Iminium catalysis nucleophiles

Iminium catalysis directly utilizes the higher reactivity of the iminium ion in comparison to the carbonyl species and facilitates Knoevenagel-type condensations, cyclo- and nucleophilic additions, and cleavage of cr-bonds adjacent to the a-carbon. Enamine catalysis on the other hand involves catalytically generated enamine intermediates that are formed via deprotonation of an iminium ion, and react with various electrophiles or undergo pericyclic reactions. ... 

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],... 

The in situ generation of an iminium ion from a carbonyl compound lowers the LUMO energy of the system. Iminium catalysis is comparable to Brpnsted- or Lewis acid activation of carbonyl compounds. The LUMO energy is lowered, the a-CH acidity increases, and nucleophilic additions including conjugate additions as well as pericyclic reactions are facilitated (Eq. 34). 

In 2005, J0rgensen et al. extended the conjugate addition of sulfur nucleophiles to a,P-unsaturated aldehydes under iminium catalysis with trimethylsilyl ether 56 (10 mol%) as catalyst [385]. Very high enantioselectivities (89-97% ee) were reported for the addition of aliphatic thiols to different aromatic and aliphatic enals at low temperatures (-24°C) where the employment of an acid cocatalyst (PhCOjH, 10 mol%) was mandatory in order to improve the reaction rate. This methodology has been incorporated into domino reactions by the same group and others to successfully prepare optically active sulfur-containing heterocyclic compounds [385, 386],... 

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. 

OxidatiV0 Enamine Catalysis. The oxidative transformation of enam-ines derived from saturated aldehydes into a,(3-unsaturated iminium ions by dehydrogenation has been independently disclosed in 2011 by Li, Wang, and co-workers [108] and by Hayashi and co-workers [109]. This chemistry provides an alternative procedure to the standard iminium catalysis, which relies on the use of a,(3-unsaturated aldehydes. Both research groups used diphenylprolynol trimethylsilyl ether as the chiral amine catalyst but while Wang employs o-iodoxybenzoic acid (IBX) as the stoichiometric oxidant [108], Hayashi s procedure relies on the use of 2,3-dichloro-5,6-dicyanoquinone (DDQ) as the oxidant [109]. This oxidation can be performed in the presence of a suitable nucleophile... 

In 2008, the groups headed by Jprgensen and Rueping contemporaneously reported the use of 1,3-diketones reacting as bis-nucleophiles with a,p-unsaturated aldehydes under iminium catalysis with a diaryl prolinol sdyl ether catalyst (Scheme 16.13) [27, 28]. This domino reaction allowed the formation of 3,4-dihydropyrans with good yields and enantioselectivities but variable diastereoselectivities in favor of the 1,3-trans derivatives, precursors of indoloquinoUzidines [29]. 

Although Diels-Alder reactions provided the first examples for the great potential of asymmetric iminium catalysis, it must be pointed out that by far the most applications of this type of catalysis in natural product syntheses have been reported for conjugate additions of different nucleophiles to iminium-activated a, 3-tmsatu-rated acceptor molecules. The following sections will give an overview based on the type of nucleophiles employed in such transformations. 

Comparing the activation mode of iminium and enamine catalysis, iminium catalysis is based on a LUMO-activation mode of the electrophile whereas enamine catalysis is based on a HOMO-activation of the nucleophile. Keeping in mind the fact that enamine and iminium species are rapidly interconverted via a two-electron redox process (proton abstraction of an iminium species results in an enamine), MacMillan and co-workers reasoned that it should be possible to interrupt this equilibrium chemically by carrying out just a one-electron oxidation of an enamine. This would then generate a three-7i-electron radical cation with a singly occupied molecular orbital (SOMO) that should be activated towards catalytic transfomiatirHis (racemic or asymmetric) not possible using classical enamine or iminium activation (Scheme 80) 316). 

In 2013, Yoshikai and Wei developed a copper-catalyzed pyridines synthesis from oximes and enals [65]. Under redox-neutral reaction conditions, with 0-acetyl ketoximes and 0 ,/3-unsaturated aldehydes as the substrates and using copper(I) salt and a secondary ammonium salt (or amine) as the catalyst system, a variety of substituted pyridines were prepared with a broad range of functional groups tolerance (Scheme 3.29). By merging iminium catalysis and copper catalyst, imder the redox activity of the copper catalyst, the reaction started to reduce the oxime N—O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediates to the final products. 

A [3+3]-type condensation of O-acetyl ketoximes and a, -unsaturated aldehydes yields pyridines " for example, Ph-(Me)C=N-OAc and trans-cinnamaldehyde (trans-Ph-CH=CH-CHO) give 2,4-diphenylpyridine (54) using copper(I) iodide as catalyst and a salt of a secondary amine only a trace of the 2,6-product is observed. A synergistic copper/iminium catalysis is proposed the oxime reacts with the copper iodide to give an iminyl copper species, Ph-(Me)C=N-Cu-X (i.e., N-O reduction), which tautomerizes to a copper(II) enamide, Ph-C(=CH2)-NH-CuX, which then acts as a nucleophile towards the iminium ion (formed from the aldehyde and 2° amine). 

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. 

Correspondingly, iminium catalysis involves nucleophilic addition to the P-position of an iminium species 8 derived from an a,P-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 1.2). 

Iminium catalysis consists in the addition of primary or secondary amines to an a,(3-unsaturated carbonyl (Scheme 11.2, eq 1). " The transient iminium ion has its lowest unoccupied molecular orbital (LUMO) lowered, activating the substrate toward the attack of a nucleophile and creating the new stereocenter. Liberation of the catalyst furnishes the enantioenriched Michael adduct. 

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... 

The Jprgensen et al. synthesis of warfarin, an anticoagulant, is another example of short drug synthesis (Scheme 11.5). Indeed, the enantioenriched product could be obtained directly by a single-step procedure. The 1,3-dicarbonyl compound 6, a powerful nucleophile, reacted without any need of extra additive on commercially available enone 7 activated by iminium formation with 8 and yielding warfarin in excellent 90% yield and a promising 80% ee. This synthesis further exemplifies the power of iminium catalysis for the fast synthesis of small dmgs. 

Melchiorre and co-workers reported the first asymmetric aziridination of a,p-unsaturated ketones using the primary amine-amino acid salt 91 (Scheme 5.39) [68]. The reaction occurred via first nucleophilic addition of A-centered nucleophile (iminium catalysis) followed by intramolecular cyclization (enamine catalysis). Essential factors for the success of the current reaction included the proper selection of nitrogen nucleophile and the addition of solid NaHCO. Under the optimized conditions, a range of cyclic or acyclic enones can be incorporated in the protocol to afford either A-CBz or A-Boc aziridines with excellent diastereo- and enantioste-reocontrol (Scheme 5.39). 

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). 

Simultaneous publication of the iminium ion catalysed hydrophosphination of a,p-unsaturated aldehydes by Melchiorre and Cordova showed diarylprolinol silyl ether 55 was effective in the conjugate addition of diphenylphosphine 74 [117, 118], Direct transformation of the products allowed for one-pot methods for the preparation of P-phosphine alcohols 75 (72-85% yield 90-98% ee), P-phosphine oxide acids 76 (65% yield 92% ee) and 3-amino phosphines 77 (71% yield 87% ee) (Scheme 34). These reports represent the first examples of the addition of P-centred nucleophiles and the resulting highly functionalised products may well have further use in asymmetric catalysis. 

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