A facile synthesis of (-)-(4R,5R)-4,5-(isopropylidenedioxy)-2-cyclopentenone, a useful precursor to D-like carbanucleosides

Article abstract of DOI:10.1081/SCC-120018765

A facile synthesis of (-)-(4R,5R)-4,5-(isopropylidenedioxy)-2-cyclopentenone ((-)-2), as a precursor to D-like carbanucleosides, is described in 5 steps from (1S,4R)-4-acetoxycyclopent-2-en-1-ol (3). Compound 3 has also been described in the literature as amenable to the formation of (+)-2, thus making both the D-like and L-like carbanucleosides available from the same readily available 3.

Full text of DOI:10.1081/SCC-120018765

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A Facile Synthesis of (-)-(4R,5R)-4,5-
(Isopropylidenedioxy)-2-cyclopentenone, a Useful
Precursor to d-Like Carbanucleosides
Xue-Qiang Yin a , Vasanthakumar P. Rajappan a , Atanu Roy a & Stewart W. Schneller a
a Department of Chemistry , Auburn University , Auburn, Alabama, USA
Published online: 16 Aug 2006.
To cite this article: Xue-Qiang Yin , Vasanthakumar P. Rajappan , Atanu Roy & Stewart W. Schneller (2003) A Facile Synthesis
of (-)-(4R,5R)-4,5-(Isopropylidenedioxy)-2-cyclopentenone, a Useful Precursor to d-Like Carbanucleosides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:9, 1477-1481, DOI:
10.1081/SCC-120018765
To link to this article: http://dx.doi.org/10.1081/SCC-120018765
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1477–1481, 2003
A Facile Synthesis of (R)-(4R,5R)-4,5-
(Isopropylidenedioxy)-2-cyclopentenone,
a Useful Precursor to D-Like Carbanucleosides
Xue-Qiang Yin, Vasanthakumar P. Rajappan,
*
Atanu Roy, and Stewart W. Schneller
Department of Chemistry, Auburn University,
Auburn, Alabama, USA
ABSTRACT
A
facile synthesis of (ꢀ)-(4R,5R)-4,5-(isopropylidenedioxy)-
2-cyclopentenone ((ꢀ)-2), as a precursor to D-like carbanucleosides,
is described in 5 steps from (1S,4R)-4-acetoxycyclopent-2-en-1-ol (3).
Compound 3 has also been described in the literature as amenable
to the formation of (þ)-2, thus making both the D-like and L-like
carbanucleosides available from the same readily available 3.
*Correspondence: Stewart W. Schneller, Department of Chemistry, Auburn
University, Auburn, AL 36849-5312, USA; E-mail: schnest@mail.auburn.edu.
1477
DOI: 10.1081/SCC-120018765
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1478
Yin et al.
INTRODUCTION
While carbanucelosides have been studied since the synthesis of
carbocyclic adenosine (1, aristeromycin) by Southern Research
Institute,[1] a renaissance has occurred with this series of compounds as
a result of their promising biological properties.[2] Our laboratory is
contributing to this revival[3] and recently sought a route to C-50 varied
D-like and L-like carbanucleosides that would begin with the Michael
addition reaction of a functionalized carbon nucleophile to the C-3
center of an appropriately protected 4,5-dihydroxy-2-cyclopentenone
(that is, (ꢀ)-2 for D-like analogs and (þ)-2 forthe L-like enantiomers)
(Sch. 1). The literature[4] provided a means to (þ)-2 but ourexperience
has shown that the existing procedures[5] to (ꢀ) 2 have limitations of
various types. Using the same starting material as described[4] for( þ)-2
(that is, (1S,4R)-4-acetoxycyclopent-2-en-1-ol (3)) we report here an
efficient and convenient route to (ꢀ)-2. This, in turn, will permit pre-
paration of the desired carbanucleosides in both the D-like and L-like
forms from a common precursor (3).
RESULTS
The synthesis of (ꢀ)-2 began with the conversion of 3 to the
monophosphate 4 via a procedure developed in our laboratories.[6]
Glycolization of 4 to 5 was followed by catalization to 6. Ammonolysis
of 6 provided 7, which was then subjected to oxidative elimination using
pyridinium chlorochromate[4,7] to give (ꢀ)-2 whose properties compared
favorably with those recently repored.[5]
Scheme 1.

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Synthesis of (R)-(4R,5R)-4,5-(Isopropylidenedioxy)-2-cyclopentenone
EXPERIMENTAL
1479
General Methods
Combustion analyses were performed by Atlantic Microlab, Inc.,
1
Norcross, GA. H spectra were recorded on a Bruker AC 250 spectrom-
eter, referenced to internal tetramethylsilane (TMS) at 0.0 ppm. The spin
multiplicities are indicated by the symbols s (singlet), d (doublet), and
m (multiplet). 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 gel,
230–400 mesh, 60 A and elution with the indicated solvent systems. Yields
refer to chromatographically and spectroscopically (1H and 13C NMR)
homogeneous materials. Carbon–phosphorus coupling was observed in
the 13C NMR spectra for 5 and 7.
(1S,2S,3S,4R)-4-Acetoxy-2,3-dihydroxycyclopentan-1-yl diethyl phosphate
(5): To an ice-watercooled solution of (1 S,4R)-4-acetoxycyclopent-2-en-1-yl
diethyl phosphate 4[6] (Sch. 2) (2.78 g, 10 mol) in acetone (20 mL) and
H2O (4 mL) was added N-methylmorpholine N-oxide (4.1 mL, 50% aq)
Scheme 2. Reaction conditions: a, N-methylmorpholine N-oxide/catalytic OsO4
in acetone/H2O; b, 2,2-dimethoxypropane/acetone/catalytic p-TsOH; c, NH3 in
MeOH; d, pyridinium chlorochromate and Celite in CH2Cl2.

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1480
Yin et al.
and OsO4 (20 mg). The mixture was then stirred at r.t. for 24 h. The solution
was evaporated under vacuum and the residue subjected to column chromato-
graphic purification with hexanes–EtOAc (1:3) to give 5 (2.05 g, 70%);
1HNMR (CDCl3) ꢀ 4.90 (m, 1H), 4.66 (m, 1H), 4.57 (s, 1H), 4.14 (m, 6H),
4.02 (s, 1H), 2.73 (m, 1H), 2.06 (m, 3H), 1.71 (m, 1H), 1.31 (m, 6H);
13CNMR[8] (CDCl3) ꢀ 170.74, 80.96, 80.87, 77.48, 76.47, 76.27, 76.20, 64.12,
35.04, 34.95, 20.82, 15.88,15.79. Anal. calcd. forC 11H21O8P: C, 42.31, H, 6.78.
Found: C, 42.10, H, 6.82.
(1S,2S,3S,4R)-4-Hydroxy-2,3-(isopropylidenedioxy)cyclopentan-1-yl
diethyl phosphate (7): Compound 5 (10.0 g, 32.05 mmol) was dissolved
in solution of anhydrous acetone (100 mL) and 2,2-dimethoxypropane
(23 mL). To this was added p-toluenesufonic acid (200 mg) and the
reaction mixture stirred at r.t. for 15 h. The mixture was then brought
to pH 7 with NH4OH. Following this, the acetone was evaporated
undervacuum. The ersidue was dissolved in EtOAc (200 mL) and this
solution washed with brine (3 Â 20 mL). The combined organic
layers were dried (MgSO4), filtered and concentrated under vacuum to
give (1S,2S,3S,4R)-4-acetoxy-2,3-(isopropylidenedioxy)cyclopentan-1-yl
diethyl phosphate (6) as a clearoil (11.75 g, 100%); 1H NMR (CDCl3)
ꢀ 5.08 (d, J ¼ 5.25, 1H), 4.73 (m, 1H), 4.63 (m, 1H), 4.06 (m, 5H),
2.06–2.40 (m, 2H), 2.04 (m, 3H), 1.28–1.48 (m, 12H). Compound 6
obtained in this manner was used directly in the next reaction without
further characterization.
A solution of 6 (2.7 g, 7.6 mmol) in dry MeOH (50 mL) saturated
with NH3 was kept at r.t. for 24 h in a Parr stainless steel sealed reaction
vessel. The volatiles were removed under reduced pressure and the
residue purified via column chromatography using CH2Cl2–MeOH
1
(40:1) to yield 7 (2.1 g, 90%); H NMR (CDCl3) ꢀ 4.78 (m, 2H), 4.62
(m, 1H), 4.06 (m, 5H), 2.30 (s, 1H), 2.11 (m, 1H), 2.04 (m, 1H),
1.28 1.48 (m, 12H); 13C NMR[8] (CDCl3) ꢀ 110.70, 86.33, 86.02, 85.08,
84.96, 83.23, 83.11, 77.17, 76.73, 64.18, 64.08, 62.52, 62.43, 37.38, 37.32,
26.28, 23.94, 16.15, 16.05. Anal. calcd. forC 12H23O7P: C, 46.44, H, 7.47.
Found: C, 46.54, H, 7.40.
(R)-(4R,5R)-4,5-(Isopropylidenedioxy)-2-cyclopentenone ((R)-2): To
solution of
a
7
(1.57 g, 5.1 mmol) in CH2Cl2 (20 mL) were
added pyridinium chlorochromate (2.47 g) and Celite (4 g). This
mixture was stirred for 24 h under N2 and filtered and
the solvent removed in vacuo. Column chromatographic purification
of the residue using hexanes–EtOAc (1:3) gave (ꢀ)-2 (0.61 g, 81%)
whose 1H and 13C NMR spectra were in agreement with literature
values.[5] Anal. calcd. forC 8H10O3: C, 62.33, H, 6.54. Found: C,
62.10, H, 6.59.

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Synthesis of (R)-(4R,5R)-4,5-(Isopropylidenedioxy)-2-cyclopentenone
1481
ACKNOWLEDGMENT
This research was supported by funds from the Department of
Health and Human Services (AI48495), which is appreciated.
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Received in the USA July 31, 2002

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