Characterization of a Reductively-Activated Elimination Pathway Relevant to the Biological Chemistry of the Kinamycins and Lomaiviticins

The lomaiviticins (1 and 2) and kinamycins (3–5) are bacterial metabolites with potent antimicrobial and antiproliferative activities. Herein we establish that 1–5 are capable of generating electrophilic acylfulvene intermediates (6) under mildly reducing conditions. These acylfulvenes 6 are formed by a multistep process comprising two-electron reduction and loss of dinitrogen to form an ortho-quinone methide, followed by elimination. Based on these studies, the structure of the product formed from 1 in DNA-cleavage assays is proposed (26). We also show that the bis(hydroxynaphthoquinone) substructures of the lomaiviticins activate the metabolites toward reduction. Finally, based on COMPARE and time-dependent cell response profiling analyses, we show that kinamycin C (4) and the monomeric lomaiviticin aglycon (24) operate by a mechanism of action that is distinct from simple diazofluorenes, such as 23

Cobalt bis(acetylacetonate)–tert-butyl hydroperoxide–triethylsilane: a general reagent combination for the Markovnikov-selective hydrofunctionalization of alkenes by hydrogen atom transfer

We show that cobalt bis(acetylacetonate) [Co(acac)2], tert-butyl hydroperoxide (TBHP), and triethylsilane (Et3SiH) constitute an inexpensive, general, and practical reagent combination to initiate a broad range of Markovnikov-selective alkene hydrofunctionalization reactions. These transformations are believed to proceed by cobalt-mediated hydrogen atom transfer (HAT) to the alkene substrate, followed by interception of the resulting alkyl radical intermediate with a SOMOphile. In addition, we report the first reductive couplings of unactivated alkenes and aryldiazonium salts by an HAT pathway. The simplicity and generality of the Co(acac)2–TBHP–Et3SiH reagent combination suggests it as a useful starting point to develop HAT reactions in complex settings

Mechanism of Nucleophilic Activation of (−)-Lomaiviticin A

(−)-Lomaiviticin A (<b>1</b>) is a <i>C</i>₂-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage is initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate the formation of the vinyl radicals <b>1·</b> and <b>2·</b> from <b>1</b> by 1,7-addition of thiols to the diazofluorenes. These radicals can affect hydrogen atom abstraction from methanol and acetone. The first addition of thiol to <b>1</b> proceeds at a much greater rate than the second. The diazosulfide <b>5</b> formed en route to <b>1·</b> has been detected at −50 °C and undergoes decomposition to <b>1·</b> with a half-life of 110 min at −20 °C under air. These data, which constitute the first direct evidence for the generation of <b>1·</b> and <b>2·</b> from <b>1</b>, provide insights into the mechanism of DNA cleavage by <b>1</b>

Synthesis of 1,3-Amino Alcohols, 1,3-Diols, Amines, and Carboxylic Acids from Terminal Alkynes

The half-sandwich ruthenium complexes <b>1</b>–<b>3</b> activate terminal alkynes toward anti-Markovnikov hydration and reductive hydration under mild conditions. These reactions are believed to proceed via addition of water to metal vinylidene intermediates (<b>4</b>). The functionalization of propargylic alcohols by metal vinylidene pathways is challenging owing to decomposition of the starting material and catalytic intermediates. Here we show that catalyst <b>2</b> can be employed to convert propargylic alcohols to 1,3-diols in high yield and with retention of stereochemistry at the propargylic position. The method is also amenable to propargylic amine derivatives, thereby establishing a route to enantioenriched 1,3-amino alcohol products. We also report the development of formal anti-Markovnikov reductive amination and oxidative hydration reactions to access linear amines and carboxylic acids, respectively, from terminal alkynes. This chemistry expands the scope of products that can be prepared from terminal alkynes by practical and high-yielding metal-catalyzed methods

Synthesis of Ketones and Esters from Heteroatom-Functionalized Alkenes by Cobalt-Mediated Hydrogen Atom Transfer

Cobalt bis­(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao–Fleming oxidation of vinylsilanes and the Arndt–Eistert homologation

Room Temperature, Palladium-Mediated <i>P</i>–Arylation of Secondary Phosphine Oxides

We show that a broad range of aryl iodides are efficiently coupled with secondary phosphine oxides using 1 mol % of a catalyst formed in situ from tris(dibenzylideneacetone)dipalladium and Xantphos (<b>1</b>). Scalemic (<i>S</i>)<i>-</i>methylphenylphosphine oxide [<b>(</b><i><b>S</b></i><b>)-2e</b>] is shown to undergo arylation without detectable stereoerosion. The application of this method to the synthesis of novel <i>P</i>-chiral phosphines and PCP ligands is demonstrated