Macmillan’s catalyst

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

Another chiral organic catalyst of major success is MacMillan s catalyst, 18, that has found widespread use in a number of relevant processes (MacMillan 2000). Immobilized versions of these catalysts for the enantioselective Diels-Alder cycloaddition of dienes with unsaturated aldehydes were developed on soluble (Benaglia et al. 2002) and insoluble supports (equation a, Scheme 7) (Benaglia 2006). 

A polymer-supported version of MacMillan s catalyst 114 has been developed by anchoring a tyrosine-derived imidazohdin-4 -one via a spacer to the monomethyl ether of PEG (Scheme 3.32) [62]. The reaction of N-benzyl-C-phenyl nitrone 115 with acrolein 116 proceeded in the presence of PEG-supported chiral imidazolidi-none and acid in wet nitromethane to give the isoxazolidine 117. The supported catalysts behaved very similarly to their nonsupported counterparts in terms of enantioselectivity, but were somewhat less efficient in terms of chemical yield. 

Proline derivatives form enamine intermediates to activate the HOMO of a nucleophile. In contrast, iminium salts are generated with MacMillan s catalyst to activate the LUMO of an electrophile. The formation of the enamine intermediate from proline is reminiscent of the general catalysis of class 1 aldolase in enzymatic catalysis [21]. 

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. 

Subsequently, MacMillan reported the second-generation MacMillan s catalyst Sb for the Friedel-Crafts alkylation reaction of pyrrole to, form a,p-unsaturated aldehydes (Equation 10.15) [32]. 

Fukuyama and co-workers constructed the [2.2.2]azabicyclohexane framework enantioselectively via the asymmetric Diels-Alder reaction and MacMillan s catalyst ent-5a and obtained a lactone without purification. Subsequent transformation led to the preparation of (—)-oseltamivir in 22% yield from benzyl chloroformate (Scheme 10.3) [37]. 

In 2007, MacMillan and co-workers reported conceptually novel reactions employing MacMillan s catalyst 5b [39]. This catalyst worked as a singly occupied molecular orbital (SOMO) catalyst in the presence of cerium (IV) ammonium nitrate (CAN) as a single-electron oxidant and the enantioselective a-allylation of aldehydes... 

After the success of Macmillan s catalysts, other types of chiral amine were disclosed and applied in the FCA reaction as activators of a,(3-unsaturated aldehydes. Reports from a few groups have revealed that diaryIprolinol silyl ethers [11], camphor sulfonyl hydrazine [12], chiral aziridin-2-yl methanols [13], and A-isopropylated bipyrrolidine [14] were efficient catalysts in the enantioselective alkylations of 4,7-dihydroindoles, 1-naphthols, and indoles. NEt3, benzoic acid, or... 

FIGURE 14.7. Resin-supported Jprgensen-Hayashi s and MacMillan s catalysts in the a-selenylation of aldehydes. 

Tu et al. reported a Macmillan s catalyst 172-catalyzed asymmetric a-alkylation of tetrahydrofuran 170 containing an a,p-unsaturated aldehyde, via which chiral spiroether 171 could be prepared (Scheme 64) [129]. The sequential [l,5]-hydride transfer/cyclization was facilitated via cascade iminium/enamine activation. The presence of strong acid was indispensable to ensure sufficient electrophilicity of the iminium intermediate. Theoretically, substrate 170 reacts with 172 to give iminium intermediate I. Owing to the steric interaction of the bulky ferf-butyl group, the E enamine II is formed preferentially upon [1,5]-HT, which exists in two possible conformers III and IV. Because of dipole repulsion between the cyclic-oxocarbe-nium and enamine moieties in conformer III, IV is the more favored conformer, which undergoes intramolecular C-C bond formation to afford the final product 171. 

In 2009, Nicolaou and coworkers [52] applied chiral 5-benzyl-2-(er(-butyl-imidazolidinones (MacMillan s catalysts) [45] to develop asymmetric Friedel-Crafts-type a-arylation of aldehydes via the enamine intermediate... 

Mechanism After the first report of iminium activation by MacMillan et al. in 2000, many studies have been made in this area. Two of the most important famihes of catalysts are MacMillan s catalysts and the TMS O-protected diaryl substituted prolinols developed independently by Jorgensen and Hayashi in 2005. 

Harmata et al. developed a catalytic asymmetric version of this cycloaddition by activating vinylogous siloxyacroldns 155 and 160 with MacMillan s catalyst 161 (Scheme 18.36) [39]. The chiral siloxyallyl iminium intermediate 162 thai proceeded to [4+3] cycloaddition at low temperatuies with 2,5-disubstituted fiirans to afford endo cycloadduct 163 exclusively in moderate to good yields and enantiomeric excesses up to 90%. 

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