Controlled acetolysis of 3,6-anhydro-5-o-benzyl-1,2-o-isopropylidene-α-D-glucofuranose: Synthesis of 1-(3′,6′-anhydro-α-D-glucofuranosyl)thymine

Article abstract of DOI:10.1081/SCC-120021846

Controlled acetolysis of 1,2-O-isopropylideneglucofuranose derivative 1 in Ac₂O:AcOH:H₂SO₄ at 0°C is reported to isolate 2-acetoxy dimethylmethylenoxy glucofuranose derivative 2 in quantitative yield. Utility of 2 for the synthesis of alpha linked nucleoside 5a is demonstrated.

Full text of DOI:10.1081/SCC-120021846

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
Controlled Acetolysis of 3,6-Anhydro-5-
o-benzyl-1,2-o-isopropylidene-α-d-
glucofuranose: Synthesis of 1-(3′,6′-Anhydro- α-d-
glucofuranosyl)thymine
Hari Babu Mereyala & Pallavi Pola
To cite this article: Hari Babu Mereyala & Pallavi Pola (2003) Controlled Acetolysis of 3,6-
Anhydro-5-o-benzyl-1,2-o-isopropylidene-α-d-glucofuranose: Synthesis of 1-(3′,6′-Anhydro-
α-d-glucofuranosyl)thymine, Synthetic Communications, 33:14, 2547-2552, DOI: 10.1081/
SCC-120021846
To link to this article: http://dx.doi.org/10.1081/SCC-120021846
Published online: 20 Aug 2006.
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 14, pp. 2547–2552, 2003
Controlled Acetolysis of 3,6-Anhydro-5-o-benzyl-
1,2-o-isopropylidene-a-D-glucofuranose:
Synthesis of 1-(30,60-Anhydro-
a-D-glucofuranosyl)thymine
*
Hari Babu Mereyala and Pallavi Pola
Organic Chemistry Division III, Indian Institute of
Chemical Technology, Hyderabad, India
ABSTRACT
Controlled acetolysis of 1,2-O-isopropylideneglucofuranose deriv-
ative 1 i n AcO:AcOH:H2SO4 at 0ꢀC is reported to isolate 2-acetoxy
2
dimethylmethylenoxy glucofuranose derivative 2 in quantitative
yield. Utility of 2 for the synthesis of alpha linked nucleoside 5a is
demonstrated.
Acetolysis reaction of sugars has been well studied to prepare
activated 1-O-acetyl saccharide synthons in carbohydrate chemistry.[1–3]
*Correspondence: Hari Babu Mereyala, Organic Chemistry Division III,
Indian Institute of Chemical Technology, Hyderabad 500 007, India; E-mail:
mereyalahb@rediffmail.com.
2547
DOI: 10.1081/SCC-120021846
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2548
Mereyala and Pola
The reaction has been earlier performed by reacting 1,2-O-isopropylidene
gluco-[4] and xylofuranose[5] derivatives with acetolysis mixture prepared
from acetic anhydride, acetic acid, and concentrated H2SO4 either in a
ratio of 1:10:0.3–0.8 (v/v)[6] or 7:3:0.1 (v/v)[7] to obtain 1,2-di-O-acetyl
derivatives.
During our work to prepare a-linked bicyclonucleoside analogues,
acetolysis of 3,6-anhydro-5-O-benzyl-1,2-O-isopropylidene-a-D-gluco-
furanose (1) was studied to prepare glycosyl donor possessing a non par-
ticipating C-2 neighboring group. We have found reaction of 1
with acetolysis mixture containing Ac2O:AcOH:conc. H2SO4 in a ratio
of 30:10:0.1 (v/v) at 0ꢀC for 50 min was the best reaction condition
required to obtain 1-O-acetyl-2-acetoxy-(a,a-dimethyl)-methylenoxy-3,6-
anhydro-5-O-benzyl-a/b-D-glucofuranose (2) in quantitative yield (Sch. 1).
Formation of 2 was evident from the appearance of gem-dimethyl groups
at ꢀ 1.41, 1.45, 1.48, and 1.58 integrating for six protons, acetyl groups
appeared as singlets at ꢀ 2.02, 2.05, 2.07, and 2.10 integrating for six
Scheme 1.

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Acetolysis Reaction of Sugars
2549
protons, anomeric proton (H-1) appeared at ꢀ 6.18 and ꢀ 6.25 integrating
for one proton. Formation of 2 was also indicated from the 13C NMR
spectrum from the appearance of quaternary carbon appearing at ꢀ 111.8
and ꢀ 112.7 and anomeric C-1 at ꢀ 95.6 and ꢀ 93.0. 2 was deacetylated by
reacting with a catalytic amount of NaOMe at RT to give 3,6-anhydro-5-
O-benzyl-1,2-dihydroxy-a/b-D-glucofuranose (3a), m.p.: 108–110ꢀC i n
quantitative yield. 3a was acetylated to the known 1,2-di-O-acetyl-3,6-
anhydro-5-O-benzyl-a/b-D-glucofuranose (3b) and was characterized by
comparison of 1H NMR spectrum with that reported in literature.[8] 2 was
coupled with bis(trimethylsilyl)thymine (4) i n CHCl2 at 0ꢀC by use of
2
Sn(IV)Cl as an activator to isolate a mixture of bicyclonucleosides, 1-(20-
O-acetyl-30,60-anhydro-50-O-benzyl-a-D-glucofuranosyl)thymine (5a) and
1-(20-O-acetyl-30,60-anhydro-50-O-benzyl-b-D-glucofuranosyl)thymine(5b)
1
in 65% yield.[9] 5a was characterized from H NMR0spectrum from the
appearance of H-10 at ꢀ 6.18 (d, J1 ,2 ¼ 3.0 Hz), H-2 at ꢀ 5.42 (d), and
5-CH3 at ꢀ 1.90 (s, 3H); thus indicating 5a to be the a- linked bicyclo-
nucleoside. 5b was characterized as the b-nucleoside by comparison of the
spectral data with that reported in literature.[10] 5a was deacetylated to
obtain 1-(30,60-anhydro-50-O-benzyl-a-D-glucofuranosyl)thymine (6) and
was characterized from 1H NMR. 6 on hydrogenolysis gave 1-(30,60-anhy-
dro-a-D-glucofuranosyl)thymine (7) and was characterized from the
0
0
appearance of H-10 at ꢀ 5.35 (d, J1 ,2 ¼ 5.8 Hz), H-6 at ꢀ 7.23 (s, 1H)
and 5-CH3 at ꢀ 1.72 (s, 3H).
0
0
In conclusion, controlled acetolysis of 3,6-anhydro-1,2-O-
isopropylidene glucofuranose derivative has been achieved to isolate
the acetoxy-a,a-dimethylmethylenoxy saccharide an intermediate useful
for preparation of a-linked nucleoside.
EXPERIMENTAL SECTION
General Methods
Flame dried glassware, commercially available solvents and reagents
were used without further purification unless otherwise stated. Melting
points were measured using capillary tubes and are uncorrected.
1H NMR spectra were measured with a Varian Gemini (200 MHz)
spectrometer, with TMS as an internal standard using CDCl3, as
solvent, 13C NMR spectra were taken with a Varian Gemini (50 MHz)
spectrometer with solutions in deuterochloroform. Mass spectra were
obtained on a VG 70-70H instrument.

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2550
Mereyala and Pola
1-O-Acetyl-2-acetoxy(a,a-dimethyl)methylenoxy-3,6-anhydro-5-O-
benzyl- a/b-D-glucofuranose (2). To a solution of 3,6-anhydro-5-O-benzyl-
1,2-O-isopropylidene-a/b-D-glucofurnaose (1) (5.0 g, 13.80 mmol) was
added freshly prepared acetolysis mixture (12 mL) using Ac2O:
AcOH:conc. H2SO4 (30:10:0.1) (v/v) ratio at 0ꢀC. The reaction mixture
was stirred at 0ꢀC for 50 min. TLC indicated the completion of the reac-
tion. The reaction mixture was quenched by addition of chilled water
(100 mL) was added and stirred for about 25 min and extracted the
compound into CHCl3 (100 mL Â 2). Combined organic layers were
washed with saturated aqueous NaHCO3 solution (100 mL), water
(100 mL), dried (Na2SO4) and concentrated to obtain a thick syrup
that was filtered on a bed of SiO2 (60–120 mesh) by eluting with
EtOAc:hexane (3:7) to obtain the title compound 2 as a thick syrup
(4.3 g, 89.0%). 1H NMR (CDCl3): ꢀ 1.41, 1.45, 1.48, 1.58 (4s, 6H,
2 Â CH3), 2.02, 2.05, 2.07, 2.10 (4s, 6H, OCOCH3), 3.80–4.05 (m, 2H,
H-6,60), 4.12–4.30 (m, 2H, H-3,4), 4.38–4.58 (m, 3H, H-2, 2 Â OCH2Ph),
5.30–5.35, 5.42–5.48 (2m, 1H, H-5a,b), 6.18, 6.25 (2d, 1H, H-1a,b,
J ¼ 3.50 Hz), 7.20–7.38 (m, 5H, Ar-H). 13C NMR (CDCl3): ꢀ 20.50,
20.90 (MeCO), 25.90, 26.30 (CH3), 27.20, 28.10 (CH3), 69.40, 70.90,
71.40, 72.60, 77.50, 78.50, 78.80, 79.00, 80.60 (CH2Ph,C-2,3,4,6), 93.00,
95.60 (C-1b,a), 111.80, 112.70 (C-5b,a), 127.40, 127.70, 128.30, 137.30
(Ar), 169.70 (CO). IR (Neat): 1740 cmÀ1 (C¼O), 1223 cmÀ1 (C-O). FAB-
MS: m/z 417 (M þ 23)þ. Anal. calcd. for C20H26O8: C, 60.90; H, 6.64.
Found: C, 61.09; H, 6.75.
3,6-Anhydro-5-O-benzyl-1,2-dihydroxy-a,b-D-glucofuranose (3a). To
a solution of 2 (0.95 g, 2.40 mmol) in CH3OH (5 mL) was added a
catalytic amount of NaOMe 1 N (0.1 mL) and left at room tempera-
ture for 2 h. The reaction mixture was neutralized with IR 120 Hþ, fil-
tered and washed with methanol. The filtrate was concentrated to obtain
3a (0.6 g, 99.3%) as a white crystalline solid (m.p.: 108–110ꢀC);
[a]D þ111.50ꢀC (c 1.0, MeOH). 1H NMR (CDCl3-DMSO-d6):
ꢀ
0
3.48–3.58 (dd, 1H, J6,6 ¼ 15.2 Hz, J5,6 ¼ 7.5 Hz, H-6), 3.75–4.02 (m,
2H, H-5,60), 4.26–4.40 (2m, 1H, H-4a,b), 4.50, 4.70 (2d, 2H,
J ¼ 12.5 Hz, 2 Â OCH2Ph), 4.52–4.63 (2m, 1H, H-3a,b), 5.20–5.25 (d,
0
0
0.25H, J1 ,2 ¼ 6.0 Hz, H-2b), 5.30–5.40 (m, 0.75H, H-2a), 5.70–5.82 (m,
0.25H, H-1b), 5.84–5.90 (d, 0.75H, H-1a), 7.20–7.30 (m, 5H, Ar-H).
FAB-MS: m/z 275 (M þ 23)þ. IR (KBr): 3305, 3360 cmÀ1 (OH), 1047,
1000 cmÀ1 (C-O). Anal. calcd. for C13H16O5: C, 61.90; H, 6.39. Found: C,
61.74; H, 6.44.
1-(20-O-Acetyl-30,60-anhydro-50-O-benzyl-a-D-glucofuranosyl)thymine
(5a). To a solution of 2 (4.25 g, 12.17 mmol) in dry CH2Cl2 (120 mL)
was added bis(trimethyl-silyl)thymine (4) (3.94 g, 14.6 mmol) and SnCl4

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Acetolysis Reaction of Sugars
2551
(1.68 mL) in CH2Cl2 (60 mL) under N2 atmosphere. The reaction mix-
ture was stirred at room temperature for 5 h. After completion of the
reaction, the reaction mixture was neutralized with saturated aqueous
NaHCO3 solution (55 mL) and filtered on a bed of celite. The filtrate
was separated, diluted with water (100 mL) and extracted into CH2Cl2
(100 mL Â 2). The combined organic phase was separated, dried
(Na2SO4) and concentrated to obtain a diastereometric mixture of 5a
and 5b and residue (4.63 g). The residue was chromatographed (SiO2,
60–120 mesh) by eluting with EtOAc:CHCl3(1:8) to elute first the title
compound 5a (1.78 g, 36%) as a syrup followed by 5b (1.40 g, 29%) as
thick syrup; 5a [a]D þ 4.85ꢀ (c 1.0, CHCl3). H NMR (CDCl3): ꢀ 1.84 (s,
1
0
00
3H, OCOCH3), 1.92 (s, 3H, 5-CH3), 3.80 (dd, 1H, J6 ,6 ¼ 9.10 Hz,
0
00
0
0
0
00
J5 ,6 ¼ 6.10 Hz, H-6 ), 4.05 (dd, 1H, J5 ,6 ¼ 6.10 Hz, H-6 ), 4.10–4.14
(m, 1H, H-50), 4.20–4.30 (m, 2H, H-30,40), 4.40, 4.540 (2d, 2H,
0
0
J ¼ 7.30 Hz, 2 Â OCH2Ph), 5.42 (d, 1H, J1 ,2 ¼ 3.0 Hz, H-2 ), 6.18 (d,
1H, H-10), 7.18–7.38 (m, 6H, 5Ar-H, 1H, H-6), 9.01 (s, 1H, NH).
FAB-MS: m/z 403 (M þ 1)þ. IR (Neat): 1693 (C¼O). Anal. calcd. for
C20H22O7N2: C, 59.70; H, 5.51; N, 6.96. Found: C, 59.58; H, 5.49;
N, 6.89.
1-(30,60-Anhydro-50-O-benzyl-a-D-glucofuranosyl)thymine (6). To a
solution of 5a (0.31 g, 0.77 mmol) in CH3OH (5 mL) was added a catalytic
amount of NaOMe (1 N, 0.1 mL) and left at room temperature for 3 h.
The reaction mixture was neutralized with IR 120 Hþ, filtered and
washed with methanol. The filtrate was concentrated to obtain 6
(0.25 g, 88.4%) as light yellow thick syrup, [a]D À24ꢀ (c 1.0, CHCl3).
1H NMR (CDCl3): ꢀ 1.82 (s, 3H, 5-CH3), 3.70–3.98 (m, 3H, H-50,60,600),
4.07–4.32 (m, 3H, H-20,30,40), 4.40, 4.50 (2d, 2H, J ¼ 10.5 Hz,
2 Â OCH2Ph), 6.18 (d, 1H, J ¼ 5.8 Hz, H-10), 7.20–7.38 (m, 6H, 5Ar-H,
H-6), 8.70 (s, 1H, NH). IR (Neat): 1690 cmÀ1 (CO). FAB-MS: m/z 360
(M þ 1)þ. Anal. calcd. for C18H20O6N2: C, 59.99; H, 5.59; N, 7.77.
Found: C, 59.85, H, 5.68; N, 7.65.
1-(30,60-Anhydro-a-D-glucofuranosyl)thymine (7). To a solution of 6
(0.12 g, 0.33 mmol) in CH3OH (8 mL) was added 5% Pd/C (5 mg) and
hydrogenated (1 atm) for 21 h. After completion of the reaction the
catalyst was filtered and residue washed with methanol. The filtrate
was concentrated to obtain the title compound 7 (0.042 g, 53.50%) as a
syrup. [a]D þ10.5ꢀ (c 1.0, H2O). H NMR (D2O): ꢀ 1.72 (s, 3H, 5-CH3),
1
3.40–3.60 (m, 2H, H-60,600), 3.75–3.85 (m, 1H, H-5), 3.90–4.80 (m, 3H,
0
H-20,30,40), 5.35 (d, 1H, J1 ,2 ¼ 5.8 Hz, H-1 ), 7.23 (s, 1H, H-6). Anal.
calcd. for C11H14O6N2: C, 48.89; H, 5.22; N, 10.37. Found: C, 48.69;
H, 5.18; N, 10.29.
0
0

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2552
Mereyala and Pola
ACKNOWLEDGMENT
PL thanks UGC-CSIR, New Delhi for financial support in the form
of a Senior Research Fellowship.
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Received in the Netherlands November 11, 2002