Synthesis of acyclic nucleosides and other C-1 substituted alditols from carbohydrates using a tandem alkoxyl radical β-fragmentation-nucleophilic addition

Article abstract of DOI:10.1016/S0040-4039(01)02016-0

The oxidative β-fragmentation of alkoxyl radicals generated from easily available carbohydrates is an efficient methodology to obtain acyclic nucleosides and other C-1 substituted alditols. In the reaction conditions an oxycarbenium ion is generated, which can be trapped by a variety of oxygen, carbon and nitrogen nucleophiles, in good yields and stereoselectivities.

Full text of DOI:10.1016/S0040-4039(01)02016-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9167–9170
Synthesis of acyclic nucleosides and other C-1 substituted
alditols from carbohydrates using a tandem alkoxyl radical
b-fragmentation–nucleophilic addition
Alicia Boto, Rosendo Herna´ndez* and Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C., Carretera de la Esperanza, 3., 38206 La Laguna, Tenerife, Spain
Received 11 October 2001; accepted 25 October 2001
Abstract—The oxidative b-fragmentation of alkoxyl radicals generated from easily available carbohydrates is an efficient
methodology to obtain acyclic nucleosides and other C-1 substituted alditols. In the reaction conditions an oxycarbenium ion is
generated, which can be trapped by a variety of oxygen, carbon and nitrogen nucleophiles, in good yields and stereoselectivities.
© 2001 Elsevier Science Ltd. All rights reserved.
The remarkable antiviral activity of some acyclic nucle-
otide and nucleoside analogues1 has stimulated the
efforts to synthesize this class of compounds and to
develop structure–activity (SAR) studies. A nucleotide
analogue, PMEA,1b,c displays an impressive in vitro
activity against retroviruses, the HIV in particular.
Several nucleoside analogues, such as acyclovir,1a
ganciclovir1a and famciclovir1f have potent antiherpes
activity. These compounds have shown that the biolog-
ical activity can be retained even with important mod-
ifications of the sugar moiety. The change of the base
unit has been studied to obtain acyclic nucleoside or
nucleotide analogues with improved bioavailability,2a
and also to achieve other activities of interest, as in the
case of triadimenol and other triazolyl fungicides that
are useful for crop protection.2b
nucleophiles (such as purine or pirimidinic bases), in
the presence of a Lewis acid, to give C-1 substituted
derivatives (V).
Moreover, this methodology could be modified to
introduce, in one step, carbon and heteroatom nucle-
ophiles onto the linear chains (Scheme 1, path b). This
would result in increased atom economy,4 as no work-
up or purification of the acetoxy intermediates (IV)
would be needed. In this article we show the feasibility
of this approach.
As a promising way to introduce modified sugar chains
and/or base units in the nucleoside analogues we
decided to study the b-fragmentation reaction of
anomeric alkoxyl radicals3 (I) (Scheme 1), derived from
carbohydrates on treatment with (diacetoxy)-
iodobenzene (DIB) and iodine. The fragmentation pro-
duced a carbon radical (II) which was oxidized in the
reaction mixture to an oxycarbenium ion (III). This, in
turn, was trapped by an acetate moiety (Scheme 1, path
a) to give the acetoxy derivatives (IV). We reasoned
that these products (IV) could be treated with different
Keywords: alcoxyl radical; fragmentation; diastereoselective synthesis;
alditols; nucleosides.
* Corresponding authors. Fax: 34-922-260135; e-mail: rhernandez@
ipnacs.csic.es
Scheme 1. Synthesis of C-1 substituted alditols.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02016-0

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A. Boto et al. / Tetrahedron Letters 42 (2001) 9167–9170
The fragmentation of carbohydrates 1a and 1b (Scheme
2) and their tandem conversion to C-1 substituted
alditols was carried out by treatment with DIB and
iodine in dry dichloromethane or acetonitrile at room
temperature, under irradiation with visible light. After 1
h, the nucleophile (Table 1) was added and then the
reaction mixture was cooled before adding the Lewis
acid. Different conditions were tried for each nucleo-
phile, and the optimized ones are shown in Table 1.
This tandem reaction afforded alditol derivatives 2, 3a,
and 4–7 (Scheme 2). The allylated derivative 2 (entry 1)
proved to be volatile, and low yields were obtained
(entry 1). However, the yields improved considerably
for the less volatile analogue 3a (entries 2 and 3). Both
2
and 3a were mainly obtained as the trans
diastereomers (trans:cis, 98:2).5
It is remarkable that the formate group withstands the
mild reaction conditions; however, it can be selectively
removed in the presence of the benzoate by treatment
Scheme 2. Synthesis of acyclic nucleoside analogues and other C-1 substituted alditols.
Table 1. One-pot oxidative b-fragmentation–nucleophilic addition
Entry
Substratea
Solvent
Nucleophileb (equiv.)
Lewis acid (equiv.)
Products (%)e
d.r. trans:cisf
1
2
3
4
5
6
1a
1b
1b
1a
1a
1a
CH2Cl2
MeCN
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
A (4.0)
A (4.0)
A (4.0)
B (4.0)
C (1.5)
D (1.5)
BF3·Et2O (3.0)c
TMSOTf (2.0)c
TMSOTf (2.0)c
TMSOTf (2.5)c
BF3·Et2O (2.5)d
TMSOTf (2.7)d
2 (21)
98:2
98:2
98:2
\99:1
\99:1
\99:1
3a (53)
3a (43)
4 (16)
5:6 (69, 6:1)
7 (61)
a In all cases, the fragmentation step was performed under nitrogen at rt, using irradiation with two 80 W tungsten filament lamps for 1 h. Dry
solvents (10 mL) containing (diacetoxyiodo)benzene (DIB) (1.2 mmol) and iodine (0.6 mmol per mmol of substrate) were used.
b A: allyltrimethylsilane; B: 1-phenyl(trimethylsilyloxy)ethylene; C: 1-(trimethylsilyl)-1H-benzotriazole; D: bis(trimethylsilyl)thymine.
c After the addition of the nucleophile, the reaction mixture was cooled to −40°C and the Lewis acid was added dropwise for 0.5 h. Then the
temperature was allowed to rise to 0°C and the reaction mixture was stirred for 2 h.
d After the addition of the nucleophile, the reaction mixture was cooled to 0°C and the Lewis acid was added dropwise for 0.5 h. Then the
temperature was allowed to rise to rt and the reaction mixture was stirred for 2 h.
e Yields are given for products purified by chromatography on silica gel.
f The diastereomeric ratio was determined by 1H NMR experiments.

A. Boto et al. / Tetrahedron Letters 42 (2001) 9167–9170
9169
with 1% NaHCO3, (methanol, rt, 1 h) affording the
alcohol 3b in 91% yield. The phenone derivative 4 was
isolated exclusively as the trans isomer,5 albeit in low
yield (entry 4). Particularly interesting were products
5–7, which are analogues of acyclic nucleosides. The
benzotriazolyl derivatives were obtained as separable
mixtures of the 1-N- and 2-N-isomers6 5 and 6, respec-
tively (entry 5), but in both cases only the trans
diastereomers were formed. Since several cyclic benzo-
triazolyl nucleosides have shown promising antitumoral
activity,7 the study of their acyclic analogues is of
interest. Analogously, many cyclic thymidine derivatives
have shown potent antiviral activity8 (such as AZT
against HIV), and the synthesis of derivatives with
modified sugar chains has been undertaken by several
groups. The thymine nucleophile was formed following
the Vorbru¨ggen protocol,9 yielding also exclusively the
trans diastereomer 7 (entry 6).
Plan Nacional de Investigacio´n Cient´ıfica, Desarrollo e
Innovacio´n Tecnolo´gica, Ministerio de Ciencia
Tecnolog´ıa
y
References
1. (a) For a recent review, see: Gao, H.; Mitra, A. K.
Synthesis 2000, 329–351; (b) For some recent articles on
acyclic nucleoside and nucleotide analogues, see: Balla-
tore, C.; McGuigan, C.; De Clercq, E.; Balzarini, J.
Bioorg. Med. Chem. Lett. 2001, 11, 1053–1056; (c) Jef-
fery, A. L.; Kim, J.-H.; Wiemer, D. F. Tetrahedron 2000,
56, 5077–5083; (d) Esposito, A.; Taddei, M. J. Org.
Chem. 2000, 65, 9245–9248; (e) McGuigan, C.; Slater, M.
J.; Parry, N. R.; Perry, A.; Harris, S. Bioorg. Med. Chem.
Lett. 2000, 10, 645–647; (f) Freer, R.; Geen, G. R.; Ram-
say, T. W.; Share, A. C.; Slater, G. R.; Smith, N. M.
Tetrahedron 2000, 56, 4589–4595.
To compare the one-step with the two-step procedure,
we studied the fragmentation of the carbohydrates 1a
and 1b to give the acetoxy derivatives 8a,b and 9a,b
(Scheme 2), and the subsequent transformation of these
acetates in the C-1 substituted alditols. When 1a was
treated with DIB and iodine in dichloromethane at
room temperature and under irradiation with visible
light, the diastereomeric 1-acetoxy derivatives 8a and 8b
were obtained in good yields (83%, 8a:8b, 21:1). Simi-
larly, the photolysis of 1b afforded derivatives 9a and 9b
in 81%, albeit with smaller stereoselectivity (9a:9b, 4:1).
The photolysis of 1a and 1b in acetonitrile yielded
smaller yields (60% for 8a,b and 61% for 9a,b,
respectively).
2. (a) Robins, M. J.; Hatfield, P. W. Can. J. Chem. 1982,
60, 547–553; (b) Im, D. S.; Cheong, C. S.; Lee, S. H.;
Youn, B. H.; Kim, S. C. Tetrahedron 2000, 56, 1309–
1314.
3. (a) Francisco, C. G.; Gonza´lez, C.; Sua´rez, E. J. Org.
Chem. 1998, 63, 8092–8093; (b) Armas, P.; Francisco, C.
G.; Sua´rez, E. Angew. Chem., Int. Ed. Engl. 1992, 31,
772–774; (c) For related works, see: Adinolfi, M.; Barone,
G.; Iadonisi, A. Synlett 1999, 65–66; (d) Kahn, N.;
Cheng, X.; Mootoo, D. R. J. Am. Chem. Soc. 1999, 121,
4918–4919; (e) Inanaga, J.; Sugimoto, Y.; Yokoyama, Y.;
Hanamoto, T. Tetrahedron Lett. 1992, 33, 8109–8112; (f)
For recent reviews on organohypervalent iodine com-
pounds in radical reactions, see: Togo, H.; Katohgi, M.
Synlett 2001, 565–581 and references cited therein; (g)
For reductive fragmentations, see: Martin, A.; Rodriguez,
M. S.; Sua´rez, E. Tetrahedron Lett. 1999, 40, 7525–7528;
(h) Francisco, C. G.; Leo´n, E.; Moreno, P.; Sua´rez, E.
Tetrahedron: Asymmetry 1988, 9, 2975–2978.
The purified diastereomeric mixtures of the acetates 8a,b
or 9a,b were then treated with the nucleophile and the
Lewis acid under similar conditions to those reported
for the one-step procedure, affording products 2, 3a, and
4–7 with excellent stereoselectivities. The overall yields
for the two-step sequence (22% for 2 from 1a, 51% for
3a from 1b, 79% for 4 from 1a, 63% for 5+6 from 1a and
76% for 7 from 1a) are comparable to those obtained
with the one-pot method. An exception is the phenone
4, whose yield improved using the two-step procedure.
However, in most cases the good yields and the opera-
tional simplicity of the one-step methodology make it
preferable to the two-step sequence.
4. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34,
259–281.
5. All compounds were fully characterized by 1H and 13C
NMR, IR, MS, HRMS or elemental analysis. The stereo-
chemistry was assigned by 1H and 2D COSY–NOESY
NMR. Selected spectroscopic data (1H NMR, MS and
HRMS or elemental analysis) for compounds 2–9 are
given.
Compound 2: Inseparable diastereomeric mixture (>98:2);
1H NMR (500 MHz, CDCl3) l major diastereomer 1.39
(3H, s), 1.42 (3H, s), 2.35 (1H, ddd, J=14.4, 7.1, 7.1 Hz),
2.44 (1H, ddd, J=14.6, 6.3, 6.3 Hz), 3.38 (3H, s), 3.62
(1H, dd, J=11.0, 5.8 Hz), 3.67 (1H, dd, J=11.0, 3.6 Hz),
3.91 (1H, dd, J=7.0, 6.3 Hz), 4.03 (1H, ddd, J=7.4, 7.3,
4.3 Hz), 5.13 (1H, dd, J=18.5, 1.4 Hz), 5.15 (1H, d,
J=10.3 Hz), 5.19 (1H, ddd, J=5.9, 5.9, 3.6 Hz), 5.88
(1H, dddd, J=17.2, 10.3, 6.9, 6.8 Hz), 8.31 (1H, s); l
minor diastereomer 1.37 (3H, s), 1.50 (3H, s), 3.39 (3H,
s), 4.43 (1H, dd, J=12.3, 6.4 Hz), 4.81 (1H, dd, J=12.3,
1.1 Hz), 5.38 (1H, dd, J=7.2, 1.1 Hz), 8.07 (1H, s). Some
signals are not described due to overlapping with the
major diastereomer signals; MS m/z (%) 229 (M+−CH3,
100); HRMS calcd for C11H17O5 229.1076, found
229.1042.
In summary, we have developed both a two-step and a
one-step methodology to obtain, in satisfactory yields
and with excellent stereoselectivities, a variety of acyclic
nucleosides and other C-1 substituted alditols from
easily available carbohydrates. Currently, all the
nucleoside analogues described are undergoing biologi-
cal evaluation as potential antibiotic, antiviral or anti-
cancer agents. The results of these studies will be
published in due course.
Acknowledgements
This work was supported by the Investigation Pro-
grammes Nos. PB96-1461 and PPQ2000-0728 of the

9170
A. Boto et al. / Tetrahedron Letters 42 (2001) 9167–9170
1
Compound 3a: Inseparable diastereomeric mixture (>
98:2); H NMR (500 MHz, CDCl3) major diastereomer l
Compound 8a: H NMR (500 MHz, CDCl3) l 1.44 (3H,
s), 1.47 (3H, s), 2.07 (3H, s), 3.34 (3H, s), 3.59 (2H, dd,
J=4.2 Hz), 4.38 (1H, dd, J=5.8, 2.3 Hz), 5.15 (1H, ddd,
J=4.4, 4.4, 4.4 Hz), 6.25 (1H, d, J=2.3 Hz), 8.09 (1H, s);
MS m/z (%) 247 (M+−CH3, 100). Anal. calcd for
C11H18O7: C, 50.38; H, 6.92. Found: C, 50.28; H, 7.02.
1
1.43 (3H, s), 1.44 (3H, s), 2.39 (1H, ddd, J=14.7, 7.1, 7.1
Hz), 2.47 (1H, ddd, J=14.6, 6.1, 4.9 Hz), 3.97 (1H, dd,
J=7.2, 7.1 Hz), 4.09 (1H, ddd, J=7.2, 7.2, 4.5 Hz), 4.46
(1H, dd, J=12.2, 7.0 Hz), 4.72 (1H, dd, J=12.2, 2.9 Hz),
5.15 (1H, dd, J=9.8, 1.4 Hz), 5.16 (1H, dd, J=18.8, 1.2
Hz), 5.44 (1H, ddd, J=6.6, 6.6, 2.8 Hz), 5.87 (1H, dddd,
J=17.1, 10.3, 6.9, 6.9 Hz), 7.45 (2H, dd, J=7.9, 7.7 Hz),
7.58 (1H, dd, J=7.5, 7.4 Hz), 8.02 (2H, d, J=7.4 Hz), 8.13
(1H, s). The signals of the minor diastereomer are over-
lapped with other signals, and could not be properly
described; MS m/z (%) 319 (M+−CH3, 43), 105 (100).
Anal. calcd for C18H22O6: C, 64.66; H, 6.63. Found: C,
64.66; H, 6.79.
1
Compound 8b: H NMR (500 MHz, CDCl3) l 1.42 (3H,
s), 1.52 (3H, s), 2.05 (3H, s), 3.40 (1H, dd, J=9.3, 3.5 Hz),
3.41 (3H, s), 3.66 (1H, dd, J=11.3, 4.9 Hz), 3.72 (1H, dd,
J=11.2, 2.1 Hz), 5.39 (1H, ddd, J=9.3, 4.9, 2.1 Hz), 6.31
(1H, d, J=3.5 Hz), 8.01 (1H, s); MS m/z (%) 247 (M+−
CH3, 73), 145 (100). Anal. calcd for C11H18O7: C, 50.38;
H, 6.92. Found: C, 50.30; H, 7.01.
1
Compound 9a: H NMR (500 MHz, CDCl3) l 1.508 (3H,
s), 1.514 (3H, s), 2.04 (3H, s), 4.44 (1H, dd, J=6.4, 2.2
Hz), 4.49 (1H, dd, J=12.3, 5.8 Hz), 4.67 (1H, dd, J=12.3,
3.1 Hz), 5.43 (1H, ddd, J=6.0, 6.0, 3.1 Hz), 6.32 (1H, d,
J=2.2 Hz), 7.46 (2H, dd, J=7.8, 7.7 Hz), 7.58 (1H, dd,
J=7.5, 7.4 Hz), 8.02 (2H, d, J=7.3 Hz), 8.13 (1H, s); MS
m/z (%) 337 (M+−CH3, 41), 105 (100). Anal. calcd for
C17H20O8: C, 57.95; H, 5.72. Found: C, 57.79; H, 5.95.
1
Compound 4: H NMR (500 MHz, CDCl3) l 1.42 (6H, s,
2×CH3), 3.26 (1H, dd, J=16.8, 4.0 Hz), 3.37 (3H, s), 3.39
(1H, dd, J=16.7, 7.5 Hz), 3.67 (1H, dd, J=11.0, 5.4 Hz),
3.71 (1H, dd, J=11.0, 3.4 Hz), 4.42 (1H, dd, J=7.4, 6.3
Hz), 4.64 (1H, ddd, J=7.6, 7.6, 4.0 Hz), 5.20 (1H, ddd,
J=5.8, 5.8, 5.4 Hz), 7.47 (2H, dd, J=7.8, 7.7 Hz), 7.57
(1H, dd, J=7.4, 7.4 Hz), 7.93 (2H, d, J=7.3 Hz), 8.07
(1H, s); MS m/z (%) 307 (M+−CH3, 4), 105 (100). Anal.
calcd for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.35; H,
6.77.
1
Compound 9b: H NMR (500 MHz, CDCl3) l 1.42 (3H,
s), 1.54 (3H, s), 2.09 (3H, s), 4.42 (1H, dd, J=9.0, 3.5 Hz),
4.46 (1H, dd, J=12.3, 6.3 Hz), 4.82 (1H, dd, J=12.3, 2.4
Hz), 5.65 (1H, ddd, J=8.7, 6.3, 2.2 Hz), 6.38 (1H, d,
J=3.5 Hz), 7.46 (2H, dd, J=7.9, 7.7 Hz), 7.58 (1H, dd,
J=7.5, 7.4 Hz), 8.02 (1H, s), 8.03 (2H, d, J=7.2 Hz); MS
m/z (%) 337 (M+−CH3, 30), 105 (100). Anal. calcd for
C17H20O8: C, 57.95; H, 5.72. Found: C, 58.06; H, 6.00.
6. (a) Ka¨ppi, R.; Kazimierczuk, Z.; Ja¨rvinen, P.; Seela, F.;
Lo¨nnberg, H. J. Chem. Soc., Perkin Trans. 2 1991, 595–
600; (b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko,
O. V. Chem. Rev. 1998, 98, 409–548 and references cited
therein.
1
Compound 5: H NMR (500 MHz, C6D6) l 1.53 (3H, s),
1.55 (3H, s), 2.91 (3H, s), 3.49 (1H, dd, J=11.0, 3.6 Hz),
3.64 (1H, dd, J=11.0, 2.9 Hz), 5.52 (1H, ddd, J=3.8, 3.8,
3.4 Hz), 5.70 (1H, dd, J=4.8, 4.8 Hz), 6.58 (1H, d, J=5.2
Hz), 7.42 (1H, dd, J=7.6, 7.6 Hz), 7.55 (1H, dd, J=7.2,
7.2 Hz), 7.70 (1H, d, J=8.6 Hz), 8.09 (1H, d, J=8.6 Hz),
8.15 (1H, s); MS m/z (%) 321 (M+, <1), 103 (100). Anal.
calcd for C15H19N3O5: C, 56.07; H, 5.96; N, 13.08. Found:
C, 56.12; H, 6.21; N, 12.85.
1
7. (a) Heightman, T. D.; Locatelli, M.; Vasella, A. Helv.
Chim. Acta 1996, 79, 2190–2200; (b) Flessner, T.; Wong,
C.-H. Tetrahedron Lett. 2000, 41, 7805–7808.
Compound 6: H NMR (500 MHz, CDCl3) l 1.37 (3H, s),
1.65 (3H, s), 2.59 (3H, s), 3.15 (1H, dd, J=11.0, 4.5 Hz),
3.18 (1H, dd, J=11.0, 3.6 Hz), 5.45 (1H, ddd, J=4.3, 4.3,
3.9 Hz), 5.63 (1H, dd, J=4.8, 4.2 Hz), 6.90 (1H, d, J=5.3
Hz), 6.90–7.00 (2H, m), 7.48 (1H, s), 7.70–7.80 (2H, m);
MS m/z (%) 321 (M+, 6), 99 (100). Anal. calcd for
C15H19N3O5: C, 56.07; H, 5.96; N, 13.08. Found: C, 56.09;
H, 6.18; N, 12.90.
8. (a) Jung, M. E.; Kiankarimi, M. J. Org. Chem. 1998, 63,
8133–8144 and references cited therein; (b) Czernecki, S.;
Valery, J. M. In Carbohydrates in Drug Design; Witczak,
Z. J.; Nieforth, K. A., Eds. Sugar-modified pyridine
nucleoside analogues with potential antiviral activity.
Marcel Dekker: New York, 1997; pp. 495–522; (c) Beach,
J. W. In Carbohydrates in Drug Design; Witczak, Z. J.;
Nieforth, K. A., Eds. Carbohydrates templates for the
synthesis of 3%-heteronucleosides. Marcel Dekker: New
York, 1997; pp. 523–549.
1
Compound 7: H NMR (500 MHz, CDCl3) l 1.47 (3H, s),
1.57 (3H, s), 1.94 (3H, s), 3.33 (3H, s), 3.61 (1H, dd,
J=10.6, 3.5 Hz), 3.63 (1H, dd, J=11.2, 4.6 Hz), 4.24 (1H,
dd, J=6.6, 6.1 Hz), 5.32 (1H, ddd, J=7.4, 4.0, 4.0 Hz),
6.24 (1H, d, J=6.2 Hz), 7.13 (1H, s), 8.09 (1H, s), 9.44
(1H, br s); MS m/z (%) 313 (M+−CH3, 20), 99 (100). Anal.
calcd for C14H20N2O7: C, 51.22; H, 6.14; N, 8.53. Found:
C, 51.09; H, 5.98; N, 8.30.
9. (a) Vorbru¨ggen, H. Acta Biochem. Pol. 1996, 43, 25–36; (b)
Drew, M. G. B.; Gorsuch, S.; Gould, J. H. M.; Mann, J.
J. Chem. Soc., Perkin Trans. 1 1999, 969–978.