New methods for the construction of selectively difluorinated carbocycles

Student thesis: Doctoral Thesis

Abstract

The design and synthesis of geminal difluoromethylated compounds is extremely important owing to their unique biological properties, such as enzyme inhibition, pKa modulation and improving metabolic stability. However, efficient methods, starting from sustainable low cost starting materials, for the introduction of the gem-difluoromethylene group into cyclic molecules are still scarce. Work towards developing the de novo synthesis of difluorinated sugar analogues by using trifluoroethanol as an inexpensive building block is presented.The Saegusa-Ito cyclisation was utilised for the construction of selectively fluorinated carbocycles. Difluorinated silyl enol ether precursors were prepared in two synthetic steps from commercially available trifluoroethanol. Protection with diethylcarbamoyl chloride was followed by dehydrofluorination/lithiation, under cryogenic conditions, and the metalated enol carbamate generated in situ trapped with either a ketone or aldehyde electrophile.Following transacylation, the enolate species could be trapped with chlorotriethylsilane to afford silyl enol ethers in good yield. Cyclisations ensued smoothly under mild conditions. A combination of copper(I) chloride and Pd(OAc)2 in acetonitrile at 70 °C proved the most effective catalytic system. α,α-Difluoroketones were often isolated as mixtures of ketone and the corresponding hydrate; however, these mixtures could be efficiently dried in a vacuum oven to deliver pure ketones.The cyclisation of difluorinated enol acetals as alternative cyclisation mediators was investigated. These precursors were also synthesised in two steps from trifluoroethanol using cryogenic lithium based chemistry. Using a catalytic 1:1 mixture of 1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride and silver hexafluoroantimonate(V), the intramolecular carbocyclisation of difluorinated enol acetals has been achieved.Difluorinated enol acetals bearing a pendant alkene group can be cyclised and reduced in situ using tetrabutylammonium borohydride in one pot to form fluorinated diol motifs. Alternatively, the cyclisation of terminal alkynes allows for the concise synthesis of fluorinated pyran scaffolds. Both cyclisation processes can be performed under mild conditions allowing for the construction of complex difluorinated cyclic systems.
Date of Award1 Oct 2017
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsCARNEGIE TRUST FOR THE
SupervisorCraig Jamieson (Supervisor) & John Murphy (Supervisor)

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