Improved Large-scale Synthesis of 5-(Perylen-3-ylethynyl)-arabino-uridine (aUY11), the Broad-Spectrum Antiviral

Full text of DOI:10.1080/00304948.2017.1343040

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Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
Improved Large-scale Synthesis of 5-(Perylen-3-
ylethynyl)-arabino-uridine (aUY11), the Broad-
Spectrum Antiviral
Alexey A. Chistov, Sergey V. Kutyakov, Arsentiy V. Guz, Irina V. Mikhura,
Alexey V. Ustinov & Vladimir A. Korshun
To cite this article: Alexey A. Chistov, Sergey V. Kutyakov, Arsentiy V. Guz, Irina V. Mikhura,
Alexey V. Ustinov & Vladimir A. Korshun (2017) Improved Large-scale Synthesis of 5-(Perylen-3-
ylethynyl)-arabino-uridine (aUY11), the Broad-Spectrum Antiviral, Organic Preparations and
Procedures International, 49:4, 377-381, DOI: 10.1080/00304948.2017.1343040
To link to this article: http://dx.doi.org/10.1080/00304948.2017.1343040
Published online: 22 Aug 2017.
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Date: 23 August 2017, At: 08:13

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Organic Preparations and Procedures International, 49:377–381, 2017
Copyright Ó 2017 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1343040
OPPI BRIEF
Improved Large-scale Synthesis of
5-(Perylen-3-ylethynyl)-arabino-uridine (aUY11),
the Broad-Spectrum Antiviral
Alexey A. Chistov, Sergey V. Kutyakov, Arsentiy V. Guz,
Irina V. Mikhura, Alexey V. Ustinov, and Vladimir A. Korshun
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
Rigid amphipathic fusion inhibitors (RAFIs), 5-arylethynyl-uracil nucleosides with bulky
aryl groups, constitute a class of compounds active against enveloped viruses.1 Deriva-
tives of perylene, a pentacyclic aromatic hydrocarbon, are the most potent among RAFI
nucleosides with IC50 values ranging from 0.2 mM to 0.005 mM.1–4 5-(Perylen-3-yl-
ethynyl)-arabino-uridine (aUY11, 1) inhibits replication of enveloped viruses (HSV-1,
influenza virus, HCV, etc.) without cytotoxic and even cytostatic activities in cell cul-
tures.2 The only reported synthetic procedure1 was complicated with a lack of availability
of a key precursor, 3-ethynylperylene, and with high polarity and reduced solubility of
the key intermediate, a 30,50-O-silyl protected peryleneethynyl nucleoside derivative.
Therefore the synthesis was performed in less than 200 mg scale with 21% yield in the
last two steps. Studies of antiviral effects in animal models, however, require multigram
quantities of this compound, thus more efficient methods of preparation are needed.
Recently, we developed multigram scale procedure for the key starting compound,
3-ethynylperylene.5 Here we report an alternative 20,30,50-O-silyl protection strategy,
a procedure affording 4.5 g aUY11 (1) with 79% yield in the last two steps.
Received November 25, 2016; in final form March 16, 2017.
Address correspondence to Vladimir A. Korshun, Shemyakin-Ovchinnikov Institute of
Bioorganic Chemistry, 117997 Moscow, Russia. E-mail: korshun@ibch.ru
377

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378
Korshun et al.
A convenient route to 5-(alkyn-1-yl)uracil nucleosides using the Sonogashira
reaction developed more than three decades ago6,7 has become widely accepted in
nucleoside chemistry.8 The key step in the synthesis of aUY11 (1) is Sonogashira
coupling of a 5-iodo nucleoside derivative with 3-ethynylperylene.
Unfortunately, peryleneethynyl nucleoside 1 is poorly soluble in any solvent, thus
limiting the possibility of its chromatographic purification after direct preparation under
Sonogashira conditions from 5-iodo-arabino-uridine. To increase the solubility of the
Sonogashira coupling product, Markiewicz 30,50-O-silyl (tetraisopropyldisiloxane-1,
3-diyl) protection of 5-iodo-arabino-uridine was used.1 However, this approach leaves
the 20-hydroxyl unprotected, thus complicating the purification procedure; starting from
5-iodo-30,50-O-(tetraisopropyldisiloxane-1,3-diyl)-arabino-uridine the desired compound
1 was prepared in two steps (Sonogashira and desilylation) with 21% yield.1
Scheme 1 Conditions: (a) I2, CAN, AcOH, 80ꢀC; (b) TBDMS-Cl, imidazole, DMF, r.t.; (c)
Pd(PPh3)4, CuI, NEt3, DMF, r.t. under Ar; (d) NEt3¢3HF, THF.
We tested another silyl protection, tert-butyldimethylsilyl (TBDMS), covering all
three hydroxyls of the nucleoside. The starting arabino-uridine 2 was iodinated with ceric
ammonium nitrate (CAN) as oxidizing agent,9 and the resulting 5-iodo-arabino-uridine 3
was silylated with TBDMS-Cl to yield protected precursor 4 (Scheme 1). The Sonoga-
shira reaction product 5 is soluble enough to purify at a multi-gram scale by column
chromatography. Compound 5 was smoothly desilylated using triethylamine trihydro-
fluoride in THF10–12 to yield pure crystalline compound 1. The yield in the two last steps
is 79%. Moreover, the product was obtained in >25 times higher scale in one run versus
the Markiewicz protection approach.
To conclude, multigram scale synthesis of 5-(perylen-3-ylethynyl)-arabino-uridine
(aUY11, 1), a potent inhibitor of enveloped viruses replication, has been developed. The
compound was prepared from arabino-uridine in four steps and 54% overall yield.
Experimental Section
Reagents and solvents were from commercial suppliers and used as received, except DMF
and methanol were used freshly distilled over CaH2. 3-Ethynylperylene was prepared as
described.5,13 500 MHz 1H and 125.7 MHz 13C NMR spectra were recorded on a Bruker
DRX-500 or Bruker Avance 500 spectrometers and referenced to DMSO-d6 (2.50 ppm
1
1
1
for H and 39.5 ppm for 13C) or CDCl3 (7.26 ppm for H and 77.16 ppm for 13C). H
NMR coupling constants are reported in hertz (Hz) and refer to apparent multiplicities.
Electrospray ionization high resolution mass spectra (ESI HRMS) were recorded using

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Broad-Spectrum Antiviral
379
Thermo Scientific Orbitrap Exactive mass spectrometer in positive ion mode. Elemental
analysis was performed on a Thermo Finnigan CHNS-analyzer/EA1112. Analytical thin
layer chromatography was performed on Kieselgel 60 F254 precoated aluminum plates
(Merck). Silica gel column chromatography was performed using Merck Kieselgel 60
0.040–0.063 mm.
5-Iodo-arabino-uridine (3)
Arabino-uridine 2 (20.01 g, 85.5 mmol), iodine (11.94 g, 47.0 mmol) and CAN (23.93 g,
42.7 mmol) were suspended in glacial acetic acid (500 mL) and stirred at 80ꢀC for 1h.
The solvent was evaporated, and the residue was coevaporated with toluene 3 £ 50 mL,
then with methanol 3 £ 50 mL. The residue was purified by recrystallization from water
(200 mL). The precipitate was filtered, washed with water (100 mL) and dried over P2O5
to give pure 5-iodo-arabino-uridine 3 (25.8 g, 82%) as white solid. Rf 0.33 (CH2Cl2–
1
MeOH, 9:1 v/v). H NMR (DMSO-d6): d 11.66 (s, 1H, H3); 8.09 (s, 1H, H6); 5.95 (d,
1H, J D 4.6 Hz, H10); 5.62 (d, 1H, J D 5.2 Hz, 20-OH); 5.47 (d, 1H, J D 4.5 Hz, 30-OH);
5.16 (t, 1H, J D 5.2 Hz, 50-OH); 4.05–3.96 (m, 1H, H20); 3.93–3.87 (m, 1H, H30); 3.76–
2
3.69 (m, 1H, H40); 3.60 (m, J D 11.6 Hz, 2H, H50). 13C NMR (DMSO-d6): d 160.68
(C4); 150.19 (C2); 146.46 (C6); 85.24 (C10); 84.53 (C40); 75.34 (C20); 74.85 (C30); 67.59
C
(C5), 60.23 (C50). ESI HRMS (m/z): calcd for C9H11IN2NaO6 392.9554; found
392.9539, [MCNa]C.
20,30,50-Tris-O-(tert-butyldimethylsilyl)-5-iodo-arabino-uridine (4)
5-Iodo-arabino-uridine 3 (6.73 g, 18.19 mmol) was dissolved in dry DMF (20 mL). Then
TBDMS-Cl (19.19 g, 127 mmol) and imidazole (17.31 g, 255 mmol) were added. After
72 h the reaction was complete (TLC control). The mixture was poured into saturated
sodium bicarbonate (100 mL) and ethyl acetate (200 mL) was added. Organic layer was
separated, washed with water (3 £ 300 mL), dried over Na2SO4 and evaporated in vacuo.
The residue was purified by column chromatography on silica gel eluting with 10% ethyl
acetate in toluene. The solvent was evaporated, and pure 4 (10.81 g, 83%) was obtained
as white foam. Rf 0.67 (CH2Cl2–Me2CO, 19:1 v/v). 1H NMR (DMSO-d6): d 11.87 (s, 1H,
H3); 7.72 (s, 1H, H6); 6.00 (d, 1H, J D 3.3 Hz, H10); 4.12 (br. s, 1H, H20); 4.04 (br. s, 1H,
H30); 3.91–3.70 (m, 3H, H40, H50); 0.93–0.73 (m, 27H, SiC(CH3)3); 0.15–(-0.17) (m,
18H, Si(CH3)2). 13C NMR (DMSO-d6): d 160.31 (C4); 149.83 (C2); 145.51 (C6); 86.10
(C10); 85.90 (C40); 77.29 (C20); 76.07 (C30); 68.44 (C5), 62.17 (C50); 25.76, 25.55, 25.49
(9C, SiC(CH3)3); 17.98, 17.55, 17.49 (3C, SiC(CH3)3); (-4.78), (-4.85), (-5.31), (-5.37),
(-5.40), (-5.59) (6C, Si(CH3)2). ESI HRMS (m/z): calcd for C27H54IN2O6Si3C 713.2329;
found 713.2320, [MCH]C.
20,30,50-Tris-O-(tert-butyldimethylsilyl)-5-(perylen-3-ylethynyl)-arabino-uridine (5)
Compounds 4 (7.97 g, 11.18 mmol) and 3-ethynylperylene (3.70 g, 13.41 mmol) were
dissolved in dry DMF (400 mL). The mixture was evacuated and purged with argon three
times to remove traces of oxygen. Then tetrakis(triphenylphosphine)palladium (1.29 g,
1.34 mmol), copper (I) iodide (427 mg, 2.68 mmol) and triethyamine (3.1 mL,
26.82 mmol) were added. The mixture was stirred overnight and then poured into aque-
ous disodium EDTA (5 g/200 mL). Ethyl acetate (500 mL) was added, and the organic
layer was washed with water (5 £ 500 mL), dried over Na2SO4 and evaporated in vacuo.