Intramolecular cycloadditions three-atom tether

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. 

The intramolecular cycloaddition of ketenes with alkenes is a versatile synthetic procedure for the preparation of bicyclo[3.2.0]heptan-6-ones and bicyclo[3.3.1]heptan-6-ones19a-b. Three-atom tethers offer the best compromise between product strain, which is prohibitive with two-atom tethers, and entropy of activation, which decreases the rate of reaction with longer tethers. Cycloadditions with four-atom tethers arc quite rarc19a,b. As in intcrmolccular cycloadditions, syn addition to the alkene normally occurs. 

The combination of the geometrical preference of the tether and the stereochemical preference of the dipolarophile substituent can be seen in the intramolecular cycloadditions of alkyl nitronates, (Scheme 2.6) (99). When the tether is restricted to two atoms, only the endo approach of the tether is observed in up to a 100 1 ratio, independent of the configuration of the disubstituted dipolarophile. However, in the case of a three-atom linker, there exists a matched and mismatched case with respect to the observed stereoselectivities. With a (Z)-configured dipolarophile, only the exo isomer was observed since the ester moiety also approaches on the exo to the nitronate. However, with an ( )-configured dipolarophile, the ester group is forced to approach in an endo manner to accommodate an exo approach of the tether, thus leading to lower selectivity. 

Intramolecular cycloaddition of nitrile ylides to olefinic dipolarophiles linked to the dipole by a three-atom chain leads to pyrazoles fused to five-membered rings. Work on stereoselectivity in such reactions has been carried out using the reactant 266 in which the alkene moiety is linked to the C-terminus via a tether that incorporates an enantiomerically pure (R) stereogenic group (165). Both diastereo-isomers 267 and 268 were isolated and it was found that the reaction showed moderate stereoselectivity favoring 267. 

The two components of the [4 + 2] cycloaddition can be linked to react intramolecularly. The dienophile can be tethered to either a- or (3-carbon of the nitroalkene, which in turn creates bicyclic fused or bridged nitronates, depending upon the regioselectivity (Figure 16.4). To date, only cycloadditions of (3-tethered nitroalkenes are known. The reaction can be used to prepare five- and six-membered rings [58], which correspond to a three- or four-atom linker between the diene and dienophile. An attempted preparation of a seven-membered ring led to an intermolecular cycloaddition instead. 

The nitronate 170 subsequently underwent thermal and intramolecular [3 - - 2] cycloaddition to afford nitroso acetal 172 in 45% yield over three steps and as a mixture of dia-stereomers (44/1). The outcome of the [3 - - 2] cycloaddition reaction was controlled by the three-atom silaketal tether in... 

Intramolecular [4-1-4]-photocycloaddition of 2-pyridones is accommodated with appropriate tether length and points of attachment (Scheme 5). When the tether is linked at the 3- and 6 - positions (45 and 49), it reinforces the preferred head-to-tail cycloaddition. With a three-atom chain, the cycloaddition of 45 yields a 2 1 mixture of trans- and cis-isomers, similar to the intermolecular reaction. A tether alcohol 45a has little effect on the formation of stereogenic centers during the cycloaddition and yields two diastereomers for both 46 and 47, epimeric at the alcohol carbon. Protection of the alcohol as the sterically demanding t-butyldimethylsilyl (TBS) ether (45h) leads to only 46 and 47. 

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