- Two-step regio- and stereoselective syntheses of [19F]- and [18F]-2-deoxy-2-(R)-fluoro-β-D-allose
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Replacement of specific hydroxyl groups by fluorine in carbohydrates is an ongoing challenge from chemical, biological, and pharmaceutical points of view. A rapid and efficient two-step, regio- and stereoselective synthesis of 2-deoxy-2-(R)-fluoro-β-d-allose (2-(R)-fluoro-2-deoxy-β-d-allose; 2-FDβA), a fluorinated analogue of the rare sugar, d-allose, is described. TAG (3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enitol or 3,4,6-tri-O-acetyl-d-glucal), was fluorinated in anhydrous HF with dilute F 2 in a Ne/He mixture or with CH3COOF at -60°C. The fluorinated intermediate was hydrolyzed in 1 N HCl and the hydrolysis product was purified by liquid chromatography and characterized by 1D 1H, 13C, and 19F NMR spectroscopy as well as 2D NMR spectroscopy and mass spectrometry. In addition, 18F-labeled 2-deoxy-2-(R)-fluoro-β-d-allose (2-[18F]FDβA) was synthesized for the first time, with an overall decay-corrected radiochemical yield of 33 ± 3% with respect to [18F]F2, the highest radiochemical yield achieved to date for electrophilic fluorination of TAG. The rapid and high radiochemical yield synthesis of 2-[18F] FDβA has potential as a probe for the bioactivity of D-allose.
- Ashique, Rezwan,Chirakal, Raman V.,Hughes, Donald W.,Schrobilgen, Gary J.
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- Acetyl Hypofluorite, the First Member of a New Family of Organic Compounds
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Some sodium salts in acetic acid-Freon 11 (CFCl3) when treated with elemental fluorine produce acetyl hypofluorite, CH3CO2F, a new electrophilic fluorinating agent.
- Rozen, Shlomo,Lerman, Ori,Kol, Moshe
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- Activation of a CH bond in polypyridine systems by acetyl hypofluorite made from F2
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Activation of the relatively inactive polypyridine backbone with strong electrophilic fluorine, originating from acetyl hypofluorite (AcOF) enables attack of the acetoxy moiety at the α position to the heteroatom. Derivatives of bipyridine, phenanthroline and terpyridine systems have been acetoxylated or oxygenated within a few minutes usually in very good yields.
- Gatenyo, Julia,Hagooly, Youlia,Vints, Inna,Rozen, Shlomo
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- METHODS AND COMPOUNDS USING IN-LOOP FLUORINATION
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This invention provides a novel method that is simple, efficient, and allows for a reliable production of fluorine- 18 (18F) radiofluorinated compounds and radiopharmaceuticals. The method comprises an "in-loop" process, where an 18F
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Page/Page column 13-14
(2020/11/12)
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- Mono and difluorination of centers α to sulfonates and phosphonates using AcOF
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Acetyl hypofluorite, made easily from diluted fluorine and AcONa is very efficient in fluorinating anionic centers. Compounds containing the moieties CH2SO2 or COCH2PO react with bases to create the corresponding anions wh
- Vints, Inna,Gatenyo, Julia,Rozen, Shlomo
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- Fluorination of aryl boronic acids using acetyl hypofluorite made directly from diluted fluorine
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Aryl boronic acids or pinacol esters containing EDG were converted in good yields and fast reactions to the corresponding aryl fluorides using the readily obtainable solutions of AcOF. In reactions with aryl boronic acids containing EWG at the para position, there are two competing forces: one directing the fluorination to take place ortho to the boronic acid and the other, toward an ipso substitution. With EWG meta to the boronic acid, substitution ipso to the boron moiety takes place in good yields.
- Vints, Inna,Gatenyo, Julia,Rozen, Shlomo
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p. 11794 - 11797
(2014/01/06)
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- Synthesis of α-fluorocarboxylates from the corresponding acids using acetyl hypofluorite
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α-Fluorocarboxylic esters and acids were synthesized in good yields. The corresponding esters and acids were converted to their ketene acetals, and these enol derivatives reacted with AcOF made directly from fluorine. This route circumvents the problems associated with nucleophilic fluorinations such as various eliminations and rearrangements. α- and β-branched carboxylic acid derivatives that cannot be directly fluorinated gave by this electrophilic fluorination the corresponding α-fluoro derivatives in good yield. Both the fluorination reaction and the preparation of AcOF are fast and suitable for [18]F incorporation into acids and esters needed for working with PET. α-Fluoroibuprofen (20) and methyl 2-fluoro-3,3,3-triphenylpropionate (32) are two examples of this general reaction.
- Rozen,Hagooly,Harduf
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p. 7464 - 7468
(2007/10/03)
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- Fluorination of Nitro Compounds with Acetyl Hypofluorite
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Various types of nitro derivatives are fluorinated to form the CFNO2 moiety in very good yields using acetyl hypofluorite (AcOF).The corresponding nitro anion, preferably prepared with NaOMe, is added quickly to a cold (-75 deg C) CFCl3 solution of AcOF,
- Rozen, Shlomo,Bar-Haim, Arie,Mishani, Eyal
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p. 6800 - 6803
(2007/10/02)
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- Chemistry of Oxaziridines. 18. Synthesis and Enantioselective Oxidations of the oxaziridines
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The synthesis and enantioselective oxidations of oxaziridines 13 are reported.These reagents are prepared in two steps from the (camphorylsulfonyl)imine 4 by treatment of the corresponding azaenolate with electrophilic halogen sources followed by biphasic oxidation of the resulting dihalo imine 6-9 with m-CPBA/K2CO3.Of these oxaziridines the dichloro reagent 13b, available on a multigram scale, affords the highest enantioselectivities for the asymmetric oxidation of sulfides to sulfoxides (42-74 percent) and for the hydroxylation of enolates (often better than 95 percent ee).In general the molecular recognition is predicted and explained in terms of minimization of nonbonded steric interactions in the transition states.For the asymmetric oxidation of sulfides to sulfoxides, secondary electronic factors related to the polarity of the sulfide and oxaziridine also play a role.Definitive evidence for chelation of the metal enolate with the C-X bond in 13 is not found.The molecular recognition is interpreted in terms of the higher reactivity of the reagents and an active-site structure which is sterically complementary with the enolate.For the asymmetric hydroxylation of the Z- and E-enolates of propiophenone (16a), the Z-enolate exhibits much higher stereoselectivity than the E-enolate: >95 percent vs 22 percent ee.
- Davis, Franklin A.,Weismiller, Michael C.,Murphy, Christopher K.,Reddy, R. Thimma,Chen, Band-Chi
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p. 7274 - 7285
(2007/10/02)
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- Utilizing Acetyl Hypofluorite for Chlorination, Bromination, and Etherification of the Pyridine System
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Acetyl hypofluorite, which is easily made from F2, possesses a strong electrophilic fluorine.This electrophile is able to attach itself to the nitrogen atom of pyridine and activate the ring toward nucleophilic attacks.The ultimate elimination of HF results in an overall easy nucleophilic displacement of the hydrogen of the important 2-position .The nucleophiles used: Clδ-, Brδ-, ROδ-, originate from solvents such as CH2Cl2, CH2Br2, and various primary alcohols.Thus, 2-halo- or 2-alkoxypyridines were formed.The reaction conditions (room temperature, very short reaction times, and good yields) transform the task of direct substitution of the pyridine ring from an extremely difficult to a very easy procedure.
- Hebel, David,Rozen, Shlomo
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p. 6298 - 6301
(2007/10/02)
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- FIRST DIRECT FLUORINATION OF TYROSINE-CONTAINING BIOLOGICALLY ACTIVE PEPTIDES
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Using acetyl hypofluorite a regiospecific electrophilic fluorination of the tyrosine ring of the N-terminal tetrapeptide amide (Tyr-D-Ala-Phe-Gly-NH2) sequence of the opiate peptide dermorphin has been achieved in good yields.
- Hebel, D.,Kirk, K.L.,Cohen, L.A.,Labroo, V.M.
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p. 619 - 622
(2007/10/02)
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- Isolation and Characterization of Acetyl Hypofluorite
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Acetyl hypofluorite, H3CC(O)OF, has been prepared by passage of diluted fluorine through solid KOAc*2HOAc and isolated by trapping at -78 deg C.It is a slightly yellow liquid (mp ca. -96 deg C) with a vapor pressure of about 4 torr at -40 deg C.Vapor-pressure measurements between -64 and -20 deg C led to an enthalpy of vaporization of 35.6 +/- 2.4 kJ/mol and an extrapolated normal boiling point of 53 +/- 6 deg C.At -78 deg C, in 1:1 (v/v) CCl4:CDCl3, its 19F NMR shift is 168.3 ppm vs.CFCl3.Its mass spectrum has been measured, as has its infrared spectrum in a solid argon matrix, and these support its identification.The vapor absorbs in the far ultraviolet, with an absorption maximum at 210 nm (ε ca. 103 L/mol*cm).The compound is of limited stability, particularly in the liquid phase, which sometimes explodes.The vapor is more stable, with a 2-h half-life at room temperature in Kel-F.The half-life is much shorter in Monel.Decomposition is inhibited by O2.Decomposition in a Kel-F container gives nearly quantitatively a 1:1 mixture of CH3F and CO2, but in a Monel apparatus or in the presence of O2, substantial amounts of H3COC(O)F are formed.
- Appelman, Evan H.,Mendelsohn, Marshall H.,Kim, Hyunyong
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p. 6515 - 6518
(2007/10/02)
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- A GAS-SOLID-PHASE MICROCHEMICAL METHOD FOR THE SYNTHESIS OF ACETYL HYPOFLUORITE
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The useful electrophilic fluorinating agent, acetyl hypofluorite, was obtained by passing F2 diluted in N2 through columns containing complexes of alkali metal acetates with acetic acid.Acetyl hypofluorite obtained from KOAc(HOAc)1.5 and o.14percent F2 in N2 was reacted with tri-O-acetyl-D-glucal in CCl3F to obtain tetra-O-acetyl-2-deoxy-2-fluoro-D-glucose in 68percent yield based on F2.These conditions are appropriate to the radiosynthesis of 18F-labeled 2-deoxy-2-fluoro-D-glucose for positron emission tomography.Important variables were the metal cation used, the ratio of HOAc to MOAc and the water content of the complex.
- Jewett, D. M.,Potocki, J. F.,Ehrenkaufer, R. E.
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p. 477 - 484
(2007/10/02)
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- A PREPARATIVE GAS-SOLID-PHASE SYNTHESIS OF ACETYL HYPOFLUORITE
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A simple gas-solid-phase synthesis of acetyl hypofluorite is described in which dilute fluorine in air or nitrogen is reacted with a solid complex of potassium acetate with acetic acid.
- Jewett, Douglas M.,Potocki, Jan F.,Ehrenkaufer, Richard E.
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- A Novel Electrophilic Fluorination of Activated Aromatic Rings Using Acetyl Hypofluorite, Suitable also for Introducing (18)F into Benzene Nuclei
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Acetyl hypofluorite (1) is a new compound that serves as a novel electrophilic fluorinating agent.It is special in the sense that, while it is very reactive, it is still a milder reagent than other fluoroxy compounds such as CF3OF or CF3COOF.It is synthesized directly from elemental fluorine and is used without any isolation or purification.The hypofluorite 1 reacts efficiently and selectively with activated aromatic rings,particularly phenol and aniline derivatives after suitable protection of the hydroxyl and the amino groups.The net result of the reaction is partly according to classical aromatic electrophilic substitution.Unlike such a substitution, however, the electrophilic fluorine atom of 1 substitutes mainly an ortho hydrogen and only occasionally small amounts of p-fluoro derivatives are found.Evidence supports the mechanism for this aromatic fluorination as being mainly an addition-elimination one.In many cases the electrophilic aromatic fluorinations can replace the classical 60-year-old Balz-Schiemann method, which until today is probably the most used procedure.Since aromatic fluorination with 1 is a very fast reaction and since 1 is produced directly from elemental fluorine, this is probably one of the best ways for introduction of the short-living radioisotope (18)F into activated aromatic rings.This will greatly encourage the synthesis of compounds suitable for use in the rapidly developing field of positron emitting transaxial tomography, which in itself depends on the efficient and easy supply of compounds possessing positron emitting isotopes.
- Lerman, Ori,Yitzhak, Tor,Hebel, David,Rozen, Shlomo
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p. 806 - 813
(2007/10/02)
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- Acetyl Hypofluorite, a New Moderating Carrier of Elemental Fluorine and Its Use in Fluorination of 1,3-Dicarbonyl Derivatives
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Elemental fluorine and most of the fluoroxy reagents do not react efficiently or cleanly with 1,3-dicarbonyl derivatives or with their corresponding metal enolates even at -75 degC.It has been found that a suspension of sodium acetate in CFCl3 or in CFCl3-AcOH, when treated with elemental fluorine, forms a new electrophilic fluorinating reagent, CH3COOF (1), which reacts with substrates without further isolation or purification.This reagent is milder than F2, CF3OF, or CF3COOF and reacts successfully where the other reagents fail.When 1 reacts with 1,3-dicarbonyl compounds, the main product is the 1,3-dioxo-2-fluoro derivative in reasonable yields.When, however, the corresponding sodium enolates were treated with 1, the yields of the monofluoro derivatives were considerably higher.In the case of 1,3-dicarbonyl derivatives with low enol content, only the sodium enolates react with 1 to produce good to very good yields of the corresponding 2-monofluoro derivatives.Thus 1 can be considered as a moderating carrier of the highly reactive F2.
- Lerman, Ori,Rozen, Shlomo
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p. 724 - 727
(2007/10/02)
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- A RAPID, STEREOSELECTIVE SYNTHESIS OF FLUORINATED CARBOHYDRATES: ADDITION OF ACETYL HYPOFLUORITE TO VINYL ETHER DERIVATES OF SUGARS
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Acetyl hypofluorite has been added to six unsaturated carbohydrates that contain a vinyl ether moiety.All reactions were rapid (5 min at -78 deg C) and gave, with one exception, high yields of isomerically pure products.The hypofluorite was shown to add
- Adam, Michael J.,Pate, Brian D.,Neeser, Jean-Richard,Hall, Laurance D.
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p. 215 - 224
(2007/10/02)
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