Aminocatalysis chiral enamines

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 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. 

A less explored mode of activation within aminocatalysis is the so-called dien-amine catalysis [37]. In this case it is an a,P-unsaturated carbonyl compound with a proton in the y position suitable for deprotonation that after condensation with a chiral amine provides a reactive nucleophile, but now two activated positions are available, making possible both a- and y-functionahzation of the substrate. This vinylogous enamine can also act as an electron-rich diene. Work published in this area is very scarce to date, and only a few ejamples of its application in total synthesis have appeared in recent years (+)-palitantin [38], a-tocopherol [39], a pungent constituent of black cardamom [40], and (R)-rotundial [41] (Figure 44.3). 

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