Stereoselective synthesis of carbocyclic L-4′-fluoro-2′,3′-dideoxyadenosine

Article abstract of DOI:10.1021/ol005665k

(Equation presented) L-(1′S,3′S)-9-[3-Fluoro-3-(hydroxymethyl)cyclopentan-1-yl]adenine 15 has been synthesized from ester 2, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 1 in six steps. The key ring closure has been accompli

Full text of DOI:10.1021/ol005665k

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1229-1231
Stereoselective Synthesis of Carbocyclic
L-4′-Fluoro-2′,3′-dideoxyadenosine
Giuseppe Gumina, Youhoon Chong, Yongseok Choi, and Chung K. Chu*
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy,
The UniVersity of Georgia, Athens, Georgia 30602-2352
dchu@rx.uga.edu
Received February 14, 2000
ABSTRACT
L-(1′S,3′S)-9-[3-Fluoro-3-(hydroxymethyl)cyclopentan-1-yl]adenine 15 has been synthesized from ester 2, which can be conveniently prepared
from 2,3-isopropylidene-D-glyceraldehyde 1 in six steps. The key ring closure has been accomplished through an intramolecular nucleophilic
substitution reaction.
Carbocyclic nucleosides have played an important role in
the search for useful antiviral or antitumoral agents in the
past 15 years.1 An outstanding achievement in this field has
been the recent approval of abacavir2 (Figure 1) for the
treatment of AIDS. From a chemical point of view, the
nonglycosidic nature of carbocyclic nucleosides has made
them a challenging target for synthetic chemists.
(1) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (b)
Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl,
R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (c) Crimmins, M. T.
Figure 1. Structures of anti-HIV drug abacavir and natural
Tetrahedron 1998, 54, 9229.
(2) (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; StClair,
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) Dobkin, J. F. Infect. Med. 1999, 16, 7.
antibiotic nucleoside nucleocidin.
Among “classical” nucleoside analogues bearing a gly-
cosidic bond, a variety of substitutions have been made on
the sugar moiety in the attempt to improve the biological
activity as well as to obtain metabolically stable derivatives.
In some cases, an electron-withdrawing substituent such as
fluorine has conferred favorable pharmacological properties,
and we3 and others4 have reported the synthesis and
biological evaluation of several 2′- and 3′-fluorinated nucleo-
sides.
(3) (a) Xiang, Y.; Kotra, L. P.; Chu, C. K.; Schinazi, R. F. Bioorg. Med.
Chem. Lett. 1995, 5, 743. (b) Xiang, Y.; Cavalcanti, S.; Chu, C. K.; Schinazi,
R. F.; Pai, S. B.; Zhu, Y.-L.; Cheng, Y.-C. Bioorg. Med. Chem. Lett. 1995,
5, 877. (c) Pai, S. B.; Liu, S.-H.; Zhu, Y.-L.; Chu, C. K.; Cheng, Y.-C.
Antimicrob. Agents Chemother. 1996, 40, 380. (d) Ma, T.; Pai, S. B.; Zhu,
Y. L.; Lin, J.-S.; Shanmuganathan, K.; Du, J.; Wang, C.; Kim, H.; Newton,
M. G.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1996, 39, 2835. (e) Ma,
T.; Lin, J.-S.; Newton, M. G.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem.
1997, 40, 2750. (f) Kotra, L. P.; Xiang, Y.; Newton, M. G.; Schinazi, R.
F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1997, 40, 3635. (g) Kotra, L.
P.; Newton, M. G.; Chu, C. K. Carbohydr. Res. 1998, 306, 69. (h) Choi,
Y.; Lee, K.; Hong, J. H.; Schinazi, R. F.; Chu, C. K. Tetrahedron Lett.
1998, 39, 4437. (i) Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz, S.;
Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1964, 7, 1320.
Lee, K.; Choi, Y.; Hong, J. H.; Schinazi, R. F.; Chu, C. K. Nucleosides
Nucleotides 1999, 18, 537.
(4) (a) Owen, G. R.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem.
1976, 41, 3010. (b) Marquez, V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki,
S.; Kelley, J. A.; Ford, H. Jr.; Driscoll, J. S. J. Med. Chem. 1990, 33, 978.
10.1021/ol005665k CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

Since the discovery of nucleocidin5 (Figure 1), several 4′-
substituted analogues have been synthesized and their
biological activities have been assessed.6
Scheme 1. Synthesis of (1′S,3′S)-9-[3-Fluoro-3-(hydroxy-
methyl)cyclopentan-1-yl]adeninea
In the case of carbocyclic analogues, however, only a few
examples have been reported, such as the synthesis of
carbocyclic 4′-fluoro-2′-deoxyguanosine from aristeromycin7
and the synthesis of carbocyclic 2′-ara-4′-R-fluorogua-
nosine.8 Carbocyclic 4′-fluoro-3′-deoxythymidine has been
identified as a side product in the synthesis of the 3′-fluoro
analogue, though it could not be purified and fully character-
ized.9
The importance of carbocyclic nucleosides as antiviral
agents as well as the potential advantage of fluorine
substitution prompted us to combine these two features into
novel L-4′-fluoro-2′,3′-dideoxy nucleosides. In view of the
fact that several carbocyclic adenosine analogues are S-
adenosylhomocysteine hydrolase inhibitors,10 we decided to
synthesize the adenosine analogue as part of a feasibility
study.
In our approach, we started from intermediate 2 (Scheme
1), which was synthesized from 2,3-isopropylidene-D-glyc-
eraldehyde 1 in fivw steps by the procedure developed in
our laboratory. This procedure was based on the [3,3]-Claisen
rearrangement, which allowed us to elaborate the fluorine
to the desired position with high stereoselectivity.11
Compound 2 was reduced to alcohol 3 by treatment with
a solution of lithium aluminum hydride (LAH) in THF at
-40 to -35 °C (Scheme 1). Benzylation of 3 gave fully
protected triol 4, which was treated with ozone in methanol
at -78 °C, followed by decomposition of the ozonide by
dimethyl sulfide, to give aldehyde 5. The Horner-Emmons-
type reaction was performed by treatment of 5 with the
sodium salt of triethyl phosphonoacetate in THF. E-Alkene
a Reagents and conditions: (a) ref 11; (b) LAH, THF, -40 to
-35 °C, 90 min; (c) NaH, THF, 0 °C to rt, 1 h, then BnBr, TBAI,
0 °C to rt, overnight; (d) O3, MeOH, -78 °C, 45 min, then Me2S,
0 °C, 2 h; (e) [(EtO)2P(O)CH2CO2Et/NaHMDS], THF, -78 °C, 1
h; (f) H2, 10% Pd/C, cyclohexane, rt, 24 h; (g) MsCl, Py, CH2Cl2,
0 °C to rt, 24 h; (h) NaH, THF, reflux, overnight; (i) NaOH/H2O,
EtOH, rt, 5 h, then AcOH, 0 °C; (j) Pb(OAc)4, CCl4, hν, reflux, 15
min, then I2, CCl4, hν, reflux, 2 h; (k) NaHCO3, 15% (v/v) water/
HMPA, 100 °C, overnight; (l) 6-chloropurine, [PPh3/DEAD], rt, 6
h; (m) NH3/MeOH, 100 °C (steel bomb), 2.5 h; (n) TBAF, THF,
rt, 30 min.
(5) Jenkins, I. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Am. Chem. Soc.
1976, 98, 3346.
6, obtained in 80% yield, was quantitatively converted to
intermediate 8 by catalytic hydrogenolysis followed by
mesylation of the resulting alcohol 7. Treatment of 8 with
sodium hydride in THF under refluxing conditions generated
the enolate which cyclized through an intramolecular nu-
cleophilic substitution reaction to produce epimeric esters 9
in 75% yield. Esters 9 were hydrolyzed to acids 10 by
treatment with a solution of sodium hydroxide in water/
ethanol 1:1, followed by careful acidification. Attempts to
oxidatively decarboxylate 10 to an alcohol or ester derivative
by using a number of different oxidants and conditions were
not successful. However, a successful oxidative iododecar-
boxylation could be achieved by the method reported by
Barton et al.:12 a mixture of acids 10 and lead tetraacetate in
carbon tetrachloride was stirred under reflux in a nitrogen
atmosphere while being illuminated with a 250 W tungsten
lamp for 15 min. Using the same conditions of refluxing
and illumination, a solution of iodine in carbon tetrachloride
was added in small portions until no more discoloration was
observed (ca. 1 h). The reaction was continued for 1 h more.
Workup and flash chromatography afforded epimeric iodides
(6) (a) Verheyden, J. P. H.; Moffatt, J. G. J. Am. Chem. Soc. 1975, 97,
4386. (b)Yang, C. -O.; Kurz, W.; Eugui, E. M.; McRoberts, M. J.;
Verheyden, J. P. H.; Kurz, L. J.; Walker, K. A. M. Tetrahedron Lett. 1992,
33, 41. (c) Yang, C.-O.; Wu, H. Y.; Fraser-Smith, E. B.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 37. (d) Lipshutz, B. H.; Sharma, S.; Kimock,
S. H.; Behling, J. R. Synthesis 1992, 191. (d) Maag, H.; Rydzewsi, R. M.;
McRoberts, M. J.; Crawford-Ruth, D.; Verheyden, J. P. H.; Prisbe, J. Med.
Chem. 1992, 35, 1440.
(7) Borthwick, A. D.; Biggadike, K.; Paternoster, I. L.; Coates, J. A. V.;
Knight, D. J. Bioorg. Med. Chem. Lett. 1993, 3, 2577.
(8) Biggadike, K.; Borthwick, A. D. J. Chem. Soc., Chem. Commun.
1990, 380.
(9) Be´res, J.; Sa´gi, G.; Baitz-Ga´cs, E.; To¨mo¨sko¨zi, I.; Gruber, L.; O¨ tvo¨s,
L. Tetrahedron 1989, 45, 6271.
(10) De Clerq, E. Nucleosides Nucleotides 1998, 17, 625.
(11) Hong, J. H.; Lee, K.; Choi, Y.; Chu, C. K. Tetrahedron Lett. 1998,
39, 3443.
(a) (EtO)2P(O)CHFCO2Et, NaHMDS, 80%; (b) (i) concd HCl, EtOH, (ii)
TBDMSCl, 70%; (c) (i) DIBAL-H, (ii) NaBH4, CeCl3, 80%, (iii) TBDMSCl,
80%; (d) (EtO)3CCH3, propionic acid, 130 °C, 70%.
(12) Barton, D. H. R.; Faro, H. P.; Serebryakov, E. P.; Woolsey, N. F.
J. Chem. Soc. 1965, 2438.
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Org. Lett., Vol. 2, No. 9, 2000

11, which were smoothly hydrolyzed by heating at 100 °C
in a solution of sodium bicarbonate in 15% water/HMPA.
Surprisingly, only the R-alcohol could be isolated from
hydrolysis of the mixture 11 (epimeric ratio ≈ 1:1). In the
reaction conditions, the R-iodide was probably not hydro-
lyzed and longer reaction times or higher temperatures caused
its decomposition. Under our best conditions, alcohol 1213
was obtained in 40% yield, and traces of the â-isomer could
be detected by proton NMR.
Mitsunobu reactions in the synthesis of nucleoside analogues
often depends on the conditions employed. In our case, a
solution of the alcohol was added to the mixture containing
6-chloropurine and the preformed complex triphenylphos-
phine/DEAD in THF,14 and the reaction was performed at
room temperature in the dark for 6 h. Removal of the solvent
and flash chromatography gave the product in 80% yield.
The 6-chloro derivative 13 was converted into protected
adenosine analogue 14 by treatment with a saturated solution
of ammonia in methanol in a steel bomb at 100 °C for 2.5
h. Desilylation of the primary alcohol by treatment with
tetrabutylammonium fluoride (TBAF) in THF resulted in the
desired carbocyclic L-4′-fluoro-2′3′-dideoxyadenosine 1515
in 98% yield.
The selectivity of the hydrolysis reaction might result from
the pseudoequatorial preference of the bulky iodide groups
in 11R and 11â (Figure 2). The attack of the water molecule
In summary, we have described a de novo synthesis of
key intermediate cyclopentanol 12. Condensation of this
intermediate with 6-chloropurine, followed by ammonolysis
and deprotection, readily provided carbocyclic L-4′-fluoro-
2′,3′-dideoxyadenosine. Furthermore, intermediate 12 can be
utilized for the syntheses of other nucleosides with the natural
as well as the unnatural heterocyclic moieties, which are in
progress.
The stereochemistry of products 12-15 has been estab-
lished by one- and two-dimensional NMR experiments. In
particular, NOEDS (1-D NOE difference spectrometry)
spectra of 15 were crucial in understanding the geometry of
the final product (and, consequently, of the precursors), since
proton H-2′â showed net NOE enhancement upon irradiation
of protons H-6′ and H-8, clearly indicating that the adenine
moiety and the 6′-methylene are in a cis relation (Scheme
2). Unfortunately, no correlation between H-1′ and H-2′ could
Figure 2. Proposed mechanism for the hydrolysis of iodides 11.
to 11R may be hampered by the hindered exocyclic meth-
ylene (P ) trimethyldimethylsilyl), whereas the 11â con-
former undergoes nucleophilic substitution by the water
molecule.
Scheme 2. NOE Correlations and Stereochemistry of 15
Alcohol 12 was condensed with 6-chloropurine under
Mitsunobu conditions to give adduct 13. The success of
(13) Colorless oil: [R]27D 2.21° (c 3.13, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 4.33 (m, 1H, CHOH), 3.69 (dd, 1H, H6′, J ) 15.6, 10.7 Hz), 3.65
(dd, 1H, H6′, J ) 16.4, 10.7 Hz), 2.14-1.74 (m, 6H, H2′, H4′, H5′), 0.89 (s,
9H), 0.07 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 106.3 (JC-F ) 175.0
Hz), 73.3, 66.2 (JC-F ) 32.0 Hz), 43.7 (JC-F ) 21.5 Hz), 34.5, 32.7 (JC-F
) 24.1 Hz), 25.8, 18.3, -5.4; HRMS (FAB) obsd, m/z 249.1699, calcd for
C12H26FO2Si, m/z 249.1686 (MH+). Anal. Calcd for C12H25FO2Si: C, 58.02;
H, 10.14. Found: C, 57.80; H, 9.96.
(14) Jenny, T. F.; Horlacher, J.; Previsani, N.; Benner, S. A. HelV. Chim.
be studied because of the cluttering of the multiplets
corresponding to protons H-2′R, H-2′â, and H-5′R.16
Antiviral activity and cytotoxicity evaluations of com-
pound 15 are in progress.
Acta 1992, 75, 1944.
(15) White solid: mp (MeOH) 167-168 °C; [R]29 -12.73° (c 0.37,
D
MeOH); UV (MeOH) λmax 260.0 (ꢀ 20890) (pH 2), 261.5 (ꢀ 19800) (pH
7), 261.5 (ꢀ 17980) (pH 11); 1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H,
H8), 8.08 (s, 1H, H2), 5.08 (m, 1H, H1′), 3.69 (dd, 1H, H6′, J ) 16.2, 12.1
Hz), 3.65 (dd, 1H, H6′, J ) 17.4, 12.1 Hz), 2.43-2.34 (m, 3H, H2′, H5′R),
2.33-2.15 (m, 1H, H4′â), 2.13-2.04 (m, 1H, H5′â), 2.00-1.86 (m, 1H, H4′R);
13C NMR (CD3OD, 100 MHz) δ 157.3, 153.5, 150.7, 141.2, 120.5, 105.9
(JC-F ) 176.6 Hz), 66.7 (JC-F ) 27.4 Hz), 56.1, 41.6 (JC-F ) 24.1 Hz),
33.7 (JC-F ) 23.8 Hz), 31.5; HRMS (FAB) obsd, m/z 252.1268, calcd for
C11H15FON5, m/z 252.1261 (MH+). Anal. Calcd for C11H14FON5: C, 52.58;
H, 5.62; N, 27.87. Found: C, 52.74; H, 5.73; N, 27.72.
Acknowledgment. This research was supported by the
U.S. Public Health Service Research Grant AI 32351 from
the National Institute of Allergy and Infectious Diseases,
NIH. We thank Dr. Michael Bartlett of the College of
Pharmacy, The University of Georgia, for performing the
high-resolution mass spectra.
(16) Thus, irradiation of H-1′ resulted in an amorphous multiplet
containing protons H-5′R and H2′R (and, maybe, some NOE enhancement
from H2′â), whereas protons H-8 and H-6′ correlated only and unequivocally
with H-2′â, which showed as a clear double double doublet (J ) 33.0,
14.2, 10.0 Hz).
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