Search

The reaction of enol esters with SelectFluor is facile and leads to the corresponding α-fluoroketones under mild conditions and, as a result, this route is commonly employed for the synthesis of medicinally important compounds such as fluorinated steroids. However, despite the use of this methodology in synthesis, the mechanism of this reaction and the influence of structure on reactivity are unclear. A rigorous mechanistic study of the fluorination of these substrates is presented, informed primarily by detailed and robust kinetic experiments. The results of this study implicate a polar two-electron process via an oxygen-stabilised carbenium species, rather than a single-electron process involving radical intermediates. The structure-reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of α-fluoroketones., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both cyclization processes can be performed under mild conditions allowing access to complex products rich in functionality. The cyclic systems are synthesized concisely (maximum four steps) from trifluoroethanol, an inexpensive fluorinated feedstock. more...

A novel 4-aminoindazole sulfonamide hit (13) was identified as a human CCR4 antagonists from testing a focussed library of compounds in the primary GTPγS assay. Replacing the indazole core with a pyrazolopyrimidine, and introduction of a methoxy group adjacent to the sulfonamide substituent, resulted in the identification of pyrazolopyrimidine 37a, which exhibited good binding affinity in the GTPγS assay (pIC 50 =7.2), low lipophilicity (clogP=2.2, chromlogD 7.4 =2.4), high LE (0.41), high solubility (CLND solubility ≥581µM), and an excellent PK profile in both the rat (F=62%) and the dog (F=100%). Further SAR investigation of the pyrazolopyrimidine suggested that substitution at N1 is tolerated, providing a suitable vector to modulate the properties, and increase the potency in a lead optimisation campaign., (Copyright © 2017 Elsevier Ltd. All rights reserved.) more...

Electronic structure calculations have been used for the effective triage of substituent effects on difluorinated vinylcyclopropane precursors and their ability to undergo vinyl cyclopropane rearrangements (VCPR). Groups which effectively stabilised radicals, specifically heteroarenes, were found to result in the lowest energy barriers. Ten novel precursors were synthesised to test the accuracy of computational predictions; the most reactive species which contained heteroarenes underwent thermal rearrangements at room temperature to afford novel difluorocyclopentenes and fluorinated benzocycloheptadienes through competing VCPR and [3,3]-rearrangement pathways, respectively. More controlled rearrangement of ethyl 3-(1'(2'2'-difluoro-3'-benzo[ d ][1,3]dioxol-5-yl)cyclopropyl)propenoate ( 22 ) allowed these competing pathways to be monitored at the same time and activation energies for both reactions were determined; E a(VCPR) = (23.4 ± 0.2) kcal mol -1 and E a([3,3]) = (24.9 ± 0.3) kcal mol -1 . Comparing our calculated activation energies with these parameters showed that no single method stood out as the most accurate for predicting barrier heights; (U)M05-2X/6-31+G* methodology remained the best for VCPR but M06-2X/6-31G* was better for the [3,3]-rearrangement. The consistency observed with (U)B3LYP/6-31G* calculations meant that it came closest to a universal method for dealing with these systems. The developed computational design model correctly predicted the observed selectivity of rearrangement pathways for both our system and literature compounds. more...

Palladium-catalysed coupling reactions based on a novel and easy-to-synthesise difluorinated organotrifluoroborate were used to assemble precursors to 6π-electrocyclisations of three different types. Electrocyclisations took place at temperatures between 90 and 240 °C, depending on the central component of the π-system; nonaromatic trienes were most reactive, but even systems that required the temporary dearomatisation of two arenyl subunits underwent electrocyclisation, albeit at elevated temperatures. Photochemical conditions were effective for these more demanding reactions. The package of methods delivered a structurally diverse set of fluorinated arenes, spanning a 20 kcal mol(-1) range of reactivity, by a flexible route., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [(125)I]-TARC binding assay with a pKi of 8.8, and the [(35)S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.) more...

Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile gave the turnover of the initial palladium(II) salt, whereas the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products, in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

Vinyl cyclopropane rearrangement (VCPR) has been utilised to synthesise a difluorinated cyclopentene stereospecifically and under mild thermal conditions. Difluorocyclopropanation chemistry afforded ethyl 3-(1'(2'2'-difluoro-3'-phenyl)cyclopropyl) propenoate as all four stereoisomers (18a, 18b, 22a, 22b) (all racemic). The trans-E isomer (18a), prepared in 70 % yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99 %). Rearrangements were monitored by (19) F NMR (100-180 °C). While cis/trans cyclopropane stereoisomerisation was facile, favouring trans-isomers by a modest margin, no E/Z alkene isomerisation was observed even at higher temperatures. Neither cis nor trans Z-alkenoates underwent VCPR, even up to much higher temperatures (180 °C). The cis-cyclopropanes underwent [3,3]-rearrangement to afford benzocycloheptadiene species. The reaction stereospecificity was explored by using electronic structure calculations, and UB3LYP/6-31G* methodology allowed the energy barriers for cyclopropane stereoisomerisation, diastereoisomeric VCPR and [3,3]-rearrangement to be ranked in agreement with experiment., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD₇.₄ <5.3 and CLND solubility >116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA₂ <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD₇.₄ (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation., (Copyright © 2014 Elsevier Ltd. All rights reserved.) more...

A DFT investigation into the mechanism for the decomposition of Grubbs 2nd generation pre-catalyst (2) in the presence of methanol, is presented. Gibbs free energy profiles for decomposition of the pre-catalyst (2) via two possible mechanisms were computed. We predict that decomposition following tricyclohexylphosphane dissociation is most favoured compared to direct decomposition of the pre-catalyst (2). However, depending on the reaction conditions, an on-pathway mechanism may be competitive with ruthenium hydride formation. more...

Experimental studies of the ring-closing metathesis reaction of 1,8-nonadiene and the ROMP reaction of cycloheptene show that the rate of isomerisation is not correlated to the initiation rate of the pre-catalyst, and that the absence of phosphine leads to a greatly increased rate of isomerisation. A range of pre-catalysts and solvents were probed and it is proposed that the isomerisation is mediated by a ruthenium hydride complex; our results are consistent with the rate-determining formation of such a species, which might be trapped in situ by tricyclohexylphosphane. more...

A knowledge-based library of aryl 2,3-dichlorophenylsulfonamides was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. X-ray diffraction studies were used to identify the pyrazole ring as a moiety that could bring about intramolecular hydrogen bonding with the sulfonamide NH and provide a clip or orthogonal conformation that was believed to be the preferred active conformation. Replacement of the core phenyl ring with a pyridine, and replacement of the 2,3-dichlorobenzenesulfonamide with 5-chlorothiophenesulfonamide provided compound 33 which has excellent physicochemical properties and represents a good starting point for a lead optimisation programme. Electronic structure calculations indicated that the preference for the clip or orthogonal conformation found in the small molecule crystal structures of 7 and 14 was in agreement with the order of potency in the biological assay. more...

Dispersion corrected density functional theory (DFT-D) has been applied to understand the performance of several palladium metal scavengers. Nine different sulfur-based ligands and three different palladium metal sets have been investigated in detail. Based on a thorough analysis of the thermodynamic binding parameters ΔH, ΔG and ΔS, we have identified the best binding modes for all scavenger ligands. Bis-monodentate coordination is favoured over chelation in ΔH and ΔG values for most of the scavenger ligands. Special attention has been paid to the ligand strain energies, which account for the structural changes of the ligands upon complexation indicating that small (5-membered) chelates are considerably less favourable than expected. Some ligands can use their longest chain (>7-atoms) to yield trans chelates, which ligands with shorter chains (≤6-atoms) are unable to form. A secondary amino nitrogen (RR'NH) is found to be the best donor with highest binding enthalpy for Pd(ii) metal systems. In terms of the strength of the initial binding interactions, -SMe > -SH; capping thiols (-SH) as thioethers (-SMe) is therefore suggested to be an effective strategy in scavenger design. These observations mark the beginning of a knowledge base of the full range of possible interactions, leading to the construction of a sulfur ligand database for the design of scavenger systems. more...

Esters of crotonic acid were brominated on a multigramme scale using a free radical procedure. A phase transfer catalysed fluorination transformed these species to the 4-fluorobut-2E-enoates reproducibly and at scale (48-53%, ca. 300 mmol). Asymmetric dihydroxylation reactions were then used to transform the butenoate, ultimately into all four diastereoisomers of a versatile fluorinated C4 building block at high enantiomeric-enrichment. The (DHQ)2AQN and (DHQD)2AQN ligands described by Sharpless were the most effective. The development and optimisation of a new and facile method for the determination of ee is also described; (19)F{(1)H} spectra recorded in d-chloroform/diisopropyl tartrate showed distinct baseline separated signals for different enantiomers. more...

The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration. Electronic structure calculations have shown that the order of events involves chalcogen atom attack at sp(3) carbon and alkyl-oxygen cleavage. The critical role of acid catalysis was shown clearly, and the importance of acid strength was demonstrated. The calculated barriers were also fully consistent with the observed order of thioamide and amide reactivity. Spontaneous ring opening involves a modest degree of C-O cleavage, moderating the extent of strain relief. On the acid-catalysed pathway, C-O cleavage is less extensive still, but proton transfer to the nucleofuge is well advanced with the carboxylic acid catalysts, and essentially complete with methanesulfonic acid., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

Initiation rates for Grubbs and Grubbs-Hoveyda second generation pre-catalysts have been measured accurately in a range of solvents. Solvatochromic fitting reveals different dependencies on key solvent parameters for the two pre-catalysts, consistent with different mechanisms by which the Grubbs and Grubbs-Hoveyda pre-catalysts initiate. more...

A recently developed method for the near-ambient generation of difluorovinylzinc reagents has facilitated the preparation of 1-(N,N-diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene and 2,2-difluoro-1-iodo-1-(2'-methoxyethoxymethoxy)ethene. The utility of these reagents has been investigated in Suzuki-Miyaura couplings with a range of potassium trifluoroborate coupling partners, with the scope of successful couplings proving wide. Deiodinated species appeared as significant side products, but a solvent change from i-PrOH to t-BuOH suppressed the pathway to these species and improved coupling yields. more...

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control. more...

Difluoroalkenylzinc reagents prepared from 1-(2'-methoxy-ethoxymethoxy)-2,2,2-trifluoroethane and 1-(N,N-diethylcarbamoyloxy)-2,2,2-trifluoroethane at ice bath temperatures underwent Negishi coupling with a range of aryl halides in a convenient one pot procedure. While significant differences between the enol acetal and carbamate reagents were revealed, the Negishi protocol compared very favourably with alternative coupling procedures in terms of overall yields from trifluoroethanol. more...

The thermodynamic effective molarities of a series of simple cycloalkenes, synthesised from α,ω-dienes by reaction with Grubbs' second generation precatalyst, have been evaluated. Effective molarities were measured from a series of small scale metathesis reactions and agreed well with empirical predictions derived from the number of rotors and the product ring strain. The use of electronic structure calculations (at the M06-L/6-311G** level of theory) was explored for predicting thermodynamic effective molarities in ring-closing metathesis. However, it was found that it was necessary to apply a correction to DFT-derived free energies to account for the entropic effects of solvation., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

A published model for revealing solvent effects on the ring-closing metathesis (RCM) reaction of diethyl diallylmalonate 7 has been evaluated over a wider range of conditions, to assess its suitability for new applications. Unfortunately, the model is too flexible and the published rate constants do not agree with experimental studies in the literature. However, by fixing the values of important rate constants and restricting the concentration ranges studied, useful conclusions can be drawn about the relative rates of RCM of different substrates, precatalyst concentration can be simulated accurately and the effect of precatalyst loading can be anticipated. Progress has also been made toward applying the model to precatalyst evaluation, but further modifications to the model are necessary to achieve much broader aims. more...

Density function theory calculations reveal that the Grubbs-Hoveyda olefin metathesis pre-catalyst is activated by the formation of a complex in which the incoming alkene substrate and outgoing alkoxy ligand are both clearly associated with the ruthenium centre. The computed energies for reaction are in good agreement with the experimental values, reported here., (© The Royal Society of Chemistry 2011) more...

The potential energy surfaces for ring-closing metathesis reactions of a series of simple α,ω-dienes which lead to 5-10 membered ring products, have been explored using density functional theory methods. We have investigated both the conformational aspects of the hydrocarbon chain during the course of the reactions, as well as the stationary structures on the corresponding potential energy surfaces. Extensive conformational searches reveal that the reaction proceeds via the conformation that would be expected for the cycloalkene product, though most unexpectedly, cyclohexene forms via complexes in boat-like conformations. The M06-L density functional has been used to map out the potential energy surfaces, and has identified metallocyclobutane fragmentation as being generally the highest barrier along the pathway. The structural variations along the pathway have been discussed for the reactant hydrocarbons of differing chain length to identify points at which cyclisation events may begin to affect reaction rates. Our study provides an excellent starting point from which to begin to learn about the way RCM reaction outcomes are controlled by diene structure. more...

In the RCM reactions of a series of simple α,ω-dienes, the relative order of reactivity has been unambiguously determined showing that cyclohexene forms faster than cyclopentene or cycloheptene. 1,5-Hexadiene inhibits the RCM of 1,7-octadiene; 1,5-hexadiene cannot progress to the RCM product (cyclobutene) but forms an unexpectedly stable cyclic η(2)-complex. more...

Difluorinated cyclohexene diols (prepared from trifluoroethanol) can be elaborated to racemic analogues of phosphorylated sugars via regioselective protection and phosphorylation of the exposed C-1 hydroxyl group. Cis-diol protection was achieved using stannylene methodology, though the regioselectivity depended on the orientation of the methyl group at C-5. UpJohn dihydroxylation is effective with the phosphotriester in place and global deprotection to the tetrol monophosphates is efficient. more...

The cycloaddition reaction of acylketenes with vinyl ethers affords an extremely direct route to 2,6-dideoxysugars and their methyl ethers. The lithium enolate of commercial 2,6,6-trimethyldioxinone 3 was fluorinated in good yield to afford fluorinated dioxinone 8. An illustrative range of fluorinated 2,6-dideoxysugar derivatives was prepared via the acetyl ketene-vinyl ether cycloadduct. Electronic structure calculations were carried out to investigate the effect of the fluorine atom on ease of formation and subsequent reaction of the (fluoroacetyl)ketene reactive intermediate. A single fluorine atom lowers the barrier to fragmentation by ca. 7.5 kJ mol(-1), consistent with experimental findings, but has almost no effect on the barrier to rate determining vinyl ether addition, or to oxoketene dimerisation. more...

A series of selectively fluorinated and other substituted UDP-D-galactose derivatives have been evaluated as substrates for Klebsiella pneumoniae UDP-D-galactopyranose mutase. This enzyme, which catalyses the interconversion of the pyranose and furanose forms of galactose as its UDP adduct, is a prospective drug target for a variety of microbial infections. We show that none of the 2''-, 3''- or 6''-hydroxyl groups of UDP-D-galactopyranose are essential for substrate binding and turnover. However, steric factors appear to play an important role in limiting the range of substitutions that can be accommodated at C-2'' and C-6'' of the sugar nucleotide substrate. Attempts to invert the C-2'' stereochemistry from equatorial to axial, changing D-galacto- to D-talo-configuration, in an attempt to exploit the higher percentage of furanose at equilibrium in the talo-series, met with no turnover of substrate. more...

Free radical bromination and nucleophilic fluorination allows the conversion of methyl sorbate into the 6-fluoro analogue which undergoes sequential asymmetric dihydroxylation reactions. A range of 6-deoxy-6-fluorosugars were prepared by using different combinations of ligands. While the enantiomeric excesses obtained were comparable to those from other 6-substituted sorbates, the regioselectivity of dihydroxylation was moderate, with both 2,3- and 4,5-diols being obtained. A successful temporary persilylation strategy was evolved to convert the products of dihydroxylation rapidly to the fluorosugars 6-deoxy-6-fluoro-L-idose, 6-fluoro-L-fucose and 6-deoxy-6-fluoro-D-galactose, which were obtained in overall yields of 4%, 6% and 8% from methyl 6-fluoro-hexa-2E,4E-dienoate . more...

Studies of a range of reactions forming cyclooctenones highlight a discrepancy between cyclization rate and cyclization efficiency. Cyclization rates change modestly as the oxygen function at the allylic position is varied, and increase upon gem-dimethylation. Cyclization efficiency has also been quantified for four substrates, revealing a range of effective molarities (EMs) of 2 orders of magnitude that are substituent dependent. The most efficient cyclization appears to result from suppression of the cross-metathesis pathway through which oligomerization begins, rather than from a particularly rapid cyclization reaction. In the presence of a Ti(IV) cocatalyst, diene monomers transform smoothly to eight-membered-ring products without the intermediacy of dimers or other oligomers, indicating that the cyclizations are kinetically and not thermodynamically controlled. The gem-dialkyl effect is also shown to be kinetic. more...

Trifluoroethanol has been elaborated, via a telescoped sequence involving a metalated difluoroenol, a difluoroallylic alcohol, [2,3]-Wittig rearrangement, and ultimately an RCM reaction and requiring minimal intermediate purification, to a number of cyclooctenone intermediates. Epoxidation of these intermediates followed by transannular ring opening or dihydroxylation, then transannular hemiacetalization delivers novel bicyclic analogues of pentopyranoses, which were elaborated (in one case) to an analogue of a glycosyl phosphate. more...

A simple enol acetal underwent rapid cleavage in acidic solution to generate a difluorinated enol, which was sufficiently long-lived to be characterized by 2D NMR in a protic solvent at ambient temperature. Density functional theory calculations on a model reaction suggest that there are significant differences in protonation transition state timing between the fluorinated and nonfluorinated enols. more...

Difluorinated alkenoate ethyl 3,3-difluoro-2-(N,N-diethylcarbamoyloxy)-2-propenoate reacts rapidly and in high yield with furan and a range of substituted furans in the presence of a tin(IV) catalyst. Non-fluorinated congener 2-(N,N-diethylcarbamoyloxy)-2-propenoate fails to react at all under the same conditions. These reactions have been explored using density functional theory (DFT) calculations. They reveal a highly polar transition state, which is stabilized by the Lewis acid catalyst SnCl(4) and by polar solvents. In the presence of both catalyst and solvent, a two-step reaction is predicted, corresponding to the stepwise formation of the two new carbon-carbon bonds via transition states which have similar energies in all cases. Our experimental observations of the lack of reaction of the non-fluorinated dienophile, the stereochemical outcomes, and the rate acceleration accompanying furan methylation are all well predicted by our calculations. The calculated free energy barriers generally correlate well with measured reaction rates, supporting a reaction mechanism in which zwitterionic character is developed strongly. An in situ ring opening reaction of exo-cycloadduct ethyl exo-2-(N,N-diethylcarbamoyloxy)-3,3-difluoro-7-oxabicyclo[2.2.1]hept-5-enyl-2-endo-carboxylate, which results in the formation of cyclic carbonate ethyl 4,4-difluoro-5-hydroxy-2-oxo-5,7a-dihydro-4H-benzo[1,3]dioxole-3a-carboxylate by a Curtin-Hammett mechanism, has also been examined. Substantial steric opposition to Lewis acid binding prevents carbonate formation from 2-substituted furans. more...

A difluorinated dienophile underwent cycloaddition reactions with a range of furans to afford cycloadducts which could be processed regio- and stereoselectively via episulfonium ions, generated by the reaction between their alkenyl groups and phenylsulfenyl chloride. The oxabicyclic products were oxidised to the phenylsulfonyl level and ring opened via E1(C)B or reductive desulfonative pathways to afford, ultimately, difluorinated cyclohexene or cyclohexane polyols. more...

Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT (19)F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers. more...

Direct precursors to analogues of pentopyranoses, 6-deoxyhexoses, and hexoses, in which a CF(2) center replaces the pyranose oxygen, have been synthesized rapidly from trifluoroethanol. A simple scaleable allylation reaction delivers ethers which undergo dehydrofluorination/metalation, followed by addition to either acrolein or cinnamaldehyde, to afford allylic alcohols. Fluorine-assisted [3,3]-rearrangement followed by reduction with sodium borohydride delivers diols, which undergo RCM smoothly to afford cyclohexene diols. more...

A (bromodifluoromethyl)alkyne has been deployed in a stereoselective route to difluorinated aldonic acid analogues, in which a Sharpless asymmetric dihydroxylation reaction and diastereoisomer separation set the stage for phenyl group oxidation. more...

Difluorinated analogues of (hydroxymethyl)conduritols can be synthesised from selected furans and a difluorinated dienophile in two reaction steps.

Topologically mobile difluorinated cyclooctenones undergo rapid, high-yielding, and completely stereoselective epoxidations with methyl(trifluoromethyl)dioxirane. The epoxides resist conventional hydrolysis but react smoothly in basic media under microwave irradiation to afford unique hemiacetals and hemiaminals in good yield. [reaction: see text] more...

A difluorodienophile, synthesised using a Stille coupling reaction underwent tin(iv)-catalysed cycloaddition with three furans to afford oxa[2.2.1]bicycloheptenes in good yield. Reduction of ester and carbamate carbonyl groups and diol protection as the acetonide set the stage for palladium-catalysed hydrostannylation in two cases. Treatment of the stannanes with methyllithium triggered ring-opening to afford highly-functionalised difluorinated cyclohexenols which could be deprotected to afford (hydroxymethyl)conduritol analogues. more...

4-Deoxy-4,4-difluoro-glycosides have been synthesised for the first time via a direct sequence involving ring-closing metathesis and indium-mediated difluoroallylation with 1-bromo-1,1-difluoropropene in water. Two protecting group strategies were explored, one to allow protection of the primary C-6 hydroxyl group throughout the sequence, while the second was intended to allow deprotection after RCM and before dihydroxylation. The benzyl ether could be used in the first role, and pivaloyl is effective in the second. Dihydroxylations were highly stereoselective and controlled by the orientation of the glycosidic C-O bond. more...

Difluorinated cyclooctenones, synthesised using RCM, can be used as templates for stereoselective oxidative transformations to products that undergo transannular reactions to afford conformationally-locked analogues of 2-deoxy-2,2-difluorosugars with different stereochemical relationships between the C-2 and C-3 hydroxyl groups. more...

Metallated haloalkenes were used to open epoxides in moderate to good yield. The homoallylic alcohols obtained underwent Swern oxidation to afford three gamma,gamma-difluorinated beta,gamma-enones, which reacted with either vinyllithium,2-lithio-2H-dihydropyran or another metallated haloalkene to afford substituted trans-1,2-divinylcyclohexanols of different degrees of stability. These intermediates underwent neutral thermal oxy-Cope rearrangements when heated in xylene in Ace tubes. The first-formed enols ketonised without loss of HF to afford a range of cyclodecenones in moderate to good yield; X-ray crystallography was used extensively for product characterisation. All substrates rearranged more rapidly than a cis/trans mixture of 1,2-divinylcyclohexanols. more...

[reaction: see text] A new route, of potential strategic importance, to a difluorosugar analogue has been developed. Key steps included a Stille coupling and a highly regio- and enantioselective dihydroxylation of a highly substituted diene. Protecting groups were chosen to enhance the reactivity of the disubstituted allylic fragment in the AD reaction and allow deprotection under orthogonal conditions. more...

Phenylsulfenyl chloride reacts with racemic endo Diels-Alder adduct 4 (DEC = CONEt(2)) to afford lactone 8, which can be reduced and protected in a series of high-yielding steps. Key sulfone 10 can be ring opened under strong base conditions to afford vinyl sulfone 11. Attempted desulfonation resulted in the formation of a monofluoroalkene, but a direct desulfonation/eliminative ring opening with strain relief delivered highly functionalized monocyclic species 16. [reaction: see text] more...

Diels-Alder and conjugate addition reactions were used to prepare precursors to a range of fully functionalized and deoxy inositol phosphate analogues.

Building block methodology from trifluoroethanol and ring-closing metathesis using a Fürstner modification of Grubbs' conditions allows the rapid synthesis of novel difluorinated cyclooctenones.

[reaction: see text]. Two consecutive palladium-catalyzed coupling reactions from a readily available difluoroenol stannane set the stage for the synthesis of a range of difluoro- and halodifluoromethyl ketones upon a variable aryl template. more...

Chromaffin-granule membranes contain two ATPases, which can be separated by (NH4)2SO4 fractionation after solubilization with detergents, or by phase segregation in Triton X-114. ATPase I (Mr 400000) is inhibited by trialkyltin, quercetin and alkylating agents, and hydrolyses both ATP and ITP. It contains up to five types of subunit, including a low-Mr hydrophobic polypeptide that reacts with dicyclohexylcarbodi-imide; these subunits are unrelated to those of mitochondrial F1F0-ATPase, as judged by size and reaction with antibodies. ATPase II (Mr 140000) is inhibited by vanadate, and is specific for ATP; it has not been extensively purified. Proton translocation by resealed chromaffin-granule 'ghosts', measured by uptake of methylamine or by quenching of the fluorescence of 9-amino-6-chloro-2-methoxyacridine, is supported by the hydrolysis of ATP or ITP, and inhibited by quercetin or alkylating agents, but not by vanadate. ATPase I must therefore be the proton translocator involved in the uptake of catecholamines and possibly of other components of the chromaffin-granule matrix, whereas ATPase II does not translocate protons. more...

Proteins exposed on the cytoplasmic face of isolated chromaffin granules were labelled by lactoperoxidase-catalysed radioiodination and by non-enzymic biotinylation. Granule membranes were then prepared, and the H+-translocating ATPase isolated by fractionation with Triton X-114. The labelling of individual ATPase subunits was assessed by polyacrylamide-gel electrophoresis, followed by autoradiography or by blotting and decoration with 125I-labelled streptavidin. Subunits of 72, 57 and kDa were strongly labelled, and could be removed from the membrane at pH 11: they are therefore extrinsic proteins. The 120 kDa subunit was also labelled, but it was not solubilized at pH 11. Photolabelling with a hydrophobic probe indicated that this subunit penetrates the bilayer, and enzymic degradation studies showed the presence of N-linked oligosaccharides; this subunit therefore spans the chromaffin-granule membrane. Labelling of the 17 kDa subunit occurred predominantly on the extracytoplasmic (matrix) face of the granule membrane. These results are consistent with this V-type ATPase having a structure that is generally similar to that of mitochondrial (F-type) ATPases, although the attachment of the 120 kDa subunit may be asymmetrical. more...

The proton-translocating adenosine triphosphatase (ATPase) of bovine chromaffin granules contains up to five different polypeptides. Its activity is inhibited by N-ethylmaleimide, and ATP protects the enzyme from inhibition. After treatment of membranes with N-[2-3H]ethylmaleimide, only one polypeptide is strongly radiolabelled: this is the largest (70 kDa) subunit of the proton-translocating ATPase. This subunit therefore contains the ATP-hydrolysing site. Two-dimensional electrophoresis reveals heterogeneity in this polypeptide. more...