Sequential Functionalizations of Carbohydrates Enabled by Boronic Esters as Switchable Protective/Activating Groups

DOI: 10.1021/acs.joc.7b01605

Source and publish data:

Journal of Organic Chemistry p. 8777 - 8791 (2017)

Update date:2022-08-11

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Authors:

Mancini, Ross S.

Lee, Jessica B.

Taylor, Mark S.

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Article abstract of DOI:10.1021/acs.joc.7b01605

Processes for site-selective, sequential functionalizations of carbohydrate derivatives are described. In these processes, a tricoordinate boronic ester initially serves as a protective group for a sugar-derived 1,2- or 1,3-diol motif, permitting functionalization of free OH groups. In a second step, addition of a Lewis base generates a tetracoordinate adduct, which serves as an activating group, enabling functionalization of one of the boron-bound oxygen atoms by a second electrophile. By combining an initial acylation, alkylation, or glycosylation step with an amine-mediated glycosylation of the boronic ester, a variety of selectively protected di- and trisaccharide derivatives can be accessed in an operationally simple fashion without purification of intermediates. This Lewis base-triggered switching of behavior from "latent" to "active" nucleophile is a unique feature of boronic esters relative to other protective groups for diol moieties in carbohydrate chemistry.

Full text of DOI:10.1021/acs.joc.7b01605

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Sequential Functionalizations of Carbohydrates Enabled by Boronic

Esters as Switchable Protective/Activating Groups

Ross S. Mancini, Jessica B. Lee, and Mark S. Taylor*

Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada

* Supporting Information

ABSTRACT: Processes for site-selective, sequential functionaliza-

tions of carbohydrate derivatives are described. In these processes,

a tricoordinate boronic ester initially serves as a protective group

for a sugar-derived 1,2- or 1,3-diol motif, permitting functionaliza-

tion of free OH groups. In a second step, addition of a Lewis base

generates a tetracoordinate adduct, which serves as an activating

group, enabling functionalization of one of the boron-bound

oxygen atoms by a second electrophile. By combining an initial

acylation, alkylation, or glycosylation step with an amine-mediated

glycosylation of the boronic ester, a variety of selectively protected

di- and trisaccharide derivatives can be accessed in an operationally simple fashion without puriﬁcation of intermediates. This

Lewis base-triggered switching of behavior from “latent” to “active” nucleophile is a unique feature of boronic esters relative to

other protective groups for diol moieties in carbohydrate chemistry.

oxygen-centered Lewis base.²⁰Our group has developed

INTRODUCTION

■

methods for site-selective activation of sugars via tetracoordi-

Eﬃcient laboratory syntheses of oligosaccharides are needed to

nate organoboron adducts, using either arylborinic acids

advance glycobiology research and to explore the development

(Ar₂BOH)^21,22or boronic acid/Lewis base combinations.^23,24

of carbohydrate-based therapeutic agents such as vaccines.^1,2

Methods for intramolecular aglycon delivery via tetracoordinate

The preparation of appropriately functionalized building blocks

organoboron adducts have also been reported.²⁵On the whole,

for oligosaccharide synthesis often requires sequential, site-

the observations described above suggest that the behavior of

selective chemical transformations of monosaccharides. Most

boronic esters can be switched from protective group

often, such sequential functionalizations are achieved by taking

(tricoordinate) to activating group (tetracoordinate) by

advantage of diﬀerences in the relative reactivity of hydroxyl

(OH) groups in sugars due to steric and electronic eﬀects.

Catalytic processes that enable sequential, multistep function-

addition of a Lewis base. We aimed to make use of this

property to develop reaction sequences in which the boronic

ester group serves initially as a protective group and then as an

alizations via acetal intermediates have also been developed.^3,4

activating group for coupling with a second electrophile

Here, we describe an approach for sequential functionalization

(Scheme 1).

of carbohydrate derivatives that takes advantage of the ability of

boronic esters to serve as either protective groups or activating

groups for diols, depending on the coordination number at the

boron center. This approach enables the one-pot synthesis of a

variety of selectively protected disaccharide and branched

trisaccharide derivatives.

The most well-established applications of boronic esters in

carbohydrate chemistry involve their use as protective groups

for 1,2- or 1,3-diol motifs.^5,6Transient protection via

tricoordinate boronic ester formation has been used to

accomplish selective acylations, glycosylations, sulfations,

alkylations, and silylations of carbohydrate derivatives.⁷⁻¹⁵

Variants employing polymer-supported boronic acids have also

been developed.¹⁶⁻¹⁸A complementary and less widely

exploited mode of reactivity for organoboron complexes of

sugars is the activation of OH groups by formation of

tetracoordinate adducts. Aoyama and co-workers demonstrated

that boronic esters of carbohydrates could be activated toward

reactions of electrophiles by coordination of a nitrogen-¹⁹or

RESULTS AND DISCUSSION

■

Sequential Acylation and Glycosylation. The prepara-

tion of selectively protected gentiobiose derivative 5a from

methyl α-^D-glucopyranoside (1a) through a bis-benzoylation/

glycosylation sequence was targeted in our initial studies (Table

1). Benzoylation of arylboronates 2a (benzoyl chloride,

pyridine solvent, 0−23 °C) proceeded eﬀectively as judged

by ¹H nuclear magnetic resonance (NMR) spectroscopy.

Previous work has shown that these conditions result in

acylation of free OH groups in carbohydrate-derived aryboronic

esters. Whereas trialkylamine bases are able to form Lewis

acid−base adducts with the boronic ester, causing reactivity of

the boron-bound oxygens with electrophiles (see below), this

reactivity was not observed in the presence of pyridine, a

Received: June 28, 2017

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deﬁcient 4-(triﬂuoromethyl)phenylboronic acid provided high-

er yields than 4-methoxyphenylboronic acid and the parent

phenylboronic acid, and triethylamine was the optimal

activating agent for the boronic acid. This observation appeared

to be qualitatively consistent with our previous work in which

an electron-deﬁcient boronic acid in combination with a

trialkylamine provided optimal results for activation of a

pyranoside toward reaction with a glycosyl halide donor.²⁴

Previous research from our laboratory had also identiﬁed 4-

(triﬂuoromethyl)phenylboronic acid as a useful protective

group for acylations, alkylations, and glycosylations of

carbohydrate derivatives,¹⁴indicating that a range of sequential

transformations could potentially be achieved. It should be

noted, however, that the data shown in Table 1 reﬂect an

interplay between the reactivity of the Lewis baseboronic

acid adduct and that of the Ag₂O-activated glycosyl bromide: a

diﬀerent result was obtained when an “armed” glycosyl chloride

was used (see below).

Scheme 1. Design Plan for Sequential Functionalization of

Carbohydrates via Boronic Esters

The sequential acylation/glycosylation protocol was em-

ployed to generate a series of partially protected disaccharide

derivatives (Scheme 2). For pyranoside triols having the manno

Table 1. Optimization of Conditions for the Synthesis of

Protected Gentiobiose Derivative 5a by Sequential

Benzoylation and Glycosylation

Scheme 2. Synthesis of Partially Protected Disaccharides

from Boronic Esters by Sequential Acylation and Coupling

with Acetobromoglucose

entry

yield of 5a (%)

Et₃N

4-(MeO)C₆H₄

4-(CF₃)C₆H₄

Me₂NCHO

Bu₃PO

N,N-dimethylpiperazine

N-methylmorpholine

Yield after puriﬁcation by ﬂash column chromatography on silica gel.

weaker Lewis base. The pyridinium hydrochloride byproduct

from the benzoylation step was removed by dilution with

toluene, ﬁltration through Celite, and removal of the solvent

under vacuum. This operation was carried out because

preliminary optimization experiments (data not shown)

indicated that pyridinium hydrochloride had an adverse eﬀect

on the yield of the glycosylation reaction, perhaps due to side

reactions with the Ag₂O activator and/or the glycosyl bromide.

Without further puriﬁcation, the intermediate bis-O-benzoy-

lated boronic esters 3a were subjected to acetobromoglucose

(4a) in the presence of a Lewis basic activator (Y:) and silver(I)

oxide as halide scavenger and base. Along with disaccharide 5a

and unreacted glycosyl acceptor, byproducts resulting from

glycosyl donor hydrolysis and elimination were observed under

these conditions. The yield of 5a was dependent on both the

arylboronic acid and the Lewis base employed: electron-

Reagents and conditions: (a) 4-(CF₃)C₆H₄B(OH)₂, toluene, 110 °C;

(b) RCOCl, pyridine, 0 °C (T = 50 °C for product 5g); (c) 4a (1.5

equiv), Et₃N (6 equiv), Ag₂O (1.5 equiv), 4 Å MS, CH₂Cl₂, 23 °C.

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conﬁguration (e.g., α-rhamnopyranoside 1b, α-mannopyrano-

side 1e), benzoylation occurred at the 4-OH group, followed by

glycosylation at O-3. For galacto-conﬁgured substrates (β-

arabinopyranoside 1c, α-galactopyranoside 1d), the 2-O-

benzoylated, β-1,3-linked products were obtained. The

selectivity for activation of the equatorial OH group of cis-

1,2-diol motifs that is generally observed for activation via

tetracoordinate boron adducts is thus maintained for these

substrates, despite the deactivating eﬀect of the vicinal acyl

protective group.²⁶A glucofuranoside substrate was also

employed, leading to acylation of the 6-OH group and

glycosylation at O-5. The regiochemical outcomes of both

steps are consistent with previous results for acylation¹⁴and

glycosylation²²of this substrate (via boronic and borinic ester

intermediates, respectively). The use of pivaloyl chloride in

place of BzCl led to the formation of gentiobiose-derived bis-

pivaloate ester 5g from α-glucopyranoside 1a. Selective

monoacylation at the less sterically hindered 2-OH group

could also be achieved using this reagent, resulting in a triol-

derived boronate that underwent selective mono-O-glycosyla-

tion (product 5h). In each case, the glycosylation step was

highly stereoselective (>20:1 β:α), with no evidence for the

protective groups have an arming eﬀect, 4b was found to be less

reactive than 4a under these conditions, presumably due to the

poorer leaving group of chloride versus bromide. This lower

reactivity is reﬂected in the longer reaction times needed for the

glycosylation using the former (48 h) versus the latter (12 h).)

The glycosylation showed high (>20:1) β-selectivity, with H

NMR spectroscopy providing no evidence for the presence of

the α-anomer in the unpuriﬁed reaction mixture. This

observation is consistent with our previous studies of borinic

acid-catalyzed couplings of α-conﬁgured glycosyl chlorides,

which proceeded with inversion of conﬁguration at the

anomeric center, likely through an associative mechanism.^28,29

The protocol was further applied to the synthesis of

disaccharides 6b−d with high levels of β-selectivity (no

detectable formation of α-conﬁgured side products) observed

in each case (Scheme 4).

Scheme 4. Synthesis of Partially Protected Disaccharides

from Boronic Esters by Sequential Acylation and Coupling

with Tetra-O-benzyl-α-^D-glucopyranosyl Chloride

formation of α-conﬁgured byproducts as judged by H NMR

spectroscopy. Although the overall yields of these processes

were relatively modest, the three-step sequence (protection,

acylation, and deprotection via glycosylation) is operationally

simple and does not require puriﬁcation of the intermediates.

Couplings with an “armed”²⁷glycosyl halide bearing ether

rather than ester protective groups were also pursued. Such

couplings would provide access to orthogonally protected

disaccharides and were also of interest from the perspective of

stereocontrol, given that anchimeric assistance could not be

relied upon to deliver the β-linkage when using a per-

benzylated donor. A signiﬁcant eﬀect of arylboronic acid

substitution on the eﬃciency of coupling with tetra-O-benzyl-α-

D-glucopyranosyl chloride (4b) was observed (Scheme 3).

Reagents and conditions: (a) PhB(OH)₂, toluene, 110 °C; (b)

RCOCl, pyridine, 0 °C (T = 50 °C for product 6d); (c) 4b (1.1

equiv), Et₃N (6 equiv), Ag₂O (1.1 equiv), 4 Å MS, CH₂Cl₂, 23 °C.

Scheme 3. Eﬀect of Boronic Acid Substitution on Eﬃciency

of Sequential Acylation/Coupling with an Armed Glycosyl

Donor

Acyl and Boronate Group Migration. When methyl α-^D-

galactopyranoside (1h) was subjected to the arylboronic acid

mediated benzoylation/glycosylation sequence, a mixture of

isomeric disaccharides 5i and 5i′ was formed (Scheme 5).

Boronic ester migration under the conditions of benzoylation

was partially responsible for this outcome: a 4:1 mixture of

isomeric benzoylated arylboronates 2i and 2i′ was obtained

prior to the glycosylation step. The galactopyranoside substrate

is prone to this type of rearrangement because both the 4,6-

and 3,4-diol motifs are able to form relatively stable boronic

esters.¹⁴Based on the 1.5:1 ratio of isomeric benzoylated

disaccharides, it is likely that further rearrangementin this

case, a concomitant migration of acyl and boronate groups

occurred under the basic conditions of the glycosylation

reaction.³⁰Using pivaloyl chloride in place of benzoyl chloride

for this series of reactions also resulted in a pair of regioisomers,

5j and 5j′. With this electrophile, acylation of the primary OH

group was favored, and the 3-O-glycosylated isomer (5j′) was

ultimately obtained as the major product.

Whereas the glycosylation did not proceed to a useful extent

upon activation of the 4-(triﬂuoromethyl)boronate intermedi-

ate with triethylamine, the disaccharide 6a was isolated in 58%

yield using the phenylboronic ester. We speculate that the

inductive electron-withdrawing eﬀect of the triﬂuoromethyl

group may attenuate the nucleophilicity of the tetracoordinate

boronate adduct to the point where coupling with the less

reactive donor becomes challenging. (Although the benzyl

Acyl migrations were also observed for couplings of

perbenzylated glucopyranosyl chloride 4b. For example, four

disaccharide products could be identiﬁed when bis-benzoylated

boronic ester 3a was coupled with 4b. These include three

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above, this substitution pattern also provided superior results

for the amine-mediated glycosylation step using disarmed

donor 4a. Condensation of pyranoside derivative 1b with 4-

(triﬂuoromethyl)phenylboronic acid, followed by treatment

with PMB trichloroacetimidate and catalytic boron triﬂuoride

diethyl etherate (BF₃·OEt₂) in dichloromethane with 4 Å

molecular sieves, resulted in a PMB-protected boronic ester

intermediate that was activated toward coupling with glycosyl

donor 4a by addition of triethylamine and Ag₂O. Protected

disaccharide 7b was isolated in 60% yield.

Scheme 5. Acylation/Glycosylation Sequences Resulting in

Mixtures of Regioisomeric Disaccharides

This approach was amenable to the synthesis of other PMB-

protected disaccharides (Scheme 7). Sequences involving bis-

Scheme 7. Preparation of PMB-Protected Disaccharides by

Sequential Etheriﬁcation and Glycosylation

Reagents and conditions: (a) 4-(CF₃)C₆H₄B(OH)₂, toluene, 110 °C;

(b) RCOCl, pyridine, 0 °C (R = Ph) or 50 °C (R = t-Bu); (c) 4a (1.5

equiv), Et₃N (6 equiv), Ag₂O (1.5 equiv), 4 Å MS, CH₂Cl₂, 23 °C; (d)

4b (1.1 equiv), Et₃N (6 equiv), Ag₂O (1.1 equiv), 4 Å MS, CH₂Cl₂, 23

°C.

products of intramolecular acyl migration (6e, 6e′ and 6e″)

along with monobenzoate 6f. Analogous migration products

were not observed under the conditions of Scheme 2,

presumably because the rate of glycosylation was higher with

4a than with 4b, as described above.

Sequential p-Methoxybenzyl (PMB) Protection and

Glycosylation. Taking advantage of a protocol developed in

our laboratory for coupling of boronic ester-protected

carbohydrate derivatives with p-methoxybenzyl trichloroaceti-

midate,¹⁴we investigated the sequential installation of PMB

and glycosyl moieties using the protection/activation approach

(Scheme 6). Our previous work had shown that the 4-

(triﬂuoromethyl)-substituted arylboronic ester was the optimal

protective group for the PMB etheriﬁcation step. As described

Conditions: (a) 4-(CF₃)C₆H₄B(OH)₂, toluene, 110 °C; (b)

PMBOC(NH)CCl₃(3 equiv), BF₃·OEt₂(2 mol %), CH₂Cl₂, 0

°C; (c) 4a (1.5 equiv), Et₃N (6 equiv), Ag₂O (1.5 equiv), 4 Å MS,

CH₂Cl₂, 23 °C; (d) PMBOC(NH)CCl₃(6 equiv), La(OTf)₃(1

mol %), CH₂Cl₂/toluene, 0 °C; (e) Ac₂O, pyridine, 23 °C; (f)

PhB(OH)₂, toluene, 110 °C; (g) 4b (1.1 equiv), Et₃N (6 equiv), Ag₂O

(1.1 equiv), 4 Å MS, CH₂Cl₂, 23 °C.

Scheme 6. Sequential Installation of p-Methoxybenzyl and

Glycosyl Moieties

etheriﬁcation of 4,6-O-boronates (1a → 7a, 1h → 7f) required

lanthanum(III) triﬂuoromethanesulfonate (La(OTf)₃) in place

of BF₃·OEt₂as Lewis acid and proceeded in lower yield than

those in which only a single PMB group was installed.

Separation of product from hydrolyzed glycosyl donor was

challenging in these cases but could be achieved after

acetylation of the free OH groups by treatment with Ac₂O

and pyridine. For the coupling of 1g with armed glycosyl

chloride 4b, the phenylboronic ester was used in place of the

triﬂuoromethyl-substituted derivative due to its increased

reactivity in the glycosylation step.

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Synthesis of Branched Trisaccharides by Sequential

Glycosylation Reactions. Application of a glycosyl donor as

the electrophile in the ﬁrst step of the boronic ester

protection−activation sequence was investigated as a way to

generate branched trisaccharides. The groups of Boons, Kaji,

and Madsen have described conditions for glycosylation of free

OH groups in sugar-derived boronates using thioglycoside

donors.^{10−12,17,18}Building on the conditions described in the

preceding section for incorporation of PMB groups, we pursued

the glycosylation of boronates using trichloroacetimidate

donors under Lewis acid catalysis. Such a protocol was

employed recently by Nagorny, Sherman, and co-workers to

achieve selective glycosylations of the macrolide antibiotic 6-

deoxyerythronolide B.¹⁵The reaction of rhamnopyranoside-

derived boronic ester 2b with armed mannosyl trichloroaceti-

midate 4c in the presence of catalytic trimethylsilyl

triﬂuoromethanesulfonate (TMSOTf) resulted in an 85%

yield of disaccharide 8 (>10:1 α:β selectivity). To isolate the

disaccharide product, the boronic ester group was deprotected

by transesteriﬁcation with aqueous basic sorbitol solution¹⁴

using Hall’s “phase-switching” protocol (Scheme 8).³¹

Activation of the intermediate boronate-protected disaccharide

with triethylamine enabled its coupling with glycosyl bromide

4a, generating branched trisaccharide 9. A comparison of the

yields of disaccharide 8 and trisaccharide 9 indicates that the

second glycosylation is the problematic step, perhaps due to the

deactivating inductive and steric eﬀects of the previously

introduced glycosyl group. A still lower yield was obtained for

the synthesis of trisaccharide 10 using armed donor 4b, in

keeping with its generally lower reactivity under the conditions

developed here for O-glycosylation of boronic esters.

Trisaccharide 11 was obtained from fucopyranoside 1g by

initial glycosylation with a xylopyranosyl trichloroacetimidate,

followed by Lewis base-mediated coupling with 4b.

Scheme 8. Coupling of a Boronic Ester Protected Acceptor

with a Glycosyl Trichloroacemidate and Synthesis of

Branched Trisaccharides by Sequential Glycosylations of

Boronic Esters with Trichloroacetimidate and Glycosyl

Halide Donors

Sequential coupling of two diﬀerent glycosyl halide donors

was also investigated. Boronic ester 2b underwent glycosylation

at the free OH group upon treatment with acetobromoglucose

4a in the presence of AgOTf and Ag₂CO₃and without an

amine additive (dichloromethane, 23 °C: Scheme 9). After

removal of the silver salts by ﬁltration through Celite, the

resulting glycosylated boronic ester intermediate was activated

by triethylamine toward coupling with glycosyl chloride 4b.

Isomeric trisaccharides 12 and 12′ were isolated in 36% and

17% yields, respectively. Presumably, the relatively low level of

site selectivity arose because 3-O-glycosylation was hampered

by the steric and electronic eﬀects of the adjacent glycosyl

moiety.

Reagents and conditions: (a) 4-(CF₃)C₆H₄B(OH)₂, toluene, 110 °C;

(b) PhB(OH)₂, toluene, 110 °C; (c) 4c (1.5 equiv), TMSOTf (5 mol

%), CH₂Cl₂, 0 °C; (d) 4a (1.5 equiv), Et₃N (6 equiv), Ag₂O (1.5

equiv), 4 Å MS, CH₂Cl₂, 23 °C (Ar = 4-(CF₃)C₆H₄), then Ac₂O,

pyridine; (e) 4b (1.1 equiv), Et₃N (6 equiv), Ag₂O (1.1 equiv), 4 Å

MS, CH₂Cl₂, 23 °C (Ar = Ph); (f) 4d (1.5 equiv), TMSOTf (10 mol

%), CH₂Cl₂, 0 °C.

Multistep Protection−Activation Reaction Sequences.

Couplings of glucopyranoside substrate 1a with three distinct

electrophiles could be achieved by carrying out two

functionalization steps prior to the boronate-cleaving glyco-

sylation (Scheme 10). Selective installation of a benzoyl ester at

the less sterically hindered 2-OH group of the 4,6-O-boronic

ester (Ar = 4-CF₃C₆H₄) was followed by a second esteriﬁcation

of the 3-OH group with PivCl. The resulting intermediate

underwent 6-O-glycosylation upon activation by triethylamine

(product 5k). In a similar way, an esteriﬁcation/glycosylation/

glycosylation sequence led to the formation of branched

trisaccharide 13 in 46% yield.

tetracoordinate adduct has been exploited to achieve sequential,

site-selective functionalizations of carbohydrate derivatives. A

variety of selectively protected disaccharide derivatives have

been prepared by acylation or etheriﬁcation of free OH groups

in the tricoordinate boronic ester intermediate followed by

addition of triethylamine and glycosylation of the resulting

tetracoordinate complex. Branched trisaccharides have been

accessed by conducting successive couplings of glycosyl donors

with the carbohydrate-derived boronic ester acceptor. The

sequence of boronate formation, functionalization, and

deprotection/glycosylation can be conducted without puriﬁca-

tion of intermediates.

CONCLUSIONS

Although parallels can often be drawn between the properties

of boronic esters and acetals/ketals, the other commonly used

protective groups for 1,2- or 1,3-diol motifs, the present study

■

The ability to switch the behavior of boronic esters from

protective groups to activating groups by formation of a

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Scheme 9. Sequential Couplings with Two Glycosyl Halide

Donors

EXPERIMENTAL SECTION

Experimental procedures and characterization data are provided below

for all new compounds reported here.

■

General Considerations. Stainless steel syringes were used to

transfer air- and moisture-sensitive liquids. Flash chromatography was

performed using 35−75 μm particle size silica gel. Thin-layer

chromatography (TLC) was performed using aluminum-backed silica

gel plates, and products were visualized by UV irradiation at 254 nm

and by staining with KMnO₄solution.

Materials. Dichloromethane was puriﬁed by passing through two

columns of activated alumina under nitrogen. Deionized water was

acquired from an in-house supply. The remainder of reagents and

solvents were purchased from commercial suppliers and used without

further puriﬁcation.

Instrumentation. H NMR spectra and ¹³C NMR spectra were

recorded on a 400, 500, or 600 MHz 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). Chemical shifts for carbon (¹³C NMR) are

reported in parts per million downﬁeld from tetramethylsilane and are

referenced to the carbon resonances of the solvent (CDCl₃: δ 77.16).

Boron (¹¹B NMR) chemical shifts are reported in parts per million

downﬁeld from boron triﬂuoride diethyl etherate and are uncorrected.

Fluorine (¹⁹F NMR) chemical shifts are reported in parts per million

downﬁeld from trichloroﬂuoromethane and are uncorrected. Data are

represented as follows; chemical shift (δ, ppm); multiplicity (s, singlet;

d, doublet; app t, apparent triplet; br s, broad singlet; m, multiplet);

integration; coupling constant (J, Hz), proton assignment. Proton

resonances were assigned based on 2-D COSY, HSQC, and HMBC

experiments. Glycosidic linkages were conﬁrmed by 2-D COSY and

HMBC experiments. Attenuated total reﬂectance infared (IR) spectra

were obtained in the solid form or as neat liquids. High-resolution

mass spectra (HRMS) experiments were carried out using a time-of-

ﬂight (TOF) mass spectrometer using an electrospray ionization (ESI)

method. Optical rotations were measured using an automatic

polarimeter.

Scheme 10. Boronic Acid Mediated Reactions of

Glucopyranoside 1a with Three Distinct Electrophiles

General Procedure A: Preparation of Carbohydrate Boro-

nates. Methyl glycoside (2.00 mmol) and arylboronic acid (2.00

mmol, 1.00 equiv) were placed in a round-bottom ﬂask equipped with

a stir bar. Toluene (10.0 mL) was added to the ﬂask, and the solution

was placed in an oil bath set at 110 °C and stirred overnight. The

solution was then cooled to room temperature, and solvent was

removed under reduced pressure. Residual water was removed from

the resulting material via azeotroping with toluene three times,

followed by drying under high vacuum to yield the desired boronic

ester. Products were used without further puriﬁcation. All compounds

were found to be stable to prolonged storage on the benchtop at room

temperature and were stored in a desiccator to limit exposure to

moisture.

General Procedure B: Sequential Reactions of Carbohydrate

Boronates with Benzoyl Chloride and Glycosyl Donor 4a. 4-

(Triﬂuoromethyl)phenylboronic acid-derived carbohydrate boronate

(0.200 mmol, prepared according to general procedure A) was

dissolved in anhydrous pyridine (0.400 mL) and cooled to 0 °C with

stirring. Benzoyl chloride (0.035 mL, 0.300 mmol, 1.50 equiv) was

added quickly to the reaction vessel, and the solution was removed

from the ice bath and allowed to warm to room temperature with

stirring for 30 min. Once complete, the reaction was diluted with

toluene and ﬁltered through a pad of tightly packed Celite followed by

removal of the solvent under reduced pressure. The crude material was

then dissolved in anhydrous dichloromethane (1.00 mL) and

transferred via syringe to an oven-dried round-bottom ﬂask charged

with stir bar and 4 Å molecular sieves. 2,3,4,6-Tetra-O-acetyl-α-^D-

glucopyranosyl bromide (0.123 g, 0.300 mmol, 1.50 equiv) and

silver(I) oxide (0.070 g, 0.300 mmol, 1.50 equiv) were added to the

solution followed by triethylamine (0.166 mL, 1.20 mmol, 6.00 equiv),

and the reaction was stirred vigorously (800 rpm or higher) at room

temperature overnight. The reaction was quenched with methanol and

ﬁltered through a pad of tightly packed Celite followed by removal of

the solvent under reduced pressure. The crude material was puriﬁed by

Reagents and conditions: (a) 4-(CF₃)C₆H₄B(OH)₂, toluene, 110 °C;

(b) BzCl, pyridine, 0 °C; (c) PivCl, pyridine, 50 °C; (d) 4a (1.5

equiv), Et₃N (6 equiv), Ag₂O (1.5 equiv), 4 Å MS, CH₂Cl₂, 23 °C. (e)

4c (1.5 equiv), TMSOTf (2 × 10 mol %), CH₂Cl₂, 0 °C.

illustrates how a distinct reactivity mode of boronic esters can

be exploited to achieve unique multistep transformations.

Benzylidene acetals can be regioselectively converted to

monobenzyl ethers by reductive C−O bond cleavage,³²but

protective group removal via selective glycosylation has not

been achieved to date. In principle, the approach described here

could be generalized by developing conditions for selective O-

functionalization of boronic esters with electrophiles other than

glycosyl donors. Room also exists to improve upon the existing

method, both in terms of the eﬃciency of the ﬁnal glycosylation

step and the practicality of the reaction conditions (glycosyl

halide donors activated by stoichiometric Ag₂O). The property

of boronic esters as “latent”³³glycosyl acceptors whose

reactivity can be triggered by addition of a Lewis base is thus

worthy of further investigation.

DOI: 10.1021/acs.joc.7b01605

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

ﬂash column chromatography on silica gel to yield the functionalized

disaccharide.

reduced pressure. The crude material was puriﬁed by ﬂash column

chromatography on silica gel to yield the functionalized disaccharide.

Methyl 2,3-Bis-O-benzoyl-6-O-(2′,3′,4′,6′-tetra-O-acetyl-β-^D-glu-

copyranosyl)-α-^D-glucopyranoside (5a). Prepared from methyl 4,6-

O-(4-(triﬂuoromethyl)phenylboronate)-α-^D-glucopyranoside (0.056 g,

0.200 mmol) according to general procedure B with the following

amendment: benzoyl chloride (0.058 mL, 0.500 mmol, 2.50 equiv).

The title compound was puriﬁed by ﬂash column chromatography on

silica gel (gradient elution, ethyl acetate in hexanes) to yield a white

amorphous solid (0.073 g, 50%). TLC: R_f= 0.47 (ethyl acetate/

hexanes 1:1). [α]²⁰_D= 38.3 (c 1.15 in CHCl₃). FTIR (powder, cm⁻¹):

3446 (br), 2960 (w), 2903 (w), 1749 (s), 1716 (s), 1366 (m), 1219

General Procedure C: Sequential Reactions of Carbohydrate

Boronates with 4-Methoxybenzyl Trichloroacetimidate and

Glycosyl Donor 4a. 4-(Triﬂuoromethyl)phenylboronic acid derived

carbohydrate boronate (0.200 mmol, prepared according to general

procedure A) was transferred to an oven-dried round-bottom ﬂask

charged with stir bar and 4 Å molecular sieves. The reaction vessel was

purged with argon and kept under an atmosphere of argon using a

balloon. Anhydrous dichloromethane (1.00 mL) was added to the ﬂask

followed by 4-methoxybenzyl trichloroacetimidate (0.125 mL, 0.600

mmol, 3.00 equiv), and the solution was cooled to 0 °C with stirring. A

0.1 M solution of boron triﬂuoride diethyl etherate in dichloromethane

was prepared fresh, and 0.040 mL of this solution (0.004 mmol, 0.020

equiv) was added slowly dropwise to the reaction mixture. The

solution was allowed to stir at 0 °C for an additional 5 min before the

ice bath was removed. Triethylamine (0.166 mL, 1.20 mmol, 6.00

equiv) was added to the reaction vessel followed by 2,3,4,6-tetra-O-

acetyl-α-^D-glucopyranosyl bromide (0.123 g, 0.300 mmol, 1.50 equiv)

and silver(I) oxide (0.070 g, 0.300 mmol, 1.50 equiv), and the reaction

was stirred vigorously (800 rpm or higher) at room temperature

overnight. The reaction was quenched with methanol and ﬁltered

through a pad of tightly packed Celite followed by removal of the

solvent under reduced pressure. The crude material was puriﬁed by

ﬂash column chromatography on silica gel to yield the functionalized

disaccharide.

(s), 1030 (s), 917 (m), 709 (s). H NMR (400 MHz, CDCl₃): δ

(ppm) 7.98−7.95 (m, 4H, ArH), 7.53−7.48 (m, 2H, ArH), 7.38−7.33

(m, 4H, ArH), 5.69 (dd, 1H, J = 10.1, 9.2 Hz, H-3), 5.25−5.20 (m,

2H, H-2, H-3′), 5.11−5.04 (m, 3H, H-1, H-2′, H-4′), 4.67 (d, 1H, J =

8.0 Hz, H-1′), 4.25 (dd, 1H, J = 12.3, 4.7 Hz, H-6′), 4.20−4.16 (m,

2H, H-6, H-6′), 3.96−3.87 (m, 2H, H-5, H-6), 3.825 (app td, 1H, J =

9.4, 5.0 Hz, H-4), 3.76−3.72 (m, 1H, H-5′), 3.41 (s, 3H, OCH₃), 3.11

(d, 1H, J = 5.0 Hz, 4-OH), 2.06 (s, 3H, CH₃CO), 2.04 (s, 3H,

CH₃CO), 2.02 (s, 3H, CH₃CO), 2.00 (s, 3H, CH₃CO). ¹³C NMR

(100 MHz, CDCl₃): δ (ppm) 170.9, 170.4, 169.5, 169.4, 167.7, 166.0,

133.6, 133.5, 130.0, 130.0, 129.3, 129.3, 128.6, 128.5, 101.2, 97.1, 74.5,

72.9, 72.1, 71.4, 71.3, 70.8, 70.1, 68.7, 68.5, 62.0, 55.5, 20.8, 20.77,

20.75, 20.72. HRMS (ESI, m/z): calcd for [C₃₅H₄₄NO₁₇] (M + NH₄)⁺

750.2604, found 750.2598.

General Procedure D: Sequential Reactions of Carbohydrate

Boronates with Benzoyl Chloride and Glycosyl Donor 4b.

Phenylboronic acid-derived carbohydrate boronate (0.200 mmol,

prepared according to general procedure A) was dissolved in

anhydrous pyridine (0.400 mL) and cooled to 0 °C with stirring.

Benzoyl chloride (0.035 mL, 0.300 mmol, 1.50 equiv) was added

quickly to the reaction vessel, and the solution was removed from the

ice bath and allowed to warm to room temperature with stirring for 30

min. Once complete, the reaction was diluted with toluene and ﬁltered

through a pad of tightly packed Celite followed by removal of the

solvent under reduced pressure. The crude material was then dissolved

in anhydrous dichloromethane (1.00 mL) and transferred via syringe

to an oven-dried round-bottom ﬂask charged with a stir bar and 4 Å

molecular sieves. 2,3,4,6-Tetra-O-benzyl-α-^D-glucopyranosyl chloride

(0.123 g, 0.220 mmol, 1.10 equiv) and silver(I) oxide (0.051 g, 0.220

mmol, 1.10 equiv) were added to the solution followed by

triethylamine (0.166 mL, 1.20 mmol, 6.00 equiv), and the reaction

was stirred vigorously (800 rpm or higher) at room temperature for 48

h. The reaction was quenched with methanol and ﬁltered through a

pad of tightly packed Celite followed by removal of the solvent under

reduced pressure. The crude material was puriﬁed by ﬂash column

chromatography on silica gel to yield the functionalized disaccharide.

General Procedure E: Sequential Reactions of Carbohydrate

Boronates with 4-Methoxybenzyl Trichloroacetimidate and

Glycosyl Donor 4b. Phenylboronic acid derived carbohydrate

boronate (0.200 mmol, prepared according to general procedure A)

was transferred to an oven-dried round-bottom ﬂask charged with a

stir bar and 4 Å molecular sieves. The reaction vessel was purged with

argon and kept under an atmosphere of argon using a balloon.

Anhydrous dichloromethane (1.00 mL) was added to the ﬂask