A flexible synthesis of carbanucleosides and 5′-nor-1′-homo carbanucleosides from a common precursor

Article abstract of DOI:10.1016/S0040-4020(02)01195-X

Enzymatic resolution of (±)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (4) provides entry into a facile 10-step route to carbanucleosides and a practical 7-step procedure to 5′-nor-1′-homo carbanucleosides. These routes are illustrated for adenine derivatives but they are adaptable to any heterocyclic base.

Full text of DOI:10.1016/S0040-4020(02)01195-X

Tetrahedron 58 (2002) 9889–9895
A flexible synthesis of carbanucleosides and 50-nor-10-homo
carbanucleosides from a common precursor
*
Vasathakumar P. Rajappan, Xueqiang Yin and Stewart W. Schneller
Department of Chemistry, Auburn University, Auburn, AL 36849-5312, USA
Received 20 May 2002; accepted 17 September 2002
Abstract—Enzymatic resolution of (^)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (4) provides entry into a facile 10-step route to
carbanucleosides and a practical 7-step procedure to 50-nor-10-homo carbanucleosides. These routes are illustrated for adenine derivatives but
they are adaptable to any heterocyclic base. q 2002 Elsevier Science Ltd. All rights reserved.
As a naturally occurring carbocyclic nucleoside (carba-
nucleoside) aristeromycin (1)1 possesses numerous biologi-
cal properties, which have stimulated studies with other
carbanucleosides.2 Our own research in this area3 has
recently required access to an efficient and flexible synthesis
of 1 and analogs of 1 altered in the heterocyclic ring (Fig. 1).
Both the goal of an efficient preparation of carbanucleosides
and the desire to have 10-homo 50-nor analogs were
conceived to be accessible from a common point, namely
racemic 1-acetoxy-4-(nitromethyl)-2-cyclopentene (4)6 and
to be based on modifying and improving upon the notable
work of Deardorff7 and Trost8 and their co-workers. Thus,
the syntheses began by treating of (^)-4 with Pseudomonas
cepacia lipase9 (Scheme 1) to provide (þ)-410 and (2)-5
with compound (þ)-4, in turn, serving as the entry into
the carbanucleosides (Scheme 2) and (2)-5 being the
starting point for the 10-homo derivatives (Scheme 3).
Confirmation that this resolution led to the enantiomers
shown occurred with the conversion of (þ)-4 to (2)-1 (vide
infra).
Concurrent with this effort has been an ongoing investi-
gation at Auburn of 50-nor carbanucleosides (represented by
2).4 The biological characteristics of this collection of
molecules prompted the search for structurally varied
derivatives, including the 10-homo series (illustrated by 3),
which are isomeric to the conventional carbanucleosides.
The 10-homo compounds were also important to our studies
of oligomers possessing the 50-nor building block.5 Such
units would render an oligomer with the same inter-base
distance as traditional oligomers, which is an arrangement
that is not possible for regular 50-nor oligomers5 due to the
hemiacetal functionality at C-40.
Glycolization/protection of (þ)-4 yielded 6 as the major
product7 along with a small amount of 7. Cyanide promoted
hydrolysis of 6 to 8 was followed by oxidation using
pyridinium chlorochromate to result in 9. Reduction of 9
Figure 1.
Keywords: carbocyclic nucleosides; antiviral; enzyme resolution.
*
Corresponding author. Tel.: þ1-334-844-5737; fax: þ1-334-844-5748; e-mail: schnest@auburn.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01195-X

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V. P. Rajappan et al. / Tetrahedron 58 (2002) 9889–9895
Scheme 1. Reaction condition: a, Pseudomonas cepacia lipase, NaOH, acetone/phosphate buffer, pH 7.0–7.2.
Scheme 2. Reaction conditions: a, (i) OsO4, NMO; (ii) acetone, 2,2-dimethoxypropane, Hþ; b, on 6, KCN (cat.); c, PCC and Celite; d, NaBH4 and CeCl3; e,
TBDMSCl/imidazole; f, on 11 (i) KMnO4, KOH, MgSO4; (ii) NaBH4; g, Ac2O, pyridine; h, Bu4NF; i, (i) on 14, 6-chloropurine, DIAD, Ph3P; (ii) NH3; j, TFA-
H2O.
with sodium borohydride selectively11 led to 10. Protection
of the newly produced secondary alcohol of 10 as the
tert-butyldimethylsilyl derivative 11 permitted a successful
Nef7 reaction. Subsequent reduction of the resulting
aldehyde occurred to give the requisite hydroxymethylene
subsituent of 12. Acetylation of 12 (to 13) and then
desilylation produced 14. Subjecting 14 to a Mitsunobu
reaction with 6-chloropurine followed by ammonolysis
gave the aristeromycin precursor 15. Acid deprotection12 of
15 yielded 1,13 whose [a]2D5 agreed with the literature
value.14
gave 16 along with a small amount of the deacetylated
derivative 17. Derivative 16 led to the desired 3 by the
following sequence: (i) Mitsunobu coupling with 6-chloro-
purine, (ii) deacetylation0(to 18), (iii) ammonolysis,15 and
(iv) deprotection of the 2 ,30-glycol.
The enantiomers of 1 and 3 would be available by treating
(^)-4 with pig liver esterase16 to give (2)-4 and (þ)-5 and
then following Schemes 2 and 3, respectively. Also, the
means illustrated herein for achieving 1 and 3 can be used to
readily11,12,17 obtain derivatives with other heterocyclic
moieties.
The synthesis of 3 (Scheme 3) began with the acetylation of
(2)-5 to (2)-4, which was converted to ent-6 via the
standard oxidation/protection sequence. Following the Nef
reaction and reduction tandem procedure of Scheme 2, ent-6
Analogs 3 and ent-3 were subjected to antiviral analysis18
and found to be inactive. Neither compound was cytotoxic
to the cells that served as hosts to the viral assays.

V. P. Rajappan et al. / Tetrahedron 58 (2002) 9889–9895
9891
Scheme 3. Reaction conditions: a, Ac2O, pyridine, CH2Cl2; b, (i) OsO4, NMO; (ii) acetone, 2,2-dimethoxypropane, pTSA; c, (i) KOH, KMnO4, MgSO4; (ii)
NaBH4; d, 6-chloropurine, DIAD, Ph3P; e, K2CO3, MeOH; f, NH3, MeOH (ref. 14); g, 0.5 N HCl.
1. Experimental
(5:1) afforded (þ)-4 (12 g, 52%, 90% ee19); [a]D25¼þ40.14
(c 0.4733, MeOH), lit.7 [a]D25¼þ83.4 (c 1.535, CH2Cl2): 1H
NMR (CDCl3) d 6.01 (br, s, 2H), 5.63 (dd, J¼10, 3 Hz, 1H),
4.53–4.34 (m, 2H), 3.40 (m, 1H), 2.57 (dt, J¼15, 8 Hz, 1H),
2.03 (s, 3H), 1.62 (dt, J¼15, 3.5 Hz, 1H); 13C NMR (CDCl3)
d 171.0, 135.5, 132.8, 79.4, 78.5, 42.6, 34.1, 21.1; Anal.
calcd for C8H11NO4: C, 51.89; H, 5.99; N, 7.56. Found: C,
52.14; H, 5.99; N, 7.38.
1.1. General
Melting points were recorded on a Meltemp II melting point
apparatus and are uncorrected. Combustion analyses were
performed by Atlantic Microlabs, Inc. Norcross, GA. 1H and
13C spectra were recorded on a Bruker AC 250 spectrometer
(operated at 250 and 62.5 MHz, respectively) all referenced
to internal tetramethylsilane (TMS) at 0.0 ppm. The spin
multiplicities are indicated by the symbols s (singlet), d
(doublet), dd (doublet of doublet), ddd (doublet of doublet
of doublet), dt (doublet of triplet), t (triplet), and m
(multiplet). The optical rotations were measured on a
Jasco P-1010 polarimeter. Reactions were monitored by
thin-layer chromatography (TLC) using 0.25 mm Whatman
Diamond silica gel 60-F254 precoated plates or using
Elution of (2)-5 was achieved using hexanes–EtOAc (1:1)
(8 g, 45%, .98% ee19), [a]2D5¼210.72 (c 0.3735, MeOH):
1H NMR (CDCl3) d 5.97(ddd, J¼9.2, 5.5, 2 Hz, 1H), 5.85(dd,
J¼5.5, 2 Hz, 1H), 4.85 (dd, J¼5.2, 4 Hz, 1H), 4.54–4.37 (m,
2H), 3.32 (m, 1H), 2.57 (ddd, J¼15, 8, 1 Hz, 1H), 1.93 (s, 1H),
1.54(dt,J¼15, 4.7 Hz, 1H);13CNMR(CDCl3)d136.7,132.1,
79.8, 74.6, 42.8, 37.3; Anal. calcd for C6H9NO3: C, 50.35; H,
6.34; N, 9.79. Found: C, 50.24; H, 6.34; N, 9.53.
˚
Silicycle (60 A) with visualization by irradiation with a
Mineralight UVGL-25 lamp or exposure to iodine vapor.
Column chromatography was performed on Whatman
1.1.2. (1R,2S,3R,4R)-1-Acetoxy-2,3-(isopropylidene-
dioxy)-4-(nitromethyl)cyclopentane (6). To an ice-H2O
cooled solution of (þ)-4 (22 g, 71 mmol) in acetone-H2O
(256:44) (300 mL) was added N-methylmorpholine N-oxide
(37 mL, 50% aq) and OsO4 (100 mg). The mixture was then
stirred at rt for 24 h. The acetone was evaporated under
reduced pressure and the residue cooled in an ice-H2O bath
and saturated Na2S2O3 solution (23 mL) added. This
mixture was stirred for 15 min and then extracted with
EtOAc (3£50 mL). The combined organic layers were
washed with ice-cold 1N HCl (2£20 mL), brine (20 mL),
dried (MgSO4), filtered and concentrated in vacuo to give a
colorless oil (21.5 g). The presumed diol was then
transferred to a dry flask and dissolved in anhydrous
acetone (50 mL). To this was added 2,2-dimethoxypropane
(35 mL) followed by p-TSA (460 mg). The reaction was
stirred at rt for 20 h. The mixture was then neutralized
(dilute NH4OH) to pH 7. After evaporation of the solvent,
the residue was extracted with Et2O (200 mL) and washed
with brine (2£100 mL). The aqueous layer was then
extracted with EtOAc (100 mL). The combined organic
layers were dried (MgSO4), filtered and the filtrate
concentrated under vacuum. Column chromatography with
hexanes–EtOAc (8:1) provided 6, Rf¼0.5 (20.16 g, 68% for
two steps) and 7 (20:1): 1H NMR for 6 (CDCl3) d 5.10 (dd,
˚
˚
silica, 230–400 mesh, 60 A or Silicycle A (200–
400 mesh) and elution with the indicated solvent system.
Yields refer to chromatographically and spectroscopically
(1H and 13C NMR) homogeneous materials.
1.1.1. (1)-(1R,4S)-1-Acetoxy-4-(nitromethyl)-2-cyclo-
pentene ((1)-4) and (2)-(1S,4R)-4-(nitromethyl)-2-
cyclopenten-1-ol ((2)-5). To a 1 L three-necked round-
bottomed flask fitted with a mechanical stirrer, a pH
electrode and a dropping funnel was added acetone
(40 mL), (^)-46 (23 g, 124 mmol) and 0.1 M phosphate
buffer (200 mL). To this mixture P. cepacia lipase (PCL)
(600 mg) was added in one portion. The pH of the solution
was maintained between 7.0 and 7.2 by slow and
intermittent addition of 1N (62 mmol) NaOH. When the
NaOH solution addition was completed, EtOAc (500 mL)
was added and the mixture filtered through a pad of Celite.
The pad was washed with EtOAc (2£150 mL). The EtOAc
layer was separated and the aqueous layer was extracted
with EtOAc (3£150 mL). The combined EtOAc extracts
were dried (anhydrous MgSO4), filtered and the filtrate
evaporated to get a light brown oil. Purification via silica gel
column chromatography by elution with hexanes–EtOAc

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V. P. Rajappan et al. / Tetrahedron 58 (2002) 9889–9895
1
J¼5, 1 Hz, 1H), 4.58 (s, 2H), 4.56–4.38 (m, 2H), 2.97 (dd,
J¼7.5, 5 Hz, 1H), 2.50 (m, 1H), 2.07 (s, 3H), 1.70 (dd,
J¼14, 6.5 Hz, 1H), 1.49 (s, 3H), 1.32 (s, 3H); 13C NMR
(CDCl3) d 169.7, 111.5, 84.7, 82.6, 78.9, 77.4, 43.8, 32.3,
26.5, 24.1, 21.3; Anal. calcd for C11H17NO6: C, 50.96; H,
6.61; N 5.40. Found: C, 51.03; H 6.68; N 5.31.
84%): H NMR (CDCl3) d 4.58 (m, 1H), 4.40 (d, J¼2 Hz,
1H), 4.36 (d, J¼1.25 Hz, 2H), 4.08 (dt, J¼10.5, 5.7 Hz, 1H),
2.90 (m, 1H), 2.55 (d, J¼5.7 Hz, 1H), 2.11 (m, 1H), 1.73 (m,
1H), 1.53 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3) d 113.5,
82.2, 79.7, 77.0, 70.5, 41.2, 35.6, 26.3, 24.6. Anal. calcd for
C9H15NO5: C, 49.76; H, 6.96; N, 6.45. Found: C, 49.57; H,
6.99; N, 6.37.
Minor isomer 7 (1.25 g, 3.4%): 1H NMR (CDCl3) d 4.99 (m,
1H), 4.76 (dd, J¼6.7, 3.5 Hz, 1H), 4.68 (m, 2H), 4.54 (dd,
J¼7.5, 7.7 Hz, 1H), 3.10 (m, 1H), 2.12 (s, 3H), 1.95 (m,
2H), 1.52 (s, 3H), 1.31 (m, 3H).
1.1.6. (1S,2S,3R,4R)-1-(tert-Butyldimethylsilyloxy)-2,3-
(isopropylidenedioxy)-4-(nitromethyl)cyclopentane
(11). To a solution of 10 (10 g, 46 mmol) and imidazole
(3.74 g, 55 mmol) in anhydrous DMF (100 mL) was added
tert-butyldimethylsilyl chloride (8.22 g, 54 mmol). The
reaction mixture was stirred, under N2, at rt for 12 h.
After evaporation of the solvent on a rotary evaporator, the
residue was dissolved CH2Cl2 (150 mL) and this solution
washed with brine (1£100 mL) and then H2O (1£80 mL).
The organic extract was dried (MgSO4), filtered and the
filtrate evaporated in vacuo. The viscous residue was
purified by column chromatography (20:1, hexanes–
EtOAc). Evaporation of the eluent afforded 11 as a colorless
syrup (11 g, 72%): 1H NMR (CDCl3) d 4.45–4.27 (m, 4H),
4.10 (dt, J¼11.7, 5 Hz, 1H), 2.87 (dt, J¼10, 5 Hz, 1H), 2.17
(dt, J¼13, 6 Hz, 1H), 1.66 (m, 1H), 1.61 (s, 3H), 1.31 (s,
3H), 0.91 (s, 9H), 0.10 (s, 6H); 13C NMR (CDCl3) d 113.0,
81.8, 80.8, 77.6, 72.0, 41.2, 35.3, 26.6, 26.1, 25.1, 18.5,
24.3, 24.7. Anal. calcd for C15H29NO5Si: C, 54.35; H,
8.75; N, 4.22. Found: C, 54.57; H, 8.86; N, 4.18.
1.1.3. (1R,2S,3R,4R)-1-Hydroxy-2,3-(isopropylidene-
dioxy)-4-(nitromethyl)cyclopentane (8). To a solution of
6 (1 g, 3.8 mmol) in MeOH (20 mL) was added KCN
(50 mg). The mixture was stirred at rt for 2 h. The solvent
was removed under reduced pressure and the residue
obtained was loaded on a silica gel column. Elution of an
impurity using a mixture of hexanes–EtOAc (7:1) was
followed by elution with a different mixture of hexanes–
EtOAc (4:1). Evaporation of the solvent from this elution
afforded 8 (850 mg) asa viscous liquid. Further purification on
a silica gel column gave an analytically pure sample of 8
(768 mg, 93%): 1H NMR (CDCl3) d 4.67–4.44 (m, 3H), 4.27
(d, J¼2.5 Hz, 1H), 4.10 (d, J¼7 Hz, 1H), 2.92 (dt, J¼12.5,
4.7 Hz, 1H), 2.30 (m, 2H), 1.63 (d, J¼14.4 Hz, 1H), 1.42 (s,
3H), 1.29 (s, 3H); 13C NMR (CDCl3) d 111.3, 87.1, 83.4, 78.5,
77.0, 44.4, 34.9, 26.8, 24.4; Anal. calcd for C9H15NO5: C,
49.76; H, 6.96; N, 6.45. Found: C, 49.57; H, 7.05; N, 6.36.
1.1.7. (1S,2S,3R,4R)-1-(tert-Butyldimethylsilyloxy)-2,3-
(isopropylidenedioxy)-4-(hydroxymethyl)cyclopentane
(12). A solution of 11 (1.22 g, 3.7 mmol) in MeOH (25 mL)
at 08C was mixed with a solution of KOH (85%) (243 mg,
3.7 mmol) in MeOH (5 mL). The mixture was stirred at 08C
for 20 min and a freshly prepared solution of KMnO4
(537.3 mg, 3.4 mmol) and MgSO4 (397.2 mg, 3.3 mmol) in
H2O (25 mL) was added dropwise, over 40 min, to the
above mixture. After the mixture was stirred at 08C for an
additional hour, the mixture was diluted with EtOAc
(100 mL) and filtered through a pad of Celite. The Celite
pad was washed with EtOAc (3£60 mL). The combined
filtrates were washed with brine (1£100 mL) and H2O
(1£100 mL), dried (MgSO4), filtered and the filtrate
evaporated in vacuo. The residue obtained was dissolved
in 2-propanol (50 mL) and brought to 08C. Sodium
borohydride (239 mg, 6.3 mmol) was added slowly to the
solution. The reaction was stirred at 08C for 60 min and then
neutralized with saturated aqueous solution of NH4Cl. The
insoluble materials were removed by filtration, H2O was
added to the filtrate and this mixture extracted with EtOAc
(3£60 mL). The combined extracts were dried (MgSO4),
filtered and the filtrate evaporated in vacuo. The residue was
loaded on a silica gel column and eluted first with hexanes–
EtOAc (10:1) to elute unreacted starting material and
impurities, and then with hexanes–EtOAc (4:1) to elute,
after evaporation of the solvent mixture, 12 as a colorless
1.1.4. (2R,3R,4R)-2,3-(isoPropylidenedioxy)-4-(nitro-
methyl)cyclopentan-1-one (9). To a stirred suspension of
Celite (10 g) and PCC (9.27 g, 43 mmol) in anhydrous
CH2Cl2 (100 mL) was added, dropwise, over a period of
15 min, a solution of 8 (4.67 g, 21.5 mmol) in anhydrous
CH2Cl2. After 15 h of stirring at rt, the suspension was
filtered through a pad of Celite and the pad was washed with
ether (500 mL). The combined filtrates were evaporated, the
residue was washed, sequentially, with saturated aqueous
NaHCO3 and brine, dried (MgSO4) and filtered. The filtrate
was evaporated in vacuo to afford a light brown residue,
which was purified via column chromatography (hexanes–
EtOAc, 7:3) to give 9 (3.5 g, 76%) as a light yellow oil: 1H
NMR (CDCl3) d 4.72 (d, J¼5.7 Hz, 1H), 4.56 (d, J¼5.7 Hz,
2H), 4.44 (d, J¼5.7 Hz, 1H), 2.98–2.91 (m, 2H), 2.29 (d,
J¼14 Hz, 1H), 1.45 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3)
d 210.6, 113.0, 79.9, 78.8, 60.5, 37.9, 36.6, 26.8, 24.8. Anal.
calcd for C9H13NO5: C, 50.23; H, 6.09; N, 6.51. Found: C,
50.39; H, 6.24; N, 6.39.
1.1.5. (1S,2S,3R,4R)-1-Hydroxy-2,3-(isopropylidene-
dioxy)-4-(nitromethyl)cyclopentane (10). A solution of 9
(3.23 g, 15 mmol) and CeCl3·7H2O (5.59 g, 15 mmol) in
MeOH (60 mL) was cooled to 08C and NaBH4 (681 mg,
18 mmol) was added slowly. The mixture was stirred at 08C
for 45 min and then neutralized with saturated aqueous
NH4Cl. The solvent was evaporated, the residue suspended
in H2O (100 mL) and this suspension extracted with EtOAc
(3£60 mL). The combined extracts were washed with brine,
dried (MgSO4), filtered and the filtrate evaporated in vacuo.
The residue was purified by column chromatography
(hexanes–EtOAc, 3:1). Evaporation of the combined
eluents gave 10 as a light yellow viscous liquid (2.75 g,
1
syrup (710 mg, 66%): H NMR (CDCl3) d 4.41 (m, 3H),
4.13 (dd, J¼4.2 Hz, 1H), 3.60–3.52 (m, 2H), 2.22 (m, 1H),
2.03 (dt, J¼12.2, 4 Hz, 1H), 1.66 (m, 1H), 1.50 (s, 3H), 1.32
(s, 3H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (CDCl3) d
111.9, 82.2, 81.1, 72.9, 64.6, 44.9, 34.5, 26.7, 26.2, 25.1,
18.6, 24.2. Anal. Calcd for C15H30O4Si: C, 59.56; H, 9.99.
Found: C, 59.28; H, 10.01.

V. P. Rajappan et al. / Tetrahedron 58 (2002) 9889–9895
9893
1.1.8. (1S,2S,3R,4R)-4-(Acetoxymethyl)-1-(tert-butyldi-
methylsilyloxy)-2,3-(isopropylidenedioxy)cyclopentane
(13). Acetic anhydride (5 mL, 50 mmol) was added to a
mixture of 12 (3.2 g, 10.6 mmol) and pyridine (6.4 mL,
80 mmol) in anhydrous CH2Cl2 (50 mL) at 08C. The
mixture was stirred at rt for 16 h. It was then brought to
08C and a cold, saturated aqueous solution of NaHCO3 was
added and this stirred for 30 min. The organic layer was
separated, washed with cold 1N HCl (2£50 mL) and H2O
(1£50 mL), dried (MgSO4), filtered and evaporated under
vacuumtogiveacolorlessliquid, whichwasfurtherpurifiedas
13 (3.12 g, 85%) by column chromatography (hexanes–
EtOAc, 10:1): 1H NMR (CDCl3) d 4.43 (m, 3H), 4.11 (m, 2H),
3.99 (ddd, J¼11, 6, 6 Hz, 1H), 2.73 (m, 1H), 2.07 (s, 3H), 1.58
(m, 1H), 1.49 (s, 3H), 1.31 (s, 3H), 1.15 (s, 9H), 0.09 (s, 6H);
13C NMR (CDCl3) d 171.2, 111.8, 82.0, 80.9, 72.9, 65.8, 41.5,
34.4, 26.7, 26.2, 25.0, 21.1, 18.6, 24.2. Anal. calcd for
C17H32O5Si: C 59.27; H 9.29. Found: C 59.56; H 9.30.
fractions containing product. Evaporation of these fractions
afforded 15 as a white powder (980 mg, 62% for two steps
based on 6-chloropurine), mp 204–2068C: 1H NMR
(DMSO-d6) d 8.28 (s, 1H), 8.16 (s, 1H), 7.26 (s, 2H), 5.04
(dd, J¼8, 4 Hz, 1H), 4.80 (m, 2H), 4.56 (dd, J¼4, 2 Hz, 1H),
3.51 (s, 2H), 2.27 (m, 3H), 1.49 (s, 3H), 1.27 (s, 3H); 13C
NMR (DMSO-d6) d 155.9, 152.2, 149.2, 139.7 119.1, 112.3,
82.8, 80.6, 61.8, 60.3, 45.3, 33.6, 27.3, 25.0. Anal. calcd for
C14H19N5O3: C, 55.07; H, 6.27; N, 22.94. Found: C, 54.85;
H, 6.13; N, 22.73.
1.1.11. 9-[(10R,20S,30R,40R)-[(20,30-(Dihydroxy)-40-(hydro-
xymethyl)cyclopentan-10-yl]adenine (1, aristeromycin).
Compound 15 (500 mg, 1.6 mmol) was dissolved in a
mixture of trifluoroacetic acid–H2O (2:1) and this solution
stirred at rt for 2 h. The solvent was removed under vacuum
and the residue was repeatedly dissolved in MeOH and
evaporated (4 times). The solid obtained in this manner was
adsorbed on silica gel and this mixture loaded on a silica gel
column. Evaporation of the product containing fractions
using CH2Cl2–MeOH (3:1) afforded 2 (360 mg 84%) as a
white solid, mp. 215–2188C. (lit.12a 214–2168C);
[a]D25¼259.6 (c 0.1362, DMF), lit.14 [a]2D5¼256 (c 0.366,
1.1.9. (1S,RS,3R,4R)-4-(Acetoxymethyl)-2,3-(isopropyli-
denedioxy)cyclopentan-1-ol (14). To a solution of 13
(2.4 g, 6.9 mmol) in freshly distilled THF (50 mL) was
added a 1N solution of tetrabutylammonium fluoride in THF
(9 mL). The mixture was stirred at rt for 2 h. After
evaporation of the solvent, the residue was loaded on a
silica gel column and the product eluted using hexanes–
EtOAc (8:1 followed by 5:1). Evaporation of the second
eluent stage gave 14 (1.4 g, 88%) as colorless syrup, which
1
DMF): H NMR (DMSO-d6) d 8.19 (s, 1H), 8.11 (s, 1H),
7.18 (s, 2H), 4.95 (d, J¼6.5 Hz, 1H), 4.73 (t, J¼6 Hz, 1H),
4.71–4.66 (m, 2H), 4.35 (dt, J¼6, 9 Hz, 1H), 3.84 (m, 1H),
3.48–3.38 (m, 2H), 2.25 (dt, J¼12, 8 Hz, 1H), 2.04–2.01
(m, 1H), 1.73–1.70 (dt, J¼12, 8.2 Hz, 1H); 13C NMR
(DMSO-d6) d 155.9, 152.0, 149.7, 140.0, 119.3, 74.5, 71.6,
63.0, 59.2, 45.3, 29.2; Anal. calcd C11H15N5O3·1.4 H2O: C,
45.48; H, 6.18; N, 24.11. Found: C, 45.81; H, 5.83; N, 23.77.
1
was used in the next step without further purification: H
NMR (CDCl3) d 4.50–4.46 (m, 3H), 4.11 (dd, J¼7, 6 Hz,
1H), 4.03 (m, 2H), 2.42 (m, 1H), 2.07 (s, 3H), 1.95 (m, 1H),
1.78 (m, 1H), 1.51 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3) d
171.4, 112.1, 82. 5, 79.6, 71.5, 65.3, 41.3, 35.0, 26.3, 24.5,
21.1. Anal. Calcd for C11H18O5·0.1H2O: C, 56.93; H, 7.90.
Found: C, 56.64; H, 7.81.
1.1.12. (2)-(1S,4R)-1-Acetoxy-4-(nitromethyl)-2-cyclo-
pentene ((2)-4). To a solution of (2)-5 (10 g, 53.9 mmol)
and Ac2O in dry CH2Cl2 (200 mL) at 08C was added
pyridine (4 g). The mixture was then stirred at rt for 20 h,
washed with ice-cooled saturated Na2CO3 (3£50 mL), 1N
HCl (3£50 mL), brine (50 mL) and dried (MgSO4). The
CH2Cl2 was evaporated under reduced pressure. The
residue was purified by Kugelrohr distillation (120–
1408C/0.25 mm Hg) to give (2)-4 (9.5 g, 90%), whose
NMR spectral properties matched those of (þ)-4.
1.1.10. 9-[(10R,20S,30R,40R)-(40-Hydroxymethyl)-20,30-(iso-
propylidinedioxy)cyclo-pentan-10-yl]adenine (15). Diiso-
propyl azodicarboxylate (DIAD) (1.01 g, 5.2 mmol) was
added dropwise to a solution of triphenylphosphine (1.34 g,
5.2 mmol) in freshly distilled THF (80 mL) kept under N2
atmosphere. The mixture was stirred for 20 min and then a
solution of 14 (1.28 g, 5.6 mmol) in dry THF (20 mL) was
added slowly. The mixture was stirred at rt for an additional
20 min and then 6-chloropurine (787 mg, 5.2 mmol) was
added. The mixture was stirred at 558C for 18 h. The solvent
was evaporated and the residue was loaded onto a silica gel
column. The faster moving impurities were successively
eluted with CH2Cl2–EtOAc (first at 50:1 and then 25:1).
This was followed by CH2Cl2–EtOAc (10:1) to elute
product and triphenylphosphine oxide, which could not be
separated under various conditions. After evaporation of the
eluent, the residue obtained (assumed to contain 50-
acetylated 15) was dried under vacuum (P2O5) and used
directly in the next reaction.
1.1.13. (1S,2R,3S,4S)-1-Acetoxy-2,3-(isopropylidene-
dioxy)-4-(nitromethyl)cyclopentane (ent-6) and
(1S,2S,3R,4S)-1-acetoxy-2,3-(isopropylidenedioxy)-4-
(nitromethyl)cyclopentane (ent-7). Following the same
procedure as described for preparing 6, (2)-4 (11 g,
0.071 mol) provided ent-6 (10.47 g, 57%) and ent-7
(625 mg, 3.4%) (Fig. 1) as colorless oils following
purification by silica gel column chromatography with
1
hexanes–EtOAc (8;1). ent-6: H NMR (CDCl3) d 5.14 (d,
J¼5 Hz, 1H), 4.35–4.64 (m, 4H), 2.99 (m, 1H), 2.50 (m,
1H), 2.11 (s, 3H), 1.70 (d, J¼6.5 Hz, 1H), 1.49 (s, 3H), 1.32
(s, 3H); 13C NMR (CDCl3) d 169.7, 111.6, 84.7, 82.6, 79.0,
77.5, 43.9, 32.4, 26.6, 24.2, 21.3. Anal. calcd for
C11H17NO6: C, 50.96; H, 6.61; N, 5.40. Found: C, 51.25;
H, 6.62; N, 5.29.
The above residue was dissolved in MeOH (30 mL)
saturated with anhydrous NH3 and heated at 1108C for
48 h in a sealed pressure apparatus. After cooling the
solution to rt and removing the insoluble material by
filtration, the solvent was evaporated and the residue was
loaded on a silica gel column. The triphenylphosphine was
eluted first with CH2Cl2 –MeOH (25:1) followed by
1
ent-7: H NMR (CDCl3) d 4.99 (m, 1H), 4.76 (dd, J¼6.7,
3.5 Hz, 1H), 4.68 (m, 2H), 4.54 (dd, J¼7.5, 7.7 Hz, 1H),
3.10 (m, 1H), 2.12 (s, 3H), 1.95 (m, 2H), 1.52 (s, 3H), 1.31
(m, 3H).

9894
V. P. Rajappan et al. / Tetrahedron 58 (2002) 9889–9895
1.1.14. (1R,2S,3R,4S)-4-Acetoxy-1-(hydroxymethyl)-2,3-
(isopropylidenedioxy)cyclopentane (16). To a stirring ice-
H2O cooled solution of ent-6 (5.9 g, 22.7 mmol) in MeOH
(50 mL) was added, dropwise, over 5 min a freshly prepared
solution of KOH (1.633 g, 0.025 mol) in MeOH (100 mL).
After an additional 15 min, a freshly prepared solution of
KMnO4 (2.84 g, 17 mmol) and MgSO4 (2.01 g, 16 mmol) in
H2O (160 mL) was added dropwise over 15 min. This
mixture was stirred at 08C for 45 min and then quenched by
passing through a pad of Celite and washing the pad with
ether. The resultant filtrate was extracted with EtOAc
(3£100 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo to give a
yellow oil (4.0 g). This unstable aldehyde was immediately
dissolved in 2-propanol (40 mL) and cooled in an ice-H2O
bath. To this was added, in one portion, NaBH4 (908 mg,
0.0227 mol). The reaction mixture was stirred at rt for 1 h,
cooled in an ice-H2O bath and then quenched with saturated
NH4Cl solution to pH 7. This mixture was extracted with
EtOAc (3£200 mL). The combined organic layers were
dried (MgSO4), filtered and the filtrate concentrated in
vacuo. Purification via column chromatography with
hexanes–EtOAc (1:1) provided 16 and 17 as colorless
oils. Compound 16 (1.25 g, 24%): 1H NMR (DMSO) d 4.83
(s, 1H), 4.69 (t, J¼5 Hz, 1H), 4.5 (d, J¼6.25 Hz, 1H), 4.41
(d, J¼6.0 Hz, 1H), 3.31 (m, 2H), 2.10–2.16 (m, 2H), 1.98
(s, 3H), 1.50 (d, J¼8.5 Hz, 1H), 1.35 (s, 3H), 1.20 (s, 3H);
13C NMR (DMSO) d 169.5, 109.8, 84.2, 81.7, 78.9, 61.9,
47.2, 31.1, 26.5, 24.1, 21.0; Anal. calcd for
C11H18O5·0.2H2O: C, 56.52; H, 7.87. Found: C, 56.61; H,
7.94.
1.1.16. 9-[(10S,20R,30S,40R)-(20,30,40-Trihydroxycyclopent-
10-yl)methyl]adenine (3). A solution of 18 (720 mg,
2.21 mmol) in MeOH (50 mL) saturated with NH3 was
heated at 1208C for two days in a Parr stainless steel sealed
reaction vessel. The solvent was evaporated under reduced
pressure and the mixture dissolved in 0.5N HCl solution
(40 mL) in MeOH. This mixture was stirred at rt for 0.5 h
and then evaporated to dryness under reduced pressure. The
residue was purified by column chromatography (MeOH–
EtOAc, 1:5) to give 3 (210 mg, 36%), which was purified
further by recrystallization from MeOH–H2O to provide 3
1
as a white solid, mp 2008C: H NMR (DMSO) d 8.13 (s,
1H), 8.12 (s, 1H), 7.17 (s, 2H), 4.73 (d, J¼4.1 Hz, 1H), 4.46
(m, 2H), 4.22 (dd, J¼6.7, 6.9 Hz, 1H), 4.02 (dd, J¼6.7,
6.9 Hz, 1H), 3.72 (m, 2H), 3.54 (d, J¼3.7 Hz, 1H), 2.30 (m,
1H), 1.86 (m, 1H), 1.03 (m, 1H); 13C NMR (DMSO) d
155.8, 152.2, 149.7, 141.02, 118.6, 77.9, 74.4, 74.0, 46.5,
42.3, 33.9; Anal. calcd for C11H15N5O3·0.5H2O: C, 48.17;
H, 5.88; N, 25.53. Found: C, 48.04; H, 5.58; N, 25.31.
Acknowledgements
This research was supported by funds from the Department
of Health and Human Services (AI 48495) and this is
appreciated. We also are indebted to the following
individuals for providing the antiviral data18 for 3 and
ent-3: Dr Erik De Clercq, Rega Institute, Leuven, Belgium;
Dr. Earl Kern, University of Alabama at Birmingham,
Birmingham, AL; and, Dr Robert Sidwell, Utah State
University, Logan, Utah.
1
Compound 17 (2.0 g, 39%): H NMR (DMSO) d 4.95 (d,
J¼3.9 Hz, 1H), 4.68 (t, J¼7.0 Hz, 1H), 4.46 (d, J¼6.0 Hz,
1H), 4.24 (d, J¼5.6 Hz, 1H), 3.90 (d, J¼3.7 Hz, 1H), 3.32 (m,
2H), 1.99 (m, 2H), 1.37 (s, 1H), 1.32 (s, 3H), 1.19 (s, 3H).
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1
white solid: mp 1618C; H NMR (DMSO) d 8.79 (s, 1H),
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9895
´
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18. Viruses used in the assays (highest concentration of 3 and
ent-3 tested, (mg/mL) were herpes simplex virus 1 and 2 (240),
human cytomegalovirus (200), varicella zoster virus (96),
vesicular stomatitis virus (400), vaccinia virus (400), cowpox
virus (100), coxsackie virus (80), parainfluenza-3 virus (200),
reo-1 virus (80), Sindbis virus (80), Punta Toro virus (200),
adenovirus-1 (200), measles (200), rhinovirus (200), influenza
A and B (200), Venezuelan equine encephalitis (200), yellow
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carbonate in methanol was used to remove the acetyl prior to
ammonolysis.
19. Enantiomeric purity was determined by proton NMR
spectroscopy in the presence of chiral shift reagent tris[3-
(heptafluoropropylhydroxymethylene)-d-camphorate.
europium (III) [Eu(hfc)3].
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