Diels iminium-activated

The amine-catalyzed Diels-Alder dimerization reaction of a, 3-unsaturated ketones in water was developed by Barbas et al. to form cyclohexanone derivatives (Eq. 12.12). They believe that the reaction proceeds via the in situ formation of 2-amino-1,3-butadiene and iminium-activated enone, as the diene and dienophile, respectively. 

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... 

In line with the mechanistic rationale of LUMO-lowering iminium activation, MacMillan hypothesized that intermediate 2, generated from the secondary amine 1 and an a,/f-un saturated aldehyde, could be activated towards cydoaddi-tion with an appropriate diene (Scheme 3.1). The Diels-Alder reaction would form iminium ion cydoadduct 5 that, in the presence of water, would hydrolyze to yield the enantioenriched product 6 and regenerate the chiral imidazolidinone catalyst 1. 

A limitation of MacMillan s approach towards iminium-activated Diels-Alder reactions has been the use of a-substituted a,/ -unsaturated aldehydes as dieno-philes. Recently, Ishihara and Nakano [31] succeeded in partially overcoming this problem by identifying a novel primary amine organocatalyst for this type of... 

Besides the use of chiral amines to activate nucleophiles via enamine formation, their use as acceptor-activating catalysts via iminium formation has resulted in the development of numerous impressive applications over the last decade. The concept of iminium activation of conjugated enones has been postulated to play a pivotal role in the biogenesis of natural products as proposed by Baldwin et al. for the key Diels-Alder step in e.g. the biosynthesis of himgravine 188-190). 

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. 

The difficult translation of SOMO activation to cyclic ketones was achieved with the help of catalyst 6, which was developed earUer for Diels-Alder reactions of cyclic ketones via iminium activation. The difficulty Hes in the fact that aldehydes and ketones exhibit largely different steric and electronic properties with respect to catalyst interactions [16]. Competitive catalyst degradation under the oxidative conditions (i.e., oxidation of the methyl group attached to furan) was circumvented by transforming the methyl into a trifluoromethyl group, or by direct replacement of the furyl ring with less electron-rich heteroaryl systems such as benzofuran (8) or benzothiophene (9), which are less sensitive to oxidation (Scheme 39.5). 

Design of iminium-enamine cascade reactions Iminium-activated Diels-Alder reactions Iminium-activated sequential [4h-2] reactions Iminium-activated [3-h2] reactions Iminium-activated sequential [3-1-2] reactions Iminium-activated [2h-1] reactions... 

A special but significant case of 6 is that of the a,p-unsaturated ketones 41 (R is a vinyl group). An intramolecular attack on the a,p-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 1.13a). The formation of 42 through an enamine-iminium sequence can also be viewed as a Diels-Alder reaction between intermediate 43 and the electrophile (Scheme 1.13b). 

Three-component reactions can be designed by incorporating suitable nucleophiles and electrophiles into iminium-activated systems (Scheme 1.40a). Furthermore, cyclic structures can be constructed if these nucleophiles and electrophiles can be incorporated into the same molecule as 111 (Scheme 1.40b). In fact, [2-i-l], [3-1-2], sequential [4-1-2], and Diels-Alder reactions have been developed, depending on the distance between nucleophilic and electrophilic positions of 111 to fnmish diverse cyclic structures. 

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]. 

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

Fig. 2 Catalytic cycles for the iminium ion activated Diels-Alder and conjugate addition reactions...

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. 

Diels-Alder cycloaddition reactions of iminium ions (Sect. 2.1.1) could take place with either the C=N bond or the C=C bond acting as the dienophile. This potential dual reactivity was investigated by Zora using the AMI semi-empirical method [231]. The results showed not only the preferred C=C reactivity (activation barrier is 4.20 kCal mol" lower than for reaction with the C=N bond) but also suggested that the reaction was stepwise. 

Additionally, investigations into imidazolidinone catalysed Diels-Alder reactions (Schemes 2 and 6) [234] have shown that iminium ions of a,P-unsaturated aldehydes and ketones have lower activation barriers for the Diels-Alder reaction with cyclopentadiene than the parent compound (13 and 11 kCal mol", respectively). It was also noted that transition structures show the formation of the bonds is concerted but highly asynchronous. 

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],... 

Aza Diels-Alder reactions of nonactivated imines have been investigated with regard to the effects of electronically neutral substituents and the influence of Lewis acids [179, 180]. Some of the synthetic applications described below nevertheless take use of the higher reactivity of iminium ions or imines activated by electron-withdrawing substituents, respectively. 

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