5′-Noraristeromycin possessing a C-1′ cyclopentyl double bond: A new carbanucleoside structural prototype

Article abstract of DOI:10.1016/j.tet.2004.02.032

Prior to this work only two examples of carbanucleosides possessing a C-1′/C-6′ double bond had been reported and they were minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential antiviral agents, the 5′-nor derivative of aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment of (1′S,2′S, 3′S,4′R,5′S)-6-chloro-9-(2′,3′- isopropylidenedioxy-6′-oxabicyclo[3.1.0]hex-4′-yl)purine (7) with sodium methoxide yielded 6 via an E′₂-like elimination pathway. A convenient way to the C-4′ epimer of 6 (that is, 17) also arose during these studies and is described. Antiviral analysis of 6 and 17 failed to produce any significant activity.

Full text of DOI:10.1016/j.tet.2004.02.032

Tetrahedron 60 (2004) 3451–3455
50-Noraristeromycin possessing a C-10 cyclopentyl double bond:
a new carbanucleoside structural prototype
*
Xue-qiang Yin and Stewart W. Schneller
Department of Chemistry, Auburn University, Chemistry Building, Auburn, AL 36849, USA
Received 12 January 2004; revised 13 February 2004; accepted 13 February 2004
Abstract—Prior to this work only two examples of carbanucleosides possessing a C-10/C-60 double bond had been reported and they were
minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential
antiviral0agents,0the050-nor derivative0of0aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment
of (100S,2 S,30S,4 R,5 S)-6-chloro-9-(2 ,3 -isopropylidenedioxy-600-oxabicyclo[3.1.0]hex-40-yl)purine (7) with sodium methoxide yielded 6 via
an E2-like elimination pathway. A convenient way to the C-4 epimer of 6 (that is, 17) also arose during these studies and is described.
Antiviral analysis of 6 and 17 failed to produce any significant activity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
relocations of 5. This class of carbanucleosides has received
very little attention.5 It is with this and the biological
properties of 4 in mind that compound 6 was sought. Its
synthesis and that of its C-30-epimer (17) and their antiviral
properties are described here (Fig. 1).
Carbanucleosides have moved to a prominent position in
biochemistry and medicinal chemistry.1 Within this class of
compounds are the unsaturated neplanocins (1-3)1a and the
50-nor carbanucleosides (for example, 50-noraristeromycin,
4).2,3 Imposing the neplanocin structure on 50-nor carba-
nucleosides (for example, 5a) would be complicated by the
participation of 5a in the enol–keto tautomeric cascade4
depicted in Scheme 1. However, the allylic alc0oholic isomer
of the 5-series0, 6 (Scheme 2), with the C-1 /C-60 (herein
designated C-1 /C-20) double bond,3 would be a neplanocin-
related analogue that would not be vulnerable to the alkene
A key step in our retrosynthetic analysis to 6 (Scheme 2)
was the selective epoxide ring opening of 7 using alkoxide60
in an E20 process involving base abstraction of the C-4
hydrogen. Compound 7 was foreseen to be available in
several steps from 6-chloropurine (8) and (2)-(4R,5R)-4,5-
(isopropylidenedioxy)cyclopent-2-en-1-one (9).7 Two
alternative procedures were considered for modifying 9
Scheme 1.
Keywords: Neplanocin analogs; Mitsunobu coupling; Epoxide ring opening; Antiviral.
*
Corresponding author. Tel.: þ1-334-844-5737; fax: þ1-334-844-5824; e-mail address: schnest@auburn.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.032

3452
X. Yin, S. W. Schneller / Tetrahedron 60 (2004) 3451–3455
Scheme 2.
Treatment of 7 with sodium methoxide at room temperature
for 2 h gave 13 (Scheme 3). On the other hand, similar
reaction conditions with epoxide 12 led to only methoxy
substitution of the 6-chloro substituent; only by refluxing for
15 h could 12 be converted to 14 (Scheme 4).
Scheme 4. Reaction conditions: (a) NaOMe, MeOH, reflux, 15 h (93%);
(b)(i) NH3, MeOH; (ii) 0.5 N HCl, MeOH (56%).
The structure of 13 was assigned by NMR methods. In that
regard, D2O exchange of the hydroxyl hydrogen along with
1H COSY permitted assignment of the hydrogens of the
cyclopentenyl ring. HMBC then showed correlation
between H-8 (8.3 ppm) and C-20 (121 ppm) (Fig. 2). The
C-200 was assigned by correlation (HMQC) with the olefinic
H-2 (assigned by 1H COSY). All other HMBC and HMQC
correlations support 13 as the structure. Furthermore, NOE
measurements demonstrated a correlation between H-40 and
H-500 (cyclopentenyl numbering) but no correlation between
H-3 and H-40 (Fig. 2). Thus, H-30 and H-40 are anti to each
other.
Figure 1. Ref. 3.
prior to a coupling with 8 (Scheme 3): (i) olefinic
epoxidation8 followed by carbonyl reduction (path a) and,
conversely, (ii) reduction of the ketone followed by
epoxidation (path b). In the former case, only the b-epoxide
10 was obtained whereas, via the latter method, both 10 and
the a-epoxide 11 were realized.9 Mitsunobu coupling of 10
(obtained from either method but pathway a was preferred
because of higher yield in less reaction time) with 8
provided 7. In a similar way, 11 yielded 12.
Figure 2.
In contrast to 13, the structure of 14 was difficult to confirm
by NMR. Thus, a chemical structure proof was sought. For
that purpose, attempts to employ a Mitsunobu inversion of
the 30-hydroxyl of 13 to compare to 14 consistently led to
loss of the cyclopentenyl ring and isolation of 6-methoxy-
purine (Scheme 5). This result is postulated to have occurred
via dual attack of 15 by the nucleophiles present under the
Scheme 3. Reaction conditions: (a)(i) t-BuOOH, Triton B, THF, MeOH
(92%); (ii) NaBH4, CeCl3·7H2O, MeOH (10 only, 75%); (b)(i) same as
(a)(ii); (ii) m-CPBA, CH2Cl2 (10, 37%; 11, 12%); (c) 6-chloropurine, Ph3P,
DIAD, THF (63% for 7; 56% for 12); (d) NaOMe, MeOH, 2 h, rt (89%);
(e)(i) NH3, MeOH; (ii) 0.5 N HCl, MeOH (73%).

X. Yin, S. W. Schneller / Tetrahedron 60 (2004) 3451–3455
3453
Scheme 5. Reaction conditions: (a) PhCO2H or p-NO2C6H4CO2H, DIAD, PPh3; (b) for R¼Bz, Nu¼NH3/MeOH or NaOMe/MeOH; for R¼p-NO2C6H4CO,
Nu¼K2CO3/MeOH.
Mitsunobu inversion conditions. Alternatively, oxidation of
13 with pyridinium chlorochromate to 16 was followed by
stereoselective reduction of this enone with Luche’s
reagent10 to yield a product whose spectral data was
identical to that previously assigned as 14 (Scheme 6).
(doublet of doublets), t (triplet), m (multiplet), and br
(broad). Coupling constants (J) are expressed in Hz.
Atlantic Microlabs, Atlanta, Georgia, performed the
elemental analyses. Reactions were monitored by thin
layer chromatography (TLC) using 0.25 mm E. Merck silica
gel 60-F254 precoated silica gel plates with visualization by
irradiation with a Mineral light UVGL-25 lamp or exposure
to iodine vapor. Column chromatography was performed on
˚
Whatman silica gel (average particle size 5–25 mm, 60 A)
and elution with the indicated solvent system. Yields refer to
chromatographically and spectroscopically (1H and 13C
NMR) homogeneous materials. The reactions were gener-
ally carried out in a N2 atmosphere under anhydrous
conditions.
2.1.1. (1S,2R,3S,4S,5S)-4-Hydroxy-2,3-isopropylidene-
dioxy-6-oxabicyclo[3.1.0]-hexane
(10)
and
Scheme 6. Reaction conditions: (a) PCC, Celite, CH2Cl2 (88%); (b) NaBH4;
CeCl3·7H2O, MeOH (85%).
(1R,2R,3S,4S,5R)-4-hydroxy-2,3-isopropylidenedioxy-6-
oxa-bicyclo[3.1.0]hexane (11). Method a. To a solution of
enone 9 (0.72 g, 4.5 mmol) and t-butyl hydrogen peroxide
(0.63 mL, 4.5 mmol, 70% wt in H2O) in THF (20 mL) in a
salt-ice bath was added Triton B (1.08 mL, 40% in MeOH)
dropwise. The reaction was then stirred for 2 h at the same
temperature. The reaction mixture was quenched by adding
ice H2O (5 mL) and the solvents removed. The residue was
extracted with EtOAc (2£10 mL) and dried (MgSO4). The
organic solvent was evaporated to give a pale yellow oil
(700 mg, 92%), which was used directly in the next step
without further purification.
The desired 6 was obtained by ammonolysis of 13 with
subsequent removal of the isopropylidene protecting group
with 0.5 N hydrochloric acid (Scheme 3).
The epimer 17 was synthesized from 14 by a route similar to
that for obtaining 6 from 13 (Scheme 4).
If desired, the L-like derivatives of 6 and 17 could be
prepared by beginning with the enantiomer of 9.11 This
procedure is also adaptable to other heterocyclic bases.12
Compounds 6 and 17 were subjected to antiviral analysis13
and found to be inactive and to display no cytotoxicity
except for 6 towards the Daudi host cells (IC50 11.3 mg/mL;
ganciclovir IC50 40 mg/mL, acyclovir IC50.50 mg/mL)
used in the Epstein-Barr assay.
To the solution of the yellow oil (600 mg, 3.52 mmol) and
CeCl3·7H2O (1.31 g) at 0 8C in MeOH (10 mL) was added
NaBH4 (170 mg, 4.59 mmol) portionwise. The reaction
mixture was stirred at 0 8C for 10 min and evaporated. The
residue was diluted with H2O (10 mL), extracted with
EtOAc (3£20 mL) and dried (MgSO4). Evaporation of the
organic solvent gave the b-epoxide 10 as a light yellow oil
(450 mg, 75%), which was pure enough for the use in the
2. Experimental
1
preparation of 7: H NMR (CDCl3) d 4.70 (d, J¼5.5 Hz,
1H), 4.49 (t, J¼5.7 Hz, 1H), 4.09 (t, J¼5.5 Hz, 1H), 3.64 (s,
1H), 3.62 (s, 1H), 2.86 (d, J¼5.4 Hz, 1H), 1.59 (s, 3H), 1.39
(s, 3H); 13C NMR (CDCl3) d 113.8, 80.5, 77.7, 68.9, 60.8,
58.4, 26.4, 24.7.
2.1. Materials and methods
Melting points were recorded on a Meltemp II melting point
1
apparatus and are uncorrected. H and 13C NMR spectra
were recorded on a Bruker AC 250 spectrometer (operated
1
Method b. To a solution of the allylic alcohol (from
reduction of the enone 914) (6.0 g, 38.9 mmol) in CH2Cl2
(100 mL) was added m-CPBA (5.25 g, 75% max by weight)
at room temperature. The mixture was refluxed for 5 days.
The reaction mixture was then diluted with CH2Cl2
(100 mL), washed with saturated Na2CO3 solution
at 250 or 62.5 MHz, respectively). All H chemical shifts
are reported in d relative to internal standard tetramethyl-
silane (TMS, d 0.00). 13C chemical shifts are reported in d
relative to CDCl3 (center of triplet, d 77.23) or relative to
DMSO-d6 (center of septet, d 39.51). The spin multiplicities
are indicated by the symbols s (singlet), d (doublet), dd

3454
X. Yin, S. W. Schneller / Tetrahedron 60 (2004) 3451–3455
(3£100 mL), brine (100 mL) and dried (MgSO4). The
organic layer was filtered and evaporated. The resulting
residue was purified by column chromatography (EtOAc/
hexanes, 1:10 and 1:2) to give some remaining starting
material, b-epoxide 10 (2.43 g, 37%) and a-epoxide 11
(0.74 g, 12%) as a light yellow oil; 11: 1H NMR (CDCl3) d
4.65 (d, J¼6.7 Hz, 1H), 4.48 (t, J¼6.8 Hz, 1H), 4.23 (d,
J¼6.7 Hz, 1H), 3.53 (d, J¼2.0 Hz, 1H), 3.49 (d, J¼2.0 Hz,
1H), 2.77 (brs, 1H), 1.59 (s, 3H), 1.33 (s, 3H); 13C NMR
(CDCl3) d 114.8, 79.3, 76.3, 70.8, 62.3, 56.7, 26.5, 26.2.
Both 10 and 11 were too unstable for microanalysis but were
of sufficient purity to use in the synthesis of 7 and 12,
respectively.
as a white solid (97 mg, 89%), mp 154 8C; 1H NMR
(CDCl3) d 8.61 (s, 1H, H-2), 8.36 (s, 1H, H-8), 6.92 (d,
J¼2.4 Hz, 1H, H-20), 5.69 (d, J¼5.6 Hz, 1H, H-50), 4.98 (m,
1H, H-30), 4.71 (d, J¼5.7 Hz, 1H, H-40), 4.21 (s, 3H, OMe),
2.25 (d, J¼5.7 Hz, 1H, OH), 1.43 (s, 3H, Me), 1.40 (s, 3H,
Me); 13C NMR (CDCl3) d 163.1, 154.7, 140.0, 140.0, 124.0,
121.1, 115.1, 86.7, 84.0, 80.3, 79.1, 56.2, 29.1, 27.8. Anal.
Calcd for C14H16N4O4: C, 55.26; H, 5.26; 18.42. Found: C,
55.09; H, 5.31; N, 18.22.
2.1.5. (30R,40R,50S)-9-(30-Hydroxy-40,50-isopropylidene-
dioxycyclopenten-10-yl)6-methoxypurine (14). To a stir-
ring solution of epoxide 12 (480 mg, 1.57 mmol) in 10 mL
of dry THF at room temperature under N2 was added
sodium methoxide solution (1 mL, 3.14 mmol, 25% wt in
MeOH). The mixture was refluxed overnight at 70 8C and
the solvents removed. To the residue was added H2O
(10 mL) and this mixture extracted with EtOAc (3£10 mL).
The combined extracts were evaporated and further purified
by column chromatography with hexanes–EtOAc (1:2) to
give 14 as a white solid (450 mg, 93%), mp 147–148 8C; 1H
NMR (CDCl3) d 8.61 (s, 1H), 8.37 (s, 1H), 6.85 (s, 1H), 5.46
(d, J¼5.5 Hz, 1H), 4.93 (t, J¼5.5 Hz, 1H), 4.90 (m, 1H),
4.21 (d, J¼0.7 Hz, 3H), 2.81 (brs, 1H, OH), 1.49 (s, 3H),
1.45 (s, 3H); 13C NMR (CDCl3) d 161.5, 153.1, 152.1,
140.5, 135.4, 122.3, 122.2, 114.0, 81.8, 77.7, 72.4, 54.6,
27.8, 26.7. Anal. Calcd for C14H16N4O4: C, 55.26; H, 5.26;
18.42. Found: C, 55.45; H, 5.36; N, 18.20.
2.1.2. (10S,20S,30S,40R,50S)-6-Chloro-9-(20,30-isopropylide-
nedioxy-60-oxabicyclo-[3.1.0]hex-40-yl)purine (7). To a
stirred suspension of 6-chloropurine (2.05 g, 13.62 mmol)
and triphenylphosphine (3.58 g, 13.62 mmol) in THF
(20 mL) at 210 8C was added, dropwise, diisopropyl
azodicarboxylate (2.48 g, 13.62 mmol). This mixture was
stirred at 210 8C for 10 min and then stirred at room
temperature for 15 min. To this mixture was added a
solution of 10 (2.3 g, 13.72 mmol) in dry THF (10 mL). The
new mixture was stirred at room temperature for 48 h and
concentrated under vacuum. Column chromatography with
hexanes–EtOAc (4:1) provided a white solid of desired 7
(2.7 g, 63%), mp 142–143 8C; 1H NMR (CDCl3) d 8.80 (s,
1H), 8.39 (s, 1H), 5.35 (t, J¼1.2 Hz, 1H), 4.94 (d, J¼3.5 Hz,
1H), 4.47 (d, J¼2.8 Hz, 1H), 3.93 (s, 1H), 3.92 (s, 1H), 1.61
(s, 3H), 1.34 (s, 3H); 13C NMR (CDCl3) d 152.6, 152.2,
151.5, 143.9, 131.5, 114.1, 85.8, 79.5, 77.4, 62.3, 59.0, 27.2,
24.7. Anal. Calcd for C13H13ClN4O3: C, 50.58; H, 4.24; N,
18.15. Found: C, 50.76; H, 4.32; N, 18.07.
Compound 14 was also prepared from 16 in the following
way: To a stirring solution of 16 (100 mg, 0.33 mmol)
(preparation below) and CeCl3·7H2O (130 mg) in MeOH
(10 mL) was added, portionwise, NaBH4 (35 mg) at 0 8C.
The mixture was then stirred at the same temperature for
10 min. The mixture was evaporated. The residue was
diluted by addition of saturated aq. NH4Cl (10 mL) and this
extracted with EtOAc (30 mL) and dried (Na2SO4).
Evaporation of solvent gave 14 as a white solid (85 mg,
85%) whose spectral properties were identical to 14
obtained from 12.
2.1.3. (10R,20S,30S,40R,50S)-6-Chloro-9-(20,30-isopropyl-
idenedioxy-60-oxabicyclo-[3.1.0]hex-40-yl)purine
(12).
To a stirring suspension of 6-chloropurine (0.635 g,
4.27 mmol) and triphenylphosphine (1.12 g, 4.27 mmol) in
THF (10 mL) at 210 8C was added, dropwise, diisopropyl
azodicarboxylate (0.8 g, 4.27 mmol). This mixture was
stirred at 210 8C for 10 min and then stirred at room
temperature for 15 min. To this mixture was then added a
solution of 11 (0.74 g, 4.3 mmol) in dry THF (5 mL). The
new mixture was stirred at room temperature for 48 h and
concentrated under vacuum. Column chromatography with
hexanes–EtOAc (4:1) provided a white solid of desired 12
(0.76 g, 56%), mp 175–176 8C; 1H NMR (CDCl3) d 8.74 (s,
1H), 8.14 (s, 1H), 5.33 (d, J¼7.0 Hz, 1H), 5.08 (s, 1H), 4.80
(d, J¼6.99 Hz, 1H), 3.92 (s, 1H), 3.68 (s, 1H), 1.60 (s, 3H),
1.29 (s, 3H); 13C NMR (CDCl3) d 152.4, 152.0, 151.5,
144.7, 114.3, 86.7, 80.2, 77.4, 60.6, 60.6, 60.4, 26.3, 26.6.
Anal. Calcd for C13H13ClN4O3: C, 50.58; H, 4.24; N, 18.15.
Found: C, 50.36; H, 4.24; N, 18.39.
2.1.6. (40S,50S)-9-(4050-Isopropylidenedioxy-10-oxocyclo-
pent-2-enyl)-6-methoxypurine (16). To a solution of 13
(152 mg, 0.5 mmol) in dry CH2Cl2 under N2 was added
PCC (324 mg, 1.5 mmol). The mixture was stirred for 1 h,
filtered with Celite and evaporated. The resulting residue
was purified by column chromatography using hexanes–
EtOAc (1:1) to give 16 as a white solid (130 mg, 88%), mp
195 8C; 1H NMR (CDCl3) d 8.67 (s, 1H), 8.45 (s, 1H), 7.32
(s, 1H), 5.69 (d, J¼5.7 Hz, 1H), 4.74 (d, J¼5.6 Hz, 1H),
4.23 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H); 13C NMR (CDCl3) d
199.0, 161.7, 159.8, 154.0, 152.2, 139.9, 122.9, 117.8,
116.9, 77.5, 54.9, 27.5, 26.4.15 Anal. Calcd for C14H14N4O4:
C, 55.63; H, 4.67; N; 18.53. Found: C, 55.71; H, 4.68; N,
18.50.
2.1.4. (30S,40R,50S)-9-(30-Hydroxy-40,50-isopropylidene-
dioxycyclopenten-10-yl)6-methoxypurine (13). To a stir-
red solution of epoxide 7 (110 mg, 0.36 mmol) in dry THF
(5 mL) at room temperature under N2 was added sodium
methoxide solution (0.217 mmol, 25% wt in MeOH). The
mixture was stirred at room temperature for 2 h and
evaporated. Water (5 mL) was added to the residue and
extracted with EtOAc (3£10 mL). The combined extracts
were dried (Mg2SO4), filtered, and evaporated to provide 13
2.1.7. (30S,40R,50S)-9-(30,40,50-Trihydroxycyclopent-1-
enyl)purine (6). A solution of 13 (160 mg, 0.53 mmol) in
MeOH (20 mL) saturated with NH3 was heated at 120 8C for
three days in a Parr stainless steel sealed reaction vessel.
The solvent was evaporated under reduced pressure and the
residue purified by column chromatography (MeOH–
CH2Cl2, 1:20) to give protected 6 as a white solid, mp

X. Yin, S. W. Schneller / Tetrahedron 60 (2004) 3451–3455
3455
219–220 8C; 1H NMR (DMSO) d 8.30 (s, 1H), 8.25 (s, 1H),
7.47 (s, 2H), 6.63 (d, J¼3.1 Hz, 1H), 5.88 (dd, J¼1.0,
6.9 Hz, 1H), 5.47 (d, J¼5.8 Hz, 1H), 4.66 (m, 1H), 4.53 (d,
J¼5.8 Hz, 1H), 1.35 (s, 3H), 1.28 (s, 3H).
sides employed in our long time investigations has designated
the methylene, which has replaced the furanose oxygen of
traditional nucleosides, as C-60. As a consequence, compound
4 was granted the trivial 50-noraristeromycin name as the
parent structure. However, to avoid confusion with systematic
cyclopentyl carbon numbering, the C-60 designation is not
utilized in describing the syntheses and experimental details
herein.
The white solid from the last step was dissolved in 0.5 N
HCl solution in MeOH (20 mL). This mixture was stirred at
room temperature for 0.5 h. The mixture was evaporated to
dryness to give a solid (100 mg, 76% after 2 steps) that was
recrystallized from MeOH/H2O to provide 6 as a white
solid, mp 167 8C dec.; [a]2D2.9¼þ42.702 (c, 0.187 DMSO);
1H NMR (DMSO) d 8.32 (s, 1H), 8.23 (s, 1H), 7.43 (s, 2H),
6.56 (d, J¼1.6 Hz, 1H), 5.24 (s, 3H), 5.01 (d, J¼5.7 Hz,
1H), 4.60 (s, 1H), 3.80 (t, J¼4.9 Hz, 1H); 13C NMR
(DMSO) d 155.9, 152.9, 149.2, 138.3, 136.0, 120.8, 119.0,
78.3, 77.1, 71.4. Anal. Calcd for C10H11N5O3·1.1H2O: C,
44.62; H, 4.90; N, 26.02. Found: C, 44.47; H, 4.74; N, 25.89.
4. Kitade, Y.; Kozacki, A.; Yatone, C. Tetrahedron Lett. 2001,
42, 433–435.
5. (a) Madhavan, G. V. B.; McGee, D. P. C.; Rydzewski, R. M.;
Boehme, R.; Martin, J. C.; Prisbe, E. J. J. Med. Chem. 1988,
31, 1798–1804, reported a small amount (3%) of (^)-i arising
during the synthesis of a fluoroaristeromycin derivative.
(b) Similarly, a low yield of ii was described by Biggadike,
K.; Borthwick, A. D.; Exall, A. M. J. Chem. Soc., Chem.
Commun. 1990, 458–459, in their preparation of the
pyrimidine analog of 20-deoxyneplanocin A.
2.1.8. (30R,40R,50S)-9-(30,40,50-Trihydroxycyclopent-1-
enyl)purine (17). Compound 17 was achieved as a white
solid from 14 in 56% yield using the same method as for the
synthesis of 6 from 13, mp 208 8C dec.; [a]2D2.9¼22.81 (c,
1
0.121 DMSO); H NMR (DMSO) d 8.37(s, 1H), 8.23 (s,
1H), 7.42, (s, 2H), 6.68 (s, 1H), 5.17 (s, 1H), 4.87 (m, 2H),
4.47 (s, 2H), 4.11 (t, J¼5.3 Hz, 1H); 13C NMR (DMSO) d
156.1 (2C), 153.2, 149.4, 138.7, 138.1, 119.3, 119.0, 71.4,
69.5.15 Anal. Calcd for C10H11O3N5·0.2H2O: C, 47.50; H,
4.51, N, 27.71. Found: C, 47.47, H, 4.45, N, 27.44.
6. Bartsch, R. A.; Zavada, J. Chem. Rev. 1980, 80, 453–492.
7. Yin, X.-q.; Rajappan, V. P.; Roy, A.; Schneller, S. W. Synth.
Commun. 2003, 33, 1477–1481.
8. (a) Yang, N. C.; Finnegan, R. A. J. Am. Chem. Soc. 1958, 80,
5845–5848. (b) Neef, G.; Baesler, S.; Depke, G.; Vierhufe, H.
Tetrahedron Lett. 1999, 40, 7969–7973.
Acknowledgements
This research was supported by funds from the Department
of Health and Human Services (AI 48495 and AI 56540),
which is appreciated. We are also indebted to the following
individuals for providing the antiviral data13 following their
standard procedures: 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. The assistance
of Dr. Lyle Castle of the Idaho State University, Pocatello,
Idaho, in using NMR to determine the structure of 13 is
gratefully acknowledged.
9. Structural assignments made after obtaining 13.
10. (a) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103,
5454–5459. (b) Lim, M.-I.; Marquez, V. E. Tetrahedron Lett.
1984, 24, 5559–5562.
11. Deardorff, D. R.; Shambayati, S.; Myles, D. C.; Heerding, D.
J. Org. Chem. 1988, 53, 3614–3615.
12. (a) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.;
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References and notes
13. Viruses subjected to 6 and 17 were influenza A (H1N1 and
H3N2), influenza B, parainfluenza-3 virus, respiratory
syncytial virus, vesicular stomatitis virus, herpes simplex
virus 1 (TKþ and TK2) and 2, human cytomegalovirus,
varicella zoster virus, Epstein-Barr virus, vaccinia virus,
cowpox virus, West Nile virus, Sindbis virus, adenovirus
type 1, measles, Punta Toro virus, rhinovirus type 2,
Venezuelan equine encephalitis, yellow fever, and HIV-1
and HIV-2. Compound 17 was also evaluated against
coxsackie virus B4 and reovirus-1.
1. (a) Marquez, V. E. Adv. Antiviral Drug Des. 1996, 2, 89–146.
(b) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319–4347.
(c) Galeone, A.; Mayol, L.; Oliviero, G.; Piccialli, G.; Varra,
M. Tetrahedron 2002, 58, 363–368. (d) Ravi, R. G.; Kim,
H. S.; Servos, J.; Zimmermanm, H.; Lee, K.; Maddilefi, S.;
Boyer, J. L.; Harden, T. K.; Jacobson, K. A. J. Med. Chem.
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2. For a leading reference, see Rajappan, V. P.; Schneller, S. W.;
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883–886.
14. Seley, K. L.; Schneller, S. W.; Rattendi, D.; Lane, S.; Bacchi,
C. J. J. Med. Chem. 1997, 40, 625–629.
15. Due to signal overlap, only nine 13C signals were observed.
3. The cyclopentyl ring numbering convention for carbanucleo-