Synthesis of 3′-azido, 2′,3′-didehydro, and 3′,4′-didehydro nucleosides from 5-alkoxymethyluracils

Article abstract of DOI:10.1007/PL00010110

Reaction of methyl 5-tert-butyldiphenylsilyl-2,3-dideoxy-3-iodo-D-threo-pentofuranoside (3) with silylated 5-alkoxymethyluracils 2a-c using trimethylsilyl trifluoromethanesulfonate as a catalyst afforded the α nucleosides 4a-c and the β nucleosides 5a-c.

Full text of DOI:10.1007/PL00010110

Monatshefte fuÈr Chemie 129, 99±109 (1998)
Synthesis of 30-Azido, 20,30-Didehydro,
and 30,40-Didehydro Nucleosides from
5-Alkoxymethyluracils
Ahmed E.-S. Abdel-Megied1, Erik B. Pedersen1;Ã, and Claus Nielsen2
1
Department of Chemistry, Odense University, DK-5230 Odense M, Denmark
2
Retrovirus Laboratory, Department of Virology, Statens Seruminstitut, DK-2300 Copenhagen,
Denmark
Summary. Reaction of methyl 5-tert-butyldiphenylsilyl-2,3-dideoxy-3-iodo-D-threo-pentofurano-
side (3) with silylated 5-alkoxymethyluracils 2a±c using trimethylsilyl tri¯uoromethanesulfonate as
a catalyst afforded the ꢀ nucleosides 4a±c and the ꢁ nucleosides 5a±c. The corresponding 30,40- and
40,50-didehydro nucleosides 6±9 were prepared in an elimination reaction by treating the iodo
nucleosides 4a±c or 5a±c with 10 equivalents of sodium methoxide in methanol under re¯ux. The
deprotected 30-azido nucleosides 10a±c and 11a±c of the AZT type as well as the 40,50-didehydro
nucleosides 7a±c and 9a±c were prepared by treating 4a±c and 5a±c, respectively, with sodium azide
and subsequently with tetrabutylammonium ¯uoride.
Keywords. Nucleosides, convergent synthesis of; Nucleosides, 30-azido-20-deoxy; Nucleosides,
20,30-didehydro; Nucleosides, 30,40-didehydro; 5-Alkoxymethyluracil nucleosides; Human immuno-
de®ciency virus; Herpes simplex virus.
Synthese von 30-Azido-, 20,30-Didehydro- und 30,40-Didehydronucleosiden aus
5-Alkoxymethyluracilen
Zusammenfassung. Reaktion von Methyl-5-tert-butyldiphenylsilyl-2,3-dideoxy-3-iodo-D-threo-
pentofuranosid (3) mit den silylierten 5-Alkoxymethyluracilen 2a±c unter Verwendung von
Trimethylsilyltri¯uormethansulfonat als Katalysator ergab die ꢀ-Nucleoside 4a±c und die ꢁ-
Nucleoside 5a±c. Die entsprechenden 30,40- und 40,50-Didehydronucleoside 6±9 wurden durch
È
Behandeln der Jodnucleoside 4a±c oder 5a±c mit 10 Aquivalenten Natriummethoxid in siedendem
Methanol uÈber eine Eliminierungsreaktion hergestell. Die entschuÈtzten 30-Azidonucleoside 10a±c
und 11a±c vom AZT-Typ wurden ebenso wie die 40,50-Didehydronucleoside 7a±c und 9a±c durch
Umsetzung von 4a±c und 5a±c mit Natriumazid und nachfolgender Behandlung mit Tetrabutyl-
ammonium¯uorid erhalten.
Introduction
Among the 20,30-dideoxynucleosides [1], 30-azido-30-deoxythymidine (AZT) is very
potent in its antiviral action against human immunode®ciency virus (HIV), and it
was the ®rst successful drug used in the treatment of patients with acquired

100
A. E.-S. Abdel-Megied et al.
immunode®ciency syndrome (AIDS) [2±4]. The application of this compound has
been met with some dif®culties due to its side effects, the key toxicity being the
suppression of bone marrow [5]. During recent years we have synthesized a large
number of 30-deoxythymidine derivatives in order to ®nd new and less toxic agents
against AIDS [6±8]. In this context we found it insuf®cient to adjust the electronic
and lipophilic parameters of the 30-substituent with those of the azido group in AZT
in order to achieve activity against HIV in MT-4 cells [9]. We have also varied the
properties of the 5-substituent in AZT by replacing methyl by C1-C6 alkoxymethyl
groups [10] to correlate a large range of lipophilicities with the activity against
HIV independently of the electron donating properties which for this series of
substituents were assumed to show very little variation. Unfortunately, the 5-
alkoxymethyl AZT analogues did not show any activity against HIV which was
ascribed to the bulkiness of the 5-substituent. Instead, a surprising but moderate
activity against HIV was found for the corresponding ꢀ anomers of the long chain
5-alkoxymethyl AZT analogues. Therefore, it was of interest to synthesize long
chain alkoxymethyl AZT analogues and their corresponding ꢀ anomers in order to
investigate their biological activity against HIV. In this work we have chosen a
strategy different from that in the previous work for the synthesis of the desired
compounds. Instead of preparing the nucleosides by coupling of the nucleobase
with an appropriately substituted 30-azidopentofuranoside, we decided to use a
suitable 30-iodopentofuranoside. In this way, after synthesizing the 30-iodo
nucleoside, it should not only be possible to obtain the AZT analogues in a
substitution reaction, but also in an elimination reaction the corresponding 20,30-
didehydro nucleosides which are the corresponding alkoxymethyl analogues of
D4T (30-deoxy-20,30-didehydrothymidine) which is also a potent drug against HIV.
Results and Discussion
5-Alkoxymethyluracils 1a±c were prepared by reaction of 5-hydroxymethyluracil
[11] with 1-heptanol, 1-octanol, and 1-decanol, respectively, using conc. HCl as a
catalyst as previously described for 1c [12]. Silylation of 1a±c with 1,1,1,3,3,3-
hexamethyldisilazane (HMDS) was performed according to Wittenburg [13] prior
to their coupling as silylated derivatives 2 with methyl 5-O-(tert-butyldiphenyl-
silyl)-2,3-dideoxy-3-iodo-ꢀ,ꢁ-D-threo-pentofuranoside (3) [14] which was accom-
plished using trimethylsilyl tri¯uoromethanesulfonate (TMS tri¯ate) as Lewis acid
È
catalyst according to the method of Vorbruggen et al. [15]. Flash chromatographic
separation gave the ꢀ nucleosides 4a±c in 24±26% and the ꢁ nucleosides 5a±c in
30±39% yield. In spite of expected sterical hindrance due to the iodine at the ꢁ site
of the furanose ring, the ꢀ/ꢁ ratio was typically 2:3. One can speculate whether the
iodo substituent can form a charge-transfer complex with the silylated uracil 2 due
to its polarizability and in this way direct the attack of the nucleobase to the ꢁ site
of the furanose ring.
Treatment of 4a±c or 5a±c with an excess of NaOMe/MeOH under re¯ux gave
a separable mixture of the ꢀ-20,30-didehydro nucleosides 6a±c (32±54%) and the
30,40-didehydro nucleosides 7a±c (20±54%) or the ꢁ-20,30-didehydro nucleosides
8a±c (37±59%) and the 30,40-didehydro nucleosides 9a±c (14±22%). We failed to
separate 6a and 7a by silica gel or reversed phase chromatography.

Azido and Didehydro Nucleosides
101
Scheme 1
Scheme 2

102
A. E.-S. Abdel-Megied et al.
The substitution reaction 4a±c was performed with 10 equivalents of sodium
azide in dry N,N-dimethylformamide (DMF) 4 h at 100ꢀC). Subsequent removal of
the silyl protecting group with tetrabutylammonium ¯uoride followed by
chromatographic puri®cation afforded the unprotected 30-azido ꢀ nucleosides
10a±c in 15±26% and the 30,40-didehydro nucleosides 7a±c in 5±9% overall yield
from 4a±c. Treatment of 5a±c under the same conditions gave the unprotected 30-
azido ꢁ nucleosides 11a±c in 17±27% and the 30,40-didehydro nucleosides 9a±c in
5±11% yield.
Scheme 3
The NMR data for compounds 6a±c and 8a±c are in close agreement with those
reported [10, 16] for the corresponding anomers of D4T. This also proves the
con®guration of compounds 4a±c and 5a±c. The con®gurations of the azido
nucleosides 10a±c and 11a±c were similarly assigned by comparison with the
NMR data of Fleet et al. [17] for ꢀ and ꢁ anomers of AZT.
Compounds 4±11 did not show any signi®cant activity at non-toxic
concentrations against HIV-1 in MT-4 cells. Expression of HIV in culture medium
was quanti®ed by HIV antigen detection assay ELISA. The same compounds were
also devoid of any activity against herpes simplex virus, type 1 (HSV-1), strain
McIntyre when tested in African green monkey kidney cell line Vero.
Experimental
Anhydrous MeCN was distilled from P2O5 followed by distillation from CaH2. All other solvents
were used after distillation. Analytical TLC plates (60 F254) and silica gel (230±400 mesh) were
purchased from Merck. 1H and 13C NMR spectra: Bruker AC 250 FT NMR Spectrometer at
1
250 MHz for H and 62.9 MHz for 13C. EI mass spectra: Varian MAT 311 A Spectrometer.

Azido and Didehydro Nucleosides
103
5-Alkoxymethyluracils (1a±b) General procedure
Conc. HCl (4.5 ml) and 5-hydroxymethyluracil (9 g, 63 mmol) were added to 1-heptanol (450 ml), 1-
octanol (450 ml), or 1-decanol (450 ml), respectively. The suspension was stirred at room
temperature for 15 min and then kept on an oil bath for 4 h at 100ꢀC; the mixture becoming
homogenous after 20 min. After cooling the crystals were collected by ®ltration and recrystallized
from ethanol-water to give 1a±b in 64±71% yield.
5-Heptyloxymethyluracil (1a)
Yield: 10.9 g (71%); m.p.: 211±212ꢀC; 1H NMR (DMSO-d6): ꢂ ˆ 0.86 (t, 3H, J ˆ 6.6 Hz, CH3), 1.25
(br s, 8H, CH2), 1.37 (m, 2H, CH2), 3.37 (t, 2H, J ˆ 6.5 Hz, OCH2), 4.05 (s, 2H, CH2O), 7, 36 (s, 1H,
6-H), 10.96 (br s, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢂ ˆ 13.7 (CH3), 21.9, 25.5, 28.4, 29.1, 31.1
(CH2), 64.1 (CH2O), 69.4 (OCH2), 109.2 (C-5), 140.1 (C-6), 151.1 (C-2), 163.6 (C-4) ppm; MS:
‡
m/z: ˆ 240 (M ); C12H20N2O3; calcd.: C 59.98, H 8.39, N 11.66; found: C 60.59, H 8.59, N 11.86.
5-Octyloxymethyluracil (1b)
Yield: 10.3 g (64%); m.p.: 208±209ꢀC; 1H NMR (DMSO-d6): ꢂ ˆ 0.86 (t, 3H, J ˆ 6.5 Hz, CH3), 1.24
(br s, 10H, CH2), 1.48 (m, 2H, CH2), 3.36 (t, 2H, J ˆ 6.5 Hz, OCH2), 4.05 (s, 2H, CH2O), 7.36 (s,
1H, 6-H), 10.94 (br s, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢂ ˆ 13.7 (CH3), 21.9, 25.5, 28.7, 29.0,
31.1 (CH2), 64.1 (CH2O), 69.4 (OCH2), 109.2 (C-5), 140.0 (C-6), 151.11 (C-2), 163.6 (C-4) ppm;
‡
MS: m/z ˆ 254 (M ); C13H22N2O3; calcd.: C 61.39, H 8.72, N 11.01; found: C 61.89, H 8.84,
N 11.21.
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢀ,ꢁ-D-threo-pentofuranosyl)-
5-alkyloxy-methyluracils (4a±c and 5a±c); General procedure
O,O0-Bis(trimethylsilyl)uracil derivatives 2a±c (12 mmol) were prepared according to the standard
procedure [13] and mixed with compound 3 (4.2 g, 8.5 mmol) in dry MeCN (60 ml). TMS tri¯ate
(2.2 ml, 12 mmol) in MeCN was slowly added dropwise at ꢁ10ꢀC. The mixture was then stirred
for 1.5±4 h at 10ꢀC, diluted with CH2Cl2 (100 ml), and washed with ice-cold saturated
aqueous NaHCO3. The aqueous solution was extracted with CH2Cl2 (2Â200 ml). The combined
organic layers were washed with cold water, dried with Na2SO4, and evaporated in vacuo to give
a crude yellow product which was chromatographed on silica gel (100 g) with petroleum ether
(65±70ꢀC)/Et2O (3:2, v/v) to give the ꢀ anomers 4a±c in 24±36% and the ꢁ anomers 5a±c in
30±39% yield.
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢀ-D-threo-pentofuranosyl)-
5-heptyloxymethyluracil (4a)
1
Yield: 1.4 g (24%); H NMR (CDCl3): ꢂ ˆ 0.86 (t, 3H, J ˆ 6.3 Hz, CH3), 1.03 (s, 9H, tert-butyl),
1.28 (m, 8H, CH2), 1.60 (m, 2H, CH2), 2.83 (m, 1H, 20-H), 3.14 (m, 1H, 20-H), 3.52 (t, 2H, J ˆ 6.7
Hz, OCH2), 3.79 (dd, 1H, J ˆ 4.7 and 10.1 Hz, 50-H) 3.93 (m, 1H, 40-H), 4.03 (dd, 1H, J ˆ 4.4 and
10.3 Hz, 50-H), 4.22 (d, 1H, J ˆ 12.8 Hz, CH2O), 4.27 (d, 1H, J ˆ 12.9 Hz, CH2O), 4.56 (m, 1H, 30-
H), 6.16 (t, 1H, J ˆ 6.0 Hz, 10-H), 7.37±7.73 (m, 11H, aryl and 6-H), 9.39 (s, 1H, NH) ppm; 13C
NMR (CDCl3): ꢂ ˆ 13.9 (CH3), 19.0 ((CH3)3C), 22.4 (CH2), 22.7 (C-30), 25.9 (CH2), 26.7
((CH3)3C), 29.0, 29.5, 31.6 (CH2), 44.7 (C-20), 64.6 (CH2O), 68.6 (C-50), 71.3 (OCH2), 83.2 (C-40),
88.2 (C-10), 112.0 (C-5), 127.7, 129.7, 132.8, 135.5 (aryl), 137.4 (C-6), 149.8 (C-2), 162.5 (C-4)
ppm.

104
A. E.-S. Abdel-Megied et al.
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢁ-D-threo-pentofuranosyl)-
5-heptyloxymethyluracil (5a)
1
Yield: 1.8 g (30%); H NMR (CDCl3): ꢂ ˆ 0.86 (t, 3H, J ˆ 6.5 Hz, CH3), 1.08 (s, 9H, tert-butyl),
1.25 (br s, 8H, CH2), 1.54 (m, 2H, CH2), 2.69 (m, 1H, 20-H), 3.28 (m, 1H, 20-H), 3.35±3.47 (m, 3H,
40-H and OCH2), 3.83 (dd, 1H, J ˆ 6.0 and 10.6 Hz, 50-H), 4.03 (dd, 1H, J ˆ 5.6 and 10.6 Hz, 50-H),
4.17 (d, 1H, J ˆ 12.6 Hz, CH2O), 4.22 (d, 1H, J ˆ 12.9 Hz, CH2O), 4.50 (m, 1H, 30-H), 6.12 (dd, 1H,
J ˆ 3.4 and 7.6 Hz, 10-H), 7.36±7.72 (m, 10H, aryl), 7.86 (s, 1H, 6-H), 8.91 (s, 1H, NH) ppm; 13C
NMR (CDCl3): ꢂ ˆ 13.9 (CH3), 19.1 ((CH3)3C), 22.5 (C-30), 23.0 (CH2), 26.0 (CH2), 26.8
((CH3)3C), 29.0 (CH2), 29.6 (CH2), 31.7 (CH2), 44.3 (C-20), 64.8 (CH2O), 68.5 (C-50), 71.0 (OCH2),
82.2 (C-40), 85.1 (C-10), 111.5 (C-5), 127.7, 129.8, 132.9, 135.4, 135.5 (aryl), 138.3 (C-6), 150.0
(C-2), 162.9 (C-4) ppm.
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢀ-D-threo-pentofuranosyl)-
5-octyloxymethyluracil (4b)
1
Yield: 2.2 g (36%); H NMR (CDCl3): ꢂ ˆ 0.87 (t, 3H, J ˆ 6.5 Hz, CH3), 1.08 (s, 9H, tert-butyl),
1.26 (br s, 10H, CH2), 1.60 (m, 2H, CH2), 2.84 (m, 1H, 20-H), 3.04 (m, 1H, 20-H), 3.51 (t, 2H, J ˆ 6.7
Hz, OCH2), 3.79 (dd, 1H, J ˆ 4.8 and 10.3 Hz, 50-H), 3.92 (m, 1H, 40-H), 4.01 (dd, 1H, J ˆ 4.4 and
10.3 Hz, 50-H), 4.24 (d, 1H, J ˆ 12.6 Hz, CH2O), 4.25 (d, 1H, J ˆ 12.9 Hz, CH2O), 4.56 (m, 1H, 30-
H), 6.15 (t, 1H, J ˆ 6.1 Hz, 10-H), 7.36±7.72 (m, 11H, aryl and 6-H), 8.94 (s, 1H, NH) ppm; 13C
NMR (CDCl3): ꢂ ˆ 13.9 (CH3), 19.1 (Me3C), 22.5 (CH2), 22.7 (C-30), 26.0 (CH2), 26.7 ((CH3)3C),
29.1, 29.3, 29.5, 31.7 (CH2), 44.7 (C-20), 64.6 (CH2O), 68.6 (C-50), 71.4 (OCH2), 83.3 (C-40), 88.3
(C-10), 112.1 (C-5), 127.7, 129.8, 132.8, 135.5 (aryl), 137.4 (C-6), 149.7 (C-2), 162.3 (C-4) ppm.
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢁ-D-threo-pentofuranosyl)-
5-octyloxymethyluracil (5b)
1
Yield: 2.3 g (38%); H NMR (CDCl3): ꢂ ˆ 0.87 (t, 3H, J ˆ 6.5 Hz, CH3), 1.08 (s, 9H, tert-butyl),
1.24 (s, 10H, CH2), 1.54 (m, 2H, CH2), 2.69 (m, 1H, 20-H), 3.27 (m, 1H, 20-H), 3.35±3.47 (m, 3H, 40-
H and OCH2), 3.83 (dd, 1H, J ˆ 5.9 and 10.7 Hz, 50-H), 4.03 (dd, 1H, J ˆ 5,5 and 10.7 Hz, 50-H),
4.16 (d, 1H, J ˆ 12.7 Hz, CH2O), 4.23 (d, 1H, J ˆ 13.0 Hz, CH2O), 4.50 (m, 1H, 30-H), 6.11 (d, 1H,
J ˆ 3.6 and 7.6 Hz, 10-H), 7.37±7.72 (m, 10H, aryl), 7.86 (s, 1H, 6-H), 8.81 (s, 1H, NH) ppm; 13C
NMR (CDCl3): ꢂ ˆ 14.0 (CH3), 19.1 ((CH3)3C), 22.5 (CH2), 23.0 (C-30), 26.1 (CH2), 26.8
((CH3)3C), 29.2, 29.3, 29.6, 31.7 (CH2), 44.3 (C-20), 64.8 (CH2O), 68.5 (C-50), 71.1 (OCH2), 82.2
(C-40), 85.1 (C-10), 111.5 (C-5), 127.7, 129.8, 132.9, 135.5 (aryl), 138.3 (C-6), 150.0 (C-2), 162.3
(C-4) ppm.
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢀ-D-threo-pentofuranosyl)-
5-decyloxymethyluracil (4c)
1
Yield: 2.2 g (34%); H NMR (CDCl3): ꢂ ˆ 0.87 (t, 3H, J ˆ 6.6 Hz, CH3), 1.08 (s, 9H, tert-butyl),
1.26 (br s, 14H, CH2), 1.59 (m, 2H, CH2), 2.84 (m, 1H, 20-H), 3.04 (m, 1H, 20-H), 3.51 (t, 2H, J ˆ 6.7
Hz, OCH2), 3.79 (dd, 1H, J ˆ 5.9 and 10.6 Hz, 50-H), 3.93 (m, 1H, 40-H), 4.00 (dd, 1H, J ˆ 5.5 and
10.7 Hz, 50-H), 4.20 (d, 1H, J ˆ 12.6 Hz, CH2O), 4.23 (d, 1H, J ˆ 12.6 Hz, CH2O), 4.53 (m, 1H, 30-
H), 6.15 (t, 1H, J ˆ 6.1 Hz, 10-H), 7.37±7.73 (m, 11H, aryl and 6-H), 9.39 (s, 1H, NH) ppm; 13C
NMR (CDCl3): ꢂ ˆ 13.9 (CH3), 19.0 ((CH3)3C), 22.5 (CH2), 22.7 (C-30), 26.0 (CH2), 26.7
((CH3)3C), 29.2, 29.3, 29.4, 29.5, 31.8, 33.3 (CH2), 44.7 (C-20), 64.6 (CH2O), 68.6 (C-50), 71.3
(OCH2), 83.3 (C-40), 88.3 (C-10), 112.1 (C-5), 127.7, 129.8, 132.8, 135.5 (aryl), 137.4 (C-6), 149.8
(C-2), 162.5 (C-4) ppm.

Azido and Didehydro Nucleosides
105
1-(5-O-tert-Butyldiphenylsilyl-2,3-dideoxy-3-iodo-ꢁ-D-threo-pentofuranosyl)-
5-decyloxymethyluracil (5c)
1
Yield: 2.2 g (35%); H NMR (CDCl3): ꢂ ˆ 0.87 (t, 3H, J ˆ 6.1 Hz, CH3), 1.08 (s, 9H, tert-butyl),
1.24 (s, 14H, CH2), 1.53 (m, 2H, CH2), 2.68 (m, 1H, 20-H), 3.28 (m, 1H, 20-H), 3.35±3.51 (m, 3H, 40-
H and OCH2), 3.83 (dd, 1H, J ˆ 5.9 and 10.7 Hz, 50-H), 4.03 (dd, 1H, J ˆ 5, 5 and 10.6 Hz, 50-H),
4.20 (d, 1H, J ˆ 12.7 Hz, CH2O), 4.23 (d, 1H, J ˆ 12.9 Hz, CH2O), 4.50 (m, 1H, 30-H), 6.16 (dd, 1H,
J ˆ 3.5 and 7.6 Hz, 10-H), 7.35±7.73 (m, 10H, aryl), 7.86 (s, 1H. 6-H), 9.46 (s, 1H, NH) ppm; 13C
NMR (CDCl3): ꢂ ˆ 14.0 (CH3), 19.1 ((CH3)3C), 22.5 (CH2), 23.0 (C-30), 26.1 (CH2), 26.8
((CH3)3C), 29.2, 29.4, 29.5, 29.6, 31.8, 33.3 (CH2), 44.3 (C-20), 64.0 (CH2O), 68.5 (C-50), 71.0
(OCH2), 82.2 (C-40), 85.1 (C-10), 111.5 (C-5), 127.7, 129.8, 132.9, 135.4, 135.5 (aryl), 138.2 (C-6),
150.2 (C-2), 162.6 (C-4) ppm.
5-Alkoxymethyl-1-(2,3-dideoxy-D-glycero-pent-2-enofuranosyl)uracils (6a±c and 8a±c);
5-Alkoxymethyl-1-(2,3-dihydro-5-hydroxymethylfuran-2-yl)uracils (7a±c and 9a±c);
General procedure
To a stirred solution of 4a±c or 5a±c (1.1 mmol) in methanol (30 ml), a solution of sodium methoxide
prepared from sodium (0.25 g, 11 mmol) and methanol (20 ml) was added. The stirred solution was
heated at re¯ux for 7±10 h. After cooling to room temperature the mixture was neutralized with
NH4Cl (0.6 g, 11 mmol). The solvent was evaporated and the crude material puri®ed by column
chromatography on silica gel (30 g) with 10% petroleum ether (60±80ꢀC)/ether.
1-(2,3-Dideoxy-ꢀ-D-glycero-pent-2-enofuranosyl)-5-(octyloxymethyl)uracil (6b)
Yield: 123 mg (32%) as white crystals; m.p.: 105±106ꢀC; 1H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.3
Hz, CH3), 1.28 (s, 10H, CH2), 1.58 (m, 2H, CH2), 3.10, (br s, 1H, OH), 3.49 (t, 2H, J = 6.6 Hz,
OCH2), 3.65 (dd, 1H, J ˆ 4.5 and 12.0 Hz, 50-H), 3.83 (dd, 1H, J ˆ 3.1 and 12.0 Hz, 50-H), 4.20 (d,
1 H, J ˆ 13.0 Hz, CH2O), 4.26 (d, 1H, J ˆ 12.8 Hz, CH2O), 5.14 (br s, 1H, 40-H), 5.92 (m, 1H, 20-H),
6.34 (m, 1H, 30-H), 7.11 (m, 1H, 10-H), 7.18 (s, 1H, 6-H), 9.70 (br, 1H, NH) ppm; MS: m/z ˆ 352
‡
(M ); peak matching: calc. 352.199, found 352.200.
1-(2,3-Dideoxy-ꢀ-D-glycero-pent-2-enofuranosyl)-5-(decyloxymethyl)uracil (6c)
Yield: 200 mg (48%); m.p.: 97±98ꢀC; 1H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.2 Hz, CH3), 1.27 (s,
14H, CH2), 1.56 (m, 2H, CH2), 3.49 (t, 2H, J ˆ 6.6 Hz, OCH2), 3.65 (dd, 1H, J ˆ 4.7 and 12.0 Hz, 50-
H), 3.83 (dd, 1H, J ˆ 3.2 and 11.9 and Hz, 50-H), 4.20 (d, 1H, J ˆ 13.3 Hz, CH2), 4.26 (d, 1H,
J ˆ 12.9 Hz, CH2O), 5.15 (br s, 1H, 40-H), 5.93 (m, 1H, 20-H), 6.34 (m, 1H, 30-H), 7.11 (m, 1H, 10-H),
‡
7.17 (s, 1H, 60-H) ppm; MS: m/z ˆ 362 (M -H2O); peak matching: calc. 380.2311, found 380.231.
(S)-1-(2,3-Dihydro-5-hydroxymethylfuran-2-yl)-5-(octyloxymethyl)uracil (7b)
1
Yield: 90 mg (23%) as an oil; H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.4 Hz, CH3) 1.27 (s, 10H,
CH2), 1.58 (m, 2H, CH2), 2.65 (m, 1H, 20-H), 3.25 (m, 1H, 20-H), 3.50 (t, 2H, J ˆ 6.7 Hz, OCH2),
4.23 (m, 4H, 50-H and CH2O), 5.05 (s, 1H, 30-H), 6.70 (dd, 1H, J ˆ 3.9 and 9.6 Hz, 10-H), 7.38 (s, 1H,
‡
60-H) ppm; MS: m/z ˆ 334 (M -H2O).
(S)-1-(2,3-Dihydro-5-hydroxymethylfuran-2-yl)-5-(decyloxymethyl)uracil (7c)
1
Yield: 85 mg (20%) as an oil; H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.4 Hz, CH3), 1.26 (s, 14H,
CH2), 1.58 (m, 2H, CH2), 2.65 (m, 1H, 20-H), 3.25 (m, 1H, 20-H), 3.50 (t, 2H, J ˆ 6.7, OCH2), 4.23

106
A. E.-S. Abdel-Megied et al.
(m, 4H, 50-H and CH2O), 5.05 (s, 1H, 30-H), 6.71 (dd, 1H, J ˆ 3.9 and 9.6 Hz, 10-H), 7.37 (s, 1H, 60-
‡
H) ppm; MS: m/z ˆ 362 (M -H2O).
1-(2,3-Dideoxy-ꢁ-D-glycero-pent-2-enofuranosyl)-5-(heptyloxymethyl)uracil (8a)
1
Yield: 205 mg (55%); m.p.: 114±115ꢀC; H NMR (DMSO-d6): ꢂ ˆ 0.86 (t, 3H, J ˆ 6.3 Hz, CH3),
1.25 (s, 8H, CH2), 1.47 (m, 2H, CH2), 3.35 (br s, 2H, OCH2), 3.58 (br s, 2H, 50-H), 4.01 (d, 2H,
J ˆ 12.1 Hz, CH2O), 4.07 (d, 1H, J ˆ 12.1 Hz, CH2O), 4.78 (br s, 1H, 40-H), 4.97 (br s, 1H, OH),
5.94 (m, 1H, 20-H), 6.43 (m, 1H, 30-H), 6.89 (br s, 1H, 10-H), 7.74 (s, 1H, 60-H), 11.38 (br s, 1H, NH)
‡
ppm; MS: m/z ˆ 338 (M ): C18H28N2O5; calcd.: C 61.24, H 7.95, N 7.95; found: C 61.07, H 8.08,
N 7.98.
1-(2,3-Dideoxy-ꢁ-D-glycero-pent-2-enofuranosyl)-5-(octyloxymethyl)uracil (8b)
1
Yield: 230 mg (59%); m.p.: 120±121ꢀC; H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 5.9 Hz, CH3), 1.27
(s, 10H, CH2), 1.56 (m, 2H, CH2), 3.47 (t, 2H, J ˆ 6,6 Hz, OCH2), 3.75 (dd, 1H, J ˆ 3.3 and 12.3 Hz,
50-H), 3.91 (m, 1H, 50-H), 4.15 (d, 1H, J ˆ 13.0 Hz, OCH2), 4.21 (d, 1H, J ˆ 12.9 Hz, CH2O), 4.92
(br s, 1H, 40-H), 5.84 (m, 1H, 20-H), 6.34 (m, 1H, 30-H), 7.04 (br s, 1H, 10-H), 7.71 (s, 1H, 6-H) ppm;
‡
MS: m/z ˆ 334 (M -H2O).
1-(2,3-Dideoxy-ꢁ-D-glycero-pent-2-enofuranosyl)-5-(decyloxymethyl)uracil (8c)
1
Yield: 154 mg (37%); m.p.: 120±122ꢀC; H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.4 Hz, CH3), 1.26
(br s, 14H, CH2), 1.57 (m, 2H, CH2), 2.65 (br s, 1H, OH), 3.48 (t, 2H, J ˆ 6.7 Hz, OCH2), 3.77 (dd,
1H, J ˆ 3.5 and 12.4 Hz, 50-H), 3.94 (m, 1H, 50-H), 4.19 (s, 2H, CH2O), 4.93 (br s, 1H, 40-H), 5.85
(m, 1H, 20-H), 6.33 (m, 1H, 30-H), 7.04 (m, 1H, 10-H), 7.71 (s, 1H, 6-H), 8.81 (s, 1H, NH) ppm; MS:
‡
m/z ˆ 362 (M -H2O); peak matching: calc. 380.234, found 380.231.
(R)-1-(2,3-Dihydro-5-hydroxymethylfuran-2-yl)-5-(heptyloxymethyl)uracil (9a)
Yield: 80 mg (22%); 1H NMR (DMSO-d6): ꢂ ˆ 0.86 (br s, 3H, CH3), 1.25 (br s, 8H, CH2), 1.46 (m,
2H, CH2), 2.60 (m, 1H, 20-H), 3.77 (m, 1H, 20-H), 3.38 (br s, 2H, OCH2), 4.07 (m, 4H, 50-H and
CH2O), 5.01 (br s, 1H, 30-H), 6.59 (dd, 1H, J ˆ 2.8 and 9.9 Hz, 10-H), 7.38, (s, 1H, 6H) ppm.
(R)-1-(2,3-Dihydro-5-hydroxymethylfuran-2-yl)-5-(octyloxymethyl)uracil (9b)
1
Yield: 55 mg (14%); H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.4 Hz, CH3), 1.28 (br s, 10H, CH2),
1.57 (m, 2H, CH2), 2.68 (m, 1H, 20-H), 3.25 (m, 1H, 20-H), 3.50 (t, 2H, J ˆ 6.5 Hz, OCH2), 4.23 (m,
4H, 50-H and CH2O), 5.05 (br s, 1H, 30-H), 6.71 (dd, 1H, J ˆ 3.8 and 9.4 Hz, 10-H), 7.37 (s, 1H, 6-H)
‡
ppm; MS: m/z ˆ 352 (M ).
(R)-1-(2,3-Dihydro-5-hydroxymethylfuran-2-yl)-5-(decyloxymethyl)uracil (9c)
1
Yield: 60 mg (14%); H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.4 Hz, CH3), 1.26 (br s, 14H, CH2),
1.57 (br s, 2H, CH2), 2.65 (m, 1H, 20-H), 3.32 (m, 1H, 20-H), 3.49 (t, 2H, J ˆ 6.5 Hz, OCH2), 4.22
(m, 4H, 50-H and CH2O), 5.04 (br s, 1H, 30-H), 6.71 (dd, 1H, J ˆ 3.9 and 9.5 Hz, 10-H), 7.37 (s, 1H,
‡
6-H), 9.58 (s, 1H, NH) ppm; MS: m/z ˆ 362 (M -H2O).

Azido and Didehydro Nucleosides
107
5-Alkoxymethyl-1-(3-azido-2,3-dideoxy-D-erythro-pentofuranosyl)uracils (10a±c and 11a±c);
General procedure
Compounds 4a±c or 5a±c (1.5 mmol) were dissolved in dry N,N-dimethylformamide (20 ml).
Sodium azide (0.99 g, 15 mmol) was added, and the mixture was stirred for 4 h at 100ꢀC. After
cooling the mixture was concentrated in vacuo and the residue partitioned between water (100 ml)
and CH2Cl2 (150 ml). The aqueous solution was extracted with CH2Cl2 (150 ml). The combined
organic phases were dried over Na2SO4 and evaporated in vacuo. The crude product was dissolved in
tetrahydrofuran (30 ml) at 0ꢀC and 1.5 ml of 1 M Bu4NF in THF was added slowly with stirring.
After 30 min at 0ꢀC the solvent was evaporated in vacuo and the crude product was chromatographed
on silica gel (40 g) with ether/petroleum ether (65±70ꢀC) (9:1) (compound 11a with petroleum ether
(65±70ꢀC)/ethyl acetate (3:2) and 11c with petroleum ether (65±70ꢀC)/ether (3:2)) to give
10a±c (15±26%) and 7a±c (5±9%) or 11a±c (17±27%) and 9a±c (5±11%).
1-(3-Azido-2,3-dideoxy-ꢀ-D-erythro-pentofuranosyl)-5-(heptyloxymethyl)uracil (10a)
Yield: 157 mg (15%); m.p.: 90±91ꢀC; IR (KBr): 2108 cmꢁ1 (N3); 1H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H,
J ˆ 6.5 Hz, CH3), 1.29 (br s, 8H, CH2), 1.61 (m, 2H, CH2), 2.17 (m, 1H, 20-H), 2.87 (m, 1H, 20-H),
3.51 (t, 2H, J ˆ 6.6 Hz, OCH2), 3.68 (m, 1H, 50-H), 3.82 (m, 1H, 50-H), 4.28 (m, 4H, 30-H, 40-H and
‡
CH2O), 6.31 (m, 1H. 10-H), 7.60 (s, 1H, 6-H) ppm; MS: m/z ˆ 381 (M ); peak matching: calc.
381.201, found 381.201.
1-(3-Azido-2,3-dideoxy-ꢀ-D-erythro-pentofuranosyl)-5-(octyloxymethyl)uracil (10b)
Yield: 280 mg (26%); m.p.: 76±79ꢀC; IR (KBr): 2108 cmꢁ1 (N3); 1H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H,
J ˆ 6.4 Hz, CH3), 1.27 (br s, 10H, CH2), 1.58 (m, 2H, CH2), 2.18 (m, 1H, 20-H), 2.56 (br s, 1H, OH),
2.80 (m, 1H, 20-H), 3.51 (t, 2H, J ˆ 6.6 Hz, OCH2), 3.69 (m, 1H, 50-H), 3.82 (m, 1H, 50-H), 4.27 (m,
4H, 30-H, 40-H and CH2O), 6.28 (dd, 1H, J ˆ 4.2 and 6.7 Hz, 10-H), 7.29 (s, 1H, 6-H), 9.15 (br s, 1H,
‡
NH) ppm; MS: m/z ˆ 395 (M ); peak matching: calc. 395.219, found 395.217.
1-(3-Azido-2,3-dideoxy-ꢀ-D-erythro-pentofuranosyl)-5-(decyloxymethyl)uracil (10c)
1
Yield: 180 mg (16%); IR (KBr): 2108 cmꢁ1 (N3); H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 6.6 Hz,
CH3), 1.27 (br s, 14H, CH2), 1.59 (m, 2H, CH2), 2.16 (m, 1H, 20-H), 2.87 (m, 1H, 20-H), 3.51 (t, 2H,
J ˆ 6.6 Hz, OCH2), 3.68 (m, 1H, 50-H), 3.83 (m, 1H, 50-H), 4.27 (m, 4H, 30-H, 40-H, CH2O), 6.30
‡
(dd, 1H, J ˆ 4.2 and 6.7 Hz, 10-H), 7.60 (s, 1H, 6-H) ppm; MS: m/z ˆ 423 (M ); peak matching: calc.
423.249, found 423.248.
1-(3-Azido-2,3-dideoxy-ꢁ-D-erythro-pentofuranosyl)-5-(heptyloxymethyl)uracil (11a)
1
Yield: 210 mg (20%) as an oil; IR (KBr): 2104 cmꢁ1 (N3); H NMR (CD3OD): ꢂ ˆ 0.89 (t, 3H,
J ˆ 5.5 Hz, CH3), 1.30 (br s, 8H, CH2), 1.57 (m, 2H, CH2), 2.42 (m, 2H, 20-H), 3.48 (t, 2H, J ˆ 6.6
Hz, OCH2), 3.74 (dd, 1H, J ˆ 4.3 and 12.1 Hz, 50-H), 3.84 (dd, 1H, J ˆ 3.3 and 12.1 Hz, 50-H), 4.20
(s, 2H, CH2O), 4.36 (m, 1H, 40-H), 4.81 (br s, 1H, OH), 6.17 (t, 1H, J ˆ 6.2 Hz, 10-H), 8.01 (s, 1H,
‡
6-H) ppm; MS: m/z ˆ 381 (M ); peak matching: calc. 381.202, found 381.201.
1-(3-Azido-2,3-dideoxy-ꢁ-D-erythro-pentofuranosyl)-5-(octyloxymethyl)uracil (11b)
Yield: 185 mg (17%) as an oil; IR (KBr): 2105 cmꢁ1 (N3); 1H NMR (CDCl3): ꢂ ˆ 0.88 (t, 3H, J ˆ 5.9
Hz, CH3), 1.27 (br s, 10H, CH2), 1.59 (m, 2H, CH2), 2.46 (m, 2H, 20-H), 3.51 (t, 2H, J ˆ 6.7 Hz,

108
A. E.-S. Abdel-Megied et al.

Azido and Didehydro Nucleosides
109
OCH2), 3.78 (m, 1H, 50-H), 3.93 (m, 2H, 30-H, 50-H), 4.24 (s, 2H, CH2O), 4.38 (m, 1H, 40-H), 6.10 (t,
‡
1H, J ˆ 6.3 Hz, 10-H), 7.72 (s, 1H, 6-H), 10.09 (br s, 1H, NH) ppm; MS: m/z ˆ 395 (M ); peak
matching: calc. 395.217, found 395.217.
1-(3-Azido-2,3-dideoxy-ꢁ-D-erythro-pentofuranosyl)-5-(decyloxymethyl)uracil (11c)
Yield: 300 mg (27%) as an oil; IR (KBr): 2104 cmꢁ1 (N3); 1H NMR (CDCl3): ꢂ ˆ 0.91 (t, 3H, J ˆ 5.6
Hz, CH3), 1.30 (br s, 14H, CH2), 1.59 (m, 2H, CH2), 2.43 (m, 2H, 20-H), 3.49 (t, 2H, J ˆ 6.6 Hz,
OCH2), 3.78 (m, 1H, 50-H), 3.84 (m, 1H, 50-H), 3.94 (m, 1H, 30-H), 4.20 (s, 2H, CH2O), 4.32 (m, 1H,
‡
40-H), 4.84 (br s, 1H, OH) 6,17 (m, 1H, 10-H), 8.03 (s, 1H, 6-H) ppm; MS: m/z ˆ 423 (M ); peak
matching: calc. 423.249, found 423.248.
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Received June 20, 1997. Accepted September 12, 1997