MacMillan’s imidazolidinon

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

The asymmetric electrophilic a-fluorination of aldehydes with 2,5-disub-stituted pyrrolidines was tested independently by Jorgensen and Barbas III, but in these reactions MacMillan s imidazolidinones (Chapter 18) or diatylprolinol silyl ethers (Chapter 8) afforded much better yields and higher enantioselectivities. 

A simple and efficient method for the preparation of a-diazo- i-hydroxy esters by the condensation of aldehydes with ethyl diazoacetate using chloromethy-lated polystyrene SIL as a heterogeneous catalyst in water was developed [66]. Moderate to excellent yields of the corresponding a-diazo-jl-hydroxy esters were obtained. The catalyst was separated by filtration and reused in five consecutive cycles without any appreciable loss of activity. Later MacMillan s imidazolidinone was noncovalently immobihzed in the pores of siHca gel with the aid of IL 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide (Mac-SILC) (SILC, supported ionic liquid catalyst) [67]. The Mac-SILC as an SIL catalyst was utilized for the enantioselective Diels-Alder reaction of cyclopentadiene and cinnamaldehyde. The Mac-SILC was more active, especially to an electron-rich dienophile, than its homogeneous counterparts, and the reaction could proceed under mild conditions. 

The asymmetric a-chlorination of aldehydes has also be achieved using SOMO catalysis (Scheme 13.21) [49]. In these reactions, saturated aldehydes condensed with MacMillan s imidazolidinone organocatalyst to form enamines. The oxidant combination of Cu(TFA)2 and Na2S20g oxidized the enamine to the radical cation (inset in Scheme 13.21), the reactive intermediate in this transformation containing... 

In a similar manner, Waldmann and coworkers described the activation of cinnamaldehyde by prolinol derivative 17 to achieve enantio- and diastereoselective Michael addition of the malonic derivative 16 to the a,p-unsaturated iminium 18 (Scheme 14.3) [9]. In order to accomplish selectivity, four organocatalysts were screened, of which were three prolinol derivatives and the previously discussed MacMillan s imidazolidinone 10. In contrast to List s example, the imidazolidinone gave poor enantioselectivity (58/53% ee), but good diastereoselectivity (4 1 dr) when... 

The synthetic utihty of [4]dendralene was dramatically improved by the Sher-burn research group in 2013 [36]. Using MacMillan s imidazolidinone organocata-lyst 126, a double DA reaction between acrolein and [4]dendralene (14), followed by an in situ reduction (to prevent epimerization of the sensitive a-carbonyl site), provided diol 127 in exquisite enantioselectivity (Scheme 12.28). The high enantiomeric ratio was a result of both cycloadditions proceeding with catalyst control, and a preference for the minor enantiomer from the first cycloaddition to form the meso stereoisomer in the second addition. A third DA reaction could be conducted with reactive dienophiles (i.e., NMM, dimethyl acetylenedicarboxylate, or benzoquinone) under noncatalyzed conditions, as illustrated by the representative example 128. This methodology was applied to [3], [6], and [8]dendralene, as well as a handful of other a,P-unsaturated carbonyl dienophiles. 

Star polymers 200 and 202 cannot penetrate each other s core and therefore are expected to maintain their catalytic integrity. On the other hand, small-molecule reagents and catalysts can freely diffuse to the core of the star polymers. MacMillan s imidazolidinone can diffuse to the core of the acid star polymer 200 to form the desired salt 201, which is an optimal iminium catalyst. Electrostatic attraction should retain 199 within the core of 200 during catalysis. The presence of strong acid p-TSA (alone or paired with imidazolidinone 199) diminishes the ability of 202 to effect iminium catalysis. Additionally, a hydrogen-bond donor catalyst 203... 

Dalton, King and Meng have applied MacMillan s imidazolidinone catalyst 296 in an enantioselective adulation of indole 294 with a-branched a,p-unsaturated aldehyde 295 as the key step in the S5mthesis of serotonin reuptake inhibitor BMS-594726 (298) (Scheme 14.93). 

A highly enantioselective Mukaiyama-Michael addition of silyl ethers, CH2= C(OSiMe3)R1, to a,/9-unsaturated aldehydes, R2CH=CHCHO, catalysed by MacMillan s chiral imidazolidinone (150), in the presence of 2,4-(N02)2C6H3C02H as an acid... 

An example of an asymmetric catalytic version was also presented in our first publication. This protocol was subsequently optimized and we developed a highly enantioselective variant using the trichloroac-etate salt of MacMillan s second generation imidazolidinone (19) as the... 

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. 

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... 

Subsequently, List reported the first organocatalytic intramolecular Michael reaction of multifunctional aldehydes 10. Although this reaction could also be catalyzed by L-proline, both diastereo- and enantioselectivity were low. MacMillan s chiral imidazolidinone 9 gave much better results and the cyclic ketoaldehydes 11 could be obtained efficiently (Scheme 36.3) [8a]. 

The organometallic sensitizer can be replaced by a purely organic dye such as eosin Y that acts as a photoredox catalyst after excitation with visible light and gives rise the more stable triplet state [26]. In the presence of eosin Y and MacMillan s trons-methyl imidazolidinone catalyst 10 and substrates (aldehyde and a-bromocarbonyl compounds) the alkylation reaction performed similarly while requiring somewhat longer reaction times at the optimal -5 °C temperature. 

Chiral amine catalysts have also been used in cascade reactions mediated by SOMO catalysis [143] and Lewis base catalysis [144]. MacMillan s group developed a powerful cascade reaction moderated by SOMO catalysis. The radical cation, generated from an enamine in condensation of imidazolidinone catalyst 208 with aldehyde 207 and subsequent oxidation by Cu oxidant, was expected to engage in a series of 6-endo-trig radical cyclizations terminated by a suitable arene to give a cyclohexadi-enyl radical. After a second oxidation, rearomatization, and liberation of the catalyst, the requisite 209 would be generated (Scheme 1.90). 

MacMillan s group demonstrated that iminium catalysis can be a general and reliable strategy for organic synthesis by employing the imidazolidinone-type catalysts successfully in a wide range of asymmetric transformations [10,12], One example is the total synthesis of the more complex natural product (-t-)-minfiensine, which was isolated from Strychnos minfiensis (Scheme 3.2) [17], Due to its unique structure and potential biological activity, (-i-)-minfiensine has also attracted considerable attention... 

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