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Intermolecular Asymmetric Halogenations of Olefins

Periodic Reporting for period 1 - AsymHalogenation (Intermolecular Asymmetric Halogenations of Olefins)

Reporting period: 2015-05-01 to 2017-04-30

The property of chirality is manifested in both molecular and macroscopic objects. Many organic molecules, including glucose and most biological amino acids, are chiral. This means that they are non-superimposable mirror images of each other, like a left and a right hand are. The two forms of a chiral molecule, called enantiomers, have identical physical and chemical properties, but they interaction with other chiral molecules can be compared with gloves; a left hand interacts differently with left- and right-hand gloves. Therefore, in designing drugs, one must be concerned about which enantiomer is the active one—the one that fits the intended receptor. Ideally, the drug should consist of the pure active isomer. In contrast to the synthesis of biomolecules by organisms where a specific enantiomer is formed, when molecules are synthesized in a laboratory, without using any template, left and right-handed molecules of a compound will form in equal amounts (racemic mixture). Consequently, the development of efficient methods toward the synthesis of chiral compounds is currently of great academic and industrial interest.
On the other hand, halogenated natural products are widely distributed in nature. For instance, approximately 5000 compounds known to be produced by living organisms are organohalogens, halogenated natural products. In approximately half of these compounds, the carbon atom to which the halogen is bound is asymmetric. Moreover, incorporation of halogen atoms in drug leads is a common strategy to modify molecules in order to vary their bioactivities and specificities.
In view of this, the main goal of this project is the development of a general methodology for the enantioselective synthesis of halogenated molecules having a chiral halonium complex as the source of chirality.
The first step of the proposed work (see original Description of Work) was the investigation of the (a) stability of the [N-X-N]+ halonium complex, and (b) the dependence of its stability on the electronic properties of the ligand. This work has been initiated during the evaluation period of the proposal and published in JACS 2016, 138, 9853. In short, the [bis(pyridine) halogen(I)]-type [N-I-N]+ complexes were demonstrated to be easily prepared and stable at room temperature, especially in the presence of electron donating functional groups. Moreover, the tetrafluoroborate counterion was found to be optimal due to the higher stability of its halonium complexes as compared to triflate, for example (Chem. Sci. 2015, 6, 3746).

Over the two years funding period, the postdoctoral researcher has optimized the synthesis of three chiral analogues of the [bis(pyridine)halogen(I)]+ complexes that the host research group has previously used to optimize the synthesis, and to gain understanding of the properties and applicability of [N-I-N]+ complexes as halonium transfer reagents. The synthetic routes are given in figure 1. Two of the synthesized ligands possess a chiral carbon two-bonds from the nitrogen that complexes iodonium ion, whereas one of them four bonds away, the latter can hence be used as a reference system that is not expected to give any chiral induction. The synthetic routes provided the target ligands in 1.5-5% overall yield from commercially available starting materials. The result of the work of the postdoctoral researcher is this collection of synthetic routes toward chiral ligands that yielded ca 50 mg of each, and hence providing the basis of a future large scale synthesis to allow the preparation of sufficient amount of the ligands for optimization of the halonium transfer reaction.

An initial attempt to obtain chiral halogenation by mixing an alkene, a chiral ligand and iodine, which halogenates even in the absence of the ligand, provided as expected high conversion but no enentioselectivity. Overall, the project has provided synthetic routes to three chiral ligands and thereby provides support for the continued work of the host group. The synthetic routes will be published at a later point, following large scale synthesis and optimization of the enantioselective halonium transfer reactions.

Besides the synthetic work, the scientist has received leadership training by co-supervision of the synthetic project work of one undergraduate student. The scientist has been given the chance to be part of the local organizing team of the International Symposium on Halogen Bonding (ISXB-2), in June 2016, and participate in the conference. Moreover, the scientist was allotted time to attend a ten weeks full time NMR course (15 ects), arranged for PhD students at the Swedish NMR center. She has also received training in presentation and defense of research ideas and results at the presentation days arranged every 3-4 months by the host group, and research training at regular research seminars arranged by the host department.
The main goal of this project, asymmetric halogenation of olefins with high enantiomeric excess, could provide a major stimulus to research in this area. Halogenated products are of strong importance not only as synthetic intermediates but also as final targets e.g. in biologically active substances. Opening a general and readily transferable asymmetric access to this class of compounds would be highly valued not only by academia but also the chemical and pharmaceutical industry.

With respect the impact of this project in the career development of the scientist, she has deepened her knowledge in the synthesis, design and characterization of chiral heterocyclic compounds as well as in the field of asymmetric catalysis and NMR spectroscopy.