A convergent approach for the synthesis of ara-neplanocin a analogues under subzero microwave assisted conditions

Article abstract of DOI:10.1080/15257770903044143

A convergent strategy for the synthesis of ara-neplanocin A analogues has been developed. Microwave assisted Mitsunobu reaction proved to be an essential tool both for the 2' - hydroxy inversion and for the coupling reaction with the heterocyclic bases. The exploitation of the present approach allowed generating a family of ara-neplanocins which biological potential is still unexplored.

Full text of DOI:10.1080/15257770903044143

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A Convergent Approach for the Synthesis
of Ara-Neplanocin a Analogues Under
Subzero Microwave Assisted Conditions
Marco Radi a , Jagadeeshwar R. Rao a , Ashok K. Jha a & Chung K.
Chu a
a College of Pharmacy , The University of Georgia , Athens ,
Georgia , USA
Published online: 29 Jul 2009.
To cite this article: Marco Radi , Jagadeeshwar R. Rao , Ashok K. Jha & Chung K. Chu (2009)
A Convergent Approach for the Synthesis of Ara-Neplanocin a Analogues Under Subzero
Microwave Assisted Conditions, Nucleosides, Nucleotides and Nucleic Acids, 28:5-7, 504-518, DOI:
10.1080/15257770903044143
To link to this article: http://dx.doi.org/10.1080/15257770903044143
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Nucleosides, Nucleotides and Nucleic Acids, 28:504–518, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903044143
A CONVERGENT APPROACH FOR THE SYNTHESIS
OF ARA-NEPLANOCIN A ANALOGUES UNDER SUBZERO
MICROWAVE ASSISTED CONDITIONS
Marco Radi, Jagadeeshwar R. Rao, Ashok K. Jha, and Chung K. Chu
College of Pharmacy, The University of Georgia, Athens, Georgia, USA
A convergent strategy for the synthesis of ara-neplanocin A analogues has been developed.
2
Microwave assisted Mitsunobu reaction proved to be an essential tool both for the 2ꢁ-β-hydroxy
inversion and for the coupling reaction with the heterocyclic bases. The exploitation of the
present approach allowed generating a family of ara-neplanocins which biological potential is still
unexplored.
Keywords Ara-neplanocin A analogues; convergent approach; microwave assisted
synthesis
INTRODUCTION
Among the different members of the neplanocin family isolated from
Ampullariella regularis,[1] neplanocin A 1 (NPA; Figure 1) has been exten-
sively studied since it showed potent antiviral and anti-tumor activity both
in vitro and in vivo.[2] The interesting biological activity of NPA seems to be
in part due to an efficient inhibition of S-adenosylhomocysteine (AdoHcy)
hydrolase.[3] However, the main drawback for the therapeutic utilization of
NPA as an antiviral agent comes from its significant cytotoxicity. In contrast
to NPA, ara-neplanocin A (2; ara-NPA) showed less cytotoxicity with still
retaining reasonable antiviral activity.[4]
However, a thorough literature search indicated that little attention
has been paid to the ara-neplanocin family of compounds. Apart from the
adenine derivative 2 (ara-NPA), only the cytosine derivative 3 (ara-NPC) has
Received 7 January 2009; accepted 28 April 2009.
Dedicated to Dr. Robins on the occasion of his 70th birthday.
This research was supported by U.S. Public Health Service research UO19 AI056540.
Address correspondence to C. K. Chu, College of Pharmacy, The University of Georgia, Athens,
GA30602. E-mail: DCHU@rx.uga.edu
504

Synthesis of ara-Neplanocin A Analogues
505
FIGURE 1 Neplanocin A (NPA, 1) and known arabino analogues 2 (ara-NPA) and 3 (ara-NPC).
been reported so far, which was evaluated only for its antitumor activity.[5]
While the ara-NPA was obtained from a divergent approach starting from
NPA in four steps,[6] the ara-NPC was obtained from a 2,2ꢁ-anhydro-uridine
intermediate, which was the byproduct of 2ꢁ-deoxygenation reaction. Con-
sidering the poor versatility of the reported approaches, we decided to
develop a convergent synthetic strategy that allows to generate a family of
base-modified ara-neplanocins of which biological potential have been un-
explored. In addition, ara-neplanocins could be considered as an attractive
template, giving access through appropriate chemical modifications of the
2ꢁ-α-hydroxy group as well as to new 2ꢁ-functionalized neplanocin-derivatives
otherwise difficult to obtain.
RESULTS AND DISCUSSION
We have recently reported a practical and convenient methodology
for the gram scale synthesis of the carbocyclic intermediate 4 in 52%
overall yield after 8 steps.[7] The cyclopentenyl moiety 4 was therefore
considered a good starting point for the construction of an arabino-type
carbocyclic intermediate which could be coupled with different nucleobases
in a convergent process.
Starting from 4, different approaches (2,3-epoxide opening, 2-keto
reduction) were tried for the inversion of the 2ꢁ-β-hydroxy group with no
success, and ultimately we focussed on the Mitsunobu reaction (Scheme 1).
The hydroxyl group in carbocyclic intermediate 4 was initially benzoylated
to obtain compound 5, which was treated with Dowex 50WX8–200 resin
at room temperature to deprotect both trityl and acetonide groups. Using
this method, both the trityl and acetonide protecting groups were removed,
however, an undesired acid catalyzed benzoyl 1,2- migration results in 2:1
mixture of compounds 6 and 7 in 54% overall yield.
To avoid the acid catalyzed 1,2-migration, allyl and benzyl protecting
groups were then used in place of the benzoyl. Unfortunaltely, subsequent
studies showed that, in the presence of these two protecting groups, the
Mitsunobu inversion at the C2 position was unsuccessful, proably due to

506
M. Radi et al.
SCHEME 1 Reagents and conditions: a) BzCl, pyridine, room temperature, 2 hours; b) Dowex, MeOH,
MW, open vessel, 65◦C, 30 minutes (two cycles); (c) t-Bu2Si(OTf)2, DMF, 0◦C, 30 minutes; (d) p-
NO2PhCO2H, Ph3P, DIAD, THF, room temperature, 16 hours.
unfavorable stereoelectronic effects. Therefore, in order to study the effect
of the electron withdrawing benzoyl group in the outcome of the Mitsunobu
reaction, we went back to optimize the deprotection of compound 5 to
improve the 6:7 ratio. Using the Dowex resin for deprotection in an open
vessel under microwave assisted conditions, it was possible to significantly
reduce the reaction time and the extent of acid catalyzed benzoyl migration.
As described in Scheme 1, the mixture of compound 6 and 7 was thus
obtained in a 11:1 ratio working in the milligram scale, while in the gram
scale a 7:1 ratio was obtained. Reacting the mixture with di-tert-butylsilyl
bis(trifluoromethanesulfonate), compound 8 was obtained after 30 minutes
while 7 was recovered unreacted. Unfortunately, the attempted inversion of
2ꢁ-β-hydroxy group in compound 8 using the standard Mitsunobu reaction
condition gave the undesired compound 9 as a result of the 1,2- benzoyl
migration and subsequent Mitsunobu reaction on the anomeric hydroxy
moiety. Surprisingly, running the Mitsunobu reaction on compound 8
under microwave assisted conditions, it was possible to cleanly invert the
configuration of the C2-hydroxyl group (Scheme 2).
The choice of the solvent used in this reaction was crucial in determin-
ing the yield of the desired compound 10, benzene (high boiling point)
in place of THF provided less decomposed materials and better yields.[8]
Compound 10 was then debenzoylated with lithium hydroxide to give
the key intermediate 11, which could be used in the coupling reaction
with the appropriate heterocyclic bases. As depicted in Scheme 2, reacting
compound 11 with N3-benzoylthymine under the standard Mitsunobu
reaction condition (room temperature), compound 12 was obtained in 35%
yield after 16 hours. Due to the higher reactivity of the allylic hydroxy
group, the desired compound 12 was obtained as single product and fully
characterized by NMR experiments. Again, the use of microwave irradiation

Synthesis of ara-Neplanocin A Analogues
507
SCHEME 2 Reagents and conditions:a) p-NO2PhCO2H, Ph3P, DIAD, benzene, MW, 180◦C, sealed tube,
5 minutes; b) THF/MeOH/H2O (3:2:1), LiOH, room temperature, 30 minutes; c) N3-benzoylthymine,
Ph3P, DIAD, THF (methods A-C).
was valuable in improving the outcome of the Mitsunobu reaction (Scheme
2). High temperature microwave assisted conditions (method B in Scheme
2) allowed to obtain the nucleoside 12 in 59% yield. However, subzero
microwave assisted condition (−40◦C), accessible by the use of a CEM
Discover CoolMate system (method C in Scheme 2), furnished the desired
compound 12 in 81% yield. The latter result can be rationalized with
the production of less byproducts at low temperature. In addition, the
comparison of methods B and C highlights that the acceleration of the
coupling reaction under the Mitsunobu condition does not seems to be
related to a thermal effect in the poor microwave absorbing THF but,
most probably, to a specific microwave effect onto the charged transition
state species.[9] Due to the difficulties encountered in the purification of
compound 12 prompted us to develop a protocol for the one-pot Mitsunobu
coupling reaction and deprotection of the silyl group of the carbocyclic
moiety as the deprotected nucleoside can be more easily purified. According
to this modified protocol, the key intermediate 11 was reacted for 5
minutes with the suitably protected nucleobase under the above desccribed
subzero microwave assisted Mitsunobu condition, and the reaction mixture
was treated with triethylamine trihydrofluoride at room temperature to
deprotect silyl group in the same reaction vessel outside the microwave
system for 30 minutes, affording the corresponding nucleosides 13, 15, 16,
and 21 (Scheme 3). Finally, deprotection or amination afforded the ara-
neplanocin derivatives 14 (ara-NPT), 17 (ara-NPA), 18 (ara-7DNPA), and 22
(ara-NPG) in good overall yields. For the synthesis of the 3-deaza analogue
20, 6-N ,N -diBoc-3-deazaadenine has been used in the coupling reaction in
order to avoid the formation of the N7-derivative[10] which is a common side
product in the synthesis of 3-deazapurine carbocyclic nucleosides.[11] The
steric hindrance exerted by the bulky diBoc-protecting group during the
coupling reaction, allowed to obtain the N9-derivative 19 as a single product

508
M. Radi et al.
SCHEME 3 Reagents and conditions: a) Ph3P, DIAD, THF, MW, −40◦C, 100 W, 5 minutes; b) Et3N·
3HF, room temperature, 30 minutes; c) Sat. NH3 in MeOH, room temperature, 1 hour; d) Sat. NH3 in
MeOH, 90◦C, 18 hours; e) 2N HCl/MeOH, 60◦C 15 hours; f) i) formic acid, 90◦C, MW, 5 minutes, ii)
Sat. NH3 in MeOH, room temperature, overnight.
which was finally deprotected with 2N HCl in methanol to give the desired
ara-3DNPA 20 (Scheme 3).
For the synthesis of the cytosine analogue 27 (ara-NPC), N3-
benzoyluracil was coupled with 11 under Mitsunobu reaction (method C)
to give nucleoside 23, which was protected at the 2ꢁ-β-hydroxy group with
tert-butyldimethylsilyl chloride, followed by debenzoylation with saturated
methanolic ammonia at room temerature gave compound 25. Ammination
at C4 using tri-isopropylbenzene sulfonyl chloride/DMAP followed by react-
ing with ammnium hydroxide gave the cytosine analogue 26 (Scheme 4).
Finally deprotection of silyl group with triethylamine trihydrofluoride gave
the desired ara-NPC analogue 27.
In conclusion, a convergent strategy for the synthesis of ara-neplanocin
A analogues has been developed. The microwave accelerated Mitsunobu
reaction proved to be an essential tool for both the synthesis of the key
intermediate 11 and the coupling reaction with the heterocyclic bases.
The exploitation of the present approach allowed to generate a family of
ara-neplanocins of which biological potentials have not been explored. In

Synthesis of ara-Neplanocin A Analogues
509
SCHEME 4 Reagents and conditions: a) Ph3P, DIAD, THF, N3-benzoyluracil, MW, −40◦C, 100 W, 5 min-
utes; b) TBDMS-Cl, imidazole, CH2Cl2, 12 hours, 50◦C; c) Saturated NH3/MeOH, room temperature,
5 hours; d) 2,4,6-triisopropylbenzenesulfonyl chloride, DMAP, Et3N, CH3CN, 20 hours, then NH4OH,
5 hours; e) Et3N·3HF, THF, 1 hour.
addition, ara-neplanocins could be considered as an attractive template giv-
ing access, through appropriate chemical modifications of the 2ꢁ-α-hydroxy
group, to new series of 2ꢁ-functionalized derivatives otherwise difficult to
obtain. Biological evaluation for all the synthesized compounds will be
reported in due course.
EXPERIMENTAL SECTION
General Procedures
Melting points were determined on a Mel-temp II laboratory device
and are uncorrected. NMR spectra were recorded on a Varian 500 MHz
Fourier Transform spectrometer; chemical shifts are reported in parts per
million-(δ), and signal are quoted as s (singlet), d (doublet), t (triplet), m
(multiplet), and dd (double of doublets). UV spectra were obtained on
a Beckman DU-650 spectrophotometer. Optical rotations were measured
on a JASCO DIP-370 digital polarimeter. TLC was performed on uniplates
(silica gel) purchased from Analtech Co.(Newark, DE, USA) and elemental
analysis were performed by Atlantic Microlab, Inc. (Norcross, GA, USA).
Microwave reactions were conducted using a CEM Benchmate Discover
Synthesis Unit (CEM Corp., Matthews, NC, USA) consisting of a continuous
focused microwave power delivery system with operator-selectable power
output from 0 to 300W. The reactions were performed in 10 mL sealed
vessel or in a 50 mL round bottom flack equipped with a tightly clamped
condenser in open vessel mode. The temperature of the contents of
the vessel was monitored using a calibrated infrared temperature control
mounted under the reaction vessel. Subambient temperature microwave
assisted reactions were conducted using a CEM-Coolmate apparatus con-
nected to the Benchmate Discover unit. This system provides a jacketed
low-temperature vessel that helps in maintaining low reaction temperature
by means of a circulating cold microwave transparent fluid. Temperature

510
M. Radi et al.
measurement is accomplished with an in situ fiber-optic probe. All exper-
iments were performed using a stirring option whereby the contents of
the vessel were stirred by means of a rotating magnetic plate located below
the floor of the microwave cavity and a Teflon-coated magnetic stir bar in the
vessel.
(1S,2S,3R)-1-Benzoyloxy-2,3-(Isopropylidenedioxy)-4-(trityloxymethyl)-
4-cyclopentene (5): (1S,2S,3R)-1-Hydrxoy-2,3-(Isopropylidenedioxy)-4-
(trityloxymethyl)-4-cyclopentene 4 (2.92 g, 6.81 mmol) was dissolved in
anhydrous pyridine (20 mL) and benzoyl chloride (1.19 mL, 10.22 mmol)
was added at 0◦C. Reaction mixture was stirred at room temperature for
3 hours, and then diluted with diethyl ether, washed 3–4 times with 1N HCl
solution, brine, dried over anhy. magnesium sulphate, and concentrated.
The residue was purified over silica gel chromatography (10% EtOAc in
hexane) to give compound 5 (3.08 g, 85%) as a white foam. M.p. 55◦C
(decomposition). [α]26D 16.37 (c 0.62, CHCl3); 1H NMR (CDCl3) δ 8.12 (d,
J = 7.32 Hz, 2H), 7.58 (t, J = 7.32 Hz, 1H), 7.44–7.48 (m, 8H), 7.23–7.33
(m, 9H), 6.11 (s, 1H), 5.62 (m, 1H), 5.05 (d, J = 5.86 Hz, 1H), 4.92 (d, J =
5.86 Hz, 1H), 3.99 (d, J = 14.65 Hz, 1H), 3.76 (d, J = 14.65 Hz, 1H), 1.33
(s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3) δ 146.83, 143.85,133.01, 130.12,
129.89, 128.62, 128.37, 127.95, 127.18, 125.08, 112.99, 87.12, 83.39, 77.47,
76.05, 61.41, 27.49, 27.17; HR-FAB MS Obsd, m/z 273.1120; Calcd. for
C16H17O4, m/z 273.1127 (M+H)+.
(1S,2S,3R)-1-Benzoyloxy-2,3-dihydroxy-4-hydroxymethyl-4-cyclopentene
(6+7): To a solution of 5 (3.08 g, 5.79 mmol) in THF: MeOH (1:3, 30 mL),
Dowex 50WX8-200 resin (9.24 g) was added and the resulting mixture was
irradiated into the microwave at 100W (65◦C) (2 × 30 minutes) under a
continuous air cooling flow. The resin was filtered off, washed several times
with MeOH and the filtrate was evaporated to dryness. The residue was
purified by flash silica gel chromatography (CH2Cl2:MeOH 9:1) to give a
7:1 mixture of compounds 6+7 (1.15 g, 68%) which was directly used in
the next step.
(1S,2S,3R)-1-Benzoyloxy-2-hydroxy-3,6-O-di-tert-butylsilanediyl-4-
cycl- opentene (8): A solution of 6+7 (1.15 g, 4.60 mmol) in
anhydrous DMF (15 mL) was cooled at 0◦C and di-tert-butylsilyl
bis(trifluoromethanesulfonate) (1.64 mL, 5.06 mmol) was added dropwise.
The resulting mixture was stirred at 0◦C for 30 minutes and then diluted
with Et2O, washed repeatedly with water, brine, dried over magnesium
sulphate and concentrated. The residue was purified by flash silica gel
chromatography (Hexane:EtOAc, 5:1) to give 8 (1.25 g, 70%) as a white
1
solid: M.p. 72◦C; [α]24 32.01 (c 0.64, CHCl3); H NMR (CDCl3) δ 8.11
D
(d, J = 7.81 Hz, 2H), 7.59 (t, J = 7.32 Hz, 1H), 7.46 (t, J = 7.32 Hz, 2H),
5.89 (s, 1H), 5.76 (m, 1H), 4.92 (d, J = 5.86 Hz, 1H), 4.78 (m, 2H), 4.62
(q, 1H), 3.02 (d, J = 7.32 Hz, 1H), 1.11 (s, 9H), 1.04 (s, 9H); 13C NMR
(CDCl3) δ 145.08, 133.04, 130.00, 129.84, 128.33, 124.94, 75.82, 70.17,

Synthesis of ara-Neplanocin A Analogues
511
63.96, 27.44, 27.06, 22.36, 20.59; HR-FAB MS Obsd, m/z 413.1801; Calcd.
for C21H30O5Si, m/z 413.1760 (M+Na)+.
(1R,2S,3R)-1-(p-Nitro-benzoyl)-2-benzoyloxy-3,6-O-di-tert-butylsilane-
diyl-4-cyclopentene (9): To a solution of compound 8 (41 mg, 0.105 mmol),
triphenylphosphine (55 mg, 021 mmol) and 4-nitrobenzoic acid
(26 mg, 0.158 mmol) in dry THF (5 mL) at 0◦C was added
diisopropylazodicarboxylate (DIAD, 42 µL, 0.21 mmol) under nitrogen
atmosphere. The mixture was stirred at room temperature for 24 hours,
and then the solvent was removed under vacuum. The residue was purified
by preparative TLC (10% EtOAc in Hexane) to give 9 (7 mg, 12%) as a
1
pale yellow oil. H-NMR (CDCl3) δ 8.30 (d, J = 8.29 Hz, 2H), 8.21 (d, J
= 8.29 Hz, 2H), 8.09 (d, J = 8.29 Hz, 2H), 7.57 (m, 1H), 7.44 (m, 2H),
6.13 (s, 1H), 5.94 (s, 1H), 5.63 (m, 1H), 5.43 (d, J = 3.8 Hz, 1H), 4.80 (d,
J = 11.0 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 0.99 (s, 9H), 0.79 (s, 9H):
13C NMR (CDCl3) δ 150.72, 148.22, 135.08, 133.14, 130.91, 129.87, 129.67,
128.32, 123.64, 122.62, 83.45, 76.98, 75.37, 63.83, 27.00, 26.60, 22.31, 20.32;
HR-FAB MS Obsd., m/z 540.2058; Calcd. for C21H30O5Si, m/z 540.2053
(M+H)+.
(1S,2R,3R)-1-Benzoyloxy-2-(p-nitro-benzoyl)-3,6-O-di-tert-butylsilane-
diyl-4-cyclopentene (10): In a microwave sealed vessel, diisopropylazodi-
carboxylate (DIAD, 778 µL, 3.97 mmol) was added dropwise to a solution
of 8 (298 mg, 0.764 mmol), triphenylphosphine (1.16 g, 4.43 mmol) and
4-nitrobenzoic acid (612 mg, 3.66 mmol) in dry benzene (5 mL) under
nitrogen atmosphere. The mixture was irradiated at 100 W (100◦C) for
5 minutes then diluted with EtOAc, washed with water, brine, dried over
magnesium sulphate, and concentrated. The residue was purified by flash
silica gel chromatography (10% EtOAc in Hexane) to give 10 (726 mg,
65%) as a pale yellow solid: M.p. 64◦C (decomposition); [α]27 82.22 (c
D
0.47, CHCl3); 1H NMR (CDCl3) δ 8.23 (m, 2H), 8.19 (m, 2H), 7.99 (d, J =
7.32 Hz, 2H), 7.51 (t, J = 7.32 Hz, 1H), 7.39 (m, 2H), 5.84 (s, 1H), 5.73 (s,
1H), 5.65 (m, 1H), 5.12 (d, J = 3.91 Hz, 1H), 4.71 (d, J = 13.6 Hz, 1H),
4.61 (d, J = 13.6 Hz, 1H), 0.97 (s, 9H), 0.95 (s, 9H); 13C NMR (CDCl3)
δ 150.67, 144.29, 135.21, 133.36, 131.08, 129.85, 129.63, 128.50, 123.64,
123.59, 87.66, 80.63, 79.54, 63.28, 27.01, 26.98, 22.25, 20.22; HR-FAB MS
Obsd, m/z 540.2058; Calcd. for C21H30O5Si, m/z 540.2089 (M+H)+.
(1S,2R,3R)-1,2-Dihydroxy-3,6-O-di-tert-butylsilanediyl-4-cyclopentene
(11): To a solution of 10 (673 mg, 1.25 mmol) in a 3:2:1 mixture of
THF/MeOH/H2O (18 mL/12 mL/6 mL), lithium hydroxide monohydrate
(183 mg, 4.37 mmol) was added and the resulting solution was stirred at
room temperature for 30 minutes. The mixture was then concentrated
under reduced pressure to a small volume, diluted with EtOAc, washed
with water, brine, dried over magnesium sulphate, and concentrated. The
residue was purified over flash silica gel (CH2Cl2:MeOH, 98:2) to give 11
(318 mg, 89%) as a white solid: M.p. 105◦C; [α]27 -20.38 (c 0.55, CHCl3);
D

512
M. Radi et al.
1H NMR (CD3OD) δ 5.56 (s, 1H), 4.67–4.73 (m, 2H), 4.54 (d, J = 13.66
Hz, 1H), 4.31 (m, 1H), 3.97 (t, J = 5.37 Hz, 1H), 1.04 (s, 9H), 0.98 (s, 9H);
13C NMR (CDCl3) δ 140.34, 126.86,, 89.57, 82.27, 77.79, 63.47, 21.98, 19.79;
Anal. Calcd.. for C14H26O4Si: C, 58.70; H, 9.15. Found: C, 58.69; H, 9.23.
(1S,2R,3R)-N3-Benzoyl-1-[2-hydroxy-3,6-O-di-tert-butylsilanediyl-4-
cycl- openten-1-yl]thymine (12): Method A: To a solution of 11 (1.0 mmol),
triphenylphosphine (2.5 mmol) and N3-benzoylthymine (1.5 mmol) in
dry THF (7mL) at 0◦C was added diisopropylazodicarboxylate (DIAD,
2.5 mmol) dropwise under nitrogen atmosphere. The reaction mixture
was stirred at room temperature for 24 hours. The residue was purified by
preparative TLC (Hexane:EtOAc, 8:2) to give 12 (35%) as solid.
Method B: In a microwave sealed vessel, diisopropylazodicarboxylate
(DIAD, 2.5 mmol) was added dropwise to a solution of 11 (1.0 mmol), triph-
enylphosphine (2.5 mmol) and N3-benzoylthymine (1.5 mmol) in dry THF
(7 mL) under nitrogen atmosphere. The mixture was irradiated at 100 W
(100◦C) for 5 minutes then concentrated. The residue was purified by
preparative TLC (Hexane:EtOAc, 8:2) to give 12 (59%) as solid.
Method C: To a solution of 11 (100 mg, 0.349 mmol), triphenylphos-
phine (229 mg, 0.873 mmol) and N3-benzoylthymine (141 mg, 0.698 mmol)
in dry THF (7 mL) was added diisopropylazodicarboxylate (DIAD, 171
µL, 0.873 mmol) dropwise under nitrogen atmosphere. The resulting
solution was irradiated at −40◦C (initial cooling fluid temperature = −50◦C,
fluid speed max) for 5 minutes at 100W then diluted with EtOAc washed
with water, brine, dried over magnesium sulphate, and concentrated. The
residue was purified by preparative TLC (Hexane:EtOAc, 8:2) to give 12
(141 mg, 81%) as a white solid: M.p. 88◦C (decomposition); [α]28 -39.99
D
(c 0.55, CHCl3); UV (CHCl3) λmax 254 nm; 1H-NMR (CDCl3) δ 7.93 (d, J =
7.32 Hz, 2H), 7.63 (m, 1H), 7.48 (m, 2H), 6.87 (s, 1H), 5.62 (s, 1H), 5.54 (m,
1H), 4.99 (s, 1H), 4.86 (d, J = 14.16 Hz, 1H), 4.72 (d, J = 14.16 Hz, 1H),
4.44 (m, 1H), 2.85 (s, 1H), 1.07 (s, 9H), 0.95 (s, 9H); 13C NMR (CDCl3) δ
151.09, 148.69, 137.40, 135.06, 131.54, 130.49, 129.20, 121.02, 110.19, 83.89,
78.70, 63.45, 60.80, 27.09, 26.91, 22.25, 20.22, 12.69; HR-FAB MS Obsd, m/z
499.2285; Calcd.. for C26H34N2O6Si, m/z 499.2264 (M+H)+.
(1S,2R,3R)-N3-Benzoyl-1-[2,3-dihydroxy-4-hydroxymethyl-4-
cyclopen- ten-1-yl]thymine (13): To a solution of 11 (30 mg, 0.113 mmol),
triphenylphosphine (74 mg, 0.281 mmol) and N3-benzoylthymine (46 mg,
0.225 mmol) in dry THF (5 mL) was added diisopropylazodicarboxylate
(DIAD, 55 µL, 0.281 mmol) dropwise under nitrogen atmosphere.
The resulting solution was irradiated at −40◦C (initial cooling fluid
temperature = −50◦C, fluid speed max) for 5 minutes at 100W then
triethylamine trihydrofluoride (37 µL, 0.225 mmol) was added and the
reaction stirred outside at room temperature for 30 minutes. Reaction
mixture was neutralized with minimum satd. NaHCO3, and evaporated.
The residue was purified by preparative TLC (CH2Cl2:MeOH, 98:2) to give

Synthesis of ara-Neplanocin A Analogues
513
13 (20 mg, 52%) as a pale yellow solid; M.p. 70◦C (decomposition); [α]26
D
5.54 (c 0.50, MeOH); UV (MeOH) λmax 252 nm; 1H NMR (CD3OD) δ 7.97
(m, 2H), 7.72 (t, J = 7.32 Hz, 1H), 7.55 (m, 2H), 7.28 (s, 1H), 5.76 (s, 1H),
5.61 (m, 1H), 4.56 (s, 1H), 4.31 (m, 2H), 4.23 (m, 1H), 1.91 (s, 3H); 13C
NMR (CD3OD) δ 150.86, 140.04, 135.07, 131.89, 130.37, 129.17, 121.98,
108.63, 81.01, 77.29, 61.59, 58.81, 11.13; HR-ESI MS Obsd. m/z 345.1083;
Calcd.. for C17H16N2O6, m/z 345.1087 (M+H)+.
(1S,2R,3R)-1-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]
thy- mine (14): Compound 13 (40 mg, 0.117 mmol) was dissolved in
saturated methanolic ammonia (10 ml) and stirred at room temperature
for 1 hour. The solvent was evaporated under vacuum and the residue was
purified on preparative TLC (CH2Cl2:MeOH, 85:15) to 14 (24 mg, 86%)
as a white solid: M.p. 65◦C (decomposition); [α]26 25.54 (c 0.50, MeOH);
D
UV (MeOH) λmax, nm: 273 (pH 2), 273.5 (pH 11), 272.0 (pH 7); 1H NMR
(CD3OD) δ 7.12 (s, 1H), 5.70 (s, 1H), 5.61–5.63 (m, 1H), 4.53 (s, 1H), 4.28
(m, 2H), 4.22–4.24 (m, 1H), 1.85 (s, 3H); 13C NMR (CD3OD) δ 165.64,
152.31, 151.98, 139.95, 122.75, 108.4, 81.0, 77.2, 61.1, 58.8, 11.14; Anal.
Calcd.. for C11H14N2O5·0.6H2O: C, 49.85; H, 5.78; N, 10.57. Found: C,
49.97; H, 5.93; N, 10.06.
(1S,2R,3R)-9-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]6-
chlo- ropurine (15): To a solution of 11 (120 mg, 0.45 mmol),
triphenylphosphine (295 mg, 1.13 mmol) and 6-chloropurine (139 mg,
0.90 mmol) in dry THF (7mL) was added Diisopropylazodicarboxylate
(DIAD, 221µL, 1.13 mmol) dropwise under nitrogen atmosphere. The
resulting solution was irradiated at −40◦C (initial cooling fluid temperature
= −50◦C, fluid speed max) for 5 minutes at 100 W then triethylamine
trihydrofluoride (147µL, 0.90 mmol) was added and the reaction stirred at
room temperature for 30 minutes. Reaction mixture was neutralized with
minimum satd. NaHCO3 and evaporated. The residue was purified by flash
silica gel chromatography (CH2Cl2:MeOH, 9:1) to give 15 (68 mg, 53%) as
a pale yellow solid: M.p. 182◦C; [α]27 -89.22 (c 0.44, MeOH); UV (MeOH)
D
1
λmax 265 nm; H NMR (CD3OD) δ 8.80 (s, 1H), 8.40 (s, 1H), 5.96 (s, 1H),
5.87 (m, 1H), 4.78 (m, 1H), 4.40 (m, 3H); 13C NMR (CD3OD) δ 153.18,
152.46, 151.44, 149.48, 146.49, 130.95, 120.72, 80.36, 77.86, 59.95, 58.54;
HR-ESI MS Obsd, m/z 283.0589; Calcd. for C11H11ClN4O3, m/z 283.0599
(M+H)+.
(1S,2R,3R)-9-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]6-
chl- oro-7-deazapurine (16): To a solution of 11 (288 mg, 1.00 mmol),
triphenylphosphine (527 mg, 2.01 mmol) and 6-chloropurine (232 mg, 1.50
mmol) in dry THF (7 mL) was added diisopropylazodicarboxylate (DIAD,
404µL, 2.01 mmol) dropwise under nitrogen atmosphere. The resulting
solution was irradiated at −40◦C for 5 minutes at 100W then triethylamine
trihydrofluoride (486 µL, 3.01 mmol) was added and the reaction stirred
at room temperature for 30 minutes. Reaction mixture was neutralized

514
M. Radi et al.
with minimum satd. NaHCO3 and evaporated. The residue was purified
by silica gel chromatography (CH2Cl2:MeOH, 9:1) to give 16 (140 mg,
55%) as a pale yellow solid: M.p. 140◦C; [α]27 -72.50 (c 0.23, MeOH); UV
D
1
(MeOH) λmax 275 nm; H-NMR (DMSO-d6) δ 8.62 (s, 1H), 7.40 (d, J =
3.5 Hz, 1H), 6.11 (d, J = 3.0 Hz, 1H), 5.81 (dd, J = 2.0, 4.5 Hz, 1H), 5.70
(d, J = 1.5 Hz, 1H), 5.25 (d, J = 6.0 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H),
4.92 (m, 1H), 4.16 (m, 3H); 13C NMR (DMSO-d6) δ 153.92, 151.68, 150.66,
150.42, 130.89, 121.08, 117.45, 98.24, 80.21, 78.51, 59.46, 58.73; HR-ESI MS
Obsd, m/z 281.0536; Calcd. for C12H12ClN3O3, 281.0567 (M+H)+.
(1S,2R,3R)-9-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]-
ade- nine (17): Compound 15 (120 mg, 0.425 mmol) was dissolved in
methanol (10 mL) and saturated with ammonia for 20 minutes at 0◦C and
heated at 90◦C for 18 hours in a steel bomb. The solvent was evaporated
under reduced pressure and the residue was purified using C18 reverse
phase silica gel column chromatography (methanol:water = 20:80) to give
17 (100 mg, 90%) as a white solid: M.p. 230◦C; [α]23D -95.83 (c 0.4, MeOH);
UV (MeOH) λmax, nm: 219, 260 (pH 11), 210, 260 (pH 2), 210, 260 (pH
1
7); H NMR (DMSO-d6) δ 8.17 (s, 1H), 7.83 (d, J = 2 Hz, 1H), 7.30 (brs,
2H), 5.73 (d, J = 1.5 Hz, 1H), 5.53 (m, 1H), 5.24 (m, 2H), 4.92 (brs, 1H),
4.56 (brs, 1H), 4.15 (m, 3H); 13C NMR (DMSO-d6) δ 156.0, 152.68, 151.66,
150.42, 129.89, 121.08, 117.45, 98.24, 80.21, 78.51, 59.46, 58.73; HR-ESI
MS Obsd, m/z 264.1086; Calcd. for C11H13N5O3, 264.1097 (M+H)+; Anal.
Calcd. for C11H13N5O3·0.33H2O: C, 49.13; H, 5.00; N, 26.04; Found: C,
49.01; H, 5.01; N, 25.97.
(1S,2R,3R)-9-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]-7-
deazaadenine (18): Compound 16 (127 mg, 0.451 mmol) was dissolved in
methanol (10 mL) and saturated with ammonia for 20 minutes at 0◦C and
heated at 90◦C for 18 hours in a steel bomb. The solvent was evaporated
under reduced pressure and the residue was purified using flash silica gel
column chromatography (methanol: CHCl3 = 1:5) to give 18 (96 mg, 81%)
as a white solid: M.p. 140◦C; [α]23 -70.27 (c 0.12, MeOH); UV (MeOH)
D
1
λmax, nm: 230, 275 (pH 2), 227, 273 (pH 11), 210, 273 (pH 7); H-NMR
(DMSO-d6) δ 8.12 (s, 1H), 7.30 (brs, 2H), 6.91 (d, J = 3.5 Hz, 1H), 6.58
(d, J = 3.5 Hz, 1H), 5.69 (d, J = 7.0 Hz, 1H), 5.66 (s, 1H), 5.21 (d, J =
6.5 Hz, 1H), 5.03 (d, J = 5.5 Hz, 1H), 4.92 (t, J = 5.5 Hz, 1H), 4.52 (m,
1H), 4.12 (m, 2H); 13C NMR (DMSO-d6) δ 157.92, 152.77, 149.89, 149.53,
124.44, 121.88, 102.70, 88.99, 80.17, 78.61, 58.67, 58.43; HR-ESI MS Obsd,
m/z 263.1142; Calcd. for C12H14N4O3, 263.1145 (M+H)+; Anal. Calcd. for
C12H14N4O3·0.2H2O: C, 54.21; H, 5.46; N, 21.07; Found: C, 54.23; H, 5.49;
N, 21.12.
(1S,2R,3R)-1-[2-Hydroxy-3,6-O-di-tert-butylsilanediyl-4-cyclopenten-
1-yl]-4-(N,N-di-tert-butyloxycarbonylamino)-imidazo[4,5-c]pyridine
(19):
To a solution of 11 (285 mg, 0.99 mmol), triphenylphosphine (391 mg,
1.49 mmol) and N ,N -diBoc-3-deazaadenine (400 mg, 1.19 mmol) in dry

Synthesis of ara-Neplanocin A Analogues
515
THF (7 mL) was added diisopropyl-azodicarboxylate (DIAD, 0.29 mL,
1.49 mmol) dropwise under nitrogen atmosphere. The resulting solution
was irradiated at −40◦C (initial cooling fluid temperature = −50◦C, fluid
speed max) for 5 minutes at 100 W then diluted with EtOAc washed with
water, brine, dried over MgSO4, and concentrated. The residue was purified
over flash silica gel chromatography (Hexane:EtOAc, 7:3) to give 19 (400
mg, 67%) as a white solid: M.p. 201◦C; [α]28 -88.99 (c 0.25, MeOH); UV
D
1
(CHCl3) λmax 211, 264 nm; H NMR (CDCl3) δ 8.21 (d, J = 6 Hz, 1H),
7.77 (s, 1H), 7.25 (d, J = 5.5 Hz, 1H), 5.83 (brs, 1H), 5.42 (d, J = 6.5 Hz,
1H), 5.08 (d, J = 3.0 Hz, 1H), 4.90 (d, J = 14 Hz, 1H), 4.75 (d, J = 14
Hz, 1H), 4.57 (q, 1H), 2.50 (d, J = 5 Hz, 1H), 1.43 (s, 18H), 1.07 (s, 9H),
0.99 (s, 9H); 13C NMR (CDCl3) δ 151.56, 147.55, 144.19, 143.77, 141.48,
140.64, 136.56, 121.37, 106.3, 83.7, 83.0, 79.3, 63.4, 60.2, 27.9, 27.8, 27.1,
26.9, 22.3, 20.2; HR-FAB MS Obsd, m/z 603.3132; Calcd. for C30H46N4O7Si,
m/z 603.3214 (M+H)+.
(1S,2R,3R)-9-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]-3-
deazaadenine (20): A mixture of 19 (180 mg, 0.299 mmol), 2N HCl in
methanol (10 mL) was heated to 60◦C for 15 hours. The mixture was
evaporated under reduced pressure and co-evaporated with methanol (3 ×
50 mL). The residue was dissolved in methanol (10 mL), neutralized with
IRA-400 (OH) resin, filtered the solution, concentrated and purified using
amine functionalized silica gel column chromatography (CH2Cl2:MeOH,
9:1) to give 20 (62 mg, 79%) as a white solid: M.p. 244◦C; [α]23 -102.88
D
(c 0.16, MeOH); UV (H2O) λmax, nm: 216, 266 (pH 2), 220, 266 (pH 11),
215, 266 (pH 7); 1H NMR (CD3OD) δ 8.00 (s, 1H), 7.72 (d, J = 6 Hz, 1H),
6.99 (d, J = 6 Hz, 1H), 5.98 (s, 1H), 5.54 (m, 1H), 4.69 (m, 1H), 4.38 (s,
2H); 13C NMR (CD3OD) δ 152.3, 150.7, 146.7, 142.7, 131.7, 128.7, 127.0,
102.5, 80.17, 78.61, 58.67, 58.43; HR-ESI MS Obsd, m/z 263.1142; Calcd.
for C12H14N4O3, 263.1145 (M+H)+; Anal. Calcd. for C12H14N4O3·0.2H2O:
C, 54.21; H, 5.46; N, 21.07; Found: C, 54.23; H, 5.49; N, 21.12.
(1S,2R,3R)-N2-Isopropylamino-9-[2,3-dihydroxy-4-hydroxymethyl-
4-cyclopenten-1-yl]6-chloropurine (21): To a solution of 11 (111 mg,
0.417 mmol), triphenylphosphine (274 mg, 1.043 mmol) and 6-chloro-
N2-isobutyrylpurine (200 mg, 0.834 mmol) in dry THF (7 mL) was added
diisopropylazodicarboxylate (DIAD, 204µL, 1.043 mmol) dropwise under
nitrogen atmosphere. The resulting solution was irradiated at −20◦C (initial
cooling fluid temperature = −50◦C, fluid speed max) for 30 minutes at
300W then triethylamine trihydrofluoride (136 µL, 0.834 mmol) was added
and the reaction stirred at room temperature for 30 minutes. Reaction
mixture was neutralized with minimum satd. NaHCO3 and evaporated. The
residue was purified by preparative TLC (CH2Cl2: MeOH, 9:1) to give 21
(62 mg, 40%) as a yellow solid: M.p. 123.5◦C (decomposition); [α]26 -7.47
D
1
(c 0.49, MeOH); UV (MeOH) λmax 233 nm; H NMR (CD3OD) δ 8.24 (s,
1H), 5.93 (s, 1H), 5.83 (m, 1H), 4.82 (m, 1H), 4.38–4.42 (m, 3H), 2.83

516
M. Radi et al.
(m, 1H), 1.27 (s, 3H), 1.26 (s, 3H); 13C NMR (CD3OD) δ 153.28, 153.17,
152.13, 149.76, 145.57, 127.60, 120.50, 80.04, 78.13, 59.62, 58.54, 35.58,
18.31; HR-ESI MS Obsd, m/z 368.1103; Calcd. for C15H18ClN5O4, 368.1126
(M+H)+.
(1S,2R,3R)-1-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]
guanine (22): In a microwave sealed vessel, a mixture of 21 (57 mg,
0.155 mmol) and formic acid (2 mL) was irradiated at 90◦C for 5 minutes
under a continuous air cooling flow and then concentrated in vacuum.
The residue was dissolved in a solution of methanol (10 mL) saturated
with ammonia and stirred at room temperature overnight. The mixture
was then evaporated to dryness, dissolved in a small amount of methanol
and precipitated by addition of diethyl ether. The solid was filtered off and
washed with diethyl ether to give 22 (37 mg, 85%) as a brown solid: M.p.
198◦C; [α]26 -95.2 (c, 0.12, H20); UV (H2O) λmax, nm: 254 (pH 2), 256
D
(pH 11), 252 (pH 7); 1H NMR (D2O) δ 7.65 (s, 1H), 5.98 (s, 1H), 5.46 (m,
1H), 4.77 (m, 1H), 4.38–4.42 (m, 3H); 13C NMR (D2O) δ 161.88; 156.83,
153.57, 141.58, 124.96, 119.00, 82.50, 80.58, 61.36, 61.18; Anal. Calcd. for
C11H13N5O4: C, 47.31; H, 4.69; N, 25.08; Found: C, 47.29; H, 4.58; N, 24.92.
(1S,2R,3R)-N3-Benzoyl-1-[2-hydroxy-3,6-O-di-tert-butylsilanediyl-4-
cyclopenten-1-yl]uracil (23): To a solution of 11 (360 mg, 1.25 mmol),
triphenylphosphine (824 mg, 3.14 mmol) and N3-benzoyluracil (472 mg,
2.51 mmol) in dry THF (70 mL) was added diisopropylazodicarboxylate
(DIAD, 632 µL, 3.14 mmol) dropwise under nitrogen atmosphere. The
resulting solution was irradiated at −40◦C (initial cooling fluid temperature
= −50◦C, fluid speed max) for 5 minutes at 100 W then diluted with EtOAc
washed with water, brine, dried over magnesium sulphate and concentrated
under reduced pressure The residue was purified by silica gel column
chromatography (Hexane:EtOAc, 8:2) to give 23 (250 mg, 41%) as a white
solid: M.p. 102◦C (decomposition); [α]28 -39.99 (c 0.55, CHCl3); 1H-NMR
D
(CDCl3) δ 7.98 (m, 2H), 7.67 (m, 1H), 7.51 (m, 2H), 7.09 (d, J = 8.0 Hz,
1H), 5.80 (d, J = 8.0 Hz, 1H), 5.63 (s, 1H), 5.59 (m, 1H), 5.01 (brs, 1H),
4.88 (dd, J = 2.0, 14 Hz, 1H), 4.75 (d, J = 14 Hz, 1H), 4.47 (m, 1H), 2.96
(s, 1H), 1.07 (s, 9H), 1.02 (s, 9H); 13C NMR (CDCl3) δ 168.78, 162.21,
150.99, 149.17, 141.61, 135.12, 131.44, 130.50, 129.82, 129.03, 128.03,
120.59, 101.54, 83.80, 78.64, 63.39, 60.87, 27.09, 26.91, 22.25, 20.22; HR-ESI
MS Obsd, m/z 485.2106; Calcd. for C25H32N2O6Si, m/z 485.2109 (M+H)+.
(1S,2R,3R)-N3-Benzoyl-1-[2-(tert-butyl-dimethylsilyloxy)-3,6-O-di-tert-
butylsilanediyl-4-cyclopenten-1-yl]uracil (24): To a solution of 23 (250 mg,
0.51 mmol), imidazole (140 mg, 2.06 mmol) in anhydrous CH2Cl2 (5
mL), was added tert-butyldimethylsilyl chloride (116 mg, 0.77 mmol)
at room temperature and stirred for 12hours at 50◦C. The solvent was
evaporated under reduced pressure and purified using silica gel column
chromatography (EtOAc:hexane = 3:7) to give 24 (202 mg, 65%) as white
1
solid: M.p. 188◦C; [α]23 -42.02 (c 0.8, CHCl3); H NMR (CDCl3) δ 7.94
D

Synthesis of ara-Neplanocin A Analogues
517
(m, 2H), 7.64 (m, 1H), 7.48 (m, 2H), 6.97 (d, J = 8.5 Hz, 1H), 5.77 (d, J
= 8.5 Hz, 1H), 5.72 (m, 1H), 5.61 (brs, 1H), 4.92 (brs, 1H), 4.81 (m, 1H),
4.68 (d, J = 13.5 Hz, 1H), 4.39 (m, 1H), 1.05 (s, 3H), 0.95 (s, 3H), 0.89
(s, 3H), 0.15 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3) δ 169.0, 162.5, 150.5,
148.0, 142.6, 135.2, 131.7, 130.7, 129.2, 122.3, 101.0, 85.1, 79.1, 63.7, 60.2,
27.2, 27.1, 27.0, 25.9, 22.4, 20.3, 18.1, −4.0, −4.5; HR-ESI MS Obsd, m/z
599.2381; Calcd. for C31H46N2O6Si2, m/z 599.2972 (M+H)+.
(1S,2R,3R)-1-[2-(tert-Butyl-dimethylsilyloxy)-3,6-O-di-tert-butylsilanediyl
-4-cyclopenten-1-yl]uracil (25): Compound 24 (200 mg, 0.334 mmol) was
dissolved in a solution of methanolic ammonia (10mL) at 0◦C and stirred
for 5 hours at room temperature. The solvent was evaporated under
reduced pressure and the residue was purified on silica gel chromatography
(CH2Cl2: MeOH, 85:15) to give 25 (150 mg, 91%) as a white solid: M.p.
195◦C; [α]23 −50.67 (c 0.47, CHCl3); UV (MeOH) λmax 267 nm; 1H NMR
D
(CDCl3) δ 8.48 (s, 1H), 6.88 (d, J = 8 Hz, 1H), 5.72 (m, 1H), 5.65 (dd, J =
2.5, 8.0 Hz, 1H), 5.58 (d, J = 1 Hz, 1H), 4.86 (t, J = 1 Hz, 1H), 4.81 (m,
1H), 4.67 (d, J = 14.5 Hz, 1H), 4.38 (m, 1H), 1.04 (s, 9H), 0.95 (s, 9H),
0.82 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3) δ 169.2; 157.2,
153.1, 147.8, 127.6, 106.5, 90.4, 84.3, 68.9, 65.2, 32.4, 32.3, 31.0, 27.7, 25.6,
23.3, 0.5, −0.0; HR-ESI MS Obsd, m/z 495.2697; Calcd. for C24H42N2O5Si2,
m/z 495.2711 (M+H)+.
(1S,2R,3R)-1-[2-(tert-Butyl-dimethylsilyloxy)-3,6-O-di-tert-butylsilanediyl
-4-cyclopenten-1-yl]cytosine (26): A mixture of 25 (250 mg, 0.53 mmol)
and 4-dimethylaminopyridine (DMAP) (131 mg, 1.07 mmol) in anhydrous
acetonitrile (15 mL), was added triethylamine (0.149 mL, 1.07 mmol)
followed by 2,4,6-triisopropylbenzenesulfonyl chloride (324 mg, 1.07 mmol)
at room temperature under nitrogen. After being stirred for 20 hours,
NH4OH (30%, 20 mL) was added and stirred for 5 hours. The mixture
was diluted with chloroform and washed with saturated aqueous NH4Cl
(3 × 20 mL) solution. The organic layer was dried over Na2SO4, filtered
and concentrated under reduced pressure. The residue was purified using
silica gel column chromatography (CH2Cl2: MeOH, 96:4) to give 26 (182
g, 73%) as a solid: M.p. 192◦C; [α]23 -56.25 (c 0.5, CHCl3); UV (MeOH)
D
λmax 275 nm; 1H NMR (CDCl3) δ 6.94 (d, J = 7.0 Hz, 1H), 5.91 (d, J = 6.5
Hz, 1H), 5.82 (d, J = 5.5 Hz, 1H), 5.58 (s, 1H), 4.87 (s, 1H), 4.78 (d, J = 14
Hz, 1H), 4.65 (d, J = 13.5 Hz, 1H), 4.38 (dd, J = 3.5, 7.5 Hz, 1H), 1.05 (s,
9H), 0.95 (s, 9H), 0.80 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3)
δ 165.21, 157.0, 146.3, 143.6, 123.9, 93.8, 85.5, 78.8, 63.7, 60.5, 27.1, 26.9,
25.6, 22.3, 20.2, 18.0, −4.9, −5.3; HR-ESI MS Obsd., m/z 494.2870; Calcd.
for C24H43N3O4Si2, m/z 494.2871 (M+H)+.
(1S,2R,3R)-1-[2,3-Dihydroxy-4-hydroxymethyl-4-cyclopenten-1-yl]
cyto- sine (27): To a solution of 26 (152 mg, 0.327 mmol) in THF (5
mL), Et3N·3HF (0.168 mL, 1.04 mmol) was added and stirred at room
temperature for 1 hour. Reaction mixture was evaporated and the residue

518
M. Radi et al.
was dissolved in methanol and neutralized with IRA-400 (OH) resin. The
resin was filtered and the filtrate concentrated and purified using amine
functionalized silica gel column chromatography (CH2Cl2: MeOH, 5:1)
to give 27 (53 mg, 71%) as a white solid: M.p. 262◦C (decomposition);
1
[α]24 + 48.2 (c 0.3, MeOH); H NMR (DMSO-d6) δ 8.84 (brs, 1H), 8.02
D
(brs, 1H), 7.28 (d, J = 7.0 Hz, 1H), 5.85 (d, J = 5.5 Hz, 1H), 5.54 9m,
2H), 5.28–4.94 (3 × brs, 3 × OH), 4.33 (s, 1H), 4.07 (m, 3H); 13C NMR
(CD3OD) δ 165.1, 157.0, 146.2, 143.5, 124.1, 93.8, 81.0, 77.8, 61.1, 56.5;
HR-ESI MS Obsd., m/z 240.0982; Calcd. for C10H13N3O4, m/z 240.0985
(M+H)+; Anal. Calcd. for C10H13N3O4: C, 50.20; H, 5.48; N, 17.57. Found:
C, 49.92; H, 5.50; N, 17.39.
REFERENCES
1. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M. Studies on neplanocinA,
new antitumor antibiotic. I. Producine organism, isolation, and characterization. J. Antibiot. 1981,
34, 359–366. a) Hayashi, M.; Yaginuma, S.; Yoshioka, H.; Nakatsu, K. Studies on neplanocin A, new
antitumor antibiotic. II. Structure determination. J. Antibiot. 1981, 34, 675–680.
2. Hoshi, A.; Yoshida, M.; go, M.; Tokuzen, R.; Fukukawwa, K.; Ueda, T. Antitumor activity of derivatives
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