Michael addition iminium catalysis

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

Chen and coworkers have reported a new domino Michael-Michael addition reaction between a,a-dicyanoalkene [26] derived from cyclohexanone and benzyli-deneacetone, resulting in a stepwise [4 + 2]-type cycloaddition to afford almost enantiopure bicyclic adduct 15. In contrast to the completely inert function of secondary ammonium salt, a primary amine, 9-amino-9-deoxyepiquinine lo [27], in combination with trifluoroacetic acid, was found to be highly efficient in the activation of the a, 3-unsaturated ketone by tandem iminium-enamine catalysis (Scheme 10.21) [28],... 

Scheme 10.21 Domino Michael-Michael addition by iminium-enamine catalysis.

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

Woodward probably conducted the most outstanding work on iminium catalysis before its rebirth in 2000. In this work. Woodward applied proUne catalysis in a triple organocascade reaction consisting of a deracemization (via aretro-Michael, Michael addition) and an intramolecular aldol reaction that determine the stereochemical outcome of the reaction (Scheme 1.5), leading to the synthesis of erythromycin [13]. 

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. 

In 2010, Chen and co-workers [134] developed the first organocatalytic asymmetric conjugate addition of a, 3-unsaturated aldehydes via iminium catalysis. In the presence of diarylprolinol silylether 7 and o-fluorobenzoic acid (OFBA), the reaction proceeded well to afford the highly valued adducts with excellent enantioselectivities and with up to outstanding diastereoselectivities (Scheme 5.67). To emphasize the synthetic utility of the reaction, a number of natural-product-like or drug-like molecules with versatile skeletons have been efficiently constructed from the corresponding Michael adducts. 

While Lewis acids normally enable l,2-additi(Mis of silyloxy furans to a,(3-unsaturated aldehydes, the MacMillan group discovered that iminium catalysis favors 1,4-additions, thus overcoming the deficiency of normal Lewis acids in Mukaiyama-Michael additions 244). The high potential of this protocol was demonstrated impressively in a short synthesis of the Penicillium spiculisporum fermentation product spiculisporic acid (262). As shown in Scheme 60, vinylogous addition of the silyloxy furan 263 to the acceptor 264 catalyzed by 228 furnished the key intermediate 265 in good enantio- and diastereoselectivity. It is worth noting that the TfOH salt of the catalyst in combination with methyl ester 266 as a Michael acceptor gave the anh-diastereomer 267 exclusively. This compound was then used for the synthesis of 5-epi-spiculisporic acid (268) (Scheme 60) 244). 

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