Gain by Strain: Precise Cuts of Cyclopropanes as Key to Molecular Complexity

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.

A ring-opening 1,3-bisfunctionalization of donor-acceptor cyclopropanes was developed. As compounds which undergo σ-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 commonly not stable. However, we were able to also involve stabilized sterically encumbered thioketenes into the ring-enlargement reaction. Intensive kinetic studies revealed the most suited systems to be used in the chemistry of donor-acceptor cyclopropanes. Such studies showed that there is strong electronic differentiation of respective substituents. We were also able to demonstrate that special aliphatic donors such as cyclopropyl are able to fulfil the role of a classical aromatic donor. With such physical-organic data in hand we were able to develop a variety of other transformations. In a synergistic catalytic approach using Rh and Lewis acid catalysis we generated carbonyl ylides as fleeting intermediates to be inserted in donor-acceptor cyclopropanes. Complex oligocyclic structures were easily accessed by such methodology. Also larger systems such as sulfur-containing seven-membered rings were obtained in (3+4)-cycloaddition reactions using thiochalcones. Respective ketenedithioacetales were exploited as ketene surrogates leading to the formal insertion of ketenes. The use of sydnones allowed a ring-opening and thus a facile functionalization of sydnones, but no cycloaddition as originally anticipated. Ring-opening three-component reactions were developed that used amides and electrophilic chalcogen components. From a conceptual point of view we outlined the similarity of the reactivity of donor-acceptor cyclopropanes with arynes leading to a multitude of novel reactions that might be realized for the two classes of compounds. Another conceptual breakthrough was the use of electric current to activate donor-acceptor cyclopropanes. So far almost all activations of donor-acceptor cyclopropanes have been realized by Lewis acids or organocatalysis. Using electricity the use of such reagents could be circumvented. In collaboration with Russian chemists we were able to show that protic ionic liquids are able to act as reagent, catalyst and solvent which was demonstrated in the field of three-membered ring chemistry.

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 utilized to enlarge the three-membered rings (not yet published). During the development of the synergistic Rh/Lewis acid catalysis we observed an unprecedented dimerization reaction of diazo carbonyls leading to complex oligocyclic motifs of rich, but distinct stereochemistry.

Periodic Reporting for period 4 - GAINBYSTRAIN (Gain by Strain: Precise Cuts of Cyclopropanes as Key to Molecular Complexity)

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