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Synlett 2005(12): 1927-1929  
DOI: 10.1055/s-2005-871582
LETTER
© Georg Thieme Verlag Stuttgart · New York

Convenient and Regioselective Synthesis of Nucleoside Phosphoramidate Monoesters

Jigang Zhua, Hua Fu*a, Yuyang Jianga,b, Yufen Zhaoa
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
b Key Laboratory of Chemical Biology, Guangdong Province, Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
Fax: +86(10)62781695; e-Mail: fuhua@mail.tsinghua.edu.cn;
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Publication History

Received 14 May 2005
Publication Date:
07 July 2005 (online)

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Abstract

We have developed a convenient and efficient method for the synthesis of nucleoside phosphoramidate monoesters. This step-wise synthesis, consisting of an ester exchange, reaction of the 5′-OH of nucleosides with fluorenylmethyl aryl phosphite, and an Atherton-Todd reaction, gave fluorenylmethyl nucleoside 5′-phosphoramidates; final removal of the fluorenylmethyl group yielded the desired target products in good yields.

Key words

phosphoramidate - ester-exchange - diphenyl phosphite - nucleoside - Atherton-Todd reaction

6

Spectroscopic data of selected compounds: Fm-U-P-LeuOCH3 ( 6bb). Overall yield from 1 to 6: 82%. 1H NMR (300 MHz, CDCl3): δ = 0.77-0.82 (d, 6 H, CH3, 3 J = 6.00 Hz), 1.26 (m, 2 H, β-CH2), 1.40 (m, 1 H, γ-CH), 3.49-3.62 (m, 4 H, OCH3, α-CH), 3.85 (m, 5′-CH2), 3.99 (Fm-CH), 4.02 (m, 1 H, 4′-CH), 4.14 (t, 1 H, 3′-CH), 4.25 (t, 1 H, 2′-CH), 5.21 (2 H, Fm-CH2), 5.81 (1 H, 1′-CH), 5.62 (d, 1 H, 3-CH), 7.74 (d, 1 H, 2-CH), 7.20-7.55 (8 H, Fm-Ar-). 13C NMR (75 MHz, CDCl3): δ = 21.67 (CH3), 22.73 (CH3), 24.54 (γ-CH), 43.84 (β-CH2), 48.09 (Fm-CH), 52.34 (OCH3), 52.86 (α-CH), 64.80 (5′-CH2), 68.46 (2′-CH), 69.84 (3′-CH), 72.40 (Fm-CH2), 83.10 (4′-CH), 89.81 (1′-CH), 102.70 (3-CH), 120.12, 124.98, 127.26, 127.97, 140.34, 141.42 (Fm-Ar), 143.17 (2-CH), 151.21 (6-C), 163.98 (3-C), 174.68 (CO). 31P NMR (121 MHz, CDCl3): δ = 8.70, 8.50. ESI-MS (Positive): m/z = 630 [M + H]+. U-P-LeuOCH 3 ( 7bb). Total yield from 1 to 7: 73%. 1H NMR (300 MHz, D2O): δ = 0.73-0.75 (d, 6 H, CH3, 3 J = 6.00 Hz), 1.38 (m, 2 H, β-CH2), 1.54 (m, 1 H, γ-CH), 3.60-3.62 (4 H, m, OCH3, α-CH), 3.83-3.94 (m, 5′-CH2), 4.12 (m, 1 H, 4′-CH), 4.18 (t, 1 H, 3′-CH), 4.23 (t, 1 H, 2′-CH), 5.84 (1 H, 1′-CH), 5.83 (d, 1 H, 3-CH), 7.85 (d, 1 H, 2-CH). 13C NMR (75 MHz, CDCl3): δ = 21.45 (CH3), 21.98 (CH3), 24.26 (γ-CH), 43.09 (d, β-CH2, 3 J P-C = 7.16 Hz), 52.61 (OCH3), 53.48 (α-CH), 63.60 (5′-CH2), 69.91 (2′-CH), 73.87 (3′-CH), 83.53 (d, 4′-CH, 3 J P-C = 8.61 Hz), 88.65 (1′-CH), 102.69 (3-CH), 141.86 (2-CH), 151.81 (6-C), 166.19 (3-C), 178.27 (CO). 31P NMR (121 MHz, D2O): δ = 7.01. ESI-MS (Negative): m/z = 450 [M - H]-.