Imidazolidinones catalysts

Figure 11.3. Computational models of the first- and second-generation imidazolidinone catalysts (9 and 11) and of the corresponding iminium ions.

Cascade Addition-Cyclization Reactions Given the importance of cascade reactions in modem chemical synthesis, the MacMillan group has proposed expansion of the realm of iminium catalysis to include the activation of tandem bond-forming processes, with a view toward the rapid constraction of natural products. In this context, the addition-cyclization of tryptamines with a,p-unsaturated aldehydes in the presence of imidazolidinone catalysts 11 or 15 has been accomplished to provide pyrroloindoline adducts in high yields and with excellent enantioselectivities (Scheme 11.3a). This transformation is successful... 

Type B enamine catalysts have been developed more recently. They include the diarylprolinol ethers (developed by the Hayashi and Jprgensen groups, e.g. 47 and its derivatives) [71-75] as well as the MacMillan imidazolidinone catalysts (e.g. 46) [76-78]. They excel in reactions where hydrogen bonding assistance is either not required or is not essential, such as a-halogenation reactions as well as some conjugate addition reactions (Scheme 12). 

Domino processes can also be performed on open-chain compounds. MacMillan and co-workers demonstrated this with their own imidazolidinone catalysts. Conjugate addition of a nucleophilic heterocycle 231 to the a,(i-unsaturated enal 230 followed by a-chlorination of the resulting enamine led to the syn products 234 in very high enantioselectivities and good sytv.anti diastereoselectivities (Scheme 38) [347]. Similar domino sequences, but with different nucleophile-electrophile partners, were also reported independently by Jprgensen [348]. 

Modifications to the architecture of the imidazolidinone catalyst provided the fnryl derivative (20) which proved to be a powerfnl catalyst for the catalytic asymmetric Diels-Alder cycloaddition of simple a,P-unsaturated ketones [50]. Although... 

Although the imidazolidinone catalysts used within these transformations are simple, cheap, readily accessible and in some cases recyclable using acid/base extraction, considerable efforts have been made to examine alternative methods to separate and recycle the catalyst with good success. Examination of the structure of imidazolidinone 22 shows two convenient points for the introduction of a polymer or fluorous support, R and R, both of which have been examined (Fig. 4). Curran has shown that identical reactivity, diastereoselectivity and enantioselectivity can be obtained using a fluorous tag (23) [53]. The catalyst can easily be recovered and recycled using F-SPE with excellent yield, purity and levels of activity. Polymer- (24) and silica-supported (25) imidazolidinones reported by Pihko [54] (R substitution)... 

Takasu examined a series of five imidazolidinone catalysts in the intramolecular conjugate addition of amides to a,p-unsaturated aldehydes to prepare a series of tetrahydroisoquinolines [114]. Although yields were high for these organo-catalytic transformations (70-90%), enantiomeric excesses were low (18-53%) showing further optimisation with regards to the co-acid and solvent are necessary to bring this potentially useful transformation in line with other reactions of this class. 

Proline catalysis leads to the anti products 3 and 4. Use of the designed imidazolidinone catalyst 11 leads to the complementary syn product 12. 

A key step in the total synthesis of the marine metabolite (—)-solanopyrone D (161) is the enantioselective organocatalytic intramolecular Diels-Alder reaction of the trienal (158) to the decalin aldehyde (160) in the presence of the imidazolidinone catalyst (159) (Scheme 45).187 Protonated 1,2-diamino-1,2-diphenylethane has been... 

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],... 

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. 

Based on the mechanistic rationales discussed earlier, it is clear that 7r-facial selectivity and reaction rates of cycloaddition reactions result exclusively from the association of imidazolidinone catalysts to the electrophilic enal component. It is, therefore, conceivable that this platform should be amenable to a range of reactions of a,/ -unsaturated carbonyl compounds, regardless of the nature of the HOMO-donor component. 

It was envisioned that the addition of an indole derived from a tryptamine to the activated iminium ion, arising from imidazolidinone catalyst 3 and an a,p-unsaturated aldehyde, would generate a C(3)-quaternary carbon-substituted indo-lium ion. As a central feature this intermediate cannot undergo re-aromatization by means of proton loss, in contrast to the analogous 3-H indole addition pathway. As a result, 5-exo-heterocyclization of the pendant ethylamine would provide the corresponding pyrroloindoline compounds. In terms of molecular complexity, this cascade sequence should allow the rapid and enantioenriched formation of stereochemically defined pyrroloindoline architecture from tryptamines and simple a,/i-unsaturated aldehydes. 

A flask containing nitrone (1 equiv) and imidazolidinone catalyst-HX (20 mol%) was charged with MeNC>2 (0.1 M), and then with the appropriate amount of H20 (3 equiv). After cooling the solution to the desired temperature, a,/ -unsaturated aldehyde (4 equiv) was added dropwise to the flask. Additional aldehyde (3 equiv) was added to the reaction mixture at 24-h intervals until the reaction was complete (96-160 h). The resulting solution was passed through a silica gel column with AcOEt. The removal of volatiles afforded an oily residue that was purified by silica gel chromatography to afford the title compound. 

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