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Title: New methods for nucleophilic fluorination
Author: Cresswell, Alex
ISNI:       0000 0004 2721 8560
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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This thesis describes investigations into the utility of boron fluorides and tetrafluoroborates as sources of nucleophilic fluorine. Chapter 1 discusses the history and importance of the field of organofluorine chemistry and outlines some of the principle motivations for the site-selective fluorination of organic molecules. Some of the most commonly useed methods of nucleophilic fluorination are briefly surveyed, with an emphasis on the formation of fluorinated stereogenic centres. Literature precedent for the use of tetrafluoroborates and boron trifluoride as nucleophilic fluorinating agents is also presented. Chapter 2 describes the development of a highly regio- and stereoselective SNi-type ring-opening fluorination of trans-β-substituted aryl epoxides using BF₃●OEt₂ as a nucleophilic fluorinating agent. This robust and scalable protocol grants efficient access to a variety of functionalised benzylic fluoride building blocks, and provides a solution to the problem of stereocontrol in the synthesis of this class of compounds. To highlight the utility of the resultant syn-fluorohydrins in the synthesis of stereodefined β-fluoro β-aryl amines, their elaboration to a range of aryl-substituted β-fluoroamphetamines is demonstrated. Chapter 3 introduces the concept of tuning the reactivity of BF₃ by replacing one or two of the fluoro ligands on boron for electron-donating alkoxy group(s). On this basis, pinacolatoboron fluoride (pinBF) [which may be prepared in situ by pre-mixing BF₃●OEt₂ and bis(O-trimethylsilyl)pinacol] is identified as a superior reagent to BF₃●OEt₂ for the ring-opening fluorination of trans-β-substituted aryl epoxides bearing electron-rich aryl groups. Chapter 4 details a highly regioselective and stereospecific SN2-type ring-opening fluorination of 2,3- and 3,4-epoxy amines using HBF₄●OEt₂ as a nucleophilic flurine source. The reactions are both operationally simple to perform and readily scalable, and proceed to completion within 5 min at ambient temperature, providing a highly practical and economical route to stereodefined amino fluorohydrins. To highlight the synthetic utility of this reaction in the preparation of pharmaceutically-important β-fluoro amines, a concise de novo asymmetric synthesis of (S,S)-3-deoxy-3-fluorosafingol is performed. Chapter 5 chronicles the successful development of a protocol for the direct hydroxyfluorination of allylic amines to the corresponding amino fluorohydrins, using m--CPBA as the oxidant and HBF₄●OEt₂ in a dual role as both the Brønstead acid N-protecting agent and nucleophilic fluorine source. With chiral allylic amines which are conformationally biased or constrained, the diastereofacial selectivity of the reaction can be controlled by altering the concentration of HBF₄●OEt₂ employed in the reaction, allowing for a diastereodivergent hydroxyfluorination process. The synthetic utility of this methodology is demonstrated via its application to the diastereodivergent synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingosine, each in 5 steps from Garner's aldehyde. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3, 4 and 5.
Supervisor: Davies, Stephen G. ; Melloney, Morris Sponsor: Syngenta
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic synthesis ; Organic chemistry ; Synthetic organic chemistry ; fluorination ; boron trifluoride ; epoxides