Synlett 2005(9): 1385-1388  
DOI: 10.1055/s-2005-868489
LETTER
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Base-Selective H-D Exchange Reaction of Nucleosides in Deuterium Oxide

Hironao Sajiki*, Hiroyoshi Esaki, Fumiyo Aoki, Tomohiro Maegawa, Kosaku Hirota
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502-8585, Japan
Fax: +81(58)2375979; e-Mail: sajiki@gifu-pu.ac.jp;
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Publikationsverlauf

Received 5 April 2005
Publikationsdatum:
27. April 2005 (online)

Abstract

We have developed an efficient and extensive deuterium incorporation method using a heterogeneous Pd/C-D2O-H2 system into the base moiety of nucleosides. The results presented here provide a deuterium gas-free, totally catalytic, and post-synthetic deuterium labeling method in D2O media.

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D2 gas [¥ 31300/10 L of D2 gas (Aldrich 36840-7) in lecture bottle] is purchased as a lecture bottle or a cylinder charged by high-pressure.

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Typical Procedure for Deuteration of Adenosine (Table 1, entry 3): Adenosine (66.8 mg, 0.25 mmol) and 10% Pd/C (6.7 mg, 10 wt% of the substrate, Aldrich) in D2O (1 mL) was stirred at 160 °C in a sealed tube under a H2 atmosphere for 24 h. After cooling, the reaction mixture was filtered using a membrane filter (Millipore Millex®-LG). The filtered catalyst was washed with boiling water (50 mL) and the combined filtrates were concentrated in vacuo to give adenosine-d 2 as a white powder (66.3 mg, 98%). The deuterium content (%) was determined by 1H NMR using 3-trimethylsilyl-1-propanesulfonic acid sodium salt (DSS) as an internal standard and confirmed by mass spectroscopy. [α]D 20 -55 (c 0.38, H2O) [adenosine Lit.16 [α]D 11 -62 (c 0.71, H2O)]. 1H NMR (400 MHz, DMSO-d 6): δ = 8.37 (s, 0.053 H), 8.12 (s, 0.042 H), 7.34-7.30 (br s, 2 H), 5.90 (d, J = 6.4 Hz, 1 H), 5.45-5.41 (m, 2 H), 5.20 (d, J = 4.9 Hz, 1 H), 4.63 (dd, J = 4.9, 6.4 Hz, 1 H), 4.16 (dd, J = 3.4, 4.4 Hz, 1 H), 3.99 (dd, J = 3.4, 3.4 Hz, 1 H), 3.72-3.67 (m, 1 H), 3.60-3.54 (m, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 156.2, 152.3 (small peak), 149.0, 139.9 (small peak), 119.3, 87.9, 85.9, 73.4, 70.6, 61.6. 2H NMR (400 MHz, DMSO): δ = 8.02 (br). MS (ES+): m/z (%) = 269 (3) [M + 2].

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Specific rotations of nucleosides: Table [1] , entry 2 [a]D 19 -60 (c 0.38, H2O) {adenosine Lit.16 [α]D 11 -62 (c 0.71, H2O)}; Table [1] , entry 3 [α]D 20 -55 (c 0.38, H2O) {adenosine Lit.16 [α]D 11 -62 (c 0.71, H2O)}; Table [1] , entry 4 [α]D 20 -19 (c 0.36, CH3OH) {deoxyadenosine [α]D 20 -20 (c 0.36, CH3OH)}; Table [2] , entry 1 [α]D 20 -59 (c 0.25, 0.02 N NaOH) {guanosine [α]D 20 -61 (c 0.30, 0.02 N NaOH)}; Table [2] , entry 2 [α]D 21 -46 (c 0.34, H2O) {inosine Lit.16 [α]D 18 -49 (c 0.9, H2O)}; Table [3] , entry 4 [α]D 21 +5 (c 0.27, H2O) {uridine Lit.16 [α]D 20 +4 (c 2)}; Table [3] , entry 7 [α]D 21 +25 (c 0.26, H2O) {cytidine Lit.16 [α]D 25 +31 (c 0.7, H2O)}; 1 [α]D 21 +18 (c 0.74, CH3Cl) {2′,3′,5′-tris-O-TBDMS-uridine [α]D 22 +22 (c 0.83, CH3Cl)}.