Enantiomeric Synthesis of L-(or 1′R,2′S)-Carbocyclic Cyclopropyl Nucleosides

Article abstract of DOI:10.1021/jo961523l

The enantiomeric synthesis of carbocyclic cyclopropyl L-nucleosides has been accomplished from L-gulonic γ-lactone. The key intermediate 3 was stereoselectively synthesized by DIBAL-H reduction and silyl protection followed by cyclopropanation from ester 2, which was in turn prepared from L-gulonic γ-lactone (1) in five steps. Desilylation of cyclopropyl intermediate 3 gave alcohol 4, which was then converted to the urea derivative 5 and cyclopropylamine 7 by Curtius rearrangement of an acyl azide. The urea intermediate 5 was utilized to prepare thymine 10, uracil 11, and cytosine 14 derivatives. The hypoxanthine, adenine, and guanine nucleosides 21, 22, and 24 were synthesized from the amino intermediate 7.

Full text of DOI:10.1021/jo961523l

J . Org. Chem. 1997, 62, 1991-1995
1991
En a n tiom er ic Syn th esis of L-(or 1′R,2′S)-Ca r bocyclic Cyclop r op yl
Nu cleosid es
Mi Gyoung Lee,†,‡ J in Fa Du,† Moon Woon Chun,‡ and Chung K. Chu*,†
Department of Medicinal Chemistry, College of Pharmacy, The University of Georgia,
Athens, Georgia 30602, and College of Pharmacy, Seoul National University, Seoul, Korea
Received August 6, 1996X
The enantiomeric synthesis of carbocyclic cyclopropyl L-nucleosides has been accomplished from
L-gulonic γ-lactone. The key intermediate 3 was stereoselectively synthesized by DIBAL-H reduction
and silyl protection followed by cyclopropanation from ester 2, which was in turn prepared from
L-gulonic γ-lactone (1) in five steps. Desilylation of cyclopropyl intermediate 3 gave alcohol 4, which
was then converted to the urea derivative 5 and cyclopropylamine 7 by Curtius rearrangement of
an acyl azide. The urea intermediate 5 was utilized to prepare thymine 10, uracil 11, and cytosine
14 derivatives. The hypoxanthine, adenine, and guanine nucleosides 21, 22, and 24 were
synthesized from the amino intermediate 7.
In tr od u ction
pure carbocyclic cyclopropyl L-nucleosides. A preliminary
account of L-cyclopropyl nucleosides has recently been
reported by us.13 We now report herein a full account of
the synthesis of these carbocyclic cyclopropyl L-nucleo-
sides.
A number of carbocyclic nucleosides have been reported
as potential anti-HIV1,2 and anti-HBV3 agents. Among
them, carbovir1 and its 6-(cyclopropylamino)purine ana-
logue4 are the most interesting compounds, and the latter
is currently undergoing clinical trials as anti-HIV agent.
As a part of our ongoing drug discovery program, we have
previously reported the asymmetric synthesis of optically
pure carbocyclic cyclopropyl D-nucleosides as potential
antiviral agents.5 Recently, several L-nucleosides includ-
ing (-)-(2′R,5′S)-1-[2-(hydroxymethyl)oxathiolan-5-yl]cy-
tosine (3TC),6-8 (-)-â-L-2′,3′-dideoxy-5-fluoro-3′-thiacyti-
dine (FTC),9 â-L-2′,3′-dideoxy-5-fluorocytidine (L-FddC),10,11
and â-L-2′-fluoro-5-methyl-1-(arabinofuranosyl)uracil (L-
FMAU)12 have been reported as potent, promising anti-
HIV and anti-HBV agents. These interesting L-nucleo-
sides prompted us to synthesize the enantiomerically
Resu lts a n d Discu ssion
For the synthesis of the target L-isomers, we utilized
the same general strategy that we developed for the
synthesis of carbocyclic cyclopropyl D-nucleosides5,13
(Scheme 1). Compound 2 was prepared from L-gulonic
γ-lactone (1) in three steps14 and converted to cyclopro-
pane 3 with the desired chirality (1R,2S,4R) in three
steps.15 Key intermediates, the urea derivative 5 for the
synthesis of pyrimidine nucleosides and the cyclopropyl-
amine derivative 7 for purine nucleosides, were derived
from the compound 3.5,13
Pyrimidine nucleosides was synthesized by utilizing
procedures known in the literature5,16,17 (Scheme 2).
Reaction of 5 with â-methoxy-R-methylacryloyl chloride
or â-methoxyacryloyl chloride followed by cyclization and
deprotection gave the diol 8 or 9. Oxidative cleavage of
the diols with NaIO4 followed by in situ reduction of the
resulting aldehyde with NaBH4 gave thymine 10 and
uracil 11 nucleosides in good yields. The protected uracil
nucleoside was converted to the desired cytosine nucleo-
side 14 through the triazole intermediate 12.5,17
Purine derivatives 21, 22, and 24 were prepared by
the reported methods5,18-22 (Scheme 3). The cyclopropyl-
amine 7 was reacted with 4,6-dichloro-5-formamidopy-
rimidine followed by cyclization with diethoxymethyl
acetate to give the 6-chloropurine 16. The treatment of
16 with mercaptoethanol and sodium methoxide or
† The University of Georgia.
‡ Seoul National University.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
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Matsukura, M.; Plattner, J . J .; Broder, S.; Mitsuya, H. Antimicrob.
Agents. Chemother. 1990, 34, 287.
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W. H.; Averett, D. R.; St. Clair, M. H.; Ayers, K. M. The 34th
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J . Org. Chem. 1995, 60, 5236.
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Nelson, D. J .; Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe, J . A.;
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S0022-3263(96)01523-X CCC: $14.00 © 1997 American Chemical Society

1992 J . Org. Chem., Vol. 62, No. 7, 1997
Lee et al.
Sch em e 1a
a
Key: (a) DIBAL-H, CH2Cl2, -78 °C; (b) TBDPSiCl, imidazole, CH2Cl2, DMF; (c) Zn(Et)2, CH2I2, CH2Cl2, 0 °C; (d) n-Bu4NF, THF; (e)
NaIO4, RuO2, K2CO3, CH3CN/CHCl3/H2O; (f) (1) Et3N, ClCO2Et; (2) NaN3, H2O; (g) toluene, 100 °C; (h) NH3, Et2O; (i) BnOH, toluene,
reflux; (j) H2, 10% Pd/C.
Sch em e 2a
a
Key: (a) â-methoxy-R-methylacryloyl chloride (for 10) or â-methoxyacryloyl chloride (for 11, 12), pyridine, CH2Cl2, 0 °C; (b) 30%
NH4OH, EtOH, 80-100 °C; (c) concd HCl, MeOH; (d) (1) NaIO4, H2O; (2) NaBH4; (e) 1,2,4-triazole, 4-chlorophenyl dichlorophosphate,
pyridine; (f) 30% NH4OH.
ammonia in refluxing methanol gave the protected hy-
poxanthine 17 or adenine 18, which was converted to the
target compounds 21 or 22 by hydrolysis and the oxida-
tion-reduction reactions used above.
The synthesis of guanine derivative 24 was accom-
plished by using procedures described by Shealy et
al.5,19-21 and Rosenguist et al.22 The precursor 23 was
obtained in 61% yield by treating 2-amino-4,6-dichloro-
pyrimidine with the amine 7 in the presence of Et3N. The
target compound 24 was then synthesized from 23 in four
steps according to the reported procedures.5,19-22
The antiviral evaluation of the synthesized L-carbocy-
clic cyclopropyl nucleosides are in progress and will be
reported elsewhere.
Exp er im en ta l Section
Melting points (mp) were uncorrected. 1H-NMR spectra
were recorded in the indicated solvents. All reactions were
monitored by thin-layer chromatography carried out on silica
gel glass plates (0.25 mm). Silica gel chromatography was
performed on silica gel 60 (230-400 mesh) using the indicated
solvents.
(1R,2S,4R)-1-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-2-
(2,2-d im eth yl-1,3-d ioxola n -4-yl)cyclop r op a n e (3). The cy-
clopropane 3 was prepared from 2 according to procedures for
its D-isomer5 in 64% overall yield as a colorless syrup: [R]25
D
+14.07° (c 0.28, CHCl3); 1H NMR (CDCl3) δ 8.20-7.30 (m,
10H), 4.21 (m, 1H), 3.90-3.70 (m, 2H), 3.50-3.30 (m, 2H), 1.47
(s, 3H), 1.38 (s, 3H), 1.25 (m, 1H), 1.03 (s, 9H), 0.90-0.70 (m,

Synthesis of Carbocyclic Cyclopropyl Nucleosides
J . Org. Chem., Vol. 62, No. 7, 1997 1993
Sch em e 3a
a
Key: (a) 4,6-dichloro-5-formamidopyrimidine, Et3N, dioxane; (b) (1) diethoxymethyl acetate, 120 °C; (2) 30% NH4OH; (c) HSCH2CH2OH,
NaOCH3, MeOH, reflux; (d) NH3, MeOH, 90 °C; (e) concd HCl, MeOH, rt; (f) 80% AcOH, rt; (g) (1) NaIO4, H2O; (2) NaBH4; (h) 2-amino-
4,6-dichloropyrimidine, Et3N, EtOH, reflux; (i) 4-ClC6H4N2+Cl-; (j) Zn dust, AcOH, EtOH, H2O; (k) concd HCl, triethyl orthoformate,
DMF.
2H), 0.38 (m, 1H). Anal. Calcd for C25H34O3Si‚0.2H2O: C,
72.48; H, 8.37. Found: C, 72.32; H, 8.25.
NH4OH (30%, 6 mL). The resulting solution was heated at
80-100 °C in a sealed bomb for 12 h. The solvent was
evaporated to dryness under reduced pressure to give the
protected thymine nucleoside, which was redissolved in MeOH
(60 mL), concd HCl (1 mL) was added, and the mixture was
stirred for 4 h at rt and then neutralized with Et3N. The
solvent was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (CHCl3-
MeOH, 10:1) to give 8 as a white solid (570 mg, 63%). To a
solution of 8 (160 mg, 0.70 mmol) in MeOH (15 mL) was added
a solution of NaIO4 (367 mg, 1.72 mmol) in water (15 mL)
dropwise, the mixture was stirred at rt for 15 min, and NaBH4
(100 mg, 2.64 mmol) was added. The mixture was stirred for
an additional 15 min and filtered. The filtrate was concen-
trated under reduced pressure, and the residue was purified
by silica gel column chromatography (CHCl3-MeOH, 10:1) and
recrystallized from EtOAc to give 10 (86 mg, 62%; overall yield
from 5, 39%): mp 180-181 °C; [R]25D +99.99° (c 0.33, MeOH);
UV (H2O) λmax 270.5 (ꢀ 10 367, pH 7), 270.5 (ꢀ 10 929, pH 2),
(1R,2S,4R)-1-(H yd r oxym et h yl)-2-(2,2-d im et h yl-1,3-d i-
oxola n -4-yl)cyclop r op a n e (4). To a solution of 3 (20 g, 48.7
mmol) in THF (100 mL) was added n-Bu4NF (49 mL, 1 M in
THF) and the mixture stirred at rt for 2 h. The solvent was
removed under reduced pressure, and the syrupy residue was
purified by silica gel column chromatography (hexanes-
EtOAc, 1:1) to give 4 as a colorless oil (7.6 g, 91%): [R]25
D
+16.80° (c 0.19, CHCl3); 1H NMR (CDCl3) δ 4.15 (dd, J ) 7.9,
6.1 Hz, 1H), 3.8-3.9 (m, 2H), 3.70 (t, J ) 7.9 Hz, 1H), 3.47
(dd, J ) 11.2, 8.3 Hz, 1H), 1.65 (br s, 1H), 1.47 (s, 3H), 1.36 (s,
3H), 1.26 (m, 1H), 1.07 (m, 1H), 0.92 (m, 1H), 0.48 (m, 1H).
Anal. Calcd for C9H16O3‚0.1H2O: C, 62.12; H, 9.38. Found:
C, 61.81; H, 9.26.
(1R,2S,4R)-2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)cyclop r o-
p ylu r ea (5) a n d (1R,2S,4R)-2-(2,2-Dim eth yl-1,3-d ioxola n -
4-yl)cyclop r op yla m in e (7). Compounds 5 and 7 were pre-
pared from 4 by using similar procedures for their D-isomers5
in 36% and 35% overall yields, respectively.
1
269.5 nm (ꢀ 10 681, pH 11); H NMR (DMSO-d6) δ 11.19 (s,
Compound 5: crystals; mp 182-183 °C; [R]25 +116.70° (c
1H), 7.46 (s, 1H), 4.30 (t, J ) 4.0 Hz, 1H), 3.22 (m, 2H), 3.05
(dd, J ) 8.0, 4.0 Hz, 1H), 1.74 (s, 3H), 1.37 (m, 1H), 1.05 (ddd,
J ) 8.0, 8.0, 4.0 Hz, 1H), 0.84 (ddd, J ) 8.0, 8.0, 4.0 Hz, 1H).
Anal. Calcd for C9H12N2O3: C, 55.10; H, 6.16; N, 14.28.
Found: C, 55.17; H, 6.21; N, 14.24.
D
1
0.29, MeOH); H NMR (CDCl3) δ 4.87 (br s, 1H), 4.66 (br s,
1H), 4.16 (dd, J ) 8.0, 6.0 Hz, 1H), 3.88 (m, 1H), 3.78 (dd, J )
8.3, 7.2 Hz, 1H), 2.75 (m, 1H), 1.43 (m, 3H), 1.36 (m, 3H), 1.12
(m, 2H), 0.76 (m, 1H). Anal. Calcd for C9H16N2O3: C, 53.99;
H, 8.05; N, 13.99. Found: C, 54.10; H, 8.10; N, 14.01.
(1R,2S)-1-[2-(Hyd r oxym eth yl)cyclop r op yl]u r a cil (11).
Using the above procedures, reaction of 5 with â-methoxy-
acryloyl chloride followed by cyclization, deprotection, and
oxidation-reduction reactions gave the uracil nucleoside 11
Compound 7: syrup; [R]25D +4.37° (c 0.50, MeOH); 1H NMR
(DMSO-d6) δ 4.10 (m, 2Η), 3.66 (m, 1H), 2.47 (m, 1H), 1.50 (s,
D2O exchangeable, 2H), 1.48 (s, 3H), 1.35 (s, 3H), 0.89 (m, 1H),
0.69 (m, 1H), 0.31 (m, 1H). Anal. Calcd for C8H15NO2: C,
61.12; H, 10.00; N, 8.97. Found: C, 60.95; H, 9.82; N, 8.69.
(1R,2S,4R)-[2-(H yd r oxym et h yl)cyclop r op yl]t h ym in e
(10). To a solution of urea 5 (700 mg, 3.50 mmol) in CH2Cl2
(10 mL) and pyridine (5 mL) was added â-methoxy-R-meth-
ylacryloyl chloride (940 mg, 7.0 mmol) at 0 °C, and the mixture
was stirred at rt for 3 h and poured into ice-water. The
organic layer was separated, and the aqueous layer was
extracted with CHCl3. The combined organic layer was dried
(Na2SO4), filtered, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography
(CHCl3-MeOH, 20:1) and redissolved in EtOH (25 mL) and
in 60% overall yield as white crystals: mp 146-148 °C; [R]25
D
+119.89° (c 0.45, MeOH); UV (H2O) λmax 265.5 (ꢀ 10 646, pH
1
7), 266.5 (ꢀ 6245, pH 2), 264.0 nm (ꢀ 7475, pH 11); H NMR
(DMSO-d6) δ 11.18 (br s, 1H), 7.58 (d, J ) 8.0 Hz, 1H), 5.48
(d, J ) 8.0 Hz, 1H), 4.38 (m, 1H), 3.34 (m, 2H), 3.09 (m, 1H),
1.38 (dd, J ) 16.0, 8.0 Hz, 1H), 1.07 (dd, J ) 16.0, 8.0 Hz,
1H), 0.84 (dd, J ) 12.0, 6.0 Hz, 1H). Anal. Calcd for
C8H10N2O3: C, 52.74; H, 5.53; N, 15.38. Found: C, 52.48; H,
5.56; N, 15.20.
(1R,2S,4R)-1-[2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)cyclo-
p r op yl]-4-1,2,4-tr ia zol-1-yl-1H-p yr im id in -2-on e (12). To
a solution of the protected uridine analogue (410 mg, 1.63

1994 J . Org. Chem., Vol. 62, No. 7, 1997
Lee et al.
mmol) prepared above in pyridine (35 mL) were added 1,2,4-
triazole (337 mg, 4.88 mmol) and 4-chlorophenyl phosphoro-
dichloridate (1.2 g, 4.89 mmol), the mixture was stirred at rt
for 3 days, and the solvent was removed under reduced
pressure. The residue was purified by silica gel column
chromatography (CHCl3-MeOH, 5:1) to give 12 as a white
solid (268 mg, 54%; overall yield from 5, 50%): mp 164-166
silica gel column chromatography (CHCl3-MeOH, 12:1) to give
17 as a white solid (180 mg, 71%): mp 228 °C dec; [R]25
D
+132.86° (c 0.11, MeOH); UV (MeOH) λmax 250.5 nm; 1H NMR
(CDCl3) δ 11.83 (br s, D2O exchangeable, 1H), 8.06 (s, 1H),
7.78 (s, 1H), 3.87 (m, 2H), 3.57 (dd, J ) 8.0, 4.0 Hz, 1H), 3.40
(m, 1H), 1.62 (m, 1H), 1.50-1.32 (m, 2H), 1.32 (s, 3H), 1.09
(m, 3H). Anal. Calcd for C13H16N4O3: C, 56.51; H, 5.84; N,
20.28. Found: C, 56.35; H, 5.82; N, 20.20.
°C; [R]25 +431.98° (c 0.25, MeOH); UV (MeOH) λmax 316.5,
D
250.5, 223.5 nm; 1H NMR (CDCl3) δ 9.27 (s, 1H), 8.12 (s, 1H),
7.88 (d, J ) 8.0 Hz, 1H), 7.01 (d, J ) 8.0 Hz, 1H), 4.10 (d, J )
8.0 Hz, 1H), 3.86 (dd, J ) 8.0, 4.0 Hz, 1H), 3.72 (m, 1H), 1.65
(m, 2H), 1.35 (s, 3H), 1.28 (m, 1H), 1.19 (s, 3H). Anal. Calcd
for C14H17N5O3.0.2 H2O: C, 54.79; H, 5.71 N, 22.81. Found:
C, 54.76; H, 5.70; N, 22.57.
(1R,2S)-9-[2-(H yd r oxym et h yl)cyclop r op yl]h yp oxa n -
th in e (21). Deprotection of compound 17 followed by oxida-
tion-reduction reaction as described above gave a crude
nucleoside, which was triturated with EtOH to obtain 21 in
50% overall yield as white crystals: mp 266-268 °C; [R]25
D
+39.21° (c 0.15, MeOH); UV (H2O) λ
254.5 (ꢀ 14 567, pH
max
7), 250.0 (ꢀ 13 847, pH 2), 250.0 nm (ꢀ 13 010, pH 11); 1H NMR
(DMSO-d6) δ 12.30 (br s, D2O exchangeable, 1H), 8.07 (s, 1H),
8.05 (s, 1H), 4.58 (t, J ) 4.0 Hz, 1H), 3.54 (m, 1H), 3.16 (m,
2H), 3.10 (m, 1H), 1.50 (m, 1H), 1.31-1.19 (m, 2H). Anal.
Calcd for C9H10N4O2: C, 52.42; H, 4.89; N, 27.17. Found: C,
52.37; H, 4.87; N, 27.07.
(1R,2S,4R)-4-Am in o-1-[2-(2,2-d im eth yl-1,3-d ioxola n -4-
yl)cyclop r op yl]-1H-p yr im id in -2-on e (13). Compound 12
(220 mg, 0.73 mmol) was dissolved in NH4OH (30%, 10 mL)
and the mixture stirred at rt for 12 h. The solvent was
evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography (CHCl3-MeOH,
12:1) to give 13 as a white solid (170 mg, 91%): mp 256-258
(1R,2S,4R)-9-[2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)cyclo-
p r op yl]a d en in e (18). A solution of 16 (220 mg, 0.75 mmol)
in methanolic ammonia (60 mL) was heated at 90 °C for 20 h
in a steel bomb. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography (CHCl3-MeOH, 20:1) to yield 18 as a white
°C; [R]25 +359.75° (c 0.30, MeOH); UV (MeOH) λmax 275 nm;
D
1H NMR (CDCl3) δ 7.34 (dd, J ) 8.0, 4.0 Hz, 1H), 7.26 (d, J )
4.0 Hz, 1H), 5.64 (dd, J ) 8.0, 4.0 Hz, 1H), 4.10 (m, 1H), 3.91
(m, 1H), 3.50-3.40 (m, 2H), 3.31 (m, 1H), 1.50 (m, 1H), 1.40
(s, 3H), 1.26 (s, 3H), 1.05 (s, 3H). Anal. Calcd for C12H17N3-
O3: C, 57.36; H, 6.82; N, 16.72. Found: C, 57.27; H, 6.81; N,
16.69.
solid (187 mg, 91%): mp 165-167 °C; [R]25 +137.31° (c 0.60,
D
1
MeOH); UV (CHCl3) λmax 260.0 nm; H NMR (CDCl3) δ 8.38
(1R,2S)-1-[2-(Hydr oxym eth yl)cyclopr opyl]cytosin e (14).
Deprotection of 13 followed by the oxidation-reduction as
described for 10 and 11 gave a crude product, which was
purified by silica gel chromatography (CHCl3-MeOH, 10:1)
to obtain the cytosine derivative 14 in 48% overall yield as
(s, 1H), 7.76 (s, 1H), 5.56 (br s, 2H), 3.92 (m, 2H), 3.58 (m,
1H), 3.30 (m, 1H), 1.61-1.50 (m, 3H), 1.29 (s, 3H), 1.14 (m,
3H). Anal. Calcd for C13H17N5O2: C, 56.72; H, 6.22; N, 25.44.
Found: C, 56.59; H, 6.34; N, 25.19.
(1R,2S)-9-[2-(Hydr oxym eth yl)cyclopr opyl]aden in e (22).
Using the above procedures, compound 18 was converted to
adenine nucleoside 22 in 75% overall yield as white crystals:
mp 125-126 °C; [R]25D +48.69° (c 0.41, MeOH); UV (H2O) λmax
260.5 (ꢀ 11 032) (pH 7), 259.0 (ꢀ 13 057, pH 2), 260.5 nm (ꢀ
10 907, pH 11); 1H NMR (DMSO-d6) δ 8.14 (s, 1H), 8.11 (s,
1H), 7.31 (br s, 2H), 4.70 (s, 1H), 3.48 (m, 1H), 3.27 (m, 1H),
3.01 (m, 1H), 1.57 (m, 1H), 1.32 (m, 1H), 1.14 (m, 1H); HRMS
calcd for (C9H11N5O + H) 206.1042, found (FAB) 206.1046.
Anal. Calcd for C9H11N5O.0.6MeOH: C, 51.37; H, 6.01; N,
31.20. Found: C, 51.57; H, 5.63; N, 30.91.
white crystals: mp 271-273 °C; [R]25 +133.50° (c 0.10,
D
1
MeOH); H NMR (DMSO-d6) δ 7.55 (d, J ) 8.0 Hz, 1H), 7.21
(br s, D2O exchangeable, 1H), 7.11 (br s, 1H), 4.33 (m, 1H),
4.14 (m, 1H), 3.07 (m, 1H), 2.88 (m, 1H), 1.39 (m, 1H), 1.07
(m, 1H), 0.70 (m, 1H). Anal. Calcd for C8H11N3O2.0.1 H2O:
C, 52.51; H, 6.17; N, 22.96. Found: C, 52.43; H, 6.17; N, 22.92.
(1R,2S,4R)-6-[[2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)cyclo-
p r op yl]a m in o]-4-ch lor o-5-for m a m id op yr im id in e (15). A
mixture of cyclopropylamine 7 (400 mg, 2.54 mmol), 4,6-
dichloro-5-formamidopyrimidine (537 mg, 2.80 mmol), and
Et3N (6 mL, 0.04 mmol) in dioxane (25 mL) was refluxed for
3 h. After being cooled to rt, the suspension was filtered, and
the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(CHCl3-MeOH, 20:1) to give 15 as a colorless syrup (680 mg,
(1R,2S,4R)-1-[(2-Am in o-4-ch lor o-6-pyr im id in yl)a m in o]-
2-(2,2-d im eth yl-1,3-d ioxola n -4-yl)cyclop r op a n e (23). To
a solution of cyclopropylamine 7 (541 mg, 3.44 mmol) in EtOH
(35 mL) were added 2-amino-4,6-dichloropyrimidine (620 mg,
3.78 mmol) and Et3N (35 mL) at rt and the mixture refluxed
for 40 h under N2. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography (CHCl3-MeOH, 25:1) to give 23 as a white
86%): [R]25 +134.55° (c 0.48, MeOH); UV (MeOH) λmax 276.5
D
(sh), 260.0, 219.0 nm; 1H NMR (CDCl3) δ 8.31 (s, 2H), 8.07 (br
s, D2O exchangeable, 1H), 4.14 (m, 1H), 3.85 (m, 2H), 3.22 (m,
1H), 2.04 (br s, D2O exchangeable, 1H), 1.58 (s, 3H), 1.34 (s,
3H), 1.21 (m, 2H), 0.80 (m, 1H). Anal. Calcd for C13H17N4-
ClO3: C, 50.39; H, 5.85; N, 16.10; Cl, 10.18. Found: C, 50.43;
H, 6.07; N, 15.82; Cl, 10.27.
solid (600 mg, 61%): mp 118-120 °C; [R]25 +151.38° (c 0.35,
D
MeOH); UV (MeOH) λmax 286.0, 237.0, 222.0 nm; 1H NMR
(CDCl3) δ 5.96 (s, 1H), 5.07 (br s, D2O exchangeable, 1H), 4.85
(br s, D2O exchangeable, 2H), 3.97 (dd, J ) 8.0, 4.0 Hz, 1H),
3.79 (m, 2H), 2.76 (m, 1H), 1.44 (s, 3H), 1.32 (s, 3H), 1.20 (m,
2H), 0.77 (m, 1H). Anal. Calcd for C12H17N4O2Cl‚0.2H2O: C,
49.99; H, 6.08; N, 19.43. Found: C, 49.72; H, 6.11; N, 19.24.
(1R,2S,4R)-9-[2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)cyclo-
p r op yl]-6-ch lor op u r in e (16). A mixture of compound 15
(1.20 g, 3.84 mmol) and diethoxymethyl acetate (20 mL) was
heated at 120 °C for 4 h. After the solvent was removed under
reduced pressure, the residue was redissolved in MeOH (30
mL) and concd NH4OH (3 mL) and stirred at rt for 1 h. The
solvent was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (CHCl3-
MeOH, 30:1) to yield 16 as a colorless syrup (1.01 g, 89%):
(1′R,2′S)-9-[(2-Hydr oxym eth yl)cyclopr opyl]gu an in e (24).
To a solution of p-chloroaniline (485 mg, 3.8 mmol) in concd
HCl (2.2 mL) and H2O (6.4 mL) was added a solution of NaNO2
(280 mg, 4.0 mmol) in H2O (3 mL) dropwise at 0 °C. The
resulting cold solution was added to a mixture of compound
23 (540 mg, 1.90 mmol), H2O (17 mL), AcOH (7 mL), and
sodium acetate trihydrate (7.2 g). The reaction mixture was
stirred at rt for 18 h and cooled in an ice bath to obtain a yellow
precipitate. The resulting solid was collected by filtration,
washed with ice-water, and dried (P2O5) under vacuum to
yield a diazo compound as a yellow solid (800 mg, 60%). To a
mixture of the diazo compound (390 mg, 1.10 mmol), H2O (27
mL), EtOH (27 mL), and AcOH (27 mL) was added Zn dust
(1.05 g), and the mixture was refluxed for 4 h and filtered.
The solvent was removed under reduced pressure, and the
residue was purified by silica gel column chromatography
(CHCl3-MeOH, 6:1) to give a diamino compound as a brown
[R]25 +140.71° (c 0.48, MeOH); UV (MeOH) λmax 265.0 nm;
D
1H NMR (CDCl3) δ 8.77 (s, 1H), 8.08 (s, 1H), 3.89 (m, 2H),
3.65 (m, 1H), 3.52 (m, 1H), 1.67-1.60 (m, 2H), 1.52 (m, 1H),
1.34 (s, 3H), 1.05 (m, 3H). Anal. Calcd for C13H15N4O2Cl: C,
52.98; H, 5.13; N, 19.01, Cl, 12.03. Found: C, 52.74; H, 5.27;
N, 18.77; Cl, 11.76.
(1R,2S,4R)-9-[2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)cyclo-
p r op yl]h yp oxa n th in e (17). To a solution of 16 (270 mg, 0.92
mmol) in MeOH (40 mL) were added NaOCH3 (198 mg, 3.66
mmol) and 2-mercaptoethanol (0.26 mL, 3.66 mmol), the
mixture was refluxed for 6 h, and the solvent was removed
under reduced pressure. The syrupy residue was purified by

Synthesis of Carbocyclic Cyclopropyl Nucleosides
J . Org. Chem., Vol. 62, No. 7, 1997 1995
1
solid (150 mg, 52%). To a stirred mixture of the diamino
compound (46 mg, 0.18 mmol), triethyl orthoformate (0.3 mL,
0.18 mmol), and DMF (3 mL) was added concd HCl (0.05 mL)
at 0 °C and the mixture stirred at rt for 16 h. The solvent
was removed under reduced pressure, and the residue was
redissolved in HCl (2 N, 4 mL). The mixture was refluxed for
3 h and neutralized with NaOH (2 N). The solvent was
removed under reduced pressure to give a crude diol nucleoside
(50 mg, 0.20 mmol), which was converted to the guanine
derivative 24 as a white solid (12 mg, 31%; overall yield from
nm (ꢀ 11 109, pH 11); H NMR (DMSO-d6) δ 10.60 (br s, D2O
exchangeable, 1H, NH), 7.66 (s, 1H), 6.61 (br s, D2O exchange-
able, 2H, NH2), 4.57 (br s, D2O exchangeable, 1H), 2.89 (m,
1H), 2.73 (m, 1H), 1.43 (m, 1H), 1.22 (m, 2H), 1.06 (m, 1H);
HRMS calcd for (C9H11N5O2 + H) 222.0991. found (FAB)
222.0985.
Ack n ow led gm en t. This research was supported in
part by U.S. Public Health Service Research Grants (AI
32351 and AI 33655).
23, 10%): mp 258-260 °C; [R]25 +50.8 (c 0.35, MeOH); UV
D
(H2O) λmax 251.5 (ꢀ 12 091, pH 7), 256.0 (ꢀ 10 928, pH 2), 267.0
J O961523L