Iminium ion catalysis

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. 

The [3+2] cycloaddition has also been shown to be effective in the reaction of azomethine imines 32 with a,P-unsaturated aldehydes by Chen and co-workers [70], A survey of seven catalysts revealed some interesting trends, with the diarylprolinol derivative 31 giving the highest yields and selectivities (40-95% yield endo. exo 1 4.3-1 49 77-96% ee for exo) with short reaction times (5-24 h) and low catalyst loading (10 mol%) (Scheme 11). The reaction was particularly sensitive to the amount of water present in the reaction medium and the choice of co-acid. This phenomenon is a reoccurring theme in many of the publications in the area of iminium ion catalysis and, as yet, no general explanation has been proposed to account for these observations. 

As previously noted (Scheme 1), prior to the explosion of interest in iminium ion catalysis as a platform for the activation of a,P-unsaturated carbonyl compounds in 2000, Yamaguchi [29-33] and Taguchi [34] showed that proline derived bi-func-tional catalysts could provide an effective platform for the ion-pair controlled conjugate addition of malonates and nitroalkanes to a, 3-unsaturated ketones with good levels of stereocontrol. 

Scheme 30 Conjugate addition of A-silyloxycarbamates using iminium ion catalysis...

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

One of the most compelling features of iminium ion catalysis is the proposed mechanistic rationale for the transformations, which leads to highly predictable reaction outcomes. Despite impressive advances and the plethora of reactions reported efforts to provide a detailed mechanistic understanding of the catalytic cycle are limited. The reported work has focussed on the Diels-Alder cycloaddition and has provided useful indicators that could be used in design of more active catalysts. 

Fig. 16 Kinetics of iminium ion catalysis using trifluoromethyl pyrrolidine...

To date, the use of computational methods to investigate iminium ion catalysis has been limited. The focus has been on rationalising the diastereo- and enantiose-lectivities observed in the laboratory, but this has largely been retrospective and the clear potential of these models as predictive tools for the design of improved catalysts or even entirely new scaffolds has yet to be realised. There are few examples of solid kinetic data in the literature making evaluation of the models difficult. 

Despite rapid progress in iminium ion catalysis it is still a maturing field and significant challenges remain if it is to become a bench-mark method of choice. The... 

The reason the ehemical community overlooked organocatalysis is complex and difficult to state. This burgeoning field is associated with many transient chemical characteristics that include the modes of catalysis (enamine and iminium ion catalysis)/ atypical reactivity and various transformations. 

Erkkil A, Majander I, Pihko PM (2007) Reviews on asymmetric iminium ion catalysis. Chem Rev 107 5416-5470. doi 10.1021/cr068388p... 

A sophisticated chemoselective 1,4-addition of silicon nucleophiles to a.P Unsaturated aldehydes (1,2- versus 1,4-addition) was disclosed by the groups of Ibrahem and Cordova, merging copper(I)-catalyzed silicon-boron bond activation with iminium ion catalysis (Scheme 13) [40]. Proline derivative (S)-68 induced good to high levels of enantiocontrol in reactions of enals with either aromatic [22a-c —> (S)-67a-c] or aliphatic substituents [22d —> (/ )-67d] in the p-position. The chemoselectivity was excellent throughout. Moreover, p,p-disubstituted substrates were also converted chemoselectively with acceptable 76% ee [(S)-69],... 

List showed that iminium ion catalysis can be coupled with chiral Brpnsted acid catalysis in the epoxidation of a-alkyl-a,p-unsaturated aldehydes (Scheme 4.25) [59]. Substrates with the a-alkyl group are less reactive than those that contain a hydrogen at the a-position, making then-nucleophilic epoxidation more challenging. The List protocol allows for the conversion of aldehyde 128 to epoxide... 

---