Sara Peeters

• Peeters, Sara; Berntsen, Linn Neerbye; Rongved, Pål & Bonge-Hansen, Tore (2019). Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin. Beilstein Journal of Organic Chemistry. ISSN 2195-951X. 15, s. 2156–2160. doi: 10.3762/bjoc.15.212. Fulltekst i vitenarkiv

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• Spydevold, Ida-Helene Kågen; Bonge-Hansen, Tore & Peeters, Sara (2022). Development of a novel method for synthesis of β-lactams by the use of diazoacetamides. Universitetet i Oslo. Vis sammendrag

  Due to the increase in antibacterial resistance, the world is in need of new, powerful antibacterial agents and synthetic methods to halter this trend. This study focused on broadening the scope of a new synthesis of β-lactams developed by Kaupang and Konradsen. The method uses carbenes generated from α-bromodiazoacetamides in an intramolecular C-H insertion reaction to generate the β-lactam moiety. With this new method, it could be possible to synthesize new β-lactam molecules. This creates an opportunity of discovering molecules with novel antibacterial properties beyond what is known today. The method was successfully applied in the syntheses of the diazoacetamides with a methyl, ethyl or isopropyl ester. Only the β-lactam with the ethyl ester was successfully synthesized from the diazoacetamides. Consequently, not enough data was available to determine how the product distribution in this synthetic step was affected by the ester. Additional focus of this thesis was on improving the synthesis of the diazoacetamides, due to a difficult purification and moderate yields. Several test reactions were conducted in order to develop a one-step synthesis of the diazoacetamides. A one-step reaction could avoid the problems in the original procedure, in addition to making the β-lactam formation more effective. The test reaction using 2,5-dioxypyrrolidin-1-yl 2-diazoacetate and methyl D-prolinate as reactants seems promising, but more work is necessary to develop the procedure further.

• Marcus, Jørgen; Bonge-Hansen, Tore & Peeters, Sara (2022). Reactivity of Halodiazoacetates and Halodiazoamides. Universitetet i Oslo. Vis sammendrag

  The work in this thesis is divided into four parts: 1. The study and development of a novel synthesis of 2,5-dioxopyrrolidin-1-yl 2-diazoacetate, a much desired building block (BB) for synthesis of diazo-esters and -amides. The existing literature procedure gave low yields. Hence, a new synthesis for making the BB was developed based on a coupling reaction of a carboxylic acid and N-hydroxysuccinimide (NHS). The reaction was optimized by investigating reaction conditions like solvent, base, concentrations, reaction temperature, reaction time and coupling reagents. The developed method gave better yield than the existing literature procedure. The scope and limitation of BB as a reagent for synthesizing diazo-amides and -esters was investigated by synthesizing a series of diazoamides and a diazoester. 2. Investigation of the thermal stability of a series of halo diazo-esters and -amides. Halo diazo-esters and amides have low thermal stability and their thermal decomposition rates have been investigated with a method based on IR spectroscopy. Significant differences in thermal stability of secondary and tertiary diazo-amides and -esters was uncovered. 3. A DFT-study of the singlet-triplet gap and the barriers towards release of N2 (g) from the diazo compound to produce the corresponding carbenes. DFT calculations were carried out to compliment the experimental results. The height of the calculated transition barriers correlated with the measured half-lives. Differences in the triplet-singlet gap for diazo-esters and -amides were uncovered. 4. A brief exploration and investigation of a few selected test reactions. The reactivity of the halo diazo-amides and -esters were briefly studied in a few selected cyclopropanation and C-H insertion reactions under catalytic conditions. Among the test reactions was rhodium catalyzed cyclopropanation of styrene, uncovering differences in the diasteromeric ratio of the cyclopropane product of Br-2,2,2-trifluoroethyl 2-diazoacetate (TFEDA) and Br-2,2,2-trichloroethyl 2-diazoacetate (TCEFA) compared to Br-ethyl diazoacetate (EDA). In test reactions with halo diazoamides no cyclopropanation or C-H insertion products were found. The products that were found in all the test reactions had gone through the same type of reaction.

• Peeters, Sara (2018). A novel method for the synthesis of quinolones. Total synthesis of Norfloxacin. Universitetet i Oslo. Vis sammendrag

  Quinolones are a class of synthetic compounds that are used as antibacterial agents since their discovery in the 1960s. Their chemical synthesis has mostly been based on ring-closing reactions, for instance the Gould-Jacobs cyclization reaction. This project demonstrates the synthesis of (fluoro)quinolones in general with a new and efficient method that employs halogenated ethyl diazoacetates in reaction with indole-derivatives; forming quinoline precursors that convert easily to quinolones. The key reaction in the new method is the synthesis of the quinoline precursor. The reaction was based on recent work in our group, and the proposed reaction mechanism was a cyclopropanation reaction between rhodium(II)-carbenoids (of α-halodiazoacetates) and indole-derivatives, followed by a ring expansion to quinoline structures. Cyclopropanation of heterocycles followed by ring expansion has historically been called the “abnormal” Reimer-Tiemann reaction. Because of its significance in this project, the reaction was investigated further by changing the catalyst and the reaction solvent. The results implicated that the original conditions still were the best for synthesis of quinoline structures, but changing the reaction solvent to toluene gave also good yields. Converting quinolines to 4-quinolones was done by alcoholysis according to a literature procedure. The halogenated ethyl diazoacetates were synthesized according to a new and safe procedure previously developed in our group. The reaction was quantitively analyzed during this project and verified quantitative conversion of ethyl diazoacetate to its halogenated-analogs. Without signs of dimerization, high yields of these species were obtained after purification by filtration through a pre-cooled silica plug. Optimization was attempted by using other methods for the synthesis of the α-halodiazoacetates that involved an extraction step rather than a filtration step. However, the original procedure still gave the best yield. The new and efficient method was used to synthesize 4-quinolone-3-carboxylic acid as a quinolone core structure, and ethyl 6,7-difluoro-4-quinolone-3-carboxylate as a fluoroquinolone key intermediate. The fluoroquinolone was reacted further in literature-based reactions to synthesize Norfloxacin as its hydrochloride salt.

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