconate rearrangement with expulsion of the corresponding leaving group. Lewis acid promoted insertion of aldehydes and ketones into the resulting allenyl/propargyl zirconocene intermediate gave after hydrolysis a series of propargylic alcohols. Insertion of carbenoids derived from chiral propargyl tosylates into organochlorozirconocenes and further 1,2-metallate rearrangement gave the final alcohols as enantiomerically enriched products. The third area was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo[4.3.0]nonane unit with four contiguous stereocentres. Zirconocene mediated co-cyclisation of the appropriate precursor provided four possible diastereoisomers. It was proved that thermodynamic equilibration of the zirconacycle gives the desired bicyclic product as a major isomer. Although the target molecule was not realised, thorough work on Zr-based total synthesis of mucosin has been achieved and a viable route for successful completion of the synthesis has also been proposed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Analysis of Student Perceptions of Just-In-Time Teaching Pedagogy in PharmD Microbiology and Immunology Courses

Just-In-Time Teaching (JiTT) active learning pedagogy is utilized by various disciplines, but its value in a professional pharmacy curriculum has not yet been demonstrated. The purpose of our research study is to implement and evaluate JiTT in a Doctor of Pharmacy (PharmD) program. The impetus in implementing JiTT into a PharmD curriculum was to provide students with an out-of-classroom learning opportunity to enhance knowledge-based skills. The current study summarizes the implementation of JiTT in four distinct instances: two iterations of the required courses “Integrated Microbiology and Virology” (Fall 2016 and Fall 2017) and “Integrated Immunology” (Winter 2016–2017 and Winter 2017–2018). JiTT included knowledge-based questions in multiple-choice format, integrated case studies, and student responses prior to the actual lecture session. After the conclusion of each course, students were asked to provide feedback on the utilization of JiTT by way of an anonymous survey. Following the Fall 2016 iteration of the Microbiology & Virology course, students found the integrated case studies to be beneficial (mean = 3.27 out of a maximum of 4, SD = 0.62), and their overall endorsement of JiTT was high (mean = 3.61 out of 4, SD = 0.50). For the other three courses included in this study, the primary dependent variable was the student’s average rating of JiTT, rated on a five-point scale. Aggregating the scores from the Fall 2017 iteration of the Integrated Microbiology & Virology course and both instances of the Immunology course, students rated JiTT very favorably (mean = 4.17 out of a maximum of 5, SD = 0.77). Students’ performances in JiTT-based courses were compared against non-JiTT-based courses. Analysis of assessment data for student’s performance on knowledge-based questions showed JiTT was helpful for student learning and JiTT-based courses had more consistent exam scores compared to non-JiTT-based courses. The current results are a promising initial step in validating the usefulness of JiTT in a pharmacy program and lays the foundation for future studies aimed at a direct comparison between a traditional lecture style and JiTT pedagogy implemented into PharmD curricula

The first total synthesis of (+)-mucosin

The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core

Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2)

The crystal structure† of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1 / SF-1 agonists (e.g. RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102, RJW103). The series based on 1-ethenyl substitution were acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes

Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides

The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery

Synthesis of homopropargyl alcohols via insertion of allenyl carbenoids into acyclic organozirconium bonds

Insertion of allenylcarbenoids (3-tosyloxy-1-lithioalk-1-ynes) into organozirconium complexes gave allenyl-zirconocenes via a 1,2-zirconate rearrangement. Trapping of the allenyl-zirconium species with aldehydes and ketones gave, after hydrolysis, a series of homopropargylalcohols. Enantioenriched products were prepared by insertion of the lithium carbenoid derived from (S)-but-3-yn-2-yl 4-toluenesulfonate into alkyl- and alkenyl-chlorozirconocenes

Analysis of Student Perceptions of Just-In-Time Teaching Pedagogy in PharmD Microbiology and Immunology Courses

Just-In-Time Teaching (JiTT) active learning pedagogy is utilized by various disciplines, but its value in a professional pharmacy curriculum has not yet been demonstrated. The purpose of our research study is to implement and evaluate JiTT in a Doctor of Pharmacy (PharmD) program. The impetus in implementing JiTT into a PharmD curriculum was to provide students with an out-of-classroom learning opportunity to enhance knowledge-based skills. The current study summarizes the implementation of JiTT in four distinct instances: two iterations of the required courses “Integrated Microbiology and Virology” (Fall 2016 and Fall 2017) and “Integrated Immunology” (Winter 2016–2017 and Winter 2017–2018). JiTT included knowledge-based questions in multiple-choice format, integrated case studies, and student responses prior to the actual lecture session. After the conclusion of each course, students were asked to provide feedback on the utilization of JiTT by way of an anonymous survey. Following the Fall 2016 iteration of the Microbiology & Virology course, students found the integrated case studies to be beneficial (mean = 3.27 out of a maximum of 4, SD = 0.62), and their overall endorsement of JiTT was high (mean = 3.61 out of 4, SD = 0.50). For the other three courses included in this study, the primary dependent variable was the student’s average rating of JiTT, rated on a five-point scale. Aggregating the scores from the Fall 2017 iteration of the Integrated Microbiology & Virology course and both instances of the Immunology course, students rated JiTT very favorably (mean = 4.17 out of a maximum of 5, SD = 0.77). Students’ performances in JiTT-based courses were compared against non-JiTT-based courses. Analysis of assessment data for student’s performance on knowledge-based questions showed JiTT was helpful for student learning and JiTT-based courses had more consistent exam scores compared to non-JiTT-based courses. The current results are a promising initial step in validating the usefulness of JiTT in a pharmacy program and lays the foundation for future studies aimed at a direct comparison between a traditional lecture style and JiTT pedagogy implemented into PharmD curricula

Controlling Extra- and Intramacrophagic Mycobacterium abscessus by Targeting Mycolic Acid Transport

Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) causing serious infections especially among cystic fibrosis patients. Extremely limited therapeutic options against M. abscessus and a rise in infections with this mycobacterium require novel chemotherapies and a better understanding of how the bacterium causes infection. Different from most RGM, M. abscessus can survive inside macrophages and persist for long durations in infected tissues. We recently delineated differences in the infective programs followed by smooth (S) and rough (R) variants of M. abscessus. Unexpectedly, we found that the S variant behaves like pathogenic slow growing mycobacteria, through maintaining a block on the phagosome maturation process and by inducing phagosome-cytosol communications. On the other hand, R variant infection triggers autophagy and apoptosis, reminiscent of the way that macrophages control RGM. However, the R variant has an exquisite capacity to form extracellular cords, allowing these bacteria to rapidly divide and evade phagocytosis. Therefore, new chemotherapeutic interventions against M. abscessus need to efficiently deal with both the reservoir of intracellular bacilli and the extracellular cords. In this context, we recently identified two chemical entities that were very effective against both M. abscessus populations. Although being structurally unrelated these two chemotypes inhibit the activity of the essential mycolic acid transporter, MmpL3. In this Perspective, we aimed to highlight recent insights into how M. abscessus interacts with phagocytic cells and how the inhibition of mycolic acid transport in this pathogenic RGM could be an efficient means to control both intracellular and extracellular populations of the bacterium