ABSTRACT
Salvinorin A (1) is natural hallucinogen that binds the human κ-opioid receptor. A total synthesis has been developed that parlays the stereochemistry of l-(+)-tartaric acid into that of (-)-1 via an unprecedented allylic dithiane intramolecular Diels-Alder reaction to obtain the trans-decalin scaffold. Tsuji allylation set the C9 quaternary center and a late-stage stereoselective chiral ligand-assisted addition of a 3-titanium furan upon a C12 aldehyde/C17 methyl ester established the furanyl lactone moiety. The tartrate diol was finally converted into the C1,C2 keto-acetate.
Subject(s)
Diterpenes, Clerodane/chemical synthesis , Furans/chemistry , Naphthalenes/chemical synthesis , Quinolizines/chemistry , Sulfur Compounds/chemistry , Titanium/chemistry , Cycloaddition Reaction , Diterpenes, Clerodane/chemistry , Humans , Ligands , Naphthalenes/chemistry , StereoisomerismABSTRACT
Several examples of a highly specific, stereoconvergent intramolecular Diels-Alder cycloaddition that led to the trans-decalin core of neo-clerodane diterpenoids are described. The relative configuration adjacent to the dienophile, which led to C4 of the decalin system, as well as the electron-withdrawing effects of various substituents and conformational rigidity of the Diels-Alder precursors were explored.
Subject(s)
Diterpenes, Clerodane/chemistry , Diterpenes/chemistry , Cycloaddition Reaction , Molecular Conformation , Molecular Structure , StereoisomerismABSTRACT
Efficient synthetic routes to the four isomers 17b-20b of the title ketone are described. Entry begins from the Wieland-Miescher homologue 3 whose pair of carbonyl groups are amenable to regiochemical manipulation. The compositions of the reaction mixtures generated under kinetic or thermodynamic control were defined by (1)H NMR analysis subsequent to chromatographic purification. The regiochemical trends are correlated with B3LYP/6-31G* calculations, the results of which conform to the preferred introduction of a 1,2- or 2,3-double bond.
