Indoles iminium catalysis, alkylation

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Austin JF, MacMillan DWC (2002) Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine Pot Iminium Catalysis. J Am Chem Soc 124 1172... 

Austin, J. E, and MacMillan, D. W. C. "Enantioselective Organocataly tic Indole Alkylations. Design of a New and Highly Efeclive Chiral Amine for Iminium Catalysis." /. Am. Chem. Soc., 124,11 (2002). 

Austin JF, MacMillan DWG Enantioselective indole alkylations. Design of a new and highly effective chiral amine for iminium catalysis. J. Am. Chem. Soc. 2002 124(7) 1172-1173. 

Asymmetric Friedel-Crafts alkylations of indoles with a,p-unsaturated carbonyl compounds have been and continue to be of significant interests in synthesizing chiral indole alkaloids. Following the very successful iminium-catalysis with enals by MacMillan s catalyst [47], Chen and Melchiorre have independently reported asymmetric Friedel-Crafts alkylation of indoles with a,P-unsaturated aryl ketones [48] using similar cinchona-alkaloid derived catalysts 77 and 91, respectively (Scheme 5.24) [49]. In both cases, the proper choice of an acidic additive has been shown to be essential for catalytic activity and stereoselectivity. 

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