Enantioselective Friedel-Crafts Arylation

The Friedel-Crafts reaction of electron-rich aromatic and heteroaromatic compounds with carbonyl acceptors is one of the fundamental reactions for forming carbon-carbon bonds. In recent years, several enantioselective approaches have been described utiMzing copper and scandium complexes as catalysts. In addition, the use of organocatalytic approaches has been considerably expanded. 

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Metal-Catalyzed Enantioselective Friedel-Crafts Arylations... 

Several examples of metal-catalyzed enantioselective Friedel-Crafts arylations to conjugated acceptor systems are known. Similar to the 1,2-addition reaction, most of the substrates are bidentate in nature to ensure a tight-binding, rigid metal-substrate interaction (Figure 8.11). 

Scheme 8.53 Enantioselective Friedel-Crafts arylation of a,P-unsaturated ketones 202.

The Friedel Crafts (F C) reaction via activation of electrophiles functionalized by a nitrogen atom, such as imines, is undoubtedly the most practical and atom eco nomical approach to introduce a nitrogen substituted side chain to aromatic com pounds. The enantioselective version of the F C reaction of nitrogen substituted substrates, including imines, with electron rich aromatic compounds enables effi cient access to enantioenriched aryl methanamine derivatives [37[. Several excellent approaches to highly enantioselective F C reactions have been established using chiral phosphoric acid catalysts. 

During recent years, asymmetric catalysis by small organic molecules has received much attention [140]. Because these reactions proceed through intermediates that are inherently less reactive, the Friedel-Crafts reactions of electron-rich (hetero)aryls generally seem to be well suited. For instance, Deng described the use of readily accessible cinchona-derived ligand 178 to perform highly enantioselective indole additions to a-ketoesters and even simple aldehydes (Scheme 8.49) [141]. Bisindole adducts, the major side products in many Lewis acid-catalyzed reactions, were formed to only a minor extent. 

Different from the hydroxyalkylation reactions using carbonyl compounds as substrates, Nicolaou s and Macmillan s groups developed independently the intramolecular asymmetric Friedel-Crafts-type a-arylation of aldehydes with electron-enriched arenes based on the SOMO activation strategy. Using chiral imidazolidione as catalyst, a series of cyclic aldehydes were obtained in good yields and enantioselectivities with cerium ammonium nitrate (CAN) as single electron transfer oxidant [46]. 

Nicolaou KC, Reingruber R, Sarlah D, Brase S (2009) Enantioselective Intramolecular Friedel-Crafts-Type a-Arylation of Aldehydes. J Am Chem Soc 131 2086... 

In 2009, Nicolaou et al. reported the asymmetric total synthesis of the antitumour natural product demethyl calamenene based on an enantioselective organocatalytic intramolecular Friedel-Crafts type a-arylation of aldehydes bearing electron-donating groups on their aromatic nucleus. This reaction, catalysed by chiral /err-butyl-3-methyl-5-benzyl-4-imidazolidinone, afforded the corresponding polycyclic products in good to high yields and with excellent enantioselectivities for a broad variety of aldehydes, as shown in Scheme 10.4. 

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