A general synthesis of 5′-azido-5′-2′,3′-O-isopropylidene nucleosides

Full text of DOI:10.1021/jo015800m

J . Org. Chem. 2001, 66, 8643-8645
8643
Ta ble 1. Con ver sion of 5′-OH (1a -e) to 5′-N3 (3a -e) for
Ad en osin e, Gu a n osin e, In osin e, Ur id in e, a n d Cytid in e
Nu cleosid es (1 m m ol Sca le in th e Sta r tin g Nu cleosid e)
A Gen er a l Syn th esis of
5′-Azid o-5′-d eoxy-2′,3′-O-isop r op ylid en e
Nu cleosid es
Fei Liu and David J . Austin*
Department of Chemistry, Yale University,
New Haven, Connecticut 06520
nucleoside
molecules
yielda
adenosine
guanosine
inosine
uridine
cytidine
1-3a
1-3b
1-3c
1-3d
1-3e
75%b
52%c
61%d
76%e
69%d
david.austin@yale.edu
Received May 28, 2001
In tr od u ction
a
b
Isolated yields. (a) DPPA (2 equiv), DBU (3 equiv), p-dioxane
(3 mL), 110 °C; (b) NaN3 (5 equiv), 15-crown-5 (0.1 equiv). c (a)
Functional group transformation at the 5′-position of
nucleosides has historically been an area of keen interest,
due predominantly to the biological importance of these
molecules.1 Recently, an efficient preparation of 5′-
carboxylic nucleosides was reported.2 A comparably
general and facile conversion of the 5′-hydroxyl group into
its 5′-azido derivative would further expand the range
of subsequent synthetic modification. The 5′-azide func-
tionality can be readily reduced to generate 5′-amino-
nucleoside nucleophiles,3 which have been reported in a
variety of subsequent transformations.4 Herein, we report
an efficient method for the preparation of 5′-azido ana-
logues of five 2′,3′-O-isopropylidene-protected purine and
pyrimidine nucleosides. The procedure is general, pro-
ceeds without cyclonucleoside side reactivity, and, for the
nucleosides evaluated thus far, does not require chemical
protection of the base functionality.
The primary difficulty in developing general and
efficient methods for the synthesis of 5′-azido purine
nucleosides lies mostly in the formation of undesired
cyclonucleosides.5 This side reactivity is primarily due
to the intramolecular substitution of the 5′-activating
group by the nucleophilic nitrogen on the base. Numerous
reports have provided solutions to this problem; however,
these methods involve electron-density reduction on the
base by using electron-withdrawing groups, which length-
ens the synthetic sequence.6 We have previously reported
a facile preparation of 5′-azido-5′-deoxy-2′,3′-O-isopropyl-
DPPA (1 equiv), DBU (1 equiv), p-dioxane (2 mL), 98 °C; (b) NaN3
(10 equiv), 15-crown-5 (0.1 equiv). (a) DPPA (2 equiv), DBU (2
equiv), p-dioxane (2 mL), 95 °C; (b) NaN3 (5 equiv), 15-crown-5
(0.1 equiv). e (a) DPPA (1.5 equiv), DBU (1 equiv), p-dioxane (2
mL), 80 °C; (b) NaN3 (5 equiv), 15-crown-5 (0.1 equiv).
d
ideneadenosine in high yield.7 In this report, our method
utilizes a phosphate triester at the 5′-position, instead
of using the conventional sulfonate or halide as the
activating group.8 The 5′-phosphate ester has a lower
propensity to be substituted by weak intramolecular
nucleophiles and therefore is selective for substitution
by strong external nucleophiles such as azides. This
activation is also strong enough that, in the case of
pyrimidine nucleosides, the intermolecular substitution
is favored over the competing cycloaddition reaction
between the newly formed 5′-azide and the C5-C6 double
bond on the pyrimidine base.9 In this report, we establish
the ability to use this method for the modification of four
other nucleosides (guanosine, inosine, uridine, and cyti-
dine) and give a full experimental description and char-
acterization of three new compounds: 5′-diphenylphos-
phoryl-2′,3′-O-isopropylideneinosine (2c), 5′-diphenylphos-
phoryl-2′,3′-O-isopropylidenecytidine (2e), and 5′-azido-
5′-deoxy-2′,3′-O-isopropylidenecytidine (3e).
Resu lts a n d Discu ssion
(1) (a) Pankiewicz, K. W.; Lesiak, K.; Watanabe, K. A. J . Am. Chem.
Soc. 1997, 119, 3691-5. (b) Kim, K. S.; Ahn, Y. H. Tetrahedron:
Asymmetry 1998, 9, 3601-5. (c) Gentle, C. A.; Harrison, S. A.; Inukai,
M.; Bugg, T. D. H. J . Chem. Soc., Perkin Trans. 1 1999, 1287-94. (d)
J acobsen, D. W.; DiGirolamo, P. M.; Huennekens, F. M. Mol. Phar-
macol. 1975, 11, 174-84. (e) Mungall, W. S.; Lemmen, L. J .; Lemmen,
K. L.; Dethmers, J . K.; Norling, L. L. J . Med. Chem, 1978, 21, 704-6.
(2) Epp, J . B.; Widlanski, T. S. J . Org. Chem. 1999, 64, 293-5.
(3) (a) Robins, M. J .; Wnuk, S. F.; Hernandez-Thirring, A. E.;
Samano, M. C. J . Am. Chem. Soc. 1996, 118, 11341-8. (b) Lakshman,
M. K.; Chaturvedi, S.; Lehr, R. E. Synth. Commun. 1994, 24, 2983-8.
(c) Holletz, T.; Cech, D. Synthesis 1994, 789-91.
(4) (a) Liu, F.; Austin, D. J . Org. Lett. 2001, 3, 2273-6. (b) Freeze,
S.; Norris, P. Heterocycles 1999, 51, 1807-17. (c) Lazrek, H. B.; Engels,
J . W.; Pfleiderer, W. Nucleosides Nucleotides 1998, 17, 1851-6. (d)
Norris, P.; Horton, D.; Levine, B. R. Heterocycles 1996, 43, 2643-56.
(e) Alonso, R.; Camarasa, M. J .; Alonso, G.; De las Heras, F. G. Eur.
J . Med. Chem. 1980, 15, 105-9.
F or m a tion of 5′-P h osp h a te Nu cleosid es 2a -e.
Synthesis of the 5′-azide nucleosides begins with activa-
tion of the 5′-hydroxyl of each isopropylidene-protected
nucleoside, as shown in Table 1. Of the five 2′,3′-O-
isopropylidene nucleosides (1a -e) examined, adenosine
1a , inosine 1c, and cytidine 1e were able to form the 5′-
phosphate ester intermediates in nearly quantitative
yields by reacting with excess diphenyl phosphoryl
(DPPA, 2 equiv) and DBU (2-3 equiv) at room temper-
ature. Facile separation of the phosphate intermediate
(7) Liu, F.; Austin, D. J . Tetrahedron Lett. 2001, 42, 3153-4.
(8) (a) Stout, M. G.; Robins, M. J .; Olsen, R. K.; Robins, R. K. J .
Med. Chem. 1969, 12, 658-62. (b) Verheyden, J . P. H.; Moffatt, J . G.
J . Org. Chem. 1970, 35, 2319-26. (c) Ceulemans, G.; Vandendriessche,
F.; Rozenski, J .; Herdewijn, P. Nucleosides Nucleotides 1995, 14, 117-
27. (d) Kvasyuk, E. I.; Kulak, T. I.; Mikhailopulo, I. A.; Charubala, R.;
Pfleiderer, W. Helv. Chim. Acta 1995, 78, 1777-84.
(9) (a) Sasaki, T.; Minamoto, K.; Suzuki, T.; Sugiura, T. J . Am.
Chem. Soc. 1978, 100, 2248-50. (b) Skaric, V.; Matulic-Adamic, J .;
J okic, M. Nucleic Acids Symp. Ser. 1987, 18, 9-12.
(5) (a) Anzai, K.; Uzawa, J . J . Org. Chem. 1984, 49, 5076-80. (b)
Anzai, K.; Uzawa, J . Can. J . Chem. 1986, 64, 2109-14. (c) Gao, X.;
Gaffney, B. L.; Hadden, S.; J ones, R. A. J . Org. Chem. 1986, 51, 755-
8. (d) Lin, L. G.; Bakthavachalam, V.; Cherian, X. M.; Czarnik, A. W.
J . Org. Chem. 1987, 52, 3113-9. (e) Kalman, T. I.; Landesman, P. W.
Nucleic Acid Chem. 1991, 4, 84-6.
(6) (a) J ahn, W. Chem. Ber. 1965, 98, 1705. (b) MacCoss, M.; Ryu,
E. K.; White, R. S.; Last, R. L. J . Org. Chem. 1980, 45, 788-94.
10.1021/jo015800m CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/09/2001

8644 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
was achieved for phosphate adenosine 2a 10 and inosine
2c, while in the case of cytidine 2e, separation was more
difficult because of the close polarity exhibited by 1e and
2e, resulting in a ca. 80% recovery of the product after
column purification.
Since the 5′-phosphate ester of guanosine 2b was not
isolated in its pure form, the conversion to its azide 3b
was conducted directly on the crude reaction mixture. It
was discovered, however, that the presence of TBAI had
an adverse effect on the one-pot conversion, resulting in
a complex mixture from which little desired product could
be isolated efficiently. Therefore, we sought to assess the
general necessity of TBAI in the conversion from the
phosphate ester to the azide. The conversion of cytidine
phosphate ester 2e to the corresponding azide 3e was
evaluated with (1) NaN3 alone and (2) NaN3 along with
a catalytic amount of 15-crown-5. After 8 h at 80 °C with
NaN3 alone, 59% of the starting material (2e) was
converted to product (3e), while the reaction with 15-
In the formation of phosphate uridine 2d ,11 a side
product was observed when excess DBU was used.
Lowering the reaction temperature to 4 °C did not reduce
the extent of side-product formation, but varying the
concentration of reaction and the equivalence of both
DPPA and DBU was effective. An optimal yield of the
desired phosphate ester 2d was achieved by applying 1.5
equiv of DPPA and 1 equiv of DBU at a 0.5 M concentra-
tion of the starting material 1d . Good separation of 2d
from the side product and residual starting material was
readily obtained to provide a 72% isolated yield.
1
crown-5 showed a 69% conversion (as indicated by H
NMR). This indicated that the presence of TBAI may not
be required for efficient conversion to the azide.
Hence, when the crude mixture of phosphate guanosine
2b was treated with excess NaN3 and a catalytic amount
of 15-crown-5, conversion to the 5′-azide 3b was observed
at 85 °C.14 This one-pot procedure for the conversion of
2b was found to be amenable for the other four bases
using 1,4-dioxane as the solvent, without the need for
TBAI. The application of appropriate equivalents of
DPPA and DBU and control of both reaction concentra-
tion and temperature allowed the 5′-phosphate interme-
diate to be formed efficiently with minimal side-product
formation (Table 1).
In summary, we have shown a mild and efficient route
for the conversion of 5′-hydroxyl nucleosides into their
5′-azido analogues. The procedure does not require a
protection strategy and is applicable for the following five
common nucleosides: adenosine, guanosine, inosine,
uridine, and cytidine. The two-step, one-pot procedure
provided the desired products in good yield for all five
bases, providing the synthesis of three previously unre-
ported nucleoside derivatives.
In the case of guanosine 1b, the 5′-phosphate formation
was most difficult. The use of excess reagents produced
multiple side products, and attempts to isolate some
desired product by column chromatography produced
only complex mixtures. When 1 equiv of DPPA and 1
equiv of DBU were used under concentrated conditions,
side-product formation was minimal, although the con-
version of the starting material was also compromised.
1
The H NMR spectrum of the crude mixture did reveal
the presence of the 5′-phosphate intermediate 2b in
addition to starting material. Isolation of 2b was prob-
lematic, and for this reason the reaction mixture was
used directly in the azide displacement, described below,
without purification.
F or m a tion of 5′-Azid o Nu cleosid es 3a -e. The azide
displacement reactions proceeded smoothly in the pres-
ence of excess sodium azide (NaN3), a catalytic amount
of tetrabutylammonium iodide (TBAI), and 15-crown-5.
A catalytic amount of TBAI was added to the reaction
mixture along with excess NaN3 and 15-crown-5 to
facilitate reactivity in a heterogeneous mixture. It was
reasoned that the TBAI and NaN3 could form the organic
azide in situ, thus providing an improved solubility
conducive to the desired bimolecular substitution reac-
tion. In addition, the presence of a cation sequester such
as 15-crown-5 would further increase the effective con-
centration of the nucleophile. Adenosine phosphate ester
2a , as reported previously, gave the desired product in
high yield, although an elevated temperature (110 °C)
was required for complete conversion.7 Uridine phosphate
ester 2d and cytidine phosphate ester 2e were converted
to their corresponding azides 3d 12 and 3e in high yields
at 80 °C. This high conversion rate was warranted by
the effective purification of the products by column
chromatography. To achieve an optimal conversion of
inosine phosphate ester 2c to its azide analogue 3c,13
careful control of temperature was required. No conver-
sion to product was achieved until the reaction temper-
ature was raised to 90 °C. However, at temperatures of
100 °C and above, a significant formation of side product
was observed. It was found that the reaction could be
carried out at 95 °C for a prolonged period of time to
provide 3c in 63% isolated yield.
Exp er im en ta l Section
Unless otherwise specified, reactions were performed under
a nitrogen atmosphere with exclusion of moisture. Dry dioxane
was purchased from Aldrich, and all other commercially avail-
able reagents were used as received. All mixtures were magneti-
cally stirred and monitored by thin-layer chromatography (TLC)
using Si250F precoated plates from J . T. Baker (0.25 mm). Flash
column chromatography was performed on 32-63 D 60 Å silica
gel from ICN SiliTech (ICN Biomedicals GmbH). 1H and 13C
NMR spectra were recorded on a Bruker Advance DPX-500 or
DPX-400 spectrometer. Chemical shifts are reported using
chloroform (1H, δ 7.24 ppm; 13C, δ 77.0 ppm) or methanol (1H, δ
3.30 ppm; 13C, δ 49.9 ppm). Infrared spectra were taken on a
Midac M-1200 FTIR spectrometer. All optical rotation data were
acquired on a Perkin-Elmer 341 Polarimeter (Na lamp, 546 nm,
20 °C). The melting points were taken on an Electrothermal
melting point apparatus. High-resolution mass analysis was
conducted at The University of Illinois Mass Spectrometry
Center.
Gen er a l P r oced u r e for th e Syn th esis of 5′-Azid o-2′,3′-
isop r op ylid en e Nu cleosid es. In a typical experiment, the
starting 2′,3′-O-isopropylidene nucleoside (1 mmol) was sus-
pended in dry 1,4-dioxane (0.5 M) at room temperature under a
nitrogen atmosphere with magnetic agitation. DPPA (1-2 equiv)
and DBU (1-3 equiv) were then added dropwise. The reaction
(10) Caputo, R.; Guaragna, A.; Pedatella, S.; Palumbo, G. Synlett
1997, 8, 917-8.
(11) Reese, C. B.; Ubasawa, A. Nucleic Acids Symp. Ser. 1980, 7,
5-21.
(14) The reaction was monitored by HPLC (C18, 70% acetonitrile in
water): t3b ) 2.8 min and t2b ) 3.6 min. Although the 5′-azide 3b has
been reported before in literature, this paper provides the first full
NMR and mass data of this compound. See: Stout, M. G.; Robins, M.
J .; Olsen, R. K.; Robins, R. K. J . Med. Chem. 1969, 12, 658-62.
(12) Falck, J . R.; Mekonnen, B.; Yu, J .; Lai, J . Y. J . Am. Chem. Soc.
1996, 118, 6096-7.
(13) Hampton, A.; Bayer, M.; Gupta, V. S.; Chu, S. Y. J . Med. Chem.
1968, 11, 1229-32.

Notes
J . Org. Chem., Vol. 66, No. 25, 2001 8645
was usually completed overnight. The reaction mixture was then
heated under nitrogen in an oil bath after the addition of sodium
azide (5-10 equiv) and 15-crown-5 (0.1 equiv). The reaction
mixture was usually allowed to stir overnight for completion.
The solvent was then evaporated, and the crude mixture was
purified by column chromatography using a gradient eluent
system (from 1:1 hexanes/ethyl acetate to 1:5 ethanol/ethyl
acetate).
(dd, J ) 2.5, 6.2 Hz, 1H), 6.09 (d, J ) 2.4 Hz, 1H), 7.95 (s, 1H),
8.23 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.4, 27.2, 52.3, 81.6,
84.4, 85.2, 90.6, 115.1, 125.6, 139.3, 145.4, 148.3, 159.1; IR (thin
film/NaCl) 3054, 2990, 2937, 2868, 2103, 1700, 1587, 1212, 1092,
1079 cm-1; HRMSFAB (m/z) calcd for C13H16N7O4 (MH+)
334.1264, found 334.1263.
5′-Azid o-5′-d eoxy-2′,3′-O-isop r op ylid en eu r id in e (3d ). For
this synthesis, 1.5 equiv of DPPA and 1 equiv of DBU were used,
and the temperature for conversion was maintained at 80 °C
5′-Azid o-5′-d eoxy-2′,3′-O-isop r op ylid en ea d en osin e (3a ).
For this synthesis, 3 equiv of DPPA and 2 equiv of DBU were
used, and the temperature was maintained at 110 °C overnight
for the conversion to the azide (white solid): mp 137-139 °C
(lit.15 140-141 °C); [R]20D +18.8° (c 0.166, CHCl3); 1H NMR (500
MHz, CDCl3) δ 1.33 (s, 3H), 1.56 (s, 3H), 3.52 (dd, J ) 5.7, 13.0
Hz, 1H), 3.57 (dd, J ) 4.7, 13.1 Hz, 1H), 4.34 (dd, J ) 5.0, 8.6
Hz, 1H), 4.95 (dd, J ) 3.5, 6.4 Hz, 1H), 5.30 (dd, J ) 2.4, 6.6 Hz,
1H), 6.07 (d, J ) 2.8 Hz, 1H), 7.06 (br s, 2H), 8.04 (s, 1H), 8.30
(s, 1H); 13C NMR (125 MHz, d4-MeOH) δ 24.0, 27.4, 52.4, 83.4,
81.7, 87.2, 84.2, 85.3, 90.7, 115.5, 119.6, 140.6, 148.36, 148.43,
153.1; IR (thin film/NaCl) 3324, 3170, 2988, 2937, 2103, 1646,
overnight to give a colorless oil: [R]20 +32.0° (c 0.068, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 1.34 (s, 3H), 1.55 (s, 3H), 3.60 (d,
J ) 5.6 Hz, 2H), 4.23 (dd, J ) 5.8, 9.2 Hz, 1H), 4.78 (dd, J )
4.4, 6.7 Hz, 1H), 4.96 (dd, J ) 2.3, 6.7 Hz, 1H), 5.65 (d, J ) 2.3
Hz, 1H), 5.74 (dd, J ) 1.8, 7.9 Hz, 1H), 7.27 (d, J ) 7.9 Hz, 1H),
8.59 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.6, 27.5, 52.7,
81.8, 84.7, 86.0, 94.9, 103.3, 115.3, 142.6, 150.2, 163.1; IR (thin
film/NaCl) 3178, 3061, 2988, 2938, 2103, 1691, 1457, 1380, 1270,
1213, 1158, 1092, 1069, 861, 812, 760 cm-1; HRMSFAB (m/z)
calcd for C12H16N5O5 (MH+) 310.1151, found 310.1151.
5′-Dip h en ylp h osp h or yl-2′,3′-O-isop r op ylid en ecyt id in e
(2e). For this synthesis, 2 equiv of DPPA and 2 equiv of DBU
1598, 1210, 1096, 1079, 869 cm-1
.
5′-Azid o-5′-d eoxy-2′,3′-O-isop r op ylid en egu a n osin e (3b).
For this synthesis, 1 equiv of DPPA and 1 equiv of DBU were
used, and the temperature was maintained at 80 °C overnight
for the conversion to the azide (white solid): mp 224 °C dec (lit.14
were used to give a colorless oil: [R]20 +27.5° (c 0.152, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H), 1.52 (s, 3H), 4.38 (m,
1H), 4.54 (m, 1H), 4.84 (dd, J ) 3.6, 6.4 Hz, 1H), 4.99 (dd, J )
1.8, 6.4 Hz, 1H), 5.71 (d, J ) 1.8 Hz, 1H), 5.78 (d, J ) 17.7 Hz,
1H), 7.18-7.40 (m, 10H), 7.60 (d, J ) 17.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 25.4, 27.3, 70.5, 82.6, 86.1, 87.7, 95.9, 97.6,
115.2, 121.1, 121.2, 126.9, 131.1, 145.9, 151.6, 151.7, 166.8; IR
(thin film/NaCl) 3334, 3201, 3068, 2988, 2940, 1724, 1652, 1490,
1286, 1213, 1189, 1162, 957, 775, 688 cm-1; HRMSFAB (m/z)
calcd for C24H26N3O8P (MH+) 516.1536, found 516.1535.
244 °C dec); [R]20 +40° (c 0.03, CHCl3); 1H NMR (500 MHz,
D
d4-MeOH) δ 1.37 (s, 3H), 1.57 (s, 3H), 3.45 (dd, J ) 4.7, 13.0
Hz, 1H), 3.54 (dd, J ) 4.7, 6.9 Hz, 1H), 4.30 (m, 1H), 5.06 (dd,
J ) 3.6, 6.3 Hz, 1H), 5.39 (dd, J ) 2.4, 6.2 Hz, 1H), 6.05 (d, J )
2.1 Hz, 1H), 7.86 (s, 1H); 13C NMR (125 MHz, d4-MeOH) δ 25.6,
27.5, 53.5, 83.4, 85.4, 87.2, 91.5, 115.5, 118.3, 138.8, 152.5, 155.4,
159.4; IR (thin film/NaCl) 3317, 3107, 2995, 2909, 2398, 2088,
1622, 1578, 1533, 1489, 1374, 1092, 1077, 1059 cm-1; HRMSFAB
(m/z) calcd for C13H16N8O4 (MH+) 349.1373, found 349.1372.
5′-Diph en ylph osph or yl-2′,3′-O-isopr opyliden ein osin e (2c).
For this synthesis, 2 equiv of DPPA and 2 equiv of DBU were
5′-Azid o-5′-d eoxy-2′,3′-O-isop r op ylid en ecytid in e (3e). For
this molecule, the temperature for conversion was maintained
at 80 °C overnight to give a white solid: mp 97-100 °C; [R]20
D
1
+46.7° (c 0.472, CHCl3); H NMR (400 MHz, CDCl3) δ 1.31 (s,
used to give a white solid: mp 152-154 °C; [R]20 -13.2° (c
3H), 1.53 (s, 3H), 3.62 (ddd, J ) 4.5, 7.1, 12.5 Hz, 2H), 4.22 (m,
1H), 4.85 (t, J ) 4.3 Hz, 1H), 5.10 (d, J ) 4.3 Hz, 1H), 5.49 (br
s, 1H), 5.70 (d, J ) 7.4 Hz, 1H), 7.27 (d, J ) 7.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 23.6, 25.7, 27.5, 53.1, 82.7, 85.3, 87.4,
95.2, 97.6, 101.2, 114.5, 144.7, 155.8, 166.5; IR (thin film/NaCl)
3335, 3179, 2988, 2937, 2102, 1650, 1490, 1376, 1287, 1275,
1210, 1090, 788, 756 cm-1; HRMSFAB (m/z) calcd for C12H16N6O4
(MNa+) 331.1131, found 331.1130.
D
1
0.078, CHCl3); H NMR (500 MHz, CDCl3) δ 1.34 (s, 3H), 1.61
(s, 3H), 4.46 (m, 3H), 4.96 (dd, J ) 3.1, 6.3 Hz, 1H), 4.97 (dd, J
) 3.6, 6.3 Hz, 1H), 6.07 (d, J ) 2.5 Hz, 1H), 7.12-7.31 (m, 10H),
7.86 (s, 1H), 8.08 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 25.3,
27.1, 67.8, 80.9, 84.4, 84.7, 90.9, 114.9, 119.9, 125.6, 129.6, 139.0,
145.1, 148.2, 150.2, 158.8; IR (thin film/NaCl) 3059, 2990, 2939,
2874, 1700, 1588, 1213, 1189, 1162, 957, 757, 689 cm-1; HRMS-
FAB (m/z) calcd for
C
25H25N4O8P (MNa+) 563.1308, found
563.1308.
Ack n ow led gm en t. The authors acknowledge finan-
cial support from the National Institutes of Health (R01
GM59673).
5′-Azid o-5′-d eoxy-2′,3′-O-isop r op ylid en ein osin e (3c). The
temperature for conversion was maintained below 95 °C over-
night to give a white solid: mp 205 °C dec (lit.13 222 °C dec);
[R]20D +17.8° (c 0.067, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.38
(s, 3H), 1.61 (s, 3H), 3.59 (ddd, J ) 4.8, 6.0, 13.1 Hz, 2H), 4.36
(dd, J ) 4.4, 8.5 Hz, 1H), 4.97 (dd, J ) 3.6, 6.3 Hz, 1H), 5.29
Su p p or tin g In for m a tion Ava ila ble: Spectra (1H and 13C
NMR) of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) MacCoss, M.; Ryu, E. K.; White, R. S.; Robert, L. L. J . Org.
Chem. 1980, 45, 788-94.
J O015800M