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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - GAINBYSTRAIN (Gain by Strain: Precise Cuts of Cyclopropanes as Key to Molecular Complexity)

Teaser

Summary

Cyclic compounds are ubiquitous in Nature. The so-called small ring compounds are only composed of three or four ring atoms. In many cases they are inert, but polarization by adjacent electron-donating and electron-accepting moieties converts them into spring-loaded entities which allow a multitude of different transformations. Simple ring-opening reactions to acyclic moieties, cycloaddition and rearrangement reactions leading to larger ring sizes are possible.
In the project GAINBYSTRAIN the team exploits the inherent ring strain of three-membered rings to realize unusual reactions which work in an atom-economic fashion. All atoms of the three-membered starting materials are also found in the product. Not special product classes of compounds are in the focus, it is more the development of a toolbox for a specific arrangement of functionalities or the construction of various scaffolds.
To develop mild, selective and environmentally benign methods to construct organic molecules is of highest importance for the society since resources such as oil, energy and time are limited and waste needs to be disposed. Modern synthetic methods address all these challenges and will help to protect our planet.

Work performed

A ring-opening 1,3-bisfunctionalization of donor-acceptor cyclopropanes was developed. As compounds which undergo Ïƒ-bond cleavage we used chalcogenyl halides (RSCl, RSBr, RSeCl and RSeBr). These highly polarized compounds were reacted with dicarboxylate-substituted cyclopropanes under Lewis acid catalysis to afford 1,3-disubstituted open-chain products. To develop an enantioselective version, we focused on another type of mechanism for this 1,3-bisfunctionalization. Therefore, we used cyclopropanes which bear an aldehyde moiety as acceptor. By developing novel congeners of MacMillan-type catalysts we were able to perform an organocatalytic ring-opening regio , diastereo- and enantioselective 1,3-chlorochalcogenation of cyclopropyl carbaldehydes.
A [3+2]-cycloaddition between naphthoquinones and D-A cyclopropanes was developed. For this purpose, tin(II) triflate as electron-donating catalyst was utilized to start a redox catalysis. Naphthoquinone was converted into nucleophilic naphthoquinone dianion which proved to be able to open the cyclopropane. The resulting species reduced further naphthoquinone while being oxidized. Thus, only a miniscule amount of tin(II) triflate was necessary. Further ring-closure in a Michael-type fashion led to the annulation of a five-membered ring; further oxidation generated highly colored electronically unusual fulvene-type structures.
Thio- and selenoketones were used as 1,2-dipoles to be inserted into respective cyclopropanes. Extensive screening was performed. Besides intermolecular versions also intramolecular versions were conducted leading to bicyclic systems. This chemistry was extended to the formal insertion of thioketenes realized via a cycloaddition-cycloreversion sequence since thioketenes are not stable.

Final results

Besides anticipated results (as proposed in the proposal) also surprising results beyond the state of the art have been achieved. A combination of redox and Lewis acid catalysis allowed the annulation of cyclopropanes to aromatic systems. Instead of carbenes and nitrenes to be inserted sulfur and selenium atoms have been utlized to enlarge the three-membered rings. In future, further unprecedented ways to exploit donor-acceptor cyclopropanes to access unusual ring-openings, cycloadditions and rearrangements will be developed. These methods will allow fast and efficient access to a variety of structural motifs which are otherwise difficult to access.