Exolendo selectivity

Since peroxy acids have a relatively low steric requirement, steric hindrance mainly arises in the epoxidation of bridged cycloalkenes.224 Marked difference in exolendo selectivity was observed in the reaction of norbomene and 7,7-dimethyl-norbomene with m-CPBA236 [Eqs. (9.60) and (9.61)] ... 

Indolones such as (40) have been exploited on a few occasions as heterodienophiles (equation 12). Cycloaddition of (40 R = Ph) with several dienes was regioselective (cf. equation 12). The reactions with ( ,Z)- and ( , )-2,4-hexadiene were syn stereoselective with respect to the diene but exolendo selectivity was not determined. With the related dienophile (40 R = C02Et), regioselectivity deteriorated in the cycloadditions. 

The exolendo selectivity of the 1,3-dipolar addition of nitrones was regulated by the titanium salt as shown in Eq. (156) [398,399]. Aza-Cope rearrangement of a sugar-derived substrate initiated by the acetal cleavage with TiCl4 proceeded diastereoselec-tively to give the open-chain product (Eq. 157) [400]. 

In the cases of dimethylsilyl IMDA precursors, the exolendo selectivity was poor. However, this ratio could be readily and quite dramatically influenced by varying the alkyl substituents on the silicon template [12]. Thus with dienol 24, tether formation with dimethylvinylsilyl chloride and subsequent IMDA reaction afforded a 4 1 mixture of exolendo products (Scheme 10-7). The ratio could be further improved to 10 1 by using a diphenylsilyl tether, and when bulky Bu groups were used, a single stereoisomer, resulting from exo addition, was observed. This example once more illustrates the potential for tuning the stereoselectivity of the reaction by varying the steric interactions with the tether. 

Scheme 10-7 The steric bulk of the dialkylsilyl tether can influence exolendo selectivity.

As compared to the Diels—Alder reaction, the 1,3-dipolar cycloaddition of nitrones with olefins generally exhibits lower levels of regio- and stereo-control exolendo selectivity), which is a consequence of significant contribution by both LUMOdipoie-HOMOdipoiarophiie and HOMOdipoie LUMOdipoiarophiie interactions (Scheme 5.28). The process is further complicated by the possibility of interconversion of the nitrone geometry in the case of acyclic nitrones. For example, the cycloaddition between methyl acrylate and C,N-diphenylnitrone is only marginally in favor of the exo mode. 

SCHEME 5.28 The exolendo selectivity in 1,3-dipolar cycloaddition of nitrones with olefins. 

XPhos and the complex of (Tf2N)Au and XPhos (186), has been reported to produce the spiro[pyrrolidin-3,2 -oxindole] derivatives (184) in <97% ee and with >20 1 exolendo selectivity from their precursors (182) and (183) (Scheme 12). ... 

Chiral palladium and platinum complexes catalyze enan-tioselective Diels-Alder reactions. Catalyst 123, for example, showed good catalytic activity as well as good enantioselectivity (Scheme 13.33) [65]. Reaction of furan with oxazolidinone-derived 124 mediated by 10 mol% 123 at —30°C in CH2CI2 provided a 3 1 mixture of exo-125 endo-126 in 76% yield. Based upon HPLC analysis, endo-126 was formed with 90% ee while exo-125 was formed with 88% ee. At higher temperatures, the exolendo selectivity was better (82 18, respectively), but the adducts were nearly racemic, and at lower temperatures, the exolendo selectivity (57 43)... 

The observed reversal of exolendo selectivity on changing alkene substituents was interpreted as follows. According to Griesbeck s concept proposed for the Paterno-Biichi reaction, it is necessary to orient the... 

The next selectivity issue, exo/endo preferences, can be predicted for both the ortho and meta modes of cycloaddition on the basis of secondly orbital interactions (FMO treatment) and by electrostatic considerations involving polarized species (54) and (27). In general, intermolecular reactions with simple al-kenes proceed with endo selectivity. Heteroatom-substituted or polarized alkenes (equation 11) give exolendo mixtures, whose composition can be explained by electrostatic considerations. Intramolecular cycloadditions of simple alkenes and arenes joined by a three-atom tether generally proceed with high exo selectivity due in part to orbital alignment effects. In all cases, alkene geometry is preserved, except for sterically encumbered alkenes, in which case excitation transfer from the arene to the alkene can occur. 

Furan adds to vinylene carbonate to produce an exolendo mixture of Diels-Alder adducts [165]. Double hydroxylation of the 7-oxanorbornene double bond is highly exo face selective (Scheme 13.88). The diol thus obtained is protected as an acetonide. Saponification of the carbonate liberates a mixture of diols that is oxidized into m 5 6>-l,5-anhydroallaric acid derivative 316. Treatment of 316 with AC2O generates the anhydride 317. Subsequent reaction of 317 with methanol gives racemic 318 that can be resolved by fractional crystallization with brucine or by chromatographic separation of the (7 )-l-((3-naphthyl)ethylamides. The individual isomers of 318 each react with ClCOOEt and Me3SiN3 in situ to provide enantiomerically pure d- and L-riboside derivatives [166]. 

The key precursor in the silphinene synthesis, arene-alkene (95), is obtained in one step from commercial materi s and provides, in accord with the above analysis, cycloadducts (96) and (9 ) (1 1) in 70% yield. Mode, regio-, exolendo- and stereo-selectivity are essentially complete. Transformation of cycloadduct (96) to silphinene involves reduction with lithium in methylamine, which proceeds with formation of the alkene radical anion and subsequent mpture of the better aligned cyclopropane bond (C-4—C-S > C-3—C-4). Requiring only three steps from commercial materials, this synthesis dramatically illustrates how complexity can be rapidly built up through strategies based on the meta cycloaddition. 

For synthetic purposes, it is necessary to achieve constitutional selectivity (fused vs. bridged products), regioselectivity (linear vs. reversed fused products), and simple diastereoselectivity (ci.s,anii cis,syn fused products and exolendo bridged products). In addition it is desirable to obtain induced diastereo- and enantioselectivity. 

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