An efficient route to acyclic C-nucleosides and fused-ring analogues of uridine from exo-glycals

Article abstract of DOI:10.1021/jo901604w

(Chemical Equation Presented) β-Amino esters prepared from activated exo-glycals are transformed into acyclic C-nucleoside with a C-4-substituted uracil derivative that can be cyclized under Mitsunobu conditions to provide a new family of fused-ring analo

Full text of DOI:10.1021/jo901604w

pubs.acs.org/joc
conformationally restricted ones obtained by formation of
An Efficient Route to Acyclic C-Nucleosides and
Fused-Ring Analogues of Uridine from exo-Glycals
links between the base and the sugar or by using multicyclic
sugar moieties,2 among them sugar- or base-modified nu-
cleosides, acyclic nucleosides,3 C-nucleosides,4 and carbanu-
cleosides.5 Spironucleosides are also attractive analogues of
nucleosides which can be regarded as C-nucleosides and as
locked nucleosides. Recently, the discovery of the herbicidal
nucleoside analogue hydantocidin6 (Figure 1) has stimulated
much interest in the synthesis of spironucleosides.7,8a
†
Gerald Enderlin, Claude Taillefumier,
†,‡
ꢀ
Claude Didierjean,§ and Yves Chapleur*,†
†
ꢀ
UMR SRSMC 7565 Nancy-Universite CNRS, Groupe
SUCRES, BP 239, F-54506 Vandoeuvre, France, ‡UMR
ꢀ
SESSIB, Universite Blaise Pascal Clermont II, CNRS,
F-63000 Clermont-Ferrand, France, and §UMR LCM3B
ꢀ
7036, Nancy-Universite CNRS, BP 239, F-54506
Vandoeuvre, France
yves.chapleur@sucres.uhp-nancy.fr
Received August 2, 2009
FIGURE 1. Some nucleoside analogues.
In this context, we are interested in opening new accesses
to some representatives of these classes of compounds.
Recently, we used exo-glycals8b easily obtained through the
Wittig reaction of sugar lactones9 as versatile starting com-
pounds for the synthesis of spironucleoside analogues, ob-
tained by cycloaddition reactions with nitrones10 or by
cyclization of intermediate β-amino esters.8a The present
study reports the use of the latter to access new spirouracil
derivatives, which led to the discovery of a yet unknown class
of conformationally restricted uridine analogues A in which
β-Amino esters prepared from activated exo-glycals are
transformed into acyclic C-nucleoside with a C-4-substi-
tuted uracil derivative that can be cyclized under Mitsu-
nobu conditions to provide a new family of fused-ring
analogues of uridine nucleoside in which the N-1 nitrogen
atom is embedded in an imino sugar ring. An analogue of
uridine of D-ribo configuration is prepared.
(3) (a) Holy, A. Antiviral Res. 2006, 71, 248. (b) Amblard, F.; Nolan, S. P.;
Agrofoglio, L. A. Tetrahedron 2005, 61, 7067. (c) Khandazhinskaya, A.;
Yasko, M.; Shirokova, E. Curr. Med. Chem. 2006, 13, 2953. (d) De Clercq, E.
Antiviral Res. 2007, 75, 1.
(4) Shaban, M. A. E.; Nasr, A. Z. The Chemistry of C-Nucleosides and
Their Analogs I: C-Nucleosides of Hetero Monocyclic Bases. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: San Diego,
CA, 1997; Vol. 68, pp 223-432.
(5) (a) Jeong, L. S.; Lee, J. A. Antiviral Chem. Chemother. 2004, 15, 235.
(b) Rodriguez, J. B.; Comin, M. J. Mini Rev. Med. Chem. 2003, 3, 95.
(6) (a) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.; Okazaki, T.;
Kawakubo, K.; Shindo, M.; Honma, T.; Tohjigamori, M.; Haneishi, T.
J. Antibiot. 1991, 44, 293. (b) Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White,
A. H. J. Org. Chem. 2005, 70, 6369.
(7) (a) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada, N.;
Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999, 64, 7081. (b) Gimisis, T.;
Castellari, C. J. Chem. Soc., Chem. Commun. 1997, 2089. (c) Estevez, J. C.;
Burton, J. W.; Estevez, R. J.; Ardron, H.; Wormald, M. R.; Dwek, R. A.;
Brown, D.; Fleet, G. W. Tetrahedron: Asymmetry 1998, 9, 2137. (d) Alvarez,
R.; Jimeno, M.-L.; Gago, F.; Balzarini, J.; Perez-Perez, M.-J.; Camarasa,
M.-J. Antiviral Chem. Chemother. 1998, 9, 333. (e) Chatgilialoglu, C.;
Gimisis, T.; Spada, G. P. Chem. Eur. J. 1999, 5, 2866. (f) Gasch, C.; Pradera,
M. A.; Salameh, B. A. B.; Molina, J. L.; Fuentes, J. Tetrahedron: Asymmetry
2001, 12, 1267. (g) Renard, A.; Lhomme, J.; Kotera, M. J. Org. Chem. 2002,
67, 1302. (h) Babu, B. R.; Keinicke, L.; Petersen, M.; Nielsen, C.; Wengel, J.
Org. Biomol. Chem. 2003, 1, 3514. (i) Roy, A.; Achari, B.; Mandal, S. B.
Tetrahedron Lett. 2006, 47, 3875. (j) Sano, H.; Mio, S.; Kitagawa, J.; Sugai, S.
Tetrahedron: Asymmetry 1994, 5, 2233. (k) Dong, S.; Paquette, L. A. J. Org.
Chem. 2006, 71, 1647. (l) Tripathi, S.; Roy, B. G.; Drew, M. G. B.; Achari, B.;
Mandal, S. B. J. Org. Chem. 2007, 72, 7427.
Nucleosides are among the most widely studied com-
pounds. As natural compounds they are part, included in
their nucleotide forms, of DNA or RNA and their synthetic
forms often show interesting biological activities as enzyme
inhibitors and are used as antibiotics with antitumor and
antiviral properties.
Many modifications of nucleoside basic structures are
allowed which can be associated with the emergence of
interesting biological properties as drug candidates or as
biological tools.1 A variety of nucleoside analogues have
been proposed going from sugar- or base-modified ones, to
(1) (a) El Alaoui, A. M.; Faraj, A.; Pierra, C.; Boudou, V.; Johnson, R.;
Mathe, C.; Gosselin, G.; Korba, B. E.; Imbach, J.-L.; et al. Antiviral Chem.
Chemother. 1996, 7, 276. (b) Gumina, G.; Olgen, S.; Chu, C. K. Antiviral
Nucleosides 2003, 77. (c) De Clercq, E.; Holy, A. Nat. Rev. Drug Discov. 2005,
4, 928. (d) Piperno, A.; Chiacchio, M. A.; Iannazzo, D.; Romeo, R. Curr.
Med. Chem. 2006, 13, 3675. (e) Kaur, H.; Babu, B. R.; Maiti, S. Chem. Rev.
2007, 107, 4672.
(8) (a) Taillefumier, C.; Thielges, S.; Chapleur, Y. Tetrahedron 2004, 60,
2213. (b) Taillefumier, C.; Chapleur, Y. Chem. Rev. 2004, 104, 263.
(9) (a) Lakhrissi, M.; Chapleur, Y. Angew. Chem., Int. Ed. 1996, 35, 750.
(b) Lakhrissi, M.; Chapleur, Y. Synlett 1991, 583.
(10) (a) Taillefumier, C.; Enderlin, G.; Chapleur, Y. Lett. Org. Chem.
2004, 1, 226. (b) Enderlin, G.; Taillefumier, C.; Didierjean, C.; Chapleur, Y.
Tetrahedron: Asymmetry 2005, 16, 2459.
(2) (a) Modified Nucleosides; Herdewijn, P., Ed.; Wiley-VCH: Weinheim,
Germany, 2008. (b) Len, C.; Mondon, M.; Lebreton, J. Tetrahedron 2008, 64,
ꢀ
ꢀ
7453. (c) Mathe, C.; Perigaud, C. Eur. J. Org. Chem. 2008, 2008, 1489. (d) Choi,
Y.; Moon, H. R.; Yoshimura, Y.; Marquez, V. E. Nucleosides, Nucleotides &
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8388 J. Org. Chem. 2009, 74, 8388–8391
Published on Web 09/30/2009
DOI: 10.1021/jo901604w
r
2009 American Chemical Society

Enderlin et al.
JOCNote
SCHEME 1. Synthesis of Anomeric Ureas
SCHEME 2. Synthesis of Acyclic and Bicyclic C-Nucleosides
the N1-C6 bond of the uracil ring is part of an imino-sugar
ring (Figure 1). Reports on nucleoside analogues in which
both the sugar and the aromatic ring systems are embedded
and retain their functionalities are scarce.11 Such conforma-
tionally restricted compounds may be useful for biological
studies.
cyclized products. Prolonged heating under thermal or mi-
crowave activation also failed to give the expected uracil
derivatives. Treatment of 3 with tetrabutylammonium fluor-
ide (TBAF) gave an efficient but slow reaction taking about
2-3 days to go to completion. An excess of TBAF acceler-
ated the reaction. The only compound isolated from this
reaction was the acyclic uridine analogue 9. No spironucleo-
side was isolated whatever the conditions used. Treatment of
3 with K2CO3 and DBU in a MeOH/H2O mixture or with LiI
in pyridine gave the same result. Finally, the most efficient
conditions were the use of sodium methoxide in methanol,
giving 9 in 85%.
Exo-glycals are useful starting materials for the synthesis
of glycoamino acids, which are considered valuable precur-
sors of heterocycles. Thus starting from the exo-glycal 1, the
known amino ester 2 was obtained by addition of benzyl-
amine followed by hydrogenation over Pd/C 10%.8a Reac-
tion of 2, isolated as a mixture of anomers, with potassium
isocyanate in glacial acetic gave the expected urea 3 in good
yield, this compound being isolated in 60% yield mainly as a
β anomer.12 NOe measurements confirmed a short distance
between the anomeric N-H of the urea and H-4 of the sugar
ring (C-glycoside numbering, see Scheme 1) establishing the
β configuration of urea 3. Crystals suitable for X-ray diffrac-
tion have been obtained and their analysis confirmed the
NMR assignments (see the SI, Figure 2). The formation of
the β urea from the anomeric mixture 2 is explained by a
faster reaction of potassium isocyanate with less crowded β
anomer 2 as compared to the R one, thus displacing the
anomeric equilibrium toward the β anomer.
The manno derivative 5 behaved similarly and gave the
amino-ester 6 again as an anomeric mixture, successfully
transformed into the urea 7 in 54% yield isolated as the R
anomer (trans arrangement of the urea and the O-4
substituent) as shown by 1H NMR.
The reaction of phenyl isocyanate with compound 2
provided 4 in 80% yield. With these ureas in hands, we
investigated their ring closure into uracil derivatives. Treat-
ment of 3 in acidic medium (camphorsulfonic acid or metha-
nesulfonic acid in dry DMF or THF) did not give any
1
The structure of 9 was established on the basis of its H
NMR spectrum showing the absence of a methylene group
and the presence of a vinylic proton at 5.7 ppm. Compound 9
gave an acetate (not shown) on acetylation confirming the
presence of a free secondary hydroxyl group. The formation
of 9 could proceed via the putative spironucleoside inter-
mediate 8. Subsequent abstraction of the acidic H-5 proton
of the six-membered ring resulted in the elimination of the
sugar ring oxygen leading to the acyclic C-nucleoside 9
(Scheme 2).13 We have previously shown that such a sugar
ring-opening occurred during cycloaddition of nitrile oxides
with exo-glycals leading to acyclic isoxazoles instead of
spiroisoxazoline. It is interesting to note that furanose
spiroisoxazolidines obtained by cycloaddition of exo-glycals
with nitrones are stable.10 The driving force of this ring
formation is obviously the formation of a conjugated double
bond leading to aromatic rings.
Almost identical results were obtained in the ring closure
of 7 giving the corresponding acyclic C-nucleosides 14 in
(11) For related fused ring systems see: (a) Hashimoto, M.; Matsumoto,
M.; Terashima, S. Tetrahedron 2003, 59, 3041. (b) Evans, P. A.; Lai, K. W.;
Zhang, H.-R.; Huffman, J. C. Chem. Commun. 2006, 844. (c) Yadav, L. D. S.;
Rai, A.; Rai, V. K.; Awasthi, C. Synlett 2007, 1905.
(12) Fairbanks, A. J.; Ford, P. S.; Watkin, D. J.; Fleet, G. W. J.
Tetrahedron Lett. 1993, 34, 3327.
(13) (a) Chu, C. K.; Suh, J. J. Heterocycl. Chem. 1986, 23, 1621. (b)
Rudloff, I.; Michalik, M.; Montero, A.; Peseke, K. Synthesis 2001, 1686. (c)
Chen, J.; Sambaiah, T.; Illarionov, B.; Fischer, M.; Bacher, A.; Cushman, M.
J. Org. Chem. 2004, 69, 6996. (d) Otero, I.; Methling, K.; Feist, H.; Michalik,
M.; Quincoces, J.; Reinke, H.; Peseke, K. J. Carbohydr. Chem. 2005, 24, 809.
(e) Sagar, R.; Kim, M.-J.; Park, S. B. Tetrahedron Lett. 2008, 49, 5080.
J. Org. Chem. Vol. 74, No. 21, 2009 8389

Enderlin et al.
SCHEME 3. Synthesis of an Azepane Imino-Sugar
JOCNote
80% yield. The N-3 substituted acyclic C-nucleoside 10 was
obtained by cyclization of 4 in 60% yield. Acetylation of the
latter gave the corresponding acetate 11, which confirmed
the open chain structure.
We reasoned that these acyclic C-nucleosides could be
elaborated to a new class of bicyclic compounds. Indeed,
under Mitsunobu activation of the O-6 group of 9, cycliza-
tion took place with the N-1 of the uracil residue producing
exclusively the fused-ring nucleoside 12 in 80% yield. Almost
identical results were obtained in the formation of 15 in 82%
yield from 14. These bicyclic compounds 12 and 15 are the
first members of a new class of modified nucleosides related
to azanucleosides14 and conformationally locked nucleo-
sides.
The structures of 12 and 15 were supported by 1H NMR,
which showed no coupling constants between H-9 and H-8
indicative of a trans relationship as expected. This config-
uration was confirmed later on from the ribo derivative 20.
Finally, acidic treatment of both compounds produced gave
the unprotected nucleosides 13 and 16, respectively.
It seemed interesting to test this ring closure on the triol 17,
which was quantitatively obtained from 9 by selective acetal
hydrolysis. The less strained azepane ring 18 was formed
preferentially together with the pyrrolidine derivative 19 in a
33:1 ratio. The structure of compound 18 was established on
the basis of 13C NMR (δ C-11 45.2 ppm) indicative of the
presence of a nitrogen atom on this carbon. Furthermore the
chemical shifts (δ H-11 3.70 and 4.80 ppm) and the large gem
coupling constant (16.2 Hz) between the two H-11 protons
indicate a strong difference in their electronic environment in
agreement with the seven-membered-ring structure shown in
Scheme 3. Analysis of HMBC connectivities showed long-
range couplings between C-2 and H-11, H-110 and thus the
existence of an N-1-C-11 bond. It is likely that this ring
closure proceeds via direct activation of the more reactive
C-11 hydroxyl group as is usual in the Mitsunobu activation
of such polyol systems. Ring closure then occurs to give
mostly the gulo-azepane 18 in 52% yield. As for 12 and 15,
compound 18 could be regarded as a member of a new class
of imino-sugar.15
SCHEME 4. Synthesis of a Bicyclic Nucleoside of ribo Config-
uration
confirmed the ribo configuration and the net inversion of
configuration during the cyclization step (see the SI, Figure
3). The final step was the deprotection of 20 by acid hydro-
lysis, giving 21 in quantitative yield (Scheme 4).
Antibiograms of compounds 11, 16, 20, and 21 on four
different strains (E. coli, E. faecalis, S. aureus, P. aeruginosa)
did not reveal any antibacterial activity.
In conclusion, β-amino esters readily obtained from exo-
glycals are useful intermediates for the preparation of uracil
heterocycles. Spironucleosides cannot be obtained because
of spontaneous elimination of the sugar ring oxygen leading
to new acyclic C-nucleosides. The latter can be cyclized to
provide the first representatives of two classes of yet un-
known fused nucleoside analogues of uridine.
We next envisioned further transformation of 12 into a
significant pentose uridine analogue of ribo configuration.
Compound 12 was transformed by three conventional steps
including the selective acid hydrolysis (TFA/H2O 1/3) of the
terminal isopropylidene protective group giving 19 in 95%
yield. The cleavage of the diol function of 19 with Malaprade
oxidation gave the corresponding aldehyde, which was
reduced without purification to produce the alcohol 20 in
65% yield over the two steps. X-ray diffraction studies
Experimental Section
Methyl 2,3-Dideoxy-4,5:7,8-di-O-isopropylidene-3-ureido-r-
D-gulo-3-octulofuranoate, 3. To a solution of β-amino-ester 2,
in neat acetic acid (2.55 g, 7.7 mmol), was added potassium
isocyanate (2.5 g, 31 mmol) and the mixture was stirred at room
temperature for 3 h. The solvent was evaporated under reduced
pressure and the residue was diluted in CH2Cl2 and washed with
a saturated solution of NaHCO3. The organic layer was dried
over MgSO4, filtrated, and evaporated. Purification by column
chromatography (hexane/ethylacetate 4:6 to 2:8) gave 3 (1.78 g,
(14) (a) Merino, P. Curr. Med. Chem. Anti-Infective Agents 2002, 1, 389.
(b) Richichi, B.; Cicchi, S.; Chiacchio, U.; Romeo, G.; Brandi, A. Tetra-
hedron Lett. 2002, 43, 4013. (c) Procopio, A.; Alcaro, S.; De Nino, A.;
Maiuolo, L.; Ortuso, F.; Sindona, G. Bioorg. Med. Chem. Lett. 2005, 15, 545.
(d) Kocalka, P.; Pohl, R.; Rejman, D.; Rosenberg, I. Nucleosides, Nucleotides
& Nucleic Acids 2005, 24, 805. (e) Mannucci, V.; Cordero, F. M.; Piperno, A.;
Romeo, G.; Brandi, A. Tetrahedron: Asymmetry 2008, 19, 1204. (f) Yang, S.;
Busson, R.; Herdewijn, P. Tetrahedron 2008, 64, 10062.
(15) (a) Li, H.; Schuetz, C.; Favre, S.; Zhang, Y.; Vogel, P.; Sinay, P.;
Bleriot, Y. Org. Biomol. Chem. 2006, 4, 1653. (b) Markad, S. D.; Karanjule,
N. S.; Sharma, T.; Sabharwal, S. G.; Dhavale, D. D. Org. Biomol. Chem.
2006, 4, 3675. (c) Liu, T.; Zhang, Y.; Bleriot, Y. Synlett 2007, 905. (d) Bande,
O. P.; Jadhav, V. H.; Puranik, V. G.; Dhavale, D. D. Tetrahedron: Asym-
metry 2007, 18, 1176. (e) Otero, J. M.; Estevez, A. M.; Soengas, R. G.;
Estevez, J. C.; Nash, R. J.; Fleet, G. W. J.; Estevez, R. J. Tetrahedron:
Asymmetry 2008, 19, 2443.
60%) as a white solid, mp 188-190 °C (from CH2Cl2): Rf 0.3
D
1
(CH2Cl2/MeOH 95:5); [R]20 -23.5 (c 1.1; CHCl3); H NMR
(250 MHz, CDCl3) δ 1.29, 1.38, 1.42, 1.45 (4s, 12H, 4 ꢀ CH3),
1.60 (m, 1H, NH), 2.98 (d, 1H, Jgem = 17.0 Hz, H-2), 3.17 (d,
1H, Jgem = 17.0 Hz, H-20), 3.72 (s, 3H, CO2CH3), 3.77 (dd, 1H,
J
gem = 8.8 Hz, J7,8 = 6.6 Hz, H-8), 4.03 (dd, 1H, J5,6 = 3.6 Hz,
J6,7 = 8.0 Hz, H-6), 4.21 (dd, 1H, Jgem = 8.8 Hz, J7,8 = 6.6 Hz,
H-80), 4.36 (m, 1H, H-7), 4.67 (d, 1H, J4,5 = 5.8 Hz, H-4), 4.72
(dd, 1H, J5,6 = 3.6 Hz, J4,5 = 5.8 Hz, H-5), 5.11 (m, 1H, NH),
5.35 (m, 1H, NH); 13C NMR (62.9 MHz, CDCl3) δ 24.7, 25.4,
8390 J. Org. Chem. Vol. 74, No. 21, 2009

Enderlin et al.
JOCNote
25.9, 26.8 (4 ꢀ CH3), 37.7 (C-2), 51.9 (CO2CH3), 65.9 (C-8),
75.1, 80.0, 82.0, 86.0 (4C, C-4, C-5, C-6, C-7), 92.6 (C-3), 109.9,
113.3 (2C acetal), 158.1 (CO(NH2)2), 170.3 (CO2CH3); IR (KBr,
ν, cm-1) 3366 (NH), 1738 (COOMe), 1674 (CO(NH2)2). Anal.
Calcd for C16H26N2O8: C, 51.33; H, 7.00; N, 7.48. Found: C,
51.49; H, 6.88; N, 7.49.
(d, 1H, J7,8 = 5.1 Hz, H-8), 5.40 (d, 1H, J7,8 = 5.1 Hz, H-7), 5.73
(s, 1H, H-5); 13C NMR (62.9 MHz, D2O) δ 30.2, 32.0 (2 ꢀ CH3),
68.1 (C-20), 71.7 (C-9), 71.3 (C-10), 82.0 (C-8), 85.1 (C-7), 101.6
(C-50), 117.0 (C-5), 154.6 (C-6), 163.7 (C-2), 169.1 (C-4).
(7S,8R,9R)-1,3-Diaza-2,4-dioxo-9-(hydroxymethyl)-7,8-O-is-
opropylidenebicyclo[4.3.0]non-5-ene, 20. To a solution of crude
compound 19 (0.050 g, 0.175 mmol) in methanol (3 mL),
cooled at 0 °C, was slowly added a solution of sodium periodate
(0.043 g, 0.20 mmol). The reaction was stirred for 1 h at room
temperature. 1,2-Ethanediol (0.1 mL) was added, the white
precipitate was filtered off, and water was added (3 mL). The
aqueous phase was extracted twice with ethyl acetate (20 mL)
and the combined organic phases were dried over magnesium
sulfate. The solvent was removed in vacuo to provide the crude
aldehyde (0.044 g, 0.17 mmol), which was dissolved in anhy-
drous methanol (3 mL). The solution was stirred and cooled at
0 °C and then sodium borohydride (0.061 g, 0.34 mmol) was
added. After 1 h, a few drops of 3 N hydrochloric acid and water
(20 mL) was added. The aqueous layer was extracted twice
with diethyl ether (20 mL) and the combined organic phases
were dried over magnesium sulfate. Filtration and evaporation
under vacuum gave the crude alcohol, which was purified by
column chromatography giving 20 (0.028 g, 65%) as a white
(10S,20R,30S,40R)-6[(30-Hydroxy-10,20,40,50-diisopropylidenedioxy)-
pentyl]uracil, 9. Compound 3 (1.5 g, 4.0 mmol) was dissolved in
anhydrous methanol (40 mL), and a fresh solution (0.5 M) of
sodium methoxide was added (8 mL, 1 equiv). After 15 min the
reaction was completed. The mixture was cooled at 0 °C and an
aqueous solution of HCl was added until the mixture was
neutral. The methanol was evaporated and the crude residue
was purified by column chromatography to afford compound 9
(1.3 g, 85%) as a white solid: Rf 0.66 (A); [R]20 þ40.7 (c 0.9;
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 1.36, 1.42, 1.65 (3s, 12H,
4 ꢀ CH3), 3.36 (m, 1H, OH), 3.65 (m, 1H, H-30), 3.79 (dd, 1H,
J
gem = 8.0 Hz, J4 ,5 = 6.5 Hz, H-50), 4.05 (dd, 1H, Jgem = 8.0
0 0
Hz, J4 ,5” = 6.5 Hz, H-500), 4.22 (m, 1H, H-40), 4.31 (d, 1H, J1 ,2
0
0
0
= 7.5 Hz, H-20), 4.95 (d, 1H, H-10), 5.68 (s, 1H, H-5), 9.20 (m,
1H, NH), 9.83 (m, 1H, NH); 13C NMR (62.9 MHz, CDCl3) δ
25.3, 25.7, 26.3, 26.9 (4 ꢀ CH3), 66.2 (C-50), 70.0, 75.5, 77.4, 78.5
(4C, C-30, C-10, C-40, C-20), 100.2 (C-5), 110.2, 111.3 (2C acetal),
151.9 (C-6), 152.1 (C-2), 165.4 (C-4); IR (KBr, ν, cm-1) 3422
(OH), 3330 (NH), 1717 (CO), 1660 ((CO(NH)2); MS (HR-ESI)
calcd for C15H22N2O7Na 365.1324, found 365.1311 [M þ Na]þ.
Anal. Calcd for C15H22N2O7: C, 52.62; H, 6.47; N, 8.18. Found:
C, 52.78; H, 6.51; N, 8.08.
solid, mp 230-2 °C: Rf 0.5 (CH2Cl2/MeOH 9:1); [R]20 -217
D
(c 1; CHCl3); 1H NMR (250 MHz, D2O) δ 1.40, 1.42 (2s, 6H, 2 ꢀ
0
CH3), 3.34 (m, 1H, OH), 3.80 (dd, 1H, J = 1.9 Hz, J1,1 = 12.2
00
Hz, H-10), 4.02 (dd, 1H, J = 2.5 Hz, J1 ,1 = 12.2 Hz, H-1 ), 4.52
(m, 1H, H-9), 4.83 (d, 1H, J7,8 = 5.5 Hz, H-8), 5.43 (d, 1H, J7,8
= 5.5 Hz, H-7), 5.71 (s, 1H, H-5); 13C NMR (62.9 MHz, D2O)
δ 25.9, 27.7 (2 ꢀ CH3), 60.2 (C-10), 67.5 (C-9), 81.0 (C-8), 81.1
(C-7), 97.7 (C-5), 113.8 (C acetal), 151.3 (C-6), 161.18 (C-2),
167.6 (C-4); IR (KBr, ν, cm-1) 3365 (NH), 3156.25 (OH), 1678
((CO), (CO(N)(NH)), (CdC)); MS (HR-ESI) calcd for
C11H14N2O5 255.0981, found 255.0986 [M þ H]þ, 277.0798
[M þ Na]þ, 531.1670 [2M þ Na]þ, 785.2621 [3M þ Na]þ.
(7S,8R,9R)-1,3-Diaza-2,4-dioxo-9-(hydroxymethyl)bicyclo[4.
3.0]non-5-ene, 21. To a solution of compound 20 (0.033 g, 0.13
mmol) in water (1 mL) was added Amberlite IR-120, Hþ form,
previously washed with methanol and water. The mixture was
stirred for 2 h. The resin was filtered off and the filtrate was
freeze-dried to yield compound 21 (0.026 g, 95%) as a white
foam: Rf 0.1 (CH2Cl2/MeOH 9:1); [R]20D -81.6 (c 0.6; H2O); 1H
NMR (250 MHz, D2O) δ 3.85 (dd, 1H, J = 2.5 Hz, Jgem = 12.3
Hz, H-10), 3.93 (dd, 1H, J = 4.8 Hz, Jgem = 12.3 Hz, H-100), 4.35
0
00
(7S,8R,9R)-1,3-Diaza-2,4-dioxo-7,8-O-isopropylidene-9-[(40S)-
20,20-dimethyl-1,3-dioxolan-40-yl]bicyclo[4.3.0]non-5-ene, 12. Acy-
clic C-nucleoside 9 (0.45 g, 1.31 mmol) and triphenylphosphine
(1 g, 3.9 mmol) were dissolved in anhydrous THF (10 mL), the
mixture was stirred at room temperature under nitrogen atmo-
sphere. Diethylazodicarboxylate (1.35 g, 7.8 mmol) was added
slowly with a syringe, then the mixture was stirred for 2 h. TLC
confirmed total disappearance of starting material. The solvent
was evaporated and the crude product was chromatographed on
a silica gel column giving the fused nucleoside 12 (0.34 g, 80%) as
a solid: Rf 0.5 (H/A 3:7); [R]20D -228.7 (c 0.7; CHCl3); 1H NMR
(250 MHz, CDCl3) δ 1.28, 1.37, 1.39, 1.45 (4s, 12H, 4 ꢀ CH3),
0
0
3.92 (dd, 1H, J5 ,5 = 9.2 Hz, J4 ,5 = 5.2 Hz, H-5 ), 4.23 (dd, 1H,
00
0
0
00
0
00
0
00
J5 ,5 = 9.2 Hz, J4 ,5 = 8.0 Hz, H-5 ), 4.53 (d, 1H, J8,9 = 1.0 Hz,
H-9), 4.67 (dd, 1H, J7,8 = 5 Hz, H-8), 4.75 (dd, 1H, H-40), 5.31
(d, 1H, H-7), 5.80 (s, 1H, H-5), 9.47 (br s, 1H, NH); 13C NMR
(62.9 MHz, CDCl3) δ 23.9, 26.2, 26.3, 27.8 (4 ꢀ CH3), 66.1 (C-
50), 66.9 (C-9), 72.6 (C-40), 77.1 (C-8), 80.1 (C-7), 98.4 (C-5),
110.8, 113.6 (2C acetal), 150.0 (C-6), 158.4 (CO(N)(NH)), 165.0
(CO); IR (KBr, ν, cm-1) 3195 NH, 1700 (CONH), 1660
(CONH). Anal. Calcd for C15H20N2O6: C, 55.54; H, 6.21; N,
8.63. Found: C, 55.37; H, 6.30; N, 8.58.
0
(t, 1H, J8,9 = 3.4 Hz, J9,1 = 2.9 Hz, H-9), 4.47 (d, 1H, J7,8 = 4.7
Hz, H-8), 5.22 (dd, 1H, J5,7 = 1.7 Hz, J7,8 = 4.7 Hz, H-7), 5.89
(d, 1H, J5,7 = 1.7 Hz, H-5); 13C NMR (62.9 MHz, D2O) δ 61.7
(C-10), 71.0 (C-9), 74.9 (C-8), 75.1 (C-7), 99.3 (C-5), 153.7 (C-6),
163.9 (C-2), 170.2 (C-4); MS (HR-ESI) calcd for C8H10N2O5Na
237.0482, found 237.0491 [M þ Naþ].
(7S,8R,9R)-1,3-Diaza-2,4-dioxo-7,8-O-isopropylidene-9-[(10S)-
20-dihydroxyethyl]bicyclo[4.3.0]non-5-ene, 19. A suspension of
compound 12 (0.35 g, 1.2 mmol) in a 1/3 mixture of trifluor-
oacetic acid and water (4 mL) was stirred vigorously at
0 °C until total dissolution, i.e., for 1 min. The mixture was
concentrated under vacuum at room temperature and coevapo-
rated several times with toluene giving crude compound 19 (340
mg, 100%) as a gum: Rf 0.2 (CH2Cl2/MeOH 9:1); 1H NMR (250
MHz, MeOH-d4) δ 1.39, 1.41 (2s, 6H, 2 ꢀ CH3), 3.72 (m, 2H, 2
Acknowledgment. We thank Dr. R. E. Duval and Prof. C.
Finance, GEVSM, UMR CNRS 7565, for biological evalua-
ꢀ
tion and Region Lorraine for financial support.
Supporting Information Available: Full experimental pro-
cedures, characterization data, copies of 1H and 13C spectra, and
crystallographic data of compounds 7 and 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
H-20), 4.17 (m, 1H, H-10), 4.64 (d, 1H, J1 ,9 = 1.9 Hz, H-9), 4.96
0
J. Org. Chem. Vol. 74, No. 21, 2009 8391