Diels-Alder reaction, with silyloxydienes

The intermolecular Diels-Alder reaction between the dibromoenone (111) and dienes (112) provides access to bicyclo[5.4.0]undecane systems (113) that are common core structures of many natural products (Scheme 32).118 The alio-threonine-derived O-(/ -biphenyl carbonyl oxy)-/i-phenyloxazaborolidi none catalyses the enan-tioselective Diels-Alder reaction of acyclic enones with dienes.119 The reversal of facial selectivity in the Diels-Alder cycloaddition of a semicyclic diene with a bro-moenone was induced by the presence of the bromo substituent in the dienophile.120 Mixed Lewis acid catalyst (AlBr3/AIMe3) catalyses the Diels-Alder reaction of hindered silyloxydienes with substituted enones to produce highly substituted cyclohexenes.121 Chiral /V-enoyl sultams have been used as chiral auxiliaries in the asymmetric Diels-Alder reactions with cyclopentadiene.122... 

Easily prepared from glycols, enones have been investigated as dienophiles. They react with butadiene under Lewis acid catalysis to form chiral cyclohexenes used in the synthesis of compactin analogs [353]. Levoglucosenone has been used in a Diels-Alder reaction with acetoxy-butadiene to construct a part of the indole alkaloid reserpine [354], and in synthetic studies toward tetrodotoxin [355]. Analogs of the anthracycline rhodomycinone have been similarly prepared [356]. [4 + 2]-Cycloaddition of the same enone with silyloxydiene allowed the creation of the fused ring system present in actinobolin [357]. 

Danishefsky has exploited his widely utilized silyloxydiene chemistry to complete a formal total synthesis of 90 (Scheme 1.20). By employing the appropriate oxidation levels for both the diene and dienophile, a resorcinyl ester possessing the required differentiation of the phenolic groups was obtained without further oxidative manipulation. To this end, the dianion of propiolic acid was alkylated with l-bromo-7-octene to give acid 98 in 68% yield. Further alkylation with methyl iodide then gave the ester 99. A Diels-Alder reaction with diene 100, a derivative of methyl acetoacetate, and alkyne 99 then furnished an initial phenolic intermediate which was protected as the benzyl ether to afford... 

Asymmetric Diels-Alder reactions. Diels-Alder reactions of aldehydes with silyloxydienes catalyzed by this chiral organoaluminum compound can proceed with high enantioselectivity. Thus reaction of benzaldehyde with the silyloxydiene 2 at... 

Scheme 60 Diels-Alder reaction of ethyl vinyl ketone with silyloxydienes...

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

Two homo Diels-Alder reactions and a hetero Diels-Alder reaction, each using a silyloxydiene, have been used in a total synthesis of vinemycinone methyl ester (236) by Danishefsky (84JA2453 85JA1285). Ketoaldehyde 231, prepared by two Diels-Alder cycloadditions, reacted with diene 230 in chloroform in the presence of Eu (fod)j to produce the silyl enol ether... 

Stereoselective oxycarborative addition is also achieved in cycloaddition and cyclooligomeriza-tion reactions. Thus, hetero-Diels-Alder reactions of dienes and aldehydes are not only catalyzed by main group Lewis acids, but also by transition metal complexes 10°. Tris[3-(heptafluoropropyl-hydroxymethylene)-( + )-camphorato]europium [( + )-Eu(hfc)3] and similar vanadium complexes have been used as the chiral catalyst in [4 + 2] cycloadditions of various achiral and chiral dienes to aldehydes63 67-101. With achiral silyloxydienes only moderate asymmetric inductions are observed, however, with chirally modified dienes, high double diastereoselectivities are achieved. Thus, the reaction of benzaldehyde with 3-terf-butyldimethylsilyloxy-l-(/-8-phenvl-menthoxy)-l.3-butadiene (1) gives (2/ .6/ )-4-wf-bntyldimethylsilyloxy-5,6-dihydro-6-phenyl-2-[(17 ,3/ ,45 )-8-phenylmenthoxy]-2f/-pyran (2) in 95% yield with a diasteieoselectivity of 25 1 ss. After crystallization and hydrolysis with trifluoroacetic acid, optically pure (2/ )-2,3-di-hydro-2-phenyl-4-(4//)-pyranone (3) is obtained in 87% yield. 

Several new methods of preparing pyran-4-ones have appeared. Silyloxydienes [such as (52)] undergo Diels-Alder reactions under Lewis catalysis with a0-unsaturated aldehydes in which the CO group takes part. This provides good yields of the dihydropyran-4-ones under mild conditions.64 65 In a related method, dichloroketene cyclizes the silyloxydiene to give good yields of the pyran-4-one (53). ... 

Scheme 7 Br0nsted-acid-catalyzed Diels-Alder reaction of unsaturated ketones with silyloxydienes.

The utility of weak-acidic Bronsted acid catalysts for the Diels-Alder reaction is often limited to reactive substrates. To overcome this drawback, Yamamoto and coworkers designed chiral N-triflyl phosphoramide 74 with higher acidity as catalyst for the enantioselective Diels-Alder reaction of ethyl -vinyl ketone (73) with electron-rich silyloxydiene 72 [32]. Various multifunctional cyclohexenes 75 can be obtained in moderate to excellent yields with high enantioselectivities (Scheme 38.21). 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

Stronger Brpnsted acid catalysts such as N-triflyl phospho-ramides. N-Triflyl phosphoramides were first apphed to the asymmetric Diels-Alder (DA) reaction of unsaturated ketones with silyloxydienes. While the established phosphoric acids demonstrated no catalytic activity, 5 mol% of N-triflyl phosphoramide 46 proved highly effective for the DA reaction of ethyl vinyl ketone with a range of sily-loxydienes, allowing access to highly enantioenriched endo products in good yields (35 to >99%, 82-92% ee) via a presumed boat transition state such as 47 (Scheme 7). 

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