DECOMPOSITION OF ORGANIC PEROXIDES AND HYDROGEN PEROXIDE BY THE IRON THIOLATES AND RELATED COMPLEXES

Disclosed herein is a method of reducing or disproportionating peroxide, comprising combining an organic chalcogenide, an iron salt, and the peroxide in the presence of an additional reductant, which can be the organic chalcogenide. The method can be used to, e.g., prepare alcohols from peroxides and to disproportionate hydrogen peroxide into water and oxygen

A click-based modular approach to introduction of peroxides onto molecules and nanostructures

Copper-promoted azide/alkyne cycloadditions (CuAAC) are explored as a tool for modular introduction of peroxides onto molecules and nanomaterials. Dialkyl peroxide-substituted alkynes undergo Cu(I)- promoted reaction with azides in either organic or biphasic media to furnish peroxide-substituted 1,2,3- triazoles. Heterolytic fragmentation of the peroxide to an aldehyde, a side reaction that appears to be related to the formation of the triazole, can be suppressed by use of excess alkyne, the presence of triethylsilane, or by use of iodoalkyne substrates. Complementary reactions of simple alkynes with azidosubstituted peroxides are much less efficient. Click reactions of alkynyl peroxyacetals are also reported; reductive fragmentation can be minimized by increasing the distance between the peroxyacetal and the alkyne. The strategy enables modular introduction of dialkyl peroxides and peroxyacetals onto gold nanoparticles, the first such process to be reported

Approaches to the Total Synthesis of Aplysiatoxin

Approaches to the synthesis of the polyacetate tumor promoter aplysiatoxin (1a) are described. The spiroketal framework was convergently constructed in a heteroatom Diels-Alder cyclization to afford spiroketal 11. The desired spirocenter stereochemistry was achieved, in a key reaction pitting steric strain against the anomeric effect, by acid-catalyzed isomerization of spiroketal 12 to spiroketal13. Subsequent manipulation furnished alcohols 16A and 16B, which were the starting materials for investigations into macrocyclization and introduction of the C-3 lactol. 16A and 16B were efficiently converted to macrolactones 23A and 23B. The macrolactones were deprotected and brominated to furnish 27A and 27B, representing both possible C-15 epimers of 3-desoxyaplysiatoxin methyl ether. Attempted removal of the phenol methyl ether proved impossible. Nuclear Overhauser effect difference spectra on 27B showed signal enhancements within the rigid spiroketal framework analogous to those observed in derivatives of the natural product. Attempted transannular remote oxidation of C-3 using a C-9 alkoxy radical derived from the nitrite ester of 16B afforded, as the predominant product, the C-9 ketone resulting from fragmentation of the initial alkoxy radical; an alternate route involving allylic oxidation of the C-3 hydroxyethyl sidechain of 16A or 16B also failed to functionalize the C-3 position. Circular dichroism (CD) spectra of 16A and 16B imply that alcohol 16B contains the natural (S) stereochemistry at the C-15 methyl ether. [Chemical structures 1a, 11, 12, 13, 16A, 16B, 23A, 23B, 27A, and 27B. See abstract in scanned thesis for details.]</p

AMPHIPHILICCYCLOBUTENES AND CYLOBUTANES

This disclosure relates to amphiphilic compounds containing a cyclobutene or cyclobutane moiety. In some embodiments, the compounds are useful for treating infection by Mycobacterium such as Mycobacterium tuberculosis. Cyclobutene containing compounds are also useful as monomers in the preparation of amphiphilic polymers

In vitro and in vivo activity of 3-alkoxy-1,2-dioxolanes against Schistosoma mansoni

Objectives Compounds characterized by a peroxidic skeleton are an interesting starting point for antischistosomal drug discovery. Previously a series of 3-alkoxy-1,2-dioxolanes, which are chemically stable cyclic peroxides, demonstrated significant in vitro activity against Plasmodium falciparum. We aimed to evaluate the potential of these compounds against Schistosoma mansoni and elucidate the roles of iron and peroxidic groups in activity. Methods Drugs were tested against juvenile and adult stages of S. mansoni in vitro and in vivo. Selected structures were assessed in vitro against schistosomes in the presence of additional iron sources. In addition, drugs were tested in vitro and in vivo against Echinostoma caproni, a non-blood-feeding intestinal fluke. Finally, the activity of non-peroxidic analogues was evaluated. Results Three dioxolanes displayed IC50s ≤20.1 μM against adult schistosomes and values as low as 4.2 μM against newly transformed schistosomula. Nonetheless, only moderate, non-significant worm burden reductions were observed after treatment of mice harbouring adult infections. Drugs lacked activity against juvenile schistosomes in vivo. Two selected dioxolanes showed in vitro activity against E. caproni down to concentrations of 5 mg/L, but none of the compounds revealed in vivo activity. All tested non-peroxidic analogues lacked activity in vitro against both parasites. Conclusions Selected dioxolanes presented interesting in vitro activity, but low in vivo activities have to be overcome to identify a lead candidate. Although the inactivity of non-peroxidic analogues underlines the necessity of a peroxide functional group, incubation of adult schistosomes with additional iron sources did not alter activity, supporting an iron-independent mode of activatio

Quorum Sensing in \u3ci\u3eCandida albicans\u3c/i\u3e: Probing Farnesol’s Mode of Action with 40 Natural and Synthetic Farnesol Analogs

The dimorphic fungus Candida albicans produces extracellular farnesol (3,7, 11-trimethyl-2,6,10-dodecatriene- 1-ol) which acts as a quorum-sensing molecule (QSM) to suppress filamentation. Of four possible geometric isomers of farnesol, only the E,E isomer possesses QSM activity. We tested 40 natural and synthetic analogs of farnesol for their activity in an N-acetylglucosamine-induced differentiation assay for germ tube formation (GTF). Modified structural features include the head group, chain length, presence or absence of the three double bonds, substitution of a backbone carbon by S, O, N, and Se heteroatoms, presence or absence of a 3-methyl branch, and the bulkiness of the hydrophobic tail. Of the 40 compounds, 22 showed QSM activity by their ability to reduce GTF by 50%. However, even the most active of the analogs tested had only 7.3% of the activity of E,E-farnesol. Structure-activity relationships were examined in terms of the likely presence in C. albicans of a farnesol binding receptor protein. Includes supplemental material

Reductive Cleavage of Organic Peroxides by Iron Salts and Thiols

Despite the low bond strength of the oxygen− oxygen bond, organic peroxides are often surprisingly resistant to cleavage by nucleophiles and reductants. As a result, achieving decomposition under mild conditions can be challenging. Herein, we explore the reactivity of a selection of peroxides toward thiolates, phenyl selenide, Fe(II) salts, and iron thiolates. Peroxides activated by conjugation, strain, or stereoelectronics are rapidly cleaved at room temperature by thiolate anions, phenylselenide, or Fe(II) salts. Under the same conditions, unhindered dialkyl peroxides are only marginally reactive; hindered peroxides, including triacetone triperoxide and diacetone diperoxide (DADP), are inert. In contrast, all but the most hindered of peroxides are rapidly (\u3c1 min at concentrations down to ∼40 mM) cleaved by mixtures of thiols and iron salts. Our observations suggest the possible intermediacy of strongly reducing complexes that are readily regenerated in the presence of stoichiometric thiolate or hydride. In the case of DADP, an easily prepared explosive of significant societal concern, catalytic amounts of iron and thiol are capable of promoting rapid and complete disproportionation. The availability of inexpensive and readily available catalysts for the mild reductive degradation of all but the most hindered of peroxides could have significant applications for controlled remediation of explosives or unwanted radical initiators

Novel Amphiphilic Cyclobutene and Cyclobutane \u3ci\u3ecis\u3c/i\u3e-C18 Fatty Acid Derivatives Inhibit \u3ci\u3eMycobacterium avium\u3c/i\u3e subsp. \u3ci\u3eparatuberculosis\u3c/i\u3e Growth

Mycobacterium avium subspecies paratuberculosis (Map) is the etiologic agent of Johne’s disease in ruminants and has been associated with Crohn’s disease in humans. An effective control of Map by either vaccines or chemoprophylaxis is a paramount need for veterinary and possibly human medicine. Given the importance of fatty acids in the biosynthesis of mycolic acids and the mycobacterial cell wall, we tested novel amphiphilic C10 and C18 cyclobutene and cyclobutane fatty acid derivatives for Map inhibition. Microdilution minimal inhibitory concentrations (MIC) with 5 or 7 week endpoints were measured in Middlebrook 7H9 base broth media. We compared the Map MIC results with those obtained previously with Mycobacterium tuberculosis and Mycobacterium smegmatis. Several of the C18 compounds showed moderate effcacy (MICs 392 to 824 μM) against Map, while a higher level of inhibition (MICs 6 to 82 μM) was observed for M. tuberculosis for select analogs from both the C10 and C18 groups. For most of these analogs tested in M. smegmatis, their effcacy decreased in the presence of bovine or human serum albumin. Compound 5 (OA-CB, 1-(octanoic acid-8-yl)-2-octylcyclobutene) was identified as the best chemical lead against Map, which suggests derivatives with better pharmacodynamics may be of interest for evaluation in animal models