Friedel imidazolidinone catalysts

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],... 

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

Inspired by the use of chiral imidazolidinones as highly enantioselective catalysts for Diels-Alder, 1,3-dipolar cycloaddition and Friedel-Crafts reactions, Tan et have synthesized a series of novel chiral imidazolines and examined their application in MBH reactions. Up to 54% ee and high yields were obtained by using stoichiometric amounts of imidazoline 175 for the MBH reactions of various aromatic aldehydes with unactivated acrylates. Furthermore, the imidazolines were also suitable promoters for reactions between aromatic aldehydes and alkyl vinyl ketone. Using 50 mol.% of imidazoline 176, which bears a chiral methylnaphthyl group, afforded adducts in high yield with up to 78% ee (Scheme 2.86). These chiral imidazolines are readily prepared from commercially available amino alcohols and can be easily recovered for reuse without loss of product enantioselectivity. 

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). 

Mac Millan and coworkers reported a multicatalytic approach by using a catalyst combination of imidazolidinone 8 and proline (Scheme 12.10). The cycle-specific Friedel-Crafts alkylation-amination of enals was studied with different nucleophilic components. For instance, the reaction of 1-methylindole as a Jt-nucleophile with the catalyst combination containing L-Pro (20 mol%) and 8 (10 mol%) provided the iyn-1,2-aryl amination adduct 23 with excellent yield (94%) and stereocontrol (syn/anti 14 1, ee 99%). Access to the corresponding anti isomer 24 was achieved by... 

In 2009, Nicolaou and coworkers [52] applied chiral 5-benzyl-2-(er(-butyl-imidazolidinones (MacMillan s catalysts) [45] to develop asymmetric Friedel-Crafts-type a-arylation of aldehydes via the enamine intermediate... 

The amino-acid-derived imidazolidinones, so-called MacMillan catalysts, efficiently form iminium ions with a, 3-unsaturated aldehydes and catalyze a Friedel-Crafts-type Michael reaction. Based on this strategy, Hanes-sian and co-workers reported on a practical asymmetric synthesis of indole derivative (S)-(—)-14, which is a precursor of drug prototype (S)-(+)-15, a candidate for treatment of migraine headaches (Scheme 27.2). In this synthesis, nitrogen-containing aldehyde 11 was able to react with 5-bromoindole 10 in the presence of (/ ,/ )-MacMillan catalyst 12 to give the adduct 13 in quantitative yield with 92% ee. 

---