Efficient and practical synthesis of D-cyclopent-2-enone, the key intermediate for the synthesis of carbocyclic nucleosides

Article abstract of DOI:10.1016/S0040-4039(02)00774-8

An efficient and practical method for the synthesis of (4R,5R)-4,5-O-isopropylidene-cyclopent-2-enone was developed from D-ribose by using a ring-closing metathesis reaction.

Full text of DOI:10.1016/S0040-4039(02)00774-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4141–4143
Efficient and practical synthesis of
D
-cyclopent-2-enone, the key
intermediate for the synthesis of carbocyclic nucleosides
Yun H. Jin and Chung K. Chu*
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens,
GA 30602-2352, USA
Accepted 18 April 2002
Abstract—An efficient and practical method for the synthesis of (4R,5R)-4,5-O-isopropylidene-cyclopent-2-enone was developed
from
D-ribose by using a ring-closing metathesis reaction. © 2002 Elsevier Science Ltd. All rights reserved.
Carbocyclic nucleosides have received much attention
since the isolation of (−)-aristeromycin 11 and (−)-
neplanocin A 22 from natural sources. More recently,
the discovery of abacavir 3,3 a prodrug of carbovir 44
against HIV marked an important milestone of carbo-
cylic nucleosides in antiviral chemotherapy. Due to the
absence of a typical glycosidic bond, carbocyclic
nucleosides are chemically and enzymatically more sta-
ble than the natural nucleosides.5 The mechanism of the
of compounds. However, the main problem for scaling
up these compounds is the availability of key intermedi-
ates such as cyclopent-2-enone 15.
Previously, several asymmetric syntheses for (−)-aris-
teromycin 1 and (−)-neplanocin A 2 have been devel-
oped.11 Several approaches utilized optically pure
starting materials such as
or
-tartaric acid.14 Optically active cyclopent-2-enone
D D
-ribonolactone,12 -ribose13
L
antiviral activity of (−)-aristeromycin
1
and (−)-
15 is the key intermediate in the synthesis of carbocyclic
nucleosides including (−)-aristeromycin 1, (−)-
neplanocin A 2 and their analogs, which can be
obtained by the ring opening and cyclization reaction
neplanocin A 2 is probably due to inhibition of S-
adenosyl homocystein (AdoHcy) hydrolase,6 which has
been considered an attractive target for antiviral
chemotherapy, interfering with the virus mRNA
maturation.7
of
D-ribonolactone or D
-ribose.15 However, these reac-
tions are highly sensitive to reaction conditions, such as
moisture and temperature, and therefore, suffer low
and inconsistent yields. Recently, a novel synthesis of
optically active cyclopent-2-enone 15 has been
As part of our drug discovery program, recently we
have developed the synthesis of enantiomerically pure
(−)-aristeromycin 1 and (−)-neplanocin A 2 analogs.8–10
We also synthesized enantiomerically pure cytosine 5
and 5-F-cytosine 6 analogs, which exhibit significant
anti-HIV and anti-West Nile Virus activities (Fig. 1).8
Therefore, additional biological evaluation of these and
other carbocyclic nucleosides required a large amount
reported.16 It has been synthesized from
D-isoascorbic
acid using ring-closing metathesis (RCM) reaction as
the key reaction. However, the synthesis of cyclopent-2-
enone 15 depended on several oxidation and reduction
steps which lowered the overall yield (23%) in a small
scale.
Figure 1.
* Corresponding author. Tel.: 1-706-542-5379; fax: 1-706-542-5381; e-mail: dchu@rx.uga.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00774-8

4142
Y. H. Jin, C. K. Chu / Tetrahedron Letters 43 (2002) 4141–4143
Scheme 1. Reagents and conditions: (a) 2,2-dimethoxypropane, p-toluenesulfonic acid, acetone, 0°C to rt, 1 h; (b) TBDMSCl,
imidazole, CH2Cl2, rt, 1 h; (c) vinylmagnesium bromide, anhydrous THF, −78°C to rt, 1 h; (d) TBAF, THF, rt, 1 h; (e) NaIO4,
H2O, rt, 1 h; (f) NaH, DMSO, methyltriphenylphosphonium bromide, THF, 0°C to reflux, 3 h; (g) Grubbs catalyst, anhydrous
,
CH2Cl2, 24°C, 4 h; (h) pyridinium chlorochromate, 4 A molecular sieve, AcOH, CH2Cl2, rt, 12 h.
In this communication, we wish to report a significantly
improved and practical method for the synthesis of
13: To a 500 mL round bottom flask filled with the
Grubbs catalyst (446 mg, 1 mol%, flushed with N2 three
times), a solution of the diene 13 (10.0 g, 0.054 mol) in
anhydrous CH2Cl2 (300 mL) was added. After stirring
optically pure
D
-cyclopent-2-enone 15 from
D-ribose in
eight steps with overall yield of 56% in a large scale (10
g scale).
,
at 24°C for 4 h, 4 A molecular sieve (20.0 g), pyri-
dinium chlorochromate (23.5 g, 0.108 mol) and acetic
acid (0.15 mL, 5 mol%) were added to the resulting
dark brown mixture. The reaction mixture was stirred
at the same temperature for 12 h and filtered over a
silica-gel pad with EtOAc. The filtrate was concentrated
in vacuo and the residue was purified by column chro-
matography on a silica-gel column with 10% hexane in
EtOAc to give cyclopetenone 15 (7.6 g, 93% yield) as
white crystals.
The isopropylidene protected derivative 8 (Scheme 1)
was obtained from D-ribose with 2,2-dimethoxypropane
in the presence of catalytic amount of p-toluenesulfonic
acid in 90% yield, followed by t-butyldimethylsilane
chloride with imidazole to afford the silylated lactol 9
in 85% yield. To introduce an olefin moiety, Grignard
reaction was carried out with vinylmagnesium bromide
to provide alcohol 10 in 100% yield. The deprotection
of the silyl group using 1 M solution of tetra-
butylammonium fluoride in THF followed by an oxida-
tive cleavage with sodium periodate afforded lactol 12.
Wittig reaction16 was carried out using NaH and
DMSO in THF to give diene 13 in 86% yield which
underwent a RCM16,17 reaction. Several RCM reaction
conditions using the Grubbs catalyst from diene 13 to
cyclopentenol 14 were investigated, among which 1%
Grubbs catalyst at 24°C in anhydrous CH2Cl2 provided
the best result to obtain cyclopentenol 14. As the
obtained cyclopentenol 14 was volatile, the desired
cyclopentenone 1518 was directly obtained in two steps
93% yield from diene 13 by PCC oxidation of cyclopen-
tenol 14 without purification.
Acknowledgements
This research was supported by grants of National
Institute of Allergy and Infectious Diseases (U01
AI48495 and AI 32351).
References
1. Kusaka, T.; Yamamoto, H.; Muroi, M.; Kishi, T.;
Mizuno, K. J. Antibiot. 1968, 21, 255.
In summary, we have developed
improved synthetic method for -cyclopent-2-enone 15
in a preparative scale, which is a versatile intermediate
for the synthesis of carbocyclic nucleosides in overall
a
significantly
2. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.;
Hayashi, M.; Otani, M. J. Antibiot. 1981, 34, 359.
3. (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W.
H.; St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N.
R.; Reardon, J. E.; Dornsife, R. E.; Averett, D. R.;
Krenitsky, T. A. Antimicrob. Agents Chemother. 1997, 41,
1082; (b) Weller, S.; Radomski, K. M.; Lou, Y.; Stein, D.
S. Antimicrob. Agents Chemother. 2000, 44, 2052.
4. Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
D
56% yield from
D-ribose.
Experimental
Procedure for the preparation of compound 15 from

Y. H. Jin, C. K. Chu / Tetrahedron Letters 43 (2002) 4141–4143
4143
5. (a) Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6,
1; (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom,
R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron
1994, 50, 10611; (c) Zhu, X. F. Nucleosides Nucleotides
Nucleic Acid 2000, 19, 651.
12. Marquez, V. E.; Lim, M. I.; Tseng, C. K.; Markovac, A.;
Priest, M. A.; Khan, M. S.; Kaskar, B. J. Org. Chem. 1988,
53, 5709.
13. Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J. Org.
Chem. 1987, 52, 5457.
14. Bestmann, H. J.; Roth, D. Angew. Chem., Int. Ed. Engl.
6. Wolfe, M. S.; Borchardt, R. T. J. Med. Chem. 1991, 34,
1521.
1990, 29, 99.
15. Ali, S. M.; Ramesh, K.; Borchart, R. T. Tetrahedron Lett.
1990, 31, 1509.
7. De Clercq, E. Antimicrob. Agents Chemother. 1985, 28,
84.
16. Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon,
H. R.; Chun, M. W.; Jung, Y. H.; Jeong, L. S. J. Org.
Chem. 2001, 61, 6490.
8. Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R.
W.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44,
3958.
17. Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
9. Song, G. Y.; Naguib, F. N.; el Kouni, M. H.; Chu, C.
K. Nucleosides Nucleotides Nucleic Acid 2001, 20, 1915.
10. Wang, P.; Gullen, B.; Newton, M. G.; Cheng, Y. C.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 1999, 42,
3390.
11. (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992,
48, 571; (b) Crimmins, M. T. Tetrahedron 1998, 54,
9229.
Soc. 1997, 119, 3887.
18. Data for 15: mp 68.5–70.3°C; [h]D −69.3° (c, 0.60, CHCl3)
[reported:16 mp 68.6–70.1°C; [h]D −70.4° (c, 0.92, CHCl3)];
1H NMR (CDCl3) l 7.61 (dd, J=2.4, 6.0 Hz, 1H), 6.22 (d,
J=6.0 Hz, 1H), 5.28 (dd, J=2.4, 5.6 Hz, 1H), 4.47 (d,
J=5.6 Hz, 1H), 1.42 (s, 3H), 1.41 (s, 3H); 13C NMR
(CDCl3) 203.2, 160.0, 134.6, 115.7, 78.8, 76.7, 27.6, 26.4.