Asymmetric Tandem Conjugate Addition and Reaction with Carbocations on Unsaturated Heterocycles

Abstract

Heterocycles possessing multiple substituents and stereogenic centers are important structural motifs in many compounds of interest. We present here stereoselective tandem transformation based on Cu‐catalyzed conjugate addition of Grignard reagents to heterocyclic Michael acceptors, which is followed by one‐pot trapping of in situ formed enolates with stabilized carbocations or their equivalents. The transformations are highly enantio‐ and diastereoselective with Josiphos‐type ferrocene ligand. The reaction of chiral metal enolates with onium compounds allows the installation of structurally attractive substituents on chromenone or piperidinone core. Moreover, cycloheptatrienyl and benzodithiolyl substituents can be further modified, thus expanding synthetic possibilities of this methodology.

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

“…As the first electrophile for trapping of the chiral enolate, we have used tropylium bistriflimide ( Scheme 2 ). Following our earlier experience, we employed the tropylium ion with the more lipophilic bis(trifluoromethane)sulfinimide (NTf 2 ) anion because of its better solubility in the applied organic solvents than the commercially available tetrafluoroborate (BF 4 ) form [ 22 – 24 ]. The cyclic urea DMEU (1,3-dimethyl-2-imidazolidinone) [ 26 ] additive was used as polar aprotic solvent, which also increases the homogeneity of the reaction mixture.…”

“…Chiral enolates generated by conjugate additions react with carbonyl compounds, imines, other Michael acceptors, or alkyl halides. Our group is developing trapping of metal enolates with stabilized carbocations and could show that magnesium enolates generated from enones [ 22 ], unsaturated amides [ 23 ], or heterocycles reacted with tropylium, dithiolylium or flavylium cations [ 24 ]. These non-traditional electrophiles allow access to structurally highly interesting motifs.…”

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

“…We have continued our exploration of enolate reactions with carbocations by studying the trapping of heterocyclic enolates 108 generated from coumarin and chromone [ 65 ]. The high enantio- and diastereoselectivity of these transformations were ensured by a Josiphos-type ferrocene ligand.…”