Maltose and maltotriose derivatives as potential inhibitors of the maltose-binding protein

FULL PAPER

DOI: 10.1002/ejoc.200701139

Maltose and Maltotriose Derivatives as Potential Inhibitors of the Maltose-

Binding Protein

Heinz Malik,^[a]Winfried Boos,^[b]and Richard R. Schmidt*^[a]

Keywords: Carbohydrates / Maltose-binding protein / Maltose transport / Inhibition / Substrate modification / Glycosid-

ation

Inhibition of substrate binding to maltose-binding protein

(MBP) was investigated with structurally modified maltose

and maltotriose derivatives that were designed based on the

X-ray analysis of maltose and maltotriose bound to MBP. In

maltose, positions 1a, 2a, 2b, 4b and 6b were modified (com-

pounds 1–3, 18a, b, 28a–c, 39 and 44) of which only the tri-

valent maltose derivatives 39 and 44 exhibited high affinity

to MBP. Maltotriose modifications were carried out at posi-

tion 6a and 6c (compounds 45–51). Compound 50, possessing

a 6a-O-propyl group, and compound 51, where the 6c-hy-

droxy group is replaced by bromide, showed higher affinity

to MBP than the parent maltotriose. Hence, the structurally

quite different compounds 39, 50 and 51 are important lead

compounds for further studies.

Germany, 2008)

Introduction

Results and Discussion

Modifications of Maltose

The active transport of substances through biological

membranes is of great importance for the uptake, for in-

stance, of nutrients and signalling molecules. The ATP-

binding-cassette (ABC) transport proteins serve this role.^[1]

The ABC transporter for maltose in Escherichia coli is sup-

ported by a maltose-binding protein (MBP) that is located

in-between the (outer) cell wall and the (inner) plasma

membrane. MBPs bind maltose (and also maltotriose and

higher oligomers) that have passed the cell wall via malto-

porin and provide it to the ABC maltose transport system

in the plasma membrane.^[1–3]Hence, blocking of this trans-

port system by inhibiting maltose and maltodextrin binding

to MBP could perhaps lead to a new type of antibacterials.

Therefore, we investigated variously modified maltose and

maltotriose derivatives for their inhibition of maltose and

maltotriose binding to MBP. The modifications are based

on X-ray analyses of substrate binding to MBP.^[4,5]Oxi-

dation and reduction products of the reducing end of

maltose and higher analogs were already investigated as in-

hibitors of maltose binding to MBP, however they did not

reach the affinity of maltose.^[6]Also maltotriose analogs

with a spacer group for the middle glycosyl residue were

prepared and investigated for this purpose^[7]and the α-glu-

cosidase inhibitor acarbose, formally a maltotetraose ana-

log, was shown to possess affinity to MBP as well.^[8]

Maltose bound to MBP shows in the X-ray analysis^[4]

Glu¹¹¹close to the 2a-hydroxy group, Asp⁶⁵close to the 2b-

hydroxy group and Glu¹⁵³close to the 4b-hydroxy group.

Therefore, it was decided to introduce at these positions

amino groups. Hence, compounds 1–3 (Scheme 1) were tar-

get molecules. It was also speculated that, because of struc-

tural similarity, aminoglycoside antibiotics like neamycine,

streptomycine, kanamycine, gentamycine and amikacine

may act as MBP inhibitors. Therefore, they were included

in this study.

For the synthesis of compounds 1–3, known glycosyl do-

nor 4^[9]and glycosyl donor 5 were required. 5 was readily

obtained from 6-O-unportected 2-azido-2-deoxy-glucopyr-

anoside 9.^[10,11]The 6-hydroxy group was replaced by the

azido group under Mitsunobu conditions^[12]affording 2,6-

diazido derivative 10. O-Desilylation with HF–pyridine

complex furnished 1-O-unprotected 11 that gave with tri-

chloroacetonitrile in the presence of DBU as base^[13]

the desired O-glucosyl trichloroacetimidate 5. As glycosyl

acceptors 4-O-unprotected glucopyranosides 6–8 were se-

lected, which have been previously prepared.^[14–16]

Glycosylation of acceptor 6 with donor 4 in ether and

triflic acid (0.05 equiv.) as catalyst at room temperature^[17]

afforded the desired α-linked disaccharide 12 in 69% yield.

Hence, with the selected electron-withdrawing protecting

group pattern in donor 4 and the selected reaction condi-

tions α-linkage in the disaccharide could be readily ob-

tained.^[13]Cleavage of the O-acetyl groups of 12 under

Zemplén conditions^[18]led to compound 13 that gave on

hydrogenolysis with Pearlman’s catalyst^[19]target molecule

[a] Fachbereich Chemie, Universität Konstanz,

Fach M 725, 78457 Konstanz, Germany

Fax: + 49-7531-883135

E-mail: Richard.Schmidt@uni-konstanz.de

[b] Fachbereich Biologie, Universität Konstanz,

78457 Konstanz, Germany

2084

Eur. J. Org. Chem. 2008, 2084–2099

Maltose and Maltotriose Derivative

found. Hydrogenolysis under the above-described condi-

tions led to target molecule 3. The ¹H NMR spectrum con-

firmed the α-linkages (J_1a,2a= J_1b,2b= 3.7 Hz).

Binding studies to MBP with compounds 1–3 showed

very low affinity compared with maltose that binds in the

low µmolar range (see below, Table 1). Similar results were

obtained for the above-mentioned aminoglycoside anti-

biotics (not shown). Hence, strengthening ionic interactions

to increase binding to MBP was not successful. Therefore,

it was decided to replace the 4b-hydroxy group of maltose

by aryl–O–CH₂CH₂–O residues. This way, glucosyl residues

could be mimicked with binding affinities in the range of

maltotriose that has a sub-µmolar K_dvalue (Table 1). This

group could also strongly inhibit transportation by the

ABC maltose transport system.

Table 1. Binding affinities of the target molecules to MBP com-

pared to maltose and maltotriose.

Compound

IC50 [µ]

K_d[µ]

Maltose

–

1–4

850

Ͼ 450

44

366

160

275

76

58

0.91

1.4

0.11

0.91

18

0.85

0.42

0.07

0.04

1

1000

Ͼ 1000

Ͼ 500

Ͼ 750

60

500

260

450

125

96

1.5

2.4

0.19

1.5

2

3

18a

18b

19

20

28a

28b

28c

29

39

44

Maltotriose

45

46

47

48

49

50

51

Scheme 1. Structure and synthesis of target molecules 1–3. Rea-

gents and conditions: a) PPh₃, DEAD, HN₃, C₆H₆, THF; b) HF,

Pyr; c) CCl₃CN, DBU, CH₂Cl₂; d) TfOH (0.05 equiv.), Et₂O, room

temp.; e) NaOMe, MeOH; f) Pd(OH)₂/C, H₂, MeOH, HCl/Et₂O;

g) TBDMSOTf (0.01 equiv.), Et₂O, room temp.; h) TBAF, HOAc,

THF; i) TMSOTf (0.01 equiv.), Et₂O, room temp.

31

1.4

0.70

0.11

0.07

1; the structural assignment was confirmed by comparison

The synthesis of target molecules 18a,b (Scheme 2) was

with previously reported physical data.^[20]Glycosylation of performed via methyl maltoside 19,^[21]its benzylidene deriv-

acceptor 7 with 4 in ether with tert-butyldimethylsilyl tri- ative 20,^[22]and the benzylation product 21,^[23]which was

fluoromethanesulfonate (TBDMSOTf) as catalyst at room transformed into the 4b-O-unprotected maltoside 22^[24]fol-

temperature afforded an 8:1 α/β-mixture of which the de- lowing literature procedures. Alkylation of 22 with 8-(triiso-

sired α-anomer 14 could be readily separated. In order to propylsilyloxy)-3,6-dioxa-octyl bromide (23) with sodium

obtain this result, variation of the catalyst and solvent had hydride as base in the presence of tetrabutylammonium io-

to be investigated, thus exhibiting the different influence of dide (TBAI) as promoter in DMF afforded compound 24.

acceptors 6 and 7 on the glycosylation result. O-Deacety- Cleavage of the silyl group with TBAF in THF (Ǟ25) and

lation of 14 (Ǟ 15), then cleavage of the 1-O-thexyl-dimeth- then replacement of the ω-hydroxy group by bromide with

ylsilyl (TDS) group with tetrabutylammonium fluoride Appel’s reagent^[25]led to intermediate 26. Reaction of 26

(TBAF) in the presence of acetic acid in THF (Ǟ16) af- with 3,5-dimethoxyphenol with NaH/TBAI in DMF gave

forded after hydrogenolysis target molecule 2 as a 3:2-mix- aryl ether derivative 27a in good yield. Similarly, from 26

ture of anomers in high overall yield. Glycosylation of ac- and 3,5-diisopropyloxyphenol analog 27b was generated.

ceptor 8 with glycosyl donor 5 in ether with TMSOTf as Hydrogenolytic O-debenzylation of 27a and 27b as de-

catalyst at room temperature^[13]furnished the desired α- scribed above led to target molecules 18a and 18b, respec-

linked disaccharide 17 in 80% yield; no β-anomer was tively.

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H. Malik, W. Boos, R. R. Schmidt

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Scheme 3. Structure and synthesis of target molecules 28a–c. Rea-

gents and conditions: a) BnBr, NaH, DMF; b) NaCNBH₃, Et₂O/

HCl; c) NaH, TBAI, DMF; d) Pd(OH)₂/C, H₂, dioxane.

Scheme 2. Structure and synthesis of target molecules 18a,b. Rea-

gents and conditions: a) PhCH(OMe)₂, TsOH (ref.^[22]); b) BnBr,

NaH, DMF (ref.^[23]); c) NaCNBH₃, Et₂O/HCl (ref.^[24]); d) NaH,

TBAI, DMF, e) TBAF, THF; f) CBr₄, PPh₃, CH₂Cl₂; g) 3,5-di-

methoxyphenol, NaH, TBAI, DMF; h) 3,5-diisopropoxyphenol,

NaH, TBAI, DMF; i) Pd(OH)₂/C, H₂, dioxane.

transformation of 36 with Appel’s reagent^[25]into 4b-O-bro-

moethylated derivative 37, and then O-alkylation of phloro-

glucine with 37 and NaH/TBAI in DMF furnished trivalent

The synthesis of 4b-O-modified target molecules 28a–c

(Scheme 3), having an unprotected glucose residue at the

reducing end and only one ethylene glycol residue, started

from known 4b,6b-O-benzylidene-maltose (29).^[22,26]Fol-

lowing benzylation under standard conditions afforded

fully protected maltoside 30; reductive cleavage of the

benzylidene ring with sodium cyanoborohydride in hydro-

gen chloride containing ether^[24]afforded known 4b-O-un-

protected compound 31.^[14,27]4b-O-Alkylation with 3,5-di-

alkoxyphenyloxyethyl bromides 32a–c furnished 33a–c that

on hydrogenolytic O-debenzylation provided target mole-

cules 28a–c. Compounds 28a–c showed for the first time

affinities to MBP in the µmolar range whereas 18a, b had

still very low affinities (Table 1). Surprisingly, all these affin-

ities to MBP were easily reached or even surpassed by sim-

ple maltose derivatives 19, 20 and 29 (Table 1).

Based on these results the multivalency effect was investi-

gated by ligating three maltose residues either via their 4b-

hydroxy groups or via their anomeric hydroxy groups for-

mally to 1,3,5-tris-O-hydroxyethylphloroglucine, thus lead-

ing to target molecules 39 and 44, respectively (Scheme 4

and Scheme 5). To this end, 4b-O-unprotected maltoside

was alkylated with tris(isopropylsilyloxy)ethyl bromide 34

with NaH/TBAI in DMF providing compound 35. Cleav-

Scheme 4. Synthesis of maltose cluster 39. Reagents and conditions:

a) BrCH₂CH₂OTIPS, NaH, TBAI, DMF; b) TBAF, THF; c) CBr₄,

PPh₃, CH₂Cl₂; d) phloroglucine, NaH, TBAI, DMF; e) Pd(OH)₂/

age of the TIPS group with TBAF in THF (Ǟ36), then C, H₂, THF.

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Maltose and Maltotriose Derivative

intermediate 38 in 52% yield. Hydrogenolytic O-deben-

zylation afforded target molecule 39. Glycosylation of 1,3,5-

tris-(hydroxyethyloxy)benzene 42,^[28]that is readily ob-

tained from 41,^[29]with O-acetyl-protected O-maltosyl tri-

chloroacetimidate 40^[13,30]as glycosyl donor and TMSOTf

as catalyst in acetonitrile at room temperature^[13]led to the

desired β-linked tris-O-maltosyloxyethyl phloroglucine

ether 43. O-Deacetylation under Zemplén conditions^[18]

furnished target molecule 44. To our delight, trivalent com-

pounds 39 and 44 showed affinities to MBP in the range of

maltose and maltotriose (Table 1).

Scheme 6. Structure and synthesis of target molecules 45–51. Rea-

gents and conditions: a) BnBr, NaH, DMF; b) CBr₄, PPh₃, CH₂Cl₂;

c) NaOMe, TBAI, 15-crown-5, DMF; d) TDS-Cl, imidazole,

CH₂Cl₂; e) NIS TfOH, Et₂O, room temp.; f) TBAF, THF; g)

H₃B·THF, Bn₂BOTf, CH₂Cl₂; h) MeI, NaH, DMF; i) Pd(OH)₂/C,

H₂, THF, H₂O, HOAc; j) PrI, NaH, DMF; k) TIPS-Cl, imidazole,

CH₂Cl₂; l) PPh₃, DEAD, HN₃, C₆H₆, CH₂Cl₂.

Scheme 5. Synthesis of maltose cluster 44. Reagents and conditions:

a) LiAlH₄, THF; b) TMSOTf (0.025 equiv.), MeCN, room temp.;

c) NaOMe, MeOH.

Modification of Maltotriose

silylation of the 6-hydroxy group in 54 with TDS-Cl and

The higher affinity of maltotriose to MBP compared imidazole in dichloromethane afforded 4-O-unportected

with maltose was reason to prepare modifications that are glucoside 57. Glycosylation of 57 as acceptor with donor

essentially designed based on the X-ray analysis of malto- 53 and N-iodosuccinimide (NIS, 2 equiv.) and catalytic

triose binding to MBP.^[5]It was speculated that substitution amounts of triflic acid (TfOH) as promoter^[34]afforded the

of water molecules in the active site by hydrophobic resi- desired α-linked maltotrioside 58 though in only 40% yield.

dues might lead to increased hydrophobic interactions and 6a-O-Deacetylation with TBAF in THF furnished 59 that

thus to increased overall binding.^[31]Therefore, following was used to introduce a 6a-O-propyl or a 6a-O-methyl

the X-ray analysis, modifications of the 6a- and/or 6c-hy- group under standard conditions affording compounds 62

droxy group were investigated. The target molecules 45–51 and 64, respectively. Reductive cleavage of the 4c,6c-O-

are compiled in Scheme 6.

benzylidene groups with the borohydride-THF complex in

For the construction of 45–51 an appropriately protected the presence of dibutylboron-trifluoromethanesulfonate^[10]

maltosyl donor and a 4-O-unprotected glucose acceptor afforded 6c-O-unprotected compounds 63 and 65. Hydro-

were chosen. This time, for the generation of the α-glyco- genolytic cleavage of the O-benzyl groups gave target mole-

sidic linkage, maltothioglycoside 53 was investigated that cules 50 and 49, respectively. The same reductive cleavage

was readily obtained from 4b,6b-O-benzylidene derivative applied to the 4c,6c-O-benzylidene group in 58 furnished

52.^[32]As acceptors glucopyranosides 56 and 57 were em- 6c-O-unportected maltotriose 60 that gave on 6c-O-methyl-

ployed, which were obtained from known glucoside 54.^[33]ation maltotrioside 61; then desilylation and hydrogenolytic

Chemoselective introduction of bromide at C-6 with O-debenzylation afforded target molecule 45.

Appel’s reagent^[25]afforded 55, which gave with sodium

The intermediate 64, required for the synthesis of target

methoxide in the presence of TBAI and crown ether 15- molecules 48 and 49, could also be obtained by glycosyla-

crown-5 in DMF 6-O-methyl-glucoside 56. Regioselective tion of acceptor 56 with donor 53 under the above-de-

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H. Malik, W. Boos, R. R. Schmidt

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scribed conditions. Reductive cleavage of the 4c,6c-O- methyl group (compound 49) and even further by a 6a-O-

benzylidene group with the boronhydride–THF complex,^[10]propyl group (compound 50), thus indicating that replace-

as mentioned earlier, led to compound 65 that was then ment of water molecules in the binding site leads to higher

transformed with methyl iodide and NaH as base into 6c- affinity to MBP than found for maltotriose. Even higher

O-methyl derivative 66. Hydrogenolytic O-debenzylation of affinity was obtained by replacement of the 6c-hydroxy

65 and 66 led to target molecules 49 and 48, respectively. group by bromide (compound 51; K_d= 40 nmol) which

Glycosylation of acceptor 6 with donor 53 under the stan- compared to the 6c-O-methyl compound 45, led to a

dard conditions furnished the desired maltotrioside 67, roughly 20-fold increase in binding affinity and compared

though in only 56% yield. Reductive cleavage of the 4c,6c- to maltotriose to a threefold higher affinity.

O-benzylidene group afforded 6c-O-unprotected compound

A few preliminary studies on maltose transport inhibi-

68 that was silylated with TIPS-Cl in the presence of imid- tion of the ABC-transporter were carried out by measuring

azole furnishing fully protected maltotrioside 69 which gave the ¹⁴C-maltose uptake by E. coli.^[35]It was observed that

on hydrogenolytic O-debenzylation target molecule 47. Tar- transport inhibition by compounds 18a,b, 28a–c and 29 fol-

get molecule 46 was readily obtained from 6c-O-unprotec- lowed the inhibitions found for maltose binding to MBP;

ted compound 60. Application of the Mitsunobu procedure hence, only compounds 28c and 29 show significant trans-

for azide introduction^[12]gave 6c-azido-6c-deoxymaltotrio- port inhibition.

side 70. Desilylation with TBAF in THF (Ǟ 71) and then

hydrogenolytic O-debenzylation led to 46. Target molecule

51 was obtained from 6c-O-unprotected compound 68 by

transformation into bromide 72 with Appel’s reagent and

then hydrogenolytic O-debenzylation.

Conclusions

Based on X-ray analyses of maltose and maltotriose

binding to MBP structural modifications were carried out.

This led to compounds 39 and 50, 51 showing higher affin-

With the exception of 6c-O-triisopropylsilyl-protected

maltotriose 47 all other target molecules exhibited excellent

ity to MBP than maltose or maltotriose, respectively. These

affinities to MBP (Table 1). It is particularly worth men-

structurally quite different lead compounds provide a good

tioning that compounds 50 and 51 having lipophilic groups

basis for further inhibition studies including detailed studies

in 6a- or 6c-position, respectively, show the highest binding

on maltose transport inhibition.

affinities to MBP.

Experimental Section

Biological Studies

General: Solvents were purified by standard procedures. NMR

The binding affinities to MBP were measured following

known procedures.^[35]From these results, the IC₅₀and the

K_dvalues were obtained^[36]which are compiled in Table 1.

As mentioned above, the replacement of maltose hydroxy

groups by amino groups as in 1–3 led to a big decrease in

binding to MBP. Also the introduction of aryl–O–

(CH₂CH₂–O)₃residues at the 4b-hydroxy group of maltose

(compounds 18a, b) did not improve this result. Surpris-

ingly, the corresponding compounds with a 4b-O-arylethy-

lene glycol residue (compounds 28a–c) showed improved af-

finity to MBP, yet they did not reach the affinities of simple

maltose derivatives as 19 and 29 or maltose. However, the

trivalent maltose derivatives 39 and 44, which were derived

from 28a–c, reached (compound 44) or even surpassed

(compound 39) the affinity of maltose to MBP. As ex-

pected, compound 39 with a nonmodified reducing end

showed the highest affinity in this series.

spectra were recorded at 22 °C on a Bruker AC 250 Cryospec or

a Bruker DRX 600 spectrometer. Tetramethylsilane (TMS) or the

resonance of the undeuterated solvent was used as internal stan-

dard; solvent CDCl₃, δ = 7.24; D₂O, δ = 4.63; [D₆]DMSO, δ =

2.49 ppm. MALDI mass spectra were recorded on a Kratos Kom-

pact Maldi 2 spectrometer and 2,5-dihydroxybenzoic acid (DHB)

was used as matrix. FAB MS spectra were obtained with a Finni-

gan MAT 312/AMD 5000 instrument; +6 kV for positive ions,

–4 kV for negative ions. Thin-layer chromatography was performed

on Merck 60 F₂₅₄silica gel plastic plates or Merck RP-18 glass

plates; compounds were visualized by treatment with a solution of

[(NH₄)₆Mo₇O₂₄·4H₂O] (20 g) and Ce(SO₄)₂(0.4 g) in 10% sulfuric

acid (400 mL) and then heating to 120 °C. Flash chromatography

was performed on J. T. Baker silica gel 60 (40–63 µm) at a pressure

of 0.3 bar. Preparative RP-18 HPLC was carried out on a Euro-

spher 100 C18 column (Fa. Knauer) with a Shimadzu LC-8A pump

and a Rainin Dynamax UV-1 detector at a flow rate of 10 mL/

min. Optical rotations were measured at 20 °C with a Büchi Polar-

Monitor using the light of the sodium  line.

The approximately tenfold higher affinity of maltotriose

to MBP than maltose indicates that the α--glucopyranosyl

residue at the nonreducing end contributes to some extent

to MBP binding. Yet, introduction of a 6c-O-methyl group

or replacement of the 6c-hydroxy group by an amino group

in maltotriose (compounds 45 and 46) led to a slight de-

crease and introduction of a 6c-O-TIPS group (compound

47) to a dramatic loss in binding. With compound 48 hav-

ing a 6a- and 6c-O-methyl group the previous affinity was

Thexyldimethylsilyl

2,6-Diazido-3,4-O-benzyl-2,6-dideoxy-β-D-

glucopyranoside (10): To a solution of 9^[10,11](200 mg, 0.379 mmol,

1 equiv.) in dry THF (5.0 mL) was added diethyl azodicarboxylate

(DEAD, 88.4 µL, 0.569 mmol, 1.5 equiv.) and triphenylphosphane

(148 mg, 0.569 mmol, 1.5 µmol, 1.5 equiv.). At room temp. a solu-

tion of HN₃(0.569 mmol, 1.5 equiv.) in benzene (225 µL) was

added. After 30 min (TLC monitoring) the reaction mixture was

diluted with NaHCO₃solution (20 mL) and ethyl acetate (20 mL).

The aqueous phase was extracted with ethyl acetate (3ϫ20 mL)

restored which could be improved by having only a 6a-O- and the solvent of the combined organic phases was then removed

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Maltose and Maltotriose Derivative

2

in vacuo. The residue was purified by flash chromatography (petro-

leum ether/ethyl acetate, 20:1) furnishing 10 (189 mg, 0.341 mmol,

90%) as colourless, highly viscous oil. TLC (petroleum ether/ethyl

(m, 5 H, PhCHH), 4.71 (d, J = 12.3 Hz, 1 H, PhCHH), 4.79 (d,

²J = 10.9 Hz, 1 H, PhCHH), 4.86 (d, J_2,1= 3.6 Hz, 1 H, 1a-H),

3

2

4.97 (dd, J_3,4= J_5,4= 9.8 Hz, 1 H, 4b-H), 5.14 (d, J = 10.9 Hz,

1 H, PhCHH), 5.39 (dd, ³J_2,3= ³J_4,3= 9.0 Hz, 1 H, 3b-H), 5.81 (d,

³J_2,1= 3.9 Hz, 1 H, 1b-H), 7.20–7.45 (m, 20 H, Ph) ppm.

C₄₆H₅₁N₃O₁₃(853.34): calcd. C 64.70, H 6.02, N 4.92; found C

64.38, H 5.96, N 4.78.

1

acetate, 5:1): R_f= 0.68. [α]_D= +10.3 (c = 1.0, CHCl₃). H NMR

(600 MHz, CDCl₃): δ = 0.21 [2s, 6 H, Si(CH₃)₂], 0.90 [4s, 12 H,

3

C(CH₃)], 1.66 [hept, J = 6.0 Hz, 1 H, CH(CH₃)₂], 3.25 (dd, J_5,6

2

3

= 5.8, J_6,6Ј= 13.0 Hz, 1 H, 6-H), 3.33 (dd, J_1,2= 7.6, J_3,2

=

10.0 Hz, 1 H, 2-H), 3.38–3.42 (m, 2 H, 3-H, 5-H), 3.46–3.50 (m, 2

Benzyl O-(2-Azido-2-deoxy-α-

D-glucopyranosyl)-(1Ǟ4)-2,3,6-tri-O-

3

H, 4-H, 6Ј-H), 4.51 (d, J_2,1= 7.6 Hz, 1 H, 1-H), 4.57 (d, ²J =

benzyl-α- -glucopyranoside (13): To a solution of 12 (270 mg,

D

11.1 Hz, 1 H, PhCHH), 4.77–4.91 (m, 3 H, PhCHH), 7.23–7.36

(m, 10 H, Ph) ppm. MALDI MS: m/z = 554 [MH⁺], 575 [MNa⁺].

C₂₈H₄₀N₆O₄Si (552.75): calcd. C 60.84, H 7.29, N 15.20; found C

60.81, H 7.11, N 14.92.

0.316 mmol) in dry methanol (6.0 mL) at room temp. was added a

solution of NaOMe in methanol (20 µL, 1.0 ). The reaction mix-

ture was stirred overnight at room temp. and then neutralised with

Amberlite IR 120 H⁺. After filtration and removal of the solvent

in vacuo the crude product was purified by flash chromatography

with silica gel (petroleum ether/ethyl acetate, 1:1) furnishing 13

(200 mg, 0.275 mmol, 87%) as colourless foam. TLC (petroleum

ether/ethyl acetate, 1:1): R_f= 0.16. [α]_D= +103.5 (c = 1.0, CHCl₃).

¹H NMR (600 MHz, CDCl₃): δ = 1.85 (br. s, 1 H, OH), 2.75–2.90

2,6-Diazido-3,4-O-benzyl-2,6-dideoxy-α/β-D-glucopyranose (11): To

a solution of 10 (726 mg, 1.31 mmol) and pyridine (5.0 mL) was

added a solution of hydrogen fluoride in pyridine (1.10 mL, 65%

HF) at room temp. The reaction mixture was stirred for 3 d at

room temp. (TLC monitoring) and diluted with NaHCO₃solution

(20 mL) and ethyl acetate (20 mL). The aqueous phase was ex-

tracted with ethyl acetate (3ϫ20 mL). The solvent of the combined

organic phases was then removed in vacuo and the residue purified

by flash chromatography (petroleum ether/ethyl acetate, 6:1) fur-

nishing 11 (503 mg, 1.23 mmol, 93%) as colourless amorphous so-

3

(2br.s, 2 H, OH), 3.01 (dd, J_1,2= 3.8, J_3,2= 9.8 Hz, 1 H, 2b-H),

3.47 (dd, ³J_3,4= ³J_5,4= 9.8 Hz, 1 H, 4b-H), 3.54–3.58 (m, 5 H, 2a-

3

2

H, 6a-H, 6Јa-H, 5b-H, 6b-H, 6Јb-H), 3.70 (dd, J_5,6= 3.7, J_6,6Ј

11.4 Hz, 1 H, 6a-H), 3.83 (ddd, J_4,5= 9.5, J_6,5= 3.7, J_5,6Ј

=

3

2

3

1.8 Hz, 1 H, 5a-H), 3.88 (dd, J_2,3

=

³J_4,3= 9.8 Hz, 1 H, 3b-H),

1

3

lid. TLC (petroleum ether/ethyl acetate, 4:1): R_f= 0.20. H NMR

3.94 (dd, J_3,4= J_5,4= 9.5 Hz, 1 H, 4a-H), 4.16 (dd, J_2,3= J_4,3

2

(250 MHz, CDCl₃): δ = 2.84 (br. s, 0.6 H, OH_α), 3.21–3.59 (m, 5.2 = 9.5 Hz, 1 H, 3a-H), 4.50–4.60 (m, 5 H, PhCHH), 4.71 (d, J =

H, OH_β, 2-H, 3-H_β, 4-H, 5-H_β, 6-H, 6Ј-H), 3.94–4.11 (m, 1.2 H, 3- 11.0 Hz, 1 H, PhCHH), 4.81–4.86 (m, 2 H, 1a-H, PhCHH), 5.12

H_α, 5-H_α), 4.53–4.66 (m, 1.4 H, 1-H_β, PhCHH), 4.75–4.94 (m, 3 (d, J = 11.0 Hz, 1 H, PhCHH), 5.71 (d, J_2,1= 3.8 Hz, 1 H, 1b-

2

3

H, PhCHH), 5.31 (d, J_2,1= 3.8 Hz, 0.6 H, 1-H_α), 7.20–7.41 (m,

10 H, Ph) ppm. MALDI MS: m/z = 433 [MNa⁺], 449 [MK⁺].

C₂₀H₂₂N₆O₄(410.43): calcd. C 58.53, H 5.40, N 20.48; found C

58.52, H 5.37, N 20.21.

H), 7.24–7.41 (m, 20 H, Ph) ppm. C₄₀H₄₅N₃O₁₀(727.81): calcd. C

66.01, H 6.23, N 5.77; found C 65.83, H 6.22, N 5.16.

O-(2-Amino-2-deoxy-α-D-glucopyranosyl)-(1Ǟ4)-α/β-D-glucopyr-

anose Hydrochloride (1): To a solution of 13 (50.0 mg, 68.7 µmol)

in methanol (5.0 mL) was added Pearlman catalyst^[19](10.0 mg).

Then the argon atmosphere was replaced completely by hydrogen.

To ensure a complete hydrogenation the pH value had to be kept

slightly acidic with HCl/Et₂O (ca. 1 equiv.). Hydrogenation was

continued overnight at room temp. After TLC monitoring the cata-

lyst was removed with celite, which was then washed with methanol

(3ϫ10 mL). The filtrate and the wash solution were combined and

the solvent removed under reduced pressure. A concentrated solu-

tion in distilled water (2–3 drops) was produced of the crude prod-

uct precipitated with ethanol. Desiccation furnished 1 (16 mg,

O-(2,6-Diazido-3,4-O-benzyl-2,6-dideoxy-α-D-glucopyranosyl) Tri-

chloroacetimidate (5): To a solution of 11 (150 mg, 0.365 mmol)

in dry CH₂Cl₂(10.0 mL) were added trichloroacetonitrile (500 µL,

3.46 mmol) and 2 drops DBU. After 3 h at room temp. the reaction

mixture was concentrated in vacuo and purified by flash

chromatography (ethyl acetate/Et₂O/triethylamine, 10:1:0.1) fur-

nishing 5 (174 mg, 0.314 mmol, 86%) as α-anomer (with traces of

the β-anomer) as colourless, highly viscous oil. TLC (petroleum

ether/ethyl acetate, 4:1): R_f= 0.59. [α]_D= +79.4 (c = 1, CHCl₃). ¹H

NMR (250 MHz, CDCl₃): δ = 3.36 (dd, ³J_5,6= 5.4, ²J_6,6Ј= 13.4 Hz,

3

1 H, 6-H), 3.52 (dd, J_1,2= 3.5, J_3,2= 12.5 Hz, 1 H, 2-H), 3.62–

41.2 µmol, 60%) as pale yellow crystals. M.p. 173–181 °C (dec.).

1

3.72 (m, 2 H, 4-H, 6Ј-H), 3.96–4.08 (m, 2 H, 3-H, 5-H), 4.62 (d, ²J TLC (EtOH/H₂O/AcOH, 5:5:0.5): R_f= 0.66. H NMR (600 MHz,

= 11.9 Hz, 1 H, PhCHH), 4.85–4.93 (m, 3 H, PhCHH), 6.41 (d, CD₃OD): δ = 3.14–3.18 (m, 1.5 H, 2a-H_β, 2b-H), 3.37–3.43 (m, 2

³J_2,1= 3.5 Hz, 1 H, 1-H), 7.21–7.41 (m, 10 H, Ph), 8.73 (s, 1 H, H, 2a-H_α, 5a-H_β, 4b-H), 3.60–3.95 (m, 8.5 H, 3a-H, 4a-H, 5a-H_α,

NH) ppm. C₂₂H₂₂Cl₃N₇O₄(554.82): calcd. C 47.63, H 4.00, N

17.67; found C 47.70, H 4.08, N 17.37.

6a-H, 6Јa-H, 3b-H, 5b-H, 6b-H, 6Јb-H), 4.47 (d, ³J_2,1= 7.5 Hz, 0.5

3

H, 1a-H_β), 5.10 (d, J_2,1= 3.8 Hz, 0.5 H, 1a-H_α), 5.50 (2d, J_2,1

=

3.8 Hz, 1 H, 1b-H) ppm. FAB MS: m/z = 342 [MH⁺], 364 [MNa⁺].

C₁₂H₂₃NO₁₀·HCl (377.77). Other physical data have already been

reported.^[20]

Benzyl O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-

(1Ǟ4)-2,3,6-tri-O-benzyl-α- -glucopyranoside (12): To a solution of

^[14](260 mg, 0.481 mmol, 1.0 equiv.) and 4^[9](300 mg, 0.631 mmol,

D-glucopyranosyl)-

D

6

1.3 equiv.) in dry diethyl ether (6.0 mL) was added trifluorometh-

anesulfonic acid (2.1 µL, 0.024 mmol, 0.05 equiv.) at room temp.

After 20 min, the reaction mixture was neutralised with triethyl-

amine and the solvent removed in vacuo. Purification by flash

chromatography (petroleum ether/ethyl acetate, 3:1) furnished 12

(241 mg, 0.33 mmol, 69%) as colourless syrup. TLC (petroleum

ether/ethyl acetate, 3:1): R_f= 0.25. [α]_D= +100.5 (c = 1.0, CHCl₃).

Thexyldimethylsilyl O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-

D-glu-

copyranosyl)-(1Ǟ4)-2-azido-3,6-di-O-benzyl-2-deoxy-β- -glucopyr-

D

anoside (14): To a solution of 7^[15](200 mg, 0.38 mmol, 1.0 equiv.)

in dry diethyl ether (2.0 mL) was added TBDMSOTf (1.0 µL,

3.8 µmol, 0.01 equiv.). Then a solution of 4^[9](235 mg, 0.49 mmol,

1.3 equiv.) in dry diethyl ether (5.0 mL) was added within 5 min at

room temp. After 30 min the reaction mixture was neutralised with

¹H NMR (600 MHz, CDCl₃): δ = 2.00, 2.01, 2.08 (3s, 9 H, triethylamine and then the solvent removed in vacuo. Purification

3

COCH₃), 3.23 (dd, J_1,2= 3.9, J_3,2= 10.6 Hz, 1 H, 2b-H), 3.55– by flash chromatography with silica gel (petroleum ether/ethyl ace-

3.59 (m, 2 H, 2a-H, 6a-H), 3.72–3.77 (m, 2 H, 6aЈ-H), 3.90–3.97 tate, 5:1) furnished an α/β-diastereomer mixture that was separated

3

2

(m, 3 H, 4a-H, 5a-H, 5b-H), 4.10 (dd, J_5,6= 3.6, J_6,6Ј= 12.5 Hz, after further chromatography (toluene/acetone, 10:1) furnishing the

1 H, 6Јb-H), 4.17 (dd, ³J_2,3= ³J_4,3= 9.0 Hz, 1 H, 3a-H), 4.48–4.61

α-diastereomer 14 (131 mg, 0.16 mmol, 41%) as colourless syrup.

Eur. J. Org. Chem. 2008, 2084–2099

www.eurjoc.org

2089

H. Malik, W. Boos, R. R. Schmidt

FULL PAPER

TLC (petroleum ether/ethyl acetate, 3:2): R_f= 0.50. [α]_D= +53.0

[MNa⁺]. C₂₆H₃₂N₆O₉·0.5H₂O (581.23): calcd. C 53.70, H 5.72, N

1

(c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ = 0.22 [2s, 6 H, 14.45; found C 53.71, H 5.87, N 13.94.

Si(CH₃)₂], 0.91 [4s, 12 H, C(CH₃)], 1.68 [hept, ³J = 6.9 Hz, 1 H,

O-(2-Amino-2-deoxy-α-

α/β-

D-glucopyranosyl)-(1Ǟ4)-2-amino-2-deoxy-

-glucopyranose Dihydrochloride (2): To a solution of 16

3

CH(CH₃)₂], 2.00, 2.02, 2.08 (3s, 9 H, COCH₃), 3.24 (dd, J_1,2

=

D

3.8, ³J_3,2= 10.6 Hz, 1 H, 2b-H), 3.39 (dd, ³J_1,2= 7.6, ³J_3,2= 9.4 Hz,

1 H, 2a-H), 3.43 (ddd, J_4,5= 9.7, J_6,5= 4.1, J_6Ј,5= 2.0 Hz, 1 H,

(50.0 mg, 0.087 mmol) in methanol (4.0 mL) was added Pearlman

catalyst^[19](10.0 mg). Then the argon atmosphere was replaced

completely by hydrogen. To ensure a complete hydrogenation the

pH value had to be kept slightly acidic with HCl/Et₂O (ca.

2 equiv.). Hydrogenation was continued overnight at room temp.

After TLC monitoring the catalyst was removed with celite, which

was then washed with methanol (3ϫ10 mL). The filtrate and the

wash solution were combined and the solvent removed under re-

duced pressure. A concentrated solution in distilled water (2–3

drops) was produced of the crude product which was precipitated

with ethanol. Desiccation furnished 2 (36 mg, 0.086 mmol, 96%)

as pale yellow crystals. RP 18-TLC (EtOH/H₂O/AcOH, 5:5:0.5): R_f

= 0.62. M.p. 162 °C (dec.). ¹H NMR (600 MHz, CD₃OD): δ = 2.86

3

5a-H), 3.51 (dd, J_2,3= J_4,3= 9.4 Hz, 1 H, 3a-H), 3.65 (dd, J_5,6

2

3

2

= 2.0, J_6,6Ј= 11.9 Hz, 1 H, 6a-H), 3.73 (dd, J_5,6= 2.4, J_6,6Ј

=

3

2

12.6 Hz, 1 H, 6b-H), 3.80 (dd, J_5,6= 3.8, J_6,6Ј= 11.9 Hz, 1 H,

3

2

6Јa-H), 3.98 (m, 2 H, 4a-H, 5b-H), 4.16 (dd, J_5,6= 3.5, J_6,6Ј

=

2

12.6 Hz, 1 H, 6Јb-H), 4.57 (m, 3 H, 1a-H, PhCHH), 4.74 (d, J =

3

12.4 Hz, 1 H, PhCHH), 4.97 (dd, J_3,4= J_5,4= 9.7 Hz, 1 H, 4b-

2

3

H), 5.06 (d, J = 10.7 Hz, 1 H, PhCHH), 5.38 (dd, J_2,3= J_4,3

=

10.6 Hz, 1 H, 3b-H), 5.78 (d, ³J_2,1= 3.8 Hz, 1 H, 1b-H), 7.26–7.36

(m, 10 H, Ph) ppm. C₄₀H₅₆N₆O₁₂Si (840.99): calcd. C 57.12, H

6.72, N 9.99; found C 57.22, H 6.69, N 9.74.

Thexyldimethylsilyl O-(2-Azido-2-deoxy-α-

D-glucopyranosyl)-

3

(dd, J_2,1= 8.2, J_3,2= 10.6 Hz, 0.4 H, 2a-H_β), 3.15–3.23 (m, 1.6

H, 2a-H_α, 2b-H), 3.36 (m, 1 H, 4b-H), 3.51 (m, 0.4 H, 5a-H_β),

3.64–3.96 (m, 8 H, 3a-H_β, 4a-H, 5a-H_α, 6a-H, 6Јa-H, 3b-H, 5b-H,

(1Ǟ4)-2-azido-3,6-di-O-benzyl-2-desoxy-β- -glucopyranoside (15):

D

To a solution of 14 (200 mg, 0.238 mmol) and dry methanol

(5.0 mL) was added a solution of NaOMe in methanol (19 µL,

1.0 ) at room temp. The reaction mixture was stirred overnight at

room temp. and then neutralised with Amberlite IR 120 H⁺. After

filtration and removal of the solvent in vacuo the crude product

was purified by flash chromatography with silica gel (toluene/ethyl

acetate, 3:2) furnishing 15 (146 mg, 0.205 mmol, 86%) as colour-

less, amorphous solid. TLC (toluene/ethyl acetate, 1:1): R_f= 0.21.

3

6b-H, 6Јb-H), 4.13 (dd, ³J_2,3= J_4,3= 9.5 Hz, 0.6 H, 2a-H_α), 4.75–

3

4.90 (m, 0.4 H, 1a-H_β), 5.33 (d, J_2,1= 3.8 Hz, 0.6 H, 1a-H_α), 5.72

3

(d, J_2,1= 3.8 Hz, 1 H, 1b-H) ppm. FAB MS: m/z = 341 [MH⁺],

363 [MNa⁺]. C₁₂H₂₄N₂O₉·2HCl (413.25).

Methyl O-(2,6-Diazido-3,4-O-benzyl-2,6-dideoxy-α-

D-glucopyrano-

syl)-(1Ǟ4)-2,3,6-tri-O-benzyl-α- -glucopyranoside (17): To a solu-

D

1

[α]_D= +51.4 (c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ =

tion of 8^[16](115 mg, 0.248 mmol, 1.0 equiv.) and 5 (165 mg,

0.297 mmol, 1.2 equiv.) in dry diethyl ether (5.0 mL) was added

TMSOTf (0.46 µL, 2.48 µmol, 0.01 equiv.) at room temp. After

20 min the reaction mixture was neutralised with triethylamine and

the solvent removed in vacuo. Purification by flash chromatography

(toluene/ethyl acetate, 100:1 Ǟ 50:1) furnished 17 (170 mg,

0.198 mmol, 80%) as colourless highly viscous oil. TLC (petroleum

ether/ethyl acetate, 4:1): R_f= 0.43. [α]_D= +40.3 (c = 1.0, CHCl₃).

¹H NMR (250 MHz, CDCl₃): δ = 3.02–3.29 (m, 3 H, 2b-H, 6b-H,

6Јb-H), 3.38 (s, 3 H, OCH₃), 3.42–3.93 (m, 8 H, 2a-H, 4a-H, 5a-H,

6a-H, 6Јa-H, 3b-H, 4b-H, 5b-H), 4.06 (dd, ³J_2,3= ³J_4,3= 10.4 Hz, 1

H, 3a-H), 4.48–4.90 (m, 10 H, 1a-H, PhCHH), 5.08 (d, ²J =

3

0.21 [2s, 6 H, Si(CH₃)₂], 0.90 [4s, 12 H, C(CH₃)], 1.68 [hept, J =

6.0 Hz, 1 H, CH(CH₃)₂],1.83 (br. s, 1 H, OH), 2.61, 2.63 (2br.s, 2

3

H, OH), 3.04 (dd, J_1,2= 3.8, J_3,2= 9.9 Hz, 1 H, 2b-H), 3.37 (dd,

³J_1,2= 7.6, J_3,2= 9.4 Hz, 1 H, 2a-H), 3.43 (m, 1 H, 5a-H), 3.50–

3

3.53 (m, 2 H, 3a-H, 4b-H), 3.62–3.67 (m, 3 H, 5b-H, 6b-H, 6a-H),

3

2

3

3.78 (dd, J_5,6= 3.8, J_6,6Ј= 11.7 Hz, 1 H, 6a-H), 3.89 (dd, J_2,3

=

³J_4,3= 9.9 Hz, 1 H, 3b-H), 3.97 (dd, J_3,4

4a-H),4.54–4.63 (m, 3 H, 1a-H, PhCHH), 4.78 (d, J = 11.0 Hz, 1

H, PhCHH), 5.04 (d, J = 11.0 Hz, 1 H, PhCHH), 5.66 (d, J_2,1

=

³J_5,4= 9.1 Hz, 1 H,

3

2

3

=

3.8 Hz, 1 H, 1b-H), 7.26–7.38 (m, 10 H, Ph) ppm. C₃₄H₅₀N₆O₉Si

(714.34): calcd. C 57.12, H 7.05, N 11.76; found C 56.48, H 6.96,

N 11.47.

3

11.5 Hz, 1 H, PhCHH), 5.67 (d, J_2,1= 3.7 Hz, 1 H, 1b-H), 7.16–

7.39 (m, 25 H, Ph) ppm. C₄₈H₅₂N₆O₉·1.5H₂O (883.40): calcd. C

65.22, H 6.27, N 9.51; found C 65.31, H 6.23, N 9.11.

O-(2-Azido-2-deoxy-α-

benzyl-2-desoxy-α/β-

D

-glucopyranosyl)-(1Ǟ4)-2-azido-3,6-di-O-

D

-glucopyranose (16): To a solution of 15

(30 mg, 0.042 mmol) in THF (0.5 mL) was added catalytic amount

of acetic acid (2.5 µL). Then TBAF solution (50 µL, 1.0  in THF)

was added portionwise to the reaction mixture and the silyl depro-

tection was tracked under TLC monitoring (0.5–5.0 h). For the pu-

rification the reaction mixture was diluted with ethyl acetate

(10.0 mL) and the organic phase washed with concentrated NaCl

solution (3 ϫ 10 mL). The aqueous phase was concentrated in

vacuo and reextracted with ethyl acetate (3ϫ10 mL). The com-

bined organic phase was dried with MgSO₄and then the solvent

removed in vacuo. Purification by flash chromatography (petro-

leum ether/ethyl acetate, 1:3) furnished 16 (21 mg, 0.036 mmol

85%) as colourless foam. In CDCl₃an anomeric mixture appears

(α/β, 3:2). TLC (ethyl acetate 100 %): R_f= 0.64. ¹H NMR

(600 MHz, CDCl₃): δ = 1.79 (br. s, 1 H, 6b-OH), 2.67 (m, 2.4 H,

Methyl O-(2,6-Diamino-2,6-dideoxy-α-

D-glucopyranosyl)-(1Ǟ4)-α-

D

-glucopyranoside Dihydrochloride (3): To a solution of 17

(52.0 mg, 60.7 µmol) in methanol (5.0 mL) was added Pearlman

catalyst^[19](15.0 mg). Then the argon atmosphere was replaced

completely by hydrogen. To ensure a complete hydrogenation the

pH value had to be kept slightly acidic with HCl/Et₂O (ca.

2 equiv.). Hydrogenation was continued overnight at room temp.

After TLC monitoring the catalyst was removed with celite, which

was then washed with methanol (3ϫ10 mL). The filtrate and the

wash solution were then combined and the solvent removed under

reduced pressure. A concentrated solution in distilled water (2–3

drops) was produced of the crude product which was precipitated

with ethanol. Desiccation furnished 3 (19 mg, 44.9 µmol, 74%) as

pale yellow, hygroscopic solid. Therefore, it was difficult to obtain

2 OH, 1a-OH_β), 3.07 (m, 1.6 H, 2b-H, 1a-OH_α), 3.37–4.14 (m, 11 a correct elemental analysis and m.p. TLC (EtOH/H₂O/TFA,

H, 2a-H, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 3b-H, 4b-H, 5b-H, 6b-

5:5:0.5): R_f= 0.78. [α]_D= +27.5 (c = 0.33, H₂O). ¹H NMR

H, 6Јb-H), 4.53–4.69 (m, 2.4 H, 1a-H_β, 2 PhCHH), 4.82 (d, ²J = (250 MHz, CD₃OD): δ = 2.99–3.54 (m, 8 H, 2a-H, 2b-H, 4b-H,

11.0 Hz, 0.4 H, PhCHH_β), 4.88 (d, ²J = 11.0 Hz, 0.6 H, PhCHH_α),

6b-H, 6bЈ-H, OCH₃), 3.55–4.01 (m, 7 H, 3a-H, 4a-H, 5a-H, 6a-H,

2

3

4.99 (d, J = 11.0 Hz, 0.6 H, PhCHH_α), 5.04 (d, J = 11.0 Hz, 0.4

6Јa-H, 3b-H, 5b-H), 4.71 (d, J_1,2= 3.7 Hz,1 H, 1a-H), 5.78 (d,

3

H, PhCHH_β), 5.37 (m, 0.6 H, 1a-H_α), 5.62 (d, J_2,1= 3.5 Hz, 1 H,

³J_1,2= 3.7 Hz, 1 H, 1b-H) ppm. FAB MS: m/z = 355 [MH⁺].

C₁₃H₂₆N₂O₉·2HCl (427.28).

1b-H), 7.25–7.40 (m, 10 H, Ph) ppm. MALDI MS: m/z = 595.0

2090

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2084–2099

Maltose and Maltotriose Derivative

8-Bromo-1-(triisopropylsilyoxy)-3,6-dioxaoctane (23): Triethylene

glycol (15.0 g, 99.89 mmol, 4.0 equiv.) was combined with tetrabro-

moethane (8.28 g, 24.97 mmol, 1 equiv.) and triphenylphosphane

(6.56 g, 24.97 mmol, 1 equiv.) under ice cooling in dry dichloro-

methane (70.0 mL). After 20 min the ice bath was removed and the

reaction mixture stirred for 2 h. Then the solvent was removed in

vacuo and the residue purified by flash chromatography (petroleum

ether/ethyl acetate, 1:1). TLC (ethyl acetate 100%) R_f= 0.48. A

solution of triphenylphosphane oxide and the monobromo com-

pound (7.0 g) was isolated and without further purification added

TIPSCl (3.48 mL, 3.17 g, 16.43 mmol) and imidazole (1.68 g,

24.65 mmol) in dry dichloromethane (50.0 mL) at room temp. Af-

ter stirring for 3 h the reaction mixture was concentrated and puri-

fied by flash chromatography (petroleum ether/ethyl acetate, 10:1)

which furnished 23 (4.38 g, 11.86 mmol, 48 %) as colourless oil.

TLC (petroleum ether/ethyl acetate, 10:1): R_f= 0.49. ¹H NMR

(250 MHz, CDCl₃): δ = 0.94–1.15 [m, 21 H, SiCH(CH)₃,

SiCH(CH)₃], 3.42 (t, ³J = 5.3 Hz, 2 H, CH₂Br), 3.52–3.70 (m, 6 H,

OCH₂), 3.72–3.88 (m, 4 H, OCH₂) ppm. C₁₅H₃₃BrO₃Si (369.42):

calcd. C 48.77, H 9.00; found C 48.82, H 8.92.

removed in vacuo and the residue purified by flash chromatography

(petroleum ether/ethyl acetate, 3:1) furnishing 26 (121 mg, 0.111

mmol, 95%) as colourless highly viscous oil. TLC (petroleum ether/

ethyl acetate, 1:1): R_f= 0.88. [α]_D= +26.8 (c = 1.0, CHCl₃). ¹H

NMR (600 MHz, CDCl₃): δ = 3.33–3.85 (m, 26 H, 2a-H, 3a-H, 5a-

H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, OCH₂,

3

OCH₃), 4.02 (dd, J_3,4= J_5,4= 9.1 Hz, 1 H, 4a-H), 4.34 (d, J_2,1

2

= 7.6 Hz, 1 H, 1a-H), 4.39 (d, J = 12.1 Hz, 1 H, PhCHH), 4.47–

3

4.63 (m, 6 H, PhCHH), 4.76–4.92 (m, 5 H, PhCHH), 5.62 (d, J_2,1

= 3 . 8 H z , 1 H , 1 b - H ) , 7 . 0 6– 7 . 3 7 ( m , 3 0 H , P h ) p p m .

C₆₁H₇₁BrO₁₃·H₂O (1110.15): calcd. C 66.00, H 6.63; found C

65.82, H 6.56.

Methyl O-{2,3,6-Tri-O-benzyl-4-O-[8-(3,5-dimethoxyphenoxy)-3,6-

dioxaoctyl]-α-D-glucopyranosyl}-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-

glucopyranoside (27a): To a solution of 26 (200 mg, 0.183 mmol),

3,5-dimethoxyphenol (28.2 mg, 0.183 mmol) and TBAI (6.8 mg,

18.3 µmol) in dry DMF (7.0 mL)was added NaH (6.6 mg,

0.275 mmol) at room temp. After 5 h the reaction was quenched

with methanol (2.0 mL) and neutralised with acetic acid. The vola-

tile components were removed in vacuo. Purification by flash

chromatography (toluene/ethyl acetate, 9:1) furnished 27a (173 mg,

0.148 mmol, 81 %) as colourless oil. TLC (toluene/ethyl acetate,

Methyl O-[2,3,6-Tri-O-benzyl-4-O-(8-triisopropylsilyloxy-3,6-di-

oxaoctyl)-α-D-glucopyranosyl]-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-gluco-

pyranoside (24): To a solution of 22^[24](200 mg, 0.223 mmol, 3:2): R_f= 0.62. [α]_D= +25.8 (c = 1.0, CHCl₃). ¹H NMR (600 MHz,

1 equiv.), 23 (165 mg, 0.446 mmol, 2 equiv.) and TBAI (8.2 mg,

CDCl₃): δ = 3.38–4.08 (m, 33 H, 2a-H, 3a-H, 4a-H, 5a-H, 6a-H,

6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, β-OCH₃, PhOCH₃,

0.022 mmol, 0.1 equiv.) in DMF (10.0 mL) at room temp. was

added portionswise NaH (9.0 mg, 0.375 mmol, 1.7 equiv.). After OCH₂^Spacer), 4.31–4.40 (m, 2 H, 1a-H, PhCHH), 4.48–4.63 (m, 6

3

4 h methanol (10.0 mL) was added and the reaction mixture con-

centrated in vacuo. The residue was purified by flash chromatog-

raphy (petroleum ether/ethyl acetate, 7:1) furnishing 24 (193 mg,

0.163 mmol, 73%) as colourless, highly viscous oil. TLC (petro-

leum ether/ethyl acetate, 5:1): R_f= 0.20. [α]_D= +30.6 (c = 1.0,

CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 0.98–1.30 [m, 21 H,

SiCH(CH)₃, SiCH(CH)₃], 3.41–3.91 (m, 26 H, 2a-H, 3a-H, 5a-H,

6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, OCH₂,

H, PhCHH), 4.75–4.97 (m, 5 H, PhCHH), 5.62 (d, J_2,1= 3.6 Hz,

1 H, 1b-H), 6.05–6.08 (m, 3 H, C₆H₃^Phloro), 7.08–7.41 (m, 30 H,

Ph) ppm. MALDI MS: m/z = 1188 [MNa⁺], 1204 [MK⁺].

C₆₉H₈₀O₁₆·0.75H₂O (1178.89): calcd. C 70.30, H 6.97; found C

70.26, H 7.18.

Methyl O-{2,3,6-Tri-O-benzyl-4-O-[8-(3,5-diisopropyloxyphenoxy)-

3,6-dioxaoctyl]-α-D-glucopyranosyl}-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-

glucopyranoside (27b): To a solution of 26 (294 mg, 0.269 mmol),

3,5-diisopropyloxyphenol (56.6 mg, 0.269 mmol) and TBAI

(9.9 mg, 0.027 mmol) in dry DMF (10.0 mL) at room temp. was

added NaH (9.7 mg, 0.404 mmol). After 5 h the reaction was

quenched with methanol (3.0 mL) and neutralised with acetic acid.

The volatile components were removed in vacuo. Purification by

flash chromatography (toluene/ethyl acetate, 9:1) furnished 27b

(166 mg, 0.136 mmol, 51%) as colourless oil. TLC (toluene/ethyl

3

OCH₃), 4.01 (dd, J_3,4= J_5,4= 8.7 Hz, 1 H, 4a-H), 4.32 (d, J_2,1

2

= 7.7 Hz, 1 H, 1a-H), 4.38 (d, J = 12.1 Hz, 1 H, PhCHH), 4.44–

4.61 (m, 6 H, PhCHH), 4.73–4.93 (m, 5 H, PhCHH), 5.58 (d, J_2,1

3

= 3.6 Hz, 1 H, 1b-H), 7.10–7.29 (m, 30 H, Ph) ppm. C₇₀H₉₂O₁₄Si

(1184.63): calcd. C 70.92, H 7.82; found C 70.49, H 7.91.

Methyl O-[2,3,6-Tri-O-benzyl-4-O-(8-hydroxy-3,6-dioxaoctyl)-α-

D-

glucopyranosyl]-(1Ǟ4)-2,3,6-tri-O-benzyl-β- -glucopyranoside (25):

D

1

To a solution of 24 (50.0 mg, 42.2 µmol, 1.0 equiv.) in THF

(3.0 mL) at room temp. was added portionwise a solution of TBAF

in THF (42.2 µL, 1.0 , 1.0 equiv.). After 30 min the reaction mix-

ture was neutralised with acetic acid and concentrated in vacuo.

The residue was purified with flash chromatography (petroleum

ether/ethyl acetate, 1:1) furnishing 25 (43.0 mg, 41.8 µmol, 99%) as

colourless highly viscous oil. TLC (petroleum ether/ethyl acetate,

acetate, 5:1): R_f= 0.38. [α]_D= +16.0 (c = 1.0, CHCl₃). H NMR

3

(250 MHz, CDCl₃): δ = 1.29 (d, J = 6.0 Hz, 12 H, OCH(CH₃)₂),

3.40–4.08 (m, 27 H, 2a-H, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 2b-H,

3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, β-OCH₃, OCH₂^Spacer), 4.29–4.62

(m, 10 H, 1a-H, OCH(CH₃)₂, PhCHH), 4.72–4.98 (m, 5 H,

3

PhCHH), 5.62 (d, J_2,1= 3.6 Hz, 1 H, 1b-H), 6.02–6.05 (m, 3 H,

C₆H₃^Phloro), 7.09–7.38 (m, 30 H, Ph) ppm. C₇₃H₈₈O₁₆·0.75H₂O

1:1): R_f= 0.13. [α]_D= +17.0 (c = 0.5, CHCl₃). ¹H NMR (600 MHz, (1221.49): calcd. C 71.78, H 7.26; found C 71.63, H 7.20.

CDCl₃): δ = 2.29 (br. s, 1 H, OH), 3.42–3.95 (m, 26 H, 2a-H, 3a-H,

Methyl O-{4-O-[8-(3,5-Dimethoxyphenoxy)-3,6-dioxaoctyl]-α-

5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, OCH₂,

D-

glucopyranosyl}-(1Ǟ4)-β-D-glucopyranoside (18a): To a solution of

3

OCH₃), 4.03 (dd, J_3,4= J_5,4= 9.0 Hz, 1 H, 4a-H), 4.33 (d, J_2,1

27a (125 mg, 107 µmol) in dioxane (10.0 mL) was added Pearlman

catalyst^[19](10.0 mg). Then the argon atmosphere was completely

replaced by hydrogen. After stirring for 2 h at room temp. the cata-

lyst was separated with celite and the celite washed with methanol

(3ϫ10 mL). Filtrate and wash solution were combined and the sol-

vent removed in vacuo. Purification by flash chromatography (ethyl

2

= 7.7 Hz, 1 H, 1a-H), 4.38 (d, J = 12.1 Hz, 1 H, PhCHH), 4.45–

4.63 (m, 6 H, PhCHH), 4.75–4.95 (m, 5 H, PhCHH), 5.62 (d, J_2,1

3

= 3.5 Hz, 1 H, 1b-H), 711–7.40 (m, 30 H, Ph) ppm. C₆₁H₇₂O₁₄

(1028.49): calcd. C 71.14, H 7.05; found C 70.78, H 7.27.

Methyl O-[2,3,6-Tri-O-benzyl-4-O-(8-bromo-3,6-dioxaoctyl)-α-

glucopyranosyl]-(1Ǟ4)-2,3,6-tri-O-benzyl-β-

D-

D

-glucopyranoside (26): acetate/EtOH, 4:1) and lyophilisation from dioxane furnished 18a

To a solution of 24 (120.0 mg, 0.117 mmol, 1.0 equiv.) and tetra-

bromomethane (77.3 mg, 0.233 mmol, 2.0 equiv.) in dry dichloro-

methane (5.0 mL) was added triphenylphosphane (61.1 mg,

0.233 mmol, 2.0 equiv.) at room temp. After 1 h the solvent was

(60 mg, 96.1 µmol, 90%) as colourless lyophilisate. TLC (ethyl ace-

tate/EtOH, 4:1): R_f= 0.10. [α]_D= +27.1 (c = 1.0, CHCl₃). ¹H NMR

(250 MHz, CD₃OD): δ = 3.11–3.23 (m, 2 H, 2a-H, 4b-H), 3.24–

3.38 (m, 1 H, 5a-H), 3.36–4.10 (m, 30 H, 3a-H, 4a-H, 6a-H, 6Јa-

Eur. J. Org. Chem. 2008, 2084–2099

www.eurjoc.org

2091

H. Malik, W. Boos, R. R. Schmidt

FULL PAPER

3

H, 2b-H, 3b-H, 5b-H, 6b-H, 6Јb-H, OCH₂^Spacer, β-OCH₃,

(250 MHz, CDCl₃): δ = 3.95 (t, J = 6.4 Hz, 2 H, CH₂Br), 4.21 (t,

3

PhOCH₃), 4.13 (d, J_2,1= 8.0 Hz, 1 H, 1a-H), 5.10 (d, J_2,1

=

³J = 6.4 Hz, 2 H, OCH₂CH₂Br), 4.99 (s, 4 H, PhCH₂), 6.18 (d,

4

3.7 Hz, 1 H, 1b-H), 6.03–6.11 (m, 3 H, C₆H₃^Phloro) ppm. ⁴J_meta= 1.8 Hz, 2 H, C₆H₂H^Phloro), 6.27 (t, J_meta= 1.8 Hz, 1 H,

C₂₇H₄₄O₁₆·1.25H₂O (647.15): calcd. C 50.11, H 7.19; found C

C₆H₂H^Phloro), 7.26–7.43 (m, 10 H, Ph) ppm. C₂₂H₂₁BrO₃(413.31):

50.07, H 7.06.

calcd. C 63.93, H 5.12; found C 63.93, H 4.87.

Methyl O-{4-O-[8-(3,5-Diisopropyloxyphenoxy)-3,6-dioxaoctyl]-α-

Benzyl O-{2,3,6-Tri-O-benzyl-4-O-[2-(3,5-dimethoxyphenoxy)ethyl]-

α-D-glucopyranosyl}-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside

D-glucopyranosyl}-(1Ǟ4)-β-D-glucopyranoside (18b): To a solution

of 27b (100 mg, 83.79 µmol) in dioxane (8.0 mL) was added Pearl-

man catalyst^[19](10.0 mg). Then the argon atmosphere was com-

pletely replaced by hydrogen. After stirring for 4 h at room temp.

the catalyst was separated with celite and the celite washed with

methanol (3ϫ10 mL). Filtrate and wash solution were combined

and the solvent removed in vacuo. Purification by flash chromatog-

raphy (ethyl acetate/EtOH, 4:1) and lyophilisation from dioxane

furnished 18b (57 mg, 84 µmol, quant. yield, colourless lyophilisate.

TLC (ethyl acetate/EtOH, 4:1): R_f= 0.15. [α]_D= +20.5 (c = 1.0,

(33a): To a solution of 31 (200 mg, 0.206 mmol, 1.0 equiv.), 32a

(215 mg, 0.824 mmol, 4.0 equiv.) and TBAI (7.6 mg, 20.6 µmol,

0.1 equiv.) in dry DMF (10.0 mL) at 0 °C was slowly added NaH

(16.3 mg, 0.824 mmol, 4.0 equiv.). After 8 h the reaction was

quenched with methanol (5.0 mL) and, if necessary, neutralised

with acetic acid. The volatile components were removed in vacuo.

Purification by flash chromatography (toluene/ethyl acetate, 20:1)

furnished 33a (181 mg, 0.157 mmol, 76%) as colourless, highly vis-

cous oil. TLC (petroleum ether/ethyl acetate, 4:1): R_f= 0.28. [α]_D

= +12.4 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 3.33–

3.56 (m, 6 H, 2a-H, 5a-H, 2b-H, 4b-H, 6b-H, 6Јb-H), 3.57–3.85

1

3

CHCl₃). H NMR (250 MHz, CD₃OD): δ = 1.27 (d, J = 6.0 Hz,

12 H, OCH(CH₃)₂), 3.15–3.23 (m, 2 H, 2a-H, 4b-H), 3.27–3.36 (m,

1 H, 5a-H), 3.40–3.88 (m, 21 H, 3a-H, 4a-H, 6a-H, 6Јa-H, 2b-

(m, 14 H, 3a-H, 6a-H, 6Јa-H, 3b-H, 5b-H, CH₂O^{S p a c e r}

,

Spacer

CHHO^Spacer, OCH₃), 3.92–4.02 (m, 2 H, 4a-H, CHHO^Spacer), 4.26

H, 3b-H, 5b-H, 6b-H, 6Јb-H, OCH₂

, β-OCH₃), 3.95 (m, 1 H,

OCHH^Spacer), 4.05 (m, 2 H, OCH₂^Spacer), 4.16 (d, J_2,1= 7.8 Hz, 1

3

(d, ²J = 12.1 Hz, 1 H, PhCHH), 4.41–4.56 (m, 7 H, 1a-H, PhCHH),

4.61 (d, J = 12.1 Hz, 1 H, PhCHH), 4.69 (d, J = 12.1 Hz, 1 H,

PhCHH), 4.70–4.90 (m, 5 H, PhCHH), 5.57 (d, J_2,1= 3.5 Hz, 1

H, 1a-H), 4.50 (hept, ³J = 6.0 Hz, 2 H, OCH(CH₃)₂), 5.13 (d, J_2,1

3

2

= 3.7 Hz, 1 H, 1b-H), 6.03 (t, J_meta= 1.8 Hz, 1 H, C₆H₂H^Phloro),

4

3

6 . 0 6 ( d , J _{m e t a}= 1 . 8 H z , 2 H , C ₆H ₂H ^{P h l o r o}) p p m .

4

H, 1b-H), 5.93 (d, ⁴J_meta= 1.9 Hz, 2 H, C₆H₂H^Phloro), 5.99 (t, ⁴J_meta

= 1.9 Hz, 1 H, C₆H₂H^Phloro), 7.01–7.39 (m, 35 H, Ph) ppm.

C₇₁H₇₆O₁₄(1153.38). Calcd. C 73.94, H 6.64; found C 73.89, H

6.70.

C₃₁H₅₂O₁₆·0.75H₂O (694.25): calcd. C 53.63, H 7.77; found C

53.61, H 7.84.

1-Bromo-2-(3,5-dimethoxyphenoxy)-1-ethane (32a): To a solution of

3,5-dimethoxyphenol (4.0 g, 25.95 mmol) in DMF (40.0 mL) and

1,2-dibromoethane (40.0 mL) was slowly (1 h) added NaH (5.00 g,

208.4 mmol) at 10 °C. After 2 h at room temp. the reaction was

quenched with the slow addition of methanol (20.0 mL), and, if

necessary, neutralised with acetic acid. The solvent was then re-

moved in vacuo. Purification by flash chromatography (petroleum

ether/ethyl acetate, 9:1) furnished 32a (4.23 g, 16.20 mmol, 62%) as

colourless oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.61.

¹H NMR (250 MHz, CDCl₃): δ = 3.61 (t, ³J = 5.9 Hz, 2 H,

CH₂Br), 3.75 (s, 6 H, OCH₃), 4.23 (t, ³J = 5.9 Hz, 2 H,

OCH₂CH₂Br), 6.05–6.12 (m, 3 H, C₆H₃^Phloro) ppm. C₁₀H₁₃BrO₃

(261.12): calcd. C 46.00, H 5.02; found C 45.93, H 4.94.

Benzyl O-{2,3,6-Tri-O-benzyl-4-O-[2-(3,5-diisopropyloxyphenoxy)-

ethyl]-α-D-glucopyranosyl}-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-glucopyr-

anoside (33b): To a solution of 31 (150 mg, 0.154 mmol, 1.0 equiv.),

32b (244 mg, 0.77 mmol, 5.0 equiv.) and TBAI (5.7 mg, 15.4 µmol,

0.1 equiv.) in dry DMF (10.0 mL) at room temp. was slowly added

NaH (18.5 mg, 0.77 mmol, 5.0 equiv.). After 4 h the reaction was

quenched with methanol (5.0 mL) and, if necessary, neutralised

with acetic acid. The volatile components were removed in vacuo.

Purification by flash chromatography (petroleum ether/ethyl ace-

tate, 5:1) furnished 33b (155 mg, 0.128 mmol, 83%) as colourless,

highly viscous oil. TLC (petroleum ether/ethyl acetate, 4:1): R_f=

0.43. [α]_D= +12.2 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃):

3

δ = 1.27 (d, J = 6.0 Hz, 12 H, CH(CH₃)₂), 3.43–3.64 (m, 6 H, 2a-

1-Bromo-2-(3,5-diisopropyloxyphenoxy)-1-ethane (32b): To a solu-

tion of 3,5-diisopropyloxyphenol (1.0 g, 4.76 mmol) in DMF

(20.0 mL) and 1,2-dibromoethane (15.0 mL) was slowly (1 h) added

NaH (1.0 g, 41.67 mol) at room temp. After 2 h at room temp. the

reaction was quenched with the slow addition of methanol

(20.0 mL) and, if necessary, neutralised with acetic acid. The sol-

vent was then removed in vacuo. Purification by flash chromatog-

raphy (petroleum ether/ethyl acetate, 11:1) furnished 32b (927 mg,

2.90 mmol, 61%) as colourless oil. TLC (petroleum ether/ethyl ace-

H, 5a-H, 2b-H, 4b-H, 6b-H, 6Јb-H), 3.70–3.88 (m, 8 H, 3a-H, 6a-

H, 6Јa-H, 3b-H, 5b-H, CH₂O^Spacer, CHHO^Spacer), 3.99–4.08 (m, 2

2

H, 4a-H, CHHO^Spacer), 4.35 (d, J = 12.1 Hz, 1 H, PhCHH), 4.34

(hept, ³J = 6.0 Hz, 2 H, CH(CH₃)₂), 4.44–4.61 (m, 7 H, 1a-H,

PhCHH), 4.62 (d, ²J = 12.1 Hz, 1 H, PhCHH), 4.76 (d, ²J =

12.1 Hz, 1 H, PhCHH), 4.80–4.84 (m, 2 H, PhCHH), 4.85–4.99 (m,

3

4

3 H, PhCHH), 5.64 (d, J_2,1= 3.8 Hz, 1 H, 1b-H), 5.97 (d, J_meta

= 2.0 Hz, 2 H, C₆H₂H^Phloro), 6.04 (t, J_meta= 2.0 Hz, 1 H,

4

C₆H₂H^Phloro), 7.09–7.39 (m, 35 H, Ph) ppm. C₇₅H₈₄O₁₄(1209.48):

1

3

tate, 4:1): R_f= 0.76. H NMR (250 MHz, CDCl₃): δ = 1.28 (d, J

= 6.5 Hz, 12 H, CH(CH)₃)₂), 3.58 (t, ³J = 6.2 Hz, 2 H, CH₂Br),

4.19 (t, J = 6.2 Hz, 2 H, OCH₂CH₂Br), 4.46 (hept, J = 6.5 Hz, 2

H, CH(CH)₃)₂), 5.98–6.08 (m, 3 H, C₆H₃^Phloro) ppm. C₁₄H₂₁BrO₃

(317.22): calcd. C 53.01, H 6.67; found C 53.23, H 6.69.

calcd. C 74.48, H 7.00; found C 74.55, H 7.14.

3

Benzyl O-{2,3,6-Tri-O-benzyl-4-O-[2-(3,5-dibenzyloxyphenoxy)-

ethyl]-α-D-glucopyranosyl}-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-gluco-

pyranoside (33c): To a solution of 31 (150 mg, 0.154 mmol,

1.0 equiv.), 32c (446 mg, 1.079 mmol, 7.0 equiv.) and TBAI

(5.7 mg, 15.4 µmol, 0.1 equiv.) in dry DMF (7.0 mL) at room temp.

was added NaH (25 mg, 1.079 mmol, 7.0 equiv.). After 5 h the reac-

tion was quenched with methanol (3.0 mL) and neutralised with

acetic acid. The volatile components were removed in vacuo. Purifi-

cation by flash chromatography (petroleum ether/ethyl acetate, 6:1)

furnished 33c (137 mg, 0.105 mmol, 68%) as colourless, highly vis-

cous oil. TLC (petroleum ether/ethyl acetate, 4:1): R_f= 0.47. [α]_D

= +11.1 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 3.32–

2-(3,5-Dibenzyloxyphenoxy)-1-bromoethane (32c): To a solution of

3,5-dibenzyloxyphenol (370 mg, 1.21 mmol) in DMF (5.0 mL) and

1,2-dibromoethane (5.0 mL) was slowly (1 h) added NaH (200 mg,

8.70 mmol) at room temp. After 2 h the reaction was quenched

with the slow addition of methanol (5.0 mL) and, if necessary, neu-

tralised with acetic acid. The solvent was then removed in vacuo.

Purification by flash chromatography (petroleum ether/ethyl ace-

tate, 10:1) furnished 32c (295 mg, 0.713 mmol, 59%) as colourless

1

oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.71. H NMR

2092

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2084–2099

Maltose and Maltotriose Derivative

3.56 (m, 6 H, 2a-H, 5a-H, 2b-H, 4b-H, 6b-H, 6Јb-H), 3.60–3.83 2-Bromo-1-(triisopropylsilyloxy)ethane (34): To a solution of 2-bro-

(m, 8 H, 3a-H, 6a-H, 6Јa-H, 3b-H, 5b-H, CH₂O, CHHO), 3.92– moethanol (1.69 mL, 3.00 g, 24.01 mmol, 1.0 equiv.) and TIPSCl

2

4.05 (m, 2 H, 4a-H, CHHO), 4.25 (d, J = 11.9 Hz, 1 H, PhCHH), (5.09 g, 26.41 mmol, 1.1 equiv.) in dry CH₂Cl₂(40.0 mL) at room

3

4.42–4.94 (m, 18 H, 1a-H, PhCHH), 5.57 (d, J_2,1= 3.6 Hz, 1 H,

temp. was added imidazole (2.45, 36.02 mmol, 1.5 equiv.). After 4 h

1b-H), 6.02 (d, J_meta= 1.8 Hz, 2 H, C₆H₂H^Phloro), 6.16 (t, J_metathe solvent was removed in vacuo and the residue purified by flash

4

= 1.8 Hz, 1 H, C₆H₂H^Phloro), 7.02–7.30 (m, 45 H, Ph) ppm.

C₈₃H₈₄O₁₄·1.5H₂O (1332.59): calcd. C 74.81, H 6.58; found C

74.53, H 6.74.

chromatography (petroleum ether/ethyl acetate, 10:1) furnishing 34

(4.26 g, 15.13 mmol, 63%) as colourless oil. TLC (petroleum ether/

ethyl acetate, 9:1): R_f= 0.85. ¹H NMR (250 MHz, CDCl₃): δ =

0.98–1.15 (m, 21 H, SiCH(CH₃)₂), 3.40 (t, ³J = 6.4 Hz, 2 H,

O-{4-O-[2-(3,5-Dimethoxyphenoxy)ethyl]-α-

D-glucopyranosyl}-

(1Ǟ4)-α/β- -glucopyranose (28a): To a solution of 33a (130 mg,

3

CH₂Br), 3.93 (t, J = 6.4 Hz, 2 H, CH₂O). C₁₁H₂₅BrOSi (281.31):

D

calcd. C 46.97, H 8.96; found C 46.79, H 8.94.

0.113 mmol) and dioxane (10.0 mL) was added Pearlman cata-

lyst^[19](20.0 mg). Then the argon atmosphere was completely re-

placed by hydrogen. After stirring for 3 h at room temp. the catalyst

was separated with celite and the celite washed with methanol (3 ϫ

10 mL). Filtrate and wash solution were combined and the solvent

removed in vacuo. Purification by flash chromatography with silica

gel (ethyl acetate/EtOH, 3:1) and lyophilisation from dioxane fur-

nished 28a (59 mg, 0.113 mmol, quant.) als colourless lyophilisate.

TLC (ethyl acetate/EtOH, 2:1): R_f= 0.11. ¹H NMR (250 MHz,

Benzyl O-{2,3,6-Tri-O-benzyl-4-O-[2-(triisopropylsilyloxy)ethyl]-α-

D

-glucopyranosyl}-(1Ǟ4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside

(35): To a solution of 31^[14,27](200 mg, 0.206 mmol, 1.0 equiv.), 34

(289 mg, 1.028 mmol, 5.0 equiv.) and TBAI (7.6 mg, 20.6 µmol,

0.1 equiv.) in dry DMF (15.0 mL) at room temp. was slowly added

NaH (24.7 mg, 1.028 mmol, 5.0 equiv.). After 4 h the reaction was

quenched with methanol (5.0 mL) and, if necessary, neutralised

with acetic acid. The solvent was removed in vacuo. Purification by

flash chromatography (petroleum ether/ethyl acetate, 20:1Ǟ10:1)

CD₃OD): δ = 3.11–4.19 (m, 22 H, 2a-H, 3a-H, 4a-H, 5a-H, 6a-H,

Spacer

6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, OCH₂

, OCH₃), furnished 35 (200 mg, 0.187 mmol, 91%) as colourless, highly vis-

3

4.47 (d, J_2,1= 7.9 Hz, 0.5 H, 1a-H_β), 5.09 (d, J_2,1= 3.6 Hz, 0.5

cous oil. TLC (petroleum ether/ethyl acetate, 4:1): R_f= 0.57. [α]_D

= +23.5 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 0.95–

1.15 (m, 21 H, SiCH(CH₃)₂), 3.41–3.89 (m, 15 H, 2a-H, 4a-H, 5a-

H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H,

3

H, 1b-H_α), 5.14 (2 d, J_2,1(α)= J_2,1(β)= 3.6 Hz, 1 H, 1b-H), 6.06–

6.12 (m, 3 H, C₆H₃^Phloro) ppm. C₂₂H₃₄O₁₄·1H₂O (540.52): calcd. C

48.89, H 6.71; found C 48.85, H 6.79.

3

CH₂O^Spacer), 4.07 (dd, J_2,3= J_4,3= 9.1 Hz, 1 H, 3a-H), 4.39 (d,

O-{4-O-[2-(3,5-Diisopropyloxyphenoxy)ethyl]-α-

D-glucopyranosyl}-

²J = 12.3 Hz, 1 H, PhCHH), 4.48–4.89 (m, 11 H, 1a-H, 10

PhCHH), 4.90–4.98 (m, 3 H, PhCHH), 5.65 (d, J_2,1= 3.6 Hz, 1

(1Ǟ4)-α/β- -glucopyranose (28b): To a solution of 33b (140 mg,

D

3

0.116 mmol) and dioxane (8.0 mL) was added Pearlman catalyst^[19]

(14.0 mg). Then the argon atmosphere was completely replaced by

hydrogen. After stirring for 5 h at room temp. the catalyst was sepa-

rated with celite and the celite washed with methanol (3 ϫ 10 mL).

Filtrate and wash solution were combined and the solvent removed

in vacuo. Purification by flash chromatography with silica gel (ethyl

acetate/EtOH, 3:1) and lyophilisation from dioxane furnished 28b

H, 1b-H), 7.11–7.38 (m, 35 H, Ph). C₇₂H₈₈O₁₂Si (1173.57): calcd.

C 73.69, H 7.56; found C 73.38, H 7.57.

Benzyl O-[2,3,6-Tri-O-benzyl-4-O-(2-hydroxyethyl)-α-

D-glucopyr-

anosyl]-(1Ǟ4)-2,3,6-tri-O-benzyl-β- -glucopyranoside (36): To a

D

solution of 35 (320 mg, 0.273 mmol) in THF (4.0 mL) at room

temp. was added portionwise a solution of TBAF in THF (273 µL,

1.0 ). After 30 min the reaction mixture was neutralised with ace-

(67 mg, 0.116 mmol, quant. as colourless lyophilisate. TLC (ethyl

1

acetate/EtOH, 4:1): R_f= 0.09. H NMR (600 MHz, CD₃OD): δ = tic acid and then concentrated in vacuo. The residue was purified

3

1.27 (d, ³J = 6.0 Hz, 12 H, CH(CH₃)₂), 3.16 (dd, J_1,2

8.5 Hz, 0.5 H, 2a-H_β), 3.21–3.52 (m, 4 H, 2a-H_α, 4a-H, 5a-H_β, 2b- nishing 36 (275 mg, 0.270 mmol, 99%) as colourless highly viscous

H, 4b-H), 3.59 (dd, ³J_2,3≈ ³J_4,3= 8.5 Hz, 0.5 H, 3a-H_β), 3.66–4.08 oil. TLC (petroleum ether/ethyl acetate, 2:1): R_f= 0.33. [α]_D

≈

³J_3,2

=

by flash chromatography (petroleum ether/ethyl acetate, 2:1) fur-

=

(m, 10 H, 3a-H_α, 5a-H_α, 6a-H, 6Јa-H, 3b-H, 5b-H, 6b-H, 6Јb-H,

+29.8 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 2.59 (br.

Spacer

OCH₂

, CHHO^Spacer), 4.11–4.17 (m, 1 H, CHHO^Spacer), 4.45– s, 1 H, OH), 3.41–3.72 (m, 11 H, 2a-H, 5a-H, 2b-H, 4b-H, 5b-H,

4.56 (m, 2.5 H, 1a-H_β, CH(CH₃)₂), 5.08 (d, J_2,1= 3.6 Hz, 0.5 H, 6b-H, 6Јb-H, CH₂O^Spacer, CH₂OH^Spacer), 3.77–3.83 (m, 4 H, 4a-H,

3

1a-H_α), 5.14, 5.15 (2d, ³J_2,1(α)= ³J_2,1(β)= 3.6 Hz, 1 H, 1b-H), 6.02–

6.08 (m, 3 H, C₆H₃^Phloro). C₂₆H₄₂O₁₄(578.26): calcd. C 53.95, H

7.32; found C 53.55, H 7.58.

6a-H, 6Јa-H, 3b-H), 4.08 (dd, J_2,3

=

³J_4,3= 9.2 Hz, 1 H, 3a-H),

3

2

4.35 (d, J = 12.1 Hz, 1 H, PhCHH), 4.45–4.63 (m, 7 H, 1a-H, 10

PhCHH), 4.64–4.75 (m, 3 H, PhCHH), 4.85–4.99 (m, 4 H,

PhCHH), 5.66 (d, J_2,1= 3.5 Hz, 1 H, 1b-H), 7.05–7.48 (m, 35 H,

3

O-{4-O-[2-(3,5-Dihydroxyphenoxy)ethyl]-α-

D-glucopyranosyl}-

Ph). C₆₃H₆₈O₁₂(1017.23): calcd. C 74.39, H 6.74; found C 74.35,

H 6.74.

(1Ǟ4)-α/β- -glucopyranose (28c): To a solution of 33c (230 mg,

D

0.176 mmol) in dioxane (10.0 mL) was added Pearlman catalyst^[19]

(20.0 mg). Then the argon atmosphere was completely replaced by

hydrogen. After stirring for 4 h at room temp. the catalyst was sepa-

rated with celite and the celite washed with methanol (3 ϫ 10 mL).

Filtrate and wash solution were combined and the solvent removed

in vacuo. Purification by flash chromatography with silica gel (ethyl

acetate/EtOH, 2:1) then with RP18-Kieselgel (CH₃CN/H₂O, 1:10)

and lyophilisation from dioxane furnished 28c (74 mg, 0.150 mmol,

Benzyl O-[2,3,6-Tri-O-benzyl-4-O-(2-bromoethyl)-α-

D-glucopyrano-

syl]-(1Ǟ4)-2,3,6-tri-O-benzyl-β- -glucopyranoside (37): To a solu-

D

tion of 36 (200 mg, 0.197 mmol, 1.0 equiv.) and tetrabromometh-

ane (326 mg, 0.983 mmol, 5.0 equiv.) in dry CH₂Cl₂(30.0 mL) at

room temp. was added triphenylphosphane (258 mg, 0.983 mmol,

5 equiv.). After 45 min the solvent was removed in vacuo and the

residue purified by flash chromatography (petroleum ether/ethyl

acetate, 5:1) furnishing 37 (187 mg, 0.173 mmol, 88%) as colourless

85%) as wine red lyophilisate. TLC (ethyl acetate/EtOH, 2:1): R_f=

1

0.10. H NMR (250 MHz, CD₃OD): δ = 3.12–4.19 (m, 16 H, 2a- highly viscous oil. TLC (petroleum ether/ethyl acetate, 4:1): R_f=

H, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-

0.49. [α]_D= +23.7 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃):

δ = 3.17–3.29 (m, 2 H, CH₂Br), 3.38–3.50 (m, 3 H, 2b-H, 4b-H,

6b-H), 3.51–3.87 (m, 9 H, 2a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 3b-H,

5b-H, 6Јb-H, CHHO^Spacer), 3.99 (m, 1 H, CHHO^Spacer), 4.08 (dd,

3

H, 6Јb-H, OCH₂^Spacer), 4.49 (d, J_2,1= 7.7 Hz, 0.5 H, 1a-H_β), 5.09

3

(d, J_2,1= 3.6 Hz, 0.5 H, 1b-H_α), 5.14 (d, J_2,1= 3.6 Hz, 1 H, 1b-

H), 5.86–5.93 (m, 3 H, C₆H₃^Phloro). C₂₀H₃₀O₁₄·1.25H₂O (516.96):

calcd. C 46.47, H 6.34; found C 46.51, H 6.35.

³J_2,3

=

³J_4,3= 9.2 Hz, 1 H, 3a-H), 4.36 (d, ²J = 12.0 Hz, 1 H,

Eur. J. Org. Chem. 2008, 2084–2099

www.eurjoc.org

2093

H. Malik, W. Boos, R. R. Schmidt

FULL PAPER

PhCHH), 4.48–5.01 (m, 14 H, 1a-H, PhCHH), 5.05 (d, J_2,1

3.4 Hz, 1 H, 1b-H), 7.08–7.45 (m, 35 H, Ph). C₆₃H₆₇BrO₁₁

(1080.12): calcd. C 70.06, H 6.25; found C 70.03, H 6.25.

3

=

(petroleum ether/ethyl acetate, 1:3) furnished 43 (106 mg,

50.34 µmol, 65%) as colourless foam. TLC (petroleum ether/ethyl

1

acetate, 1:3): R_f= 0.23. [α]_D= +35.4 (c = 1.0, CHCl₃). H NMR

(600 MHz, CDCl₃): δ = 1.85–2.23 (m, 63 H, CH₃CO), 3.68 (m, 3

H, 5a-H, 5aЈ-H, 5aЈЈ-H), 3.84–4.11 (m, 21 H, 4a-H, 4aЈ-H, 4aЈЈ-H,

5b-H, 5bЈ-H, 5bЈЈ-H, 6b-H, 6bЈ-H, 6bЈЈ-H, 6 CH₂O^Spacer), 4.12–

4.26 (m, 6 H, 6Јb-H, 6ЈbЈ-H, 6ЈbЈЈ-H, 6a-H, 6aЈ-H, 6aЈЈ-H), 4.46

(dd, ³J_5,6= 1.9, ²J_6,6Ј= 10.0 Hz, 3 H, 6Јa-H, 6ЈaЈ-H, 6ЈaЈЈ-H), 4.64

1,3,5-Tris{2-[benzyl O-(2,3,6-Tri-O-benzyl-4-yl-α-

D-glucopyrano-

syl)-(1Ǟ4)-2,3,6-tri-O-benzyl-β- -glucopyranoside]ethyloxy}-

D

benzene (38): To a solution of 37 (176 mg, 163 µmol), water-free

phloroglucine (7.0 mg, 55.5 µmol) and TBAI (6.0 mg, 16.3 µmol)

in dry DMF (6.0 mL) at room temp. was added NaH (20.0 mg,

833 µmol) over 3 d. Then the reaction was quenched with methanol

(5.0 mL) and, if necessary, neutralised with acetic acid. The solvent

was removed in vacuo. Purification by flash chromatography (pe-

troleum ether/ethyl acetate, 3:1) furnished 38 (90 mg, 28.8 µmol,

52%) as colourless highly viscous oil. TLC (petroleum ether/ethyl

3

(d, J_2,1= 7.8 Hz, 3 H, 1a-H, 1aЈ-H, 1aЈЈ-H), 4.78–4.86 (m, 6 H,

3

2a-H, 2aЈ-H, 2aЈЈ-H, 2b-H, 2bЈ-H, 2bЈЈ-H), 5.03 (dd, J_3,4= 1.9,

3

2

²J_5,4= 9.8 Hz, 3 H, 4b-H, 4bЈ-H, 4bЈЈ-H), 5.24 (dd, J_2,3= J_4,3

=

9.1 Hz, 3 H, 3a-H, 3aЈ-H, 3aЈЈ-H), 5.33 (dd, ³J_2,3= ²J_4,3= 10.0 Hz,

3 H, 3b-H, 3bЈ-H, 3bЈЈ-H), 5.38 (d, ³J_2,1= 3.7 Hz, 3 H, 1b-H, 1bЈ-

H, 1bЈЈ-H), 6.02 (s, 3 H, C₆H₃^Phloro). MALDI MS: m/z = 2154

[MK⁺]. FAB MS: m/z = 2137 [MNa⁺], 2287 [(MNaI)Na⁺]; (abs.

mass 2112.65). C₉₀H₁₂₀O₅₇·H₂O (2131.91): calcd. C 50.70, H 5.77;

found C 50.73, H 5.87.

1

acetate, 2:1): R_f= 0.67. [α]_D= +11.1 (c = 1.0, CHCl₃). H NMR

(600 MHz, CDCl₃): δ = 3.43–3.51 (m, 9 H, 2b-H, 2bЈ-H, 2bЈЈ-H,

4b-H, 4bЈ-H, 4bЈЈ-H, 6b-H, 6bЈ-H, 6bЈЈ-H), 3.52–3.67 (m, 9 H, 2a-

H, 2aЈ-H, 2aЈЈ-H, 5a-H, 5aЈ-H, 5aЈЈ-H, 6Јb-H, 6ЈbЈ-H, 6ЈbЈЈ-H),

3.68–3.95 (m, 24 H, 3a-H, 3aЈ-H, 3aЈЈ-H, 6a-H, 6aЈ-H, 6aЈЈ-H, 6Јa-

1,3,5-Tris-{2-[O-(α-D-glucopyranosyl)-(1Ǟ4)-β-D-glucopyranosyl-

H, 6ЈaЈ-H, 6ЈaЈЈ-H, 3b-H, 3bЈ-H, 3bЈЈ-H, 5b-H, 5bЈ-H, 5bЈЈ-H, oxy]ethyloxy}benzene (44): To a solution of 43 (50.0 mg,

3CH₂O^Spacer, 3CHHO^Spacer), 3.97–4.11 (m, 6 H, 4a-H, 4aЈ-H, 4aЈЈ- 23.65 µmol) in dry methanol (15.0 mL) was added sodium methyl-

2

H, 3CHHO), 4.31 (d, J = 12.1 Hz, 3 H, PhCHH), 4.48–4.60 (m,

ate in methanol (10.0 µL, 1.0 ). After stirring for 2 d at room

2

18 H, 1a-H, 1aЈ-H, 1aЈЈ-H, PhCHH), 4.61 (d, J = 12.0 Hz, 3 H, temp. the reaction mixture was neutralised with Amberlite IR 120

PhCHH), 4.67 (d, ²J = 12.1 Hz, 3 H, PhCHH), 4.70–4.85 (m, 9 H,

H⁺and then the solvent removed in vacuo. Purification by flash

3

PhCHH), 4.86–4.99 (m, 9 H, PhCHH), 5.64 (d, J_2,1= 3.4 Hz, 3 chromatography (CH₃CN/H₂O, 1:8, RP-18) furnished 44 (25 mg,

H, 1b-H, 1bЈ-H, 1bЈЈ-H), 5.90 (s, 3 H, C₆H₃^Phloro), 7.09–7.39 (m, 20.34 µmol, 86 %) as colourless lyophilisate (D₂O). RP-18 TLC

105 H, Ph). MALDI MS: m/z = 3140 [MNa⁺]. FAB MS: m/z = (CH₃CN/H₂O, 1:8): R_f= 0.29. [α]_D= +36.6 (c = 1.0, H₂O). ¹H

3146 [MNa⁺], 3297 [(MNaI)Na⁺]; (abs. mass 3121.41). C₁₉₅H₂₀₄O₃₆NMR (600 MHz, D₂O): δ = 3.21 (dd, J_1,2= 8.0, J_3,2= 9.0 Hz, 3

3

(3123.74): calcd. C 74.98, H 6.58; found C 74.58, H 6.78.

H, 2a-H, 2aЈ-H, 2aЈЈ-H), 3.29 (dd, J_3,4= J_5,4= 8.7 Hz, 3 H, 4b-

H, 4bЈ-H, 4bЈЈ-H), 3.42–3.48 (m, 6 H, 5a-H, 5aЈ-H, 5aЈЈ-H, 2b-H,

2bЈ-H, 2bЈЈ-H), 3.49–3.69 (m, 18 H, 3a-H, 3aЈ-H, 3aЈЈ-H, 4a-H,

4aЈ-H, 4aЈЈ-H, 6a-H, 6aЈ-H, 6aЈЈ-H, 3b-H, 3bЈ-H, 3bЈЈ-H, 5b-H,

5bЈ-H, 5bЈЈ-H, 6b-H, 6bЈ-H, 6bЈЈ-H), 3.70–3.78 (m, 6 H, 6Јa-H,

1,3,5-Tris-{2-[O-(4-yl-α- -glucopyranosyl)-(1Ǟ4)-α/β-D-gluco-

D

pyranoside]ethyloxy}benzene (39): To a solution of 38 (55.0 mg,

17.61 µmol) in THF (7.0 mL) was added Pearlman catalyst^[19]

(10.0 mg). Then the argon atmosphere was completely replaced by

hydrogen. After 2 d at hydrogen overpressure of 0.1 bar the catalyst

was separated with celite in order to quench the reaction. The celite

was washed with methanol (3ϫ10 mL). Filtrate and wash solution

were combined and the solvent removed in vacuo. The residue was

purified with RP-18-silica gel (CH₃CN/H₂O, 1:4) by flash

chromatography and lyophilised from D₂O furnishing 39 (22 mg,

17.61 µmol, quant. as colourless lyophilisate in D₂O (anomeric ra-

6ЈaЈ-H, 6ЈaЈЈ-H, 6Јb-H, 6ЈbЈ-H, 6ЈbЈЈ-H), 3.88–3.95 (m, 3 H,

3

CHHO^Spacer), 4.06–4.15 (m, 9 H, CHHO^Spacer), 4.43 (d, J_2,1

=

8.0 Hz, 3 H, 1a-H, 1aЈ-H, 1aЈЈ-H), 5.27 (d, ³J_2,1= 3.7 Hz, 3 H, 1b-

H, 1bЈ-H, 1bЈЈ-H), 6.20 (s, 3 H, C₆H₃^Phloro). FAB MS: m/z = 1231

[MH⁺], 1253 [MNa⁺], 1269 [MK⁺]; (abs. mass 1230.43).

C₄₈H₇₈O₃₆·4H₂O (1303.18): calcd. C 44.24, H 6.65; found C 44.23,

H 6.57.

1

tio α/β, 2:3). RP-18 DC (CH₃CN/H₂O, 1:4): R_f= 0.63. H NMR

(600 MHz, D₂O): δ = 3.17 (dd, J_1,2= 7.9 Hz, J_3,2= 9.0 Hz, 1.8 (1Ǟ4)-2,3,6-tri-O-benzyl-1-thio-β-

H, 2a-H_β, 2aЈ-H_β, 2aЈЈ-H_β), 3.30 (dd, J_3,4

Ethyl O-(2,3-Di-O-Benzyl-4,6-O-benzylidene-α-

-glucopyranoside (53): To a

solution of 52^[32](7.9 g, 16.65 mmol, 1.0 equiv.) in dry DMF

D-glucopyranosyl)-

3

D

3

=

³J_5,4= 9.5 Hz, 3 H,

4b-H, 4bЈ-H, 4bЈЈ-H), 3.43–3.57 (m, 9 H, 2a-H_α, 2aЈ-H_α, 2aЈЈ-H_α, (150.0 mL) was added benzyl bromide (10.88 mL, 15.66 g,

4a-H, 4aЈ-H, 4aЈЈ-H, 5a-H_β, 5aЈ-H_β, 5aЈЈ-H_β, 2b-H, 2bЈ-H, 2bЈЈ- 91.58 mmol, 5.5 equiv.). Then NaH (2.20 g, 91.58 mmol, 5.5 equiv.)

H), 3.61–3.90 (m, 22.2 H, 3a-H_α, 3aЈ-H_α, 3aЈЈ-H_α, 3a-H_β, 3aЈ-H_β,

3aЈЈ-H_β, 5a-H_α, 5aЈ-H_α, 5aЈЈ-H_α, 6a-H, 6aЈ-H, 6aЈЈ-H, 6Јa-H, 6ЈaЈ- dition of methanol (20 mL) destroyed excess NaH and the reaction

H, 6ЈaЈЈ-H, 3b-H, 3bЈ-H, 3bЈЈ-H, 5b-H, 5bЈ-H, 5bЈЈ-H, 6b-H, 6bЈ- mixture was neutralised with acetic acid. The solvent was then re-

was added portionwise over 2 h at room temp. After 20 h slow ad-

H, 6bЈЈ-H, 6Јb-H, 6ЈbЈ-H, 6ЈbЈЈ-H), 3.91–3.96 (m, 3 H, moved in vacuo and the residue dissolved in distilled water (50 mL)

3

CHHO^Spacer), 4.04–4.14 (m, 9 H, CHHO^Spacer), 4.54 (d, J_2,1

=

and ethyl acetate (250 mL). The aqueous phase was washed with

ethyl acetate (3ϫ100 mL) and the combined organic phases dried

with MgSO₄. Purification by flash chromatography (petroleum

3

7.9 Hz, 1.8 H, 1a-H_β, 1aЈ-H_β, 1aЈЈ-H_β), 5.12 (d, J_2,1= 3.6 Hz, 1.2

H, 1a-H_α, 1aЈ-H_α, 1aЈЈ-H_α), 5.30 (d, ³J_2,1= 3.4 Hz, 3 H, 1b-H, 1bЈ-

H, 1bЈЈ-H), 6.22 (s, 3 H, C₆H₃^Phloro). FAB MS: m/z = 1231 [MH⁺], ether/ethyl acetate, 5:1) furnished 53 (10.5 g, 11.32 mmol, 68%) as

1253 [MNa⁺]; (abs. mass 1230.43). C₄₈H₇₈O₃₆·5H₂O (1321.20): highly viscous oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f=

1

calcd. C 43.64, H 6.71; found C 43.79, H 6.86.

0.56. [α]_D= +2.0 (c = 1.0, CHCl₃). H NMR (250 MHz, CDCl₃):

δ = 1.31 (t, 3 H, ³J = 7.4 Hz, SCH₂CH₃), 2.65–2.86 (m, 2 H,

SCH₂CH₃), 3.44–4.20 (m, 12 H, 2a-H, 3a-H, 4a-H, 5a-H, 6a-H,

6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H), 4.42–4.96 (m, 1a-

1,3,5-Tris-{2-[O-(2,3,4,6-tetra-O-acetyl-α- -glucopyranosyl)-(1Ǟ4)-

2,3,6-tri-O-acetyl-β- -glucopyranosyloxy]-ethyloxy}benzene (43): To

D

a solution of 42^[28](20.0 mg, 77.44 µmol, 1.0 equiv.) in dry acetoni-

trile (4.0 mL) was added TMSOTf (0.35 µL, 1.94 µmol,

0.025 equiv.) and then slowly at room temp. a solution of 40^[13,30]

(200 mg, 255.6 µmol, 3.3 equiv.) in dry acetonitrile (3.0 mL). After

1 h the reaction mixture was neutralised with triethylamine and

then concentrated in vacuo. Purification by flash chromatography

3

H, 10 PhCHH), 5.52 (s, 1 H, PhCH), 5.67 (d, 1 H, J_1,2= 3.9 Hz,

1b-H), 7.08–7.51 (m, 30 H, Ph). C₅₆H₆₀O₁₀S (925.15): calcd. C

72.70, H 6.54; found C 73.06, H 6.54.

Benzyl O-2,3-Di-O-benzyl-6-bromo-6-deoxy-α-

D-glucopyranoside

(55): To a solution of 54 (200 mg, 0.444 mmol, 1.0 equiv.) and tetra-

2094

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2084–2099

Maltose and Maltotriose Derivative

bromomethane (177 mg, 0.533 mmol, 1.2 equiv.) in dry CH₂Cl₂

NMR (600 MHz, CDCl₃): δ = 0.08, 0.10 [2s, 6 H, Si(CH₃)₂], 0.83–

(20.0 mL) was added triphenylphosphane (140 mg, 0.533 mmol, 0.88 [m, 12 H, 2 C(CH₃)₂], 1.53–1.64 [m, 1 H, CH(CH₃)₂], 3.46–

1.2 equiv.) at room temp. After 4 h the solvent was removed in

vacuo and the residue purified by flash chromatography (petroleum

ether/ethyl acetate, 8:1) furnishing 55 (140 mg, 0.273 mmol, 61%)

as colourless highly viscous oil. TLC (petroleum ether/ethyl acetate,

3.57 (m, 3 H, 2a-H, 2b-H, 2c-H), 3.58–3.69 (m, 3 H, 4c-H, 6b-H,

6c-H), 3.77–3.92 (m, 6 H, 4a-H, 5a-H, 6a-H, 6Јa-H, 6Јb-H, 5c-H),

3.94–3.97 (m, 1 H, 5b-H), 3.98–4.09 (m, 2 H, 3b-H, 3c-H), 4.10–

4.19 (m, 3 H, 3a-H, 4b-H, 6Јc-H), 4.43–4.62 (m, 7 H, PhCHH),

2:1): R_f= 0.78. [α]_D= +61.1 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, 4.63–4.71 (m, 2 H, PhCHH), 4.72–4.78 (m, 3 H, PhCHH), 4.80 (d,

CDCl₃): δ = 2.25 (s, 1 H, OH), 3.44–3.56 (m, 3 H, 2-H, 4-H, 6-H), ³J_2,1= 3.4 Hz, 1 H, 1a-H), 4.84–4.96 (m, 3 H, PhCHH), 5.03 (d,

3

3.63 (dd, J_5,6Ј= 1.9, J_6,6Ј= 11.0 Hz, 1 H, 6Ј-H), 3.77–3.89 (m, 2 ²J = 11.5 Hz, 1 H, PhCHH), 5.53 (s, 1 H, PhCH), 5.62 (d, J_2,1

=

2

3

H, 3-H, 5-H), 4.54 (d, J = 11.5 Hz, 1 H, PhCHH), 4.57–4.65 (m,

3.4 Hz, 1 H, 1b-H), 5.70 (d, J_2,1= 3.7 Hz, 1 H, 1c-H), 7.02–7.56

2

2 H, PhCHH), 4.69 (d, J = 11.5 Hz, 1 H, PhCHH), 4.76 (d, J = (m, 45 H, Ph). C₈₉H₁₀₂O₁₆Si (1455.87): calcd. C 73.43, H 7.06;

3

11.5 Hz, 1 H, PhCHH), 4.88 (d, J_2,1= 3.5 Hz, 1 H, 1-H), 5.05 (d, found C 73.45, H 7.10.

²J = 11.5 Hz, 1 H, PhCHH), 7.25–7.46 (m, 15 H, Ph). MALDI

Benzyl O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-α- -glucopyranoside (59): To a solution of 58 (400 mg,

0.275 mmol) in THF (12.0 mL) was added at room temp. portion-

D-glucopyranosyl)-

MS: m/z = 536, 538 [MNa⁺], 552, 554 [MK⁺]. C₂₇H₂₉BrO₅

D

(513.43): calcd. C 63.16, H 5.69; found C 63.07, H 5.65.

D

Benzyl 2,3-Di-O-Benzyl-6-O-methyl-α-D-glucopyranoside (56): To a

solution of 55 (120 mg, 0.234 mmol, 1.0 equiv.), TBAI (8.64 mg, wise a solution of TBAF in THF (275 µL, 1.0 ). After 20 h the

0.023 mmol, 0.1 equiv.) and crown ether 15-crown-5 (103 mg, reaction mixture was neutralised with acetic acid and then the mix-

0.468 mmol, 2.0 equiv.) in dry DMF (10.0 mL) was added portion-

ture concentrated in vacuo. The residue was purified by flash

wise sodium methoxide (126 mg, 2.34 mmol, 10.0 equiv.) at room chromatography (petroleum ether/ethyl acetate, 3:1) furnishing 59

temp. After 3 d at room temp. the reaction mixture was neutralised

with acetic acid and after aqueous workup purified by flash

chromatography (toluene/ethyl acetate, 5:1) furnishing 56 (52 mg,

0.112 mmol, 48%) as colourless, highly viscous oil. TLC (toluene/

(294 mg, 0.224 mmol, 81%) as colourless, highly viscous oil. TKC

(petroleum ether/ethyl acetate, 3:1): R_f= 0.19. [α]_D= +39.0 (c =

1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 3.00 (m, 1 H, OH),

3

3.46 (dd, J_1,2= 3.7, J_3,2= 9.8 Hz, 1 H, 2c-H), 3.51 (dd, J_1,2

=

ethyl acetate, 5:1): R_f= 0.26. [α]_D= +56.6 (c = 1.0, CHCl₃). ¹H 3.8, ³J_3,2= 9.8 Hz, 1 H, 2b-H), 3.55–3.67 (m, 4 H, 2a-H, 6b-H, 4c-

NMR (600 MHz, CDCl₃): δ = 2.33 (br. s, 1 H, OH), 3.38 (s, 3 H,

H, 6c-H), 3.68–3.79 (m, 4 H, 5a-H, 6a-H, 6Јb-H, 5c-H), 3.82 (dd,

2

3

2

OCH₃), 3.50–3.62 (m, 4 H, 2-H, 4-H, 6-H, 6Ј-H), 3.74 (m, 1 H, 5- ³J_3,4= J_5,4= 9.2 Hz, 1 H, 4a-H), 3.88 (dd, J_2,3= J_4,3= 9.5 Hz,

3

H), 3.85 (dd, J_2,3= J_4,3= 9.2 Hz, 1 H, 3-H), 4.51–4.58 (m, 2 H,

PhCHH), 4.63 (d, ²J = 11.9 Hz, 1 H, PhCHH), 4.70–4.76 (m, 2 H,

1 H, 3c-H), 3.92–4.01 (m, 3 H, 5a-H, 3b-H, 6Јa-H), 4.08 (dd, J_3,4

²J_5,4= 9.8 Hz, 1 H, 4b-H), 4.11–4.17 (m, 2 H, 3a-H, 6Јc-H),

=

3

2

PhCHH), 4.85 (d, J_2,1= 3.5 Hz, 1 H, 1-H), 5.03 (d, J = 11.5 Hz,

1 H, PhCHH), 7.25–7.44 (m, 15 H, Ph). C₂₈H₃₂O₆(464.22): calcd.

C 71.39, H 6.94; found C 71.48, H 6.93.

4.37–4.63 (m, 8 H, PhCHH), 4.64–4.80 (m, 5 H, PhCHH), 4.82–

4.88 (m, 3 H, 1a-H, PhCHH), 5.08 (d, ²J = 11.9 Hz, 1 H, PhCHH),

3

5.54 (s, 1 H, PhCH), 5.59 (d, J_2,1= 3.7 Hz, 1 H, 1b-H), 5.72 (d,

³J_2,1= 3.7 Hz, 1 H, 1c-H), 6.99–7.55 (m, 45 H, Ph). C₈₁H₈₄O₁₆

Benzyl O-2,3-Di-O-benzyl-6-O-thexyldimethylsilyl-α-D-glucopyr-

anoside (57): To a solution of 54 (3.30 g, 7.325 mmol, 1.0 equiv.)

(1313.55): calcd. C 74.07, H 6.44; found C 73.86, H 6.33.

in dry CH₂Cl₂(40.0 mL) was added thexyldimethylsilyl chloride

(1.58 mL, 1.44 g, 8.06 mmol, 1.1 equiv.) and imidazole (0.748 g, tri-O-benzyl-α-

Benzyl O-(2,3,4-Tri-O-benzyl-α-

-glucopyranosyl)-(1Ǟ4)-2,3-di-O-benzyl-6-O-thex-

yldimethylsilyl-α- -glucopyranoside (60): To a solution of 58

(100 mg, 68.7 µmol, 1.0 equiv.) in dry CH₂Cl₂(5.0 mL) was added

a solution of borane in THF (0.687 mL, 1.0 ) and then a solution

of Bu₂BOTf in CH₂Cl₂(10 µL, 1.0 ). After 24 h excess borane

complex was destroyed with methanol (20 mL) and the reaction

mixture neutralised with triethylamine. The reaction mixture was

concentrated in vacuo and purified by flash chromatography (pe-

troleum ether/ethyl acetate, 4:1) furnishing 60 (90 mg, 61.8 µmol,

D-glucopyranosyl)-(1Ǟ4)-O-(2,3,6-

D

10.99 mmol, 1.5 equiv.) at room temp. After 5 h (TLC monitoring)

the solvent was removed in vacuo and the residue purified by flash

chromatography (petroleum ether/ethyl acetate, 10:1) furnishing 57

(4.34 g, 7.325 mmol, quant. as colourless oil. TLC (petroleum

ether/ethyl acetate, 8:1): R_f= 0.42. [α]_D= +48.2 (c = 1.0, CHCl₃).

¹H NMR (250 MHz, CDCl₃): δ = 0.08, 0.09 [2s, 6 H, Si(CH₃)₂],

0.78–0.89 [m, 12 H, 2 C(CH₃)₂], 1.59 [hept, ³J = 6.6 Hz, 1 H,

CH(CH₃)₂], 2.58 (br. s, 1 H, OH), 3.41–3.55 (m, 2 H, 2-H, 4-H),

3.59–3.76 (m, 3 H, 5-H, 6-H, 6Ј-H), 3.84 (dd, ³J_2,3= ³J_4,3= 8.5 Hz,

D

90%) as colourless highly viscous oil. TLC (petroleum ether/ethyl

1 H, 3-H), 4.48–4.83 (m, 6 H, 1-H, 5 PhCHH), 4.97 (d, ²J = acetate, 3:1): R_f= 0.45. [α]_D= +61.8 (c = 1.0, CHCl₃). H NMR

1

11.2 Hz, 1 H, PhCHH), 7.19–7.44 (m, 15 H, Ph). C₃₅H₄₈O₆Si

(592.85): calcd. C 70.91, H 8.16; found C 71.04, H 8.14.

(600 MHz, CDCl₃): δ = 0.09, 0.11 [2s, 6 H, Si(CH₃)₂], 0.83–0.88

[m, 12 H, 2C(CH₃)₂], 1.56–1.68 [m, 1 H, CH(CH₃)₂], 3.39 (dd, ³J_1,2

3

= 3.4, J_3,2= 10.6 Hz, 1 H, 2c-H), 3.46–3.56 (m, 4 H, 2a-H, 2b-H,

Benzyl O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-6-O-thexyldimethylsilyl-α- -glucopyranoside (58): To a solu-

D-glucopyranosyl)-

4c-H, 6c-H), 3.57–3.65 (m, 2 H, 6b-H, 6Јc-H), 3.69 (m, 1 H, 5b-

H), 3.78–3.96 (m, 7 H, 4a-H, 5a-H, 6a-H, 6Јa-H, 5b-H, 6Јb-H, 3c-

H), 3.99–4.08 (m, 2 H, 3b-H, 4b-H), 4.15 (dd, ³J_2,3= ³J_4,3= 8.9 Hz,

1 H, 3a-H), 4.44–4.65 (m, 10 H, PhCHH), 4.72–4.79 (m, 3 H,

D

tion of 57 (2.14 g, 3.61 mmol, 1.0 equiv.) and 53 (5.00 g, 5.40 mmol,

1.5 equiv.) in dry diethyl ether (200 mL) was added N-iodosuccin-

imide (1.21 g, 5.40 mmol, 1.5 equiv.) at room temp. The reaction

was then initiated with catalytic amounts of trifluoromethane sul-

fonic acid (1.6 µL, 0.005 equiv.). After 30 min the reaction mixture

was washed with NaHCO₃solution (50.0 mL) and Na₂SO₃solu-

tion (3ϫ50 mL) and dried with MgSO₄. The reaction mixture was

then concentrated in vacuo and the residue purified by flash

chromatography (toluene/ethyl acetate, 75:1) furnishing 58 (2.10 g,

3

PhCHH), 4.80 (d, J_2,1= 3.3 Hz, 1 H, 1a-H), 4.82–4.94 (m, 4 H,

3

PhCHH), 5.03 (d, ²J = 11.5 Hz, 1 H, PhCHH), 5.58 (d, J_2,1

=

3

3.3 Hz, 1 H, 1c-H), 5.63 (d, J_2,1= 3.3 Hz, 1 H, 1b-H), 7.04–7.48

(m, 45 H, Ph). C₈₉H₁₀₄O₁₆Si (1457.88): calcd. C 73.32, H 7.19;

found C 73.09, H 7.24.

Benzyl O-(2,3,4-Tri-O-benzyl-6-O-methyl-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-6-O-thexyldimethylsilyl-α- -glucopyranoside (61): To a solu-

D-glucopyranosyl)-

D

0.319 mmol, 40%) as colourless, highly viscous oil. TLC (toluene/

D

1

ethyl acetate, 50:1): R_f= 0.37. [α]_D= +47.9 (c = 1.0, CHCl₃). H tion of 60 (150 mg, 0.103 mmol, 1.0 equiv.) in dry DMF (6.5 mL)

Eur. J. Org. Chem. 2008, 2084–2099

www.eurjoc.org

2095

H. Malik, W. Boos, R. R. Schmidt

FULL PAPER

was added methyl iodide (19.3 µL 43.9 mg, 0.309 mmol, 3.0 equiv.)

at room temp. and then NaH (7.4 mg, 0.309 mmol, 3.0 equiv.). Af-

ter 28 h methanol (10.0 mL) was added to quench the reaction and

then triethylamine (0.5 mL). The reaction mixture was neutralised

with acetic acid, the solvent removed in vacuo and the residue puri-

fied by flash chromatography (petroleum ether/ethyl acetate, 5:1)

furnishing 61 (132 mg, 89.61 µmol, 87%) as colourless, highly vis-

cous oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.68. [α]_D

PhCHH), 5.02 (d, ²J = 11.5 Hz, 1 H, PhCHH), 5.52–5.56 (m, 2 H,

1b-H, PhCHH), 5.72 (d, J_2,1= 3.6 Hz, 1 H, 1c-H), 7.03–7.52 (m,

45 H, Ph). C₈₄H₉₀O₁₆(1355.63): calcd. C 74.42, H 6.69; found C

74.26, H 6.75.

3

Benzyl O-(2,3,4-Tri-O-benzyl-α-

tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-benzyl-6-O-pro-

pyl-α- -glucopyranoside (63): To a solution of 62 (110 mg,

D-glucopyranosyl)-(1Ǟ4)-O-(2,3,6-

D

81.14 µmol) in dry CH₂Cl₂(5.0 mL) was added a solution of bo-

rane in THF (0.81 mL, 1.0 ) and then a solution of Bu₂BOTf in

CH₂Cl₂(20 µL, 1.0 ). After 72 h the excess borane complex was

destroyed with methanol (10 mL) and the reaction mixture neutral-

ised with triethylamine. The mixture was concentrated in vacuo and

then purified by flash chromatography (petroleum ether/ethyl ace-

tate, 3:1) furnishing 63 (76 mg, 55.99 µmol, 69 %) as colourless,

highly viscous oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f=

0.30. [α]_D= +48.0 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃):

1

= +61.0 (c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ = 0.08,

0.10 [2s, 6 H, Si(CH₃)₂], 0.82–0.89 [m, 12 H, 2C(CH₃)₂], 1.61 [hept,

3

³J = 6.8 Hz, 1 H, CH(CH₃)₂], 3.20 (s, 3 H, OCH₃), 3.31 (dd, J_5,6

3

= 2.0, J_6,6Ј= 9.7 Hz, 1 H, 6c-H), 3.42 (dd, J_5,6= 2.4, J_6,6Ј

=

3

9.5 Hz, 1 H, 6Јc-H), 3.45 (dd, J_1,2= 3.4, J_3,2= 10.4 Hz, 1 H, 2c-

H), 3.48–3.55 (m, 2 H, 2a-H, 2b-H), 3.59–3.62 (m, 2 H, 6a-H, 4c-

H), 3.64–3.73 (m, 1 H, 5c-H), 3.77–3.95 (m, 7 H, 4a-H, 5a-H, 6Јa-

H, 5b-H, 6b-H, 6Јb-H, 3c-H), 3.99–4.06 (m, 2 H, 3b-H, 4b-H), 4.14

3

(dd, J_2,3

=

³J_4,3= 8.9 Hz, 1 H, 3a-H), 4.42–4.59 (m, 10 H,

3

δ = 0.77 (t, J = 7.4 Hz, 3 H, OCH₂CH₂CH₃), 1.44–1.53 (m, 2 H,

PhCHH), 4.73–4.80 (m, 4 H, 1a-H, PhCHH), 4.81–4.87 (m, 3 H,

PhCHH), 4.89 (d, ²J = 11.4 Hz, 1 H, PhCHH), 5.00 (d, ²J =

11.5 Hz, 1 H, PhCHH), 5.61 (d, ³J_2,1= 3.4 Hz, 1 H, 1b-H), 5.67 (d,

³J_2,1= 3.4 Hz, 1 H, 1c-H), 7.05–7.49 (m, 45 H, Ph). C₉₀H₁₀₆O₁₆Si

(1471.91): calcd. C 73.44, H 7.26; found C 73.39, H 7.40.

OCH₂CH₂CH₃), 1.63 (br. s, 1 H, OH), 3.22–3.37 (m, 3 H, 2c-H,

OCH₂CH₂CH₃), 3.39–3.49 (m, 4 H, 6a-H, 2b-H, 4c-H, 6c-H),

3.50–3.58 (m, 3 H, 2a-H, 6b-H, 6Јc-H), 3.59–3.63 (m, 1 H, 5c-H),

3

2

3.70 (dd, J_5,6= 3.4, J_6,6Ј= 11.2 Hz, 1 H, 6Јa-H), 3.74–3.82 (m, 3

3

H, 5a-H, 5b-H, 6Јb-H), 3.83 (dd, J_2,3

=

³J_4,3= 8.9 Hz, 1 H, 3c-

H), 3.90–4.01 (m, 3 H, 4a-H, 3b-H, 4b-H), 4.04 (dd, ³J_2,3= ³J_4,3

=

O-(6-O-Methyl-α-

D-glucopyranosyl)-(1Ǟ4)-O-(α-D-glucopyrano-

syl)-(1Ǟ4)-α/β- -glucopyranose (45): To a solution of 61 (120 mg,

D

8.4 Hz, 1 H, 3a-H), 4.35–4.57 (m, 10 H, PhCHH), 4.63–4.70 (m, 3

H, PhCHH), 4.73–4.81 (m, 4 H, 1a-H, PhCHH), 4.84 (d, ²J =

11.5 Hz, 1 H, PhCHH), 4.97 (d, ²J = 11.5 Hz, 1 H, PhCHH), 5.48–

5.52 (m, 2 H, 1b-H, 1c-H), 7.02–7.46 (m, 45 H, Ph). C₈₄H₉₂O₁₆

(1356.64): calcd. C 74.31, H 6.83; found C 73.89, H 7.15.

81.53 µmol, 1.0 equiv.) in THF (10.0 mL) at room temp. was added

portionwise a solution of TBAF in THF (244.6 µL, 1.0 ,

3.0 equiv.). After 24 h the reaction mixture was neutralised with

acetic acid and then concentrated in vacuo. The residue was puri-

fied by flash chromatography (petroleum ether/ethyl acetate, 2:1).

The intermediate (90 mg) was then dissolved in THF/H₂O/AcOH,

300:50:1 (7.0 mL) and Pearlman catalyst^[19](15.0 mg) added. Then

the argon atmosphere was completely replaced by hydrogen. After

72 h at room temp. the catalyst was separated with celite and the

celite washed with methanol/water (3ϫ10 mL). Filtrate and wash

solution were combined and the solvent removed in vacuo. The

residue was purified by flash chromatography (H₂O 100%; RP-18)

and lyophilised from D₂O furnishing 45 (32 mg, 61.72 µmol, 76%)

as colourless lyophilisate (α/β, 2:3; D₂O). TLC RP-18 (H₂O 100%):

O-(α-

D-Glucopyranosyl)-(1Ǟ4)-O-(α-

D-glucopyranosyl)-(1Ǟ4)-6-O-

propyl-α-

D

-glucopyranoside (50): To a solution of 63 (55 mg,

40.5 µmol) in THF/H₂O, 5:1 (6.0 mL) was added Pearlman cata-

lyst^[19](15 mg) and catalytic amounts of acetic acid (10 µL). Then

the argon atmosphere was completely replaced by hydrogen. After

72 h at room temp. the catalyst was separated with celite and the

celite washed with methanol/water (3ϫ10 mL). Filtrate and wash

solution were combined and the solvent removed in vacuo. The

residue was purified by flash chromatography (CH₃CN/H₂O, 1:50;

RP-18) and then lyophilised from D₂O furnishing 50 (22 mg,

40.5 µmol, quant. as colourless lyophilisate (α/β, 2:3; D₂O). TLC

RP-18 (CH₃CN/H₂O, 1:50): R_f= 0.45. ¹H NMR (250 MHz, D₂O):

1

3

R_f= 0.58. H NMR (250 MHz, D₂O): δ = 3.10 (dd, J_1,2= J_3,2

=

8.2 Hz, 0.6 H, 2a-H_β), 3.17–3.32 (m, 4 H, 4c-H, OCH₃), 3.33–3.83

(m, 16.4 H, 2a-H_α, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H,

4b-H, 5b-H, 6b-H, 6Јb-H, 2c-H, 3c-H, 5c-H, 6c-H, 6Јc-H), 4.46 (d,

3

δ = 0.75 (t, J = 7.4 Hz, 3 H, OCH₂CH₂CH₃), 1.42 (qt, J = JЈ =

3

³J_2,1= 8.0 Hz, 0.6 H, 1a-H_β), 5.04 (d, J_2,1= 3.7 Hz, 0.4 H, 1a-

7.4 Hz, 2 H, OCH₂CH₂CH₃), 3.10 (dd, J_1,2= J_3,2= 8.5 Hz, 0.6

H, 2a-H_β), 3.20–3.91 (m, 19.4 H, 1a-H_α, 3a-H, 4a-H, 5a-H, 6a-H,

6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, 2c-H, 3c-H, 4c-H,

5c-H, 6c-H, 6Јc-H, OCH₂CH₂CH₃), 4.47 (d, J_2,1= 8.0 Hz, 0.6 H,

2a-H_β), 5.04 (d, J_2,1= 3.6 Hz, 0.4 H, 1a-H_α), 5.21 (d, J_2,1

H_α), 5.17–5.25 (m, 2 H, 1b-H, 1c-H). C₁₉H₃₄O₁₆·1.75H₂O (550.00):

calcd. C 41.49, H 6.87; found C 41.33, H 6.62.

3

Benzyl O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-6-O-n-propyl- -glucopyranoside (62): To a solution of 59

D-glucopyranosyl)-

3

=

D

3.7 Hz, 1 H, 1c-H), 5.22–5.27 (m, 1 H, 1b-H). MALDI MS: m/z =

D

569 [MNa⁺], 585 [MK⁺]. C₂₁H₃₈O₁₆(546.52).

(150 mg, 0.114 mmol, 1.0 equiv.) in dry DMF (10.0 mL) was added

n-propyl iodide (111 µL, 194 mg, 1.142 mmol, 10.0 equiv.) at room

temp. and then NaH (27.4 mg, 1.142 mmol, 10.0 equiv.). After 72 h

methanol (10.0 mL) was added to quench the reaction. Then the

solvent was removed in vacuo and the residue purified by flash

chromatography (petroleum ether/ethyl acetate, 4:1) furnishing 62

(111 mg, 81.85 µmol, 72%) as colourless, highly viscous oil. TLC

(petroleum ether/ethyl acetate, 3:1): R_f= 0.48. [α]_D= +47.1 (c =

1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 0.83 (t, ³J = 7.4 Hz,

Benzyl O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-6-O-methyl-α- -glucopyranoside (64): To a solution of 56

(200 mg, 0.431 mmol, 1.0 equiv.) and 53 (598 mg, 0.646 mmol,

1.5 equiv.) in dry diethyl ether (15.0 mL) at room temp. was added

N-iodosuccinimide (145 mg, 0.646 mmol, 1.5 equiv.). Then the re-

action was started with catalytic amounts of trifluoromethanesulfo-

nic acid (0.38 µL, 0.65 mg, 4.31 µmol, 0.01 equiv.). After 30 min

D-glucopyranosyl)-

D

3 H, OCH₂CH₂CH₃), 1.48–1.55 (m, 2 H, OCH₂CH₂CH₃), 3.31– the reaction mixture was washed with NaHCO₃solution (5.0 mL)

3.34 (m, 2 H, OCH₂CH₂CH₃), 3.46–3.54 (m, 3 H, 6a-H, 2b-H, 2c- and Na₂SO₃solution (3ϫ10 mL) and dried with MgSO₄. The resi-

H), 3.55–3.65 (m, 4 H, 2a-H, 6b-H, 4c-H, 6c-H), 3.75–3.92 (m, 5 due was concentrated in vacuo and purified by flash chromatog-

H, 5a-H, 6Јa-H, 6Јb-H, 5c-H), 3.93–4.09 (m, 3 H, 4a-H, 3b-H, raphy (toluene/ethyl acetate, 10:1) furnishing 64 (423 mg,

3c-H), 4.10–4.23 (m, 3 H, 3a-H, 4b-H, 6c-H), 4.42–4.61 (m, 7 H, 0.319 mmol, 74%) as colourless, highly viscous oil. TLC (petro-

PhCHH), 4.62–4.75 (m, 5 H, PhCHH), 4.77–4.94 (m, 4 H, 1a-H, leum ether/ethyl acetate, 3:1): R_f= 0.47. [α]_D= +56.7 (c = 1.0,

2096

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Eur. J. Org. Chem. 2008, 2084–2099

Maltose and Maltotriose Derivative

CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 3.24 (s, 6 H, OCH₃),

ethylamine (0.5 mL) and the reaction mixture neutralised with ace-

tic acid. The solvent was removed in vacuo and the residue purified

by flash chromatography (petroleum ether/ethyl acetate, 3:1) fur-

3

2

3

3.36 (dd, J_5,6= 2.0, J_6,6Ј= 9.3 Hz, 1 H, 6a-H), 3.49 (dd, J_1,2

=

3

3.6, ³J_3,2= 9.4 Hz, 1 H, 2c-H), 3.54 (dd, ³J_1,2= 3.4, J_3,2= 9.7 Hz,

1 H, 2b-H), 3.56–3.70 (m, 4 H, 2a-H, 6b-H, 4c-H, 6c-H), 3.74 (dd, nishing 66 (134 mg, 99.44 µmol, 88%) as colourless, highly viscous

2

³J_5,6= 2.0, J_6,6Ј= 9.6 Hz, 1 H, 6Јa-H), 3.77–3.81 (m, 1 H, 5b-H),

oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.35. [α]_D

=

3

3.82–3.89 (m, 3 H, 5a-H, 6Јb-H, 5c-H), 3.94 (dd, J_2,3

= =

³J_4,3

+64.9 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 3.21 (br.

9.6 Hz, 1 H, 3c-H), 3.98–4.06 (m, 2 H, 4a-H, 3b-H), 4.11–4.19 (m, s, 3 H, 6c-OCH₃), 3.28 (br. s, 3 H, 6a-OCH₃), 3.35 (dd, ³J_5,6= 2.0,

3 H, 3a-H, 4b-H, 6c-H), 4.41–4.60 (m, 7 H, PhCHH), 4.61–4.76 ²J_6,6Ј= 10.2 Hz, 1 H, 6c-H), 3.38 (dd, J_5,6= 2.0, J_6,6Ј= 9.5 Hz,

3

2

(m, 5 H, PhCHH), 4.79 (d, ²J = 11.6 Hz, 1 H, PhCHH), 4.81–4.88

1 H, 6a-H), 3.41–3.50 (m, 2 H, 6Јc-H, 2b-H), 3.53 (dd, J_1,2= 3.3,

3

(m, 2 H, 1a-H, PhCHH), 4.94 (d, ²J = 11.6 Hz, 1 H, PhCHH), 5.08 ²J_3,2= 8.8 Hz, 1 H, 2b-H), 3.56–3.67 (m, 3 H, 2a-H, 6b-H, 4c-H),

2

3

(d, J = 11.6 Hz, 1 H, PhCHH), 5.55 (s, 1 H, PhCH), 5.65 (d, J_2,13.69–3.80 (m, 3 H, 6Јa-H, 5b-H, 5c-H), 3.82–3.92 (m, 3 H, 5a-H,

= 3.3 Hz, 1 H, 1b-H), 5.72 (d, ³J_2,1= 3.7 Hz, 1 H, 1c-H), 7.01–7.53

(m, 45 H, Ph). C₈₂H₈₆O₁₆(1326.59): calcd. C 74.19, H 6.53; found

C 73.71, H 6.27.

6Јb-H, 3c-H), 3.96–4.06 (m, 2 H, 3b-H, 4a-H), 4.07–4.18 (m, 2 H,

3a-H, 4b-H), 4.42–4.60 (m, 10 H, PhCHH), 4.67–4.87 (m, 7 H, 1a-

H, PhCHH), 4.91 (d, ²J = 11.5 Hz, 1 H, PhCHH), 5.06 (d, ²J =

3

11.6 Hz, 1 H, PhCHH), 5.63 (d, J_2,1= 3.2 Hz, 1 H, 1b-H), 5.67

Benzyl O-(2,3,4-Tri-O-benzyl-α-

tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-benzyl-6-O-

methyl-α- -glucopyranoside (65): To a solution of 64 (400 mg,

D-glucopyranosyl)-(1Ǟ4)-O-(2,3,6-

3

(d, J_2,1= 3.3 Hz, 1 H, 1c-H), 7.08–7.48 (m, 45 H, Ph). C₈₃H₉₀O₁₆

D

(1343.62): calcd. C 74.20, H 6.75; found C 73.87, H 6.76.

D

0.301 mmol) in dry CH₂Cl₂(15.0 mL) was added a solution of bo-

rane in THF (3.01 mL, 1.0 ) and then a solution of Bu₂BOTf in

CH₂Cl₂(100 µL, 1.0 ). After 72 h the excess borane complex was

destroyed with methanol (20 mL) and the reaction mixture neutral-

ised with triethylamine. The mixture was concentrated in vacuo and

then purified by flash chromatography (petroleum ether/ethyl ace-

tate, 2:1) furnishing 65 (338 mg, 0.254 mmol, 84%) as colourless,

O-(6-O-Methyl-α-

syl)-(1Ǟ4)-6-O-methyl-α/β-

D

-glucopyranosyl)-(1Ǟ4)-O-(α-

D-glucopyrano-

D-glucopyranose (48): To a solution of

66 (150 mg, 0.112 mmol) in THF (10.0 mL) was added Pearlman

catalyst^[19](20.0 mg). Then the argon atmosphere was completely

replaced by hydrogen. After 72 h at room temp. the catalyst was

separated with celite and the celite washed with methanol

(3ϫ10 mL). Filtrate and wash solution were combined and the

solvent removed in vacuo. The residue was purified by flash

highly viscous oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f=

1

0.10. δ = +74.2 (c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ chromatography (CH₃CN/H₂O, 1:50; RP-18) and then lyophilised

= 1.63 (br. s, 1 H, OH), 3.26 (s, 3 H, OCH₃), 3.33–3.40 (m, 2 H, from D₂O furnishing 48 (53 mg, 0.101 mmol, 90%) as colourless

6a-H, 2c-H), 3.43–3.56 (m, 3 H, 2b-H, 4c-H, 6c-H), 3.57–3.70 (m,

4 H, 2a-H, 6b-H, 5c-H, 6Јc-H), 3.71–3.77 (m, 2 H, 6Јa-H, 5b-H), 0.45. HNMR (250 MHz, D₂O): δ = 3.05 (dd, J_1,2= 8.0, J_3,2

3.84–3.90 (m, 3 H, 5a-H, 6Јb-H, 3c-H), 3.95–4.09 (m, 3 H, 3b-H, 8.9 Hz, 0.6 H, 2a-H_β), 3.12–3.28 (m, 7 H, 4c-H, 6a-OCH₃, 6c-

4b-H, 4a-H), 4.13 (dd, ³J_2,3= ²J_4,3= 8.8 Hz, 1 H, 3a-H), 4.41–4.63

OCH₃), 3.29–3.88 (m, 16.4 H, 2a-H_α, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-

lyophilisate (α/β, 2:3; D₂O). TLC RP-18 (CH₃CN/H₂O, 1:50): R_f=

1

3

=

(m, 10 H, PhCHH), 4.65–4.88 (m, 7 H, 1a-H, PhCHH), 4.91 (d, ²J H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, 2c-H, 3c-H, 5c-H, 6c-

3

= 11.5 Hz, 1 H, PhCHH), 5.07 (d, ²J = 11.6 Hz, 1 H, PhCHH),

H, 6Јc-H), 4.42 (d, J_2,1= 8.0 Hz, 0.6 H, 1a-H_β), 4.99 (d, J_2,1=

3

5.55 (d, ³J_2,1= 3.4 Hz, 1 H, 1c-H), 5.65 (d, J_2,1= 3.3 Hz, 1 H, 1b-

3.7 Hz, 0.4 H, 1a-H_α), 5.18 (d, J_2,1= 3.6 Hz, 1 H, 1c-H), 5.22 (d,

³J_2,1= 3.4 Hz, 1 H, 1b-H). C₂₀H₃₆O₁₆·2.5H₂O (577.53): calcd. C

41.59, H 7.16; found C 41.60, H 6.86.

H), 7.07–7.47 (m, 45 H, Ph). C₈₂H₈₈O₁₆(1329.59): calcd. C 74.08,

H 6.67; found C 73.96, H 6.66.

O-(α-

D-Glucopyranosyl)-(1Ǟ4)-O-(α-

D-glucopyranosyl)-(1Ǟ4)-6-O-

Benzyl O-(2,3-Di-O-benzyl-4,6-O-benzylidene-α-

D-glucopyranosyl)-

methyl-α/β-

D

-glucopyranose (49): To a solution of 65 (150 mg, (1Ǟ4)-O-(2,3,6-tri-O-benzyl-α-

D

-glucopyranosyl)-(1Ǟ4)-2,3,6-tri-

0.113 mmol) in THF (10.0 mL) was added Pearlman catalyst^[19]

(20.0 mg). Then the argon atmosphere was completely replaced by

hydrogen. After 72 h at room temp. the catalyst was separated with

celite and the celite washed with methanol (3ϫ10 mL). Filtrate

and wash solution were combined and the solvent removed in

vacuo. The residue was purified by flash chromatography (CH₃CN/

H₂O, 1:100; RP-18) and then lyophilised from D₂O furnishing 49

(59 mg, 0.113 mmol, quant. as colourless lyophilisate (α/β, 2:3;

O-benzyl-α-D-glucopyranoside (67): To a solution of 6 (77.9 mg,

0.144 mmol, 1.0 equiv.) and 53 (200 mg, 0.216 mmol, 1.0 equiv.) in

dry diethyl ether (10 mL) at room temp. was added N-iodosuccin-

imide (48.6 mg, 0.216 mmol, 1.5 equiv.). The reaction was started

with catalytic amounts of trifluoromethanesulfonic acid (0.2 µL,

0.01 equiv.). After 30 min the reaction mixture was washed with

NaHCO₃solution (10.0 mL) and Na₂SO₃solution (3ϫ15 mL) and

dried with MgSO₄. The reaction mixture was concentrated in vacuo

and the residue purified by flash chromatography (a. toluene/ethyl

acetate, 50:1; b. toluene/ethyl acetate, 20:1) furnishing 67 (113 mg,

80.64 µmol, 56%) as colourless foam. TLC (toluene/ethyl acetate,

D₂O). TLC RP-18 (CH₃CN/H₂O, 1:100): R_f= 0.84. ¹H NMR

3

(250 MHz, D₂O): δ = 3.10 (dd, J_1,2

=

³J_3,2= 8.3 Hz, 0.6 H, 2a-

H_β), 3.16–3.31 (m, 4 H, 4c-H, OCH₃), 3.32–3.91 (m, 16.4 H, 1a-

H_α, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b- 20:1): R_f= 0.39. [α]_D= +52.0 (c = 1.0, CHCl₃). ¹H NMR

3

H, 6Јb-H, 2c-H, 3c-H, 5c-H, 6c-H, 6Јc-H), 4.48 (d, J_2,1= 8.0 Hz,

(600 MHz, CDCl₃): δ = 3.48–3.68 (m, 8 H, 2a-H, 6a-H, 6Јa-H, 2b-

3

0.6 H, 1a-H_β), 5.04 (d, J_2,1= 3.5 Hz, 0.4 H, 1a-H_α), 5.21 (d, J_2,1

H, 6b-H, 2c-H, 4c-H, 6c-H), 3.75–3.92 (m, 4 H, 5a-H, 5b-H, 6Јb-

3

= 3.5 Hz, 1 H, 1c-H), 5.28 (d, J_2,1= 3.5 Hz, 1 H, 1b-H).

H, 5c-H), 3.97 (dd, J_2,3

=

³J_4,3= 9.6 Hz, 1 H, 3c-H), 4.00–4.17

C₁₉H₃₄O₁₆·1.5H₂O (545.49): calcd. C 41.84, H 6.84; found C 41.65,

H 6.57.

(m, 5 H, 3a-H, 4a-H, 3b-H, 4b-H, 6c-H), 4.38–4.59 (m, 10 H,

PhCHH), 4.60–4.75 (m, 4 H, PhCHH), 4.77–4.87 (m, 3 H, 1a-H,

PhCHH), 4.92 (d, ²J = 11.6 Hz, 1 H, PhCHH), 5.06 (d, ²J =

11.5 Hz, 1 H, PhCHH), 5.53 (s, 1 H, PhCH), 5.60 (d, ³J_2,1= 3.2 Hz,

1 H, 1b-H), 5.71 (d, ³J_2,1= 3.7 Hz, 1 H, 1c-H), 7.04–7.51 (m, 50 H,

Ph). C₈₈H₉₀O₁₆(1403.67): calcd. C 75.30, H 6.46; found C 74.89, H

6.47.

Benzyl O-(2,3,4-Tri-O-benzyl-6-O-methyl-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-6-O-methyl-α- -glucopyranoside (66): To a solution of 65

D-glucopyranosyl)-

D

(150 mg, 0.113 mmol, 1.0 equiv.) in dry DMF (6.0 mL) at room

temp. was added methyl iodide (21.2 µL, 48.1 mg, 0.339 mmol,

3.0 equiv.) and then NaH (8.1 mg, 0.339 mmol, 3.0 equiv.). After Benzyl O-(2,3,4-Tri-O-benzyl-α-

D-glucopyranosyl)-(1Ǟ4)-O-(2,3,6-

24 h the reaction was quenched with methanol (10.0 mL) and tri- tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3,6-tri-O-benzyl-α-D-

D

Eur. J. Org. Chem. 2008, 2084–2099

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2097

H. Malik, W. Boos, R. R. Schmidt

FULL PAPER

glucopyranoside (68): To a solution of 67 (160 mg, 0.114 mmol) in

dry CH₂Cl₂(20.0 mL) was added a solution of borane in THF

(1.14 mL, 1.0 ) and then a solution of Bu₂BOTf in CH₂Cl₂

(25 µL, 1.0 ). After 72 h the excess borane complex was destroyed

with methanol (10 mL) and the reaction mixture neutralised with

triethylamine. The deposit was concentrated in vacuo and purified

by flash chromatography (petroleum ether/ethyl acetate, 3:1) fur-

nishing 68 (136 mg, 96.9 µmol, 85%) as colourless, highly viscous

Benzyl O-(6-Azido-2,3,4-tri-O-benzyl-6-deoxy-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-6-O-thexyldimethylsilyl-α- -glucopyranoside (70): 60

D-glucopyranosyl)-

D

(150 mg, 0.103 mmol, 1.0 equiv.) was dissolved with diisopropyl

azodicarboxylate (DIAD) (29.8 µL, 31.1 mg, 0.155 mmol,

1.5 equiv.) and triphenylphosphane (41 mg, 0.155 mmol, 1.5 equiv.)

in dry CH₂Cl₂(8.0 mL). At room temp. a solution of HN₃(6.7 mg,

0.155 mmol, 1.5 equiv.) in benzene (50 µL). After 3 h (TLC moni-

toring) the reaction mixture was diluted with NaHCO₃solution

(10 mL) and ethyl acetate (10 mL). The aqueous phase was ex-

tracted with ethyl acetate (3ϫ20 mL). The solvent was removed

oil. TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.27. [α]_D

=

+63.0 (c = 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 1.61 (br.

3

s, 1 H, OH), 3.37 (dd, ³J_1,2= 3.5, J_3,2= 9.5 Hz, 1 H, 2c-H), 3.43–

3.52 (m, 4 H, 2b-H, 6b-H, 4c-H, 6c-H), 3.53–3.65 (m, 4 H, 2a-H, from the combined organic phases in vacuo, then the residue puri-

6a-H, 5c-H, 6Јc-H), 3.68 (dd, ³J_5,6= 2.2, ³J_6,6Ј= 10.9 Hz, 1 H, 6Јb-

H), 3.81–3.93 (m, 4 H, 5a-H, 6Јa-H, 5b-H, 3c-H), 3.99–4.10 (m, 3

fied by flash chromatography (toluene/ethyl acetate, 50:1) furnish-

ing 70 (104 mg, 70.04 µmol, 68%) as colourless, highly viscous oil.

H, 4a-H, 3b-H, 4b-H), 4.14 (dd, ³J_2,3= ³J_4,3= 9.5 Hz, 1 H, 3a-H), TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.73. [α]_D= +75.5

1

4.36–4.62 (m, 12 H, PhCHH), 4.66–4.72 (m, 2 H, PhCHH), 4.73–

(c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ = 0.10, 0.12 (2s,

4.86 (m, 5 H, 1a-H, PhCHH), 4.91 (d, ²J = 11.6 Hz, 1 H, PhCHH), 6 H, Si(CH₃)₂), 0.84–0.89 (m, 12 H, 2C(CH₃)₂), 1.62 (hept, ³J =

2

3

5.06 (d, J = 11.5 Hz, 1 H, PhCHH), 5.56 (d, J_2,1= 3.4 Hz, 1 H,

6.8 Hz, 1 H, CH(CH₃)₂), 3.13 (dd, J_5,6= 3.3, J_6,6Ј= 12.5 Hz, 1

1c-H), 5.62 (d, ³J_2,1= 3.4 Hz, 1 H, 1b-H), 7.04–7.49 (m, 50 H, Ph). H, 6c-H), 3.29 (dd, J_5,6Ј= 2.5, J_6,6Ј= 12.5 Hz, 1 H, 6Јc-H), 3.45

3

C₈₈H₉₂O₁₆(1405.69): calcd. C 75.19, H 6.60; found C 74.78, H (dd, J_1,2= 3.5, J_3,2= 9.4 Hz, 1 H, 2c-H), 3.46–3.58 (m, 3 H, 2a-

6.97.

3

H, 2b-H, 4c-H), 3.66 (dd, J_5,6= 2.0, J_6,6Ј= 10.9 Hz, 1 H, 6b-H),

3.78–3.95 (m, 8 H, 4a-H, 5a-H, 6a-H, 6Јa-H, 5b-H, 6Јb-H, 3c-H,

3

Benzyl O-(2,3,4-Tri-O-benzyl-6-O-triisopropylsilyl-α-D-glucopyr-

5c-H), 4.03 (dd, J_2,3= J_4,3= 9.2 Hz, 1 H, 3b-H), 4.09 (dd, J_3,4

3

anosyl)-(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α-

D-glucopyranosyl)-(1Ǟ4)-

= J_5,4= 9.3 Hz, 1 H, 4b-H), 4.16 (dd, J_2,3= J_4,3= 9.2 Hz, 1 H,

3a-H), 4.43–4.61 (m, 10 H, PhCHH), 4.70–4.78 (m, 3 H, PhCHH),

4.81 (d, J_2,1= 3.3 Hz, 1 H, 1a-H), 4.82–4.95 (m, 4 H, PhCHH),

2,3,6-tri-O-benzyl-α- -glucopyranoside (69): To a solution of 68

D

3

(300 mg, 0.213 mmol, 1.0 equiv.) in dry CH₂Cl₂(10.0 mL) at room

temp. was added triisopropylsilyl chloride (100.68 µL, 90.62 mg,

0.47 mmol, 2.2 equiv.) and imidazole (44 mg, 0.640 mmol,

3.0 equiv.). After 50 h (TLC monitoring) the solvent was removed

in vacuo and the residue purified by flash chromatography (petro-

leum ether/ethyl acetate, 3:1) furnishing 69 (304 mg, 0.195 mmol,

92%) as colourless, highly viscous oil. TLC (petroleum ether/ethyl

2

5.04 (d, J = 11.5 Hz, 1 H, PhCHH), 5.62–5.67 (m, 2 H, 1b-H, 1c-

H), 7.05–7.49 (m, 45 H, Ph). C₈₉H₁₀₃N₃O₁₅Si (1482.90): calcd. C

72.09, H 7.00, N 2.83; found C 71.88, H 7.07, N 2.45.

Benzyl O-(6-Azido-2,3,4-tri-O-benzyl-6-deoxy-α-

(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3-di-O-

benzyl-α- -glucopyranoside (71): To a solution of 70 (70 mg,

D-glucopyranosyl)-

D

1

acetate, 3:1): R_f= 0.67. [α]_D= +55.0 (c = 1.0, CHCl₃). H NMR

47.21 µmol, 1.0 equiv.) in THF (5.0 mL) at room temp. was added

portionwise a solution of TBAF in THF (94.4 µL, 1 , 2.0 equiv.).

After 40 h the reaction mixture was neutralised with acetic acid

and the deposit concentrated in vacuo. The residue was purified by

flash chromatography (petroleum ether/ethyl acetate, 3:1) furnish-

ing 71 (58 mg, 43.26 µmol, 92%) as colourless, highly viscous oil.

TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.18. [α]_D= +76.0

(600 MHz, CDCl₃): δ = 0.95–1.04 (m, 21 H, SiCH(CH₃)₂), 3.42

3

(dd, J_1,2= 3.5, J_3,2= 9.1 Hz, 1 H, 2c-H), 3.53–3.57 (m, 3 H, 2b-

H, 6b-H, 6a-H), 3.58–3.64 (m, 2 H, 2a-H, 5c-H), 3.67–3.75 (m, 3

3

H, 6Јa-H, 4c-H, 6c-H), 3.80 (dd, J_5,6= 2.5, J_6,6Ј= 10.7 Hz, 1 H,

3

6Јc-H), 3.84 (dd, J_5,6= 2.5, J_6,6Ј= 10.8 Hz, 1 H, 6Јb-H), 3.87–

3.94 (m, 3 H, 5a-H, 5b-H, 3c-H), 4.01–4.20 (m, 4 H, 3a-H, 4a-H,

3b-H, 4b-H), 4.39–4.63 (m, 11 H, PhCHH), 4.68–4.91 (m, 1a-H,

PhCHH), 4.93 (d, ²J = 11.7 Hz, 1 H, PhCHH), 5.06 (d, ²J =

11.5 Hz, 1 H, PhCHH), 5.63 (d, ³J_2,1= 3.2 Hz, 1 H, 1b-H), 5.66 (d,

³J_2,1= 3.4 Hz, 1 H, 1c-H), 7.10–7.48 (m, 50 H, Ph). C₉₇H₁₁₂O₁₆Si

(1562.03): calcd. C 74.59, H 7.23; found C 74.49, H 7.27.

1

(c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ = 3.00 (br. s, 1

3

H, OH), 3.16 (dd, J_5,6= 3.4, J_6,6Ј= 12.6 Hz, 1 H, 6c-H), 3.26

3

(dd, J_5,6Ј= 2.5, J_6,6Ј= 12.6 Hz, 1 H, 6Јc-H), 3.36–3.44 (m, 2 H,

2c-H, 4c-H), 3.55 (dd, ³J_1,2= 3.6, J_3,2= 8.8 Hz, 1 H, 2b-H), 3.58–

3

3.65 (m, 3 H, 2a-H, 6b-H, 5c-H), 3.66–3.75 (m, 2 H, 6a-H, 6Јb-H),

3.76–3.83 (m, 3 H, 5a-H, 4b-H, 3c-H), 3.93–4.01 (m, 3 H, 6Јa-H,

O-(6-O-Triisopropylsilyl-α-

D-glucopyranosyl)-(1Ǟ4)-O-(α-D-gluco-

3

3b-H, 5b-H), 4.07 (dd, J_3,4= ³J_5,4= 9.5 Hz, 1 H, 4a-H), 4.17 (dd,

pyranosyl)-(1Ǟ4)-α/β- -glucopyranose (47): To a solution of 69

D

3

³J_2,3= J_4,3= 9.7 Hz, 1 H, 3a-H), 4.41–4.63 (m, 10 H, PhCHH),

(200 mg, 0.128 mmol) in dioxane (8.0 mL) was added Pearlman

catalyst^[19](20 mg). Then the argon atmosphere was completely re-

placed by hydrogen. After 5 h at room temp. the catalyst was sepa-

rated with celite and the celite washed with methanol/water

(3ϫ10 mL). Filtrate and wash solution were combined and the sol-

vent removed in vacuo. The residue was purified by flash

chromatography (CH₃CN/H₂O, 1:1; RP-18) and then lyophilised

from D₂O furnishing 47 (85 mg, 0.128 mmol, quant. as colourless

lyophilisate (α/β, 2:3; D₂O). TLC RP-18 (CH₃CN/H₂O, 1:1): R_f=

4.67 (d, ²J = 11.4 Hz, 1 H, PhCHH), 4.69–4.76 (m, 3 H, PhCHH),

4.77–4.88 (m, 4 H, 1a-H, PhCHH), 5.08 (d, ²J = 11.8 Hz, 1 H,

PhCHH), 5.47 (d, ³J_2,1= 3.5 Hz, 1 H, 1c-H), 5.71 (d, ³J_2,1= 3.8 Hz,

1 H, 1b-H), 7.01–7.48 (m, 45 H, Ph). C₈₁H₈₅N₃O₁₅(1339.60): calcd.

C 72.57, H 6.39, N 3.13; found C 72.11, H 6.36, N 2.75.

O-(6-Amino-6-deoxy-α-

pyranosyl)-(1Ǟ4)-α/β- -glucopyranoside (46): To a solution of 71

(175 mg, 0.132 mmol) in THF/H₂O, 7:1 (17.0 mL) was added Pearl-

D-glucopyranosyl)-(1Ǟ4)-O-(α-D-gluco-

D

0.50. ¹H NMR (250 MHz, D₂O): δ = 0.80–1.18 (m, 21 H, man catalyst^[19](15 mg) and catalytic amounts of acetic acid

SiCH(CH₃)₂), 3.05–3.23 (m, 1.6 H, 2a-H_β, 4c-H), 3.33–3.97 (m,

16.4 H, 2a-H_α, 3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H,

(20 µL). Then the argon atmosphere was completely replaced by

hydrogen. After 72 h at room temp. the catalyst was separated with

5b-H, 6b-H, 6Јb-H, 2c-H, 3c-H, 4c-H, 5c-H, 6c-H, 6Јc-H), 4.48 (d, celite and the celite washed with methanol/water (3ϫ10 mL). Fil-

3

³J_2,1= 8.0 Hz, 0.6 H, 1a-H_β), 5.06 (d, J_2,1= 3.5 Hz, 0.4 H, 1a-

trate and wash solution were combined and the solvent removed in

H_α), 5.16–5.28 (m, 2 H, 1b-H, 1c-H). MALDI MS: m/z = 683 vacuo. The residue was purified by flash chromatography (EtOH/

[MNa⁺], 699 [MK⁺]. C₂₇H₅₂O₁₆Si·2H₂O (696.81): calcd. C 46.54,

H 8.10; found C 46.35, H 7.72.

H₂O/HCl, 10:1000:1; RP-18) and then lyophilised as hydrochloride

from D₂O furnishing 46 (35 mg, 66 µmol, 50%) as colourless lyo-

2098

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2084–2099

Maltose and Maltotriose Derivative

[4] J. C. Spurlino, G. Y. Lu, F. A. Quiocho, J. Biol. Chem. 1991,

266, 5205–5219.

philisate (α/β, 2:3; D₂O). TLC RP-18 (H₂O/AcOH, 100:1): R_f=

0.81. ¹H NMR (250 MHz, D₂O): δ = 2.93–4.92 (m, 18 H, 2a-H,

3a-H, 4a-H, 5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H,

[5] F. A. Quiocho, J. C. Spurlino, L. E. Rodseth, Structure 1997, 5,

997–1015.

3

6Јb-H, 2c-H, 3c-H, 4c-H, 5c-H, 6c-H, 6Јc-H), 4.48 (d, J_2,1

=

[6] T. Ferenci, M. Muir, K.-S. Lee, D. Maris, Biochim. Biophys.

Acta 1986, 860, 44–50.

3

7.9 Hz, 0.6 H, 1a-H_β), 5.05 (d, J_2,1= 3.4 Hz, 0.4 H, 1a-H_α), 5.26–

3

5.32 (m, 1 H, 1b-H), 5.45 (d, J_2,1= 3.7 Hz, 1 H, 1c-H). MALDI

[7]

[8]

J. Lehmann, L. Ziser, Carbohydr. Res. 1990, 205, 93–103.

C. Brunkhorst, C. Anderson, E. Schneider, J. Bacteriol. 1999,

181, 2612–2619.

MS: m/z = 526 [MNa⁺], 542 [MK⁺]. C₁₈H₃₃NO₁₅·HCl (539.92).

The physical data are in accordance with the literature.^[37]

[9]

G. Grundler, R. R. Schmidt, Liebigs Ann. Chem. 1984, 1826–

Benzyl O-(2,3,4-Tri-O-benzyl-6-bromo-6-deoxy-α-

syl)-(1Ǟ4)-O-(2,3,6-tri-O-benzyl-α- -glucopyranosyl)-(1Ǟ4)-2,3,6-

tri-O-benzyl-α- -glucopyranoside (72): To a solution of 68 (110 mg,

D-glucopyrano-

1847.

D

[10]

[11]

L. Jang, T. H. Chan, Tetrahedron Lett. 1998, 39, 355–358.

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O. Mitsunobu, Synthesis 1981, 1–28.

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D

78.25 µmol, 1.0 equiv.) and tetrabromomethane (39 mg,

0.117 mmol, 1.5 equiv.) in dry CH₂Cl₂(10.0 mL) at room temp. was

added triphenyl phosphane (31 mg, 0.117 mmol, 1.5 equiv.). After

6 h the solvent was removed in vacuo and the residue purified by

flash chromatography (petroleum ether/ethyl acetate, 4:1) furnish-

ing 72 (101 mg, 68.9 µmol, 88%) as colourless, highly viscous oil.

TLC (petroleum ether/ethyl acetate, 3:1): R_f= 0.59. [α]_D= +57.0

[12]

[13]

[14]

P. J. Garegg, H. Hultberg, S. Wallin, Carbohydr. Res. 1982, 108,

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449–464.

[16]

1

3

(c = 1.0, CHCl₃). H NMR (600 MHz, CDCl₃): δ = 3.37 (dd, J_5,6

3

= 2.0, J_6,6Ј= 11.0 Hz, 1 H, 6c-H), 3.43–3.50 (m, 2 H, 2c-H, 6Јc-

T. Eisele, H. Ishida, G. Hummel, R. R. Schmidt, Liebigs Ann.

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1975, 53, 2182–2188.

H), 3.52–3.69 (m, 5 H, 2a-H, 6a-H, 2b-H, 6b-H, 4c-H), 3.74 (dd,

³J_5,6= 2.5, ³J_6,6Ј= 10.9 Hz, 1 H, 6Јa-H), 3.77–3.83 (m, 1 H, 5c-H),

[17]

3.85–3.99 (m, 4 H, 5a-H, 5b-H, 6Јb-H, 3c-H), 4.02–4.12 (m, 3 H,

[18]

[19]

3

4a-H, 3b-H, 4b-H), 4.17 (dd, J_2,3

=

³J_4,3= 9.8 Hz, 1 H, 3a-H),

4.43–4.64 (m, 11 H, PhCHH), 4.67–4.79 (m, 4 H, PhCHH), 4.81–

4.90 (m, 3 H, 1a-H, PhCHH), 4.91–4.96 (m, 2 H, PhCHH), 5.09

[20]

[21]

[22]

[23]

[24]

[25]

2

3

(d, J = 11.6 Hz, 1 H, PhCHH), 5.64 (d, J_2,1= 3.4 Hz, 1 H, 1b-

3

H), 5.67 (d, J_2,1= 3.5 Hz, 1 H, 1c-H), 7.03–7.50 (m, 50 H, Ph).

C₈₈H₉₁BrO₁₅(1468.59): calcd. C 71.97, H 6.25; found C 71.77, H

6.34.

O-(6-Bromo-6-deoxy-α-

D-glucopyranosyl)-(1Ǟ4)-O-(α-D-gluco-

pyranosyl)-(1Ǟ4)-α/β- -glucopyranose (51): To a solution of 72

D

(244 mg, 0.166 mmol) in dioxane (15.0 mL) was added Pearlman

catalyst^[19](20 mg). Then the argon atmosphere was completely re-

placed by hydrogen. After 8 h at room temp. the catalyst was

separated with celite and the celite washed with methanol/water

(3ϫ10 mL). Filtrate and wash solution were combined and the sol-

vent removed in vacuo. The residue was purified by flash

chromatography (CH₃CN/H₂O, 1:100; RP-18) and then lyophilised

from D₂O furnishing 51 (71 mg, 0.125 mmol, 75%) as colourless

K. Bock, H. Pedersen, Acta Chem. Scand., B 1987, 41, 617–

628.

R. Appel, Angew. Chem. 1975, 87, 863–874; Angew. Chem. Int.

Ed. Engl. 1975, 14, 801–820.

N. S. Mani, Indian J. Chem. Sect., B 1989, 28, 602–603.

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2902.

K. E. Krakowiak, J. Heterocycl. Chem. 1998, 35, 519–524.

A. K. Kulyassa, P. Herczegh, F. J. Sztaricskai, J. Antibiot. 2000,

53, 1207–1211.

J. Michel, Dissertation, University of Konstanz, Germany,

1983.

H. J. Böhm, G. Klebe, H. Kubinyi, Wirkstoffdesign, Spektrum

Verlag, Heidelberg, Berlin, Oxford, 1996, pp. 95–111.

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46, 143–148.

[26]

[27]

[28]

[29]

lyophilisate (α/β, 2:3; D₂O). TLC RP-18 (CH₃CN/H₂O, 1:100): R_f

3

= 0.52. ¹H NMR (250 MHz, D₂O): δ = 3.10 (dd, J_1,2

= =

³J_3,2

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

8.2 Hz, 0.6 H, 2a-H_β), 3.24–3.89 (m, 17.4 H, 2a-H_α, 3a-H, 4a-H,

5a-H, 6a-H, 6Јa-H, 2b-H, 3b-H, 4b-H, 5b-H, 6b-H, 6Јb-H, 2c-H,

3

3c-H, 4c-H, 5c-H, 6c-H, 6Јc-H), 4.49 (d, J_2,1= 8.0 Hz, 0.6 H, 1a-

3

H_β), 5.10 (d, J_2,1= 3.6 Hz, 0.4 H, 1a-H_α), 5.19–5.30 (m, 2 H, 1b-

H, 1c-H). MALDI MS: m/z = 589, 591 [MNa⁺], 605, 507 [MK⁺].

C₁₈H₃₁BrO₁₅(567.34).

G. H. Veeneman, S. H. V. Leeuwen, J. H. Van Boom, Tetrahe-

dron Lett. 1990, 31, 1331–1334.

Acknowledgments

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This work was supported by the Deutsche Forschungsgemeinschaft

and the Fonds der Chemischen Industrie.

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Received: November 30, 2007

Published Online: February 28, 2008

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www.eurjoc.org

2099

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Maltose and maltotriose derivatives as potential inhibitors of the maltose-binding protein

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