Chiral Imidazolidinone MacMillans Catalyst

Chiral imidazolidin-4-ones operate as chiral secondary amines to activate aldehydes by enamine formation. Enamines of imidazolidin-4-one and hydrocinnamaldehyde 

Comprehensive Enantioselective Organocatalysis Catalysts, Reactions, and Applications, First Edition. 

2004 the first enantioselective a-chlorination in the presence of catalytic amounts of imidazolidinone was described by MacMillan et al. [9]. In particular, the introduction of fluorine is of considerable interest since fluorine-substituted bioactive compounds are metabolicaUy stable and are detectors of hydrogen bonding capacity. In 

For the synthesis of chiral a-fluoroamines via asymmetric fluorination of aldehydes see Reference [12]. Finally, this method was also used for the synthesis of a-fluorinated capsaicin [13] and an agonist of the GPR119 receptor [14]. 

By deployment of lithium chloride or sodium chloride-as a source of chlorine-a-chlorina ted enolizable aldehydes are accessible in the presence of a Ce(IV) 

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In line with the mechanistic rationale of LUMO-lowering iminium activation, MacMillan hypothesized that intermediate 2, generated from the secondary amine 1 and an a,/f-un saturated aldehyde, could be activated towards cydoaddi-tion with an appropriate diene (Scheme 3.1). The Diels-Alder reaction would form iminium ion cydoadduct 5 that, in the presence of water, would hydrolyze to yield the enantioenriched product 6 and regenerate the chiral imidazolidinone catalyst 1. 

Alder reactions, 1,3-dipolar cycloadditions (Jen et al. 2000), and conjugate additions of electron rich aromatic and heteroaromatic compounds can be catalyzed using chiral amino acid derived imidazolidinones as catalysts (Scheme 17 Eqs. 35-38 Paras and MacMillan 2001, 2002 Austin and MacMillan 2002 Brown et al. 2003b). In addition, highly enantioselective epoxidations (Marigo et al. 2005b) and cyclopropana-tions (Kunz and MacMillan 2005) have recently been developed. 

Together with the diarylprolinol silyl ethers (Jprgensen-Hayashi catalysts) [54] shown in the first row of Figure 2.3, the chiral imidazolidinones devised by MacMillan are the most usual catalysts for iminium activation. Some representative examples are shown in Figure 2.16. 

In some cases, using the silyl enol ethers form of nucleophiles in the asymmetric Michael reactions is necessary for ensuring high reactivity and selectivity. MacMillan and co-workers [113] developed the first enantioselective organocata-lytic Mukaiyama-Michael reaction for the synthesis of enantioenriched 7-butenolide architecture in 2003. In the presence of chiral imidazolidinone catalyst 120 with acid additive, the reactions of silyloxy furan 118 with simple a,(3-unsaturated aldehydes... 

MacMillan et al. studied the reactivity of transient enamines formed with organocatalysts with hypervalent iodine reagents in the presence of metal catalysts (Scheme 26.5a). They found that Cu(l) salts can be used in combination with chiral imidazolidinones to perform a-electrophilic trifluoromethylation [47], arylation [48], and vinylation [49] of aldehydes. As suggested by the authors, the most likely mechanism involves a copper-mediated I-O bond cleavage furnishing a highly... 

Cooperative catalysis using chiral imidazolidinones and metal catalysts is not restricted to carbon electrophiles. In 2012, the MacMillan group [50] disclosed a general approach to undertake enantioselective -oxidation of aldehydes with TEMPO by combining organocatalysis with copper catalysis (Scheme 26.5b). 

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