Catalytic Hydroxycyclopropanol Ring-Opening Carbonylative Lactonization to Fused Bicyclic Lactones

Abstract

A novel palladium-catalyzed ring opening carbonylative lactonization of readily available hydroxycyclopropanols was developed to efficiently synthesize tetrahydrofuran (THF) or tetrahydropyran (THP)-fused bicyclic γ-lactones, two privileged scaffolds often found in natural products. The reaction features mild reaction conditions, good functional group tolerability, and scalability. Its application was demonstrated in a short total synthesis of (±)-paeonilide. The fused bicyclic γ-lactone products can be easily diversified to other medicinally important scaffolds, which further broadens the application of this new carbonylation method.

Assembling Chiral Center of Heterocycles by Palladium-Catalyzed Asymmetric Hydrocarbonylation

“…As a kind of tetrahydrofuran-fused bicyclic -lactone, cis-2,8-dioxabicyclo-[3.3.0]octan-3-one is one of the privileged structural scaffolds shared by a large number of natural products. Inspired by Dai's work on exploiting the Pdcatalyzed oxidative ring-opening carbonylative lactonization of hydroxycyclopropanol to construct the racemate of this tetrahydrofuran-fused bicyclic -lactone, 22 we developed the alternative access by taking the Pd-catalyzed diastereoselective hydroesterification of enantiomeric -hydroxy--methylene-butanoic acid 18 as the key step (Scheme 7). 23 Since the presence of a chiral center in the alkene substrate, the high diastereoselectivity of hydroes-terfication was directed by the chiral bisphosphine ligand with matched chirality.…”

“…Once the condensation between the hydroxyl group and the carboxyl group occurred prior to the methoxycarbonylation, the afforded side product -methylene--butyrolactone (21) lost the reactivity of methoxycarbonylation. When either the hydroxyl or the carboxyl group in the alkene substrate was methylated (22)(23)(24), the reactivity of alkene methoxycarbonylation also dramatically diminished. Through the reduction of chiral -carboxymethyl--butyrolactone product to the hemiacetal intermediate followed by the oxidation of such hemiacetal, chiral tetrahydrofuran-fused bicyclic -lactone 20 was constructed in high diastereomeric ratio (Scheme 7).…”

Catalysis‐Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester

“…Hydrolysis of the acetal mixture did not simplify the purification, with the resulting hydroquinone being equally difficult to separate. We then tested our reported conditions (Pd(OAc) 2 and DDQ) for synthesizing bicyclic lactones [23] and were delighted to find these conditions were also efficient for synthesizing oxaspirolactones. After replacing 1,4‐benzoquinone with DDQ, 14 was cleanly produced in even higher yield (67 %) without any evidence of trans ‐acetalization.…”

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

“…Very recently, Dai and coworkers extended the Pdcatalyzed carbonylative transformation of hydroxycyclopropanols to achieve the synthesis of fused bicyclic lactones (Scheme 33a). 54 Thus, substrates bearing a hydroxyalkyl group at the 2-position of cyclopropanol underwent cyclopropanol ring opening and carbonylative lactonization in the presence of Pd(OAc)2 catalyst under CO atmosphere to afford tetrahydrofuran-or tetrahydropyran-fused γ-lactones. A low concentration (0.01 M) was crucial to achieve high yields.…”