Photoredox activation of SF₆ for fluorination, on-demand automated titration of organometallic reagents in continuous flow, and progress toward an enantioselective synthesis of bedaquiline
Author(s)McTeague, T. Andrew (Thomas Andrew)
Massachusetts Institute of Technology. Department of Chemistry.
Timothy F. Jamison.
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Chapter 1: Photoredox Activation of SF₆ for Fluorination [chemical formula] We report the first practical use of SF₆ as a fluorinating reagent in organic synthesis. Photoredox catalysis enables the in situ conversion of SF6, an inert gas, into an active fluorinating species using visible light and photoredox catalysis. Under these conditions, deoxyfluorination of allylic alcohols is affected with high chemoselectivity and is tolerant of a wide range of functional groups. Application of the methodology in a continuous-flow setup achieves comparable yields to those obtained with a batch setup, while providing drastically increased material throughput of valuable allylic fluoride products. Further studies are necessary to reveal mechanistic details but preliminary experiments indicate that the mechanism of this deoxyfluorination may share features with that of the chlorination of alcohols with thionyl chloride proceeding through activation of the alcohol and subsequent substitution. Although several substrates exhibit a preference for retention of stereochemistry, similar to reactions with thionyl chloride, additional investigations revealed that this selectivity is also dependent on the structure of the substrate. Chapter 2. Automated On-demand Titration of Organometallic Reagents in Continuous Flow [chemical formula] The development of the first automated organometallic titration system using continuous flow is described. In this system, the desired organometallic reagent at variable flow rate is combined with a constant stream of colorimetric indicator and the end-point of the titration is monitored via inline UV/Vis spectroscopy and LabVIEW interface. Through an iterative process, precisions of 2±% can be achieved. In the described configuration, three titrants (N-pivaloyl-o-toluidine, 4-phenylbenzylidene benzylamine, salicylaldehyde phenylhydrazone) can be used for the titration of a wide array of organometallic species (RLi, RMgX, MHMDS) in molarities ranging from 0. 1M to 4.9M. In removing user intervention from the titration process, the developed system greatly reduces the safety hazards associated with handling pyrophoric organometallics and minimizes user-related error. Additionally, the UV/Vis spectrometer enables a level of precision to be achieved that is unattainable with the naked eye. The system also provides the possibility to be integrated with batch and continuous flow reactions, allowing organometallic reagents to be used in at highly accurate concentrations and without re-exposure to the user. Chapter 3. Progress Toward an Enantioselective Synthesis of Bedaquiline [chemical formula] Herein we describe progress toward an enantioselective synthesis of bedaquiline, a novel pharmaceutical used for the treatment of multi-drug resistant tuberculosis. In our efforts, several provisional routes have been investigated and assessed for feasibility. Although decarboxylative arylation, hydrogen atom-transfer, and sulfur-ylide epoxidation proved ineffective for the in these routes, our latest efforts are focused on a much more precedented asymmetric epoxidation which will be the subject of future work. During these investigations, the synthesis of the final epoxide intermediate of our route has been achieved on multi-gram scale, albeit in a racemic fashion. Our proposed route uses readily available, inexpensive starting materials, and would afford bedaquiline in six steps.
Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2017.Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry.
Massachusetts Institute of Technology