Chiral enamine intramolecular Michael reaction

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

A variety of a,a-dicyanoalkenes derived from aryl ketones have also been extensively explored under the same catalytic conditions, and in general the vinylogous Michael adducts were obtained due to the steric hindrance in the following enamine catalysis by primary amine lo [28]. Nevertheless, an interesting domino Michael-Michael-retro-Michael reaction was observed for a,a-dicyanoalkenes derived from acetophenone and propiophenone, giving a facile process to chiral 2-cyclohexen-l-one derivatives. It was noteworthy that a kinetic resolution was observed in the intramolecular Michael addition step (Scheme 10.22). 

An alternative and useful method for intramolecular conjugate addition when the Michael donor is a ketone is the formation of an enamine and its reaction with a Michael acceptor. This can be advantageous as enamine formation occurs under reversible conditions to allow the formation of the product of greatest thermodynamic stability. Treatment of the ketone 40 with pyrrolidine and acetic acid leads to the bicyclic product 41, formed by reaction of only one of the two possible regio-isomeric enamines (1.51). Such reactions can be carried out with less than one equivalent of the secondary amine and have recently been termed organo-catalysis (as opposed to Lewis acid catalysis with a metal salt). The use of chiral secondary amines can promote asymmetric induction (see Section 1.1.4). 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

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. 

The second class of chiral organocatalysts recently involved in domino Michael reactions of other-than-C-nucleophiles is constituted by the cinchona alkaloid family. In this area, Melchiorre et al. have involved a chiral primary amine salt derived from 9-amino-(9-deoxy)-epz-hydroquinine to induce chirality in aziridinations of enones. This domino iminium-enamine intramolecular sequence afforded a series of chiral protected aziridines derived from both... 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

There is an interesting variant of this reaction which involves the use of tert-butyldimethylsilyloxyacetaldehyde as Michael donors and chiral primary amine thiourea bifunctional catalyst 37b (Scheme 2.13). In this case, the diastereoselectivity of the reaction changed from the usually observed syn relative stereochemistry at the final Michael adduct to the formation of the anti diastereoisomer as the major product. This change in diastereoselectivity was explained in terms of the generation of a Z-enamine intermediate assisted by the formation of an intramolecular hydrogen bond between the secondary... 

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