Synthesis of Cyclopropyl-Fused Carbocyclic Nucleosides via the Regioselective Opening of Cyclic Sulfites

Article abstract of DOI:10.1021/jo990010m

The syntheses of some carbocyclic nucleosides that are conformationally locked as "northern" mimics of antiviral active, ring-expanded oxetanocin analogues are reported. The target compounds derived their rigid conformation from a common bicyclo[3.1.0]hexane template. The uracil (3a), cytosine (3b), and adenine (3c) analogues were synthesized from an intermediate cyclic sulfite (12a) that underwent selective ring opening with nucleophiles. Reaction of 12a with sodium azide provided access to the uracil and cytosine analogues (3a and 3b) after construction of the pyrimidine rings, and reaction with the sodium salt of adenine provided an efficient convergent approach to 3c. The preponderance of the undesired N-7 regioisomer obtained from the coupling of 12a with 2-amino-6-chloropurine was unanticipated. Hence, the diol derivative 11 was selectively protected and coupled under Mitsunobu conditions to give, after deprotection, the desired guanine analogue 3d. With the exception of the guanine analogue, the cyclic sulfite chemistry described here represents a useful alternative as a general approach to carbocyclic nucleosides. None of the target nucleosides 3a-d demonstrated significant antiviral activity against HIV-1, HSV-1, HSV-2, and HCMV. Relative to other conformationally rigid, northern carbocyclic analogues that have shown good anti-HSV and anti-HCMV activities, it is concluded that the hydroxymethyl group is a poor substitute for the hydroxyl group in these rigid bicyclic nucleoside templates.

Full text of DOI:10.1021/jo990010m

J . Org. Chem. 1999, 64, 4733-4741
4733
Syn th esis of Cyclop r op yl-F u sed Ca r bocyclic Nu cleosid es via th e
Regioselective Op en in g of Cyclic Su lfites†
Hyung Ryong Moon,‡ Hea Ok Kim,§ Moon Woo Chun,| and Lak Shin J eong*,‡
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea, Department of Industrial Safety and Hygiene, Kyungin Women’s College,
Incheon 407-050, Korea, and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Victor E. Marquez
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, NIH,
Bethesda, Maryland 20892
Received J anuary 4, 1999
The syntheses of some carbocyclic nucleosides that are conformationally locked as “northern” mimics
of antiviral active, ring-expanded oxetanocin analogues are reported. The target compounds derived
their rigid conformation from a common bicyclo[3.1.0]hexane template. The uracil (3a ), cytosine
(3b), and adenine (3c) analogues were synthesized from an intermediate cyclic sulfite (12a ) that
underwent selective ring opening with nucleophiles. Reaction of 12a with sodium azide provided
access to the uracil and cytosine analogues (3a and 3b) after construction of the pyrimidine rings,
and reaction with the sodium salt of adenine provided an efficient convergent approach to 3c. The
preponderance of the undesired N-7 regioisomer obtained from the coupling of 12a with 2-amino-
6-chloropurine was unanticipated. Hence, the diol derivative 11 was selectively protected and
coupled under Mitsunobu conditions to give, after deprotection, the desired guanine analogue 3d .
With the exception of the guanine analogue, the cyclic sulfite chemistry described here represents
a useful alternative as a general approach to carbocyclic nucleosides. None of the target nucleosides
3a -d demonstrated significant antiviral activity against HIV-1, HSV-1, HSV-2, and HCMV. Relative
to other conformationally rigid, northern carbocyclic analogues that have shown good anti-HSV
and anti-HCMV activities, it is concluded that the hydroxymethyl group is a poor substitute for
the hydroxyl group in these rigid bicyclic nucleoside templates.
In tr od u ction
thymidine shows a characteristic 2′-endo/3′-exo ring
pucker (2T3) resulting from the dominant gauche effect
interaction between the 4′-oxygen and the 3′-hydroxyl
group over the anomeric effect.8 Loss of the furanose
oxygen in carbathymidine, however, abolishes these two
effects, causing the carbocyclic ring to adopt a rare 1′-
exo pucker (1E, P ) 126°).5 In solution, 4′-oxonucleosides
exist in equilibrium between a 2′-endo/3′-exo (2T3, south-
ern, P ) 180°) conformation and a 2′-exo/3′-endo (3T2,
northern, P ) 0°) conformation separated by an energy
barrier in the range of 3-4 kcal/mol. However, when a
nucleoside or nucleotide binds to its target enzyme, only
one form of the two possible conformations takes part in
drug-receptor interactions.10 Since it is known that a
favorable energy difference of as low as 1.3 kcal/mol can
result in a 10-fold decrease in the binding constant of a
ligand with its receptor,11 differences in binding can vary
between 100- to 1000-fold, depending on the preferred
conformation of the nucleoside ligand. This conforma-
tional difference between 4′-oxonucleosides and the cor-
responding carbocyclic nucleosides may explain why
carbocyclic nucleosides, in general, show less potent
biological activity than their nucleoside counterparts.
The rationale for the synthesis of carbocyclic nucleo-
sides in which the furanose ring oxygen of 4′-oxonucleo-
sides is substituted by a methylene group was to stabilize
the hydrolytically and enzymatically scissile glycosyl
bond with minimal structural disturbances.1-4 However,
the fact that most conventional carbocyclic nucleosides
have generally exhibited poorer biological potencies than
the corresponding 4′-oxonucleosides would suggest that
the conformational differences between furanose and
cyclopentane rings might be partially responsible for the
observed differences in biological potency. J udging from
the published X-ray structures of some carbocyclic nu-
cleosides, they appear to crystallize with an unusual ring
pucker relative to 4′-oxonucleosides.5-7 For example,
* (Tel) 82-2-3277-3466. (Fax) 82-2-3277-2851. (E-mail) lakjeong@
mm.ewha.ac.kr.
† A preliminary account has been published in: J eong, L. S.;
Marquez, V. E. Tetrahedron Lett. 1996, 37, 2353.
‡ Ehwa Womans University.
§ Kyungin Women’s College.
| Seoul National University.
(1) Marquez, V. E.; Lim, M.-I. Med. Res. Rev 1986, 6, 1.
(2) Bothwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(3) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.
(4) Marquez, V. E. Carbocyclic Nucleosides. In Advances in Antiviral
Drug Design; Vol 2, De Clercq, E., Ed., J ai Press: Greenwich,
Connecticut, USA, 1996; Vol. 2, pp 89-146.
(5) Kalman, A.; Koritzanszky, T.; Beres, J .; Sagi, G. Nucleosides
Nucleotides 1990, 8, 1121.
(6) Kishi, T.; Moroui, M.; Nishikawa, M.; Kamiya, K.; Mizuno, K.
J . Chem. Soc. Chem. Commun. 1967, 852.
(7) Highcock, R. M.; Hilpert, H.; Myers, P. L.; Roberts, S. M.; Storer,
R. J . Chem. Soc., Perkin Trans 1 1991, 1127.
(8) Altona, C.; Sundaralingam, M. J . Am. Chem. Soc. 1972, 94, 8320.
(9) Saenger, W. Principles of Nucleic Acid Structure; Springer-
Verlag: New York, 1984.
(10) Wang, Z.; Quiocho, F. A. Biochemistry 1998, 37, 8314.
(11) Wang, S.; Milne, G. W. A.; Nicklaus, M. C.; Marquez, V. E.;
Lee, J .; Blumberg, P. M. J . Med. Chem. 1994, 37, 1326.
10.1021/jo990010m CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

4734 J . Org. Chem., Vol. 64, No. 13, 1999
Moon et al.
One of the strategies that can be used in carbocyclic
nucleosides to regain the ring pucker characteristic of
typical nucleosides is to construct them on a rigid bicyclic
system employing either oxirane or cyclopropane rings
fused to the five-member cyclopentane moiety.22-24 In this
report, we present the results of the cyclopropane-fused
alternative utilizing a bicyclo[3.1.0]hexane system to
generate analogues of ring-expanded oxetanocins carry-
ing different purine and pyrimidine bases. The selected
targets (3) represent conformationally rigid northern
conformers equivalent in conformation to the antivirally
active ring-enlarged oxetanocins 2a and 2b. The synthe-
sis of the target nucleosides was achieved linearly for the
pyrimidine analogues through a completely regioselective
ring-opening reaction of an intermediate cyclic sulfite
with sodium azide or directly, in a convergent manner,
by a similar reaction with the appropriate purine base.
F igu r e 1.
Resu lts a n d Discu ssion
Therefore, one can hypothesize that if a carbocyclic
nucleoside with a 1′-exo ring pucker was forced to take a
more conventional southern or northern conformation,
biological potency could be recovered.
The strategy for these syntheses was to utilize cyclic
sulfites25 as epoxide surrogates for the preparation of the
desired nucleosides. All syntheses started from our
versatile cyclopentenone 4, which underwent quantita-
tive reduction to the allylic alcohol 5 (Scheme 1).26
Simmons-Smith cyclopropanation of 5 produced the
bicyclo[3.1.0]hexane intermediate 6 in 90% yield.23 Acid-
catalyzed equilibration of 6 in acetone produced the
isomeric acetonide 7 (57%) with recovered starting mate-
rial (42%). Repeated isomerization afforded the desired
product 7 almost quantitatively. Oxidation of 7 with
tetrapropylammonium perruthenate(VII) (TPAP)27 and
N-methylmorpholine N-oxide (NMO) gave ketone 8 (100%),
which was converted to the 2-ylidene 9 (90%) after Wittig
reaction with methyltriphenylphosphonium bromide and
n-butyllithium at 0 °C. Hydroboration-oxidation28 of 9
proceeded through the favored attack of the borane from
the less hindered convex â-side to give preferentially 10a
over 10b by a 10:1 ratio. The primary hydroxyl group of
10a was treated with benzyl bromide to give the corre-
sponding benzyl ether (88%), which was followed by the
quantitative removal of the acetonide to give the cis-diol
11. Compound 11 was converted to the cyclic sulfite 12a ,
which served as a pseudo-glycosyl donor for the synthesis
of the target carbocyclic nucleosides. Because cyclic
sulfates are better leaving groups than the cyclic sulfites,
the cyclic sulfate 12b was also synthesized and tested
as an epoxide surrogate.29,30
Oxetanocin A [9-(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-
oxetanyl)adenine (1a )]12,13 (Figure 1) was the first re-
ported naturally occurring nucleoside containing a four-
membered sugar ring. Oxetanocin A, as well as the
carbocyclic analogues, cyclobutyl-A (1b) and cyclobutyl-G
(1c), showed potent anti-HIV activity in ATH8 cells.14,15
In addition, cyclobutyl-G (lobucavir) has shown excellent
activity against HSV-1, HSV-2, HCMV, murine CMV,
and HBV, and clyclobutyl-A appears to be more potent
than acyclovir against VZV.15-17
A ring-expanded analogue of oxetanocin A, 2′,3′-dideoxy-
3′-C-hydroxymethyl adenosine (2a ), was later shown to
have anti-HIV activity comparable to that of 1a ,18 and
the similarly branched cytosine analogue 2b was also
reported to be a very effective antiviral agent.19 In
support of these observations, a molecular modeling
study revealed that the more stable northern conformer
of 2a superimposed well on 1a and that the disposition
of the hydroxymethyl substituents was almost coincident.
This allowed the hydroxyl groups in 1a and 2a to be in
an almost identical location as in a natural 2′-deoxy
nucleoside.18 However, the corresponding carbocyclic,
ring-expanded analogue 2c was totally devoid of anti-
HIV activity in either CEM or ATH8 cells, probably
because of the unfavorable sugar conformation of the
cyclopentane ring.20,21
In addition to the cyclic sulfite/sulfate method, an
alternative approach shown in Scheme 2 was attempted.
(12) Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii,
A.; Takita, T. J . Antibiot. 1986, 39, 1623.
(13) Nakamura, H.; Hasegawa, S.; Shimada, N.; Fujii, A.; Takita,
T.; Iitaka, Y. J . Antibiot. 1986, 39, 1626.
(14) Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham,
H.; Herrin, T.; Plattner, J . J .; Erikson, J .; Clement, J .; Swanson, R.;
Shipkowtz, N.; Hardy, D.; Marsh, K.; Arnett, G.; Shannon, W.; Broder,
S.; Mitsuya, H. J . Med. Chem. 1990, 33, 1281.
(20) Boumchita, H.; Legraverend, M.; Bisagni, E. Heterocycles 1991,
32, 1785.
(21) Buenger, G.; Marquez, V. E. Tetrahedron Lett. 1992, 33, 3707.
(22) Rodriguez, J . B.; Marquez, V. E.; Nicklaus, M. C.; Barchi, J .
J .,J r. Tetrahedron Lett. 1993, 34, 6233.
(23) Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetra-
hedron Lett. 1994, 35, 2331.
(15) Hayashi, S. Norbeck, D. W.; Rosenbrook, W.; Fine, R. L.;
Matsukura, M.; Plattner, J . J .; Broder, S.; Mitsuya, H. Antimicrob.
Agents Chemother. 1990, 34, 287.
(16) Nishiyama, Y.; Yamamoto, N.; Yamada, Y.; Daikoku, T.;
Ishikawa, Y.-I.; Takahashi, K. J . Antibiot. 1989, 42, 1854.
(17) Slusarchyk, W. A.; Young, M. G.; Bisachi, G. S.; Hocksetin, D.
R.; Zahler, R. Tetrahedron Lett. 1989, 30, 6453.
(18) Tseng, C. K.-H.; Marquez, V. E.; Milne, G. W. A.; Wysocki, R.
J ., J r.; Mitsuya, H.; Shirasaki, T.; Driscoll, J . S. J . Med. Chem. 1991,
10, 291.
(19) Sterzycki, R. Z.; Martin, J . C.; Wittman, M.; Brankovan, V.;
Yang, H.; Hitchcock, M. J .; Mansuri, M. M. Nucleosides Nucleotides
1991, 10, 291.
(24) Rodriguez, J . B.; Marquez, V. E.; Nicklaus, M. C.; Mitsuya, H.;
Barchi, J . J ., J r. J . Med. Chem. 1994, 37, 3389.
(25) (a) Lohray, B. B. Synthesis 1992, 1035. (b) Lohray, B. B.; Ahuha,
J . R. J . Chem. Soc., Chem. Commun. 1991, 95. (c) Gao, Y.; Zepp, C. M.
Tetrahedron Lett. 1991, 32, 3155.
(26) Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markiva, A.; Priest,
M. A.; Khan, M. S.; Kaskar, B. J . Org. Chem. 1988, 53, 5709.
(27) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. Chem.
Commun. 1987, 1625.
(28) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. Tetrahedron
Lett 1989, 30, 1483.
(29) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(30) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655.

Cyclopropyl-Fused Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 13, 1999 4735
Sch em e 1
Sch em e 2
sulfite 12a was used throughout this work as the
preferred pseudo-glycosyl donor, despite its poorer leav-
ing group capability. Besides its synthetic utility, 12a
proved to be a very stable and easy reagent to store. The
rigid boat conformation of the bicyclo[3.1.0]hexane sys-
tem, which for these class of compounds has been
extensively confirmed by X-ray crystallography and NMR
analysis,22-24,36 makes the assignment of the stereochem-
istry particularly straightforward. The simplicity of the
NMR spectrum of the anticipated azide regioisomer 16,
where two H-C-C-H dihedral angles are close to 90°,
allows for an easy characterization. For example, irradia-
tion of the H-2 multiplet at δ 2.79 caused the H-3 doublet
at δ 4.28 to coalesce into a singlet. This situation could
not be the case for the alternative regioisomer (Figure
2). It is important to emphasize that this type of assign-
ment works only in this system and could not be applied
to the flexible, carbocyclic counterparts.
This method relied on the regioselective cleavage of
acetonide 10a to the diol derivative 13 after treatment
with methylmagnesium iodide (87%).31 Selective benzyl
protection of diol 13 to the monobenzylate 14 was
achieved using organotin chemistry (92%),32 and Barton
deoxygenation33 of the secondary alcohol in 14 afforded
the corresponding carbocyclic sugar 15 (90%). Unfortu-
nately, removal of the tert-butyl ether group from 15
under a variety of conditions led to extensive decomposi-
tion, possibly through an unstable carbocation intermedi-
ate. For that reason, this methodology was abandoned
in favor of the cyclic sulfite/sulfate approach.
In a model reaction to test the regioselective opening
of the cyclic sulfite versus the cyclic sulfate, the less
reactive cyclic sulfite 12a was treated with sodium azide
in DMF at 100 °C (Scheme 3), whereas the more reactive
cyclic sulfate 12b was reacted at 0 °C in the same solvent.
The cyclic sulfite provided a clean carbocyclic azide
product 16 in 81% yield, but the cyclic sulfate gave only
a 47% yield of the same product after hydrolytic cleavage
of the resulting sulfate with dilute sulfuric acid. This
result may reflect the greater instability of 12b even
under mild reaction conditions.34,35 Therefore, cyclic
The uracil derivative 3a was synthesized following a
linear approach from the carbocyclic azide 16 obtained
from cyclic sulfite 12a (Scheme 3). Silyl protection of the
carbocyclic azide 16 with tert-butyldimethylsilyl trifluo-
romethanesulfonate (96%), followed by catalytic hydro-
genation, gave the amino derivative 17 (100%). The uracil
ring was constructed from 17 according to published
methods37 to give 18. Before deoxygenation of the second-
ary alcohol in 18, the N3-position of the uracil moiety was
protected as the N3-benzoyl derivative (94%). Following
removal of the silyl ether group (90%), the secondary
alcohol was removed under Barton deoxygenation condi-
tions33 to give 19 (44%). Sequential removal of the N3-
benzoyl group with sodium methoxide and the benzyl
ethers by catalytic transfer hydrogenation provided the
target uracil nucleoside 3a (50%). This compound was
converted to the cytosine derivative 3b in the conven-
tional manner.38
For the synthesis of the adenine derivative 3c (Scheme
3), the adenine anion generated with NaH/18-crown-6 in
DMF at 80 °C was successfully condensed with cyclic
sulfite 12a at 120 °C to give 20 (50%), along with
(31) Kawana, M.; Emoto, S. Bull. Chem. Soc. J pn. 1980, 53, 230.
(32) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
(33) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans
1 1975, 1574.
(34) Ko, S. Y. J . Org. Chem. 1995, 60, 6250.
(35) Lang, H.; Moser, H. E. Helv. Chim. Acta 1994, 77, 1527.
(36) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford,
H., J r.; Feldman, R. J .; Mitsuya, H.; George, C.; Barchi, J . J ., J r. J .
Am. Chem. Soc. 1998, 120, 2780.
(37) Shealy, Y. F.; O′dell, C. A. J . Heterocycl. Chem. 1976, 13, 1015.
(38) Divakar, K. J .; Reese, C. B. J . Chem. Soc., Perkin Trans 1 1982,
1171.

4736 J . Org. Chem., Vol. 64, No. 13, 1999
Moon et al.
Sch em e 3
the case of the uracil analogue, provided the target
adenosine analogue 3c (83%).
Condensation of cyclic sulfite 12a with 2-amino-6-
chloropurine to obtain the guanine derivative resulted
in a very low yield (10-15%) of the desired product in
favor of the N-7 isomer. Therefore, the guanine derivative
3d was approached differently as shown in Scheme 4.
The diol 11 was selectively protected with tert-butyl-
diphenylsilyl chloride at 10 °C to give 21 (100%). Deoxy-
genation of 21 under Barton conditions33 (44%), followed
by desilylation with n-tetrabutylammonium fluoride,
gave the hydroxy derivative 22 (85%). Mitsunobu cou-
pling39 of 22 with 2-acetamido-6-chloropurine for 15 h at
65 °C afforded the protected nucleoside 23 (38%). Base-
catalyzed hydrolysis of the 6-chloro substituent with
concomitant loss of the N-acetyl group gave the protected
guanine derivative 24 (81%). As before, removal of the
benzyl ethers by catalytic transfer hydrogenation
afforded the final target guanine analogue 3d (93%). The
1H NMR spectrum of the target guanine analogue 3d also
conformed to the expected pattern observed and dis-
cussed previously for 3c.
F igu r e 2.
recovered starting material 12a and diol 11 (ca. 40-50%).
As before, the ring-opening reaction proceeded with
complete regioselectivity. Proton NMR spectroscopy of 20
also confirmed the structure unambiguously by virtue of
the same diagnostic coupling constants typical of the boat
conformation of the bicyclo[3.1.0]hexane system. Indeed,
irradiation of the H-2′ multiplet at δ 3.05 caused the H-3′
doublet at δ 4.12 to coalesce into a singlet. The secondary
hydroxyl group of 20 was deoxygenated under Barton
conditions33 (73%), and removal of the benzyl ethers
under catalytic transfer hydrogenation conditions, as in
The antiviral activity of the target nucleosides 3a -d
against HIV-1, HSV-1, HSV-2, and HCMV was investi-
gated. Unfortunately, all the compounds were neither
antivirally active nor cytotoxic to the host cells up to
concentrations of 100 µg/mL. To become biologically
active, nucleosides require conversion to the triphosphate
stage prior to interacting with target cellular or viral
(39) (a) Bannal, C.; Chavis, C.; Lucas, M. J . Chem. Soc., Perkin
Trans 1 1994, 1401. (b) J enny, T. F.; Horlacher, J .; Previsani, N.;
Benner, S. A. Helv. Chim. Acta 1992, 75, 1944.

Cyclopropyl-Fused Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 13, 1999 4737
Sch em e 4
of 623 (5.0 g, 17.2 mmol) and p-TsOH‚H2O (1.63 g, 8.59 mmol)
in acetone (100 mL) was refluxed for 2 h. NEt3 was added to
neutralize the mixture, and volatiles were removed. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate ) 3:1) to give 7 (2.85 g, 57%) as a
colorless syrup, together with recovered 6 (2.0 g): [R]25D ) 8.3°
(c 0.65, CHCl3); 1H NMR (CDCl3) δ 0.61 (dd, 1 H, J ) 5.4, 8.3
Hz), 1.12 (pseudo t, 1 H, J ) 4.1, 5.1 Hz), 1.29 (s, 3 H), 1.52 (s,
3 H), 1.60 (quintet, 1 H, J ) 4.5, 8.8 Hz), 2.33 (br s, 1 H), 3.12
(d, 1 H, J ) 10.3 Hz), 3.77 (d, 1 H, J ) 10.3 Hz), 4.51 (m, 3 H),
4.59 (pseudo t, 1 H, J ) 5.9, 7.0 Hz), 4.82 (pseudo t, 1 H, J )
5.7, 6.1 Hz), 7.25-7.39 (m, 5 H). Anal. Calcd for C17H22O4: C,
70.33; H, 7.63. Found: C, 70.27; H, 7.60.
enzymes. It was presumed that the rigid northern
conformation in these nucleosides (3a -d ) might make
them good substrates for the various cellular or viral
kinases responsible for nucleotide formation by virtue of
their conformational similarity with 1a and the most
stable conformers of 2a ,b. However, with just the nega-
tive antiviral results, it is impossible to know at which
stage the compounds failed as substrates. Relative to
other conformationally rigid northern carbocyclic ana-
logues that showed good anti-HSV and anti-HCMV
activities,40 it is safe to conclude at this moment that the
hydroxymethyl group is a poor substitute for the hydroxyl
group in these rigid bicyclic nucleoside templates.
In summary, we have accomplished the synthesis of
several cyclopropyl-fused carbocyclic nucleosides using
a cyclic sulfite intermediate as an epoxide surrogate.
Although cyclic sulfites have been sparsely used in
organic syntheses, they proved to be stable and suf-
ficiently reactive to warrant a more extensive application
as alternatives to epoxides. In addition, the operation is
simpler than with cyclic sulfates, which require ad-
ditional cleavage of the resulting sulfate. It can be
concluded that the cyclic sulfite described here represents
a useful alternative as a general approach to the syn-
thesis of carbocyclic nucleosides.41
(1R,3S,4S,5S)-1-[(Ben zyloxy)m et h yl]-3,4-(isop r op yli-
d en ed ioxy)-2-oxo-bicyclo[3.1.0]h exa n e (8). To a solution
of 7 (3.0 g, 0.01 mol), N-methylmorpholine N-oxide (1.83 g,
0.015 mol), and molecular seives (0.5 g/mmol, 5.19 g) in CH2-
Cl2 (2 mL/mmol) (20.7 mL) was added TPAP (0.18 g, 0.5 mmol)
at ambient temperature, and the mixture was stirred for 40
min. The dark mixture was filtered through a short silica gel
pad, washed with CH2Cl2, and evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate ) 3:1) to give 8 (3.0 g, 100%) as a colorless syrup: [R]25
D
) 33.2° (c 0.37, CHCl3); IR (neat) 1740 cm-1 (CdO); H NMR
1
(CDCl3) δ 1.30 (m, 1 H), 1.25 (s, 3 H), 1.49 (s, 3 H), 1.50 (m, 1
H), 2.31 (m, 1 H), 3.21 (d, 1 H, J ) 10.9 Hz), 4.08 (d, 1 H, J )
10.9 Hz), 4.15 (d, 1 H, J ) 8.1 Hz), 4.50 (m, 2 H), 4.92 (m, 1
H), 7.20-7.39 (m, 5 H). Anal. Calcd for C17H20O4: C, 70.82;
H, 6.99. Found: C, 70.80; H, 7.04.
(1S,3R,4S,5S)-1-[(Ben zyloxy)m et h yl]-3,4-(isop r op yli-
d en ed ioxy)-2-C-m eth ylen ebicyclo[3.1.0]h exa n e (9). To a
suspension of methyltriphenylphosphonium bromide (4.3 g,
12.0 mmol) in THF (20 mL) was added n-BuLi (7.5 mL, 1.6 M
in hexane, 12.0 mmol) at 0 °C, followed by the dropwise
addition of 8 (2.0 g, 6.9 mmol). The mixture was stirred further
at 0 °C for 30 min. Ether was added, and a white solid
precipitated out. The mixture was filtered through a short
silica gel pad, washed with ether, and evaporated. The residue
was purified by silica gel column chromatography (hexane/
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H and
13C NMR data were recorded on either 250 or 300 MHz NMR
spectrometers using tetramethylsilane (TMS) as an internal
standard. Chemical shifts are reported in ppm (δ), and
coupling constants are reported in hertz. The abbreviations
used are as follows: s (singlet), d (doublet), m (multiplet), q
(quartet), t (triplet), dd (doublet of doublet), td (triplet of
doublet), and br s (broad singlet). Elemental analyses were
performed by Atlantic Microlab, Inc., Norcross, GA and Ewha
Womans University, general instrument laboratory, Seoul,
Korea. Anhydrous benzene, methylene chloride, and THF were
distilled over CaH2, P2O5, and Na/benzophenone prior to use,
respectively.
ethyl acetate ) 4:1) to give 9 (1.8 g, 90%) as a colorless syrup:
1
[R]25 ) 43.3° (c 0.55, CHCl3); H NMR (CDCl3) δ 1.01 (dd, 1
D
H, J ) 4.8, 8.4 Hz), 1.25 (t, 1 H, J ) 4.5 Hz), 1.29 (s, 3 H),
1.49 (s, 3 H), 1.85 (m, 1 H), 3.42 (d, 1 H, J ) 10.5 Hz), 3.65 (d,
1 H, J ) 10.5 Hz), 4.50 (s, 2 H), 4.85 (m, 2 H), 5.29 (s, 2 H),
7.20-7.39 (m, 5 H). Anal. Calcd for C18H22O3: C, 75.50; H,
7.74. Found: C, 75.41; H, 7.77.
(1S,2R,3R,4S,5S)-1-[(Ben zyloxy)m eth yl]-2-h yd r oxy-3,4-
(isop r op ylid en ed ioxy)bicyclo[3.1.0]h exa n e (7). A solution
(1S ,2S ,3R ,4S ,5S )-1-[(Be n zyloxy)m e t h yl]-2-h yd r oxy-
m et h yl-3,4-(isop r op ylid en ed ioxy)b icyclo[3.1.0]h exa n e
(10a ) a n d Its C-2 Ep im er (10b). To a solution of 9 (2.4 g,
8.36 mmol) in THF (30 mL) was added BH3‚THF (16.72 mL,
(40) Siddiqui, M. A.; Ford, H., J r.; George, C.; Marquez, V. E.
Nucleosides Nucleotides 1996, 15, 235.
(41) Crimmins, M. T. Tetrahedron 1998, 54, 9229.

4738 J . Org. Chem., Vol. 64, No. 13, 1999
Moon et al.
1 M in THF, 16.72 mmol) at 0 °C. The mixture was stirred
further at 0 °C for 4 h. NaBO3‚H2O (2.75 g, 27.59 mmol) and
H2O (15 mL) were added carefully, and the mixture was stirred
at ambient temperature for 12 h. The mixture was diluted with
CH2Cl2 and H2O. The organic layer was washed with brine,
dried (MgSO4), and evaporated. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate ) 2:1)
to give 10a (2.30 g, 90%) and 10b (0.24 g, 9%) as colorless
syrups.
(1.5 mL) were added NaIO4 (0.080 g, 0.38 mmol) and RuCl3-
3H2O (2 mg), and the mixture was stirred at ambient tem-
perature for 15 min. After the addition of ether (80 mL) and
H2O (40 mL), the organic layer was washed first with brine
and then with NaHCO3 solution, dried (MgSO4), and evapo-
rated. The residue was filtered through a silica gel pad using
ether as eluant to give 12b (0.07 g, 67%), which was im-
mediately used for the next reaction because of its unstable
nature.
(1S,2S,3R,4S,5S)-1-[(Ben zyloxy)m eth yl]-4-ter t-bu tyloxy-
3-h yd r oxy-2-h yd r oxym eth ylbicyclo[3.1.0]h exa n e (13). To
a solution of 10a (1.0 g, 3.28 mmol) in benzene/ether (5:1) (60
mL) was added MeMgI (6.6 mL, 3 M in ether, 19.8 mmol) at
ambient temperature, and the mixture was heated to 70 °C
for 48 h. Following the careful addition of 1 N HCl (5 mL), the
mixture was stirred further for 10 min at ambient temperature
before the addition of CH2Cl2 (100 mL) and H2O (40 mL). The
organic layer was washed with brine, dried (MgSO4), and
evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate ) 2:1) to give 13 (0.91
g, 87%) as a colorless syrup: [R]25D ) 31.6° (c 0.25, CHCl3); 1H
NMR (CDCl3) δ 0.50 (m, 1 H), 1.10 (br s, 1 H), 1.20 (s, 9 H),
1.29 (m, 1 H), 1.35 (m, 1 H), 2.46 (m, 1 H), 2.75 (br s, 1 H),
3.20 (d, 1 H, J ) 10.0 Hz), 3.57 (d, 1 H, J ) 10.0 Hz), 3.82 (m,
2 H), 3.90 (t, 1 H, J ) 6.3 Hz), 4.31 (t, 1 H, J ) 5.9 Hz), 4.51
(s, 2 H), 7.25-7.48 (m, 5 H). Anal. Calcd for C19H28O4: C, 71.22;
H, 8.80. Found: C, 71.15; H, 8.80.
Com p ou n d 10a : [R]25 ) 0.6° (c 1.07, CHCl3); 1H NMR
D
(CDCl3) δ 0.70 (m, 1 H), 1.15 (m, 1 H), 1.20 (s, 3 H), 1.45 (s, 3
H), 1.52 (m, 1 H), 2.01 (m, 1 H), 3.08 (d, 1 H, J ) 9.9 Hz), 3.50
(br s, 1 H), 3.61 (d, 1 H, J ) 9.9 Hz), 3.72 (m, 2 H), 4.50 (dd,
2 H, J ) 11.9, 14.8 Hz), 4.69 (pseudo t, 1 H, J ) 6.9, 8.0 Hz),
4.85 (pseudo t, 1 H, J ) 5.6, 6.2 Hz), 7.25-7.48 (m, 5 H). Anal.
Calcd for C18H24O4: C, 71.03; H, 7.94. Found: C, 71.09; H,
7.99.
Com p ou n d 10b: [R]25 ) 20.9° (c 1.27, CHCl3); 1H NMR
D
(CDCl3) δ 0.62 (dd, 1 H, J ) 4.6, 8.6 Hz), 1.00 (pseudo t, 1 H,
J ) 4.4, 4.6 Hz), 1.25 (s, 3 H), 1.42 (s, 3 H), 1.75 (quintet, 1 H,
J ) 4.6, 9.0 Hz), 2.25 (m, 1 H), 2.90 (d, 1 H, J ) 10.7 Hz), 3.48
(br s, 1 H), 3.55 (m, 1 H), 3.82 (m, 1 H), 3.92 (d, 1 H, J ) 10.7
Hz), 4.49 (s, 2 H), 4.60 (d, 1 H, J ) 7.0 Hz), 4.90 (pseudo t, 1
H, J ) 6.4, 6.5 Hz), 7.25-7.48 (m, 5 H). Anal. Calcd for
C
18H24O4: C, 71.03; H, 7.94. Found: C, 70.95; H, 7.99.
(1S,2S,3R,4S,5S)-1,2-Di[(b en zyloxy)m et h yl]-3,4-d ih y-
d r oxy-bicyclo[3.1.0]h exa n e (11). To a solution of 10a (1.3
g, 4.3 mmol) in THF (30 mL) was added NaH (60% in oil) (0.21
g, 5.16 mmol) at 0 °C, followed by BnBr (0.77 mL, 6.45 mmol)
and n-Bu4NI (0.24 g, 6.45 mmol), and the mixture was refluxed
for 15 h. Glacial AcOH was added to reach neutrality, and the
mixture was diluted with ether and H2O. The organic layer
was washed with brine, dried (MgSO4), and evaporated. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate ) 7:1) to give 1,2-dibenzyloxymethyl-
3,4-(isopropylidenedioxy) bicyclo[3.1.0]hexane (1.50 g, 88%) as
(1S,2S,3R ,4S,5S)-4-ter t-Bu t yloxy-1,2-d i[(b en zyloxy)-
m eth yl]-3-h yd r oxy-bicyclo[3.1.0]h exa n e (14). A solution
of 13 (0.85 g, 2.66 mmol) and bistributyltin oxide (1.01 mL,
2.0 mmol) in toluene (30 mL) was refluxed for 15 h using a
Dean-Stark apparatus. BnBr (0.41 mL, 3.46 mmol) and n-Bu4-
NBr (0.43 g, 1.33 mmol) were added, and the mixture was
heated to 105 °C for 15 h. The mixture was evaporated and
the residue was purified by silica gel column chromatography
(hexane/ethyl acetate ) 20:1 to 8:1) to give 14 (1.00 g, 92%)
a colorless syrup: [R]25 ) 13.9° (c 0.36, CHCl3); 1H NMR
as a colorless syrup: [R]25 ) 12.0° (c 0.54, CHCl3); H NMR
1
D
D
(CDCl3) δ 0.52 (dd, 1 H, J ) 4.7, 8.8 Hz), 1.00 (pseudo t, 1 H,
J ) 4.6, 6.4 Hz), 1.22 (s, 3 H), 1.48 (s, 3 H), 1.60 (m, 1 H), 2.91
(quintet, 1 H, J ) 7.5, 9.6 Hz), 3.09 (d, 1 H, J ) 10.1 Hz), 3.82
(m, 3 H), 4.43 (s, 2 H), 4.50 (s, 2 H), 4.67 (pseudo t, 1 H, J )
6.8, 6.9 Hz), 4.88 (pseudo t, 1 H, J ) 5.6, 6.1 Hz), 7.25-7.39
(m, 10 H). Anal. Calcd for C35H30O4: C, 76.12; H, 7.66. Found:
C, 76.03; H, 7.68.
A solution of 1,2-dibenzyloxymethyl-3,4-(isopropylidenedi-
oxy)bicyclo[3.1.0]hexane (1.50 g, 3.80 mmol) and 1 N HCl (10
mL) in THF/MeOH (30 mL, 1:1) was refluxed for 10 h. The
mixture was evaporated and coevaporated with toluene. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate ) 1:1) to give 11 (1.35 g, 100%) as a
colorless syrup: [R]25D ) 51.4° (c 0.70, CHCl3); 1H NMR (CDCl3)
δ 0.36 (m, 1 H), 1.23 (t, 1 H, J ) 4.6 Hz), 1.49 (quintet, 1 H,
J ) 4.4, 8.6 Hz), 2.55 (br s, 1 H), 2.61 (br s, 1 H), 2.75 (m, 1
H), 3.23 (d, 1 H, J ) 10.4 Hz), 3.49 (d, 1 H, J ) 10.4 Hz), 3.75
(m, 2 H), 4.18 (t, 1 H, J ) 6.2 Hz), 4.42-4.58 (m, 5 H), 7.25-
7.50 (m, 10 H). Anal. Calcd for C22H26O4: C, 74.51; H, 7.44.
Found: C, 74.46; H, 7.39.
(1S,2S,3R,4S,5S)-1,2-Di[(ben zyloxy)m eth yl]-3,4-su lfin -
yld ioxy-bicyclo[3.1.0]h exa n e (12a ). To a solution of 11 (0.70
g, 1.97 mmol) in CH2Cl2 (3 mL) were added NEt3 (1.1 mL, 7.88
mmol) and SOCl2 (0.22 mL, 2.96 mmol) at 0 °C. The mixture
was stirred further at 0 °C for 5 min. After the addition of
ether (100 mL) and H2O (50 mL), the organic layer was washed
with brine, dried (MgSO4) and evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate ) 5:1) to give a diasteromeric mixture of sulfoxides
12a (0.63 g, 80%) as a colorless syrup: 1H NMR (CDCl3) δ 0.65
(m, 1 H), 0.81 (m, 1 H), 1.65 (m, 1 H), 3.09 (m, 2 H), 3.23 (m,
1 H), 3.68 (m, 2 H), 4.48 (m, 4 H), 5.09 (t, 1 H, J ) 7.2 Hz),
5.37 (t, 1 H, J ) 6.7 Hz), 5.48 (t, 1 H, J ) 7.2 Hz), 5.61 (t, 1 H,
J ) 6.1 Hz), 7.25-7.39 (m, 10 H). Anal. Calcd for C22H24O5S:
C, 65.98; H, 6.04; S, 8.01. Found: C, 65.91; H, 6.07; S, 8.07.
(1S,2S,3R,4S,5S)-1,2-Di[(ben zyloxy)m eth yl]-3,4-su lfon -
yld ioxy-bicyclo[3.1.0]h exa n e (12b). To a solution of 12a
(0.10 g, 0.25 mmol) in CCl4 (1 mL), CH3CN (1 mL), and H2O
(CDCl3) δ 0.35 (m, 1 H), 1.25 (s, 9 H), 1.31 (m, 1 H), 1.62 (m,
1 H), 2.75 (m, 1 H), 3.12 (d, 1 H, J ) 10.2 Hz), 3.61-3.85 (m,
3 H), 3.97 (t, 1 H, J ) 6.2 Hz), 4.32 (t, 1 H, J ) 5.4 Hz), 4.40-
4.61 (m, 4 H), 7.15 (br s, 1 H), 7.21-7.48 (m, 10 H). Anal. Calcd
for C26H34O4‚0.5CH2Cl2: C, 70.26; H, 7.78. Found: C, 70.07;
H, 8.14.
(1R,2S,4R,5S)-4-ter t-Bu tyloxy-1,2-di[(ben zyloxy)m eth yl]-
bicyclo[3.1.0]h exa n e (15). To a solution of 14 (0.47 g, 1.15
mmol) in THF (15 mL) were added CS2 (1.04 mL, 17.25 mmol)
and NaH (0.11 g, 60% suspension in oil, 2.88 mmol), and the
mixture was stirred at ambient temperature for 1 h. MeI (2.16
mL, 34.5 mmol) was added, and the mixture was stirred at
ambient temperature for another 2 h. The mixture was
neutralized with AcOH and evaporated. The residue was
diluted with CH2Cl2 (100 mL) and H2O (30 mL), and the
organic layer was washed with brine, dried (MgSO4), and
evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate ) 7:1) to give the
intermediate xanthate (0.50 g, 88%) as a yellow solid: 1H NMR
(CDCl3) δ 0.50 (m, 1 H), 0.85 (m, 1 H), 1.18 (s, 9 H), 1.35 (m,
1 H), 2.50 (s, 3 H), 3.05 (m, 1 H), 3.20 (d, 1 H, J ) 10.2 Hz),
3.49 (pseudo t, 1 H, J ) 8.1, 9.1 Hz), 3.65 (m, 1 H), 3.68 (d, 1
H, J ) 10.2 Hz), 4.31-4.65 (m, 5 H), 6.25 (t, 1 H, J ) 6.4 Hz),
7.25-7.48 (m, 10 H).
To a solution of the xanthate (0.46 g, 0.92 mmol) in benzene
(15 mL) were added Et3B (1.10 mL, 1 M in hexane, 1.1 mmol)
and n-Bu3SnH (0.39 mL, 1.38 mmol), and the mixture was
stirred at ambient temperature for 2 h. TLC showed no
difference between starting material and product. The mixture
was evaporated, and the residue was purified by silica gel
column chromatography (hexane/ethyl acetate ) 10:1) to give
15 (0.33 g, 90%) as a colorless syrup: 1H NMR (CDCl3) δ 0.35
(m, 1 H), 0.90 (m, 1 H), 1.18 (s, 9 H), 1.25 (m, 1 H), 1.32 (m, 1
H), 1.98 (m, 1 H), 2.55 (m, 1 H), 3.21 (d, 1 H, J ) 10.2 Hz),
3.33 (pseudo t, 1 H, J ) 8.0, 9.1 Hz), 3.61 (m, 1 H), 3.68 (d, 1
H, J ) 10.2 Hz), 4.31 (m, 1 H), 4.48 (s, 4 H), 7.25-7.48 (m, 10
H). Anal. Calcd for C26H34O3: C, 79.15; H, 8.69. Found: C,
79.44; H, 8.48.

Cyclopropyl-Fused Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 13, 1999 4739
(1S,2S,3R,4R,5S)-4-Azid o-1,2-d i[(ben zyloxy)m eth yl]-3-
h yd r oxybicyclo[3.1.0]h exa n e (16). Meth od A. To a solution
of 12a (0.70 g, 1.75 mmol) in DMF (10 mL) was added NaN3
(0.23 g, 3.5 mmol), and the mixture was heated to 100 °C for
10 h. After the addition of EtOAc (200 mL) and H2O (50 mL),
the organic layer was washed with brine (100 mL), dried
(MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate ) 5:1) to
a solution of silver cyanate (0.819 g, 5.46 mmol) in anhydrous
benzene (4 mL) was added a solution of â-ethoxyacryloyl
chloride (0.294 g, 6.00 mmol) in anhydrous benzene (3.8 mL)
at 10 °C, and the mixture was stirred at the same temperature
for 30 min and then filtered. To this filtrate was added a
solution of 17 (0.807 g, 1.73 mmol) in anhydrous benzene (3
mL) at 10 °C, and the mixture was stirred at the same
temperature for 30 min and then evaporated. The residue was
purified by silica gel column chromatography (methylene
chloride/methanol ) 42:1) to give the (1S,2S,3R,4R,5S)-3-(tert-
butyldimethylsilyloxy)-1,2-di[(benzyloxy)methyl]-4-[(3-ethoxy-
acryloyl)ureido]bicyclo [3.1.0]hexane (0.964 g, 92%) as a syrup.
To a solution of (1S,2S,3R,4R,5S)-3-(tert-butyldimethyl-
silyloxy)-1,2-di[(benzyloxy)methyl]-4-[(3-ethoxyacryloyl)ureido]-
bicyclo[3.1.0]hexane (0.266 g, 0.44 mmol) in anhydrous DMF
(5.5 mL) was added ammonium hydroxide (3 mL), and the
mixture was stirred overnight at 100 °C. The reaction mixture
was evaporated and the residue was purified by silica gel
column chromatography (hexane/ethyl acetate ) 1.5:1) to give
18 (0.096 g, 39%) as a syrup: UV (MeOH) λmax 260 nm; 1H
NMR (CDCl3) δ 0.01 (s, 3 H), 0.19 (s, 3 H), 0.63 (m, 1 H), 0.88
(s, 9 H), 1.25 (m, 1 H), 1.44 (t, 1 H, J ) 4.3 Hz), 2.84 (m, 1 H),
3.10 (d, 1 H, J ) 9.9 Hz), 3.58 (dd, 1 H, J ) 6.6, 9.0 Hz), 3.67
(dd, 1 H, J ) 6.8, 9.0 Hz), 3.97 (dd, 1 H, J ) 1.5, 6.3 Hz), 4.20
(d, 1 H, J ) 9.9 Hz), 4.44 (d, 1 H, J ) 11.0 Hz), 4.45 (d, 1 H,
J ) 11.7 Hz), 4.50 (d, 1 H, J ) 11.0 Hz), 4.56 (d, 1 H, J ) 11.7
Hz), 4.74 (s, 1 H), 5.28 (dd, 1 H, J ) 2.0, 8.0 Hz), 7.25-7.37
(m, 10 H), 7.91 (br s, 1 H), 8.24 (d, 1 H, J ) 8.0 Hz). Anal.
Calcd for C32H42N2O5Si: C, 68.29; H, 7.52; N, 4.98. Found: C,
68.35; H, 7.61; N, 4.96.
give 16 (0.56 g, 81%) as a colorless syrup: [R]25 ) -59.1° (c
D
0.44, MeOH); IR (neat) 2094 cm-1 (N3); 1H NMR (CDCl3) δ 0.61
(m, 1 H, Ha-6), 1.25 (m, 1 H, Hb-6), 1.40 (m, 1 H, H-5), 2.79
(m, 1 H, H-2), 3.38 (d, 1 H, J ) 10.5 Hz, BnOCHa), 3.48 (d, 1
H, J ) 10.5 Hz, BnOCHb), 3.68 (pseudo t, 1 H, J ) 9.3, 9.5
Hz, BnOCHaa), 3.71 (s, 1 H, H-4), 3.90 (dd, 1 H, J ) 5.4, 9.5
Hz, BnOCHbb), 4.28 (d, 1 H, J ) 5.0 Hz, H-3), 4.48 (m, 4 H, 2
× C6H5CH2), 7.28-7.39 (m, 10 H, 2 × C6H5). Anal. Calcd for
C
22H25N3O3: C, 69.64; H, 6.64; N, 11.07. Found: C, 69.47; H,
6.61; N, 10.96.
Meth od B. To a solution of 12b (0.07 g, 0.17 mmol) in DMF
(3 mL) was added NaN3 (0.027 g, 0.43 mmol) at 0 °C, and the
solution was stirred at the same temperature for 30 min. DMF
was evaporated, and the residue was treated with a mixture
of 1 N H2SO4 (1 mL) and THF (5 mL) and was left stirring
overnight at ambient temperature. After treatment with
CHCl3 (200 mL) and H2O (50 mL), the organic layer was
washed with brine (100 mL) and NaHCO3 solution (30 mL),
dried (MgSO4), and evaporated. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate ) 5:1)
to give 16 (0.03 g, 47%) as a colorless syrup identical to that
obtained from method A.
(1S,2S,3R,4R,5S)-4-Am in o-3-(ter t-bu tyldim eth ylsilyloxy)-
1,2-d i[(b en zyloxy)m et h yl]b icyclo[3.1.0]h exa n e (17). (1)
P r ep a r a tion of 4-Azid o-3-(ter t-bu tyld im eth ylsilyloxy)-
1,2-d i[(ben zyloxy) m eth yl]bicyclo[3.1.0]h exa n e. To a solu-
tion of 16 (0.681 g, 1.79 mmol) and pyridine (0.16 mL, 1.98
mmol) in anhydrous methylene chloride (16 mL) was added
TBDMSOTf (0.45 mL, 1.96 mmol) at 0 °C. The mixture was
stirred at the same temperature for 1 h, diluted with meth-
ylene chloride (150 mL), washed with brine (30 mL), dried
(MgSO4), filtered, and evaporated. The residue was purified
by silica gel column chromatography (hexane/ethyl acetate )
10:1) to give the 4-azido-3-(tert-butyldimethylsilyloxy)-1,2-di-
[(benzyloxy)methyl]bicyclo[3.1.0]hexane (0.852 g, 96%) as a
syrup: 1H NMR (CDCl3) δ 0.01 (s, 3 H), 0.05 (s, 3 H), 0.58 (m,
1 H), 0.85 (s, 9 H), 1.21 (m, 1 H), 1.39 (m, 1 H), 2.75 (m, 1 H),
3.42 (d, 1 H, J ) 10.2 Hz), 3.58 (s, 1 H), 3.65 (m, 3 H), 4.15 (d,
1 H, J ) 6.2 Hz), 4.45 (m, 4 H), 7.27-7.35 (m, 10 H). This
compound was used without further purification in the next
step.
(2) R ed u ct ion . To a solution of 4-azido-3-(tert-butyldi-
methylsilyloxy)-1,2-di[(benzyloxy)methyl] bicyclo[3.1.0]hexane
(0.852 g, 1.73 mmol) in methylene chloride (8 mL) and
methanol (8 mL) was added Lindlar’s catalyst (0.05 g). The
resulting mixture was stirred overnight at ambient temper-
ature under hydrogen, filtered, and evaporated. The residue
was purified by silica gel column chromatography (hexane/
ethyl acetate ) 2:1) to give 17 (0.807 g, 100%) as a syrup: 1H
NMR (CDCl3) δ 0.01 (s, 3 H), 0.03 (s, 3 H), 0.42 (m, 1 H), 0.82
(s, 2 H), 1.18 (s, 9 H), 2.33 (br s, 2 H), 2.89 (m, 1 H), 3.11 (s, 1
H), 3.22 (d, 1 H, J ) 10.0 Hz), 3.62 (d, 2 H, J ) 6.7 Hz), 3.71
(d, 1 H, J ) 10.0 Hz), 3.98 (d, 1 H, J ) 5.4 Hz), 4.44 (m, 4 H),
7.20-7.38 (m, 10 H). Anal. Calcd for C28H41NO3Si: C, 71.90;
H, 8.84; N, 2.99. Found: C, 71.88; H, 8.92; N, 3.26.
(1S,2S,3R,4R,5S)-3-(ter t-Bu tyld im eth ylsilyloxy)-1,2-d i-
[(ben zyloxy)m eth yl]-4-(2,4(1H,3H)-d ioxop yr im id in -1-yl)-
bicyclo[3.1.0]h exa n e (18). A mixture of ethyl â-ethoxyacry-
late (2.99 g, 20.74 mmol) and 2 N sodium hydroxide (11.3 mL,
22.6 mmol) was refluxed for 1 h and cooled to 0 °C. The mixture
was filtered, and the filter cake was treated with 2 N sodium
hydroxide and evaporated to give the sodium â-ethoxyacrylate
(1.516 g, 53%). To a solution of sodium â-ethoxyacrylate (1.516
g, 10.99 mmol) in anhydrous ethyl ether (20 mL) was added
thionyl chloride (2 mL, 27.42 mmol), and the mixture was
refluxed for 4 h, kept overnight, and evaporated. The residue
was distilled to give the â-ethoxyacryloyl chloride (0.35 g). To
(1S,2S,4S,5S)-4-[N3-Ben zoyl-2,4-(1H)-d ioxop yr im id in -
1-yl]-1,2-d i[(ben zyloxy)m eth yl]bicyclo[3.1.0]h exa n e (19).
(1) P r ep a r a t ion of (1S,2S,3R,4S,5S)-4-[N3-Ben zoyl-2,4-
(1H)-d ioxop yr im id in -1-yl]-3-(ter t-bu tyld im eth ylsilyloxy)-
1,2-d i[(b en zyloxy)m et h yl]b icyclo[3.1.0]h exa n e. To
a
solution of 18 (0.108 g, 0.19 mmol) in anhydrous pyridine (3
mL) was added benzoyl chloride (0.11 mL, 0.95 mmol), and
the mixture was stirred overnight at 70 °C. After the mixture
was allowed to reach ambient temperature, methanol (1 mL)
was added and stirred for 10 min, before reducing to dryness.
The residue was diluted with ethyl acetate (100 mL), washed
with saturated NaHCO3 solution and brine, dried (MgSO4),
filtered, and evaporated. Purification by silica gel column
chromatography(hexane/ethylacetate)4:1)gave(1S,2S,3R,4S,5S)-
4-[N3-benzoyl-2,4-(1H)-dioxopyrimidin-1-yl]-3-(tert-butyldi-
methylsilyloxy)-1,2-di[(benzyloxy)methyl]bicyclo [3.1.0]hexane
(0.120 g, 94%) as a syrup.
(2) P r ep a r a tion of (1S,2S,3R,4R,5S)-4-[N3-Ben zoyl-2,4-
(1H)-d ioxop yr im id in -1-yl]-1,2-d i [(ben zyloxy)m eth yl]-3-
h yd r oxybicyclo[3.1.0]h exa n e. To a solution of (1S,2S,3R,-
4S,5S)-4-[N3-benzoyl-2,4-(1H)-dioxopyrimidin-1-yl]-3-(tert-
butyldimethylsilyloxy)-1,2-di[(benzyloxy)methyl]bicyclo[3.1.0]-
hexane (0.116 g, 0.16 mmol) in anhydrous THF (4 mL) was
added n-tetrabutylammonium fluoride (0.19 mL, 1.0 M solu-
tion in THF, 0.19 mmol), and the mixture was stirred at room
temperature for 3 h. The reaction mixture was evaporated,
and the residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate ) 2:1) to give (1S,2S,3R,4R,5S)-
4-[N3-benzoyl-2,4-(1H)-dioxopyrimidin-1-yl]-1,2-di[(benzyloxy)-
methyl]-3-hydroxybicyclo[3.1.0]hexane (0.087 g, 90%) as a
syrup: 1H NMR (CDCl3) δ 0.77 (m, 1 H), 0.90 (m, 1 H), 1.35
(m, 1 H), 2.36 (br s, 1 H), 2.95 (m, 1 H), 3.13 (d, 1 H, J ) 10.1
Hz), 3.66-3.77 (m, 2 H), 4.07 (d, 1 H, J ) 10.1 Hz), 4.14 (d, 1
H, J ) 6.6 Hz), 4.47-4.57 (m, 4 H), 4.98 (s, 1 H), 5.41 (d, 1 H,
J ) 8.1 Hz), 7.26-7.92 (m, 15 H), 8.28 (d, 1 H, J ) 8.1 Hz).
Anal. Calcd for C33H32N2O6: C, 71.72; H, 5.84; N, 5.07.
Found: C, 72.01; H, 6.04; N, 5.04.
(3) P r ep a r a tion of th e Xa n th a te. A solution of (1S,2S,3R,-
4R,5S)-4-[N3-benzoyl-2,4-(1H)-dioxopyrimidin-1-yl]-1,2-di[(benzyl-
oxy)methyl]-3-hydroxybicyclo[3.1.0]hexane (0.090 g, 0.16 mmol),
carbon disulfide (0.1 mL, 1.66 mmol), and methyl iodide (0.1
mL, 1.61 mmol) in anhydrous THF (3 mL) was treated with
sodium hydride (0.008 g, 60% suspension in mineral oil, 0.19
mmol) at 0 °C, and the mixture was stirred at that tempera-
ture for 1 h. After neutralization with acetic acid and evapora-

4740 J . Org. Chem., Vol. 64, No. 13, 1999
Moon et al.
tion of the solvent, the residue was purified by silica gel column
chromatography (hexane/ethyl acetate ) 2:1) to give the
xanthate (0.066 g, 63%) as a syrup.
was stirred at ambient temperature for 10 min. After the
addition of methylene chloride (50 mL), the mixture was
washed with saturated NaHCO3 solution and brine, dried
(MgSO4), filtered, and evaporated. The residue was used in
the next step without further purification. To a solution of this
residue in 1,4-dioxane (2 mL) was added ammonium hydroxide
(28%, 0.5 mL), and the mixture was stirred at ambient
temperature for 15 h. After removal of all volatiles, the residue
was dissolved in methanolic ammonia (3 mL) and stirred
overnight at ambient temperature. The reaction mixture was
evaporated, and the residue was purified by silica gel column
chromatography (methylene chloride/methanol ) 4:1) to give
(4) Deoxygen a tion . To a solution of the xanthate (0.063
g, 0.10 mmol) in anhydrous benzene (3 mL) were added
triethylborane (0.15 mL, 1.0 M solution in hexanes, 0.15 mmol)
and tributyltin hydride (0.04 mL, 0.15 mmol), and the mixture
was stirred at ambient temperature for 30 min. The reaction
mixture was evaporated, and the residue was purified by silica
gel column chromatography (hexane/ethyl acetate ) 2:1) to
give 19 (0.037 g, 70%) as a syrup: 1H NMR (CDCl3) δ 0.83-
0.94 (m, 2 H), 1.35 (m, 1 Η), 1.53 (m, 1 H), 1.84 (dd, 1 H, J )
8.2, 15.1 Hz), 2.95 (m, 1 H), 3.19 (d, 1 H, J ) 9.9 Hz), 3.41 (dd,
1 H, J ) 6.3, 9.2 Hz), 3.57 (dd, 1 H, J ) 6.6, 9.2 Hz), 4.23 (d,
1 H, J ) 9.9 Hz), 4.46-4.58 (m, 4 H), 4.94 (d, 1 H, J ) 6.8
Hz), 5.41 (d, 1 H, J ) 8.0 Hz), 7.26-7.50 (m, 10 H), 7.60-7.93
(m, 5 H), 8.35 (d, 1 H, J ) 9.6 Hz). Anal. Calcd for
3b (0.006 g, 51%) as a solid: mp 231 °C; [R]25 ) 48.1° (c 0.1,
D
MeOH); UV (H2O) λmax 276 nm (ꢀ 7 950); 1H NMR (DMSO-d6)
δ 0.56-0.71 (m, 2 H), 1.28 (m, 1 H), 1.48-1.65 (m, 2 H), 3.35-
3.54 (m, 4 H), 3.86 (dd, 1 H, J ) 5.1, 11.7 Hz), 4.74 (t, 1 H, J
) 5.1 Hz), 4.82 (d, 1 H, J ) 6.3 Hz), 5.11 (t, 1 H, J ) 7.3 Hz),
5.76 (d, 1 H, J ) 7.3 Hz), 7.00 (br s, 1 H), 7.05 (br s, 1 H), 7.95
(d, 1 H, J ) 7.3 Hz). Anal. Calcd for C12H17N3O3: C, 57.36; H,
6.82; N, 16.72. Found: C, 57.38; H, 6.73; N, 16.32.
C
33H32N2O5: C, 73.86; H, 6.01; N, 5.22. Found: C, 73.76; H,
6.25; N, 5.24.
(1S,2S,4S,5S)-4-[2,4-(1H,3H)-Dioxop yr im id in -1-yl]-1,2-
d ih yd r oxym eth yl-bicyclo[3.1.0]h exa n e (3a ). (1) P r ep a r a -
tion of (1S,2S,4S,5S)-1,2-Di[(ben zyloxy)m eth yl]-4-[2,4-
(1H,3H)-d ioxop yr im id in -1-yl]bicyclo[3.1.0]h exa n e. To a
solution of 19 (0.050 g, 0.09 mmol) in anhydrous methanol (2
mL) was added 1 N sodium methoxide (0.02 mL, 0.02 mmol),
and the mixture was stirred at ambient temperature for 1 h
and neutralized with AcOH. The reaction mixture was evapo-
rated, and the residue was diluted with ethyl acetate (50 mL).
The organic layer was washed with brine, dried (MgSO4),
filtered, and evaporated. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate ) 1:1.5) to
give the (1S,2S,4S,5S)-1,2-di[(benzyloxy)methyl]-4-[2,4-(1H,3H)-
dioxopyrimidin-1-yl]bicyclo[3.1.0]hexane (0.020 g, 50%) as a
(1S,2S,3R,4R,5S)-4-(6-Am in o-9-p u r in yl)-1,2-d i[(b en z-
yloxy)m eth yl]-3-h ydr oxy-bicyclo[3.1.0]h exa n e (20). A sus-
pension of adenine (0.13 g, 0.96 mmol), 18-crown-6 (0.21 g,
0.80 mmol), and NaH (60% in oil, 0.032 g, 0.80 mmol) in DMF
(10 mL) was heated to 80 °C for 3 h. After a solution of 12a
(0.13 g, 0.32 mmol) was added, the mixture was heated to 120
°C for 72 h. The mixture was poured into H2O (30 mL),
extracted with EtOAc (200 mL), dried (MgSO4), and evapo-
rated. The residue was purified by silica gel column chroma-
tography (CHCl3/MeOH ) 30:1) to give a single regioisomer
20 (0.075 g, 50%) as a colorless syrup, plus recovered 11 (0.035
g) and 12a (0.03 g): [R]25D ) 4.44° (c 0.18, MeOH); UV (MeOH)
λmax 265 nm; 1H NMR (CDCl3) δ 0.70 (m, 1 H, Ha-6′), 1.45 (m,
1 H, Hb-6′), 1.57 (m, 1 H, H-5′), 3.05 (m, 1 H, H-2′), 3.15 (d, 1
H, J ) 10.1 Hz, BnOCHa), 3.69 (d, 2 H, J ) 7.3 Hz, BnOCH2),
3.90 (d, 1 H, J ) 10.1 Hz, BnOCHb), 4.12 (d, 1 H, J ) 6.5 Hz,
H-3′), 4.45 (s, 2 H, C6H5CH2), 4.59 (s, 2 H, C6H5CH2), 4.99 (s,
1 H, H-4′), 6.09 (br s, 2 H, NH2), 7.20-7.39 (m, 10 H, 2 x C6H5),
8.32 (s, 1 H, H-2), 8.60 (s, 1 H, H-8). Anal. Calcd for
1
syrup: UV (MeOH) λmax 262 nm; H NMR (CDCl3) δ 0.67 (m,
1 H), 0.69 (m, 1 H), 1.29 (dd, 1 H, J ) 6.4, 12.6 Hz), 1.45-1.58
(m, 1 H), 1.77 (dd, 1 H, J ) 8.6, 15.5 Hz), 2.82-2.95 (m, 1 H),
3.17 (d, 1 H, J ) 9.9 Hz), 3.41 (dd, 1 H, J ) 6.1, 9.2 Hz), 3.55
(dd, 1 H, J ) 6.6, 9.2 Hz), 4.20 (d, 1 H, J ) 9.9 Hz), 4.46 (d, 1
H, J ) 19.9 Hz), 4.47 (d, 1 H, J ) 11.3 Hz), 4.54 (d, 1 H, J )
11.3 Hz), 4.54 (d, 1 H, J ) 19.9 Hz), 4.93 (d, 1 H, J ) 6.7 Hz),
5.31 (dd, 1 H, J ) 2.5, 8.1 Hz), 7.18-7.39 (m, 10 H), 7.98 (br
s, 1 H), 8.22 (d, 1 H, J ) 8.1 Hz).
C
27H29O3N5: C, 68.77; H, 6.20; N, 14.85. Found: C, 68.49; H,
6.27; N, 14.65.
(1S ,2S ,4S ,5S )-4-(6-Am in o-9-p u r in yl)-1,2-d ih yd r oxy-
m et h ylb icyclo[3.1.0]h exa n e (3c). To a suspension of 20
(0.10 g, 0.21 mmol) in THF (15 mL) were added CS2 (0.25 mL,
4.2 mmol) and NaH (0.025 g, 60% suspension in oil, 0.63
mmol), and the mixture was stirred at ambient temperature
for 1.5 h. MeI (0.26 mL, 4.2 mmol) was added at 0 °C, and the
mixture was further stirred at 0 °C for 1 h. Following
neutralization with AcOH and evaporation of all volatiles, the
residue was diluted with CH2Cl2 (50 mL) and H2O (20 mL).
The organic layer was washed with brine, dried (MgSO4), and
evaporated. The residue was purified by silica gel column
chromatography (CHCl3/MeOH ) 30:1) to give the xanthate
(0.070 g) as a yellow solid, which was used for the next
reaction.
To a solution of the xanthate (0.07 g, 0.12 mmol) in benzene
(2 mL) were added Et3B (0.15 mL, 1 M in hexane, 0.15 mmol)
and n-Bu3SnH (0.05 mL, 0.18 mmol), and the mixture was
stirred at ambient temperature for 15 min. The mixture was
evaporated, and the residue was purified by silica gel column
chromatography (CHCl3/MeOH ) 30:1) to give 4-(6-amino-9-
purinyl)-1,2-di[(benzyloxy)methyl]bicyclo[3.1.0]hexane (0.070
g, 73%) as a colorless syrup, but contaminated with an
impurity: 1H NMR (CDCl3) δ 0.70 (m, 1 H), 1.30 (m, 1 H),
1.57 (m, 2 H), 1.81 (m, 1 H), 2.98 (m, 1 H), 3.20 (d, 1 H, J )
9.9 Hz), 3.30 (dd, 1 H, J ) 6.4, 9.1 Hz), 3.55 (dd, 1 H, J ) 6.4,
9.2 Hz), 4.05 (d, 1 H, J ) 9.9 Hz), 4.41 (s, 2 H), 4.59 (s, 2 H),
5.08 (d, 1 H, J ) 6.8 Hz), 5.90 (br s, 2 H), 7.20-7.41 (m, 10
H), 8.32 (s, 1 H), 8.69 (s, 1 H).
(2) Deben zyla tion . To a suspension of palladium black
(0.044 g) in methanol (2 mL) was added (1S,2S,4S,5S)-1,2-di-
[(benzyloxy)methyl]-4-[2,4-(1H,3H)-dioxopyrimidin-1-yl]bicyclo-
[3.1.0]hexane (0.022 g, 0.05 mmol) in methanol (2 mL) and
formic acid (0.12 mL). The mixture was stirred at 50 °C for 1
h and filtered through a Celite pad. The filtrate was evapo-
rated, and the residue was purified by silica gel column
chromatography (methylene chloride/methanol ) 10:1) to give
3a (0.013 g, 100%) as a hygroscopic solid: [R]25 ) 270.0° (c
D
0.02, MeOH); UV (H2O) λmax 265 nm (ꢀ 7 990); 1H NMR
(DMSO-d6) δ 0.65-0.73 (m, 2 H), 1.35 (dd, 1 H, J ) 3.6, 8.4
Hz), 1.47-1.63 (m, 1 H), 1.71 (dd, 1 H, J ) 8.0, 14.6 Hz), 3.35-
3.59 (m, 4 H), 3.92 (dd, 1 H, J ) 5.1, 11.4 Hz), 4.72 (t, 1 H, J
) 5.1 Hz), 4.79 (d, 1 H, J ) 6.6 Hz), 5.11 (t, 1 H, J ) 5.0 Hz),
5.65 (d, 1 H, J ) 8.0 Hz), 8.01 (d, 1 H, J ) 8.0 Hz), 11.29 (s,
1 H). Anal. Calcd for C12H16N2O4: C, 57.13; H, 6.39; N, 11.10.
Found: C, 57.22; H, 6.14; N,11.03.
(1S,2S,4S,5S)-4-(4-Am in o-2(1H)-oxop yr im id in -1-yl)-1,2-
d ih yr oxym eth yl-bicyclo[3.1.0]h exa n e (3b). A solution of
3a (0.012 g, 0.05 mmol) in anhydrous pyridine (2 mL) was
treated with acetic anhydride (0.05 mL, 0.53 mmol), and the
mixture was stirred at ambient temperature for 5 h. The
residue obtained after evaporation of all the volatiles was
diluted with ethyl acetate (50 mL); washed with diluted HCl,
saturated NaHCO3 solution and brine; dried (MgSO4); filtered;
and evaporated. The residue was used in the next step without
further purification.
A solution of 1,2,4-triazole (0.079 g, 1.14 mmol) and phos-
phorus oxychloride (0.09 mL, 0.97 mmol) in acetonitrile (3 mL)
was treated with triethylamine (0.13 mL, 0.93 mmol) and the
above residue in acetonitrile (1 mL). The mixture was stirred
at ambient temperature for 15 h. Additional triethylamine (0.1
mL) and water (0.3 mL) were added, and the reaction mixture
A suspension of 4-(6-amino-9-purinyl)-1,2-di[(benzyloxy)-
methyl]bicyclo[3.1.0]hexane (0.04 g, 0.088 mmol) and pal-
ladium black (0.050 g) in 5% HCO2H in MeOH (20 mL) was
stirred at ambient temperature for 72 h. The mixture was
filtered, washed with MeOH, and evaporated. The residue was
purified by silica gel column chromatography (CHCl3/MeOH

Cyclopropyl-Fused Carbocyclic Nucleosides
J . Org. Chem., Vol. 64, No. 13, 1999 4741
) 8:1) to give 3c (0.020 g, 83%) as a white solid: mp 232 °C;
(1S,2S,4S,5S)-4-(2-Aceta m id o-6-ch lor o-p u r in -9-yl)-1,2-
d i[(ben zyloxy)m eth yl]bicyclo[3,1,0]h exa n e (23). To a sus-
pension of triphenylphospine (0.15 g, 0.58 mmol) and 2-ace-
tamino-6-chloropurine (0.122 g, 0.58 mmol) in anhydrous THF
(4 mL) was added diethyl azodicarboxylate (0.1 mL, 0.64 mmol)
at ambient temperature, and the mixture was vigorously
stirred at the same temperature for 10 min. To this reaction
mixture was added a solution of 22 (0.065 g, 0.19 mmol) in
anhydrous THF (3 mL), and the mixture was refluxed over-
night. Hexanes (5 mL) was added to the reaction mixture, and
the precipitate was filtered off. The organic layer was evapo-
rated, and the residue was purified by silica gel column
chromatography (hexanes:ethyl acetate ) 1:1.5) to give 23
(0.039 g, 38%) as a syrup: 1H NMR (CDCl3) δ 0.70 (dd, 1 H, J
) 6.1, 8.5 Hz), 0.81 (dd, 1 H, J ) 4.0, 6.1 Hz), 1.57-1.69 (m,
2 H), 1.84 (dd, 1 H, J ) 7.6, 14.7 Hz), 2.55 (s, 3H), 2.92-3.04
(m, 1 H), 3.15 (d, 1 H, J ) 10.0 Hz), 3.41 (dd, 1 H, J ) 6.4, 9.3
Hz), 3.55 (dd, 1H, J ) 6.2, 9.3 Hz), 4.06 (d, 1 H, J ) 10.0 Hz),
4.46 (s, 2 H), 4.56 (d, 1 H, J ) 12.5 Hz), 4.62 (d, 1 H, J ) 12.5
Hz), 5.05 (d, 1 H, J ) 6.1 Hz), 7.28-7.38 (m, 10 H), 8.01 (s, 1
H), 8.93 (s, 1 H). Anal. Calcd for C29H30ClN5O3: C, 65.47; H,
5.68; N, 13.16. Found: C, 65.23; H, 5.39; N, 13.09.
[R]25 ) -10.7° (c 0.15, MeOH); UV (H2O) λmax 260 nm (ꢀ 16
D
1
880); H NMR (CD3OD) δ 0.79 (m, 1 H, Ha-6′), 0.85 (m, 1 H,
Hb-6′), 1.65 (m, 2 H, H-5′ and Ha-3′), 1.90 (dd, 1 H, J ) 8.1,
14.8 Hz, Hb-3′), 2.75 (m, 1 H, H-2′), 3.60 (m, 3 H, CH2OH and
CHaOH), 3.92 (d, 1 H, J ) 11.7 Hz, CHbOH), 4.99 (d, 1 H, J )
6.4 Hz, H-4′), 8.20 (s, 1 H, H-2), 8.50 (s, 1 H, H-8); 13C NMR
(CD3OD) δ 10.6, 28.0, 35.5, 42.2, 57.3, 64.2, 65.9, 80.0, 120.3,
141.0, 150.1, 153.6, 157.3. Anal. Calcd for C13H17N5O2: C,
56.72; H, 6.22; N, 25.44. Found: C, 56.80; H, 6.27; N, 25.65.
(1S,2S,3R,4S,5S)-4-(ter t-Bu tyld ip h en ylsilyloxy)-1,2-d i-
[(ben zyloxy)m eth yl]-3-h yd r oxybicyclo[3.1.0]h exa n e (21).
To a solution of 11 (0.314 g, 0.89 mmol) and imidazole (0.145
g, 2.13 mmol) in anhydrous methylene chloride (10 mL) was
added tert-butyldiphenylsilyl chloride (0.28 mL, 1.08 mmol)
at 0 °C, and the mixture was stirred at 10 °C for 5 h. The
reaction mixture was diluted with ethyl acetate (100 mL);
washed with diluted HCl (15 mL × 2), saturated NaHCO3
solution, and brine; dried (MgSO4); filtered; and evaporated.
The residue was purified by silica gel column chromatography
(hexane/ethyl acetate ) 9:1) to give 21 (0.525 g, 100%) as a
syrup; 1H NMR (CDCl3) δ 0.32 (dd, 1 H, J ) 5.2, 8.3 Hz), 1.08
(s, 9 H), 1.15 (dd, 1 H, J ) 4.3, 8.3 Hz), 1.41 (t, 1 H, J ) 4.6
Hz), 2.63 (pseudo q, 1 H, J ) 6.6, 6.9, 7.1 Hz), 2.96 (s, 1 H),
3.05 (d, 1 H, J ) 10.2 Hz), 3.57 (d, 1 H, J ) 10.2 Hz), 3.70 (dd,
1 H, J ) 6.3, 9.2 Hz), 3.82 (pseudo t, 1 H, J ) 8.2, 9.1 Hz),
4.03 (t, 1 H, J ) 6.1 Hz), 4.34 (d, 1 H, J ) 12.5 Hz), 4.39 (d, 1
H, J ) 12.5 Hz), 4.48-4.54 (m, 2 H), 4.61 (d, 1 H, J ) 12.2
Hz), 7.19-7.43 (m, 20 H). Anal. Calcd for C38H44O4Si: C, 76.99;
H, 7.48. Found: C, 76.59; H, 7.09.
(1S,2S,4S,5S)-1,2-Di[(ben zyloxy)m eth yl]-4-gu a n in -9-yl-
bicyclo[3.1.0]h exa n e (24). To a solution of 23 (0.023 g, 0.04
mmol) in 1,4-dioxane (3 mL) was added 1 N sodium hydroxide
(0.43 mL, 0.43 mmol), and the mixture was stirred at 95 °C
for 7 h. After evaporation of all the volatiles, the residue was
purified by silica gel column chromatography (methylene
chloride:methanol ) 20:1) to give 24 (0.017 g, 81%) as a
(1S,2S,4R,5S)-1,2-Di[(b en zyloxy)m et h yl]-3-h yd r oxy-
b icyclo[3.1.0]h exa n e (22). (1) P r ep a r a t ion of t h e Xa n -
th a te. To a suspension of sodium hydride (0.013 g, 60%
suspension in oil, 0.33 mmol) in anhydrous THF (2 mL) was
added a solution of 21 (0.123 g, 0.21 mmol) in THF (3 mL) at
0 °C, and the mixture was stirred at the same temperature
for 5 min and then at ambient temperature for 10 min. To
this mixture were added carbon disulfide (0.13 mL, 2.16 mmol)
and methyl iodide (0.13 mL, 2.10 mmol) at ambient temper-
ature, and the reaction mixture was stirred at the same
temperature for 1 h before it was reduced to dryness. The
xanthate was used in the next step without further purifica-
tion.
(2) Deoxygen a tion . To a solution of the xanthate in
anhydrous benzene (15 mL) were added triethylborane (0.32
mL, 1.0 M solution in hexanes, 0.32 mmol) and tributyltin
hydride (0.09 mL, 0.33 mmol), and the mixture was stirred
overnight at ambient temperature. After evaporation of all the
volatiles, the residue was purified by silica gel column chro-
matography (hexane/ethyl acetate ) 9:1) to give the 4-(tert-
butyldiphenylsilyloxy)-1,2-di[(benzyloxy)methyl]bicyclo[3.1.0]-
hexane (0.038 g, 44%) as a syrup with recovered starting
material (0.034 g): 1H NMR (CDCl3) δ 0.38 (dd, 1 H, J ) 5.4,
8.0 Hz), 0.99 (m, 1 H), 1.03 (s, 9 H), 1.11 (pseudo td, 1 H, J )
2.3, 8.6 Hz), 1.18-1.28 (m, 1 H), 1.98 (td, 1 H, J ) 7.7, 13.2
Hz), 2.39-2.51 (m, 1 H), 3.16 (d, 1 H, J ) 10.3 Hz), 3.34 (dd,
1 H, J ) 7.6, 9.1 Hz), 3.56 (d, 1 H, J ) 10.3 Hz), 3.62 (dd, 1 H,
J ) 5.9, 9.1 Hz), 4.39 (s, 2 H), 4.47 (s, 2 H), 4.47-4.56 (m, 1
H), 7.22-7.69 (m, 10 H).
(3) Desilyla tion . To a solution of 4-(tert-butyldiphenylsil-
yloxy)-1,2-di[(benzyloxy)methyl]-bicyclo[3.1.0]hexane (0.13 g,
0.23 mmol) in THF (3 mL) was added n-tetrabutylammonium
fluoride (0.34 mL, 0.34 mmol, 1.0 M solution in THF), and the
mixture was stirred overnight at room temperature. The
reaction mixture was diluted with ethyl acetate (100 mL),
washed with brine, dried (MgSO4), filtered, and evaporated.
The residue was purified by silica gel column chromatography
(hexanes:ethyl acetate ) 1.5:1) to give 22 (0.065 g, 85%) as a
syrup: 1H NMR (CDCl3) δ 0.43 (dd, 1 H, J ) 5.6, 7.9 Hz), 0.88-
0.98 (m, 2 H), 1.38 (d, 1 H, J ) 5.8 Hz), 1.46-1.52 (m, 1 H),
2.14 (td, 1 H, J ) 7.9, 13.3 Hz), 2.56-2.69 (m, 1 H), 3.27 (d, 1
H, J ) 10.3 Hz), 3.38 (dd, 1 H, J ) 7.2, 9.2 Hz), 3.62 (dd, 1 H,
J ) 6.0, 9.2 Hz), 3.68 (d, 1 H, J ) 10.3 Hz), 4.48 (s, 2 H), 4.49
(s, 2 H), 4.54-4.59 (m, 1 H), 7.26-7.35 (m, 10 H). Anal. Calcd
for C22H26O3: C, 78.07; H, 7.74. Found: C, 78.47; H, 7.47.
1
syrup: UV (MeOH) λmax 254 nm; H NMR (DMSO-d6) δ 0.74
(dd, 1 H, J ) 5.4, 8.3 Hz, Ha-6′), 0.89 (dd, 1 H, J ) 4.1, 5.4 Hz,
Hb-6′), 1.63-1.67 (m, 2 H, H-5′ and Ha-3′), 1.79 (dd, 1 H, J )
7.5, 14.3 Hz, Hb-3′), 2.87-2.97 (m, 1 H, H-2′), 3.41-3.49 (m, 2
H, BnOCHa and BnOCHaa), 3.69 (dd, 1 H, J ) 6.5, 9.3 Hz,
BnOCHbb), 4.06 (d, 1 H, J ) 10.0 Hz, BnOCHb), 4.55 (s, 2 H,
C6H5CH2), 4.61 (s, 2 H, C6H5CH2), 4.75 (d, 1 H, J ) 5.9 Hz,
H-4′), 6.57 (br s, 2 H, NH2), 7.33-7.46 (m, 10 H, 2 x C6H5),
8.09 (s, 1 H, H-8), 10.71 (br s, 1 H, NH). Anal. Calcd for
C
27H29N5O3: C, 68.77; H, 6.20; N, 14.85. Found: C, 68.99; H,
6.08; N, 15.11.
(1S ,2S ,4S ,5S )-1,2-Dih yd r o x ym e t h yl-4-gu a n in -9-y l-
bicyclo[3.1.0]h exa n e (3d ). To a suspension of 24 (0.017 g,
0.04 mmol) and palladium black (0.015 g) in methanol (3 mL)
was added formic acid (0.7 mL, 18.55 mmol) at ambient
temperature, and the mixture was stirred at 50 °C for 30 min.
The reactiom mixture was allowed to cool to ambient temper-
ature and filtered, and the solvent was evaporated. The residue
was purified by silica gel column chromatography (methylene
chloride/methanol ) 5:1) to give 3d (0.010 g, 93%) as a white
solid: mp 231 °C; [R]25 ) 14.3° (c 0.1, MeOH); UV (H2O) λmax
D
1
254 nm (ꢀ 14 850); H NMR (DMSO-d6) δ 0.67 (dd, 1 H, J )
5.5, 8.3 Hz, Ha-6′), 0.79 (dd, 1 H, J ) 4.0, 5.5 Hz, Hb-6′), 1.49-
1.62 (m, 2 H, H-5′ and Ha-3′), 1.74 (dd, 1 H, J ) 7.3, 14.3 Hz,
Hb-3′), 3.39-3.60 (m, 4 H, H-2′, CH2OH and CHaOH), 3.91 (dd,
1 H, J ) 5.0, 11.3 Hz, CHbOH), 4.70 (d, 1 H, J ) 6.1 Hz, H-4′),
4.76 (t, 1 H, J ) 5.1 Hz, OH), 5.16 (t, 1 H, J ) 5.0 Hz, OH),
6.61 (br s, 2 H, NH2), 8.08 (s, 1 H, H-8), 10.73 (br s, 1 H, NH);
13C NMR (DMSO-d6) δ 9.60, 26.40, 34.12, 34.56, 54.70, 62.72,
63.70, 104.68, 116.83, 135.67, 150.91, 153.60, 157.23. Anal.
Calcd for C13H17N5O3: C, 53.60; H, 5.88; N, 24.04. Found: C,
53.39; H, 5.96; N, 23.98.
Ack n ow led gm en t. This research was supported by
a grant from the Korea Science and Engineering Foun-
dation (KOSEF 961-0718-107-2). The authors wish to
thank Dr. Chong-Kyo Lee (Korea Research Institute of
Chemical Technology) for the antiviral activity testing.
J O990010M