Aminocatalysis 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... 

List B. Asymmetric aminocatalysis. Synlett 2001 1675-1686. Notz W, Tanaka F, Barbas III CF. Enamine-based organocatalysis with proline and diamines the development of direct catalytic asymmetric aldol, Mannich, Michael, and Diels-Alder reactions. Acc. Chem. Res. 2004 37 580-591. 

Very recently, Lu and coworkers successfully applied aminocatalysis via the enamine intermediate to the Michael addition of cyclic ketones to vinyl sulfones 181 [56]. In the presence of the cinchonidine-derived primary amine salt 179, the Michael reactions between vinyl sulfones 181 and cyclic ketones 180 proceeded smoothly, affording the desired adduct 182 in very high yield and with excellent enantioselectivity (up to 97% ee) (Scheme 9.63). They also successfully applied this methodology to the synthesis of sodium cyclamate. However, this protocol gave poor yields and ee values for acyclic ketones. 

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 conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

The asymmetric a-allqrlation of carbonyl compounds constitutes one of the fundamental organic transformations for the construction of carbon-carbon bonds, and has long been the Achilles heel for asymmetric aminocatalysis. Towards a solution to this long-standing problem, Jacobsen and coworkers have shown that the enantioselective a-allqrlation of a-arylpropionaldehydes with diarylbromonethane can be carried out under the catalysis of primary-amine thiourea 39 (Scheme 19.60). Catalyst 39 reacted with the aldehyde to form an enamine, followed by a S -l-type substitution induced by the bromide anion. 

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. 

Iminium Catalysis. Together with enamine catalysis, iminium catalysis is the most prominent activation mode in asymmetric aminocatalysis [61]. Initial work was carried out on cycloadditions [10, 62], but it was rapidly extended to... 

On the wave of such impressive results, other notable research groups addressed their efforts to the development of alternative and complementary triple cascade procedures. For instance, amazing contributes have been published, over the years, by Melchiorre et al. that successfully suggested a practical synthesis of several spirocyclic oxindoles and then-analogues [72]. Exploiting the enamine-iminium-enamine activation mode of aminocatalysis, the organocatalytic triple cascade process disclosed by the Spanish group provided the stereoselective construction of all-carbon quaternary... 

SOMO Activation Within the field of aminocatalysis, asymmetric organo-SOMO (singly occupied molecular orbital) catalysis has recently emerged as a powerful technique for the preparation of optically active compounds. In this context, MacMillan and coworkers described in 2008 the formation of y-oxyaldehydes from aldehydes and styrenes by organo-SOMO catalysis [25]. The condensation between the amine catalyst 46 and an aldehyde gave rise to an enamine intermediate, which was then oxidized by ceric ammonium nitrate (CAN) to give a radical cation. Reaction of this radical cation with a nonactivated olefin, namely styrene, led to the... 

Although aminocatalysis of the aldol reaction via enamine intermediates is an important enzymatic strategy and several bioorganic studies of the subject have appeared, applications in preparative organic synthesis, particularly in intermolecular aldol addition reactions, have been published only sporadically. Despite the often-used Mukaiyama-aldol reaction of enol ethers and Stork s vell-developed enamine chemistry [37, 38], aldolizations of preformed enamines are rare. One report describes Le vis acid-catalyzed aldolizations of preformed enamines vith aldehydes that furnish aldol addition products [39]. Aldol condensation reactions of preformed enamines vith aldehydes have also been described [40]. Only enamine-catalytic aldolizations, vhich are primary and secondary amine-catalyzed aldol reactions, vill be discussed in this chapter, ho vever. 

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). 

Covalent Modes of Catalysis-Developing MCRs by Asymmetric Aminocatalysis 11301 Ehamine - Jhninium - Enamine Sequence... 

Distinct from the classical aminocatalysis, Tsogoeva and co-workers documented the first example of enol activation in the typical Mannich-type reaction catalyzed by primary amine-thiourea 63 (Scheme 5.48) [76], The isotope experiments exclude the involvement of a covalent enamine/iminium intermediate and theoretical calculation proves an enol type transition state in this reaction. 

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