Lewis acid-mediated Diels-Alder reactions

Oppolzer and colleagues performed pioneering work on the application of chiral sultam based dienophiles in asymmetric Diels-Alder reactions. The bomanesultam based dienophiles provided excellent de values in the Lewis acid mediated Diels-Alder reactions with a wide variety of dienes179. The efficiency of the simpler toluene-2,a-sultam based dienophiles was also studied180. Chiral auxiliary 282 proved superior to 283 and 284 in the aluminum Lewis acid catalyzed Diels-Alder reactions of its A-acryloyl derivative with cyclopentadiene, 1,3-butadiene and isoprene, affording the adducts with >90% de. 

Saigo and co-workers reasoned that, by analogy, high levels of diastereofacial discrimination could be achieved in the Lewis acid-mediated Diels-Alder reaction of dienes with oxazolidinone 108-derived dienophiles. Indeed, excellent regioselectivities (endo. exo) and diastereoselectivities were reached in the Diels-Alder reaction of 109 with cyclic and acyclic dienes using Et2AlCl as the activator (Scheme 24.28).107 The selectivities obtained actually surpassed those reported with cis-1 -amino-2-indanol 1 as the chiral auxiliary (93% de) (see Scheme 24.16).82 The additional bulk... 

An important challenge in the asymmetric catalytic Diels-Alder reaction is the use of simple ketone dienophiles to obtain high enantioselectivity. Indeed, the success of chiral Lewis acid-mediated Diels-Alder reactions is founded upon the use of dienophiles such as aldehydes, esters, quinones [36-43], and bidentate chelating carbonyls [44-47], where high levels of lone pair discrimination are achieved in the metal association step, an organizational event that is essential for enantiocontrol. In contrast, Lewis acid coordination to ketone dienophiles is generally non-selective, since the participating lone pairs are positioned in similar steric and electronic environments (Eq. 4). The ability for diastereomeric activa-... 

Asymmetric Diels-Alder reaction of 2-azadienes with acrylates using Cu(OTf)2 as a Lewis acid has been reported (Sch. 53) [99]. The reaction gives the exo product (244) with high enantioselectivity. Copper Lewis acid-mediated Diels-Alder reactions of thiabutadienes with oxazolidinone acrylate 196 have also been reported [100]. 

Figure 39 Model A for Lewis acid mediated Diels-Alder reactions...

Tamariz et al. developed an access to 1-methoxycarbazoles 225 via hydrolysis of 3-arylbenzoxazol-2-ones 223 and subsequent palladium(II)-mediated oxidative cyclization of the resulting diarylamines 224 (Scheme 54) [213, 214]. The required benzoxazol-2-ones 223 are obtained by regioselective Lewis acid-catalyzed Diels-Alder reaction of 4,5-dimethylene-3-aryl-l,3-oxazolidm-2-ones with alk-enes followed by aromatization using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). 

In Scheme 10, examples of eaiantioseleetive cycloadditions with formation of three-, four-, five-, and six-membered carbocyclic or heterocyclic rings are presented, to demonstrate the use of Ti-TADDOLates as Lewis acids. The Diels-Alder reaction has, so far, been studied most extensively, and many protocols have been proposed for the preparation of the Ti catalyst, of which as little as 5 mol-% and as much as several equivalents were employed (more often than not, Lewis acids bind strongly to the products of reactions they have mediated cf. the classical Friedel-Crafts acylation with AICI3 ). 

The use of aminoindanol-derived bisoxazolines in conjunction with copper Lewis acids led to improvements in the enantioselectivity of the Diels-Alder reaction (Sch. 44) [83]. Changes in stereoselectivity with small changes in ligand structure have also been noted (compare 198 and 200) [84], Copper also strongly coordinates phosphorus ligands. The use of PN chiral ligands in Cu(OTf)2-mediated Diels-Alder reactions has been reported [85]. 

Since the first report on Ti-TADDOLate-mediated Diels-Alder reactions [97,98] several studies of the same reaction have been reported these have shown that Ti-TADDOLate is an efficient chiral Lewis acid in enantioselective Diels-Alder reactions. Polymer- and dendrimer-supported Ti-TADDOLates have been reported and their catalytic activity in several enantioselective reactions has been evaluated [59]. Various kinds of polymeric TADDOLs were prepared both by chemical modification (Eq. 22) and by copolymerization (Eq. 23). 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

The chemistry and utility of zinc-based Lewis acids are similar to those of their magnesium analogs. Their mild Lewis acidity promotes several synthetic reactions, such as Diels-Alder reactions, hetero Diels-Alder reactions,229 radical-mediated reactions,230 ene-type cyclization, and Simmons-Smith reactions. 

Microwave heating has also been employed for performing retro-Diels-Alder cycloaddition reactions, as exemplified in Scheme 6.94. In the context of preparing optically pure cross-conjugated cydopentadienones as precursors to arachidonic acid derivatives, Evans, Eddolls, and coworkers performed microwave-mediated Lewis acid-catalyzed retro-Diels-Alder reactions of suitable exo-cyclic enone building blocks [193, 194], The microwave-mediated transformations were performed in dichloromethane at 60-100 °C with 0.5 equivalents of methylaluminum dichloride as catalyst and 5 equivalents of maleic anhydride as cyclopentadiene trap. In most cases, the reaction was stopped after 30 min since continued irradiation eroded the product yields. The use of short bursts of microwave irradiation minimized doublebond isomerization. 

The Lewis acid-mediated reactions of 2-aza-l,3-dienes and aldehydes, resulting in tetrahydro-l,3-oxazin-4-one derivatives, were explained in terms of the competitive existence of two reaction pathways a [4+2] hetero-Diels-Alder cycloaddition reaction and a Mukaiyama aldol reaction <2001TA439>. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Asymmetric intramolecular hetero-Diels-Alder reactions mediated by a sulfinyl group not directly bonded to n systems involved in the cycloadditions have also been reported [177]. Thus, Lewis acid catalysed intramolecular cyclization of tt -sulfinyl-a,/Lunsaturated ketone, shown in Scheme 108, gave mixtures of... 

A Lewis acid-base complex, TiCl4-SbPh3, mediates the allylation of 2-(benzyloxy)propanal with allyltributyl-stannane, where a homoallyl alcohol is obtained with a high yy/z-selectivity (Equation (5)).40 The same complex is also effective for Diels-Alder reaction of an acrylate of (A)-ethyl lactate with cyclopentadiene, where an endo-adduct is formed predominantly with high diastereoselectivity and without polymerization of cyclopentadiene (Equation (6)). 

Chiral Lewis acids have been employed by Yamamoto et al. [197 -199] in order to carry out enantioselective aza Diels-Alder reactions starting from achiral substrates however, these transformations required stoichiometric amounts of the chiral mediator 3-16 which was generated in situ from (fl)-binaphthol and triphenylborate. The best results were obtained with the pyridine derivative 3-14 which afforded the desired cycloadduct 3-15 in high optical purity (Fig. 3-5). Using chiral imines, the authors found a high level of double asymmetric induction, and this methodology could be applied to the enantioselective total synthesis of two piperidine alkaloids. 

Highly diastereoselective Lewis acid mediated aza-Diels-Alder reactions of chiral auxiliary derivatized 2H-azirines have been studied (02T5983,03JOC9958,03CC1150). The cycloaddition proceeded with high diastereoselectivity (97% de), with the absolute stereochemistry of the major product confirmed by X-ray crystallography. Without the presence of a Lewis acid, no diastereoselectivity was obtained at room temperature. 

A Lewis acid-mediated two-fold asymmetric Michael addition allows access to c( s-decalin derivatives. The reaction of the trimethylsilylenol ether of acety Icyclohexene with phenylmenthyl acrylate in the presence of Diethylaluminum Chloride (eq 7) yields the decalone in 64% yield (70% de). This has been shown not to be a Diels-Alder reaction. If the reaction is worked-up early, the initial Michael adduct can be isolated. ... 

Lewis acid-mediated reactions can be classified into two groups (Fig. 4). In the first (type 1) the complex between substrate and Lewis-acid reagent produces the product. Claisen rearrangement promoted by a Lewis-acid catalyst is a typical example of this type. Some complexes formed between Lewis acids and substrates are, however, stable enough to react with a variety of reagents from outside the system to generate the product (type 2). The Diels-Alder reaction between Lewis acid-activated unsaturated carbonyl compounds and dienes is an example of type 2 reactions. 

The exceptionally bulky Lewis acid MAD has a distinct steric effect on stereoselectivity in the Diels-Alder reaction of cyclic dienes and a,/3-unsaturated aldehydes, as exemplified by the MAD-mediated highly exo-selective cycloaddition of methacrolein and cyclopentadiene (Sch. 130) [169],... 

The earliest report of a reaction mediated by a chiral three coordinate aluminum species describes an asymmetric Meerwein-Poimdorf-Verley reduction of ketones with chiral aluminum alkoxides which resulted in low induction in the alcohol products [1]. Subsequent developments in the area were sparse until over a decade later when chiral aluminum Lewis acids began to be explored in polymerization reactions, with the first report describing the polymerization of benzofuran with catalysts prepared from and ethylaluminum dichloride and a variety of chiral compounds including /5-phenylalanine [2]. Curiously, these reports did not precipitate further studies at the time because the next development in the field did not occur until nearly two decades later when Hashimoto, Komeshima and Koga reported that a catalyst derived from ethylaluminum dichloride and menthol catalyzed the asymmetric Diels-Alder reaction shown in Sch. 1 [3,4]. This is especially curious because the discovery that a Diels-Alder reaction could be accelerated by aluminum chloride was known at the time the polymerization work appeared [5], Perhaps it was because of this long delay, that the report of this asymmetric catalytic Diels-Alder reaction was to become the inspiration for the dramatic increase in activity in this field that we have witnessed in the twenty years since its appearance. It is the intent of this review to present the development of the field of asymmetric catalytic synthesis with chiral aluminum Lewis acids that includes those reports that have appeared in the literature up to the end of 1998. This review will not cover polymerization reactions or supported reactions. The latter will appear in a separate chapter in this handbook. 

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