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Efforts toward the total synthesis of (–)-Bousangine A and the development of bioorthogonal tools for applications in chemical biology

Shajan, Femil , Joseph
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Thesis/Dissertation
Date
2025-12
Advisor
Wang, Rongsheng, E
Committee member
Kim, Daniel, K
Sieburth, Scott, McN
Blass, Benjamin, E
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Department
Chemistry
Subject
Organic chemistry
 Chemistry
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Abstract
This dissertation presents the development of novel synthetic methodologies and chemical biology tools that bridge small molecule chemistry, peptide chemistry, and bioconjugation. First, a synthetic route toward (–)-Bousangine A, an unreported Aspidosperma alkaloid congener, is demonstrated using a 2-N-sulfinyl metallo-1,3-dieneamine (2-NSMD)-driven Domino Michael/Michael annulation reaction. A direct N-animation strategy was established for late-stage N–N bond formation, transforming amines into hydrazines or Boc-protected derivatives via anomeric amide electrophiles. The process proceeds through N-iminophosphorane intermediates, which can be hydrolyzed to hydrazines or converted to hydrazides. The operational simplicity, mild conditions, and compatibility with bioactive molecules highlight its broad applicability. Biocompatible linkers for phototriggered drug delivery systems are highly demanding. Herein, we showcase Tetrazene molecular scaffolds as novel biocompatible, photolabile handles. A variety of secondary amine-derived cyclic tetrazenes, including both homo- and heterodimers, were synthesized using anomeric amides as electrophilic nitrogen synthons. Upon reaction with an anomeric amide, the N-Nitrene generated in situ from the amines is dimerized to furnish the corresponding tetrazenes. We discovered these scaffolds can be photocleaved under biomimetic conditions using iridium-mediated photocatalysis. Translating this technology to perform biorthogonal photocleavage in live mammalian cells is in progress. The potential of tetrazene as a photocleavable linker for antibody-drug conjugates is demonstrated as proof of concept. Finally, the unique reactivity of a dimeric dimethylamine hypervalent selenium compound was harnessed for dual labeling of phenolic molecules under biocompatible conditions. This chemistry has been successfully applied to small molecules and peptides, with ongoing efforts focused on the selective profiling of DOPA post-translational modifications in peptides and proteins. Collectively, this work expands the synthetic toolbox for constructing complex molecules, site-selective bioconjugation, and targeted chemical biology applications, offering versatile strategies for drug discovery and therapeutic development.
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