Boronic esters as protective groups in carbohydrate chemistry: processes for acylation, silylation and alkylation of glycoside-derived boronates

Article abstract of DOI:10.1039/C6OB02278B

Procedures for selective installation of acyl, silyl ether and para-methoxybenzyl (PMB) ether groups to glycoside substrates have been developed, employing phenylboronic esters as protected intermediates. The sequence of boronic ester formation, functiona

Full text of DOI:10.1039/C6OB02278B

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Biomolecular Chemistry
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Boronic esters as protective groups in carbohydrate
chemistry: processes for acylation, silylation and
alkylation of glycoside-derived boronates†
Cite this: DOI: 10.1039/c6ob02278b
Ross S. Mancini, Jessica B. Lee and Mark S. Taylor*
Procedures for selective installation of acyl, silyl ether and para-methoxybenzyl (PMB) ether groups to
glycoside substrates have been developed, employing phenylboronic esters as protected intermediates.
The sequence of boronic ester formation, functionalization and deprotection can be accomplished with
only a single purification step, and the boronic acid component can be recovered and reused after
deprotection. Key advances include the identification of reaction conditions for installation of PMB groups
in the presence of boronic esters, and the use of the ‘phase switching’ protocol developed by Hall and
co-workers as an efficient method for boronic ester cleavage. The relatively mild conditions for boronate
deprotection are tolerant of several functional groups, including esters, silyl ethers, ketals and
thioglycosides.
Received 18th October 2016,
Accepted 31st October 2016
DOI: 10.1039/c6ob02278b
www.rsc.org/obc
cations of organoboron compounds in carbohydrate syn-
Introduction
thesis,7 we set out to determine whether efficient and practical
The formation of cyclic boronic esters from boronic acids and protocols for selective functionalization of carbohydrates could
carbohydrate derivatives was first reported more than 60 years be developed based on the use of boronic esters as temporary
ago.1,2 Condensations of this type have been applied exten- blocking groups for 1,2- or 1,3-diol groups.
sively in glycoscience, including in drug delivery and in the
Protection of carbohydrate-derived diols as cyclic boronic
sensing and separation of carbohydrate derivatives.3 Boronic esters has been explored in several previous studies.8 Boronic
ester formation generally occurs at 1,2- or 1,3-diol groups, the ester protective groups have been used to facilitate the syn-
same motifs that engage in cyclic ketal and acetal formation. thesis of mannofuranosides,9 β-mannopyranosides,10 functio-
However, whereas acetals and ketals are employed routinely as nalized hexitols and sialic acid derivatives.11 They have been
protective groups for such motifs,4–6 applications of boronic combined with stannylene acetal activating groups to achieve
acids for this purpose are relatively uncommon. Among the selective acylations and sulfations of pyranosides.12 The facile
factors that may have contributed to this difference are the formation and cleavage of boronic esters are advantageous fea-
rather sensitive nature of boronic esters, not only to hydrolysis tures in polymer-supported synthesis, as demonstrated by
under mild acidic or basic conditions, but also to proteode- applications of boronic acid-functionalized, cross-linked poly-
boronation, oxidation and nucleophilic attack; and the cost of styrene as a protective group for pyranosides.13,14 Recently,
arylboronic acids, which generally exceeds those of the selective sulfations15 and glycosylations16 of pyranosides and
reagents used for acetal and ketal formation. Although the free sugars have been achieved using arylboronic acids as tran-
fragility of boronic esters is a disadvantage for certain appli- sient protective groups. Despite these significant advances,
cations, it could also represent an opportunity to develop oper- boronic esters are not generally viewed as being viable alterna-
ationally simple reaction sequences that occur under mild con- tives to acetals and ketals for partial installation of widely
ditions and with high functional group tolerance. The second employed protective groups such as esters, silyl ethers and
issue – the cost of boronic acids – could be mitigated by reco- benzyl ethers. Here, we describe procedures for selective instal-
vering and recycling this reagent. Based on these consider- lation of acyl, silyl ether and para-methoxybenzyl (PMB) ether
ations, and as part of a broader program focused on appli- groups to pyranoside and furanoside substrates, employing
phenylboronic esters as protected intermediates. The sequence
of boronic ester formation, functionalization and deprotection
can be accomplished with only a single purification step, and
the boronic acid component can be recovered and reused after
deprotection. Key advances include the identification of
Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
E-mail: mtaylor@chem.utoronto.ca
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all new compounds. See DOI: 10.1039/c6ob02278b
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reaction conditions for installation of PMB groups in the pres-
M
aqueous sodium hydroxide solution, but it was
ence of boronic esters, and the use of the ‘phase switching’ accompanied by saponification of the ester groups.
protocol developed by Hall and co-workers17 as an efficient
method for boronic ester hydrolysis.
It has been observed that carbohydrate-derived boronic
esters can show appreciable stability under aqueous con-
ditions, and that their rates of hydrolysis appear to depend on
the configuration and substitution pattern of the carbohydrate
moiety.8,11,15,18 It is presumably for this reason that most
authors have opted for ‘non-hydrolytic’ methods such as oxi-
dation16 or transesterification9,15 to liberate boronic ester-
protected diols in carbohydrate chemistry. Indeed, treatment
of 2a with pinacol in refluxing toluene overnight yielded the
desired diol 3a and phenylboronic acid pinacol ester, which
could be separated by flash column chromatography. Although
this approach was effective, the requirement for a prolonged
heating step and the inability to directly recover the phenyl-
boronic acid component were drawbacks.
We speculated that an efficient method for transesterifica-
tion-based cleavage of sugar-derived boronic esters could be
developed based on the ‘phase switching’ concept pioneered
by Hall and co-workers.17 Hall’s group showed that boronic
acids can be separated from other organic compounds by
liquid–liquid extraction, taking advantage of the pH-switch-
able complexation of the boronic acid with sorbitol, a sugar
alcohol. Extraction with a basic solution of sorbitol in water
draws the boronic acid into the aqueous phase through for-
mation of a tetracoordinate boronate. Acidification of this
phase releases the boronic acid, which can be extracted into
organic solvent. This method has not been applied to boronic
esters, but we anticipated that transesterification of the sugar-
derived boronates with sorbitol could be relatively rapid under
the basic conditions of the liquid–liquid extraction. Indeed,
washing an ethyl acetate solution of 2a with a 1 M aqueous
solution of sorbitol and sodium carbonate resulted in quanti-
tative cleavage of the boronic ester to give 3a, which was parti-
tioned to organic solvent, while phenylboronic acid was
sequestered in the aqueous phase as the sorbitol-bound boro-
nate. Diester 3a was isolated in 80% yield (from 1a, on 5 mmol
scale) after purification by flash column chromatography on
silica gel, while phenylboronic acid was recovered in 77% yield
after acidification of the aqueous extract followed by extraction
with ethyl acetate. Overall, the preparation of 3a from 1a was
accomplished in a ‘one-pot’ operation: diol protection and
acylation were conducted in the same flask and without purifi-
cation of intermediates, while deprotection was carried out
during the phase-switching aqueous workup.
Results and discussion
Acylation and silylation of sugar-derived boronates
We selected 2,3-bis-benzoylation of methyl α-D-glucopyrano-
side as a model reaction for our initial studies (Scheme 1).
Acylation of sugar-derived boronates is well established,8,13
meaning that we could focus on developing an operationally
simple protection–acylation–deprotection protocol that would
facilitate isolation of the sugar-derived product and recovery of
the boronic acid component. Condensation with phenylboro-
nic acid generated the 4,6-O-boronate quantitatively and
without need for purification, by heating the reaction com-
ponents to reflux in toluene, followed by evaporation of the
solvent. The resulting material was subjected to benzoyl chlor-
ide (BzCl) in pyridine at 0 °C. As anticipated, analysis of an
aliquot of the reaction mixture by 1H NMR spectroscopy
showed clean conversion to the 2,3-benzoylated boronic ester
intermediate 2a after 1 hour.
Hydrolysis of the boronic ester proved to be more challen-
ging. Solutions of boronate 2a in ethyl acetate could be recov-
ered unchanged after washing with aqueous solutions of
hydrochloric acid (1 M) or sodium bicarbonate (saturated).
The boronate was also stable towards flash column chromato-
graphy on silica gel, eluting with 10→20% acetone in dichloro-
methane. Stirring in an acetone/water mixture at room temp-
erature, conditions that have been used to cleave functiona-
lized carbohydrate derivatives from a polystyreneboronic acid
solid support,13,14 resulted in recovery of the boronic ester.
Similar results were obtained upon treatment with a metha-
nol/water mixture and with a 1 M aqueous hydrochloric acid/
acetone mixture. Hydrolysis could be accomplished using a 1
The protocol depicted in Scheme 1 proved to be useful for
the synthesis of a variety of mono- or dibenzoylated glycosides
(Fig. 1). The reactions were generally conducted on 5 mmol
scale, leading to the isolation of gram quantities of the pro-
ducts shown. Recovery of the phenylboronic acid reagent was
carried out in each case, and the recovery yields (which ranged
from 67% to 80%) are listed in the Experimental section. The
method could be applied to gluco-, galacto- and mannopyrano-
sides, but with these last substrates, prior protection of the
6-OH group was necessary. Condensation of phenylboronic
acid with ‘free’ methyl α-D-mannopyranoside led to the
Scheme 1 Bis-benzoylation of methyl α-D-glucopyranoside by protec-
tion as a phenylboronic ester. Phase-switching workup is used to
deprotect the boronic ester and to separate the carbohydrate product
from the boronic acid component.
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Fig. 2 Partially silylated carbohydrate derivatives prepared using
boronic ester protection. Reaction conditions: (1) substrate (5.0 mmol),
PhB(OH)2 (1.0 equiv.), toluene, 110 °C; (2) chlorotriethylsilane (TESCl),
pyridine, 0 °C; (3) phase-switching workup with 1 M aqueous sorbitol/
Na2CO3. For details, see the Experimental section. Yields after purifi-
cation by flash chromatography on silica gel are listed. a Reaction was
carried out using tert-butyl(chloro)dimethylsilane (TBSCl) at 60 °C.
takes place under the silylation conditions. Indeed, 1H NMR
spectroscopic analysis of the unpurified reaction mixture after
the silylation step showed the presence of the isomeric boro-
nates 2e and 2e′ in a 3.6 : 1 ratio, which is in good agreement
with the ratio of isolated yields of 4e and 4e′ (Scheme 2).
Prolonging the reaction time for silylation from 30 minutes to
two hours caused an increase in the amount of 2e′, and the
2,3-bis-O-silylated boronate could be favored by conducting the
silylation for 18 hours at 50 °C. After phase-switch workup, the
latter silylation protocol led to the isolation of 4e′ in 50% yield.
These results suggest that 2e is the kinetically preferred
product, while 2e′ is thermodynamically favored. Kinetically
Fig. 1 Partially acylated carbohydrate derivatives prepared using
boronic ester protection. Reaction conditions: (1) substrate (5.0 mmol),
PhB(OH)2 (1.0 equiv.), toluene, 110 °C; (2) acylating agent, pyridine, 0 °C;
(3) phase-switching workup with 1 M aqueous sorbitol/Na2CO3. For
details, see the Experimental section. Yields after purification by flash
chromatography on silica gel are listed. a Reaction was carried out on
2.0 mmol scale. b PhB(OH)2 recovered from a previous experiment was
used in the reaction. c Deprotection was conducted by transesterifica-
tion with pinacol (toluene, 110 °C).
formation of the bis-boronate and recovery of unprotected controlled formation of 2e could arise under a Curtin–
pyranoside, regardless of the stoichiometry used. It appears Hammett scenario wherein the 4,6-O-boronate rearranges to a
that the rate of formation of the second boronic ester exceeds less stable 3,4-O-boronate, which undergoes rapid silylation at
that of the first. Consistent with previous observations,18 this the primary 6-OH group. The ability to convert 2e to 2e′ by pro-
method was applicable to the synthesis of a partially acylated longed heating suggests that migration of both the boronic
thioglycoside (3g). The synthesis of 3f demonstrates that an ester and silyl groups can occur under these conditions,
isopropylidene ketal group is tolerant of the conditions for for- leading to the more stable 4,6-O-boronate product.20 Evidence
mation and cleavage of boronic esters. It should also be noted of boronate migration was also observed in the synthesis of
that the 3,5-O-boronate was formed selectively from glucofurano- bis-benzoylated galactopyranoside 3e (Fig. 1): the 2,6-bis-ben-
side 1f, thus leading to benzoylation of the free 6-OH group.
zoylated regioisomer was obtained as a side product in 15%
Fluorenylmethyl carbonate (OFmoc) and pivaloyl ester yield. However, in this case, heating and/or prolonged reaction
(OPiv) protective groups could also be installed efficiently times did not lead to a change in the distribution of isomers.
using this protocol (products 3h, 3i). Selective installation of The benzoylation reaction is likely under kinetic control, with
the pivaloyl group19 occurred at the less sterically hindered migration of benzoyl groups being less rapid than that of tri-
2-OH group of the α-D-glucopyranoside-derived boronic ester. ethylsilyl groups in this system. The galactopyranoside is
However, acyl migration was observed under the basic con-
ditions of the phase-switch deprotection, leading to the iso-
lation of both 2-O-Piv and 3-O-Piv products in 66% and 15%
yield, respectively. Migration of the pivaloyl group was sup-
pressed by changing the conditions for cleavage of the boronic
ester, using transesterification with pinacol in refluxing
toluene in place of the phase-switch workup. In this way, the
yield of 3i was improved to 72%.
In a similar way, partially silylated pyranosides were pre-
pared using this protocol (Fig. 2). The formation of the bis-
silylated isomers 4e and 4e′ from methyl α-D-galactopyranoside 1e
merits further comment. Condensation of 1e with phenylboro-
nic acid resulted in the clean formation of the 4,6-O-boronate,
and yet the 2,6-bis-silylated derivative was the predominant
Scheme 2 Formation of isomeric bis-silylated boronates 2e and 2e’.
Isomer ratios were determined by integration of the signals corres-
ponding to the anomeric OCH3 groups in the 1H NMR spectrum of
product, indicating that migration of the boronic ester group unpurified reaction mixtures.
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unique among substrates 1a–1g in having a triol moiety that
can form two relatively stable boronic ester isomers, and analo-
gous isomerizations were not observed in the other reactions
studied here.
Alkylation of sugar-derived boronates
Although ethers (especially benzyl ethers) are useful protective
groups in carbohydrate chemistry, alkylation reactions of
hydroxy groups in glycoside-derived boronates have not been
reported. (It should be noted, however, that regioselective
O-alkylations of pyranosides have been achieved by activation
as tetracoordinate boronic ester–amine adducts.21) Duggan
and co-workers prepared the 1,6-bis-benzyl ether of mannitol
by treating the hexitol-derived bis-boronic ester with benzyl
bromide and sodium hydride in DMF solvent.11 However,
upon subjecting the boronic ester derived from PhB(OH)2 and
1a to these conditions, we obtained a complex mixture. We
speculated that the boronic ester group might undergo side
reactions with alkoxides, and turned our attention to trichlor-
oacetimidates, alkylating agents that are reactive under Lewis
or Brønsted acidic conditions. Our initial attempts at using
benzyl trichloroacetimidate for bis-alkylation of 1a led to
incomplete conversion under relatively mild activation con-
ditions (10 mol% BF3·OEt2, dichloromethane, 4 Å molecular
sieves, 0 °C), and decomposition under more forcing activation
conditions (50 mol% trifluoromethanesulfonic acid). However,
promising results were obtained using the more reactive para-
methoxybenzyl trichloroacetimidate, which gave a 28% yield of
bis-alkylated product 5a (Table 1, entry 1). Variation of the
boronic ester component revealed that 4-methoxyphenylboro-
Fig. 3 Carbohydrate-derived para-methoxybenzyl (PMB) ethers pre-
pared using boronic ester protection. Reaction conditions: (1) substrate
(5.0 mmol), 4-(trifluoromethyl)phenylboronic acid (1.0 equiv.), toluene,
110 °C; (2) PMBOC(vNH)CCl3, La(OTf)3 (1 mol%), toluene, 0 °C; (3)
phase-switching workup with 1 M aqueous sorbitol/Na2CO3. For details,
see the Experimental section. Yields after purification by flash chromato-
graphy on silica gel are listed. a 1 : 1 Toluene/dichloromethane was used
as the solvent. b Reaction was carried out on 1.6 mmol scale using ArB
(OH)2 recovered from a previous experiment.
nic acid gave inferior results, while 4-(trifluoromethyl)phenyl-
boronic acid resulted in a higher yield (entries 2 and 3). This
trend may reflect the higher stability of the electron-deficient
boronic ester under the alkylation conditions.22,23 A further
improvement was achieved by using lanthanum(III) trifluoro-
methanesulfonate (La(OTf)3) as the Lewis acid activator in
place of BF3·OEt2.24 Using a mixture of dichloromethane and
toluene as the solvent, 5a was obtained in 60% yield, as deter-
mined by 1H NMR using an internal standard.
The optimized conditions for installation of PMB groups
were carried out on preparative (5 mmol) scale for a range of
glycoside substrates, using the phase-switch deprotection
described above (Fig. 3). The protocol is compatible with silyl
groups (products 5c and 5d) and an isopropylidene ketal
(product 5f), but could not be applied to thioglycoside 1g, pre-
sumably due to competing S-alkylation and subsequent
decomposition. Given that 4-(trifluoromethyl)phenylboronic
acid is more expensive than PhB(OH)2, the ability to recover
this reagent after the phase-switching deprotection (78–91%
recovered yields: see the Experimental section) is noteworthy.
Table 1 Optimization of conditions for bis-alkylation of boronic esters
of 1aa
Sequential functionalizations of methyl α-D-glucopyranoside
The ability to install a pivaloyl group selectively at O-2 of the
phenylboronate of methyl α-D-glucopyranoside (Fig. 1, product
3i) suggested the possibility of generating differentially pro-
tected products by further functionalization of the free 3-OH
group. Indeed, sequential addition of PivCl and BzCl in pyri-
dine, without any workup or purification of the intermediate
monoacylated boronic ester, resulted in the efficient formation
of the expected differentially acylated product (Scheme 3).
After phase-switch deprotection and purification by flash
chromatography on silica gel, pyranoside 6a was isolated in
80% yield.
Entry Boronic acid
Lewis acid Solvent
Yieldb
1
2
3
4
5
6
C6H5B(OH)2
4-(OCH3)-C6H4B(OH)2 BF3·OEt2
4-(CF3)-C6H4B(OH)2
4-(CF3)-C6H4B(OH)2
4-(CF3)-C6H4B(OH)2
4-(CF3)-C6H4B(OH)2
BF3·OEt2
CH2Cl2
CH2Cl2
30%
15%
35%
45%
45%
60%
BF3·OEt2
La(OTf)3
La(OTf)3
La(OTf)3
CH2Cl2
CH2Cl2
PhCH3
CH2Cl2/PhCH3
c
a Reaction conditions: (1) 1a (0.1 mmol), ArB(OH)2 (1.0 equiv.),
toluene, 110 °C; (2) 4-(methoxy)benzyl trichloroacetimidate (6.0
equiv.), Lewis acid (5.0 mol%), solvent, 0 °C; (3) phase-switch workup.
b NMR yield using 1,3,5-trimethoxybenzene as internal standard.
c A 1 : 1 mixture of the two solvents was used.
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itself to streamlined operations wherein isolation and purifi-
cation of intermediates can be minimized or avoided.
Experimental
General methods
Stainless steel syringes were used to transfer air- and moisture
sensitive liquids. Flash chromatography was performed using
silica gel (60 Å, 230–400 mesh). Thin-layer chromatography
(TLC) was performed using aluminum-backed silica gel plates,
products were visualized by UV irradiation at 254 nm and by
staining with KMnO4 solution. Toluene and dichloromethane
used in alkylation chemistry was purified by passing through
two columns of activated alumina under nitrogen. Deionized
water was acquired from an in-house supply. Pyridine used for
regioselective reactions with PivCl was dried over calcium
hydride with stirring at 80 °C prior to use. The remainder of
reagents and solvents were purchased from Sigma-Aldrich,
Caledon or Alfa Aesar and were used without further purifi-
cation. Nuclear magnetic resonance (NMR) solvents were pur-
chased from Cambridge Isotope Laboratories. Proton nuclear
magnetic resonance (1H NMR) spectra and carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on a
400 MHz Varian Mercury spectrometer or 400 MHz Bruker
spectrometer. Chemical shifts for protons are reported in parts
per million (ppm) downfield from tetramethylsilane and are
referenced to residual protium in the NMR solvent (CDCl3:
δ 7.26; DMSO-d6: δ 2.50). Chemical shifts for carbon (13C NMR)
are reported in parts per million downfield from tetramethyl-
silane and are referenced to the carbon resonances of
the solvent (CDCl3: δ 77.16; DMSO-d6: δ 39.52). Data are
Scheme 3 Sequential functionalizations of a boronic ester-protected
glucopyranoside.
Sequential installation of pivaloyl and para-methoxybenzyl
groups was also achieved. 4-(Trifluoromethyl)phenylboronic
acid, the optimal protecting group for the PMB installation
protocol (see above), was used in this case. After the reaction
with PivCl was complete, the pyridinium chloride byproduct
was removed by precipitation and filtration, and a solvent
switch from pyridine to toluene was conducted. Without
further purification, the intermediate arylboronate was sub-
jected to the trichloroacetimidate and La(OTf)3, followed by
phase-switch deprotection. Product 7a was obtained in 43%
yield over this reaction sequence.
Conclusions
In summary, installation of acyl, silyl and para-methoxybenzyl represented as follows: chemical shift (δ, ppm); multiplicity
groups to glycoside substrates can be accomplished in a pre- (s, singlet; d, doublet; app t, apparent triplet; br s, broad
paratively useful way by employing boronic esters as protective singlet; m, multiplet); integration; coupling constant (J, Hz),
groups for cis-1,2- or 1,3-diol motifs. The sequence of protec- proton assignment. Proton resonances were assigned based on
tion, functionalization and deprotection can be conducted in 2-D COSY and HSQC experiments. High-resolution mass
one pot, which is not typically the case for similar operations spectra (HRMS) were obtained on a VS 70-250S (double focus-
using acetal or ketal protective groups. For the most part, the ing) mass spectrometer at 70 eV using either electrospray
boronic esters are sufficiently robust to enable efficient acyla- ionization (ESI) or direct analysis in real time (DART)
tion and silylation under standard conditions, although methods. Infrared (IR) spectra were obtained on a Fourier-
boronic ester migration led to mixtures of products for the α-D- transform IR instrument equipped with a single-bounce
galactopyranoside substrate. Using PMB trichloroacetimidate diamond/ZnSe ATR accessory. Spectral features are represented
and La(OTf)3, we were able to expand the scope of available as follows: wavenumber (cm−1); intensity (s, strong; m,
transformations of glycoside-derived boronic esters to include medium; w, weak; br, broad). Optical rotations were measured
alkylation. The use of the phase-switching workup to enable on an automatic polarimeter. Specific rotation values are
both the deprotection of the boronic ester and the separation reported in 10−1 deg cm2 g−1 (c g per 100 mL in CHCl3).
of the glycoside and boronic acid components contributed in
General procedure A: regioselective benzoylation of methyl
an important way to the overall efficiency of the processes glycosides. Methyl glycoside (5.00 mmol) and phenylboronic
described here. These relatively mild conditions for boronic acid (0.610 g, 5.00 mmol, 1.00 equiv.) were placed in a round
ester hydrolysis are tolerant of several functional groups, bottom flask equipped with stir bar. Toluene (25.0 mL) was
including esters, silyl ethers, ketals and thioglycosides. added to the flask and the solution was placed in an oil bath
Overall, our results suggest that boronic esters have features set at 110 °C and stirred overnight. The solution was then
that may be complementary to those of acetals and ketals. cooled to room temperature and solvent was removed under
Boronic esters are arguably less well suited to multistep reac- reduced pressure. Residual water was removed from the result-
tion sequences, but their relatively facile deprotection lends ing material by azeotroping with toluene three times, followed
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by drying under high vacuum to yield the desired boronic temperature. Neat hydrochloric acid was added slowly until
ester. This material was then dissolved in anhydrous pyridine the solution reached pH 1–2. The solution was then trans-
(10.0 mL) and cooled to 0 °C with stirring. Benzoyl chloride ferred to a separatory funnel and washed three times with
(0.870 mL, 7.50 mmol, 1.50 equiv.) was added quickly to the ethyl acetate. The combined organic extracts were washed with
reaction vessel, and the solution was removed from the ice brine and then dried over magnesium sulfate, filtered and con-
bath and allowed to warm to room temperature. The reaction centrated under reduced pressure to yield a white solid.
was allowed to stir for 30 minutes before verifying complete 1H NMR spectroscopy showed that the material contained
conversion by 1H NMR spectroscopic analysis of a 10 μL some residual sorbitol-bound boronic acid. Thus, the solid
aliquot of the reaction mixture. Once complete, the reaction was transferred to a 250 mL Erlenmeyer flask and suspended
was diluted with toluene and filtered through a pad of tightly in water, which was acidified to pH 1 with addition of a 6.0 M
packed Celite followed by removal of the solvent under solution of aqueous hydrochloric acid. The resulting suspen-
reduced pressure. The crude material was then dissolved in sion was brought to a boil with vigorous stirring until the solid
200 mL ethyl acetate and transferred to a separatory funnel was completely dissolved. After cooling, the solution was trans-
containing 200 mL of a 1.0 M sorbitol/1.0 M sodium carbonate ferred to a separatory funnel, washed three times with ethyl
aqueous solution and shaken by hand for five minutes. The acetate and the organic phases were combined before washing
organic phase was collected and the aqueous phase was with brine solution. The organic phase was then dried over
washed with ethyl acetate an additional three times. The com- magnesium sulfate, filtered and solvent removed under
bined organic extracts were dried over magnesium sulfate, reduced pressure to yield the boronic acid.
filtered and solvent was removed under reduced pressure to
Methyl 2,3-bis-O-benzoyl-α-D-glucopyranoside (3a). Prepared
yield the crude product, which was then purified by flash from methyl α-D-glucopyranoside (0.971 g, 5.00 mmol) accord-
chromatography on silica gel (gradient elution, acetone in ing to general procedure A with the following amendment:
dichloromethane).
benzoyl chloride (1.700 mL, 15.00 mmol, 3.00 equiv.). The title
General procedure B: regioselective PMB protection of compound was isolated as an amorphous white solid (1.619 g,
methyl glycosides. Methyl glycoside (5.00 mmol) and 4-(tri- 80%). NMR data were consistent with previous literature
fluoromethyl)phenylboronic acid (0.950 g, 5.00 mmol, reports.13 1H NMR (400 MHz, CDCl3): δ (ppm) 7.98–7.95
1.00 equiv.) were placed in a round bottom flask equipped (m, 4H, o-ArH), 7.52–7.46 (m, 2H, p-ArH), 7.38–7.32 (m, 4H,
with stir bar. Toluene (25.0 mL) was added to the flask and the m-ArH), 5.76 (dd, 1H, J = 10.1, 9.0 Hz, H-3), 5.22 (dd, 1H, J =
solution was placed in an oil bath set at 110 °C and stirred 10.1, 3.6 Hz, H-2), 5.13 (d, 1H, J = 3.6 Hz, H-1), 3.99–3.90
overnight. The solution was then cooled to room temperature (m, 3H, H-4, H-6, H-6), 3.88–3.84 (m, 1H, H-5), 3.42 (s, 3H,
and solvent was removed under reduced pressure. Residual OCH3), 3.42 (br s, 1H, 6-OH), 2.40 (br s, 1H, 4-OH).
water was removed from the resulting material by azeotroping Phenylboronic acid was recovered according to general
with toluene three times, followed by drying under high procedure C (0.471 g, 77%).
vacuum to yield the desired boronic ester. This material was
Methyl 4-O-benzoyl-α-L-rhamnopyranoside (3b). Prepared
then dissolved in anhydrous toluene (25.0 mL) and cooled to from methyl α-L-rhamnopyranoside (0.891 g, 5.00 mmol)
0 °C with stirring. Lanthanum(III) trifluoromethanesulfonate according to general procedure A to yield the title compound
(29.0 mg, 0.0500 mmol, 0.0100 equiv.) was then added, fol- as an amorphous white solid (1.156 g, 82%). NMR data were
lowed by dropwise addition of 4-methoxybenzyl trichloro- consistent with previous literature reports.13 1H NMR
acetimidate (3.10 mL, 15.00 mmol, 3.00 equiv.) over (400 MHz, CDCl3):
δ (ppm) 8.04–8.02 (m, 2H, o-ArH),
25 minutes. The reaction was allowed to stir for an additional 7.59–7.55 (m, 1H, p-ArH), 7.45–7.41 (m, 2H, m-ArH), 5.07
1
five minutes before verifying complete conversion by H NMR (app t, 1H, J = 9.3 Hz, H-4), 4.75 (d, 1H, J = 1.1 Hz, H-1),
spectroscopic analysis of a 10 μL aliquot of the reaction 4.02–3.91 (m, 3H, H-2, H-3, H-5), 3.40 (s, 3H, OCH3), 3.35 (br s,
mixture. Once complete, the reaction was quenched with tri- 1H, OH), 3.19 (br s, 1H, OH), 1.28 (d, 3H, J = 6.3 Hz, CH3).
ethylamine followed by removal of the solvent under reduced Phenylboronic acid was recovered according to general
pressure. The crude material was then dissolved in 200 mL procedure C (0.448 g, 73%).
ethyl acetate and transferred to a separatory funnel containing
Methyl 2-O-benzoyl-6-O-(tert-butyldimethylsilyl)-α-D-galacto-
200 mL of a 1.0 M sorbitol/1.0 M sodium carbonate aqueous pyranoside (3c). Prepared from methyl 6-O-(tert-butyldimethyl-
solution and shaken by hand for five minutes. The organic silyl)-α-D-galactopyranoside (0.617 g, 2.00 mmol) according to
phase was collected and the aqueous phase was washed with general procedure A with the following amendments: phenyl-
ethyl acetate an additional three times. The combined organic boronic acid (0.244 g, 2.00 mmol, 1.00 equiv.), benzoyl chlor-
extracts were dried over magnesium sulfate, filtered and ide (0.350 mL, 3.00 mmol, 1.50 equiv.), toluene (10.0 mL), pyri-
solvent was removed under reduced pressure to yield the crude dine (4.00 mL). The title compound was isolated as an amor-
product, which was then purified by flash chromatography on phous white solid (0.721 g, 87%). NMR data were in agreement
silica gel (gradient elution, acetone in dichloromethane).
with previous literature reports.25 1H NMR (400 MHz, CDCl3):
General procedure C: recovery of boronic acid from aqueous δ (ppm) 8.09–8.06 (m, 2H, o-ArH), 7.57–7.53 (m, 1H, p-ArH),
extract. Modified from literature procedure.17 Aqueous extract 7.45–7.41 (m, 2H, m-ArH), 5.27 (dd, 1H, J = 10.0, 3.8 Hz, H-2),
containing sorbitol-bound boronate was stirred at room 5.03 (d, 1H, J = 3.8 Hz, H-1), 4.18–4.17 (m, 1H, H-4), 4.12
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(dd, 1H, J = 10.0, 3.5 Hz, H-3), 3.97–3.89 (m, 2H, H-6, H-6), 5.5 Hz, H-6), 4.09–3.98 (m, 3H, H-3, H-4, H-5), 1.37 (s, 3H, CH3),
3.85–3.82 (m, 1H, H-5), 3.28 (s, 3H, OCH3), 0.91 (s, 9H, 1.23 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): δ (ppm)
(CH3)3CSi), 0.11 (s, 3H, CH3Si), 0.11 (s, 3H, CH3Si).
Methyl 4-O-benzoyl-6-O-(tert-butyldimethylsilyl)-α-D-manno- 72.9, 67.5, 65.2, 26.6, 26.2. HRMS (DART, m/z) Calculated
pyranoside (3d). Prepared from methyl 6-O-(tert-butyldimethyl- for [C16H21O7] (M
H)+ 325.12873; Found: 325.12870.
165.7, 133.3, 129.9, 129.2, 128.6, 110.6, 104.5, 84.7, 80.1,
+
silyl)-α-D-mannopyranoside (1.542 g, 5.00 mmol) according to Phenylboronic acid was recovered according to general
general procedure A to yield the title compound as a colorless procedure C (0.485 g, 80%).
gummy solid (1.632 g, 79%). TLC Rf = 0.61 (acetone/dichloro-
Phenyl 2,3-bis-O-benzoyl-1-thio-β-D-glucopyranoside (3g).
methane 1 : 4). [α]2D0 = 41.5 (c 0.92 in CHCl3). FTIR (powder, Prepared from phenyl 1-thio-β-D-glucopyranoside (0.545 g,
cm−1): 3420 (br), 2954 (w), 2935 (w), 2857 (w), 1718 (m), 2.00 mmol) according to general procedure A with the follow-
1316 (w), 1261 (s), 1106 (s), 1065 (s), 1027 (s), 970 (m), 834 (s), ing amendments: benzoyl chloride (0.700 mL, 6.00 mmol,
1
776 (s), 708 (s). H NMR (400 MHz, CDCl3): δ (ppm) 8.06–8.03 3.00 equiv.), toluene (10.0 mL), pyridine (4.0 mL). The title
(m, 2H, o-ArH), 7.61–7.57 (m, 1H, p-ArH), 7.48–7.43 (m, 2H, compound was isolated as an amorphous white solid (0.659 g,
m-ArH), 5.22 (app t, 1H, J = 9.6 Hz, H-4), 4.82 (d, 1H, J = 69%). NMR data were consistent with previous literature
1.5 Hz, H-1), 4.05 (dd, 1H, J = 9.4, 3.5 Hz, H-3), 3.98 (dd, 1H, reports.27 1H NMR (400 MHz, CDCl3): δ (ppm) 7.98–7.93
J = 3.5, 1.5 Hz, H-2), 3.92–3.88 (m, 1H, H-5), 3.80 (d, 2H, J = (m, 4H, ArH), 7.55–7.49 (m, 2H, ArH), 7.48–7.44 (m, 2H, ArH),
4.2 Hz, H-6, H-6), 3.43 (s, 3H, OCH3), 0.85 (s, 9H, (CH3)3CSi), 7.41–7.35 (m, 4H, ArH), 7.33–7.26 (m, 3H, ArH), 5.45–5.40
0.00 (s, 3H, CH3Si), 0.00 (s, 3H, CH3Si). 13C NMR (100 MHz, (m, 2H, H-2, H-3), 5.00–4.95 (m, 1H, H-1), 4.03 (dd, 1H, J =
CDCl3): δ (ppm) 167.4, 133.6, 130.0, 129.6, 128.6, 100.5, 71.4, 12.0, 3.3 Hz, H-6), 3.96–3.87 (m, 2H, H-4, H-6), 3.66–3.61
70.89, 70.87, 70.8, 63.0, 55.1, 26.0, 18.4, −5.25, −5.29. HRMS (m, 1H, H-5), 3.20 (br s, 1H, OH), 2.1 (br s, 1H, OH).
(DART, m/z) Calculated for [C20H33O7Si] (M + H)+ 413.19955;
Methyl
2-O-fluorenylmethyloxycarbonyl-6-O-(tert-butlydi-
Found: 413.19978.
methylsilyl)-α-D-galactopyranoside (3h). Prepared from methyl
Methyl 2,3-bis-O-benzoyl-α-D-galactopyranoside (3e). Prepared 6-O-(tert-butyldimethylsilyl)-α-D-galactopyranoside (0.617 g,
from methyl α-D-galactopyranoside (0.971 g, 5.00 mmol) 2.00 mmol) according to general procedure A with the follow-
according to general procedure A with the following amend- ing amendments: phenylboronic acid (0.244 g, 2.00 mmol,
ment: benzoyl chloride (1.700 mL, 15.00 mmol, 3.00 equiv.). 1.00 equiv.), 9-fluorenylmethoxycarbonyl chloride (0.776 g,
The title compound was isolated as an amorphous white solid 3.00 mmol, 1.50 equiv.) instead of benzoyl chloride as the
(1.133 g, 56%). NMR data were consistent with previous litera- electrophile, toluene (10.0 mL), pyridine (4.0 mL). The title
ture reports.26 1H NMR (400 MHz, CDCl3): δ (ppm) 8.00–7.95 compound was isolated as an amorphous white solid
(m, 4H, ArH), 7.52–7.47 (m, 2H, ArH), 7.38–7.33 (m, 4H, ArH), (0.840 mg, 79%). TLC Rf = 0.83 (acetone/dichloromethane
5.70–5.69 (m, 2H, H-2, H-3), 5.21 (d, 1H, J = 1.9 Hz, H-1), 4.47 1 : 4). [α]2D0 = 35.4 (c 1.10 in CHCl3). FTIR (powder, cm−1):
(dd, 1H, J = 2.6, 1.2 Hz, H-4), 4.06–3.99 (m, 2H, H-5, H-6), 3.95 3432 (br), 2958 (w), 2937 (w), 2856 (w), 1743 (m), 1450 (m),
(dd, 1H, J = 11.3, 4.0 Hz, H-6), 3.44 (s, 3H, OCH3). NMR 1388 (w), 1256 (s), 1097 (s), 1035 (s), 988 (m), 836 (s), 734 (s).
data for the minor regioisomer methyl 2,6-bis-O-benzoyl-α-D- 1H NMR (400 MHz, CDCl3): δ (ppm) 7.78–7.75 (m, 2H, ArH),
galactopyranoside (3e′): 1H NMR (400 MHz, CDCl3): δ (ppm) 7.65–7.62 (m, 2H, ArH), 7.43–7.39 (m, 2H, ArH), 7.34–7.30
8.10–8.05 (m, 4H, o-ArH), 7.61–7.57 (m, 2H, p-ArH), 7.48–7.43 (m, 2H, ArH), 4.99 (d, 1H, J = 3.8 Hz, H-1), 4.95 (dd, 1H, J = 9.9,
(m, 4H, m-ArH), 5.28 (dd, 1H, J = 10.1, 3.7 Hz, H-2), 5.08 3.8 Hz, H-2), 4.48–4.40 (m, 2H, (O-2)CH2), 4.29 (app t, 1H, J =
(d, 1H, J = 3.7 Hz, H-1), 4.72 (dd, 1H, J = 11.5, 6.8 Hz, H-6), 7.4 Hz, (O-2)CH2CH), 4.17 (dd, 1H, J = 3.4, 1.2 Hz, H-4), 4.06
4.52 (dd, 1H, J = 11.5, 6.8 Hz, H-6), 4.23–4.17 (m, 2H, H-3, (dd, 1H, J = 9.9, 3.4 Hz, H-3), 3.95 (dd, 1H, J = 10.8, 5.2 Hz,
H-5), 4.12 (dd, 1H, J = 3.8, 1.1 Hz, H-4), 3.41 (s, 3H, OCH3), H-6), 3.91 (dd, 1H, J = 10.8, 4.5 Hz, H-6), 3.82–3.79 (m, 1H,
3.00 (br s, 1H, OH), 2.90 (br s, 1H, OH). 13C NMR (100 MHz, H-5), 3.41 (s, 3H, OCH3), 3.41 (br s, 1H, OH), 2.66 (br s, 1H,
CDCl3): δ (ppm) 167.2, 166.8, 133.6, 133.5, 130.1, 129.9, 129.8, OH), 0.92 (s, 9H, (CH3)3CSi), 0.11 (s, 3H, CH3Si), 0.11 (s, 3H,
129.6, 128.63, 128.58, 97.7, 72.5, 69.5, 68.5, 67.8, 63.6, 55.7.
CH3Si). 13C NMR (100 MHz, CDCl3) δ (ppm) 155.4, 143.5,
1,2-O-Isopropylidene-6-O-benzoyl-α-D-glucofuranose
(3f). 143.4, 141.44, 141.41, 128.02, 128.01, 127.33, 127.28, 125.4,
Prepared from 1,2-O-isopropylidene-α-D-glucofuranose (1.101 g, 120.17, 120.16, 97.5, 75.5, 70.6, 70.4, 69.1, 68.7, 63.7, 55.5,
5.00 mmol) according to general procedure A to yield the title 46.8, 26.0, 18.4, −5.3, −5.4. HRMS (ESI, m/z) Calculated for
compound as an amorphous white solid (1.491 g, 92%). TLC [C28H42O8Si] (M + NH4)+ 548.2667; Found: 548.2674.
Rf = 0.45 (acetone/dichloromethane 1 : 4). [α]2D0 = 2.7 (c 1.27 in
Methyl 2-O-trimethylacetyl-α-D-glucopyranoside (3i). Methyl
CHCl3). FTIR (powder, cm−1): 3487 (m), 3458 (w), 2945 (w), α-D-glucopyranoside (0.971 g, 5.00 mmol) and phenylboronic
2897 (w), 1687 (s), 1456 (w), 1378 (w), 1322 (m), 1288 (s), acid (0.610 g, 5.00 mmol, 1.00 equiv.) were placed in a round
1213 (m), 1138 (m), 1064 (s), 1005 (s), 952 (m), 881 (m), 782 (m), bottom flask equipped with stir bar. Toluene (25.0 mL) was
713 (s), 619 (m). 1H NMR (400 MHz, DMSO-d6): δ (ppm) added to the flask and the solution was placed in an oil bath
8.03–8.00 (m, 2H, o-ArH), 7.68–7.64 (m, 1H, p-ArH), 7.55–7.51 set at 110 °C and stirred overnight. The solution was then
(m, 2H, m-ArH), 5.82 (d, 1H, J = 3.7 Hz, H-1), 5.30 (d, 1H, J = cooled to room temperature and solvent was removed under
4.9 Hz, OH), 5.21 (d, 1H, J = 5.9 Hz, OH), 4.46 (dd, 1H, J = 11.3, reduced pressure. Residual water was removed from the result-
2.0 Hz, H-6), 4.41 (d, 1H, J = 3.7 Hz, H-2), 4.20 (dd, 1H, J = 11.3, ing material by azeotroping with toluene three times, followed
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by drying under high vacuum to yield the desired boronic placed in an oil bath set at 110 °C and stirred overnight. The
ester. This material was then dissolved in anhydrous pyridine solution was then cooled to room temperature and solvent was
(10.0 mL) and cooled to 0 °C with stirring. Trimethylacetyl removed under reduced pressure. Residual water was removed
chloride (0.740 mL, 6.00 mmol, 1.20 equiv.) was added quickly from the resulting material by azeotroping with toluene three
to the reaction vessel, and the solution was removed from the times, followed by drying under high vacuum to yield the
ice bath and allowed to warm to room temperature. The reac- desired boronic ester. This material was then dissolved in
tion was allowed to stir for 30 minutes, at which point anhydrous pyridine (10.0 mL) with stirring, and tert-butyldi-
1H NMR spectroscopic analysis of a 10 μL aliquot of the reac- methylsilyl chloride (1.130 g, 7.50 mmol, 1.50 equiv.) was
tion mixture showed approximately 20–25% of unreacted start- added to the reaction vessel. The solution was heated to 60 °C
ing material. Additional trimethylacetyl chloride (0.200 mL, and stirred for two days before cooling to room temperature.
1
1.62 mmol) was added and the reaction was stirred for an After verifying complete conversion by H NMR spectroscopic
additional 30 minutes before another aliquot was taken and analysis of a 10 μL aliquot of the reaction mixture, the reaction
complete conversion was observed by 1H NMR spectroscopy. was diluted with toluene and filtered through a pad of tightly
Once complete, the reaction was diluted with toluene and packed Celite, followed by removal of the solvent under
filtered through a pad of tightly packed Celite, followed by reduced pressure. The crude material was then dissolved in
removal of the solvent under reduced pressure. The crude 200 mL of a 1.0 M sorbitol/1.0 M sodium carbonate aqueous
material was then dissolved in toluene (25.0 mL) and pinacol solution and shaken by hand for five minutes. The organic
(2.950 g, 25.00 mmol, 5.00 equiv.) was added to the flask phase was collected and the aqueous phase was washed with
before heating the solution to 110 °C and stirring overnight. ethyl acetate an additional three times. The combined organic
The solution was then cooled to room temperature and solvent extracts were dried over magnesium sulfate, filtered and
was removed under reduced pressure to yield the crude solvent was removed under reduced pressure to yield the crude
product, which was then purified by flash chromatography on product which was then purified by flash chromatography on
silica gel (gradient elution, acetone in dichloromethane) to silica gel (gradient elution, acetone in dichloromethane) to
yield the desired product as an amorphous white solid yield the desired product as an amorphous white solid
(1.002 g, 72%). NMR data were consistent with previous litera- (1.388 g, 95%). TLC Rf = 0.53 (acetone/dichloromethane 1 : 4).
ture reports.28 1H NMR (400 MHz, CDCl3): δ (ppm) 4.88 [α]D20 = −32.1 (c 1.25 in CHCl3). FTIR (powder, cm−1): 3465
(d, 1H, J = 3.8 Hz, H-1), 4.63 (dd, 1H, J = 9.9, 3.8 Hz, H-2), (br), 2936 (m), 2858 (m), 1462 (w), 1405 (w), 1249 (m), 1114 (s),
3.98–3.93 (m, 1H, H-3), 3.88–3.84 (m, 2H, H-6, H-6), 3.67–3.61 1061 (s) 976 (m), 880 (s), 833 (s), 774 (s), 673 (s). 1H NMR
(m, 2H, H-4, H-5), 3.36 (s, 3H, OCH3), 1.23 (s, 9H, (CH3)3CCO).
(400 MHz, CDCl3): δ (ppm) 4.65 (d, 1H, J = 1.6 Hz, H-1), 3.90
Methyl 2,3-bis-O-(triethylsilyl)-α-D-glucopyranoside (4a). (dd, 1H, J = 3.5, 1.6 Hz, H-2), 3.69 (dd, 1H, J = 8.8, 3.5 Hz, H-3),
Prepared from methyl α-D-glucopyranoside (0.971 g, 3.63–3.56 (m, 1H, H-5), 3.44 (app t, 1H, J = 9.0 Hz, H-4), 3.35
5.00 mmol) according to general procedure A with the follow- (s, 3H, OCH3), 2.33 (br s, 2H, 2-OH, 3-OH), 1.26 (d, 3H, J = 6.3
ing amendment: instead of benzoyl chloride, chlorotriethyl- Hz, CH3), 0.90 (s, 9H, (CH3)3CSi), 0.13 (s, 3H, CH3Si), 0.10
silane (2.500 mL, 15.00 mmol, 3.00 equiv.) was used as the (s, 3H, CH3Si). 13C NMR (100 MHz, CDCl3): δ (ppm) 100.6,
electrophile. The title compound was isolated as a colorless oil 75.0, 72.3, 71.4, 68.2, 55.0, 26.1, 18.4, 18.2, −3.7, −4.3. HRMS
(1.769 g, 84%). It should be noted that the product de- (DART, m/z) Calculated for [C13H32NO5Si] (M
+
NH4)+
composes upon prolonged storage at room temperature and 310.20497; Found: 310.20448. Phenylboronic acid was re-
should be stored at −20 °C. TLC Rf = 0.67 (acetone/dichloro- covered according to general procedure C (0.469 g, 77%).
methane 1 : 4). [α]2D0 = 31.6 (c 1.65 in CHCl3). FTIR (neat,
Methyl 2,6-bis-O-(triethylsilyl)-α-D-galactopyranoside (4e).
cm−1): 3385 (br), 2953 (m), 2911 (m), 2877 (m), 1460 (w), 1413 Prepared from methyl α-D-galactopyranoside (0.971 g,
(w), 1238 (w), 1194 (w), 1150 (s) 1116 (s), 1090 (m), 1046 (s), 5.00 mmol) according to general procedure A with the follow-
1
1010 (s), 836 (m), 732 (s), 674 (m). H NMR (400 MHz, CDCl3): ing amendment: instead of benzoyl chloride, chlorotriethyl-
δ (ppm) 4.62 (d, 1H, J = 3.5 Hz), 3.83–3.77 (m, 3H, H-3, H-6, silane (2.500 mL, 15.00 mmol, 3.00 equiv.) was used as the
H-6), 3.63–3.58 (m, 1H, H-5), 3.50 (dd, 1H, J = 9.0, 3.5 Hz, H-2), electrophile. The title compound was isolated as a colorless oil
3.41 (dd, 1H, J = 9.8, 8.4 Hz, H-4), 3.36 (s, 3H, OCH3), 2.30 (br (1.254 g, 59%). It should be noted that the product decom-
s, OH), 2.09 (br s, OH), 0.99–0.95 (m, 18H, 6 × (CH3CH2Si)), poses upon storage at room temperature and should be stored
0.70–0.59 (m, 12H, 6 × (CH2Si)). 13C NMR (100 MHz, CDCl3): at −20 °C. TLC Rf = 0.73 (acetone/dichloromethane 1 : 4).
δ (ppm) 100.6, 75.3, 73.8, 72.2, 70.8, 62.8, 55.1, 7.1, 6.9, 5.5, [α]2D0 = 32.1 (c 1.06 in CHCl3). FTIR (powder, cm−1): 3453 (br),
5.2. HRMS (ESI, m/z) Calculated for [C19H42NaO6Si2] (M + Na)+ 2953 (m), 2911 (m), 2877 (m), 1458 (w), 1414 (w), 1355 (w),
445.2412; Found: 445.2416. Phenylboronic acid was recovered 1238 (w), 1192 (w), 1131 (s), 1095 (s), 1049 (s), 1005 (s),
1
according to general procedure C (0.491 g, 81%).
937 (m), 831 (m), 728 (s). H NMR (400 MHz, CDCl3): δ (ppm)
Methyl 4-O-(tert-butyldimethylsilyl)-α-L-rhamnopyranoside 4.68 (d, 1H, J = 3.6 Hz, H-1), 4.11 (dd, 1H, J = 3.3, 1.2 Hz, H-4),
(4b). Methyl α-L-rhamnopyranoside (0.891 g, 5.00 mmol) and 3.95 (dd, 1H, J = 9.6, 3.6 Hz, H-2), 3.91 (dd, 1H, J = 10.3,
phenylboronic acid (0.610 g, 5.00 mmol, 1.00 equiv.) were 5.7 Hz, H-6), 3.87–3.80 (m, 2H, H-3, H-6), 3.80–3.77 (m, 1H,
placed in a round bottom flask equipped with stir bar. H-5), 3.39 (s, 3H, OCH3), 2.88 (s, 1H, 4-OH), 2.37 (s, 1H, 3-OH),
Toluene (25.0 mL) was added to the flask and the solution was 0.99–0.95 (m, 18H, 6 × (CH3CH2Si)), 0.67–0.56 (m, 12H,
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6 × (CH2Si)). 13C NMR (100 MHz, CDCl3): δ (ppm) 100.3, 70.8, butyldimethylsilyl)-α-D-galactopyranoside (0.487 g, 1.58 mmol)
70.6, 69.9, 69.6, 62.8, 55.3, 6.82, 6.81, 5.0, 4.4. HRMS (ESI, m/z) according to general procedure B with the following amend-
calc’d for C19H42NaO6Si2 [M + Na]+ 445.2412; found 445.2415.
ments: 4-(trifluoromethyl)phenylboronic acid (300 mg,
Methyl 2,3-bis-O-(triethylsilyl)-α-D-galactopyranoside (4e′). 1.58 mmol, 1.00 equiv.), 4-methoxybenzyl trichloroacetimidate
Prepared from methyl α-D-galactopyranoside (0.971 g, (0.980 mL, 4.74 mmol, 3.00 equiv.), lanthanum(III) trifluoro-
5.00 mmol) according to general procedure A with the follow- methanesulfonate (9.00 mg, 0.0158 mmol, 0.0100 equiv.),
ing amendment: instead of benzoyl chloride, chlorotriethyl- toluene (8.0 mL). The title compound was isolated as an amor-
silane (2.500 mL, 15.00 mmol, 3.00 equiv.) was used as the phous white solid (0.455 g, 67%). TLC Rf = 0.62 (acetone/di-
electrophile. The title compound was isolated as a colorless oil chloromethane 1 : 4). [α]2D0 = 35.1 (c 1.19 in CHCl3). FTIR
(0.356 g, 17%). It should be noted that the product decom- (powder, cm−1): 3420 (br), 2933 (w), 2859 (w), 1612 (w),
poses upon storage at room temperature and should be stored 1515 (m), 1250 (s), 1079 (s), 1048 (s), 1017 (s), 965 (m), 833 (s),
at −20 °C. TLC Rf = 0.46 (acetone/dichloromethane 1 : 9). 772 (s), 750 (m). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.29–7.26
[α]2D0 = 38.0 (c 1.06 in CHCl3). FTIR (powder, cm−1): 3445 (br), (m, 2H, o-ArH), 6.88–6.85 (m, 2H, m-ArH), 4.65 (d, 1H, J =
29.53 (m), 2912 (m), 2877 (m), 1458 (w), 1413 (w), 1355 (w), 3.5 Hz, H-1), 4.60 (s, 2H, ArCH2), 4.07–4.05 (m, 1H, H-4),
1238 (w), 1194 (w), 1138 (s), 1100 (s), 1040 (s), 1005 (s), 849 (s), 3.95–3.90 (m, 1H, H-3), 3.85 (dd, 1H, J = 10.3, 5.8 Hz, H-6),
1
728 (s). H NMR (400 MHz, CDCl3): δ (ppm) 4.69 (d, 1H, J = 3.81–3.73 (m, 5H, H-5, H-6, ArOCH3), 3.71 (dd, 1H, J = 9.7,
3.5 Hz, H-1), 3.98–3.92 (m, 2H, H-3, H-6), 3.88–3.78 (m, 4H, 3.8 Hz, H-2), 3.33 (s, 3H, OCH3), 2.91 (d, 1H, J = 1.8 Hz, 4-OH),
H-2, H-4, H-5, H-6), 3.38 (s, 3H, OCH3), 2.44 (br s, 2H, 4-OH, 2.61 (d, 1H, J = 3.8 Hz, 3-OH), 0.88 (s, 9H, (CH3)3CSi), 0.07
6-OH), 0.99–0.94 (m, 18H, 6 × (CH3CH2Si)), 0.69–0.61 (m, 12H, (s, 3H, CH3Si), 0.07 (s, 3H, CH3Si). 13C NMR (100 MHz, CDCl3):
6 × (CH2Si)). 13C NMR (100 MHz, CDCl3): δ (ppm) 100.7, 71.9, δ (ppm) 159.6, 130.3, 129.8, 114.1, 98.0, 76.6, 72.7, 69.7, 69.6,
71.3, 70.3, 68.9, 63.3, 55.4, 7.0, 6.9, 5.2, 5.1. HRMS (ESI, m/z) 69.4, 63.0, 55.4, 55.3, 25.9, 18.4, −5.3, −5.4. HRMS (ESI, m/z)
Calculated for [C19H42NaO6Si2] (M + Na)+ 445.2412; Found: Calculated for [C21H36NaO7Si] (M + Na)+ 451.2123; Found:
445.2410.
451.2120.
Methyl
2,3-bis-O-(p-methoxybenzyl)-α-D-glucopyranoside
Methyl 4-O-(p-methoxybenzyl)-6-O-(dimethyl-tert-butylsilyl)-
(5a). Prepared from methyl α-D-glucopyranoside (0.971 g, α-D-mannopyranoside (5d). Prepared from methyl 6-O-(tert-
5.00 mmol) according to general procedure B with the follow- butyldimethylsilyl)-α-D-mannopyranoside (1.542 g, 5.00 mmol)
ing amendments: a 1 : 1 mixture of toluene and dichloro- according to general procedure B to yield the title compound
methane (by volume) was used as the solvent, and 4-methoxy- as an amorphous white solid (1.430 g, 67%). TLC Rf = 0.43
benzyl trichloroacetimidate (6.20 mL, 30 mmol, 6.00 equiv.) (acetone/dichloromethane 1 : 4). [α]D20
= 23.36 (c 1.37 in
was added to the reaction in one portion prior to the addition CHCl3). FTIR (powder, cm−1): 3335 (br), 2952 (w), 2929 (w),
of lanthanum(III) trifluoromethanesulfonate at 0 °C. The title 2856 (w), 1615 (w), 1515 (m), 1249 (m), 1094 (s), 1063 (s),
1
compound was isolated as a colorless syrup (1.112 g, 51%). 1026 (s), 965 (m), 832 (s), 779 (s). H NMR (400 MHz, CDCl3):
NMR data were consistent with previous literature reports.29 δ (ppm) 7.30–7.27 (m, 2H, o-ArH), 6.91–6.87 (m, 2H, m-ArH),
1H NMR (400 MHz, CDCl3): δ (ppm) 7.31–7.27 (m, 4H, o-ArH), 4.70–4.63 (m, 3H, H-1, ArCH2), 3.90–3.85 (m, 4H, H-2, H-3,
6.91–6.86 (m, 4H, m-ArH), 4.94 (d, 1H, J = 11.2 Hz, ArCH), 4.72 H-6, H-6), 3.81 (s, 3H, ArOCH3), 3.64 (dd, 1H, J = 9.8, 8.5 Hz,
(d, 1H, J = 11.8 Hz, ArCH), 4.62 (d, 1H, J = 11.2 Hz, ArCH), 4.61 H-4), 3.57–3.52 (m, 1H, H-5), 3.34 (s, 3H, OCH3), 1.97 (br s, 2H,
(d, 1H, J = 11.8 Hz, ArCH), 4.55 (d, 1H, J = 3.6 Hz, H-1), 3.81 2-OH, 3-OH), 0.92 (s, 9H, (CH3)3CSi), 0.10 (s, 3H, CH3Si), 0.09
(s, 3H, ArOCH3), 3.80 (s, 3H, ArOCH3), 3.80–3.70 (m, 3H, H-3, (s, 3H, CH3Si). 13C NMR (100 MHz, CDCl3): δ (ppm) 159.6,
H-6, H-6), 3.62–3.58 (m, 1H, H-5), 3.49–3.44 (m, 2H, H-2, H-4), 130.7, 129.8, 114.2, 100.5, 75.5, 74.4, 72.1, 71.8, 71.1, 62.6,
3.37 (s, 3H, OCH3). 4-(Trifluoromethyl)phenylboronic acid was 55.4, 54.9, 26.1, 18.5, −5.0, −5.2. HRMS (ESI, m/z) Calculated
recovered according to general procedure C (0.857 g, 90%).
for [C21H36NaO7Si] (M + Na)+ 451.2123; Found: 451.2124.
Methyl 4-O-(p-methoxybenzyl)-α-L-rhamnopyranoside (5b). 4-(Trifluoromethyl)phenylboronic acid was recovered accord-
Prepared from methyl α-L-rhamnopyranoside (0.891 g, ing to general procedure C (0.860 g, 91%).
5.00 mmol) according to general procedure B to yield the title
Methyl 2,3-bis-O-(p-methoxybenzyl)-α-D-galactopyranoside
compound as an amorphous white solid (1.074 g, 72%). NMR (5e). Prepared from methyl α-D-galactopyranoside (0.971 g,
data were consistent with previous literature reports.30 5.00 mmol) according to general procedure B with the follow-
1H NMR (400 MHz, CDCl3): δ (ppm) 7.29–7.26 (m, 2H, o-ArH), ing amendments: a 1 : 1 mixture of toluene and dichloro-
6.90–6.88 (m, 2H, m-ArH), 4.68 (d, 1H, J = 11.1 Hz, ArCH), 4.64 methane (by volume) was used as the solvent, and 4-methoxy-
(d, 1H, J = 11.1 Hz, ArCH), 4.63 (d, 1H, J = 1.6 Hz, H-1), benzyl trichloroacetimidate (6.20 mL, 30 mmol, 6.00 equiv.)
3.91–3.77 (m, 5H, H-2, H-3, ArOCH3), 3.71–3.64 (m, 1H, H-5), was added to the reaction in one portion prior to the addition
3.34–3.29 (m, 4H, H-4, OCH3), 2.59 (d, 1H, J = 3.8 Hz, OH), of lanthanum(III) trifluoromethanesulfonate at 0 °C. The title
2.45 (d, 1H, J = 5.0 Hz, OH), 1.34 (d, 3H, J = 6.3 Hz, CH3). compound was isolated as a colorless syrup (1.270 g, 58%).
4-(Trifluoromethyl)phenylboronic acid was recovered accord- TLC Rf = 0.34 (acetone/dichloromethane 1 : 4). [α]2D0 = 11.7
ing to general procedure C (0.818 g, 86%).
(c 1.75 in CHCl3). FTIR (powder, cm−1): 3460 (br), 2940 (w),
Methyl 2-O-(p-methoxybenzyl)-6-O-(tert-butyldimethylsilyl)- 2909 (w), 2840 (w), 1612 (m), 1512 (s), 1466 (w), 1244 (s),
α-D-galactopyranoside (5c). Prepared from methyl 6-O-(tert- 1088 (s), 1032 (s), 961 (m), 819 (m). 1H NMR (400 MHz,
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CDCl3): δ (ppm) 7.30–7.26 (m, 4H, o-ArH), 6.90 (m, 4H, Once complete, the reaction was diluted with toluene and
m-ArH), 4.74 (d, 1H, J = 11.8 Hz, ArCH), 4.73 (d, 1H, J = filtered through a pad of tightly packed Celite followed by
11.2 Hz, ArCH), 4.63–4.57 (m, 3H, H-1, ArCH, ArCH), 4.01 (dd, removal of the solvent under reduced pressure. The crude
1H, J = 3.2, 1.1 Hz, H-4), 3.92–3.87 (m, 1H, H-6), 3.85–3.72 material was then dissolved in 200 mL ethyl acetate and trans-
(m, 10H, H-2, H-3, H-5, H-6, ArOCH3, ArOCH3), 3.36 (s, 3H, ferred to a separatory funnel containing 200 mL of a 1.0 M
OCH3). 13C NMR (100 MHz, CDCl3): δ (ppm) 159.6, 159.5, sorbitol/1.0 M sodium carbonate aqueous solution and shaken
130.6, 130.3, 129.8, 129.6, 114.1, 114.0, 98.7, 77.1, 75.3, 73.3, by hand for five minutes. The organic phase was collected and
72.8, 69.4, 69.0, 63.2, 55.51, 55.43, 55.42. HRMS (ESI, m/z) the aqueous phase was washed with ethyl acetate an additional
Calculated for [C23H30NaO8] (M + Na)+ 457.1833; Found: three times. The combined organic extracts were dried over
457.1838. 4-(Trifluoromethyl)phenylboronic acid was recovered magnesium sulfate, filtered and solvent was removed under
according to general procedure C (0.865 g, 91%).
reduced pressure to yield the crude product which was then
1,2-O-Isopropylidene-6-O-(p-methoxylbenzyl)-α-D-glucofura- purified by flash chromatography on silica gel (gradient
nose (5f). Prepared from 1,2-O-isopropylidene-α-D-glucofura- elution, acetone in dichloromethane) to yield the desired
nose (1.101 g, 5.00 mmol) according to general procedure B to product as an amorphous white solid (1.655 g, 87%). TLC
yield the title compound as an amorphous white solid Rf = 0.41 (acetone/dichloromethane 1 : 4). [α]2D0 = 64.7 (c =
(1.442 g, 84%). TLC Rf = 0.39 (acetone/dichloromethane 1 : 4). 15.8 mg mL−1, CHCl3). FTIR (powder, cm−1): 3415 (br),
[α]2D0 = −0.89 (c 1.01 in CHCl3). FTIR (powder, cm−1): 3396 2970 (w) 2935 (w), 1721 (s), 1452 (w), 1270 (s), 1156 (s),
(br), 2994 (w), 2933 (w), 2867 (w), 2839 (w), 1612 (w), 1513 (m), 1120 (s), 1038 (s), 1026 (s), 916 (m), 710 (s). 1H NMR (400 MHz,
1376 (w), 1246 (s), 1215 (m), 1167 (m), 1071 (s), 1017 (s), CDCl3): δ (ppm) 8.01–7.98 (m, 2H, o-ArH), 7.57–7.55 (m, 1H,
956 (m), 885 (m), 851 (m), 818 (m). 1H NMR (400 MHz, CDCl3): p-ArH), 7.46–7.41 (m, 2H, m-ArH), 5.56 (dd, 1H, J = 10.1,
δ (ppm) 7.28–7.24 (m, 2H, ArH), 6.90–6.87 (m, 2H, ArH), 5.96 9.0 Hz, H-3), 4.99 (dd, 1H, J = 10.1, 3.7 Hz, H-2), 4.92 (d, 1H,
(d, 1H, J = 3.7 Hz, H-1), 4.53–4.51 (m, 3H, H-2, ArCH2), J = 3.7 Hz, H-1), 3.95–3.78 (m, 4H, H-4, H-5, H-6, H-6), 3.42
4.32–4.31 (m, 1H, H-3), 4.21–4.18 (m, 1H, H-5), 4.09 (dd, 1H, (s, 3H, OCH3), 3.06 (br s, 1H, 6-OH), 2.05 (br s, 1H, 4-OH), 1.06
J = 6.2, 2.7 Hz, H-4), 3.81 (s, 3H, OCH3), 3.75 (dd, 1H, J = 9.9, (s, 9H, (CH3)3CCO). 13C NMR (100 MHz, CDCl3): δ (ppm)
3.4 Hz, H-6), 3.60 (dd, 1H, J = 9.9, 6.0 Hz, H-6), 1.48 (s, 3H, 178.1, 167.6, 133.7, 130.0, 129.3, 128.6, 97.3, 74.6, 71.5, 70.6,
CH3), 1.32 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ (ppm) 70.2, 62.3, 55.7, 38.9, 27.0. HRMS (DART, m/z) Calculated
159.6, 129.7, 129.6, 114.1, 111.8, 105.1, 85.3, 80.0, 76.1, 73.5, for [C19H27O8] (M
+
H)+ 383.17059; Found: 383.17129.
70.9, 69.8, 55.4, 27.0, 26.3. HRMS (DART, m/z) Calculated Phenylboronic acid was recovered according to general
for [C17H24NO7] (M + NH4)+ 358.18658; Found: 358.18674. procedure C (0.488 g, 80%).
4-(Trifluoromethyl)phenylboronic acid was recovered accord-
ing to general procedure C (0.746 g, 79%).
Methyl 2-O-trimethylacetyl-3-O-(p-methoxybenzyl)-α-D-gluco-
pyranoside (7a). Methyl α-D-glucopyranoside (0.971 g,
Methyl 2-O-trimethylacetyl-3-O-benzoyl-α-D-glucopyranoside 5.00 mmol) and 4-(trifluoromethyl)phenylboronic acid
(6a). Methyl α-D-glucopyranoside (0.971 g, 5.00 mmol) and (0.950 g, 5.00 mmol, 1.00 equiv.) were placed in a round
phenylboronic acid (0.610 g, 5.00 mmol, 1.00 equiv.) were bottom flask equipped with stir bar. Toluene (25.0 mL) was
placed in a round bottom flask equipped with stir bar. added to the flask and the solution was placed in an oil bath
Toluene (25.0 mL) was added to the flask and the solution was set at 110 °C and stirred overnight. The solution was then
placed in an oil bath set at 110 °C and stirred overnight. The cooled to room temperature and solvent was removed under
solution was then cooled to room temperature and solvent was reduced pressure. Residual water was removed from the result-
removed under reduced pressure. Residual water was removed ing material via azeotroping with toluene three times, followed
from the resulting material by azeotroping with toluene three by drying under high vacuum to yield the desired boronic
times, followed by drying under high vacuum to yield the ester. This material was then dissolved in anhydrous pyridine
desired boronic ester. This material was then dissolved in (10.0 mL) and cooled to 0 °C with stirring. Trimethylacetyl
anhydrous pyridine (10.0 mL) and cooled to 0 °C with stirring. chloride (0.740 mL, 6.00 mmol, 1.20 equiv.) was added quickly
Trimethylacetyl chloride (0.740 mL, 6.00 mmol, 1.20 equiv.) to the reaction vessel, and the solution was removed from the
was added quickly to the reaction vessel, and the solution was ice bath and allowed to warm to room temperature. The reac-
removed from the ice bath and allowed to warm to room temp- tion was allowed to stir for 30 minutes before 1H NMR spectro-
erature. The reaction was allowed to stir for 30 minutes before scopic analysis of a 10 μL aliquot of the reaction mixture,
a 10 μL aliquot was removed and analysed by 1H NMR which showed approximately 20% of unreacted starting
spectroscopy, which showed approximately 20–25% of material. Additional trimethylacetyl chloride (0.110 mL,
unreacted starting material. Additional trimethylacetyl chloride 0.890 mmol) was added and the reaction was stirred for an
(0.170 mL, 1.38 mmol) was added and the reaction was stirred additional 30 minutes before another aliquot was taken and
for an additional 30 minutes before another aliquot was taken complete conversion was observed by 1H NMR spectroscopy.
and complete conversion was observed by 1H NMR spectro- The reaction was diluted with toluene and filtered through a
scopy. Next, benzoyl chloride (0.870 mL, 7.50 mmol, pad of tightly packed Celite followed by removal of the solvent
1.50 equiv.) was added quickly to the reaction vessel and the under reduced pressure. The crude material was then dis-
mixture allowed to stir for one hour at room temperature. solved in toluene (25.0 mL) and cooled to 0 °C. Lanthanum(III)
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trifluoromethanesulfonate (29.0 mg, 0.0500 mmol, 0.0100 equiv.)
was then added, followed by dropwise addition of 4-methoxyl-
benzyl trichloroacetimidate (3.10 mL, 15.00 mmol, 3.00 equiv.)
over 25 minutes. 1H NMR spectroscopic analysis of a 10 μL
aliquot of the reaction mixture showed little reactivity.
Additional lanthanum(III) trifluoromethanesulfonate (58.6 mg,
0.0500 mmol, 0.0200 equiv.) was added followed by 4-methoxy-
benzyl trichloroacetimidate (1.04 mL, 5.00 mmol, 1.00 equiv.);
this addition procedure was repeated four times. The reaction
was quenched with triethylamine followed by removal of the
solvent under reduced pressure. The crude material was then
dissolved in 200 mL ethyl acetate and transferred to a separa-
tory funnel containing 200 mL of a 1.0 M sorbitol/1.0 M
sodium carbonate aqueous solution and shaken by hand for
five minutes. The organic phase was collected and the
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1031 (s), 912 (m), 820 (m). 1H NMR (400 MHz, CDCl3): δ (ppm)
7.26–7.22 (m, 2H, o-ArH), 6.89–6.85 (m, 2H, m-ArH), 4.92
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(d, 1H, J = 3.7 Hz, H-1), 4.80 (d, 1H, J = 11.1 Hz, ArCH), 4.71 15 K. Fukuhara, N. Shimada, T. Nishino, E. Kaji and
(dd, 1H, J = 9.9, 3.7 Hz, H-2), 4.56 (d, 1H, J = 11.1 Hz, ArCH), K. Makino, Eur. J. Org. Chem., 2016, 902–905.
3.86–3.74 (m, 6H, H-3, H-6, H-6, ArOCH3), 3.66–3.56 (m, 2H, 16 E. Kaji, D. Yamamoto, Y. Shirai, K. Ishige, Y. Arai,
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1H, 6-OH), 1.25 (s, 9H, (CH3)3CCO). 13C NMR (100 MHz,
CDCl3): δ (ppm) 178.1, 159.5, 130.5, 129.5, 114.2, 97.2, 79.4,
74.9, 73.9, 70.9, 70.4, 62.4, 55.5, 55.4, 38.9, 27.2. HRMS (DART,
m/z) Calculated for [C20H34NO8] (M + NH4)+ 416.22844; Found:
416.22950.
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