Friedel MacMillan

More recently, MacMillan has introduced the amine catalysts 42 and 45, readily available from L-phenylalanine, methylamine, and acetone or pivalaldehyde, respectively (Schemes 4.15 and 4.16). The broad potential of these materials in enan-tioselective organocatalysis was first proven in Diels-Alder reactions [28] and nitrone cydoadditions [29]. In 1,4-addition of C-nudeophiles MacMillan et al. later showed that Friedel-Crafts reactions of pyrroles with enals can be made highly enantioselective (Scheme 4.15) [30]. 

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],... 

Ouellet SG, Tuttle JB, MacMillan DWC (2005) Enantioselective organocatalytic hydride reduction. J Am Chem Soc 127 32-33 Paras NA, MacMillan DWC (2001) New strategies in organic catalysis the first enantioselective organocatalytic Friedel-Crafts alkylation. J Am Chem Soc... 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

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]. 

SCHEME 8.34. Intramolecular Friedel-Crafts-type a-arylation of aldehydes reported by Nicolau et al. [141] and MacMillan and co-workers [140],... 

Different from the hydroxyalkylation reactions using carbonyl compounds as substrates, Nicolaou s and Macmillan s groups developed independently the intramolecular asymmetric Friedel-Crafts-type a-arylation of aldehydes with electron-enriched arenes based on the SOMO activation strategy. Using chiral imidazolidione as catalyst, a series of cyclic aldehydes were obtained in good yields and enantioselectivities with cerium ammonium nitrate (CAN) as single electron transfer oxidant [46]. 

MacMillan and co-workers [79] pioneered the development of entirely organo-catalyzed cascade reactions. In his seminal report, iminium-catalyzed Friedel-Crafts reactions were followed by enamine-catalyzed a-chlorinations (Scheme 13.40). In this same report, an iminium-catalyzed conjugate reduction was followed by an enamine-catalyzed a-chlorination (not shown). In both of these cascade reactions, a single catalyst was used for both the iminium- and enamine-mediated reactions. Alternatively, MacMillan demonstrated that it was possible to use one catalyst for an iminium-catalyzed conjugate reduction and a different catalyst for an enamine-catalyzed a-fluorination (Scheme 13.40) [79]. Such cycle-specific cascade reactions allow access to both the anti (shown) and syn diastereomers of the product simply by using the opposite enantiomer of the catalyst for one of the two reactions in the cascade. 

Very recently, MacMillan et al. applied an intermolecular combined Friedel-Crafts-type conjugate addition/cyclization procedure as a key step in the total synthesis of diazonamide A (297) (271). Diazonamides are secondary metabolites isolated from the marine ascidian Diazona sp. (272, 273). Diazonamide A (297) was found to be a potent antimitotic member of this structurally unique family, exhibiting low nanomolar G/50 values towards different human cancer cell lines (272, 274). The unique structure of two 12-membered macrocycles that are conjoined through a triaryl-substituted quaternary stereogenic center (C-10) that is embedded in a furanoindoline core makes this compound a very interesting and... 

Paras NA, MacMillan DWC (2(X)1) New Strategies in Organic Catalysis The First Enantioselective Organocatalytic Friedel-Crafts Alkylation. J Am Chan Soc 123 4370... 

Lee S, MacMillan DWC (2007) Organocatalytic Vinyl and Friedel-Crcfis Alkylations with Trifluoroborate Salts. J Am Chem Soc 129 15438... 

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... 

The generation of an iminium ion of a, 3-unsaturated carbonyl compounds lowers the LUMO energy. As a result, the cx-CH acidity increases as well as the ability to participate in conjugate additions. The first organocatalyzed 1,4-addition to a,j3-unsaturated aldehydes was reported by the MacMillan group [78]. For theoretical explorations of the configurative outcome of Michael additions of pyrroles and indoles to crotonaldehyde see Reference [79]. This transformation has been widely used in Friedel-Crafts alkylations of a,(5-unsaturated carbonyl compounds (see Reference [lb] and reports cited therein). Comparable examples of this transformation with ( )-crotonaldehyde in the intermolecular series were found in aryl alkylation with trifluoroborate (58 and 60) [80], indole alkylation (62) [81], Friedel-Crafts alkylation of electron-rich benzenes (64) [82], and Friedel-Crafts alkylation with phosphonates (65) [83] (Scheme 4.21). 

The influence of microwave irradiation was also investigated in organocatalytic Diels-Alder and Friedel-Crafts reactions. Mosse and Alexakis [34] studied the asymmetric Diels-Alder reaction between cyclopentadiene and cinnamaldehyde catalyzed by a first-generation MacMillan imidazolidinium-HCl salt in MeOH/ H2O. Comparable results were obtained (72-82%, 78-85% ee) using microwave... 

The first organocatalytic asymmetric carbon nucleophilic addition to enals was reported by MacMillan in 2001 [15]. MacMillan reported the first Friedel-Craft alkylation between N-substituted pyrroles and enals promoted by catalyst 7. The reaction renders the final compounds in good yields and enantioselectivities (Scheme 33.4). 

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. 

While a Friedel-Crafts mechanism involving ionic intermediates cannot be ruled out, MacMillan proposed an alternative mechanism that includes a radical intermediate (Scheme 7.16). An enammonium radical cation is considered to be generated from a chiral iminium ion via one-electron oxidation, and then undergoes a cyclization reaction. A second one-electron oxidation, followed by re-aromatization, completes the catalytic cycle. Theoretical calculations for the reaction depicted in Scheme 7.16 indicated that the radical mechanism would favor ort/to-selective cyclization, while a Friedel-Crafts mechanism would result in para-selective cyclization. Since the reaction gave the ort/zo-selective cyclization product as a major product, the radical pathway is plausible. ... 

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

More recently, Lee and MacMillan developed the addition of heteroaryl boronic acids to a,p-unsaturated aide-hyde by what was called a Friedel-Crafts-type reaction. Applying this methodology, the straightforward synthesis of frondosin, a potential treatment against inflammatory... 

Lee S, MacMillan DWG Organocatalytic vinyl and Friedel-Grafts alkylations with trifluoroborate salts. J. Am. Chem. Soc. 2007 129(50) 15438-15439. 

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