Iminium catalysis concept

Another important application of the iminium catalysis concept has been the development of enantioselective Type I [15, 30] and Type II [15] intramolecular Diels-Alder reactions (IMDA). (For experimental details see Chapter 14.18.3). For these transformations, both catalysts 1 and 3 proved to be highly efficient, as demonstrated by both the short and effective preparation of the marine methabo-lite solanapyrone D via Type I IMDA (Scheme 3.4, top) and the development of an early example of an enantioselective, catalytic Type II IMDA reaction (Scheme 3.4, bottom) [35]. Importantly, cycloadducts incorporating ether and quaternary carbon functionalities could be efficiently produced. 

It was in 2000 that Barbas and List reported their well-known proline-cat-alyzed enantioselective intermolecular aldol reaction (Scheme 1.4), as the culmination of a research which started in the 1990s with the use of aldolase antibodies as catalysts for the aldol reaction. Trying to provide a mechanistic rationale for understanding these reactions, and with the evidence of enamine intermediates participating in the reaction in hand, they developed the proline-catalyzed intermolecular aldol reaction in an attempt to mimic the enzyme s behavior. Another important landmark in this context was the introduction of the iminium catalysis concept by MacMillan, related to the enantioselective... 

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

The development of enamine catalysis parallels that of iminium catalysis (Scheme 3) [24], Like iminium catalysis, the concept took a long time to mature, and also required a key discovery - the discovery of intermolecular proline-catalyzed aldol reactions by List and coworkers in 2000 [23] - to set the field in motion. The timeline of historical developments of enamine catalysis is outlined in Scheme 4. 

The Diels-Alder reaction is a valuable transformation for the construction of complex carbocycles, and represents arguably one of the most powerful approaches in organic chemistry. In particular, catalytic enantioselective variants have received unprecedented attention [22], representing an appealing starting point for the development of MacMillan s concept of iminium catalysis. 

Chiral asymmetric epoxidations have been intensively investigated due to the fundamental importance of epoxides in organic chemistry [69, 70], Nevertheless, catalytic asymmetric Lewis acid epoxidation of a,/i-unsaturated aldehydes remains a challenge to chemists. Recently, Jorgensen and co-workers developed the first asymmetric approach to epoxides of enals, in which chiral pyrrolidine 11 was used as catalyst and H2O2 as oxidant, thus following the concept of iminium catalysis (Scheme 3.9) [71-73]. Importantly, reaction conditions are tolerant to a variety of functionalities and this chemical transformation proceeds in different solvents, with no loss of enantioselectivity. (For experimental details see Chapter 14.13.1). 

When summing up the recent achievements in iminium-activated natural product synthesis, the importance and versatility of this methodology cannot be overemphasized. Besides enamine catalysis, it is due particularly to the considerable achievements made in iminium catalysis that asymmetric organocatalysis has received so much attention over the last few years. As depicted in this chapter, the LUMO-lowering concept originally introduced by MacMillan has found widespread applications in natural product synthesis. In addition, it has been shown, that this activation mode works very well in cascade approaches. This methodology should become more widely utilized in the future (Table 2). 

In the range of the study of new processes to improve the atom efficiency, the discovering versatility of a catalyst as multifunctional catalyst in a transformation is important. On the strength of this concept. Jiao and coworkers reported an enantioselective reduction and alkylation reaction of a,p-unsaturated aldehydes with alcohols, in which the ammonium salt catalyst performed three kinds of catalytic functions, namely, iminium catalysis, enamine catalysis, and acid catalysis [90]. 

Iminium-based organocatalysis is somewhat less explored than enamine-based organocatalysis and has been mostly used in the activation of a,/S-conjugated aldehydes and ketones. Therefore, this type of catalysis has unsurprisingly been the subject of a limited number of studies under the umbrella of the metal-organic cooperative catalysis concept. In 2011, the Cdrdova group [55] reported the first enantioselective and chemoselective /3-silyl addition to a./S-unsaturated aldehydes using copper salts and chiral pyrrolidine derivatives as catalysts. As proposed, the chiral secondary amine forms an iminium salt with... 

Iminium catalysis is another key catalytic concept in aminocatalysis. Initialworkwas disclosed by MacMillan for the Diels-Alder reaction of cyclopentadiene and a,P-unsaturated aldehydes [12], but it was rapidly extended to Michael additions (including Friedel-Crafts reactions). Now iminium catalysis has been established as a general mode for nucleophilic addition to a,]3-unsaturated carbonyl compounds. 

In 2005, Huang et al. reported a tandem asymmetric conjugate reduction-fluorina-tion reaction by an efficient combination of iminium and enamine catalysis using two distinct secondary amine catalysts [16]. This method offered direct access to chiral multifunctionalized aldehydes from P-substituted enals and electrophilic florinated reagents in a biomimetic way (Schane 9.13). The diastereoselectivity of the products varied depending on the catalyst combination (Scheme 9.14). The chemistry presented here demonstrated for the first time the power of the multicatalysis process for control of the product diastereoselectivity based on the cycle-specific catalysis concept. 

The ability of the diarylprolinol catalysts to participate in both enamine- and iminium-ion achvations makes them ideal for the sequential addition of nucleophiles and electrophiles through cascade catalysis (Scheme 2.8). Conjugate addition of a nucleophile to the iminium ion forms a transient enamine intermediate 3, which can effectively react with an electrophile in the a-position, forming an a,P-disubstituted adduct. This process commonly proceeds to afford the products in good yields and with high enantio- and diastereoselectivities. If the nucleophile and electrophile are part of the same molecule, cyclic products are obtained. The cascade concept has been widely explored and some illustrative examples are given below [13, 17]. 

Since its rediscovery by MacMillan in 2000, iminium activation catalysis has become a key catalytic concept in organocatalysis. After initial work centered on cycloadditions, Michael additions became the main area of interest and it is now estabhshed as a general strategy for the asymmetric conjugate addition of nucleophiles to a,P-unsaturated compounds. 

This study provided one of the first demonstrations [24] that chiral secondary amines can integrate orthogonal activation modes of carbonyl compounds (enamine and iminium ion catalysis) into more elaborate reaction sequences, catalyzing more than one stereocontroUed bond-forming event As detailed in Section 42.2.2, this concept greatly permeated and boosted future developments in the field of asymmetric organocatalytic MCRs. 

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