Diverse Natural Products from Dichlorocyclobutanones: An Evolutionary Tale

Abstract

11-Nor PGE2 was prepared in our laboratory several years ago and used to obtain the corresponding ring-expanded γ-butyrolactam, γ-butyrolactone, and cyclopentanone derivatives. 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 preparation of α,α-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 prepared by using dichloroketene-olefin cycloaddition, followed by regioselective one-carbon ring expansion with diazomethane. Importantly, it was also found that natural γ-butyrolactones (e.g., β-oxygenated γ-butyrolactones, lactone fatty acids) could be secured through regioselective Baeyer-Villiger oxidation of cycloadducts with m-CPBA and that naturally occurring γ-butyrolactam derivatives (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, γ-butyrolactones, and γ-butyrolactam derivatives 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 addition, considerable useful chemistry has been developed in the context of this synthesis program. This includes new methods for olefin vicinal dicarboxylation, β-methylene-γ-butyrolactonization, γ-butyrolactone and δ-valerolactone α-methylenations, transesterification, angelic ester synthesis, chiral enol and ynol ether preparations, 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 chemistry of dichlorocyclobutanones for possible solutions to problems in organic synthesis.

Protonation of γ‐Butyrolactone and γ‐Butyrolactam

“…Many natural products include a γ‐butyrolactone or γ‐butyrolactam moiety as structural element [1,2] . Especially the γ‐butyrolactone motif is present in about 10 % of all natural products [3–5] .…”

“…Especially the γ‐butyrolactone motif is present in about 10 % of all natural products [3–5] . In total syntheses, a common strategy to synthesize the γ‐butyrolactone motif is the Baeyer‐Villinger oxidation [2,6] . Herein, an ester is formed from a ketone by using peroxyacids or peroxides.…”

“…Herein, an ester is formed from a ketone by using peroxyacids or peroxides. The Beckmann rearrangement instead, which is used to obtain γ‐butyrolactam motifs, is the rearrangement of an oxime into an amide under ring expansion [2,7] . Another synthesis strategy for both cyclic compounds is the catalyzed cyclodehydration of the corresponding hydroxyl acid, [8] respectively amino acid [9] .…”

“…Many natural products include a γ-butyrolactone or γ-butyrolactam moiety as structural element. [1,2] Especially the γbutyrolactone motif is present in about 10 % of all natural products. [3][4][5] In total syntheses, a common strategy to synthesize the γ-butyrolactone motif is the Baeyer-Villinger oxidation.…”

“…[3][4][5] In total syntheses, a common strategy to synthesize the γ-butyrolactone motif is the Baeyer-Villinger oxidation. [2,6] Herein, an ester is formed from a ketone by using peroxyacids or peroxides. The Beckmann rearrangement instead, which is used to obtain γ-butyrolactam motifs, is the rearrangement of an oxime into an amide under ring expansion.…”