Study of the endocyclic versus exocyclic C-O bond cleavage pathways of α- And β-methyl furanosides

Article abstract of DOI:10.1021/jo3027438

The activation and ring-opening of methyl furanosides in the four natural sugar scaffolds (ribo, lyxo, arabino, and xylo) efficiently afforded acyclic thioacetals with high S_N2-like selectivity at the acetal center in the presence of Me₂

Full text of DOI:10.1021/jo3027438

Article
pubs.acs.org/joc
Study of the Endocyclic versus Exocyclic C−O Bond Cleavage
Pathways of α- and β‑Methyl Furanosides
Olivier St-Jean,† Michel Prevost,† and Yvan Guindon*,†,‡,§
́
†Bio-organic Chemistry, Institut de recherches cliniques de Montrea
́
l (IRCM), Montrea
l, C.P. 6128, succursale Centre-ville, Montrea
§Department of Chemistry, McGill University, Montrea
l, Quebec, Canada H3A 2K6
́
l, Queb
́
ec, Canada H2W 1R7
ec, Canada H3C 3J7
‡Dep
́
artement de Chimie, Universite
́
de Montrea
́
́
l, Queb
́
́
́
S
* Supporting Information
ABSTRACT: The activation and ring-opening of methyl furanosides in
the four natural sugar scaffolds (ribo, lyxo, arabino, and xylo) efficiently
afforded acyclic thioacetals with high SN2-like selectivity at the acetal
center in the presence of Me2BBr and thiophenol. The stereochemical
outcome of these reactions provides important mechanistic insights into
the activation pathway of five-membered semicyclic acetals. The
thioacetal products should find applications in oligosaccharides synthesis and allow further development of acyclic strategies
for the synthesis of novel nucleoside analogues.
oxocarbenium A (pathway A), whereas activation of the O5
oxygen would result in an endocyclic C1−O5 bond cleavage to
generate acyclic oxocarbenium B (pathway B). Stereoelectronic
assistance of antiperiplanar lone pair of electrons is proposed to
facilitate both C−O bond cleavage modes.4 Nucleophilic attack
of a water molecule on the oxocarbenium intermediates leads,
respectively, to the formation of cyclic and acyclic hemiacetals.
The latter can cyclize back to the starting glycoside with
probable anomerization. Alternatively, the loss of methanol
could lead to the cyclic hemiacetal (lactol). As described herein,
other nucleophiles allow trapping of the products from these
two distinct pathways.
The preferred pathway for a given transformation at a
semicyclic acetal center is not trivial to determine (Figure 1).
The exocyclic cleavage is by far the most invoked reaction
pathway and is supported by numerous kinetic studies,4a,5 but
experimental and computational studies performed on pyrano-
sides and related compounds confirmed that the endocyclic
cleavage pathway exists and cannot be ruled out.5,6 Recently,
evidence from bicyclic tetrahydropyranyl acetal hydrolysis
reaction showed that, although the exocyclic pathway would
be energetically favored over the endocyclic pathway for α-
anomers, both pathways would compete for the hydrolysis of β-
anomers.2b Other recent studies indicate that anomerization of
α and β glycosides bearing a 2,3-cyclic protecting group
proceeds by the endocyclic mechanism and that release of inner
ring strain would promote this reaction pathway.2a,7
INTRODUCTION
■
Carbohydrates are key structural elements of numerous
biological molecules essential for life. Ribose or deoxyribose
five-membered ring sugars constitute, for example, the
backbones of DNA and RNA. The carbohydrate portion
(glycans) of glycoproteins and lipoproteins is also crucial for a
multitude of biological processes including cell-to-cell recog-
nition, molecular trafficking, endocytosis, and signal trans-
duction.1 These features make them interesting targets for
drugs against cancers and viral proliferation. The chemistry of
carbohydrates has been developed and studied extensively, yet
there is still an open question concerning the mechanism
through which certain enzymatic or chemical reactions
proceeds at the anomeric center.2 This controversy originates
from the unsymmetrical nature of the semicyclic acetal
functionality of carbohydrates that allows for two plausible
reaction pathways, namely the exocyclic and the endocyclic
pathways (Figure 1).3 The hydrolysis of glycosides would
proceed through exocyclic C1−O1 bond cleavage after
activation of the O1 oxygen group to form a cyclic
Furanosides have received much less attention than pyrano-
sides regarding the endocyclic versus exocyclic question.
Nevertheless, interesting kinetic studies performed on five-
membered ring sugars indicated that they undergo hydrolysis
with negative entropy of activation,8 in clear contrast with the
Received: December 18, 2012
Published: March 13, 2013
Figure 1. Exocyclic (A) versus endocyclic cleavage (B) pathways.
© 2013 American Chemical Society
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positive values found for pyranosides.9 A first proposed
mechanism that accounts for these activation parameters
involves a bimolecular displacement of the protonated C1-
methoxy group by water concerted with the cleavage of the
exocyclic C−O bond (C, Figure 2).8 Alternatively, the addition
anion nucleophile that can trap reactive intermediates at low
temperatures before they can further react or equilibrate.12
Addition of this Lewis acid to methyl furanosides would
therefore generate acyclic and cyclic mixtures of bromoethers,
which could react at low temperature with phenylthiol and a
base (DIEA) to provide isolable thioacetals. The relative
basicity of the O5 and O1 sites of activation and the presence of
stabilizing or destabilizing stereoelectronic interactions brought
by the different furanoside substituents in their preferred
conformations are among the various factors likely to influence
both modes of acetal cleavage and, thus, the observed mixtures
of acyclic or cyclic thioacetals products. Substitution reactions
at acetal centers have been proposed to occur through an array
of mechanisms in the presence of a Lewis acid that range from
fully SN1 reactions involving oxocarbenium intermediates4a,13
to SN2-like displacements of contact ions pairs,14 or
alternatively, SN2-like displacements with oxocarbenium
character (exploded transition states15).16 The configurations
of the thioacetal moieties formed were therefore carefully
determined in order to gain mechanistic insights.
Figure 2. Suggested hydrolytic cleavage mechanisms for methyl
furanosides.8,10
In the present study, we show that a clear preference for the
endocyclic cleavage is observed in the presence of Me2BBr,
giving access to acyclic thioacetals from the four natural methyl
furanosides in high yields. Interestingly, the stereochemical
outcome of the ring-opening reactions reveals that they
proceed with SN2-like selectivity, similar to what was
hypothesized for hydrolysis reactions in aqueous media (E,
Figure 2). We also show that the configuration of the
furanosides clearly has an impact on both the reactivity and
the preference for endocyclic versus exocyclic cleavage. The
semicyclic or acyclic acetals obtained, which bear a thioether
group that can be chemoselectively activated under mild
conditions, are synthetically useful acyclic glycosyl donors for
the development of strategies to generate nucleoside analogues
and for the synthesis of new oligosaccharides and glycans.11,16b
of water could occur through a bimolecular displacement
concerted with the cleavage of the endocyclic C−O bond (D).
Lastly, water was proposed to perform nucleophilic addition on
rapidly equilibrating intermediates with oxocarbenium character
(E, Figure 2).8 Further mechanistic investigations and 18O
labeling studies of furanosides with electron-donating or
electron-withdrawing aglycones gave support to the endocyclic
cleavage pathway but did not allow discrimination between
pathways involving transition state D or scenario E (Figure
2).10 The configuration of the 5-membered ring substituents
was also shown to have an important impact on rates of
hydrolysis, which were consistently greater than for pyranosi-
des.8,10b−d
In the context of developing new approaches for the
synthesis of nucleoside analogues,11 we decided to investigate
ring-opening reactions with readily available methyl furanosides
in the presence of Me2BBr (Figure 3). Me2BBr has been shown
to efficiently activate acetal groups while carrying a bromide
RESULTS AND DISCUSSION
■
Endocyclic versus exocyclic acetal cleavage preference was
investigated by performing nucleophilic substitution reactions
in presence of Me2BBr from the four benzylated α and β
natural sugar scaffolds (Tables 1 and 2). After treatment of
these furanosides with the Lewis acid in CH2Cl2 at −78 °C,
DIEA and phenylthiol were added to generate thioacetals at
low temperature. The relative stereochemistry of all acyclic
thioacetals was determined by performing syn elimination of
their corresponding sulfoxide to provide enol ethers with E or Z
configurations allowing for unambiguous assignment of the
1
parent thioacetal by H NMR spectroscopy.
Activation of the ribo scaffold using the above conditions
revealed that the anomeric configuration has a clear impact on
the preferred cleavage pathway (entries 1 and 2, Table 1).
Whereas the α-ribo anomer yielded preferentially cyclic
thiophenyl ribofuranoside 2b, the β-ribo anomer provided
acyclic thioacetal 3b in good yield. This reactivity pattern was
intriguing, but even more surprising was the selective formation
of only the 1,2-anti diastereoisomer 3b (entry 2, Table 1).
Acyclic thioacetals were formed from both the α- and β-xylo
furanosides with, respectively, high 1,2-syn or good 1,2-trans
selectivity at the acetal center (entries 3 and 4, Table 1). The
observed selectivities of these reactions are clearly not
consistent with an SN1 mechanism and strongly suggested
that the substitution reactions are occurring through two
consecutive SN2-like displacements. The lower diastereoselec-
Figure 3. Exocyclic versus endocyclic cleavage with methyl lyxofurano-
side (depicted with SN2-like selectivity for pathway B).
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Table 1. Cleavage and Substitutions of α- and β-Methyl
Furanosides (Ribo and Xylo Series)
Table 2. Cleavage and Substitutions of α- and β-Methyl
Furanosides (Arabino and Lyxo Series)
a
Ratios were determined by 1H NMR spectroscopic analysis of
b
unpurified products. Conditions: 2.0 equiv of Me2BBr in CH2Cl2 at
a
Ratios were determined by 1H NMR spectroscopic analysis of
−78 °C. After the mixture was stirred for 30 min, 3.0 equiv of DIEA
and 2.5 equiv of PhSH were added.
b
unpurified products. Conditions: 2.0 equiv of Me2BBr in CH2Cl2 at
−78 °C. After the mixture was stirred for 30 min, 3.0 equiv of DIEA
c
and 2.5 equiv of PhSH were added. Reaction performed at −20 °C.
tivity noted for the formation 5b from 4b and the conversion of
cyclic α-methyl ribofuranoside (2a,b) to thiofuranoside suggest
that competing SN1 like mechanism are at play at the ring
cleavage or substitution steps.
Cleavage and Substitution of 2-Alkoxy THF-acetals. In
order to investigate the individual contribution of the different
ring substituents on selectivity and reactivity, different methoxy
tetrahydrofurans were prepared and treated with Me2BBr under
the conditions previously described for the methyl furanosides
substitutions (Tables 1 and 2). Our first model study involved
semicyclic acetals with a C2-alkoxy group (Table 3). 1,2-trans-
Acetal 11a and 1,2-cis-acetal 11b gave acyclic products 12a and
12b with high diastereoselectivies at 78 °C (entries 1 and 5,
Table 3).
The high selectivity observed for the cleavage and
substitution of 1,2-trans and 1,2-cis THF acetal is consistent
with two consecutive SN2-like displacements at the acetal center
(Figure 4). SN2-like acetal substitutions have been proposed to
benefit from the rehybridization of the sp3 lone pair of the
oxygen into 2pz orbital in the transition state (TS) with
formation of a partial double bond. This lone pair participation
would stabilize C−O bond breaking and C−Br bond forming
Methyl furanosides in the arabino and lyxo scaffolds were
next examined (Table 2). Acyclic thioacetals were selectively
obtained over their cyclic counterparts from α-arabino-, α-lyxo,
and β-lyxofuranosides (entries 1, 4, and 5, Table 2). The
configuration at the anomeric carbon of the starting material
was always conserved in the acyclic thioacetal products,
consistent with predominant SN2-like selectivity for both the
ring-opening reaction and the subsequent displacement of
acyclic bromoethers. β-Arabinofuranoside 6b was the only
methyl furanoside studied that remained unreacted at −78 °C
in the presence of Me2BBr followed by the addition of
thiophenol (entry 2, Table 2). At higher temperature (−20 °C),
α-thiofuranoside 8b was formed, albeit in low yield (entry 3,
Table 2). The lower SN2-like selectivity (1:9) for the formation
of 10b from 9a (entry 4, Table 2) also suggests that some
product formation occurred through a competing SN1 pathway.
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temperature an SN1 mechanism pathway involving free
oxocarbenium intermediates becomes competitive (entry 2,
Table 3). Along with the equimolar mixture of 12a and 12b
obtained, traces of cyclic products 13a and 13b were formed.
These cyclic thiofuranosides were the major products at higher
temperature and with prolonged stirring time in presence of the
Lewis acid, prior to cooling the reaction at low temperature and
addition thiophenol (entries 3 and 4, Table 3). Higher
temperatures could therefore also promote a thermodynamic
equilibration in favor of the cyclic bromoethers. The cyclic
bromoether would then convert to thiofuranosides 13a and
13b, after the addition of thiophenol at −78 °C (Figure 4).
Acyclic bromoether intermediates could not be isolated or
observed directly by 1H NMR spectroscopy at low temperature,
we therefore designed an experimental strategy to confirm that
the displacement of these intermediates by phenylthiol was
occurring through the proposed SN2-like mechanism at −78
°C. This mechanism would infer that the observed ratios of
thioacetals would originate from a corresponding ratio of
acyclic bromoethers. By varying the ratio of bromoethers we
should therefore vary similarly the ratio of the final hemi-
thioacetals. As reported in entry 1 (Table 3), a ratio of 11 to 1
(1,2-anti:1,2-syn) was noted at −78 °C with the monosub-
stituted 11a (solution A), while a 1.3:1 ratio (1,2-anti:1,2-syn)
was obtained when the reaction was performed at 0 °C
(solution B). In order to vary the ratio of bromoethers, known
volumes of each solution (B in A) were combined before
adding DIEA and phenylthiol at −78 °C (Table 4). Table 4
Table 3. Endocyclic versus Exocyclic Cleavage for C2-
Benzyloxy Methyl THF-acetals
a
Ratios were determined by 1H NMR spectroscopic analysis of
b
unpurified products. Conditions: 2.0 equiv of Me2BBr in CH2Cl2 at T
(°C). After the mixture was stirred for 30 min, 3.0 equiv of DIEA and
c
2.5 equiv of PhSH were added at −78 °C. The reaction was stirred 2h
at 25 °C before the addition of PhSH and DIEA.
Table 4. Displacement of Anomeric Mixtures of Acyclic
Bromoethers at −78 °C
ratio of solution A and B
a
b
c,d
A
B
calcd dr
12a:12b
obsd dr
entry (T1 = −78 °C) (T1 = 0 °C)
12a:12b
1
2
3
4
5
6
1
11:1
1.3:1
3:1
1
3
1
1
1
d
d
d
d
1
1
3
6
3.7:1
6:1
6:1
8.5:1
8:1
9.6:1
10:1
a
b
The reactions mixtures remained at −78 °C. Me2BBr was added at
−78 °C; the temperature was then raised to 0 °C for 30 min and then
c
lowered to −78 °C. At −78 °C, prescribed volumes of solution A and
d
B were mixed and then treated with DIEA and PhSH. Ratios were
determined by 1H NMR spectroscopic analysis of the unpurified
reaction mixtures.
Figure 4. Impact of temperature on endo- versus exocyclic C−O bond
summarizes the results obtained when various volumes for each
experiment were combined and reacted with the thiophenol
and DIEA. As reported in entries 3−6, an excellent correlation
was observed between the calculated and experimental ratio of
thioacetals, suggesting a direct relation between the bromoa-
cetals obtained in the first step and in the final products.
Cleavage and Substitution of 2-Deoxy THF-acetals.
The 2-deoxy systems studied did not exhibit any diaster-
eoselectivity at the C1 center and the distribution of acyclic and
cyclic products varied with different substitution patterns at C3
and C4 (Tables 5 and 6). Activation of THF acetals 14a and
cleavage pathways.
processes.4a The stereoelectronic assistance of the oxygen lone
pair to reach the SN2-like TS depicted at Figure 4 is also at the
origin of the exoanomeric effect in the ground state.
The effect of temperature on the outcome of the formation
of the bromoethers was next studied with C2-methoxy THF
acetal by varying only the temperature at which the Me2BBr
was added (Table 3). The loss of SN2-like selectivity at 0 °C for
the reaction of 11a with Me2BBr suggests that at higher
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Table 5. Endocyclic versus Exocyclic Cleavage for C3- and
C4-Alkyl THF Acetals
Table 6. Endocyclic versus Exocyclic Cleavage for 2-
Deoxyribose and 2-Deoxyxylose
a
Ratios were determined by 1H NMR spectroscopic analysis of
a
Ratios were determined by 1H NMR spectroscopic analysis of
b
unpurified reaction mixtures. Conditions: 2.0 equiv of Me2BBr in
b
unpurified products. Conditions: 2.0 equiv of Me2BBr in CH2Cl2 at
CH2Cl2 at −78 °C. After the mixture was stirred for 30 min, 3.0 equiv
c
−78 °C. After the mixture was stirred for 30 min, 3.0 equiv of DIEA
of DIEA and 2.5 equiv of PhSH were added. The relative
c
and 2.5 equiv of PhSH were added. Previously reported result by our
configuration was not determined.
d
group.6d Relative stereochemistry was not determined.
SN1 versus SN2-like Pathways for the Cleavage of 2-
Deoxy and 2-Alkoxy THF-acetals. The stereochemical
outcome for 2-deoxy and 2-alkoxy THF-acetals indicates that
these two families of substrates undergo endocyclic C−O bond
cleavages through different mechanisms (Tables 1 and 6). The
two successive displacement reactions involved could be
influenced strongly by the presence of an electron-withdrawing
group at C2. This reactivity trend could relate to the rate
enhancement measured for hydrolysis reaction of 2-deoxypyr-
anosides versus their corresponding pyranosides, which has
been attributed to destabilization of oxocarbenium intermedi-
ates with an electron-withdrawing group at C2.9,17 For the same
reason, formation of acyclic bromoethers would occur through
free 2-deoxy acyclic oxocarbeniums (Figure 5). Nucleophilic
additions on these 2-deoxy species are expected to proceed
with marginal diastereoselectivity,13 consistent with the
mixtures of thioacetals obtained after treatment of the reaction
mixture with thiophenol. Conversely, in the presence of a C2-
alkoxy group, free acyclic oxocarbenium formation would be
14b with a benzyloxy group at C3 afforded acyclic products 15a
and 15b in high yields (entries 1 and 2, Table 5). The 1,4-trans
THF-acetal 16a gave exclusively thiofuranosides 18a and 18b,
whereas THF-acetal 16b with a 1,4-cis configuration provided
mainly acyclic thioacetals 17 in 64% yield, along with
thiofuranosides 18 in 18% yield (entries 3 and 4, Table 5).
Both acyclic and 1,4-substituted cyclic products were formed
unselectively as 1:1 mixtures of diastereoisomers.
The endocyclic versus exocyclic cleavage preference was next
examined with 2-deoxyfuranosides in the ribo and xylo series
(Table 6). Thiofuranosides 21a,b were the only products
obtained from α-deoxyribofuranoside 19a, while the β-
deoxyribofuranoside 19b exclusively afforded acyclic thioacetals
20a,b (entries 1 and 2). Nucleophilic substitution of α-
deoxyxylofuranoside 22a gave thiofuranosides 24a,b in 69%
yield and acyclic thioacetals 23a,b in 21% yield, whereas β-
deoxyxylofuranoside 22b only afforded acyclic thioacetals 23a,b
(entries 3 and 4, Table 6).
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Figure 6. TS leading to cyclic or acyclic oxocarbenium intermediates
from ribofuranoside 1a.
likely destabilizing (Figure 6). The formation of acyclic
bromoethers would therefore occur more readily through the
other envelope conformation in TS J, where the orientation of
the C2-hydrogen bond is correctly aligned to provide
stabilization.
Figure 5. Endocyclic C−O bond cleavage mechanisms for ribo- and
deoxyribofuranosides.
hampered and the SN2-like pathway likely predominates to give
acyclic thioacetals with high selectivity after two consecutive
displacements (Figure 5).18
CONCLUSION
■
Endocyclic versus Exocyclic Cleavage. We can conclude
from the present study that tetrahydrofuran derivatives have a
strong propensity to furnish acyclic products in presence of
Me2BBr. These results are therefore suggestive that the exo
anomeric effect (Figure 5) and the resulting stereoelectronic
assistance of the exocyclic oxygen lone pairs is dominant in 5-
membered rings. A noteworthy difference between C2-oxy and
C2-deoxy systems was also observed in our study. The former
showed a strong bias in fully substituted furanosides to cleave
through the endocyclic pathway, with the notable α-ribofurano-
side exception. α-Furanosides in the 2-deoxy series rather gave
mainly cyclic products. This trend could be attributed in part to
the greater ring strain energy released during the ring-opening
reaction with more substituted systems. The conformational
preference of the furanosides studied could represent another
important factor influencing their reactivity by favoring the
endo- or the exoanomeric effects, which would in turn
modulate the relative basicity of the O1′ and O5 and the
subsequent chemoselectivity of the activation by Me2BBr.
Furanosides generally undergo pseudorotation at the ground
state through nonplanar envelope and twist conformers, which
are influenced by different stereoelectronic effects, such as
gauche interactions between vicinal alkoxy groups.19
At the transition-state level, the orientation of the ring
substituents in low energy envelope conformation could allow
stabilizing stereoelectronic effects influencing the formation of
endocyclic or exocyclic oxonium intermediates (SN1 or
“exploded SN2-like”).20 The preference for C2-endo TS H
could provide a bias, for example, toward exocyclic cleavage of
α-ribofuranoside 1a (Figure 6) because the oxocarbenium
intermediate displays a pseudoaxial C3-alkoxy group that
provides electrostatic stabilization and a C2 carbon−hydrogen
bond properly oriented for σ donation to the electron-poor
anomeric center. These stabilizing stereoelectronic effects have
been invoked in the context of C-glycosylation reactions of five-
membered ring oxocarbenium intermediates.20b Conversely,
the antiperiplanar orientation of C2-alkoxy group with the
emerging exocyclic oxocarbenium species in TS I should not
allow any significant stabilization by sigma donation and is
In summary, the present study unveils another facet of the
reactivity of five-membered semicyclic acetals with a Lewis acid
(Me2BBr). These ring-opening reactions likely proceed
predominantly through two consecutive SN2-like nucleophilic
displacements at the anomeric center to provide acyclic
thioacetals. The presence of a C2-alkoxy group is necessary
to maintain the high SN2-like selectivity for the ring-opening
reaction. The general preference for endocyclic cleavage
pathway in the reactions studied could be attributed to the
greater conformational flexibility of exocyclic C1−O1 bond,
allowing more optimal antiperiplanar alignment for stereo-
electronic assistance. The ring strain release for the opening of
five-membered rings could also represent an important factor
that enhances exocyclic cleavage in five-membered rings. The
stereochemical outcome of the ring-opening reaction should
allow for a broader general understanding of fundamental effect
regarding the reactivity of methyl furanosides.
EXPERIMENTAL SECTION
■
General Comments. The characterization data for compounds
11a, 11b, 12a, 12b, 13a, and 13b was previously reported by our
group.15d All reactions requiring anhydrous conditions were carried
out under an atmosphere of nitrogen or argon in flame-dried glassware
using standard syringe techniques. Dimethylboron bromide was used
as a 2.0 M solution in dichloromethane and was synthesized by a
known method.21 1H NMR spectra were recorded on 400 and 500
MHz NMR spectrometers using CDCl3 (δ = 7.26 ppm) as the internal
reference. 13C NMR spectra were recorded at 100 or 125 MHz using
CDCl3 (δ = 77.16 ppm) as the internal reference. Infrared spectra
were recorded on a FT-IR spectrophotometer 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, and FAB mass spectra were recorded with or without
ionization. Optical rotations were recorded in dichloromethane unless
otherwise noted (c in g of substrate/100 mL of solvent l = 1 dm).
General Experimental Method for the Formation of Acyclic
and Cyclic Thioacetals from Methyl Furanosides (Procedure 1).
To a cooled (−78 °C) solution of methyl α-D-ribofuranoside 1a22
(0.060 g, 0.14 mmol) in CH2Cl2 (2.4 mL, 0.06 M) was added
dropwise a 2.0 M solution of dimethylboron bromide in CH2Cl2 (0.14
mL, 0.28 mmol). The reaction mixture was stirred at −78 °C for 30
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min before addition of i-Pr2EtN (0.072 mL, 0.42 mmol) and
benzenethiol (0.036 mL, 0.35 mmol). After the solution was cooled
for 2 h at −78 °C, Ambersep 900 OH basic resin was added, and the
reaction mixture was allowed to warm to ambient temperature over 15
= 11.3 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 11.3 Hz, 1H),
4.49 (d, J = 11.9 Hz, 1H), 4.43 (d, J = 11.9 Hz, 1H), 4.01 (s, 2H), 3.93
(dd, J = 5.7, 11.4 Hz, 1H), 3.49 (s, 3H), 3.42−3.20 (m, 2H), 2.61 (d, J
= 5.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.3, 138.2, 138.0,
135.0, 133.0, 132.5, 129.1, 128.6, 128.50, 128.57, 128.39, 128.31,
127.89, 127.87, 127.8, 127.6, 93.0, 82.7, 79.2, 75.6, 75.2, 73.4, 71.3,
70.5, 56.9; IR (film) νmax 3451, 3055, 3031, 2928, 2867, 1453, 1073;
HRMS calcd for C33H36NaO5S+ (M + Na+) 567.2176, found 567.2154
(−3.9 ppm).
(1S,2S,3R,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-ol (7b). The representative procedure 1 was followed using
methyl α-D-arabinofuranoside 6a22 (0.050 g, 0.12 mmol), a 2.0 M
solution of Me2BBr in CH2Cl2 (0.12 mL, 0.24 mmol), PhSH (0.031
mL, 0.30 mmol), and i-Pr2EtN (0.063 mL, 0.36 mmol) in CH2Cl2 (2
mL). 1H NMR spectroscopic analysis of the unpurified product
indicated formation of acyclic thioacetal 7b as a single diastereomer.
The resulting yellowish oil was purified by flash chromatography
1
min. The mixture was filtered and concentrated in vacuo. H NMR
spectroscopic analysis of the unpurified product indicated formation of
a pair of diastereomers in a 1:4 (2a:2b; 1,2-trans:1,2-cis) ratio. The
resulting yellowish oil was purified by flash chromatography (15:85
EtOAc/hexanes) to afford an inseparable mixture of 2 as a thick oil
(0.055 g, 79%). 1H NMR spectroscopic data obtained for 2a,b
correlate with previously reported data.23
(1R,2R,3R,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-ol (3b). The representative procedure 1 was followed using
methyl β-D-ribofuranoside 1b22 (0.050 g, 0.12 mmol), a 2.0 M solution
of Me2BBr in CH2Cl2 (0.12 mL, 0.24 mmol), PhSH (0.031 mL, 0.3
mmol), and i-Pr2EtN (0.063 mL, 0.36 mmol) in CH2Cl2 (2 mL). The
1
reaction was stirred 3 h at −78 °C and 90 min at 0 °C. H NMR
spectroscopic analysis of the unpurified product indicated formation of
acyclic thioacetal 3b as a single diastereoisomer. The resulting
yellowish oil was purified by flash chromatography (20:80 EtOAc/
(20:80 EtOAc/hexanes) to afford 7b as a thick oil (0.045 g, 77%):
1
[α]25 +28.5 (c 0.720, CH2Cl2); Rf 0.15 (20:80 EtOAc/hexanes); H
D
NMR (500 MHz, CDCl3) δ 7.44 (dd, J = 1.9, 7.5 Hz, 2H), 7.35−7.20
(m, 18H), 4.93 (d, J = 6.5 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.58 (d,
J = 11.2 Hz, 1H), 4.56 (s, 2H), 4.49 (d, J = 11.9 Hz, 1H), 4.45 (d, J =
11.9 Hz, 1H), 4.06 (dd, J = 3.4, J = 7.0 Hz, 1H), 3.92−3.91 (m, 1H),
3.86 (dd, J = 3.4, J = 6.5 Hz, 1H), 3.53 (d, J = 4.5 Hz, 2H), 3.50 (s,
3H), 2.62 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 138.3, 138.2,
138.1, 133.7, 133.4, 129.0, 128.7, 128.5, 128.44, 128.40, 128.34,
128.30, 128.2, 128.0, 127.8, 127.8, 91.8, 80.8, 78.3, 75.0, 73.8, 73.5,
71.1, 70.5, 57.0; IR (film) νmax 3480, 3066, 3031, 2921, 2861, 1453,
1069; HRMS calcd for C33H36NaO5S+ (M + Na+) 567.2176, found
567.2192 (+2.8 ppm).
hexanes) to afford 3b as a thick oil (0.048 g, 83%): [α]25 −2.20 (c
D
1
0.92, CH2Cl2); Rf 0.24 (40:60 Et2O/hexanes); H NMR (500 MHz,
CDCl3) δ 7.53 (dd, J = 1.8, 7.6 Hz, 2H), 7.37−7.28 (m, 16H), 7.19−
7.17 (m, 2H), 5.11 (d, J = 5.6 Hz, 1H), 4.90 (d, J = 11.3 Hz, 1H), 4.70
(d, J = 11.3 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9 Hz,
1H), 4.41 (d, J = 11.4 Hz, 1H), 4.35 (d, J = 11.4 Hz, 1H), 4.22−4.18
(m, 1H), 4.04−4.01 (m, 2H) 3.66 (s, 1H), 3.65 (d, J = 1.4 Hz, 1H),
3.50 (s, 3H), 2.65 (d, J = 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
138.4, 138.28, 138.23, 134.8, 132.6, 129.1, 128.5, 128.4, 128.4, 128.2,
128.0, 127.8, 127.7, 127.7, 127.6, 127.5, 92.6, 81.9, 79.3, 75.2, 73.4,
72.8, 71.4, 71.1, 56.9; IR (film) νmax 3478, 3061, 3029, 2926, 2866,
1453, 1089; HRMS calcd for C33H36NaO5S+ (M + Na+) 567.2176,
found 567.2183 (+1.2 ppm).
(1S,2S,3R,4R)-2,3-Bis(benzyloxy)-4-(benzyloxymethyl)-1-
(phenylthio)tetrahydrofuran (8b). The representative procedure 1
was followed using methyl β-D-arabinofuranoside 6b22 (0.025 g, 0.06
mmol), a 2.0 M solution of Me2BBr in CH2Cl2 (0.060 mL, 0.12
mmol), PhSH (0.015 mL, 0.15 mmol), and i-Pr2EtN (0.031 mL, 0.18
mmol) in CH2Cl2 (1 mL). The reaction was stirred at −20 °C instead
(1S,2R,3S,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-ol (5a). The representative procedure 1 was followed using
methyl α-D-xylofuranoside 4a22 (0.050 g, 0.12 mmol), a 2.0 M solution
of Me2BBr in CH2Cl2 (0.2 mL, 0.24 mmol), PhSH (0.031 mL, 0.30
1
of −78 °C. H NMR spectroscopic analysis of the unpurified product
1
mmol), and i-Pr2EtN (0.063 mL, 0.36 mmol) in CH2Cl2 (2 mL). H
indicated formation of cyclic thioacetal 8b as a single diastereoisomer.
The resulting yellowish oil was purified by flash chromatography
(20:80 EtOAc/hexanes) to afford 8b as a thick oil (0.011 g, 37%). 1H
NMR spectroscopic data obtained for 8b correlate with previously
reported data.24
NMR spectroscopic analysis of the unpurified product indicated the
formation of a pair of acyclic thioacetal diastereomers in a 20:1 (5a:5b;
1,2-syn:1,2-anti) ratio. 13C and 1H NMR data for the minor isomer 5b
correlate with the data obtained for the major isomer 5b obtained
from 4b under the same reaction conditions. The resulting yellowish
oil was purified by flash chromatography (20:80 EtOAc/hexanes) to
afford 5a as a thick oil (0.030 g, 51%): [α]25D +7.64 (c 0.72, CH2Cl2);
Rf 0.18 (20:80 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.57−7.55 (m, 2H), 7.39−7.29 (m, 18 H), 4.98 (d, J = 4.8 Hz, 1H),
4.92 (d, J = 11.1 Hz, 1H), 4.82 (d, J = 11.3 Hz, 1H), 4.71 (d, J = 11.1
Hz, 1H), 4.63 (d, J = 11.3 Hz, 1H), 4.52 (d, J = 11.9 Hz, 1H), 4.47 (d,
J = 11.9 Hz, 1H), 4.06−4.02 (m, 2H), 3.99 (dd, J = 3.0, 5.7 Hz, 1H),
3.56−3.47 (m, 2H), 3.46 (s, 3H), 2.72 (d, J = 6.2 Hz, 1H); 13C NMR
(125 MHz, (CD3)2CO) δ 140.0, 139.8, 139.5, 136.4, 132.9, 129.7,
128.9, 128.82, 128.78, 128.5, 128.38, 128.36, 128.1, 128.0, 127.9,
127.8, 95.8, 83.4, 81.6, 76.5, 75.9, 74.6, 73.4, 72.0, 57.7; IR (film) νmax
3450, 3031, 2927, 2861, 1450, 1072; HRMS calcd for C33H36NaO5S+
(M + Na+) 567.2176, found 567.2165 (−1.9 ppm).
(1S,2S,3S,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-2-ol (10b). The representative procedure 1 was followed using
methyl α-D-lyxofuranoside 9a22 (0.060 g, 0.14 mmol), a 2.0 M solution
of Me2BBr in CH2Cl2 (0.14 mL, 0.28 mmol), PhSH (0.036 mL, 0.35
mmol), and i-Pr2EtN (0.073 mL, 0.42 mmol) in CH2Cl2 (2.3 mL).
The reaction mixture was stirred for 3 h at −78 °C and 90 min at 0 °C.
1H NMR spectroscopic analysis of the unpurified product indicated
formation of a pair of acyclic thioacetal diastereomers in a 1:9
(10a:10b; 1,2-syn/1,2-anti) ratio. 13C and 1H NMR spectroscopic data
for the minor isomer 10a correlate with the data obtained for the
major isomer from 9b, which were formed under the same reaction
conditions. The resulting yellowish oil was purified by flash
chromatography (20:80 EtOAc/hexanes) to afford 10b as a thick oil
(0.048 g, 64%): [α]25D −2.72 (c 1.03, CH2Cl2); Rf 0.32 (30:70 EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.54−7.52 (m, 2H), 7.43 (d,
J = 7.1 Hz, 2H), 7.39−7.28 (m, 14H), 7.24−7.22 (m, 2H), 5.06 (d, J =
3.6 Hz, 1H), 5.00 (d, J = 11.0 Hz, 1H), 4.80 (d, J = 10.9 Hz, 1H), 4.58
(d, J = 11.8 Hz, 1H), 4.53−4.46 (m, 3H), 4.20−4.15 (m, 2H), 3.97 (d,
J = 7.3 Hz, 1H), 3.62−3.52 (m, 2H), 3.51 (s, 3H), 2.78 (d, J = 6.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 138.13, 138.12, 138.0, 135.4,
132.4, 129.2, 128.49, 128.45, 128.40, 128.2, 128.1, 128.0, 127.93,
127.91, 127.8, 127.4, 92.9, 82.3, 77.6, 75.9, 73.9, 73.4, 71.4, 69.5, 56.5;
IR (film) νmax 3480, 3030, 2934, 2861, 1453, 1212, 1073, 1026; HRMS
calcd for C33H36NaO5S+ (M + Na+) 567.2176, found 567.2160 (−2.8
ppm).
(1R,2R,3S,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-ol (5b). The representative procedure 1 was followed using
methyl β-D-xylofuranoside 4b22 (0.050 g, 0.12 mmol), a 2.0 M solution
of Me2BBr in CH2Cl2 (0.12 mL, 0.24 mmol), PhSH (0.031 mL, 0.30
1
mmol), and i-Pr2EtN (0.063 mL, 0.36 mmol) in CH2Cl2 (2 mL). H
NMR spectroscopic analysis of the unpurified product indicated a pair
of acyclic thioacetals diastereomers in a 1:8 (5a:5b 1,2-syn:1,2-anti)
1
1
ratio. 13C and H NMR data for the minor isomer correlate with H
and 13C spectroscopicdata of isomer 5a obtained from 4a, under the
same reaction conditions. The resulting yellowish oil was purified by
flash chromatography (20:80 EtOAc/hexanes) to afford 5b as a thick
oil (0.054 g, 91%): [α]25 +31.7 (c 1.02, CH2Cl2); Rf 0.38 (30:70
(1R,2S,3S,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-ol (10a). The representative procedure 1 was followed using
methyl β-D-lyxofuranoside 9b22 (0.017 g, 0.04 mmol), a 2.0 M solution
D
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.52−7.50 (m, 2H),
7.37−7.26 (m, 18H), 5.02 (s, 1H), 4.86 (d, J = 11.0 Hz, 1H), 4.78 (d, J
2941
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Article
of Me2BBr in CH2Cl2 (0.04 mL, 0.08 mmol), PhSH (0.010 mL, 0.10
mmol), and i-Pr2EtN (0.021 mL, 0.12 mmol) in CH2Cl2 (0.7 mL). 1H
NMR spectroscopic analysis of the unpurified product indicated the
formation a pair of acyclic thioacetal diastereomers in a 20:1 (10a:10b;
2929, 2873, 1474, 1455, 1438, 1113, 1062; HRMS calcd for
C18H22NaO3S+ (M + Na+) 341.1182, found 341.1182 (+0.01 ppm).
(2S,5S)-2-(Benzyloxymethyl)-5-methoxytetrahydrofuran (16a).
Compound 16a was prepared following a Castillon procedure.27 13C
and 1H NMR spectroscopic data for 16a correlate with the previously
1
1,2-syn/1,2-anti) ratio. 13C and H NMR data for the minor isomer
1
reported data: [α]25 +81.4 (c 1.03, CH2Cl2); H NMR (500 MHz,
10b correlate with the data obtained for the major isomer 9a under the
same reaction conditions. The resulting yellowish oil was purified by
flash chromatography (20:80 EtOAc/hexanes) to afford 10a as a thick
D
CDCl3) 7.39−7.28 (m, 5H), 5.09 (d, J = 5.1 Hz, 1H), 4.63 (d, J = 12.2
Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.31 (qd, J = 5.1, 7.4 Hz, 1H),
3.54−3.58 (m, 2H), 3.38 (s, 3H), 2.12−1.98 (m, 2H), 1.90−1.85 (m,
1H), 1.71−1.65 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 138.4,
128.4, 127.8, 105.6, 77.0, 73.5, 72.6, 54.8, 32.0, 26.0; HRMS calcd for
oil (0.015 g, 71%): [α]25 −24.9 (c 1.03, CH2Cl2); Rf 0.41 (30:70
D
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.47−7.46 (m, 2H),
7.35−7.23 (m, 18H), 4.96 (d, J = 4.2 Hz, 1H), 4.79 (d, J = 11.1 Hz,
1H), 4.69 (d, J = 11.1 Hz, 1H), 4.59−4.46 (m, 4H), 4.15−4.13 (m,
1H), 4.08−4.06 (m, 1H), 3.95−3.94 (m, 1H), 3.55 (d, J = 5.8 Hz,
2H), 3.45 (s, 3H), 2.95 (d, J = 5.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 138.2, 138.1, 138.04, 138.00, 135.47, 132.45, 129.2, 129.0,
128.4, 128.3, 128.09, 127.97, 127.92, 127.8, 127.4, 127.3, 94.1, 81.1,
78.3, 74.6, 73.8, 73.4, 71.3, 70.0, 57.2; IR (film) νmax 3487, 3062, 3031,
2928, 2867, 1456, 1109; HRMS calcd for C33H36NaO5S+ (M + Na+)
567.2176, found 567.2156 (−3.5 ppm).
+
C13H18NaO3 (M + Na+) 245.1148, found 245.1145 (−1.5 ppm).
(2S,5R)-2-(Benzyloxymethyl)-5-methoxytetrahydrofuran (16b).
Compound 16b was prepared following Castillon procedure.27 13C
and 1H NMR spectroscopic data for 16b correlate with the previously
reported data: [α]25D +82.8 (c 1.14, CH2Cl2); Rf 0.26 (20:80; EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) 7.39−7.30 (m, 5H), 5.01 (d, J
= 4.5 Hz, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H),
4.34−4.28 (m, 1H), 3.55 (dd, J = 7.0, 9.8 Hz, 1H), 3.50 (dd, J = 4.8,
9.8 Hz, 1H), 3.33 (s, 3H), 2.03−1.89 (m, 3H), 1.79−1.71 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 138.4, 128.4, 127.8, 127.7, 105.4, 79.2,
74.7, 73.4, 54.5, 32.8, 26.4; HRMS calcd for C13H18NaO3+ (M + Na+)
245.1148, found: 245.1147 (−0.42 ppm).
( )-(2S,4R)-4-(Benzyloxy)-2-methoxytetrahydrofuran (14a) and
( )-(2R,4R)-4-(Benzyloxy)-2-methoxytetrahydrofuran (14b). To a
cooled (−78 °C) solution of 4-(benzyloxy)dihydrofuran-2(3H)-one25
(2.0 g, 10 mmol) in dichloromethane (100 mL, 0.1 M) was added a
1.0 M solution of DIBAL-H in toluene (12.5 mL, 12.5 mmol). The
resulting mixture was stirred for 2 h before addition of MeOH (33 mL,
0.3 M) and then treated with concentrated HCl (1 mL). The reaction
mixture was stirred for 12 h at 25 °C before the organic layer was
separated and the aqueous layer extracted three times with
dichloromethane (100 mL). The combined organic layers were
dried with anhydrous magnesium sulfate, filtered, and concentrated in
vacuo. The oily residue was purified by flash chromatography eluting
with (30:70 EtOAc/hexanes) to afford a colorless liquid as pure 14a
(0.998 g, 46%) and pure 14b (0.090 g, 4%) along with an anomeric
mixture (0.140 g, 6%).
(2S)-1-(Benzyloxy)-5-methoxy-5-(phenylthio)pentan-2-ol (17a,b).
The representative procedure 1 was followed using 16b (0.145 g, 0.65
mmol), a 2.0 M solution of Me2BBr in CH2Cl2 (0.65 mL, 1.3 mmol),
PhSH (0.17 mL, 1.6 mmol), and i-Pr2EtN (0.34 mL, 1.9 mmol) in
1
CH2Cl2 (6.5 mL). H NMR spectroscopic analysis of the unpurified
product indicated a pair of acyclic thioacetals diastereomers in a 1:1
(17a:17b) ratio and a pair of cyclic thiofuranoside diastereoisomers in
a 1:1 (18a:18b) ratio. The resulting yellowish oil was purified by flash
chromatography (25:75 EtOAc/hexanes) to afford the thiofuranoside
18 (0.035 g, 18%) and the acyclic thioacetal 17 as liquids in an
inseparable diastereomeric mixture (0.139 g, 64%). 17a and 17b
mixture: Rf 0.27 (40:60 EtOAc/hexanes); [α]25 0.45 (c 1.11,
14a: Rf 0.43 (30:70 EtOAc/hexanes); 1H NMR (500 MHz,
DMSO) δ 7.36−7.27 (m, 5H), 4.96 (dd, J = 1.2, 5.9 Hz, 1H), 4.47 (d,
J = 11.9 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 4.19−4.14 (m, 1H), 3.97
(dd, J = 6.2, 9.1 Hz, 1H), 3.67 (dd, J = 4.9, 9.2 Hz, 1H), 3.23 (s, 3H),
2.20 (ddd, J = 5.8, 7.9, 13.9 Hz, 1H), 1.85 (d, J = 14.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 138.2, 128.6, 128.0, 127.8, 105.0, 76.9,
71.8, 71.6, 55.2, 39.0; IR (film) νmax 2891, 1452, 1367, 1432, 1205,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) 7.51−7.48 (m, 4H), 7.39−
7.27 (m, 16H), 4.70−4.65 (m, 2H), 4.55 (s, 4H), 3.82−3.78 (m, 2H),
3.52−3.46 (m, 2H), 3.50 (s, 3H), 3.49 (s, 3H), 3.35−3.31 (m, 2H),
2.36 (bs, 2H), 2.02−1.93 (m, 2H), 1.90−1.82 (m, 2H), 1.70−1.58 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 138.0, 133.8, 133.6, 133.2,
133.1, 128.8, 128.6, 127.9, 127.8, 127.7, 127.6, 90.93, 90.91, 74.55,
74.54, 73.47, 73.46, 70.1, 70.0, 55.7, 55.6, 32.1, 31.9, 29.9, 29.8; IR
(film) νmax 3451(bs), 3062, 3025, 2928, 2960, 1583, 1475, 1452, 1080,
1025; HRMS calcd for C19H24NaO3S+ (M + Na+) 355.1338, found
355.1339 (+0.13 ppm).
+
1043; HRMS calcd for C12H16NaO3 (M + Na+) 231.0992, found
231.0993 (−0.44 ppm).
14b: Rf 0.45 (30:70 EtOAc/hexanes); 1H NMR (500 MHz,
DMSO) δ 7.36−7.27 (m, 5H), 5.09 (dd, J = 2.5, 5.4 Hz, 1H), 4.43 (s,
2H), 4.25 (dddd, J = 1.7, 3.0, 4.6, 6.3 Hz, 1H), 3.87 (d, J = 9.8 Hz,
1H), 3.75 (dd, J = 4.6, 9.9 Hz, 1H), 3.21 (s, 3H), 2.08 (ddd, J = 3.5,
4.9, 14.1 Hz, 1H), 2.01 (ddd, J = 2.5, 6.5, 14.1 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 138.0, 128.4, 127.7, 105.1, 78.2, 71.2, 70.8, 55.0,
39.8; IR (film) νmax 2910, 1452, 1346, 1207, 1108, 1043; HRMS calcd
(2S,5R)-2-(Benzyloxymethyl)-5-(phenylthio)tetrahydrofuran
(18a) and (2S,5S)-2-(Benzyloxymethyl)-5-(phenylthio)-
tetrahydrofuran (18b). The representative procedure 1 was followed
using 16a (0.130 g, 0.58 mmol), a 2.0 M solution of Me2BBr in
CH2Cl2 (0.6 mL, 1.17 mmol), PhSH (0.148 mL, 1.45 mmol), and i-
Pr2EtN (0.303 mL, 1.74 mmol) in CH2Cl2 (5.8 mL). 1H NMR
spectroscopic analysis of the unpurified product indicated a pair of
cyclic thioacetal diastereomers in a 1:1.1 (18a:18b) ratio. The
resulting yellowish oil was purified by flash chromatography (5:95
EtOAc/hexanes) to afford 18a,b (0.142 g, 82%) .
+
for C12H16NaO3 (M + Na+) 231.0992, found 231.0992.
( )-2-(Benzyloxy)-4-methoxy-4-(phenylthio)butan-1-ol (15a,b).
The representative procedure 1 was followed using 14a (0.040 g,
0.19 mmol), a 2.0 M solution of Me2BBr in CH2Cl2 (0.19 mL, 0.38
mmol), PhSH (0.048 mL, 0.48 mmol), and i-Pr2EtN (0.099 mL, 0.57
18a: Rf 0.50 (40:60 EtOAc/hexanes); [α]25 237.9 (c 1.03,
D
1
1
mmol) in CH2Cl2 (1.9 mL). H NMR spectroscopic analysis of the
CH2Cl2); H NMR (500 MHz, CDCl3) 7.55−7.53 (m, 2H), 7.37−
unpurified product indicated a pair of acyclic thioacetal diastereomers
in a 1:1.25 (15a:15b)26 ratio. The resulting yellowish oil was purified
by flash chromatography (20:80 EtOAc/hexanes) to afford 15a,b as a
liquid in an inseparable diastereomeric mixture (0.057 g, 93%): Rf 0.15
7.24 (m, 8H), 5.61 (dd, J = 3.9, 6.8 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H),
4.59 (d, J = 12.2 Hz, 1H), 4.37−4.32 (m, 1H), 3.70 (dd, J = 6.4, 10.0
Hz, 1H), 3.58 (dd, J = 5.1, 10.0 Hz, 1H), 2.42−2.34 (m, 1H), 2.16−
2.06 (m, 2H), 1.90 (ddd, J = 8.7, 12.8, 15.7 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 138.4, 135.4,131.4, 128.9, 128.4, 127.8, 127.6, 127.0,
87.4, 80.4, 73.54, 73.52, 33.0, 28.2; IR (film) νmax 3062, 3025, 2934,
2861, 1583, 1479, 1440, 1052, 1024; HRMS calcd for C18H20NaO2S+
(M + Na+) 323.1076, found 323.1078 (+08 ppm).
1
(30:70 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.49−7.31
(m, 20H), 4.81 (t, J = 6.5 Hz, 1H, 15a), 4.75 (dd, J = 3.6, 9.6 Hz, 1H,
15b), 4.60 (d, J = 11.6 Hz, 1H), 4.57 (s, 2H), 4.52 (d, J = 11.6 Hz,
1H), 3.83−3.69 (m, 4H), 3.54 (dd, J = 6.0, 11.8 Hz, 1H), 3.51 (s, 3H,
15a), 3.49−3.45 (m, 1H), 3.44 (s, 3H, 15b), 2.18−2.11 (m, 2H),
2.01−1.96 (m, 2H), 1.88−1.83 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 138.4, 138.3, 133.9, 132.7, 132.5, 129.0, 128.9, 128.68,
128.64, 128.05, 128.02, 128.00, 127.93, 127.90, 87.8, 87.0, 77.4, 76.8,
72.1, 71.9, 64.1, 63.9, 55.94, 55.92, 38.7, 37.4; IR (film) νmax 3444,
18b: Rf 0.57 (40:60 EtOAc/hexanes); [α]25 221.8 (c 1.13,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) 7.56−7.54 (m, 2H), 7.38−
7.23 (m, 8H), 5.74 (dd, J = 4.1, 7.1 Hz, 1H), 4.61 (s, 2H), 4.46 (tt, J =
4.6, 7.3 Hz, 1H), 3.61 (dq, J = 4.6, 10.4 Hz, 2H), 2.45 (dddd, J = 5.7,
7.0, 9.9, 13.0 Hz, 1H), 2.15−2.07 (m, 1H), 2.03 (dddd, J = 4.1, 6.3,
2942
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The Journal of Organic Chemistry
Article
Figure 7. Stereochemical proof of structure for acyclic thioacetals 3b, 5a, 5b, 7b, 10a, and 10b.
8.6, 12.9 Hz, 1H), 1.80 (dddd, J = 6.4, 7.4, 9.3, 11.8 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 138.4, 135.8, 131.2, 128.9, 128.5, 127.8,
127.7, 126.9, 87.7, 77.8, 73.4, 71.8, 32.8, 27.4; IR (film) νmax 3062,
3025, 2940, 2863, 1583, 1479, 1450, 1069, 1024; HRMS calcd for
C18H20NaO2S+ (M + Na+) 323.1076, found 323.1072 (−1.0 ppm).
(2R,3S)-1,3-Bis(benzyloxy)-5-methoxy-5-(phenylthio)pentan-2-ol
(20a,b). The representative procedure 1 was followed using 19b28
(0.050 g, 0.15 mmol), a 2.0 M solution of Me2BBr in CH2Cl2 (0.15
mL, 0.30 mmol), PhSH (0.039 mL, 0.38 mmol), and i-Pr2EtN (0.079
mL, 0.46 mmol) in CH2Cl2 (2.5 mL). 1H NMR spectroscopic analysis
of the unpurified product indicated a pair of acyclic thioacetal
diastereomers in a 1.3:1 (20a:20b)26 ratio. The resulting yellowish oil
was purified by flash chromatography (5:95 EtOAc/CH2Cl2) to afford
20a (0.034 g, 52%) with 20b (0.018 g, 27%) as liquids.
(24a:24b) ratio with the corresponding acyclic thioacetals in a 1.4:1
(23a:23b)26 ratio. The resulting yellowish oil was purified by flash
chromatography (20:80 EtOAc/hexanes) to afford thiofuranoside 24a
(0.022 g, 15%), thiofuranoside 24b (0.079 g, 54%), and an inseparable
mixture of acyclic thioacetal 23a,b (0.034 g, 21%). Compound 24a,b
was previously reported in the literature, but without complete
characterization data, which are therefore provided herein.
23a,b: Rf 0.24 (30:70; EtOAc/hexanes); [α]25 +0.48 (c 0.099,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.46−7.44 (m, 4H), 7.36−
7.26 (m, 26H), 4.78−4.74 (m, 2H), 4.58−4.46 (m, 8H), 3.86−3.73
(m, 4H), 3.51−3.43 (m, 4H), 3.46 (s, 3H, 23a), 3.40 (s, 3H, 23b),
2.46 (d, J = 5.3 Hz, 1H, 23a), 2.34 (d, J = 6.1 Hz, 1H, 23b), 2.10 (ddd,
J = 3.7, 9.0, 14.3 Hz, 1H, 23b), 2.05 (t, J = 6.2 Hz, 2H, 23a), 2.00−
1.95 (m, 1H, 23b); 13C NMR (125 MHz, CDCl3) δ 138.4, 138.3,
138.1, 138.0, 134.0, 133.8, 132.9, 132.6, 128.94, 128.91, 128.6, 128.5,
128.08, 128.07, 127.96, 127.95, 127.92, 127.91, 127.88, 127.87, 127.78;
IR (film) νmax 3445, 3062, 3031, 2926, 2867, 1454, 1096, 1070, 1026;
HRMS calcd for C26H30O4NaS (M + Na+) 461.1757, found 461.1755
(−0.36 ppm).
20a: Rf 0.41 (10:90 EtOAc/CH2Cl2); [α]25 −48.8 (c 0.60,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.48−7.46 (m, 2H), 7.38−
7.28 (m, 13H), 4.82 (dd, J = 3.3, 10.0 Hz, 1H), 4.62 (d, J = 11.4 Hz,
1H), 4.52 (d, J = 1.9 Hz, 2H), 4.50 (d, J = 11.5 Hz, 1H), 3.91 (qd, J =
4.3, 8.6 Hz, 1H), 3.73 (ddd, J = 3.4, 4.5, 9.5 Hz, 1H), 3.55−3.50 (m,
2H), 3.38 (s, 3H), 2.40 (d, J = 4.0 Hz, 1H), 2.10−2.04 (m, 1H), 1.97
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 138.4, 138.0, 133.8, 133.2,
128.9, 128.6, 128.1, 128.0, 127.94, 127.91, 127.7, 87.2, 73.6, 72.9, 72.2,
70.9, 55.6, 38.1; IR (film) νmax 3463 (bs), 3068, 3031, 2922, 2867,
1450, 1067; HRMS calcd for C26H30NaO4S+ (M + Na+) 461.1757,
found: 461.1764 (+1.5 ppm).
24a: Rf 0.40 (30:70 EtOAc/hexanes); [α]25 −170.8 (c 1.16,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz, 2H),
7.37−7.23 (m, 13H), 5.57 (dd, J = 4.3, 7.9 Hz, 1H), 4.67 (d, J = 4.5
Hz, 1H), 4.65 (d, J = 4.4 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.49 (d, J
= 12.1 Hz, 1H), 4.27 (td, J = 5.1, 6.7 Hz, 1H), 4.22 (dt, J = 2.8, 5.3 Hz,
1H), 3.94 (dd, J = 5.1, 10.2 Hz, 1H), 3.88 (dd, J = 6.6, 10.2 Hz, 1H),
2.56 (ddd, J = 5.7, 7.8, 13.7 Hz, 1H), 2.32 (ddd, J = 2.9, 4.2, 14.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 138.4, 138.1, 136.4, 130.9,
128.9, 128.5, 128.4, 127.9, 127.8, 127.69, 128.66, 126.8, 86.2, 82.6,
77.6, 73.6, 71.5, 69.6, 38.9; IR (film) νmax 3062, 3029, 2864, 1453,
1094, 1064; HRMS calcd for C25H26NaO3S+ (M + Na+) 429.1495,
found 429.1493 (−0.38 ppm).
20b: Rf 0.28 (10:90 EtOAc/CH2Cl2); [α]25 +2.67 (c 0.30,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 3.0, 6.5 Hz,
2H), 7.39−7.26 (m, 13H), 4.87 (t, J = 6.5 Hz, 1H), 4.56−4.51 (m,
4H), 3.91−3.87 (m, 1H), 3.81−3.78 (m, 1H), 3.52 (s, 3H), 3.51−3.47
(m, 2H), 2.62 (d, J = 3.8 Hz, 1H), 2.13 (td, J = 6.7, 13.7 Hz, 1H), 2.01
(ddd, J = 4.0, 6.6, 14.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
138.2, 138.0, 134.0, 132.6, 128.9, 128.57, 128.56, 128.06, 128.00,
127.9, 127.8, 127.8, 87.8, 77.4, 73.6, 72.4, 71.7, 70.9, 56.0, 36.2; IR
(film) νmax 3475 (bs), 3068, 3037, 2928, 2867, 1456, 1091; HRMS
calcd for C26H30NaO4S+ (M + Na+) 461.1757, found 461.1765 (+1.6
ppm).
24b: Rf 0.45 (30:70 EtOAc/hexanes); [α]25 +132.7 (c 0.95,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.2 Hz, 2H),
7.36−7.23 (m, 13H), 5.79 (t, J = 6.8 Hz, 1H), 4.64 (d, J = 11.9 Hz,
1H), 4.60 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.47 (d, J =
12.1 Hz, 1H), 4.38 (dt, J = 3.8, 5.9 Hz, 1H), 4.20−4.19 (m, 1H), 3.90
(dd, J = 6.0, 10.1 Hz, 1H), 3.79 (dd, J = 5.9, 10.1 Hz, 1H), 2.61 (ddd, J
= 1.4, 7.1, 14.2 Hz, 1H), 2.13−2.08 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 138.4, 138.1, 135.4, 131.3, 128.9, 128.6, 128.5, 127.88,
127.84, 127.7, 127.6, 127.1, 85.8, 80.4, 78.2, 73.6, 71.6, 68.0, 39.2; IR
(film) νmax 3062, 3031, 2922, 2864, 1453, 1093, 1060; HRMS calcd for
C25H26NaO3S+ (M + Na+) 429.1495, found 429.1489 (−1.2 ppm).
(2R,3R)-1,3-Bis(benzyloxy)-5-methoxy-5-(phenylthio)pentan-2-ol
(23a,b) and (2R,3R)-3-(Benzyloxy)-2-(benzyloxymethyl)-5-
(phenylthio)tetrahydrofuran29 (24a,b). The representative procedure
1 was followed using known compound 22a30 (0.119 g, 0.36 mmol), a
2.0 M solution of Me2BBr in CH2Cl2 (0.36 mL, 0.72 mmol), PhSH
(0.093 mL, 0.91 mmol), and i-Pr2EtN (0.188 mL, 1.1 mmol) in
1
CH2Cl2 (3.6 mL). H NMR spectroscopic analysis of the unpurified
product indicated a pair of cyclic thioacetal diastereomers in a 1:3
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Article
Synthesis of Olefins and Proof of Structures. The relative
stereochemistry of thioacetals 3b, 5a, 5b, 7b, 10a, and 10b was
determined by H NMR correlations of the corresponding Z- or E-
olefin, obtained after a two step oxidation−syn-elimination sequence
(Figure 7 and Table 7).31 Thioacetal S1 was confirmed by X-ray
crystallographic analysis. Detailed analysis of the E- and Z-
configurations of analogous olefins was reported previously by our
group.15d
(3×) with EtOAc. The combined organic layers were dried on
anhydrous magnesium sulfate, filtered, and concentrated in vacuo. H
1
1
NMR spectroscopic analysis of the unpurified product indicated S2 as
a single diastereoisomer. The resulting yellowish oil was purified by
flash chromatography (10:90 EtOAc/hexanes) to afford S2 (0.037 g,
80%) as an oil. S2 (0.051 g, 99%) was also generated following
representative procedure 3 from thioacetal S3 (0.061 g, 0.094 mmol),
m-CPBA (0.020 g, 0.094 mmol), NaHCO3 (0.012 g, 0.14 mmol) in
CH2Cl2 (0.7 mL), and toluene (0.6 mL).
(3R,4R,Z)-2,3,5-Tris(benzyloxy)-1-methoxypent-2-en-4-yl ben-
Table 7. Chemical Shift (δ ppm) Correlation for Olefins S5
and S7
zoate (S2): [α]25 +8.00 (c 1.25, CH2Cl2); Rf 0.58 (20:80 EtOAc/
D
1
hexanes); H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 2H),
7.59 (dd, J = 7.9, 15.4 Hz, 1H), 7.45 (dd, J = 7.7 Hz, 2H), 7.41 (d, J =
7.1 Hz, 2H), 7.33−7.26 (m, 13H), 5.73 (s, 1H), 5.56 (td, J = 3.8, 7.4
Hz, 1H), 5.10 (d, J = 11.7 Hz, 1H), 5.04 (d, J = 11.7 Hz, 1H), 4.63 (d,
J = 12.0 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.50 (d, J = 12.2 Hz, 1H),
4.38 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 7.3 Hz, 1H), 3.97 (d, J = 3.8 Hz,
2H), 3.59 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.8, 138.5,
138.4, 138.3, 136.7, 135.2, 133.5, 132.9, 130.7, 129.9, 128.4, 128.34,
128.27, 127.9, 127.8, 127.7, 127.6, 127.6, 127.5, 73.3, 73.2, 73.1, 70.4,
68.7, 60.5; IR (film) νmax 3037, 2928, 2861, 1719, 1452, 1272, 1109,
H1
H2
H3
H4
S5 (E)
S7 (Z)
3.45 (s)
6.01 (s)
4.88 (d)
4.75(d)
4.65 (d)
5.14(d)
5.03 (d)
δZ > δE
+
1030; HRMS calcd for C34H34NaO6 (M + Na+) 561.2248, found
561.2244 (−0.7 ppm).
3.59 (s)
5.68 (s)
3.94 (d)
(1R,2R,3R,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-yl benzoate (S3). The representative procedure 2 was
followed using thioacetal 3b (0.260 g, 0.5 mmol), 4-DMAP (0.305 g,
2.5 mmol), and BzCl (0.17 mL, 1.5 mmol) in CH2Cl2 (5 mL). The
resulting yellowish oil was purified by flash chromatography (20:80
Et2O/hexanes) to afford S3 as a thick oil (0.293 g, 90%): [α]25D +2.6
δZ > δE
δZ < δE
δZ < δE
General Experimental Method for the Preparation of
Benzoates from Alcohols 3b, 5a, 5b, 7b, and 10b with
(Procedure 2). To a cooled (0 °C) solution of thioacetal 7b
(0.030 g, 0.06 mmol) in CH2Cl2 (0.6 mL, 0.1 M) was added 4-
(dimethylamino)pyridine (0.037 g, 0.30 mmol) with benzoyl chloride
(0.021 mL, 0.18 mmol). The reaction mixture was maintained at 0 °C
for 2 h before addition of a saturated solution of sodium bicarbonate.
The organic layer was separated, and the aqueous layer was extracted
(3×) with EtOAc. The combined organic layers were dried on
1
(c 1.5, CH2Cl2); Rf 0.21 (10% Et2O/hexanes); H NMR (500 MHz,
CDCl3) δ 8.06 (d, J = 7.6 Hz, 2H), 7.60 (dd, J = 7.4 Hz, 1H), 7.53 (d,
J = 2.0 Hz, 1H), 7.53−7.51 (m, 1H), 7.47 (dd, J = 7.7 Hz, 2H), 7.42−
7.41 (m, 2H), 7.36−7.28 (m, 16H), 5.89−5.86 (m, 1H), 5.09 (d, J =
4.3 Hz, 1H), 4.97 (d, J = 11.1 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.73
(d, J = 11.3 Hz, 1H), 4.58 (d, J = 12.2 Hz, 1H), 4.50 (dd, J = 12.1 Hz,
2H), 4.30 (dd, J = 3.3, 6.3 Hz, 1H), 4.09 (dd, J = 4.6, 6.1 Hz, 1H),
3.97−3.90 (m, 2H), 3.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
165.7, 138.3, 138.2, 138.1, 135.2, 133.1, 132.5, 130.4, 129.8, 129.1,
128.51, 128.47, 128.41, 128.37, 128.2, 128.0, 127.8, 127.7, 127.6,
127.4, 92.7, 81.8, 79.1, 75.0, 73.5, 73.4, 73.1, 68.8, 56.8; IR (film) νmax
3478, 3061, 3029, 2926, 2866, 1453, 1089; HRMS calcd for
C40H40NaO6S+ (M + Na+) 671.2438, found 671.2462 (+3.6 ppm).
(1S,2R,3S,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-yl Benzoate (S4). The representative procedure 2 was
followed using thioacetal 5a (0.165 g, 0.25 mmol), 4-DMAP (0.153 g,
1.25 mmol), and BzCl (0.087 mL, 0.75 mmol) in CH2Cl2 (2.5 mL).
The resulting yellowish oil was purified by flash chromatography
1
anhydrous magnesium sulfate, filtered, and concentrated in vacuo. H
NMR spectroscopic analysis of the unpurified product indicated S1 as
a pair of diastereomers in a 1:18 (1,2-syn:1,2-anti) ratio. The resulting
yellowish oil was purified by flash chromatography (5:95 acetone/
hexanes) to afford S1 (0.025 g, 66%) as a white crystal. Slow
evaporation of a EtOAc/hexanes solution afforded a suitable crystal for
X-ray analysis (CIF, Supporting Information).
(1S,2S,3R,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-yl benzoate (S1): mp = 88.7 °C; [α]25 +28.5 (c 0.72,
D
CH2Cl2); Rf 0.35 (20:80 EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.84 (d, J = 7.3 Hz, 2H), 7.58 (dd, J = 7.4 Hz, 1H), 7.54 (d,
J = 7.1 Hz, 2H), 7.41 (dd, J = 7.8 Hz, 2H), 7.36−7.19 (m, 18H), 5.39
(td, J = 4.1, 5.9 Hz, 1H), 4.95 (d, J = 6.9 Hz, 1H), 4.84 (d, J = 11.5 Hz,
1H), 4.81 (d, J = 11.5 Hz, 1H), 4.77 (d, J = 10.6 Hz, 1H), 4.60 (dd, J =
4.0, 6.1 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H),
4.45 (d, J = 10.6 Hz, 1H), 4.00 (dd, J = 3.5, 10.9 Hz, 1H), 3.89−3.84
(m, 2H), 3.56 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.4, 138.5,
138.2, 134.0, 133.1, 130.1, 129.8, 129.0, 128.6, 128.4, 128.3, 128.2,
128.1, 128.0, 127.90, 127.82, 127.79, 127.71, 127.70, 127.6, 91.9, 81.0,
78.7, 75.7, 75.1, 73.4, 73.3, 68.1, 57.0; IR (film) νmax 3068, 3031, 2928,
2879, 1718, 1462, 1270, 1109, 1069, 1109, 1069; HRMS calcd for
C40H40NaO6S+ (M + Na+) 671.2443, found 671.2458 (+2.2 ppm).
General Experimental Method for the syn-Elimination via
Sulfoxides (Procedure 3). To a cooled (0 °C) solution of
benzoylated thioacetal S1 (0.055 g, 0.08 mmol) in CH2Cl2 (0.7 mL,
0.14 M) was added m-chloroperbenzoic acid (0.018 g, 0.08 mmol, 77%
w/w in H2O). The reaction mixture was maintained at 0 °C for 30 min
before addition of saturated solution of sodium bicarbonate. The
organic layer was separated, and the aqueous layer was extracted (3×)
with EtOAc. The combined organic layers were dried on anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. To a solution
of the oily residue in toluene (0.7 mL, 0.2 M) was added sodium
bicarbonate (0.018 g, 0.12 mmol). The reaction mixture was reflux at
110 °C for 2 h before cooling at ambient temperature. Water was then
added, the layers were separated, and the aqueous layer was extracted
(10:90 acetone/hexanes) to afford S4 as a thick oil (0.178 g, 85%):
1
[α]25 −6.67 (c 1.20, CH2Cl2); Rf 0.23 (20% acetone/hexanes); H
D
NMR (500 MHz, CDCl3) δ 8.13 (d, J = 7.5 Hz, 2H), 7.64−7.59 (m,
3H), 7.50 (dd, J = 7.7 Hz, 2H), 7.42−7.28 (m, 18H), 5.71 (dd, J = 5.4,
9.9 Hz, 1H), 5.08 (d, J = 6.1 Hz, 1H), 5.02 (d, J = 11.0 Hz, 1H), 4.85
(d, J = 11.5 Hz, 1H), 4.82 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 11.0 Hz,
1H), 4.53 (d, J = 12.2 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.40 (dd, J =
5.2 Hz, 1H), 4.00−3.98 (m, 1H), 3.83 (dd, J = 4.1, 10.7 Hz, 1H), 3.71
(dd, J = 5.5, 10.7 Hz, 1H), 3.45 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 166.0, 138.5, 138.3, 138.0, 134.7, 133.1, 132.4, 130.1, 129.8, 129.0,
128.45, 128.42, 128.38, 128.31, 128.2, 127.9, 127.7, 127.66, 127.62,
127.2, 92.7, 79.5, 78.0, 75.2, 73.9, 73.52, 73.06, 68.6, 56.3; IR (film)
νmax 3062, 3035, 2879, 1724, 1462, 1273, 1097, 738, 702; HRMS calcd
for C40H40NaO6S+ (M + Na+) 671.2438, found 671.2461 (+3.4 ppm).
(3S,4R,E)-2,3,5-Tris(benzyloxy)-1-methoxypent-2-en-4-yl Ben-
zoate (S5). The representative procedure 3 was followed using
thioacetal S4 (0.050 g, 0.09 mmol), m-CPBA (0.020 g, 0.09 mmol),
NaHCO3 (0.011 g, 0.14 mmol) in CH2Cl2 (0.6 mL), and toluene (0.5
mL). 1H NMR spectroscopic analysis of the unpurified product
indicated the formation of S5 as a single diastereoisomer. The resulting
yellowish oil was purified by flash chromatography (30:70 EtOAc/
hexanes) to afford S5 as a thick oil (0.034 g, 81%): [α]25 −18.5 (c
D
1.00, CH2Cl2); Rf 0.34 (40:60 EtOAc/hexanes); 1H NMR (500 MHz,
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CDCl3) δ 8.05 (d, J = 7.2 Hz, 2H), 7.55 (dd, J = 7.4 Hz, 1H), 7.42 (dd,
J = 7.7 Hz, 2H), 7.32−7.21 (m, 15H), 6.01 (s, 1H), 5.78−5.75 (m,
1H), 4.88 (d, J = 7.9 Hz, 1H), 4.75 (d, J = 11.6 Hz, 1H), 4.64 (dd, J =
10.3, 11.7 Hz, 2H), 4.56 (d, J = 12.2 Hz, 1H), 4.46 (d, J = 12.3 Hz,
2H), 3.80 (dd, J = 3.0, 11.1 Hz, 1H), 3.73 (dd, J = 5.8, 11.2 Hz, 1H),
3.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.3, 140.4, 138.8,
138.4, 137.3, 134.3, 132.8, 130.8, 130.0, 128.5, 128.31, 128.26, 128.17,
128.0, 127.9, 127.7, 127.5, 127.42, 127.38, 73.7, 73.2, 72.6, 71.4, 70.6,
69.2, 60.5; IR (film) νmax 3062, 2928, 2873, 1730, 1444, 1273, 1201,
5.1, 9.8 Hz, 1H), 4.99 (d, J = 5.3 Hz, 1H), 4.88 (d, J = 10.9 Hz, 1H),
4.81 (d, J = 11.3 Hz, 1H), 4.76 (d, J = 11.2 Hz, 1H), 4.67 (d, J = 10.9
Hz, 1H), 4.47−4.41 (m, 3H), 3.88 (dd, J = 5.2 Hz, 1H), 3.74 (dd, J =
4.0, 10.7 Hz, 1H), 3.60 (dd, J = 5.9, 10.7 Hz, 1H), 3.51 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 166.0, 138.3, 138.2, 138.0, 133.8, 133.2,
133.1, 132.4, 130.1, 129.9, 128.8, 128.47, 128.38, 128.37, 128.31,
128.1, 127.71, 127.65, 127.63, 127.5, 92.4, 81.1, 78.1, 75.2, 75.1, 73.3,
73.1, 68.4, 56.9; IR (film) νmax 3068, 3031, 2940, 2855, 1719, 1596,
1452, 1270, 1069, 1026; HRMS calcd for C40H40NaO6S+ (M + Na+)
671.2443, found 671.2425 (−2.7 ppm).
+
1115, 1067; HRMS calcd for C34H34NaO6 (M + Na+) 561.2248,
found 561.2249 (+0.18 ppm).
(1S,2S,3S,4R)-2,3,5-Tris(benzyloxy)-1-methoxy-1-(phenylthio)-
pentan-4-yl Benzoate (S6). The representative procedure 2 was
followed using thioacetal 10b (0.050 g, 0.09 mmol), 4-DMAP (0.055
g, 0.45 mmol), and BzCl (0.031 mL, 0.27 mmol) in CH2Cl2 (1 mL).
The resulting yellowish oil was purified by flash chromatography
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra are available for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20:80 EtOAc/hexanes) to afford S6 as a thick oil (0.057 g, 89%):
1
[α]25 +19.5 (c 1.15, CH2Cl2); Rf 0.44 (20:80 EtOAc/hexanes); H
D
NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 7.4
Hz, 1H), 7.49 (d, J = 6.9 Hz, 2H), 7.45 (dd, J = 7.8 Hz, 2H), 7.39 (d, J
= 7.4 Hz, 2H), 7.33−7.27 (m, 16H), 5.74 (dt, J = 2.2, 6.1 Hz, 1H),
5.18 (d, J = 3.0 Hz, 1H), 4.89 (d, J = 10.4 Hz, 1H), 4.69−4.53 (m,
5H), 4.22 (dd, J = 2.0, 7.6 Hz, 1H), 4.07 (dd, J = 2.9, 7.7 Hz, 1H),
3.86−3.78 (m, 2H), 3.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
166.1, 138.4, 138.02, 138.00, 135.7, 133.1, 133.0, 132.1, 130.3, 123.0,
129.1, 129.0, 128.48, 128.46, 128.43, 128.3, 127.88, 127.80, 127.75,
127.70, 127.2, 92.4, 82.2, 77.2, 75.6, 74.3, 73.3, 72.2, 68.2, 56.5; IR
(film) νmax 3062, 3031, 2922, 2861, 1718, 1453, 1269, 1109, 1026;
HRMS calcd for C40H40NaO6S+ (M + Na+) 671.2438, found 671.2418
(−2.9 ppm).
AUTHOR INFORMATION
Corresponding Author
*E-mail: yvan.guindon@ircm.qc.ca.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science and Engineering Research
Council (NSERC) and the FQRNT for funding this research. A
National Cancer Institute of Canada (NCIC) scholarship to
M.P. is also gratefully acknowledged and we thank Murray
Bailey and Christiane Yoakim for their work on related systems.
(3S,4R,Z)-2,3,5-Tris(benzyloxy)-1-methoxypent-2-en-4-yl Ben-
zoate (S7). The representative procedure 3 was followed using
thioacetal S6 (0.050 g, 0.09 mmol), m-CPBA (0.020 g, 0.09 mmol),
NaHCO3 (0.011 g, 0.14 mmol) in CH2Cl2 (0.6 mL), and toluene (0.5
mL) and was stirred 16 h at 110 °C. 1H NMR spectroscopic analysis of
the unpurified product indicated the formation of S5:S7 (E:Z) as a
pair of diastereomers in a 1:5 ratio. The resulting yellowish oil was
purified by flash chromatography (30:70 EtOAc/hexanes) to afford S7
as a thick oil (0.024 g, 67%). Representative procedure 3 was also
followed using benzoylated thioacetals S4:S8 (dr 1:13) (0.050 g, 0.08
mmol), m-CPBA (0.018 g, 0.08 mmol), NaHCO3 (0.011 g, 0.12
mmol) in CH2Cl2 (0.6 mL), and toluene (0.5 mL). 1H NMR
spectroscopic analysis of the unpurified product indicated S5:S7 (E/Z)
as a pair of diastereomers in a 1:13 ratio. The resulting yellowish oil
was purified by flash chromatography (30:70 EtOAc/hexanes) to
afford S7 as a thick oil (0.031 g, 74%): [α]25D −38.9 (c 0.66, CH2Cl2);
Rf 0.33 (20:80 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.10
(d, J = 7.3 Hz, 2H), 7.59 (dd, J = 7.4 Hz, 1H), 7.45 (dd, J = 7.8, 15.7
Hz, 4H), 7.36−7.25 (m, 13H), 5.68−5.67 (m, 2H), 5.14 (d, J = 11.5
Hz, 1H), 5.03 (d, J = 11.5 Hz, 1H), 4.60 (d, J = 12.4 Hz, 1H), 4.55 (d,
J = 12.2 Hz, 1H), 4.45 (d, J = 12.2 Hz, 1H), 4.36 (d, J = 12.4 Hz, 1H),
3.94 (d, J = 7.3 Hz, 1H), 3.79 (dd, J = 3.2, 11.0 Hz, 1H), 3.72 (dd, J =
5.4, 11.0 Hz, 1H), 3.59 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
166.2, 138.3, 138.2, 135.72, 135.68, 132.9, 132.8, 130.6, 130.0, 128.5,
128.38, 128.35, 128.33, 128.2, 127.82, 127.77, 127.68, 127.59, 127.52,
77.4, 73.8, 73.6, 73.2, 70.0, 69.0, 60.6; IR (film) νmax 3062, 3031, 2940,
2867, 1719, 1452, 1273, 1108, 1067, 1029; HRMS calcd for
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