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Metal-free C–H insertion via flow photolysis of aryldiazoacetates 3–5 with increased reaction efficiency in the presence of 4,4′-dimethoxybenzophenone.

Over the past 20 years reports of sulfonyl migrations have appeared, frequently described as ‘unusual’ and ‘unexpected’. This comprehensive review compiles, for the first time, sulfonyl migrations reported over the last 20 years including formal 1,2-, 1,3-, 1,4-, 1,5-, 1,6- and 1,7-sulfonyl shifts, occurring through either radical or polar processes, either inter- or intramolecularly. Discussion of the sulfonyl migrations is structured according to reaction type, i.e. nitrogen–carbon, nitrogen–oxygen, nitrogen–nitrogen, oxygen–carbon (including anionic and non-anionic thia-Fries rearrangements), oxygen–oxygen and carbon–carbon migrations. Discussion of the underlying mechanisms for the migrations is included, with particular attention afforded to the principal techniques utilised for their elucidation, namely isotopic-labelling, crossover experiments, density functional theory calculations and electron paramagnetic resonance spectroscopy amongst others.

Herein, we report the preparation and use of m-carboxybenzenesulfonyl azide as a diazo transfer reagent. This compound is an inexpensive and potentially scalable alternative to many of the diazo transfer reagents currently available, most of which have hazards associated with their use. Its usefulness and suitability as a diazo transfer reagent was assessed on the basis of cost, safety and its effectiveness in diazo transfer to a variety of different substrates.

The synthesis of a range of novel α-sulfenyl-β-chloroenones from the corresponding α-sulfenylketones, via a NCS mediated chlorination cascade, is described. The scope of the reaction has been investigated and compounds bearing alkyl- and arylthio substituents have been synthesised. In most instances, the Z α-sulfenyl-β-chloroenones were formed as the major products, while variation of the substituent at the β-carbon position led to an alteration in stereoselectivity. Stille cross-coupling with the Z α-sulfenyl-β-chloroenones led to selective formation of Z sulfenyl chalcones, while the E α-sulfenyl-β-chloroenones did not react under the same conditions. Oxidation of the Z α-sulfenyl-β-chloroenones was followed by isomerisation, leading to the E α-sulfinyl-β-chloroenones. Stille cross-coupling with the E α-sulfinyl-β-chloroenones produced the E sulfinyl chalcones. Either the E or Z sulfinyl chalcones can be obtained by altering the sequence of oxidation and Stille cross-coupling.

The marine transaminase, P-ω-TA, can be employed for the transamination from 1-aminotetralins and 1-aminoindanes with differentiation of stereochemistry at both the site of reaction and at a remote stereocentre resulting in formation of ketone products with up to 93% ee. While 4-substituents are tolerated on the tetralin core, the presence of 3- or 8-substituents is not tolerated by the transaminase. In general P-ω-TA shows capacity for remote diastereoselectivity, although both the stereoselectivity and efficiency are dependent on the specific substrate structure. Optimum efficiency and selectivity are seen with 4-haloaryl-1-aminotetralins and 3-haloaryl-1-aminoindanes, which may be associated with the marine origin of this enzyme.

Rhodium-catalysed S–H insertion of α-diazo-γ-butyrolactams has been successfully telescoped using continuous processing with in situ generated triflyl azide in flow and deacylative diazo transfer, incorporating real-time reaction monitoring of the final process outflow by IR spectroscopy. Significantly, the α-diazo-γ-butyrolactam reaction stream was sufficiently pure to progress to the rhodium-catalysed S–H insertion step without detrimental impact on the rhodium catalyst or the reaction efficiency.

Intramolecular C–H insertion reactions of α-diazocarbonyl compounds typically proceed with preferential five-membered ring formation. However, the presence of a heteroatom such as nitrogen can activate an adjacent C–H site towards insertion resulting in regiocontrol issues. In the case of α-diazoacetamide derivatives, both β- and γ-lactam products are possible owing to this activating effect. Both β- and γ-lactam products are powerful synthetic building blocks in the area of organic synthesis, as well as a common scaffold in a range of natural and pharmaceutical products and therefore C–H insertion reactions to form such compounds are attractive processes.

Correction for ‘Enantioselective copper catalysed intramolecular C–H insertion reactions of α-diazo-β-keto sulfones, α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent’ by Amy E. Shiely et al., Org. Biomol. Chem., 2017, 15, 2609–2628.

Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2′-deoxynucleotide 5′-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.

Synthetic methodology for the generation of novel 1,2,5-oxathiazole-S-oxides from cycloaddition of nitrile oxide dipoles with α-oxo sulfines generated in situ via the α-sulfinyl carbenes derived from α-diazosulfoxides is described. Experimental evidence and mechanistic rationale for the unanticipated interconversion of the diastereomeric 1,2,5-oxathiazole-S-oxide cycloadducts are discussed. Notably, using rhodium acetate as a catalyst at 0 °C under traditional batch conditions led to the selective formation and isolation of the kinetic isomers, while, in contrast, using continuous flow thermolysis, optimal conditions for the synthesis and isolation of the thermodynamic isomers were established.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including beta-ketoesters, beta-ketoamides, malonate esters and beta-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an alpha-diazocarbonyl in > 98% purity without any column chromatography.

Efforts to combine the intramolecular nitroaldol reaction with lipase-catalysed resolution of the resulting nitroaldol adduct in a one-pot dynamic kinetic resolution (DKR) are described. Significant challenges were encountered in the combination of the two systems. trans-2-Methyl-2-nitrocyclohexyl acetate (±)-3b was isolated in excellent enantiopurity (>98% ee) via a sequential DKR sequence where the lipase-mediated resolution and base-mediated interconversion of 2-methyl-2-nitrocyclohexanol 2 were effected alternately, demonstrating the feasibility of this approach initially. Further work showed, for the first time, evidence that a DKR-type system is possible for 2. Reaction engineering allowed the design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity.

In the present study, the synthesis of a range of novel 24-amino-25,26,27-trinorlanost-8-ene derivatives including 24-piperadino-trinorlanost-8-enes, 24-piperazino-trinorlanost-8-enes, 24-morpholino-trinorlanost-8-enes, and 24-diethylamino-trinorlanost-8-enes is reported and their cytotoxic and apoptotic potential evaluated in U937 cell lines. Excellent IC₅₀ results for piperidine and 1-(2-hydroxyethyl)piperazine derivatives have been observed (IC₅₀ values of 1.9 μM and 2.7 μM in U937 cells, respectively).

A systematic investigation of the influence of substitution at positions C-2 and C-3 on the azulenone skeleton, based on NMR characterisation, is discussed with particular focus on the impact of the steric and electronic characteristics of substituents on the position of the norcaradiene-cycloheptatriene (NCD-CHT) equilibrium. Variable temperature (VT) NMR studies, undertaken to enable the resolution of signals for the equilibrating valence tautomers revealed, in addition, interesting shifts in the equilibrium.

Enantioselectivities in C-H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C-H insertion reactions of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.

α-Carboxy nucleoside phosphonates (α-CNPs) are modified nucleotides that represent a novel class of nucleotide-competing reverse transcriptase (RT) inhibitors (NcRTIs). They were designed to act directly against HIV-1 RT without the need for prior activation (phosphorylation). In this respect, they differ from the nucleoside or nucleotide RTIs [N(t)RTIs] that require conversion to their triphosphate forms before being inhibitory to HIV-1 RT. The guanine derivative (G-α-CNP) has now been synthesized and investigated for the first time. The (L)-(+)-enantiomer of G-α-CNP directly and competitively inhibits HIV-1 RT by interacting with the substrate active site of the enzyme. The (D)-(-)-enantiomer proved inactive against HIV-1 RT. In contrast, the (+)- and (-)-enantiomers of G-α-CNP inhibited herpes (i.e. HSV-1, HCMV) DNA polymerases in a non- or uncompetitive manner, strongly indicating interaction of the (L)-(+)- and the (D)-(-)-G-α-CNPs at a location different from the polymerase substrate active site of the herpes enzymes. Such entirely different inhibition profile of viral polymerases is unprecedented for a single antiviral drug molecule. Moreover, within the class of α-CNPs, subtle differences in their sensitivity to mutant HIV-1 RT enzymes were observed depending on the nature of the nucleobase in the α-CNP molecules. The unique properties of the α-CNPs make this class of compounds, including G-α-CNP, direct acting inhibitors of multiple viral DNA polymerases. ispartof: Biochemical Pharmacology vol:136 pages:51-61 ispartof: location:England status: published

Intramolecular rhodium(II)-catalysed aromatic addition (Buchner) reactions of a range of α- and β-substituted α-diazoketones are reported. Both steric and electronic effects are evident for the aromatic additions investigated. In general, highly efficient aromatic addition is achieved through use of rhodium carboxylates bearing electronegative ligands, such as rhodium trifluoroacetate, while aromatic addition employing rhodium catalysts with more electron-donating ligands, such as rhodium caprolactam, is less efficient. Excellent levels of diastereoselectivity are possible for this process in the presence of rhodium acetate and rhodium caprolactam, however, a reduction in diastereocontrol is generally associated with use of the more reactive, electronegative catalysts. Interestingly, these catalyst effects can be overcome through the steric effects of the substituents on the α-diazoketone substrates, with the presence of sterically bulky substituents at the 2- or 3-position rendering the aromatic addition essentially catalyst independent in terms of efficiency and diastereocontrol.

The first examples of asymmetric copper-catalysed intramolecular C-H insertion reactions of 2-sulfonyl-2-diazoacetamides are described; trans γ-lactams with up to 82% ee are achieved with the CuCl2-bisoxazoline-NaBARF catalyst system. The reactions generally display high efficiency and high trans selectivity, and also a strong regiochemical preference for insertion to lead to the formation of 5-membered rings over 4-membered rings. In cases where there are competing C-H insertion pathways available, to form sulfolanes or thiopyrans, only the insertion into the amide chain to form γ-lactams is observed. With phenylsulfonyl derivatives, a minor competing C-H insertion pathway leading to β-lactams is seen; interestingly, changing the identity of the copper ligand changes the product ratio of β/γ-lactams. The copper catalysed reactions compare favorably in terms of efficiency and enantioselectivity to the corresponding reactions catalysed by commercially available chiral rhodium catalysts.

Steric and electronic effects in the copper-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and alkyl benzyl sulfides have been investigated. The presence of an aryl group directly attached to the sulfur is essential to afford sulfoxides with high enantioselectivities, with up to 97% ee for 2-naphthyl benzyl sulfoxide, the highest enantioselectivity achieved to date for copper-catalysed asymmetric sulfoxidation. In contrast, the benzyl substituent can be replaced by sterically comparable groups with no effect on enantioselectivity. Copper-mediated oxidation of substituted aryl benzyl sulfides display modest steric and electronic effects resulting in comparable or lower enantioselectivities to those obtained with the unsubstituted benzyl phenyl sulfide.

Aims The potato glycoalkaloids, α-chaconine, α-solanine and solanidine, along with potato peel extracts were investigated for potential anti-inflammatory effects in vitro. Their potential to reduce two biomarkers of inflammation, cytokine and nitric oxide (NO) productions, were assessed in the stimulated Jurkat and macrophage models, respectively. Main methods Cytokine and nitric oxide productions were stimulated in Jurkat and Raw 264.7 macrophages with Concanavalin A (Con A; 25 μg/ml) and lipopolysaccaride (LPS; 1 μg/ml), respectively. Selective concentrations of glycoalkaloids and potato peel extracts were added simultaneously with Con A or LPS for 24 h to investigate their potential to reduce inflammatory activity. Key findings α-Chaconine and solanidine significantly reduced interleukin-2 (IL-2) and interleukin-8 (IL-8) productions in Con A-induced Jurkat cells. The potato peel extracts did not influence cytokine production. In LPS-stimulated Raw macrophages, α-solanine, solanidine and two potato peel extracts significantly reduced induced NO production. Significance Our findings suggest that sub-cytotoxic concentrations of potato glycoalkaloids and potato peel extracts possess anti-inflammatory effects in vitro and with further investigation may be useful in the prevention of anti-inflammatory diseases.

Herein, we describe in full our investigations into the synthesis of grassypeptolide A (1) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late-stage introduction of sensitive bis(thiazoline) heterocycles and 31-membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly inhibited cancer cell proliferation in a dose-dependent manner. It induced cancer cell apoptosis, which was associated with increased cleavage of poly(ADP-ribose) polymerase (PARP) and decreased expression of bcl-2 and bcl-xL. Furthermore, grassypeptolide A also caused cell cycle redistribution by increasing cells in the G1 phase and decreasing cells in the S and G2 phases. In addition, cell cycle arrest was correlated with downregulation of cyclin D and upregulation of p27 and p21.

The cytotoxic effects of the oxidised derivatives of the phytosterols, stigmasterol and β-sitosterol, have previously been shown to be similar but less potent than those of the equivalent cholesterol oxides in the U937 cell line. The objective of the present study was to compare the cytotoxic effects of the oxidised derivatives of synthetic mixtures of campesterol and dihydrobrassicasterol in both the U937 and HepG2 cell lines. The parent compounds consisted of a campesterol: dihydrobrassicasterol mix at a ratio of 2:1 (2CMP:1DHB) and a dihydrobrassicasterol:campesterol mix at a ratio of 3:1 (3DHB:1CMP). The 2CMP:1DBH oxides were more cytotoxic in the U937 cells than the 3DBH:1CMP oxides but the difference in cytotoxicity was less marked in the HepG2 cells. The order of toxicity of the individual oxidation products was found to be similar to that previously observed for cholesterol, β-sitosterol and stigmasterol oxidation products in the U937 cell line. There was an increase in apoptotic nuclei in U937 cells incubated with the 7-keto and 7β-OH derivatives of both 2CMP:1DHB and 3DHB:1CMP and also in the presence of 3DHB:1CMP-3β,5α,6β-triol and 2CMP:1DHB-5β,6β-epoxide. An additional oxidation product synthesised from 2CMP:1DHB, 5,6,22,23-diepoxycampestane, was cytotoxic but did not induce apoptosis. These results signify the importance of campesterol oxides in the overall paradigm of phytosterol oxide cytotoxicity.

The use of the intramolecular Buchner cyclisation of an α-diazoketone as an approach to the synthesis of daucane sesquiterpenes is described; in particular the synthesis of the cis-fused analogue of dihydro CAF-603. The key step in the synthesis is the intramolecular Buchner cyclisation, which provides the bicyclo[5.3.0]decane framework with the required stereochemistry at the quaternary centre generated in the cyclisation. A synthetic route enabling access to an asymmetric synthesis is also outlined.

Asymmetric copper-catalysed intramolecular C–H insertion reactions of α-diazosulfones in the presence of various group I salts are reported leading to substantial variation in reaction efficiencies and enantioselectivities. The borate additives NaBARF and KBARF were found to be the most effective additives for permitting highly enantioselective syntheses with short reactions times and high efficiency. Significantly, direct evidence of the critical role of the additive in enantioselective carbenoid reactions has been secured.

Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium–BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.

HIV-1 reverse transcriptase (RT) catalytically incorporates individual nucleotides into a viral DNA strand complementing an RNA or DNA template strand; the polymerase active site of RT adopts multiple conformational and structural states while performing this task. The states associated are dNTP binding at the N site, catalytic incorporation of a nucleotide, release of a pyrophosphate, and translocation of the primer 3'-end to the P site. Structural characterization of each of these states may help in understanding the molecular mechanisms of drug activity and resistance and in developing new RT inhibitors. Using a 38-mer DNA template-primer aptamer as the substrate mimic, we crystallized an RT/dsDNA complex that is catalytically active, yet translocation-incompetent in crystals. The ability of RT to perform dNTP binding and incorporation in crystals permitted obtaining a series of structures: (I) RT/DNA (P-site), (II) RT/DNA/AZTTP ternary, (III) RT/AZT-terminated DNA (N-site), and (IV) RT/AZT-terminated DNA (N-site)/foscarnet complexes. The stable N-site complex permitted the binding of foscarnet as a pyrophosphate mimic. The Mg(2+) ions dissociated after catalytic addition of AZTMP in the pretranslocated structure III, whereas ions A and B had re-entered the active site to bind foscarnet in structure IV. The binding of foscarnet involves chelation with the Mg(2+) (B) ion and interactions with K65 and R72. The analysis of interactions of foscarnet and the recently discovered nucleotide-competing RT inhibitor (NcRTI) α-T-CNP in two different conformational states of the enzyme provides insights for developing new classes of polymerase active site RT inhibitors.

As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 A resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

Phytosterols are increasingly used as health supplements in functional foods and are associated with having both positive and negative effects on health. Given this disparity, an investigation of their full individual biological profile is imperative in order to assure food safety. This paper describes the de novo synthesis of pure phytosterols in multigram scale and we report the first synthesis of the key phytosterol dihydrobrassicasterol along with a comparison of routes to campesterol. A detailed spectroscopic analysis is included with full assignment of the 13 C NMR spectroscopic data of both compounds, mixtures and their precursors leading to the potential use of NMR spectroscopy as a tool for analysis of these sterol mixtures.

Development of rhodium catalysed O–H insertion reactions employing α-diazophosphonates with appropriately protected adenosine, uridine and thymidine derivatives is described. This synthetic methodology leads, following deprotection, to novel phosphononucleoside derivatives bearing a carboxylic acid moiety adjacent to the phosphonate. Protection strategies are critical to the success of the key O–H insertion. There are two important aspects: avoiding competing insertion pathways or catalyst poisoning, and being able to achieve deprotection without degradation of the phosphononucleosides.

A selective β-oxidation of a series of α-sulfanyl amides to the corresponding β-oxo-α-sulfanyl amides is described. This selective efficient oxidation of an unfunctionalised methyl or methylene group occurs under mild conditions, involving three sequential transformations conducted without isolation of the intermediates. Critically neither the sulfur nor the reactive α-CH bond is affected in the overall process.

This review provides an overview of the norcaradiene–cycloheptatriene equilibrium with particular emphasis on the influence of substitution on the position of equilibrium. Figure options Download full-size image Download as PowerPoint slide

The purpose of this review is to provide an overview of the development of asymmetric catalysts for C-H insertion reactions over the past two decades, focusing on the application of these catalysts in the decomposition of α-diazocarbonyl compounds. Given the rapid pace of development in the field of enantioselective C-H insertion chemistry, an up-to-date review of this type is warranted. While recent reviews22,23 have dissected their content into intramolecular and intermolecular processes, this article is differentiated in extending this division to include classification of C-H insertion reactions according to product type. Thus, catalytic methods for the asymmetric synthesis of carbocyclic compounds, oxygen-containing heterocycles, nitrogen-containing heterocycles and sulfur-containing heterocycles are readily identifiable. Due to the diversity of compounds resulting from intermolecular C-H insertion processes, classification of reactions by product type was not attempted in this section of the review.

Efficient synthesis and characterisation of a series of aryl benzyl NH-sulfoximines are described. While N-protected versions of aryl benzyl sulfoximines have been previously described, reports of their deprotection are very limited, presumably due to lability under the typically harsh deprotection conditions which can be employed with the less reactive aryl alkyl derivatives. Use of N-cyanosulfoximines as key intermediates overcomes these difficulties leading to an effective synthetic route to these compounds.

Copper-catalysed intramolecular C–H insertion reactions of α-diazo-β-keto esters and α-diazo-β-keto phosphonates are described, with moderate-to-good levels of enantioselectivity achieved for reactions employing the borate additive sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF). Notably, the first example of asymmetric induction reported to date for intramolecular C–H insertion of an α-diazo-β-keto phosphonate is also described.

The palladium-catalysed decarboxylative cross-coupling of heterocyclic aromatic carboxylates and aryl halides is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and tetrabutylammonium bromide (TBAB). Utilizing a mixed solvent system consisting of N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), the cross-coupling system operated at temperatures ranging from 80 to 140 °C.

Asymmetric copper-catalysed intramolecular C-H insertion reactions of a series of α-diazo-β-keto sulfones are reported. Enantioselectivities of up to 82% ee were achieved in moderate to good yield. These results represent the highest level of enantiocontrol achieved to date for a copper-catalysed cyclopentanone synthesis via C-H insertion.

2-Benzenesulfonylcyclopentanone 1 and cyclohexanone 2 undergo efficient dynamic kinetic resolution on treatment with baker's yeast, under a range of conditions including in organic solvents, to form the corresponding cis -2-benzenesulfonylcycloalkanols 5 and 6 in excellent enantiopurity. Reduction of larger ring derivatives is much less efficient.

Decomposition of α-diazosulfoxides using rhodium carboxylate or carboxamide catalysts proceeds via a Wolff type rearrangement to form α-oxo sulfine intermediates, which can be trapped as cycloadducts with dienes. In the absence of a diene trap, dimerisation of the sulfine intermediate is observed.

Diazo transfer adjacent to sulfoxides to form stable α-diazo-β-oxo sulfoxides has been achieved in cyclic systems.

Introduction of a benzenesulfonylmethyl group at the unactivated γ-carbon of carboxylic acid derivatives has been achieved through a combination of rhodium acetate catalysed carbenoid CH insertion and baker's yeast mediated kinetic resolution. Access to the two complementary enantiomeric series of 6 with excellent enantiocontrol is possible.

A novel manganese reagent, generated from KMnO4 and Me(3)SiCl, in the presence of a quaternary ammonium salt, is shown to smoothly dichlorinate alkenes, open epoxides and chemoselectively oxidise sulfides to sulfoxides. (C) 1997 Elsevier Science Ltd.

Efficient kinetic resolution of 2-benzenesulfonylcyclopentanones 1 , bearing 3-alkyl, 3-aryl, or 3-benzyl substituents, has been achieved by bakers' yeast mediated reduction. With the unsubstituted 2-benzenesulfonylcyclopentanone 1a , efficient asymmetric reduction to form (1 S ,2 R )- cis -2-benzenesulfonylcyclopentanol 2a is observed under the same conditions. Excellent enantioselectivities (up to > 95% ee) are obtained.

Efficient kinetic resolution of 2-benzenesulfonylcyclopentanones1, bearing 3-alkyl, 3-aryl, or 3-benzyl substituents, has been achieved by bakers' yeast mediated reduction. With the unsubstituted 2-benzenesulfonylcyclopentanone1a, efficient asymmetric reduction to form (1S,2R)-cis-2-benzenesulfonylcyclopentanol2a is observed under the same conditions. Excellent enantioselectivities (up to > 95% ee) are obtained.

The ability of phytosterol compounds to reduce plasma serum cholesterol levels in humans is well investigated. However, phytosterols are structurally similar to cholesterol with a double bond at the C5-6 position and are therefore susceptible to oxidation. Much research has been carried out on the biological effects of cholesterol oxidation products (COPs) in vitro. In contrast, there is less known about phytosterol oxidation products (POPs). From previous studies, it is apparent that oxidized derivatives of the phytosterols, β-sitosterol and stigmasterol, are cytotoxic in vitro but are less potent than their COP counterparts. In the present study, the cytotoxic and apoptotic potential of oxidized derivatives of dihydrobrassicasterol (DHB) including 5α,6α-epoxyergostan-3β-ol (α-epoxide), 5β,6β-epoxyergostan-3β-ol (β-epoxide), ergost-5-en-7-on-3β-ol (7-keto), ergost-5-ene-3β,7β-diol (7-β-OH), and ergostane-3β,5α,6β-triol (triol) were evaluated in the U937 and HepG2 cell lines. In general, 7-keto, 7-β-OH, and triol derivatives had a significant cytotoxic impact on U937 and HepG2 cells. The oxides appear to be more toxic toward U937 cells. In line with previous findings, the POPs investigated in this study were less potent than the equivalent COPs. The results add to the body of data on the toxicity of individual POPs.

The Diels–Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide, sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for stereoselective construction of Diels–Alder cycloadducts.

Dietary exposure to phytosterols has increased in recent years due to the incorporation of these compounds into cholesterol-lowering products. Previous studies have investigated the cytotoxic effects of the oxidized derivatives of β-sitosterol and determined that phytosterol oxidation products (POP) have a similar but less potent toxicity compared to their cholesterol equivalents. In the present study, the cytotoxicity of the oxidized derivatives of stigmasterol were investigated in the U937 cell line. The stigmasta-5,22-diene-3β,7β-diol (7β-OH), 5,6-epoxystigmasta-22,23-diol (epoxydiol), 5,6,22,23-diepoxystigmastane (diepoxide), and (22R,23R)-stigmast-5-ene-3β,22,23-triol (22R,23R-triol) derivatives were identified as the most cytotoxic, and the mode of cell death was identified as apoptosis in cells incubated with 7β-OH, epoxydiol, and diepoxide stigmasterol. The antioxidants α-tocopherol, γ-tocopherol, and β-carotene did not protect against apoptosis induced by 7β-OH and diepoxide stigmasterol; however, α-tocopherol was found to protect against epoxydiol-induced apoptosis. The cellular antioxidant, glutathione, was depleted and the apoptotic protein, Bcl-2, was down-regulated by the stigmasterol oxides identified as apoptotic.