Meike Niggemann

Calcium-Catalyzed Friedel–Crafts Alkylation at Room Temperature

Friedel–Crafts reactions are among the oldest and most efficient C C bond-forming processes for the functionalization of aromatic compounds. A vivid interest in the synthesis of polycyclic aromatics, core structures of innumerable, biologically active natural products having continuing industrial and academic impact, has recently revived the research field of Friedel–Crafts reactions. Most of the original Friedel–Crafts procedures have now been replaced by environmentally more compatible catalytic approaches. An additional step on the way towards ecologically and economically beneficial arylations was the use of alcohols as electrophiles, wherein water is the only by-product accompanying the transformation of these readily available substrates. Ideally, a coupled catalytic process as depicted in Scheme 1 would be a conceivable reaction.

Calcium‐Based Lewis Acid Catalysts

Recently, Lewis acidic calcium salts bearing weakly coordinating anions such as Ca(NTf₂)₂, Ca(OTf)₂, CaF₂ and Ca[OCH(CF₃)₂]₂ have been discovered as catalysts for the transformation of alcohols, olefins and carbonyl compounds. High stability towards air and moisture, selectivity and high reactivity under mild reaction conditions render these catalysts a sustainable and mild alternative to transition metals, rare-earth metals or strong Brønsted acids.

The alkynyl moiety as a donor for donor-acceptor cyclopropanes.

The first trans-selective [3 + 2]-cycloaddition of a new type of donor-acceptor cyclopropane with aldehydes is presented. 2,2-Disubstituted cyclopropanes, bearing an alkyne moiety as the sole donor entity, were transformed to highly substituted tetrahydrofurans in the presence of a catalytic amount of Ca(NTf2)2/Bu4NPF6. The protocol allows for an easy access to tetrahydrofurans bearing a versatile alkyne substituent at the quarternary 2-position under very mild reaction conditions.

Calcium‐Catalyzed Cyclopropanation

Cyclopropane-containing heterocycles are essential structural units in many natural products and pharmaceuticals. The stereoselective formation of highly substituted cyclopropanes has been a particularly fascinating challenge for many synthetic chemists. A highly elegant way to assemble the cyclopropane ring with its substituents in one step is a cascade reaction in which multiple C C bonds are formed. Owing to their propensity to act as p-acids for carbophilic activation, noble-metal complexes have become popular catalysts in this research field over the last decade. Reactive intermediates in gold-catalyzed cycloisomerization reactions have been described either as cationic or carbenoid species. In the cationic rendition, gold-stabilized homoallyl cations are in equilibrium with the corresponding, also stabilized, cyclopropyl cations. First precedent indicates the same type of equilibrium in analogous, nonstabilized homoallenyl cations II (Scheme 1). Trapping the carbocation in its cyclopropyl

Highly chemoselective calcium-catalyzed propargylic deoxygenation.

A calcium-catalyzed direct reduction of propargylic alcohols and ethers has been accomplished by using triethylsilane as a nucleophilic hydride source. At room temperature a variety of secondary propargylic alcohols was deoxygenated to the corresponding hydrocarbons in excellent yields. Furthermore, for the first time, a catalytic deoxygenation of tertiary propargylic alcohols was generally applicable. The same protocol was suitable for an efficient reduction of secondary as well as tertiary propargylic methyl, benzyl and allyl ethers. Substrates containing an additional keto-, ester or secondary hydroxyl function were reduced with exceptional chemoselectivity at the propargylic position.

Diastereoselective synthesis of indanes and tetralins via intramolecular Friedel-Crafts reaction.

An easy access to tetralin and indane skeletons has been developed using a diastereoselective intramolecular Friedel-Crafts alkylation. Treatment of diastereomeric mixtures of benzyl carbinols with a catalytic amount of Ca(NTf2)2/Bu4NPF6 yields the respective tetralin or indane in good yields with high levels of regio- and diastereoselectivity.

Calcium-catalyzed carboarylation of alkynes.

The first transition-metal-free carboarylation of alkynes with commercial and readily available alcohols as alkylating agents was realized in the presence of an environmentally benign calcium catalyst. Thereby, a novel protocol for the one-step synthesis of highly congested, all-carbon tetrasubstituted alkenes, as incorporated in potentially bioactive, complex dihydronaphthalene, chromene and dihydroquinoline structures, is provided. The reaction features an unprecedented, particularly wide substrate scope, good functional-group tolerance and simple experimental operation under mild reaction conditions.

Calcium-Catalyzed Formal [2+2+2] Cycloaddition

A formal intermolecular [2+2+2] cycloaddition reaction of enynes to aldehydes is presented, which can be realized in the presence of a simple and benign calcium catalyst. The reaction proceeds with excellent chemo, regio- and diastereoselectivity and leads to a one-step assembly of highly interesting bicyclic building blocks containing up to three stereocenters from simple precursors via a new type of skeletal rearrangement of enynes. The observed diastereoselectivity is accounted for by two different mechanistic proposals. The first one engages mechanistic prospects arising from a gold catalyzed reaction in the absence of the stabilizing gold substituent. The second proposal involves an unprecedented cyclization-carbonyl allene ene reaction-hydroalkoxylation cascade.

Calcium-Catalyzed Dynamic Multicomponent Reaction

The reversible formation of covalent bonds enabled by the remarkably high Lewis acidity of our calcium-based catalyst system was used for the development of a new type of multicomponent reaction. Accordingly, a pharmacologically interesting bicyclic amine was amplified from a highly efficient dynamic equilibrium. The product is formed with full diastereoselectivity, and as typical for our calcium-catalyzed reactions, precautions for the exclusion of air and moisture are unnecessary.

Novel Approach to the Lundurine Alkaloids: Synthesis of the Tetracyclic Core

The tetracyclic core of the lundurine family of alkaloids has been synthesized by a novel approach that features a double ring-closing olefin metathesis to form the five-and eight-membered rings.