Stereoselective Synthesis of Fluoro-homoneplanocin A as a Potential Antiviral Agent

Abstract

Fluoro-homoneplanocin A (4) was synthesized from d-ribose, via the enyne ring-closing metathesis of 9, the stereoselective opening of epoxide 23a with fluoride, and a simultaneous oxidation-elimination reaction. The key intermediate 8 is expected to serve as a versatile intermediate for the synthesis of carbanucleosides.

Structure–Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities

“…13 However, unlike the successful openings of the one-carbon homologated α-and β-epoxides with fluoride (n-Bu 4 NH 2 F 3 , KHF 2 ), the same fluorination reactions of 9a and 9b did not give the desired fluorinated compounds, 10a and 10b, respectively. The bulky trityl protecting group may have prevented the approach of the fluoride anion to the epoxide.…”

“…The combined organic layers were washed with brine (25 mL), dried over anhydrous MgSO 4 , and evaporated. The crude residue was purified by flash silica gel column chromatography (hexanes/ethyl acetate = 2:1) to give 10 (1.13 g, 70%) as a white foam: [α] D 25 −9.5°(c 0.70, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ 1.35 (s, 3H), 1.52 (s, 3H), 2.59 (d, J = 9.6 Hz, 1H), 2.94 (s, 1H), 3.24 (dd,J = 2.8,9.6 Hz,1H),3.40 (dd,J = 0.8,9.6 Hz,1H),4.22 (dd,J = 2.8,6.0 Hz,1H),1H),4.53 (dt,J = 2.0,6.0 Hz,1H),4.70 (dd,J = 7.2,7.6 Hz,1H),9 H),6H); 13 1 Hz),112.3,127.5,128.8,128.9,143.5;19 F NMR (376 MHz) (2R,3S,4S,5R)-2-Fluoro-3-hydroxy-4,5-(O-isopropylidenedioxy) -3-(trityloxymethyl)cyclopentanone (11) and (4R,5R)-2-Fluoro-4,5-(O-isopropylidenedioxy)-3-(trityloxymethyl)-cyclopent-2-ene-1-one (12). To a stirred solution of 10 (0.56 g, 1.21 mmol) in dry DMSO (10 mL) and benzene (12 mL) were added EDCI (0.70g, 3.63 mmol), pyridine (0.15 mL, 1.81 mmol), and TFAA (0.097 mL, 1.81 mmol), and the reaction mixture was stirred at rt for 15 h, quenched with water (15 mL), and extracted with EtOAc (30 mL).…”

“…8 (1R,4R,5S)-2-Fluoro-4,5-(O-isopropylidenedioxy)-3-(trityloxymethyl)cyclopent-2-ene-1-ol (13). To a solution of 12 (1.23 g, 2.76 mmol) in MeOH (25 mL) were added CeCl 3 ·7H 2 O (1.02 g, 274 mmol) and NaBH 4 (0.1 g, 263 mmol) at 0°C, and the mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (30 mL) and evaporated to half volume.…”

“…1 H NMR (400 MHz, CDCl 3 , with DIAD byproduct impurity) δ 1.03 (s, 3H), 1.08 (s, 3H), 1.27 (s,9H),2H),2H),4.64 (d,J = 5.2 Hz,1H),5.30 (d,J = 6.0 Hz,1H),5.59 (d,J = 8.8 Hz,1H),6H),4H),7.97 (s,1H),8.75 (s,1H 2H),4.56 (d,J = 5.2 Hz,1H),5.14 (d,J = 5.2 Hz,1H),5.71 (s,1H),5.99 (s,1H),6H),4H),8.13 (s,1H), 8.90 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 19.40, 26.30, 27.11, 27.62, 29.91, 31.97, 61.65, 67.22, 76.67, 84.68, 85.19, 112.90, 121.67, 128.05, 130.12, 133.55, 135.75, 143.85, 146.60, 152.62, 152.91 (1S,2R,5S) 5-(6-Chloropurine-9-yl)-3-hydroxyethylcyclopent-3-en-1,2-diol (23). 13 Compound 20 (1.0 g with DIAD byproduct) was dissolved in trifluoroacetic acid (5 mL) and water (5 mL) at 0°C, and the mixture was stirred at room temperature for 4 h. The mixture was evaporated and coevaporated with MeOH. The crude residue was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 10:1) to give 23 ( 61, 60.81, 67.43, 76.32, 78.46, 126.36, 132.77, 147.04, 149.88, 151.29, 152.90, 153.45.…”

“…Herein, we report the stereoselective synthesis of the neplanocin A analogue 5, using stereoselective epoxidation, the regio-and stereoselective fluorination, and their AdoHcy hydrolase inhibitory activity along with their antiviral and anticancer activities. 13 …”