A diastereoselective synthesis of 5'-substituted-uridine derivatives

Article abstract of DOI:10.1021/jo501410m

A straightforward strategy for the synthesis of 5'-substituted-uridine derivatives is described. It relies on the introduction of various substituents at C-5' at the last step of the synthesis by regioselective nucleophilic opening of a unique epoxide that provides access to a small library of compounds. This epoxide results from the diastereoselective epoxidation, performed at a multigram scale, of a uridine-derived alkene. The configuration of the newly created 5' asymmetric center has been unambiguously assigned by X-ray diffraction analysis.

Full text of DOI:10.1021/jo501410m

Note
pubs.acs.org/joc
A Diastereoselective Synthesis of 5′-Substituted-Uridine Derivatives
Mickael J. Fer,† Pierre Doan,† Thierry Prange,‡ Sandrine Calvet-Vitale,*,†
́
̈
and Christine Gravier-Pelletier*,†
†Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Universite
Saints Peres, 75006 Paris, France
‡Laboratoire de Cristallographie et RMN Biologiques, Universite
́
Paris Descartes, UMR 8601 CNRS, 45 rue des
̀
́
Paris-Descartes, Faculte des Sciences Pharmaceutiques et
́
Biologiques, UMR 8015 CNRS, 4 avenue de l′Observatoire, 75006 Paris, France
S
* Supporting Information
ABSTRACT: A straightforward strategy for the synthesis of 5′-substituted-uridine derivatives is described. It relies on the
introduction of various substituents at C-5′ at the last step of the synthesis by regioselective nucleophilic opening of a unique
epoxide that provides access to a small library of compounds. This epoxide results from the diastereoselective epoxidation,
performed at a multigram scale, of a uridine-derived alkene. The configuration of the newly created 5′ asymmetric center has
been unambiguously assigned by X-ray diffraction analysis.
ucleotides and nucleosides are key compounds involved
in major biological processes, such as nucleic acids and
diastereoselective reaction on a trigonal carbon atom located at
the C-5 or C-5′ position of a sugar or a nucleoside derivative.
Thus, the diastereoselective reduction of the corresponding
ketone has been described from a ribose16 or a nucleoside17
derivative. In a complementary manner, various nucleophiles,
such as enolates,18 allylborane,19 dialkyl phosphites,20
TMSCN,21 or Grignard reagents,22 have also been introduced
on an aldehyde at the C-5′ position. However, with few
exceptions,17a,22b,c the reactions usually proceed with modest
diastereoselectivities (about 2/1). Additionally, an asymmetric
center has been generated at C-5′ from a nucleoside-derived
aldehyde by a sulfur ylide approach,23 leading to a disubstituted
epoxide as a single diastereoisomer, the configuration of which
having recently been revised.24 The 5′ stereogenic center has
also been generated from an alkene at C-5′ by Sharpless
asymmetric epoxidation,25 aminohydroxylation,26 and asym-
metric dihydroxylation.27 In the latter two cases, the use of a
complex chiral reagent led to the corresponding epoxide with
good to high diastereoselectivities (dr 86/14 for
(DHQD)2AQN26 and dr 84/16 to 98/2 for AD-mix α27).
When these reactions were carried out without a chiral ligand26
or with AD-mix β,27b the diastereoselectivity drops to 2/1 or 1/
1, showing that, in the latter case, the stereochemistry of the
substrate has a stronger impact on the course of the oxidation
than the one of the chiral reagent. In summary, even if several
methods have been developed to control the 5′ carbon atom
stereochemistry, the development of a strategy providing access
N
proteins synthesis, cell signaling, enzyme regulation, and
metabolism. Indeed, many nucleoside analogues are already
clinically used as antiviral1 and antitumoral agents.2 However,
their efficiency is sometimes reduced by the appearance of
resistance mechanisms.3 The availability of new nucleoside
derivatives,4 therefore, is still of prime importance. Among the
numerous nucleoside analogues previously described, only a
few display a stereogenic center at their C-5′ position. This
particular structure is typical of complex nucleoside antibiotics,
such as tunicamycins,5 liposidomycins,6 caprazamycins,7 and
muraymycins8 (Figure 1). These natural compounds isolated
from Streptomyces species are natural inhibitors9 of the bacterial
transferase MraY,10,11 and their stereochemistry at C-5′ has
been proven to be crucial for their biological activity.9 Other
examples of 5′-substituted nucleoside analogues are the
synthetic nucleoside β-(5′S)-hydroxyphosphonate derivatives
that have been developed as 5′-nucleotidase inhibitors
containing a nonhydrolyzable P−C bond.12 It is noteworthy
that a 5′R configuration was shown to be detrimental to
nucleotidase inhibition.13
A number of synthetic methods toward 5′-substituted
nucleosides have already been described. In several of these
approaches, the 5′ stereogenic center is intrinsically present
within the starting material belonging to the chiral pool. Indeed,
many syntheses of nucleosides analogues were achieved from D-
allofuranose,14 the nucleobase being later introduced under
Vorbruggen conditions.15 However, despite its generality, this
̈
strategy usually requires long multistep synthesis. More
Received: June 24, 2014
frequently, this 5′ stereogenic center is newly created by a
© XXXX American Chemical Society
A
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Note
a
Scheme 1. Synthesis of Epoxide 4
a
Reagents and conditions: (a) IBX, acetonitrile, 45 min ; (b)
CH3PPh3 Br−, t-BuOK, 0 °C, 10 min, then rt, 1 h, then 2, 0 °C, 10
min, then rt, 16 h, 61% over two steps; (c) see Table 1.
+
pTSA, furnishing the corresponding primary alcohol 1,18b
followed by oxidation of the 5′ position with 2-iodoxybenzoic
acid (IBX)30 to give 2 after simple filtration. Then, Wittig
olefination in the presence of methyltriphenyl phosphonium
bromide in excess and freshly sublimated potassium tert-
butoxide as a base readily afforded the alkene 3 in 61% overall
yield from 1.
With this alkene 3 in hand, we next turned to the epoxidation
reaction (Scheme 1). It was first attempted with commercially
available and inexpensive meta-chloroperbenzoic acid (m-
CPBA) in excess (3 equiv), in dichloromethane, in the
presence of sodium bicarbonate as a base to neutralize the
meta-chlorobenzoic acid formed in the reaction (Table 1, entry
1). After 3 days at 30 °C, the reaction remained uncompleted,
leading to a 75/25 mixture of diastereoisomers at C5′. Isolation
of the major diastereoisomer 4a by flash chromatography was
achieved in only 23% yield, due to its delicate separation from
the starting alkene 3. In the absence of a base, the conversion
was slightly improved (entry 2). Attempts to carry out the
reaction in refluxing chloroform did not improve the yield,
probably due to m-CPBA decomposition (entry 3). Increasing
the amount of m-CPBA to 4 equiv (entry 4) allowed total
conversion of alkene 3, but it required 3 days at 30 °C so that
4a was isolated in a modest 36% yield due to the formation of
numerous byproducts. However, we were delighted to observe
that the use of 5 equiv of m-CPBA (entry 5) speeded up the
reaction, leading to its completion in only 16 h and provided
pure 4a in a good 70% yield. Surprisingly, 4b proved to
decompose on silica gel so that only an analytical sample could
be isolated to confirm its structure. Such an instability of 4b
could result from an intramolecular nucleophilic opening of the
epoxide by uracil, leading to the corresponding anhydro
derivative14a possibly followed by silyl protective group
migration. It is noteworthy to mention that decreasing the
temperature to 0 °C (entry 6) did not improve the
Figure 1. Examples of natural 5′-substituted-uridine derivatives.
to a large variety of 5′-substituted nucleoside derivatives is still
particularly challenging. In the context of our ongoing program
dedicated to new MraY inhibitors,28 we have focused our study
on 5′-substituted-uridine derivatives.
We report herein a straightforward, diastereoselective, and
multigram scale synthesis of new 5′-substituted-uridine
derivatives. Our strategy toward the targeted compounds is
depicted in Figure 2. A wide variety of alcohol A would result
from the regioselective nucleophilic ring opening of a unique
epoxide B that would be obtained by oxidation of the terminal
alkene C derived from commercially available uridine.
We first focused on the synthesis of alkene 3 (Scheme 1)
from the aldehyde 2 that was synthesized according to known
routes.29 The latter was obtained on a 13 g scale after a three-
step sequence involving the persilylation of uridine by an excess
of tert-butyldimethylsilyl chloride in the presence of imidazole28
and subsequent selective deprotection of the 5′ position with
Figure 2. Retrosynthesis toward the targeted compounds.
B
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Note
Table 1. Conditions for the Epoxidation of the Alkene 3
a
a
entry
t (h)
T (°C)
mCPBA (equiv)
solvent
additive
4/3 ratio
4a/4b ratio
4a yield (%)
1
2
3
4
5
6
72
72
24
72
16
30
30
62
30
30
0
3
3
3
4
5
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
NaHCO3
86/14
91/9
75/25
75/25
75/25
75/25
75/25
75/25
23
32
28
36
70
100/0
>98/2
100/0
63/37
b
128
5
n.d.
a
b
1
Determined by H NMR of the crude mixture. Not determined.
diastereoisomeric ratio while the reaction remained uncom-
pleted after 7 days.
epoxide 5′S-4a and the corresponding phenol in DMF in the
presence of potassium carbonate33 to provide 8b in 62% yield
or 8c in 66% yield. Sodium thiophenolate generated by
treatment of thiophenol with sodium methoxide34 efficiently
achieved the epoxide 5′S-4b opening at 100 °C in DMF to
furnish the thioether 9 in 73% yield. We next turned to the
introduction of carbon nucleophiles. Toward this goal, the
epoxide 5′S-4a was opened by potassium cyanide in the
presence of ammonium chloride35 to afford the β-cyano alcohol
10 in 68% yield. Then, the opening of epoxide 5′S-4a by
acetylide ions was also envisaged. First attempts with Grignard
reagents such as ((trimethylsilyl)ethynyl)magnesium bromide
or ((triethylsilyl)ethynyl)magnesium bromide resulted in
epoxide ring opening by bromide ions, leading to 11 in 67%
or 74% yield, respectively. It should be noted that the
compound 11 was also prepared in 79% yield by direct
nucleophilic opening of epoxide 5′S-4a by lithium bromide in
THF in the presence of boron trifluoride etherate36 as a Lewis
acid. Finally, the alkyne group was successfully introduced by
using lithium trimethylsilylacetylide in the presence of BF3·
Et2O, furnishing the targeted homopropargylic alcohol 12 in
77% yield. This reaction benefits from a large scope, and in all
cases, a complete regioselectivity was observed in favor of the
opening on the less sterically hindered pole of the epoxide.
Moreover, a temporary uracile protection was unnecessary
since no intramolecular nucleophilic opening by the uracile
moiety was observed.14a The secondary alcohols 5−12
constitute advanced valuable intermediates for the synthesis
of new 5′-substituted-uridine nucleoside derivatives.
With the pure major epoxide 4a in hand, we turned to the
determination of its absolute configuration at C-5′. Attempts of
crystallization of the latter in ethanol gave successful results,
and X-ray diffraction analysis of the resulting monocrystal (see
the Supporting Information) allowed us to unambiguously
attribute the S configuration to the C-5′ carbon atom of the
major epoxide 4a. It should be noted that the C-5′
configuration of 4a matches that of liposidomycins, capraza-
mycins, and muraymycins. The stereochemistry at the C-5′
carbon atom of the major epoxide 4a is in agreement with an
approach of the m-CPBA predominantly on the Si face of the
double bond. Considering the conformation of the alkene 3 in
which the 1,3-allylic strains are minimized (Figure 3), the O-3′-
silyl group would hinder the alkene Re face, disfavoring an
electrophilic addition onto this face and promoting m-CPBA
attack on the Si face.
Figure 3. Conformation of the alkene 3 minimizing the 1,3-allylic
strains.
To take advantage of the synthetic potential of epoxide 4a as
a chiral building block for the synthesis of 5′-substituted-uridine
derivatives, we next studied its ring opening with various
halogen-, carbon-, nitrogen-, oxygen-, or sulfur-containing
nucleophiles (Scheme 2), which are key functional groups to
introduce chemical diversity.
We have developed a new route toward 5′-substituted-uridine
derivatives, a challenging structure encountered in biologically
active compounds such as complex nucleoside antibiotics for
which only a few synthetic routes are described. It involves the
multigram scale, diastereoselective, and direct epoxidation of a
uridine-alkene derivative that is obtained from commercially
available uridine in only four steps. The major diastereoisomer
epoxide 4a was isolated in a 70% yield, and the S configuration
at its C-5′ carbon atom has been unambiguously assigned by X-
ray diffraction analysis. The chemical diversity was then
introduced at the ultimate step of the synthesis, by a totally
regioselective ring opening of this key intermediate with various
nucleophiles, affording the corresponding secondary alcohols in
good yield.
We first focused on the reaction of aliphatic or aromatic
primary amines with epoxide 5′S-4a, which was carried out by a
simple and mild heating at 40 °C in methanol,31 giving the
corresponding β-amino alcohols 5a−c in 68−71% yield.
Opening of the epoxide 5′S-4a by a secondary amine such as
morpholine led to 5d in 76% yield. Amino acid derivatives, for
instance alanine or serine methyl esters, could also be
introduced according to the same procedure, providing the
corresponding N-alkyl amino acids 6a and 6b in 73% and 69%
yield, respectively. However, in the case of serine, a slight
epimerization was observed at the α carbon atom (85:15 dr).
Opening of the epoxide 5′S-4a with azide ions in the presence
of ammonium chloride32 afforded the azido alcohol 7 in 72%
yield. Benzyl alcoholate generated by the action of sodium
hydride in benzylic alcohol required heating at 60 °C in DMF
to achieve the epoxide 5′S-4a opening and gave 8a in 66%
yield. Softer nucleophiles such as potassium phenolate or 4-
bromophenolate could also be introduced by heating the
EXPERIMENTAL SECTION
■
General Experimental Methods. When needed, reactions were
carried out under an argon atmosphere. They were monitored by thin-
layer chromatography with precoated silica on aluminum foil. Flash
chromatography was performed with silica gel 60 (40−63 μm); the
solvent systems were given v/v. Spectroscopic 1H and 13C NMR, MS,
and/or analytical data were obtained using chromatographically
1
homogeneous samples. H NMR (500 MHz) and 13C NMR (125
MHz) spectra were recorded in CDCl3 unless indicated. Chemical
C
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Note
a
Scheme 2. Ring-Opening Reactions of the Epoxide 5′S-4a
a
Reagents and conditions: (a) Amine, MeOH, 40 °C, 16 h; (b) NaN3, DMF, 70 °C, 16 h; (c) NaH, BnOH, 60 °C, 16 h; (d) PhOH or 4-Br-PhOH,
K2CO3, DMF, 50 °C, 16 h; (e) PhSH, MeONa, DMF, 100 °C, 16 h; (f) KCN, NH4CI, DMF, 100 °C, 16 h; (g) LiBr, BF3.OEt2, THF, −50 °C, 5
min then rt, 1 h; (h) Trimethylsilylacetylene, n-BuLi, BF3·OEt2, −78 to −10 °C, 16 h.
shifts (δ) are reported in ppm and coupling constants are given in Hz.
For each compound, detailed peak assignments have been made
according to COSY, HSQC, and HMBC experiments. The numbering
of molecules is indicated in the Supporting Information. Optical
rotations were measured with a sodium (589 nm) lamp at 20 °C.
Melting points were measured on a hot bench. IR spectra were
recorded on an FT-IR spectrophotometer, and the wavelengths are
reported in cm−1. Low-resolution mass spectra (LRMS) were recorded
with an ion trap mass analyzer under electrospray ionization (ESI) in
positive ionization mode detection or atmospheric pressure chemical
ionization (APCI). High-resolution mass spectra (HRMS) were
recorded with a TOF mass analyzer under electrospray ionization
(ESI) in positive ionization mode.
5′-Methylideneuridine 3. To a solution of alcohol 1 (13.19 g,
27.9 mmol, 1 equiv) in acetonitrile (450 mL) was added IBX (23.4 g,
83.7 mmol, 3 equiv). The mixture was refluxed for 45 min, cooled to
rt, and filtrated on a Celite pad. The solid was washed with EtOAc, and
the filtrate was concentrated in vacuo. The crude aldehyde 2 (13.13 g,
quantitative yield) was dried by coevaporation with toluene and used
without further purification (all spectral data were in agreement with
the literature).18b At 0 °C, under Ar, to a well-stirred suspension of
methyltriphenylphosphonium bromide (29.9 g, 83.7 mmol, 3 equiv) in
THF (180 mL) was added freshly sublimated potassium tert-butoxide
(9.4 g, 83.7 mmol, 3 equiv). The bright yellow suspension was stirred
at 0 °C for 10 min and then at rt for 1 h. The crude aldehyde 2 was
dissolved in THF (180 mL), transferred into a dropping funnel, and
slowly added to the solution of ylide at 0 °C. The mixture was
vigorously stirred at 0 °C for 10 min and then at rt for 16 h. The
mixture was diluted in DCM (300 mL), and the reaction was
quenched by addition of a saturated aqueous solution of NH4Cl (100
mL). The aqueous phase was extracted with DCM (4 × 200 mL), and
the combined organic layers were dried over Na2SO4, filtrated, and
concentrated in vacuo. The crude foam (45 g) was purified by flash
chromatography (cyclohexane/EtOAc = 7/3 to 1/1), and the alkene 3
was obtained as a white foam (7.93 g, 61% yield); Rf = 0.43
(cyclohexane/EtOAc = 7/3); mp 210−212 °C; [α]D + 79 (c 1.0,
1
CH2Cl2); IR (film) 3628w, 2859s, 2356m 1695s, 1263m; H NMR δ
9.92 (br s, 1H, NH), 7.42 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.92 (ddd, 1H,
JH5′‑H6′a = 17.0 Hz, JH5′‑H6′b = 10.0 Hz, JH5′‑H4′ = 7.5 Hz, H5′), 5.76 (d,
1H, JH5‑H6 = 8.0 Hz, JH5‑NH = 1.5 Hz, H5), 5.67 (d, 1H, JH1′‑H2′ = 2.5
Hz, H1′), 5.45 (d, 1H, JH6′a‑H5′ = 17.0 Hz, H6′a), 5.35 (d, 1H, JH6′b‑H5′
=
10.0 Hz, H6′b), 4.48 (t, 1H, JH4′‑H3′ = 7.5 Hz, JH4′‑H5′ = 7.5 Hz, H4′),
4.21 (dd, 1H, JH2′‑H3′ = 4.0 Hz, JH2′‑H1′ = 2.5 Hz, H2′), 3.78 (dd, 1H,
JH3′‑H2′ = 4.0 Hz, JH3′‑H4′ = 7.5 Hz, H3′), 0.91 (s, 9H, -C(CH3)3), 0.89
(s, 9H, -C(CH3)3), 0.15, 0.09, 0.06, 0.05 (4s, 12H, -(CH3)2); 13C
NMR δ 163.9 (C4), 150.3 (C2), 139.8 (C6), 134.9 (C5′), 119.3 (C6′),
102.2 (C5), 91.8 (C1′), 84.2 (C4′), 75.5 (C2′), 75.3 (C3′), 25.9, 25.9
(-C(CH3)3), 18.2, 18.1 (-C(CH3)3), −4.1, −4.4, −4.5, −4.7
+
(-(CH3)2); HRMS APCI+ calcd for C22H41N2O5Si2 (M + H)+
469.2549, found 469.2557.
5′(S)-C-(Butylaminomethyl)-2′,3′-di-O-(tert-butyldimethyl-
silyl)uridine 4a. To a solution of alkene 3 (6.73g, 14.36 mmol, 1
equiv) in DCM (260 mL) was added m-CPBA (77% stabilized, 16.09
g, 71.8 mmol, 5 equiv). The mixture was stirred at 30 °C for 16 h and
then cooled to rt, and the reaction was quenched by addition of a 10%
aqueous solution of Na2S2O3 (150 mL). The aqueous phase was
extracted with DCM (3 × 200 mL), and the combined organic layers
were washed with a 10% aqueous solution of NaHCO3 (100 mL), and
water (100 mL), dried over Na2SO4, filtrated, and concentrated in
vacuo. The crude white foam revealed to be a 75/25 mixture of
1
epoxides 4a/4b as determined by H NMR of the crude and was
purified by flash chromatography (cyclohexane/EtOAc = 8/2 to 7/3)
to afford the major diastereoisomer 4a as a white foam (4.90 g, 70%
yield). An analytical sample of the minor 4b could also be isolated.
D
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Note
Data for major isomer 4a: Rf = 0.31 (cyclohexane/EtOAc = 7/3); mp
Hz, JH6′a‑H5′ = 9.0 Hz, H6′a), 2.80 (dd, 1H, JH6′b‑H6′a = 13.0 Hz, JH6′b‑H5′
= 4.0 Hz, H6′b), 0.87 (s, 9H, -C(CH3)3), 0.86 (s, 9H, -C(CH3)3), 0.07,
0.06, 0.06, 0.05 (4s, 12H, -(CH3)2); 13C NMR δ 163.4 (C4), 150.7
(C2), 141.4 (C6), 139.6 (C8′), 128.7 (CHar), 128.3 (CHar), 127.4
(CHar), 102.1 (C5), 90.2 (C1′), 85.2 (C4′), 75.3 (C2′), 72.1 (C3′), 67.6
(C5′), 53.5 (C7′), 51.6 (C6′), 25.9, 25.8 (-C(CH3)3), 18.2, 18.1
(-C(CH3)3), −4.2, −4.5, −4.6, −4.7 (-(CH3)2); HRMS APCI+ calcd
186−190 °C; [α]D + 39 (c 1.0, CH2Cl2); IR (film) 3216w, 2860m,
1
1696s, 1472m; H NMR δ 8.99 (br s, 1H, NH), 7.78 (d, 1H, JH6‑H5
8.5 Hz, H6), 5.85 (d, 1H, JH1′‑H2′ = 3.0 Hz, H1′), 5.76 (dd, 1H, JH5‑H6
8.5 Hz, JH5‑NH = 1.5 Hz, H5), 4.28 (dd, 1H, JH2′‑H1′ = 3.0 Hz, JH2′‑H3′
=
=
=
1.0 Hz, H2′), 4.11−4.08 (m, 2H, H3′, H4′), 3.20−3.19 (m, 1H, H5′),
2.93 (dd, 1H, JH6′a‑H6′b = 5.0 Hz, JH6′a‑H5′ = 2.5 Hz, H6′a), 2.88 (t, 1H,
JH6′b‑H6′a = 5.0 Hz, JH6′b‑H5′ = 5.0 Hz, H6′b), 0.94 (s, 9H, -C(CH3)3),
+
for C29H50N3O6Si2 (M + H)+ 592.3233, found 592.3242.
0.90 (s, 9H, -C(CH3)3), 0.14, 0.13, 0.10, 0.09, (4s, 12H, -(CH3)2); 13
C
5′(S)-C-(N′-Phenyl-N-methyl)-2′,3′-di-O-(tert-butyldimethylsilyl)-
uridine 5c. Compound 5c was synthesized according to the general
procedure for epoxide ring opening by amine from epoxide 4a (80 mg,
0.165 mmol, 1 equiv) and aniline (30 μL, 0.33 mmol, 2 equiv). Flash
chromatography (DCM/Et2O = 9/1) of the crude afforded 5c as a
white foam (65 mg, 68% yield): Rf = 0.28 (cyclohexane/EtOAc = 1/
1); mp 88−92 °C; [α]D + 2 (c 0.4, CH2Cl2); IR (film) 3418br, 2929w,
1781w, 1686s, 1462m; 1H NMR δ 9.24−9.08 (br s, 1H, NH), 7.72 (d,
1H, JH6‑H5 = 8.0 Hz, H6), 7.17 (t, 2H, JH9′‑H8′ = JH9′‑H10′ = 8.0 Hz, H9′),
6.77 (t, 1H, JH10′‑H9′ = 8.0 Hz, H10′), 6.70 (d, 1H, JH8′‑H9′ = 8.0 Hz,
H8′), 5.72 (d, 1H, JH5‑H6 = 8.0 Hz, H5), 5.52 (d, 1H, JH1′‑H2′ = 5.0 Hz,
NMR δ 163.4 (C4), 150.5 (C2), 139.9 (C6), 102.7 (C5), 88.9 (C1′),
79.6 (C4′), 75.6 (C2′), 73.5 (C3′), 51.5 (C5′), 44.3 (C6′), 25.9, 25.9
(-C(CH3)3), 18.2, 18.1 (-C(CH3)3), −4.2, −4.5, −4.6, −4.7
+
(-(CH3)2); HRMS ESI+ calcd for C22H41N2O6Si2 (M + H)+
485.2498, found 485.2499. Data for 4b: white powder, Rf = 0.27
(cyclohexane/EtOAc = 7/3); mp 177−180 °C; [α]D − 46 (c 0.26,
1
CH2Cl2); IR (film) 2857br, 1693s, 1462m, 1257m, 865m; H NMR δ
8.42 (br s, 1H, NH), 7.43 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.82 (d, 1H,
J
H1′‑H2′ = 5.5 Hz, H1′), 5.78 (dd, 1H, JH5‑H6 = 8.0 Hz, JH5‑NH = 2.0 Hz,
H5), 4.34 (dd, 1H, JH2′‑H1′ = 5.5 Hz, JH2′‑H3′ = 4.0 Hz, H2′), 4.13 (t, 1H,
H4′‑H3′ = JH4′‑H5′ = 3.0 Hz, H4′), 3.87 (dd, 1H, JH3′‑H2′ = 4.0 Hz, JH3′‑H4′
H1′), 4.94−4.60 (br s, 2H, NH), 4.51 (t, 1H, JH2′‑H1′ = 5.0 Hz, JH2′‑H3′
=
J
5.0 Hz, H2′), 4.17 (t, 1H, JH3′‑H2′ = 5.0 Hz, JH3′‑H4′ = 5.0 Hz, H3′),
4.04−4.03 (m, 1H, H4′), 3.97−3.94 (m, 1H, H5′), 3.70−3.62 (br s, 1H,
OH), 3.33 (dd, 1H, JH6′a‑H6′b = 13.0 Hz, JH6′a‑H5′ = 8.0 Hz, H6′a), 3.30
(dd, 1H, JH6′b‑H6′a = 13.0 Hz, JH6′b‑H5′ = 5.0 Hz, H6′b), 0.88 (s, 9H,
-C(CH3)3), 0.87 (s, 9H, -C(CH3)3), 0.06, 0.05, 0.04, 0.02 (4s, 12H,
-(CH3)2); 13C NMR δ 163.4 (C4), 150.6 (C2), 147.2 (C7′), 142.9 (C6),
129.7 (C9′), 119.2 (C10′), 127.4 (C8′), 102.4 (C5), 93.4 (C1′), 86.3
(C4′), 73.6 (C2′), 72.8 (C3′), 68.6 (C5′), 48.3 (C6′), 25.9, 25.8
(-C(CH3)3), 18.2, 18.1 (-C(CH3)3), −4.3, −4.5, −4.6, −4.7
= 3.0 Hz, H3′), 3.27 (dt, 1H, JH5′‑H6′a = 4.5 Hz, JH5′‑H6′b = JH5′‑H4′ = 3.0
Hz, H5′), 2.94 (t, 1H, JH6′a‑H6′b = JH6′a‑H5′ = 4.5 Hz, H6′a), 2.73 (dd, 1H,
JH6′b‑H6′a = 4.5 Hz, JH6′b‑H5′ = 3.0 Hz, H6′b), 0.92 (s, 9H, -C(CH3)3),
0.89 (s, 9H, -C(CH3)3), 0.11, 0.09, 0.07, 0.05, (4s, 12H, -(CH3)2); 13
C
NMR δ 162.8 (C4), 150.2 (C2), 140.8 (C6), 102.8 (C5), 90.1 (C1′),
84.7 (C4′), 74.9 (C2′), 71.7 (C3′), 51.4 (C5′), 45.7 (C6′), 25.9, 25.9
(-C(CH3)3), 18.2, 18.1 (-C(CH3)3), −4.1, −4.5, −4.5, −4.8
+
(-(CH3)2); HRMS ESI+ calcd for C22H41N2O6Si2 (M + H)+
485.2498, found 485.2492
+
(-(CH3)2); HRMS APCI+ calcd for C28H48N3O6Si2 (M + H)+
General Procedure for Epoxide Ring Opening by Amine. To
a solution of epoxide (80 mg, 0.165 mmol, 1 equiv) in methanol (1
mL) was added the appropriate amine (0.33 mmol, 2 equiv). The
resulting solution was heated at 40 °C for 16 h, concentrated in vacuo,
and purified by flash chromatography.
578.3076, found 578.3076.
5′(S)-C-(Morpholino-N-methyl)-2′,3′-di-O-(tert-butyldimethyl-
silyl)uridine 5d. Compound 5d was synthesized according to the
general procedure for epoxide ring opening by amine from epoxide 4a
(80 mg, 0.165 mmol, 1 equiv) and morpholine (28 μL, 0.33 mmol, 2
equiv). Flash chromatography (cyclohexane/EtOAc = 1/1) of the
crude afforded 5d as a white foam (71 mg, 76% yield): Rf = 0.19
(cyclohexane/EtOAc = 1/1); mp 102−106 °C; [α]D + 24 (c 0.4,
5′(S)-C-(N′-Butyl-N-methyl)-2′,3′-di-O-(tert-butyldimethylsilyl)-
uridine 5a. Compound 5a was synthesized according to the general
procedure for epoxide ring opening by amine from epoxide 4a (80 mg,
0.165 mmol, 1 equiv) and butylamine (32 μL, 0.33 mmol, 2 equiv).
Flash chromatography (DCM/MeOH/Et3N = 95/5/0.3%) of the
crude afforded 5a as a white foam (63 mg, 69% yield): Rf = 0.15
(DCM/MeOH/Et3N = 95/5/0.3%); mp 100−104 °C; [α]D + 9 (c
1
CH2Cl2); IR (film) 3418br, 2930m, 1693s, 1462m; H NMR δ 9.83−
9.64 (br s, 1H, NH), 8.16 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.77 (d, 1H,
JH1′‑H2′ = 3.0 Hz, H1′), 5.71 (d, 1H, JH5‑H6 = 8.0 Hz, H5), 4.22 (t, 1H,
1
0.25, CH2Cl2); IR (film) 3055br, 2957s, 1686s, 1463m; H NMR δ
JH2′‑H1′ = 4.0 Hz, JH2′‑H3′ = 4.0 Hz, H2′), 4.18 (t, 1H, JH3′‑H2′ = 4.0 Hz,
8.05 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 6.09−5.80 (br s, 3H, NH, OH), 5.74
JH3′‑H4′ = 4.0 Hz, H3′), 3.88−3.84 (m, 2H, H4′, H5′), 3.77−3.70 (m,
4H, H8′), 2.73 (t, 1H, JH6′a‑H6′b = JH6′a‑H5′ = 12.0 Hz, H6′a), 2.68−2.64
(m, 2H, H7′a), 2.47−2.43 (m, 2H, H7′b), 2.39 (dd, 1H, JH6′b‑H6′a = 13.0
Hz, JH6′b‑H5′ = 3.0 Hz, H6′b), 0.89 (s, 9H, -C(CH3)3), 0.88 (s, 9H,
-C(CH3)3), 0.11, 0.09, 0.07 (3s, 12H, -(CH3)2); 13C NMR δ 163.9
(C4), 150.6 (C2), 141.2 (C6), 101.2 (C5), 89.9 (C1′), 83.7 (C4′), 75.5
(C2′), 71.8 (C3′), 67.0 (C8′), 64.6 (C5′), 61.0 (C6′), 53.5 (C7′), 25.9,
25.8 (-C(CH3)3), 18.2, 18.1 (-C(CH3)3), −4.2, −4.5, −4.7, −4.8
(d, 1H, JH1′‑H2′ = 4.5 Hz, H1′), 5.70 (d, 1H, JH5‑H6 = 8.0 Hz, H5), 4.26
(t, 1H, JH2′‑H1′ = 4.5 Hz, JH2′‑H3′ = 4.5 Hz, H2′), 4.16 (t, 1H, JH3′‑H2′
=
4.5 Hz, JH3′‑H4′ = 4.5 Hz, H3′), 3.90−3.87 (m, 2H, H5′, H4′), 2.85 (dd,
1H, JH6′a‑H6′b = 13.0 Hz, JH6′a‑H5′ = 9.0 Hz, H6′a), 2.80 (dd, 1H, JH6′b‑H6′a
= 13.0 Hz, JH6′b‑H5′ = 4.0 Hz, H6′b), 2.79−2.70 (m, 2H, H7′), 1.56 (qt,
2H, JH8′‑H7′ = JH8′‑H9′ = 8.0 Hz, H8′), 1.34 (sext, 2H, JH9′‑H8′ = JH9′‑H10′
=
8.0 Hz, H9′), 0.89 (t, 2H, JH10′‑H9′ = 8.0 Hz, H10′), 0.87 (s, 9H,
-C(CH3)3), 0.85 (s, 9H, -C(CH3)3), 0.06, 0.04, (2s, 12H, -(CH3)2);
13C NMR δ 164.2 (C4), 150.9 (C2), 141.6 (C6), 102.3 (C5), 90.2 (C1′),
85.6 (C4′), 75.1 (C2′), 72.4 (C3′), 66.9 (C5′), 51.6 (C6′), 48.9 (C7′),
30.9 (C8′), 26.0, 25.9 (-C(CH3)3), 20.3 (C9′), 18.2, 18.1 (-C(CH3)3),
13.9 (C10′), −4.2, −4.5, −4.6, −4.7 (-(CH3)2); HRMS APCI+ calcd for
+
(-(CH3)2); HRMS APCI+ calcd for C26H50N3O7Si2 (M + H)+
572.3182, found 572.3189.
5′(S)-C-(Methyl-L-alaninate-N-methyl)-2′,3′-di-O-(tert-butyl-
dimethylsilyl)uridine 6a. Compound 6a was synthesized according to
the general procedure for epoxide ring opening by amine from epoxide
4a (80 mg, 0.165 mmol, 1 equiv) and L-alanine methyl ester (30 μL,
0.33 mmol, 2 equiv). Flash chromatography (cyclohexane/EtOAc = 4/
6) of the crude afforded 6a as a white foam (70 mg, 73%): Rf = 0.22
(cyclohexane/EtOAc = 4/6); mp 82−88 °C; [α]D + 15 (c 1.0,
CH2Cl2); IR (film) 3418br, 2929w, 1781w, 1686s, 1462m; 1H NMR δ
8.06 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.76 (d, 1H, JH1′‑H2′ = 4.0 Hz, H1′),
5.73 (d, 1H, JH5‑H6 = 8.0 Hz, H5), 4.28 (t, 1H, JH2′‑H1′ = 4.0 Hz, JH2′‑H3′
= 4.0 Hz, H2′), 4.18 (t, 1H, JH3′‑H2′ = 4.0 Hz, JH3′‑H4′ = 4.0 Hz, H3′),
3.90−3.87 (m, 1H, H4′), 3.76−3.74 (br s, 1H, NH), 3.73 (s, 3H, -O-
+
C26H52N3O6Si2 (M + H)+ 558.3389, found 558.3389.
5′(S)-C-(N′-Benzyl-N-methyl)-2′,3′-di-O-(tert-butyldimethylsilyl)-
uridine 5b. Compound 5b was synthesized according to the general
procedure for epoxide ring opening by amine from epoxide 4a (80 mg,
0.165 mmol, 1 equiv) and benzylamine (36 μL, 0.33 mmol, 2 equiv).
Flash chromatography (cyclohexane/EtOAc = 1/1) of the crude
afforded 5b as a white foam (69 mg, 71% yield): Rf = 0.17
(cyclohexane/EtOAc = 1/1); mp 88−92 °C; [α]D + 22 (c 0.25,
CH2Cl2); IR (film) 3418br, 2929w, 1781w, 1686s, 1462m; 1H NMR δ
8.03 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 7.32−5.21 (m, 5H, Har), 5.72 (d, 1H,
CH3), 3.44 (q, 1H, JH7′‑H8′ = 7.0 Hz, H7′), 2.84 (dd, 1H, JH6′a‑H6′b
=
J
H1′‑H2′ = 4.0 Hz, H1′), 5.66 (d, 1H, JH5‑H6 = 8.0 Hz, H5), 4.94−4.60 (br
13.0 Hz JH6′a‑H5′ = 9.0 Hz, H6′a), 2.74 (dd, 1H, JH6′b‑H6′a = 13.0 Hz,
JH6′b‑H5′ = 4.0 Hz, H6′b), 1.35 (d, 3H, JH8′‑H7′ = 7.0 Hz, H8′), 0.90 (s,
9H, -C(CH3)3), 0.89 (s, 9H, -C(CH3)3), 0.09, 0.08, 0.07 (3s, 12H,
-(CH3)2); 13C NMR δ 175.5 (-CO-OCHH3), 163.6 (C4), 150.6 (C2),
141.5 (C6), 102.2 (C5), 90.2 (C1′), 85.2 (C4′), 75.2 (C2′), 72.4 (C3′),
s, 2H, NH), 4.23 (t, 1H, JH2′‑H1′ = 4.0 Hz, JH2′‑H3′ = 4.0 Hz, H2′), 4.15
(t, 1H, JH3′‑H2′ = 4.0 Hz, JH3′‑H4′ = 4.0 Hz, H3′), 3.88−3.87 (m, 1H,
H4′), 3.84 (d, 1H, JH7′a‑H7′b = 13.0 Hz, H7′a), 3.80 (d, 1H, JH7′b‑H7′a
=
13.0 Hz, H7′b), 3.74−3.71 (m, 1H, H5′), 2.85 (dd, 1H, JH6′a‑H6′b = 13.0
E
dx.doi.org/10.1021/jo501410m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
67.7 (C5′), 56.1 (C7′), 52.2 (-CO-OCH3), 50.1 (C6′), 26.0, 25.9
5.67 (d, 1H, JH1′‑H2′ = 4.5 Hz, H1′), 4.62 (d, 1H, JH7′a‑H7′b = 12.0 Hz,
H7′a), 4.58 (d, 1H, JH7′b‑H7′a = 12.0 Hz, H7′b), 4.30 (t, 1H, JH2′‑H1′ = 4.5
Hz, JH2′‑H3′ = 4.5 Hz, H2′), 4.18 (t, 1H, JH3′‑H2′ = 4.5 Hz, JH3′‑H4′ = 4.5
Hz, H3′), 4.01 (dd, 1H, JH4′‑H3′ = 4.5 Hz, JH4′‑H5′ = 1.0 Hz, H4′), 3.99−
3.96 (m, 1H, H5′), 3.63 (t, 1H, JH6′a‑H6′b = 9.5 Hz, JH6′a‑H5′ = 9.5 Hz,
H6′a), 3.60 (dd, 1H, JH6′b‑H6′a = 9.5 Hz, JH6′b‑H5′ = 4.5 Hz, H6′b), 3.10−
3.07 (m, 1H, OH), 0.91 (s, 9H, -C(CH3)3), 0.90 (s, 9H, -C(CH3)3),
0.09, 0.08, 0.08, (3s, 12H, -(CH3)2); 13C NMR δ 163.1 (C4), 150.4
(C2), 141.7 (C6), 137.8 (C8′), 128.7 (C9′), 128.1 (C11′), 127.4 (C10′),
102.1 (C5), 91.3 (C1′), 83.9 (C4′), 74.9 (C2′), 73.7 (C7′), 71.9 (C3′),
71.9 (C6′), 69.1 (C5′), 26.0, 25.9 (-C(CH3)3), 18.2, 18.1 (-C(CH3)3),
−4.2, −4.5, −4.6, −4.7 (-(CH3)2); HRMS APCI+ calcd for
(-C(CH3)3), 19.3 (C8′), 18.2, 18.1 (-C(CH3)3), −4.2, −4.5, −4.6, −4.7
+
(-(CH3)2); HRMS APCI+ calcd for C26H50N3O8Si2 (M + H)+
588.3131, found 588.3138.
5′(S)-C-(Methyl-serinate-N-methyl)-2′,3′-di-O-(tert-butyl-
dimethylsilyl)uridine 6b. Compound 6b was synthesized according to
the general procedure for epoxide ring opening by amine from epoxide
4a (80 mg, 0.165 mmol, 1 equiv) and L-serine methyl ester (39 mg,
0.33 mmol, 2 equiv). Flash chromatography (cyclohexane/EtOAc = 4/
6) of the crude afforded 6b as a white foam (68 mg, 69% yield) as an
inseparable 85/15 mixture of diastereoisomers at the α carbon atom
(the major diastereoisomer is labeled by“*” and the minor one by“°” in
NMR description): Rf = 0.21 (cyclohexane/EtOAc = 4/6); IR (film)
+
C29H49N2O7Si2 (M + H)+ 593.3073, found 593.3076.
1
3355br, 2953m, 2928m, 1686s, 1446m; H NMR δ 8.11 (d, 0.15H,
General Procedure for Epoxide Ring Opening by Phenol
Derivatives. To a solution of epoxide 4a (80 mg, 0.165 mmol, 1
equiv) and phenol derivative (2 equiv) in dry DMF (1 mL) was added
potassium carbonate (0.25 equiv). The suspension was heated at 50
°C for 16 h, cooled to rt, and diluted in DCM (10 mL) and brine (10
mL). The aqueous layer was extracted with DCM (3 × 10 mL), and
the combined organic layers were dried over Na2SO4, filtrated, and
concentrated in vacuo. The residue was purified by flash
chromatography.
J
H6°‑H5° = 8.0 Hz, H6°), 7.97 (d, 0.85H, JH6*‑H5* = 8.0 Hz, H6*), 5.74 (d,
1H, JH5‑H6 = 8.0 Hz, H5), 5.71 (d, 0.15H, JH1′°‑H2′° = 4.5 Hz, H1′°),5.67
(d, 0.85H, JH1′*‑H2′* = 4.5 Hz, H1′*), 5.07−4.54 (br s, 2H, NH), 4.37 (t,
0.85H, JH2′*‑H1′* = 4.5 Hz, JH2′*‑H3′* = 4.5 Hz, H2′*), 4.27 (t, 0.15H,
JH2′°‑H1′° = 4.5 Hz, JH2′°‑H3′° = 4.5 Hz, H2′°), 4.19 (t, 1H, JH3′‑H2′ = 4.5
Hz, JH3′‑H4′ = 4.5 Hz, H3′), 3.95−3.89 (m, 2H, H4′, H8′a), 3.84−3.82
(m, 1H, H5′), 3.80−3.78 (m, 1H, H8′b), 3.77, 3,73 (2s, 3H, -O-CH3),
3.49 (t, 1H, JH7′‑H8′a = JH7′‑H8′b = 4.5 Hz, H7′), 2.99 (dd, 1H, JH6′a‑H6′b
=
12.5 Hz JH6′a‑H5′ = 9.0 Hz, H6′a), 2.80 (dd, 1H, JH6′b‑H6′a = 12.5 Hz,
JH6′b‑H5′ = 4.0 Hz, H6′b), 0.90 (s, 9H, -C(CH3)3), 0.88 (s, 9H,
-C(CH3)3), 0.08, 0.07, 0.06 (3s, 12H, -(CH3)2); 13C NMR δ 172.7
(-CO-OCHH3), 163.9 (C4), 150.8 (C2), 142.2 (C6), 102.2 (C5), 91.3
(C1′), 86.0 (C4′), 75.2 (C2′°), 74.6 (C2′*), 72.5 (C3′), 68.6 (C5′°), 68.2
(C5′*), 63.2 (C8′°), 62.7 (C8′*), 62.7 (C7′), 52.6 (-CO-OCH3), 50.9
(C6′), 25.9, 25.9 (-C(CH3)3), 18.2, 18.1 (-C(CH3)3), −4.2, −4.6, −4.6,
5′(S)-C-(Phenyloxymethyl)-2′,3′-di-O-(tert-butyldimethylsilyl)-
uridine 8b. Compound 8b was synthesized according to the general
procedure for epoxide ring opening with phenol derivatives from
epoxide 4a (80 mg, 0.165 mmol, 1 equiv) and phenol (31 mg, 0.33
mmol, 2 equiv). Flash chromatography of the residue (cyclohexane/
EtOAc = 8/2 to 7/3) afforded 8b as a white film (59 mg, 62%): Rf =
0.60 (cyclohexane/EtOAc = 1/1); [α]D + 12 (c 0.5, CH2Cl2); IR
(film) 2954m, 2927m, 1684s, 1462m; 1H NMR δ 8.41 (br s, 1H, NH),
7.84 (d, 1H, JH6‑H5 = 8.5 Hz, H6), 7.32−7.29 (m, 2H, H9′), 7.00−6.97
(m, 1H, H10′), 6.95−6.91 (m, 2H, H8′), 5.72 (dd, 1H, JH5‑H6 = 8.5 Hz,
JH5‑NH = 2.5 Hz, H5), 5.62 (d, 1H, JH1′‑H2′ = 5.0 Hz, H1′), 4.46 (t, 1H,
+
−4.7 (-(CH3)2)); HRMS APCI+ calcd for C26H50N3O9Si2 (M + H)+
604.3080, found 604.3075.
5′(S)-C-(Azidomethyl)-2′,3′-di-O-(tert-butyldimethylsilyl)uridine
7. To a solution of epoxide 4a (1 g, 2.1 mmol, 1 equiv) in DMF (25
mL) were successively added NaN3 (520 mg, 8.4 mmol, 4 equiv) and
NH4Cl (220 mg, 4.2 mmol, 2 equiv). The resulting suspension was
heated at 70 °C for 16 h, cooled to rt, and diluted with Et2O (30 mL)
and brine (30 mL). The aqueous phase was extracted with Et2O (3 ×
40 mL), and the combined organic layers were washed with water (2 ×
30 mL), dried over Na2SO4, filtrated, and concentrated in vacuo. Flash
chromatography of the residue (cyclohexane/EtOAc = 6/4) afforded
azido alcohol 7 as a white foam (820 mg, 72% yield): Rf = 0.60
(cyclohexane/EtOAc = 1/1); mp 80−84 °C; [α]D − 11 (c 0.5,
J
J
H2′‑H1′ = 4.5 Hz, JH2′‑H3′ = 4.5 Hz, H2′), 4.26 (t, 1H, JH3′‑H2′ = 4.5 Hz,
H3′‑H4′ = 4.5 Hz, H3′), 4.18 (dd, 1H, JH4′‑H3′ = 4.5 Hz, JH4′‑H5′ = 1.0 Hz,
H4′), 4.17−4.12 (m, 1H, H5′), 4.12 (t, 1H, JH6′a‑H6′b = 9.0 Hz, JH6′a‑H5′
=
9.0 Hz, H6′a), 4.06 (dd, 1H, JH6′b‑H6′a = 9.0 Hz, JH6′b‑H5′ = 4.5 Hz, H6′b),
3.39−3.29 (m, 1H, OH), 0.93 (s, 9H, -C(CH3)3), 0.90 (s, 9H,
-C(CH3)3), 0.13, 0.12, 0.09, 0.08, (4s, 12H, -(CH3)2); 13C NMR δ
162.9 (C4), 158.4 (C7′), 150.4 (C2), 142.3 (C6), 129.7 (C9′), 121.5
(C10′), 114.7 (C8′), 102.3 (C5), 92.5 (C1′), 84.5 (C4′), 74.2 (C2′), 72.3
(C3′), 69.3 (C6′), 69.1 (C5′), 26.0, 25.9 (-C(CH3)3), 18.3, 18.1
(-C(CH3)3), −4.2, −4.5, −4.6 (-(CH3)2); HRMS ESI− calcd for
1
CH2Cl2); IR (film) 2955m, 2932m, 2096s, 1686s, 1472w; H NMR δ
−
C28H45N2O7Si2 (M − H)− 577.2771, found 577.2733.
9.83 (br s, 1H, NH), 7.71 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.75 (d, 1H,
JH5‑H6 = 8.0 Hz, H5), 5.45 (d, 1H, JH1′‑H2′ = 5.0 Hz, H1′), 4.53 (t, 1H,
5′(S)-C-(4-Bromo-phenyloxymethyl)-2′,3′-di-O-(tert-butyl-
dimethylsilyl)uridine 8c. Compound 8c was synthesized according to
the general procedure for epoxide ring opening with phenol derivatives
from epoxide 4a (80 mg, 0.165 mmol, 1 equiv) and 4-bromo-phenol
(57 mg, 0.33 mmol, 2 equiv). Flash chromatography of the residue
(cyclohexane/EtOAc = 8/2 to 7/3) afforded 8c as a white film (71 mg,
66% yield): Rf = 0.60 (cyclohexane/EtOAc = 1/1); [α]D + 13 (c 0.5,
CH2Cl2); IR (film) 3585br, 2952m, 2857m, 1682s, 1489m; 1H NMR δ
8.49 (br s, 1H, NH), 7.76 (d, 1H, JH6‑H5 = 8.5 Hz, H6), 7.40−7.37 (m,
2H, H9′), 6.82−6.79 (m, 2H, H8′), 5.72 (dd, 1H, JH5‑H6 = 8.0 Hz,
JH5‑NH = 2.5 Hz, H5), 5.55 (d, 1H, JH1′‑H2′ = 5.0 Hz, H1′), 4.50 (t, 1H,
J
H2′‑H1′ = JH2′‑H3′ = 5.0 Hz, H2′), 4.18 (dd, 1H, JH3′‑H2′ = 5.0 Hz, JH3′‑H4′
= 4.0 Hz, H3′), 4.04−4.01 (m, 1H, H4′), 3.93−3.90 (m, 1H, OH),
3.85−3.80 (m, 1H, H5′), 3.52 (dd, 1H, JH6′a‑H6′b = 12.0 Hz, JH6′a‑H5′
=
8.0 Hz, H6′a), 3.40 (dd, 1H, JH6′b‑H6′a = 12.0 Hz, JH6′b‑H5′ = 5.0 Hz,
H6′b), 0.91 (s, 9H, -C(CH3)3), 0.87 (s, 9H, -C(CH3)3), 0.09, 0.08,
0.06, 0.04, (4s, 12H, -(CH3)2); 13C NMR δ 163.9 (C4), 150.7 (C2),
143.2 (C6), 102.3 (C5), 93.9 (C1′), 85.5 (C4′), 73.5 (C2′), 72.6 (C3′),
69.5 (C5′), 54.1 (C6′), 25.9, 25.9 (-C(CH3)3), 18.1, 18.0 (-C(CH3)3),
−4.3, −4.6, −4.6, −4.7 (-(CH3)2); HRMS APCI+ calcd for
+
C22H42N5O6Si2 (M + H)+ 528.2668, found 528.2669.
J
J
H2′‑H1′ = 5.0 Hz, JH2′‑H3′ = 5.0 Hz, H2′), 4.25 (t, 1H, JH3′‑H2′ = 5.0 Hz,
H3′‑H4′ = 5.0 Hz, H3′), 4.01 (dd, 1H, JH4′‑H3′ = 5.0 Hz, JH4′‑H5′ = 1.0 Hz,
5′(S)-C-(Benzyloxymethyl)-2′,3′-di-O-(tert-butyldimethylsilyl)-
uridine 8a. NaH (60% dispersion in mineral oil, 20 mg, 0.49 mmol, 3
equiv) was added to a solution of benzylic alcohol (54 mg, 0.49 mmol,
3 equiv) in THF (1 mL). At 0 °C, a solution of epoxide 4a (80 mg,
0.165 mmol, 1 equiv) in THF (500 μL) was added dropwise. The
suspension was heated at 60 °C for 16 h, cooled to rt, and diluted in
DCM (10 mL) and saturated NH4Cl aqueous solution (10 mL). The
aqueous layer was extracted with DCM (3 × 10 mL), and the
combined organic layers were dried over Na2SO4, filtrated, and
concentrated in vacuo. Flash chromatography of the residue
(cyclohexane/EtOAc = 8/2 to 7/3) afforded 8a as a white film (64
mg, 66% yield): Rf = 0.44 (cyclohexane/EtOAc = 1/1); [α]D + 23 (c
H4′), 4.15−4.11 (m, 1H, H5′), 4.08 (t, 1H, JH6′a‑H6′b = 9.0 Hz, JH6′a‑H5′
=
9.0 Hz, H6′a), 3.60 (dd, 1H, JH6′b‑H6′a = 9.0 Hz, JH6′b‑H5′ = 5.5 Hz, H6′b),
3.48−3.42 (m, 1H, OH), 0.93 (s, 9H, -C(CH3)3), 0.90 (s, 9H,
-C(CH3)3), 0.12, 0.09, 0.07, (3s, 12H, -(CH3)2); 13C NMR δ 162.9
(C4), 157.5 (C7′), 150.4 (C2), 142.6 (C6), 132.6 (C9′), 116.5 (C8′),
113.7 (C10′), 102.3 (C5), 93.2 (C1′), 84.7 (C4′), 73.9 (C2′), 72.4 (C3′),
69.5 (C6′), 69.0 (C5′), 26.0, 25.9 (-C(CH3)3), 18.2, 18.1 (-C(CH3)3),
−4.2, −4.5, −4.6, −4.6 (-(CH3)2); HRMS ESI+ calcd for C28H46-
+
BrN2O7Si2 (M + H)+ 657.2021, found 657.2024.
5′(S)-C-(Phenylthiomethyl)-2′,3′-di-O-(tert-butyldimethylsilyl)-
uridine 9. To a solution of epoxide 4a (80 mg, 0.165 mmol, 1 equiv)
and thiophenol (84 μL, 0.83 mmol, 5 equiv) in dry DMF was added
sodium methoxide (23 mg, 0.41 mmol, 2.5 equiv). The resulting
1
0.8, CH2Cl2); IR (film) 3384br, 2952m, 2929m, 1682s, 1471m; H
NMR δ 8.50 (br s, 1H, NH), 7.97 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 7.39−
7.31 (m, 5H, Har), 5.70 (dd, 1H, JH5‑H6 = 8.0 Hz, JH5‑NH = 2.5 Hz, H5),
F
dx.doi.org/10.1021/jo501410m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
suspension was heated at 100 °C for 16 h, cooled to rt, and diluted in
Et2O (10 mL) and a saturated aqueous solution of NaHCO3 (10 mL).
The aqueous phase was extracted with Et2O (3 × 10 mL), and the
combined organic layers were washed with brine (10 mL) and water
(10 mL), dried over Na2SO4, filtrated, and concentrated in vacuo.
Flash chromatography of the residue (cyclohexane/EtOAc = 6/4)
afforded 9 as a white powder (71 mg, 73% yield): Rf = 0.76
(cyclohexane/EtOAc = 1/1); mp 190−192 °C; [α]D − 13 (c 1.0,
CH2Cl2); IR (film) 3201br, 2950m, 2885m, 1697s, 1464m; 1H NMR δ
9.24 (br s, 1H, NH), 7.84 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 7.41−7.31 (m,
2H, H8′), 7.32−7.29 (m, 2H, H9′), 7.25−7.22 (m, 1H, H10′), 5.73 (dd,
1H, JH5‑H6 = 8.0 Hz, JH5‑NH = 2.0 Hz, H5), 5.57 (d, 1H, JH1′‑H2′ = 4.5
Hz, H1′), 4.42 (t, 1H, JH2′‑H1′ = 4.5 Hz, JH2′‑H3′ = 4.5 Hz, H2′), 4.14 (t,
1H, JH3′‑H2′ = 4.5 Hz, JH3′‑H4′ = 4.5 Hz, H3′), 4.09 (dd, 1H, JH4′‑H3′ = 4.5
Hz, JH4′‑H5′ = 1.0 Hz, H4′), 3.72−3.69 (m, 1H, H5′), 3.59−3.53 (br s,
1H, OH), 3.16 (dd, 1H, JH6′a‑H6′b = 14.0 Hz, JH6′a‑H5′ = 7.5 Hz, H6′a),
3.13 (dd, 1H, JH6′b‑H6′a = 14.0 Hz, JH6′b‑H5′ = 6.5 Hz, H6′b), 0.88 (s, 9H,
-C(CH3)3), 0.84 (s, 9H, -C(CH3)3), 0.06, 0.05, 0.04, 0.00 (4s, 12H,
-(CH3)2); 13C NMR δ 163.5 (C4), 150.5 (C2), 142.5 (C6), 134.2 (C7′),
130.6 (C8′), 129.3 (C9′), 127.2 (C10′), 102.2 (C5), 92.7 (C1′), 85.5
(C4′), 74.2 (C2′), 72.5 (C3′), 67.9 (C5′), 38.5 (C6′), 25.9 (-C(CH3)3),
18.2, 18.1 (-C(CH3)3), −4.3, −4.6, −4.6, −4.8 (-(CH3)2) HRMS
71.1 (C5′), 34.0 (C6′), 26.0, 25.9 (-C(CH3)3), 18.2, 18.1 (-C(CH3)3),
−4.3, −4.5, −4.5, −4.8, (-(CH3)2); HRMS APCI+ calcd for
+
C22H42BrN2O6Si2 (M + H)+ 565.1759, found 565.1761.
5′(S)-C-(Trimethylsilylacetylenylmethyl)-2′,3′-di-O-(tert-butyl-
dimethylsilyl)uridine 12. At −78 °C, to a solution of alkyne (2.29 g,
23.35 mmol, 4 equiv) in dry THF (35 mL) was dropwise added n-
BuLi (1.9 M in hexane, 12.3 mL, 23.35 mmol, 4 equiv). The resulting
solution was stirred at −78 °C for 1 h. At −78 °C were successively
added dropwise a solution of epoxide 4a (2.83 g, 5.84 mmol, 1 equiv)
in freshly distillated THF (35 mL) and BF3·Et2O (2.9 mL, 23.35
mmol, 4 equiv). The resulting solution was allowed to warm from −78
to −10 °C, and the mixture was diluted in DCM. A saturated aqueous
solution of NH4Cl was then added (20 mL), and the aqueous phase
was extracted with DCM (3 × 40 mL). The combined organic phases
were dried over Na2SO4, filtrated, and concentrated in vacuo. Flash
chromatography of the residue (cyclohexane/EtOAc = 8/2 to 7/3)
afforded 12 as a white powder (2.63 g, 77% yield): Rf = 0.60
(cyclohexane/EtOAc = 1/1); mp 192−196 °C; [α]D − 5 (c 0.5,
CH2Cl2); IR (film) 2954m, 2501w, 2857m, 1690s, 1472m; 1H NMR δ
8.79 (br s, 1H, NH), 7.59 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.74 (dd, 1H,
JH5‑H6 = 8.0 Hz, JH5‑NH = 2.0 Hz, H5), 5.48 (d, 1H, JH1′‑H2′ = 6.0 Hz,
H1′), 4.60 (dd, 1H, JH2′‑H1′ = 6.0 Hz, JH2′‑H3′ = 5.0 Hz, H2′), 4.20−4.16
(m, 2H, H3′, H4′), 3.88−3.82 (m, 1H, H5′), 3.57−3.50 (m, 1H, OH),
2.60 (dd, 1H, JH6′a‑H6′b = 17.0 Hz, JH6′a‑H5′ = 7.0 Hz, H6′a), 2.49 (dd,
1H, JH6′b‑H6′a = 17.0 Hz, JH6′b‑H5′ = 8.0 Hz, H6′b), 0.93 (s, 9H,
-C(CH3)3), 0.88 (s, 9H, -C(CH3)3), 0.16 (s, 9H, -Si-(CH3)3) 0.11,
0.06, 0.00, (3s, 12H, -(CH3)2); 13C NMR δ 163.1 (C4), 150.4 (C2),
143.5 (C6), 102.7 (C8′), 102.4 (C5), 93.9 (C1′), 87.6 (C7′), 86.6 (C4′),
73.3 (C2′), 73.0 (C3′), 69.9 (C5′), 26.0, 25.9 (-C(CH3)3), 25.8 (C6′),
18.2, 18.0 (-C(CH3)3), 0.19 (-(CH3)3), −4.3, −4.4, −4.5, −4.8
+
APCI+ calcd for C28H47N2O6 SSi2 (M + H)+ 595.2688, found
595.2696.
5′(S)-C-(Cyanomethyl)-2′,3′-di-O-(tert-butyldimethylsilyl)uridine
10. Warning! HCN gas. The reaction should be performed in a fumehood.
To a solution of epoxide 4a (80 mg, 0.165 mmol, 1 equiv) in DMF (1
mL) were successively added KCN (88 mg, 1.32 mmol, 8 equiv) and
NH4Cl (13.3 mg, 0.25 mmol, 1.5 equiv). The resulting suspension was
heated at 100 °C for 16 h, cooled to rt, and diluted with Et2O (10 mL)
and water (10 mL). The aqueous phase was extracted with Et2O (3 ×
10 mL), and the combined organic layers were washed with brine (1 ×
10 mL), dried over Na2SO4, filtrated, and concentrated in vacuo. Flash
chromatography of the residue (cyclohexane/EtOAc = 6/4) afforded
10 as a white foam (57 mg, 68% yield): Rf = 0.21 (cyclohexane/EtOAc
= 6/4); mp 118−120 °C; [α]D − 78 (c 0.8, CH2Cl2); IR (film) 2929m,
+
(-(CH3)2) HRMS APCI+ calcd for C27H51N2O6Si3 (M + H)+
583.3049, found 583.3055.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. X-ray
crystallographic data of 4a in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
2857m, 1686s, 1431w; H NMR δ 9.44 (br s, 1H, NH), 7.48 (d, 1H,
JH6‑H5 = 8.0 Hz, H6), 5.80 (dd, 1H, JH5‑H6 = 8.0 Hz, JH5‑NH = 2.0 Hz,
H5), 5.36 (d, 1H, JH1′‑H2′ = 7.0 Hz, H1′), 4.70 (dd, 1H, JH2′‑H1′ = 7.0 Hz,
JH2′‑H3′ = 4.5 Hz, H2′), 4.48−4.43 (m, 1H, OH), 4.20 (dd, 1H, JH3′‑H2′
= 4.5 Hz, JH3′‑H4′ = 2.5 Hz, H3′), 4.09−4.03 (m, 2H, H4′, H5′), 2.71
(dd, 1H, JH6′a‑H6′b = 17.0 Hz, JH6′a‑H5′ = 7.5 Hz, H6′a), 2.80 (dd, 1H,
JH6′b‑H6′a = 17.0 Hz, JH6′b‑H5′ = 6.0 Hz, H6′b), 0.92 (s, 9H, -C(CH3)3),
0.87 (s, 9H, -C(CH3)3), 0.11, 0.06, −0.01, (3s, 12H, -(CH3)2); 13C
NMR δ 163.3 (C4), 150.7 (C2), 144.2 (C6), 117.5 (C7′), 102.7 (C5),
95.8 (C1′), 87.3 (C4′), 72.9 (C2′), 72.3 (C3′), 67.6 (C5′), 26.0, 25.9
(-C(CH3)3), 23.1 (C6′), 18.2, 18.1 (-C(CH3)3), −4.3, −4.4, −4.5, −4.8
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: christine.gravier-pelletier@parisdescartes.fr (C.G.-P.).
*E-mail: sandrine.calvet-vitale@parisdescartes.fr (S.C.-V.).
Notes
The authors declare no competing financial interest.
+
(-(CH3)2); HRMS APCI+ calcd for C23H42N3O6Si2 (M + H)+
512.2607, found 512.2609.
ACKNOWLEDGMENTS
5′(S)-C-(Bromomethyl)-2′,3′-di-O-(tert-butyldimethylsilyl)uridine
11. At −50 °C, under argon, to a suspension of epoxide 4a (40 mg,
0.08 mmol, 1 equiv) and lithium bromide (12.9 mg, 0.15 mmol, 1.8
equiv) in THF (1 mL) was added boron trifluoride etherate (12 μL,
0.09 mmol, 1.1 equiv). The reaction mixture was stirred at −50 °C for
5 min and then at rt for 1 h. After addition of NaHCO3 10%, the
aqueous phase was extracted with DCM (3 × 10 mL). The combined
organic layers were dried over Na2SO4, filtrated, and concentrated in
vacuo. Flash chromatography of the residue (cyclohexane/EtOAc = 6/
4) afforded 11 as a white powder (37 mg, 79% yield): Rf = 0.53
(cyclohexane/EtOAc = 1/1); mp 202−204 °C; [α]D − 16 (c 1.0,
CH2Cl2); IR (film) 3385br, 2953m, 1683s, 1472m, 1259m; 1H NMR δ
9.59 (br s, 1H, NH), 7.62 (d, 1H, JH6‑H5 = 8.0 Hz, H6), 5.76 (d, 1H,
JH5‑H6 = 8.0 Hz, H5), 5.46 (d, 1H, JH1′‑H2′ = 5.0 Hz, H1′), 4.58 (t, 1H,
JH2′‑H1′ = JH2′‑H3′ = 5.0 Hz, H2′), 4.28 (d, 1H, JH4′‑H3′ = 3.0 Hz, H4′),
4.18 (dd, 1H, JH3′‑H2′ = 5.0 Hz, JH3′‑H4′ = 3.0 Hz, H3′), 3.99−3.95 (m,
1H, OH), 3.94−3.90 (m, 1H, H5′), 3.50 (dd, 1H, JH6′a‑H6′b = 11.5 Hz,
■
We thank the “Centre National de la Recherche Scientifique”
and the “Minister
̀
e de l′Enseignement Super
́
ieur et de la
Recherche” for financial support of this work and for a Ph.D.
grant to M.J.F. We would like to thank M. Pirocchi and the staff
of the FIP Beamline for advice during XRD data collections at
́
ESRF, Grenoble, France. Assia Hessani (Universite Paris
Descartes) is gratefully acknowledged for mass spectra analyzes.
Proofreading of this article was done by Paris Descartes
University’s Language Center (Centre de Langues de la Maison
́
des Langues, Universite Paris Descartes).
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̌
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