title: Trimethylenemethane diyl mediated tandem cycloaddition reactions: mechanism based design of synthetic strategies.
abstract: Several criteria for the measure of synthetic strategies toward "ideal synthesis" are available to guide the design and evaluation of the synthetic strategies toward the target molecules. One strategy toward "ideal synthesis" is developing a multistep reaction that involves dramatic change in complexity. Biogenesis of natural products and mechanistic investigation of complicated organic transformation provide good inspiration for design of new synthetic strategies. Trimethylenemethane diradical (TMM diyl), first introduced only as a theoretically interesting structure 60 years ago, gained interests of physical organic chemistry when it was first detected by Dowd. Study of characteristics and properties of TMM diyl was accelerated in a great deal when Koebrich observed dimeric hydrocarbon products from the reaction of 1,1-dibromo-2-methylhexa-1,5-diene with MeLi. Berson followed the mechanistic investigation of the reaction that involved 2-methylenecyclopentane-1,3-diyl, and thoroughly studied physical and chemical properties of the TMM diyl. This lead to the development of intramolecular [2 + 3] TMM diyl cycloaddition reaction for the construction of linearly fused triquinanes by Little. We envisioned that the generation of a TMM diyl through cycloaddition reaction discovered by Koebrich and [2 + 3] cycloaddition reaction of the TMM diyl could be combined together to form polyquinane structures. A cycloaddition reaction sequence of generating a TMM diyl from a alkylidene carbene of 2-methylhexa-1,5-diene structure in the presence of another olefin was designed and executed to produce linearly fused and angularly fused triquinanes depending on the connectivity of the second double bond. The successful transformation also inspired design of a tandem cycloaddition reaction strategy of using unprecedented tetrahydrocyclopentapyrazole to TMM diyl transformation. The new design involves two [2 + 3] cycloaddition reactions of 6-diazohexa-1,2-diene with an olefin attached at a proper position. When a diazo functionality is produced, the initial [2 + 3] cycloaddition reaction generates the TMM diyl, which undergoes the second [2 + 3] cycloaddition reaction to form triquinanes with high efficiency. The first tandem strategy involves a massive reorganization of molecular connectivity as one C═C double bond was cleaved and four C-C bonds were formed. The second tandem strategy connected two double bonds with one carbon center to form four C-C bonds without breaking any bond. The developed tandem strategies were readily applied to the total synthesis of natural products, especially triquinanes. Thus, the total syntheses of hirsutene, ceratopicanol, pentalenene and panaginsene with structural revision were achieved and the strategy was extended to the total synthesis of crinipellins (tetraquinane natural products). The newly designed tandem strategies not only demonstrated the efficiency and effectiveness of the process but also provided future opportunity of studying TMM diyl mediated reactions for designing variety of synthetic strategies.
authors.affiliation: Molecular-Level Interface Research Center, Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, 305-701 Korea.
authors.forename: Hee-Yoon
authors.initials: HY
authors.lastname: Lee