A stereoselective approach to β-L-arabino nucleoside analogues: Synthesis and cyclization of acyclic 1′,2′-syn N, O-Acetals

Article abstract of DOI:10.1021/jo3012754

Reported herein is a novel and versatile strategy for the stereoselective synthesis of unnatural β-l-arabinofuranosyl nucleoside analogues from acyclic N,OTMS-acetals bearing pyrimidine and purine bases. These unusual acetals undergo a C1′ to C4′ cyclization where the OTMS of the acetal serves as the nucleophile to generate 2′-oxynucleosides with complete retention of configuration at the C1′ acetal center. N,OTMS-acetals are obtained diastereoselectively from additions of silylated nucleobases onto acyclic polyalkoxyaldehydes in the presence of MgBr ₂·OEt₂. The strategy reported is addressing important synthetic challenges by providing stereoselective access to unnatural l-nucleosides starting from easily accessible pools of d-sugars and, as importantly, by allowing the formation of the sterically challenging 1′,2′-cis nucleosides. A wide variety of nucleoside analogues were synthesized in 7-8 steps from easily accessible d-xylose.

Full text of DOI:10.1021/jo3012754

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pubs.acs.org/joc
A Stereoselective Approach to β‑L‑Arabino Nucleoside Analogues:
Synthesis and Cyclization of Acyclic 1′,2′-syn N,O‑Acetals
Starr Dostie,†,§ Michel Prevost,† and Yvan Guindon*,†,‡,§
́
†Bio-organic Chemistry Laboratory, Institut de Recherches Cliniques de Montrea
́
l (IRCM), 110 avenue des Pins Ouest, Montrea
́
l,
Queb
‡Department of Chemistry, Universite
§Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montrea
́
ec H2W 1R7, Canada
́
de Montrea
́
l, C.P. 6128, succursale Centre-Ville, Montrea
́ ́
l, Quebec H3C 3J7, Canada
́
l, Quebec H3A 2K6, Canada
́
S
* Supporting Information
ABSTRACT: Reported herein is a novel and versatile strategy for the
stereoselective synthesis of unnatural β-L-arabinofuranosyl nucleoside
analogues from acyclic N,OTMS-acetals bearing pyrimidine and purine
bases. These unusual acetals undergo a C1′ to C4′ cyclization where
the OTMS of the acetal serves as the nucleophile to generate 2′-
oxynucleosides with complete retention of configuration at the C1′
acetal center. N,OTMS-acetals are obtained diastereoselectively from
additions of silylated nucleobases onto acyclic polyalkoxyaldehydes in the presence of MgBr2·OEt2. The strategy reported is
addressing important synthetic challenges by providing stereoselective access to unnatural L-nucleosides starting from easily
accessible pools of D-sugars and, as importantly, by allowing the formation of the sterically challenging 1′,2′-cis nucleosides. A
wide variety of nucleoside analogues were synthesized in 7−8 steps from easily accessible D-xylose.
cytotoxicity as compared to their D-enantiomers.8 A single
versatile method addressing these two synthetic challenges
would be a useful tool for medicinal chemists in order to
investigate new and improved biologically active nucleoside
analogues as exemplified by the HBV antiviral agent Clevudine
(Figure 1).9
INTRODUCTION
■
Many therapeutically relevant nucleoside analogues that have
been used for the treatment of leukemia display arabino
scaffolds with 1′,2′-cis arrangements between the nucleobase
attached at the anomeric center and the electron withdrawing
group attached at C2′ (Figure 1).1 This particular stereo-
We previously developed an approach to generate two series
of nucleoside analogues from a common acyclic thioaminal
(Scheme 1A).10 These acyclic intermediates can undergo two
distinct intramolecular cyclization processes. A first mode of
Scheme 1
Figure 1. Anticancer and antiviral agents with a 1′,2′-cis relative
stereochemistry and/or in the L-series.
chemical arrangement was demonstrated to increase the rate of
monophosphorylation by dCK (deoxycytidine kinase), a critical
step for the pharmacological activity of numerous nucleoside
analogues.2 The 1′,2′-cis relationship represents an important
synthetic challenge since it cannot be obtained by anchimeric
assistance of a neighboring group.3 The nucleobase must be
delivered from the most hindered face of the sugar moiety.4,5
Since the discovery of L-3TC,6 the interest of the medicinal
chemistry community for the L-series has grown exponentially,
as demonstrated by the number of compounds and clinical uses
investigated (cancer, HBV, HIV).7 L-Analogues have been
shown to have increased antiviral activity with reduced
Received: June 19, 2012
Published: August 8, 2012
© 2012 American Chemical Society
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cyclization leads to D-1′,2′-trans nucleoside analogues (C4′ →
C1′ cyclization). The second mode of cyclization yields L-1′,2′-
cis-4′-thionucleosides (C1′ → C4′ cyclization). In both
cyclization processes, the stereochemistry of the nucleoside
obtained is provided by the acyclic thioaminal precursor. This is
in contrast with other acyclic approaches where the stereo-
chemistry of the anomeric center is determined during the
cyclization step.11 The efficiency and versatility of this approach
convinced us to investigate the cyclization of 1′,2′-syn acyclic
N,O-acetals allowing access to L-1′,2′-cis nucleoside analogues
starting from common D-sugars (Scheme 1B). Herein, we
report a cyclization protocol for acyclic N,OTMS-acetals, which
are accessed with high 1′,2′-syn diastereoselectivity by addition
of silylated nucleobases to aldehydes with MgBr2·OEt2, a
bidentate Lewis acid. In the cyclization reaction, the OTMS of
the acetal serves as the putative nucleophile involved in the
displacement of the leaving group at the C4′ position with
inversion of configuration.
3.16 The resulting secondary alcohol was successfully protected
with a nosyl group, and subsequent ozonolysis provided the
C4-nosylate protected aldehyde 4 in high yield.
The coupling step was then examined with these aldehydes
bearing a leaving group at C4 (Table 1). Interestingly, the 1′,2′-
Table 1. N,OTMS-Acetal Formation
ab
,
entry
nucleobase
Thymine
P
yield (%)
1
Ms (5a)
Ns (6a)
74
62
61
63
66
54
57
58
71
65
49
2
“
3
Uracil
Ms (7a)
Ns (8a)
4
“
5
Adenine
Ms (9a)
Ns (10a)
Ms (11a)
Ns (12a)
Ms (13a)
Ns (14a)
Ms (15a)
RESULTS AND DISCUSSION
■
6
“
At the onset of our study to synthesize L-nucleoside analogues
from acyclic precursors, we realized that the simple extension of
our previous work to selectively prepare the targeted N,O-
acyclic acetals was unsuccessful. Indeed, using the acetal as
opposed to the thioacetal (Scheme 1) led to poor
diastereoselectivity in the addition step.10,12 A different scenario
was therefore considered: the addition of silylated nucleobases
onto aldehydes derived from D-sugars, followed by intra-
molecular displacement of a leaving group. Two major hurdles
were identified and had to be circumvented to render this
strategy efficient. The acyclic N,OTMS-acetals had to be
generated with high syn diastereoselectivity and the chemical
stability of these intermediates had to be sufficient to withstand
a cyclization protocol.13 Although silyloxy ethers have been
suggested to be involved in intramolecular reactions,14 we
anticipated a reduced nucleophilicity of the oxygen in the
N,OTMS-acetal that could compromise the planned cyclization.
This cyclization, which had not been previously reported in the
literature, was evaluated experimentally.
7
5F-Uracil
8
“
9
Cytosine
10
11
“
N4−AcCytosine
a
All N,OTMS-acetals were formed with >20:1 diastereoselectivity for
b
the 1′,2′-syn isomer. Silylated base (2.0−4.0 equiv), MgBr2·OEt2
(1.5−2.0 equiv), −40 °C.
syn N,OTMS-acetals 5a (P = Ms) and 6a (P = Ns) were
obtained with high diastereoselectivity (>20:1)17 when silylated
thymine in the presence of 2.0 equiv of MgBr2·OEt2 were
reacted in acetonitrile with aldehydes 2 or 4 (entries 1 and 2).
Contrary to our initial apprehensions, we were able to isolate
these N,OTMS-acetals 5a and 6a in 74 and 62% yields,
respectively, with standard aqueous workup and flash
chromatography. Persilylated uracil provided the N,OTMS-
acetals 7a and 8a in high diastereoselectivity as well (Table 1,
entries 3 and 4). Although introduction of purine bases is
known to be challenging, we were pleased that the adenosine
N,OTMS-acetals 9a and 10a could be synthesized with high
regio-(N9) and diastereoselectivity (Table 1, entries 5 and 6).
Couplings of silylated 5F-uracil and cytosine proved to be as
effective (entries 7−10). A slightly lower yield was noticed with
N4−AcCytosine 15a (entry 11). Formation of N9-guanosine
N,OTMS-acetals was unsuccessful, possibly due to competing
N3 and N7 nucleophilic sites.
The desired 1′,2′-syn diastereoselectivity could result from
the addition of persilylated nucleobase (Nu) on the opposite
side of the C2 substituent of five-membered ring magnesium
chelate A (Scheme 3). The generated alkoxyde intermediate B
would then be either silylated intramolecularly or intermolec-
ularly by a second persilylated nucleobase. Five-membered
magnesium chelates have previously been shown to form
preferentially over six-membered chelates, which could be
generated by chelation of the C3 alkoxy group.18
Diastereoselective Synthesis of N,OTMS-Acetals. In
order to investigate the nucleobase coupling onto an acyclic
aldehyde, we elected to synthesize two aldehydes bearing either
a mesylate or a nosylate at C4, the latter being a better leaving
group. Aldehyde 2 was prepared by oxidation of the mesylate
protected dithioacetal S1 (Scheme 2).15 A similar approach
with the corresponding nosylate dithioacetal led to a mixture of
products, including cyclic thiofuranosides. An alternate strategy
to access the requisite aldehyde 4 was therefore developed
(Scheme 2). The partially protected sugar derived from D-
xylose was subjected to a Wittig reaction to give acyclic alkene
Scheme 2. Formation of Aldehydes 2 and 4
Cyclization of N,OTMS-Acetals. We then sought to find
conditions allowing C1′ → C4′cyclization without epimeriza-
tion of the stereogenic center at C1′. The cyclization of
N,OTMS-acetals bearing a mesylate at C4′ did not occur
directly after coupling in the presence of MgBr2·OEt2 at low
temperatures, and warming the reaction mixtures only provided
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Scheme 3. Bidentate pathway leading to 1′,2′-syn N,O-
Table 3. SN2-Like Cyclization of C4′-Nosylate N,OTMS-
a
Acetals
Acetals
entry
N,OTMS-acetal
product
conditions
yield (%)
1
2
6a (Thymine)
16a
“
D
E
77
63
74
61
17
60
63
45
28
46
8
the corresponding aldehyde 2. Alternative conditions were
therefore examined to cyclize the mesylate series.19 When 5a
was heated at 140 °C for 3 h in DMSO, only trace amounts of
the cyclized product were observed (Table 2, entry 1).20
“
3
8a (Uracil)
17a
“
D
E
4
“
5
10a (Adenine)
18a
“
D
E
6
“
Table 2. SN2-Like Cyclization of C4′-Mesylate N,OTMS-
7
12a (5F-Uracil)
19a
“
D
E
a
Acetals
8
“
9
14a (Cytosine)
20a
“
D
E
10
“
b
11
21a (N4−AcCyt)
22a
“
D
E
12
“
52
a
Conditions D: 90 °C, 3 h. Conditions E: 90 °C, 3 h, Al(OiPr)3 (3.0
b
equiv). N,OTMS-N4−AcCytosine acetal 21a was synthesized through
acetylation of the 1′,2′-syn cytosine acetal 14a.
entry
N,OTMS-acetal
product
conditions
yield (%)
1
2
3
4
5
6
7
5a (Thymine)
16a
“
A
B
C
B
C
B
C
traces
34
Satisfying results were also achieved with uracil and 5F-uracil
using this simple procedure (entries 3 and 7). Low yields were
noted, however, for N,OTMS-acetals bearing adenine, cytosine
and N4−AcCytosine nucleobases (Table 3, entries 5, 9, and
11). The addition of Al(OiPr)3 was thus considered. Whereas
no improvements were noted for the thymine, uracil and 5F-
uracil cases (entries 2, 4 and 8), significantly higher yields were
noted with adenine (entry 6, 60% yield), along with cytosine
and its derivative (entries 10 and 12). The role of the Lewis
acid in these reactions has yet to be elucidated, but its acidic
character could allow for complexation to the sulfonate oxygens
of the C4′ protecting group, enhancing its leaving group
ability.23
In the course of the synthesis of 1′,2′-cis analogue 20a
bearing cytosine as the nucleobase (Table 3, entry 10), we
observed the formation of primary alcohol 23 in a 1:2 ratio with
the cyclized nucleoside 20a (Scheme 4). This side product
could form through an intramolecular or an intermolecular SN2
displacement of the C4′-Ns by the carbonyl group of the
“
“
“
52
7a (Uracil)
17a
“
49
“
57
9a (Adenine)
18a
“
40
“
38
a
Conditions A: 140 °C, 3 h. Conditions B: 140 °C, 3 h, Al(OiPr)3 (3.0
equiv). Conditions C: 180 °C, MW, 10 min, Al(OiPr)3 (0.6 equiv).
Addition of Lewis acids such as Al(OiPr)3 have been shown to
facilitate cyclization reactions proceeding via the displacement
of mesylate to form oxetane rings.21 We were pleased to note
that upon addition of Al(OiPr)3, the desired L-1′,2′-cis
nucleoside analogue 16a could be isolated in 34% yield
(Table 2, entry 2) with a >20:1 diastereoselectivity consistent
with an SN2-like intramolecular cyclization. The C1′ → C4′
cyclization was further investigated using microwave heating.
Optimization of the cyclization conditions (180 °C for 10 min
using 0.6 equiv of Al(OiPr)3) resulted in improved yields for
the thymine and uracil 1′,2′-cis nucleoside analogues 16a and
17a (Table 2, entries 3 and 5). The same conditions resulted in
a 40% yield of the adenosine nucleoside analogue 18a using
conventional heating (entry 6) and a 38% yield with microwave
heating (entry 7). The main advantages of using microwave
conditions are a much faster reaction time (180 °C for 10 min
vs 140 °C for 3 h) with a lower amount of aluminum Lewis acid
(0.6 equiv vs 3.0 equiv). In all the above cyclizations, residual
starting material was not detected in the crude reaction
mixtures. The low yields obtained were therefore attributed to
decomposition of the starting N,OTMS-acetals at these high
cyclization temperatures. We thus turned our attention to the
nosylate series bearing a better leaving group at C4′.22
Scheme 4. Formation of Side-Product 23
When heated at only 90 °C, N,OTMS-acetal 6a bearing a
nosylate group cyclized in good yields (Table 3, entry 1) to
provide L-1′,2′-cis nucleoside analogue 16a (77% yield).
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cytosine moiety. The formation of only one regioisomer
suggests that the intramolecular displacement prevails. The
resulting cyclic intermediate 24 would collapse to the
corresponding aldehyde 25 with rearomatization of the
cytosine. In the presence of Al(OiPr)3, the aldehyde would
then undergo a Meerwein-Ponndorf-Verley (MPV) reduction24
to furnish primary alcohol 23. This side product was formed in
various amounts with the other nucleobases in the presence of
Al(OiPr)3. It is noteworthy that adenine precursors did not lead
to this side product.
In all the nucleobase coupling reactions, the N,OTMS-acetals
were purified prior to cyclization. Since some acetal cleavage
was suspected on silica gel, cyclization of the crude acetals was
tested. The L-1′,2′-cis nucleoside analogues were formed over
two steps using the crude 1′,2′-syn N,OTMS-acetal product for
the C1′ → C4′ cyclization. It was observed that the yields of L-
1′,2′-cis analogues obtained from cyclization of crude N,OTMS-
acetals were consistent with those obtained from the purified
acetals. This indicates that there is no need to purify the 1′,2′-
syn N,OTMS-acetals prior to C1′ → C4′ cyclization, rendering
the process even simpler.
unveiled yet another possibility (Figure 2). This experiment
indicates that cyclization of 6a proceeds within 47 h at room
temperature with the formation of an intermediate species that
completely converts to product. Despite the fact that we could
1
not isolate this intermediate, observed H NMR characteristics
are in good agreement with a hemiaminal arising from in situ
deprotection of the OTMS acetal. As seen in Figure 2, NMR
chemical shifts that may correspond to H1′ and H4′ of the
intermediate are very similar to those of the starting material,
suggesting that the acetal center and nosylate protecting group
are still present. It is also interesting to note that there are no
NMR signals corresponding to an additional silyl protecting
group, which further indicates that 6a has indeed been
deprotected to the corresponding hemiaminal 26.26 The
cyclization could therefore occur through the hemiaminal
generated after in situ deprotection of the N,OTMS-acetal with
retention of configuration at C1′ (Figure 2, Path B). In the
course of these NMR experiments, the hemiaminal 26 did not
decompose to aldehyde 4 with loss of the thymine nucleobase.
In order to confirm that the C1′ → C4′ cyclization proceeds
with retention of configuration at C1′, a 1′,2′-anti N,OTMS-
acetal was synthesized and cyclized (Scheme 5). This opposite
Mechanistic Insights for the C1′ → C4′ Cyclization.
Different scenarios were considered for the mechanism of C1′
→ C4′ cyclization. It was first hypothesized that the oxygen of
the N,OTMS-acyclic acetal could serve as the nucleophile
displacing the leaving group at C4′ to form the L-nucleosides
(Figure 2, Path A). Alternatively, the reacting intermediate in
the cyclization could involve a hexacoordinate silicon complex25
in the presence of DMSO that would increase the
Scheme 5. Synthesis and Cyclization of 1′,2′-anti N,OTMS-
Acetal 7b
1
nucleophilicity of the oxygen. H NMR spectroscopic analysis
of the C1′ → C4′ cyclizations of nosylated acetals in DMSO-d6
1′,2′-anti configuration was generated with poor selectivity
(1′,2′-syn:1′,2′-anti; 1:3) in presence of TMSOTf, but a pure
fraction of the 1′,2′-anti product could be separated by flash
chromatrography. Cyclization of 7b provided only the L-1′,2′-
trans nucleoside analogue 17b (>20:1), as determined by the
1H NMR of the crude reaction mixture.
The retention of configuration at C1′ for the C1′ → C4′
cyclization was also further examined in the nosylate series
(Scheme 6). A 1:2 mixture of 6a:6b was prepared by coupling
Scheme 6. Synthesis and Cyclization of a Mixture of
N,OTMS-Acetals 6a and 6b
1
Figure 2. H NMR spectra during cyclization of 1′,2′-syn N,OTMS-
acetal 6a at 25 °C where t1 = 0 h, t2 = 7 h, t3 = 14 h, t4 = 21 h, t5 = 47 h.
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reaction mixture was maintained for 16 h at 25 °C and diluted with
distilled water (50 mL). The aqueous layer was extracted with ether (3
× 50 mL), and the combined organic layers were washed with
saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatog-
raphy (hexanes/EtOAc, 80:20) provided 1 (9.15 g, 77%) as a yellow
aldehyde 4 with silylated thymine in presence of TMSOTf
(Scheme 6). The 1′,2′-syn and anti N,OTMS-acetals could not
be separated and were therefore cyclized as a mixture in
DMSO-d6. The corresponding 1:2 mixture of the L-1′,2′-cis and
trans nucleoside analogues 16a and 16b was obtained cleanly as
expected.
solid: Rf = 0.2 (hexanes/EtOAc, 80:20); [α]25 −11.0 (c 1.00,
D
CH2Cl2); mp 55−57 °C; Formula C30H38O4S2; MW 526.7503 g/mol;
IR (neat) νmax 3450, 2925, 1452 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.40−7.21 (m, 15H), 4.91 (d, J = 11.1 Hz, 1H), 4.81 (d, J = 2.1 Hz,
1H), 4.78 (d, J = 2.1 Hz, 1H), 4.56−4.43 (m, 3H), 4.12 (dd, J = 7.4,
3.0 Hz, 1H), 4.03 (d, J = 3.0 Hz, 1H), 3.99−3.94 (m, 2H), 3.54 (dd, J
= 9.5, 6.7 Hz, 1H), 3.43 (dd, J = 9.5, 5.5 Hz, 1H), 2.81−2.61 (m, 4H),
2.50 (s, 1H), 1.26 (t, J = 4.7 Hz, 3H), 1.23 (t, J = 4.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 138.4, 138.1, 137.8, 128.31, 128.30,
128.23, 128.16, 127.73, 127.69, 127.67, 127.63, 127.4, 83.2, 79.8, 75.3,
75.0, 73.2, 71.3, 69.8, 53.2, 25.9, 25.2, 14.5, 14.4 ppm; HRMS calcd for
C30H38O4NaS2 [M + Na+] 549.2104, found 549.2105 (−0.8 ppm).
(−)-(2R,3R,4R)-1,3,4-tris(Benzyloxy)-5,5-bis(ethylthio)-
pentan-2-yl methanesulfonate (S1). To a 0.2 M solution of
dithioacetal 1 (3.99 g, 7.57 mmol) in CH2Cl2 (38 mL) at −40 °C were
added Et3N (1.6 mL, 11.35 mmol, 1.5 equiv) and MsCl (0.77 mL, 9.84
mmol, 1.3 equiv). The reaction was maintained for 30 min at −40 °C
and 2 h at 0 °C. 1 N HCl (5 mL) was then added to the reaction
mixture. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL),
and the combined organic layers were washed with saturated aqueous
NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and
concentrated in vacuo. S1 was obtained as a colorless oil and used
as a crude mixture for the next reaction. Purification by flash
chromatography (hexanes/EtOAc, 80:20) of an aliquot of the reaction
mixture allowed for characterization of S1: Rf = 0.43 (hexanes/EtOAc,
CONCLUSIONS
■
We have reported a novel strategy for the synthesis of valuable
L-1′,2′-cis nucleoside analogues from unusual 1′,2′-syn
N,OTMS-acetals bearing pyrimidine as well as purine bases.
In order to diastereoselectively generate these acyclic
precursors, we have developed a methodology that involves
addition of silylated nucleobases onto polyalkoxyaldehydes in
the presence of MgBr2·OEt2 through a suggested Cram-chelate
transition state. These N,OTMS-acetals can undergo unprece-
dented C1′ → C4′ cyclization with complete retention of
configuration at C1′. NMR studies of the reaction may have
unveiled a possible mechanism involving an in situ deprotection
of the N,OTMS-acetals. This strategy provides a stereoselective
access to unnatural L-nucleosides starting from easily accessible
pools of D-sugars. As importantly, this methodology addresses
the challenging synthesis of 1′,2′-cis nucleosides. Finally, this
sequence has proven to be reliable and versatile for a variety of
nucleobases.
EXPERIMENTAL SECTION
■
General Comments. All reactions requiring anhydrous conditions
were carried out under an atmosphere of nitrogen or argon in flame-
dried glassware using standard syringe techniques. Dichloromethane,
acetonitrile, toluene and dimethylsulfoxide were dried with 4 Å
molecular sieves prior to use. The 4 Å molecular sieves (1−2 mm
beads) were activated by heating at 180 °C for 48 h under a vacuum
prior to adding to new bottles of solvent purged with argon.
Commercially available reagents were used as received unless
otherwise noted. Silylated bases were prepared by known methods.27
Ambersep 900 OH basic resin obtained from commercial sources was
rinsed thoroughly with methanol and acetone, kept under a vacuum
for 16 h and stored at 25 °C. Flash chromatography was performed on
silica gel 60 (0.040−0.063 mm) using forced flow flash chromatog-
raphy or an automated flash purification system. Analytical thin-layer
chromatography (TLC) was carried out on precoated (0.25 mm) silica
gel aluminum plates. Visualization was performed with UV short
wavelength and/or revealed with ammonium molybdate or potassium
permanganate solutions. 1H NMR spectra were recorded at room
temperature on 400 and 500 MHz NMR spectrometers as indicated.
The data are reported as follows: chemical shift in ppm referenced to
residual solvent (CDCl3 δ 7.26 ppm), multiplicity (s = singlet, apps =
apparent singlet, d = doublet, dd = doublet of doublets, ddd = doublet
of doublets of doublets, appdd = apparent doublet of doublets, t =
triplet, appt = apparent triplet, m = multiplet), coupling constants
(Hz), and integration. 13C NMR spectra were recorded at room
temperature using 100 or 125 MHz as indicated. The data are reported
as follows: chemical shift in ppm referenced to residual solvent
(CDCl3 δ 77.16 ppm). Infrared spectra were recorded using a FTIR
spectrophotometer on a NaCl support, and signals are reported in
cm−1. Mass spectra were recorded either through electrospray
ionization (ESI) or electron impact (EI) on an instrument operating
at 70 eV. An Orbitrap mass analyzer was used for HRMS
measurements. Optical rotations were measured at room temperature
from the sodium D line (589 nm) using CH2Cl2 as solvent unless
80:20); [α]25 −8.70 (c 1.00, CH2Cl2); Formula C31H40O6S3; MW
D
1
604.8407 g/mol; IR (neat) νmax 3030, 2926, 1357, 1173 cm−1; H
NMR (400 MHz, CDCl3) δ 7.38−7.25 (m, 15H), 4.96−4.90 (m, 2H),
4.81 (d, J = 11.4 Hz, 1H), 4.72 (d, J = 10.9 Hz, 1H), 4.63 (d, J = 11.4
Hz, 1H), 4.44 (dd, J = 28.8, 11.7 Hz, 2H), 4.23 (dd, J = 6.1, 4.4 Hz,
1H), 4.18 (d, J = 4.5 Hz, 1H), 4.00 (dd, J = 6.1, 4.5 Hz, 1H), 3.72 (dd,
J = 11.2, 7.1 Hz, 1H), 3.57 (dd, J = 11.3, 3.1 Hz, 1H), 3.00 (s, 3H),
2.86−2.60 (m, 4H), 1.29−1.26 (m, 3H), 1.25−1.23 (m, 3H) ppm; 13C
NMR (100.6 MHz, CDCl3) δ 138.2, 137.8, 137.3, 128.53, 128.47,
128.43, 128.34, 128.0, 127.99, 127.93, 127.91, 127.7, 81.7, 81.4, 78.7,
75.4, 75.1, 73.3, 69.7, 52.7, 38.7, 25.5, 25.2, 14.6, 14.7 ppm; HRMS
calcd for C31H40O6NaS3 [M + Na+] 627.1879, found 627.1902 (2.8
ppm).
(−)-(2R,3R,4R)-1,3,4-tris(Benzyloxy)-5-oxopentan-2-yl meth-
anesulfonate (2). To a 0.1 M solution of S1 (4.58 g, 7.57 mmol) in a
3:1 mixture of acetone (90 mL):H2O (30 mL) at 0 °C were added 2,6-
lutidine (7.0 mL, 60.5 mmol, 8.0 equiv) and NBS (11.0 g, 60.5 mmol,
8.0 equiv). After the reaction was maintained for 15 min at 0 °C, a
15% solution of Na2S2O3 (100 mL) was added. The aqueous layer was
extracted with ether (3 × 100 mL), and the combined organic layers
were washed with 1 N HCl (50 mL), saturated aqueous NaHCO3 (50
mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc, 80:20)
provided aldehyde 2 (2.89 g, 77%) as a yellowish oil: Rf = 0.13
(hexanes/EtOAc, 80:20); [α]25 −26.4 (c 1.00, CH2Cl2); Formula
D
C27H30O7S; MW 498.5879 g/mol; IR (neat) νmax 3031, 1732, 1357,
1
1175 cm−1; H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 0.8 Hz, 1H),
7.39−7.24 (m, 15H), 4.95−4.89 (m, 1H), 4.70 (d, J = 11.7 Hz, 1H),
4.63 (d, J = 11.3 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 4.48 (d, J = 11.8
Hz, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.38 (d, J = 11.8 Hz, 1H), 4.19
(dd, J = 6.0, 3.9 Hz, 1H), 3.91 (dd, J = 3.9, 0.8 Hz, 1H), 3.75 (dd, J =
11.1, 3.7 Hz, 1H), 3.56 (dd, J = 11.1, 5.7 Hz, 1H), 2.94 (s, 3H) ppm;
13C NMR (100.6 MHz, CDCl3) δ 201.8, 137.3, 136.8, 136.4, 128.7,
128.58, 128.57, 128.56, 128.45, 128.42, 128.3, 128.1, 128.0, 81.4, 80.3,
77.3, 74.7, 73.39, 73.37, 68.4, 38.2 ppm; HRMS calcd for
C27H30O7NaS [M + Na+] 521.1604, found 521.1589 (−2.1 ppm).
(2R,3S,4S)-1,3,4-tris(Benzyloxy)hex-5-en-2-ol (3). The re-
ported procedure for the formation of 3 was slightly modified.16a n-
Butyllithium (2.5 M in hexane, 2.86 mL, 7.15 mmol, 3.0 equiv) was
otherwise noted and calculated using the formula αD = (100)αobs/(
(c)), where c = (g of substrate/100 mL of solvent) and = 1 dm.
(−)-(2R,3S,4R)-1,3,4-tris(Benzyloxy)-5,5-bis(ethylthio)-
pentan-2-ol (1). To a solution of methyl 2,3,5-tri-O-benzy-D-xylo-
furanoside15 (9.85 g, 23 mmol) in EtSH (9.8 mL, 131.5 mmol, 5.8
equiv) was added concentrated HCl (13.6 mL, 7.5 equiv). The
S
·
S
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added dropwise to a stirred suspension of methyltriphenylphospho-
nium bromide (2.5 g, 7.15 mmol, 3.0 equiv previously dried with
benzene) in dry THF (0.55 M,13 mL) at 0 °C. The resulting yellowish
mixture was maintained for 2 h at 25 °C. The reaction mixture was
cooled to 0 °C before dropwise addition of 2,3,5-O-tribenzyl-D-
xylofuranose16b,c (1.0 g, 2.4 mmol) in dry THF (0.3 M, 8 mL). A
cream-colored precipitate appeared, and the reaction mixture was
refluxed for 2 h at 100 °C. After cooling to 25 °C, silica gel (1.5 g) was
added to the reaction mixture, and the solvent was removed in vacuo.
The resulting crude mixture was dissolved in ether (100 mL) and
passed through a silica gel pad. The mixture was again concentrated in
vacuo. Purification by flash chromatography (hexanes/EtOAc, 70:30)
General Procedure A: Preparation of N,OTMS-Acetals. To a
solution of aldehyde 2 or 4 in MeCN (0.1 M) at −40 °C were
successively added silylated base (2.0−4.0 equiv of a 0.6 M solution in
CH2Cl2) and MgBr2·OEt2 (2.0 equiv). The reaction mixture was
maintained for 4 h at −40 °C, followed by addition of saturated
aqueous NaHCO3 (2 mL). The aqueous layer was extracted with ethyl
acetate (3 × 5 mL), and the combined organic layers were washed
with brine (5 mL), dried over MgSO4 and concentrated in vacuo.
(−)-(2R,3R,4R,5S)-1,3,4-tris(Benzyloxy)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)-
pentan-2-yl methanesulfonate (5a). Following general procedure
A, silylated thymine (0.56 mL of a 0.64 M solution in CH2Cl2, 0.36
mmol, 2.0 equiv) and MgBr2·OEt2 (92 mg, 0.36 mmol, 2.0 equiv) were
added to a solution of aldehyde 2 (89 mg, 0.18 mmol) in MeCN (1.8
mL). 1H NMR spectroscopic analysis of the unpurified product
indicated the formation of a single diastereomer (>20:1). Purification
by flash chromatography (hexanes/EtOAc, 70:30) provided 5a (92
1
provided 3 (0.70 g, 70%) as a yellow oil. H NMR spectroscopic data
correlate with the previously reported data for the enantiomer of 3:28
Formula C27H30O4; MW 418.5247 g/mol; 1H NMR (500 MHz,
CDCl3) δ 7.34−7.25 (m, 15H), 5.87 (ddd, J = 17.9, 10.4, 7.8 Hz, 1H),
5.36 (d, J = 25.0 Hz, 1H), 5.36 (s, 1H), 4.86 (d, J = 11.2 Hz, 1H), 4.63
(d, J = 11.8 Hz, 1H), 4.56 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 11.9 Hz,
1H), 4.43 (d, J = 11.9 Hz, 1H), 4.39 (d, J = 11.8 Hz, 1H), 4.13−4.08
(m, 1H), 3.95−3.91 (m, 1H), 3.62 (dd, J = 6.5, 2.6 Hz, 1H), 3.45 (dd,
J = 9.5, 6.1 Hz, 1H), 3.42 (dd, J = 9.5, 6.3 Hz, 1H), 2.43 (s, 1H).
(+)-(2R,3R,4S)-1,3,4-tris(Benzyloxy)hex-5-en-2-yl 4-nitroben-
zenesulfonate (S3). To a 0.2 M solution of 3 (2 g, 4.8 mmol) in
CH2Cl2 (24 mL) at 0 °C was added NsCl (2.12 g, 9.6 mmol, 2.0
equiv). A 0.4 M solution of DMAP (0.47 g, 3.83 mmol, 0.8 equiv) and
Et3N (2.4 mL, 17.2 mmol, 3.6 equiv) in CH2Cl2 (10 mL) was then
added dropwise. The reaction mixture was refluxed for 16 h at 50 °C,
and 1 N HCl (5 mL) was added. The aqueous layer was extracted with
CH2Cl2 (3 × 50 mL), and the combined organic layers were washed
with brine (50 mL), dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc, 85:15)
provided S3 (2.25 g, 78%) as a yellow oil: Rf = 0.26 (hexanes/
mg, 74%) as a white foam: Rf = 0.13 (hexanes/EtOAc, 70:30); [α]25
D
−52.9 (c 1.16, CDCl3); Formula C35H44N2O9SiS; MW 696.8824 g/
mol; IR (neat) νmax 3191, 1691 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.39−7.19 (m, 14H), 7.08 (dd, J = 6.5, 2.9 Hz, 2H), 6.18 (d, J = 2.3
Hz, 1H), 4.99−4.93 (m, 1H), 4.81 (d, J = 11.1 Hz, 1H), 4.68 (d, J =
3.1 Hz, 1H), 4.65 (d, J = 3.1 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.47
(d, J = 11.7 Hz, 1H), 4.29 (d, J = 11.1 Hz, 1H), 4.03 (dd, J = 6.7, 5.1
Hz, 1H), 3.89 (dd, J = 10.0, 5.7 Hz, 1H), 3.84 (dd, J = 10.1, 5.8 Hz,
1H), 3.80 (dd, J = 6.6, 2.3 Hz, 1H), 3.11 (s, 3H), 1.83 (s, 3H), 0.15 (s,
9H) ppm; NH signal missing possibly due to exchange in CDCl3; 13C
NMR (100.6 MHz, CDCl3) δ 164.4, 150.2, 137.6, 137.48, 136.52,
128.6, 128.45, 128.41, 128.34, 128.25, 128.18, L-127.9, 127.7, 127.6,
109.4, 79.6, 79.3, 77.5, 76.8, 75.3, 75.2, 73.3, 68.2, 38.7, 12.3, −0.40
ppm; HRMS calcd for C35H45N2O9SiS [M + H+] 697.2610, found
697.2619 (0.6 ppm).
EtOAc, 85:15); [α]25 +0.950 (c 1.26, CH2Cl2); Formula
(−)-(2R,3R,4R,5S)-1,3,4-tris(Benzyloxy)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)-
pentan-2-yl 4-nitrobenzenesulfonate (6a). Following general
procedure A, silylated thymine (1.4 mL of a 0.62 M solution in
CH2Cl2, 0.84 mmol, 2.0 equiv) and MgBr2·OEt2 (218 mg, 0.84 mmol,
2.0 equiv) were added to a solution of aldehyde 4 (255 mg, 0.42
D
C33H33NO8S; MW 603.6820 g/mol; IR (neat) νmax 2869, 1531,
1349, 1185 cm−1; 1H NMR 8.00−7.88 (m, 4H), 7.38−7.24 (m, 11H),
7.18 (dd, J = 6.8, 2.4 Hz, 2H), 7.14 (dd, J = 6.8, 2.4 Hz, 2H), 5.89
(ddd, J = 17.6, 10.0, 7.5 Hz, 1H), 5.38 (d, J = 5.1 Hz, 1H), 5.35 (s,
1H), 4.96 (ddd, J = 6.5, 5.8, 2.7 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H),
4.58 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H), 4.31 (d, J = 11.7
Hz, 1H), 4.24 (d, J = 11.8 Hz, 1H), 4.15 (d, J = 11.7 Hz, 1H), 3.95
(dd, J = 7.4, 4.0 Hz, 1H), 3.76 (dd, J = 6.6, 4.0 Hz, 1H), 3.66 (dd, J =
11.5, 2.7 Hz, 1H), 3.45 (dd, J = 11.5, 5.6 Hz, 1H). 13C NMR (125
MHz, CD3Cl) δ 150.2, 142.9, 137.8, 137.7, 137.4, 134.4, 129.1, 128.55,
128.51, 128.4, 128.3, 128.1, 127.98, 127.96, 127.91, 127.8, 123.9,
120.1, 83.9, 79.8, 79.2, 74.9, 73.3, 70.5, 68.9 ppm; HRMS calcd for
C33H34NO8S [M + H+] 604.2000, found 604.2018 (2.9 ppm).
1
mmol) in MeCN (4.2 mL). H NMR spectroscopic analysis of the
unpurified product indicated the formation of a single diastereomer
(>20:1). Purification by flash chromatography (hexanes/EtOAc,
70:30) provided 6a (209 mg, 62%) as a white foam: Rf = 0.19
(hexanes/EtOAc, 70:30); [α]25 −33.3 (c 0.840, CH2Cl2); Formula
D
C40H45N3O111SiS; MW 803.9493 g/mol; IR (neat) νmax 3032, 1690,
1531 cm−1; H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 8.06−7.94
(m, 4H), 7.39−7.20 (m, 12H), 7.14 (dd, J = 6.5, 2.9 Hz, 2H), 7.06
(dd, J = 7.2, 2.0 Hz, 2H), 6.29 (d, J = 3.1 Hz, 1H), 5.07 (ddd, J = 6.8,
6.3, 3.5 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 4.55 (dd, J = 12.6, 11.5 Hz,
2H), 4.33 (d, J = 11.5 Hz, 1H), 4.30 (d, J = 2.8 Hz, 1H), 4.28 (d, J =
2.4 Hz, 1H), 3.95 (dd, J = 6.7, 5.8 Hz, 1H), 3.84 (dd, J = 10.9, 3.4 Hz,
1H), 3.72−3.65 (m, 2H), 1.84 (s, 3H), 0.18 (s, 9H) ppm; 13C NMR
(125 MHz, CDCl3) δ 163.7, 150.3, 149.7, 142.8, 137.5, 137.4, 137.3,
136.5, 129.3, 128.68, 128.62, 128.59, 128.53, 128.48, 128.28, 128.24,
128.1, 127.8, 123.9, 109.8, 83.7, 78.7, 77.4, 75.8, 74.79, 74.77, 73.5,
68.7, 12.5, −0.24 ppm; HRMS calcd for C40H46O11N3SiS [M + H+]
804.2617, found 804.2635 (2.3 ppm).
(+)-(2R,3R,4R)-1,3,4-tris(Benzyloxy)-5-oxopentan-2-yl 4-ni-
trobenzenesulfonate (4). A 0.025 M solution of S3 (1.27 g, 2.1
mmol) in CH2Cl2 (84 mL) was cooled to −78 °C and bubbled with
O3 in O2 atmosphere for 40 min. TLC indicated the disappearance of
the starting material. The system was purged with N2 to remove the
unreacted O3. Et3N (0.60 mL, 4.19 mmol, 2.0 equiv) was added to the
reaction mixture, which was warmed to 25 °C for 30 min, followed by
the addition of 1 N HCl (2 mL). The aqueous layer was extracted with
ether (3 × 50 mL), and the combined organic layers were washed with
brine (50 mL), dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc, 70:30)
provided 4 (1.07 g, 84%) as a brown oil: Rf = 0.37 (hexanes/
EtOAc, 70:30); [α]25D +14.5 (c 2.37, CH2Cl2); Formula C32H31NO9S;
MW 605.6548 g/mol; IR (neat) νmax 2870, 1535, 1369, 1186 cm−1; 1H
NMR (500 MHz, CDCl3) δ 9.61 (s, 1H), 8.03−8.00 (m, 2H), 7.93−
7.89 (m, 2H), 7.39−7.34 (m, 3H), 7.34−7.25 (m, 8H), 7.18−7.12 (m,
4H), 4.96 (ddd, J = 6.2, 5.7, 3.0 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H),
4.47 (d, J = 1.2 Hz, 2H), 4.43 (d, J = 11.7 Hz, 1H), 4.31 (d, J = 11.6
Hz, 1H), 4.21−4.17 (m, 2H), 3.90 (d, J = 3.6 Hz, 1H), 3.69 (dd, J =
11.5, 3.0 Hz, 1H), 3.45 (dd, J = 11.5, 5.6 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 201.9, 150.4, 142.2, 137.1, 136.9, 136.4, 129.3, 128.8,
128.72, 128.69, 128.59, 128.47, 128.36, 128.29, 128.04, 128.03, 124.0,
82.4, 81.7, 77.4, 74.8, 73.54, 73.45, 68.4 ppm; HRMS calcd for
(2R,3R,4R)-1,3,4-tris(Benzyloxy)-5-(5-methyl-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)pentan-2-yl
4-nitrobenzenesulfonate (6a and 6b). To a solution of aldehyde 4
(96 mg, 0.16 mmol) in CH2Cl2 (0.1 M, 1.6 mL) at 0 °C were
successively added silylated thymine (0.87 mL of a 0.64 M solution in
CH2Cl2, 0.55 mmol, 3.5 equiv) and TMSOTf (57 μL, 0.32 mmol, 2.0
equiv). The reaction mixture was maintained at 0 °C for 5 h, followed
by addition of saturated aqueous NaHCO3 (2 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 5 mL), and the combined organic
layers were washed with brine (5 mL), dried over MgSO4 and
concentrated in vacuo. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a 1:2 mixture of 1′,2′-
syn and anti diastereomers. Purification by flash chromatography
(hexanes/EtOAc, 70:30) did not allow for separation of the
+
C32H35N2O9S [M + NH4 ] 623.2058, found 623.2047 (−1.7 ppm).
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diastereomers and provided a mixture of 6a and 6b (87 mg, 68%) as a
white foam: Rf = 0.19 (hexanes/EtOAc, 70:30); Representative NMR
resonances, 1H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H, isomer a),
8.51 (s, 1H, isomer b), 8.07−7.95 (m, 8H, isomer a and b), 7.35−7.24
(m, 24H, isomer a and b), 7.22 (dd, J = 7.3, 2.0 Hz, 2H, isomer b),
7.14 (dd, J = 6.5, 2.9 Hz, 2H, isomer a), 7.06 (dd, J = 7.2, 2.1 Hz, 2H,
isomer a), 7.01 (dd, J = 6.9, 2.4 Hz, 2H, isomer b), 6.29 (d, J = 3.1 Hz,
1H, isomer a), 6.21 (d, J = 5.2 Hz, 1H, isomer b), 5.26−5.20 (m, 1H,
isomer b), 5.07 (ddd, J = 6.9, 6.4, 3.5 Hz, 1H, isomer a), 4.81 (dd, J =
21.4, 11.5 Hz, 2H, isomer b), 4.67 (d, J = 11.7 Hz, 1H, isomer a), 4.55
(appt, J = 11.7 Hz, 2H, isomer a), 4.34 (d, J = 11.5 Hz, 1H, isomer a),
4.30 (d, J = 5.2 Hz, 1H, isomer a), 4.28 (d, J = 4.9 Hz, 1H, isomer a),
4.20 (d, J = 11.6 Hz, 2H, isomer b), 4.05−3.98 (m, 2H, isomer b),
3.97−3.93 (m, 1H, isomer a), 3.85 (dd, J = 10.9, 3.4 Hz, 1H, isomer
a), 3.73−3.68 (m, 2H, isomer b), 3.66 (dd, J = 7.4, 3.1 Hz, 2H, isomer
a), 3.41−3.32 (m, 2H, isomer b), 1.84 (s, 3H, isomer a), 1.79 (d, J =
0.7 Hz, 3H, isomer b), 0.18 (s, 9H, isomer a), 0.14 (s, 9H, isomer b)
ppm; 13C NMR (125 MHz, CDCl3) δ 163.7 (isomer a), 163.6 (isomer
b), 150.6 (isomer b), 150.4 (isomer b), 150.3 (isomer a), 149.7
(isomer a), 142.8 (isomer a), 142.5 (isomer b), 137.5 (isomer a),
137.41 (isomer a), 137.38 (isomer b), 137.34, 137.1 (isomer b), 136.8
(isomer b), 136.5 (isomer a), 129.30 (isomer b), 129.25(isomer a),
128.68, 128.62 (isomer a), 128.58, 128.52 (isomer a), 128.49 (isomer
a), 128.47 (isomer b), 128.44 (isomer b), 128.38 (isomer b), 128.28
(isomer a), 128.23 (isomer a), 128.20 (isomer b), 128.18 (isomer b),
128.07 (isomer a), 127.81 (isomer a, 127.79 (isomer b), 123.96
(isomer b), 123.94 (isomer a), 110.6 (isomer b), 109.8 (isomer a),
83.7 (isomer a), 82.9 (isomer b), 79.3 (isomer b), 78.7 (isomer a),
77.4 (isomer a), 76.9 (isomer b), 75.8 (isomer a), 75.5 (isomer b),
75.06 (isomer b), 74.77 (isomer a), 73.5 (isomer a), 73.1 (isomer b),
68.9 (isomer b), 68.6 (isomer a), 12.6 (isomer b), 12.5 (isomer a),
−0.25 (isomer a), −0.29 (isomer b) ppm.
diastereomers was obtained. 7b: Rf = 0.49 (hexanes/EtOAc, 50:50);
[α]25 +24.6 (c 1.15, CDCl3); Formula C34H42N2O9SiS; MW
D
1
682.8558 g/mol; IR (neat) νmax 3188, 2955, 1685 cm−1; H NMR
(500 MHz, CDCl3) δ 8.05 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.35−
7.31 (m, 15H), 6.14 (d, J = 5.0 Hz, 1H), 5.53 (dd, J = 8.1, 2.1 Hz, 1H),
5.18−5.13 (m, 1H), 4.82 (d, J = 11.4 Hz, 1H), 4.78 (d, J = 11.6 Hz,
1H), 4.64 (d, J = 11.5 Hz, 1H), 4.55 (d, J = 11.4 Hz, 1H), 4.45 (d, J =
11.7 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H), 3.97 (dd, J = 7.4, 5.2 Hz, 1H),
3.71 (dd, J = 10.8, 7.8 Hz, 1H), 3.56 (dd, J = 7.5, 2.6 Hz, 1H), 3.40
(dd, J = 10.8, 3.5 Hz, 1H), 3.05 (s, 3H), 0.11 (s, 9H) ppm; 13C NMR
(125 MHz, CDCl3) δ 162.7, 150.4, 141.2, 137.4, 137.34, 137.32, 128.8,
128.63, 128.62, 128.59, 128.34, 128.27, 128.18, 128.13, 128.0, 102.2,
80.9, 79.9, 78.7, 76.8, 75.5, 75.4, 73.3, 69.6, 38.8, −0.33 ppm; HRMS
calcd for C34H43N2O9SiS [M + H+] 683.2453, found 683.2459 (0.8
ppm).
(−)-(2R,3R,4R,5S)-1,3,4-tris(Benzyloxy)-5-(2,4-dioxo-3,4-di-
hydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)pentan-2-yl 4-
nitrobenzenesulfonate (8a). Following general procedure A,
silylated uracil (0.70 mL of a 0.74 M solution in CH2Cl2, 0.51
mmol, 2.0 equiv) and MgBr2·OEt2 (132 mg, 0.51 mmol, 2.0 equiv)
were added to a solution of aldehyde 4 (154 mg, 0.26 mmol) in
1
MeCN (2.6 mL). H NMR spectroscopic analysis of the unpurified
product indicated the formation of a single diastereomer (>20:1).
Purification by flash chromatography (hexanes/EtOAc, 50:50)
provided 8a (127 mg, 63%) as a white foam: Rf = 0.53 (hexanes/
EtOAc, 50:50); [α]25 −34.0 (c 1.32, CH2Cl2); Formula
D
C39H43N3O11SiS; MW 789.9227 g/mol; IR (neat) νmax 3167, 2873,
1687, 1532 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.13 (s, 1H), 8.03−
7.96 (m, 4H), 7.49 (d, J = 8.1 Hz, 1H), 7.35−7.25 (m, 11H), 7.15 (dd,
J = 6.5, 2.9 Hz, 2H), 7.08 (dd, J = 7.4, 1.7 Hz, 2H), 6.31 (d, J = 2.9 Hz,
1H), 5.62 (dd, J = 8.1, 2.1 Hz, 1H), 5.11 (ddd, J = 6.7, 6.0, 3.4 Hz,
1H), 4.65 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 4.6 Hz, 1H), 4.52 (d, J =
4.5 Hz, 1H), 4.37−4.27 (m, 3H), 3.94 (dd, J = 7.1, 5.7 Hz, 1H), 3.86
(dd, J = 10.9, 3.3 Hz, 1H), 3.72−3.66 (m, 2H), 0.20 (s, 9H).; 13C
NMR (125 MHz, CDCl3) δ 163.47, 150.29, 149.75, 142.90, 141.73,
137.38, 137.27, 136.33, 129.19, 128.78, 128.68, 128.58, 128.55, 128.46,
128.29, 128.21, 128.06, 127.83, 123.91, 101.45, 83.94, 78.18, 77.52,
75.65, 74.71, 74.59, 73.49, 68.66, −0.30 ppm; HRMS calcd for
C39H44O11N3SiS [M + H+] 790.2460, found 790.2461 (0.12 ppm).
(−)-(2R,3R,4R,5S)-5-(6-Amino-9H-purin-9-yl)-1,3,4-tris-
(benzyloxy)-5-(trimethylsilyl)oxy)pentan-2-yl methanesulfo-
nate (9a). Following general procedure A, silylated adenine (0.60
mL of a 0.71 M solution in CH2Cl2, 0.43 mmol, 4.0 equiv) and
MgBr2·OEt2 (28 mg, 0.11 mmol, 1.0 equiv) were added to a solution
of aldehyde 2 (53 mg, 0.11 mmol) in MeCN (1.1 mL) and maintained
at −20 °C for 16 h. 1H NMR spectroscopic analysis of the unpurified
product indicated the formation of a single diastereomer (>20:1).
Purification by flash chromatography (hexanes/EtOAc, 0:100)
provided 9a (50 mg, 66%) as a white foam: Rf =0.40 (hexanes/
(−)-(2R,3R,4R,5S)-1,3,4-tris(Benzyloxy)-5-(2,4-dioxo-3,4-di-
hydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)pentan-2-yl
methanesulfonate (7a). Following general procedure A, silylated
uracil (0.45 mL of a 0.69 M solution in CH2Cl2, 0.312 mmol, 2.0
equiv) and MgBr2·OEt2 (81 mg, 0.312 mmol, 2.0 equiv) were added to
a solution of aldehyde 2 (78 mg, 0.16 mmol) in MeCN (1.6 mL). 1H
NMR spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1). Purification by flash
chromatography (hexanes/EtOAc, 50:50) provided 7a (64 mg, 61%)
as a white foam: Rf = 0.31 (hexanes/EtOAc, 50:50); [α]25 −58.6 (c
D
0.910, CH2Cl2); Formula C34H42N2O9SiS; MW 682.8558 g/mol; IR
1
(neat) νmax 3190, 2955, 1687 cm−1; H NMR (500 MHz, CDCl3) δ
8.61 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.36−7.25 (m, 13H), 7.10 (dd, J
= 7.0, 2.1 Hz, 2H), 6.18 (d, J = 2.6 Hz, 1H), 5.59 (dd, J = 8.1, 2.0 Hz,
1H), 4.98−4.95 (m, 1H), 4.77 (d, J = 11.1 Hz, 1H), 4.66 (d, J = 11.1
Hz, 1H), 4.62 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 11.7 Hz, 1H), 4.47 (d,
J = 11.7 Hz, 1H), 4.32 (d, J = 11.2 Hz, 1H), 4.02−3.98 (m, 1H), 3.88
(dd, J = 10.2, 5.2 Hz, 1H), 3.82 (dd, J = 10.2, 5.8 Hz, 1H), 3.76 (dd, J
= 6.6, 2.7 Hz, 1H), 3.07 (s, 3H), 0.16 (s, 9H) ppm; 13C NMR (125
MHz, CDCl3) δ 163.2, 149.7, 141.8, 137.6, 137.5, 136.5, 128.9, 128.68,
128.66, 128.56, 128.54, 128.4, 128.2, 127.99, 127.87, 101.3, 80.4, 78.6,
77.9, 76.6, 75.3, 75.1, 73.6, 68.6, 38.8, −0.26 ppm; HRMS calcd for
C34H43N2O9SiS [M + H+] 683.2453, found 683.2456 (0.5 ppm).
(+)-(2R,3R,4R,5R)-1,3,4-tris(Benzyloxy)-5-(2,4-dioxo-3,4-di-
hydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)pentan-2-yl
methanesulfonate (7b). To a solution of aldehyde 2 (54 mg, 0.11
mmol) in CH2Cl2 (0.1 M, 1.1 mL) at 0 °C were successively added
silylated uracil (0.77 mL of a 0.5 M solution in CH2Cl2, 0.38 mmol, 3.5
equiv) and TMSOTf (30 μL, 0.16 mmol, 1.5 equiv). The reaction
mixture was maintained at 0 °C for 16 h, followed by addition of
saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), and the combined organic layers were
washed with brine (5 mL), dried over MgSO4 and concentrated in
vacuo. 1H NMR spectroscopic analysis of the unpurified product
indicated the formation of a 1:3 mixture of 1′,2′-syn and anti
diastereomers. Purification by flash chromatography (hexanes/EtOAc,
50:50) provided 7b as a white foam. A total of 33 mg (45%) of pure
1′,2′-anti diastereomer 7b and a mixture of 1′,2′-syn and anti
EtOAc, 0:100); [α]25 −14.2 (c 1.00, CH2Cl2); Formula
D
C35H43N5O7SiS; MW 705.8957 g/mol; IR (neat) νmax 3299, 3135,
1
1680, 1605 cm−1; H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.96
(s, 1H), 7.37−7.20 (m, 13H), 7.08 (dd, J = 6.4, 2.8 Hz, 2H), 6.42 (d, J
= 4.0 Hz, 1H), 5.80 (s, 2H), 5.02 (appdd, J = 10.3, 5.7 Hz, 1H), 4.64
(s, 2H), 4.54 (d, J = 11.1 Hz, 1H), 4.47 (s, 2H), 4.31 (d, J = 11.1 Hz,
1H), 4.00−3.95 (m, 1H), 3.90 (dd, J = 6.0, 5.5 Hz, 1H), 3.85 (dd, J =
10.6, 4.3 Hz, 1H), 3.74 (dd, J = 10.6, 5.9 Hz, 1H), 3.10 (s, 3H), 0.07
(s, 9H) ppm; 13C NMR (100.6 MHz, CDCl3) δ 155.4, 153.0, 148.9,
139.9, 137.64, 137.61, 136.8, 128.62, 128.60, 128.55, 128.458, 128.457,
128.16, 128.15, 127.95, 127.85, 119.4, 81.0, 79.1, 77.9, 76.5, 75.1, 74.9,
73.5, 68.8, 38.7, −0.29 ppm; HRMS calcd for C35H44N5O7SiS [M +
H+] 706.2725, found 706.2724 (−0.2 ppm).
(−)-(2R,3R,4R,5S)-5-(6-Amino-9H-purin-9-yl)-1,3,4-tris-
(benzyloxy)-5-((trimethylsilyl)oxy)pentan-2-yl 4-nitrobenzene-
sulfonate (10a). Following general procedure A, silylated adenine
(1.5 mL of a 0.69 M solution in CH2Cl2, 0.99 mmol, 4.5 equiv) and
MgBr2·OEt2 (58 mg, 0.22 mmol, 1.0 equiv) were added to a solution
of aldehyde 4 (135 mg, 0.22 mmol) in MeCN (2.2 mL) and
1
maintained at −40 °C for 6 h. H NMR spectroscopic analysis of the
unpurified product indicated the formation of a single diastereomer
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The Journal of Organic Chemistry
Featured Article
(>20:1). Purification by flash chromatography (hexanes/EtOAc,
50:50) provided 10a (98 mg, 54%) as a white foam: Rf = 0.21
(1.3 mL of a 0.71 M solution in CH2Cl2, 0.92 mmol, 3.5 equiv) and
MgBr2·OEt2 (102 mg, 0.39 mmol, 1.5 equiv) were added to a solution
of aldehyde 2 (131 mg, 0.26 mmol) in MeCN (2.6 mL) and
maintained at −20 °C for 16 h. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a single diastereomer
(>20:1). Purification by flash chromatography (acetone/DCM, 50:50)
provided 13a (128 mg, 71%) as a white foam: Rf = 0.19 (acetone/
(hexanes/EtOAc, 50:50); [α]25 −6.0 (c 1.0, CH2Cl2); Formula
D
C40H44N6O9SiS; MW 812.9627 g/mol; IR (neat) νmax 3333, 3129,
1644, 1531 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 8.01−
7.93 (m, 4H), 7.91 (s, 1H), 7.31−7.22 (m, 11H), 7.10 (dd, J = 6.5, 2.9
Hz, 2H), 7.08 (dd, J = 6.4, 2.8 Hz, 2H), 6.44 (d, J = 4.5 Hz, 1H), 5.66
(s, 2H), 5.11−5.06 (m, 1H), 4.49 (d, J = 13.1 Hz, 3H), 4.41 (d, J =
11.3 Hz, 1H), 4.26 (dd, J = 27.3, 11.6 Hz, 2H), 3.93 (appt, J = 4.4 Hz,
1H), 3.82−3.78 (m, 2H), 3.59 (dd, J = 11.2, 6.0 Hz, 1H), 0.06 (s, 9H)
ppm; 13C NMR (125 MHz, CDCl3) δ 155.3, 153.1, 150.3, 149.1,
142.8, 139.9, 137.44, 137.38, 136.8, 129.2, 128.58, 128.54, 128.50,
128.49, 128.25, 128.24, 128.23, 128.1, 127.9, 123.9, 119.4, 83.9, 78.9,
77.7, 75.9, 74.7, 74.6, 73.4, 68.7, −0.30 ppm; HRMS calcd for
C40H45N6O9SiS [M + H+] 813.2733, found 813.2756 (2.9 ppm).
(−)-(2R,3R,4R,5S)-1,3,4-tris(Benzyloxy)-5-(5-fluoro-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)-
pentan-2-yl methanesulfonate (11a). Following general proce-
dure A, silylated 5F-uracil (1.0 mL of a 0.63 M solution in CH2Cl2,
0.62 mmol, 3.5 equiv) and MgBr2·OEt2 (92 mg, 0.355 mmol, 2.0
equiv) were added to a solution of aldehyde 2 (89 mg, 0.18 mmol) in
MeCN (1.8 mL) and maintained at −20 °C for 16 h. 1H NMR
spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1). Purification by flash
chromatography (hexanes/EtOAc, 50:50) provided 11a (71 mg, 57%)
DCM, 50:50); [α]25 −85.9 (c1.02, CH2Cl2); Formula
D
C34H43N3O8SSi; MW 681.8710 g/mol; IR (neat) νmax 3333, 2955,
1645, 1494 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 7.4 Hz,
1H), 7.34−7.24 (m, 13H), 7.13 (dd, J = 6.6, 2.8 Hz, 2H), 6.31 (d, J =
1.9 Hz, 1H), 5.71 (d, J = 7.4 Hz, 1H), 4.98 (appdd, J = 10.4, 5.7 Hz,
1H), 4.83 (d, J = 11.1 Hz, 1H), 4.59 (appt, J = 10.8 Hz, 2H), 4.51 (d, J
= 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 10.9 Hz, 1H),
4.01 (dd, J = 7.1, 4.5 Hz, 1H), 3.92−3.83 (m, 3H), 3.15 (s, 3H), 0.14
(s, 9H) ppm; NH2 signal missing possibly due to exchange in CDCl3; 13
C
NMR (125 MHz, CDCl3) δ 165.9, 155.5, 142.7, 137.9, 137.7, 137.3,
128.531, 128.529, 128.5, 128.4, 128.3, 128.1, 127.9, 127.85, 127.81,
93.9, 79.9, 79.6, 78.3, 77.2, 75.6, 75.3, 73.5, 68.5, 38.8, −0.15 ppm;
HRMS calcd for C34H44N3O8SiS [M + H+] 682.2613, found 682.2626
(1.9 ppm).
(−)-(2R,3R,4R,5S)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-
1,3,4-tris(benzyloxy)-5-((trimethylsilyl)oxy)pentan-2-yl 4-nitro-
benzenesulfonate (14a). Following general procedure A, silylated
cytosine (1.1 mL of a 0.59 M solution in CH2Cl2, 0.66 mmol, 3.5
equiv) and MgBr2·OEt2 (73 mg, 0.28 mmol, 1.5 equiv) were added to
a solution of aldehyde 4 (114 mg, 0.19 mmol) in MeCN (1.9 mL) and
as a white foam: Rf = 0.49 (hexanes/EtOAc, 50:50); [α]25 −28.5 (c
D
2.27, CH2Cl2); Formula C34H41FN2O9SiS; MW 700.8462 g/mol; IR
1
1
(neat) νmax 3185, 2955, 1707 cm−1; H NMR (500 MHz, CDCl3) δ
maintained at −40 °C for 6 h. H NMR spectroscopic analysis of the
unpurified product indicated the formation of a single diastereomer
(>20:1). Purification by flash chromatography (hexanes/EtOAc,
0:100) provided 14a (96 mg, 65%) as a white foam: Rf = 0.41
9.04 (d, J = 4.6 Hz, 1H), 7.48 (d, J = 6.2 Hz, 1H), 7.38−7.26 (m,
13H), 7.08 (dd, J = 6.4, 2.9 Hz, 2H), 6.13 (s, 1H), 4.98−4.95 (m, 1H),
4.79 (d, J = 11.2 Hz, 1H), 4.69 (d, J = 11.2 Hz, 1H), 4.65 (d, J = 11.4
Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.29 (d,
J = 11.4 Hz, 1H), 4.01 (dd, J = 6.6, 5.6 Hz, 1H), 3.89 (dd, J = 10.2, 5.2
Hz, 1H), 3.83 (dd, J = 10.2, 5.8 Hz, 1H), 3.76 (dd, J = 6.8, 2.5 Hz,
1H), 3.09 (s, 3H), 0.16 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3) δ
156.8 (d, J = 26.6 Hz), 148.2, 140.6, 138.7, 137.5 (d, J = 9.6 Hz),
136.3, 129.090, 129.089, 128.75, 128.69, 128.56, 128.49, 128.3, 128.0,
127.9, 126.1 (d, J = 34.2 Hz), 80.3, 78.5, 78.1, 76.5, 75.4, 75.1, 73.6,
68.5, 38.9, −0.30 ppm; HRMS calcd for C34H42FN2O9SiS [M + H+]
701.2359, found 701.2364 (0.7 ppm).
(hexanes/EtOAc, 0:100); [α]25 −56.9 (c 2.07, CH2Cl2); Formula
D
C39H44N4O10SiS; MW 788.9380 g/mol; IR (neat) νmax 3331, 2956,
1
1658, 1529, 1486, 1185 cm−1; H NMR (500 MHz, CDCl3) δ 7.99
(apps, 4H), 7.52 (d, J = 7.4 Hz, 1H), 7.30−7.22 (m, 11H), 7.17−7.13
(m, 2H), 7.09−7.06 (m, 2H), 6.42 (d, J = 2.8 Hz, 1H), 5.64 (d, J = 7.3
Hz, 1H), 5.12−5.08 (m, 1H), 4.66 (d, J = 11.3 Hz, 1H), 4.43 (dd, J =
11.2, 2.6 Hz, 2H), 4.36−4.25 (m, 3H), 3.89 (dd, J = 11.8, 5.4 Hz, 2H),
3.74 (dd, J = 10.8, 5.9 Hz, 2H), 0.16 (s, 9H) ppm; NH2 signal missing
possibly due to exchange in CDCl3; 13C NMR (125 MHz, CDCl3)
δ165.7, 155.4, 150.4, 143.0, 142.9, 137.70, 137.69, 137.2, 129.5, 128.7,
128.55, 128.54, 128.51, 128.294, 128.292, 128.09, 128.06, 127.9, 124.0,
93.8, 83.9, 78.8, 78.1, 76.3, 75.1, 74.6, 73.6, 68.9, −0.06 ppm; HRMS
calcd for C39H45N4O10SiS [M + H+] 789.2620, found 789.2629 (1.1
ppm).
(−)-(2R,3R,4R,5S)-1,3,4-tris(Benzyloxy)-5-(5-fluoro-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-((trimethylsilyl)oxy)-
pentan-2-yl 4-nitrobenzenesulfonate (12a). Following general
procedure A, silylated 5F-uracil (1.3 mL of a 0.69 M solution in
CH2Cl2, 0.89 mmol, 3.5 equiv) and MgBr2·OEt2 (132 mg, 0.51 mmol,
2.0 equiv) were added to a solution of aldehyde 4 (155 mg, 0.26
(−)-(2R,3R,4R,5S)-5-(4-Acetamido-2-oxopyrimidin-1(2H)-yl)-
1,3,4-tris(benzyloxy)-5-((trimethylsilyl)oxy)pentan-2-yl metha-
nesulfonate (15a). Following general procedure A, silylated N4−
AcCytosine (1.3 mL of a 0.60 M solution in CH2Cl2, 0.75 mmol, 2.0
equiv) and MgBr2·OEt2 (193 mg, 0.75 mmol, 2.0 equiv) were added to
a solution of aldehyde 2 (186 mg, 0.37 mmol) in MeCN (3.7 mL) and
1
mmol) in MeCN (2.6 mL) and maintained at −20 °C for 16 h. H
NMR spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1). Purification by flash
chromatography (hexanes/EtOAc, 70:30) provided 12a (121 mg,
58%) as a white foam: Rf = 0.24 (hexanes/EtOAc, 70:30); [α]25
D
1
maintained at 0 °C for 16 h. H NMR spectroscopic analysis of the
−37.2 (c 0.990, CDCl3); Formula C39H42FN3O11SiS; MW 807.9132
1
g/mol; IR (neat) νmax 3181, 2872, 1706, 1532 cm−1; H NMR (500
unpurified product indicated the formation of a single diastereomer
(>20:1). Purification by flash chromatography (hexanes/EtOAc,
50:50) provided 15a (133 mg, 49%) as a white foam: Rf = 0.12
MHz, CDCl3) δ 8.04−7.97 (m, 4H), 7.45 (d, J = 6.2 Hz, 1H), 7.36−
7.25 (m, 11H), 7.14 (dd, J = 6.4, 2.9 Hz, 2H), 7.01 (dd, J = 7.6, 1.5 Hz,
2H), 6.22 (s, 1H), 5.11 (ddd, J = 7.0, 6.4, 3.4 Hz, 1H), 4.65 (d, J =
11.5 Hz, 1H), 4.59 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H),
4.35 (d, J = 11.5 Hz, 1H), 4.29 (d, J = 11.5 Hz, 1H), 4.20 (d, J = 11.5
Hz, 1H), 3.94 (dd, J = 7.0, 6.0 Hz, 1H), 3.82 (dd, J = 10.9, 3.4 Hz,
1H), 3.70−3.61 (m, 2H), 0.20 (s, 9H) ppm; NH signal missing possibly
due to exchange in CDCl3; ∼10% aldehyde remaining in product; 13C
NMR (125 MHz, CDCl3) δ 156.4 (d, J = 26.9 Hz), 150.4, 147.8,
143.0, 140.6, 138.7, 137.3 (d, J = 12.3 Hz), 135.9, 129.2, 129.1, 128.9,
128.8, 128.7, 128.54, 128.46, 128.38, 128.1, 127.9, 126.1 (d, J = 34.1
Hz), 123.9, 83.9, 78.0, 77.7, 75.5, 74.9, 74.5, 73.6, 68.6, −0.27 ppm;
HRMS calcd for C39H43O11FN3SiS [M + H+] 808.2366, found
808.2360 (−0.72 ppm).
(hexanes/EtOAc, 50:50); [α]25 −92.4 (c 1.41, CH2Cl2); Formula
D
C36H45N3O9SiS; MW 723.9077 g/mol; IR (neat) νmax 3030, 2956,
1719, 1669, 1496 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.63 (s, 1H),
7.90 (d, J = 7.5 Hz, 1H), 7.36−7.23 (m, 14H), 7.06 (dd, J = 6.8, 2.4
Hz, 2H), 6.32 (d, J = 1.8 Hz, 1H), 5.02−4.98 (m, 1H), 4.82 (d, J =
11.0 Hz, 1H), 4.65 (d, J = 11.0 Hz, 1H), 4.58 (d, J = 11.1 Hz, 1H),
4.54 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 4.16 (d, J = 11.1
Hz, 1H), 4.06 (dd, J = 7.2, 4.7 Hz, 1H), 3.96−3.88 (m, 3H), 3.18 (s,
3H), 2.27 (s, 3H), 0.14 (s, 9H) ppm; 13C NMR (125 MHz, CDCl3) δ
170.7, 162.8, 154.7, 146.4, 137.70, 137.66, 136.8, 128.7, 128.66,
128.59, 128.51, 128.311, 128.309, 128.1, 127.9, 127.8, 95.9, 79.7, 79.1,
78.6, 77.0, 75.6, 75.4, 73.6, 68.3, 38.8, 25.0, −0.20 ppm; HRMS calcd
for C36H46N3O9SiS [M + H+] 724.2719, found 724.2739 (2.8 ppm).
(−)-(2R,3R,4R,5S)-5-(4-Acetamido-2-oxopyrimidin-1(2H)-yl)-
1,3,4-tris(benzyloxy)-5-((trimethylsilyl)oxy)pentan-2-yl 4-nitro-
(−)-(2R,3R,4R,5S)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-
1,3,4-tris(benzyloxy)-5-((trimethylsilyl)oxy)pentan-2-yl metha-
nesulfonate (13a). Following general procedure A, silylated cytosine
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The Journal of Organic Chemistry
Featured Article
benzenesulfonate (21a). To a 0.3 M solution of 14a (0.33 g, 0.42
mmol) in CH2Cl2 (1.5 mL) at 0 °C were added Ac2O (80 μL, 0.85
mmol, 2.0 equiv) and pyridine (0.14 mL, 1.69 mmol, 4.0 equiv). The
reaction was maintained for 2 h at 25 °C and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc, 50:50)
provided 21a (271 mg, 77%) as a white form: Rf = 0.35 (hexanes/
= 7.2, 2.0 Hz, 2H), 6.31 (d, J = 5.2 Hz, 1H), 4.59 (d, J = 11.9 Hz, 1H),
4.57−4.50 (m, 3H), 4.43 (d, J = 11.7 Hz, 1H), 4.40 (d, J = 11.6 Hz,
1H), 4.24 (dd, J = 5.0, 4.2 Hz, 1H), 4.13 (dd, J = 5.5, 4.1 Hz, 1H),
4.08−4.05 (m, 1H), 3.72 (dd, J = 10.5, 4.0 Hz, 1H), 3.66 (dd, J = 10.5,
4.3 Hz, 1H), 1.68 (d, J = 0.7 Hz, 3H) ppm; HRMS calcd for
C31H33N2O6 [M + H+] 529.2333, found 529.2342 (1.7 ppm).
(−)-1-((2S,3R,4S,5S)-3,4-bis(Benzyloxy)-5-((benzyloxy)-
methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
(17a). Following general procedure D, a solution of N,OTMS-acetal
EtOAc, 50:50); [α]25 −63.2 (c 1.43, CH2Cl2); Formula
D
C41H46N4O11SSi; MW 830.9746 g/mol; IR (neat) νmax 3031, 2956,
1662, 1529, 1492 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.18 (s, 1H),
8.02 (apps, 4H), 7.84 (d, J = 7.5 Hz, 1H), 7.32−7.25 (m, 10H), 7.24−
7.21 (m, 2H), 7.18−7.15 (m, 2H), 7.00 (d, J = 6.5 Hz, 2H), 6.42 (d, J
= 2.3 Hz, 1H), 5.15−5.11 (m, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.49 (d,
J = 11.2 Hz, 1H), 4.44 (d, J = 11.3 Hz, 1H), 4.37 (d, J = 11.4 Hz, 1H),
4.33 (d, J = 11.7 Hz, 1H), 4.15 (d, J = 11.3 Hz, 1H), 3.95 (appt, J = 6.6
Hz, 1H), 3.92 (dd, J = 10.8, 3.7 Hz, 1H), 3.79 (dd, J = 10.8, 5.9 Hz,
1H), 3.75 (dd, J = 6.0, 2.5 Hz, 1H), 2.26 (s, 3H), 0.15 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 170.4, 162.4, 154.5, 150.3, 146.5, 142.8,
137.5, 137.4, 136.5, 129.4, 128.70, 128.67, 128.51, 128.47, 128.41,
128.35, 128.1, 128.0, 127.9, 123.9, 95.7, 83.8, 78.8, 77.8, 75.9, 74.9,
74.7, 73.5, 68.6, 25.1, −0.20 ppm; HRMS calcd for C41H47N4O11SiS
[M + H+] 831.2726, found 831.2734 (0.95 ppm).
General Procedure B: C1′ → C4′ Cyclization of N,OTMS-
Acetals with C4′-Ms Using Conventional Heating. L-Nucleoside
analogues 16a, 17a, and 18a were first cyclized from their respective
N,OTMS-acetals 5a, 7a, and 9a with a C4′-Ms using conventional
heating. A 0.06 M solution of N,OTMS-acetal in anhydrous DMSO
was added to a 15 mL thick-walled glass test tube and heated with
Al(OiPr)3 (3.0 equiv). The test tube was sealed with a Teflon cap, and
the reaction mixture was maintained for 3 h in a 140 °C sand bath.
The reaction mixture was cooled to 25 °C followed by addition of
brine (2 mL) and 1 M NaOH (1 mL, to break emulsion formation).
The aqueous layer was extracted with ethyl acetate (3 × 5 mL). The
combined organic layers were then dried over MgSO4 and
concentrated in vacuo.
General Procedure C: C1′ → C4′ Cyclization of N,OTMS-
Acetals with C4′-Ms Using Microwave Heating. L-Nucleoside
analogues 16a, 17a, and 18a were cyclized from their respective
N,OTMS-acetals 5a, 7a, and 9a with a C4′-Ms using microwave
heating. A 0.06 M solution of N,OTMS-acetal in anhydrous DMSO
was added to a glass test tube fitted for microwave conditions and
heated with Al(OiPr)3 (0.6 equiv). The test tube was sealed, and the
reaction mixture was maintained for 10 min at 180 °C in the
microwave. The reaction mixture was cooled to 25 °C followed by
addition of brine (2 mL) and 1 M NaOH (1 mL, to break emulsion
formation). The aqueous layer was extracted with ethyl acetate (3 × 5
mL). The combined organic layers were then dried over MgSO4 and
concentrated in vacuo.
General Procedures D and E: C1′ → C4′ Cyclization of
N,OTMS-Acetals with C4′-Ns Using Conventional Heating. A
0.06 M solution of N,OTMS-acetal in anhydrous DMSO was added to
a 15 mL thick-walled glass test tube and heated with Al(OiPr)3 [0
equiv (procedure D) or 3.0 equiv (procedure E)]. The test tube was
sealed with a Teflon cap, and the reaction mixture was maintained for
3 h in a 90 °C sand bath. The reaction mixture was cooled to 25 °C
followed by addition of brine (2 mL) and 1 M NaOH (1 mL, to break
emulsion formation). The aqueous layer was extracted with ethyl
acetate (3 × 5 mL). The combined organic layers were then dried over
MgSO4 and concentrated in vacuo.
1
8a (151 mg, 0.19 mmol) was heated in DMSO (3.2 mL). H NMR
spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1). Purification by flash
chromatography (hexanes/EtOAc, 50:50) provided 17a (73 mg, 74%)
as a colorless gum: Rf = 0.38 (hexanes/EtOAc, 50:50); [α]25D −71.2 (c
1.50, CDCl3); Formula C30H30N2O6; MW 514.5690 g/mol; IR (neat)
1
νmax 3190, 2919, 1690 cm−1; H NMR (500 MHz, CDCl3) δ 9.15 (s,
1H), 7.62 (dd, J = 8.1, 0.9 Hz, 1H), 7.37−7.24 (m, 13H), 7.14 (d, J =
7.5 Hz, 2H), 6.30 (d, J = 4.9 Hz, 1H), 5.47 (d, J = 8.1 Hz, 1H), 4.58
(d, J = 11.9 Hz, 1H), 4.54−4.46 (m, 3H), 4.43 (d, J = 11.6 Hz, 1H),
4.39 (d, J = 11.6 Hz, 1H), 4.26−4.22 (m, 1H), 4.10−4.08 (m, 2H),
3.69 (dd, J = 10.3, 2.1 Hz, 1H), 3.64 (dd, J = 10.3, 2.4 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl3) δ 163.7, 150.6, 142.1, 137.6, 137.4,
136.7, 128.6, 128.57, 128.55, 128.2, 128.1, 128.04, 127.89, 127.869,
127.867, 101.2, 84.4, 81.9, 80.9, 80.5, 73.5, 73.2, 72.2, 68.7 ppm;
HRMS calcd for C30H31N2O6 [M + H+] 515.2177, found 515.2159
(−3.4 ppm).
(+)-1-((2R,3R,4S,5S)-3,4-bis(Benzyloxy)-5-((benzyloxy)-
methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
(17b). Following general procedure B, a solution of N,OTMS-acetal
7b (70 mg, 0.10 mmol) and Al(OiPr)3 (63 mg, 0.31 mmol, 3.0 equiv)
was heated in DMSO (1.7 mL). 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a single diastereomer
(>20:1). Purification by flash chromatography (hexanes/EtOAc,
50:50) provided 17b (21 mg, 39%) as a colorless gum: Rf = 0.31
(hexanes/EtOAc, 50:50); [α]25 +32.1 (c 0.860, CDCl3); Formula
D
C30H301N2O6; MW 514.5690 g/mol; IR (neat) νmax 3171, 2923, 1686
cm−1; H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.42 (d, J = 8.2
Hz, 1H), 7.37−7.25 (m, 13H), 7.13 (dd, J = 6.6, 2.8 Hz, 2H), 6.07 (s,
1H), 5.60 (dd, J = 8.2, 2.3 Hz, 1H), 4.76 (d, J = 12.1 Hz, 1H), 4.64−
4.57 (m, 3H), 4.52 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 11.8 Hz, 1H),
4.37 (d, J = 11.8 Hz, 1H), 4.11 (s, 1H), 3.99 (s, 1H), 3.65 (dd, J = 9.8,
6.7 Hz, 1H), 3.57 (dd, J = 9.8, 6.8 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3) δ 163.2, 150.1, 140.6, 137.9, 137.3, 136.8, 128.72, 128.67,
128.60, 128.3, 128.2, 127.98, 127.935, 127.932, 127.90, 101.4, 91.2,
86.5, 85.6, 82.9, 73.6, 72.3, 72.0, 69.8 ppm; HRMS calcd for
C30H31N2O6 [M + H+] 515.2177, found 515.2177 (0.07 ppm).
(−)-9-((2S,3R,4S,5S)-3,4-bis(Benzyloxy)-5-((benzyloxy)-
methyl)tetrahydrofuran-2-yl)-9H-purin-6-amine (18a). Follow-
ing general procedure E, a solution of N,OTMS-acetal 10a (205 mg,
0.25 mmol) and Al(OiPr)3 (155 mg, 0.76 mmol, 3.0 equiv) was heated
in DMSO (4.2 mL). 1H NMR spectroscopic analysis of the unpurified
product indicated the formation of a single diastereomer (>20:1).
Purification by flash chromatography (hexanes/EtOAc, 0:100)
provided 18a (81 mg, 60%) as a colorless gum. 1H NMR spectroscopic
data correlate with the commercially available enantiomer of 18a:29 Rf
= 0.37 (hexanes/EtOAc, 0:100); [α]25 −9.50 (c 1.18, CDCl3);
D
Formula C31H31N5O4; MW 537.5089 g/mol; IR (neat) νmax 3318,
3156, 2914, 1653, 1599 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.33 (s,
1H), 8.18 (s, 1H), 7.37−7.25 (m, 10H), 7.22−7.17 (m, 3H), 6.92 (dd,
J = 7.3, 1.7 Hz, 2H), 6.51 (d, J = 4.3 Hz, 1H), 5.73 (s, 2H), 4.61 (d, J =
11.9 Hz, 1H), 4.54 (d, J = 12.0 Hz, 3H), 4.27 (dd, J = 5.1, 2.3 Hz, 2H),
4.26 (s, 1H), 4.22 (s, 1H), 4.21−4.18 (m, 1H), 3.69 (d, J = 4.9 Hz,
2H) ppm; 13C NMR (125 MHz, CDCl3) δ 155.4, 153.0, 149.9, 141.1,
137.8, 137.5, 136. 6, 128.65, 128.62, 128.55, 128.2, 128.1, 128.0,
127.93, 127.92, 127.89, 119.2, 83.4, 81.9, 81.5, 80.9, 73.5, 72.9, 72.3,
69.2 ppm; HRMS calcd for C31H32N5O4 [M + H+] 538.2449, found
538.2443 (−1.0 ppm).
(−)-1-((2S,3R,4S,5S)-3,4-bis(Benzyloxy)-5-((benzyloxy)-
methyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-
dione (16a). Following general procedure D, a solution of N,OTMS-
1
acetal 6a (100 mg, 0.12 mmol) was heated in DMSO (2.1 mL). H
NMR spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1). Purification by flash
chromatography (hexanes/EtOAc, 50:50) provided 16a (50 mg, 77%)
1
as a colorless gum. H NMR spectroscopic data correlate with the
previously reported data for the enantiomer of 16a:10 Rf = 0.26
(hexanes/EtOAc, 50:50); [α]25 −53.3 (c 0.940, CDCl3); Formula
D
(−)-1-((2S,3R,4S,5S)-3,4-bis(Benzyloxy)-5-((benzyloxy)-
methyl)tetrahydrofuran-2-yl)-5-fluoropyrimidine-2,4(1H,3H)-
dione (19a). Following general procedure D, a solution of N,OTMS-
1
C31H32N2O6; MW 528.5956 g/mol; H NMR (500 MHz, CDCl3) δ
8.38 (s, 1H), 7.44 (d, J = 1.1 Hz, 1H), 7.38−7.25 (m, 13H), 7.15 (dd, J
7184
dx.doi.org/10.1021/jo3012754 | J. Org. Chem. 2012, 77, 7176−7186

The Journal of Organic Chemistry
Featured Article
1
acetal 12a (119 mg, 0.15 mmol) was heated in DMSO (2.5 mL). H
NMR spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1). Purification by flash
chromatography (hexanes/EtOAc, 50:50) provided 19a (50 mg, 63%)
as a colorless gum: Rf = 0.36 (hexanes/EtOAc, 50:50); [α]25D −35.8 (c
0.760, CDCl3); Formula C30H29FN2O6; MW 532.5595 g/mol; IR
9.02 (s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.38−7.22 (m, 14H), 7.08 (dd, J
= 6.9, 2.4 Hz, 2H), 6.37 (d, J = 4.5 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H),
4.50 (d, J = 11.6 Hz, 2H), 4.43 (d, J = 8.5 Hz, 1H), 4.40 (d, J = 8.2 Hz,
1H), 4.37 (dd, J = 4.5, 2.9 Hz, 1H), 4.31 (d, J = 11.7 Hz, 1H), 4.21−
4.17 (m, 1H), 4.01 (dd, J = 4.1, 3.0 Hz, 1H), 3.65 (d, J = 5.2 Hz, 2H),
2.23 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.3, 162.5, 155.2,
146.7, 137.7, 137.4, 137.1, 128.7, 128.63, 128.59, 128.15, 128.13,
127.97, 127.94, 127.93, 127.91, 95.8, 86.7, 81.7, 81.5, 81.2, 73.5, 73.3,
72.1, 69.0, 25.1 ppm; HRMS calcd for C32H34N3O6 [M + H+]
556.2442, found 556.2446 (0.7 ppm).
1
(neat) νmax 3186, 2922, 1717 cm−1; H NMR (500 MHz, CDCl3) δ
9.31 (d, J = 4.2 Hz, 1H), 7.85 (d, J = 6.4 Hz, 1H), 7.40−7.25 (m,
13H), 7.16 (d, J = 7.4 Hz, 2H), 6.28 (d, J = 5.0 Hz, 1H), 4.58 (dd, J =
11.8, 4.6 Hz, 2H), 4.55−4.49 (m, 2H), 4.45 (s, 2H), 4.26 (appt, J = 4.2
Hz, 1H), 4.14−4.08 (m, 2H), 3.70 (dd, J = 10.3, 3.6 Hz, 1H), 3.63
(dd, J = 10.4, 3.8 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 156.9
(d, J = 26.5 Hz), 149.1, 139.9 (d, J = 235.8 Hz), 137.40, 137.36, 136.7,
128.7, 128.671, 128.666, 128.4, 128.2, 128.1, 128.0, 127.93, 127.88,
126.4 (d, J = 34.8 Hz), 84.6, 82.1, 80.8, 80.7, 73.6, 73.4, 72.4, 68.5
ppm; HRMS calcd for C30H30FN2O6 [M + H+] 533.2082, found
533.2074 (−1.5 ppm).
Preparation of L-Nucleoside Analogues Using DMSO-d6. 1-
((2S,3R,4S,5S)-3,4-bis(Benzyloxy)-5-((benzyloxy)methyl)-
tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(16a and 16b). A 1:2 mixture of N,OTMS-acetals 6a and 6b (25 mg,
0.031 mmol) in DMSO-d6 (0.06 M, 0.52 mL) was placed in an NMR
tube. The reaction mixture was maintained at 90 °C for 3 h in a sand
bath and then cooled to 25 °C. Nucleoside analogue 16a was formed
in 33% and analogue 16b in 54% on the basis of comparison of the
area of the residual DMSO-d6 solvent peak at 2.50 ppm (d1 relaxation
time was set to 10 s) with the area of the acetal center peak of the
starting material taken before heating the reaction mixture. Brine (0.2
mL) and 1 M NaOH (0.2 mL, to break emulsion formation) were
added to the reaction mixture. The aqueous layer was extracted with
ethyl acetate (3 × 0.5 mL), and the combined organic layers were
dried over MgSO4 and concentrated in vacuo. The expected
corresponding 1:2 mixture of L-1′,2′-cis and trans nucleoside analogues
(−)-4-Amino-1-((2S,3R,4S,5S)-3,4-bis(benzyloxy)-5-
((benzyloxy)methyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
(20a) and (+)-(2S,3R,4S)-4-((4-Aminopyrimidin-2-yl)oxy)-2,3,5-
tris(benzyloxy)pentan-1-ol (23). Following general procedure E, a
solution of N,OTMS-acetal 14a (95 mg, 0.12 mmol) and Al(OiPr)3
1
(74 mg, 0.36 mmol, 3.0 equiv) was heated in DMSO (2.0 mL). H
NMR spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer (>20:1), however, with a 2:1
mixture of nucleoside analogue 20a and primary alcohol 23.
Purification by flash chromatography (hexanes/EtOAc, 0:100)
provided 20a (28 mg, 46%) and 23 (11 mg, 18%) as colorless gums.
1
16a and 16b was obtained. H NMR spectroscopic data of the crude
reaction mixture in CDCl3 correlate with the enantiomers of 16a and
16b that have previously been reported in the literature.10
20a: Rf = 0.06 (hexanes/EtOAc, 0:100); [α]25 −109 (c 0.900,
D
CDCl3); Formula C30H31N3O5; MW 513.5842 g/mol; IR (neat) νmax
3347, 2925, 1626, 1481 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.68 (d,
J = 7.4 Hz, 1H), 7.37−7.22 (m, 13H), 7.16−7.12 (m, 2H), 6.38 (d, J =
4.6 Hz, 1H), 5.57 (d, J = 7.4 Hz, 1H), 4.57−4.49 (m, 3H), 4.46−4.39
(m, 2H), 4.35−4.29 (m, 2H), 4.14−4.11 (m, 1H), 4.01 (dd, J = 4.5,
3.0 Hz, 1H), 3.65 (d, J = 4.9 Hz, 2H) ppm; NH2 signal missing possibly
due to exchange in CDCl3; 13C NMR (125 MHz, CDCl3) δ 165.3,
155.6, 143.8, 137.9, 137.5, 137.3, 128.60, 128.58, 128.55, 128.07,
128.06, 127.96, 127.90, 127.892, 127.890, 93.2, 85.9, 82.1, 81.4, 80.8,
73.5, 73.2, 72.1, 69.2 ppm; HRMS calcd for C30H32N3O5 [M + H+]
514.2336, found 514.2346 (1.9 ppm).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Stereochemical proofs and H NMR and 13C NMR spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yvan.guindon@ircm.qc.ca.
■
The N1 regiochemistry and 1′,2′-cis configuration of 20a was
confirmed by comparison of the 13C NMR spectrum of the
debenzylated nucleoside with its commercially available enantiomer:30
13C NMR (125 MHz, DMSO) δ 165.6, 155.2, 142.9, 92.4, 85.7, 84.8,
ACKNOWLEDGMENTS
Funding for this research has been granted from Natural
Sciences and Engineering Research Council (NSERC) and
■
76.3, 74.8, 61.1 ppm.
23: Rf = 0.31 (hexanes/EtOAc, 0:100); [α]25D +3.5 (c 0.71, DCM);
Formula C30H33N3O5; MW 515.6001 g/mol; IR (neat) νmax 3340,
3207, 2923, 1626, 1595 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.96 (d,
J = 5.8 Hz, 1H), 7.34−7.24 (m, 15H), 6.08 (d, J = 5.7 Hz, 1H), 5.37−
5.33 (m, 1H), 4.95 (s, 2H), 4.82 (d, J = 11.2 Hz, 1H), 4.70 (d, J = 11.2
Hz, 1H), 4.63 (d, J = 1.2 Hz, 2H), 4.59 (d, J = 12.0 Hz, 1H), 4.55 (d, J
= 12.0 Hz, 1H), 4.17 (dd, J = 7.0, 2.8 Hz, 1H), 4.00 (dd, J = 10.7, 4.0
Hz, 1H), 3.94 (dd, J = 10.7, 6.1 Hz, 1H), 3.86 (d, J = 3.1 Hz, 2H),
3.73−3.69 (m, 1H) ppm; OH signal missing possibly due to exchange in
CDCl3; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.5, 157.2, 138.6,
138.5, 138.3, 128.5, 128.42, 128.38, 128.273, 128.271, 128.1, 127.8,
127.70, 127.69, 99.8, 80.4, 80.3, 76.4, 75.1, 73.7, 73.1, 68.9, 62.5 ppm;
HRMS calcd for C30H34N3O5 [M + H+] 516.2493, found 516.2498
(0.9 ppm).
́ ́
Fonds Quebecois de la Recherche sur la Nature et les
Technologies (FQRNT). NSERC and FQRNT scholarships
to S.D. are also gratefully acknowledged.
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