An efficient route to pyrimidine nucleosides with the 2,3-anhydro-β-D-lyxofuranosyl stereochemistry

Article abstract of DOI:10.1055/s-2003-40335

Described is the efficient preparation of 2,3-anhydro-β-D-lyxofuranosyl pyrimidine nucleosides via the coupling of a 2,3-anhydrosugar-containing glycosyl donor (5 or 6) with a silylated nucleoside base. The products are obtained with a high degree of stereoselectivity and in 65-77% yield.

Full text of DOI:10.1055/s-2003-40335

LETTER
1271
An Efficient Route to Pyrimidine Nucleosides with the 2,3-Anhydro-b-D-lyxo-
furanosyl Stereochemistry
Efficient
R
oute to
h
Pyrimidine
r
N
ucleos
i
ides stopher S. Callam, Rajendrakumar Reddy Gadikota, Todd L. Lowary*
Department of Chemistry, The Ohio State University, Columbus, Ohio 43210, USA
E-mail: lowary.2@osu.edu
Received 27 March 2003
Dedicated to the memory of Raymond U. Lemieux.
O
Abstract: Described is the efficient preparation of 2,3-anhydro-b-
D-lyxofuranosyl pyrimidine nucleosides via the coupling of a 2,3-
anhydrosugar-containing glycosyl donor (5 or 6) with a silylated
nucleoside base. The products are obtained with a high degree of
stereoselectivity and in 65–77% yield.
R
NH
R
O
O
N
O
HO
O
O
S(O)Tol
Key words: epoxides, glycosylations, carbohydrates, nucleosides,
anhydrosugars
1, R = H
5, R = OBz
6, R = N3
2, R = CH3
3, R = F
4, R = I
2,3-Anhydro-b-D-lyxofuranosyl nucleosides (e.g., 1–4,
Figure 1) are important intermediates in the synthesis of
nucleoside derivatives, through further modification of
the epoxide ring.1 These compounds are particularly use-
ful for the preparation of b-arabinofuranosyl nucleotides
as nucleophilic opening of the epoxide generally proceeds
by regioselective attack of the nucleophile at C–3 of the
furanose ring.1,2 In addition, some of these compounds
have been shown to be weak antiviral agents.3
OTMS
NHBz
N
R
N
N
OTMS
N
OTMS
7, R = H
8, R = CH3
9, R = F
11
10, R = I
O
O
R
To date, the methods described in the literature for the
preparation of 2,3-anhydronucleosides all involve the in-
stallation of the epoxide ring on a preformed nucleo-
side.1,2,4 Thus, the synthesis of derivatives possessing non-
natural bases requires first the synthesis of the parent nu-
cleoside followed by further reactions to form the oxirane
ring. More convergent routes to this class of compounds
are desirable.
R
NH
NH
N
O
N
O
N3
BzO
O
O
O
O
16, R = H
17, R = CH3
18, R = F
12, R = H
13, R = CH3
14, R = F
15, R = I
We describe here an efficient route for the synthesis of
pyrimidine nucleosides possessing the 2,3-anhydro-b-D-
lyxofuranosyl stereochemistry. As outlined in Scheme 1,
the products are formed with a high degree of stereoselec-
tivity in a single step upon glycosylation of a silylated py-
rimidine base with a glycosyl sulfoxide5 in which the
epoxide moiety is already in place (5 or 6, Figure 1).
NHBz
N
NH2
N
N
O
N
O
BzO
HO
O
O
O
O
19
20
R
B
O
O
R
1. Tf2O, DTBMP
2. Silylated base
O
O
NHBz
OTMS
N
S(O)Tol
N
N
N
N
N
5, R = OBz
6, R = N3
12−15,19, R = OBz
16−18, R = N3
N
N
NHBz
TMS
TMS
Scheme 1 Approach to 2,3-anhydro-b-D-lyxofuranosyl pyrimidine
nucleosides.
21
22
Figure 1 Structures of nucleosides, persilylated nucleoside bases
and glycosyl donors.
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1271,1274,ftx,en;S03403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1272
C. S. Callam et al.
LETTER
The targets chosen for synthesis were nucleosides 12–19
(Figure 1). The donor used for the synthesis of 12–15 and
19, glycosyl sulfoxide 5, was prepared as previously de-
scribed.6 The 5¢-azido nucleosides 16–18 were obtained
starting with sulfoxide 6, which was easily synthesized as
outlined in Scheme 2 from the known thioglycoside 23.7
Thus, treatment6 of 23 with diphenylphosporyl azide,
triphenylphosphine, and diisopropylazodicarboxylate af-
forded an 82% yield of azido epoxy thioglycoside 24.8
Subsequent oxidation of 24 with MCPBA6 provided 69 in
83% yield as a single sulfoxide stereoisomer; however,
the stereochemistry at sulfur was not established.
Figure 2 X-ray crystal structure of 14.
OH
HO
N3
O
a
O
O
STol
R
furanose rings. In an effort to assign the stereochemistry
in the nucleosides produced by this method, we therefore
measured the 1JC1-H1 magnitudes in these compounds. Un-
fortunately, as could be expected19 given the substantial
differences in electronegativity between the nucleoside
bases and the oxygen-containing aglycones studied in our
HO
24, R = STol
6, R = S(O)Tol
b
23
Scheme 2 Synthesis of 6. (a) (PhO)2P(O)N3 (1.2 equiv), Ph3P (2.5
equiv), diisopropylazodicarboxylate (2.5 equiv), THF, 0 ºC → r.t.,
82%. (b) MCPBA (1.1 equiv), CH2Cl2, –78 ºC → r.t., 83%.
1
previous investigation, the magnitudes of these JC1-H1
With donors 5 and 6 in hand, their use in the synthesis of
nucleosides was explored. The activation protocol used
for these glycosylations involved10 first treating the sul-
foxide donor with triflic anhydride in the presence of 2,6-
di-tert-butyl-4-methyl pyridine at –78 °C, followed a few
minutes later by the addition of the persilylated nucleoside
base (7–11).11 As detailed in Table 1, for a variety of
pyrimidine bases the yields of these glycosylations were
uniformly good, ranging between 65% and 77% and a
single nucleoside product was isolated following chroma-
tography.
values did not fall within the ranges previously estab-
lished by us. We could not, therefore, use this coupling
constant to unequivocally assign the anomeric stereo-
chemistry in 12–19. However, we note that the measured
1JC1-H1 values are all very similar (see Table 1) and there-
fore these data support our earlier proposed assignment of
the anomeric stereochemistry in 17 and 18 as b.
Table 1 Synthesis of 2,3-Anhydro-b-D-lyxofuranosyl Pyrimidine
Nucleosides from 5 and 6a
Donor
Nucleotide Product
Base
Yield (%)b 1JC1-H1 (Hz)
Data obtained for these products was consistent with their
proposed structures as 2,3-anhydro-b-D-lyxofuranosyl
nucleosides.12 Confirmation of the structures of benzoates
12–15, and 19 was obtained by removal of the benzoate
ester with sodium methoxide to provide known nucleo-
sides 1–4, and 20.13 In addition, we were successful in ob-
taining an X-ray crystal structure of 14 (Figure 2),14 which
clearly demonstrates the cis relationship between the nu-
cleoside and the epoxide ring. For the 5¢-azido derivative
16, the NMR spectra obtained were identical to those pre-
viously reported.15 For compounds 17 and 18 we propose
the anomeric stereochemistry is also b, given not only the
high fidelity of the glycosylation method,6,16 but also the
close similarities in the NMR spectra of 17 and 18, with
those measured on 16.
5
5
5
5
6
6
6
5
7
8
12
13
14
15
16
17
18
19
68
73
70
77
74
69
71
65
178.9
179.5
178.7
179.0
179.3
179.9
178.7
180.2
9
10
7
8
9
11
a See ref.10 for glycosylation procedure.
b Isolated yield following chromatography.
In a previous investigation,17 we demonstrated that the un-
ambiguous determination of anomeric stereochemistry in
2,3-anhydrosugar glycosides can be most straightfor-
wardly and reliably done through measurement of the
1JC1-H1. In glycosides in which the anomeric hydrogen is
In summary, we have described the efficient synthesis of
2,3-anhydro-b-D-lyxofuranoyl pyrimidine nucleosides
via a highly convergent route. The method should enable
the synthesis of a range of other nucleoside analogs either
directly from these compounds (e.g., via opening of the
epoxide ring or the use of iodouridine derivative 15 in pal-
ladium catalyzed cross coupling reactions20) or though the
reaction of 5 and 6 with other persilylated pyrimidine
1
trans to the epoxide moiety, JC1-H1 = 163-168 Hz, and
1
when this hydrogen is cis to the oxirane ring, JC1-H1
=
171-174 Hz. Other parameters generally used for assign-
ing anomeric configuration in furanosides18 (3JH1-H2 or the
chemical shift of C-1) are not diagnostic in 2,3-anhydro-
Synlett 2003, No. 9, 1271–1274 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Efficient Route to Pyrimidine Nucleosides
1273
Hz), 3.83 (d, 1 H, J = 2.8 Hz), 3.59 (dd, 1 H, J = 6.2 Hz, 12.5
Hz), 3.49 (dd, 1 H, J = 6.2 Hz, 12.5 Hz) 2.36 (s, 3 H); 13
NMR (125.7 MHz, CDCl3, dC) 134.0, 129.9, 129.8, 128.3,
96.0, 74.3, 57.7, 55.8, 48.9, 21.0. Anal. Calcd for
derivatives. In this regard, we note that in order to further
expand the utility of this method we have also attempted
the reaction of 5 and 6 with the adenine and guanine de-
rivatives 21 and 22. However, only very low yields of the
products were formed and it appears that the method is, at
this time, limited to the synthesis of pyrimidine nucleo-
sides.
C
C12H13N3O3S: C, 51.60, 4.69. Found: C, 51.66; H, 4.73.
(10) General Procedure for Glycosylations. Donor 5 or 6 (0.5
mmol), 2,6-di-tert-butyl-4-methyl pyridine (513 mg, 2.5
mmol), 4 Å molecular sieves (0.1 g) were dried for 3 h under
vacuum in the presence of P2O5. To this mixture was added
CH2Cl2 (10 mL) and the reaction mixture was cooled to –78
°C. Triflic anhydride (0.17 mL, 0.6 mmol) was added and
the mixture was allowed to stir for 10 min before a solution
of the persilylated nucleoside (7–11, 0.6 mmol) in CH2Cl2
(1.0 mL) was added dropwise via syringe over 2 min. After
15 min, the reaction mixture turned dark brown/green and a
saturated solution of NaHCO3 was added before the solution
was allowed to warm to room temperature. The resulting
solution was filtered through Celite, dried, filtered, and
concentrated to yield a crude oil that was purified by
chromatography.
Acknowledgment
This work was supported by the National Institutes of Health and
the OSU Spectroscopy Institute. CSC’s contributions to this work
were supported first by a GAANN fellowship from the U.S. Depart-
ment of Education, later by an American Chemical Society Division
of Organic Chemistry Fellowship sponsored by Aventis Pharma-
ceuticals, and finally by a Presidential Fellowship provided by the
Ohio State University Graduate School.
(11) Nishimura, T.; Iwai, I. Chem. Pharm. Bull. 1964, 12, 352.
(12) 12: Oil; Rf 0.09 (2:1, hexanes/EtOAc); [a]D +37.2 (c 1.0,
CH3OH); 1H NMR (CDCl3, dH) 8.04 (dd, 2 H, J = 1.2 Hz, 8.0
Hz), 7.65–7.61 (m, 2 H), 7.50 (dd, 2 H, J = 8.0 Hz, 8.0 Hz),
6.36 (s, 1 H), 5.72 (d, 1 H, J = 8.2 Hz), 4.73 (dd, 1 H, J = 3.8
Hz, 3.8 Hz), 4.59 (dd, 1 H, J = 3.7 Hz, 12.2 Hz), 4.50 (dd, 1
H, J = 3.9 Hz, 12.2 Hz), 4.12 (d, 1 H, J = 2.8 Hz), 4.01 (d, 1
H, J = 2.8 Hz); 13C NMR (CDCl3, dC) 166.5, 164.4, 151.0,
141.5, 133.9, 129.8, 129.7, 129.2, 128.9, 102.3, 82.5, 77.4,
64.4, 57.0, 56.6; HRMS (ESI) calcd for (M + Na)
References
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C16H14N2O6: 353.0750, found 353.0761. 13: Oil; Rf 0.15
1
(2:1, hexanes/EtOAc); [a]D +89.1 (c 1.0, CH3OH); H NMR
(CDCl3, dH) 8.01 (dd, 2 H, J = 1.2 Hz, 8.1 Hz), 7.50 (dddd, 1
H, J = 1.2 Hz, 1.2 Hz, 7.4 Hz, 7.4 Hz), 7.39 (dd, 2 H, J = 8.0
Hz, 8.0 Hz), 6.23 (s, 1 H), 4.71–4.60 (m, 2 H), 4.35 (dd, 1 H,
J = 3.8 Hz, 3.8 Hz), 4.00 (s, 2 H), 1.81 (s, 3 H); 13C NMR
(CDCl3, dC) 166.6, 164.0, 151.1, 136.9, 133.8, 130.1, 129.8,
128.9, 111.7, 81.7, 75.5, 62.7, 56.1, 55.9, 12.9; HRMS (ESI)
calcd for (M + Na) C17H16N2O6: 367.0906, found 367.0921.
14: Oil; Rf 0.10 (2:1, hexanes/EtOAc); [a]D +73.8 (c 1.0,
CH3OH); 1H NMR (CDCl3, dH) 7.92 (dd, 2 H, J = 1.2 Hz, 8.2
Hz), 7.59 (d, 1 H, J = 6.2 Hz), 7.52 (dddd, 1 H, J = 1.2 Hz,
1.2 Hz, 7.4 Hz, 7.4 Hz), 7.39 (dd, 2 H, J = 8.0 Hz, 8.0 Hz),
6.24 (s, 1 H), 4.63 (dd, 1 H, J = 3.8 Hz, 3.8 Hz), 4.49 (dd, 1
H, J = 3.7 Hz, 12.2 Hz), 4.38 (dd, 1 H, J = 3.5 Hz, 12.2 Hz),
4.00 (d, 1 H, J = 2.8 Hz), 3.89 (d, 1 H, J = 2.8 Hz); 13C NMR
(CDCl3, dC) 166.6, 157.9 (d, J = 26.3 Hz), 149.7, 140.9 (d, J
= 236.4 Hz), 134.1, 129.9, 129.3, 129.0, 125.7 (d, J = 34.9
Hz). 82.7, 64.4, 57.1, 56.7; HRMS (ESI) calcd for (M + Na)
C16H13FN2O6: 371.0655, found 371.0667. A small amount
of this material was recrystallized from a 10:1 mixture of
dichloromethane and hexanes to provide a sample for X-ray
crystallography. 15: Oil; Rf 0.29 (2:1, hexanes/EtOAc); [a]D
+93.3 (c 1.0, CH3OH); 1H NMR (CDCl3, dH) 8.17 (d, 2 H,
J = 1.2 Hz, 8.1 Hz), 8.05 (s, 1 H), 7.59 (dddd, 1 H, J = 1.2
Hz, 1.2 Hz, 7.4 Hz, 7.4 Hz), 7.49 (dd, 2 H, J = 7.9 Hz, 7.9
Hz), 6.17 (s, 1 H), 4.75 (dd, 1 H, J = 5.0 Hz, 12.0 Hz), 4.63
(dd, 1 H, J = 5.0 Hz, 12.0 Hz), 4.41 (dd, 1 H, J = 4.7 Hz, 4.7
Hz), 4.02–4.01 (m, 2 H); 13C NMR (CDCl3, dC) 166.9, 160.9,
150.8, 145.8, 133.8, 130.1, 129.7, 129.0, 82.1, 75.9, 69.3,
62.7, 56.2, 56.0; HRMS (ESI) calcd for (M + Na)
Nucleotides 1992, 11, 391. (c) Reichman, U.; Hollenberg,
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(8) 24: White solid, mp 68–69 °C; Rf 0.61 (hexanes/EtOAc,
5:1); [a]D +129.0 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3, d) 7.31 (d, 2 H, J = 8.0 Hz), 7.18 (d, 2 H, J = 8.0 Hz),
5.51 (s, 1 H), 4.09 (dd, 1 H, J = 6.2 Hz, 6.2 Hz), 3.97 (d, 1 H,
J = 2.8 Hz), 3.77 (d, 1 H, J = 2.8 Hz), 3.55 (dd, 1 H, J = 6.2
Hz, 12.5 Hz), 3.46 (dd, 1 H, J = 6.2 Hz, 12.5 Hz) 2.38 (s, 3
H); 13C NMR (125.7 MHz, CDCl3, d) 134.4, 129.9, 129.8,
128.3, 86.9, 75.1, 57.7, 55.6, 49.8, 21.0. Anal. Calcd for
C12H13N3O2S: C, 54.74; H 4.98. Found: C, 54.70; H, 4.95.
(9) 6: White solid, mp 77–78 °C; Rf 0.66 (3:1, hexanes/EtOAc,);
[a]D –161.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3, dH)
7.31 (d, 2 H, J = 8.0 Hz), 7.18 (d, 2 H, J = 8.0 Hz), 5.58 (s,
1 H), 4.12 (dd, 1 H, J = 6.2 Hz, 6.2 Hz), 3.99 (d, 1 H, J = 2.8
C16H13IN2O6: 478.9716, found 478.9722. 17: Oil; Rf 0.16
(2:1, hexanes/EtOAc); [a]D +41.3 (c 1.0, CH3OH); 1H NMR
(CDCl3, dH) 7.44 (d, 1 H, J = 1.2 Hz), 6.36 (s, 1 H), 4.14 (dd,
1 H, J = 5.9 Hz, 5.9 Hz), 3.95 (d, 1 H, J = 2.8 Hz), 3.86 (d, 1
H, J = 2.8 Hz), 3.60 (d, 2 H, J = 5.9 Hz), 1.90 (d, 3 H, J = 1.2
Hz); 13C NMR (CDCl3, dC) 164.5, 151.2, 136.9, 111.7, 81.6,
Synlett 2003, No. 9, 1271–1274 ISSN 1234-567-89 © Thieme Stuttgart · New York

1274
C. S. Callam et al.
LETTER
Sultanova, V. S.; Abdrakhmanov, I. B.; Tolstikov, G. A.
Bash. Khim. Zh. 1996, 3, 24. (d) 20: Ref. 2c.
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Acta Crystallogr., Sect. E., submitted.
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76.1, 56.2, 55.5, 50.6, 12.9; HRMS (ESI) calcd for (M + Na)
C10H11N5O4: 288.0709, found 288.0720. 18: Oil; Rf 0.11
(2:1, hexanes/EtOAc); [a]D +33.6 (c 1.0, CH3OH); 1H NMR
(CDCl3, dH) 7.76 (d, 1 H, J = 6.1 Hz), 6.17 (d, 1 H, J = 1 Hz),
4.21 (dd, 1 H, J = 6.0 Hz, 6.0 Hz), 4.01 (d, 1 H, J = 2.8 Hz),
3.94 (d, 1 H, J = 2.8 Hz), 3.68–3.61 (m, 2 H); 13C NMR
(CDCl3, dC) 162.1 (d, J = 26.4 Hz), 149.6, 140.9 (d, J = 236.8
Hz) 125.4 (d, J = 38.5 Hz), 82.9, 76.2, 56.0, 55.7, 50.4;
HRMS (ESI) calcd for (M + Na) C9H8FN5O4: 292.0458,
found 292.0467. 19; Oil; Rf 0.21 (2:1, hexanes/EtOAc); [a]D
+65.4 (c 1.0, CH3OH); 1H NMR (CDCl3, dH) 8.06–8.03 (m,
3 H), 7.95 (d, 2 H, J = 7.4 Hz), 7.62–7.57 (m, 3 H), 7.51–7.45
(m, 4 H), 6.24 (s, 1 H), 4.75 (dd, 1 H, J = 5.4 Hz, 11.9 Hz),
4.61 (dd, 1 H, J = 4.6 Hz, 11.9 Hz), 4.49 (dd, 1 H, J = 4.9 Hz,
5.4 Hz), 4.16 (d, 1 H, J = 2.8 Hz), 4.00 (d, 1 H, J = 2.8 Hz),
13C NMR (CDCl3, dC) 169.0, 166.9, 160.9, 159.0, 133.9,
133.5, 130.0, 129.6, 129.1, 128.9, 128.3, 97.9, 84.2, 76.5,
62.7, 56.9, 56.3; HRMS (ESI) calcd for (M + Na)
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C23H19N3O6: 456.1172, found 456.1168.
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Synlett 2003, No. 9, 1271–1274 ISSN 1234-567-89 © Thieme Stuttgart · New York