Complete Diastereocontrol in Intramolecular 1,3-Dipolar Cycloadditions of 2-Substituted 5-Hexenyl and 5-Heptenyl Nitrones: Application to the Synthesis of the beta-Lactam Antibiotic 1beta-Methylthienamycin

The diastereoselectivity of intramolecular 1,3-dipolar cycloadditions of 2-substituted 5-hexenyl and 5-heptenyl nitrones to give 6-substituted and 3,6-disubstituted perhydrocyclopenta[c]isoxazoles has been investigated. An alkyl or aryl substituent at C2 completely controls the stereochemistry of the ring juncture and, in the case of the 5-heptenyl systems, also the stereochemistry of the 3-methyl group. Thus one stereocenter controls the formation of the other three to give a product with four contiguous stereocenters. The use of an ethylene ketal substituent in these systems allows the reaction to be carried out at much lower temperatures, an example of the gem-dialkoxy effect. This cycloaddition process has been used in an efficient formal total synthesis of the potent beta-lactam antibiotic, 1beta-methylthienamycin.