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

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.

nucleosides - palladium - reaction - H-D exchange - base-selective

References

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2a Ruth TL. Oligonucleotides and their Analogues   IRL Press; London: 1991. 

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4 Very recently an attractive method for monitoring reaction kinetics using ²H NMR was reported: Durazo A. Abu-Omar MM. Chem. Commun.  2002,  66 

5a Gani D. Young DW. J. Chem. Soc., Chem. Commun.  1983,  576 

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9

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.

10 Sajiki H. Hattori K. Aoki F. Yasunaga K. Hirota K. Synlett  2002,  1149 

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11b Maegawa T. Akashi A. Esaki H. Aoki F. Sajiki H. Hirota K. Synlett  2005,  845 

Matsubara et al. also reported interesting Pd/C-catalyzed H-D exchange reactions under hydrothermal conditions, see:

12a Matsubara S. Yokota Y. Oshima K. Chem. Lett.  2004,  33:  294 

12b Yamamoto M. Yokota Y. Oshima K. Matsubara S. Chem. Commun.  2004,  1714 

12c Yamamoto M. Oshima K. Matsubara S. Org. Lett.  2004,  6:  5015 

13

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].

14

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)}.

15 Although Matsubara et al. recently reported quite interesting H-D exchange reaction of primary alcohols at the α-position using RuCl₂(PPh₃)₂ as a catalyst, we observed no competitive deuterium incorporation into the sugar moieties, see: Takahashi M. Oshima K. Matsubara S. Chem. Lett.  2005,  34:  192 

16 The Merck Index 13^th Ed.   Merck & Co., Inc.; Whitehouse Station: 2001.