Total Synthesis of (±)-Cavicularin: Control of Pyrone Diels–Alder Regiochemistry Using Isomeric Vinyl Sulfones

An intramolecular pyrone Diels–Alder reaction–elimination retro-Diels–Alder cascade of a vinyl sulfone was used in the synthesis of cavicularin, a molecule possessing conformational chirality. The vinyl sulfone substitution pattern allowed for regiocontrol in the Diels–Alder cascade event

Enantioselective Ullmann Ether Couplings: Syntheses of (−)-Myricatomentogenin, (−)-Jugcathanin, (+)-Galeon, and (+)-Pterocarine

The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. The reactions were used to prepare the diarylether heptanoid natural products (−)-myricatomentogenin, (−)-jugcathanin, (+)-galeon, and (+)-pterocarine

Chirality in Diarylether Heptanoids: Synthesis of Myricatomentogenin, Jugcathanin, and Congeners

The syntheses of myricatomentogenin, jugcathanin, galeon, pterocarine, and acerogenin L are reported. Synthetic material was used to measure their optical activities and free energy of activation for racemization. The natural enantiomers of myricatomentogenin, jugcathanin, galeon, and pterocarine were determined to have the same p<i>R</i> absolute stereochemistry. Acerogenins L and C are achiral compounds

Total Synthesis of Russuphelol: A Case of Mistaken Chirality

The chlorohydroquinone tetramer, russuphelol, does not have stereocenters; however, it was reported as a chiral optically active substance with stable enantiomeric conformations. The natural product is synthesized in six steps and 14% overall yield. Synthetic material was used to experimentally investigate its chiral properties

Structural Revision of Garuganin IV and 1,9′-Didesmethylgaruganin III through Total Synthesis

The chemical structures of garuganin IV and 1,9′-didesmethylgaruganin III were misassigned. The structures were revised on the basis of analysis of the NMR data, and the revisions were verified through total synthesis

Total Synthesis of (±)-Goniomitine via Radical Translocation

The aspidosperma alkaloid goniomitine was synthesized in six steps from 2-ethyl-δ-valerolactam. The convergent strategy features an Ullman coupling to assemble the required carbon atoms. A complexity-generating radical translocation reaction was used to build the indole architecture

Reductive Synthesis of Aminal Radicals for Carbon–Carbon Bond Formation

Aminal radicals were generated by reduction of the corresponding amidine or amidinium ion. The intermediate radicals participate in C–C bond-forming reactions to produce fully substituted aminal stereocenters. No toxic additives or reagents are required. More than 30 substrate combinations are reported, and chemical yields are as high as 99%

Formation of Carbon–Carbon Bonds Using Aminal Radicals

Aminal radicals were generated by radical translocation processes. For the first time, it is shown that they participate in carbon–carbon bond forming reactions. Either stannane or silane hydrogen atom donors are suitable for the reaction. More than 30 substrate combinations are reported, and chemical yields are as high as 91%

The Garuganin and Garugamblin Diarylether Heptanoids: Total Synthesis and Determination of Chiral Properties Using Dynamic NMR

The synthesis of the garuganin and garugamblin diarylether heptanoids using an intramolecular Ullmann coupling is reported. Alkene stereoisomers, vinylogous ester regioisomers, and β-diketone congeners are also synthesized. The chiral properties and free energies of activation for racemization of the garuganin and garugamblin diarylether heptanoids and congeners are determined using dynamic NMR methods. A combination of techniques including coalescence measurements, line shape analysis, and selective inversion experiments are used to measure racemization barriers. None of the garuganin or garugamblin diarylether heptanoids are chiral, despite their reported specific rotation values

Oxidative Release of Copper from Pharmacologic Copper Bis(thiosemicarbazonato) Compounds

Intracellular delivery of therapeutic or analytic copper from copper bis-thiosemicabazonato complexes is generally described in terms of mechanisms involving one-electron reduction to the Cu­(I) analogue by endogenous reductants, thereby rendering the metal ion labile and less strongly coordinating to the bis-thiosemicarbazone (btsc) ligand. However, electrochemical and spectroscopic studies described herein indicate that one-electron oxidation of Cu^II(btsc) and Zn^IIATSM (btsc = diacetyl-bis­(4-methylthiosemicarbazonato)) complexes occurs within the range of physiological oxidants, leading to the likelihood that unrecognized oxidative pathways for copper release also exist. Oxidations of Cu^II(btsc) by H₂O₂ catalyzed by either myeloperoxidase or horseradish peroxidase, by HOCl and taurine chloramine (which are chlorinating agents generated primarily in activated neutrophils from MPO-catalyzed reactions), and by peroxynitrite species (ONOOH, ONOOCO₂^–) that can form under certain conditions of oxidative stress are demonstrated. Unlike reduction, the oxidative reactions proceed by irreversible ligand oxidation, culminating in release of Cu­(II). 2-Pyridylazoresorcinol complexation was used to demonstrate that Cu­(II) release by reaction with peroxynitrite species involved rate-limiting homolysis of the peroxy O–O bond to generate secondary oxidizing radicals (NO₂^•, ^•OH, and CO₃^•–). Because the potentials for Cu^II(btsc) oxidation and reduction are ligand-dependent, varying by as much as 200 mV, it is clearly advantageous in designing therapeutic methodologies for specific treatments to identify the operative Cu-release pathway