Organocatalytic Conversion of Nucleosides to Furanoid Glycals

Article abstract of DOI:10.1021/acs.joc.1c00555

A class of organocatalysts that are highly active for the conversion of 2′-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH, were shown to effectively mediate persilylation of 2′-deoxynucleosides

Full text of DOI:10.1021/acs.joc.1c00555

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Organocatalytic Conversion of Nucleosides to Furanoid Glycals
Edna Mao, Cheol K. Chung, Yining Ji, Yu-hong Lam, and Peter E. Maligres*
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ABSTRACT: A class of organocatalysts that are highly active for the
conversion of 2′-deoxynucleosides to furanoid glycals have been
discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH,
were shown to effectively mediate persilylation of 2′-deoxynucleosides
allowing the elimination of the nucleobase giving the corresponding
glycal. These mild conditions were demonstrated in the syntheses of
glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this
methodology.
Scheme 1. One-Step Eliminations to Form Furanoid Glycals
INTRODUCTION
■
Furanoid glycals are key intermediates in the syntheses of
nucleosides, carbohydrates, and their derivatives, which are
commonly investigated for antiviral, anticancer, and anti-
bacterial properties.1 In addition, furanoid glycals are easily
accessible sources of defined stereocenters, making them good
chiral building blocks for the synthesis of natural products and
biological molecules.2 As such, there has been considerable
effort toward the development of methods for forming these
glycals.2 Previously reported methods involve the installation
of the double bond of the glycal from a ribose or deoxyribose
derivative, through a base-mediated elimination of a leaving
group3 or activation and subsequent reductive elimination of
the 2 and 3 substituents.4 The molybdenum-catalyzed
intramolecular cyclo-isomerization of alkynols prepared via
multistep routes was also reported to form furanoid glycals.5
Many of these methods require undesirably harsh reaction
conditions and reagents such as those used in dissolving metal
reductions (lithium, sodium, or zinc), toxic reagents (selenium
compounds for oxidation/elimination), and involve cumber-
some multistep syntheses to arrive at the appropriate precursor
(such as the phenylselenyltetrahydrofurans, the alkynols for the
Mo-catalyzed cyclizations, and the furanosyl halides for
reductive eliminations) for the glycal-forming step.
formation of undesired polymeric byproducts. In addition,
there was a necessity to remove ammonia gas, which was
evolved over the course of the reaction since the reaction
between HMDS and ammonium sulfate is reversible. Failure to
remove the gas resulted in hindrance of the reaction and
decomposition, which posed a significant concern on a larger
scale. In addition, the aqueous workup can also result in the
undesired hydrolysis of the trimethylsilyl protecting groups,
especially with the extended operation time typically required
on a larger scale. Despite these shortcomings, we were
attracted to the simplicity and cost-effectiveness of this
approach. We sought to find reaction conditions for the
silylation and elimination of thymidine to form furanoid
glycals, which were milder, higher yielding, and reliable.
RESULTS AND DISCUSSION
■
The simplest preparation of furanoid glycals in the literature to
the best of our knowledge is a one-step reaction starting with
inexpensive (<$1/g), commercially available thymidine
(Scheme 1) by Pedersen et al.6 The reaction, using HMDS
and ammonium sulfate, presumably involves formation of the
powerful silylating agent bistrimethylsilyl sulfate from the
reaction of HMDS with ammonium sulfate followed by in situ
per-silylation of thymidine, resulting in the relatively quick
elimination of the nucleobase to form the glycal. However, this
method involved high temperatures, a large excess of HMDS
used as a solvent, and variable yields attributed to the
Received: March 8, 2021
Published: May 25, 2021
https://doi.org/10.1021/acs.joc.1c00555
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 7529−7536
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With the aforementioned goals in mind, an extensive screen
of catalysts was undertaken; selected results are shown (Table
1). Initially, (PhSO2)2NH showed promising results achieving
can mediate the transfer of the remaining trimethylsilyl group
from N-(trimethylsilyl)acetamide (MSA), the transfer of the
trimethylsilyl group from MSA is much slower requiring
extended heating, leading to decomposition. Thus, 1 equiv of
BSA per required silyl group transfer was used (2 equiv for
silylation to form bis-TMS-thymine 2a and 1 equiv of BSA for
silylation of each alcohol present in the nucleoside starting
material). The use of the more reactive and expensive N,O-
bis(trimethylsilyl)trifluoroacetamide (BSTFA) did not allow
the reduction of silylating agents required for reaction
completion.
Table 1. Selected Results from the Catalyst Screena
The addition of 2,6-lutidine or 2,4,6-collidine minimized the
acid-catalyzed elimination of 1 to the furan (Scheme 2) by
Scheme 2. Decomposition of Glycal
neutralization of trace adventitious acid. As a result, rapid
conversion with a virtually quantitative yield, independent of
the reaction scale, was observed for the formation of the bis-
trimethylsilyl glycal 1 from thymidine on a >100 g scale. Glycal
1 was found to be unstable to storage unless a base is added to
suppress the facile elimination to the furan. An array of
commercially available deoxynucleosides was also subjected to
the optimized reaction conditions to further demonstrate the
scope of this method (Table 2).
a
Reaction conditions: 4.0 equiv of HMDS in 10 vol toluene at reflux.
b
Conversion by HPLC area % (210 nm) monitoring conversion of
c
thymidine to thymine (after sample hydrolysis). Reaction mixture
discoloration was observed with the formation of varying amounts
d
(20−40%) of polymeric byproducts. X refers to the carbonyl on the
e
Table 2. Formation of Bis-TMS Glycal from
Deoxynucleosides
saccharin. 15−25% formation of a bis-glycosylated byproduct was
f
observed. 50% formation of a bis-glycosylated byproduct was
g
observed. Entry 5: pentafluorophenol (X = O), pentafluorothiophe-
nol (X = S); entry 6: benzamide (X = O), thiobenzamide (X = S),
selenobenzamide (X = Se); entry 7: urea (X = O), thiourea (X = S),
selenourea (X = Se); entry 8: [Ph2PO]2NH (X = O), [Ph2PS]2NH 5a
(X = S), [Ph2PSe]2NH 5b (X = Se).
high conversion with only a 1 mol % catalyst, but the assay
yield was <80% due to the formation of a bis-glycosylated
impurity,7 necessitating vacuum distillation for isolation of
pure 1. After further screening, we found the thio-derivatives to
be more active catalysts than the oxy-derivatives (entries 4−6,
Table 1), likely due to the better silylating ability of the TMS-
thio analogues. A further boost in catalytic activity was
observed going from the thio- to the seleno-derivatives (entries
7 and 8, Table 1). The dithiophosphorimide 5a (X = S, entry
8, Table 1) was identified as a highly active silyl transfer
catalyst, which was effective for the formation of glycals as low
as 0.5 mol %. The diselenophosphorimide 5b (X = Se, entry 8,
Table 1) was even more active giving full conversion even with
a 0.05 mol % catalyst. The assay yields of glycal 1 from
thymidine using 5a or 5b were >98%. To the best of our
knowledge, these organocatalysts have not been previously
reported to demonstrate any activity in silylations. Instead,
they have primarily been used as ligands for inorganic and
organometallic chemistry.8
BSA
assay
a
entry
nucleoside (2′-deoxy)
thymidine 2
deoxyuridine 6
nucleobase
(equiv)
% yield
1
2
3
4
2b
6a
7a
8a
4.5
4.5
4.5
3.5
10
3.5
4.5
5.5
>98
87
97
74
82
85
0
deoxycytidine 7
N4-acetyldeoxycytidine 8
deoxyguanosine 9
deoxyinosine 10
b
5
9a
6
7
8
10a
11a
12a
deoxyadenosine 11
N2-isobutyryldeoxyguanosine
0
12
9
3-methylthymidine 2c
2d
4.5
0
Additionally, since effectively eliminating ammonia gener-
ated from HMDS was challenging, an alternative silylating
agent was desired. We identified N,O-bis(trimethylsilyl)-
acetamide (BSA) as a suitable silylating agent, which did not
raise such issues upon reaction scale-up. Although the catalyst
a
Assay yield determined by quantitative 1H NMR of the crude
reaction mixture, glycal peaks integrated against the internal standard
(2,6-lutidine). All reactions reached >99% conversion. Commercially
available deoxyguanosine is a hydrate with variable amounts of
moisture; thus, use of 5 equiv of BSA resulted in low conversion.
b
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To our delight, pyrimidine-based deoxynucleosides 2, 6, 7,
and 8 reacted smoothly to give the glycal 1 in 87−98% yields.
Previously, Pedersen et al.’s reported method6 did not result in
glycal formation from purine nucleosides. In agreement with
the literature, 2′-deoxyadenosine 11 did not yield any glycal.
Interestingly, under these reaction conditions, purine nucleo-
sides deoxyguanosine 9 and deoxyinosine 10 smoothly
produced glycal. In contrast, the N2-protected deoxyguanosine
12 and the N-methylated thymidine 2c did not result in any
observable conversion. While the nucleobases on 11, 12, and
2b are potentially able to be silylated to generate the positively
charged ion, this alone is not enough to affect the elimination,
indicating the dependence on the ease of the persilylated
cationic nucleoside intermediate for the elimination to
proceed.
Despite the labile TMS groups, 1 can withstand the aqueous
workup at smaller scales. However, some desilylation as well as
decomposition of the glycal to the furan side product inevitably
occurs (Scheme 2), especially after silica gel chromatography.
The loss of the TMS groups from 1 during aqueous workup
can be avoided by the addition of iPrOH, which in the
presence of catalyst 5a desilylates MSA forming the volatile
iPrOTMS and acetamide, which can simply be removed by
filtration after dilution with hexane. Then, evaporation afforded
the pure glycal without chromatographic purification.
substrates, requiring 24 h for full conversion, potentially due to
ring strain in the glycal. Trityl-protected glycals, which have
not been previously synthesized in this fashion, also produced
products, although glycal 19a was obtained in a much lower
yield than glycal 20a due to the instability of the trimethylsilyl
group. Thus, a variety of protected glycals can be synthesized
from easily accessible precursors. In accordance with a
previous report of this reaction using HMDS and ammonium
sulfate,6 thymidine 21 bearing a 3′-ester group did not
successfully convert to glycal even under our basic reaction
conditions; instead, crude NMR shows the full conversion of
the starting material into its furfuryl alcohol derivative
(Scheme 2).
Subsequently, we explored a few differentially substituted
nucleosides (Table 4). 5′-Silylated 2′,3′-dideoxythymidine 22
gave the corresponding 3′-deoxyglycal in excellent yield. The
glycal was also much more stable than its 3′-hydroxy
counterparts, and no decomposition to furfuryl alcohol was
observed even upon extended storage at room temperature due
to the lack of the leaving group at the 3′ position. 3′-Azido
thymidine (AZT) 23 did not give any glycal product due to
elimination to form the furan. In contrast to deoxynucleosides
21 and 23, the 3′-Boc-protected amine 24 readily formed the
glycal in a modest 73% yield, and the minimal elimination
product was observed throughout the reaction and upon
workup. 5′O-Tritylated deoxythymidine in the xylo config-
uration (25) formed the product also, resulting in a glycal with
a 5′,3′-syn configuration. The 2′-α and -β fluoro uridines 26
and 27 resulted in no conversion under the reaction
conditions. In theory, the electron-withdrawing fluoro
substituent should lower the pKa of the 2′-proton, enhancing
reactivity. However, the substitution of the 2′-position from a
hydrogen to a fluorine enhances the stability of the N-
glycosidic bond,9 and this effect seems to dominate. Similarly,
the N-glycosidic bond is also stronger in a ribonucleoside than
a deoxynucleoside. Accordingly, ribo-thymidines 28 and 29
both failed to give any conversion. In contrast, a methyl
substituent on the 2′-position allowed the reaction to proceed.
A 2:1 mixture of diastereomers of 30 was subjected to the
reaction, giving glycal 30a in a modest 70% yield due to
decomposition of 30a during the workup forming the furan.
The major (alpha/beta) methyl isomer was consumed more
rapidly than the minor diastereomer likely due to steric effects;
full conversion to glycal was seen after 24 h. This indicates that
the mechanism likely involves simple E2 elimination of the
positively charged bis-silylated nucleobase or proceeds via an
oxonium ion intermediate where either of the 2′-protons can
be abstracted to give the glycal.
Early mechanistic studies were conducted to better under-
stand the reactivity of the dithiophosphorimide catalyst (Figure
1). The energies of the silylated versions of [Ph2PS]2NH and
its phosphine oxide equivalent [Ph2PO]2NH were compared.
It was found that the Si−S bond is weaker than the Si−O
bond, such that the thiophosphorimide was preferentially
silylated at the N-position, while the oxo derivative prefers to
be silylated at the oxygen. Additionally, the DFT-computed
energetics of proton transfer between [Ph2PO]2NH and 5a
predicted 5a to be more acidic by 3.8 pKa units in toluene,
making 5a a superior leaving group during the silyl transfer
reaction (see the Supporting Information). Furthermore, the
diselenophosphorimide 5b was predicted to be more acidic
than 5a by 1.7 pKa units, suggesting that the selenium
derivative should be even more active than the sulfur-based
Next, we examined the reactivity of nucleosides differentially
protected on the ribose (Table 3). All the protected
Table 3. Differentially Protected Glycals
deoxynucleoside/
glycal
BSA
(equiv)
isolated
% yield
entry
R1
R2a
1
2
3
4
5
13/13a
14/14a
15/15a
16/16a
17/17a
18/18a
19/19a
20/20a
21/21a
TBDMS
TBDMS
TBDPS
TBDPS
TBDPS
TIPDS
trityl
H/TMS
TBDMS
H/TMS
TBDPS
TBDMS
TIPDS
H/TMS
TBDMS
Piv
3.5
2.5
3.5
2.5
2.5
2.5
3.5
2.5
3.5
63
93
91
89
89
70
53
85
b
6
7
8
9
trityl
trityl
c
0, (82)
a
Deoxynucleoside starting material with an unprotected hydroxyl
group is trimethylsilylated over the course of the reaction. The silyl
b
groups are retained during workup of the glycal. Reaction complete
c
after 24 h. No glycal product was observed, even with 1 equiv of
triethylamine added to the reaction as a base to prevent elimination to
the furan; 82% of tritylfurfuryl ether was isolated.
nucleosides were either commercially available or readily
synthesized from commercial materials. Reactions with 5′ and
3′ silyl-protected thymidines proceeded smoothly, giving full
conversion in less than 3 h. In general, TBDPS-protected
glycals gave higher yields than their TBDMS-protected
counterparts, perhaps owing to the differences in the
robustness of the protecting groups. The cyclic 1,1,3,3-
tetraisopropyl-1,3-disiloxanediyl (TIPDS)-protected deoxyur-
idine 18 was also eliminated to give the protected glycal in 70%
yield, although the reaction was considerably slower than other
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Table 4. Differentially Substituted Nucleosides
a
entry
nucleoside/glycal
R1
R2
R3
BSA (equiv)
isolated % yield
a
1
2
3
4
22/22a
23/23a
24/24a
25/25a
26/26a
27/27a
28/28a
29/29a
TBDPS
H
H/TMS
trit
H
H
H
H
TIPDS
H
N3
NHBoc
β-OH
β-OH
β-OH
β-OH
α-OH
OTIPDS
H
H
H
H
β-F
α-F
β-OH
α-OH
2.5
3.5
4.5
3.5
3.5
3.5
5.5
5.5
2.5
92
f
0, (83)
a
73
a
83
c
b
5
6
0
0
0
0
c
b
b
7
8
9
b
c
e
d
a
30/30a
Me
70
a
b
c
d
e
Isolated yield. Assay yield (HPLC, NMR) after 24−48 h. Nucleobase was uracil. 3:1 mixture of diastereomers. Reaction complete after 24 h.
f
No glycal product was observed, even with 1 equiv of triethylamine added to the reaction mixture as a base to prevent elimination to the furan;
83% of furfuryl alcohol was isolated as its TMS ether.
Chem Impex International, Sigma-Aldrich, Carbosynth, Angene, AK
Scientific, Activate Scientific). Organocatalysts 5a and 5b10 and
nucleosides 13,6b 14,6b 15,6b 16,6b 17,6b 20,11 and 2412 were
synthesized according to literature procedures. Glycals 1,6a 13a,13
14a,6b 15a,6a 16a,6b 17a,6b 18a,14 and 22a15 are known in the
literature and were compared to reported data. Infrared spectra were
recorded on a Nicolet 6700 FT-IR spectrometer and are reported in
1
reciprocal centimeters (cm−1). H NMR spectra were recorded on a
Bruker 400, 500, or 600 MHz spectrometer. Chemical shifts are
reported in parts per million (ppm) referenced to the residual solvent
resonance (CDCl3: δ 7.24, CD2Cl2: δ 5.32). Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), integration, and coupling
constants (Hz). 13C NMR spectra were recorded on a Bruker 101 or
Figure 1. Energy calculations for the organocatalyst and related
derivatives.
126 MHz spectrometer with complete proton decoupling. Chemical
shifts are reported in ppm from tetramethylsilane with the solvent as
the internal reference (CDCl3: δ 77.0, CD2Cl2: δ 53.84, CD3CN: δ
1.93). Chromatography was performed using a Teledyne ISCO
catalyst, which was confirmed experimentally also, effectively
Combiflash Rf 200i with RediSep Rf Gold-prepacked silica gel
catalyzing the reaction at 0.05 mol %. Preliminary experiments
columns. HRMS data was obtained on a Bruker Solarix FT-ICR MS.
also revealed that the dithiophosphorimide catalyst is able to
catalyze the trimethylsilylation of hindered secondary and
tertiary alcohols in the presence of BSA or HMDS under mild
conditions and will be reported in due course.
All samples were introduced to the system via direct infusion
(infusion rate 180 μL/h) and analyzed under ESI positive mode.
General Procedure for the Formation of Bis-TMS-Glycal 1
for the Catalyst Screen. In an 8 mL vial, deoxynucleoside (1
mmol), catalyst (0.01 equiv, 5 mg), 2,6-lutidine (0.5 equiv, 58 μL), 1
mL of heptane, 1 mL of toluene, and the specified amount of BSA
were added under a nitrogen atmosphere. The reaction was stirred at
100 °C for 3 h. Reaction progress was monitored via HPLC by the
presence of the starting material. NMR of the crude reaction mixture
was taken in deuterated methylene chloride, and the internal standard
(2,6-lutidine) was used to determine the assay yield.
Trimethyl(((2R,3S)-3-((trimethylsilyl)oxy)-2,3-dihydrofuran-2-yl)-
methoxy)silane (1). 1H NMR (400 MHz, CD2Cl2) δ 6.52 (d, J = 2.7
Hz, 1H), 5.08 (t, J = 2.6 Hz, 1H), 4.87 (t, J = 2.5 Hz, 1H), 4.32 (td, J
= 6.4, 2.6 Hz, 1H), 3.60 (ddd, J = 83.6, 10.6, 6.4 Hz, 2H), 0.20 (s,
9H), 0.19 (s, 9H). 13C NMR (101 MHz, CD2Cl2) δ 149.5, 104.0,
89.3, 76.3, 62.7, −0.3, −0.5.
General Procedure for Synthesis of Glycals. In an 8 mL vial,
deoxynucleoside (1 mmol), catalyst (0.01 equiv, 5 mg), 2,6-lutidine
(0.5 equiv, 58 μL), 1 mL of heptane, 1 mL of toluene, and the
specified amount of BSA were added under a nitrogen atmosphere.
The reaction was stirred at 100 °C until completion. Reaction
progress was monitored via HPLC and NMR of the crude mixture by
the presence of the starting material. After the starting material was
completely consumed, the reaction mixture was extracted with
methylene chloride and water. The organic layer was washed four
to five times with water and once with brine and then dried over
CONCLUSIONS
■
In summary, we report an updated method on the silylation-
elimination reaction of deoxynucleosides to form furanoid
glycals. This reaction is mediated by a highly effective
organocatalyst with unprecedented silyl transfer activity. The
developed conditions are mild and scalable, allowing access to
large quantities of a variety of protected and differentially
substituted glycals, which are highly useful precursors for the
syntheses of nucleosides and other biomolecules. The
preparation of several unnatural nucleosides using these glycals
will be reported in due course. Since the new conditions
require a minimal amount of catalyst and produce virtually
pure products, the unstable glycals can often be used without
further purification.
EXPERIMENTAL SECTION
■
General Information. Solvents and reagents were purchased
from commercial sources and used as received. Nucleosides 2, 6, 7, 8,
9, 10, 11, 18, 19, 23, 25, 26, 27, 28, and 29 were purchased from
commercial sources (Combi-Blocks, Alfa Aesar, Acros Organics,
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anhydrous sodium sulfate. The organic phase was passed through a
plug of neutral alumina and washed with two volumes of heptane. The
filtrate was concentrated in vacuo to give the product. (Glycal
products not bearing TMS ethers can also be purified by column
chromatography.) The crude reaction mixture was directly injected
onto a prepacked column and eluted with hexanes with 1%
triethylamine.
tert-Butyldimethyl(((2R,3S)-3-((trimethylsilyl)oxy)-2,3-dihydro-
furan-2-yl)methoxy)silane (13a). 13a was prepared according to the
general procedure from 13 (1 mmol, 356 mg) to yield a colorless oil
(190 mg, 63%). FT-IR (ATR, neat): 1610, 1485, 1440, 1260, 1080
cm−1. 1H NMR (500 MHz, CD2Cl2) δ 6.47 (d, J = 2.6 Hz, 1H), 5.02
(t, J = 2.6 Hz, 1H), 4.84 (t, J = 2.5 Hz, 1H), 4.25 (td, J = 6.1, 2.6 Hz,
1H), 3.68 (dd, J = 10.6, 5.7 Hz, 1H), 3.49 (dd, J = 10.6, 6.5 Hz, 1H),
0.90 (s, 9H), 0.13 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). 13C{1H} NMR
(126 MHz, CD2Cl2) δ 149.5, 103.9, 89.4, 76.1, 63.3, 26.2, 18.1, 0.6,
−5.10, −5.13.
Trimethyl(((2R,3S)-2-((trityloxy)methyl)-2,3-dihydrofuran-3-yl)-
oxy)silane (19a). 19a was prepared according to the general
procedure from 19 (1 mmol, 471 mg) to yield a pale yellow oil
(230 mg, 53%). FT-IR (ATR, neat): 1610, 1495, 1450, 1250, 1075
cm−1. 1H NMR (500 MHz, CD2Cl2) δ 7.66−7.17 (m, 15H), 6.55 (d,
J = 2.5 Hz, 1H), 5.05 (t, J = 2.6 Hz, 1H), 4.83 (t, J = 2.4 Hz, 1H),
4.34 (td, J = 5.2, 3.0 Hz, 1H), 3.15 (d, J = 5.3 Hz, 2H), 0.07 (s, 9H).
13C{1H} NMR (126 MHz, CD2Cl2) δ 149.7, 144.5, 129.2, 128.5,
128.4, 127.7, 127.6, 104.2, 88.4, 76.6, 64.3, 0.6. HRMS (ESI/FT-ICR)
m/z: [M + Na]+ calcd for C27H30NaO3Si+ 453.1856; found 453.1854.
tert-Butyldimethyl(((2R,3S)-2-((trityloxy)methyl)-2,3-dihydrofur-
an-3-yl)oxy)silane (20a). 20a was prepared according to the general
procedure from 20 (1 mmol, 585 mg) to yield a colorless oil (400 mg,
1
85%). FT-IR (ATR, neat): 1610, 1450, 1250, 1080 cm−1. H NMR
(500 MHz, CD2Cl2) δ 7.79−7.06 (m, 15H), 6.59 (d, J = 2.5 Hz, 1H),
5.10 (t, J = 2.6 Hz, 1H), 4.89 (t, J = 2.4 Hz, 1H), 4.37 (td, J = 5.2, 3.1
Hz, 1H), 3.19 (h, J = 5.5 Hz, 1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s,
3H). 13C{1H} NMR (126 MHz, CD2Cl2) δ 149.6, 144.5, 129.2,
128.5, 128.4, 127.7, 127.6, 104.3, 88.6, 77.0, 64.4, 26.2, 18.5, −4.0,
−4.2. HRMS (ESI/FT-ICR) m/z: [M + Na]+ calcd for
C30H36NaO3Si+ 495.2326; found 495.2323.
(S)-tert-Butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane
(22a). 22a was prepared according to the general procedure from 22
(0.6 mmol, 279 mg). The crude reaction mixture was directly purified
by column chromatography on silica gel with hexanes and 1%
triethylamine, to yield a colorless oil (186 mg, 92%). FT-IR (ATR,
neat): 1620, 1425, 1120, 1050 cm−1. 1H NMR (400 MHz, CD2Cl2) δ
7.84−7.24 (m, 10H), 6.28 (q, J = 2.4 Hz, 1H), 4.87 (q, J = 2.5 Hz,
1H), 4.66 (ddt, J = 10.5, 7.3, 5.3 Hz, 1H), 3.86−3.60 (m, 1H), 2.65
(ddt, J = 15.2, 10.5, 2.3 Hz, 1H), 2.46 (ddt, J = 15.2, 7.4, 2.4 Hz, 1H),
1.06 (s, 9H). 13C{1H} NMR (101 MHz, CD2Cl2) δ 145.6, 136.2,
135.5, 134.3, 130.2, 128.2, 99.6, 81.9, 66.6, 31.7, 27.2, 19.7.
tert-Butyl(((2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-
furan-2-yl)methoxy)dimethylsilane (14a). 14a was prepared accord-
ing to the general procedure from 14 (1 mmol, 471 mg) to yield a
colorless oil (320 mg, 93%). FT-IR (ATR, neat): 1615, 1475, 1465,
1
1250, 1080 cm−1. H NMR (500 MHz, CD2Cl2) δ 6.47 (dd, J = 2.6,
0.8 Hz, 1H), 5.01 (t, J = 2.6 Hz, 1H), 4.87 (td, J = 2.6, 0.8 Hz, 1H),
4.29 (td, J = 6.0, 2.8 Hz, 1H), 3.69 (dd, J = 10.7, 5.7 Hz, 1H), 3.51
(dd, J = 10.7, 6.3 Hz, 1H), 0.90 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H),
0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (126 MHz,
CD2Cl2) δ 149.1, 103.6, 89.1, 76.1, 63.0, 26.1, 26.0, 18.5, 18.2, −4.1,
−4.3, −5.2, −5.2.
tert-Butyldiphenyl(((2R,3S)-3-((trimethylsilyl)oxy)-2,3-dihydrofur-
an-2-yl)methoxy)silane (15a). 15a was prepared according to the
general procedure from 15 (1 mmol, 481 mg) to yield a colorless oil
(390 mg, 91%). FT-IR (ATR, neat): 1610, 1430, 1250, 1080 cm−1
.
1H NMR (500 MHz, CD3CN) δ 7.70 (m, 4H), 7.51−7.37 (m, 6H),
tert-Butyl((2S,3S)-2-(hydroxymethyl)-2,3-dihydrofuran-3-yl)-
carbamate (24a). 24a was prepared according to the general
procedure from 24 (1 mmol, 485 mg) to yield a yellow oil (157 mg,
6.54 (d, J = 2.6 Hz, 1H), 5.08 (t, J = 2.6 Hz, 1H), 4.95 (m, 1H), 4.30
(td, J = 5.5, 2.8 Hz, 1H), 3.73 (dd, J = 11.0, 5.6 Hz, 1H), 3.67 (dd, J =
11.0, 5.3 Hz, 1H), 1.08 (s, 9H), 0.14 (s, 9H). 13C{1H} NMR (126
MHz, CD3CN) δ 149.0, 135.5, 133.3, 133.3, 129.9, 127.8, 117.3,
103.7, 88.8, 75.4, 63.7, 26.2, 18.9, −0.6.
1
73%). FT-IR (ATR, neat): 1710, 1695, 1380, 1250, 1055 cm−1. H
NMR (400 MHz, CD2Cl2) (rotamers) δ 6.71−6.24 (m, 1H), 4.95 (t,
J = 2.2 Hz, 1H), 4.86−4.48 (m, 2H), 4.41−4.13 (m, 1H), 3.92−3.60
(m, 2H), 1.46 (s, 9H), 0.16 (s, 9H). 13C{1H} NMR (101 MHz,
CD2Cl2) (rotamers) δ 149.41, 147.92, 102.06, 101.03, 89.58, 85.89,
80.58, 64.38, 60.31, 28.70, 27.74, 1.86, −0.23. HRMS (ESI/FT-ICR)
m/z: [M + Na]+ calcd for C13H25NNaO4Si+ 310.1445; found
310.1447.
tert-Butyl(((2R,3S)-3-((tert-butyldiphenylsilyl)oxy)-2,3-dihydro-
furan-2-yl)methoxy)diphenylsilane (16a). 6a was prepared accord-
ing to the general procedure from 16 (1 mmol, 705 mg) to yield a
yellow oil (530 mg, 89%). FT-IR (ATR, neat): 1610, 1430, 1110,
1
1080 cm−1. H NMR (500 MHz, CD3CN) δ 7.66−7.62 (m, 4H),
7.55−7.51 (m, 4H), 7.45−7.32 (m, 12H), 6.51 (d, J = 2.2 Hz, 1H),
4.94 (dt, J = 2.8, 0.9 Hz, 1H), 4.91 (t, J = 2.6 Hz, 1H), 4.42 (ddd, J =
5.7, 4.3, 2.9 Hz, 1H), 3.42 (dd, J = 11.1, 4.0 Hz, 1H), 3.36 (dd, J =
11.1, 4.0 Hz, 1H), 1.01 (s, 9H), 0.90 (s, 9H). 13C{1H} NMR (126
MHz, CD3CN) δ 150.5, 136.7, 136.6, 136.4, 136.4, 134.8, 134.7,
134.2, 134.2, 130.9, 130.9, 130.8, 128.8, 128.7, 128.7, 118.3, 104.3,
89.9, 77.9, 64.8, 27.3, 27.1, 19.7, 19.5.
Trimethyl(((2R,3R)-2-((trityloxy)methyl)-2,3-dihydrofuran-3-yl)-
oxy)silane (25a). 25a was prepared according to the general
procedure from 25 (1 mmol, 485 mg) to yield a colorless oil (356
mg, 83%). FT-IR (ATR, neat): 1610, 1490, 1450, 1250, 1050 cm−1.
1H NMR (500 MHz, CD2Cl2) δ 7.76−7.10 (m, 15H), 6.61 (d, J = 2.6
Hz, 1H), 5.07 (t, J = 2.6 Hz, 1H), 4.79 (dd, J = 6.7, 2.5 Hz, 1H), 4.40
(td, J = 8.0, 3.4 Hz, 1H), 3.42 (dd, J = 10.7, 8.3 Hz, 1H), 3.23 (dd, J =
10.7, 3.4 Hz, 1H), −0.08 (s, 9H). 13C{1H} NMR (126 MHz, CD2Cl2)
δ 150.0, 144.7, 129.3, 128.4, 127.6, 104.6, 84.6, 73.7, 63.2, 0.1. HRMS
(ESI/FT-ICR) m/z: [M + Na]+ calcd for C27H30NaO3Si+ 453.1856;
found 453.1853.
tert-Butyldiphenyl(((2R,3S)-3-((trimethylsilyl)oxy)-2,3-dihydrofur-
an-2-yl)methoxy)silane (17a). 17a was prepared according to the
general procedure from 17 (1 mmol, 595 mg) to yield a colorless oil
(416 mg, 89%). FT-IR (ATR, neat): 1610, 1475, 1465, 1430, 1250,
1
1080 cm−1. H NMR (500 MHz, CD2Cl2) δ 7.79−7.08 (m, 10H),
(6aR,9aS)-2,2,4,4-Tetraisopropyl-9-methyl-6a,9a-dihydro-6H-
furo[3,2-f ][1,3,5,2,4]trioxadisilocine (30a). 30a was prepared
according to the general procedure from 30 (0.725 mmol, 352 mg)
to yield a colorless oil (188 mg, 70%). FT-IR (ATR, neat): 1680,
1465, 1080 cm−1. 1H NMR (500 MHz, CD2Cl2) δ 6.15 (s, 1H), 5.07
(d, J = 4.3 Hz, 1H), 4.38 (dt, J = 10.9, 4.6 Hz, 1H), 4.13 (dd, J = 11.0,
4.6 Hz, 1H), 3.65 (t, J = 11.1 Hz, 1H), 1.71 (s, 3H), 1.36−0.96 (m,
28H). 13C{1H} NMR (126 MHz, CD2Cl2) δ 142.0, 111.5, 88.4, 80.5,
64.4, 29.0, 17.4, 17.3, 17.2, 17.0, 16.9, 16.7, 16.7, 13.9, 13.7, 13.6,
13.2, 12.5. HRMS (ESI/FT-ICR) m/z: [M + Na]+ calcd for
6.48 (d, J = 2.5 Hz, 1H), 5.04 (t, J = 2.6 Hz, 1H), 4.94 (t, J = 2.3 Hz,
1H), 4.32 (td, J = 5.4, 2.9 Hz, 1H), 3.71 (dd, J = 10.9, 5.6 Hz, 1H),
3.64 (dd, J = 10.9, 5.3 Hz, 1H), 1.05 (s, 9H), 0.88 (s, 9H), 0.07 (s,
6H). 13C{1H} NMR (126 MHz, CD2Cl2) δ 149.6, 136.2, 134.0,
130.3, 128.3, 104.2, 89.7, 76.6, 64.4, 27.1, 26.2, 19.7, 18.5, −4.0, −4.2.
1,4-Anhydro-2-deoxy-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-
1,3-diyl)-D-erythro-pent-1-entiol (18a). 18a was prepared according
to the general procedure from 18 (1 mmol, 471 mg) to yield a yellow
oil (250 mg, 70%). FT-IR (ATR, neat): 1620, 1470, 1385, 1250, 1085
cm−1. 1H NMR (400 MHz, CD2Cl2) δ 6.43 (dd, J = 2.6, 1.4 Hz, 1H),
5.27 (ddd, J = 4.1, 2.4, 1.5 Hz, 1H), 5.06 (t, J = 2.6 Hz, 1H), 4.37 (dt,
J = 11.3, 4.5 Hz, 1H), 4.13 (dd, J = 11.0, 4.6 Hz, 1H), 3.59 (t, J = 11.2
Hz, 1H), 1.27−0.83 (m, 28H). 13C{1H} NMR (101 MHz, CD2Cl2) δ
148.8, 103.3, 89.0, 78.4, 64.6, 18.0, 17.8, 17.8, 17.6, 17.5, 17.4, 17.3,
17.2, 14.2, 13.8, 13.5, 13.1.
+
C18H36NaO4Si2 395.2044; found 395.2043.
Larger-Scale Preparation of Trimethyl(((2R,3S)-3-
((trimethylsilyl)oxy)-2,3-dihydrofuran-2-yl)methoxy)silane (1). Thy-
midine (121 g, 500 mmol), N-(diphenylphosphorothioyl)-P,P-
diphenylphosphinothioic amide (5a, [Ph2PS]2NH, 2.22 g, 5.00
mmol), 2,6-lutidine (29.1 mL, 250 mmol), heptane (847 mL), and
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Article
toluene (363 mL) were added to a 5 L three-necked RB flask that was
equipped with a nitrogen inlet adapter, a thermocouple probe, and a
mechanical stirrer. The mixture was heated in an oil bath at 102 °C
(internal temperature). N,O-Bis(trimethylsilyl)acetamide (208 mL,
2.13 mmol) was added dropwise over 25 min via an addition funnel;
the mixture became homogenous 25 min after the end of addition.
After 3 h at 99−103 °C, NMR analysis indicated <0.5% thymidine
and 100% assay yield (using 2,6-lutidine as an internal standard). The
reaction mixture was transferred dropwise to iPrOH (308 mL, 4.00
mol) in another 5 L three-necked RB flask, which was heated in an oil
bath set at 52 °C and equipped with a nitrogen inlet adapter,
thermocouple probe, and mechanical stirrer at 7.5 cc per minute over
4 h via a programmable Vaportech V3 pump with a bath. The
resulting slurry was maintained at 50−51 °C for 1.5 h. The mixture
was cooled to 10 °C over 1 h and filtered on a sintered glass filter
funnel. The filter cake was washed with heptane (605 mL). The
combined filtrates were filtered through a plug of neutral alumina
(activated Brockmann 1, 42 g), washing the plug with heptane (75
mL). The filtrate was concentrated to ca. 300 mL volume; NMR
analysis indicated a 98% assay yield (relative to the added
trimethylmethane internal standard). The concentrated solution was
fractionally vacuum distilled (0.1 mm Hg) using a vacuum jacketed
Vigreux distilling head (Chemglass CG-1247-09). The first fraction
boiling at <30 °C consisting of heptane, iPrOTMS, and 2,6-lutidine
was collected in a receiver and cooled in a dry ice acetone bath. The
second fraction boiling at 30−55 °C consisting of 2,6-lutidine, a small
amount (<3 mol %) of the TMS ether of furfuryl alcohol, and a trace
(<3 mol %) of 1 was collected in a receiver and cooled to −20 °C.
The third fraction boiling at 55−75 °C consisting of glycal 1 with 1
mol % 2,6-lutidine (124.7 g, 95% of glycal 1) was collected as a
colorless liquid in a receiver and cooled to 0 °C. The distillation
residue consisted of mostly the catalyst 5a.
NMR (500 MHz, CD2Cl2) δ 7.92−7.87 (m, 8H), 7.48−7.45 (m, 4H),
7.39−7.35 (m, 8H), 1.73 (br s, 1H). 13C NMR (126 MHz, CD2Cl2) δ
132.7 (dd, JC−P = 97.9, 5.7 Hz), 132.1 (t, JC−P = 6.5 Hz), 131.8 (t,
JC−P = 1.4 Hz), 127.9 (t, JC−P = 6.5 Hz). 31P NMR (203 MHz,
CD2Cl2) δ 51.8 (d, JP−Se = 792 Hz).
(2R,3S,5R)-5-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl Pivalate (21). To a
round-bottom flask were added 19 (2.42 g, 5.00 mmol), pivalic
anhydride (2.03 mL, 10.0 mmol, 2 equiv), DMAP (0.061 g, 0.500
mmol, 0.1 equiv), and pyridine (20 mL). The reaction was stirred for
24 h at room temperature. After reaction completion, as determined
by TLC, ethyl acetate and saturated aqueous sodium bicarbonate
were added. The layers were separated, and the aqueous layer was
washed with ethyl acetate three times. The organic layers were
combined and dried with anhydrous magnesium sulfate. The solution
was concentrated to give a clear oil. The crude mixture crystallized on
standing overnight. The crystals were washed with water and hexane
to give product 21 (2.56 g, 90%) as a crystalline white solid. mp =
127−130 °C. FT-IR (ATR, neat): 1725, 1705, 1680, 1440, 1160
1
cm−1. H NMR (500 MHz, CD3CN) δ 9.25 (s, 1H), 7.52 (s, 1H),
7.48 (d, J = 7.3 Hz, 6H), 7.34 (dt, J = 27.7, 7.3 Hz, 9H), 6.31 (dd, J =
8.4, 6.0 Hz, 1H), 5.43−5.38 (m, 1H), 4.08 (q, J = 2.9 Hz, 1H), 3.43
(d, J = 6.8 Hz, 1H), 3.40−3.34 (m, 1H), 2.54−2.44 (m, 1H), 2.39
(ddd, J = 14.3, 5.9, 2.0 Hz, 1H), 1.49 (s, 3H), 1.20 (s, 9H). 13C{1H}
NMR (126 MHz, CD3CN) δ 179.1, 165.1, 152.0, 145.2, 137.0, 130.0,
129.5, 128.9, 112.1, 88.6, 85.7, 85.1, 75.8, 65.3, 39.7, 38.5, 27.7, 12.7.
+
HRMS (ESI/FT-ICR) m/z: [M + Na]+ calcd for C34H36N2NaO6
591.2466; found 591.2462.
1-((2R,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-
tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (22).
In a dry round-bottom flask equipped with a magnetic stir bar,
2′,3′-dideoxythymidine (500 mg, 2.21 mmol), DMAP (13.5 mg,
0.111 mmol, 0.05 equiv), tert-butylchlorodiphenylsilane (690 μL, 2.65
mmol, 1.2 equiv), and DMF (5 mL) were added. The reaction was
stirred for 24 h at room temperature, and reaction progress was
monitored by HPLC. Upon completion, the reaction was extracted
with ethyl acetate and water, and the organic layer was washed with
aqueous sodium bicarbonate, followed by water and brine. The
organic phase was dried over anhydrous magnesium sulfate and
evaporated to give the crude product, which was purified by flash
chromatography (50:50 hexanes/ethyl acetate) to give the product 22
as a clear oil (964 mg, 94%). NMR data was consistent with the
literature.16
N-(Diphenylphosphorothioyl)-P,P-diphenylphosphinothioic
Amide, [Ph2PS]2NH (5a). N,N-Bis(diphenylphosphino)amine (5.01 g,
13.0 mmol, Strem Chemicals, Inc.), sulfur (0.834 g, 26.0 mmol), and
toluene (20 mL) were heated to 100 °C for 16 h giving a white
suspension. This was allowed to cool to 25 °C over 2 h. Hexane (10
mL) was added, and the mixture was stirred for 1 h. The white solid
was filtered off; washed with CS2 (15 mL) to remove sulfur, toluene
(15 mL), and finally hexane (20 mL); and dried under a nitrogen
stream to provide 5a (5.26 g, 92% yield) as a white crystalline solid.
1H NMR (500 MHz, CD2Cl2) δ 7.94−7.85 (m, 8H), 7.49−7.46 (m,
4H), 7.39−7.36 (m, 8H), 4.51 (br s, 1H). 13C NMR (126 MHz,
CD2Cl2) δ 134.0 (dd, JC−P = 106.2, 2.6 Hz), 132.3 (m), 128.6 (t, JC−P
= 6.8 Hz). 31P NMR (203 MHz, CD2Cl2) δ 56.1.
1-((6aR,8R,9aS)-2,2,4,4-Tetraisopropyl-9-methyltetrahydro-6H-
furo[3,2-f ][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-
dione (30). In a dry 100 mL three-necked round-bottom flask, 30b17
(1.00 g, 2.07 mmol), 10% palladium on carbon (200 mg), and
methanol (50 mL) were added. The flask was vacuumed and
backfilled with nitrogen three times with stirring. A hydrogen balloon
was attached, and the flask was vacuumed and backfilled with
hydrogen three times and then filled with hydrogen. The reaction was
stirred at room temperature and atmospheric pressure for 3 h, after
which the reaction was deemed complete by HPLC. The reaction was
filtered through a Celite pad and washed with methanol. The solution
was concentrated to give the crude product 30, which was purified by
column chromatography (50:50 hexanes/ethyl acetate) to give the
product as a clear oil and a 1.9:1 mixture of diastereomers (900 mg,
N-(Diphenylphosphorothioyl)-P,P-diphenylphosphinoselenoic
Amide, [Ph2PSe]2NH (5b). Sodium bisulfite (81.0 g, 780 mmol) was
dissolved in water (300 mL) and was added dropwise over 2 h to a
magnetically stirred solution of selenium dioxide (36.1 g, 325 mmol)
in water (600 mL) in a 1 L Wheaton bottle open to the air in an ice
bath. The internal temperature did not exceed 12 °C during addition.
The mixture was allowed to warm to room temperature overnight.
The originally colorless solution gradually turned yellow and darkened
ultimately depositing amorphous selenium as a brick-red solid. If this
mixture was allowed to heat up >70 °C during the addition, the
precipitated selenium turns to a much denser less reactive black solid.
The brick-red solid was filtered off and washed with water (200 mL),
then acetone (100 mL), and finally (100 mL) hexane. The solid was
dried under a nitrogen stream to give red amorphous elemental
selenium (23.5 g). N,N-Bis(diphenylphosphino)amine (5.01 g, 13.0
mmol, Strem Chemicals, Inc.), red amorphous selenium (2.05 g, 26.0
mmol), and toluene (20 mL) were heated gradually up to 100 °C over
6 h. The suspension was stirred at 100 °C for 20 h giving a white
suspension. This was allowed to cool to 25 °C over 2 h. Hexane (10
mL) was added, and the mixture was stirred for 1 h. The white solid
was filtered off, washed with 1:1 toluene−hexane (15 mL) and hexane
(20 mL), and dried under a nitrogen stream to provide 5b (6.80 g,
96% yield) as a white crystalline solid. This material was stored under
nitrogen in the dark in the freezer; otherwise, exposure to light and air
resulted in the development of a pale pink color after several days. 1H
1
90%). FT-IR (ATR, neat): 1695, 1465, 1390, 1260, 1035 cm−1. H
NMR (400 MHz, CD3CN) δ 9.18 (br s, 1H), 7.68 (major, d, J = 8.1
Hz, 1H), 7.63 (minor, d, J = 8.1 Hz, 1H), 7.25 (minor, m, 1H), 6.17
(major, d, J = 7.4 Hz, 1H), 5.66 (minor, d, J = 3.6 Hz, 1H), 5.62
(major, d, J = 8.1 Hz, 1H), 5.47 (minor, t, J = 7.5 Hz, 1H), 4.23−3.90
(m, 3H), 3.79 (major, d, J = 8.5 Hz, 1H), 2.72−2.59 (major, m, 1H),
2.42 (minor, td, J = 7.3, 3.6 Hz, 1H), 1.18−0.96 (m, 32H). 13C{1H}
NMR (101 MHz, CD3CN) δ 163.1, 162.9, 150.6, 150.5, 140.2, 139.7,
117.3, 101.3, 89.8, 85.6, 83.8, 83.1, 73.0, 70.1, 61.5, 60.1, 44.0, 42.4,
16.9, 16.9, 16.8, 16.7, 16.7, 16.6, 16.5, 16.5, 16.5, 16.4, 13.5, 13.2,
12.9, 12.8, 12.8, 12.7, 12.5, 12.4, 10.7, 10.1. HRMS (ESI/FT-ICR) m/
z: [M + Na]+ calcd for C22H40N2NaO6Si2+ 507.2317; found 507.2314.
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Article
Synthesis of Glycal 1 from Thymidine Using (PhSO2)2NH as
a Catalyst and Isolation of the Bis-Glycosylated Byproduct. A
mixture of thymidine (3.63 g, 15.0 mmol), dibenzenesulfonimide,
(PhSO2)2NH (44.6 mg, 0.15 mmol), HMDS (12.7 mL, 60.0 mmol),
Et3N (21.0 μL, 0.150 mmol), and heptane (36 mL) was heated to
reflux under nitrogen (with allowance for escape of ammonia via a
bubbler) for 18 h to give homogenous amber solution. HPLC
indicated >99% conversion, and the mixture was cooled to 20 °C.
2,4,6-Collidine (1.00 mL, 7.5 mmol) and iPrOH (0.193 mL, 2.500
mmol) were added, and the mixture was stirred for 1 h. Ethanol
(0.730 mL, 12.50 mmol) was added over 40 min, and the mixture was
stirred for 1 h. The resulting slurry was filtered, and the filter cake was
washed with heptane (15 mL). The filter cake was dried under a
nitrogen stream to provide thymine (1766 mg, 14.00 mmol, 93%
yield). The filtrate was concentrated at <30 °C under vacuum (<5
torr) to 5 mL of a yellow oily residue. The residue was distilled under
a rotary vane oil pump vacuum (0.04−0.03 Torr) with an oil bath at
100 °C during a 10 min period. The distillate was collected in a
receiver cooled in an ice bath to give glycal 1 as a colorless mobile
liquid (3.11 g, 80 wt % pure by NMR with 20 wt % collidine, 9.56
mmol, 64% yield). A viscous pale amber gummy distillation residue
remained (815 mg) in the receiver. A stream of nitrogen was passed
over the residue with stirring at 50 °C for 60 h to remove any
remaining collidine and glycal to provide the bis-glycosylated
byproduct as a gum (781 mg, 16%) containing some polymeric
https://pubs.acs.org/10.1021/acs.joc.1c00555
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Xiaxuan Yan for HRMS analyses and Ryan Cohen
and Mikhail Reibarkh for NMR analyses.
REFERENCES
■
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1
materials (as shown by DOSY NMR) for analysis. H NMR (600
MHz, CDCl3) δ 7.49 (s, 1H), 6.70 (m, 1H), 6.19 (m, 1H), 4.45 (m,
1H), 4.28 (m, 1H), 3.85−3.65 (m, 6H), 2.73 (m, 1H), 2.17 (m, 2H),
1.97 (m, 1H), 1.81 (s, 3H), 0.10−0.01 (m, 36H). 13C{1H} NMR
(151 MHz, CDCl3) δ 163.0, 150.3, 133.9, 109.9, 87.4, 87.3, 85.5, 82.3,
72.7, 71.2, 63.6, 61.7, 41.2, 37.7, 13.3, 0.0, −0.1, −0.5, −0.7. HRMS
(ESI/FT-ICR) m/z: [M + Na]+ calcd for C27H54NaO8Si4+ 669.2855;
found 669.2855.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00555.
Characterizations of 1, 5a, 5b, 13a−30a, 21, 22, 30, and
bis-glycosylated byproduct; computational data for 5a
and 5b (PDF)
(4) (a) Pontikis, R.; Wolf, J.; Monneret, C.; Florent, J.-C. A new
route to 2′-C-methylene nucleoside analogs, inhibitors of ribonucleo-
tide reductase. Tetrahedron Lett. 1995, 36, 3523. (b) Diaz, R. R.;
Melgarejo, C. R.; Cubero, I. I.; López-Espinosa, M. T. P. Synthesis of
furanose glycals from furanose 1,2-diols and their cyclic thiocarbonate
esters. Carbohydr. Res. 1997, 300, 375.
AUTHOR INFORMATION
Corresponding Author
■
Peter E. Maligres − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0002-2237-9002;
Email: Peter_maligres@merck.com
(5) McDonald, F. E.; Gleason, M. M. Asymmetric Synthesis of
Nucleosides via Molybdenum-Catalyzed Alkynol Cycloisomerization
Coupled with Stereoselective Glycosylations of Deoxyfuranose
Glycals and 3-Amidofuranose Glycals. J. Am. Chem. Soc. 1996, 118,
6648.
(6) (a) Larsen, E.; Jørgensen, P. T.; Sofan, M. A.; Pedersen, E. B. A
New and Easy Synthesis of Silylated Furanoid Glycals in One Step
from Nucleosides. Synthesis 1994, 1994, 1037−1038. (b) Cameron,
M. A.; Cush, S. B.; Hammer, R. P. Facile Preparation of Protected
Furanoid Glycals from Thymidine. J. Org. Chem. 1997, 62, 9065−
9069. (c) Thymidine is commercially available for <$1/g from several
suppliers including Accela ChemBio Inc., Ambeed Inc., Angene
Chemical International Ltd., Combi-Blocks Inc. and Oakwood
Products Inc.
(7) The bisglycosylated byproduct is presumably formed by reaction
of thymidine with the intermediate oxonium ion 4 generating
predominantly one diastereomer (ROESY). Some higher molecular
weight species are also formed (DOSY).
Authors
Edna Mao − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; Present Address: Department of Chemistry,
Princeton University, Princeton, New Jersey 08544,
United States (E.M.).
Cheol K. Chung − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0001-5658-4306
Yining Ji − Department of Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United
States; orcid.org/0000-0002-9650-6844
(8) (a) Haiduc, I. Inorganic Experiments. In Inorganic (Carbon-Free)
Chelate Rings: A Dithioimidodiphosphinato Ligand and Some of its Metal
Complexes; Woolins, J. D., Ed.; VCH: Weinheim, Germany, 1994; pp.
145−149. (b) Haiduc, I.; Silaghi-Dumitrescu, I. Inorganic (Carbon-
Free) Chelate Rings. Coord. Chem. Rev. 1986, 74, 127−270.
Yu-hong Lam − Department of Computational and Structural
Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0002-4946-1487
Complete contact information is available at:
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J. Org. Chem. 2021, 86, 7529−7536

The Journal of Organic Chemistry
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