| Several reactivity modes of nonconjugated 1,n-dialkynyl systems have been developed, leading to the synthesis of unique chemotypes. Diynes tethered to alpha,beta-unsaturated carbonyl compounds were prepared and underwent intramolecular [2+2+2] cyclizations using Wilkinson's catalyst under microwave-promoted conditions. This strategy was applied to the first total synthesis of the naturally occurring alcyopterosin I. The intermediate cyclohexadienes were either aromatized to the corresponding benzene rings or could be trapped with a variety of electron deficient heterodienophiles, including singlet oxygen, thioaldehydes, and aryl- and acylnitroso compounds, giving densely functionalized hetero Diels-Alder cycloadducts in high levels of regio- and diastereoselectivity. Post-modifications of these cycloadducts furnished additional unique heterocycles.;A Diels-Alder/retro Diels-Alder strategy for the synthesis of homochiral 4-substituted cyclohexenones using a chiral anthracene auxiliary was investigated. This methodology involved cycloaddition with p-benzoquinone followed by regio- and diastereoselective transformations on the mounted dienophile and a microwave-promoted cycloreversion to unmask the cyclohexenone. Application to the first total syntheses of the anticancer natural products candenatenins B and C produced the targets in 88% and 90% ee, respectively. The attempted cycloreversion of a more complex diyne-tethered cyclohexenone cycloadduct led to the isolation of a novel tetracycle through a tandem ene/[4+2] process.;Finally, two intramolecular cyclization modes of 1,n-dialkynes in the presence of In(III) catalysts were discovered. Dipropargylic ethers underwent a 6-endo-dig hydrobrominative cyclization mediated by InBr3 to give exocyclic vinyl bromides, while 1,7- and 1,8-dialkynyl ethers reacted via a hydrative cyclization pathway optimized with InI 3 and p-TSA cocatalyst to produce 2,2-disubstituted tetrahydrofuran products bearing an exocyclic enone appendage. For this latter transformation, the highest yields were obtained for substrates bearing propargylic termini with nucleophilic aryl groups. An initially proposed mechanism involved initial activation of the homopropargylic alkyne through an indium chelation with the ether oxygen, followed by a 7-endo- or 7- exo-dig closure for the 1,7- or 1,8-diyne substrates, respectively. Elimination to the enone, followed by protonation and five-membered ring closure would lead to the observed THE products. To gain further mechanistic insight, deuterium-labeling experiments were performed and suggested a pathway involving either an isomerization step or allenic intermediate. |
