Département de chimie moléculaire

11-Nor PGE₂ was prepd. in our lab. several years ago and used to obtain the corresponding ring-expanded gamma-butyrolactam, gamma-butyrolactone, and cyclopentanone derivs. The conversion of a cyclobutanone into a cyclopentanone had relatively little precedent and merited further study. It was soon found that the presence of a single chlorine adjacent to the carbonyl not only greatly accelerated the reaction with ethereal diazomethane, but also substantially enhanced its regioselectivity; not surprisingly, a second chlorine further increased both.The confluence of this finding and the discovery by Krepski and Hassner that the presence of phosphorus oxychloride significantly improved the Zn-mediated dehalogenation procedure for the prepn. of alpha,alpha-dichlorocyclobutanones from olefins provided the starting point for decades' worth of exciting adventures in natural product synthesis. A wide variety of naturally occurring 5-membered carbocycles (e.g., hirsutanes, cuparenones, bakkanes, guaianolides, azulenes) could thus be prepd. by using dichloroketene-olefin cycloaddn., followed by regioselective one-carbon ring expansion with diazomethane. Importantly, it was also found that natural gamma-butyrolactones (e.g., beta-oxygenated gamma-butyrolactones, lactone fatty acids) could be secured through regioselective Baeyer-Villiger oxidn. of cycloadducts with m-CPBA and that naturally occurring gamma-butyrolactam derivs. (e.g., amino acids, pyrrolidines, pyrrolizidines, indolizidines) could be efficiently obtained by regioselective Beckmann ring expansion of the adducts with O-(mesitylenesulfonyl)hydroxylamine (Tamura's reagent). These 5-membered carbocycles, gamma-butyrolactones, and gamma-butyrolactam derivs. were generally secured in enantiopure form through the use of either intrinsically chiral olefins or olefins bearing Stericol, a highly effective chiral auxiliary developed specifically for this "three-atom olefin annelation" approach.In addn., considerable useful chem. has been developed in the context of this synthesis program. This includes new methods for olefin vicinal dicarboxylation, beta-methylene-gamma-butyrolactonization, gamma-butyrolactone and δ-valerolactone alpha-methylenations, transesterification, angelic ester synthesis, chiral enol and ynol ether prepns., dichloroacetylene synthesis, and trans, trans hydroxy triad introduction.This versatile dichlorocyclobutanone-centered approach to natural product synthesis, together with the attendant new methods that have been developed, forms the basis of this Account, which is presented as an evolutionary tale. It is hoped that the Account will stimulate other research groups to seek to exploit the rich chem. of dichlorocyclobutanones for possible solns. to problems in org. synthesis.