Synthesis of S-linked carbohydrate analogues via a Ferrier reaction

Available online at www.sciencedirect.com

Tetrahedron 64 (2008) 2832e2854

www.elsevier.com/locate/tet

David Ellis ^a, Sarah E. Norman ^b, Helen M.I. Osborn ^c,

*

^aPﬁzer Ltd, Sandwich, Kent CT13 9NJ, UK

^bSchool of Chemistry, University of Reading, Whiteknights, Reading, Berkshire RG6 6AD, UK

^cSchool of Pharmacy, University of Reading, Whiteknights, Reading, Berkshire RG6 6AD, UK

Received 26 September 2007; received in revised form 21 December 2007; accepted 10 January 2008

Available online 16 January 2008

Abstract

In this work, the synthetic utility of the Ferrier reaction to access S-linked disaccharides and S-linked glycoamino acids has been probed.

Signiﬁcantly, entry to a range of 1,4- and 1,6-S-linked disaccharides has been achieved using glycals derived from glucose and galactose,

and sulfur containing coupling partners derived from methyl a-^D-glucopyranoside. Access to S-linked glycoamino acids and glycopeptides

has also been achieved using protected cysteine and homocysteine coupling partners within the Ferrier reaction. Functionalisation of the Ferrier

products, for example, via dihydroxylation using OsO₄or amino acid coupling, and deprotection of the targets have also been achieved. In this

way, entry to materials of interest as mimics of biologically interesting disaccharides and glycopeptides has been realised, including targets

derived from rare sugars such as talopyranose and gulopyranose.

1. Introduction

as hydrolytically stable structural probes for enzyme sites,^5e7

where they are able to participate in hydrogen bonding, and as

accurate carbohydrate mimics. As a result of the need for

S-linked carbohydrates, various methods for their preparation

have been reported including Lewis acid catalysed condensa-

tion between a glycosyl acceptor containing an SH group

and a suitable glycosyl donor, S_N2-like displacement of

a good leaving group of a glycosyl acceptor with a 1-thiolate

or of a glycosyl halide with a sugar thiolate, and Michael

addition of thiolates to a,b-unsaturated systems.^6,8e12The

work reported herein advances the synthetic capability for pre-

paring S-linked disaccharides by developing a new method for

entry to such targets using a Ferrier reaction between a range

of glycals and a range of sulfur containing carbohydrates.

The Ferrier reaction involves the reaction between a glycal (a

carbohydrate with an endocyclic alkene) and a nucleophile in

the presence of a Lewis acid or promoter. The glycal undergoes

an allylic rearrangement with substitution of the nucleophile at

the anomeric position.¹³Mild reaction conditions and forma-

tion of a double bond offer the potential for further functional-

isation, highlighting the synthetic utility of this methodology.

Oxygen, carbon and sulfur nucleophiles have already proved

popular as the nucleophilic components for the synthesis of

It is now well established that carbohydrates are involved in

a multitude of biological processes including cellecell recog-

nition, differentiation and adhesion. Moreover, the elucidation

of the roles of carbohydrates in a range of disease processes

such as cancer, viral and bacterial infections, and immunother-

apy has received considerable recent attention.¹As a result,

it is now recognised that carbohydrates and their derivatives

offer considerable potential as a new generation of therapeutic

agents,²and much synthetic effort has been channelled into

the synthesis of both natural and unnatural carbohydrates,

and their mimics. In some cases carbohydrate-based drugs

have demonstrated limited stability in vivo, due to processing

by glycosidase enzymes, but it has been illustrated that syn-

thetic derivatives such as S-linked glycosides, in which the

interglycosidic oxygen atom has been replaced with a sulfur

atom, can be of enhanced utility.^3,4S-Linked oligosaccharides

are also of interest for additional biological studies, including

* Corresponding author. Fax: þ44 (0)118 378 4644.

E-mail address: h.m.i.osborn@reading.ac.uk (H.M.I. Osborn).

doi:10.1016/j.tet.2008.01.042

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

OH

2833

functionalised glycosides. In addition, carbohydrate derived

alkenes have been incorporated to allow entry to C-linked disac-

charides.¹⁴Although thiol nucleophiles have been incorporated

within a Ferrier strategy,^15e20the reaction has not been studied

for the synthesis of S-linked disaccharides. Therefore, as an

extension to this methodology and due to the biological utility

of the S-linked disaccharide targets, this programme has inves-

tigated for the ﬁrst time the feasibility of using sulfur containing

carbohydrates as the nucleophilic components within the

Ferrier reaction to allow access to S-linked disaccharides. If

successful this will provide materials to further probe the hy-

pothesis that disaccharide derivatives can potentially display

more speciﬁc inhibitory activity of glycosidase enzymes com-

pared with monosaccharide inhibitors.²¹This is believed to be

a result of the disaccharides including steric and charge infor-

mation of both glycosyl moieties, which are liberated during

the glycosidase-catalysed hydrolysis and the aglycon to which

it is attached. Monosaccharide mimics often inhibit several

types of enzymes, with disaccharides and oligosaccharides

being expected to be more selective for enzymes and lectins.

As such disaccharide mimics represent more selective ligands

for lectin and oligosaccharide receptors.²²

Ph

O

HO

O

Ph

O

BnO

HO

i

ii

O

HO

OMe

BnO

7

OMe

6

iii

OH

SH

SAc

v

iv

O

BnO

OMe

8

9

10

Scheme 2. Synthesis of thiol (10). (i) a,a-Dimethoxytoluene, p-TsOH, DMF,

50 ^ꢀC, 2 h, 73%. (ii) BnBr, TBAI, DMF, overnight, 86%. (iii) LiAlH₄, AlCl₃,

Et₂O, CH₂Cl₂, D, 2 h, 74%. (iv) DEAD, PPh₃, thioacetic acid, THF, overnight,

60%. (v) N₂H₄$H₂O, acetic acid, DMF, 0.5 h, 96%.

Owing to the success of LiBF₄as the Lewis acid in Ferrier

reactions involving sulfur nucleophiles,¹⁵it was decided to em-

ploy the same in the preparation of the S-linked disaccharides.

First, the O-acetate-protected thiol (5) was subjected to the

Ferrier reaction with tri-O-acetyl-^D-glucal (11) and LiBF₄

(1.2 equiv) in acetonitrile (Scheme 3). After leaving the reaction

mixture to stir for 8 h at room temperature, the reaction was

quenched and the residue puriﬁed by column chromatography.

Pleasingly, this afforded the desired 1,6-S-linked disaccharide

(12) in 89% yield after puriﬁcation by column chromatography

as an anomeric mixture of 10:1, a/b as determined by ¹H NMR

and NOESY spectroscopic analyses.

2. Results and discussion

The ﬁrst stage of the research programme involved the

synthesis of primary thiols 5 and 10 to potentially allow access

to 1,6-S-linked disaccharides. To probe the inﬂuence of the

protecting groups within the nucleophilic component on the

efﬁciency of the Ferrier reaction, electron withdrawing (ace-

tate) and electron donating (benzyl) protecting groups were

incorporated within the thiol acceptors. The per-O-acetate-

protected derivative (5)²³and the per-O-benzyl protected

analogue (10)^24,25were prepared from methyl a-D-glucopyra-

noside according to the literature procedures, as illustrated in

Schemes 1 and 2, respectively.

OAc

O

AcO

OAc

SH

i

O

AcO

S

AcO

O

OMe

AcO

11

5

AcO

OMe

12

Scheme 3. (i) LiBF₄, MeCN, 8 h, 89%, a:b 10:1.

OH

OTBDMS

O

OTBDMS

O

HO

i

ii

HO

AcO

When this reaction was repeated with the benzyl protected

analogue (10), the desired disaccharide (13) was afforded in

75% yield after 4 h at room temperature, in an anomeric ratio

of 10:1, a/b (Scheme 4). The anomeric ratios of both reactions

were consistent with the previous studies on the Ferrier reac-

tion with sulfur nucleophiles.¹⁵

Presumably, the shorter reaction time of 4 h compared with

8 h for the reaction of 10 versus 5 reﬂects the greater nucleo-

philicity of the thiol (10). To fully probe this potential tuning

HO

OMe

AcO

2

OMe

1

iii

OH

SH

SAc

O

v

iv

O

AcO

OMe

3

4

5

OAc

O

Scheme 1. Synthesis of thiol (5). (i) TBDMSeCl, imidazole, DMF, overnight.

(ii) Ac₂O, Py, overnight, 77% (over two steps). (iii) Aq acetic acid (80%),

50 ^ꢀC, 2 h, 86%. (iv) DEAD, PPh₃, thioacetic acid, THF, overnight, 78%.

(v) N₂H₄$H₂O, acetic acid, DMF, 0.5 h, 86%.

AcO

OAc

SH

i

O

AcO

BnO

S

BnO

O

OMe

BnO

For both acetate and benzyl ether protected systems, the thio-

acetate was deprotected using hydrazine monohydrate when

the material was required, therefore preventing dimerisation

of the free thiol moiety.

11

10

BnO

OMe

13

Scheme 4. (i) LiBF₄, MeCN, 4 h, 75%, a:b 10:1.

2834

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

Table 1 (continued)

Table 1

Reaction of the thiol acceptors 5 and 10 with a range of glycals using LiBF₄

(1.2 equiv) or BF₃$OEt₂(0.1 equiv) as activator

Thiol Glycal Reaction Lewis

time

Product

Yield (%),

anomeric

ratio (a/b)

acid

Thiol Glycal Reaction Lewis

time

Product

Yield (%),

anomeric

ratio (a/b)

OAc

O

acid

AcO

OAc

O

S

AcO

10

15

10 min

BF₃$OEt₂

52, a-only

O

BnO

S

OMe

5

11

8 h

LiBF₄

89, 10:1

O

AcO

21

OAc

AcO

OMe

O

12

S

AcO

10

16

4 h

BF₃$OEt₂

53, a-only

OAc

O

AcO

O

BnO

OMe

S

22

O

AcO

5

14

48 h

LiBF₄

15, 10:1

AcO

OMe

OAc

O

OAc

AcO

17

O

AcO

OAc

2-OAc glucal

15

OAc

O

AcO

glucal

11

galactal

14

2-OAc galactal

16

S

AcO

5

15

48 h

LiBF₄

15, 10:1

O

AcO

Figure 1. Glycal acceptors for the Ferrier reaction.

AcO

effect both the O-acetate and the O-benzyl protected thiols

were subjected to further reactions with three additional glycal

donors, 14e16 (Table 1).^26e28Tri-O-acetyl-D-galactal (14)

was commercially available, and the 2-OAc glucal (15) and

galactal (16) derivatives were prepared from the respective

1-bromopyranosides after treatment with DBU (Fig. 1).²⁹

Pleasingly, reaction of the O-acetate and O-benzyl pro-

tected thiols 5 and 10 with galactal (14) afforded the required

1,6-S-linked disaccharides 17 and 20, however, longer reaction

times were required compared to the previous studies with tri-

O-acetyl-^D-glucal. The tuning effect was still evident; hence,

O-benzyl thiol (10) afforded a higher yield of 20 than that

was achieved from the O-acetate-protected thiol (5) (for which

15% of disaccharide (17) was achieved) (Table 1). Reactions

of glycals 15 and 16 using LiBF₄as activator proved less

successful with thiol 10 than with 5. In an attempt to optimise

the reactions, heating was applied, however, this offered no

advantage. Alternative Lewis acids (SnCl₄, Yb(OTf)₃, ZrCl₂,

BF₃$OEt₂) were also utilised within the Ferrier reaction, and

for the reactions of thiol (10) with glycals 15 and 16 this proved

the key to success with BF₃$OEt₂allowing rapid entry to disac-

charides 21 and 22, respectively, with good conversion yields.

Next, a C-4 secondary thiol was also prepared from methyl

a-^D-glucopyranoside (Scheme 5)²⁴to potentially allow access

to 1,4-S-linked disaccharides via the Ferrier reaction. This

extension of the methodology was expected to be particularly

challenging given the reduced nucleophilicity of the secondary

thiol compared to the primary thiols, owing to both steric and

18

OAc

AcO

O

S

AcO

5

16

48 h

LiBF₄

33, 3:2

O

AcO

OMe

19

OAc

O

AcO

S

O

10

11

4 h

LiBF₄

75, 10:1

BnO

13

OAc

AcO

O

S

10

14

48 h

LiBF₄

33, 10:1

O

BnO

OMe

20

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2835

Table 2

Ferrier reaction of the secondary thiol 27 with glycals under BF₃$OEt₂

activation

electronic effects. However, 1,4-linked saccharides are of par-

ticular interest due to their common occurrence in nature and

hence S-analogues of these targets are likely to be of signiﬁ-

cant biological interest.

Thiol Glycal Time

Temp

Product

Yield (%),

anomeric

ratio (a/b)

When the secondary thiol (27) was reacted with tri-O-

acetyl-^D-glucal and a Lewis acid, the results were surprising.

Initial attempts at the reaction using LiBF₄failed to yield

any disaccharide product, with only starting materials being

isolated from the reaction mixture. As LiBF₄is reported to

be a weak source of BF₃$OEt₂,³⁰it was hoped that a stronger

source of BF₃$OEt₂may promote the desired reaction. Indeed,

when BF₃$OEt₂was employed, a very fast reaction was ob-

served at room temperature as evidenced by TLC analysis of

the reaction mixture, but a complex mixture of products was

formed. However, pleasingly, when the reaction was repeated

at a lower temperature (ꢁ10 ^ꢀC), the desired disaccharide (28)

was formed in 72% yield as a single isomer (Scheme 6). Fol-

lowing this success, tri-O-acetyl-^D-galactal was also subjected

to the reaction with thiol (27). Gratifyingly, good yields of the

OAc

O

OBn

O

AcO

S

27

11

10 min ꢁ10 ^ꢀC

20 min ꢁ10 ^ꢀC

72, a-only

AcO

OMe

28

OAc

AcO

O

OBn

O

S

27

14

68, a-only

AcO

OMe

29

OAc

O

AcO

OH

OBn

Ph

O

i

O

Ph

O

AcO

HO

ii

S

O

AcO

O

27

15

16

58, a-only

65, a-only

O

AcO

HO

AcO

OMe

AcO

OMe

6

23

30

OAc

AcO

iii

O

OBn

O

OBn

O

OBn

O

2 h

rt

I

O

S

AcO

v

iv

AcO

AcS

AcO

HO

AcO

OMe

AcO

OMe

31

26

25

24

vi

disaccharide, via dihydroxylation, was investigated. It was en-

visaged that this would allow access to fully hydroxylated

sugar mimics, which would be of particular interest as glyco-

sidase inhibitors and structural probes. As sulfur oxidation was

not required, stoichiometric equivalents of OsO₄were utilised

to obviate the need for a co-oxidant.³¹Representative S-linked

disaccharides were subjected to dihydroxylation by stirring

with OsO₄in pyridine for 24 h. The unpuriﬁed products of

these reactions were treated with acetic anhydride and pyri-

dine to effect O-acetylation and assist with isolation and puri-

ﬁcation of the hydroxylated derivatives. For the glucal systems

(12, 13 and 28), where both the anomeric substituent and the

4-OAc were located below the ring, all dihydroxylations oc-

curred exclusively from the upper face of the molecule, result-

ing in formation of mannose derived S-linked glycoconjugates

(32, 34 and 36, respectively) (Scheme 7, Table 3).

OBn

O

HS

AcO

OMe

27

Scheme 5. Synthesis of (27). (i) a,a-Dimethoxytoluene, p-TsOH, DMF, 50 ^ꢀC,

2 h, 73%. (ii) Ac₂O, Py, overnight, 92%. (iii) NaCNBH₃, HCl _ꢀin Et₂O, THF,

˚

4 A MS, 20 min, 56%. (iv) I₂, PPh₃, imidazole, toluene, 80 C, overnight,

62%. (v) KSAc, DMF, 90 ^ꢀC, 2 h, 70%. (vi) N₂H₄$H₂O, acetic acid, DMF,

30 min, 65%.

1,4-S-linked disaccharide (29) again resulted after only a short

reaction time (Table 2). In addition, the 2-OAc glucal (15) and

galactal (16) derivatives also gave good yields of their respec-

tive disaccharides 30 and 31.

With access to a range of S-linked disaccharides achieved,

functionalisation of the 2,3-glycal moiety within the

For the galactal systems (17, 20 and 29), where the anomeric

substituent and the 4-OAc substituent were trans, dihydroxyl-

ation occurred from both faces with reaction from the top face

predominantly affording talose derived glycoconjugates and

reaction from the lower face affording gulose derived glycocon-

jugates. The ratio of the products was determined by ¹H NMR

spectroscopic analysis and the assignment of talose or gulose

was ascertained by NOESY spectroscopic analysis. Both

OAc

OBn

O

AcO

OBn

O

AcO

i

HS

AcO

S

AcO

OMe

AcO

11

OMe

28

27

Scheme 6. BF₃$OEt₂, CH₂Cl₂, ꢁ10 ^ꢀC, 10 min, 72%.

2836

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

OAc

of these sugars are considered rare sugars and are therefore

sought-after targets for biological studies.

R₁

OAc

O

R

AcO

To complete the synthesis of the S-linked disaccharides, de-

protection of the derivatives was required. This was achieved

readilyforrepresentativeacetate-protectedcompoundsdescribed

herein, i.e., the 1,6- and 1,4-S-linked Ferrier products 12 and 17,

and28and 29, aswellasthe dihydroxylated1,6-and 1,4-S-linked

products 32and 33, and 36and 37, toafford38e45, in near quan-

titativeyield, via treatment with potassium carbonate inmethanol

for 2 h. The therapeutic utilities of these materials are now being

assessed in a number of programmes within our laboratories.

As a ﬁnal part of this research programme to potentially

access S-linked glycoamino acids and glycopeptides, Bze^L-

CysOEt (46) and Bze^DL-HcyOMe (48) were used as the nucle-

ophilic components within the Ferrier methodology. Again, such

targets have been reported in the literature to be of therapeutic

potential and hence are of interest from both synthetic and bio-

logical perspectives.^8,32The amino acids were protected before

being subjected to theFerrierreaction conditions. For both ^L-cys-

teine and ^DL-homocysteine, the amine functionality was ﬁrst pro-

tected as a benzoyl amide, and for homocysteine the thiolactone

ring was cleaved with NaOMe/MeOH affording the methyl ester

of homocysteine (Scheme 8).³³

i

S

R₃

R = OAc, R₁= H

R = H, R₁= OAc

R₃see table

R = OAc, R₁= H

R = H, R₁= OAc

R₃see table

Scheme 7. Dihydroxylation reaction of the S-linked disaccharides. (i) OsO₄,

Py, overnight, then Ac₂O, Py, overnight.

Table 3

Dihydroxylation reactions

Disaccharide

Yield (%)

Product

Tal/Gul

OAc

AcO

O

S

12

63

n/a

O

AcO

OMe

32

OAc

AcO

O

SH

OEt

O

S

i

OEt

17

13

20

56

52

57

1:0.4

O

N

H

AcO

ClH_.H₂N

O

AcO

OMe

46

33

OAc

SH

S

OAc

O

AcO

S

O

ii

iii

O

OMe

HN

N

H

S

O

NH_2.HCl

n/a

O

BnO

47

BnO

48

OMe

34

OAc

Scheme 8. Preparation of 46 and 48. (i) Benzoic acid, oxalyl chloride, CH₂Cl₂,

DMF, 30 min, then ^L-CysOEt$HCl, Py, CH₂Cl₂, DMF, overnight, 77%. (ii)

Benzoyl chloride, CH₂Cl₂, NEt₃, overnight, 50%. (iii) NaOMe, MeOH,

30 min, quant.

AcO

O

S

As in other areas of this programme, both LiBF₄and

BF₃$OEt₂were used as the Lewis acids for the Ferrier reaction

but the best results were generally observed with BF₃$OEt₂(Ta-

ble 4). With LiBF₄, after 4 h at room temperature, the reaction

between cysteine (46) and glucal (11) afforded the desired

glycoamino acid (49) in 72% yield and as an anomeric ratio

of 2:1, a/b (Scheme 9). When the Lewis acid was changed to

1:0.4

O

BnO

OMe

35

OAc

O

AcO

OBn

AcO

O

S

28

83

AcO

n/a

AcO

OAc

OMe

36

O

SH

OEt

OAc

AcO

O

i

OAc

O

AcO

N

H

S

O

OBn

OEt

N

H

11

46

29

76

1:0.4

O

S

O

AcO

49

AcO

OMe

Scheme 9. (i) LiBF₄, MeCN, 4 h, 72%, a/b 2:1 or BF₃$OEt₂, CH₂Cl₂, 10 min,

87%.

37

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2837

Table 4

Ferrier reactions with amino acids 46 and 48

Amino acid

Glycal

Lewis acid

Reaction time

Temp

Product

Yield (%), anomeric

ratio (a/b)

46

11

LiBF₄

BF₃$OEt₂

4 h

10 min

rt

72, 2:1

87, a-only

OAc

O

AcO

S

O

OEt

N

H

O

49

46

14

LiBF₄

BF₃$OEt₂

16 h

1.5 h

rt

60, 2:1

77, a-only

OAc

O

AcO

S

O

OEt

N

H

O

51

46

15

LiBF₄

BF₃$OEt₂

16 h

10 min

50 ^ꢀC

rt

22, 4:1

68, a-only

OAc

O

AcO

S

AcO

OEt

HN

O

52

46

16

LiBF₄

16 h

60 ^ꢀC

25, 3:1

OAc

O

S

O

OEt

HN

O

53

BF₃$OEt₂

2.5 h

rt

63, a-only

OAc

AcO

O

S

AcO

OEt

HN

O

54

(continued on next page)

2838

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

Table 4 (continued)

Amino acid

Glycal

Lewis acid

Reaction time

Temp

Product

Yield (%), anomeric

ratio (a/b)

48

11

LiBF₄

BF₃$OEt₂

16 h

10 min

rt

89, 2:1

64, a-only

OAc

O

AcO

S

OMe

O

NH

50

48

14

LiBF₄

BF₃$OEt₂

48 h

1.5 h

rt

65, 2:1

42, a-only

OAc

AcO

O

S

OMe

O

NH

55

48

15

LiBF₄

BF₃$OEt₂

d

2 h

50 ^ꢀC

rt

d

No reaction

60, a-only

OAc

O

AcO

S

AcO

OMe

O

NH

56

48

16

LiBF₄

BF₃$OEt₂

d

2 h

50 ^ꢀC

rt

d

No reaction

58, a-only

OAc

AcO

O

S

AcO

OMe

O

NH

57

BF₃$OEt₂the reaction proceeded more quickly and resulted in

87% yield of the glucoamino acid (49) after only 10 min at

room temperature.

For the homocysteine analogue (48), reaction with glucal

(11) under LiBF₄promotion gave the desired glycoamino

acid (50) in 89% yield, in an anomeric ratio of 2:1, a/b (Scheme

10). Unfortunately, even after extensive puriﬁcation via column

chromatography, separation of the anomers was not possible.

However, when using BF₃$OEt₂, the reaction proceeded in

10 min at room temperature with a yield of 64% with only

the a-anomer being formed.

As observed previously during formation of the S-linked di-

saccharides using LiBF₄, when glycals other than 11 were uti-

lised longer reaction times and lower yields generally resulted.

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2839

Again, the effect of heating on the reaction proﬁle was investi-

gated and higher temperatures served to enhance the reactions

with 2-OAc glucal (15) and 2-OAc galactal (16), hence after

heating overnight at 50 or 60 ^ꢀC, respectively, the desired gly-

coamino acids 52 and 53 were obtained in 22 and 25% yields,

respectively. For the 2-OAc galactalecysteine system, elimina-

tion occurred during the reaction, resulting in the formation of

an enone system 53.³⁴

BF₃$OEt₂, the desired glycoamino acids 56 and 57 were

formed after 2 h at room temperature in 60 and 58% yields,

respectively.

Although the full synthetic and biological potential of these

compounds is still being assessed within our laboratories,

initial results have shown that S-linked glycoamino acids 49

and 51 are also suitable substrates for peptide coupling reac-

tions. Thus after removal of the N-Boc protecting groups

from 58 and 59 and coupling with Boc(OBn)e^L-SerOH or

Boce^L-AlaOH in the presence of PyBOP, dipeptides 60 and

61 were accessed in 86 and 84% yield, respectively. Hence ac-

cess to S-linked glycopeptides has also proved possible within

this study (Scheme 11).

OAc

O

S

O

OEt

N

H

In addition to incorporating the disaccharides within the

dihydroxylation strategy, the glycoamino acid derivatives

were also oxidised to the fully hydroxylated sugars. As with

the disaccharide systems, when the glucal conjugates 49 and

50 were subjected to the reaction conditions, only the mannose

derivatives 62 and 64 were formed. For the galactal conjugates

51 and 55, mixtures of talose and gulose derivatives resulted,

with the talose products being favoured (Table 5).

Finally, removal of the acetate, Boc, benzoyl and ester

protecting groups within the representative glycoamino acid

derivatives 50 and 55, and 58 and 59 was attempted using stan-

dard protocols. Although generally successful, racemisation of

the cysteine derivatives was observed, and in some cases only

partial deprotection of the ester functionality occurred. Never-

theless, entry to targets 66, 67, 70 and 71 was achieved, thus

providing access to materials of biological interest.

O

53

However, when the Lewis acid was exchanged for

BF₃$OEt₂, vastly decreased reaction times and improved

yields were again observed for these systems. Moreover, the

reactions now proceeded with excellent stereoselectivity and

only the a-anomers were isolated from the reactions (Table

4). Most accentuated were the reactions with the 2-OAc gly-

cals 15 and 16, which showed increased yields for the reac-

tions with cysteine analogues, to afford 52 and 54. Here,

yields increased from 22 and 25% to 68 and 63%,

on moving from activation by LiBF₄to BF₃$OEt₂. Further im-

provement was seen in the reactions between the 2-OAc gly-

cals 15 and 16 and the homocysteine coupling partner 48.

Using LiBF₄, no reaction was observed as the long reaction

times lead only to homocysteine thiolactone reforming in the

reaction mixture. When the Lewis acid was exchanged for

3. Conclusion

The value of the Ferrier reaction for affording S-linked

saccharide targets has been demonstrated, with entry to 1,6-

and 1,4-S-linked disaccharides and S-linked glycoamino acids

proving effective in synthetically useful yields. In many cases

the reactions have proceeded with complete stereoselectivity.

Further functionalisation of the Ferrier products has proved

possible, for example, via peptide coupling of the glycoamino

acids and dihydroxylation of the S-linked disaccharides. Again

these reactions have proceeded in excellent yields to afford bi-

ologically and therapeutically interesting targets. Deprotection

of the targets has also been realised to afford materials whose

biological and therapeutic properties are now being assessed.

OAc

SH

O

OAc

AcO

O

i

O

AcO

S

OMe

N

H

O

OMe

N

11

48

H

O

50

Scheme 10. (i) LiBF₄, MeCN, overnight, 89%, a/b 2:1 or BF₃$OEt₂, CH₂Cl₂,

10 min, 64%.

OAc

R

O

R₁

O

R₁

i

ii

S

O

OEt

BocHN

OEt

N

H

N

H

O

R₂

R = H, R₁= OAc 49

R = OAc, R₁= H 51

R = H, R₁= OAc 58

R = OAc, R₁= H 59

R = H, R₁= OAc, R₂= OBn 60

R = OAc, R₁= H, R₂= H 61

Scheme 11. Peptide coupling of 49 and 51. (i) Boc₂O, DMAP, THF, overnight, 92%, then N₂H₄$H₂O, EtOH, 0 ^ꢀC, 2 h, quant. (ii) For R¼H, R₁¼OAc: 4 N HCl in

dioxane, then, N-BoceL-Sere(OBn)eOH, PyBOP, NEt₃, CH₂Cl₂, 30 min, 86%. For R¼OAc, R₁¼H: 4 N HCl in dioxane, then, N-BoceL-AlaeOH, PyBOP, NEt₃,

CH₂Cl₂, 40 min (84%).

2840

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

Table 5

Dihydroxylation reactions with the glycoamino acids

The residue was subjected to puriﬁcation by column

chromatography.

Glycoamino acid

Yield (%)

Product

Tal/Gul

Method B. To a stirred solution of thiol (1 equiv) and glycal

(1.2 equiv) in dry CH₂Cl₂(5 ml/mmol) under an atmosphere

of argon (cooled to the speciﬁed temperature) was added

BF₃$OEt₂(0.1 equiv). The reaction mixture was stirred until

the reaction was shown to have reached completion by TLC

analysis. The reaction was then quenched by the addition of

satd aq NaHCO₃and extracted with CH₂Cl₂. The combined

extracts were then dried (MgSO₄), ﬁltered and concentrated

in vacuo. The crude residue was then subjected to puriﬁcation

by column chromatography.

OAc

O

AcO

S

O

OEt

49

57

n/a

N

H

O

62

OAc

O

AcO

4.1.1. Methyl 2,3,4-tri-O-acetyl-6-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-glucopyranosyl)-6-thio-a-D-glucopyranoside

(12)

S

O

OEt

51

62

1:0.4

N

H

By following method A, tri-O-acetyl-^D-glucal (11) (74 mg,

0.27 mmol) and methyl 2,3,4-tri-O-acetyl-6-thio-a-^D-gluco-

pyranoside (5) (109 mg, 0.3 mmol) were stirred at room tem-

perature for 8 h to afford, after puriﬁcation by column

chromatography (1:1 hexane/ethyl acetate), 12 as a colourless

oil (133 mg, 89%, a/b 10:1). R_f0.3 (1:1 hexane/ethyl acetate);

[a]²_D⁰þ244 (c 0.35, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 2.01

(3H, s, OC(O)CH₃), 2.04 (3H, s, OC(O)CH₃), 2.08 (3H, s,

OC(O)CH₃), 2.09 (3H, s, OC(O)CH₃), 2.10 (3H, s,

OC(O)CH₃), 2.69 (1H, dd, J 6.5, 14.0 Hz, H-6), 2.99 (1H, dd,

J 3.0, 14.0 Hz, H-6), 3.42 (3H, s, OCH₃), 4.01 (1H, ddd, J

3.0, 6.5, 9.5 Hz, H-5), 4.14e4.18 (1H, m, H-6⁰), 4.25e4.31

(2H, m, H-5⁰, H-6⁰), 4.87 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.92

(1H, d, J 3.5 Hz, H-1), 5.06 (1H, app. t, J 10.0 Hz, H-4), 5.37

(1H, ddd, J 2.0, 4.0, 9.0 Hz, H-4⁰), 5.46 (1H, app. dt, 9.5,

10.0 Hz, H-3), 5.61e5.64 (1H, m, H-1⁰), 5.81 (1H, app. dt, J

2.0, 10.0 Hz, H-3⁰), 5.93 (1H, ddd, J 2.0, 3.0, 10.0 Hz, H-2⁰).

¹³C NMR (CDCl₃, 100 MHz) 20.7 (OAc), 20.8 (OAc), 20.8

(OAc), 21.0 (OAc), 32.1 (C-6), 55.5 (OMe), 62.8 (C-6⁰), 65.1

(C-4⁰), 66.9 (C-5⁰), 68.5 (C-5), 70.0 (C-3), 70.9 (C-2), 71.2

(C-4), 80.1 (C-1⁰), 96.6 (C-1), 127.4 (C-3⁰), 128.6 (C-2⁰),

169.8 (C]O), 170.1 (C]O), 170.2 (C]O), 170.3 (C]O),

170.8 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ12843 (OMe), 1746

(C]O), 1371 (OMe), 732 (C]C), 605 (CS). LRMS m/z 549

(1%, MþH^þ), 430 (14%), 428 (58%), 415 (100%). HRMS

(CI, MþH^þ), found: 549.1658; C₂₃H₃₃O₁₃S requires:

549.1642.

O

63

OAc

O

AcO

S

OMe

O

50

56

n/a

O

NH

64

OAc

AcO

OAc

O

S

OMe

O

55

1:0.4

O

NH

65

4. Experimental section

4.1.2. Methyl 2,3,4-tri-O-benzyl-6-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-glucopyranosyl)-6-thio-a-D-glucopyranoside

(13)

4.1. The Ferrier reactions

By following method A, tri-O-acetyl-^D-glucal (11) (98 mg,

0.36 mmol) and methyl 2,3,4-tri-O-benzyl-6-thio-a-^D-gluco-

pyranoside (10) (208 mg, 0.43 mmol) were stirred at room tem-

perature for 4 h to afford, after puriﬁcation by column

chromatography (3:1 hexane/ethyl acetate), 13 as a colourless

oil (186 mg, 75%, a/b 10:1). R_f0.2 (3:1 hexane/ethyl acetate);

[a]²_D⁰þ104.3 (c 0.65, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 2.05

(3H, s, OC(O)CH₃), 2.09 (3H, s, OC(O)CH₃), 2.83 (1H, dd, J

6.5, 14.0 Hz, H-6), 3.14 (1H, dd, J 2.5, 14.0 Hz, H-6), 3.40

(3H, s, OCH₃), 3.50 (1H, app. t, J 9.5 Hz, H-4), 3.53 (1H, dd,

Method A. To a stirred solution of thiol (1 equiv) and glycal

(1.2 equiv) in dry acetonitrile (2 ml/mmol) under an atmo-

sphere of argon was added lithium tetraﬂuoroborate solution

in acetonitrile (1.2 equiv). The reaction mixture was stirred

at room temperature (unless otherwise stated) until the reac-

tion was shown to have reached completion by TLC analysis.

The reaction mixture was quenched by the addition of water

and then extracted with CH₂Cl₂. The combined extracts

were dried (MgSO₄), ﬁltered and concentrated in vacuo.

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2841

J 3.5, 9.5 Hz, H-2), 3.88 (1H, ddd, J 2.5, 6.5, 9.5 Hz, H-5), 4.00

(1H, app. t, J 9.0 Hz, H-3), 4.12 (1H, dd, J 4.5, 14.0 Hz, H-6⁰),

4.26e4.30 (2H, m, H-5⁰, H-6⁰), 5.39 (1H, ddd, J 1.5, 3.5, 8.5 Hz,

H-4⁰), 4.58 (1H, d, J 3.5 Hz, H-1), 4.63 (1H, d, J 11.0 Hz,

OCH₂Ph), 4.67 (1H, d, J 12.0 Hz, OCH₂Ph), 4.81 (1H, d, J

12.0 Hz, OCH₂Ph), 4.81 (1H, d, J 11.0 Hz, OCH₂Ph), 4.92

(1H, d, J 12.0 Hz, OCH₂Ph), 5.00 (1H, d, J 11.0 Hz, OCH₂Ph),

5.66 (1H, dd, J 2.0, 3.0 Hz, H-1⁰), 5.79 (1H, dt, J 1.5, 10.0 Hz,

H-3⁰), 5.92 (1H, ddd, J 2.0, 3.0, 10.0 Hz, H-2⁰), 7.20e7.40

(15H, m, ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.8 (OAc),

21.0 (OAc), 32.9 (C-6), 55.3 (OMe), 62.9 (C-6⁰), 65.0 (C-4⁰),

66.8 (C-5⁰), 69.9 (C-5), 73.4 (OCH₂Ph), 75.2 (OCH₂Ph), 75.8

(OCH₂Ph), 80.1 (C-2 and C-4), 80.5 (C-1⁰), 81.9 (C-3), 98.0

(C-1), 127.0 (C-3⁰), 127.7 (ArCH), 127.9 (ArCH), 128.1

(ArCH), 128.3 (ArCH), 128.5 (ArCH), 128.9 (C-2⁰), 138.1

(ArC), 138.6 (ArC), 170.3 (C]O), 170.8 (C]O). IR n_max

(thin ﬁlm)/cm^ꢁ11741 (C]O), 1370 (OMe), 755 (CH_arom),

668 (CeS). LRMS m/z 692 (4%, MþH^þ), 572 (12%), 559

(100%), 479 (95%), 447 (30%), 341 (62%). HRMS (CI,

MþH^þ), found: 692.2644; C₃₈H₄₄O₁₀S requires: 692.2655.

2,3,4-tri-O-acetyl-6-thio-a-^D-glucopyranoside (5) (195 mg,

0.58 mmol) were stirred at room temperature for 48 h to afford,

after puriﬁcation by column chromatography (3:2 hexane/ethyl

acetate), 18 as a colourless oil (42 mg, 15%, a/b 10:1). R_f0.5

1

(3:2 hexane/ethyl acetate); [a]²_D⁰þ275 (c 0.35, CHCl₃). H

NMR (CDCl₃, 400 MHz) 2.00 (3H, s, OC(O)CH₃), 2.04 (3H, s,

OC(O)CH₃), 2.07 (3H, s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃),

2.10(3H, s, OC(O)CH₃),2.19(3H, s, OC(O)CH₃), 2.68(1H, dd,J

6.5, 14.5 Hz, H-6), 2.98 (1H, dd, J 3.0, 14.5 Hz, H-6), 3.42 (3H, s,

OCH₃), 4.00 (1H, ddd, J 3.0, 6.5, 9.5 Hz, H-5), 4.20 (1H, dd, J

2.5, 12.0 Hz, H-6⁰), 4.26 (1H, dd, J 5.0, 12.0 Hz, H-6⁰), 4.31

(1H, ddd, J 2.5, 5.0, 7.5 Hz, H-5⁰), 4.84 (1H, dd, J 3.5, 10.0 Hz,

H-2), 4.90 (1H, d, J 3.5 Hz, H-1), 5.07 (1H, app. t, J 10.0 Hz,

H-4), 5.43e5.50 (2H, m, H-3, H-4⁰), 5.66 (1H, dd, J 1.0,

2.5 Hz, H-3⁰), 5.72 (1H, s, H-1⁰). ¹³C NMR (CDCl₃, 100 MHz)

20.7 (OAc), 20.7 (OAc), 20.8 (OAc), 20.9 (OAc), 21.0 (OAc),

31.8 (C-6), 55.4 (OMe), 62.4 (C-6⁰), 64.8 (C-4⁰), 67.3 (C-5⁰),

68.5 (C-5), 69.9 (C-3), 70.8 (C-2), 71.0 (C-4), 80.0 (C-1⁰), 96.6

(C-1), 114.8 (C-2⁰), 147.1(C-3⁰), 168.1 (C]O), 169.8 (C]O),

170.1 (C]O), 170.2 (C]O), 170.7 (C]O). IR n_max(thin

ﬁlm)/cm^ꢁ11745 (C]O). LRMS m/z 629 (80%, MþNa^þ), 603

(11%), 301 (12%), 251 (100%), 223 (33%). HRMS (ESI

MþNa^þ), found: 629.1509; C₂₅H₃₄O₁₅SNa requires: 629.1516.

4.1.3. Methyl 2,3,4-tri-O-acetyl-6-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-galactopyranosyl)-6-thio-a-D-glucopyranoside

(17)

By following method A, tri-O-acetyl-^D-galactal (14)

(121 mg, 0.27 mmol) and methyl 2,3,4-tri-O-acetyl-6-thio-a-

D-glucopyranoside (5) (180 mg, 0.53 mmol) were stirred at

room temperature for 48 h to afford, after puriﬁcation by col-

umn chromatography (1:1 hexane/ethyl acetate), 17 as a colour-

less oil (36 mg, 15%, a/b 10:1). R_f0.3 (1:1 hexane/ethyl

acetate); [a]²_D⁰þ59.0 (c 0.85, CHCl₃). ¹H NMR (CDCl₃,

400 MHz) 2.00 (3H, s, OC(O)CH₃), 2.04 (3H, s, OC(O)CH₃),

2.07 (3H, s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.08 (3H,

s, OC(O)CH₃), 2.63 (1H, dd, J 6.5, 14.5 Hz, H-6), 2.99 (1H,

dd, J 3.0, 14.5 Hz, H-6), 3.43 (3H, s, OCH₃), 4.00 (1H, ddd, J

3.0, 6.5, 9.5 Hz, H-5), 4.19 (1H, dd, J 7.5, 11.5 Hz, H-6⁰),

4.24 (1H, dd, J 5.5, 11.5 Hz, H-6⁰), 4.51 (1H, ddd, J 2.5, 5.5,

7.5 Hz, H-5⁰), 4.87 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.91 (1H, d,

J 3.5 Hz, H-1), 5.05 (1H, app. t, J 9.5 Hz, H-4), 5.08 (1H, dd,

J 2.5, 5.0 Hz, H-4⁰), 5.46 (1H, dd, J 9.5, 10.0 Hz, H-3), 5.71

(1H, dd, J 1.5, 3.0 Hz, H-1⁰), 6.05 (1H, ddd, J 1.5, 5.0,

10.0 Hz, H-3⁰), 6.10 (1H, dd, J 3.0, 10.0 Hz, H-2⁰). ¹³C NMR

(CDCl₃, 100 MHz) 20.7 (OAc), 20.8 (OAc), 20.9 (OAc), 31.3

(C-6), 55.5 (OMe), 62.6 (C-6⁰), 63.4 (C-4⁰), 66.8 (C-5⁰), 68.6

(C-5), 70.0 (C-3), 70.9 (C-2), 71.2 (C-4), 79.6 (C-1⁰), 96.6

(C-1), 124.2 (C-3⁰), 131.5 (C-2⁰), 169.8 (C]O), 170.1

(C]O), 170.2 (C]O), 170.3 (C]O), 170.7 (C]O). IR n_max

(thin ﬁlm)/cm^ꢁ11746 (C]O), 1371 (OMe), 605 (CeS).

LRMS m/z 571 (90%, MþNa^þ), 393 (50%), 335 (100%,

C₁₃H₁₉O₈S), 295 (40%), 251 (35%), 201 (37%). HRMS (ESI

MþNa^þ), found: 571.1461; C₂₃H₃₂O₁₃SNa requires: 571.1461.

4.1.5. Methyl 2,3,4-tri-O-acetyl-6-S-(3-deoxy-2,4,6-tri-O-

acetyl-a-^D-galactopyranosyl)-6-thio-a-D-glucopyranoside

(19)

By following method A, 2,3,4,6-tetra-O-acetyl-1,5-anhydro-^D-

lyxo-hex-1-enitol (16) (107 mg, 0.32 mmol) and methyl 2,3,4-tri-

O-acetyl-6-thio-a-^D-glucopyranoside (5) (131 mg, 0.38 mmol)

were stirred at room temperature for 48 h to afford, after puriﬁca-

tion by column chromatography (3:2 hexane/ethyl acetate), 19 as

a colourless oil (64 mg, 33%, a/b 3:2). R_f0.5 (3:2 hexane/ethyl ac-

etate); [a]²_D⁰þ121 (c 0.40, CHCl₃). ¹H NMR (CDCl₃, 400 MHz)

2.00 (3H, s, OC(O)CH₃), 2.03 (3H, s, OC(O)CH₃), 2.07 (3H, s,

OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.10 (3H, s, OC(O)CH₃),

2.18 (3H, s, OAc), 2.73 (1H, dd, J 3.0, 13.5 Hz, H-6), 2.83 (1H,

dd, J 8.5, 13.5 Hz, H-6), 3.43 (3H, s, OCH₃), 3.95 (1H, ddd, J

3.0, 8.5, 12.5 Hz, H-5), 4.09 (1H, ddd, J 2.0, 6.0, 12.5 Hz, H-5⁰),

4.18e4.23 (2H, m, H-6⁰), 4.86 (1H, dd, J 3.5, 10.0 Hz, H-2),

4.88e4.95 (2H, m, H-1, H-4), 5.22 (1H, dt, J 2.0, 6.0 Hz, H-4⁰),

5.44 (1H, dd, J 9.5, 10.0 Hz, H-3), 5.54 (1H, app. t, J 1.5 Hz, H-

1⁰), 5.92 (1H, dd, J 1.5, 6.0 Hz, H-3⁰). ¹³C NMR (CDCl₃,

100 MHz) 20.7 (OAc), 20.7 (OAc), 20.8 (OAc), 30.2 (C-6), 55.5

(OMe), 62.5 (C-6⁰), 64.9 (C-4⁰), 69.1 (C-5), 70.0 (C-3), 70.9 (C-

2), 71.9 (C-4), 74.0 (C-5⁰), 79.4 (C-1⁰), 95.6 (C-1), 114.1 (C-3⁰),

150.1 (C-2⁰), 168.1 (C]O), 169.7 (C]O), 170.1 (C]O), 170.2

(C]O), 170.5 (C]O), 170.7 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ1

1744 (C]O). LRMS m/z 607 (1%, MþH^þ), 487 (26%), 444

(20%), 180 (37%), 169 (100%), 130 (49%). HRMS (CI,

MþH^þ), found: 607.1691; C₂₅H₃₅O₁₅S requires: 607.1697.

4.1.4. Methyl 2,3,4-tri-O-acetyl-6-S-(3-deoxy-2,4,6-tri-O-

acetyl-a-^D-glucopyranosyl)-6-thio-a-D-glucopyranoside

(18)

4.1.6. Methyl 2,3,4-tri-O-benzyl-6-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-galactopyranosyl)-6-thio-a-D-glucopyranoside

(20)

By following method A, 2,3,4,6-tetra-O-acetyl-1,5-anhydro-

D-arabino-hex-1-enitol (15) (159 mg, 0.48 mmol) and methyl

By following method A, tri-O-acetyl-^D-galactal (14)

(106 mg, 0.39 mmol) and methyl 2,3,4-tri-O-benzyl-6-thio-a-

2842

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

D-glucopyranoside (10) (225 mg, 0.46 mmol) were stirred at

room temperature for 3 days. Column chromatography (3:1

to 2:1 hexane/ethyl acetate) failed to separate the title com-

pound from unreacted tri-O-acetyl-^D-galactal. For characterisa-

tion and puriﬁcation purposes, the mixture was deprotected with

K₂CO₃(4 mg) in methanol (3 mL) and puriﬁed by column chro-

matography (1:2 hexane/ethyl acetate). The deprotected prod-

uct was then reacetylated using pyridine and acetic anhydride,

and after puriﬁcation by column chromatography (2:1 hexane/

ethyl acetate), 20 was yielded as a colourless oil (88 mg, 33%

a/b 10:1). R_f0.3 (2:1 hexane/ethyl acetate); [a]²_D⁰þ7.6 (c

1.15, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 1.98 (3H, s,

OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.77 (1H, dd, J 6.5,

14.0 Hz, H-6), 3.12 (1H, dd, J 2.5, 14.0 Hz, H-6), 3.38 (3H, s,

OCH₃), 3.47e3.56 (2H, m, H-2, H-4), 3.87 (1H, ddd, J 2.5,

6.5, 9.5 Hz, H-5), 3.98 (1H, app. t, J 9.5 Hz, H-3), 4.15 (1H,

dd, J 7.5, 11.5 Hz, H-6⁰), 4.25 (1H, dd, J 6.0, 11.5 Hz, H-6⁰),

4.51 (1H, ddd, J 2.5, 6.0, 7.5 Hz, H-5⁰), 4.56 (1H, d, J 3.5 Hz,

H-1), 4.62 (1H, d, J 11.0 Hz, OCH₂Ph), 4.66 (1H, d, J

12.0 Hz, OCH₂Ph), 4.79 (1H, d, J 12.0 Hz, OCH₂Ph), 4.80

(1H, d, J 11.0 Hz, OCH₂Ph), 4.91 (1H, d, J 11.0 Hz, OCH₂Ph),

4.98 (1H, d, J 11.0 Hz, OCH₂Ph), 5.07 (1H, dd, J 2.5, 5.0 Hz, H-

4⁰), 5.73e5.77 (1H, m, H-1⁰), 6.02 (1H, ddd, J 1.5, 5.0, 10.0 Hz,

H-3⁰), 6.07 (1H, dd, J 3.0, 10.0 Hz, H-2⁰), 7.25e7.38 (15H, m,

ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.7 (OAc), 20.9 (OAc),

32.1 (C-6), 55.3 (OMe), 62.5 (C-6⁰), 63.3 (C-4⁰), 66.7 (C-5⁰),

70.0 (C-5), 73.4 (OCH₂Ph), 75.4 (OCH₂Ph), 75.8 (OCH₂Ph),

80.0 (C-1⁰), 80.0 (C-2 or C-4), 80.1 (C-2 or C-4), 81.9 (C-3),

97.9 (C-1), 123.9 (C-3⁰), 127.7 (ArCH), 127.9 (ArCH), 128.2

(ArCH), 128.5 (ArCH), 131.9 (C-2⁰), 138.1 (ArC), 138.6

(ArC), 170.3 (C]O), 170.6 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ1

1744 (C]O), 1230, 1072 and 1049 (CH_arom). LRMS m/z 693

(3%, MþH^þ), 662 (36%), 661 (100%), 601 (24%). HRMS

(CI, MþH^þ), found: 693.2744; C₃₈H₄₅O₁₀S requires:

693.2577.

5.72 (1H, br s, H-1⁰), 7.25e7.36 (15H, m, ArCH). ¹³C NMR

(CDCl₃, 100 MHz) 20.8 (OAc), 20.9 (OAc), 32.3 (C-6), 55.3

(OMe), 62.5 (C-6⁰), 64.8 (C-4⁰), 67.1 (C-5), 69.9 (C-5⁰), 73.2

(OCH₂Ph), 75.2 (OCH₂Ph), 75.7 (OCH₂Ph), 79.8 and 79.9

(C-2 and C-4), 80.6 (C-1⁰), 81.8 (C-3), 97.8 (C-1), 114.6 (C-

3⁰), 127.7 (ArCH), 128.1 (ArCH), 128.3 (ArCH), 128.5

(ArCH), 138.0 (ArC), 138.2 (ArC), 138.3 (ArC), 138.6 (ArC),

147.3 (C-2⁰), 167.9 (C]O), 170.2 (C]O), 170.8 (C]O). IR

n_max(thin ﬁlm)/cm^ꢁ11745 (C]O), 1230 (OMe), 1072 and

1049 (CH_arom). LRMS m/z 773 (48%, MþNa^þ), 768 (100%,

MNH^þ₄), 732 (21%), 617 (6%), 331 (9%). HRMS (ESI,

MþNH^þ₄), found: 768.3023; C₄₀H₅₀O₁₂NS requires: 768.3054.

4.1.8. Methyl 2,3,4-tri-O-benzyl-6-S-(3-deoxy-2,4,6-di-O-

acetyl-a-^D-galactopyranosyl)-6-thio-a-D-glucopyranoside

(22)

By following method B, 2,3,4,6-tetra-O-acetyl-1,5-anhydro-

D-lyxo-hex-1-enitol (16) (49 mg, 0.15 mmol) and methyl

2,3,4-tri-O-acetyl-6-thio-a-^D-glucopyranoside (10) (60 mg,

0.12 mmol) were stirred at room temperature for 5 h to afford,

after puriﬁcation by column chromatography (3:1 hexane/ethyl

acetate), 22 as a colourless oil (49 mg, 53%, a-only). R_f0.5 (3:1

1

hexane/ethyl acetate); [a]²_D⁰þ72 (c 0.33, CHCl₃). H NMR

(CDCl₃, 500 MHz) 2.05 (3H, s, OC(O)CH₃), 2.06 (3H, s,

OC(O)CH₃), 2.10 (3H, s, OC(O)CH₃), 2.75 (1H, dd, J 6.5,

14.0 Hz, H-6), 3.11 (1H, dd, J 2.0, 14.0 Hz, H-6), 3.39 (3H, s,

OMe), 3.46e3.52 (2H, m, H-2, H-4), 3.84e3.89 (1H, m, H-

5⁰), 3.99 (1H, app. t, J 9.5 Hz, H-3), 4.19 (1H, dd, J 4.5,

12.0 Hz, H-6⁰), 4.22e4.27 (1H, m, H-5), 4.37 (1H, dd, J 5.0,

12.0 Hz, H-6⁰), 4.57 (1H, d, J 3.5 Hz, H-1), 4.60 (1H, d, J

11.0 Hz, OCH₂Ph), 4.66 (1H, d, J 12.0 Hz, OCH₂Ph), 4.79

(1H, d, J 12.0 Hz, OCH₂Ph), 4.80 (1H, d, J 11.0 Hz, OCH₂Ph),

4.91 (1H, d, J 10.5 Hz, OCH₂Ph), 4.99 (1H, d, J 10.5 Hz,

OCH₂Ph), 5.52e5.58 (1H, m, H-4⁰), 5.80e5.84 (2H, m, H-1⁰,

H-3⁰), 7.25e7.52 (15H, m, ArCH). ¹³C NMR (CDCl₃,

125 MHz) 20.7 (OAc), 20.8 (OAc), 32.2 (C-6), 55.3 (OMe),

62.1 (C-4), 64.4 (C-6⁰), 66.6 (C-5⁰), 69.9 (C-5), 73.4 (OCH₂Ph),

75.1 (OCH₂Ph), 75.7 (OCH₂Ph), 80.1 and 80.2 (C-2 and C-4),

81.9 (C-3), 84.3 (C-1⁰), 97.9 (C-1), 114.9 (C-3⁰), 127.1e129.7

(ArCH), 134.4e138.1 (ArC), 146.4 (C-2⁰), 170.5 (C]O),

170.9 (C]O), 171.8 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11746

(C]O), 1072 and 1049 (CH_arom). LRMS m/z 773 (62%,

MþNa^þ), 768 (100%, MþNH^þ₄), 735 (29%), 666 (98%), 617

(63%). HRMS (ESI, MþNH^þ₄), found: 768.3019;

C₄₀H₅₀O₁₂NS requires: 768.3054.

4.1.7. Methyl 2,3,4-tri-O-benzyl-6-S-(3-deoxy-2,4,6-di-O-

acetyl-a-^D-glucopyranosyl)-6-thio-a-D-glucopyranoside

(21)

By following method B, 2,3,4,6-tetra-O-acetyl-1,5-anhydro-

D-arabino-hex-1-enitol (15) (41 mg, 0.12 mmol) and methyl

2,3,4-tri-O-acetyl-6-thio-a-^D-glucopyranoside (10) (50 mg,

0.1 mmol) were stirred at ꢁ10 ^ꢀC for 10 min to afford, after pu-

riﬁcation by column chromatography (3:1 hexane/ethyl ace-

tate), 21 as a colourless oil (48 mg, 52%, a-only). R_f0.3 (3:1

1

hexane/ethyl acetate); [a]²_D⁰þ243 (c 0.14, CHCl₃). H NMR

(CDCl₃, 400 MHz) 2.04 (3H, s, OC(O)CH₃), 2.05 (3H, s,

OC(O)CH₃), 2.06 (3H, s, OC(O)CH₃), 2.77 (1H, dd, J 6.5,

14.0 Hz, H-6), 3.11 (1H, dd, J 2.5, 14.0 Hz, H-6), 3.38 (3H, s,

OCH₃), 3.43e3.54 (2H, m, H-2, H-4), 3.85 (1H, ddd, J 2.5,

6.5, 12.0 Hz, H-5⁰), 4.00 (1H, app. t, J 9.0 Hz, H-3), 4.15

(1H, dd, J 2.5, 12.0 Hz, H-6⁰), 4.21e4.35 (2H, m, H-5, H-6⁰),

4.57 (1H, d, J 3.5 Hz, H-1), 4.62 (1H, d, J 10.0 Hz, OCH₂Ph),

4.67 (1H, d, J 12.0 Hz, OCH₂Ph), 4.78 (1H, d, J 12.0 Hz,

OCH₂Ph), 4.80 (1H, d, J 10.0 Hz, OCH₂Ph), 4.90 (1H, d, J

11.0 Hz, OCH₂Ph), 4.99 (1H, d, J 11.0 Hz, OCH₂Ph), 5.47

(1H, app. dt, J 2.0, 9.0 Hz, H-4⁰), 5.63 (1H, d, J 2.0 Hz, H-3⁰),

4.1.9. Methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(2,3-dideoxy-

4,6-di-O-acetyl-a-^D-glucopyranosyl)-6-thio-a-D-

glucopyranoside (28)

By following method B, methyl 2,3-di-O-acetyl-6-O-benzyl-

4-thio-a-^D-glucopyranoside (27) (165 mg, 0.4 mmol) and tri-

O-acetyl-^D-glucal (11) (140 mg, 0.5 mmol) were stirred at

ꢁ10 ^ꢀC for 10 min to afford, after puriﬁcation by column chro-

matography (2:1 hexane/ethyl acetate), 28 as a colourless oil

(184 mg, 72% a-only). R_f0.3 (2:1 hexane/ethyl acetate);

[a]²_D⁰þ138 (c 0.5, CHCl₃). H NMR (CDCl₃, 400 MHz) 2.06

1

(3H, s, OC(O)CH₃), 2.06 (3H, s, OC(O)CH₃), 2.07 (3H, s,

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2843

OC(O)CH₃), 2.10 (3H, s, OC(O)CH₃), 3.10 (1H, app. t, J

10.5 Hz, H-4), 3.41 (3H, s, OMe), 3.82e3.96 (2H, m, H-6),

3.98e4.14 (2H, m, H-5 and H-5⁰), 4.16e4.32 (2H, m, H-6⁰),

4.58 (1H, d, J 12.0 Hz, OCH₂Ph), 4.65 (1H, d, J 12.0 Hz,

OCH₂Ph), 4.83 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.94 (1H, d, J

3.5 Hz, H-1), 5.28e5.37 (1H, m, H-4⁰), 5.48 (1H, app. t, J

10.5 Hz, H-3), 5.64e5.67 (1H, m, H-1⁰), 5.78e5.83 (2H, m,

H-2⁰and H-3⁰), 7.26e7.35 (5H, m, ArCH). ¹³C NMR

(CDCl₃, 100 MHz) 20.8 (OAc), 20.8 (OAc), 21.0 (OAc), 47.0

(C-4), 55.4 (OMe), 62.5 (C-6⁰), 64.5 (C-4⁰), 67.3 (C-5⁰), 69.8

(C-6), 70.2 (C-5), 72.1 (C-3), 72.2 (C-2), 73.4 (OCH₂Ph),

81.3 (C-1⁰), 97.0 (C-1), 127.5 (C-3⁰), 127.7 (ArCH), 128.2

(ArCH), 128.3 (C-2⁰), 128.4 (ArCH), 138.0 (ArC), 169.6

(C]O), 170.2 (C]O), 170.4 (C]O), 170.7 (C]O). IR n_max

(thin ﬁlm)/cm^ꢁ11744 (C]O), 1370 (OMe), 1241 (CH_arom).

LRMS m/z 597 (1%, MþH^þ), 567 (10%), 476 (20%), 463

(32%), 213 (86%), 111 (100%). HRMS (ESI, MþNa^þ), found:

619.1799; C₂₈H₃₆O₁₂SNa requires: 619.1826.

acetate), 30 as a colourless oil (88 mg, 58%, a-only). R_f0.3

(2:1 hexane/ethyl acetate); [a]²_D⁰þ99 (c 1, CHCl₃). H NMR

1

(CDCl₃, 400 MHz) 2.05 (3H, s, OC(O)CH₃), 2.06 (3H, s,

OC(O)CH₃), 2.07 (3H, s, OC(O)CH₃), 2.09 (3H, s,

OC(O)CH₃), 2.13 (3H, s, OC(O)CH₃), 3.12 (1H, app. t, J

10.5 Hz, H-4), 3.40 (3H, s, OMe), 3.81e3.93 (3H, m, H-5

and H-6), 4.02 (1H, dd, J 2.5, 12.0 Hz, H-6⁰), 4.04e4.10 (1H,

m, H-5⁰), 4.17 (1H, dd, J 4.0, 12.0 Hz, H-6⁰), 4.59 (1H, d, J

12.0 Hz, OCH₂Ph), 4.65 (1H, d, J 12.0 Hz, OCH₂Ph), 4.81

(1H, dd, J 3.5, 10.0 Hz, H-2), 4.93 (1H, d, J 3.5 Hz, H-1),

5.45 (1H, app. dt, J 2.0, 9.5 Hz, H-4⁰), 5.55 (1H, app. t, J

10.5 Hz, H-3), 5.64 (1H, d, J 1.5 Hz, H-3⁰), 5.71 (1H, s,

H-1⁰), 7.28e7.35 (5H, m, ArCH). ¹³C NMR (CDCl₃,

100 MHz) 20.8 (OAc), 20.8 (OAc), 20.9 (OAc), 21.0 (OAc),

45.6 (C-4), 55.4 (OMe), 52.1 (C-6⁰), 64.3 (C-4⁰), 69.7 (C-6),

70.0 (C-5), 72.2 (C-2), 72.7 (C-3), 73.5 (OCH₂Ph), 80.7

(C-1⁰), 97.0 (C-1), 115.7 (C-3⁰), 127.7 (ArCH), 127.7

(ArCH), 128.5 (ArCH), 138.0 (ArC), 145.7 (C-2⁰), 168.0

(C]O), 169.7 (C]O), 170.1 (C]O), 170.3 (C]O), 170.6

(C]O). IR n_max(thin ﬁlm)/cm^ꢁ11746 (C]O), 1217 (CH_arom),

756 (C]C). LRMS m/z 643 (9%), 623 (6%, M^þꢁOMe), 595

(100%), 535 (75%), 521 (68%), 395 (46%), 271 (75%),

169 (66%). HRMS (CI, M^þꢁOMe), found: 623.1804;

C₂₉H₃₅O₁₃S requires: 623.1798.

4.1.10. Methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(2,3-

dideoxy-4,6-di-O-acetyl-a-^D-galactopyranosyl)-6-thio-a-D-

glucopyranoside (29)

By following method B, methyl 2,3-di-O-acetyl-6-O-benzyl-

4-thio-a-^D-glucopyranoside (27) (90 mg, 0.23 mmol) and tri-

O-acetyl-^D-galactal (14) (76 mg, 0.28 mmol) were stirred at

ꢁ10 ^ꢀC for 20 min to afford, after puriﬁcation by column chro-

matography (2:1 hexane/ethyl acetate), 29 as a colourless oil

(95 mg, 68% a-only). R_f0.4 (2:1 hexane/ethyl acetate); [a]_D²⁰

4.1.12. Methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(3-deoxy-

2,4,6-tri-O-acetyl-a-^D-galactopyranosyl)-4-thio-a-D-

glucopyranoside (31)

1

þ19.6 (c 1, CHCl₃). H NMR (CDCl₃, 400 MHz) 2.03 (3H,

By following method B, methyl 2,3-di-O-acetyl-6-O-benzyl-

4-thio-a-^D-glucopyranoside (27) (56 mg, 0.14 mmol) and

2,3,4,6-tetra-O-acetyl-1,5-anhydro-^D-lyxo-hex-1-enitol (16)

(57 mg, 0.17 mmol) were stirred at room temperature for 2 h

to afford, after puriﬁcation by column chromatography (2:1

hexane/ethyl acetate), 31 as a colourless oil (62 mg, 65%, a-

only). R_f0.2 (2:1 hexane/ethyl acetate); [a]²_D⁰þ44.8 (c 0.5,

CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 2.03 (3H, s, OC(O)CH₃),

2.06 (3H, s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.09 (3H, s,

OC(O)CH₃), 2.15 (3H, s, OC(O)CH₃), 3.11 (1H, app. t, J

10.5 Hz, H-4), 3.40 (3H, s, OMe), 3.82e4.00 (3H, m, H-5

and H-6), 4.17 (2H, d, J 6.5 Hz, H-6⁰), 4.53 (1H, ddd, J 2.5,

6.5, 6.5 Hz, H-5⁰), 4.60 (1H, d, J 12.0 Hz, OCH₂Ph), 4.65

(1H, d, J 12.0 Hz, OCH₂Ph), 4.82 (1H, dd, J 3.5, 10.0 Hz,

H-2), 4.93 (1H, d, J 3.5 Hz, H-1), 5.24 (1H, dd, J 2.5, 6.0 Hz,

H-4⁰), 5.56 (1H, app. t, J 10.5 Hz, H-3), 5.80 (1H, s, H-1⁰),

5.84 (1H, d, J 6.0 Hz, H-3⁰), 7.26e7.36 (5H, m, ArCH). ¹³C

NMR (CDCl₃, 100 MHz) 21.0 (OAc), 21.0 (OAc), 21.0

(OAc), 21.1 (OAc), 45.5 (C-4), 55.6 (OMe), 62.0 (C-6⁰), 64.1

(C-4⁰), 67.2 (C-5⁰), 70.0 (C-5), 70.2 (C-6), 72.4 (C-2), 73.0

(C-3), 73.6 (OCH₂Ph), 80.8 (C-1⁰), 97.1 (C-1), 113.2 (C-3⁰),

127.8 (ArCH), 127.9 (ArCH), 128.0 (ArCH), 128.6 (ArCH),

128.7 (ArCH), 138.3 (ArC), 148.8 (C-2⁰), 168.0 (C]O),

169.9 (C]O), 170.4 (C]O), 170.6 (C]O), 170.6 (C]O).

IR n_max(thin ﬁlm)/cm^ꢁ11745 (C]O), 1371 (OMe),

1237 (CH_arom). LRMS m/z 677 (76%, MþNa^þ), 672 (100%,

MþNH^þ₄), 570 (16%), 521 (22%), 331 (7%). HRMS

(ESI, MþNH₄^þ), found: 672.2303; C₃₀H₄₂O₁₄NS requires:

672.2326.

s, OC(O)CH₃), 2.06 (3H, s, OC(O)CH₃), 2.06 (3H, s,

OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 3.11 (1H, app. t, J

11.0 Hz, H-4), 3.41 (3H, s, OMe), 3.85e4.01 (3H, m, H-5

and H-6), 4.12e4.24 (2H, m, H-6⁰), 4.31 (1H, ddd, J 2.5, 6.5,

6.5 Hz, H-5⁰), 4.59 (1H, d, J 12.0 Hz, OCH₂Ph), 4.66 (1H, d,

J 12.0 Hz, OCH₂Ph), 4.84 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.94

(1H, d, J 3.5 Hz, H-1), 5.05 (1H, dd, J 2.5, 5.0 Hz, H-4⁰),

5.48 (1H, app. t, J 10.5 Hz, H-3), 5.73 (1H, d, J 2.0 Hz, H-

1⁰), 5.97e6.07 (2H, m, H-2⁰and H-3⁰), 7.26e7.36 (5H, m,

ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.8 (OAc), 20.8

(OAc), 46.6 (C-4), 55.4 (OMe), 62.3 (C-6⁰), 62.8 (C-4⁰), 67.1

(C-5⁰), 69.9 (C-6), 70.1 (C-5), 72.2 (C-2 and C-3), 73.3

(OCH₂Ph), 80.9 (C-1⁰), 97.0 (C-1), 124.0 (C-3⁰), 127.7

(ArCH), 128.4 (ArCH), 131.2 (C-2⁰), 138.1 (ArC), 169.6

(C]O), 170.2 (C]O), 170.4 (C]O), 170.5 (C]O). IR n_max

(thin ﬁlm)/cm^ꢁ11745 (C]O), 1371 (OMe), 789 (C]C).

LRMS m/z 597 (1%, MþH^þ), 476 (13%), 463 (19%), 213

(100%), 153 (23%). HRMS (CI, MþH^þ), found: 597.2023;

C₂₈H₃₇O₁₂S requires: 597.2006.

4.1.11. Methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(3-deoxy-

2,4,6-tri-O-acetyl-a-^D-glucopyranosyl)-6-thio-a-D-

glucopyranoside (30)

By following method B, methyl 2,3-di-O-acetyl-6-O-benzyl-

4-thio-a-^D-glucopyranoside (27) (90 mg, 0.23 mmol) and

2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-arabino-hex-1-enitol (15)

(76 mg, 0.28 mmol) were stirred at ꢁ10 ^ꢀC for 20 min to afford,

after puriﬁcation by column chromatography (2:1 hexane/ethyl

2844

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

4.2. General method for dihydroxylation

puriﬁcation by column chromatography (1:1 to 1:2 hexane/ethyl

acetate), 33 as a colourless oil (31 mg, 56%). R_f0.1 (1:1 hexane/

ethyl acetate); [a]_D²⁰þ171.8 (c 0.43, CHCl₃). ¹H NMR (CDCl₃,

400 MHz) 2.00 (3H, s, OC(O)CH₃), 2.03 (3H, s, OC(O)CH₃),

2.07 (3H, s, OC(O)CH₃), 2.07 (3H, s, OC(O)CH₃), 2.08 (3H,

s, OC(O)CH₃), 2.13 (3H, s, OC(O)CH₃), 2.16 (3H, s,

OC(O)CH₃), 2.61 (1H, dd, J 6.5, 14.5 Hz, H-6), 2.84 (1H, dd,

J 3.0, 14.5 Hz, H-6), 3.41 (3H, s, OMe), 3.95 (1H, ddd, J 3.0,

6.5, 9.5 Hz, H-5), 4.08 (1H, dd, J 7.0, 11.5 Hz, H-6⁰), 4.16

(1H, dd, J 5.5, 11.5 Hz, H-6⁰), 4.69 (1H, ddd, J 1.5, 5.5,

7.0 Hz, H-5⁰), 4.85 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.90 (1H, d,

J 3.5 Hz, H-1), 5.02 (1H, dd, J 1.5, 4.0 Hz, H-4⁰), 5.04 (1H,

app. t, J 9.5 Hz, H-4), 5.24 (1H, app. t, J 3.5 Hz, H-3⁰), 5.32

(1H, dd, J 3.5, 6.0 Hz, H-2⁰), 5.46 (1H, app. t, J 9.5 Hz, H-3),

5.59 (1H, d, J 6.0 Hz, H-1⁰). ¹³C NMR (CDCl₃, 100 MHz)

20.7 (OAc), 20.7 (OAc), 21.0 (OAc), 31.6 (C-6), 55.3 (OMe),

61.9 (C-6⁰), 64.8 (C-5⁰), 66.6 (C-2⁰and C-3⁰), 68.2 (C-4⁰), 68.4

(C-5), 70.0 (C-3), 70.8 (C-2), 71.1 (C-4), 82.2 (C-1⁰), 96.6 (C-

1), 169.2 (C]O), 169.5 (C]O), 169.7 (C]O), 169.8

(C]O), 170.1 (C]O), 170.2 (C]O), 170.5 (C]O). IR n_max

(thin ﬁlm)/cm^ꢁ11746 (C]O), 1370 (OMe). LRMS m/z 689

(61%, MþNa^þ), 684 (100%, MþNH^þ₄), 516 (5%), 331 (10%).

HRMS (ESI^ꢁ, MꢁH), found: 665.1769; C₂₇H₃₇O₁₇S requires:

665.1752.

To a stirred solution of the S-linked glycoconjugate (1 equiv)

in anhydrous pyridine (3 mL) under an atmosphere of argon

was added osmium(VIII) tetroxide (1 equiv) in anhydrous pyr-

idine (3 mL). The reaction mixture was stirred at room temper-

ature until the reaction was shown to have reached completion

by TLC analysis (ethyl acetate) and then 40% aq sodium hydro-

gen sulﬁte (3 mL), water (3 mL) and pyridine (1 mL) were

added, and the mixture was stirred for a further 2 h. The mixture

was then diluted with water (5 mL) and extracted with CH₂Cl₂

(3ꢂ10 mL). The combined extracts were dried (MgSO₄), ﬁl-

tered and concentrated in vacuo. The crude product was then

per-O-acetylated by dissolving in pyridine (6 mL) and acetic

anhydride (3 mL). The solution was stirred overnight at room

temperature and then concentrated in vacuo. The residue was

taken up in ethyl acetate (5 mL) and washed with 1 N HCl

(5 mL) and brine (3 mL), dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was then subjected to puriﬁcation

by column chromatography.

4.2.1. Methyl 2,3,4-tri-O-acetyl-6-S-(2,3,4,6-tetra-O-acetyl-

a-^D-mannopyranosyl)-6-thio-a-D-glucopyranoside (32)

Following the general method, methyl 2,3,4-tri-O-acetyl-

6-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-glucopyranosyl)-6-thio-

a-^D-glucopyranoside (12) (55 mg, 0.1 mmol) was stirred with

osmium tetroxide (25 mg, 0.1 mmol) at room temperature for

2 h. Subsequent per-O-acetylation afforded, after puriﬁcation

by column chromatography (1:1 to 1:2 hexane/ethyl acetate),

32 as a colourless oil (42 mg, 63%). R_f0.2 (1:1 hexane/ethyl ace-

tate); [a]²_D⁰þ99 (c 0.65, CHCl₃). ¹H NMR (CDCl₃, 400 MHz)

1.98 (3H, s, OC(O)CH₃), 2.00 (3H, s, OC(O)CH₃), 2.03 (3H, s,

OC(O)CH₃), 2.06 (3H, s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃),

2.10 (3H, s, OC(O)CH₃), 2.17 (3H, s, OC(O)CH₃), 2.65 (1H, dd,

J 7.5, 14.0 Hz, H-6), 2.83 (1H, dd, J 3.0, 14.0 Hz, H-6), 3.42

(3H, s, OMe), 3.96 (1H, ddd, J 3.0, 7.5, 10.5 Hz, H-5), 4.07

(1H, dd, J 1.5, 12.0 Hz, H-6⁰), 4.27e4.38 (2H, m, H-5⁰and H-

6⁰), 4.87 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.91 (1H, d, J 3.5 Hz,

H-1), 4.99 (1H, app. t, J 9.5 Hz, H-4), 5.26 (1H, dd, J 3.5,

9.5 Hz, H-4⁰), 5.28e5.36 (3H, m, H-1⁰, H-2⁰and H-3⁰), 5.45

(1H, app. t, J 9.5 Hz, H-3). ¹³C NMR (CDCl₃, 100 MHz) 20.6

(OAc), 20.7 (OAc), 20.9 (OAc), 31.5 (C-6), 55.6 (OMe), 62.3

(C-6⁰), 66.1 (C-2⁰or C-3⁰), 68.2 (C-5), 69.2 (C-5⁰), 69.3 (C-

4⁰), 69.9 (C-3), 70.8 (C-2⁰or C-3⁰), 70.8 (C-2), 71.3 (C-4),

82.3 (C-1⁰), 96.9 (C-1), 169.7 (C]O), 169.8 (C]O), 169.8

(C]O), 169.9 (C]O), 170.1 (C]O), 170.2 (C]O), 170.7

(C]O). IR n_max(thin ﬁlm)/cm^ꢁ11746 (C]O), 1370 (OMe).

HRMS (CI, M^þꢁOAc), found: 607.1696; C₂₅H₃₅O₁₅S

requires: 607.1697.

4.2.3. Methyl 2,3,4-tri-O-benzyl-6-S-(2,3,4,6-tetra-O-acetyl-

a-^D-mannopyranosyl)-6-thio-a-D-glucopyranoside (34)

Following the general method, methyl 2,3,4-tri-O-benzyl-

6-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-glucopyranosyl)-6-thio-

a-^D-glucopyranoside (13) (73 mg, 0.1 mmol) was stirred with

osmium tetroxide (27 mg, 0.1 mmol) at room temperature over-

night. Subsequent per-O-acetylation afforded, after puriﬁcation

by column chromatography (2:1 to 1:1 hexane/ethyl acetate),

34 as a colourless oil (44 mg, 52%). R_f0.3 (1:1 hexane/ethyl ac-

etate); [a]²_D⁰þ110 (c 0.21, CHCl₃). H NMR (CDCl₃, 400 MHz)

1.98 (3H, s, OC(O)CH₃), 1.99 (3H, s, OC(O)CH₃), 2.10 (3H, s,

OC(O)CH₃), 2.13 (3H, s, OC(O)CH₃), 2.71 (1H, dd, J 6.5,

14.0 Hz, H-6), 3.00 (1H, dd, J 2.5, 14.0 Hz, H-6), 3.37 (3H, s,

OMe), 3.45e3.52 (2H, m, H-2, H-4), 3.82 (1H, ddd, J 2.5,

6.5, 9.5 Hz, H-5), 3.98 (1H, app. t, J 9.0 Hz, H-3), 4.05 (1H,

dd, J 7.0, 11.5 Hz, H-6⁰), 4.14 (1H, dd, J 6.0, 11.5 Hz, H-6⁰),

4.48 (1H, d, J 3.5 Hz, H-1), 4.61 (1H, d, J 11.0 Hz, OCH₂Ph),

4.67 (1H, d, J 12.0 Hz, OCH₂Ph), 4.78 (1H, d, J 12.0 Hz,

OCH₂Ph), 4.79 (1H, d, J 11.0 Hz, OCH₂Ph), 4.91 (1H, d, J

11.0 Hz, OCH₂Ph), 4.99 (1H, d, J 11.0 Hz, OCH₂Ph), 5.02

(1H, dd, J 2.0, 4.5 Hz, H-4⁰), 5.22 (1H, app. t, J 3.5 Hz, H-3⁰),

5.32 (1H, dd, J 3.5, 6.0 Hz, H-2⁰), 5.60 (1H, d, J 6.0 Hz, H-

1⁰), 7.26e7.38 (15H, m, ArCH). ¹³C NMR (CDCl₃,

100 MHz) 20.7 (OAc), 20.9 (OAc), 32.2 (C-6), 55.1 (OMe),

61.7 (C-6⁰), 64.8 (C-5⁰), 66.6 and 66.8 (C-2⁰and C-3⁰), 68.2

(C-4⁰), 69.9 (C-5), 73.2 (OCH₂Ph), 75.1 (OCH₂Ph), 75.7

(OCH₂Ph), 79.8 and 79.9 (C-2 and C-4), 81.8 (C-3), 82.3 (C-

3⁰), 97.8 (C-1), 127.7e128.4 (ArCH), 138.1 (ArC), 138.6

(ArC), 170.1 (C]O), 170.2 (C]O), 170.3 (C]O), 170.8

(C]O). IR n_max(thin ﬁlm)/cm^ꢁ11744 (C]O), 1371 (OMe),

1237 (CH_arom). LRMS m/z 833 (47%, MþNa^þ), 828 (100%,

4.2.2. Methyl 2,3,4-tri-O-acetyl-6-S-(2,3,4,6-tetra-O-acetyl-

a-^D-talopyranosyl)-6-thio-a-D-glucopyranoside (33)

Following the general method, methyl 2,3,4-tri-O-acetyl-6-S-

(2,3-dideoxy-4,6-di-O-acetyl-a-^D-galactopyranosyl)-6-thio-a-

D-glucopyranoside (17) (45 mg, 0.08 mmol) was stirred with

osmium tetroxide (21 mg, 0.08 mmol) at room temperature

overnight. Subsequent per-O-acetylation afforded, after

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2845

MþNH^þ₄), 649 (24%), 489 (37%), 395 (8%). HRMS (ESI^ꢁ,

MꢁH), found: 809.2859; C₄₂H₅₀O₁₄S requires: 809.2843.

(1H, d, J 3.5 Hz, H-1), 5.15 (1H, dd, J 3.5, 10.0 Hz, H-3⁰),

5.22 (1H, dd, J 1.5, 3.5 Hz, H-2⁰), 5.29 (1H, d, J 1.5 Hz, H-

1⁰), 5.46 (1H, app. t, J 10.0 Hz, H-3), 7.26e7.37 (5H, m,

ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.6 (OAc), 20.7

(OAc), 20.8 (OAc), 20.9 (OAc), 47.0 (C-4), 55.5 (OMe), 62.0

(C-6), 65.8 (C-3⁰), 69.4 (C-5), 70.1 (C-5⁰), 70.2 (C-6), 71.0

(C-3), 71.6 (C-2⁰), 72.2 (C-2), 73.5 (OCH₂Ph), 83.4 (C-1⁰),

97.0 (C-1), 127.7 (ArCH), 127.8 (ArCH), 128.4 (ArCH),

137.9 (ArC), 169.6 (C]O), 169.7 (C]O), 169.9 (C]O),

170.3 (C]O), 170.5 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11746

(C]O), 1370 (OMe), 1223 (CH_arom). LRMS m/z 732 (100%,

MþNH^þ₄), 583 (5%), 483 (8%), 331 (21%). HRMS (ESI^ꢁ,

MꢁH), found: 713.2137; C₃₂H₄₁O₁₆S requires: 713.2116.

4.2.4. Methyl 2,3,4-tri-O-benzyl-6-S-(2,3,4,6-tetra-O-acetyl-

a-^D-talopyranosyl)-6-thio-a-D-glucopyranoside (35)

Following the general method, methyl 2,3,4-tri-O-benzyl-6-

S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-galactopyranosyl)-6-thio-

a-D-glucopyranoside (20) (30 mg, 0.04 mmol) was stirred with

osmium tetroxide (12 mg, 0.04 mmol) at room temperature

overnight. Subsequent per-O-acetylation afforded, after puriﬁ-

cation by column chromatography (2:1 to 1:1 hexane/ethyl ac-

etate), 35 as a colourless oil (20 mg, 57%). R_f0.3 (1:1 hexane/

ethyl acetate); [a]_D²⁰þ59 (c 0.13, CHCl₃). H NMR (CDCl₃,

1

500 MHz) 1.99 (3H, s, OC(O)CH₃), 2.04 (3H, s, OC(O)CH₃),

2.05 (3H, s, OC(O)CH₃), 2.15 (3H, s, OC(O)CH₃), 2.74 (1H,

dd, J 6.5, 14.0 Hz, H-6), 3.00 (1H, dd, J 2.5, 14.0 Hz, H-6),

3.37 (3H, s, OMe), 3.49 (1H, app. t, J 9.0 Hz, H-4), 3.55 (1H,

dd, J 3.5, 9.5 Hz, H-2), 3.81e3.75 (1H, m, H-5), 3.98 (1H,

app. t, J 9.5 Hz, H-3), 4.01e4.05 (1H, m, H-6⁰), 4.24e4.34

(2H, m, H-5⁰, H-6⁰), 4.55 (1H, d, J 3.5 Hz, H-1), 4.59 (1H, d,

J 11.0 Hz, OCH₂Ph), 4.66 (1H, d, J 12.0 Hz, OCH₂Ph),

4.76e4.81 (2H, m, OCH₂Ph), 4.91 (1H, d, J 11.0 Hz, OCH₂Ph),

4.98 (1H, d, J 11.0 Hz, OCH₂Ph), 5.26 (1H, dd, J 3.0, 10.0 Hz,

H-4⁰), 5.31 (1H, app. t, J 9.5 Hz, H-3⁰), 5.35 (1H, dd, J 1.5,

3.0 Hz, H-2⁰), 5.36e5.39 (1H, m, H-1⁰), 7.24e7.37 (15H, m,

ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.6 (OAc), 20.7

(OAc), 20.9 (OAc), 32.0 (C-6), 55.3 (OMe), 62.3 (C-6⁰), 66.2

(C-5⁰), 69.1 (C-2⁰and C-3⁰), 69.3 (C-4⁰), 69.7 (C-5), 73.5

(OCH₂Ph), 75.2 (OCH₂Ph), 75.7 (OCH₂Ph), 79.8 and 80.2

(C-2 and C-4), 81.8 (C-3), 82.7 (C-3⁰), 97.3 (C-1), 127.6

(ArCH), 127.9 (ArCH), 128.1 (ArCH), 128.4 (ArCH), 138.1

(ArC), 138.6 (ArC), 170.1 (C]O), 170.2 (C]O), 170.3

(C]O), 170.8 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11745

(C]O), 1371 (OMe), 1237 (CH_arom). LRMS m/z 833 (37%,

MþNa^þ), 828 (100%, MþNH^þ₄), 779 (6%), 483 (7%), 331

(8%). HRMS (ESI^ꢁ, MꢁH), found: 809.2839; C₄₂H₅₀O₁₄S

requires: 809.2843.

4.2.6. Methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(2,3,4,6-tetra-

O-acetyl-a-^D-talopyranosyl)-6-thio-a-D-glucopyranoside

and methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(2,3,4,6-tetra-

O-acetyl-a-^D-gulopyranosyl)-6-thio-a-D-glucopyranoside

(37)

Following the general method, methyl 6-O-benzyl-2,3-di-O-

acetyl-4-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-galactopyrano-

syl)-6-thio-a-^D-glucopyranoside (29) (32 mg, 0.05 mmol) was

stirred with osmium tetroxide (14 mg, 0.05 mmol) at room tem-

perature for 18 h. Subsequent per-O-acetylation afforded, after

puriﬁcation by column chromatography (2:1 to 1:1 hexane/

ethyl acetate), 37 as a colourless oil (29 mg, 76%, 1:0.4 Tal/

Gul). Tal: R_f0.2 (2:1 hexane/ethyl acetate); [a]²_D⁰þ118 (c

0.105, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 2.01 (3H, s,

OC(O)CH₃), 2.03 (3H, s, OC(O)CH₃), 2.03 (3H, s, OC(O)CH₃),

2.05 (3H, s, OC(O)CH₃), 2.12 (3H, s, OC(O)CH₃), 2.14 (3H, s,

OC(O)CH₃), 2.99 (1H, app. t, J 10.5 Hz, H-4), 3.41 (3H, s,

OMe), 3.82e3.98 (3H, m, H-5, H-6), 4.02e4.08 (2H, m, H-

6⁰), 4.46 (1H, ddd, J 1.5, 6.5, 6.5 Hz, H-5⁰), 4.59 (1H, d, J

12.0 Hz, OCH₂Ph), 4.67 (1H, d, J 12.0 Hz, OCH₂Ph), 4.82

(1H, dd, J 3.5, 10.0 Hz, H-2), 4.93 (1H, d, J 3.5 Hz, H-1),

4.95 (1H, dd, J 1.5, 4.0 Hz, H-4⁰), 5.22 (1H, app. t, J 3.5 Hz,

H-3⁰), 5.25 (1H, dd, J 3.0, 6.0 Hz, H-2⁰), 5.47 (1H, app. t, J

10.5 Hz, H-3), 5.59 (1H, d, J 6.0 Hz, H-1⁰), 7.27e7.38 (5H,

m, ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.6 (OAc), 20.7

(OAc), 20.8 (OAc), 20.8 (OAc), 20.9 (OAc), 46.5 (C-4), 55.4

(OMe), 61.9 (C-6⁰), 66.2 (C-3⁰), 66.4 (C-2⁰), 67.9 (C-4⁰), 69.7

(C-6), 70.6 (C-5), 71.9 (C-3), 72.2 (C-2), 73.4 (OCH₂Ph),

82.7 (C-1⁰), 97.0 (C-1), 127.7 (ArCH), 127.7 (ArCH), 128.4

(ArCH), 138.1 (ArC), 169.0 (C]O), 169.4 (C]O), 169.8

(C]O), 170.3 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11752

(C]O). Gul: R_f0.2 (2:1 hexane/ethyl acetate); [a]²_D⁰þ56 (c

0.11, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 1.99 (3H, s,

OC(O)CH₃), 2.02 (3H, s, OC(O)CH₃), 2.05 (3H, s, OC(O)CH₃),

2.08 (3H, s, OC(O)CH₃), 2.11 (3H, s, OC(O)CH₃), 2.12 (3H, s,

OC(O)CH₃), 3.10 (1H, app. t, J 11.0 Hz, H-4), 3.40 (3H, s,

OMe), 3.81e3.98 (3H, m, H-5, H-6), 4.09 (2H, d, J 6.5 Hz,

H-6⁰), 4.31 (1H, app. dt, J 1.5, 6.5 Hz, H-5⁰), 4.59 (1H, d, J

12.0 Hz, OCH₂Ph), 4.64 (1H, d, J 12.0 Hz, OCH₂Ph), 4.82

(1H, dd, J 3.5, 10.0 Hz, H-2), 4.93 (1H, d, J 3.5 Hz, H-1),

5.04e5.11 (2H, m, H-2⁰and H-4⁰), 5.21e5.29 (1H, m, H-3⁰),

5.42e5.44 (1H, m, H-1⁰), 5.47 (1H, app. t, J 10.0 Hz, H-3),

7.26e7.36 (5H, m, ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.5

4.2.5. Methyl 6-O-benzyl-2,3-di-O-acetyl-4-S-(2,3,4,6-tetra-

O-acetyl-a-^D-mannopyranosyl)-6-thio-a-D-glucopyranoside

(36)

Following the general method, methyl 6-O-benzyl-2,3-di-O-

acetyl-4-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-glucopyranosyl)-

6-thio-a-^D-glucopyranoside (28) (50 mg, 0.08 mmol) was

stirred with osmium tetroxide (21 mg, 0.08 mmol) at room tem-

perature for 20 min. Subsequent per-O-acetylation afforded,

after puriﬁcation by column chromatography (2:1 to 1:1 hex-

ane/ethyl acetate), 36 as a colourless oil (50 mg, 83%). R_f0.3

(1:1 hexane/ethyl acetate); [a]²_D⁰þ95 (c 0.3, CHCl₃). ¹H

NMR (CDCl₃, 400 MHz) 2.00 (3H, s, OC(O)CH₃), 2.05 (3H,

s, OC(O)CH₃), 2.06 (3H, s, OC(O)CH₃), 2.07 (3H, s,

OC(O)CH₃), 2.09 (3H, s, OC(O)CH₃), 2.13 (3H, s, OC(O)CH₃),

3.10 (1H, app. t, J 10.5 Hz, H-4), 3.40 (3H, s, OMe), 3.78e3.93

(3H, m, H-5 and H-6), 3.95 (1H, dd, J 2.5, 12.5 Hz, H-6⁰), 4.09

(1H, app. t, J 2.5, 4.5, 10.0 Hz, H-5⁰), 4.23 (1H, dd, J 4.5,

12.5 Hz, H-6⁰), 4.59 (1H, d, J 12.0 Hz, OCH₂Ph), 4.62 (1H, d,

J 12.0 Hz, OCH₂Ph), 4.81 (1H, dd, J 3.5, 10.0 Hz, H-2), 4.93

2846

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

(OAc), 20.6 (OAc), 20.7 (OAc), 20.8 (OAc), 20.9 (OAc), 46.6

(C-4), 55.4 (OMe), 61.4 (C-6⁰), 65.4 (C-2⁰or C-4⁰), 65.6 (C-

3⁰), 68.2 (C-5⁰), 69.4 (C-6), 69.5 (C-2⁰or C-4⁰), 70.6 (C-5),

72.2 (C-2), 73.4 (OCH₂Ph), 83.7 (C-1⁰), 97.0 (C-1), 127.6

(ArCH), 128.4 (ArCH), 138.1 (ArC), 169.0 (C]O), 169.4

(C]O), 169.8 (C]O), 170.3 (C]O). IR n_max(thin ﬁlm)/

cm^ꢁ11752 (C]O), 1223 (CH_arom). LRMS m/z 737 (55%,

MþNa^þ), 732 (100%, MþNH^þ₄), 688 (9%), 571 (8%), 483

(7%), 331 (22%). HRMS (ESI^ꢁ, MꢁH), found: 713.2130;

C₃₂H₄₁O₁₆S requires: 713.2116.

10 min to afford, after puriﬁcation by column chromatography

(2:1 hexane/ethyl acetate, 1% triethylamine), 50 as a colourless

oil (100 mg, 64% a-only). R_f0.3 (2:1 hexane/ethyl acetate). ¹H

NMR (CDCl₃, 400 MHz) 2.07 (3H, s, OC(O)CH₃), 2.08 (3H, s,

OC(O)CH₃), 2.10e2.22 (1H, m, SCH₂CH₂), 2.33e2.39 (1H,

m, SCH₂CH₂), 2.67e2.86 (2H, m, SCH₂CH₂), 3.79 (3H, s,

OMe), 4.17e4.29 (3H, m, H-5, H-6), 4.91e4.96 (1H, m,

NHCH), 5.28 (1H, ddd, J 2.5, 5.5, 8.0 Hz, H-4_b), 5.36 (1H,

ddd, J 2.0, 4.5, 9.0 Hz, H-4), 5.43 (1H, d, J 3.0 Hz, H-1_b),

5.55e5.57 (1H, m, H-1), 5.79 (1H, dt, J 1.5, 10.0 Hz, H-3),

5.87e5.95 (3H, m, H-3, H-2), 6.85 (1H, dd, J 8.0, 13.5 Hz,

NH), 6.93e6.97 (1H, m, NH_b), 7.42e7.55 (3H, m, ArCH),

7.80e7.85 (2H, m, ArCH). ¹³C NMR (CDCl₃, 100 MHz)

20.7 (OAc), 20.8 (OAc), 21.0 (OAc), 27.9 and 28.4 (SCH₂CH₂),

33.0 and 33.2 (SCH₂CH₂), 51.8, 52.0 and 52.2 (NHCH), 52.7

(OMe), 62.8 and 63.1 (C-6), 65.0 (C-4), 66.9 (C-5), 79.4,

80.3 and 81.0 (C-1), 127.1 (ArCH), 127.2 (ArCH), 127.7 and

127.8 (C-3), 128.6 (C-2), 130.0 (ArCH), 131.9 (ArCH), 133.7

(ArC), 167.1 (C]O), 167.2 (C]O), 170.3 (C]O), 170.9

(C]O), 172.5 (C]O), 172.6 (C]O). IR n_max(thin ﬁlm)/

cm^ꢁ11739 (C]O), 1661 (C]O), 669 (CH_arom). LRMS m/z

466 (1%, MþH^þ), 345 (23%), 252 (32%), 213 (37%), 153

(57%), 111 (100%). HRMS (CI, MþH^þ), found: 466.1533;

C₂₂H₂₈NO₈S requires: 466.1536.

4.3. Ferrier reactions with cysteine and homocysteine

4.3.1. N-Benzoyl-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-

glycopyranosyl)-^L-cysteine ethyl ester (49)

Following method A, N-benzoyl-^L-cysteine ethyl ester (46)

(120 mg, 0.47 mmol) and tri-O-acetyl-^D-glucal (11) (107 mg,

0.39 mmol) were stirred at room temperature for 4.5 h to afford,

after puriﬁcation by column chromatography (2:1 hexane/ethyl

acetate), 49 as a white powder (131 mg, 72%, a/b 2:1).

Following method B, N-benzoyl-^L-cysteine ethyl ester (46)

(50 mg, 0.19 mmol) and tri-O-acetyl-^D-glucal (11) (64 mg,

0.24 mmol) were stirred at room temperature for 10 min to af-

ford, after puriﬁcation by column chromatography (2:1 hexane/

ethyl acetate), 49 as a white powder (80 mg, 87% a-only). R_f0.4

(2:1 hexane/ethyl acetate); mp 124e126 ^ꢀC; [a]_D²⁰þ117.8 (c

1.2, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 1.31 (3H, t, J

7.0 Hz, OCH₂CH₃), 1.96 (3H, s, OC(O)CH₃), 2.08 (3H, s,

OC(O)CH₃), 3.18 (1H, dd, J 3.0, 15.0 Hz, SCH₂), 3.44 (1H,

dd, J 5.0, 15.0 Hz, SCH₂), 4.16e4.32 (5H, m, H-5, H-6,

OCH₂CH₃), 5.29e5.36 (2H, m, NHCH, H-4), 5.54 (1H, dt, J

2.0, 3.0 Hz, H-1), 5.80 (1H, dt, J 2.0, 10.0 Hz, H-3), 5.95

(1H, ddd, J 2.0, 3.0, 10.0 Hz, H-2), 7.40e7.46 (2H, m,

ArCH), 7.48e7.53 (1H, m, ArCH), 7.75 (1H, d, J 9.0 Hz,

NH), 7.86e7.91 (2H, m, ArCH). ¹³C NMR (CDCl₃,

100 MHz) 14.3 (OCH₂CH₃), 20.5 (OAc), 21.0 (OAc), 36.8

(SCH₂), 52.8 (C-4), 61.8 (OCH₂CH₃), 62.8 (C-6), 64.5

(NHCH), 67.9 (C-5), 82.4 (C-1), 127.0 (ArCH), 127.4 (C-3),

128.4 (C-2), 128.5 (ArCH), 131.8 (ArCH), 133.8 (ArC),

167.2 (C]O), 170.1 (C]O), 170.2 (C]O), 170.8 (C]O).

IR n_max(thin ﬁlm)/cm^ꢁ11734 (C]O), 1654 (C]O), 1524

(NHCO), 908 (CH_arom), 732 (CH_arom). LRMS m/z 466 (64%,

MþH^þ), 345 (100%), 332 (33%), 252 (21%), 213 (53%).

HRMS (CI, MþH^þ), found: 466.1548; C₂₂H₂₈NO₈S requires:

466.1535.

4.3.3. N-Benzoyl-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-

galactopyranosyl)-^L-cysteine ethyl ester (51)

Following method A, N-benzoyl-^L-cysteine ethyl ester (46)

(194 mg, 0.7 mmol) and tri-O-acetyl-^D-galactal (14) (173 mg,

0.6 mmol) were stirred at room temperature overnight to afford,

after puriﬁcation by column chromatography (3:1 to 1:1 pen-

tane/ethyl acetate), 51 as a white powder (155 mg, 60%,

a/b 2:1).

Following method B, N-benzoyl-^L-cysteine ethyl ester (46)

(50 mg, 0.19 mmol) and tri-O-acetyl-^D-galactal (14) (64 mg,

0.24 mmol) were stirred at room temperature for 1.5 h to afford,

after puriﬁcation by column chromatography (2:1 hexane/ethyl

acetate), 51 as a white powder (70 mg, 77% a-only). R_f0.3 (2:1

hexane/ethyl acetate); mp 157e159 ^ꢀC; [a]_D²⁰ꢁ5.3 (c 0.73,

1

CHCl₃). H NMR (CDCl₃, 400 MHz) 1.27 (3H, t, J 7.0 Hz,

OCH₂CH₃), 1.90 (3H, s, OC(O)CH₃), 2.06 (3H, s, OC(O)CH₃),

3.14 (1H, dd, J 3.5, 14.5 Hz, SCH₂), 3.46 (1H, dd, J 4.5,

14.5 Hz, SCH₂), 4.05e4.13 (1H, m, H-6), 4.18e4.29 (3H, m,

H-6, OCH₂CH₃), 4.48 (1H, ddd, J 2.5, 4.0, 7.5 Hz, H-5), 5.04

(1H, dd, J 2.5, 5.5 Hz, H-4), 5.24 (1H, ddd, J 3.5, 4.5, 8.5 Hz,

NHCH), 5.59 (1H, dd, J 2.0, 3.5 Hz, H-1), 6.00 (1H, ddd, J

2.0, 5.5, 10.0 Hz, H-3), 6.10 (1H, dd, J 3.5, 10.0 Hz, H-2),

7.38e7.46 (2H, m, ArCH), 7.49 (1H, tt, J 1.0, 6.5 Hz, ArCH),

7.57 (1H, d, J 8.5 Hz, NH), 7.83e7.88 (2H, m, ArCH). ¹³C

NMR (CDCl₃, 100 MHz) 14.4 (OCH₂CH₃), 20.6 (OAc), 20.9

(OAc), 36.5 (SCH₂), 52.9 (NHCH), 61.9 (OCH₂CH₃), 62.8

(C-6), 63.2 (C-4), 68.0 (C-5), 82.3 (C-1), 123.8 (C-3), 127.5

(ArCH), 128.6 (ArCH), 131.6 (ArCH), 132.0 (C-2), 134.1

(ArC), 167.5 (C]O), 170.2 (C]O), 170.3 (C]O), 170.9

(C]O). IR n_max(thin ﬁlm)/cm^ꢁ11749 (C]O), 1655

(C]O). HRMS (CI, MþH^þ), found: 466.1530; C₂₂H₂₈NO₈S

requires: 466.1535.

4.3.2. N-Benzoyl-S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-

glucopyranosyl)-^DL-homocysteine methyl ester (50)

Following method A, N-benzoyl-^DL-homocysteine methyl

ester (48) (100 mg, 0.39 mmol) and tri-O-acetyl-^D-glucal

(11) (129 mg, 0.47 mmol) were stirred at room temperature

overnight to afford, after puriﬁcation by column chromatogra-

phy (2:1 hexane/ethyl acetate, 1% triethylamine), 50 as a

colourless oil (161 mg, 89%, a/b 2:1).

Following method B, N-benzoyl-^DL-homocysteine methyl

ester (48) (85 mg, 0.33 mmol) and tri-O-acetyl-^D-glucal (11)

(109 mg, 0.4 mmol) were stirred at room temperature for

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2847

4.3.4. N-Benzoyl-S-(3-deoxy-2,4,6-tri-O-acetyl-a-D-

glucopyranosyl)-^L-cysteine ethyl ester (52)

cm^ꢁ11741 (C]O), 1647 (C]O), 771 (C]C). LRMS m/z

524 (100%, MþH^þ), 464 (11%), 422 (47%), 404 (35%), 271

(7%). HRMS (CI, MþH^þ), found: 524.1605; C₂₄H₃₀NO₁₀S re-

quires: 524.1590.

Following method A, N-benzoyl-L-cysteine ethyl ester (46)

(74 mg, 0.29 mmol) and 2,3,4,6-tetra-O-acetyl-1,5-anhydro-^D-

arabino-hex-1-enitol (15) (81 mg, 0.24 mmol) were stirred at

50 ^ꢀC to afford, after puriﬁcation by column chromatography

(3:1 to 1:1 pentane/ethyl acetate), 52 as a colourless oil

(37 mg, 22%, a/b 4:1).

4.3.6. Ethyl 3-((2R)-6-(acetoxymethyl)-3-oxo-3,6-dihydro-

2H-pyran-2-ylthio)-2-benzamidopropanoate (53)

Following method A, N-benzoyl-^L-cysteine ethyl ester (46)

(144 mg, 0.57 mmol) and 2,3,4,6-tetra-O-acetyl-1,5-anhydro-

D-lyxo-hex-1-enitol (16) (156 mg, 0.47 mmol) were stirred at

60 ^ꢀC to afford, after puriﬁcation by column chromatography

(3:1 to 1:1 pentane/ethyl acetate), 53 as a colourless oil

Following method B, N-benzoyl-^L-cysteine ethyl ester (46)

(57 mg, 0.23 mmol) and 2,3,4,6-tetra-O-acetyl-1,5-anhydro-^D-

arabino-hex-1-enitol (15) (62 mg, 0.18 mmol) were stirred at

room temperature for 15 min to afford, after puriﬁcation by col-

umn chromatography (3:2 hexane/ethyl acetate), 52 as a colour-

less oil (80 mg, 68%, a-only). R_f0.5 (3:2 hexane/ethyl acetate);

1

(60 mg, 25%, a/b 3:1). R_f0.3 (1:1 pentane/ethyl acetate). H

NMR (CDCl₃, 500 MHz) 1.29 (3H, t, J 7.0 Hz, OCH₂CH₃mi-

nor), 1.31 (3H, t, J 7.0 Hz, OCH₂CH₃major), 1.94 (3H, s,

OC(O)CH₃minor), 1.96 (3H, s, OC(O)CH₃major), 3.09 (1H,

dd, J 5.5, 14.0 Hz, SCH₂minor), 3.32 (1H, dd, J 3.5, 14.5 Hz,

SCH₂major), 3.44 (1H, dd, J 5.0, 14.5 Hz, SCH₂major),

3.50 (1H, dd, J 4.5, 14.5 Hz, SCH₂minor), 4.13e4.33 (10H,

m, OCH₂CH₃, H-5, H-6 major and minor), 5.23e5.28 (1H,

m, NHCH minor), 5.33 (1H, ddd, J 3.5, 5.0, 8.5 Hz, NHCH ma-

jor), 5.49 (1H, s, H-1 major), 5.64 (1H, s, H-1 minor), 5.85 (1H,

dd, J 1.0, 6.0 Hz, H-3 minor), 6.18 (1H, dd, J 3.0, 10.5 Hz, H-3

major), 6.46 (1H, d, J 3.5 Hz, H-4 minor), 6.95 (1H, dd, J 1.5,

10.5 Hz, H-4 major), 7.18 (1H, d, J 7.5 Hz, NH minor),7.36e

7.56 (6H, m, ArCH major and minor), 7.62 (1H, d, J 8.5 Hz,

NH major), 7.78e7.93 (4H, m, ArCH major and minor). ¹³C

NMR (CDCl₃, 100 MHz) 14.0 (OCH₂CH₃major and minor),

21.0 (OAc major), 21.5 (OAc minor), 34.1 (SCH₂minor),

36.4 (SCH₂major), 52.4 (NHCH minor), 52.7 (NHCH major),

61.8 (OCH₂CH₃minor), 62.1 (OCH₂CH₃major), 64.2 (C-6 ma-

jor), 64.3 (C-6 minor), 67.5 (C-5 major), 67.9 (C-5 minor), 82.4

(C-1 minor), 85.9 (C-1 major), 110.6 (C-4 minor), 113.0 (C-3

minor), 127.2 (C-3 major), 127.1 (ArCH), 127.5 (ArCH),

127.9 (ArCH), 128.3 (ArCH), 128.7 (ArCH), 131.0 (ArC),

131.1 (ArC), 131.7 (ArC), 131.9 (ArC), 132.0 (ArC), 147.8

(C-4 major), 166.9 (C]O), 167.1 (C]O), 170.1 (C]O),

170.4 (C]O), 170.6 (C]O), 177.2 (C]O). IR n_max(thin

ﬁlm)/cm^ꢁ11741 (C]O), 1648 (C]O). HRMS (CI, MþH^þ),

found: 422.1287; C₂₀H₂₃NO₇S requires: 422.1273.

1

[a]²_D⁰þ134.5 (c 1.15, CHCl₃). H NMR (CDCl₃, 400 MHz)

1.30 (3H, t, J 7.0 Hz, OCH₂CH₃), 1.97 (3H, s, OC(O)CH₃),

2.08 (3H, s, OC(O)CH₃), 2.17 (3H, s, OC(O)CH₃), 3.18 (1H,

dd, J 3.0, 15.0 Hz, SCH₂), 3.46 (1H, dd, J 4.5, 15.0 Hz,

SCH₂), 4.15e4.36 (5H, m, H-5, H-6, OCH₂CH₃), 5.30 (1H,

ddd, J 3.0, 4.5, 8.0 Hz, NHCH), 5.43 (1H, dt, J 2.0, 9.0 Hz,

H-4), 5.52 (1H, br s, H-1), 5.66 (1H, d, J 2.0 Hz, H-3), 7.39e

7.46 (2H, m, ArCH), 7.49e7.55 (1H, m, ArCH), 7.61 (1H, d,

J 8.0 Hz, NH), 7.84e7.89 (2H, m, ArCH). ¹³C NMR (CDCl₃,

100 MHz) 14.2 (OCH₂CH₃), 20.5 (OAc), 20.9 (OAc), 20.9

(OAc), 36.6 (SCH₂), 52.8 (NHCH), 61.9 (OCH₂CH₃), 62.5

(C-6), 64.4 (C-4), 68.2 (C-5), 82.4 (C-1), 115.1 (C-3), 127.3

(ArCH), 128.5 (ArCH), 131.9 (ArCH), 133.7 (ArC), 146.2

(C-2), 167.3 (C]O), 168.9 (C]O), 169.9 (C]O), 170.1

(C]O), 170.7 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11742

(C]O), 1651 (C]O). LRMS m/z 524 (50%, MþH^þ), 464

(21%), 422 (100%), 404 (26%), 131 (19%). HRMS (CI,

MþH^þ), found: 524.1588; C₂₄H₃₀NO₁₀S requires: 524.1590.

4.3.5. N-Benzoyl-S-(3-deoxy-2,4,6-tri-O-acetyl-a-^D-

galactopyranosyl)-^L-cysteine ethyl ester (54)

Following method B, N-benzoyl-^L-cysteine ethyl ester (46)

(50 mg, 0.2 mmol) and 2,3,4,6-tetra-O-acetyl-1,5-anhydro-^D-

lyxo-hex-1-enitol (16) (78 mg, 0.24 mmol) were stirred at

room temperature for 2.5 h to afford, after puriﬁcation by col-

umn chromatography (2:1 to 3:2 hexane/ethyl acetate), 54 as

a white powder (65 mg, 63%, a-only). R_f0.2 (2:1 hexane/ethyl

acetate); mp 167e169 ^ꢀC; [a]_D²⁰ꢁ9.7 (c 0.35, CHCl₃). ¹H NMR

(CDCl₃, 400 MHz) 1.30 (3H, t, J 7.0 Hz, OCH₂CH₃), 1.93 (3H,

s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.18 (3H, s,

OC(O)CH₃), 3.16 (1H, dd, J 3.5, 15.0 Hz, SCH₂), 3.51 (1H,

dd, J 4.5, 15.0 Hz, SCH₂), 4.12 (1H, dd, J 8.0, 12.0 Hz, H-6),

4.25 (2H, q, J 7.0 Hz, OCH₂CH₃), 4.29 (1H, dd, J 4.0,

12.0 Hz, H-6), 4.50 (1H, ddd, J 2.5, 4.0, 8.0 Hz, H-5), 5.26

(1H, dd, J 2.5, 6.0 Hz, H-4), 5.25e5.30 (1H, m, NHCH), 5.61

(1H, d, J 1.0 Hz, H-1), 5.84 (1H, dd, J 1.0, 6.0 Hz, H-3),

7.42e7.54 (4H, m, NH and ArCH), 7.85e7.89 (2H, m,

ArCH). ¹³C NMR (CDCl₃, 100 MHz) 14.2 (OCH₂CH₃), 20.4

(OAc), 20.8 (OAc), 21.0 (OAc), 36.4 (SCH₂), 52.8 (NHCH),

61.9 (OCH₂CH₃), 62.4 (C-6), 64.4 (C-4), 67.9 (C-5), 82.6 (C-

1), 112.4 (C-3), 127.3 (ArCH), 128.5 (ArCH), 131.9 (ArCH),

133.6 (ArC), 149.0 (C-2), 167.5 (C]O), 167.8 (C]O), 169.9

(C]O), 170.1 (C]O), 170.8 (C]O). IR n_max(thin ﬁlm)/

4.3.7. N-Benzoyl-S-(2,3-dideoxy-4,6-di-O-acetyl-^D-

galactopyranosyl)-^DL-homocysteine methyl ester (55)

Following method A, N-benzoyl-^DL-homocysteine methyl

ester (48) (244 mg, 0.96 mmol) and tri-O-acetyl-^D-galactal

(14) (314 mg, 1.2 mmol) were stirred at room temperature for

48 h to afford, after puriﬁcation by column chromatography

(2:1 hexane/ethyl acetate, 1% triethylamine), 55 as a colourless

oil (290 mg, 65%, a/b 2:1).

Following method B, N-benzoyl-^DL-homocysteine methyl

ester (48) (85 mg, 0.33 mmol) and tri-O-acetyl-^D-galactal (14)

(109 mg, 0.4 mmol) were stirred at room temperature for

1.5 h to afford, after puriﬁcation by column chromatography

(2:1 hexane/ethyl acetate, 1% triethylamine), 55 as a colourless

oil (65 mg, 42% a-only). R_f0.3 (2:1 hexane/ethyl acetate). ¹H

NMR (CDCl₃, 400 MHz) 2.01 (3H, s, OC(O)CH₃), 2.09 (3H,

s, OC(O)CH₃), 2.11e2.27 (1H, m, SCH₂CH₂), 2.31e2.46

2848

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

(1H, m, SCH₂CH₂), 2.64e2.76 (1H, m, SCH₂CH₂), 2.78e2.91

(1H, m, SCH₂CH₂), 3.08 and 3.09 (3H, s, OMe anomers), 4.13e

4.29 (2H, m, H-6 anomers), 4.47e4.54 (1H, m, H-5), 4.86e

4.99 (1H, m, NHCH), 5.06e5.10 (1H, m, H-4), 5.62e5.66

(1H, m, H-1), 6.01e6.12 (2H, m, H-2, H-3 anomers), 6.84

(1H, t, J 8.5 Hz, NH), 7.42e7.57 (3H, m, ArCH), 7.79e7.91

(2H, m, ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.6e21.0

(OAc), 26.9e27.7 (SCH₂CH₂), 32.3 (SCH₂CH₂), 51.8

(NHCH), 62.6 (C-6), 63.2 (C-4), 66.8 (C-5), 79.1 (C-1_b), 80.3

(C-1_a), 124.4 (C-3), 127.0 (ArCH), 127.5 (ArCH), 127.9

(ArCH), 128.2 (ArCH), 128.6 (ArCH), 131.5 (C-2), 131.9 (C-

2), 131.7 (ArC), 167.5 (C]O), 170.7 (C]O), 171.0 (C]O),

172.9 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11740 (C]O), 1651

(C]O). LRMS m/z 505 (45%), 466 (68%, MþH^þ), 346

(44%), 252 (57%), 213 (100%), 153 (78%). HRMS (CI,

MþH^þ), found: 466.1520; C₂₂H₂₇NO₈S requires: 466.1535.

m, SCH₂CH₂, SCH₂CH₂), 3.77 and 3.79 (3H, s, OMe epimers),

4.06e4.13 (1H, m, H-5), 4.16e4.33 (2H, m, H-6), 4.48e4.55

(1H, m, NHCH), 5.22e5.29 (1H, m, H-4), 5.67 (1H, d, J

10.0 Hz, H-1), 5.84 (1H, d, J 5.5 Hz, H-3), 6.96e7.17 (1H,

m, NH epimers), 7.37e7.56 (3H, m, ArCH), 7.77e7.88 (2H,

m, ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.6 (OAc), 20.7

(OAc), 20.9 (OAc), 27.2 and 27.7 (SCH₂CH₂), 32.2 and

34.9 (SCH₂CH₂), 52.5 (NHCH), 52.7 (OMe), 62.2 (C-6), 64.4

(C-4), 67.0 (C-5), 80.6 (C-1), 112.3 (C-3), 127.1 (ArCH),

128.6 (ArCH), 131.9 (ArCH), 133.5 (ArC), 149.6 (C-2),

167.1 (C]O), 167.9 (CeO), 170.5 (C]O), 170.6 (C]O),

172.4 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11745 (C]O), 1651

(C]O). LRMS m/z 524 (62%, MþH^þ), 506 (28%), 505

(100%), 404 (51%), 169 (19%). HRMS (CI, MþH^þ), found:

524.1567; C₂₄H₃₀NO₁₀S requires: 524.1590.

4.3.10. N-tert-Butoxycarbonyl-O-benzyl-^L-serine-S-(2,3-

dideoxy-4,6-di-O-acetyl-a-^D-glucopyranosyl)-L-cysteine

ethyl ester (60)

4.3.8. N-Benzoyl-S-(3-deoxy-2,4,6-tri-O-acetyl-a-^D-

glucopyranosyl)-^DL-homocysteine methyl ester (56)

Following method B, N-benzoyl-^DL-homocysteine methyl

ester (48) (125 mg, 0.5 mmol) and 2,3,4,6-tetra-O-acetyl-1,5-

anhydro-^D-arabino-hex-1-enitol (15) (195 mg, 0.6 mmol)

were stirred at room temperature for 2 h to afford, after puriﬁ-

cation by column chromatography (2:1 hexane/ethyl acetate,

1% triethylamine), 56 as a colourless oil (155 mg, 60%). R_f

To a stirred solution of N-tert-butoxycarbonyl-S-(2,3-deoxy-

4,6-tri-O-acetyl-a-^D-glucopyranosyl)-L-cysteine ethyl ester (58)

(25 mg, 0.05 mmol) in CH₂Cl₂(3 mL) was added 4 N HCl in di-

oxane (3 mL). The solution was stirred for 2 h and then concen-

trated in vacuo. The residue was taken up in CH₂Cl₂(3 mL), and

N-tert-butoxy-O-benzyl-^L-serine (17 mg, 0.06 mmol), PyBOP

(33 mg, 0.07 mmol) and triethylamine (0.02 mL, 0.14 mmol)

were added with stirring. The resultant solution was stirred for

1 h and diluted with CH₂Cl₂(10 mL), washed with 0.5 M HCl

(10 mL), NaHCO₃(10 mL) and brine (10 mL), dried (MgSO₄),

ﬁltered and concentrated in vacuo. The crude product was puri-

ﬁed by column chromatography (2:1 hexane/ethyl acetate, 1%

triethylamine) to yield 60 as a colourless oil (33 mg, 95%). R_f

0.4 (2:1 hexane/ethyl acetate); [a]²_D⁰þ158 (c 0.25, CHCl₃). ¹H

NMR (CDCl₃, 400 MHz) 1.27 (3H, t, J 7.0 Hz, OCH₂CH₃),

1.44 (9H, s, C(CH₃)₃), 2.07 (3H, s, OC(O)CH₃), 2.11 (3H, s,

OC(O)CH₃), 3.09e3.21 (2H, m, SCH₂), 3.59 (1H, dd, J 5.0,

9.0 Hz, OCH₂), 3.98 (1H, dd, J 3.5, 9.0 Hz, OCH₂), 4.13e4.45

(6H, m, H-5, H-6, OCH₂CH₃, SereNHCH), 4.52 (2H, AB, J

12.0 Hz, OCH₂Ph), 4.97 (1H, app. dt, J 4.0, 8.0 Hz, Cyse

NHCH), 5.22e5.29 (1H, m, H-4), 5.35e5.40 (1H, m, H-1),

5.53 (1H, d, J 6.5 Hz, SereNH), 5.64e5.72 (2H, m, H-2, H-3),

7.28e7.38 (5H, m, ArCH), 7.58 (1H, d, J 8.0 Hz, CyseNH).

¹³C NMR (CDCl₃, 100 MHz) 14.2 (OCH₂CH₃), 20.8 (OAc),

21.0 (OAc), 28.3 (C(CH₃)₃), 35.3 (SCH₂), 52.9 (CyseNHCH),

54.5 (SereNHCH), 61.8 (OCH₂CH₃), 62.9 (C-6), 65.0 (C-4),

67.7 (C-5), 70.5 (OCH₂), 73.5 (OCH₂Ph), 80.4 (C(CH₃)₃), 81.6

(C-1), 126.5 (C-3), 127.9 (ArCH), 128.5 (ArCH), 128.9 (C-2),

137.5 (ArC), 155.5 (C]O), 169.6 (C]O), 170.2 (C]O),

170.3 (C]O), 171.0 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11740

(C]O), 1664 (C]O). HRMS (EI, MþNa^þ), found: 661.2393;

C₃₀H₄₂N₂O₁₁SNa requires: 661.2407.

1

0.3 (2:1 hexane/ethyl acetate). H NMR (CDCl₃, 400 MHz)

2.04 (3H, s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.14 (3H,

s, OC(O)CH₃), 2.12e2.23 (1H, m, SCH₂CH₂), 2.28e2.39

(1H, m, SCH₂CH₂), 2.63e2.87 (2H, m, SCH₂CH₂), 2.11e

2.27 (1H, m, SCH₂CH₂), 2.31e2.46 (1H, m, SCH₂CH₂),

2.64e2.76 (1H, m, SCH₂CH₂), 2.78e2.91 (1H, m, SCH₂CH₂),

3.78 and 3.79 (3H, s, OMe epimers), 4.10e4.38 (3H, m, H-5, H-

6), 4.84e4.98 (1H, m, NHCH), 5.33e5.51 (1H, m, H-4), 5.58

(1H, d, J 9.0 Hz, H-3), 5.65 (1H, br s, H-1), 6.96e7.17 (1H,

m, NH epimers), 7.36e7.55 (3H, m, ArCH), 7.78e7.87 (2H,

m, ArCH). ¹³C NMR (CDCl₃, 100 MHz) 20.7 (OAc), 20.9

(OAc), 27.7 and 28.4 (SCH₂CH₂), 32.2e33.2 (SCH₂CH₂),

52.6 (NHCH), 52.7 (OMe), 62.4 (C-6), 64.7 (C-4), 67.3 (C-

5), 81.0 (C-1), 115.9 (C-3), 127.1 (ArCH), 128.6 (ArCH),

131.8 (ArCH), 133.6 (ArC), 146.8 (C-2), 167.3 (C]O),

168.3 (CeO), 170.0 (C]O), 170.7 (C]O), 172.4 (C]O).

IR n_max(thin ﬁlm)/cm^ꢁ11744 (C]O), 1650 (C]O). LRMS

m/z 566 (17%), 524 (100%, MþH^þ), 505 (62%), 404 (57%),

169 (20%). HRMS (CI, MþH^þ), found: 524.1586;

C₂₄H₃₀NO₁₀S requires: 524.1590.

4.3.9. N-Benzoyl-S-(3-deoxy-2,4,6-tri-O-acetyl-a-^D-

galactopyranosyl)-^DL-homocysteine methyl ester (57)

Following method B, N-benzoyl-^DL-homocysteine methyl

ester (48) (125 mg, 0.5 mmol) and 2,3,4,6-tetra-O-acetyl-1,5-

anhydro-^D-lyxo-hex-1-enitol (16) (195 mg, 0.6 mmol) were

stirred at room temperature for 2 h to afford, after puriﬁcation

by column chromatography (2:1 hexane/ethyl acetate, 1% tri-

ethylamine), 57 as a white powder (149 mg, 58%). R_f0.4 (2:1

4.3.11. N-tert-butoxycarbonyl-^L-alanine-S-(2,3-dideoxy-4,6-

di-O-acetyl-a-^D-galactopyranosyl)-L-cysteine ethyl ester

(61)

To a stirred solution of N-tert-butoxycarbonyl-S-(2,3-deoxy-

4,6-tri-O-acetyl-a-^D-galactopyranosyl)-L-cysteine ethyl ester

1

hexane/ethyl acetate). H NMR (CDCl₃, 400 MHz) 2.02 (3H,

s, OC(O)CH₃), 2.08 (3H, s, OC(O)CH₃), 2.15 (3H, s,

OC(O)CH₃), 2.29e2.43 (1H, m, SCH₂CH₂), 2.62e2.90 (3H,

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2849

(59) (34 mg, 0.07 mmol) in CH₂Cl₂(3 ml) was added 4 N HCl

in dioxane (3 mL). The solution was stirred for 2 h and then

concentrated in vacuo. The residue was taken up in CH₂Cl₂

(3 mL), and N-tert-butoxy-L-alanine (15 mg, 0.08 mmol), Py-

BOP (46 mg, 0.09 mmol) and triethylamine (0.02 mL,

0.18 mmol) were added with stirring. The resultant solution

was stirred for 1 h and diluted with CH₂Cl₂(10 mL), washed

with 0.5 M HCl (10 mL), NaHCO₃(10 mL) and brine

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

The crude product was puriﬁed by column chromatography

(2:1 hexane/ethyl acetate, 1% triethylamine) to yield 61 as

a white solid (35 mg, 94%). R_f0.3 (2:1 hexane/ethyl acetate);

mp 96e99 ^ꢀC. ¹H NMR (CDCl, 400 MHz) 1.28 (3H, t, J

7.0 Hz, OCH₂CH₃), 1.39 (3H, d, J 7.0 Hz, AlaeMe), 1.44

(9H, s, C(CH₃)₃), 2.08 (3H, s, OC(O)CH₃), 2.11 (3H, s,

OC(O)CH₃), 3.11 (1H, dd, J 4.0, 14.5 Hz, SCH₂), 3.26 (1H,

dd, J 5.0, 14.5 Hz, SCH₂), 4.22 (2H, q, J 7.0 Hz, OCH₂CH₃),

4.20e4.25 (1H, m, AlaeNHCH), 4.26 (1H, dd, J 7.5,

11.5 Hz, H-6), 4.37 (1H, dd, J 5.5, 11.5 Hz, H-6), 4.45 (1H,

ddd, J 2.5, 5.5, 7.5 Hz, H-5), 4.93 (1H, app. dt, J 4.0 8.0 Hz,

CyseNHCH), 5.06 (1H, dd, J 2.5, 5.0 Hz, H-4), 5.16 (1H, d,

J 5.5 Hz, AlaeNH), 5.52e5.56 (1H, m, H-1), 6.01 (1H, ddd,

J 1.5, 5.0, 10.0 Hz, H-3), 6.07 (1H, dd, J 3.0, 10.0 Hz, H-2),

7.23 (1H, d, J 8.0 Hz, CyseNH). ¹³C NMR (CDCl₃,

100 MHz) 14.2 (OCH₂CH₃), 18.6 (AlaeMe), 20.8 (OAc),

28.3 (C(CH₃)₃), 35.0 (SCH₂), 50.1 (AlaeNHCH), 52.4 (Cyse

NHCH), 61.9 (OCH₂CH₃), 62.5 (C-6), 63.0 (C-4), 67.5

(C-5), 80.1 (C(CH₃)₃), 81.4 (C-1), 123.8 (C-3), 131.4 (C-2),

155.3 (C]O), 169.9 (C]O), 170.3 (C]O), 170.8 (C]O),

172.6 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11740 (C]O), 1677

(C]O), 756 (C]C). HRMS (CI, MþH^þ), found: 533.2172;

C₂₃H₃₇N₂O₁₀S requires: 533.2169.

(C]O), 170.6 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11746

(C]O), 1664 (C]O), 1224 (CH_arom). LRMS m/z 584 (37%,

MþH^þ), 403 (19%), 331 (100%), 251 (23%), 218 (25%), 169

(57%). HRMS (CI, MþH^þ), found: 584.1788; C₂₆H₃₄NO₁₂S

requires: 584.1802.

4.3.13. N-Benzoyl-S-(2,3,4,6-tetra-O-acetyl-a-^D-

talopyranosyl)-L-cysteine ethyl ester (63)

Following the general method, N-benzoyl-S-(2,3-dideoxy-

4,6-di-O-acetyl-a-^D-galactopyranosyl)-L-cysteine ethyl ester

(51) (53 mg, 0.1 mmol) was stirred with osmium tetroxide

(28 mg, 0.1 mmol) at room temperature overnight. Subsequent

per-O-acetylation afforded, after puriﬁcation by column chro-

matography (1:1 to 1:2 hexane/ethyl acetate), 63 as a colourless

oil (41 mg, 62%). R_f0.2 (1:1 hexane/ethyl acetate); [a]²_D⁰þ87 (c

0.2, CHCl₃). ¹H NMR (CDCl₃, 400 MHz) 1.31 (3H, t, J 7.0 Hz,

OCH₂CH₃), 1.86 (3H, s, OC(O)CH₃), 2.07 (3H, s, OC(O)CH₃),

2.13 (3H, s, OC(O)CH₃), 2.16 (3H, s, OC(O)CH₃), 2.99 (1H,

dd, J 3.0, 15.0 Hz, SCH₂), 3.46 (1H, dd, J 4.5, 15.0 Hz,

SCH₂), 3.98 (1H, dd, J 8.0, 11.5 Hz, H-6), 4.19e4.35 (3H, m,

H-6, OCH₂CH₃), 4.66 (1H, ddd, J 1.5, 4.0, 8.0 Hz, H-5), 4.99

(1H, dd, J 1.5, 4.0 Hz, H-4), 5.25 (1H, app. t, J 3.5 Hz, H-3),

5.28e5.31 (1H, m, NHCH), 5.32 (1H, dd, J 3.5, 6.0 Hz, H-2),

5.46 (1H, d, J 6.0 Hz, H-1), 7.40e7.53 (3H, m, ArCH), 7.59

(1H, d, J 9.0 Hz, NH), 7.85e7.89 (2H, m, ArCH). ¹³C NMR

(CDCl₃, 100 MHz) 14.3 (OCH₂CH₃), 20.4 (OAc), 20.7

(OAc), 20.8 (OAc), 20.9 (OAc), 37.9 (SCH₂), 52.9 (NHCH),

61.7 (OCH₂CH₃), 62.4 (C-6), 65.9 (C-5), 66.4 (C-2 or C-3),

66.6 (C-2 or C-3), 68.3 (C-4), 85.3 (C-1), 127.4, 128.5 and

131.9 (ArCH), 133.8 (ArC), 167.4 (C]O), 168.9 (C]O),

169.4 (C]O), 169.8 (C]O), 170.1 (C]O), 170.7 (C]O).

IR n_max(thin ﬁlm)/cm^ꢁ11745 (C]O), 1656 (C]O), 1216

(CH_arom), 758 (CH_arom). LRMS m/z 584 (7%, MþH^þ), 403

(11%), 331 (29%), 180 (76%), 180 (100%). HRMS (CI,

MþH^þ), found: 584.1821; C₂₆H₃₄NO₁₂S requires: 584.1831.

4.3.12. N-Benzoyl-S-(2,3,4,6-tetra-O-acetyl-a-^D-

mannopyranosyl)-^L-cysteine ethyl ester (62)

Following the general method, N-benzoyl-S-(2,3-dideoxy-

4,6-di-O-acetyl-a-^D-glycopyranosyl)-L-cysteine ethyl ester

(49) (148 mg, 0.3 mmol) was stirred with osmium tetroxide

(100 mg, 0.4 mmol) at room temperature overnight. Subse-

quent per-O-acetylation afforded, after puriﬁcation by column

chromatography (1:1 to 1:2 hexane/ethyl acetate), 62 as a col-

ourless oil (106 mg, 57%). R_f0.4 (1:1 hexane/ethyl acetate);

4.3.14. N-Benzoyl-S-(2,3,4,6-tetra-O-acetyl-a-^D-

mannopyranosyl)-^DL-homocysteine methyl ester (64)

Following the general method, N-benzoyl-S-(2,3-dideoxy-

4,6-di-O-acetyl-^D-glucopyranosyl)-DL-homocysteine methyl

ester (50) (30 mg, 0.06 mmol) was stirred with osmium tetrox-

ide (16 mg, 0.06 mmol) at room temperature overnight. Subse-

quent per-O-acetylation afforded, after puriﬁcation by column

chromatography (1:1 to 1:2 hexane/ethyl acetate, 1% triethyl-

amine), 64 as a colourless oil (22 mg, 56%). R_f0.2 (1:1 hex-

1

[a]²_D⁰þ56 (c 1.25, CHCl₃). H NMR (CDCl₃, 400 MHz) 1.31

(3H, t, J 7.0 Hz, OCH₂CH₃), 1.95 (3H, s, OC(O)CH₃), 1.99

(3H, s, OC(O)CH₃), 2.05 (3H, s, OC(O)CH₃), 2.15 (3H, s,

OC(O)CH₃), 3.22 (1H, dd, J 3.5, 14.5 Hz, SCH₂), 3.39 (1H,

dd, J 4.5, 14.5 Hz, SCH₂), 4.18e4.22 (2H, m, H-6), 4.27 (2H,

q, J 7.0 Hz, OCH₂CH₃), 4.33 (1H, ddd, J 3.5, 5.0, 10.0 Hz,

H-5), 5.17 (1H, dd, J 3.5, 10.0 Hz, H-3), 5.23e5.32 (3H, m,

H-1, H-4, NHCH), 5.38 (1H, dd, J 1.5, 3.5 Hz, H-2), 7.39e

7.48 (3H, m, ArCH, NH), 7.53 (1H, tt, J 2.0, 7.5 Hz, ArCH),

7.85e7.90 (2H, m, ArCH). ¹³C NMR (CDCl₃, 100 MHz)

14.2 (OCH₂CH₃), 20.5 (OAc), 20.6 (OAc), 20.7 (OAc), 20.9

(OAc), 36.1 (SCH₂), 52.1 (NHCH), 62.1 (OCH₂CH₃), 62.4

(C-6), 66.0 (C-4), 69.0 (C-2), 70.0 (C-5), 71.2 (C-3), 84.2 (C-

1), 127.3, 128.5 and 132.0 (ArCH), 133.6 (ArC), 167.0

(C]O), 169.7 (C]O), 169.8 (C]O), 169.9 (C]O), 170.1

1

ane/ethyl acetate). H NMR (CDCl₃, 500 MHz) 1.98 (3H, s,

OC(O)CH₃), 2.04 (3H, s, OC(O)CH₃), 2.08 (3H, s,

OC(O)CH₃), 2.15 (3H, s, OC(O)CH₃), 2.13e2.19 (1H, m,

SCH₂CH₂), 2.26e2.44 (1H, m, SCH₂CH₂), 2.60e2.84 (2H,

m, SCH₂CH₂), 3.80 (3H, s, OMe), 4.00e4.17 (1H, m, H-6),

4.30 (1H, ddd, J 4.0, 5.0, 12.5 Hz, H-5), 4.32e4.40 (1H, m,

H-6), 4.81e5.14 (1H, m, NHCH), 5.23 (1H, dd, J 3.5,

10.0 Hz, H-3), 5.25e5.31 (2H, m, H-1, H-4), 5.33 (1H, dd, J

1.5, 3.5 Hz, H-2), 6.79 (1H, app. t, J 8.0 Hz, NH), 7.41e7.56

(3H, m, ArCH), 7.77e7.95 (2H, m, ArCH). ¹³C NMR

(CDCl₃, 125 MHz) 20.6 (OAc), 20.7 (OAc), 20.9 (OAc), 27.4

(SCH₂CH₂), 32.7 (SCH₂CH₂), 52.5 (NHCH), 62.4 (C-6), 66.2

2850

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

(C-4), 69.2 (C-5), 69.3 (C-3), 70.9 (C-2), 82.4 (C-1), 127.1e

128.6 (ArCH), 131.9 (ArC), 167.1 (C]O), 169.7 (C]O),

169.7 (C]O), 169.9 (C]O), 170.6 (C]O), 172.3 (C]O).

IR n_max(thin ﬁlm)/cm^ꢁ11745 (C]O), 1665 (C]O), 1223

(CH_arom). LRMS m/z 606 (100%, MþNa^þ), 584 (21%,

MH^þ), 524 (24%), 442 (27%), 331 (32%). HRMS (ESI,

MþH^þ), found: 584.1789; C₂₆H₃₄NO₁₂S requires: 584.1801.

Method C. A stirred solution of S-linked glycoamino acid

(1 equiv) and DMAP (0.2 equiv) and di-tert-butyl dicarbonate

(2 equiv) in anhydrous THF (3 mL/mmol) was stirred under an

atmosphere of argon at room temperature overnight. The re-

sultant solution was then diluted with methanol (3 mL/

mmol) and N₂H₄$H₂O (4 equiv) was added, the solution was

then stirred for a further 2 h, and then poured into CH₂Cl₂

(10 mL) and washed with 1 N HCl (10 mL), NaHCO₃

(10 mL) and brine (10 mL), dried (MgSO₄), ﬁltered and con-

centrated in vacuo. The residue was subjected to puriﬁcation

by column chromatography.

Method D. To a stirred solution of Boc-protected S-linked

glycoamino acid (1 equiv) in anhydrous ethanol (1 mL/

mmol) under an atmosphere of argon was added NaOEt

(0.1 equiv). The reaction mixture was stirred at room temper-

ature until the reaction was shown to have reached completion

by TLC analysis. The reaction mixture was then neutralised by

the addition of Amberlite IR120H^þ, ﬁltered and concentrated

in vacuo. The crude residue was then taken up in anhydrous

CH₂Cl₂(3 mL/mmol) and cooled to 0 ^ꢀC. TFA (2 equiv) was

added and stirred until the reaction was shown to have reached

completion by TLC analysis, and then concentrated in vacuo.

Method E. To a stirred solution of Boc-protected S-linked

glycoamino acid (1 equiv) in anhydrous methanol (1 mL/

mmol) under an atmosphere of argon was added NaOMe

(0.1 equiv). The reaction mixture was stirred at room temper-

ature until the reaction was shown to have reached completion

by TLC analysis. The reaction was then neutralised by the

addition of Amberlite IR120H^þ, ﬁltered and concentrated in

vacuo. The crude residue was then taken up in anhydrous

CH₂Cl₂(3 ml/mmol) and cooled to 0 ^ꢀC. TFA (2 equiv) was

added and stirred until the reaction was shown to have reached

completion by TLC analysis, and then concentrated in vacuo.

4.3.15. N-Benzoyl-S-(2,3,4,6-tetra-O-acetyl-a-^D-

talopyranosyl)-^DL-homocysteine methyl ester (65)

Following the general method, N-benzoyl-S-(2,3-dideoxy-

4,6-di-O-acetyl-^D-galactopyranosyl)-DL-homocysteine methyl

ester (55) (30 mg, 0.06 mmol) was stirred with osmium tetrox-

ide (16 mg, 0.06 mmol) at room temperature overnight. Subse-

quent per-O-acetylation afforded, after puriﬁcation by column

chromatography (1:1 to 1:2 hexane/ethyl acetate, 1% triethyl-

amine), 65 as a colourless oil (21 mg, 55%). R_f0.4 (1:2

1

hexane/ethyl acetate). H NMR (CDCl₃, 500 MHz) 2.00 (3H,

s, OC(O)CH₃), 2.04 (3H, s, OC(O)CH₃), 2.11 (3H, s,

OC(O)CH₃), 2.13 (3H, s, OC(O)CH₃), 2.24e2.42 (1H, m,

SCH₂CH₂), 2.53e2.88 (3H, m, SCH₂CH₂, SCH₂CH₂), 3.79

(3H, s, OMe), 4.05e4.18 (2H, m, H-6), 4.87e4.95 (1H, m,

NHCH), 4.99e5.03 (1H, m, H-4), 5.21e5.25 (1H, m, H-3),

5.28e5.38 (1H, m, H-1), 5.46 (1H, app. t, J 6.5 Hz, H-2),

6.94 (1H, d, J 7.5 Hz, NH), 7.43e7.57 (3H, m, ArCH),

7.78e7.89 (2H, m, ArCH). ¹³C NMR (CDCl₃, 125 MHz)

20.6 (OAc), 20.7 (OAc), 20.9 (OAc), 28.2 (SCH₂CH₂), 33.1

(SCH₂CH₂), 52.0 (NHCH), 61.8 (C-6), 66.7 (C-4), 67.9 (C-

5), 68.2 (C-3), 80.6 (C-2), 82.8 (C-1), 127.1 (ArCH), 127.2

(ArCH), 128.6 (ArCH), 131.9 (ArC), 169.4 (C]O), 172.4

(C]O). IR n_max(thin ﬁlm)/cm^ꢁ11744 (C]O), 1655

(C]O), 1216 (CH_arom). LRMS m/z 606 (100%, MþNa^þ),

584 (26%, MH^þ), 331 (56%), 279 (8%), 169 (5%). HRMS

(ESI, MþH^þ), found: 584.1807; C₂₆H₃₄NO₁₂S requires:

584.1801.

4.4.1. Methyl 6-S-(2,3-dideoxy-a-^D-glucopyranosyl)-6-thio-

a-^D-glucopyranoside (38)

4.4. General method: deprotection

Following method A, methyl 2,3,4-tri-O-acetyl-6-S-(2,3-di-

deoxy-4,6-di-O-acetyl-a-^D-glucopyranosyl)-6-thio-a-D-gluco-

pyranoside (12) (14 mg, 0.02 mmol) and K₂CO₃(3 mg,

0.002 mmol) were stirred overnight to afford 38 as a colourless

Method A. To a stirred solution of S-linked disaccharide

(1 equiv) in anhydrous methanol (1 mL/mmol) under an atmo-

sphere of argon was added K₂CO₃(0.1 equiv) or NaOMe

(0.1 equiv). The reaction mixture was stirred at room temper-

ature until the reaction was shown to have reached completion

by TLC analysis. The reaction mixture was then neutralised by

the addition of Amberlite IR120 H^þ, ﬁltered and concentrated

in vacuo.

Method B. A stirred solution of S-linked glycoamino acid

(1 equiv) and DMAP (0.2 equiv) and di-tert-butyl dicarbonate

(2 equiv) in anhydrous THF (3 mL/mmol) was stirred under an

atmosphere of argon at room temperature overnight. The re-

sultant solution was then diluted with ethanol (3 mL/mmol)

and N₂H₄$H₂O (4 equiv) was added, the solution was then

stirred for a further 2 h, and then poured into CH₂Cl₂

(10 mL) and washed with 1 N HCl (10 mL), NaHCO₃

(10 mL) and brine (10 mL), dried (MgSO₄), ﬁltered and con-

centrated in vacuo. The residue was subjected to puriﬁcation

by column chromatography.

oil (8 mg, quant.). [a]²_D⁰þ103 (c 0.43, H₂O). H NMR (D₂O,

1

400 MHz) 2.86 (1H, dd, J 8.0, 14.0 Hz, H-6), 3.29 (1H, dd, J

3.0, 14.0 Hz, H-6), 3.38e3.45 (1H, m, H-4), 3.34 (3H, s,

OMe), 3.59 (1H, dd, J 4.0, 10.0 Hz, H-2), 3.36 (1H, dd, J 9.0,

10.0 Hz, H-3), 3.78 (1H, dd, J 6.0, 12.5 Hz, H-6⁰), 3.83 (1H,

dd, J 2.5, 7.5, 10.0 Hz, H-5), 3.91 (1H, dd, J 2.5, 12.5 Hz, H-

6⁰), 3.96 (1H, ddd, J 2.5, 6.0, 8.5 Hz, H-5⁰), 4.20 (1H, ddd, J

2.0, 3.5, 13.0 Hz, H-4⁰), 4.78e4.81 (1H, m, H-1), 5.68e5.72

(1H, m, H-1⁰), 5.90 (1H, dt, J 1.5, 10.0 Hz, H-3⁰), 5.96 (1H,

ddd, J 2.0, 2.0, 10.0 Hz, H-2⁰). ¹³C NMR (D₂O, 100 MHz)

35.2 (C-6), 58.0 (OMe), 63.7 (C-6⁰), 65.4 (C-4⁰), 73.1 (C-5),

74.1 (C-2), 74.8 (C-5⁰), 75.1 (C-4), 75.8 (C-3), 82.4 (C-1⁰),

102.1 (C-1), 130.0 (C-3⁰), 133.4 (C-2⁰). IR n_max(thin ﬁlm)/

cm^ꢁ13443 (OH). LRMS m/z 339 (8%, MH^þ), 180 (9%), 161

(52%), 135 (100%). HRMS (CI, MþH^þ), found: 339.1123;

C₁₃H₂₃O₈S requires: 339.1114.

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2851

4.4.2. Methyl 6-S-(2,3-dideoxy-a-D-galactopyranosyl)-6-

thio-a-^D-glucopyranoside (39)

(5H, m, ArCH). ¹³C NMR (MeOD, 100 MHz) 49.9 (C-4),

55.7 (OMe), 62.8 (C-4⁰), 62.8 (C-6⁰), 71.7 (C-5), 71.9 (C-6),

73.4 (C-3), 73.4 (C-5⁰), 74.5 (OCH₂Ph), 80.7 (C-1⁰), 101.4

(C-1), 128.7 (C-3⁰), 128.9 (ArCH), 129.0 (ArCH), 129.3

(ArCH), 129.3 (ArCH), 130.5 (C-2⁰), 139.7 (ArC). IR n_max

(thin ﬁlm)/cm^ꢁ13443 (OH). LRMS m/z 429 (20%, MþH^þ),

428 (43%, M), 380 (23%), 379 (100%), 129 (23%). HRMS

(CI, MþH^þ), found: 429.1578; C₂₀H₂₉SO₈requires: 429.1583.

Following method A, methyl 2,3,4-tri-O-acetyl-6-S-(2,3-di-

deoxy-4,6-di-O-acetyl-a-^D-galactopyranosyl)-6-thio-a-D-glu-

copyranoside (17) (20 mg, 0.04 mmol) and K₂CO₃(1 mg,

0.004 mmol) were stirred for 2 h to afford 39 as a colourless

1

oil (12 mg, quant.). [a]²_D⁰þ118 (c 0.35, MeOH). H NMR

(D₂O, 400 MHz) 2.54 (1H, dd, J 7.5, 14.0 Hz, H-6), 2.98 (1H,

dd, J 2.5, 14.0 Hz, H-6), 3.10e3.15 (1H, m, H-4), 3.16 (3H, s,

OMe), 3.28 (1H, dd, J 3.5, 9.5 Hz, H-2), 3.32e3.36 (1H, m,

H-3), 2.48e3.70 (3H, m, H-5, H-6⁰), 3.70 (1H, dd, J 2.5,

4.5 Hz, H-4⁰), 3.96 (1H, ddd, 2.5, 4.0, 6.5 Hz, H-5⁰), 4.46e

4.56 (1H, m, H-1), 5.46 (1H, d, J 2.0 Hz, H-1⁰), 5.73e5.79

(2H, m, H-2⁰, H-3⁰). ¹³C NMR (D₂O, 100 MHz) 34.4 (C-6),

57.8 (OMe), 63.9 (C-6⁰), 72.0 (C-4⁰), 73.0 (C-5), 74.0 (C-2),

74.2 (C-5⁰), 74.9 (C-4), 75.6 (C-3), 82.3 (C-1⁰), 102.0 (C-1),

130.1 (C-3⁰), 132.0 (C-2⁰). IR n_max(thin ﬁlm)/cm^ꢁ13443

(OH). LRMS m/z 395 (100%, MþNa^þ), 390 (2%), 335 (9%),

331 (32%), 323 (4%). HRMS (ESI^ꢁ, MꢁH), found: 337.0952;

C₁₃H₂₁O₈S requires: 337.0957.

4.4.5. Methyl 6-S-(-^D-mannopyranosyl)-6-thio-a-D-

glucopyranoside (42)

Following method A, methyl 2,3,4-tri-O-acetyl-6-S-(2,3,4,6-

tetra-O-acetyl-a-^D-mannopyranosyl)-6-thio-a-D-glucopyrano-

side (32) (25 mg, 0.04 mmol) and K₂CO₃(2 mg, 0.004 mmol)

were stirred for 2 h to afford 42 as a white powder (14 mg,

quant.). Mp 192e193.5 ^ꢀC; [a]_D²⁰þ141 (c 0.51, H₂O). ¹H

NMR (D₂O, 400 MHz) 2.66 (1H, dd, J 8.0, 14.0 Hz, H-6),

3.02 (1H, dd, J 2.5, 14.0 Hz, H-6), 3.23 (1H, dd, J 9.0,

9.5 Hz, H-4), 3.28 (3H, s, OMe), 3.43 (1H, dd, J 3.5, 9.5 Hz,

H-2), 3.46e3.51 (1H, m, H-4⁰), 3.53 (1H, app. t, J 9.5 Hz, H-

3), 3.61e3.69 (3H, m, H-3⁰, H-5, H-6⁰), 3.73 (1H, dd, J 2.5,

12.5 Hz, H-6⁰), 3.84 (1H, ddd, J 2.5, 6.0, 8.0 Hz, H-5⁰), 3.91

(1H, dd, J 1.5, 3.5 Hz, H-2⁰), 4.60e4.80 (1H, m, H-1), 5.20

(1H, d, J 1.5 Hz, H-1⁰). ¹³C NMR (D₂O, 100 MHz) 31.8 (C-

6), 55.4 (OMe), 61.1 (C-6⁰), 67.3 (C-3), 70.3 (C-3⁰), 71.4 (C-

5), 71.6 (C-2), 71.9 (C-2⁰), 72.6 (C-4), 73.3 (C-4⁰), 73.6 (C-

5⁰), 84.9 (C-1⁰), 99.6 (C-1). IR n_max(thin ﬁlm)/cm^ꢁ13443

(OH). LRMS m/z 417 (100%, MCOOH), 400 (7%), 371

(26%, MꢁH), 348 (18%). HRMS (ESI^ꢁ, MCO₂H), found:

417.1070; C₁₄H₂₅O₁₂S requires: 417.1067.

4.4.3. Methyl 6-O-benzyl-4-S-(2,3-dideoxy-a-^D-

glucopyranosyl)-4-thio-a-^D-glucopyranoside (40)

Following method A, methyl 6-O-benzyl-2,3-di-O-acetyl-4-

S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-glucopyranosyl)-6-thio-a-

D-glucopyranoside (28) (42 mg, 0.07 mmol) and K₂CO₃(1 mg,

7ꢂ10^ꢁ6mmol) were stirred for 2 h to afford 40 as a white pow-

der (30 mg, quant.). [a]²_D⁰þ164 (c 0.13, MeOH). H NMR

1

(MeOD, 400 MHz) 2.77 (1H, app. t, J 10.5 Hz, H-4), 3.44

(1H, dd, J 3.5, 9.5 Hz, H-2), 3.45 (3H, s, OMe), 3.64 (1H, dd,

J 7.0, 12.0 Hz, H-6⁰), 3.85e4.05 (7H, m, H-3, H-5, H-6, H-4⁰,

H-5⁰, H-6⁰), 4.63 (2H, s, OCH₂Ph), 4.76 (1H, d, J 3.5 Hz, H-

1), 5.85e5.91 (3H, m, H-1⁰, H-2⁰, H-3⁰), 7.28e7.43 (5H, m,

ArCH). ¹³C NMR (MeOD, 100 MHz) 49.6 (C-4), 55.7

(OMe), 62.7 (C-6⁰), 64.1 (C-4⁰or C-3), 71.7 (C-5 or C-5⁰),

71.9 (C-6), 73.7 (C-4⁰or C-3), 74.1 (C-5 or C-5⁰), 74.5 (C-2

and OCH₂Ph), 80.7 (C-1⁰), 101.4 (C-1), 128.2 (C-3⁰), 128.7

(ArCH), 128.9 (ArCH), 129.4 (ArCH), 129.4 (ArCH), 132.9

(C-2⁰), 139.7 (ArC). IR n_max(thin ﬁlm)/cm^ꢁ13443 (OH).

LRMS m/z 429 (1%, MþH^þ), 428 (5%, M), 331 (100%), 245

(10%), 169 (65%). HRMS (ESI, MþNH^þ₄), found: 446.1842;

C₂₀H₃₂O₈NS requires: 446.1849.

4.4.6. Methyl 6-S-(-^D-talopyranosyl)-6-thio-a-D-

glucopyranoside (43)

Following method A, methyl 2,3,4-tri-O-acetyl-6-S-(2,3,4,6-

tetra-O-acetyl-a-^D-talopyranosyl)-6-thio-a-D-glucopyranoside

(33) (13 mg, 0.02 mmol) and K₂CO₃(1 mg, 0.002 mmol) were

stirred for 2 h to afford 43 as a white powder (7 mg, quant.). Mp

212e214 ^ꢀC; [a]_D²⁰þ140 (c 0.5, H₂O). ¹H NMR (D₂O,

400 MHz) 2.91 (1H, dd, J 8.0, 14.0 Hz, H-6), 3.27 (1H, dd, J

2.5, 14.0 Hz, H-6), 3.48 (1H, dd, J 9.0, 9.5 Hz, H-4), 3.53

(3H, s, OMe), 3.68 (1H, dd, J 3.5, 9.5 Hz, H-2), 3.70e3.77

(1H, m, H-4⁰), 3.78 (1H, app. t, J 9.5 Hz, H-3), 3.86e3.95

(3H, m, H-3⁰, H-5, H-6⁰), 3.99 (1H, dd, J 2.0, 12.0 Hz, H-6⁰),

4.10 (1H, ddd, J 2.0, 6.0, 8.5 Hz, H-5⁰), 4.16 (1H, dd, J 1.5,

3.5 Hz, H-2⁰), 4.88 (1H, d, J 3.5 Hz, H-1), 5.45 (1H, d, J

1.5 Hz, H-1⁰). ¹³C NMR (D₂O, 100 MHz) 31.8 (C-6), 55.4

(OMe), 61.1 (C-6), 67.3 (C-3), 70.2 (C-4⁰), 71.3 (C-3⁰), 71.5

(C-2), 71.9 (C-2⁰), 72.5 (C-4), 73.2 (C-5), 73.5 (C-5⁰), 84.8

(C-1⁰), 99.5 (C-1). IR n_max(thin ﬁlm)/cm^ꢁ13443 (OH).

LRMS m/z 395 (100%, MþNa^þ), 331 (30%), 209 (52%), 164

(27). HRMS (ESI, MþNa^þ), found: 395.0998; C₁₃H₂₄O₁₀SNa

requires: 395.0988.

4.4.4. Methyl 6-O-benzyl-4-S-(2,3-dideoxy-a-^D-

galactopyranosyl)-4-thio-a-^D-glucopyranoside (41)

Following method A, methyl 6-O-benzyl-2,3-di-O-acetyl-4-

S-(2,3-dideoxy-4,6-di-O-acetyl-a-^D-galactopyranosyl)-6-thio-

a-^D-glucopyranoside (29) (33 mg, 0.06 mmol) and K₂CO₃

(1 mg, 6ꢂ10^ꢁ6mmol) were stirred for 2 h to afford 41 as awhite

powder (23 mg, quant.). Mp 178e182 ^ꢀC; [a]_D²⁰þ57 (c 1.05,

MeOH). ¹H NMR (MeOD, 400 MHz) 3.73 (1H, app. t, J

10.5 Hz, H-4), 3.40 (1H, dd, J 3.5, 9.5 Hz, H-2), 3.41 (3H, s,

OMe), 3.76 (2H, d, J 6.0 Hz, H-6⁰), 3.83 (1H, dd, J 2.5,

5.0 Hz, H-4⁰), 3.85e3.98 (3H, m, H-5, H-6), 4.01 (1H, app. t,

J 10.0 Hz, H-3), 4.18 (1H, ddd, J 2.5, 6.0, 6.0 Hz, H-5⁰), 4.59

(2H, s, OCH₂Ph), 4.73 (1H, d, J 3.5 Hz, H-1), 5.94e5.97 (2H,

m, H-1⁰, H-2⁰), 5.98 (1H, dd, J 2.5, 5.0 Hz, H-3⁰), 7.26e7.37

4.4.7. Methyl 6-O-benzyl-4-S-(-^D-mannopyranosyl)-6-thio-

a-D-glucopyranoside (44)

Following method A, methyl 6-O-benzyl-2,3-di-O-acetyl-4-

S-(2,3,4,6-tetra-O-acetyl-a-^D-mannopyranosyl)-6-thio-a-D-

2852

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

glucopyranoside (36) (15 mg, 0.02 mmol) and K₂CO₃(1 mg,

0.003 mmol) were stirred for 2 h to afford 44 as a colourless

oil (10 mg, quant.). [a]²_D⁰þ97 (c 0.21, MeOH). ¹H NMR

(MeOD, 400 MHz) 2.83 (1H, app. t, J 11.0 Hz, H-4), 3.38

(3H, s, OMe), 3.44 (1H, dd, J 3.5, 9.5 Hz, H-2), 3.61 (1H,

dd, J 3.0, 9.5 Hz, H-3⁰), 3.67 (1H, app. t, J 9.0 Hz, H-4⁰),

3.71 (1H, dd, J 6.0, 11.5 Hz, H-6⁰), 3.81e3.99 (6H, m, H-3,

H-5, H-5⁰, H-6, H-6⁰), 4.02 (1H, dd, J 1.5, 3.0 Hz, H-2⁰),

4.60 (1H, d, J 14.0 Hz, OCH₂Ph), 4.64 (1H, d, J 14.0 Hz,

OCH₂Ph), 4.76 (1H, d, J 3.5 Hz, H-1), 5.61 (1H, d, J

1.5 Hz, H-1⁰), 7.28e7.42 (5H, m, ArCH). ¹³C NMR (MeOD,

100 MHz) 47.0 (C-4), 55.4 (OMe), 62.3 (C-6⁰), 68.4 (C-4⁰),

71.2 (C-3), 71.4 (C-6), 72.7 (C-3⁰), 73.7 (C-2⁰), 73.9 (C-5),

74.2 (C-2), 75.3 (C-5⁰), 86.3 (C-1⁰), 101.1 (C-1), 128.3

(ArCH), 128.6 (ArCH), 129.0 (ArCH), 137.9 (ArC). IR n_max

(thin ﬁlm)/cm^ꢁ13443 (OH). LRMS m/z 485 (100%, MþNa^þ),

483 (7%), 331 (2%), 251 (9%). HRMS (ESI^ꢁ, MꢁH), found:

461.1480; C₂₀H₂₉O₁₀S requires: 461.1482.

SCH₂), 4.17e4.33 (5H, m, H-5, H-6, OCH₂CH₃), 4.62e4.69

(1H, m, H), 5.33 (1H, ddd, J 2.0, 4.0, 9.0 Hz, H-4), 5.46e5.51

(1H, m, H-1), 5.79 (1H, app. dt, J 2.0, 10.0 Hz, H-3), 5.92 (1H,

ddd, J 2.0, 3.0, 10.0 Hz, H-2), 6.02 (1H, d, J 9.0 Hz, NH). ¹³

C

NMR (CDCl₃, 100 MHz) 14.2 (OCH₂CH₃), 20.8 (OAc), 21.0

(OAc), 28.3 (^tBu), 36.3 (SCH₂), 53.8 (C), 61.6 (OCH₂CH₃),

63.1 (C-6), 64.7 (C-4), 67.4 (C-5), 79.9 (C(CH₃)₃), 82.2 (C-1),

127.2 (C-3), 128.5 (C-2), 155.5 (C]O), 170.2 (C]O), 170.6

(C]O), 170.9 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11743.4

(C]O), 1716.1 (C]O). HRMS (EI MþNa^þ), found:

484.1607; C₂₀H₃₁NO₉SNa requires: 484.1617.

4.4.10. N-tert-Butoxycarbonyl-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-galactopyranosyl)-L-cysteine ethyl ester (59)

Following method B, N-benzoyl-S-(2,3-dideoxy-4,6-tri-O-

acetyl-a-^D-galactopyranosyl)-L-cysteine ethyl ester (51) (75 mg,

0.16 mmol), DMAP (4 mg, 0.03 mmol) and di-tert-butyl dicar-

bonate (70 mg, 0.32 mmol) were stirred at room temperature

overnight, after subsequent treatment with N₂H₄$H₂O

(0.03 mL, 6.4 mmol) afforded, after puriﬁcation by column chro-

matography (2:1 hexane/ethyl acetate, 1% triethylamine), 59 as

a white solid (68 mg, 92%). R_f0.4 (2:1 hexane/ethyl acetate);

mp 178e182 ^ꢀC; [a]_D²⁰ꢁ62.5 (c 0.3, CHCl₃). ¹H NMR (CDCl₃,

4.4.8. Methyl 6-O-benzyl-4-S-(-^D-talopyranosyl)-6-thio-a-D-

glucopyranoside (45)

Following method A, methyl 6-O-benzyl-2,3-di-O-acetyl-4-

S-(2,3,4,6-tetra-O-acetyl-a-^D-talopyranosyl)-6-thio-a-D-gluco-

pyranoside (37) (18 mg, 0.03 mmol) and K₂CO₃(1 mg,

0.003 mmol) were stirred for 2 h to afford 45 as a colourless

oil (12 mg, quant.). [a]²_D⁰þ71 (c 0.54, MeOH). ¹H NMR

(MeOD, 400 MHz) 2.66 (3H, app. t, J 9.5 Hz, H-4), 3.41 (3H,

s, OMe), 3.44 (1H, dd, J 3.5, 9.5 Hz, H-2), 3.69 (1H, dd, J 4.5,

11.5 Hz, H-6⁰), 3.73e3.80 (2H, m, H-4⁰, H-6⁰), 3.81e3.91

(3H, m, H-3, H-3⁰, H-5⁰), 3.96 (1H, dd, J 2.0, 11.0 Hz, H-6),

4.01 (1H, dd, J 5.0, 11.0 Hz, H-6), 4.17 (1H, dd, J 3.0, 6.0 Hz,

H-2⁰), 4.32e4.40 (1H, m, H-5), 4.59 (1H, d, J 11.5 Hz,

OCH₂Ph), 4.63 (1H, d, J 11.5 Hz, OCH₂Ph), 4.73 (1H, d, J

3.5 Hz, H-1), 5.42 (1H, d, J 6.0 Hz, H-1⁰), 7.24e7.41 (5H, m,

ArCH). ¹³C NMR (MeOD, 100 MHz) 51.9 (C-4), 55.7

(OMe), 62.8 (C-6⁰), 67.4 (C-2⁰), 69.6 (C-5), 71.1 (C-4), 71.7

(C-6), 72.2, 73.1 and 73.6 (C-3, C-3⁰and C-5⁰), 74.3 (C-2),

74.4 (OCH₂Ph), 87.6 (C-1⁰), 101.4 (C-1), 128.6 (ArCH),

128.9 (ArCH), 129.3 (ArCH), 138.1 (ArC). IR n_max(thin

ﬁlm)/cm^ꢁ13443 (OH). LRMS m/z 485 (46%, MNa^þ), 483

(77%), 461 (100%, M-H), 331 (2%), 251 (9%). HRMS (ESI^ꢁ,

MꢁH), found: 461.1491; C₂₀H₂₉O₁₀S requires: 461.1482.

t

400 MHz) 1.28 (3H, t, J 7.0 Hz, OCH₂CH₃), 1.45 (9H, s, Bu),

2.09 (3H, s, OC(O)CH₃), 2.16 (3H, s, OC(O)CH₃), 3.02 (1H,

dd, J 3.5, 14.5 Hz, SCH₂), 3.38 (1H, dd, J 5.0, 14.5 Hz, SCH₂),

4.17e4.33 (4H, m, H-6, OCH₂CH₃), 4.49 (1H, ddd, J 2.5, 5.0,

7.5 Hz, H-5), 4.62e4.70 (1H, m, H-6), 5.07 (1H, dd, J 2.5,

5.0 Hz, H-4), 5.52e5.57 (1H, m, H-1), 6.00e6.03 (1H, m, NH),

6.04 (1H, ddd, J 1.5, 5.0, 10.0 Hz, H-3), 6.10 (1H, dd, J 3.0,

10.0 Hz, H-2). ¹³C NMR (CDCl₃, 100 MHz) 14.2 (OCH₂CH₃),

20.8 (OAc), 20.8 (OAc), 28.3 (^tBu), 36.3 (SCH₂), 53.8 (C), 61.6

(OCH₂CH₃), 62.9 (C-6), 63.1 (C-4), 67.5 (C-5), 79.9

(C(CH₃)₃), 82.1 (C-1), 123.9 (C-3), 131.4 (C-2), 155.5 (C]O),

170.3 (C]O), 170.6 (C]O), 170.9 (C]O). IR n_max(thin

ﬁlm)/cm^ꢁ11743 (C]O), 1719 (C]O). HRMS (CI, MH^þ),

found: 462.1805; C₂₀H₃₂NO₉S requires: 462.1798.

4.4.11. S-(2,3-Dideoxy-a-^D-glucopyranosyl)-DL-cysteine

(66)

Following method D, N-tert-butoxycarbonyl-S-(2,3-di-

deoxy-4,6-tri-O-acetyl-a-^D-glucopyranosyl)-L-cysteine ethyl

ester (58) (31 mg, 0.07 mmol) and NaOEt (1 mg, 0.1 mmol)

were stirred for 2 h at room temperature, after cooling to

0 ^ꢀC, stirring with triﬂuoroacetic acid (2 mL) for 30 min af-

forded 66 was a colourless oil (17 mg, quant.). ¹H NMR

(D₂O, 400 MHz) 3.23 (1H, dd, J 3.5, 6.0 Hz, SCH₂), 3.55e

3.85 (3H, m, H-5, H-6), 3.96e4.02 (1H, m, NHCH), 4.30

(1H, dd, J 4.5, 6.0 Hz, H-4), 5.55 (1H, br s, H-1), 5.73e5.84

(2H, m, H-2, H-3). ¹³C NMR (D₂O, 100 MHz) 32.9 (SCH₂),

53.5 (NHCH), 61.1 and 62.7 (C-6), 70.1 (C-5), 72.9 (C-4),

82.0 (C-1), 114.3 and 118.9 (C-3), 126.7 and 131.4 (C-2),

163.0 and 163.5 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ13443

(OH). LRMS m/z 250 (100%, MþH^þ), 249 (26%, M^þ), 134

(28%), 129 (43%). HRMS (ESI, MH^þ), found: 250.0753;

C₉H₁₆NO₅S requires: 250.0749.

4.4.9. N-tert-Butoxycarbonyl-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-glucopyranosyl)-L-cysteine ethyl ester (58)

Following method B, N-benzoyl-S-(2,3-dideoxy-4,6-tri-O-

acetyl-a-^D-glucopyranosyl)-L-cysteine ethyl ester (49) (140 mg,

0.3 mmol), DMAP (4 mg, 0.03 mmol) and di-tert-butyl dicar-

bonate (129 mg, 0.6 mmol) were stirred at room temperature

overnight, after subsequent treatment with N₂H₄$H₂O

(0.05 mL, 1.2 mmol) afforded, after puriﬁcation by column chro-

matography (2:1 hexane/ethyl acetate, 1% triethylamine), 58 as

a white solid (127 mg, 92%). R_f0.4 (2:1 hexane/ethyl acetate);

mp 134e135 ^ꢀC; [a]_D²⁰þ100.8 (c 0.25, CHCl₃). ¹H NMR

(CDCl₃, 400 MHz) 1.27 (3H, t, J 7.0 Hz, OCH₂CH₃), 1.43 (9H,

s, ^tBu), 2.09 (3H, s, OC(O)CH₃), 2.16 (3H, s, OC(O)CH₃), 3.04

(1H, dd, J 3.5, 14.5 Hz, SCH₂), 3.34 (1H, dd, J 5.0, 14.5 Hz,

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

2853

4.4.12. S-(2,3-Dideoxy-a-D-galactopyranosyl)-DL-cysteine

ethyl ester (67)

triethylamine), 69 as a white solid (64 mg, 88%). R_f0.4 (2:1 hex-

ane/ethyl acetate); mp 151e154 ^ꢀC. ¹H NMR (CDCl₃,

250 MHz) 1.44 (9H, s, C(CH₃)₃), 1.94e2.25 (2H, m,

SCH₂CH₂), 2.09 (6H, s, OC(O)CH₃), 2.58e2.84 (2H, m,

SCH₂CH₂), 3.75 (3H, s, OMe), 4.10e4.55 (4H, m, NHCH, H-

5, H-6), 5.07 (1H, dd, J 2.5, 4.5 Hz, H-4), 5.10e5.13 (1H, m,

NH), 5.62 (1H, br s, H-1), 5.59e6.13 (2H, m, H-2, H-3). ¹³C

NMR (CDCl₃, 63 MHz) 21.2 (OAc), 28.0 (SCH₂CH₂), 28.6

(C(CH₃)₃), 33.6 (SCH₂CH₂), 52.6 (OMe), 52.8 (NHCH), 63.0

(C-6), 63.7 (C-4), 67.1 (C-5), 80.1 (C-1), 80.7 (C(CH₃)₃),

124.4 (C-3), 132.0 (C-2), 155.7 (C]O), 170.6 (C]O), 171.0

(C]O), 173.0 (C]O). IR n_max(thin ﬁlm)/cm^ꢁ11743

(C]O), 1716 (C]O). LRMS m/z 462 (6%, MþH^þ), 406

(11%), 284 (11%), 213 (90%), 111 (100%). HRMS (CI,

MH^þ), found: 462.1802; C₂₀H₃₂NO₉S requires: 462.1798.

Following method D, N-tert-butoxycarbonyl-S-(2,3-di-

deoxy-4,6-tri-O-acetyl-a-^D-galactopyranosyl)-L-cysteine ethyl

ester (59) (32 mg, 0.07 mmol) and NaOEt (1 mg, 0.1 mmol)

were stirred for 2 h at room temperature, after cooling to

0 ^ꢀC, stirring with triﬂuoroacetic acid (2.5 mL) for 30 min af-

1

forded 67 as a colourless oil (19 mg, quant.). H NMR (D₂O,

250 MHz) 1.09e1.19 (3H, m, OCH₂CH₃), 2.86e3.30 (3H, m,

SCH₂, H-6), 3.62e3.71 (3H, m, NHCH, H-5, H-6), 3.82e

3.86 (2H, m, OCHCH), 4.45e4.67 (1H, m, H-4), 5.60 (1H, br

s, H-1), 5.87e6.00 (2H, m, H-2, H-3). ¹³C NMR (D₂O,

63 MHz) 17.6 (OCH₂CH₃), 29.8 (SCH₂), 59.7 (NHCH), 60.4

(C-6), 61.1 (OCH₂CH₃), 64.5 (C-5), 78.4 (C-4), 82.2 (C-1),

127.8 (C-3), 137.3 (C-2), 168.5 (C]O). IR n_max(thin ﬁlm)/

cm^ꢁ13443 (OH). LRMS m/z 300 (15%, MþNa^þ), 278 (32%,

MH^þ), 277 (26%, M^þ), 148 (23%), 129 (35%). HRMS (ESI,

M), found: 277.0990; C₁₁H₂₀NO₅S requires: 277.0984.

4.4.15. S-(2,3-Dideoxy-a-^D-glucopyranosyl)-DL-

homocysteine methyl ester (70)

Following method E, N-tert-butoxycarbonyl-S-(2,3-di-

deoxy-4,6-tri-O-acetyl-a-^D-glucopyranosyl)-DL-homocysteine

methyl ester (68) (20 mg, 0.05 mmol) and NaOMe (1 mg,

0.1 mmol) were stirred for 2 h at room temperature, after cool-

ing to 0 ^ꢀC, stirring with triﬂuoroacetic acid (3 mL) for 2 h

afforded 70 as a colourless oil (12 mg, quant.). ¹H NMR

(MeOD, 400 MHz) 1.95e2.09 (2H, m, SCH₂CH₂), 2.66e

2.95 (2H, m, SCH₂CH₂), 3.35 (3H, s, OMe), 3.72e3.82 (1H,

m, H-6), 3.83e3.93 (2H, m, H-5, H-6), 4.13e4.18 (1H, m,

H-4), 4.21e4.34 (1H, m, NHCH), 5.60 (1H, br s, H-1),

5.83e5.91 (2H, m, H-2, H-3). ¹³C NMR (MeOD, 100 MHz)

28.4 and 28.9 (SCH₂CH₂), 32.8 (SCH₂CH₂), 49.4 (OMe),

53.8 (NHCH), 62.3 (C-6), 62.6 (C-5), 73.1 (C-4), 80.9 (C-1),

127.9 (C-3), 132.3 (C-2), 167.2 (C]O). IR n_max(thin ﬁlm)/

cm^ꢁ13443 (OH), 1716 (C]O). LRMS m/z 295 (10%,

MNH^þ₄), 278 (100%, MþH^þ), 230 (32%), 129 (28%).

HRMS (ESI^ꢁ, MꢁH), found: 276.0892; C₁₁H₁₈NO₅S re-

quires: 276.0906.

4.4.13. N-tert-Butoxycarbonyl-S-(2,3-dideoxy-4,6-tri-O-

acetyl-a-^D-glucopyranosyl)-DL-homocysteine methyl ester

(68)

Following method C, N-benzoyl-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-glucopyranosyl)-DL-homocysteine methyl ester (50)

(60 mg, 0.12 mmol), DMAP (1 mg, 0.03 mmol) and di-tert-bu-

tyldicarbonate (56 mg, 0.25 mmol) were stirredat roomtemper-

ature overnight, after subsequent treatment with N₂H₄$H₂O

(0.03 ml, 0.5 mmol) afforded, after puriﬁcation by column chro-

matography (2:1 hexane/ethyl acetate, 1% triethylamine), 68 as

a white solid (48 mg, 80%). R_f0.3 (2:1 hexane/ethyl acetate). ¹H

NMR (CDCl₃, 400 MHz) 1.46 (9H, s, C(CH₃)₃), 1.91e2.06

(1H, m, SCH₂CH₂), 2.09 (3H, s, OC(O)CH₃), 2.10 (3H, s,

OC(O)CH₃), 2.13e2.25 (1H, m, SCH₂CH₂), 2.62e2.83 (2H,

m, SCH₂CH₂), 3.75 (3H, s, OMe), 4.15e4.33 (3H, m, H-5, H-

6), 4.38e4.48 (1H, m, NHCH), 5.10 (1H, d, J 8.0 Hz, NH),

5.33e5.40 (1H, m, H-4), 5.52e5.57 (1H, m, H-1), 5.57 (1H,

dd, J 1.5, 10.5 Hz, H-3), 5.87e5.95 (1H, m, H-2). ¹³C NMR

(CDCl₃, 100 MHz) 20.8 (OAc), 21.0 (OAc), 27.9 (SCH₂CH₂),

28.3 (C(CH₃)₃), 33.2 and 33.3 (SCH₂CH₂), 52.5 (OMe), 52.8

(NHCH), 62.9 and 63.0 (C-6), 65.0 and 65.1 (C-4), 66.9 (C-5),

80.2 and 80.3 (C-1), 81.1 (C(CH₃)₃), 127.3 (C-3), 128.7 (C-2),

170.3 (C]O), 170.8 (C]O), 170.9 (C]O), 172.7 (C]O). IR

n_max(thin ﬁlm)/cm^ꢁ11744 (C]O), 1716 (C]O). LRMS m/z

484 (100%, MþNa^þ), 301 (11%), 251 (24%), 239 (11%).

HRMS (CI, MþH^þ), found: 462.1799; C₂₀H₃₂NO₉S requires:

462.1798.

4.4.16. S-(2,3-Dideoxy-a-^D-galactopyranosyl)-DL-

homocysteine methyl ester (71)

Following method E, N-tert-butoxycarbonyl-S-(2,3-di-

deoxy-4,6-tri-O-acetyl-a-^D-galactopyranosyl)-DL-homocys-

teine methyl ester (69) (24 mg, 0.05 mmol) and NaOMe

(1 mg, 0.1 mmol) were stirred for 2 h at room temperature, af-

ter cooling to 0 ^ꢀC, stirring with triﬂuoroacetic acid (3 mL) for

1

2 h afforded 71 as a colourless oil (13 mg, quant.). H NMR

(D₂O, 250 MHz) 1.82e2.40 (2H, m, SCH₂CH₂), 2.42e2.90

(2H, m, SCH₂CH₂), 3.62 and 3.67 (3H, s, OMe epimers),

3.69e4.10 (5H, m, NHCH, H-4, H-5, H-6), 5.89e5.97 (1H,

m, H-1), 6.24e6.32 (2H, m, H-2, H-3). ¹³C NMR (D₂O,

63 MHz) 29.3 (SCH₂CH₂), 38.2 (SCH₂CH₂), 44.2 (OMe),

51.2 (NHCH), 60.8 (C-6), 68.8 (C-5), 75.3 (C-4), 84.4 (C-1),

112.5 and 118.6 (C-3), 142.2 (C-2), 162.4 (C]O). IR n_max

(thin ﬁlm)/cm^ꢁ13443 (OH), 1717 (C]O). LRMS m/z 300

(22%, MþNa^þ), 295 (26%, MNH^þ₄), 278 (100%, MH^þ), 230

(28%), 129 (56%). HRMS (ESI^ꢁ, MꢁH), found: 276.0898;

C₁₁H₁₈NO₅S requires: 276.0906.

4.4.14. N-tert-Butoxycarbonyl-S-(2,3-dideoxy-4,6-tri-O-

acetyl-a-^D-galactopyranosyl)-DL-homocysteine methyl ester

(69)

Following method C, N-benzoyl-S-(2,3-dideoxy-4,6-di-O-

acetyl-a-^D-galactopyranosyl)-DL-homocysteine methyl ester

(55) (65 mg, 0.14 mmol), DMAP (1 mg, 0.03 mmol) and di-

tert-butyl dicarbonate (60 mg, 0.28 mmol) were stirred at

room temperature overnight, after subsequent treatment with

N₂H₄$H₂O (0.03 ml, 0.55 mmol) afforded, after puriﬁcation

by column chromatography (2:1 hexane/ethyl acetate, 1%

2854

D. Ellis et al. / Tetrahedron 64 (2008) 2832e2854

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Acknowledgements

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S.E.N. is grateful to Pﬁzer Ltd and the EPSRC for provision

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Peter Heath for his considerable assistance with NMR analysis

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Article Doi

Synthesis of S-linked carbohydrate analogues via a Ferrier reaction

DOI: 10.1016/j.tet.2008.01.042

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