Chiral synthesis of carbocyclic analogues of L-ribofuranosides

Full text of DOI:10.1021/jo9812330

J . Org. Chem. 1999, 64, 4173-4178
4173
and â-L-2′-fluoro-5-methylarabinofuranosyl uracil (L-
FMAU)17 have shown promising antiviral activity. Both
L-nucleosides, 3TC and FTC, exhibit more potent anti-
viral activity against HIV and hepatitis B virus (HBV)
and decreased toxicity in comparison to their D-counter-
parts.13,18 Therefore, it was of interest to synthesize the
corresponding L-carbocyclic nucleosides in anticipation of
interesting antiviral activity. We have previously re-
ported a preliminary account of L-cyclopentyl carbocyclic
nucleoside.19 In this paper, we report the experimental
details, X-ray structure, and confirmation of L-cyclopentyl
carbocyclic ribonucleosides.
Ch ir a l Syn th esis of Ca r bocyclic An a logu es
of L-r ibofu r a n osid es
Peiyuan Wang, Luigi A. Agrofoglio,
M. Gary Newton,† and Chung K. Chu*
Department of Pharmaceutical and Biomedical Sciences,
College of Pharmacy, and Department of Chemistry,
The University of Georgia, Athens, Georgia 30602
Received J une 25, 1998
In tr od u ction
Natural products, D-(-)-aristeromycin and neplanocin
A, are representatives of biologically interesting carbocy-
clic nucleosides. Natural as well as synthetic carbocyclic
nucleosides1,2 have shown interesting antitumor3 and
antiviral activities against cytomegalovirus,4 herpes vi-
rus,5 hepatitis B virus,6 and human immunodeficiency
virus (HIV).7,8 Carbocyclic nucleosides possess an in-
creased metabolic stability against nucleoside phospho-
rylases9 because of the absence of a true glycosidic bond.
Among them, carbovir7 and 6-cyclopropylaminopurine
analogue, 1592U89(Abacavir),10 are the most interesting
compounds due to their potent anti-HIV activities.
1592(Abacavir) has recently been approved by the FDA.
Recently, a novel carbocyclic nucleoside, BMS-200475,
has been reported to exhibit potent anti-HBV activity,
and it is currently undergoing phase II clinical trials.11
In recent years, a number of L-nucleosides, including
(-)-(2′R, 5′S)-1-(2-hydroxymethyloxathiolan-5-yl)cytosine
(3TC),12,13 (-)-â-L-2′,3′-dideoxy-5-fluoro-3′-thiacytidine
(FTC),14 â-L-2′,3′-dideoxy-5-fluorocytidine (L-FddC),15,16
Resu lts a n d Discu ssion
The total synthesis of racemic aristeromycin and its
analogues has been described by Shealy et al.20 The first
enantiospecific synthesis of the natural D-(-)-aristero-
mycin was reported by Arita et al.21 by a chemicoenzy-
matic approach. Several optically active L-carbocyclic
nucleosides have been prepared by the resolution from
racemic mixtures by enzymatic methods,1,2,22 and no total
synthetic methods had been reported until our paper
appeared.19 Therefore, it was of interest to develop
procedures for asymmetric synthesis of optically active
L-cyclopentyl carbocyclic nucleosides.
A retrosynthetic analysis indicates that L-cyclopentyl
carbocyclic nucleosides can be prepared by direct coupling
of a functionalized carbocyclic moiety with the corre-
sponding heterocycles or construction of the desired
heterocycles by linear approaches from cyclopentylamine.
For the synthesis of L-cyclopentyl nucleosides, we selected
the (+)-cyclopentanol 3 as a chiral intermediate, which
was prepared from the chiral enone 1.23 The procedure
for the synthesis of L-aristeromycin 13 is analogous to
the synthetic methodology of D-aristeromycin previously
reported by Borchardt and co-workers.31 Treatment of 1
* To whom correspondence should be addressed. Tel: (706) 542-
5379. Fax: (706) 542-5381. E-mail: DChu@RX.UGA.EDU.
† Department of Chemistry.
(1) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.
(2) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(3) Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1.
(4) Slusarchyk, W. A.; Young, M. G.; Bisacchi, G. S.; Hockstein, D.
R.; Zahler, R. Tetrahedron Lett. 1989, 30, 6453.
(5) Borthwick, A. D.; Kirk, B. E.; Biggadike, K.; Exall, A. M.; Butt,
S.; Roberts, S. M.; Knight, D. J .; Coates, J . A. V.; Ryan, D. M. J . Med.
Chem. 1991, 34, 907.
(6) Price, P. M.; Banerjee, R.; J effrey, A. M.; Acs, G. Hepatol. 1992,
16, 8.
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Cheng, Y.-C. J . Med. Chem. 1994, 37, 798.
(16) Gosselin, G.; Schinazi, R. F.; Sommadossi, J .-P.; Mathe, C.;
Bergogne, M.-C.; Aubertin, A.-M.; Kirn, A.; Imbach, J .-L. Antimicrob.
Agents Chemother. 1994, 38, 1292.
(17) Chu, C. K.; Ma, T. W.; Shanmuganathan, K.; Wang, C. G.;
Xiang, Y. J .; Pai, S. B.; Yao, G.-Q.; Sommadossi, J .-P.; Cheng, Y.-C.
Antimicrob. Agents Chemother. 1995, 39, 979.
(18) Chang, C. N.; Doong, S. L.; Zhou, J . H.; Beach, J . W.; J eong, L.
S.; Chu, C. K.; Tsai, C. H.; Cheng, Y.-C. J . Biol. Chem. 1992, 267,
13938.
(7) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17.
(8) Hayashi, S.; Norbeck, D. W.; Rosenbrook, W.; Fine, R. L.;
Matsukura, M.; Plattner, J . J .; Broder, S.; Mitsuya, H. Antimicrob.
Agents Chemother. 1990, 34, 287.
(19) Wang, P. Y.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K.
Tetrahedron Lett. 1997, 38, 4207.
(9) Herdewijn, P.; De Clerq, E.; Balzarini, J .; Vanderhaeghe, H. J .
Med. Chem. 1985, 28, 550.
(10) Daluge, S. M.; Good, S. S.; Martin, M. T.; Tibbels, S. R.; Miller,
W. H.; Averett, D. R.; St. Clair, M. H.; Ayers, K. M. The 34th
Interscience Conference on Antimicrobial Agents and Chemotherapy;
Orlando, FL, October 1994; Abstract.
(11) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris, J . P.; Innaimo,
S.; J acobs, G. A.; Kocy, O.; Lapointe, P.; Martel, A.; Merchant, Z.;
Slusarchyk, W. A.; Sundeen, J . E.; Young, M. G.; Colonno, R.; Zahler,
R. Bioorg. Med. Chem. Lett. 1997, 7, 127.
(12) Belleau, B.; Dixit, D.; Nguyen-Ba, N.; Kraus, J . L. 5th Inter-
national Conference on AIDS, Montreal, Canada, J une 4-9, 1989;
Paper no. T.C.O.I., p 515.
(20) Shealy, Y. F.; Clayton, J . D. J . Am. Chem. Soc. 1966, 88, 3885.
(21) Arita, M,; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J . Am. Chem.
Soc. 1983, 105, 4049.
(22) Secrist, J . A., III; Montgomery, J . A.; Shealy, Y. F.; O’Dell, C.
A.; Clayton, S. J . J . Med. Chem. 1987, 30, 746.
(23) Ali, S. M.; Ramesh, K.; Borchardt, R. Tetrahedron Lett. 1990,
31, 1509.
(24) Shealy, Y. F.; O′Dell, C. A. Thorpe, M. C. J . Heterocycl. Chem.
1981, 18, 383.
(25) Shealy, Y. F.; O′Dell, C. A. J . Heterocycl. Chem. 1976, 13, 1015.
(26) Sung, W. L. J . Org. Chem. 1982, 47, 3623.
(27) Harnden, M. R.; Wyatt, P. G.; Boyd, M. R.; Sutton, D. J . Med.
Chem. 1990, 33, 187.
(13) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; J eong, L. S.; Beach, J . W.; Choi, W.-B.; Yeola, S.; Liotta,
D. C. Antimicrob. Agents Chemother. 1992, 36, 672.
(14) Furman, P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.;
Nelson, D. J .; Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe, J . A.;
Tuttle, J . V.; Miller, W. H.; Condreay, L.; Averett, D. R.; Schinazi, R.
F.; Painter, G. R. Antimicrob. Agents Chemother. 1992, 36, 2686.
(28) Shealy, Y. F.; Clayton, J . D. J . Am. Chem. Soc. 1969. 91, 3075.
(29) Shealy, Y. F.; Clayton, J . D. J . Pharm. Sci. 1973, 62, 1432.
(30) X-ray data for compound 13: crystal dimension, 0.40 × 0.20 ×
0.20 mm; crystal color, habit: colorless, needle; empirical formula,
C
11H15N5O3; formula weight, 265.27; crystal system, orthorhombic;
lattice parameters a ) 6.87(2) Å, b ) 12.25(1) Å, c ) 13.893(4) Å; space
group, P212121(#19); Z ) 4.
10.1021/jo9812330 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/11/1999

4174 J . Org. Chem., Vol. 64, No. 11, 1999
Notes
Sch em e 1a
a
Reagents: (a) (t-BuOCH2)2CuLi, t-BuOMe/THF, -30 °C, 30 min; (b) DIBAL-H, CH2Cl2, -78 °C, 2 h; (c) (CF3SO2)2O, py, 0 °C, 30 min
(for 4); (d) CH3SO2Cl, Et3N, CH2Cl2, 0 °C, 45 min (for 6); (e) adenine/NaH, 18-crown-6, DMF, 0-20 °C, 30 h; (f) LiN3, DMF, 140 °C, 4 h;
(g) 5% Pd/C, EtOH, rt, 20 psi, 1.5 h; (h) â-methoxy-R-methacryloyl isocyanate, DMF, -20 to 20 °C, 10 h (for 9) or â-methoxyacryloyl
isocyanate, DMF, -20 to 20 °C, 10 h (for 11); (i) 30% NH4OH, EtOH/dioxane (1:1), 80-100 °C, 10 h; (j) CF3CO2H/H2O (2:1), 50 °C, 3 h;
(k) p-chlorophenylphosphorodichloridate, 1,2,4-triazole, rt, 2 d; (l) 30% NH4OH, dioxane, rt, 16 h.
with lithium bis(tert-butoxymethyl)cuprate gave optically
pure cyclopentanone 2 as a single isomer in 87% yield.
Reduction of cyclopentanone 2 with diisobutylaluminum
hydride gave R-alcohol 3 in 82% yield. The treatment of
compound 3 with trifluoromethanesulfonic anhydride
gave triflate 4, which reacted with the sodium salt of
adenine and 18-crown-6 in DMF to provide the protected
nucleoside 5 in 32% yield. Due to the low yields of the
coupling reactions of the triflate 4 with heterocyclic bases,
a modified linear approach was applied. Reaction of 3
with methanesulfonyl chloride afforded the mesyl deriva-
tive 6 in quantitative yield. The treatment of 6 with
lithium azide in hot DMF for 4 h gave the azide 7 in 89%
yield. Hydrogenation of 7 in the presence of 5% Pd/C at
20 psi for 1.5 h afforded the amino derivative 8 (Scheme
1).
(34%), which was deblocked with trifluoroacetic acid/H2O
to afford the final cytosine nucleoside 15 in 90% yield
(Scheme 1).
The inosine derivative was synthesized by the modified
procedure of Harnden et al (Scheme 2).27 The cyclopen-
tylamine 8 reacted with 4,6-dichloro-5-formamidopyrim-
idine in the presence of triethylamine to provide 16 in
80% yield. Cyclization of 16 with diethoxymethyl acetate
gave the 6-chloropurine derivative 17 in 96% yield. The
treatment of 17 with mercaptoethanol and sodium meth-
oxide in refluxing methanol gave the hypoxanthine
analogue 18 in 96% yield. Compound 18 was deblocked
with trifluoroacetic acid/H2O to afford the hypoxanthine
nucleoside 19 in 91% yield. The 6-mercaptopurine ana-
logue 20 was obtained by the treatment of 17 with
thiourea in refluxing ethanol followed by the deblocking
procedure described above. The guanine derivative 23
was prepared by the procedure described by Shealy et
al.28,29 The coupling reaction of cyclopentylamine 8 with
2-amino-4,6-dichloropyrimidine in the presence of tri-
ethylamine afforded compound 21. The isopropylidene
group of 21 was selectively removed by a mixture of concd
HCl and MeOH (1:75, v/v) to obtain a diol. Diazotization
of the obtained diol with (p-chlorophenyl)diazonium
chloride followed by the reaction with zinc dust gave
diamino derivative 22. The treatment of 22 with triethyl
orthoformate in the presence of concd HCl followed by
the treatment with 2 N HCl afforded the desired guanine
derivative 23.
The synthetic methodology reported by Shealy et al.24,25
was applied for the preparation of thymine and uracil
analogues from 8. Reaction of 8 with â-methoxy-R-
methacryloyl isocyanate and â-methoxy acryloyl isocy-
anate followed by treatment with 30% NH4OH at 80-
100 °C gave the thymine 9 and uracil 11 derivatives,
respectively. Removal of the protective groups of 9 and
11 with trifluoroacetic acid/H2O (2:1) at 50-60 °C for 3
h afforded the thymine 10 and uracil 12 nucleosides,
respectively. L-Aristeromycin 13 was obtained by the
deprotection of 5 with trifluoroacetic acid/H2O in 80%
yield. Preparation of the cytosine derivative 15 was
accomplished by the reported method.26 Treatment of 11
with 4-chlorophenyl dichlorophosphate and 1,2,4-triazole
followed by the hydrolysis with concd NH4OH gave 14
The nucleosides obtained were characterized by spec-
troscopic methods comparing to those of known D-isomers
or racemic forms. Furthermore, the configuration of
compound 13 has been unambiguously determined by
(31) Wolfe, M. S.; Anderson, B. L.; Borcherding, D. R.; Borchardt,
R. T. J . Org. Chem. 1990, 55, 4712.

Notes
J . Org. Chem., Vol. 64, No. 11, 1999 4175
Sch em e 2a
a
Reagents: (a) 4,6-dichloro-5-formamidopyrimidine, Et3N, dioxane, reflux, 1.5 h; (b) diethoxymethylacetate, 120-130 °C, 12 h; (c)
HSCH2CH2OH, NaOMe, MeOH, reflux, 24 h; (d) CF3CO2H/H2O (2:1), 50 °C, 3 h; (e) thiourea, EtOH, reflux, 1 h; (f) 2-amino-4,6-
dichloropyrimidine, Et3N, EtOH, reflux, 48 h; (g) (1) HCl/MeOH, rt, 2 h, (2) p-ClC6H4N2Cl. rt, 18 h; (h) Zn/AcOH, H2O/EtOH, 70 °C, 20
min; (i) CH(OEt)3, HCl; (j) 2 N HCl, reflux, 5 h.
the internal standard. Column chromatography was performed
on silica gel G (TLC grade, >440 mesh).
(2S,3S,4S)-4-(ter t-Bu t oxym et h yl)-2,3-(isop r op ylid en e-
d ioxy)-1-cyclop en ta n on e (2). Potassium tert-butoxide (16.43
g, 146.4 mmol) was suspended in anhydrous tert-butylmethyl
ether (525 mL) under nitrogen. After being cooled to -78 °C,
the well-stirred mixture was treated with sec-butyllithium (1.3
M in cyclohexane, 112.7 mL, 146.4 mmol) over 10 min. After
the mixture was stirred for 2.5 h at -78 °C, a solution of LiBr
(2 M, 145 mL) in THF was added dropwise over 10 min at -78
°C, and the resulting solution was stirred at -15 °C for 30 min.
Upon recooling to -78 °C, a solution of CuBr‚SMe2 (15.05 g,
71.75 mmol) in diisopropyl sulfide (75 mL) was added dropwise
over 10 min. The resulting viscous dark solution was stirred for
1 h at -78 °C and treated with a solution of the enone 1 (7.4 g,
48 mmol) in THF (67 mL) over 5 min. The reaction mixture was
allowed to warm to -30 °C over 15 min. After 30 min at -30
°C, 1:1 acetic acid-methanol (168 mL) was added and the
mixture poured into 1680 mL of NH4Cl/NH4OH (pH ) 9). After
removal of the aqueous layer, the organic layer was washed with
F igu r e 1. ORTEP drawing of compound 13.
a 1:1 mixture of saturated NH4Cl and 3% NH4OH solutions (3
× 400 mL) and then brine (400 mL). The organic phase was dried
(MgSO4), filtered, concentrated, and purified through flash silica
gel column chromatography with 2-5% EtOAc in hexanes to
30
single-crystal X-ray crystallography
(Figure 1). The
X-ray study indicated that L-aristeromycin 13 adopts a
sugar puckering with the pseudorotation phase angle P
) 226.6° and νmax ) 46.16°, the 5′-OH orientation γ )
-171.2° (C3′-C4′-C6′-O6′), and the base orientation ø )
124.5° (C5′-C1′-N9-C4).
Anti-HIV and anti-HBV activities of the synthesized
compounds were evaluated in PBM and 2.2.15 cells,
respectively. The cytosine 15 and 6-mercaptopurine 20
exhibit weak activity against HIV with EC50 values of
53 and 49.8 µM, respectively, while they do not show any
significant anti-HBV activity up to10 µM. No significant
activities of other synthesized nucleosides were observed
against HBV and HIV. The toxicities of these nucleosides
were also assessed, and these compounds did not exhibit
any significant toxicities at concentration up to 100 µM
in CEM, PBM, and Vero cells.
give 2 (10.13 g, 87.1%) as a solid: mp 64-65 °C; [R]26 185.36°
D
(c 1.15, CHCl3); 1H NMR (CDCl3) δ 4.62 (d, J ) 5.3 Hz, 1H),
4.23 (d, J ) 5.3 Hz, 1H), 3.50 (dd, J ) 2.3, 8.5 Hz, 1H), 3.35 (dd,
J ) 2.6, 8.5 Hz, 1H), 2.71 (dd, J ) 8.9,17.9 Hz, 1H), 2.54 (d, J )
8.9 Hz, 1H), 2.05 (d, J ) 17.9 Hz, 1H), 1.43 (s, 3H), 1.35 (s, 3H),
1.11 (s, 9H); HR-FAB MS obsd: m/z 243.1596, calcd for C13H23O4
m/z 243.1596 (M + H)+. Anal. Calcd for C13H22O4: C, 64.44; H,
9.15. Found: C, 64.18; H, 9.13.
(1R,2R,3S,4S)-4-(ter t-Bu toxym eth yl)-2,3-(isopr opyliden e-
d ioxy)cyclop en t a n -1-ol (3). Diisobutylaluminum hydride
(DIBAL-H, 59.44 mL, 1 M in CH2Cl2) was added dropwise over
5 min to a solution of ketone 2 (9.6 g, 39.62 mmol) in anhydrous
CH2Cl2 (480 mL) at 0-5 °C. The reaction mixture was stirred
for 2.5 h at this temperature and then cautiously quenched with
MeOH (480 mL). The colloidal suspension was concentrated, and
the white solid was treated with ether (600 mL). The suspension
was filtered, washing thoroughly with Et2O (3 × 300 mL), and
the filtrate was concentrated to give an oil that was purified by
flash silica gel column chromatography eluted with 5-10%
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H NMR
spectra were recorded at 400 MHz with tetramethylsilane as
EtOAc in hexanes to give 3 (7.95 g, 82.1%) as a syrup: [R]25
D
11.81° (c 1.4, CHCl3); 1H NMR (CDCl3) δ 4.45 (m, 2H), 4.24 (m,
1H), 3.32(dd, J ) 4.4, 8.8 Hz, 1H), 3.21 (dd, J ) 4.6, 8.8 Hz,

4176 J . Org. Chem., Vol. 64, No. 11, 1999
Notes
1H), 2.45 (d, J ) 8.9 Hz, 1H, D2O exchangeable), 2.22 (m, 1H),
1.84-1.88 (m, 2H), 1.36 (s, 3H), 1.49 (s, 3H), 1.14 (s, 9H); HR-
FAB MS obsd; m/z 245.1728, calcd for C13H25O4 m/z 245.1753
(M + H)+. Anal. Calcd for C13H24O4‚0.25H2O: C, 62.74; H, 9.92.
Found: C, 62.73; H, 9.80.
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy) cyclop en ta n -1-yl]th ym in e (9). Dried silver cy-
anate (3.04 g) was added to a solution of â-methoxy-R-
methacryloyl chloride (1.274 g, 9.46 mmol) in anhydrous benzene
(13.2 mL). The resulting mixture was heated under reflux for
0.5 h and allowed to cool to room temperature. After the solid
phase had settled, 6.33 mL of the supernatant solution that
contained â-methoxy-R-methacryloyl isocyanate was added to a
solution of amine 8 (crude 820 mg) in dried DMF (16 mL) at
-15 to -20 °C during 15 min. The reaction mixture was stirred
at -20 °C for 2 h and then at room temperature for 8 h under
nitrogen. The mixture was evaporated under reduced pressure,
and the residue was purified by flash silica gel column chroma-
tography with 5% MeOH in CHCl3 to give a solid. A 550 mg
portion of this solid was dissolved in dioxane (4 mL), ethanol (4
mL), and aqueous ammonia (30%, 3 mL). The reaction mixture
was heated at 80-100 °C in a sealed bomb for 10 h. The solution
was evaporated to dryness. The residue was purified by flash
silica gel column chromatography with 0.3% MeOH in CHCl3
to give 9 (314 mg, 55%) as a solid: mp 154-156 °C; [R]25D 35.53°
(1′S,2′R,3′S,4′S)-9-[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy)cyclop en ta n -1-yl]a d en in e (5). Trifluoromethane-
sulfonic anhydride (1.1 g, 4.50 mmol) in CH2Cl2 (5 mL) was
added dropwise to a solution of alcohol 3 (849 mg, 3.48 mmol)
in CH2Cl2 (14 mL) and pyridine (84 mL) over 10 min at 0-5 °C.
The reaction mixture was stirred at 0-5 °C for 30 min and then
quenched with water (5 mL). The organic layer was separated,
washed with water (2 × 30 mL), dried (MgSO4), filtered, and
concentrated to afford triflate 4 as an oil that was used for next
step without further purification. The triflate 4 in dried DMF
(4 mL) at 0 °C was added to an adenine suspension, which
contained adenine (1.357 g, 10.04 mmol), sodium hydride (254
mg, 10.04 mmol), and 18-crown-6 (2.604 g, 10.04 mmol) in
anhydrous DMF, heated to 70 °C under nitrogen for 4 h and
then cooled to 0-5 °C. The reaction mixture was stirred at 0 °C
for 9 h and then at room temperature for 24 h. The mixture
was filtered and the filtrate washed with saturated KCl (2 ×
150 mL), dried (MgSO4), filtered, and concentrated to dryness.
The residue was purified by preparative silica gel plates with
2% MeOH in CHCl3 and triturated with 2-propanol and ether
(1:2) to give 5 (400 mg, 32%): UV (MeOH) λmax 261 nm; 1H NMR
(CDCl3) δ 8.35 and 7.93 (two s, 2H), 5.65 (br s, 2H, exchangeable
with D2O), 5.00 (t, J ) 6.3 Hz, 1H), 4.82 (m, 1H), 4.62 (dd, J )
4.5, 6.9 Hz, 1H), 3.56 (dd, J ) 4.3, 8.8 Hz, 1H), 3.47 (dd, J )
5.8, 8.9 Hz, 1H), 2.54 (m, 1H), 2.43 (m, 1H), 2.36 (m, 1H), 1.58
(s, 3H), 1.32 (s, 3H), 1.23 (s, 9H); HR-FAB MS obsd; m/z
362.2190, calcd for C18H28N5O3 m/z 362.2192 (M + H)+.
(1R,2R,3S,4S)-4-(ter t-Bu toxym eth yl)-2,3-(isopr opyliden e-
d ioxy)-1-[(m eth ylsu lfon yl)oxy]cyclop en ta n e (6). Methane-
sulfonyl chloride (2.366 g, 20.66 mmol) was added dropwise to
a solution of alcohol 3 (4.886 g, 20 mmol) and triethylamine
(3.643 g, 36 mmol) in CH2Cl2 (130 mL) at 0 °C. After 45 min,
the reaction mixture was quenched with cold water (200 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 150 mL),
and the organic layers were combined, washed with brine (150
mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash silica gel column
chromatography with 10% EtOAc in hexanes to give 6 (quantita-
tive yield) as a colorless oil: [R]25D 29.6° (c 1.6, CHCl3); 1H NMR
(CDCl3) δ 5.10 (m, 1H), 4.60 (m, 1H), 4.39 (d, J ) 4 Hz, 1H),
3.30 (dd, J ) 4.0, 8.0 Hz, 1H), 3.19 (dd, J ) 4.0, 8.0 Hz, 1H),
3.01 (s, 3H), 2.15 (m, 2H), 1.85 (m, 1H), 1.42 (s, 3 H), 1.26 (s,
3H), 1.10 (s, 9H). Anal. Calcd for C14H28O6S: C, 52.15; H, 8.13;
S, 9.94. Found: C, 52.27; H, 8.06; S, 9.83.
1
(c 0.53, CHCl3); UV (MeOH) λmax 272.5 nm; H NMR (CDCl3) δ
7.08 (s, 1H), 4.68 (m, 2H), 4.46 (m, J ) 4.2, 6.0 Hz), 3.46 (m,
2H), 2.33 (m, 2H), 1.97 (m, 1H,), 1.93 (s, 3H), 1.54 (s, 3H), 1.30
(s, 3H), 1.20 (s, 9H). Anal. Calcd for C18H28N2O5: C, 61.34; H,
8.01; N, 7.95. Found: C, 61.25; H, 8.04; N, 7.89.
(1′S,2′R,3′S,4′S)-1-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl]th ym in e (10). Compound 9 (118 mg, 0.335
mmol) was dissolved in 15 mL of CF3CO2H/H2O (2:1) and heated
to 50-60 °C for 3 h. The solution was then concentrated, and
the residue was purified by flash silica gel column chromatog-
raphy with 8-9% MeOH in CHCl3 to give 10 (68 mg, 79.3%) as
a foam: mp 122-124 °C (hygroscopic); [R]24 42.49° (c 0.41,
D
MeOH); UV (H2O) λmax 273 nm (ꢀ 9236, pH 2), 273 nm (ꢀ 8686,
1
pH 7), 272 nm (ꢀ 7032, pH 11); H NMR (DMSO-d6) δ 11.19 (s,
1H, D2O exchangeable), 7.54 (s, 1H, 6-H), 4.81 (d, J ) 6.5 Hz,
1H, D2O exchangeable), 4.66 (t, J ) 5.2 Hz, 1H, D2O exchange-
able), 4.60 (m, 1H), 4.54 (d, J ) 4.1 Hz, 1H, D2O exchangeable),
3.96 (m, 1H), 3.69 (m, 1H), 3.39 (m, 2H), 1.88-1.96 (m, 2H), 1.76
(s, 3H), 1.23 (m, 1H); 13C NMR (CDCl3) δ 164.16, 151.64, 138.52,
109.24, 73.38, 71.61, 63.17, 59.85, 44.98, 28.04, 12.39; FAB-MS
m/e 257 (M + H)+. Anal. Calcd for C11H16N2O5‚0.75H2O: C,
48.96; H, 6.54; N, 10.38. Found: C, 48.87; H, 6.51; N, 10.20.
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy)cyclop en ta n -1-yl]u r a cil (11). Dried silver cyan-
ate (4.50 g) was added to a solution of â-methoxy acryloyl
chloride (1.68 g, 14 mmol) in anhydrous benzene (18.5 mL). The
resulting mixture was heated under reflux for 0.5 h and allowed
to cool to room temperature. After the solid phase had settled,
12 mL of the supernatant solution that contained â-methoxy-
acryloyl isocyanate was added within 15 min to a solution of
amine 8 (1.6 g, 6.6 mmol) in dried DMF (30 mL) at -15 to -20
°C under nitrogen. The following procedure is same as the
(1S,2R,3S,4S)-1-Azid o-4-(ter t-bu toxym eth yl)-2,3-(isop r o-
p ylid en ed ioxy)cyclop en ta n e (7). A solution of 6 (6.4 g, 20
mmol) in dry DMF (230 mL) in the presence of lithium azide
(9.792 g, 200 mmol) was heated at 140 °C for 4 h with stirring.
After the reaction was completed, the reaction mixture was
concentrated to ca. 100 mL, diluted with ethyl acetate (1 L), and
then washed with water (400 mL), saturated brine (400 mL),
and water (400 mL) successively. The organic layer was dried
(MgSO4), filtered, and concentrated. The resulting yellow oil was
purified by flash silica gel column chromatography with 1%
EtOAc in hexanes to give 7 (4.776 g, 88.7%) as oil: [R]27D 48.92°
conversion of 8 to 9 to give 11 in 74% yield as a syrup: [R]25
D
43.16° (c 0.67, CHCl3); UV (MeOH) λmax 266.5 nm; 1H NMR
(CDCl3) δ 7.35 (d, J ) 8.0 Hz, 1H), 5.73 (d, J ) 8.0 Hz, 1H), 4.72
(m, 2H), 4.48 (m, 1H), 3.46 (m, 2H), 2.37 (m, 2H), 1.97 (m, 1H),
1.55 (s, 3H), 1.30 (s, 3H), 1.19 (s, 9H). Anal. Calcd for C17H26N2O5‚
0.5H2O: C, 58.77; H, 7.83; N, 8.06. Found: C, 58.77; H, 7.69; N,
7.82.
(1′S,2′R,3′S,4′S)-1-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl]u r a cil (12). Conversion of 11 to 12 was ac-
complished using a procedure similar to that described for 10.
The obtained residue was purified by flash silica gel column
chromatography with 9% MeOH in CHCl3 to give 12 (112 mg,
1
(c 0.97, CHCl3): IRneat 2104 cm-1 (N3); H NMR (CDCl3) δ 4.47
(dd, J ) 2.0, 6.0 Hz, 1H), 4.39 (dd, J ) 2.2, 6.0 Hz, 1H), 3.96 (m,
1H), 3.37 (dd, J ) 6.8, 8.7 Hz, 1H), 3.28 (dd, J ) 6.8, 8.7 Hz,
1H), 2.28 (m, 2H), 1.71 (m, 1H), 1.45 (s, 3H), 1.29 (s, 3H), 1.18
(s, 9H); HR-FAB MS obsd m/z 270.1818, calcd for C13H24N3O3
m/z 270.1818 (M + H)+.
85.6%) as a foam (hygroscopic): [R]26 56.59° (c 0.61, MeOH);
D
UV (H2O) λmax 267.5 nm (ꢀ 9915, pH 2), 267.5 nm (ꢀ 9720, pH
7), 266.5 nm (ꢀ 7227, pH 11); 1H NMR (DMSO-d6) δ 11.23 (s,
1H, D2O exchangeable), 7.69 (d, J ) 8.0 Hz, 1H), 5.60 (dd, J )
2.2, 7.92 Hz, 1H), 4.61-4.87 (m, 2H, D2O exchangeable), 4.64
(dd, J ) 9.8, 18.9 Hz, 1H), 3.98 (dd, J ) 5.3, 9.3 Hz, 1H), 3.71
(dd, J ) 2.1, 5.0 Hz, 1H), 3.43 (m, 2H), 2.01 (m, 1H), 1.93 (m,
1H), 1.25 (m, 1H); FAB-MS m/e 243 (M + 1)+. Anal. Calcd for
(1S,2R,3S,4S)-4-(ter t-Bu toxym eth yl)-2,3-(isop r op yliden e-
d ioxy)-1-cyclop en ta n a m in e (8). A suspension of compound
7 (890 mg, 3.3 mmol) and 5% Pd/C (240 mg) in absolute EtOH
(70 mL) was shaken under 20 psi of H2 for 1.5 h. The reaction
mixture was filtered and the filtrate evaporated to give crude 8
(800 mg), which was used for the next step without further
purification: 1H NMR (CDCl3) δ 4.49 (dd, J ) 2.6, 6.1 Hz, 1H),
4.23 (dd, J ) 2.4, 6.0 Hz, 1H), 3,42 (m, 3H), 2.31 (m, 2H), 1.92
(br s, 2H, exchangeable with D2O), 1.46 (s, 3H), 1.39 (m, 1H),
1.29 (s, 3H), 1.19 (s, 9H); HR-FAB MS obsd m/z 244.1911, calcd
for C13H26NO3 m/z 244.1923 (M + H)+.
C
10H14N2O5‚0.2MeOH: C, 49.27; H, 6.00; N, 11.26. Found: C,
48.99; H, 6.10; N,10.87.
(1′S,2′R,3′S,4′S)-9-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl]a d en in e (13). A mixture of compound 5 (350
mg, 0.97 mmol) and CF3CO2H/H2O (2:1, 30 mL) was heated at

Notes
J . Org. Chem., Vol. 64, No. 11, 1999 4177
50 °C for 3 h. The reaction mixture was concentrated to dryness.
The residue was dissolved in MeOH, and then Et2O was added.
The mixture was allowed to stand overnight, filtered, and
washed with MeOH to give 13 (205 mg, 80%) as a white solid:
chromatography with 20% EtOAc in hexanes to give 17 (1.53 g,
96%) as a syrup: [R]26 38.36° (c 1.31, CHCl3); UV (MeOH) λmax
D
1
265 nm; H NMR (CDCl3) δ 8.75 and 8.27 (two s, 2H), 4.93 (m,
2H), 4.62 (dd, J ) 4.2, 6.6 Hz, 1H), 3.54 (dd, J ) 4.2, 8.9 Hz,
1H), 3.49 (dd, J ) 5.5, 8.9 Hz, 1H), 2.59 (m, 1H), 2.47 (m, 1H),
2.39 (m, 1H), 1.58 (s, 3H), 1.32 (s, 3H), 1.20 (s, 9H). Anal. Calcd
for C18H25ClN4O3: C, 56.76; H, 6.62; N,14.71. Found: C, 56.64;
H, 6.64; N, 14.58.
(1′S,2′R,3′S,4′S)-9-[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy)cyclop en ta n -1-yl]h yp oxa n th in e (18). A mixture
of chloropurine analogue 17 (190 mg, 0.5 mmol), 2-mercapto-
ethanol (0.14 mL, 1.99 mmol), and NaOMe (100 mg, 2 mmol) in
methanol (25 mL) was refluxed for 24 h. The mixture was then
cooled, neutralized with glacial acetic acid, and concentrated
under reduced pressure. The resulting residue was purified by
flash silica gel column chromatography with 3% MeOH in CHCl3
mp 215-217 °C dec; [R]25 55.45° (c 0.38, DMF) [lit.22 mp 208-
D
210 °C; [R]23 51.1° (c 0.3, DMF); lit31 for the (-)-enantiomer,
D
mp 211-213 °C dec; [R]25D -56° (c 0.366, DMF)]; UV (H2O) λmax
259.5 nm (ꢀ 171 69, pH 2), 261.0 nm (ꢀ 17 639, pH 7), 261.5 nm
1
(ꢀ 17 120, pH 11); H NMR (DMSO-d6) δ 8.20 and 8.12 (two s,
2H), 7.19 (br s, 2H, D2O exchangeable), 4.94 (d, J ) 6.6 Hz, 1H,
D2O exchangeable), 4.73 (t, J ) 5.3 Hz, 1H), 4.66-4.71 (m, 2H,
D2O exchangeable), 4.34 (dt, J ) 6.2, 9.1 Hz, 1H), 3.84 (m, 1H),
3.48-3.54 (m, 2H), 2.23 (dt, J ) 8.1, 8.8 Hz, 1H), 2.02-2.06 (m,
1H), 1.68-1.76 (m, 1H); FAB-MS m/e 266 (M + H)+. Anal. Calcd
for C11H15N5O3: C, 49.81; H, 5.70; N, 26.40. Found: C, 49.84;
H, 5.67; N, 26.26.
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy)cyclop en ta n -1-yl]cytosin e (14). 4-Chlorophenyl
dichlorophosphate (705 mg, 2.87 mmol) and 1,2,4-triazole (407
mg, 5.89 mmol) were added to a solution of compound 11 (300
mg, 0.887 mmol) in dried pyridine (15 mL) at 0 °C. The mixture
was stirred at room temperature for 2 days and then evaporated
in vacuo to dryness under 40 °C. The residue was dissolved in
CH2Cl2 (40 mL), and the solution was washed with H2O (2 × 30
mL) and saturated NaHCO3 (30 mL). The organic layer was
dried (MgSO4), filtered, and concentrated to dryness. The residue
was stirred in a mixture of 30% aqueous ammonia (20 mL) and
1,4-dioxane (20 mL) at room temperature for 16 h, and the sol-
vent was removed to dryness. The residue was purified by flash
silica gel column chromatography with 5% MeOH in CHCl3 to
give 14 (102 mg, 34.1%) as a solid: mp 134-136 °C; [R]27D 14.81°
(c 0.28, CHCl3); UV (MeOH) λmax 276 nm; 1H NMR (CDCl3) δ
7.36 (d, J ) 7.2 Hz, 1H,), 5.64 (d, J ) 7.3 Hz, 1H), 4.93 (dd, J )
4.7, 6.7 Hz, 1H), 4.52 (t, J ) 5.7 Hz, 1H), 4.43 (m, 1H), 3.55 (dd,
J ) 4.2, 8.7 Hz, 1H), 3.39 (dd, J ) 6.7, 8.6 Hz, 1H), 2.27-2.36
(m, 2H), 2.16 (m, 1H), 1.62 (br s, 2H), 1.52 (s, 3H), 1.29 (s, 3H,),
1.18 (s, 9H). Anal. Calcd for C17H27N3O4‚0.1CHCl3: C, 58.79; H,
7.82; N, 12.03. Found: C, 58.59; H, 7.82; N, 11.93.
(1′S,2′R,3′S,4′S)-1-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl]cytosin e (15). Conversion of 14 (156 mg, 0.46
mmol) to 15 was accomplished using a procedure similar to that
described for 10. The residue was separated by HPLC (1% of
MeOH in H2O) to give 15 (103 mg, 92%) as a solid: mp 164-
166 °C; [R]29D 55.58° (c 0.97, MeOH); UV (H2O) λmax 284.5 nm (ꢀ
8708, pH 2), 275 nm (ꢀ 6424, pH 7), 275 nm (ꢀ 6586, pH 11);
1HNMR (DMSO-d6) δ 8.50 (br s, 1H, D2O exchangeable), 7.88
(d, J ) 7.6 Hz, 1H), 7.83 (br s, 1H, D2O exchangeable), 5.91 (d,
J ) 7.6 Hz, 1H), 4.87 (br s, 1H, D2O exchangeable), 4.68 (br s,
2H, D2O exchangeable), 4.62 (dd, J ) 10.1, 19.3 Hz, 1H), 3.99
(m, 1H), 3.73 (m, 1H), 3.38 (m, 2H), 2.04 (dt, J ) 8.7, 8.6, 12.7
Hz, 1H), 1.93 (m, 1H), 1.27 (m, 1H). FAB-MS m/e 242 (M + H)+.
Anal. Calcd for C10H15N3O4‚0.5H2O: C, 47.99; H, 6.44; N, 16.79.
Found: C, 47.92; H, 6.08; N, 16.63.
to give 18 (174 mg, 96.2%) as a solid: mp 226-227 °C; [R]27
D
37.31° (c 0.69, CHCl3); UV (MeOH) λmax 249.5 nm; 1H NMR
(CDCl3) δ 8.08 and 7.94 (two s, 2H), 4.91 (t, J ) 6.2 Hz, 1H),
4.82 (m, 1H), 4.60 (dd, J ) 4.5, 6.7 Hz, 1H), 3.53 (dd, J ) 4.3,
8.8 Hz, 1H), 3.47 (dd, J ) 5.8, 8.9 Hz, 1H), 2.55 (m, 1H), 2.44
(m, 1H), 2.31 (m, 1H), 1.58 (s, 3H), 1.33 (s, 3H), 1.20 (s, 9H).
Anal. Calcd for C18H25N4O6‚0.25H2O: C, 58.92; H, 7.30; N,15.27.
Found: C, 58.71; H, 7.10; N, 15.06.
(1′S,2′R,3′S,4′S)-9-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl] h yp oxa n th in e (19). A mixture of compound
18 (164 mg, 0.453 mmol), CF3CO2H (10 mL), and H2O (5 mL)
was stirred at 50-60 °C for 3 h. The solution was concentrated
to dryness and the residue triturated with a mixture of MeOH
(1 mL) and ether (4 mL) to give 19 (110 mg, 91.2%) as a white
solid: mp 245-247 °C dec; [R]29 48.73° (c 0.26, DMF) [lit.22 for
D
the (-)-enantiomer: mp 237 °C dec; [R]25D -48.9° (c 0.2, DMF)];
UV (D2O) λmax 250 nm (ꢀ 11 297, pH 2), 250 nm (ꢀ 11 790, pH
7), 254.5 nm (ꢀ 12 476, pH 11); 1H NMR (DMSO-d6) δ 12.05 (br
s, 1H, D2O exchangeable), 8.16 and 8.01 (two s, 2H), 4.93 (br s,
1H, D2O exchangeable), 4.64-4.71 (m, 3H), 4.26 (dd, J ) 5.3,
9.2 Hz, 1H), 3.80 (m, 1H), 3.46 (m, 2H), 2.21 (dt, J ) 8.6, 8.7,
13.0 Hz, 1H), 2.01 (m, 1H), 1.63 (m, 1H); FAB-MS m/e 267 (M
+ H)+. Anal. Calcd for C11H14N4O4: C, 49.62; H, 5.30; N, 21.04.
Found: C, 49.51; H, 5.26; N, 20.98.
(1′S,2′R,3′S,4′S)-9-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl]-6-m er p a p top u r in e (20). A solution of com-
pound 17 (274 mg, 0.72 mmol) and thiourea (140 mg, 1.84 mmol)
in ethanol (15 mL) was refluxed for 1 h. Upon cooling, the
reaction mixture was concentrated to dryness. The residue was
purified by silica gel column chromatography with 2-3% MeOH
in CHCl3 to a solid (142 mg). A mixture of the obtained solid
(115 mg), CF3CO2H (8 mL), and H2O (4 mL) was stirred at 50-
60 °C for 3 h. The solution was concentrated to dryness and the
residue triturated with a mixture of MeOH (2 mL) to give 20
(89 mg, 54%) as a white solid: mp 260 °C dec; [R]27 60.41° (c
D
0.50, DMF); UV (H2O) λmax 321.5 nm (ꢀ 11 042, pH 2), 319 nm (ꢀ
1
12 549, pH 7), 310.5 nm (ꢀ 12 923, pH 11); H NMR (DMSO-d6
(1′S,2′R,3′S,4′S)-6-[[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy) cyclop en ta n -1-yl]a m in o]-4-ch lor o-5-for m a m i-
d op yr im id in e (16). A solution of compound 8 (788 mg, 3.24
mmol), 4,6-dichloro-5-formamidopyrimidine (740 mg, 3.7 mmol),
and triethylamine (8 mL) in 1,4-dioxane (33 mL) was stirred at
reflux for 1.5 h. After cooling, the suspension was filtered and
the solvent removed. The residue was purified by flash silica
gel column chromatography with 20-40% EtOAc in hexanes to
+ D2O) δ 8.37 and 8.17 (two s, 2H), 4.71 (dd, J ) 9.5, 19.0 Hz,
1H), 4.25 (dd, J ) 5.2, 9.2 Hz, 1H), 3.80 (dd, J ) 2.4, 4.9 Hz,
1H), 3.40-3.49 (m, 2H), 2.24 (dt, J ) 8.6, 8.7, 12.8 Hz, 1H), 2.03
(m, 1H), 1.65 (m, 1H); HR-FAB MS obsd m/z 283.0857, calcd for
C
11H15N4O3S m/z 283.0865 (M + H)+. Anal. Calcd for C11H14N4-
O3S‚0.75H2O: C, 44.66; H, 5.28; N, 18.94; S, 10.84. Found: C,
44.51; H, 4.95; N, 18.91; S, 10.64.
(1′S,2′R,3′S,4′S)-2-Am in o-4-[[4-(ter t-b u t oxym et h yl)-2,3-
(isop r op ylid en ed ioxy)cyclop en t a n -1-yl]a m in o]-6-ch lor o-
p yr im id in e (21). A suspension of compound 7 (960 mg, 3.56
mmol) and 5% Pd/C (260 mg) in absolute EtOH (75 mL) was
shaken under 20 psi of H2 for 1.5 h. The reaction mixture was
filtered and the filtrate evaporated to give crude 8 (820 mg),
which was used for the next step without further purification.
To a solution of cyclopentylamine 8 in EtOH (65 mL) were added
2-amino-4,6-dichloropyrimidine (890 mg, 5.43 mmol) and Et3N
(0.5 mL) at room temperature and the mixture refluxed for 48
h under nitrogen. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography (0-0.2% MeOH in CHCl3) to give 21 (1.145 g,
give 16 (1.04 g, 80.5%) as a white solid: mp 163-164 °C; [R]27
D
1
94.24° (c 0.35, CHCl3); H NMR (CDCl3) δ 8.40 (s, 1H), 8.39 (s,
1H,), 7.00 (br s, 1H, D2O exchangeable), 4.40-4.68 (m, 3H), 3.45
(m, 2H), 2.58 (m, 1H), 2.45 (m, 1H), 2.39 (m, 1H), 1.51 (s, 3H),
1.30 (s, 3H), 1.20 (s, 9H). Anal. Calcd for C18H27ClN4O4: C, 54.20;
H, 6.82; Cl: 8.89; N, 14.06. Found: C, 54.29; H, 6.86; Cl: 8.85;
N, 13.99.
(1′S,2′R,3′S,4′S)-9-[4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy) cyclop en ta n -1-yl]-6-ch lor op u r in e (17). A solu-
tion of compound 16 (1.67 g, 4.19 mmol) in diethoxymethyl
acetate (30 mL) was heated at 120-130 °C for 12 h. After the
solvent was removed under reduced pressure, the residue was
dissolved in MeOH (12 mL) and concd ammonium hydroxide (3.7
mL). The reaction mixture was stirred at room temperature for
1 h. The solvent was removed and coevaporated with EtOH to
dryness. The residue was purified by flash silica gel column
86.7%) as a solid: mp 74-76 °C; [R]26 -37.45° (c 0.62, CHCl3);
D
UV (MeOH) λmax 286.0 nm, 237.5 nm, 213.5 nm; 1H NMR
(CDCl3) δ 6.42 (d, 1H, D2O exchangeable), 5.71(s, 1H), 4.31-
4.53 (2 d, 2H), 3.39-3.59 (m, 3H), 2.64 (m, 1H), 2.39 (m, 1H),

4178 J . Org. Chem., Vol. 64, No. 11, 1999
Notes
1.48 (s, 3H), 1.45 (m, 1H), 1.29 (s, 3H), 1.27 (s, 9H); HR-FAB
MS obsd m/z 371.1810, calcd for C17H28ClN4O3 m/z 371.1850 (M
+ H)+. Anal. Calcd for C17H27ClN4O3: C, 55.05; H, 7.34; N, 15.11.
Found: C, 55.16; H, 7.31; N, 15.07.
(1′S,2′R,3′S,4′S)-9-[-2,3-Dih yd r oxy-4-(h yd r oxym eth yl)cy-
clop en ta n -1-yl]gu a n in e (23). A mixture of 22 (130 mg, 0.36
mmol), triethyl orthoformate (3 mL), concd HCl (75 µL), and
DMF (1.5 mL) was stirred at 0-5 °C for 8 h and then at room
temperature for 8 h. After the solvent was removed under
reduced pressure, the residue was stirred in 50% HOAc (4 mL)
for 16 h at room temperature. The mixture was concentrated,
and the residue was stirred in ammonia-methanol (10 mL) at
room temperature for 4 h. The mixture was concentrated again
to dryness. The residue was dissolved in 2 N HCl (10 mL), and
the mixture was heated under reflux for 5 h. The mixture was
then concentrated in vacue at 50 °C. Several portions of ethanol
(3 × 5 mL) were added and evaporated in vacuo. The residue
was triturated with a mixture of MeOH and ether, allowed to
stand, and filtered to give 23 (46 mg, 46%) as a white solid: mp
250 °C dec; [R]27D 39.99° (c 0.21, DMF); UV (H2O) λmax 254.5 nm
(ꢀ 9300, pH 2), 252.5 nm (ꢀ 10 976, pH 7), 268.0 nm (ꢀ 8241, pH
11); 1H NMR (DMSO-d6 + D2O) δ 8.64 (s, 1H), 4.61 (dd, J ) 9.3,
8.4 Hz, 1H), 4.21 (dd, J ) 5.2, 9.2 Hz, 1H), 3.80 (m, 1H), 3.42
(m, 2H), 2.22 (m, 1H), 2.00 (m, 1H), 1.55 (m, 1H); HR-FAB MS
obsd m/z 282.1202, calcd for C11H16N5O4 m/z 282.1202 (M + H)+.
Anal. Calcd for C11H15N5O4‚H2O: C, 44.15; H, 5.73; N, 23.40.
Found: C, 44.09; H, 5.64; N, 23.27.
(1′S,2′R,3′S,4′S)-4-[[4-(ter t-Bu toxym eth yl)-2,3-d ih yd r oxy-
cyclop e n t a n -1-yl]a m in o]-6-ch lor o-2,5-d ia m in op yr im i-
d in e (22). A solution of compound 21 (1.86 g, 5.02 mmol) in
MeOH (200 mL) containing concd HCl (2.67 mL) was stirred at
room temperature for 2 h. The reaction mixture was neutralized
with solid NaHCO3 at 0 °C, and the mixture was concentrated
to dryness. The residue was washed with MeOH and filtered.
The filtrate was concentrated to dryness, and the residue was
used in the next step without further purification. To a solution
of p-chloroaniline (1.00 g, 7.84 mmol) in concd HCl (4.55 mL)
and water (9.1 mL) was added a solution of NaNO2 (593.5 mg,
8.60 mmol) in water (7.3 mL) dropwise at 0 °C. The resulting
cold solution was added to the solution of the above residue in
water (34 mL), AcOH (34 mL), and sodium acetate trihydrate
(14.55 g) at 0-5 °C. The reaction mixture was stirred at room
temperature for 18 h and the yellow solid precipitated. The solid
was collected by filtration and purified by silica gel column
chromatography with 1-5% MeOH in CHCl3 to give a yellowish
solid (1.89 g). Zinc dust (2.61 g, 350 mesh) was added to a
mixture of the yellowish solid (1.88 g), THF (34 mL), ethanol
(34 mL), water (30 mL), and acetic acid (3.02 mL) at 70 °C, and
the mixture was stirred at this temperature for 20 min. The
reaction mixture was filtered and the filtrate concentrated to
dryness. The residue was purified by silica gel column chroma-
tography with 1-3% MeOH in CHCl3 to give 22 (890 mg, 52%)
Ack n ow led gm en t. This research was supported by
the U.S. Public Health Research grants (AI 32351 and
AI33655). We thank Dr. Raymond F. Schinazi of Emory
University, Veterans Administration (Atlanta), and Dr.
Y.-C. Cheng of Yale University for anti-HIV and anti-
HBV evaluations, respectively. We thank Dr. Michael
Bartlett of the University of Georgia for performing the
mass spectroscopy.
as a foam: [R]28 -4.05° (c 0.45, MeOH); UV λmax 204, 304 nm
D
(pH 7), λmax 237.5, 298.5 nm (pH 1); 1H NMR (DMSO-d6 + D2O)
δ 4.16 (dd, J ) 8.2, 16.0 Hz, 1H), 3.65 (m, 2H), 3.20-3.30 (m,
2H), 2.18 (m, 1H), 1.90 (m, 1H), 1.11 (s, 9H), 1.00 (m, 1H); HR-
FAB MS obsd; m/z 346.1677, calcd for C14H25ClN5O3 m/z
346.1646 (M + H)+. Anal. Calcd for C17H24ClN5O3‚0.27H2O: C,
47.94; H, 7.03; N, 19.96. Found: C, 48.32; H, 6.63; N, 19.56.
J O9812330