Efficient synthesis of 4′-cyclopropylated carbovir analogues with use of ring-closing metathesis from glycolate

Article abstract of DOI:10.1080/15257770802400065

The first synthetic route of novel 4′-cyclopropylated carbovir analgues is described. The construction of cyclopropylated quaternary carbon at 4′-position of carbocyclic nucleosides was successfully made via sequential Johnson's orthoester rearrangement and ring-closing metathesis (RCM) starting from ethyl glycolate. Synthesized compounds 15 and 16 showed moderate antiviral activity without any cytotoxicity up to 100 μmol. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802400065

Nucleosides, Nucleotides and Nucleic Acids, 27:1186–1196, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802400065
EFFICIENT SYNTHESIS OF 4ꢀ-CYCLOPROPYLATED CARBOVIR
ANALOGUES WITH USE OF RING-CLOSING METATHESIS FROM
GLYCOLATE
Lian Jin Liu, Jin Cheol Yoo, and Joon Hee Hong
College of Pharmacy, Chosun University, Republic of Korea
The first synthetic route of novel 4ꢁ-cyclopropylated carbovir analgues is described. The
2
construction of cyclopropylated quaternary carbon at 4ꢁ-position of carbocyclic nucleosides was
successfully made via sequential Johnson’s orthoester rearrangement and ring-closing metathesis
(RCM) starting from ethyl glycolate. Synthesized compounds 15 and 16 showed moderate antiviral
activity without any cytotoxicity up to 100 µmol.
Keywords Carbocyclic nucleoside; antiviral agents; ring-closing metathesis; Claisen
rearrangement
INTRODUCTION
The finding that thymidine analogue with 4ꢁ-azido[1] and 4ꢁ-cyano
group[2] show significant inhibitory activity against HIV proliferation has
stimulated the synthesis of 4ꢁ-substituted nucleoside analogues. Recently,
4ꢁ-homologated stavudine[3] thiostavudine[4] analogue, especially ethenyl
and ethynyl, are molecules of considerable interest. One of reasons for
this prominence arises from the notable biological activities as antiviral and
antitumor agents.
Carbocyclic nucleosides[5] are a group of compounds structurally sim-
ilar to natural nucleosides in which the furanose oxygen is replaced by a
methylene group. Replacement of the furanose ring oxygen by carbon is of
particular interest since the resulting carbocyclic nucleosides possess greater
metabolic stability to the phosphorylase,[6] which cleave the glycosidic bond
Received 31 January 2008; accepted 30 July 2008.
This study was supsported by the Technology Development Program for Agriculture and Forestry,
Ministry of Agriculture and Forestry, 2008.
Address correspondence to Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
1186

Efficient Synthesis of 4ꢁ-Cyclopropylated Carbovir Analogues
1187
FIGURE 1 Structure of potent carbocyclic nucleosides.
of nucleosides. The recent discovery of 2ꢁ,3ꢁ-olefinic carbocyclic nucleosides,
such as carbovir[7] and abacavir,[8] which are potent anti-HIV agents, have
increased interests in the search for novel nucleosides in this class of
compounds (Figure 1).
Stimulated by these interesting molecular structures and antiviral ac-
tivity relationship, we have determined to synthesize novel classes of nu-
cleoside comprising 4ꢁ-alkylated carbocyclic nucleoside with an additional
cyclopropyl group which has a similar electron density as those of double or
triple bond.
In this context, we describe a very convenient and general syn-
thetic procedure for nucleosides using reiterative three step sequences
([3,3]-sigmatropic rearrangement,[9] RCM,[10] and Pd(0)-catalyzed allylic
alkylation[11]). As shown in Scheme 1, we envisioned that ring-closing
metathesis of proper divinyls 10, which could be readily synthesized via
sequential [3,3]-sigmatropic rearrangement and carbonyl addition start-
ing from ethyl glycolate 1, would produce cyclopropylated cyclopentene
11β.
Silyl protection of the alcohol of commercially available starting material
1 followed by hydrolysis gave carboxylic acid derivative 3, which was trans-
formed to Weinreb amide 4 by the treatment of DCC and DMAP coupling
reagent.[12] Conversion of the amide 4 to cyclopropyl ketone derivative 5
turned out to be successful under the usual carbonyl addition condition
(cyclopropylMgBr, THF, −78◦C). Subjection of 5 to Horner-Wadsworth-
Emmons (HWE) reaction condition[13] provided α,β-unsaturated ethyl
ester 6 as cis/trans isomeric mixtures. It is unnecessary to separate the
isomers, because they will be merged into one isomer in next reaction. Ester
6 was reduced to allylic alcohol 7 by using diisobutylaluminum hydride,
which underwent regular Johnson’s orthoester Claisen rearrangement using
triethyl orthoacetate to give γ ,δ–unsaturated ester 8. Direct conversion of
the ester 8 to the aldehyde 9 was possible by slow addition of DIBALH in the
toluene solvent system at –78◦C. The aldehyde 9 was subjected to carbonyl
addition by CH2 CHMgBr to yield inseparable diastereomeric mixture 10
by a non-stereoselective manner.

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L. J. Liu et al.
SCHEME 1 Synthesis route of aldehyde intermediate 9.
Without separation, divinyl 10 was subjected to standard RCM condition
using second generation Grubbs catalyst [(Im)Cl2PCy3RuCHPh][14] to pro-
vide cyclopentenol 11α and 11β, respectively. The relative stereochemical
assignments were readily made based on NMR studies. Upon the irradiation
of C1-H, different NOE pattern was observed at the protons of compound
11β [methyloxy-H (0.1%) & cyclopropyl-H (0.5)], from those of compound 11α
[methyloxy-H (0.6%) & cyclopropyl-H (0.2)] (Figure 2).
FIGURE 2 NOE comparisons of compound 11α and 11β.

Efficient Synthesis of 4ꢁ-Cyclopropylated Carbovir Analogues
1189
The allylic functionalization using palladium(0)-catalyzed reactions
have been the central role in synthetic organic chemistry. We have
successfully applied this methodology to the synthesis of desired nucleoside.
Cyclopentenol 11β was transformed to 12 using ethyl chloroformate,
which was coupled with 2-amino-6-chloropurine anions generated by
NaH/DMSO with use of catalyst [tris(dibenzylidene-acetone)-dipalladium
1
(0)-chloroform] adduct to provide nucleoside analogue 13. Based on H
NMR integration study, the product mixtures indicated no N7 isomer (less
than 5%) formed in the reaction of 12. The analysis of the N7 and N9
1
coupling products is readily accomplished by H NMR. Since the proton
at the 8-position of the purine is well separated and readily distinguished
in the two region-isomers. The C-8 isomers proton of the N9 isomer is
typically upfield of the the N7 isomer.[15] Removal of silyl protection group
of 13 was preformed by the treatment of tetrabutylammonium fluoride
(TBAF) to give nucleoside 14, which was treated with cyclopropylamine
in EtOH under reflux to provide the desired 4ꢁ-cyclopropylated abacavir
analogue 15. Treatment of compound 14 with 2-mercaptoethanol and
sodium methoxide in methanol, followed by hydrolysis with acetic acid gave
the desired acyclic nucleoside 16 (Scheme 2).
The antiviral assay against several viruses such as the human immun-
odeficiency virus 1 (HIV-1), herpes simplex virus-1,2 (HSV-1,2) and human
cytomegalovirus (HCMV) was performed. As shown in Table 1, compound
15 and 16 exhibited moderate antiviral activity against HCMV in the Davis
cell without any cytotoxicity up to 100 µmol.[16] It is believed that the
arrangement between the 4ꢁ-branched carbocyclic nucleoside analogues
may be conformationally similar to natural nucleosides containing ribose.
Hence, the presence of cyclopropyl group at the 4ꢁ-position of nucleosides
could be supposed to enhance the level of phosphorylation by kinase to
produce the active monophosphate form.
In summary, an efficient synthetic method of 4ꢁ-cyclopropylated carbo-
cyclic nucleoside from ethyl glycolate was developed. On the basis of this
TABLE 1 The antiviral activity of the synthesized compounds
HIV-1
HSV-1
HSV-2
HCMV
Cytotoxicity
EC50(µM)
EC50(µM)
EC50(µM)
EC50(µM)
CC50(µM)
15
16
AZT
GCV
ACV
56.2
44.7
0.008
ND
77.3
99
ND
ND
0.3
99
99
ND
ND
ND
12.7
20.1
ND
0.55
ND
99
99
2.25
>10
>100
ND
AZT: Azidothymidine; GCV: Ganciclovir; ACV: Acyclovir.
ND: Not Determined.
EC50(µM): Concentration required to inhibit 50% of the virus induced cytopathicity.
CC50(µM): Concentration required to reduce the cell viability by 50%.

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L. J. Liu et al.
SCHEME 2 Synthesis route of taregt nucleosides.
strategy, the syntheses of other nucleosides such as vinylated or acetylated
carbocyclic nucleosides with different nucleobases are in progress.
EXPERIMENTAL SECTION
The melting points were determined on a Mel-temp II laboratory
device and are uncorrected. The NMR spectra were recorded on a JEOL
300 Fourier transform spectrometer (JEOL, Tokyo, Japan). The chemical
shifts are reported in parts per million (δ) and the signals are quoted
as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and dd
(doublet of doublets). The elemental analyses were performed using a
Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA). TLC was
performed on Uniplates (silica gel) purchased from Analtech Co. (Newark,
DE, USA). Unless specified otherwise, all reactions were carried out in a N2
atmosphere. Dry dichloromethane, benzene and pyridine were obtained by
distillation from CaH2. Dry THF was obtained by distillation from Na and
benzophenone immediately before use.

Efficient Synthesis of 4ꢁ-Cyclopropylated Carbovir Analogues
1191
(tert-Butyldimethylsilyloxy)-acetic acid ethyl ester (2): To a solution of
ethyl glycolate 1 (10 g, 0.096 mol) and imidazole (8.8 g, 0.144 mol) in
CH2Cl2 (200 mL), TBDMSCl (15.97 g, 0.106 mol) was added slowly at
0◦C, and stirred for 5 hours at the same temperature. The reaction solvent
was evaporated under reduced pressure. The residue was extracted twice
with diethyl ether and water. The combined organic layer was dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (EtOAc/hexane,
1:20) to give compound 2 (19.9 g, 95%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 4.12 (s, 2H), 4.08 (q, J = 6.9 Hz, 2H), 1.17 (t, J = 6.9 Hz, 3H),
0.81 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3) δ 171.61.80, 60.66, 25.69, 18.35,
14.12, −5.50;
(tert-Butyldimethylsilyloxy) acetic acid (3): A solution of KOH (2.57 g,
59.53 mmol) in EtOH (20 mL) was slowly added to a solution of 2 (10 g,
45.79 mmol) in EtOH (200 mL) at 0◦C. The mixture was stirred overnight at
room temperature and concentrated under reduced pressure. The residue
was dissolved in water (200 mL) and carefully neutralized with c-HCl
solution to pH 3∼4. The solution was extracted with EtOAc two times. The
organic layer was washed with brine and dried over anhydrous MgSO4,
filtered and evaporated. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:3) to give 3 (7.84 g, 90%) as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 4.12 (s, 2H), 0.82 (s, 9H), 0.01 (s, 6H); 13
NMR (CDCl3) δ 171.02, 61.90, 25.55, 18.71, −5.57.
C
2-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (4): To so-
lution of acid derivative 3 (5.0 g, 26.27 mmol) in a anhydrous CH2Cl2
(150 mL), N ,O-dimethylhydroxylamine hydrochloride (3.06 g, 31.44
mmol), DMAP (317 mg, 2.6 mmol), DCC (6.48 g, 31.4 mmol), and triethy-
lamine (3.18 g, 31.44 mmol) was sequentially added to reaction mixture.
The solution was stirred overnight at room temperature. After addition of
methanol (5 mL) and acetic acid (5 mL), the mixture was stirred for 1 hour
and neutralized with saturated aqueous NaHCO3 solution. The resulting
solid was filtered off through a short pad of Celite and the filtrate was
concentrated in vacuum. The resulting residue was purified by silica gel
column chromatography (EtOAc/hexane, 1:1.5) to give Weinreb amide 4
1
(5.21g, 85%) as a colorless oil: H NMR (CDCl3, 300 MHz) δ 4.48 (s, 2H),
3.57 (s, 3H), 3.05 (s, 3H), 0.80 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3) δ
171.63, 61.00, 60.56, 52.63, 31.67, 25.54, 18.49, −5.61.
2-(tert-Butyldimethylsilyloxy)-1-cyclopropyl-ethanone (5): To a solution
of Weinreb amide 4 (2.5 g, 10.71 mmol) in dry THF (60 mL) was slowly
added cyclopropylmagnesium bromide (25.70 mL, 0.5 M solution in THF)
at 0◦C. After 4 hours, saturated NH4Cl solution (16 mL) was added, and
the reaction mixture was slowly warmed to room temperature. The mixture
was extracted with EtOAc (2 × 60 mL). The combined organic layer was
dried over MgSO4, filtered, and evaporated. The residue was purified by

1192
L. J. Liu et al.
silica gel column chromatography (EtOAc/hexane, 1:10) to give 5 (1.65 g,
1
72%) as colorless oil: H NMR (CDCl3, 300 MHz) δ 4.21 (s, 2H), 2.18-2.10
(m, 1H), 1.17 (m, 2H), 0.97 (m, 2H), 0.82 (s, 9H), 0.02 (s, 6H); 13C
NMR (CDCl3) δ 210.41, 69.61, 25.76, 18.34, 16.11, 11.27, −5.46; Anal.
Calcd. for C11H22O2Si · 0.5 EtOAc: C, 60.41; H, 10.14. Found: C, 60.49; H,
10.01.
(E) and (Z)-4-(tert-Butyldimethylsilyloxy)-3-cyclopropyl-but-2-enoic acid
ethyl ester (6): To a suspension of sodium hydride (0.5 g, 20.8 mmol) in
distilled THF (100 mL) was added drop wise triethyl phosphonoacetate
(4.66 g, 20.8 mmol) at 0◦C and the mixture was stirred at room temper-
ature for 1 hour. The ketone 5 (4.46 g, 20.8 mmol) was added to this
mixture and the mixture was for 2 hours. The solution was neutralized
with AcOH (5 mL) and poured into H2O (100 mL) and extracted with
EtOAc. The organic layer was washed with brine and dried over anhydrous
MgSO4, filtered and evaporated. The residue was purified by silica gel
column chromatography (EtOAc/hexane, 1:15) to give 6 (4.73 g, 80%)
as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.96 (s, 1H), 4.15
(m, 4H), 2.21 (m, 1H), 1.19-1.09 (m, 2H), 0.97 (m, 2H), 0.83 (s, 9H),
0.02.
(E) and (Z)-4-(tert-Butyldimethylsilyloxy)-3-cyclopropyl-but-2-en-1-ol (7):
To a solution of 6 (5.0 g, 17.57 mmol) in CH2Cl2 (100 mL), DIBALH
(36.9 mL, 1.0 M solution in hexane) was added slowly at −20◦C, and
stirred for 1 hour at the same temperature. To the mixture, methanol
(35 mL) was added. The mixture was stirred at room temperature for 2
hours, and the resulting solid was filtered through a Celite pad. The filtrate
was concentrated under vacuum and the residue was purified by silica gel
column chromatography (EtOAc/hexane, 1:5) to give alcohol 7 (3.87 g,
91%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.69 (s, 1H), 4.19 (d,
J = 6.8 Hz, 2H), 4.04 (s, 2H), 2.23 (m, 1H), 1.17-1.07 (m, 2H), 0.95 (m, 2H),
0.81 (m, 9H), 0.01 (m, 6H).
( )-3-(t-Butyldimethylsilyloxymethyl)-3-cyclopropyl-pent-4-enoic acid et-
hyl ester (8): A solution of allylic alcohol 7 (8.4 g, 34.66 mmol) in triethyl or-
thoacetate (150 mL) and 0.3 mL of propionic acid was heated at 135–140◦C
overnight, with stirring under condition for distillative removal of ethanol.
The excess of triethyl orthoacetate was distilled off and the residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:20) to give
8 (8.66 g, 80%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.90 (d, J =
10.6 Hz, 1H), 5.87 (d, J = 11.2 Hz, 1H), 5.03 (d, J = 1.2 Hz, 1H), 5.03 (d,
J = 7.6 Hz, 1H), 4.03 (q, J = 7.2 Hz, 2H), 3.44 (d, J = 9.4 Hz, 1H), 3.42
(d, J = 9.4 Hz, 1H), 2.42 (d, J = 3.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 0.82
(s, 9H), 0.46 (m, 1H), 0.28-0.21 (m, 4H), 0.01 (s, 6H); 13C NMR (CDCl3) δ
171.96, 143.18, 114.04, 69.82, 60.07, 41.30, 25.82, 18.23, 14.56, 11.26, 8.46,
−5.50; Anal. Calcd. for C17H32O3Si: C, 65.33; H, 10.32. Found: C, 65.42; H,
10.27.

Efficient Synthesis of 4ꢁ-Cyclopropylated Carbovir Analogues
1193
( )-3-(t-Butyldimethylsilyloxymethyl)-3-cyclopropyl-pent-4-enal (9): To a
solution of 8 (3.0 g, 9.6 mmol) in toluene (40 mL), DIBALH (7.1 mL, 1.5 M
solution in toluene) was added slowly at −78◦C, and stirred for 20 minutes
at the same temperature. To the mixture, methanol (10 mL) was added.
The mixture was stirred at room temperature for 1 hour, and the resulting
solid was filtered through a Celite pad. The filtrate was concentrated under
vacuum and the residue was purified by silica gel column chromatography
1
(EtOAc/hexane, 1:15) to give 9 (1.72 g, 67%) as a colorless oil: H NMR
(CDCl3, 300 MHz) δ 9.78 (s, 1H), 5.92 (dd, J = 17.7, 11.1 Hz, 1H), 5.21
(d, J = 11.1 Hz, 1H), 5.14 (d, J = 17.7 Hz, 1H), 3.50 (d, J = 9.4 Hz, 1H),
3.32 (d, J = 9.4 Hz, 1H), 2.43-2.37 (m, 2H), 0.82 (s, 9H), 0.52 (m, 1H), 0.29
(m, 4H), 0.02 (s, 6H); 13C NMR (CDCl3) δ 203.11, 142.32, 112.21, 69.86,
51.32, 42.54, 25.82, 18.45, 10.98, 6.72, −5.61; Anal. Calcd. for C15H28O2Si ·
1.0EtOAc: C, 63.99; H, 10.17. Found: C, 64.12; H, 9.98.
(rel)-(3R and 3S,5S)-5-(t-Butyldimethylsilyloxymethyl)-5-cyclopropyl-
hepta-1,6-dien-3-ol (10): To a solution of 9 (3.1 g, 11.55 mmol) in dry
THF (50 mL) was slowly added vinyl magnesiumbromide (13.86 mL, 1.0 M
solution in THF) at −78◦C. After 3 hours, saturated NH4Cl solution (10 mL)
and water (50 mL) was sequentially added, and the reaction mixture was
slowly warmed to room temperature. The mixture was extracted with
EtOAc (2 × 50 mL). The combined organic layer was dried over MgSO4,
filtered, and evaporated. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:15) to give 10 (2.7 g, 79%) as colorless
1
oil: H NMR (CDCl3, 300 MHz) δ 6.05-5.77 (m, 2H), 5.25-4.97 (m, 4H),
4.22 (m, 1H), 3.47 (m, 2H), 1.68-1.55 (m, 2H), 0.81 (s, 9H), 0.50 (m, 1H),
0.37-0.30 (m, 4H), 0.02 (m, 6H).
(rel)-(1R,4S)-4-(t-Butyldimethylsilyloxymethyl)-4-cyclopropyl-cyclopent-
2-enol (11β); and (rel)-(1S,4S)-4-(t-Butyldimethylsilyloxymethyl)-4-cyclop-
ropyl-cyclopent-2-enol (11α): To a solution of 10 (1.37 g, 4.62 mmol) in dry
CH2Cl2 (10 mL) was added 2nd generation Grubbs catalyst (127 mg 0.15
mmol). The reaction mixture was refluxed overnight, and cooled to room
temperature. The mixture was concentrated in vacuum, and residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:10) to
give cyclopentenol 11β (521 mg, 42%) and 11α (508 mg, 41%) as colorless
oils, respectively. Cyclopentenol 11β: 1H NMR (CDCl3, 300 MHz) δ 5.86 (d,
J = 5.4 Hz, 1H), 5.47 (d, J = 5.6 Hz, 1H), 4.52 (dd, J = 7.6, 1.2 Hz, 1H),
3.35 (s, 2H), 1.85 (dd, J = 14.2, 6.8 Hz, 1H), 1.68 (dd, J = 14.2, 2.4 Hz,
1H), 0.83 (s, 9H), 0.55 (m, 1H), 0.37-0.29 (m, 4H), 0.01 (s, 6H): 13C NMR
(CDCl3) δ 140.49, 133.98, 76.35, 68.99, 49.91, 44.78, 25.54,18.48, 12.54,
7.90, −5.57; Anal. Calcd. for C18H32O4Si: C, 63.49; H, 9.47. Found: C, 63.36;
H, 9.58.
1
Cyclopentenol 11α: H NMR (CDCl3, 300 MHz) δ 5.78-5.69 (m, 2H),
4.80 (dd, J = 6.4, 1.2 Hz, 1H), 3.33 (s, 2H), 2.19 (dd, J = 13.6, 7.4 Hz, 1H),
1.32 (dd, J = 13.6, 4.4 Hz, 1H), 0.84 (s, 9H), 0.56 (m, 1H), 0.28-0.22 (m,

1194
L. J. Liu et al.
4H), 0.01 (s, 6H): 13C NMR (CDCl3) δ 140.95, 132.65, 76.78, 69.97, 51.21,
43.54, 25.58, 18.48, 10.58, 7.34, −5.48; Anal. Calcd. for C18H32O4Si · 0.5
EtOAc: C, 65.33; H, 10.32. Found: C, 65.36; H, 10.41.
(rel)-(1R,4S)-1-Ethoxy carbonyloxy-4-(t-butyldimethylsilyloxymethyl)-4-
cyclopropyl-cyclopent-2-ene (12): To a solution of 11β (1.94 g, 7.21 mmol)
in anhydrous pyridine (8 mL) was added ethyl chloroformate (1.38 mL,
14.43 mmol) and DMAP (85 mg, 0.7 mmol). The reaction mixture was
stirred overnight at room temperature. The reaction mixture was quenched
with saturated NaHCO3 solution (1 mL) and concentrated in vacuum. The
residue was extracted with EtOAc, dried over MgSO4, filtered, and con-
centrated. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:10) to give 11 (1.77 g, 72%) as colorless syrup: 1H NMR
(CDCl3, 300 MHz) δ 5.88 (d, J = 5.6 Hz, 1H), 5.72 (dd, J = 5.6, 2.4 Hz,
1H), 5.52 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.31 (s, 2H), 1.89 (dd, J = 14.2,
7.6 Hz, 1H), 1.69 (dd, J = 14.2, 4.0 Hz, 1H), 1.25 (t. J = 7.2 Hz, 3H), 0.82
(s, 9H), 0.58 (m, 1H), 0.30-0.23 (m, 4H), 0.01 (s, 6H): 13C NMR (CDCl3) δ
154.89, 144.90, 127.67, 83.41, 70.11, 63.21, 51.21, 40.56, 25.71, 18.48, 14.71,
11.98, 6.45, −5.58; Anal. Calcd. for C18H32O4Si: C, 63.49; H, 9.47. Found: C,
63.36; H, 9.58.
(rel)-(1ꢁR,4ꢁS)-9-[4-(t-Butyldimethylsilyloxymethyl)-4-cyclopropyl-cyclop-
ent-2-en-1-yl] 2-amino-6-chloropurine (13): To a pure NaH (12 mg, 0.49
mmol) in anhydrous DMSO (3.0 mL) was added 2-amino-6-chloropurine
(83 mg, 0.49 mmol). The reaction mixture was stirred for 30 minutes
at 50–55◦C and cooled to room temperature. Simultaneously, P(O-i-Pr)3
(0.048 mL, 0.11 mmol) was added to a solution of Pd2(dba)3.CHCl3
(2.3 mg, 1.25 µmol) in anhydrous THF (2.0 mL), which was stirred for
30 minutes. To the nucleosidic base solution of DMSO was sequentially
added catalyst solution of THF and 12 (150 mg, 0.44 mmol) dissolved in
anhydrous THF (2 mL). The reaction mixture was stirred overnight at
refluxing temperature and quenched with water (1 mL). The reaction
solvent was removed in vacuum. The residue was purified by silica gel
column chromatography (MeOH/CH2Cl2, 1:15) to give 13 (78 mg, 42%)
as a white solid. mp 168–171◦C; 1H NMR (CDCl3, 300 MHz) δ 7.91 (s, 1H),
6.02 (d, J = 5.4 Hz, 1H), 5.80-5.71 (m, 2H), 5.30 (br s, 2H), 3.60 (d, J = 9.4
Hz, 1H), 3.49 (d, J = 9.4 Hz, 1H), 2.32 (dd, J = 14.2, 8.8 Hz, 1H), 2.00 (dd,
J = 14.2, 5.6 Hz 1H), 0.84 (s, 9H), 0.58 (m, 1H), 0.31-0.22 (m, 4H), 0.02
(s, 6H); 13C NMR (CDCl3) δ 159.32, 154.34, 151.79, 144.36, 140.76, 133.73,
124.32, 70.42, 60.42, 52.54, 41.87, 25.45, 18.54, 13.01, 6.98, −5.65; Anal.
Calcd. for C20H30ClN5OSi · 0.8MeOH: C, 56.06; H, 7.51; N, 15.71. Found:
C, 55.89; H, 7.64; N, 15.79.
(rel)-(1ꢁR,4ꢁR)-9-[4-(Hydroxymethyl)-4-cyclopropyl-cyclopent-2-en-1-yl] 2
-amino-6-chloropurine (14): To a solution of 13 (88 mg, 0.21 mmol) in THF
(5 mL) was TBAF (0.31 mL, 1.0 M solution in THF) at 0◦C. The mixture was
stirred at room temperature for 5 hours, and concentrated. The residue was

Efficient Synthesis of 4ꢁ-Cyclopropylated Carbovir Analogues
1195
purified by silica gel column chromatography (MeOH/CH2Cl2, 1:5) to give
14 (46 mg, 71%) as a white solid: mp 172–174◦C; 1H NMR (DMSO-d6, 300
MHz) δ 7.88 (s, 1H), 5.96 (d, J = 6.2 Hz, 1H), 5.71-5.60 (m, 2H), 4.97 (t, J
= 5.4 Hz, 1H), 3.54 (d, J = 9.4 Hz, 1H), 3.42 (d, J = 9.4 Hz, 1H), 2.27 (dd, J
= 14.0, 8.8 Hz, 1H), 1.98 (dd, J = 14.0, 5.4 Hz 1H), 0.56 (m, 1H), 0.30 (m,
4H); 13C NMR (DMSO-d6) δ 159.42, 154.55, 150.48, 143.89, 141.76, 133.56,
124.78, 68.56, 61.42, 53.76, 42.28, 12.76, 6.39; Anal. Calcd. for C14H16ClN5O
· 0.5MeOH: C, 54.12; H, 5.64; N, 21.76. Found: C, 53.98; H, 5.52; N, 21.82.
(rel)-(1ꢁR,4ꢁR)-9-[4-(Hydroxymethyl)-4-cyclopropyl-cyclopent-2-en-1-yl] 2
-amino-6-cyclopropylpurine (15): Cyclopropyl amine (0.173 mL, 1.98 mmol)
was added to a solution of compound 14 (121 mg, 0.396 mmol) in EtOH (15
mL) and refluxed for 6 hours. After cooling, the reaction mixture was con-
centrated under reduced pressure. The residue was purified by silica gel col-
umn chromatography (MeOH/CH2Cl2, 1:5) to give compound 15 (76 mg,
59%) as a solid: mp 186–188; 1H NMR (DMSO-d6, 300 MHz) δ 7.90 (s, 1H),
5.87 (d, J = 6.2 Hz, 1H), 5.68 (d, J = 6.2 Hz, 1H), 5.30 (dd, J = 8.0, 2.0
Hz, 1H), 4.99 (t, J = 5.4 Hz, 1H), 3.32 (d, J = 9.0 Hz, 1H), 3.21 (d, J =
9.2 Hz, 1H), 2.31 (dd, J = 14.2, 8.6 Hz, 1H), 2.04 (dd, J = 14.2, 5.2 Hz
1H), 0.71–0.59 (m, 2H), 0.32-0.17 (m, 8H); 13C NMR (DMSO-d6) δ 159.21,
154.11, 150.40, 144.10, 141.45, 132.54, 125.02, 67.32, 62.54, 52.21, 42.22,
13.21, 12.79, 7.02, 6.32; Anal. Calcd. for C17H22N6O · 1.0H2O: C, 59.28; H,
7.02; N, 24.40. Found: C, 59.40; H, 6.90; N, 24.38.
(rel)-(1ꢁR,4ꢁR)-9-[4-(Hydroxymethyl)-4-cyclopropyl-cyclopent-2-en-1-yl]2-
amino-6-hydroxypurine (16): 2-Mercaptoethanol (0.135 mL, 1.935 mmol)
and NaOMe (1.755 mL, 1.755 mmol, 1.0 M solution in MeOH) was added
to a solution of compound 14 (101 mg, 0.33 mmol) in MeOH (13 mL),
and heated overnight under reflux. After cooling, the reaction mixture
was neutralized with a few drops of glacial AcOH and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/CH2Cl2, 1:6) to give compound 16 (65 mg, 69%)
as a solid: mp 178–180; 1H NMR (DMSO-d6, 300 MHz) δ 7.96 (s, 1H), 5.80
(d, J = 6.2 Hz, 1H), 5.39 (m, 2H), 4.94 (t, J = 5.4 Hz, 1H), 3.56 (d, J =
9.2 Hz, 1H), 3.45 (d, J = 9.2 Hz, 1H), 2.35 (dd, J = 14.0, 8.6 Hz, 1H), 1.96
(dd, J = 14.0, 5.6 Hz 1H), 0.53-0.57 (m, 1H), 0.29-0.33 (m, 4H); 13C NMR
(DMSO-d6) δ 160.19, 155.87, 150.91, 144.42, 142.28, 134.56, 125.11, 68.79,
62.08, 52.88, 44.00, 13.14, 6.97; Anal calc for C14H17N5O2 · 1.0MeOH: C,
56.41; H, 6.62; N, 21.93. Found: C, 56.32; H, 6.72; N, 22.07.
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