scholarly journals Synthesis, Characterization and HPLC Analysis of the (1S,2S,5R)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 906
Author(s):  
Sergio Rodríguez-Arévalo ◽  
Eugènia Pujol ◽  
Sònia Abás ◽  
Carles Galdeano ◽  
Carmen Escolano ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Receptor Agonist ◽  
Hplc Analysis ◽  
Bioactive Compound ◽  
Crystallographic Analysis ◽  
X Ray ◽  
Cryo Electron Microscopy ◽  
Stereogenic Centers ◽  
Initial Starting ◽  
Clinical Candidate

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.

THE REACTION OF UNSATURATED CARBOHYDRATES WITH CARBON MONOXIDE AND HYDROGEN: V. ABSOLUTE STEREOCHEMISTRY OF ANHYDRODEOXYHEPTITOLS FROM 3,4,6-TRI-O-ACETYL-D-GLUCAL. STEREOCHEMISTRY OF HYDROFORMYLATION. CONFORMATIONAL ANALYSIS

1965 ◽  
Vol 43 (5) ◽  
pp. 1375-1381 ◽  
Author(s):  
Alex Rosenthal ◽  
Hans J. Koch
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Carbon Monoxide ◽  
Absolute Configuration ◽  
Sodium Iodide ◽  
Crystallographic Analysis ◽  
X Ray ◽  
Dicobalt Octacarbonyl ◽  
The Absolute ◽  
Compound Ii ◽  
Absolute Stereochemistry

3,4,6-Tri-O-acetyl-D-glucal reacted with carbon monoxide and hydrogen in the presence of dicobalt octacarbonyl to yield a mixture of two epimeric anhydrodeoxyheptitols, namely, 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-D-manno-heptitol (I) and 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-D-gluco-heptitol (II). De-O-acetylation of the mixture, followed by chromatographic separation, yielded crystalline 2,6-anhydro-3-deoxy-D-manno-heptitol (III) and 2,6-anhydro-3-deoxy-D-gluco-heptitol (IV). Reaction of the mixture of heptitols (I) and (II) with p-bromobenzenesulfonyl chloride, followed by fractional crystallization of the brosylates, gave pure 4,5,7-tri-O-acetyl-2,6-anhydro-1-O-(p-bromophenylsulfonyl)-3-deoxy-D-gluco-heptitol (VII). The absolute configuration of (VII) has been previously established by X-ray crystallographic analysis. The absolute configuration of (III) was established by correlation with that of (VII). The conversion of compound (II) into various derivatives is described.Reaction of 3,4,6-tri-O-acetyl-D-glucal with carbon monoxide and deuterium afforded 2,6-anhydro-3-deoxy-D-manno-heptitol-1,1,3-2H3 (XIII) and 2,6-anhydro-3-deoxy-D-gluco-heptitol-1,1,3-2H3 (XIV). Examination of the nuclear magnetic resonance (n.m.r.) spectra of the normal and deuterated anhydrodeoxyheptitols confirmed the structural assignments and showed that cis addition to the double bond took place to give (XIV).Comparison of the exchange reaction of sodium iodide with 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-1-O-tosyl-D-gluco-heptitol (VIII) and with 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-1-O-tosyl-D-manno-heptitol (XV) revealed that the equatorial primary tosyloxy group of (VIII) was exchanged by iodine twice as readily as the axial primary tosyloxy group of (XV).

scholarly journals Styryllactones and Acetogenins from the Fruits of Goniothalamus macrocalyx

2014 ◽  
Vol 9 (4) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Quy Hung Trieu ◽  
Huong Doan Thi Mai ◽  
Van Cuong Pham ◽  
Marc Litaudon ◽  
Françoise Gueritte ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
Cell Lines ◽  
Mass Spectrometer ◽  
Natural Resource ◽  
Absolute Configuration ◽  
Mcf7 Cell ◽  
Crystallographic Analysis ◽  
Kb Cells ◽  
X Ray ◽  
Orbitrap Mass Spectrometer

Two new styryllactones, macrocalactone (1) and 3-deoxycardiobutanolide (2), were isolated from the fruits of Goniothalamus macrocalyx Ban (Annonaceae), together with seven known compounds including four acetogenins, annonacin (3), solamin (4), isoannonacin (5), trans-murisolinone (6), and three other compounds, 7-acetylaltholactone (7), β-caryophyllene-8R,9R-oxide (8) and 2-(2′-hydroxytetracosanoylamino)-octadecane-l,3,4-triol (9). Their structures were determined by spectroscopic and MS analysis. The absolute configuration of I was determined by X-ray crystallographic analysis. The structures of the acetogenins were confirmed by liquid chromatography coupled to a hybrid quadrupole-time of flight mass spectrometer, using post-column lithium infusion. The results were compared with the fragmentation obtained with a hybrid linear trap-orbitrap mass spectrometer. Compound 7 had cytotoxicity against KB, HepG2, Lu, and MCF7 cell lines with IC50 values of 13.1, 23.7, 26.3 and 60.2 μM, respectively, whereas annonacin (3) was selectively active against KB cells (IC50 value of 6.5 μM). The discovery of 3-deoxycardiobutanolide (2) from the fruits of this plant revealed that G. macrocalyx could be a valuable natural resource to obtain this compound as it has been previously reported to have a significant cytotoxicity against different cancer cell lines, especially HL-60 cells.

scholarly journals 2,4-Dimethyl-3,4-O-isopropylidene-L-arabinono-1,5-lactone

2007 ◽  
Vol 63 (3) ◽  
pp. o1128-o1130 ◽  
Author(s):  
Kathrine V. Booth ◽  
David J. Watkin ◽  
Sarah F. Jenkinson ◽  
George W. J. Fleet
Keyword(s):  
Absolute Configuration ◽  
Crystallographic Analysis ◽  
Starting Material ◽  
Relative Configuration ◽  
X Ray ◽  
Boat Form ◽  
The Absolute

The relative configuration at C-2 of 2,4-dimethyl-3,4-O-isopropylidene-L-arabinono lactone, C10H16O5, which exists in the boat form, was unequivocally established by X-ray crystallographic analysis. The absolute configuration was determined by the use of 2-C-methyl-D-ribonolactone as a starting material.

Relative and Absolute Structure Assignments of Alkenes Using Crystalline Osmate Derivatives for X-Ray Analysis

2019 ◽  
Author(s):  
Alexander S. Burns ◽  
Charles dooley ◽  
Paul R. Carlson ◽  
Joseph W. Ziller ◽  
Scott Rychnovsky
Keyword(s):  
Absolute Configuration ◽  
Osmium Tetroxide ◽  
Heavy Atom ◽  
Crystallographic Analysis ◽  
Enol Ethers ◽  
X Ray ◽  
Silyl Enol Ethers ◽  
Absolute Structure ◽  
Structure Of Liquid

<div><div><p>Osmium tetroxide and TMEDA form stable crystalline adducts with alkenes. The structure of liquid alkenes can be determined through X-ray analysis of these derivatives. Osmium, a heavy atom, facilitates the crystallographic analysis and the determination of the absolute configuration using common Mo X-ray sources. The utility of this method for assigning structures and absolute configurations was demonstrated on a number of unsaturated substrates that include simple alkenes, enones, enol ethers, and silyl enol ethers.</p></div></div>

Absolute Konfiguration von (+)-1,2,3,4,6,7,8,8a-Octahydro-6-isochinolon- 8a-carbonsäuremethylester und die Stereochemie einer Kupfer-katalysierten asymmetrischen Michael-Reaktion / Absolute Configuration of Methyl (+)-1,2,3,4,6,7,8,8a-Octahydro-6-isoquinolone-8a-carboxylate and Stereochemistry of a Copper-Catalyzed Asymmetric Michael Reaction

2004 ◽  
Vol 59 (4) ◽  
pp. 375-379 ◽  
Author(s):  
Jens Christoffers ◽  
Wolfgang Frey ◽  
Heiko Scharl ◽  
Angelika Baro
Keyword(s):  
Absolute Configuration ◽  
Michael Addition ◽  
Michael Reaction ◽  
Addition Product ◽  
Crystallographic Analysis ◽  
Subsequent Reaction ◽  
X Ray ◽  
Quaternary Stereocenter ◽  
Asymmetric Michael Reaction

AbstractEnantiopure Boc-protected piperidine derivative (+)-5c, with a quaternary stereocenter, was obtained by copper-catalyzed, L-valine diethylamide-mediated Michael reaction. For determination of the absolute configuration, 5c was derivatized by cyclization with pyrrolidine/AcOH to give compound 6 with bicyclo[4.4.0]-constitution, deprotection of the amino function with TFA and subsequent reaction with 2-iodobenzoic acid to yield the crystalline bicyclic amide 7. X-ray crystallographic analysis confirmed the constitution of compounds 5c and 6 and established the (R) configuration of 7. Thus, starting Michael addition product (+)-5c has to be (S) configured, because an epimerization at the quaternary stereocenter is excluded. This result is in accordance with our working model of the Cu-catalyzed, auxiliary-assisted Michael reaction.

Sterols from a Vietnamese Wood-Rotting Phellinus sp.

2007 ◽  
Vol 62 (2) ◽  
pp. 289-292 ◽  
Author(s):  
Dang Ngoc Quang ◽  
Dang Dinh Bach ◽  
Yoshinori Asakawa
Keyword(s):  
Nitric Oxide ◽  
Absolute Configuration ◽  
Methanolic Extract ◽  
Uv Spectroscopy ◽  
2D Nmr ◽  
Crystallographic Analysis ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
X Ray ◽  
Ir And Uv Spectroscopy

Phytochemical examination of the methanolic extract from fruit bodies of an unidentified Vietnamese Phellinus species led to the isolation of four compounds, one of which is a new steroid, 25-hydroxy-ergosta-7,24(28)-dien-3β -ol, named phellinol, together with senexonol, trametenolic acid B and ergosta-4,6,8(14),22-tetraen-3-one. Their structures were determined by 2D NMR, MS, IR and UV spectroscopy. In addition, the absolute configuration of senexonol was established by X-ray crystallographic analysis of its p-bromobenzoate derivative as 22(R)-hydroxy-4(S),14(S)- dimethyl-cholesta-8,24-dien-3-one. All compounds moderately suppressed the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) in RAW 264.7 cells.

scholarly journals Punctaporonins N–S, New Caryophyllene Sesquiterpenoids from Cytospora sp.

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Yan Li ◽  
Qingbin Wang ◽  
Xingzhong Liu ◽  
Yongsheng Che
Keyword(s):  
Nmr Spectroscopy ◽  
Absolute Configuration ◽  
Hela Cells ◽  
Crystallographic Analysis ◽  
X Ray ◽  
The Absolute

Six new caryophyllene sesquiterpenoids, punctaporonins N–S (1–6), and three known ones, 6-hydroxypunctaporonins B (7), A (8), and E (9), have been isolated from solid cultures of Cytospora sp. The structures of 1–6 were elucidated primarily by NMR spectroscopy. The absolute configuration of 1 was assigned by X-ray crystallographic analysis of its S-MTPA ester. Compounds 2, 5, and 6 showed modest cytotoxicity against HeLa cells.

A One-Pot Intramolecular Tandem Michael–Aldol Annulation Reaction for the Synthesis of Chiral Pentacyclic Terpenes

Synthesis ◽  
2019 ◽  
Vol 51 (21) ◽  
pp. 3964-3972
Author(s):  
Jianyu Lu ◽  
Serkan Koldas ◽  
Huafang Fan ◽  
John Desper ◽  
Victor W. Day ◽  
...  
Keyword(s):  
Michael Addition ◽  
Aldol Condensation ◽  
Crystallographic Analysis ◽  
Side Chain ◽  
One Pot ◽  
X Ray ◽  
Double Ring ◽  
Stereogenic Centers

A chiral tricyclic terpene possessing a 6,6,6-tricyclic framework and a 3,3-dimethyl-7-oxooctylidenyl side chain undergoes a double ring-closing reaction to give two chiral pentacyclic terpenes in a ratio of 4:3 via an intramolecular Michael addition followed by aldol condensation under basic conditions. Three new stereogenic centers are introduced in the initial Michael annulation reaction. Stereoselective installation of an ethoxycarbonyl group at C17 of the two pentacyclic terpenes separately gives the corresponding highly functionalized pentacyclic terpenoids with seven stereogenic centers. The structures and stereochemistry of key intermediates and products are established through X-ray crystallographic analysis. A mechanism is proposed for explaining the stereochemistry in the Michael annulation reaction.

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