Skip to main content
Log in

An effective and convenient synthesis of cordycepin from adenosine

  • Original Paper
  • Published:
Chemical Papers Aims and scope Submit manuscript

Abstract

Cordycepin is a purine nucleoside analog with potent and diverse biological activities. Herein, we designed two methods to synthesize cordycepin. One method mainly converted the 3′-OH group into an iodide group and further dehalogenation to yield the final product. Although this method presented a short synthetic procedure, the synthesis had a low overall yield, resulting in only 13.5% overall yield. To improve the overall yield of cordycepin, another synthetic route was studied, which consisted of four individual steps: (1) 5′-OH protection (2) esterification (3) -O-tosyl (-OTs) group removal (4) deprotection. The key step in the synthetic method involved the conversion of 5′-O-triphenylmethyladenosine to 3′-O-tosyl-5′-O-triphenylmethyladenosine, using LiAlH4 as reducing agent. The main advantages of this route were an acceptable total product yield and the commercial availability of all starting materials. The optimal reaction conditions for each step of the route were identified. The overall yield of cordycepin obtained from adenosine as the starting material was 36%.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10

Similar content being viewed by others

References

  • Ahn Y, Park S, Lee S, Shin S, Choi DH (2000) Cordycepin: selective Growth Inhibitor Derived from Liquid Culture of Cordyceps militaris against Clostridium spp. J Agric Food Chem 48:2744–2748. doi:10.1021/jf990862n

    Article  CAS  Google Scholar 

  • Aman S, Anderson DJ, Connolly TJ, Crittall AJ, Ji G (2000) From adenosine to 3′-deoxyadenosine: development and scale up. Org Process Res Dev 4:601–605. doi:10.1021/op000209x

    Article  CAS  Google Scholar 

  • Bentley HR, Cunningham KG, Spring FS (1951) 509. Cordycepin, a metabolic product from cultures of Cordyceps militaris (Linn.) link. Part II. The structure of cordycepin. J Chem Soc. doi:10.1039/JR9510002301

    Google Scholar 

  • Cunningham KG, Manson W, Spring FS, Hutchinson SA (1950) Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.) Link. Nature 166:949. doi:10.1038/166949a0

    Article  CAS  Google Scholar 

  • Grouiller A, Essadiq H, Najib B, Moliere P (1987) Regioselective O-p-toluenesulfonylation of nucleosides under solid/liquid phase-transfer conditions. Synthesis 1987:1121–1122. doi:10.1055/s-1987-28193

    Article  Google Scholar 

  • Guo P, Kai Q, Gao J, Lian ZQ, Wu CM, Wu CA, Zhu HB (2010) Cordycepin prevents hyperlipidemia in hamsters fed a high-fat diet via activation of AMP-activated protein kinase. J Pharmacol Sci 113:395–403. doi:10.1254/jphs.10041FP

    Article  CAS  Google Scholar 

  • Holbein S, Wengi A, Decourty L, Freimoser FM, Jacquier A, Dichtl B (2009) Cordycepin interferes with 3′ end formation in yeast independently of its potential to terminate RNA chain elongation. RNA 15:837–849. doi:10.1261/rna.1458909

    Article  CAS  Google Scholar 

  • Hunter KW, Crawford NP, Alsarraj J (2008) Mechanisms of metastasis. Breast Cancer Res 10:135–166. doi:10.1186/bcr1988

    Article  Google Scholar 

  • Katayama S, Takamatsu S, Naito M, Tanji S, Ineyama T, Izawa K (2006) A synthesis of 3′-α-fluoro-2′,3′-dideoxyadenosine via a bromine rearrangement during fluorination with MOST reagent. Cheminform 127:524–528. doi:10.1002/chin.200638182

    CAS  Google Scholar 

  • Li Q, Yang R, Ruan Z, Hu T, Ding H, Xiao Q (2013) Total synthesis of cordycepin. Chin J Organ Chem 33:1340–1344. doi:10.6023/cjoc201303009

    Article  CAS  Google Scholar 

  • Ma L, Zhang S, Du M (2015) Cordycepin from Cordyceps militaris prevents hyperglycemia in alloxan-induced diabetic mice. Nutr Res 35:431–439. doi:10.1016/j.nutres.2015.04.011

    Article  CAS  Google Scholar 

  • McDonald FE, Gleason MM (1996) Asymmetric synthesis of nucleosides via molybdenum-catalyzed alkynol cycloisomerization coupled with stereoselective glycosylations of deoxyfuranose glycals and 3-amidofuranose glycals. J Am Chem Soc 118:6648–6659. doi:10.1021/ja960581l

    Article  CAS  Google Scholar 

  • Moreau C, Kirchberger T, Swarbrick JM, Bartlett SJ, Fliegert R, Yorgan T, Bauche A, Harneit A, Guse AH, Potter BV (2013) Structure-activity relationship of adenosine 5′-diphosphoribose at the transient receptor potential melastatin2 (TRPM2) channel: rational design of antagonists. J Med Chem 56:10079–10102. doi:10.1021/jm401497a

    Article  CAS  Google Scholar 

  • Morio I, Masakatsu K (1967) Synthesis of purine cyclonucleoside having 8,3′-O-anhydro linkage. Chem Pharm Bull 15:1261–1262. doi:10.1248/cpb.15.1261

    Article  Google Scholar 

  • Müller WE, Weiler BE, Charubala R, Pfleiderer W, Leserman L, Sobol RW, Suhadolnik RJ, Schröder HC (1991) Cordycepin analogues of 2′,5′-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase. Biochemistry 30:2027–2033. doi:10.1021/bi00222a004

    Article  Google Scholar 

  • Ni H, Zhou XH, Li HH, Huang WF (2009) Column chromatographic extraction and preparation of cordycepin from Cordyceps militaris waster medium. J Chromatogr, B: Anal Technol Biomed Life Sci 877:2135–2141. doi:10.1016/j.jchromb.2009.06.009

    Article  CAS  Google Scholar 

  • Noh EM, Youn HJ, Jung SH, Han JH, Jeong YJ, Chung EY, Jung JY, Kim BS, Lee SH, Lee YR (2010) Cordycepin inhibits TPA-induced matrix metalloproteinase-9 expression by suppressing the MAPK/AP-1 pathway in MCF-7 human breast cancer cells. Int J Mol Med 25:255–260. doi:10.3892/ijmm_00000338

    CAS  Google Scholar 

  • Ohta Y, Lee JB, Hayashi K, Fujita A, Park DK, Hayashi T (2011) In vivo anti-influenza virus activity of an immunomodulatory acidic polysaccharide isolated from Cordyceps militaris grown on germinated soybeans. J Agric Food Chem 55:10194–10199. doi:10.1021/jf0721287

    Article  Google Scholar 

  • Rao YK, Fang SH, Wu WS, Yewmin T (2010) Constituents isolated from Cordyceps militaris suppress enhanced inflammatory mediator’s production and human cancer cell proliferation. J Ethnopharmacol 131:363–367. doi:10.1016/j.jep.2010.07.020

    Article  CAS  Google Scholar 

  • Shiragami H, Tanaka Y, Uchida Y, Iwagami H, Izawa K, Yukawa T (1992) A novel method for the synthesis of ddA and F-ddA via regioselective 2′-O-deacetylation of 9-(2,5-DI-O-Acetyl-3-bromo-3-deoxy-β-d-xylofuranosyl)adenine. Nucleosides Nucleotides 11:391–400. doi:10.1080/07328319208021713

    Article  CAS  Google Scholar 

  • Sugar AM, Mccaffrey RP (1998) Antifungal activity of 3′-deoxyadenosine (Cordycepin). Antimicrob Agents Chemother 42:1424–1427

    CAS  Google Scholar 

  • Takamatsu S, Katayama S, Naito M, Yamashita K, Ineyama T, Izawa K (2006) A facile synthetic method for 3′-α-fluoro-2′,3′-dideoxyadenosine. Nucleosides, Nucleotides Nucleic Acids 35:711–713. doi:10.1002/chin.200403214

    Google Scholar 

  • Todd A, Ulbricht TLV (1960) 656 Deoxynucleosides and related compounds Part IX A synthesis of 3′-deoxyadenosine. J Chem Soc. doi:10.1039/JR9600003275

    Google Scholar 

  • Townsend AP, Roth S, Williams HE, Stylianou E, Thomas NR (2009) New s-adenosyl-l-methionine analogues: synthesis and reactivity studies. Org Lett 11:2976–2979. doi:10.1021/ol9009859

    Article  CAS  Google Scholar 

  • Tuli HS, Sharma AK, Sandhu SS, Kashyap D (2013) Cordycepin: a bioactive metabolite with therapeutic potential. Life Sci 93:863–869. doi:10.1016/j.lfs.2013.09.030

    Article  CAS  Google Scholar 

  • Vodnala SK, Lundback T, Yeheskieli E, Sjoberg B, Gustavsson AL, Svensson R, Olivera GC, Eze AA, de Koning HP, Hammarstrom LG, Rottenberg ME (2013) Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis. J Med Chem 56:9861–9873. doi:10.1021/jm401530a

    Article  CAS  Google Scholar 

  • Wagner D, Verheyden JPH, Moffatt JG (1974) Preparation and synthetic utility of some organotin derivatives of nucleosides. J Org Chem 5:24–30. doi:10.1021/jo00915a005

    Article  Google Scholar 

  • Wong YY, Moon A, Duffin R, Barthet-Barateig A, Meijer HA, Clemens MJ, de Moor CH (2010) Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction. J Biol Chem 285:2610–2621. doi:10.1074/jbc.M109.071159

    Article  CAS  Google Scholar 

  • Zhou X, Meyer CU, Schmidtke P, Zepp F (2002) Effect of cordycepin on interleukin-10 production of human peripheral blood mononuclear cells. Eur J Pharmacol 453:309–317. doi:10.1016/S0014-2999(02)02359-2

    Article  CAS  Google Scholar 

  • Zhou X, Luo L, Dressel W, Shadier G, Krumbiegel D, Schmidtke P, Zepp F, Meyer CU (2008) Cordycepin is an immunoregulatory active ingredient of Cordyceps sinensis. Am J Chin Med 36:967–980. doi:10.1142/S0192415X08006387

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Science Foundation of China (No. 21576295).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shian Zhong.

Additional information

Shen Huang and Hui Liu contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2937 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, S., Liu, H., Sun, Y. et al. An effective and convenient synthesis of cordycepin from adenosine. Chem. Pap. 72, 149–160 (2018). https://doi.org/10.1007/s11696-017-0266-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11696-017-0266-9

Keywords

Navigation