MacMillan imidazolidinone catalyst

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). 

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... 

At present, one of the most successful catalysts for enamine activation has been proline (2). Proline is a cheap, widely and commercially available amino acid that can be found in both enantiomeric forms and, as such, represents a remarkable synthetic alternative to many established asymmetric catalysts. Given such attractive features, it has become the catalyst of choice for many enamine-catalyzed processes. However, various more recent studies have demonstrated that proline is not a universal catalyst for transformations that involve the a-functionalization of ketone or aldehyde carbonyls. Indeed, these studies have demonstrated that the iminium catalysts developed by MacMillan (imidazolidinones) and Jprgensen (pyrrolidines) are also highly effective for enamine activation with respect to... 

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]. 

In addition, immobilized catalysts related to the MacMillan imidazolidinone-type organocatalyst 5 have been used for the asymmetric Diels-Alder reaction (Section... 

Dissymmetric ferrocenyldiphosphines have been synthesized from (R)-(+)-N, N -dimethylaminoethylferrocene. The diphosphines have been used as ligands in asymmetric transfer hydrogenation of acetophenone in the presence of ruthenium catalysts.297 Asymmetric transfer hydrogenation of a,/S-unsaturated aldehydes with Hantzsch dihydropyridines and a catalytic amount of MacMillan imidazolidinone salt (12) leads to the saturated carbonyl compounds in high yields and excellent chemo-and enantio-selectivities.298 ... 

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. 

Around the same time, MacMillan and co-workers developed imidazolidinone Sa (Figure 10.6) and demonstrated its catalytic activity in the Diels-Alder reaction (Equation 10.14) [31]. MacMillan s catalyst works as animinium ion catalyst, thereby lowering the LUMO level, as shown in Figure 10.7. 

Scheme 7.2 MacMillan et al. introducing imidazolidinone catalysts and the merged iminium—enamine process.

MacMillan has reported examples of synergistic catalysis in which copper salts are used. Although these results were driven by ad hoc hypotheses, most of these transformations are related to a Cu(i)/Cu(m) catalytic cycle. In any case, the superior performances offered by copper(i) salts, compared to strong Lewis acids tested in the processes, is an indication that the Lewis acidity of the metal salt is not playing a decisive role in these transformations. The complexation of the enamine 7i-system with Cu(iii)-R is expected to lead to rjl-iminium organocopper species that, upon reductive elimination, will form a carbon-carbon bond and liberate the active Cu(i) catalyst. Hydrolysis of the resulting iminium will also release the imidazolidinone catalyst to complete the organocatalytic cycle as shown in Scheme 18.7. 

In some cases, using the silyl enol ethers form of nucleophiles in the asymmetric Michael reactions is necessary for ensuring high reactivity and selectivity. MacMillan and co-workers [113] developed the first enantioselective organocata-lytic Mukaiyama-Michael reaction for the synthesis of enantioenriched 7-butenolide architecture in 2003. In the presence of chiral imidazolidinone catalyst 120 with acid additive, the reactions of silyloxy furan 118 with simple a,(3-unsaturated aldehydes... 

Soon afterward, MacMillan and co-workers [142, 143] also reported enantio-selective intramolecular a-arylation of aldehydes via organo-SOMO catalysis. [Fe(Phen)3l [PFsl 3, instead of CAN, as a single-electron oxidant together with designed imidazolidinone catalysts LXVIII and LXIX were found to be optimal for reaction efficiency and enantioselectivity (Scheme 8.35). Moreover, ortho selectivity, when 1,3-disubstituted aromatic systems were used, was observed. Methodologies presented by Nicolaou and MacMillan represent a useful tool for the total synthesis of various naturally occurring compounds, such as dimethyl calamenene, tashiromine, and so on. 

One year later, an extension of organo-photoredox catalysis into enantioselective a-trifluoromethylation and a-perfluoroalkylation of aldehydes was reported by MacMillan and co-workers [150, 151] that was accomplished by using a readily available iridium photocatalyst [Ir(ppy)2(dtb-bpy)]" and a commercial imidazolidinone catalyst (Scheme 8.38). A broad range of perfluoroalkyl iodides and bromides as well as a variety of aldehydes bearing various functional or bulky groups afforded corresponding a-fluoroalkylated products in high yields with excellent diastereo-and enantioselectivity (up to 99% ee). 

MacMillan and co-workers [57] have applied the SOMO activation developed in their lab for the enantioselective synthesis of chiral cyclohexanes. Enolizable aldehydes bearing a nucleophile such a tiophene (87) react with an alkene (88) catalyzed by imidazolidinone catalyst XXVII. The final cyclohexanes 89 were afforded in good yields and excellent enantioselectivities (Scheme 10.25). 

Later, MacMillan and Lee [176] found that hypervalent iodine reagents were also suitable oxidants for the asymmetric epoxidation of enals, using the imidazolidinone catalyst 109 (Scheme 12.31). Optimal results were obtained by controlled release of monomeric iodosobenzene from an iminoiodinane source (NsNIPh) and a mild acid (AcOH). 

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

MacMillan and co-workers [45] reported an organocatalytic Michael addition in their total synthesis of flustramine B (120) in 2004 (Scheme 17.20). Organocatalytic Michael addition of indole 116 to acrolein 118 using imidazolidinone catalyst 117... 

In 2005, MacMillan and co-workers [52] employed their second-generation imidazolidinone catalyst 117 for the organocatalytic total synthesis of solanapyrone D (139) as shown in Scheme 17.24. Diels-Alder cycloaddition of aldehyde 137 using catalyst 117 provided bicycle 138 in 71% yield (20 1 dr, 90% ee), which was transformed into solanapyrone D (139) in a straightforward manner. 

Epoxides can also be accessed asymmetrically using hypervalent iodine reagents in combination with imidazolidinone catalysts 78 (Scheme 30). The methodology developed by MacMillan et al. includes participation of hypervalent iodine reagent in a 1,4-heteroconjugate addition reaction for the organocatalytic, asymmetric epoxidation of a,p-unsaturated aldehydes 77. This organocatalytic reaction allows for the enantioselective formation of epoxides 78 from a wide array of electronically and sterically diverse a,p-unsaturated aldehydes [92]. 

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