Intramolecular, addition Diels-Alder reactions

Intramolecular ionic Diels-Alder reactions were carried out in highly polar media to afford carbocyclic ring systems. The strategy, which obviates the need for high temperatures and pressures, features in situ generation of heteroatom-stabUized allyl cations that undergo subsequent (4 + 2) cycloaddition at ambient temperature. Typically, reactions were complete within 1 hour after addition of substrate. Some cycloadducts were the result of a concerted process, whereas others were formed via a stepwise reaction mechanism (Grieco, 1996). 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

The first example of a true positive high pressure effect on the enantioselectivity was found for the intramolecular hetero-Diels-Alder reaction of the l-oxa-1,3-butadiene (173) in the presence of the Narasaka catalyst (164) to give the two enantiomeric bridged cycloadducts 174 and 175 (Scheme 8.44) [80]. At atmospheric pressure the two enantiomers were formed with 4.5 % ee, whereas at 500 MPa an increase to 20.4 % ee was observed which corresponds to a AAV = —(1.7 + 0.2) cm mol . In addition, the yield was improved from 50 to 89 %. It was assumed that under high pressure complexes of different stoichiometry may be formed which are more favorable towards a facial selective addition. However, a clear interpretation of the results cannot be given at this point. 

Oppolzer et al. devised a clever total synthesis of lysergic acid (40) that has as its key step an intramolecular imino Diels-Alder reaction (Scheme 2-XIII). A thermal retro-Diels-Alder reaction of 39 liberating cyclopen-tadiene was used to afford a diene oxime ether which cyclized to give a tetracyclic indole as a 3 2 mixture of diastereomers. Three additional steps served to convert this adduct to ( )-lysergic acid (40). Of particular interest here is the fact that simple oximino compounds are not normally reactive dienophUes, and the intramolecularity of the conversion is apparently crucial to the success of this transformation. 

A DFT study, involving M05-2X and B3LYP functionals, has been used to investigate the catalytic effect of water on the intramolecular polar Diels-Alder reaction of benzo-quinone in the synthesis of the diterpenoid, Elisabethin A. The addition of LiCl to the... 

Tietze also reported an increase in the enantioselectivity of a cycloaddition reaction which was carried out in the presence of a chiral Lewis acid under high pressure. The intramolecular hetero Diels-Alder reaction (HIMDA) [68] of the benzyli-dine compound 186 proceeds by a mcte-addition to give two enantiomeric bridged cycloadducts 187 and 188 (Scheme 45). At ambient pressure (dichloromethane, RT, 31 h), in the presence of the chiral titanium Lewis acid catalyst, product 187 was formed preferentially (with 4.5% ee). In addition to die increase in chemical yield obtained at normal pressure (from 50%), enantioselectivity of the cycloaddition at 5 kbar was increased to (20.4% ee), in favor of the (-) enantiomer 188. 

MacMillan s group advanced the iminium activation strategy to intramolecular Diels-Alder reactions with good diastereoselectivity (up to 20 1) and enantioselectivity [61]. The strategy was applied in the total synthesis of (-i-)-hapalindole Q [62]. A novel binaphthyl-based diamine was utilized to catalyze Diels-Alder reaction of a,P-unsaturated aldehydes with unprecedented high exo selectivity [63]. It was reported that the same reaction was also catalyzed by diphenylprolinol silyl ether and an acid as cocatalyst [64]. However, with the same reactants and the same catalyst, an ene reaction took place instead without an acid additive. Diels-Alder reactions of 2-vinylindoles and a,p-unsaturated aldehydes were also developed [65]. 

Having completed the intramolecular nitroso-Diels-Alder reaction, the shape of the bicyclic oxazinolactam 188 allowed for a diastereoselective successive addition of two nucleophiles (Scheme 41.40). The addition of methylmag-nesium bromide into 188 at 0°C because the carbonyl is activated by the N O bond, followed by sodium boro-hydride in acetic acid, delivers the cis-2,6 disubstituted piperidine precursor 190. The diastereoselectivity could be explained by the fact that the presence of the oxazino ring would force the C4a substituent of the N-alkoxypiperidi-nium unit 189 into a pseudoequatorial position, and the stereoelectronically axial attack of the hydride led diaster-eoselectively to the desired compound 190, which was eventually transformed into (-)-lepadin B 191. 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers111 in the intramolecular Diels-Alder reaction of the a, jS-unsaturated sulfone moiety of 165 (equation 117). Thus, when the sulfone 165 is heated in 1,2-dichlorobenzene for 6h, the steroidal compound 166 can be obtained in 62% yield. The compound 166 produces estrone (167) by elimination of benzenesulfinic acid and subsequent hydrogenation of the formed double bond. The stereoselectivity of the addition reflects a transition state in which the p-tosyl group occupies the exo position to minimize the steric repulsion between methyl and t-butoxy groups and the o-quinodimethane group as shown in equation 117. 

Another enantiospecific synthesis of longifolene shown in Scheme 13.32 used an intramolecular Diels-Alder reaction as a key step. An alcohol intermediate was resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the dihydropyrone ring was introduced by 7-addition of the ester enolate of methyl 3-methylbutenoate, followed by cyclization. 

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

Bicyclic derivatives. Polyhydroxylated carbo-bicyclic derivatives may be regarded as carbasugars with the rigid structure resulting from the presence of the additional carbocyclic ring. The most convenient way for construction of the bicyclic skeleton consists of the Diels-Alder reaction of properly functionalized trienes (intramolecular version) or dienes and olefins (intermolecular). 

The reversal of the thermal decomposition of 6 to ethylene and vinylacetylene cannot be utilized to generate 6, since, according to a quantum-chemical analysis, the reaction is slightly endergonic and requires a large free activation enthalpy (0.9 and 42 kcal mol-1, respectively) [59]. The intramolecular variant of this process as well as the addition of typical dienophiles of the normal Diels-Alder reaction to divinylace-tylenes will be discussed at the end of Section 6.3.3. 

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