Imidazolidinone catalysis

Reports depicting organocascades involving more than one Diels-Alder reaction are scarce. However, under imidazolidinone catalysis, achiral dendralenes and enals as dienophiles are able to undergo a double Diels-Alder cascade with high efficiency and enantioselectivities (Scheme 7.30) [48]. 

King HD, Meng Z, Denhart D, Mattson R, Kimura R, Wu D, Gao Q, Macor JE. Enantioselective synthesis of a highly potent selective serotonin reuptake inhibitor. An application of imidazolidinone catalysis to the alkylation of indoles with an a,(3-disubstituted a,(3-unsaturated aldehyde. Org. Lett. 2005 7(16) 3437-3440. 

Imidazolidinone catalysis was also coupled with Lewis acid catalysis to effect trifluoromethylation of aldehydes (Scheme 15.108). In this instance the Lewis acid was required to activate the trifluoromethyl bearing Togni s reagent, a suitable electrophile for the reaction process. It was found that the best yields and enantiomeric excesses were obtained when copper(i) chloride was used. 

In a serial mode (Fig. 36.1), one experimental step (in catalysis research this is usually the preparation of the ligand or the catalyst) is repeated n times before moving on to the next step. The only difference with traditional research is that the complete experiment (synfhesis/testing/analysis) is carried out for a set of catalysts rather than for an individual species. For example, a library of ligands from the same class can be assembled via traditional organic synthesis prior to its testing in catalysis. (A library of compounds is a rather large collection of different compounds with some common features and usually the same function, for example triarylphosphines or imidazolidinones.) Ideally, the compounds in the library can be structurally varied in at least two positions to ere-... 

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... 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

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

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],... 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

The imidazolidinone ring of biotin is the business end and it is well suited for the reactions in which it is involved. Perrin and Dwyer have shown that the exchange of the protons attached to the nitrogen atoms occurs sufficiently rapidly that the conjugate base is a reasonable intermediate for any reaction in which substitution for the proton occurs, as in carboxylation (49). The need for acid catalysis, which had been proposed, is not consistent with this observation. 

Removal of a proton from 1,2-disubstituted diazetidinones (91) results in an instantaneous ring-expansion to imidazolidinones (92) in a similar reaction to Stevens rearrangement <86JOCl537>. Another interesting rearrangement to pyrroloimidazoles (94) has been described from trisubstituted aziridine (93) using base catalysis <85JOC2220>. Both reactions are shown in Scheme 16. 

Iminic derivatives of (4R,55)-l,5-dimethyl-4-phenyhmidazolidin-2-one have been dia-stereoselectively alkylated with activated alkyl halides or electrophilic olefins either under phase transfer catalysis (PTC) conditions or in the presence of the phosphazene base BEMP at —20°C in the presence of lithium chloride (LiCl). Hydrolysis of the alkylated imino imides gave (5)-a-amino acids with recovery of the imidazolidinone chiral auxihary [18]. 

Modern strategies in organic catalysis based on iminium activation using imidazolidinones as catalysts 06AA79. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

Scheme 18.3 Catalytic cycle of iminium catalysis with imidazolidinone and electrophilicity of the intermediates obtained.

---