Cycloadditions with carbonyl dienophiles

Zr-Catalyzed Enantioselective Cycloadditions 6.2.11.1 Cycloadditions with carbonyl dienophiles 

Collins and co-workers have performed studies in the area of catalytic enantioselective Diels—Alder reactions, in which ansa-metallocenes (107, Eq. 6.17) were utilized as chiral catalysts [100]. The cycloadditions were typically efficient (-90% yield), but proceeded with modest stereoselectivities (26—52% ee). The group IV metal catalyst used in the asymmetric Diels—Alder reaction was the cationic zirconocene complex (ebthi)Zr(OtBu)-THF (106, Eq. 6.17). Treatment of the dimethylzirconocene [101] 106 with one equivalent of t-butanol, followed by protonation with one equivalent of HEt3N -BPh4, resulted in the formation of the requisite chiral cationic complex (107), 

These recent results illustrate for the first time that metallocene-based chiral Lewis acids can serve effectively in providing [4+2] cycloaddition products with excellent levels of enantiofacial selectivity. Perhaps more importantly, the reported NMR studies and the observed dramatic solvent effect should pave the way for future endeavors in the rational design of better chiral metallocenes. 

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The other recent examples of asymmetric syntheses involving Danishefsky s diene focused on hetero Diels-Alder reactions. Shibasaki and Feng separately reported asymmetric reactions with carbonyl dienophiles. Shibasaki demonstrated successful asymmetric reactions of ketones using a chiral Cu(I)-Walphos catalyst. Feng used a chiral A,iV -dioxide/In(OTf)3 catalyst in asymmetric cycloaddition reactions of aldehydes. Imine dienophiles are also amenable to asymmetric Diels-Alder reactions with Danishefsky s diene. Wulff reported enantioselective reactions using a VAPOL-B(OPh)3 catalyst system, while Snapper and Hoveyda disclosed silver-catalyzed enantioselective aza Diels-Alder reactions. ... 

The dihydropyrans resulting from an oxa Diels-Alder reaction represent valuable intermediates for the synthesis of numerous natural compounds. In particular, they exhibit many structural elements of carbohydrates. It is therefore not surprising that both the normal electron demand cycloaddition of dienes to carbonyl dienophiles as well as the reaction of 1-oxa-l,3-butadienes with electron-rich alkenes have extensively been used for the synthesis of sugar derivatives. Nevertheless, various approaches to other natural products have been worked out by means of these powerful tools. 

Cycloadditions with these heterodienophiles are usually regioselective and are in accord with FMO theory. The reactions are syn selective with the diene component. Other stereochemical features of the process are outlined in some of the examples described below, as well as in previous reviews. -" It should also be mentioned that only aldehydes and some ketones act as dienophiles. Except for rare exceptions, other types of carbonyl compounds apparently do not participate in Diels-Alder cycloadditions. 

Pyrrolidone 41, obtained by literature procedures from phenylalanine, was acylated adjacent to the amide carbonyl to give 42, followed by oxidation to the dienophile 43. The ensuing cycloaddition with diene 40 afforded the funtionalized octahydroisoindole 44 in 77% yield from 41. The reaction mixture from the room-temperature Diels-Alder reaction was contaminated with small amounts of an undetermined isomeric by-product (44 by-product >15 1). The additional carbons required for the macrocyclic ring were now appended via a cleverly conceived sulfur-ylide ring expansion. 

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. 

Hexafluoroacetone alkoxycarbonylimines 29, exhibiting biphilic properties, act as 1,3-heterodienes or as dienophiles in [2 + 4] cycloadditions. With cyclopentadiene they react as dienophiles forming [2 + 4] cycloadducts, for example, 2-alkoxy-carbonyl-3,3-bis(trifluormethyl)-2-azabicyclo[2.2.1]hept-5-ene 30 (95IZV1809)... 

Mesomeric betaines (e.g., (158)) undergo 1,4-dipolar cycloadditions with various electron-rich dienophiles thus, with l-A, A -diethylaminopropyne, for example, the adduct (159) is obtained. When heated this expels carbonyl sulfide to generate a-pyridone (160) (Scheme 28) <93TL5408>. 

The methods for generating acyl ketenes (Scheme 7-V) and their subsequent in situ participation in [4 + 2] cycloadditions with a wide range of hetero- or olefinic and acetylenic dienophiles (Scheme 7-VI), including acyl ketenes,185 186,197 carbonyl compounds, 86-188 nitriles,1874,189,191 isocyanates and isothiocyanates,1864,190,191 ketenes,191 imines,1864,1874,191,192 carbo-diimides,l87c 190,191,193 ynamines,194 ketene acetals,1864,195 enol ethers,1864,191,196 and V-sulfinylamines197 have been extensively reviewed.5,9,12 Two reports have detailed the 4-n- participation of allenic ketones in [4 + 2] cycloaddition reactions [Eq. (51)].198,199... 

Only the E,3E stereoisomer of the 2-azadiene was found to be reactive under the reaction conditions. Consequently, each of the piperidine products was found to possess the cis 2-phenyl, 5-methyl relative stereochemistry. Moreover, the cycloaddition products derived from reactions of enol ethers possessed the all-cis 2-phenyl-4-alkoxy-5-methyl stereochemistry necessarily derived from exclusive endo cycloaddition. Dienophile geometry is maintained during the course of the [4 + 2] cycloaddition, and no products derived from a potential stepwise, addition-cyclization reaction were detected. Representative neutral and electron-deficient dienophiles failed to undergo cycloaddition. A related boron trifluoride etherate-catalyzed [4 + 2] cycloaddition of simple 2-aza-l,3-butadienes with carbonyl compounds provides 5,6-dihydro-2//-l,3-ox-azines and appears to proceed preferentially through an endo [4 + 2] transition state although evidence supporting a stepwise, addition-cycli-zation was occasionally detected.630... 

Camphorsulfonyl chlorides 45 readily form amides by reaction with amines. On reduction of the carbonyl group, alcohols, e.g., 46 and 47, are obtained which are extremely useful auxiliaries for many purposes. Thus, esters are formed with carboxylic acids which may then undergo enolate reactions (SectionsD.1.1.1.3.2., D.l.5.2.1., D.3. and D.7.1.) or act as dienophiles and dipolar-ophiles (Sections D.l.6.1.1.1.2.2.1. and D.l.6.1.2.1.). Enol ethers of these auxiliaries give [2 + 2] cycloadditions with dichloroketene (Section D.l.6.1.3.), while carbamate derivatives have been used in acyliminium reactions (Section D.l.4.5.). Generally, steric hindrance in the sulfonamide group improves the stereoselectivity of the reactions and, therefore, the amides with diisopropylamine and dicyclohexylamine are used as auxiliaries both enantiomers of the dicyclohexyl derivative are commercially available. 

Carbonyl diisocyanate (46) was shown to undergo a Diels-Alder type of cycloaddition with azomethines to give 2,3,6,7-tetrahydro-4/7,8/7-[l,3,5]triazino[2,l-Z>][l,3,5]oxadiazin-4,8-diones (16) (Scheme 5). A large variety of the triazino[2,l-ft][l,3,5]oxadiazines were realized by the suitable selection of dienophiles. Thus, l,3,5-triazino[2,l-Z>][l,3,5]oxadiazines (17), (18 R = NMe), and (19) and were synthesized by the reaction of carbonyl diisocyanate with alkyl or aryl isocyanates, dimethyl cyanamide, or aliphatic carbodiimides, respectively <86CB1133>. Due to the high reactivity of the cumulated double bonds, carbonyl diisocyanate (46) was also found to undergo [4 + 2] cycloadditions with cyclohexanone to yield cyclohexan-l-spiro-9 -[l,3,5]-oxadiazino-[3,4-e][l,3,5j-dioxazin-5 -spiro-l"-cyclohexane-2, 7 -dione (47) (Scheme 6) <76LA1634>. 

Another important group of dienophiles of the a,p-unsaturated carbonyl class are quinones. 1,4-Benzoquinone reacts readily with butadiene at room temperature to give a high yield of the mono-adduct, tetrahydronaphthaquinone (3.8) under more vigorous conditions a bis-adduct is obtained which can be converted into anthraquinone by oxidation of an alkaline solution with atmospheric oxygen. As with other dienophiles, alkyl substitution on the double bond leads to a decrease in activity and cycloaddition of monoalkyl 1,4-benzoquinones with dienes occurs preferentially at the unsubstituted double bond. In addition to steric effects, electronic effects can play a part, such that cycloaddition occurs at the more electron-deficient double bond of the benzoquinone. The first step in an approach to the steroid ring system makes use of such selectivity (3.9). ... 

Chelation is also thought to play an important part in directing the facial selectivity of cycloadditions with the camphor sultam auxiliary. A variety of dienes can be used and adducts are obtained with very high diastereomeiic excesses. Both inter-and intramolecular cycloaddition reactions are amenable to the use of a chiral auxiliary. An intramolecular example is illustrated in Scheme 3.93, in which the diene and dienophile are tethered and in which cycloaddition leads to predominantly one of the two diastereomeric trans-fusQd bicyclic (endo) products. The dienophile is thought to adopt the s-cis conformation, with the aluminium atom complexed to the carbonyl and one of the two sulfone oxygen atoms. 

Particularly effective catalysts are the chiral copper(ll) bisoxazoline complexes 66 and 134 (3.96). Best results are obtained when the dienophile has two sites for co-ordination to the metal. For example, the catalyst chelates to the two carbonyl groups of acrylimide dienophiles (as in structure 135) and cycloaddition with a diene leads to the adduct in high yield and with high optical purity (3.97). ... 

In both cases, the mechanism of the reactions can be described like an ene-yne metathesis catalyzed by the Ru-NHC complex [82], followed by a Diels-Alder reaction. The mechanism of these reactions (exemplified for the synthesis of 81) is depicted in Scheme 5.59. Initial [2+2] cycloaddition between the alkyne and the olefin stemming from the metallic carbene achieves metallacyclobutene 158. Subsequently, cycloelimination and [2+2] cycloaddition with the alkene reagent give 159. A second cycloelimination generates a diene (by-product) and the active catalytic species 160, which initiates the catalytic cycle following successive cycloadditions and cycloeliminations up to afford diene 82. Finally, a Diels-Alder reaction between diene 82 and a,p-nnsatnrated carbonyls (dienophile) produces exclusively the syn-(endo-)ptod ict 81. 

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