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Distal Two-Bond versus Three-Bond Electronegative Oxo-Substituent Effect Controls the Kinetics and Thermodynamics of the Conversion of a C-Nitroso Function to the Corresponding Oxime in the Conformationally Locked Pentofuranose (Bicyclo[2.2.1]heptane) System
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 16, 7266-7276 p.Article in journal (Refereed) Published
Abstract [en]

We report the high-yielding and scalable diastereospecific synthesis of isomeric bicyclo [2.2.1]heptane-7- and -8-oximes and their corresponding C-nitroso derivatives, which are the key intermediates for the synthesis of carbanucleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitrosobicycloheptane system requires any external base in DMSO-d(6) to afford the corresponding oxime, and no reverse isomerization from the oxime to the C-nitroso compound was observed. The conversion of the (C8-S)-nitroso compound to the E/Z-oximes was similar to 8 times faster (at 40 degrees C) than that of the (C7-R)-nitroso derivative. The mechanism involves first-order reaction kinetics for the conversion of either the (C7-R)- or (C8-S)-nitroso derivative to the corresponding E/Z-oximes. The lower rate of conversion of the (C7-R)-nitroso compound to the corresponding crimes compared with that of the (C8-S)-nitroso derivative is attributed to the fact that the acidic H8 ionizing center is two bonds away from the OPMB group on C1 in the latter whereas H7 is three bonds away from the C1 OMe group in the former, making the effect of the electron-withdrawing group on C1 stronger in the latter.

Place, publisher, year, edition, pages
2014. Vol. 79, no 16, 7266-7276 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-231998DOI: 10.1021/jo500266kISI: 000340517600002OAI: oai:DiVA.org:uu-231998DiVA: diva2:747005
Available from: 2014-09-15 Created: 2014-09-12 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Novel Pentofuranose Chemistry to Modulate RNA Function
Open this publication in new window or tab >>Novel Pentofuranose Chemistry to Modulate RNA Function
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chemical modifications of oligonucleotides provide an important tool to understand how the natural substrate works as well as how to improve their biochemical and biological properties as potential therapeutics and diagnostics. Our carba-LNA (2',4'-carba-bridged Locked Nucleic Acid) modified oligo-DNA or -RNA have been found to be useful to modulate oligo-RNA and -DNA activity. This thesis is based on four papers: Paper I (J. Org. Chem. 2010, 75, 7112-7128) deals with the synthesis of 2',4'-propylene-bridged (Carba-ENA) thymidine and its analogues. These carba-ENA nucleosides have been subsequently incorporated into 15mer antisense oligodeoxynucleotides (AON), and their affinity toward complementary mRNA and DNA, as well as their nuclease resistance and RNase H recruitment capability have been investigated in comparison with those of the native and ENA counterparts. Paper II (J. Org. Chem. 2012, 77, 6855–6872) illustrates the synthesis of dimethylbicyclo[2.2.1]heptane and a diastereomeric mixture of oxabicyclo[2.2.1]heptanes by the free-radical ring-closure reaction approach. The role of steric factors for different chair- and the boat-like transition states was evaluated involving the 5-exo radical ring closure reaction to a tethered olefin. Paper III (J. Org. Chem. 2012, 77, 9747-9755) shows an unusual strain releasing reaction of 1-mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane by a base-promoted substitution at the chiral C3 followed by spontaneous concerted ring opening involving the most strained C2-C3-C4 bonds (with bond angle 94°) and the C2 bridgehead leading to anti-endo elimination of the C1-mesyloxy group by the conjugate base of adenine or thymine to give two diastereomeric C3'(S) and C3'(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene, and a mechanistic rational has been formulated. Paper IV (J. Org. Chem. 2014, 79, 7266−7276) focuses on the diastereospecific synthesis of E/Z bicyclo[2.2.1]heptane-7- and oxabicyclo[2.2.1]heptane-8-oximes and their corresponding C-nitroso derivatives. The comparative kinetic and thermodynamic studies of the conversions of the C-nitroso side products to the required oximes have been delineated leading to the synthesis of desmethyl sugar derivatives.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1189
Keyword
pentofuranose chemistry, conformationally locked nucleoside, carbocyclic-LNA, bicyclo[2.2.1]heptane
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-233898 (URN)978-91-554-9069-0 (ISBN)
Public defence
2014-11-28, A1:104b, Uppsala university , BMC, Husargatan 3, Uppsala, 14:15 (English)
Opponent
Supervisors
Available from: 2014-11-06 Created: 2014-10-13 Last updated: 2015-02-13Bibliographically approved

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Karimiahmadabadi, MansourehErfan, SayehFöldesi, AndrásChattopadhyaya, Jyoti

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