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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TransNic (Enantioselective Nickel-Catalyzed trans-Carbometallative Couplings and Cyclizations)

Teaser

Summary

\"\"\"Alkenylmetal species\"\" are versatile synthetic intermediates in chemistry, which, in their simplest form, are composed of a metal atom bonded to a two-carbon fragment. Alkenylmetal species are used in a wide range of reactions to produce numerous important chemical building blocks. In the Host Laboratory, a new method to access alkenylmetal species resulting from formal anti-carbometallation was discovered. This process involves an initial syn-addition to a carbon-carbon triple bond to give an alkenylmetal species that then undergoes reversible E/Z isomerization to the anti-product which is responsible for further functionalization. In the original discovery, nickel was used as the metal, and the resulting alkenylnickel species was used to react with another group in the same molecule to form a cyclic compound. The key feature about this reversible E/Z isomerization reaction is that it enables reactions to proceed that would otherwise be impossible on the basis of geometric constraints.

The original objectives of this project were to:
(a) Define the scope and limitations of this method in producing a wide range of cyclic compounds.
(b) Develop variants of these reactions that are able to give products selectively as a single enantiomer (which is defined as a non-superimposable mirror-image form). The ability to produce compounds as single enantiomers is very important because the exact function of compounds within biological systems (e.g. if the compounds are to be used as medicines) often depends upon which mirror image they exist in.

The work in this project was highly successful, which led us to further develop and expand the chemistry in the same area. These new methods were successful in producing a wide range of cyclic products in good yields under mild reaction conditions, and at the time of writing, this research has been published in two articles in a leading general chemistry journal. The remaining work is being currently being prepared for publication (Scheme 1â€“3).
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Work performed

At the beginning of this project, the Fellow expanded upon the preliminary results already obtained in the Host Laboratory in enantioselective arylative cyclizations of alkynes tethered to a Z-allylic phosphate, to give enantioenriched chiral tetrahydropridines (Scheme 1). The Fellow successfully expanded the scope of the reaction to encompass a range of diverse examples, and this was published in Angew. Chem. Int. Ed. 2017, 56, 8216.

Inspired by these results, the Fellow decided to investigate whether electrophiles other than Z-allylic phosphates could be used, and he discovered that the method could be used for the enantioselective synthesis of highly functionalized chiral cyclopentenones by reaction of arylboronic acids with malonate esters tethered to an alkyne (Scheme 2). This work was published in Angew. Chem. Int. Ed. 2018, 57, 9122.

After these highly encouraging results, the Fellow also found that alkyne-tethered amides were also applicable to this chemistry and they produces highly functionalized pyrroles (Scheme 3). Pyrroles are highly important structures found in many naturally occurring and biologically active compounds. At the time of writing, this work is currently being prepared for publication.

Dissemination Activities:
At the time of writing, two papers have been published in a leading general chemistry journal while the remaining results are currently being prepared for publication as a communication. There are some final experiments which need to be completed, and this is being done by colleagues of the Fellow. We anticipate this will be completed in the next month or two, with manuscript submission to follow shortly thereafter. This work has also been presented in research seminars in industry and at conferences within the UK and internationally.

Training and Career Progression of the Fellow:
When the Fellowship began, the Fellow had expertise in gold mediated chemistry, and medicinal chemistry rather than in the development of new organic reactions using nickel catalysis, which is the main area of this project. Therefore, the Fellow had to learn new skills and gain new knowledge, but did this very successfully. At the end of this project, the Fellow is now highly trained in this area. Currently, the Fellow is searching for a new postdoctoral/research scientist position to consolidate his skills in preparation for an independent research career.

Final results

The main finding of this fellowship is a new way to conduct the enantioselective synthesis of tetrahydropyridines, cyclopentenones, and multisubstituted pyrroles under mild reaction conditions from simple starting materials using nickel catalysis. The key feature for the success of these reactions is a previously underappreciated mode of chemical reactivity: the reversible E/Z-isomerization of alkenylnickel species. Notably, alkenylnickel have been shown to react enantioselectively with various classes of tethered electrophiles such as Z-allylic phosphates, malonate esters, and amides. We expect that the principles behind this mild method of carbometallation-cyclization could be used to design related reactions in future, which could open up new methods for complex molecule synthesis.