Thiohydroxamic Esters Research Articles

Protecting group-free radical decarboxylation of bile acids: Synthesis of novel steroidal substituted maleic anhydrides and maleimides and evaluation of their cytotoxicity on C6 rat glioma cells

We report the first Barton radical decarboxylation of unprotected bile acids via in situ irradiation of their thiohydroxamic esters in the presence of citraconic anhydride and citracoimide, leading to the synthesis a series of steroidal maleic anhydrides and maleimides as novel hybrid bile acids. The cytotoxic activities were evaluated on C6 rat glioma cells.

ChemInform Abstract: Radical Annulation Methodology. 2-Vinylcyclopentane Derivative Formation by a (3 + 2) Cycloaddition Reaction.

Abstract By thermally or photolytically induced decomposition of O-acyl derivatives of N-hydroxypyridine-2-thione or other thiohydroxamic esters, in the presence of an excess of electron deficient olefins, 2-vinylcyclopentane derivatives were obtained. This sequence of addition/cyclization/elimination reaction is mediated by a phenylthio radical.

ChemInform Abstract: Further Observations on the Thermal Stability of N-Hydroxy-2- thiopyridone Esters: Improved Decarboxylative Radical Additions to Olefins.

Decarboxylative radical addition onto olefins via thiohydroxamate esters can be considerably improved by heating and irradiating the reaction mixture; compound 10 can thus be obtained in 64% yield in one operation from acid chloride 6.

ChemInform Abstract: Homolytic Substitution on Selenium: Formation of Selenium-Containing Heterocycles by Direct Carbon-Selenium Bond Formation.

Thiohydroxamic esters derived from 5-(benzylseleon)pentanoic acid, 6-(benzylseleno)hexanoic acid and 7-(benzylseleno)heptanoic acid decompose smoothly upon irradiation, with the loss of carbon dioxide, to give tetrahydroselenophene, selenane and selenopane in good yield.

Investigation of Barton esters as radical photoinitiators

AbstractDifferent photoinitiators based on Barton thiohydroxamic esters,O‐acyl‐N‐hydroxy‐pyridine‐2(1H)‐thione andO‐acyl‐N‐hydroxy‐thiazole‐2(3H)‐thione derivatives, were tested in photopolymerization reactions through time‐resolved FTIR spectroscopy. Good rates of polymerization and final monomer conversion were obtained for some compounds. The excited state processes, investigated by time resolved absorption spectroscopy, lie on a fast singlet state cleavage leading to thiyl and alkyl radicals. Both the pyridine‐2(1H)‐thiyl and alkyl radicals are able to initiate a polymerization, in contrast with the thiazole‐2(3H)‐thiyl radical. A triplet state is observed for some derivatives. Computational studies help to describe the excited state properties and show a strong difference in the spin localization in the formed thiyl initiating radicals. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Decarboxylative Radical Azidation Using MPDOC and MMDOC Esters

An efficient radical-mediated decarboxylative azidation of aliphatic carboxylic acids has been developed. The success of this transformation hinges on the use of a new type of thiohydroxamate esters (MPDOC esters). These esters are more stable than the classical Barton esters and less prone to rearrange under radical conditions. In the case of alpha-alkoxy and alpha-amino acids, optimal results are obtained with the even more stable MMDOC esters developed recently by Kim.

Decarboxylative Allylation and Vinylation Approach of Thiohydroxamate Esters.

Barton's O-acyl thiohydroxamates are very useful to generate alkyl radicals from carboxylic acids via O-acyl thiohydroxamates 1,2 and have been used to form carboncarbon bonds by reacting with sulfonyl cyanides 3 and activated olefins. 4 However, Barton esters 1 have some limitations because they are very reactive, thereby yielding a byproduct resulting from attacking the thiocarbonyl group of Barton ester by alkyl radicals. This problem was solved to some extent by using less reactive O-acyl thiohydroxamates 6 in radical acylation approach. 5,6

Decarboxylative Allylation and Vinylation Approach of Thiohydroxamate Esters

Barton's O-acyl thiohydroxamates are very useful to generate alkyl radicals from carboxylic acids via O-acyl thiohydroxamates 1,2 and have been used to form carboncarbon bonds by reacting with sulfonyl cyanides 3 and activated olefins. 4 However, Barton esters 1 have some limitations because they are very reactive, thereby yielding a byproduct resulting from attacking the thiocarbonyl group of Barton ester by alkyl radicals. This problem was solved to some extent by using less reactive O-acyl thiohydroxamates 6 in radical acylation approach. 5,6

Studies Related to Carba‐pyranoses: A Radical Decarboxylation Approach to Monocarba‐disaccharides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Studies related to carba-pyranoses: a radical decarboxylation approach to monocarba-disaccharides.

(1--> 1), (1--> 3) and (1--> 4) acetal-linked monocarba-disaccharides have been synthesised from a series of glucosylated gamma- and delta-lactonic acids prepared from common intermediate, obtained from the Diels-Alder reaction of maleic anhydride and (E)-1-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-3-(trimethylsiloxy)buta-1,3-diene 1. Thiohydroxamic ester 14, prepared from gamma-lactonic acid 9, gave, upon treatment with tert-butyl thiol and light, the lactone 15. Subsequent lithium aluminium hydride reduction and acetylation gave the (1--> 3) acetal-linked monocarbadisaccharides 1,6-di-O-acetyl-3-O-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl)-2,4-dideoxy-5a-carba-beta-L-threo-hexopyranose 16. In a similar manner, protected monocarba-disaccharides 13, 19, 30, and 35 possessing L-ido, L-xylo, D-arabino and L-ido configurations of the carba-pyranose ring have been prepared. Treatment of thiohydroxamic esters 14 and 17 with either tert-butyl thiol or trityl thiol, dimethyl sulfide, oxygen and light gave alcohols 20 and 22. Subsequent lithium aluminium hydride reduction and aceytlation gave the monocarbadisaccharides 1,4,6-tri-O-acetyl-3-O-[2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl]-2-deoxy-5a-carba-beta-L-arabino-hexopyranose 21 and 1,2,4,6-tetra-O-acetyl-3-O-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyl)-5a-carba-beta-L-glucopyranose 23 respectively.

Decarboxylative acylation approach of thiohydroxamate esters

A decarboxylative acylation approach is achieved with thiohydroxamate ester 6, which is less reactive and more stable than Barton’s ester 1.

The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) and related steroidal inhibitors.

Abiraterone (17-(3-pyridyl)androsta-5,16-dien-3beta-ol, 1) is a potent inhibitor (IC50 4 nM for hydroxylase) of human cytochrome P45017alpha. To assist in studies of the role of the 16,17-double bond in its mechanism of action, the novel 17alpha-(4-pyridyl)androst-5-en-3beta-ol (5) and 17beta-(3-pyridyl)-16,17alpha-epoxy-5alpha-androst-3beta-ol (6) were synthesized. 3beta-Acetoxyetienic acid was converted in three steps into 5 via photolysis of the thiohydroxamic ester 8. Oxidation of an appropriate 16,17-unsaturated precursor (21) with CrO3-pyridine afforded the acetate (23) of 6. Inhibition of the enzyme by 1, the similarly potent 5,6-reduced analogue 19 (IC50 5 nM), and the 4, 16-dien-3-one 26 (IC50 3 nM) and by the less potent (IC50 13 nM) 3,5, 16-triene 25 is slow to occur but is enhanced by preincubation of the inhibitor with the enzyme. Inhibition following preincubation with these compounds is not lessened by dialysis for 24 h, implying irreversible binding to the enzyme. In contrast under these conditions the still potent (IC50 27 nM) 17alpha-(4-pyridyl)androst-5-en-3beta-ol (5) showed partial reversal after 5 h of dialysis and complete reversal of inhibition after 24 h. This behavior was also shown by the less potent 16,17-reduced 3-pyridyl compounds 3 and 24. Further, in contrast to the compounds (1, 19, 25, 26) with the 16,17-double bond, the inhibition of the enzymic reaction was not enhanced by preincubation either with 5 or with the 17beta-pyridyl analogues 3, 4, and 24 which also lack this structural feature. The results show that the 16,17-double bond is necessary for irreversible binding of these pyridyl steroids to cytochrome P45017alpha. However oxidation to an epoxide is probably not involved since epoxide 6 was only a moderately potent inhibitor (IC50 260 nM).

Exclusive Free Radical Mechanisms of Cellular Photosensitization

In order to determine the specific effects of radical-induced reactions in the absence of complicating excited-state pathways, four different thiohydroxamic esters and their parent molecule, N-hydroxypyridine-2(1H)-thione, have been studied in murine L1210 leukemia cells for their ability to produce photobiological damage. Irradiation (lambda exc = 355 nm) of cells in the presence of thiopyridone esters, specific photolytic precursors of sulfur-, carbon- and oxygen-centered radicals, caused toxicity that was unambiguously demonstrated to result from radical photosensitization mechanisms. Cellular morphological changes were observed following irradiation but apoptosis was not found to take place. A good correlation was evident between lipid peroxidation, measured by the thiobarbituric acid method, and phototoxicity, assessed by the trypan blue exclusion assay, indicating that the ester derivatives exert their effects mainly in plasma and/or subcellular membranes. Irradiation performed under deaerated conditions also induced significant phototoxicity but the effects of deaeration were dependent on the ester used and are discussed in terms of the nature of the primary radical species generated in each case. Irradiation of L1210 cells in the presence of N-hydroxypyridine-2(1H)-thione, a nonspecific, photochemical source of hydroxyl radical, was also found to trigger phototoxicity and lipid peroxidation. However in this case, photodamage cannot yet be definitely attributed to a radical or type II mechanism although the apparent oxygen independence of phototoxicity would indicate that type II contribution is not significant.

Oxidative Decarboxylation of Podocarpic Acid Derivatives

The radical decarboxylation–sulfoxide cycloelimination of 2′-pyridylthio esters formed from a series of podocarpic acid derivatives gives Δ4(18) -alkenes in high yield. An exception is the 13-nitro acid (2) which affords a thiohydroxamic ester (28), the relative stability of which is attributed to inhibition of the radical chain reaction by the nitro group. The stereochemistry of the pyridyl sulfide (18) has been confirmed by X-ray crystallography.

Free radical mediated construction of small ring compounds: the double annulation of bicyclo[3.1.0]hex-2-enes

A free radical approach to fused cyclopropane derivatives is described. Homolytic decomposition of thiohydroxamic esters 4a-e in the presence of dimethyl acetylenedicarboxylate affords bicyclo[3.1.0]hex-2-enes 6a-e in moderate yields.

Homolytic substitution by iminyl radical at selenium: A free-radical route to 1,2-benzoselenazoles

Thiohydroxamic esters (3) derived from the O-car☐ymethyl oxime derivatives (2) of 2-(benzylseleno)-benzaldehyde (1: R = H), 2-(benzylseleno)acetophenone (1: R = Me) and 2-(benzylseleno)propiophenone (1: R = Et) decompose smoothly, upon irradiation, with the loss of carbon dioxide and formaldehyde to give the 1,2-benzoselenazoles (5). The reaction presumably involves the iminyl radical intermediate (4) which undergoes intramolecular free-radical homolytic substitution at selenium to afford the product (5).

ChemInform Abstract: Ring Contraction Reactions of 2‐O‐Methanesulfonates of α‐Hydroxy‐ γ‐lactones in Aqueous Medium to Oxetane‐2‐carboxylic Acids: A Convenient Synthesis of 3′‐O‐Methyloxetanocin and a Formal Synthesis of Oxetanocin.

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Homolytic substitution at selenium: ring closure of ω-(benzylseleno)alkyl radicals

The ring closure of a series of ω-(benzylseleno)alkyl radicals ( 1) has been studied. Thiohydroxamic esters derived from ω-(benzylseleno)alkanoic acids decompose smoothly, upon irradiation, with the loss of carbon dioxide to afford 5– and 6– membered selenium-containing rings in 78 – 95% yield. The thiohydroxamic ester derived from 7-(benzylseleno)heptanoic acid affords the 7-membered heterocycle, selenopane in approximately 50% yield. These reactions presumably involve intramolecular free radical homolytic substitution at selenium and appear to proceed readily for both primary and secondary carbon-centered radicals. The 5-(benzylseleno)hex-2-yl radical ( 1f) appears to ring close without stereoselectivity, to give a 1:1 mixture of cis - and trans -2,4-dimethyltetrahydroselenophene, a finding in keeping with molecular mechanics (MM2) calculations.

Ring contraction reactions of 2-O-methanesulfonates of α-hydroxy-γ-lactones in aqueous medium to oxetane-2-carboxylic acids: A convenient synthesis of 3′-O-methyloxetanocin and a formal synthesis of oxetanocin

Barton decarboxylative rearrangement 15 of thiohydroxamic ester 17 directly provided the key oxetanosyl-thiopyridyl glycosides 18 which were successfully coupled to N-benzoyladenine. A two-step ring contraction of the tosylate 7 to the oxetane-2-carboxamide 23 is described. Attempted ring contraction of the triflate 24 gave the unexpected products 25 and 26. A ring expansion reaction (e.g. 14a → 21a) was also observed.

Sequential radical addition/cyclization/β-elimination reactions. 3- exo- and 5- exo-cycloaddition reactions of 5-phenylthio-3-pentenyl and 5-phenylthio-3-pentynyl radicals

Sequential radical addition/5-exo-cyclization/β-elimination reactions, accomplished by thermally or photolytically induced decompositions of O-acyl derivatives of N-hydroxypyridine-2-thione or other thiohydroxamic esters of 6-phenylthio-4-hexenoic acid 11 in the presence of an excess of radicophilic olefins, afforded the 2-vinylcyclopentane derivatives 13 in 50–90% yields, while decompositions of thiohydroxami esters or 6-phenylthio-4-hexynoic acids 24, under the same experimental conditions and in the presence of electron deficient olefins, afforded the corresponding 2-vinylidenecyclopentane (2-exo-allenic cyclopentane) derivatives 2 (61–72%). However, when decompositions of thiohydroxamic esters 39 were carried out in boiling toluene solution without radicophilic olefins, 3-exo-cyclization took place and the corresponding 2-vinylcyclopropane derivatives 40 were obtained in 43–60% yields.