Iminium activation strategy

In order to test the iminium-activation strategy, MacMillan first examined the capacity of various amines to enantioselectively catalyze the Diels-Alder reaction between dienes and a,/ -unsaturated aldehyde dienophiles [6]. Preliminary experimental findings and computational studies proved the importance of four objectives in the design of a broadly useful iminium-activation catalyst (1) the chiral amine should undergo efficient and reversible iminium ion formation (2) high... 

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... 

Following similar iminium activation strategies using prolinol-derived organocatalysts, highly functionalized chiral cyclohexanone derivatives [192], dihydropyranone compounds [193], and polysubstituted cyclopentanones [194] have been also synthesized. 

The iminium activation strategy with the trifunctional chiral primary amine 28, which was used in the y-selective conjugate addition of y-butenolides (Scheme 28), also proved highly effective for promoting reaction with the y-butyrolactam (Scheme 32, first line) [52]. Although various chiral diamines, amino thioureas, and amino sulfonamides were evaluated during the optimization study, none of these catalysts gave rise to impressive levels of diastereoselectivity. Eventually, a bulky acid additive, such as the protected tryptophan derivative (V-Boc-L-Trp-OH),... 

MacMillan s group advanced the iminium activation strategy to intramolecular Diels-Alder reactions with good diastereoselectivity (up to 20 1) and enantioselectivity [61]. The strategy was applied in the total synthesis of (-i-)-hapalindole Q [62]. A novel binaphthyl-based diamine was utilized to catalyze Diels-Alder reaction of a,P-unsaturated aldehydes with unprecedented high exo selectivity [63]. It was reported that the same reaction was also catalyzed by diphenylprolinol silyl ether and an acid as cocatalyst [64]. However, with the same reactants and the same catalyst, an ene reaction took place instead without an acid additive. Diels-Alder reactions of 2-vinylindoles and a,p-unsaturated aldehydes were also developed [65]. 

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)] ... 

Lelais G, MacMillan DWC. Modem strategies in organic catalysis the advent and development of iminium activation. Aldri-chim. Acta 2006 39 79-87. 

G. Lelais and D.W. MacMillan, Modem Strategies in Organic Catalysis the Advent and Development of Iminium Activation, Aldrichimica Acta 39 79-87 2006. 

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

Amine Catalysis (Via Iminium Ion Activation). a,p-Unsaturated aldehydes and ketones are common Michael acceptors susceptible to be activated by an amine catalyst via ion iminium formation [64]. This general activation strategy for enals and enones has been applied to aza-Michael reactions with relative success [65]. One complication of the approach is that both the catalyst and the nucleophile are amine species that could mix their preconceived roles and lead to either catalyst... 

More recently, following the same strategy, Vicario and co-workers [60] described the first example of the use of hydrazone derivatives as nucleophiles in aza-Michael initiated cascades under iminium activation, opening an efficient enantioselective entry to functionalized dihydropyridazines (Scheme 16.30). 

As described by Cordova et al., the strategy of combining transition metal-catalysed nucleophilic activation with chiral amine-catalysed iminium activation allows the enantioselective conjugate silyl addition to a,p-unsaturated aldehydes [115]. The reaction proceeds with good 1,4-selectivity and moderate enantio-selectivity when p,p-disubstituted unsaturated aldehydes are used as substrates, as exemplified in Scheme 77. The silylated products are versatile adducts that can be easily converted to protected 1,3-diols and p-functionalised esters. 

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. 

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