Convenient and Regioselective Synthesis of Nucleoside Phosphoramidate Monoesters

Jigang Zhu; Hua Fu; Yuyang Jiang; Yufen Zhao

doi:10.1055/s-2005-871582

LETTER

Convenient and Regioselective Synthesis of Nucleoside Phosphoramidate Monoesters

Jigang Zhu^a, Hua Fu*^a, Yuyang Jiang^a,b, Yufen Zhao^a
^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;

Abstract

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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

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References

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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]^-.