GROUP-14 ORGANOMETALLIC REAGENTS .11. MACROCYCLIC POLYLACTONES BY CATALYZED CYCLOOLIGOMERIZATION - TETRA[(S)-BETA-BUTYROLACTONE]

The synthesis of the elusive macrotetrolide 2 of 3-hydroxybutyric acid has been approached by cyclooligomerization of enantiomerically pure (S)-beta-butyrolactone (3), promoted by the catalytic system 2,2-dibutyl-1,3,2-dioxastannolane/dibutyltin dichloride (DOS/DTC). The product has been isolated in 10% yield, demonstrating that it is not inaccessible, and its structure has been proven by X-ray crystal structure analysis. DOS/DTC afforded a thermodynamically controlled cyclooligomerization mixture, which was analyzed by means of a revised version of the Jacobson-Stockmayer theory, providing an evaluation of the effective molarity (EM) parameter for the formation of the tetrameric macrolide. The EM value was found to be five times lower than the corresponding value for tetra(beta-propiolactone), its strainless unsubstituted analogue. The observed EM allowed a quantitative measure (1.1 kcal mol-1) of the strain induced in the 16-membered macrotetrolide by the introduction of a methyl group into four homochiral stereocenters of the ring. Such relatively small strain is sufficient to depress to an appreciable extent the yield of 2 that can be expected from a thermodynamically controlled reaction. The possible origin of the observed strain is discussed.