Palladium-Catalyzed Cyanation of Nucleobases: Total Synthesis of Toyocamycin, Sangivamycin, and a Mycalisine A Precursor

Abstract

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.

Key words

nucleosides - toyocamycin - sangivamycin - palladium catalysis - cyanation - late-stage modification

Publication History

Received: 22 March 2023

Accepted after revision: 24 April 2023

Accepted Manuscript online:
24 April 2023

Article published online:
25 May 2023

• References and Notes

• 1 Dong X, Tang J, Hu C, Bai J, Ding H, Xiao Q. Molecules 2019; 24: 737
• 2 Roy V, Agrofoglio LA. Drug Discovery Today 2022; 27: 1945
• 3a Vangeel L, Chiu W, De Jonghe S, Maes P, Slechten B, Raymenants J, André E, Leyssen P, Neyts J, Jochmans D. Antiviral Res. 2022; 198: 105252
• 3b Scotti C, Barlow JW. Nat. Prod. Commun. 2022; 17: 1
• 4 Seley-Radtke KL, Yates MK. Antiviral Res. 2018; 154: 66
• 5 Bhakuni DS, Rawat DS. Bioactive Marine Natural Products . Springer; New York: 2005
• 6 Perrone D, Marchesi E, Preti L, Navacchia ML. Molecules 2021; 26: 3100
• 7 Shaughnessy HK. Molecules 2015; 20: 9419
• 8 Kapdi AR, Sanghvi YS. In Palladium-Catalyzed Modification of Nucleosides, Nucleotides and Oligonucleotides . Kapdi AR, Maiti D, Sanghvi YS. Elsevier; Amsterdam: 2018: 1
• 9 Markley JC, Chirakul P, Sologub D, Sigurdsson ST. Bioorg. Med. Chem. Lett. 2001; 11: 2453
• 10 Ding H, Ruan Z, Kou P, Dong X, Bai J, Xiao Q. Mar. Drugs 2019; 17: 226
• 11 Chang CT. C, Edwards MW, Torrence PF, Mertes MP. J. Med. Chem. 1979; 22: 1137
• 12 Bhattacharya BK, Rao TS, Revankar GR. J. Chem. Soc., Perkin Trans. 1 1995; 1543
• 13 Neetha M, Afsina CM. A, Aneeja T, Anilkumar G. RSC Adv. 2020; 10: 33683
• 14 Fatiadi AJ. In Triple-Bonded Functional Groups . Patai S, Rappoport Z. Wiley; Chichester: 1983
• 15 Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC. J. Med. Chem. 2010; 53: 7902
• 16 Yan G, Zhang Y, Wang J. Adv. Synth. Catal. 2017; 359: 4068
• 17 Kapdi A, Gayakhe V, Sanghvi YS, Garcia J, Lozano P, da Silva I, Perez J, Serrano JL. RSC Adv. 2014; 4: 17567
• 18 Bhilare S, Shet H, Sanghvi YS, Kapdi AR. Molecules 2020; 25: 1645
• 19 Murthy Bandaru SS, Bhilare S, Schulzke C, Kapdi AR. Chem. Rec. 2021; 21: 188
• 20 Nauth AM, Opatz T. Org. Biomol. Chem. 2019; 17: 11
• 21 Senecal TD, Shu W, Buchwald SL. Angew. Chem. Int. Ed. 2013; 52: 10035
• 22 Cohen DT, Buchwald SL. Org. Lett. 2015; 17: 202
• 23 Zhang X, Xia A, Chen H, Liu Y. Org. Lett. 2017; 19: 2118
• 24 Wang X, Zhi B, Baum J, Chen Y, Crockett R, Huang L, Eisenberg S, Ng J, Larsen R, Martinelli M, Reider R. J. Org. Chem. 2006; 71: 4021
• 25 Di Francesco ME, Avolio S, Pompei M, Pesci S, Monteagudo E, Pucci V, Giuliano C, Fiore F, Rowley M, Summa V. Bioorg. Med. Chem. 2012; 20: 4801
• 26 Clough DW, Wigdahl BL, Parkhurst JR. Antimicrob. Agents Chemother. 1978; 14: 126
• 27 Guerniou V, Gasparutto D, Sauvaigo S, Favier A, Cadet J. Nucleosides, Nucleotides Nucleic Acids 2003; 22: 1073
• 28 Mycalasine 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-d ₆): 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
• 30 Porcari AR, Townsend LB. Nucleosides Nucleotides 1999; 18: 153
• 31 Toyocamycin (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-d ₆): 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
• 33 Rao KV. J. Med. Chem. 1968; 11: 939
• 34 Ingale SA, Leonard P, Seela F. J. Org. Chem. 2018; 83: 8589