Hetero Diels-Alder reaction chiral Lewis acids

Intramolecular versions of the ene reaction using Lewis acids can be applied to nonconjugated dienes. Thus, 2.8-dienoic acid derivatives lead to cyclohexane systems27. Side products in this conversion stem from intramolecular hetero-Diels-Alder cycloaddition. Chiral Lewis acids, such as titanium alkoxidcs modified with tartaric acid derived chiral diols, lead to asymmetric induction with up to 98% ee27,88. 

Catalytic enantioselective hetero-Diels-Alder reactions are covered by the editors of the book. Chapter 4 is devoted to the development of hetero-Diels-Alder reactions of carbonyl compounds and activated carbonyl compounds catalyzed by many different chiral Lewis acids and Chapter 5 deals with the corresponding development of catalytic enantioselective aza-Diels-Alder reactions. Compared with carbo-Diels-Alder reactions, which have been known for more than a decade, the field of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds and imines (aza-Diels-Alder reactions) are very recent. 

Scheme 2.169. Chiral 1,3-dicarbonyl compounds and chiral Lewis acids for the dominr Knoevenagel/hetero-Diels-Alder reaction.

Starting from Fluoral Fluoral (trifluoroacetaldehyde) is an unstable gas that must be prepared before use by dehydration of the corresponding hydrate (commercially available). In spite of this limitation, fluoral itself has been used as a substrate in various reactions. Among the most recent examples, carbonyl-ene and hetero-Diels-Alder reactions deserve mention. The use of chiral Lewis acid... 

Evans has reported that the cationic C2-symmetric chiral Lewis acid Cu(ll)bis(oxazoline) complex promotes the hetero-Diels-Alder reaction of 0 ,/3-unsaturated acyl phosphonates with enol ethers to give the cycloadducts with excellent ee (Scheme 52). As well as simple dihydropyrans, various fused bis-dihydropyrans are also reported <1998JA4895, 2000JA1635>. 

Several chiral Lewis acid catalysts have been used for asymmetric hetero Diels-Alder reactions. Jprgensen applied chiral bis(oxazoline)/Cu(II) catalyst to asymmetric hetero Diels-Alder... 

A series of trivalent lanthanoid complexes, scandium, and ytterbium tris-(R)-(-)-1,1 -binaphthyl-2,2 -diyl phosphonate, have been introduced as new chiral and stable Lewis acids for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene and aldehydes. 2,6-Lutidine was found to be an effective additive to improve the enantioselectivity up to 89% ee [66] (Eq. 8A.42). 

The choice of solvent has had little, if any, influence on the majority of Diels-Alder reactions.210,211 Although the addition of a Lewis acid might be expected to show more solvent dependence, generally there appears to be little effect on asymmetric induction.118129 However, a dramatic effect of solvent polarity has been observed for chiral metallocene triflate complexes.212 The use of polar solvents, such as nitromethane and nitropropane, leads to a significant improvement in the catalytic properties of a copper Lewis acid complex in the hetero Diels-Alder reaction of glyoxylate esters with dienes.213... 

The first report of the use of enantiomerically pure lanthanoid complexes as chiral Lewis acids for Diels-Alder-type reactions appeared in 1983.90 As shown in Figure 37, in the presence of (+)-Eu(hfc)3(tris(3-(heptafluoropropylhydroxy-methylene)-(+)-camphorato)europium(III)), usually utilized as a chiral shift reagent for NMR study, the hetero-Diels-Alder reaction of benzaldehyde (54) with compound 167 has been found to give 168 in 50% ee. 

Many Diels-Alder or hetero-Diels-Alder reactions (catalyzed by chiral Lewis acids) have been described in the literature. The first example involving an asymmetric amplification was disclosed by Narasaka et al. in 1989.53... 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

Clearly, an important feature will be the selectivity of these reactions. In this respect, the control of endo- and exo-selectivity using different Lewis acids, the induced diastereoselectivity with chiral heterobutadienes as well as chiral heterodienophiles and finally the use of chiral Lewis acids for the enantioselec-tive synthesis will be discussed. In recent time some attention has been paid to hetero Diels-Alder reactions in aqueous solutions and in the presence of inor-... 

Good results were also obtained with lithium perchlorate in dichloromethane and diethyl ether. It has been shown that the lithium cation acts as a Lewis acid and the effects are not due to an internal pressure [80]. The acceleration is much more pronounced for hetero Diels-Alder reactions as compared to the allcarbon cycloadditions. With chiral aldehydes a high level of chelation control has been observed (see later) [81,82]. 

The enantioselective hetero Diels-Alder reaction of 1-oxa-1,3-butadienes using chiral non-racemic Lewis acids is a widely unexplored field. The first successful example was the intramolecular cycloaddition of the heterodiene 2-194,... 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

Diene complexes containing alkene or diene substituents undergo Diels Alder reactions in good yields. Hetero-Diels Alder reactions have also been reported. Chirahty transfer is observed upon reaction of chiral diene iron tricarbonyl complexes. Reaction of the chiral complex (101) with cyclopentadiene in the presence of a Lewis acid give (102) with a relatively high chirahty transfer from the metal complex (Scheme 162). 

The remarkable affinity of the silver ion for hahdes can be conveniently applied to accelerate the chiral palladium-catalyzed Heck reaction and other reactions. Enantioselectivity of these reactions is generally increased by addition of silver salts, and hence silver(I) compounds in combination with chiral ligands hold much promise as chiral Lewis acid catalysts for asymmetric synthesis. Employing the BINAP-silver(I) complex (8) as a chiral catalyst, the enantioselective aldol addition of tributyltin enolates (9) to aldehydes (10) has been developed." This catalyst is also effective in the promotion of enantioselective allylation, Mannich, ene, and hetero Diels-Alder reactions. 

Asymmetric catalytic hetero Diels-Alder reactions give access to synthetically important substituted heterocycles [45]. Asymmetric oxa Diels-Alder reactions involving aldehydes and ketones and catalyzed by chiral Lewis acid catalysts can be performed with a high degree of chiral induction [46]. The field is much less advanced that of the corresponding catalytic enantioselective aza Diels-Alder reactions. 

Chiral tridentate chromium(III) complexes catalyze highly enantio- and diastereo-selective hetero-Diels-Alder reaction between various aldehydes and dienes with one oxygen substituent (Sch. 60) [206]. Complex formation between catalysts and aldehydes could not be detected by IR and the successful use of acetone as a solvent casts doubt on a simple Lewis acid mechanism. 

Hetero Diels-Alder reactions between prochiral aldehydes and activated dienes such as 84 are also known to be catalyzed by Lewis acids (Eq. 26) and catalysis by chiral Lewis acids supported by dimethylpolysiloxane (83a) has been investigated [100]. Enantio-selectivity up to 43 % ee was achieved by use of polymeric Lewis acids. 

Tietze, L F, Schneider, C, Montenbiuck, A, Asymmetric 1,6-induction in hetero-Diels-Alder reactions of chiral oxabutadienes for a de novo synthesis of enantiomerically pure carbohydrates Lewis acid dependent reversal of facial selectivity, Angew. Chem. Int. Ed. Engl., 33,980-982, 1994. 

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