Allene Functionalization via Bicyclic Methylene Aziridines: Development of Methods for the Synthesis of Heteroatom Stereotriads, Discovery of Dynamic Ag Catalysis, and Applications Toward the Total Synthesis of Jogyamycin

Many biologically active molecules contain three or more contiguous heteroatom stereocenters (`triads'), but rapid installation of these motifs can be a strategic challenge when one must consider the abundance of possible patterns and stereochemical configurations. In order to accomplish the synthesis of these motifs, we have focused our efforts to develop methods that allow rapid construction of heteroatom stereotriads from allenes. This was accomplished with bicylic methylene aziridine intermediates that are synthesized by an intramolecular metal catalyzed nitrene transfer reaction on an allene. In the first portion of this dissertation, the methylene aziridine's fate will follow an `electrophile then nucleophile' approach. In chapter 2, this strategy yields N,N,X spiroaminals from intermediate diazaspiro[2.2]pentane intermediates. Chapter 3 will focus on a unique rearrangement of these spiroaminals to yield N,O,N stereotriads. Chapter 4 will center on the synthesis of O,O,N stereotriads via dihydroxylation of the methylene aziridine.;In our efforts to synthesize methylene aziridines, we found it increasingly difficult to control the outcome of nitrene transfer reactions. In the second portion of this thesis, Chapter 6, 7, and 8 will detail our efforts to control the selectivity of amination. Chapter 6 examines a method to control for C-H aminated allenes through substrate dependence by Rh catalyzed C-H amination of propargyl C-H bonds which can then be transformed into the desired allene. Chapter 7 will introduce a Ag nitrene transfer catalyst system that is capable of selective allene aziridination. The work in Chapter 8 then evolves this system by demonstrating that this Ag catalyst can be modified by adjustments in ligand stoichiometry. This simple alteration to the system reveals a catalyst that is capable of favoring the C-H insertion products over aziridine products. The consequence of these results gave rise to we now refer to as "dynamic catalysis".;The last chapter of this thesis will delve into our attempts to synthesize the natural product jogyamycin with our allene fuctionalization protocols. These attempts demonstrate that our allene functionalization methods are viable for generating rapid and densely functionalized aminocyclopentitols, which will provide useful synthetically diversified variants of the jogyamycin core for biological evaluation.