Keten acetals Diels-Alder reaction with

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

Nitrile, azo, and nitroso groups, and even the oxygen molecule, take part in such reactions, and acetylenic triple bonds in particular confer reactivity as philodiene. As for dienes, so for philodienes the reactivity depends on the constitution. Activating groups particularly favor addition. The most reactive components include <%,/ -unsaturated carbonyl compounds such as acrolein, acrylic acid, maleic acid and its anhydride, acetylenedicarboxylic acid, p-benzo-quinone and cinnamaldehyde, as well as saturated nitriles and <%,/ -unsaturated nitro compounds. Tetracyanoethylene also reacts with dienes.41,42 Conjugation of the double bond to an active group is not absolutely essential for a philodiene, for dienes add under certain conditions also to philodienes with isolated double bonds examples of the latter type are vinyl esters and vinyl-acetic acid. Ketenes do not undergo the Diels-Alder reaction with dienes, but instead yield cyclobutanone derivatives 43,44... 

In reactions of the chiral 3-tosyl-2//-pyran-2-one A with ketene acetals (7) moderate selectivities were observed. 2-Substituted 1,3-butadienes with a chiral sulfoxide group have been studied in asymmetric Diels-Alder reactions with maleimide. These reactions have been found to proceed smoothly and highly stereoselective at 25°C. 

It took another 35 years until the first (and still the only known) enantioselective total synthesis of (/ )-ochratoxin a (326), and therefore of ochratoxins A and B, was published by Gill et al. in 2002 (264, 265). Scheme 6.1 shows six steps of the nine-step synthesis, which was achieved with 10% overall yield. The first three steps of the procedure are not shown and comprise the preparation of 327 from (/ )-2-methyloxirane according to ref. (266). Ketene dimethyl acetal and acetylenic ester 327 react in an intermolecular cycloaddition to give 328. This diene undergoes a Diels-Alder reaction with methyl propiolate to yield 329. Lactonization ( 330), demethylation ( 331), chlorination ( 332), and methyl ester cleavage finally furnished enantiomerically pure ochratoxin a (326) (267). 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

Diels-Alder reactions have featured heavily during the period of review. Ar-Vinyl-2-oxazolidinone has been reported as a dienophile for the first time, including the preparation of various tetrahydro-277,77/-pyrano[4,3-. ]pyrans <2002SL952>. The heterodiene cycloaddition reaction of 3-formylchromone with a series of ketene acetals formed from C2-symmetric l,2-diarylethane-l,2-diols is completely diastereoselective (Scheme 40) <1995J(P1)2293>. 

Efficient synthetic methods have been developed for the synthesis of 4-functionalized quinolines mediated by triflic acid.703 Electron-rich, highly reactive ethynyl ketene-S,5-acetals react readily with arylamines and aldehydes in an aza-Diels-Alder reaction to afford the desired products [Eq. (5.256)]. Arylimines and ethynyl ketene-S,5-acetals react similarly (60-70% yields). 

Chiral dienes have proved to be less popular in asymmetric Diels-Alder reactions than their chiral dienophile counterparts. This is primarily a result of the problem of designing a molecule that incorporates a chiral moiety, such as the formation of a chiral isoprenyl ether or vinyl ketene acetal.187-190 In addition, diastereoselectivities often are not high,54 191-199 as illustrated by the cycloaddition of the chiral butadiene 5 with acrolein (Scheme 26.4). Improved stereoselection is observed through the use of double asymmetric induction, although this is a somewhat wasteful protocol.35,54 177 200... 

The hetero-Diels-Alder reaction is amongst the most efficient processes for the synthesis of six-membered heterocyclic ring systems. Solvent-free conditions have been used to improve reactions of heterodienophiles and heterodynes with low reactivities. Cado et al. (1997) have described the hetero-Diels-Alder reaction of ethyl lH-perimidine-2-acetate as heterocyclic ketene aminal with ethyl propiolate nnder solvent-free conditions with focused microwave irradiation. The new fused perimi-dines (23) were obtained in good yields (67-98%). 

Cado, R, Jacquault, P, Dozias, M.J., Bazureau, J.P., and Hamelin, J. 1997. Tandem conjugate carbon addition-intermolecularhetero Diels-Alder reactions using ethyl IH-perimidine-2-acetate as a ketene aminal with heating or microwave activation. Journal of Chemical Research, 176-77. 

Three successive [2+4] cycloadditions were used in the synthesis of the pentacyclic methyl ether of G-2N by Kraus and Zhao [92] and later, by a slightly modified procedure, also of the natural product G-2N (118) [93] (Scheme 31). Thermal reaction of the cyclobutanol 112 with acrylic ester gave the dihydronaphthalene 113 which was demethylated by treatment with boron tribromide and converted into the exocyclic ketene acetal 114. This unstable diene was reacted in a second cycloaddition with 2,6-dichlorobenzoquinone (115) to afford the tetracyclic chloroquinone 116. In a last Diels-Alder reaction, ring E was anella-ted by treatment of 116 with l-methoxy-l,3-bis[(trimethylsilyl)oxy]-l,3-buta-diene (117) to yield the pentacyclic natural product G-2N (118) [93]. 

---