Iminium catalysis, -4-imidazolidinone

Cascade Addition-Cyclization Reactions Given the importance of cascade reactions in modem chemical synthesis, the MacMillan group has proposed expansion of the realm of iminium catalysis to include the activation of tandem bond-forming processes, with a view toward the rapid constraction of natural products. In this context, the addition-cyclization of tryptamines with a,p-unsaturated aldehydes in the presence of imidazolidinone catalysts 11 or 15 has been accomplished to provide pyrroloindoline adducts in high yields and with excellent enantioselectivities (Scheme 11.3a). This transformation is successful... 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Scheme 18.3 Catalytic cycle of iminium catalysis with imidazolidinone and electrophilicity of the intermediates obtained.

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. 

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

With respect to the catalysts of choice, the MacMillan imidazolidinones 77 emerged as the most commonly used ones in iminium catalysis, but also cinchona alkaloid-based amines like 115 as well as the Hayashi-Jprgensen catalysts 85 have been highly successful in this field [31,47]. 

Based on these results the following reaction pathway can be assumed. Iminium catalysis is reahzed by the use of chiral imidazolidinones. The subsequent enamine catalysis (HOMO achvation) is realized by deployment of proline. The anti-configured products were detected by application of L-proline, whereas the use of D-proline determines the syn[Pg.90]

It is believed that monofunctional imidazolidinones are optimal for iminium catalysis but without the necessary structural features to participate in bifunctional enamine catalysis (e.g., activation of electrophiles via electrostatic interaction). Conversely, proline has proved to be an enamine catalyst for which bifunctional activation is a standard mode of operation aCTOss a variety of transformation types, yet it is generally ineffective as an iminium catalyst with enals or enones. Therefore, a combination of imidazoUdinone and proline may provide a dual-catalyst system that could fully satisfy the chemoselectivify requirements for cycle-specific catalysis [136]. 

Star polymers 200 and 202 cannot penetrate each other s core and therefore are expected to maintain their catalytic integrity. On the other hand, small-molecule reagents and catalysts can freely diffuse to the core of the star polymers. MacMillan s imidazolidinone can diffuse to the core of the acid star polymer 200 to form the desired salt 201, which is an optimal iminium catalyst. Electrostatic attraction should retain 199 within the core of 200 during catalysis. The presence of strong acid p-TSA (alone or paired with imidazolidinone 199) diminishes the ability of 202 to effect iminium catalysis. Additionally, a hydrogen-bond donor catalyst 203... 

MacMillan s group demonstrated that iminium catalysis can be a general and reliable strategy for organic synthesis by employing the imidazolidinone-type catalysts successfully in a wide range of asymmetric transformations [10,12], One example is the total synthesis of the more complex natural product (-t-)-minfiensine, which was isolated from Strychnos minfiensis (Scheme 3.2) [17], Due to its unique structure and potential biological activity, (-i-)-minfiensine has also attracted considerable attention... 

Iminium catalysis is one of the most powerful methods for the introduction of a nucleophile in -position of an a,(3-unsaturated carbonyl. Various nucleophiles can be entered such as N, O, C, aryl, and heteroaryl nucleophiles in usually high levels of stereoselectivity. To obtain these high enantioselectivities, two catalysts have seemed to be more general as soon as aldehydes are involved. Diaryl-prolinol silyl ethers and MacMillan imidazolidinones have found applications in numerous processes (Scheme 11.3). These catalysts are... 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

Modern strategies in organic catalysis based on iminium activation using imidazolidinones as catalysts 06AA79. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

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. 

MacMillan has reported examples of synergistic catalysis in which copper salts are used. Although these results were driven by ad hoc hypotheses, most of these transformations are related to a Cu(i)/Cu(m) catalytic cycle. In any case, the superior performances offered by copper(i) salts, compared to strong Lewis acids tested in the processes, is an indication that the Lewis acidity of the metal salt is not playing a decisive role in these transformations. The complexation of the enamine 7i-system with Cu(iii)-R is expected to lead to rjl-iminium organocopper species that, upon reductive elimination, will form a carbon-carbon bond and liberate the active Cu(i) catalyst. Hydrolysis of the resulting iminium will also release the imidazolidinone catalyst to complete the organocatalytic cycle as shown in Scheme 18.7. 

Scheme 18.6 Stereoselective reaction by combination of iminium and enamine catalysis with imidazolidinones.

Almost simultaneously, MacMillan and colleagues developed a similar MCR based on the iminium ion-enamine activation of enals (Scheme 42.11) [33]. They used the chiral imidazolidinone catalyst 41 to combine the enantioselective conjugate additions of a large number of diverse carbon-based nucleophiles with the a-chlorination of the resulting aldehyde intermediate 42, which proceeds under enamine catalysis [35]. The reaction sequence is accompanied by a high syn-selectivity and excellent enantioselectivities. 

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