Chiral asymmetric aminocatalysis

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

The plane of symmetry bisecting varenicline means that it is meso, rather than chiral. Nevertheless, in combination with a chiral additive such as tartaric acid or camphorsulfonic add (CSA), it may still be possible to achieve asymmetric induction via aminocatalysis. In such a scenario, a nucleophilic enamine formed from varenicline might be desymmetrized by selective protonation of one of the two heteroaromatic nitrogens. Alternatively, the enamine might effect asymmetric induction merely by virtue of the chiral environment resulting from the presence of either one or two chiral camphorsulfonate counterions. However, varenicline... 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

The first example of catal34ic asymmetric functionalization of arenes under metal-fi ee conditions was documented by MacMillan and coworkers in 2002 under aminocatalysis regime [1]. The combination of chiral imidazoUdinone 38a with enals 37 resulted into the formation of covalent aggregates (i.e., iminium ion 39) featuring a lower LUMO (lowest unoccupied molecular orbital) energy with respect to the alde-hydic precursor. Therefore, the chirally modified electrophile 39 can enter the catal3dic cycle characterized by a diastereoselective nucleophilic attack of electron-rich benzenes followed by the restoring of the catalytically active secondary amine via hydrolysis of the immonium salt 40 (Scheme 5.12). 

Bringing together the concept of aminocatalysis and the activation mode of chiral phosphoric acids. List and co-workers introduced the concept of asymmetric counter anion directed catalysis (ACDC) and they applied this idea to the asymmetric reduction of enals 47 (Scheme 23) [ 135]. The catalytic species is formed by an achiral ammonium ion 60 and a chiral phosphate anion 59 derived from 3,3 -bis(2,4,6-triisopropylphenyl)-1,1 -binaphthyl-2,2 -diyl hydrogen phosphate 9 (TRIP). 

The asymmetric inverse-electron-demand aza-Diels-Alder reaction of Af-Ts-1-aza-l,3-butadienes derived from 3-argiocarbonylcoumarins and acetaldehyde has also been developed using chiral aminocatalysis, giving tricyclic chroman-2-one derivatives in high enantioselectivities (up to 95% ee) [35]. 

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