One-pot synthesis of acyclic nucleosides from carbohydrate derivatives, by combination of tandem and sequential reactions

Article abstract of DOI:10.1021/jo701608p

(Chemical Equation Presented) The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucle

Full text of DOI:10.1021/jo701608p

One-Pot Synthesis of Acyclic Nucleosides from Carbohydrate
Derivatives, by Combination of Tandem and Sequential Reactions
Alicia Boto,*,† Da´cil Herna´ndez,† Rosendo Herna´ndez,*,† and Eleuterio AÄ lvarez‡
Instituto de Productos Naturales y Agrobiolog´ıa del CSIC, AVda. Astrof´ısico Francisco Sa´nchez 3,
38206-La Laguna, Tenerife, Spain, and Instituto de InVestigaciones Qu´ımicas (CSIC-USe), Isla de la
Cartuja, AVda. Ame´rico Vespucio, 49, 41092-SeVilla, Spain
alicia@ipna.csic.es; rhernandez@ipna.csic.es
ReceiVed July 23, 2007
The design of processes which combine tandem and sequential reactions allows the transformation of
readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis
of acyclic nucleosides, which are potential antiviral compounds, from readily available carbohydrates.
The reaction conditions are mild, compatible with most functional groups. Depending on the starting
sugar, both common and uncommon acyclic chains can be prepared. These polyhydroxylated chains can
be combined with different bases to generate diversity.
Introduction
analogues, the acyclic phosphonates adefovir 4, tenofovir 5, and
cidofovir 6 are clinically used to treat hepatitis B, AIDS,1a,c-f
and cancer-associated human papilloma virus infections.2a,b
The development of nucleoside and nucleotide analogues has
generated much interest, since many have displayed potent
antiviral,1 cytotoxic,1b,2 or antiparasitic3 activities. To optimize
their potency, selectivity, or hydrolytic stability, different
changes in the base and sugar moieties have been explored.
Thus, the replacement of the sugar ring by acyclic chains has
generated nucleoside analogues such as acyclovir 1 (Figure 1),
ganciclovir 2, and penciclovir 3, active against herpes simplex,
varicella zoster, and cytomegalovirus.1a Among the nucleotide
(1) (a) For interesting introductions to the subject, see: de Clercq, E.
AntiViral Res. 2005, 67, 56-75. (b) Holy´, A. Synthesis and biological
activity of isopolar acyclic nucleotide analogs. In Recent AdVances in
Nucleosides: Chemistry and Chemotherapy; Chu, C. K., Ed.; Elsevier: New
York, 2002; pp 167-238. (c) For other reviews, see: de Clercq, E. Biochem.
Pharmacol. 2007, 73, 911-922. (d) de Clercq, E. AntiViral Res. 2007, 75,
1-13. (e) Lee, W. A.; Martin, J. C. AntiViral Res. 2006, 71, 254-259. (f)
Holy´, A. AntiViral Res. 2006, 71, 248-253. (g) Meier, C. Eur. J. Org.
Chem. 2006, 1081-1102. (h) Meier, C.; Balzarini, J. AntiViral Res. 2006,
71, 282-292. (i) Griffiths, P. D. AntiViral Res. 2006, 71, 192-200. (j)
Biron, K. K. AntiViral Res. 2006, 71, 154-163. (k) Golankiewicz, B.;
Ostrowski, T. AntiViral Res. 2006, 71, 134-140. (l) de Clercq, E. ReV.
Med. Virol. 2004, 14, 289-300. (m) de Clercq, E. Trends Pharmacol. Sci.
2002, 23, 456-458. (n) Fung, H. B.; Stone, E. A.; Piacenti, F. J. Clin.
Ther. 2002, 24, 1515-1548. (o) Gao, H.; Mitra, A. K. Synthesis 2000, 329-
351.
* Address correspondence to this author. Phone: +34-922-260112 (ext. 267).
Fax: +34-922-260135.
† Instituto de Productos Naturales y Agrobiolog´ıa del CSIC.
‡ Instituto de Investigaciones Qu´ımicas (CSIC-USe).
10.1021/jo701608p CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/07/2007
J. Org. Chem. 2007, 72, 9523-9532
9523

Boto et al.
SCHEME 2. Synthesis of Substrates 10 and 11
SCHEME 3. Synthesis of Substrates 12 and 13
FIGURE 1. Antiviral acyclic nucleoside and nucleotide analogues.
SCHEME 1. Preparation of Acyclic Nucleoside Analogues
with Different Bases, Chain Lengths, and Functional Groups
substrates. Ideally, the purification of synthetic intermediates
should be avoided, in order to save time and materials and to
reduce the waste.
Our group is currently developing acyclic nucleoside ana-
logues 7 (Scheme 1), with different bases, chain lengths, and
functional groups. At least one hydroxy group is left unprotected,
Fuelled by these successes, there is an active search for new
nucleoside1,4 or nucleotide1,5 analogues, to treat other viral
diseases or to overcome possible resistances. To obtain the
maximum possible diversity, methodologies are needed which
can generate many analogues in few steps from readily available
(4) (a) For some recent articles on nucleoside analogues, see: Zhang,
X.; Amer, A.; Fan, X.; Balzarini, J.; Neyts, J.; de Clercq, E.; Prichard, M.;
Kern, E.; Torrence, P. F. Bioorg. Chem. 2007, 35, 221-232. (b) Vejcik, S.
M.; Horton, D. Carbohydr. Res. 2007, 342, 806-818. (c) Tang, Y.;
Muthyala, R.; Vince, R. Bioorg. Med. Chem. 2006, 14, 5866-5875. (d)
Krisˇtafor, V.; Raic´-Malic´, S.; Cetina, M.; Kralj, M.; Sˇuman, L.; Pavelic´,
K.; Balzarini, J.; de Clercq, E.; Mintas, M. Bioorg. Med. Chem. 2006, 14,
8126-8138. (e) d’A. Lucero, B.; Gomes, C. R. B.; de P. P. Frugulhetti, I.
C.; Faro, L. V.; Alvarenga, L.; de Souza, M. C. B. V.; de Souza, T. M. L.;
Ferreira, V. F. Bioorg. Med. Chem. Lett. 2006, 16, 1010-1013. (f) Zhou,
S.; Kern, E. R.; Gullen, E.; Cheng, Y. C.; Drach, J. C.; Tamiya, S.; Mitsuya,
H.; Zemlicka, J. J. Med. Chem. 2006, 49, 6120-6128. (g) Barral, K.;
Balzarini, J.; Neyts, J.; de Clercq, E.; Hider, R. C.; Camplo, M. J. Med.
Chem. 2006, 49, 43-50. (h) Amblard, F.; Aucagne, V.; Guenot, P.; Schinazi,
R. F.; Agrofoglio, L. A. Bioorg. Med. Chem. 2005, 13, 1239-1248. (i)
Janeba, Z.; Balzarini, J.; Andrei, G.; Snoeck, R.; de Clercq, E.; Robins, M.
J. J. Med. Chem. 2005, 48, 4690-4696. (j) Koszytkowska-Stawin´ska, M.;
Sas, W. Tetrahedron Lett. 2004, 45, 5437-5440. (k) Herna´ndez, A. I.;
Balzarini, J.; Rodr´ıguez-Barrios, F.; San-Fe´lix, A.; Karlsson, A.; Gago, F.;
Camarasa, M. J.; Pe´rez-Pe´rez, M. J. Bioorg. Med. Chem. Lett. 2003, 13,
3027-3030 and references cited therein.
(2) (a) For a review, see: Abdulkarim, B.; Bourhis, J. Lancet Oncol.
2001, 2, 622-630. (b) For some articles on the subject, see: Tristram, A.;
Fiander, A. Gynecol. Oncol. 2005, 99, 652-655. (c) Votruba, I.; Pomeisl,
K.; Tloust’ova´, E.; Holy´, A.; Otova´, B. Biochem. Pharmacol. 2005, 69,
1517-1521. (d) He, L.; Liu, Y.; Zhang, W.; Li, M.; Chen, Q. Tetrahedron
2005, 65, 8505-8511. (e) Ha´jek, M.; Matulova´, N.; Votruba, I.; Holy´, A.;
Tloustova´, E. Biochem. Pharmacol. 2005, 70, 894-900. (f) Bobkova´, K.;
Otova´, B.; Marinov, I.; Mandys, V.; Panczak, A.; Votruba, I.; Holy´, A.
Anticancer Res. 2000, 20, 1041-1048 and references cited therein.
(3) (a) For a review on the antiviral, cytotoxic, and antiprotozoal
activities, see: Holy´, A. Curr. Pharm. Des. 2003, 9, 2567-2592. (b) For
articles on antibacterial and antiparasitic activities, see: Srivastav,
N. C.; Manning, T.; Kunimoto, D. Y.; Kumar, R. Bioorg. Med. Chem. 2007,
15, 2045-2053. (c) Nguyen, C.; Ruda, G. F.; Schipani, A.; Kasinathan,
G.; Leal, I.; Musso-Buendia, A.; Kaiser, M.; Brun, R.; Ruiz-Pe´rez, L. M.;
Sahlberg, B. L.; Johansson, N. G.; Gonza´lez-Pacanowska, D.; Gilbert, I.
H. J. Med. Chem. 2006, 49, 4183-4195. (d) Smeijsters, L. J.; Franssen, F.
F.; Naesens, L.; de Vries, E.; Holy´, A.; Balzarini, J.; de Clercq, E.;
Overdulve, J. P. Int. J. Antimicrob. Agents 1999, 12, 53-61.
9524 J. Org. Chem., Vol. 72, No. 25, 2007

One-Pot Synthesis of Acyclic Nucleosides
SCHEME 4. Synthesis of Acetoxy Acetals 20 and 21
SCHEME 5. Synthesis of Acetoxy Acetals 22 and 23
wide range of acyclic nucleosides 7 could be prepared from
sugar derivatives 9 in just one step. Such a procedure would be
very useful for a high-throughput screening and to avoid
troublesome separations in a scaled-up synthesis. Herein we
show the feasibility of this approach.
to allow the phosphorylation of the analogue and its incorpora-
tion to the viral nucleic acid chain. By the choice of appropriate
Y groups, further elongation of the nucleic acid chain is hindered
(Y * OH) or, alternatively, nonfunctional, distorted chains are
formed.
The preparation of analogues 7 with polyhydroxylated chains
(Y ) OR) could be carried out by reaction of the silylated base
(or aromatic organometallic reagents) with aldehydes, acetals,
or acetoxyacetals (such as compound 8). These acyclic inter-
mediates can be obtained from carbohydrates 9, according to
different methodologies.1-5
We reasoned that this procedure could be shortened by the
use of tandem and sequential reactions.6 For instance, we have
reported that the tandem radical scission-oxidation of sugar
derivatives 9 with (diacetoxyiodo)benzene and iodine affords
acetoxy acetals 8.7 Depending on the starting sugar, both
common and uncommon acyclic chains can be prepared. If this
tandem reaction could be coupled with the introduction of
nitrogen nucleophiles (such as pyrimidine and purine bases), a
Results and Discussion
The substrates for the fragmentation reaction, compounds
10-13 (Schemes 2 and 3), are ribose, mannose, and rhamnose
derivatives, which were synthesized in a few steps by conven-
tional carbohydrate methodologies. Substrate 10 (Scheme 2)
was prepared from known benzyl 2,3-O-isopropylideneribose
14,8 which was methylated to compound 15. Removal of
the benzyl protecting group afforded the fragmentation sub-
strate 10.
The 5-benzoyloxy analogue 11 (Scheme 2) was synthesized
from ribose derivative 169,10 by cleavage of the 5-silyloxy
function followed by transposition of the anomeric benzoyl
group. The major product was, however, 1-O-benzoyl-2,3-O-
isopropylidene ribose 17.10
The mannose derivative 12 (Scheme 3) was prepared from
known p-methoxybenzyl 2,3-O-isopropylidene mannofuranose
18,11 by methylation to compound 19 and cleavage of the
anomeric protecting group. The rhamnose substrate 13 was
synthesized according to reported procedures.12
Prior to developing the one-pot scission-base addition
process, we studied the tandem radical fragmentation-oxidation
(5) (a) For some recent articles on nucleotide analogues, see: Krecˇ-
merova´, M.; Holy´, A.; P´ıskala, A.; Masoj´ıdkova´, M.; Andrei, G.; Naesens,
L.; Neyts, J.; Balzarini, J.; de Clercq, E.; Snoeck, R. J. Med. Chem. 2007,
50, 1069-1077. (b) Choo, H.; Beadle, J. R.; Chong, Y.; Trahan, J.; Hostetler,
K. Y. Bioorg. Med. Chem. 2007, 15, 1771-1779. (c) Valiaeva, N.; Beadle,
J. R.; Aldern, K. A.; Trahan, J.; Hostetler, K. Y. AntiViral Res. 2006, 72,
10-19. (d) Horejs´ı, K.; Andrei, G.; de Clercq, E.; Snoeck, R.; Pohl, R.;
Holy´, A. Bioorg. Med. Chem. 2006, 14, 8057-8065. (e) Beadle, J. R.; Wan,
W. B.; Ciesla, S. L.; Keith, K. A.; Hartline, C.; Kern, E. R.; Hostetler, K.
Y. J. Med. Chem. 2006, 49, 2010-2015. (f) Barral, K.; Priet, S.; Sire, J.;
Neyts, J.; Balzarini, J.; Canard, B.; Alvarez, K. J. Med. Chem. 2006, 49,
7799-7806. (g) Sauerbrei, A.; Meier, C.; Meerbach, A.; Schiel, M.; Helbig,
B.; Wutzler, P. AntiViral Res. 2005, 67, 147-154.
(6) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Enders,
D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570-
1581. (c) Nicolaou, K. C.; Edmons, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134-7186. (d) Pellissier, H. Tetrahedron 2006, 62,
1619-1665 (Part A) and Tetrahedron 2006, 62, 2143-2173 (Part B). (e)
Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354-366. (f)
Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005,
105, 1001-1020. (g) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed.
2004, 43, 3754-3760. (h) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem.
ReV. 1996, 96, 195-206. (i) Tietze, L. F. Chem. ReV. 1996, 96, 115-136
and references cited therein.
(7) (a) Boto, A.; Herna´ndez, D.; Herna´ndez, R. Org. Lett. 2007, 9, 1721-
1724. (b) Boto, A.; Herna´ndez, R.; Sua´rez, E. Tetrahedron Lett. 2001, 42,
9176-9170. (c) Francisco, C. G.; Gonza´lez, C.; Sua´rez, E.; J. Org. Chem.
1998, 63, 8092-8093. (d) de Armas, P.; Francisco, C. G.; Sua´rez, E. Angew.
Chem., Int. Ed. Engl. 1992, 31, 772-774. (e) For a review on the
modification of carbohydrates through radical chemistry, see: Hansen, S.
G.; Skrydstrup, T. Top. Curr. Chem. 2006, 264, 135-162.
(8) Duvold, T.; Francis, G. W.; Papaioannou, D. Tetrahedron Lett. 1995,
36, 3153-3156.
(9) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R.
Synthesis 1990, 1031-1032.
(10) Francisco, C. G.; Gonza´lez, C.; Sua´rez, E. J. Org. Chem. 1998, 63,
2099-2109.
(11) Zhao, H.; Hans, S.; Cheng, Y.; Mootoo, D. R. J. Org. Chem. 2001,
66, 1761-1767.
(12) (a) Angyal, S. J.; Pickles, V. A.; Ahluwalia, R. Carbohydr. Res.
1967, 3, 300-307. (b) For previous steps, see: Ferroud, D.; Collard, J.;
Klick, M.; Dupuis-Hamelin, C.; Mauvais, P.; Lassaigne, P.; Bonnefoy, A.;
Musicki, B. Biorg. Med. Chem. Lett. 1999, 9, 2881-2886. (c) Collins, P.
M.; Travis, A. S. J. Chem. Soc., Perkin Trans. 1 1980, 779-786. (d) Bedini,
E.; Parrilli, M.; Unverzagt, C. Tetrahedron Lett. 2002, 43, 8879-
8882.
J. Org. Chem, Vol. 72, No. 25, 2007 9525

Boto et al.
TABLE 1. Addition of Bis(TMS)thymine to Acetoxy Acetals
20-23
TABLE 2. Addition of Bis(trimethylsilyl)-4-N-benzoylcytosine to
Acetates 20-23
a Condition A: Acetates 20-23, CH2Cl2, 0 °C, BF3‚OEt2, base, 0.5 h.
Then 0 °Cfrt, 2 h. Yields are given for products purified by chromatog-
raphy. b Condition B: Similar to condition A, using TMSOTf as the Lewis
acid and MeCN as the solvent. c The dr was determined by 1H NMR
experiments.
a Condition A: Acetates 20-23, CH2Cl2, 0 °C, BF3‚OEt2, base, 0.5 h.
Then 0 °Cfrt, 2 h. Yields are given for products purified by chromatog-
raphy. b Condition B: Similar to condition A, using TMSOTf as the Lewis
acid and MeCN as the solvent. c The dr was determined by 1H NMR
experiments.
reaction, in the absence of nitrogen nucleophiles. The scission
of carbohydrate substrates 10 and 11 (Scheme 4) was carried
out by treatment with (diacetoxyiodo)benzene (DIB) and iodine
in dry dichloromethane at room temperature (26 °C), under
irradiation with visible light (80-W tungsten-filament lamp).
After 1 h, the acetoxy acetals 20 and 21 were isolated in good
yields and stereoselectivities.
The first step of this tandem reaction was the generation of
anomeric alkoxyl radicals, which underwent â-scission to the
C-radicals 10a or 11a (Scheme 4). These intermediates probably
reacted with iodine, forming unstable 1-iodoethers 10b or 11b.
The extrusion of iodide generated the oxycarbenium ions 10c
or 11c,13 which were trapped by acetoxy ions from the reagent,
affording acetals 20 and 21.
To our delight, the desired acyclic nucleosides 24-33 (Table
1) were obtained in good to excellent yields. The 1′,2′-trans
diastereomers were the major or exclusive ones, since the
nucleophilic addition took place from the less hindered side of
the oxycarbenium ions. The stereochemistry of compound 29
was confirmed by X-ray analysis.15
Although the diastereoselectivity is mainly controlled by the
dioxolane ring, the chain substituents also play a significant role.
Thus, the reaction of acetate 20 (with a 4-methoxy group)
afforded exclusively the 1′,2′-trans nucleoside 28, while acetate
21 (with a bulkier 4-benzoyloxy group) gave a separable mixture
of the trans and cis nucleosides 29 and 30 (29:30, 2:1). Besides,
while the furanose substrates 20 and 22 afforded the corre-
sponding acyclic nucleosides in excellent trans stereoselectivity,
the pyranose substrate 23 gave mixtures of the trans and cis
isomers (trans:cis, 5:1).
In a similar way, the mannose and rhamnose derivatives 12
and 13 were transformed into their acetoxy acetals 22 and 23
(Scheme 5).
The acetates 20-23 were then treated with Lewis acids, to
regenerate the oxycarbenium ions, and bis(trimethylsilyl)thymine
(Table 1) or bis(trimethylsilyl)-4-N-benzoylcytosine (Table 2).
Different Lewis acids and solvents were tried, in order to
optimize the reaction conditions. The best ones proved to be
boron trifluoride in dichloromethane (condition A) and TMSOTf
in acetonitrile (condition B). The nucleophiles were prepared
from thymine and cytosine by using the Vorbru¨ggen protocol,
since the commercial reagents gave inferior results.14
(14) (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.
(15) Crystallographic data for the compounds studied in the solid state
have also been deposited in the Cambridge Crystallographic Data Centre
as nos. CCDC-645469 (29), CCDC-645470 (36), CCDC-645471 (37), and
CCDC-645472 (45). These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12, Union Road Cambridge CB21EZ, UK; fax (+44)
1223-336-033; e-mail deposit@ccdc.cam.ac.uk).
(13) For a related mechanistic proposal, see: Boto, A.; Herna´ndez, R.;
Leo´n, Y.; Murgu´ıa, J. R.; Rodr´ıguez-Afonso, A. Eur. J. Org. Chem. 2005,
673-682.
9526 J. Org. Chem., Vol. 72, No. 25, 2007

One-Pot Synthesis of Acyclic Nucleosides
TABLE 3. Addition of Halogenated Pyrimidine Bases to Acetates 20-23
a Conditon A: Acetates 20-23, CH2Cl2, 0 °C, BF3‚OEt2, base, 0.5 h, then 0 °Cfrt, 2 h. b Condition B: Similar to A, using TMSOTf as the Lewis acid
1
and MeCN as the solvent. c The dr was determined by H NMR.
To study the effect of substituents on the pyrimidine ring,
bis(TMS) derivatives of iodo- and fluorouracil were used as
nucleophiles (Table 3). The reaction of the iodouracil reagent
proceeded as expected, under both conditions A and B, affording
the acyclic nucleosides 34-37 in excellent yield. While the
acetates 20 and 22 gave exclusively the trans derivatives 34
and 35, the acetate 23 afforded a diastereomer mixture (36:37,
2:1). The structures of compounds 36 and 37 were confirmed
by X-ray analysis.
The activity of these dimeric nucleoside derivatives is currently
being tested.16
Once the two-step fragmentation and base addition procedure
was optimized, its one-pot version was explored. Thus, the
tandem scission-oxidation reaction was the first step of a
sequential process (Table 4). Different reaction conditions were
tried: when the scission was carried out in CH2Cl2 and then
boron trifluoride (or TMSOTf) and the nucleophile was added,
the acyclic nucleosides were formed in low yields. If the scission
was carried out in acetonitrile, followed by Lewis acid (BF3‚
OEt2 or TMSOTf) and nucleophile addition, poor yields were
obtained. Finally, an in situ solvent-replacement strategy gave
excellent results: after the fragmentation step, the solvent (CH2-
Cl2) was removed under vacuum, and the crude residue was
When the addition was repeated with the fluorouracil reagent
under condition B, the desired nucleosides 38, 40, and 41 were
isolated in good yield. However, when condition A was used
with acetoxy acetals 20 and 23, an unexpected result was
obtained. The bis(silylated) fluorouracil reacted as a bidentate
nucleophile, and the dimeric products 39 and 42 were formed.
Surprisingly, no monomeric products 38 or 41 were detected.
(16) For examples of other type of dimeric acyclic nucleosides, see:
Dola´kova´, P.; Drac´ınsky´, M.; Holy´, A. AntiViral Res. 2007, 74, 109 (A72).
J. Org. Chem, Vol. 72, No. 25, 2007 9527

Boto et al.
TABLE 4. One-Pot Fragmentation-Nucleophilic Addition
a For comparison, the global yields for the two-step procedure were as follows: 24 (82%), 25 (81%), 26 (74%) + 27 (14%), 28 (70%), 29 (53%) + 30
(28%), 31 (67%), 32 (69%) + 33 (10%), 34 (73%), 35 (80%), 36 (76%) + 37 (5%), 38 (71%) + 39 (0%), 40 (80%), 41 (74%) + 42 (7%).
redissolved in acetonitrile and treated with TMSOTf and the
nucleophile at 0 °C (method C).
addition of (trimethylsilyl)benzotriazole and bis(trimethylsilyl)-
benzyloxypurine to acetates 20-23 is shown in Table 5.
The overall yields for the one-step process are comparable
or superior to those obtained with the two-step procedure.
Moreover, since no workup or purification of the acetoxy
intermediates 20-23 is needed, time is saved and the amount
of waste is reduced.17
The addition of benzotriazolyl and purine nucleophiles was
tried next. Since several cyclic benzotriazolyl nucleosides have
shown promising antitumor activity,18 the study of their acyclic
analogues is of interest. On the other hand, many commercial
antivirals present purine bases, as commented on before. The
The benzotriazolyl and purine derivatives from ribose and
mannose (products 43, 44, 47, and 48) were exclusively 1,2-
trans diastereomers. The reaction with rhamnose afforded a
separable mixture of the 1,2-trans and 1,2-cis diastereomers (45:
46, 3:1; 49:50, 1.5:1). The stereochemistry of the trans diaste-
reomer 45 was confirmed by X-ray analysis. Again, the one-
pot process gave similar or superior yields to the two-step
procedure.
To be biologically active, the acyclic nucleosides must be
phosphorylated and incorporated to the nucleic acid chain, so
at least one hydroxy group must be left unprotected (Scheme
6). The formate group generated during the scission step can
be easily cleaved by treatment with NaHCO3 (1% in methanol,
(17) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(18) (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.
9528 J. Org. Chem., Vol. 72, No. 25, 2007

One-Pot Synthesis of Acyclic Nucleosides
TABLE 5. Formation of Benzotriazolyl and Purine Nucleosides
a Yields are given for purified products.
rt, 1 h), and therefore, the alcohols 51-58 (Scheme 6) were
formed in very good yields.
the replacement of the 1-alkoxy group by other functionalities.
Derivatives with different hydrosolubility and hydrolytic stability
will be prepared, to determine their biological activities.
The mild conditions are compatible with most protecting
groups; however, the substrate can affect the reaction results.
The cytosine derivative 28 was transformed into the alcohol 55
without cleavage of the benzamide group. In contrast, the
cytosine derivative 32 gave product 56, where both the formate
and the benzamide group have been hydrolyzed.
The free alcohols 51-58 and the formate derivatives 24-50
are analogues of antiviral acyclic nucleosides such as penciclovir
3.19 Besides, the free alcohols can be used as precursors of other
drug candidates such as acyclic nucleotide analogues (O-
methylphosphonates, phosphates, etc.).1 In this moment, we are
engaged in the preparation of new nucleoside and nucleotide
derivatives, with different bases and chain substituents, and in
Conclusion
This work highlights how readily available precursors can
be directly transformed into high-value products by a rational
combination of tandem and sequential reactions. The one-pot
conversion of carbohydrates into acyclic nucleosides proceeded
in good to excellent yields, and in many cases, with good to
excellent stereoselectivities. This sequential process is initiated
by a tandem radical fragmentation-oxidation reaction, which
generates an oxycarbenium ion. This intermediate is trapped
by addition of nitrogen nucleophiles, such as purine, pyrimidine,
or benzotriazolyl bases. The reaction conditions are mild,
compatible with most functional groups. The method is opera-
tionally simple, and environmentally friendly: no purification
of intermediates is needed, and the reagents have low toxicity.
Highly functionalized chains can be obtained, and the modifica-
tion of these chains can afford new derivatives. An important
(19) The antiviral activity of compounds 24-58 is currently under study,
and will be published in due time. Previously, their cytotoxic activity was
tested with three tumour cell lines: MCF7 (breast), NCI-H460 (lung), and
SF-268 (glioma), displaying little cytotoxicity, as needed for a selective
antiviral compound.
J. Org. Chem, Vol. 72, No. 25, 2007 9529

Boto et al.
SCHEME 6. Cleavage of the Formate Group
50.38; H, 6.92. Found: C, 50.28; H, 7.02. Product (1S)-20:
amorphous; [R]D -68 (c 0.14, CHCl3); IR (CHCl3) 1731, 1228
diversity can be generated by a combination of different bases
and polyhydroxylated chains.
1
cm-1; H NMR (500 MHz) δH 1.41 (3H, s), 1.51 (3H, s), 2.05
(3H, s), 3.41 (3H, s), 3.66 (1H, dd, J ) 4.9, 11.3 Hz), 3.72 (1H,
dd, J ) 2.3, 11.2 Hz), 4.38 (1H, dd, J ) 3.5, 9.2 Hz), 5.39 (1H,
ddd, J ) 2.1, 4.9, 9.3 Hz), 6.31 (1H, d, J ) 3.5 Hz), 8.01 (1H, s);
13C NMR (125.7 MHz) δC 21.1 (CH3), 26.1 (CH3), 28.1 (CH3),
59.4 (CH3), 69.6 (CH), 71.5 (CH2), 76.0 (CH), 93.2 (CH), 112.7
(C), 159.5 (CH), 170.1 (C); MS m/z (rel intensity) 247 (M+ - Me,
73), 203 (M+ - MeCO2, 19), 145 (M+ - [(Me2CdO + MeCO2],
100); HRMS calcd for C10H15O7 247.0818, found 247.0812; calcd
for C6H9O4 145.0501, found 145.0482. Anal. Calcd for C11H18O7:
C, 50.38; H, 6.92. Found: C, 50.30; H, 7.01.
Experimental Section
General Procedure for the â-Fragmentation of Carbohydrate
Derivatives 10-13. To a solution of the carbohydrate (1.0 mmol)
in dry CH2Cl2 (10 mL) under nitrogen were added (diacetoxyiodo)-
benzene (DIB) (386 mg, 1.2 mmol) and iodine (254 mg, 1.0 mmol).
The reaction mixture was stirred at room temperature (26 °C) under
irradiation with visible light (80-W tungsten-filament lamp) for 1
h. Then it was poured into aqueous 10% sodium thiosulfate
(Na2S2O3) and extracted with dichloromethane. The organic layer
was washed with brine, dried on Na2SO4, filtered, and evaporated
under vacuum. The residue was purified by chromatography on
silica gel (hexanes/EtOAc), yielding the purified acetoxy acetals
20-23.
(1R)- and (1S)-Acetoxy-3-O-formyl-1,2-isopropylidene-4-O-
benzoyl-D-erythritol ((1R)-21 and (1S)-21). Separable mixture of
the (1R)-21 (65%) and the (1S)-21 (16%) (global yield, 81%). When
the â-scission was carried out in acetonitrile, smaller yields were
obtained (61%, (1R)-21:(1S)-21, 4:1). Product (1R)-21: crystalline
solid; mp 78-81 °C (from n-hexane); [R]D +51 (c 0.56, CHCl3);
(1R)- and (1S)-Acetoxy-3-O-formyl-1,2-isopropylidene-4-O-
methyl-D-erythritol ((1R)-20 and (1S)-20). Separable mixture of
the (1R)-20 (79%) and the (1S)-20 (4%) (global yield, 83%). When
the â-scission was carried out in acetonitrile, smaller yields were
obtained (60%, (1R)-20:(1S)-20, 21:1). Product (1R)-20: amor-
1
IR (CHCl3) 3089, 3067, 1732, 1602 cm-1; H NMR (500 MHz)
δH 1.51 (3H, s), 1.52 (3H, s), 2.04 (3H, s), 4.44 (1H, dd, J ) 2.2,
6.4 Hz), 4.49 (1H, dd, J ) 5.8, 12.3 Hz), 4.67 (1H, dd, J ) 3.1,
12.3 Hz), 5.43 (1H, ddd, J ) 3.1, 6.0, 6.0 Hz), 6.32 (1H, d, J )
2.2 Hz), 7.46 (2H, dd, J ) 7.7, 7.8 Hz), 7.58 (1H, dd, J ) 7.4, 7.5
Hz), 8.02 (2H, d, J ) 7.3 Hz), 8.13 (1H, s); 13C NMR (125.7 MHz)
δC 21.1 (CH3), 26.7 (CH3), 27.4 (CH3), 62.6 (CH2), 70.0 (CH),
80.5 (CH), 96.1 (CH), 113.6 (C), 128.5 (2 × CH), 129.4 (C), 129.7
(2 × CH), 133.4 (CH), 159.7 (CH), 166.0 (C), 169.9 (C); MS m/z
(rel intensity) 337 (M+ - Me, 41), 235 (M+ - [OAc + Me2Cd
O)], 2), 105 ([PhCO]+, 100); HRMS calcd for C16H17O8 337.0923,
found 337.0924; calcd for C7H5O 105.0340, found 105.0358. Anal.
Calcd for C17H20O8: C, 57.95; H, 5.72. Found: C, 57.79; H, 5.95.
phous; [R]D +82 (c 0.11, CHCl3); IR (CHCl3) 1733, 1230 cm-1
;
1H NMR (500 MHz) δH 1.44 (3H, s), 1.47 (3H, s), 2.07 (3H, s),
3.34 (3H, s), 3.58 (2H, d, J ) 4.2 Hz), 4.38 (1H, dd, J ) 2.3, 5.8
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); 13C NMR (125.7 MHz) δC 21.1 (CH3), 26.5
(CH3), 27.2 (CH3), 59.2 (CH3), 70.3 (CH2), 70.9 (CH), 80.4 (CH),
95.9 (CH), 112.9 (C), 159.9 (CH), 169.9 (C); MS m/z (rel intensity)
247 (M+ - Me, 100), 145 (M+ - [Me2CdO + MeCO2], 92);
HRMS calcd for C10H15O7 247.0818, found 247.0811; calcd for
C6H9O4 145.0501, found 145.0496. Anal. Calcd for C11H18O7: C,
9530 J. Org. Chem., Vol. 72, No. 25, 2007

One-Pot Synthesis of Acyclic Nucleosides
Product (1S)-21: colorless crystals; mp 71-72 °C (from n-hexane);
[R]D -69 (c 0.63, CHCl3); IR (CHCl3) 3098, 3066, 1732, 1602
Cl2. The organic layer was dried on Na2SO4, filtered, and evaporated
under vacuum. The residue was purified by chromatography on
silica gel (hexanes/EtOAc) to give the acyclic nucleosides.
Method B (Reaction of the Acetoxy Acetals with Silylated
Nitrogen Bases and Lewis Acids). To a solution of the acetoxy
acetal (0.2 mmol) in dry CH3CN (2 mL), at 0 °C and under nitrogen,
was added freshly prepared nucleophile (0.3-0.4 mmol) and then
trimethylsilyl triflate (TMSOTf) (46 µL, 89 mg, 0.4 mmol) was
injected dropwise for 15 min. The stirring was continued at rt for
3 h, followed by the usual workup and purification.
Method C (One-Pot Procedure). The reaction flask was
attached to a standard vacuum/nitrogen system. The photolysis was
performed as in Method A and then the solvent was removed under
vacuum. The flask was flushed with nitrogen and the crude residue
was redissolved in acetonitrile (2 mL) and treated as described in
Method B.
1
cm-1; H NMR (500 MHz) δH 1.42 (3H, s), 1.54 (3H, s), 2.09
(3H, s), 4.42 (1H, dd, J ) 3.5, 9.0 Hz), 4.46 (1H, dd, J ) 6.3, 12.3
Hz), 4.82 (1H, dd, J ) 2.4, 12.3 Hz), 5.65 (1H, ddd, J ) 2.2, 6.3,
8.7 Hz), 6.38 (1H, d, J ) 3.5 Hz), 7.46 (2H, dd, J ) 7.7, 7.9 Hz),
7.58 (1H, dd, J ) 7.4, 7.5 Hz), 8.02 (1H, s), 8.03 (2H, d, J ) 7.2
Hz); 13C NMR (127.5 MHz) δC 21.1 (CH3), 26.0 (CH3), 28.1 (CH3),
63.9 (CH2), 68.3 (CH), 76.5 (CH), 93.0 (CH), 113.0 (C), 128.5 (2
× CH), 129.6 (C), 129.7 (2 × CH), 133.3 (CH), 159.3 (CH), 166.1
(C), 170.0 (C); MS m/z (rel intensity) 337 (M+ - Me, 100), 235
(M+ - [OAc + Me2CdO], 45); HRMS calcd for C16H17O8
337.0923, found 337.0875. Anal. Calcd for C17H20O8: C, 57.95;
H, 5.72. Found: C, 58.06; H, 6.00.
(1S)-1-Acetoxy-3-O-formyl-1,2-O-isopropylidene-4,5-di-O-
methyl-D-arabinitol (22). The acetate was obtained as the 1,2-
trans isomer (82%). Colorless crystals; mp 49-51 °C (from EtOAc/
n-hexane); [R]D -51 (c 0.35, CHCl3); IR (CHCl3) 1746, 1732, 1114
(4-N-Benzoyl)-1-[(1S)- (29) and (4-N-Benzoyl)-1-[(1R)-4-O-
benzoyl-3-O-formyl-1,2-O-isopropylidene-D-erythritol-1-yl]cy-
tosine (30). Compounds 29 and 30 were obtained from acetoxy
acetal 21, using bis(trimethylsilyl)-4-N-benzoylcytosine as the
nucleophile. Method A: 61% for product 29 and 28% for product
30. Method B: 66% for product 29 and 33% for product 30. One-
pot procedure (Method C) from 2,3-O-isopropylidene-4-O-benzoyl-
D-ribofuranose 11: 59% for product 29 and 40% for product 30.
Compound 29: colorless crystals; mp 199-201 °C (from CH2Cl2/
MeOH); [R]D -23 (c 0.19, CHCl3); IR (CHCl3) 3406, 3112, 3090,
1
cm-1; H NMR (500 MHz) δH 1.48 (3H, s), 1.49 (3H, s), 2.07
(3H, s), 3.33 (3H, s), 3.36 (1H, dd, J ) 4.5, 10.6 Hz), 3.45 (3H, s),
3.52 (1H, ddd, J ) 4.4, 4.4, 7.8 Hz), 3.58 (1H, dd, J ) 3.1, 10.6
Hz), 4.53 (1H, dd, J ) 2.3, 3.8 Hz), 5.25 (1H, dd, J ) 4.0, 7.9
Hz), 6.13 (1H, d, J ) 2.3 Hz), 8.11 (1H, s); 13C NMR (125.7 MHz)
δC 21.1 (CH3), 26.9 (CH3), 27.1 (CH3), 58.4 (CH3), 59.3 (CH3),
69.9 (CH), 70.4 (CH2), 78.3 (CH), 80.8 (CH), 96.5 (CH), 113.2
(C), 159.9 (CH), 170.0 (C); MS m/z (rel intensity) 291 (M+ - Me,
48), 89 ([MeOCH2CHOMe]+, 100), 59 ([Me2CdOH]+, 93); HRMS
calcd for C12H19O8 291.1080, found 291.1062; calcd for C4H9O2
89.0602;, found 89.0615. Anal. Calcd for C13H22O8: C, 50.98; H,
7.24. Found: C, 50.92; H, 6.91.
1
3068, 1728, 1706, 1672, 1627, 1602, 1553, 1480 cm-1; H NMR
(500 MHz) δH 1.58 (3H, s), 1.59 (3H, s), 4.35 (1H, dd, J ) 5.7,
5.8 Hz), 4.52 (1H, dd, J ) 6.5, 12.2 Hz), 4.72 (1H, dd, J ) 3.4,
12.2 Hz), 5.81 (1H, ddd, J ) 3.3, 6.4, 6.5 Hz), 6.30 (1H, d, J )
5.1 Hz), 7.42 (2H, dd, J ) 7.7, 7.7 Hz), 7.50 (2H, dd, J ) 7.5, 7.6
Hz), 7.55 (1H, dd, J ) 7.4, 7.4 Hz), 7.60 (1H, dd, J ) 7.3, 7.4
Hz), 7.61 (1H, br b), 7.91 (1H, d, J ) 7.1 Hz), 7.92 (2H, d, J )
7.5 Hz), 7.99 (2H, d, J ) 7.4 Hz), 8.12 (1H, s), 9.10 (1H, br s);
13C NMR (125.7 MHz, 60 °C) δC 27.0 (CH3), 27.6 (CH3), 62.8
(CH2), 70.2 (CH), 81.1 (CH), 86.0 (CH), 97.7 (CH), 112.8 (C),
127.7 (2 × CH), 128.4 (2 × CH), 129.0 (2 × CH), 129.6 (C),
129.7 (2 × CH), 133.1 (C), 133.2 (2 × CH), 143.2 (CH), 154.2
(C), 159.7 (CH), 162.4 (C), 166.0 (C), 166.7 (C); MS m/z (rel
intensity) 507 (M+, <1), 215 (N-benzoylcytosine+, 6), 105 ([Ph-
CO]+, 100); HRMS calcd for C26H25N3O8 507.1642, found
507.1650; calcd for C7H5O 105.0340, found 105.0404. Anal. Calcd
for C26H25N3O8: C, 61.53; H, 4.97; N, 8.28. Found: C, 61.75; H,
5.11; N, 8.00. Crystal data20 for C26H25N3O8: Mr ) 507.49,
colorless needle (0.15 × 0.10 × 0.05 mm3) from methanol;
orthorhombic, space group P212121 (no. 19), a ) 7.2301(2) Å, b
) 17.5814(8) Å, c ) 19.1174(8) Å, V ) 2430.11(16) Å,3 Z ) 4,
Fcalcd ) 1.387 g cm-3, λ(Mo KR1) ) 0.71073 Å, F(000) ) 1064,
µ ) 0.104 mm-1, T ) 100(2) K. 24500 Reflections were collected
from a Bruker-AXS X8Kappa APEX II CCD diffractometer in the
range 6.02 < 2θ < 61.08° and 4188 independent reflections [R(int)
) 0.0686] were used in the structural analysis. Reflections were
corrected for Lorentz polarization effects and absorption applied
by (SADABS).20a The structure was solved by direct methods (SIR-
97)20b and refined against all F2 data by full-matrix least-squares
techniques (SHELXTL-6.12)20c to R1 ) 0.0420, wR2 ) 0.0855 [I
> 2σ(I)], and to R1 ) 0.0790, wR2 ) 0.0983 for all data, with a
Goodness-of-fit on F2, S ) 1.022 and 335 parameters. The
asymmetric unit of the structure is formed by one molecule of
compound 29. Because of a large su on the Flack parameter of
0.0(8), the Friedel pairs were averaged in the refinement (MERG
(1R/S)-1-Acetoxy-5-deoxy-4-O-formyl-1,2-O-isopropylidene-
3-O-methyl-L-arabinitol (23). Acetate 23 was obtained as an
inseparable diastereomer mixture (89%, trans/cis, 5:1). Colorless
oil; [R]D +25 (c 0.52, CHCl3); IR (CHCl3) 1751, 1724, 1179 cm-1
;
1H NMR (500 MHz) major diastereomer δH 1.35 (3H, d, J ) 6.5
Hz), 1.46 (3H, s), 1.48 (3H, s), 2.09 (3H, s), 3.44 (1H, dd, J ) 4.6,
4.6 Hz), 3.54 (3H, s), 4.25 (1H, dd, J ) 2.8, 4.4 Hz), 5.13 (1H,
dddd, J ) 5.7, 5.8, 6.3, 6.3 Hz), 6.19 (1H, d, J ) 2.7 Hz), 8.03
(1H, s); minor diastereomer δH 1.28 (3H, d, J ) 6.6 Hz), 1.39 (3H,
s), 1.52 (3H, s), 2.12 (3H, s), 3.59 (3H, s), 3.65 (1H, dd, J ) 3.9,
10.0 Hz), 4.03 (1H, dd, J ) 3.8, 10.0 Hz), 4.96 (1H, dddd, J )
3.2, 6.6, 6.6, 6.6 Hz), 6.21 (1H, d, J ) 3.3 Hz), 8.01 (1H, s); 13C
NMR (125.7 MHz) major diastereomer δC 15.6 (CH3), 21.2 (CH3),
26.4 (CH3), 26.7 (CH3), 60.8 (CH3), 70.9 (CH), 81.5 (CH), 82.5
(CH), 97.0 (CH), 113.1 (C), 160.1 (CH), 170.5 (C); minor
diastereomer δC 14.6 (CH3), 21.2 (CH3), 25.8 (CH3), 28.2 (CH3),
60.8 (CH3), 69.7 (CH), 80.2 (CH), 81.0 (CH), 92.5 (CH), 111.8
(C), 159.9 (CH), 170.5 (C); MS m/z (rel intensity) 261 (M+ - Me,
26), 125 (M+ - [(MeCO2H + Me + MeO + OCHO)], 100);
HRMS calcd for C11H17O7 261.0974, found 261.0978; calcd for
C7H9O2 125.0603, found 125.0585. Anal. Calcd for C12H20O7: C,
52.17; H, 7.30. Found: C, 52.32; H, 7.18.
Preparation of Trimethylsilyl Derivatives of the Nitrogen
Bases. Some trimethylsilyl derivatives from the nitrogen bases are
commercial products, but they gave variable yields. However, the
reagents can be readily prepared as follows. The bases (0.4 mmol)
and N,O-bis(trimethylsilyl)acetamide (297 µL, 244 mg, 1.2 mmol)
under nitrogen were heated to 130 °C and stirred for 1 h. The
mixture was then cooled to rt and dry toluene (1 mL) was added;
the volatiles were removed under vacuum, and the operation was
repeated twice. The reagent was used in the next step without further
purification.
Synthesis of Acyclic Nucleosides. Method A (Reaction of the
Acetoxy Acetals with Silylated Nitrogen Bases and Lewis Acids).
To a solution of the acetate (0.2 mmol) in dry CH2Cl2 (2 mL) at 0
°C and under nitrogen was added dropwise freshly prepared
nucleophile (0.3-0.4 mmol) and boron trifluoride etherate (51 µL,
57 mg, 0.4 mmol). The mixture was stirred for 30 min, then was
poured into aqueous saturated NaHCO3 and extracted with CH2-
(20) (a) Area-Detector Absorption Correction. SADABS within SAINT+
package, v. 7.06, 1996, BRUKER-AXS Inc., 5465 East Cheryl Parkway,
Madison, WI. (b) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.
L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115-119. (c) Program for Structure
Solution, Refinement and Presentation, BRUKER-AXS Inc., 5465 East
Cheryl Parkway, Madison, WI. (d) Flack, H. D. Acta Crystallogr. 1983,
A39, 876-881.
J. Org. Chem, Vol. 72, No. 25, 2007 9531

Boto et al.
4 command). Thereby, the absolute configuration of new chiral
center C1′ has been assigned as S by reference to other unchanging
chiral centers in the synthetic procedure of known absolute
configuration. All the non-hydrogen atoms were refined with
anisotropic displacement parameters. A few reflections to low angle
that present values very much below their calculated values, possibly
partially covered for “beam stopper”, were eliminated at the end
of the refinement (OMIT command). The hydrogen atoms were
included from calculated positions and refined riding on their
respective carbon atoms with isotropic displacement parameters.
The final difference map displayed no electron density higher than
(1H, ddd, J ) 3.8, 3.9, 7.4 Hz), 5.32 (1H, ddd, J ) 3.9, 3.9, 7.5
Hz), 6.25 (1H, dd, J ) 1.6, 5.6 Hz), 6.51 (1H, d, J ) 6.0 Hz), 7.36
(1H, d, JHF ) 5.3 Hz), 8.06 (2H, s); 13C NMR (125.7 MHz) δC
26.2 (CH3), 27.2 (CH3), 27.7 (CH3), 28.6 (CH3), 59.2 (CH3), 59.4
(CH3), 70.2 (CH2), 70.7 (CH2), 70.9 (CH), 72.1 (CH), 74.3 (CH),
78.1 (CH), 83.2 (CH), 84.6 (CH), 111.9 (C), 112.4 (C), 121.8 (CH,
JCF ) 33.9 Hz), 140.0 (C, JCF ) 237.8 Hz), 148.5 (C), 156.2 (C,
JCF ) 26.9 Hz), 159.9 (CH), 160.0 (CH); MS m/z (rel intensity)
519 (M+ - Me, 3), 145 ([4-(1,2-dimethoxyethyl)-2,2-dimethyl-
1,3-dioxolane - H - Me2CdO)]+, 100); HRMS calcd for C21H28-
FN2O12 519.1626, found 519.1615; calcd for C6H9O4 145.0501,
found 145.0573. Anal. Calcd for C22H31FN2O12: C, 49.44; H, 5.85;
N, 5.24. Found: C, 49.24; H, 5.75; N, 5.25.
6-Benzyloxy-9-[(1R)-3-O-formyl-1,2-O-isopropylidene-4,5-di-
O-methyl-D-arabinitol-1-yl]purine (48). Compound 48 was ob-
tained from acetoxy acetal 22, using trimethylsilyl-6-benzyloxy-
purine as the nucleophile. Method A: 80%. Method B: 76%. One-
pot procedure (Method C) from 2,3-O-isopropylidene-5,6-di-O-
methyl-D-mannofuranose 12: 68%. Yellow oil; [R]D -18 (c 0.42,
CHCl3); IR (CHCl3) 1732, 1600, 1117, 1046 cm-1; 1H NMR (500
MHz) δH 1.55 (3H, s), 1.58 (3H, s), 3.24 (3H, s), 3.30 (3H, s),
3.34 (1H, dd, J ) 3.9, 10.5 Hz), 3.53 (1H, ddd, J ) 3.6, 3.8, 7.4
Hz), 3.58 (1H, dd, J ) 3.4, 10.5 Hz), 5.20 (1H, dd, J ) 5.1, 5.1
Hz), 5.39 (1H, dd, J ) 4.6, 7.4 Hz), 5.66 (1H, d, J ) 12.5 Hz),
5.69 (1H, d, J ) 12.4 Hz), 6.17 (1H, d, J ) 5.6 Hz), 7.31 (1H, dd,
J ) 7.2, 7.3 Hz), 7.35 (2H, dd, J ) 6.9, 7.7 Hz), 7.52 (2H, d, J )
7.2 Hz), 8.10 (1H, s), 8.23 (1H, s), 8.55 (1H, s); 13C NMR (125.7
MHz) δC 26.9 (CH3), 27.5 (CH3), 58.0 (CH3), 59.2 (CH3), 68.5
(CH2), 69.8 (CH2), 69.8 (CH), 78.6 (2 × CH), 83.5 (CH), 112.4
(C), 121.9 (C), 128.1 (CH), 128.3 (2 × CH), 128.4 (2 × CH), 136.0
(C), 140.7 (CH), 151.8 (C), 152.3 (CH), 160.2 (CH), 160.5 (C);
MS m/z (rel intensity) 472 (M+, 10), 246 (M+ - benzyloxypurine,
38), 226 ([benzyloxypurine]+, 56), 91 ([PhCH2]+, 100); HRMS
calcd for C23H28N4O7 472.1958, found 472.1886; calcd for C7H7
91.0548, found 91.0563. Anal. Calcd for C23H28N4O7: C, 58.47;
H, 5.97; N, 11.86. Found: C, 58.63; H, 5.85; N, 11.59.
0.240 e Å-3
.
Compound 30: Colorless crystals; mp 123-126 °C (from
MeOH); [R]D +81 (c 0.23, CHCl3); IR (CHCl3) 3406, 3109, 3067,
1
1732, 1668, 1625, 1602, 1555, 1481 cm-1; H NMR (500 MHz)
δH 1.49 (3H, s), 1.70 (3H, s), 4.41 (1H, dd, J ) 6.3, 12.3 Hz), 4.70
(1H, dd, J ) 2.4, 12.3 Hz), 4.79 (1H, dd, J ) 5.4, 9.4 Hz), 5.23
(1H, ddd, J ) 2.1, 6.2, 8.9 Hz), 6.72 (1H, d, J ) 5.4 Hz), 7.41
(2H, dd, J ) 7.7, 7.8 Hz), 7.51 (2H, dd, J ) 7.6, 7.7 Hz), 7.54
(1H, dd, J ) 7.4, 7.4 Hz), 7.61 (1H, dd, J ) 7.4, 7.4 Hz), 7.64
(1H, br b), 7.82 (1H, d, J ) 7.4 Hz), 7.91 (2H, br d, J ) 7.1 Hz),
7.94 (1H, s), 7.97 (2H, d, J ) 7.5 Hz), 9.10 (1H, br b); 13C NMR
(125.7 MHz) δC 24.4 (CH3), 26.3 (CH3), 63.8 (CH2), 67.0 (CH),
75.9 (CH), 83.1 (CH), 97.6 (CH), 111.2 (C), 127.6 (2 × CH), 128.5
(2 × CH), 129.1 (2 × CH), 129.3 (C), 129.7 (2 × CH), 132.9 (C),
133.2 (CH), 133.3 (CH), 144.5 (CH), 155.1 (C), 159.4 (CH), 162.4
(C), 165.9 (C), 166.5 (C); MS m/z (rel intensity) 507 (M+, 1), 492
(M+ - Me, 2), 105 ([PhCO]+, 100); HRMS calcd for C26H25N3O8
507.1642, found 507.1680; calcd for C7H5O 105.0340, found
105.0365. Anal. Calcd for C26H25N3O8: C, 61.53; H, 4.97; N, 8.28.
Found: C, 61.78; H, 5.08; N, 7.91.
1-[(1S)-3-O-Formyl-1,2-O-isopropylidene-4-O-methyl-D-eryth-
ritol-1-yl]-5-fluorouracil (38). Compound 38 was obtained from
acetoxy acetal 20, using bis(trimethylsilyl)-5-fluorouracil as the
nucleophile. Method B: 86%. One-pot procedure (Method C) from
2,3-O-isopropylidene-4-O-methyl-D-ribofuranose 10: 81%. Syrup;
[R]D -23 (c 0.50, CHCl3); IR (CHCl3) 3381, 1727, 1714, 1671,
1
1165 cm-1; H NMR (500 MHz) δH 1.47 (3H, s), 1.56 (3H, s),
Acknowledgment. This work was supported by the Inves-
tigation Programmes PPQ2000-0728 and PPQ2003-01379 of
the Plan Nacional de Investigacio´n Cient´ıfica, Desarrollo e
Innovacio´n Tecnolo´gica, Ministerio de Educacio´n y Ciencia,
and Ministerio de Ciencia y Tecnolog´ıa, Spain. We also
acknowledge financial support from FEDER funds. D.H. thanks
the CSIC-Gobierno de Canarias, CSIC (I3P), and Ministerio
de Educacio´n y Ciencia (Plan Nacional FPU) for their fellow-
ships. We thank FAES FARMA S.A. for their help in determin-
ing the cytotoxic activity of compounds 24-58.
3.32 (3H, s), 3.62 (2H, d, J ) 4.1 Hz), 4.22 (1H, dd, J ) 5.8, 6.9
Hz), 5.32 (1H, ddd, J ) 4.0, 4.0, 7.1 Hz), 6.18 (1H, dd, J ) 1.4,
5.6 Hz), 7.38 (1H, d, JHF ) 5.8 Hz), 8.06 (1H, s), 9.87 (1H, br s);
13C NMR (125.7 MHz) δC 27.2 (CH3), 27.6 (CH3), 59.3 (CH3),
70.2 (CH2), 70.7 (CH), 78.3 (CH), 84.2 (CH), 111.9 (C), 123.3
(CH, JCF ) 34.1 Hz), 140.9 (C, JCF ) 240.1 Hz), 148.9 (C), 156.6
(C, JCF ) 26.8 Hz), 160.1 (CH); MS m/z (rel intensity) 317 (M+ -
Me, 16), 145 ([M + H]+ - [fluorouracil + Me2CdO], 100); HRMS
calcd for C12H14FN2O7 317.0785, found 317.0770; calcd for C6H9O4
145.0501, found 145.0472. Anal. Calcd for C13H17FN2O7: C, 46.99;
H, 5.16; N, 8.43. Found: C, 47.02; H, 5.41; N, 8.17.
1,3-Bis[(1S)-3-O-Formyl-1,2-O-isopropylidene-4-O-methyl-D-
erythritol-1-yl]-5-fluorouracil (39). Product 39 was obtained from
the acetoxy acetal (1S/R)-20, using Method A, with bis(trimethyl-
silyl)-5-fluorouracil as the nucleophile: 75%. Amorphous; [R]D -20
Supporting Information Available: Synthesis and spectro-
scopic data of starting materials 10-13, the acyclic nucleosides
24-28, 31-37, 40-47, 49, and 50, and the alcohols 51-58;
1
ORTEP drawings for compounds 29, 36, 37, and 45; H and 13C
1
(c 0.51, CHCl3); IR (CHCl3) 1731, 1694, 1679, 1168 cm-1; H
NMR spectra for compounds 24-58; and crystal structure data (in
CIF format) for compounds 29, 36, 37, and 45. This material is
available free of charge via the Internet at http://pubs.acs.org.
NMR (500 MHz) δH 1.43 (3H, s), 1.49 (3H, s), 1.58 (3H, s), 1.59
(3H, s), 3.30 (3H, s), 3.35 (3H, s), 3.59 (1H, dd, J ) 4.3, 10.5 Hz),
3.61 (1H, dd, J ) 3.6, 10.7 Hz), 3.63 (2H, d, J ) 4.0 Hz), 4.19
(1H, dd, J ) 5.7, 7.2 Hz), 4.96 (1H, dd, J ) 6.4, 6.6 Hz), 5.24
JO701608P
9532 J. Org. Chem., Vol. 72, No. 25, 2007