95 results found
Rojas JJ, Bull J, 2023, Oxetanes in drug discovery campaigns, Journal of Medicinal Chemistry, ISSN: 0022-2623
The oxetane ring is an emergent, underexplored motif in drug discovery that shows attractive properties such as low molecular weight, high polarity and marked 3-dimensionality. Oxetanes have garnered further interest as isosteres of carbonyl groups and as molecular tools to fine-tune physicochemical properties of drug compounds such as pKa, LogD, aqueous solubility and metabolic clearance. This perspective highlights recent applications of oxetane motifs in drug discovery campaigns (2017–2022), with emphasis on the effect of the oxetane on medicinally relevant properties and on the building blocks used to incorporate the oxetane ring. Based on this analysis, we provide an overview of the potential benefits of appending an oxetane to a drug compound, as well as potential pitfalls, challenges, and future directions.
Antermite D, White A, Casarrubios L, et al., 2023, On the mechanism and selectivity of palladium catalyzed C(sp3)–H arylation of pyrrolidines and piperidines at unactivated C4 positions: discovery of an improved dimethylamino-quinoline amide directing group, ACS Catalysis, Vol: 13, Pages: 9597-9615, ISSN: 2155-5435
Directed C–H functionalization is a powerful means to functionalize otherwise unreactive C‒H bonds, for which aminoquinoline amides provide a powerful and frequently used directing group. Saturated N-heterocycles are crucial motifs in medicinal chemistry. However, the C–H functionalization of N-heterocycles has posed considerable chal-lenges, often giving incomplete conversions. On unsymmetrical substrates, poorly understood regio- and stereoselectivity considerations have prevented more forcing conditions and further limited yields. Here we present a combined experimental and computational study on the regio- and stereoselective C4 arylation of pyrrolidines and piperidines with C3 aminoquinoline amide directing groups. Detailed mechanistic experiments are presented including deuteration, kinetics investigations, and isolation of palladacycles. The palladacycle formation is reversible and proceeds preferentially at C4, though activation of both C–H bonds at C4, cis and trans to the directing group, occurs equally. The cis-selectivity results from strain in the trans-palladacycle (ΔΔGtrans-cis ~6 kcal∙mol–1), that is retained in subsequent transition states. Hence, the oxidative addition step is stereodetermining. However, the turnover-limiting step for the catalytic cycle is reductive elimination, and reduced rates and yields were observed with electron poor aryl iodides. Importantly, kinetics experiments reveal a rapid loss of active Pd catalyst, likely due to the build-up of iodide, and a role for K2CO3/PivOH in catalyst turnover. Finally, we present the discovery of an improved 4-dimethylamine-8-aminoquinoline directing group (DMAQ). This removable auxiliary achieves >2x rate acceleration, generally im-proved yields, as well as improved cis-selectivity, by promoting reductive elimination. A broad reaction scope of aryl iodides is demonstrated, including the late-stage functionalization of drug compounds which is enabled by t
Saejong P, Rojas JJ, Denis C, et al., 2023, Synthesis of oxetane and azetidine ethers as ester isosteres by Brønsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols, Organic and Biomolecular Chemistry, Vol: 21, Pages: 5553-5559, ISSN: 1477-0520
Oxetanes and azetidines continue to draw significant interest in medicinal chemistry, as small, polar and non-planar motifs. Oxetanes also represent interesting surrogates for carbonyl-containing functional groups. Here we report a synthesis of 3,3- disubstituted oxetane- and azetidine-ethers, with comparisons made to the ester functional group. The tertiary benzylic alcohols of the 4-membered rings are selectively activated using Brønsted acid catalysis and reacted with simple alcohols to form the ethers and maintain the oxetane ring intact. This approach avoids the use of strong bases and halide alkylating agents and allows alcohol libraries to be leveraged. Oxetane ethers demonstrate excellent chemical stability across a range of conditions and an improved stability vis-à-vis analogous esters under basic and reducing conditions.
Higham J, Ma T, Bull J, 2023, Dual copper and aldehyde catalyzed transient C-H sulfonylation of benzylamines, Organic Letters, Vol: 25, Pages: 5285-5290, ISSN: 1523-7052
This study reports the first example of using a dual catalytic system with copper(II) acetate and 2-hydroxynicotinaldehyde to achieve transient C(sp2)–H sulfonylation of benzylamines with sulfinate salts via a dynamically formed imine directing group. Manganese(IV) oxide was identified as an effective oxidant and base. Computational DFT investigations suggest that the TDG lowers the energy barrier for an acetate-mediated, turnover limiting C–H activation step and subsequent combination of the cupracycle with a RSO2 radical.
Dubois M, Rojas J, Broderick H, et al., 2023, Visible light photoredox-catalyzed decarboxylative alkylation of 3-aryl-oxetanes and azetidines via benzylic tertiary radicals and implications of benzylic radical stability, Journal of Organic Chemistry, Vol: 88, Pages: 6476-6488, ISSN: 0022-3263
4-Membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond for-mation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question sys-tematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic ox-etane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radi-cals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acry-lates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more 𝜋-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible.
Briggs E, Ma TK, Zhong Z, et al., 2023, Synthesis of Enantioenriched NH-Sulfoximines by NH Transfer to Sulfoxides Using Ammonium Carbamate and (Diacetoxyiodo)benzene, Organic Syntheses, Vol: 100, Pages: 186-198, ISSN: 0078-6209
Piticari A-S, Larionova N, Bull J, 2023, C–H Functionalization of saturated heterocycles beyond the C(2) position, Transition-Metal-Catalyzed C-H Functionalization of Heterocycles (Wiley)
Bull J, 2023, Synthesis of aza-S(VI) motifs, Phosphorus Sulfur and Silicon and the Related Elements, Vol: 198, Pages: 471-477, ISSN: 1042-6507
Sulfoximines and sulfonimidamides are of interest as design options for medicinal chemists. This article describes the development of methods for the synthesis of sulfoximines by metal-free NH-transfer to sulfoxides, and NH/O transfer to sulfides, using convenient sources of ammonia and hypervalent iodine reagents. Similarly, sulfonimidamides are prepared from sulfenamides. Methods for the preparation of enantioenriched sulfonimidoyl fluorides are also described, as is their stereospecific reactions with amines and Grignard reagents. This work was presented at the 29th International Symposium on the Organic Chemistry of Sulfur (Guelph, July 2022).
Tota A, Spennacchio M, Briggs E, et al., 2023, Synthesis of NH-sulfoximines from sulfides using ammonium carbamate and (Diacetoxyiodo)benzene to transfer NH and O, Organic Syntheses, Vol: 100, Pages: 48-60, ISSN: 0078-6209
Preparation of (4-Bromophenyl)(imino)(methyl)-λ6-sulfanone
Luisi R, Bull J, 2023, Synthesis of sulfoximines and sulfonimidamides using hypervalent iodine mediated NH transfer, Molecules, Vol: 28, Pages: 1-15, ISSN: 1420-3049
The development of NH transfer reactions using hypervalent iodine and simple sources of ammonia has facilitated the synthesis of sulfoximines and sulfonimidamides for applications across the chemical sciences. Perhaps most notably, the methods have been widely applied in medicinal chemistry and in the preparation of biologically active compounds, including in the large-scale preparation of an API intermediate. This review provides an overview of the development of these synthetic methods involving an intermediate iodonitrene, since our initial report in 2016 on the conversion of sulfoxides to sulfoximines. This review covers the NH transfer to sulfoxides and sulfinamides, and the simultaneous NH/O transfer to sulfides and sulfenamides to form sul-foximines and sulfonimidamides respectively. The mechanism of the reactions and identification of key intermediates are discussed. Developments in the choice of reagents and in the reaction conditions and set-ups used are described.
Rojas Munoz J, Bull J, 2023, 3-(4-Methoxyphenyl)-3-oxetanesulfonyl fluoride, Encyclopedia of Reagents for Organic Synthesis
Reagent used for the defluorosulfonylative coupling of 3-aryloxetane to a range of nucleophiles; serving as stable precursor to oxetane carbocations through the loss of sulfur dioxide and fluoride by mild thermal activation (60 °C)
Rojas JJ, Bull JA, 2023, 4-Membered Ring Carbocations: A Positive Development in the Synthesis of 3,3-Disubstituted Oxetanes and Azetidines, Chimia, Vol: 77, Pages: 192-195, ISSN: 0009-4293
4-Membered heterocycles are low molecular weight polar scaffolds with intriguing potential for drug discovery. Despite their unquestionable value, methods to access such heterocycles remain scant. Here, we describe the generation of oxetane- and azetidine-benzylic carbocations as a general strategy to access valuable 3,3-disubstituted derivatives.
Zhong Z, Chesti J, Armstrong A, et al., 2022, Synthesis of Sulfoximine Propargyl Carbamates under Improved Conditions for Rhodium Catalyzed Carbamate Transfer to Sulfoxides, JOURNAL OF ORGANIC CHEMISTRY, Vol: 87, Pages: 16115-16126, ISSN: 0022-3263
Higham J, Bull J, 2022, Amine-catalyzed copper-mediated C–H sulfonylation of benzaldehydes via a transient imine directing group, Angewandte Chemie International Edition, Vol: 61, Pages: 1-8, 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, Vol: 58, Pages: 5387-5390, 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
<jats:title>Abstract</jats:title><jats:p>Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This has been prompted by both pioneering works taking sulfoximine containing compounds into clinical trials and the concurrent development of powerful synthetic methods. This review covers recent developments in the synthesis of sulfoximines concentrating on developments since 2015. This includes extensive developments in both S−N and S−C bond formations. Flow chemistry processes for sulfoximine synthesis are also covered. Finally, subsequent transformations of sulfoximines, particularly in N‐functionalization are reviewed, including N−S, N−P, N−C bond forming processes and cyclization reactions.</jats:p>
Goundry W, Parker J, Bull J, 2021, AstraZeneca explores new frontiers through academic collaborations, Chemistry World, Vol: 18, Pages: 50-51, ISSN: 1473-7604
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
<jats:title>Abstract</jats:title><jats:p>Differential scanning calorimetry (DSC) is increasingly used as evidence to support a favourable safety profile of novel chemistry, or to highlight the need for caution. DSC enables preliminary assessment of the thermal hazards of a potentially energetic compound. However, unlike other standard characterisation methods, which have well defined formats for reporting data, the current reporting of DSC results for thermal hazard assessment has shown concerning trends. Around half of all results in 2019 did not include experimental details required to replicate the procedure. Furthermore, analysis for thermal hazard assessment is often only conducted in unsealed crucibles, which could lead to misleading results and dangerously incorrect conclusions. We highlight the specific issues with DSC analysis of hazardous compounds currently in the organic chemistry literature and provide simple “best practice” guidelines which will give chemists confidence in reported DSC results and the conclusions drawn from them.</jats:p>
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.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.