A protected form of (1S,2R,3S,4R)-4-aminocyclopentane-1,2,3-triol, a useful precursor to 5′-nor carbocyclic nucleosides

Article abstract of DOI:10.1081/SCC-100105336

5′-Nor carbocyclic nucleosides have been found to possess a variety of meaningful biological properties. One of the building blocks for this class of compounds is (1S,2R,3S,4R)-4-aminocyclopentane-1,2,3-triol. To date, the reported routes to this compound are not particularly facile. Thus, a convenient route to this triol in its protected isopropylidene form (2) from (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate. This will facilitate the preparation of new 5′-nor carbocyclic nucleosides in the "D-ribo-like" configuration. This method is also adaptable to the "L-like" series and the 2′- and 3′-deoxy analogs.

Full text of DOI:10.1081/SCC-100105336

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A PROTECTED FORM OF (1S,2R,3S,4R)-4-
AMINOCYCLOPENTANE-1,2,3-TRIOL, A USEFUL
PRECURSOR TO 5′-NOR CARBOCYCLIC NUCLEOSIDES
Vasanthakumar P. Rajappan a , Vishnumurthy R. Hegde a & Stewart W. Schneller b
a Department of Chemistry, Auburn University, Auburn, AL, 36849-5312, U.S.A.
b Department of Chemistry, Auburn University, Auburn, AL, 36849-5312, U.S.A.
Published online: 15 Aug 2006.
To cite this article: Vasanthakumar P. Rajappan , Vishnumurthy R. Hegde & Stewart W. Schneller (2001) A PROTECTED
FORM OF (1S,2R,3S,4R)-4-AMINOCYCLOPENTANE-1,2,3-TRIOL, A USEFUL PRECURSOR TO 5′-NOR CARBOCYCLIC
NUCLEOSIDES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:18, 2849-2854, DOI: 10.1081/SCC-100105336
To link to this article: http://dx.doi.org/10.1081/SCC-100105336
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SYNTHETIC COMMUNICATIONS, 31(18), 2849–2854 (2001)
A PROTECTED FORM OF (1S,2R,3S,4R)-
4-AMINOCYCLOPENTANE-1,2,3-TRIOL,
A USEFUL PRECURSOR TO 50-NOR
CARBOCYCLIC NUCLEOSIDES
Vasanthakumar P. Rajappan, Vishnumurthy R. Hegde,1
and Stewart W. Schneller*
Department of Chemistry, Auburn University,
Auburn, AL 36849-5312
ABSTRACT
50-Nor carbocyclic nucleosides have been found to possess a
variety of meaningful biological properties. One of the build-
ing blocks for this class of compounds is (1S,2R,3S,4R)-4-
aminocyclopentane-1,2,3-triol. To date, the reported routes
to this compound are not particularly facile. Thus, a conve-
nient route to this triol in its protected isopropylidene form
(2) from (+)-(1R,4S )-4-hydroxy-2-cyclopenten-1-yl acetate.
This will facilitate the preparation of new 50-nor carbocyclic
nucleosides in the ‘‘D-ribo-like’’ configuration. This method is
also adaptable to the ‘‘L-like’’ series and the 20- and 30-deoxy
analogs.
*Corresponding author.
2849
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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INTRODUCTION
Reports on the biological activity of both enantiomers of 50-nor-
aristeromycin2,3 (1, as the (À)-antipode) and related derivatives4,5 have
prompted considerable interest in the 50-nor carbocyclic series of nucleosides6
as potential medicinal agents2–5 and oligomer building blocks.7,8 We recently
sought a facile route to other derivatives in this series that possessed bases
other than the standard naturally occurring purines and pyrimidines. For this
purpose, a convenient preparation of the protected cyclopentylamine (2),
which could be employed in a de novo type process6b,9 to the new analogs,
was desired.
A review of the literature showed that a racemic10 and a chiral11 syn-
thesis of 2 were available. However, since chiral 2 was needed for our
studies, the numerous steps in one literature procedure11a and limited flex-
ibility in another11b to this material led to developing a procedure more
adaptable to modification in the cyclopentyl ring and to scale-up. This
route is described here.
RESULTS
Beginning with (+)-(1S,4R)-4-phthalimidyl-2-cyclopenten-1-ol (3)12
(available from (+)-(1R,4S )-4-hydroxy-2-cyclopenten-1-yl acetate13) near
quantitative glycolization using standard conditions (N-methylmorpholine

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N-oxide, osmium tetroxide) led to 4.14 Protection of the 2,3-dihydroxy
groups of 4 as an isopropylidene unit (5) was followed by removal of
the phthalyl group (with methylamine) to give 2 in 48% overall yield
from (+)-(1R,4S )-4-hydroxy-2-cyclopenten-1-yl acetate. The properties of
2 compared favorably with those reported.10,11
Compound 3 is also a convenient precursor to the 20- and 30-deoxy
50-nor carbocyclic nucleoside series15 whereas the enantiomer of 3 would
avail a means to the ‘‘L-like’’ derivatives.3,4
EXPERIMENTAL
General Methods
Melting points were recorded on a Meltemp II melting point appara-
tus and are uncorrected. Combustion analyses were performed by Atlantic
Microlab, Inc., Norcross, GA. 1H spectra were recorded on a Bruker
AC 250 spectrometer, referenced to internal tetramethylsilane (TMS) at
0.0 ppm. The spin multiplicities are indicated by the symbols s (singlet), d
(doublet), t (triplet), m (multiplet) and br (broad). Reactions were monitored
by thin-layer chromatography (TLC) using 0.25 mm Whatman Diamond
silica gel 60-F254 precoated plates with visualization by irradiation with a
Mineralight UVGL-25 lamp. Column chromatography was performed on
Whatman silica, 230–400 mesh, 60 A and elution with the indicated solvent
system. Yields refer to chromatographically and spectroscopically (1H and
13C NMR) homogeneous materials.
(+)-(1S,4R)-4-Phthalimidyl-2-cyclopenten-1-ol (3). To a solution of
the potassium salt of phthalimide (3.84 g, 20.5 mmol) in anhydrous
(DMSO (20 mL) were added triphenylphosphine (300 mg, 6 mol%) and
tetrakis(triphenylphosphine)palladium (800 mg, 4 mol%). The mixture was
stirred for 5 min and a solution of (+)-(1R,4S )-4-hydroxy-2-cyclopenten-1-
yl acetate13 (2.84 g, 20 mmol) in freshly distilled THF (100 mL) was added to
the above mixture. The flask containing this new mixture was immediately
transferred to an oil bath preheated at 50ꢀC and the mixture was stirred for
16 h. The solvents were removed under reduced pressure and the residue
slurried in CH2Cl2 (200 mL) and filtered. The clear filtrate was washed with
brine (150 mL), dried (Na2SO4) and filtered. After removal of the solvent
under reduced pressure, the residue was purified by column chromatography
using the solvent systems in the following order: hexane–AcOEt (20 : 1),
hexane–AcOEt (10 : 1), and hexane–AcOEt (5 : 1). Removal of the final sol-
vent mixture afforded 3 (3.2g, 70%) as a light yellow solid, mp 63–64 ꢀC
(lit.12 69–71ꢀC); H NMR (DMSO-d6) d 1.92(dt, J ¼ 12.5 and 5 Hz, 1H),
1

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RAJAPPAN, HEGDE, AND SCHNELLER
2.61 (dt, J ¼ 12.5 and 7.5 Hz, 1H), 4.65 (m, 1H), 5.00 4.62 (m, 1H), 5.20
(dt, J ¼ 7.5 Hz, 1H), 5.88 (dd, J ¼ 5 Hz, 14 Hz, 1H), 5.96 (dd, J ¼ 7.5 Hz,
14 Hz, 1H), 7.84 (s, 4H). Anal. calcd for C13H11NO3: C, 68.11; H, 4.84;
N, 6.11. Found: C, 67.97; H, 4.81; N, 6.20.
(1S,2R,3S,4R)-4-(N-Phthalimidyl)cyclopentane-1,2,3-triol (4). A mix-
ture of 3 (1.71 g, 7.5 mmol), N-methylmorpholine N-oxide (3 mL of 50%
aq. solution, 14 mmol), and a catalytic amount of OsO4 (60 mg) were stirred
in acetone (20 mL) at room temp. for 2.5 h during which time the reaction
was complete as judged by tlc (CH2Cl2-MeOH, 4:1) analysis. Removal of
the solvent under reduced pressure gave a residue to which 10% NaHSO3
solution (20 mL) was added. The mixture was acidified to pH 2–3 using 5%
H2SO4 and then extracted several times with AcOEt. The extracts were
combined, dried over anhydrous Na2SO4, filtered and the filtrate concen-
trated to a small volume. The new residue was collected and washed with
hexane-AcOEt (8:1) and dried (P2O5) to give 4 (1.75 g, 88%) as a white
powder, mp 176–178ꢀC; H NMR (DMSO-d6) d 1.89 (m, 1H, H-5), 2.15
1
(m, 1H, H-5), 3.70–4.54 (m, 4H, H-1, H-2, H-3, H-4), 4.66 (d, J ¼ 3.7 Hz,
1H, OH), 4.90 (d, J ¼ 5 Hz, 1H, OH), 4.96 (d, J ¼ 2.5 Hz, H, OH), 7.85
(s, 4H, aromatic). Anal. calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32.
Found: C, 59.18; H, 5.00; N, 5.34.
(1S,2R,3S,4R)-4-(N-Phthalimidyl)-2,3-O-isopropylidenecyclopentane-
1,2,3-triol (5). To a solution of 4 (2g, 0.76 mmol) in dry acetone (60 mL) and
2,2-dimethoxypropane (5 mL) in a 100 mL round-bottom flask was added
a small crystal of p-toluenesulfonic acid under N2. This mixture was stirred
at room temp. overnight and was then passed through a pad of silica
gel. The resulting solution was evaporated under reduced pressure and the
residue extracted with AcOEt (2ꢁ50 mL). The combined extracts were dried
(Na2SO4), filtered, and the filtrate concentrated in vacuo to provide a residue
that was triturated with hexane to afford 5 (1.95 g, 84%) as an off-white
powder, mp 90–92ꢀC; 1H NMR (DMSO-d6) d 1.21 (s, 3H, Me), 1.43 (s, 3H,
Me), 2.08–2.30 (m, 2H, H-5), 3.96–4.48 (m, 3H, H-2, H-3, H-4), 4.96–5.01
(m, 2H, H-1 and OH), 7.86 (s, 4H, aromatic). Anal. calcd for C16H17NO5:
C, 63.36; H, 5.65; N, 4.62. Found: C, 63.29; H, 5.63; N, 4.62.
(1S,2R,3S,4R)-4-Amino-2,3-O-isopropylidenecyclopentane-1,2,3-triol
(2). A 33% solution of methylamine in absolute EtOH (60 mL) was added to
a stirred suspension of 5 (1.5 g) in absolute EtOH (40 mL). After stirring for
5 min at room temp. the mixture was refluxed for 2h during which time the
reaction was complete (tlc analysis, 4:1 CH2Cl2-MeOH). The mixture was
cooled to room temp. and the solvent evaporated on a rotary evaporator.
The residue was adsorbed on silica gel (2g); this was then loaded onto a
silica gel column and, in turn, eluted (15 : 1, CH2Cl2 : MeOH) to remove the
target compound. Evaporation of the solvent followed by trituration of the

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2853
residue using hexane yielded 2 (800 mg, 92%) as a white powder; mp
126–127ꢀC (lit.11 126–127ꢀC); 1H NMR (DMSO-d6) d 1.19 (s, 3H, Me), 1.25
(s, 3H, Me), 1.35 (m, 1H, H-5), 1.50 (m, 1H, H-5), 1.95 (m, 3H, NH2, OH),
3.22 (d, J ¼ 5 Hz, 1H, H-4), 3.89 (d, J ¼ 2.5 Hz, 1H, H-1), 4.38 (d, J ¼ 5 Hz,
.
1H, H-2), 4.45 (d, J ¼ 5 Hz, 1H, H-3). Anal. calcd for C8H15NO3 0:1
MeOH: C, 55.18, H, 8.75; N, 7.94. Found: C, 54.98; H, 8.48; N, 7.77.
ACKNOWLEDGMENT
This research was supported by funds from the Department of Health
and Human Services (AI31718 and AI48495), which is appreciated.
REFERENCES
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14. Compound 4 was the only product of this reaction. The lack of the
b-glycol product is apparently due to hindrance to the OsO4 to the top
face of 3 by the bulky phthalimide group that may be held in the
interfering orientation by hydrogen bonding between the hydrogen
of the C-1 hydroxyl and a carbonyl oxygen of the phthalimide ring.
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Received in the USA November 29, 2000

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