Boronic Acids as Phase-Transfer Reagents for Fischer Glycosidations in Low-Polarity Solvents

Article abstract of DOI:10.1021/acs.joc.7b01880

Protocols employing phenylboronic acid as a phase-transfer reagent for Fischer glycosidations in low-polarity organic solvents are described. In addition to providing rate acceleration, the formation of a substrate-derived boronic ester alters the course of the reaction by selective promotion of a furanoside- or pyranoside-selective pathway. Computational modeling of the relative energies of the glycoside-derived boronic esters provides results that are qualitatively consistent with the observed distributions of furanoside versus pyranoside products. The boronic esters that are obtained as direct products of these reactions serve as protected intermediates for the synthesis of functionalized glycosides. Complexation of particular diol groups by the boronic acid also enables selective transformations of mixtures of carbohydrates.

Full text of DOI:10.1021/acs.joc.7b01880

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX-XXX
Boronic Acids as Phase-Transfer Reagents for Fischer Glycosidations
in Low-Polarity Solvents
Sanjay Manhas and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: Protocols employing phenylboronic acid as a phase-transfer reagent for Fischer glycosidations in low-polarity
organic solvents are described. In addition to providing rate acceleration, the formation of a substrate-derived boronic ester alters
the course of the reaction by selective promotion of a furanoside- or pyranoside-selective pathway. Computational modeling of
the relative energies of the glycoside-derived boronic esters provides results that are qualitatively consistent with the observed
distributions of furanoside versus pyranoside products. The boronic esters that are obtained as direct products of these reactions
serve as protected intermediates for the synthesis of functionalized glycosides. Complexation of particular diol groups by the
boronic acid also enables selective transformations of mixtures of carbohydrates.
Limited precedent exists for using boronic acids as phase-
transfer reagents or catalysts in carbohydrate chemistry.
Boronic acids have been investigated as additives for enzyme-
catalyzed transformations of sugars in organic solvents.7,8 For
example, the solubilizing effect of phenylboronic acid facilitated
the β-glucosidase-catalyzed condensation of glucose to form
mixtures of disaccharides in benzene. Boric acid (B(OH)3) was
used to promote copper-catalyzed aminoalkynylation reactions
of unprotected sugars in dioxane.9 Although a phase-transfer
effect was not mentioned, the authors proposed that boric
acid−carbohydrate adducts were intermediates in these
processes. We sought to employ in situ boronic ester formation
to accelerate the Fischer glycosidation,10 the prototypical
protective-group free glycosidation,11 and an important
preparative method. In the initially reported protocol, hydrogen
chloride was employed as catalyst and the glycosyl acceptor
(alcohol) as the solvent. Although refinements have been
described, including the use of alternative solvents12 and
catalysts,13 the method remains primarily applicable to low-
boiling acceptors that can be used in large excess and in
situations where the desired glycoside is the product of
thermodynamic control.
INTRODUCTION
■
Interactions between boronic acids and sugars have been
applied in diverse ways in molecular recognition, including in
the design of receptors for mono- and oligosaccharides, affinity
materials for glycosylated molecules, and probes for molecular
imaging.1 These interactions have also been employed in
carbohydrate synthesis, primarily to protect 1,2- or 1,3-diol
motifs through boronic ester formation,2 although activation of
such motifs as tetracoordinate organoboron adducts has also
been demonstrated.3 Complexation of an organoboron
compound not only influences the reactivity of the sugar but
can also alter its solubility properties. Smith and co-workers
took advantage of this effect by employing hydrophobic
boronic acids as transporters of sugars across lipid membranes.4
Another illustration of this phenomenon is the “phase
switching” approach developed by the group of Hall, whereby
boronic acids are drawn into aqueous solvent through
complexation with a water-soluble sugar alcohol.5 A related
effect has been employed to achieve chemoselective oxidations
of arylboron reagents.6 Here, we describe studies aimed at using
the phase-transfer properties of boronic acids to enable
chemical transformations of unprotected carbohydrates in
organic media. We show that phenylboronic acid promotes
Fischer glycosidations of free sugars in low-polarity (hydro-
carbon or chlorinated hydrocarbon) solvents. In addition to
increasing the reaction rate, the formation of sugar-derived
boronic esters influences the distribution of furanoside and
pyranoside products, providing access to isomers distinct from
those obtained under conventional conditions.
RESULTS AND DISCUSSION
■
Reaction Optimization. The condensation of D-mannose
and n-octanol, catalyzed by (S)-camphorsulfonic acid (CSA),
was used as a model reaction to assess the effect of arylboronic
Received: July 27, 2017
© XXXX American Chemical Society
A
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acids on Fischer glycosidations in low-polarity solvents (Table
1). To determine the product distributions, the obtained
furanosides under the conditions of Fischer glycosidation with
concurrent isopropylidene ketal formation.22
When methyl α-mannopyranoside was subjected to the
conditions shown in Table 1, entry 4, furanoside 1a was
generated, but the rate of this reaction was lower than that
using mannose as the substrate (Scheme 1). This result
Table 1. Effect of Boronic Acids on the Condensation of D-
Mannose and n-Octanol in Low-Polarity Solvents
Scheme 1. Conversion of Methyl α-Mannopyranoside to α-
a
1a in the Presence of PhB(OH)2.
a
a
entry
solvent
R
1a (%)
2a (%)
1
2
3
4
5
6
7
8
DCE
b
<5
60
<5
70
40
30
45
10
15
5
DCE
Ph
b
heptane
heptane
heptane
heptane
heptane
heptane
<5
<5
<5
<5
<5
<5
a
Yield determined by 1H NMR spectroscopy using a quantitative
Ph
Ph
c
internal standard.
3,5-(CF3)2C6H3
4-(MeO)C6H4
cyclohexyl
suggests that the presence of the boronic acid alters both the
kinetics and the thermodynamics of the glycosidation reaction.
Computational modeling provided further support for the idea
that the boronic acid changes the relative energies of the
furanoside and pyranoside isomers in a way that is consistent
with the outcome of this reaction (see below).
a
Yields were determined by 1H NMR spectroscopic analysis of
unpurified, peracetylated reaction mixtures using 1,2,3-trimethoxyben-
zene as a quantitative internal standard. α/β > 20:1 for 1a, >10:1 for
b
c
2a. Results in the absence of boronic acid. Using 1 equiv of
PhB(OH)2.
Product Distributions in Phenylboronic Acid Pro-
moted Fischer Glycosidations. To further probe the effect
of boronic ester formation on pyranoside/furanoside selectivity,
we carried out glycosidations of hexose, pentose, and 6-
deoxysugar substrates using n-octanol as acceptor in the
presence of PhB(OH)2 (Scheme 2). As described in the
preceding section, the mixtures of glycosides were acetylated
after phase-switching workup to enable determinations of
mixtures of glycosides (after a phase-switching workup with
basic aqueous sorbitol solution to cleave boronic ester groups
and separate the glycoside product from phenylboronic
acid5,14) were peracetylated and subjected to analysis by H
1
nuclear magnetic resonance (NMR) spectroscopy without
further purification. Glycosidations conducted in 1,2-dichloro-
ethane (DCE) or heptane solvent were low-yielding in the
absence of the boronic acid additive due to the poor solubility
of the carbohydrate substrate (entries 1 and 3). Addition of
PhB(OH)2 (2 equiv relative to D-mannose) increased the
glycosylation yields to 60% in DCE and 70% in heptane
(entries 2 and 4). The use of 1 equiv of PhB(OH)2 rather than
two gave rise to a diminished yield (entry 5). Substituted
arylboronic acids did not result in improved glycosidation
yields, and an alkylboronic acid was ineffective (entries 6−8).
In addition to the increase in reaction rate relative to the
background, a noteworthy feature of the boronic acid-promoted
reactions is the isolation of the furanoside (1a), rather than the
pyranoside product 2a. α-Mannopyranosides, the products of
thermodynamic control, predominate for typical Fischer
glycosidations. Indeed, the pyranoside was the major product
in DCE in the absence of PhB(OH)2 (entry 1). The synthesis
of furanosides by Fischer glycosidation is often challenging: the
level of selectivity for these products of kinetic control generally
depends on the substrate, catalyst, and reaction conditions.15
Mannofuranosides of the type generated in this reaction display
liquid crystalline properties and show promise as prospective
nonionic surfactants.16 Based on the optimal loading of boronic
acid, it appears that the formation of a mannose-derived bis-
boronic ester brings the substrate into organic solution while
favoring a furanoside-selective pathway, in a manner reminis-
cent of the effects of certain metal cations on product
distributions in Fischer glycosidations.17,18 Several previously
reported methods for furanoside synthesis rely on the
formation of boronic ester or borate intermediates.16,19−21
Another relevant prior observation is the selective formation of
1
product distributions by H NMR spectroscopy. A pattern of
behavior emerged, with isomers capable of forming stable
boronic esters at nonanomeric OH groups (as depicted by the
intermediate structures in Scheme 2) generally being favored.
These structural proposals are consistent with previous work on
sugar-derived boronic esters23 and are in keeping with the
optimal loadings of PhB(OH)2 for these reactions: 2 equiv
relative to carbohydrate substrate for mannose and allose versus
one for the other sugars.
The formation of furanosides from substrates having an
erythro relationship between the C2 and C3 hydroxy groups
(mannose, allose, rhamnose, lyxose, ribose) likely reflects the
stability of boronic esters derived from cis-1,2-diol moieties on
five-membered rings. Substrates lacking this motif (e.g.,
galactose, fucose, arabinose) gave rise to pyranosides, allowing
for boronic ester formation at either the 4,6- or 3,4-diol groups.
Glucose forms a particularly stable furanose-derived bis-boronic
ester,24 but this involves coordination of the anomeric OH
group and thus suppresses the formation of the reactive, open-
chain aldehyde form.25 Accordingly, glucose did not undergo
Fischer glycosidation in the presence of PhB(OH)2. By
employing N-acetylglucosamine in place of glucose, the
formation of a five-membered boronic ester involving the
anomeric OH group is prevented. Glycosidation reactivity was
restored, resulting in a mixture of furanoside and pyranoside
products. Formation of cyclic boronic esters via coordination of
1,3-diaxial OH groups has been documented.23,26 This
coordination mode may account for the formation of
pyranoside products from pentose substrates having an
1
accessible C4 chair conformer (xylose, ribose).
B
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Article
a
Scheme 2. Product Distributions for Boronic Acid Promoted Fischer Glycosidations of Hexoses and Pentoses with Octanol
a
Products were isolated as mixtures of isomeric glycosides. The yields of individual isomers were calculated by multiplying the overall yield by the
1
fraction of each isomer, as determined by H NMR spectroscopic analysis.
Computational modeling of glycoside-derived boronic esters
lent further support to the proposed intermediate structures
shown in Scheme 2 and to the idea that furanosides can be the
products of thermodynamic control in the presence of a
boronic acid (Figure 1). The relative gas-phase energies of ethyl
glycoside derived boronic esters were calculated using density
functional theory using the B3LYP functional and the 6-
31+G(d,p) basis set. These calculations were carried out for
each of the parent hexose and pentose substrates shown in
Scheme 2. The isomer corresponding to the major isolated
product from the reactions with n-octanol (indicated using the
gray boxes in Scheme 2) was calculated to be the lowest in
energy for six of the seven sugars. The exception was the ribose-
derived product, where the calculations suggested that the 2,4-
O-boronic ester of the pyranoside would be marginally more
stable, whereas the furanoside was the major product. A similar
issue appears to be at play for the reaction of D-xylose, where
the significant energy difference between pyranoside and
furanoside products suggested by the calculations is at odds
with the roughly 1:1 mixture that was obtained in the
experiment. In both cases, the product arising from a boronic
ester at 1,3-diaxial positions of the pyranoside 1C4 conformation
was formed to a lesser extent than would be expected based on
the calculated energies. One explanation for this behavior is that
the reactions are not fully under thermodynamic control and
that the formation of the pyranoside-derived products is
C
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sidation. The boronic acid mediated protocol was employed
to synthesize a range of glycoside products (Scheme 3).
Scheme 3. Synthesis of Glycosides by Boronic Acid
Promoted Condensation and Phase-Switching Workup
a
b
c
2 equiv of PhB(OH)2 was used. Heptane was used as the solvent. 2
equivalents of glycosyl acceptor was used.
Carbohydrate substrates that gave primarily one isomeric
glycoside, based on the product distribution data from Scheme
2, were selected for these preparative glycosidations. After
deprotection of the obtained boronic esters by washing with
aqueous basic sorbitol solution, the glycosides were purified by
column chromatography on silica gel. The phase-switching
deprotection also enables straightforward recovery of the
phenylboronic acid by acidification of the aqueous phase and
extraction with organic solvent. For example, the recovery of
PhB(OH)2 was 80% for the synthesis of octyl mannofuranoside
3a. The protocol enables the installation of anomeric
substituents that can serve as protective groups (benzyl
glycoside 3c) and/or precursors to glycosyl donors (pentenyl
glycoside 3d).27 The synthesis of dihydrocholesterol derivative
3b in heptane solvent is an example of a transformation that
would be difficult under conventional Fischer glycosidation
conditions. It is noteworthy that only 2 equiv of glycosyl
acceptor were employed in this reaction, which generates 5
equiv of water as a byproduct. The ability to obtain a 62% yield
of glycoside under such conditions presumably reflects the low
solubility of water in heptane, which may help to suppress the
rate of the reverse reaction.
The results of glycosidation reactions conducted in the
absence of PhB(OH)2 provided further evidence for the
important role played by the arylboronic acid promoter
(Scheme 3). Glycosidations of the D-mannose and D-galactose
did not proceed to an appreciable extent when PhB(OH)2 was
omitted, presumably due to the low solubility of these hexoses
in heptane and dichloroethane. The more soluble substrates
rhamnose and lyxose showed background reactivity under the
conditions shown in Scheme 3, but in both cases, the major
Figure 1. Calculated relative gas-phase energies of ethyl glycoside
derived boronic esters using density functional theory with the B3LYP
functional and the 6-31+G(d,p) basis set. The boxed structures
correspond to the major isomers obtained upon glycosidation with n-
octanol in DCE (Scheme 2). Isomers shown in gray were not obtained
from the glycosidation reactions with n-octanol shown in Scheme 2.
kinetically unfavorable because of the low concentration of the
1
pyranoside C4 conformer. It should also be noted that the
calculations do not provide quantitative agreement with the
observed stereochemical outcomes. Such agreement was not
anticipated, given that there are appreciable differences in steric
demand between ethyl and octyl groups and that gas-phase
calculations at this level of theory are unlikely to adequately
account for anomeric and other effects (thermodynamic or
kinetic) related to glycoside configuration.
Preparation of Glycosides and Selectively Acylated
Derivatives by Boronic Acid Promoted Fischer Glyco-
D
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product was the pyranoside rather than the furanoside that was
obtained in the presence of PhB(OH)2.
Scheme 5. Selective, Boronic Acid Mediated Glycosidation
of Mannose in the Presence of Glucose and/or Galactose
The boronic ester groups installed in the glycosidation
reaction can be exploited as protective groups for the one-pot
synthesis of partially functionalized glycoside derivatives
(Scheme 4). The intermediate boronic esters were treated
Scheme 4. Preparation of Partially Benzoylated
Carbohydrate Derivatives by Sequential Boronic Acid
Mediated Glycosidation and Acylation
1
distributions by H NMR spectroscopy. In a similar way, a
competition experiment between D-galactose and D-mannose
resulted in selective formation of the mannofuranoside. Finally,
selective glycosidation of a three-component mixture (3:1:1
mannose/glucose/galactose) was conducted, leading to a 65%
yield of 1a. This composition was chosen to mimic the sugar
content of softwood-derived hemicelluloses, a promising
renewable chemical resource.33 Selective reactions of this type
may be useful for synthesizing nonionic surfactants and other
value-added products from biomass-derived mixtures of
carbohydrates.
CONCLUSIONS
■
In summary, phenylboronic acid promotes Fischer glycosida-
tions in low-polarity organic solvents through the formation of
substrate-derived boronic esters. In addition to providing rate
acceleration, the arylboronic acid alters the course of the
reaction by selective promotion of a furanoside- or pyranoside-
selective pathway. Phase-switching deprotection enables
cleavage of the boronic esters that are generated as direct
products of these reactions, and facilitates the separation of the
glycoside and boronic acid components. Alternatively, the
boronic esters can serve as useful protected intermediates for
the synthesis of functionalized glycosides. Complexation of
particular diol groups by the boronic acid can also be used to
conduct selective transformations of mixtures of carbohydrates.
We anticipate that this approach will be amenable to other
selective transformations of sugars in organic solvents.
with excess benzoyl chloride and pyridine prior to phase-
switching deprotection, generating diol products 5 and 6a−d.
In each case, the site of benzoylation was consistent with the
structure of the glycoside-derived boronic ester depicted in
Scheme 2. Partially acylated glycosides having the substitution
patterns shown in Scheme 4 have been used as building blocks
in the synthesis of steroidal glycoside and oligosaccharide
natural products.28,29 Previous applications of boronic esters as
protective groups in carbohydrate chemistry suggest that it may
be possible to extend upon this result further by installing other
groups such as ethers, silyl ethers, and glycosyl moieties after
the glycosidation step.2,14,30−32
Another enabling feature of the arylboronic acid mediated
phase transfer protocol is the ability to conduct selective
glycosidations of mixtures of carbohydrates (Scheme 5). Not
only differences in affinity of the various carbohydrates for
phenylboronic acid, but also variations in the solubility (mono-
versus bis-boronates) or reactivity (accessibility of open-chain
isomer) of the substrate-derived boronic esters could
potentially give rise to selectivity in these types of competition
experiments. Indeed, the reaction of n-octanol with a 1:1
mixture of D-glucose and D-mannose in heptane solvent under
the optimized conditions gave a 65% yield of α-mannofurano-
side 1a, without detectable formation of glucose-derived
products. As described above for Scheme 1, acetylation was
employed to facilitate determination of yields and product
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under an argon
atmosphere, unless specifically indicated. Stainless steel needles and
gastight syringes were used to transfer air- and moisture-sensitive
liquids. Flash chromatography was performed using neutral silica gel.
Analytical TLC was carried out using aluminum-backed silica gel 60
F254 plates and visualized using short-wave UV light or KMnO4 stain
with appropriate heating.
Materials. Reagent grade 1,2-dichloroethane was obtained from a
sealed 1 L bottle under a balloon of argon. Distilled water was
obtained from an in-house supply. Commercially available phenyl-
boronic acid was recrystallized before using. All other commercially
available reagents and chemicals were used without further
purification.
Instrumentation. 1H and 13C NMR spectra were recorded in
CDCl3, d6-DMSO, or D2O solutions using a spectrometer equipped
with a 5 mm cryogenically cooled probe at 500 or 700 MHz (1H) and
126 MHz (13C) at ambient temperature. Chemical shifts are reported
E
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in parts per million (ppm) relative to tetramethylsilane with the
solvent resonance resulting from incomplete deuteration as the
internal standard. Spectral features are tabulated in the following
order: chemical shift (δ, ppm); multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, complex multiplet; app t-apparent triplet);
number of protons; coupling constants (J, Hz); assignment.
Assignments are based on analysis of coupling constants, COSY,
HSQC, and HMBC spectra. High-resolution mass spectra (HRMS)
were carried out using a time-of-flight mass spectrometer equipped
with a direct analysis in real time (DART) ion source. Attenuated total
reflectance infrared (IR) spectra were obtained in the solid form or as
a neat liquid, as indicated. Spectral features are tabulated as follows:
wavenumber (cm−1); intensity (s, strong; m, medium; w, weak; br,
broad). Specific rotations are reported in (deg·mL)/(g·dm) and
concentrations c in g/100 mL.
temperature. The excess benzoyl chloride was quenched with
methanol at 0 °C and stirred for 30 min at room temperature. The
reaction mixture was concentrated under reduced pressure and
subjected to the basic sorbitol workup described in general procedure
A but using EtOAc as the organic solvent. The combined organic
extracts were dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel.
Condensation of n-Octanol and D-Mannose (Scheme 2,
Products 1a and 2a). The reaction was conducted on a 0.2 mmol
scale (36.0 mg of D-mannose) according to general procedure A.
Dichloroethane was used as the reaction solvent, and diethyl ether was
used as solvent for the aqueous sorbitol workup. Purification was by
flash chromatography on silica gel (hexanes/ethyl acetate, 100:0 →
75:25). The mixture of glycosides was obtained as a colorless oil.
Combined yield = 62.1 mg, 0.135 mmol, 67%. Isomer Ratio (1H
NMR): 89:4:6 α-1a (H-3): β-1a (H-3): α-2a (H-1).
General Procedure A. Determination of product distributions for
phenylboronic acid-mediated Fischer glycosidation after phase-switch-
ing deprotection and peracetylation.
1
n-Octyl 2,3,5,6-Tetra-O-acetyl-α-D-mannofuranoside (α-1a). H
To a 2 dram vial containing a magnetic stir bar was added free sugar
(0.20 mmol, 1 equiv), (1S)-(+)-10-camphorsulfonic acid (CSA) (0.05
mmol, 0.25 equiv), and phenylboronic acid (0.2 mmol, 1 equiv or 0.4
mmol, 2 equiv) depending on the donor. Anhydrous 1,2-dichloro-
ethane or heptane was added to the vial (0.2 M, 1 mL), followed by n-
octanol (1.0 mmol, 5 equiv). The reaction mixture was purged with
argon, quickly capped, sealed with Teflon tape/parafilm, and stirred at
80 °C. After 24 h, the solvent was removed by rotary evaporation. The
residue was dissolved in roughly 50 mL of diethyl ether (Et2O). A
minimum amount of basic sorbitol solution (1 M Na2CO3 and 1 M D-
sorbitol in water) aqueous sorbitol solution was added (∼10 mL per
0.2 mmol boronic acid), and the mixture was shaken vigorously in a
separatory funnel for 5 min. The combined aqueous extracts were
back-extracted three times with Et2O. The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. Residual n-octanol was removed as an azeotrope
with water by adding roughly 2 mL of water and concentrating under
reduced pressure at 60 °C. The resulting residue was concentrated into
a 2 dram vial containing a magnetic stir bar. Acetic anhydride (1 mL)
and pyridine (1 mL) were added, and the mixture was stirred at room
temperature overnight. The reaction mixture was concentrated under
reduced pressure at 55 °C. Residual pyridine/acetic anhydride was
removed as an azeotrope with toluene by adding roughly 3 mL of
toluene and concentrating under reduced pressure at 55 °C. This
process was repeated twice. The composition of the mixture
(pyranoside/furanoside, α/β) was determined at this point by 1H
NMR analysis. The assignments of the resonances used to determine
the isomer ratios are reported for each case. The material was then
purified by flash chromatography on silica gel without an effort to
separate the isomeric glycosides. The combined yields are reported
below. When possible, a fraction containing a single product was
concentrated and used to obtain 1H and 13C NMR spectral data
(provided as Supporting Information), which were used for structural
assignments.
NMR (700 MHz, CDCl3): δ 5.56 (m, 1H, H-3), 5.26 (m, 1H, H-5),
5.16 (dd, J = 5.1, 2.9 Hz, 1H, H-2), 5.07 (d, J = 2.9 Hz, 1H, H-1), 4.54
(dd, J = 12.3, 2.3 Hz, 1H, H-6b), 4.35 (dd, J = 8.9, 4.4 Hz, 1H, H-4),
4.13 (dd, J = 12.3, 5.7 Hz, 1H, H-6a), 3.65 (m, 1H, n-octyl CH2), 3.41
(m, 1H, n-octyl CH2), 2.05 (s, 3H, −OAc), 2.05 (s, 3H, −OAc), 2.03
(s, 3H, −OAc), 2.00 (s, 3H, −OAc), 1.54 (m, 2H, n-octyl), 1.33−1.21
(m, 10 H, n-octyl), 0.87 (t, J = 7.0 Hz, 3H, n-octyl-CH3). 13C NMR
(126 MHz, CDCl3): δ 170.8, 169.8, 169.6, 169.6, 105.1, 76.4, 75.7,
70.8, 69.1, 68.4, 63.1, 31.9, 29.6, 29.5, 29.4, 26.1, 22.8, 20.9, 20.9, 20.6,
20.5, 14.2.
n-Octyl 2,3,5,6-Tetra-O-acetyl-β-D-mannofuranoside (β-1a). 1H
NMR (700 MHz, CDCl3): δ 5.61 (dd, J = 5.6, 5.0 Hz, 1H, H-3), 5.28
(m, 1H, H-5), 5.18 (d, J = 4.8 Hz, 1H, H-1), 4.94 (dd, J = 5.6, 4.8 Hz,
1H, H-2), 4.61 (dd, J = 12.3, 2.4 Hz, 1H, H-6a), 4.31 (dd, J = 9.5, 5.0
Hz, 1H, H-4), 4.17 (dd, J = 12.3, 4.6 Hz, 1H, H-6b), 3.72−3.64 (m,
1H, n-octyl CH2), 3.45 (m, 1H, n-octyl CH2), 2.08 (s, 3H, −OAc),
2.07 (s, 3H, −OAc), 2.07 (s, 3H, −OAc), 2.00 (s, 3H, −OAc), 1.66−
1.54 (m, 2H, n-octyl), 1.36−1.23 (m, 10H, n-octyl), 0.89 (m, 3H, n-
octyl-CH3). 13C NMR (126 MHz, CDCl3): δ 100.0 (C1).
1
n-Octyl 2,3,4,6-Tetra-O-acetyl-α-D-mannopyranoside (α-2a). H
NMR (700 MHz, CDCl3): δ 5.35 (dd, J = 10.0, 3.5 Hz, 1H, H-3), 5.27
(app t, J = 10.0 Hz, 1H, H-4), 5.23 (dd, J = 3.5, 1.8 Hz, 1H, H-2), 4.80
(d, J = 1.8 Hz, 1H, H-1), 4.28 (dd, J = 12.1, 5.3 Hz, 1H, H-6a), 4.11
(dd, J = 12.1, 2.4 Hz, 1H, H-6b), 3.98 (m, 1H, H-5), 3.72−3.64 (m,
1H, n-octyl CH2), 3.45 (m, 1H, n-octyl CH2), 2.15 (s, 3H, −OAc),
2.10 (s, 3H, −OAc), 2.04 (s, 3H, −OAc), 1.99 (s, 3H, −OAc), 1.66−
1.54 (m, 2H, n-octyl), 1.36−1.23 (m, 10H, n-octyl), 0.89 (m, 3H, n-
octyl-CH3). 13C NMR (126 MHz, CDCl3): δ 97.6 (C1) carbon shift is
consistent with the literature value.34 IR (thin film, cm−1): 1746 (s),
1371 (m), 1221 (s), 1034 (s). HRMS (DART+): calcd for
C22H40NO10 [M + NH4]+ 478.2652, found 478.2657.
Condensation of n-Octanol and D-Galactose (Scheme 2,
Products 2b). The reaction was conducted on 0.2 mmol scale (36.0
mg of D-galactose) according to general procedure A. Dichloroethane
was used as the reaction solvent, and diethyl ether was used as solvent
for the aqueous sorbitol workup. Purification was by flash
chromatography on silica gel (hexanes/ethyl acetate, 100:0 →
75:25). The mixture of glycosides was obtained as a colorless oil.
Combined yield = 55.6 mg, 0.121 mmol, 60%. Isomer ratio (1H
NMR): 69:26:5 α-2b (H-4):β-2b (H-4):acyclic dioctyl acetal by-
product.
General Procedure B. Phenylboronic acid mediated Fischer
glycosidation and phase-switching deprotection.
The glycosidation and phase-switching workup (using diethyl ether
or ethyl acetate as the organic solvent for the extraction) were
conducted as described in general procedure A. The combined organic
extracts were dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel.
1
n-Octyl 2,3,4,6-Tetra-O-acetyl-α-D-galactopyranoside (α-2b). H
General Procedure C. Synthesis of partially benzoylated glyco-
NMR (500 MHz, CDCl3): δ 5.45 (dd, J = 3.4, 1.4 Hz, 1H, H-4),
5.36−5.33 (m, 1H, H-3), 5.12−5.09 (m, 2H, H-2, H-1), 4.23−4.20
(m, 1H, H-5), 4.10 (dd, J = 11.3, 6.4 Hz, 1H, H-6a), 4.08 (dd, J = 11.3,
7.0 Hz, 1H, H-6b), 3.67 (dt, J = 9.8, 6.6 Hz, 1H, n-octyl CH2), 3.41
(dt, J = 9.8, 6.6 Hz, 1H, n-octyl CH2), 2.13 (s, 3H, −OAc), 2.07 (s, 3H,
−OAc), 2.04 (s, 3H, −OAc), 1.98 (s, 3H, −OAc), 1.58 (m, 2H, n-
octyl), 1.35−1.22 (m, 10H, n-octyl), 0.88 (t, J = 7.1 Hz, 3H, n-octyl
CH3). 13C NMR (126 MHz, CDCl3): δ 170.5, 170.5, 170.4, 170.2,
96.2, 68.8, 68.4, 68.3, 67.8, 66.3, 62.0, 31.9, 29.4, 29.4, 29.4, 26.2, 22.8,
sides by sequential Fischer glycosidation and acylation.
The glycosidation was conducted as described in general procedure
A. After 24 h, the solvent was removed by rotary evaporation. Residual
water and acceptor were removed as an azeotrope with toluene by
adding roughly 3 mL of toluene and concentrating under reduced
pressure at 50 °C. This process was repeated two to three times. The
resulting residue was dissolved in pyridine (0.5 M, 250 μL) and cooled
to 0 °C. Benzoyl chloride was added (2 equiv per free hydroxyl)
dropwise, and the reaction was stirred for 1.5 h as it warmed to room
F
DOI: 10.1021/acs.joc.7b01880
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
20.9, 20.8, 20.8, 20.8, 14.2. The spectral data is consistent with
previous reports.35
n-Octyl 2,3,4,6-Tetra-O-acetyl-β-D-galactopyranoside (β-2b). H
5.35 (dd, J = 5.4, 1.6 Hz, 1H), 5.28 (ddd, J = 9.4, 4.7, 2.4 Hz, 1H), 5.01
(d, J = 1.8 Hz, 1H), 4.61 (dd, J = 12.2, 2.4 Hz, 1H), 4.51 (dd, J = 9.3,
5.4 Hz, 1H), 4.17 (dd, J = 12.3, 4.8 Hz, 1H), 4.08−4.04 (m, 1H), 3.69
(dt, J = 9.5, 6.5 Hz, 1H), 3.43 (dt, J = 9.5, 6.5 Hz, 1H), 2.08 (s, 3H),
2.04 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.62−1.51 (m, 2H), 1.37−
1.23 (m, 12H), 0.90−0.86 (m, 3H). 13C NMR (126 MHz, CDCl3): δ
170.8, 170.0, 169.9, 169.7, 106.7, 75.2, 69.2, 69.1, 63.4, 62.2, 32.0, 29.7,
29.5, 29.4, 26.2, 22.8, 21.0, 14.3. IR (thin film, cm−1): 3312 (br, w),
1745 (s), 1667 (m), 1370 (s), 1225 (s), 1032 (s). HRMS (DART+):
calcd for C22H38NO9 [M + H]+ 460.2547, found 460.2555.
Condensation of n-Octanol and L-Rhamnose (Scheme 2,
Products 1e and 2e). The reaction was conducted on 0.2 mmol scale
(36.4 mg of L-rhamnose monohydrate) according to general procedure
A. Dichloroethane was used as the reaction solvent, and diethyl ether
was used as solvent for the aqueous sorbitol workup. Purification was
by flash chromatography on silica gel (hexanes/ethyl acetate, 100:0 →
75:25). The mixture of glycosides was obtained as a colorless oil.
Combined yield = 63.5 mg, 0.158 mmol, 79%. Isomer ratio (1H
NMR): 83:8:8:1 α-1e (H-3):β-1e (H-3):α-2e (H-1):β-2e (H-2).
n-Octyl 2,3,5-tri-O-acetyl-α-L-rhamnofuranoside (α-1e). 1H NMR
(500 MHz, CDCl3): δ 5.56 (app t, J = 4.7 Hz, 1H, H-3), 5.15 (dd, J =
5.2, 3.0 Hz, 1H, H-2), 5.10−5.04 (m, 2H, H-1, H-5), 4.13 (dd, J = 8.6,
4.3 Hz, 1H, H-4), 3.67 (dt, J = 9.5, 6.7 Hz, 1H, n-octyl CH2), 3.43 (dt,
J = 9.5, 6.6 Hz, 1H, n-octyl CH2), 2.04 (s, 3H, −OAc), 2.03 (s, 3H,
−OAc), 1.97 (s, 3H, −OAc), 1.59−1.52 (m, 2H, n-octyl), 1.31 (d, J =
6.2 Hz, 3H, rhamno-CH3), 1.29−1.20 (m, 10H, n-octyl), 0.87 (t, J =
7.0 Hz, 3H, n-octyl-CH3). 13C NMR (126 MHz, CDCl3): δ 170.0,
169.7, 169.6, 105.0, 79.8, 76.7, 70.9, 69.0, 67.5, 31.9, 29.6, 29.4, 29.4,
26.1, 22.8, 21.2, 20.6, 20.5, 17.5, 14.2.
1
NMR (500 MHz, CDCl3): δ 5.37 (dd, J = 3.5, 1.2 Hz, 1H, H-4), 5.19
(dd, J = 10.5, 8.0 Hz, 1H, H-2), 5.01 (dd, J = 10.5, 3.5 Hz, 1H, H-3),
4.44 (d, J = 8.0 Hz, 1H, H-1), 4.17 (dd, J = 11.2, 6.4 Hz, 1H, H-6a),
4.12 (dd, J = 11.2, 7.1 Hz, 1H, H-6b), 3.91−3.85 (m, 2H, H-5, n-octyl
CH2), 3.46 (m, 1H, n-octyl CH2), 2.14 (s, 3H, −OAc), 2.04 (s, 3H,
−OAc), 2.04 (s, 3H, −OAc), 1.97 (s, 3H, −OAc), 1.64−1.48 (m, 2H,
n-octyl), 1.33−1.20 (m, 10H, n-octyl), 0.87 (t, J = 7.1 Hz, 3H, n-octyl
CH3). 13C NMR (126 MHz, CDCl3): 170.5, 170.4, 170.3, 169.5,
101.5, 71.1, 70.7, 70.4, 69.1, 67.2, 61.4, 31.9, 29.5, 29.4, 29.4, 25.9,
22.8, 20.9, 20.8, 20.7, 14.2.
Condensation of n-Octanol and D-Allose (Scheme 2, Product 1c).
The reaction was conducted on 0.2 mmol scale (36.0 mg of D-allose)
according to general procedure A. Dichloroethane was used as the
reaction solvent, and diethyl ether was used as solvent for the aqueous
sorbitol workup. Purification was by flash chromatography on silica gel
(hexanes/ethyl acetate, 100:0 → 75:25). The mixture of glycosides
was obtained as a colorless oil. Yield = 57.1 mg, 0.124 mmol, 62%.
Isomer ratio (1H NMR): 93:7 α-1c (H-3):unidentified glycoside.
n-Octyl 2,3,5,6-Tetra-O-acetyl-β-D-allofuranoside (α-1c). 1H
NMR (700 MHz, CDCl3): δ 5.48 (dd, J = 6.5, 4.9 Hz, 1H, H-3),
5.20 (dd, J = 4.9, 1.0 Hz, 1H, H-2), 5.14 (ddd, J = 6.7, 5.7, 3.2 Hz, 1H,
H-5), 4.98 (d, J = 1.0 Hz, 1H, H-1), 4.44 (dd, J = 12.2, 3.2 Hz, 1H, H-
6a), 4.22 (app t, J = 6.6 Hz, 1H, H-4), 4.12 (dd, J = 12.2, 5.7 Hz, 1H,
H-6b), 3.67 (dt, J = 9.4, 6.7 Hz, 1H, n-octyl CH2), 3.37 (dt, J = 9.4, 6.8
Hz, 1H, n-octyl CH2), 2.10 (s, 3H, −OAc), 2.06 (s, 3H, −OAc), 2.05
(s, 6H, 2 × −OAc), 1.55 (m, 2H, n-octyl), 1.34−1.22 (m, 10 H, n-
octyl), 0.87 (t, J = 7.1 Hz, 3H, n-octyl CH3). 13C NMR (126 MHz,
CDCl3): δ 170.6, 169.9, 169.7, 169.4, 105.6, 78.7, 75.1, 72.1, 71.9, 68.9,
62.6, 31.9, 29.4, 29.4, 29.3, 26.1, 22.7, 20.9, 20.8, 20.7, 20.6, 14.2. IR
(thin film, cm−1): 1747 (s), 1371 (m), 1220 (s), 1042 (br, s). HRMS
(DART+): calcd for C22H40NO10 [M + NH4]+ 478.2652, found
478.2649.
n-Octyl 2,3,5-Tri-O-acetyl-β-L-rhamnofuranoside (β-1e). 1H NMR
(500 MHz, CDCl3): δ 5.60 (dd, J = 5.6, 4.9 Hz, 1H, H-3), 5.16 (d, J =
4.9 Hz, 1H, H-1), 5.11 (dd, J = 9.1, 6.2 Hz, 1H, H-5), 4.93 (dd, J = 5.6,
4.9 Hz, 1H, H-2), 4.02 (dd, J = 9.1, 4.9 Hz, 1H, H-4), 3.68 (dt, J = 9.7,
6.7 Hz, 1H, n-octyl CH2), 3.40 (dt, J = 9.7, 6.5 Hz, 1H, n-octyl CH2),
2.07 (s, 3H, −OAc), 2.06 (s, 3H, −OAc), 1.97 (s, 3H, −OAc), 1.61−
1.52 (m, 2H, n-octyl), 1.34 (d, J = 6.2 Hz, 3H, rhamno-CH3), 1.33−
1.22 (m, 10H, n-octyl), 0.90−0.86 (m, 3H, n-octyl-CH3). 13C NMR
(126 MHz, CDCl3): δ 170.3, 170.1, 169.9, 100.0, 79.9, 72.0, 68.9, 68.8,
68.5, 32.0, 29.7, 29.4, 29.4, 26.2, 22.8, 21.2, 20.7, 20.7, 17.6, 14.2.
n-Octyl 2,3,4-Tri-O-acetyl-α-L-rhamnopyranoside (α-2e). Minor
peaks as a mixture with the α-1e. 1H NMR (500 MHz, CDCl3): δ 5.29
(dd, J = 10.1, 3.5 Hz, 1H, H-3), 5.21 (dd, J = 3.5, 1.8 Hz, 1H, H-2),
4.70 (d, J = 1.7 Hz, 1H, H-1). 13C NMR (126 MHz, CDCl3): δ 170.3,
170.2, 170.1, 97.5, 71.4, 70.2, 69.3, 68.4, 66.3. NMR spectroscopy data
for n-octyl 2,3,4-tri-O-acetyl-α-L-rhamnopyranoside is consistent with
previously reported.36
Condensation of n-Octanol and N-Acetyl-D-glucosamine
(Scheme 2, Products 1d and 2d). The reaction was conducted
on 0.2 mmol scale (42.4 mg of N-acetyl-D-glucosamine) according to
general procedure A. Dichloroethane was used as the reaction solvent,
and diethyl ether was used as solvent for the aqueous sorbitol workup.
Purification was by flash chromatography on silica gel (hexanes/ethyl
acetate, 100:0 → 75:25). The mixture of glycosides was obtained as a
colorless oil. Combined yield = 37.6 mg, 0.082 mmol, 41%. Isomer
ratio (1H NMR): 33:12:55 α-1d (H-3):β-1d (H-3):α-2d (H-1).
n-Octyl-2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-α-D-glucopyra-
1
noside (α-2d). H NMR (700 MHz, CDCl3): δ 5.64 (d, J = 9.5 Hz,
n-Octyl 2,3,4-Tri-O-acetyl-β-L-rhamnopyranoside (β-2e). Minor
peaks as a mixture with the β-1e. 1H NMR (500 MHz, CDCl3): δ 5.45
(dd, J = 3.2, 1.1 Hz, 1H, H-2), 5.08−5.03 (m, 1H, H-4), 4.99 (dd, J =
10.1, 3.3 Hz, 1H, H-3), 4.59 (d, J = 1.1 H-1), 3.84 (dt, J = 9.3, 6.7 Hz,
1H, n-octyl CH2), 3.54−3.43 (m, 2H, H-5, n-octyl CH2). 13C NMR
(126 MHz, CDCl3): δ 170.6, 170.3, 170.0, 98.5, 71.4, 70.9, 70.7, 70.4,
69.3. IR (thin film, cm−1): 1748 (s), 1372 (m), 1228 (s), 1031 (s).
HRMS (DART+): calcd for C20H38NO8 [M + NH4]+ 420.2597, found
420.2601.
1H, NH), 5.20 (dd, J = 10.7, 9.4 Hz, 1H, H-3), 5.10 (dd, J = 10.2, 9.4
Hz, 1H, H-4), 4.81 (d, J = 3.7 Hz, 1H, H-1), 4.32 (ddd, J = 10.7, 9.4,
3.7 Hz, 1H, H-2), 4.22 (dd, J = 12.3, 4.6 Hz, 1H, H-6a), 4.08 (dd, J =
12.3, 2.4 Hz, 1H, H-6b), 3.93 (ddd, J = 10.2, 4.6, 2.4 Hz, 1H, H-5),
3.67 (dt, J = 9.8, 6.8 Hz, 1H, n-octyl CH2), 3.42 (dt, J = 9.8, 6.8 Hz,
1H, n-octyl CH2), 2.08 (s, 3H, −OAc), 2.02 (s, 3H, −OAc), 2.01 (s,
3H, −OAc), 1.62−1.57 (m, 2H, n-octyl), 1.37−1.21 (m, 12H, n-octyl),
0.88 (t, J = 7.1 Hz, 3H, n-octyl). 13C NMR (126 MHz, CDCl3): δ
171.5, 170.8, 169.9, 169.4, 97.3, 71.6, 68.7, 68.3, 67.8, 62.2, 52.0, 31.9,
29.4, 29.4, 29.4, 26.3, 23.4, 22.8, 20.9, 20.9, 20.8, 14.2.
Condensation of n-Octanol and D-Fucose (Scheme 2,
Product 2f). The reaction was conducted on 0.2 mmol scale (32.8
mg of D-fucose) according to general procedure A. Dichloroethane was
used as the reaction solvent, and diethyl ether was used as solvent for
the aqueous sorbitol workup. Purification was by flash chromatography
on silica gel (hexanes/ethyl acetate, 100:0 → 75:25). The mixture of
glycosides was obtained as a colorless oil. Combined yield = 49.1 mg,
0.122 mmol, 61%. Isomer Ratio (1H NMR): 70:23:7 α-2f (H-3): β-2f
(H-3): acyclic dioctyl acetal byproduct.
n-Octyl-2-acetamido-2-deoxy-3,5,6-tri-O-acetyl-α-D-glucofura-
1
noside (α-1d). H NMR (700 MHz, CDCl3): δ 6.01 (d, J = 7.7 Hz,
1H, NH), 5.41 (dd, J = 5.9, 4.4 Hz, 1H, H-3), 5.22 (ddd, J = 8.3, 5.6,
2.5 Hz, 1H, H-5), 5.09 (d, J = 5.2 Hz, 1H, H-1), 4.51 (dd, J = 12.2, 2.5
Hz, 1H, H-6a), 4.45 (ddd, J = 7.7, 5.2, 4.4 Hz, 1H, H-2), 4.29 (dd, J =
8.3, 5.9 Hz, 1H, H-4), 4.15 (dd, J = 12.2, 5.6 Hz, 1H, H-6b), 3.70 (dt, J
= 9.7, 6.6 Hz, 1H, n-octyl CH2), 3.45 (dt, J = 9.7, 6.6 Hz, 1H, n-octyl
CH2), 2.05 (s, 6H, 2 × -OAc), 2.00 (s, 3H, −OAc), 1.98 (s, 3H,
−OAc), 1.58 (m, 2H, n-octyl), 1.36−1.21 (m, 12H, n-octyl), 0.88 (t, J
= 7.1 Hz, 3H, n-octyl CH3). 13C NMR (126 MHz, CDCl3): δ 170.7,
170.0, 170.0, 169.9, 100.0, 76.0, 74.6, 68.6, 68.4, 63.1, 58.6, 31.9, 29.6,
29.5, 29.5, 29.4, 26.3, 23.3, 22.8, 21.0, 20.9, 20.9, 14.2.
n-Octyl 2,3,4-Tri-O-acetyl-α-D-fucopyranoside (α-2f). 1H NMR
(500 MHz, CDCl3): δ 5.35 (dd, J = 10.9, 3.4 Hz, 1H, H-3), 5.29 (dd, J
= 3.4, 1.3 Hz, 1H, H-4), 5.10 (dd, J = 10.9, 3.7 Hz, 1H, H-2), 5.04 (d, J
= 3.7 Hz, 1H, H-1), 4.15 (dq, J = 6.5, 6.0, 1.0 Hz, 1H, H-5), 3.66 (dt, J
= 9.8, 6.5 Hz, 1H, n-octyl CH2), 3.40 (dt, J = 9.8, 6.6 Hz, 1H, n-octyl
CH2), 2.16 (s, 3H, −OAc), 2.06 (s, 3H, −OAc), 1.98 (s, 3H, −OAc),
n-Octyl-2-acetamido-2-deoxy-3,5,6-tri-O-acetyl-β-D-glucofura-
1
noside (β-1d). H NMR (700 MHz, CDCl3): δ 5.63 (s, 1H, N-H),
G
DOI: 10.1021/acs.joc.7b01880
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The Journal of Organic Chemistry
Article
1.57 (m, 2H, n-octyl), 1.37−1.23 (m, 10H, n-octyl), 1.13 (d, J = 6.6
Hz, 3H, fucose-CH3), 0.88 (t, J = 7.1 Hz, 3H, n-octylCH3). 13C NMR
(126 MHz, CDCl3): δ 170.8, 170.6, 170.2, 96.2, 71.4, 68.7, 68.5, 68.3,
64.3, 32.0, 29.5, 29.4, 29.4, 26.2, 22.8, 21.0, 20.9, 20.8, 16.0, 14.2.
n-Octyl 2,3,4-Tri-O-acetyl-β-D-fucopyranoside (β-2f). 1H NMR
(500 MHz, CDCl3): δ 5.22 (dd, J = 3.5, 1.2 Hz, 1H, H-4), 5.18 (dd, J
= 10.5, 8.0 Hz, 1H, H-2), 5.01 (dd, J = 10.5, 3.5 Hz, 1H, H-3), 4.41 (d,
J = 8.0 Hz, 1H, H-1), 3.89 (m, 1H, n-octyl CH2), 3.79 (qd, J = 6.4, 1.2
Hz, 1H, H-5), 3.44 (m, 1H, n-octyl CH2), 2.16 (s, 3H, −OAc), 2.04 (s,
3H, −OAc), 1.98 (s, 3H, −OAc), 1.64−1.50 (m, 2H, n-octyl), 1.36−
1.23 (m, 10H, n-octyl), 1.22 (d, J = 6.4 Hz, 3H, fucose-CH3), 0.87 (t, J
= 7.1 Hz, 3H, n-octyl-CH3). 13C NMR (126 MHz, CDCl3): δ 170.9,
170.4, 169.6, 101.3, 71.5, 70.5, 70.2, 69.2, 69.2, 31.9, 29.5, 29.4, 29.4,
26.0, 22.8, 20.9, 20.9, 20.8, 16.2, 14.2. IR (thin film, cm−1): 1745 (s),
1369 (m), 1221 (s), 1048 (br, s). HRMS (DART+): calcd for
C20H38NO8 [M + NH4]+ 420.2597, found 420.2597.
Condensation of n-Octanol and D-Lyxose (Scheme 2,
Product 1g). The reaction was conducted on 0.2 mmol scale (30.0
mg of D-lyxose) according to general procedure A. Dichloroethane was
used as the reaction solvent, and diethyl ether was used as solvent for
the aqueous sorbitol workup. Purification was by flash chromatography
on silica gel (hexanes/ethyl acetate, 100:0 → 75:25). The mixture of
glycosides was obtained as a colorless oil. Combined yield = 48.4 mg,
0.125 mmol, 62%. Isomer ratio (1H NMR): 91:6:3 α-1g (H-2):β-1g
(H-4):unidentified glycoside.
6.4 Hz, 1H, n-octyl CH2), 3.61 (dd, J = 13.0, 1.8 Hz, 1H, H-5b), 3.44
(dt, J = 9.6, 6.7 Hz, 1H, n-octyl CH2), 2.12 (s, 3H, −OAc), 2.05 (m,
3H, −OAc), 2.01 (s, 3H, −OAc), 1.56 (m, 2H, n-octyl), 1.35−1.21 (m,
10H, n-octyl), 0.87 (t, J = 7.0 Hz, 3H, n-octyl-CH3). 13C NMR (126
MHz, CDCl3): δ 170.5, 170.3, 169.5, 101.1, 70.4, 69.9, 69.4, 67.9, 63.2,
31.9, 29.6, 29.4, 29.4, 26.0, 22.8, 21.1, 20.9, 20.8, 14.2. IR (thin film,
cm−1): 1745 (s), 1371 (m), 1219 (s), 1062 (s), 1011 (s). HRMS
(DART+): calcd for C19H36NO8 [M + NH4]+ 406.2441, found
406.2436.
Condensation of n-Octanol and D-Xylose (Scheme 2,
Products 1i and 2i). The reaction was conducted on 0.2 mmol
scale (30.0 mg of D-xylose) according to general procedure A.
Dichloroethane was used as the reaction solvent, and diethyl ether was
used as solvent for the aqueous sorbitol workup. Purification was by
flash chromatography on silica gel (hexanes/ethyl acetate, 100:0 →
75:25). The mixture of glycosides was obtained as a colorless oil.
Combined yield = 46.8 mg, 0.121 mmol, 60%. Isomer Ratio (1H
NMR): 29:19:13:39 α-1i (H-5a):β-1i (H-3):α-2i (H-1):β-2i (H-5b).
n-Octyl 2,3,4-Tri-O-acetyl-α-D-xylopyranoside (α-2i). 1H NMR
(500 MHz, CDCl3): δ 5.48 (app t, J = 9.8 Hz, 1H, H-3), 4.99 (d, J =
3.7 Hz, 1H, H-1), 4.98−4.93 (m, 1H, H-4), 4.78 (dd, J = 10.1, 3.7 Hz,
1H, H-2), 3.76 (dd, J = 10.9, 5.9 Hz, 1H, H-5a), 3.67 (dt, J = 9.8, 6.6
Hz, 1H, n-octyl CH2), 3.62 (app t, J = 10.8 Hz, 1H, H-5b), 3.38 (dt, J
= 9.8, 6.7 Hz, 1H, n-octyl CH2), 2.06 (s, 3H, −OAc), 2.03 (s, 6H,
−OAc), 1.62−1.56 (m, 2H, n-octyl), 1.40−1.23 (m, 10H, n-octyl),
0.88 (t, J = 7.0 Hz, 3H, n-octyl-CH3). 13C NMR (126 MHz, CDCl3): δ
170.4, 170.2, 170.1, 95.7, 71.3, 69.9, 69.7, 68.7, 58.4, 32.0, 29.4, 29.4,
29.4, 26.2, 22.8, 20.9, 20.9, 20.9, 14.2.
n-Octyl 2,3,5-Tri-O-acetyl-α-D-lyxofuranoside (α-1g). 1H NMR
(500 MHz, CDCl3): δ 5.58 (m, 1H, H-3), 5.20 (dd, J = 5.2, 1.7 Hz,
1H, H-2), 5.05 (d, J = 1.7 Hz, 1H, H-1), 4.46 (m, 1H, H-4), 4.24 (dd, J
= 11.7, 4.7 Hz, 1H, H-5a), 4.18 (dd, J = 11.7, 7.4 Hz, 1H, H-5b), 3.69
(m, 1H,, n-octyl CH2), 3.41 (m, 1H,, n-octyl CH2), 2.08 (s, 3H,
−OAc), 2.07 (s, 3H, −OAc), 2.07 (s, 3H, −OAc), 1.55 (m, 2H, n-
octyl), 1.33−1.21 (m, 10 H, n-octyl), 0.87 (t, J = 7.0 Hz, 3H, n-octyl-
CH3). 13C NMR (126 MHz, CDCl3): δ 170.8, 169.8, 169.6, 104.6,
75.6, 75.2, 71.3, 68.6, 63.2, 31.9, 29.6, 29.4, 29.3, 26.1, 22.8, 21.0, 20.7,
20.6, 14.2.
n-Octyl 2,3,5-Tri-O-acetyl-α-D-xylofuranoside (α-1i). 1H NMR
(500 MHz, CDCl3): δ 5.53 (app t, J = 6.3 Hz, 1H, H-3), 5.24 (d, J =
4.6 Hz, 1H, H-1), 4.94 (dd, J = 5.9, 4.6 Hz, 1H, H-2), 4.49−4.46 (m,
1H, H-4), 4.19 (dd, J = 12.0, 5.4 Hz, 1H, H-5a), 4.11 (dd, J = 12.0, 4.6
Hz, 1H, H-5b), 3.70 (dt, J = 9.6, 6.5 Hz, 1H, n-octyl CH2), 3.40−3.36
(m, 1H, n-octyl CH2), 2.09 (s, 3H, −OAc), 2.08 (s, 3H, −OAc), 2.07
(s, 3H, −OAc), 1.60−1.48 (m, 2H, n-octyl), 1.36−1.18 (m, 10H, n-
octyl), 0.88−0.86 (t, J = 7.0 Hz, 3H, n-octyl-CH3). 13C NMR (126
MHz, CDCl3): δ 170.7, 170.4, 170.4, 99.2, 77.3, 75.0, 73.4, 68.9, 62.1,
32.0, 29.6, 29.4, 29.4, 26.1, 22.8, 21.0, 20.8, 20.7, 14.2.
n-Octyl 2,3,5-Tri-O-acetyl-β-D-lyxofuranoside (β-1g). 1H NMR
(500 MHz, CDCl3): δ 5.59 (app t, J = 5.9 Hz, 1H, H-3), 5.17 (d, J =
4.7 Hz, 1H, H-1), 4.99 (dd, J = 6.2, 4.8 Hz, 1H, H-2), 4.39 (m, 1H, H-
4), 4.28 (dd, J = 11.5, 5.4 Hz, 1H, H-5a), 4.22 (dd, J = 11.5, 7.5 Hz,
1H, H-5b), 3.72 (m, 1H,, n-octyl CH2), 3.42 (m, 1H,, n-octyl CH2),
2.11 (s, 3H, −OAc), 2.08 (s, 3H, −OAc), 2.07 (s, 3H, −OAc), 1.56 (m,
2H, n-octyl), 1.37−1.22 (m, 10 H, n-octyl), 0.88 (t, J = 7.0 Hz, 3H, n-
octylCH3). 13C NMR (126 MHz, CDCl3): δ 170.8, 170.2, 170.0,
100.0, 75.9, 71.6, 69.1, 68.8, 63.7, 32.0, 29.6, 29.5, 29.4, 26.2, 22.8,
21.0, 20.8, 20.7, 14.2. IR (thin film, cm−1): 1747 (s), 1371 (m), 1223
(s), 1091 (s), 1032 (s). HRMS (DART+): calcd for C19H36NO8 [M +
NH4]+ 406.2441, found 406.2444.
n-Octyl 2,3,5-Tri-O-acetyl-β-D-xylofuranoside (β-1i). 1H NMR
(500 MHz, CDCl3): δ 5.32 (broad dd, J = 6.0 Hz, 1H, H-3), 5.09
(broad s, 1H, H-2), 4.96 (broad s, 1H, H-1), 4.57 (m, 1H, H-4), 4.27
(dd, J = 11.6, 5.5 Hz, 1H, H-5a), 4.22 (dd, J = 11.6, 7.3 Hz, 1H, H5b),
3.72−3.67 (m, 1H, n-octyl CH2), 3.43−3.39 (m, 1H, n-octyl CH2),
2.11−2.02 (m, 9H, −OAc), 1.56 (m, 2H, n-octyl), 1.39−1.18 (m, 10H,
n-octyl), 0.88 (t, J = 7.0 Hz, 3H, n-octyl-CH3).
n-Octyl 2,3,4-Tri-O-acetyl-β-D-xylopyranoside (β-2i). 1H NMR
(500 MHz, CDCl3): δ 5.15 (app t, J = 8.6 Hz, 1H, H-3), 4.96−4.93
(m, 1H, H-4), 4.91 (dd, J = 8.6, 6.8 Hz, 1H, H-2), 4.46 (d, J = 6.8 Hz,
1H, H-1), 4.11 (dd, J = 11.9, 5.1 Hz, 1H, H-5a), 3.80 (m, 1H, n-octyl
CH2), 3.45 (m, 1H, n-octyl CH2), 3.35 (dd, J = 11.9, 8.8 Hz, 1H, H-
5b), 2.11−2.02 (m, 9H, −OAc), 1.56 (m, 2H, n-octyl), 1.39−1.18 (m,
10H, n-octyl), 0.88 (t, J = 7.0 Hz, 3H, n-octyl-CH3). 13C NMR (126
MHz, CDCl3): (mixture of products) δ 170.7, 170.3, 170.0, 170.0,
169.6, 169.5, 106.0 (β-D-fur C-1), 100.8 (β-D-pyr C1), 80.9, 78.1,
75.1, 71.6, 71.0, 69.9, 69.1, 68.4, 63.4, 62.1, 32.0, 32.0, 29.6, 29.6, 29.5,
29.4, 29.4, 26.2, 26.0, 22.8, 21.0, 20.9, 20.9, 20.9, 20.9, 20.8, 14.2, 14.2.
IR (thin film, cm−1): 1747 (s), 1369 (m), 1217 (s), 1043 (br, s).
HRMS (DART+): calcd for C19H36NO8 [M + NH4]+ 406.2441, found
406.2437.
Condensation of n-Octanol and D-Arabinose (Scheme 2,
Product 2h). The reaction was conducted on 0.2 mmol scale (30.0
mg of D-arabinose) according to general procedure A. Dichloroethane
was used as the reaction solvent, and diethyl ether was used as solvent
for the aqueous sorbitol workup. Purification was by flash
chromatography on silica gel (hexanes/ethyl acetate, 100:0 →
75:25). The mixture of glycosides was obtained as a colorless oil.
Combined yield = 72.9 mg, 0.188 mmol, 94%. Isomer ratio (1H
NMR): 22:62:12:4 α-2h (H-3):β-2h (H-1):acyclic dioctyl acetal
byproduct:unidentified glycoside.
n-Octyl 2,3,4-Tri-O-acetyl-β-D-arabinopyranoside (β-2h). 1H
NMR (500 MHz, CDCl3): δ 5.37−5.33 (m, 2H, H-3. H-4), 5.14
(dd, J = 10.1, 3.6 Hz, 1H, H-2), 5.06 (d, J = 3.6 Hz, 1H, H-1), 3.95
(dd, J = 13.0, 1.5 Hz, 1H, H-5a), 3.70−3.63 (m, 2H, H-5b, n-octyl
CH2), 3.39 (dt, J = 9.8, 6.6 Hz, 1H, n-octyl CH2), 2.14 (s, 3H, −OAc),
2.07 (s, 3H, −OAc), 2.01 (s, 3H, −OAc), 1.61−1.54 (m, 2H, n-octyl),
Condensation of n-Octanol and D-Ribose (Scheme 2,
Products 1j and 2j). The reaction was conducted on 0.2 mmol
scale (30.0 mg of D-ribose) according to general procedure A.
Dichloroethane was used as the reaction solvent, and diethyl ether was
used as solvent for the aqueous sorbitol workup. Purification was by
flash chromatography on silica gel (hexanes/ethyl acetate, 100:0 →
75:25). The mixture of glycosides was obtained as a colorless oil.
Combined yield = 52.5 mg, 0.135 mmol, 68%. Isomer ratio (1H
NMR): 4:75:21 α-1j (H-3):β-1j (H-3): β-2j (H-1).
1.37−1.24 (m, 10H, n-octyl), 0.88 (t, J = 7.1 Hz, 3H, n-octyl-CH3). 13
C
NMR (126 MHz, CDCl3): δ 170.6, 170.6, 170.2, 96.5, 69.4, 68.7, 68.7,
67.5, 60.4, 32.0, 29.5, 29.5, 29.4, 26.2, 22.8, 21.1, 21.0, 20.9, 14.2.
n-Octyl 2,3,4-Tri-O-acetyl-α-D-arabinopyranoside (α-2h). 1H
NMR (500 MHz, CDCl3): δ 5.24 (m, 1H, H-4), 5.17 (dd, J = 9.3,
6.9 Hz, 1H, H-2), 5.03 (dd, J = 9.3, 3.5 Hz, 1H, H-3), 4.39 (d, J = 6.9
Hz, 1H, H-1), 4.01 (dd, J = 13.0, 3.4 Hz, 1H, H-5a), 3.84 (dt, J = 9.6,
n-Octyl 2,3,5-Tri-O-acetyl-β-D-ribofuranoside (β-1j). 1H NMR
(500 MHz, CDCl3): δ 5.33 (dd, J = 6.9, 4.8 Hz, 1H, H-3), 5.24−
H
DOI: 10.1021/acs.joc.7b01880
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The Journal of Organic Chemistry
Article
5.22 (dd, J = 4.8, 1.0 Hz, 1H, H-2), 4.98 (d, J = 1.0 Hz, 1H, H-1), 4.33
(dd, J = 11.7, 3.9 Hz, 1H, H-5a), 4.30−4.26 (m, 1H, H-4), 4.11 (dd, J
= 11.7, 6.1 Hz, 1H, H-5b), 3.70 (dt, J = 9.4, 6.7 Hz, 1H, n-octyl CH2),
3.37 (dt, J = 9.4, 6.7 Hz, 1H, n-octyl CH2), 2.11 (s, 3H, −OAc), 2.09
(s, 3H, −OAc), 2.05 (s, 3H, −OAc), 1.58−1.51 (m, 2H, n-octyl),
18.5, 12.0, 11.9. IR (thin film, cm−1): 3329 (br, m), 2931 (s), 1082
(m), 1010 (s). HRMS (DART+): calcd for C33H62NO6 [M + NH4]+
20
568.4577, found 568.4580. [α]D +71 (c 0.28, CHCl3/MeOH 1:1).
Benzyl α-L-Rhamnofuranoside (3c). The reaction was conducted
on 0.2 mmol scale (36.4 mg of L-rhamnose monohydrate) according to
general procedure B. Dichloroethane was used as the reaction solvent,
and ethyl acetate was used as solvent for the aqueous sorbitol workup.
Purification was by flash chromatography on silica gel (hexanes/ethyl
acetate, 85:15 → 0:100). The title compound was obtained as a
colorless oil. Yield = 30.4 mg, 0.120 mmol, 60%. 1H NMR (700 MHz,
D2O): 7.49−7.41 (m, 5H, aromatic CH), 5.18 (d, J = 4.2 Hz, 1H, H-
1), 4.81 (d, J = 11.5 Hz, 1H, benzyl CH2), 4.68 (d, J = 11.5 Hz, 1H,
benzyl CH2), 4.36 (dd, J = 4.7, 3.1 Hz, 1H, H-3), 4.21 (dd, J = 4.7, 4.2
Hz, 1H, H-2), 4.06 (dq, J = 8.1, 6.3 Hz, 1H, H-5), 3.92 (dd, J = 8.1, 3.1
Hz, 1H, H-4), 1.28 (d, J = 6.3 Hz, 3H, CH3). 13C NMR (126 MHz,
D2O): δ 136.8, 128.7, 128.4, 128.3, 106.9, 83.5, 76.9, 71.0, 70.9, 64.8,
19.1. 13C NMR chemical shifts were consistent with previous reports.38
1.33−1.23 (m, 10H, n-octyl), 0.88 (t, J = 7.1 Hz, 3H, n-octyl CH3). 13
C
NMR (126 MHz, CDCl3): δ 170.8, 169.8, 169.8, 105.4, 78.4, 74.9,
71.8, 68.5, 65.0, 32.0, 29.6, 29.5, 29.3, 26.2, 22.8, 20.9, 20.8, 20.7, 14.2.
n-Octyl 2,3,5-Tri-O-acetyl-α-D-ribofuranoside (α-1j). 1H NMR
(500 MHz, CDCl3): δ 5.24 (d, J = 4.5 Hz, 1H, H-1), 5.14 (m, J = 7.3,
4.2 Hz, 1H, H-3), 4.95 (dd, J = 7.3, 4.5 Hz, 1H, H-2), 4.36 (dd, J =
12.0, 3.1 Hz, 1H, H-5a), 4.28−4.25 (m, 1H, H-4), 4.20 (dd, J = 12.0,
4.2 Hz, 1H, H-5b), 3.72 (m, 1H, n-octyl CH2), 3.48 (m, 1H, n-octyl
CH2), 2.12 (s, 3H, −OAc), 2.11 (s, 3H, −OAc), 2.09 (s, 3H, −OAc),
1.61−1.53 (m, 2H), 1.35−1.21 (m, 10H), 0.88 (t, J = 7.1 Hz, 3H, n-
octylCH3).
n-Octyl 2,3,4-Tri-O-acetyl-β-D-ribopyranoside (β-2j). 1H NMR
(500 MHz, CDCl3): δ 5.37 (app t, J = 3.6 Hz, 1H, H-3), 5.16 (m, 1H,
H-4), 5.05−5.03 (m, 1H, H-2), 4.79 (d, J = 3.1 Hz, 1H, H-1), 3.99
(dd, J = 12.7, 2.6 Hz, 1H, H-5a), 3.77 (dd, J = 12.7, 3.8 Hz, 1H, H-5b),
3.72 (dt, J = 9.6, 6.7 Hz, 1H, n-octyl CH2), 3.44 (dt, J = 9.6, 6.6 Hz,
1H, n-octyl CH2), 2.13 (s, 3H, −OAc), 2.12 (s, 3H, −OAc), 2.04 (s,
3H, −OAc), 1.63−1.52 (m, 2H, n-octyl), 1.37−1.20 (m, 10H, n-octyl),
0.88 (t, J = 7.0 Hz, 3H, n-octylCH3). 13C NMR (126 MHz, CDCl3)
(mixture of minor products): δ 170.8, 170.6, 170.3, 170.1, 170.1,
169.9, 100.6, 98.4, 78.9, 70.9, 70.1, 69.0, 68.8, 68.7, 68.5, 67.1, 66.0,
63.6, 61.2, 32.0, 32.0, 29.6, 29.5, 29.5, 29.4, 29.4, 26.2, 26.1, 22.8, 22.8,
21.1, 21.1, 20.9, 14.2. IR (thin film, cm−1): 1745 (s), 1370 (s), 1221
(s), 1072 (m). HRMS (DART+): calcd for C19H36NO8 [M + NH4]+
406.2441, found 406.2439.
[α]D −81 (c 0.20, MeOH) [lit.34 −83 (c 1.6, MeOH)].
20
n-Pentenyl β-D-Ribofuranoside (3d). The reaction was conducted
on 0.2 mmol scale (30.0 mg of D-ribose) according to general
procedure B. Dichloroethane was used as the reaction solvent, and
ethyl acetate was used as solvent for the aqueous sorbitol workup.
Purification was by flash chromatography on silica gel (methylene
chloride/methanol, 100:0 → 90:10). The title compound was
obtained as a clear oil. Isolated yield = 26.0 mg, 0.119 mmol, 60%.
1H NMR (500 MHz, CDCl3): δ 5.79 (m, 1H, CH-pentenyl), 5.05−
4.99 (m, 1H, CH2-pentenyl), 4.97 (m, 1H, CH2-pentenyl), 4.93 (br s,
1H, H-1), 4.29 (m, 1H, H-3), 4.04 (m, 2H, H-2, H-4), 3.79−3.63 (m,
3H, H-5a, H-5b, R−O−CH2−pentenyl), 3.47−3.40 (m, 1H, R−O−
CH2−pentenyl), 2.16−2.04 (m, 2H, pentenyl−CH2), 1.77−1.60 (m,
2H, pentenyl−CH2). 13C NMR (126 MHz, CDCl3): 137.9, 115.3,
107.6, 84.0, 75.6, 71.8, 68.1, 63.7, 30.2, 28.8. Characterization data
n-Octyl α-D-Mannofuranoside (3a). The reaction was conducted
on 0.2 mmol scale (36.0 mg of D-mannose) according to general
procedure B. Heptane was used as the reaction solvent, and diethyl
ether was used as solvent for the aqueous sorbitol workup. After the
phase-switching workup, residual octanol was removed as an azeotrope
with water by adding roughly 2 mL of water and concentrating under
reduced pressure at 60 °C. This process was repeated three to five
times. Purification was by flash chromatography on silica gel
(methylene chloride/methanol, 100:0 → 90:10). The title compound
were consistent with previous reports.39 [α]D −55 (c 0.15, MeOH).
20
n-Octyl α-D-Lyxofuranoside (3e). The reaction was conducted on
0.2 mmol scale (30.0 mg of D-lyxose) according to general procedure
B. Dichloroethane was used as the reaction solvent, and diethyl ether
was used as solvent for the aqueous sorbitol workup. After the phase-
switching workup, residual octanol was removed as an azeotrope with
water, by adding roughly 2 mL of water and concentrating under
reduced pressure at 60 °C. This process was repeated 3−5 times.
Purification was by flash chromatography on silica gel (methylene
chloride/methanol, 100:0 → 95:5). The title compound was obtained
1
was obtained as a white solid. Yield = 45.6 mg, 0.156 mmol, 78%. H
NMR (500 MHz, DMSO-d6): δ 4.99 (d, J = 7.1 Hz, 1H, −OH2), 4.74
(d, J = 1.5 Hz, 1H, H-1), 4.74 (d, J = 7.0 Hz, 1H, −OH3), 4.58−4.56
(m, 1H, −OH5), 4.35 (t, J = 5.8 Hz, 1H − OH6), 4.00 (ddd, J = 7.0,
4.7, 2.6 Hz, 1H, H-3), 3.82 (ddd, J = 7.1, 4.7, 3.8 Hz, 1H, H-2), 3.74−
3.67 (m, 2H, H-4, H-5), 3.59−3.50 (m, 2H, H-6a, n-octyl CH2), 3.33
(m, 1H, H-6b), 3.32−3.28 (m, 1H, n-octyl CH2), 1.52−1.42 (m, 2H,
n-octyl), 1.26 (m, 10H, n-octyl), 0.88−0.82 (m, 3H, n-octylCH3). 13C
NMR (126 MHz, DMSO-d6): δ 107.6, 79.6, 76.8, 70.7, 69.5, 67.6,
63.4, 31.2, 29.3, 28.8, 28.7, 25.6, 22.1, 14.0. IR (thin film, cm−1): 3351
(br, m), 1335 (m), 1086 (s), 1014 (s), 801 (s). HRMS (positive ion
mode (DART+)): calcd for C14H29O6 [M + H]+: 293.1964, found
293.1967. [α]D20: +73 (c 0.20, CHCl3/MeOH 1:1). Mp: 86−87.5 °C
(lit.37 mp 89.7 °C (Et2O)).
1
as a colorless oil. Yield = 29.7 mg, 0.113 mmol, 57%. H NMR (700
MHz, CDCl3): δ 4.95 (broad s, 1H, H-1), 4.59 (dd, J = 7.0, 5.3 Hz,
1H, H-3), 4.18 (m, 1H, H-4), 4.00 (app d, J = 5.3 Hz, 1H, H-2), 3.96−
3.87 (m, 2H, H-5a, H-5b), 3.65 (dt, J = 9.6, 6.8 Hz, 1H, n-octyl CH2),
3.41 (dt, J = 9.5, 6.6 Hz, 1H, n-octyl CH2), 1.58−1.51 (m, 2H, n-
octyl), 1.37−1.20 (m, 10H, n-octyl), 0.92−0.85 (m, 3H, n-octylCH3).
13C NMR (126 MHz, CDCl3): δ 106.4, 78.0, 74.9, 72.5, 68.1, 61.2,
32.0, 29.7, 29.5, 29.4, 26.2, 22.8, 14.3. IR (thin film, cm−1): 3357 (br,
m), 2924 (s), 1461 (m), 1098 (s), 1029 (s). HRMS (DART+): calcd
for C13H27O5 [M + H]+ 263.1859, found 263.1852. [α]D20 +39 (c 0.18,
CHCl3/MeOH 1:1).
Dihydrocholesteroyl α-D-Mannofuranoside (3b). The reaction was
conducted on 0.2 mmol scale (36.0 mg of D-mannose) according to
general procedure B. Heptane was used as the reaction solvent, and
diethyl ether was used as solvent for the aqueous sorbitol workup.
Purification was by flash chromatography on silica gel (methylene
chloride/methanol, 100:0 → 90:10). The title compound was
obtained as an amorphous white solid. Yield = 61.4 mg, 0.112
n-Octyl D-Galactopyranoside (4a, 3.3:1 α:β Mixture). The reaction
was conducted on 0.2 mmol scale (36.0 mg of D-galactose) according
to general procedure B. Dichloroethane was used as the reaction
solvent, and diethyl ether was used as solvent for the aqueous sorbitol
workup. After the phase-switching workup, residual octanol was
removed as an azeotrope with water by adding roughly 2 mL of water
and concentrating under reduced pressure at 60 °C. This process was
repeated three to five times. Purification was by flash chromatography
on silica gel (methylene chloride/methanol, 100:0 → 90:10). The title
compound was obtained as a translucent oil (mixture of anomers).
Yield = 40.6 mg, 0.139 mmol, 69%. α:β = 3.3:1 (based on integration
of H-1 resonances in the H NMR spectrum). H NMR (500 MHz,
methanol-d4): δ 4.80 (d, J = 3.4 Hz, 1H, H-1α), 4.20 (d, J = 7.5 Hz,
1H, H-1β), 3.92−3.59 (m, 9H, H-4α, n-octyl CH2β, H-4β, H-5α, H-
2α, H-6aβ, H-3α, H-6bβ, n-octyl CH2α, H-6aα, H-6bα), 3.57−3.39
(m, 2H, n-octyl CH2β, H-5β, H-3β, n-octyl CH2α), 1.71−1.56 (m, 3H,
n-octylα + n-octylβ), 1.44−1.24 (m, 16H, n-octylα + n-octylβ), 0.93−
1
mmol, 56%. H NMR (500 MHz, DMSO-d6): δ 4.96 (d, J = 7.0 Hz,
1H, −OH-2), 4.88 (d, J = 3.9 Hz, 1H, H-1), 4.71 (d, J = 4.6 Hz, 1H,
−OH-3), 4.55 (d, J = 5.3 Hz, 1H, −OH-5), 4.35 (t, J = 5.7 Hz, 1H,
−OH-6), 3.99 (ddd, J = 7.5, 4.6, 3.0 Hz, 1H, H-3), 3.77 (m, 1H, H-2),
3.72 (dd, J = 8.2, 3.0 Hz, 1H, H-4), 3.70−3.64 (m, 1H, H-5), 3.54
(ddd, J = 11.1, 5.6, 2.9 Hz, 1H, H-6a), 3.45−3.36 (m, 1H, C-H-
dihydrocholesterol), 3.33−3.25 (m, 1H, H-6b), 1.99−0.56 (m, 46H,
dihydrocholesterol C-Hs). 13C NMR (126 MHz, DMSO-d6): δ 106.0,
79.4, 77.1, 76.4, 70.6, 69.5, 63.4, 56.0, 55.7, 53.7, 44.3, 42.2, 36.4, 36.0,
35.6, 35.2, 35.1, 35.0, 31.7, 28.4, 27.8, 27.4, 23.8, 23.2, 22.7, 22.4, 20.8,
1
1
I
DOI: 10.1021/acs.joc.7b01880
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The Journal of Organic Chemistry
Article
0.88 (m, n-octylCH3α + n-octylCH3β). 13C NMR (125 MHz,
methanol-d4): δ 105.0, 100.3, 76.6, 75.0, 72.6, 72.3, 71.6, 71.1, 70.8,
70.3, 69.2, 62.7, 62.4, 33.0, 33.0, 33.0, 30.8, 30.6, 30.6, 30.4, 27.4, 27.1,
23.7, 14.4. Characterization data were consistent with those reported
previously.40
O-CH2-CHCH2, H-6a), 3.95 (dd, J = 11.8, 4.3 Hz, 1H, H-6b); β
anomer δ 8.02−7.96 (m, 4H, aromatic C-H), 7.53−7.49 (m, 2H,
aromatic C-H), 7.40−7.34 (m, 4H, aromatic C-H), 5.80 (m, 2H,
CH=CH2, H-2), 5.30 (m, 1H, H-3), 5.26−5.22 (m, 1H, CHCH2),
5.14−5.12 (m, 1H, CHCH2), 4.77 (d, J = 8.0 Hz, 1H, H-1), 4.39
(m, 1H, H-4), 4.39−4.35 (m, 1H, R-O-CH2-CHCH2), 4.20−4.16
(m, 1H, R-O-CH2-CHCH2), 4.06−4.03 (m, 1H, H-6a), 3.97−3.93
(m, 1H, H-6b), 3.77 (m, 1H, H-5). 13C NMR (126 MHz, CDCl3):
(anomeric mixture) δ 166.2, 166.0, 165.9, 165.5, 133.7, 133.6, 133.5,
133.4, 133.3, 130.0, 129.9, 129.9, 129.9, 129.9, 129.7, 129.5, 129.5,
129.2, 128.6, 128.6, 128.5, 128.5, 117.8, 117.7, 100.5, 96.1, 74.5, 74.3,
71.2, 70.3, 70.0, 69.7, 69.3, 68.9, 68.9, 68.6. IR (thin film, cm−1): 3436
(br, m), 1714 (s), 1602 (w), 1264 (s), 1067(s), 706 (s). HRMS
(DART+): calcd for C23H28NO8 [M + NH4]+ 446.1815, found
446.1818.
n-Pentenyl 5-O-Benzoyl-β-D-ribofuranoside (5). The reaction was
conducted on 0.2 mmol scale (30.0 mg of D-ribose) according to
general procedure C. Dichloroethane was used as the reaction solvent,
and ethyl acetate was used as solvent for the aqueous sorbitol workup.
Purification was by flash chromatography on silica gel (methylene
chloride/methanol, 100:0 → 97:3) The title compound was obtained
1
as a white film. Yield = 34.6 mg, 0.107 mmol, 54%. H NMR (500
MHz, CDCl3): δ 8.07 (m, 2H, aromatic C-H), 7.57 (m, 1H, aromatic
C-H), 7.44 (m, 2H, aromatic C-H), 5.78−5.69 (m, 1H, CH-pentenyl),
4.99−4.95 (m, 2H, CHCH2-pentenyl, H-1), 4.94−4.91 (m, 1H,
CH2-pentenyl), 4.58 (dd, J = 11.8, 4.0 Hz, 1H, H-5a), 4.44−4.39 (m,
2H, H-5b, H-3), 4.24 (m, 1H, H-4), 4.09 (d, J = 4.8 Hz, 1H, H-2),
3.72−3.67 (m, 1H, R-O-CH2-pentenyl), 3.39−3.33 (m, 1H, R-O-CH2-
pentenyl), 2.03 (m, 2H, pentenyl-CH2), 1.58 (m, 2H, pentenyl-CH2).
13C NMR (126 MHz, CDCl3): δ 166.8, 138.1, 138.1, 133.4, 129.9,
129.9, 128.5, 115.0, 107.3, 81.1, 75.4, 72.3, 67.6, 65.4, 30.3, 28.7. IR
(thin film, cm−1): 3410 (br, m), 1715 (s), 1270 (s), 1106 (s), 708 (s).
HRMS (DART+): calcd for C17H26NO6 [M + NH4]+ 340.1760, found
n-Pentenyl 2-O-Benzoyl-α-D-fucopyranoside (6c, 4.8:1 α:β
Mixture). The reaction was conducted on 0.2 mmol scale (32.8 mg
of D-fucose) according to general procedure C. Dichloroethane was
used as the reaction solvent, and ethyl acetate was used as solvent for
the aqueous sorbitol workup. Purification was by flash chromatography
on silica gel (hexanes/ethyl acetate, 100:0 → 50:50). The title
compound was obtained as a white film. Combined yield = 39.5 mg,
0.092 mmol, 46%. α:β = 4.8:1 (based on integration of the resonances
1
1
20
corresponding to H-2(α) and H-1(β) in the H NMR spectrum). H
NMR (500 MHz, CDCl3): α anomer δ 8.10−8.05 (m, 2H, aromatic
C-H), 7.60−7.56 (m, 1H, aromatic C-H), 7.47−7.43 (m, 2H, aromatic
C-H), 5.79−5.72 (m, 1H, CH-pentenyl), 5.19 (dd, J = 10.2, 3.9 Hz,
1H, H-2), 5.07 (d, J = 3.9 Hz, 1H, H-1), 4.96−4.90 (m, 2H, CH2-
pentenyl), 4.19 (dd, J = 10.2, 3.4 Hz, 1H, H-3), 4.09 (m, 1H, H-5),
3.87 (dd, J = 3.4, 1.2 Hz, 1H, H-4), 3.71 (m, 1H, R-O-CH2-pentenyl),
3.43 (m, 1H, R-O-CH2-pentenyl), 2.10 (m, 2H, pentenyl-CH2), 1.67
(m, 2H, pentenyl-CH2), 1.33 (d, J = 6.7 Hz, 3H, CH3); β anomer δ
8.07−8.03 (m, 2H, aromatic C-H), 7.60−7.55 (m, 1H, aromatic C-H),
7.47−7.43 (m, 2H, aromatic C-H), 5.69 (m, 1H, CH-pentenyl), 5.10
(app t, J = 8.0 Hz, 1H,, H-2), 4.90−4.82 (m, 2H, CH2-pentenyl), 4.53
(d, J = 8.0 Hz, 1H, H-1), 3.92−3.88 (m, 1H, R-O-CH2-pentenyl),
3.81−3.76 (m, 2H, H-3, H-4), 3.71 (m, 1H, H-5), 3.55−3.49 (m, 1H,
R-O-CH2-pentenyl), 2.01 (m, 2H, pentenyl−CH2), 1.63 (m, 2H,
pentenyl-CH2), 1.40 (d, J = 6.5 Hz, 3H, CH3). 13C NMR (126 MHz,
CDCl3): α anomer δ 167.3, 138.1, 138.0, 133.5, 130.0, 129.8, 128.6,
115.1, 96.6, 72.6, 72.6, 69.2, 67.7, 65.5, 30.4, 28.8, 16.3; β anomer δ
167.5, 138.1, 133.5, 130.0, 129.8, 128.5, 114.9, 101.0, 74.7, 73.6, 72.1,
70.5, 69.2, 30.0, 29.9, 28.8, 16.5. IR (thin film, cm−1): 3393 (br, m),
1720 (s), 1641 (w), 1269 (s), 1067 (s), 705 (s). HRMS (DART+):
calcd for C18H28NO6 [M + NH4]+ 354.1917, found 354.1914.
340.1762. [α]D −35 (c 0.22, CHCl3).
Isopropyl 2,3-Di-O-benzoyl-α-D-galactopyranoside (6a, 4:1 α:β
Mixture). The reaction was conducted on 0.2 mmol scale (36.0 mg of
D-galactose) according to general procedure C. Dichloroethane was
used as the reaction solvent, and ethyl acetate was used as solvent for
the aqueous sorbitol workup. Purification was by flash chromatography
on silica gel (hexanes/ethyl acetate, 100:0 → 50:50). The title
compound was obtained as a colorless oil. (mixture of anomers
isolated) Combined yield = 54.4 mg, 0.126 mmol, 63%. α:β = 4:1
(based on integration of the resonances corresponding to H-1(α) and
1
1
H-3(β) in the H NMR spectrum). H NMR (500 MHz, CDCl3): α
anomer δ 8.03−7.96 (m, 4H, aromatic C-H), 7.54−7.48 (m, 2H,
aromatic C-H), 7.41−7.35 (m, 4H, aromatic C-H), 5.70 (dd, J = 10.6,
3.0 Hz, 1H, H-3), 5.65 (dd, J = 10.6, 3.6 Hz, 1H, H-2), 5.42 (d, J = 3.6
Hz, 1H, H-1), 4.47 (dd, J = 3.0, 1.3 Hz, 1H, H-4), 4.20−4.15 (ddd, J =
5.0, 4.4, 1.3 Hz, 1H, H-5), 4.01 (dd, J = 11.8, 5.0 Hz, 1H, H-6a), 3.93
(dd, J = 11.8, 4.4 Hz, 1H, H-6b) 3.91 (m, 1H, CH-isopropyl), 1.25 (d,
J = 6.1 Hz, 3H, CH3), 1.07 (d, J = 6.1 Hz, 3H, CH3); β anomer δ
8.02−7.95 (m, 4H, aromatic C-H), 7.55−7.48 (m, 2H, aromatic C-H),
7.41−7.36 (m, 4H, aromatic C-H), 5.71(dd, J = 10.4, 8.0 Hz, 1H, H-
2), 5.28 (dd, J = 10.4, 3.2 Hz, 1H, H-3), 4.77 (d, J = 8.0 Hz, 1H, H-1),
4.37 (dd, J = 3.2, 1.0 Hz, 1H, H-4), 4.03 (dd, J = 11.9, 6.1 Hz, 1H, H-
6a), 3.99 (m, 1H, CH-isopropyl), 3.93 (dd, J = 11.9, 4.5 Hz, 1H, H-
6b), 3.78 (ddd, J = 6.1, 4.5, 1.0 Hz, 1H, H-5), 1.24 (d, J = 6.2 Hz, 3H,
CH3), 1.07 (d, J = 6.1 Hz, 3H, CH3). 13C NMR (126 MHz, CDCl3):
(anomeric mixture) δ 166.3, 166.1, 166.0, 165.5, 133.5, 133.5, 133.3,
133.2, 130.0, 129.9, 129.9, 129.9, 129.8, 129.8, 129.7, 129.6, 129.2,
128.6, 128.5, 128.5, 100.5 (C-1β), 95.4 (C-1α), 74.6, 74.4, 73.1, 71.4,
71.4, 70.0, 70.0, 69.1, 69.1, 68.5, 63.5, 62.7, 23.5, 23.4, 22.1, 21.9. IR
(thin film, cm−1): 3443 (br, m), 1717 (s), 1451 (m), 1272 (s), 1104
(s), 711 (s). HRMS (DART+): calcd for C23H30NO8 [M + NH4]+
448.1971, found 448.1974.
n-Pentenyl 2-O-Benzoyl-β-D-arabinopyranoside (6d, 3.2:1 β:α
Mixture). The reaction was conducted on 0.2 mmol scale (30.0 mg of
D-arabinose) according to general procedure C. Dichloroethane was
used as the reaction solvent, and ethyl acetate was used as solvent for
the aqueous sorbitol workup. Purification was by flash chromatography
on silica gel (hexanes/ethyl acetate, 100:0 → 50:50). The title
compound was obtained as a white oily film. Combined yield = 28.3
mg, 0.0878 mmol, 44%. β:α = 3.2:1 (based on integration of the
1
resonances corresponding to H-3(β) and H-1(α) in the H NMR
1
spectrum). H NMR (500 MHz, CDCl3): β anomer δ 8.09−8.04 (m,
2H, aromatic C-H), 7.57 (m, 1H, aromatic C-H), 7.48−7.41 (m, 2H,
aromatic C-H), 5.76 (m, 1H, CH-pentenyl), 5.23 (dd, J = 10.0, 3.7 Hz,
1H, H-2), 5.09 (d, J = 3.7 Hz, 1H, H-1), 4.96−4.90 (m, 2H, CH2-
pentenyl), 4.20 (dd, J = 10.0, 3.6 Hz, 1H, H-3), 4.06 (m, J = 3.6, 1.8
Hz, 1H, H-4), 3.93 (dd, J = 12.6, 1.6, 1H, H-5a), 3.78 (dd, J = 12.6, 2.0
Hz, 1H, H-5b), 3.72 (dt, J = 9.9, 6.3 Hz, 1H, Ara-O-CH2-pentenyl),
3.42 (dt, J = 9.9, 6.4 Hz, 1H, Ara-O-CH2-pentenyl), 2.11 (m, 2H,
pentenyl-CH2), 1.67 (m, 2H, pentenyl−CH2); α anomer δ 8.06−8.02
(m, 2H, aromatic C-H), 7.59 (m, 1H, aromatic C-H), 7.49−7.43 (m,
2H, aromatic C-H), 5.78 (m, 1H, CH-pentenyl), 5.21 (dd, J = 5.1, 3.3
Hz, 1H, H-2), 5.01 (m, 1H, CH2-pentenyl), 4.98 (m, 1H, CH2-
pentenyl), 4.77 (d, J = 3.3 Hz, 1H, H-1), 4.05−3.98 (m, 2H, H-3, H-
4), 3.84 (dt, J = 9.8, 6.5 Hz, 1H, Ara-O-CH2-pentenyl), 3.79 (dd, J =
11.9, 8.3 Hz, 1H, H-5a), 3.70 (dd, J = 11.9, 4.4 Hz, 1H, H-5b), 3.51
(dt, J = 9.8, 6.5 Hz, 1H, Ara-O-CH2-pentenyl),), 2.15−2.08 (m, 2H,
Allyl 2,3-Di-O-benzoyl-α-D-galactopyranoside (6b, 2:1 α:β
Mixture). The reaction was conducted on 0.2 mmol scale (36.0 mg
of D-galactose) according to general procedure C. Dichloroethane was
used as the reaction solvent, and ethyl acetate was used as solvent for
the aqueous sorbitol workup. Purification was by flash chromatography
on silica gel (hexanes/ethyl acetate, 100:0 → 50:50). The title
compound was obtained as a colorless oil. (mixture of anomers
isolated) Combined yield = 39.5 mg, 0.092 mmol, 46%. α:β = 2:1
1
(based on integration of H-1 resonances in the H NMR spectrum).
1H NMR (500 MHz, CDCl3): α anomer δ 8.02−7.96 (m, 4H,
aromatic C-H), 7.53−7.49 (m, 2H, aromatic C-H), 7.40−7.34 (m, 4H,
aromatic C-H), 5.89−5.80 (m, 1H, CHCH2), 5.75−5.71 (m, 2H, H-
2, H-3), 5.36 (d, J = 2.6 Hz, 1H, H-1), 5.33−5.27 (m, 1H, CHCH2),
5.17−5.13 (m, 1H, CHCH2), 4.49 (m, 1H, H-4), 4.28−4.22 (m,
1H, R-O-CH2-CHCH2), 4.12 (m, 1H, H-5), 4.09−4.00 (m, 2H, R-
J
DOI: 10.1021/acs.joc.7b01880
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
pentenyl-CH2), 1.73 (m, 2H, pentenyl-CH2). 13C NMR (126 MHz,
CDCl3): β anomer δ 167.2, 138.0, 133.5, 130.0, 129.7, 128.6, 115.1,
96.9, 72.8, 69.7, 68.3, 67.8, 62.1, 30.3, 28.8; α anomer δ 165.9, 137.7,
133.7, 130.0, 129.4, 128.6, 115.4, 98.1, 71.4, 69.8, 68.6, 65.4, 60.9, 30.3,
28.6. IR (thin film, cm−1): 3368 (br, s), 1713 (s), 1641 (w), 1269 (s),
1012 (s), 709 (s). HRMS (DART+): calcd for C17H26NO6 [M +
NH4]+ 340.1760, found 340.1769.
coordinates, energies, and frequencies for calculated
structures, and 1H and 13C NMR spectra for new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mtaylor@chem.utoronto.ca.
ORCID
Benzyl L-Rhamnopyranoside (8.3:1 α:β Mixture). The reaction was
conducted on 0.2 mmol scale (36.4 mg of L-rhamnose monohydrate)
according to general procedure B, without phenylboronic acid.
Dichloroethane was used as the reaction solvent, and ethyl acetate
was used as solvent for the aqueous workup. Purification was by flash
chromatography on silica gel (DCM/methanol, 100:0 → 90:10). The
title compound was obtained as a colorless oil. Yield of anomeric
mixture = 34.0 mg, 0.134 mmol, 67%. α:β = 8.3:1 (based on
integration of the resonances corresponding to H-1(α) and H-1(β) in
Mark S. Taylor: 0000-0003-3424-4380
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
1
the H NMR spectrum). H NMR (500 MHz, CDCl3): δ 7.35−7.24
(m, 6H), 4.88−4.84 (d, J = 11.8 Hz, 0.11 H, CH2Ph-β), 4.83−4.78 (br
s, 1H, H-1α), 4.68−4.63 (d, J = 11.9 Hz, 1H, CH2Ph-α), 4.60−4.56 (d,
J = 11.8 Hz, 0.13H, CH2Ph-β), 4.47−4.42 (d, J = 11.9 Hz, 1H, CH2Ph-
α), 4.42−4.41 (br s, 0.12H, H-1β), 3.97−3.89 (dd, J = 3.4, 1.6 Hz,
1H), 3.84−3.74 (m, 1H), 3.70−3.62 (dq, J = 9.4, 6.3 Hz, 1H), 3.50−
3.43 (t, J = 9.6 Hz, 1H), 3.43−3.35 (m, 0H), 3.22−3.15 (dq, J = 8.9,
6.1 Hz, 0H), 1.32−1.23 (d, J = 6.3 Hz, 4H). 13C NMR (126 MHz,
CDCl3): 137.3 (α), 136.7 (β), 128.7(β), 128.6 (α), 128.5 (β), 128.3
(β), 128.1 (α), 128.0 (α), 99.1 (α-C1), 98.2 (β-C1), 74.1 (β), 73.0
(α), 72.9 (β), 72.2 (β), 71.8 (α), 71.2 (β), 71.1 (α), 70.7 (β), 69.3 (α),
68.4 (α), 17.7. The spectral data is consistent with previous reports.41
n-Octyl D-Lyxopyranoside (4:1 α:β Mixture). The reaction was
conducted on 0.2 mmol scale (30.0 mg of D-lyxose) according to
general procedure B, without phenylboronic acid. Dichloroethane was
used as the reaction solvent, and diethyl ether was used as solvent for
the aqueous workup. Purification was by flash chromatography on
silica gel (methylene chloride/methanol, 100:0 → 95:5). The title
compound was obtained as a colorless oil. Yield of anomeric mixture =
29.6 mg, 0.113 mmol, 56%. α:β = 4:1 (based on integration of the
Dr. Graham Garrett (University of Toronto) is gratefully
acknowledged for advice and assistance with the computational
modeling. This research was funded by NSERC (Discovery
Grants and Canada Research Chairs Programs), the Canada
Foundation for Innovation (Project Nos. 17545 and 19119),
and the Province of Ontario.
REFERENCES
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resonances corresponding to H-1(α) and H-1(β) in the H NMR
spectrum). 1H NMR (500 MHz, CDCl3): α-anomer δ 4.72 (d, J = 2.5
Hz, 1H, H-1), 3.94−3.86 (m,2H, H-4, H-2), 3.82−3.77 (dd, J = 8.7,
3.3 Hz, 1H, H-3), 3.76−3.71 (dd, J = 11.1, 4.9 Hz, 1H, H-5a), 3.71−
3.64 (dt, J = 9.6, 6.9 Hz, 1H, n-octylCH2), 3.54−3.46 (dd, J = 11.1, 9.4
Hz, 1H, H-5b), 3.44−3.36 (dt, J = 9.6, 6.7 Hz, 1H, n-octylCH2), 1.62−
1.53 (m, 2H, n-octylCH2), 1.39−1.21 (m, 12H), 0.94−0.84 (m, 3H);
β-anomer (minor) δ 4.75 (d, J = 2.8 Hz, 1H), 4.05−3.97 (dd, J = 12.6,
2.6 Hz, 1H, H-5a), 3.97−3.90 (m, 2H, H-4, H-2), 3.84−3.79 (dt, J =
9.7, 6.8 Hz, 1H, n-octylCH2), 3.79−3.76 (m, 1H, H-3), 3.48 (m, 1H,
n-octylCH2), 3.43 (m, 1H, H-5b), 1.67−1.58 (m, 2H), 1.38−1.20 (m,
12H), 0.93−0.84 (m, 3H). 13C NMR (126 MHz, CDCl3): α-anomer δ
100.2, 71.9, 70.7, 68.4, 67.7, 62.7, 32.0, 29.6, 29.6, 29.4, 26.2, 22.8,
14.2; β-anomer δ 100.2, 72.7, 69.9, 69.6, 66.6, 60.8, 31.9, 29.6, 29.5,
29.3, 26.3, 22.8, 14.2. The spectral data for the major anomer is
consistent with previous reports.42
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Computational Methods. DFT calculations were carried out
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possible cyclic boronic esters involving complexation of cis- or
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corresponded to minima (no imaginary frequencies) on the potential
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ASSOCIATED CONTENT
* Supporting Information
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1
NMR spectral data for peracetylated glycosides from
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K
DOI: 10.1021/acs.joc.7b01880
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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DOI: 10.1021/acs.joc.7b01880
J. Org. Chem. XXXX, XXX, XXX−XXX