Neighbouring group participation during glycosylation: Do 2-substituted ethyl ethers participate?

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FULL PAPER

DOI: 10.1002/ejoc.201402260

Neighbouring Group Participation During Glycosylation: Do 2-Substituted

Ethyl Ethers Participate?

Daniel J. Cox,^[a]Govind P. Singh,^[b]Andrew J. A. Watson,^[b]and Antony J. Fairbanks*^[b]

Keywords: Synthetic methods / Carbohydrates / Glycosylation / Neighboring-group effects / Diastereoselectivity

The development of new protecting groups that undergo

neighbouring group participation (NGP) via six-membered

ring intermediates to promote the formation of α-1,2-cis glyc-

osidic linkages complements the established use of 5-ring

NGP in terms of stereochemical outcome. A selection of glyc-

osyl donors was synthesised that possessed novel 2-iodo- and

2-(phenylseleno)ethyl ether protecting groups in an attempt

to promote highly α-selective glycosylation by 6-ring NGP.

Although the fully armed donors produced α-glucosides as

the predominant reaction products, low-temperature NMR

studies did not show NGP by the observation of cyclised re-

action intermediates. The corresponding disarmed glycosyl

donors were unexpectedly less stereoselective. NMR spec-

troscopy revealed that the 2-iodoethyl ether did not partici-

pate in any of the glycosylation processes; however, the 2-

(phenylseleno)ethyl ether did participate, and β-configured

cyclic intermediates were observed. The fact that consider-

able amounts of β-glycoside product were formed in these

latter cases indicated that the predominant reaction pathway

to product did not occur through the observed cyclic species.

Clearly, a fine balance exists during glycosylation reactions,

and the reaction pathway to product depends on a variety of

factors. Notably, the formation of cyclised intermediates by

6-ring NGP is not on its own sufficient to ensure high levels

of α-stereoselectivity.

control of stereochemistry of glycosylation by NGP of re-

mote thioethers and by the use of cyclic β-configured do-

nors to promote α-glycoside formation.

Introduction

The issue of control of anomeric stereochemistry during

glycosylation reactions represents a challenge that has yet

to be completely addressed by the synthetic chemist. Al-

though 1,2-trans glycosidic linkages can usually be synthe-

sised with high levels of stereocontrol through classical 5-

ring neighbouring group participation (NGP) of 2-O-acyl-

protected glycosyl donors,^[1]the stereocontrolled synthesis

of 1,2-cis glycosidic linkages is considerably more diffi-

cult.^[2]

The use of new types of NGP, for example the intermedi-

acy of a six-membered-ring intermediate, to enforce the for-

mation of 1,2-cis glycosidic linkages, represents an attract-

ive proposition which, in theory, could be applied generally

to access all α-1,2-cis glycosides (e.g. α-gluco, α-galacto and

so on). Boons has been a pioneer of this field, and in a

series of seminal works^[3]has described significant ad-

vances, such as the use of chiral auxiliaries at the 2-position

of donors that operate through 6-ring NGP to control the

diastereoselectivity of glycosylation. Turnbull^[4]has also

been active in a similar vein, and has reported both the

As can been seen in Figure 1 the situation for 6-ring

NGP during a glycosylation process is complicated by the

potential for two different configurations of any cyclic inter-

mediate, and also the equilibria between a glycosyl cation

(or other acyclic intermediate) and these cyclic species. It

may be expected that a glycosyl cation should react with a

glycosyl acceptor (ROH) in a predominantly non-selective

fashion, whereas a trans-decalin cyclic intermediate should

react to preferentially produce the α-glycoside product.

Conversely, nucleophilic attack of an acceptor directly on

the cis-decalin intermediate should lead to the β-glycoside.

In the Boons^[3]and Turnbull^[4]systems the judicious placing

of a substituent on the ethyl group, which adopts an equa-

torial position in the trans-decalin intermediate promotes

the formation of this species, and results in high levels of

α-selectivity. In contrast to this situation, Demchenko has

reported the synthesis and use of 2-O-picolyl-protected

glycosyl donors that are proposed to react through cyclic 6-

ring intermediates, but which have been shown to preferen-

tially produce the β-glycoside product through an α-config-

ured cis decalin-type intermediate.^[5]

[a] Department of Chemistry, Chemistry Research Laboratory,

University of Oxford,

Mansfield Road, Oxford, OX1 3TA, UK

Our work began by reasoning that any glycosyl donor

possessing a 2-O-ethyl ether,^[6]in which the 2-position was

substituted by a heteroatom, could show a tendency to pro-

mote α-glucoside formation. Although the Boons and

Turnbull approaches do produce high levels of α-selectivity,

[b] Department of Chemistry, University of Canterbury,

Private Bag 4800, Christchurch 8140, New Zealand

E-mail: antony.fairbanks@canterbury.ac.nz

www.chem.canterbury.ac.nz

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402260.

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

FULL PAPER

Figure 1. Postulated equilibria between the glycosyl cation and 6-ring intermediates arising from NGP of 2-substituted ethyl ethers, and

the stereochemical consequences for the outcome of glycosylation.

the installation of the additional stereogenic centre that is

required in the side chain does complicate the approach to

an extent. We recently disclosed the synthesis and utility

of a series of 2-O-(thiophen-2-yl)-methyl-protected glycosyl

donors in stereoselective α-glycosylation reactions.^[7]Fol-

lowing this report our attention turned to the use of softer

atoms at the 2-position of an ethyl ether to increase the

propensity for 6-ring NGP, and increase the levels of α-

selectivity produced. This paper reports the synthesis and

glycosylation reactions of a variety of differently protected

glycosyl donors that possess 2-O-ethyl ethers, which are

substituted with Se and I, and also includes NMR studies

that reveal the extent to which NGP operates within these

systems.

Results and Discussion

Studies on Fully Armed Donors

Both selenium and iodine are known to participate as

neighbouring functional groups in a variety of substitution

processes.^[8]Moreover the 2-(phenylseleno) ethyl ether was

reported as an alcohol protecting group back in 1975,^[9]but

has found little application since that point of time. A series

of glycosyl donors possessing either Se or I at the 2-postion

of a 2-O-ethyl ether were therefore targeted. Owing to the

operational simplicity by which the 2-hydoxyl may be differ-

entiated from the others through the intermediacy of a 1,2-

orthoester, donors that possessed “arming” benzyl ether

protection of the other three hydroxy groups were targeted

for the first study (Scheme 1).

Synthesis of Donors

Direct conversion of glycosyl donors possessing a free

Scheme 1. (i) O₃, CH₂Cl₂/MeOH, –78 °C, 15 min; then NaBH₄,

OH group at position-2 into the corresponding substituted

ethyl ethers proved more problematic than expected, and so

more indirect routes were adopted that involved 2-O-allyl

ethers as intermediates. Ozonolysis of known glycosyl fluor-

ide 1^[10]with a reductive work-up gave alcohol 2 that under-

–78 °C to room temp., 1 h, 81%; (ii) I₂, PPh₃, imidazole, THF, re-

flux, 16 h, 89%; (iii) PhSeH, NaH, THF, reflux, 16 h, 86%. (iv) O₃,

CH₂Cl₂/MeOH, –78 °C, 15 min; then NaBH₄, –78 °C to room

temp., 1 h, 85%; (v) I₂, PPh₃, imidazole, THF, reflux, 16 h, 76%;

(vi) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 3 h, 84 %; (vii) PhSeH, NaH,

THF, reflux, 16 h, 81%; (viii) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 3 h,

went an Appel reaction^[11]with I₂, PPh₃and imidazole, to 88%.

2

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Neighbouring Group Participation During Glycosylation

give iodide 3. Treatment of 3 with sodium phenylselenide, with low anomeric selectivity (α/β ratio, 1.5:1; Table 1, En-

pre-formed by reaction of phenylselenol with NaH, gave try 4). However, reduction of the reaction temperature to –

donor 4 in excellent yield. Corresponding trichloroacetim- 78 °C increased the observed stereoselectivity (α/β ratio, 5:1;

idate donors 8 and 10 were made by an analogous route. Table 1, Entry 6), without significantly altering the yield.

Thus ozonolysis of known hemiacetal 5^[12]followed by re-

Attention then turned to the glycosylation of 2-iodoethyl

ductive work-up gave diol 6. Appel reaction of 6 was selec-

tive for the primary hydroxy group, and gave iodide 7 in

76% yield. Reaction of 7 with trichloroacetonitrile and 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) gave trichloroacetim-

idate donor 8. Alternatively treatment of 7 with sodium

phenyl selenide gave hemiacetal 9, which was readily con-

verted into trichloroacetimidate donor 10.

protected glycosyl donors 3 and 8. Glycosyl fluoride 3 was

activated with supra-stoichiometric quantities of BF₃·OEt₂,

and produced disaccharide 11a in good to moderate yields.

The α-selectivity, though slightly lower than that observed

with the corresponding 2-(phenylseleno) ethyl ether, again

increased with a decrease in temperature. Reaction of tri-

chloroacetimidate 8 with diacetone galactose gave a higher

yield of 11a than with the fluoride donor and again α-selec-

tivity was also observed. Overall the results were marginally

better than those observed for fluoride donor 3 (α/β ratio,

3.5:1; Table 1, Entry 12), though the level of stereocontrol

still fell short of the α-selectivity observed with the corre-

sponding 2-(phenylseleno)ethyl ether.

Glycosylation Reactions

Donors 3, 4, 8 and 10 were glycosylated with diacetone

galactose as a model acceptor. The 2-(phenylseleno) ethyl

ether protected donors 4 and 10 were investigated first.

Glycosyl fluoride 4 was activated by using BF₃·OEt₂

Se-containing trichloroacetimidate donor 10 was then

(1.5 equiv.). Unlike the case of the equivalent 2-O-(thio- glycosylated with a small selection of other acceptors

phen-2-yl) methyl protected glycosyl donor,^[6]good yields (Table 2). Glycosylation with methanol as an acceptor pro-

of disaccharide 11b were observed, and TLC analysis indi- duced methyl glycoside 14 in good yield, but without any

cated that the reactions progressed cleanly. The preference stereocontrol (α/β ratio, 1:1; Table 2, Entry 1). This result

for α-selectivity was also encouraging. This selectivity in- was in line with the outcome of glycosylation of the corre-

creased with a decrease in reaction temperature and the best sponding 2-O-(thiophen-2-ylmethyl) protected trichloroace-

results were obtained at –78 °C (α/β ratio, 4.5:1; Table 1, timidate donor,^[7]which had revealed that the stereoselecti-

Entry 3). This selectivity was substantially better than the vity of the reaction was dependent upon the steric bulk of

selectivity observed for the corresponding 2-O-(thiophen-2- the glycosyl acceptor. Reaction with the gluco primary

yl) methyl protected glycosyl fluoride donor.^[7]Glycosyl- alcohol acceptor 12 produced disaccharide 15 in a reaction

ation of corresponding trichloroacetimidate donor 10 with that was α-selective (α/β ratio, 2:1; Table 2, Entry 2). Like-

diacetone galactose with a catalytic amount of trimethylsilyl wise reaction with the secondary alcohol acceptor 13 pro-

trifluoromethanesulfonate (TMSOTf) as activator at 0 °C duced the corresponding disaccharide 16 with a similar

produced disaccharide 11b in an excellent yield of 88%, but level of stereocontrol (α/β ratio, 2:1; Table 2, Entry 3).

Table 1. Glycosylation of diacetone galactose (2 equiv.) with donors 3, 4, 8 and 10.

Entry Glycosyl donor

Activation conditions^[a]

Time [h]

Temperature [°C]

Yield of 11 [%]

α/β ratio^[b]

1

2

3

4

5

6

7

8

4

A

B

A

B

1.5

2.5

5

0.5

1

1.5

2.5

5

0

74

70

62

88

83

80

74

70

62

84

78

75

1:1

2.25:1

4.5:1

1.5:1

3:1

5:1

1:1

2:1

3:1

1:1

2:1

–40

–78

0

–40

–78

0

–40

–78

0

–40

–78

4

10

3

9

3

10

11

12

8

1

2

4

8

3.5:1

[a] Activation conditions: A: BF₃·OEt₂(1.5 equiv.). B: TMSOTf (0.1 equiv.). [b] Anomeric ratios were determined by integration of appro-

1

priate peaks in the H NMR spectra.

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FULL PAPER

Table 2. Glycosylation^[a]of donor 10 with a variety of acceptors.

NGP, or whether it was a result of other possible effects,

could be best revealed by NMR studies. Boons and

Turnbull have performed low-temperature NMR spectro-

scopic experiments on activated glycosyl donors and dem-

onstrated NGP through cross correlation between C-1 on

the donor and the H-8a/b methylene protons on the substi-

tuted ethyl group, as well as significant changes in the

chemical shifts of H1 and H8a/b. NMR spectroscopic stud-

ies were therefore performed on donors 8 and 10. Both

compounds were activated in the absence of acceptor at

–78 °C in CD₂Cl₂by addition of a stoichiometric amount

of TMSOTf, and NMR spectra were obtained. For iodo-

substituted donor 8 one major species^[13]was observed by

NMR spectroscopy, but there was no obvious shift in the

signal for either H-8a/b or H-1 upon activation (see Sup-

porting Information). In addition, no cross-correlation

could be observed between C-1 and H8a/b. Studies then

turned to 2-(phenylseleno) donor 10. However, there was

no obvious shift in the signal for either H-8a/b or H-1 upon

activation. In addition, no cross-correlation was observed

between C-1 and H-8a/b. These NMR spectroscopic studies

provide strong supporting evidence that NGP is not respon-

sible for the levels of α-selectivity observed when glycosyl-

ation reactions are performed with these fully armed do-

nors. A combination of steric, electronic and/or ion pairing

effects are probably responsible for the increased α-selectiv-

ity observed relative to corresponding per-benzylated donor

17.

[a] Reaction conditions: acceptor (2.0 equiv.), TMSOTf (0.1 equiv.),

–78 °C, CH₂Cl₂. [b] Anomeric ratios were determined by integra-

1

tion of appropriate peaks in the H NMR spectra.

To place these observed stereoselectivities in context,

control reactions were undertaken with the per-benzylated

trichloroacetimidate donor 17 under identical reaction con-

ditions (Scheme 2). These reactions ranged from being very

β-selective to non-selective. When methanol was used as ac-

ceptor methyl glycoside 18 was formed as a mixture of ano-

mers in an α:β ratio of 1:7, whereas when monosaccharide

12 was used as the acceptor disaccharide 19 was formed as

a 1:1 mixture of anomers. These control reactions implied

that the α-stereoselectivity observed by using 3, 4, 8 and 10

as glycosyl donors was a result of the presence of the 2-

iodo and 2-(phenylseleno) ethyl ether protecting groups.

Studies on Disarmed Donors

Boons recently reported an interesting observation that

the use of glycosyl donors that possessed disarming protect-

ing groups resulted in more stereoselective glycosylation re-

actions.^[3d]In this paper he postulated a dynamic equilib-

rium between cyclic intermediates and the acyclic glycosyl

cation (Figure 1), and a Curtin–Hammett scenario in which

electron-donating protecting groups on the donor led to in-

creased reaction through the open chain form in a non-

stereoselective process. If such an effect were general then

all of the above donors, which possess only “arming”

benzyl protecting groups, should in fact be the least stereo-

selective variants. Furthermore it was postulated that per-

haps cyclic intermediates had not been observed in the

NMR spectroscopic studies performed above because of the

electron donating protecting groups, which favoured the

acyclic cation. The corollary to this situation is that electron

withdrawing “disarming” protecting groups on a donor will

destabilise any glycosyl cation intermediate, and so should

increase the preponderance of neighbouring groups to par-

ticipate. Therefore the current study was extended to inves-

tigate the effects that both inductive and torsional disarm-

ing of the donors may have on the stereochemical outcome

Scheme 2. (i) MeOH (2.0 equiv.) TMSOTf (0.1 equiv.), –78 °C,

CH₂Cl₂; (ii) 12 (2.0 equiv.), TMSOTf (0.1 equiv.), –78 °C, CH₂Cl₂.

NMR Studies

Whether the increased α-selectivity observed with the do- of the reaction, with the objective to obtain further en-

nors possessing substituted ethyl ethers (relative to their hancements in α-stereoselectivity and to observe NGP by

benzylated counterpart) was the direct result of 6-ring NMR spectroscopy.

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Neighbouring Group Participation During Glycosylation

Synthesis of Donors

nophenol. Finally, both 24 and 26 were converted into

corresponding trichloroacetimidates 25 and 27 for use as

glycosyl donors.

Next, several “partially disarmed” donors were synthe-

sised (Scheme 4). Known p-methoxyphenyl (PMP) glycos-

ide 28^[16]was converted into benzylidene derivative 29, after

which regioselective benzylation via an intermediate tin

acetal gave benzyl ether 30, in which the 2-hydroxy re-

Because higher yields had been obtained for glycosyl-

ation of the trichloroacetimidates, attention focused solely

on their use as donors. Initially, per-acetylated versions of

the 2-iodoethyl and 2-(phenylseleno) ethyl donors were syn-

thesised as shown in Scheme 3.

Table 3. Glycosylation^[a]of diacetone galactose with donors 25, 27,

34, 36, 39 and 41.

Scheme 3. (i) allyl iodide, Ag₂O, DMF, 45 %; (ii) MeOH, HCl,

89 %; (iii) (a) O₃, CH₂Cl₂, –78 °C, 15 min then add Me₂S;

(b) NaBH₃CN, CH₂Cl₂, AcOH, 0 °C, 54%; (iv) I₂, PPh₃, imidazole,

THF, reflux, 16 h, 78%; (v) PhSeH, iPr₂NEt, DMF, room temp.,

16 h, 90 %; (vi) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 3 h, 81 %;

(vii) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 3 h, 92%.

Several routes to selectively access the 2-hydroxy of gluc-

ose met with either failure or complications during purifica-

tion, so piperidine derivative 20, which is readily available

from glucose penta-acetate in a single step, was used.^[14]Al-

lylation of the free hydroxy group of 20 with allyl iodide

and silver oxide gave allyl ether 21. Hydrolysis of the gly-

cosyl piperidine gave hemiacetal 22, which was subjected

to a sequence of ozonolysis and reduction to give diol 23.

Particular care was required during the reduction step to

avoid either reduction of the hemiacetal, or loss of acetate

protection. The best yields were achieved by using sodium

cyanoborohydride as the reducing agent. An Appel reaction

allowed conversion of the primary hydroxy into an iodide

to give 24, the structure of which was confirmed by X-ray

crystallography (see Supporting Information).^[15]At-

tempted conversion to selenide 26 by using selenophenol

and sodium hydride as base led to the formation of the

corresponding cyclic ether as the sole reaction product.

However, this transformation could be achieved in high

[a] Reaction conditions: acceptor (2.0 equiv.), TMSOTf (0.1 equiv.),

–78 °C, CH₂Cl₂. [b] Anomeric ratios were determined by integra-

1

yield by the use Hunig’s base in conjunction with sele- tion of appropriate signals in the H NMR spectra.

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Scheme 4. (i) (a) NaOMe, MeOH, 1.5 h; (b) CSA, PhCH(OMe)₂, DMF, 8 h, 56% over two steps; (ii) (a) Bu₂SnO, MeOH, reflux, 24 h;

(b) BnBr, CsF, DMF, 72 h, 43%; (iii) NaH, allyl bromide, DMF, 0 °C, 4 h, 72%; (iv) (a) AcOH, H₂O, 60 °C; (b) Ac₂O, pyridine, DMAP,

91 %; (v) (a) O₃, CH₂Cl₂, –78 °C; (b) NaBH₃CN, CH₂Cl₂, AcOH; (c) I₂, PPh₃, imidazole, THF, reflux, 16 h, 20 % over 3 steps;

(vi) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 3 h, 89%; (vii) PhSeH, NaH, THF, reflux, 16 h, 75%; (viii) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 3 h, 74%;

(ix) O₃, CH₂Cl₂/MeOH, –78 °C then add NaBH₄, 73%; (x) I₂, PPh₃, imidazole, THF, reflux, 24 h, 39%; (xi) Cl₃CCN, DBU, CH₂Cl₂,

0 °C, 8 h, 96%; (xii) PhSeH, NaH, THF, reflux, 16 h, 66%; (xiii) Cl₃CCN, DBU, CH₂Cl₂, 0 °C, 8 h, 92%.

mained free. Allylation of 30 then provided divergent allyl position, were similarly non-stereoselective, and produced

ether 31. Hydrolysis of the 4,6-benzylidene and acetylation mixtures in which the β-anomer predominated. Finally, tor-

provided diacetate 32. This was followed by ozonolysis and sionally deactivated and conformationally restricted 4,6-

reduction, which also resulted in removal of the anomeric benzylidene donors 39 and 41 also displayed low stereose-

PMP protecting group, and immediate Appel reaction to lectivity, again in favour of the undesired β-anomer.

yield iodide 33, which was then converted into correspond-

These results contrasted markedly with the expectation

ing trichloroacetimidate donor 34. Alternatively, nucleo- that the disarmed donors should result in more stereoselec-

philic substitution of the iodine in 33 by phenyl selenide tive glycosylation reactions than the fully armed ones, based

gave phenylseleno hemiacetal 35, which was then converted on the premise that they should be more likely to undergo

into trichloroacetimidate 36. Alternatively, direct ozonolysis NGP. Furthermore the small preference for β-selectivity ob-

and reduction of 31 gave diol 37, which was then converted served for these donors was the converse of the stereoselec-

into corresponding iodo- and 2-(phenylseleno)ethyl tri- tivity with the corresponding tri-benzylated donors, which

chloroacetimidate donors 39 and 41 by using identical reac- were predominantly α-selective.

tion sequences.

NMR Studies

Glycosylation Reactions

A systematic study was undertaken into the glycosylation

To try and rationalise these findings a second series of

of donors 25, 27, 34, 36, 39 and 41 (Table 3). In contrast to NMR studies was undertaken to investigate if NGP occurs

initial expectations, all of these donors were considerably for the disarmed donors. Compounds were activated in the

less α-stereoselective than their tri-benzylated counterparts absence of acceptor at –78 °C in CD₂Cl₂by the addition of

8 and 10. Tri-acetylated “fully disarmed” donors 25 and 27 a stoichiometric amount of TMSOTf, and NMR spectra

reacted to produce anomeric mixtures of products, in which were recorded. For the three iodoethyl donors, 25, 34 and

the undesired β-anomer predominated. Corresponding di- 39, no obvious NMR signal shifts in H8 or H-1 upon acti-

acetates 34 and 36, which possessed a benzyl ether at the 3- vation, nor were any cross correlations observed between

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Neighbouring Group Participation During Glycosylation

C-1 and H-8a/b in the HMBC spectra observed, which indi-

cates that NGP did not occur for these disarmed iodo-sub-

stituted donors. For donor 25 two materials were observed

by NMR spectroscopy in a ratio that corresponded to the

ratio of stereoisomers formed in the product.

However, for the corresponding phenylseleno donors 27,

36 and 41 evidence of NGP was observed in all cases (Fig-

ure 2). For per-acetylated donor 27 two compounds were

formed upon activation (Figure 2, a), both of which were

β-configured as confirmed by both the J_H1,H2(9–10 Hz)

and the J_H1,C1coupling constants (168 Hz). Both materials

showed cross correlation between C-1 and H-8eq in the

HMBC spectrum, indicating that NGP occurs. The NMR

spectroscopic data suggest that both materials are β-config-

ured cyclised intermediates, but differ in that the Ph group

attached to Se is either axial or equatorial.^[17]For activation

of donor 36, which possesses two disarming acetate groups

at positions-4 and 6 and an arming benzyl ether at position-

3, two compounds were produced upon activation, which

showed corresponding shifts in the signals for H-1 and

H8a/b, and also cross correlation in the HMBC spectrum

between C-1 and H8, indicating that NGP occurred (Fig-

ure 2, b). Similar evidence for cyclisation was observed for

4,6-benzylidene protected donor 41 (Figure 2, c); namely

shifts in the signals for H-1 and H8a/b and cross-corre-

lations between C-1 and H-8eq.

The NMR studies indicated that NGP did indeed occur

for all of the disarmed phenylseleno donors, even though

these compounds were less α-selective than fully armed ben-

zylated donor 10, which did not undergo NGP according

to NMR spectroscopy. Evidence that a cyclic intermediate

is formed upon activation of a donor does not mean neces-

sarily that this is the reactive species through which glyc-

osylation occurs. Notably, although all of the cyclic inter-

mediates observed were β-configured, as indicated by NMR

spectroscopic coupling constants, significant amounts of β-

glycoside product were formed, indicating that most reac-

tion must take place via intermediates not seen by NMR

spectroscopy.

Deprotection

As a conclusion to this work the deprotection of two

synthesised disaccharides was undertaken to demonstrate

the ability of these substituted ethyl ethers to act as protect-

ing groups.

Figure 2. Low temperature NMR spectra of: (a) donor 27; (b) do-

nor 36 and (c) donor 41, before and after activation at –78 °C in

CD₂Cl₂. Changes in chemical shift were observed for H-1 and H-

8a/b upon activation, and cross-correlations were seen between C-

1 and H-8eq in the HMBC spectra. The observed J_H1,H2(9–10 Hz)

and J_H1,C1(168 Hz) coupling constants indicated that cyclic species

were β-configured.

Scheme 5. (i) H₂O₂, THF, 1 h; reflux 1 h; NIS, H₂O/THF, 16 h,

76%; (ii) KOtBu, THF, reflux, 3 h; NIS, H₂O/THF, 16 h, 73%.

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

FULL PAPER

Since selenoxides readily undergo syn elimination, oxi-

dation of a 2-(phenylseleno) ethyl ether can be followed by

elimination to give a vinyl ether, which can then be removed

hydrolytically. Accordingly, a sample of disaccharide 11b

was treated with hydrogen peroxide in tetrahydrofuran

(THF). By heating the mixture to reflux the elimination

step was affected, and subsequent treatment of the so-

formed vinyl ether with N-iodosuccinimide (NIS) in THF/

H₂O afforded deprotected disaccharide 48 in 76% yield

(Scheme 5). The 2-iodoethyl ether was removed in a similar

manner, again via an intermediate vinyl ether. Thus, treat-

ment of 11a with potassium tert-butoxide in THF at reflux

temperatures affected elimination to give a vinyl ether,

which was immediately treated with NIS in THF/H₂O to

afford 48 in 73% yield.

Experimental Section

General: All reactions involving moisture-sensitive reagents were

performed under an atmosphere of argon or nitrogen by using stan-

dard vacuum Schlenk-line techniques. All glassware for such reac-

tions was flame-dried and cooled under an atmosphere of argon.

Reactions conducted at –78 °C were cooled by means of an acet-

one/dry-ice bath; those conducted at –40 °C by were cooled means

of an acetonitrile/dry-ice bath; those conducted at 0 °C were cooled

by means of an ice bath. Solvent was removed under reduced pres-

sure by using a Büchi^TMrotary evaporator. Diethyl ether, toluene,

dichloromethane and acetonitrile were dried by passing them

through a column of activated basic alumina. THF was distilled

from sodium/benzophenone under an argon atmosphere prior to

use. N,N-Dimethylformamide (DMF), pyridine and methanol were

purchased from Aldrich in sure/seal^TMbottles. All other solvents

were used as supplied (analytical or HPLC grade) without purifica-

tion. Petroleum ether refers to the fraction of light petroleum ether

boiling in the range 40–60 °C. Reagents were used as supplied with-

out further purification unless otherwise stated. Thin Layer

Chromatography (TLC) was carried out on Merck Silica Gel

60F₂₅₄aluminium-backed plates. Visualisation of the plates was

achieved by using a UV lamp (λ_max= 254 or 365 nm), ammonium

molybdate (5% in 2 m H₂SO₄), sulfuric acid (5% in EtOH), iodine,

vanillin, and/or potassium permanganate. Flash column

chromatography was carried out with Sorbsil C60 40/60 silica.

Melting points were recorded with a Kofler hot-block. Proton and

carbon nuclear magnetic resonance spectra were recorded with

Bruker DPX200 (200 MHz), Bruker DPX250 (250 MHz), Bruker

DPX 400 (400 MHz), Bruker AV400 (400 MHz), and Bruker

AV500 (500 MHz) spectrometers. All chemical shifts are quoted rel-

ative to the residual solvent as an internal standard. ¹H and ¹³C

spectra were assigned by using COSY, DEPT, HSQC, HMBC,

TOCSY and DPFGSE-TOCSY techniques. Low-resolution mass

spectra were recorded with a Micromass Platform 1 spectrometer

or a Micromass LCT Premier spectrometer by using atmospheric

pressure electrospray ionisation in either positive or negative po-

larity. High-resolution mass spectra were recorded by Mr Robin

Procter, Dr Lingzhi Gong, or Mr Colin Sparrow with either a Wal-

ters 2790-Micromass LCT electrospray ionisation or a Bruker FT-

ICR mass spectrometer by using electrospray ionisation or chemi-

cal ionisation techniques as stated. Optical rotations were measured

with a Perkin–Elmer 241 polarimeter with a water-jacketed 1 cm³

cell with a path length of 1 dm. Concentrations (c) are given in

g/100 cm³, solvent and temperature are recorded. Microanalyses

were performed by the Inorganic Chemistry Laboratory Elemental

Analysis service at the University of Oxford.

Conclusions

In an attempt to promote highly stereoselective α-gly-

cosylation by 6-ring NGP, a selection of glycosyl donors

were synthesised that possess new 2-iodoethyl-ether and 2-

(phenylseleno)ethyl-ether protecting groups at the 2-posi-

tion. The “fully-armed” tri-benzylated donors produced α-

glucosides as the predominant reaction products. However,

low temperature NMR studies did not provide evidence of

NGP by the observable formation of cyclised reaction inter-

mediates. A subsequent investigation with corresponding

disarmed glycosyl donors unexpectedly revealed them to be

less stereoselective than their fully armed counterparts. For

the disarmed donors low-temperature NMR studies re-

vealed the 2-iodoethyl ether did not participate in any of the

glycosylation processes. In contrast, the 2-(phenylseleno)-

ethyl ether was shown to participate, and in all three cases

β-configured cyclic intermediates were observed by NMR

spectroscopy. However, the fact that considerable amounts

of β-glycoside product were formed from glycosylation of

the Se-containing donors indicated that the predominant

reaction pathway to product did not occur via the observed

cyclic species.

It can be concluded from these investigations that selen-

ium is a better participating group than iodine, and is there-

fore more likely to form the basis of a useful achiral partici-

pating neighbouring group designed to promote α-glycoside

formation. However this work demonstrates that formation

of a cyclised intermediate alone is not sufficient to ensure a

3,4,6-Tri-O-benzyl-2-O-(2-hydroxyethyl)-β-D-glucopyranosyl Fluor-

ide (2): A solution of allyl ether 1^[10](121 mg, 0.246 mmol) in

CH₂Cl₂/methanol (3 mL, 1:1) was treated with ozone at –78 °C un-

til the solution turned blue. The reaction was quenched by the ad-

high level of selectivity during glycosylation. Likewise it dition of NaBH₄(42 mg, 1.105 mmol) in small portions over

10 min. The reaction mixture was warmed to room temperature

and then concentrated in vacuo. The residue was purified by flash

column chromatography (petroleum ether/ethyl acetate, 4:1) to af-

shows that glycosylation of disarmed donors is not neces-

sarily more stereoselective than that of the corresponding

fully armed compounds, even if the latter do show a lower

propensity to undergo NGP because of protecting group

stabilisation of a glycosyl cation or other acyclic intermedi-

ate. An extremely subtle balance exists between alternative

reaction pathways during glycosylation. Further fine-tuning

of protecting group structure is required to develop a reli-

able achiral variant that affects high levels of α-selectivity

through 6-ring NGP.

ford alcohol 2 (101 mg, 81%) as a colourless oil. [α]²_D⁵= +30.0 (c

1

= 1.0 in CHCl ). IR (KBr): ν

= 3480 (br., OH) cm^–1. H NMR

˜

3

max

(400 MHz, CDCl₃): δ = 2.40 (br. s, 1 H, -CH₂CH₂OH), 3.51 (m, 1

H, H-2), 3.60 (a dt, J = 9.6, J = 3.0 Hz, 1 H, CHHЈCH₂OH), 3.63–

3.84 (m, 7 H, H-3, H-4, H-6, H-6Ј, CHHЈ₂CH₂OH, CH₂CH₂OH),

3.91 (ddd, J_4,5= 10.9, J_5,6= 5.1, J_5,6Ј= 3.0 Hz, 1 H, H-5) 4.57,

4.66 (ABq, J_AB= 12.1 Hz, 2 H, PhCH₂), 4.59, 4.84 (ABq, J_AB

10.9 Hz, 2 H, PhCH₂), 4.91 (br. s, 2 H, PhCH₂), 5.19 (dd, J_1,2

=

8

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Neighbouring Group Participation During Glycosylation

7.1, J_1,F52.8 Hz, 1 H, H-1), 7.17–7.42 (m, 15 H, 15ϫAr-H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 62.3 (CH₂CH₂OH), 68.2 (t, C-

75.0 (3ϫPhCH₂), 75.0 (C-5), 75.5 (C-4), 82.2 (C-2, J_2,F= 22.1 Hz),

83.3 (C-3), 109.5 (C-1, J_1,F= 214.7 Hz), 127.0, 127.8, 127.8, 127.9,

6), 73.7, 73.9, 75.0 (3 x t, 3ϫPhCH₂), 74.8 (d, C-5), 75.8 (t, 127.9, 128.4, 128.5, 129.1, 129.7 (9ϫArCH), 137.8, 137.9, 138.3

CH₂CH₂OH), 77.2 (d, C-4), 81.9 (dd, J_2,F= 22.4 Hz, C-2), 83.2 (d,

C-3), 109.7 (dd, J_1,F= 215.7 Hz, C-1), 127.8, 128.0, 128.0, 128.0,

(3ϫArC) ppm. MS (ES⁺): m/z (%) = 659 (100) [M + Na⁺]. HRMS

(ES⁺): calcd. for C₃₅H₃₇O₅FSeNa (M + Na⁺) 659.1685; found

128.5, 128.5, 128.6, 128.6 (8ϫd, 8ϫAr-CH), 137.7, 137.8, 137.8 659.1698. C₃₅H₃₇FO₅Se (635.63): calcd. C 66.35, H 6.34; found C

(3ϫs, 3 ϫAr-C) ppm. MS (ES⁺): m/z (%) = 519 (90) [M + Na⁺],

514 (100) [M + NH₄⁺]. HRMS (ES⁺): calcd. for C₂₉H₃₃FO₆Na (M

+ Na⁺) 519.2153; found 519.2148. C₂₉H₃₃FO₆(496.57): calcd. C

70.14, H 6.70; found C 70.38, H 6.87.

66.40, H 6.45.

3,4,6-Tri-O-benzyl-2-O-(2-hydroxyethyl)-α/β-D-glucopyranose (6): A

solution of allyl ether 5^[12](121 mg, 0.246 mmol) in CH₂Cl₂/meth-

anol (3 mL, 1:1) was treated with ozone at –78 °C until the solution

turned blue. The reaction was quenched by the addition of NaBH₄

(42 mg, 1.105 mmol) in small portions over 10 min. The reaction

mixture was warmed to room temperature and then concentrated in

vacuo. The residue was purified by flash column chromatography

(petroleum ether/ethyl acetate, 4:1) to afford 3,4,6-tri-O-benzyl-2-

O-(2-hydroxyethyl)ether-α/β-d-glucopyranose 6 (101 mg, 76%) as a

3,4,6-Tri-O-benzyl-2-O-(2-iodoethyl)-β-D-glucopyranosyl Fluoride

(3): Alcohol 2 (0.250 g, 0.504 mmol) was dissolved in freshly dis-

tilled THF (5 mL) under an atmosphere of argon. A mixture iodine

(0.191 g, 0.756 mmol), imidazole (0.051 g, 0.756 mmol) and PPh₃

(0.147 g, 0.756 mmol) were added as a solution in THF (5 mL) and

the reaction heated to reflux. After 16 h, TLC (petroleum ether/

ethyl acetate, 4:1) indicated formation of a single major product

(R_f0.6) and complete consumption of starting material (R_f0.2).

The reaction was cooled to room temp. and concentrated in vacuo.

The resulting residue was purified by flash column chromatography

(petroleum ether/ethyl acetate, 10:1) to afford iodide 3 (0.272 g,

89%) as a white crystalline solid, m.p. 61–63 °C (petroleum ether/

colourless oil. IR (KBr): ν

= 3470 (br., OH) cm^–1. ¹H NMR

˜

max

[400 MHz, CDCl₃, 5:1 mixture of α:β anomers observed, major α

anomer quoted]: δ = 3.31 (m, 1 H, H-2), 3.50–3.75 (m, 8 H, H-3,

H-4, H-6, H-6’, OCH₂CH₂OH, OCH₂CH₂OH), 3.90 (m, 1 H, H-

5) 4.57, 4.66 (ABq, J_AB= 12.1 Hz, 2 H, PhCH₂), 4.59, 4.84 (ABq,

J_AB= 10.9 Hz, 2 H, PhCH₂), 4.91 (br. s, 2 H, PhCH₂), 5.38 (dd,

ethyl acetate). [α]²_D⁵= –4.7 (c = 1.0 in CHCl ). IR (KBr): ν

=

J_1,2= 3.3 Hz, 1 H, H-1), 7.14–7.35 (m, 15 H, 15ϫAr-H) ppm. ¹³

C

˜

3

max

1

3850 (br., C–I) cm^–1. H NMR (400 MHz, CDCl₃): δ = 3.12–3.16

(m, 2 H, OCH₂CH₂I), 3.35 (ddd, J_1,2= 6.9, J_2,3= 8.7, J_2,F12.4 Hz,

1 H, H-2), 3.46–3.50 (m, 1 H, H-5), 3.54 (at, J = 8.7 Hz, 1 H, H-

3), 3.59–3.65 (m, 3 H, H-4, H-6, H-6’), 3.79–3.85 (m, 1 H,

OCHHЈCH₂I), 3.93–3.99 (m, 1 H, OCHHЈCH₂I), 4.46, 4.54 (ABq,

J_AB= 11.8 Hz, 2 H, PhCH₂), 4.46, 4.72 (ABq, J_AB= 11.2 Hz, 2

H, PhCH₂), 4.74, 4.88 (ABq, J_AB= 11.1 Hz, 2 H, PhCH₂), 5.09

(dd, J_1,2= 6.9, J_1,F52.6 Hz, 1 H, H-1), 7.06–7.29 (m, 15 H,

15ϫAr-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 2.5 (OCH₂-

CH₂I), 68.2 (C-6), 72.9 (OCH₂CH₂I), 73.6, 74.8, 75.0 (3ϫPhCH₂),

74.8 (C-5), 76.9 (C-4), 82.2 (C-2, J_2,F= 22.4 Hz), 83.3 (C-3), 109.5

(C-1, J_1,F= 215.70 Hz), 127.8, 127.8, 127.9, 127.9 (4ϫArCH),

128.4, 128.5 (2ϫArC) ppm. MS (ES⁺): m/z (%) = 629 (95) [M +

Na⁺], 624 (100) [M + NH₄⁺]. HRMS (ES⁺): calcd. for C₂₉H₃₂O₅F-

INa [M + Na⁺] 629.1176; found 629.1180. C₂₉H₃₂FIO₅(606.47):

calcd. C 57.43, H 5.32; found C 57.46, H 5.34.

NMR (100 MHz, CDCl₃): δ = 62.2 (OCH₂CH₂OH), 68.7 (C-6),

70.3 (C-5), 72.6, 73.5, 74.2 (3 ϫPhCH₂), 75.8 (OCH₂CH₂OH),

78.0, 80.9, 81.6 (C-2, C-3, C-4), 90.9 (C-1), 127.8, 127.9, 127.9,

128.0, 128.4, 128.4, 128.5, 128.5 (8ϫAr-CH), 137.7, 137.8, 137.8

(3ϫAr-C) ppm. MS (ES⁺): m/z (%) = 517 (100) [M + Na⁺]. HRMS

(ES⁺): calcd. for C₂₉H₃₄O₇Na [M + Na⁺] 517.2202; found

517.2210. C₂₉H₃₄O₇(494.58): calcd. C 70.43, H 6.93; found C

70.55, H 6.99.

3,4,6-Tri-O-benzyl-2-O-(2-iodoethyl)-α/β-D-glucopyranose (7): Diol

6 (0.249 g, 0.504 mmol) was dissolved in freshly distilled THF

(5 mL) under an atmosphere of argon. A mixture of iodine

(0.191 g, 0.756 mmol), imidazole (0.051 g, 0.756 mmol) and PPh₃

(0.147 g, 0.756 mmol) were added as a solution in THF (5 mL) and

the reaction heated to reflux. After 16 h, TLC (petroleum ether/

ethyl acetate, 4:1) indicated formation of a single major product

(R_f0.4) and complete consumption of the starting material (R_f0.1).

The reaction was cooled to room temp. and concentrated in vacuo.

The resulting residue was purified by flash column chromatography

(petroleum ether/ethyl acetate, 6:1) to afford iodide 7 (0.231 g,

3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-β-D-glucopyranosyl

Fluoride (4): PhSeH (0.079 mL, 0.500 mmol) was added to a stirred

suspension of NaH (0.012 g, 0.500 mmol) in THF (5 mL). After

30 min, iodide 3 (0.242 g, 0.400 mmol) was added as a solution in

THF (5 mL) and the reaction heated to reflux. After 16 h, TLC

(petroleum ether/ethyl acetate, 4:1) indicated formation of a single

major product (R_f0.5) and complete consumption of starting mate-

rial (R_f0.6). The reaction was diluted with CH₂Cl₂(20 mL) and

washed with water (20 mL). The aqueous layer was then extracted

with CH₂Cl₂(2ϫ 20 mL) and the combined organic extracts were

washed with saturated sodium hydrogen carbonate (20 mL) then

brine (20 mL). The organic phase was dried (MgSO₄), filtered, and

concentrated in vacuo. The resulting residue was purified by flash

column chromatography (petroleum ether/ethyl acetate, 10:1) to af-

ford selenide 4 (0.218 g, 86%) as a pale yellow oil. [α]²_D⁵= +2.5 (c

1

76%) as a colourless oil. H NMR [400 MHz, CDCl₃, 5:1 mixture

of α:β anomers observed, major α anomer quoted]: δ = 3.12–3.16

(m, 2 H, OCH₂CH₂I), 3.35 (dd, J_1,2= 3.3, J_2,3= 8.2Hz, 1 H, H-

2), 3.46–3.55 (m, 2 H, H-4, H-5), 3.59–3.65 (m, 3 H, H-4, H-6, H-

6’), 3.79–3.85 (m, 1 H, OCHHЈCH₂I), 3.93–3.99 (m, 1 H,

OCHHЈCH₂I), 4.46, 4.54 (ABq, J_AB= 11.8 Hz, 2 H, PhCH₂), 4.46,

4.72 (ABq, J_AB= 11.2 Hz, 2 H, PhCH₂), 4.74, 4.88 (ABq, J_AB

=

11.1 Hz, 2 H, PhCH₂), 5.35 (d, J_1,2= 3.3 Hz, 1 H, H-1), 7.06–7.29

(m, 15 H, 15ϫAr-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 3.0

(OCH₂CH₂I), 68.5 (C-6), 70.5 (OCH₂CH₂I), 72.0, 73.5, 75.0

(3ϫPhCH₂), 74.8 (C-5), 76.9 (C-4), 82.2 (C-2), 83.3 (C-3), 91.5 (C-

1), 127.8, 127.8, 127.9, 127.9 (4 ϫ ArCH), 128.4, 128.5

(2ϫArC) ppm. MS (ES⁺): m/z (%) = 627 (95) [M + Na⁺], 622 (100)

[M + NH₄⁺]. HRMS (ES⁺): calcd. for C₂₉H₃₃O₆INa [M + Na⁺]

627.1220; found 627.1210. C₂₉H₃₃IO₆(604.48): calcd. C 57.62, H

5.50; found C 57.51, H 5.58.

1

= 1.0 in CHCl₃). H NMR (400 MHz, CDCl₃): δ = 3.08 (m, 2 H,

OCH₂CH₂SePh), 3.39–3.46 (m, 1 H, H-2), 3.56–3.63 (m, 2 H, H-

3, H-5), 3.68–3.74 (m, 3 H, H-4, H-6, H-6’), 3.88–3.94 (m, 1 H,

OCHHЈCH₂SePh), 4.03–4.09 (m, 1 H, OCHHЈCH₂SePh), 4.55,

4.64 (ABq, J_AB= 12.3 Hz, 2 H, PhCH₂), 4.55, 4.82 (ABq, J_AB

=

10.6 Hz, 2 H, PhCH₂), 4.79, 4.94 (ABq, J_AB= 11.0 Hz, 2 H,

PhCH₂), 5.09 (dd, J_1,2= 6.6, J_1,F52.8 Hz, 1 H, H-1), 7.16–7.36 (m,

20 H, 20ϫAr-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 27.0

(OCH₂CH₂SePh), 68.3 (C-6), 71.9 (OCH₂CH₂SePh), 73.6, 74.8,

O-[3,4,6-Tri-O-benzyl-2-O-(2-iodoethyl)-α/β-D-glucopyranosyl] Tri-

chloroacetimidate (8): Hemiacetal 7 (0.773 g, 1.28 mmol) was dis-

solved in freshly distilled CH₂Cl₂(8 mL) at 0 °C under an argon

atmosphere. DBU (0.078 mL, 0.51 mmol) was added followed by

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

acetate, 7:1, with 1% added triethylamine) to afford trichloroacet-

FULL PAPER

trichloroacetonitrile (1.31 mL, 12.8 mmol). After 5 h, TLC (petro-

leum ether/ethyl acetate, 4:1, with 1% added triethylamine) indi-

cated the formation of a single product (R_f0.6) and complete con-

sumption of the starting material (R_f0.4). The reaction was con-

centrated in vacuo and the resulting residue was purified by flash

column chromatography (petroleum ether/ethyl acetate, 7:1, with

1% added triethylamine) to afford trichloroacetimidate 8 (0.835 g,

imidate 10 (0.901 g, 88%) as a colourless oil. IR (KBr): ν

=

˜

max

3345 (w, NH), 1662 (s, C=N) cm^–1. ¹H NMR [400 MHz, CDCl₃,

15:1 mixture of α:β anomers observed, major α anomer quoted]: δ

= 3.02–3.09 (m, 2 H, OCH₂CH₂SePh), 3.60–4.04 (m, 8 H, H-2, H-

3, H-4, H-5, H-6, H-6’, OCH₂CH₂SePh), 4.48, 4.63 (ABq, J_AB

=

11.3 Hz, 2 H, PhCH₂), 4.52, 4.84 (ABq, J_AB= 10.6 Hz, 2 H,

PhCH₂), 4.83, 5.00 (ABq, J_AB= 12.0 Hz, 2 H, PhCH₂), 6.69 (d,

J_1,2= 3.4 Hz, 1 H, H-1), 7.10–7.34 (m, 20 H, 29ϫAr-H), 8.54 (br.

s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 26.9

84%) as a colourless oil. IR (KBr): ν

= 3345 (w, NH), 1659 (s,

˜

max

C=N) cm^–1. ¹H NMR [400 MHz, CDCl₃, 15:1 mixture of α:β ano-

mers observed, major α anomer quoted]: δ = 3.14–3.17 (m, 2 H,

OCH₂CH₂I), 3.60–4.04 (m, 8 H, H-2, H-3, H-4, H-5, H-6, H-6’, (OCH₂CH₂SePh), 68.3 (C-6), 70.3 (OCH₂CH₂SePh), 73.5, 73.7,

OCH₂CH₂I), 4.49, 4.63 (ABq, J_AB= 12.0 Hz, 2 H, PhCH₂), 4.54,

4.87 (ABq, J_AB= 10.6 Hz, 2 H, PhCH₂), 4.83, 5.00 (ABq, J_AB

75.1 (3ϫArCH₂), 73.1, 78.5, 81.0, 84.4 (C-2, C-3, C-4, C-5), 94.0

[OC(NH)CCl₃], 97.5 (C-1), 126.2, 126.6, 127.0, 127.1, 127.3, 127.7,

127.7, 127.9, 128.1, 128.4, (10ϫAr-CH), 137.8, 138.0, 138.6, 138.8

(4ϫAr-C), 164.0 (s, C=NH) ppm. MS (ES⁺): m/z (%) = 795 (100)

=

10.8 Hz, 2 H, PhCH₂), 6.67 (d, J_1,2= 3.4 Hz, 1 H, H-1), 7.11–

7.29 (m, 15 H, 15ϫAr-H), 8.61 (br. s, 1 H, NH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 3.0 (OCH₂CH₂I), 68.0 (C-6), 70.5 (OCH₂- [M + NH₄⁺]. HRMS (ES⁺): calcd. for C₃₇H₃₈Cl₃NO₆SeNa [M +

CH₂I), 73.5, 73.6, 75.0, 75.4 (3ϫArCH₂), 73.5, 78.8, 81.2, 84.4 (C- Na⁺] 800.0828; found 800.0821.

2, C-3, C-4, C-5), 94.4 [OC(NH)CCl₃], 97.6 (C-1), 126.2, 126.6,

General Method A: To a flame-dried round-bottom flask contain-

126.9, 127.7, 127.8, 127.9, 128.1, 128.4, (8ϫAr-CH), 137.8, 138.0,

ing activated 3 Å molecular sieves (0.100 g) was added a solution

of the glycosyl fluoride donor (125 mm) and the glycosyl acceptor

138.6 (3ϫAr-C), 163.8 (s, C=NH) ppm. MS (ES⁺): m/z (%) = 765

(100) [M + NH₄⁺]. HRMS (ES⁺): calcd. for C₃₁H₃₃Cl₃NO₆INa [M

(2 equiv.) in freshly distilled CH₂Cl₂. The reaction mixture was

+ Na⁺] 770.0316; found 770.0319.

cooled to the designated temperature under an argon atmosphere,

3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-glucopyranose

then BF₃·OEt₂(1.5 equiv.) was added. The reaction was monitored

by TLC (toluene/ethyl acetate, 9:1) until the formation of a major

product (typically R_f≈ 0.4) and complete consumption of starting

material (typically R_f≈ 0.7) was observed. The reaction was

quenched with saturated sodium hydrogen carbonate solution and

filtered through Celite^®. The mixture was diluted with CH₂Cl₂,

washed with saturated sodium hydrogen carbonate solution and

the aqueous layer extracted with CH₂Cl₂. The combined organic

extracts were washed with brine, dried (MgSO₄), filtered, and con-

centrated in vacuo. The resulting residue was purified by flash col-

umn chromatography (typically toluene/ethyl acetate, 15:1).

(9): PhSeH (0.079 mL, 0.500 mmol) was added to a stirred suspen-

sion of NaH (0.012 g, 0.500 mmol) in THF (5 mL). After 30 min,

iodide 7 (0.242 g, 0.400 mmol) was added as a solution in THF

(5 mL) and the reaction heated to reflux. After 16 h, TLC (petro-

leum ether/ethyl acetate, 4:1) indicated formation of a single prod-

uct (R_f0.3) and complete consumption of starting material (R_f0.4).

The reaction was diluted with CH₂Cl₂(20 mL) and washed with

water (20 mL). The aqueous layer was then extracted with CH₂Cl₂

(2ϫ 20 mL) and the combined organic extracts were washed with

saturated sodium hydrogen carbonate (20 mL) then brine (20 mL).

The organic phase was dried (MgSO₄), filtered, and concentrated

in vacuo. The resulting residue was purified by flash column

chromatography (petroleum ether/ethyl acetate, 10:1) to afford sele-

nide 9 (0.205 g, 81%) as a pale yellow oil. ¹H NMR [400 MHz,

CDCl₃, 5:1 mixture of α:β anomers observed, major α anomer

General Method B: To a flame-dried round-bottom flask contain-

ing activated molecular sieves (3 Å) (0.100 g) was added a solution

of the trichloroacetimidate donor (125 mm) and the glycosyl ac-

ceptor (2 equiv.) in freshly distilled CH₂Cl₂. The reaction mixture

was cooled to the designated temperature under an argon atmo-

sphere, then TMSOTf (0.1 equiv.) was added. The reaction was

monitored by TLC (toluene/ethyl acetate, 9:1) until the formation

of a major product (R_ftypically about 0.4) and complete consump-

tion of starting material (R_ftypically about 0.6) was observed. The

reaction was quenched with saturated sodium hydrogen carbonate

solution and filtered through Celite^®. The mixture was diluted with

CH₂Cl₂, washed with saturated sodium hydrogen carbonate solu-

tion, and the aqueous layer extracted with CH₂Cl₂. The combined

organic extracts were washed with brine, dried (MgSO₄), filtered,

and concentrated in vacuo. The resulting residue was purified by

flash column chromatography (typically toluene/ethyl acetate,

15:1).

quoted]: δ = 3.02–3.07 (m, 2 H, OCH₂CH₂SePh), 3.35 (dd, J_1,2

=

3.3, J_2,3= 8.2 Hz, 1 H, H-2), 3.41–3.55 (m, 2 H, H-4, H-5), 3.59–

3.65 (m, 3 H, H-4, H-6, H-6’), 3.79–3.85 (m, 1 H, OCHHЈCH₂-

SePh), 3.93–3.99 (m, 1 H, OCHHЈCH₂SePh), 4.45, 4.53 (ABq, J_AB

= 11.8 Hz, 2 H, PhCH₂), 4.46, 4.72 (ABq, J_AB= 11.2 Hz, 2 H,

PhCH₂), 4.70, 4.83 (ABq, J_AB= 11.1 Hz, 2 H, PhCH₂), 5.25 (d,

J_1,2= 3.3 Hz, 1 H, H-1), 7.06–7.37 (m, 20 H, 20ϫAr-H) ppm. ¹³

C

NMR (100 MHz, CDCl₃): δ = 26.9 (OCH₂CH₂SePh), 68.9 (C-6),

70.3 (OCH₂CH₂SePh), 72.0, 73.5, 75.0 (3ϫPhCH₂), 74.8, 76.9,

82.2, 83.3 (C-2, C-3, C-4, C-5), 91.5 (C-1), 127.0, 127.2, 127.6,

127.7,127.7, 127.9, 127.9, 128.0, 128.3, 128.4 (10ϫArCH), 131.5,

132.6, 132.8, 133.3 (4ϫArC) ppm. MS (ES⁺): m/z (%) = 657 (95)

[M + Na⁺], 652 (100) [M + NH₄⁺]. HRMS (ES⁺): calcd. for

C₃₅H₃₈O₆SeNa [M + Na⁺] 657.1731; found 657.1719. C₃₅H₃₈O₆Se

(633.64): calcd. C 66.34, H 6.04; found C 66.51, H 6.23.

3,4,6-Tri-O-benzyl-2-O-(2-iodoethyl)-α/β-

1:2,3:4-di-O-isopropylidene-α- -galactopyranoside (11a): Disacchar-

ide 11a, a colourless oil. H NMR [400 MHz, CDCl₃, 1:1 mixture

glucopyranosyl} Trichloroacetimidate (10): Hemiacetal 9 (0.812 g, of α:β anomers observed]: δ = 1.34 (br. s, 12 H, 2 ϫ CH₃α,

D-glucopyranosyl-(1Ǟ6)-

D

1

O-{3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-

1.28 mmol) was dissolved in freshly distilled CH₂Cl₂(8 mL) at 0 °C

under an argon atmosphere. DBU (0.078 mL, 0.51 mmol) was

added followed by trichloroacetonitrile (1.31 mL, 12.8 mmol). Af-

ter 5 h, TLC (petroleum ether/ethyl acetate, 4:1, with 1% added

triethylamine) indicated the formation of a single product (R_f0.6)

and complete consumption of the starting material (R_f0.4). The

reaction was concentrated in vacuo and the resulting residue was

purified by flash column chromatography (petroleum ether/ethyl

2ϫCH₃β), 1.46, 1.47, 1.53, 1.55 (4ϫs, 2 ϫ, 12 HCH₃α, 2ϫCH₃β),

3.12–3.16 (m, 4 H, OCH₂CH₂Iα/β), 3.40 (m, 1 H, H-5_bβ), 3.46 (at,

J = 8.0 Hz, 1 H, H-2_bβ), 3.50–3.79 (m, 10 H, H-2_aα, H-5_aα, H-2_aβ,

H-5_aβ, H-2_bα, H-5_bα, H-6_bα, H-6Ј_bα, H-6_bβ, H-6Ј_bβ), 3.97–4.63 (m,

20 H, H-3_aα, H-4_aα, H-6_aα, H-6Ј_aα, H-3_aβ, H-4_aβ, H-4_bβ, H-6_aβ,

H-6Ј_aβ, H-3_bα, H-4_bα, H-1_aβ, H-3_aβ, OCH₂CH₂Iα/β), 4.71–5.25

(m, 12 H, 6ϫPhCH₂α, 6ϫPhCH₂β), 4.95 (d, J_1,2= 4.1 Hz, 1 H,

H-1_bα), 5.55 (d, J_1,2= 5.0 Hz, 1 H, H-1_aβ), 5.60 (d, J_1,2= 5.0 Hz,

10

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Neighbouring Group Participation During Glycosylation

1 H, H-1_aα), 7.07–7.29 (m, 30 H, 15 ϫ Ar-CHα, 15 ϫ Ar-

CHβ) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 4.6, 4.7 (OCH₂-

3.16 (s, 3 H, OMeβ), 3.39 (dd, J_2,3= 9.7, J_3,4= 2.9 Hz, 1 H, H-

3_bβ), 3.43 (m, 1 H, H-3_aβ), 3.50 (dd, J_1,2= 3.4, J_2,3= 9.6 Hz, 2 H,

CH₂Iα/β), 66.3, 66.4 (C-6_aα, C-6_aβ), 68.2, 68.7, (C-6_bα, C-6_bβ), H-2_aα), 3.61–3.66 (m, 2 H, H-2_aβ, H-6_bβ), 3.73–3.87 (m, 10 H, H-

70.1, 70.3 (OCH₂CH₂Iα/β), 73.2, 75.4, 75.3 (3ϫ ArCH₂), 70.6,

70.9, 71.4, 71.5, 74.7, 77.6, 79.5, 81.0, 81.2, 84.3 (C-2_a-C-5_aα/β, C-

2_b-C-5_bα/β), 94.9 (d, C-1_aβ), 96.0 (d, C-1_aα), 97.0 (d, C-1_bα), 103.4

(d, C-1_bβ), 126.0, 126.5, 126.6, 127.2, 127.6, 127.7, 127.9, 128.1,

128.2, 128.4 (10ϫAr-CH), 137.9, 138.1, 138.3, 138.7, 140.9, 141.2

(6ϫAr-C) ppm. MS (ES⁺): m/z (%) = 869 (100) [M + Na⁺]. HRMS

(ES⁺): calcd. for C₄₁H₅₁O₁₁INa [M + Na⁺] 869.2374; found

6_aα, H-6_bα, H-6Ј_bα, H-4_aβ, H-4_bβ, H-6_aβ, H-6Ј_bβ), 3.88–3.94 (m, 4

H, H-4_aα, H-5_aα), 3.96–4.08 (m, 8 H, H-4_bα, H-6Ј_aα, H-5_aβ,

OCH₂CH₂SePhα/β), 4.11 (dd, J_2,3= 10.2, J_3,4= 2.7 Hz, 2 H, H-

3_bα), 4.16 (dd, J_1,2= 7.5, J_2,3= 9.7 Hz, 1 H, H-2_bβ), 4.21–4.32 (m,

10 H, H-2_bα, H-3_aα, H-5_bα, PhCH₂α, H-5_bβ, PhCH₂β), 4.34–4.38

(m, 3 H, PhCH₂α, H-6Ј_aβ), 4.44 (d, J_1,2= 7.5 Hz, 2 H, H-1_bβ),

4.46–5.13 (m, 28 H, H-1_aα, 8ϫPhCHHЈα, H-1_aβ, 10ϫPhCHHЈβ),

869.2381. C₄₁H₅₁IO₁₁(846.75): calcd. C 58.16, H 6.07; found C 5.29 (d, J_1,2= 3.4 Hz, 2 H, H-1_bα), 7.04–7.45 (m, 105 H, 35ϫAr-

58.25, H 6.13.

Hα, 35ϫAr-Hβ) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = 54.9, 55.0,

68.7, 69.0, 70.0, 70.7, 71.3, 72.7, 72.8, 73.0, 73.5, 73.7, 74.7, 74.8,

75.1, 75.2, 75.3, 75.5, 76.2, 78.3, 78.6, 78.6, 79.9, 81.1, 81.2, 82.3,

82.4, 82.7, 98.2, 98.4, 104.6, 127.4, 127.6, 127.7, 127.8, 128.0, 128.1,

128.2, 128.2, 128.4, 128.5, 128.5, 128.6, 128.6, 138.7, 139.2, 139.2,

139.5, 139.7, 139.8 ppm. MS (ES⁺): m/z (%) = 1103 (100) [M +

Na⁺]. HRMS (ES⁺): calcd. for C₆₃H₆₈O₁₁SeNa [M + Na⁺]

1103.3825; found 1103.3830. C₆₃H₆₈O₁₁Se (1080.18): calcd. C

70.05, H 6.35; found C 70.12, H 6.39.

3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-glucopyranos-

yl-(1Ǟ6)-1:2,3:4-di-O-isopropylidene-α-D-galactopyranoside (11b):

1

Disaccharide 11b, a pale yellow oil. H NMR (400 MHz, CDCl₃)

[1:1 mixture of α:β anomers observed]: δ = 1.34 (br. s, 12 H,

2ϫCH₃α, 2ϫCH₃β), 1.46, 1.47, 1.53, 1.55 (4ϫs, 2 ϫ, 12 HCH₃α,

2ϫCH₃β), 3.10–3.14 (m, 4 H, OCH₂CH₂SePhα/β), 3.44 (m, 1 H,

H-5_bβ), 3.50 (at, J = 8.4 Hz, 1 H, H-2_bβ), 3.54–3.86 (m, 10 H, H-

2_aα, H-5_aα, H-2_aβ, H-5_aβ, H-2_bα, H-5_bα, H-6_bα, H-6Ј_bα, H-6_bβ, H-

6Ј_bβ), 3.99 (at, J = 9.4 Hz, 1 H, H-4_bβ), 4.04–4.65 (m, 20 H, H-

3_aα, H-4_aα, H-6_aα, H-6Ј_aα, H-3_aβ, H-4_aβ, H-6_aβ, H-6Ј_aβ, H-3_bα,

H-4_bα, H-1_aβ, H-3_aβ, OCH₂CH₂SePhα/β), 4.74–5.31 (m, 12 H,

6ϫPhCH₂α, 6ϫPhCH₂β), 4.98 (d, J_1,2= 4.1 Hz, 1 H, H-1_bα), 5.52

(d, J_1,2= 5.1 Hz, 1 H, H-1_aβ), 5.57 (d, J_1,2= 5.1 Hz, 1 H, H-1_aα),

7.08–7.38 (m, 40 H, 20ϫAr-CHα, 20ϫAr-CHβ) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 26.8, 26.9 (OCH₂CH₂SePhα/β), 66.3, 66.9

(C-6_aα, C-6_aβ), 68.3, 68.7, (C-6_bα, C-6_bβ), 70.5, 70.6 (OCH₂CH₂Se-

Phα/β), 73.5, 75.1, 75.8 (3ϫArCH₂), 70.7, 70.9, 71.2, 71.5, 74.7,

77.6, 79.5, 81.1, 81.6, 84.3 (C-2_a-C-5_aα/β, C-2_b-C-5_bα/β), 95.4 (d,

C-1_aβ), 96.2 (d, C-1_aα), 97.1 (d, C-1_bα), 104.4 (d, C-1_bβ), 126.0,

126.5, 126.6, 127.2, 127.6, 127.7, 127.9, 128.1, 128.2, 128.4

(10 ϫ Ar-CH), 137.9, 138.1, 138.3, 138.7, 140.9, 141.2 (6 ϫAr-

C) ppm. MS (ES⁺): m/z (%) = 899 (100) [M + Na⁺]. HRMS (ES⁺):

calcd. for C₄₇H₅₆O₁₁SeNa [M + Na⁺] 899.2886; found 899.2880.

C₄₇H₅₆O₁₁Se (875.91): calcd. C 64.45, H 6.44; found C 64.23, H

6.58.

3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-α/β-

D-glucopyranos-

yl-(1Ǟ4)-methyl-2,3,6-tri-O-benzyl-α- -glucopyranoside (16): Gene-

D

ral Method B with trichloroacetimidate 10 (125 mm) and acceptor

13 (2 equiv.) gave disaccharide 16 as a colourless oil. ¹H NMR

[400 MHz, CDCl₃, 2:1 mixture of α:β anomers observed]: δ = 3.09–

3.13 (m, 6 H, OCH₂CH₂SePhα/β), 3.16 (s, 6 H, OMeα), 3.18 (s, 3

H, OMeβ), 3.39 (dd, J_2,3= 9.5, J_3,4= 2.2 Hz, 1 H, H-3_bβ), 3.43–

3.47 (m, 2 H, H-3_aβ, H-2_aα), 3.61–3.66 (m, 2 H, H-2_aβ, H-6_bβ),

3.70–3.84 (m, 10 H, H-6_aα, H-6_bα, H-6Ј_bα, H-4_aβ, H-4_bβ, H-6_aβ,

H-6Ј_bβ), 3.88–3.94 (m, 4 H, H-4_aα, H-5_aα), 3.93–4.05 (m, 8 H, H-

4_bα, H-6Ј_aα, H-5_aβ, OCH₂CH₂SePhα/β), 4.09 (dd, J_2,3= 10.0, J_3,4

= 3.0 Hz, 2 H, H-3_bα), 4.16 (dd, J_1,2= 7.1, J_2,3= 9.7 Hz, 1 H, H-

2_bβ), 4.21–4.32 (m, 10 H, H-2_bα, H-3_aα, H-5_bα, PhCH₂α, H-5_bβ,

PhCH₂β), 4.34–4.38 (m, 3 H, PhCH₂α, H-6Ј_aβ), 4.47 (d, J_1,2

=

7.1 Hz, 2 H, H-1_bβ), 4.53–5.10 (m, 28 H, H-1_aα, 8ϫPhCHHЈα, H-

1_aβ, 10ϫPhCHHЈβ), 5.25 (d, J_1,2= 3.4 Hz, 2 H, H-1_bα), 7.08–7.44

(m, 105 H, 35ϫAr-Hα, 35ϫAr-Hβ) ppm. ¹³C NMR (100 MHz,

C₆D₆): δ = 54.8, 55.2, 68.6, 69.2, 70.1, 70.4, 71.6, 72.6, 72.9, 73.0,

73.5, 73.6, 74.7, 74.8, 75.1, 75.2, 75.4, 75.5, 76.0, 78.0, 78.6, 78.7,

79.4, 80.9, 81.1, 82.3, 82.5, 82.7, 98.2, 98.7, 104.5, 127.1, 127.6,

127.7, 127.8, 128.0, 128.1, 128.2, 128.3, 128.3, 128.4, 128.5, 128.6,

128.8, 138.7, 139.0, 139.1, 139.3, 139.3, 139.4 ppm. MS (ES⁺): m/z

(%) = 1103 (100) [M + Na⁺]. HRMS (ES⁺): calcd. for C₆₃H₆₈O₁₁-

SeNa [M + Na⁺] 1103.3825; found 1103.3830]. C₆₃H₆₈O₁₁Se

(1080.18): calcd. C 70.05, H 6.35; found C 70.12, H 6.39.

Methyl 3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-gluco-

pyranoside (14): General Method B with trichloroacetimidate 10

(125 mm) and MeOH (2 equiv.) gave methyl glycoside 14 as a

colourless oil. ¹H NMR [400 MHz, CDCl₃, 1:1 mixture of α:β ano-

mers observed]: δ = 3.10–3.14 (m, 4 H, OCH₂CH₂SePhα/β), 3.38–

3.50 (m, 4 H, H-2α, H-2β, H-5α, H-5β), 3.60 (br. s, 2 H, CH₃α/β),

3.61–3.65 (m, 4 H, H-3α, H-3β, H-4α, H-4β), 3.68–3.78 (m, 4 H,

H-6α, H-6β, H-6Јα, H-6Јβ), 4.02–4.05 (m, 4 H, OCH₂CH₂SePhα/

β), 4.29 (d, J_1,2= 7.8 Hz, 1 H, H-1β), 4.31 (d, J_1,2= 3.0 Hz, 1 H,

H-1α), 4.51–4.98 (m, 12 H, 3ϫAr-CHα, 3ϫAr-CHβ), 7.15–7.43

(m, 40 H, 20ϫAr-CHα, 20ϫAr-CHβ) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 26.8, 26.9 (OCH₂CH₂SePhα/β), 57.1 (CH₃), 68.8 (C-

6), 70.5 (OCH₂CH₂SePhα/β), 75.1, 75.3, 75.8 (3ϫArCH₂), 74.9 (C-

5), 77.8 (C-3), 81.9 (d, C-2), 84.4 (d, C-4), 104.5 (d, C-1), 126.8,

127.6, 127.6, 127.7, 127.8, 127.9, 128.0, 128.4, 128.4, 129.3 (10ϫd,

10ϫAr-CH), 138.0, 138.1, 138.5, 142.9 (4ϫs, 4 ϫAr-C) ppm. MS

(ES⁺): m/z = 666 [M + NH₄⁺] (100). HRMS (ES⁺): calcd. for

C₃₆H₄₀O₆SeNa [M + Na⁺] 671.1888; found 671.1880. C₃₆H₄₀O₆Se

(647.67): calcd. C 66.76, H 6.23; found C 66.70, H 6.28.

N-(3,4,6-Tri-O-acetyl-2-O-allyl-β-D-glucopyranosyl)piperidine

(21):^[18]Alcohol 20^[14](18.67 g, 50 mmol) and Ag₂O (12.75 g,

1.1 equiv.) were mixed in anhydrous DMF (50 mL) and stirred un-

der N₂. Allyl iodide (25 g, 3 equiv.) was then added dropwise to the

reaction and the mixture was stirred for 16 h. Analysis by TLC

(eluent; petroleum ether/EtOAc, 3:1) showed complete conversion

to the product (R_f0.3). The reaction was then filtered and concen-

trated under vacuum. The residue was then dissolved in CHCl₃

(100 mL) before washing with H₂O (150 mL). The organic layer

was then dried (MgSO₄), filtered, and concentrated under vacuum.

The crude material was then purified by flash column chromatog-

raphy (eluent; petroleum ether/EtOAc, 3:1). The product (9.34 g,

45% yield) was isolated as a colourless solid, m.p. 106–108 °C [ref.

103 °C].^[18][α]_D= + 17.7 (c = 1.0 CHCl₃) [ref. [α]_D= + 18 (c = 1.3

CHCl₃)].^{[18] 1}H NMR (500 MHz, CDCl₃): δ = 1.46–1.59 [m, 6 H,

N(CH₂CH₂)₂CH₂], 2.01 [s, 3 H, C(O)CH₃], 2.04 [s, 3 H, C(O)CH₃],

2.06 [s, 3 H, C(O)CH₃], 2.60–2.63 [m, 2 H, N(CH₂CH₂)₂CH₂],

3,4,6-Tri-O-benzyl-2-O-[2-(phenylselenyl)ethyl]-α/β-

yl-(1Ǟ6)-methyl-2,3,4-tri-O-benzyl-α- -glucopyranoside (15): Gene-

ral Method B with trichloroacetimidate 10 (125 mm) and acceptor

12 (2 equiv.) gave disaccharide 15 as a colourless oil. ¹H

NMR[400 MHz, CDCl₃, 2:1 mixture of α:β anomers observed]: δ

D-glucopyranos-

D

= 3.08–3.12 (m, 6 H, OCH₂CH₂SePhα/β), 3.14 (s, 6 H, OMeα), 2.85–2.89 [m, 2 H, N(CH₂CH₂)₂CH₂], 3.51–3.57 (m, 2 H, H-2 and

Eur. J. Org. Chem. 0000, 0–0

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

CDCl₃, mixture of α:β anomers observed]: δ = 2.02 [s, 3 H, C(O)-

FULL PAPER

H-5), 3.94 (d, J = 9.5 Hz, 1 H, H-1), 4.05–4.09 (m, 2 H, H-6 and

O-CH₂-CH=CH₂), 4.21 (dd, J = 12.0 5.0 Hz, 1 H, H-6Ј), 4.34 (dd, CH₃], 2.03 [s, 3 H, C(O)CH₃], 2.04 [s, 3 H, C(O)CH₃], 2.06 [s, 3 H,

J = 12.5 5.0 Hz, 1 H, O-CH₂-CH=CH₂), 4.89 (t, J = 9.5 Hz, 1 H, C(O)CH₃], 2.07 [s, 3 H, C(O)CH₃], 2.08 [s, 3 H, C(O)CH₃], 3.36

H-4), 5.10 (t, J = 9.5 Hz, 1 H, H-3), 5.15 (dd, J = 10.5 0.5 Hz, 1

H, CH=CH₂), 5.22 (dd, J = 17.5 1.5 Hz, 1 H, CH=CH₂), 5.79–

5.86 (m, 1 H, CH=CH₂) ppm. ¹³C NMR (126 MHz, CDCl₃): δ =

(dd, J = 9.2 8.0 Hz, 1 H, H-2_β), 3.56 (dd, J = 9.6 3.6 Hz, 1 H, H-

2_α), 3.66–3.75 (m, 7 H, H-5_β, 2 ϫ OCH₂CH₂OH and OCH₂-

CH₂OH), 3.80–3.84 (m, 2 H, OCH₂CH₂OH), 4.09–4.15 (m, 2 H,

20.8 [q, C(O)CH₃], 20.9 [q, C(O)CH₃], 21.0 [q, C(O)CH₃], 24.8 [t, H-6_αand H-6_β), 4.21–4.29 (m, 3 H, H-5_α, H-6Ј_αand H-6Ј_β), 4.78

N(CH₂CH₂)₂CH₂], 26.3 [t, N(CH₂CH₂)₂CH₂], 49.3 [t, N-

(CH₂CH₂)₂CH₂], 62.7 (t, C-6), 69.2 (d, C-4), 72.5 (t, O-CH₂-

CH=CH₂), 72.8 (d, C-2), 73.8 (d, C-5), 75.5 (d, C-3), 96.0 (d, C-

(d, J = 7.6 Hz, 1 H, H-1_β), 4.99–5.05 (m, 2 H, H-4_αand H-4_β),

5.14 (app. t, J = 9.6 9.2 Hz, 1 H, H-3_β), 5.40 (app. t, J = 9.6 Hz, 1

H, H-3_α), 5.43 (d, J = 3.2 Hz, 1 H, H-1_α) ppm. ¹³C NMR

1), 117.0 (t, CH=CH₂), 135.2 (d, CH=CH₂), 170.1 (s, C=O), 170.3 (100 MHz, CDCl₃): δ = 20.8 [q, C(O)CH₃], 20.8 [q, C(O)CH₃], 20.9

(s, C=O), 170.9 (s, C=O) ppm. HRMS (ESI-TOF): calcd. for [q, C(O)CH₃], 20.9 [q, C(O)CH₃], 21.0 [q, C(O)CH₃], 61.8 (t,

C₂₀H₃₁NO₈H⁺[M + H⁺] 414.2122; found 414.2138.

OCH₂CH₂OH), 62.2 (t, OCH₂CH₂OH), 62.3 (t, C-6_α), 62.3 (t, C-

6_β), 67.5 (d, C-5_α), 68.5 (d, C-4_α), 68.7 (d, C-4_β), 71.9 (d, C-5_β),

72.0 (d, C-3_α), 72.8 (t, OCH₂CH₂OH), 74.4 (t, OCH₂CH₂OH), 74.6

(d, C-3_β), 78.6 (d, C-2_α), 81.5 (d, C-2_β), 90.8 (d, C-1_α), 96.8 (d, C-

1_β), 169.9 (s, C=O), 169.9 (s, C=O), 170.6 (s, C=O), 170.8 (s, C=O),

170.9 (s, C=O), 171.0 (s, C=O) ppm. HRMS (ESI-TOF): calcd. for

C₁₄H₂₂Cl₃O₁₀Na⁺373.1105; found 373.1102.

2-O-Allyl-3,4,6-tri-O-acetyl-α,β-

D-glucopyranose (22): Piperidine 21

(500 mg, 1.2 mmol) was dissolved in MeOH (25 mL) and stirred

under N₂. Aqueous HCl (1.0 m, 1.5 equiv.) was added and the reac-

tion was stirred overnight. After 16 h, TLC [eluent; petroleum

ether/EtOAc, 3:2) showed complete consumption of the starting

material (R_f0.7) and appearance of the product (R_f0.2). The reac-

tion was then diluted with toluene (50 mL) before concentrating

under vacuum. The residue was then evaporated with toluene

(2ϫ50 mL). The crude material was then purified by flash column

chromatography (eluent; petroleum ether/EtOAc, 3:2) to give hemi-

3,4,6-Tri-O-acetyl-2-O-(2-iodoethyl)-α/β-D-glucopyranose (24): Diol

23 (490 mg, 1.4 mmol) was dissolved in THF (30 mL) under N₂. To

this was added imidazole (143 mg, 1.5 equiv.), triphenylphosphine

(551 mg, 1.5 equiv.), and iodine (533 mg, 1.5 equiv.). Once the io-

dine had been added the reaction was purged with N₂for 10 min

before heating to reflux overnight. The next day the reaction was

1

acetal 22 (374 mg, 89% yield) as a yellow oil. H NMR [400 MHz,

CDCl₃, mixture of α:β anomers observed]: δ = 2.02 [s, 3 H, C(O)-

CH₃], 2.02 [s, 3 H, C(O)CH₃], 2.05 [s, 6 H, 2ϫC(O)CH₃], 2.08 [s, cooled to room temperature before filtering. The solution was then

3 H, C(O)CH₃], 2.09 [s, 3 H, C(O)CH₃], 3.11 (br. s, 1 H, OH), 3.33 concentrated under vacuum before purifying by flash column

(dd, J = 9.6 7.6 Hz, 1 H, H-2_β), 3.57 (dd, J = 9.6 3.6 Hz, 1 H, H- chromatography (eluent; petroleum ether/EtOAc, 3:2. R_f0.21) to

2_α), 3.69–3.74 (m, 1 H, H-5), 4.07–4.15 (m, 5 H, CH₂CH=CH₂, H- afford iodide 24 (503 mg, 78% yield) as a colourless oil. ν

6, H-6 and H-6Ј), 4.20–4.35 (m, 4 H, H-5, CH₂CH=CH₂and H- (neat) 3460 (br. s, O-H), 1748 (s, C=O) cm^–1. H NMR (400 MHz,

6Ј), 4.77 (dd, J = 7.6 4.8 Hz, 1 H, H-1_β), 4.98–5.03 (m, 2 H, H-4_αCDCl₃) [mixture of α:β anomers observed]: δ = 2.02 [s, 3 H, C(O)-

=

˜

max

1

and H-4_β), 5.12–5.30 (m, 5 H, H-3_βand CH₂CH=CH₂), 5.35–5.42 CH₃], 2.03 [s, 3 H, C(O)CH₃], 2.08 [s, 3 H, C(O)CH₃], 2.08 [s, 3 H,

(m, 2 H, H-1_αand H-3_α), 5.79–5.89 (m, 2 H, CH₂CH=CH₂) ppm. C(O)CH₃], 2.09 [s, 6 H, 2 ϫ C(O)CH₃], 3.19–3.23 (m, 4 H,

¹³C NMR (100 MHz, CDCl₃): δ = 20.8 [q, C(O)CH₃], 20.8 [q, 2ϫOCH₂CH₂I), 3.31 (dd, J = 9.6 7.6 Hz, 1 H, H-2_β), 3.57 (dd, J

C(O)CH₃], 20.9 [q, C(O)CH₃], 20.9 [q, C(O)CH₃], 21.0 [q, C(O)-

CH₃], 62.2 (t, C-6), 62.4 (t, C-6), 67.5 (d, C-5), 68.5 (d, C-4), 68.7

(d, C-4), 71.9 (d, C-5 and C-3), 72.4 (t, CH₂CH=CH₂), 73.5 (t,

= 9.6 3.6 Hz, 1 H, H-2_α), 3.70–3.74 (m, 1 H, H-5_β), 3.80–3.92 (m,

3 H, OCH₂CH₂I), 4.07–4.15 (m, 3 H, H-6_α, H-6_βand OCH₂CH₂I),

4.20–4.30 (m, 3 H, H-5_α, H-6Ј_α7 H-6Ј_β), 4.78 (d, J = 7.6 Hz, 1 H,

CH₂CH=CH₂), 74.0 (d, C-3), 77.1 (d, C-2_α), 79.8 (d, C-2_β), 91.2 H-1_β), 4.97–5.03 (m, 2 H, H-4_αand H-4_β), 5.16 (app. t, J = 9.6 Hz,

(d, C-1_α), 97.4 (d, C-1_β), 117.5 (t, CH₂CH=CH₂), 118.4 (t,

1 H, H-3_β), 5.39–5.44 (m, 2 H, H-1_αand H-3_α) ppm. ¹³C NMR

CH₂CH=CH₂), 134.0 (d, CH₂CH=CH₂), 134.5 (d, CH₂CH=CH₂), (100 MHz, CDCl₃): δ = 2.7 (t, OCH₂CH₂I), 3.1 (t, OCH₂CH₂I),

169.9 (s, C=O), 170.0 (s, C=O), 170.3 (s, C=O), 170.3 (s, C=O),

170.9 (s, C=O), 170.9 (s, C=O) ppm. HRMS (ESI-TOF): calcd. for

C₁₅H₂₂O₉Na⁺[M + Na⁺] 369.1156; found 369.1169.

20.7 [q, C(O)CH₃], 20.8 [q, C(O)CH₃], 20.9 [q, C(O)CH₃], 21.2 [q,

C(O)CH₃], 21.2 [q, C(O)CH₃], 62.2 (t, C-6_α), 62.3 (t, C-6_β), 67.5

(d, C-5_α), 68.5 (d, C-4_α), 68.7 (d, C-4_β), 71.7 (d, C-3_α), 71.8 (d, C-

5_β), 72.0 (t, OCH₂CH₂I), 73.2 (t, OCH₂CH₂I), 73.7 (d, C-3_β), 78.4

(d, C-2_α), 80.8 (d, C-2_β), 91.0 (d, C-1_α), 97.1 (d, C-1_β), 169.9 (s,

C=O), 170.0 (s, C=O), 170.3 (s, C=O), 170.3 (s, C=O), 170.9 (s,

C=O), 170.9 (s, C=O) ppm. HRMS (ESI-TOF): calcd. for

C₁₄H₂₁IO₉Na⁺483.0122; found 483.0133.

3,4,6-Tri-O-acetyl-2-O-(2-hydroxyethyl)-α/β-D-glucopyranose (23):

Allyl ether 22 (10.74 g, 31 mmol) was dissolved in CH₂Cl₂(300 mL)

under N₂and cooled to –78 °C. Ozone was then bubbled through

the solution for 90 min until it turned a deep blue. The excess ozone

was then removed by bubbling N₂through the solution until the

colour had dissipated. Dimethyl sulfide (11.4 mL, 5 equiv.) was

then added and the solution warmed to room temperature over an

hour. The reaction was then concentrated under vacuum to remove

the excess dimethyl sulfide before re-dissolving in CH₂Cl₂(300 mL)

and acetic acid (11.7 mL, 6.6 equiv.). The solution was then cooled

to 0 °C and sodium cyanoborohydride (3.90 g, 2 equiv.) was added

portion wise before the reaction was left to stir overnight. The next

day the reaction was quenched by the addition of H₂O (50 mL).

Brine (200 mL) was then added and the organic layer separated

before the aqueous layer was extracted with CH₂Cl₂(2ϫ200 mL).

The combined organic layers were then dried (MgSO₄), filtered,

and concentrated under vacuum before purifying by flash column

chromatography (eluent; EtOAc/petroleum ether, 5:1. R_f0.35 and

O-[3,4,6-Tri-O-acetyl-2-O-(2-iodoethyl)]-α/β-D-glucopyranose Tri-

chloroacetimidate (25): Hemiacetal 24 (503 mg, 1.1 mmol) was dis-

solved in was dissolved in CH₂Cl₂(10 mL) under N₂. To this was

added trichloroacetonitrile (1.1 mL, 10 equiv.) and DBU (0.07 mL,

0.4 equiv.). The reaction was then left to stir overnight. The next

day the reaction was concentrated under vacuum and the residue

purified by flash column chromatography (eluent; petroleum ether/

EtOAc. R_f0.42 and 0.19) to afford trichloroacetimidate 25 (535 mg,

1

81% yield) as a yellow oil. H NMR [400 MHz, CDCl₃, 5.1:1 mix-

ture of α:β anomers observed, major α anomer quoted]: δ = 2.04

[s, 3 H, C(O)CH₃], 2.07 [s, 3 H, C(O)CH₃], 2.09 [s, 3 H, C(O)CH₃],

3.15 (app. t, 2 H, CHCH₂I), 3.73–3.79 (m, 2 H, H-2 and

CH₂CH₂I), 3.90–3.95 (m, 1 H, CH₂CH₂I), 4.09–4.15 (m, 1 H, H-

6), 4.20 (ddd, J = 10.2 4.0 1.6 Hz, 1 H, H-5), 4.28 (dd, J = 12.6

4.2 Hz, 1 H, H-6Ј), 5.11 (app. t, J = 10.0 9.6 Hz, 1 H, H-4), 5.46

0.26) to afford diol 23 (5.90 g, 54% yield) as a colourless oil. ν

=

˜

max

(neat) 3446 (br. s, O-H), 1748 (s, C=O) cm^–1. H NMR [400 MHz,

1

12

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Neighbouring Group Participation During Glycosylation

(app. t, J = 9.6 Hz, 1 H, H-3), 6.58 (d, J = 3.2 Hz, 1 H, H-1), 8.68

HRMS (ESI-TOF): calcd. for C₂₂H₂₆Cl₃NO₉SeNa⁺655.9702;

(br. s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 2.1 (t, found 655.9707.

CH₂CH₂I), 20.8 [q, C(O)CH₃], 20.8 [q, C(O)CH₃], 21.2 [q, C(O)-

p-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-β-D-glucopyranos-

CH₃], 61.7 (t, C-6), 68.0 (d, C-4), 70.1 (d, C-5), 71.5 (d, C-3), 72.1

(t, CH₂CH₂I), 77.3 (d, C-2), 97.6 [s, OC(NH)CCl₃], 93.5 (d, C-1),

161.2 (C=NH), 169.8 (s, C=O), 170.1 (s, C=O), 170.6 (s,

C=O) ppm. HRMS (ESI-TOF): calcd. for C₁₆H₂₁Cl₃INO₉Na⁺[M

+ Na⁺] 625.9219; found 625.9217.

ide (29): Sodium methoxide (0.250 g, 4.63 mmol) was dissolved in

anhydrous methanol (150 mL) and the solution was stirred at room

temp. PMP glycoside 28^[16](21.0 g, 46.3 mmol) was added portion-

wise and the mixture was stirred at room temp. under a nitrogen

atmosphere. After 90 min, TLC (petroleum ether/ethyl acetate, 1:1),

indicated formation of a single product (R_f0) and complete con-

sumption of starting material (R_f0.5). The mixture was concen-

trated in vacuo. DMF (75 mL), benzaldehydedimethylacetal

(8.30 mL, 55.0 mmol) and camphor sulfonic acid (CSA; 2.20 g,

9.30 mmol) were added and the mixture was rotated in a round

bottomed flask on a rotator evaporator at 60 °C under pressure of

240 mbar for 8 h. After this time TLC (petroleum ether/ethyl acet-

ate, 3:2) showed formation of a major product (R_f0.1) and com-

plete consumption of starting material (R_f0.5). The reaction was

quenched by the addition of triethylamine (0.97 mL, 6.94 mmol)

and then concentrated in vacuo. The residue was dissolved in ethyl

acetate (1 L), then washed with water (2 ϫ 300 mL), brine

(100 mL), dried (MgSO₄), filtered, and concentrated in vacuo.

Recrystallization (propanol/methanol) yielded diol 29 (10.0 g,

56%), m.p. 192–195 °C. [α]²_D⁰= – 51.3 (c = 1.0 in MeOH). IR (KBr):

3,4,6-Tri-O-acetyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-glucopyranose

(26): Iodide 24 (690 mg, 1.5 mmol) was dissolved in DMF (10 mL)

under N₂. Hunig’s base (0.32 mL, 1.2 equiv.) and benzeneselenol

(0.19 mL, 1.2 equiv.) were added, and the mixture was stirred at

room temp. After 16 h, the reaction was concentrated under vac-

uum and purified by flash column chromatography (eluent; petro-

leum ether/EtOAc, 3:2. R_f0.2) to afford selenide 26 (664 mg, 90%

1

yield) as a yellow oil. ν

= (neat) 1748 (s, C=O) cm^–1. H NMR

˜

max

[400 MHz, CDCl₃, mixture of α:β anomers observed]: δ = 2.02 and

2.03 [12 H, C(O)CH₃ϫ4], 2.08 [6 H, C(O)CH₃ϫ2], 2.95–3.06 (m,

4 H, OCH₂CH₂SePh), 3.15 (br. s, 1 H, OH), 3.26 (1 H, at, J = 8.8

8.4 Hz, H-2_β), 3.49–3.52 (m, 2 H, H-2_αand OH), 3.69–3.72 (m, 1

H, H-5_β), 3.79–3.86 (m, 3 H, OCH₂CH₂SePh), 4.00–4.14 (m, 3 H,

OCH₂CH₂SePh, H-6_αand H-6_β), 4.20–4.30 (m, 3 H, H-5_α, H-6Ј_α

and H-6Ј_β), 4.74 (dd, 1 H, J = 7.6 4.8 Hz, H-1_β), 4.99 (2 H, at, J

= 10.0 9.6 Hz, H-4_αand H-4_β), 5.13 (1 H, at, J = 9.6 Hz, H-3_β),

5.32 (br. s, 1 H, H-1_α), 5.37 (1 H, at, J = 9.6 Hz, H-3_α), 7.25–7.27

(m, 6 H, ArH), 7.49–7.50 (m, 4 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 20.7 [q, C(O)CCH₃], 20.7 [q, C(O)CCH₃],

20.8 [q, C(O)CCH₃], 21.0 [q, C(O)CCH₃], 27.2 (t, OCH₂CH₂SePh),

27.4 (t, OCH₂CH₂SePh), 62.1, 62.3 (2ϫt, C-6), 67.5 (d, C-5_α), 68.5

(d, C-4_αand C-4_β), 68.7 (t, OCH₂CH₂SePh), 70.9 (d, C-3_α), 71.8

(d, C-5_β), 71.8 (t, OCH₂CH₂SePh), 74.0 (d, C-3_β), 78.3 (d, C-2_α),

80.9 (d, C-2_β), 90.9 (d, C-1_α), 97.1 (d, C-1_β), 127.2, 127.4, 129.2,

129.3, 129.3, 129.7, 132.7, 132.9 (8ϫArC), 169.9 (s, C=O), 170.0

(s, C=O), 170.3 (s, C=O), 170.3 (s, C=O), 170.9 (s, C=O), 170.9 (s,

C=O) ppm. HRMS (ESI-TOF): calcd. for C₂₀H₂₆O₉SeNa⁺

513.0635; found 513.0640.

ν

= 3560 (br., OH) cm^–1. ¹H NMR (400 MHz, CD₃OD): δ =

˜

max

3.52–3.56 (m, 3 H, H-2, H-3 and H-4), 3.72–3.84 (m, 5 H, H-5, H-

6, -OCH₃), 4.28–4.32 (dd, J_6,6’= 10.4, J_6Ј55.0 Hz, 1 H, H-6Ј), 5.60

(s, 1 H, -CHPh), 4.91 (d, J_1,2= 8 Hz, 1 H, H-1), 6.83–7.04 (m, 9

H, Aromatic-H) ppm. ¹³C NMR (100 MHz, CD₃OD): 155.8–114.7

(8 C, Ar-C), 102.2 (d, C-1), 101.8 (d, CHPh), 80.2 (d, C-4), 74.2 (d,

C-3), 72.5 (d, C-2), 68.0 (d, C-5), 66.0 (t, C-6), 54.2 (q, -OMe) ppm.

HRMS (ES⁺): calcd. for C₂₀H₂₂O₇Na [M + Na⁺] 397.1263; found

397.1263.

p-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-β-D-glucopyranos-

ide (30): Diol 29 (6.50 g, 17.4 mmol) was dissolved in methanol

(200 mL). Dibutyl tin oxide (5.20 g, 20.8 mmol) was added and the

reaction was stirred at reflux temperatures for 24 h. The solvent

was then removed and the residue was dissolved in DMF (200 mL),

and the mixture was stirred at room temp. Benzyl bromide

(2.47 mL, 20.8 mmol) and caesium fluoride (3.42 g, 34.7 mmol)

were added and the solution was stirred for 72 h, after which TLC

(petroleum ether/ethyl acetate, 2:1) showed the formation of a

major product (R_f0.5), but TLC (CH₂Cl₂/diethyl ether, 19:1)

showed a major spot at R_f0.8 and minor spots at R_f0.9. The

mixture was concentrated in vacuo, and the residue extracted with

CH₂Cl₂(400 mL), and the organic layer was treated with KF solu-

tion (400 mL, 1M conc.), dried (MgSO₄), filtered and concentrated

in in vacuo. Recrystallization (methanol) yielded benzyl ether 30

O-{3,4,6-Tri-O-acetyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-

glucopyranosyl} Trichloroacetimidate (27): Hemiacetal 26 (245 mg,

0.5 mmol) was dissolved in CH₂Cl₂(10 mL) under N₂. Trichloro-

acetonitrile (0.5 mL, 10 equiv.) and DBU (0.03 mL, 0.4 equiv.) were

added, and the reaction was stirred at room temp. After 16 h, TLC

(petroleum ether/EtOAc, 1:1) showed complete consumption of the

starting material (R_f0.3) and the formation of two new spots for

the product (R_f0.6 and 0.7). The reaction was then concentrated

under vacuum and purified by flash column chromatography (elu-

ent; petroleum ether/EtOAc, 3:1. R_f0.30 and 0.18) to afford tri-

chloroacetimidate 27 (291 mg, 92% yield) as a yellow oil. ν

=

˜

(3.50 g, 43%) as white crystalline solid, m.p. 198–201 °C. [α]²_D⁰

–22.1 (c = 1.0 in CHCl ). IR (KBr): ν

= 3560 (br., OH) cm^–1.

=

max

(neat) 1748 (s, C=O) 1674 (s, C=N) cm^–1. ¹H NMR (400 MHz,

CDCl₃) [mixture of α:β anomers observed, major α anomer

quoted]: δ = 2.03 and 2.04 [6 H, 2ϫs, 2 ϫC(O)CH₃], 2.06 [s, 3 H,

C(O)CH₃], 2.92–2.98 (m, 2 H, OCH₂CH₂SePh), 3.68–3.75 (m, 2 H,

H-2 and OCH₂CH₂SePh), 3.85–3.91 (m, 1 H, OCH₂CH₂SePh),

4.09 (dd, 1 H, J = 12.4 1.6 Hz, H-6), 4.16–4.20 (m, 1 H, H-5), 4.27

(dd, 1 H, J = 12.4 4.4 Hz, H-6Ј), 5.09 (1 H, at, J = 10.0 9.6 Hz, H-

4), 5.43 (1 H, at, J = 10.0 9.6 Hz, H-3), 6.54 (d, 1 H, J = 3.2 Hz,

H-1), 7.24–7.26 (m, 3 H, ArH), 7.46–7.49 (m, 2 H, ArH), 8.63 (br.

s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.8 [q,

C(O)CH₃], 20.8 [q, C(O)CH₃], 21.0 [q, C(O)CH₃], 26.9 (t,

˜

3

max

¹H NMR (400 MHz, CDCl₃): δ = 2.53 (br. s, 1 H, OH), 3.50–3.59

(m, 1 H, H-5), 3.71–3.86 (m, 7 H, H-2, H-3, H-4, H-6, -OCH₃),

4.37 (m, 1 H, H-6Ј), 4.90 (d, J_1,2= 8 Hz, 1 H, H-1), 4.83, 5.00

(ABq, J_AB= 12 Hz, 2 H, -OCH₂Ph), 5.60 (s, 1 H, CHPh), 6.82–

7.51 (14 H, 14 H, Aromatic-H) ppm. ¹³C NMR (100 MHz,

CD₃OD): 55.6 (q, -OMe), 66.6 (t, C-6), 68.7 (d, C-5), 74.1 (d, C-

2), 74.7 (t, CH₂Ph), 80.2 (d, C-4), 81.2 (d, C-3), 101.3 (d, CHPh),

102.5 (d, C-1), 159.2–114.6 (14 C, Ar-C) ppm. HRMS (ES⁺): calcd.

for C₂₇H₂₈O₇Na [M + Na⁺] 487.1733; found 487.1732.

OCH₂CH₂SePh), 61.7 (t, C-6), 68.1 (d, C-4), 70.1 (d, C-5), 71.1 (t, p-Methoxyphenyl 2-O-Allyl-3-O-benzyl-4,6-O-benzylidene-β-D-

OCH₂CH₂SePh), 71.6 (d, C-3), 77.2 (d, C-2), 93.5 (d, C-1), 97.6

[OC(NH)CCl₃], 127.3, 129.3, 129.7, 132.9 (4 ϫ ArC), 161.2 (s,

C=NH), 170.0 (s, C=O), 170.1 (s, C=O), 170.7 (s, C=O) ppm.

glucopyranoside (31): Alcohol 30 (3.00 g, 6.40 mmol) was dissolved

in anhydrous DMF (20 mL) and a suspension of sodium hydride

(0.330 g, 13.7 mmol) in anhydrous DMF (20 mL) was added at

Eur. J. Org. Chem. 0000, 0–0

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

FULL PAPER

0 °C under a nitrogen atmosphere. Allyl bromide (1.17 mL,

13.7 mmol) was then added slowly. The reaction was warmed to

room temp. and stirred. After 4 h TLC (petroleum ether/ethyl acet-

ate, 4:1) showed complete consumption of starting material (R_f0.1)

and formation of a single product (R_f0.3). The reaction was then

quenched by the addition of methanol (20 mL) and concentrated

in vacuo. The resulting residue was dissolved in CH₂Cl₂(30 mL),

washed with water (2ϫ15 mL), brine (15 mL) and dried (MgSO₄),

ozone was then removed by bubbling N₂through the solution until

the colour had dissipated. Dimethyl sulfide (3.7 mL, 50 mmol) was

then added, and the solution was warmed to room temperature

over an hour. The reaction was then concentrated under vacuum

to remove the excess dimethyl sulfide before re-dissolving in a mix-

ture of CH₂Cl₂(150 mL) and acetic acid (4.0 mL, 66.0 mmol). The

solution was then cooled to 0 °C and sodium cyanoborohydride

(1.51 g, 24 mmol) was added portion wise, and the reaction was left

filtered, and concentrated in vacuo. Purification by flash to stir. After 16 h, TLC (petroleum ether/ethyl acetate, 1:4) showed

chromatography (petroleum ether/ethyl acetate, 6:1) yielded allyl the formation of a major product (R_f0.2) and the complete disap-

ether 31 (2.33 g, 72%) as white crystalline solid, m.p. 177–180 °C.

pearance of starting material (R_f0.95). The reaction was then

quenched by the addition of H₂O (25 mL). Brine (100 mL) was

1

[α]²_D⁰= –34.6 (c = 1.0 in CHCl₃). H NMR (400 MHz, CDCl₃): δ

= 3.56 (m, 1 H, H-5), 3.62 (m, 1 H, H-2), 4.98 (m, 2 H, -OCHHЈPh, then added, the organic layer separated, and the aqueous layer was

H-1), 4.85 (d, J_gem= 11.2 Hz, 1 H, -OCHHЈ₂Ph), 4.49 (m, 2 H, re-extracted with CH₂Cl₂(2ϫ100 mL). The combined organic ex-

-OCH₂CH=CH₂), 4.37 (m, 1 H, H-6Ј), 3.71–3.86 (m, 6 H, H-3, H- tracts were then dried (MgSO₄), filtered, concentrated in vacuo and

4, H-6, -OCH₃), 5.21 (d, J_Z= 10 Hz, 1 H, -OCH₂CH=CHzH_E),

5.35 (d, J_E= 16 Hz, 1 H, -OCH₂CH=CHzH_E), 5.59 (s, 1 H,

CHPh), 6.00 (m, 1 H, -OCH₂CH=CH₂), 6.84–7.52 (m, 14 H, Aro-

purified by flash column chromatography (petroleum ether/ethyl

acetate, 1:4) to afford 3-O-benzyl-4,6-diacetyl-2-O-(2-hydroxy-

ethyl)-α/β-d-glucopyranose (2.00 g) as a colourless oil which was

matic-H) ppm. ¹³C NMR (100 MHz, CD₃OD): 55.6 (q, -OMe), used directly in the next step. The residue was then dissolved in

68.7 (d, C-5), 66.2 (t, C-6), 74.282 (d, C-2), 75.1 (t, CH₂Ph), 80.8 THF (100 mL) under a nitrogen atmosphere. I₂(1.92 g,

(d, C-4), 81.1 (d, C-3), 81.6 (t, -OCH₂CH=CH₂), 101.2 (d, CHPh), 7.55 mmol), imidazole (0.514 g, 7.55 mmol) and PPh₃(1.98 g,

103.3 (d, C-1), 114.6–155.6 (14C, Ar-C, -OCH₂CH=CH₂, 7.55 mmol) were added, and the reaction mixture was heated to

-OCH₂CH=CH₂) ppm. HRMS (ES⁺): calcd. for C₃₀H₃₂O₇Na [M reflux. After 16 h, TLC (petroleum ether/ethyl acetate, 2:1) indi-

+ Na⁺] 527.2046; found 527.2051.

cated formation of a major product (R_f0.3) and complete con-

sumption of starting material (R_f0.0). The reaction was cooled to

room temp. and concentrated in vacuo. The resulting residue was

purified by flash chromatography (petroleum ether/ethyl acetate,

5:2) to afford iodide 33 (1.00 g, 20%) as colourless oil. IR (KBr):

p-Methoxyphenyl 2-O-Allyl-3-O-benzyl-4,6-di-O-acetyl-β-D-gluco-

pyranoside (32): Acetic acid (aq. 80%, 6 mL) was added to a solu-

tion of benzylidene acetal 31 (100 mg, 0.200 mmol) in CH₂Cl₂

(1 mL). The reaction mixture was then stirred at 60 °C. After 48 h,

TLC (petroleum ether/ethyl acetate, 3:1) indicated formation of a

major product (R_f0.1) and complete consumption of starting mate-

rial (R_f0.8). The mixture was diluted with CH₂Cl₂(10 mL) and

washed with saturated aq. NaHCO₃(2ϫ15 mL), dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was dissolved in

the mixture of Ac₂O/pyridine (1:1, 5 mL) and 4-dimethylaminopyr-

idine (DMAP; 0.005 g, 0.040 mmol) was added, and the mixture

was stirred at room temp. After 16 h, TLC (petroleum ether/ethyl

acetate, 3:1) indicated the formation of a major product (R_f0.3)

and complete consumption of the starting material (R_f0.1). The

mixture was then co-evaporated with toluene (4ϫ25 mL). The re-

sulting residue was purified by flash column chromatography (pe-

troleum ether/ethyl acetate, 4:1) to afford diacetate 32 (0.091 g,

91%) as a white crystalline solid, m.p. 63–65 °C (petroleum ether/

ethyl acetate). [α]²_D⁰= –62.8 (c = 1.0 in CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 1.93, 2.06 (2ϫs, 6 H, 2ϫCOCH₃) 3.82

(m, 3 H, H-2, H-4, H-5), 3.78 (s, 3 H, -OCH₃), 4.07–4.11 (dd, J_6,6Ј

ν

_max= 1744 (s, C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃) [1:1 mix-

˜

ture of α/β anomers observed]: δ = 1.92, 1.93, 2.06, 2.07 (12 H,

4ϫs, 2 ϫCOCH₃α, 2ϫCOCH₃β), 3.03 (br. s, 2 H, -OH α, -OH

β), 3.22–3.30 (m, 6 H, -OH β, -OCH₂CH₂I α, OCH₂CH₂I β, H-2

α/β), 3.52–3.62 (m, 3 H, H-2 α/β, H-3 α, H-3 β), 3.87–4.22 (m, 10

H, H-6 α, H-6 β, H-6Ј α, H-6Ј β, -OCH₂CH₂I α, -OCH₂CH₂I β,

H-4 α, H-4 β), 3.82–4.17 (m, 5 H, -OCHHЈCH₂I β, -OCHHЈCH₂I

α, -OCHHЈCH₂I β, H-6Ј α, H-6Ј β), 4.63–4.88 (m, 5 H, CH₂Ph α,

CH₂Ph β, H-1 β), 4.98–5.03 (m, 2 H, H-5 α, H-5 β), 5.37 (d, J_1,2

= 2.8 Hz, 1 H, H-1 α), 7.25–7.35 (m, 10 H, 5ϫAr-CH α, 5ϫAr-

CH β) ppm. ¹³C NMR (100 MHz, CDCl₃): 2.9, 3.3 (2ϫt, -OCH₂-

CH₂I α, -OCH₂CH₂I β), 20.7, 20.7, 20.7, 20.7 (4ϫq, 2ϫCOCH₃

α, 2ϫCOCH₃β), 62.2, 62.4 (2ϫt, C-6 α, C-6 β), 68.0, 68.0 (2ϫd,

C-2 α, C-2 β), 69.5, 69.6 (2ϫt, -OCH₂CH₂I α, -OCH₂CH₂I β),

75.4, 75.7 (2ϫt, -CH₂Ph α, -CH₂Ph β), 72.1, 73.1, 78.6, 80.7, 81.3,

83.4 (6ϫd, C-3 α, C-3 β, C-4 α, C-4 β, C-5 α, C-5 β), 91.2 (d, C-

1 β), 97.4 (d, C-1 α), 127.7–128.4 (6ϫd, 3ϫAr-CH α, 3ϫAr-CH

β), 138.1, 138.1 (Ar-C α, Ar-C β), 169.6–171.4 (4C, 2ϫCH₃CO α,

2ϫCH₃CO β) ppm. HRMS (ES⁺): calcd. for C₁₉H₂₅O₈NaI [M +

Na⁺] 531.0492; found 531.0494.

= 9.2, J_6,5= 3.8 Hz, 1 H, H-6), 4.21–4.25 (dd, J_6Ј,6= 9.2, J_6Ј,5

=

3.8 Hz, 1 H, H-6Ј), 4.29–4.33 (dd, J_gem= 9.2, J_vic3.8 Hz, 1 H,

-OCHHЈCH=CH₂), 4.47–4.51 (dd, J_gem= 9.2, J_vic3.8 Hz, 1 H,

-OCHHЈCH=CH₂), 4.67, 4.87 (ABq, J_AB= 11.2 Hz, 2 H, CH₂Ph),

4.81 (d, J_1,2= 11.2 Hz, 1 H, H-1), 5.05 (at, J = 8 Hz, 1 H, H-3),

5.19 (d, J_z= 10 Hz, 1 H, -OCH₂CH=H_EH_Z), 5.86 (d, J_E= 16 Hz,

1 H, -OCH₂CH=H_EH_Z) 6.01 (m, 1 H, -OCH₂CH=CH₂), 6.79–7.52

(m, 9 H, Aromatic-H) ppm. ¹³C NMR (100 MHz, CDCl₃): 20.7,

20.7 (2ϫq, 2ϫCOCH₃) 55.6 (q, -OMe), 62.5 (t, C-6), 69.6 (d, C-

3), 73.8 (t, -OCH₂CH=CH₂) 75.2 (t, CH₂Ph) 72.0, 81.3, 81.4 (3ϫd,

C-2, C-4, C-5), 102.8 (d, H-1), 114.5 (t, -OCH₂CH=CH₂), 117.3–

128.4 (5ϫd, ArC-H), 134.7 (-OCH₂CH=CH₂), 138.2, 151.3, 155.5

(3ϫs, Ar-C), 169.5, 170.7 (2ϫs, 2 ϫCOCH₃) ppm. HRMS (ES⁺):

calcd. for C₂₇H₃₂O₉Na [M + Na⁺] 523.1944; found 523.1945.

3-[O-Benzyl-4,6-di-O-acetyl-2-O-(2-iodoethyl)-α/β-D-glucopyranos-

yl] Trichloroacetimidate (34): Hemiacetal 33 (0.144 g, 0.283 mmol)

was dissolved in distilled CH₂Cl₂(3 mL) under a nitrogen atmo-

sphere and cooled to 0 °C. DBU (0.017 mL, 0.112 mmol), and tri-

chloroacetonitrile (0.284 mL, 2.83 mmol), were added, and the re-

action mixture was allowed to stir. After 8 h, TLC [petroleum ether/

ethyl acetate, 2:1, with 1% triethanolamine (TEA)] indicated the

formation of a major product (R_f0.5), and the complete consump-

tion of starting material (R_f0.1). The reaction was cooled to room

temp. and concentrated in vacuo. The resulting residue was purified

by flash chromatography (petroleum ether/ethyl acetate, 3:1, with

1 % TEA) to afford trichloroacetimidate 34 (0.164 g, 89 %) as

3-O-Benzyl-4,6-di-O-acetyl-2-O-(2-iodoethyl)-α/β-D-glucopyranose

(33): PMP glycoside 32 (5.00 g, 10.00 mmol) was dissolved in

CH₂Cl₂(150 mL) under N₂, and cooled to –78 °C. Ozone was then

bubbled through the solution until it turned deep blue. The excess

colourless oil. IR (KBr): ν_max= 1740 (s, C=O), 1672 (s, C=N) cm^–1.

˜

¹H NMR (400 MHz, CDCl₃) [2:1 mixture of α/β anomers ob-

served]: δ = 1.93, 1.95, 2.05 (12 H, 2ϫs, 2 ϫCOCH₃α, 2ϫCOCH₃

14

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Neighbouring Group Participation During Glycosylation

β), 3.18 (m, 4 H, -OCH₂CH₂I α, OCH₂CH₂I β), 3.62–4.25 (m, 14

H, -OCH₂CH₂I α, OCH₂CH₂I β, H-5 α, H-5 β, H-3 α, H-3 β, H-

material (R_f0.2). The reaction was warmed to room temp. and

concentrated in vacuo. The resulting residue was purified by flash

chromatography (petroleum ether/ethyl acetate, 4:1, with 1% TEA)

6 α, H-6 β, H-6Ј α, H-6Ј β, H-4 α, H-4 β) 4.67, 4.90 (ABq, J_AB

=

11.6 Hz, 4 H, CH₂Ph α, CH₂Ph β), 5.08 (m, 2 H, H-2 α, H-2 β), to afford trichloroacetimidate 36 (0.177 g, 74%) as colourless oil.

5.73 (d, J_1,2= 8 Hz, 1 H, H-1 β), 6.53 (d, J_1,2= 3.2 Hz, 1 H, H-1 IR (KBr): ν

= 3319 (w, N–H), 1745 (s, C=O), 1673 (s,

˜

max

α), 7.25–7.35 (m, 10 H, 5ϫAr-CH α, 5ϫAr-CH β), 8.62, 8.71 (N- C=N) cm^–1. ¹H NMR (400 MHz, CDCl₃) [50:1 mixture of α/β ano-

H α, N-H β) ppm. ¹³C NMR (100 MHz, CDCl₃): 2.1, 2.2 (2ϫt, mers observed, major α anomer quoted]: δ = 1.95, 2.04 (6 H, 2ϫs,

-OCH₂CH₂I α, -OCH₂CH₂I β), 20.6, 20.6, 20.7, 20.7 (4 ϫ q,

2ϫCOCH₃α, 2ϫCOCH₃β), 61.8, 61.9 (2ϫt, C-6 α, C-6 β), 68.8,

2ϫCOCH₃) 3.01 (m, 2 H, -OCH₂CH₂SePh), 3.67 (dd, J_2,3= 9.6,

J_1,2= 3.2 Hz, 1 H, H-2), 3.79–3.97 (m, 3 H, OCH₂CH₂SePh, H-

69.3 (2ϫd, C-2 α, C-2 β), 70.5, 71.8 (2ϫt, -CH₂Ph α, -CH₂Ph β), 3), 4.04–4.21 (m, 3 H, H-6, H-6Ј, H-4), 4.64, 4.87 (ABq, J_AB

=

72.8, 73.3 (2ϫt, -OCH₂CH₂I α, -OCH₂CH₂I β), 70.5, 71.8, 75.3,

77.3, 77.9, 79.9 (6ϫd, C-3 α, C-3 β, C-4 α, C-4 β, C-5 α, C-5 β),

81.0, 81.3 (2ϫs, CCl₃α, CCl₃β) 93.7 (d, C-1 β), 97.6 (d, C-1 α),

127.7, 127.8, 127.9, 128.0, 128.3, 128.4 (6 C, 3ϫAr-CH α, 3ϫAr-

11.2 Hz, 2 H, -OCH₂Ph), 5.09 (at, J = 10 Hz, 1 H, H-5), 6.51 (d,

J_1,2= 3.6 Hz, 1 H, H-1), 7.23–7.48 (m, 10 H, Ar-CH), 8.60 (s,

1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): 20.6, 20.7 (2ϫq,

2ϫCOCH₃), 26.9 (t, -OCH₂CH₂SePh), 61.8 (t, C-6), 68.7 (d, C-5),

CH β), 138.1, 138.1 (Ar-C α, Ar-C β), 160.8, 160.9 (2ϫs, C=NH 70.4, 70.6 (2ϫt, CH₂Ph, -OCH₂CH₂SePh), 75.2 (d, C-3), 77.9 (d,

α, C=NH β), 169.5, 169.5, 170.6, 170.6 (4ϫs, 4C, 2 ϫCH₃CO α,

2ϫCH₃CO β) ppm. HRMS (ES⁺): calcd. for C₂₁H₂₅NO₈Cl₃INa

[M + Na⁺] 673.9588; found 673.9589.

C-4), 93.07 (d, C-1), 127.1, 127.7, 127.9, 128.3, 129.1, 129.7, 132.7,

138.2 (8 C, 12 ϫ Ar-C), 161.0 (s, C=NH), 169.5, 170.6 (2 ϫ s,

2 ϫ COCH₃) ppm. HRMS (ES⁺): calcd. for C₂₇H₃₀O₈NCl₃SeNa

[M + Na⁺] 704.0100; found 704.0098.

3-O-Benzyl-4,6-di-O-acetyl-2-O-[2-(phenylselenyl)ethyl]-α/β-D-

glucopyranose (35): Selenophenol (0.140 mL, 1.30 mmol) was

3-O-Benzyl-4,6-O-benzylidene-2-O-(2-hydroxyethyl)-α/β-

D-gluco-

added to a stirred suspension of sodium hydride (60% dispersion

pyranose (37): A solution of PMP glycoside 31 (0.200 g,

in mineral oil, 0.016 g, 0.650 mmol) in THF (5 mL). After 30 min, 0.400 mmol) in CH₂Cl₂/MeOH (9 mL, 2:1) was treated with ozone

iodide 33 (0.240 g, 0.470 mmol) was added as a solution in THF

(5 mL), and the reaction was then heated to reflux. After 16 h, TLC

(toluene/ethyl acetate, 2:1) indicated the formation of a single

major product (R_f0.55) and the complete consumption of starting

material (R_f0.50). The reaction was cooled and diluted with

at –78 °C until the solution turned blue. The reaction was quenched

by the addition of NaBH₄(27 mg, 0.72 mmol) in small portions

over 10 min. At this point TLC (CH₂Cl₂/MeOH, 195:5) showed the

formation of a major product (R_f0.4) and complete disappearance

of starting material (R_f0.95). The reaction mixture was warmed to

CH₂Cl₂(20 mL) and washed with water (20 mL). The aqueous room temp. and then concentrated in vacuo. The residue was dis-

layer was then extracted with CH₂Cl₂(2ϫ20 mL) and the com-

bined organic extracts were washed with saturated aq. sodium hy-

drogen carbonate solution (20 mL) and brine (20 mL). The organic

phase was dried (MgSO₄), filtered, and concentrated in vacuo. The

resulting residue was purified by flash column chromatography (pe-

troleum ether/ethyl acetate, 4:1) to afford selenide 35 (0.190 g, 75%)

solved in ethyl acetate (20 mL), then washed with saturated sodium

hydrogen carbonate solution (2 ϫ 5 mL), brine (5 mL), dried

(MgSO₄), filtered, and concentrated in vacuo. Purification by flash

column chromatography (CH₂Cl₂/MeOH, 97:3) followed by

recrystallization (petroleum ether/ethyl acetate) yielded diol 37

(0.117 g, 73%) as white crystalline solid, m.p. 148–151 °C (petro-

as colourless oil. IR (KBr): ν = 1740 (s, C=O), 1672 (s, C=N) cm^–1.

leum ether/ethyl acetate). IR (KBr): ν

= 3400 (br., O–H) cm^–1.

max

˜

¹H NMR (400 MHz, CDCl₃) [1:1 mixture of α/β anomers ob-

¹H NMR (400 MHz, CDCl₃) [1:1.4 mixture of α/β anomers ob-

served]: δ = 1.90–2.09 (m, 12 H, 2ϫCOCH₃α, 2ϫCOCH₃β), served]: δ = 3.34 (at, J = 8 Hz, 1 H, H-2 β), 4.46 (m, 1 H,

3.03–3.08 (m, 4 H, OCH₂CH₂SePh α, OCH₂CH₂SePh β), 3.14 (br. -OCHHЈCH₂OH α), 3.58 (dd, J_2,3= 12, J_1,2= 3.6 Hz, 1 H, H-2

s, 1 H, -OH α/-OH β) 3.26 (at, J = 5.0 Hz, 1 H, H-2 β), 3.46–3.58

(m, 3 H, H-2 α, H-3 α, H-3 β), 3.48–3.58 (m, 4 H, H-4 α, H-4 β,

H-5 α, H-5 β), 3.80–4.23 (m, 12 H, OCH₂CH₂SePh α, OCH₂CH_2-

SePh β, H-6Ј α, H-6Ј β, H-6 α, H-6 β), 4.60–4.85 (m, 4 H, PhCH₂

α), 3.78–3.83 (m, 10 H, -OCH₂CH₂OH α, -OCH₂CH₂OH β,

-OCHHЈCH₂OH β, H-3 α, H-3 β, H-5 α, H-6 α, H-6 β), 3.84–3.93

(m, 2 H, -OCHHЈCH₂OH α, -OCHHЈCH₂OH β), 4.00 (at, J =

8 Hz, 1 H, H-4 α), 4.09 (m, 1 H, H-5 β), 4.29–4.36 (m, 2 H, H-6Ј

α, H-6Ј β), 4.73 (d, J_1,2= 8 Hz, 1 H, H-1 β), 4.77, 4.97 (ABq, J_AB

= 12 Hz, 4 H, CH₂Ph α, CH₂Ph β), 5.34 (d, J_1,2= 3.6 Hz, 1 H, H-

1 α), 5.57 (s, 1 H, CHPh β), 5.58 (s, 1 H, CHPh α), 7.26–7.48 (m,

20 H, 10ϫAr-CH α, 10ϫAr-CH β) ppm. ¹³C NMR (100 MHz,

CDCl₃): 62.2 (C-5 β), 62.3, 62.5 (-OCH₂CH₂OH α, -OCH₂CH₂OH

β), 66.2 (-OCH₂CH₂OH α), 68.7 (C-6 β), 69.0 (C-6 α), 73.0 (C-5

α), 74.5 (-OCH₂CH₂OH β), 75.0, 75.2 (-CH₂Ph α, -CH₂Ph β), 77.8

α, PhCH₂β), 4.97 (at, J = 9.2 Hz, 1 H, H-1 β), 5.29 (d, J_1,2

=

3.3 Hz, 1 H, H-1 α), 7.26–7.49 (m, 20 H, 10ϫAr-CH α, 10ϫAr-

CH β) ppm. ¹³C NMR (100 MHz, CDCl₃): 20.7, 20.7, 20.7, 20.7

(4ϫq, 2ϫCOCH₃α, 2ϫCOCH₃β), 27.3, 27.6 (2ϫt, OCH₂CH_2-

SePh α, OCH₂CH₂SePh β), 62.2, 62.4 (2ϫt, C-6 α, C-6 β), 68.0,

69.4 (2 ϫ t, C-5 α, C-5 β), 69.6, 70.7 (2 ϫ t, OCH₂CH₂SePh α,

OCH₂CH₂SePh β), 72.0, 72.1 (2ϫt, CH₂Ph α, CH₂Ph β), 75.2,

75.3, 78.6, 80.7, 81.4, 83.5 (6ϫd, C-2 α, C-2 β, C-3 α, C-3 β, C-4 (C-4 α), 80.5, 80.8 (C-3 α, C-3 β), 81.8 (C-4 β), 82.2, 83.4 (C-2 α,

α, C-4 β), 91.1 (d, C-1 β), 97.2 (d, C-1 α), 127.1, 127.2, 127.3, 127.5,

C-2 β), 91.7 (C-1 α), 97.4 (C-1 β), 101.2, 101.3 (-CHPh α, -CHPh

β), 126.0–134.5 (16 C, 8ϫAr-CH α, 8ϫAr-CH β) ppm. HRMS

127.6, 127.7, 127.8, 127.9, 128.4, 129.1, 129.2, 129.3, 132.6, 132.8,

138.2, 138.3 (16 ϫ Ar-C), 169.5, 169.6, 170.8, 170.8 (4C, (ES⁺): calcd. for C₂₂H₂₆O₇Na [M + Na⁺] 425.1576; found

2 ϫ CH₃CO α, 2 ϫ CH₃CO β) ppm. HRMS (ES⁺): calcd. for

425.1575.

C₂₅H₃₀O₈NaSe [M + Na⁺] 561.1000; found 561.0998.

3-O-Benzyl-4,6-O-benzylidene-2-O-(2-iodoethyl)-α/β-D-glucopyr-

3-{O-Benzyl-4,6-diacetyl-2-O-[2-(phenylselenyl)ethyl]-α/β-

D

-

anose (38): Diol 37 (0.214 g, 0.500 mmol) was stirred in THF

glucopyranosyl} Trichloroacetimidate (36): Hemiacetal 35 (0.190 g, (10 mL) under a nitrogen atmosphere. I₂(0.191 g, 0.760 mmol),

0.353 mmol) was dissolved in distilled CH₂Cl₂(10 mL) and stirred

under a nitrogen atmosphere. The solution was cooled to 0 °C, and

imidazole (0.051 g, 0.760 mmol) and PPh₃(0.200 g, 0.760 mmol)

were added. The reaction mixture was then heated to reflux. After

DBU (0.018 mL, 0.118 mmol) and trichloroacetonitrile (0.354 mL, 24 h, TLC (petroleum ether/ethyl acetate, 2:1) indicated the forma-

3.53 mmol) were added sequentially. After 8 h, TLC (petroleum

ether/ethyl acetate, 2:1, with 1% TEA) indicated the formation of

a major product (R_f0.7) and the complete consumption of starting

tion of a major product (R_f0.3), and complete consumption of

starting material (R_f0.1). The reaction was then cooled to room

temp. and concentrated in vacuo. The resulting residue was purified

Eur. J. Org. Chem. 0000, 0–0

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

FULL PAPER

by flash chromatography (petroleum ether/ethyl acetate, 5:1) to af-

ford iodide 38 (0.112 g, 39%) as white crystalline solid, m.p. 179–

182 °C. ¹H NMR (400 MHz, CDCl₃) [1:1.6 mixture of α/β anomers

resulting residue was purified by flash column chromatography (pe-

troleum ether/ethyl acetate, 4:1) to afford selenide 40 (0.210 g, 66%)

as a white crystalline solid, m.p. 128–130 °C (petroleum ether/ethyl

observed]: δ = 3.08 (br. s, 1 H, -OH α), 3.27 (m, 7 H, -OH β, H-2 acetate). ¹H NMR (400 MHz, CDCl₃) [1.4:1 mixture of α/β ano-

α, H-2 β, H-3 α, H-3 β, H-4 α, H-4 β), 3.50 (m, 1 H, H-5 α), 3.69

mers observed]: δ = 3.05–3.08 (m, 4 H, OCH₂CH₂SePh α,

(m, 6 H, H-5 β, -OCH₂CH₂I α, -OCH₂CH₂I β, -OCHHЈCH₂I α), OCH₂CH₂SePh β), 3.22 (at, J = 5.0 Hz, 1 H, H-2 β), 3.39–3.44 (m,

3.82–4. 17 (m, 5 H, -OCHHЈ CH₂I β, -O CHHЈ CH₂I α, 4 H, H-2 α, H-3 α, H-3 β), 3.49–3.97 (m, 8 H, H-4 α, H-4 β, H-5

-OCHHЈCH₂I β, H-6Ј α, H-6Ј β), 3.35 (m, 2 H, -OCHHЈCH₂- α, H-5 β, H-6Ј α, H-6Ј β), 4.02–5.00 (m, 4 H, OCH₂CH₂SePh α,

OH α, -OCHHЈCH₂OH β), 4.48 (d, J_1,2= 8 Hz, 1 H, H-1 β), 4.81, OCH₂CH₂SePh β), 4.29–4.36 (m, 2 H, H-6 α, H-6 β), 4.74–4.92

4.96 (ABq, J_AB= 12 Hz, 4 H, CH₂Ph α, CH₂Ph β), 5.36 (d, J_1,2

=

(m, 5 H, PhCH₂α, PhCH₂β, H-1 β), 4.26 (d, J_1,2= 3.3 Hz, 1 H,

3.6 Hz, 1 H, H-1 α), 5.58 (s, 2 H, CHPh α, CHPh β), 7.27–7.50 (m, H-1 α), 7.26–7.49 (m, 30 H, 15ϫAr-CH α, 15ϫAr-CH β) ppm.

20 H, 10ϫAr-CH α, 10ϫAr-CH β) ppm. ¹³C NMR (100 MHz, ¹³C NMR (100 MHz, CDCl₃): 27.4, 27.9 (2ϫt, OCH₂CH₂SePh α,

CDCl₃): 3.2, 3.6 (-OCH₂CH₂I α, -OCH₂CH₂I β), 62.5, 66.3 (C-6

α, C-6 β), 68.6, 69.0 (-OCH₂CH₂I α, -OCH₂CH₂I β), 72.5, 73.5 (C-

5 α, C-5 β), 75.1, 75.2 (-CH₂Ph α, -CH₂Ph β), 78.1 (C-4 α), 80.5,

80.6 (C-3 α, C-3 β), 81.6 (C-4 β), 82.0, 83.6 (C-2 α, C-2 β), 92.1

(C-1 α), 97.4 (C-1 β), 101.2, 101.3 (-CHPh α, -CHPh β), 126.0–

138.5 (16 C, 8ϫAr-CH α, 8ϫAr-CH β) ppm. HRMS (ES⁺): calcd.

for C₂₂H₂₅O₆NaI [M + Na⁺] 535.0590; found 535.0594.

OCH₂CH₂SePh β), 62.5, 66.4 (2ϫd, C-5 α, C-5 β), 68.7, 69.0 (2ϫt,

C-6 α, C-6 β), 71.2, 72.4 (2ϫt, OCH₂CH₂SePh α, OCH₂CH₂SePh

β), 75.0, 75.1 (2ϫt, CH₂Ph α, CH₂Ph β), 78.1, 80.5, 80.7, 81.5,

81.8, 83.8 (6ϫd, C-2 α, C-2 β, C-3 α, C-3 β, C-4 α, C-4 β), 91.9

(d, C-1 α), 97.5 (d, C-1 β), 101.2, 101.3 (2ϫd, CHPh α, CHPh β),

126.0–132.8 (24ϫAr-C) ppm. HRMS (ES⁺): calcd. for C₂₈H₃₀O_6-

SeNa [M + Na⁺] 565.1105; found 565.1105.

3-[O-Benzyl-4,6-O-benzylidene-2-O-(2-iodoethyl)-α/β-

D

-glucopyr-

3-{O-Benzyl-4,6-O-benzylidene-2-O-[2-(phenylselenyl)ethyl]-α/β-D-

anosyl] Trichloroacetimidate (39): Hemiacetal 38 (0.091 g,

0.178 mmol) was dissolved in distilled CH₂Cl₂(3 mL) under a ni-

trogen atmosphere and stirred a 0 °C. DBU (0.011 mL,

0.071 mmol) and trichloroacetonitrile (0.182 mL, 1.78 mmol) were

glucopyranosyl} Trichloroacetimidate (41): Hemiacetal 40 (0.060 g,

0.111 mmol) was dissolved in distilled CH₂Cl₂(2.5 mL) under a

nitrogen atmosphere. The stirred solution was cooled to 0 °C, and

to it were added sequentially DBU (0.005 mL, 0.044 mmol) and

sequentially. After 8 h, TLC (petroleum ether/ethyl acetate, 3:1, trichloroacetonitrile (0.143 mL, 1.11 mmol). After 8 h, TLC (petro-

with 1% TEA) indicated the formation of a major product (R_f

0.4) and complete consumption of starting material (R_f0.2). The

reaction was warmed to room temp. and concentrated in vacuo.

The resulting residue was purified by flash chromatography (petro-

leum ether/ethyl acetate, 7:1, with 1% TEA) to afford trichloroacet-

leum ether/ethyl acetate, 3:1, with 1% TEA) indicated formation

of a major product (R_f0.5) and complete consumption of starting

material (R_f0.2). The reaction was warmed to room temp. and

concentrated in vacuo. The resulting residue was purified by flash

chromatography (petroleum ether/ethyl acetate, 8:1, with 1% TEA)

to afford trichloroacetimidate 41 (0.072 g, 92%) as colourless oil.

imidate 39 (0.112 g, 96%) as colourless oil. IR (KBr): ν

= 3451

˜

max

(w, N–H), 1674 (s, C=N) cm^–1. ¹H NMR (400 MHz, CDCl₃) [3.5:1

IR (KBr): ν

= 3350 (w, N–H), 1673 (s, C=N) cm^–1. ¹H NMR

˜

max

mixture of α/β anomers observed]: δ = 3.15 (m, 4 H, -OCH₂CH₂I

(400 MHz, CDCl₃) [1.6:1 mixture of α/β anomers observed]: δ =

α, -OCH₂CH₂I β), 3.56–3.87 (m, 6 H, H-3 α, H-3 β, -OCH₂CH₂I 2.99–3.04 (m, 5 H, -OCH₂CH₂SePh α, OCH₂CH₂SePh β, H-5 α/

α, - OCH₂CH₂I β), 3.89–4.09 (m, 8 H, H-2 α, H-2 β, H-4 α, H-4 β), 3.49–3.79 (m, 7 H, H-2 α, H-2 β, H-3 α, H-3 β, H-4 α, H-4 β,

β, H-5 α, H-5 β, H-6Ј α, H-6Ј β), 4.32–4.36 (dd, J_6,6Ј= 10.4, J_6,5

=

H-5 α/β), 3.84–3.92 (m, 2 H, OCH₂CH₂SePh α/β), 3.94–4.08 (m, 4

H, OCH₂CH₂SePh α/β, H6Ј α, H-6Ј β), 4.33 (dd, J_6,6Ј= 10.4, J_6,5

= 5.4 Hz, 1 H, H-6 α), 4.38 (dd, J_6,6Ј= 10.4, J_6,5= 5.4 Hz, 1 H,

H-6 β), 4.79–4.93 (m, 4 H, CH₂Ph α, CH₂Ph β), 5.56 (s, 1 H, CHPh

4.8 Hz, 1 H, H-6 α), 4.38–4.42 (dd, J_6,6Ј= 10.4, J_6,5= 4.8 Hz, 1 H,

H-6 β), 4.85, 4.93 (ABq, J_AB= 12 Hz, 4 H, CH₂Ph α, CH₂Ph β),

5.57 (s, 1 H, CHPh β), 5.59 (s, 1 H, CHPh α), 5.84 (d, J_1,2= 7.8 Hz,

1 H, H-1 β), 6.51 (d, J_1,2= 3.6 Hz, 1 H, H-1 α), 7.26–7.51 (m, 20 β), 5.58 (s, 1 H, CHPh α), 5.80 (d, J_1,2= 7.8 Hz, 1 H, H-1 β), 6.48

H, 10ϫAr-CH α, 10ϫAr-CH β), 8.62 (s, 1 H, NH α), 8.73 (s, 1 (d, J_1,2= 4.0 Hz, 1 H, H-1 α), 7.26–7.51 (m, 30 H, 15ϫAr-CH α,

H, NH β) ppm. ¹³C (100 MHz, CDCl₃): 2.3, 2.4 (-OCH₂CH₂I α, 15ϫAr-CH β), 8.57 (s, 1 H, NH α), 8.69 (s, 1 H, NH β) ppm. ¹³C

-OCH₂CH₂I β), 65.1, 66.6 (C-6 α, C-6 β), 68.5, 68.7 (-OCH₂CH₂I

α, -OCH₂CH₂I β), 72.4, 74.0 (C-5 α, C-5 β), 75.1, 75.2 (-CH₂Ph

NMR (100 MHz, CDCl₃): 26.7, 26.9 (-OCH₂CH₂SePh α,

-OCH₂CH₂SePh β), 65.1, 66.6 (C-6 α, C-6 β), 68.6, 68.7

α, -CH₂Ph β), 77.3, 77.7, 79.6, 80.5, 81.1 (C-2 α, C-2 β, C-3 α, C- (-OCH₂CH₂SePh α, -OCH₂CH₂SePh β), 71.2, 72.8 (C-5 α, C-5 β),

3 β, C-4 α, C-4 β), 81.2, 81.4 (CCl₃α, CCl₃β), 94.6 (C-1 α), 97.9 75.0, 75.2 (-CH₂Ph α, -CH₂Ph β), 77.7, 79.7, 80.6, 81.0, 81.1, 81.3

(C-1 β), 101.3, 101.3 (-CHPh α, -CHPh β), 125.9–138.4 (16 C, (C-2 α, C-2 β, C-3 α, C-3 β, C-4 α, C-4 β), 94.5, 94.5 (CCl₃α, CCl₃

8ϫAr-CH α, 8ϫAr-CH β), 161.3 (C=NH). HRMS (ES⁺): calcd.

β), 98.0, 98.0 (C-1 α, C-1 β), 101.3, 101.3 (-CHPh α, -CHPh β),

125.9–138.4 (24 C, 12 ϫAr-CH α, 12 ϫAr-CH β), 161.0, 161.2

( C = N H α , C = N H β ) p p m . H R M S ( E S ⁺) : c a l c d . f o r

C₃₀H₃₀O₆NCl₃SeNa [M + Na⁺] 708.0192; found 708.0198.

for C₂₄H₂₅NO₆Cl₃INa [M + Na⁺] 677.9684; found 677.9694.

3-O-Benzyl-4,6-O-benzylidene-2-O-[2-(phenylselenyl)ethyl]-α/β-D-

glucopyranose (40): Selenophenol (0.120 mL, 1.15 mmol) was

added to a stirred suspension of sodium hydride (60% dispersion

in mineral oil, 0.018 g, 0.750 mmol) in THF (5 mL). After 30 min,

iodide 38 (0.300 g, 0.590 mmol) was added as a solution in THF

(5 mL), and the reaction mixture was then heated to reflux. After

16 h, TLC (toluene/ethyl acetate, 2:1) indicated the formation of

a single product (R_f0.65), and complete consumption of starting

material (R_f0.60). The reaction mixture was cooled, diluted with

CH₂Cl₂(20 mL), and washed with water (20 mL). The aqueous

layer was then extracted with CH₂Cl₂(2ϫ20 mL), and the com-

bined organic extracts were washed with saturated aq. sodium hy-

drogen carbonate solution (20 mL) and brine (20 mL). The organic

phase was dried (MgSO₄), filtered, and concentrated in vacuo. The

3,4,6-Tri-O-acetyl-2-O-(2-iodoethyl)-α/β-

1:2,3:4-di-O-isopropylidene- -galactopyranoside (42): General

Method B gave disaccharide 42 as a colourless oil (67 mg, 76%

D-glucopyranosyl-(1Ǟ6)-

D

1

yield). ν

= (neat) 1751 (s, C=O). H NMR (400 MHz, CDCl₃)

˜

max

[mixture of α:β anomers observed]: δ = 1.32 [3ϫs, 9 H, (C)CH₃],

1.33 [2ϫs, 6 H, (C)CH₃], 1.43 [s, 3 H, (C)CH₃], 1.45 [s, 3 H, (C)

CH₃], 1.51 [s, 3 H, (C)CH₃], 2.01 [s, 3 H, C(O)CH₃], 2.02 [s, 3 H,

C(O)CH₃], 2.06 [s, 3 H, C(O)CH₃], 2.08 [s, 3 H, C(O)CH₃], 2.09

[2ϫs, 6 H, C(O)CH₃], 3.18–3.23 (m, 4 H, OCH₂CH₂I), 3.32 (dd,

J = 9.6 8.4 Hz, 1 H, H-2_bβ), 3.54 (dd, J = 9.6 3.6 Hz, 1 H, H-2_bα),

3.62–3.84 (m, 6 H, 2ϫOCH₂CH₂I, H-5_bα, H-5_bβ, H-6_aα and H-

6_aβ), 3.87–3.93 (m, 1 H, OCH₂CH₂I), 3.98–4.10 (m, 6 H, H-5_aα,

16

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42260

/KAP1

Date: 11-06-14 17:48:50

Pages: 20

Neighbouring Group Participation During Glycosylation

1

H-5_aβ, H-6Ј_aα, H-6Ј_aβ, H-6_bα, H-6_bβ), 4.16–4.21 (m, 3 H, OCH_2-

CH₂I, H-2_aα and H-2_aβ), 4.26–4.33 (m, 4 H, H-4_aα, H-4_aβ, H-6Ј_bα

oil. H NMR (400 MHz, [D₆]DMSO) [1:2 mixture of α/β anomers

observed]: = 1.25–1.44 (m, 24 H, 4ϫCH₃α, 4ϫCH₃β), 1.91–1.96

and H-6Ј_bβ), 4.48 (d, J = 7.6 Hz, 1 H, H-1_bβ), 4.59–4.63 (m, 2 H, (m, 12 H, 2ϫCOCH₃α, 2ϫCOCH₃β), 3.20–3.29 (m, 5 H, OCH_2-

H-3_aα and H-3_aβ), 4.97–5.03 (m, 2 H, H-4_bα and H-4_bβ), 5.04 (d, CH₂I α, OCH₂CH₂I β, H-5_bα/β), 3.49–3.94 (m, 14 H, H-2_aα, H-

J = 1.2 Hz, 1 H, H-1_bα), 5.14 (at, J = 9.6 9.2 Hz, 1 H, H-3_bβ), 5.39 2_aβ, H-3_aα, H-3_aβ, H-4_aα, H-4_aβ, H-3_bα, H-3_bβ, H-5_bα/β, H-

(at, J = 10.0 9.6 Hz, 1 H, H-3_bα), 5.50–5.52 (m, 2 H, H-1_aα and

H-1_aβ) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 2.6 (t, OCH_2-

CH₂I), 3.9 (t, OCH₂CH₂I), 20.8 [q, C(O)CH₃], 20.8 [q, C(O)CH₃],

20.9 [2ϫq, C(O)CH₃], 21.2 [q, C(O)CH₃], 21.3 [q, C(O)CH₃], 24.5

6_bα, H-6_bβ, H-6Ј_bα, H-6Ј_bβ, -OCHHЈCH₂I α/β), 4.03–4.09 (m,

3 H, -OCHHЈCH₂I α, -OCHHЈCH₂I β, -OCHHЈCH₂I α/β), 4.20–

4.33 (m, 4 H, H-5_aα, H-5_aβ, H-4_bα, H-4_bβ), 4.33–4.47 (m, 4 H,

H-6_aα, H-6_aβ, H-6Ј_aα, H-6Ј_aβ), 4.51 (d, 1 H, J_1,28 Hz, H-1_aβ),

[q, (C)CH₃], 24.9 [q, (C)CH₃], 25.1 [q, (C)CH₃], 25.1 [q, (C)CH₃], 4.55–4.82 (m, 6 H, CH₂Ph α, CH₂Ph β, H-2_bα, H-2_bβ), 5.01 (d,

26.1 [q, (C)CH₃], 26.2 [q, (C)CH₃], 26.3 [q, (C)CH₃], 26.3 [q, (C)- 1 H, J_1,2= 3.5 Hz, H-1_aα), 5.43 (d, 2 H, J_1,2= 4.8 Hz, H-1_bα, H-1_b

CH₃], 62.1 (t, C-6_bα), 62.2 (t, C-6_bβ), 67.5 (d, C-5_aα), 67.5 (d, C- β), 7.25–7.33 (m, 10 H, 5ϫAr-CHα, 5ϫAr-CHβ) ppm. ¹³C NMR

5_aβ), 67.7 (t, OCH₂CH₂I), 68.7 (d, C-4_bα), 68.7 (d, C-4_bβ), 70.5 (d,

(100 MHz, [D₆]DMSO): δ = 5.7, 5.8 (2ϫt, OCH₂CH₂I α, OCH_2-

C-4_aα), 70.6 (d, C-4_aβ), 70.7 (t, C-6_aα), 70.8 (t, C-6_aβ), 70.9 (d, C- CH₂I β), 20.9, 20.9, 21.0, 21.0 (4ϫq, 2ϫCOCH₃α, 2ϫCOCH₃

3_aα), 71.0 (d, C-3_aβ), 71.4 (d, C-2_aα), 71.5 (d, C-2_aβ), 71.7 (2ϫd,

C-5_bβ and C-5_bα), 71.7 (d, C-3_bα), 73.1 (t, OCH₂CH₂I), 73.7 (d,

β), 24.6, 24.7, 24.8, 25.1, 25.2, 25.3, 26.3, 26.4 (4ϫq, CH₃α, 4ϫq,

CH₃β), 62.4, 62.5 (2ϫt, C-6_bα, C-6_bβ), 66.2, 66.5 (2ϫt, C-6_aα,

C-3_bβ), 78.1 (d, C-2_bα), 79.6 (d, C-2_bβ), 96.4 (d, C-1_aβ), 96.5 (d, C-6_aβ), 67.3, 67.4 (2ϫt, OCH₂CH₂I α, OCH₂CH₂I β), 69.7, 69.8

C-1_aα), 97.2 (d, C-1_bα), 104.0 (d, C-1_bβ), 108.8 [s, (C)CH₃], 108.9 (2ϫt, ArCH₂α, ArCH₂β), 70.1, 70.2, 70.3, 70.4, 70.5, 70.6, 70.8,

[s, (C)CH₃], 109.4 [s, (C)CH₃], 109.6 [s, (C)CH₃], 169.9 (s, C=O), 70.9, 71.0, 72.8, 74.6, 74.8, 78.5, 79.8, 80.9, 82.1 (16ϫd, C-2_aα,

170.0 (s, C=O), 170.2 (s, C=O), 170.3 (s, C=O), 170.8 (s, C=O),

C-3_aα, C-4_aα, C-5_aα, C-2_aβ, C-3_aβ, C-4_aβ, C-5_aβ, C-2_bα, C-

170.9 (s, C=O) ppm. HRMS (ESI-TOF): calcd. for C₂₆H₃₉IO₁₄H⁺3_bα, C-4_bα, C-5_bα, C-2_bβ, C-3_bβ, C-4_bβ, C-5_bβ), 96.1, 96.1 (2

[M + H⁺] 703.1457; found 703.1463 and 725.1285 [M + Na⁺].

3,4,6-Tri-O-acetyl-2-O-[2-(phenylselenyl)ethyl]-α/β- -glucopyranos-

yl-(1Ǟ6)-1:2,3:4-di-O-isopropylidene- -galactopyranoside (43): Ge-

neral Method B gave disaccharide 43 as a yellow oil (69 mg, 75%

X d, C-1_bα, C-1_bβ) 96.6 (d, C-1_aβ), 98.0 (d, C-1_aα), 108.2, 108.3,

108.7, 108.8 [4ϫs, C(CH₃)₂ϫ2 α, C(CH₃)₂ϫ2 β], 127.8, 127.9,

128.1, 128.2, 128.5, 128.6 (6ϫd, Ar-CH), 138.9, 139.0 (2ϫs, Ar-

C), 169.8, 169.8, 170.5, 170.5 (4ϫs, 4 C, 2ϫCH₃CO α, 2ϫCH₃CO

β) ppm. HRMS (ES⁺): calcd. for C₃₄H₄₃O₁₁INa [M + Na⁺]

777.1748; found 777.1752.

D

1

yield). ν

= (neat) 1749 (s, C=O). H NMR (400 MHz, CDCl₃)

˜

max

[ mix t ure of α: β a no m er s o bs e r ve d] : δ = 1 . 2 9 [s, 3 H,

(C)CH₃], 1.30 [s, 3 H, (C)CH₃], 1.32 [s, 3 H, (C)CH₃], 1.33 [s, 3 H,

(C)CH₃], 1.42 [s, 3 H, (C)CH₃], 1.44 [s, 3 H, (C)CH₃], 1.48 [s, 3 H,

3-O-Benzyl-4,6-diacetyl-2-O-[2-(phenylselenyl)ethyl]-α/β-

D-gluco-

pyranosyl-(1Ǟ6)-1:2,3:4-di-O-isopropylidene- -galactopyranoside

D

(C)CH₃], 1.56 [s, 3 H, (C)CH₃], 2.00 [s, 3 H, C(O)CH₃], 2.00 [s, 3 (45): General Method B gave disaccharide 45 (0.140 g, 94%) as a

H, C(O)CH₃], 2.01 [s, 3 H, C(O)CH₃], 2.03 [s, 3 H, C(O)CH₃], 2.07

colourless oil. ¹H NMR (400 MHz, CD₃CN) [1:4 mixture of α/β

[s, 3 H, C(O)CH₃], 2.08 [s, 3 H, C(O)CH₃], 2.94–3.07 (m, 4 H, anomers observed]: δ = 1.32–1.53 (m, 24 H, 4ϫCH₃α, 4ϫCH₃

OCH₂CH₂SePh), 3.30 (dd, J = 9.2 7.6 Hz, 1 H, H-2_bβ), 3.49 (dd, β), 1.96–2.03 (m, 12 H, 2ϫCOCH₃α, 2ϫCOCH₃β), 3.10–3.14

J = 10 3.6 Hz, 1 H, H-2_bα), 3.62–3.90 (m, 8 H, 3ϫOCH₂CH₂SePh,

H-5_aα, H-5_aβ, H-5_bβ, H-6_aα and H-6_aβ), 3.98–4.11 (m, 7 H, H-5_aα, 2 H, H-2_aα, H-2_aβ), 3.93 (m, 10 H, H-5_bα, H-5_bβ, H-6_aα, H-6_a

H-5_aβ, H-5_bα, H-6Ј_aα, H-6Ј_aβ, H-6_bα, H-6_bβ), 4.15–4.21 (m, 3 H, β, H-6Ј_aα, H-6Ј_aβ, H-6_bα, H-6_bβ, H-6Ј_bα, H-6Ј_bβ), 3.91–4.02

OCH₂CH₂SePh, H-4_aα and H-4_aβ), 4.25–4.32 (m, 4 H, H-2_aα and (m, 7 H, -OCH₂CH₂SePh α/β, H-3_aα, H-3_aβ, H-4_aα, H-4_aβ),

H-2_aβ, H-6Ј_bα, H-6Ј_bβ), 4.47 (d, J = 7.6 Hz, 1 H, H-1_bβ), 4.57– 4.21–4.40 (m, 5 H, -OCH₂CH₂SePh α/β, H-5_aβ, H-5_aβ), 4.41–4.62

4.61 (m, 2 H, H-3_aα and H-3_aβ), 4.96–5.01 (m, 2 H, H-4_bα and H- (m, 2 H, H-2_bα, H-2_bβ), 4.71–4.78 (m, 2 H, H-3_bα, H-3_bβ), 4.45

4_bβ), 5.02 (d, J = 3.6 Hz, 1 H, H-1_bα), 5.10 (at, J = 9.6 9.2 Hz, 1 (d, J_1,2= 8 Hz, 1 H, H-1_aβ), 4.58–4.89 (m, 8 H, CH₂Ph α, CH₂Ph

H, H-3_bβ), 5.36 (at, J = 9.6 Hz, 1 H, H-3_bα), 5.49–5.51 (m, 2 H, β, H-4_bα, H-4_bβ, H-5_bα, H-5_bβ), 5.03 (d, J_1,2= 3.5 Hz, 1 H, H-

(m, 4 H, OCH₂CH₂SePh α, OCH₂CH₂SePh β), 3.24 (at, J = 6.8 Hz,

H-1_aα and H-1_aβ), 7.23–7.26 (m, 6 H, ArH), 7.46–7.50 (m, 4 H,

ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.8 [q, C(O)CH₃],

20.8 [q, C(O)CH₃], 20.9 [q, C(O)CH₃], 21.0 [q, C(O)CH₃], 24.5 [q,

1_aα), 5.49 (d, J_1,2= 4 Hz, 2 H, H-1_bα, H-1_bβ), 7.27–7.53 (m, 20 H,

10ϫAr-CHα, 10ϫAr-CHβ) ppm. ¹³C NMR (100 MHz, CD₃CN):

19.9, 19.9, 20.1, 21.1 (4ϫq, 2ϫCOCH₃α, 2ϫCOCH₃β), 23.7,

(C)CH₃], 24.7 [q, (C)CH₃], 25.1 [q, (C)CH₃], 25.1 [q, (C)CH₃], 26.1 23.8 (2ϫt, OCH₂CH₂SePh α, OCH₂CH₂SePh β), 24.2, 24.3, 24.4,

[q, (C)CH₃], 26.1 [q, (C)CH₃], 26.2 [q, (C)CH₃], 26.3 [q, (C)CH₃], 25.3, 25.3, 25.4, 25.4, 26.7 (8ϫq, 4ϫCH₃α, 4ϫCH₃β), 62.2, 62.2

27.0 (t, OCH₂CH₂SePh), 27.3 (t, OCH₂CH₂SePh), 62.1 (t, C-6_bα),

62.2 (t, C-6_bβ), 66.3 (d, C-5_bα), 67.4 (d, C-5_aα), 67.6 (d, C-5_aβ),

(2ϫt, OCH₂CH₂SePh α, OCH₂CH₂SePh β), 66.3, 66.8, 67.3, 67.5

(4ϫt, C-6_aα, C-6_aβ, C-6_bα, C-6_bβ), 69.4, 69.7 (2ϫd, C-2_bα, C-

68.1 (t, OCH₂CH₂SePh), 68.7 (d, C-4_bα), 68.7 (d, C-4_bβ), 70.3 (t, 2_bβ), 70.3, 70.4, 70.5, 70.6, 70.7, 70.9, 71.0, 71.3, 71.4, 71.8 (8ϫd,

C-6_aα), 70.5 (t, C-6_aβ), 70.7 (d, C-2_aα), 70.7 (d, C-2_aβ), 70.9 (d, C-

3_aβ), 70.9 (d, C-3_aα), 71.5 (2ϫd, C-4_aα and C-4_aβ), 71.7 (d, C-

C-3_aα, C-4_aα, C-5_aα, C-3_aβ, C-4_aβ, C-5_aβ, C-3_bα, C-4_bα, C-

3_bβ, C-4_bβ), 74.7, 74.9 (2ϫt, ArCH₂α, ArCH₂β), 80.3, 81.2

5_bβ), 71.9 (d, C-3_bα), 72.1 (t, OCH₂CH₂SePh), 73.9 (d, C-3_bβ), 78.1 (2ϫd, C-2_aα, C-2_aβ), 78.4, 82.2 (2ϫd, C-5_bα, C-5_bβ), 96.2 (d,

(d, C-2_bα), 79.7 (d, C-2_bβ), 96.4 (d, C-1_aα), 96.4 (d, C-1_aβ), 97.2 C-1_aβ), 96.5 (d, C-1_aα), 103.7, 103.7 (2ϫd, C-1_bα, C-1_bβ), 108.4,

(d, C-1_bα), 104.0 (d, C-1_bβ), 108.8 [s, (C)CH₃], 108.9 [s, (C)CH₃],

109.4 [s, (C)CH₃], 109.6 [s, (C)CH₃], 126.9, 127.3, 129.2, 129.3,

129.7, 130.4, 132.5, 132.9 (8 ϫ ArC), 169.9 (s, C=O), 170.0 (s,

C=O), 170.3 (s, C=O), 170.3 (s, C=O), 170.8 (s, C=O), 170.9 (s,

C=O) ppm. HRMS (ESI-TOF): calcd. for C₃₂H₄₄O₁₄SeH⁺[M +

H⁺] 733.1972; found 733.1972 and 755.1797 [M + Na⁺].

108.4, 108.9, 108.9 [4ϫs, C(CH₃)₂ϫ2 α, C(CH₃)₂ϫ2 β], 126.6–

131.7 (12ϫ d, Ar-CH), 131.8, 131.9, 138.7, 138.9 (4ϫ s, Ar-C),

169.6, 169.6, 170.3, 170.3 (4 C, 2ϫCH₃CO α, 2ϫCH₃CO β) ppm.

HRMS (ES⁺): calcd. for C₃₇H₄₈O₁₃SeNa [M + Na⁺] 803.2156;

found 803.2168.

3-O-Benzyl-4,6-O-benzylidene-2-O-(2-iodoethyl)-α/β-

D-glucopyran-

3-O-Benzyl-4,6-O-benzylidene-2-O-(2-iodoethyl)-α/β-

D-glucopyra-

osyl-(1Ǟ6)-1:2,3:4-di-O-isopropylidene- -galactopyranoside (46):

D

n

o

s

-

General Method B gave disaccharide 46 (0.176 g, 77%) as a colour-

less oil; H NMR (400 MHz, CDCl₃) [1:2 mixture of α/β anomers

1

yl-(1Ǟ6)-1:2,3:4-di-O-isopropylidene-

D-galactopyranoside (44): Ge-

neral Method B gave disaccharide 44 (0.130 g, 81%) as a colourless

observed]: δ = 1.35, 1.37, 1.47, 1.56, 1.58, 1.61, 1.63 (8ϫs, 24 H,

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D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

FULL PAPER

4ϫCH₃α, 4ϫCH₃β), 3.27–3.34 (m, 5 H, OCH₂CH₂I α, OCH₂- (R_f0.4). The reaction was cooled to room temp. and then NIS

CH₂I β, H-5b α), 3.40 (m, 1 H, H-5bβ), 3.53 (m, 1 H, H-5a α), (0.381 mmol) and water (1 mL) were added and the reaction stirred

3.60–3.87 (m, 9 H, H-2a α, H-2a β, H-5a β, H-2b α, H-4 b α, H-4 for 16 h, after which TLC indicated the formation of a single prod-

b β, H-5b α, H-5b β, H-6Јa α/β), 3.93–4.09 (m, 9 H, H-2a α, H-2a

β, H-3a α, H-3a β, H-4a α, H-4b β, H-6b α, H-6b β, H-6Јa α/β),

uct (R_f0.2) The reaction was diluted with CH₂Cl₂(20 mL) and

washed with water (20 mL). The aqueous layer was then extracted

4.16–4.24 (m, 2 H, OCH₂CH₂I α/β), 4.33–4.47 (m, 4 H, OCH₂CH₂I with CH₂Cl₂(2ϫ20 mL) and the combined organic extracts were

α/β, H-6a α, H-6_aβ), 4.50 (d, J_1,2= 8 Hz, 1 H, H-1a β), 4.61 (m, washed with saturated sodium hydrogen carbonate (20 mL) then

2 H, H-6Јb α, H-6Ј b), 4.82–4.93 (m, 4 H, CH₂Ph α, CH₂Ph β), brine (20 mL). The organic phase was dried (MgSO₄), filtered, and

5.05 (d, J_1,2= 3.5 Hz, 1 H, H-1a α), 5.56 (s, 4 H, CHPh α, CHPh

β, H-1b α, H-1b β), 7.27–7.50 (m, 20 H, 10ϫAr-CHα, 10ϫAr-

CHβ) ppm. ¹³C NMR (100 MHz, CDCl₃): 3.8, 3.9 (OCH₂CH₂I α,

OCH₂CH₂I β), 24.5, 24.8, 24.9, 25.0, 25.9, 26.0, 26.1, 26.2 (4ϫq,

CH₃α, 4ϫq, CH₃β), 62.5, 65.7 (2ϫt, C-6a α, C-6a β), 66.0, 66.8,

concentrated in vacuo. The resulting residue was purified by flash

column chromatography (toluene/ethyl acetate, 6:1) to afford

alcohol 48 (0.137 g, 76%) as a colourless oil. These data are in

agreement with those reported in the literature. ¹H NMR

(400 MHz, CDCl₃) [5:1 mixture of α:β anomers observed, major α-

(2ϫt, C-6b α, C-6b β), 67.4, 68.7 (2ϫt, OCH₂CH₂I α, OCH₂CH₂I anomer quoted]: δ = 1.34, 1.35, 1.45, 1.54 (4ϫs, 12 H, 4ϫCH₃),

β), 69.0, 70.4 (2ϫt, ArCH₂α, ArCH₂β), 70.6, 70.7, 70.8, 70.9,

71.4, 72.0, 73.6, 75.2, 76.7, 77.3, 78.2, 80.4, 80.6, 81.4, 82.1, 82.5

(16ϫd, C-2a–C-5a α, C-2a–C-5a β, C-2b–C-5b α, C-2b–C-5b β),

96.4 (d, C-1a β), 98.0 (d, C-1a α), 101.1 (d, C-1b α), 101.3 (d, C-

1b β), 104.5, 104.5 (d, CHPh α, CHPh β), 108.7, 108.7, 109.4, 109.5

[s, C(CH₃)₂ϫ2 α, C(CH₃)₂ϫ2 β], 126.0, 126.5, 126.6, 127.2, 127.6,

3.63–3.79 (m, 6 H, H-2_b, H-3_b, H-4_b, H-6_b, H-6Ј_b, H-6_a), 3.85 (ddd,

J = 9.9, J = 3.0, J = 2.2 Hz, 1 H, H-5_b), 3.91 (m, 1 H, H-6Ј_a), 3.99–

4.01 (m, 1 H, H-5_a), 4.25 (dd, J = 7.9, J = 1.9 Hz, 1 H, H-4_a), 4.34

(dd, J_1,2= 4.9, J_2,3= 2.2 Hz, 1 H, H-2_a), 4.63 (dd, J_2,3= 2.2, J_3,4

= 7.8 Hz, 1 H, H-3_a), 4.49, 4.83 (ABq, J = 10.3 Hz, 2 H, PhCH₂),

4.50, 4.64 (ABq, J = 11.7 Hz, 2 H, PhCH₂), 4.93 (d, J_1,2= 3.2 Hz,

127.7, 127.9, 128.1, 128.2, 128.3, 128.4, 129.0 (12 ϫ d, Ar-CH), 1 H, H-1_b), 4.82, 4.98 (ABq, J = 10.7 Hz, 2 H, PhCH₂), 5.53 (d,

137.3, 137.4, 138.3, 138.6 (4ϫs, Ar-C) ppm. HRMS (ES⁺): calcd.

J_1,2= 4.9 Hz, 1 H, H-1_a), 7.12–7.41 (m, 15 H, 15ϫAr-H) ppm. MS

for C₃₄H₄₃O₁₁INa [M + Na⁺] 777.1748; found 777.1752.

(ES⁺): m/z = 715 [M + Na⁺] (100).

3-O-Benzyl-4,6-O-benzylidene-2-O-[2-(phenylselenyl)ethyl]-α/β-

glucopyranosyl-(1Ǟ6)-1:2,3:4-di-O-isopropylidene-

oside (47): General Method B gave disaccharide 47 (0.065 g, 93%)

D

-

Method 2: Disaccharide 11a (α:β ratio 3.5:1) (0.215 g, 0.254 mmol)

D

-galactopyran- was dissolved in freshly distilled THF (10 mL) under an atmo-

sphere of argon. KOtBu (0.5 mL, 1 m solution in THF) was added

as a colorless oil. H NMR (400 MHz, CDCl₃) [1:3 mixture of α/ and the reaction was heated at reflux for 3 h, after which TLC

1

β anomers observed]: δ = 1.34 (br. s, 12 H, 2ϫCH₃α, 2ϫCH₃β),

1.46, 1.47, 1.53, 1.55 (14ϫs, 12 H, 2ϫCH₃α, 2ϫCH₃β), 3.06–

(toluene/ethyl acetate, 9:1) indicated the formation of a major prod-

uct (R_f0.5) and complete consumption of starting material (R_f0.4).

3.18 (m, 4 H, OCH₂CH₂SePh α, OCH₂CH₂SePh β, H-5_bα), 3.40 The reaction was cooled to room temp. and then NIS (0.381 mmol)

(m, 1 H, H-5_bβ), 3.53 (m, 1 H, H-5_aα), 3.49 (dd, J_6,6Ј= 8.2, J_5,6and water (1 mL) were added and the reaction stirred for 16 h,

= 3.2 Hz, 1 H, H-6_bα), 3.58–3.82 (m, 8 H, H-2_aα, H-2_aβ, H-5_aafter which indicated the formation of a single product (R_f0.2) The

β, H-2_bα, H-4_bα, H-4_bβ, H-5_bα, H-5_bβ), 3.84–4.13 (m, 7 H, H- reaction was diluted with CH₂Cl₂(20 mL) and washed with water

2_aα, H-2_aβ, H-3_aα, H-3_aβ, H-4_aα, H-4_bβ, H-6_bβ), 4.16–4.24

(20 mL). The aqueous layer was then extracted with CH₂Cl₂

(m, 4 H, OCH₂CH₂I α/β, H-6_aα/β H-6Ј_aα, H-6Ј_aβ), 4.33–4.47 (m, (2ϫ20 mL) and the combined organic extracts were washed with

3 H, OCH₂CH₂I α/β, H-6_aα/β), 4.48 (d, J_1,2= 8 Hz, 1 H, H-1_aβ), saturated sodium hydrogen carbonate (20 mL) then brine (20 mL).

4.61 (m, 2 H, H-6Ј_bα, H-6Ј_b), 4.80–4.88 (m, 4 H, CH₂Ph α, CH₂Ph The organic phase was dried (MgSO₄), filtered, and concentrated

β), 5.02 (d, J_1,2= 3.5 Hz, 1 H, H-1_aα), 5.53 (s, 4 H, CHPh α, CHPh

β, H-1_bα, H-1_bβ), 7.27–7.50 (m, 30 H, 15ϫAr-CHα, 15ϫAr-

CHβ) ppm. ¹³C NMR (100 MHz, CDCl₃): 24.4, 24.6 (OCH₂CH₂I

α, OCH₂CH₂I β), 24.9, 25.0, 25.9, 26.0, 26.1, 26.2, 27.0, 27.1 (4ϫq,

CH₃α, 4ϫq, CH₃β), 62.5, 62.5 (2ϫt, C-6_aα, C-6_aβ), 65.8, 66.0

(2ϫt, C-6b α, C-6b β), 66.9, 67.3 (2ϫt, OCH₂CH₂I α, OCH₂CH₂I

β), 68.9, 69.0 (2ϫt, ArCH₂α, ArCH₂β), 70.2, 70.4, 70.6, 70.7,

70.8, 70.9, 71.3, 72.4, 75.0, 75.1, 78.2, 80.5, 80.6, 81.3, 82.0, 82.4

(16ϫd, C-2_aα, C-3_aα, C-4_aα, C-5_aα, C-2_aβ, C-3_aβ, C-4_aβ, C-

5_aβ, C-2_bα, C-3_bα, C-4_bα, C-5_bα, C-2_bβ, C-3_bβ, C-4_bβ, C-5_b

β), 96.3 (d, C-1_aβ), 98.0 (d, C-1_aα), 101.1 (d, C-1_bα), 101.2 (d,

C-1_bβ), 104.6, 104.6 (d, CHPh α, CHPh β), 108.6, 108.6, 109.2,

109.4 [s, C(CH₃)₂ϫ2 α, C(CH₃)₂ϫ2 β], 126.0, 126.5, 126.6,126.9,

127.2, 127.3 127.6, 127.7, 127.8, 127.9, 128.1, 128.2, 128.3, 128.4,

129.0, 129.1, 129.2, 130.4 (18 ϫd, Ar-CH), 132.2, 132.6, 137.3,

137.4, 138.3, 138.6 (6 ϫ s, Ar-C) ppm. HRMS (ES⁺): calcd. for

C₄₀H₄₈O₁₁SeNa [M + Na⁺] 807.2260; found 807.2258.

in vacuo. The resulting residue was purified by flash column

chromatography (toluene/ethyl acetate, 6:1) to afford alcohol 48

(0.128 g, 73%) as a colourless oil identical to the material described

above.

Supporting Information (see footnote on the first page of this arti-

cle): X-ray crystallographic data, spectra for all compounds and

low-temperature NMR studies.

Acknowledgments

The authors gratefully acknowledge the British Engineering and

Physical Sciences Research Council (EPSRC) (DTA award to

D. J. C.) for financial support.

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3,4,6-Tri-O-benzyl-α/β-

D-glucopyranosyl-(1Ǟ6)-1:2,3:4-di-O-iso-

propylidene-α-

D

-galactopyranoside (48):^[19,20]Method 1: Disacchar-

ide 11b (α:β ratio 5:1) (0.223 g, 0.254 mmol) was dissolved in

freshly distilled THF (10 mL) under an atmosphere of argon. The

reaction was cooled to 0 °C and H₂O₂(1 mL, 30% solution in

THF) was added. The reaction was warmed to room temp. and

stirred for 1 h, then heated at reflux for a further 1 h, after which

TLC (toluene/ethyl acetate, 9:1) indicated the formation of a major

product (R_f0.5) and complete consumption of starting material

18

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Pages: 20

Neighbouring Group Participation During Glycosylation

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C-1 δ = 95 ppm.

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Received: May 14, 2014

gew. Chem. 1975, 87, 863–874.

Published Online: ᭿

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Job/Unit: O42260

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Pages: 20

D. J. Cox, G. P. Singh, A. J. A. Watson, A. J. Fairbanks

FULL PAPER

Glycosylation

D. J. Cox, G. P. Singh, A. J. A. Watson,

A. J. Fairbanks* .............................. 1–20

Neighbouring Group Participation During

Glycosylation: Do 2-Substituted Ethyl

Ethers Participate?

The propensity of 2-iodo- or 2-(phenyl-

seleno)ethyl ethers moieties at the 2-pos-

ition of a glycosyl donor to participate in

glycosylation reactions depends on both

the nature of the nucleophile (SeϾϾI), and

the protecting groups on the other

hydroxys of the glycosyl donor. The forma-

tion of β-configured 6-ring cyclic inter-

mediates is not alone sufficient to ensure

high levels of α-selectivity.

Keywords: Synthetic methods / Carbo-

hydrates / Glycosylation / Neighboring-

group effects / Diastereoselectivity

20

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Article Doi

Neighbouring group participation during glycosylation: Do 2-substituted ethyl ethers participate?

DOI: 10.1002/ejoc.201402260

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Authors:

Article abstract of DOI:10.1002/ejoc.201402260

Full text of DOI:10.1002/ejoc.201402260

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