Neighboring group participation in glycosylation reactions by 2,6-disubstituted 2-O-benzoyl groups: A mechanistic investigation

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Neighboring Group Participation

in Glycosylation Reactions by 2,6-

Disubstituted 2-O-Benzoyl groups: A

Mechanistic Investigation

Rohan J. Williams ^a, Nathan W. McGill ^a, Jonathan M. White ^a

Spencer J. Williams ^a

&

^aSchool of Chemistry and Bio21 Molecular Science and

Biotechnology Institute , University of Melbourne , Parkville,

Victoria, 3010, Australia

Published online: 08 Sep 2010.

To cite this article: Rohan J. Williams , Nathan W. McGill , Jonathan M. White & Spencer J. Williams

(2010) Neighboring Group Participation in Glycosylation Reactions by 2,6-Disubstituted 2-O-Benzoyl

groups: A Mechanistic Investigation, Journal of Carbohydrate Chemistry, 29:5, 236-263, DOI:

10.1080/07328303.2010.508141

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Journal of Carbohydrate Chemistry, 29:236–263, 2010

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ISSN: 0732-8303 print / 1532-2327 online

DOI: 10.1080/07328303.2010.508141

Neighboring Group

Participation in Glycosylation

Reactions by 2,6-Disubstituted

2-O-Benzoyl groups: A

Mechanistic Investigation

Rohan J. Williams, Nathan W. McGill, Jonathan M. White,

and Spencer J. Williams

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute,

University of Melbourne, Parkville, Victoria 3010, Australia

Variable yields and glycosylation stereoselectivity were obtained for NIS/TfOH-medi-

ated reaction of 4-methoxyphenyl 2,4,6-tetra-O-acetyl-β-D-galactopyranoside and thio-

galactosides bearing acetyl, benzoyl, 2,6-dimethoxylbenzoyl, 2,4,6-trimethylbenzoyl, or

2,6-dichlorobenzoyl groups at the 2-positions and acetyl at the remainder. X-ray struc-

tures of 4-methylphenyl 2,3,4,6-tetra-O-(2,4,6-trimethylbenzoyl)-1-thio-β-D-galactopyr

anoside and 4-methylphenyl 3,4-O-isopropylidene-2,6-di-O-(2,4,6-trimethylbenzoyl)-

1-thio-β-D-galactopyranoside revealed slightly distorted ⁴C₁chair conformations.

Variable temperature NMR revealed that activation of 4-methylphenyl 2,3,4,6-

tetra-O-(2,4,6-trimethylbenzoyl)-1-thio-β-D-galactopyranoside afforded only dioxole-

nium ion, whereas 4-methylphenyl 3,4,6-tri-O-acetyl-2-O-(2,4,6-trimethylbenzoyl)-1-

thio-β-D-galactopyranoside gave a 1:1 mixture of dioxolenium ion and glycosyl triﬂate.

However, the reaction intermediates formed from these deactivated donors do not inﬂu-

ence the glycosylation stereoselectivity; instead, it is inﬂuenced by steric and electronic

interactions at the transition states.

Keywords Glycosylation Reactions; 2,6-Disubstituted 2-O-Benzoyl Groups

Received May 11, 2010; accepted July 10, 2010.

Rohan J. Williams and Nathan W. McGill contributed equally to this work.

Address correspondence to Spencer J. Williams, School of Chemistry and Bio21 Molec-

ular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria

3010, Australia. E-mail: sjwill@unimelb.edu.au

236

Mechanistic Studies of 2,6-Disubstituted Benzoates

237

INTRODUCTION

Neighboring group participation is a widely used strategy for stereocontrol

in the formation of the glycosidic linkage. The use of 2-O-acyl groups on the

glycosyl donor as a neighboring group has been employed for more than a cen-

tury to effect the formation of the 1,2-trans linkage.^[1]The involvement of the

neighboring group is implicit in the observation of 1,2-trans-linked products

and compelling evidence for the formation of intermediate 1,2-cis-dioxolenium

ions has been gathered through their isolation in crystalline form,^[2]through

their spectroscopic observation as reaction intermediates,^[3,4]and by compu-

tational studies.^[5]More recently, other neighboring groups have been em-

ployed at the 2-position including 2-picolinyl,^[6]2-O-phosphoryl,^[7]and 2-deoxy-

2-dibenzylamino^[8]groups. Neighboring group participation by groups at more

remote sites, namely the 3-, 4-, and 6-positions of a hexopyranose, has been

widely invoked in a range of different systems,^[9]although a recent mechanis-

tic study provided support only for neighboring group participation from the

3-position.^[10]A new twist on the concept of neighboring group participation

has been pioneered by Boons et al., who have reported that a (1S)-phenyl-2-

(phenylsulfanyl)ethyl ester can perform neighboring group participation yield-

ing 1,2-cis-α-glycosides through an intermediate sulfonium ion that forms part

of a trans-decalin-like ring system.^[11,12]

Despite the widespread use of neighboring group participation to control

the anomeric stereochemistry of glycosylation reactions, there are a range of

troublesome side reactions that commonly occur (Fig. 1a). These include trans-

esteriﬁcation, orthoester formation, and incomplete stereocontrol leading to

the formation of signiﬁcant amounts of 1,2-cis products. Transesteriﬁcation

refers to the transfer of the 2-O-acyl group from the donor to the acceptor,^[13]

and the resulting donor-derived intermediates can go on to form 1,2-linked

oligosaccharides^[14,15]or 2-hydroxyglycosides.^[16]Orthoesters are formed from

nucleophilic attack by the acceptor alcohol at the central carbon of the dioxole-

nium ion intermediate. Orthoester formation is more pronounced under ba-

sic conditions and in some cases is a function of anomeric stereochemistry

of the donor.^[17]In many cases the orthoesters can be rearranged by treat-

ment with acid,^[18]and orthoesters are frequently used as glycosyl donors in

their own right,^[18]but in other cases the orthoester cannot be induced to re-

arrange in a productive fashion.^[19]It has been argued that there is a mech-

anistic link between the formation of orthoesters and transesteriﬁcation, and

computational studies have suggested that in some cases, despite proceeding

through a common dioxolenium ion intermediate, these two processes are in

fact mechanistically distinct.^[20]In some glycosylation reactions, despite the

presence of a neighboring vicinal ester group, ineffective stereocontrol is ob-

served.^[21,22]An extreme example of this was provided by Kong and coworkers,

who reported that 3-O-alkyl-2-O-benzoyl galactosyl donors provide excellent

R.J. Williams et al.

238

a)

O

activation

R'OH

O

OR'

O

LG

O

OCOR

R

β-glycoside

only

R'OH

RCO₂R'

O

OR'

HO

OR'

R

α- and β-glycosides

orthoester

transesterification

b)

c)

Me

O

= Mez

= Moz

= Cloz

O

R

O

Me

O

OMe O

P

OMe

sterically unhindered

at dioxolenium carbon

sterically hindered

at dioxolenium carbon

Cl

O

Cl

Figure 1: (a) Mechanism of glycosylation with neighboring group participation, and side

reactions leading to poor stereoselectivity, orthoester formation, and transesteriﬁcation.

(b) Comparison of dioxolenium ion intermediates arising from standard and 2,6-disubstituted

benzoyl groups. (c) Protecting groups investigated in this work: Mez = 2,4,6-trimethylbenzoyl;

Moz = 2,6-dimethoxybenzoyl; Cloz = 2,6-dichlorobenzoyl.

cis-α-stereoselectivity.^[23]Poor stereocontrol is likely a result of a mismatched

pair, where steric and/or electronic factors destabilize the transition state lead-

ing to the 1,2-trans-glycosidic bond, but not the corresponding transition state

leading to the 1,2-cis-glycosidic bond. Evidence for this has been corroborated

by studies applying the principle of double stereodifferentiation using enan-

tiomeric pairs of glycosyl donors.^[24]

We have recently reported studies aimed at the synthesis of the β-D-

galactopyranose-1,3-β-D-galactopyranose linkage found within plant arabino-

galactan proteins.^[25]Signiﬁcant difﬁculties were noted in the use of various 2-

O-acyl groups as neighboring groups including transesteriﬁcation, orthoester

formation, and poor stereoselectivity. Similar problems have been reported by

others and appear to be especially pronounced for D-galacto-conﬁgured glyco-

syl donors.^[21,23,26]In our case these problems were at least partially overcome

through the use of a 2,4,6-trimethylbenzoyl (Mez) group, the ortho substituents

Mechanistic Studies of 2,6-Disubstituted Benzoates

239

of which were proposed to sterically block the central carbon of the dioxolenium

ion intermediate (Fig. 1b).^[20,27]However, despite this enticing mechanistic ra-

tionale, we found that in at least one case, an orthoester was isolated as the

major product using a 2-O-Mez protected glycosyl donor.^[25]Here we report on

a systematic investigation of the outcome of glycosylation reactions of glycosyl

donors bearing a range of 2-O-acyl groups, and in particular 2,6-disubstituted

benzoyl groups (Fig. 1c). We report X-ray structures that provide insight into

the ground state structures of two glycosyl donors that give signiﬁcantly differ-

ent stereoselectivity in glycosylation reactions. Finally, using low-temperature

NMR spectroscopy, we studied the reaction intermediates formed upon activa-

tion of the donors, providing mechanistic insight into the variable stereoselec-

tivity seen in glycosylations using these donors.

RESULTS AND DISCUSSION

To systematically explore the effect of different 2-O-acyl groups on the outcome

of a model glycosylation, we prepared the model donors 1–5. These compounds

have a common set of acetyl protecting groups at the 3-, 4-, and 6-positions,

but vary in the nature of the acyl group at the 2-position. 1,3,4,6-Tetra-O-

acetyl-α-D-galactopyranose 6 was obtained from β-D-galactopyranose penta-

acetate by treatment with aqueous CF₃CO₂H according to the procedure of

Chittenden.^[28]Acylation of 6 with benzoyl (Bz), 2,6-dimethoxylbenzoyl (Moz),

2,4,6-trimethylbenzoyl (Mez), or 2,6-dichlorobenzoyl (Cloz) chlorides afforded

the corresponding esters 7–10 (Sch. 1). BF₃.Et₂O-catalyzed thioglycosylation

provided the thioglycosides 2–4 in moderate yield, but gave products that were

difﬁcult to purify. In practice it proved better to convert 7–10 to the glycosyl

bromides (with HBr in AcOH), followed by thioglycosylation in the presence of

aqueous base with a phase-transfer catalyst, tetrabutylammonium hydrogen

sulfate.

The model glycosyl acceptor 11 was chosen as it represents a challenging

substrate to glycosylate, being a secondary alcohol that is sterically hindered

and electronically deactivated by the ﬂanking electron-withdrawing protect-

ing groups on the upper and lower faces of the sugar ring. The acceptor 11

was prepared from 4-methoxyphenyl β-D-galactopyranoside^[29]in a three-step

route involving (a) stannylene-acetal mediated regioselective allylation at O-

3, (b) acetylation, and (c) deallylation using PdCl₂(Sch. 2). Much lower yields

were obtained when sequential isomerization/hydrolysis with Wilkinson’s cat-

alyst/DABCO/aq. HCl or Pd-C/p-TsOH was used for the deallylation.

Glycosylation reactions of the acceptor 11 with the donors 1–5 were per-

formed using N-iodosuccinimide and triﬂic acid in CH₂Cl₂(Table 1). The tetra-

acetate thioglycoside 1 was a very poor glycosyl donor and provided the disac-

charide in only 36% yield but with excellent stereoselectivity (1:35, α:β); 9%

R.J. Williams et al.

240

AcO

OAc

O

OAc

O

a

HO

RO

OAc

6

7 R = Bz, 93%

8 R = Mez, 100%

9 R = Moz, 100%

10 R = Cloz, 100%

AcO

OAc

O

method b or c

STol

RO

R

method b method c

1

2

3

4

5

Ac

Bz

Mez

Moz

Cloz

−

44%

42%

31%

0%

76%

74%

37%

66%

Scheme 1: Reagents and conditions: (a) RCl, pyr, DMAP; (b) HSTol, F₃BOEt₂, (CH₂Cl)₂, 65^◦C;

(c) (i) HBr, AcOH, CH₂Cl₂; (ii) HSTol, Bu₄NHSO₄, CH₂Cl₂, 1 M Na₂CO₃.

HO

AllO

OH

O

HO

OH

O

a

b

OMp

HO

12

AcO

AllO

AcO

HO

OAc

O

OAc

c

O

OMp

AcO

13

11

Scheme 2: Reagents and conditions: (a) (i) Bu₂SnO, toluene, reﬂux; (ii) Bu₄NBr, allyl bromide,

reﬂux, 72%; (b) Ac₂O, pyr, 70%; (c) PdCl₂, MeOH/toluene (3:1), 69%.

of the transesteriﬁcation product was also isolated (Table 1, entry 1). The 2-

O-benzoyl donor 2 provided a somewhat improved yield (44%) and marginally

poorer stereoselectivity (1:10, α:β; Table 1, entry 2). In all cases the use of the

2,6-disubstituted benzoates as neighboring groups, glycosyl donors 3–5, pro-

vided improved yields, with no transesteriﬁcation products observed; however,

greatly varying stereoselectivity was observed. The mesitoate 3 gave the best

yield of disaccharide (66%) but with a poor stereoselectivity (1:2, α:β; Table 1,

Mechanistic Studies of 2,6-Disubstituted Benzoates

241

Table 1: Outcome of glycosylations of acceptor 11 by the glycosyl donors 1–5, 16

and 19

Entry

Donor

R₁

R₂

Product

Yield (%)^a

β/α ratio

1

2

3

4

5

6

7

1

2

Ac

27a,b

28a,b

29a,b

30a,b

31a,b

32

36^b

44

66

56

63

57

32

35:1

10:1

2:1

Ac

Bz

3

Ac

Mez

Moz

Cloz

Mez

Moz

4

5

16

19

Ac

19:1

1.3/1

β only

Ac

Mez

Moz

c

33

—

^aReagents and conditions: NIS (2.5 equiv), TfOH (0.25 equiv), 0^◦C, CH₂Cl₂.

^b9% of the transesteriﬁed product, 4-methoxyphenyl 2,3,4,6-tetra-O-acetyl-β-D-galacto

pyranoside, was isolated.

^cThe product(s) of the glycosylation could not be adequately puriﬁed; after saponiﬁcation

(LiOH in MeOH) of the crude mixture, the β-anomer of the deprotected disaccharide was

isolated in the indicated yield.

entry 3); the 2,6-dichlorobenzoate 5 gave a similar yield (63%) and stereose-

lectivity (1:1.3, α:β; Table 1, entry 4); and the 2,6-dimethoxybenzoate 4 gave

a slightly poorer yield (56%) but with excellent stereoselectivity (1:19, α:β;

Table 1, entry 5). Two conclusions can be drawn from these results. First,

the presence of ortho substituents on the benzoyl group affords a signiﬁcant

improvement in yield of the glycosylation reaction, possibly through limiting

orthoester formation and transesteriﬁcation. Second, despite the presence of

the ester group at the 2-position, neighboring group participation cannot be

guaranteed, with variable stereoselectivity being observed.

The results reported stand in contrast with recently reported work us-

ing glycosyl donors bearing more than one 2,6-disubstituted benzoyl group.

Whitﬁeld and coworkers have reported that 3,4-di-O-isopropylidene thiogalac-

tosides bearing 2,6-dimethoxybenzoyl or 2,6-dimethylbenzoyl groups at the 2-

and 6-positions, 14 and 15, were effective β-selective glycosyl donors for a

polymeric PEG-based primary alcohol,^[14,20]and we recently showed that a

tetramesitoate thiogalactoside 16 provided excellent yields and stereoselec-

tivity in the glycosylation of the alcohol 11 (Scheme 3).^[25]However, we ob-

served a signiﬁcantly different outcome when using the closely related 3,4-di-

O-isopropylidene-protected thioglycoside 17 in glycosylations of the secondary

alcohol 11. In this case the orthoester 18 was the major product (63%); this

orthoester could not be rearranged to a glycoside product.^[25]

R.J. Williams et al.

242

O

OMez

O

RO

O

OR

O

OR

O

OMez

O

AcO

O

OAc

O

STol

SEt

STol

O

OMp

O

RO

MezO

17

AcO

14 R = Mez

15 R = Moz

16 R = Mez

19 R = Moz

25 R = Bz

18

AcO

MezO

OAc

O

OMez

O

MezO

OMez

O

AcO

OAc

O

MezO

OTf

MezO

OTf

20

21

22

23

BnO

OBn

O

OAc

O

AcO

STol

BzO

26

AcO

24

Scheme 3.

These results suggested that subtle changes in the nature of the protect-

ing groups at remote positions on the glycosyl donor can afford dramatically

different outcomes. We were therefore prompted to examine the effect of glyco-

sylations using the synthetically more accessible donors, tetramesitoate 16^[25]

and tetra-(2,6-dimethoxybenzoate) 19. Despite our best efforts, we were unable

to prepare the tetra-(2,6-dichlorobenzoate) derivative—it appears that under

the forcing conditions required for the installation of four 2,6-dichlorobenzoyl

groups, side reactions prevented accumulation of product. Under similar con-

ditions to that used previously, tetramesitoate 16 afforded the disaccharide

in 57% yield, with only the β-anomer being observed (Table 1, entry 6); we

have reported that after extensive optimization this yield could be improved to

80%.^[25]Finally, the tetra-(2,6-dimethoxybenzoate) 19 was a particularly poor

glycosyl donor and puriﬁcation of the products of the reaction was challeng-

ing; ultimately a 32% yield of the deprotected β-linked disaccharide was ob-

tained (Table 1, entry 7). These results clearly show that the outcome of these

glycosylations depend subtly on the nature of the protecting groups on the

carbohydrate, particularly those remote from the anomeric centre. The poor

stereoselectivity and lower yields seen for glycosylations with the donors 3–5

were unexpected and encouraged us to take a closer look at the underlying

chemistry.

We wondered whether the presence of more than one 2,6-disubstituted

benzoate ester on the glycosyl donor could lead to steric crowding so that the

Mechanistic Studies of 2,6-Disubstituted Benzoates

243

Figure 2: ORTEP diagram of single crystal X-ray structure of tetramesitoate thiogalactoside

16. Only ring carbons are numbered for clarity. Thermal ellipsoids are at 50% probability.

remote groups may buttress against one another to impede the ability of the

acyl group at position 2 to provide anchimeric assistance, or alternatively may

distort the pyranose ring conformation and thereby inﬂuence the stereoselec-

tivity. We therefore determined the X-ray structures of the tetra-O-mesitoyl

donor 16 and the 3,4-O-isopropylidene protected donor 17 (Figs. 2 and 3). In-

spection of these structures reveals no unexpected distortion of the pyranose

4

ring, with both rings being found in approximate C₁conformations. In par-

ticular, the conformation of 17 is very similar to that seen for ethyl 2,6-di-

O-benzoyl-3,4-O-isopropylidene-1-thio-β-D-galactoside,^[30]suggesting that the

mesitoyl group does not result in signiﬁcant conformational changes compared

to a benzoyl group. In this case and as has been seen elsewhere, the presence

of the 3,4-O-isopropylidene group in 17 results in only limited ﬂattening of

the pyranose ring from a classical ⁴C₁conformation to a slightly distorted ⁴C₁

conformation.^[31]In 17 the endo methyl group of the isopropylidene acetal is

˚

found 4.6 A from the anomeric carbon, and has the potential to cause substan-

tial steric repulsion with a nucleophile that approaches from the β-face. In the

case of the tetramesitoate 18, the individual mesitoate groups are well spaced

and encapsulate the upper face of the carbohydrate ring, raising the likelihood

of signiﬁcant steric interactions with a glycosyl acceptor approaching from the

β-face. However, there is no evidence for antagonistic interactions of the remote

mesitoate groups preventing neighboring group participation by the mesitoate

at C2. One signiﬁcant difference seen with mesitoyl groups relative to benzoyl

R.J. Williams et al.

244

Figure 3: ORTEP diagram of single crystal X-ray structure of isopropylidene thiogalactoside

17. Only ring carbons are numbered for clarity. Thermal ellipsoids are at 50% probability.

groups is a change in the orientation of the acyl carbonyl group relative to the

aromatic ring. For example, in ethyl 2,6-di-O-benzoyl-3,4-O-isopropylidene-1-

thio-β-D-galactoside,^[30]the torsion angles for O C( O) C_ipsoC_orthoare close

to zero, whereas for 16 or 17, the corresponding angles fall in the range of 41^◦

to 79^◦. In particular, the angle for O C( O) C_ipsoC_orthofor the mesitoyl at

C2 is 61^◦for both 16 and 17. This may have some impact on the energy of the

transition state leading to the formation of a dioxolenium ion intermediate, as

discussed later.

We next investigated the nature of the reaction intermediates formed

upon activation of the glycosyl donors. In recent years variable temperature

NMR has become a valuable ally in the study of intermediates formed in

glycosylation reactions.^[3,4,11,32]Typically, studies with thioglycosides and sul-

foxides have utilized highly soluble activator systems, such as Tf₂O/DTBMP,

Tf₂O/benzenesulﬁnylpiperidine/DTBMP, or TolSOTf/DTBMP, or electrochem-

ical methods. Surprisingly, despite its widespread use as a promoter for gly-

cosylation reactions, we are not aware of any case where NIS/TfOH has been

investigated in NMR experiments. Possibly, this is due to the poor solubility

Mechanistic Studies of 2,6-Disubstituted Benzoates

245

of NIS, especially at low temperatures. However, insight into activation with

NIS would be of broad interest as this is a widely used reagent that is readily

available. We found that while NIS is poorly soluble in chloroform at low tem-

perature, upon addition of one equivalent of TfOH a homogeneous solution is

obtained, presumably composed of iodonium triﬂate and succinimide (or possi-

bly of protonated NIS with a triﬂate counterion). Accordingly, we undertook a

series of low-temperature NMR experiments in which the thioglycosides 3 or

16 were dissolved in CDCl₃and treated with one equivalent of both NIS and

TfOH, in the absence of acceptor alcohol, so as to allow the accumulation of

possible reaction intermediates.

Addition of TfOH to a suspension of donor 16 and NIS in CDCl₃at –60^◦C

1

led immediately to an intensely purple-colored solution. Inspection of the H

NMR spectrum revealed that the donor 16 was converted predominantly to

a new species characterized by its anomeric proton signal at δ 6.74 ppm (d,

J = 3.5 Hz). When slowly warmed in 10^◦C increments, this species remained

stable even at –20^◦C; however, upon warming to –10^◦C a new set of signals

was formed, characterized by a new anomeric signal at δ_H7.57 ppm (d, J =

7.4 Hz), and δ_C111.1 ppm assigned to the anomeric carbon of the dioxole-

nium ion. These data are consistent with the ﬁrst formed product being the

glycosyl triﬂate 20, which upon warming is converted to the dioxolenium ion

21 that comprises the major species at 0^◦C (Fig. 4a). Owing to the nature of

the protecting groups, substantial overlap of the anomeric signal of the diox-

olenium ion 21 and the aromatic region was observed with the assignment of

1

signals being substantially assisted by the use of H-¹H COSY experiments.

The characteristics of these compounds are similar to related dioxolenium ions

Figure 4: (a) Partial 100-MHz ¹³C NMR spectrum obtained in CDCl₃upon activation of 16

with NIS/TfOH at –60^◦C followed by warming to 0^◦C. (b) Partial 100-MHz ¹³C NMR spectrum

obtained in CDCl₃upon activation of 3 with NIS/TfOH at –60^◦C followed by warming to 0^◦C.

R.J. Williams et al.

246

reported by Huang and coworkers, who observed δ_C113.3 and 114.2 ppm for

the anomeric carbons, and δ_H7.35 and δ_H7.34 ppm for the anomeric protons,

of dioxolenium ions formed from 24 and 26, respectively.^[4]On the other hand,

Huang and coworkers reported anomeric protons at δ_H6.57 and 6.21 ppm, and

anomeric carbons at δ_C104.1 and 104.4 ppm, for glycosyl triﬂates formed from

acylated glycosyl donors 24 and 25, respectively.^[4]

When the monomesitoate 3 was activated under the same conditions at

–60^◦C, an approximately 1:1 mixture of two major compounds was formed.

One compound was characterized by the presence of signals at δ_H6.47 ppm (d,

J = 3.5 Hz) and δ_C103.5 ppm, which was assigned as the glycosyl triﬂate 22.

The second compound possessed signals at δ_H7.64 ppm (d, J = 8.2 Hz) and δ_C

111.0 ppm, which was assigned as the dioxolenium ion 23. In this case upon

warming to 0^◦C the approximately equimolar ratio of 22 and 23 was essentially

unchanged (Fig. 4b).

Interpretation of the role of reactive intermediates in glycosylation reac-

tions is complicated by the potential for their facile interconversion with other

intermediates, allowing for the operation of a Curtin-Hammett scenario where

the product distribution is determined by the relative energetic barriers for

product formation, rather than the barriers for their interconversion. In the

case of a glycosylation reaction without groups capable of neighboring group

participation, two scenarios can be envisioned: an S_N2-like process, such as

that seen in the halide-ion catalyzed glycosylations of Lemieux^[33]and the β-

mannosylation methodology of Crich,^[34]wherein either β- or α-conﬁgured in-

termediates are the reactive intermediates, leading to α- or β-conﬁgured prod-

ucts, respectively; and an S_N1 process, wherein glycosyl cations are formed,

which may react to give products of either α- or β-anomeric stereochemistry.

In the case of glycosyl donors capable of neighboring group participation, two

main intermediates are likely to be present: the glycosyl cation and the dioxole-

nium ion intermediate. In some cases, as highlighted by the studies of Huang

and coworkers, a glycosyl triﬂate may also be an important intermediate.^[4]

It can be expected that reaction with the glycosyl triﬂate or dioxolenium ion

should lead only to β-product, whereas reaction with the glycosyl cation can

lead to both α- and β-product, with the energetic barriers to each anomer be-

ing nonequal. It is therefore not possible to use product analysis to distinguish

between the formation of β-anomer by reaction of an acceptor with a glyco-

syl cation, an α-triﬂate, or a dioxolenium ion. Similarly, the formation of an

α-anomer may occur through the intermediacy of a glycosyl cation or a

β-triﬂate in the reaction pathway, the latter especially in cases of activated

and therefore highly reactive donors.

In our case all preparative glycosylation reactions were performed at 0^◦C

and above. Based on the NMR experiments, for the donor 16 the dioxolenium

ion intermediate was the major species present, and the excellent stereoselec-

tivity noted with this donor suggests that the dioxolenium ion simply reacts in

Mechanistic Studies of 2,6-Disubstituted Benzoates

247

an S_N2-like fashion affording the β-galactoside as the major product. Applica-

tion of the Curtin-Hammett principle suggests that either the glycosyl cation

is not present as an intermediate in this system, or if it is, the barrier for

its reaction to give an α-anomer must be high relative to the reaction of the

nucleophile with the dioxolenium ion or the β-face of the glycosyl cation. On

the other hand, in the case of the donor 3, poor stereoselectivity is observed,

and the α-anomer most likely arises from reaction on the α-face of a glycosyl

cation. This suggests that the glycosyl triﬂate (and possibly the dioxolenium

ion) observed in the NMR studies of 3 must be in a facile equilibrium with

the glycosyl cation. In the case of the acceptor 11 it seems reasonable to sug-

gest that its hindered nature likely results in a high barrier for an S_N2-like

reaction with the glycosyl triﬂate or dioxolenium ions, thereby allowing for the

possibility of reaction with trace amounts of a more reactive glycosyl cation.

It is interesting to compare our results with those of Crich and cowork-

ers^[3]and of Huang and coworkers,^[4]who studied the intermediates formed

upon activation of 2-O-acyl glycosyl donors. Crich and coworkers used a range

of tri-O-benzoyl-D-xylosyl donors and noted that donors derived from this rela-

tively electron-rich sugar (possessing one less electron-withdrawing protecting

group than a hexopyranose) readily formed a dioxolenium ion and gave ex-

cellent β-stereoselectivity in glycosylation reactions.^[3]Huang and coworkers

studied the intermediates formed upon activation of the tetraacetate 24, the

tetrabenzoate 25, and the 2-O-benzoyl-3,4,6-tri-O-benzyl-protected galactoside

26 with TolSOTf.^[4]Activation of the tetraacetate 24 led to a mixture of gly-

cosyl triﬂate and dioxolenium ion at low temperature, but upon heating this

converted exclusively to the glycosyl triﬂate. Activation of the tetrabenzoate

25 led to a smooth formation of a glycosyl triﬂate, with no changes observed at

varying temperatures. Finally, activation of the electron-rich donor 26 resulted

in clean formation of a dioxolenium ion. When used in a preactivation protocol

involving the initial activation of the glycosyl donor prior to addition of the al-

cohol, all of the glycosyl donors 24, 25, and 26 afforded only β-linked products.

Why does subtle variation in the nature of the remote protecting groups in

3 and 16 lead to different pools of activated intermediates and different stere-

ochemical outcomes? The nature of the protecting groups must play a crucial

role in determining the stability of the intermediates formed. Ester-protecting

groups are electron-withdrawing and destabilize a glycosyl cation, so the for-

mation of a dioxolenium ion or a glycosyl triﬂate will enable charge dispersal or

elimination, respectively. Based on the fact that mesitoates are more electron

withdrawing than acetates but more electron donating than benzoates, the

stability of the glycosyl cations derived from the donors would follow the series

24 > 25 > 3 > 16. With regard to the formation of a dioxolenium ion, while

a 2,4,6-trimethylphenyl group is electron rich relative to a phenyl or methyl

group, its donor properties are complicated by the fact that when oriented or-

thogonal to the π-system of the dioxolenium ion it will be less able to stabilize

R.J. Williams et al.

248

the positive charge, possibly disfavoring the formation of a dioxolenium ion

from both 3 and 16. However, the dioxolenium ion is observed in both cases

and so the precise reason for speciation into a glycosyl triﬂate or dioxolenium

ion remains unclear.

For all of the donors investigated by Huang and coworkers, good stere-

oselectivity is observed irrespective of the existence of the activated interme-

diate as a glycosyl triﬂate, a dioxolenium ion, or a mixture of the two, so it

seems reasonable to suggest either that (a) glycosyl triﬂates or dioxolenium

ions derived from glycosyl donors bearing 2-O-acyl groups can both react in an

S_N2-like fashion, or more likely (2) a Curtin-Hammett scenario operates where

the reaction intermediates freely interconvert and the product distribution de-

pends on the interactions that occur at the transition states. On this basis we

are led to the conclusion that the poor anomeric stereoselectivity observed in

glycosylations with the donor 3 arises because of high barriers leading from

the dioxolenium ion and/or glycosyl triﬂate to product, such that equilibration

with trace amounts of a glycosyl cation can afford signiﬁcant amounts of an

α-linked product. In our case the poor reactivity of 3 is likely exacerbated by the

hindered and deactivated nature of the secondary alcohol acceptor 11, which

results in a mismatched pairing in the transition state leading to the β-product

from the dioxolenium ion or glycosyl triﬂate. This mismatch is less severe in

the reactions of the glycosyl cation leading to the α-anomer, which is a likely

representative of the pool of reaction intermediates. Finally, on the basis of the

X-ray structure for 17, we ascribe the formation of the orthoester 18 from the

glycosyl donor 17 to facile formation of a dioxolenium ion that is hindered from

top face attack to give a β-anomer by the endo methyl of the isopropylidene

group; instead, nucleophilic attack at the orthoester carbon predominates.

One ﬁnal issue that merits discussion is the effect of the ortho methyl

groups on the mesitoyl group in the reaction pathways leading to glycosyl

cations and dioxolenium ions. In particular, the X-ray structures reveal that

the orientation of the carbonyl group to the aromatic ring for the mesitoyl

groups differ signiﬁcantly to the corresponding orientation in benzoyl groups,

owing to the steric interactions preventing coplanarity. DFT calculations by

the Whitﬁeld group suggest that for neighboring group participation by mono-

cyclic glycopyranosyl cations there is a transition state to the formation of the

dioxolenium ion of rotation of the C2-O2 bond.^[35]In contrast, DFT calcula-

tions of the corresponding transformation of the bicyclic 2,6-di-O-acetyl-3,4-

O-isopropylidene-D-galactopyranosyl cation revealed that the transition state

is conformational interconversion and that nucleophilic attack by the carbonyl

group to give the dioxolenium ion was essentially barrierless.^[30]The similarity

of the crystal structures of 17 and ethyl 2,6-di-O-benzoyl-3,4-O-isopropylidene-

1-thio-β-D-galactoside suggests that these two compounds will start from a

similar ground state and that they can adopt similar conformations. However,

the change in the torsional angle for the aromatic ring and the carbonyl group

Mechanistic Studies of 2,6-Disubstituted Benzoates

249

should result in a signiﬁcant alteration in reactivity of this group, which may

affect the energy of the transition state between the glycosyl cation to the diox-

olenium ion.

These studies reiterate the challenges in deﬁning general glycosylation

conditions and that individual solutions to certain challenging glycosylations

may require the use of unusual protecting groups and empirical investigation

of the effect of changes of remote protecting groups on the reactivity and stere-

oselectivity of glycosyl donors. On the basis of this work and previous studies,

2,6-disubstituted benzoates have the potential to overcome some side reac-

tions, such as transesteriﬁcation, in challenging β-galactosylations; however,

these groups do not altogether prevent orthoester formation and in some cases

provide incomplete anomeric stereocontrol.

EXPERIMENTAL

General experimental details have been provided previously.^[36]

4-Methoxyphenyl 3-O-allyl-β-D-galactopyranoside (12)

A suspension of 4-methoxyphenyl β-D-galactopyranoside^[25](7.80 g,

27.2 mmol) and Bu₂SnO (8.80 g, 35.4 mmol) in toluene (150 mL) was reﬂuxed

for 18 h with azeotropic removal of H₂O. The solvent was evaporated under

reduced pressure and the residue was dissolved in THF (100 mL). Bu₄NBr

(9.64 mg, 29.9 mmol) and allyl bromide (16.5 g, 136 mmol) were added to the

solution, which was reﬂuxed for 2 h. Evaporation of the solvent gave a residue,

which was puriﬁed by ﬂash chromatography (100% EtOAc) to give 12 (6.37 g,

72%) as colorless crystals, mp 138–139^◦C, lit.^[37]139–140^◦C; [α]_D²¹–13^◦(c 1.0 in

MeOH) lit.^[37][α]_D²⁰–9^◦(c 1.0 in MeOH); ¹H NMR (500 MHz, d₄-MeOH): δ 3.41

(1 H, dd, J_2,3= 10.0, J_3,4= 3.0, H3), 3.61 (1 H, m, H5), 3.76 (3 H, s, OCH₃),

3.76–3.81 (2 H, m, H6, 6), 3.86 (1 H, dd, J_1,2= 8.0, J_2,3= 10.0, H2), 3.92 (1

H, d, H4), 4.16 (2 H, m, CH₂CHCH₂O), 4.76 (1 H, d, H1), 5.18–6.07 (3 H, m,

CH₂CHCH₂O), 6.84–7.09 (4 H, m, Ar); ¹³C NMR (125 MHz, CD₃OD): δ 56.2 (1

C, OCH₃), 62.5, 67.1, 71.6, 76.9, 82.3 (5 C, C2,3,4,5,6), 72.0 (1 C, CH₂CHCH₂O),

104.2 (1 C, C1), 115.6–156.8 (6 C, Ar), 117.6,136.6 (2 C, CH₂CHCH₂O); m/z

(ESI⁺) 349.1258 (C₁₆H₂₂Na O₇[M + Na]⁺requires 349.1258).

4-Methoxyphenyl 2,4,6-tri-O-acetyl-3-O-allyl-β-D-

galactopyranoside (13)

A solution of acetic anhydride (0.30 mL, 3.2 mmol) and allyl ether 12

(105 mg, 0.322 mmol) in pyridine (5 mL) at 0^◦C was stirred for 2 h. The mix-

ture was diluted with CH₂Cl₂(20 mL). The organic phase was washed with aq.

HCl (1 M, 20 ml), sat. aq. NaHCO₃(20 mL), and brine (10 mL). The organic

phase was dried (MgSO₄) and evaporated to afford an off-white amorphous

solid, which was recrystallized from EtOAc/pet. spirit to afford 13 (101 mg,

R.J. Williams et al.

250

70%) as colorless crystals, mp 131–132^◦C, lit.^[38]130–131^◦C; [α]_D+18^◦(c 1.0

20

1

in CHCl₃), lit.^[38][α]_D+ 24^◦(c 1.5 in CHCl₃); H NMR (400 MHz, CDCl₃): δ

2.07–2.17 (9 H, 3 × s, 3 × Ac), 3.58 (1 H, dd, J_2,3= 10.0, J_3,4= 3.6, H3), 3.77

(3 H, s, OCH₃), 3.88–4.17 (3 H, m, H5, CH₂CHCH₂O), 4.20 (2 H, m, H6,6),

4.86 (1 H, d, J_1,2= 8.0, H1), 5.17–5.28 (2 H, m, CH₂CHCH₂O), 5.34 (1 H, dd,

H2), 5.46 (1 H, dd, H4), 6.80–6.98 (4 H, m, Ar); ¹³C NMR (100 MHz, CDCl₃):

δ 20.7–20.9 (3 C, 3 × s, 3 × Ac), 55.6 (1 C, OCH₃), 62.0, 65.9, 70.33, 70.7, 76.6

(5 C, C2,3,4,5,6), 71.1 (1 C, CH₂CHCH₂O), 100.8 (1 C, C1), 114.4–155.6 (6 C,

Ar), 117.5–134.0 (2 C, CH₂CHCH₂O), 169.4–170.5 (3 C, 3 × C O); m/z (ESI⁺)

475.1575 (C₂₂H₂₈NaO₁₀[M + Na]⁺requires 475.1575).

4-Methoxyphenyl 2,4,6-tri-O-acetyl-β-D-galactopyranoside (11)

A suspension of triacetate 13 (998 mg, 2.21 mmol) and PdCl₂(60 mg,

0.34 mmol) in 3:1 MeOH/toluene (25 mL) was stirred at rt for 3.5 h. The

mixture was concentrated under reduced pressure and puriﬁed by ﬂash chro-

matography (70% EtOAc/pet. spirits) to afford a residue, which was recrys-

tallized from EtOAc/pet. spirits to afford 11 (628 mg, 69%) as ﬁne colorless

needles, mp 134–135^◦C, lit.^[25]; [α]_D+ 2^◦(c 0.9 in CHCl₃) (Found: C, 55.64;

22

1

H, 5.88. C₁₉H₂₄O₁₀requires C, 55.34; H, 5.87%); H NMR (500 MHz, CDCl₃):

δ 2.06–2.20 (9 H, 3 × s, 3 × Ac), 2.70 (1 H, d, J_3,OH= 6.5, OH), 3.77 (3 H, s,

OCH₃), 3.91 (1 H, ddd, J_2,3= 10.0, J_3,4= 3.5, H3), 3.94 (1 H, ddd, J_4,5= 1.0,

J_5,6= 6.5, J_5,6= 6.5, H5), 4.18–4.19 (2 H, m, H6,6), 4.87 (1 H, d, J_1,2= 8.0,

H1), 5.22 (1 H, dd, H2), 5.37 (1 H, dd, H4), 6.80–6.98 (4 H, m, Ar); ¹³C NMR

(125 MHz, CDCl₃): δ 20.7–20.9 (3 C, 3 × s, 3 × Ac), 55.7 (1 C, OCH₃), 61.9,

69.5, 71.3, 71.4, 72.6 (5 C, C2,3,4,5,6), 100.5 (1 C, C1), 114.5–155.7 (6 C, Ar),

170.4–171.1 (3 C, 3 × C O); m/z (ESI⁺) 435.1260 (C₁₉H₂₄NaO₁₀[M + Na]⁺

requires 435.1262).

Method A: Esteriﬁcation of 1,3,4,6-tetra-O-acetyl-α-D-

galactopyranose (6)

A mixture of acid chloride (2–4 equiv.), 2-hydroxy tetraacetate 6 (1 equiv.),

and DMAP (1 equiv.) in pyridine was stirred at 55^◦C for 18 h. The reaction

was quenched with HCl (3 M) and extracted with CH₂Cl₂. The organic extract

was washed with HCl (3 M), sat. aq. NaHCO₃, and brine. The organic phase

was dried (MgSO₄) and evaporated to afford an oil, which was puriﬁed by ﬂash

chromatography.

Method B: Preparation of β-D-thiogalactosides by Lewis

acid-catalyzed thioglycosylation

BF₃.Et₂O (1 equiv.) was added dropwise to a solution of anomeric acetate

(1 equiv.) and thiocresol (1.1 equiv.) in dry (CH₂Cl)₂at 0^◦C. The reaction was

Mechanistic Studies of 2,6-Disubstituted Benzoates

251

heated to 65^◦C until TLC indicated consumption of the starting material. The

mixture was quenched with H₂O and cooled. The solution was washed with

sat. aq. NaHCO₃and brine and the organic phase dried (MgSO₄). The solvent

was evaporated to give a residue, which was puriﬁed by ﬂash chromatography

to afford the thiogalactoside.

Method C: Procedure for preparation of β-D-thiogalactosides

via α-D-galactosyl bromides

HBr in AcOH (40% vol/vol, 1 mL per 1 g of tetraacetate) was added to a

solution of anomeric acetate in CH₂Cl₂and the solution stirred at rt until TLC

indicated consumption of the starting material. The mixture was diluted with

ice-cold H₂O and extracted with CH₂Cl₂. The organic extract was washed with

H₂O and sat. aq. NaHCO₃. The organic phase was dried (MgSO₄) and evapo-

rated to afford crude D-galactosyl bromide as a colorless residue. Thiocresol (3

equiv.) was added to a two-phase system containing the crude D-galactosyl bro-

mide (1 equiv.), Bu₄NHSO₄(1 equiv.), CH₂Cl₂, and aq. 1 M Na₂CO₃(2 mL per

1 mmol of bromide). After being stirred overnight the mixture was extracted

with CH₂Cl₂and the organic phase washed with sat. aq. NaHCO₃, H₂O, and

brine. The organic phase was dried (MgSO₄) and evaporated to afford a yellow

residue, which was puriﬁed to yield the thiogalactoside.

1,3,4,6-Tetra-O-acetyl-2-O-benzoyl-α-D-galactopyranose (7)

According to Method A, benzoyl chloride (2.02 g, 14.4 mmol), 6^[28](2.50 g,

7.18 mmol), and DMAP (0.09 g, 0.72 mmol) in pyridine (5 mL) and CH₂Cl₂

(25 mL) were stirred for 1 h at rt. Workup gave a white residue, which was

recrystallized to afford 7 (3.02 g, 93%) as a white powder; mp 104–105^◦C

1

(EtOAc/pet. spirit), H NMR (500 MHz, CDCl₃): δ 1.91–2.14 (12 H, 4 × s, 4 ×

Ac), 4.08 (1 H, dd, J_5,6= 6.5, J_6,6= 11.5, H6), 4.13 (1 H, dd, J_5,6= 7.0, H6),

4.36 (1 H, ddd, J_4,5= 1.0, H5), 5.50–5.56 (3 H, m, H2, H3, H4), 6.49 (1 H, d,

J_1,2= 3.5, H1), 7.38–7.92 (5 H, m, Ph); ¹³C NMR (125.6 MHz, CDCl₃): δ 20.41,

20.45, 20.61 (4C, 4 × CH3), 61.08, 66.99, 67.29, 67.41, 68.60 (5C, C2,3,4,5,6),

89.52 (1C, C1), 128.40, 128.77, 129.53, 133.43 (6C, Ar), 165.20, 168.53, 169.95,

170.14 (5C, 5 × C O); m/z (ESI⁺) 475.1210 (C₂₁H₂₄NaO₁₁[M + Na]⁺requires

475.1211).

1,3,4,6-Tetra-O-acetyl-2-O-mesitoyl-α-D-galactopyranose (8)

According to Method A, 2,4,6-trimethylbenzoyl chloride (1.05 g,

5.74 mmol), 6 (0.500 g, 1.44 mmol), and DMAP (0.176 g, 1.44 mmol) in pyridine

(5 mL) yielded an orange residue upon workup. Flash chromatography (30%

EtOAc/pet. spirits) gave 8 (0.71 g) as a white residue; mp 110–113^◦C (EtOH),

¹H NMR (500 MHz, CDCl₃): δ 2.01–2.22 (12 H, 4 × s, 4 × Ac), 2.23 (6 H, s, 2 ×

ArCH₃), 2.29 (3 H, s, ArCH₃), 4.11 (1 H, dd, J_5,6= 6.5, J_6,6= 11.5, H6), 4.15 (1

H, dd, J_5,6= 7.0, H6), 4.35 (1 H, ddd, J_4,5= 1.0, H5), 5.42 (1 H, dd, J_2,3= 11.0,

R.J. Williams et al.

252

J_3,4= 3.5, H3), 5.55 (1 H, dd, H4), 5.63 (1 H, dd, J_1,2= 4.0, H2), 6.56 (1 H,

d, H1), 6.85 (2 H, s, Ar); ¹³C NMR (125.6 MHz, CDCl₃): δ 20.44, 20.58, 20.62,

20.74 (4C, 4 × CH₃), 55.82, 55.99 (3C, 3 × MeAr), 61.14, 66.39, 67.51, 68.38

(5C, C2,3,4,5,6), 89.16 (1C, C1), 131.44, 132.16 (6C, Ar), 157.28, 158.24, 160.74,

165.21, 168.63 (5C, 5 × C O).

1,3,4,6-Tetra-O-acetyl-2-O-(2,6-dimethoxybenzoyl)-α-D-

galactopyranose (9)

According to Method A, 2,6-dimethoxybenzoyl chloride (1.15 g, 5.73 mmol),

6 (0.500 g, 1.44 mmol), and DMAP (0.176 g, 1.44 mmol) yielded an orange

residue upon workup. Flash chromatography (50% EtOAc/pet. spirits) afforded

9 (0.74 g) as a white residue; mp 143–145^◦C (EtOAc/pet. spirit), ¹H NMR

(500 MHz, CDCl₃): δ 2.02–2.20 (12 H, 4 × s, 4 × Ac), 3.77–3.83 (6 H, 2 × s,

2 × OCH₃), 4.11 (1 H, dd, J_5,6= 6.5, J_6,6= 11.0, H6), 4.14 (1 H, dd, J_5,6= 7.0,

H6), 4.33 (1 H, ddd, J_4,5= 1.0, H5), 5.42 (1 H, dd, J_2,3= 11.0, J_3,4= 3.0, H3),

5.52 (1 H, dd, H4), 5.65 (1 H, dd, J_1,2= 4.0, H2), 6.50 (1 H, d, H1), 6.53 (2 H,

m, Ar), 7.29 (1 H, m, Ar); ¹³C NMR (125.6 MHz, CDCl₃): δ 20.37, 20.51, 20.55,

20.67 (4C, 4 × CH₃), 55.77, 55.93 (2C, 2 × MeOAr), 61.08, 66.34, 67.46, 68.32

(5C, C2,3,4,5,6), 89.16 (1C, C1), 131.40, 132.13 (6C, Ar), 157.23, 158.17, 160.68,

165.16, 168.57 (5C, 5 × C O); m/z (ESI⁺) 535.1420 (C₂₃H₂₈NaO₁₃[M + Na]⁺

requires 535.1422).

1,3,4,6-Tetra-O-acetyl-2-O-(2,6-dichlorobenzoyl)-α-D-

galactopyranose (10)

According to Method A, 2,6-dichlorobenzoyl chloride (3.94 g, 18.8 mmol),

6 (1.64 g, 4.70 mmol), and DMAP (0.574 g, 4.70 mmol) afforded a brown oil

upon workup. Flash chromatography (20% EtOAc/toluene) afforded 10 (2.03

g, 83%) as a yellow oil; ¹H NMR (500 MHz, CDCl₃): δ 2.02–2.22 (12 H, 4 × s,

4 × Ac), 4.13 (2 H, m, H6, 6), 4.33 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.0, J_5,6= 7.0,

H5), 5.47 (1 H, dd, J_2,3= 9.5, J_3,4= 3.0, H3), 5.54 (1 H, dd, H4), 5.64 (1 H,

dd, J_1,2= 3.5, H2), 6.54 (1 H, d, H1), 7.14–7.33 (3 H, m, Ar); ¹³C NMR (125.6

MHz, CDCl₃): δ 20.78, 20.81, 20.99 (4C, 4 × CH₃), 61.20, 67.35, 67.90, 67.91,

68.47 (5C, C2,3,4,5,6), 88.91 (C1), 128.10, 131.51, 131.84, 132.75 (Ar), 168.70,

168.86, 170.10, 170.30, 170.47 (5C, 5 × C O).

4-Methylphenyl 3,4,6-tri-O-acetyl-2-O-benzoyl-1-thio-β-D-

galactopyranoside (2)

(i) According to Method B, a solution of tetra-acetate 7 (3.02 g, 6.67 mmol),

thiocresol (0.828 g, 6.67 mmol), and BF₃.Et₂O (0.819 mL, 6.67 mmol) in

(CH₂Cl)₂(10 mL) was stirred for 3.5 h at 65^◦C. Workup gave a residue, which

was recrystallized from EtOAc/pet. spirits affording 2 (1.51 g, 44%) as a white

powder, mp 185–187^◦C, [α]_D+34^◦(c 1.1 in CHCl₃); ¹H NMR (500 MHz,

20

Mechanistic Studies of 2,6-Disubstituted Benzoates

253

CDCl₃): δ 1.90–2.15 (9 H, 3 × s, 3 × Ac), 2.34 (3 H, s, ArCH₃), 4.00 (1 H,

ddd, J_4,5= 1.0, J_5,6= 6.5, H5), 4.16 (1 H, dd, J_6,6= 11.0, H6), 4.23 (1 H, dd,

J_5,6= 7.0, H6), 4.81 (1 H, d, J_1,2= 10.0, H1), 5.23 (1 H, dd, J_2,3= 10.0, J_3,4

=

3.5, H3), 5.47 (1 H, dd, H4), 5.49 (1 H, dd, H2), 7.09–7.38 (4 H, m, ArCH₃),

7.38–8.04 (5 H, m, Ph); ¹³C NMR (125 MHz, CDCl₃): δ 20.8–21.4 (4 C, 4 ×

CH₃), 61.9, 67.6, 68.2, 72.9, 74.8 (5 C, C2,3,4,5,6), 87.5 (1 C, C1), 128.8–138.7

(12 C, Ar), 165.4–170.6 (4 C, 4 × C O); m/z (ESI⁺) 539.1350 (C₂₆H₂₈NaO₉S

[M + Na]⁺requires 539.1346).

(ii) According to Method C, treatment of tetra-acetate 7 (0.579 g,

1.28 mmol) with HBr in AcOH (0.58 mL) for 1 h gave the intermediate bro-

mide (0.61 g) as a white residue. Treatment of the residue (0.61 g, 1.28 mmol)

with thiocresol (0.48 g, 3.84 mmol), Bu₄NHSO₄(0.43 g, 1.28 mmol), and 1 M

NaHCO₃(2.60 mL) gave a residue, which was recrystallized from EtOH to af-

ford 2 (0.51 g, 76% over the two steps) as a white powder.

4-Methylphenyl 3,4,6-tri-O-acetyl-2-O-mesitoyl-1-thio-β-D-

galactopyranoside (3)

(i) According to Method B, a solution of tetra-acetate 8 (1.29 g, 2.61 mmol),

thiocresol (0.32 g, 2.61 mmol), and BF₃.Et₂O (0.32 mL, 2.61 mmol) in (CH₂Cl)₂

(5 mL) was stirred for 5.5 h at 65^◦C. Workup gave a residue, which was re-

crystallized from EtOH to yield 3 (0.62 g, 42%) as white needles, mp 147^◦C,

[α]_D+ 10^◦(c 1.0 in CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 1.99–2.16 (9 H, 3 ×

19

s, 3 × Ac), 2.29–2.36 (12 H, s, ArCH₃), 3.93 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.5,

J_5,6= 6.5, H5), 4.14 (1 H, dd, J_6,6= 11.5, H6), 4.22 (1 H, dd, H6), 4.71 (1 H, d,

J_1,2= 10.0, H1), 5.07 (1 H, dd, J_2,3= 10.0, J_3,4= 3.5, H3), 5.46 (1 H, dd, H4),

5.54 (1 H, dd, H2), 6.86 (2 H, s, C₆H₂), 7.11 (2 H, m, C₆H₄), 7.44 (2 H, m, C₆H₄);

¹³C NMR (125 MHz, CDCl₃): δ 20.5–21.4 (7 C, 7 × CH₃), 61.8, 67.3, 67.6, 72.8,

74.3 (5 C, C2,3,4,5,6), 87.1 (1 C, C1), 128.8–140.0 (12 C, Ar), 168.7–170.6 (4 C,

4 × C O); m/z (ESI⁺) 581.1819 (C₂₉H₃₄NaO₉S [M + Na]⁺requires 581.1816).

(ii) According to Method C, treatment of tetra-acetate 8 (0.42 g, 0.84 mmol)

with HBr in AcOH (0.42 mL) for 45 min gave the intermediate bromide

(0.44 g) as a yellow oil. Treatment of the crude bromide (0.44 g, 0.84 mmol)

with thiocresol (3.12 g, 2.52 mmol), Bu₄NHSO₄(2.85 g, 0.84 mmol), and 1 M

NaHCO₃(1.70 mL) gave a residue, which was recrystallized from EtOH to af-

ford 3 (0.31 g, 74% over the two steps) as a white powder.

4-Methylphenyl 3,4,6-tri-O-acetyl-2-O-(2,6-dimethoxybenzoyl)-1-

thio-β-D- galactopyranoside (4)

(i) According to Method B, a solution of tetra-acetate 9 (1.6 g, 3.8 mmol),

thiocresol (0.47 g, 3.8 mmol), and BF₃.Et₂O (0.47 mL, 3.8 mmol) in (CH₂Cl)₂

(5 mL) was stirred for 4 h at 65^◦C. Workup gave a residue, which was recrystal-

lized from EtOH, affording 4 (0.58 g, 31%) as a white powder, mp 159–160^◦C,

[α]_D²⁰–1^◦(c 1.1 in CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 2.02–2.12 (9 H, 3 × s,

R.J. Williams et al.

254

3 × Ac), 2.35 (3 H, s, ArCH₃), 3.81 (6 H, s, 2 × OCH₃), 3.93 (1 H, ddd, J_4,5

=

1.0, J_5,6= 6.5, J_5,6= 6.5, H5), 4.13 (1 H, dd, J_6,6= 11.0, H6), 4.21 (1 H, dd,

H6), 4.71 (1 H, d, J_1,2= 10.0, H1), 5.11 (1 H, dd, J_2,3= 10.0, J_3,4= 3.5, H3),

5.39 (1 H, dd, H2), 5.41 (1 H, dd, H4), 6.56 (2 H, m, Ar), 7.12 (2 H, m, Ar), 7.33

(1 H, m, Ar), 7.49 (2 H, m, Ar); ¹³C NMR (125 MHz, CDCl₃): δ 20.9–21.4 (4 C,

4 × CH₃), 56.2 (1 C, OCH₃), 61.9, 67.6, 67.7, 72.6, 74.5 (5 C, C2,3,4,5,6), 86.3 (1

C, C1), 104.3, 112.6–138.7 (12 C, Ar), 157.8–170.7 (4 C, 4 × C O); m/z (ESI⁺)

599.1558 (C₂₈H₃₂NaO₁₁S [M + Na]⁺requires 599.1558).

(ii) According to Method C, treatment of 9 (0.77 g, 1.5 mmol) with HBr in

AcOH (1.50 mL) for 45 min gave the intermediate bromide (0.81 g) as a yellow

oil. Treatment of the crude bromide (0.81 g, 1.5 mmol) with thiocresol (0.56 g,

4.5 mmol), Bu₄NHSO₄(0.51 g, 1.5 mmol), and 1 M NaHCO₃(3.0 mL) gave a

residue, which was recrystallized from EtOH to afford 4 (0.15 g, 17% over the

two steps) as white needles.

4-Methylphenyl 3,4,6-tri-O-acetyl-2-O-(2,6-dichlorobenzoyl)-1-

thio-β-D- galactopyranoside (5)

According to Method C, treatment of tetra-acetate 10 (1.1 g, 2.2 mmol) with

HBr in AcOH (2.2 mL) for 5 h gave the intermediate bromide (1.2 g) as a white

residue. Treatment of the crude bromide (1.2 g, 2.2 mmol) with thiocresol (0.81

g, 6.5 mmol), Bu₄NHSO₄(0.74 g, 2.2 mmol), and 1 M NaHCO₃(4.30 mL) gave

a residue, which was puriﬁed by ﬂash chromatography (15% EtOAc/toluene)

to afford 5 (1.27 g, 66% over two steps) as a colorless oil. [α]_D+37^◦(c 0.9 in

20

CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 2.00–2.13 (9 H, 3 × s, 3 × Ac), 2.36 (3 H,

s, ArCH₃), 3.95 (1 H, ddd, J_4,5= 1.0, J_5,6= 7.0, J_5,6= 7.0, H5), 4.15 (1 H, dd,

J_6,6= 11.5, H6), 4.23 (1 H, dd, H6), 4.74 (1 H, d, J_1,2= 10.0, H1), 5.13 (1 H, dd,

J_2,3= 9.5, J_3,4= 3.0, H3), 5.46 (1 H, dd, H4), 5.49 (1 H, dd, H2), 7.14 (2 H, m,

ArCH₃), 7.24–7.35 (3 H, m, C₆H₃), 7.49 (2 H, m, ArCH₃); ¹³C NMR (125 MHz,

CDCl₃): δ 20.9–21.7 (5 C, 5 × CH₃), 61.8, 67.3, 69.1, 72.5, 74.4 (5 C, C2,3,4,5,6),

86.3 (1 C, C1), 125.5–133.8 (12 C, Ar), 163.2–170.6 (4 C, 4 × C O); m/z (ESI⁺)

607.0567 (C₂₆H₂₆NaO₉S [M + Na]⁺requires 607.0567).

4-Methylphenyl 2,3,4,6-tetra-O-(2,6-dimethoxybenzoyl)-1-thio-β-

D-galactopyranoside (19)

A mixture of 2,6-dimethoxybenzoyl chloride (2.80 g, 14.0 mmol), 4-

methylphenyl 1-thio-β-D-galactopyranoside^[39](0.40 g, 1.4 mmol), and DMAP

(0.17 g, 1.4 mmol) in pyridine (12 mL) was stirred at 80^◦C for 2 d. The mix-

ture was quenched with H₂O (50 mL) and cooled to rt. The mixture was then

diluted with CH₂Cl₂(50 mL) and washed with aq. HCl (3 M, 3 × 50 mL), sat.

aq. NaHCO₃(1 × 50 mL), and brine (1 × 50 mL). The organic phase was dried

(MgSO₄) and evaporated to afford a viscous oil, which was puriﬁed by ﬂash

chromatography (EtOAc/pet. spirits 40%) yielding 19 (0.95 g, 72%) as a color-

less glass; [α]_D–72^◦(c 1.0 in CHCl₃); H NMR (500 MHz, CDCl₃): δ 2.19 (3

H, s, ArCH₃), 3.54–3.82 (24 H, 4 × s, 4 × Ar(OCH₃)₂), 4.19 (1 H, ddd, J_4,5

19

1

=

Mechanistic Studies of 2,6-Disubstituted Benzoates

255

1.0, J_5,6= 7.0, J_5,6= 7.0, H5), 4.49 (1 H, dd, J_6,6= 11.5, H6), 4.49 (1 H, dd,

H6), 4.81 (1 H, d, J_1,2= 10.0, H1), 5.51 (1 H, dd, J_2,3= 10.0, H2), 5.71 (1 H, dd,

J_3,4= 3.0, H3), 6.00 (1 H, d, H4), 6.44–7.32 (12 H, 4 × C₆H₃), 6.72–7.42 (4 H,

m, C₆H₄); ¹³C NMR (125 MHz, CDCl₃): δ 21.1 (1 C, ArCH₃), 55.6–56.0 (8 C, 8 ×

OCH₃), 63.3, 68.0, 68.3, 72.4, 75.3 (5 C, C2,3,4,5,6), 86.1 (1 C, C1), 103.4–140.4

(30 C, Ar), 163.6–166.2 (4 C, 4 × C O); m/z (ESI⁺) 965.2663 (C₄₉H₅₀NaO₁₇S

[M + Na]⁺requires 965.2661).

Method D: NIS/TfOH promoted glycosylation of 11 with

thioglycosides

TfOH (0.25 equiv.) was added to thiogalactoside donor (1.1–1.2 equiv.), ac-

˚

ceptor 11 (1 equiv.), NIS (2.5 equiv.), and freshly activated 4 A molecular sieves

in dry CH₂Cl₂at 0^◦C. When TLC indicated complete consumption of the donor,

the reaction was quenched with sat. aq. NaHCO₃and 0.5 M sodium thiosulfate

solution. The mixture was ﬁltered and extracted with CH₂Cl₂and the organic

extract was washed with sat. aq. NaHCO₃and brine. The organic phase was

dried (MgSO₄) and evaporated to give a crude residue, which was puriﬁed by

ﬂash chromatography.

4-Methoxyphenyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl-

(1→3)-2,4,6-tri-O-acetyl-β-D-galactopyranoside (27a) and

4-Methoxyphenyl 2,3,4,6-tetra-O-acetyl-β-D-

galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (27b)

According to Method D, thiogalactoside donor 1 (250 mg, 0.550 mmol)

and acceptor 11 (210 mg, 0.509 mmol) gave, after ﬂash chromatography (50%

EtOAc/pet. spirits), the transesteriﬁed product 4-methoxyphenyl 2,3,4,6-tetra-

O-acetyl-β-D-galactopyranoside (32 mg, 9%) as white crystals, which was iden-

tiﬁed by comparison to authentic material. Next to elute was the α-linked

1

disaccharide 27a (4 mg, 1%) as a colorless oil; H NMR (500 MHz, CDCl₃):

δ 1.96–2.18 (21 H, 7 × s, 7 × Ac), 3.78 (3 H, s, OCH₃), 3.93 (1 H, ddd, J_4,5

=

1.0, J_5,6= 6.0, J_5,6= 6.5, H5^A), 3.95–4.24 (5 H, m, (H6,6)^A, (H3,6,6)^B), 4.93

(1 H, ddd, J_4,5= 1.0, J_5,6= 6.0, J_5,6= 6.0, H5^B), 4.84 (1 H, d, J_1,2= 7.5, H1^B),

5.17 (1 H, dd, J_2,3= 10.5, J_3,4= 3.5, H3^A), 5.18 (1 H, dd, J_1,2= 3.5, J_2,3

=

10.0, H2^A), 5.28 (1 H, d, J_1,2= 3.5, H1^A), 5.41 (1 H, dd, J_4,5= 1.0, H4^B), 5.47

(1 H, dd, H4^A), 5.49 (1 H, dd, J_2,3= 10.5, H2^B), 6.81–6.95 (4 H, m, Ar). Last

to elute was the β-linked disaccharide 27b (144 mg, 35%) as a colorless oil; ¹H

NMR (500 MHz, CDCl₃): δ 1.98–2.18 (21 H, 7 × s, 7 × Ac), 3.78 (3 H, s, OCH₃),

3.88 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.0, J_5,6= 6.5, H5^A), 3.92 (1 H, dd, J_2,3

=

10.0, J_3,4= 3.0, H3^B), 3.94 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.0, J_5,6= 6.5, H5^B),

4.11–4.22 (4 H, m, (H6,6)^A, (H6,6)^B), 4.60 (1 H, d, J_1,2= 7.5, H1^A), 4.82 (1 H,

d, J_1,2= 8.0, H1^B), 4.95 (1 H, dd, J_2,3= 10.5, J_3,4= 3.5, H3^A), 5.12 (1 H, dd,

H2^B), 5.36 (1 H, dd, H4^B), 5.44 (1 H, dd, H2^A), 5.48 (1 H, dd, H4^A), 6.81 (2 H,

R.J. Williams et al.

256

m, Ar), 6.94 (2 H, m, Ar); ¹³C NMR (125 MHz, CDCl₃): δ 20.8–20.1 (7 C, 7 ×

Ac), 55.9 (1 C, OCH₃), 61.2, 62.4, 67.0, 68.8, 69.0, 70.9, 71.1, 71.8, 76.1 (10 C,

(C2,3,4,5,6)^A, (C2,3,4,5,6)^B), 100.8, 101.4 (2 C, C1^A,1^B), 114.8–155.9 (6 C, Ar),

169.2–170.7 (7 C, 7 × C O); m/z (ESI⁺) 765.2213 (C₃₃H₄₂NaO₁₉[M + Na]⁺

requires 765.2213).

4-Methoxyphenyl 3,4,6-tri-O-acetyl-2-O-benzoyl-α-D-

galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (28a) and 4-Methoxyphenyl

3,4,6-tri-O-acetyl-2-O-benzoyl-β-D-galactopyranosyl-(1→3)-

2,4,6-tri-O-acetyl-β-D-galactopyranoside (28b)

According to Method D, thiogalactoside donor 2 (290 mg, 0.561 mmol) and

acceptor 11 (210 mg, 0.509 mmol) gave, after ﬂash chromatography (50%–60%

EtOAc/pet. spirits), the α-linked disaccharide 28a (16 mg, 4%) as a colorless

1

oil; H NMR (500 MHz, CDCl₃): δ 1.44–2.19 (18 H, 6 × s, 6 × Ac), 3.77 (3 H,

s, OCH₃), 3.88 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.5, J_5,6= 6.5, H5^B), 3.97 (1 H, dd,

J_2,3= 10.0, J_3,4= 3.0, H3^B), 4.03–4.25 (4 H, m, (H6,6)^A, (H6,6)^B) 4.34 (1 H, ddd,

J_4,5= 1.5, J_5,6= 6.5, J_5,6= 6.5, H5^A), 4.82 (1 H, d, J_1,2= 7.5, H1^B), 5.38 (1 H,

dd, J_2,3= 10.5, J_3,4= 3.0, H3^A), 5.39 (1 H, dd, H4^B), 5.44 (1 H, d, J_1,2= 3.5,

H1^A), 5.46–5.50 (2 H, m, H2^A, H2^B), 6.80–6.94 (4 H, m, Ar), 7.45–8.07 (5 H, m,

Ph). Next to elute was the β-linked disaccharide 28b (0.16 g, 40%) as a colorless

oil, [α]_D+37^◦(c 1.1 in CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 1.58–2.18 (18 H,

20

6 × s, 6 × Ac), 3.74 (3 H, s, OCH₃), 3.87 (1 H, dd, J_2,3= 10.0, J_3,4= 4.0, H3^B),

3.89 (1 H, ddd, J_4,5= 0.5, J_5,6= 6.0, J_5,6= 6.0, H5^B), 3.96 (1 H, ddd, J_4,5= 1.0,

J_5,6= 6.0, J_5,6= 6.0, H5^A), 4.10–4.21 (4 H, m, (H6,6)^A,(H6,6)^B), 4.72 (1 H, d,

J_1,2= 7.5, H1^A), 4.74 (1 H, d, J_1,2= 7.5, H1^B), 5.18 (1 H, dd, J_2,3= 10.5, J_3,4

3.0, H3^A), 5.35 (1 H, dd, H2^B), 5.41 (1 H, dd, H4^B), 5.42 (1 H, dd, H2^A), 5.48

(1 H, dd, H4^A), 6.74–6.86 (4 H, m, Ar), 7.44–7.98 (5 H, m, Ph); ¹³C NMR (125

MHz, CDCl₃): δ 20.4–21.0 (6 C, 6 × Ac), 55.7 (1 C, OCH₃), 61.2, 62.7, 67.1, 68.8,

69.6, 70.4, 70.9, 71.2, 71.9 (10 C, (C2,3,4,5,6)^A, (C2,3,4,5,6)^B), 100.9, 101.7 (2

C, C1^A,C1^B), 114.6–155.8 (12 C, Ar), 164.9–170.7, 170.8 (7 C, 7 × C O); m/z

(ESI⁺) 827.2369 (C₃₈H₄₄NaO₁₉[M + Na]⁺requires 827.2369).

4-Methoxyphenyl 3,4,6-tri-O-acetyl-2-O-mesitoyl-α-D-

galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (29a) and 4-Methoxyphenyl

3,4,6-tri-O-acetyl-2-O-mesitoyl-β-D-galactopyranosyl-(1→3)-

2,4,6-tri-O-acetyl-β-D-galactopyranoside (29b)

According to Method D, thiogalactoside donor 3 (310 mg, 0.561 mmol) and

acceptor 11 (210 mg, 0.509 mmol) gave, after ﬂash chromatography (40%–50%

EtOAc/pet. spirits), the α-linked disaccharide 29a (93 mg, 22%) as a colorless

Mechanistic Studies of 2,6-Disubstituted Benzoates

257

oil, which was crystallized from EtOH to afford white needles, mp 203–205^◦C,

¹H NMR (500 MHz, CDCl₃): δ 1.59–2.19 (18 H, 6 × s, 6 × Ac), 2.28–2.35 (9 H,

s, ArCH₃), 3.78 (3 H, s, OCH₃), 3.88 (1 H, ddd, J_4,5= 0.5, J_5,6= 6.5, J_5,6= 7.0,

H5^A), 3.94 (1 H, dd, J_2,3= 10.0, J_3,4= 3.5, H3^B), 4.06–4.24 (4 H, m, (H6,6)^A,

(H6,6)^B), 4.30 (1 H, ddd, J_4,5= 0.5, J_5,6= 6.5, J_5,6= 7.0, H5^B), 4.82 (1 H, d,

J_1,2= 8.0, H1^B), 5.23 (1 H, dd, J_2,3= 11.0, J_3,4= 3.5, H3^A), 5.33 (1 H, d, J_1,2

=

3.0, H1^A), 5.40 (1 H, dd, H4^B), 5.45 (1 H, dd, H2^B), 5.54 (1 H, dd, H4^A), 5.67 (1

H, dd, H2^A), 6.81–6.94 (6 H, m, Ar); ¹³C NMR (125 MHz, CDCl₃): δ 19.4–21.3 (6

C, 6 × Ac), 55.9 (1 C, OCH₃), 61.8, 61.9, 64.5, 66.5, 67.1, 68.0, 68.3, 69.7, 71.3,

72.7 (10 C, (C2,3,4,5,6)^A, (C2,3,4,5,6)^B), 93.6, 101.2 (2 C, C1^A,C1^B), 114.8–156.0

(12 C, Ar), 168.2–170.6 (7 C, 7 × C O); m/z (ESI⁺) 869.2843 (C₄₁H₅₀NaO₁₉

[M + Na]⁺requires 869.2839). Next to elute was the β-linked disaccharide 29b

(190 mg, 44%) as a colorless oil, which was crystallized from EtOH to afford

white needles, mp 173–174^◦C, [α]_D+36^◦(c 1.0 in CHCl₃); ¹H NMR (500 MHz,

20

CDCl₃): δ 1.64–2.22 (18 H, 6 × s, 6 × Ac), 2.26 (6 H, s, 2 × C₆H₂CH₃), 2.28 (3 H,

s, C₆H₂CH₃), 3.76 (3 H, s, OCH₃), 3.92 (1 H, ddd, J_4,5= 1.0, J_5,6= 7.0, J_5,6

=

7.0, H5^A), 3.95 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.0, J_5,6= 6.5, H5^B), 4.05 (1 H, dd,

J_2,3= 10.0, J_3,4= 3.0, H3^B), 4.11–4.27 (4 H, m, (H6,6)^A, (H6,6)^B), 4.71 (1 H, d,

J_1,2= 8.0, H1^A), 4.79 (1 H, d, J_1,2= 8.0, H1^B), 5.03 (1 H, dd, J_2,3= 10.5, J_3,4

=

3.0, H3^A), 5.42 (1 H, dd, H4^B), 5.48 (1 H, dd, H4^A), 5.37–5.42 (2 H, m, H2^A,

H2^B), 6.78–6.89 (6 H, m, Ar); ¹³C NMR (125 MHz, CDCl₃): δ 20.2–21.4 (6 C, 6 ×

Ac), 55.9 (1 C, OCH₃), 61.2, 62.4, 66.9, 69.1, 69.6, 71.0, 71.1, 71.3, 72.0, 75.3

(10 C, (C2,3,4,5,6)^A,(C2,3,4,5,6)^B), 101.5, 101.1 (2 C, C1^A,C1^B), 114.7–155.8 (12

C, Ar), 168.2–170.7 (7 C, 7 × C O); m/z (ESI⁺) 869.2844 (C₄₁H₅₀NaO₁₉[M +

Na]⁺requires 869.2839).

4-Methoxyphenyl 3,4,6-tri-O-acetyl-2-O-(2,6-dimethoxybenzoyl)-

α-D-galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (30a) and 4-Methoxyphenyl

3,4,6-tri-O-acetyl-2-O-(2,6-dimethoxybenzoyl)-β-D-

galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (30b)

According to Method D, thiogalactoside donor 4 (320 mg, 0.561 mmol)

and acceptor 11 (206 mg, 0.506 mmol) gave, after ﬂash chromatography (60%

EtOAc/pet. spirits), the α-linked disaccharide 30a (12 mg, 2%) as a colorless

1

oil; H NMR (500 MHz, CDCl₃): δ 2.01–2.19 (18 H, 6 × s, 6 × Ac), 3.78 (3 H,

s, OCH₃), 3.84 (6 H, s, 2 × OCH₃), 4.10–4.21 (5 H, m, (H5,6,6)^A, (H2,3)^B), 4.36

(2 H, m, (H6,6)^B), 4.53 (1 H, ddd, J_4,5= 0.5, J_5,6= 6.0, J_5,6= 6.0, H5^B), 4.91

(1 H, d, J_1,2= 8.5, H1^B), 5.02 (1 H, dd, J_2,3= 10.0, J_3,4= 3.0, H3^A), 5.44 (1

H, dd, J_1,2= 3.5, H2^A), 5.47 (1 H, d, H1^A), 5.50 (1 H, dd, H4^A), 5.62 (1 H, dd,

J_3,4= 3.0, H4^B), 6.82–6.96 (4 H, m, Ar), 7.33 (3 H, m, C₆H₄). Next to elute was

R.J. Williams et al.

258

the β-linked disaccharide 30b (230 mg, 54%) as a colorless oil, [α]_D+39^◦(c

20

1

1.1 in CHCl₃); H NMR (500 MHz, CDCl₃): δ 2.01–2.21 (18 H, 6 × s, 6 × Ac),

3.76 (3 H, s, OCH₃), 3.81 (6 H, s, 2 × OCH₃), 3.88 (1 H, ddd, J_4,5= 0.5, J_5,6

=

6.5, J_5,6= 7.0, H5^A), 3.96 (1 H, dd, J_2,31 = 0.0, J_3,4= 3.0, H3^B), 4.11–4.24 (5

H, m, (H6,6)^A, (H5,6,6)^B), 4.71 (1 H, d, J_1,2= 8.0, H1^A), 4.75 (1 H, d, J_1,2

=

8.0, H1^B), 5.04 (1 H, dd, J_2,3= 10.5, J_3,4= 3.5, H3^A), 5.36 (1 H, dd, H2^B), 5.37

(1 H, dd, H2^A), 5.38 (1 H, dd, H4^A), 5.49 (1 H, dd, J_3,4= 3.0, H4^B), 6.87 (2 H,

m, C₆H₄), 6.77–6.90 (4 H, m, Ar), 6.87 (3 H, m, C₆H₄); ¹³C NMR (125 MHz,

CDCl₃): δ 19.8–21.0 (6 C, 6 × Ac), 55.9, 56.1, 56.6 (3 C, OCH₃), 61.3, 62.4, 67.1,

68.2, 69.1, 69.4, 70.8, 71.0, 71.5, 71.9 (10 C, (C2,3,4,5,6)^A, (C2,3,4,5,6)^B), 101.2,

101.5 (2 C, C1^A,1^B), 114.7–158.4 (12 C, Ar), 164.4–170.7 (7 C, 7 × C O); m/z

(ESI⁺) 887.2582 (C₄₀H₄₈NaO₂₁[M + Na]⁺requires 887.2580).

4-Methoxyphenyl 3,4,6-tri-O-acetyl-2-O-(2,6-dichlorobenzoyl)-α-

D-galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (31a) and 4-Methoxyphenyl

3,4,6-tri-O-acetyl-2-O-(2,6-dichlorobenzoyl)-β-D-

galactopyranosyl-(1→3)-2,4,6-tri-O-acetyl-β-D-

galactopyranoside (31b)

According to Method D, thiogalactoside donor 5 (320 g, 0.561 mmol)

and acceptor 11 (210 g, 0.509 mmol) gave, after ﬂash chromatography (30%

EtOAc/pet. spirits), the α-linked disaccharide 31a (120 mg, 27%) as a colorless

oil, [α]_D+73^◦(c 1.1 in CHCl₃); H NMR (500 MHz, CDCl₃): δ 1.88–2.18 (18

H, 6 × s, 6 × Ac), 3.78 (3 H, s, OCH₃), 3.87 (1 H, ddd, J_4,5= 1.0, J_5,6= 7.0,

J_5,6= 7.0, H5^A), 3.93 (1 H, dd, J_2,3= 10.0, J_3,4= 3.5, H3^B), 4.01–4.13 (4 H, m,

(H6,6)^A, (H6,6)^B), 4.21 (1 H, ddd, J_4,5= 1.0, J_5,6= 6.5, J_5,6= 6.5, H5^B), 4.22

(1 H, dd, J_1,2= 8.0, H2^B), 4.80 (1 H, d, H1^B), 5.30 (1 H, d, H1^A), 5.38 (1 H, dd,

J_3,4= 3.5, H4^A), 5.45 (1 H, dd, J_2,3= 10.0, H3^A), 5.51 (1 H, dd, H4^B), 5.58 (1 H,

dd, H2^A), 6.81–6.94 (4 H, m, C₆H₄), 7.32–7.40 (3 H, m, C₆H₃); ¹³C NMR (125

MHz, CDCl₃): δ 20.3–21.1 (6 C, 6 × Ac), 55.9 (1 C, OCH₃), 61.1, 62.1, 66.7, 67.6,

67.7, 68.0, 69.1, 70.5, 71.5, 71.8 (10 C, (C2,3,4,5,6)^A, (C2,3,4,5,6)^B), 97.0, 101.2

(2 C, C1^A,1^B), 114.8–156.0 (12 C, Ar), 169.4–170.7 (7 C, 7 × C O); m/z (ESI⁺)

895.1592 (C₃₈H₄₂NaCl₂O₁₉[M + Na]⁺requires 895.1597). Next to elute was

23

1

the β-linked disaccharide 31b (160 mg, 36%) as a colorless oil, [α]_D+25^◦(c

24

1

1.1 in CHCl₃); H NMR (500 MHz, CDCl₃): δ 1.79–2.23 (18 H, 6 × s, 6 × Ac),

3.76 (3 H, s, OCH₃), 3.91–4.27 (7 H, m, (H5,6,6)^A, (H2,3,5,6,6)^B), 4.76 (1 H, d,

J_1,2= 8.0, H1^B), 5.30 (1 H, d, J_1,2= 8.0, H1^A), 5.37 (1 H, dd, J_2,3= 10.0, H2^A),

5.42 (1 H, dd, J_4,5= 1.0, H4^B), 5.46 (1 H, dd, J_3,4= 3.5, H3^A), 5.48 (1 H, dd,

J_4,5= 1.0, H4^A), 6.78–6.90 (4 H, m, Ar), 7.31–7.38 (3 H, m, C₆H₄); ¹³C NMR

(125 MHz, CDCl₃): δ 20.7–21.2 (6 C, 6 × Ac), 55.9 (1 C, OCH₃), 61.1, 62.3, 62.6,

67.0, 69.2, 70.7, 70.8, 71.1, 72.0, 76.0 (10 C, (C2,3,4,5,6)^A, (C2,3,4,5,6)^B), 100.8,

Mechanistic Studies of 2,6-Disubstituted Benzoates

259

101.2 (2 C, C1^A,C1^B), 114.7–154.7 (12 C, Ar), 169.5–170.9 (7 C, 7 × C O); m/z

(ESI⁺) 895.1591 (C₃₈H₄₂NaCl₂O₁₉[M + Na]⁺requires 895.1597).

Variable Temperature NMR Studies: Representative Procedure

To a suspension of the thioglycoside 3 (10 mg, 0.023 mmol) and NIS

(5.7 mg, 0.025 mmol) in CDCl₃(1 mL) in a 5-mm NMR tube at –78^◦C was

added TfOH (2.2 µL, 0.025 mmol), and the mixture dissolved by gentle vortex-

ing. The glycosyl triﬂate 22 (anomeric δ_H: 6.47 ppm [d, J = 3.5 Hz]; anomeric

δ_C: 103.5 ppm) and dioxolenium ion 23 (anomeric δ_H: 7.64 ppm [d, J = 8.2 Hz];

anomeric δ_C: 111.0 ppm) were instantly formed. The mixture of 22 and 23 was

allowed to warm at 10 ^◦C/10 min with monitoring by 400 MHz 1H and 100 MHz

¹³C NMR spectroscopies.

Crystallography

Intensity data were collected with an Oxford Diffraction Sapphire CCD

diffractometer using Cu-Ka radiation (graphite crystal monochromator λ =

1.54184); the temperature during data collection was maintained at 130.0(1)

K using an Oxford Cryosystems cooling device.

Crystal data for 16

C₅₃H₅₈O₉S, M = 871.05, T = 130.0(2) K, λ = 1.5418, Orthorhombic, space

˚

group P2₁2₁2₁a = 15.0642(2), b = 15.4036(2), c = 19.9343(2) A, V = 4625.6(1)

A , Z = 4, D_c= 1.251 mg/M⁻³µ(Cu-Kα) 1.082 mm⁻¹, F(000) = 1856, crystal size

3

˚

0.5 × 0.4 × 0.35 mm. 17327 reﬂections measured, 8226 independent reﬂections

(R_int= 0.0253), the ﬁnal R was 0.0352 [I > 2σ(I)] and wR(F²) was 0.0882 (all

data).

Crystal data for 17

C₃₆H₄₂O₇S, M = 618.76, T = 130.0(2) K, λ = 1.5418, Monoclinic, space

◦

˚

group P2₁a = 16.9919(3), b = 6.0300(1), c = 18.2773(3) A, β = 117.288(2) , V =

1664.30(5) A , Z = 2, D_c= 1.235 mg/M⁻³µ(Cu-Kα) 1.245 mm⁻¹, F(000) = 660,

3

˚

crystal size 0.45 × 0.4 × 0.3 mm. 9405 reﬂections measured, 5270 independent

reﬂections (R_int= 0.0202), the ﬁnal R was 0.0332 [I > 2σ(I)] and wR(F²) was

0.0923 (all data).

Supporting information

NMR spectra for compounds 2–5, 7–10, 19, 27–29, 31; representative vari-

able temperature NMR spectra; and coordinates for the crystal structures are

available online. Crystallographic data ﬁles for the structures reported in this

paper have been deposited with the Cambridge Crystallographic Data Centre

R.J. Williams et al.

260

as ﬁles CCDC-784498 and CCDC-784499 and are available on request from

http://ww w .ccdc.cam.ac.uk/. (these details will be added upon acceptance)

ACKNOWLEDGEMENTS

This work was supported by Biosupplies Australia Ltd. and the Australian Re-

search Council. NWM is a grateful recipient of the Albert Shimmins Memorial

Award.

REFERENCES

1. Koenigs, W.; Knorr, E. Ueber einige derivate des Traubensuckers und der Galac-

tose. Ber. Dtsch. Chem. Ges. 1901, 34, 957–981; (x) Michael, A. On the synthesis of

helicin and phenoglucoside. Am. Chem. J. 1879, 1, 305.

2. Paulsen, H.; Herold, C.P. Carboxoniumverbindungen in der Kohlenhydratchemie,

X. Untersuchungen zur Acetoxonium-Umlagerung von D-glucose zu D-idose. Chem.

Ber. 1970, 103, 2450–2462.

3. Crich, D.; Dai, Z.; Gastaldi, S. On the role of neighboring group participation

and ortho esters in β-xylosylation: ¹³C NMR observation of a bridging 2-phenyl-1,3-

dioxalenium ion. J. Org. Chem. 1999, 64, 5224–5229.

4. Zeng, Y., Wang, Z.; Whitﬁeld, D.; Huang, X. Installation of electron-donating pro-

tective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the

preactivation-based glycosylation method. J. Org. Chem. 2008, 73, 7952–7962.

5. Nukada, T.; Be´rces, A.; Zgierski, M.Z.; Whitﬁeld, D.M. Exploring the mechanism

of neighboring group assisted glycosylation reactions. J. Am. Chem. Soc. 1998, 120,

13291–13295.

6. Smoot, J.T.; Pornsuriyasak, P.; Demchenko, A.V. Development of an arming partic-

ipating group for stereoselective glycosylation and chemoselective oligosaccharide syn-

thesis. Angew. Chem. Int. Ed. 2005, 44, 7123–7126.

7. (a) Yamada, T.; Takemura, K.; Yoshida, J.-i.; Yamago, S. Dialkylphosphates as

stereodirecting protecting groups in oligosaccharide synthesis. Angew. Chem. Int. Ed.

2006, 45, 7575–7578 (b) Crich, D.; Hutton, T.K.; Banerjee, A.; Jayalath, P.; Picione, J.

Disarming, non-participating 2-O-protecting groups in manno- and rhamnopyranosyla-

tion: scope and limitations of sulfonates, vinylogous esters, phosphates, cyanates, and

nitrates, Tetrahedron: Asymmetry. 2005, 16, 105–119.

8. Jiao, H.; Hindsgaul, O. The 2-N,N-dibenzylamino group as a participating group

in the synthesis of β-glycosides. Angew. Chem. Int. Ed. 1999, 38, 346–348.

9. (a) Cheng, Y.-P.; Chen, H.-P.; Lin, C.-C. A convenient and highly stereoselective

approach for α-galactosylation performed by galactopyranosyl dibenzyl phosphite with

remote participating groups. Tetrahedron Lett. 2002, 43, 7721–7723 (b) Demchenko,

A.V.; Rousson, E.; Boons, G.-J. Stereoselective 1,2-cis-galactosylation assisted by re-

mote neighboring group participation and solvent effects. Tetrahedron Lett. 1999, 40,

6523–6526 (c) Ustyuzhanina, N.; Komarova, B.; Zlotina, N.; Krylov, V.; Gerbst, A.;

Tsvetkov, Y.; Nifantiev, N. Stereoselective α-glycosylation with 3-O-acetylated-D-gluco

donors. Synlett 2006, 921–923.

10. Crich, D.; Hu, T.; Cai, F. Does neighboring group participation by non-vicinal esters

play a role in glycosylation reactions? Effective probes for the detection of bridging

intermediates, J. Org. Chem. 2008, 73, 8942–8953.

Mechanistic Studies of 2,6-Disubstituted Benzoates

261

11. (a) Kim, J.H.; Yang, H.; Park, J.; Boons, G.J. A general strategy for stereoselective

glycosylations. J. Am. Chem. Soc. 2005, 127, 12090–12097 (b) Fascione, M.A.; Adshead,

S.J.; Stalford, S.A.; Kilner, C.A.; Leach, A.G.; Turnbull, W.B. Stereoselective glycosyla-

tion using oxathiane glycosyl donors. Chem. Commun. 2009, 5841–5843.

12. (a) Kim, J.H.; Yang, H.; Boons, G.J. Stereoselective glycosylation reactions with

chiral auxiliaries. Angew. Chem. Int. Ed. 2005, 44, 947–949 (b) Boltje, T.J.; Kim,

J.H.; Park, J.; Boons, G.J. Chiral-auxiliary-mediated 1,2-cis-glycosylations for the solid-

supported synthesis of a biologically important branched α-glucan. Nat. Chem. Biol.

2010, 2, 552–557.

13. (a) Stick, R.V.; Tilbrook, D.M.G.; Williams, S.J. 1,6-Epithio- and 1,6-episeleno-β-

D-glucopyranose: useful adjuncts in the synthesis of 6-deoxy-β-D-glucosides. Aust. J.

Chem. 1999, 52, 685–693 (b) Ziegler, T.; Kova´c, P.; Glaudemans, C.P.J. Transesteriﬁ-

cation during glycosylation promoted by silver triﬂuoromethanesulfonate. Liebigs Ann.

Chem. 1990, 613–615.

14. Nukada, T.; Be´rces, A.; Whitﬁeld, D.M. Acyl transfer as a problematic side reaction

in polymer-supported oligosaccharide synthesis. J. Org. Chem. 1999, 64, 9030–9045.

15. Lee, R.T.; Lee, Y.C.

A facile synthesis of 2-O-(α-D-mannopyranosyl)-α-D-

mannopyranosides. Carbohydr. Res. 1995, 271, 131–136.

16. Liu, M.-Z.; Fan, H.-N.; Guo, Z.-W.; Hui, Y.-Z. One-step glycosylation and selective

deprotection of peracetylated monosaccharides for facile syntheses of allyl glycosides

with a free C-2 hydroxyl group. Carbohydr. Res. 1996, 290, 233–237.

17. Lemieux, R.U.; Morgan, A.R. Preparation and conﬁgurations of tri-O-acetyl-α-D-

glucopyranose 1,2-(orthoesters). Can. J. Chem. 1965, 43, 2199–2204.

18. Kong, F. Recent studies on reaction pathways and applications of sugar or-

thoesters in synthesis of oligosaccharides. Carbohydr. Res. 2007, 342, 345–373.

19. (a) Franks, N.E.; Montgomery, R. Stereoselective ring-opening of β-D-

mannopyranose 1,2-(alkylorthoacetates). Carbohydr. Res. 1967, 3, 511–512; (b) Franks,

N.E.; Montgomery, R. Stereoselective ring opening of β-D-mannopyranose 1,2-(alkyl or-

thoacetates). Carbohydr. Res. 1968, 6, 286–298; (c) Mehta, S.; Pinto, M. Phenyl seleno-

glycosides as versatile glycosylating agents in oligosaccharide synthesis and the chem-

ical synthesis of disaccharides containing sulfur and selenium. In Modern Methods in

Carbohydrate Synthesis; Khan S.H., O’Neill, R.A., Eds; Harwood Academic Publishers;

Amsterdam, 1996; 107 (d) Perlin, A.S. Methanolysis of carbohydrate orthoesters. Can.

J. Chem. 1963, 41, 555–561.

20. Be´rces, A.; Whitﬁeld, D.M.; Nukada, T.; do Santos, Z.I., Obuchowska, A.; Krepin-

sky, J.J. Is acyl migration to the aglycone avoidable in 2-acyl assisted glycosylation

reactions? Can. J. Chem. 2004, 82, 1157–1171.

21. (a) Kova´c, P.; Taylor, R.B.; Glaudemans, C.P.J. General synthesis of (1–3)-β-D-

galacto oligosaccharides and their methyl β-glycosides by a stepwise or a blockwise

approach. J. Org. Chem. 1985, 50, 5323–5333 (b) Yang, F.; Du, Y. Synthesis of oligosac-

charide derivatives related to those from sanqi, a Chinese herbal medicine from Panax

notoginseng. Carbohydr. Res. 2002, 337, 485–491 (c) Yang, F.; He, H.; Du, Y.; Lu¨, M.

Unexpected α-stereochemical outcomes of attempted β-glycosylations. Carbohydr. Res.

2002, 337, 1165–1169 (d) Jacquinet, J.-C. An expeditious preparation of various sulfo-

forms of the disaccaride β-D-Galp-(1→3)-D-Galp, a partial structure of the linkage re-

gion of proteoglycans, as their 4-methoxyphenyl β-D-glycosides. Carbohydr. Res. 2004,

339, 349–359; (e) Li, A.; Kong, F. Syntheses of β-(1→6)-branched β-(1→3)-linked D-

galactans that exist in the rhizomes of Atractylodes lancea DC. Carbohydr. Res. 2005,

340, 1949–1962 (f) Chen, L.; Kong, F. A practical synthesis of β-D-GlcA-(1->3)-β-D-Gal-

(1->3)-β-D-Gal-(1->4)-D-Xyl, a part of the common linkage region of a glycosaminogly-

can. Carbohydr. Res. 2002, 337, 1373–1380.

R.J. Williams et al.

262

22. Geyer, K.; Seeberger, P.H. Optimization of glycosylation reactions in a microreac-

tor. Helv. Chim. Acta 2007, 90, 395–403.

23. Chen, L.; Kong, F. Unusual alpha-glycosylation with galactosyl donors with

a C2 ester capable of neighboring group participation. Tetrahedron Lett. 2003, 44,

3691–3695.

24. Spijker, N.M.; van Boeckel, C.A.A. Double stereodifferentiation in carbohydrate

coupling reactions: the mismatched interaction of donor and acceptor as an unprece-

dented factor governing the α/β ratio of glycoside formation. Angew. Chem. Int. Ed.

1991, 30, 180–183.

25. McGill, N.W.; Williams, S.J. 2,6-Disubstituted benzoates as neighboring groups

for enhanced diastereoselectivity in β-galactosylation reactions: synthesis of β-1,3-

linked oligogalactosides related to arabinogalactan proteins, J. Org. Chem. 2009, 74,

9388–9398.

26. Kova´c, P.; Glaudemans, C.P.J. An efﬁcient, unambiguous synthesis of methyl 3-O-

β-D-galactopyranosyl-β-D-galactopyranoside—further studies on the speciﬁcity of anti-

galactopyranan monoclonal-antibodies. Carbohydr. Res. 1985, 142, 158–164.

27. (a) Nunomura, S.; Mori, M.; Ito, Y.; Ogawa, T. A total synthesis of Forssman

glycolipid, globopentaosyl ceramide Iv3GalNAc-α-Gb4cer. Tetrahedron Lett. 1989, 30,

6713–6716 (b) Nunomura, S.; Mori, M.; Ito, Y.; Ogawa, T. Synthetic studies on cell-

surface glycans. 67. A total synthesis of para-Forssman glycolipid isolated from human-

erythrocyte membrane. Tetrahedron Lett. 1989, 30, 5619–5622.

28. Chittenden, G.J.F.

A simpliﬁed synthesis of α-D-galactopyranose 1,3,4,6-

tetraacetate. Carbohydr. Res. 1988, 183, 140–143.

29. Robertson, A. Synthesis of glucosides. Part II. The preparation of some galacto-

sides, J. Chem. Soc. 1929, 1820–1823.

30. Be´rces, A.; Enright, G.; Nukada, T.; Whitﬁeld, D.M. The conformational origin of

the barrier to the formation of neighboring group assistance in glycosylation reactions:

a dynamical density functional theory study. J. Am. Chem. Soc. 2001, 123, 5460.

31. Barili, P.L.; Catelani, G.; Fabrizi, G.; Lamba, D. Structure elucidation of methyl

3,4-O-isopropylidene-α- and β-D-galactopyranosides by NMR and X-ray analysis. Car-

bohydr. Res. 1993, 243, 165–176.

32. (a) Callam, C.S.; Gadikota, R.R.; Krein, D.M.; Lowary, T.L. 2,3-Anhydrosugars in

glycoside bond synthesis. NMR and computational investigations into the mechanism

of glycosylations with 2,3-anhydrofuranosyl glycosyl sulfoxides. J. Am. Chem. Soc.

2003, 125, 13112–13119 (b) Nokami, T.; Shibuya, A.; Tsuyama, H.; Suga, S.; Bowers,

A.A.; Crich, D.; Yoshida, J. Electrochemical generation of glycosyl triﬂate pools. J. Am.

Chem. Soc. 2007, 129, 10922–10928 (c) Honda, E.; Gin, D.Y. C2-hydroxyglycosylation

with glycal donors. Probing the mechanism of sulfonium-mediated oxygen transfer to

glycal enol ethers. J. Am. Chem. Soc. 2002, 124, 7343–7352 (d) Liu, J.; Gin, D.Y. C2-

amidoglycosylation. Scope and mechanism of nitrogen transfer. J. Am. Chem. Soc. 2002,

124, 9789–9797 (e) Garcia, B.A.; Gin, D.Y. Dehydrative glycosylation with activated

diphenyl sulfonium reagents J. Am. Chem. Soc. 2000, 122, 4269–4279 (f) Gildersleeve,

J.; Pascal, Jr, R.A.; Kahne, D. Sulfenate intermediates in the sulfoxide glycosylation

reaction. J. Am. Chem. Soc. 1998, 120, 5961–5969 (g) Crich, D.; Sun, S. Are glycosyl

1

triﬂates intermediates in the sulfoxide glycosylation method? A chemical and H, ¹³C

and ¹⁹F NMR spectroscopic investigation. J. Am. Chem. Soc. 1997, 119, 11217 (h) Stal-

ford, S.A.; Kilner, C.A.; Leach, A.G.; Turnbull, W.B. Neighbouring group participation

vs. addition to oxacarbenium ions: studies on the synthesis of mycobacterial oligosac-

charides. Org. Biomol. Chem. 2009, 7, 4842–4852 (i) Ito, Y.; Ando, H.; Wada, M.;

Kawai, T.; Ohnish, Y.; Nakahara, Y. On the mechanism of p-methoxybenzylidene

Mechanistic Studies of 2,6-Disubstituted Benzoates

263

assisted intramolecular aglycon delivery. Tetrahedron 2001, 57, 4123–

4132.

33. Lemieux, R.U.; Hendriks, K.B.; Stick, R.V.; James, K. Halide ion catalyzed glycosi-

dations. Syntheses of α-linked disaccharides. J. Am. Chem. Soc. 1975, 97, 4056.

34. Crich, D.; Sun, S. Formation of β-mannopyranosides of primary alcohols using the

sulfoxide method. J. Org. Chem. 1996, 61, 4506–4507.

35. Whitﬁeld, D.M.; Nukada, T. DFT studies of the role of C-2-O-2 bond ro-

tation in neighboring-group glycosylation reactions. Carbohydr. Res. 2007, 342,

1291–1304.

36. Dinev, Z.; Gannon, C.T.; Egan, C.; Watt, J.A.; McConville, M.J.; Williams, S.J.

Galactose-derived phosphonate analogues as potential inhibitors of phosphatidylinosi-

tol biosynthesis in mycobacteria. Org. Biomol. Chem. 2007, 5, 952–959.

37. Goto, F.; Ogawa, T. Synthesis of a sulfated glycopeptide corresponding to the

carbohydrate-protein linkage region of proteoglycans—β-D-GlcA-(1→3){(SO₃Na→4)}-

β-D-Gal-(1→3)-β-D-Gal-(1→4)-β-D-Xyl-(1→3)-Ser. Tetrahedron Lett. 1992, 33,

5099–5102.

38. Tamura, J.; Nishihara, J. Synthesis of phosphorylated and sulfated glycosyl

serines in the linkage region of the glycosaminoglycans. J. Org. Chem. 2001, 66,

3074–3083.

39. Yde, M.; De Bruyne, C.K. Synthesis of para-substituted phenyl 1-thio-β-D-

galactopyranosides. Carbohydr. Res. 1973, 26, 227–229.

Article Doi

Neighboring group participation in glycosylation reactions by 2,6-disubstituted 2-O-benzoyl groups: A mechanistic investigation

DOI: 10.1080/07328303.2010.508141

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