Synthesis of 1-(3′,6′-anhydro-2′-deoxy-β-D-glucofuranosyl)-thymine

Article abstract of DOI:10.1081/SCC-120003393

Synthesis of bicyclic nucleoside 5 is described by coupling of 3 with bis(trimethylsilyl)thymine by use of Sn(IV)Cl as an activator. Synthesis of bicyclic 2′-deoxy analog 1 from 5 by radical deoxygenation of methylxanthate ester 6 is reported.

Full text of DOI:10.1081/SCC-120003393

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
SYNTHESIS OF 1-(3′,6′-ANHYDRO-2′-DEOXY- β-d-
GLUCOFURANOSYL)-THYMINE
Hari Babu Mereyala & Pallavi Pola
To cite this article: Hari Babu Mereyala & Pallavi Pola (2002) SYNTHESIS OF 1-(3′,6′-
ANHYDRO-2′-DEOXY- β-d-GLUCOFURANOSYL)-THYMINE, Synthetic Communications, 32:16,
2453-2458, DOI: 10.1081/SCC-120003393
To link to this article: http://dx.doi.org/10.1081/SCC-120003393
Published online: 16 Aug 2006.
Submit your article to this journal
Article views: 18
View related articles
Citing articles: 5 View citing articles
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of Newcastle, Australia]
Date: 28 March 2017, At: 07:53

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONS
Vol. 32, No. 16, pp. 2453–2458, 2002
SYNTHESIS OF
1-(30,60-ANHYDRO-20-DEOXY-
b-D-GLUCOFURANOSYL)-THYMINE
*
Hari BabuMereyala and Pallavi Pola
Organic Chemistry Division III, Indian Institute of
Chemical Technology, Hyderabad 500 007, India
ABSTRACT
Synthesis of bicyclic nucleoside 5 is described by coupling of
3 with bis(trimethylsilyl)thymine by use of Sn(IV)Cl as an
activator. Synthesis of bicyclic 20-deoxy analog 1 from 5 by
radical deoxygenation of methylxanthate ester 6 is reported.
Synthesis of strained unusual oligonucleotides containing bicyclic
nucleosides that form stable complexes with DNA and RNA gained enor-
mous interest as they have been shown to be potent, but non-selective
inhibitors of cyclic nucleotide phosphodiesterases.[1] Thus, 1,5-dioxabicyclo-
[3.3.0]-octane believed to act as mimetic of ribose phosphate in cyclic
nucleotides has been used as a template related to griseolic acid to design
therapeutically useful compounds.[2] Bicyclic oligonucleosides have greater
affinity for complementary RNA or DNA, C-30 exo conformation is predic-
tive of anti HIV activity.[3] Thus, bicyclic nucleoside analogues incorporating
*Corresponding author. E-mail: haribabu@iict.ap.nic.in
2453
DOI: 10.1081/SCC-120003393
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2454
MEREYALA AND POLA
fused methylene group,[4] oxirane,[5] oxetane[6] have been shown to inhibit
HIV replication. Several bicyclic nucleosides have been earlier synthesised
and tested for in vitro inhibitory effects on the replication of HIV-I.[7,8]
Due to our research programme directed towards synthesis of bicyclic
nucleosides we have synthesised 1-(30,60-anhydro-20-deoxy-b-D-glucofurano-
syl)-thymine (1), as a potential antiviral compound (Scheme 1).
D-Glucose was transformed to 1,2-di-O-acetyl-3,6-anhydro-5-O-
benzyl-ꢀ/b-D-glucofuranose (3) by literature described methods via
1,2-O-isopropylideneꢀ-D-glucofuranose-5,6-carbonate[9] (2).Couplingof1,2-
di-O-acetyl-3,6-anhydro-5-O-benzyl-ꢀ/b-D-glucofuranose (3) with bis(tri-
methylsilyl)thymine was performed by use of Sn(IV)Cl as an activator at
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1-(30,60-ANHYDRO-20-DEOXY-b-D-GLUCOFURANOSYL)-THYMINE
2455
room temperature to obtain the bicyclic nucleoside 4 in 70% yield.[10] 4 was
characterised by H NMR spectrum from the appearance of H-10 at ꢁ 6.15
1
0
0
(d, J1 ,2 ¼ 5.0 Hz) and 5-CH3 at ꢁ 1.80 as a singlet. 4 on reaction with
a catalytic amount of NaOMe in methanol at room temperature gave
1-(30,60-anhydro-50-O-benzyl-b-D-glucofuranosyl)-thymine (5) as a crystalline
solid (m.p.: 158ꢀC). 5 was characterised by H NMR spectrum from the
1
appearance of H-10 at ꢁ 5.85 as
a singlet. Reaction of 5 with
CS2/NaH/MeI in dry THF at 0ꢀC resulted in the formation of methyl
xanthate ester 6 that on reduction with Bu3SnH in toluene containing a
catalytic amount of AIBN at reflux temperature gave 20-deoxy bicyclic
nucleoside 7 in good yield.[11] 7 was characterised from the H NMR spec-
1
trum by the appearance of H-20 protons at ꢁ 2.30 (dd, J2 ,2 ¼ 15.7 Hz,
0
00
0
00
0
0
0
00
00,30
J1 ,2 ¼ 4.4 Hz, H-2 ), 2.65 (ddd, J1 ,2 ¼ 6.75 Hz, J2 ¼ 4.4 Hz, H-2 ) and
H-10 at ꢁ 6.30 (dd, H-10) as a multiplet. 7 on reductive debenzylation with
5% Pd/C at 1 atm hydrogen pressure gave 1 in good yield. 1 was charac-
1
terised from H NMR spectrum from the appearance of 5-CH3 at ꢁ 1.92 (s)
and H-10 at ꢁ 6.45 (dd, J1 ,2 ¼ 3.33 Hz, J1 ,2 ¼ 4.95 Hz).
In conclusion, a general protocol for synthesis of novel bicyclic nucleo-
sides 1 and 7 has been developed via the key bicyclic sugar derivative 3.
Applicability of this route for the synthesis of various bicyclic analogs of
1 and 7 is in progress.
0
0
0
00
EXPERIMENTAL SECTION
General Methods
Flame dried glassware, commercially available solvents and reagents
were used without further purification unless otherwise stated. Melting
1
points were measured using capillary tubes and are uncorrected. H NMR
spectra were measured with a Varian Gemini (200 MHz) spectrometer,
with TMS as an internal standard using CDCl3, as solvent. 13C NMR spec-
tra were taken with a Varian Gemini (50 MHz) spectrometer with solutions
in deuterochloroform. Mass spectra were obtained on a VG 70-70H
instrument.
1 - ( 20-O-Acetyl-30,60-anhydro-50-O-benzyl-b-D-glucofuranosyl)-thymine
(4): To a solution of 1,2-di-O-acetyl-3,6-anhydro-5-O-benzyl-ꢀ/b-D-glucofur-
anose (3) (0.5 g, 1.50 mmol) in dry CH2Cl2 (5 mL) was added bis(trimethyl-
silyl) thymine (0.5 g, 1.8 mmol) and SnCl4 (0.1 mL) in CH2Cl2 (3 mL) under
N2 atmosphere. The reaction mixture was stirred at room temperature for
16 h. After completion of the reaction, the reaction mixture was diluted with
CH2Cl2 (20 mL), neutralised with saturated aqueous NaHCO3 solution

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2456
MEREYALA AND POLA
(5 mL) and filtered on a bed of celite. The filtrate was separated, added water
(25 mL) and extracted the compound into CH2Cl2 (2 Â 25 mL). The com-
bined organic phase was dried (Na2SO4) and concentrated to obtain 4
(0.4 g, 69.5%) as a thick syrup. [ꢀ]D þ 97.2ꢀ(c 1.0, CHCl3); 1H NMR
(CDCl3): ꢁ 1.80 (s, 3H, CH3), 2.12 (s, 3H, OCOCH3), 3.85–4.10 (m, 2H,
0
H-6,600), 4.21 (dt, 1H, J4 ,5 ¼ J5 ,6 ¼ 4.8 Hz, J5 ,6 ¼ 4.5 Hz, H-5 ), 4.48
0
0
0
0
0
00
0
0
0
0
0
(dd, 1H, J2 ,3 ¼ 1.5 Hz, J3 ,4 ¼ 4.0 Hz, H-3 ), 4.55 (d, 1H, J ¼ 12.5 Hz,
OCH2Ph), 4.70 (d, 1H, OCH2Ph),0 4.75 (d, 1H, H-40), 5.20 (dd, 1H,
0
0
0
J1 ,2 ¼ 4.0 Hz, H-2 ), 6.18 (d, 1H, H-1 ), 7.30–7.45 (s, 5H, ArH), 7.50 (s, 1H,
H-6), 8.50 (s, 1H, NH); FAB-MS: m/z 403 (M þ 1)þ, 425 (M þ 23)þ; Anal.
Calcd. for C20H22O7N2 (402): C, 59.69; H, 5.51; N, 6.96%. Found: C, 59.52;
H, 5.43; N, 6.87%.
1-(30,60-Anhydro-50-O-benzyl-b-D-glucofuranosyl)-thymine (5): To a solu-
tion of 4 (0.4 g, 1 mmol) in CH3OH (5 mL) was added NaOMe 1N (1.5 mL)
and left the reaction mixture at room temperature for 2 h. The reaction
mixture was neutralised with IR 120 Hþ, filtered and washed with methanol.
The filtrate was concentrated to obtain 5 (0.3 g, 86%) as a white crystalline
solid (m.p.: 158ꢀC); [ꢀ]D þ 136ꢀ (c 1.0, CHCl3); H NMR (CDCl3): ꢁ 1.75
1
0
0
00
0
0
(s, 1H, CH3), 3.80 (dd, 1H, J6 ,6 ¼ 11.4 Hz, J5 ,6 ¼ 4.2 Hz, H-6 ), 3.98 (dd,
00
0
0
0
00
0
0
1H, J5 ,6 ¼ 8.5 Hz, H-6 ), 4.40 (d, 1H, J3 ,4 ¼ 2.8 Hz, H-3 ), 4.45 (s, 1H, H-2 ),
0
0
0
4.48 (dd, 1H, J4 ,5 ¼ 4.2 Hz, H-4 ), 4.55, 4.68 (dd, 2H, J ¼ 11.4 Hz,
2 Â OCH2Ph), 5.06 (ddd, 1H, H-50), 5.85 (s, 1H, H-10), 7.29–7.41 (m, 5H,
ArH), 8.02 (s, 1H, H-6), 10.08 (s, 1H, NH). 13C NMR (CDCl3): ꢁ 17.2 (C-
5), 72.2, 7.26 (C-60, CH2Ph), 79.6, 79.8, 82.2, 88.0 (C-20,30,40,50), 96.0 (C-10),
110.0 (C-5), 127.8, 128.2, 136.4, 136.8 (Ar, C-6), 151.6 (C-2), 162.4 (C-4).
Anal. Calcd. for C18H20O6N2. C, 59.99; H, 5.59; N, 7.77%. Found: C,
59.81; H, 5.48; N, 7.62%.
1-(30,60-Anhydro-50-O-benzyl-20-O-methylthiocarbonyloxy-b-D-glucofu-
ranosyl)-thymine (6): To a solution of 5 (0.2 g, 0.6 mmol) in THF (5 mL) was
added NaH (0.04 g, 1.7 mmol) and CS2 (1 mL) at 0ꢀC and stirred for 15 min.
followed by addition of MeI (1 mL) at 0ꢀC and stirred the reaction mixture at
room temperature for 20 min. After completion of the reaction, chilled water
(25 mL) was added and extracted the compound into EtOAc (2 Â 25 mL).
Combined organic layers were dried (Na2SO4) and concentrated to obtain
a thick syrupwhich was filtered on a bed of SiO (60–120 mesh) by eluting
2
with EtOAc : hexane (1 : 1) to obtain the compound 6 (0.24 g, 91%) as a thick
syrup. [ꢀ]D þ 70.3ꢀ (c 1.0, CHCl3); 1H NMR (CDCl3): ꢁ 1.84 (s, 3H, CH3), 2.62
0
0
00
0
0
(s, 3H, SMe), 3.94 (dd, 1H, J6 ,6 ¼ 10 Hz, J5 ,6 ¼ 5.0 Hz, H-6 ), 4.06 (dd, 1H,
00
0
0
00
0
0
J5 ,6 ¼ 7.0 Hz, H-6 ), 4.30 (dt, 1H, J4 ,5 ¼ 5.0 Hz, H-5 ), 4.54 (d, 1H,
0
0
0
J ¼ 12 Hz, OCH2Ph), 4.62 (d, 1H, J3 ,4 ¼ 4.0 Hz, H-3 ), 4.74 (d, 1H, OCH2Ph),
4.82 (dd, 1H, H-40), 5.96 (d, 1H, J1 ,2 ¼ 3.0 Hz, H-2 ), 6.31 (d, 1H, H-1 ), 7.30–
0
0
0
0
7.40 (s, 5H, ArH), 7.52 (s, 1H, H-6), 9.16 (s, 1H, NH). FABMS : m/z 451

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1-(30,60-ANHYDRO-20-DEOXY-b-D-GLUCOFURANOSYL)-THYMINE
2457
(M þ 1)þ; Anal. Calcd. for C20H22O6N2S2: C, 53.33; H, 4.92; N, 6.22%.
Found: C, 53.11; H, 4.79; N, 6.11%.
1-(30,60-Anhydro-50-O-benzyl-20-deoxy-b-D-glucofuranosyl)-thymine (7):
To a solution of 6 (0.2 g, 0.04 mmol) in distilled toluene (5 mL) was added
Bu3SnH (0.3 g, 1.2 mmol), a catalytic amount of AIBN and refluxed for 5 h
under N2 atmosphere. After completion of the reaction toluene was concen-
trated and the syrupy residue was chromatographed (SiO2, 60–120 mesh)
eluted with EtOAc : hexane (1 : 1) to obtain the title compound 7 (0.13 g,
72.0%) as a thick syrup. [ꢀ]D þ 108.4ꢀ (c 1.0, CHCl3); H NMR (CDCl3):
1
0
0
00
0
0
ꢁ 1.78 (s, 3H, CH3), 2.30 (dd, 1H, J2 ,2 ¼15.7 Hz, J1 ,2 ¼ 4.4 Hz, H-2 ), 2.65
00
0
00
0
00
00
0
(ddd, 1H, J1 ,2 ¼ 6.75 Hz, J2 ,3 ¼ 4.4 Hz, H-2 ), 3.80–4.00 (m, 2H, H-6 ,6 ),
0
0
0
0
00
0
0
4.28 (dt, 1H, J4 ,5 ¼ J5 ,6 ¼ 6.75 Hz, J5 ,6 ¼ 9.0 Hz, H-5 ), 4.52 (d, 1H,
0
0
0
0
J ¼ 11 Hz, OCH2Ph), 4.62 (2dd, 2H, J3 ,4 ¼ 4.4 Hz, H-3 ,4 ), 4.72 (d, 1H,
OCH2Ph), 6.30 (dd, 1H, H-10), 7.30–7.40 (m, 5H, ArH), 7.82 (s, 1H, H-6),
8.45 (s, 1H, NH). FABMS: m/z 345 (M þ 1)þ, 367 (M þ 23)þ. Anal. Calcd. for
C18H20O5N2:C, 62.78; H, 5.85; N, 8.14%. Found:C, 62.54; H, 5.76; N, 8.02%.
1-(30,60-Anhydro-20-deoxy-b-D-glucofuranosyl)-thymine (1): To a solu-
tion of 7 (0.1 g, 0.2 mmol) in CH3OH (10 mL) was added 5% Pd/C (5 mg)
and hydrogenated (1 atm) for 16 h. After completion of the reaction the
catalyst was filtered and washed with methanol. The filtrate was concentrated
to obtain the title compound 1 (0.06 g, 83%) as a syrup. [ꢀ]D þ 22.80ꢀ(c 1.0,
CHCl3); 1H NMR (CDCl3): ꢁ 1.92 (s, 1H, CH3), 2.26 (dd, 1H, J2 ,2 ¼ 15.5 Hz,
0
00
0
0
00
0
0
0
00
J1 ,2 ¼ 4.95 Hz, H-2 ), 2.50–2.70 (m, 1H, H-2 ), 3.85 (dd, 1H, J6 ,6 ¼ 9.9 Hz,
00
0
0
0
00
J5 ,6 ¼ 4.40 Hz, H-6 ), 4.00 (dd, 1H, J5 ,6 ¼ 5.5 Hz, H-6 ), 4.35–4.80 (m, 3H,
H-30,40,50), 6.45 (dd, 1H, J1 ,2 ¼ 3.33 Hz, H-1 ), 7.70 (s, 1H, H-6), 9.56 (s, 1H,
NH); Anal. Calcd. for C11H14O5N2: C, 51.96; H, 5.55; N, 11.02%. Found: C,
51.71; H, 5.43; N, 10.93%.
0
0
00
ACKNOWLEDGMENT
PP thanks UGC-CSIR, New Delhi for financial support in the form of
a Junior Research Fellowship.
REFERENCES
1. (a) Zamecnick, P.C.; Stephenson, M.L. Proc. Nat. Acad. Sci. USA 1978,
75, 280; (b) Stephenson, M.L.; Zamecnick, P.C. ibid 1978, 75, 285; c)
Helene, C. Anti-cancer Drug Design 1991, 6, 569.
2. Nakagawa, F.; Okazaki, T.; Naito, A.; Iijima, Y.; Yamazaki, M.
J. Antibiotics 1985, 38, 823.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2458
MEREYALA AND POLA
3. (a) Van Roey, P.; Taylor, E.W.; Chu, C.K.; Schinazi, R.F. Ann. NY
Acad. Sci. 1990, 29, 616; (b) Taylor, E.W.; Van Roey, P.; Schinazi,
R.F.; Chu, C.K. Antiviral Chem. Chemother. 1990, 1, 163.
4. (a) Okabe, M.; Sun, R.C. Tetrahedron Lett. 1989, 30, 2203; (b)
Beard, A.R.; Butler, P.I.; Mann, J.; Partlett, N.K. Carbohydr. Res.
1990, 87, 205.
5. Webb, T.R.; Mitsuya, H.; Broder, S.; J. Med. Chem. 1988, 31, 1475.
6. Counde, O.-Y.; Kurz, W.; Eugui, E.M.; McRoberts, M.J.; Verheyden,
J.H.P.; Kurz, L.J.; Walker, K.A.M. Tetrahedron Lett. 1992, 33, 41.
7. Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533.
8. Pineda Molas, M.; Isabel Matheu, M.; Sergio Castillon. Tetrahedron
1999, 55, 14649.
9. (a) Elmer, J.; Reist Roland, Spencer, R.; Baker, B.R. J. Org. Chem.
1958, 23, 1958; (b) Hall, L.D.; Hough, L. J. Chem. Soc. Perkin Trans. I
1963, 5301.
10. Vorbruggen, H.; Hofle, G. Chem. Ber. 1981, 114, 1256.
11. Barton, D.H.R.; McCombie, S.W. J. Chem. Soc. Perkin Trans. I 1975,
1574.
Received in the UK March 28, 2001