Vinylogous enamine activation

Later on, Christmann, et al. developed an organocatalytic intramolecular Diels-Alder reaction of a,P-unsaturated dialdehydes, providing the bicyclic systems (such as decalins 13), [8] (Scheme 3.3). The mechanism was assumed to undergo the vinylogous enamine activation [9], followed by a rapid IMDA reaction and subsequent 6-hydride elimination. On the other hand, the synthesis of the cytotoxic marine natural product amaminol B (16) was achieved by Christmann and his co-workers with the key step of the organocatalytic IMDA reaction of 14, Scheme 3.4 [10]. 

This type of catalyst was also employed by Christmann et al. to promote the asymmetric intramolecular Diels Alder reaction of tethered a,p-unsaturated dialdehydes in the presence of benzoic acid as a co-catalyst through vinylogous enamine activation. The corresponding cycloadducts were obtained in good yields and excellent enantioselectivities of up to 98% ee, as shown in Scheme 6.6. When one of the aldehyde functions was replaced by an a,p-unsaturated ketone as the acceptor, no formal [4 -I- 2] cycloaddition was observed instead, a direct enantioselective vinylogous Michael addition occurred. 

The use of an amine catalyst for the activation of an a,(3-unsaturated carbonyl group as a nucleophile represents a very useful extension of the concept of enamine activation. By transmission of the nucleophilic properties of an enamine to an adjacent olefin (vinylogy), the dienamine can be considered to be a compound bearing two nucleophilic sites (the a- and the y-position) and furthermore it can react as an electron-rich diene in [4 + 2] cycloadditions. This concept was introduced in 2006 by Jorgensen et al. who successfully applied it for the stereoselective y-amination of a,(3-unsaturated carbonyl compounds (166) (Scheme 43). 

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). 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

The observed excellent stereoselectivities (dr=91 9 to >95 5, 94 to >99% ee) could be ascribed to the steric hindrance created by the employed catalyst in each step of the catalytic cycle reported below (Scheme 2.56). Once the chiral amine (S)-70 activates the acrolein 131 as electrophile by generating the vinylogous iminium ion A, the indole 171 performs an intermolecular Friedel-Crafts-type reaction. The resulting enamine B acts as nucleophile in the Michael addition of the nitroalkene 140 leading to the iminium ion D, which upon hydrolysis liberates the catalyst and yields the intermediate aldehyde 173. The latter compound enters in the second cycle by reacting with the iminium ion A, previously formed by the free catalyst. The subsequent intramolecular enamine-mediated aldol reaction of E completes the ring closure generating the intermediate F, which after dehydration and hydrolysis is transformed in the desired indole 172. 

Furthermore, the asymmetric catalysis of 27 could accommodate vinylogous aza-enamines as a source of an alkenyl unit, and the use of 27d bearing the 2,6-dimethyl-4-(l-adamantyl)phenyl groups as catalyst led to the establishment of the general and highly enantioselective formal alkenylation of N-benzoyl imines [77]. Since the oxidative transformation of an aza-enamine moiety of the product into a nitrile functionality appeared feasible as described above, this method offered facile access to optically active y-amino a,P-unsaturated nitriles (Scheme 7.50). 

Dienamine is a recent extension of the enamine concept to extended donors by using the principle of vinylogy. By extension of the enamine to conjugated dienamine starting from alkyl substituted enals or enones, it allows for the functionalization of a,p-unsaturated carbonyls in a- or 7-position using various electrophiles (Scheme 11.26). This potential of amine catalysts to promote extended functionalization is highly interesting, but because of its relative infancy, few synthetic applications of such activation have been reported to date. 

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