4'- and 1'-methyl-substituted 5'-norcarbanucleosides.

Article abstract of DOI:10.1021/jo030238g

5'-norcarbocyclic nucleosides have been found to possess a variety of meaningful biological properties. Derivatives of these compounds possessing substituents at the hydroxyl and heterocyclic ring bearing carbon atoms have not been described. As entries i

Full text of DOI:10.1021/jo030238g

4′- a n d 1′-Meth yl-Su bstitu ted 5′-Nor ca r ba n u cleosid es
Atanu Roy and Stewart W. Schneller*
Department of Chemistry, Auburn University, Auburn, Alabama 36849-5312
schnest@auburn.edu
Received J uly 22, 2003
5′-Norcarbocyclic nucleosides have been found to possess a variety of meaningful biological
properties. Derivatives of these compounds possessing substituents at the hydroxyl and heterocyclic
ring bearing carbon atoms have not been described. As entries into these compounds, the 4′- and
1′-methyl derivatives of 5′-noraristeromycin (2 and 3) have been prepared from a common cyclopentyl
precursor 8. The synthetic methods developed are adaptable to 5′-norcarbanucleosides possessing
a variety of heterocyclic bases and in the L-like configuration. In turn, the products from such
syntheses will lend themselves to a number of structural and biochemical investigations relevant
to carbanucleosides in general. Compounds 2 and 3 lack antiviral properties and were not cytotoxic.
In tr od u ction
As part of our ongoing research into the biological
properties of 5′-norcarbanucleosides (as represented by
the adenine derivative 1, Figure 1),1 a synthetic means
adaptive to various C-4′ and C-1′ substituents from a
common precursor was desired. Such compounds were
seen as not only specifically relevant to the 5′-nor studies
but also to carbanucleosides in general.2-7 To develop a
synthetic plan, the C-4′ and C-1′ methyl derivatives of
both D-like (2 and 3, respectively) and L-like 5′-noraris-
teromycin were set as the prototype target compounds.
The results of this effort are reported here.
F IGURE 1. 5′-Noraristeromycins.
etate (4) could serve as the starting point. Thus, treat-
ment of 4 with tert-butyldimethylsilyl chloride (Scheme
1) gave the O-silylated compound 5. This product was
converted into 7 by, first, deacetylation to 69 followed by
oxidation with pyridinium chlorochromate (PCC). When
enone 7 was subjected to reaction with methyllithium,
the 1,2-adduct 810 was obtained (vide infra for structure
assignment). Desilylation of 8 produced 9, which was
selectively acetylated to provide allylic acetate 10. A Pd-
(0)-mediated coupling between 10 and the sodium salt
of adenine11 provided 11. Dihydroxylation of 11 with
osmium tetraoxide/N-methylmorpholine N-oxide gave the
desired 2.
Resu lts a n d Discu ssion
A retrosynthetic analysis to 2 suggested that readily
available1c,8 (-)-(1S,4R)-4-hydroxy-2-cyclopenten-1-yl ac-
(1) (a) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.; Andrei,
G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1992, 35, 3372-3377.
(b) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck, R.;
Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1994, 37, 551-
554. (c) Seley, K. L.; Schneller, S. W.; Rattendi, D.; Bacchi, C. J . J .
Med. Chem. 1997, 40, 622-624. (d) Seley, K. L.; Schneller, S. W.;
Kroba, B. Nucleosides Nucleotides 1997, 16, 2095-2099. (e) Rajappan,
V.; Schneller, S. W.; Williams, S. L.; Kern, E. R. Bioorg. Med. Chem.
2002, 10, 883-886.
(2) See, for example: (a) Gurjar, M. K.; Maheshwar, K. J . Org.
Chem. 2001, 66, 7552-7554. (b) Hegedus, L. S.; Hervert, K. L.; Matsui,
S. J . Org. Chem. 2002, 67, 4076-4080. (c) Ko, O. H.; Hong, J . H.
Tetrahedron Lett. 2002, 43, 6399-6402.
(3) See, for example: (a) Cappellacci, L.; Barboni, G.; Palmieri, M.;
Pasqualini, M.; Grifantini, M.; Costa, B.; Martini, C.; Franchetti, P.
J . Med. Chem. 2002, 45, 1196-1202. (b) Kumamoto, H.; Murasaki,
M.; Haraguchi, K.; Anamura, A.; Tanaka, H. J . Org. Chem. 2002, 67,
6124-6130. (c) Haraguchi, K.; Itoh, Y.; Matsumoto, K.; Hashimoto,
K.; Nakamura, K.; Tanaka, H. J . Org. Chem. 2003, 68, 2006-2009.
(4) Choi, Y.; George, C.; Strazewski, P.; Marquez, V. Org. Lett. 2002,
4, 589-592.
The structure of 2 was assigned using 2-D NMR
spectroscopy. DQ-COSY was employed to determine the
chemical shifts of the cyclopentyl protons. This was
followed by a NOESY experiment to ascertain the ster-
(8) (a) Laumen, K.; Reimerdes, E. H.; Schneider, M. Tetrahedron
Lett. 1985, 26, 407-410. (b) Laumen, K.; Schneider, M. Tetrahedron
Lett. 1984, 25, 5875-5878.
(9) Seley, K. L.; Schneller, S. W.; De Clercq, E. J . Org. Chem. 1997,
62, 5645-5646.
(5) See, for example: (a) Koshkin, A. A.; Fensholdt, J .; Pfundheller,
H. M.; Lomholt, C. J . Org. Chem. 2001, 66, 8504-8512. (b) Morita,
K.; Hasegawa, C.; Kaneko, M.; Tsutsumi, S.; Sone, J .; Ishikawa, T.;
Imanishi, T.; Koizumi, M. Bioorg. Med. Chem. Lett. 2002, 12, 73-76.
(6) Das, S. R.; Schneller, S. W.; Balzarini, J .; De Clercq, E. Bioorg.
Med. Chem. 2002, 10, 457-460.
(10) Gao, Z.-G.; Kim, S.-K.; Biadatti, T.; Chen, W.; Lee, K.; Barak,
D.; Kim, S. G.; J ohnson, C. R.; J acobson, K. A. J . Med. Chem. 2002,
45, 4471-4484.
(11) (a) Trost, B. M.; Kuo, G. H.; Benneche, T. J . Am. Chem. Soc.
1988, 110, 621-622. (b) Peel, M. R.; Sternbach, D. D.; J ohnson, M. R.
J . Org. Chem. 1991, 56, 4990-4993.
(7) Crimmins, M. T. Tetrahedron 1998, 54, 9229-9272.
10.1021/jo030238g CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003
J . Org. Chem. 2003, 68, 9269-9273
9269

Roy and Schneller
SCHEME 1a
SCHEME 2 a
a
Reagents: (a) TBDMSCl, imidazole;9 (b) K2CO3 in MeOH; (c)
PCC, (d) MeLi; (e) Bu4NF; (f) Ac2O, pyridine; (g) Pd2(dba)3‚CHCl3
and 1,3-dppp in THF combined with adenine/NaH in DMF; (h)
OsO4, NMO. TBDMS ) t-BuMe2Si.
a
Reagents: (a) Ph3P/DlAD, THF; (b) K-10 clay, EtOAc/MeOH/
H2O (1:6:2); (c) PhCO2H, DlAD, PPh3; (d) OsO4, NMO; (e) NH3 in
MeOH; (f) acetone, 2,2-dimethoxypropane, H+; (g) KCN, MeOH;
(h) ClCH2CO2H, DlAD, PPh3, (i) NH3 in MeOH; (j) dilute HCl.
TABLE 1. NOE En h a n cem en ts Obser ved in 2
protons
% enhancement
4′-Me (δ 1.22), HR-5′ (δ 2.40)
H-1′ (δ 4.70), H-5′R (δ 2.40)
H-3′â (δ 3.51), H-2′â (δ 4.65)
H-3′â (δ 3.51), H-5′â (δ 1.82)
H-2′â (δ 4.65), H-5′â (δ 1.82)
H-3′â (δ 3.51), H-1′R (δ 4.70)
H-2′â (δ 4.65), H-1′R (δ 4.70)
10.3
7.1
7.3
3.6
3.4
droxylation of 15 to the “down” diol15 16 was followed by
ammonolysis to 3.
The most striking feature of the NMR of 3 was that
its 1′-methyl group appeared as a singlet downfield (δ
1.70) relative to the 4′-methyl group of 2 (δ 1.22), due
apparently to the anisotropic effect of the adenine ring
on the 1′-methyl substituent. The stereochemical assign-
ment for the 1′-methyl in 3 arose by correlating the
confirmed structure of 2 with the common precursor 8,
incorporating the known inversion of configuration that
accompanies the Mitsunobu reaction16 (leading to 13 and
step c of Scheme 2) and the documented preference for
dihydroxylation trans to the hetereocyclic base15 (step d
of Scheme 2).
The C-4′ epimeric derivative of 3 (21, Scheme 2) was
prepared from 16 by, first, isopropylidenation to 17
followed by removal of the benzoyl group to 18. The
Mitsunobu reaction of 18 with chloroacetic acid17 pro-
duced 19. Ammonolysis of 19 (to 20) with subsequent
deprotection gave 21. Compound 21 was desired to serve
as a representative of the epi 5′-nor series where some
biological activity has been found.18
none observed
none observed
eochemical configuration. In this manner, a correlation
existed between the C-4′ methyl protons (δ 1.22) and the
H-5′R (δ 2.40)12 (Table 1). Had the product been epimeric
at C-4′ (“up” methyl group) there would have been a
correlation between the methyl protons with H-5′â (δ
1.82) and H-3′â (δ 3.51), which was not observed. The
R-configuration of the C-4′ methyl apparently arose due
to the presence of the bulky TBDMS on the top face of 7
(Scheme 1) that influenced the stereochemistry of the
methyllithium reaction.10
The configuration of the 2′,3′-diol of 2 was established
by NOE correlations between H-3′â (δ 3.51) and H-5′â (δ
1.82) and between H-2′â (δ 4.65) and H-5′â (δ 1.82) (Table
1). Further support was seen by the lack of NOE
enhancement between H-1′ and either H-2′ or H-3′ as a
result of their trans relationship.
A retrosynthetic pathway to 3 suggested that 8 (Scheme
1), which had been employed in the preparation of 2,
could serve as its precursor. In that regard, subjecting 8
to a Mitsunobu reaction with 6-chloropurine (12)13 yielded
13 (Scheme 2). Desilylation of 13 provided 14. Inversion
of the C-4′ center of 14 was accomplished by a second
Mitsunobu reaction with benzoic acid14 to give 15. Dihy-
The enantiomers of 2 and 3 would be available by
beginning with the enantiomer of 419 and following
(15) The stereochemical assignment is supported by: (a) Da Silva,
A. D.; Coimbra, E. S.; Fourrey, J .-L.; Machado, A. S.; Ge´ro, M. R.
Tetrahedron Lett. 1993, 34, 6745-6748. (b) Kitade, Y.; Kozaki, A.;
Miwa, T.; Nakanishi, M. Tetrahedron 2002, 58, 1271-1277. (c) Siddiqi,
S. M.; Chen, X.; Rao, J .; Schneller, S. W.; Ikeda, S.; Snoeck, R.; Andrei,
G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1995, 38, 1035-1038.
(16) Kitade, Y.; Kozaki, A.; Yatome, C. Tetrahedron Lett. 2001, 42,
433-435.
(12) The 5′ here is referring to the cyclopentyl ring methylene and
should not be confused with the 5′-nor designation that is used to
represent the parent carbanucleosides that are the focus of this paper.
(13) Seley, K. L.; Schneller, S. W.; Korba, B. J . Med. Chem. 1998,
41, 2168-2170.
(14) Amici, M. D.; Micheli, C. D.; Molteni, G.; Pitre´, D.; Carrea, G.;
Riva, S.; Spezia, S.; Zetta, L. J . Org. Chem. 1991, 56, 67-72.
(17) Saiah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1992,
33, 4317-4320, (b) Hughes, D. L.; Reamer, R. A. J . Org. Chem. 1996,
61, 2967-2971. (c) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1990,
31, 5253-5256.
(18) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck,
R.; Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1994, 37,
1382-1384.
9270 J . Org. Chem., Vol. 68, No. 24, 2003

4′- and 1′-Methyl-Substituted 5′-Norcarbanucleosides
a colorless oil: 1H NMR (CDCl3) δ 0.12 (s, 6H), 0.91 (s, 9H),
2.25 (dd, 1H, J ) 1.7, 18.1 Hz), 2.71 (dd, 1H, J ) 5.9, 18.1
Hz), 4.99 (m, 1H), 6.18 (d, 1H, J ) 5.4 Hz), 7.46 (dd, 1H, J )
1.9, 5.4 Hz); 13C NMR (CDCl3) δ -4.5, 18.3, 26.1, 45.2, 71.1,
134.6, 164.1, 206.7. Anal. Calcd for C11H20O2Si‚0.25EtOAc: C,
61.49; H, 9.46. Found: C, 61.67; H, 9.29.
Schemes 1 and 2 (as a representative, see the Experi-
mental Section for ent-2). Also, the means illustrated
herein for achieving 2 and 3 and their enantiomers can
be used to readily20-22 obtain 5′-norcarbanucleosides with
heterocyclic moieties other than adenine.
Compounds 2, 3, and 21 were evaluated for antiviral
activity toward the following viruses: hepatitis B, influ-
enza A, influenza B, parainfluenza-3, respiratory syncy-
tial, varicella zoster (TK+ and TK-), cytomegalo, vesicular
stomatitis, coxsackie B4, reo, herpes simplex 1 (TK+ and
TK-) and 2, human immunodeficiency, vaccinia, and
cowpox. No activity was found for any of the compounds,
nor was there any cytotoxicity to the viral host cells.23
(1R,4S)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-4-m et h ylcy-
clop en t-2-en -4-ol (8). To a solution of compound 7 (5.86 g,
27.64 mmol) in anhydrous ether (100 mL) at -40 °C was added
MeLi (24 mL, 1.4 M) via syringe over a period of 20 min. The
reaction mixture was stirred at -40 °C for 3 h and then
quenched with saturated solution of NH4Cl (50 mL). The
organic layer was separated; the aqueous layer was extracted
with ether (3 × 50 mL); the organic layers were combined,
dried (Na2SO4), and evaporated to dryness; and the residue
was purified via column chromatography eluting with hexanes/
EtOAc (4:1) to afford 3.8 g (60%) of 8 as a colorless syrup: 1H
NMR (CDCl3) δ 0.10 (s, 6H), 0.91 (s, 9H), 1.33 (s, 3H), 1.8 (dd,
1H, J ) 9.3, 17.9 Hz), 2.3 (m, 1H), 2.56 (brs, 1H), 4.80 (brs,
1H), 5.76 (dd, 1H, J ) 2.0, 5.7 Hz), 5.88 (d, 1H, J ) 5.7 Hz);
13C NMR (CDCl3) δ -4.0, 18.3, 26.2, 27.4, 51.5, 76.2, 81.7,
135.3, 141.1. Anal. Calcd for C12H24O2Si‚0.25H2O: C, 61.88;
H, 10.60. Found: C, 61.67; H, 10.29.
(1S,4R)-1-Meth ylcyclop en t-2-en e-1,4-d iol (9). A solution
of 8 (1.83 g, 8.0 mmol) in anhydrous THF (50 mL) and Bu4NF
(1.0 M solution in THF, 15 mL, 15 mmol) was stirred at room
temperature for 3 h. The solvent was evaporated under
reduced pressure, and the residue was purified via column
chromatography eluting with EtOAc/MeOH (49:1) to afford
0.57 g (62.3%) of 9 as a colorless syrup: 1H NMR (CDCl3) δ
1.36 (s, 3H), 1.82 (dd, 1H, J ) 2.4, 14.3 Hz), 2.37 (m, 1H), 3.0
(brs, 2H), 4.70 (m, 1H), 5.83 (dd, 1H, J ) 3.7, 5.5 Hz), 5.87 (m,
1H); 13C NMR (CDCl3) δ 27.4, 50.2, 76.8, 82.1, 135.0, 142.1.
Anal. Calcd for C6H10O2: C, 63.14; H, 8.83. Found: C, 63.27;
H, 8.52.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Melting points are uncorrected.
1H and 13C NMR spectra were determined at 250 and 62.5
MHz, respectively. All 1H chemical shifts are reported in δ
relative to internal standard tetramethylsilane (TMS, δ 0.00).
13C chemical shifts are reported in δ relative to CDCl3 (center
of triplet, δ 77.23) or relative to DMSO-d6 (center of septet, δ
39.51). The spin multiplicities are indicated by the symbols s
(singlet), d (doublet), t (triplet), m (multiplet), and br (broad).
Optical rotations were determined using the sodium-D line.
Reactions were monitored by thin-layer chromatography (TLC)
using 0.25 mm silica gel 60-F254 precoated silica gel plates with
visualization by irradiation with a UV lamp or exposure to
iodine vapor. Column chromatography was performed on silica
gel (average particle size 5-25 µm, 60 Å) and elution with the
indicated solvent system. Yields refer to chromatographically
and spectroscopically (1H and 13C NMR) homogeneous materi-
als. The reactions were generally carried out in a N2 atmo-
sphere under anhydrous conditions.
(1R,4S)-4-Hydr oxy-4-m eth yl-2-cyclopen ten -1-yl Acetate
(10). To a chilled stirred solution of 9 (0.8 g, 7.0 mmol) in dry
CH2Cl2 (25 mL) were added pyridine (0.66 g, 8.58 mmol) and
Ac2O (0.9 g, 9.24 mmol). The reaction mixture was stirred
overnight at room temperature. Then it was treated with
saturated NaHCO3 solution (50 mL), stirred vigorously with
ice-cold 1 N HCl (50 mL) and brine (2 × 50 mL), dried (Na2-
SO4), and evaporated under reduced pressure. The residue was
purified via column chromatography, eluting with hexanes/
EtOAc (1:4) to give 0.85 g (77.62%) of 10 as a colorless syrup:
1H NMR (CDCl3) δ 1.39 (s, 3H), 1.91 (dd, 1H, J ) 3.6, 14.5
Hz), 2.03 (s, 3H), 2.46 (m, 1H), 3.00 (m, 1H), 5.55 (m, 1H),
5.84 (dd, 1H, J ) 2.1, 5.5 Hz), 6.00 (m, 1H); 13C NMR (CDCl3)
δ 22.1, 27.4, 51.3, 77.0, 82.2, 135.0, 142.2, 170.2. Anal. Calcd
for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.43; H, 7.85.
(1R,4S)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-h yd r oxycy-
clop en t-2-en e (6). To a suspension of K2CO3 (5.18 g, 37.54
mmol) in MeOH (100 mL) was added 59 (8.0 g, 31.25 mmol)
followed by stirring at room temperature for 30 min. The
solvent was removed under reduced pressure and the residue
dissolved in ether (300 mL) and the ether solution washed with
brine (3 × 100 mL), dried (Na2SO4), and evaporated. The
residue was purified via column chromatography eluting with
hexanes/EtOAc (4:1) to afford 6.32 g (94.5%) of 6 as a colorless
oil: 1H NMR (CDCl3) δ 0.003 (s, 6H), 0.81 (s, 9H), 1.42 (dt,
1H, J ) 4.5, 9.1 Hz), 2.12 (s, 1H), 2.58 (dt, 1H, J ) 6.9, 9.2
Hz), 4.49 (t, 1H, J ) 5.8 Hz), 4.55 (t, 1H, J ) 5.2 Hz), 5.78 (d,
1H, J ) 4.5 Hz), 5.84 (d, 1H, J ) 4.5 Hz); 13C NMR (CDCl3) δ
-4.0, 18.8, 26.0, 45.2, 75.6, 75.9, 136.4, 137.3. Anal. Calcd for
C
11H22O2Si: C, 61.63; H, 10.34. Found: C, 61.33; H, 10.39.
(1′R,4′S)-4′-Meth yl-1′-(6-am in o-9H-pu r in -9-yl)cyclopen t-
2′-en -4′-ol (11). To a suspension of adenine (680 mg, 5.04
mmol) in dry DMF (30 mL) was added NaH (135 mg, 5.34
mmol, 95% dry powder), and the mixture was heated to 70 °C
with stirring for 30 min. To this suspension was added a
solution of a complex generated by the addition of tris-
(dibenzylideneacetone)dipalladium(0)‚CHCl3 (20 mg, 0.02 mmol)
and 1,3-bis(diphenyl)phosphinopropane (30 mg, 0.072 mmol)
to 720 mg (4.62 mmol) of allylic acetate 10 in dry THF (30
mL) with stirring for 15 min. The resulting mixture was stirred
at 60 °C for 2 days. The volatiles were removed by rotary
evaporation. The residue was then purified via column chro-
matography eluting with CH3OH/CH2Cl2 (1:4). The fractions
containing product were combined and the solvent was re-
moved under reduced pressure to give 342 mg (32.2%) of 11
(1R)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]cyclop en t-2-en -4-
on e (7). To a stirred suspension of pyridinium chlorochromate
(17.13 g, 79.5 mmol, 2.0 equiv) in dry CH2Cl2 (250 mL) was
added dropwise a solution of 6 (8.4 g, 39.25 mmol) in CH2Cl2
(40 mL). After 14 h, Et2O (750 mL) was added, and the reaction
mixture was filtered through silica gel. The filtrate was
concentrated in vacuo. The crude material was chromato-
graphed (9:1 hexanes/EtOAc) to afford 7.0 g (84.13%) of 7 as
(19) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides Nucleo-
tides 1993, 12, 267-278.
(20) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J .; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J . Med. Chem. 2001, 44, 3985-3993.
(21) (a) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K. J .
Org. Chem. 1999, 64, 4173-4178. (b) Song, G. Y.; Naguib, F. N. M.; el
Kouni, M. H.; Chu, C. K. Nucleosides Nucleotides Nucleic Acids 2001,
20, 1915-1925.
1
as a white solid: mp 122.4 °C; H NMR (DMSO-d6) δ 1.34 (s,
3H), 2.15 (dd, 1H, J ) 7.0, 14.1 Hz), 2.40 (t, 1H, J ) 13.3 Hz),
4.70 (brs, 1H), 5.36 (m, 1H), 5.68 (dd, 1H, J ) 2.3, 5.3 Hz),
6.15 (m, 1H), 7.29 (s, 2H), 8.11 (s, 1H), 8.12 (s, 1H); 13C NMR
(DMSO-d6) δ 27.7, 47.0, 57.8, 80.1, 119.0, 128.6, 139.6, 143.6,
148.7, 152.0, 156.0. Anal. Calcd for C11H13N5O: C, 57.13; H,
5.67; N, 30.28. Found: C, 57.25; H, 5.59; N, 30.17.
(22) Santana, L.; Teijeira, M.; Tera´n, C.; Uriarte, E.; Vida, D.
Synthesis 2001, 1532-1538.
(23) For leading references on the procedures used for the assays,
see refs 1d, 6, 13, and: Barnard, D. L.; Stowell, V. D.; Seley, K. L.;
Hegde, V. R.; Das, S. R.; Rajappan, V. P.; Schneller, S. W.; Smee, D.
F.; Sidwell, R. W. Antiviral Chem. Chemother. 2001, 12, 241-250.
J . Org. Chem, Vol. 68, No. 24, 2003 9271

Roy and Schneller
(1′R,2′S,3′S,4′S)-4′-Meth yl-1′-(6-a m in o-9H-p u r in -9-yl)cy-
clop en ta n e-2′,3′,4′-tr iol (2). To a solution of 11 (200 mg, 0.87
mmol) in THF/H2O (10:1, 20 mL) was added a 50% aqueous
solution of N-methylmorpholine N-oxide (0.26 mL, 1.13 mmol)
and OsO4 (25 mg). The reaction mixture was stirred at room
temperature for 24 h until TLC showed no remaining starting
material. The solvent was removed by rotary evaporation, and
the residue was coevaporated with EtOH (3 × 50 mL) to give
a gummy material. This crude material was purified by column
chromatography (eluent EtOAc/MeOH, 4:1) to afford 2 (161
and diisopropyl azodicarboxylate (1.56 mL, 7.68 mmol) was
added over a period of 10 min. This mixture was stirred at
-20 °C for 20 min to yield a white precipitate of triphen-
ylphosphine-diisopropyl azodicarboxylate complex. To this
latter complex as a suspension were added a solution of 14
(1.60 g, 6.40 mmol) in dry THF (20 mL) and benzoic acid (939
mg, 7.68 mmol). The cooling bath was removed, and the
reaction mixture was stirred at room temperature for 2 h. After
evaporation of the reaction mixture to dryness, the residue
was purified via flash chromatography eluting with hexanes/
EtOAc (3:1) to afford 15 (1.55 g, 67%) as a white solid: mp
mg, 70.2%) as a white solid: mp 202-203 °C; [R]25 -4.0 (c
D
0.81, MeOH); 1H NMR (DMSO-d6) δ 1.22 (s, 3H), 1.82 (dd, 1H,
J ) 4.4, 14.2 Hz), 2.40 (t, 1H, J ) 10.95 Hz), 3.51 (d, 1H, J )
2.1 Hz), 4.65 (t, 1H, J ) 2.4 Hz), 4.70 (m, 1H), 4.95 (d, 1H,
J ) 2.2 Hz), 5.03 (d, 1H, J ) 4.3 Hz), 5.56 (s, 1H), 7.30 (s,
2H), 8.11 (s, 1H), 8.15 (s, 1H); 13C NMR (DMSO-d6) δ 23.5,
42.8, 59.3, 77.4, 77.5, 79.0, 119.1, 140.0, 149.1, 151.9, 156.1.
Anal. Calcd for C11H15N5O3: C, 49.81; H, 5.70; N, 26.40.
Found: C, 49.98; H, 5.64; N, 26.34.
1
171.3-172.1 °C; H NMR (CDCl3) δ 1.89 (s, 3H), 2.57 (d, 1H,
J ) 13.16 Hz), 2.87 (dd, 1H, J ) 5.98, 13.20 Hz), 4.95 (d, 1H,
J ) 4.5 Hz), 6.06 (d, 1H, J ) 5.4 Hz), 6.28 (dd, 1H, J ) 4.8,
5.4 Hz), 7.43 (t, 2H, J ) 7.6 Hz), 7.55 (d, 1H, J ) 7.5 Hz), 8.03
(d, 2H, J ) 7.7 Hz), 8.42 (s, 1H), 8.74 (s, 1H); 13C NMR (CDCl3)
δ 26.9, 48.2, 71.4, 75.1, 128.6 (2C), 129.9 (2C), 130.7, 131.5
(2C), 133.3 (2C), 139.8, 144.7, 150.6, 151.6, 166.2. Anal. Calcd
for C18H15N4O2Cl: C, 60.94; H, 4.26; N, 15.79. Found: C, 60.61;
H, 4.53; N, 15.91.
(1′S,2′R,3′R,4′R)-4′-Meth yl-1′-(6-a m in o-9H-p u r in -9-yl)-
cyclop en t a n e-2′,3′,4′-t r iol (en t-2). Beginning with (+)-
(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate19 (enantiomer of
4) and following Schemes 1 and 2 produced ent-2: mp 202-
203 °C; [R]25D +3.9 (c 0.76, MeOH); 1H NMR (DMSO-d6) δ 1.21
(s, 3H), 1.82 (dd, 1H, J ) 4.4, 14.2 Hz), 2.40 (t, 1H, J ) 10.96
Hz), 3.51 (d, 1H, J ) 2.1 Hz), 4.65 (t, 1H, J ) 2.4 Hz), 4.70 (m,
1H), 4.96 (d, 1H, J ) 2.2 Hz), 5.03 (d, 1H, J ) 4.3 Hz), 5.56 (s,
1H), 7.29 (s, 2H), 8.11 (s, 1H), 8.15 (s, 1H); 13C NMR (DMSO-
d6) δ 23.4, 42.8, 59.3, 77.4, 77.4, 79.0, 119.1, 140.0, 149.1 151.9,
156.1. Anal. Calcd for C11H15N5O3: C, 49.81; H, 5.70; N, 26.40.
Found: C, 49.96; H, 5.66; N, 26.33.
(1′S,2′R,3′S,4′R)-2′,3′-Dih yd r oxy-4′-m eth yl-4′-(6-ch lor o-
9H-p u r in -9-yl)cyclop en t-1′-yl Ben zoa te (16). To a solution
of 15 (1.00 g, 2.82 mmol) in THF/H2O (9:1, 60 mL) was added
a 50% aqueous solution of N-methylmorpholine N-oxide (1.3
mL, 5.64 mmol) and OsO4 (40 mg). Following stirring at room
temperature for 24 h, the solvent was removed by rotary
evaporator and the residue coevaporated with EtOH (3 × 50
mL) to give a gummy material. This crude material was
purified by flash chromatography (eluent EtOAc/hexanes, 3:2)
to afford 16 (905 mg, 82.3%) as a white solid: mp 181.4-182.3
°C; 1H NMR (CDCl3) δ 1.86 (s, 3H), 2.09 (d, 1H, J ) 13.57
Hz), 2.85 (dd, 1H, J ) 6.3, 13.57 Hz), 3.41 (brs, 1H) 4.21 (brs,
1H), 4.36 (d, 2H, J ) 8.47 Hz) 4.68 (d, 1H, J ) 6.1 Hz), 7.35 (t,
2H, J ) 7.7 Hz), 7.51 (d, 1H, J ) 7.68 Hz), 7.96 (d, 2H, J )
7.8 Hz), 8.22 (s, 1H), 8.64 (s, 1H); 13C NMR (CDCl3) δ 28.6,
44.7, 67.6, 75.2, 78.7, 80.7, 128.8 (2C), 130.1 (2C), 133.1, 133.6,
145.3, 150.6, 151.4, 152.1, 152.4, 167.1. Anal. Calcd for
(1′R,4′R)-4′-[(ter t-Bu tyld im eth ylsilyl)oxy]-1′-m eth yl-1′-
(6-ch lor o-9H-p u r in -9-yl)-2′-cyclop en ten e (13). A solution
of triphenyphosphine (8.10 g, 30.81 mmol) in dry THF (100
mL) was cooled to -20 °C (dry ice bath), and diisopropyl
azodicarboxylate (6.1 mL, 30.81 mmol) was added over a period
of 10 min. This mixture was stirred at -20 °C for 20 min to
yield a white precipitate of the triphenylphosphine-diisopropyl
azodicarboxylate complex. To this latter complex as a suspen-
sion were added 6-chloropurine (4.40 g, 28.46 mmol) and a
solution of 8 (5.40 g, 23.7 mmol) in dry THF (30 mL). The
cooling bath was removed, and the reaction mixture was
stirred at room temperature for 24 h. The solvent was removed
under reduced pressure, and the residue was purified via
column chromatography eluting with hexanes/EtOAc (3:1) to
C
18H17N4O4Cl: C, 55.61; H, 4.41; N, 14.41. Found: C, 55.74;
H, 4.52; N, 14.28.
(1′R,2′S,3′R,4′S)-1′-Met h yl-1′-(6-a m in o-9H -p u r in -9-yl)-
cyclop en ta n e-2′,3′,4′-tr iol (3). A solution of 16 (100 mg, 0.26
mmol) in dry MeOH (40 mL) was saturated with NH3. This
mixture was heated in a Parr stainless steel sealed reaction
vessel at 120 °C for 24 h. After being cooled to room temper-
ature, the reaction mixture was evaporated to dryness and the
residue purified by flash chromatography using EtOAc/MeOH
1
afford 2.60 g (30%) of 13 as a white solid: mp 154.6 °C; H
NMR (CDCl3) δ 0.12 (s, 6H), 0.82 (s, 9H), 1.90 (s, 3H), 2.17 (d,
1H, J ) 13.9 Hz), 2.87 (dd, 1H, J ) 6.67, 13.94 Hz), 4.90 (d,
1H, J ) 4.5 Hz), 6.12 (d, 1H, J ) 4.6 Hz), 6.18 (dd, 1H, J )
4.6, 5.53 Hz), 8.02 (s, 1H), 8.68 (s, 1H); 13C NMR (CDCl3) δ
-4.5, 18.3, 26.0, 28.2, 48.2, 71.1, 77.3, 132.9, 134.3, 140.2,
143.4, 151.4, 151.5, 152.0. Anal. Calcd for C17H25N4OClSi: C,
55.95; H, 6.90; N, 15.35. Found: C, 55.89; H, 6.96; N, 15.29.
(1′R,4′R)-1′-Meth yl-1′-(6-ch lor o-9H-p u r in -9-yl)-2′-cyclo-
p en ten -4′-ol (14). A mixture of 13 (1 g, 2.74 mmol) and K-10
clay (1.37 g) in EtOAc/MeOH/H2O (45 mL) (1:6:2) were stirred
at 75 °C for 8 h. The reaction mixture was then filtered
through Celite and washed with MeOH. The combined filtrates
were concentrated and the residue coevaporated (3×) with
EtOAc/toluene (1:2) under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/EtOAc
(1:1) to afford 14 (490 mg, 71%) as a white solid: mp 165.5-
166.8 °C; 1H NMR (CDCl3) δ 1.88 (s, 3H), 2.41 (d, 1H, J )
12.81 Hz), 2.79 (dd, 1H, J ) 5.7, 12.82 Hz), 4.39 (d, 1H, J )
5.9 Hz), 4.71 (d, 1H, J ) 5.2 Hz), 6.12 (d, 1H, J ) 4.8 Hz),
6.19 (dd, 1H, J ) 4.7, 5.54 Hz), 8.22 (s, 1H), 8.74 (s, 1H); 13C
NMR (CDCl3) δ 26.3, 41.7, 67.7, 75.7, 132.9, 134.3, 144.0, 144.2,
151.3, 151.5, 152.1. Anal. Calcd for C11H11N4OCl: C, 52.70; H,
4.42; N, 22.35. Found: C, 52.52; H, 4.54; N, 22.39.
(5:1) to afford 3 (50 mg, 73.3%) as a white solid: mp 221.4-
1
222.5 °C; [R]22 + 41.57 (c 0.14, MeOH); H NMR (DMSO-d6)
D
δ 1.70 (s, 3H), 1.97 (d, 1H, J ) 12.80 Hz), 2.95 (dd, 1H, J )
5.6, 12.90 Hz), 3.46 (brs, 1H) 4.05 (d, 1H, J ) 5.4 Hz), 4.37
(brs, 1H), 4.57 (d, 1H, J ) 4.1 Hz), 4.85 (brs, 1H), 5.08 (d, 1H,
J ) 4.1 Hz), 7.18 (s, 2H), 8.16 (s, 1H), 8.20 (s, 1H); 13C NMR
(DMSO-d6) δ 26.5, 43.1, 65.2, 75.1, 77.2, 79.5, 119.4, 140.4,
149.7, 151.7, 156.0. Anal. Calcd for C11H15N5O3: C, 49.81; H,
5.70; N, 26.40. Found: C, 50.01; H, 5.73; N, 26.21.
(1′S,2′R,3′S,4′R)-2′,3′-(Isop r op ylid en ed ioxy)-4′-m eth yl-
4′-(6-ch lor o-9H-p u r in -9-yl)cyclop en t-1′-yl Ben zoa te (17).
Compound 16 (1.00 g, 2.57 mmol) was dissolved in a solution
of dry acetone (30 mL) and 2,2-dimethoxypropane (10 mL). To
this was added p-toluenesulfonic acid (150 mg) and the
reaction mixture stirred at room temperature for 12 h. The
mixture was then brought to pH 7 with NH4OH. Following
this, the acetone was evaporated under vacuum. The residue
was dissolved in EtOAc (100 mL), and this solution was
washed with brine (3 × 25 mL). The combined organic layers
were dried (Na2SO4) and filtered, and the filtrate was concen-
trated under vacuum to give a crude residue, which was
purified by column chromatography (eluent EtOAc/hexanes,
1:3) to afford 17 (892 mg, 81.1%) as a white solid: mp 165.4-
166.7 °C; 1H NMR (CDCl3) δ 1.25 (s, 3H), 1.42 (s, 3H), 1.87 (s,
3H), 2.42 (d, 1H, J ) 12.87 Hz), 2.80 (dd, 1H, J ) 5.7, 13.00
Hz), 4.75 (d, 1H, J ) 5.46 Hz), 4.92 (d, 1H, J ) 5.44 Hz), 5.13
(1′S,4′R)-4′-Meth yl-4′-(6-ch lor o-9H-p u r in -9-yl)-2′-cyclo-
p en ten -1′-yl Ben zoa te (15). A solution of triphenylphosphine
(2.02 g, 7.68 mmol) in dry THF (50 mL) was cooled to -20 °C,
9272 J . Org. Chem., Vol. 68, No. 24, 2003

4′- and 1′-Methyl-Substituted 5′-Norcarbanucleosides
(d, 1H, J ) 8.82 Hz), 7.38 (t, 2H, J ) 7.9 Hz), 7.50 (d, 1H, J )
7.88 Hz), 7.98 (d, 2H, J ) 8.10 Hz), 8.36 (s, 1H), 8.78 (s, 1H);
13C NMR (CDCl3) δ 25.4, 27.2, 27.3, 44.8, 68.6, 77.8, 86.2, 87.4,
111.7, 128.6 (2C), 129.9 (2C), 131.3, 133.1, 133.2, 145.2, 150.9,
152.0 (2C), 166.2. Anal. Calcd for C21H21N4O4Cl: C, 58.81; H,
4.94; N, 13.06. Found: C, 58.74; H, 4.92; N, 13.08.
pound 19 (200 mg, 0.5 mmol) afforded 90 mg (77.57%) of 20
as white crystals: mp 195.7-196.8 °C; 1H NMR (DMSO-d6) δ
1.15 (s, 3H), 1.17 (s, 3H), 1.73 (s, 3H), 2.44 (d, 1H, J ) 13.08
Hz), 2.75 (dd, 1H, J ) 5.70, 13.00 Hz), 4.04 (d, 1H, J ) 5.65
Hz), 4.52 (d, 1H, J ) 5.10 Hz), 5.14 (d, 1H, J ) 5.20 Hz), 5.34
(brs, 1H), 7.15 (s, 2H), 8.10 (s, 1H), 8.13 (s, 1H); 13C NMR
(DMSO-d6) δ 24.3, 25.8, 26.7, 43.0, 67.6, 75.0, 83.0, 86.0, 111.7,
119.3, 140.2, 149.6, 151.6, 155.9. Anal. Calcd for C14H19N5O3:
C, 55.07; H, 6.27; N, 22.94. Found: C, 54.94; H, 6.22; N, 22.74.
(1′R,2′S,3′R,4′R)-1′-Meth yl-1′-(6-a m in o-9H-p u r in -9-yl)-
cyclop en ta n e-2′,3′,4′-tr iol (21). The compound 20 (80 mg,
0.26 mmol) was dissolved in 0.5 N HCl in MeOH (25 mL). This
reaction mixture was stirred for 30 min at room temperature
and the solution evaporated under reduced pressure to yield
a residue that was azeotroped with MeOH. The resultant
residue was dissolved in MeOH, and the pH adjusted to 7 by
treating the solution with IRA 400 (basic) resin. The resin was
removed by filtration and washed with MeOH. The combined
filtrates were evaporated under reduced pressure to produce
a residue that was purified by column chromatography using
EtOAc/MeOH (4:1) as eluent to give 21 (55.00 mg, 79.14%) as
a white crystalline solid: mp 212.5-213.4 °C; [R]22D -18.23 (c
0.12, MeOH); 1H NMR (DMSO-d6) δ 1.68 (s, 3H), 1.94 (d, 1H,
J ) 12.70 Hz), 2.97 (dd, 1H, J ) 5.5, 12.80 Hz), 3.68 (brs, 1H)
4.00 (d, 1H, J ) 5.2 Hz), 4.21 (brs, 1H), 4.61 (d, 1H, J ) 4.2
Hz), 4.93 (brs, 1H), 5.11 (d, 1H, J ) 4.2 Hz), 7.16 (s, 2H), 8.14
(s, 1H), 8.19 (s, 1H); 13C NMR (DMSO-d6) δ 26.5, 43.0, 65.1,
75.1, 77.1, 79.4, 119.4, 140.4, 149.7, 151.6, 156.0. Anal. Calcd
for C11H15N5O3: C, 49.81; H, 5.70; N, 26.40. Found: C, 50.02;
H, 5.54; N, 26.39.
(1′R,2′S,3′R,4′S)-2′,3′-(Isop r op ylid en ed ioxy)-1′-m eth yl-
1′-(6-ch lor o-9H-p u r in -9-yl)cyclop en t a n -4′-ol (18). To a
solution of 17 (850 mg, 1.98 mmol) in MeOH was added four
drops of H2O and a catalytic amount of KCN (40 mg). The
mixture was stirred at room temperature for 2.5 h. After
evaporation of the reaction mixture to dryness, the residue
was purified via flash chromatography (eluent hexanes/EtOAc,
1:1) to afford 18 (580 mg, 90.10%) as a white solid: mp 174.2-
175.1 °C; 1H NMR (CDCl3) δ 1.24 (s, 3H), 1.43 (s, 3H), 1.79 (s,
3H), 2.32 (d, 1H, J ) 12.86 Hz), 2.70 (dd, 1H, J ) 5.6, 13.08
Hz), 3.72 (brs, 1H), 4.74 (d, 1H, J ) 5.08 Hz), 4.90 (d, 1H, J )
5.05 Hz), 5.15 (d, 1H, J ) 8.56 Hz), 8.07 (s, 1H), 8.63 (s, 1H);
13C NMR (CDCl3) δ 24.4, 26.3, 26.7, 42.6, 68.1, 77.7, 86.4, 87.0,
111.7, 131.9, 146.1, 150.6, 151.7, 151.8. Anal. Calcd for
C14H17N4O3Cl: C, 51.78; H, 5.28; N, 17.25. Found: C, 51.74;
H, 5.22; N, 17.08.
(1′R,2′R,3′S,4′R)-2′,3′-(Isop r op ylid en ed ioxy)-4′-m eth yl-
4′-(6-ch lor o-9H-p u r in -9-yl)cyclop en t-1′-yl Ch lor oa ceta te
(19). To a solution of 18 (250 mg, 0.77 mmol) in anhydrous
toluene (30 mL) were added triphenylphosphine (405 mg, 1.54
mmol) and dry chloroacetic acid (146 mg, 1.54 mmol). To this
stirred solution diisopropyl azodicarboxylate (0.31 mL, 1.54
mmol) was added dropwise, causing a slightly exothermic
reaction. The resulting pale yellow solution was stirred at room
temperature for 16 h. The volatile components were then
removed in vacuo, and the residue was purified via flash
chromatography eluting with hexanes/EtOAc (3:1) to afford
19 (220 mg, 71.20%) as a white solid: mp 161.8-162.5 °C; 1H
NMR (CDCl3) δ 1.23 (s, 3H), 1.41 (s, 3H), 1.86 (s, 3H), 2.43 (d,
1H, J ) 12.85 Hz), 2.80 (dd, 1H, J ) 5.65, 13.07 Hz), 4.07 (s,
2H), 4.70 (d, 1H, J ) 5.45 Hz), 4.87 (d, 1H, J ) 5.44 Hz), 5.08
(d, 1H, J ) 8.82 Hz), 8.34 (s, 1H), 8.73 (s, 1H); 13C NMR
(CDCl3) δ 24.5, 26.3, 26.5, 37.4, 44.8, 68.6, 77.5, 84.6, 87.6,
111.1, 132.2, 145.6, 151.5, 152.1, 152.4, 166.4. Anal. Calcd for
Ack n ow led gm en t. This research was supported by
funds from the Department of Health and Human
Services (AI 48495 and AI 56540), whose support is
appreciated. We also thank Dr. Erik De Clercq, the Rega
Institute, Leuven, Belgium; Dr. Earl Kern, University
of Alabama at Birmingham, Birmingham, AL; Dr. Brent
Korba, Georgetown University, Washington, DC; and
Dr. Robert Sidwell, Utah State University, Logan, UT,
for the antiviral testing. We are grateful to Dr. Lyle
Castle, Idaho State University, Pocatello, ID, for his
assistance with the NMR structural determinations.
C
16H18N4O4Cl2: C, 47.89; H, 4.52; N, 13.96. Found: C, 47.63;
H, 4.54; N, 13.99.
(1′R,2′S,3′R,4′R)-2′,3′-(Isop r op ylid en ed ioxy)-1′-m eth yl-
1′-(6-a m in o-9H-p u r in -9-yl)cyclop en ta n -4′-ol (20). Employ-
ing the same ammonolysis procedure that produced 3, com-
J O030238G
J . Org. Chem, Vol. 68, No. 24, 2003 9273