Carbon dioxide undergoes a Pd-catalyzed [3+2] cycloaddition with trimethylenemethane (TMM) under mild conditions (1 atm, 75 degrees C, 30 min) to produce a gamma-butyrolactone product in 63% yield, when the Pd-TMM complex is generated from 2-(acetoxymethyl)-3-(trimethylsilyl)propene. The reaction reported here is more rapid than the all-carbon [3+2] cycloaddition, and only the gamma-butyrolactone is produced in a competition experiment. With substituted substrates, the reaction is completely regioselective, producing the product derived from the kinetic Pd-TMM complex.

Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring-formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with β- or γ-dicarbonyl systems. These processes embrace a variant of metallacycle-mediated annulation chemistry where initial alkyne–carbonyl coupling is followed by a second, now intramolecular, stereoselective C–C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring.

Graphical abstract

Short formal syntheses of the antitumor antibiotics porothramycins A and B from a commercially available ester of the unnatural amino acid 3-(3-pyridyl)alanine are presented. A rearrangement cascade that presumably involves a Zincke-type pyridinium ring-opening followed by cyclization of a pendant nucleophilic amide generates the salient pyrroline ring of the alkaloids.

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.