Synthesis of a New Furanoid Glycal Auxiliary

Article abstract of DOI:10.1007/s00706-005-0342-7

A route is investigated for the synthesis of 3-O-allyl-1,4-anhydro-5-O- tert-butyldiphenylsilyl-2-deoxy-D-erythro-pent-1-enitol. The highest overall yield was obtained when 5′-O-(tert-butyldiphenylsilyl)thymidine was converted to the corresponding furanoi

Full text of DOI:10.1007/s00706-005-0342-7

Monatshefte f€ur Chemie 136, 1641–1644 (2005)
DOI 10.1007/s00706-005-0342-7
Synthesis of a New Furanoid
Glycal Auxiliary
Youssef L. Aly# and Erik B. Pedersen
ꢀ
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark,
DK-5230 Odense M, Denmark
Received November 17, 2004; accepted (revised) December 21, 2004
Published online July 21, 2005 # Springer-Verlag 2005
Summary. A route is investigated for the synthesis of 3-O-allyl-1,4-anhydro-5-O-tert-butyldiphenyl-
silyl-2-deoxy-D-erythro-pent-1-enitol. The highest overall yield was obtained when 50-O-(tert-
butyldiphenylsilyl)thymidine was converted to the corresponding furanoid glycal and subsequently
3-O-allylated.
Keywords. 1,4-Anhydropentenitols; Elimination; Carbohydrates; Furanoid glycals; Nucleosides.
Introduction
The synthesis of furanose glycals has received great attention because they have
been used as key intermediates in the preparation of structurally diverse biologi-
cally active compounds such as polyether antibiotics [1], 6-epi-leukotrienes C and
D [2], antiviral and antitumor C-nucleosides [3], ꢀ-arabino nucleosides [4], 20,30-
dideoxynucleosides [5], and 20-deoxynucleosides [6] with remarkable antiviral and
antitumor activities [7].
Electrophilic addition reactions to a furanoid glycal have been used as key steps
in the synthesis of 20,30-dideoxyadenine (ddA) and 20,30-didehydro-20,30-dideoxy-
thymidine (d4T) [8]. Glycals can be used for the synthesis of aryl C-glycosides
and C-nucleosides which have potential antiviral and antitumor activity [9] and for
the synthesis of novel base pairing moieties in oligonucleotides [10]. Several meth-
ods have been reported for the synthesis of substituted glycals [1, 11–16]. The
simplest method was described by the group of Pedersen in 1994 [17], and this
method was used by Hammer et al. [18] and later by Quirion et al. [19], and
Beigelman and coworkers [20] to prepare additional furanoid glycals. The method
is highly effective and is based on elimination of thymine base upon heating
ꢀ
Corresponding author. E-mail: ebp@chem.sdu.dk
#
On leave from Chemistry Department, Faculty of Education Kafr El-Sheikh branch Tanta
University, Kafr El-Sheikh, Egypt

1642
Y. L. Aly and E. B. Pedersen
Scheme 1
thymidine nucleosides in 1,1,1,3,3,3-hexamethyldisilazane (HMDS) under reflux in
the presence of ammonium sulfate.
A literature survey showed that our glycal synthesis has been well accepted
by the chemistry community and has been used in the synthesis of C-nucleosides
[21–27], D-ribitol [20], Buergerinin [28], cyclic phosphonomethylphosphinates
[29], and 20-C-branched nucleosides [19, 30]. Due to the interest of furanoid
glycals we describe in this paper the synthesis of a new silyl and allyl protected
furanoid glycal, which we think is a suitable auxiliary for the synthesis of glyco-
sides and nucleosides.
Results and Discussions
The glycal 4 was prepared in three steps starting from the nucleoside 1. Refluxing 1
with HMDS in the presence of ammonium sulfate for 6 h under nitrogen afforded
the 50-O silyl protected glycal 2 having an additional protection with a 30-O
trimethylsilyl group [17]. The latter protecting group was removed by treatment
with ammonia in methanol at room temperature to give the glycal 3 [18]. This
compound was converted to the target glycal 4 by reaction with allyl bromide in
the presence of sodium hydride in dry THF under nitrogen at room temperature in
35% overall yield from compound 1 (Scheme 1).
It was also attempted to use a reverse reaction sequence by 3-O-allylation of the
silylated thymidine 1 before formation of the glycal. Although the last step pro-
duced the glycal 4 in 38% yield, the overall yield was only 6% due to formation of
a complex mixture of triallyl (3-N, 30-O, 50-O), diallyl (3-N, 30-O and 30-O, 50-O),
and monoallyl (30-O) thymidine derivatives in the allylation step. The latter only
being formed in 15% yield.
Experimental
1
NMR spectra were recorded on a Varian Gemini 2000 NMR spectrometer at 300 MHz for H and
75MHz for 13C with TMS as an internal standard. MALDI mass spectra were recorded on an IonSpec
Fourier Transform Ion Cyclotron Resonance Mass Spectrometer. Melting points were determined on a
B€uchi melting point apparatus. The progress of reactions was monitored by TLC (DC-alufolio 60 F254
from Merck. For column chromatography Merck silica gel (0.040–0.063mm) was used. Solvents used
for column chromatography were distilled prior to use, while reagents were used as purchased.
)

Synthesis of a New Furanoid Glycal Auxiliary
1643
1,4-Anhydro-5-O-(tert-butyldiphenylsilyl)-2-deoxy-D-erythro-pent-1-enitol (3)
A solution of 8.52g 2 [17] (20.0 mmol) in 50 cm3 MeOH=NH3 was stirred at room temperature for
48h. The solvent was removed in vacuo, and the residue chromatographed on a silica gel column using
petroleum ether (60–80ꢁC): EtOAc (8:2, v:v) to give 5.24 g (74%) 3. NMR spectra were in accordance
with Ref. [17].
3-O-Allyl-1,4-anhydro-5-O-tert-butyldiphenylsilyl-2-deoxy-D-erythro-pent-1-enitol
(4, C24H30O3Si)
To a solution of 3 (1.74 g, 4.9 mmol) in 60 cm3 of dry THF was added 588mg NaH (60%, 25.4mmol)
and 1.22 g of allyl bromide (10 mmol) under N2. After the reaction had been stirred at room tempera-
ture for 24h the reaction mixture was quenched with 1 cm3 MeOH and the solvent was removed
in vacuo. The residue was diluted with 200 cm3 EtOAc and filtered. The solvent was removed in vacuo,
and the residue chromatographed on a silica gel column using petroleum ether (60–80ꢁC): EtOAc (3:2,
v:v) to give 980 mg (52%) 4. Pale yellow oil; 1H NMR (CDCl3, 300 MHz): ꢁ ¼ 1.06 (s, 9H, 3 ꢂ CH3),
3.59 (dd, 1H, J ¼ 10.6, 6.1 Hz, 5-H), 3.75 (dd, 1H, J ¼ 10.8, 5.3 Hz, 5-H), 3.99 (m, 2H, OCH2),
4.48–4.50 (m, 3H, 4-H, OCH2), 5.13 (t, 1H, J ¼ 2.4 Hz, 3-H), 5.17–5.18 (m, 3H, CH2¼CH, 2-H),
5.86–5.95 (m, 1H, CH¼CH2), 6.53 (d, 1H, J ¼ 2.5 Hz, 1-H), 7.37–7.68 (m, 10H, Harom) ppm;
13C NMR (CDCl3, 75 MHz): ꢁ ¼ 19.23 ((CH3)3C), 26.75 (3 ꢂ CH3), 63.51 (C-5), 68.59 (C-3), 82.54
(OCH2), 86.07 (C-4), 100.47 (C-2), 116.85 (CH2¼CH), 127.70, 129.76, 133.17, 134.85 (Carom), 135.57
(CH¼CH2), 150.39 (C-1) ppm; HRMS (MALDI, peak matching): m=z ¼ 417.1853 (Mþ Naþ;
calcd. 417.1856).
Acknowledgement
Nucleic Acid Center is funded by the Danish National Research Foundation for studies on nucleic acid
chemical biology.
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