Intramolecular Pyridinium Oxide Cycloadditions: Systematic Study of Substitution, Diastereoselectivity, and Regioselectivity.

Intramolecular pyridinium oxide cycloadditions form complex polycyclic nitrogenous architectures. The diastereoselectivity and regioselectivity of pyridinium oxide cycloadditions was systematically investigated for the first time using complex substrates. Predictably high levels of diastereoselectivity and regioselectivity are observed, which can be attributed to minimization of steric (syn-pentane) and torsional strain in the products. The reaction is reversible under the reaction conditions, and it is stereospecific with respect to the dipolarophile geometry.

Ultrafast Dynamics and Photoresponse of a Fungi-Derived Pigment Xylindein from Solution to Thin Films.

Organic semiconductor materials have recently gained momentum due to their non-toxicity, low cost, and sustainability. Xylindein is a remarkably photostable pigment secreted by fungi that grow on decaying wood, and its relatively strong electronic performance is enabled by π-π stacking and hydrogen-bonding network that promote charge transport. Herein, femtosecond transient absorption spectroscopy with a near-IR probe was used to unveil a rapid excited-state intramolecular proton transfer reaction. Conformational motions potentially lead to a conical intersection that quenches fluorescence in the monomeric state. In concentrated solutions, nascent aggregates exhibit a faster excited state lifetime due to excimer formation, confirmed by the excimer→charge-transfer excited-state absorption band of the xylindein thin film, thus limiting its optoelectronic performance. Therefore, extending the xylindein sidechains with branched alkyl groups may hinder the excimer formation and improve optoelectronic properties of naturally derived materials.

Regioselective Synthesis of Benzofuranones and Benzofurans.

Reaction of 3-hydroxy-2-pyrones with nitroalkenes bearing ester groups gives benzofuranones. The reaction allows regioselective preparation of the benzofuranones with programmable substitution at any position. Complex substitution patterns are readily created. The substituted benzofuranones can be converted to substituted benzofurans.

Regioselective Formation of Substituted Indoles: Formal Synthesis of Lysergic Acid.

A Diels-Alder reaction-based strategy for the synthesis of indoles and related heterocycles is reported. An intramolecular cycloaddition of alkyne-tethered 3-aminopyrones gives 4-substituted indolines in good yield and with complete regioselectivity. Additional substitution is readily tolerated in the transformation, allowing synthesis of complex and non-canonical substitution patterns. Oxidative conditions give the corresponding indoles. The strategy also allows the synthesis of carbazoles. The method was showcased in a formal synthesis of lysergic acid.

Synthetic Studies toward Bazzanin K: Regioselective and Chemoselective Three-Component Suzuki Coupling.

The terphenyl substructure of the chiral cyclophane natural product bazzanin K was constructed. The key step involved sequential Suzuki couplings of a nonsymmetric dibromobenzene, which can be performed as a two-step process or as a one-pot three-component coupling. The key step represented a regioselective coupling of a dibromobenzene, as well as a chemoselective coupling of phenyl bromides in the presence of phenyl chlorides. Terphenyl intermediates displayed atropdiastereoisomerism, and they were converted to a single phenanthrene target by way of ring-closing metathesis.

Total Synthesis of (-)-Cephalotaxine and (-)-Homoharringtonine via Furan Oxidation-Transannular Mannich Cyclization.

Homoharringtonine and its congener cephalotaxine were synthesized. Oxidative ring-opening of a furan unveils an amine-tethered dicarbonyl, which undergoes spontaneous transannular Mannich cyclization. The cascade builds the full cephalotaxine substructure in a single operation in 60 % yield. A Noyori reduction enabled synthesis of the title compounds with excellent enantioselectivity (krel =278).

Total Synthesis of Leuconoxine, Melodinine†E, and Mersicarpine through a Radical Translocation-Cyclization Cascade.

The Aspidosperma alkaloids leuconoxine, melodinine E, and mersicarpine were synthesized. The approach features a key cascade radical reaction. A 1,5-hydrogen atom transfer is followed by spontaneous 5-exo-trig cyclization to construct the central indoline architecture. Late-stage differentiation of the radical cyclization product by chemoselective oxidation allows production of either the leuconoxine/melodinine E or mersicarpine structure.

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 CuII(btsc) and ZnIIATSM (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 CuII(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 CuII(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.

Regioselective Suzuki couplings of non-symmetric dibromobenzenes: alkenes as regiochemical control elements.

The regiochemical outcome of Suzuki couplings of non-symmetric dibromobenzenes is investigated. Selectivities are dependent on the proximity of the bromine atom to alkene substituents, not on steric or electronic effects. Extension to a one-pot three-component Suzuki reaction leads to efficient terphenyl syntheses.

The nature of persistent conformational chirality, racemization mechanisms, and predictions in diarylether heptanoid cyclophane natural products.

Restricted rotations of chemical bonds can lead to the presence of persistent conformational chirality in molecules lacking stereocenters. We report the development of first-of-a-kind predictive rules that enable identification of conformational chirality and prediction of racemization barriers in the diarylether heptanoid (DAEH) natural products that do not possess stereocenters. These empirical rules-of-thumb are based on quantum mechanical computations (SCS-MP2/∞//B3LYP/6-31G*/PCM) of racemization barriers of four representative DAEHs. Specifically, the local symmetry of ring B and the E/Z configuration of the vinylogous acid/ester are critical in determining conformational chirality in the DAEH natural product family.

Enantioselective and regioselective pyrone Diels-Alder reactions of vinyl sulfones: total synthesis of (+)-cavicularin.

The total synthesis of (+)-cavicularin is described. The synthesis features an enantio- and regioselective pyrone Diels-Alder reaction of a vinyl sulfone to construct the cyclophane architecture of the natural product. The Diels-Alder substrate was prepared by a regioselective one-pot three-component Suzuki reaction of a non-symmetric dibromoarene.

Synthesis of bis(indole) alkaloids from Arundo donax: the ynindole Diels-Alder reaction, conformational chirality, and absolute stereochemistry.

Bis(indole) alkaloids from Arundo donax were synthesized using the first ynindole Diels-Alder reaction. The alkaloids are chiral, having stable enantiomeric conformations with half-lives of racemization of t1/2 = 4150-25100 seconds at room temperature. Their absolute stereochemistry was determined using the exciton chirality method.

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.

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 ß-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.

Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core.

Golgi-modifying properties of the spongian diterpene macfarlandin E (MacE) and a synthetic analog, t-Bu-MacE, containing its 2,7-dioxabicyclo[3.2.1]octan-3-one moiety are reported. Natural product screening efforts identified MacE as inducing a novel morphological change in Golgi structure defined by ribbon fragmentation with maintenance of the resulting Golgi fragments in the pericentriolar region. t-Bu-MacE, which possesses the substituted 2,7-dioxabicyclo[3.2.1]octan-3-one but contains a tert-butyl group in place of the hydroazulene subunit of MacE, was prepared by chemical synthesis. Examination of the Golgi-modifying properties of MacE, t-Bu-MacE, and several related structures revealed that the entire oxygen-rich bridged-bicyclic fragment is required for induction of this unique Golgi organization phenotype. Further characterization of MacE-induced Golgi modification showed that protein secretion is inhibited, with no effect on the actin or microtubule cytoskeleton being observed. The conversion of t-Bu-MacE and a structurally related des-acetoxy congener to substituted pyrroles in the presence of primary amines in protic solvent at ambient temperatures suggests that covalent modification might be involved in the Golgi-altering activity of MacE.

Chromatographic preparation of food-grade prebiotic oligosaccharides with defined degree of polymerization.

Prebiotic oligosaccharides are of widespread interest in the food industry due to their potential health benefits. This has triggered a need for research into their sensory properties. Such research is currently limited due to the lack of available food-grade oligosaccharide preparations with specific degree of polymerization (DP). The aim of this study was to develop economical approaches for the preparation and characterization of prebiotic oligosaccharides differing with respect to composition and DP. Such preparations were prepared by chromatographic fractionation of commercially available prebiotic mixtures using microcrystalline cellulose stationary phases and aqueous ethanol mobile phases. This approach is shown to work for the preparation of food-grade fructooligosaccharides of DP 3 and 4, galactooligosaccharides of DP 3 and 4, and xylooligosaccharides of DP 2-4. Methods for the characterization of the different classes of oligosaccharides are also presented including those addressing purity, identity, total carbohydrate content, moles per unit mass, and DP.

Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes.

The synthesis and direct comparison of the chemical reactivity of the two highly oxidized bicyclic lactone fragments found in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system, including an examination of several possibilities for the key bridging cyclization reaction, are described. In addition, the first synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the pericentriolar region that is characteristic of macfarlandin E.

High-yielding oxidation of ß-hydroxyketones to ß-diketones using o-iodoxybenzoic acid.

The oxidation of ß-hydroxyketones to ß-diketones was systematically investigated. o-Iodoxybenzoic acid (IBX) was found to be efficient, operationally easy, and superior to other common oxidants. The reaction is suitable for milligram- to gram-scale oxidations.

Regioselective Synthesis of Substituted Carbazoles, Bicarbazoles, and Clausine C.

Substituted carbazoles are efficiently constructed from 3-triflato-2-pyrones and alkynyl anilines. Multiple substituents are tolerated on the carbazole, and complete control of regiochemistry is observed. Complicated and sterically congested substitution patterns are produced. This strategy is also used to prepare substituted bicarbazoles and related biaryls. Finally, the method was showcased in a synthesis of the carbazole natural product clausine C.

Synthesis of Highly Substituted Phenols and Benzenes with Complete Regiochemical Control.

Substituted phenols are requisite molecules for human health, agriculture, and diverse synthetic materials. We report a chemical synthesis of phenols, including penta-substituted phenols, that accommodates programmable substitution at any position. This method uses a one-step conversion of readily available hydroxypyrone and nitroalkene starting materials to give phenols with complete regiochemical control and in high chemical yield. Additionally, the phenols can be converted into highly and even fully substituted benzenes.