Friedel-Crafts reactions asymmetric synthesis

The Friedel-Crafts reaction is one of the most important and versatile tools for the formation of carbon-carbon bonds in the synthesis of substituted aromatic and heteroaromatic compounds present in numerous natural products and drugs. Catalytic asymmetric variants using either metal complexes or organic molecules attracted considerable attention over the last few years. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

Kadyrov R, Riermeier TH (2003) Highly enantioselective hydrogen-transfer reductive amination catalytic asymmetric synthesis of primary amines. Angew Chem Int Ed Engl 42 5472-5474 Kang Q, Zhao ZA, You SL (2007) Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. J Am Chem Soc 129 1484-1485... 

Jorgensen, K. A. Asymmetric Friedel-Crafts reactions Cataiytic enantioselective addition of aromatic and heteroaromatic C-H bonds to activated aikenes, carbonyi compounds, and imines. Synthesis 2003,1117-1125. 

In 2009, Nicolaou and co-workers reported an organocatalytic total synthesis of demethyl calamenene (168), a potent cytotoxic agent, which is a beautiful application of SOMO-activated catalysis (Scheme 17.29) [68]. The key step involved an asymmetric intramolecular Friedel-Crafts reaction of aldehyde 166 to achieve the bicyclic aldehyde 167 using imidazolidinone 122 as a SOMO-activated catalyst (56% yield, 90% ee). 

Both chiral Brpnsted and Lewis acids have been useful in asymmetric Friedel-Crafts reactions. For example, the chiral Brpnsted acid 40 was used in the asymmetric synthesis of chiral fluorenes from an achiral indole and the biarylaldehyde 39 (Scheme 1.11) [32]. Initial steps in the conversion lead to the ion pair 42. Through ion pairing with the electrophilic carbocation, the chiral anion... 

For other examples of use of chiral phosphoric acid as catalyst in the synthesis of indole derivatives, see (a) Q. Kang, Z.-A. Zhao, S.-L. You, Tetrahedron 2009, 65, 1603-1607. Enantioselective synthesis of (3-indolyl)glycine derivatives via asymmetric Friedel-Crafts reaction between indoles and glyoxylate imines. (b) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem. Int. Ed. 2009, 48, 2553-2556. Activation of hemiaminal ethers by chiral Brpnsted acids for facile access to enantioselective two-carbon homologation using enecarbamates. 

Recently, the Michael-type asymmetric Friedel-Crafts reaction of electron-deficient alkenes has been established as an important route to chiral benzylic stereocentres. " However, applications of this methodology for the synthesis of all-carbon quaternary stereocentres are conspicuously limited. PFMonosubstituted nitroalkenes have turned out to be active substrates in... 

The synthesis of STRIP was achieved according to the route shown in Scheme 17. In a simultaneous report, Ling, Wang, and coworkers showed that the corresponding naphthyl-substituted SPlNOL-derived phosphoric acid is a competent catalyst for the venerable asymmetric Friedel-Crafts reaction of indoles with imines [44], giving comparable results to BlNOL-derived phosphoric acids. Subsequently, several groups have utilized SPlNOL-based phosphoric acids as Brpnsted... 

Most recently, a dual catalytic Friedel-Crafts reaction that merges organocatalysis and transition metal catalysis for the asymmetric synthesis of annulated pyrroles has been achieved. 

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