Synthesis of novel 4′-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues

Article abstract of DOI:10.1080/15257770.2010.535802

Novel 4′-cyclopropyl-5′-norcarbocyclic adenosine phosphonic acid analogues were designed and racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using triple Grignard addition and ring-closing metathesis (RCM) as

Full text of DOI:10.1080/15257770.2010.535802

Nucleosides, Nucleotides and Nucleic Acids, 29:905–919, 2010
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2010.535802
SYNTHESIS OF NOVEL 4ꢀ-CYCLOPROPYL-5ꢀ-NORCARBOCYCLIC
ADENOSINE PHOSPHONIC ACID ANALOGUES
Guang Huan Shen and Joon Hee Hong
BK-21 Project Team, College of Pharmacy, Chosun University, Kwangju, Republic of Korea
Novel 4ꢁ-cyclopropyl-5ꢁ-norcarbocyclic adenosine phosphonic acid analogues were designed and
2
racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using
triple Grignard addition and ring-closing metathesis (RCM) as key reactions. To improve cellular
permeability and enhance the anti-HIV activity of this phosphonic acid, SATE phosphonodiester
nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 17,
18, 19, 21, and 23 were subjected to antiviral screening against HIV-1. Compound 23 exhibits
enhanced anti-HIV activity than its parent nucleoside phosphonic acid 18.
Keywords anti-HIV agents; 4ꢁ-cyclopropane branched nucleoside; phosphonic acid nu-
cleosides
INTRODUCTION
Several branched nucleosides[1] have been synthesized and evaluated as
potent antiviral agents. Among them, 4ꢁ-vinyl-d4T (1)[2] and 4ꢁ-ethynyl-d4T
(2),[2] which have an additional double or triple bond at the 4ꢁ-position, were
reported to have potent anti-HIV activities (Figure 1). Molecular modeling
studies demonstrated the presence of a hydrophobic 4ꢁ-pocket that could
accommodate these substitutions and contribute to the observed enhance-
ment in potency in anti-HIV activity.[3]
Recently, 4ꢁ-branched-5ꢁ-norcarbocyclic phosphonic acid analogues,
such as 4ꢁ-vinyl-cpAP (3)[3] and 4ꢁ-ethynyl-cpAP (4),[3] have encouraged the
search for novel nucleosides as potential anti-HIV agents among this class of
compounds.[4] The phosphonate has certain advantages over its phosphate
counterpart as it is metabolically stable because its phosphorus-carbon bond
is not susceptible to hydrolytic cleavage.[5] The spatial location of the oxygen
atom, namely the β-position from the phosphorus atom in the nucleoside
analogue, plays a critical role in the antiviral activity. This increased antiviral
Received 16 August 2010; accepted 26 October 2010.
Address correspondence to Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
905

906
G. H. Shen and J. H. Hong
O
N
O
CH3
CH3
HN
HN
O
HO
N
O
HO
O
O
4'-ethynyl-d4T (2)
4'-vinyl-d4T(1)
NH2
N
NH2
N
N
N
O
O
N
N
N
N
P
OH
O
P
OH
O
HO
HO
4'-vinyl-cpAP (3)
4'-ethynyl-cpAP (4)
FIGURE 1 Synthesis of 4ꢁ-branched nucleoside analogues as potent anti-HIV agents.
viral activity with this oxygen atom may be attributed to the increased bind-
ing capacity of the phosphonate analogues to target enzymes.[6] Moreover,
a phosphonate nucleoside analogue can skip the requisite first phosphoryla-
tion, which is a crucial step for the activation of nucleosides. This is frequently
a limiting step in the phosphorylation sequence, which ultimately leads to
triphosphates.[7]
Stimulated by these findings that 4ꢁ-branched nucleoside analogues and
5ꢁ-norcarbocyclic nucleoside phosphonate have excellent biological activ-
ities, we sought to synthesize a novel class of nucleosides comprising 4ꢁ-
cyclopropane branched carbocyclic-5ꢁ-norcarbocyclic phosphonic acid ana-
logues in order to search for more effective therapeutics against HIV and to
provide analogues for probing the conformational preferences of enzymes
associated with the nucleoside kinases of nucleosides and nucleotides.
As depicted in Scheme 1, the target compounds were prepared from
protected propionaldehyde, 5.[8] The aldehyde functional group of 5 was
subjected to carbonyl addition reaction by cyclopropylmagensium bromide
to furnish the secondary alcohol 6, which was subjected to oxidation using
pyridium chlorochromate (PCC)[9] to provide ketone derivative 7. The cor-
responding ketone group of 7 was again subjected to an addition reaction
with vinylmagnesium bromide to give the tertiary hydroxyl analogue 8, which
was successfully protected using p-methoxybenzyl chloride (PMBCl)[10] to
provide compound 9. Removal of the silyl protecting group of 9 using t-
butylammonium fluoride (TBAF) gave the primary alcohol 10, which was
oxidized to the aldehyde 11 using Swern oxidation conditions[11] (DMSO,

4ꢁ-Cyclopropyl-5ꢁ-Norcarbocyclic Adenosine Analogues
907
O
HO
i
O
ii
OTBDMS
OTBDMS
OTBDMS
5
6
7
iii
HO
PMBO
PMBO
PMBO
iv
OTBDMS
v
OTBDMS
OH
10
9
8
vi
X
Y
PMBO
PMBO
OH
viii
vii
O
13a: X = OH, Y = H
13b: X = H, Y = OH
11
12
SCHEME 1 Synthesis of cyclopentenol intermediate. Reagents: i) cyclopropylMgBr, THF; ii) PCC,
CH2Cl2; iii) vinylMgBr, THF; iv) PMBCI, NaH, DMF; v) TBAF, THF; vi) (COCI)2, DMSO, TEA; vii)
vinylMgBr, THF; viii) Grubbs (II), CH2CI2.
oxalyl chloride, TEA). The aldehyde 11 was subjected to nucleophilic Grig-
nard conditions[12] with vinylmagnesium bromide to give divinyl 12, which
was subjected to ring-closing metathesis (RCM) conditions using second
generation Grubbs catalyst (C46H65Cl2N2PRu)[13] to provide cyclopropane-
substituted cyclopentenol 13a (36%) and 13b (37%), which were readily
separated by silica gel column chromatography. The nuclear Overhauser
enhancement (NOE) experiments with cyclopentenols 13a and 13b con-
firmed these assignments. As expected, NOE enhancements were found
between the cis-oriented hydrogens. Upon irradiation of C1-H, weak NOE
patterns were observed at the proximal hydrogens of compound 13b [C4-
CH- (0.78%)] versus those of compound 13a [C4-CH- (1.21%)] (Figure 2).
H
OH
PO
H
PO
H
OH
H
13a
13b
FIGURE 2 NOE differences between the proximal hydrogens of 13a and 13b.

908
G. H. Shen and J. H. Hong
Cl
N
Cl
N
N
N
N
N
ii
i
N
13b
HO
N
PMBO
14
15
iii
Cl
NH2
N
O
EtO P
N
O
EtO P
N
N
N
N
iv
N
O
EtO
N
O
EtO
17
16
SCHEME 2 Synthesis of 5ꢁ-norcarbocylic adenosine phosphonate. Reagents: i) 6-chloropurine, DEAD,
PPh3, THF; ii) DDQ, CH2CI2/H2O (10:1); iii) (EtO)2POCH2OTf, LiO-t-Bu, THF, iv) NH3/MeOH,
70◦C.
To synthesize the desired 5ꢁ-norcarbocyclic adenosine nucleoside ana-
logues, the protected cyclopentenol 13b was treated with 6-chloropurine
under Mitsunobu conditions[14] (DEAD and PPh3). Slow addition of diethyl
azodicarboxylate (DEAD) to a mixture of cyclopentenol 13b, triphenylphos-
phine and the 6-chloropurine in anhydrous tetrahydrofuran (THF) solvent
gave a yellow solution, which was stirred for 2 hours at −40◦C and further
stirred overnight at room temperature to give the protected 6-chloropurine
analogue 14 as an only N 9-regioisomer [UV (MeOH) λmax 264.0 nm].[15]
The PMB protection group was removed with 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ)[16] to produce the 5ꢁ-nornucleoside analogue 15,
which was treated with diethylphosphonomethyl triflate[17] using lithium
t-butoxide to yield the nucleoside phosphonate analogue 16 (Scheme 2).
The chlorine group of 16 was then converted to amine with methanolic am-
monia at 70◦C to give the corresponding adenine phosphonate derivative
17.4 Hydrolysis of 17 by treatment with bromotrimethylsilane in CH3CN in
the presence of 2,6-lutidine gave an adenine phosphonic acid derivative 18
(Scheme 3).[18]
In order to synthesize the 2ꢁ,3ꢁ-dihydroxy nucleoside analogues, the pro-
tected nucleosides 17 was subjected to vicinal hydroxylation conditions[19]
using catalytic amount of OsO4 and NMO to give the 19 (27%) and 20
(26%), respectively.[20] As shown in Figure 3, the stereochemistry was read-
ily determined by NOE experiment. On irradiation of C1-H, relatively strong

4ꢁ-Cyclopropyl-5ꢁ-Norcarbocyclic Adenosine Analogues
909
NH2
O
N
N
i
HO P
HO
17
N
N
O
ii
18
NH2
N
NH2
N
O
RO P
O
N
N
N
EtO P
EtO
N
N
and
O
N
RO
O
OH
HO
OH
HO
20
19: R = Et
21: R = H
i
SCHEME 3 Synthesis of 5ꢁ-norcarbocylic adenosine phosphonates and phosphonic acids. Reagents: i)
TMSBr, 2,6-lutidine, CH3CN; ii) OsO4, NMO, acetone/t-BuOH/H2O (6:1:1).
NOE was observed at C2-H and C3-H of 20, which showed 1ꢁ,2ꢁ,3ꢁ-cis relation-
ships. But relatively weak NOE was observed at C2-H and C3-H of 19, which
means the 1ꢁ,2ꢁ- and 1ꢁ,3ꢁ-trans relationships. The adenosine phosphonic
acid 21 was synthesized from 19 by the similar procedures described for 18
(Figure 3).
To synthesize the thioester prodrug analogue, compound 18 was reacted
with thioester 22[21] in the presence of 1-(2-mesitylenesulfonyl)-3-nitro-1H-
1,2,4-triazole (MSNT)[22] to provide the bis(SATE) derivative as a target
compound 23 (Scheme 4).
O
O
EtO P
EtO P
A
EtO O
A
EtO O
1
4
1
4
H
H
2
3
2
3
OH
H
HO
H
H
H
HO OH
19
20
FIGURE 3 NOE relationships between the proximal hydrogens of 19 and 20.

910
G. H. Shen and J. H. Hong
NH2
N
NH2
N
O
O
HO P
N
N
O
N
N
S
i
O P
N
HO O
O
N
O O
O
S
OH
S
22
18
23
SCHEME 4 Synthesis of target bis(SATE) prodrug of adenine analogue 23. Reagents: i) thioester, 22,
1-(2-mestiylenesulfonyl)-3-nitro-1H-1,2,4-triazole, pyridine.
The synthesized nucleoside phosphonate and phosphonic acid ana-
logues 17, 18, 19, 21, and 23 were then evaluated for antiviral activity against
human immunodeficiency virus. The procedures for measuring the antivi-
ral activity toward wild-type HIV and cytotoxicity have been reported pre-
viously.[23] As shown in Table 1, nucleoside phosphonic acid 23 exhibited
increased anti-HIV activity than its parent nucleoside phosphonic acid 18.
However, nucleoside analogues 17, 19 and 21 did not show anti-HIV activity
or cytotoxicity at concentrations up to 100 µM.
In summary, based on the potent anti-HIV activity of 4ꢁ-branched nucleo-
side and 5ꢁ-norcarbocyclic nucleoside analogues, we have designed and suc-
cessfully synthesized novel 4ꢁ-cyclopropyl-5ꢁ-norcarbocyclic nucleoside ana-
logues starting from propionaldehyde.
The synthesized nucleoside prodrug 23 exhibited slight improvement
in cell-based activity compared with phosphonic acid 18. Although SATE
protecting group as a prodrug scaffold was introduced, the antiviral activity
was slightly increased.
TABLE 1 Anti-HIV activity of synthesized compounds
Compound no.
anti-HIV EC50 (µM)c
Cytotoxicity CC50 (µM)d
17
18
19
21
62.5
18.6
>100
>100
9.8
98
90
>100
>100
65
23
AZTa
PMEAb
0.01
0.51
100
10
aAZT: azidothymidine.
bPMEA: 9-[2-(phosphonomethoxy)ethyl]adenine.
cEC50(µM): Concentration (µM) required to inhibit the replication of HIV-1 by 50%.
dCC50(µM): Concentration (µM) required to reduce the viability of unaffected cells by 50%.

4ꢁ-Cyclopropyl-5ꢁ-Norcarbocyclic Adenosine Analogues
EXPERIMENTAL
911
Melting points 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). Ultra-
violet (UV) spectra were obtained on a Beckman DU-7 spectrophotometer
(Beckman, South Pasadena, CA, USA). 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
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, benzene and pyridine were obtained by distillation from
CaH2. Dry THF was obtained by distillation from Na and benzophenone
immediately prior to use.
( )-3-(t-Butyldimethylsilanyloxy)-1-cyclopropyl-propan-1-ol (6)
To a solution of 5 (2.0 g, 10.62 mmol) in dry THF (20 mL) was slowly
added cyclopropylmagnesium bromide (25.49 mL, 0.5 M solution in THF)
at −25◦C; the mixture was stirred 4 hours at 0◦C. Saturated NH4Cl solution
(15 mL) was added to the mixture, which was slowly warmed to room tem-
perature (room temperature). The mixture was diluted with water (100 mL)
and extracted with EtOAc (2 × 100 mL). 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
1
(EtOAc/hexane, 1:10) to give 6 (1.93 g, 79%) as a colorless oil: H NMR
(CDCl3, 300 MHz) δ 3.82 (t, J = 5.2 Hz, 2H), 3.21 (m, 1H), 1.61 (m, 2H),
0.92 (m, 1H), 0.81 (s, 9H), 0.39–0.18 (m, 4H), 0.02 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 73.6, 60.2, 41.5, 25.3, 19.5, 18.5, 3.1, 2.3, −5.3.
˚
3-(t-Butyldimethylsilanyloxy)-1-cyclopropyl-propan-1-one (7): 4A molec-
ular sieves (3.8 g) and PCC (3.91 g, 18.13 mmol) were added slowly to a
solution of compound 6 (1.66 g, 7.2 mmol) in CH2Cl2 (60 mL) at 0◦C, and
the mixture was stirred overnight at room temperature. An excess of diethyl
ether (150 mL) was then added to the mixture. The mixture was stirred
vigorously for 3 hours at room temperature, and the resulting solid was fil-
tered through a short silica gel column. The filtrate was concentrated under
vacuum and purified by silica gel column chromatography (EtOAc/hexane,
1:30) to give compound 7 (1.26 g, 77%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 4.09 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 6.4 Hz, 1H), 2.29 (m, 1H),
1.23 (m, 2H), 1.03 (m, 2H), 0.81 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3, 75
MHz) δ 208.6, 60.8, 43.2, 25.5, 18.9, 18.3, 11.4, −5.6.

912
G. H. Shen and J. H. Hong
( )-5-(t-Butyldimethylsilanyloxy)-3-cyclopropyl-pent-1-en-3-ol (8): To a
solution of 7 (3.5 g, 15.32 mmol) in dry THF (50 mL), vinylmagnesium
bromide (18.46 mL, 1.0 M solution in THF) was slowly added at −10◦C
and stirred 5 hours at 0◦C. Saturated NH4Cl solution (18 mL) was added to
the mixture, which was slowly warmed to room temperature. The mixture
was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL).
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, 1:15) to give 8 (2.55 g, 65%)
as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.91 (m, 1H), 5.26–5.19 (m,
2H), 3.80 (t, J = 5.8 Hz, 2H), 1.65 (dd, J = 5.7, 2.6 Hz, 2H), 0.95 (m, 1H),
0.82 (s, 9H), 0.46–0.23 (m, 4H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
143.5, 114.2, 79.2, 59.1, 43.5, 25.5, 20.1, 18.2, 3.5, 2.9, -5.2; Anal. Calc. for
C14H28O2Si: C, 65.57; H, 11.00; Found: C, 65.54; H, 10.98.
( )-t-Butyl-[3-(4-methoxybenzyloxy)-3-cyclopropyl-pent-4-
enyloxy]-dimethylsilane (9)
NaH (60% in mineral oil, 330 mg, 8.3 mmol) was added portion-wise
to a cooled (0◦C) solution of tertiary alcohol 8 (1.77 g, 6.93 mmol) and
p-methoxybenzyl chloride (1.03 mL, 7.62 mmol) in DMF (30 mL). The
reaction mixture was stirred at room temperature overnight. The solvent was
removed in vacuo and the residue was diluted with H2O (110 mL) followed by
extraction with diethyl ether (2 × 110 mL). The combined organic layer was
washed with brine, dried over anhydrous MgSO4, and concentrated under
vacuum. The residue was purified by silica gel column chromatography
1
(EtOAc/hexane, 1:15) to give 9 (1.98 g, 76%) as a colorless oil. H NMR
(CDCl3, 300 MHz) δ 7.29–7.24 (m, 2H), 6.91–6.85 (m, 2H), 5.89 (m, 1H),
5.28–5.22 (m, 2H), 4.49 (s, 2H), 3.81 (s, 3H), 3.76 (t, J = 6.2 Hz, 2H), 1.62
(m, 2H), 0.98 (m, 1H), 0.81 (s, 9H), 0.44–0.23 (m, 4H), 0.02 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 159.4, 143.7, 130.6, 129.3, 116.3, 114.1, 80.1, 73.0,
58.7, 56.2, 41.8, 25.3, 19.9, 18.4, 4.1, 3.6, -5.5; Anal. Calc. for C22H36O3Si
(+0.5 EtOAc): C, 68.52; H, 9.58; Found: C, 68.48; H, 9.60.
( )-3-(4-Methoxybenzyloxy)-3-cyclopropyl-pent-4-en-1-ol (10)
To a solution of 9 (1.05 g, 2.78 mmol) in THF (20 mL), TBAF (3.33 mL,
1.0 M solution in THF) was added at 0◦C. The mixture was stirred overnight
at room temperature and concentrated in vacuo. The residue was purified
by silica gel column chromatography (Hexane/EtOAc, 5:1) to give 10 (649
mg, 89%): 1H NMR (CDCl3, 300 MHz) δ 7.31–7.27 (m, 2H), 6.95–6.87 (m,
2H), 5.90 (m, 1H), 5.25–5.19 (m, 2H), 4.51 (s, 2H), 3.79 (s, 3H), 3.57 (t, J =
6.2 Hz, 2H), 1.60 (m, 2H), 0.93 (m, 1H), 0.41 (m, 2H), 0.25 (m, 2H); 13C
NMR (CDCl3, 75 MHz) δ 159.7, 144.0, 131.2, 129.7, 117.1, 114.8, 79.8, 72.6,

4ꢁ-Cyclopropyl-5ꢁ-Norcarbocyclic Adenosine Analogues
913
57.8, 54.8, 40.2, 18.9, 3.6, 3.2; Anal. Calc. for C16H22O3: C, 73.25; H, 8.45;
Found: C, 73.28; H, 8.42.
( )-3-(4-Methoxybenzyloxy)-3-cyclopropyl-pent-4-enal (11)
To a stirred solution of oxalyl chloride (215 mg, 1.7 mmol) in CH2Cl2 (14
mL) was added a solution of DMSO (265 mg, 3.4 mmol) in CH2Cl2 (5.0 mL)
dropwise at –78◦C. The resulting solution was stirred at –78◦C for 10 minutes,
and a solution of alcohol 10 (223 mg, 0.85 mmol) in CH2Cl2 (10 mL) was
added dropwise. The mixture was stirred at –78◦C for 30 minutes and TEA
(0.947 mL, 6.8 mmol) was added. The resulting mixture was warmed to
0◦C and stirred for 30 minutes. H2O (15 mL) was added, and the solution
was stirred at room temperature for 30 minutes. The mixture was diluted
with water (130 mL) and then extracted with EtOAc (2 × 130 mL). The
combined organic layer was washed with brine, dried over anhydrous MgSO4
and filtered. The filtrate was concentrated in vacuo and the residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:15) to give
aldehyde compound 11 (208 mg, 94%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 9.86 (s, 1H), 7.30–7.25 (m, 2H), 6.94–6.88 (m, 2H), 5.91 (m,
1H), 5.27–5.21 (m, 2H), 4.66 (s, 2H), 3.74 (s, 3H), 2.58–2.49 (dd, J = 8.6,
4.0 Hz, 2H), 0.89 (m, 1H), 0.39 (m, 2H), 0.32 (m, 2H); 13C NMR (CDCl3, 75
MHz) δ 202.7, 159.3, 142.9, 130.8, 129.1, 116.7, 114.2, 76.1, 71.2, 57.3, 51.9,
19.7, 4.8, 4.2.
(rel)-(3R and 3S,5S)- 5-(4-Methoxybenzyloxy)-5-cyclopropyl-
hepta-1,6-dien-3-ol (12)
Divinyl analogue 12 was synthesized as a diastereomeric mixture from
1
aldehyde 11 by a procedure similar to that described for 8: yield 79%; H
NMR (CDCl3, 300MHz) δ 7.31–7.26 (m, 2H), 6.91–6.85 (m, 2H), 5.96–5.87
(m, 2H), 5.17–4.99 (m, 4H), 4.64 (s, 2H), 3.91 (m, 1H), 3.76 (s, 3H),
1.67–1.58 (m, 2H), 0.93–0.84 (m, 1H), 0.40–0.27 (m, 4H); 13C NMR (CDCl3,
75 MHz) δ 160.4, 159.7, 141.5, 140.7, 131.8, 129.8, 128.4, 117.8, 116.7, 115.5,
114.7, 78.2, 72.0, 68.1, 56.9, 44.3, 20.2, 5.1, 4.6, 3.8.
(rel)-(1S,4S)-4-(4-Methoxy-benzyloxy)-4-cyclopropylcyclopent-2-
enol (13a) and (rel)-(1R,4S)-4-(4-methoxy-benzyloxy)-4-
cyclopropylcyclopent-2-enol (13b)
To a solution of 12 (260 mg, 0.901 mmol) in dry methylene chloride
(7 mL) was added second generation Grubbs catalyst (40.0 mg, 0.0471
mmol). The reaction mixture was refluxed overnight and cooled to room
temperature. The mixture was concentrated in vacuo, and the residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:10) to give
1
cyclopentenol 13a (84 mg, 36%) and 13b (86 mg, 37%). Data for 13a: H

914
G. H. Shen and J. H. Hong
NMR (CDCl3, 300 MHz) δ 7.31 (m, 2H), 6.88–6.79 (m, 2H), 5.65 (d, J =
5.4 Hz, 1H), 5.34 (m, 1H), 4.69 (s, 2H), 4.08 (m, 1H), 3.78 (s, 3H), 2.20
(dd, J = 13.6. 8.2 Hz, 1H), 2.06 (dd, J = 13.5, 6.6 Hz, 1H), 0.93 (m, 1H),
0.41–0.34 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 159.8, 138.8, 136.9, 131.4,
128.5, 117.1, 88.7, 73.1, 67.9, 57.3, 39.2, 18.2, 5.9; Anal. Calc. for C16H20O3
(+0.5 EtOAc): C, 71.02; H, 7.94; Found: C, 70.95; H, 7.97.
Data for 13b: 1H NMR (CDCl3, 300 MHz) δ 7.32–7.28 (m, 2H), 6.87 (m,
2H), 5.68 (d, J = 5.5 Hz, 1H), 5.38–5.34 (m, 1H), 4.71 (s, 2H), 4.01 (m,
1H), 3.75 (s, 3H), 2.28 (dd, J = 13.8. 8.6 Hz, 1H), 2.10–2.05 (dd, J = 13.7,
6.8 Hz, 1H), 0.97 (m, 1H), 0.43 (m, 2H), 0.31 (m, 2H); 13C NMR (CDCl3, 75
MHz) δ 160.2, 139.1, 135.6, 131.8, 129.3, 118.0, 87.4, 72.2, 67.9, 56.9, 38.8,
17.9, 6.2, 5.7; Anal. Calc. for C16H20O3: C, 73.82; H, 7.74; Found: C, 73.79;
H, 7.72.
(rel)-(1ꢀR,4ꢀS)-9-[4-Cyclopropyl-(4-methoxybenzyloxy)-cyclopent-
2-enyl]-6-chloropurine (14)
To a solution containing compound 13b (161 mg, 0.62 mmol), triph-
enylphosphine (440 mg, 1.68 mmol) and 6-chloropurine (191 mg, 1.24
mmol) in anhydrous THF (12.0 mL), diethyl azodicarboxylate (DEAD)
(0.226 mL, 1.24 mmol) was added dropwise at –40◦C for 10 minutes un-
der nitrogen. The reaction mixture was stirred for 2 hours at the same
temperature under nitrogen and further stirred overnight at room temper-
ature. The solvent was concentrated in vacuo and the residue was purified by
silica gel column chromatography (EtOAc/hexane, 3:1) to give compound
14 (96 mg, 39%): m.p. 165–167◦C; UV (MeOH) λmax 264.0 nm: 1H NMR
(CDCl3, 300 MHz) δ 8.76 (s, 1H), 8.38 (s, 1H), 7.30–7.25 (m, 2H), 6.92–6.87
(m, 2H), 5.66 (d, J = 5.6 Hz, 1H), 5.36 (m, 1H), 4.69 (s, 2H), 4.44 (m, 1H),
3.72 (s, 3H), 2.31 (dd, J = 13.7. 8.8 Hz, 1H), 2.11–2.07 (dd, J = 13.8, 7.0
Hz, 1H), 0.92 (m, 1H), 0.41 (m, 2H), 0.35 (m, 2H); 13C NMR (CDCl3, 75
MHz) δ 159.5, 151.8, 150.8, 145.7, 138.6, 134.9, 132.5, 131.5, 129.1, 117.6,
86.8, 73.5, 57.6, 54.7, 36.2, 19.3, 6.8; Anal. Calc. for C21H21ClN4O2 (+ 1.0
MeOH): C, 61.60; H, 5.87; N, 13.06; Found: C, 61.56; H, 5.90; N, 13.10.
(rel)-(1ꢀR,4ꢀS)-9-(4-Cyclopropyl-4-hydroxycyclopent-2-enyl)-6-
chloropurine (15)
To a solution of compound 14 (420 mg, 1.058 mmol) in CH2Cl2/H2O
(12 mL, 10:1 v/v) was added DDQ (358 mg, 1.58 mmol), and the mixture
was stirred overnight at room temperature. Saturated NaHCO3 (2.0 mL)
was added to quench the reaction, which was then stirred for 1 hours
at room temperature. The mixture was diluted with water (160 mL) and
extracted with CH2Cl2 (3 × 160 mL). The combined organic layer was
dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in

4ꢁ-Cyclopropyl-5ꢁ-Norcarbocyclic Adenosine Analogues
915
vacuo and the residue was purified by silica gel column chromatography
(EtOAc/hexane/MeOH, 4:1:0.03) to give compound 15 (199 mg, 68%):
m.p. 176–178◦C; UV (MeOH) λmax 264.5 nm; 1H NMR (DMSO-d6, 300 MHz)
δ 8.74 (s, 1H), 8.39 (s, 1H), 5.64 (d, J = 5.4 Hz, 1H), 5.32 (dd, J = 5.5, 4.0
Hz, 1H), 4.51 (m, 1H), 2.28 (dd, J = 13.8. 8.7 Hz, 1H), 2.10–2.04 (m, 1H),
0.96 (m, 1H), 0.42 (m, 2H), 0.33 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ
151.9, 150.3, 149.2, 137.2, 134.8, 132.4, 86.5, 56.7, 39.6, 18.6, 7.1, 6.7; Anal.
Calc. for C13H13ClN4O (+1.5 MeOH): C, 62.55; H, 5.89; N, 17.25; Found:
C, 62.59; H, 5.92; N, 17.20.
(rel)-(1ꢀR,4ꢀS)-Diethyl [9-(4-Hydroxy-4-cyclopropylcyclopent-
2-en-1-yl)-6-chloropurine] methylphosphonate (16)
Both LiOt-Bu (2.32 mL of 0.5 M solution in THF, 1.24 mmol) and a
solution of diethyl phosphonomethyltriflate (348 mg, 1.16 mmol) in 8.0 mL
of THF were slowly added to a solution of the 6-chloropurine analogue 15
(160 mg, 0.58 mmol) in 7.0 mL of THF at –30◦C and stirred overnight at
room temperature under nitrogen. The mixture was quenched by adding
saturated NH4Cl solution (5 mL) and further diluted with additional H2O
(100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The
combined organic layer was dried over anhydrous MgSO4 and concentrated
in vacuo. The residue was purified by silica gel column chromatography
(MeOH/Hexane/EtOAc, 0.03:4:1) to give 16 (143 mg, 58%) as a foamy
solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.76 (s, 1H), 8.50 (s, 1H), 5.65 (d,
J = 5.3 Hz, 1H), 5.39 (dd, J = 5.5, 4.4 Hz, 1H), 4.51 (m, 1H), 4.31 (m,
4H), 3.98 (d, J = 8.0 Hz, 2H), 2.31–2.23 (dd, J = 13.8. 8.8 Hz, 1H), 2.09
(dd, J = 13.7, 6.8 Hz, 1H), 1.39 (m 6H), 0.97 (m, 1H), 0.43–0.35 (m, 4H);
13C NMR (DMSO-d6, 75 MHz) δ 151.9, 151.2, 150.5, 146.0, 137.7, 133.3,
132.5, 88.7, 66.3, 65.8, 64.5, 55.3, 36.7, 19.3, 17.2, 7.6, 6.6; Anal. Calc. for
C18H24ClN4O4P (+ 1.0 MeOH): C, 49.73; H, 6.15; N, 12.21; Found: C, 49.69;
H, 6.18; N, 12.16.
(rel)-(1ꢀR,4ꢀS)-Diethyl [9-(4-Hydroxy-4-cyclopropylcyclopent-
2-en-1-yl)-adenine] methylphosphonate (17)
A solution of 16 (202 mg, 0.473 mmol) in saturated methanolic ammo-
nia (12 mL) was stirred overnight at 70◦C in a steel bomb, and the volatiles
were evaporated. The residue was purified by silica gel column chromatog-
raphy (MeOH/CH2Cl2, 1:7) to give 17 (111 mg, 58%) as a white solid: m.p.
149–151◦C; UV (MeOH) λmax 260.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ
8.29 (s, 1H), 8.12 (s, 1H), 5.68 (d, J = 5.5 Hz, 1H), 5.39 (m, 1H), 4.50 (m,
1H), 4.35–4.41 (m, 4H), 4.02 (d, J = 8.1 Hz, 2H), 2.30–2.24 (dd, J = 13.7. 8.8
Hz, 1H), 2.12–2.06 (m, 1H), 1.41–1.35 (m 6H), 0.90 (m, 1H), 0.44 (m, 2H),
0.34 (m, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 155.2, 152.6, 150.7, 141.7,

916
G. H. Shen and J. H. Hong
138.1, 134.7, 120.2, 89.3, 65.7, 64.1, 63.2, 54.9, 37.1, 20.2, 16.8, 7.5, 6.3; Anal.
Calc. for C18H26N5O4P: C, 53.07; H, 6.43; N, 17.19; Found: C, 53.01; H, 6.38;
N, 17.25.
(rel)-(1ꢀR,4ꢀS)-[9-(4-Cyclopropylcyclopenten-1-yl)-adenine]
-4-methylphosphonic acid (18)
To a solution of the phosphonate 17 (149 mg, 0.35 mmol) in anhy-
drous CH3CN (10 mL) and 2,6-lutidine (0.815 mL, 7.0 mmol) was added
trimethylsilyl bromide (0.535 mg, 3.5 mmol). The mixture was heated
overnight at 70◦C under nitrogen gas and then concentrated in vacuo. The
residue was partitioned between CH2Cl2 (70 mL) and distilled purified wa-
ter (70 mL). The aqueous layer was washed with CH2Cl2 (2 × 50 mL) and
then freeze-dried to give phosphonic acid 18 (88 mg, 72%) as a yellowish
foam: UV (H2O) λmax 260.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.28 (s,
1H), 8.09 (s, 1H), 5.69 (d, J = 5.4 Hz, 1H), 5.37 (dd, J = 5.5, 4.2 Hz, 1H),
4.52 (m, 1H), 4.17 (d, J = 8.0 Hz, 2H), 2.31 (dd, J = 13.7, 8.8 Hz, 1H),
2.13–2.08 (dd, J = 13.8, 6.9 Hz, 1H), 0.88 (m, 1H), 0.37–0.31 (m, 4H); 13
C
NMR (DMSO-d6, 75 MHz) δ 154.8, 151.8, 149.5, 140.3, 138.6, 133.8, 119.6,
88.6, 64.7, 55.2, 36.7, 17.9, 6.7; Anal. Calc. for C14H18N5O4P (+2.0 H2O): C,
50.64; H, 5.72; N, 18.08; Found: C, 50.59; H, 5.68; N, 18.12.
(rel)-(1ꢀR,2ꢀS,3ꢀS,4ꢀS)-Diethyl [9-(2,3-dihydroxy-4-
cyclopropylcyclopent-1-yl)-adenine]-4- methylphosphonate (19)
and (rel)-(1ꢀR,2ꢀR,3ꢀR,4ꢀS)-diethyl [9-(2,3-dihydroxy-4-
cyclopropylcyclopent-1-yl)-adenine]-4-methylphosphonate (20)
Compound 17 (236 mg, 0.58 mmol) was dissolved in a cosolvent system
(10 mL) (acetone: t-BuOH: H2O = 6:1:1) along with 4-methylmorpholine N -
oxide (135 mg, 1.16 mmol). Subsequently, OsO4 (0.29 mL, 4% wt% in H2O)
was added. The mixture was stirred overnight at room temperature and
quenched with saturated Na2SO3 solution (5 mL). The resulting solid was
removed by filtration through a pad of Celite, and filtrate was concentrated
in vacuo. The residue was purified by silica gel column chromatography
(MeOH/CH2Cl2, 1:5) to give 19 (69 mg, 27%) and 20 (66 mg, 26%) as a
solid: compound 19: m.p. 151–153◦C; UV (H2O) λmax 259.5 nm; 1H NMR
(DMSO-d6, 300 MHz) δ 8.27 (s, 1H), 8.17 (s, 1H), 4.23–4.16 (m, 4H), 4.10
(d, J = 8.0 Hz, 2H), 3.81 (m, 1H), 3.69 (d, J = 5.6 Hz, 1H), 3.31 (m,
1H), 2.15–2.08 (dd, J = 13.6, 8.7 Hz, 1H), 1.95–1.90 (dd, J = 13.8, 6.8 Hz,
1H), 1.35–1.32 (m 6H), 0.92 (m, 1H), 0.38 (m, 2H), 0.30 (m, 2H); 13C NMR
(DMSO-d6, 75 MHz) δ 155.4, 152.6, 150.1, 142.7, 119.8, 86.2, 76.8, 70.5, 66.4,
64.6, 63.5, 47.5, 29.2, 19.6, 17.8, 7.8, 6.9; Anal. Calc. for C18H28N5O6P (+ 1.5
MeOH): C, 47.85; H, 7.00; N, 14.30; Found: C, 47.79; H, 7.03; N, 14.26.

4ꢁ-Cyclopropyl-5ꢁ-Norcarbocyclic Adenosine Analogues
917
Compound 20: m.p. 144–146◦C; UV (H2O) λmax 261.0 nm; 1H NMR
(DMSO-d6, 300 MHz) δ 8.29 (s, 1H), 8.18 (s, 1H), 4.32–4.25 (m, 4H), 4.16
(d, J = 8.1 Hz, 2H), 3.82 (m, 1H), 3.62 (d, J = 5.5 Hz, 1H), 3.35 (dd, J =
5.6, 4.0 Hz, 1H), 2.17 (dd, J = 13.8, 8.6 Hz, 1H), 1.98–1.89 (dd, J = 13.7, 7.0
Hz, 1H), 1.36 (m 6H), 0.90 (m, 1H), 0.42 (m, 2H), 0.35 (m, 2H); 13C NMR
(DMSO-d6, 75 MHz) δ 154.9, 152.2, 149.7, 143.2, 120.7, 85.6, 75.2, 67.5, 65.2,
64.7, 48.0, 27.8, 18.9, 17.2, 6.4; Anal. Calc. for C18H28N5O6P (+1.0 MeOH):
C, 48.20; H, 6.81; N, 14.79; Found: C, 48.15; H, 6.77; N, 14.84.
(rel)-(1ꢀR,2ꢀS,3ꢀS,4ꢀS)-[9-(2,3-Dihydroxy-4-cyclopropylcyclopent-
1-yl)] adenine]-4- methylphosphonic acid (21)
Final adenosine phosphonic acid 21 was synthesized from 19 using the
similar procedure described for 18 as a light yellow foamy solid: yield 67%;
UV (H2O) λmax 260.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.31 (s, 1H), 8.19
(s, 1H), 4.12 (d, J = 8.1 Hz, 2H), 3.67 (d, J = 5.4 Hz, 1H), 3.35 (m, 1H),
2.18–2.11 (dd, J = 13.8, 8.8 Hz, 1H), 1.93 (dd, J = 13.7, 6.9 Hz, 1H), 0.90
(m, 1H), 0.39–0.33 (m, 4H); 13C NMR (DMSO-d6, 75 MHz) δ 154.6, 153.7,
151.3, 143.2, 119.3, 87.1, 77.4, 68.52, 65.7, 48.1, 27.4, 18.8, 6.2, 5.7; Anal.
Calc. for C14H20N5O6P (+ 3.0 H2O): C, 38.27; H, 5.96; N, 15.94; Found: C,
38.34; H, 6.01; N, 15.89.
(rel)-(1ꢀR,4ꢀS)-Bis(SATE) phosphoester of [9-(4-
methyloxyphosphonate-4-cyclopropylcyclopentyl)] adenine (23)
A solution of adenine phosphonic acid derivative 18 (59 mg, 0.169 mmol)
and tri-n-butylamine (94 mg, 0.510 mmol) in methanol (3.8 mL) was mixed
for 30 minutes and concentrated under reduced pressure. The residue was
thoroughly dried with anhydrous ethanol and toluene. The resulting foamy
solid was dissolved in anhydrous pyridine (10 mL) to which thioester 22
(519 mg, 3.2 mmol) and 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole
(201 mg, 0.678 mmol) were added. The mixture was stirred overnight at
room temperature and quenched with tetrabutylammonium bicarbonate
buffer (10.0 mL, 1 M solution, pH 8.0). The mixture was concentrated
under reduced pressure and the residue was diluted with water (58 mL) and
extracted with CHCl3 (62 mL) two times. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and evaporated. The residue
was purified by silica gel column chromatography (MeOH/Hexane/EtOAc,
0.06:3:1) to give 23 (42 mg, 39%) as a white solid: m.p. 124–125◦C; UV
(MeOH) λmax 262.0 nm; 1H NMR (CDCl3, 300 MHz) δ 8.32 (s, 1H), 8.15 (s,
1H), 5.58 (d, J = 5.6 Hz, 1H), 5.33 (dd, J = 5.7, 4.0 Hz, 1H), 4.51 (m, 1H),
4.20 (d, J = 8.1 Hz, 2H), 3.92 (m, 4H), 3.18–3.16 (m, 4H), 2.26 (dd, J =
13.6, 8.9 Hz, 1H), 2.12–2.08 (dd, J = 13.7, 6.7 Hz, 1H), 1.23–1.19 (m, 18),
0.89 (m, 1H), 0.38–0.32 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 204.4, 154.5,

918
G. H. Shen and J. H. Hong
152.5, 149.0, 144.2, 128.2, 124.4, 118.2, 84.7, 65.3, 64.9, 62.3, 54.9, 48.3, 35.8,
31.4, 26.2, 17.3, 6.8; Anal. Calc. for C28H42N5O6PS2 (+1.0 MeOH): C, 51.84;
H, 6.90; N, 10.42; Found: C, 51.78; H, 6.87; N, 10.38.
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