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Synthesis 2008(8): 1233-1240  
DOI: 10.1055/s-2008-1042942
PAPER
© Georg Thieme Verlag Stuttgart · New York

Diastereoselective Synthesis of d-erythro- and d-threo-Isoxazolidinyl ­Nucleosides

Eva Hýrošováa, Lubor Fišera*a, Jozef Kožíšekb, Marek Froncb
a Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak Republic
Fax: +421(2)52968560; e-Mail: lubor.fisera@stuba.sk;
b Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak Republic­
Further Information

Publication History

Received 14 November 2007
Publication Date:
18 March 2008 (online)

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Abstract

The synthesis of isoxazolidinyl nucleosides based on the Vorbrüggen nucleosidation of 5-acetoxyisoxazolidines 5 and 9 is reported. The 1,3-dipolar cycloaddition of d-erythro-nitrone 4 with vinyl acetate proceeded with respectable anti-facial (84:16) and endo-facial (72:28) diastereoselectivity to give the diastereomeric isoxazolidines 5-7. The reaction of d-threo-nitrone 8 with vinyl acetate is more selective and proceeds with excellent anti-facial preference producing only two diastereomers 9 and 10, although four diastereomers are possible. The condensation of the acetoxyisoxazolidines 5 and 9 with silylated uracil, thymine, N-acetylcytosine, N 2-acetylguanine, and purines proceeded with moderate to excellent stereoselectivity with formation of the expected isoxazolidinyl β- and α-nucleosides. The stereoselectivity of the addition of silylated nucleobase is depended on the structure of the substituent at C3 originating from the starting chiral nitrone and on the attacking nucleobase.

Key words

nucleosides - isoxazolidines - cycloadditions - C-glycosyl nitrones - stereoselective synthesis

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6

Crystal data of compound 5: C23H37NO6Si, M = 451.63, orthorhombic, P212121, a = 9.764 (1) Å, 10.393 (1) Å, 25.479 (2) Å, V = 2585.6 (4) Å3, Z = 4, Dx = 1.160 mg m-3, µ (Mo-Kα) = 0.126 mm-1, F(000) = 976, colorless block, 0.104 × 0.146 × 0.782 mm-3, 65565 diffractions measured (Rint = 0.067), 6751 unique, wR2 = 0.1545, conventional R = 0.0483 on I values of 2882 diffractions with I > 2.0σ(I), (Δ/σ)max = 0.001), S = 0.902 for all data and 280 parameters. Unit cell determination and intensity data collection (θmax = 29.58°) were performed on a Gemini R diffractometer [10] at 198 (1) K. Structure solution was done busing direct methods [11] and refinements were achieved by full-matrix least-squares method [11] on F**2. Further details of the crystal structure investigation can be obtained from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (CCDC deposition no. 667909).
Crystal data of compound 10: C23H37NO6Si, M = 451.63, orthorhombic, P212121, a = 11.724 (1)Å, 20.530 (2) Å, 20.887 (1) Å, V = 5027.5 (2) Å3, Z = 8, Dx = 1.193 mg m-3, µ (Mo-Kα) = 0.1246 mm-1, F(000) = 1952, colorless block, 0.186 × 0.237 × 0.723 mm-3, 120826 diffractions measured (Rint = 0.043), 10249 unique, wR2 = 0.0904, conventional R = 0.0360 on I values of 7674 diffractions with I > 2.0σ(I), (Δ/σ)max = 0.001), S = 1.043 for all data and 561 parameters. Unit cell determination and intensity data collection (θmax = 26.37°) were performed on a Gemini R diffractometer [10] at 100 (1) K. Structure solution was done busing direct methods [11] and refinements were achieved by full-matrix least-squares method [11] on F**2. Further details of the crystal structure investigation can be obtained from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (CCDC deposition no. 667908).

7

Brandenburg, K. DIAMOND, Visual Information System for Crystal Structures, Bonn, Germany.

10

Oxford Diffraction (2007), CrysAlis CCD and CrysAlis RED, Oxford Diffraction Ltd, Abingdon, Oxfordshire, England.

11

Sheldrick, G. M. SHELXS97 and SHEXL97, University of Göttingen, Germany, 1997.