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. Author manuscript; available in PMC: 2011 Aug 4.
Published in final edited form as: Bull Chem Soc Ethiop. 2010;24(3):439–446. doi: 10.4314/bcse.v24i3.60692

N-6 Substituted Deoxygenated Derivatives of L-like 5'-Noraristeromycin

Henry Yu 1, Tesfaye Serbessa 1,*
PMCID: PMC3149869  NIHMSID: NIHMS251158  PMID: 21822360

Abstract

Several N-6 substituted derivatives (4–11) of (+)-4'-deoxy-5'-noraristeromycin (2) and its unsaturated counterpart (3) have been prepared. The derivatives are designed to systematically vary the hydrophobic/hydrophilic balance of the lead compounds. These compounds were evaluated against a large number of viruses but, no significant antiviral activity was observed. Also, no cytotoxicity to host cells was found.

Keywords: L-like, Carbocyclic Nucleosides, HBV

Introduction

Carbocyclic nucleosides, modified nucleosides in which the oxygen of the sugar moiety is replaced by a methylene group, have been the subject of numerous investigations since the discovery of the antiviral properties of aristeromycin [1] and neplanocin A [2], two such naturally occurring compounds (Figure 1). These nucleosides owe their antiviral activity to an inhibition of S-adenosyl-L-homocysteine (SAH) hydrolase, a cellular enzyme that catalyses the hydrolysis of S-adenosyl-L-homocysteine, which is both a by-product and biofeedback inhibitor of methylation reactions interfering with viral messenger RNA maturation [3,4]. Carbocyclic nucleosides show limited susceptibility to enzymatic degradation as a consequence of the absence of the natural N-glycosidic bond and have proven to be clinically useful antiviral agents as evidenced by the approval of abacavir for the treatment of human immunodeficiency virus (HIV AIDS) [5].

Figure 1.

Figure 1

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Biologically active cabrocyclic nucleosides

The hepatitis B virus (HBV) is hepatotropic virus that causes acute and chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). An estimated 350 million people worldwide are chronically infected with the virus [6]. Despite the recent advances in the treatment and prevention of HBV, poor response rates to the current interventions, emergence of resistance and high rate of incidence of side effects remain a serious challenge [7–9]. Also, end-stage liver disease complications caused by chronic hepatitis B in patients co-infected with HIV highlight the need for new therapeutic agents [10].

The significant anti-HBV activity of (+)-5'-noraristeromycin, 1, an L-like carbocyclic nucleoside (L-like nucleosides have opposite stereochemistry of the natural D-nucleosides), was reported in 1997 [11] (Figure 2). The 4'-deoxy derivative, 2, was subsequently synthesized and investigation of its biological activity against HBV showed a 10-fold increase [12]. The unsaturated counterpart, 3, has a slightly lower activity with a reduced cytotoxicity. To investigate the effect of changes in lipophilicity of 2 and 3 on their activity toward HBV, several N-6 substituted derivatives (4–11) were designed and synthesized (Figure 2).

Figure 2.

Figure 2

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Structures of lead and target compounds

Chemistry

The retro synthetic analysis of this class of compounds revealed that derivatives (4–7) can be synthesized from the protected alcohol 12 and 6-chloropurine, 13 (Scheme 1). The steps used to realize the synthesis of the target compounds are shown in Scheme 2. Mitsunobu coupling [13,14] of 12, which was derived by catalytic hydrogenation from the unsaturated counterpart 19 [15,16], with 6-chloropurine led to 14. Reaction of 14 with various primary amines [17] yielded 15–18. Removal of the isopropyldene group [12] with acidic resin gave targets 4–7.

Scheme 1.

Scheme 1

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Retrosynthetic approach

Scheme 2.

Scheme 2

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Synthesis of targets 4–7

The same approach was used for the synthesis of 8–11. The allylic alcohol 19 [15,16], was coupled with 6-chloropurine under Mitsunobu conditions to give 20 (Scheme 3). Reaction of the chloronucleoside 20 with several primary amines led to a series of compounds (21–24) which were deprotected [12] with acidic resin to yield 8–11. Scheme 3

Scheme 3.

Scheme 3

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Synthesis of targets 8–11

Antiviral analysis

To investigate their biological potential, 4–11 were subjected to antiviral screening versus hepatitis B virus (HBV), Epstein-Barr Virus (EBV), Human Cytomegalovirus (HCMV), Varicella-Zoster Virus (VZV), Hepatitis C Virus (HCV), West Nile Virus, Yellow Fever Virus, Pichinde, herpes simplex-1, herpes simplex-2, herpes simplex-1 (TK−), vaccinia, vesicular stomatitis, coxsackie B4, respiratory syncytial, parainfluenza 3, reovirus-1, Sindbis, Venezuelan Equine Encephalitis Virus (VEE), and Punta Toro. No significant activity was found. Also, no cytotoxicity arose in the cell lines used in the antiviral assays.

Conclusion

The synthesis of several N-6 substituted deoxygenated derivatives of L-like 5'-noraristeromycin has been achieved. The introduction of N-6 alkyl groups resulted in the loss of significant antiviral potency probably because of increased hydrophobicity and/or diminished hydrogen bonding with target macromolecule. Currently, the synthesis of several 2'- and 3'-deoxy derivatives of (+)-4'-deoxy-5'-noraristeromycin, 2, is underway as part of an ongoing effort to determine the structural entities necessary for activity.

Experimental Section

General Methods

Melting points were recorded on a Meltemp II point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Bruker AC 250 Spectrometer (operated at 250 or 62.9 MHz, respectively) or AC 400 Spectrometer (operated at 400 or 100 MHz, respectively). All 1H chemical shifts are reported in δ relative to the internal standard tetramethylsilane (TMS, δ 0.00 ppm). 13C chemical shifts are reported in δ relative to CDCl3 (center of triplet, δ 77.23 ppm) or relative to DMSO-d6 (center of septet, δ 39.51 ppm). The spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). Elemental analyses were performed by the Atlantic Microlabs, Atlanta, Georgia. Reactions were monitored by thin-layer chromatography (TLC) using 0.25 mm E. Merck silica gel 60-F254 precoated silica gel plates with visualization by irradiation with a Mineralight UVGL-25 lamp or exposure to iodine vapor. Column chromatography was performed on Whatman silica gel (average particle size 5–25 μm, 60 Å) and elution with the indicated solvent system. Yields refer to chromatographically and spectroscopically (1H and 13C NMR) homogeneous materials.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopentan-1'-yl]-6-chloro-9H-purine (14)

A suspension of 6-chloropurine (2.5 g, 16 mmol) and triphenylphosphine (4.2 g, 16 mmol) in anhydrous THF (80 mL) was chilled to −20 °C and treated with a drop wise addition of diisopropyl azodicarboxylate (DIAD) (3.3 g, 16 mmol). The reaction mixture was stirred for 10 min at the same temperature, after which the acetone-dry ice bath was removed and stirring was continued for 15 min. This was followed by addition of a solution of 12 (3.2 g, 20 mmol) in anhydrous THF (80 mL) and the reaction mixture was stirred at room temperature for 2 h and then at 55 °C for 24 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography eluting with EtOAc/hexanes (1:2) to yield 14 (3.0 g, 64%) as a white solid: mp 109–110 °C; 1H-NMR (CDCl3) δ 1.35 (s, 3H), 1.55 (s, 3H), 2.13–2.24 (m, 3H), 2.53–2.58 (m, 1H), 4.90–5.00 (m, 3H), 8.06 (s, 1H), 8.76 (s, 1H); 13C-NMR (CDCl3) δ 24.3, 26.7, 29.7, 31.5, 63.2, 80.7, 85.0, 111.6, 132.1, 144.0, 151.4, 151.8, 152.0; Anal. for (C13HI5O2N4Cl) C, H, N.

General Experimental Procedure (15–18)

To a solution of 14 (0.9 g, 3 mmol) in THF (100 mL) was added the corresponding amine (methylamine in THF 2 M, 15 mL, cyclopropylamine 1.7 g, cyclopentylamine 2.6 g, and cycloheptylamine 3.4 g). For compounds 15 and 16, the mixture was heated at 85 °C for 24 h in a sealed steel bomb where as it was refluxed for 24 h for 17 and 18. The volatiles were evaporated and the residue was purified by column chromatography using EtOAc/hexanes.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopentan-1'-yl]-6-methylamino-9H-purine (15)

EtOAc/hexanes (4:1), gummy solid (76%): 1H-NMR (DMSO-d6) δ 1.25 (s, 3H), 1.44 (s, 3H), 1.86–1.88 (m, 1H), 2.03–2.10 (m, 2H), 2.26–2.29 (m, 1H), 2.95 (brs, 3H), 4.76–4.78 (m, 1H), 4.88–4.91 (m, 2H), 7.67 (brs, 1H), 8.13 (s, 1H), 8.22 (s, 1H); 13C-NMR (DMSO-d6) δ 24.2, 26.5, 27.0, 29.1, 30.6, 60.7, 80.0, 84.4, 110.2, 139.0, 152.4, 155.0; Anal. for (C14H19O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopentan-1'-yl]-6-cyclopropylamino-9H-purine (16)

EtOAc/hexanes (3:1), gummy solid (66%): 1H-NMR (CDCl3) δ 0.62–0.69 (m, 2H), 0.90–0.95 (m, 2H), 1.35 (s, 3H), 1.51 (s, 3H), 2.07–2.20 (m, 3H), 2.48–2.58 (m, 1H), 3.03–3.04 (m, 1H), 4.81–4.83 (m, 1H), 4.95–5.01 (m, 2H), 5.91 (brs, 1H), 7.67 (s, 1H), 8.48 (s, 1H); 13C-NMR (CDCl3) δ 7.5, 23.8, 24.3, 26.7, 29.6, 31.5, 62.3, 76.7, 77.2, 77.8, 80.8, 85.1, 111.3, 120.3, 138.4, 149.2, 153.4, 156.0; Anal. for (CI6H21O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopentan-1'-yl]-6-cyclopentylamino-9H-purine (17)

EtOAc/hexanes (1:1), gummy solid (77%): 1H-NMR (CDCl3) δ1.34 (s, 3H), 1.53 (s, 3H), 1.55–1.77 (m, 8H), 2.10–2.18 (m, 4H), 2.48 (m, 1H), 4.81–4.82 (m, 1H), 4.94–5.00 (m, 2H), 5.69 (brs, 1H), 7.64 (s, 1H), 8.39 (s, 1H); 13C-NMR (CDCl3) δ 23.8, 24.3, 26.7, 29.5, 31.5, 33.6, 52.6, 62.2, 80.8, 85.1, 111.3, 120.1, 138.1, 153.3, 154; Anal. for (C18H25O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopentan-1'-yl]-6-cycloheptylamino-9H-purine (18)

EtOAc/hexanes (1:1), gummy solid (60%): 1H-NMR (CDCl3) δ 1.34 (s, 3H), 1.53 (s, 3H), 1.48–1.68 (m, 10H), 2.04–2.09 (m, 6H), 2.31–2.34 (m, 1H), 4.80–4.82 (m, 1H), 4.94–5.00 (m, 2H), 5.64 (d, 1H, J=8 Hz), 7.64 (s, 1H), 8.37 (s, 1H); 13C-NMR (CDCl3) δ 24.1, 24.4, 26.8, 28.5, 29.7, 31.6, 35.5, 62.3, 73.5, 80.9, 85.2, 111.3, 138.1, 153.4, 154.2; Anal. for (C20H29O2N5) C, H, N.

General Experimental Procedure (4–7, and 8–11)

To a solution of the amine substituted nucleosides 15–18 and 21–24 (0.6 g) in MeOH (70mL) was added Dowex 50×8 acidic resin beads (6 g) and the mixture was refluxed for 24 h. After the solvent was removed, the residue was loaded onto a Dowex resin column and the product was eluted with 50 % NH4OH. Following removal of the NH4OH by evaporation, the residue was co-evaporated with EtOH (3 × 20 mL), and purified by silica gel column eluting with MeOH/CH2Cl2.

Preparation of (1'S,2'R,3'S)-1'-(6-methylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopentane (4)

MeOH/CH2Cl2 (1:20), white solid (86 %): mp 162–164 °C; 1H-NMR (DMSO-d6) δ 1.65–1.66 (m, 1H), 1.98–1.99 (m, 1H), 2.10–2.23 (m,2H), 2.97 (brs, 3H), 4.01 (brs, 1H), 4.38–4.41 (m, 1H), 4.66–4.72 (m, 2H), 4.92–4.94 (m,1H), 7.60 (brs, 1H), 8.17 (s, 1H), 8.20 (s, 1H); 13H-NMR (DMSO-d6) δ 25.8, 27.0, 28.9,59,70.5, 76.3, 119.9, 140.1, 148.8, 152.0, 155.0; Anal. for (C11H15O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-cyclopropylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopentane (5)

MeOH/CH2Cl2 (1 :20), white solid (74%): mp 206–207 °C; 1H-NMR (DMSO-d6) δ 0.59–0.62 (m, 2H), 0.70–0.72 (m, 2H), 1.62–1.65 (m, 1H), 1.96–1.98 (m, 1H), 2.11–2.22 (m, 2H), 3.01 (brs, 1H), 4.00–4.01 (m, 1H), 4.36–4.41 (m, 1H), 4.66–4.72 (m, 2H), 4.92 (d, 1H, J=8 Hz), 7.79 (d, 1H, J=4 Hz), 8.18 (s, 1H), 8.21 (s, 1H); 13C-NMR (CDCl3) δ 6.4, 24.9, 25.7, 28.8, 54.9, 59.5, 70.5, 76,2, 119.8, 140.3, 151.9, 155.6; Anal.for (C13H17O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-Cyclopentylamino-9H-purin-9-yl)-2' ,3'-dihydroxycyclopentane (6)

MeOH/CH2Cl2 (1:30), white solid (84%): mp 187–189 °C; 1H-NMR (DMSO-d6) δ 1.56–1.71 (m, 8H), 1.95–2.18 (m, 5H), 4.00 (brs, 1H), 4.38–4.40 (m, 1H), 4.68–4.72 (m, 2H), 4.94 (d, 1H, J=5 Hz), 7.57 (d, 1H, J=7.5 Hz), 8.17 (s, 1H); 13C-NMR(CDCl3) δ 23.5, 25.8, 28.9, 32.3, 59.5, 70.5, 76.3, 140.0, 151.9, 154; Anal. for (C15H21O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-cycloheptylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopentane (7)

MeOH/CH2Cl2 (1:40), white solid (79%): mp 192–193 °C; 1H-NMR (DMSO-d6) δ 1.45–1.65 (m, 11 H), 1.86–2.17 (m, 6H), 4.00 (brs, 1H), 4.36–4.40 (m, 1H), 4.66–4.71 (m, 2H), 4.94 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=7.5 Hz), 8.16 (s, 2H); 13C-NMR (CDCl3) δ 23.8, 25.7, 27.8, 28.8, 59.5, 70.5, 76.2, 140.0, 152.0, 153.6; Anal. for (C17H25O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopent-4'-en-1'-yl]-6-chloro-9H-purine (20)

A suspension of 6-chloropurine (5.0 g, 32 mmol) and triphenylphosphine (8.4 g, 32 mmol) in anhydrous THF (100 mL) was chilled to −20 °C and treated with a drop wise addition of diisopropyl azodicarboxylate (DIAD) (6.6 g, 32 mmol). The reaction mixture was stirred for 10 minutes at the same temperature, after which the acetone-dry ice bath was removed and stirring was continued for 15 minutes. This was followed by addition of a solution of 19 (6.2 g, 40 mmol) in anhydrous THF (80 mL) and the reaction mixture was stirred at room temperature for 2 h and at 55 °C for 24 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography eluting with EtOAc/hexanes (1:2) to yield 20 (5.8 g, 61 %) as a white solid: 13C-NMR (CDCl3) δ 1.38 (s, 3H), 1.52 (s, 3H), 4.73 (d, 1H, J=5 Hz), 5.54 (d, 1H, J=5 Hz), 5.72 (s, 1H), 5.98 (d, 1H, J=5 Hz), 6.41 (d, 1H, J=5 Hz), 8.01 (s, 1H), 8.79 (s, 1H) 13C-NMR (CDCl3) δ 25.9, 27.5, 66.4, 83.9, 84.8, 112.9, 128.8, 132.1, 139.4, 143.4,151.2, 151.4, 152.4; Anal. for (C13H13O2N4Cl) C, H, N.

General Experimental Procedure (21–24)

To a solution of 20 (1.0g, 3.4mmol) in THF (70mL) was added the corresponding amine (methylamine in THF 2 M, 20 mL, cyclopropylamine 1.9 g, cyclopentylamine 2.4 g, and cycloheptylamine 3.8 g). For compounds 21 and 22, the mixture was heated at 85 °C for 24 h in a sealed steel bomb where as it was refluxed for 24 h for 23 and 24. The volatiles were evaporated and the residue was purified by column chromatography using EtOAc/hexanes.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopent-4'-en-1'-yl]-6-methylamino-9H-purine (21)

EtOAc/hexanes (2:1), gummy solid (61 %): 1H-NMR (DMSO-d6) δ 1.27 (s, 3H), 1.39 (s, 3H), 2.94 (brs, 3H), 4.68 (d, 1H, J=5 Hz), 5.48–5.52 (m, 2H), 5.97–6.00 (m, 1H), 6.26 (d, 1H, J=5 Hz), 7.74 (brs, 1H), 7.96 (s, 1H), 8.22 (s, 1H) 13C-NMR (DMSO-d6) δ 25.6, 27.2, 64.6, 83.3, 84.5, 111.1, 130.2, 137.2, 138. 8, 152.6, 155.0; Anal. for (C14H17O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopent-4'-en-1'-yl]-6-cyclopropylamino-9H-purine (22)

EtOAc/hexanes (3:1), gummy solid (58%): 1H-NMR (CDCl3) δ 1.39 (s, 3H), 1.48 (s, 3H), 1.55–1.63 (m, 3H), 2.21–2.25 (m, 2H), 4.66 (d, 1H, J=5 Hz), 5.39 (d, 1H, J=5 Hz), 5.45 (s, 1H), 5.79 (d, 1H, J=5 Hz), 5.92–5.96 (m, 1H), 6.35–6.38 (m, 1H) 7.66 (s, 1H), 8.39 (s, 1H) 13C-NMR (CDCl3) δ 23.1, 24.9, , 34.5, 65.7, 82.2, 84.1, 110.6, 122.3, 136.6, 138.3, 151.1, 152.7 Anal. for (C16H19O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopent-4'-en-1'-yI]-6-cyclopentylamino-9H-purine (23)

EtOAc/hexanes (1:1), gummy solid (70%): 1H-NMR (CDCl3) δ 1.36 (s, 3H), 1.50 (s, 3H), 1.52–1.80 (m, 7H), 2.10–2.17 (m, 2H), 4.69 (d, 1H, J=5 Hz), 5.49 (d, 1H, J=5 Hz), 5.63 (s, 1H), 5.79 (d, 1H, J=5 Hz), 5.95–5.98 (m, 1H), 6.32–6.36 (m, 1H) 7.60 (s, 1H), 8.43 (s, 1H) 13C-NMR (CDCl3) δ 23.9, 25.9, 27.5, 33.6, 65.6, 84.2, 84.8, 112.6, 129.8, 137.6, 138.3, 153.7, 154.7; Anal. for (C18H23O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-9-[2',3'-(Isopropylidenedioxy)cyclopent-4'-en-1'-yl]-6-cycloheptylamino-9H-purine (24)

EtOAc/hexanes (1:1), (60%) as a gummy solid: 1H-NMR (DMSO-d6) δ 1.27 (s, 3H), 1.38 (s, 3H), 1.44–1.65 (m, 11H), 1.85–1.88 (m, 2H), 4.68 (d, 1H, J=5 Hz), 5.47–5.52 (m, 2H), 5.96–5.99 (m, 1H), 6.26 (d, 1H, J=5 Hz), 7.57 (d, 1H, J=5 Hz) 7.95 (s, 1H), 8.19 (s, 1H) 13C-NMR (DMSO-d6) δ 23.7, 23.8, 25.6, 27.2, 64.5, 83.3, 84.5, 111.1, 130.2, 137.2, 138.7, 152.6, 153.1; Anal. for (C20H27O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-methylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopent-3-ene (8)

MeOH/CH2Cl2 (1:20), white solid (66%): mp 164–166°C; 1H-NMR (DMSO-d6) δ 2.94 (brs, 3H), 4.27–4.32 (m, 1H), 4.54 (brs, 1H), 4.93–4.97(m, 1H), 5.07–5.12 (m, 1H), 5.37 (m, 1H), 5.98 (d, 1H, J=5 Hz), 6.12 (d, 1H, J=5 Hz), 7.66 (brs, 1H), 8.06 (s, 1H), 8.19 (s, 1H) 13H-NMR (DMSO-d6) δ 64.7, 72.6, 76.2, 132.5, 136.0, 139.4,152.3,155.0; Anal. for (C11H13O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-cyclopropylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopent-3-ene (9)

MeOH/CH2Cl2 (1:20), white solid (69%): mp 185–187°C; 1H-NMR (DMSO-d6) δ 0.60–0.71 (m, 4H), 3.05 (brs, 1H), 4.32 (s, 1H), 4.54 (s, 1H), 4.95 (d, 1H, J= 5Hz), 5.10 (d, 1H, J=5 Hz), 5.39 (s, 1H), 6.00 (s, 1H), 6.13 (s, 1H), 7.87 (s, 1H), 8.08(s, 1H), 8.21 (s, 1H) 13C-NMR (DMSO-d6) δ 6.4, 23.9, 64.6, 72.5, 76.2, 119.5, 132.5, 135.9, 139.5, 152.2, 155.5; Anal. for (C13H15O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-cyclopentylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopent-3-ene (10)

MeOH/CH2Cl2 (1 :30), white solid (60%): mp 170–172 °C 1H-NMR (DMSO-d6) δ 1.23–1.71 (m,7H), 1.93–194 (m, 2H), 4.30 (d, 1H, J=5 Hz), 4.54 (brs,1H), 4.94 (d, 1H, J=5 Hz), 5.09 (d, 1H, J=5 Hz), 5.38 (brs, 1H), 5.98 (brs, 1H), 6.12 (brs, 1H), 7.61 (d, 1H, J=5 Hz), 8.07 (s, 1H), 8.16 (s, 1H) 13C-NMR (CDCl3) δ 23.9, 33.6, 65.1, 73.0, 76.6, 112.6, 132.7, 136.4, 144.3, 153.7, 154.7; Anal. for (C15H19O2N5) C, H, N.

Preparation of (1'S,2'R,3'S)-1'-(6-cycloheptylamino-9H-purin-9-yl)-2',3'-dihydroxycyclopent-3-ene (11)

MeOH/CH2Cl2 (1:40), white solid (71 %): mp 125–127 °C 1H-NMR (DMSO-d6) δ 1.44–1.65 (m, 11H), 1.86–1.89 (m, 2H), 4.31 (brs, 1H), 4.55 (brs, 1H), 4.96 (brs, 1H), 5.11 (brs, 1H), 5.38–5.40 (m, 1H), 5.97–6.00 (m, 1H), 6.11–6.15 (m, 1H), 7.50 (d, 1H, J=7.5 Hz), 8.07 (s, 1H), 8.17 (s, 1H) 13C-NMR (DMSO-d6) δ 23.5, 27.5, 27.5, 50.4, 64.3, 72.3, 75.9, 132.2, 135.6, 138.9, 151.9, 153.2; Anal. for (C17H23O2N) C, H, N.

Acknowledgments

This research was supported by funds from the Department of Health and Human Services (AI 83926), which is appreciated. We would also like to thank Dr. Erik De Clercq, the Rega Institute, Leuven Belgium; Dr. Earl Kern, University of Alabama at Birmingham, Birmingham, AL; Dr. Brent Korba, Georgetown University, Washington, DC; and Dr. Robert Sidwell, Utah State University, Ogden, UT for the antiviral testing.

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