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Final Report Summary - HALOCHIRAL (Asymmetric Halogenation of Olefins Involving Intermolecular Nucleophiles)

Chiral molecules are of tremendous importance in all areas of chemistry. In organic molecules, chirality is observed when a carbon atom is asymmetric, i.e. it has four different substituents. The field of research concerned with producing chiral compounds in a controlled and predictable way, asymmetric synthesis, is one of the largest areas in the chemical sciences today, both in academic and industrial institutions. Especially in biologically active molecules, the chirality of a compound plays a crucial role for the observed activity. After many decades of intensive research, we command a vast pool of methods to produce, control and define chiral centers in synthetic chemistry for rational access to many desired products. However, there still exist certain transformations that cannot be executed with satisfactory control of stereochemistry, however desirable this might be. One of them is the asymmetric halogenation of olefins, where a molecule containing a double bond is subjected to the asymmetric addition of a halogen atom. Typically, in situ attack of a nucleophile follows. For the case where this nucleophile is not yet present in the molecule, i.e. attacking intramolecularly, but instead is a totally different molecule approaching the reaction site in intermolecular fashion; no reports of successful methods exist in literature.

Therefore, the project HALOCHIRAL was dedicated to the development of a general methodology for the asymmetric halogenation of olefins in conjunction with an intermolecular nucleophilic attack on the generated electrophilic intermediate. This is expected to improve the scope of feasible olefins and also increase the range of possible nucleophiles. In methodology relying on intramolecular attack of the nucleophile, there is always the need for the synthesis of complex achiral substrates, which will be circumvented when intermolecular nucleophiles can be used instead.

The chiral products should be obtained with a high degree of regio- and enantioselectivity and the compounds needed to form the stoichiometric reagent can in principle be recycled. Such a method will be strongly embraced by the pharmaceutical industry, who are in desperate need of new, efficient ways to generate chirality, and by many other fields such as the material sciences.

In this project synthetic routes were developed for the first enantioselective electrophilic halogenation reagents. One of the ligands synthesized allows investigation of the electronic needs for stabilization of the key intermediate, whereas the second provides a model compound for the first intermolecular enantioselective halogenation reagent.

The obtained results are an important step on the way to a deepened understanding of how substituents can be used to control the kinetics of the planned halogenation reaction. Synthetic access has been established towards the production of ligands incorporating chiral centers in order to produce a chiral environment during the halogenation reaction that is close enough to the reaction site to transfer the chirality to the product. In continuation of this work, a pathway for the asymmetric halogenation of olefins may be developed.

Related information

Reported by

GOETEBORGS UNIVERSITET
Sweden
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