Synthesis of 2,6-disubstituted pyridin-3-yl C-2′-deoxyribonucleosides through chemoselective transformations of bromo-chloropyridine C-nucleosides

Article abstract of DOI:10.1039/c3ob40774h

2-Bromo-6-chloro- and 6-bromo-2-chloropyridin-3-yl deoxyribonucleosides were prepared by the Heck coupling of bromo-chloro-iodopyridines with TBS-protected deoxyribose glycal. Some of their Pd-catalyzed cross-coupling reactions proceeded chemoselectively at the position of the bromine, whereas nucleophilic substitutions were unselective and gave mixtures of products. The mono-substituted intermediates were used for another coupling or nucleophilic substitution giving rise to a small library of title 2,6-disubstituted pyridine C-deoxyribonucleosides. The title nucleosides did not exert antiviral or cytostatic effects. is

Full text of DOI:10.1039/c3ob40774h

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Synthesis of 2,6-disubstituted pyridin-3-yl C-2’-
deoxyribonucleosides through chemoselective
transformations of bromo-chloropyridine
C-nucleosides†
Cite this: Org. Biomol. Chem., 2013, 11,
4702
Tomáš Kubelka,a Lenka Slavětínská,a Václav Eignera and Michal Hocek*a,b
2-Bromo-6-chloro- and 6-bromo-2-chloropyridin-3-yl deoxyribonucleosides were prepared by the Heck
coupling of bromo-chloro-iodopyridines with TBS-protected deoxyribose glycal. Some of their Pd-cata-
lyzed cross-coupling reactions proceeded chemoselectively at the position of the bromine, whereas
nucleophilic substitutions were unselective and gave mixtures of products. The mono-substituted inter-
mediates were used for another coupling or nucleophilic substitution giving rise to a small library of title
2,6-disubstituted pyridine C-deoxyribonucleosides. The title nucleosides did not exert antiviral or cyto-
static effects.
Received 17th April 2013,
Accepted 20th May 2013
DOI: 10.1039/c3ob40774h
www.rsc.org/obc
reactions of the corresponding 2,4-dichloropyrimidine
C-nucleoside intermediate. Here we report on the synthesis of
Introduction
C-Nucleosides are important analogues of natural nucleosides a series of 2,6-disubstituted pyridine C-nucleosides.
useful for many applications in medicinal chemistry and
chemical biology.1 Diverse aryl and hetaryl-C-2′-deoxyribo-
nucleosides were extensively studied as candidates for novel
base-pairs in the quest for extension of the genetic alphabet
and some of their artificial base-pairs were efficiently repli-
Results and discussion
In our previous synthesis of 2,4-disubstituted pyrimidine
C-nucleosides,6 we have advantageously used the different
reactivities of the two chlorines in 2,4-dichloropyrimidine for
regioselective reactions. However, in the analogous 2,6-dichloro-
pyridine C-nucleosides, the reactivity of the chlorines is com-
parable and thus no selectivity would be expected. Therefore
our strategy for the target 2,6-disubstituted pyridin-3-yl C-2′-
deoxyribonucleosides was based on chemoselective transform-
ations7,8 of either 2-bromo-6-chloro- or 6-bromo-2-chloropyridin-
3-yl C-deoxyribonucleoside intermediates.
cated by DNA polymerases with high fidelity.2 Moreover, some
pyridine C-nucleosides have been used as probes for studying
the mechanism of polymerases.3 Most of the current
approaches to the synthesis of C-nucleosides suffer from mod-
erate efficiency and/or stereoselectivity.1 Our group has develo-
ped
a
modular approach4 based on the synthesis of
halogenated (het)aryl C-nucleoside intermediates and their
functionalization by Pd-catalyzed cross-couplings, aminations,
carbonylations or hydroxylations. Very recently, the same
approach was used even for the functionalization of C-nucleo-
side triphosphate derivatives.5 Apart from the variation of
one substituent, the synthesis of a 2D library of 2,4-disubsti-
tuted pyrimidin-5-yl C-2′-deoxyribonucleosides has been
developed6 through two consecutive regioselective cross-coupling
The synthesis of both bromo-chloropyridine C-nucleoside
intermediates started from 3′-O-TBS-protected glycal 1 which
can be easily prepared in three steps from thymidine.9 The
Heck coupling of 6-bromo-2-chloro-3-iodopyridine with glycal
1 in the presence of Pd(OAc)2, tris(pentafluorophenyl)phos-
phine and silver carbonate was performed in freshly distilled
chloroform at 70 °C (Scheme 1). After 10 hours all starting
material was consumed and, because partial desilylation was
observed by TLC, the crude reaction mixture was directly
treated with Et3N·3HF in THF to give fully deprotected ketone
2 in 52% yield (for two steps) as a pure β-anomer. The sub-
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic, Gilead & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6,
Czech Republic. E-mail: hocek@uochb.cas.cz; Tel: +420 220183324
bDepartment of Organic Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 8, CZ-12843 Prague 2, Czech Republic
sequent stereoselective reduction of
proceeded smoothly giving rise to the desired C-2′-deoxyribo-
nucleoside intermediate 3 in very good 85% yield. The crystal
2 by NaBH(OAc)3
†Electronic supplementary information (ESI) available: Copies of all NMR
spectra. CCDC 927314 and 927315. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3ob40774h
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Fig. 1 Crystal structures of compounds (a) 3 (CCDC 927315) and (b) 8b (CCDC
927314).
Scheme 1 Reagents and conditions: (i) 1. Pd(OAc)2, (PhF5)3P, Ag2CO3, CHCl3,
70 °C, 10 h; 2. Et3N·3HF, THF, rt, 15 min; (ii) NaBH(OAc)3, AcOH, CH3CN, 0 °C,
5 min; (iii) TBSCl, imidazole, DMF, rt, 14 h.
C-nucleoside 8b was also confirmed by X-ray analysis (Fig. 1).
In contrast, cross-coupling of the isomeric 2-bromo-6-chloro-
pyridine intermediate 7 with 1.1 equivalents of Me3Al was
completely nonselective and only an unseparable mixture of
the starting compound and both products of mono-substi-
tution was obtained.
structure of 6-bromo-2-chloropyridine C-nucleoside 3 was
determined by X-ray diffraction, which independently con-
firmed its β-configuration (Fig. 1). Re-protection of 3 by treat-
ment with TBSCl gave the silylated C-nucleoside 4 in 78%
yield. An analogous Heck coupling of 1 with 2-bromo-6-chloro-
3-iodopyridine under the same conditions as above gave regio-
isomeric ketone 5 in 59% yield (for two steps) (Scheme 1).
Subsequent reduction by NaBH(OAc)3 afforded C-2′-deoxyribo-
nucleoside 6 in 87% yield, which was again silylated to give
the desired protected nucleoside intermediate 7 in excellent
92% yield.
Having the free (3 and 6) as well as the protected (4 and 7)
key bromo-chloropyridine C-nucleoside intermediates, we
investigated the chemoselectivity of cross-coupling reactions
and nucleophilic substitutions. The bromine atom should be
more reactive than chlorine but, on the other hand, steric and
other factors can also play a role.
The cross-coupling of protected 6-bromo-2-chloropyridine
C-nucleoside 4 with 1.1 equiv. of Me3Al in the presence of
Pd(PPh3)4 proceeded chemoselectively to give 2-chloro-6-
methylpyridine 8a as the only product in excellent 87% yield
(Scheme 2). When the same reaction was performed with 4
equiv. of Me3Al and prolonged reaction time, the product of
disubstitution 9a was isolated in 80% yield. Deprotection of 8a
and 9a with Et3N·3HF afforded free C-nucleosides 8b (89%)
and 9b (88%). The structure of free 2-chloro-6-methylpyridine
Mono-methylated 2-chloropyridine nucleoside 8a was used
for a series of follow-up transformations (Scheme 2). The Sono-
gashira cross-coupling with trimethylsilylacetylene catalyzed
by Pd(PPh3)2Cl2 followed by ammonolysis afforded 2-ethynyl-6-
methylpyridine C-nucleoside 10a (56%). Pd-catalyzed Hartwig–
Buchwald amination10 with a mixture of LiN(SiMe3)2 and
Ph3SiNH2 gave 2-amino-6-methylpyridine C-nucleoside 11a in
68% yield. Deprotection of silylated intermediates 10a and 11a
furnished free C-nucleosides 10b (65%) and 11b (82%). The
reaction of unprotected 2-chloro-6-methylpyridine C-nucleo-
side 8b with sodium methoxide in MeOH was very sluggish
(full conversion was accomplished only after 10 days of
heating at 120 °C) but finally gave 2-methoxy-6-methylpyridine
C-nucleoside 12 in good 77% yield. Attempted Pd-catalyzed
hydroxylation11 using KOH and t-butyl-XPhos did not proceed
and only the starting compound and some degradation pro-
ducts were observed (probably due to instability of the pyri-
done product4f).
The Suzuki–Miyaura cross-coupling of 2-bromo-6-chloro-
pyridine C-nucleoside 7 with 0.9 equivalent of phenylboronic
acid in the presence of Ph(PPh3)4 at 60 °C proceeded chemo-
selectively at position 2 by displacement of the bromine to afford
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Scheme 2 Reagents and conditions: (i) 1.1 equiv. Me3Al, Pd(PPh3)4, heptane, 70 °C, 3 h; (ii) 4 equiv. Me3Al, Pd(PPh3)4, heptane, 70 °C, 12 h; (iii) Et3N·3HF, THF, rt,
14 h; (iv) 1. TMSA, Pd(PPh3)2Cl2, CuI, Et3N, DMF, 90 °C; 2. NH3, MeOH, rt, 30 min; (v) LiN(SiMe3)2, Ph3SiNH2, CyJohnPhos, Pd2(dba)3, THF, 50 °C, 3 h; (vi) MeONa,
MeOH, 120 °C, 10 d; (vii) KOH, t-butyl-XPhos, Pd2dba3, 100 °C.
6-chloro-2-phenylpyridine C-nucleoside 13a in 63% yield liquid ammonia12 in an autoclave using temperatures up to
(Scheme 3). When we used 3 equiv. of phenylboronic acid and 120 °C but in all cases only the starting material was recovered
increased the temperature to 100 °C, 2,6-diphenylpyridine and we did not observe any reaction. Surprisingly, attempted
C-nucleoside 14a was obtained as a product of double substi- Buchwald–Hartwig aminations of protected intermediates 4 or
tution in excellent 95% yield. An analogous reaction of regio- 7 did not work either. Nucleophilic substitution of 6 with
isomeric 6-bromo-2-chloropyridine C-nucleoside 4 with 1 equiv. NaOMe proceeded only at elevated temperature (80 °C) to give
of phenyl boronic acid afforded an unseparable mixture of the an unseparable mixture of the starting compound and both
starting compound with the product of substitution of the mono-substituted derivatives. The same reaction at higher
bromine atom at position 6. Silylated nucleosides 13a and 14a temperature (120 °C) led to complex mixtures. It seems that
were deprotected using Et3N·3HF to obtain free C-nucleosides the mono-substituted intermediates (containing an electron-
13b (91%) and 14b (81%).
donating substituent) are deactivated for another nucleophilic
Mono-substituted 6-chloro-2-phenylpyridine C-nucleoside substitution.
13a was then used for subsequent cross-coupling reactions.
Next we studied nucleophilic substitutions with sodium
Hartwig–Buchwald amination with LiN(SiMe3)2 gave 6-amino- methanethiolate (Scheme 4). The reaction of silylated inter-
2-phenylpyridine C-nucleoside 15a in excellent 91% yield. mediate 4 with 10 equivalents of NaSMe in DMF at 80 °C led
Cross-coupling with trimethylaluminum afforded 6-methyl-2- to double substitution with simultaneous deprotection (due to
phenylpyridine C-nucleoside 16a in excellent 91% yield. Depro- basic conditions) affording 2,6-bis(methylsulfanyl)pyridine
tection of silylated intermediates gave free C-nucleosides 15b C-nucleoside 17 in good 79% yield. The reaction of 4 with 1.2
(67%) and 16b (85%).
equivalents of sodium methanethiolate at rt in DMF gave a
In order to introduce amino or methoxy groups, we have mixture of both mono-substituted derivatives 18a and 19a in
studied the reactivity of intermediates 3 and 6 in nucleophilic the ratio ca. 1 : 1. Luckily, we were able to separate them using
substitutions. Our previous studies6 showed good regioselec- the flash purification system with a very slow gradient of
tivity of nucleophilic aminations of 2,4-dichloropyrimidine hexanes to 1% EtOAc in hexanes to obtain 2-chloro-6-(methyl-
C-nucleoside. Therefore, we tested reactions of 3 or 6 with sulfanyl)pyridine C-nucleoside 18a (48%) and 6-bromo-2-
methanolic ammonia or copper(I)-catalyzed reaction with (methylsulfanyl)pyridine C-nucleoside 19a (43%). Pd-catalyzed
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Scheme 4 Reagents and conditions: (i) MeSNa 10 equiv., DMF, 80 °C, 12 h; (ii)
MeSNa 1.2 equiv., DMF, rt, 12 h; (iii) Et3N·3HF, THF, rt, 14 h; (iv) Me3Al, Pd-
(PPh3)4, 90 °C, 12 h.
Scheme 3 Reagents and conditions: (i) 0.9 equiv. PhB(OH)2, Pd(PPh3)4, K2CO3,
PhMe, 60 °C, 12 h; (ii) 3 equiv. PhB(OH)2, Pd(PPh3)4, K2CO3, PhMe, 100 °C, 12 h;
(iii) Et3N·3HF, THF, rt, 14 h; (iv) LiN(SiMe3)2, CyJohnPhos, Pd2(dba)3, THF, 60 °C,
12 h; (v) Pd(PPh3)4, Me3Al, THF, 70 °C, 12 h.
Unfortunately, only deprotection was observed despite having
tried many different conditions.
The Stille cross-coupling reaction was used for the synthesis
of bipyridine and terpyridine C-nucleosides (Scheme 6). The
reaction of 4 with tributyl(2-pyridyl)stannane catalyzed by
PdCl2(PPh3)2 gave only compound 24a, as a product of chemo-
selective replacement of the bromine atom, in very good 82%
yield even when we used 2 equiv. of stannane. The palladium
catalyst is probably strongly coordinated to the bipyridine scaffold
and any second reaction is prevented. In contrast, the Stille
cross-coupling catalyzed by Pd(PPh3)4 cleanly afforded terpyri-
dine C-nucleoside 25a, as a product of double substitution, in
excellent 92% yield. Deprotection gave bi- and terpyridine
C-nucleosides 24b and 25b which could be used in metalla-
base pairs.14
Finally, we attempted to introduce a vinyl group by Fürst-
ner’s Fe-catalyzed cross-coupling reaction15 with vinylmagne-
sium bromide (Scheme 7). Unfortunately the cross-coupling
did not proceed and, instead, the magnesiation of the bromo-
pyridine occurred which, after hydrolytic work-up, gave chloro-
pyridine 26a, as a product of debromination, in moderate 47%
yield. Also this compound was deprotected to free nucleoside
26b.
methylation of compounds 18a or 19a with trimethylalumi-
num gave two regioisomeric methyl-(methylsulfanyl)pyridine
C-nucleosides 20a (49%) and 21a (58%). All silylated com-
pounds were deprotected to afford free C-nucleosides 18b–21b.
Attempted Sonogashira chemoselective cross-couplings of 4
with (trimethylsilyl)acetylene (TMSA) (Scheme 5) were very
difficult to perform since the desired 2-chloro-6-(TMS-ethynyl)-
pyridine C-nucleoside was unseparable from starting inter-
mediate 4. Finally, we found out that Sonogashira cross coup-
ling with 1 equiv. of trimethylsilylacetylene catalyzed by
Pd(PPh3)2Cl2 followed by direct amonolysis gave us a separable
mixture of starting compound 4 (37%) and desired product
22a in acceptable 53% yield. When we performed the same
reaction with the excess of trimethylsilylacetylene (10 equiv.)
and increased the temperature to 90 °C, the product of disub-
stitution, protected 2,6-bis(ethynyl)pyridine C-nucleoside 23a,
was isolated in excellent 95% yield. In order to convert the
ethynyl groups to acetyl, we have prepared partially and fully
deprotected bis(ethynyl)pyridine C-nucleosides 23b and 23c
and attempted a gold catalyzed hydration of the triple bond.13
All the title free nucleosides were subjected to biological
activity screening. The cytotoxic activity in vitro was studied on
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Scheme 7 Reagents and conditions: (i) vinylMgBr, Fe(acac)3, rt, 12 h; (ii)
Et3N·3HF, THF, rt, 14 h.
the following cell cultures: (i) human promyelocytic leukemia
HL60 cells (ATCC CCL 240); (ii) human cervix carcinoma HeLa
S3 cells (ATCC CCL 2.2); (iii) human T lymphoblastoid
CCRF-CEM cell line (ATCC CCL 119), and (iv) hepatocellular
carcinoma cells HepG2 (ATCC HB 8065). Cell viability was
determined following a 3-day incubation using a metabolic
2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carb-
oxanilide (XTT) based method.16 The antiviral activity was
tested against HCV genotype 1A, 1B and 2A replicons.17 None
of the nucleosides showed any significant cytotoxicity or anti-
viral activity in these assays at concentrations up to 10 μM.
Conclusions
Scheme 5 Reagents and conditions: (i) 1. 1 equiv. TMSA, Pd(PPh3)2Cl2, CuI,
Et3N, DMF, 60 °C; 2. NH3, MeOH, rt, 30 min; (ii) 10 equiv. TMSA, Pd(PPh3)2Cl2,
CuI, Et3N, DMF, 90 °C; (iii) Et3N·3HF, THF, rt, 14 h; (iv) NH3, MeOH, rt, 30 min; (v)
NaAuCl4, MeOH, H2O, 80 °C, 6–72 h; (vi) TBAF, THF, rt, 12 h.
Systematic study of the chemoselectivity of cross-coupling reac-
tions and nucleophilic substitutions of regioisomeric 2-bromo-
6-chloro- and 6-bromo-2-chloropyridin-3-yl deoxyribo-nucleo-
sides 7 and 4 was performed. The cross-couplings generally
proceeded with good chemoselectivity at the position of the
bromine but the choice of the starting compound depended
on the separability of the mono-substituted products from the
starting compound. On the other hand, nucleophilic substi-
tution with NaSMe was unselective giving a separable mixture
of both mono-substituted products, whereas the reactions with
ammonia or NaOMe did not proceed or led to complex mix-
tures (at elevated temperature). The mono-substituted halo-
pyridine C-nucleoside intermediates were used for another
coupling or SN to give a small library of 2,6-disubstituted
pyridin-3-yl C-deoxyribonucleosides. None of the title nucleo-
sides exerted any antiviral or cytostatic activity in concen-
trations up to 10 μM. Some of the disubstituted pyridine
nucleosides will be converted to triphosphates and further
tested for polymerase incorporation in the quest for the
extension of the genetic alphabet.2
Experimental
All cross-coupling reactions were carried out in evacuated
flame-dried glassware with magnetic stirring under an argon
atmosphere. THF, toluene, and hexanes were dried and dis-
tilled from sodium–benzophenone. Other reagents were pur-
chased from commercial suppliers and used as received. NMR
Scheme 6 Reagents and conditions: (i) 2 equiv. 2-pyridylSnBu3, PdCl2(PPh3)2,
DMF, 100 °C, 12 h; (ii) 2 equiv. 2-pyridylSnBu3, Pd(PPh3)4, toluene, 110 °C, 12 h;
(iii) Et3N·3HF, THF, rt, 14 h.
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spectra were recorded on a 400 MHz spectrometer (1H at dried flask containing a solution of the nucleoside 2 (1.48 g,
400 MHz, 13C at 100.6 MHz), a 500 MHz spectrometer (1H at 4.83 mmol) in a mixture of AcOH–CH3CN 1/10 (50 mL) at 0 °C
500 and 13C MHz at 125.8), and/or a 600 MHz spectrometer under argon. After 5 min, all of the starting material was con-
(1H at 600 MHz, 13C at 151 MHz). The samples were measured sumed and a solution of EtOH–H2O 1/1 (10 mL) was added to
in CDCl3 using TMS as an internal standard or in DMSO-d6 neutralize the solution. Then the solvents were evaporated in
referenced to the residual solvent signal (1H NMR δ 2.50 ppm, vacuum, and the crude product was chromatographed on
13C NMR 39.7 ppm). Chemical shifts are given in ppm (δ scale) silica gel in a gradient of chloroform to 5% MeOH in chloro-
and coupling constants ( J) in hertz. Complete assignment of form. Nucleoside 3 (1.27 g, 85%) was isolated as a white foam.
all NMR signals was performed using a combination of HRMS (ESI) for C10H11BrClNO3: [M + H] calculated, 307.9684;
2D-NMR (H,H-COSY, H,C-HSQC, and H,C-HMBC) experiments found, 307.9684. 1H NMR (500 MHz, CD3OD) 1.78 (ddd, 1H,
and configurations were established by two-dimensional Jgem = 13.1 Hz, J2′a,1′ = 10.0 Hz, J2′a,3′ = 6.0 Hz, H-2′a); 2.47 (ddd,
ROESY spectra. High performance flash chromatography 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.7 Hz, J2′b,3′ = 2.0 Hz, H-2′b); 3.68
(HPFC) purifications were performed with Biotage SP1 appar- (dd, 1H, Jgem = 11.8 Hz, J5′a,4′ = 5.0 Hz, H-5′a); 3.71 (dd, 1H,
atus on KP-Sil and KP-C18-HS columns. Cytostatic16 and anti- Jgem = 11.8 Hz, J5′b,4′ = 4.5 Hz, H-5′b); 3.97 (td, 1H, J4′,5′a = J4′,5′b
HCV17 activity screening was performed according to literature 4.7 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.32 (bdtd, 1H, J3′,2′a = 5.9 Hz,
=
procedures.
J3′,4′ = J3′,2′b = 2.4 Hz, J3′,1′ = 0.5 Hz, H-3′); 5.32 (ddq, 1H, J1′,2′a
10.0 Hz, J1′,2′b = 5.7 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.6 Hz, H-1′); 7.57
(dd, 1H, J5,4 = 8.1 Hz, J5,1′ = 0.6 Hz, H-5); 8.02 (dd, 1H, J4,5
=
General procedure for the deprotection of the TBDMS group
=
Et3N·3HF (320 μL, 1.95 mmol) was added to a solution of sily- 8.1 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz, CD3OD):
lated C-nucleoside (0.4 mmol) in THF (2 mL), and the mixture 42.98 (CH2-2′); 63.66 (CH2-5′); 74.10 (CH-3′); 77.18 (CH-1′);
was stirred at room temperature for 14 h. After the reaction 89.27 (CH-4′); 128.66 (CH-5); 138.16 (C-3); 139.46 (C-6); 139.96
was completed (TLC in hexanes–EtOAc 10 : 1), solvents were (CH-4); 148.45 (C-2). IR spectrum (KBr): 3349, 3297, 3061,
removed under reduced pressure, and the crude product was 1573, 1542, 1485, 1419, 1220, 1097, 1062, 1047, 823, 735.
chromatographed on silica gel (20 g) eluted with a gradient
of chloroform to 15% MeOH in chloroform to give free dimethylsilyl)-D-ribofuranose (4). Imidazole (1.27 g, 18.6
C-nucleosides. mmol) and then TBDMSCl (4.49 mg, 29.8 mmol) were added
1β-(6-Bromo-2-chloropyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
1β-(6-Bromo-2-chloropyridin-3-yl)-1,2,3-trideoxy-3-oxo-D-ribo- to a flame-dried flask containing a solution of the nucleoside
furanose (2). Freshly distilled CHCl3 (20 mL) was added to an 3 (2.3 g, 7.45 mmol) in dry DMF (50 mL) at 0 °C under argon
argon-purged, flame-dried flask containing Pd(OAc)2 (390 mg, and the solution was allowed to warm to room temperature
1.74 mmol) and P(PhF5)3 (1.85 g, 3.47 mmol), and the mixture and was stirred for 14 h. The reaction mixture was then poured
was stirred at room temperature for 30 min. This solution was into a saturated solution of NaCl (100 mL) and extracted with
then added via a syringe to a mixture of 6-bromo-2-chloro-3- EtOAc (3 × 30 mL). Collected organic fractions were washed
iodopyridine (3.32 g, 10.42 mmol), glycal 1 (2.00 g, 8.68 mmol) with a saturated NaCl solution, dried over MgSO4, and the sol-
and Ag2CO3 (3.58 g, 13.02 mmol) in CHCl3 (20 mL), and the vents were evaporated under vacuum. The crude product was
reaction mixture was stirred at 70 °C for 10 h. The reaction chromatographed on silica gel in a gradient of hexanes to 5%
mixture was then cooled and filtered on a pad of Celite and EtOAc in hexanes to give the desired nucleoside 4 (3.1 g, 78%)
eluted with CHCl3. Solvents were removed under vacuum, the as a colorless oil. HRMS (ESI) for C22H39BrClNO3Si2: [M + H]
crude product was dissolved in THF (100 mL), Et3N·3HF calculated, 536.1413; found, 536.1413. 1H NMR (500 MHz,
(2 mL; 12.3 mmol) was added and the solution was stirred at rt CDCl3) 0.084, 0.086 and 0.094 (4 × s, 4 × 3H, CH3Si); 0.89 and
for 15 min. The solvents were removed under vacuum, and the 0.91 (2 × s, 2 × 9H, ((CH3)3C)); 1.70 (ddd, 1H, Jgem = 12.6 Hz,
crude product was chromatographed on silica gel eluting with J2′a,1′ = 9.4 Hz, J2′a,3′ = 5.6 Hz, H-2′a); 2.41 (ddd, 1H, Jgem
=
a gradient of chloroform to 1% MeOH in chloroform to give 2 12.6 Hz, J2′b,1′ = 5.9 Hz, J2′b,3′ = 2.5 Hz, H-2′b); 3.71 (dd, 1H, Jgem
(1.38 g, 52% for two steps) as a yellow oil. HRMS (ESI) for = 10.9 Hz, J5′a,4′ = 4.6 Hz, H-5′a); 3.76 (dd, 1H, Jgem = 10.9 Hz,
C10H9BrClNO3: [M − H] calculated, 303.9382; found, 303.9382. J5′b,4′ = 3.3 Hz, H-5′b); 3.97 (ddd, 1H, J4′,5′a = 4.6 Hz, J4′,5′b
1H NMR (500 MHz, CDCl3) 2.26 (dd, 1H, Jgem = 18.2 Hz, J2′a,1′
3.3 Hz, J4′,3′ = 2.6 Hz, H-4′); 4.38 (dtd, 1H, J3′,2′a = 5.6 Hz, J3′,4′
10.6 Hz, H-2′a); 3.18 (dd, 1H, Jgem = 18.2 Hz, J2′b,1′ = 6.2 Hz, J3′,2′b = 2.6 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.33 (bddq, 1H, J1′,2′a
H-2′b); 3.99–4.05 (m, 2H, H-5′); 4.11 (t, 1H, J4′,5′a = J4′,5′b
=
=
=
=
=
9.4 Hz, J1′,2′b = 5.9 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.7 Hz, H-1′); 7.39 (dd,
3.4 Hz, H-4′); 5.43 (ddt, 1H, J1′,2′a = 10.6 Hz, J1′,2′b = 6.2 Hz, 1H, J5,4 = 8.0 Hz, J5,1′ = 0.6 Hz, H-5); 7.90 (dd, 1H, J4,5 = 8.0 Hz,
J1′,4 = J1′,5 = 0.7 Hz, H-1′); 7.52 (bd, 1H, J5,4 = 8.1 Hz, H-5); 7.97 J4,1′ = 0.7 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): −5.49, −5.41,
(dd, 1H, J4,5 = 8.1 Hz, J4,1′ = 0.7 Hz, H-4). 13C NMR (125.7 MHz, −4.76 and −4.62 (CH3Si); 17.98 and 18.29 ((CH3)3C); 25.75
CDCl3): 43.70 (CH2-2′); 61.51 (CH2-5′); 73.30 (CH-1′); 82.08 and 25.87 ((CH3)3C); 42.30 (CH2-2′); 63.22 (CH2-5′);
(CH-4′); 127.52 (CH-5); 134.64 (C-3); 137.72 (CH-4); 139.64 73.65 (CH-3′); 75.84 (CH-1′); 87.95 (CH-4′); 127.01 (CH-5);
(C-6); 147.73 (C-2); 212.08 (C-3′). IR spectrum (KBr): 3436, 137.08 (C-3); 138.08 (CH-4), 138.38 (C-6); 147.48 (C-2). IR
3095, 3068, 1760, 1574, 1546, 1426, 1221, 1033, 829, 736.
spectrum (CCl4): 3093, 3060, 2956, 2897, 1575, 1545, 1472,
1β-(6-Bromo-2-chloropyridin-3-yl)-1,2-dideoxy-D-ribofuranose 1463, 1424, 1407, 1390, 1362, 1257, 1223, 1098, 1030, 1006,
(3). NaBH(OAc)3 (1.53 g, 7.25 mmol) was added to a flame- 939, 838, 671.
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1β-(2-Bromo-6-chloropyridin-3-yl)-1,2,3-trideoxy-3-oxo-D-ribo- 10.18 mmol) and then TBDMSCl (2.45 mg, 16.3 mmol) were
furanose (5). Freshly distilled CHCl3 (18 mL) was added to an added to a flame-dried flask containing a solution of the
argon-purged, flame-dried flask containing Pd(OAc)2 (562 mg, nucleoside 6 (1.26 g, 4.07 mmol) in dry DMF (25 mL) at 0 °C
2.34 mmol) and P(PhF5)3 (2.49 g, 4.69 mmol), and the mixture under argon and the solution was allowed to warm to room
was stirred at room temperature for 30 min. This solution was temperature and was stirred for 14 h. The reaction mixture was
then added via a syringe to a mixture of 2-bromo-6-chloro- then poured into a saturated solution of NaCl (100 mL) and
3-iodopyridine (4.48 g, 14.06 mmol), glycal
1 (2.70 g, extracted with EtOAc (3 × 50 mL). Collected organic fractions
11.72 mmol) and Ag2CO3 (4.83 g, 17.58 mmol) in CHCl3 were washed with a saturated NaCl solution, dried over MgSO4,
(18 mL), and the reaction mixture was stirred at 70 °C for 10 h. and the solvents were evaporated under vacuum. The crude
The reaction mixture was then cooled and filtered on a pad of product was chromatographed on silica gel in a gradient of
Celite and eluted with CHCl3. Solvents were then removed in hexanes to 3% EtOAc in hexanes to give the desired nucleoside
vacuum, the crude product was dissolved in THF (100 mL),
Et3N·3HF (3 mL; 18.5 mmol) was added and the solution was C22H39BrClNO3Si2: [M
7
(2.01 g, 92%) as
a
+
colorless oil. HRMS (ESI) for
H] calculated, 536.1413; found,
stirred at rt for 15 min. The solvents were removed under 536.1412. 1H NMR (500 MHz, CDCl3) 0.085, 0.089 and 0.10
vacuum, and the crude product was chromatographed on (4 × s, 4 × 3H, CH3Si); 0.90 and 0.91 (2 × s, 2 × 9H, ((CH3)3C));
silica gel eluting with a gradient of chloroform to 1% MeOH in 1.68 (ddd, 1H, Jgem = 12.6 Hz, J2′a,1′ = 9.4 Hz, J2′a,3′ = 5.6 Hz,
chloroform to give 5 (2.12 g, 59% for two steps) as a yellow H-2′a); 2.45 (ddd, 1H, Jgem = 12.6 Hz, J2′b,1′ = 5.9 Hz, J2′b,3′
=
foam. HRMS (ESI) for C10H9BrClNO3: [M − H] calculated, 2.6 Hz, H-2′b); 3.72 (dd, 1H, Jgem = 10.9 Hz, J5′a,4′ = 4.5 Hz,
303.9382; found, 303.9384. 1H NMR (500 MHz, CDCl3) 2.23 H-5′a); 3.77 (dd, 1H, Jgem = 10.9 Hz, J5′b,4′ = 3.3 Hz, H-5′b); 3.97
(dd, 1H, Jgem = 18.2 Hz, J2′a,1′ = 10.6 Hz, H-2′a); 3.21 (dd, 1H, (ddd, 1H, J4′,5′a = 4.5 Hz, J4′,5′b = 3.3 Hz, J4′,3′ = 2.6 Hz, H-4′);
Jgem = 18.2 Hz, J2′b,1′ = 6.2 Hz, H-2′b); 3.98–4.04 (m, 2H, H-5′); 4.38 (bdtd, 1H, J3′,2′a = 5.6 Hz, J3′,4′ = J3′,2′b = 2.7 Hz, J3′,1′
4.11 (t, 1H, J4′,5′a = J4′,5′b = 3.3 Hz, H-4′); 5.41 (ddt, 1H, J1′,2′a 0.6 Hz, H-3′); 5.31 (ddq, 1H, J1′,2′a = 9.4 Hz, J1′,2′b = 5.9 Hz,
10.6 Hz, J1′,2′b = 6.2 Hz, J1′,4 = J1′,5 = 0.7 Hz, H-1′); 7.37 (dd, 1H, J1′,3′ = J1′,4 = J1′,5 = 0.6 Hz, H-1′); 7.26 (dd, 1H, J5,4 = 8.1 Hz, J5,1′
=
=
=
J5,4 = 8.1 Hz, J5,1′ = 0.6 Hz, H-5); 8.03 (dd, 1H, J4,5 = 8.1 Hz, 0.6 Hz, H-5); 7.95 (dd, 1H, J4,5 = 8.1 Hz, J4,1′ = 0.7 Hz, H-4).
J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): 43.85 (CH2- 13C NMR (125.7 MHz, CDCl3): −5.50, −5.42, −4.76 and −4.62
2′); 61.44 (CH2-5′); 74.87 (CH-1′); 82.19 (CH-4′); 123.91 (CH-5); (CH3Si); 17.98 and 18.28 ((CH3)3C); 25.74 and 25.87 ((CH3)3C);
136.72 (C-3); 137.85 (CH-4); 139.30 (C-2); 149.75 (C-6); 212.23 42.47 (CH2-2′); 63.21 (CH2-5′); 73.65 (CH-3′); 77.50 (CH-1′);
(C-3′). IR spectrum (KBr): 3428, 3095, 3071, 2924, 2854, 1760, 88.00 (CH-4′); 123.41 (CH-5); 138.08 (CH-4); 139.00 and 139.07
1630, 1575, 1546, 1460, 1429, 1224, 1057, 1032, 831, 735.
(C-2,3); 148.66 (C-6). IR spectrum (CCl4): 3093, 3059, 2956,
1β-(2-Bromo-6-chloropyridin-3-yl)-1,2-dideoxy-D-ribofuranose 2897, 1577, 1545, 1472, 1463, 1406, 1390, 1362, 1278, 1258,
(6). NaBH(OAc)3 (2.9 g, 13.7 mmol) was added to a flame- 1097, 939, 891, 838.
dried flask containing a solution of the nucleoside 5 (2.8 g,
1β-(2-Chloro-6-methylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
9.13 mmol) in a mixture of AcOH–CH3CN 1/10 (80 mL) at 0 °C dimethylsilyl)-D-ribofuranose (8a). Me3Al (1.5 mL, 1.5 mmol,
under argon. After 5 min, all of the starting material was con- 1.1 equiv., 1 M in heptane) was added to a flame-dried flask
sumed and a solution of EtOH–H2O 1/1 (20 mL) was added to containing 4 (729 mg, 1.36 mmol) and Pd(PPh3)4 (161 mg,
neutralize the solution. Then the solvents were evaporated in 0.14 mmol, 10 mol%) under argon. The mixture was stirred at
vacuum, and the crude product was chromatographed on 70 °C for 3 h, quenched by pouring into saturated NaH2PO4
silica gel in a gradient of chloroform to 5% MeOH in chloro- (50 mL), and extracted with EtOAc (3 × 50 mL). The crude
form. Nucleoside 6 (2.45 g, 87%) was isolated as a white foam. product was chromatographed on silica gel eluting with a gra-
HRMS (ESI) for C10H11BrClNO3: [M + H] calculated, 307.9684; dient of hexanes to 5% EtOAc in hexanes to give 8a (555 mg,
found, 307.9683. 1H NMR (500 MHz, CD3OD) 1.76 (ddd, 1H, 87%) as a colorless oil. HRMS (ESI) for C23H42ClNO3Si2:
Jgem = 13.1 Hz, J2′a,1′ = 10.0 Hz, J2′a,3′ = 6.0 Hz, H-2′a); 2.51 (ddd, [M + H] calculated, 472.2465; found, 472.2465. 1H NMR
1H, Jgem = 13.1 Hz, J2′b,1′ = 5.8 Hz, J2′b,3′ = 2.1 Hz, H-2′b); 3.69 (500 MHz, CDCl3) 0.083, 0.085, 0.087 and 0.093 (4 × s, 4 × 3H,
(dd, 1H, Jgem = 11.8 Hz, J5′a,4′ = 5.0 Hz, H-5′a); 3.72 (dd, 1H, CH3Si); 0.90 and 0.91 (2 × s, 2 × 9H, ((CH3)3C)); 1.70 (ddd, 1H,
Jgem = 11.8 Hz, J5′b,4′ = 4.4 Hz, H-5′b); 3.97 (btd, 1H, J4′,5′a = J4′,5′b Jgem = 12.7 Hz, J2′a,1′ = 9.5 Hz, J2′a,3′ = 5.6 Hz, H-2′a); 2.40 (ddd,
= 4.7 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.32 (dddd, 1H, J3′,2′a = 6.0 Hz, 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.8 Hz, J2′b,3′ = 2.5 Hz, H-2′b); 2.51
J3′,4′ = 2.7 Hz, J3′,2′b = 2.1 Hz, J3′,1′ = 0.6 Hz, H-3′); 5.31 (ddq, 1H, (s, 3H, CH3); 3.69 (dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 4.9 Hz,
J1′,2′a = 10.0 Hz, J1′,2′b = 5.8 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.6 Hz, H-1′); H-5′a); 3.77 (dd, 1H, Jgem = 10.8 Hz, J5′b,4′ = 3.5 Hz, H-5′b); 3.96
7.44 (dd, 1H, J5,4 = 8.1 Hz, J5,1′ = 0.6 Hz, H-5); 8.07 (dd, 1H, J4,5
=
(ddd, 1H, J4′,5′a = 4.9 Hz, J4′,5′b = 3.5 Hz, J4′,3′ = 2.6 Hz, H-4′);
8.1 Hz, J4,1′ = 0.7 Hz, H-4). 13C NMR (125.7 MHz, CD3OD): 43.18 4.38 (dtd, 1H, J3′,2′a = 5.6 Hz, J3′,4′ = J3′,2′b = 2.6 Hz, J3′,1′ = 0.7 Hz,
(CH2-2′); 66.65 (CH2-5′); 74.09 (CH-3′); 78.88 (CH-1′); 89.32 H-3′); 5.37 (bdd, 1H, J1′,2′a = 9.5 Hz, J1′,2′b = 5.8 Hz, H-1′); 7.06
(CH-4′); 124.95 (CH-5); 139.94 (C-2); 139.99 (CH-4); 140.20 (C-3); (dm, 1H, J5,4 = 7.8 Hz, H-5); 7.88 (dd, 1H, J4,5 = 7.8 Hz, J4,1′
149.82 (C-6). IR spectrum (KBr): 3376, 3267, 3098, 3059, 1574, 0.8 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): −5.48, −5.42,
1548, 1486, 1470, 1267, 1070, 1044, 1017, 949, 932, 898. −4.76 and −4.62 (CH3Si); 17.98 and 18.29 ((CH3)3C); 23.71
=
1β-(2-Bromo-6-chloropyridin-3-yl)-1,2-dideoxy-3,5-di-O- (CH3); 25.76 and 25.88 ((CH3)3C); 42.42 (CH2-2′); 63.33
(t-butyldimethylsilyl)-D-ribofuranose (7). Imidazole (0.69 g, (CH2-5′); 73.73 (CH-3′); 76.14 (CH-1′); 87.74 (CH-4′); 122.18
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(CH-5); 134.16 (C-3); 136.10 (CH-4); 147.50 (C-2); 157.50 (C-6). (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.4 Hz, J2′a,3′ = 6.0 Hz, H-2′a);
IR spectrum (CCl4): 3068, 2956, 2898, 1597, 1569, 1555, 1471, 2.28 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.4 Hz, J2′b,3′ = 1.8 Hz,
1462, 1435, 1407, 1389, 1376, 1362, 1257, 1220, 1097, 1031, H-2′b); 2.47 (s, 3H, CH3-6); 2.49 (s, 3H, CH3-2); 3.67–3.71 (m,
1006, 939, 838.
2H, H-5′); 3.95 (td, 1H, J4′,5′a = J4′,5′b = 4.9 Hz, J4′,3′ = 2.7 Hz,
1β-(2-Chloro-6-methylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose H-4′); 4.33 (bdt, 1H, J3′,2′a = 6.0 Hz, J3′,4′ = J3′,2′b = 2.2 Hz, H-3′);
(8b). Compound 8b was prepared from 8a (225 mg, 5.30 (dd, 1H, J1′,2′a = 10.4 Hz, J1′,2′b = 5.4 Hz, H-1′); 7.11 (bd, 1H,
0.93 mmol) by the general procedure to yield 8b (103 mg, J5,4 = 8.0 Hz, H-5); 7.88 (d, 1H, J4,5 = 8.0 Hz, H-4). 13C NMR
89%) as a yellow solid. HRMS (ESI) for C11H14ClNO3: [M + H] (125.7 MHz, CD3OD): 21.20 (CH3-2); 23.30 (CH3-6); 43.24
calculated, 244.0735; found, 244.0737. 1H NMR (500 MHz, (CH2-2′); 63.84 (CH2-5′); 74.32 (CH-3′); 77.38 (CH-1′); 89.01
CD3OD): 1.77 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′
=
(CH-4′); 122.59 (CH-5); 134.68 (C-3); 135.88 (CH-4); 155.09
6.0 Hz, H-2′a); 2.45 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.7 Hz, (C-2); 157.15 (C-6). IR spectrum (KBr): 3307, 1598, 1583, 1476,
J2′b,3′ = 2.0 Hz, H-2′b); 2.48 (s, 3H, CH3); 3.68 (dd, 1H, Jgem
11.8 Hz, J5′a,4′ = 5.0 Hz, H-5′a); 3.71 (dd, 1H, Jgem = 11.8 Hz,
J5′b,4′ = 4.7 Hz, H-5′b); 3.97 (td, 1H, J4′,5′a = J4′,5′b = 4.8 Hz, J4′,3′
=
1455, 1381, 1282, 1142, 1058, 1031, 976, 961.
1β-(2-Ethynyl-6-methylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
dimethylsilyl)-D-ribofuranose (10a). DMF (3 mL) and TMSA
=
2.7 Hz, H-4′); 4.32 (dddd, 1H, J3′,2′a = 6.0 Hz, J3′,4′ = 2.7 Hz, (415 μL, 2.96 mmol) were added through a septum to an
J3′,2′b = 2.0 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.36 (bdd, 1H, J1′,2′a = 10.1 argon-purged vial containing 8a (280 mg, 0.59 mmol),
Hz, J1′,2′b = 5.7 Hz, H-1′); 7.25 (dm, 1H, J5,4 = 7.8 Hz, H-5); 8.02 Pd(PPh3)2Cl2 (42 mg, 0.06 mmol), CuI (1 mg, 0.005 mmol) and
(dd, 1H, J4,5 = 7.8 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz, Et3N (827 μL, 5.93 mmol). The resulting mixture was stirred at
CD3OD): 23.24 (CH3); 43.20 (CH2-2′); 63.77 (CH2-5′); 74.16 90 °C for 8 h. The reaction mixture was then cooled and fil-
(CH-3′); 77.44 (CH-1′); 89.12 (CH-4′); 123.97 (CH-5); 135.38 tered on a pad of Celite and eluted with CHCl3. Solvents were
(C-3); 138.20 (CH-4); 148.33 (C-2); 159.17 (C-6). IR spectrum then removed in vacuum, the crude product was dissolved in
(KBr): 3356, 3230, 3066, 2986, 2919, 1599, 1554, 1463, 1439, methanolic ammonia (26%, 10 mL) and the solution was
1379, 1171, 1061, 1040, 938.
stirred at rt for 30 min. The solvents were removed under
1β-(2,6-Dimethylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl- vacuum, and the crude product was chromatographed on
dimethylsilyl)-D-ribofuranose (9a). Me3Al (1.4 mL, 1.4 mmol, silica gel eluting with a gradient of hexanes to 8% EtOAc in
4.0 equiv., 1 M in heptane) was added to a flame-dried flask hexanes to give 10a (153 mg, 56% for two steps) as a colorless
containing 4 (193 mg, 0.36 mmol) and Pd(PPh3)4 (42 mg, oil. HRMS (ESI) for C25H43NO3Si2: [M
+ H] calculated,
0.036 mmol, 10 mol%) under argon. The mixture was stirred at 462.2854; found, 462.2853. 1H NMR (500 MHz, DMSO-d6):
70 °C for 12 h, quenched by pouring into saturated NaH2PO4 0.07, 0.08 and 0.09 (4 × s, 4 × 3H, CH3Si); 0.87 and 0.89 (2 × s,
(50 mL), and extracted with EtOAc (3 × 50 mL). The crude 2 × 9H, (CH3)3C)); 1.73 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′
=
product was chromatographed on silica gel eluting with a gra- 10.2 Hz, J2′a,3′ = 5.2 Hz, H-2′a); 2.22 (ddd, 1H, Jgem = 12.7 Hz,
dient of hexanes to 9% EtOAc in hexanes to give 9a (130 mg, J2′b,1′ = 5.5 Hz, J2′b,3′ = 1.9 Hz, H-2′b); 2.43 (s, 3H, CH3-6); 3.61
80%) as a colorless oil. HRMS (ESI) for C24H45NO3Si2: [M + H] (dd, 1H, Jgem = 10.9 Hz, J5′a,4′ = 5.9 Hz, H-5′a); 3.72 (dd, 1H,
calculated, 452.3011; found, 452.3010. 1H NMR (500 MHz, Jgem = 10.9 Hz, J5′b,4′ = 4.0 Hz, H-5′b); 3.85 (ddd, 1H, J4′,5′a
CDCl3): 0.08 and 0.09 (4 × s, 4 × 3H, CH3Si); 0.90 and 0.91 5.9 Hz, J4′,5′b = 4.0 Hz, J4′,3′ = 1.9 Hz, H-4′); 4.37 (bdt, 1H, J3′,2′a
=
=
(2 × s, 2 × 9H, ((CH3)3C)); 1.73 (ddd, 1H, Jgem = 12.6 Hz, J2′a,1′
=
5.2 Hz, J3′,4′ = J3′,2′b = 1.9 Hz, H-3′); 4.50 (s, 1H, CHuC-2); 5.37
10.0 Hz, J2′a,3′ = 5.5 Hz, H-2′a); 2.17 (ddd, 1H, Jgem = 12.6 Hz, (bdd, 1H, J1′,2′a = 10.2 Hz, J1′,2′b = 5.5 Hz, H-1′); 7.28 (d, 1H, J5,4
J2′b,1′ = 5.5 Hz, J2′b,3′ = 2.0 Hz, H-2′b); 2.52 (s, 3H, CH3-2); 2.53 = 8.1 Hz, H-5); 7.79 (bd, 1H, J4,5 = 8.1 Hz, H-4). 13C NMR
(s, 3H, CH3-6); 3.67 (dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 5.2 Hz, (125.7 MHz, DMSO-d6): −5.34, −5.26, −4.64 and −4.53 (CH3Si);
H-5′a); 3.78 (dd, 1H, Jgem = 10.8 Hz, J5′b,4′ = 3.6 Hz, H-5′b); 3.95 17.89 and 18.10 ((CH3)3C); 23.72 (CH3-6); 25.86 and 25.92
(ddd, 1H, J4′,5′a = 5.2 Hz, J4′,5′b = 3.6 Hz, J4′,3′ = 2.3 Hz, H-4′); ((CH3)3C); 42.44 (CH2-2′); 63.38 (CH2-5′); 74.28 (CH-3′); 76.11
4.41 (bdtd, 1H, J3′,2′a = 5.6 Hz, J3′,4′ = J3′,2′b = 2.2 Hz, J3′,1′
=
(CH-1′); 80.86 (CHuC-2); 84.26 (CHuC-2); 87.55 (CH-4′);
0.5 Hz, H-3′); 5.28 (dd, 1H, J1′,2′a = 10.0 Hz, J1′,2′b = 5.4 Hz, 123.66 (CH-5); 133.72 (CH-4); 137.87 (C-3); 138.36 (C-2); 157.47
H-1′); 6.99 (d, 1H, J5,4 = 8.0 Hz, H-5); 7.79 (d, 1H, J4,5 = 7.9 Hz, (C-6). IR spectrum (CCl4): 3310, 3062, 2956, 2929, 2897, 2858,
H-4). 13C NMR (125.7 MHz, CDCl3): −5.48, −5.40, −4.70 and 2523, 2803, 2113, 1585, 1566, 1472, 1463, 1445, 1406, 1389,
−4.64 (CH3Si); 17.99 and 18.31 ((CH3)3C); 21.52 (CH3-2); 23.72 1361, 1370, 1275, 1258, 1177, 1098, 1087, 1006, 939, 838, 652,
(CH3-6); 25.78 and 25.89 ((CH3)3C); 42.84 (CH2-2′); 63.49 632.
(CH2-5′); 74.05 (CH-3′); 76.07 (CH-1′); 87.70 (CH-4′); 121.11
1β-(2-Ethynyl-6-methylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose
(CH-5); 133.37 (C-3); 134.11 (CH-4); 153.59 (C-2); 155.70 (C-6). IR (10b). Compound 10b was prepared from 10a (97 mg,
spectrum (CCl4): 3068, 2956, 2930, 2897, 2858, 1596, 1578, 1471, 0.11 mmol) by the general procedure to yield 10b (32 mg,
1463, 1450, 1406, 1390, 1372, 1362, 1290, 1257, 1090, 940, 838.
65%) as a yellow foam. HRMS (ESI) for C13H15NO3: [M + Na]
1β-(2,6-Dimethylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (9b). calculated, 256.0944; found, 256.0944. 1H NMR (500 MHz,
Compound 9b was prepared from 9a (152 mg, 0.34 mmol) by DMSO-d6): 1.66 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz,
the general procedure to yield 9b (66 mg, 88%) as a yellow J2′a,3′ = 5.6 Hz, H-2′a); 2.20 (ddd, 1H, Jgem = 12.7 Hz, J2′b,1′
solid. HRMS (ESI) for C12H17NO3: [M H] calculated, 5.6 Hz, J2′b,3′ = 1.7 Hz, H-2′b); 2.43 (s, 3H, CH3-6); 3.46
224.1281; found, 224.1281. H NMR (500 MHz, CD3OD): 1.81 (dm, 1H, Jgem = 11.5 Hz, H-5′a); 3.51 (ddd, 1H, Jgem = 11.5 Hz,
=
+
1
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J5′b,OH = 5.6 Hz, J5′b,4′ = 4.8 Hz, H-5′b); 3.80 (btd, 1H, J4′,5′a
=
OH-3′); 5.76 (bs, 2H, NH2); 6.34 (bdd, 1H, J5,4 = 7.4 Hz, J5,LR =
J4′,5′b = 5.0 Hz, J4′,3′ = 2.2 Hz, H-4′); 4.37 (m, 1H, H-3′); 4.50 (s, 0.6 Hz, H-5); 7.26 (bd, 1H, J4,5 = 7.4 Hz, H-4). 13C NMR
1H, CHuC-2); 4.79 (t, 1H, JOH,5′a = JOH,5′b = 5.7 Hz, OH-5′); 5.12 (125.7 MHz, DMSO-d6): 23.68 (CH3); 39.76 (CH2-2′); 61.72
(d, 1H, JOH,3′ = 3.8 Hz, OH-3′); 5.34 (bdd, 1H, J1′,2′a = 10.2 Hz, (CH2-5′); 72.13 (CH-3′); 78.13 (CH-1′); 87.82 (CH-4′); 111.08
J1′,2′b = 5.6 Hz, H-1′); 7.28 (d, 1H, J5,4 = 8.1 Hz, H-5); 7.86 (bd, (CH-5); 115.60 (C-3); 135.83 (CH-4); 155.00 (C-6); 156.60 (C-2).
1H, J4,5 = 8.1 Hz, H-4). 13C NMR (125.7 MHz, DMSO-d6): 23.72 IR spectrum (KBr): 3393, 3317, 3200, 3149, 3086, 2951, 2919,
(CH3-6); 42.77 (CH2-2′); 62.41 (CH2-5′); 72.58 (CH-3′); 76.05 2773, 1626, 1595, 1587, 1444, 1379, 1347, 1328, 1281, 1185,
(CH-1′); 81.10 (CHuC-2); 84.10 (CHuC-2); 88.00 (CH-4′); 1100, 1081, 1042, 977, 938, 831.
123.75 (CH-5); 134.14 (CH-4); 138.33 and 138.44 (C-2,3); 157.27
1β-(2-Methoxy-6-methylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose
(C-6). IR spectrum (KBr): 3366, 3064, 2980, 2929, 2106, 2095, (12). MeONa (605 mg, 11 mmol) was added to a solution of
1590, 1567, 1449, 1378, 1346, 1332, 1288, 1179, 1161, 1118, the nucleoside 8b (53 mg, 0.22 mmol) in methanol (10 mL)
1083, 1062, 1050, 969, 938, 655, 639.
and the mixture was stirred for 10 days at 120 °C. Then the sol-
1β-(2-Amino-6-methylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl- vents were evaporated under vacuum. The crude product was
dimethylsilyl)-D-ribofuranose (11a). LiN(SiMe3)2 (1.6 mL, chromatographed on silica gel in a gradient of chloroform to 6%
1.6 mmol, 3 equiv. 1.0 M solution in THF) was added to a MeOH in chloroform to give 12 (40 mg, 77%) as a white solid.
flame-dried and argon-purged flask containing 8a (255 mg, HRMS (ESI) for C12H17NO4: [M + Na] calculated, 262.1050;
1
0.54 mmol), Ph3SiNH2 (297 mg, 1.1 mmol), Pd2(dba)3 (28 mg, found, 262.1050. H NMR (500 MHz, CD3OD): 1.77 (ddd, 1H,
0.027 mmol,
5
mol%), and (biphenyl-2-yl)dicyclohexyl- Jgem = 13.1 Hz, J2′a,1′ = 10.2 Hz, J2′a,3′ = 6.0 Hz, H-2′a); 2.31 (ddd,
phosphane (38 mg, 0.11 mmol, 20 mol%), and the mixture 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.6 Hz, J2′b,3′ = 1.9 Hz, H-2′b); 2.40
was stirred at 50 °C for 3 h. After cooling to room temperature, (s, 3H, CH3-6); 3.64 (dd, 1H, Jgem = 11.6 Hz, J5′a,4′ = 5.1 Hz,
the reaction mixture was diluted with Et2O (30 mL), and H-5′a); 3.66 (dd, 1H, Jgem = 11.6 Hz, J5′b,4′ = 5.2 Hz, H-5′b); 3.91
washed with 2 M HCl (10 mL) and 1 M NaOH (15 mL). The (s, 3H, CH3O); 3.92 (td, 1H, J4′,5′a = J4′,5′b = 5.2 Hz, J4′,3′ = 2.7 Hz,
crude product was chromatographed on silica gel eluting with H-4′); 4.27 (dddd, 1H, J3′,2′a = 6.0 Hz, J3′,4′ = 2.7 Hz, J3′,2′b
a gradient of hexanes to 17% EtOAc in hexanes to give 11a 1.9 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.26 (bdd, 1H, J1′,2′a = 10.2 Hz,
(167 mg, 68%) as colorless oil. HRMS (ESI) for J1′,2′b = 5.6 Hz, H-1′); 6.77 (dm, 1H, J5,4 = 7.4 Hz, H-5); 7.71 (dd, 1H,
=
a
C23H44N2O3Si2: [M + H] calculated, 453.2963; found, 453.2963. J4,5 = 7.4 Hz, J4,1′ = 0.9 Hz, H-4). 13C NMR (125.7 MHz, CD3OD):
1H NMR (500 MHz, CDCl3) 0.07, 0.079, 0.081 and 0.09 (4 × s, 4 23.69 (CH3-6); 42.93 (CH2-2′); 53.54 (CH3O-2); 64.01 (CH2-5′);
× 3H, CH3Si); 0.90 (2 × s, 2 × 9H, ((CH3)3C)); 1.86 (ddd, 1H, 74.32 (CH-3′); 76.08 (CH-1′); 88.69 (CH-4′); 116.83 (CH-5);
Jgem = 12.8 Hz, J2′a,1′ = 5.6 Hz, J2′a,3′ = 1.6 Hz, H-2′a); 2.35 (s, 3H, 122.92 (C-3); 136.38 (CH-4); 155.78 (C-6); 161.26 (C-2). IR spec-
CH3); 2.38 (ddd, 1H, Jgem = 12.8 Hz, J2′b,1′ = 10.8 Hz, J2′b,3′ = 6.5 trum (KBr): 3386, 3079, 2988, 2951, 2923, 2853, 1603, 1588,
Hz, H-2′b); 3.77 (dd, 1H, Jgem = 11.1 Hz, J5′a,4′ = 2.4 Hz, H-5′a); 1461, 1444, 1383, 1327, 1246, 1192, 1116, 1089, 1082, 1049,
3.83 (dd, 1H, Jgem = 11.1 Hz, J5′b,4′ = 3.0 Hz, H-5′b); 3.90 (bq, 1031, 966, 942, 821.
1H, J4′,5′a = J4′,5′b = J4′,3′ = 2.7 Hz, H-4′); 4.45 (bddd, 1H, J3′,2′b
6.5 Hz, J3′,4′ = 2.9 Hz, J3′,2′a = 1.6 Hz, H-3′); 5.01 (dd, 1H, J1′,2′b
=
=
1β-(6-Chloro-2-phenylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
dimethylsilyl)-D-ribofuranose (13a). K2CO3 (86 mg, 0.62 mmol),
10.8 Hz, J1′,2′a = 5.6 Hz, H-1′); 5.31 (bs, 2H, NH2); 6.42 (bd, 1H, Pd(PPh3)4 (24 mg, 0.02 mmol, 5 mol%), PhB(OH)2 (45 mg,
J5,4 = 7.4 Hz, H-5); 7.19 (d, 1H, J4,5 = 7.4 Hz, H-4). 13C NMR 0.37 mmol, 0.9 equiv.) and starting nucleoside 7 (222 mg,
(125.7 MHz, CDCl3): −5.57, −5.51, −4.72 and −4.58 (CH3Si); 0.41 mmol) were dissolved in toluene (2 mL) under argon, and
18.02 and 18.43 ((CH3)3C); 23.73 (CH3); 25.80 and 25.88 the mixture was stirred at 60 °C for 12 h. The reaction mixture
((CH3)3C); 39.94 (CH2-2′); 62.93 (CH2-5′); 73.55 (CH-3′); 80.27 was concentrated under reduced pressure, and the crude
(CH-1′); 88.23 (CH-4′); 112.11 (CH-5); 114.81 (C-3); 137.04 product was chromatographed on silica gel eluting with a gra-
(CH-4); 155.94 (C-6); 156.38 (C-2). IR spectrum (CCl4): 3488, dient of hexanes to 1% EtOAc in hexanes to give 13a (140 mg,
3372, 3062, 2956, 2930, 2896, 2585, 1609, 1595, 1582, 1472, 63%) as a colorless oil. HRMS (ESI) for C28H44ClNO3Si2:
1463, 1445, 1408, 1390, 1374, 1362, 1258, 1097, 1006, 938, 837. [M + H] calculated, 534.2621; found, 534.2621. 1H NMR
1β-(2-Amino-6-methylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (500 MHz, CDCl3): −0.01, 0.02, 0.09 and 0.10 (4 × s, 4 × 3H,
(11b). Compound 11b was prepared from 11a (97 mg, CH3Si); 0.82 and 0.92 (2 × s, 2 × 9H, ((CH3)3C)); 1.81 (ddd, 1H,
0.11 mmol) by the general procedure to yield 11b (85 mg, Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz, J2′a,3′ = 5.4 Hz, H-2′a); 1.96 (ddd,
82%) as a yellow solid. HRMS (ESI) for C11H16N2O3: [M + H] 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.3 Hz, J2′b,3′ = 1.9 Hz, H-2′b); 3.67
calculated, 225.1234; found, 225.1234. 1H NMR (500 MHz, (dd, 1H, Jgem = 10.9 Hz, J5′a,4′ = 4.8 Hz, H-5′a); 3.74 (dd, 1H,
DMSO-d6): 1.88 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′ = 5.6 Hz, J2′a,3′
1.8 Hz, H-2′a); 2.03 (ddd, 1H, Jgem = 12.7 Hz, J2′b,1′ = 10.5 Hz, 4.8 Hz, J4′,5′b = 3.3 Hz, J4′,3′ = 2.1 Hz, H-4′); 4.36 (dtd, 1H, J3′,2′a
J2′b,3′ = 6.3 Hz, H-2′b); 2.21 (s, 3H, CH3); 3.50 (ddd, 1H, Jgem
=
Jgem = 10.9 Hz, J5′b,4′ = 3.3 Hz, H-5′b); 3.85 (ddd, 1H, J4′,5′a
=
=
=
5.5 Hz, J3′,4′ = J3′,2′b = 2.0 Hz, J3′,1′ = 0.6 Hz, H-3′); 5.22 (bddq,
11.5 Hz, J5′a,OH = 5.4 Hz, J5′a,4′ = 3.9 Hz, H-5′a); 3.54 (ddd, 1H, 1H, J1′,2′a = 10.2 Hz, J1′,2′b = 5.3 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.6 Hz,
Jgem = 11.5 Hz, J5′b,OH = 4.9 Hz, J5′b,4′ = 3.6 Hz, H-5′b); 3.73 (td, H-1′); 7.30 (dd, 1H, J5,4 = 8.3 Hz, J5,1′ = 0.7 Hz, H-5); 7.38–7.46
1H, J4′,5′a = J4′,5′b = 3.8 Hz, J4′,3′ = 2.8 Hz, H-4′); 4.20 (m, 1H, (m, 5H, H-o,m,p-Ph); 8.05 (dd, 1H, J4,5 = 8.3 Hz, J4,1′ = 0.6 Hz,
H-3′); 4.91 (dd, 1H, J1′,2′b = 10.5 Hz, J1′,2′a = 5.6 Hz, H-1′); 4.93 (t, H-4). 13C NMR (125.7 MHz, CDCl3): −5.51, −5.39, −4.80 and
1H, JOH,5′a = JOH,5′b = 5.2 Hz, OH-5′); 5.02 (d, 1H, JOH,3′ = 4.1 Hz, −4.76 (CH3Si); 17.86 and 18.31 ((CH3)3C); 25.67 and 25.89
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((CH3)3C); 44.62 (CH2-2′); 63.53 (CH2-5′); 74.20 (CH-3′); 75.74 (CH-p-Ph-2); 128.59 (CH-m-Ph-6); 128.80 (CH-p-Ph-6); 129.22
(CH-1′); 87.91 (CH-4′); 123.01 (CH-5); 128.23 and 128.95 (CH-o-Ph-2); 134.17 (C-3); 135.75 (CH-4); 139.16 (C-i-Ph-6);
(CH-o,m-Ph); 128.58 (CH-p-Ph); 134.90 (C-3); 137.99 (CH-4); 139.94 (C-i-Ph-2); 155.58 (C-6); 157.17 (C-2). IR spectrum
138.33 (C-i-Ph); 149.33 (C-6); 157.84 (C-2). IR spectrum (CCl4): (CCl4): 3110, 3086, 3064, 3034, 2956, 2897, 1602, 1588, 1576,
3087, 3063, 3034, 2956, 2989, 1575, 1558, 1496, 1471, 1463, 1563, 1495, 1472, 1463, 1442, 1406, 1389, 1361, 1280, 1258,
1408, 1388, 1361, 1257, 1088, 1027, 1006, 939, 838.
1096, 1030, 939, 838.
1β-(6-Chloro-2-phenylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose
1β-(2,6-Diphenylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (14b).
(13b). Compound 13b was prepared from 13a (160 mg, Compound 14b was prepared from 14a (205 mg, 0.36 mmol)
0.30 mmol) by the general procedure to yield 13b (84 mg, by the general procedure to yield 14b (100 mg, 81%) as a white
91%) as a white solid. HRMS (ESI) for C22H21NO3: [M + H] solid. HRMS (ESI) for C22H21NO3: [M
+
H] calculated,
calculated, 348.1594; found, 348.1593. 1H NMR (500 MHz, 348.1594; found, 348.1593. H NMR (500 MHz, CD3OD): 2.01
CD3OD): 2.01 (ddd, 1H, Jgem = 13.2 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′ (ddd, 1H, Jgem = 13.2 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′ = 5.9 Hz, H-2′a);
1
=
5.9 Hz, H-2′a); 2.06 (ddd, 1H, Jgem = 13.2 Hz, J2′b,1′ = 5.8 Hz, 2.06 (ddd, 1H, Jgem = 13.2 Hz, J2′b,1′ = 5.8 Hz, J2′b,3′ = 2.0 Hz,
J2′b,3′ = 2.0 Hz, H-2′b); 3.70 (m, 1H, H-5′a); 3.72 (m, 1H, H-5′b); H-2′b); 3.70 (m, 1H, H-5′a); 3.72 (m, 1H, H-5′b); 3.85 (btd, 1H,
3.85 (btd, 1H, J4′,5′a = J4′,5′b = 4.7 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.31 J4′,5′a = J4′,5′b = 4.7 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.31 (bdddd, 1H,
(bdddd, 1H, J3′,2′a = 5.9 Hz, J3′,4′ = 2.8 Hz, J3′,2′b = 1.9 Hz, J3′,1′
=
J3′,2′a = 5.9 Hz, J3′,4′ = 2.8 Hz, J3′,2′b = 1.9 Hz, J3′,1′ = 0.6 Hz, H-3′);
0.6 Hz, H-3′); 5.24 (bddq, 1H, J1′,2′a = 10.1 Hz, J1′,2′b = 5.8 Hz, 5.24 (bddq, 1H, J1′,2′a = 10.1 Hz, J1′,2′b = 5.8 Hz, J1′,3′ = J1′,4
=
J1′,3′ = J1′,4 = J1′,5 = 0.6 Hz, H-1′); 7.41 (m, 1H, H-p-Ph-6); J1′,5 = 0.6 Hz, H-1′); 7.41 (m, 1H, H-p-Ph-6); 7.44–7.49 (m, 3H,
7.44–7.49 (m, 3H, H-m-Ph-6, H-p-Ph-2); 7.50 (m, 2H, H-m-Ph- H-m-Ph-6, H-p-Ph-2); 7.50 (m, 2H, H-m-Ph-2); 7.55 (m, 2H, H-o-
2); 7.55 (m, 2H, H-o-Ph-2); 7.85 (dd, 1H, J5,4 = 8.3 Hz, J5,1′
=
Ph-2); 7.85 (dd, 1H, J5,4 = 8.3 Hz, J5,1′ = 0.6 Hz, H-5); 8.01 (m,
0.6 Hz, H-5); 8.01 (m, 2H, H-o-Ph-6); 8.22 (dd, 1H, J4,5 = 8.3 Hz, 2H, H-o-Ph-6); 8.22 (dd, 1H, J4,5 = 8.3 Hz, J4,1′ = 0.5 Hz, H-4).
J4,1′ = 0.5 Hz, H-4). 13C NMR (125.7 MHz, CD3OD): 44.89 13C NMR (125.7 MHz, CD3OD): 44.89 (CH2-2′); 63.86 (CH2-5′);
(CH2-2′); 63.86 (CH2-5′); 74.42 (CH-3′); 77.59 (CH-1′); 89.06 74.42 (CH-3′); 77.59 (CH-1′); 89.06 (CH-4′); 121.00 (CH-5);
(CH-4′); 121.00 (CH-5); 128.22 (CH-o-Ph-6); 129.33 (CH-m-Ph- 128.22 (CH-o-Ph-6); 129.33 (CH-m-Ph-2); 129.43 (CH-p-Ph-2);
2); 129.43 (CH-p-Ph-2); 129.72 (CH-m-Ph-6); 130.10 (CH-p-Ph- 129.72 (CH-m-Ph-6); 130.10 (CH-p-Ph-6); 130.32 (CH-o-Ph-2);
6); 130.32 (CH-o-Ph-2); 135.29 (C-3); 137.71 (CH-4); 140.31 (C-i- 135.29 (C-3); 137.71 (CH-4); 140.31 (C-i-Ph-6); 141.23 (C-i-Ph-2);
Ph-6); 141.23 (C-i-Ph-2); 157.47 (C-6); 159.02 (C-2). IR spectrum 157.47 (C-6); 159.02 (C-2). IR spectrum (KBr): 3412, 3110, 3083,
(KBr): 3412, 3084, 3061, 3031, 1574, 1559, 1495, 1449, 1277, 3059, 3031, 1602, 1587, 1574, 1562, 1493, 1282, 1075, 1046,
1146, 1083, 1075, 1024, 1000, 940, 831.
1028, 941.
1β-(2,6-Diphenylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
1β-(6-Amino-2-phenylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
dimethylsilyl)-D-ribofuranose (14a). K2CO3 (129 mg, 0.93 mmol), dimethylsilyl)-D-ribofuranose (15a). LiN(SiMe3)2 (1.5 mL,
Pd(PPh3)4 (21 mg, 0.0185 mmol, 5 mol%), PhB(OH)2 (135 mg, 1.5 mmol, 3 equiv. 1.0 M solution in THF) was added to a
1.11 mmol, 3 equiv.) and starting nucleoside 7 (200 mg, flame-dried and argon-purged flask containing 14a (262 mg,
0.37 mmol) were dissolved in toluene (2 mL) under argon, and 0.49 mmol), Pd2(dba)3 (45 mg, 0.049 mmol, 10 mol%), and
the mixture was stirred at 100 °C for 12 h. The reaction (biphenyl-2-yl)dicyclohexylphosphane (35 mg, 0.098 mmol,
mixture was concentrated under reduced pressure, and the 20 mol%), and the mixture was stirred at 60 °C for 12 h. After
crude product was chromatographed on silica gel eluting with cooling to room temperature, the reaction mixture was diluted
a gradient of hexanes to 1% EtOAc in hexanes to give 14a with Et2O (30 mL), washed with 2 M HCl (10 mL) and 1 M
(205 mg, 95%) as a colorless oil. HRMS (ESI) for C34H49NO3Si2: NaOH (15 mL). The crude product was chromatographed on
[M + H] calculated, 576.3324; found, 576.3323. 1H NMR silica gel eluting with a gradient of hexanes to 20% EtOAc in
(500 MHz, CDCl3): 0.04, 0.06, 0.12 and 0.14 (4 × s, 4 × 3H, hexanes to give 15a (230 mg, 91%) as a colorless oil. HRMS
CH3Si); 0.86 and 0.96 (2 × s, 2 × 9H, ((CH3)3C)); 1.91 (ddd, 1H, (ESI) for C28H46N2O3Si2: [M + H] calculated, 515.3120; found,
Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz, J2′a,3′ = 5.4 Hz, H-2′a); 2.03 (ddd, 515.3118. 1H NMR (500 MHz, CDCl3): 0.01, 0.02, 0.085 and
1H, Jgem = 12.7 Hz, J2′b,1′ = 5.3 Hz, J2′b,3′ = 1.9 Hz, H-2′b); 3.71 0.093 (4 × s, 4 × 3H, CH3Si); 0.82 and 0.93 (2 × s, 2 × 9H,
(dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 5.1 Hz, H-5′a); 3.80 (dd, 1H, ((CH3)3C)); 1.86 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz,
Jgem = 10.8 Hz, J5′b,4′ = 3.5 Hz, H-5′b); 3.90 (ddd, 1H, J4′,5′a
5.1 Hz, J4′,5′b = 3.5 Hz, J4′,3′ = 2.2 Hz, H-4′); 4.42 (bdt, 1H, J3′,2′a
5.4 Hz, J3′,4′ = J3′,2′b = 2.1 Hz, H-3′); 5.33 (bdd, 1H, J1′,2′a
=
=
=
J2′a,3′ = 5.4 Hz, H-2′a); 1.93 (ddd, 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.4
Hz, J2′b,3′ = 1.9 Hz, H-2′b); 3.64 (dd, 1H, Jgem = 10.7 Hz, J5′a,4′
5.2 Hz, H-5′a); 3.74 (dd, 1H, Jgem = 10.7 Hz, J5′b,4′ = 3.5 Hz, H-5′
=
10.2 Hz, J1′,2′b = 5.3 Hz, H-1′); 7.38–7.45 (m, 2H, H-p-Ph-2,6); b); 3.79 (ddd, 1H, J4′,5′a = 5.2 Hz, J4′,5′b = 3.5 Hz, J4′,3′ = 2.1 Hz,
7.44–7.49 (m, 4H, H-m-Ph-2,6); 7.57 (m, 2H, H-o-Ph-2); 7.74 H-4′); 4.36 (dt, 1H, J3′,2′a = 5.4 Hz, J3′,4′ = J3′,2′b = 2.0 Hz, H-3′);
(dd, 1H, J5,4 = 8.2 Hz, J5,1′ = 0.6 Hz, H-5); 8.08 (m, 2H, H-o-Ph- 5.10 (dd, 1H, J1′,2′a = 10.2 Hz, J1′,2′b = 5.3 Hz, H-1′); 6.51 (bd, 1H,
6); 8.14 (bd, 1H, J4,5 = 8.2 Hz, H-4). 13C NMR (125.7 MHz, J5,4 = 8.5 Hz, H-5); 7.36 (m, 1H, H-p-Ph); 7.39 (m, 2H, H-m-Ph);
CDCl3): −5.47, −5.36, −4.78 and −4.74 (CH3Si); 17.88 and 7.41 (m, 2H, H-o-Ph); 7.77 (d, 1H, J4,5 = 8.5 Hz, H-4). 13C NMR
18.33 ((CH3)3C); 25.70 and 25.92 ((CH3)3C); 44.53 (CH2-2′); (125.7 MHz, CDCl3): −5.50, −5.39, −4.78 and −4.75 (CH3Si);
63.61 (CH2-5′); 74.28 (CH-3′); 76.16 (CH-1′); 87.78 (CH-4′); 17.86 and 18.31 ((CH3)3C); 25.68 and 25.91 ((CH3)3C); 44.29
119.21 (CH-5); 127.07 (CH-o-Ph-6); 128.06 (CH-m-Ph-2); 128.11 (CH2-2′); 63.68 (CH2-5′); 74.29 (CH-3′); 76.02 (CH-1′); 87.45
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Organic & Biomolecular Chemistry
(CH-4′); 108.00 (CH-5); 124.93 (C-3); 127.90 (CH-p-Ph); 128.03
1β-(6-Methyl-2-phenylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose
(CH-m-Ph); 128.84 (CH-o-Ph); 137.26 (CH-4); 139.65 (C-i-Ph); (16b). Compound 16b was prepared from 16a (144 mg,
155.80 (C-2); 156.81 (C-6). IR spectrum (CCl4): 2506, 3407, 0.28 mmol) by the general procedure to yield 16b (68 mg,
3301, 3169, 3084, 3063, 3030, 2956, 2897, 1631, 1610, 1572, 85%) as a white solid. HRMS (ESI) for C17H19NO3: [M + H]
1496, 1473, 1464, 1444, 1410, 1389, 1361, 1290, 1256, 1097, calculated, 286.1438; found, 286.1438. 1H NMR (500 MHz,
1029, 939, 838.
CD3OD): 1.93 (ddd, 1H, Jgem = 13.2 Hz, J2′a,1′ = 10.2 Hz, J2′a,3′ =
1β-(6-Amino-2-phenylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose 5.9 Hz, H-2′a); 1.99 (ddd, 1H, Jgem = 13.2 Hz, J2′b,1′ = 5.8 Hz,
(15b). Compound 15b was prepared from 15a (200 mg, J2′b,3′ = 1.9 Hz, H-2′b); 2.54 (s, 3H, CH3-6); 3.64–3.71 (m, 2H,
0.39 mmol) by the general procedure to yield 15b (70 mg, H-5′); 3.80 (bddd, 1H, J4′,5′a = 5.0 Hz, J4′,5′b = 4.5 Hz, J4′,3′
67%) as a yellow solid. HRMS (ESI) for C16H18N2O3: [M + H] 2.7 Hz, H-4′); 4.27 (bdddd, 1H, J3′,2′a = 6.0 Hz, J3′,4′ = 2.7 Hz,
calculated, 287.1390; found, 287.1390. 1H NMR (500 MHz, J3′,2′b = 1.9 Hz, J3′,1′ = 0.6 Hz, H-3′); 5.10 (bdd, 1H, J1′,2′a
DMSO-d6): 1.84 (ddd, 1H, Jgem = 12.8 Hz, J2′a,1′ = 5.9 Hz, J2′a,3′ 10.2 Hz, J1′,2′b = 5.8 Hz, H-1′); 7.32 (bd, 1H, J5,4 = 8.1 Hz, H-5);
=
=
=
2.1 Hz, H-2′a); 1.88 (ddd, 1H, Jgem = 12.8 Hz, J2′b,1′ = 10.1 Hz, 7.42 (m, 2H, H-o-Ph); 7.43–7.51 (m, 3H, H-m,p-Ph); 8.09 (d, 1H,
J2′b,3′ = 5.4 Hz, H-2′b); 3.40–3.49 (m, 2H, H-5′); 3.60 (bddd, 1H, J4,5 = 8.1 Hz, H-4). 13C NMR (125.7 MHz, CD3OD): 23.38
J4′,5′a = 5.3 Hz, J4′,5′b = 4.8 Hz, J4′,3′ = 2.2 Hz, H-4′); 4.15 (m, 1H, (CH3-6); 44.85 (CH2-2′); 63.82 (CH2-5′); 74.36 (CH-3′); 77.47
H-3′); 4.71 (bt, 1H, JOH,5′a = JOH,5′b = 5.6 Hz, OH-5′); 4.85 (dd, (CH-1′); 89.02 (CH-4′); 124.14 (CH-5); 129.40 (CH-m-Ph); 129.52
1H, J1′,2′b = 10.1 Hz, J1′,2′a = 5.8 Hz, H-1′); 4.85 (d, 1H, JOH,3′
=
(CH-p-Ph); 130.11 (CH-o-Ph); 134.25 (C-3); 137.65 (CH-4); 140.70
3.8 Hz, OH-3′); 6.13 (bs, 2H, NH2); 6.54 (bd, 1H, J5,4 = 8.6 Hz, (C-i-Ph); 158.02 (C-6); 158.29 (C-2). IR spectrum (KBr): 1595,
H-5); 7.38–7.46 (m, 5H, H-o,m,p-Ph); 7.67 (bd, 1H, J4,5 = 8.6 Hz, 1573, 1496, 1476, 1447, 1380, 1281, 1146, 1086, 1040, 961.
H-4). 13C NMR (125.7 MHz, DMSO-d6): 43.08 (CH2-2′); 62.61
1β-[2,6-Bis(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-D-ribo-
(CH2-5′); 72.71 (CH-3′); 75.47 (CH-1′); 87.54 (CH-4′); 108.25 furanose (17). MeSNa (59 mg, 0.84 mmol) was added to a
(CH-5); 122.25 (C-3); 128.02 (CH-m,p-Ph); 129.13 (CH-o-Ph); solution of the nucleoside 4 (45 mg, 0.084 mmol) in DMF
137.98 (CH-4); 139.50 (C-i-Ph); 154.35 (C-2); 157.89 (C-6). IR (2 mL) and the mixture was stirred for 12 h at 80 °C. Then the
spectrum (KBr): 3358, 3217, 3059, 1621, 1600, 1571, 1496, solvents were evaporated under vacuum. The crude product
1444, 1217, 1181, 1158, 1074, 1047, 830.
was chromatographed on silica gel in a gradient of chloroform
1β-(6-Methyl-2-phenylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl- to 7% MeOH in chloroform to give 17 (19 mg, 79%) as a pale
dimethylsilyl)-D-ribofuranose (16a). Me3Al (0.92 mL, 0.92 yellow solid. HRMS (ESI) for C12H17NO3S2: [M + Na] calculated,
1
mmol, 3.0 equiv., 1 M in heptane) was added to a flame- 310.0542; found, 310.0542. H NMR (500 MHz, CD3OD): 1.75
dried flask containing a solution of 14a (164 mg, 0.31 mmol) (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′ = 6.0 Hz, H-2′a);
and Pd(PPh3)4 (36 mg, 0.031 mmol, 10 mol%) in THF (5 mL). 2.36 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.6 Hz, J2′b,3′ = 2.0 Hz,
The mixture was stirred at 70 °C for 12 h, quenched by H-2′b); 2.57 (s, 3H, CH3S-6); 2.59 (s, 3H, CH3S-2); 3.67–3.70 (m,
pouring into saturated NaH2PO4 (50 mL), and extracted with 2H, H-5′); 3.92 (td, 1H, J4′,5′a = J4′,5′b = 4.9 Hz, J4′,3′ = 2.8 Hz,
EtOAc (3 × 50 mL). The crude product was chromatographed H-4′); 4.30 (dddd, 1H, J3′,2′a = 6.1 Hz, J3′,4′ = 2.8 Hz, J3′,2′b
on silica gel eluting with a gradient of hexanes to 6% EtOAc in 2.0 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.27 (ddq, 1H, J1′,2′a = 10.1 Hz, J1′,2′b
hexanes to give 16a (144 mg, 91%) as a colorless oil. HRMS 5.6 Hz, J1′,4 = J1′,5 = J1′,3′ = 0.7 Hz, H-1′); 6.93 (dd, 1H, J5,4
(ESI) for C29H47NO3Si2: [M + H] calculated, 514.3167; found, 8.1 Hz, J5,1′ = 0.6 Hz, H-5); 7.65 (dd, 1H, J4,5 = 8.1 Hz, J4,1′
=
=
=
=
514.3166. 1H NMR (500 MHz, CDCl3): −0.01, 0.02, 0.08 and 0.8 Hz, H-4). 13C NMR (125.7 MHz, CD3OD): 11.46 and 11.56
0.10 (4 × s, 4 × 3H, CH3Si); 0.82 and 0.92 (2 × s, 2 × 9H, (CH3S-2,6); 41.24 (CH2-2′); 62.13 (CH2-5′); 72.62 (CH-3′); 75.06
((CH3)3C)); 1.81 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz, (CH-1′); 87.16 (CH-4′); 115.88 (CH-5); 130.16 (C-3); 132.32 (CH-4);
J2′a,3′ = 5.4 Hz, H-2′a); 1.93 (ddd, 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.3 Hz, 155.15 (C-2); 157.48 (C-6). IR spectrum (KBr): 3411, 2989, 2924,
J2′b,3′ = 1.9 Hz, H-2′b); 2.62 (s, 3H, CH3-6); 3.66 (dd, 1H, Jgem
=
1565, 1543, 1430, 1418, 1335, 1308, 1217, 1049, 962, 840, 778.
10.8 Hz, J5′a,4′ = 5.1 Hz, H-5′a); 3.75 (dd, 1H, Jgem = 10.8 Hz,
1β-[2-Chloro-6-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-3,5-
J5′b,4′ = 3.5 Hz, H-5′b); 3.83 (ddd, 1H, J4′,5′a = 5.1 Hz, J4′,5′b
3.5 Hz, J4′,3′ = 2.2 Hz, H-4′); 4.36 (dtd, 1H, J3′,2′a = 5.4 Hz, J3′,4′
J3′,2′b = 2.0 Hz, J3′,1′ = 0.5 Hz, H-3′); 5.18 (dd, 1H, J1′,2′a
=
=
=
di-O-(t-butyldimethylsilyl)-D-ribofuranose
(48 mg, 0.69 mmol, 1.2 equiv.) was added to a solution of the
nucleoside 4 (310 mg, 0.58 mmol) in DMF (5 mL) and the
(18a). MeSNa
10.2 Hz, J1′,2′b = 5.3 Hz, H-1′); 7.16 (d, 1H, J5,4 = 8.1 Hz, H-5); mixture was stirred for 12 h at rt. Then the solvents were evapo-
7.38 (m, 1H, H-p-Ph); 7.40–7.44 (m, 4H, H-o,m-Ph); 7.97 (d, 1H, rated under vacuum. The crude product was purified using
J4,5 = 8.1 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): −5.49, −5.39, high performance flash chromatography with a gradient of
−4.81 and −4.76 (CH3Si); 17.85 and 18.31 ((CH3)3C); 24.06 hexanes to 1% EtOAc in hexanes to give products 18a (141 mg,
(CH3-6); 25.68 and 25.90 ((CH3)3C); 44.49 (CH2-2′); 63.59 48%) as a white solid and 19a (136 mg, 43%) as a white solid.
(CH2-5′); 74.23 (CH-3′); 76.06 (CH-1′); 87.72 (CH-4′); 122.38 Compound 18a: HRMS (ESI) for C23H42ClNO3SSi2: [M + H] cal-
(CH-5); 128.14 (CH-p-Ph); 128.18 (CH-m-Ph); 128.97 (CH-o-Ph); culated, 504.2185; found, 504.2183. 1H NMR (500 MHz, CDCl3)
132.93 (C-3); 135.53 (CH-4); 139.32 (C-i-Ph); 156.52 (C-2,6). IR 0.082, 0.084 and 0.09 (4 × s, 4 × 3H, CH3Si); 0.90 and 0.91
spectrum (CCl4): 3110, 3083, 3061, 3029, 2956, 2930, 2897, (2 × s, 2 × 9H, ((CH3)3C)); 1.70 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′
2858, 1593, 1569, 1495, 1471, 1463, 1406, 1389, 1371, 1361, 9.5 Hz, J2′a,3′ = 5.6 Hz, H-2′a); 2.37 (ddd, 1H, Jgem = 12.7 Hz,
=
1289, 1257, 1095, 1030, 1006, 939, 838.
J2′b,1′ = 5.9 Hz, J2′b,3′ = 2.5 Hz, H-2′b); 2.56 (s, 3H, CH3S-6); 3.69
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(dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 4.8 Hz, H-5′a); 3.76 (dd, 1H, (62 mg, 78%) as a white solid. HRMS (ESI) for C11H14BrNO3S:
Jgem = 10.8 Hz, J5′b,4′ = 3.5 Hz, H-5′b); 3.95 (ddd, 1H, J4′,5′a
5.7 Hz, J4′,5′b = 3.5 Hz, J4′,3′ = 2.6 Hz, H-4′); 4.38 (dtd, 1H, J3′,2′a
=
=
[M + Na] calculated, 341.9770; found, 341.9771. 1H NMR
(500 MHz, CD3OD): 1.73 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′
=
5.7 Hz, J3′,4′ = J3′,2′b = 2.5 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.35 (ddq, 1H, 10.0 Hz, J2′a,3′ = 6.0 Hz, H-2′a); 2.42 (ddd, 1H, Jgem = 13.1 Hz,
J1′,2′a = 9.4 Hz, J1′,2′b = 5.8 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.7 Hz,H-1′); J2′b,1′ = 5.7 Hz, J2′b,3′ = 2.0 Hz, H-2′b); 2.55 (s, 3H, CH3S-2); 3.67
7.08 (dd, 1H, J5,4 = 8.1 Hz, J5,1′ = 0.6 Hz, H-5); 7.80 (dd, 1H, (dd, 1H, Jgem = 11.8 Hz, J5′a,4′ = 5.0 Hz, H-5′a); 3.70 (dd, 1H,
J4,5 = 8.1 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): Jgem = 11.8 Hz, J5′b,4′ = 4.6 Hz, H-5′b); 3.93 (td, 1H, J4′,5′a
=
−5.48, −5.40, −4.75 and −4.62 (CH3Si); 13.51 (CH3S-6); 17.99 J4′,5′b = 4.8 Hz, J4′,3′ = 2.8 Hz, H-4′); 4.31 (dddd, 1H, J3′,2′a = 6.0
and 18.30 ((CH3)3C); 25.77 and 25.88 ((CH3)3C); 42.47 (CH2-2′); Hz, J3′,4′ = 2.8 Hz, J3′,2′b = 2.0 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.24 (ddq,
63.32 (CH2-5′); 73.72 (CH-3′); 76.01 (CH-1′); 87.76 (CH-4′); 1H, J1′,2′a = 10.0 Hz, J1′,2′b = 5.7 Hz, J1′,4 = J1′,5 = J1′,3′ = 0.7 Hz,
120.24 (CH-5); 132.38 (C-3); 135.72 (CH-4); 147.97 (C-2); 158.71 H-1′); 7.24 (dd, 1H, J5,4 = 8.0 Hz, J5,1′ = 0.6 Hz, H-5); 7.74 (dd,
(C-6). IR spectrum (CCl4): 3078, 3058, 2956, 2897, 1587, 1537, 1H, J4,5 = 8.0 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz,
1472, 1439, 1408, 1390, 1373, 1361, 1318, 1258, 1096, 939, 838. CD3OD): 13.38 (CH3S-2); 42.71 (CH2-2′); 63.72 (CH2-5′); 74.22
1β-[6-Bromo-2-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-3,5- (CH-3′); 76.47 (CH-1′); 88.96 (CH-4′); 124.18 (CH-5); 136.32 (C-3);
di-O-(t-butyldimethylsilyl)-D-ribofuranose (19a). HRMS (ESI) 136.36 (CH-4); 140.71 (C-6); 158.53 (C-2). IR spectrum (KBr):
for C23H42BrNO3SSi2: [M + H] calculated, 548.1680; found, 3380, 3324, 3066, 1569, 1540, 1409, 1307, 1209, 1045, 948.
548.1675. 1H NMR (500 MHz, CDCl3) 0.09, 0.098, 0.100 and
0.11 (4 × s, 4 × 3H, CH3Si); 0.91 and 0.93 (2 × s, 2 × 9H, di-O-(t-butyldimethylsilyl)-D-ribofuranose
((CH3)3C)); 1.68 (ddd, 1H, Jgem = 12.6 Hz, J2′a,1′ = 9.4 Hz, J2′a,3′ (0.48 mL, 0.48 mmol, 2.0 equiv., 1 M in heptane) was added to
5.6 Hz, H-2′a); 2.38 (ddd, 1H, Jgem = 12.6 Hz, J2′b,1′ = 5.9 Hz, a flame-dried flask containing a solution of 18a (130 mg,
J2′b,3′ = 2.6 Hz, H-2′b); 2.59 (s, 3H, CH3S-2); 3.70 (dd, 1H, Jgem 0.24 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol, 10 mol%) in
10.9 Hz, J5′a,4′ = 4.9 Hz, H-5′a); 3.78 (dd, 1H, Jgem = 10.9 Hz, THF (3 mL). The mixture was stirred at 90 °C for 12 h,
1β-[2-Methyl-6-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-3,5-
(20a). Me3Al
=
=
J5′b,4′ = 3.5 Hz, H-5′b); 3.95 (ddd, 1H, J4′,5′a = 4.9 Hz, J4′,5′b
3.5 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.39 (dtd, 1H, J3′,2′a = 5.6 Hz, J3′,4′
J3′,2′b = 2.7 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.27 (ddq, 1H, J1′,2′a
=
=
=
quenched by pouring into saturated NaH2PO4 (50 mL), and
extracted with EtOAc (3 × 50 mL). The crude product was
chromatographed on silica gel eluting with a gradient of
9.4 Hz, J1′,2′b = 5.9 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.7 Hz, H-1′); 7.15 (dd, hexanes to 6% EtOAc in hexanes to give 20a (61 mg, 49%) as a
1H, J5,4 = 8.0 Hz, J5,1′ = 0.6 Hz, H-5); 7.67 (dd, 1H, J4,5 = 8.0 Hz, colorless oil. HRMS (ESI) for C24H45NO3SSi2: [M + H] calcu-
J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): −5.48, −5.41, lated, 484.2731; found, 484.2731. 1H NMR (500 MHz, CDCl3)
−4.76 and −4.61 (CH3Si); 13.35 (CH3S-2); 17.99 and 18.30 0.08 and 0.09 (2 × s, 2 × 6H, CH3Si); 0.90 and 0.91 (2 × s, 2 ×
((CH3)3C); 25.78 and 25.89 ((CH3)3C); 41.82 (CH2-2′); 63.24 9H, ((CH3)3C)); 1.72 (ddd, 1H, Jgem = 12.6 Hz, J2′a,1′ = 10.0 Hz,
(CH2-5′); 73.73 (CH-3′); 75.03 (CH-1′); 87.57 (CH-4′); 122.85 J2′a,3′ = 5.6 Hz, H-2′a); 2.15 (ddd, 1H, Jgem = 12.6 Hz, J2′b,1′
=
(CH-5); 134.71 (CH-4); 135.45 (C-3); 139.46 (C-6); 157.09 (C-2). 5.5 Hz, J2′b,3′ = 2.0 Hz, H-2′b); 2.48 (s, 3H, CH3-2); 2.54 (s, 3H,
IR spectrum (CCl4): 3057, 2956, 2897, 1571, 1543, 1472, 1463, CH3S-6); 3.67 (dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 5.2 Hz, H-5′a);
1414, 1390, 1374, 1310, 1288, 1216, 1097, 1030, 961, 939, 838.
3.77 (dd, 1H, Jgem = 10.8 Hz, J5′b,4′ = 3.6 Hz, H-5′b); 3.94 (ddd,
1β-[2-Chloro-6-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-D-ribo- 1H, J4′,5′a = 5.2 Hz, J4′,5′b = 3.6 Hz, J4′,3′ = 2.3 Hz, H-4′); 4.41 (bdt,
furanose (18b). Compound 18b was prepared from 18a 1H, J3′,2′a = 5.6 Hz, J3′,4′ = J3′,2′b = 2.2 Hz, H-3′); 5.26 (bdd, 1H,
(141 mg, 0.28 mmol) by the general procedure to yield 18b J1′,2′a = 10.1 Hz, J1′,2′b = 5.5 Hz, H-1′); 6.99 (bd, 1H, J5,4 = 8.2 Hz,
(66 mg, 86%) as a white solid. HRMS (ESI) for C11H14ClNO3S: H-5); 7.68 (d, 1H, J4,5 = 8.2 Hz, H-4). 13C NMR (125.7 MHz,
[M + Na] calculated, 298.0275; found, 298.0277. 1H NMR CDCl3): −5.48, −5.39, −4.69 and −4.64 (CH3Si); 13.52 (CH3S-6);
(500 MHz, CD3OD): 1.77 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′
=
17.99 and 18.31 ((CH3)3C); 21.92 (CH3-2); 25.78 and 25.90
10.1 Hz, J2′a,3′ = 6.0 Hz, H-2′a); 2.42 (ddd, 1H, Jgem = 13.1 Hz, ((CH3)3C); 42.86 (CH2-2′); 63.50 (CH2-5′); 74.06 (CH-3′); 76.03
J2′b,1′ = 5.6 Hz, J2′b,3′ = 1.9 Hz, H-2′b); 2.53 (s, 3H, CH3S-6); 3.68 (CH-1′); 87.67 (CH-4′); 118.61 (CH-5); 131.61 (C-3); 133.44
(dd, 1H, Jgem = 11.8 Hz, J5′a,4′ = 5.0 Hz, H-5′a); 3.70 (dd, 1H, (CH-4); 154.56 (C-2); 157.15 (C-6). IR spectrum (CCl4): 3062,
Jgem = 11.8 Hz, J5′b,4′ = 4.6 Hz, H-5′b); 3.95 (td, 1H, J4′,5′a = J4′,5′b 2956, 2897, 1583, 1560, 1472, 1450, 1408, 1389, 1373, 1361,
= 4.8 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.31 (dddd, 1H, J3′,2′a = 6.0 Hz, 1315, 1258, 1098, 1088, 939, 838.
J3′,4′ = 2.7 Hz, J3′,2′b = 1.9 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.34 (ddq, 1H,
1β-[2-Methyl-6-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-D-ribo-
J1′,2′a = 10.1 Hz, J1′,2′b = 5.6 Hz, J1′,4 = J1′,5 = J1′,3′ = 0.7 Hz, H-1′); furanose (20b). Compound 20b was prepared from 20a (54 mg,
7.21 (dd, 1H, J5,4 = 8.2 Hz, J5,1′ = 0.6 Hz, H-5); 7.90 (dd, 1H, J4,5 0.11 mmol) by the general procedure to yield 20b (20 mg,
= 8.2 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR (125.7 MHz, CD3OD): 69%) as a white solid. HRMS (ESI) for C12H17NO3S: [M + H]
13.48 (CH3S-6); 43.23 (CH2-2′); 63.77 (CH2-5′); 74.19 (CH-3′); calculated, 256.1002; found, 256.1002. 1H NMR (500 MHz,
77.38 (CH-1′); 89.11 (CH-4′); 121.34 (CH-5); 133.08 (C-3); 137.46 CD3OD): 1.84 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.4 Hz, J2′a,3′
(CH-4); 149.04 (C-2); 160.92 (C-6). IR spectrum (KBr): 3333, 6.0 Hz, H-2′a); 2.28 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.5 Hz,
3284, 1048, 1585, 1576, 1543, 1425, 1317, 1219, 957, 832. J2′b,3′ = 1.8 Hz, H-2′b); 2.52 (s, 3H, CH3-2); 2.58 (s, 3H, CH3S-6);
=
1β-[6-Bromo-2-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-D-ribo- 3.66–3.72 (m, 2H, H-5′); 3.95 (td, 1H, J4′,5′a = J4′,5′b = 4.8 Hz, J4′,3′
furanose (19b). Compound 19b was prepared from 19a = 2.7 Hz, H-4′); 4.34 (dddd, 1H, J3′,2′a = 6.0 Hz, J3′,4′ = 2.7 Hz,
(136 mg, 0.25 mmol) by the general procedure to yield 19b J3′,2′b = 1.8 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.29 (bddq, 1H, J1′,2′a
=
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10.4 Hz, J1′,2′b = 5.5 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.6 Hz, H-1′); 7.22 (dt,
1β-(2-Chloro-6-ethynylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl-
1H, J5,4 = 8.4 Hz, J5,LR = 0.6 Hz, H-5); 7.96 (bd, 1H, J4,5 = 8.4 Hz, dimethylsilyl)-D-ribofuranose (22a). DMF (2 mL) and TMSA
H-4). 13C NMR (125.7 MHz, CD3OD): 13.92 (CH3S-6); 20.73 (CH3- (35 μL, 0.25 mmol, 0.8 equiv.) were added through a septum to
2); 43.21 (CH2-2′); 63.78 (CH2-5′); 74.30 (CH-3′); 77.06 (CH-1′); an argon-purged vial containing 4 (170 mg, 0.32 mmol),
89.13 (CH-4′); 120.06 (CH-5); 133.70 (C-3); 137.11 (CH-4); 155.32 Pd(PPh3)2Cl2 (22 mg, 0.032 mmol), CuI (1 mg, 0.005 mmol)
(C-2); 159.20 (C-6). IR spectrum (KBr): 3301, 2989, 2929, 2857, and Et3N (89 μL, 0.64 mmol). The resulting mixture was stirred
1580, 1560, 1448, 1435, 1386, 1270, 1088, 1050, 1026.
1β-[6-Methyl-2-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-3,5- tered on a pad of Celite and eluted with CHCl3. Solvents were
di-O-(t-butyldimethylsilyl)-D-ribofuranose (21a). Me3Al then removed under vacuum, the crude product was dissolved
at 60 °C for 12 h. The reaction mixture was then cooled and fil-
(0.40 mL, 0.40 mmol, 2.0 equiv., 1 M in heptane) was added to in methanolic ammonia (28%, 10 mL) and the solution was
a flame-dried flask containing solution of 19a (103 mg, stirred at rt for 1 h. The solvents were removed under vacuum,
0.20 mmol) and Pd(PPh3)4 (23 mg, 0.020 mmol, 10 mol%) in and the crude product was chromatographed on silica gel
THF (2 mL). The mixture was stirred at 90 °C for 12 h, eluting with a gradient of hexanes to 3% EtOAc in hexanes to
quenched by pouring into saturated NaH2PO4 (50 mL), and give 22a (81 mg, 53% for two steps) as a colorless oil. A portion
extracted with EtOAc (3 × 50 mL). The crude product was of starting material 4 (65 mg, 37%) was also isolated during
chromatographed on silica gel eluting with a gradient of chromatography. HRMS (ESI) for C24H40ClNO3Si2: [M + H]
hexanes to 5% EtOAc in hexanes to give 21a (53 mg, 58%) as a calculated, 482.2308; found, 482.2307. 1H NMR (500 MHz,
colorless oil. HRMS (ESI) for C24H45NO3SSi2: [M + H] calcu- CDCl3): 0.08, 0.086 and 0.093 (4 × s, 4 × 3H, CH3Si); 0.89 and
lated, 484.2731; found, 484.2732. 1H NMR (500 MHz, CDCl3) 0.91 (2 × s, 2 × 9H, ((CH3)3C)); 1.71 (ddd, 1H, Jgem = 12.6 Hz,
0.08, 0.09 and 0.10 (4 × s, 4 × 3H, CH3Si); 0.90 and 0.92 (2 × s, J2′a,1′ = 9.4 Hz, J2′a,3′ = 5.6 Hz, H-2′a); 2.44 (ddd, 1H, Jgem
2 × 9H, ((CH3)3C)); 1.69 (ddd, 1H, Jgem = 12.6 Hz, J2′a,1′ = 9.4 12.6 Hz, J2′b,1′ = 6.0 Hz, J2′b,3′ = 2.6 Hz, H-2′b); 3.16 (s, 1H,
Hz, J2′a,3′ = 5.7 Hz, H-2′a); 2.35 (ddd, 1H, Jgem = 12.6 Hz, J2′b,1′ CuCH); 3.71 (dd, 1H, Jgem = 10.9 Hz, J5′a,4′ = 4.7 Hz, H-5′a);
=
=
5.8 Hz, J2′b,3′ = 2.5 Hz, H-2′b); 2.48 (s, 3H, CH3-6); 2.58 (s, 3H, 3.77 (dd, 1H, Jgem = 10.9 Hz, J5′b,4′ = 3.4 Hz, H-5′b); 3.98 (ddd,
CH3S-2); 3.67 (dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 5.2 Hz, H-5′a); 1H, J4′,5′a = 4.7 Hz, J4′,5′b = 3.4 Hz, J4′,3′ = 2.6 Hz, H-4′); 4.38 (dtd,
3.78 (dd, 1H, Jgem = 10.8 Hz, J5′b,4′ = 3.7 Hz, H-5′b); 3.93 (ddd, 1H, J3′,2′a = 5.6 Hz, J3′,4′ = J3′,2′b = 2.6 Hz, J3′,1′ = 0.7 Hz, H-3′);
1H, J4′,5′a = 5.2 Hz, J4′,5′b = 3.7 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.38 (dtd, 5.38 (bddq, 1H, J1′,2′a = 9.4 Hz, J1′,2′b = 6.0 Hz, J1′,3′ = J1′,4 = J1′,5
=
1H, J3′,2′a = 5.7 Hz, J3′,4′ = J3′,2′b = 2.6 Hz, J3′,1′ = 0.6 Hz, H-3′); 0.7 Hz, H-1′); 7.39 (dd, 1H, J5,4 = 7.9 Hz, J5,1′ = 0.6 Hz, H-5);
5.33 (bdd, 1H, J1′,2′a = 9.4 Hz, J1′,2′b = 5.8 Hz, H-1′); 6.82 (bd, 8.01 (dd, 1H, J4,5 = 7.9 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR
1H, J5,4 = 7.7 Hz, H-5); 7.66 (dd, 1H, J4,5 = 7.7 Hz, J4,1′ = 0.8 Hz, (125.7 MHz, CDCl3): −5.50, −5.42, −4.77 and −4.63 (CH3Si);
H-4). 13C NMR (125.7 MHz, CDCl3): −5.46, −5.39, −4.75 and 17.98 and 18.28 ((CH3)3C); 25.74 and 25.86 ((CH3)3C); 42.31
−4.59 (CH3Si); 12.94 (CH3S-2); 18.01 and 18.32 ((CH3)3C); (CH2-2′); 63.20 (CH2-5′); 73.63 (CH-3′); 76.12 (CH-1′); 78.03
24.09 (CH3-6); 25.80 and 25.91 ((CH3)3C); 42.06 (CH2-2′); 63.39 (CuCH); 81.51 (CuCH); 87.89 (CH-4′); 129.39 (CH-5); 135.96
(CH2-5′); 73.86 (CH-3′); 75.41 (CH-1′); 87.41 (CH-4′); 118.46 (CH-4); 138.26 (C-3); 140.34 (C-6); 148.22 (C-2). IR spectrum
(CH-5); 132.52 (CH-4); 132.99 (C-3); 154.61 (C-2); 156.42 (C-6). (CCl4): 3309, 2956, 2898, 2123, 1582, 1546, 1472, 1463, 1441,
IR spectrum (CCl4): 3060, 2956, 2897, 1585, 1573, 1472, 1463, 1390, 1361, 1336, 1258, 1174, 1097, 1060, 939, 838.
1407, 1390, 1374, 1361, 1311, 1258, 1210, 1097, 1077, 1031,
971, 963, 939, 838.
1β-(2-Chloro-6-ethynylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose
(22b). Compound 22b was prepared from 22a (91 mg,
1β-[6-Methyl-2-(methylsulfanyl)pyridin-3-yl]-1,2-dideoxy-D-ribo- 0.19 mmol) by the general procedure to yield 22b (41 mg,
furanose (21b). Compound 21b was prepared from 21a 85%) as a yellow solid. HRMS (ESI) for C12H12ClNO3: [M − H]
(108 mg, 0.22 mmol) by the general procedure to yield 21b calculated, 252.0433; found, 252.0433. 1H NMR (500 MHz,
(46 mg, 81%) as a white solid. HRMS (ESI) for C12H17NO3S: CD3OD): 1.78 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.0 Hz, J2′a,3′
[M + Na] calculated, 278.0821; found, 278.0822. 1H NMR 5.9 Hz, H-2′a); 2.50 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.8 Hz,
(500 MHz, CD3OD): 1.73 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ J2′b,3′ = 2.0 Hz, H-2′b); 3.69 (dd, 1H, Jgem = 11.8 Hz, J5′a,4′
=
=
=
10.1 Hz, J2′a,3′ = 6.1 Hz, H-2′a); 2.39 (ddd, 1H, Jgem = 13.1 Hz, 5.0 Hz, H-5′a); 3.72 (dd, 1H, Jgem = 11.8 Hz, J5′b,4′ = 4.5 Hz,
J2′b,1′ = 5.7 Hz, J2′b,3′ = 2.0 Hz, H-2′b); 2.47 (s, 3H, CH3-6); 2.55 H-5′b); 3.80 (s, 1H, CHuC); 3.99 (td, 1H, J4′,5′a = J4′,5′b = 4.7 Hz,
(s, 3H, CH3S-2); 3.66–3.72 (m, 2H, H-5′); 3.93 (td, 1H, J4′,5′a
J4′,5′b = 5.0 Hz, J4′,3′ = 2.8 Hz, H-4′); 4.30 (dddd, 1H, J3′,2′a
=
=
J4′,3′ = 2.9 Hz, H-4′); 4.33 (bdt, 1H, J3′,2′a = 5.9 Hz, J3′,4′ = J3′,2′b
2.4 Hz, H-3′); 5.37 (bddq, 1H, J1′,2′a = 10.0 Hz, J1′,2′b = 5.8 Hz,
=
6.1 Hz, J3′,4′ = 2.8 Hz, J3′,2′b = 2.0 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.31 J1′,4 = J1′,5 = J1′,3′ = 0.5 Hz, H-1′); 7.53 (bd, 1H, J5,4 = 7.9 Hz, H-5);
(bdd, 1H, J1′,2′a = 10.1 Hz, J1′,2′b = 5.7 Hz, H-1′); 6.94 (dt, 1H, J5,4 8.14 (dd, 1H, J4,5 = 7.9 Hz, J4,1′ = 0.9 Hz, H-4). 13C NMR
= 7.8 Hz, J5,LR = 0.6 Hz, H-5); 7.73 (dd, 1H, J4,5 = 7.8 Hz, J4,1′
=
(125.7 MHz, CD3OD): 43.05 (CH2-2′); 63.67 (CH2-5′); 74.11
0.8 Hz, H-4). 13C NMR (125.7 MHz, CD3OD): 13.15 (CH3S-2); (CH-3′); 77.44 (CH-1′); 80.40 (CHuC); 82.12 (CHuC); 89.23
23.99 (CH3-6); 43.01 (CH2-2′); 63.84 (CH2-5′); 74.31 (CH-3′); (CH-4′); 128.05 (CH-5); 138.01 (CH-4); 139.22 (C-3); 141.99
76.92 (CH-1′); 88.80 (CH-4′); 119.77 (CH-5); 133.88 (C-3); 134.17 (C-6); 149.13 (C-2). IR spectrum (KBr): 3302, 3275, 2121, 1630,
(CH-4); 156.15 (C-2); 158.08 (C-6). IR spectrum (KBr): 3395, 1581, 1545, 1363, 1332, 1208, 1130, 1072, 1064, 1045, 995, 846.
3060, 2926, 1584, 1471, 1432, 1374, 1172, 1069, 1049, 963, 946,
911, 827, 722.
1β-[2,6-Bis(trimethylsilylethynyl)pyridin-3-yl]-1,2-dideoxy-3,5-
di-O-(t-butyldimethylsilyl)-D-ribofuranose (23a). DMF (4 mL)
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and TMSA (360 μL, 2.6 mmol) were added through a septum to (C-3). IR spectrum (CCl4): 3309, 3066, 2956, 2897, 2115, 1579,
an argon-purged vial containing 4 (138 mg, 0.26 mmol), 1554, 1472, 1463, 1445, 1406, 1390, 1361, 1275, 1258, 1180,
Pd(PPh3)2Cl2 (18 mg, 0.026 mmol), CuI (1 mg, 0.005 mmol) 1098, 1083, 1006, 939, 838.
and Et3N (725 μL, 5.2 mmol). The resulting mixture was stirred
1β-[2,6-Bis(ethynyl)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose
at 90 °C for 12 h. The reaction mixture was then cooled and fil- (23c). Compound 23c was prepared from 23a (192 mg,
tered on a pad of Celite and eluted with CHCl3. The solvents 0.31 mmol) by the general procedure to yield 23c (51 mg, 67%)
were removed under vacuum, and the crude product was chro- as an orange solid. HRMS (ESI) for C14H13NO3: [M + Na] calcu-
matographed on silica gel eluting with a gradient of hexanes lated, 266.0788; found, 266.0786. 1H NMR (500 MHz, DMSO-
to 1% EtOAc in hexanes to give 23a (150 mg, 95%) as a color- d6): 1.68 (ddd, 1H, Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz, J2′a,3′
=
less oil. HRMS (ESI) for C32H57NO3Si4: [M + H] calculated, 5.6 Hz, H-2′a); 2.26 (ddd, 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.7 Hz,
1
616.3488; found, 616.3490. H NMR (500 MHz, CDCl3): 0.083, J2′b,3′ = 1.8 Hz, H-2′b); 3.59 (m, 2H, H-5′); 3.84 (td, 1H, J4′,5′a
0.085 and 0.089 (3 × s, 4 × 3H, CH3Si); 0.24 and 0.26 (2 × s, 2 × J4′,5′b = 4.9 Hz, J4′,3′ = 2.2 Hz, H-4′); 4.21 (m, 1H, H-3′); 4.36 (s,
9H, (CH3)3Si)); 0.90 and 0.91 (2 × s, 2 × 9H, ((CH3)3C)); 1.74 1H, CHuC-6); 4.65 (s, 1H, CHuC-2); 4.83 (bt, 1H, JOH,5′a
=
=
(ddd, 1H, Jgem = 12.7 Hz, J2′a,1′ = 9.6 Hz, J2′a,3′ = 5.7 Hz, H-2′a); JOH,5′b = 5.6 Hz, OH-5′); 5.17 (d, 1H, JOH,3′ = 3.8 Hz, OH-3′); 5.36
2.41 (ddd, 1H, Jgem = 12.7 Hz, J2′b,1′ = 6.0 Hz, J2′b,3′ = 2.3 Hz, (bdd, 1H, J1′,2′a = 10.2 Hz, J1′,2′b = 5.7 Hz, H-1′); 7.59 (bd, 1H,
H-2′b); 3.72 (dd, 1H, Jgem = 10.8 Hz, J5′a,4′ = 4.6 Hz, H-5′a); 3.77 J5,4 = 8.1 Hz, H-5); 8.01 (dd, 1H, J4,5 = 8.2 Hz, J4,1′ = 0.7 Hz,
(dd, 1H, Jgem = 10.8 Hz, J5′b,4′ = 3.4 Hz, H-5′b); 3.98 (ddd, 1H, H-4). 13C NMR (125.7 MHz, DMSO-d6): 42.60 (CH2-2′); 62.31
J4′,5′a = 4.6 Hz, J4′,5′b = 3.4 Hz, J4′,3′ = 2.5 Hz, H-4′); 4.39 (dtd, 1H, (CH2-5′); 72.54 (CH-3′); 76.04 (CH-1′); 80.14 (CHuC-2); 80.63
J3′,2′a = 5.7 Hz, J3′,4′ = J3′,2′b = 2.4 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.54 (CHuC-6); 82.48 (CHuC-6); 85.35 (CHuC-2); 88.16 (CH-4′);
(ddq, 1H, J1′,2′a = 9.6 Hz, J1′,2′b = 6.0 Hz, J1′,3′ = J1′,4 = J1′,5
=
127.67 (CH-5); 134.56 (CH-4); 139.50 (C-2); 140.82 (C-6); 141.78
0.7 Hz, H-1′); 7.36 (dd, 1H, J5,4 = 8.1 Hz, J5,1′ = 0.7 Hz, H-5); (C-3). IR spectrum (KBr): 3428, 3299, 3070, 2107, 1579, 1558,
7.92 (dd, 1H, J4,5 = 8.1 Hz, J4,1′ = 0.8 Hz, H-4). 13C NMR 1447, 1235, 1078, 1050, 1026, 846.
(125.7 MHz, CDCl3): −5.51, −5.41, −4.74 and −4.56 (CH3Si);
1β-[2-Chloro-6-(2-pyridyl)pyridin-3-yl]-1,2-dideoxy-3,5-di-O-
−0.32 and −0.30 ((CH3)3Si); 18.37 and 18.32 ((CH3)3C); 25.88 (t-butyldimethylsilyl)-D-ribofuranose (24a). DMF (2.5 mL)
and 25.90 ((CH3)3C); 43.17 (CH2-2′); 63.49 (CH2-5′); 74.07 was added to a flame-dried and argon-purged flask, containing
(CH-3′); 76.82 (CH-1′); 88.06 (CH-4′); 94.68 and 100.17 4 (100 mg, 0.19 mmol), and PdCl2(PPh3)2 (7 mg, 0.0095 mmol,
(2 × CuCSi); 100.91 (CuCSi-2); 103.29 (CuCSi-6); 126.94 5 mol%). After 5 min of stirring at room temperature, tributyl
(CH-5); 133.37 (CH-4); 140.32 (C-2); 141.47 (C-3); 141.73 (C-6). (2-pyridyl)stannane (0.25 mL, 0.76 mmol, 4.0 equiv.) was
IR spectrum (CCl4): 3067, 2958, 2899, 2161, 1576, 1553, 1472, added, and mixture was heated to 100 °C for 12 h. The crude
1463, 1444, 1408, 1390, 1362, 1258, 1252, 1232, 1097, 1031, reaction mixture was diluted with Et2O (300 mL), washed with
939, 846.
2 M HCl (80 mL) and saturated NaHCO3 (100 mL). After evap-
1β-(2,6-Bis(ethynyl)pyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyl- oration of the solvents under reduced pressure, the crude
dimethylsilyl)-D-ribofuranose (23b). Methanolic ammonia product was chromatographed on silica gel eluting with a gra-
(25%, 10 mL) was added to a flask containing nucleoside 23a dient of hexanes to 3% EtOAc in hexanes to obtain 24a (82 mg,
(287 mg, 0.47 mmol) and the mixture was stirred for 30 min at 82%) as a colorless oil. HRMS (ESI) for C27H43ClN2O3Si2:
room temperature. Then the solvents were evaporated under [M + H] calculated, 535.2574; found, 535.2574. 1H NMR
vacuum and the crude product was chromatographed on silica (500 MHz, CDCl3): 0.098, 0.100, 0.107 and 0.109 (4 × s, 4 × 3H,
gel in a gradient of hexanes to 6% EtOAc in hexanes to give CH3Si); 0.91 and 0.92 (2 × s, 2 × 9H, ((CH3)3C)); 1.77 (ddd, 1H,
23b (167 mg, 76%) as a colorless oil. HRMS (ESI) for Jgem = 12.7 Hz, J2′a,1′ = 9.6 Hz, J2′a,3′ = 5.6 Hz, H-2′a); 2.46 (ddd,
C26H41NO3Si2: [M + Na] calculated, 494.2517; found, 494.2516. 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.9 Hz, J2′b,3′ = 2.4 Hz, H-2′b); 3.74
1H NMR (500 MHz, DMSO-d6): 0.07, 0.08 and 0.09 (4 × s, 4 × (dd, 1H, Jgem = 10.9 Hz, J5′a,4′ = 4.8 Hz, H-5′a); 3.81 (dd, 1H,
3H, CH3Si); 0.86 and 0.89 (2 × s, 2 × 9H, (CH3)3C)); 1.76 (ddd, Jgem = 10.9 Hz, J5′b,4′ = 3.5 Hz, H-5′b); 4.00 (ddd, 1H, J4′,5′a
1H, Jgem = 12.7 Hz, J2′a,1′ = 10.2 Hz, J2′a,3′ = 5.2 Hz, H-2′a); 2.28 4.8 Hz, J4′,5′b = 3.5 Hz, J4′,3′ = 2.6 Hz, H-4′); 4.42 (dtd, 1H, J3′,2′a
=
=
(ddd, 1H, Jgem = 12.7 Hz, J2′b,1′ = 5.5 Hz, J2′b,3′ = 1.9 Hz, H-2′b); 5.7 Hz, J3′,4′ = J3′,2′b = 2.5 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.45 (ddq, 1H,
3.61 (dd, 1H, Jgem = 10.9 Hz, J5′a,4′ = 6.1 Hz, H-5′a); 3.72 (dd, J1′,2′a = 9.6 Hz, J1′,2′b = 5.9 Hz, J1′,3′ = J1′,4 = J1′,5 = 0.7 Hz, H-1′);
1H, Jgem = 10.9 Hz, J5′b,4′ = 4.0 Hz, H-5′b); 3.88 (ddd, 1H, J4′,5′a
6.1 Hz, J4′,5′b = 4.0 Hz, J4′,3′ = 1.9 Hz, H-4′); 4.37 (bdt, 1H, J3′,2′a
=
=
7.33 (dd, 1H, J5,4 = 7.5 Hz, J5,6 = 4.8 Hz, J5,3 = 1.2 Hz, H-5-py);
7.82 (td, 1H, J4,5 = J4,3 = 7.8 Hz, J4,6 = 1.8 Hz, H-4-py); 8.14 (dd,
5.2 Hz, J3′,4′ = J3′,2′b = 1.9 Hz, H-3′); 4.38 (s, 1H, CHuC-6); 4.67 1H, J4,5 = 8.0 Hz, J4,1′ = 0.8 Hz, H-4); 8.35 (bd, 1H, J5,4 = 8.0 Hz,
(s, 1H, CHuC-2); 5.37 (bdd, 1H, J1′,2′a = 10.2 Hz, J1′,2′b = 5.5 Hz, H-5); 8.40 (dt, 1H, J3,4 = 8.0 Hz, J3,5 = J3,6 = 1.0 Hz, H-3-py); 8.67
H-1′); 7.59 (bd, 1H, J5,4 = 8.1 Hz, H-5); 7.92 (dd, 1H, J4,5
=
(ddd, 1H, J6,5 = 4.8 Hz, J6,4 = 1.8 Hz, J6,3 = 0.9 Hz, H-6-py).
8.1 Hz, J4,1′ = 0.7 Hz, H-4). 13C NMR (125.7 MHz, DMSO-d6): 13C NMR (125.7 MHz, CDCl3): −5.47, −5.37, −4.75 and −4.62
−5.35, −5.27, −4.66 and −4.55 (CH3Si); 17.88 and 18.09 (CH3Si); 18.00 and 18.31 ((CH3)3C); 25.77 and 25.90 ((CH3)3C);
((CH3)3C); 25.85 and 25.91 ((CH3)3C); 42.14 (CH2-2′); 63.32 42.47 (CH2-2′); 63.30 (CH2-5′); 73.76 (CH-3′); 76.30 (CH-1′);
(CH2-5′); 74.29 (CH-3′); 76.11 (CH-1′); 79.93 (CHuC-2); 80.78 87.89 (CH-4′); 119.89 (CH-5); 121.43 (CH-3-py); 124.06
(CHuC-2); 82.39 (CHuC-6); 85.52 (CHuC-6); 87.72 (CH-4′); (CH-5-py); 136.73 (CH-4); 137.21 (CH-4-py); 137.65 (C-3); 147.92
127.56 (CH-5); 134.11 (CH-4); 139.54 (C-2); 140.93 (C-6); 141.11 (C-2); 148.96 (CH-6-py); 154.50 (C-2-py); 154.79 (C-6). IR
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spectrum (CCl4): 2956, 2897, 1588, 1568, 1472, 1463, 1445, (125.7 MHz, CDCl3): −5.46, −5.33, −4.77 and −4.65 (CH3Si);
1390, 1361, 1340, 1258, 1218, 1174, 1071, 1054, 939, 838. 17.98 and 18.34 ((CH3)3C); 25.76 and 25.93 ((CH3)3C); 44.75
1β-[2-Chloro-6-(2-pyridyl)pyridin-3-yl]-1,2-dideoxy-D-ribofura- (CH2-2′); 63.65 (CH2-5′); 74.42 (CH-3′); 76.58 (CH-1′); 87.92
nose (24b). Compound 24b was prepared from 24a (207 mg, (CH-4′); 121.11 (CH-5); 121.95 (CH-3-py-6); 122.89 (CH-5-py-2);
0.39 mmol) by the general procedure to yield 24b (102 mg, 123.89 (CH-5-py-6); 124.54 (CH-3-py-2); 136.57 (CH-4); 136.74
86%) as a white solid. HRMS (ESI) for C15H15ClN2O3: [M + H] (CH-4-py-2); 138.4 (CH-4-py-6); 138.77 (C-3); 147.89 (CH-6-py-
calculated, 307.0844; found, 307.0844. 1H NMR (500 MHz, 2,6); 152.35 (C-6); 153.65 (C-2); 155.12 (C-2-py-6); 157.91 (C-2-
CD3OD): 1.84 (ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′
=
py-2). IR spectrum (CCl4): 3088, 3065, 2956, 2929, 2897, 285, 7,
6.0 Hz, H-2′a); 2.54 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.7 Hz, 1590, 1586, 1577, 1566, 1556, 1472, 1462, 1456, 1434, 1425,
J2′b,3′ = 2.0 Hz, H-2′b); 3.72 (dd, 1H, Jgem = 11.8 Hz, J5′a,4′
=
1389, 1361, 1257, 1173, 1147, 1095, 1040, 1031, 1006, 939, 838.
5.0 Hz, H-5′a); 3.75 (dd, 1H, Jgem = 11.8 Hz, J5′b,4′ = 4.5 Hz, H-5′
1β-[2,6-Bis(2-pyridyl)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose
b); 4.01 (td, 1H, J4′,5′a = J4′,5′b = 4.8 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.36 (25b). Compound 25b was prepared from 25a (209 mg,
(dddd, 1H, J3′,2′a = 6.0 Hz, J3′,4′ = 2.7 Hz, J3′,2′b = 2.0 Hz, J3′,1′ 0.36 mmol) by the general procedure to yield 25b (110 mg,
0.7 Hz, H-3′); 5.44 (ddq, 1H, J1′,2′a = 10.1 Hz, J1′,2′b = 5.7 Hz, J1′,4 87%) as a white solid. HRMS (ESI) for C20H19N3O3: [M + H]
=
= J1′,5 = = J1′,3′ = 0.7 Hz, H-1′); 7.46 (ddd, 1H, J5,4 = 7.6 Hz, J5,6
4.9 Hz, J5,3 = 1.2 Hz, H-5-py); 7.96 (ddd, 1H, J4,3 = 8.0 Hz, J4,5
7.6 Hz, J4,6 = 1.8 Hz, H-4-py); 8.25 (dd, 1H, J4,5 = 8.0 Hz, J4,1′
0.8 Hz, H-4); 8.30 (bd, 1H, J5,4 = 8.0 Hz, H-5); 8.35 (dt, 1H, J3,4
=
=
=
=
calculated, 350.1499; found, 350.1498. 1H NMR (500 MHz,
CD3OD): 1.94 (ddd, 1H, Jgem = 13.3 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′
6.2 Hz, H-2′a); 2.35 (ddd, 1H, Jgem = 13.3 Hz, J2′b,1′ = 5.7 Hz,
J2′b,3′ = 2.0 Hz, H-2′b); 3.72 (dd, 1H, Jgem = 11.7 Hz, J5′a,4′
=
=
8.0 Hz, J3,5 = J3,6 = 1.1 Hz, H-3-py); 8.65 (ddd, 1H, J6,5 = 4.9 Hz, 5.0 Hz, H-5′a); 3.74 (dd, 1H, Jgem = 11.7 Hz, J5′b,4′ = 4.5 Hz,
J6,4 = 1.8 Hz, J6,3 = 0.9 Hz, H-6-py). 13C NMR (125.7 MHz, H-5′b); 3.89 (btd, 1H, J4′,5′a = J4′,5′b = 4.8 Hz, J4′,3′ = 2.9 Hz, H-4′);
CD3OD): 43.20 (CH2-2′); 63.76 (CH2-5′); 74.19 (CH-3′); 77.64 4.30 (dddd, 1H, J3′,2′a = 6.2 Hz, J3′,4′ = 2.9 Hz, J3′,2′b = 2.0 Hz, J3′,1′
(CH-1′); 89.22 (CH-4′); 121.14 (CH-5); 122.68 (CH-3-py); 125.72 = 0.6 Hz, H-3′); 5.62 (dd, 1H, J1′,2′a = 10.1 Hz, J1′,2′b = 5.7 Hz,
(CH-5-py); 138.33 (CH-4); 138.80 (C-3); 139.05 (CH-4-py); 149.22 H-1′); 7.44 (ddd, 1H, J5,4 = 7.5 Hz, J5,6 = 4.9 Hz, J5,3 = 1.2 Hz,
(C-2); 150.14 (CH-6-py); 155.57 (C-2-py); 156.02 (C-6). IR spec- H-5-py-6); 7.48 (m, 1H, H-5-py-2); 7.93 (ddd, 1H, J4,3 = 8.0 Hz,
trum (KBr): 3420, 3336, 3096, 3066, 1587, 1573, 1547, 1478, J4,5 = 7.5 Hz, J4,6 = 1.8 Hz, H-4-py-6); 7.98–8.01 (m, 2H, H-3,4-
1434, 1256, 1173, 1149, 993, 1063, 1047, 993.
py-2); 8.38 (bd, 1H, J5,4 = 8.3 Hz, H-5); 8.40 (bd, 1H, J4,5 =
1β-[2,6-Bis(2-pyridyl)pyridin-3-yl]-1,2-dideoxy-3,5-di-O-(t-butyl- 8.3 Hz, H-4); 8.46 (dt, 1H, J3,4 = 8.0 Hz, J3,5 = J3,6 = 1.1 Hz, H-3-
dimethylsilyl)-D-ribofuranose (25a). Toluene (3.0 mL) was py-6); 8.65 (ddd, 1H, J6,5 = 4.9 Hz, J6,4 = 1.8 Hz, J6,3 = 0.9 Hz,
added to a flame-dried and argon-purged flask, containing 4 H-6-py-6); 8.68 (dt, 1H, J6,5 = 4.9 Hz, J6,4 = J6,3 = 1.4 Hz, H-6-py-
(159 mg, 0.29 mmol), and Pd(PPh3)4 (65 mg, 0.058 mmol, 2). 13C NMR (125.7 MHz, CD3OD): 45.16 (CH2-2′); 63.87
20 mol%). After 5 min of stirring at room temperature, tributyl (CH2-5′); 74.36 (CH-3′); 77.73 (CH-1′); 89.01 (CH-4′); 121.89
(2-pyridinyl)stannane (0.38 mL, 1.16 mmol, 4.0 equiv.) was (CH-5); 122.68 (CH-3-py-6); 124.62 (CH-5-py-2); 125.31 (CH-5-
added, and the mixture was heated to 110 °C for 12 h. The py-6); 125.85 (CH-3-py-2); 137.62 (CH-4); 138.47 (CH-4-py-2);
crude reaction mixture was diluted with Et2O (300 mL), and 138.73 (CH-4-py-6); 138.91 (C-3); 149.38 (CH-6-py-2); 150.11
washed with 2 M HCl (80 mL) and saturated NaHCO3 (CH-6-py-6); 155.26 (C-6); 155.51 (C-2); 157.08 (C-2-py-6);
(100 mL). After evaporation of the solvents under reduced 159.27 (C-2-py-2). IR spectrum (KBr): 3415, 3088, 3062, 2929,
pressure, the crude product was chromatographed on silica gel 1590, 1575, 1565, 1557, 1473, 1455, 1434, 1425, 1353, 1254,
eluting with a gradient of hexanes to 12% EtOAc in hexanes to 1201, 1174, 1150, 1095, 1071, 1050, 1021, 942, 855.
obtain 25a (197 mg, 92%) as a colorless oil. HRMS (ESI) for
1β-(2-Chloropyridin-3-yl)-1,2-dideoxy-3,5-di-O-(t-butyldimethyl-
C32H47N3O3Si2: [M + H] calculated, 578.3229; found, 578.3229. silyl)-D-ribofuranose (26a). Vinylmagnesium chloride (1 M solu-
1H NMR (500 MHz, CDCl3): 0.08, 0.09, 0.11 and 0.13 (4 × s, 4 × tion in THF, 1 mL, 1.0 mmol) was added dropwise to a flame-
3H, CH3Si); 0.90 and 0.93 (2 × s, 2 × 9H, ((CH3)3C)); 1.91 (ddd, dried flask containing a solution of the nucleoside 4 (100 mg,
1H, Jgem = 12.8 Hz, J2′a,1′ = 10.0 Hz, J2′a,3′ = 5.6 Hz, H-2′a); 2.50 0.19 mmol) and Fe(acac)3 (13 mg, 0.038 mmol) in dry THF
(ddd, 1H, Jgem = 12.8 Hz, J2′b,1′ = 5.4 Hz, J2′b,3′ = 2.0 Hz, H-2′b); (3.0 mL) under Ar. The reaction mixture was then stirred at rt
3.73 (dd, 1H, Jgem = 10.7 Hz, J5′a,4′ = 5.2 Hz, H-5′a); 3.81 (dd, for 12 h. Then the mixture was poured onto a mixture of ice
1H, Jgem = 10.7 Hz, J5′b,4′ = 3.5 Hz, H-5′b); 3.93 (ddd, 1H, J4′,5′a
5.2 Hz, J4′,5′b = 3.5 Hz, J4′,3′ = 2.3 Hz, H-4′); 4.42 (bdt, 1H, J3′,2′a
5.5 Hz, J3′,4′ = J3′,2′b = 2.2 Hz, H-3′); 5.74 (bdd, 1H, J1′,2′a
10.0 Hz, J1′,2′b = 5.4 Hz, H-1′); 7.33 (dd, 1H, J5,4 = 7.6 Hz, J5,6
=
=
=
=
(100 mL) and NH4Cl (1 g), and extracted with chloroform (3 ×
100 mL). Evaporation of the organic phase followed by column
chromatography on silica gel eluting with a gradient of
hexanes to 4% EtOAc in hexanes afforded the nucleoside 26a
4.9 Hz, J5,3 = 1.2 Hz, H-5-py-2); 7.39 (m, 1H, H-5-py-6); 7.87 (td, (40 mg, 47%) as
a
colorless oil. HRMS (ESI) for
1H, J4,5 = J4,3 = 7.7 Hz, J4,6 = 1.2 Hz, H-4-py-2); 7.91 (H-4-py-6); C22H40ClNO3Si2: [M
8.11 (dt, 1H, J3,4 = 7.9 Hz, J3,5 = J3,6 = 1.1 Hz, H-3-py-2); 8.36 480.2126. H NMR (500 MHz, CDCl3): 0.086, 0.088, 0.090 and
(bd, 1H, J4,5 = 8.3 Hz, H-4); 8.53 (bd, 1H, J5,4 = 8.3 Hz, H-5); 0.10 (4 × s, 4 × 3H, CH3Si); 0.89 and 0.92 (2 × s, 2 × 9H,
+ Na] calculated, 480.2128; found,
1
8.58 (bd, 1H, J3,4 = 8.0 Hz, H-3-py-6); 8.67 (ddd, 1H, J6,5
4.9 Hz, J6,4 = 1.9 Hz, J6,3 = 1.0 Hz, H-6-py-2); 8.75 (ddd, 1H, J6,5 5.5 Hz, H-2′a); 2.44 (ddd, 1H, Jgem = 12.6 Hz, J2′b,1′ = 5.9 Hz,
= 5.0 Hz, J6,4 = 1.7 Hz, J6,3 = 0.8 Hz, H-6-py-6). 13C NMR J2′b,3′ = 2.5 Hz, H-2′b); 3.71 (dd, 1H, Jgem = 10.9 Hz, J5′a,4′
=
((CH3)3C); 1.73 (ddd, 1H, Jgem = 12.6 Hz, J2′a,1′ = 9.5 Hz, J2′a,3′ =
=
4716 | Org. Biomol. Chem., 2013, 11, 4702–4718
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4.8 Hz, H-5′a); 3.78 (dd, 1H, Jgem = 10.9 Hz, J5′b,4′ = 3.5 Hz, Data were collected at 190 (2) K on an Xcalbur Onyx CCD dif-
H-5′b); 3.99 (ddd, 1H, J4′,5′a = 4.8 Hz, J4′,5′b = 3.5 Hz, J4′,3′
=
fractometer with graphite monochromated Cu-Kα radiation. The
2.6 Hz, H-4′); 4.39 (dt, 1H, J3′,2′a = 5.5 Hz, J3′,4′ = J3′,2′b = 2.6 Hz, structure was solved by charge flipping methods1 using the
H-3′); 5.40 (dd, 1H, J1′,2′a = 9.5 Hz, J1′,2′b = 5.9 Hz, H-1′); 7.23 CRYSTALS suite of programs2 and anisotropically refined by
(dd, 1H, J5,4 = 7.7 Hz, J5,6 = 4.6 Hz, H-5); 8.03 (dd, 1H, J4,5
=
full matrix least squares on F squared value to final R = 0.038
7.6 Hz, J4,6 = 1.3 Hz, H-4); 8.28 (bd, 1H, J6,5 = 4.6 Hz, H-6). and Rw = 0.095 using 4688 independent reflections (Θmax
=
13C NMR (125.7 MHz, CDCl3): −5.49, −5.42, −4.76 and −4.62 77.4°) and 291 parameters. The absolute configuration on
(CH3Si); 17.99 and 18.28 ((CH3)3C); 25.75 and 25.86 ((CH3)3C); stereogenic centers was confirmed by refinement of the Flack
42.32 (CH2-2′); 63.28 (CH2-5′); 73.71 (CH-3′); 76.14 (CH-1′); parameter (resulting value −0.008 (12)). The structure was
87.82 (CH-4′); 122.68 (CH-5); 135.86 (CH-4); 137.67 (C-3); deposited into the Cambridge Structural Database under
147.93 (CH-6); 148.50 (C-2). IR spectrum (CCl4): 2956, 2899, number CCDC 927314.
1582, 1566, 1472, 1463, 1449, 1390, 1362, 1336, 1258, 1209,
1172, 1057, 1031, 1006, 968, 838.
1β-(2-Chloropyridin-3-yl)-1,2-dideoxy-D-ribofuranose (26b).
Compound 26b was prepared from 26a (80 mg, 0.17 mmol) by
Acknowledgements
the general procedure to yield 26b (32 mg, 82%) as a white This work was supported by institutional support from the
solid. HRMS (ESI) for C10H12ClNO3: [M + Na] calculated, Academy of Sciences of the Czech Republic (RVO: 61388963)
1
252.0398; found, 252.0398. H NMR (500 MHz, CD3OD): 1.78 and Charles University, by a grant from the Czech Science
(ddd, 1H, Jgem = 13.1 Hz, J2′a,1′ = 10.1 Hz, J2′a,3′ = 6.0 Hz, H-2′a); Foundation (P207/11/0344) and by Gilead Sciences, Inc. The
2.50 (ddd, 1H, Jgem = 13.1 Hz, J2′b,1′ = 5.7 Hz, J2′b,3′ = 2.0 Hz, authors thank Mrs Eva Tloušťová (IOCB) for cytostatic and
H-2′b); 3.70 (dd, 1H, Jgem = 11.8 Hz, J5′a,4′ = 5.0 Hz, H-5′a); 3.72 Dr Y.-J. Lee and Dr G. Bahador (Gilead Sciences, Inc.) for anti-
(dd, 1H, Jgem = 11.8 Hz, J5′b,4′ = 4.6 Hz, H-5′b); 3.99 (td, 1H, HCV screening.
J4′,5′a = J4′,5′b = 4.8 Hz, J4′,3′ = 2.7 Hz, H-4′); 4.33 (dddd, 1H,
J3′,2′a = 6.0 Hz, J3′,4′ = 2.7 Hz, J3′,2′b = 2.0 Hz, J3′,1′ = 0.7 Hz, H-3′); 5.38
(ddpent, 1H, J1′,2′a = 10.1 Hz, J1′,2′b = 5.7 Hz, J1′,4 = J1′,5 = J1′,6
=
Notes and references
J1′,3′ = 0.7 Hz, H-1′); 7.41 (ddd, 1H, J5,4 = 7.7 Hz, J5,6 = 4.8 Hz,
J5,1′ = 0.6 Hz, H-5); 8.17 (ddd, 1H, J4,5 = 7.7 Hz, J4,6 = 2.0 Hz,
J4,1′ = 0.8 Hz, H-4); 8.27 (ddd, 1H, J6,5 = 4.8 Hz, J6,4 = 2.0 Hz,
J6,1′ = 0.5 Hz, H-6). 13C NMR (125.7 MHz, CD3OD): 43.11
(CH2-2′); 63.72 (CH2-5′); 74.13 (CH-3′); 77.46 (CH-1′); 89.17
(CH-4′); 124.54 (CH-5); 137.86 (CH-4); 138.87 (C-3); 149.10
(CH-6); 149.33 (C-2). IR spectrum (KBr): 3359, 1630, 1580, 1571,
1450, 1442, 1389, 1181, 1073, 1063, 1043, 1023, 951.
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Crystallographic data for 4
M = 308.55 g mol−1, monoclinic system, space group P21,
a = 8.9755 (9) Å, b = 6.9472 (5) Å, c = 9.1777 (9) Å, β = 90.968 (9)°,
Z = 2, V = 572.19 (9) Å3, Dc = 1.791 g cm−3, μ(Cu-Kα) =
7.002 mm−1, crystal dimensions of 0.58 × 0.56 × 0.21 mm.
Data were collected at 170 (2) K on an Xcalbur Onyx CCD diffr-
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structure was solved by charge flipping methods18 using the
CRYSTALS suite of programs19 and anisotropically refined by
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=
0.042 using 2220 independent reflections (Θmax = 77.3°) and
147 parameters. The absolute configuration on stereogenic
centers was confirmed by refinement of the Flack parameter
(resulting value −0.02 (2)). The structure was deposited into
the Cambridge Structural Database under number CCDC
927315.
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Crystallographic data for 8b
M = 243.69 g mol−1, monoclinic system, space group P21,
a = 5.3111 (3) Å, b = 11.1077 (6) Å, c = 19.5383 (13) Å, β = 96.676 (6)°,
Z = 4, V = 1144.84 (12) Å3, Dc = 1.414 g cm−3, μ(Cu-Kα) =
2.908 mm−1, crystal dimensions of 0.49 × 0.37 × 0.26 mm.
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4718 | Org. Biomol. Chem., 2013, 11, 4702–4718
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