Installation of cyano group functionality onto nucleosides has always been a challenging task for chemists, and catalytic protocols developed for simple aryl substrates have, in most cases, failed to replicate their success when applied to nucleobase or sugar moieties of nucleosides. Given the importance of the cyano and amide functionalities in nucleoside chemistry, we herein disclose an efficient Pd-catalyzed cyanation protocol specifically applied to iodo nucleobases. Furthermore, the developed cyanation method has been explored for the synthesis of naturally occurring and bioactive nucleosides such as toyocamycin, sangivamycin, and a mycalisine A precursor.
28Mycalasine A Precursor 6
A clean, dried, 25 mL Schleck tube equipped with a magnetic stirrer bar was charged with Pd2(dba)3 (2.8 mg, 0.3 mol%), Xantphos (3.5 mg, 0.6 mol%), and DMA (0.5 mL), and the mixture was stirred at rt under N2 for 5 min. Iodo nucleoside 5 (120 mg, 0.3 mmol) was then added, followed by Zn(CN)2, (22 mg, 0.18 mmol) and DMA (0.5 mL), and the resultant mixture was stirred at 85 °C for 12 h until the reaction was complete [TLC; CH2Cl2–MeOH (90:10)]. The product was purified by column chromatography [silica gel, CH2Cl2–MeOH (90:10)] to give an off-white solid; yield: 57 mg (75%).
IR (FT-IR): 2224.03 cm–1 (CN). 13C {1H} NMR (101 MHz, DMSO-d6): δ = 157.43, 153.96, 150.51, 132.67, 115.72, 101.69, 88.38, 83.42, 83.39, 79.73, 73.76, 61.54, 57.99.
29
Bastea LI,
Hollant LM. A,
Döppler HR,
Reid EM,
Storz P.
Sci. Rep. 2019; 9: 16588
31Toyocamycin (10)
A clean, dried, 25 mL Schleck tube equipped with a magnetic stirrer bar was charged with Pd2(dba)3 (3.2 mg, 0.35 mol%), Xantphos (4.05 mg, 0.7 mol%), and DMA (0.5 mL), and the mixture was stirred at rt under N2 for 5 min. Iodo nucleoside 9 (140 mg, 0.35 mmol) was added, followed by Zn(CN)2 (25 mg, 0.21 mmol) and DMA (0.5 mL), and the resultant mixture was stirred at 85 °C for 12 h until the reaction was complete [TLC, CH2Cl2–MeOH (90:10)]. The product was purified by column chromatography [silica gel, CH2Cl2–MeOH (90:10)] to give a white solid; yield: 82 mg (79%).
IR (FT-IR): 2223.7 cm–1 (CN). 13C {1H} NMR (101 MHz, DMSO-d6): δ = 157.43, 153.95, 150.57, 132.79, 115.74, 101.68, 88.22, 85.91, 83.38, 74.72, 70.63, 61.63.
32
De Clercq E,
Balzarini J,
Madej D,
Hansske F,
Robins MJ.
J. Med. Chem. 1987; 30: 481
