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1.
Chemistry ; 25(21): 5574-5585, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30724406

RESUMO

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.

2.
J Org Chem ; 83(16): 8888-8905, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29978696

RESUMO

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.

3.
Bioorg Med Chem ; 25(20): 5327-5340, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28801066

RESUMO

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 (pIC50=7.2), low lipophilicity (clogP=2.2, chromlogD7.4=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.


Assuntos
Receptores CCR4/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
4.
Chemistry ; 22(34): 12166-75, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27415819

RESUMO

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.

5.
Eur J Med Chem ; 115: 14-25, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26991939

RESUMO

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.


Assuntos
Endocitose/efeitos dos fármacos , Pirimidinas/farmacologia , Receptores CCR4/antagonistas & inibidores , Compostos de Espiro/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores CCR4/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
6.
Chem Sci ; 7(10): 6369-6380, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28451092

RESUMO

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; Ea(VCPR) = (23.4 ± 0.2) kcal mol-1 and Ea([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.

7.
Chemistry ; 21(52): 19119-27, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26564395

RESUMO

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.

8.
Chemistry ; 20(44): 14305-16, 2014 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-25212120

RESUMO

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.


Assuntos
Ciclopentanos/química , Ciclopentanos/síntese química , Compostos de Vinila/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Isomerismo , Estereoisomerismo , Termodinâmica
9.
Bioorg Med Chem ; 22(15): 4298-311, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24909677

RESUMO

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.


Assuntos
Benzimidazóis/química , Receptores CCR4/antagonistas & inibidores , Sulfonamidas/química , Compostos Aza/química , Humanos , Indazóis/química , Ligação Proteica , Receptores CCR4/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
10.
Dalton Trans ; 43(22): 8493-8, 2014 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-24756359

RESUMO

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.

11.
Org Biomol Chem ; 12(11): 1779-92, 2014 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-24515101

RESUMO

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.


Assuntos
Pirazóis/química , Receptores CCR4/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Regulação Alostérica , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
12.
Dalton Trans ; 43(12): 4674-9, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24488325

RESUMO

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.


Assuntos
Alcenos/química , Fosfinas/química , Rutênio/química , Catálise , Isomerismo
13.
Dalton Trans ; 43(2): 469-78, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24113810

RESUMO

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.

14.
Beilstein J Org Chem ; 9: 2660-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24367430

RESUMO

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.

15.
Chemistry ; 19(29): 9655-62, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23765429

RESUMO

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.


Assuntos
Carbono/química , Calcogênios/química , Éteres Cíclicos/química , Oxazóis/síntese química , Oxigênio/química , Tiazóis/síntese química , Tioamidas/síntese química , Catálise , Computadores Moleculares , Micro-Ondas , Oxazóis/química , Solventes , Tiazóis/química , Tioamidas/química
16.
Dalton Trans ; 42(12): 4110-3, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23183998

RESUMO

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.


Assuntos
Alcenos/química , Solventes/química , Catálise , Complexos de Coordenação/química , Rutênio/química
17.
J Org Chem ; 77(15): 6384-93, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22769401

RESUMO

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.


Assuntos
Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Iodados/síntese química , Temperatura , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Iodados/química , Estrutura Molecular , Estereoisomerismo
18.
J Org Chem ; 77(2): 991-8, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22148579

RESUMO

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.


Assuntos
Compostos de Flúor/síntese química , Nortropanos/síntese química , Alcaloides de Solanáceas/síntese química , Compostos de Flúor/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Nortropanos/química , Alcaloides de Solanáceas/química , Estereoisomerismo , Termodinâmica
19.
Org Biomol Chem ; 9(24): 8328-39, 2011 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22064968

RESUMO

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.


Assuntos
Hidrocarbonetos Fluorados/química , Compostos Organometálicos/síntese química , Temperatura , Trifluoretanol/química , Estrutura Molecular , Compostos Organometálicos/química , Estereoisomerismo
20.
Chemistry ; 17(46): 13087-94, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-21971759

RESUMO

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.


Assuntos
Cicloparafinas/química , Algoritmos , Catálise , Ciclização , Cicloparafinas/síntese química , Dimerização , Estrutura Molecular , Termodinâmica
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