Synthesis of 4-thiofuranoid 1,2-glycals and their application to stereoselective synthesis of 4'-thionucleosides

Article abstract of DOI:10.1016/S0040-4039(00)00366-X

Convenient one-pot procedures using iodine monochloride have been developed for the preparation of two 4-thio-1,2-glycals from readily available starting materials and for their β-anomer selective conversion into 2'-iodo-4'-thionucleosides. Conditions for

Full text of DOI:10.1016/S0040-4039(00)00366-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3265–3268
Synthesis of 4-thiofuranoid 1,2-glycals and their application to
stereoselective synthesis of 40-thionucleosides
J. Allen Miller,∗ Ashley W. Pugh and G. Mustafa Ullah
Department of Medicinal Chemistry, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS, UK
Received 7 February 2000; accepted 28 February 2000
Abstract
Convenient one-pot procedures using iodine monochloride have been developed for the preparation of two 4-
thio-1,2-glycals from readily available starting materials and for their β-anomer selective conversion into 20-iodo-
40-thionucleosides. Conditions for the reductive de-iodination of these iodonucleosides have been established and
hence routes to a range of 20-deoxy-40-thionucleosides become feasible. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: 4-thio-1,2-glycals; stereoselective addition; 20-deoxy-40-thionucleosides.
Over the last two decades or so, furanoid 1,2-glycals have emerged as synthetically accessi-
ble intermediates1 and, subsequently, have been of value in stereoselective syntheses of nucleoside
analogues.2 For the preparation of conventional pyrimidine and purine nucleosides, the required regio-
and stereoselective trans-addition to the double bond of the glycal is initiated by a soft electrophile and
then completed via trapping, at the 1-position of the glycal, by a silylated base. The usefulness of glycals
in anomer selective nucleoside synthesis is therefore dependent upon the facial selectivity of the addition,
which, precedence suggests, is largely controlled by the ligands at C-3 and C-4.3
Another feature of recent nucleoside literature has been the renewed interest in 40-thionucleosides,4
particularly evident for the 20-deoxy series. It therefore seemed apposite to study the generation of 4-
thiofuranoid 1,2-glycals, then novel in the chemical literature, and hence investigate their application to
stereoselective synthesis of 40-thionucleosides. After our studies were initiated, examples of protected 4-
thio-1,2-glycals were described by Swedish and Japanese groups.5 A general synthesis of 1-substituted
4-thio-1,2-glycals has also appeared.6 Here we report the synthesis of two 4-thio-1,2-glycals direct
from readily available benzylthio glycosides,7 and then their application to pyrimidine 40-thionucleoside
synthesis. Our synthesis, outlined in Scheme 1, uses the glycosides (1) and (2), each of which is an
anomeric mixture, and can be conveniently prepared on the multi-gram scale.7 For the generation of
∗
Corresponding author. Protherics PLC, Beechfield House, Lyme Green Business Park, Macclesfield, Cheshire SK11 0JL,
UK. Tel: +0044 1625 500555; fax: 0044 1625 500666; e-mail: allen.miller@protherics.com (J. A. Miller)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00366-X
tetl 16643

3266
glycals (3) and (4), the preferred method uses iodine monochloride (ICl) in the presence of 2,6-di-t-butyl-
4-methylpyridine, and routinely gives 60–70% yields. The expensive base appears to be desirable for
reproducibility and ease of work-up, but, fortunately, it can be recovered and reused. Both (3) and (4) can
be stored at −10°C under nitrogen, and are stable enough to be purified by rapid flash chromatography,
although they are not stable enough to permit microanalysis, and (4), in particular, decomposes to 2-
hydroxymethylthiophene upon standing in solution at room temperature.
Scheme 1. Reagents: (i) ICl or NIS, 2,6-di-t-butyl-4-methylpyridine; (ii) 2,4-bis-trimethylsilyloxy-5-ethylpyrimidine
Using additions to (3) and (4) as probes (see Scheme 1), it was found that N-iodosuccinimide
(NIS) and ICl were preferred over other agents used previously2 for nucleoside synthesis. One of our
long-term targets was a β-selective synthesis of 20-deoxy-40-thionucleosides,8 because normal coupling
methodology produces at best a 3:2-ratio in favour of the α-anomer, and, moreover, anomer separation
is exceedingly tedious. With thioglycal (3) and 2,4-bis-trimethylsilyloxy-5-ethylpyrimidine, the anomer
ratio (5):(6) was about 3:2 in favour of the β-isomer, the structure of which was confirmed by NOE
difference spectroscopy. For example, for (5) it was shown that irradiation at H-6 enhanced the signals
for H-30 and H-20, but not that for H-40, thus confirming the β-configuration. With the L-xylothioglycal
(4) a ratio of about 20:1 for (7):(8) was achieved. In (4), the presence of both the ligands on the same
face of the thioglycal dictates that productive interaction with the iodine occurs largely on the opposite
face, and, in turn, this controls the preference for β-nucleoside formation in the main product (7). By
comparison, the di-benzylated oxygen glycal analogue of (4) gave a ratio of about 9:1 in favour of the
β-isomer.3
The observation that ICl could replace NIS in the above additions suggested that a one-pot route
from glycal precursor, e.g. (2), to iodonucleoside, e.g. (7), may be possible, and would have the merit
of avoiding the need to handle sensitive glycal intermediates. As shown in Scheme 2, (7) was prepared
in yields of about 70%, using 2,4-bis-trimethylsilyloxy-5-ethylpyrimidine8 as the trapping base. Initial
attempts to de-iodinate the diastereomeric mixture of (7) and (8), using tributyltin hydride and azobis-
isobutyronitrile at 80°C in toluene, resulted in predominant ring-opening by breaking the sulphur to
anomeric carbon bond — a mode not seen in the oxygen series. We subsequently found that heating at
45–60°C in toluene led to good yields of (9), which was then debenzylated9 to give (10). Stereochemical
assignment to (10) was based on accepted NMR shift and coupling data,10 and was confirmed by

3267
NOE difference spectroscopy. These findings are entirely consistent with the only other report5b on the
thioglycal addition route to β-20-deoxy-40-thionucleosides. Our use of ICl leads to a three-step sequence
from (2), whereas the previous route5b requires seven steps from (2).
Scheme 2. Reagents: (i) ICl, 2,6-di-t-butyl-4-methylpyridine; (ii) 2,4-bis-trimethylsilyloxy-5-ethylpyrimidine; (iii) Bu3SnH,
AIBN, toluene; (iv) BBr3/CH2Cl2, −78°C
In principle, this type of sequence opens the way to anomer selective syntheses of a whole range of 40-
thionucleosides, which are of potential interest in the fields of anti-viral and anti-tumour chemotherapy.4
Details of key experimental procedures are given below.
General procedure for the preparation of 4-thio-1,2-glycals. Compound (3): Thioglycoside (1) (0.5
g, 1.15 mmol) was dissolved in dry dichloromethane (5 ml) whilst stirring under nitrogen at 0°C. 2,6-
Di-t-butyl-4-methylpyridine (0.47 g, 2.29 mmol) was added and the reaction mixture stirred for 10 min,
before adding a solution of iodine monochloride (0.224 g, 1.38 mmol) in dichloromethane (2 ml) over
10 min. The mixture was allowed to warm up to room temperature and then stirred for a further 3 h,
before quenching with a saturated solution of sodium thiosulphate and extracting with dichloromethane
(3×10 ml). The combined extracts were washed with water, then with brine and dried over magnesium
sulphate. After evaporating the solvent, the crude product was purified by flash chromatography. Elution
with ethyl acetate:light petroleum (bp 40–60°C) (1:9) gave the desired glycal (3)11 as a pure (TLC) oil
(0.230 g, 64%).
Preferred one-pot procedure for the preparation of 20-iodonucleosides. Compound (7): Thioglycoside
(2) (0.436 g, 1.00 mmol) was dissolved in dry dichloromethane (20 ml) under nitrogen at 0°C, and 2,6-
di-t-butyl-4-methylpyridine (0.41 g, 2.00 mmol) was added to the stirred solution. Iodine monochloride
(0.195 g, 1.20 mmol) in dichloromethane (5 ml) was added dropwise over 10 min and the mixture stirred
at 0°C until all of the thioglycoside starting material had been consumed (as shown by TLC). A solution
of freshly prepared bis-silylated base made from 5-ethyluracil (0.288 g, 2.00 mmol) in dichloromethane
(10 ml) was added at 0°C, followed by a solution of a further portion of iodine monochloride (0.195 g,
1.20 mmol) in dichloromethane (5 ml). The reaction mixture was allowed to warm to room temperature,
and stirring was continued overnight. A saturated solution of sodium thiosulphate was added and
the reaction mixture extracted with chloroform (3×20 ml), before drying the combined extracts over
magnesium sulphate. 1H NMR of the crude product showed the β:α-anomer ratio to be 20:1. The crude
product was purified by flash chromatography. The iodonucleoside (7)12 (0.404 g, 70%) was a white
powder, mp 103–104°C.
Procedure for reductive de-iodination and debenzylation. Compounds (9) and (10): Iodonucleoside
(7) (1.0 g, 1.73 mmol) and azobis-isobutyronitrile (100 mg) were dissolved in dry toluene (10 ml) and
this solution was added dropwise over 20 min to a solution of tributyltin hydride (1.4 ml, 5.2 mmol)
in dry toluene (30 ml) stirred under argon at 45°C. The temperature was gradually raised to 60°C and
stirring maintained until reduction was complete (4–5 h). After cooling to room temperature, a saturated
solution of ammonium chloride (50 ml) was added and the mixture extracted with ethyl acetate (3×3
ml). The organic phase was washed with brine and dried over magnesium sulphate. After removal of the

3268
solvents, the crude reaction product was purified by flash chromatography, eluting with ethyl acetate:light
petroleum (40–60°C) (1:1) to give nucleoside (9)13 (0.6 g), as a thick syrup. This was then debenzylated
using a solution of boron tribromide (1.73 g, 4 mol equiv.) in dichloromethane at −78°C.9 After
flash column chromatography with chloroform:methanol (1:1) and then recrystallization from aqueous
methanol, nucleoside (10)14 (0.272 g, 58%) was isolated as a white solid, mp 189.5–191°C.
References
1. Cheng, J. C.; Hacksell, U.; Daves, G. D. J. Org. Chem. 1985, 50, 2778–2780; Abramski, W.; Chmielewski, M. J. Carbohydr.
Chem. 1994, 13, 125–128; Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661–6666; Kassou, M.;
Castillon, S. Tetrahedron Lett. 1994, 35, 5513–5516; Bravo, F.; Kassou, M.; Castillon, S. ibid. 1999, 40, 1187–1190.
2. Kim, C. U.; Lu, B. Y.; Martin, J. C. J. Org. Chem. 1991, 56, 2642–2647; Kim, C. U.; Misco, P. F. Tetrahedron Lett. 1992, 33,
5733–5736; Grewal, G.; Kaila, N.; Frank, R. W. J. Org. Chem. 1992, 57, 2084–2092; Kawakami, H.; Ebata, T.; Koseki, K.;
Okano, K.; Matsumoto, K.; Matsushita, H. Heterocycles 1993, 36, 665–669; Wang, J.; Wurster, J. A.; Wilson, L. J.; Liotta,
D. Tetrahedron Lett. 1993, 34, 4881–4884; Chow, K.; Danishefsky, S. J. Org Chem. 1990, 55, 4211–4214.
3. El-Laghdach, A.; Diaz, Y.; Castillon, S. Tetrahedron Lett. 1993, 34, 2821–2822; Diaz, Y.; El-Laghdach, A.; Castillon, S.
Tetrahedron 1997, 53, 10 921–10 938.
4. For a review, see: Wnuk, S. F. Tetrahedron 1993, 49, 9877–9936. For selected leading references, see: Secrist, J. A.; Tiwari,
K. N.; Riordan, J. M.; Montgomery, J. A. J. Med. Chem. 1991, 34, 2361–2366; Tiwari, K. N.; Montgomery, J. A.; Secrist, J.
A. Nucleosides, Nucleotides 1995, 14, 675–686; Yoshimura, Y.; Wanatabe, M.; Satoh, H.; Ashida, N.; Ijichi, K.; Sakata, S.;
Machida, H.; Matsuda, A. J. Med. Chem. 1997, 40, 2177–2183; Yoshimura, Y.; Kitano, K.; Satoh, H.; Wanatabe, M.; Miura,
S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822–823; Dyson, M. R.; Coe, P. L.; Walker, R. T. J. Med.
Chem. 1991, 34, 2782–2786; Uenishi, J.; Motoyama, M.; Nishiyama, Y.; Wakabayashi, S. J. Chem. Soc., Chem. Commun.
1991, 1421–1422; Uenishi, J.; Takahashi, K.; Motoyama, M.; Akashi, H.; Sasaki, T. Nucleosides, Nucleotides 1994, 13,
1347–1361; Young, R. J.; Shaw-Ponter, S.; Thomson, J. B.; Miller, J. A.; Cumming, J. G.; Pugh, A. W.; Rider, P. Bioorg.
Med. Chem. Lett. 1995, 5, 2599–2604.
5. (a) Synthesis: Branalt, J.; Kvarnstrom, I.; Niklasson, G.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. J. Org. Chem.
1994, 59, 1783–1788; Branalt, J.; Kvarnstrom, I.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. J. Org. Chem. 1994, 59,
4430–4432; (b) Addition reactions: Haraguchi, K.; Nishikawa, A.; Sasakura, E.; Tanaka, H.; Nakamura, K. T.; Miyasaka, T.
Tetrahedron Lett. 1998, 39, 3713–3716.
6. O’Neil, I. A.; Hamilton, K. M.; Miller, J. A.; Young, R. J. Synlett. 1995, 151–152.
7. Dyson, M. R.; Coe, P. L.; Walker, R. T. Carbohydr. Res. 1991, 216, 237–238; Tiwari, K. N.; Montgomery, J. A.; Secrist, J.
A. Nucleosides, Nucleotides 1993, 12, 841–846.
8. Our prime focus was a β-selective synthesis of 1-(20-deoxy-40-thio-β-D-erythro-pentofuranosyl)-5-ethyluracil and related
structures as anti-herpes agents — see: Rahim, S. G.; Trivedi, N.; Bogunovic-Batchelor, M. V.; Hardy, G. W.; Mills, G.;
Selway, J. W. T.; Littler, E.; Coe, P.; Basnak, I.; Whale, R. F.; Walker, R. T. J. Med. Chem. 1996, 39, 789–795.
9. Bellon, L.; Barascut, J.-L.; Limpach, J.-L. Nucleosides, Nucleotides 1992, 11, 1467–1479.
10. Ewing, D. F.; Mackenzie, G. Nucleosides, Nucleotides 1996, 15, 809–820.
11. Thioglycal (3): 1H NMR (CDCl3) δ 3.42 (dd appearing as t, J=4 Hz, 1H, 50-CHOCH2Ph) and 3.58 (dd, J=4 and 3 Hz, 1H,
50-CHOCH2Ph), 3.95 (m, 1H, 40-CHS), 4.55 (m, 4H, 2×PhCH2O), 4.90 (bs, 1H, 30-CHOCH2Ph), 5.70 (dd, 1H, HC_C),
6.45 (d, J=3 Hz, 1H, SCH_C), 7.30 (m, 10H, 2×Ph). MS (m/z) 312 (M)+, 221 (M−CH2Ph)+, 204 (M−HOCH2Ph)+.
C19H20O2S requires: 312.
12. β-Iodonucleoside (7): 1H NMR (CDCl3) δ 0.9 (t, J=7 Hz, 3H, CH3CH2-), 1.9–2.2 (m, 2H, CH3CH2-), 3.8 (m, 3H, 50-CH2
and 40-CHS), 4.25 (dd, appears as t, J=6 Hz, 1H, 20-CHI), 4.55 (m, 4H, 2×OCH2Ph), 4.7 (dd, appears as t, J=6 Hz, 1H,
30-CHOCH2Ph), 6.28 (d, J=6 Hz, 1H, 10-CH), 7.25–7.4 (m, 10H, 2×Ph), 7.65 (s, 1H, 6-H), 9.75 (bs, 1H, NH). MS (m/z)
578 (M)+. Anal (C25H27O4N2SI): C, H, N.
1
13. β-Nucleoside (9): H NMR (CDCl3) δ 0.9 (t, J=7 Hz, 3H, CH3CH2-), 2.0–2.2 (m, 2H, CH3 CH2-), 2.3–2.6 (m, 2H, 20-
CH2), 3.8–4.1 (m, 3H, 50-CH2 and 40-CHS), 4.8 (dd appears as t, J=6 Hz, 1H, 30-CHOCH2Ph), 4.48 and 4.62 (two s, 4H,
2×OCH2Ph), 6.35 (dd, J=6 Hz, 4Hz, 1H, 10-CH), 7.2–7.4 (m, 10H, 2×Ph), 7.98 (s, 1H, C-6 CH), 9.0 (bs, 1H, NH).
14. β-Nucleoside (10): 1H NMR (CDCl3) δ 1.1 (t, J=7 Hz, 3H CH3CH2-), 2.2–2.6 (m, 4H, CH3CH2- and 20-CH2), 3.7 (m, 1H,
40-CH), 3.9 and 4.05 (dd, J=11, 7 Hz, 2H, 50-CH2OH), 4.5 (m, 1H, 30-CH), 4.7 (bs, 2H, two OH), 6.28 (dd, J=7, 3 Hz, 1H,
10-CH), 8.33 (s, 1H, C-6 CH). MS (m/z) 272 (M+). Anal (C11H16N2O4S): C, H, N.