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Chem Asian J. 2011 Feb 1;6(2):510-6. doi: 10.1002/asia.201000596. Epub 2010 Dec 22.

DFT study of chiral-phosphoric-acid-catalyzed enantioselective Friedel-Crafts reaction of indole with nitroalkene: bifunctionality and substituent effect of phosphoric acid.

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Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, 13-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.


The enantioselective Friedel-Crafts reaction of indoles with nitroalkenes proceeds catalytically by means of a chiral-phosphoric-acid catalyst to afford products with high enantioselectivities (up to 91% ee). The use of a 3,3'-SiPh(3)-substituted (R)-binol-derived (binol=1,1'-binaphthyl-2,2'-diol) catalyst and a free indole that bears an N-H moiety is essential to achieving high enantioselectivity as well as high yield. To elucidate the reaction mechanism and the origin of the high enantioselectivity, DFT calculations were carried out. The reaction proceeded through a cyclic transition state formed by the two-point binding of both substrates to the conjugated O-P-O moiety of the catalyst, in which indoles and nitroalkenes could be simultaneously activated by Brønsted acidic (proton) and basic (phosphoryl oxygen) sites, respectively. The enantioselectivity was entirely controlled by the steric effect between the 3,3'-substituent group on the (R)-binol-derived phosphoric acid catalyst and the indole ring. When the sterically demanding SiPh(3) group was used as the 3,3'-substituent group, the energy difference between the most-stable diastereomeric transition states that afforded the S and R products was increased to lead to the high enantioselectivity in agreement with the experimental results.


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