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James A Bull - One of the best experts on this subject based on the ideXlab platform.
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lithium catalyzed thiol alkylation with tertiary and secondary alcohols synthesis of 3 sulfanyl Oxetanes as bioisosteres
Chemistry: A European Journal, 2018Co-Authors: Rosemary A Croft, Chulho Choi, James J Mousseau, James A BullAbstract:: 3-Sulfanyl-Oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan-3-ols, a mild and inexpensive Li catalyst enables chemoselective C-OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisosteres for thioesters due to their similar shape and electronic properties. Under the same conditions, various π-activated secondary and tertiary alcohols are also successful. Derivatization of the Oxetane sulfide linker provides further novel Oxetane classes and building blocks. Comparisons of key physicochemical properties of the Oxetane compounds to selected carbonyl and methylene analogues indicate that these motifs are suitable for incorporation into drug discovery efforts.
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Oxetanes recent advances in synthesis reactivity and medicinal chemistry
Chemical Reviews, 2016Co-Authors: James A Bull, Owen A Davis, Rosemary A Croft, Robert Doran, Kate F MorganAbstract:The four-membered Oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochemical properties as a stable motif in medicinal chemistry and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new Oxetane derivatives. This review takes an overview of the literature for the synthesis of Oxetane derivatives, concentrating on advances in the last five years up to the end of 2015. These methods are clustered by strategies for preparation of the ring and further derivatization of preformed Oxetane-containing building blocks. Examples of the use of Oxetanes in medicinal chemistry are reported, including a collation of Oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally, examples of Oxetane derivatives in ring-opening and ring-expansion reactions are described.
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recent advances in the synthesis of 2 substituted Oxetanes
Synlett, 2015Co-Authors: Owen A Davis, James A BullAbstract:Recent interest in Oxetanes in medicinal chemistry and as synthetic intermediates has led to the development of a number of methods for the synthesis of more functionalized and highly substituted Oxetane derivatives. Here we review cyclization approaches for the preparation of 2-substituted Oxetanes. Methods involving C–O bond formation, as well as recently developed C–C bond forming cyclization strategies are highlighted.
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Studies on the synthesis, stability and conformation of 2-sulfonyl-Oxetane fragments
Organic & Biomolecular Chemistry, 2015Co-Authors: Kate F Morgan, Ian A Hollingsworth, James A BullAbstract:2-(Arylsulfonyl)Oxetanes have been prepared as new structural motifs of interest for medicinal chemistry. These are designed to fit within fragment space and be suitable for screening in fragment based drug discovery, as well as being suitable for further elaboration or incorporation into drug-like compounds. The Oxetane ring is constructed through an efficient C–C bond forming cyclisation which allows the incorporation of a wide range of aryl-sulfonyl groups. Furthermore, biaryl-containing compounds can be accessed through Suzuki–Miyaura coupling from halogenated derivatives. With a number of Oxetane containing fragment compounds available, their pH stability was assessed, indicating good half-life values for mono-substituted aryl sulfonyl Oxetanes across the pH range (1 to 10). Solubility and metabolic stability data is also reported. Finally, the conformation of the fragments is assessed computationally, providing an indication of possible binding orientations.
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synthesis of di tri and tetrasubstituted Oxetanes by rhodium catalyzed oh insertion and cc bond forming cyclization
Angewandte Chemie, 2014Co-Authors: Owen A Davis, James A BullAbstract:Oxetanes offer exciting potential as structural motifs and intermediates in drug discovery and materials science. Here an efficient strategy for the synthesis of Oxetane rings incorporating pendant functional groups is described. A wide variety of Oxetane 2,2-dicarboxylates were accessed in high yields, including functionalized 3-/4-aryl- and alkyl-substituted Oxetanes and fused Oxetane bicycles. Enantioenriched alcohols provided enantioenriched Oxetanes with complete retention of configuration. The Oxetane products were further derivatized, while the ring was maintained intact, thus highlighting their potential as building blocks for medicinal chemistry.
Sophie M. Guillaume - One of the best experts on this subject based on the ideXlab platform.
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α ω epoxide Oxetane and dithiocarbonate telechelic copolyolefins access by ring opening metathesis cross metathesis polymerization romp cm of cycloolefins in the presence of functional symmetric chain transfer agents
Polymers, 2018Co-Authors: E. Vanbiervliet, S. Fouquay, G. Michaud, F. Simon, Jeanfrancois Carpentier, Sophie M. GuillaumeAbstract:Epoxide- and Oxetane-α,ω-telechelic (co)polyolefins have been successfully synthesized by the tandem ring-opening metathesis polymerization (ROMP)/cross-metathesis (CM) of cyclic olefins using Grubbs' second-generation catalyst (G2) in the presence of a bifunctional symmetric alkene epoxide- or Oxetane-functionalized chain-transfer agent (CTA). From cyclooctene (COE), trans,trans,cis-1,5,9-cyclododecatriene (CDT), norbornene (NB), and methyl 5-norbornene-2-carboxylate (NBCOOMe), with bis(oxiran-2-ylmethyl) maleate (CTA 1), bis(Oxetane-2-ylmethyl) maleate (CTA 2), or bis(Oxetane-2-ylmethyl) (E)-hex-3-enedioate (CTA 3), well-defined α,ω-di(epoxide or Oxetane) telechelic PCOEs, P(COE-co-NB or -NBCOOMe)s, and P(NB-co-CDT)s were isolated under mild operating conditions (40 or 60 °C, 24 h). The Oxetane CTA 3 and the epoxide CTA 1 were revealed to be significantly more efficient in the CM step than CTA 2, which apparently inhibits the reaction. Quantitative dithiocarbonatation (CS₂/LiBr, 40 °C, THF) of an α,ω-di(epoxide) telechelic P(NB-co-CDT) afforded a convenient approach to the analogous α,ω-bis(dithiocarbonate) telechelic P(NB-co-CDT). The nature of the end-capping function of the epoxide/Oxetane/dithiocarbonate telechelic P(NB-co-CDT)s did not impact their thermal signature, as measured by DSC. These copolymers also displayed a low viscosity liquid-like behavior and a shear thinning rheological behavior.
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α,ω-epoxide, Oxetane, and dithiocarbonate telechelic copolyolefins Access by ring-opening metathesis/cross-metathesis polymerization (ROMP/CM) of cycloolefins in the presence of functional symmetric chain-transfer agents
Polymers, 2018Co-Authors: E. Vanbiervliet, S. Fouquay, G. Michaud, F. Simon, J.-f. Carpentier, Sophie M. GuillaumeAbstract:Epoxide- and Oxetane-α,ω-telechelic (co)polyolefins have been successfully synthesized by the tandem ring-opening metathesis polymerization (ROMP)/cross-metathesis (CM) of cyclic olefins using Grubbs' second-generation catalyst (G2) in the presence of a bifunctional symmetric alkene epoxide- or Oxetane-functionalized chain-transfer agent (CTA). From cyclooctene (COE), trans,trans,cis-1,5,9-cyclododecatriene (CDT), norbornene (NB), and methyl 5-norbornene-2-carboxylate (NBCOOMe), with bis(oxiran-2-ylmethyl) maleate (CTA 1), bis(Oxetane-2-ylmethyl) maleate (CTA 2), or bis(Oxetane-2-ylmethyl) (E)-hex-3-enedioate (CTA 3), well-defined α,ω-di(epoxide or Oxetane) telechelic PCOEs, P(COE-co-NB or -NBCOOMe)s, and P(NB-co-CDT)swere isolated undermild operating conditions (40 or 60 °C, 24 h). The Oxetane CTA3 and the epoxide CTA1were revealed to be significantly more efficient in the CM step than CTA 2, which apparently inhibits the reaction. Quantitative dithiocarbonatation (CS2/LiBr, 40 °C, THF) of an α,ω-di(epoxide) telechelic P(NB-co-CDT) afforded a convenient approach to the analogous α,ω-bis(dithiocarbonate) telechelic P(NB-co-CDT). The nature of the end-capping function of the epoxide/Oxetane/dithiocarbonate telechelic P(NB-co-CDT)s did not impact their thermal signature, as measured by DSC. These copolymers also displayed a low viscosity liquid-like behavior and a shear thinning rheological behavior.
Goncalo J L Bernardes - One of the best experts on this subject based on the ideXlab platform.
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site selective modification of proteins with Oxetanes
Chemistry: A European Journal, 2017Co-Authors: Omar Boutureira, Nuria Martinezsaez, Kevin M Brindle, Andre A Neves, Goncalo J L Bernardes, Francisco CorzanaAbstract:Oxetanes are four-membered ring oxygen heterocycles that are advantageously used in medicinal chemistry as modulators of physicochemical properties of small molecules. Herein, we present a simple method for the incorporation of Oxetanes into proteins through chemoselective alkylation of cysteine. We demonstrate a broad substrate scope by reacting proteins used as apoptotic markers and in drug formulation, and a therapeutic antibody with a series of 3-Oxetane bromides, enabling the identification of novel handles (S-to-S/N rigid, non-aromatic, and soluble linker) and reactivity modes (temporary cysteine protecting group), while maintaining their intrinsic activity. The possibility to conjugate Oxetane motifs into full-length proteins has potential to identify novel drug candidates as the next-generation of peptide/protein therapeutics with improved physicochemical and biological properties.
E. Vanbiervliet - One of the best experts on this subject based on the ideXlab platform.
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α ω epoxide Oxetane and dithiocarbonate telechelic copolyolefins access by ring opening metathesis cross metathesis polymerization romp cm of cycloolefins in the presence of functional symmetric chain transfer agents
Polymers, 2018Co-Authors: E. Vanbiervliet, S. Fouquay, G. Michaud, F. Simon, Jeanfrancois Carpentier, Sophie M. GuillaumeAbstract:Epoxide- and Oxetane-α,ω-telechelic (co)polyolefins have been successfully synthesized by the tandem ring-opening metathesis polymerization (ROMP)/cross-metathesis (CM) of cyclic olefins using Grubbs' second-generation catalyst (G2) in the presence of a bifunctional symmetric alkene epoxide- or Oxetane-functionalized chain-transfer agent (CTA). From cyclooctene (COE), trans,trans,cis-1,5,9-cyclododecatriene (CDT), norbornene (NB), and methyl 5-norbornene-2-carboxylate (NBCOOMe), with bis(oxiran-2-ylmethyl) maleate (CTA 1), bis(Oxetane-2-ylmethyl) maleate (CTA 2), or bis(Oxetane-2-ylmethyl) (E)-hex-3-enedioate (CTA 3), well-defined α,ω-di(epoxide or Oxetane) telechelic PCOEs, P(COE-co-NB or -NBCOOMe)s, and P(NB-co-CDT)s were isolated under mild operating conditions (40 or 60 °C, 24 h). The Oxetane CTA 3 and the epoxide CTA 1 were revealed to be significantly more efficient in the CM step than CTA 2, which apparently inhibits the reaction. Quantitative dithiocarbonatation (CS₂/LiBr, 40 °C, THF) of an α,ω-di(epoxide) telechelic P(NB-co-CDT) afforded a convenient approach to the analogous α,ω-bis(dithiocarbonate) telechelic P(NB-co-CDT). The nature of the end-capping function of the epoxide/Oxetane/dithiocarbonate telechelic P(NB-co-CDT)s did not impact their thermal signature, as measured by DSC. These copolymers also displayed a low viscosity liquid-like behavior and a shear thinning rheological behavior.
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α,ω-epoxide, Oxetane, and dithiocarbonate telechelic copolyolefins Access by ring-opening metathesis/cross-metathesis polymerization (ROMP/CM) of cycloolefins in the presence of functional symmetric chain-transfer agents
Polymers, 2018Co-Authors: E. Vanbiervliet, S. Fouquay, G. Michaud, F. Simon, J.-f. Carpentier, Sophie M. GuillaumeAbstract:Epoxide- and Oxetane-α,ω-telechelic (co)polyolefins have been successfully synthesized by the tandem ring-opening metathesis polymerization (ROMP)/cross-metathesis (CM) of cyclic olefins using Grubbs' second-generation catalyst (G2) in the presence of a bifunctional symmetric alkene epoxide- or Oxetane-functionalized chain-transfer agent (CTA). From cyclooctene (COE), trans,trans,cis-1,5,9-cyclododecatriene (CDT), norbornene (NB), and methyl 5-norbornene-2-carboxylate (NBCOOMe), with bis(oxiran-2-ylmethyl) maleate (CTA 1), bis(Oxetane-2-ylmethyl) maleate (CTA 2), or bis(Oxetane-2-ylmethyl) (E)-hex-3-enedioate (CTA 3), well-defined α,ω-di(epoxide or Oxetane) telechelic PCOEs, P(COE-co-NB or -NBCOOMe)s, and P(NB-co-CDT)swere isolated undermild operating conditions (40 or 60 °C, 24 h). The Oxetane CTA3 and the epoxide CTA1were revealed to be significantly more efficient in the CM step than CTA 2, which apparently inhibits the reaction. Quantitative dithiocarbonatation (CS2/LiBr, 40 °C, THF) of an α,ω-di(epoxide) telechelic P(NB-co-CDT) afforded a convenient approach to the analogous α,ω-bis(dithiocarbonate) telechelic P(NB-co-CDT). The nature of the end-capping function of the epoxide/Oxetane/dithiocarbonate telechelic P(NB-co-CDT)s did not impact their thermal signature, as measured by DSC. These copolymers also displayed a low viscosity liquid-like behavior and a shear thinning rheological behavior.
Arjan W. Kleij - One of the best experts on this subject based on the ideXlab platform.
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catalytic one pot Oxetane to carbamate conversions formal synthesis of drug relevant molecules
Advanced Synthesis & Catalysis, 2016Co-Authors: Wusheng Guo, Jeroen Rintjema, Victor Laserna, Arjan W. KleijAbstract:Oxetanes are versatile building blocks in drug-related synthesis to induce property-modulating effects. Whereas related oxiranes are widely used in coupling chemistry with carbon dioxide (CO2) to afford value-added commodity chemicals, Oxetane/CO2 couplings remain extremely limited despite the recent advances in the synthesis of these four-membered heterocycles. Here we report an effective one-pot three-component reaction (3CR) strategy for the coupling of (substituted) Oxetanes, amines and CO2 to afford a variety of functionalized carbamates with excellent chemoselectivity and good yields. The process is mediated by an aluminium-based catalyst under relatively mild conditions and the developed catalytic methodology can be applied to the formal synthesis of two pharmaceutically relevant carbamates with the 3CR being a key step.
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highly chemoselective catalytic coupling of substituted Oxetanes and carbon dioxide
Chemistry: A European Journal, 2015Co-Authors: Jeroen Rintjema, Eduardo C Escuderoadan, Eddy Martin, Arjan W. KleijAbstract:The chemoselective coupling of Oxetanes and carbon dioxide to afford functional, heterocyclic organic compounds known as six-membered cyclic carbonates remains a challenging topic. Here, an effective method for their synthesis relying on the use of Al catalysis is described. The catalytic reactions can be carried out with excellent selectivity for the cyclic carbonate product tolerating various (functional) groups present in the 2- and 3-position(s) of the Oxetane ring. The presented methodology is the first general approach towards the formation of six-membered cyclic carbonates (6MCCs) through Oxetane/CO2 coupling chemistry. Apart from a series of substituted six-membered cyclic carbonates, also the unprecedented room-temperature coupling of Oxetanes and CO2 is disclosed giving, depending on the structural features of the substrate, a variety of five- and six-membered heterocyclic products. A mechanistic rationale is presented for their formation and support for the intermediary presence of a carbonic acid derivative is given. The presented functional carbonates may hold great promise as building blocks in organic synthesis and the development of new, biodegradable polymers.
