Imidazolidinones chiral

Further illustrations of the value of isoxazole and Heck methodologies in flavone synthesis have been published (95ACS524) and a route to 3-aminoflavone-8-acetic acid has been described (95TL1845). The use of an imidazolidinone chiral auxiliary enables isoflavans to be formed in good yield and in high enantiomeric excess from phenacyl chlorides (95CC1317). 

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]. 

Scheme 18.5 Enantioselective reduction of unsaturated aldehydes by Hantzsch ester and imidazolidinone chiral catalysts.

Figure 18.4 Natural products obtained by the use of imidazolidinone chiral catalysts. 

We therefore prepared a new chiral ligand, (l ,J )-isopropylidene-2,2 -bis[4-(o-hy-droxybenzyl)oxazoline)], hereafter designated J ,J -BOX/o-HOBn. To our delight, the copper(II) complex catalyst prepared from J ,J -BOX/o-HOBn ligand and Cu(OTf)2 was quite effective (Scheme 7.45). Especially, the reaction of O-benzylhydroxylamine with l-crotonoyl-3-isopropyl-2-imidazolidinone in dichloromethane (0.15 m) at -40°C in the presence of J ,J -BOX/o-HOBn-Cu(OTf)2 (10 mol%) provided the maximum enantioselectivity of 94% ee. 

Chiral N-(2-bromo)crotonoyl imidazolidinones react with ammonia to give N-unsubstituted aziridines (Scheme 4.24) [31]. 

An asymmetric version of this reaction was achieved by the use of complexes derived from chiral imidazolidinones. For example, the reaction of Danishefsky s diene with these chiral complexes occurs with both high exo endo selectivity and high facial selectivity at the dienophile [103] (Scheme 56). 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

Several chiral ligands have been developed for use with the rhodium catalysts, among them are pyrrolidinones and imidazolidinones.207 For example, the lactamate of pyroglutamic acid gives enantioselective cyclopropanation reactions. 

An enantioselective organocatalytic 1,3-DC reaction, based on the activation of a,fi-unsaturated aldehydes through the reversible formation of iminium ions with chiral imidazolidinones 100, was described. Good levels of asymmetric induction and diastereocontrol were achieved (up to 94% ee and 94 6 dr) <00JA9874>. 

Trifluorothreonine is one of the rare fluorinated compounds found in nature (cf. Chapter 4). The best method for the synthesis of fluorothreonines is the acylation of an equivalent of glycinate anion by a fluoroacetic derivative. The four stereoisomers of monofluorothreonine have been prepared. A completely stereoselective chiral approach involves the alkylation of the Seebach imidazolidinone by fluoroacetyl chloride (Figure 5.16). ... 

In a similar way, chiral, nonracemic 5-alkyl-4-imidazolidinones 8 can be prepared from chiral, nonracemic a-ami no acids 53. The enantiomerically pure starting material is transformed into the intermediate imine 6, which is cyclized with acid, then A -acylated. The major diastereomer, the more stable /ram-isomer, is obtained enantiomerically pure. The minor, enantiomerically pure ci.s-isomer can also be isolated from this product mixture3. Alternatively, the civ-isomer can be prepared by heating the imine 6 with benzoic acid anhydride, which results in a good yield and d.r. However, due to some raeemization during the reaction, the ee is <100%. 

Since the chirality of the center undergoing electrophilic attack is destroyed on enolate formation, the enantiomerically pure civ-isomer of the 5-alkyl-2-/cr -butyl-4-imidazolidinone 8, after alkylation and hydrolysis, gives the enantiomer of the a-alkyl-a-amino acid obtained on alkylation of the trans-isomer 8 provided that the cis- and trans-isomers have been prepared from the same enantiomer of the starting amino acid3. 

Deprotonation of either the (4S.5R)- or (4/ ,5S)-enantiomer of 3-acyl-1,5-dimelhyl-4-phenyl-2-imidazolidinones 4 by lithium cyclohexylisopropylamide (LICA)1 or diisopropylamide2 furnishes chiral, supposedly chelated enolates, very similar to those enolates obtained from 2-oxazolidi-nones (see Section 1.1.1.3.3.4.2.1.). With LICA the. yyn-enolate is formed exclusively, as shown by O-silylation of the enolate with /ert-butylchlorodimethylsilane1. Attack of an electrophile, such as a haloalkane, from the less hindered side furnishes products (usually crystalline) with a moderate to high degree of diastereoselectivity (see Tabled)1 2. The diastereoselectivities observed in comparable alkylation reactions of the 3-acyl-4-cyclohexyl-l,5-dimethylimidazo-lidinone 3b are superior to those obtained with the 4-phenyl derivative 3a2,7. Thus, as also observed in similar alkylations with oxazolidinones10 (see Section 1.1.1.3.3.4.2.1), a phenyl substituent on the chiral auxiliary seems to be relatively inefficient as a steric control element. 

The predicted low enantiocontrol from reactions performed with methallyl diazoacetate (Eq. 5.18) was borne out in reactions catalyzed by Rh2(MEPY)4 and Rh2(MEOX)4, but when chiral imidazolidinone-ligated dirhodium(II) was used, enantioselectivity rose to 89% ee (Table 5.8) [89]. The use of CuPF6/7b also caused relatively high enantiocontrol (87% ee) [92] which, however, decreases to 82% ee when the methyl group of 36 was replaced by n-butyl, whereas with Rh2(4S-MPPIM)4 the enantiopurity of the product corresponding to 37 was 93% ee. The A-3-phenylpropanoyl substituents of Rh2(4S-MPPIM)4 help to create a more conformationally restrictive environment that leads to enhanced enantiocontrol. 

By far the greatest advances in enantiocontrolled C-H insertion reactions have been provided by Doyle and co-workers with chiral dirhodium(II) carboxamidate catalysts [7,10]. The key development here is the creation of chiral imidazolidinone-ligated dirhodium catalysts 22 to control diastereoselectivity and enhance enantiocontrol [122]. A significant example of the power of this methodology is the insertion reactions of cycloalkyl diazoacetates. With cyclohexyl diazoacetate, for example, four products are possible via C-H insertion constituted in two pairs of diastereoisomers (Eq. 5.28). 

Chiral pyrrolidine derivatives, proline, and amino acid-derived imidazolidinones mediate the asymmetric epoxidation of ,/i-unsalurated aldehydes. Protected a,a-diphenyl-2-prolinol catalyses the asymmetric formation of 2-epoxyaldehydes, with hydrogen peroxide or sodium percarbonate as the oxygen sources, with 81-95% conversion with up to 96 4 dr and 98% ee.204... 

The chiral imidazolidinone 45 also catalyzes the Mukaiyama-Michael reaction between 2-silyloxy furans and a,/ -unsaturated aldehydes, affording enantiomeri-cally highly enriched y-butenolides (Scheme 4.18) [33]. For optimum catalytic performance, hydroxyl additives are necessary, and addition of 2 equiv. water proved best. 

The MacMillan group has also shown that cycloaddition reactions (see also Chapter 8) can be performed highly diastereo- and enantioselectively. The [3+2]-cycloaddition of nitrones and a,/i-un saturated carbonyl compounds in the presence of 20 mol% of a phenylalanine-derived imidazolidinone acid salt led to products with 99% ee [32]. An example of an enantioselective rearrangement reaction (see also Section 13.6) with 99% ee has been reported by the Fu group [33], who used 2 mol% of a planar chiral DMAP derivative as catalyst. 

Direct enantioselective catalytic a-fluorination of aldehydes has been carried out using jV-fluorobenzenesulfonimide [F-N-(02SPh)2] and a chiral secondary amine (an imidazolidinone) to provide enamine organocatalysis.295... 

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... 

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. 

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