Hetero-Diels-Alder reaction esters

Similar transformations have been performed with Danishefsky s diene and glyoxylate esters [85] catalyzed by bis (oxazoHne)-metal complexes to afford the hetero Diels-Alder product in 70% isolated yield and up to 72% ee. Jorgensen [86,87] reported a highly enantioselective, catalytic hetero Diels-Alder reaction of ketones and similar chiral copper(II) complexes leading to enantiomeric excesses up to 99% (Scheme 31, reaction 2). They also described [88] a highly diastereo- and enantioselective catalytic hetero Diels-Alder reaction of /I, y-imsaturated a-ketoesters with electron-rich alkenes... 

Tocopheryl)propionic acid (50) is one of the rare examples that the o-QM 3 is involved in a direct synthesis rather than as a nonintentionally used intermediate or byproduct. ZnCl2-catalyzed, inverse hetero-Diels-Alder reaction between ortho-qui-none methide 3 and an excess of <2-methyl-C,<9-bis-(trimethylsilyl)ketene acetal provided the acid in fair yields (Fig. 6.37).67 The o-QM 3 was prepared in situ by thermal degradation of 5a-bromo-a-tocopherol (46). The primary cyclization product, an ortho-ester derivative, was not isolated, but immediately hydrolyzed to methyl 3-(5-tocopheryl)-2-trimethylsilyl-propionate, subsequently desilylated, and finally hydrolyzed into 50. 

Jorgensen s group44a carried out the reaction using the anhydrous form of chiral bis(oxazoline) coordinated copper complex. Complex 106 containing 83 as the chiral ligand was found to be the most effective. As shown in Scheme 5-32, the asymmetric hetero Diels-Alder reaction of //.y-unsaturated a-keto esters with acyclic enol ethers results in products with excellent yield and enantioselectivity. 

Jorgensen s group reported the aza Diels-Alder reactions in the presence of several chiral catalysts.52 They found that chiral bis(oxazoline) ligands 81, 83, 103, 104, and 105, which were effective in asymmetric oxo hetero Diels-Alder reactions, induced the aza Diels-Alder reaction of a-imino ester with Danishefsky s diene with only poor to moderate enantioselectivity. Selected results are listed in Scheme 5-40. 

TABLE 9.18. HETERO-DIELS-ALDER REACTION OE DANISHEFSKY S DIENE WITH GLYOXYLATE ESTERS"... 

TABLE 9.18 HETERO DIELS-ALDER REACTION OF DANISHEFSKY S DIENE WITH GLYOXYLATE ESTERS, 558... 

Furo[3,4-f]pyranones are produced by an intramolecular hetero-Diels-Alder reaction of a,/3-unsaturated 7-keto esters, 81. The Horner-Wadsworth-Emmons reaction of phosphonates with a-diketones is used to assemble compounds 81 (Scheme 17) <2004TL4297>. 

Dihydrofuran reacts with /3,7-unsaturated a-keto esters with copper or zinc complex catalysts to generate furo[2,3-/ ]pyran derivatives in good yields with high stereoselectivity. The synthesis proceeds via an inverse electron demand hetero-Diels-Alder reaction <2000CC459>. 

Solid-phase three-component domino-Knoevenagel-hetero-Diels-Alder reaction can also be performed using a resin-linked 1,3-dicarbonyl compound such as 100 with aldehydes and an enol ether to give dihydropyrans 102 via the intermediately formed 1-oxa-l,3-butadiene 101 (Scheme 5.18) [30], The resin can be deaved off after the reaction by solvolysis, for instance using sodium methanolate to give the corresponding methyl ester 103 as a mixture of diastereomers. The overall yield varies from 12 to 37% and the selectivity from 1 1 to 1 5 in favor of the tis-product depending on the applied aldehyde. The crude dihydropyrans thus obtained are reasonably pure (> 90% HPLC). 

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... 

A hetero-Diels-Alder reaction has been used to prepare racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran (9). This ester 9 was resolved by Bacillus lentus protease to provide the R-isomer. Reduction, protection, and ozonolysis provided the bis-mesylate 10 (Scheme 26.9), a key intermediate in the synthesis of the PKC (protein kinase C) inhibitor LY333531 (ll).278 This resolution approach was used because it was more efficient than an asymmetric Diels-Alder reaction. 

The enamine (287 R3 = Bn, R1 + R2 = (CH2)20(CH2)2) reacts with ethyl benzoylacetate affording heterocycle (99) (87JHC111). Enamines (287 R3 = Me, R1, R2 = various groups) react with the ester (288) giving products (289) in moderate yield and related enamines behave similarly in this hetero-Diels-Alder reaction <85AP(318)648>. 

The combination of two all-carbon and one hetero Diels-Alder reaction in the presence of catalytic amounts of Eu(fod)3 of 2-2 and 2-3 to give 2-4 was used in the synthesis of vincomycinone B2 methyl ester 2-5, Scheme 2-2 [71]. 

Azo compounds like esters or imides of azo dicarboxylic acid act as reactive dienophiles in normal electron demand hetero Diels-Alder reactions due to the strong activation caused by two electron-withdrawing moieties. In the last years, considerable attention has focused on alkyl and phenyl derivatives of 1,2,4-tria-zoline-3,5-diones since their cycloadditions to chiral dienes proceed with often excellent facial selectivities. Thus, when reacting an oxapropellane derived diene with N -methyltriazolinedione, Paquette et al. obtained the cycloadduct as single diastereomer, but both maleic anhydride and N-phenyl maleimide were distinctly less reactive and turned out to undergo cycloadditions with poor selectivities [289]. 

Enaminothiones react smoothly with heterodienophiles such as azo esters as well [419]. Very recently, thioacetylindoles which also may be conceived as ena-minothioketones have been subjected to hetero Diels-Alder reactions with numerous electron-deficient dienophiles [420]. 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

For the enantioselective hetero Diels-Alder reaction, very similar bis(oxazoline) complexes proved to be highly efficient [28]. The conversion of several unsaturated keto-esters 59 with ethyl-vinyl ether 60 gave cycloaddition products 61 in 97-99% ee. 

Inverse electron demand hetero-Diels-Alder reactions of acyl phosphonates or a-keto ester heterodienes and enol ethers are also catalyzed by (5, iS )-t-Bu-box complexes. High levels of enantioselectivity are obtained with y-alkyl-, -aryl-, -alkoxy-... 

Miscellaneous. There are several other reports on the application of this ligand to catalytic asymmetric reactions, although enantioselectivities are modest. Those reports include the Mukaiyama-Michael reaction, allylation of aldehydes, asymmetric Diels-Alder reaction, Mukaiyama-Aldol reaction of ketomalonate, aziridination reaction of a-imino esters, and asymmetric hetero-Diels-Alder reaction. ... 

Copper Lewis acids have also found utility in hetero-Diels-Alder reactions. In these transformations the Lewis acid can activate either the diene or the dienophile and both types of reaction have been reported. Evans et al. have evaluated unsaturated acyl phosphonates [95] and acyl esters (amides) [87] as dienes in hetero-Diels-Alder reactions. The reactions proceed with excellent chemical efficiency and high stereoselectivity with as little as 0.2 mol % of the catalyst (Sch. 50). The reaction tolerates a variety of substituents on the diene and the dienophile. A square-planar model 226 wherein the phosphonate and the carbonyl groups form a chelate with copper, and addition occurring from the less hindered face, accounts for the selectivity observed. It is interesting to note that the reaction of 185 with phosphonate 228 gives 230, an inverse-electron-demand product, in preference to the normal Diels-Alder adduct 229. This unusual reaction pathway has been attributed to the electron-withdrawing capacity of the phosphonate group. 

In contrast to the above reactions, J0rgensen et al. have also reported hetero-Diels-Alder reactions wherein acyl esters are used as dienophiles and are activated by the copper Lewis acid (Sch. 51) [96]. Both keto (232) and aldehyde (235) groups can be used in the reaction. The reactions proceed with very low catalyst loading (0.05 mol %) attesting to the excellent activation by the copper Lewis acid. The authors have applied this methodology in the total synthesis of actinidiolide 237 [97]. 

Iron(III) 2-ethylhexanoate is a catalyst for the stereoselective hetero-Diels-Alder reaction of ethyl ( )-4-oxobutenoate with alkyl vinyl ethers to give ci5 -2-alkoxy-3,4-dihydro-2//-pyran-4-carboxylic acid ethyl esters with a high diastereoselectivity (Sch. 57) [203],... 

Lanthanide Lewis acids catalyze many of the reactions catalyzed by other Lewis acids, for example, the Mukaiyama-aldol reaction [14], Diels-Alder reactions [15], epoxide opening by TMSCN and thiols [14,10], and the cyanosilylation of aldehydes and ketones [17]. For most of these reactions, however, lanthanide Lewis acids have no advantages over other Lewis acids. The enantioselective hetero Diels-Alder reactions reported by Danishefsky et al. exploited one of the characteristic properties of lanthanides—mild Lewis acidity. This mildness enables the use of substrates unstable to common Lewis acids, for example Danishefsky s diene. It was recently reported by Shull and Koreeda that Eu(fod)3 catalyzed the allylic 1,3-transposition of methoxyace-tates (Table 7) [18]. This rearrangement did not proceed with acetates or benzoates, and seemed selective to a-alkoxyacetates. This suggested that the methoxy group could act as an additional coordination site for the Eu catalyst, and that this stabilized the complex of the Eu catalyst and the ester. The reaction proceeded even when the substrate contained an alkynyl group (entry 7), or when proximal alkenyl carbons of the allylic acetate were fully substituted (entries 10, 11 and 13). In these cases, the Pd(II) catalyzed allylic 1,3-transposition of allylic acetates was not efficient. 

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