Heparan sulfate degradation via reductive homolysis of its N-chloro derivatives

The highly basic heme enzyme myeloperoxidase (MPO), which is released by activated phagocytes, catalyzes the production of the potent oxidant hypochlorite (HOCl) from H(2)O(2) and chloride ions (Cl(-)). Heparan sulfate proteoglycans are key components of the extracellular matrix and cell surfaces and are known to bind MPO avidly via their negatively charged heparan sulfate chains. Reaction of heparan sulfate with HOCl generates polymer-derived N-chloro derivatives (chloramines, dichloramines, N-chlorosulfonamides, and chloramides). In this study, it is shown that heparan sulfate N-chloro derivatives are decomposed in the presence of redox-active transition-metal ions and superoxide (O(2)(*-)). These processes initiate polymer modification/fragmentation. Radical intermediates in these processes have been identified by EPR spectroscopy and spin trapping. Evidence has been obtained that the N-chloro derivatives undergo reductive homolysis to nitrogen-centered (aminyl, N-chloroaminyl, sulfonamidyl, and amidyl) radicals that generate carbon-centered radicals via rapid, intramolecular hydrogen atom abstraction reactions (1,2- and/or 1,5-shifts). In the case of the sulfonamidyl radicals, rearrangement via 1,2-shifts and beta-scission of the resultant C-2 carbon-centered radicals to yield SO(3)(*-) and C-2 imines is near quantitative based on the yield of SO(4)(2-), the decomposition product of SO(3)(*-). The formation of strand breaks and chromophores during these reactions is attributed to the formation and subsequent heterolytic rearrangement of the C-2 imines. The degradation of heparan sulfate via reductive homolysis of its N-chloro derivatives may be of significance at sites of inflammation, where MPO-derived HOCl is produced in high concentration and transition-metal ions and O(2)(*-) are known to be present or generated.     

Rate constants for 1,5- and 1,6-hydrogen atom transfer reactions of mono-, di-, and tri-aryl-substituted donors, models for hydrogen atom transfers in polyunsaturated fatty acid radicals

Rate constants for 1,5- and 1,6-hydrogen atom transfer reactions in models of polyunsaturated fatty acid radicals were measured via laser flash photolysis methods. Photolyses of PTOC (pyridine-2-thioneoxycarbonyl) ester derivatives of carboxylic acids gave primary alkyl radicals that reacted by 1,5-hydrogen transfer from mono-, di-, and tri-aryl-substituted positions or 1,6-hydrogen transfer from di- and tri-aryl-substituted positions to give UV-detectable products. Rate constants for reactions in acetonitrile at room temperature ranged from 1 x 10(4) to 4 x 10(6) s(-1). The activation energies for a matched pair of 1,5- and 1,6-hydrogen atom transfers giving tri-aryl-substituted radicals were approximately equal, as were the primary kinetic isotope effects, but the 1,5-hydrogen atom transfer reaction was 1 order of magnitude faster at room temperature than the 1,6-hydrogen atom transfer reaction due to a less favorable entropy of activation for the 1,6-transfer reaction. Solvent effects on the rate constants for the 1,5-hydrogen atom transfer reaction of the 2-[2-(diphenylmethyl)phenyl]ethyl radical at ambient temperature were as large as a factor of 2 with the reaction increasing in rate in lower polarity solvents. Hybrid density functional theory computations for the 1,5- and 1,6-hydrogen atom transfers of the tri-aryl-substituted donors were in qualitative agreement with the experimental results.     

Sulfonyl Nitrene and Amidyl Radical: Structure and Reactivity

Photocatalytic generation of nitrenes and radicals can be used to tune or even control their reactivity. Photocatalytic activation of sulfonyl azides leads to the elimination of N₂ and the resulting reactive species initiate C−H activations and amide formation reactions. Here, we present reactive radicals that are generated from sulfonyl azides: sulfonyl nitrene radical anion, sulfonyl nitrene and sulfonyl amidyl radical, and test their gas phase reactivity in C−H activation reactions. The sulfonyl nitrene radical anion is the least reactive and its reactivity is governed by the proton coupled electron transfer mechanism. In contrast, sulfonyl nitrene and sulfonyl amidyl radicals react via hydrogen atom transfer pathways. These reactivities and detailed characterization of the radicals with vibrational spectroscopy and with DFT calculations provide information necessary for taking control over the reactivity of these intermediates.     

Chemistry of 1-Alkoxy-1-glycosyl Radicals: The Manno- and Rhamnopyranosyl Series. Inversion of alpha- to beta-Pyranosides and the Fragmentation of Anomeric Radicals

The formation and stereoselective quenching of 1-mannopyranosyl radicals by a tributyltin hydride-mediated intramolecular 1,5-hydrogen abstraction sequence is described. A competing process is 1,4-hydrogen atom abstraction leading principally to glucopyran-2-ulosides. Fragmentation of the anomeric radical resulting in the formation of ring opened products is a problem in certain series. The chemistry is dictated to a considerable extent by the nature of the protecting groups employed with the 4,6-benzylidene series and, for rhamnose, the Ley 3,4-dispiroketal, being particularly susceptible to the 1,4-hydrogen atom abstraction but less to the fragmentation. Photochemical conditions are described, in which these side reactions are practically eliminated, and applied to the inversion of an alpha- to a beta-mannoside in a disaccharide.     

Iodine Catalysis for C(sp3)–H Fluorination with a Nucleophilic Fluorine Source

Iodine catalysis was developed for aliphatic fluorination through light-promoted homolytic C−H bond cleavage. The intermediary formation of amidyl radicals enables selective C−H functionalization via carbon-centered radicals. For the subsequent C−F bond formation, previous methods have typically been limited by a requirement for electrophilic fluorine reagents. We here demonstrate that the intermediary instalment of a carbon–iodine bond sets the stage for an umpolung, thereby establishing an unprecedented nucleophilic fluorination pathway.     

p-Nitrobenzenesulfenate esters as precursors for laser flash photolysis studies of alkyl radicals

A series of p-nitrobenzenesulfenate esters was used in laser flash photolysis (LFP) studies to generate alkoxyl radicals that fragmented to give the (2,2-diphenylcyclopropyl)methyl radical. Rate constants for the beta-scission reactions increased as a function of the carbonyl compound produced in the fragmentation reaction in the order CH2O < MeCHO < Me2CO < PhCHO < Ph2CO and increased with increasing solvent polarity. For alkoxyl radicals that fragment to produce benzaldehyde and benzophenone, the beta-scission reactions are faster than 1,5-hydrogen atom abstractions when the incipient carbon radical is as stable as a secondary alkyl radical, and this entry to carbon radicals can be used in LFP kinetic studies.     

Tantallaaziridines: from synthesis to catalytic applications

Tantallaaziridines are a class of organometallic compounds containing three-membered rings that include a tantalum, carbon and nitrogen atom. Closely related complexes containing the related iminoacyl ligand can be used as starting materials for tantallaaziridine synthesis. Tantallaaziridines can also be synthesized by reduction of imines or β-hydrogen abstraction of amides to give stable, isolable complexes. Tantallaaziridines possess a reactive Ta-C bond that can undergo stoichiometric transformations with unsaturated organic molecules to give new organometallic products. Upon quenching of such reactions with aqueous workup, selectively substituted small molecule amines can be prepared. Tantallaaziridines have also been proposed as catalytic intermediates in the direct α-alkylation of amines, hydroaminoalkylation, by exploiting the β-hydrogen abstraction route to regenerate the catalytically active species. Recent progress and remaining challenges in the field will be discussed.     

Novel fragmentation reaction of 2-alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones

2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, gamma-hydroxycyclohexenones, and/or gamma-butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and gamma-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted gamma-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.     

Amidyl Radical Directed γ-C(sp3)−H Functionalization with Silyl Enol Ethers via Photoredox Catalysis

Herein we reported an efficient photoredox-catalyzed reaction for site-selective C(sp³)−H functionalization of carboxamides with silyl enol ethers as radical acceptors. The reaction proceeded through amidyl radical-directed 1,5-hydrogen atom transfer (1,5-HAT) and C(sp³)−C(sp³) bond formation via radical addition of silyl enol ethers. The process features mild conditions and high functional-group tolerance, allowing the preparation of a series of carboxamides with pendant carbonyl moieties.     

Photolysis of 1-alkylcycloalkanols in the presence of (diacetoxyiodo)benzene and I2. Intramolecular selectivity in the beta-scission reactions of the intermediate 1-alkylcycloalkoxyl radicals

The C-C beta-scission reactions of 1-alkylcycloalkoxyl radicals, generated photochemically by visible light irradiation of CH2Cl2 solutions containing the parent 1-alkylcycloalkanols, (diacetoxy)iodobenzene (DIB), and I2, have been investigated through the analysis of the reaction products. The 1-alkylcycloalkoxyl radicals undergo competition between ring opening and C-alkyl bond cleavage as a function of ring size and of the nature of the alkyl substituent. With the 1-propylcycloheptoxyl, 1-propylcyclooctoxyl,and 1-phenylcyclooctoxyl radicals, formation of products deriving from an intramolecular 1,5-hydrogen atom abstraction reaction from the cycloalkane ring has also been observed. The results are discussed in terms of release of ring strain associated to ring opening, stability of the alkyl radical formed by C-alkyl cleavage, and with cycloheptoxyl and cyclooctoxyl radicals, also in terms of the possibility of achieving a favorable geometry for intramolecular hydrogen atom abstraction.     

Dispiro-1,2,4-trioxane analogues of a prototype dispiro-1,2,4-trioxolane: mechanistic comparators for artemisinin in the context of reaction pathways with iron(II)

Single electron reduction of the 1,2,4-trioxane heterocycle of artemisinin (1) forms primary and secondary carbon-centered radicals. The complex structure of 1 does not lend itself to a satisfactory dissection of the electronic and steric effects that influence the formation and subsequent reaction of these carbon-centered free radicals. To help demarcate these effects, we characterized the reactions of achiral dispiro-1,2,4-trioxolane 4 and dispiro-1,2,4-trioxanes 5-7 with ferrous bromide and 4-oxo-TEMPO. Our results suggest a small preference for attack of Fe(II) on the nonketal peroxide oxygen atom of 1. For 4, but not for 5 and 6, there was a strong preference for attack of Fe(II) on the less hindered peroxide bond oxygen atom. The steric hindrance afforded by a spiroadamantane in a five-membered trioxolane is evidently much greater than that for a corresponding six-membered trioxane. Unlike 1, 5-7 fragment by entropically favored beta-scission pathways forming relatively stable alpha-oxa carbon-centered radicals. These data suggest that formation of either primary or secondary carbon-centered radicals is a necessary but insufficient criterion for antimalarial activity of 1 and synthetic peroxides.     

A General Approach to Site‐Specific,Intramolecular C−H Functionalization Using Dithiocarbamates

Intramolecular hydrogen atom transfer is an established approach for the site‐specific functionalization of unactivated, aliphatic C−H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C−H halogenations or intramolecular aminations. Herein, we report a site‐specific C−H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N‐dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.     

A General Approach to Site‐Specific,Intramolecular C−H Functionalization Using Dithiocarbamates

Intramolecular hydrogen atom transfer is an established approach for the site‐specific functionalization of unactivated, aliphatic C?H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C?H halogenations or intramolecular aminations. Herein, we report a site‐specific C?H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N‐dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.     

Mass spectrometry in structural and stereochemical problems—CCXLIV : The influence of substituents and stereochemistry on the mass spectral fragmentation of progesterone

The complete high resolution mass spectra of progesterone (Δ⁴-pregnene-3,20-dione) and twenty-nine stereoisomers and alkyl substituted analogs have been analyzed with the aid of the recently developed computer program INTSUM. Progesterone analogs with “normal” configuration at the six chiral skeletal carbon atoms give rise to abundant ions corresponding to cleavage of the 1–2 and 3–4 bonds (ketene elimination), to cleavage of the 6–7 and 9–10 bonds (ring B cleavage), and to cleavage of the 13–17 and 15–16 bonds (partial ring D cleavage); these reactions are frequently followed by elimination of alkyl radicals. Alkyl groups at C-6 and C-10 exert a pronounced influence on the formation and fragmentation of the [M-ketene] ions. Reversal of configuration at C-10 increases the importance of ring B cleavage, whereas reversal at C-17 favors the partial cleavage of ring D. The fragmentation of 17-alkylprogesterones differs significantly from the general pattern, with acetyl loss (cleavage of the 17–20 bond) and partial ring D cleavage as the predominating reactions. Loss of ring D by cleavage of the 13–17 and 14–15 bonds is not an important reaction of progesterones. Direct interaction of the two ketonic functions was not observed.     

Annulation of the cyclohexane ring by tandem free radical alkylation of a nonactivated delta-carbon atom-intramolecular carbanion cycloalkylation

Annulation of the cyclohexane ring by a combination of free radical and ionic reactions sequences was achieved. Free radical alkylation of the remote nonactivated delta-carbon atom involves addition of delta-carbon radicals, generated by 1,5-hydrogen transfer in alkoxy radical intermediates, to radicophilic olefins, while the polar sequence involves enolate anions as intermediates which undergo a cycloalkylation reaction. Thus, the cyclohexane ring was constructed using diverse acyclic and cyclic structures as precursors of alkoxy radicals.     

Radical carbonylation of ω-alkynylamines leading to α-methylene lactams. Synthetic scope and the mechanistic insights

Tin hydride mediated radical carbonylation and cyclization reaction was investigated using a variety of ω-alkynyl amines as substrates. In this reaction α-methylene and α-stannylmethylene lactams having five to eight membered rings were obtained as principal products. In cases where the nitrogen has a substituent capable of giving stable radicals, such as an α-phenethyl group, the lactam ring formation again took place with extrusion of an α-phenethyl radical. Coupled with the subsequent protodestannylation procedure (TMSCl plus MeOH), these reactions provide a useful entry to α-methylene lactams with incorporation of CO as a lactam carbonyl group. In cases where the amines do not have a substituent acting as a radical leaving group, a reaction course involving a 1,4-H shift is chosen so as to liberate tin radicals ultimately. Thus the proposed mechanism involves (i) nucleophilic attack of amine nitrogen onto a carbonyl group of α,β-unsaturated acyl radicals/α-ketenyl radicals via lone pair-π* interaction, which leads to zwitterionic radical species, (ii) the subsequent proton shift from N to O to give hydroxyallyl radicals, (iii) 1,4-hydrogen shift from O to C, and (iv) β-scission to give lactams with liberation of tin radicals. DFT calculations reveal that the 1,4-hydrogen shifts, the key step of the reaction mechanism, can proceed under usual reaction conditions. On the other hand, an S(H)i type reaction to give lactams may be the result of the β-scission of the similar zwitterionic radical intermediates. DFT calculations also predict that an S(H)i type reaction would result when the intermediate has a good (radical) leaving group such as a phenethyl group.     

Ammonia-promoted fragmentation of 2-alkyl- and 2,4-dialkyl-3-iodo-1- oxocyclohexan-2,4-carbolactones

2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo ammonia-promoted fragmentation reactions to provide butenolides, gamma-butyrolactone, and/or beta,gamma-epoxycyclohexanones. Product distribution is governed by the relative size of the substituents at C-2 and C-4 of the cyclohexanones. Butenolide amide, the major product from the fragmentation, is further converted into their respective piperidinone and pyrrolidine derivatives.     

Electrochemically Enabled Intramolecular Aminooxygenation of Alkynes via Amidyl Radical Cyclization

An electrochemical synthesis of oxazol‐2‐ones and imidazol‐2‐ones has been developed via 5‐exo‐dig cyclization of propargylic carbamates‐ and ureas‐derived amidyl radicals. The electrosynthesis relies on the dual function of 2,2,6,6‐tetramethylpiperidin‐ 1‐yl)oxyl (TEMPO) as a redox mediator for amidyl radical formation and an oxygen atom donor. The reactions are conducted under mild conditions using a simple setup and provide convenient access to functionalized oxazol‐2‐ones and imidazol‐2‐ones from readily available materials.     

Radiation-induced destruction of hydroxyl-containing amino acids and dipeptides

The yields of molecular products resulting from radiolysis of hydroxyl-containing amino acids and dipeptides under various conditions were determined. The possibility of a new radiation-induced destruction pathway has been shown for serine and threonine, as well as for the dipeptides having residues of these amino acids at the N-terminal part of the respective molecule. This process includes formation of N-centered radicals from the starting molecules followed by their decomposition with elimination of side substituents. On radiolysis, serine and threonine were also shown to undergo free-radical destruction to form acetaldehyde and acetone, respectively. A mechanism has been proposed including consecutive stages of fragmentation of α-hydroxyl-containing carbon-centered radicals with elimination of ammonia and decomposition of the secondary radicals with elimination of CO₂. The yields of CO₂ obtained on radiolysis of serine and threonine were significantly higher (except for solutions at pH 12) than those for alanine and valine, which have no hydroxyl groups in their structures. The obtained data indicate that the hydroxyl-containing amino acids occupy a special place among other amino acids as regards the variety of radiation-induced reactions which they may undergo due to their structural features.     

Ion-molecule reaction of alkanenitriles and transition-metal ions in the gas phase: A study on fragmentation mechanism of the adducts

Gas-phase ion-molecule reactions between transition-metal ions (Mn +, Fe+, Co+, Ni +) and propionitri1e and acetonitrile were investigated. Ion-molecule adducts were prepared in a modified fast atom bombardment source and their metastable and collision-induced fragmentations, occurring in the frrst held-free region of an E/B configuration instrument, were studied by means of B/E linked scans. The experimental data suggest a coexistence of both “end-on” and “side-on” coordination modes; the former undergoes ligand detachment alone, whereas the latter loses methyl and ethyl radicals by insertion of M+ into organic substrates and further produces ethylene via a l3-hydrogen transfer. An order for the bonding energy of RCN-M+ is also suggested: RCN-Ni+> RCN-Co+> RCN-Fe+> RCNMn+.