Regio- and stereoselective synthesis of 2′-β-substituted-fluoroneplanocin A analogues as potential anticancer agents

Article abstract of DOI:10.1039/c5ob01348h

A series of 2′-β-substituted-6′-fluoro-cyclopentenyl-pyrimidines and -purines 8 and 9 were successfully synthesized from D-ribose in a regio- and stereoselective manner. The functionalization at the C2-position of 6′-fluoro-cyclopentenyl nucleosides was a

Full text of DOI:10.1039/c5ob01348h

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Regio- and stereoselective synthesis of
2’-β-substituted-fluoroneplanocin A analogues
as potential anticancer agents†
Cite this: DOI: 10.1039/c5ob01348h
Akshata Nayak,a,b Pramod K. Sahu,a Jayoung Song,a Sang Kook Leea and
Lak Shin Jeong*a
A series of 2’-β-substituted-6’-fluoro-cyclopentenyl-pyrimidines and -purines 8 and 9 were successfully
synthesized from D-ribose in a regio- and stereoselective manner. The functionalization at the C2-posi-
tion of 6’-fluoro-cyclopentenyl nucleosides was achieved via regioselective protection of a hydroxyl
group at the C3-position and stereoselective formation of C2-triflate followed by direct SN2 reaction with
a fluoro or azido nucleophile. All the synthesized compounds were evaluated for their anticancer activities
in several tumor cell lines, but were found to be neither active nor toxic.
Received 3rd July 2015,
Accepted 21st July 2015
DOI: 10.1039/c5ob01348h
www.rsc.org/obc
Introduction
Modified nucleosides which are good substrates for cellular
kinases, but resistant to other host enzymes such as phos-
phorylases which cleave the glycosidic bond of natural nucleo-
sides, are in need for the development of useful therapeutic
agents. One of the ways has been isosteric replacement of the
furanose oxygen of ribose moieties with methylene groups
which are referred as carbocyclic nucleosides.1–3 This modifi-
cation resulted in the substantial metabolic stability towards
phosphorylases and hydrolases eliminating the labile glyco-
sidic bond. Interestingly, these carbanucleosides are also
recognized by the same enzymes that recognize normal
nucleosides. A number of carbocyclic nucleosides are endowed
with potent biological activities, especially antiviral and
anticancer properties (Fig. 1).4,5
A naturally occurring neplanocin A (1)6,7 is a representative
carbanucleoside, exhibiting potent antiviral and antitumor
activities. Its mechanism of action8–11 has been well explored
and elucidated; phosphorylation at the 5′-position by adeno-
sine kinase and subsequent metabolism by a cellular enzyme
leads to anticancer effect, while the broad-spectrum antiviral
activity is correlated with the potent inhibitory effect against
S-adenosylhomocysteine (SAH) hydrolase.12 The corresponding
cytosine analogue 213 was also synthesized and reported to
exhibit potent anticancer activity. It is phosphorylated intra-
Fig. 1 The rationale for the design of target nucleosides.
cellularly to its triphosphate which then acts as a potent
inhibitor of CTP synthetase and thus produces a profound
depletion of CTP as well as CDP, dCDP, and dCTP pools.13 On
the basis of the structures of 1 and 2, the corresponding
6′-fluoro analogues 314 and 415 were synthesized. Compound 3
was reported to be a dual acting inhibitor of SAH hydrolase
along with excellent antiviral activity against the vesicular sto-
matitis virus (VSV) (EC50 = 0.43 µM),14 while compound 4 was
reported to show a different mode of action16 from 2. It was
found that after being activated by uridine–cytidine kinase
aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National
University, Seoul 151-742, Korea. E-mail: lakjeong@snu.ac.kr; Tel: +82-2-880-7850
bCollege of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob01348h
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Therefore, based on these findings, it was interesting to
design and synthesize the 2′-β-substituted-6′-fluorocyclopente-
nyl-pyrimidines and -purines 8 and 9 which hybridized the
structures of 6′-fluorocarbanucleosides 1–4 and 2′-β-substi-
tuted nucleosides 5–7 and to evaluate their inhibitory activity
against several tumor cell lines. In addition, the unusual gem-
difluoro intermediate obtained during the synthesis of the
target nucleosides was also converted to another final nucleo-
side 10 (Fig. 2), which may serve as the bioisostere of
(−)-neplanocin F (11).20
Fig. 2 The structure of bioisosteric compound 10 of (−)-neplanocin
F (11).
Results and discussion
(UCK), 4 is triphosphorylated and incorporated into DNA and
RNA16 and/or inhibits DNA methyltransferase (DNMT).15
On the other hand, hydrogen or hydroxyl at the C2-position
of furanose moiety plays a unique role in differentiating DNA
and RNA. Thus, natural and modified nucleosides containing
substituents other than hydrogen or hydroxyl groups at this
position further encouraged the investigation of the biological
properties of nucleosides.17 As a result substitution at the 2′-
position of ribose moiety with fluorine afforded new nucleo-
side analogues such as FMAU (5) or F-ara-C (6) with potent
antiviral and anticancer properties, respectively (Fig. 1).17,18 In
addition 2′-β-azido derivative 719 was also reported to display
considerable biological activities.
For the functionalization at the C2 position with fluoride or
azide, we decided to utilize the regioselective protection of the
allylic hydroxyl group of diol 18 with bulky protecting groups
such as trityl (Tr), tert-butyldiphenylsilyl (TBDPS), or trimethyl-
acetyl (Piv). The key intermediate 18 was synthesized from
D-ribose, as shown in Scheme 1.
D-Ribose was converted to a known cyclopentenone 12,
according to our previously published procedure.21 Iodination
of 12 followed by reduction with NaBH4 and protection of the
resulting allylic alcohol with the TBDPS group afforded 13.14
Because the benzyl protecting group gave better result than the
Tr or TBDPS group in the electrophilic fluorination reaction,14
Scheme 1 Synthesis of the key intermediate 18. Reagents and conditions: (a) I2, pyridine, THF, rt, 4 h; (b) NaBH4, CeCl3·7H2O, MeOH, 0 °C, 30 min;
(c) TBDPSCl, imidazole, DMF, 40 °C, 12 h; (d) (CH3)3Al, MC, 0 °C to rt, 2 h; (e) BnBr, NaH, TBAI, DMF, rt, 3 h; (f ) N-fluorobenzene sulfonimide, n-BuLi,
THF, 78 °C, 1 h; (g) n-Bu4NF, THF, rt, 2 h; (h) PMBCl, NaH, TBAI, DMF, rt, 3 h; (i) 2 N HCl/THF (1 : 1), 35 °C, 18 h.
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Scheme 2 Synthesis of glycosyl donors 22 and 23 containing fluoro substituent. Reagents and conditions: (a) Piv-Cl, DIPEA, DMAP, CH2Cl2, −10 °C,
2 h; (b) DAST, pyridine, CH2Cl2, 45 °C, 18 h; (c) DDQ, CH2Cl2, rt, 18 h.
the trityl group was replaced with the benzyl group under mild
conditions. Selective removal of the trityl group in 13 was
achieved by using trimethylaluminium in the presence of aceto-
nide to give 14 which was again protected with the benzyl
group to yield 15. Compound 15 was converted to 6-fluoro
derivative 16 via known procedures14 involving electrophilic
fluorination with n-butyllithium and N-fluorobenzene sulfona-
mide (NFSI) followed by TBDPS deprotection. Treatment of 16
with p-methoxybenzyl chloride (PMB-Cl) afforded 17 which
was subjected to acidic hydrolysis to give diol 18, which is a
good substrate for selective C2 functionalization.
To obtain desired regioselective protection at the 3′-hydroxyl
group, diol 18 was protected with bulky protecting groups
such as TBDPS, Tr, or Piv, but only the Piv group resulted in
Scheme 3 Plausible mechanism for the formation of gem-difluoro
derivative 20.
regioselective protection of the 3′-hydroxyl group over the 2′-
hydroxyl group, giving the desired isomer 19a and its regio-
isomer 19b in a 5 : 1 ratio, which were very difficult to be separ-
ated by silica gel chromatography (Scheme 2). Treatment of a
In the first step, substrate 19b reacted with DAST, forming
mixture of 19a and 19b with N,N-diethylaminosulfur trifluor- an alkoxyaminosulfur difluoride intermediate. In the 2nd step,
ide (DAST) yielded the desired 2′-β-fluoro analogue 21 (57%) as the fluoride attacked the C6 carbon of the intermediate via the
a major product along with geminal difluoro derivative 20 SN2′ mechanism, instead of direct SN2 attack at the C3 carbon,
(14%) as a minor product. It is believed that the desired resulting in the formation of gem-difluoro derivative 20.
product 21 was directly generated from 19a through SN2 reac- Though compound 20 was an undesired product, its structural
tion, while difluoro derivative 20 was derived from 19b via SN2′ similarity to (−)-neplanocin F20 inspired us to use this inter-
reaction, whose mechanism of action is illustrated in mediate to develop a novel (−)-neplanocin F analogue. The
Scheme 3. This reaction gave the same results as that of each structure of geminal difluoro derivative 20 was easily con-
1
of isolated isomers 19a and 19b.
firmed by H NMR, which shows a singlet at 6.0 ppm, corres-
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Scheme 4 Stereo- and regioselective synthesis of 2’-β-azido glycosyl donor 27. Reagents and conditions: (a) DPPA, Ph3P, THF, 0 °C to 60 °C; (b)
Tf2O, pyridine, rt, 1 h; (c) NaN3, DMF, rt, 1 h; (d) DDQ, CH2Cl2, rt, 18 h; (e) TBAF, THF, rt, 12 h.
ponding to vinylic 3-H of 20. Further confirmation was pro- synthesized in Scheme 2 was also derived from triflate 26 by
vided by 19F NMR showing 2 peaks, one at −108.4 ppm and treating with n-tetrabutylammonium fluoride (TBAF) followed
another at −109.3 ppm with the coupling constant 255.3 Hz, by the removal of the PMB group.
corresponding to geminal F,F coupling. Removal of the PMB
group in compounds 20 and 21 with DDQ afforded the glycosyl 9b were accomplished using the Mitsunobu reaction as the key
donors 22 and 23, respectively. step (Scheme 6). Condensation of glycosyl donors 23 and 27
Syntheses of 2′-β-substituted purine nucleosides 8a, 9a, and
Another glycosyl donor, 2′-β-azido derivative 27 was syn- with 6-chloropurine under the standard Mitsunobu conditions
thesized as shown in Scheme 4. We first tried the Mitsunobu yielded the N9-6-chloropurine derivatives [UV(CH2Cl2) λmax
reaction with diphenylphosphoryl azide (DPPA). However, the 262 nm], which after a short flash silica gel column chromato-
Mitsunobu reaction of a mixture of 19a and 19b with DPPA did graphy, were treated with tert-butanolic ammonia solution at
not afford any desired SN2′ product 24 or SN2 product 25, as 120 °C to afford adenosine derivatives 28 and 29, respectively.
depicted in Scheme 2. This might be attributed to difficulty in Treatment of 28 and 29 with 10% boron tribromide solution in
forming an alkoxy intermediate because of steric clashes methylene chloride followed by the removal of the pivaloyl
between bulky protecting groups. Thus, we decided to utilize group upon treatment with methanolic ammonia at 45 °C
direct SN2 displacement of the triflate with the azide. When a afforded the final nucleosides 8a and 9a, respectively.
mixture of 19a and 19b was treated with triflic anhydride, only Compound 9a was further reduced to yield the 2′-β-amino-
desired C2-triflate 26 was surprisingly obtained as a single fluoroneplanocin A analogue 9b.
regioisomer. The plausible mechanism for the sole formation
In a similar manner, gem-difluoro intermediate 22 was con-
of 26 is explained in Scheme 5.
verted to the (−)-neplanocin F analogue 10, as shown in
Compounds 19a and 19b are first equilibrated to form the Scheme 7. Mitsunobu condensation of 22 with 6-chloropurine
common cyclic intermediate I by intramolecular attack of the at 60 °C yielded the 6-chloro derivative 30, which was treated
hydroxyl group to carbonyl carbon of the pivaloyl moiety. The with tert-butanolic ammonia at 120 °C to furnish adenosine
cyclic intermediate I is then opened up in two routes. Route a derivative 31. Subsequent removal of benzyl and pivaloyl pro-
is much more favored than route b because of steric hindrance tecting groups from 31 produced gem-difluoro nucleoside 10.
between PMB and Piv groups, affording desired derivative 26
Synthesis of 2′-β-substituted pyrimidine nucleosides 8b–d
as a sole regioisomer. The 2′-β-azido glycosyl donor 27 was and 9c–e is shown in Scheme 8. The 2′-β-fluoro glycosyl donor
then obtained via direct nucleophilic displacement of triflate 23 was condensed with N3-benzoyluracil and -thymine under
26 with sodium azide in DMF followed by the removal of the the Mitsunobu conditions and then treated with BBr3 to give the
PMB group with DDQ. The same 2-β-fluoro glycosyl donor 23, 2′-β-fluoro derivatives 32 and 33, respectively. Removal of the
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Scheme 5 Plausible mechanism for the sole formation of 26.
Scheme 6 Synthesis of 2’-β-substituted purine nucleosides 8a, 9a, and 9b. Reagents and conditions: (a) 6-chloropurine, DIAD, PPh3, THF, rt, 18 h;
(b) NH3/tBuOH, 120 °C, sealed tube, 12 h; (c) BBr3, CH2Cl2, −78 °C, 3 h; (d) NH3/MeOH, 40 °C, 18 h; (e) PPh3, NH4OH, THF/H2O, rt, 18 h.
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Scheme 7 Synthesis of gem-difluoro substituted (−)-neplanocin F analogue 10. Reagents and conditions: (a) 6-chloropurine, DIAD, PPh3, THF, 60 °
C, 18 h; (b) NH3/tBuOH, 120 °C, sealed tube, 12 h; (c) BBr3, CH2Cl2, −78 °C, 3 h; (d) NH3/MeOH, 40 °C, 18 h.
Scheme 8 Synthesis of 2’-β-substituted pyrimidine nucleosides 8b–d and 9c–e. Reagents and conditions: (a) N3-benzoyluracil or N3-benzoylthy-
mine, DIAD, PPh3, THF, rt, 18 h; (b) BBr3, MC, −78 °C, 3 h; (c) NH3/MeOH, 40 °C, 15 h; (d) (i) Ac2O, pyridine, rt, 2 h, (ii) POCl3, 1,2,4-triazole, CH3CN, 0
°C to rt, 18 h, (iii) NH4OH/1,4-dioxane, rt, 15 h.
protecting groups of 32 and 33 yielded the uracil derivative 8b (A549), human colon cancer cell line (HCT-116), human breast
and the thymine derivative 8c. The 2′-β-azido glycosyl donor 27 cancer cell line (MDA-MB-231), human prostate cancer cell line
was similarly converted to the uracil derivative 9c and the (PC3), human liver cancer cell line (SK-Help-1), and human
thymine derivative 9d. Uracil derivatives 32 and 34 were converted stomach cancer cell line (SNU-638).22 Unlike the 2′-hydroxyl
to the 2′-β-fluorocytosine derivative 8d and 2′-β-azidocytosine derivatives 1–4, showing potent antitumor activities, all of the
derivative 9e, respectively, by a conventional method.
synthesized compounds did not exhibit promising anticancer
All the synthesized 2′-β-substituted-fluoroneplanocin A ana- activity up to 100 µM, indicating that the 2′-hydroxyl group is
logues 8a–d and 9a–e and gem-difluoro (−)-neplanocin F ana- essential for biological activity in this series. The change of the
logue 10 were evaluated for their cytotoxic activity against sugar conformation from the ribo configuration to the arabino
several human cell lines such as human lung cancer cell line or 2-deoxyribo configuration might decrease the favorable
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interaction between the compound and the cellular polymer- silane (13).23 To a stirred solution of 12 (42.0 g, 98.47 mmol)
ase, resulting in a loss of biological activity.
in anhydrous THF (450 mL) at −10 °C was added iodine
(87.5 g, 344.7 mmol) portionwise followed by pyridine (56 mL,
393.88 mmol) under a N2 atmosphere and the resulting solu-
tion was stirred at room temperature for 4 h. The reaction
mass was quenched with saturated sodium thiosulfate solu-
Conclusions
In summary, a series of 2′-β-substituted-fluoroneplanocin A tion at 0 °C until the solution becomes colorless. The aqueous
analogues 8 and 9 were successfully synthesized from D-ribose portion was extracted with ethyl acetate (500 mL). The organic
in a regio- and stereoselective manner. During the introduc- layer was further washed with water (200 mL), brine (200 mL),
tion of a 2′-β-fluoro group with DAST, unusual geminal- dried over anhydrous MgSO4, filtered and concentrated under
difluoro product 20 was formed via the SN2′ reaction along reduced pressure. The residue obtained was purified by flash
with the desired 2′-β-fluoro derivative 21. It was discovered that silica gel column chromatography (hexane : EtOAC = 7 : 1) to
triflation of the 2-hydroxyl or 3-hydroxyl group with the neigh- give ketone (38.0 g, 70%) as a white foam. To a solution of
boring pivaloyl acyl group resulted in the sole formation of ketone (38.0 g, 68.79 mmol) in methanol (400 mL) were added
C2-triflate 26 because of steric effects between protecting cerium(III) chloride heptahydrate (28.2 g, 75.67 mmol) and
groups. This triflate 26 was utilized for the regio- and stereo- sodium borohydride (2.82 g, 75.67 mmol) at 0 °C and the
selective synthesis of 2′-β-azido- and 2′-β-fluoro derivatives by mixture was stirred at 0 °C for 1 h. The reaction mixture was
treating with sodium azide and n-tetrabutylammonium quenched with water (250 mL) and partially concentrated
fluoride, respectively. All glycosyl donors 22, 23, and 27 were under reduced pressure to remove methanol. The aqueous
converted to the pyrimidine and purine nucleosides using the portion was extracted with ethyl acetate (250 mL × 2). The
Mitsunobu reaction as the key step. However, none of the syn- organic layer was washed with brine (150 mL × 2), dried over
thesized compounds showed significant biological activities. anhydrous MgSO4, filtered, and concentrated under reduced
Despite lack of biological activities, it is believed that this pressure to give α-hydroxy intermediate (25.0 g) as a yellow
study will greatly contribute to understanding the essential syrup.
structural requirements for biological activities of this class
To a stirred solution of α-hydroxy intermediate (25.0 g,
of carbocyclic nucleosides. This in turn will contribute to the 45.11 mmol) in anhydrous DMF (250 mL) were added imid-
design and synthesis of novel antitumor nucleosides.
azole (9.21 g, 135.35 mmol) and TBDPSCl (28.72 mL,
112.79 mmol) at 0 °C under nitrogen. The resulting solution
was stirred at room temperature for 16 h, quenched with
water (200 mL), and extracted with diethyl ether (200 mL × 2).
The combined organic layers were dried over anhydrous
MgSO4, filtered, and evaporated. The crude residue obtained
Experimental section
General methods
1H NMR spectra (CDCl3, CD3OD, or DMSO-d6) were recorded was purified by flash silica gel column chromatography
on a Varian Unity Invoa 400 MHz instrument. The 1H NMR (hexane : EtOAc = 15 : 1) to give 1323 (32.5 g, 90%) as a white
1
data are reported as peak multiplicities: s for singlet, d for foam: H NMR (CDCl3, 400 MHz) δ 1.15 (s, 9H), 1.27 (s, 3H),
doublet, dd for doublet of doublets, t for triplet, q for quartet, 1.31 (s, 3H), 3.80 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H),
br s for broad singlet, and m for multiplet. Coupling constants 4.07 (t, J = 5.6 Hz, 1H), 4.48 (d, J = 4.4 Hz, 1H), 4.95 (d, J =
are reported in hertz. 13C NMR spectra (CDCl3, CD3OD, or 5.6 Hz, 1H), 7.20–7.50 (m, 21H), 7.81–7.84 (m, 4H).
DMSO-d6) were recorded on a Varian Unity Inova 100 MHz
((3aR,6R,6aR)-6-(tert-Butyldiphenylsilyloxy)-5-iodo-2,2-dimethyl-
instrument. 19F NMR spectra (CDCl3 or CD3OD) were recorded 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (14).
on a Varian Unity Inova 376 MHz instrument. The chemical To a stirred solution of 13 (30.00 g, 37.84 mmol) in anhydrous
shifts were reported as parts per million (δ) relative to the methylene chloride (300 mL) was added trimethylaluminium
solvent peak. Optical rotations were determined on Jasco III (47.3 mL, 94.59 mmol) dropwise at −10 °C under nitrogen and
in an appropriate solvent. UV spectra were recorded on the resulting solution was slowly allowed to reach room temp-
U-3000 made by Hitachi in methanol or water. Infrared spectra erature and stirred for an additional 2 h. The reaction mixture
were recorded on FT-IR (FTS-135) made by Bio-Rad. Melting was cooled to 0 °C, quenched with ammonium chloride
points were determined on a Buchan B-540 instrument and (200 mL) slowly and extracted with methylene chloride
are uncorrected. Reactions were checked with TLC (Merck pre- (150 mL × 2). The combined organic layers were washed
coated 60F254 plates). Flash column chromatography was per- with brine (100 mL × 2), dried over anhydrous MgSO4, filtered,
formed on silica gel 60 (230–400 mesh, Merck). Reagents were and concentrated under reduced pressure. The residue
purchased from Aldrich Chemical Co. Solvents were obtained was purified by flash silica gel column chromatography
from local suppliers. All the anhydrous solvents used were (hexane : EtOAc = 3 : 1) to give 14 (18.00 g, 86%) as a white
1
redistilled over CaH, P2O5, or sodium/benzophenone prior to foam: [α]2D5 = +6.1 (c 5.0, CH2Cl2); H NMR (CDCl3, 400 MHz)
the reaction.
δ 1.16 (s, 3H), 1.22 (s, 3H), 1.40 (s, 9H), 4.04 (t, J = 5.2 Hz, 1H),
((3aR,4R,6aR)-tert-Butyl-5-iodo-2,2-dimethyl-6-(trityloxymethyl)- 4.28–4.40 (m, 2H), 4.52–4.54 (m, 1H), 4.80 (d, J = 5.6 Hz, 1H),
4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenyl- 7.30–7.47 (m, 6 H), 7.81–7.85 (m, 4 H); 13C NMR (CDCl3,
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100 MHz) δ 19.8, 26.7, 27.3, 27.6, 62.6, 71.0, 75.9, 79.0, 83.1, t, J = 6.0, 7.2 Hz, 1H), 7.26–7.42 (m, 5H); 13C NMR (100 MHz,
105.5, 112.1, 127.5, 127.7, 128.0, 128.2, 129.9 (d, J = 3.9 Hz), CDCl3) δ 26.5, 27.8, 61.3, 69.3 (d, J = 8.4 Hz), 73.1, 74.0 (d, J =
133.7, 134.1, 136.1, 136.6, 136.7; MS (ESI+): Calculated: 7.6 Hz), 78.6 (d, J = 10.0 Hz), 112.7, 115.3 (d, J = 5.4 Hz), 128.0,
573.0934 for C25H31IO4SiNa (M + Na)+, found: 573.0926.
128.6, 138.1, 157.8, 159.2 (d, J = 288.4 Hz); 19F NMR (376 MHz,
((3aR,4R,6aR)-6-(Benzyloxymethyl)-5-iodo-2,2-dimethyl-4,6a- CDCl3) δ −129.3; MS (ESI): Calculated: 295.1346 for C16H20FO4
dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)(tert-butyl)diphenyl- (M + H)+, found: 295.1342.
silane (15).14 To a stirred suspension of sodium hydride
(3aR,4R,6aR)-6-(Benzyloxymethyl)-5-fluoro-4-(4-methoxybenzyl-
(6.5 g, 163.48 mmol, 60% dispersion in mineral oil) in THF oxy)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole
(100 mL) was added a solution of 14 (18.00 g, 32.7 mmol) in (17). To a stirred ice cooled solution of 16 (2.8 g, 9.51 mmol)
THF (100 mL) at 0 °C and the mixture was stirred at room in DMF (30 mL) was added sodium hydride (1.52 g,
temperature for 30 min. To this solution, tetrabutylammonium 38.05 mmol, 60% dispersion in mineral oil) portionwise at
iodide (6.0 g, 16.35 mmol) and benzyl bromide (5.81 mL, 0 °C and the mixture was stirred at room temperature under a
49.05 mmol) were added at 0 °C and the reaction mixture was N2 atmosphere for 30 min. To this resulting solution, tetra-
continued to be stirred at room temperature for 4 h and then butylammonium iodide (1.76 g, 4.76 mmol) and 4-methoxy-
slowly poured into ice cold water (150 mL). The solution was benzyl chloride (1.55 mL, 11.42 mmol) were added at 0 °C and
further diluted with water (100 mL) and extracted with ethyl the mixture was allowed to stir at the same temperature for
acetate (100 mL × 2). The combined organic layers were 15 min, later at room temperature for 3 h. The reaction
washed with sodium thiosulfate solution (100 mL), dried over mixture was carefully poured into ice-cold water (50 mL) and
anhydrous MgSO4, filtered, and concentrated under reduced extracted with EtOAc (30 mL × 2). The combined organic layers
pressure. The residue was purified by silica gel column chrom- were washed with sodium thiosulfate solution (50 mL), dried
atography (hexane : EtOAc = 9 : 1) to give 15 (19.0 g, 95%) as a over anhydrous MgSO4, filtered and concentrated under
1
colorless oil: H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 1.23 (s, reduced pressure. The resulting residue was purified by flash
3H), 1.36 (s, 3H), 4.03 (t, J = 5.6 Hz, 1H), 4.18 (d, J = 11.6 Hz, silica gel column chromatography (hexane : EtOAc = 9 : 1) to
1H), 4.25 (d, J = 11.6 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.51 (d, give 17 (3.17 g, 81%) as a thick yellow syrup: [α]2D5 = −3.23
1
J = 5.6 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 5.6 Hz, (c 2.1, CH2Cl2); H NMR (CDCl3, 400 MHz) δ 1.42 (s, 3H), 1.48
1H), 7.34 (m, 11H), 7.82 (m, 4H); 13C NMR (CDCl3, 100 MHz) (s, 3H), 3.81 (s, 3H), 4.07–4.11 (m, 1H), 4.30–4.32 (m, 2H),
δ 19.8, 26.9, 27.3, 27.6, 68.2, 73.1, 77.5, 79.2, 82.4, 108.2, 111.9, 4.47–4.61 (m, 3H), 4.69 (superimposed ddd, J = 3.2, 5.6, 8.8
127.5, 127.7, 127.8, 127.9, 128.5, 129.9, 133.0, 134.1, 136.7, 136.7, Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 5.00 (dd, J = 6.0, 6.4 Hz, 1H),
138.3, 144.9. Remaining data matched with the earlier report.14
6.88–6.91 (m, 2H), 7.26–7.35 (m, 7H); 13C NMR (100 MHz,
(3aS,4R,6aR)-6-(Benzyloxymethyl)-5-fluoro-2,2-dimethyl-4,6a- CDCl3) δ 26.8, 27.7, 55.4, 61.3, 71.9, 72.9, 74.8 (d, J = 7.3 Hz),
dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (16).14 To a stirred 75.0 (d, J = 18.3 Hz), 78.5 (d, J = 9.6 Hz), 112.7, 114.0, 116.1 (d,
solution of 15 (2.85 g, 4.45 mmol) and N-fluorobenzene sulfo- J = 4.4 Hz), 127.8, 127.9, 128.5, 129.8, 130.0, 138.1, 157.8 (d, J =
nimide (2.1 g, 6.67 mmol) in dry THF (40 mL) was added 289.2 Hz), 159.5; 19F NMR (376 MHz, CDCl3) δ −126.8;
n-butyllithium (8.34 mL, 13.35 mmol, 1.6 M solution in MS (ESI): Calculated: 437.1740 for C24H27FNaO5 (M + Na)+,
hexanes) dropwise at −78 °C under a N2 atmosphere and the found: 437.1687.
resulting solution was stirred at the same temperature for an
(1R,2R,5R)-3-(Benzyloxymethyl)-4-fluoro-5-(4-methoxybenzyl-
additional 1 h. The reaction mixture was quenched with satu- oxy)cyclopent-3-ene-1,2-diol (18). A solution of 17 (0.5 g,
rated ammonium chloride solution (50 mL) and extracted with 1.21 mmol) in 2 N HCl/THF (1 : 1) (5 mL) was stirred at 30 °C
ethyl acetate (25 mL × 2). The combined organic layers were for 18 h. The reaction mixture was neutralized with saturated
washed with brine solution (30 mL), dried over anhydrous NaHCO3 (5 mL) solution, diluted with water (10 mL) and
MgSO4, filtered, and concentrated under reduced pressure. extracted with EtOAc (15 mL × 3). The combined organic layers
The crude residue was purified by flash silica gel column were dried over anhydrous MgSO4, filtered, and concentrated
chromatography (hexane : EtOAc = 30 : 1) to give an inseparable under reduced pressure. The resulting residue was purified by
mixture of 5-F and 5-H derivatives (1.8 g) as a colorless oil. To flash silica gel column chromatography (hexane : EtOAc =
a stirred solution of a mixture of above derivatives (1.8 g, 1.5 : 1) to give 18 (0.35 g, 78%) as a white solid: [α]2D5 = +62.66
3.38 mmol) in THF (25 mL) was added tetrabutylammonium (c 0.3, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 2.76 (d, J = 6.8 Hz,
fluoride (5 mL, 1.69 mmol, 1.0 M solution in THF) at 0 °C and 1H), 3.24 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 4.07–4.18 (m, 2H),
the mixture was stirred at room temperature for 2 h and 4.21–4.24 (m, 2H), 4.46–4.56 (m, 3H), 4.70 (s, 2H), 6.88–6.91
evaporated. The crude residue was purified by flash silica gel (m, 2H), 7.26–7.35 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 55.4,
column chromatography (hexane : EtOAc = 5 : 1) to give 1614 61.5, 67.8 (d, J = 7.7 Hz), 71.4 (d, J = 7.8 Hz), 73.0, 73.1, 75.9 (d,
(0.85 g, 65% for 2 steps) as a colorless syrup and 5-H derivative J = 19.4 Hz), 114.1, 119.3 (d, J = 3.1 Hz), 128.0, 128.6, 129.4,
(0.1 g, 8% for 2 steps) as a colorless syrup:
129.9, 138.0, 159.5 (d, J = 287.9 Hz), 159.7; 19F NMR (376 MHz,
1
Compound 16. [α]2D5 = +42.3 (c 1.0, CHCl3); H NMR (CDCl3,
400 MHz) δ 1.42 (s, 3H), 1.46 (s, 3H), 2.83 (d, J = 8.4 Hz, 1H),
4.06–4.10 (m, 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.47–4.58 (m, 3H),
4.69 (superimposed ddd, J = 3.6, 6.0, 9.6 Hz, 1H), 5.06 (pseudo
CDCl3)
δ
−126.1; MS (ESI+): Calculated: 397.1427
for C21H23FNaO5 (M + Na)+, found: 397.1391.
(1R,4R,5R)-2-(Benzyloxymethyl)-3-fluoro-5-hydroxy-4-(4-methoxy-
benzyloxy)cyclopent-2-enyl pivalate (19a) and (1R,2R,5R)-3-
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(benzyloxymethyl)-4-fluoro-2-hydroxy-5-(4-methoxybenzyloxy)- room temperature for 18 h. The reaction mixture was
cyclopent-3-enyl pivalate (19b). To a stirred solution of 18 quenched with saturated NaHCO3 solution and extracted with
(1.26 g, 3.37 mmol) in methylene chloride (20 mL) were added methylene chloride twice. The combined organic layers were
DMAP (0.062 g, 0.15 mmol), DIPEA (1.75 mL, 10.1 mmol), and washed with brine and water, dried over anhydrous MgSO4, fil-
trimethylacetyl chloride (0.45 mL, 3.7 mmol) at −10 °C and tered and concentrated under reduced pressure. The residue
the resulting solution was stirred at the same temperature for obtained was purified by flash silica gel column chromato-
an additional 2 h and quenched with saturated NaHCO3 graphy (hexane : EtOAc = 4 : 1) to yield the hydroxy derivative
(15 mL) solution. The aqueous phase was extracted with 22 or 23, respectively.
methylene chloride (15 mL × 2). The combined organic layers
(1R,5R)-3-(Benzyloxymethyl)-4,4-difluoro-5-hydroxycyclopent-2-
were washed with brine (20 mL), dried over anhydrous MgSO4, enyl pivalate (22). Yellow syrup. Yield: 82%; [α]2D5 = −62.8
filtered, and concentrated under reduced pressure. The crude (c 5.07, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 1.22 (s, 9H), 1.57
residue obtained was purified by flash silica gel column (br s, 1H), 2.37 (dd, J = 2.4, 10.4 Hz), 4.19–4.40 (m, 3H),
chromatography (hexane : EtOAc = 9 : 1) to give 19a and 19b as 4.58–4.59 (m, 2H), 5.48–5.51 (m, 1H), 6.35–6.37 (m, 1H),
a 5 : 1 inseparable mixture as predicted by 1H NMR.
7.26–7.39 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 21.7, 27.8,
(1R,5R)-3-(Benzyloxymethyl)-4,4-difluoro-5-(4-methoxybenzyl- 39.0, 55.4, 64.0, 71.3 (dd, J = 1.8, 12.2 Hz), 72.6, 72.8 (d, J = 7.1
oxy)cyclopent-2-enyl pivalate (20) and (1R,4R,5S)-2-(benzyloxy- Hz), 73.1, 122.7 (d, J = 248.7 Hz), 127.7, 127.9, 128.5, 131.9 (m),
methyl)-3,5-difluoro-4-(4-methoxybenzyloxy)cyclopent-2-enyl 137.4, 142.6 (dd, J = 22.8, 25.7 Hz), 165.2, 168.5, 177.5;
pivalate (21). To a stirred solution of 19a and 19b (0.37 g, 19F NMR (CDCl3, 400 MHz), δ −108.4 (dt, JC–F = 7.5, 255.3
0.8 mmol) in methylene chloride (10 mL) were added pyridine Hz, 1F), −109.2 (dd, JC–F = 10.2, 255.3 Hz, 1F); MS (ESI+):
(0.26 mL, 3.19 mmol) and DAST (0.37 mL, 2.79 mmol) at 0 °C Calculated: 363.1384 for C18H22F2NaO4 (M + H)+, found:
and the reaction mixture was heated to 45 °C for 18 h. The 363.1382.
reaction mixture was cooled to room temperature, quenched
(1R,4R,5R)-2-(Benzyloxymethyl)-3,5-difluoro-4-hydroxycyclo-
with saturated NaHCO3 (10 mL) solution and extracted with pent-2-enyl pivalate (23). Yellow syrup. Yield: 80%; [α]2D5 = −2.8
methylene chloride (10 mL × 2). The combined organic layers (c 1.82, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 1.17 (s, 9H), 3.24
were washed with brine (10 mL), dried over anhydrous MgSO4, (d, J = 6.8 Hz, 1H), 3.91–3.95 (m, 1H), 4.17 (d, J = 12.1 Hz, 1H),
filtered, and concentrated under reduced pressure. The crude 4.47 (dd, JAB = 12.1 Hz, 2H), 4.67–4.74 (m, 1H), 4.82 (d, JH–F
=
residue was purified by flash silica gel column chromato- 50.0 Hz, 1H), 5.60–5.68 (m, 1H), 7.25–7.36 (m, 5H); 13C NMR
graphy (hexane : EtOAc = 9 : 1) to yield 20 (0.05 g, 14%) and 21 (CDCl3, 100 MHz) δ 27.1, 39.0, 60.5, 73.0, 74.4 (dd, J = 21.7,
(0.21 g, 57%) as thick yellow syrups.
29.5 Hz), 75.7 (dd, J = 7.7, 31.0 Hz), 101.1 (dd, JC–F = 7.3, 200.0
Compound 20. [α]D25 = −55.04 (c 4.5, CH2Cl2); 1H NMR
(CDCl3, 400 MHz) δ 1.14 (s, 9H), 3.80 (s, 3H), 4.09–4.28 (m,
3H), 4.54–4.57 (m, 3H), 4.68 (d, J = 11.2 Hz, 1H), 5.62–5.64 (m,
1H), 6.24–6.25 (m, 1H), 6.84–6.87 (m, 2H), 7.24–7.38 (m, 7H);
13C NMR (CDCl3, 100 MHz) δ 27.3, 39.0, 55.4, 64.0, 70.6 (d, J =
8.6 Hz), 73.1, 73.3, 78.04–78.51 (m), 113.9, 127.9, 128.1, 128.7,
129.4, 129.9, 132.0 (t, J = 8.6 Hz), 137.7, 142.1 (t, J = 24.4 Hz),
Hz), 114.3 (d, J = 3.9, 7.0 Hz), 128.1, 128.6, 137.6, 157.5 (dd, JC–F
=
7.8, 288.0 Hz), 178.1; 19F NMR (376 MHz, CDCl3) δ −129.3,
−190.8; MS (ESI+): Calculated: 363.1384 for C18H22F2NaO4
(M + Na)+, found: 363.1377.
(1R,4R,5R)-2-(Benzyloxymethyl)-3-fluoro-4-(4-methoxybenzyloxy)-
5-(trifluoromethyl sulfonyloxy)cyclopent-2-enyl pivalate (26).
To a stirred solution of 19a and 19b (0.05 g, 0.11 mmol) in pyri-
dine (2 mL) was added trifluoromethanesulphonic anhydride
(0.037 mL, 0.22 mmol) dropwise at 0 °C and the mixture was
stirred for an additional 30 min. The reaction mixture
was quenched with saturated NaHCO3 (5 mL) solution and
extracted with methylene chloride (10 mL). The organic layer
was washed with brine (10 mL), dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The result-
ing residue was taken for the next step as such immediately.
For analytical purpose the residue was purified by short flash
silica gel column chromatography (hexane : EtOAc = 10 : 1) to
give 26 (0.05 g, 81%) as a yellow syrup: 1H NMR (CDCl3,
400 MHz) δ 1.17 (s, 9H), 3.80 (s, 3H), 3.96 (dd, J = 2.8, 12 Hz,
1H), 4.21 (d, J = 12.4 Hz, 1H), 4.43–4.51 (m, 3H), 4.65 (dd, J =
11.2, 11.6 Hz, 2H), 5.10 (t, J = 6.0 Hz, 1H), 5.90 (t, J = 5.6 Hz,
1H), 6.86–6.89 (m, 2 H), 7.25–7.40 (m, 7H).
160.0, 178.2; 19F NMR (CDCl3, 400 MHz), δ −108.4 (dt, JC–F
=
7.5, 255.3 Hz, 1F), −109.2 (dd, JC–F = 10.2, 255.3 Hz, 1F);
MS (ESI+): Calculated: 483.1959 for C26H30F2NaO5 (M + Na)+,
found: 483.1908.
Compound 21. [α]D25 = +10.15 (c 4.5, CH2Cl2); 1H NMR
(CDCl3, 400 MHz) δ 1.18 (s, 9H), 3.80 (s, 3H), 3.90–3.94 (m,
1H), 4.17 (d, J = 12.4 Hz, 1H), 4.42–4.54 (m, 3H), 4.65 (d, J =
11.2 Hz, 2H), 4.84 (d, JF–H = 50.0 Hz, 1H), 5.71–5.78 (m, 1H),
6.88–6.91 (m, 2H), 7.24–7.35 (m, 7H); 13C NMR (CDCl3,
100 MHz) δ 27.2, 39.0, 55.5, 60.5, 72.3, 73.0, 75.2 (dd, J = 8.1,
30.1 Hz), 80.1 (dd, J = 19.8, 27.9 Hz), 100.2 (dd, JC–F = 192.3,
7.3 Hz), 114.2, 115.2 (m), 128.0, 128.6, 129.1, 129.9, 137.7,
156.7 (dd, JC–F = 8.1, 288.5 Hz), 159.8, 177.6; 19F NMR
(376 MHz, CDCl3) δ −123.1, −185.7; MS (ESI+): Calculated:
483.1959 for C26H30F2NaO5 (M + Na)+, found: 483.1916.
General procedure for PMB deprotection
Alternative synthesis of 21
To a stirred solution of PMB protected derivative 20 or 21 To a stirred solution of 26 (1.5 g, 2.54 mmol) in THF (30 mL)
(1 equiv.) in CH2Cl2/H2O (10 : 1) was added DDQ (2 equiv.) at was added tetrabutylammonium fluoride (5.08 mL,
room temperature and the reaction mixture was stirred at 5.08 mmol, 1.0 M solution in THF) at room temperature under
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a N2 atmosphere and the resulting solution was stirred at condensed product, which was taken for next step with DIAD
room temperature for 12 h. The reaction mixture was evapo- impurities.
rated and the crude residue was purified by flash silica gel
Amination. A solution of the condensed product (1 equiv.)
column chromatography (hexane : EtOAc = 9 : 1) to yield 21 in saturated NH3/tBuOH (10 mL) was stirred at 110 °C for 16 h.
(0.68 g, 58%) as a thick yellow syrup, whose spectroscopic data The reaction mixture was cooled to room temperature and con-
were identical to those of the authentic sample.
centrated under reduced pressure. The residue was further
(1R,4R,5S)-5-Azido-2-(benzyloxymethyl)-3-fluoro-4-(4-methoxy- purified by flash silica gel column chromatography (CH2Cl2 :
benzyloxy)cyclopent-2-enyl pivalate (25). To a stirred solution MeOH = 30 : 1) to yield adenine derivative 28, 29, or 31.
of 26 (3.0 g, 5.08 mmol) in DMF (30 mL) was added sodium
(1R,4S,5R)-4-(6-Amino-9H-purin-9-yl)-2-(benzyloxymethyl)-3,5-
azide (0.49 g, 7.61 mmol) portionwise at room temperature difluoro-cyclopent-2-enyl pivalate (28). Yellow foam. Yield:
under a N2 atmosphere and the resulting solution was stirred 74% (for 2 steps); UV (CH2Cl2) λmax 257 nm; [α]2D5 = −161 (c 0.2,
1
at the same temperature for an additional 3 h. The reaction CH2Cl2); H NMR (CDCl3, 400 MHz) δ 1.20 (s, 9H), 4.12–4.16
mixture was quenched with water (50 mL) and then extracted (m, 1H), 4.33 (d, J = 12.4 Hz, 1H), 4.60 (dd, J = 11.6, 12.0 Hz,
with EtOAc (25 mL × 2). The combined organic layers were 2H), 5.25 (d, JH–F = 49.6 Hz, 1H), 6.13–6.21 (m, 2H), 7.30–7.38
washed with brine (2 × 25 mL), dried over anhydrous MgSO4, (m, 5H), 8.07 (s, 1H), 8.17 (s, 1H); 13C NMR (CDCl3, 100 MHz)
filtered, and concentrated under reduced pressure. The crude δ 27.3, 27.4, 27.9, 39.8, 56.9 (t, J = 19.8 Hz), 61.4, 73.8, 78.7 (dd,
residue was purified by flash silica gel column chromato- J = 8.4, 29.0 Hz), 91.5 (dd, JC–F = 5.3, 196.8 Hz), 118.7, 120.0,
graphy (hexane : EtOAc = 15 : 1) to give 25 (1.85 g, 75%) as a 129.0, 129.1, 129.4, 139.0, 142.0, 151.2, 154.2, 154.7 (d, JC–F
=
yellow syrup. [α]D25
=
+49.4 (c 1.75, CH2Cl2); IR (film) 285.3 Hz), 157.4, 178.9; 19F NMR (376 MHz, CDCl3) δ −121.3,
2105.2 cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.18 (s, 9H), 3.82 (s, −192.2; MS (ESI+): Calculated: 458.2004 for C23H26F2N5O3
4H), 3.93–3.96 (m, 1H), 4.18 (d, J = 12.0 Hz, 1H), 4.26 (t, J = 2.8 (M + H)+, Found: 458.1997.
Hz, 1H), 4.46 (dd, J = 11.6, 12.0 Hz, 2H), 4.65 (dd, J = 11.2, 11.6
(1R,4S,5R)-4-(6-Amino-9H-purin-9-yl)-5-azido-2-(benzyloxy-
Hz, 2H), 5.57 (dd, J = 3.2, 7.6 Hz, 1H), 6. 89–6.92 (m, 2H), methyl)-3-fluoro-cyclopent-2-enyl pivalate (29). Yellow syrup.
7.26–7.37 (m, 7H); 13C NMR (CDCl3, 100 MHz) δ 27.1, 39.0, Yield: 72% (for 2 steps); UV (MeOH) λmax 260 nm; [α]2D5 = +14.7
55.5, 60.6, 70.40 (d, J = 27.6 Hz), 72.6, 75.5 (d, J = 7.7 Hz), 80.5 (c 1.75, CH2Cl2); IR (KBr) 2110.4 cm−1 1H NMR (CDCl3,
;
(d, J = 19.4 Hz), 114.2, 115.3 (d, J = 7.0 Hz), 128.0, 128.0, 128.1, 400 MHz) δ 1.20 (s, 9H), 4.12–4.16 (m, 1H), 4.33 (d, J = 12.4 Hz,
128.6, 129.2, 129.9, 137.7, 157.7 (d, JC–F = 287.9 Hz), 159.8, 1H), 4.60 (dd, J = 11.6, 12.0 Hz, 2H), 5.25 (d, 1H), 6.13–6.21 (m,
177.7; 19F NMR (376 MHz, CDCl3) δ −123.5; MS (ESI+): Calcu- 2H), 7.30–7.38 (m, 5H), 8.07 (s, 1H), 8.17 (s, 1H); 13C NMR
lated: 506.2067 for
C
26H30FN3NaO5 (M
+
Na)+, found: (CDCl3, 100 MHz) δ 27.3, 27.4, 27.9, 39.8, 56.9, 61.4, 73.8, 78.7,
506.2005.
91.5, 118.7, 120.0, 129.0, 129.1, 129.4, 139.0, 142.0, 151.2,
(1R,4R,5R)-5-Azido-2-(benzyloxymethyl)-3-fluoro-4-hydroxy- 154.2, 154.7 (d, JC–F = 285.3 Hz), 157.4, 178.9; 19F NMR
cyclopent-2-enylpivalate (27). Compound 25 was converted to (376 MHz, CDCl3) δ −121.3; MS (ESI+): Calculated: 481.2112 for
27 according to the same procedure used for the synthesis of C23H26FN8O3 (M + H)+, Found: 481.2110.
22 and 23. Yield: 73%; [α]2D5 = +57.7 (c 1.8, CH2Cl2); IR (film)
(1R,5S)-5-(6-Amino-9H-purin-9-yl)-3-((benzyloxy)methyl)-4,4-
2109.2 cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.19 (s, 9H), 2.85 (s, difluorocyclopent-2-enyl pivalate (31). White solid. Yield: 60%
1H), 3.81–3.83 (m, 1H), 3.93–3.97 (m, 1H), 4.16 (d, J = 12.0 Hz, (for 2 steps); UV (MeOH) λmax 259 nm; [α]2D5 = +54.4 (c 1.8,
1H), 4.43–4.51 (m, 3H), 5.56–5.58 (m, 1H), 7.26–7.37 (m, 5H); MeOH); 1H NMR (CD3OD, 400 MHz) δ 4.31 (s, 2H), 4.62 (s,
13C NMR (CDCl3, 100 MHz) δ 27.1, 60.6, 72.0 (d, J = 6.9 Hz), 2H), 4.70–4.77 (m, 1H), 5.39–5.41(m, 1H), 6.41 (s, 1H),
73.1, 75.5 (d, J = 7.7 Hz), 114.6 (d, J = 7.0 Hz), 128.1, 128.1, 7.26–7.40 (m, 5H), 8.13 (s, 1H), 8.17 (s, 1H); 13C NMR (CD3OD,
128.7, 137.6, 157.7 (d, JC–F = 287.1 Hz), 159.8, 178.0; 19F NMR 100 MHz) δ 47.1, 61.9 (d, J = 8.1 Hz), 63.7, 73.0, 78.9 (t, J =
(376 MHz, CDCl3) δ −126.0; MS (ESI+): Calculated: 386.1492 for 24.9 Hz), 119.5, 122.4, 124.8, 127.3, 128.4, 128.5, 129.0,
C18H22FN3NaO4 (M + Na)+, found: 386.1485.
134.2–134.4 (m), 138.3, 138.9 (dd, J = 19.7, 27.1 Hz), 141.2,
149.9, 153.3, 157.2; 19F NMR (CDCl3, 376 MHz), δ −105.7 (d,
J = 252.3 Hz, 1F), −111.3 (d, J = 252.3 Hz, 1F); MS (ESI+): Calcu-
lated: 374.1429 for C18H18F2N5O2 (M + H)+, Found: 374.1430.
General procedure for Mitsunobu condensation and
amination
Mitsunobu
condensation. Diisopropylazidocarboxylate
General procedure for debenzylation and depivaloylation
(DIAD) (9.16 mmol) in THF was added to a stirred solution of
6-chloropurine or pyrimidine base (4.4 mmol) and triphenyl-
Debenzylation. Boron tribromide (3 equiv.) (1 M solution in
phosphine (Ph3P) (4.4 mmol) in anhydrous THF under N2 at methylene chloride) was added dropwise to a stirred solution
0 °C and the mixture was stirred at the same temperature for of protected nucleoside 28, 29, or 31 (1 equiv.) in methylene
15 min. To this mixture was added a solution of glycosyl donor chloride (15 mL) at −78 °C under a N2 atmosphere and the
22, 23 or 27 (2.93 mmol) in THF and the reaction mixture was mixture was stirred at the same temperature for an additional
allowed to warm to room temperature and stirred for an 2 h. The reaction mixture was quenched with MeOH and neu-
additional 16 h. The reaction mixture was concentrated under tralized with pyridine. After removal of the solvent under
reduced pressure and the crude residue obtained was purified reduced pressure, the reaction mixture was further diluted
by short flash silica gel column chromatography to give a with water and extracted with methylene chloride twice. The
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combined organic layers were washed with brine, dried over lated: 281.1162 for C11H14FN6O2 (M + H)+, Found: 281.1161;
anhydrous MgSO4, filtered and concentrated under reduced [α]2D5 = −34.0 (c 0.45, MeOH); 1H NMR (CD3OD, 400 MHz) δ 3.6
pressure. The crude residue obtained was purified by flash (m, 1H), 4.17 d, J = 13.2 Hz, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.77
silica gel column chromatography (CH2Cl2 : MeOH = 19 : 1) (s, 1H), 5.66 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 8.21(s, 1H);
to yield debenzylated derivatives.
13C NMR (CD3OD, 100 MHz) δ 51.9, 57.3 (d, J = 17.3 Hz),
Depivaloylation. A solution of debenzylated derivatives 59.5 (d, J = 4.3 Hz), 77.7 (d, J = 6.7 Hz), 118.7, 124.5,
(1 equiv.) in saturated NH3/MeOH (5 mL) was stirred at 40 °C 140.1, 148.7, 150.1, 151.6, 152.3, 155.6; 19F NMR (376 MHz,
for 18 h. The reaction mixture was concentrated under reduced CD3OD) δ −132.2.
pressure and the crude residue was purified by flash silica gel
column chromatography (CH2Cl2 : MeOH = 9 : 1) to yield
General procedure for the synthesis of 32–35
8a, 9a, or 10.
The glycosyl donors 23 and 27 were converted to the pyrimi-
(1R,4S,5R)-4-(6-Amino-9H-purin-9-yl)-3,5-difluoro-2-hydroxy- dine nucleosides 32–35 using the Mitsunobu condensation
methyl)cyclopent-2-en-ol (8a). White solid. Yield: 65% (for and debenzylation described earlier.
2 steps); m.p.: 192–194 °C; UV (MeOH) λmax 259 nm; MS (ESI+):
(1R,4S,5R)-4-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,5-
Calculated: 284.0959 for C11H12F2N5O2 (M + H)+, Found: difluoro-2-(hydroxy-methyl)cyclopent-2-enyl
pivalate (32).
284.0958; [α]2D5 = −60.58 (c 0.17, MeOH); 1H NMR (CDCl3, Yellow foam. Yield: 65%; UV (MeOH) λmax 261 nm; MS (ESI+):
400 MHz) δ 4.18–4.22 (m, 1H), 4.48 (d, J = 13.2 Hz, 1H), Calculated: 345.1262 for C15H19F2N2O5 (M + H)+, Found:
5.01–5.17 (m, 2H), 6.02–6.06 (m, 1H), 8.08 (s, 1H), 8.23 (s, 1H); 345.1257; [α]2D5 = −113 (c 0.2, CH2Cl2); 1H NMR (CDCl3,
13C NMR (CDCl3, 100 MHz) δ 53.9, 56.8 (dd, J = 18.3, 21.2 Hz), 400 MHz) δ 1.25 (s, 9H), 2.90 (s, 1H), 3.96 (d, J = 16.0 Hz, 1H),
76.3 (dd, JC–F = 7.3, 27.8 Hz), 94.5 (dd, JC–F = 5.1, 196.3 Hz), 4.48 (d, J = 14.0 Hz, 1H), 5.15 (d, JH–F = 49.6 Hz, 1H), 5.80–5.86
120.0, 124.3, 141.5, 141.6, 151.3, 151.6 (d, JC–F = 282.7 Hz), (m, 2H), 6.03 (s, 1H), 7.09–7.12 (m, 1H), 9.31 (s, 1H); 13C NMR
153.8, 154.2, 157.5; 19F NMR (376 MHz, CDCl3) δ −127.5, (CDCl3, 100 MHz) δ 27.3, 39.2, 53.7, 57.1 (t, J = 18.3 Hz), 77.1,
−192.6.
89.7 (dd, JC–F = 5.1, 194.2 Hz), 102.9, 121.4, 141.5, 151.3,
(1R,4S,5R)-4-(6-Amino-9H-purin-9-yl)-5-azido-3-fluoro-2-(hydroxy- 152.3 (d, JC–F = 286.3 Hz), 163.0, 179.3; 19F NMR (376 MHz,
methyl)cyclopent-2-enol (9a). White solid. Yield: 66% (for CDCl3) δ −127.9, −198.7.
2 steps); m.p.: 180–182 °C; UV (MeOH) λmax 260 nm; MS (ESI+):
(1R,4S,5R)-3,5-Difluoro-2-(hydroxymethyl)-4-(5-methyl-2,4-
Calculated: 307.1067 for C11H12FN8O2 (M + H)+, Found: dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)cyclopent-2-enyl pivalate
307.1067; [α]2D5 = −175.5 (c 0.2, MeOH); IR (KBr) 2114.9 cm−1
;
(33). Yellow foam. Yield: 66%; UV (MeOH) λmax 265 nm;
1H NMR (CD3OD, 400 MHz) δ 4.19 (d, J = 13.2 Hz, 1H), 4.32 MS (ESI+): Calculated: 359.1419 for C16H21F2N2O5 (M + H)+,
(dd, J = 4.4, 7.2 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H), 4.94–4.96 (m, Found: 359.1414; [α]2D5 = −163.5 (c 0.2, CH2Cl2); 1H NMR
1H), 5.90 (d, J = 7.6 Hz, 1H), 8.06 (s, 1H), 8.24 (s, 1H); 13C NMR (CDCl3, 400 MHz) δ 1.25 (s, 9H), 1.94 (s, 3H), 3.01 (s, 1H),
(CD3OD, 100 MHz) δ 53.8, 57.4 (d, J = 21.7 Hz), 68.5 (d, J = 3.94–3.98 (m, 1H), 4.50 (d, J = 14.0 Hz, 1H), 5.14 (d, JH–F
6.2 Hz), 77.1 (d, J = 6.9 Hz), 120.1, 125.6, 141.2, 151.2 (d, JC–F 50.0 Hz, 1H), 5.83 (dd, J = 5.6, 18.4 Hz, 1H), 6.01 (s, 1H), 6.90
282.7 Hz), 151.4, 154.2, 157.5; 19F NMR (376 MHz, CD3OD) (s, 1H), 9.38 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 12.6, 27.3,
δ −131.0. 39.2, 53.7, 56.8 (m), 77.0, 89.7 (dd, JC–F = 5.1, 193.7 Hz), 111.4,
=
=
(1R,5S)-5-(6-Amino-9H-purin-9-yl)-4,4-difluoro-3-(hydroxymethyl)- 121.0, 137.2, 151.5, 152.4, 152.8 (d, JC–F = 286.9 Hz), 163.8,
cyclopent-2-enol (10). White solid. Yield: 50% (for 2 steps); 179.3; 19F NMR (376 MHz, CDCl3) δ −127.6, −198.8.
m.p.: 230–232 °C; UV (MeOH) λmax 260 nm; MS (ESI+): Calcu-
(1R,4S,5R)-5-Azido-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
lated: 284.0959 for C11H12F2N5O2 (M + H)+, Found: 284.0979; yl)-3-fluoro-2-(hydroxy-methyl)cyclopent-2-enyl pivalate (34).
[α]2D5 = +52.3 (c 1.75, MeOH); 1H NMR (CD3OD, 400 MHz) Yellow foam. Yield: 64%; UV (MeOH) λmax 260 nm; MS (ESI+):
δ 4.31–4.42 (m, 2H), 4.67–4.74 (m, 1H), 5.37–5.40 (m, 1H), 6.33 Calculated: 368.1370 for C15H19FN5O5 (M + H)+, Found:
(s, 1H), 8.14 (s, 1H), 8.19 (s, 1H); 13C NMR (CD3OD, 100 MHz) 368.1364; [α]2D5 = −40.62 (c 1.6, CH2Cl2); IR (KBr) 2120.1 cm−1
;
δ 57.8, 63.7 (m), 80.9 (t, J = 25.4 Hz), 121.4, 123.8, 126.3, 1H NMR (CD3OD, 400 MHz) δ 1.21 (s, 9H), 3.97 (dt, J = 2.0,
128.8, 132.7–132.9 (m), 142.4, 144.7, 151.8, 154.8, 158.31; 13.2 Hz, 1H), 4.25 (dt, J = 2.4, 7.2 Hz, 1H), 4.37–4.41 (m, 1H),
19F NMR (CDCl3, 376 MHz), δ −106.3 (d, J = 248.1 Hz, 1F), 5.71 (m, 2H), 5.90 (s, 1H), 7.21 (dd, J = 1.6, 8.4 Hz, 1H);
−112.7 (d, J = 252.0 Hz, 1F).
13C NMR (CDCl3, 100 MHz) δ 27.3, 39.5, 53.4, 58.4, 78.8,
(1R,4S,5R)-5-Amino-4-(6-amino-9H-purin-9-yl)-3-fluoro-2-(hydroxy- 102.7, 122.5, 142.4, 152.3, 152.7 (d, JC–F = 284.1 Hz), 164.9,
methyl)cyclopent-2-enol (9b). To a solution of 9a (0.05 g, 179.0; 19F NMR (376 MHz, CDCl3) δ −123.2.
0.15 mmol) in THF (4 mL) was added triphenylphosphine
(1R,4S,5R)-5-Azido-3-fluoro-2-(hydroxymethyl)-4-(5-methyl-2,4-
(0.3 mmol) at 0 °C. To this solution, ammonium hydroxide dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)cyclopent-2-enyl pivalate
(0.5 mL) and water (0.1 mL) were added and the reaction (35). Yellow foam. Yield: 52%; UV (MeOH) λmax 265 nm; MS
mixture was stirred at room temperature overnight. The reac- (ESI+): Calculated: 382.1527 for C16H21FN5O5 (M + H)+, Found:
tion mixture was concentrated under reduced pressure and the 382.1522; [α]2D5 = −93.6 (c 1.75, MeOH); IR (KBr) 2115.6 cm−1
;
residue was purified by reverse phase column chromatography 1H NMR (CD3OD, 400 MHz) δ 1.25 (s, 9H), 1.95 (s, 3H), 3.98
(CH3CN : H2O = 9 : 1) to give 9b (0.04 g, 80%) as a white solid: (d, J = 13.6 Hz, 1H), 4.37 (d, J = 7.6 Hz, 1H), 4.36–4.50 (m, 2H),
m.p.: 135–137 °C; UV (MeOH) λmax 260 nm; MS (ESI+): Calcu- 5.70 (s, 1H), 5.99 (s, 1H), 6.86 (s, 1H), 9.7 (s, 1H); 13C NMR
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(CDCl3, 100 MHz) δ 12.5, 27.0, 39.0, 53.3, 56.9, 62.6, 78.3 (d, J = (10 mL) were added pyridine (0.35 mL, 4.35 mmol) and acetic
7.8 Hz), 111.4, 121.6, 136.3, 151.6, 152.2 (d, JC–F = 287.3 Hz), anhydride (0.25 mL, 2.62 mmol) at 0 °C, and the mixture was
163.8, 179.20; 19F NMR (376 MHz, CDCl3) δ −122.4.
stirred at room temperature for 16 h. The reaction mixture was
quenched with water (10 mL) and extracted with methylene
chloride (15 mL). The organic layer was washed with brine,
General procedure for the synthesis of 8b, 8c, 9c, and 9d
The pivaloyl derivatives 32–35 were converted to 8b, 8c, 9c, and dried over anhydrous MgSO4, filtered, and evaporated. The
9d, respectively, using the same procedure (NH3/MeOH, 40 °C, residue was purified by short silica gel column chromato-
15 h) described earlier.
graphy (hexane : EtOAc = 4 : 1) to give acetyl derivative as a
1-((1S,4R,5R)-2,5-Difluoro-4-hydroxy-3-(hydroxymethyl)cyclopent- yellow syrup (0.27 g, 81%).
2-enyl)pyrimidine-2,4(1H,3H)-dione (8b). White solid. Yield:
An ice cold solution of 1,2,4-triazole (0.49 g, 7.12 mmol) in
73%; m.p.: 182–184 °C; UV (MeOH) λmax 261 nm; MS (ESI+): anhydrous acetonitrile (5 mL) was treated with phosphorus
Calculated: 261.0687 for C10H11F2N2O4 (M + H)+, Found: oxychloride (0.66 mL, 7.12 mmol) at 0 °C under a N2 atmo-
261.0683; [α]2D5 = −16.2 (c 1.2, MeOH); 1H NMR (CD3OD, sphere and the mixture was stirred at the same temperature
400 MHz) δ 1.89 (s, 3H), 4.14 (dt, J = 2.4, 12.8 Hz, 1H), 4.43 (d, for 30 min. To this solution, acetylated derivative (0.27 g,
J = 13.2 Hz, 1H), 4.83–5.02 (m, 2H), 5.70 (d, J = 8.0 Hz, 1H), 0.71 mmol) in acetonitrile (5 mL) and triethylamine (0.99 mL,
5.90–591 (m, 1H), 7.38–7.41 (m, 1H); 13C NMR (CDCl3, 7.12 mmol) were added and the reaction mixture was stirred at
100 MHz) δ 53.8, 58.5 (t, J = 18.0 Hz), 75.9–76.3 (m), 94.2 (dd, room temperature for 16 h. The reaction mixture was evapor-
JC–F = 5.6, 193.7 Hz), 102.6, 125.2, 144.0, 151.6 (d, JC–F = 282.2 Hz), ated and the orange residue obtained was redissolved in
152.9, 166.0; 19F NMR (376 MHz, CDCl3) δ −131.6, −196.6.
1-((1S,4R,5R)-2,5-Difluoro-4-hydroxy-3-(hydroxymethyl)cyclopent- The organic layer was washed with brine, dried over anhydrous
2-enyl)-5-methyl-pyrimidine-2,4(1H,3H)-dione (8c). White MgSO4, filtered and evaporated. The residue obtained was dis-
methylene chloride (20 mL) and extracted with water (10 mL).
solid. Yield: 66%; m.p.: 181–183 °C; UV (MeOH) λmax 265 nm; solved in solution of NH4OH (3 mL) in 1,4-dioxane (5 mL) and
MS (ESI+): Calculated: 275.0843 for C11H13F2N2O4 (M + H)+, the mixture was allowed to stir at room temperature for 16 h.
1
Found: 275.0839; [α]2D5 = −39 (c 0.2, MeOH); H NMR (CD3OD, The reaction mixture was concentrated under reduced pressure
400 MHz) δ 1.88 (s, 3H), 3.02–3.32 (m, 1H), 4.14 (dt, J = 2.4, and the residue was purified by flash silica gel column chrom-
10.8 Hz, 1H), 4.44 (d, J = 13.2 Hz, 1H), 4.85–5.02 (m, 2H), atography to yield 36, which was converted to target derivative
5.49 (s, 1H), 5.89 (s, 1H), 7.21 (s, 1H); 13C NMR (CDCl3, 8d as a white solid, using the same procedure used for the syn-
100 MHz) δ 12.2, 53.7, 58.2 (t, 18.3 Hz), 76.2 (dd, J = 7.7, 28.3 thesis of 8b, 8c, 9c, and 9d. Yield: 71% (3 steps); m.p.:
Hz), 94.3 (dd, JC–F = 6.1, 194.5 Hz), 111.5, 124.8, 139.4, 207–208 °C; UV (MeOH) λmax 271 nm; MS (ESI+): Calculated:
152.0 (d, JC–F = 282.0 Hz), 153.1, 166.3; 19F NMR (376 MHz, 260.0847 for C10H12F2N3O3 (M + H)+, Found: 260.0843; [α]2D5
=
1
CDCl3) δ −131.4, −195.9.
−18 (c 0.2, MeOH); H NMR (CD3OD, 400 MHz) δ 4.14 (dt, J =
1-((1S,4R,5R)-5-Azido-2-fluoro-4-hydroxy-3-(hydroxymethyl)- 2.4, 13.2 Hz, 1H), 4.43 (d, J = 12.8 Hz, 1H), 4.80–5.03 (m, 2H),
cyclopent-2-enyl)pyrimidine-2,4(1H,3H)-dione
(9c). White 5.89 (d, J = 7.6 Hz, 1H), 6.0 (s, 1H), 7.37 (dt, J = 1.6, 7.6 Hz,
solid. Yield: 50%; m.p.: 170–172 °C; UV (MeOH) λmax 262 nm; 1H); 13C NMR (CD3OD, 100 MHz) δ 53.7, 59.4 (t, J = 18.3 Hz),
MS (ESI+): Calculated: 306.0615 for C10H10FN5NaO4 (M + Na)+, 76.1 (dd, J = 7.4, 28.6 Hz), 94.1 (dd, JC–F = 5.9, 194.1 Hz), 96.0,
Found: 306.0614; [α]2D5 = −62.3 (c 1.3, MeOH); IR (KBr) 124.7, 144.4, 152.6 (d, JC–F = 282.7 Hz), 159.0, 167.8; 19F NMR
1
2117 cm−1; H NMR (CD3OD, 400 MHz) δ 4.11–4.14 (m, 1H), (376 MHz, CDCl3) δ −131.5, −196.2.
4.21–4.24 (m, 1H), 4.40 (d, J = 13.2 Hz, 1H), 4.73 (s, 1H), 5.74
4-Amino-1-((1S,4R,5R)-5-azido-2-fluoro-4-hydroxy-3-(hydroxy-
(d, J = 8.0 Hz, 1H), 5.85 (s, 1H), 7.14 (s, 1H); 13C NMR (CD3OD, methyl)cyclopent-2-enyl)pyrimidin-2(1H)-one (9e). Compound
100 MHz) δ 53.7, 58.8, 64.4, 67.8, 77.1 (d, J = 7.0 Hz), 102.9, 34 was converted to 9e according to the same procedure used
126.5, 143.1, 151.4 (d, JC–F = 281.8 Hz), 153.1, 166.0; 19F NMR in the synthesis of 8d: white solid; yield: 66% (3 steps); m.p.:
(376 MHz, CD3OD) δ −130.44.
173–175 °C; UV (MeOH) λmax 273 nm; MS (ESI+): Calculated:
1-((1S,4R,5R)-5-Azido-2-fluoro-4-hydroxy-3-(hydroxymethyl)- 283.0955 for C10H12FN6O3 (M + H)+, Found: 283.0952; [α]2D5
=
1
cyclopent-2-enyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(9d). −34.1 (c 0.44, MeOH); IR (KBr) 2115.8 cm−1; H NMR (CD3OD,
White solid. Yield: 75%; m.p.: 172–174 °C; UV (MeOH) λmax 400 MHz) δ 4.12 (dt, J = 1.6, 13.6 Hz, 1H), 4.20–4.22 (m, 1H),
265 nm; MS (ESI+): Calculated: 298.0952 for C11H13FN5O4 4.40 (d, J = 13.2 Hz, 1H), 4.69 (s, 1H), 5.92 (d, J = 7.6 Hz, 1H),
(M + H)+, Found: 298.0948; [α]D25 = −88.5 (c 1.75, MeOH); 5.96 (s, 1H), 7.33 (dd, J = 2.0, 7.6 Hz, 1H); 13C NMR (CD3OD,
IR (KBr) 2112.7 cm−1 1H NMR (CD3OD, 400 MHz) δ 1.90 (s, 100 MHz) δ 53.7, 59.7, 68.0, 77.0 (d, J = 6.1 Hz), 96.3, 125.9,
;
3H), 4.10–4.22 (m, 2H), 4.37 (d, J = 12.8 Hz, 1H), 4.74 (s, 1H), 143.6, 152.1 (d, JC–F = 282.5 Hz), 159.1, 167.7; 19F NMR
5.85 (s, 1H), 7.14 (s, 1H); 13C NMR (CD3OD, 100 MHz) δ 12.3, (376 MHz, CD3OD) δ −130.2.
53.6, 58.6, 67.83, 77.0 (d, J = 4.7 Hz), 112.0, 126.2, 138.3, 151.4
(d, JC–F = 282.5 Hz), 153.3, 166.3; 19F NMR (376 MHz, CD3OD)
δ −130.2.
Acknowledgements
4-Amino-1-((1S,4R,5R)-2,5-difluoro-4-hydroxy-3-(hydroxymethyl)- This work was supported by the grant from Mid-career
cyclopent-2-enyl)pyrimidin-2(1H)-one (8d). To
a
stirred Research Program (370C-20130120) of National Research
suspension of 32 (0.3 g, 0.87 mmol) in methylene chloride Foundation (NRF) of Korea.
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Paper
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