Trans Addition of B-X Reagents Across Polarized Triple Bonds and Development of Sphingosine-1-Phosphate Transport Inhibitors

Organoboron compounds are ubiquitous in organic chemistry. Fundamental transformations utilizing organoboron compounds are a necessary addition to any organic chemist's synthetic toolbox. In addition to their extensive use as synthetic intermediates, organoboron compounds are being increasingly studied for their material and medicinal properties. Excitingly, significant advances have been made over the years towards the synthesis of a wide variety of organoboron substrates. In the case of vinylboronic acids, synthesis primarily occurs through cis addition of boron reagents across triple bonds. However, methods affording trans addition products are scarce. Furthermore, many current methods rely on the use of expensive and toxic transition-metal catalysts. Herein, we describe the development of trans addition of boron reagents across polarized triple bonds to afford novel vinylboronic acids. Emphasis is placed on the transition metal-free nature of the reactions as well as the regio- and stereoselectivity observed in the products. In addition, the synthetic utility of the resulting trans addition products is demonstrated in the synthesis of biologically relevant molecules. We first describe the Brønsted base-mediated trans silaboration of propiolamides in which two functional groups with orthogonal reactivity are simultaneously installed. We then go on to describe an organocatalyzed trans hydroboration of propiolate esters as well as a complementary Brønsted base-mediated trans hydroboration reaction of propiolamides. To conclude this portion, we demonstrate how the products from the previous methods can be used to synthesize difluoroborylacrylamides which possess unique and versatile reactivity. Herein we disclose the first small-molecule inhibitors of the sphingosine-1-phosphate (S1P) transporter spinster homolog 2 (SPNS2). While little is known in regard to the structure and function of SPNS2, previous studies have demonstrated the vital role SPNS2 plays in S1P mediated processes and have identified SPNS2 as a potential clinical target. For example, SPNS2 is critical to S1P-mediated lymphocyte egress from primary lymphoid tissues. Thus, small molecule inhibition of SPNS2 represents a novel therapeutic strategy for the treatment of autoimmune disorders such as multiple sclerosis. In this study, we report the discovery of small molecule inhibitors that display low micromolar activity using a novel yeast-based SPNS2 assay. Inhibitor structure-activity-relationship studies led to the discovery of the imidazole-based amine inhibitor 7.54. Furthermore, administration of 7.54 to mice recapitulates the lymphopenic phenotype observed in previous SPNS2 knockout studies.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2020

Author dc:creator

• Fritzemeier, Russell Glenn

Chair dc:contributor.committeechair

• Santos, Webster L.

Committee members dc:contributor.committeemember

• Tanko, James M.
• Kingston, David G. I.
• Carlier, Paul R.

• Boron
• Hydroboration
• Oxaborole
• Sphingosine-1-phosphate

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

vt_gsexam:24617

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/105043