Stereoselectivity three-atom tethers

Tethering of 2-pyridones can enforce the non-preferred head-to-head regiochemistry. For a three-atom tether, this cycloaddition is highly efficient but without stereoselectivity, for both the head-to-head tethered 55 (Scheme 7) and the tah-to-tail tethered isomer. The four-carbon tethered 58, however, only undergoes isomerizationd ... 

If the tether consists of three atoms (-RCH—X-( ) - (n= 1)), the stereoselectivity of the process is very high, and trans isomer 188a prevails among the reaction products, regardless of the composition of the tether, due to the endo approach of the tether to the Z isomer of the nitronate. An increase in the length of the tether to four atoms (n = 2) leads to a sharp decrease in selectivity of cycloaddition, and cis isomer (188b) prevails among the reaction products. Evidently, the latter isomer is formed as a result of the exo approach of the tether to the nitronate. 

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. 

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