Organic Peroxides in Radical Chemistry and Stereochemical Study of the Intramolecular Schmidt Reaction

Organic peroxides and organic azides are highly energetic functional groups and have been utilized in many synthetic applications for over a hundred years. The first part of this thesis focuses on organic peroxides as a source of radicals. After a general introduction to organic peroxides in radical chemistry in chapter 1, peroxyoxalates and diacyl peroxides move into the focus of this thesis (chapters 2-5). Di-tert-butyl peroxyoxalates (DTBPO) was found to be an ideal radical initiator in the key step of our short enantioselective synthesis of the natural product (+)-brefeldin C described in chapter 2. Inspired by the thermal decomposition of DTBPO, peroxyoxalates were studied as a source of tertiary alkoxy radicals. An operationally simple method to access these radicals from tertiary alkyl hydroperoxides was developed using oxalyl chloride and is presented in chapter 3. The alkoxy radicals have been used in particular for the synthesis of various 4’ functionalized alcohols via 1,5-hydrogen atom transfer and subsequent trapping of the relocated radical with a suitable radical trap. The one-pot procedure is fast, does not require workup after the reaction, and yields the functionalized alcohols in moderate to excellent yields. Unpublished results from work using this method and investigations on an analogous mechanism based on borinate radicals are compiled in chapter 4. Due to the unstable nature of organic peroxides and the hazards associated with their handling, a safer approach to their synthesis and direct use in continuous flow was investigated in chapter 5. It has been found that clean dilauroyl peroxide can be formed in excellent yield and can be used directly as an initiator in a subsequent reaction that is connected in series. In the second part of this thesis, the stereochemical challenges of the intramolecular Schmidt reaction and the strategies to address them are introduced in chapter 6. Our investigations to control the stereochemistry of the triflate-mediated intramolecular Schmidt reaction are summarized in two draft manuscripts in chapters 7 and 8. Our group has developed a protocol to run the reaction under nonacidic conditions using azidotriflates: After an initial intramolecular SN2 reaction between the azide and the triflate moiety, an intermediate aminodiazonoium salt is formed, which undergoes a stereoselective 1,2-shift with concomitant N2 elimination. The substitution has been found to proceed highly stereospecifically. The formed iminium triflate is reduced diastereoslectively in a second step to the bicyclic amine. Remarkably, the chiral alcohol center controls the entire process and thus only one of the four possible diastereomers is obtained in a highly selective manner. The method has been used for the concise synthesis of a lehmizidine- and an indolizidine alkaloid that represent components of myrmicaria melanogaster ant venom. It was further investigated whether the method is applicable to access bridgehead-functionalized azabicycles from the corresponding prefunctionalized azidoalcohols. The results of this study complement previous finding that have been conducted in two precedent PhD theses and are presented in the last chapter of this thesis

Locating Guest Molecules inside Metal–Organic Framework Pores with a Multilevel Computational Approach

Molecular docking has traditionally mostly been employed in the field of protein–ligand binding. Here, we extend this method, in combination with DFT-level geometry optimizations, to locate guest molecules inside the pores of metal–organic frameworks. The position and nature of the guest molecules tune the physicochemical properties of the host–guest systems. Therefore, it is essential to be able to reliably locate them to rationally enhance the performance of the known metal–organic frameworks and facilitate new material discovery. The results obtained with this approach are compared to experimental data. We show that the presented method can, in general, accurately locate adsorption sites and structures of the host–guest complexes. We therefore propose our approach as a computational alternative when no experimental structures of guest-loaded MOFs are available. Additional information on the adsorption strength in the studied host–guest systems emerges from the computed interaction energies. Our findings provide the basis for other computational studies on MOF–guest systems and contribute to a better understanding of the structure–interaction–property interplay associated with them

Locating Guest Molecules inside Metal-Organic Framework Pores with a Multilevel Computational Approach

Molecular docking has traditionally mostly been employed in the field of protein- ligand binding. Here, we extend this method, in combination with DFT-level geometry optimizations, to locate guest molecules inside the pores of metal-organic frameworks. The position and nature of the guest molecules tune the physicochemical properties of the host-guest systems. Therefore, it is essential to be able to reliably locate them to rationally enhance the performance of the known metal-organic frameworks and facilitate new material discovery. The results obtained with this approach are compared to experimental data. We show that the presented method can, in general, accurately locate adsorption sites and structures of the host-guest complexes. We therefore propose our approach as a computational alternative when no experimental structures of guest-loaded MOFs are available. Additional information on the adsorption strength in the studied host-guest systems emerges from the computed interaction energies. Our findings provide the basis for other computational studies on MOF-guest systems and contribute to a better understanding of the structure-interaction-property interplay associated with them

Determination of Plutonium and Uranium Radionuclides in Glacier Ice Samples by MC-ICP-MS

A radiochemical procedure for the determination of plutonium (Pu) and uranium (U) radionuclides in ice samples by multicollector inductively coupled plasma mass spectrometer (MC-ICP-MS) is presented. Pu and U radionuclides are preconcentrated by coprecipitation and then separated by extraction chromatography. The purified Pu and U fractions are analyzed by MC-ICP-MS. Detection limits of 2 × 10 –3 and 3 × 10–6 mBq kg–1 were achieved for 239Pu and 236U, respectively. Surface ice samples collected from the Gauli glacier (Switzerland) were analyzed by this method. The surface of the Gauli Glacier retains historical records of 239Pu, 240Pu and 236U from the nuclear weapon testing (NWT) period. Pu and U radionuclides were found to be consistent in terms of pattern, showing two peaks possibly related to the two main periods of the NWTs (1954–1958 and 1961–1963). 3H measurements, also released by the NWT, further confirmed the Pu and U results. The 240Pu/239Pu ratio ranged from 0.14 to 0.25, and 236U/ 239Pu ranged from 0.14 to 0.81. The Pu atom ratios ranged within the limits of global fallout in the most intensive period of NWT (1952 to 1962)

Stereoselective and Stereospecific Triflate‐Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons

The stereoselectivity and stereospecificity of the triflate-mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride-mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)-(cis)-3-propylindolizidine and (−)-(cis)-3-butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported

A Short Synthesis of (+)-Brefeldin C via Enantioselective Radical Hydroalkynylation

A very concise total synthesis of (+)-brefeldin C starting from 2-furanylcyclopentene is described. This approach is based on an unprecedented enantioselective radical hydroalkynylation process to introduce the two cyclopentane stereocenters in a single step. The use of a furan substituent allows to achieve a high trans diastereoselectivity during the radical process and it contains the four carbon atoms C1–C4 of the natural product in an oxidation state closely related to the one of the target molecule. The eight-step synthesis require six product purifications and it provides (+)-brefeldin C in 18% overall yield.</div

Mapping the age of ice of Gauligletscher combining surface radionuclide contamination and ice flow modeling

In the 1950s and 1960s, specific radionuclides were released into the atmosphere as a result of nuclear weapons testing. This radioactive fallout left its signature on the accumulated layers of glaciers worldwide, thus providing a tracer for ice particles traveling within the gravitational ice flow and being released into the ablation zone. For surface ice dating purposes, we analyze here the activity of 239Pu, 240Pu and 236U radionuclides derived from more than 200 ice samples collected along five flowlines at the surface of Gauligletscher, Switzerland. It was found that contaminations appear band-wise along most of the sampled lines, revealing a V-shaped profile consistent with the ice flow field already observed. Similarities to activities found in ice cores permit the isochronal lines at the glacier from 1960 and 1963 to be identified. Hence this information is used to fine-tune an ice flow/mass balance model, and to accurately map the age of the entire glacier ice. Our results indicate the strong potential for combining radionuclide contamination and ice flow modeling in two different ways. First, such tracers provide unique information on the long-term ice motion of the entire glacier (and not only at its surface), and on the long-term mass balance, and therefore offer an extremely valuable data tool for calibrating ice flows within a model. Second, the dating of surface ice is highly relevant when conducting “horizontal ice core sampling”, i.e., when taking chronological samples of surface ice from the distant past, without having to perform expensive and logistically complex deep ice-core drilling. In conclusion, our results show that an airplane which crash-landed on the Gauligletscher in 1946 will likely soon be released from the ice close to the place where pieces have emerged in recent years, thus permitting the prognosis given in an earlier model to be revised considerably

Mapping the age of ice of Gauligletscher combining surface radionuclide contamination and ice flow modeling

In the 1950s and 1960s, specific radionuclides were released into the atmosphere as a result of nuclear weapons testing. This radioactive fallout left its signature on the accumulated layers of glaciers worldwide, thus providing a tracer for ice particles traveling within the gravitational ice flow and being released into the ablation zone. For surface ice dating purposes, we analyze here the activity of 239Pu, 240Pu and 236U radionuclides derived from more than 200 ice samples collected along five flowlines at the surface of Gauligletscher, Switzerland. It was found that contaminations appear band-wise along most of the sampled lines, revealing a V-shaped profile consistent with the ice flow field already observed. Similarities to activities found in ice cores permit the isochronal lines at the glacier from 1960 and 1963 to be identified. Hence this information is used to fine-tune an ice flow/mass balance model, and to accurately map the age of the entire glacier ice. Our results indicate the strong potential for combining radionuclide contamination and ice flow modeling in two different ways. First, such tracers provide unique information on the long-term ice motion of the entire glacier (and not only at its surface), and on the long-term mass balance, and therefore offer an extremely valuable data tool for calibrating ice flows within a model. Second, the dating of surface ice is highly relevant when conducting “horizontal ice core sampling”, i.e., when taking chronological samples of surface ice from the distant past, without having to perform expensive and logistically complex deep ice-core drilling. In conclusion, our results show that an airplane which crash-landed on the Gauligletscher in 1946 will likely soon be released from the ice close to the place where pieces have emerged in recent years, thus permitting the prognosis given in an earlier model to be revised considerably.ISSN:1994-0416ISSN:1994-042

Stereoselective and Stereospecific Triflate Mediated Intramolecular Schmidt Reaction: Easy Access to Alkaloid Skeletons

The stereoselectivity and stereospecificity of the triflate mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicylic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (–)-(cis)-3-propylindolizidine and (–)-(cis)-3-butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.<br /