Sequential ring-closing metathesis and nitrone cycloaddition on glucose-derived substrates: A divergent approach to analogues of spiroannulated carbanucleosides and conformationally locked nucleosides

Article abstract of DOI:10.1021/jo0606554

The carbohydrate-derived substrate 3-C-allyl-1,2:5,6-di-O-isopropylidene- α-D-allofuranose was judiciously manipulated for preparing suitable synthons, which could be converted to a variety of isoxazolidino-spirocycles and -tricycles through the applicati

Full text of DOI:10.1021/jo0606554

Sequential Ring-Closing Metathesis and Nitrone Cycloaddition on
Glucose-Derived Substrates: A Divergent Approach to Analogues of
Spiroannulated Carbanucleosides and Conformationally Locked
Nucleosides
Sk. Sahabuddin,† Ashim Roy,† Michael G. B. Drew,‡ Biswajit Gopal Roy,†
Basudeb Achari,† and Sukhendu B. Mandal*,†
Department of Chemistry, Indian Institute of Chemical Biology, JadaVpur, 4, Raja S. C. Mullick Road,
Kolkata 700 032, India, and Department of Chemistry, UniVersity of Reading,
Whiteknights, Reading RG6 6AD, U.K.
sbmandal@iicb.res.in
ReceiVed March 27, 2006
The carbohydrate-derived substrate 3-C-allyl-1,2:5,6-di-O-isopropylidene-R-D-allofuranose was judiciously
manipulated for preparing suitable synthons, which could be converted to a variety of isoxazolidino-
spirocycles and -tricycles through the application of ring-closing metathesis (RCM) and intramolecular
nitrone cycloaddition (INC) reactions. Cleavage of the isoxazolidine rings of some of these derivatives
by tranfer hydrogenolysis followed by coupling of the generated amino functionalities with 5-amino-
4,6-dichloropyrimidine furnished the corresponding chloropyrimidine nucleosides, which were elaborated
to spiroannulated carbanucleosides and conformationally locked bicyclo[2.2.1]heptane/oxa-bicyclo[3.2.1]-
octane nucleosides. However, use of higher temperature for the cyclization of one of the chloropyrimidines
led to the dimethylaminopurine analogue as a sole product, formed via nucleophilic displacement of the
chloro group by dimethylamine generated from DMF.
Various synthetic strategies have been reported in recent years
to generate nucleoside analogues, particularly in search of
effective and nontoxic antiviral and antitumor agents. The
discovery of the natural carbanucleosides aristeromycin,1 nepl-
anocin A,2 and neplanocin C3 (conformationally rigid bicyclic
nucleoside) having antibiotic and antitumor properties prompted
the development of a number of synthetic carbanucleoside
analogues endowed with important therapeutic properties.4,5
Even though these analogues are resistant to the cleavage of
the glycosidic linkage by phosphorylases and hydrolases,6 they
are often less effective than their furanose counterparts. The
reduced activity may be due to the conformational flexibility
of the cyclopentane ring as compared to furanose in the context
* Corresponding author. Fax: +91 (33) 24735197.
† Indian Institute of Chemical Biology.
‡ University of Reading.
(4) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385.
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Mizuno, K. J. Antibiot. 1968, 21, 255.
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M. J. Antibiot. 1981, 34, 359.
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Goodchild, J. Top. Antibiot. Chem. 1982, 6, 99. (c) Buchanan, J. G.;
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10.1021/jo0606554 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/30/2006
5980
J. Org. Chem. 2006, 71, 5980-5992

Spiroannulated Carbanucleosides and Nucleosides
of pseudorotational cycle.7 Thus, to confer metabolic stability
as well as conformational rigidity in either furanose or cyclo-
pentane ring, much attention has been given to the structural
modifications of nucleosides, leading to a plethora of confor-
mationally restricted nucleosides. These include, among others,8
the bicyclo[3.1.0]hexane-derived carbanucleosides 1 and 2
prepared by the Altman9 and Marquez10 groups, Leumann’s11
and Nielsen’s12 tricyclic sugar derivatives 3 and 4, and Wengel’s
locked system 5.13
In addition, any bulky substituent fused to the pentose/
cyclopentane ring of the nucleosides in a spirocyclic manner
would be expected to confer conformational rigidity to the
nucleosides. In this connection, the laboratories of Miyasaka14
and Paquette,15 in addition to others,16-20 have reported the
synthesis of C1′-spiro,14,16 C2′-spiro,18 C3′-spiro,19 and C4′-
spironucleosides,15 which included 5/5 and 6/5 spironucleo-
sides17,20 as conformationally restricted or biased analogues with
FIGURE 1. A strategy for the synthesis of spirofused carbocyclic
nucleosides.
usual/unusual bases. The added advantage of the spiro structure
at C4′ in the normal nucleosides21 is that the free radical-induced
degradation of the ribose ring of nucleosides or nucleotides by
C-4′-H abstraction can be prevented, although this does not
concern the carbanucleosides. Thus, synthesis of nucleosides
of the type 6 has also been receiving attention in recent years.22
On the basis of these literature reports, we embarked upon
the synthesis of a new family of spiroannulated carbocyclic
nucleosides and conformationally locked bicyclic nucleoside
analogues from sugar-based substrates. Toward this endeavor,
we envisioned two approaches for the construction of 5/6- and
5/5-spirorings on a carbohydrate backbone. In the first (Figure
1A), ring-closing metathesis (RCM) of an appropriate glucose-
derived precursor possessing olefin functionalities (C-allyl and
(7) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205.
(8) (a) Obika, S.; Andoh, J.; Sugimoto, T.; Miyashita, K.; Imanishi, T.
Tetrahedron Lett. 1999, 40, 6465. (b) Wang, G.; Girardet, J.-L.; Gunic, E.
Tetrahedron 1999, 55, 7707. (c) Wang, G.; Gunic, E.; Girardet, J.-L.;
Stoisavljevic, V. Bioorg. Med. Chem. Lett. 1999, 9, 1147. (d) Wang, G.
Tetrahedron Lett. 2000, 41, 7139. (e) Kim, K. S.; Jacobson, K. A. Org.
Lett. 2003, 5, 1665.
(9) (a) Altmann, K. H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetrahe-
dron Lett. 1994, 35, 2331. (b) Altmann, K. H.; Imwinkelried, R.; Kesselring,
R.; Rihs, G. Tetrahedron Lett. 1994, 35, 7625.
(10) (a) Rodriguez, J. B.; Marquez, V. E.; Nicklaus, M. C.; Barchi, J. J.,
Jr. Tetrahedron Lett. 1993, 34, 6233. (b) Rodriguez, J. B.; Marquez, V. E.;
Nicklaus, M. C.; Mitsua, H.; Barchi, J. J., Jr. J. Med. Chem. 1994, 37,
3389. (c) Ezzitouni, A.; Barchi, J. J., Jr.; Marquez, V. E. J. Chem. Soc.,
Chem. Commun. 1995, 1345. (d) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni,
A.; Russ, P.; Wang, J.; Wagner, R. W.; Matteucci, M. D. J. Med. Chem.
1996, 39, 3739. (e) Ezzitouni, A.; Marquez, V. E. J. Chem. Soc., Perkin
Trans. 1 1997, 1073. (f) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui,
M. A.; Ford, H., Jr.; Feldman, R. J.; Mitsua, H.; George, C.; Barchi, J. J.,
Jr. J. Am. Chem. Soc. 1998, 120, 2780. (g) Marquez, V. E.; Russ, P.; Alonso,
R.; Siddiqui, M. A.; Hernandez, S.; George, C.; Nicklaus, M. C.; Dal, F.;
Ford, H., Jr. HelV. Chim. Acta 1999, 82, 2119. (h) Shin, K. J.; Moon, H.
R.; George, C.; Marquez, V. E. J. Org. Chem. 2000, 65, 2172.
(11) (a) Tarkoy, M.; Bolli, M.; Leumann, C. HelV. Chim. Acta 1994,
77, 716. (b) Bolli, M.; Trafelet, H. U.; Leumann, C. Nucleic Acids Res.
1996, 24, 4660. (c) Hildbrand, S.; Leumann, C. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1968. (d) Steffens, R.; Leumann, C. J. Am. Chem. Soc.
1997, 119, 11548. (e) Steffens, R.; Leumann, C. J. Am. Chem. Soc. 1999,
121, 3249. (f) Meier, R.; Gru¨schow, S.; Leumann, C. HelV. Chim. Acta
1999, 82, 1813.
(13) (a) Singh, S. K.; Nielsen, P.; Koshkin, A. A.; Wengel, J. Chem.
Commun. 1998, 455. (b) Koshkin, A. A.; Singh, S. K.; Nielsen, P.;
Rajwanshi, V. K.; Kumar, R.; Meldgaard, M.; Olsen, C. E.; Wengel, J.
Tetrahedron 1998, 54, 3607. (c) Koshkin, A. A.; Rajwanshi, V. K.; Wengel,
J. Tetrahedron Lett. 1998, 39, 4381. (d) Singh, S. K.; Wengel, J. Chem.
Commun. 1998, 1247. (e) Singh, S. K.; Kumar, R.; Wengel, J. J. Org. Chem.
1998, 63, 10035. (f) Koshkin, A. A.; Nielsen, P.; Meldgaard, M.; Rajwanshi,
V. K.; Singh, S. K.; Wengel, J. J. Am. Chem. Soc. 1998, 120, 13252. (g)
Rajwanshi, V. K.; Håkansson, A. E.; Sørensen, M. D.; Pitsch, S.; Singh, S.
K.; Kumar, R.; Nielsen, P.; Wengel, J. Angew. Chem., Int. Ed. Engl. 2000,
39, 1656. (h) KværnØ, L.; Wengel, J. J. Org. Chem. 2001, 66, 5498. (i)
Bryld, T.; Sørensen, M. D.; Nielsen, P.; Koch, T.; Nielsen, C.; Wengel, J.
J. Chem. Soc., Perkin Trans. 1 2002, 1655.
(14) (a) Kittaka, A.; Tanaka, H.; Odanaka, Y.; Ohnuki, K.; Yamaguchi,
K.; Miyasaka, T. J. Org. Chem. 1994, 59, 3636. (b) Kittaka, A.; Tanaka,
H.; Yamada, N.; Miyasaka, T. Tetrahedron Lett. 1996, 37, 2801. (c) Kittaka,
A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada, N.; Nakamura, K. T.;
Miyasaka, T. J. Org. Chem. 1999, 64, 7081.
(12) (a) Nielsen, P.; Peterson, M.; Jacobsen, J. P. J. Chem. Soc., Perkin
Trans. 1 2000, 3706. (b) Ravn, J.; Thorup, N.; Nielsen, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 1855.
J. Org. Chem, Vol. 71, No. 16, 2006 5981

Sahabuddin et al.
O-allyl) at C-3 would be followed by didehydroxylation to
introduce unsaturation between C-5 and C-6. Intramolecular
nitrone cycloaddition (INC) reaction thereafter between the
nitrone at C-1 and the olefin moiety at C-5 would generate a
fused isoxazolidine derivative. Subsequent hydrogenolytic fis-
sion of the isoxazolidine ring would form a tricyclic 5/6-
spirofused ring, which could be utilized to install nucleoside
bases on the amino group of the spirocycle. In an alternative
method, we hoped to build a 6/5-spirofused bicyclic compound
from a 3-C-allyl-5,6-didehydroxy intermediate (D-glucose de-
rived) through appropriate RCM, double bond reduction, and
INC reaction (Figure 1B), and elaborate the spirocycle to the
corresponding spirofused carbocyclic nucleoside. If, however,
the double bond in the RCM product is not reduced, it could
itself be submitted to INC reaction with a nitrone generated at
C-1 (Figure 2A), leading to structurally novel tricyclic com-
pounds en route to confomationally locked bicyclic nucleosides.
Another approach could be to utilize (Figure 2B) the 3-O-allyl-
5,6-didehydroxy glucose/allose derivative for RCM reaction,
which has been known to furnish dihydropyran derivatives. INC
reaction of the ring double bond of these with the C-1 nitrone
could give dihydropyran fused tricyclic products for the
generation of locked bicyclic nucleosides. The present article
deals with the results on the generation of spirocyclic carba-
nucleosides and locked nucleosides with bicyclo[2.2.1] heptane
and oxa-bicyclo[3.2.1] octane ring systems.
Results and Discussion
Synthesis of Spirocycles 11, 14, 19, 20, 23, and 24.
Diallylated compound 8, generated from the D-glucose-derived
substrate 723 through O-allylation, furnished (Scheme 1) the
spirocycle 9 upon ring-closing metathesis reaction24 using the
first generation Grubbs catalyst. Selective deprotection of the
5,6-O-isopropylidene ring with dilute HOAc and subsequent
olefination between C-5 and C-6 (glucose numbering) by
treatment with triphenyl phosphine-imidazole-iodine in refluxing
FIGURE 2. A strategy for the synthesis of conformationally locked
nucleosides.
SCHEME 1a
(15) (a) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.
Org. Lett. 2001, 3, 4039. (b) Paquette, L. A.; Owen, D. R.; Bibart, R. T.;
Seekamp, C. K. Org. Lett. 2001, 3, 4043. (c) Paquette, L. A.; Hartung, R.
E.; France, D. J. Org. Lett. 2003, 5, 869. (d) Paquette, L. A.; Fabris, F.;
Gallou, F.; Dong, S. J. Org. Chem. 2003, 68, 8625. (e) Paquette, L. A.;
Kahane, A. L.; Seekamp, C. K. J. Org. Chem. 2004, 69, 5555. (f) Dong,
S.; Paquette, L. A. J. Org. Chem. 2005, 70, 1580. (g) Hortung, R.; Paquette,
L. A. J. Org. Chem. 2005, 70, 1597. (h) Paquette, L. A.; Dong, S. J. Org.
Chem. 2005, 70, 5655.
(16) Gimisis, T.; Chatgilialoglu, C. J. Org. Chem. 1996, 61, 1908.
(17) Gasch, C.; Pradera, M. A.; Salameh, B. A. B.; Molina, J. L.; Fuentes,
J. Tetrahedron: Asymmetry 2001, 12, 1267.
(18) Ravindra Babu, B.; Keinicke, L.; Petersen, M.; Nielsen, C.; Wengel,
J. Org. Biomol. Chem. 2003, 1, 3514.
a Reagents and conditions: (a) NaH, allyl bromide, THF, reflux, 4 h;
(b) [Cl2(Pcy3)2RudCHPh], CH2Cl2, rt, 6 h, N2; (c) HOAc-H2O (3:1), rt,
overnight; (d) Ph3P, imidazole, I2, toluene, reflux, 6 h; (e) 4% H2SO4,
CH3CN-H2O (3:1), rt, 24 h; (f) BnNHOH, dry EtOH, reflux, 4 h, N2.
(19) Nielsen, P.; Larsen, K.; Wengel, J. Acta Chem. Scand. 1996, 50,
1030.
(20) Singha, K.; Roy, A.; Dutta, P. K.; Tripathi, S.; Sahabuddin, S.;
Achari, B.; Mandal, S. B. J. Org. Chem. 2004, 69, 6507.
(21) (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991,
30, 1387. (b) Pratbiel, G.; Bernadou, J.; Meunier, B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 746.
(22) Paquette, L. A. Aust. J. Chem. 2004, 57, 7.
(23) Patra, R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal, N.; Mandal, S.
B. Tetrahedron 1996, 52, 11265.
(24) (a) Amblard, F.; Nolan, S. P.; Agrofoglio, L. A. Tetrahedron 2005,
61, 7067. (b) Montembault, M.; Bourgougnon, N.; Lebreton, J. Tetrahedron
Lett. 2002, 43, 8091. (c) Chen, X.; Wiemer, D. F. J. Org. Chem. 2003, 68,
6597. (d) Busca, P.; Etheve-Quelquejeu, M.; Valery, J.-M. Tetrahedron Lett.
2003, 44, 9131. (e) Sorensen, A. M.; Nielsen, P. Org. Lett. 2000, 2, 4217.
(f) Gurjar, M. K.; Maheswar, K. J. Org. Chem. 2001, 66, 7552.
toluene25 yielded 10. Removal of 1,2-acetonide protection
followed by reaction of the latent aldehyde with N-benzyl
hydroxylamine in ethanol smoothly afforded the isoxazolidi-
nospirocycle 11 through a nonisolable nitrone intermediate at
C-1. However, hydrogenation of the double bond in 11 with
Pd/C (10%) in EtOH failed to afford the corresponding dihydro
compound in good yield. Attempted cleavage of the isoxazo-
lidine ring26 with simultaneous reduction of the olefin moiety
(25) Shing, T. K. M.; Wong, C.-H.; Yip, T. Tetrahedron: Asymmetry
1996, 7, 1323.
5982 J. Org. Chem., Vol. 71, No. 16, 2006

Spiroannulated Carbanucleosides and Nucleosides
SCHEME 2a
a Reagents and conditions: (a) H2-Pd/C (10%), EtOH, rt, 4 h; (b) HOAc-H2O (3:1), rt, 14 h; (c) Ph3P, imidazole, I2, toluene, reflux; 6 h; (d) 4% H2SO4,
CH3CN-H2O (3:1), rt, 24 h; (e) BnNHOH, EtOH, reflux, 4 h, N2.
SCHEME 3a
a Reagents and conditions: (a) HOAc-H2O (3:1), rt, overnight; (b) Ph3P, imidazole, I2, toluene, reflux, 6 h; (c) [Cl2(Pcy3)2RudCHPh], CH2Cl2, rt, 6 h,
N2; (d) H2-Pd/C (10%), EtOH, rt; (e) NaH, allyl bromide, THF, reflux, 5 h, N2; (f) 4% H2SO4, CH3CN-H2O (3:1), rt, 24 h; (g) BnNHOH, dry EtOH, rt,
20 h.
SCHEME 4a
using cyclohexene and Pd/C was also found to be unsuccessful;
a mixture of several uncharacterized products was obtained.
Next, we altered our sequence to reduce the double bond of
9 before proceeding to the subsequent steps. Thus, the spirocycle
9 was hydrogenated with Pd/C (10%) in EtOH (Scheme 2) to
produce the dihydro derivative 12, which on selective depro-
tection of the 5,6-acetonide moiety and olefination as described
above furnished 13. When the spirocycle 13 was subjected to
sequential removal of protection from 1,2 hydroxyl groups
followed by INC reaction involving the masked aldehyde
generated at C-1 and the olefin function at C-5, the reaction
went off smoothly, yielding the desired product 14.
The other approach en route to 6/5-spirocycles involved the
introduction of an olefin moiety in 7 by didehydroxylation to
produce 15 (Scheme 3). Ring-closing metathesis reaction
MeOH, 10 °C, 45 min; (d) BnNHOH, dry EtOH, rt, 20 h.
between the olefins in 15 furnished 16, which on hydrogenation
to 17 followed by allylation of the tertiary hydroxyl group
afforded 18. Deprotection of its 1,2 hydroxyl groups with diluted
H2SO4 followed by nitrone formation at the hemiacetal center
with N-benzyl hydroxylamine set in motion spontaneous cy-
clization, affording two isomeric spiro compounds 19 (45%)
and 20 (33%).
When O-allylation of 16 was performed without reducing the
cyclic double bond, 21 could be isolated (Scheme 4). Depro-
tection of the 1,2 hydroxyl groups and subsequent treatment
with an aqueous solution of NaIO4 produced a nor aldehyde
22. INC reaction with BnNHOH now preferentially involved
the allyl group, generating the spirocycle 23 accompanied by
its formate 24, retaining C-1 of sugar. Compound 24 could be
converted to 23 by hydrolysis with dilute alkali solution.
a Reagents and conditions: (a) NaH, allyl bromide, THF, reflux, 5 h,
N2; (b) 4% H2SO4, CH3CN-H2O (3:1), rt, 24 h; (c) NaIO4 (aqueous),
The structures of the products were deduced from spectral
1
analyses (IR, H NMR, 13C NMR, MS). The appearance of a
1
two-proton multiplet at δ 5.84 in the H NMR spectrum of 9
testified to the formation of a dihydro pyran ring. The 1H NMR
spectrum of 10 exhibited signals for dCH2 protons along with
three more olefinic proton (methine) signals. The gross structure
of 11 was deduced from the appearance of one double doublet
at δ 3.64 for CHNBn together with two doublets at δ 3.66 and
1
3.73 for two CHOH in its H NMR spectrum. The absence of
the olefinic proton signal and appearance instead of upfield
1
methylene signals in the H NMR spectrum of 12 confirmed
the absence of the double bond. However, appropriate signals
for vinyl protons were present in the 1H NMR spectrum of 13.
1
The absence of olefinic proton and carbon signals in the H
and 13C NMR spectra of 14 clearly suggested its gross structure.
The 13C NMR as well as mass spectra of these products were
also in good agreement with the proposed structures. The cis
(26) Collins, P. M.; Ashwood, M. S.; Eder, H.; Wright, S. H. B.;
Kennedy, D. J. Tetrahedron Lett. 1990, 34, 3585.
J. Org. Chem, Vol. 71, No. 16, 2006 5983

Sahabuddin et al.
SCHEME 5a
a Reagents and conditions: (a) Pd/C (10%), cyclohexene, EtOH, reflux, 5 h; (b) 5-amino-4,6-dichloropyrimidine, n-butanol, Et3N, reflux, 30 h; (c) HC(OEt)3,
p-TSA, DMF, 10 °C, 16 h; (d) MeOH, NH3, sealed tube, 100 °C, 40 h.
stereochemistry of the ring juncture in 14 was confirmed by its
X-ray crystal structure analysis.27 Similar ring juncture stere-
ochemistry in 11 as indicated was thus suggested.
H3′a-H6′a proved more helpful, suggesting the indicated structure
based on the calculated dihedral angles for the H-C3′a-C6′a-H
unit [15° for R-Hs and 1° for â-Hs in the energy minimized
structures obtained using Chem Office, version 6.0]. The
appearance of one singlet at δ 7.61 and the downfield shift of
H-1 signal in the 1H NMR spectrum of 24 indicated the presence
of a formate ester, which could be converted to 23 by base
hydrolysis.
1
The H NMR spectrum of 15 showed characteristic signals
assignable to the olefinic protons. Besides, appropriate signals
were detected in its 13C NMR spectrum for olefinic methylene
and methine carbons, respectively. The mass spectrum exhibited
a pseudomolecular ion at m/z 249 (MNa)+, confirming the
structure of the compound. The appearance of two signals
Synthesis of Spirofused Carbocyclic Nucleosides 26-28,
30, 31, and 33. The successful synthesis of the tricyclic
spirocycle 14 by the application of RCM and INC reactions on
appropriate glucose-derived substrates prompted us to attempt
the synthesis of [5/6]-spirofused carbocyclic nucleosides. Thus,
transfer hydrogenolysis of 14 (Pd/C, cyclohexane, EtOH) was
performed to cleave the isoxazolidine ring (Scheme 5). The
product, a trihydroxy aminospirocycle, was directly coupled with
5-amino-4,6-dichloropyrimidine to obtain the pyrimidinyl spi-
rocycle 25 (50%). Construction of a purine ring from the
pyrimidine ring in 25 was achieved by the treatment of triethyl
orthoformate in acidic medium. This furnished both the chlo-
ropurine-spironucleoside 26 (32%) and the dimethylaminopu-
rine-spironucleoside 27 (∼7%). The chloronucleoside 26 on
ammonolysis with a saturated solution of ammonia in methanol
furnished 28 in good yield. The formation of 27 could be
rationalized via nucleophilic displacement of the chloro group
by dimethylamine generated in the reaction medium from
DMF.28
1
(multiplets) for olefinic protons in the H NMR spectrum of
16, and the disappearance of olefinic protons signals in the
corresponding spectrum of 17, among other evidence, suggested
their structures as shown. The presence of an allyl group in 18
was evident from the characteristic olefinic proton signals at
1
the appropriate region in its H NMR spectrum. However, the
spectra for 19 and 20 proved less helpful for deducing the
structures, as signals for many of the protons overlapped with
each other. Only the absence of olefinic proton signals and the
1
presence of aromatic proton signals in their H NMR spectra,
coupled with the location of a peak at 328 (MNa)+ in the mass
spectra for both of the compounds, proved helpful in deducing
their gross isomeric structures. Finally, the structures and relative
stereochemistries of the spirocycles were deduced from the
X-ray analyses.27 For the crystals of 19, there are two molecules
in the asymmetric unit with equivalent geometries.
The five olefinic proton signals and two methyl signals in
1
the H NMR spectrum of 21 were indicative of the structure.
Although the INC reaction of the aldehyde 22 could have
afforded either a six-membered or a five-membered isoxazoli-
dine (or a mixture of the two) depending upon the mode of
cyclization, the gross structure 23 (for the major product) was
evident from the presence of two methylene carbon signals at
∼70 ppm in the 13C NMR spectrum, indicating the presence of
two -CH2O- linkages. The involvement of the double bond
of the allyl group in 22 during the INC reaction was also
confirmed by the absence of the characteristic signals for the
Similarly, hydrogenolysis of 19 followed by coupling of the
generated amino derivative with 5-amino-4,6-dichloropyrimidine
furnished (Scheme 6) the pyrimidine nucleoside 29 (76%),
which was converted to the purine nucleoside 30 (80%). The
target nucleoside derivative 31 became available by simple
substitution of the chloro group of 30 with amino group.
On the other hand, although the spirocycle 20 could be
transformed (Scheme 7) into the pyrimidine nucleoside 32
(44%), further cyclization using triethyl orthoformate failed to
furnish the corresponding chloropurine nucleoside, when the
reaction was carried out at the usual temperature (10 °C).
Attributing the reluctance to steric hindrance faced by the amino
substituent, which should be oriented in axial direction and
facing 1,3-diaxial interaction with a cyclopentane ring residue,
we attempted to carry out the reaction at a raised temperature
(25 °C). The cyclization did occur under this condition, but the
product was the dimethylaminopurine nucleoside 33 isolated
in poor yield.
1
olefinic protons of the allyl group in the H NMR spectra of
both 23 and 24.
For 23 and 24, the stereochemistry of the spirocyclic carbon
and the carbon bearing OH/OCHO must be the same as that of
the corresponding carbons in D-glucose, because these centers
were not disturbed during the reaction sequence. The cis ring
juncture is energetically favored in case of bicyclo[3.3.0]octane
system, and thus the H’s at the ring juncture of both these
spirocycles could have been either in R or in â orientation. Yet
the distinction between the two could not be made from the
NOESY spectrum of 23. The observed J value (8.4 Hz) for
(28) Roy, A.; Chakrabarty, K.; Dutta, P. K.; Bar, N. C.; Basu, N.; Achari,
B.; Mandal S. B. J. Org. Chem. 1999, 64, 2304.
(27) ORTEP diagram(s) are given in the Supporting Information.
5984 J. Org. Chem., Vol. 71, No. 16, 2006

Spiroannulated Carbanucleosides and Nucleosides
SCHEME 6a
a Reagents and conditions: (a) Pd/C (10%), cyclohexene, EtOH, reflux, 5 h; (b) 5-amino-4,6-dichloropyrimidine, n-butanol, Et3N, reflux, 30 h; (c) HC(OEt)3,
p-TSA, DMF, 10 °C, 16 h; (d) NH3, MeOH, sealed tube, 100 °C, 40 h.
SCHEME 7a
SCHEME 8a
a Reagents: (a) Diluted H2SO4 (4%), CH3CN-H2O (3:1); (b) BnNHOH,
a Reagents and conditions: (a) Pd/C (10%), cyclohexene, EtOH, reflux,
5 h; (b) 5-amino-4,6-dichloropyrimidine, n-butanol, Et3N, reflux, 30 h; (c)
HC(OEt)3, p-TSA, DMF, 25 °C, 8 h.
EtOH.
The 1H-1H COSY spectrum of 35 clearly identified most of
the signals, including those of all ring juncture protons. The
stereochemistries for C-8, C-1, and C-9 of this compound are
the same as for the corresponding centers in 21. Those of the
newly formed stereocenters (C-6, C-3, and C-7) follow from
the constraints of the fused ring system.
When 16 (of which 21 is the O-allyl ether) was subjected to
a similar INC reaction after deprotection of 1,2 hydroxyl groups
(Scheme 9), it generated the tricyclic product 36 (50% overall
yield). Cleavage of the isoxazolidine moiety of 36 and subse-
quent coupling with 5-amino-4,6-dichloropyrimidine furnished
37 (50%), converted uneventfully to the chloropurine nucleoside
38 (70%) and subsequently to 39 under usual reaction condi-
tions.
In contrast to the 5/6-spirocyclic systems, the synthesis of
nucleosides with 5/5-spirocyclic ring, beginning with the
spirocycle 23, failed to occur. This appears likely to be due to
steric hindrance offered by the neighboring spirocyclic ring,20
as the amino function generated would be located next to the
central carbon atom.
The indicated structure of 25 was derived from the observa-
tion of a one-proton signal assignable to aromatic H-2 in its 1H
NMR spectrum, and of four aromatic carbon signals along with
one for the spirocyclic carbon at δ 77.5 in the 13C NMR
spectrum. Also, the FAB mass spectrum for 25 showed peaks
for the (MH)+ ion and for the (MNa)+ ion as expected for the
assigned structure. Transformation of the pyrimidine ring to a
purine moiety (in 26) could be ascertained by the appearance
The structures of 36-39 were also elucidated from spectral
1
analyses. The striking feature in the H NMR spectrum of 36
1
of two aromatic proton singlets in the H NMR spectrum and
was the absence of the olefinic proton signals, which were
present in the similar spectrum of 16 along with the presence
of signals characteristic of benzylic protons in it. The observation
of five aromatic carbon signals in the 13C NMR spectrum.
Compound 27 exhibited an extra proton signal at δ 3.29 as a
singlet (6H), pointing to the presence of NMe2. This compound
showed expected pseudomolecular ion peaks in the ESI mass
spectrum. The structures of other nucleosides 29-33 were
similarly determined by spectral analyses.
1
of a one-proton singlet at δ 7.80 in the H NMR spectrum as
well as of four carbon signals for the pyrimidine ring in the
13C NMR spectrum of 37 indicated its structure. The appearance
1
of two one-proton singlets in the H NMR spectrum and five
carbon signals in the aromatic region in the 13C NMR spectrum
of 38 confirmed the formation of the purine ring. Mass spectral
analysis detected the presence of chlorine atom in 37 and 38,
but its absence in 39.
Synthesis of Tricyclic Compounds 35 and 36: Conversion
of 36 to Conformationally Locked Bicyclic Nucleosides 38
and 39. We have demonstrated with 21 that deprotection of
the 1,2-acetonide moiety, conversion to the lower homologue
aldehyde, and subsequent treatment with N-benzyl hydroxyl-
amine furnished spirocycles 23 and 24 only, the INC reaction
occurring exclusively through involvement of the allyl group.
The endocyclic double bond perhaps refrained from participating
in the cyclization, as the expected tricyclic product would have
a four-membered ring. This constraint would not be there if
the NaIO4 treatment is avoided. It therefore seemed interesting
to us to see the results of the INC reaction under this condition.
Thus, compound 21 was subjected to 1,2-acetonide deprotection
and then treatment with N-benzyl hydroxylamine for in situ
generation of the nitrone 34 (Scheme 8). Subsequent cyclization
was indeed observed to involve exclusively the cyclopentene
olefin moiety to afford 35; no product derived from the
participation of the other olefin was isolated.
Synthesis of the Tricyclic Compound 42 and Its Conver-
sion to Conformationally Constrained Nucleosides 44 and
45. The successful involvement of the cyclopentene double bond
of 16 in undergoing INC reaction with a nitrone generated at
C-1 suggested its possible extension to other related compounds
with the hope of generating new ring systems. Thus, the
substrate 4029 was subjected to deprotection of the 1,2-
isopropylidene moiety by treatment with diluted H2SO4 and
subsequent INC reaction with N-benzyl hydroxylamine. This
smoothly yielded 42 in 80% yield (Scheme 10). The structure
and relative stereochemistry of 42 was confirmed by an X-ray
crystal structure analysis.27
(29) Haque, A.; Panda, J.; Ghosh, S. Indian J. Chem. 1999, 38B, 8.
J. Org. Chem, Vol. 71, No. 16, 2006 5985

Sahabuddin et al.
SCHEME 9a
a Reagents: (a) Diluted H2SO4, CH3CN-H2O (3:1); (b) BnNHOH, EtOH; (c) Pd/C (10%), cyclohexene, EtOH; (d) 5-amino-4,6-dichloropyrimidine,
n-butanol, Et3N; (e) HC(OEt)3, p-TSA, DMF; (f) NH3, MeOH.
SCHEME 10a
a Reagents and conditions: (a) 4% H2SO4, CH3CN-H2O (3:1), rt, 24 h; (b) BnNHOH, reflux, EtOH, 4 h, N2.
SCHEME 11a
a Reagents and conditions: (a) Pd/C (10%), cyclohexene, EtOH, reflux, 5 h; (b) 5-amino-4,6-dichloropyrimidine, n-butanol, Et3N, reflux, 30 h; (c) HC(OEt)3,
p-TSA, DMF, 10 °C, 16 h; (d) NH3, MeOH, sealed tube, 100 °C, 40 h.
SCHEME 12a
tion with the other substituent in axial disposition, which is quite
likely to occur, and this favors the cyclization process.
In conclusion, judicious applications of ring-closing meta-
thesis (RCM) and intramolecular 1,3-dipolar cycloaddition (INC)
reactions on D-glucose-derived substrates have permitted entry
to new classes of spiroannulated carbanucleosides and confor-
mationally locked bicyclic nucleosides. The precursor assembly
for RCM as well as INC reactions appears simple, making the
strategy an attractive one. X-ray crystal structure determinations
on some of the products have conclusively established the
structures. The scope of the strategy to synthesize other ring
systems is under study.
a Reagents and conditions: (a) 4% H2SO4, CH3CN-H2O (3:1), rt, 24 h;
(b) BnNHOH, dry EtOH, reflux, 4 h, N2.
Opening of the isoxazolidine moiety of 42 (Scheme 11)
followed by reaction with 5-amino-4,6-dichloropyrimidine
generated 43 (41% yield). Construction of the purine ring
furnished chloropurine nucleoside 44 (73%). Transformation of
44 to 45 was smoothly accomplished by ammonia treatment.
The structures of 43-45 were elucidated from spectral analyses
in the usual way.
The bicyclic compound 46,30 an isomer of 40, however, failed
to afford any cyclized product (Scheme 12) upon deprotection
of the acetonide function followed by reaction with N-benzyl
hydroxylamine. Model studies reveal that this requires both of
the substituents of the dihydropyran ring to assume axial
orientation, which is energetically unfavorable. In the cis-series,
however, the hydroxyl group may remain in equatorial orienta-
Experimental Section
(3aR,4′R,5R,6R,6aR)-6-Allyl-6-allyloxy-5-(2,2-dimethyl[1,3]-
dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (8).
To a refluxing mixture of 7 (200 mg, 0.7 mmol), tetrabutylammo-
nium bromide (27 mg, 0.08 mmol), NaOH solution (50%, 10 mL),
and benzene (10 mL) was added allyl bromide (3 × 0.3 mL) over
10 h. The mixture was cooled, washed with H2O, dried (Na2SO4),
and evaporated to give a material, which was purified by column
chromatography on silica gel. Elution with CHCl3-petroleum ether
(3:7) afforded a solid, which was recrystallized from petroleum
ether to furnish 8 (190 mg, 80%) as a semisolid mass.
1
8. [R]27 +48.7 (c 0.72, CHCl3). H NMR (CDCl3, 300 MHz):
D
δ 1.32, 1.36, 1.43, 1.57 (4 × 3H s), 2.32 (dd, 1H, J ) 7.5, 15 Hz),
(30) Leeuwenburgh, M. A.; Kulker, C.; Duynstee, H. I.; Overkleeft, H.
S.; van der Marcel, G. A.; van Boom, J. H. Tetrahedron 1999, 55, 8253.
2.65 (dd, 1H, J ) 6.6, 15 Hz), 3.93 (m, 1H), 4.08-4.21 (m, 4H),
5986 J. Org. Chem., Vol. 71, No. 16, 2006

Spiroannulated Carbanucleosides and Nucleosides
4.30 (brdd, 1H, J ) 5.0, 12.0 Hz), 4.41 (d, 1H, J ) 3.6 Hz), 5.09-
5.33 (m, 4H), 5.58 (d, 1H, J ) 3.6 Hz), 5.87-6.04 (m, 2H). ESIMS,
m/z: 363 (MNa)+. Anal. Calcd for C18H28O6: C, 63.51; H, 8.29.
Found: C, 63.30; H, 8.28.
Column chromatography of this on silica gel using EtOAc-
petroleum ether (3:22) as eluent yielded 11 (1.15 g, 60%).
11. mp 97-99 °C. [R]25D +34.6 (c 1.25, CHCl3). IR (KBr): νmax
3384, 1607, 1496, 1433, 1348, 1100, 1079, 1024, 772, 734, 710
cm-1. 1H NMR (CDCl3 + D2O, 300 MHz): δ 2.33 (m, 2H), 3.20
(m, 1H), 3.64 (partially merged dd, 1H, J ) 5.0, 9.4 Hz), 3.66 (d,
1H, J ) 4.8 Hz), 3.73 (d, 1H, J ) 5.0 Hz), 3.74 (dd, 1H, J ) 3.3,
9.0 Hz), 3.82 (d, 1H, J ) 13.0 Hz), 4.01 (d, 1H, J ) 13.0 Hz),
4.16 (dd, 1H, J ) 8.0, 9.0 Hz), 4.39 (d, 1H, J ) 16.3 Hz, with
further fine splitting), 4.53 (d, 1H, J ) 16.3 Hz with further fine
splitting), 5.84 (m, 2H), 7.31 (m, 5H). 13C NMR (CDCl3, 75
MHz): δ 29.1 (CH2), 53.3 (CH), 60.7 (CH2), 64.8 (CH2), 69.9
(CH2), 75.9 (CH), 79.6 (C), 81.3 (CH), 82.4 (CH), 122.2 (CH),
126.5 (CH), 127.9 (CH), 129.9 (2 × CH), 129.3 (2 × CH), 137.4
(C). EIMS, m/z: 303 (M+), 190, 161, 91. Anal. Calcd for C17H21-
NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.28; H, 6.92; N,
4.38.
(1R,3R,4R,4′R,5R)-3,4-Isopropylidenedioxy-1-(2,2-dimethyl-
[1,3]dioxolan-4-yl)-2,6-dioxa-spiro[4.5]dec-8-ene (9). To a solu-
tion of 8 (0.50 g, 1.47 mmol) in dry distilled CH2Cl2 (250 mL),
degassed by N2 gas, was added Grubbs catalyst (0.69 g, 5 mol %),
and the mixture was stirred at room temperature for 6 h under N2
atmosphere. The solvent was evaporated in a rotary evaporator to
a blackish gummy residue, which was purified by column chro-
matography on silica gel. Elution with EtOAc-petroleum ether (1:
24) furnished 9 (0.40 g, 87%) as a gum.
9. [R]27 +106.7 (c 0.85, CHCl3). IR (neat): νmax 1635, 1598,
D
1
1455, 1377, 1248, 1217, 1076, 1010 cm-1. H NMR (CDCl3, 300
MHz): δ 1.34, 1.35, 1.45, 1.60 (4 × 3H s), 1.67 (m, 1H), 2.50 (m,
1H), 3.95 (dd, 1H, J ) 6.0, 8.3 Hz), 4.04-4.09 (m, 2H), 4.14 (t,
1H, J ) 6.0 Hz), 4.26 (brd, 1H, J ) 16.5 Hz), 4.41 (d, 1H, J ) 3.6
Hz, including a merged signal, 1H), 5.65 (d, 1H, J ) 3.6 Hz), 5.84
(m, 2H). 13C NMR (CDCl3, 75 MHz): δ 25.7 (CH3), 26.9 (CH2 +
CH3), 27.0 (CH3), 27.4 (CH3), 64.1 (CH2), 67.7 (CH2), 74.0 (CH),
80.2 (C), 81.6 (CH), 82.6 (CH), 104.1 (CH), 110.0 (C), 113.4 (C),
121.4 (CH), 127.8 (CH). EIMS, m/z: 311 (M - 1)+, 297 (M -
15)+. Anal. Calcd for C16H24O6: C, 61.52; H, 7.74. Found: C,
61.38; H, 7.72.
(1S,3R,4R,4′S,5R)-3,4-O-Isopropylidene-1-(2,2-dimethyl[1,3]-
dioxolan-4-yl)-2,6-dioxa-spiro[4.5]decane (12). To a solution of
9 (0.60 g, 1.92 mmol) in dry ethanol (20 mL) was added Pd/C
(10%, 0.15 g). Air was removed from the solution by applying
suction, and then H2 gas was passed through the reaction mixture
from a balloon with stirring at room temperature for 4 h. The
catalyst was filtered off, and the solvent was evaporated under
reduced pressure to obtain a gummy material, which was purified
by column chromatography on silica gel. Elution with EtOAc-
petroleum ether (3:47) furnished 12 (0.513 g, 85%) as a white
semisolid mass.
(1R,3R,4R,5R)-3,4-Isopropylidenedioxy-1-vinyl-2,6-dioxa-spiro-
[4.5]dec-8-ene (10). Compound 9 (1.00 g, 3.20 mmol) was
dissolved in a HOAc-H2O (3:1) mixture (20 mL), and the solution
was stirred at room temperature overnight. The solvent was
evaporated, and the last traces of HOAc were removed azeotropi-
cally using toluene (3 × 20 mL) to furnish the 5,6-dihydroxy
spirocycle (0.70 g) as a thick gum, which was used in the next
step after drying over P2O5 under vacuum. To a solution of the
above gum (0.50 g, 1.84 mmol) in freshly distilled dry toluene (40
mL) were added Ph3P (1.80 g, 6.87 mmol) and imidazole (0.47 g,
6.87 mmol), and the mixture was heated slowly. When the solution
started to reflux, iodine (0.70 g, 2.76 mmol) was added portionwise,
and the heating was continued for 6 h under N2 atmosphere. The
solvent was evaporated, and the residue was extracted with toluene
(2 × 30 mL). The combined extract was washed with sodium
thiosulfate (2 × 20 mL) solution and water (2 × 20 mL), dried
(Na2SO4), and evaporated to give a crude residue, which was
purified by column chromatography on silica gel using EtOAc-
petroleum ether (1:24) as eluent to furnish 10 (0.36 g, 47%).
12. [R]28 +70.8 (c 1.2, CHCl3). IR (KBr): νmax 1455, 1375,
D
1
1249, 1219, 1084, 1024, 876 cm-1. H NMR (CDCl3, 300 MHz):
δ 1.36 (s, 6H), 1.44 (s, 3H), 1.60 (s, 3H), 1.64-1.86 (m, 6H), 3.67
(m, 1H), 3.91-3.96 (m, 2H), 3.99-4.05 (m, 2H), 4.16 (dd, 1H, J
) 6.0, 12.5 Hz), 4.61 (d, 1H, J ) 3.6 Hz), 5.68 (d, 1H, J ) 3.6
Hz). 13C NMR (CDCl3, 75 MHz): δ 19.9 (CH2), 25.7 (CH2), 25.8
(CH3), 26.9 (2 × CH3), 27.1 (CH2), 27.4 (CH3), 65.2 (CH2), 67.2
(CH2), 74.0 (CH), 80.0 (CH), 81.2 (C), 82.3 (CH), 104.1 (CH),
109.5 (C), 113.1 (C). ESIMS, m/z: 337 (MNa)+. Anal. Calcd for
C16H26O6: C, 61.13; H, 8.34. Found: C, 60.90; H, 8.18.
(1R,3S,4R,5S,6aR)-3,4-Isopropylidenedioxy-1-vinyl-2, 6-dioxa-
spiro[4.5]decane (13). Spirocycle 12 (1.20 g, 3.82 mmol) was
dissolved in 30 mL of HOAc-H2O (3:1), and the solution was
stirred at room temperature for 14 h. Evaporation of the solvent
furnished a gummy residue. The last traces of HOAc were removed
by coevaporation with toluene to give a crude gum (0.75 g), the
toluene solution (50 mL) of which was treated with Ph3P (2.69 g,
10.27 mmol), imidazole (0.697 g, 10.27 mmol), and I2 (1.04 g,
4.10 mmol) according to the procedure described for 10. Usual
workup and purification afforded 13 (0.60 g, 65%).
10. mp 48-50 °C. [R]25 +129.4 (c 0.91, CHCl3). IR (KBr):
D
νmax 1647, 1436, 1378, 1255, 1216, 1105, 1066, 1014 cm-1. H
1
NMR (CDCl3, 300 MHz): δ 1.35 (s, 3H, including a merged signal,
1H), 1.62 (s, 3H), 2.34 (m, 1H), 4.21 (dd, 1H, J ) 2.0, 16.0 Hz),
4.42 (d, 1H, J ) 3.6 Hz, including a merged signal, 1H), 4.56 (d,
1H, J ) 5.5 Hz), 5.30 (d, 1H, J ) 10.7 Hz, with fine splitting),
5.44 (d, 1H, J ) 17.3 Hz, with fine splitting), 5.72 (d, 1H, J ) 3.8
Hz), 5.76-5.87 (m, 3H). 13C NMR (CDCl3, 75 MHz): δ 26.7
(CH2), 26.9 (CH3), 27.2 (CH3), 63.9 (CH2), 80.5 (C), 81.6 (CH),
81.7 (CH), 104.2 (CH), 113.7 (C), 118.7 (CH2), 121.9 (CH), 127.0
(CH), 132.7 (CH). EIMS, m/z: 223 (M - 15)+. Anal. Calcd for
C13H18O4: C, 65.53; H, 7.61. Found: C, 65.50; H, 7.54.
(3aR,4R,5R,6S,6aR)-1-Benzyl-spiro[cyclopent[d]isoxazole-5.6′-
(5,6-dihydro-2H-pyran)]-4,6-diol (11). Compound 10 (1.50 g, 6.30
mmol) was dissolved in 40 mL of 4% H2SO4 in CH3CN-H2O (3:
1), and the solution was stirred at room temperature for 24 h. The
solution was neutralized with solid CaCO3 and filtered, and the
solvent was evaporated under reduced pressure to obtain an
anomeric mixture of the 1,2-dihydroxy compound (1.00 g), which
was used in the next step without further purification. This material
was dissolved in dry ethanol (30 mL), N-benzyl hydroxylamine
(0.75 g, 6.06 mmol) was added to it, and the solution was heated
at reflux for 4 h under N2. TLC showed complete disappearance
of the starting material. The solvent was evaporated, and the residue
was extracted with CHCl3 (3 × 20 mL) to furnish a yellowish mass.
13. mp 45-46 °C. [R]28D +75.8 (c 1.02, CHCl3). IR (KBr): νmax
1644, 1448, 1315, 1250, 1214, 1167, 1088, 1025, 994, 928, 877
1
cm-1. H NMR (CDCl3, 300 MHz): δ 1.38 (s, 3H), 1.59-1.80
(m, 6H, overlapping one s, 3H at δ 1.61), 3.66 (m, 1H), 3.91 (d,
1H, J ) 11.0 Hz), 4.44 (d, 1H, J ) 5.5 Hz), 4.64 (d, 1H, J ) 3.6
Hz), 5.29 (d, 1H, J ) 10.5 Hz, with further fine splitting), 5.40 (d,
1H, J ) 17.4 Hz, with further fine splitting), 5.73 (d, 1H, J ) 3.6
Hz, merged with a m, 1H). 13C NMR (CDCl3, 75 MHz): δ 19.9
(CH2), 25.8 (CH2), 26.5 (CH2), 26.8 (CH3), 27.3 (CH3), 65.4 (CH2),
79.2 (CH), 81.8 (C), 82.4 (CH), 104.2 (CH), 113.0 (C), 118.5 (CH2),
132.8 (CH). ESIMS, m/z: 263 (MNa)+. Anal. Calcd for C13H20O4:
C, 64.98; H, 8.39. Found: C, 64.69; H, 8.33.
(3aR,4R,5R,6S)-1-Benzyl-spiro[cyclopent[d]isoxazole-5.2′-tet-
rahydropyran]-4,6-diol (14). Compound 13 (0.50 g, 2.08 mmol)
was dissolved in H2SO4 (4%) in CH3CN-H2O (3:1, 25 mL), and
the solution was kept at room temperature for 24 h. The solution
was neutralized with solid CaCO3 and filtered, and the solvent was
evaporated under reduced pressure to obtain an anomeric mixture
of the 1,2-dihydroxy compound (0.36 g) as a gum, which without
purification was used in the next step. This material was dissolved
in dry ethanol (30 mL), treated with N-benzyl hydroxylamine (0.265
J. Org. Chem, Vol. 71, No. 16, 2006 5987

Sahabuddin et al.
g, 2.16 mmol), and the solution was heated at reflux for 4 h. The
solvent was evaporated under reduced pressure to obtain a residue.
The residue was extracted with CHCl3 (2 × 25 mL), the CHCl3
solution was dried (Na2SO4), and the solvent was evaporated to
afford a crude product, which was purified by column chromatog-
raphy using silica gel. Elution with EtOAc-petroleum ether (3:
22) furnished 14 (0.46 g, 72%).
1H), 4.36 (d, 1H, J ) 3.6 Hz), 5.82 (d, 1H, J ) 3.6 Hz). 13C NMR
(CDCl3, 75 MHz): δ 23.7 (CH2), 27.2 (CH3), 27.4 (CH3), 30.5
(CH2), 35.4 (CH2), 83.4 (CH), 87.9 (C), 88.0 (CH), 105.8 (CH),
112.7 (C). ESIMS, m/z: 223 (MNa)+. Anal. Calcd for C10H16O4:
C, 59.98; H, 8.05. Found: C, 59.73; H, 8.00.
(3aR,4aR,7aR,7bR)-7a-Allyloxy-2,2-dimethyl Hexahydrocy-
clopenta[4,5]furo[2,3-d][1,3]dioxole (18). To a solution of 17 (1.0
g, 5.0 mmol) in dry THF (30 mL) at 10 °C was added oil-free
sodium hydride (200 mg, 8.34 mmol) portionwise under N2. The
mixture was stirred at room temperature for 30 min. Allyl bromide
(0.7 mL) was added, and the mixture was heated at reflux for 5 h
under N2. After the mixture was cooled to ∼10 °C, NH4Cl solution
(saturated) was added to destroy excess NaH. The solvent was
evaporated in vacuo, and the residue was extracted with CHCl3 (2
× 30 mL). The CHCl3 solution was washed with water (2 × 20
mL), dried (Na2SO4), and evaporated to obtain the crude product,
which was purified by column chromatography on silica gel using
EtOAc-petroleum ether (1:49) as the eluent to furnish 18 (1.04 g,
87%) as a thick syrup.
14. mp 140-142 °C. [R]28 +33.3 (c 0.92, CHCl3). IR (KBr):
D
νmax 3388, 1025, 997, 824, 759 cm-1. H NMR (CDCl3 + D2O,
1
300 MHz): δ 1.53 (m, 2H), 1.69-1.84 (m, 4H), 3.15 (m, 1H),
3.58-3.64 (m, 2H), 3.69-3.74 (m, 2H), 3.80 (d, 1H, J ) 13.0
Hz), 3.88 (m, 1H), 4.00 (d, 1H, J ) 13.0 Hz), 4.02 (partially merged
dd, 1H, J ) 6.0, 10.8 Hz), 4.16 (t, 1H, J ) 8.4 Hz), 7.31 (m, 5H).
13C NMR (DMSO-d6, 75 MHz): δ 19.0 (CH2), 25.4 (CH2), 29.5
(CH2), 51.4 (CH), 58.8 (CH2), 63.8 (CH2), 68.4 (CH2), 74.7 (CH),
79.4 (C), 80.3 (CH), 81.6 (CH), 126.8 (CH), 127.9 (2 × CH), 128.8
(2 × CH), 138.2 (C). ESIMS, m/z: 306 (MH)+, 328 (MNa)+. Anal.
Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.56;
H, 7.48; N, 4.30.
(3aR,5R,6R,6aR)-6-Allyl-2,2-dimethyl-5-vinyl-tetrahydrofuro-
[2,3-d][1,3]dioxol-6-ol (15). Following the earlier procedure (as
described for 10), addition of Ph3P (1.89 g, 7.21 mmol), imidazole
(0.49 g, 7.2 mmol), and I2 (0.73 g, 2.89 mmol) to a solution of
5,6-dihydroxy derivative of 7 (0.5 g, 1.92 mmol) [obtained from 7
through removal of isopropylidene group by dilute HOAc] in dry
distilled toluene (40 mL)) afforded 15 (260 mg, 60%) as a white
crystalline solid after purification by column chromatography on
silica gel using an EtOAc-petroleum ether (1:24) mixture as the
eluent.
18. [R]28 +67.8 (c 2.00, CHCl3). IR (neat): νmax 1644, 1377,
D
1218, 1166, 1117, 1071, 927, 877 cm-1. H NMR (CDCl3, 300
1
MHz): δ 1.35 (s, 3H), 1.50 (m, 1H), 1.58 (s, 3H), 1.83 (m, 4H),
1.96 (m, 1H), 4.01 (dd, 1H, J ) 5.7, 12.0 Hz), 4.15 (dd, 1H, J )
5.0, 12.0 Hz, with further fine splitting), 4.47 (d, 2H, J ) 3.6 Hz),
5.15 (dd, 1H, J ) 1.5, 10.4 Hz), 5.29 (dd, 1H, J ) 3.3, 17.1 Hz,
with further fine splitting), 5.78 (d, 1H, J ) 3.6 Hz), 5.89-6.02
(m, 1H). 13C NMR (CDCl3, 75 MHz): δ 22.9 (CH2), 26.9 (CH3),
27.0 (CH3), 30.1 (CH2), 31.7 (CH2), 66.1 (CH2), 81.9 (CH), 86.7
(CH), 92.9 (C), 105.8 (CH), 112.6 (C), 116.2 (CH2), 135.0 (CH).
ESIMS, m/z: 263 (MNa)+. Anal. Calcd for C13H20O4: C, 64.98;
H, 8.39. Found: C, 64.73; H, 8.40.
15. mp 97-98 °C. [R]27D +51.2 (c 1.48, CHCl3). IR (KBr): νmax
1
3467, 1643, 1381, 1108, 1076, 1003 cm-1. H NMR (CDCl3, 300
MHz): δ 1.36 (s, 3H), 1.59 (s, 3H), 2.07 (dd, 1H, J ) 8.4, 14.6
Hz), 2.39 (ddd, 1H, J ) 1.3, 6.0, 14.6 Hz), 2.67 (d, 1H, J ) 1.3
Hz), 4.29 (d, 1H, J ) 5.6 Hz), 4.34 (d, 1H, J ) 3.9 Hz), 5.12 (brd,
1H, J ) 17.0 Hz), 5.17 (brd, 1H, J ) 9.3 Hz), 5.31 (td, 1H, J )
1.4, 1.4, 10.8 Hz), 5.41 (td, 1H, J ) 1.5, 1.5, 17.0 Hz), 5.75 (d,
1H, J ) 3.9 Hz), 5.78-5.96 (m, 2H). 13C NMR (CDCl3, 75 MHz):
δ 26.9 (2 × CH3), 36.8 (CH2), 79.7 (C), 81.0 (CH), 83.6 (CH),
103.8 (CH), 112.6 (C), 118.7 (CH2), 119.2 (CH2), 131.8 (CH), 133.1
(CH). ESIMS, m/z: 249 (MNa)+. Anal. Calcd for C12H18O4: C,
63.70; H, 8.02. Found: C, 63.48; H, 7.80.
(3aR,4aR,7aR,7bR)-2,2-Dimethyl-3a,4a,7,7b-tetrahydrocy-
clopenta[4,5]furo[2,3-d][1,3]dioxol-7a-ol (16). To a solution of
15 (500 mg, 2.21 mmol) in dry dichloromethane (250 mL) degassed
by N2 gas was added Grubbs catalyst (56 mg, 0.068 mmol, 3 mmol
%), and the mixture was stirred at room temperature for 6 h under
N2 atmosphere. The solvent was evaporated in a rotary evaporator
to a black gummy residue. It was purified by column chromatog-
raphy on silica gel using an EtOAc-petroleum ether (1:24) mixture
as the eluent to furnish 16 (380 mg, 87%) as a crystalline solid.
16. mp 68-70 °C. [R]27D +72.2 (c 0.72, CHCl3). IR (KBr): νmax
3523, 1664, 1614, 1379, 1233, 1075, 990, 947, 876 cm-1. 1H NMR
(CDCl3, 300 MHz): δ 1.41 (s, 3H), 1.62 (s, 3H), 2.54 (d, 1H, J )
18.0 Hz), 2.66 (td, 1H, J ) 2.0, 2.0, 18.0 Hz), 3.05 (s, 1H), 4.40
(d, 1H, J ) 3.6 Hz), 4.79 (s, 1H), 5.83 (m, 1H), 5.87 (d, 1H, J )
3.6 Hz), 6.00 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 27.5 (CH3),
27.9 (CH3), 43.5 (CH2), 83.5 (CH), 85.9 (C), 92.4 (CH), 106.7 (CH),
113.6 (C), 129.7 (CH), 136.0 (CH). ESIMS, m/z: 221 (MNa)+.
Anal. Calcd for C10H14O4: C, 60.59; H, 7.12. Found: C, 60.49; H,
7.10.
(1R,2R,3′aS,7′S,7′aR)-1′-Benzyl-spiro[cyclopenta-1.6′-tetrahy-
dropyran[3,4-d]-isoxazole]-2,7′-diol (19) and (1R,2R,3′aR,7′S,7′aS)-
1-Benzyl-spiro[cyclopenta-1.6′-tetrahydropyran[3,4-d]-isoxazole]-
2,7′-diol (20). Compound 18 (0.5 g, 2.08 mmol) was treated with
25 mL of 4% H2SO4 in CH3CN-H2O (3:1) using the procedure
identical to that adopted for the generation of 11 to furnish an
anomeric mixture of 1,2-dihydroxy derivative (316 mg), which after
drying (P2O5) was used directly in the next step. A solution of the
above mixture (150 mg, 0.75 mmol) in dry ethanol (30 mL) was
treated with N-benzyl hydroxylamine (132 mg, 1.07 mmol), and
the solution was heated at reflux for 6 h. Usual workup and
purification by column chromatography on silica gel using EtOAc-
petroleum ether (2:23) as the eluting solvent furnished 19 (102 mg,
45%) and 20 (75 mg, 33%), respectively, as light yellow crystalline
solids.
19. mp 128-129 °C. [R]30 +7.9 (c 1.16, CHCl3). IR (KBr):
D
νmax 3430, 3311, 1453, 1430, 1221, 1074, 700 cm-1. H NMR
1
(CDCl3 + D2O, 300 MHz): 1.46-2.00 (m, 6H), 2.91 (m, 1H),
3.18 (t, 1H, J ) 7.5 Hz), 3.71-3.91 (m, 5H), 4.01-4.05 (m, 2H),
4.22 (t, 1H, J ) 8.0 Hz), 7.34 (m, 5H). 13C NMR (CDCl3, 75
MHz): δ 21.2 (CH2), 25.4 (CH2), 33.3 (CH2), 39.3 (CH), 58.5
(CH2), 61.0 (CH2), 66.7 (CH), 67.6 (CH), 68.7 (CH2), 80.6 (CH),
85.3 (C), 127.5 (CH), 128.3 (2 × CH), 129.3 (2 × CH), 136.2 (C).
ESIMS, m/z: 306 (MH)+, 328 (MNa)+. Anal. Calcd for C17H23-
NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.81; H, 7.57; N,
4.38.
20. mp 150-152 °C. [R]29D -101.0 (c 1.62, CHCl3). IR (KBr):
1
νmax 3434, 1449, 1382, 1320, 1098, 1035 cm-1. H NMR (CDCl3
(3aR,4aR,7aR,7bR)-2,2-Dimethyl Hexahydrocyclopenta[4,5]-
furo[2,3-d][1,3]dioxol-7a-ol (17). A solution of 16 (1.20 g, 6.06
mmol) in dry ethanol (20 mL) was hydrogenated in the presence
of Pd/C (10%, 150 mg). Usual workup and purification by column
chromatography on silica gel and elution using EtOAc-petroleum
ether (3:47) afforded 17 (1.09 g, 90%) as a semisolid mass.
+ D2O, 300 MHz): δ 1.49 (m, 1H), 1.75 (m, 2H), 2.08-2.17 (m,
3H), 2.88 (m, 1H), 3.40 (dd, 1H, J ) 4.0, 6.7 Hz), 3.54 (dd, 1H,
J ) 3.4, 8.0 Hz), 3.68 (dd, 1H, J ) 6.6, 11.7 Hz), 3.76 (dd, 1H, J
) 9.8, 11.4 Hz), 3.93 (d, 1H, J ) 14.0 Hz), 3.97-4.02 (m, 2H),
4.18 (d, 1H, J ) 4.0 Hz), 4.31 (d, 1H, J ) 14.0 Hz), 7.23-7.42
(m, 5H). 13C NMR (CDCl3, 75 MHz): δ 20.8 (CH2), 27.4 (CH2),
33.2 (CH2), 42.5 (CH), 60.1 (CH2), 62.8 (CH2), 64.5 (CH), 67.3
(CH2), 68.7 (CH), 81.0 (CH), 85.0 (C), 126.9 (CH), 128.1 (2 ×
CH), 128.5 (2 × CH), 137.9 (C). ESIMS, m/z: 328 (MNa)+. Anal.
17. [R]29 +28.4 (c 0.82, CHCl3). IR (KBr): νmax 3439, 1378,
D
1
1218, 1106, 1035, 1063, 1003, 755 cm-1. H NMR (CDCl3, 300
MHz): δ 1.37 (s, 3H), 1.58 (s, 3H), 1.73-1.88 (m, 7H), 4.22 (s,
5988 J. Org. Chem., Vol. 71, No. 16, 2006

Spiroannulated Carbanucleosides and Nucleosides
Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.58;
H, 7.48; N, 4.30.
(1S,2R,3R,4R,5R)-2-(5-Amino-6-chloropyrimidin-4-ylamino)-
3-hydroxymethyl-6-oxa-spiro[4.5]decane-1,4-diol (25). Com-
pound 14 (0.40 g, 1.30 mmol) (dried over P2O5) was dissolved in
dry ethanol (20 mL), Pd/C (10%, 0.130 g) and cyclohexene (2 mL)
were added, and the solution was heated at reflux under N2
atmosphere for 5 h. The catalyst was filtered off, and the solvent
was evaporated in vacuo to obtain a crude trihydroxy amine
derivative31 (0.270 g), which was dried (over P2O5). To the above
amine (0.270 g, 1.24 mmol) dissolved in dry n-BuOH (25 mL)
were added 5-amino-4,6-dichloropyrimidine (297 mg, 1.81 mmol,
1.5 equiv) and Et3N (2 mL), and the mixture was heated at reflux
for 30 h under N2. The solvent was evaporated in vacuo to give a
semisolid residue, the aqueous solution of which was washed with
CH2Cl2 (2 × 20 mL). The aqueous part was evaporated to a thick
oil, which was purified by reverse phase flash chromatography using
water as the eluent to furnish 25 (206 mg, 50%).
(3aR,4aR,7aR,7bR)-7a-Allyloxy-2,2-dimethyl-4a,7,7a,7b-tet-
rahydrocyclopenta[4,5]furo[2,3-d][1,3]dioxole (21). Compound
16 (0.5 g, 2.52 mmol) was allylated using allyl bromide (0.30 mL,
417 mg, 3.45 mmol), oil-free sodium hydride (100 mg, 4.17 mmol),
and dry THF (20 mL) to furnish 21 (470 mg, 78%) as a thick syrup
following the procedure described in the preparation of 18.
21. [R]27 +44.8 (c 0.63, CHCl3). IR (neat): νmax 1641, 1377,
D
1220, 1186, 874 cm-1. H NMR (CDCl3, 300 MHz): δ 1.40 (s,
1
3H), 1.61 (s, 3H), 2.35 (brd, 1H, J ) 17.7 Hz), 2.78 (td, 1H, J )
2.0, 2.0, 17.7 Hz), 4.00 (m, 1H), 4.21 (m, 1H), 4.49 (d, 1H, J )
3.6 Hz), 5.01 (brs, 1H), 5.14 (ddd, 1H, J ) 1.6, 3.3, 10.3 Hz), 5.29
(ddd, 1H, J ) 1.6, 3.3, 17.1 Hz), 5.81 (d, 1H, J ) 3.3 Hz), 5.87-
5.95 (m, 3H). 13C NMR (CDCl3, 75 MHz): δ 27.8 (CH3), 28.1
(CH3), 40.5 (CH2), 67.5 (CH2), 84.1 (CH), 91.0 (CH), 91.6 (C),
107.1 (CH), 114.2 (C), 116.8 (CH2), 131.0 (CH), 134.7 (CH), 135.5
(CH). ESIMS, m/z: 261 (MNa)+. Anal. Calcd for C13H18O4: C,
65.53; H, 7.61. Found: C, 65.28; H, 7.53.
25. mp 110-112 °C (shrinks). [R]26 -46.2 (c 0.48, CH3OH).
D
IR (KBr): νmax 3343, 3256, 1582, 1423, 1075, 978, 932, 850, 764
cm-1. 1H NMR (D2O, 300 MHz): δ 1.51 (m, 2H), 1.65-1.74 (m,
4H), 2.34 (m, 1H), 3.41 (dd, 1H, J ) 4.0, 11.7 Hz), 3.56 (dd, 1H,
J ) 5.2, 11.7 Hz), 3.72 (d, 1H, J ) 8.6 Hz), 3.74 (d, 1H, J ) 9.6
Hz), 4.00 (m, 2H), 4.56 (t, 1H, J ) 10.2 Hz), 7.83 (s, 1H). 13C
NMR (D2O, 75 MHz): δ 19.2 (CH2), 25.1 (CH2), 30.3 (CH2), 45.6
(CH), 56.0 (CH), 59.6 (CH2), 65.6 (CH2), 77.1 (CH), 77.5 (C),
81.1 (CH), 123.1 (C), 140.3 (C), 148.4 (CH), 154.9 (C). ESIMS,
m/z: 345 (MH+, for Cl35), 347 (MH+, for Cl37), 367 (MNa+, for
Cl35), 369 (MNa+, for Cl37). Anal. Calcd for C14H21ClN4O4: C,
48.77; H, 6.14; N, 16.25. Found: C, 48.62; H, 6.00; N, 16.03.
[1S,2R,3′aR,6′aS]-1′-Benzyl-spiro[cyclopent-1.6′-tetrahydro-
furo(3,4-d)isoxazole]-3,4-en-2-ol (23) and [1S,2R,3′aR,6′aS]-1-
Benzyl-2-formyloxyspiro[cyclopent-1.6′-tetrahydrofuro(3,4-d)-
isoxazole]-3,4-ene (24). Compound 21 (330 mg, 1.39 mmol) was
dissolved in 25 mL of 4% H2SO4 in CH3CN-H2O (3:1) and stirred
at room temperature for 24 h. Usual workup as described earlier
for 11 afforded the crude anomeric mixture of 1,2-dihydroxy
derivative, which was used directly in the next step. To a solution
of this mixture (200 mg, 1.01 mmol) in MeOH (25 mL) at ∼10 °C
was added an aqueous solution (5 mL) of NaIO4 (260 mg, 1.21
mmol) dropwise with vigorous stirring. After being stirred at the
same temperature for 45 min, the mixture was filtered and the
solvent was evaporated. The residue was dissolved in CHCl3 (30
mL), and the CHCl3 solution was washed with water (2 × 20 mL)
and dried (Na2SO4). Evaporation of the solvent afforded the crude
aldehyde 22 (150 mg) as a thick liquid, which was dried (P2O5)
and used for further reaction in the next step. This compound (150
mg, 0.89 mmol) dissolved in dry ethanol (30 mL) was treated with
N-benzyl hydroxylamine (164 mg, 1.33 mmol), and the solution
was stirred at room temperature for 20 h. The solvent was
evaporated to a gummy residue, which was purified by column
chromatography on silica gel. Elution with EtOAc-petroleum ether
(2:23) furnished 23 (114 mg, 47%) as a solid material. On the other
hand, EtOAc-petroleum ether (1:9) eluted 24 (70 mg, 29%) as a
thick liquid.
(1S,2R,3R,4R,5R)-2-(6-Chloropurin-9-yl)-3-hydroxymethyl-6-
oxa-spiro[4.5]decane-1,4-diol (26) and (1S,2R,3R,4R,5R)-2-(6-
Dimethylaminopurin-9-yl)-3-hydroxymethyl-6-oxa-spiro[4.5]-
decane-1,4-diol (27). To a solution of the aminopyrimidine
derivative 25 (42 mg, 0.122 mmol) dissolved in dry DMF (4 mL)
were added p-TSA (35 mg, 0.183 mmol) and HC(OEt)3 (2 mL),
and the reaction mixture was stirred at 10 °C for 16 h under N2.
The solvent was removed under vacuum, the residue was dissolved
in MeOH (5 mL), and the solution was treated with Dowex-OH-
resin for 5 h to neutralize the acid. It was then filtered, and the
filtrate was evaporated to give a crude residue, which was subjected
to flash column chromatography using reverse phase material.
Elution with water furnished the chloronucleoside 26 (32 mg, 74%)
and 27 (3.0 mg, 6.8%) as foamy solids.
26. [R]27D -22.0° (c 0.44, CH3OH). IR (KBr): νmax 3410, 1639,
1
1596, 1570, 1385, 1343, 1081, 1044, 957 cm-1. H NMR (D2O,
300 MHz): δ 1.50 (brs, 2H), 1.76 (brs, 4H), 2.55 (m, 1H), 3.27
(d, 2H, J ) 5.7 Hz), 3.81 (d, 1H, J ) 8.7 Hz), 4.05 (m, 2H), 4.62
(d, 1H, J ) 10.2 Hz), 5.18 (t, 1H, J ) 10.5 Hz), 8.55 (s, 1H), 8.63
(s, 1H). 13C NMR (D2O, 75 MHz): δ 19.1 (CH2), 25.1 (CH2), 29.8
(CH2), 45.6 (CH), 59.5 (CH2), 60.2 (CH), 65.7 (CH2), 76.7 (CH),
77.6 (C), 78.0 (CH), 131.3 (C), 147.6 (CH), 150.5 (C), 152.0 (CH),
153.0 (C). ESIMS, m/z: 377 (MNa+, for Cl35), 379 (MNa+, for
Cl37). Anal. Calcd for C15H19ClN4O4: C, 50.78; H, 5.40; N, 15.79.
Found: C, 50.72; H, 5.32; N, 15.50.
27. 1H NMR (D2O, 300 MHz): δ 1.52 (brs, 2H), 1.77 (brs, 4H),
2.50 (m, 1H), 3.18-3.33 (s, 6H at δ 3.29, merged with a m, 2H),
3.78 (d, 1H, J ) 8.5 Hz), 4.05 (m, 2H), 4.49 (d, 1H, J ) 10.5 Hz),
5.04 (t, 1H, J ) 10.8 Hz), 8.04 (s, 2H). ESIMS, m/z: 364 (MH)+,
386 (MNa)+.
23. mp 57-58 °C. [R]29D -67.8 (c 1.06, CHCl3). IR (KBr): νmax
1
3492, 1611, 1385, 1038, 856 cm-1. H NMR (CDCl3, 500 MHz):
δ 2.38 (d, 1H, J ) 17.5 Hz), 3.05 (dd, 1H, J ) 1.2, 17.5 Hz), 3.40
(m, 1H), 3.69 (dd, 1H, J ) 4.0, 9.5 Hz), 3.74 (dd, 1H, J ) 3.0, 8.7
Hz), 3.83 (d, 1H, J ) 12.9 Hz), 3.98 (dd, 1H, J ) 6.8, 9.3 Hz),
4.05 (d, 1H, J ) 12.9 Hz), 4.19-4.24 (m, 2H), 4.29 (brs, 1H),
5.72 (m, 1H), 6.00 (m, 1H), 7.24-7.38 (m, 5H). 13C NMR (CDCl3,
75 MHz): δ 38.5 (CH2), 48.5 (CH), 60.8 (CH2), 70.6 (CH2), 70.7
(CH), 70.8 (CH2), 81.1 (CH), 93.2 (C), 127.4 (CH), 128.3 (2 ×
CH), 129.0 (2 × CH), 130.0 (CH), 134.9 (CH), 137.2 (C). FABMS,
m/z: 274 (MH)+. Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01;
N, 5.12. Found: C, 70.11; H, 7.00; N, 5.06.
24. [R]29 -75.9 (c 1.54, CHCl3). IR (KBr): νmax 1716, 1614,
D
1455, 1322, 1180, 1024, 712 cm-1. H NMR (CDCl3, 300 MHz):
1
(1S,2R,3R,4R,5R)-2-(6-Aminopurin-9-yl)-3-hydroxymethyl-6-
oxa-spiro[4.5]decane-1,4-diol (28). Compound 26 (28 mg, 0.08
mmol) was dissolved in a saturated solution of ammonia in MeOH
(5 mL) and heated at 100 °C in a sealed tube for 40 h. The sealed
tube was cooled, broken, and NH3 gas was removed by heating at
40 °C. The solvent was evaporated to obtain a crude mass, which
δ 2.47 (d, 1H, J ) 18.0 Hz), 3.11 (d, 1H, J ) 18.0 Hz), 3.38 (m,
1H), 3.72-3.81 (m, 2H), 3.88 (d, 1H, J ) 8.3 Hz), 4.00 (dd, 1H,
J ) 6.5, 9.5 Hz), 4.08 (d, 1H, J ) 12.6 Hz), 4.25 (t-like, 1H, J )
8.0 Hz), 5.43 (s, 1H), 5.69 (m, 1H), 6.14 (m, 1H), 7.29-7.39 (m,
5H), 7.61 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 39.0 (CH2), 48.3
(CH), 60.9 (CH2), 70.8 (CH2), 70.9 (CH), 71.1 (CH2), 82.2 (CH),
92.1 (C), 126.6 (CH), 127.4 (CH), 128.3 (2 × CH), 129.2 (2 ×
CH), 136.8 (C), 137.6 (CH), 160.2 (CH). EIMS, m/z: 301 (M+),
272, 256. Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.49; H, 6.31; N, 4.48.
(31) 1H NMR (D2O, 300 MHz): δ 1.47 (m, 2H), 1.62 (m, 2H), 1.69
(m, 2H), 2.13 (m, 1H), 3.25-3.38 (m, 2H), 3.56 (d, 1H, J ) 9.0 Hz), 3.68
(d, 2H, J ) 5.5 Hz), 3.93 (t, 2H, J ) 5.5 Hz). ESIMS, m/z: 218 (MH)+.
J. Org. Chem, Vol. 71, No. 16, 2006 5989

Sahabuddin et al.
was purified by flash chromatography using reverse phase material
and water as eluent to furnish 28 (22 mg, 83%) as a foamy solid.
28. mp 124-125 °C (shrinks), 175-177 °C (melts). [R]29D -37.9
(c 0.35, CH3OH). IR (KBr): νmax 3343, 3219, 1647, 1603, 1079,
(1R,5R,8R,9R,10R)-9-(5-Amino-6-chloropyrimidin-4-ylamino)-
8-hydroxymethyl-6-oxa-spiro[4.5]decane-1,10-diol (32). Com-
pound 20 (130 mg, 0.43 mmol) was hydrogenolyzed, and the
aminospirocycle thus obtained was converted to the chloropyrimi-
dine derivative 32 (65 mg, 44%) as gum as described earlier (in
the preparation of 29).
1
1040 cm-1. H NMR (D2O, 300 MHz): δ 1.51 (brs, 2H), 1.77
(brs, 4H), 2.51 (m, 1H), 3.22-3.34 (m, 2H), 3.79 (d, 1H, J ) 8.6
Hz), 4.05 (m, 2H), 4.51 (d, 1H, J ) 10.5 Hz), 5.05 (t, 1H, J )
10.5 Hz), 8.10 (s, 1H), 8.12 (s, 1H). 13C NMR (D2O, 300 MHz):
δ 19.1 (CH2), 25.1 (CH2), 29.9 (CH2), 45.7 (CH), 59.3 (CH), 59.6
(CH2), 65.7 (CH2), 76.9 (CH), 77.6 (C), 78.2 (CH), 118.9 (C), 142.1
(CH), 150.5 (C), 152.9 (CH), 155.9 (C). ESIMS, m/z: 336 (MH)+,
358 (MNa)+. Anal. Calcd for C15H21N5O4: C, 53.72; H, 6.31; N,
20.88. Found: C, 53.48; H, 6.25; N, 20.60.
32. [R]25 -8.3 (c 1.17, MeOH). IR (KBr): νmax 3392, 1642,
D
1
1579, 1501, 1424, 1110, 1032, 855, 758 cm-1. H NMR (D2O,
300 MHz): δ 1.56-1.72 (m, 4H), 1.82 (m, 1H), 2.03 (m, 1H),
2.14 (m, 1H), 3.66 (dd, 1H, J ) 4.0, 11.0 Hz), 3.71-3.80 (m, 2H),
3.87 (dd, 1H, J ) 3.0, 12.5 Hz), 3.94 (d, 1H, J ) 3.0 Hz), 4.40 (d,
1H, J ) 3.3 Hz), 4.57 (dd, 1H, J ) 3.0, 5.4 Hz), 7.80 (s, 1H). 13
C
NMR (D2O, 75 MHz): δ 19.6 (CH2), 33.1 (CH2), 33.7 (CH2), 38.4
(CH), 50.2 (CH), 59.9 (CH2), 61.8 (CH2), 68.5 (CH), 73.8 (CH),
89.8 (C), 123.2 (C), 140.2 (C), 148.0 (CH), 153.3 (C). ESIMS,
m/z: 345 (MH+, for Cl35), 347 (MH+, for Cl37). Anal. Calcd for
C14H21ClN4O4: C, 48.77; H, 6.14; N, 16.25. Found: C, 48.52; H,
6.12; N, 16.13.
(1R,5R,8S,9S,10R)-9-(5-Amino-6-chloropyrimidin-4-ylamino)-
8-hydroxymethyl-6-oxa-spiro[4.5]decane-1,10-diol (29). A solu-
tion of 19 (130 mg, 0.426 mmol) in dry ethanol (20 mL) was
hydrogenolyzed with Pd/C (10%, 40 mg) and cyclohexene (2 mL)
as described earlier. Usual workup followed by drying (P2O5) of
the residue yielded a trihydroxy aminospirocycle (88 mg) as a thick
oil. This oil was dissolved in dry n-BuOH and treated with 5-amino-
4,6-dichloro pyrimidine (91 mg, 0.56 mmol) and Et3N (2 mL) (using
procedure as adopted for the preparation of 25). Usual workup and
purification by flash chromatography using H2O-MeOH (9:1)
furnished 29 (102 mg, 80%) as a foamy solid.
(1R,5R,8R,9R,10R)-9-(6-Dimethylaminopurin-9-yl)-8-hydroxy-
methyl-6-oxa-spiro[4.5]decane-1,10-diol (33). To a solution of 32
(50 mg, 0.145 mmol) in freshly distilled dry DMF (4 mL) were
added p-TSA (42 mg, 0.218 mmol) and HC(OEt)3 (2 mL); the
mixture was stirred under N2 at 10 °C for 16 h and then at room
temperature for 8 h. The solvent was removed in vacuo to a gummy
residue. This residue was dissolved in MeOH (5 mL), and Dowex-
OH- resin was added portionwise to neutralize the acid. The crude
nucleoside was purified by reverse phase column chromatography
using water-MeOH as eluent to furnish 33 (8 mg, 15%) as an
amorphous solid.
29. mp 170-171 °C. [R]26 -62.4 (c 7.8, MeOH). IR (KBr):
D
ν
max 3362, 1585, 1465, 1424, 1103, 1030, 853 cm-1. 1H NMR (D2O,
300 MHz): δ 1.50-1.71 (m, 3H), 1.88-1.96 (m, 3H), 2.26 (m,
1H), 3.69-3.77 (m, 4H), 3.99 (t-like, 1H, J ) 5.5 Hz), 4.03 (d,
1H, J ) 10.4 Hz), 4.27 (dd, 1H, J ) 4.5, 10.4 Hz), 7.80 (s, 1H).
13C NMR (D2O, 75 MHz): δ 20.2 (CH2), 26.3 (CH2), 33.0 (CH2),
40.1 (CH), 53.2 (CH), 58.5 (CH2), 61.3 (CH2), 67.1 (CH), 80.8
(CH), 88.2 (C), 123.4 (C), 140.1 (C), 148.1 (CH), 154.1 (C).
ESIMS, m/z: 345 (MH+, for Cl35), 347 (MH+, for Cl37), 367
(MNa+, for Cl35), 369 (MNa+, for Cl37). Anal. Calcd for C14H21-
ClN4O4: C, 48.77; H, 6.14; N, 16.25. Found: C, 48.58; H, 6.02;
N, 16.05.
(1R,5R,8S,9S,10R)-9-(6-Chloropurin-9-yl)-8-hydroxymethyl-
6-oxa-spiro[4.5]decane-1,10-diol (30). Compound 29 (48 mg,
0.139 mmol) dissolved in dry DMF (4 mL) was converted into the
foamy material 30 (40 mg, 80%) using HC(OEt)3 (2 mL) and p-TSA
(40 mg, 0.209 mmol) through the procedure described in the
preparation of 26.
33. 1H NMR (DMSO-d6, 300 MHz): δ 1.58-1.67 (m, 4H), 1.85
(m, 1H), 2.00-2.09 (m, 2H), 3.07 (d, 1H, J ) 10.5 Hz), 3.85 (brs,
3H), 4.14 (brs, 1H), 4.31 (brs, 1H), 4.55 (brs, 1H), 4.90 (brs, 1H),
5.10 (brs, 1H), 5.75 (brs, 1H), 8.22 (s, 1H), 8.32 (s, 1H), the signal
1
for NMe2 merged under solvent peak. H NMR (DMSO-d6, 300
MHz at 60 °C): δ 1.57-1.71 (m, 4H), 1.90 (m, 1H), 2.05 (m,
1H), 2.21 (m, 1H), 3.18 (d, 1H, J ) 10.5 Hz), 3.49 (s, 6H, NMe2),
3.77 (t-like, 1H, J ) 8.5 Hz), 3.90 (brs, 1H), 4.20 (brs, 1H), 4.31
(brs, 1H), 4.59 (brs, 1H), 5.19 (brd, 1H, J ) 3.0 Hz), 5.55 (brs,
1H), 8.21 (s, 1H), 8.22 (s, 1H). 13C NMR (DMSO-d6, 75 MHz):
δ 20.7 (CH2), 35.0 (CH2), 35.5 (CH2), 38.8 (CH), 54.8 (CH), 58.9
(CH2), 61.9 (CH2), 67.9 (CH), 72.5 (CH), 90.2 (C), 119.5 (C), 140.0
(CH), 151.2 (C), 152.4 (CH), 155.2 (C), C-signal due to NMe2
merged under solvent peak. ESIMS, m/z: 364 (MH)+, 386 (MNa)+.
Anal. Calcd for C17H25N5O4: C, 56.18; H, 6.93; N, 19.27. Found:
C, 56.10; H, 6.72; N, 19.02.
30. [R]26D -105.8 (c 1.26, MeOH). IR (KBr): νmax 3393, 1593,
1565, 1340, 1219, 1088 cm-1. 1H NMR (D2O, 300 MHz): δ 1.53-
1.74 (m, 3H), 2.00 (m, 3H), 2.39 (m, 1H), 3.48 (dd, 1H, J ) 5.2,
11.0 Hz), 3.77-3.93 (m, 3H), 4.03 (t, 1H, J ) 6.5 Hz), 4.92 (d,
1H, J ) 11.8 Hz), 4.99 (dd, 1H, J ) 4.7, 11.8 Hz), 8.64 (s, 1H),
8.69 (s, 1H). 13C NMR (DMSO-d6, 75 MHz): δ 20.4 (CH2), 23.5
(CH2), 32.9 (CH2), 42.5 (CH), 57.1 (CH2), 58.2 (CH), 60.4 (CH2),
63.9 (CH), 81.1 (CH), 86.9 (C), 130.9 (C), 146.9 (CH), 148.9 (C),
151.4 (CH), 152.4 (C). ESIMS, m/z: 377 (MNa+, for Cl35), 379
(MNa+, for Cl37). Anal. Calcd for C15H19ClN4O4: C, 50.78; H,
5.40; N, 15.79. Found: C, 50.53; H, 5.25; N, 15.61.
(1R,3R,6R,7S,8R,9S)-1-Allyloxy-5-benzyl-4-oxa-5-aza-tricyclo-
[4.2.1.03,7]nonane-8,9-diol (35). Compound 21 (75 mg, 0.31 mmol)
was converted to the anomeric mixture of 1,2-dihydroxy derivative
(45 mg, 73%) using 4% H2SO4 in CH3CN-H2O (3:1) (25 mL).
To a solution of the above material (0.23 mmol) in dry EtOH (25
mL) was added N-benzyl hydroxylamine (34 mg, 0.28 mmol), and
the solution was heated at reflux for 4 h. The solvent was evaporated
in vacuo to afford a gummy residue, which was purified by column
chromatography on silica gel using EtOAc-petroleum ether (3:
22) as the eluent to furnish 35 (52 mg, 75%) as a crystalline solid.
(1R,5R,8S,9S,10R)-9-(6-Aminopurin-9-yl)-8-hydroxymethyl-
6-oxa-spiro[4.5]decane-1,10-diol (31). Chloropurine 30 (35 mg,
0.099 mmol) was converted into aminopurine 31 (28 mg, 85%) as
a foamy solid using the same procedure as described previously
for 28.
35. mp 159-160 °C. [R]29 +82.9 (c 0.96, CHCl3). IR (KBr):
D
νmax 3509, 3354, 1645, 1308, 1176, 1072, 1050, 753, 732 cm-1
.
1H NMR (CDCl3, 300 MHz): δ 1.52 (d, 1H, J ) 13.5 Hz), 1.75
(dd, 1H, J ) 7.5, 13.5 Hz), 3.08 (dt, 1H, J ) 2.0, 5.3 Hz), 3.16
(brd, 1H, J ) 4.3 Hz, exchangeable), 3.48 (brs, 1H, exchangeable),
3.78 (d, 1H, J ) 12.9 Hz), 3.84 (d, 1H, J ) 5.0 Hz), 3.91 (d, 1H,
J ) 12.9 Hz), 3.95 (brs, 1H), 4.01 (dd, 1H, J ) 5.5, 12.0 Hz with
fine splitting), 4.09 (dd, 1H, J ) 6.0, 12.0 Hz with fine splitting),
4.14 (brs, 1H), 4.50 (dd, 1H, J ) 5.7, 7.2 Hz), 5.18 (dd, 1H, J )
1.2, 10.2 Hz), 5.30 (dd, 1H, J ) 1.5, 17. 0 Hz), 5.89-6.02 (m,
1H), 7.27-7.37 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 33.8
(CH2), 48.6 (CH), 63.3 (CH2), 66.6 (CH2), 73.2 (CH), 73.4 (CH),
78.5 (CH), 82.4 (C), 117.3 (CH2), 127.4 (CH), 128.3 (2 × CH),
129.1 (2 × CH), 134.6 (CH), 136.6 (C), one CH not discernible.
31. mp: 99-100 °C (shrinks), 184-185 °C (melts). [R]26D -99.4
(c 0.65, MeOH). IR (KBr): νmax 3342, 1649, 1604, 1479, 1381,
1
1084, 1044, 953, 648 cm-1. H NMR (D2O, 300 MHz): δ 1.46-
1.75 (m, 3H), 1.92-2.07 (m, 3H), 2.30 (m, 1H), 3.37 (dd, 1H, J )
4.5, 11.0 Hz), 3.73-3.88 (m, 3H), 4.00 (t, 1H, J ) 6.4 Hz), 4.79-
4.94 (2H, merged with HOD signal), 8.13 (s, 1H), 8.19 (s, 1H).
13C NMR (D2O, 75 MHz): δ 20.3 (CH2), 24.9 (CH2), 32.8 (CH2),
42.0 (CH), 57.4 (CH), 58.4 (CH2), 61.8 (CH2), 64.9 (CH), 81.7
(CH), 88.5 (C), 119.0 (C), 141.5 (CH), 149.9 (C), 153.0 (CH), 156.0
(C). ESIMS, m/z: 358 (MNa)+. Anal. Calcd for C15H21N5O4: C,
53.72; H, 6.31; N, 20.88. Found: C, 53.70; H, 6.28; N, 20.80.
5990 J. Org. Chem., Vol. 71, No. 16, 2006

Spiroannulated Carbanucleosides and Nucleosides
ESIMS, m/z: 326 (MNa)+, 304 (MH)+. Anal. Calcd for C17H21-
NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.09; H, 6.91; N,
4.38.
Cl37). Anal. Calcd for C12H13ClN4O4: C, 46.09; H, 4.19; N, 17.92.
Found: C, 45.88; H, 4.18; N, 17.75.
(1R,2S,3R,4S,5R,7R)-3-(6-Aminopurin-9-yl)-bicyclo[2.2.1]hep-
tane-1,2,5,7-tetraol (39). Chloropurine 38 (40 mg, 0.128 mmol)
was converted to 39 (31 mg, 83%) as foam (hygroscopic) through
amination as described earlier for the preparation of 31.
(1R,3R,6R,7S,8R,9S)-5-Benzyl-4-oxa-5-aza-tricyclo[4.2.1.03,7]-
nonane-1,8,9-triol (36). A solution of 16 (500 mg, 2.52 mmol) in
4% H2SO4 in CH3CN-H2O (3:1) 25 mL) was stirred at room
temperature for 24 h. Usual workup afforded the crude anomeric
mixture of 1,2-dihydroxy derivative (287 mg), which was used in
the next step without further purification. N-Benzyl hydroxylamine
(258 mg, 2.1 mmol) was added to a solution of the above anomeric
mixture (280 mg, 1.77 mmol) in dry ethanol (30 mL), and the
solution was heated at reflux for 4 h. The solvent was evaporated
in vacuo to a gummy residue, which was purified by column
chromatography on silica gel using with an EtOAc-petroleum ether
(7:13) mixture as eluent, affording 36 (326 mg, 70%) as an
amorphous solid.
39. [R]26 -11.2 (c 0.56, MeOH). IR (KBr): νmax 3386 (br),
D
3159 (br), 1660, 1402 cm-1. H NMR (D2O, 300 MHz): δ 1.44
1
(dd, 1H, J ) 3.8, 13.5 Hz), 2.22 (dd, 1H, J ) 10.8, 13.5 Hz), 2.79
(m, 1H), 3.93 (s, 1H), 4.22 (m, 1H), 4.61 (1H, merged with HOD),
5.21 (t, 1H, J ) 3.9 Hz), 8.22 (s, 1H), 8.40 (s, 1H). 13C NMR
(D2O, 75 MHz): 39.9 (CH2), 46.4 (CH), 65.1 (CH), 66.7 (CH),
75.5 (CH), 78.0 (CH), 80.1 (C), 118.7 (C), 144.0 (CH), 148.8 (CH),
149.8 (C), 153.1 (C). ESIMS, m/z: 294 (MH)+. Anal. Calcd for
C12H15N5O4: C, 49.14; H, 5.16; N, 23.88. Found: C, 49.02; H,
5.08; N, 23.60.
(1S,4S,7R,8S,9R,10S)-6-Benzyl-2,5-dioxa-6-aza-tricyclo[5.2.1.04,8]-
decane-9,10-diol (42). Compound 4029 (500 mg, 2.53 mmol) was
treated with 4% H2SO4 in CH3CN-H2O (3:1) (25 mL) following
the method described earlier for 35. Usual workup followed by
reaction of the generated hemi-acetal with N-benzyl hydroxylamine
(340 mg, 2.76 mmol) in dry EtOH (30 mL) furnished 42 (405 mg,
61%) as a white crystalline solid material after purification by
column chromatography using EtOAc-petroleum ether (3:22) as
the eluent.
36. mp 107-108 °C. [R]27 +52.4 (c 0.99, MeOH). IR (KBr):
D
ν
max 3423, 3253, 1160, 1118, 752, 717, 694 cm-1. 1H NMR (C5D5N,
300 MHz): δ 1.72 (d, 1H, J ) 13.0 Hz), 2.01 (dd, 1H, J ) 7.3,
13.0 Hz), 3.33 (m, 1H), 3.88 (d, 1H, J ) 13.0 Hz), 4.06 (d, 1H, J
) 13.0 Hz), 4.27 (m, 2H), 4.37 (brs, 1H), 4.56 (t-like, 1H, J ) 6.5
Hz), 6.15 (d, 1H, J ) 3.9 Hz, exchangeable), 6.95 (brs, 1H,
exchangeable), 7.12 (d, 1H, J ) 4.7 Hz, exchangeable), 7.22-
7.31 (m, 3H), 7.49 (d, 2H, J ) 7.0 Hz). 13C NMR (D2O, 75 MHz):
δ 39.1 (CH2), 49.1 (CH), 63.1 (CH2), 73.7 (CH), 74.3 (CH), 78.0
(C), 79.0 (CH), 79.5 (CH), 128.5 (CH), 129.1 (2 × CH), 130.3 (2
× CH), 136.3 (C). FABMS, m/z: 264 (MH)+. Anal. Calcd for
C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.59; H, 6.52;
N, 5.16.
42. mp 166-167 °C. [R]28 +39.5 (c 2.3, CHCl3). IR (neat):
D
ν
max 3351 (br), 1343, 1119, 1082, 1056, 728 cm-1. 1H NMR (CDCl3
+ D2O, 300 MHz): δ 3.47 (m, 1H), 3.55 (s, 2H), 3.78 (d, 1H, J )
13.0 Hz), 3.83 (d, 1H, J ) 6.0 Hz), 3.94 (t-like, 2H, J ) 6.3 Hz),
4.06 (s, 1H), 4.56 (partially merged d, 1H, J ) 10.0 Hz), 4.59 (s,
1H), 7.34 (m, 5H). 13C NMR (DMSO-d6, 75 MHz): δ 51.0 (CH),
62.4 (CH2), 62.7 (CH2), 71.5 (CH), 77.8 (CH), 77.9 (CH), 82.2
(CH), 84.2 (CH), 127.9 (CH), 128.9 (2 × CH), 130.0 (2 × CH),
138.7 (C). ESIMS, m/z: 264 (MH+). Anal. Calcd for C14H17NO4:
C, 63.87; H, 6.51; N, 5.32. Found: C, 63.63; H, 6.47; N, 5.08.
(1S,4S,5S,6R,7S,8R)-6-(5-Amino-6-chloro-pyrimidin-4-ylamino)-
2-oxa-bicyclo[3.2.1]octane-4,7,8-triol (43). Compound 42 (200 mg,
0.76 mmol) in dry ethanol (20 mL) was hydrogenolyzed using Pd/C
(10%, 40 mg) and cyclohexene (2 mL) by refluxing under N2 for
5 h. Usual workup furnished the corresponding trihydroxy amine,
which was dried (P2O5) for further reaction. This amine (114 mg,
0.65 mmol) in dry n-BuOH was coupled with 5-amino-4,6-
dichloropyrimidine (160 mg, 0.975 mmol) in the presence of Et3N
(2 mL) following the procedure described earlier for 37 to afford
43 (80 mg, 41%) as a foam.
(1R,2S,3R,4S,5R,7R)-3-(5-Amino-6-chloro-pyrimidin-4-ylami-
no)-bicyclo[2.2.1]heptane-1,2,5,7-tetraol (37). Compound 36 (200
mg, 0.76 mmol) dissolved in ethanol (20 mL) was hydrogenolyzed
in the presence of Pd/C (50 mg) and cyclohexene (2 mL) at the
refluxing temperature under N2 for 5 h. The catalyst was filtered
off, and the solvent was evaporated in vacuo to obtain the crude
amine (120 mg), which was dried (over P2O5) and used in the next
step. The crude amine (120 mg, 0.69 mmol) dissolved in dry
n-BuOH was reacted with 5-amino-4,6-dichloropyrimidine (135 mg,
0.82 mmol) in the presence of Et3N (2 mL) as described earlier for
29. Usual workup and purification by flash chromatography on
reverse phase material eluting with water furnished 37 (104 mg,
50%) as a foamy solid.
37. [R]27 +35.8 (c 0.85, MeOH). IR (KBr): νmax 3504, 3415,
D
3301, 1585, 1510, 1432, 1340, 1060, 1003, 850, 637 cm-1. 1H NMR
(D2O, 300 MHz): δ 1.32 (dd, 1H, J ) 4.0, 13.4 Hz), 2.17 (dd, 1H,
J ) 10.7, 13.4 Hz), 2.44 (dd, 1H, J ) 2.4, 4.0 Hz), 3.58 (t, 1H, 2.4
Hz), 3.83 (s, 1H), 4.35 (m, 1H), 4.77 (s, 1H), 7.80 (s, 1H). 13C
NMR (D2O, 75 MHz): δ 39.7 (CH2), 45.1 (CH), 62.0 (CH), 67.9
(CH), 78.3 (CH), 79.9 (C), 81.0 (CH), 123.0 (C), 140.4 (C), 148.8
(CH), 154.5 (C). FABMS, m/z: 303 (MH+, for Cl35), 305 (MH+,
for Cl37), 325 (MNa+, for Cl35), 327 (MNa+, for Cl37). Anal. Calcd
for C11H15ClN4O4: C, 43.64; H, 4.99; N, 18.51. Found: C, 43.48;
H, 4.88; N, 18.35.
43. mp 225-226 °C (dec). [R]28 -3.3 (c 1.35, D2O). IR
D
(KBr): νmax 3443, 3388, 3312, 1640, 1585, 1503, 1423, 1325, 1037,
1
781 cm-1. H NMR (D2O, 300 MHz): δ 2.89 (m, 1H), 3.27 (t,
1H, J ) 11.0 Hz), 3.81-3.88 (m, 2H), 3.93 (s, 1H), 4.02-4.11
(m, 2H), 4.43 (t, 1H, J ) 4.6 Hz), 7.89 (s, 1H). 13C NMR (D2O,
75 MHz): δ 48.8 (CH), 63.4 (CH), 64.6 (CH2), 67.8 (CH), 74.9
(CH), 79.6 (CH), 81.2 (CH), 123.1 (C), 140.6 (C), 149.0 (CH),
155.2 (C). ESIMS, m/z: 325 (MNa+, for Cl35), 327 (MNa+, for
Cl37). Anal. Calcd for C11H15ClN4O4: C, 43.64; H, 4.99; N, 18.51.
Found: C, 43.60; H, 4.89; N, 18.26.
(1R,2S,3R,4S,5R,7R)-3-(6-Chloropurin-9-yl)-bicyclo[2.2.1]hep-
tane-1,2,5,7-tetraol (38). Compound 37 (165 mg, 0.546 mmol) in
dry DMF (4 mL) was treated with HC(OEt)3 (2 mL) in the presence
of p-TSA (156 mg, 0.819 mmol) as described earlier for the
preparation of 30. Usual workup as well as purification afforded
38 (119 mg, 70%) as a foamy solid.
(1S,4S,5S,6R,7S,8R)-6-(6-Chloropurin-9-yl)-2-oxa-bicyclo-
[3.2.1]octane-4,7,8-triol (44). Compound 43 (165 mg, 0.55 mmol)
was dissolved in dry DMF (4 mL) and treated with HC(OEt)3 (2
mL) and p-TSA‚H2O (156 mg, 0.82 mmol) using the previously
described procedure. Usual workup as well as purification of the
crude residue furnished 44 (125 mg, 73%) as a foamy material.
38. [R]26 -56.5 (c 0.75, MeOH). IR (KBr): νmax 3393, 1593,
D
1402, 1222, 1095, 1014, 638 cm-1. 1H NMR (D2O, 300 MHz): δ
1.45 (dd, 1H, J ) 3.6, 13.5 Hz), 2.22 (dd, 1H, J ) 10.7, 13.5 Hz),
2.83 (brs, 1H), 3.94 (s, 1H), 4.22 (m, 1H), 4.67 (1H, merged with
HOD), 5.30 (t-like, 1H, J ) 3.9 Hz), 8.64 (s, 1H), 8.73 (s, 1H).
13C NMR (D2O, 75 MHz): δ 39.8 (CH2), 46.1 (CH), 65.4 (CH),
66.6 (CH), 75.3 (CH), 77.9 (CH), 80.1 (C), 131.1 (C), 148.1 (CH),
149.9 (C), 151.8 (CH), 152.4 (C). ESIMS, m/z: 313 (MH+, for
Cl35), 315 (MH+, for Cl37), 335 (MNa+, for Cl35), 337 (MNa+, for
44. mp 216-218 °C (dec). [R]26 -15.5 (c 0.86, MeOH). IR
D
(KBr): νmax 3333, 1592, 1342, 1224, 1041, 946, 820 cm-1. 1H NMR
(D2O, 300 MHz): δ 3.36-3.43 (m, 2H), 3.81 (dd, 1H, J ) 7.0,
12.0 Hz), 3.94-3.99 (m, 2H), 4.08 (s, 1H), 5.28 (t, 1H, J ) 5.3
Hz), 5.53 (dd, 1H, J ) 1.4, 5.0 Hz), 8.70 (s, 1H), 8.87 (s, 1H). 13
C
NMR (D2O, 75 MHz): δ 50.1 (CH), 64.1 (CH2), 65.6 (CH), 66.8
(CH), 73.2 (CH), 74.4 (CH), 81.5 (CH), 131.4 (C), 146.9 (CH),
150.2 (C), 151.9 (CH), 153.1 (C). ESIMS, m/z: 336 (MNa+, for
J. Org. Chem, Vol. 71, No. 16, 2006 5991

Sahabuddin et al.
Cl35), 338 (MNa+, for Cl37). Anal. Calcd for C12H13ClN4O4: C,
46.09; H, 4.19; N, 17.92. Found: C, 46.00; H, 4.02; N, 17.76.
(1S,4S,5S,6R,7S,8R)-6-(6-Aminopurin-9-yl)-2-oxa-bicyclo[3.2.1]-
octane-4,7,8-triol (45). Compound 44 (20 mg, 0.064 mmol) was
transformed into the foamy solid 45 (16 mg, 85%) by heating with
a saturated solution of methanolic ammonia, adopting a procedure
similar to that described earlier for the preparation of 28.
Acknowledgment. A grant from the Department of Science
and Technology (Govt. of India) supported this work. We
gratefully acknowledge the Council of Scientific and Industrial
Research for providing Senior Research Fellowships (to A.R.
and B.G.R.) and an Emeritus Scientist scheme (to B.A.). We
also thank EPSRC and the University of Reading for funds for
the ImagePlate System.
45. mp 219-220 °C (dec). [R]26 -14.9 (c 0.33, MeOH). IR
D
(KBr): νmax 3393, 3336, 1656, 1609, 1483, 1415, 1316, 1259, 1032,
729, 643 cm-1. 1H NMR (D2O, 300 MHz): δ 3.26 (brs, 1H), 3.36
(t, 1H, J ) 11.0 Hz), 3.79 (dd, 1H, J ) 7.0, 12.0 Hz), 3.90 (s, 1H),
3.92 (partially merged signal, 1H), 4.04 (s, 1H), 5.03 (t, 1H, J )
5.4 Hz), 5.36 (d, 1H, J ) 3.9 Hz, with fine splitting), 8.13 (s, 1H),
8.43 (s, 1H). 13C NMR (D2O, 75 MHz): δ 50.0 (CH), 64.2 (CH2),
64.8 (CH), 66.9 (CH), 73.5 (CH), 74.6 (CH), 81.4 (CH), 119.2
(C), 141.3 (CH), 150.5 (C), 152.5 (CH), 155.6 (C). ESIMS, m/z:
316 (MNa)+, 294 (MH)+. Anal. Calcd for C12H15N5O4: C, 49.14;
H, 5.16; N, 23.88. Found: C, 48.90; H, 5.02; N, 23.58.
Supporting Information Available: Crystallographic data
(Table 1), cif files and ORTEP diagrams for 14, 19, 20, and 42,
experimental details for X-ray crystallography, general experimental
1
details, copies of H and 13C NMR spectra of 9-21, 23-26, 28-
1
39, 42-45, and the H NMR spectrum of 27. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0606554
5992 J. Org. Chem., Vol. 71, No. 16, 2006