81 results found
Higham J, Bull J, 2022, Amine-Catalyzed Copper-Mediated C–H Sulfonylation of Benzaldehydes via a Transient Imine Directing Group, Angewandte Chemie International Edition, ISSN: 1433-7851
Transient directing groups (TDGs) can provide a powerful means for C–H functionalization without requiring additional steps for directing group introduction and removal. We report the first use of a TDG in combination with copper to effect C–H functionalization. The regioselective copper mediated beta–C(sp2)–H sulfonylation of aldehydes with sulfinate salts is accomplished using catalytic β-alanine to form a transient imine. A broad range of sulfonylated benzaldehydes are prepared using copper fluoride as both copper source and oxidant, involving a [5,6] cupracyclic intermediate. gamma-(peri)-Sulfonylation of napthyl and phenanthrenyl carboxaldehydes is achieved through [6,6] cupracyclic intermediates. Further derivatisation of the aldehyde products is demonstrated. Kinetic experiments and Hammett analysis suggest the turnover limiting step to be a concerted asynchronous C–H cleavage via a dearomative Wheland-type transition state.
Greed S, Symes O, Bull J, 2022, Stereospecific Reaction of Sulfonimidoyl Fluorides with Grignard Reagents for the Synthesis of Enantioenriched Sulfoximines, Chemical Communications, ISSN: 1359-7345
Sulfonimidoyl halides have previously shown poor stability and selectivity in reaction with organometallic reagents. Here we report the preparation of enantioenriched sulfonimidoyl fluorides and their stereospecific reaction at sulfur with Grignard reagents. Notably the first enantioenriched alkyl sulfonimidoyl fluorides are prepared, including methyl. The nature of the N-group is important to the success of the stereocontrolled sequence to sulfoximines.
Rojas Munoz J, Torrisi E, Dubois M, et al., 2022, Oxetan-3-ols as 1,2-bis-Electrophiles in a brønsted acid catalyzed synthesis of 1,4-Dioxanes, Organic Letters, Vol: 24, ISSN: 1523-7052
Annulations that combine di-acceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles, and 1,2-diols. Brønsted acid Tf2NH catalyzes both the selec-tive activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring-opening of the oxetane. High regio and diastereoselectivity is achieved with unsymmetrical diols. The substituted dioxanes and fused bicyclic products present interesting motifs for drug discovery and can be further functionalized.
Piticari A-S, Antermite D, Higham J, et al., 2022, Stereoselective palladium-catalyzed C(sp3)–H mono-arylation of piperidines and tetrahydropyrans with a C(4) directing group, Advanced Synthesis and Catalysis, Vol: 364, ISSN: 1615-4150
A selective Pd-catalyzed C(3)–H cis-functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono- and cis-selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other reported heterocycle C(sp3)–H functionalization reactions, which is facilitated by a DoE optimization. A one-pot C–H functionalization-epimerization procedure provides the trans-3,4-disubstituted isomers directly. Divergent aminoquinoline removal is accomplished with the installation of carboxylic acid, alcohol, amide and nitrile functional groups. Overall fragment compounds suitable for screening are generated in 3-4 steps from readily-available heterocyclic carboxylic acids.
Rojas J, Croft R, Sterling A, et al., 2022, Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides, Nature Chemistry, Vol: 14, Pages: 160-169, ISSN: 1755-4330
Bioisosteres provide valuable design elements for medicinal chemists to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides, an extremely common pharmacophore, but are rarely examined due to the lack of available synthetic methods. Here, we describe a new class of reactions for sulfonyl fluorides to form aminooxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate determining step, followed by a chemoselective nucleophile coupling step.
Rojas J, Bull J, 2022, Oxetanes and Oxetenes—Monocyclic, Comprehensive Heterocyclic Chemistry IV, Pages: 212-212
Dubois M, Croft R, Ding Y, et al., 2021, Investigating 3,3-diaryloxetanes as potential bioisosteres through matched molecular pair analysis, RSC Medicinal Chemistry, Vol: 12, Pages: 2045-2052, ISSN: 2632-8682
Oxetanes have received increasing interest in medicinal chemistry as attractive polar and low molecular weight motifs. The application of oxetanes as replacements for methylene, methyl, gem-dimethyl and carbonyl groups has been demonstrated to often improve chemical properties of target molecules for drug discovery purposes. The investigation of the properties of 3,3-diaryloxetanes, particularly of interest as a benzophenone replacement, remains largely unexplored. With recent synthetic advances in accessing this motif we studied the effects of 3,3-diaryloxetanes on the physicochemical properties of ‘drug-like’ molecules. Here, we describe our efforts in the design and synthesis of a range of drug-like compounds for matched molecular pair analysis to investigate the viability of the 3,3-diaryloxetane motif as a replacement group in drug discovery. We conclude that the properties of the diaryloxetanes and ketones are similar, and generally superior to related alkyl linkers, and that diaryloxetanes provide a potentially useful new design element.
Craven GB, Briggs EL, Zammit CM, et al., 2021, Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides, The Journal of Organic Chemistry, Vol: 86, Pages: 7403-7424, ISSN: 0022-3263
Boddy A, Bull J, 2021, Stereoselective synthesis and applications of spirocyclic oxindoles, Organic Chemistry Frontiers, Vol: 8, Pages: 1026-1084, ISSN: 2052-4110
The development of novel synthetic strategies to form new chemical entities in a stereoselective manner is an ongoing significant objective in organic and medicinal chemistry. This review analyses the development of new stereoselective approaches to spirocyclic oxindoles with spiro-(3- to 8-membered rings). It highlights the importance of these structures for applications in medicinal chemistry, as intermediates or final products in total synthesis and as model compounds for the development of enantioselective catalytic methodologies.
Tota A, Colella M, Carlucci C, et al., 2021, N−N Bond Formation Using an Iodonitrene as an Umpolung of Ammonia: Straightforward and Chemoselective Synthesis of Hydrazinium Salts, Advanced Synthesis and Catalysis, Vol: 363, Pages: 194-199, ISSN: 1615-4150
The formation of hydrazinium salts by N−N bond formation has typically involved the use of hazardous and difficult to handle reagents. Here, mild and operationally simple conditions for the synthesis of hydrazinium salts are reported. Electrophilic nitrogen transfer to the nitrogen atom of tertiary amines is achieved using iodosylbenzene as oxidant and ammonium carbamate as the N-source. The resulting process is highly chemoselective and tolerant to other functional groups. A wide scope is reported, including examples with bioactive molecules. Insights on the structure of hydrazinium salts were provided by X-ray analysis. (Figure presented.).
Greed S, Briggs E, Idiris F, et al., 2020, Synthesis of highly enantioenriched sulfonimidoyl fluorides and sulfonimidamides by stereospecific SuFEx reaction, Chemistry: A European Journal, Vol: 26, Pages: 12533-12538, ISSN: 0947-6539
Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, NBoc-sulfinamide salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemized by fluoride ions. Conditions are developed which trap fluoride, and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100% es) generating sulfonimidamides with up to 99% ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalization reactions, exemplified by coupling with a selection of complex amines in marketed drugs.
Higham J, Bull JA, 2020, Transient imine directing groups for the C–H functionalisation of aldehydes, ketones and amines: an update 2018-2020, Organic and Biomolecular Chemistry, Vol: 18, Pages: 7291-7315, ISSN: 1477-0520
The use of pre-installed directing groups has become a popular and powerful strategy to control site selectivity in transition metal catalysed C–H functionalisation reactions. However, the necessity for directing group installation and removal reduces the efficiency of a directed C–H functionalisation method. To overcome this limitation, taking inspiration from organocatalytic methodologies, the use of transient directing groups has arisen. These methods allow for a transient ligand to be used, potentially in catalytic quantities, without the need for discrete installation or removal steps, enabling the discovery of more efficient, and mechanistically intriguing, dual catalytic methods. This review summarises recent developments in this fast moving field covering >70 new methodologies, highlighting new directing group designs and advances in mechanistic understanding. It covers progress since 2018, providing an update to our previous review of the field.
Green SP, Wheelhouse KM, Payne AD, et al., 2020, On the Use of Differential Scanning Calorimetry for Thermal Hazard Assessment of New Chemistry: Avoiding Explosive Mistakes, Angewandte Chemie International Edition, Vol: 59, Pages: 15798-15802, ISSN: 1433-7851
Dubois MAJ, Smith MA, White AJP, et al., 2020, Short Synthesis of Oxetane and Azetidine 3-Aryl-3-carboxylic Acid Derivatives by Selective Furan Oxidative Cleavage, Organic Letters, Vol: 22, Pages: 5279-5283, ISSN: 1523-7060
Coleman JA, Navratna V, Antermite D, et al., 2020, Chemical and structural investigation of the paroxetine-human serotonin transporter complex, eLife, Vol: 9, ISSN: 2050-084X
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
Tota A, Carlucci C, Pisano L, et al., 2020, Synthesis of glycosyl sulfoximines by a highly chemo- and stereoselective NH- and O-transfer to thioglycosides, Organic & Biomolecular Chemistry, Vol: 18, Pages: 3893-3897, ISSN: 1477-0520
<p>The first highly stereoselective sulfoximine formation directly from sulfides is achieved in the preparation of unprecedented glycosyl sulfoximines. X-ray analysis and a computational model establish the configuration at sulfur.</p>
Higham J, Bull JA, 2020, Copper catalysed oxidative α-sulfonylation of branched aldehydes using the acid enhanced reactivity of manganese(IV) oxide, Chemical Communications, Vol: 56, Pages: 4587-4590, ISSN: 1359-7345
The oxidative coupling of secondary aldehydes and sulfinate salts is achieved using copper catalysis to form a-sulfonyl aldehydes. The use of an acidic co-solvent is important to adjust the oxidation potential of MnO2 as oxidant. A broad range of sulfonylated aldehydes is prepared, and their further functionalisation is demonstrated. A dual ionic/radical pathway mechanism is proposed.
St John-Campbell S, White AJP, Bull JA, 2020, Methylene C(sp<sup>3</sup>)–H β,β′-Diarylation of Cyclohexanecarbaldehydes Promoted by a Transient Directing Group and Pyridone Ligand, Organic Letters, Vol: 22, Pages: 1807-1812, ISSN: 1523-7060
Green S, Wheelhouse K, Payne A, et al., 2020, Thermal stability and explosive hazard assessment of diazo compounds and diazo transfer reagents, Organic Process Research and Development, Vol: 24, Pages: 67-84, ISSN: 1083-6160
Despite their wide use in academia as metal-carbene precursors, diazo compounds are often avoided in industry owing to concerns over their instability, exothermic decomposition and potential explosive behaviour. The stability of sulfonyl azides and other diazo-transfer reagents is relatively well understood, but there is little reliable data available for diazo compounds. This work firstly collates available sensitivity and thermal analysis data for diazo-transfer reagents and diazo compounds to act as an accessible reference resource. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and accelerating rate calorimetry (ARC) data for the model donor/acceptor diazo compound ethyl (phenyl)diazoacetate is presented. We also present a rigorous DSC dataset with 43 other diazo compounds, enabling direct comparison to other energetic materials to provide a clear reference work to the academic and industrial chemistry communities. Interestingly, there is a wide range of onset temperatures (Tonset) for this series of compounds which varied between 75 and 160 °C. The thermal stability variation depends on the electronic effect of substituents and the amount of charge delocalisation. A statistical model is demonstrated to predict the thermal stability of differently substituted phenyl diazoacetates. A maximum recommended process temperature (TD24) to avoid decomposition is estimated for selected diazo compounds. Average enthalpy of decomposition (∆HD) for diazo compounds without other energetic functional groups is −102 kJ mol−1. Several diazo transfer reagents are analyzed using the same DSC protocol and found to have higher thermal stability, which is in general agreement with reported values. For sulfonyl azide reagents an average ∆HD of −201 kJ mol−1 is observed. High quality thermal data from ARC experiments shows the initiation of decomposition for ethyl (phenyl)diazoacetate to be 60 °C , compared to 100 °C for t
Brown P, Tan A-C, El-Esawi MA, et al., 2019, Large expert-curated database for benchmarking document similarity detection in biomedical literature search, Database: the journal of biological databases and curation, Vol: 2019, Pages: 1-66, ISSN: 1758-0463
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.
Antermite D, Bull JA, 2019, Transition Metal-Catalyzed Directed C(sp(3))-H Functionalization of Saturated Heterocycles, SYNTHESIS-STUTTGART, Vol: 51, Pages: 3171-3204, ISSN: 0039-7881
Croft RA, Dubois MAJ, Boddy AJ, et al., 2019, Catalytic Friedel-Crafts Reactions on Saturated Heterocycles and Small Rings for sp<sup>3</sup>-sp<sup>2</sup> Coupling of Medicinally Relevant Fragments, European Journal of Organic Chemistry, Vol: 2019, Pages: 5385-5395, ISSN: 1434-193X
gem-Diarylheterocycles display a wide range of biological activity. Here we present a systematic study into the formation of 4- to 6-membered O- and N-heterocycles and cyclobutanes bearing the diaryl motif through a catalytic Friedel–Crafts reaction from the corresponding benzylic alcohols. 3,3-Diaryltetrahydrofurans, 4,4-diaryltetrahydropyrans, 3,3-diarylpyrrolidines, 4,4-diaryl-piperidines, as well as diarylcyclobutanes are examined, with results for 3,3-diaryloxetanes and 3,3-diarylazetidines presented for comparison. Three catalytic systems are investigated for each substrate [Ca(II), Li(I) and Fe(III)], across preinstalled aromatic groups of differing electronic character. In most cases examined, the diaryl product is obtained directly from the alcohol with good yields using the most appropriate catalyst system. In the absence of a nucleophile, the olefins from the 5- and 6-membered substrates by elimination of water are obtained under the same reaction conditions.
Briggs EL, Tota A, Colella M, et al., 2019, Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-amino-lambda(6)-sulfanenitrile Intermediate, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 58, Pages: 14303-14310, ISSN: 1433-7851
St John-Campbell S, Bull JA, 2019, Base Metal Catalysis in Directed C(sp<sup>3</sup>)−H Functionalisation, Advanced Synthesis and Catalysis, Vol: 361, Pages: 3662-3682, ISSN: 1615-4150
Directed C(sp3)−H functionalisation has made enormous progress in recent years, but has largely been restricted to catalysis using noble metals, particularly palladium. However, since 2013, there have been prominent advances that exploit the reactivity of abundant first row transition metals for a multitude of new bond formations. The use of base metal catalysis for C−H functionalisation can provide huge advantages in terms of cost and sustainability compared to methods using noble metals. This review covers all examples, to the end 2018, of auxiliary-assisted, base metal-catalysed C(sp3)−H functionalisation reactions. Successful examples are reported for Fe, Co, Ni and Cu catalysis with monodentate or bidentate directing groups for C−N, C−O, C−S and C−C bond forming reactions. This review aims to highlight the current state of this field and potential for expansion and so scope and limitations are highlighted. Notably, examples to date have required sterically activated α-disubstituted substrates, particularly propanamide derivatives with bidentate directing groups, such as 8-aminoquinoline amides. Monodentate quinoline and thioamide directing groups have also been used with Co catalysis for C−N and C−C bond formations. Mechanistic details are provided to outline the nature of the proposed organometallic intermediates and potential reaction pathways. We hope this review will stimulate further developments in this growing and important field. (Figure presented.).
St John-Campbell S, Bull JA, 2019, Intramolecular palladium(<scp>ii</scp>)/(<scp>iv</scp>) catalysed C(sp<sup>3</sup>)–H arylation of tertiary aldehydes using a transient imine directing group, Chemical Communications, Vol: 55, Pages: 9172-9175, ISSN: 1359-7345
<p>Indane-aldehydes are formed using palladium catalysis and a transient directing group to promote intramolecular C–H functionalisation with aryl bromides.</p>
Dubois MAJ, Lazaridou A, Choi C, et al., 2019, Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols, Journal of Organic Chemistry, Vol: 84, Pages: 5943-5956, ISSN: 0022-3263
New small-ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron-donating aromatics are successful, proceeding via an azetidine carbocation. The N-carboxybenzyl group is a requirement for good reactivity and enables the NH-azetidine to be revealed. Further reactions of the azetidine sulfides demonstrate their potential for incorporation in drug discovery programs.
Green SP, Payne AD, Wheelhouse KM, et al., 2019, Diazo-Transfer Reagent 2-Azido-4,6-dimethoxy-1,3,5-triazine Displays Highly Exothermic Decomposition Comparable to Tosyl Azide, JOURNAL OF ORGANIC CHEMISTRY, Vol: 84, Pages: 5893-5898, ISSN: 0022-3263
Boddy AJ, Cordier C, Goldberg K, et al., 2019, Acid-mediated ring-expansion of 2,2-disubstituted azetidine carbamates to 6,6-disubstituted 1,3-oxazinan-2-ones, Organic Letters, Vol: 21, Pages: 1818-1822, ISSN: 1523-7052
The ring expansion of 2-ester-2-aryl-azetidine carbamates can be achieved using Brønsted acids to form 6,6-disubstituted 1,3-oxazinan-2-ones. The reaction is rapid at room temperature with Boc or Cbz derivatives, and proceeds with excellent yield (up to 96%) and broad substrate scope. Derivatives of drug compounds and natural products are incorporated. The combina-tion of this ring expansion in a 3-step N–H insertion/cyclization/expansion (NICE) sequence is applied to directly access medicinally relevant scaffolds from acyclic precursors.
Boultwood T, Bull J, 2019, Synthesis of selenoaziridines: a study on stereochemical outcomes of the reaction of aziridine radicals and anions generated from iodoaziridines, ACS Omega, Vol: 4, Pages: 870-879, ISSN: 2470-1343
The synthesis of a new functional group in the form of selenyl-substituted aziridines is described. Selenoaziridines are stereoselectively prepared by functionalization of intact aziridine precursors involving radical and anionic intermediates. Radicals are generated from cis-N-Ts iodoaziridines by activation of the C–I bond using alkoxides as a source of single electrons. These form predominantly trans-substituted seleno-aziridines dependent on the size of the diselenide. cis-Aziridinyllithiums generated by Li–I exchange also react with diselenides stereospecifically to form a range of cis-selenoaziridines. Proposals for the stereochemical outcome are presented.
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