Synthesis of novel 2'-spirocyclopropyl-5'-deoxyphosphonic acid furanosyl nucleoside analogues as potent antiviral agents

Article abstract of DOI:10.1080/15257770.2012.695839

Novel 5-deoxyfuranosyl purine phosphonic acid analogues with 2-electropositive moiety, such as spirocyclopropanoid, were designed and synthesized from commercially available diethyl malonate. Condensation reaction successfully proceeded from a glycosyl donor 15 at low reaction temperature in Vorbruggen conditions to give desired phosphonate analogues 16b and 23b. The synthesized nucleotide analogues 19, 22, 26, and 29 were subjected to antiviral screening against HIV-1. Adenine phosphonic acid analogue 22 shows significant anti-HIV activity (EC₅₀ = 7.9 μM).

Full text of DOI:10.1080/15257770.2012.695839

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Synthesis of Novel 2′-
Spirocyclopropyl-5′- Deoxyphosphonic
Acid Furanosyl Nucleoside Analogues as
Potent Antiviral Agents
Guang Huan Shen a & Joon Hee Hong a
a BK21 Project Team, College of Pharmacy, Chosun University,
Kwangju, Republic of Korea
Version of record first published: 01 Aug 2012.
To cite this article: Guang Huan Shen & Joon Hee Hong (2012): Synthesis of Novel 2′-
Spirocyclopropyl-5′- Deoxyphosphonic Acid Furanosyl Nucleoside Analogues as Potent Antiviral Agents,
Nucleosides, Nucleotides and Nucleic Acids, 31:7, 503-521
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Nucleosides, Nucleotides and Nucleic Acids, 31:503–521, 2012
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2012.695839
SYNTHESIS OF NOVEL 2ꢀ-SPIROCYCLOPROPYL-5ꢀ-
DEOXYPHOSPHONIC ACID FURANOSYL NUCLEOSIDE ANALOGUES
AS POTENT ANTIVIRAL AGENTS
Guang Huan Shen and Joon Hee Hong
BK21 Project Team, College of Pharmacy, Chosun University, Kwangju, Republic of Korea
Novel 5ꢁ-deoxyfuranosyl purine phosphonic acid analogues with 2 ꢁ-electropositive moiety, such
2
as spirocyclopropanoid, were designed and synthesized from commercially available diethyl mal-
onate. Condensation reaction successfully proceeded from a glycosyl donor 15 at low reaction tem-
perature in Vorbruggen conditions to give desired phosphonate analogues 16b and 23b. The synthe-
sized nucleotide analogues 19, 22, 26, and 29 were subjected to antiviral screening against HIV-1.
Adenine phosphonic acid analogue 22 shows significant anti-HIV activity (EC50 = 7.9 µM).
Keywords Anti-HIV agents; 2ꢁ-spirocyclopropyl-5ꢁ-deoxyphosphonic acid analogue;
Vorbruggen reaction
INTRODUCTION
As mimics of nucleoside monophosphates, nucleotide analogues exert
their antiviral effect following sequential activation by cellular kinases to their
diphosphate derivatives (nucleoside triphosphate analogues), which act as
potent inhibitors of viral DNA polymerases.[1] A selective inhibition for these
enzymes as opposed to host cell DNA polymerases is critical for the potential
use of such compounds as drugs. Various attempts to improve the selectivity
index have led to rigid nucleoside analogues modified in their furanose ring
system by introduction of unsaturations, sometimes with an electropositive
moiety in 2ꢁ-position. Recently, nucleoside with an exomethylene 1[2] or with
a spirocyclopropane moiety 2[3] in place of the carbon atom of the furanose
ring was reported to show antiviral activity (Figure 1).
In the literature, several 5ꢁ-phosphate isosteres have been adopted to
prepare nucleoside phosphonates. As shown in Figure 1, compounds 3[4] and
4
[5] are simple 5ꢁ-deoxynucleoside phosphonates, in which the 5ꢁ-oxygen of
a nucleoside phosphate is either removed or replaced by a methylene group.
Received 24 April 2012; accepted 17 May 2012.
Address correspondence to Dr. Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
503

504
G. H. Shen and J. H. Hong
O
N
NH2
N
HN
N
O
O
HO
HO
O
O
F
2
1
HO
HO
F
O
O
N
N
N
NH
NH2
NH
O
O
HO P
HO
HO P
HO
N
O
O
O
3
HO OH
4
FIGURE 1 Structures of 2ꢁ-modified or 5ꢁ-deoxynucleoside analogues as potent antiviral agents.
All of the resultant phosphonates mimic the overall shape and geometry of
a nucleoside monophosphate.
Stimulated by these findings that 2ꢁ-electropositive nucleoside analogues
and 5ꢁ-deoxyphosphonic acid nucleosides have excellent antiviral activi-
ties, we sought to synthesize a novel class of nucleosides comprising 2ꢁ-
spirocyclopropyl-5ꢁ-deoxyphosphonic acid analogues in order to search for
more effective therapeutics against human immunodeficiency virus (HIV)
and to provide analogues for probing the conformational preferences of en-
zymes associated with the nucleoside kinases of nucleosides and nucleotides.
As depicted in Scheme 1, the target compounds were prepared from
monosilyl-cyclopropanoid 5, which was readily prepared from diethyl
malonate by the previously reported procedure.[6] For the homologation,
Swern oxidation[7] of alcohol 5 gave an aldehyde 6, which was subjected to
the Wittig reaction[8] to give compound 7. Hydroboration[9] and oxidation
of corresponding olefin 7 provided alcohol derivative 8, which was oxidized
using the similar Swern conditions described for compound 6 in 91% yields.
Carbonyl addition reaction by vinylmagensium bromide furnished the allylic
alcohol 10, which was successfully protected using p-methoxybenzyl chloride
(PMBCl)[10] to provide compound 11. Removal of the silyl protecting group
of compound 11 using tetra n-butylammonium fluoride (TBAF) gave the
primary alcohol 12, which was oxidized to the aldehyde 13 using the same ox-
idation conditions as described for compound 9 in 71% two-step yields. The
p-methoxybenzyl (PMB) protection group was removed with 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ)[11] to produce a lactol analogue 14
in 63% yields. The lactol 14 was acetylated in pyridine to furnish the key

2 ꢁ-Spirocyclopropyl-5ꢁ-Deoxyphosphonic Acid Analogues
505
O
HO
OTBS
OTBS
ref. 6
i
Diethyl malonate
OTBS
93%
6
5
ii
82%
HO
OTBS
OTBS
O
i
iii
68%
91%
9
8
7
iv
76%
OPMB
OTBS
OPMB
OH
OH
vi
81%
v
OTBS
67%
11
12
10
88%
i
OPMB
CHO
O
O
OH
OAc
ix
86%
vii
63%
14
15
13
Reagents: i) (COCl)2, DMSO, TEA, CH2Cl2; ii) n-BuLi, Ph3PCH3I, PPh3, THF;
iii) (a) BH3/THF; (b) NaOH, H2O2, H2O; iv) VinylMgBr, THF; v) PMBCl, DMF,
NaH; vi) TBAF, THF; vii) DDQ, CH2Cl2, H2O; ix) Ac2O, pyridine.
SCHEME 1 Synthesis of 2-spirocyclopropyl furanose glycosyl donor.
intermediate 15 in 86% yields as a glycosyl donor (Scheme 1). The synthesis
of adenine nucleoside was carried out by condensation of compound 9
with silylated 6-chloropurine using trimethylsilyl trifluoromethanesulfonate
(TMSOTf) as a catalyst in dichloroethene (DCE) to give protected 6-
chloropurine derivative 16a (32%) and 16b (33%), respectively. A complete
nuclear Overhauser effect (NOE) study allowed an unambiguous determi-
nation of their respective stereochemistry (Figure 2). For compound 16b,
strong NOE (1.1%) of H-1ꢁ ↔ H-4ꢁ, which showed 1ꢁ,4ꢁ-cis relationships,
was observed. According to this result, the 4ꢁ-vinyl and 2ꢁ-purine base of
compound 16b were located on the β face. On the other hand, for 16a com-
pound, weak NOE (0.7%), such as H-1ꢁ ↔ H-4ꢁ, was assigned to the 1ꢁ,4ꢁ-trans
relationships.
Cross-metathesis[12] of compound 16b with diethylphosphonate using
the 2nd generation Grubbs catalyst[13] gave vinylidene phosphonate nucle-
oside analogue 17 in a 61% yield. The chlorine group of purine analogue
17 was then converted to amine with methanolic ammonia at 64◦C to give a

506
G. H. Shen and J. H. Hong
Cl
N
H
O
N
0.7%
N
H
N
N
N
5
N
O
16a
1
N
2
4
H
H
3
Cl
1.1%
16b
FIGURE 2 NOE differences between the proximal hydrogens of 16a and 16b.
corresponding adenosine phosphonate derivative 18. Hydrolysis of diethyl
phosphonate functional groups of compound 18 by treatment with bro-
motrimethylsilane (TMSBr) in acetonitrile (CH3CN) in the presence of 2,6-
lutidine gave an adenosine phosphonic acid derivative 19.[14] The vinylidene
phosphonate was saturated in transfer catalytic hydrogenation conditions to
give ethyl phosphonate nucleoside analogue 20. The adenine phosphonic
acid analogue 22 was prepared through similar reaction conditions such as
ammonolysis and hydrolysis described for the preparation of compound 19
(Scheme 2).
For the synthesis of guanine analogues, 2-fluoro-6-chloropurine[15] was
condensed with glycosyl donor in similar conditions used for the conden-
sation of 6-chloropurine. The Vorbruggen coupling[16] of acetate 15 with
2-fluoro-6-chloropurine gives analogue 23a (31%) and 23b (30%), respec-
tively. Cross-metathesis of compound 23b with diethylvinylphosphonate pro-
vided compound 24 in a 61% yield.
Bubbling ammonia into the compound 24 gave separable 2-fluoro-6-
aminopurine analogue[17] 25a (17%) and 2-amino-6-chloropurine analogue
25b (45%), respectively. 2-Amino-6-chloropurine derivative 25b was treated
with TMSBr to provide phosphonic acid and sequentially treated sodium
methoxide and 2-mercaptoethanol in methanol to give desired guanine
vinylidene phosphonic acid 26 (Scheme 3).[18] The guanine phosphonic
acid analogue 29 was synthesized from compound 24 via transfer catalytic
hydrogenation, ammonolysis, and hydrolysis using similar conditions as de-
scribed for the synthesis of adenine derivative 26, respectively.
The antiviral activity of phosphonate nucleosides is mostly explained
by their intracellular metabolism to their diphosphates followed by
incorporation into the viral genome and chain termination.[19] MT-4 cells (1
× 105 cell/mL) were infected with HIV-1 (HTLV-IIIB strain) at a multiplicity
of infection (MOI) of 0.02 and were cultured in the presence of various
concentrations of the test compounds. After a four-day incubation at 37◦C,
the number of viable cells was monitored by the 3-(4,5-di-methylthiazole-2-
yl)-2,5-diphenyltetrazolium bromide method. The cytotoxicity of the com-
pounds was evaluated in parallel with their antiviral activity, based on the vi-
ability of mock-infected cells.[20] The synthesized compounds 19, 22, 26, and

2 ꢁ-Spirocyclopropyl-5ꢁ-Deoxyphosphonic Acid Analogues
507
Cl
N
Cl
N
N
N
N
O
OAc
i
N
N
and
N
O
O
15
16b (33%)
16a (32%)
ii 61%
Cl
N
Cl
N
N
N
N
N
N
N
v
O
O
76%
EtO P
EtO
EtO P
EtO
O
O
20
iii
17
54%
iii
59%
NH2
N
NH2
N
N
N
N
N
O
EtO P
EtO
N
O
EtO P
EtO
O
N
O
18
iv
21
76%
NH2
N
iv
78%
NH2
N
N
N
N
O
HO P
HO
O
N
N
N
O
HO P
HO
O
19
22
Reagents: i) silylated 6-chloropurine, TMSOTf, DCE; ii) Vinyldiethylphosphonate,
Grubbs cat.(II) CH2Cl2; iii) NH3/MeOH; iv) TMSBr, 2,6-lutidine, CH3CN. v) Pd/C,
cyclohexene, MeOH.
SCHEME 2 Synthesis of 2ꢁ-spirocyclopropyl-5ꢁ-deoxyphosphonic acid adenine analogues.
29 were tested against HIV-1. Especially, the adenine analogue 22 did show
moderate antiviral activity against HIV-1 (Table 1), indicating that this virus
might allow the sugar moiety for diphosphorylation or some affinity of its
diphosphate toward viral polymerases. However, other 5ꢁ-deoxyphosphonic

508
G. H. Shen and J. H. Hong
Cl
Cl
N
N
N
N
N
N
i
O
OAc
N
N
F
F
O
O
and
15
23b (30%)
61%
23a (31%)
ii
Cl
Cl
N
N
N
N
N
N
N
O
O
v
F
N
EtO P
EtO
F
66%
EtO P
EtO
O
O
24
iii
27
iii
X
N
X
N
N
N
O
N
N
Y
O
EtO P
EtO
N
O
Y
N
EtO P
EtO
O
25a: X = NH2, Y = F (17%)
25b: X = Cl, Y = NH2 (45%)
28a: X = NH2, Y = F (15%)
28b: X = Cl, Y = NH2 (41%)
64%
iv
iv 56%
O
O
N
N
N
N
NH
NH2
NH
NH2
O
HO P
HO
O
HO P
HO
N
N
O
O
29
Reagents: i) Silylated 2-fluoro-6-chloropurine, TMSOTf, DCE; ii)
26
vinyldiethylphosphonate, Grubbs cat.(II) CH2Cl2; iii) NH3, DME, rt; iv)
(a) TMSBr, 2,6-lutidine, CH3CN; (b) NaOMe, HSCH2CH2OH, MeOH;
v) Pd/C, cyclohexene, MeOH.
SCHEME 3 Synthesis of 2ꢁ-spirocyclopropyl-5ꢁ-deoxyphosphonic acid guanine analogues.

2 ꢁ-Spirocyclopropyl-5ꢁ-Deoxyphosphonic Acid Analogues
509
acid nucleoside analogues showed weak or lack of anti-HIV activity at con-
centrations up to 100 µM.
In summary, based on the potent anti-HIV activity of 2ꢁ-electropositive
nucleosides and 5ꢁ-deoxyphosphonic acid nucleoside analogues, we
have designed and successfully synthesized novel 2ꢁ-spirocyclopropyl-5ꢁ-
deoxyphosphonic acid nucleoside analogues starting from diethyl malonate.
The synthesized adenine analogue 22 exhibited improvement in cell-based
activity compared with 2ꢁ-modified guanine phosphonic acid analogues 26
and 29. Since spirocyclopropanations of guanine nucleoside derivatives are
not perfect mimics for ribofuranose moiety, the mechanisms of virus inhi-
bition, that is, either phosphorylation or inhibition of RNA synthesis, might
be impaired in these compounds. As potent anti-hepatitis C virus (anti-
HCV) agents, syntheses of (bis)S-acyl-2-thioethyl ((bis)SATE)-prodrug of
compounds 19 and 22 are in progress in our laboratory.
EXPERIMENTAL
Melting points (mp) were determined on a Mel-temp II laboratory device
and are uncorrected. NMR spectra were recorded on a JEOL 300 Fourier
transform spectrometer (JEOL, Tokyo, Japan); chemical shifts are reported
in parts per million (δ) and signals are reported as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), and dd (doublet of doublets). UV spec-
tra were obtained on a Beckman DU-7 spectrophotometer (Beckman, South
Pasadena, CA, USA). Mass spectrometry (MS) spectra were collected in elec-
trospray ionization (ESI) mode. The elemental analyses were performed us-
ing a Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA). Thin
TABLE 1 Median effective (EC50) and inhibitory (IC50) concentration of synthesized nucleoside
analogues
Anti-HIV-1
Cytotoxicity
Compound no.
EC50 (µM)c
IC50 (µM)d
19
22
21
7.9
90
80
26
54
98
29
43
0.002
0.39
98
>100
>100
AZTa
PMEAb
aAZT: azidothymidine.
bPMEA: 9-[2-(phosphonomethoxy)ethyl]adenine.
cEC50(µM): EC50 values are for 50% inhibition of virus production as indicated by supernatant RT
levels.
dIC50(µM): IC50 values indicate 50% inhibition of cell growth.

510
G. H. Shen and J. H. Hong
layer chromatography (TLC) was performed on Uniplates (silica gel) pur-
chased from Analtech Co. (7558, Newark, DE, USA). All reactions were car-
ried out under an atmosphere of nitrogen unless otherwise specified. Dry
dichloromethane (CH2Cl2), benzene, and pyridine were obtained by distilla-
tion from calcium hydride (CaH2). Dry tetrahydrofuran (THF) was obtained
by distillation from Na and benzophenone immediately prior to use.
1-(t-Butyldimethylsilanyloxymethyl)cyclopropanecarbaldehyde
(6)
To a stirred solution of oxalyl chloride (254 mg, 2.0 mmol) in CH2Cl2
(12 mL) was added a solution of dimethyl sulfoxide (DMSO) (234 mg,
3.0 mmol) in CH2Cl2 (8.0 mL) dropwise at −78◦C. The resulting solution
was stirred at −78◦C for 10 minutes, and a solution of alcohol 5 (216 mg,
1.0 mmol) in CH2Cl2 (12 mL) was added dropwise. The mixture was stirred at
−78◦C for 20 minutes and triethanolamine (TEA) (608 mg, 6.01 mmol) was
added. The resulting mixture was warmed to 0◦C and stirred for 30 minutes.
Water (H2O) (30 mL) was added, and the solution was stirred at room tem-
perature (rt) for 30 minutes. The mixture was diluted with H2O (150 mL)
and then extracted with ethyl acetate (EtOAc) 150 mL two times. The com-
bined organic layer was washed with brine, dried over anhydrous magnesium
sulfate (MgSO4), and filtered. The filtrate was concentrated under reduced
pressure and the residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:20) to give aldehyde compound 6 (199 mg, 93%) as a col-
orless oil: 1H NMR (CDCl3, 300 MHz) δ 9.79 (s, 1H), 3.99 (s, 2H), 0.75–0.63
(m, 4H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 204.2, 73.5,
25.4, 18.42, 8.7, −5.5; Anal. calcd. for C11H22O2Si: C, 61.63; H, 10.34; found:
C, 61.59; H, 10.32; MS m/z 215 (M+H)+.
t-Butyldimethyl-(1-vinyl-cyclopropylmethoxy)silane (7)
To ylide solution methyltriphenylphosphonium iodide (376 mg,
0.925 mmol), triphenylphosphine (28.5 mg, 0.11 mmol), 1.6 M
n-butyllithium solution (0.578 mL, 0.925 mmol) in dry THF (7.0 mL) at
−78◦C was dropwise added to a solution of olefin 6 (198 mg, 0.925 mmol)
in dry THF (7 mL). The reaction mixture was warmed to rt and stirred for
5 hours, quenched by saturated sodium bicarbonate (NaHCO3) solution.
The reaction mixture was partitioned between saturated NaHCO3 solution
and EtOAc. The organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined extracts were dried over anhydrous
sodium sulfate, filtered, concentrated in vacuum, and chromatographed
(hexane-EtOAc, 20:1) to afford compound 7 (161 mg, 82%) as a colorless
oil. 1H NMR (CDCl3, 300 MHz) δ 5.34 (m, 1H), 5.05–4.96 (m, 2H), 3.75 (m,

2 ꢁ-Spirocyclopropyl-5ꢁ-Deoxyphosphonic Acid Analogues
511
2H), 1.02–0.94 (m, 2H), 0.82 (s, 9H), 0.35–0.31 (m, 2H), 0.02 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 148.8, 109.3, 77.6, 25.5, 24.8, 18.4, 6.4, −5.3; Anal.
calcd. for C12H24OSi: C, 67.86; H, 11.39; found: C, 67.82; H, 11.37; MS m/z
213 (M+H)+.
2-[1-(t-Butyldimethylsilanyloxymethyl)cyclopropyl]ethanol (8)
Anhydrous THF solution of 1 M borane/THF complex (11.1 mL,
11.1 mmol) was stirred at 0◦C under a nitrogen atmosphere and was treated
dropwise with compound 7 (1.0 g, 4.715 mmol) in THF (10 mL). The solu-
tion was stirred at rt for 2.5 hours. After cooling, the mixture was subsequently
treated with THF/H2O (8.5 mL, 1:1, v/v), 2 N sodium hydroxide (NaOH)
(8.85 mL), and 30% hydrogen peroxide (H2O2) (7.35 mL). The turbid mix-
ture was stirred at rt for 2 hours. Diethylether (50 mL) was added to the
reaction mixture, which was then washed twice with ice/water (15 mL) and
saturated sodium chloride (NaCl) solution (15 mL). After drying over anhy-
drous MgSO4, the solvents were evaporated and the residue was purified by
silica gel column chromatography (EtOAc/hexane, 1:10) to give compound
1
8 (738 mg, 68%) as a colorless oil. H NMR (CDCl3, 300 MHz) δ 3.72 (m,
2H), 3.49 (t, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 2H), 0.94–0.90 (m, 2H),
0.81 (s, 9H), 0.37–0.32 (m, 2H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
77.5, 59.1, 41.3, 25.6, 18.7, 17.3, 6.1, −5.5; Anal. calcd. for C12H26O2Si (+0.5
EtOAc): C, 61.26; H, 11.02; found: C, 61.28; H, 11.03; MS m/z 231 (M+H)+.
[1-(t-Butyldimethylsilanyloxymethyl)cyclopropyl]acetaldehyde (9)
Aldehyde 9 was synthesized from compound 8 using the similar Swern ox-
idation conditions described for compound 6. Yield 91%; 1H NMR (CDCl3,
300 MHz) δ 9.81 (s, 1H), 3.73 (m, 2H), 2.36 (s, 2H), 1.01–0.94 (m, 2H), 0.82
(s, 9H), 0.35–0.30 (m, 2H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 199.7,
78.2, 53.4, 25.3, 18.2, 15.8, 7.2, −5.3; Anal. calcd. for C12H24O2Si: C, 63.10;
H, 10.59; found: C, 63.09; H, 10.61; MS m/z 229 (M+H)+.
( )-1-[1-(t-Butyldimethylsilanyloxymethyl)cyclopropyl]but-3-en-2-
ol (10)
To a solution of compound 9 (1.1 g, 4.8 mmol) in dry THF (10 mL), vinyl
magnesium bromide (5.28 mL, 1.0 M solution in THF) was slowly added
at −30◦C and stirred for 5 hours at 0◦C. Saturated ammonium chloride
(NH4Cl) solution (6 mL) was added to the mixture, which was slowly warmed
to rt. The mixture was diluted with H2O (80 mL) and extracted with EtOAc
(80 mL) two times. The combined organic layer was washed with brine, dried
over anhydrous MgSO4, filtered, and evaporated in vacuo. The residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:13) to give

512
G. H. Shen and J. H. Hong
compound 10 (935 mg, 76%) as a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ 5.91–5.89 (m, 1H), 5.25–5.22 (m, 2H), 3.92 (m, 1H), 3.73 (s, 2H), 1.43
(m, 1H), 1.11–1.05 (m, 2H), 0.82–0.79 (s, 11H), 0.36–0.32 (m, 1H), 0.02
(s, 6H); 13C NMR (CDCl3, 75 MHz) δ 141.3, 114.6, 80.1, 71.5, 45.7, 25.3,
18.6, 16.1, 6.9, −5.6; Anal. calcd. for C14H28O2Si (+0.5 EtOAc): C, 63.95; H,
10.73; found: C, 63.98; H, 10.72; MS m/z 257 (M+H)+.
( )-t-Butyl-{1-[2-(4-methoxybenzyloxy)-but-3-enyl]cyclopropyl
methoxy}dimethylsilane (11)
Sodium hydride (NaH) (60% in mineral oil, 78.6 mg, 1.99 mmol)
was added portionwise to a cooled (0◦C) solution of alcohol 10 (426 mg,
1.662 mmol) and PMBCl (0.246 mL, 1.82 mmol) in anhydrous DMF (10 mL).
The reaction mixture was stirred overnight at rt. The solvent was removed
in vacuo and the residue was diluted with H2O (80 mL) followed by ex-
traction with diethyl ether (80 mL) two times. The combined organic layer
was washed with brine, dried over anhydrous MgSO4, and concentrated un-
der vacuum. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:15) to give compound 11 (419 mg, 67%) as a colorless
oil. 1H NMR (CDCl3, 300 MHz) δ 7.28–7.22 (m, 2H), 6.91–6.85 (m, 2H), 5.91
(m, 1H), 5.25–5.21 (m, 2H), 4.64 (s, 2H), 3.73 (s, 3H), 3.70–3.66 (m, 2H),
3.54 (m, 1H), 1.40 (m, 2H), 1.15–1.10 (m, 1H), 0.82 (s, 9H), 0.67–0.63 (m,
2H), 0.35–0.31 (m, 1H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 159.7,
141.5, 133.3, 127.6, 121.4, 115.8, 114.5, 80.4, 73.5, 46.2, 25.5, 18.5, 16.2, 7.3,
−5.4; Anal. calcd. for C22H36O3Si: C, 70.16; H, 9.63; found: C, 70.19; H, 9.65;
MS m/z 377 (M+H)+.
( )-{1-[2-(4-Methoxybenzyloxy)-but-3-enyl]cyclopropyl}methanol
(12)
To a solution of compound 11 (1.63 g, 4.33 mmol) in THF (15 mL),
TBAF (5.11 mL, 1.0 M solution in THF) was added at 0◦C. The mixture
was stirred overnight at rt and concentrated in vacuum. The residue was
purified by silica gel column chromatography (hexane/EtOAc, 4:1) to give
compound 12 (920 mg, 81%): 1H NMR (CDCl3, 300 MHz) δ 7.33–7.24 (m,
2H), 6.94–6.86 (m, 2H), 5.91–5.86 (m, 1H), 5.25–5.20 (m, 2H), 4.63 (s,
2H), 3.74 (s, 3H), 3.58–3.51 (m, 3H), 1.40 (m, 2H), 1.07–1.02 (m, 1H),
0.43–0.38 (m, 2H), 0.19–0.15 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 159.4,
141.7, 132.4, 127.9, 118.1, 115.0, 77.2, 74.1, 73.4, 56.0, 45.3, 13.5, 6.5; Anal.
calcd. for C16H22O3: C, 73.25; H, 8.45; found: C, 73.29; H, 8.42; MS m/z 263
(M+H)+.

2 ꢀ-Spirocyclopropyl-5ꢀ-Deoxyphosphonic Acid Analogues
513
( )-1-[2-(4-Methoxy-benzyloxy)-but-3-enyl]cyclopropanecarbal
dehyde (13)
Aldehyde derivative 13 was synthesized from compound 12 by the similar
Swern oxidation procedure as described for compound 6 or 9: yield 88%;
1H NMR (CDCl3, 300 MHz) δ 9.87 (s, 1H), 7.31–7.24 (m, 2H), 6.91–6.85
(m, 2H), 5.90–5.88 (m, 1H), 5.24–5.19 (m, 2H), 4.65 (s, 2H), 3.74 (s, 3H),
3.54 (m, 1H), 1.73–1.70 (m, 2H), 1.11–1.05 (m, 1H), 0.69–0.63 (m, 2H),
0.32–0.27 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 200.7, 159.3, 141.1, 130.7,
129.3, 117.0, 114.2, 74.2, 73.3, 55.4, 41.3, 29.1, 13.6, 7.1; Anal. calcd. for
C16H20O3: C, 73.82; H, 7.74; found: C, 73.79; H, 7.76; MS m/z 261 (M+H)+.
(rel)-(1R,4S) and (1S,4S)-4-Vinyl-2-spirocyclopropyl-tetrahydro
furan-1-ol (14)
To a solution of compound 13 (80.9 mg, 0.311 mmol) in CH2Cl2/H2O
(6 mL, 10:1 v/v) was added DDQ (70.6 mg, 0.311 mmol), and the mixture was
stirred overnight at rt. Saturated NaHCO3 (0.4 mL) was added to quench
the reaction, which was then stirred for 3 hours at rt. The mixture was
diluted with H2O (60 mL) and extracted with CH2Cl2 (3 × 60 mL). The
combined organic layer was dried over anhydrous MgSO4 and filtered. The
filtrate was concentrated in vacuum and the residue was purified by silica
gel column chromatography (EtOAc/hexane, 1:3) to give compound 14
(27 mg, 63%): 1H NMR (DMSO-d6, 300 MHz) δ 5.92–5.88 (m, 1H), 5.47 (m,
1H), 5.25–5.22 (m, 2H), 4.45–4.41 (m, 1H), 1.78–1.75 (m, 2H), 1.09–1.02
(m, 1H), 0.70–0.63 (m, 2H), 0.33–0.26 (m, 1H).
( )-Acetic acid (4-vinyl-2-spirocyclopropyl-tetrahydrofuran-1-yl)
ester (15)
To a solution of compound 14 (450 mg, 3.21 mmol) and 4-
dimethylaminopyridine (DMAP) (20 mg) in anhydrous pyridine (8 mL),
acetic anhydride (Ac2O) (491 mg, 4.81 mmol) was slowly added, and the
mixture was stirred overnight under nitrogen. The pyridine was evapo-
rated under reduced pressure and co-evaporated with toluene. The residue
was diluted with H2O (100 mL), extracted with EtOAc (100 mL), dried
over MgSO4, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:20) to give compound 9 (503 mg, 86%) as a colorless oil:
1H NMR (DMSO-d6, 300 MHz) δ 6.18 (d, J = 4.2 Hz, 1H), 5.91–5.86 (m,
1H), 5.26–5.22 (m, 2H), 4.46–4.42 (m, 1H), 2.02 (s, 3H), 1.79–1.74 (m, 2H),
1.10–1.02 (m, 1H), 0.69–0.62 (m, 2H), 0.35–0.28 (m, 1H).

514
G. H. Shen and J. H. Hong
(rel)-(1ꢀS,4ꢀS)-9-(4ꢀ-Vinyl-2ꢀ-spirocyclopropyl-tetrahydrofuran-1ꢀ-yl)
6-chloropurine (16a) and (rel)-(1ꢀR,4ꢀS)-9-(4ꢀ-vinyl-2ꢀ-spirocyclo
propyl-tetrahydrofuran-1ꢀ-yl)6-chloropurine (16b)
6-Chloropurine (216 mg, 1.4 mmol), anhydrous hexamethyldisilazane
(HMDS) (10 mL), and a catalytic amount of ammonium sulfate (14 mg)
were refluxed to a clear solution, and the solvent was distilled under anhy-
drous conditions. The residue was dissolved in anhydrous 1,2-dichloroethane
(8 mL). To this mixture, a solution of compound 15 (255 mg, 0.6 mmol)
in dry DCE (10 mL) and TMSOTf (311 mg, 1.4 mmol) was added, and the
resulting mixture was stirred for 12 hours at rt. The reaction mixture was
quenched with 5.0 mL of saturated NaHCO3 and stirred for 1 hour. The re-
sulting solid was filtered through a Celite pad, and the filtrate was extracted
with CH2Cl2 (80 mL) two times. The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under vacuum. The residue
was purified by silica gel column chromatography (EtOAc/hexane/MeOH,
4:1:0.01) to give compound 16a (52 mg, 32%) and 16b (54 mg, 33%): data
1
for 16a: H NMR (CDCl3, 300 MHz) δ 8.71 (s, 1H), 8.37 (s, 1H), 5.95 (d,
J = 1.8 Hz, 1H), 5.88 (m, 1H), 5.26–5.23 (m, 2H), 4.46 (m, 1H), 1.82 (dd,
J = 10.8, 6.8 Hz, 1H), 1.70 (dd, J = 10.9, 8.2 Hz, 1H), 1.08–1.02 (m, 1H),
0.71–0.65 (m, 2H), 0.38–0.32 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 151.7,
151.4, 151.0, 144.4, 141.4, 131.7, 114.5, 98.5, 73.5, 41.2, 26.4, 14.3, 7.1; Anal.
calcd. for C13H13ClN4O (+0.5 MeOH): C, 55.01; H, 5.13; N, 19.01; found:
1
C, 54.98; H, 5.14; N, 18.99; MS m/z 277 (M+H)+. Data for 16b: H NMR
(CDCl3, 300 MHz) δ 8.73 (s, 1H), 8.38 (s, 1H), 5.95 (d, J = 1.9 Hz, 1H),
5.88 (m, 1H), 5.25–5.21 (m, 2H), 4.45 (m, 1H), 1.84 (dd, J = 10.6, 7.6 Hz,
1H), 1.70 (dd, J = 10.7, 8.0 Hz, 1H), 1.10–1.04 (m, 1H), 0.69–0.62 (m,
2H), 0.36–0.31 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 151.5, 151.0, 150.7,
144.1, 141.2, 131.3, 114.1, 97.1, 74.2, 43.5, 27.8, 13.8, 6.5; Anal. calcd. for
C13H13ClN4O: C, 56.42; H, 4.74; N, 20.25; found: C, 56.37; H, 4.76; N, 20.22;
MS m/z 277 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4ꢀ-vinyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)6-chloropurine}phosphonate (17)
To a CH2Cl2 (4.0 mL) solution of 6-chloropurine derivative 16b
(150 mg, 0.542 mmol) and diethyl vinylphosphonate (355 mg, 2.168 mmol),
2nd-generation Grubbs catalyst (18.42 mg, 0.0217 mmol) was added. The
reaction mixture was refluxed for 24 hours under dry argon (Ar) gas and
concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc/n-Hexane/MeOH, 4:1:0.02) to give com-
1
pound 17 (136 mg, 61%) as a form: H NMR (CDCl3, 300 MHz) δ 8.74 (s,
1H), 8.34 (s, 1H), 6.68 (dd, J = 17.0, 22.4 Hz, 1H), 6.12 (dd, J = 17.1, 19.4.
Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 4.49 (m, 1H), 4.12–4.06 (m, 4H), 1.85

2 ꢀ-Spirocyclopropyl-5ꢀ-Deoxyphosphonic Acid Analogues
515
(dd, J = 10.6, 6.8 Hz, 1H), 1.72 (d, J = 10.6, 8.2 Hz, 1H), 1.32 (m, 6H),
1.09–1.04 (m, 1H), 0.71–0.65 (m, 2H), 0.31–0.24 (m, 1H); 13C NMR (CDCl3,
75 MHz) δ 151.6, 151.4, 151.1, 149.6, 145.6, 132.3, 116.7, 97.2, 74.6, 63.8,
63.3, 41.7, 24.7, 15.2, 13.2, 7.2; Anal. calcd. for C17H22ClN4O4P: C, 48.59; H,
5.89; N, 12.59; found: C, 48.61; H, 5.91; N, 12.57; MS m/z 413 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4ꢀ-vinyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)adenine}phosphonate (18)
A solution of compound 17 (166 mg, 0.4 mmol) in saturated methano-
lic ammonia (7 mL) was stirred overnight at 64◦C in a steel bomb, and the
volatiles were evaporated. The residue was purified by silica gel column chro-
matography (MeOH/CH2Cl2, 1:10) to give compound 18 (92 mg, 59%) as a
white solid: mp 179–181◦C; UV (MeOH) λmax 260.5 nm; 1H NMR (DMSO-d6,
300 MHz) δ 8.38 (s, 1H), 8.16 (s, 1H), 6.65 (dd, J = 17.0, 21.8 Hz, 1H), 6.15
(dd, J = 17.0, 19.0. Hz, 1H), 5.94 (d, J = 2.1 Hz, 1H), 4.40 (m, 1H), 4.13–4.05
(m, 4H), 1.82 (dd, J = 10.8, 6.8 Hz, 1H), 1.70 (d, J = 10.7, 8.6 Hz, 1H),
1.37 (m, 6H), 1.11–1.07 (m, 1H), 0.64–0.60 (m, 2H), 0.27–0.22 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 155.3, 152.6, 150.4, 148.8, 141.7, 119.2, 116.8, 96.9,
73.8, 62.8, 62.4, 42.4, 25.8, 16.7, 12.9, 6.6; Anal. calcd. for C17H24N5O4P:
C, 51.90; H, 6.15; N, 17.80; found: C, 51.91; H, 6.12; N, 17.83; MS m/z 394
(M+H)+.
(rel)-(1ꢀR,4ꢀS)-9-(4ꢀ-Vinyl-2ꢀ-spirocyclopropyl-tetrahydrofuran-1ꢀ-
yl)adenine}phosphonic acid (19)
To a solution of the phosphonate 18 (165 mg, 0.419 mmol) in an-
hydrous CH3CN (10 mL) and 2,6-lutidine (0.898 mL, 8.38 mmol) was
added trimethylsilyl bromide (641 mg, 4.19 mmol). The mixture was heated
overnight at 75◦C under nitrogen gas and then concentrated in vacuo.
The residue was partitioned between CH2Cl2 (100 mL) and purified H2O
(100 mL). The aqueous layer was washed with CH2Cl2 (2 × 70 mL) and then
freeze-dried to give phosphonic acid 19 (107 mg, 76%) as a yellowish foam:
UV (H2O) λmax 261.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.33 (s, 1H),
8.16 (s, 1H), 6.64 (dd, J = 17.0, 21.8 Hz, 1H), 6.17 (dd, J = 17.2, 18.6 Hz,
1H), 5.97 (dd, J = 2.0 Hz, 1H), 4.47 (m, 1H), 1.85 (dd, J = 10.6, 6.8 Hz, 1H),
1.67 (dd, 10.6, 8.2 Hz, 1H), 1.13–1.08 (m, 1H), 0.66–0.61 (m, 2H), 0.31–0.27
(m, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 155.5, 152.4, 150.5, 149.5, 141.6,
120.1, 116.3, 98.6, 74.5, 41.3, 25.7, 13.2, 7.1; Anal. calcd. for C13H16N5O4P
(+2.0 H2O): C, 41.82; H, 5.40; N, 18.76; found: C, 41.79; H, 5.38; N, 18.74;
MS m/z 338 (M+H)+.

516
G. H. Shen and J. H. Hong
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4ꢀ-ethyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)6-chloropurine}phosphonate (20)
A solution of vinyl phosphonate nucleoside analogue 17 (225 mg,
0.546 mmol) in methanol (6 mL) was added to 10% Pd/C (8 mg) and cyclo-
hexene (3 mL) under Ar. The reaction mixture was refluxed for 20 hours.
The reaction mixture was filtered through a pad of Celite, evaporated, and
purified by silica gel column chromatography using methanol and methy-
lene chloride (10:1) to give ethyl phosphonate analogue 20 (172 mg, 76%)
as a white solid: mp 174–176◦C; 1H NMR (CDCl3, 300 MHz) δ 8.74 (s, 1H),
8.33 (s, 1H), 5.92 (d, J = 1.9 Hz, 1H), 4.16–4.11 (m, 4H), 3.74 (m, 1H),
2.21–2.12 (m, 4H), 1.63 (m, 6H), 1.09–1.04 (m, 1H), 0.62–0.57 (m, 2H),
0.29–0.23 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 151.7, 151.5, 151.1, 145.1,
132.4, 98.4, 71.5, 62.9, 62.4, 42.0, 25.3, 19.4, 14.2, 13.1, 7.3; Anal. calcd. for
C17H24ClN4O4P (+1.0 MeOH): C, 48.38; H, 6.31; N, 12.54; found: C, 48.41;
H, 6.29; N, 12.53; MS m/z 415 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4ꢀ-ethyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)adenine}phosphonate (21)
Adenine derivative 21 was prepared from 6-chloropurine analogue 20 by
the similar ammonolysis procedure as described for compound 18: yield
54%; mp 172–174◦C; UV (MeOH) λmax 261.5 nm; 1H NMR (DMSO-d6,
300 MHz) δ 8.34 (s, 1H), 8.13 (s, 1H), 5.91 (d, J = 2.1 Hz, 1H), 4.12–4.07
(m, 4H), 3.76 (m, 1H), 2.18–2.12 (m, 4H), 1.60–1.55 (m, 6H), 1.11–1.07 (m,
1H), 0.65–0.59 (m, 2H), 0.34–0.27 (m, 1H); 13C NMR (DMSO-d6, 75 MHz) δ
155.6, 152.5, 151.4, 141.5, 120.1, 99.1, 72.6, 63.2, 62.8, 41.7, 24.8, 19.1, 15.4,
14.3, 6.8; Anal. calcd. for C17H26N5O4P: C, 51.64; H, 6.63; N, 17.71; found:
C, 51.61; H, 6.64; N, 17.68; MS m/z 396 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-{9-(4ꢀ-Ethyl-2ꢀ-spirocyclopropyl-tetrahydrofuran-1ꢀ-
yl)adenine}phosphonic acid (22)
Phosphonic acid 22 was synthesized from compound 21 using the similar
hydrolysis condition as described for compound 19: yield 78%, UV (H2O)
λmax 261.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.34 (s, 1H), 8.15 (s, 1H),
5.92 (s, 1H), 3.75 (m, 1H), 2.12–2.07 (m, 4H), 1.12–1.08 (m, 1H), 0.67–0.59
(m, 2H), 0.36–0.31 (m, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 155.3, 152.5,
150.6, 141.7, 119.4, 97.8, 72.5, 41.5, 28.4, 25.3, 19.1, 13.7, 7.2; Anal. calcd.
for C13H18N5O4P (+1.0 H2O): C, 43.69; H, 5.64; N, 19.60; found: C, 43.69;
H, 5.66; N, 19.62; MS m/z 340 (M+H)+.

2 ꢁ-Spirocyclopropyl-5ꢁ-Deoxyphosphonic Acid Analogues
517
(rel)-(1ꢀS,4ꢀS)-(4ꢀ-Vinyl-2ꢀ-spirocyclopropyl-tetrahydrofuran-1ꢀ-yl)2-
fluoro-6-chloropurine (23a) and (rel)-(1ꢀR,4ꢀS)-(4ꢀ-vinyl-2ꢀ-spiro
cyclopropyl-tetrahydrofuran-1ꢀ-yl)2-fluoro-6-chloropurine (23b)
Condensation of compound 15 with 2-fluoro-6-chloropurine under the
similar Vorbruggen condensation conditions as described for compounds
16a and 16b to give compounds 23a and 23b, respectively: data for 23a: yield
31%; UV (MeOH) λmax 268.0 nm; 1H NMR (CDCl3, 300 MHz) δ 8.48 (s,
1H), 5.96 (s, 1H), 5.88 (m, 1H), 5.25–5.22 (m, 2H), 4.45 (m, 1H), 1.85 (dd,
J = 10.6, 8.6 Hz, 1H), 1.71 (dd, J = 10.5, 6.4 Hz, 1H), 1.14–1.09 (m, 1H),
0.69–0.64 (m, 2H), 0.32–0.21 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 154.7,
152.1, 149.3, 147.7, 144.6, 141.2, 128.4, 115.2, 98.5, 72.5, 41.2, 25.3, 13.6, 7.8;
Anal. calcd. for C13H12ClFN4O (+0.5 MeOH): C, 52.18; H, 4.54; N, 18.03;
found: C, 52.21; H, 4.56; N, 18.01; MS m/z 295 (M+H)+. Data for 23b: yield
30%; UV (MeOH) λmax 269.5 nm; 1H NMR (CDCl3, 300 MHz) δ 8.45 (s, 1H),
5.95 (d, J = 2.2 Hz, 1H), 5.84 (m, 1H), 5.26–5.21 (m, 2H), 4.47 (m, 1H),
1.86 (dd, J = 10.5, 6.2 Hz, 1H), 1.78 (dd, J = 10.6, 8.8 Hz, 1H), 1.09–1.02
(m, 1H), 0.66–0.60 (m, 2H), 0.29–0.22; 13C NMR (CDCl3, 75 MHz) δ 154.4,
151.8, 148.9, 147.2, 143.8, 140.7, 128.5, 114.8, 99.2, 73.3, 40.9, 24.8, 14.2, 6.9;
Anal. calcd. for C13H12ClFN4O: C, 52.98; H, 4.10; N, 19.01; found: C, 52.95;
H, 4.08; N, 19.02; MS m/z 295 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4ꢀ-vinyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)2-fluoro-6-chloropurine}phosphonate (24)
Phosphonate nucleoside analogue 24 was prepared from compound 23b
using the similar cross-metathesis procedure as described for compound 17:
1
yield 61%; H NMR (CDCl3, 300 MHz) δ 8.46 (s, 1H), 6.69 (dd, J = 21.4,
17.0 Hz, 1H), 6.22 (dd, J = 19.2, 17.1 Hz, 1H), 5.98 (d, J = 2.1 Hz, 1H),
4.14–4.09 (m, 4H), 1.84 (dd, J = 10.6, 8.4 Hz, 1H), 1.71 (dd, J = 10.7,
6.6 Hz, 1H), 1.34 (m, 6H), 1.08–0.99 (m, 1H), 0.59–0.52 (m, 2H), 0.28–0.23
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 154.8, 152.4, 149.2, 144.7, 130.4, 115.8,
98.2, 74.7, 62.9, 62.5, 41.2, 21.8, 13.7, 7.5; Anal. calcd. for C17H21ClFN4O4P
(+1.0 MeOH): C, 46.71; H, 5.44; N, 12.10; found: C, 46.69; H, 4.45; N, 12.09;
MS m/z 431(M+H)+.
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4ꢀ-vinyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)2-fluoro-6-aminopurine}phosphonate (25a) and
(rel)-(1ꢀR,4ꢀS)-diethyl{9-(4ꢀ-vinyl-2ꢀ-spirocyclopropyl-tetrahydro
furan-1ꢀ-yl)2-amino-6-chloropurine}phosphonate (25b)
Dry ammonia gas was bubbled into a stirred solution of compound 24
(210 mg, 0.487 mmol) in dimethyl ether (DME) (8.5 mL) overnight at rt.
The salts were removed by filtration and the filtrate was concentrated under

518
G. H. Shen and J. H. Hong
reduced pressure. The residue was purified by silica gel column chromatog-
raphy (MeOH/CH2Cl2, 1:10) to give compounds 25a (34 mg, 17%) and 25b
(93 mg, 45%), respectively: data for 25a: UV (MeOH) λmax 260.5 nm; 1H
NMR (DMSO-d6, 300 MHz) δ 8.19 (s, 1H), 7.75 (br s, NH2, 2H), 6.67 (dd, J
= 20.8, 17.2 Hz, 1H), 6.24 (dd, J = 20.8, 17.1 Hz, 1H), 5.92 (d, J = 2.0 Hz,
1H), 4.14–4.08 (m, 4H), 1.69 (s, 6H), 1.06–0.95 (m, 1H), 0.62–0.54 (m, 2H),
0.30–0.23 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 155.5, 152.2, 148.8, 147.2,
142.5, 124.7, 117.5, 97.6, 74.2, 63.5, 62.9, 62.4, 40.9, 25.3, 13.9, 8.0; Anal.
calcd. for C17H23FN5O4P (+0.5 MeOH): C, 49.18; H, 5.89; N, 16.38; found:
C, 49.21; H, 5.91; N, 16.36; MS m/z 412 (M+H)+. Data for 25b: UV (MeOH)
λmax 308.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.12 (s, 1H), 7.67 (br s,
NH2, 2H), 6.70 (dd, J = 21.6, 16.9 Hz, 1H), 6.22 (dd, J = 17.0, 21.5 Hz,
1H), 5.96 (d, J = 1.8 Hz, 1H), 4.15–4.06 (m, 4H), 3.75 (d, J = 6.9 Hz, 1H),
3.62 (d, J = 6.8 Hz, 1H), 2.31 (dd, J = 6.4, 10.6 Hz, 1H), 2.19–2.11 (m, 1H),
1.71 (m, 6H), 1.11–1.06 (m, 1H), 0.67–0.59 (m, 2H), 0.34–0.29 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 158.5, 154.3, 151.2, 149.5, 141.6, 124.5, 117.5, 97.7,
73.6, 63.2, 62.8, 41.6, 24.7, 14.2, 7.6; Anal. calcd. for C17H23ClN5O4P (+1.0
MeOH): C, 47.01; H, 5.92; N, 15.23; found: C, 47.04; H, 5.90; N, 15.21; MS
m/z 428 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-9-{(4ꢀ-Vinyl-2ꢀ-spirocyclopropyl-tetrahydrofuran-1ꢀ-
yl)guanine}phosphonic acid (26)
To a solution of compound 25 (135 mg, 0.316 mmol) dry CH3CN
(13 mL) was added trimethylsilyl bromide (0.0728 mL, 5.52 mmol) at rt.
After this mixture was stirred for 24 hours, the solvent was removed, and co-
evaporated three times with methanol. The residue was dissolved in MeOH
(13.0 mL) and 2-mercaptoethanol (86.4 µL, 1.266 mmol) and methoxides
(NaOMe) (67.2 mg, 1.266 mmol) was added to the mixture. The mixture
was refluxed for 12 hours under N2, cooled, neutralized with glacial acetic
acid (AcOH), and evaporated to dryness under vacuum. The residue was
purified by chromatography on a column of preparative reversed-phase C18
silica gel eluting H2O to give compound 25 (34.5 mg, 64%) as a yellowish
form. UV (H2O) λmax 254.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ 10.6 (br
s, NH, 1H), 8.12 (s, 1H), 7.05 (br s, NH2, 2H), 6.65 (dd, J = 20.4, 17.6 Hz,
1H), 6.14 (dd, J = 19.3, 17.6 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H), 1.82 (dd,
J = 6.8, 10.4 Hz, 1H), 1.74 (dd, J = 8.6, 10.4 Hz, 1H), 1.12–1.05 (s, 1H),
0.67–0.61 (m, 2H), 0.32–0.27 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 157.6,
154.5, 152.5, 148.9, 136.5, 117.5, 114.7, 98.5, 75.4, 63.4, 62.8, 41.7, 25.3, 13.1,
7.9; Anal. calcd. for C13H16N5O5P (+1.0 H2O): C, 42.05; H, 4.88; N, 18.86;
found: C, 42.08; H, 4.90; N, 18.85; MS m/z 354 (M+H)+.

2 ꢁ-Spirocyclopropyl-5ꢁ-Deoxyphosphonic Acid Analogues
519
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4-ethyl-tetrahydrofuran-1-yl)2-fluoro-6-
chloropurine}phosphonate (27)
Compound 27 was synthesized from compound 24 by the similar transfer
catalytic hydrogenation procedure as described for compound 20: yield 66%;
1H NMR (CDCl3, 300 MHz) δ 8.41 (s, 1H), 5.95 (d, J = 2.0 Hz, 1H), 4.15–4.11
(m, 4H), 3.77 (s, 1H), 2.24–2.17 (m, 4H), 1.11–1.05 (m, 1H), 0.61–0.55 (m,
2H), 0.31–0.27 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 154.7, 152.1, 147.5,
144.6, 127.9, 98.3, 70.4, 63.6, 62.1, 41.7, 28.7, 25.5, 19.1, 13.9, 6.6; Anal. calcd.
for C17H23ClFN4O4P (+1.0 MeOH): C, 46.51; H, 5.85; N, 12.05; found: C,
46.49; H, 5.84; N, 12.02; MS m/z 433 (M+H)+.
(rel)-(1ꢀR,4ꢀS)-Diethyl{9-(4-ethyl-tetrahydrofuran-1-yl)2-fluoro-6-
aminopurine}phosphonate (28a) and (rel)-(1ꢀR,4ꢀS)-diethyl
{9-(4-ethyl-tetrahydrofuran-1-yl)2-amino-6-chloropurine}
phosphonate (28b)
Ammonolysis of compound 27 using the same procedure described for
compound 25a gave 28a and 28b, respectively: data for 28a: yield 15%; UV
(MeOH) λmax 261.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.18 (s, 1H), 7.76
(br s, NH2, 2H, D2O exchangeable), 5.98 (d, J = 2.2 Hz, 1H), 3.75 (m,
1H), 2.54–2.44 (m, 4H), 1.63 (dd, J = 8.0, 10.6 Hz, 1H), 1.52 (dd, J =
6.0, 10.7 Hz, 1H), 1.42 (m, 6H), 0.99–0.92 (m, 1H), 0.54–0.47 (m, 2H),
0.21–0.16 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 154.8, 152.0, 147.1, 142.8,
124.3, 97.5, 72.1, 63.2, 62.5, 61.9, 43.0, 29.5, 24.6, 18.5, 13.5, 8.1; Anal. calcd.
for C17H25FN5O4P (+1.0 MeOH): C, 48.53; H, 6.56; N, 15.72; found: C,
48.55; H, 6.55; N, 15.70; MS m/z 414 (M+H)+. Data for 28b: yield 41%;
UV (MeOH) λmax 307.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (s, 1H),
7.68 (br s, NH2, 2H, D2O exchangeable), 5.96 (d, J = 2.1 Hz, 1H), 3.77
(m, 1H), 2.36–2.30 (m, 4H), 1.70 (dd, J = 8.5, 10.7 Hz, 1H), 1.54 (dd, J =
6.2 Hz, 10.6 Hz, 1H), 1.35 (m, 6H), 1.02–0.91 (m, 1H), 0.56–0.48 (m, 2H),
0.22–0.18 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 157.8, 153.2, 150.6, 143.5,
124.8, 98.5, 77.7, 63.2, 62.6, 42.1, 29.4, 24.7, 18.8, 13.1, 7.4; Anal. calcd. for
C17H25ClN5O4P (+1.0 MeOH): C, 46.80; H, 6.33; N, 15.16; found: C, 46.80;
H, 6.35; N, 15.14; MS m/z 430.
(rel)-(1ꢀR,4ꢀS)-9-{(4-Ethyl-tetrahydrofuran-1-yl)guanine}
phosphonic acid (29)
Nucleoside phosphonic acid 29 was synthesized by the hydrolysis condi-
tions used for compound 26. Yield 56%; UV (H2O) λmax 253.5 nm; 1H NMR
(DMSO-d6, 300 MHz) δ 10.5 (br s, NH, H, D2O exchangeable), 8.07 (s, 1H),
7.01 (br s, NH2, 2H, D2O exchangeable), 5.95 (d, J = 2.4 Hz, 1H), 3.76 (m,
1H), 2.30–2.23 (m, 4H), 1.67 (dd, J = 8.2, 10.6 Hz, 1H), 1.52 (dd, J = 6.6,
10.5 Hz, 1H), 0.98–0.90 (m, 1H), 0.48–0.41 (m, 2H), 0.24–0.19 (m, 1H); 13C

520
G. H. Shen and J. H. Hong
NMR (CDCl3, 75 MHz) δ 157.5, 154.3, 152.1, 136.7, 118.0, 96.2, 74.3, 63.4,
62.9, 42.5, 28.7, 25.2, 19.0, 14.3, 7.6; Anal. calcd. for C13H18N5O5P (+2.0
H2O): C, 39.90; H, 5.66; N, 17.89; found: C, 39.88; H, 5.68; N, 17.91; MS m/z
356 (M+H)+.
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