Stereoselective N -glycosylation of 2-deoxythioribosides for fluorescent nucleoside synthesis

Article abstract of DOI:10.1021/jo3014929

An efficient method for the N-2-deoxyribosylation of modified nucleobases by 2-deoxythioriboside donors is reported. In the presence of an in situ silylated nucleobase, thioglycosides can be activated with NIS/HOTf to give nucleosides in high yields and w

Full text of DOI:10.1021/jo3014929

Article
pubs.acs.org/joc
Stereoselective N‑Glycosylation of 2‑Deoxythioribosides for
Fluorescent Nucleoside Synthesis
Guillaume Mata and Nathan W. Luedtke*
Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: An efficient method for the N-2-deoxyribosylation of modified nucleobases by 2-deoxythioriboside donors is
reported. In the presence of an in situ silylated nucleobase, thioglycosides can be activated with NIS/HOTf to give nucleosides in
high yields and with good β-selectivity. By tuning the protecting groups on the C3 and C5 hydroxyls, α/β ratios ranging from
1.0:4.0 to 4.5:1.0 can be obtained. This strategy is applicable to the synthesis of various nucleosides, including ring-expanded
pyrimidine derivatives containing sulfur that have previously been reported in low yields. The utility of this approach is further
demonstrated by the synthesis of fluorescent nucleosides analogues such as quinazoline and oxophenothiazine that should find
broad utility in DNA-folding and recognition studies.
INTRODUCTION
■
Due to their broad spectrum of antiviral and antitumor
activities, the synthesis of nucleoside analogues has been a key
focus of medicinal chemistry for nearly 40 years.1−3 More
recently, modified nucleosides and nucleotides have emerged as
tools for manipulating genetic processes,4−6 as fluorescent
probes for studying DNA folding and recognition,7,8 and as
metabolic labels for cellular DNA in vivo.9,10 In many cases,
these applications require synthetic nucleosides with ring-
expanded nucleobases that exhibit unique photophysical and/or
chemical reactivities.
Synthetic strategies that access 2′-β-deoxynucleosides
typically involve N-glycosylation of ribofuranosyl derivatives.
Stereoselectivity for the desired β-anomer can be achieved by
using 1-O-acetylribofuranosyl derivatives that mediate a C2-O-
ester neighboring group effect (Figure 1, route A). Using this
approach, high stereoselectivity and good yields can be
obtained, but subsequent 2′-deoxygenation procedures must
be performed to obtain the desired 2′-D-deoxyribonucleosides.
This requires two to four additional synthetic steps; therefore
resulting in only low to moderate overall yields.11−14 In
addition, commonly used deoxygenation reactions that proceed
via radical elimination are not compatible with haloheterocyclic
derivatives.15,16 An alternative approach for 2′-deoxygenation
using a photosensitized electron-transfer reaction has recently
been reported,17,18 but this elegant strategy is incompatible
with fluorescent nucleobases that act as electron acceptors.19
Glycosylation reactions that employ protected 2-deoxyribo-
sides as glycosyl donors provide a more direct pathway to the
synthesis of 2′-β-deoxynucleosides, but previously reported
examples of N-2-deoxyribosylation suffer from modest yields
Figure 1. Strategies for stereoselective N-glycosylation of heterocyclic
acceptors.
and poor β-selectivity. The most commonly reported approach
utilizes the commercially available 2-deoxy-3,5-di-O-p-toluoyl-
α-D-erythro-pentofuranosyl chloride as the glycosyl donor
(Figure 1, route B). Although it has been successfully used
for the stereoselective glycosylation of purine analogues via an
SN2-type mechanism under basic conditions,20,21 this donor
suffers from a number of significant drawbacks for pyrimidine
Received: July 24, 2012
© XXXX American Chemical Society
A
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derivatives under Lewis acidic conditions.22,23 The long
reaction times needed for weak nucleophiles can result in
epimerization and the formation of α-nucleosides as the major
product.24,25 Its instability in solution can also result in low to
moderate yields of the isolated coupling products, as well as
inseparable α/β anomeric mixtures of nucleosides.25−30 More-
over, direct modification of the C3 and C5 hydroxyl groups is
not normally feasible due to the lability of the anomeric
chloride. The development of new and efficient stereoselective
reactions for constructing 2′-β-D-deoxyribonucleosidic linkages
therefore remains an important goal.
Scheme 1. Formation of the Thioether Aglycon
In recent decades, extensive efforts in oligosaccharide
chemistry have revealed a wide variety of efficient glycosylation
reactions for the stereoselective synthesis of O-glycosidic bonds
in complex carbohydrates. These include the utilization of
classic glycosyl donors such as glycosyl bromides, chlorides,
acetates, trichloroacetimidates, thioglycosides, and, more
recently, the introduction of glycosyl sulfoxides, iodides, and
phosphites.31−35 Relatively few of these established method-
ologies have been applied for N-glycosylation reactions or in
nucleoside synthesis. A small handful of 2-deoxyribose
thioglycosides have been developed as glycosyl donors but
have been used only for the N-glycosylation of natural
pyrimidine nucleobases, which are known to exhibit facile
reactions with a wide variety of glycosyl donors.36−38 In
contrast, unnatural nucleobase acceptors with extended surface
areas are highly problematic N-glycosidic acceptors.39
tions were therefore performed with the combined thioglyco-
sides 4β and 4α to afford esters 5−7 (Scheme 2) that were
obtained as anomeric mixtures (α/β = 1.0:1.8). Thioglycoside 5
was obtained in 90% yield by acetylation with Ac2O, and
thioglycosides 6 and 7 were obtained after treatment with
benzoyl chloride (BzCl) or p-methoxybenzoyl chloride
(PMBCl), in 87% and 78% yields, respectively. On the basis
of previous studies by Zhang and co-workers,44 we were
interested in a possible neighboring group participation by an
N-acetylglycine residue at the C3 position. Enantiopure
thioglycosides 8α and 8β containing C3-O-N-acetylglycine
were therefore prepared using N,N′-diisopropylcarbodiimide
(DIC) as a coupling reagent.
Given the growing importance of fluorescent 2′-deoxynu-
cleosides,7 we become interested in the development of a new
2-deoxyribose donor for robust β-selective N-glycosylation
Scheme 2. Synthesis of C3-Substituted 2-Deoxythioriboside
a
Donors 5−8
reactions in high yields. Here we report Vorbruggen-type40−42
̈
N-2-deoxyribosilation of 2-deoxythioribosides by ring-expanded
nucleobase analogues that exhibit limited solubility and poor
nucleophilicity (Figure 1, route C). 6-Bromoquinazoline-2,4-
(1H,3H)-dione was selected as an initial model for evaluating
these N-glycosylation reactions, since quinazoline-2,4-(3H)-
dione β-nucleosides are synthesized in low yield25 and are of
particular interest for further elaboration into fluorescent
nucleoside analogs. Following optimization of the thioglycoside
donor, a variety of other, highly challenging, nucleobases were
glycosylated in moderate to high yields and good β-selectivity.
RESULTS
■
Synthesis of 2-Deoxythioriboside Donors. Our study
started with the preparation of variable 2-deoxythioriboside
donors by systematic variation of the functional groups at the
C3 and C5 positions. Thioglycosides are especially amenable to
this approach because of their high stability under a wide range
of reaction conditions. To generate the thioether aglycon,
commercially available 1,3,5-tri-O-acetyl-2-deoxy-D-ribose 1 was
treated with 1.02 equiv of p-toluenethiol (pTolSH) and
BF3·Et2O at −78 °C to afford thioglycoside donor 2 (Scheme
1). The resulting 2-deoxythioriboside was obtained in 92%
yield on a 30 g scale as an anomeric mixture (α/β = 1.0:1.8).
Deacetylation of 2 was then conducted using K2CO3 in a
mixture of MeOH/CH2Cl2 to give diol 3 in 98% yield.
Regioselective silylation of 5-OH with triisopropylsilyl chloride
(TIPSCl) afforded compounds 4β (56%) and 4α (31%), which
were readily separated using preparative scale silica gel
chromatography.
a
Reagents and conditions: (a) Ac2O, Et3N, DMAP, MeCN, rt, 2 h; (b)
BzCl, Et3N, DMAP, pyridine, CH2Cl2, rt, 2 h; (c) PMBCl, Et3N,
DMAP, pyridine, CH2Cl2, rt, 16 h; (d) N-Ac-Gly-OH, DIC, DMAP,
CH2Cl2, rt, 12 h.
On the basis of previous studies,45 we also focused our
attention on C3−5-O-silylated cyclic functional groups that can
induce conformational restrictions and therefore influence
stereoselectivity during glycosylation. C3−5-O-silylated thio-
glycosides 9 and 10 containing six- and eight-membered rings
were therefore prepared from 3 in 83% and 93% yield,
respectively (Scheme 3). Finally, in order to provide a direct
comparison of differences in chemical reactivity between
thioglycosides and the commonly used 2-deoxy-3,5-di-O-p-
toluoyl-α-D-erythro-pentofuranosyl chloride, compound 11 was
synthesized in 86% yield.
Upon the basis of previous studies,43 we anticipated that an
ester group at C3 may provide anchimeric assistance, enhancing
the β-selectivity of N-glycosylation. C3-O-Esterification reac-
N-2-Deoxyribosilation of 2-Deoxythioriboside Do-
nors. With the 2-deoxythioriboside donors 2 and 5−11 in
B
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action was carried out starting with in situ silylation of the
acceptor nucleobase 12 (NuH, 1.2 equiv) with N,O-bis-
(trimethylsilyl)acetamide (BSA, 2.5 equiv) in CH2Cl2 for 2 h,
followed by addition of the 2-deoxythioriboside donor (2−11,
1.0 equiv) and sequential addition of N-iodosuccinimide (NIS,
1.2 equiv) and trimethylsilyl trifluoromethanesulfonate
(TMSOTf, 0.6 equiv).46 The isolated yields and α/β ratios
Scheme 3. Synthesis of C3,5-O-Silylated Six- and Eight-
Membered Ring 2-Deoxythioriboside Donors 9−11
a
1
(as determined by H NMR of the crude reactions) of these
reactions are summarized in Table 1.
When thioglycoside 11 (α/β = 1.0:1.8) was activated by a
combination of NIS and TMSOTf, the desired coupling
products 14α and 14β were isolated in 72% yield with the β-
anomer as the major product (α/β = 1.0:1.6). While this
diastereoisomeric mixture was not separable using chromato-
graphic methods, the major β-nucleoside 14β could be isolated
via precipitation from EtOAc. The relative regio- and
a
1
stereochemistry of 14β was confirmed by 2D H−13C HMBC
Reagents and conditions: (a) tBu2SiOTf2, 2,6-lutidine, CH2Cl2/
1
and H−1H ROESY experiments. Upon the basis of the α/β
DMF, 0 °C to rt, 16 h; (b) TIPDSCl, pyridine, 0 °C to rt, 12 h; (c) p-
toluoyl chloride, Et3N, DMAP, pyridine, CH2Cl2, rt, 16 h.
ratio and total isolated yield, the desired β-nucleoside 14β was
obtained in 43% yield. In comparison, the commonly used α-
glycoside chloride 13α was activated under standard conditions
by CuI in a 48 h reaction to afford 58% yield of the expected
hand, we investigated their reactivity in the N-glycosylation of
6-bromoquinazoline-2,4-(1H,3H)-dione (12, NuH). This re-
Table 1. N-2-Deoxyribosilation of 6-Bromoquinazoline-2,4-(1H,3H)-dione (12, NuH) by 2-Deoxythioriboside Donors
a
b
1
Isolated yield for both anomers. Ratio determined by H NMR analysis of the crude mixture.
C
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product, but in a highly α-selective fashion (α/β = 3.5:1.0).
This is consistent with previous reports on N-glycosylation of
quinazoline-2,4-(3H)-dione by 13α,25 where the β-nucleoside
was obtained in only 13% yield. Similar poor yields for N-
glycosylation of other nucleobase acceptors by 13α have also
been reported.27,30
corresponding nucleosides 21α and 21β in 68% yield in a
highly α-selective fashion (α/β = 4.5:1.0).
Scope of the N-2-Deoxyribosylation of Ring-Ex-
panded Pyrimidine Nucleobases. Having indentified
thioglycoside 5 as an excellent donor for high-yielding, β-
selective N-2-deoxyribosylation of 6-bromoquinazoline-2,4-
(1H,3H)-dione, we explored the scope of this reaction in
constructing 2′-β-D-deoxyribonucleosidic linkages known to be
highly challenging. N-Heterocyclic nucleobases 25−28 were
therefore synthesized according to known procedures from
their corresponding starting materials 34−37. The correspond-
ing β-nucleosides 31β−33β have been shown to exhibit useful
fluorescent properties upon incorporation into DNA.48
However, all previous syntheses of these nucleosides have
been achieved in low yields by using the α-glycoside chloride
method for 31β (isolated after three steps in 9%24 and 3%26,27),
the 2′-deoxygenation method for 32β (isolated after five steps
in 16%),13 or the sodium salt method for 33β (isolated after 2
steps in 14%).30,39
Table 2 summarizes our results for N-2-deoxyribosylation
using thioglycoside donor 5. Reactions with quinazoline-2,4-
(1H,3H)-dione 24 and 5-methoxyquinazoline-2,4-(1H,3H)-
dione 25 furnished the expected nucleosides in high yield,
83% and 80%, respectively, and with good β-selectivity (29α/
29β = 1.0:1.8 and 30α/30β = 1.0:1.7). Optimal yields were
obtained by increasing the solubility of the heterocyclic
nucleobase 26−28 by presilylation with hexamethyldisilazane
(HMDS) at 110 °C before being subjected to the standard
reaction conditions. Benzo[g]quinazoline-2,4-(1H,3H)-dione
26, containing an even larger aromatic surface, gave the desired
products (31α/31β = 1.0:1.8) in 70% yield.
The use of thioglycoside 2 (entry 3) afforded the coupling
products 15α and 15β in a similar overall yield (76%) as
thioglycoside 11, but the β-selectivity was lost (α/β = 1.2:1.0).
As compared to 2, thioglycoside 5 exhibited enhanced β-
selectivity (α/β = 1.0:1.8) and a slightly higher isolated yield of
84%. The introduction of a C5-O-TIPS group into thioglyco-
side 5 also enabled facile and quantitative separation of the α/β
anomeric mixture from multigram reactions using silica gel
chromatography (TLC ΔRf = 0.2) to afford 54% isolated yield
of the β-nucleoside 16β, after only a 2 min reaction time.
Consistent with an SN1 pathway involving an oxocarbenium ion
intermediate, enantiopure thioglycoside 5β was submitted to
the same reaction conditions and afforded the exact same
anomeric ratio of nucleoside as thioglycoside 5 (α/β = 1.0:1.8).
The modest differences in yield and stereoselectivity
exhibited by donor 5 versus 2 can be explained by the
armed−disarmed concept, where the electron-withdrawing C5-
O-acetyl group present in donor 2 is replaced by the electron-
donating C5-O-TIPS group.47 This change can “arm” the
glycosyl donor by stabilizing the formation of the oxocarbe-
nium ion intermediate (Figure 2). To further evaluate this
Given the use of NIS for thioglycoside activation in these
reactions, cross-reactivity with sulfur-containing groups was a
particular concern. However, thieno[3,2-d]pyrimidine-2,4-
dione 27 containing a thiophene group furnished the desired
nucleosides in 73% yield and in good β-selectivity (32α/32β =
1.0:2.0). Furthermore, when thioether 28 was subjected to
glycosylation with 5, the desired nucleosides were obtained in
46% yield with the β-anomer as the major product (33α/33β =
Figure 2. Arming and disarming effect in thioglycosides 2 and 5.
concept in the context of 2′-deoxyribonucleoside synthesis, a
competition experiment was conducted where a mixture of
thioglycosides 2 (1 equiv) and 5 (1 equiv) competed in the
same reaction mixture with a limited amount of the nucleobase
(12, 1 equiv) and using an excess of activator (NIS, 3 equiv).
Consistent with faster oxocarbenium ion formation by
thioglycoside 5, a 2-fold difference in product ratio was
observed in the crude product mixture (15/16 = 1.0:2.0).
Use of thioglycosides 6 and 7 furnished the expected
products in high yields, 83% and 80%, respectively (entry 6 and
7). Contrary to our expectations,43 a constant β-selectivity was
observed for the benzoyl ester as well as for the more electron-
donating p-methoxybenzoyl ester at the C3 position. These
results suggest that simple C3-O-ester groups do not act as
directing groups in these reactions. However, donors 8α and
8β, containing N-acetylglycine groups,44 exhibited highly
stereoselective formation of the β-anomer (α/β = 1.0:4.0),
albeit with lower overall isolated yield of 51% under these
reaction conditions.
1
1.0:2.5). The structure of 33β was confirmed by 2D H−1H
ROESY, where correlations between H1′ and H4′, H1′ and H2α′,
H6 and H1′, H6 and H2β′, as well as H6 and H5′, were observed
(see Supporting Information).
DISCUSSION
■
Mechanistic Considerations. During 2-deoxyribosylation
reactions involving thioglycoside donors, an oxocarbenium
intermediate is formed by elimination of the activated thioether
aglycon. Evidence for an SN1 pathway is provided by the
enantiopure thioglycoside 5β (entry 5, Table 1), which gives
the exact same anomeric ratio of nucleoside products as the
1.0:1.8 (α/β) mixture of thioglycoside 5 (entry 4, Table 1).
The presence of an oxocarbenium intermediate is further
supported by the scope of the glycosylation reaction described
in Table 2, where thioglycoside 5 afforded roughly the same α/
β mixtures, independent of the nucleobase structure. Reactions
utilizing the common α-glycosyl chloride donor 13α, in
contrast, proceed via SN2-type pathways, where competing
anomerization reactions to the β-glycosyl chloride can result in
α-nucleosides as the major product.24
In contrast to 8, thioglycoside 9 containing the C3−5-O-
silylated six-membered ring was found to be α-selective (α/β =
1.8:1.0, entry 9). In this reaction, the coupling products 20α
and 20β were obtained in 50% yield, and unreacted starting
material was recovered. More importantly, thioglycoside 10
containing the C3−5-O-silylated eight-membered ring gave the
In SN1 reactions involving an 2-deoxyribofuranoside
oxocarbenium intermediate, two conformations are possible,
where C3 is situated either above or below the C2−C1−O−C4
D
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Table 2. Scope of the N-2-Deoxyribosylation of 2-Deoxythioriboside 5 with Ring-Expanded Pyrimidine Nucleobases
a
b
c
Isolated yield of the combined anomers. Ratio determined by 1H NMR analysis of the crude mixture. The direct separation of the anomers was
d
not realized. The yield was calculated from the isolated yield of the mixture and the α/β selectivity of the reaction. The nucleobase was first
presilylated in HMDS at 110 °C for 10 h (See the general procedure in the Experimental Section).
49,50
3
plane, to give the E or E3 conformer, respectively.
The
group at C3 principally governs the lowest energy conformer,
adopting a pseudoaxial orientation in the case of an alkoxy
group. A useful model to explain diastereoselective reactions on
such five-membered rings was proposed by Woerpel et al,49,50
where a nucleophile preferentially attacks from the inside face
of the oxocarbenium envelope to give the α-product. In
contrast to this model, the NIS/TMSOTf promoted N-
glycosylation of thioglycoside donors provides primarily the
β-anomer. This can be observed with thioglycosides 5−7 but in
particular with thioglycoside 8, whose enhanced stereo-
selectivity is supported by a C1−3-anchimeric participation
mechanism (Figure 3, intermediate A).44 It is possible that,
under our reaction conditions, a counterion occupies the inside
face of the oxocarbenium envelope and/or the large steric bulk
of the silylated nucleobase causes a change in preference from
“inside” to “outside” attack of the nucleophile.
Figure 3. Plausible oxocarbenium ions for the preferred formation of
α- and β-nucleosides.
Woerpel’s and Ito’s groups have reported that conforma-
tional perturbations present in fused rings can also mediate
stereoelectronic effects.45,51 For example, when C3−C4 are
tethered, only a diequatorial oxocarbenium ion should be
accessible (Figure 3, intermediate B).51 The resulting 3E
E
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molecular sieves (MS 4 Å, 2-fold mass excess as compared to the
donor) was added BSA (2.5 equiv) dropwise over a 5 min period. The
solution was stirred at room temperature for 2 h (complete dissolution
was observed after 0.5 h). This solution was then cooled to 0 °C and
the thioglycoside donor (1.0 equiv) in CH2Cl2 was added via cannula.
After 5 min, NIS (1.2 equiv) and TMSOTf (0.6 equiv) or TfOH (0.4
equiv) were added (a deep red solution was formed) and the reaction
mixture was stirred for 2 min at 0 °C. The reaction was then quenched
with aq sat. Na2S2O3 and extracted with aq sat. NaHCO3 and CH2Cl2
(three times each). The combined organic layers were dried over
MgSO4, filtered, and evaporated in vacuo and subjected to column
chromatography using silica gel (hexane/EtOAc). Prior to glyco-
sylation of heterocyclic acceptors 26−28 (1.2 equiv), each nucleobase
was first heated in HMDS (4 mL) with a catalytic amount of
(NH4)2SO4 at 110 °C for 10 h. The mixture was then evaporated and
dried under vacuum and the residue used immediately.
Preparation of the Heterocyclic Acceptors. Following
literature procedures, 5-methoxyquinazolin-2,4-(1H,3H)-dione52 25,
benzo[g]quinazoline-2,4-(1H,3H)-dione26 26, and thieno[3,2-d]-
pyrimidine-2,4-(1H,3H)-dione12 27 were prepared. 1,3-Diaza-2-
oxophenothiazine 28 was also prepared according to a literature
procedure30 and was converted to the corresponding silylated
compound 38 for full spectroscopic characterization (Scheme 4).
conformer gives the opposite stereoselectivity of N-glycosyla-
tion as compared to the unconstrained thioglycosides, where 9
and 10 give α-anomers as primary products. These results
suggest that the selectivity of the reaction is governed by the
conformation of the oxocarbenium as well as anchimeric effects.
CONCLUSIONS
■
Here we report an efficient method for N-2-deoxyribosylation
of challenging heterocyclic nucleobases. Thioglycosides provide
a highly attractive alternative to the commonly used α-glycoside
chloride for stereoselective synthesis of β-nucleosides. Thio-
glycoside donors can be activated in the presence of an in situ
silylated nucleobase using NIS/HOTf as promoters. By tuning
the protecting groups at the C3 and C5 hydroxyls, α/β ratios
ranging from 1.0:4.0 to 4.5:1.0 were obtained. This method is
compatible with highly challenging expanded nucleobases that
were converted into 2′-deoxynucleosides in good yields and β-
selectivity. 2-Deoxythioriboside coupling reactions tolerate a
wide variety of functional groups in the nucleobase structure,
including thiophene and thioether groups. Interestingly, all the
coupling products where obtained after only 2 min reaction
times with nearly the same α/β selectivity, suggesting a
common, highly reactive oxocarbenium intermediate. As
compared to other more commonly used methodologies, this
approach can provide enhanced yields, β-selectivity, shorter
reaction times, and a broader scope of nucleobase substrates.
Thioglycosides therefore provide a powerful means for the
synthesis of nucleoside analogues as new fluorescent probes
and drug candidates that can expand our current understanding
of DNA biology.
Scheme 4. Synthesis of the Silylated 1,3-Diaza-2-
oxophenothiazine 38
EXPERIMENTAL SECTION
1,3-Diaza-2-O-trimethylsilylphenothiazine (38). 1,3-Diaza-2-
oxophenothiazine 28 (0.119 g, 0.547 mmol) was suspended in HMDS
(4 mL) and stirred at 110 °C for 18 h. The solvent was evaporated and
the residue was dried under vacuum to give compound 38 as a yellow
solid: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.14 (s, 1H), 6.99
(t, J1 = 7.3 Hz, 1H), 6.93−6.85 (m, 2H), 6.58 (d, J1 = 7.6 Hz, 1H),
0.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.4, 160.3, 152.6,
137.8, 127.7, 126.8, 124.5, 117.4, 116.1, 104.2, 0.4; IR (neat) ν 3238,
1557, 1408, 1249, 1019, 848, 757 cm−1. 28: HR-ESI MS (m/z) [M +
H]+ calcd for C10H8N3OS 218.038 80, found 218.038 24.
■
General Information. Starting materials were obtained in the
highest commercial grades and used without further purification.
Commercially available 1,3,5-tri-O-acetyl-2-deoxy-D-ribose 1 was
purified by flash column chromatography on silica gel (hexane/
EtOAc, 6:4) prior to use. All reactions sensitive to moisture and/or air
were carried out under an atmosphere of argon in dry, freshly distilled
solvents under anhydrous conditions using oven-dried glassware.
Commercially available dichloromethane (CH2Cl2) and acetonitrile
(MeCN) were purified by a solvent purification system under an
atmosphere of argon immediately prior to use. Commercially available
anhydrous pyridine was used directly without further drying. Analytical
thin-layer chromatography was performed on precoated 250 μm layer
thickness silica gel 60 F254 plates. Visualization was performed by
ultraviolet light and staining with a 15% H2SO4 solution in EtOH/
H2O. Flash column chromatography was performed using 40−63 μm
silica gel using compressed air. 1H NMR spectra were recorded on 400
and 500 MHz spectrometers; residual solvent peaks were used as
p-Tolyl-3,5-di-O-acetyl-1-thio-2-deoxy-α,β-D-ribofuranoside
(2). To a stirring solution of 1,3,5-tri-O-acetyl-2-deoxy-α,β-D-ribose 1
(30.34 g, 116.58 mmol) at −78 °C in CH2Cl2 (420 mL) was added p-
TolSH (14.77 g, 118.91 mmol). After 5 min, BF3·OEt2 (50.36 mL,
408.03 mmol) was added dropwise. The reaction mixture was stirred
for 20 min and then quenched with aq sat. NaHCO3. The resulting
solution was extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over MgSO4, filtered, and evaporated in
vacuo. The crude material was subjected to column chromatography
on silica gel (hexane/EtOAc, 8:2) to give an inseparable isomer
mixture of thioglycoside 2 (α/β = 1.0:1.8, 34.78 g, 92%) as a colorless
internal standards: DMSO (quint, δH = 2.50 ppm), CHCl3 (s, δH
=
7.26 ppm). 13C NMR spectra were recorded on 400 and 500 MHz
spectrometers, with δ relative to DMSO (δ 40.5 ppm) or CHCl3 (δ
77.23 ppm). Coupling constants (J) are reported in hertz (Hz). The
following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext =
sextet, m = multiplet, dd = doublet−doublet, ddd = doublet−doublet−
doublet, dt = doublet−triplet, dq = doublet−quartet, br = broad. Mass
spectra were obtained on a quadrupole ion trap instrument equipped
with a atmospheric pressure ion (API) source. High-resolution
electrospray mass spectra (HR-ESI MS) were recorded on a QTOF-
MS instrument. Infrared spectra were recorded on a FTIR
spectrometer.
1
oil: Rf (hexane/EtOAc, 7:3) 0.36; H NMR (2D COSY, 500 MHz,
CDCl3) 2α, δ 7.36−7.33 (m, 2H), 7.07−7.05 (m, 2H), 5.43 (dd, J1 =
8.9 Hz, J2 = 5.9 Hz, 1H, H1), 5.09 (dt, J1 = 6.1 Hz, J2 = 1.7 Hz, 1H,
H3), 4.20−4.06 (m, 3H, H5, H5 and H4), 2.31 (ddd, J1 = 14.3, J2 = 6.0
Hz, J3 = 1.9 Hz, 1H, H2), 2.27 (s, 3H), 2.20−2.14 (m, 1H, H2), 2.00 (s,
3H), 1.98 (s, 3H); 2β, δ 7.36−7.33 (m, 2H), 7.07−7.05 (m, 2H), 5.60
(dd, J1 = 7.8 Hz, J2 = 3.0 Hz, 1H, H1), 5.00 (ddd, J1 = 7.6 Hz, J2 = 4.4
Hz, J3 = 3.0 Hz, 1H, H3), 4.41 (q, J1 = 4.5 Hz, 1H, H4), 4.25 (dd, J1 =
12.0 Hz, J2 = 3.6 Hz, 1H, H5), 4.20−4.14 (m, 1H, H5), 2.73 (dt, J1 =
15.5 Hz, J2 = 7.8 Hz, 1H, H2), 2.26 (s, 3H), 2.08−2.04 (m, 1H, H2),
2.04 (s, 3H), 2.01 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.4,
170.3, 170.2, 170.1, 137.6, 137.0, 132.7, 131.5, 131.3, 129.4, 87.5, 86.0,
82.8, 80.1, 75.3, 73.7, 63.7, 63.2, 39.0, 37.9, 20.91, 20.88, 20.77, 20.74,
20.61, 20.56; IR (neat) ν 2952, 1737, 1493, 1366, 1222, 1048, 1018,
General Procedure for the One-Pot BSA/NIS/TMSOTf-
Mediated N-2-Deoxyribosylation of Thioglycoside Donor
with Heterocyclic Acceptor (A). To a suspension of the
heterocyclic acceptor (1.2 equiv) in CH2Cl2 (0.06 M) with activated
F
dx.doi.org/10.1021/jo3014929 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
809 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for C16H20O5SNa
347.092 91, found 347.092 45.
thioglycoside 5 (α/β = 1.0:1.8, 2.04 g, 90%) as a colorless oil: Rf
(hexane/EtOAc, 9:1) 0.38; H NMR (2D COSY, 500 MHz, CDCl3)
1
p-Tolyl-1-thio-2-deoxy-α,β-D-ribofuranoside (3). To a stirring
solution of thioglycoside 2 (α/β = 1.0:1.8, 20.0 g, 61.65 mmol) in a
mixture of MeOH/CH2Cl2 (202.5 mL, 4:1) was added K2CO3 (18.74
g, 135.64 mmol). The reaction mixture was stirred at room
temperature for 2 h and then quenched with a solution of HCl (500
mL, 1 N). The mixture was extracted with CHCl3 (3 × 400 mL),
dried, filtered, and evaporated in vacuo. The crude material was
subjected to column chromatography on silica gel (CH2Cl2/MeOH,
95:5) to give an inseparable isomer mixture of thioglycoside 3 (α/β =
1.0:1.8, 14.46 g, 98%) as a colorless oil: Rf (CH2Cl2/MeOH, 94:6)
5α, δ 7.41−7.39 (m, 2H), 7.12−7.10 (m, 2H), 5.47 (dd, J1 = 7.7, J2 =
3.5 Hz, 1H, H1), 5.31−5.29 (m, 1H, H3), 4.08 (t, J1 = 5.1 Hz, 1H, H4),
3.84−3.81 (m, 1H, H5), 3.58 (dd, J1 = 10.5 Hz, J2 = 6.6 Hz, 1H, H5),
2.33−2.31 (m, 1H, H2), 2.32 (s, 3H), 2.26−2.21 (m, 1H, H2), 2.04 (s,
3H), 1.07−1.04 (m, 21H); 5β, δ 7.41−7.39 (m, 2H), 7.12−7.10 (m,
2H), 5.68 (dd, J1 = 7.7 Hz, J2 = 3.0 Hz, 1H, H1), 5.24−5.22 (m, 1H,
H3), 4.32 (q, J1 = 3.3 Hz, 1H, H4), 3.93 (dd, J1 = 10.8 Hz, J2 = 3.3 Hz,
1H, H5), 3.83 (dd, J1 = 14.4 Hz, J2 = 3.7 Hz, 1H, H5), 2.81−2.77 (m,
1H, H2), 2.32 (s, 3H), 2.11−2.09 (m, 1H, H2), 2.09 (s, 3H), 1.07−
1.04 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 170.8, 170.3, 137.6,
136.9, 132.7, 132.3, 131.5, 130.5, 129.7, 129.6, 88.1, 86.4, 86.0, 84.4,
76.0, 74.9, 63.99, 63.91, 39.9, 38.4, 21.20, 21.16, 21.14, 18.10, 18.09,
18.05, 18.03, 12.0; IR (neat) ν 2942, 2892, 2866, 1741, 1240, 1065,
1017, 882, 773 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C23H38O4SSiNa 461.215 78, found 461.215 09.
1
0.25; H NMR (2D COSY, 400 MHz, CDCl3) 3α, δ 7.41−7.39 (m,
2H), 7.14−7.12 (m, 2H), 5.64−5.61 (m, 1H, H1), 4.40−4.37 (m, 1H,
H3), 4.00 (q, J1 = 4.0 Hz, 1H, H4), 3.70−3.68 (m, 1H, H5), 3.60 (dd, J1
= 12.0 Hz, J2 = 4.3 Hz, 1H, H5), 2.37−2.34 (m, 1H, H2), 2.29 (s, 3H),
2.30 (s, 2H), 2.40−2.17 (m, 1H, H2); 3β, δ 7.41−7.39 (m, 2H), 7.14−
7.12 (m, 2H), 5.63 (dd, J1 = 7.4 Hz, J2 = 3.4 Hz, 1H, H1), 4.27 (ddd, J1
= 7.5 Hz, J2 = 4.6 Hz, J3 = 3.8 Hz, 1H, H3), 4.16 (q, J1 = 4.0 Hz, 1H,
H4), 3.78 (dd, J1 = 12.0 Hz, J2 = 3.7 Hz, 1H, H5), 3.70 (dd, J1 = 12.0
Hz, J2 = 4.0 Hz, 1H, H5), 2.64 (dt, J1 = 14.2 Hz, J2 = 7.4 Hz, 1H, H2),
2.33 (s, 3H), 2.30 (s, 2H), 2.04 (dt, J1 = 13.8 Hz, J2 = 3.5 Hz, 1H, H2);
13C NMR (100 MHz, CDCl3) δ 138.0, 132.6, 132.3, 130.9, 130.0,
p-Tolyl-3-O-benzoyl-1-thio-5-O-triisopropylsilyl-2-deoxy-
α,β-D-ribofuranoside (6). To a stirring solution of thioglycoside 4
(α/β = 1.0:1.8, 0.405 g, 1.02 mmol) in CH2Cl2 (7.3 mL) were added
pyridine (0.80 mL), Et3N (0.20 mL, 1.43 mmol), BzCl (0.14 mL, 1.23
mmol), and DMAP (0.012 g, 0.10 mmol). The reaction mixture was
stirred at room temperature for 2 h and then quenched with a solution
of HCl (30 mL, 1 N). The resulting solution was extracted with
CH2Cl2 (2 × 30 mL), and the combined organic layers were dried,
filtered, and evaporated in vacuo. The crude material was subjected to
column chromatography on silica gel (hexane/EtOAc, 95:5) to give an
inseparable isomer mixture of thioglycoside 6 (α/β = 1.0:1.8, 0.445 g,
129.9, 88.3, 87.3, 86.5, 85.6, 72.8, 72.3, 62.9, 62.4, 42.1, 41.9, 21.32,
21.29; IR (neat) ν 3386, 2921, 2872, 1492, 1079, 1038, 808, 500 cm−1;
HR-ESI MS (m/z) [M + Na]+ calcd for C12H16O3SNa 263.071 79,
found 263.071 25.
p-Tolyl-1-thio-5-O-triisopropylsilyl-2-deoxy-α-D-ribofurano-
side (4α) and p-Tolyl-1-thio-5-O-triisopropylsilyl-2-deoxy-β-D-
ribofuranoside (4β). To a stirring solution of thioglycoside 3 (α/β =
1.0:1.8, 14.0 g, 58.26 mmol) in CH2Cl2 (320 mL) were added TIPSCl
(14.96 mL, 69.91 mmol) and imidazole (4.82 g, 69.91 mmol). The
reaction mixture was stirred at room temperature for 16 h and then
quenched with H2O (400 mL). The resulting solution was extracted
with CH2Cl2 (2 × 300 mL), and the combined organic layers were
dried, filtered, and evaporated in vacuo. The crude material was
subjected to column chromatography on silica gel (CH2Cl2/MeOH,
99:1) to give the separable isomers of thioglycoside 4α and 4β (19.64
g, 85%) as colorless oils. 4α: Rf (CH2Cl2/MeOH, 96:4) 0.63; 1H
NMR (2D COSY, 400 MHz, CDCl3) δ 7.39 (d, J1 = 8.0 Hz, 2H), 7.10
(d, J1 = 7.8 Hz, 2H), 5.55 (t, J1 = 7.0 Hz, 1H, H1), 4.39 (quint, J1 = 3.4
Hz, 1H, H3), 3.95−3.01 (m, 1H, H4), 3.85 (dd, J1 = 9.9 Hz, J2 = 4.7
Hz, 1H, H5), 3.50 (t, J1 = 9.3 Hz, 1H, H5), 2.30 (s, 3H), 2.35−2.29 (m,
1H, H2), 2.23−2.16 (m, 1H, H2), 2.07 (s, br, 1H), 1.10−1.05 (m,
21H); 13C NMR (100 MHz, CDCl3) δ 137.6, 132.7, 130.5, 129.7,
87.4, 86.1, 74.0, 64.7, 40.5, 21.2, 18.13, 18.11, 12.0; IR (neat) ν 3419,
2940, 2923, 2864, 1492, 1461, 1129, 1066, 996, 881, 807, 773, 680,
503 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for C21H36O3SSiNa
419.205 21, found 419.204 93. 4β: Rf (CH2Cl2/MeOH, 96:4) 0.44; 1H
NMR (2D COSY, 400 MHz, CDCl3) δ 7.40 (d, J1 = 7.4 Hz, 2H), 7.11
(d, J1 = 7.7 Hz, 2H), 5.64 (dd, J1 = 7.3 Hz, J2 = 3.4 Hz, 1H, H1), 4.34−
4.31 (m, 1H, H3), 4.16 (q, J1 = 4.2 Hz, 1H, H4), 3.93 (dd, J1 = 10.1 Hz,
J2 = 3.5 Hz, 1H, H5), 3.70 (dd, J1 = 10.1 Hz, J2 = 5.8 Hz, 1H, H5),
2.73−2.65 (m, 1H, H2), 2.33 (s, br, 1H), 2.33 (s, 3H), 2.05 (dt, J1 =
13.9 Hz, J2 = 3.3 Hz, 1H, H2), 1.08−1.05 (m, 21H); 13C NMR (100
MHz, CDCl3) δ 137.6, 132.2, 131.3, 129.8, 87.1, 85.8, 73.9, 64.4, 41.6,
21.3, 18.15, 18.12, 12.08, 12.06; IR (neat) ν 3419, 2940, 2923, 2864,
1492, 1461, 1127, 1062, 881, 806, 773, 681, 501 cm−1; HR-ESI MS
(m/z) [M + Na]+ calcd for C21H36O3SSiNa 419.205 21, found
419.204 42.
1
87%) as a colorless oil: Rf (hexane/EtOAc, 9:1) 0.50; H NMR (2D
COSY, 500 MHz, CDCl3) 6α, δ 8.02 (d, J1 = 8.0 Hz, 2H), 7.59−7.54
(m, 1H), 7.47−7.43 (m, 4H), 7.13−7.10 (m, 2H), 5.57−5.53 (m, 2H,
H1 and H3), 4.26 (t, J1 = 5.7 Hz, 1H, H4), 3.92−3.90 (m, 1H, H5), 3.67
(dd, J1 = 10.1 Hz, J2 = 6.4 Hz, 1H, H5), 2.47 (dd, J1 = 14.2 Hz, J2 = 5.7
Hz, 1H, H2), 2.41−2.37 (m, 1H, H2), 2.34 (s, 3H), 1.08−1.05 (m,
21H); 6β, δ 8.12 (d, J1 = 18.0 Hz, 2H), 7.59−7.54 (m, 1H), 7.47−7.43
(m, 4H), 7.13−7.10 (m, 2H), 5.78 (d, J1 = 5.8 Hz, 1H, H1), 5.57−5.53
(m, 1H, H3), 4.49 (d, J1 = 2.9 Hz, 1H, H4), 4.03 (dd, J1 = 10.9 Hz, J2 =
3.0 Hz, 1H, H5), 3.91 (dd, J1 = 11.1 Hz, J2 = 2.4 Hz, 1H, H5), 2.90−
2.84 (m, 1H, H2), 2.32 (s, 3H), 2.32−2.30 (m, 1H, H2), 1.08−1.05 (m,
21H); 13C NMR (125 MHz, CDCl3) δ 166.5, 166.0, 137.8, 137.1,
133.34, 133.32, 132.9, 132.5, 131.7, 130.6, 130.2, 130.1, 130.0, 129.84,
129.82, 129.81, 129.80, 128.6, 128.5, 88.7, 86.7, 86.2, 85.1, 76.7, 75.7,
64.15, 64.14, 40.2, 38.8, 21.3, 21.2, 18.22, 18.21, 18.16, 18.14, 12.1; IR
(neat) ν 2942, 2892, 2866, 1719, 1271, 1110, 1066, 882, 773, 711
cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for C28H40O4SSiNa
523.231 43, found 523.230 68.
p-Tolyl-3-O-p-methoxybenzoyl-1-thio-5-O-triisopropylsilyl-
2-deoxy-α,β-D-ribofuranoside (7). To a stirring solution of
thioglycoside 4 (α/β = 1.0:1.8, 0.30 g, 0.76 mmol) in CH2Cl2 (4.0
mL) were added pyridine (0.4 mL), Et3N (157 μL, 1.13 mmol), p-
anisoyl chloride (PMBCl, 0.193 g, 1.13 mmol), and DMAP (0.018 g,
0.151 mmol). The reaction mixture was stirred at room temperature
for 16 h and then quenched with a solution of HCl (20 mL, 0.5 N).
The resulting solution was extracted with CH2Cl2 (2 × 20 mL), and
the combined organic layers were dried, filtered, and evaporated in
vacuo. The crude material was subjected to column chromatography
on silica gel (hexane/EtOAc, 9:1) to give an inseparable isomer
mixture of thioglycoside 7 (α/β = 1.0:1.8, 0.313 g, 78%) as a colorless
1
oil: Rf (hexane/EtOAc, 9:1) 0.35; H NMR (2D COSY, 400 MHz,
CDCl3) 7α, δ 7.98 (d, J1 = 9.0 Hz, 2H), 7.46 (d, J1 = 8.0 Hz, 2H),
7.14−7.10 (m, 2H), 6.92−6.89 (m, 2H), 5.57 (dd, J1 = 9.5 Hz, J2 = 5.7
Hz, 1H, H1), 5.52−5.49 (m, 1H, H3), 4.27−4.25 (m, 1H, H4), 3.93−
3.88 (m, 1H, H5), 3.84 (s, 3H), 3.68 (dd, J1 = 10.5 Hz, J2 = 6.2 Hz, 1H,
H5), 2.49 (dd, J1 = 14.2 Hz, J2 = 5.7 Hz, 1H, H2), 2.39 (dd, J1 = 9.5 Hz,
J2 = 5.8 Hz, 1H, H2), 2.32 (s, 3H), 1.10−1.05 (m, 21H); 7β, δ 8.08 (d,
J1 = 8.5 Hz, 2H), 7.45 (d, J1 = 7.8 Hz, 2H), 7.11 (d, J1 = 7.8 Hz, 2H),
6.94 (d, J1 = 8.5 Hz, 2H), 5.78 (dd, J1 = 7.7 Hz, J2 = 2.2 Hz, 1H, H1),
5.51 (d, J1 = 7.1 Hz, 1H, H3), 4.48 (d, J1 = 2.9 Hz, 1H, H4), 4.03 (dd,
J1 = 10.9 Hz, J2 = 3.1 Hz, 1H, H5), 3.91 (dd, J1 = 10.9 Hz, J2 = 3.1 Hz,
1H, H5), 3.86 (s, 3H), 2.86 (quint, J1 = 7.2 Hz, 1H, H2), 2.32 (s, 3H),
p-Tolyl-3-O-acetyl-1-thio-5-O-triisopropylsilyl-2-deoxy-α,β-
D-ribofuranoside (5). To a stirring solution of thioglycosides 4α and
4β (α/β = 1.0:1.8, 2.05 g, 5.17 mmol) in MeCN (35 mL) were added
Et3N (0.86 mL, 6.20 mmol), Ac2O (0.58 mL, 6.20 mmol), and DMAP
(0.063 g, 0.52 mmol). The reaction mixture was stirred at room
temperature for 2 h and then quenched with H2O (50 mL). The
resulting solution was extracted with CH2Cl2 (2 × 50 mL), and the
combined organic layers were dried, filtered, and evaporated in vacuo.
The crude material was subjected to column chromatography on silica
gel (hexane/EtOAc, 93:7) to give an inseparable isomer mixture of
G
dx.doi.org/10.1021/jo3014929 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2.30−2.27 (m, 1H, H2), 1.10−1.05 (m, 21H); 13C NMR (100 MHz,
CDCl3) δ 166.1, 165.7, 163.6, 137.7, 136.9, 132.8, 132.5, 132.0, 131.8,
131.5, 130.6, 129.75, 129.72, 122.5, 122.4, 113.8, 113.7, 88.7, 86.6,
86.2, 85.2, 76.3, 75.3, 64.12, 64.10, 55.5, 40.2, 38.7, 21.25, 21.21, 18.17,
18.15, 18.11, 18.08, 12.0; IR (neat) ν 2937, 2865, 1712, 1605, 1273,
1254, 1166, 1098, 881, 769 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd
for C29H42O5SSiNa 553.241 99, found 553.240 99.
CDCl3) 9α, δ 7.43−7.40 (m, 2H), 7.15−7.11 (m, 2H), 5.46 (dd, J1 =
8.6 Hz, J2 = 2.6 Hz, 1H, H1), 4.33 (dd, J1 = 9.3 Hz, J2 = 4.8 Hz, 1H,
H4), 3.84−3.55 (m, 3H, H3, H5 and H5), 2.42−2.34 (m, 2H, H2 and
H2), 2.33 (s, 3H), 1.06 (s, 6H), 1.01 (s, 6H), 0.96 (s, 6H); 9β, δ 7.43−
7.40 (m, 2H), 7.15−7.11 (m, 2H), 5.51 (dd, J1 = 8.0 Hz, J2 = 7.1 Hz,
1H, H1), 4.38 (dd, J1 = 9.0 Hz, J2 = 4.8 Hz, 1H, H4), 4.04−3.98 (m,
1H, H3), 3.92−3.82 (m, 2H, H5 and H5), 2.81 (dt, J1 = 12.7 Hz, J2 =
7.1 Hz, 1H, H2), 2.32 (s, 3H), 1.87 (ddd, J1 = 12.6 Hz, J2 = 9.8 Hz, J3 =
8.1 Hz, 1H, H2), 1.06 (s, 6H), 1.01 (s, 6H), 0.96 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 138.7, 137.6, 134.3, 131.9, 131.5, 129.84, 129.81,
129.0, 85.6, 84.7, 79.0, 75.7, 75.2, 74.9, 68.2, 67.7, 39.7, 39.2, 27.6,
27.5, 27.34, 27.33, 22.8, 22.6, 21.32, 21.28, 20.29, 20.20; IR (neat) ν
2962, 2933, 2887, 2859, 1473, 1127, 1065, 1050, 900, 827, 808, 753,
652, 418 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C20H32O3SSiNa 403.173 91, found 403.173 38.
p-Tolyl-3-O-(N-acetyl)-glycyl-1-thio-5-O-triisopropylsilyl-2-
deoxy-α-D-ribofuranoside (8α). To a stirring solution of thioglyco-
side 4α (0.50 g, 1.26 mmol) in CH2Cl2 (8.0 mL) were added N-
acetylglycine (0.177 g, 1.51 mmol), DCI (0.24 mL, 1.51 mmol), and
DMAP (0.01 g, 0.078 mmol). The reaction mixture was stirred at
room temperature for 12 h and then quenched with aq sat. NaHCO3
(40 mL). The resulting solution was extracted with CH2Cl2 (2 × 40
mL) and the combined organic layers were dried, filtered, and
evaporated in vacuo. The residue was taken up in a mixture of hexane/
EtOAc (5 mL, 10:1) and the precipitate was filtered off through cotton
in a glass pipet. The resulting solution was evaporated and the crude
material was subjected to column chromatography on silica gel
(hexane/EtOAc, 1:1) to give thioglycoside 8α (0.565 g, 91%) as a
colorless oil: Rf (hexane/EtOAc, 1:1) 0.23; 1H NMR (2D COSY, 400
MHz, CDCl3) δ 7.37 (d, J1 = 8.2 Hz, 2H), 7.09 (d, J1 = 7.9 Hz, 2H),
6.29 (t, br, 1H), 5.43 (dd, J1 = 9.4 Hz, J2 = 5.8 Hz, 1H, H1), 5.35 (d, J1
= 5.6 Hz, 1H, H3), 4.08−4.03 (m, 1H, H4), 3.97 (ddd, AB system, J1 =
27.5 Hz, J2 = 18.3 Hz, J3 = 5.2 Hz, 2H), 3.79 (dd, J1 = 10.6 Hz, J2 = 4.2
Hz, 1H, H5), 3.53 (dd, J1 = 10.6 Hz, J2 = 6.6 Hz, 1H, H5), 2.36−2.32
(m, 1H, H2), 2.29 (s, 3H), 2.26−2.19 (m, 1H, H2), 1.99 (s, 3H),
1.05−1.03 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 170.4, 169.6,
137.8, 132.8, 130.1, 129.7, 86.3, 85.7, 77.4, 63.7, 41.5, 38.2, 23.5, 22.9,
18.07, 18.06, 11.9; IR (neat) ν 3333, 2941, 2891, 2865, 1750, 1656,
1541, 1463, 1381, 1193, 1064, 882, 683 cm−1; HR-ESI MS (m/z) [M
+ Na]+ calcd for C25H41NO5SSiNa 518.237 24, found 518.236 53.
p-Tolyl-3-O-(N-acetyl)-glycyl-1-thio-5-O-triisopropylsilyl-2-
deoxy-β-D-ribofuranoside (8β). To a stirring solution of 4β (0.50 g,
1.26 mmol) in CH2Cl2 (8.0 mL) were added N-acetylglycine (0.177 g,
1.51 mmol), DCI (0.24 mL, 1.51 mmol), and DMAP (0.01 g, 0.078
mmol). The reaction mixture was stirred at room temperature for 12 h
and then quenched with aq sat. NaHCO3 (40 mL). The resulting
solution was extracted with CH2Cl2 (2 × 40 mL), and the combined
organic layers were dried, filtered, and evaporated in vacuo. The
residue was taken up in a mixture of hexane/EtOAc (5 mL, 10:1) and
the precipitate was filtered off through cotton in a glass pipet. The
resulting solution was evaporated and the crude material was subjected
to column chromatography on silica gel (hexane/EtOAc, 1:1) to give
thioglycoside 8β (0.53 g, 85%) as a colorless oil: Rf (hexane/EtOAc,
5:5) 0.25; 1H NMR (2D COSY, 400 MHz, CDCl3) δ 7.38 (d, J1 = 8.2
Hz, 2H), 7.10 (d, J1 = 8.0 Hz, 2H), 6.07 (s, br, 1H), 5.69 (dd, J1 = 7.7
Hz, J2 = 2.7 Hz, 1H, H1), 5.33 (dt, J1 = 6.8 Hz, J2 = 2.2 Hz, 1H, H3),
4.32 (q, J1 = 3.1 Hz, 1H, H4), 4.07 (dd, J1 = 5.3 Hz, J2 = 1.9 Hz, 2H),
3.92 (dd, J1 = 10.9 Hz, J2 = 3.2 Hz, 1H, H5), 3.82 (dd, J1 = 10.9 Hz, J2
= 3.4 Hz, 1H, H5), 2.77 (quint, J1 = 7.5 Hz, 1H, H2), 2.32 (s, 3H), 2.14
(dt, J1 = 14.6 Hz, J2 = 2.4 Hz, 1H, H2), 2.04 (s, 3H), 1.07−1.04 (m,
21H); 13C NMR (100 MHz, CDCl3) δ 170.3, 169.8, 137.3, 131.9,
131.7, 129.8, 88.3, 84.7, 76.3, 63.8, 41.8, 39.8, 23.1, 21.2, 18.1, 18.0,
12.0; IR (neat) ν 3333, 2942, 2866, 1750, 1659, 1549, 1493, 1383,
1193, 1064, 882, 679 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C25H41NO5SSiNa 518.237 24, found 518.236 81.
p-Tolyl-3,5-O-(tetraisopropylsiloxane-1,3-diyl)-1-thio-2-
deoxy-α,β-D-ribofuranoside (10). To a stirring solution of
thioglycoside 3 (α/β = 1.0:1.8, 0.150 g, 0.62 mmol) in pyridine (0.8
mL) at 0 °C was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane
(TIPDSCl, 0.21 mL, 0.655 mmol). The reaction mixture was stirred at
room temperature for 12 h and then MeOH was added. The resulting
solution was diluted with CH2Cl2 (10 mL) and washed with H2O and
brine. The organic layer was dried, filtered, and evaporated in vacuo.
The crude material was subjected to column chromatography on silica
gel (hexane/EtOAc, 98:2) to give an inseparable isomer mixture of
thioglycoside 10 (α/β = 1.0:1.8, 0.279 g, 93%) as a colorless oil: Rf
(hexane/EtOAc, 96:4) 0.34; 1H NMR (2D COSY, 400 MHz, CDCl3)
10α, δ 7.42−7.39 (m, 2H), 7.11−7.08 (m, 2H), 5.47 (dd, J1 = 7.2 Hz,
J2 = 3.8 Hz, 1H, H1), 4.41 (q, J1 = 5.7 Hz, 1H, H3), 4.07−3.90 (m, 2H,
H5 and H5), 3.88−3.85 (m, 1H, H4), 2.47−2.41 (m, 1H, H2), 2.40−
2.34 (m, 1H, H2), 2.34 (s, 3H), 1.11−1.04 (s, 32H); 10β, δ 7.42−7.39
(m, 2H), 7.11−7.08 (m, 2H), 5.53 (t, J1 = 6.6 Hz, 1H, H1), 4.31 (q, J1
= 7.2 Hz, 1H, H3), 4.00 (dd, J1 = 11.8 Hz, J2 = 2.8 Hz, 1H, H5), 3.99−
3.91 (m, 2H, H4 and H5), 2.74 (dt, J1 = 15.4 Hz, J2 = 7.6 Hz, 1H, H2),
2.33 (s, 3H), 2.07−2.00 (m, 1H, H2), 1.11−1.04 (s, 32H); 13C NMR
(100 MHz, CDCl3) δ 137.9, 137.0, 133.1, 132.3, 131.53, 131.52, 130.2,
129.79, 129.70, 129.69, 85.9, 85.7, 85.5, 81.7, 74.3, 71.1, 65.4, 61.8,
42.0, 40.6, 21.27, 21.23, 17.74, 17.67, 17.65, 17.57, 17.56, 17.54, 17.55,
17.54, 17.50, 17.48, 17.46, 17.44, 17.32, 17.31, 17.22, 17.16, 17.15,
17.13, 13.6, 13.5, 13.3, 13.1; IR (neat) ν 2944, 2892, 2867, 1464, 1137,
1081, 1054, 1035, 999, 885, 776, 692 cm−1; HR-ESI MS (m/z) [M +
Na]+ calcd for C24H42O4SSi2Na 505.224 00, found 505.223 53.
p-Tolyl-3,5-di-O-p-toluoyl-1-thio-2-deoxy-α,β-D-ribofurano-
side (11). To a stirring solution of thioglycoside 3 (α/β = 1.0:1.8,
0.150 g, 0.62 mmol) in CH2Cl2 (4.5 mL) at 0 °C were added pyridine
(0.5 mL), Et3N (0.19 mL, 1.37 mmol), DMAP (0.031 g, 0.25 mmol),
and p-toluoyl chloride (0.18 mL, 1.37 mmol). The reaction mixture
was stirred at room temperature for 16 h and the color of the solution
changed from orange to green. The resulting solution was diluted with
CH2Cl2 (10 mL) and washed with HCl (10 mL, 1 N) and brine. The
organic layer was dried, filtered, and evaporated in vacuo. The crude
material was subjected to column chromatography on silica gel
(hexane/EtOAc, 95:5 → 90:10) to give an inseparable isomer mixture
of thioglycoside 11 (α/β = 1.0:1.8, 0.255 g, 86%) as a colorless oil: Rf
1
(hexane/EtOAc, 9:1) 0.16; H NMR (2D COSY, 400 MHz, CDCl3)
11α, δ 8.05−7.92 (m, 4H), 7.49−7.45 (m, 2H), 7.27−7.22 (m, 4H),
7.13−7.09 (m, 2H), 5.64 (dd, J1 = 8.8 Hz, J2 = 5.9 Hz, 1H, H1), 5.53−
5.49 (m, 1H, H3), 4.56−4.48 (m, 3H, H4, H5 and H5), 2.57−2.40 (m,
2H, H2 and H2), 2.42−2.40 (m, 6H), 2.29 (s, 3H); 10β, δ 8.05−7.92
(m, 4H), 7.49−7.45 (m, 2H), 7.27−7.22 (m, 4H), 7.13−7.09 (m, 2H),
5.80 (dd, J1 = 7.6 Hz, J2 = 2.5 Hz, 1H, H1), 5.53−5.49 (m, 1H, H3),
4.79 (q, J1 = 4.0 Hz, 1H, H4), 4.65−4.61 (m, 2H, H5 and H5), 2.98−
2.91 (m, 1H, H2), 2.40−2.33 (m, 1H, H2), 2.42−2.40 (m, 6H), 2.33 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 165.9, 144.2, 144.1,
143.8, 143.7, 138.0, 137.7, 137.4, 133.3, 132.23, 132.02, 132.01,
132.00, 131.7, 129.9, 129.87, 129.85, 129.84, 129.77, 129.76, 129.75,
129.4, 129.25, 129.23, 129.19, 129.17, 127.17, 127.15, 126.9, 126.8,
88.3, 86.4, 83.2, 81.3, 76.0, 74.80, 64.4, 64.0, 39.6, 38.5, 21.76, 21.74,
21.72, 21.16. IR (neat) ν 2358, 2338, 1716, 1608, 1268, 1177, 1104,
p-Tolyl-3,5-O-(di-tert-butylsilylene)-1-thio-2-deoxy-α,β-D-ri-
bofuranoside (9). To a stirring solution of thioglycoside 3 (α/β =
1.0:1.8, 0.150 g, 0.62 mmol) in a mixture of CH2Cl2/DMF (6 mL, 5:1)
at 0 °C were added di-tert-butylsilylbistrifluoromethanesulfonate
(tBu2SiOTf2, 0.24 mL, 0.75 mmol) and 2,6-lutidine (0.30 g, 2.81
mmol). The reaction mixture was stirred at room temperature for 16 h
and then MeOH was added. The resulting solution was evaporated in
vacuo and the residue was taken in CH2Cl2 (10 mL) and washed with
H2O and brine. The organic layer was dried, filtered, and evaporated in
vacuo. The crude material was subjected to column chromatography
on silica gel (hexane/EtOAc, 98:2) to give an inseparable isomer
mixture of thioglycoside 9 (α/β = 1.0:1.8, 0.197 g, 83%) as a white
solid: Rf (hexane/EtOAc, 98:2) 0.22; 1H NMR (2D COSY, 400 MHz,
H
dx.doi.org/10.1021/jo3014929 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
906, 752, 726 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C28H28O5SNa 499.155 52, found 499.154 90.
COSY and ROESY, 400 MHz, CDCl3) 15α, δ 9.67 (s, br, 1H), 8.32
(d, J1 = 2.5 Hz, 1H), 7.67 (dd, J1 = 9.0 Hz, J2 = 2.5 Hz, 1H), 7.53 (d, J1
= 9.0 Hz, 1H), 6.77 (t, J1 = 7.8 Hz, 1H, H1′), 5.31−5.27 (m, 1H, H3′),
4.62 (q, J1 = 4.6 Hz, 1H, H4′), 4.32 (dd, J1 = 12.0 Hz, J2 = 3.4 Hz, 1H,
H5′), 4.25 (dd, J1 = 12.1 Hz, J2 = 5.1 Hz, 1H, H5′), 2.88−2.81 (m, 1H,
H2′), 2.66−2.60 (m, 1H, H2′), 2.14−2.11 (m, 6H); 15β, δ 9.69 (s, br,
1H), 8.31 (d, J1 = 2.5 Hz, 1H), 7.70 (dd, J1 = 9.0 Hz, J2 = 2.5 Hz, 1H),
7.50 (d, J1 = 9.0 Hz, 1H), 6.68 (t, J1 = 7.8 Hz, 1H, H1′), 5.41−5.37 (m,
1H, H3′), 4.46−4.38 (m, 2H, H5′ and H5′), 4.20 (q, J1 = 3.8 Hz, 1H,
H4′), 3.03 (dt, J1 = 16.4 Hz, J2 = 8.3 Hz, 1H, H2′), 2.24−2.19 (m, 1H,
H2′), 2.14−2.11 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 170.7,
170.65, 170.63, 170.5, 160.8, 160.7, 150.0, 149.8, 138.8, 138.4, 137.77,
137.75, 131.55, 131.53, 118.5, 118.0, 117.9, 117.2, 117.1, 85.3, 84.6,
81.4, 81.1, 74.1, 73.3, 64.2, 63.6, 34.4, 34.3, 21.07, 21.06, 21.04, 21.02;
IR (neat) ν 3005, 1733, 1715, 1699, 1220, 1050, 772 cm−1; HR-ESI
MS (m/z) [M + Na]+ calcd for C17H17BrN2O7Na 463.011 68, found
463.011 08.
1′-(3′,5′-Di-O-p-toluoyl-2′-deoxy-α-D-ribofuranoside)-6-bro-
moquinazoline-2,4-(3H)-dione (14α) and 1′-(3′,5′-Di-O-p-tol-
uoyl-2′-deoxy-β-D-ribofuranoside)-6-bromoquinazoline-2,4-
(3H)-dione (14β). Starting from Thioglycoside 11. According to the
general procedure A, the isomer mixture of nucleosides 14α and 14β
(α/β = 1.0:1.6, 0.390 g, 72%) were obtained as off-white foams after
column chromatography on silica gel (hexane/EtOAc, 6:4) using 6-
bromoquinazoline-2,4-(1H,3H)-dione 12 (0.264 g, 1.10 mmol), BSA
(0.56 mL, 2.28 mmol), thioglycoside 11 (α/β = 1.0:1.8, 0.435 g, 0.91
mmol), NIS (0.247 g, 1.10 mmol), and TMSOTf (100 μL, 0.55
mmol). The β-nucleoside 14β was separated from 14α via
precipitation in EtOAc (two precipitations allowed complete removal
1
of the α-nucleoside): Rf (hexane/EtOAc, 6:4) 0.26; H NMR (2D
COSY and ROESY, 500 MHz, CDCl3) 14β, δ 9.14 (s, 1H), 8.25 (d, J1
= 2.5 Hz, 1H), 7.95 (d, J1 = 1.5 Hz, 2H), 7.94 (d, J1 = 1.5 Hz, 2H),
7.52 (d, J1 = 9.0 Hz, 1H), 7.28−7.25 (m, 4H), 6.97 (dd, J1 = 8.9 Hz, J2
= 2.5 Hz, 1H), 6.86 (t, J1 = 8.2 Hz, 1H, H1′), 5.81 (ddd, J1 = 8.2 Hz, J2
= 4.8 Hz, J3 = 3.2 Hz, 1H, H3′), 4.91 (dd, J1 = 12.2 Hz, J2 = 2.9 Hz, 1H,
H5′), 4.66 (dd, J1 = 12.3 Hz, J2 = 4.0 Hz, 1H, H5′), 4.45 (q, J1 = 4.0 Hz,
1H, H4′), 3.12 (dt, J1 = 17.0 Hz, J2 = 8.5 Hz, 1H, H2′), 2.44 (s, 3H),
2.41 (s, 3H), 2.41−2.38 (m, 1H, H2′); 13C NMR (100 MHz, CDCl3) δ
166.3, 166.2, 160.5, 149.8, 144.6, 144.5, 138.5, 138.0, 131.3, 130.0,
129.9, 129.5, 129.4, 127.1, 126.5, 118.5, 118.2, 117.1, 84.4, 81.6, 73.5,
63.3, 34.4, 21.94, 21.92; IR (neat) ν 3218, 3073, 1703, 1603, 1483,
1465, 1311, 1266, 1177, 1093, 1019, 751, 729, 502 cm−1; HR-ESI MS
(m/z) [M + Na]+ calcd for C29H25BrN2O7Na 615.074 28, found
615.074 35.
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-α-D-ribofura-
noside)-6-bromoquinazoline-2,4-(3H)-dione (16α) and 1′-(3′-
O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-β-D-ribofuranoside)-6-
bromoquinazoline-2,4-(3H)-dione (16β). According to the general
procedure A, the separable isomer mixture of nucleosides 16α (0.766
g, 30%) and 16β (1.352 g, 54%) was obtained as off-white foams after
column chromatography on silica gel (hexane/EtOAc, 8:2 → 6:4)
using 6-bromo-quinazoline-2,4-(1H,3H)-dione 12 (1.312 g, 5.44
mmol), BSA (2.77 mL, 11.34 mmol), thioglycoside 5 (α/β =
1.0:1.8, 1.99 g, 4.54 mmol), NIS (1.22 g, 5.44 mmol), and TMSOTf
1
(0.49 mL, 2.72 mmol). 16α: Rf (hexane/EtOAc, 7:3) 0.28; H NMR
(2D COSY and ROESY, 500 MHz, CDCl3) δ 9.75 (s, br, 1H), 8.32 (d,
J1 = 1.6 Hz, 1H), 7.68 (dd, J1 = 9.1 Hz, J2 = 1.6 Hz, 1H), 7.64 (d, J1 =
9.1 Hz, 1H), 7.05 (t, J1 = 7.8 Hz, 1H, H1′), 5.52 (d, J1 = 8.5 Hz, 1H,
H3′), 4.38 (s, 1H, H4′), 4.00 (d, J1 = 9.7 Hz, 1H, H5′), 3.94 (dd, J1 =
10.8 Hz, J2 = 2.1 Hz, 1H, H5′), 2.87−2.81 (m, 1H, H2′), 2.43 (ddd, J1 =
14.6 Hz, J2 = 7.6 Hz, J3 = 3.8 Hz, 1H, H2′), 2.14 (s, 1H), 1.11−1.08
(m, 21H); 13C NMR (125 MHz, CDCl3) δ 170.7, 160.9, 150.0, 138.1,
137.3, 131.3, 118.6, 116.8, 86.2, 84.8, 75.7, 65.7, 35.2, 21.2, 18.13,
18.11, 12.0; IR (neat) ν 3191, 3072, 2941, 2865, 2360, 2341, 1741,
1706, 1691, 1603, 1483, 1462, 1360, 1311, 1229, 1015, 882, 681, 503
cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for C24H35BrN2O6SiNa
Starting from α-Glycosyl Chloride 13α. To a suspension of 6-
bromoquinazoline-2,4-(1H,3H)-dione 12 (0.720 g, 0.175 mmol) in
CH2Cl2 (12 mL) with activated molecular sieves (MS 4 Å, 2-fold mass
excess as compared to the donor) was added BSA (0.37 mL, 1.50
mmol) dropwise over a 5 min period. The solution was stirring at
room temperature for 2 h (the complete dissolution was observed after
0.5 h). This solution was then cooled to 0 °C and the α-glycoside
chloride 13α (0.233 g, 0.60 mmol) in CH2Cl2 was added. After 5 min,
CuI (0.137 g, 0.72 mmol) was added and the reaction mixture was
stirred for 48 h at room temperature. The solution was then filtered
through Celite, washed with aq sat. NaCl and extracted with CH2Cl2
(three times). The combined organic layers were dried over MgSO4,
filtered, and evaporated in vacuo. The crude material was subjected to
column chromatography on silica gel (CH2Cl2/MeOH, 98.5:1.5) to
give the inseparable isomers of nucleosides 14α and 14β (α/β =
3.5:1.0, 0.206 g, 58%) as an off-white foam: Rf (hexane/EtOAc, 6:4)
1
577.134 55, found 577.133 45. 16β: Rf (hexane/EtOAc, 7:3) 0.14; H
NMR (2D COSY, 500 MHz, CDCl3) δ 9.39 (s, br, 1H), 8.32 (d, J1 =
2.5 Hz, 1H), 7.87 (d, J1 = 9.1 Hz, 1H), 7.62 (dd, J1 = 9.1 Hz, J2 = 2.5
Hz, 1H), 6.82 (dd, J1 = 9.5 Hz, J2 = 6.2 Hz, 1H, H1′), 5.52−5.50 (m,
1H, H3′), 4.11−4.03 (m, 3H, H4′, H5′ and H5′), 2.85−2.81 (m, 1H,
H2′), 2.16−2.14 (m, 1H, H2′), 2.14 (s, 3H), 1.21−1.07 (m, 21H); 13
C
1
0.28; H NMR (2D COSY and ROESY, 400 MHz, CDCl3) 14α, δ
NMR (125 MHz, CDCl3) δ 170.8, 160.8, 150.3, 138.3, 137.8, 131.2,
119.4, 118.6, 117.17 84.2, 84.0, 72.7, 62.6, 33.9, 21.1, 18.14, 18.13,
12.0; IR (neat) ν 3196, 3064, 2942, 2865, 2360, 2341, 1739, 1698,
1603, 1483, 1465, 1361, 1318, 1236, 1015, 881, 680, 504 cm−1; HR-
ESI MS (m/z) [M + Na]+ calcd for C24H35BrN2O6SiNa 577.134 55,
found 577.133 35.
9.38 (s, br, 1H), 8.32 (d, J1 = 2.2 Hz, 1H), 7.96−7.94 (m, 4H), 7.68−
7.62 (m, 2H), 7.29−7.23 (m, 4H), 7.02 (t, J1 = 7.8 Hz, 1H, H1′), 5.62
(quint, J1 = 4.5 Hz, 1H, H3′), 4.91 (q, J1 = 3.7 Hz, 1H, H4′), 4.70 (dd,
J1 = 12.0 Hz, J2 = 4.6 Hz, 1H, H5′), 4.55 (dd, J1 = 12.0 Hz, J2 = 3.6 Hz,
1H, H5′), 3.02 (dt, J1 = 16.3 Hz, J2 = 8.2 Hz, 1H, H2′), 2.78 (ddd, J1 =
14.5 Hz, J2 = 7.6 Hz, J3 = 4.6 Hz, 1H, H2′), 2.44 (s, 3H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3) 14α and 14β, δ 166.4, 166.3, 166.2,
160.6, 160.5, 149.9, 149.8, 144.8, 144.6, 144.5, 144.2, 138.4, 138.3,
137.9, 137.8, 131.5, 131.3, 130.0, 129.92, 129.91, 129.90, 129.89,
129.87, 129.8, 129.5, 129.46, 129.44, 129.35, 129.32, 129.30, 129.2,
127.1, 126.8, 126.5, 118.6, 118.4, 118.19, 118.18, 117.1, 117.0, 85.6,
84.4, 81.8, 81.5, 75.2, 73.4, 64.9, 63.3, 34.8, 34.4, 21.92, 21.90, 21.89,
21.85; IR (neat) ν 3208, 1705, 1604, 1483, 1465, 1362, 1310, 1267,
1177, 1094, 1020, 750, 503 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd
for C29H25BrN2O7Na 615.074 28, found 615.074 44.
1′-(3′-O-Benzoyl-5′-O-triisopropylsilyl-2′-deoxy-α-D-ribofur-
anoside)-6-bromoquinazoline-2,4-(3H)-dione (17α) and 1′-(3′-
O-Benzoyl-5′-O-triisopropylsilyl-2′-deoxy-β-D-ribofuranoside)-
6-bromoquinazoline-2,4-(3H)-dione (17β). According to the
general procedure A, the separable isomer mixture of nucleosides
17α (0.075 g, 32%) and 17β (0.120 g, 51%) was obtained as off-white
foams after column chromatography on silica gel (hexane/EtOAc, 8:2
→ 7:3) using 6-bromo-quinazoline-2,4-(1H,3H)-dione 12 (0.110 g,
0.455 mmol), BSA (0.23 mL, 0.948 mmol), thioglycoside 6 (α/β =
1.0:1.8, 0.190 g, 0.379 mmol), NIS (0.102 g, 0.455 mmol), and
TMSOTf (41 μL, 0.228 mmol). 17α: Rf (hexane/EtOAc, 7:3) 0.40;
1H NMR (2D COSY, 400 MHz, CDCl3) δ 9.35 (s, br, 1H), 8.34 (d, J1
1′-(3′,5′-Di-O-acetyl-2′-deoxy-α,β-D-ribofuranoside)-6-bro-
moquinazoline-2,4-(3H)-dione (15α and 15β). According to the
general procedure A, the inseparable isomer mixture of nucleosides
15α and 15β (α/β = 1.2:1.0, 0.207 g, 76%) was obtained as an off-
white foam after column chromatography on silica gel (hexane/
EtOAc, 1:1) using 6-bromo-quinazoline-2,4-(1H,3H)-dione 12 (0.178
g, 0.74 mmol), BSA (0.38 mL, 1.54 mmol), thioglycoside 2 (α/β =
1.0:1.8, 0.20 g, 0.62 mmol), NIS (0.166 g, 0.74 mmol), and TMSOTf
= 2.3 Hz, 1H), 8.08 (d, J1 = 7.8 Hz, 2H), 7.78 (d, J1 = 9.1 Hz, 1H),
7.64 (t, J1 = 7.5 Hz, 1H), 7.59 (dd, J1 = 9.1 Hz, J2 = 2.4 Hz, 1H), 7.52
(t, J1 = 7.7 Hz, 2H), 7.19 (t, J1 = 7.8 Hz, 1H, H1′), 5.77 (d, J1 = 7.9 Hz,
1H, H3′), 4.56 (s, 1H, H4′), 4.15 (d, J1 = 9.3 Hz, 1H, H5′), 4.03 (dd, J1
= 10.6 Hz, J2 = 2.0 Hz, 1H, H5′), 3.03−2.95 (m, 1H, H2′), 2.62 (ddd, J1
= 15.8 Hz, J2 = 7.3 Hz, J3 = 3.2 Hz, 1H, H2′), 1.15−1.13 (m, 21H); 13
C
1
(66 μL, 0.37 mmol): Rf (hexane/EtOAc, 4:6) 0.33; H NMR (2D
NMR (100 MHz, CDCl3) δ 166.3, 160.7, 150.0, 138.1, 137.5, 133.8,
I
dx.doi.org/10.1021/jo3014929 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
131.4, 129.7, 129.6, 128.8, 118.8, 118.7, 116.9, 86.4, 85.2, 76.6, 66.1,
35.4, 18.2, 18.1, 12.0; IR (neat) ν 3186, 3071, 2942, 2865, 1716, 1692,
1603, 1483, 1463, 1314, 1269, 1248, 1095, 773, 710 cm−1; HR-ESI MS
(m/z) [M + Na]+ calcd for C29H37BrN2O6SiNa 639.150 20, found
1′-(3′,5′-O-(Di-tert-butylsilylene)-2′-deoxy-α,β-D-ribofurano-
side)-6-bromoquinazoline-2,4-(3H)-dione (20α and 20β). Ac-
cording to the general procedure A, the inseparable isomer mixture of
nucleosides 20α and 20β (α/β = 1.8:1.0, 0.164 g, 50%) was obtained
as a white solid after column chromatography on silica gel (hexane/
EtOAc, 8:2) using 6-bromoquinazoline-2,4-(1H,3H)-dione 12 (0.190
g, 0.788 mmol), BSA (0.40 mL, 1.642 mmol), thioglycoside 9 (α/β =
1.0:1.8, 0.350 g, 0.657 mmol), NIS (0.177 g, 0.788 mmol), and
1
639.149 05. 17β: Rf (hexane/EtOAc, 7:3) 0.27; H NMR (2D COSY,
400 MHz, CDCl3) δ 9.79 (s, br, 1H), 8.33 (d, J1 = 2.1 Hz, 1H), 8.06
(d, J1 = 8.0 Hz, 2H), 7.91 (d, J1 = 9.1 Hz, 1H), 7.65 (dd, J1 = 8.7 Hz, J2
= 2.0 Hz, 1H), 7.58 (t, J1 = 7.6 Hz, 1H), 7.45 (t, J1 = 7.6 Hz, 2H), 6.92
(dd, J1 = 9.3 Hz, J2 = 6.3 Hz, 1H, H1′), 5.79−5.76 (m, 1H, H3′), 4.22−
4.11 (m, 3H, H4′, H5′ and H5′), 3.02−2.94 (m, 1H, H2′), 2.30 (dd, J1 =
15.3 Hz, J2 = 6.6 Hz, 1H, H2′), 1.16−1.11 (m, 21H); 13C NMR (100
MHz, CDCl3) δ 166.2, 160.8, 150.2, 138.5, 137.8, 133.5, 131.2, 129.9,
129.6, 128.6, 119.4, 118.6, 117.1, 84.3, 84.2, 73.3, 62.8, 34.2, 18.19,
18.17, 12.1; IR (neat) ν 3187, 3066, 2943, 2865, 1713, 1603, 1485,
1467, 1316, 1270, 1105, 773, 711 cm−1; HR-ESI MS (m/z) [M + Na]+
calcd for C29H37BrN2O6SiNa 639.150 20, found 639.149 48.
1
TMSOTf (71 μL, 0.394 mmol): Rf (hexane/EtOAc, 8:2) 0.23; H
NMR (2D COSY, 400 MHz, CDCl3) 20α, δ 9.77 (s, br, 1H), 8.35 (d,
J1 = 2.5 Hz, 1H), 7.75 (d, J1 = 2.5 Hz, 1H), 7.29 (d, J1 = 9.2 Hz, 1H),
6.45 (dd, J1 = 9.2 Hz, J2 = 6.4 Hz, 1H, H1′), 4.50−4.33 (m, 3H, H3′,
H4′ and H5′), 3.92 (dd, J1 = 9.7 Hz, J2 = 8.9 Hz, 1H, H5′), 3.09−3.02
(m, 1H, H2′), 2.53 (dt, J1 = 12.8 Hz, J2 = 6.5 Hz, 1H, H2′), 1.13−1.06
(m, 18H); 20β, δ 9.80 (s, br, 1H), 8.33 (d, J1 = 2.5 Hz, 1H), 7.73 (d, J1
= 2.5 Hz, 1H), 7.37 (d, J1 = 9.1 Hz, 1H), 6.39 (dd, J1 = 9.6 Hz, J2 = 3.6
Hz, 1H, H1′), 4.81 (q, J1 = 8.8 Hz, 1H, H3′), 4.50−3.37 (m, 1H, H5′),
4.10 (t, J1 = 10.4 Hz, 1H, H5′), 3.71 (ddd, J1 = 10.4 Hz, J2 = 8.9 Hz, J3
= 5.0 Hz, 1H, H4′), 2.90 (ddd, J1 = 6.5 Hz, J2 = 3.5 Hz, J3 = 2.1 Hz, 1H,
H2′), 2.32−2.28 (m, 1H, H2′), 1.13−1.06 (m, 18H); 13C NMR (100
MHz, CDCl3) δ 161.1, 161.0, 149.6, 149.1, 139.9, 139.7, 138.18,
138.15, 131.7, 131.5, 118.3, 118.2, 117.1, 116.9, 116.3, 116.5, 84.9,
84.2, 78.4, 77.6, 76.2, 75.5, 68.2, 67.5, 35.8, 34.4, 27.7, 27.6, 27.4, 27.3,
22.85, 22.82, 20.4, 20.3; IR (neat) ν 2967, 2934, 2893, 2859, 1700,
1603, 1472, 1316, 1052, 826, 772, 749, 426 cm−1; HR-ESI MS (m/z)
[M + Na]+ calcd for C21H29BrN2O5SiNa 519.092 68, found 519.091
74.
1′-(3′-O-p-Methoxybenzoyl-5′-O-triisopropylsilyl-2′-deoxy-
α-D-ribofuranoside)-6-bromoquinazoline-2,4-(3H)-dione (18α)
and 1′-(3′-O-p-Methoxybenzoyl-5′-O-triisopropylsilyl-2′-
deoxy-β-D-ribofuranoside)-6-bromoquinazoline-2,4-(3H)-
dione (18β). According to the general procedure A, the separable
isomer mixture of nucleosides 18α (0.072 g, 30%) and 18β (0.123 g,
50%) was obtained as off-white foams after column chromatography
on silica gel (hexane/EtOAc, 8:2 → 6:4) using 6-bromoquinazoline-
2,4-(1H,3H)-dione 12 (0.109 g, 0.452 mmol), BSA (0.23 mL, 0.942
mmol), thioglycoside 7 (α/β = 1.0:1.8, 0.20 g, 0.377 mmol), NIS
(0.102 g, 0.452 mmol), and TMSOTf (62 μL, 0.226 mmol). 18α: Rf
(hexane/EtOAc, 7:3) 0.38; 1H NMR (2D COSY, 400 MHz, CDCl3) δ
8.69 (s, br, 1H), 8.33 (d, J1 = 2.3 Hz, 1H), 8.02 (d, J1 = 8.8 Hz, 2H),
7.78 (d, J1 = 9.1 Hz, 1H), 7.61 (dd, J1 = 9.1 Hz, J2 = 2.4 Hz, 1H), 7.17
(t, J1 = 7.8 Hz, 1H, H1′), 6.99 (d, J1 = 8.8 Hz, 2H), 5.73 (d, J1 = 7.9 Hz,
1H, H3′), 4.54 (s, 1H, H4′), 4.14 (dd, J1 = 10.8 Hz, J2 = 1.8 Hz, 1H,
H5′), 4.03 (dd, J1 = 10.8 Hz, J2 = 2.1 Hz, 1H, H5′), 3.91 (s, 3H), 3.00−
2.92 (m, 1H, H2′), 2.59 (ddd, J1 = 14.9 Hz, J2 = 7.5 Hz, J3 = 3.2 Hz,
1H, H2′), 1.15−1.12 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 166.1,
164.1, 160.4, 149.8, 138.1, 137.6, 131.8, 131.4, 121.9, 118.9, 118.7,
116.9, 114.1, 86.5, 85.3, 76.3, 66.2, 55.7, 35.5, 18.21, 18.19, 12.0; IR
(neat) ν 2960, 2940, 2866, 1715, 1604, 1462, 1258, 1095, 772, 418
cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for C30H39BrN2O7SiNa
1′-(3′,5′-O-(Tetraisopropylsiloxane-1,3-diyl)-2′-deoxy-α-D-ri-
bofuranoside)-6-bromoquinazoline-2,4-(3H)-dione (21α). Ac-
cording to the general procedure A, the nucleosides 21α (0.139 g,
56%) was obtained as an off-white foam after column chromatography
on silica gel (hexane/EtOAc, 9:1 → 8:2) using 6-bromoquinazoline-
2,4-(1H,3H)-dione 12 (0.120 g, 0.497 mmol), BSA (0.26 mL, 1.035
mmol), thioglycoside 21 (α/β = 1.0:1.8, 0.200 g, 0.414 mmol), NIS
(0.112 g, 0.497 mmol), and TMSOTf (45 μL, 0.248 mmol). 21α: Rf
1
(hexane/EtOAc, 8:2) 0.23; H NMR (2D COSY and ROESY, 500
MHz, CDCl3) δ 9.53 (s, br, 1H), 8.34 (d, J1 = 2.5 Hz, 1H), 7.75 (dd, J1
= 9.1 Hz, J2 = 2.5 Hz, 1H), 7.49 (d, J1 = 9.1 Hz, 1H), 6.68 (dd, J1 = 9.8
Hz, J2 = 6.6 Hz, 1H, H1′), 4.69 (q, J1 = 7.5 Hz, 1H, H3′), 4.29 (sext, J1
= 3.6 Hz, 1H, H4′), 4.02 (dd, J1 = 12.1 Hz, J2 = 3.6 Hz, 1H, H5′), 3.88
(dd, J1 = 12.1 Hz, J2 = 7.0 Hz, 1H, H5′), 2.86−2.79 (m, 1H, H2′),
2.57−2.52 (m, 1H, H2′), 1.11−1.04 (m, 28H); 13C NMR (100 MHz,
CDCl3) δ 160.8, 150.1, 138.5, 137.9, 131.5, 118.6, 117.9, 117.0, 84.3,
84.1, 72.9, 63.5, 36.3, 17.7, 17.62, 17.60, 17.5, 17.4, 17.3, 17.2, 17.1,
13.6, 13.4, 13.1, 12.7, IR (neat) ν 2943, 2867, 1708, 1603, 1483, 1465,
1315, 1143, 1118, 1091, 885, 774, 705 cm−1; HR-ESI MS (m/z) [M +
Na]+ calcd for C25H39BrN2O6Si2Na 621.142 77, found 621.142 73.
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-α-D-
ribofuranoside)quinazoline-2,4-(3H)-dione (29α) and 1′-(3′-O-
Acetyl-5′-O-triisopropylsilyl-2′-deoxy-β-D-ribofuranoside)-
quinazoline-2,4-(3H)-dione (29β). According to the general
procedure A, the separable isomer mixture of nucleosides 29α
(0.065 g, 30%) and 29β (0.116 g, 53%) was obtained as off-white
foams after column chromatography on silica gel (hexane/EtOAc, 8:2
→ 6:4) using quinazoline-2,4-(1H,3H)-dione 24 (0.089 g, 0.547
mmol), BSA (0.28 mL, 1.14 mmol), thioglycoside 5 (α/β = 1.0:1.8,
0.20 g, 0.456 mmol), NIS (0.113 g, 0.502 mmol), and HOTf (16 μL,
0.182 mmol). 29α: Rf (hexane/EtOAc, 7:3) 0.29; 1H NMR (2D
COSY and ROESY, 400 MHz, CDCl3) δ 9.17 (s, br, 1H), 8.22 (dd, J1
= 7.9 Hz, J2 = 1.6 Hz, 1H), 7.73 (d, J1 = 7.8 Hz, 1H), 7.64−7.60 (m,
1H), 7.29−7.25 (m, 1H), 7.05 (t, J1 = 7.8 Hz, 1H, H1′), 5.53 (ddd, J1 =
8.5 Hz, J2 = 4.0 Hz, J3 = 2.5 Hz, 1H, H3′), 4.42 (d, J1 = 2.4 Hz, 1H,
H4′), 4.01 (dd, J1 = 10.8 Hz, J2 = 2.5 Hz, 1H, H5′), 3.96 (dd, J1 = 10.8
Hz, J2 = 2.8 Hz, 1H, H5′), 2.87−2.80 (m, 1H, H2′), 2.54 (ddd, J1 = 14.5
Hz, J2 = 7.6 Hz, J3 = 4.0 Hz, 1H, H2′), 2.14 (s, 3H), 1.16−1.08 (m,
21H); 13C NMR (100 MHz, CDCl3) δ 170.8, 161.9, 150.2, 139.3,
134.6, 129.0, 123.7, 117.0, 116.7, 86.1, 84.6, 75.7, 65.6, 35.1, 21.2,
18.16, 18.14, 12.0; IR (neat) ν 3210, 3065, 2942, 2856, 2363, 2363,
1704, 1687, 1609, 1483, 1386, 1313, 1231, 772, 686 cm−1; HR-ESI MS
(m/z) [M + Na]+ calcd for C24H36N2O6SiNa 499.22403, found
1
669.160 76, found 669.159 57. 18β: Rf (hexane/EtOAc, 7:3) 0.23; H
NMR (2D COSY, 400 MHz, CDCl3) δ 8.94 (s, br, 1H), 8.33 (d, J1 =
2.3 Hz, 1H), 8.01 (d, J1 = 8.8 Hz, 2H), 7.92 (d, J1 = 9.1 Hz, 1H), 7.65
(dd, J1 = 9.0 Hz, J2 = 2.3 Hz, 1H), 6.93 (d, J1 = 8.8 Hz, 1H), 6.89 (dd,
J1 = 9.8 Hz, J2 = 6.5 Hz, 1H, H1′), 5.75−5.72 (m, 1H, H3′), 4.19−4.12
(m, 3H, H4′, H5′ and H5′), 3.88 (s, 3H), 2.99−2.91 (m, 1H, H2′), 2.27
(dd, J1 = 14.1 Hz, J2 = 6.4 Hz, 1H, H2′), 1.20−1.11 (m, 21H); 13C
NMR (100 MHz, CDCl3) δ 165.9, 163.9, 160.5, 149.9, 138.5, 137.9,
132.0, 131.3, 122.0, 119.5, 118.6, 117.2, 113.9, 84.5, 84.3, 73.0, 62.9,
55.6, 34.3, 18.23, 18.21, 12.1; IR (neat) ν 2960, 2940, 2866, 1715,
1605, 1257, 1218, 1065, 772, 417 cm−1; HR-ESI MS (m/z) [M + Na]+
calcd for C30H39BrN2O7SiNa 669.160 76, found 669.159 68.
1′-(3′-O-(N-Acetyl)-glycyl-5′-O-triisopropylsilyl-2′-deoxy-β-
D-ribofuranoside)-6-bromoquinazoline-2,4-(3H)-dione (19β).
According to the general procedure A, nucleoside 19β (0.150 g,
41%) was obtained as an off-white foam after column chromatography
on silica gel (hexane/EtOAc, 1:9 → 0:1) using 6-bromoquinazoline-
2,4-(1H,3H)-dione 12 (0.175 g, 0.726 mmol), BSA (0.37 mL, 1.513
mmol), thioglycoside 8α or 8β (0.30 g, 0.605 mmol), NIS (0.164 g,
0.726 mmol), and TMSOTf (66 μL, 0.363 mmol). 19β: Rf (hexane/
EtOAc, 1:9) 0.24; 1H NMR (2D COSY, 400 MHz, CDCl3) δ 10.06 (s,
1H), 8.19 (d, J1 = 2.5 Hz, 1H), 7.80 (d, J1 = 9.1 Hz, 1H), 7.59 (dd, J1 =
9.1 Hz, J2 = 2.5 Hz, 1H), 6.73 (dd, J1 = 9.3 Hz, J2 = 6.2 Hz, 1H, H1′),
6.45 (t, J1 = 5.3 Hz, 1H), 5.59−5.56 (m, 1H, H3′), 4.08 (d, J1 = 5.4 Hz,
2H), 4.06−4.01 (m, 3H, H4′, H5′ and H5′), 2.90−2.82 (m, 1H, H2′),
2.19 (ddd, J1 = 14.1 Hz, J2 = 6.2 Hz, J3 = 2.1 Hz, 1H, H2′), 2.05 (s,
3H), 1.16−1.07 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 170.7,
169.9, 160.8, 150.2, 138.5, 137.7, 131.0, 119.2, 118.4, 117.0, 84.1, 84.0,
74.0, 62.7, 41.6, 33.9, 22.9, 18.11, 18.09, 12.0; IR (neat) ν 3225, 2943,
2866, 1706, 1603, 1484, 1467, 1187 cm−1; HR-ESI MS (m/z) [M +
Na]+ calcd for C26H38BrN3O7SiNa 634.156 01, found 634.155 05.
J
dx.doi.org/10.1021/jo3014929 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
499.22307. 29β: Rf (hexane/EtOAc, 7:3) 0.22; H NMR (2D COSY
and ROESY, 400 MHz, CDCl3) δ 9.54 (s, br, 1H), 8.22 (dd, J1 = 7.9
Hz, J2 = 1.6 Hz, 1H), 7.95 (d, J1 = 8.6 Hz, 1H), 7.60−7.56 (m, 1H),
7.28−7.25 (m, 1H), 6.85 (dd, J1 = 9.5 Hz, J2 = 6.7 Hz, 1H, H1′), 5.54
(ddd, J1 = 7.9 Hz, J2 = 4.1 Hz, J3 = 2.2 Hz, 1H, H3′), 4.09−4.03 (m,
3H, H4′, H5′ and H5′), 2.97−2.89 (m, 1H, H2′), 2.14 (dd, J1 = 6.3 Hz,
J2 = 2.2 Hz, 1H, H2′), 2.10 (s, 3H), 1.12−1.09 (m, 21H); 13C NMR
(100 MHz, CDCl3) δ 170.8, 161.9, 150.6, 139.5, 135.0, 128.8, 123.9,
117.5, 116.9, 84.2, 84.0, 72.9, 62.7, 33.9, 21.1, 18.17, 18.15, 12.1; IR
(neat) ν 3210, 3066, 2942, 2865, 1740, 1690, 1609, 1483, 1386, 1314,
1239, 772, 686 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C24H36N2O6SiNa 499.224 03, found 499.223 39.
113.2, 85.2, 84.1, 74.1, 63.2, 34.5, 21.2, 18.1, 18.1, 12.1; IR (neat) ν
3192, 3055, 2942, 2864, 1737, 1691, 1632, 1602, 1476, 1384, 1234,
1065, 881, 731, 682 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C28H38N2O6SiNa 549.239 68, found 549.238 71.
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-α,β-D-
ribofuranoside)thieno[3,2-d]pyrimidine-2,4-(3H)-dione (32α
and 32β). According to the general procedure A, the inseparable
isomer mixture of nucleosides 32α and 32β (α/β = 1.0:2.0, 0.16 g,
73%) was obtained as an off-white foam after column chromatography
on silica gel (hexane/EtOAc, 7:3 → 6:4) using thieno[3,2-
d]pyrimidine-2,4-(3H)-dione 27 (0.092 g, 0.547 mmol), BSA (0.28
mL, 1.14 mmol), thioglycoside 5 (α/β = 1.0:1.8, 0.20 g, 0.456 mmol),
NIS (0.113 g, 0.502 mmol), and HOTf (16 μL, 0.182 mmol): Rf
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-α,β-D-ribofur-
anoside)-5-methoxyquinazoline-2,4-(3H)-dione (30β and 30α).
According to the general procedure A, the inseparable isomer mixture
of nucleosides 30α and 30β (α/β = 1.0:1.7, 0.184 g, 80%) was
obtained as an off-white foam after column chromatography on silica
gel (hexane/EtOAc, 4:6 → 3:7) using 5-methoxyquinazoline-2,4-
(3H)-dione 25 (0.105 g, 0.547 mmol), BSA (0.28 mL, 1.14 mmol),
thioglycoside 5 (α/β = 1.0:1.8, 0.20 g, 0.456 mmol), NIS (0.112 g,
0.502 mmol), and HOTf (16 μL, 0.182 mmol): Rf (hexane/EtOAc,
3:7) 0.25; 1H NMR (2D COSY and ROESY, 500 MHz, CDCl3) 30α,
δ 9.24 (s, 1H), 7.46 (t, J1 = 8.6 Hz, 1H), 7.21 (d, J1 = 8.7 Hz, 1H), 6.89
(t, J1 = 7.9 Hz, 1H, H1′), 6.74−6.70 (m, 1H), 5.47−5.45 (m, 1H, H3′),
4.37−4.36 (m, 1H, H4′), 4.00−3.90 (m, 2H, H5′ and H5′), 3.89 (s,
3H), 2.77−2.10 (m, 1H, H2′), 2.54 (ddd, J1 = 14.4 Hz, J2 = 7.7 Hz, J3 =
4.3 Hz, 1H, H2′), 2.08 (s, 3H), 1.13−1.05 (s, 21H); 30β, δ 9.36 (s,
1H), 7.44−7.42 (m, 2H), 6.74−6.70 (m, 2H, H1′), 5.47−5.45 (m, 1H,
H3′), 4.00−3.90 (m, 3H, H4′, H5′, and H5′), 3.89 (s, 3H), 2.95−2.89
(m, 1H, H2′), 2.04 (s, 3H), 2.04−1.99 (m, 1H, H2′), 1.13−1.05 (m,
21H); 13C NMR (125 MHz, CDCl3) δ 178.6, 170.77, 170.75, 170.6,
161.6, 161.5, 160.4, 160.3, 150.3, 150.15, 150.14, 141.9, 141.7, 135.15,
135.12, 134.8, 109.4, 108.7, 86.3, 84.25, 84.24, 83.8, 75.3, 72.9, 65.2,
62.6, 56.4, 56.3, 34.7, 33.6, 21.0, 20.9, 17.99, 17.98, 11.9, 11.8; IR
(neat) ν 3221, 2942, 2865, 1706, 1599, 1489, 1270, 772 cm−1; HR-ESI
MS (m/z) [M + Na]+ calcd for C25H38N2O7SiNa 529.234 60, found
529.233 82.
1
(hexane/EtOAc, 7:3) 0.16; H NMR (2D COSY, 500 MHz, CDCl3)
32α, δ 9.45 (s, br, 1H), 7.73 (d, J1 = 5.4 Hz, 1H), 7.39 (d, J1 = 5.4 Hz,
1H), 6.87 (t, J1 = 7.3 Hz, 1H, H1′), 5.50−5.48 (m, 1H, H3′), 4.37 (d, J1
= 2.0 Hz, 1H, H4′), 4.00 (dd, J1 = 11.0 Hz, J2 = 2.2 Hz, 1H, H5′), 3.93
(dd, J1 = 10.8 Hz, J2 = 2.8 Hz, 1H, H5′), 2.94−2.87 (m, 1H, H2′),
2.34−2.28 (m, 1H, H2′), 2.09 (s, 3H), 1.16−1.09 (m, 21H); 32β, δ
9.60 (s, br, 1H), 7.81 (d, J1 = 5.4 Hz, 1H), 7.62 (d, J1 = 5.4 Hz, 1H),
6.72 (dd, J1 = 10.0 Hz, J2 = 5.4 Hz, 1H, H1′), 5.50−5.48 (m, 1H, H3′),
4.12 (dd, J1 = 11.3 Hz, J2 = 2.3 Hz, 1H, H5′), 4.06−3.98 (m, 2H, H4′
and H5), 2.56 (ddd, J1 = 17.8 Hz, J2 = 10.0 Hz, J3 = 7.8 Hz, 1H, H2′),
2.21 (dd, J1 = 13.9 Hz, J2 = 5.7 Hz, 1H, H2′), 2.10 (s, 3H), 1.16−1.09
(m, 21H); 13C NMR (125 MHz, CDCl3) δ 170.9, 170.7, 158.2, 158.0,
151.3, 151.0, 144.0, 134.7, 134.6, 120.2, 118.4, 115.6, 115.4, 86.6, 85.2,
84.8, 83.9, 75.6, 73.1, 65.6, 62.9, 36.7, 35.0, 21.2, 18.2, 18.1, 12.0; IR
(neat) ν 3187, 3057, 2942, 2865, 1740, 1698, 1486, 1236, 1220, 772
cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for C22H34N2O6SSiNa
505.180 45, found 505.179 42.
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-α-D-ribofura-
noside)-1,3-diaza-2-oxophenothiazine (33α) and 1′-(3′-O-Ace-
tyl-5′-O-triisopropylsilyl-2′-deoxy-β-D-ribofuranoside)-1,3-
diaza-2-oxophenothiazine (33β). According to the general
procedure A, the separable isomer mixture of nucleosides 33α
(0.040 g, 13%) and 33β (0.100 g, 33%) was obtained as yellow solids
after column chromatography on silica gel (hexane/EtOAc, 4:6 → 0:1)
using 1,3-diaza-2-oxophenothiazine 28 (0.148 g, 0.684 mmol), BSA
(0.35 mL, 1.425 mmol), thioglycoside 5 (α/β = 1.0:1.8, 0.25 g, 0.570
mmol), NIS (0.141 g, 0.627 mmol), and HOTf (20 μL, 0.228 mmol).
Compound 33α was precipitated in a mixture of hexane/EtOAc. 33α:
Rf (hexane/EtOAc, 2:8) 0.33; 1H NMR (2D COSY, 400 MHz,
CDCl3) δ 7.33 (s, 1H), 7.11−7.07 (m, 1H), 7.08−6.94 (m, 3H), 6.19
(d, J1 = 6.4 Hz, 1H, H1′), 5.32 (d, J1 = 6.0 Hz, 1H, H3′), 4.45 (t, J1 =
2.8 Hz, 1H, H4′), 3.92 (dd, J1 = 11.0 Hz, J2 = 2.6 Hz, 1H, H5′), 3.84
(dd, J1 = 11.0 Hz, J2 = 3.4 Hz, 1H, H5′), 2.88−2.81 (m, 1H, H2′), 2.27
(d, J1 = 15.3 Hz, 1H, H2′), 2.02 (s, 3H), 1.09−1.05 (m, 21H); 13C
NMR (100 MHz, CDCl3) δ 170.1, 158.2, 134.5, 134.2, 128.1, 126.3,
126.0, 118.6, 116.5, 96.0, 89.4, 88.9, 75.3, 64.3, 39.6, 21.2, 18.1, 12.0;
IR (neat) ν 2942, 2865, 1741, 1655, 1470, 1444, 1415, 1254, 1129,
1094, 1013, 882, 751 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd for
C26H37N3O5SSiNa 554.212 09, found 554.211 39. 33β: Rf (hexane/
EtOAc, 2:8) 0.20; 1H NMR (2D COSY, 400 MHz, CDCl3) δ 7.57 (s,
1H), 7.24 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 7.08−7.04 (m, 1H),
6.95−6.88 (m, 2H), 6.34 (dd, J1 = 8.8 Hz, J2 = 5.3 Hz, 1H, H1′), 5.32
(d, J1 = 6.2 Hz, 1H, H3′), 4.11 (d, J1 = 1.7 Hz, 1H, H4′), 3.99 (d, J1 =
2.0 Hz, 2H, H5′ and H5′), 2.59 (dd, J1 = 13.9 Hz, J2 = 5.0 Hz, 1H, H2′),
2.10−2.03 (m, 1H, H2′), 2.07 (s, 3H), 1.20−1.10 (m, 21H); 13C NMR
(100 MHz, CDCl3) δ 170.8, 160.8, 154.6, 135.9, 133.7, 127.7, 126.0,
124.6, 118.5, 116.7, 97.4, 86.5, 86.0, 75.5, 63.9, 39.1, 21.1, 18.2, 12.1;
IR (neat) ν 2941, 2864, 1741, 1654, 1623, 1593, 1435, 1419, 1232,
1192, 1120, 1006, 759, 682 cm−1; HR-ESI MS (m/z) [M + Na]+ calcd
for C26H37N3O5SSiNa 554.212 09, found 554.211 59.
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-α-D-
ribofuranoside)benzo[g]quinazoline-2,4-(3H)-dione (31α) and
1′-(3′-O-Acetyl-5′-O-triisopropylsilyl-2′-deoxy-β-D-
ribofuranoside)benzo[g]quinazoline-2,4-(3H)-dione (31β). Ac-
cording to the general procedure A, the separable isomer mixture of
nucleosides 31α (0.060 g, 25%) and 31β (0.107 g, 45%) was obtained
as off-white foams after column chromatography on silica gel (hexane/
EtOAc, 8:2 → 7:3) using benzo[g]quinazoline-2,4-(3H)-dione 26
(0.116 g, 0.547 mmol), BSA (0.28 mL, 1.14 mmol), thioglycoside 5
(α/β = 1.0:1.8, 0.20 g, 0.456 mmol), NIS (0.113 g, 0.502 mmol), and
1
HOTf (16 μL, 0.182 mmol). 31α: Rf (hexane/EtOAc, 7:3) 0.30; H
NMR (2D COSY, 400 MHz, CDCl3) δ 8.98 (s, br, 1H), 8.83 (s, 1H),
8.07 (s, 1H), 7.96 (d, J1 = 8.0 Hz, 1H), 7.82 (d, J1 = 8.2 Hz, 1H), 7.61
(td, J1 = 6.8 Hz, J2 = 1.1 Hz, 1H), 7.49 (td, J1 = 6.9 Hz, J2 = 1.1 Hz,
1H), 7.17 (t, J1 = 7.8 Hz, 1H, H1′), 5.62 (ddd, J1 = 8.6 Hz, J2 = 3.6 Hz,
J3 = 2.3 Hz, 1H, H3′), 4.55 (d, J1 = 2.3 Hz, 1H, H4′), 4.07 (dd, J1 = 10.7
Hz, J2 = 2.5 Hz, 1H, H5′), 4.01 (dd, J1 = 10.7 Hz, J2 = 2.8 Hz, 1H, H5′),
2.92−2.84 (m, 1H, H2′), 2.65 (ddd, J1 = 14.5 Hz, J2 = 7.5 Hz, J3 = 3.8
Hz, 1H, H2′), 2.21 (s, 3H), 1.16−1.12 (m, 21H); 13C NMR (100
MHz, CDCl3) δ 170.9, 161.8, 150.1, 136.6, 134.1, 130.9, 129.7, 129.5,
129.1, 127.6, 126.2, 116.6, 114.0, 86.6, 84.9, 76.2, 65.9, 34.9, 21.5, 18.2,
18.1, 12.1; IR (neat) ν 3191, 3060, 2941, 2865, 1739, 1709, 1684,
1632, 1602, 1474, 1230, 1122, 1013, 880, 743 cm−1; HR-ESI MS (m/
z) [M + Na]+ calcd for C28H38N2O6SiNa 549.239 68, found 549.238
1
97. 31β: Rf (hexane/EtOAc, 3:7) 0.20; H NMR (2D COSY, 400
MHz, CDCl3) δ 8.93 (s, br, 1H), 8.81 (s, 1H), 7.95 (d, J1 = 8.2 Hz,
1H), 7.92 (s, 1H), 7.83 (d, J1 = 8.2 Hz, 1H), 7.61 (td, J1 = 6.9 Hz, J2 =
1.2 Hz, 1H), 7.50 (td, J1 = 6.9 Hz, J2 = 1.1 Hz, 1H), 6.72 (t, J1 = 7.4
Hz, 1H, H1′), 5.57 (quint, J1 = 3.9 Hz, 1H, H3′), 4.20−4.16 (m, 1H,
H4′), 4.09−4.08 (m, 2H, H5′ and H5′), 3.32−3.24 (m, 1H, H2′), 2.20
(ddd, J1 = 14.2 Hz, J2 = 7.4 Hz, J3 = 3.7 Hz, 1H, H2′), 2.12 (s, 3H),
1.15−1.05 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 170.5, 161.9,
149.8, 136.7, 135.4, 131.0, 129.7, 129.4, 129.2, 127.9, 126.4, 116.3,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR, 13C NMR, 2D COSY, and 2D ROESY
spectra of compounds 2−33. This material is available free of
charge via the Internet at http://pubs.acs.org.
K
dx.doi.org/10.1021/jo3014929 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(35) Crich, D.; Pedersen, C. M.; Bowers, A. A.; Wink, D. J. J. Org.
Chem. 2007, 72, 1553.
(36) Young, R. J.; Shawponter, S.; Hardy, G. W.; Mills, G.
AUTHOR INFORMATION
Corresponding Author
*E-mail: luedtke@oci.uzh.ch
■
Tetrahedron Lett. 1994, 35, 8687.
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Notes
The authors declare no competing financial interest.
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and activators were tested. The use of a weaker activating agent such as
NBS resulted in lower yields and increased reaction times. A
temperature of 0 °C was found to be optimal, because lower
temperatures resulted in incomplete conversion and higher temper-
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ACKNOWLEDGMENTS
■
This work was made possible by support from the Swiss
National Science Foundation (#130074) and the University of
Zurich.
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