ARTICLE pubs.acs.org/joc Preparation of Nucleosides Derived from 2-Nitroimidazole and D-Arabinose, D-Ribose, and D-Galactose by the Vorbru€ggen Method and Their Conversion to Potential Precursors for Tracers To Image Hypoxia Anna Schweifer and Friedrich Hammerschmidt* Institute of Organic Chemistry, University of Vienna, W€ahringerstrasse 38, A-1090 Vienna, Austria bS Supporting Information ABSTRACT: 2-Nitroimidazole was silylated using hexaethyldisilazane and then reacted with 1-O-acetyl derivatives of D-arabinose, D-ribose, and D-galactose in acetonitrile at mild temperatures ( 20 C to rt), catalyzed by triethylsilyl triﬂate (Vorbr€uggen conditions). The α-anomer was formed in the former case and the β- anomers in the latter two cases (highly) selectively. When D-arabinose and D-ribose were silylated with tert-butyldiphenylsilyl chloride in pyridine at the hydroxyl groups at C-5 and acetylated at the other ones in a one-pot reaction, mixtures of anomeric 1-O-acetyl derivatives were obtained. These were coupled by the Vorbr€uggen method and then deblocked at C-5 and tosylated to give precursors for tracers to image hypoxia in four steps without using Hg(CN)2 necessary for other methods. The Vorbr€uggen conditions enable a shorter route to azomycin nucleoside analogues than the previous coupling procedures. ’ INTRODUCTION A large body of evidence indicates that tumor hypoxia has a negative prognosis predictive value for solid tumor progression, likeliness of metastasis and tumor prognosis, likeliness of metas- tasis, and overall survival.1 3 In addition, tumor cell hypoxia has a negative eﬀect on anticancer treatment because of resistance to radiation.4,5 Accordingly, it is important to identify and localize tumor hypoxia in the management and treatment of cancer patients. Contrary to invasive methods based on the oxygen electrode system6 to determine the oxygenation distribution in the tumor, noninvasive ones7,8 are based on imaging using radiolabeled (123I, 124I, 125I, 18F, 60Cu, 62Cu, 64Cu) tracers 1 6 (Figure 1), preferably 18F-labeled 2-nitroimidazoles. The tracer's primary cellular uptake results from diﬀusion and parti- tion-based retention in lipophilic tissue. The 2-nitroimidazole (azomycin)-based tracers are thought to be reduced in hypoxic cells to reactive intermediates, which bind to macromolecular components. Thus, they tend to be accumu- lated in sites of hypoxia and can be used for imaging purposes with single-photon-emission tomography (SPECT) and posi- tron emission tomography (PET), the latter being the method of choice. Indeed, a number of radiotracers for viable hypoxic cells in solid tumors are being evaluated clinically.9 The initial imaging studies of tumor hypoxia used iodine-123-labeled iodoazomycin arabinoside (α-IAZA, 4) with SPECT10 and ﬂuorine-18-labeled ﬂuoromisonidazole (FMISO, 1) with PET.11,12 Recently, [18F]ﬂuoroerythronitroimidazole ([18F]FETNIM, 2) was stu- died as a hypoxia imaging agent.13 The copper complex copper- (II) diacetylbis(N4-methylthiosemicarbazone) (Cu-ATMS, 3) labeled with the positron emitter 60Cu, 62Cu, or 64Cu is another promising hypoxic imaging agent under evaluation.14 Figure 1. Radiolabeled tracers for imaging hypoxia. More recently, the ﬂuoroazomycin arabinoside α-[18F]FAZA (5) has been studied extensively alone and relative to FMISO.15 It was found that α-[18F]FAZA and [18F]FMISO are taken up selelctively in vitro and in vivo in hypoxic cells.16 Machulla et al. observed that α-[18F]FAZA shows biokinetics superior to that of [18F]FMISO and is, thus, a promising PET tracer for visualization of solid tumor hypoxia. The 125I- and 124I-labeled Received: April 7, 2011 Published: September 09, 2011 r 2011 American Chemical Society 8159 dx.doi.org/10.1021/jo200727k | J. Org. Chem. 2011, 76, 8159–8167