Synthesis of cis - And trans-α-l-[4.3.0]bicyclo-DNA monomers for antisense technology: Methods for the diastereoselective formation of bicyclic nucleosides

Article abstract of DOI:10.1021/jo401166q

Two α-l-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C₃′ and C₅′ have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular l-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C₅′ positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.

Full text of DOI:10.1021/jo401166q

Article
pubs.acs.org/joc
Synthesis of cis- and trans-α‑L‑[4.3.0]Bicyclo-DNA Monomers for
Antisense Technology: Methods for the Diastereoselective
Formation of Bicyclic Nucleosides
Stephen Hanessian,*,† Benjamin R. Schroeder,† Bradley L. Merner,† Bin Chen,† Eric E. Swayze,‡
and Punit P. Seth*,‡
†Department of Chemistry, Universite
́ ́ ́ ́
de Montreal, Montreal, Quebec H3C 3J7, Canada
‡Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., Carlsbad, California 92010, United States
S
* Supporting Information
ABSTRACT: Two α-L-ribo-configured bicyclic nucleic acid
modifications, represented by analogues 12 and 13, which are
epimeric at C3′ and C5′ have been synthesized using a
carbohydrate-based approach to build the bicyclic core structure.
An intramolecular L-proline-mediated aldol reaction was
employed to generate the cis-configured ring junction of analogue
12 and represents a rare application of this venerable organo-
catalytic reaction to a carbohydrate system. In the case of
analogue 13, where a trans-ring junction was desired, an
intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired
stereochemistry at the C5′ positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation
reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences,
and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA.
However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.
Other research groups have investigated the effects of linearly
annulating the furanose rings of designed nucleoside systems,
which also provides conformational restriction of the sugar
pucker (Figure 1). Leumann and co-workers appended a five-
membered carbocyclic ring to the furanose system of DNA to
give bicyclo-DNA (bc-DNA) 3.6−8 Even though this strategy of
conformational constraint resulted in simultaneous restriction
of the torsion angles γ and δ in bc-DNA, it did not improve
thermal stability relative to DNA (ΔTm = 0 to +0.5 °C/mod vs
RNA). The lack of improvement in binding affinity was
attributed to restriction of the torsion angle γ in the ap range, a
consequence of the pseudoequatorial orientation of the 5′-OH
group, as opposed to the +sc range seen in normal DNA. To
rectify this, Leumann designed tricyclo-DNA (tc-DNA) 4
(ΔTm = +2−4 °C/mod vs RNA) by appending a cyclopropane
ring onto the annulated cyclopentane ring of bc-DNA.9,10
However, subsequent structural studies showed that improve-
ment in duplex thermal stability with tc-DNA results from a
compensatory change in the torsion angles β and γ.11
Interestingly, Imanishi showed that the torsion angle γ can be
restricted in the +sc range in a [3.3.0] bicyclic ring system using
the N5′-phosphoramidate-linked 5′-amino-3′,5′-bridged nucleic
acid analogue 5.12 This modification was found to be stabilizing
(ΔTm = +2 °C/mod vs RNA) relative to DNA, bc-DNA, and
INTRODUCTION
■
Conformational restriction of the ribose or deoxyribose sugar
moieties of nucleoside monomers has been an area of intense
research interest in recent years.1 Chemically modified
oligonucleotides which incorporate these monomers are being
investigated as small-interfering RNAs (siRNAs) and as
antisense agents for post-translational control of gene
expression.2 Structural modifications that restrict the con-
formation of the furanose ring in the C3′-endo (N-type or
northern) or C2′-endo (S-type or southern) sugar puckers while
maintaining Watson−Crick base-pairing properties are partic-
ularly well-suited for the antisense approach. These analogues
improve binding affinity of the modified oligonucleotides
(ONs) for DNA and RNA complements, as measured by
increased duplex stability in thermal denaturation experiments
(Tm). One of the most successful examples of such structural
modifications has come from independent reports by Imanishi3
and Wengel,4 who have described the synthesis and base-
pairing properties of 2′,4′-bridged nucleic acids (BNA),
commonly known as locked nucleic acids (LNAs, i.e., 1 and
2; Figure 1). The 1,4-dioxabicyclo[2.2.1]heptane core of these
nucleoside monomers locks the ribose sugar moiety in the N-
type conformation, and oligonucleotides that incorporate this
modification show significant increases in duplex thermo-
stability (ΔTm = +4−10 °C/mod vs RNA), which makes them
useful for diagnostic and antisense applications.5
Received: June 4, 2013
© XXXX American Chemical Society
A
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Figure 1. Structurally modified nucleic acid analogues.
5′-amino DNA. Imanishi has also described the synthesis and
hybridization properties of [4.3.0] bicyclic nucleic acid
analogues 6−8. The furanose ring in all of these modifications
is locked in the S-type conformation, however, these analogues
proved to be moderately to extremely destabilizing relative to
DNA (ΔTm = −3 to −10 °C/mod vs RNA).13,14 Nielsen and
co-workers have reported the synthesis of the α-L-ribo-
configured version (9) of the [4.3.0] bicyclic nucleoside 6.15
Unfortunately, they were unable to convert the 5′O-DMTr-
protected nucleoside to the corresponding phosphoramidite for
incorporation into oligonucleotide sequences. However, they
evaluated the C3′/C4′ epimer (10) of analogue 9 in Tm studies
and found it to be extremely destabilizing relative to DNA
(ΔTm = −10 °C/mod vs RNA).
In an attempt to further refine the hybridization properties of
bc-DNA (3), Leumann and co-workers synthesized a
homologated analogue of the nucleic acid that contains a
bicyclo[4.3.0]nonane core structure as in 11 (Figure 2).16 The
cyclohexane ring system in 11 is expected to orient the 5′-OH
group in either an axial (desired) or equatorial (undesired)
orientation. Molecular modeling experiments indicated that the
undesired conformation B (torsion angle γ in the ap range) was
3.2 kcal/mol lower in energy in comparison to conformation A
(torsion angle γ in the +sc range) in nucleoside monomer 11.
Evaluation of oligonucleotides containing 11 in thermal
denaturation experiments indicated that this modification was
slightly destabilizing relative to DNA (ΔTm = −0.7 to −2.3 °C/
mod vs RNA), except when introduced in tandem, where it was
found to be slightly stabilizing (ΔTm = +0.7 °C/mod vs RNA).
As part of our own efforts in de novo design of nucleic acid
mimics for antisense applications, we wanted to evaluate the
properties of nucleoside modification 12, which is essentially
the α-L-configured version of nucleoside 11. Wengel and co-
workers17,18 previously evaluated all eight stereoisomers of
LNA (1) and showed that α-L-LNA (2, i.e., the C1′ epimer of
ent-LNA) possesses similar hybridization properties in compar-
Figure 2. Rational design of bicyclo-DNA (bc-DNA) analogue 12.
ison to 1 (ΔTm = +5−+10 °C/mod vs RNA). Given the
interesting structural and biophysical properties of α-L-LNA-
modified oligonucleotides, a number of related analogues were
synthesized and investigated as potential agents for use in
oligonucleotide-based diagnostic and therapeutic antisense
applications.19 Our own investigation of this interesting nucleic
acid scaffold has recently led to synthetic, biophysical, and
biological studies of several α-L-LNA analogues.20 In addition,
we have also described the duplex stabilizing properties of a
tricyclic α-L-LNA analogue, which provides unprecedented
increases in duplex thermal stability by simultaneously locking
the sugar pucker (N-type conformation) and restricting
rotation around the torsion angle γ.21 In line with this work,
we proposed to study the α-L-configured DNA analogue 12 and
its C3′/C5′ epimer 13, which lack the 2′,4′-oxamethylene bridge
of α-L-LNA but have restricted rotation around the torsion
angle γ. Conformational analysis of the cyclohexane ring in 12
suggested that the six-membered ring can exist in two chair
conformations (Figure 2). Conformer A is capable of orienting
the nucleobase, 5′-OH, and 3′-OH groups in precisely the same
orientation as that observed for α-L-LNA monomers in an
NMR-derived structure of a modified duplex with RNA (see
overlay structure, Figure 2),22 while conformer B would orient
these vectors in distinctly different trajectories. In contrast, the
cyclohexane ring in 13 was expected to exist in a single chair
conformation (5′-OH equatorial and 3′-OH axial) by virtue of
B
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the increased rigidity of the trans-fused ring system. However, it
was not clear if conformer A or B would be preferred when 12
was incorporated into oligonucleotide sequences, and paired,
versus complementary nucleic acids, or if modifications such as
13 could be useful to stabilize oligonucleotide duplexes. To
investigate these issues, we undertook the synthesis of 12 and
13 and studied the biophysical properties of the modified
oligonucleotides.
synthesis of 12 and 13, respectively, with high diastereoslec-
tivity. Following a protocol that had been developed by
Danishefsky and co-workers,25 treatment of 18 with allyl-
trimethylsilane in the presence of boron trifluoride diethyl
etherate furnished 21 as a single diastereomer. However,
obtaining the epimeric and (R)-configured homoallyic alcohol
intermediate to be used in the synthesis of 17 proved to be
more challenging (Table 1). Variation of the Lewis acid and
nucleophile source were systematically explored, and it was
discovered that the combination of 3.0 equiv of magnesium
bromide diethyl etherate and 2.0 equiv of allyltributyltin at −78
°C in dichloromethane gave the best results (94%, dr = 4:1;
Table 1, entry 8). It is possible that use of allyltributylstannane
in combination with MgBr·OEt2 is operative under chelation
control to give the C5-epi-21 isomer as the major product.
Benzylation of 21, followed by selective cleavage of the Nap
ether protecting group using DDQ,26,33 gave 22 in 66% yield
over two steps. Sequential oxidation reactions, first of the C3
alcohol in 22 to 23 and then of the terminal olefin according to
Smith and co-workers27 gave diketone 24. At this juncture, the
opportunity presented itself to utilize the mild catalytic
conditions of the Hajos−Parrish−Eder−Sauer−Weichert re-
action23 to circumvent any possible epimerization and to ensure
isolation of the desired β-hydroxy ketone, which would later be
the site (tertiary alcohol) of phosphoramidite formation to be
used in oligonucleotide synthesis. It was also discovered that
heating the reaction mixture in DMSO (or DMF) significantly
shortened the reaction time while giving yields comparable to
those obtained at room temperature.28 The stereochemistry of
the newly created stereogenic centers at C3 and C5 were
assigned on the basis of an X-ray crystal structure obtained for
the PMB ether 26.28
RESULTS AND DISCUSSION
■
It was envisaged that both α-L-[4.3.0]bicyclo-DNA analogues
12 and 13 could originate from L-arabinose as a common
chiron (Scheme 1). In the case of cis-α-L-[4.3.0]bicyclo-DNA
Scheme 1. Retrosynthetic Analysis of [4.3.0]Bicyclo-DNA
Monomers 12 and 13
Reduction of β-hydroxy ketone 25 using the Evans−
Saksena29 protocol gave alcohol 27, which was directly
converted to the thiocarbonyl imidazole derivative and then
subjected to a Barton−McCombie30 radical deoxygenation
reaction in the presence of Bu3SnH in refluxing toluene to give
28 in 72% yield for the three-step sequence (Scheme 3).
Cleavage of the isopropylidene group with DOWEX 50W8X
acidic resin and acetylation gave a diastereomeric mixture of
diacetates 29. Application of the Vorbruggen reaction
̈
conditions31 furnished nucleoside 30 in 95% yield. After
serving its role in securing the correct β-orientation of the
thymine nucleobase via neighboring group participation, the
C2′-OAc group was cleaved and the C2′ alcohol was converted
to thiocarbamate 31 (52% over two steps) and then subjected
to another radical deoxygenation reaction to give 32 in 80%
yield. Hydrogenolysis of the benzyl ether, followed by
alkylation of the resulting free alcohol as the 4,4′-dimethoxy-
trityl ether, completed the synthesis of cis-α-L-[4.3.0]bicyclo-
DNA monomer 12.
The synthesis of the second bicyclic nucleoside target 13
commenced with a diastereoselective allylation reaction of the
common aldehyde intermediate 18, which gave the desired (R)-
configured homoallylic alcohol C5-epi-21 in excellent yield
(93%, dr = 4:1, vide infra, Table 1, entry 8). A similar
protecting group and oxidation sequence that had been
developed for the synthesis of 12 was employed here to give
ketone 34 (Scheme 4). Reaction with vinylmagnesium bromide
in THF led to 35 as a single isomer. Unlike the synthetic route
to 12 (Scheme 3), where the carbocyclic ring was formed
before the thymine nucleobase was introduced, it was critical to
reverse these synthetic operations in the synthesis of analogue
(12), a key reaction would involve an intramolecular L-proline-
catalyzed aldol reaction23 of diketone 15. The (S)-configured
homoallylic alcohol present in 16 could be installed via a
diastereoselective Sakurai allylation reaction of 18. The
synthetic blueprint of trans-α-L-[4.3.0]bicyclo-DNA (13) relied
on the construction of the carbocyclic ring of the nucleoside
monomer via a ring-closing metathesis reaction from diene 17,
also obtained via a diastereoselective allylation reaction. The
tertiary alcohol at C3 would originate from a stereoselective
Grignard vinylation of a ketone.
To this end, L-arabinose was converted to isopropylidene
derivative 19 using a known two-step procedure (Scheme 2).24
Protection of the remaining free hydroxyl group as the O-Nap
ether (Nap = 2-naphthylmethyl), followed by cleavage of the
TBDPS group, furnished primary alcohol 20 (Scheme 2).
Oxidation of 20 under Parikh−Doering reaction conditions
gave the desired aldehyde precursor 18 in 94% yield. With this
key synthetic intermediate in hand, attention was turned to
finding optimal allylation reaction conditions that would give
the desired S- and R-configured homoallylic alcohols, for the
C
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a
Scheme 2. Synthesis of Tricyclic Ketone 25
a
Conditions: (a) TBDPSCl, imidazole, DMF, 60 °C, 4 h; (b) CuSO4, H2SO4, acetone, 23 °C, 1 h; (c) NapBr, NaH, TBAI, DMF/THF (1/1), 23
°C, 2 h; (d) TBAF, THF, 23 °C, 4 h; (e) SO3·pyridine, i-Pr2NEt, CH2Cl2/DMSO (5/1), −20 to 0 °C, 30 min; (f) allylTMS, BF3·Et2O, CH2Cl2, −78
°C, 2 h, dr > 20:1; (g) NaH, BnBr, TBAI, DMF/THF (1/1), 23 °C, 2 h; (h) DDQ, CH2Cl2/H2O (9/1), 23 °C, 6 h; (i) PCC, NaOAc, CH2Cl2, 23
°C, 6 h; (j) O2, PdCl2, Cu(OAc)2, H2O/DMA (1/7), 23 °C, 24 h; (k) L-proline, DMSO, 55 °C, 24 h.
13. Others have reported unwanted side reactions to occur
when related trans-1-oxabicyclo[4.3.0]nonane systems have
been subjected to acidic hydrolysis of a C1,C2-isopropylidene
group,32 and a similar result was observed with the C3/C5-
epimer of 28. Therefore, treatment of 35 with DOWEX
50W8X, acetylation of the resulting mixture of diastereomeric
Table 2). In the first sequence (A1), we introduced 12 into a
stretch of dT nucleotides as either single (A2) or tandem
incorporations (A3) of the modified nucleotide. We also
incorporated 12 between purine nucleotides using a second
oligonucleotide sequence (A4) to provide a sequence context
for the Tm experiments. A single incorporation of 12 (A2)
produced a −3.7 °C reduction in duplex thermal stability when
paired with its complementary RNA strand, while two
incorporations in tandem were also destabilizing (A3, ΔTm
−2.9 °C/mod). Three incorporations of the modified
nucleotide 12 introduced at positions 5, 8, and 10 of
oligonucleotide A4 were slightly less destabilizing (A5, ΔTm
−1.5 °C/mod). We also measured the ability of 12 to stabilize
oligonucleotides from 3′-exonuclease digestion by treating
oligonucleotide A7 with snake venom phosphodiesterase. We
found that modification 12 can provide a significant improve-
ment in nuclease stability relative to unmodified DNA
oligonucleotide A6 (Figure 3).
diols, and application of the Vorbruggen reaction furnished 37
̈
in 81% yield over three steps. Exposure of 37 to Grubbs’
second-generation catalyst, followed by hydrogenation of the
resulting cyclohexene ring and cleavage of the C2′-OAc group,
afforded bicyclic nucleoside 38. Barton−McCombie deoxyge-
nation gave 39, which was converted to DMTr ether 13. Unlike
similar deoxygenation reactions on nucleoside systems, which
have been reported to be low-yielding and problematic with
respect to reproducibility,16 all Barton−McCombie deoxygena-
tion reactions that were used in the synthesis of 12 and 13
proved to be uneventful and straightforward.
Nucleoside analogues 12 and 13 were converted to the
corresponding phosphoramidites 40 and 41, respectively.
However, only phosphoramidite 40 could be successfully
incorporated into oligonucleotide sequences using a standard
protocol.34 Unfortunately, all attempts to incorporate phos-
phoramidite 41 (Scheme 5) into oligonucleotides using the
conditions employed for the incorporation of 40 were
unsuccessful. The inability to incorporate nucleosides with
trans-fused bicyclic ring systems into oligonucleotides has been
documented previously.14,15
Oligonucleotides were synthesized in over 90% yield at 2 μM
scale on an automated DNA synthesizer using dT-controlled
pore glass (CPG) polymer support for A2 and A3, and dC−
CPG support for A5 as described previously.34
The duplex stabilizing properties of 12 were evaluated using
single, double, and triple incorporations of the modified
nucleotide into two oligonucleotide sequences (A1 and A4,
CONCLUSIONS
■
In conclusion, we report the synthesis and duplex-forming
properties of oligonucleotides modified with cis-α-L-[4.3.0]-
bicyclo-DNA monomer (12). Synthesis of the nucleoside
phosphoramidite was accomplished in 23 steps starting from
commercially available L-arabinose. The synthesis features the
use of key diastereoselective C−C bond forming reactions,
including a Sakurai allylation reaction and an intramolecular L-
proline-catalyzed aldol reaction. Evaluation of oligonucleotides
modified with 12 in UV-monitored thermal denaturation
experiments revealed that this modification has a slight
destabilizing effect upon oligonucleotide duplex formation.
Structural analysis of modification 12 suggests that one
conformation of the cis-fused bicyclic ring system is capable
of orienting the nucleobase, 3′-OH, and the 5′-phosphodiester
D
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Table 1. Optimization of Stereoselective Allylation
Reactions of Common Aldehyde Precursor 18
Scheme 3. Completion of the Synthesis of cis-α-L-
[4.3.0]Bicyclo-DNA 12
a
allyl source
dr
isolated
(amt
Lewis acid
solvent/
(21:C5-
yield
a
b
c
entry
1
(equiv))
(amt (equiv)) temp (°C) epi-21)
(%)
A (1.75)
A (2.5)
B (2.0)
B (1.5)
B (2.0)
A (2.0)
B (2.0)
B (2.0)
B (2.0)
B (2.0)
BF3·OEt2
CH2Cl2/− >20:1
86
(2.0)
78
2
Ti3CI4 (1.5)
Ti3CI4 (1.1)
ZnCI4 (1.1)
CH2Cl2/− decomp
78
3
CH2Cl2/− 1:1
50
82
78
4
CH2 CI2/
−78
5:1
e
5
LiCIO4 (5 M Et2O/25
in Et2 O)
nr
6
MgBr2·OEt2
(1.1)
CH2Cl2/− 1:1
86
77
78
7
MgBr2·OEt2
(3.0)
CH2Cl2/− 5:1
78
d
8
MgBr2·OEt2
(3.0)
CH2Cl2/− 1:4
93
78
9
MgBr2·OEt2
(5.0)
CH2Cl2/− 1:4
90
81
a
Conditions: (a) Me4NBH(OAc)3, AcOH, MeCN, 0−23 °C, 12 h;
(b) Im2CS, DMAP, CH2Cl2, 23 °C, 24 h; (c) Bu3SnH, AIBN, PhMe,
110 °C, 30 min; (d) DOWEX 50W8X, H2O/1,4-dioxane (1/1), 23
°C, 48 h; (e) Ac2O, pyridine, 23 °C, 24 h; (f) thymine, BSA, MeCN,
80 °C, 1 h, then 0 °C, TMSOTf, 0−50 °C, 24 h, then TBAF, THF 23
°C, 30 min; (g). K2CO3, MeOH, 23 °C, 24 h; (h) Im2CS, DMAP,
CH2Cl2, 23 °C, 24 h; (i) Bu3SnH, AIBN, PhMe, 110 °C, 1 h; (j) H2,
Pd(OH)2/C, MeOH/THF (1/1), 23 °C, 24 h; (k) DMTrCl, 2,6-
lutidine, pyridine/CH2Cl2 (1/1), 40 °C, 8 h.
78
10
MgBr2·OEt2
(3.0)
CH2Cl2/
23
2:1
a
b
1
dr was determined from the H NMR spectrum of the isolated
c
mixture of 21 and C5-epi-21. Isolated overall yield of 21 and 27.
74% yield of 27 after chromatography. nr = no reaction.
received from chemical suppliers. Reagents were purchased and used
without further purification. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous material, unless otherwise
stated. Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm silica plates that were visualized
using a UV lamp (254 nm) and developed with iodine vapor, an
aqueous solution of cerium ammonium molybdate, or an ethanolic
solution of p-anisaldehyde. Flash chromatography36 was performed
using 40−63 μm (230−400 mesh) silica gel, and all column
dimensions are reported as height × diameter in centimeters. NMR
spectra were recorded at 300 or 400 MHz, calibrated using residual
undeuterated solvent as an internal reference (CHCl3, δ 7.26 ppm;
CHD2OD, δ 3.31 ppm), and reported in parts per million relative to
trimethylsilane (TMS, δ 0.00 ppm) as follows: chemical shift
(multiplicity, coupling constant (Hz), integration). The following
abbreviations were used to explain multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd =
doublet of doublets, dt = doublet of triplets. High-resolution mass
spectra (HRMS) were recorded on a TOF mass spectrometer using
electrospray ionization time-of-flight reflectron experiments. Melting
points are given as ranges and are reported in °C. Specific rotation
measurements are reported in units of deg cm3 g−1 dm−1.
d
e
linkages in the same general orientation as those observed for
α-L-LNA, while restricting rotation around the torsion angle γ.
However, modification 12 lacks the 2′,4′-bridging substituent,
which locks the furanose sugar ring of α-L-LNA in an N-type
conformation. In the absence of structural data, it is difficult to
predict if the destabilization produced by 12, when
incorporated into oligonucleotides A2, A3, and A5, is a
consequence of the added steric bulk of the appended six-
membered ring, the lack of a 2′,4′-bridging motif, or
conformational mobility of the cis-fused ring system.
Oligonucleotide A7 harboring tandem incorporations of 12
provided a 285-fold improvement in nuclease stability relative
to unmodified DNA. Further structural refinements of 12 to
help dissect the contributions of these variables to oligonucleo-
tide duplex stability are currently in progress.35
EXPERIMENTAL SECTION
■
1,2-O-Isopropylidene-3-O-(2-naphthylmethyl)-β-L-arabino-
General Procedures. All nonaqueous reactions were run in an
oven (120 °C) or flame-dried glassware under a positive pressure of
argon, with exclusion of moisture from reagents and glassware, using
standard techniques for manipulating air-sensitive compounds, unless
otherwise stated. Anhydrous tetrahydrofuran, diethyl ether, toluene,
and dichloromethane were obtained by passing these solvents through
activated columns of alumina, while all other solvents were used as
pentodialdofuranose (18). Hunig’s base (2.35 g, 18.2 mmol) and
̈
sulfur trioxide pyridine complex (2.89 g, 18.2 mmol), as a solution in
DMSO (15 mL), were added sequentially to a stirred −20 °C solution
of 20 (2.00 g, 6.05 mmol) in 9/1 dichloromethane/DMSO (54 mL).
After 10 min, diethyl ether (100 mL) was added, followed by a 0 °C
solution of brine (250 mL). The layers were separated, and the
aqueous phase was extracted with diethyl ether (3 × 100 mL). The
E
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a
Scheme 4. Synthesis of trans-α-L-[4.3.0]Bicyclo-DNA (13) from Common Aldehyde Precusor 18
a
Conditions: (a) allyltributylstannane, MgBr2 Et2O, CH2Cl2, −78 °C, 3 h, dr = 4:1; (b) NaH, BnBr, TBAI, DMF/THF (1/1), 23 °C, 16 h; (c)
DDQ, H2O/CH2Cl2 (1/9), 23 °C, 4 h; (d) PCC, NaOAc, CH2Cl2, 23 °C, 16 h; (e) vinylmagnesium bromide, THF, 0 °C, 30 min; (f) DOWEX
50W8X, H2O/1,4-dioxane (1/1), 50 °C, 12 h; (g) Ac2O, pyridine, 0−23 °C, 18 h; (h) thymine, BSA, MeCN, 80 °C, 1 h, then 0 °C, TMSOTf, 0−50
°C, 24 h; (i) TBAF, THF, 23 °C, 30 min; (j) Grubbs second-generation catalyst (5 mol %), CH2Cl2, 23 °C, 1 h; (k) H2, Pd/C, MeOH, 23 °C, 2 h;
(l) K2CO3, MeOH, 23 °C, 12 h; (m) PhOC(S)Cl, pyridine/CH2Cl2 (1/1), 23 °C, 6 h; (n) Bu3SnH, AIBN, PhMe, 110 °C, 30 min; (o) H2,
Pd(OH)2/C, MeOH/THF (1/1), 23 °C, 24 h; (p) DMTrCl, 2,6-lutidine, pyridine/CH2Cl2 (1/1), 40 °C, 24 h.
combined organic extracts were washed with 0.5 M HCl (3 × 100
mL), water (100 mL), and a saturated NaHCO3 solution (100 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was dissolved in toluene (50 mL) and concentrated under
reduced pressure three times to remove residual amounts of pyridine.
The resulting colorless oil was dried under high vacuum and used in
further experiments without purification (1.87 g, 94%): Rf = 0.30 (1:4
Scheme 5. Synthesis of Phosphoramidites 40 and 41 for
Oligonucleotide Synthesis
20
1
EtOAc/hexanes); [α]D +13 (c 0.37, CHCl3); H NMR (400 MHz,
CDCl3) δ 9.82 (s, 1H), 7.88−7.81 (m, 4H), 7.53−7.44 (m, 3H), 6.13
(d, J = 3.6 Hz, 1H), 4.79 (d, J = 11.6 Hz, 1H), 4.74 (d, J = 11.6 Hz,
1H), 4.68 (d, J = 3.6 Hz, 1H), 4.60 (s, 1H), 4.41 (s, 1H), 1.47 (s, 3H),
1.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.8, 134.3, 133.3,
133.2, 129.2, 128.6, 128.4, 128.1, 127.9, 127.0, 126.5, 126.3, 125.7,
125.4, 112.3, 106.7, 88.9, 85.0, 83.0, 72.2, 26.3, 25.7; HRMS (ESI)
calcd for C19H21O5 [M + H]+ m/z 329.1384, found 329.1380.
1,2-O-Isopropylidene-3-O-(2-naphthylmethyl)-β-L-arabino-
furanose (20). A solution of 1924 (7.00 g, 16.3 mmol) in 1/1 DMF/
THF (10 mL), and 2-(bromomethyl)naphthalene (4.32 g, 19.6 mmol)
were added to a stirred 0 °C slurry of NaH (60% dispersion in oil, 1.31
g, 32.7 mmol) and tetrabutylammonium iodide (3.01 g, 8.15 mmol) in
Table 2. Sequence, Analytical Data, Duplex Stabilizing Properties, and Nuclease Stability Profile of Modified Oligonucleotides
a
b
b
ODN
mod
DNAC
mass calcd
mass found
sequence (5′ to 3′)
ΔTm/mod (°C) vs RNA
ΔTm/mod (°C) vs DNA
T1/2 (min)
A1
A2
A3
A4
A5
A6
A7
3633.4
3673.4
3713.5
3645.2
3765.6
3588.4
3668.5
3632.9
3672.9
3713.0
3645.5
3765.1
3588.0
3668.0
d(GCGTTTTTTGCT)
d(GCGTTTTTTGCT)
d(GCGTTTTTTGCT)
d(CCAGTGATATGC)
d(CCAGTGATATGC)
d(TTTTTTTTTTTT)
d(TTTTTTTTTTTT)
control
−3.7
−2.9
control
−8.8
−7.6
12
12
c
DNA
control
control
12
DNAC
−1.5
−4.6
0.22
62.7
12
a
b
Bold and underlined letters indicates modified nucleotide. Base code: T = thymine, U = uracil, C = cytosine, A = adenine, G = guanine. Tm values
were measured in 10 mM sodium phosphate buffer (pH 7.2) containing 100 mM NaCl and 0.1 mM EDTA. Sequence of RNA complement 5′-
r(AGCAAAAAACGC)-3′ for A1−A3 and 5′-r(GCAUAUCACUGG)-3′ for A4 and A5. Sequence of DNA complement 5′-d(AGCAAAAAACGC)-
c
3′ for A1−A3 and 5′- d(GCAUAUCACUGG)-3′ for A4 and A5. DNA oligonucleotides were purchased from commercial vendors and used as
supplied.
F
dx.doi.org/10.1021/jo401166q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
20.0 mmol) was added and the resulting solution was stirred at −78
°C for 3 h. The reaction mixture was poured directly into a 0 °C
solution of saturated NaHCO3 (100 mL) and further diluted with
dichloromethane (100 mL). The layers were separated, and the
aqueous phase was extracted with dichloromethane (3 × 100 mL).
The combined organic extracts were washed with brine (100 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (25 × 2 cm; 1/5
EtOAc/hexanes) to give 21 as a colorless solid (3.63 g, 86%): Rf =
20
0.42 (1:4 EtOAc/hexanes); mp 74−78 °C; [α]D −3.4 (c 1.7,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.86−7.82 (m, 4H), 7.52−
7.48 (m, 3H), 6.00 (d, J = 3.9 Hz, 1H), 5.98−5.87 (m, 1H), 5.21−5.15
(m, 2H), 4.81 (d, J = 11.6 Hz, 1H), 4.75 (d, J = 11.6 Hz, 1H), 4.72 (d,
J = 3.9 Hz, 1H), 4.33 (d, J = 2.4 Hz, 1H), 4.06 (dd, J = 4.2, 2.7 Hz,
1H), 3.95−3.89 (m, 1H), 2.55−2.47 (m, 1H), 2.28−2.18 (m, 1H),
1.56 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 134.9,
134.3, 133.4, 133.2, 128.5, 128.1, 127.9, 127.0, 126.4, 126.2, 125.9,
118.7, 112.9, 105.8, 87.9, 85.5, 82.6, 77.6, 72.0, 70.2, 37.8, 27.4, 26.5;
HRMS (ESI) calcd for C22H26O5Na [M + Na]+ m/z 393.1673, found
393.1679.
1,2-O-Isopropylidene-5-O-benzyl-6-deoxy-6-C-vinyl-β-L-al-
trofuranose (22). Sodium hydride (60% dispersion in oil, 0.130 g,
3.24 mmol), benzyl bromide (0.831 g, 4.86 mmol), and
tetrabutylammonium iodide (0.120 g, 0.324 mmol) were added
sequentially to a stirred 0 °C solution of 21 (0.600 g, 1.62 mmol) in 1/
1 DMF/THF (20 mL). The cooling bath was removed, and the
reaction mixture was warmed to room temperature. After 2 h, the
reaction mixture was cooled to 0 °C and methanol (2 mL), diethyl
ether (100 mL), and water (100 mL) were added sequentially. The
layers separated, and the aqueous phase was extracted with diethyl
ether (3 × 100 mL). The combined organic extracts were washed with
a saturated solution of NaHCO3 (3 × 100 mL) and brine (100 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (19 × 2 cm; 1/9
EtOAc/hexanes) to give the benzyl ether as a colorless oil (0.728 g,
98%): Rf = 0.70 (1/3 EtOAc/hexanes); [α]D20 +23 (c 1.2, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.90−7.81 (m, 4H), 7.56−7.49 (m, 3H),
7.43−7.31 (m, 5H), 6.13−5.97 (m, 2H), 5.34−5.21 (m, 2H), 4.85−
4.73 (m, 4H), 4.56 (d, J = 11.4 Hz, 1H), 4.29−4.23 (m, 2H), 3.87−
3.81 (m, 1H), 2.75−2.68 (m, 1H), 2.61−2.51 (m, 1H), 1.54 (s, 3H),
1.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.3, 135.1, 134.1,
133.4, 133.2, 128.44, 128.36, 128.1, 128.0, 127.8, 127.7, 126.8, 126.2,
126.1, 125.9, 118.0, 112.3, 106.1, 86.0, 85.1, 82.8, 77.6, 72.1, 71.5, 34.8,
27.0, 26.1; HRMS (ESI) calcd for C29H36O5N [M + NH4]+ m/z
478.2588, found 478.2599. DDQ (1.66 g, 7.32 mmol) was added to a
vigorously stirred solution of the above ether (1.68 g, 3.66 mmol) in
1/9 water/dichloromethane (100 mL). After 6 h, a 10% solution of
NaHSO3 (100 mL) was added and the layers were separated. The
aqueous phase was extracted with dichloromethane (3 × 50 mL), and
the combined organic extracts were washed with a saturated solution
of NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (24 × 2 cm; 1/3 EtOAc/hexanes) to
afford 22 as a colorless oil (0.931 g, 79%): Rf = 0.16 (1:4 EtOAc/
hexanes); [α]D20 +43 (c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.36−7.29 (m, 5H), 5.98−5.88 (m, 1H), 5.87 (d, J = 4.0 Hz, 1H),
5.21−5.12 (m, 2H), 4.71 (d, J = 11.2 Hz, 1H), 4.53−4.48 (m, 2H),
4.34−4.31 (m, 1H), 3.82 (dd, J = 6.4, 2.8 Hz, 1H), 3.77−3.72 (m,
1H), 2.65−2.58 (m, 1H), 2.45−2.38 (m, 1H), 2.22 (d, J = 3.6 Hz,
1H), 1.45 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
137.9, 133.6, 128.5, 128.1, 127.9, 118.1, 112.5, 105.5, 87.4, 86.8, 78.1,
76.8, 71.9, 34.6, 26.9, 26.2; HRMS (ESI) calcd for C18H24O5Na [M +
Na]+ m/z 343.1516, found 343.1529.
Figure 3. Nuclease stability profiles of oligonucleotides A6 (top) and
A7 (bottom) after incubation with snake venom phosphodiesterase.
1/1 DMF/THF (90 mL). The cooling bath was removed, and the
reaction mixture was warmed to room temperature. After 2 h, the
reaction mixture was cooled to 0 °C and methanol (2 mL), diethyl
ether (250 mL), and water (100 mL) were added sequentially. The
layers were separated, and the aqueous phase was extracted with
diethyl ether (3 × 100 mL). The combined organic extracts were
washed with a saturated solution of NaHCO3 (100 mL) and brine
(100 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(26 × 3 cm; 1/9 EtOAc/hexanes) to afford the 3-Nap ether as a
20
colorless oil (7.78 g, 84%): Rf = 0.31 (1/9 EtOAc/hexanes); [α]D
1
+5.7 (c 0.87, CHCl3); H NMR (400 MHz, CDCl3) δ 7.88−7.80 (m,
4H), 7.74−7.66 (m, 4H), 7.52−7.37 (m, 9H), 6.03 (d, J = 4.0 Hz,
1H), 4.89 (d, J = 12.0 Hz, 1H), 4.85 (d, J = 12.0 Hz, 1H), 4.82 (d, J =
4.0 Hz, 1H), 4.43−4.38 (m, 2H), 4.00−3.92 (m, 2H), 1.46 (s, 3H),
1.40 (s, 3H), 1.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.7,
135.1, 133.40, 133.35, 133.2, 129.90, 129.84, 128.5, 128.1, 127.89,
127.85, 126.7, 126.3, 126.1, 125.8, 112.6, 105.9, 85.4, 85.3, 82.9, 77.4,
71.9, 63.6, 27.1, 26.9, 26.3, 19.3; HRMS (ESI) calcd for C35H44NO5Si
[M + NH4]+ m/z 586.2983, found 586.2995. Tetrabutylammonium
fluoride (1.0 M in THF, 7.3 mL, 7.3 mmol) was added to a stirred
solution of the ether (3.75 g, 6.59 mmol) in THF (50 mL). After 4 h, a
saturated solution of NaHCO3 (10 mL) was added and the resulting
mixture was further diluted with EtOAc (200 mL). The layers were
separated and the organic phase was washed with a saturated solution
of NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography (21 × 2 cm; 1:2 EtOAc/hexanes) to give 20 as a
20
colorless oil (2.03 g, 93%): Rf = 0.55 (1:1 EtOAc/hexanes); [α]D
1
−8.0 (c 1.7, CHCl3); H NMR (400 MHz, CDCl3) δ 7.89−7.81 (m,
4H), 7.54−7.46 (m, 3H), 5.98 (d, J = 4.4 Hz, 1H), 4.84−4.74 (m,
3H), 4.31−4.26 (m, 1H), 4.08−4.04 (m, 1H), 3.81−3.75 (m, 2H),
2.29 (br s, 1H), 1.56 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 134.7, 133.2, 133.1, 128.3, 127.9, 127.7, 126.6, 126.2, 126.1,
125.6, 112.8, 105.6, 85.7, 85.2, 82.8, 77.4, 71.8, 62.6, 27.1, 26.3; HRMS
(ESI) calcd for C19H22O5Na [M + Na]+ m/z 353.1359, found
353.1368.
1,2-O-Isopropylidene-3-keto-5-O-benzyl-6-deoxy-6-C-vinyl-
β-L-altrofuranose (23). A solution of 22 (0.930 g, 2.90 mmol) in
dichloromethane (20 mL) was added to a stirred 0 °C slurry of PCC
(1.88 g, 8.70 mmol), anhydrous sodium acetate (0.726 g, 8.85 mmol),
and 4 Å molecular sieves in dichloromethane (80 mL). The cooling
bath was removed, and the reaction mixture was warmed to room
temperature. After 6 h, diethyl ether (100 mL) and silica gel (ca. 2 g)
1,2-O-Isopropylidene-3-O-(2-naphthylmethyl)-6-deoxy-6-C-
vinyl-β-L-altrofuranose (21). Boron trifluoride diethyl etherate was
added to a stirred −78 °C solution of aldehyde 18 (3.75 g, 11.4 mmol)
in dichloromethane (200 mL). After 5 min, allyltrimethylsilane (2.28 g,
G
dx.doi.org/10.1021/jo401166q | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
were added. The resulting mixture was filtered under vacuum through
a short pad of silica gel (3 cm) and washed diethyl ether (100 mL).
The filtrate was concentrated under reduced pressure, and the residue
was purified by flash chromatography (22 × 2 cm; 1/4 EtOAc/
hexanes) to afford 23 as a colorless oil (0.907 g, 98%): Rf = 0.46 (1:3
EtOAc/hexanes); [α]D +11 (c 0.42, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.38−7.28 (m, 5H), 6.01 (d, J = 4.0 Hz, 1H), 5.93−5.81 (m,
1H), 5.21−5.09 (m, 2H), 4.67 (d, J = 11.6 Hz, 1H), 4.60 (d, J = 11.6
Hz, 1H), 4.40 (d, J = 4.0 Hz, 1H), 4.21 (d, J = 5.6 Hz, 1H), 3.88−3.82
(m, 1H), 2.55−2.50 (m, 2H), 1.49 (s, 3H), 1.39 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.2, 138.0, 134.0, 128.4, 128.1, 127.8, 118.2,
114.9, 102.6, 81.3, 78.6, 77.0, 72.5, 35.1, 27.0, 26.7; HRMS (ESI) calcd
for C18H22O5Na [M + Na]+ m/z 341.1359, found 341.1364.
1,2-O-Isopropylidene-3-keto-5-O-benzyl-6-deoxy-6-C-ace-
tyl-β-L-altrofuranose (24). PdCl2 (0.156 g, 0.879 mmol) and
Cu(OAc)2 (0.319 g, 1.76 mmol) were added to a stirred solution of
23 (2.80 g, 8.79 mmol) in 7/1 DMA/H2O (77 mL). The reaction
mixture was purged with a balloon of oxygen gas and subsequently
maintained under an atmosphere of oxygen gas (via an oxygen-filled
balloon). After 48 h, the reaction mixture was filtered through a pad of
Celite. The filtrate was diluted with diethyl ether (200 mL) and water
(100 mL), the layers were separated, and the aqueous phase was
extracted with diethyl ether (3 × 100 mL). The combined organic
extracts were washed with a saturated solution of NaHCO3 (100 mL)
and brine (100 mL), dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(23 × 3 cm; 3/7 EtOAc/hexanes) to give 24 as a colorless oil (2.33 g,
79%): Rf = 0.48 (1:2 EtOAc/hexanes); [α]D20 −18.9 (c 1.11, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.32−7.26 (m, 5H), 5.89 (d, J = 4.0
Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H), 4.35 (d,
J = 4.4 Hz, 1H), 4.33−4.28 (m, 1H), 4.15 (d, J = 5.6 Hz, 1H), 2.92−
2.87 (m, 1H), 2.76−2.68 (m, 1H), 2.09 (s, 3H), 1.46 (s, 3H), 1.31 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 207.0, 206.2, 137.9, 128.3, 128.1,
127.7, 115.0, 102.5, 81.5, 76.9, 75.2, 73.4, 45.1, 30.9, 26.9, 26.6; HRMS
(ESI) calcd for C18H22O6Na [M + Na]+ m/z 357.1309, found
357.1322.
hexanes); [α]D20 −16.3 (c 1.32, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.87−7.79 (m, 4H), 7.51−7.44 (m, 3H), 5.97 (d, J = 4.0 Hz, 1H),
5.95−5.82 (m, 1H), 5.13−5.07 (m, 2H), 4.85 (d, J = 12.0 Hz, 1H),
4.77−4.70 (m, 2H), 4.08−4.02 (m, 2H), 3.83−3.77 (m, 1H), 2.52 (br
s, 1H), 2.31−2.26 (m, 2H), 1.57 (s, 3H), 1.38 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 134.6, 134.3, 133.4, 133.3, 128.6, 128.1, 127.9, 126.9,
126.5, 126.3, 125.8, 117.8, 113.2, 105.6, 87.9, 85.4, 83.4, 72.2, 70.4,
38.3, 27.2, 26.6; HRMS (ESI) calcd for C22H26O5Na [M + Na]+ m/z
393.1673, found 393.1678.
20
1
(3aR,4aS,5S,7R,8aS,8bR)-5-(Benzyloxy)-2,2-dimethylhexa-
hydro[1,3]dioxolo[4,5-b]benzofuran-7,8a(4aH)-diol (27). A sol-
ution of 25 (0.860 g, 2.57 mmol) in acetonitrile (15 mL) was added to
a stirred 0 °C solution of Me4NBH(OAc)3 (3.38 g, 12.9 mmol) and
acetic acid (1.54 g, 25.7 mmol) in acetonitrile (15 mL). The cooling
bath was removed, and the reaction mixture was warmed to room
temperature. After 4 h, the reaction mixture was poured into water
(100 mL) and diluted with EtOAc (100 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (3 × 50
mL). The combined organic extracts were washed with a saturated
solution of NaHCO3 (100 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (15 × 2 cm; 9/1 EtOAc/hexanes) to give 27 as
20
a colorless foam (0.821 g, 95%): Rf = 0.60 (EtOAc); [α]D −1.5 (c
1
0.34, CHCl3); H NMR (400 MHz, CDCl3) δ 7.36−7.26 (m, 5H),
5.73 (d, J = 5.2 Hz, 1H), 4.60 (s, 2H), 4.48 (d, J = 5.2 Hz, 1H), 3.91
(d, J = 4.0 Hz, 1H), 3.86−3.80 (m, 1H), 3.68−3.64 (m, 1H), 3.14 (br
s, 1H), 2.83 (br s, 1H), 2.18−2.11 (m, 1H), 1.91−1.72 (m, 3H), 1.57
(s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.2, 128.5,
127.9, 127.8, 115.8, 103.9, 89.3, 79.5, 78.4, 77.4, 73.0, 70.8, 65.8, 38.9,
35.2, 27.2, 26.8; HRMS (ESI) calcd for C18H24O6Na [M + Na]+ m/z
359.1465, found 359.1472.
(3aR,4aS,5S,8aS,8bR)-5-(Benzyloxy)-2,2-dimethylhexahydro-
[1,3]dioxolo[4,5-b]benzofuran-8a(4aH)-ol (28). 1,1′-Thiocarbo-
nyldiimidazole (0.522 g, 2.92 mmol) and DMAP (0.030 g, 0.24
mmol) were added to a stirred solution of 27 (0.821 g, 2.44 mmol) in
dichloromethane (25 mL). After 24 h, the reaction mixture was diluted
with dichloromethane (100 mL) and water (100 mL). The layers were
separated, and the organic phase was washed with a saturated solution
of NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (20 × 2 cm; 2/1 EtOAc/hexanes) to
give the thiocarbonyl imidazole ester as a colorless foam (1.01 g, 93%):
Rf = 0.33 (2:1 EtOAc/hexanes); [α]D20 +11 (c 0.38, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.35 (s, 1H), 7.58 (s, 1H), 7.36−7.22 (m, 5H),
7.00 (s, 1H), 5.80 (d, J = 4.8 Hz, 1H), 5.72−5.65 (m, 1H), 5.21 (br s,
1H), 4.65 (s, 2H), 4.59 (d, J = 5.2 Hz, 1H), 4.01 (d, J = 3.6 Hz, 1H),
3.87−3.82 (m, 1H), 2.46−2.41 (m, 1H), 2.23−2.07 (m, 3H), 1.57 (s,
3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.0, 137.91,
137.2, 130.2, 129.1, 128.5, 128.3, 127.9, 127.8, 125.4, 117.9, 115.8,
104.1, 89.3, 80.3, 79.0, 78.0, 72.2, 71.2, 34.4, 31.0, 27.1, 26.9 HRMS
(ESI) calcd for C22H27N2O6S [M + H]+ m/z 447.1584, found
447.1597. A solution of tributyltin hydride (0.370 g, 1.27 mmol) and
AIBN (0.010 mg, 0.042 mmol) in toluene (2 mL) was added dropwise
to a stirred 110 °C solution of the above ester (0.189 g, 0.423 mmol)
in toluene (20 mL). After 15 min, the reaction mixture was
concentrated under reduced pressure and the residue was purified
by flash chromatography (16 × 1 cm; 1/2 EtOAc/hexanes) to give 28
as a colorless oil (0.115 g, 85%): Rf = 0.66 (3:2 EtOAc/hexanes);
(3aR,4aS,5S,8aS,8bR)-5-(Benzyloxy)-8a-hydroxy-2,2-
dimethylhexahydro[1,3]dioxolo[4,5-b]benzofuran-7(4aH)-one
(25). L-Proline (0.109 g, 0.950 mmol) was added to a stirred solution
of 24 (1.27 g, 3.80 mmol) in DMF (80 mL) at room temperature.
After 3 days, the reaction mixture was diluted with diethyl ether (500
mL) and water (150 mL). The layers were separated, and the aqueous
phase was extracted with diethyl ether (3 × 100 mL). The combined
organic extracts were washed with a saturated solution of NaHCO3
(200 mL) and brine (200 mL), dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (18 × 2 cm; 2/3 EtOAc/hexanes) to give 25 as a
colorless oil (0.990 g, 78%). For an alternate procedure that involves
heating the reaction in DMSO as solvent, see the Supporting
20
Information, Table SI1: Rf = 0.28 (1/1 EtOAc/hexanes); [α]D −68
(c 0.87, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.33−7.28 (m, 5H),
5.90 (d, J = 3.2 Hz, 1H), 4.71 (d, J = 12.4 Hz. 1H), 4.61 (d, J = 12.4
Hz, 1H), 4.38 (d, J = 3.2 Hz, 1H), 4.14 (d, J = 4.0 Hz, 1H), 4.08−4.02
(m, 1H), 3.75 (s, 1H), 3.20 (d, J = 16.4 Hz, 1H), 2.69−2.60 (m, 1H),
2.41−2.32 (m, 2H), 1.44 (s, 3H), 1.28 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 208.9, 137.9, 128.5, 127.9, 127.8, 115.3, 104.6, 89.3, 84.9,
78.1, 77.4, 72.11, 71.6, 47.0, 39.8, 27.4, 27.0; HRMS (ESI) calcd for
C18H22O6Na [M + Na]+ m/z 357.1309, found 357.1325.
20
1
1,2-O-Isopropylidene-3-O-(2-naphthylmethyl)-6-deoxy-6-C-
vinyl-α-D-galactofuranose (epi-21). Magnesium bromide diethyl
etherate (14.9 g, 57.9 mmol) and allyltrimethylsilane (7.68 g, 23.2
mmol) were added to a stirred −78 °C solution of 18 (3.81 g, 11.6
mmol) in dichloromethane (100 mL) . After 2 h, the reaction mixture
was poured into an ice-cold solution of saturated NaHCO3 (200 mL).
The layers were separated, and the aqueous phase was extracted with
dichloromethane (2 × 100 mL). The combined organic extracts were
washed with brine (200 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (32 × 3 cm; 1/4 EtOAc/hexanes) to give C5-
epi-21 as a colorless oil (3.27 g, 76%): Rf = 0.50 (3/7 EtOAc/
[α]D −4.0 (c 0.10, CHCl3); H NMR (400 MHz, CDCl3) δ 7.37−
7.28 (m, 5H), 5.76 (d, J = 5.2 Hz, 1H), 4.65−4.58 (m, 2H), 4.52 (d, J
= 4.8 Hz, 1H), 3.98 (d, J = 3.6 Hz, 1H), 3.62−3.56 (m, 1H), 1.94−
1.64 (m, 4H), 1.58 (s, 3H), 1.52−1.41 (m, 2H), 1.33 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 138.7, 128.5, 127.9, 127.7, 115.6, 104.0,
89.3, 80.6, 78.8, 74.6, 70.5, 29.7, 27.2, 26.7, 25.7, 19.6; HRMS (ESI)
calcd for C18H24O5Na [M + Na]+ m/z 343.1516, found 343.1521.
(3R,3aS,7S,7aS)-7-(Benzyloxy)-3a-hydroxyoctahydrobenzo-
furan-2,3-diyl Diacetate (29). DOWEX 50W-8X ionic exchange
resin (0.450 g) was added to a stirred solution of 28 (0.463 g, 1.45
mmol) in 1/1 dioxane/H2O (10 mL). After 3 days, the reaction
mixture was filtered through a sintered-glass crucible, which was
H
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washed with water (50 mL) and EtOAc (50 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (5 × 50
mL). The combined organic extracts were washed with a saturated
solution of NaHCO3 (100 mL) and brine (100 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (16 × 1 cm; EtOAc) to
give the hemiacetal as a colorless solid (0.386 g, 95%). Acetic
anhydride (1.93 g, 18.9 mmol) was added to a stirred 0 °C solution of
the hemiacetal (0.386 g, 1.38 mmol) in pyridine (30 mL). The cooling
bath was removed, and the reaction mixture was warmed to room
temperature. After 16 h, the reaction mixture was diluted with EtOAc
(50 mL) and poured into ice water (100 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (3 × 50
mL). The combined organic extracts were washed with 0.5 M HCl (3
× 100 mL), water (100 mL), a saturated solution of NaHCO3 (100
mL), and brine (100 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (25 × 2 cm; 1/2 EtOAc/hexanes) to give 29 as
(0.597 g, 96%), which was used without further purification: Rf = 0.18
20
1
(3/1 EtOAc/hexanes); [α]D −53 (c 0.45, CHCl3); H NMR (400
MHz, CD3OD) δ 7.50 (d, J = 1.2 Hz, 1H), 7.36−7.25 (m, 5H), 5.68
(d, J = 6.4 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0 Hz,
1H), 4.49 (d, J = 2.8 Hz, 1H), 4.37 (d, J = 6.4 Hz, 1H), 3.71−3.64 (m,
1H), 1.90 (s, 3H), 1.81−1.57 (m, 6H); 13C NMR (75 MHz, CD3OD)
δ 166.5, 152.6, 139.8, 139.7, 129.5, 129.1, 128.8, 111.6, 93.0, 82.2, 81.5,
79.3, 77.0, 71.6, 29.4, 26.9, 20.4, 12.4; HRMS (ESI) calcd for
C20H25N2O6 [M + H]+ m/z 389.1707, found 389.1722. 1,1′-
Thiocarbonyl imidazole (0.114 g, 0.639 mmol) and DMAP (6 mg,
0.049 mmol) were added to a stirred 0 °C solution of the alcohol
(0.191 g, 0.491 mmol) in dichloromethane (12 mL). The cooling bath
was removed, and the resulting solution was warmed to room
temperature. After 18 h, the reaction mixture was diluted with
dichloromethane (50 mL) and the resulting solution was washed with
water (100 mL), a saturated solution of NaHCO3 (100 mL), and brine
(100 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(17 × 1.5 cm; 4/1 EtOAc/hexanes) to give 31 as a colorless foam
20
a colorless oil (0.421 g, 86%): Rf = 0.68 (2/1 EtOAc/hexanes); [α]D
−72 (c 0.071, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.34−7.22 (m,
5H), 6.21 (d, J = 3.6 Hz, 1H), 4.94 (d, J = 3.2 Hz, 1H), 4.64−4.55 (m,
2H), 4.37 (d, J = 3.2 Hz, 1H), 3.69 (s, 1H), 3.61−3.54 (m, 1H), 2.11
(s, 3H), 2.06 (s, 3H), 1.84−1.77 (m, 1H), 1.66−1.47 (m, 4H), 1.31−
1.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.9, 169.8, 138.5,
128.4, 127.7, 127.6, 98.7, 88.9, 79.8, 79.2, 77.4, 74.4, 70.5, 28.6, 25.3,
21.3, 20.5, 19.3; HRMS (ESI) calcd for C19H24O7Na [M + Na]+ m/z
387.1414, found 387.1421.
20
(0.224 g, 92%): Rf = 0.23 (4/1 EtOAc/hexanes); [α]D −37 (c 0.17,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 8.30 (s, 1H),
7.46 (s, 1H), 7.35−7.29 (m, 6H), 7.11 (s, 1H), 6.92 (s, 1H), 6.37 (d, J
= 5.4 Hz, 1H), 5.72 (d, J = 5.1 Hz, 1H), 5.36 (br s, 1H), 4.68−4.57
(m, 2H), 3.77−3.70 (m, 1H), 1.88 (s, 3H), 1.84−1.57 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 183.4, 164.2, 150.7, 138.0, 137.9, 137.1,
130.4, 128.4, 128.3, 127.8, 127.7, 117.8, 111.4, 90.5, 89.6, 81.3, 78.9,
74.7, 71.0, 29.7, 25.5, 19.1, 12.5; HRMS (ESI) calcd for C24H27N4O6S
[M + H]+ m/z 499.1646, found 499.1650.
(2R,3R,3aS,7S,7aS)-7-(Benzyloxy)-3a-hydroxy-2-(5-methyl-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)octahydrobenzo-
furan-3-yl Acetate (30). N,O-Bis(trimethylsilyl)acetamide (1.66 g,
8.15 mmol) was added to a stirred slurry of thymine (0.411 g, 3.25
mmol) in anhydrous acetonitrile (40 mL). The mixture was heated to
80 °C for 1 h and cooled to 0 °C, and a solution of 29 (0.593 g, 1.63
mmol) in acetonitrile (10 mL) was added, followed by the addition of
TMSOTf (0.722 g, 3.25 mmol). The resulting mixture was heated to
50 °C for 12 h, cooled to 0 °C, and treated with a saturated solution of
NaHCO3 (1 mL). Ethyl acetate (250 mL) and a saturated solution of
NaHCO3 (100 mL) were added and the layers separated. The aqueous
phase was extracted with EtOAc (3 × 100 mL), and the combined
organic extracts were washed with brine (100 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
dried under high vacuum for 30 min and then dissolved in THF (10
mL). TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol) was added, and the
resulting solution was stirred at room temperature. After 30 min, ethyl
acetate (50 mL) and a saturated solution of NaHCO3 (50 mL) were
added. The layers were separated, and the aqueous phase was extracted
with EtOAc (3 × 25 mL). The combined organic extracts were washed
with brine (100 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (18 × 1.5 cm; 1/1 EtOAc/hexanes) to give 30 as a
1-((2R,3aR,7S,7aS)-7-(Benzyloxy)-3a-hydroxyoctahydroben-
zofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (32). Trib-
utyltin hydride (0.231 g, 0.792 mmol) and AIBN (0.002 mg, 0.01
mmol), as a solution in toluene (2 mL), were added to a stirred a 110
°C of 31 (0.066 g, 0.132 mmol) in toluene (10 mL). After 30 min, the
reaction mixture was concentrated under pressure and the residue was
purified by flash chromatography (16 × 1 cm; 4/1 EtOAc/hexanes) to
give 32 as a colorless oil (0.039 g, 80%): Rf = 0.30 (4/1 EtOAc/
hexanes); [α]D20 +2.6 (c 0.31, MeOH); 1H NMR (300 MHz, CDCl3)
δ 10.53 (s, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.35−7.26 (m, 5H), 6.16
(dd, J = 5.4, 1.8 Hz, 1H), 4.64 (d, J = 12.6 Hz, 1H), 4.59 (d, J = 12.6
Hz, 1H), 4.18 (d, J = 4.8 Hz, 1H), 3.85−3.77 (m, 1H), 2.82−2.74 (m,
1H), 2.25 (d, J = 14.4 Hz, 1H), 2.03−1.95 (m, 1H), 1.92−1.86 (m,
1H), 1.81 (s, 3H), 1.65−1.58 (m, 2H), 1.41−1.32 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 164.5, 151.1, 138.4, 138.0, 128.4, 127.5, 127.3,
108.6, 87.8, 86.7, 75.2, 71.8, 43.8, 34.9, 26.6, 17.0, 12.4; HRMS (ESI)
calcd for C20H24N2O5Na [M + Na]+ m/z 395.1577, found 395.1596.
1-((2R,3aR,7S,7aS)-7-(Bis(4-methoxyphenyl)(phenyl)-
methoxy)-3a-hydroxyoctahydrobenzofuran-2-yl)-5-methyl-
pyrimidine-2,4(1H,3H)-dione (12). Pearlman’s catalyst (0.015 g,
0.022 mmol) was added to a stirred solution of 32 (0.169 g, 0.45
mmol) in 1/1 THF/MeOH (10 mL). A balloon filled with hydrogen
gas was placed over the reaction mixture, and after 24 h, EtOAc (5
mL) and MeOH (5 mL) were added. The resulting slurry was filtered
through a short pad of Celite, and the filtrate was concentrated under
reduced pressure. The residue was dissolved in 1/1 pyridine/
dichloromethane (4 mL), and DMTrCl (0.41 g, 1.2 mmol) and 2,6-
lutidine (0.13 g, 1.2 mmol) were added. The resulting solution was
stirred and heated to 40 °C. After 24 h, dichloromethane (10 mL) was
added and the resulting solution was washed with a saturated solution
of sodium bicarbonate (2 × 10 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure to give cis-α-L-[4.3.0]bc-DNA
(12) as a solid (0.20 g, 75% over two steps), which was used directly in
the next step: 1H NMR (300 MHz, acetone-d6) δ 10.15 (s, 1H), 7.68−
7.41 (m, 7H), 7.39−7.20 (m, 3H), 6.96−6.87 (m, 4H), 6.20 (t, J = 7.0
Hz, 1H), 4.17 (s, 1H), 3.92−3.87 (m, 1H), 3.82 (s, 6H), 2.95 (s, 1H),
2.47 (dd, J = 12.9, 6.8 Hz, 1H), 2.13−2.03 (m, 1H), 1.95 (d, J = 1.2
Hz, 3H), 1.66−1.58 (m, 2H), 1.51−1.40 (m, 2H), 1.35−1.29 (m, 1H),
1.13−1.03 (m, 1H); 13C NMR (75 MHz, acetone-d6) δ 164.5, 159.6,
151.3, 147.4, 138.0, 137.9, 136.7, 131.3, 131.2, 129.3, 128.4, 127.5,
113.8, 113.7, 110.6, 87.3, 85.3, 84.5, 78.1, 71.8, 55.5, 46.7, 34.6, 27.8,
20
colorless foam (0.582 g, 83%): Rf = 0.34 (1/1 EtOAc/hexanes); [α]D
1
−56 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 9.08 (br s, 1H),
7.36−7.28 (m, 5H), 7.09 (d, J = 1.2 Hz, 1H), 5.82 (d, J = 5.6 Hz, 1H),
5.36 (d, J = 6.0 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.59 (d, J = 12.4
Hz, 1H), 4.56 (d, J = 3.2 Hz, 1H), 3.87 (br s, 1H), 3.70−3.64 (m, 1H),
2.13 (s, 3H), 1.91 (s, 3H), 1.88−1.85 (m, 1H), 1.79−1.74 (m, 1H),
1.72−1.49 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 172.3, 163.6,
150.4, 138.2, 136.7, 128.4, 127.70, 127.66, 111.6, 89.5, 85.2, 81.4, 78.2,
74.9, 70.8, 29.1, 25.4, 20.5, 19.0, 12.6; HRMS (ESI) calcd for
C22H26N2O7Na [M + Na]+ m/z 453.1632, found 453.1643.
O-((2R,3R,3aS,7S,7aS)-7-(Benzyloxy)-3a-hydroxy-2-(5-meth-
yl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)octahydrobenzo-
furan-3-yl) 1H-Imidazole-1-carbothioate (31). Potassium carbo-
nate (0.022 g, 0.16 mmol) was added to a stirred solution of 30 (0.690
g, 1.60 mmol) in MeOH (10 mL). After 18 h, the reaction mixture was
concentrated under reduced pressure and the residue was dissolved in
EtOAc (50 mL). Water (50 mL) was added, and the layers were
separated. The aqueous phase was extracted with EtOAc (4 × 25 mL),
and the combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure to afford a colorless foam
I
dx.doi.org/10.1021/jo401166q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
20.5, 12.9; LRMS (ESI) calcd for C34H36N2O7Na [M + Na]+ m/z
607.2, found 607.3.
NH4Cl (50 mL). The layers were separated, and the aqueous phase
was extracted with EtOAc (2 × 50 mL). The combined organic
extracts were washed with brine (50 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography (15 × 3 cm; 1/9 EtOAc/hexanes) to give 35 as
1,2-O-Isopropylidene-5-O-benzyl-6-deoxy-6-C-vinyl-α-D-gal-
actofuranose (33). Sodium hydride (60% dispersion in oil, 0.456 g,
11.4 mmol), benzyl bromide (1.95 g, 11.4 mmol), and tetrabuty-
lammonium iodide (0.324 g, 0.877 mmol) were added to a stirred 0
°C solution of epi-21 (3.25 g, 8.77 mmol) in 1/1 DMF/THF (100
mL). The cooling bath was removed, and the reaction mixture was
warmed to room temperature. After 4 h, the reaction mixture was
cooled to 0 °C and MeOH (5 mL) was added, followed by diethyl
ether (300 mL) and water (100 mL). The layers were separated, and
the aqueous phase was extracted with diethyl ether (3 × 100 mL). The
combined organic extracts were washed with a saturated solution of
NaHCO3 (3 × 100 mL) and brine (100 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (21 × 2 cm; 1/9 EtOAc/hexanes) to
give the corresponding benzyl ether as a colorless oil (3.68 g, 91%): Rf
20
a colorless oil (2.17 g, 88%): Rf = 0.50 (1/9 EtOAc/hexanes); [α]D
+1.2 (c 0.26, MeOH); 1H NMR (300 MHz, CDCl3) δ 7.39−7.21 (m,
5H), 5.93−5.77 (m, 2H), 5.73 (d, J = 4.2 Hz, 1H), 5.46 (dd, J = 15.6,
1.2 Hz, 1H), 5.19 (dd, J = 9.3, 1.2 Hz, 1H), 5.12−5.03 (m, 2H), 4.76
(d, J = 11.4 Hz, 1H), 4.61 (d, J = 11.4 Hz, 1H), 4.33 (d, J = 4.2 Hz,
1H), 3.87−3.75 (m, 2H), 3.30 (s, 1H), 2.53−2.46 (m, 1H), 2.21−2.16
(m, 1H), 1.63 (s, 3H), 1.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
140.3, 138.6, 134.6, 128.1, 127.9, 127.3, 117.1, 115.5, 114.5, 103.9,
87.1, 87.0, 78.0, 77.1, 73.0, 35.3, 27.5, 27.3; HRMS (ESI) calcd for
C20H26O5Na [M + Na]+ m/z 369.1673, found 369.1671.
1,2-O-Diacetyl-5-O-benzyl-6-deoxy-3,6-C-divinyl-D-gulofura-
nose (36). DOWEX 50W-8X ionic exchange resin (1.50 g) was added
to a stirred solution of 35 (1.75 g, 5.04 mmol) in 1/1 dioxane/water
(10 mL). After 48 h, the reaction mixture was filtered through a
sintered-glass crucible and the collected resin was washed with water
(50 mL) and EtOAc (50 mL). The layers were separated, and the
aqueous phase was extracted with EtOAc (5 × 50 mL). The combined
organic extracts were washed with a saturated solution of NaHCO3
(100 mL) and brine (100 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure to give a colorless oil, which was
immediately dissolved in pyridine (40 mL), cooled to 0 °C, and stirred
with acetic anhydride (4.24 g, 41.2 mmol). The cooling bath was
remove,d and the reaction mixture was warmed to room temperature.
After 16 h, EtOAc (100 mL) was added and the resulting mixture was
poured into ice water (100 mL). The layers were separated, and the
aqueous phase was extracted with EtOAc (3 × 100 mL). The
combined organic extracts were washed with a saturated solution of
NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography (20 × 2 cm; 1/3 EtOAc/hexanes) to give 36 as
a colorless oil (dr = 6:1) (1.81 g, 92%) [major diastereomer]: Rf = 0.50
20
1
= 0.56 (1/4 EtOAc/hexanes); [α]D −30 (c 0.89, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.88−7.81 (m, 4H), 7.53−7.46 (m, 3H), 7.31−
7.28 (m, 5H), 5.96−5.85 (m, 2H), 5.14−5.08 (m, 2H), 4.85 (d, J =
11.6 Hz, 1H), 4.75 (dd, J = 3.2, 1.2 Hz, 1H), 4.66−4.63 (m, 2H), 4.57
(d, J = 11.6 Hz, 1H), 4.09−4.05 (m, 2H), 3.67−3.62 (m, 1H), 2.46−
2.41 (m, 2H), 1.56 (s, 3H), 1.44 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 138.4, 134.52, 134.47, 133.1, 133.0, 128.2, 128.1, 127.9, 127.8, 127.6,
127.4, 126.9, 126.2, 126.0, 125.8, 117.3, 113.5, 104.7, 85.9, 84.8, 82.5,
77.7, 72.7, 71.9, 35.6, 27.4, 27.0; HRMS (ESI) calcd for C29H32O5Na
[M + Na]+ m/z 483.2142, found 483.2138. DDQ (2.71 g, 11.9 mmol)
was added to a vigorously stirred solution of the above product (2.75
g, 5.96 mmol) in 9/1 dichloromethane/water (70 mL). After 4 h, a
10% solution of NaHSO3 (100 mL) was added and the layers were
separated. The aqueous phase was extracted with dichloromethane (3
× 50 mL), and the combined organic extracts were washed with a
saturated solution of NaHCO3 (100 mL) and brine (100 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (24 × 2 cm; 3/7 EtOAc/
hexanes) to give 33 as a colorless oil (1.34 g, 70%): Rf = 0.13 (1/4
20
1
20
1
(3/7 EtOAc/hexanes); [α]D −109 (c 1.35, CHCl3); H NMR (400
MHz, CDCl3) δ 7.35−7.27 (m, 5H), 6.27 (d, J = 3.6 Hz, 1H), 5.85−
5.74 (m, 2H), 5.49 (dd, J = 15.6, 1.6 Hz, 1H), 5.52−5.10 (m, 4H),
4.71 (d, J = 11.2 Hz, 1H), 4.66 (s, 1H), 4.48 (d, J = 11.2 Hz, 1H), 4.08
(d, J = 2.8 Hz, 1H), 3.82−3.74 (m 1H), 2.53 (t, J = 7.2 Hz, 2H), 2.08
(s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 169.5,
136.8, 136.6, 133.3, 128.5, 128.4, 128.1, 118.5, 117.1, 98.8, 82.7, 81.2,
80.7, 76.3, 71.8, 34.7, 21.1, 20.6; HRMS (ESI) calcd for C21H26O7Na
[M + Na]+ m/z 413.1571, found 413.1563.
EtOAc/hexanes); [α]D −9.2 (c 0.61, CHCl3); H NMR (300 MHz,
CDCl3) δ 7.37−7.24 (m, 5H), 5.95−5.81 (m, 1H), 5.81 (d, J = 4.2 Hz,
1H), 5.17−5.06 (m, 2H), 4.72 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.7
Hz, 1H), 4.48 (dd, J = 3.0, 1.2 Hz, 1H), 4.19−4.14 (m, 1H), 3.89−
3.86 (m, 1H), 3.70−3.64 (m, 1H), 3.06 (d, J = 3.9 Hz, 1H), 2.45−2.29
(m, 2H), 1.49 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
138.3, 134.4, 128.2, 127.9, 127.5, 117.4, 113.1, 104.6, 87.6, 87.5, 77.9,
75.6, 72.8, 35.5, 27.1, 26.5; HRMS (ESI) calcd for C18H24O5Na [M +
Na]+ m/z 343.1516, found 343.1525.
1-(2-O-Acetyl-5-O-benzyl-6-deoxy-3,6-C-divinyl-β-D-
gulofuranosyl)thymine (37). N,O-Bis(trimethylsilyl)acetamide
(4.50 g, 22.1 mmol) was added to a stirred slurry of thymine (1.12
g, 8.85 mmol) in anhydrous acetonitrile (70 mL), and the resulting
mixture was heated to 80 °C. After 1 h, the reaction mixture was
cooled to 0 °C and a solution of 36 (1.72 g, 4.42 mmol) in anhydrous
acetonitrile (10 mL) and TMSOTf (1.97 g, 8.85 mmol) were added.
The cooling bath was removed, and the reaction mixture was heated to
50 °C for 12 h, upon which a 0 °C solution of saturated NaHCO3 (5
mL) was added. The resulting mixture was diluted with EtOAc (250
mL) and a saturated solution of NaHCO3 (100 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (3 × 100
mL). The combined organic extracts were washed with brine (100
mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was dried under high vacuum for 30 min and
dissolved in THF (50 mL), and TBAF (1.0 M in THF, 4.42 mL, 4.42
mmol) was added. The reaction mixture was stirred at room
temperature for 30 min and then diluted with EtOAc (100 mL) and
a saturated solution of NaHCO3 (100 mL). The layers were separated,
and the aqueous phase was extracted with EtOAc (3 × 100 mL). The
combined organic extracts were washed with brine (100 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (18 × 3 cm; 2/1 EtOAc/
hexanes) to give nucleoside 37 as a colorless foam (1.80 g, 89%): Rf =
1,2-O-Isopropylidene-3-keto-5-O-benzyl-6-deoxy-6-C-vinyl-
α-D-galactofuranose (34). A solution of 33 (2.54 g, 7.92 mmol), in
dichloromethane (25 mL) was added to a stirred 0 °C solution of
PCC (5.17 g, 24.0 mmol) and NaOAc (2.00 g, 24.3 mmol) in
dichloromethane (100 mL). The cooling bath was removed, and the
reaction mixture was warmed to room temperature. After 3 h, silica gel
(1 g) and diethyl ether (400 mL) were added. The resulting slurry was
filtered through a short plug (3 cm) of silica gel. The filtrate was
concentrated under reduced pressure, and the residue was purified by
flash chromatography (14 × 3 cm; 1/3 EtOAc/hexanes) to give 34 as
20
a colorless oil (2.28 g, 90%): Rf = 0.59 (3/7 EtOAc/hexanes); [α]D
1
−14 (c 0.73, CHCl3); H NMR (300 MHz, CDCl3) δ 7.33−7.23 (m,
5H), 6.01 (d, J = 4.5 Hz, 1H), 5.85−5.71 (m, 1H), 5.18−5.04 (m,
2H), 4.64 (d, J = 11.4 Hz, 1H), 4.57 (d, J = 11.4 Hz, 1H), 4.36 (d, J =
4.2 Hz, 1H), 4.15 (d, J = 4.5 Hz, 1H), 3.82−3.78 (m, 1H), 2.51−2.46
(m, 2H), 1.40 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
207.6, 137.8, 133.6, 128.0, 128.0, 127.4, 118.1, 115.1, 102.4, 82.9, 77.6,
76.9, 73.0, 34.9, 26.9, 26.8; HRMS (ESI) calcd for C18H22O5Na [M +
Na]+ m/z 341.1359, found 341.1356.
1,2-O-Isopropylidene-5-O-benzyl-6-deoxy-3,6-C-divinyl-α-D-
gulofuranose (35). Vinylmagnesium bromide (1.0 M solution in
THF, 21 mL, 21 mmol) was added dropwise to a stirred 0 °C solution
of 34 (2.28 g, 7.16 mmol) in anhydrous THF (100 mL). After 10 min,
a saturated solution of NH4Cl (0.1 mL) was added, followed by
EtOAc (100 mL) and an additional phase of a saturated solution of
20
1
0.48 (7/3 EtOAc/hexanes); [α]D −64 (c 0.85, CHCl3); H NMR
J
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The Journal of Organic Chemistry
Article
(400 MHz, CDCl3) δ 9.89 (br s, 1H), 7.36−7.28 (m, 5H), 7.04 (s,
1H), 5.92 (d, J = 5.6 Hz, 1H), 5.86−5.75 (m, 2H), 5.69 (d, J = 6.9 Hz,
1H), 5.53 (d, J = 16.9 Hz, 1H), 5.31 (d, J = 10.6 Hz, 1H), 5.19−5.11
(m, 2H), 4.97 (s, 1H), 4.71 (d, J = 11.0 Hz, 1H), 4.52 (d, J = 11.0 Hz,
1H), 4.42 (d, J = 3.1 Hz, 1H), 3.87−3.82 (m, 1H), 2.53−2.47 (m,
2H), 2.06 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.3, 164.2, 150.7, 137.3, 136.8, 135.5, 133.3, 128.6, 128.6, 128.4,
128.3, 118.7, 118.3, 111.2, 89.9, 83.2, 80.9, 78.1, 76.8, 72.2, 34.9, 20.6,
12.5; HRMS (ESI) calcd for C24H32N3O7 [M + NH4]+ m/z 474.2235,
found 474.2240.
1-((2R,3R,3aS,7R,7aS)-7-(Benzyloxy)-3,3a-dihydroxyoctahy-
drobenzofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(38). Grubbs’ second-generation catalyst (0.020 g, 0.024 mmol) was
added to a stirred solution of 37 (0.440 g, 0.963 mmol) in
dichloromethane (60 mL). The reaction mixture was heated to 40
°C for 20 min, cooled to room temperature, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(18 × 1.5 cm; 4/1 EtOAc/hexanes) to give a colorless foam (0.389 g,
94%): Rf = 0.68 (9/1 EtOAc/hexanes); [α]D20 −1.4 (c 0.37, CHCl3);
1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.37−7.24 (m, 5H), 7.17
resulting solution was washed with water (100 mL), a saturated
solution of NaHCO3 (100 mL), and brine (100 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (17 × 1.5 cm; 3/2
EtOAc/hexanes) to give a colorless oil (0.224 g, 92%): Rf = 0.50 (2/1
20
1
EtOAc/hexanes); [α]D +1.1 (c 0.18, CHCl3); H NMR (400 MHz,
CDCl3) δ 9.53 (s, 1H), 7.40−7.25 (m, 8H), 7.13−7.09 (m, 3H), 6.27
(d, J = 6.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 12.0 Hz,
1H), 4.66 (d, J = 12.0 Hz, 1H), 4.30 (d, J = 9.2 Hz, 1H), 4.08−4.04
(m, 1H), 2.94 (s, 1H), 2.16−2.13 (m, 1H), 1.98 (m, 1H), 1.91 (s, 3H),
1.85−1.81 (m, 1H), 1.71−1.58 (m, 2H), 1.41−1.24 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 194.4, 164.3, 153.5, 150.7, 138.9, 137.4,
129.8, 128.4, 127.7, 127.6, 127.0, 121.7, 111.6, 90.5, 87.7, 86.3, 79.4,
77.4, 75.6, 72.0, 32.0, 30.4, 19.7, 12.6; HRMS (ESI) calcd for
C27H29N2O7S [M + H]+ m/z 525.1690, found 525.1696. A toluene
(10 mL) solution of tributyltin hydride (1.10 g, 3.79 mmol) and AIBN
(10 mg, 0.063 mmol) were added dropwise to a stirred 110 °C
solution of the above product (0.330 g, 0.631 mmol) in toluene (65
mL). After 30 min, the reaction mixture was concentrated under
reduced pressure and the residue was purified by flash chromatography
(16 × 2 cm; 4/1 EtOAc/hexanes) to give nucleoside 39 as a colorless
(s, 1H), 6.20 (d, J = 6.6 Hz, 1H), 5.98 (d, J = 9.6 Hz, 1H), 5.80−5.75
(m, 1H), 5.57 (d, J = 6.6 Hz, 1H), 4.80 (d, J = 5.57, 1H), 4.64 (d, J =
12.0 Hz, 1H), 4.48−4.42 (m, 1H), 4.39−4.35 (m, 1H), 3.44 (s, 1H),
2.81−2.77 (m, 1H), 2.23−2.15 (m, 4H), 1.93 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.7, 164.3, 150.8, 138.5, 136.8, 132.0, 128.4, 127.9,
127.7, 127.6, 124.7, 111.6, 90.3, 86.2, 77.5, 77.0, 72.8, 72.1, 34.0, 20.8,
12.6; HRMS (ESI) calcd for C22H24N2O7Na [M + Na]+ m/z
451.1476, found 451.1487. A solution of the above product (0.255 g,
0.595 mmol) in THF (5 mL) was added to a stirred slurry of 10% Pd/
C (0.050 g) in THF (5 mL). The resulting slurry was purged with a
balloon of hydrogen gas and then maintained under an atmosphere of
hydrogen gas (balloon). After 2 h, the reaction mixture was diluted
with ethyl acetate (10 mL) and filtered through a pad of Celite 545,
and the filtrate was concentrated under reduced pressure. The residue
was purified by flash chromatography (19 × 1.5 9/1 EtOAc/hexanes)
20
foam (0.196 g, 83%): Rf = 0.21 (4/1 EtOAc/hexanes); [α]D +40 (c
1
0.12, CHCl3); H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.37−
7.25 (m, 6H), 6.44−6.39 (m, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.65 (d, J
= 12.0 Hz, 1H), 3.95−3.92 (m, 1H), 3.73 (d, J = 9.2 Hz, 1H), 3.22 (s,
1H), 2.70 (dd, J = 7.6, 6.0 Hz, 1H), 2.15−2.11 (m, 1H), 1.98−1.85
(m, 6H), 1.67−1.64 (m, 1H), 1.41−1.39 (m, 1H), 1.25−1.22 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 164.4, 150.9, 139.0, 135.3, 128.4,
127.7, 127.6, 111.3, 89.7, 86.7 79.3, 76.2, 72.0, 46.0, 32.9, 30.7, 20.1,
12.8; HRMS (ESI) calcd for C20H24N2O5Na [M + Na]+ m/z
395.1577, found 395.1578.
1-((2R,3aS,7R,7aS)-7-(Bis(4-methoxyphenyl)(phenyl)-
methoxy)-3a-hydroxyoctahydrobenzofuran-2-yl)-5-methyl-
pyrimidine-2,4(1H,3H)-dione (13). Pearlman’s catalyst (0.031 g,
0.044 mmol) was added to a stirred solution of 39 (0.185 g, 0.497
mmol) in 1/1 THF/MeOH (20 mL). A balloon filled with hydrogen
gas was placed over the reaction mixture, and after 24 h, EtOAc (10
mL) and MeOH (10 mL) were added. The resulting slurry was filtered
through a short pad of Celite, and the filtrate was concentrated under
reduced pressure. The residue was dissolved in 1/1 pyridine/
dichloromethane (8 mL) and DMTrCl (0.483 g, 1.43 mmol) and
2,6-lutidine (0.153 g, 1.43 mmol) were added. The resulting solution
was stirred and heated to 40 °C. After 24 h, dichloromethane (20 mL)
was added and the resulting solution was washed with a saturated
solution of sodium bicarbonate (2 × 20 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on a silica column previously
neutralized with NEt3 (16 × 2 cm; 3/1 EtOAc/hexanes) to give trans-
α-L-[4.3.0]bc-DNA (13) as an orange solid (0.153 g, 53% over two
steps), which was used directly in the next step: Rf = 0.44 (3:1 EtOAc/
20
to give a colorless foam (0.183 g, 72%): Rf = 0.55 (EtOAc); [α]D
1
+2.3 (c 0.30, CHCl3); H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H),
7.37−7.24 (m, 5H), 7.15 (s, 1H), 6.13 (d, J = 6.4 Hz, 1H), 5.45 (d, J =
6.4 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.12
(d, J = 9.2 Hz, 1H), 4.05−3.99 (m, 1H), 2.84 (s, 1H), 2.17−2.12 (m,
4H), 1.94 (s, 3H), 1.83−1.78 (m, 2H), 1.69−1.65 (m, 1H), 1.50−1.47
(m, 1H), 1.31−1.26 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.4,
164.2, 151.0, 138.8, 136.3, 128.4, 127.7, 127.6, 111.7, 89.3, 87.9, 79.4,
78.9, 77.4, 75.6, 72.0, 31.7, 30.5, 20.8, 19.7, 12.7; HRMS (ESI) calcd
for C22H26N2O7Na [M + Na]+ m/z 453.1632, found 453.1643.
Potassium carbonate (0.0057 g, 0.042 mmol) was added to a stirred
solution of the above product (0.180 g, 0.418 mmol) in MeOH (10
mL). After 6 h, the reaction mixture was concentrated under reduced
pressure and the residue was dissolved in EtOAc (50 mL). Water (50
mL) was added, and the layers were separated. The aqueous phase was
extracted with EtOAc (5 × 25 mL), and the combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography (10 × 2
cm; EtOAc) to give nucleoside 38 as a colorless foam (0.160 g, 99%):
Rf = 0.40 (EtOAc); [α]D20 −3.1 (c 0.36, CHCl3); 1H NMR (400 MHz,
CD3OD) δ 7.52 (d, J = 1.2 Hz, 1H), 7.35−7.22 (m, 5H), 5.88 (d, J =
6.8 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 11.6 Hz, 1H), 4.37
(d, J = 6.8 Hz, 1H), 4.08 (d, J = 9.6 Hz, 1H), 3.97−3.95 (m, 1H),
2.13−2.10 (m, 1H), 1.89 (s, 3H), 1.87−1.76 (m, 2H), 1.67−1.63 (m,
1H), 1.42−1.40 (m, 1H), 1.27−1.24 (m, 1H); 13C NMR (100 MHz,
CD3OD) δ 165.5, 151.8, 139.2, 138.8, 128.3, 127.9, 127.5, 110.9, 92.3,
87.4, 78.7, 78.5, 76.4, 71.8, 30.7, 30.5, 19.9, 11.3; HRMS (ESI) calcd
for C20H25N2O6 [M + H]+ m/z 389.1707, found 389.1712.
1
hexanes); H NMR (300 MHz, acetone-d6) δ 10.25 (s, 1H), 8.04 (s,
1H), 7.75 (d, J = 1.0 Hz, 2H), 7.65(d, J = 7.2 Hz, 4H), 7.56 (d, J = 8.9
Hz, 4H), 7.50 (d, J = 8.9 Hz, 4H), 7.32−7.19 (m, 6H), 6.88 (dd, J =
9.0, 2.4 Hz, 8H), 6.42 (dd, J = 7.6, 6.3 Hz, 2H), 4.27−4.09 (m, 4H),
3.99−3.87 (m, 2H), 3.80 (s, 6H), 3.79 (s, 6H), 2.54 (dd, J = 13.1, 6.2
Hz, 2H), 2.22 (dd, J = 13.1, 7.9 Hz, 2H), 1.98 (d, J = 0.7 Hz, 6H),
1.85−1.79 (m, 2H), 1.57−1.13 (m, 10H); 13C NMR (75 MHz,
acetone-d6) δ 164.6, 159.43, 159.36, 151.4, 147.7, 138.5, 138.2, 136.7,
131.4, 131.4, 129.4, 128.2, 127.2, 113.5, 110.6, 88.8, 86.64, 86.57, 79.4,
79.1, 72.5, 55.39, 55.37, 46.4, 33.7, 32.8, 20.9, 12.8.
(2R,3aR,7S,7aS)-7-(Bis(4-methoxyphenyl)(phenyl)methoxy)-
2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-
hexahydrobenzofuran-3a(4H)-yl 2-Cyanoethyl-N,N-diisopro-
pylphosphoramidite (40). 2-Cyanoethyl-N,N-diisopropylchloro-
phosphoramidite (0.16 mL, 0.68 mmol) was added to a stirred
solution of nucleoside 12 (0.20 g, 0.34 mmol), diisopropylethylamine
(0.13 mL, 0.68 mmol), and N-methylimidazole (2 drops) in CH2Cl2
(2 mL). After 1 h, the reaction mixture was diluted with EtOAc (10
mL) and the organic layer was washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure.
1-((2R,3aS,7R,7aS)-7-(Benzyloxy)-3a-hydroxyoctahydroben-
zofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (39). O-
Phenyl chlorothionoformate (0.360 g, 2.09 mmol) was added to a
stirred −20 °C solution of 38 (0.162 g, 0.418 mmol) in 1/1 pyridine/
dichloromethane (20 mL). The cooling bath was removed, and the
reaction mixture was warmed to room temperature. After 6 h, the
reaction mixture was diluted with dichloromethane (50 mL) and the
K
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Purification by flash chromatography (15 × 2 cm; 2/1 EtOAc/
hexanes) gave phosphoramidite 40 as a white foam (0.17 g, 64%): 1H
NMR (300 MHz, CDCl3) δ 8.07 (br s, 1H), 7.62−7.14 (m, 17H), 6.81
(d, J = 7.5 Hz, 5H), 6.01 (d, J = 6.4 Hz, 1H), 3.90−3.36 (m, 14H),
2.88−2.44 (m, 4H), 2.21−1.88 (m, 6H), 1.50−1.34 (m, 3H), 1.32−
0.77 (m, 23H); 31P NMR (121 MHz, CDCl3) δ 143.0, 141.0; LRMS
(ESI) calcd for C43H53N4O8PNa [M + Na]+ m/z 785.4, found 785.4.
(2R,3aS,7R,7aS)-7-(Bis(4-methoxyphenyl)(phenyl)methoxy)-
2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-
hexahydrobenzofuran-3a(4H)-yl 2-Cyanoethyl-N,N-diisopro-
pylphosphoramidite (41). 2-Cyanoethyl-N,N-diisopropylchloro-
phosphoramidite (0.12 mL, 0.5 mmol) was added to a stirred solution
of nucleoside 13 (0.15 g, 0.25 mmol), diisopropylethylamine (0.09
mL, 0.5 mmol), and N-methylimidazole (2 drops) in dichloromethane
(1.5 mL). After 1 h, the reaction mixture was diluted with EtOAc (10
mL) and the organic layer was washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by chromatography (15 × 2 cm; 1/1 EtOAc/hexanes)
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1
gave phosphoramidite 41 as a white foam (0.12 g, 61%): H NMR
(300 MHz, CDCl3) δ 7.68−7.37 (m, 13H), 7.32−7.09 (m, 14H), 6.80
(d, J = 6.4 Hz, 9H), 6.34 (br s, 1H), 6.25−6.08 (m, 1H), 4.14 (br s,
2H), 3.79 (br s, 23H), 3.64−3.30 (m, 9H), 3.22−3.04 (m, 1H), 2.75
(br s, 2H), 2.55 (br s, 3H), 2.05 (br s, 12H), 1.83 (d, J = 6.6 Hz, 2H),
1.60 (br s, 22H), 1.31 (br s, 5H), 1.15−0.97 (m, 20H), 0.90 (d, J = 5.7
Hz, 9H), 0.64 (br s, 2H); 31P NMR (121 MHz, CDCl3) δ 142.3,
139.8; LRMS (ESI) calcd for C43H53N4O8PNa [M + Na]+ m/z 785.4,
found 785.4.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Figures, tables, and a CIF file giving compounds referred to in
the Experimental Section (unnumbered in Schemes), temper-
ature and solvent studies of the L-proline-catalyzed aldol
1
reaction of 24, H and 13C NMR spectra of new compounds,
and crystallographic data for compound 26. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for S.H.: stephen.hanessian@umontreal.ca.
*E-mail for P.P.S.: pseth@isisph.com.
■
Notes
(21) Hanessian, S.; Schroeder, B. R.; Giacometti, R. D.; Merner, B.
L.; Østergaard, M. E.; Swayze, E. E.; Seth, P. P. Angew. Chem., Int. Ed.
2012, 51, 11242−11245.
The authors declare no competing financial interest.
(22) Petersen, M.; Hakansson, A. E.; Wengel, J.; Jacobsen, J. P. J. Am.
̊
ACKNOWLEDGMENTS
We are grateful for financial support from the NSERC and
FQRNT. We thank Benoıt Deschen
■
Chem. Soc. 2001, 123, 7431−7432.
(23) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
1971, 10, 496−497. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem.
1974, 39, 1619−1621.
̂
̂
es-Simard for X-ray
crystallographic analyses and Robert D. Giacometti for
assistance with preparing the paper.
́
(24) Genu-Dellac, C.; Gosselin, G.; Imbach, J.-L. Carbohydr. Res.
1991, 216, 249−255.
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