1,3-Cycloaddition reverse stereoselectivity

Cycloaddition involves the combination of two molecules in such a way that a new ring is formed. The principles of conservation of orbital symmetry also apply to concerted cycloaddition reactions and to the reverse, concerted fragmentation of one molecule into two or more smaller components (cycloreversion). The most important cycloaddition reaction from the point of view of synthesis is the Diels-Alder reaction. This reaction has been the object of extensive theoretical and mechanistic study, as well as synthetic application. The Diels-Alder reaction is the addition of an alkene to a diene to form a cyclohexene. It is called a [47t + 27c]-cycloaddition reaction because four tc electrons from the diene and the two n electrons from the alkene (which is called the dienophile) are directly involved in the bonding change. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with describing the reaction as a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, that of ethylene with butadiene ... 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

Methylmagnesium bromide (191) exerts a great influence on the stereoselectivity of the reactions between mesitonitrile oxide 10 and the Baylis-Hillman adducts 192. In the absence of a Grignard reagent, a mixture of isomers is formed in which compounds 194 are the main products. The presence of a Grignard reagent reverses the stereoselectivity (Scheme 9.59). When Fisera [107] performed these reactions under microwave irradiation, the reaction times decreased from days to less than 5 min without any loss of stereoselectivity for noncatalyzed cycloadditions, but with a small change in the stereoselectivity in the chelated reactions. 

Nitrones derived from cyclic acetals of D-erythrose (479) and (689) and of D-threose (480) and (690), reacted with N -phenylmaleimide D15a to afford the corresponding diastereomeric isoxazolidines (691-706) (Scheme 2.295). The stereoselectivity is dependent on the substituents in the nitrone. In the case of nitrones (479) and (689) the cycloaddition is exo-selective. It was observed that microwave irradiation decreased the reaction times of the cycloadditions dramatically. For example, for nitrone (689) and dipolarophile D15a the reaction time decreased from 11 h to 8 min and for nitrone (690) and D15a it decreased from 3 h to 10 min. Moreover, microwave irradiation reversed the ratio of erythro-frans/erythro-r/.v adducts from 63 37 to 39 55, see compound (689). Cycloadditions of the chiral maleimides D15b and D15c are less stereoselective (817). 

Initially, a complex of nitroalkene (42) with LA (A) is reversibly formed. The efficient concentration of the latter is determined by the reaction conditions and the nature of heterodiene (42) and LA. This complex acts as a Michael substrate and adds alkene (43) to give bipolar adduct B, which undergoes cycliza-tion to give cationic intermediate C. The latter eliminates LA to yield target nitronate (35). In the case of nonconcerted cycloaddition, ionic intermediate B can undergo different isomerization reactions, some of which are considered below. The stereoselectivity of the process depends on the reactive conformation... 

Ab initio calculations also confirm that the use of an allyl magnesium alkoxide in place of the alcohol functionality will lead to high or complete stereoselectivity (138). When homoallylic alcohols are used, the Kanemasa protocol afforded the respective isoxazolines with poor stereoselectivity ( 55 45) in the case of terminal aUcenes, but with very high diastereoselectivity (up to 96 4) in the reaction of cis-1,2-disubstituted olefins (136). Extension of this concept to the reaction of a-silyl allyl alcohols also proved feasible and produced the syn (threo) adducts as nearly pure diastereomers (>94 6) (137). Thus, the normal stereoselectivity of the cycloaddition to the Morita-Baylis-Hillman adducts (anti > syn, see above) can be reversed by prior addition of a Grignard reagent (176,177). Both this reversal... 

Unlike thermal [2 + 2] cycloadditions which normally do not proceed readily unless certain structural features are present (see Section 1.3.1.1.), metal-catalyzed [2 + 2] cycloadditions should be allowed according to orbital symmetry conservation rules. There is now evidence that most metal-catalyzed [2 + 2] cycloadditions proceed stepwise via metallacycloalkanes as intermediates and both their formation and transformation are believed to occur by concerted processes. In many instances such reactions occur with high regioselectivity. Another mode for [2 + 2] cyclodimerization and cycloadditions involves radical cation intermediates (hole-catalyzed) obtained from oxidation of alkcnes by strong electron acceptors such as triarylammini-um radical cation salts.1 These reactions are similar to photochemical electron transfer (PET) initiated [2 + 2] cyclodimerization and cycloadditions in which an electron acceptor is used in the irradiation process.2 Because of the reversibility of these processes there is very little stereoselectivity observed in the cyclobutanes formed. 

Recently, substantial progress in stereochemistry of the cycloaddition reaction has been reported [34], Cycloaddition between optically active oxadiene 13 and l-acetoxy-2-ethoxy-ethylene, promoted by dimethylaluminum chloride, leads to dihydropyran 14, with a very high endo-exo stereoselectivity (54 1) and in an almost quantitative yield (see Scheme 6). When trimethylsilyl triflate was used as the promoter in this reaction, the reverse endo-exo selectivity (1 5) has been noted. The dihydropyrans obtained served as substrates for the synthesis of (3-d- and 3-L-mannopyranosides [34]. 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

An AMI semiempirical method was used to investigate the Diels-Alder cycloaddition reactions of vinyl sulfenes with buta-1,3-dienes.156 The reactivity and stereoselectivity of vinyl boranes have been reviewed.157 Aromatic methyleneamines undergo reverse-electron-demand Diels-Alder reactions with cyclopentadiene, norbom-ene, and vinyl sulfides.158... 

These results are compatible with stereochemical predictions derived through orbital symmetry theory, assuming a one-step n2s - -n2a addition. But secondary deuterium kinetic isotope effects on the allene plus allene thermal (2+2) cycloaddition seem to require a two-step mechanism with formation of an intermediate 44>, and as Moore and coworkers fully realized 83> stereoselective formation and reactions of 2,2 -biallylene intermediates will equally well account for the product ratios. In their rationale, two allenes approach and distort through simultaneous conrotatory twistings to give the perpendicular 2,2 -biallylene intermediate, which closes to form products in a disrotatory fashion. The experimentally observed stereochemical selectivity is equally compatible with a reversed order of rotatory motions disrotatory joining of two allenic reactants followed by conrotatory closure to create the 1,2-dimethylenecyclobutane products 83>. 

Similarly, the cycloaddition of chiral thiocarbonyl 5-oxides, derived From optically active TV-substituted 5-phenyl- or S-(4-methylphenyl)-5-(l-trimethylsilylethyl)sulfoximides with 2,3-di-methyl-1,3-butadiene, is completely stereoselective affording TV-substituted 3,6-dihydro-2,4,5-tri-methyl-2-[(5)-5-phenyl- or 5-(4-methylphenyl)sulfonimidoyl)]-2//-thiopyran 1-oxides as single diastereomers, determined by 1H-NMR spectroscopy using shift reagents and analytical reverse-phase HPLC85,87. 

Nitrone cycloaddition reactions are reversible, thereby offering the opportunity to change stereoselection from that of kinetic to thermodynamic control, should the selectivities associated with these path-... 

Organoaluminum and Sn(IV) Lewis acid-mediated [3 + 2] cycloadditions of oxa-zoles and aldehydes or diethyl ketomalonate have been observed [116]. The reactions are highly regioselective, with stereoselectivity highly dependent upon the Lewis acid used (Eq. 76). For example, the (BINOL)AlMe-promoted reaction between benzal-dehyde and the oxazole furnishes the oxazoline with a transicis ratio of 2 98. The selectivity is reversed with SnCU which results in a transicis ratio of 85 15. trans-5-Sub-stituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes [117]. 

A stereoselective Diels-Alder reaction between furan and acrylimide yielded bicyclic adduct 32 that could be recrystalhzed to isomeric purity (Scheme 25) [84]. The cycloaddition reaction was reversible at higher temperatures and resulted in preferential formation of racemic exo isomer. Cycloadduct 32 was elaborated in six steps to e t-shikimic acid. 

Dithiophthalimide 12 is also known to be a reactive thiocarbonyl dienophile.30 A few examples of cycloadditions of 12 with unsymmetrical dienes are shown in Scheme 5-XH. In general, these cycloadditions show excellent regioselectivity with dienes other than isoprene. In addition, they proceed with fair stereoselectivity. These reactions, like many of the thiocarbonyl additions discussed in this chapter, are reversible on heating at about 90°C. 

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