Diene syntheses Lewis acid-catalyzed

The most important development within the field of Diels-Alder chemistry during the past two decades must be considered to be the design and application of chiral Lewis acid catalysts. From the mid 80s on, the number of literature reports about the design and application of chiral Lewis acids in the synthesis of chiral Diels-Alder adducts from achiral precursors grew exponentially, but it started to level off and decrease again in the mid 90s. Several excellent reviews about the application of chiral Lewis acids in Diels-Alder reactions have been published41,43 44. In this section, the recent literature about the chiral Lewis acid catalyzed all-carbon Diels-Alder reactions of dienes with dienophiles is reviewed, which, as such, has not been reviewed before. 

The Lewis acid-catalyzed reaction of the endoperoxide of 1-methoxycarbonylpyrrole with enol ethers presents an interesting route to 2-alkylpyrroles (Scheme 30) (79TL3477, 80H(14)102>. In the case of the reaction with l-(trimethylsilyloxy)buta-l,3-diene, the reaction provides a viable route to indole, which, with only slight modification, can also be employed in the synthesis of 4-substituted indoles <8lH(l6)959>. The endoperoxide reacts with 1-methylpyrrole to produce the l,l -disubstituted 2,2 -bipyrrole in low yield. 

The synthetic value of this reaction has been enhanced by the development of a wide range of methodologies for glycal synthesis from 0-acylatcd glycosyl halides1 or from noncarbohydrate precursors. By use of the Lewis acid-catalyzed diene-aldehyde cyclocondensation reaction, glycals of natural and non-natural sugars can be obtained (Scheme 4).31... 

Scheme 4. Synthesis of glycals by Lewis acid-catalyzed diene-aldehyde cyclocondensation reaction (P-R2 gluco series a-R2 galacto series).

A particularly elegant example is the application of Danishefsky s diene [107] to the total synthesis of carbohydrates and carbohydrate derivatives. While it was known that activated aldehydes undergo cycloaddition with electron-rich dienes, the process was not efficient with typical aldehydes under thermal conditions. A major breakthrough was realized [108] with the development of the Lewis acid-catalyzed diene-aldehyde cyclocondensation (LACDAC) reaction, which provided a new strategy for the synthesis of carbohydrates and other polyoxygenated natural products (Scheme 1.4) [109],... 

A similar approach to enantiomericaUy pure norbornene derivatives was developed by Nouguier et al. who employed l,3 2,4-di-0-methylene acetals of pentitols as chiral templates [62]. Hence, the 5-(5-acryloyl-D-arabinatol derivative 82 underwent highly stereoselective Lewis acid catalyzed cycloaddition with cyclopentadiene, giving 83 (Scheme 10.28). The stereochemical outcome of the reaction was explained in terms of the chelate complex 84, in which the chair-like dioxane ring and the acrylic moiety are fixed in two parallel planes, forcing the diene to approach the cisoid acrylate from the ii-face. The synthesis and utihty of various methylene protected glycosides have also been reported by this group [63-66]. 

The critical step in the enantioselective and stereocontrolled total synthesis of eunicenone A by E.J. Corey et al. was the highly efficient chiral Lewis acid catalyzed intermolecular Diels-Alder cycloaddition reaction The diene component was mixed with 5 equivalents of 2-bromoacrolein and 0.5 equivalents of the chiral oxazaborolidine catalyst in CH2CI2 at -78 °C for 48h. The reaction gave 80% of the desired cycloadduct in 97% ee and the endolexo selectivity was 98 2. 

Generation of a diene from a polymer-bound benzocyclobutane [320] The polymer-bound benzocyclobutene (358) can be converted into a very reactive diene upon thermal 47r-conrotatory ring opening. The resulting diene (359) can react with a series of dienophiles containing heteroatoms to afford a series of heterocycles (Scheme 75). Lewis acid-catalyzed reductive alkylation concluded the synthesis to give 363. 

The major development in the Lewis acid catalyzed reaction came in 1981 when Danishefsky and coworkers reported that ZnCh and BF3-OEt2 catalyze the cyclocondensation of silyloxy dienes with unactivated aldehydes. The use of these Lewis acid catalysts permits a variety of simple aldehydes to be used in the reaction (Table 2). Danishefsky also critically evaluated the mechanism and stereochemistry of the cyclocondensation reaction with a series of dienes, aldehydes and catalysts. These studies resulted in conditions to control the relative and absolute stereochemistry of the reaction and allowed the use of this chemistry in natural product synthesis. 

Lewis acid catalyzed versions of [4 4- 2] cycloadditions are restricted to functionalized dieno-philes. Nonfunetionalized alkenes and alkynes cannot be activated with Lewis acids and in thermal [4 + 2] cycloadditions these suhstrates usually show low reactivity. It has been reported that intcrmolecular cycloaddition of unactivated alkynes to dienes can be accelerated with low-va-lent titanium, iron or rhodium catalysts via metal-mediated - -complex formation and subsequent reductive elimination39 44. Usually, however, low product selectivities are observed due to side reactions, such as aromatization, isomerization or oligomerization. More effective are nickel-catalyzed intramolecular [4 4- 2]-dienyne cycloadditions which were developed for the synthesis of polycycles containing 1.4-cyclohexadienes45. Thus, treatment of dienyne 1, derived from sorbic acid, with 10mol% of Ni(cod)2 and 30 mol % of tris(o-biphenyl) phosphite in tetrahydrofuran at room temperature affords bicyclic 1,4-dienes 2, via intramolecular [4 + 2] cycloaddition, with excellent yield and moderate to complete diastereocontrol by substituents attached to the substrate. The reaction is sensitive towards variation in the catalyst and the ligand. 

Lewis acid catalyzed [4 + 2] cycloaddition of chiral dienes to carbonyl dienophiles is still an unexplored area. Such an approach has been applied to the synthesis of spectinomycin analogs. Cycloadditions of the two dienes 1 and 5 have been investigated. The reaction of diene 1 with acetaldehyde in the presence of Eu(fod)3 proceeds with 60% yield and gives a 5.7 1 ratio of adducts 3 and 4 d.r. [(2/ , 65 )/(2/ , 6/ )] 85 15. Under the same conditions, diene 5 produces adduct 6 as a single product with 50% yield55. 

Menthol [(—)-l] has been used as a chiral ligand for aluminum in Lewis acid catalyzed Diels-Alder reactions with surprising success2 (Section D.l.6.1.1.1.2.2.1). The major part of its application is as a chiral auxiliary, by the formation of esters or ethers. Esters with carboxylic acids may be formed by any convenient esterification technique. Esters with saturated carboxylic acids have been used for the formation of enolates by deprotonation and subsequent addition or alkylation reactions (Sections D.l.1.1.3.1. and D.l.5.2.3.), and with unsaturated acids as chiral dienes or dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.), as chiral dipolarophiles in 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), as chiral partners in /(-lactam formation by [2 + 2] cycloaddition with chlorosulfonyl isocyanate (SectionD.l.6.1.3.), as sources for chiral alkenes in cyclopropanations (Section D.l.6.1.5.). and in the synthesis of chiral allenes (Section B.I.). Several esters have also been prepared by indirect techniques, e.g.,... 

Hetero Diels-Alder cycloaddition reactions are of great importance in organic chemistry for the synthesis of six-membered heterocyclic ring systems. " In the past heterodienophiles and -dienes with one or more oxygen, nitrogen or sulfur atoms have been examined in thermal and Lewis acid-catalyzed reactions. " ... 

Lewis acid-catalyzed regio- and stereo-specific high pressure diene synthesis O... 

The use of simple aryl or alkyl ketones in the synthesis of a variety of substituted S-lactones via Lewis acid-catalyzed cyclocondensations has been reported (Midland and Graham, 1984). In addition, it was shown that changes in substitution pattern on the diene (1,1-dialkoxy- in the case of Brasard s diene, single alkoxy substitution at the 1-position of Danishefsky s diene) were reflected in changes in diastereoselec-tivity induced by particular Lewis acids. Europium(III) catalysts improved diastereoselectivity in the cyclocondensation of Brasard s diene, implying a chelation-controlled addition that was much more efficient than additions catalyzed by zinc chloride or boron trifluoride etherate. 

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