Synthesis of novel di- and trisaccharide mimetics with non-glycosidic amino bridges

FULL PAPER

DOI: 10.1002/ejoc.200600958

Synthesis of Novel Di- and Trisaccharide Mimetics with Non-Glycosidic Amino

Bridges

Janna Neumann,^[a]Saskia Weingarten,^[a]and Joachim Thiem*^[a]

Keywords: Carbohydrates / Saccharide mimetics / Enzymatic glycosylation / Reductive amination / Dess–Martin oxidation /

Non-glycosidically amino-bridged saccharides

Synthesis of novel di- and trisaccharides using enzymatic

glycosylation, Dess–Martin oxidation and reductive amin-

ation allows rapid access to the target structures. Thus, a

novel class of glycomimetics was obtained having nitrogen

inserted as bridging atom between two non-anomeric posi-

tions. Novel di- and trisaccharide mimetics were designed

using N-acetylglucosamine as a basis structure. A third

monosaccharide unit was attached via an unnatural sugar–

sugar bond without participation of the anomeric center.

Their synthesis, proceeding via oxidation, glycosylation and

reductive amination, required only a few steps, thus allowing

rapid access to the target structures. Generation of the novel

pseudo-disaccharide was achieved by Dess–Martin oxidation

and a subsequent reductive amination.

Germany, 2007)

thetic access to such glycomimetics in a few facile and high

yielding steps. Of utmost importance are selective reactions,

and both classical chemical as well as enzyme-catalysed

transformations have to be considered. Due to the complex-

ity of conventional oligosaccharide synthesis, enzymatic

methods have experienced growing interest,^[2–6]since no

protection and deprotection steps are required and thus a

rapid access to natural oligosaccharides is provided. How-

ever, so far application of enzymes for the formation of un-

natural compounds is poorly investigated. Therefore, spe-

cial emphasis in this project was on investigating enzymes

for such a synthetic task.

As a common structural element in many biologically

important glycoconjugates, such as N-linked oligosaccha-

rides, human milk oligosaccharides^[7]and ligands of various

lectins,^[8–10]N-acetyl-lactosamine (LacNAc) represented a

promising basis for the design of interesting glycomimetics.

To provide an element of resistance to enzymatic degrada-

tion another monosaccharide unit should be attached to the

disaccharide via an unnatural sugar-sugar bond, without

participation of anomeric centers (Figure 1). It can be ex-

pected that such a bond would not be cleaved by glycosid-

ases. Further, the additional carbohydrate substituent may

be supposed to exhibit a masking effect for the intraglycos-

idic LacNAc linkage^[11]and thus prevent its cleavage by gly-

cosidases as well.

Introduction

The important role of carbohydrate derivatives in vital

biological recognition processes has increasingly stimulated

efforts in glycoconjugate research. Thus, biology studies re-

quire facile accesses to substantial quantities of complex

oligosaccharides and glycoconjugates. Unnatural and modi-

fied oligosaccharides are needed as potential drug candi-

dates as well as for the investigation of glycoconjugate

structure-function relationships in biochemical processes.

However, in contrast to other classes of natural products

the synthesis of oligosaccharides needs individual protect-

ing and activating groups and linking strategies. Universally

applicable methodologies are seldomly available, thus

mostly multiple step synthetic pathways are required. On

the other hand carbohydrate components are often rather

labile in vivo, since they are rapidly metabolised. Therefore,

unnatural or modified oligosaccharides are of interest for

investigation of glycoconjugate structure-function relation-

ships as well as modulation or inhibition of biochemical

processes. Such components termed glycomimetics are

mostly non-natural carbohydrate-derived structures, which

imitate or mimic the function of specific natural carbo-

hydrate derivatives.^[1]It can be expected that they show en-

hanced stability in vivo, particularly towards glycosidases

and thus allow to study specific biological properties.

In this contribution an approach toward a novel class of

glycomimetics is described. Emphasis was less on the syn-

thesis of certain structures, but rather on the development

of a fast and convenient methodology, which allows syn-

Most previously described glycomimetics^[12]contain

carba-^[13]or azasugars, with the ring-oxygen substituted by

carbon or nitrogen,^[14,15]or as in the C-glycosides having

carbon instead of the anomeric oxygen.^[16]Here it was en-

visaged to have nitrogen as a flexible bridging atom between

two non-anomeric positions to arrive at a novel class of

glycomimetics, not described so far.

[a] University of Hamburg, Faculty of Science, Department of

Chemistry,

Martin-Luther-King-Platz 6, 20146 Hamburg, Germany

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Figure 1. General synthetic Scheme.

Thus, a synthetic approach to such glycomimetics start-

ing with the three components A to C was dissected into

three tasks: derivatization to generate aldehyde- or amino-

functionalized saccharides, glycosylation to give LacNAc

disaccharides and reductive amination to join the corre-

sponding units (Figure 1).

substituted donor 5 was achieved in three steps. Esterifica-

tion of 1 at C-6 with sulfonic acids gave the tosylate 2 or

the mesylate 3 straightforwardly. Since the tosylate 2 could

be too bulky to be accepted in the enzymatic glycosylation,

the smaller mesylate 3 was prepared as well. Both sulfonates

could be transferred into the desired azide 4 in 60% yield

with some 4-nitrophenyl 3,6-anhydro-β--galactopyrano-

side as by-product. Final reduction of 4 in a Staudinger

reaction gave the crystalline amine 5 in 94% yield.^[17]

It was further of interest to investigate whether or not a

donor structure with an aldehyde functionality would be

accepted by this β-galactosidase. Therefore, the monosac-

charide 13^[18]was synthesized bearing a substituent which

can be transformed into an aldehyde group by ozonolysis.

Starting with diacetone--galactose (7)^[19]the 6-O-allyl

ether 8 was prepared by phase-transfer catalysis according

Results and Discussion

Synthesis of Modified Galactosyl Donors

Modified galactose units B to be attached enzymatically

to N-acetylglucosamine structures A employing the β-galac-

tosidase (Bacillus circulans) to form β 1–4-linked LacNAc

structures require the formation of various p-nitrophenyl β-

-galactopyranosides (Scheme 1). Synthesis of the 6-amino- to Paulsen et al.^[20]Further peracetylation, followed by re-

Scheme 1. Synthesis of modified pNPGal derivatives.

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J. Neumann, S. Weingarten, J. Thiem

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gioselective deacetylation at the anomeric center, then

transformation into the trichloroacetimidate 10,^[21]glycosy-

lation with p-nitrophenol and deacetylation gave the β-gal-

actopyranoside 12. Employing the 6,7-olefin derivative 9,^[22]

transformation into compound 11 and further into 13 was

performed correspondingly.

Cleavage of the olefinic compound 13 by ozonolysis led

to the aldehyde 6 in a 47% yield. A much more efficient

synthesis of aldehyde 6 could be performed by selective oxi-

dation of pNP β--galactopyranoside (1). Best yields were

obtained by galactose oxidase catalysed oxidation,^[23]which

gave the product 6 in nearly quantitative yield.

amido group at C-2 is required to control the regioselectiv-

ity, in other cases, e.g. with a hydroxyl group at C-2, a mix-

ture of β 1–3-, β 1–4-, and β 1–6-linked regioisomeric disac-

charides were obtained.^[25]

Glycosidases often show a considerable flexibility with

respect to variation of acceptor structures, but are mostly

restricted to special donor structures. Concerning the β-gal-

actosidase from Bacillus circulans different saccharides were

recognized as acceptor molecules, however so far, there

were only two derivatised galactosides published as donor

molecules for the β-galactosidase from Bacillus circul-

ans.^[23,25,26]These results indicate that the primary alcohol

function does not seem to be essential for recognition by

the enzyme.

With the array of pNP galactopyranosides (Scheme 1) it

could be investigated whether or not and to which extent

β-Galactosidase Catalysed Glycosylation

A synthetic access to the LacNAc-type disaccharides can these could function as donor substrates for β-galactosidase

be achieved in a few steps, carrying out the glycosylation from Bacillus circulans. As uniform acceptor substrates 2-

by chemo-enzymatic methods. For this, an appropriate en- acetamido-2-deoxy--glucopyranose (14) as well as allyl 2-

zyme is the β-galactosidase from Bacillus circulans which acetamido-2-deoxy-α--glucopyranoside (15) were used in

catalyses the formation of a β 1–4 linkage, between a galac- the enzymatic glycosylation. Reactions with compound 15

tosyl donor and a 2-acetamido-glycosyl acceptor. The gal- were performed at room temperature for 3 days, while reac-

actosidase from B. circulans is especially attractive for ex- tions with GlcNAc (14) required 3 h at 55 °C.^[27]Under

ploitation, due to its high yields and its extraordinary re- these conditions, neither the 6-O-mesylate 3 nor the 6-

gioselectivity. Generally, the β 1–4-linked product is formed azido-6-deoxy 4 compounds were accepted by the enzyme.

almost exclusively, with less than 5% β 1–6 isomer. Yields However, reaction of amine 5 with acceptor 15 could be

range from 18 to 66%, depending on the donor’s leaving achieved and resulted in the formation of allyl 6-amino-6-

group and the utilized acceptor. These synthetic yields are deoxy-β--galactopyranosyl-(1Ǟ4)-2-acetamido-2-deoxy-

quite considerable under the aspect that the natural task of α--glucopyranoside (21). Surprisingly, the 6,7-olefin struc-

glycosidases is to cleave oligosaccharides. As donor leaving ture 13 could be readily glycosylated to give both the disac-

groups, glucose, p-nitrophenol and o-nitrophenol are com- charides allyl 6,7-dideoxy-β--galacto-hept-6-enopyranosyl-

mon but also others were investigated.^[24]The acceptor may (1Ǟ4)-2-acetamido-2-deoxy-α--glucopyranoside (23) and

have a glucosyl or a galactosyl α/β-configuration with its 6,7-dideoxy-β--galacto-hept-6-enopyranosyl-(1Ǟ4)-2-acet-

anomeric center either unprotected or protected. An acet- amido-2-deoxy--glucopyranose (18) in 31% and 20%

Scheme 2. Enzymatic galactosylation employing modified pNPGal donors.

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yield, respectively. Again, 4-nitrophenyl 6-O-allyl-β--galac-

topyranoside (12) was not recognized. Reaction of the C-6

oxidized donor 4-nitrophenyl β--galacto-hexodialdopyr-

anoside^[23](6) could be confirmed, and the disacccharide

allyl β--galacto-hexodialdopyranosyl-(1Ǟ4)-2-acetamido-

2-deoxy-α--glucopyranoside (22) was isolated in 68%

yield. Further reactions employing the donors pNP-Fuc

(16) and pNP-Ara (17) led to disaccharides 19 (66%) and

24 (76%) as well as 20 (6%) and 25 (13%), (Scheme 2) indi-

cating excellent substrate properties of the 6-deoxy--gal-

acto derivative in contrast to the -arabino derivative. All

yields refer to the amount of donor substrates used in the

reactions.

2-amino-1,5-anhydro-glucitol 29 were selected. The linkage

formation was easily done with sodium cyanoborohydride

in aqueous methanol at pH 6 and room temperature. Thus,

the 2–6 via N-linked Gal-GlcN structures 32–34 could be

obtained in 80%, almost quantitative, and 74% yield,

respectively. In the latter case as side product the cyano ad-

duct 34b was observed in 24% yield.

Treatment of the same aldehyde with the 6-amino

GlcNAc components 30 and 31, obtained by Staudinger

reduction^[33]from the corresponding 6-azido precursors^[34]

again in about 50% yield gave the N-linked Gal-GlcNAc

structures 35 and 36 this time via a 6–6 bridge. In both

these cases the cyano adducts 35b and 36b (Scheme 3) ap-

peared as side products in 10–30% yield.

En route to more advantageous preparation of aldehydo

sugar derivatives the Dess–Martin oxidation^[35]could be

employed. Treatment of the GlcNAc glycosides 15^[36]and

37^[37]as well as the 1,5-anhydro-glucitol derivative 38^[38]

with freshly prepared periodinane^[39]gave the aldehydo

compounds 39–41. Without optimization they could be ob-

tained in up to 50% yield.

Thus, the β-galactosidase from B. circulans showed a

high flexibility with regard to C-6-modified galactopyrano-

side donor substrates.

Reductive Amination

According to the general Scheme linking of the ald-

ehydo- and amino-functionalized saccharide units would

As above, their transfer into 2–6 via N-linked disaccha-

have to be performed mildly by reductive amination.^[28–30]ride mimetics could be accomplished with allyl α--glucosa-

For initial studies the easily accessible diisopropylidene al- mine 28 and 2-amino-1,5-anhydro-glucitol 29. Thus com-

dehydo galactose 26^[19,31]was chosen. As 2-amino sugars pounds 43 and 44 were prepared in 50–80%, respectively.

the glucoamine derivatives 27^[32]and 28, obtained from 15 Correspondingly, with benzyl α-galactosamine 42 the mi-

using a method according to Wong et al.,^[23]as well as the metic structure 45 (Scheme 4) was obtained in 80% yield.

Scheme 3. Synthesis of disaccharide mimetics by reductive amination I.

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Scheme 4. Synthesis of disaccharide mimetics by reductive animation II.

Finally it was of interest to employ a disaccharide alde- as the substrate for the reductive aminations. As amino

hyde with monosaccharide amines along the original out- monosaccharide structures the 2-amino-1,5-anhydro-gluci-

line. Thus, the C-6Ј-oxidized LacNAc 22, obtained in good tol 29 and the benzyl glycoside of the 6-amino GlcNAc 31

yields by galactosidase-catalyzed glycosylation was chosen were selected. Following the facily employed standard con-

Scheme 5. Reductive amination towards novel trisaccharide mimetics.

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potassium phosphate buffer (1 mL) pH 7.0 was added. The reac-

tion mixture was stirred for 3 d at room temperature. The reaction

was stopped by short heating to 100 °C. The solvents were removed

by freeze drying, and the residue was purified by gelpermeation

chromatography using biogel P2 and water as eluent.

ditions the reductive amination gave in quite satisfying

yields the novel trisaccharide derivatives 46 and 47

(Scheme 5) comprising 6–6- and 6–2-N-linked glycosylated

LacNAc mimetics. At room temperature complete

conversion of the starting materials needed 4 days but by

General Procedure 2: β-Galactosidase-catalysed glycosylation with

2-acetamido-2-deoxy--glucopyranose (14) as acceptor: Glycosyl

donor (150 µmol) and 2-acetamido-2-deoxy--glucopyranose (14)

(300 mg, 1.36 mmol, 9 equiv.) were dissolved in 50 m sodium ace-

tate buffer (4 mL) pH 5.0 at 55 °C. Then a solution of 10 mg β-

galactosidase (80 µL, 4 U) from B. circulans in 50 m potassium

phosphate buffer (1 mL) pH 7.0 was added. The reaction mixture

was incubated for 3 h at 55 °C, during which time the solution be-

came bright yellow. The reaction was stopped by short heating to

100 °C. The solvents were removed by freeze drying, and the resi-

due was purified by gelpermeation chromatography using biogel P2

and water as the eluent.

performing the reaction at 100 °C in

a

micro-

wave oven

achieved.

a remarkable acceleration to 5 min was

Conclusion

To summarize the results, facile and rapid accesses to

novel glycomimetics were elaborated employing among

other reactions galactose oxidase-catalysed oxidation of

pNP β--galactopyranoside, β-galactosidase-catalysed gly-

cosylation, and finally reductive aminations with amino-

functionalized carbohydrate units. The yields over all steps

were up to about 50%. The enzymatic glycosylation with β-

galactosidase (from Bacillus circulans) showed considerable

flexibility for the enzyme substrates thus allowing for the

synthesis of unusual disaccharide derivatives. Dess–Martin

oxidation was found to be a selective chemical method to

oxidize primary alcohol groups to aldehyde groups which

could be reacted selectively with amino-functionalized

carbohydrates to form novel pseudo-disaccharides. The for-

mation of naturally occurring β-glycosides from easily

cleavable α-allyl LacNAc structures will be addressed in fur-

ther studies.

Reductive Amination. General Procedure 3: To a solution of alde-

hyde (0.15 mmol) and amine (0.45 mmol, 3 equiv.) in methanol

(1 mL) was added water dropwise to reach complete solution. The

pH of the solution was adjusted to 6 using either a 1  solution of

glacial acetic acid in methanol or a solution of 10% triethylamine

in methanol. Then a 0.3  methanolic sodium cyanoborohydride

solution (0.2 to 0.25 mL) was added. The reaction mixture was

stirred overnight and then concentrated. The residue was purified

by column chromatography.

General Procedure 4: To a solution of aldehyde (0.36 mmol) in

methanol (2.5 mL) and amine (1.02 mmol) in methanol (1.0 mL)

was added water dropwise to reach complete solution. The pH of

the solution was adjusted to 6 using a solution of 10% triethyl-

amine in methanol (0.05 mL). Then a 0.3  methanolic sodium cy-

anoborohydride solution (0.6 mL) was added and the mixture was

stirred at room temp. overnight. The solution was concentrated and

the residue was purified by gelpermeation chromatography on se-

phadex LH20 (water/methanol, 1:1).

Experimental Section

General Remarks: TLC was performed on aluminium sheets coated

with silica gel 60 (Merck) with UV detection by heating with

H₂SO₄(10% in EtOH). Aldehydes were detected by heating with

2,4-dinitrophenylhydrazine (0.2  HCl) and amino-functionalized

compounds with ninhydrine (0.2  EtOH). Column chromatog-

raphy was carried out on silica gel 60 (0.04–0.063 mm; Merck).

Gelpermeation chromatography was carried out on Biogel P2 or

Biogel P4 with bidistilled water or on Sephadex LH20 with bidis-

tilled water/methanol (1:1). NMR spectra were recorded with a

Bruker AMX-400 NMR (¹³C: 100 MHz) or a DRX-500 NMR

spectrometer (¹³C: 125 MHz) and analyzed with the solvent peaks

as references. Mass spectra were recorded with a Bruker Biflex II

(MALDI-TOF, positive reflection mode, matrix: 2,5-dihydroxyben-

zoic acid) and with a VG Analytical 70–250S mass spectrometer

(FAB mass spectra, m-nitrobenzyl alcohol). Melting points were

determined with apotec melting point apparatus and are uncor-

rected. The optical rotations were measured on a Perkin–Elmer 341

polarimeter at 20 °C.

Staudinger Reduction. General Procedure 5: The azide (1 mmol) was

dissolved in THF/H₂O (4:1, 45 mL) and treated with tri-

phenylphosphane (0.36 g, 1.36 mmol, 1.4 equiv.) and silica gel

(1.00 g). The reaction mixture was stirred overnight at 50 °C, then

the solvent was removed under reduced pressure and the residue

purified by column chromatography.

4-Nitrophenyl 6-O-Tosyl-β-D-galactopyranoside (2): To a solution of

compound 1 (1.80, 5.97 mmol) in pyridine (25 mL) was added

dropwise at 0 °C tosyl chloride (1.40 g, 7.34 mmol) dissolved in

pyridine (5.5 mL). After stirring for 2 h at room temperature the

reaction was quenched by adding water (100 mL). The product was

extracted using ethyl acetate, and the organic phase was washed

with 5% hydrochloric acid, water and then dried with MgSO₄. Af-

ter filtration the solvent was removed under reduced pressure and

the residue was purified by column chromatography on silica gel

(DCM/MeOH, 7:1) to give 2 (1.40 g, 51%) as a colourless solid,

1

m.p. 81 °C, [α]²_D⁰= –100 (c = 0.5, CH₃OH). H NMR (500 MHz,

Enzymes were from Sigma Aldrich (β-Galactosidase: Lactase, EC

3.2.1.23, Biolacta^®; Galactose Oxidase: -Galactose: oxygen 6-ox-

idoreductase, EC 1.1.3.9).

MeOD): δ = 8.19 (m, 2 H, pNP), 7.74 (m, 2 H, CH-Ts), 7.31 (m,

2 H, CH-Ts), 7.17 (m, 2 H, pNP), 5.00 (d, J_1,2= 7.9 Hz, 1 H, 1-

H), 4.31 (dd, J_5,6a= 4.1, J_6a,6b= 10.7 Hz, 1 H, 6a-H), 4.27 (dd,

Enzymatic Glycosylation. General Procedure 1: β-Galactosidase-ca-

talysed glycosylation with allyl 2-acetamido-2-deoxy-α--glucopyr-

anoside (15) as acceptor: Glycosyl donor (100 µmol) and allyl 2-

J_5,6b= 7.9 Hz, 1 H, 6b-H), 4.05 (dd, 1 H, 5-H), 3.89 (d, J_3,4=

3.5 Hz, 1 H, 4-H), 3.81 (dd, J_2,3= 9.8 Hz, 1 H, 2-H), 3.61 (dd, 1

H, 3-H), 2.40 (s, 3 H, CH₃-Ts) ppm. ¹³C NMR (100 MHz, MeOD):

acetamido-2-deoxy-α--glucopyranoside (15) (261 mg, 1 mmol, δ = 164.11, 146.95, 144.29, 134.71 (2ϫ C-pNP, 2ϫ C-Ts), 131.37

10 equiv.) were dissolved in 50 m potassium phosphate buffer

(1.4 mL) pH 7.0 and acetonitrile (1.4 mL). Then a solution of

10 mg β-galactosidase (142 µL, 7 U) from B. circulans in 50 m

(CH-Ts), 129.62 (CH-Ts), 127.10 (CH-pNP), 118.19 (CH-pNP),

102.15 (C-1), 74.76, 74.73 (C-3, C-5), 72.08 (C-2), 71.16 (C-6),

70.35 (C-4), 21.93 (CH₃-Ts) ppm.

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4-Nitrophenyl 6-O-Mesyl-β-

D

-galactopyranoside (3): To a solution

188 °C (dec.), [α]²_D⁰= –66 (c = 0.28, CH₃OH). ¹H NMR (400 MHz,

MeOD): δ = 8.30 (m, 2 H, pNP), 7.33 (m, 2 H, pNP), 5.16 (d, J_1,2

= 7.6 Hz, 1 H, 1-H), 3.99 (d, J_3,4= 3.3 Hz, 1 H, 4-H), 3.93 (m, 2

of compound 1 (180 mg 0.598 mmol) in pyridine (7.5 mL), mes-

ylchloride (57.5 µL, 0.745 mmol) was added dropwise at 0 °C. After

stirring for 5.5 h at 0 °C the reaction was quenched by addition of

water. The solution was concentrated and the residue was purified

by column chromatography on silica gel (DCM/MeOH, 7:1). Prod-

uct 3 (143 mg, 63%) was obtained as a colourless solid; m.p.

155 °C, [α]²_D⁰= –93 (c = 0.25, CH₃OH). ¹H NMR (400 MHz, D₂O):

δ = 8.12 (m, 2 H, pNP), 7.10 (m, 2 H, pNP), 5.10 (d, J_1,2= 7.6 Hz,

H, 2-H, 5-H), 3.72 (dd, J_2,3= 9.7 Hz, 1 H, 3-H), 3.22 (dd, J_5,6a

=

7.6, J_6a,6b= 13.5 Hz, 1 H, 6a-H), 3.10 (dd, J_5,6b= 4.3 Hz, 1 H, 6b-

H) ppm. ¹³C NMR (100 MHz, MeOD): δ = 164.22 (C-pNP),

143.00 (C-pNP), 127.08 (CH-pNP), 118.06 (CH-pNP), 102.44 (C-

1), 75.71 (C-5), 74.89 (C-3), 72.09 (C-2), 71.43 (C-4), 42.90 (C-6)

ppm. C₁₂H₁₆N₂O₇(300.3): calcd. C 48.00, H 5.37, N 9.33; found

1 H, 1-H), 4.41 (dd, J_5,6a= 3.8, 1 H, J_6a,6b= 11.2 Hz, 6a-H), 4.35 C 44.55, H 5.69, N 7.74. Contamination of amine 5 was detected.

(dd, J_5,6b= 8.2 Hz, 1 H, 6b-H), 4.11 (dd, 1 H, 5-H), 3.93 (d, J_3,4

4-Nitrophenyl β-D-galacto-Hexodialdo-1,5-pyranoside (6)

= 3.3 Hz, 1 H, 4-H), 3.75 (dd, J_2,3= 10.2 Hz, 1 H, 2-H), 3.67 (dd,

1 H, 3-H), 3.00 (s, 3 H, CH₃-Ms) ppm. ¹³C NMR (100 MHz, D₂O):

δ = 162.05 (C-pNP), 146.95 (C-pNP), 126.44 (CH-pNP), 116.85

(CH-pNP), 100.06 (C-1), 73.42 (C-5), 72.61 (C-3), 70.50 (C-2),

70.03 (C-6), 68.50 (C-4), 36.95 (CH₃-Ms) ppm. C₁₃H₁₇NO₁₀S

(379.3): calcd. C 41.16, H 4.52, N 3.69; found C 41.10, H 4.65, N

3.68.

Synthesis by Ozonolysis: Under argon a solution of compound 13

(300 mg, 1.01 mmol) and sodium hydrogen carbonate (128 mg) in

dry DCM/MeOH (5:1, 6 mL) was cooled to –50 °C. Ozone was

added until the reaction mixture remained blue after 2.5 h. Excess

of ozone was removed by discharging argon through the flask.

Then triphenylphosphane (291 mg) was added and the mixture was

stirred at room temperature for 36 h. The reaction mixture was

concentrated and the residue was purified by column chromatog-

raphy (DCM/MeOH, 9:1) to give 6 (143 mg, 47%) as a colourless

solid.

4-Nitrophenyl 6-Azido-6-deoxy-β-D-galactopyranoside (4)

Synthesis Starting from Tosylate 2: Compound

2

(1.46 g,

3.21 mmol) and sodium azide (1.05 g, 16.2 mmol) were dissolved

in dry DMF (40 mL) and stirred for 14 h at 80 °C. Then the reac-

tion mixture was cooled to room temperature and concentrated.

The residue was taken up in ethyl acetate, washed with water, dried

with MgSO₄, filtered, concentrated in vacuo and subsequently

purified by flash chromatography on silica gel (DCM/MeOH, 12:1)

to give 4 (0.63 g, 60%).

Synthesis by Enzymatic Oxidation: A solution of compound 1

(303 mg, 1.01 mmol) and 500 m aqueous copper sulfate (10 µL)

in potassium phosphate buffer pH 7 (14 mL) were treated with cat-

alase (90 µL, 3120 U) and galactose-oxidase (90 µL, 90 U) under

oxygen atmosphere at room temperature for one day. The reaction

was stopped by adding methanol (4 mL), the solvent was evapo-

rated and the water was removed by freeze drying. The crude prod-

uct (580 mg) contained product and salts. 102 mg of the crude

product were purified by column chromatography (DCM/MeOH,

10:1) to give 6 (55 mg, 98%) as hydrate; m.p. 154 °C, [α]²_D⁰= –87 (c

= 0.15, H₂O), R_F= 0.29 (DCM/MeOH, 7:1). ¹H NMR (400 MHz,

Synthesis Starting from Mesylate 3: Compound

3 (117 mg,

0.31 mmol) and sodium azide (100 mg, 1.54 mmol) were dissolved

in dry DMF (4 mL) and stirred for 5 h at 80 °C. Then the reaction

mixture was cooled to room temperature and concentrated. The

residue was purified by flash chromatography on silica gel (DCM/

MeOH, 12:1) to give 4-nitrophenyl 3,6-anhydro-β--galactopyr-

anoside (53 mg, 60%) and 4-nitrophenyl 6-azido-6-deoxy-β--gal-

actopyranoside (4) (39 mg, 39%).

D₂O): δ = 8.24 (m, 2 H, pNP), 7.22 (m, 2 H, pNP), 5.16 (d, J_1,2

7.9 Hz, 1 H, 1-H), 5.11 (d, J_5,6= 7.4 Hz, 1 H, 6-H), 4.14 (d, J_3,4

=

3.3 Hz, 1 H, 4-H), 3.85 (dd, J_2,3= 9.2 Hz, 1 H, 2-H), 3.75 (dd, 1

H, 3-H), 3.61 (d, 1 H, 5-H) ppm. ¹³C NMR (100 MHz, D₂O): δ =

142.96 (C-pNP), 126.49 (CH-pNP), 116.87 (CH-pNP), 100.52 (C-

1), 88.46 (C-6), 77.66 (C-5), 72.77 (C-3), 70.58 (C-2), 68.43 (C-4)

ppm.

4-Nitrophenyl 6-Azido-6-deoxy-β-D-galactopyranoside (4): Colour-

less solid, m.p. 205 °C (dec.), [α]²_D⁰= –224 (c = 0.15, CH₃OH). H

NMR (400 MHz, MeOD): δ = 8.22 (m, 2 H, pNP), 7.25 (m, 2 H,

pNP), 5.08 (d, J_1,2= 7.6 Hz, 1 H, 1-H), 3.93 (ddd, J_4,5= 1.0, J_5,6a

1

= 8.4 Hz, 1 H, 5-H), 3.84 (m, 2 H, 2-H, 4-H), 3.65 (dd, J_6a,6b

=

6-O-Allyl-D-galactopyranose (8): 1. Allyl bromide (31 mL), tetrabu-

12.7 Hz, 1 H, 6a-H), 3.63 (dd, J_2,3= 9.9, J_3,4= 3.3 Hz, 1 H, 3-H),

3.35 (dd, J_5,6b= 4.1 Hz, 1 H, 6b-H) ppm. ¹³C NMR (100 MHz,

MeOD): δ = 127.01 (CH-pNP), 118.08 (CH-pNP), 102.31 (C-1),

76.38 (C-5), 74.85 (C-3), 72.15, 70.90 (C-2, C-4), 52.94 (C-6) ppm.

C₁₂H₁₄N₄O₇(326.3): calcd. C 44.17, H 4.32, N 17.17; found C

44.19, H 4.52, N 16.54.

tylammonium hydrogen sulfate (6.53 g), and compound 7^[19]

(5.07 g, 19.5 mmol) were vigorously stirred in a mixture consisting

of dichloromethane (400 mL) and 50% sodium hydroxide solution

(400 mL). After 5 h at room temperature the layers were separated.

The aqueous layer was extracted with dichloromethane, the com-

bined organic layers were washed with water, dried with MgSO₄,

filtered and concentrated. Purification by column chromatography

(PE/EE, 6:1) yielded 6-O-allyl-1,2:3,4-di-O-isopropylidene-α--gal-

actopyranose (4.57 g, 78%). Colourless syrup, [α]²_D⁰= –60 (c = 0.5,

CHCl₃), ref.^[40][α]²_D⁰= –71.8, ref.^[40]b.p._0.03= 86 °C, R_F= 0.39 (PE/

EE, 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 5.79 (ddd, J_CH-All,=CH2t

4-Nitrophenyl 3,6-Anhydro-β-D

-galactopyranoside: ¹H NMR

(400 MHz, [D₆]DMSO): δ = 8.21 (m, 2 H, pNP), 7.19 (m, 2 H,

pNP), 5.82 (d, J_2-OH,2= 4.6 Hz, 1 H, 2-OH), 5.44 (s, 1 H, 1-H),

5.38 (d, J_4-OH,4= 3.8 Hz, 1 H, 4-OH), 4.27 (dd, J_4,5= 1.8 Hz, 1 H,

4-H), 4.22 (dd, J_5,6b= 2.8 Hz, 1 H, 5-H), 4.09 (d, J_2,3= 4.6 Hz, 1

H, 3-H), 4.05 (dd, 1 H, 2-H), 3.85 (d, J_6a,b= 9.7 Hz, 1 H, 6a-H),

3.80 (dd, 1 H, 6b-H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ =

162.00 (C-pNP), 141.80 (C-pNP), 126.17 (CH-pNP), 116.89 (CH-

pNP), 99.67 (C-1), 80.91 (C-3), 78.57 (C-5), 72.54 (C-2), 69.94 (C-

6), 69.38 (C-4) ppm.

= 17.3, J_CH-All,=CH2c= 10.7 Hz, 1 H, CH-All), 5.41 (d, J_1,2

=

5.1 Hz, 1 H, 1-H), 5.15 (dd, J_=CH2c,=CH2t= 1.5 Hz, 1 H, =CH_2t-

All), 5.05 (d, 1 H, =CH_2c-All), 4.47 (dd, J_2,3= 2.5, J_3,4= 8.1 Hz,1

H, 3-H), 4.19 (dd, 1 H, 2-H), 4.13 (dd, J_4,5= 2.0 Hz, 1 H, 4-H),

3.94–3.90 (m, 2 H, -CH₂-All), 3.85 (dd, J_5,6a= 5.6, J_5,6b= 6.6 Hz,

1 H, 5-H), 3.53 (dd, J_6a,6b= 10.2 Hz, 1 H, 6a-H), 3.46 (dd, 1 H,

6b-H), 1.42 (s, 3 H, -CH₃), 1.32 (s, 3 H, -CH₃), 1.21 (s, 3 H, -CH₃),

1.19 (s, 3 H, -CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 134.22

(CH-All), 117.50 (=CH₂-All), 109.61 [-C(CH₃)₂], 108.81

[-C(CH₃)₂], 96.80 (C-1), 74.00 (-CH₂-All), 72.86 (C-4), 71.20 (C-3),

4-Nitrophenyl 6-Amino-6-deoxy-β-D-galactopyranoside (5): Azide 4

(90 mg, 0.27 mmol) was reacted according to general procedure 5.

The product was purified by flash chromatography on silica gel [1.

EE/MeOH (2:1) + 3% pyridine, 2. EE/MeOH (1:4) + 3% pyridine].

The amine 5 (76 mg, 94%) could be isolated as a yellow solid. M.p.

1136

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Eur. J. Org. Chem. 2007, 1130–1144

Saccharide Mimetics with Non-Glycosidic Amino Bridges

FULL PAPER

71.10 (C-2), 69.02 (C-6), 67.15 (C-5), 26.22, 26.05, 25.00, 24.45

(4ϫ -CH₃) ppm.

2,3,4-tri-O-acetyl-6-O-allyl--galactopyranose (2.42 g, 6.99 mmol)

was dissolved in dry dichloromethane (27 mL) and treated with

trichloroacetonitrile (8.72 mL, 86.96 mmol, 12.44 equiv.). A solu-

tion of 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) in dry dichloro-

methane (1.0 mL, 0.78 mmol DBU) was added dropwise, until the

reaction mixture became deep brown. Stirring was continued at

room temperature for 2.5 h, then the mixture was concentrated and

purified by column chromatography (PE/EE, 3:1) to give 10 (1.86 g,

54%) as a colourless solid; m.p. 112 °C, R_F= 0.75 (PE/EE, 1:1),

2. To a solution of 0.10  hydrochloric acid (1060 mL, 106 mmol,

1.02 equiv.) and methanol (105 mL) was added 6-O-allyl-1,2:3,4-di-

O-isopropylidene-α--galactopyranose (31.36 g, 104.4 mmol). Af-

ter stirring for 2.5 h at 90 °C the reaction mixture was cooled to

room temperature, neutralized with saturated sodium hydrogen car-

bonate solution and concentrated. Inorganic salts were removed by

filtration through silica gel (chloroform/methanol, 6:1) to give 8

(26.02 g) as crude brown syrup, which was used in the following

reaction without further purification.

1

[α]²_D⁰= +100 (c = 0.50, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

8.56 (s, 1 H, =NH), 6.47 (d, J_1,2= 3.5 Hz, 1 H, 1-H), 5.74 (dddd,

J_CH-All,=CH2c= 10.4, J_CH-All,=CH2t= 17.3, J_{CH2-All,CH-All}= 4.4,

J_{CH2-All,CH-All}= 5.7 Hz, 1 H, CH-All), 5.54 (d, J_3,4= 2.7, J_4,5

=

A small amount of 8 was crystallized, washed with chloroform and

characterized: colourless solid, m.p. 85 °C, [α]²_D⁰= –10 (c = 0.38,

H₂O), R_F= 0.70 (EE/MeOH/H₂O, 7:3:1). ¹H NMR (400 MHz,

0.8 Hz, 1 H, 4-H), 5.37 (dd, J_2,3= 11.1 Hz, 1 H, 3-H), 5.30 (dd, 1

H, 2-H), 5.15 (dd, J_=CH2c,=CH2t= 1.3 Hz, 1 H, =CH₂-All), 5.09 (dd,

1 H, =CH₂-All), 4.32 (dd ≈ t, J_5,6a= 6.0, J_5,6b= 6.6 Hz, 1 H, 5-

H), 3.91 (dd, J_{CH2-All,CH2-All}= 12.9 Hz, 1 H, -CH₂-All), 3.82 (dd,

1 H, -CH₂-All), 3.47 (dd, J_6a,6b= 9.9 Hz, 1 H, 6a-H), 3.38 (dd, 1

H, 6b-H), 2.09 (s, 3 H, -CH₃), 1.96 (s, 3 H, -CH₃), 1.94 (s, 3 H,

-CH₃) ppm. ¹³C (125 MHz, CDCl₃): δ ≈ 170.4 (3ϫ CO-Ac), 134.44

(CH-All), 118.07 (=CH₂-All), 94.15 (C-1), 72.84 (CH₂-All), 71.06

(C-2), 70.52 (C-3), 68.38 (C-4), 67.83 (C-6), 66.71 (C-5), ≈ 21.1 (3ϫ

CH₃-Ac) ppm.

MeOD): δ = 6.11 (m, 1 H, CH-All), 5.47 (dd, J_=CH2c,=CH2t

=

0.8 Hz, 1 H, =CH_2c-All), 5.33 (m, J_CH-All,=CH2t= 17.3 Hz, 2 H,

=CH_2t-All, 1-H), 4.34 (dd ≈ t, J_5,6a= 6.6, J_5,6b= 5.6 Hz, 1 H, 5-

H), 4.22 (m, 3 H, 2-H, -CH₂-All), 4.06 (dd, J_3,4= 3.1, J_4,5= 1.3 Hz,

1 H, 4-H), 3.96 (dd, 1 H, 3-H), 3.92 (dd, J_1,2= 3.6, J_2,3= 10.4 Hz,

1 H, 2-H), 3.84 (m, 2 H, 6a-H, 6b-H) ppm. ¹³C NMR (100 MHz,

MeOD): δ = 136.50, 136.47 (CH-All), 117.79 (=CH₂-All), 99.11

(C-1β), 94.63 (C-1α), 75.40, 74.15 (C-5), 73.73, 73.67 (-CH₂-All),

71.68, 71.61 (C-4), 71.28, 71.11 (C-6), 71.02, 70.81, 70.44 71.20 (C-

3, C-2) ppm.

2,3,4-Tri-O-acetyl-6,7-dideoxy-α-D-galacto-hept-6-enopyranosyl

Trichloroacetimidate (11): Compound 9^[22](12.90 g, 2.9 mmol) was

dissolved and stirred in dry pyridine (40 mL). Acetic anhydride

(7.4 mL, 78.3 mmol) was added and the reaction mixture was

stirred at room temperature overnight. Then pyridine was removed

2,3,4-Tri-O-acetyl-6-O-allyl-α-

D-galactopyranosyl

Trichloroacet-

imidate (10): Compound 8 (1.46 g, 6.76 mmol) dissolved in pyridine

(90 mL) was cooled in an ice bath, and acetic anhydride (18 mL)

was added dropwise. After 19 h stirring at room temperature the by co-distillation with toluene (50 mL), and the product was puri-

reaction mixture was diluted with toluene (30 mL), concentrated,

codistilled with toluene, and the crude 1,2,3,4-tetra-O-acetyl-6-O-

allyl--galactopyranose was dried in vacuo. 1,2,3,4-Tetra-O-acetyl-

6-O-allyl--galactopyranose (2.85 g, 7.34 mmol) was dissolved in

DMF (5.9 mL), ammonium carbonate (1.06 g, 13.58 mmol,

1.85 equiv.) was added and the reaction mixture was stirred at room

temperature overnight. Dilution with dichloromethane (70 mL)

was followed by excessive washing with brine. The aqueous phases

were extracted with dichloromethane (30 mL), the combined or-

ganic phases dried with Na₂SO₄, filtered and concentrated. The

product was isolated by column chromatography (toluene/EE, 1:1)

to give 2,3,4-tri-O-acetyl-6-O-allyl--galactopyranose (1.59 g, 62%)

fied by column chromatography (PE/EE, 4:1) to give 1,2,3,4-tetra-

O-acetyl-6,7-dideoxy--galacto-hept-6-enopyranose (3.30 g, 74%).

This intermediate was dissolved in dry DMF (19 mL), hydrazine

acetate (0.93 g, 15.7 mmol) was added and the mixture was stirred

for 2 h at 60 °C. The reaction was terminated by addition of ethyl

acetate (60 mL) and brine, then washed with water, dried with

Na₂SO₄and concentrated in vacuo. After purification by column

chromatography (PE/EE, 3:1) 2,3,4-tri-O-acetyl-6,7-dideoxy--gal-

acto-hept-6-enopyranose was isolated as a colourless oil (934 mg,

25%). ¹H NMR (400 MHz, CDCl₃): δ = 5.66 (dddd, J_5,6= 5.1 Hz,

1 H, 6-H), 5.46 (d, J_1α,2α= 3.3 Hz, 1 H, 1α-H), 5.40–5.02 (m, J_6,7c

= 10.7, J_6,7t= 16.3 Hz, 5 H, 2α+β-H, 3α+β-H, 4α+β-H, 7aα+β-H,

7bα+β-H), 4.74–4.66 (m, 2 H, 5α-H, 1β-H), 4.20–4.17 (m, 1 H, 5β-

H), 2.05 (s, 3 H, Ac), 2.02 (s, 3 H, Ac), 1.92 (s, 3 H, Ac) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 171.70 (CO-Ac), 171.00 (CO-Ac),

170.98 (CO-Ac), 133.07 (C-6), 118.18 (C-7), 95.90 (C-1β), 90.77 (C-

1α), 74.12 (C-5β), 71.55, 69.19, 68.35 (C-2, C-3, C-4), 20.99, 20.96,

20.90 (3ϫ CH₃-Ac) ppm. Under argon a solution of 2,3,4-tri-O-

acetyl-6,7-dideoxy--galacto-hept-6-enopyranose (2.38 g,

7.87 mmol) in dry dichloromethane (30 mL) was treated with trich-

loroacetonitrile (9.8 mL) and 1.6 mL of a solution of DBU

(0.73 mL) in dry dichloromethane (5.5 mL). The red-brown col-

oured solution was stirred for 2.5 h at room temperature, then con-

as a colourless solid; m.p. 108 °C, R_F= 0.62 (PE/EE, 1:1), [α]²_D⁰

=

+91 (c = 0.35, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 5.99

(dddd, J_CH-All,=CH2c= 8.9, J_CH-All,=CH2t= 17.3, J_{CH2-All,CHAll}= 5.9,

J_{CH2-All,CHAll}= 6.1 Hz, 1 H, CH-All), 5.65 (d, J_1α,2α= 3.8 Hz, 0.72

H, 1α-H), 5.61 (d, J_3α,4α= 3.4, J_4,5= 0.8 Hz, 0.72 H, 4α-H), 5.55

(dd, 0.72 H, 3α-H), 5.40 (dd, J_=CH2c,=CH2t= 1.5 Hz, 1 H, =CH_2t-

All), 5.34 (dd, 1 H, =CH_2c-All), 5.30 (dd, J_2α,3α= 10.9 Hz, 0.72 H,

2α-H), 5.26 (dd, J_2β,3β= 10.9, J_3β,4β= 2.8 Hz, 0.28 H, 3β-H), 5.21

(dd, J_1β,2β= 7.7 Hz, 0.28 H, 2β-H), 4.87 (d, 0.28 H, 1β-H), 4.59

(dd, J_5α,6aα= 7.4, J_5α,6bα= 4.7 Hz, 0.72 H, 5α-H), 4.16 (dd, 0.28

H, -CH₂-Allβ), 4.13 (dd, J_{CH2-All,CH2-All}= 13.1, J_CH2-All,=CH2

=

1.8 Hz, 0.72 H, -CH₂-Allα), 4.10 (dd, 0.72 H, -CH₂-Allα), 4.09 (d, centrated and the residue was purified by flash chromatography

0.28 H, 4β-H), 4.07 (dd, 0.28 H, -CH₂-Allβ), 4.03 (dd, J_5β,6aβ

=

(PE/EE, 6:1). Product 11 (2.63 g, 75%) was obtained as a colourless

solid; m.p. 92 °C, [α]²_D⁰= +128 (c = 0.75, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 8.57 (s, 1 H, NH), 6.58 (d, J_1,2= 3.6 Hz,

1 H, 1-H), 5.64 (ddd, J_6,7c= 10.7, J_6,7t= 17.3 Hz, 1 H, 6-H), 5.47

6.7, J_5β,6bβ= 4.9 Hz, 0.28 H, 5β-H), 3.71 (dd, J_6aβ,6bβ= 10.1 Hz,

0.28 H, 6aβ-H), 3.64 (dd, J_6aα,6bα= 10.8 Hz, 0.72 H, 6aα-H), 3.58

(dd, 0.28 H, 6bβ-H), 3.57 (dd, 0.72 H, 6bα-H), 2.26 (s, 3 H, Ac),

2.22 (s, 3 H, Ac), 2.13 (s, 3 H, Ac) ppm. ¹³C NMR (125 MHz, (dd, J_4,5= 1.0 Hz, 1 H, 4-H), 5.41 (dd, J_2,3= 10.7, J_3,4= 3.1 Hz,

CDCl₃): δ ≈ 170.5 (3ϫ CO-Ac), 134.33 (CH-All), 118.42 (-CH₂- 1 H, 3-H), 5.32 (dd, 1 H, 2-H), 5.30 (ddd, J_7c,7t= 1.3 Hz, 1 H, 7_t-

Allα), 118.22 (-CH₂-Allβ), 96.19 (C-1β), 90.96 (C-1α), 72.78 (-CH₂-

All); 69.40 (C-2), 68.26 (C-6), 68.22 (C-4), 67.94 (C-3), 67.71 (C-

H), 5.19 (ddd, 1 H, 7_c-H), 4.66 (dd, J_5,6= 5.3 Hz, 1 H, 5-H), 2.07

(s, 3 H, Ac), 1.96 (s, 3 H, Ac), 1.94 (s, 3 H, Ac) ppm. ¹³C NMR

5), ≈21.0 (3ϫ CH₃-Ac) ppm. C₁₇H₂₂NO₉Cl₃(490.7): MALDI- (100 MHz, CDCl₃): δ = 170.65, 170.53, 170.43 (3ϫ CO-Ac), 161.40

TOF-MS: m/z = 385.01 [M + Na]⁺, 369.08 [M + K]⁺. Under argon

(-C=NH), 131.93 (C-6), 119.20 (C-7), 94.19 (C-1), 72.37 (C-5),

Eur. J. Org. Chem. 2007, 1130–1144

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1137

J. Neumann, S. Weingarten, J. Thiem

70.21 (C-4), 68.17 (C-3), 67.41 (C-2), 21.10, 21.00, 20.97 (3ϫ CH₃- All), 5.39 (dd, 1 H, =CH₂-All), 5.25 (d, J_1,2= 7.6 Hz, 1 H, 1-H),

FULL PAPER

Ac) ppm.

4.29–4.25 (m, 2 H, -CH₂-All), 4.17–4.11 (m, 2 H, 4-H, 5-H), 4.06

(dd, J_2,3= 9.7 Hz, 1 H, 2-H), 3.94 (dd, J_5,6a= 4.8, J_6a,6b= 10.2 Hz,

4-Nitrophenyl 6-O-Allyl-β-D-galactopyranoside (12): Under argon

1 H, 6a-H), 3.91 (dd, J_5,6b= 3.3 Hz, 1 H, 6b-H), 3.84 (dd, J_3,4

=

compound 10 (1.86 g, 3.79 mmol) was dissolved in dry dichloro-

methane (10 mL), cooled to –10 °C and stirred. Then p-nitrophenol

(525 mg, 3.79 mmol) and boron trifluoride–diethyl ether (0.5 mL,

3.79 mmol) were added. The reaction mixture was stirred at –10 °C

for 2.5 h then diluted with dichloromethane (7 mL) and neutralized

with saturated aqueous sodium hydrogen carbonate solution. The

organic phase was washed with water, dried with Na₂SO₄, filtered

and concentrated in vacuo. The remaining residue was purified by

column chromatography (PE/EE, 3:1) to give 4-nitrophenyl 2,3,4-

tri-O-acetyl-6-O-allyl-β--galactopyranoside (935 mg, 53%). N-

(2,3,4-Tri-O-acetyl-6-O-allyl-α--galactopyranosyl)trichloroacet-

amide (658 mg, 35%) and 4-nitrophenyl 2,3,4-tri-O-acetyl-6-O-al-

lyl-α--galactopyranoside (14 mg, 11%) were isolated as by-prod-

ucts.

3.3 Hz, 1 H, 3-H) ppm. ¹³C NMR (100 MHz, MeOD): δ = 164.34

(C-pNP), 142.76 (C-pNP), 136.48 (CH-All), 126.95 (CH-pNP),

118.18 (CH-pNP), 117.43 (=CH₂-All), 102.55 (C-1), 76.13 (C-4 or

C-5), 75.09 (C-3), 73.68 (-CH₂-All), 72.39 (C-2), 70.88 (C-6), 70.72

(C-4 or C-5) ppm. C₁₅H₁₉NO₈(341.3): calcd. C 52.78, H 5.61, N

4.10; found C 52.62, H 5.64, N 3.89. FAB-MS: m/z = 342.2 [M +

H]⁺.

4-Nitrophenyl 6,7-Dideoxy-β-D-galacto-hept-6-enopyranoside (13):

Under argon compound 11 (223 mg, 0.50 mmol) and p-nitrophenol

(70 mg, 0.50 mmol) were dissolved in dichloromethane (1 mL) and

cooled to –10 °C. Boron trifluoride etherate (12 µL) was added and

stirred for 2 h at this temperature. The solution was neutralized

with saturated sodium hydrogen carbonate solution and extracted

with dichloromethane. The organic layers were washed with water,

dried and concentrated. The residue was purified by column

chromatography (PE/EE, 4:1). 4-Nitrophenyl 2,3,4-tri-O-acetyl-6,7-

dideoxy-β--galacto-hept-6-enopyranoside (145 mg, 68%) was ob-

tained as a colourless solid; m.p. 162 °C (ref.^[41]164 °C), [α]²_D⁰= +6

4-Nitrophenyl 2,3,4-Tri-O-acetyl-6-O-allyl-β-D-galactopyranoside:

Colourless foam, [α]²_D⁰= –2 (c = 0.60, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 8.14 (m, 2 H, pNP), 7.03 (m, 2 H, pNP), 5.76 (dddd,

J_CH-All,=CH2c= 10.4, J_CH-All,=CH2t= 17.8 Hz, 1 H, CH-All), 5.45

(dd, J_2,3= 10.2 Hz, 1 H, 2-H), 5.44 (dd, J_4,5= 0.8 Hz, 1 H, 4-H),

5.17 (dddd ≈ dq, J_=CH2c,=CH2t= 1.8 Hz, 1 H, =CH_2t-All), 5.13

(dddd ≈ dq, J_CH2-All,=CH2= 1.8 Hz, 1 H, =CH_2c-All), 5.09 (d, J_1,2

= 7.9 Hz, 1 H, 1-H), 5.07 (dd, J_3,4= 3.6 Hz, 1 H, 3-H), 3.97 (ddd

≈ dt, J_5,6a= 5.8, J_5,6b= 5.4 Hz, 1 H, 5-H), 3.93–3.88 (m, 2 H,

-CH₂-All), 3.51–3.47 (m, 2 H, 6a-H, 6b-H), 2.11 (s, 3 H, Ac), 2.00

(s, 3 H, Ac), 1.95 (s, 3 H, Ac) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 170.68, 170.48, 169.71 (3ϫ CO-Ac), 161.82 (C-pNP), 143.56

(C-pNP), 134.37 (CH-All), 126.21 (CH-pNP), 118.04 (=CH₂-All),

117.03 (CH-pNP), 99.17 (C-1), 73.70 (C-5), 72.91 (-CH₂-All), 71.22

(C-3), 69.00 (C-4), 68.18 (C-6), 67.79 (C-2), 21.11, 21.06, 20.97 (3ϫ

CH₃-Ac) ppm. C₂₁H₂₅NO₁₁(467.4): calcd. C 53.96, H 5.39, N 3.00;

found C 52.91, H 5.46, N 2.61.

1

(c = 0.27, CHCl₃), R_F= 0.07 (PE/EE, 4:1). H NMR (400 MHz,

CDCl₃): δ = 8.14 (m, 2 H, pNP), 7.03 (m, 2 H, pNP), 5.69 (ddd,

J_5,6= 4.8, J_6,7c= 10.9, J_6,7t= 17.3 Hz, 1 H, 6-H), 5.47 (dd, J_1,2

=

7.9, J_2,3= 10.4 Hz, 1 H, 2-H), 5.41 (dd, J_3,4= 3.3, J_4,5= 1.1 Hz, 1

H, 4-H), 5.34 (ddd, J_7c,7t= 1.3 Hz, 1 H, 7_t-H), 5.23 (ddd, 1 H, 7_c-

H), 5.16 (d, 1 H, 1-H), 5.13 (dd, 1 H, 3-H), 4.35 (m, 1 H, 5-H),

2.09 (s, 3 H, Ac), 1.95 (s, 3 H, Ac) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 170. 68, 170.48, 169.71 (3ϫ CO-Ac), 161.82 (C-pNP),

143.56 (C-pNP), 131.49 (C-6), 126.22 (CH-pNP), 119.24 (C-7),

117.00 (CH-pNP), 99.07 (C-1), 74.57 (C-5), 71.20 (C-3), 69.48 (C-

4), 68.82 (C-2), 21.09, 21.00, 20.97 (3ϫ CH₃-Ac) ppm. C₁₉H₂₁NO₁₀

(423.4), MALDI-TOF-MS: m/z = 446.1 [M + Na]⁺, 462.0

[M + K]⁺. To a suspension of 4-nitrophenyl 2,3,4-tri-O-acetyl-6,7-

dideoxy-β--galacto-hept-6-enopyranoside (535 mg, 1.26 mmol) in

methanol (3.3 mL) was added a solution of a 25% aqueous ammo-

nia (0.38 mL) in methanol (1.1 mL). After stirring for 24 h at room

temperature the solution was concentrated and the residue dried

under vacuum. Product 13 (375 mg, 100 %) was obtained as a

colourless solid; m.p. 174–178 °C (ref.^[42]173 °C), [α]²_D⁰= –95 (c =

0.20, CH₃OH), R_F= 0.41 (CH₂Cl₂/MeOH, 7:1). ¹H NMR

(400 MHz, MeOD): δ = 8.24 (m, 2 H, pNP), 7.25 (m, 2 H, pNP),

6.00 (ddd, J_5,6= 5.4, J_6,7t= 10.7, J_6,7c= 17.0 Hz, 1 H, 6-H), 5.39

(ddd, J_7c,7t= 1.3 Hz, 1 H, 7_t-H), 5.26 (ddd, 1 H, 7_c-H), 5.11 (d, J_1,2

= 7.6 Hz, 1 H, 1-H), 4.32 (dd, J_4,5= 1.0 Hz, 1 H, 5-H), 3.90–3.87

(m, 2 H, 2-H, 4-H), 3.68 (dd, J_2,3= 9.8, J_3,4= 3.5 Hz, 1 H, 3-H)

ppm. ¹³C NMR (100 MHz, MeOD): δ = 162.82 (C-pNP), 142.76

(C-pNP), 134.46 (C-6), 125.49 (CH-pNP), 116.55 (CH-pNP),

116.47 (C-7), 100.94 (C-1), 76.17 (C-5), 73.59 (C-3), 71.55, 70.66

(C-2, C-4) ppm. C₁₃H₁₅NO₇(297.2): FAB-MS: m/z = 298.2 [M +

H]⁺.

N-(2,3,4-Tri-O-acetyl-6-O-allyl-β-D-galactopyranosyl)trichloroacet-

amide: ¹H NMR (400 MHz, CDCl₃): δ = 7.38 (dd, J_1,NH= 8.7 Hz,

1 H, NH), 5.76 (dddd, J_CH2-All,-CH= 5.9, J_CH-All,=CH2c= 10.1,

J_CH-All,=CH2t= 17.3 Hz, 1 H, CH-All), 5.47 (dd, J_3,4= 3.4, J_4,5

=

1.0 Hz, 1 H, 4-H), 5.17 (dddd ≈ dq, J_=CH2c,=CH2t= 2.5 Hz, 1 H,

=CH_2t-All), 5.14 (dd, J_2,3= 8.7 Hz, 1 H, 3-H), 5.13–5.09 (m, 2 H,

2-H, =CH_2c-All), 5.06 (dd, J_1,2= 8.9 Hz, 1 H, 1-H), 3.95–3.90 (m,

2 H, 5-H, -CH₂-All), 3.84 (dddd ≈ ddt, J_CH2-All,=CH2= 1.8,

J_{CH2-All,-CH2-All}= 12.7 Hz, 1 H, -CH₂-All), 3.50 (dd, J_5,6a= 5.6,

J_6a,6b= 9.9 Hz, 1 H, 6a-H), 3.39 (dd, J_5,6b= 8.9 Hz, 1 H, 6b-H),

2.09 (s, 3 H, Ac), 1.99 (s, 3 H, Ac), 1.94 (s, 3 H, Ac) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 171.83 (3ϫ CO-Ac), 162.37 (-NH-

CO-), 134.42 (CH-All), 118.24 (=CH₂-All), 80.90 (C-1), 74.48 (C-

5), 72.84 (-CH₂-All), 71.04, 68.73 (C-2, C-3), 67.97 (C-4), 67.50 (C-

6), 21.06, 20.96 (3ϫ CH₃-Ac) ppm. C₁₇H₂₂NO₉Cl₃(490.7):

MALDI-TOF-MS: m/z = 490.30, 492.30 [M + H]⁺, 512.16, 514.16,

516.16 [M + Na]⁺, 528.12, 530.11, 532.10 [M + K]⁺. 4-Nitrophenyl

2,3,4-tri-O-acetyl-6-O-allyl-β--galactopyranoside (222 mg,

0.47 mmol) was dissolved in methanol (1.2 mL) and treated with a

solution of 25% aqueous ammonia (140 µL) in methanol (400 µL).

The reaction mixture was stirred overnight at room temperature

and upon complete deprotection, evaporated to dryness in vacuo.

The residue was purified by flash chromatography (DCM/MeOH,

10:1) to give 12 (60 mg, 37%) as a colourless solid; m.p. 149 °C,

6,7-Dideoxy-β-

D-galacto-hept-6-enopyranosyl-(1Ǟ4)-2-acetamido-

2-deoxy- -glucopyranose (18): Compounds 13 (10 mg, 34 µmol)

D

and 14 (75 mg, 340 µmol, 10 equiv.) were reacted according to ge-

neral procedure 2. Disaccharide 18 (3 mg, 20%) was obtained as a

colourless, amorphous solid. [α]²_D⁰= +224 (c = 0.13, H₂O), R_F

=

0.36 (iPrOH/NH₃/H₂O, 5:1:2). ¹H NMR (400 MHz, D₂O): δ = 5.73

(ddd, J_5Ј,6Ј= 5.1, J_6Ј,7Јc= 10.9, J_6Ј,7Јt= 17.6 Hz, 1 H, 6Ј-H), 5.18

(dd, J_7Јc,7Јt= 1.3 Hz, 1 H, 7Ј_t-H), 5.14 (dd, 1 H, 7Ј_c-H), 5.02 (d,

J_1α,2= 2.3 Hz, 0.7 H, 1α-H), 4.52 (d, J_1β,2= 7.6 Hz, 0.3 H, 1β-H),

4.28 (d, J_1Ј,2Ј= 7.9 Hz, 1 H, 1Ј-H), 4.07 (m, 1 H, 5Ј-H), 3.80–3.32

(m, 9 H, 2-H, 3-H, 4-H, 5-H, 6a-H, 6b-H, 2Ј-H, 3Ј-H, 4Ј-H), 1.85

1

[α]²_D⁰= –94 (c = 0.175, MeOH). H NMR (400 MHz, MeOD): δ =

8.43 (d, 2 H, pNP), 7.47 (d, 2 H, pNP), 6.14 (dddd, J_CH-All,=CH2c

= 10.4, J_CH-All,=CH2t= 17.3, J_{CH2-All,CH-All}= 5.3, J_{CH2-All,CH-All}

=

6.6 Hz, 1 H, CH-All), 5.51 (dd, J_=CH2c,=CH2t= 1.8 Hz, 1 H, =CH₂-

1138

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Eur. J. Org. Chem. 2007, 1130–1144

Saccharide Mimetics with Non-Glycosidic Amino Bridges

(s, 3 H, NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ = 133.47 (C- 5Ј), 68.62 (-CH₂-All), 67.43 (C-4Ј), 62.68 (C-6), 52.59 (C-2), 38.02

FULL PAPER

6Ј), 118.14 (C-7Ј), 103.50, 103.34 (C-1Ј), 95.27 (C-1β), 90.94 (C-

1α), 79.24, 78.82 (C-4β), 75.76 (C-4α), 75.64 (C-5Ј), 75.25, 72.92,

71.83, 71.06, 70.92, 70.67, 70.61, 69.68, 68.96 (C-3, C-5, C-2Ј, C-

3Ј, C-4Ј), 60.50, 60.38 (C-6), 56.63 (C-2β), 54.12 (C-2α), 22.57,

22.28 (CH₃-NHAc) ppm.

(C-6Ј), 21.30–19.60 (7ϫ CH₃-Ac) ppm.

Allyl β- -galacto-Hexodialdo-1,5-pyranosyl-(1Ǟ4)-2-acetamido-2-

D

deoxy-α-glucopyranoside (22): Compounds 6 (70 mg, 0.22 mmol)

and 15 (300 mg, 1.15 mmol) were reacted in 50 m potassium

phosphate buffer pH 7.0 (4 mL) after addition of a solution con-

sisting of 10 mg β-galactosidase (600 µL, 30 U) from B. circulans

β-D-Fucopyranosyl-(1Ǟ4)-2-acetamido-2-deoxy-D-glucopyranose

(19): Compounds 16 (40 mg, 140 µmol) and 14 (300 mg, in 50 m potassium phosphate buffer pH 7.0 (1 mL). After stirring

1.36 mmol, 10 equiv.) were reacted according to general procedure

2. Disaccharide 20 (34 mg, 66%) was obtained as an amorphous

yellow solid. [α]²_D⁰= –10 (c = 0.10, H₂O), R_F= 0.36 (EE/MeOH/

for three days at room temperature water was removed by freeze-

drying. The residue was purified by gel permeation chromatog-

raphy on Sephadex LH 20 using EE/EE (1:1:1) EE/EE (11:11:11)

methanol/water (1:1) to give 22 (65 mg, 68%) as a colourless solid;

H₂O, 7:3:1). ¹H NMR (400 MHz, D₂O): δ = 5.33 (d, J_1α,2α

=

2.3 Hz, 0.6 H, 1α-H), 4.63 (m, 0.4 H, 1β-H), 4.56 (d, J_1Ј,2Ј= 7.9 Hz, m.p. 219 °C (dec.), [α]²_D⁰= +7 (c = 0.15, H₂O), R_F= 0.31 (iPrOH/

1 H, 1Ј-H), 4.12–4.06 (m, 1.1 H, 5α-H, 6aα-H), 4.04–3.95 (m, 4 H,

2α-H, 3α-H, 6bα-H, 5β-H, 6aβ-H, 6bβ-H, 5Ј-H), 3.89 (d, J_3Ј,4Ј

NH₃/H₂O, 5:1:2). ¹H NMR (400 MHz, D₂O): δ = 6.05 (dddd,

J_CH-All,=CH2c= 10.7, J_CH-All,=CH2t= 17.3, J_{CH-All,CH2-All}= 5.6,

=

3.3 Hz, 1 H, 4Ј-H), 3.82–3.77 (m, 2.8 H, 4α-H, 2β-H, 3β-H, 4β-H,

3Ј-H), 3.63 (m, J_2Ј,3Ј= 9.9 Hz, 1 H, H-2Ј), 2.18 (s, 3 H, NHAc),

1.38 (d, J_5Ј,6Ј= 6.4 Hz, 3 H, 6Ј-H) ppm. ¹³C NMR (100 MHz,

D₂O): δ = 173.78 (CO-NHAc), 103.39 (C-1Ј), 95.21 (C-1β), 90.91

J_{CH-All,CH2-All}= 6.6 Hz, 1 H, CH-All), 5.44 (dd, J_=CH2c,=CH2t

1.5 Hz, 1 H, =CH₂-All), 5.35 (dd, 1 H, =CH₂-All), 5.21 (d, J_5Ј,6Ј

7.1 Hz, 1 H, 6Ј-H), 5.01 (d, J_1,2= 3.1 Hz, 1 H, 1-H), 4.57 (d, J_1Ј,2Ј

= 8.1 Hz, 1 H, 1Ј-H), 4.30 (dd, J_{CH2-All,CH2-All}= 13.2 Hz, 1 H,

=

(C-1α), 79.88 (C-4α), 75.11 (C-4β), 73.09 (C-3Ј), 72.92 (C-3β), 71.56 -CH₂-All), 4.17 (d, J_3Ј,4Ј= 3.6 Hz, 1 H, 4Ј-H), 4.12 (dd, 1 H, -CH₂-

(C-4Ј), 71.46 (C-5Ј), 71.05 (C-2Ј), 70.54 (C-3α), 69.68 (C-5), 60.52, All), 4.03–3.91 (m, 5 H, 2-H, 3-H, 5-H, 6a-H, 6b-H), 3.81 (dd, 1

60.37 (C-6α and β), 56.00 (C-2β), 54.09 (C-2α), 22.56, 22.27 (CH₃- H, 4-H), 3.75 (dd, J_2Ј,3Ј= 10.7 Hz, 1 H, 3Ј-H), 3.64 (dd, 1 H, 2Ј-

NHAcα and β), 15.70 (C-6Ј) ppm.

H), 3.54 (dd, 1 H, 5Ј-H), 2.11 (s, 3 H, NHAc) ppm. ¹³C NMR

(100 MHz, D₂O): δ = 175.00 (CO-NHAc), 133.93 (CH-All), 118.34

(=CH₂-All), 103.60 (C-1Ј), 96.12 (C-1), 88.39 (C-6Ј), 80.04 (C-4),

77.29 (C-5Ј), 72.83 (C-3Ј), 71.08 (C-2Ј), 70.82 (C-5), 70.06 (C-3),

68.97 (-CH₂-All), 68.38 (C-4Ј), 60.35 (C-6), 53.59 (C-2), 22.23

(CH₃-NHAc) ppm. C₁₇H₂₄NO₁₁(421.4): MALDI-TOF-MS: m/z =

444.2 [M + Na]⁺, 460.1 [M + K]⁺.

α- -Arabinopyranosyl-(1Ǟ4)-2-acetamido-2-deoxy-D-glucopyranose

L

(20): Compounds 17 (40 mg, 150 µmol) and 14 (300 mg,

1.36 mmol), were reacted according to general procedure 2. Disac-

charide 20 (3 mg, 6%) was obtained. ¹H NMR (400 MHz, D₂O):

δ = 5.15 (br. s, 0.6 H, 1α-H), 4.67 (d, 0.4 H, 1β-H), 4.33 (d, 1 H,

1Ј-H), 3.93–3.76 (m, 6 H, 2α-H, 3-H, 5-H, 6a-H, 6b-H, 4Ј-H, 5aЈ-

H), 3.64–3.59 (m, 4 H, 2β-H, 4-H, 3Ј-H, 5bЈ-H), 3.55–3.46 (m, 1.6

Allyl 6,7-Didesoxy-β-

D-galacto-hept-6-enopyranosyl-(1Ǟ4)-2-acet-

H, 4α-H or 4β-H, 2Ј-H), 1.99 (s, 3 H, NHAc) ppm. ¹³C NMR amido-2-desoxy-α-

D-glucopyranoside (23): Compounds 13 (32 mg,

(100 MHz, D₂O): δ = 103.76 (C-1Ј), 95.26 (C-1β), 90.96 (C-1α), 108 µmol) and 15 (224 mg, 861 µmol) were reacted according to

79.20 (C-4), 72.63 (C-3Ј), 71.38 (C-2Ј), 70.70, 69.51, 68.70 (C-3, C- general procedure 1. Disaccharide 23 (14 mg, 31%) was obtained

5, C-4Ј), 66.81 (C-5Ј), 60.32 (C-6), 54.22 (C-2), 22.29 (CH₃-NHAc) as a colourless syrup. [α]²_D⁰= –136 (c = 0.25, H₂O), R_F= 0.59 (EE/

ppm.

MeOH/H₂O, 7:3:1). ¹H NMR (400 MHz, D₂O): δ = 5.83 (dddd,

J_CH-All,=CH2c= 10.4, J_CH-All,=CH2t= 23.4, J_{CH-All,CH2-All}= 5.3,

J_{CH-All,CH2-All}= 5.1 Hz, 1 H, CH-All), 5.78 (ddd, J_6Ј,7Јc= 10.9,

J_6Ј,7Јt= 17.6 Hz, 1 H, 6Ј-H), 5.24 (m, J_7Јc,7Јt= 1.8 Hz, 1 H, 7Ј_c-H),

5.20 (m, 2 H, =CH₂-All, 7Ј_t-H), 5.12 (dd, J_=CH2c,=CH2t= 1.5,

J_CH2-All,=CH2= 1.5 Hz, 1 H, =CH₂-All), 4.80 (d, J_1,2= 3.1 Hz, 1

H, 1-H), 4.38 (d, J_1Ј,2Ј= 7.9 Hz, 1 H, 1Ј-H), 4.12 (dd, J_4Ј,5Ј= 1.3,

Allyl 6-Amino-6-deoxy-β-D-galactopyranosyl-(1Ǟ4)-2-acetamido-2-

deoxy-α-D-glucopyranoside (21): Compounds 5 (36 mg, 116 µmol)

and 15 (300 mg, 1.16 mmol, 10 equiv.) were reacted according to

the general procedure 1 to give 356 mg yellow solid raw material

of 21. 114 mg were dissolved in dry pyridine (2 mL), cooled in a

water bath and to this solution acetic anhydride (1 mL) was added

dropwise. After stirring for 24 h at room temperature co-distillation

with toluene was performed three times. The residue thus obtained

was purified two times by column chromatography [PE/EE (1:4)

and DCM/MeOH (6:1)]. Pure allyl 6-acetamido-2,3,4-tri-O-acetyl-

6-deoxy-β--galactopyranosyl-(1Ǟ4)-2-acetamido-3,6-di-O-acetyl-

2-deoxy-α--glucopyranoside (2 mg, ≈ 10 %) was isolated. ¹H

NMR (500 MHz, MeOD): δ = 5.87 (dddd, J_CH-All,=CH2c= 10.7,

J_CH-All,=CH2t= 17.0, J_{CH-All,CH2-All}= 6.3 Hz, 1 H, CH-All), 5.23 (d,

1 H, =CH₂-All), 5.17 (d, J_3Ј,4Ј= 3.5 Hz, 1 H, 4Ј-H), 5.14–5.09 (m,

2 H, =CH₂-All, 3-H), 4.95 (dd, J_2Ј,3Ј= 10.4 Hz, 1 H, 3Ј-H), 4.89

J_5Ј,6Ј= 5.3 Hz, 1 H, 5Ј-H), 4.09 (dddd ≈ ddt, J_{CH2-All,CH2-All}

13.0 Hz, 1 H, -CH₂-All), 3.91 (dddd ≈ ddt, 1 H, -CH₂-All), 3.82–

3.71 (m, 6 H, 2-H, 3-H, 5-H, 6a-H, 6b-H, 4Ј-H), 3.59 (m, J_3Ј,4Ј

=

3.6 Hz, 2 H, 3Ј-H, 4-H), 3.42 (dd, J_2Ј,3Ј= 9.9 Hz, 1 H, 2Ј-H), 1.92

(s, 3 H, NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ = 175.00 (CO-

NHAc), 133.93, 133.44 (C-6Ј, CH-All), 118.34, 118.11 (C-7Ј,

=CH₂-All), 103.43 (C-1Ј), 96.17 (C-1), 79.65 (C-4), 75.60 (C-5Ј),

72.90 (C-3Ј), 71.03 (C-2Ј), 70.96, 70.89, 69.92 (C-3, C-5, C-4Ј),

68.97 (-CH₂-All), 60.23 (C-6), 53.65 (C-2), 22.22 (CH₃-NHAc)

ppm.

(dd, 1 H, 2Ј-H), 4.69 (d, J_1,2= 3.8 Hz, 1 H, 1-H), 4.55 (d, J_1Ј,2Ј

=

Allyl β-D-Fucopyranosyl-(1Ǟ4)-2-acetamido-2-deoxy-α-D-glucopyr-

7.9 Hz, 1 H, 1Ј-H), 4.37 (dd, J_5,6a= 1.9, J_6a,6b= 12.0 Hz, 1 H, 6a-

anoside (24): Compounds 16 (33 mg, 116 µmol) and 15 (302 mg,

H), 4.13–4.08 (m, 2 H, -CH₂-All, 2-H), 4.04 (dd, J_5,6b= 6.0 Hz, 1 1.16 mmol) were reacted according to general procedure 1. Disac-

H, 6b-H), 3.95 (dd, J_{CH2-All,CH2-All}= 12.9 Hz, 1 H, -CH₂-All), 3.84– charide 24 (36 mg, 76%) was obtained as a colourless syrup. [α]²_D⁰

3.79 (m, 2 H, 5-H, 5Ј-H), 3.75 (dd, J_3,4= 8.8, J_4,5= 10.1 Hz, 1 H,

4-H), 3.36 (dd, J_5Ј,6aЈ= 8.2, J_6aЈ,6bЈ= 13.6 Hz, 1 H, 6aЈ-H), 3.12 NMR (400 MHz, D₂O): δ = 5.80–5.65 (m, 1 H, CH-All), 5.14 (d,

(dd, J_5Ј,6bЈ= 6.3 Hz, 1 H, 6bЈ-H), 2.04 (s, 3 H, Ac), 2.00 (s, 3 H, J_CH-All,=CH2c= 10.4 Hz, 1 H, =CH₂-All), 5.02 (d, J_CH-All,=CH2t

= +52 (c = 0.25, H₂O), R_F= 0.56 (iPrOH/NH₃/H₂O, 5:1:2). ¹H

=

Ac), 1.96 (s, 3 H, Ac), 1.94 (s, 3 H, Ac), 1.83 (s, 6 H, 2ϫ Ac), 1.81 17.3 Hz, 1 H, =CH₂-All), 4.71 (d, J_1,2= 3.1 Hz, 1 H, 1-H), 4.20 (d,

(s, 3 H, Ac) ppm. ¹³C NMR (100 MHz, MeOD): δ = 131.68 (CH- J_1Ј,2Ј= 7.6 Hz, 1 H, 1Ј-H), 4.00 (dd, J_{CH-All,CH2-All}= 5.6,

All), 117.49 (=CH₂-All), 100.85 (C-1Ј), 96.35 (C-1), 76.48 (C-4),

71.58 (C-3, C-3Ј), 69.75 (C-2Ј und C-5 or C-5Ј), 69.06 (C-5 or C-

J_{CH2-All,CH2-All}= 12.5 Hz, 1 H, -CH₂-All), 3.92 (dd, J_{CH-All,CH2-All}

= 5.4 Hz, 1 H, -CH₂-All), 3.91 (dd, J_2,3= 10.7 Hz, 1 H, 2-H), 3.88–

Eur. J. Org. Chem. 2007, 1130–1144

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1139

J. Neumann, S. Weingarten, J. Thiem

FULL PAPER

3.78 (m, 5 H, 3-H, 5-H, 6a-H, 6b-H, 5Ј-H), 3.72 (d, J_3Ј,4Ј= 3.3 Hz, Allyl 2-Acetamido-6-amino-2,6-dideoxy-α-D-glucopyranoside (30):

1 H, 4Ј-H), 3.66–3.60 (m, 2 H, 4-H, 3Ј-H), 3.46 (dd, J_2Ј,3Ј= 9.7 Hz,

1 H, 2Ј-H), 1.82 (s, 3 H, NHAc), 1.01 (d, J_5Ј,6Ј= 6.4 Hz, 3 H, 6Ј-

Allyl 2-acetamido-6-azido-2,6-dideoxy-α--glucopyranoside^[34]

(128 mg, 0.45 mmol) was reacted according to general procedure 5

H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 174.78 (CO-NHAc), and the product purified by column chromatography [EE/MeOH

133.97 (CH-All), 118.36 (=CH₂-All), 103.37 (C-1Ј), 96.19 (C-1), (1:9) + 3% pyridine]. Product 30 (113 mg, 97%) could be obtained

79.83 (C-4), 73.11 (C-3Ј), 71.56 (C-4Ј), 71.46 (C-3 or C-5Ј), 71.06

as a colourless solid; m.p. 168 °C (dec.), [α]²_D⁰= +40 (c = 0.22,

(C-2Ј), 70.92 (C-3 or C-5Ј), 71.01 (C-5), 69.00 (-CH₂-All), 60.31 (C- H₂O), R_F= 0.08 [EE/MeOH (1:9) + 3 % pyridine]. ¹H NMR

6), 53.67 (C-2), 22.24 (CH₃-NHAc), 15.71 (C-6Ј) ppm.

Allyl α- -Arabinopyranosyl-(1Ǟ4)-2-acetamido-2-deoxy-α-D-gluco-

(400 MHz, D₂O): δ = 5.93 (dddd, J_CH-All,=CH2c= 10.4, J_CH-All,=CH2t

= 17.3, J_{CH-All,CH2-All}= 5.3, J_{CH-All,CH2-All}= 6.1 Hz 1 H, CH-All),

L

5.43 (d, 1 H, =CH₂-All), 5.34 (dd, 1 H, =CH₂-All), 4.89 (d, J_1,2

3.6 Hz, 1 H, 1-H), 4.19 (dddd ≈ ddt, J_{CH2-All,CH2-All}= 13.0 Hz, 1

H, -CH₂-All), 4.01 (dddd ≈ ddt, 1 H, -CH₂-All), 3.89 (dd, J_2,3

=

pyranoside (25): Compounds 17 (32 mg, 116 µmol) and 15 (302 mg,

1.16 mmol) were reacted according to general procedure 1. Disac-

charide 25 (6 mg, 13%), was obtained as a colourless syrup. [α]²_D⁰

= +40 (c = 0.20, H₂O), R_F= 0.60 (iPrOH/NH₃/H₂O, 5:1:2). ¹H

NMR (400 MHz, D₂O): δ = 5.97–5.86 (m, 1 H, CH-All), 5.31 (dd,

J_CH-All,=CH2c= 10.7, J_CH2c,CH2t= 1.5 Hz, 1 H, =CH₂-All), 5.22 (dd,

J_CH-All,=CH2t= 17.3 Hz, 1 H, =CH₂-All), 4.89 (d, J_1,2= 3.3 Hz, 1

H, 1-H), 4.33 (d, J_{1 Ј , 2 Ј}= 7.6 Hz, 1 H, 1Ј-H), 4.17 (dd,

J_{CH-All,CH2-All}= 5.3, J_{CH2-All,CH2-All}= 13.2 Hz, 1 H, -CH₂-All), 4.00

(dd, J_{CH-All,CH2-All}= 6.4 Hz, 1 H, -CH₂-All), 3.93–3.78, 3.67–3.61

(2ϫ m, 1ϫ 7 H, 1ϫ 3 H, 2-H, 3-H, 4-H, 5-H, 6a-H, 6b-H, 3Ј-H,

4Ј-H, 5aЈ-H, 5bЈ-H), 3.51 (dd, J_2Ј,3Ј= 9.7 Hz, 1 H, 2Ј-H), 2.00 (s,

3 H, NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ = 173.00 (CO-

NHAc), 133.98 (CH-All), 118.35 (=CH₂-All), 103.75 (C-1Ј), 96.24

(C-1), 79.15 (C-4), 72.64 (C-3Ј), 71.38 (C-2Ј), 71.07 (C-5), 69.84 (C-

3), 68.98 (-CH₂-All), 68.69 (C-4Ј), 66.80 (C-5Ј), 60.25 (C-6), 53.79

(C-2), 22.25 (CH₃-NHAc) ppm.

=

10.7 Hz, 1 H, 2-H), 3.71 (dd, J_3,4= 8.9 Hz, 1 H, 3-H), 3.63 (ddd,

J_4,5= 9.9, J_5,6a= 2.5, J_5,6b= 7.4 Hz, 1 H, 5-H), 3.35 (dd, 1 H, 4-

H), 2.98 (dd, J_6a,6b= 13.7 Hz, 1 H, 6a-H), 2.76 (dd, 1 H, 6b-H),

2.00 (s, 3 H, NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ = 174.86

(CO-NHAc), 134.07 (CH-All), 118.31 (=CH₂-All), 96.40 (C-1),

72.55 (C-5), 72.04 (C-4), 71.37 (C-3), 68.86 (-CH₂-All), 54.11 (C-

2), 41.79 (C-6), 22.27 (CH₃-NHAc) ppm. C₁₁H₂₀N₂O₅(260.3):

calcd. C 50.75, H 7.74, N 10.76; found C 50.09, H 7.54, N 9.37.

Benzyl 2-Acetamido-6-amino-2,6-dideoxy-D-glucopyranoside (31):

Benzyl 2-acetamido-6-azido-2,6-dideoxy--glucopyranoside^[43]

(1.54 g, 4.58 mmol) was reacted according to general procedure 5

and the product purified by column chromatography [EE/MeOH

(4:1) + 3% pyridine]. Product 31 (986 mg, 69%) could be isolated

as a colourless solid; m.p. 175 °C, [α]²_D⁰= +182 (c = 0.50, H₂O), R_F

1

Allyl 2-Amino-2-deoxy-α-D-glucopyranoside (28): Compound 15

= 0.57 [PrOH/H₂O (7:3) + 1% NH₃]. H NMR (400 MHz, D₂O):

(915 mg, 3.5 mmol) and barium hydroxide octahydrate (14.18 mg,

44.9 mmol) in water (74 mL) were stirred for 3 h at 120 °C. After

cooling to room temperature, the precipitate was filtered and the

filtrate was treated with dry ice to remove the barium salts. The

solvent was removed by freeze drying to give 28 (920 mg, 100%)

as an amorphous, colourless solid. [α]²_D⁰= +59 (c = 0.65, MeOH),

δ = 7.28–7.00 (m, 5 H, CH-Bn), 4.69 (d, J_1,2= 3.6 Hz, 1 H, 1-H),

4.55 (d, J_{CH2-Bn,CH2-Bn}= 12.2 Hz, 1 H, CH₂-Bn), 4.33 (d, 1 H,

-CH₂-Bn), 3.70 (dd, J_2,3= 10.7 Hz, 1 H, 2-H), 3.52 (dd, J_3,4

=

8.7 Hz, 1 H, 3-H), 3.45 (ddd, J_4,5= 9.9, J_5,6a= 2.8, J_5,6b= 7.4 Hz,

1 H, 5-H), 3.05 (dd, 1 H, 4-H), 2.85 (dd, J_6a,6b= 13.5 Hz, 1 H, 6a-

H), 2.60 (dd, 1 H, 6b-H), 1.76 (s, 3 H, NHAc) ppm. ¹³C NMR

(100 MHz, D₂O): δ = 128.33, 128.17, 127.79 (CH-Bn), 96.65 (C-1),

73.01 (C-4), 72.20 (C-5), 71.37 (C-3), 69.44 (-CH₂-Bn), 54.36 (C-

2), 42.55 (C-6), 21.43 (CH₃-NHAc) ppm.

1

R_F= 0.07 (DCM/MeOH, 4:1). H NMR (400 MHz, MeOD): δ =

5.96 (dddd, J_{C H - A l l , = C H 2 c}= 10.4, J_{C H - A l l , = C H 2 t}= 17.3,

J_{CH-All,CH2-All}= 5.3, J_{CH-All,CH2-All}= 6.1 Hz, 1 H, CH-All), 4.81

(dddd ≈ dq, J_CH2-All,=CH2= 1.4 Hz, 1 H, =CH₂-All), 5.18 (dddd ≈

dq, J_CH2-All,=CH2= 1.5 Hz 1 H, =CH₂-All), 4.89 (d, J_1,2= 3.6 Hz,

1 H, 1-H), 4.24 (dddd ≈ ddt, J_{CH2-All,CH2-All}= 13.0 Hz, 1 H, -CH₂-

All), 4.01 (dddd ≈ ddt, 1 H, -CH₂-All), 3.80 (dd, J_5,6a= 2.3, J_6a,6b

= 12.0 Hz, 1 H, 6a-H), 3.69 (dd, J_5,6b= 5.6 Hz, 1 H, 6b-H), 3.58

(ddd, J_4,5= 9.9 Hz, 1 H, 5-H), 3.53 (dd ≈ t, 1 H, 3-H or 4-H), 3.31

(dd, 1 H, 3-H or 4-H), 2.71 (dd, J_2,3= 9.9, J_3,4= 9.7 Hz, 1 H, 2-H)

ppm. ¹³C NMR (100 MHz, MeOD): δ = 135.81 (CH-All), 118.08

(=CH₂-All), 99.20 (C-1), 75.72 (C-3 or C-4), 74.65 (C-5), 72.35 (C-

3 or C-4), 69.77 (-CH₂-All), 63.01 (C-6), 57.25 (C-2) ppm.

(6-Deoxy-1,2:3,4-di-O-isopropylidene-α-

D-galactopyranos-6-yl)-

(1,3,4,6-tetra-O-acetyl-2-deoxy-β- -glucopyranos-2-yl)amine (32):

D

The aldehyde 26^[19,31](134 mg, 0.51 mmol) and amine 27^[32]

(460 mg, 1.20 mmol) were stirred in methanol (5 mL) and reacted

according to general procedure 3. After purification by column

chromatography (PE/EE, 4:3) pure 32 (114 mg, 38%) was isolated

as a yellow syrup. R_F= 0.14 (PE/EE, 4:3). ¹H NMR (500 MHz,

CDCl₃): δ = 5.45 (d, J_1Ј,2Ј= 8.5 Hz, 1 H, 1Ј-H), 5.38 (d, J_1,2

=

4.7 Hz, 1 H, 1-H), 4.97 (dd, 1 H, 3Ј-H or 4Ј-H), 4.93 (dd, 1 H, 3Ј-

H or 4Ј-H), 4.48 (dd, J_2,3= 2.2, J_3,4= 7.9 Hz, 1 H, 3-H), 4.21 (dd,

1 H, 2-H), 4.19 (dd, 1 H, 6aЈ-H), 4.60 (dd, J_4,5= 1.6 Hz, 1 H, 4-

H), 3.97 (dd, 1 H, 6bЈ-H), 3.69–3.62 (m, 2 H, 5-H, 5Ј-H), 2.83 (dd,

J_5,6a= 7.3, J_6a,6b= 12.3 Hz, 1 H, 6a-H), 2.78 (dd, J_2Ј,3Ј= 9.1 Hz,

1 H, 2Ј-H), 2.75 (dd, J_5,6b= 7.3 Hz, 1 H, 6b-H), 2.06 (s, 3 H, Ac),

1.98 (s, 3 H, Ac), 1.97 (s, 3 H, Ac), 1.93 (s, 3 H, Ac), 1.45 (s, 3 H,

-CH₃), 1.34 (s, 3 H, -CH₃), 1.23 (s, 3 H, -CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 171.15, 170.12, 169.44 (4ϫ CO-Ac), 109.67

[C(CH₃)₂], 96.73 (C-1), 95.09 (C-1Ј), 74.03 (C-3Ј or C-4Ј), 72.91 (C-

5Ј), 71.80 (C-4), 71.14 (C-3), 70.99 (C-2), 68.86 (C-3Ј or C-4Ј),

67.06 (C-5), 62.26 (C-6Ј), 61.14 (C-2Ј), 47.68 (C-6), 26.46, 26.39,

25.37, 24.92 (4ϫ CH₃), 21.47, 21.39, 21.15, 21.12 (4ϫ CH₃-Ac)

ppm. C₂₆H₃₉NO₁₄(589.6): FAB-MS: m/z = 590.3 [M + H]⁺.

2-Amino-1,5-anhydro-2-deoxy-D-glucitol Hydrochloride (29): 2-

Acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy--glucitol

(41)^[38](0.6 g, 1.81 mmol) was solved in 2.5  hydrochloric acid

(5.0 mL) and stirred for 2 h at 110 °C. The reaction mixture was

evaporated and the residue was solved in ethanol (1.0 mL). Diethyl

ether was added until precipitation was completed. The residue was

filtered and recrystallised from propanol/ethanol (1:1). Compound

29 (204 mg, 57%) could be obtained as a colourless solid; m.p.

190 °C, [α]²_D⁰= +17.8 (c = 1, H₂O), R_F= 0.34 (iPrOH/NH₃/H₂O,

1

5:1:2). H NMR (400 MHz, D₂O): δ = 4.28 (dd, J_1a,2= 5.1, J_1a,1b

= 11.2 Hz, 1 H, 1a-H), 3.98 (dd, J_5,6a= 2.3, J_6a,6b= 12.2 Hz, 1 H,

6a-H), 3.81 (dd, J_5,6b= 5.3 Hz, 1 H, 6b-H), 3.71 (dd, J_3,4= 8.4,

J_4,5= 10.4 Hz, 1 H, 4-H), 3.64 (dd, 1 H, 1b-H), 3.54 (dd, J_2,3

9.7 Hz, 1 H, 3-H), 3.49 (ddd, 1 H, 5-H), 3.38 (ddd, 1 H, 2-H) ppm. (Allyl-2-deoxy-α-

¹³C NMR (100 MHz, D₂O): δ = 80.96 (C-5), 73.98 (C-4), 70.16 (C- propylidene-α-

-galactopyranos-6-yl)amine (33): The aldehyde 26

=

D

-glucopyranosid-2-yl)(6-deoxy-1,2:3,4-di-O-iso-

D

3), 65.88 (C-1), 61.01 (C-6), 51.74 (C-2) ppm. C₆H₁₄ClNO₄(199.6):

calcd. C 36.17, H 7.09, N 7.03; found C 36.22, H 7.07, N 7.02.

(47 mg, 0.18 mmol) and amine 28 (103 mg, 0.47 mmol) were re-

acted following general procedure 3. After purification by column

1140

www.eurjoc.org

Eur. J. Org. Chem. 2007, 1130–1144

Saccharide Mimetics with Non-Glycosidic Amino Bridges

FULL PAPER

chromatography (DCM/MEOH, 14:1) 33 (84 mg, 100%) could be

isolated as an amorphous, colourless solid. [α]²_D⁰= +23 (c = 1.00,

CH₃OH), R_F= 0.61 (DCM/MeOH, 4:1). ¹H NMR (400 MHz,

MeOD): δ = 5.98 (dddd, J_CH-All,=CH2c= 10.4, J_CH-All,=CH2t= 17.0,

J_{CH-All,CH2-All}= 5.6, J_{CH-All,CH2-All}= 6.4 Hz, 1 H, CH-All), 5.53 (d,

J_1,2= 5.1 Hz, 1 H, 1-H), 5.35 (dd, 1 H, =CH₂-All), 5.20 (dd, 1 H,

=CH₂-All), 5.06 (d, J_1Ј,2Ј= 3.3 Hz, 1 H, 1Ј-H), 4.65 (dd, J_2,3= 2.3,

J_3,4= 7.9 Hz, 1 H, 3-H), 4.38 (dd, 1 H, 2-H), 4.29–4.22 (m, 2 H,

4-H, -CH₂-All), 4.07 (ddt, J_{CH2-All,CH2-All}= 12.7 Hz, 1 H, -CH₂-

All), 3.96 (ddd, J_4,5= 1.8, J_5,6a= 8.4, J_5,6b= 3.6 Hz, 1 H, 5-H),

3.82 (dd, J_5Ј6aЈ= 2.3, J_6aЈ,6bЈ= 11.7 Hz, 1 H, 6aЈ-H), 3.69 (dd, J_5Ј,6bЈ

= 5.6 Hz, 1 H, 6bЈ-H), 3.63 (dd, J_3Ј,4Ј= 9.2, J_4Ј,5Ј= 9.7 Hz, 1 H,

4Ј-H), 3.57 (ddd, 1 H, 5Ј-H), 3.32 (m, J_2Ј,3Ј= 10.4 Hz, 1 H, 3Ј-H),

3.05 (dd, J_6a,6b= 12.7 Hz, 1 H, 6a-H), 2.91 (dd, 1 H, 6b-H), 2.73

(dd, 1 H, 2Ј-H), 1.55 (s, 3 H, -CH₃), 1.42 (s, 3 H, -CH₃), 1.36 (s, 3

H, -CH₃), 1.34 (s, 3 H, -CH₃) ppm. ¹³C NMR (100 MHz, MeOD):

δ = 135.81 (CH-All), 118.50 (=CH₂-All), 110.90 [C(CH₃)₂], 98.20

(C-1), 97.01 (C-1Ј), 74.27, 74.02, (C-3Ј, C-5Ј), 73.52 (C-4), 72.62

(C-3), 72.56 (C-4Ј), 72.25 (C-2), 69.68 (-CH₂-All), 68.22 (C-5),

63.23 (C-2Ј), 63.23 (C-6Ј), 48.42 (C-6), 29.79, 26.69, 25.56, 24.99

(4ϫ CH₃) ppm.

3Ј), 71.03 (C-4, C-4Ј, C-4*, C-4Ј*), 70.85 (C-2*), 70.77 (C-2), 70.64

(C-3*), 70.58 (C-3), 68.81 (C-5*), 68.70 (C-1Ј*), 68.30 (C-1Ј), 67.86

(C-5), 62.06 (C-6Ј), 62.03 (C-6Ј*), 59.27 (C-2Ј*), 57.82 (C-2Ј), 50.90

(C-6*), 48.97 (C-6), 25.18, 25.08, 24.05, 23.97, 23.65, 23.60 (4ϫ

CH₃, 4ϫ CH₃*) ppm.

(Allyl-2-acetamido-2,6-dideoxy-α-

1,2:3,4-di-O-isopropylidene-α- -galactopyranos-6-yl)amine (35) and

N-(Allyl-2-acetamido-2,6-dideoxy-α- -glucopyranosid-6-yl)-6-

amino-6-deoxy-1,2:3,4-di-O-isopropylidene- -glycero-α- -galacto-

D-glucopyranosid-6-yl)(6-deoxy-

D

D,

L

D

heptopyranurononitrile (35b): The aldehyde 26 (44 mg, 0.17 mmol)

and amine 30 (96 mg, 0.37 mmol) were reacted according to general

procedure 3. After purification by column chromatography (DCM/

MeOH, 12:1) 35 (35 mg, 41%) could be isolated as an amorphous,

colourless solid. The byproduct 35b (10 mg, 11%) could also be

isolated.

35: [α]²_D⁰= +21 (c = 0.65, CH₃OH), R_F= 0.39 (DCM/MeOH, 4:1).

¹H NMR (500 MHz, MeOD): δ = 5.95 (dddd, J_CH-All,=CH2c= 10.4,

J_CH-All,=CH2t= 17.3, J_{CH-All,CH2-All}= 5.1, J_{CH-All,CH2-All}= 6.0 Hz,

1 H, CH-All), 5.58 (d, J_1,2= 5.0 Hz, 1 H, 1-H), 5.35 (dd, 1 H,

=CH₂-All), 5.22 (dd, 1 H, =CH₂-All), 4.90 (d, J_1Ј,2Ј= 3.5 Hz, 1 H,

1Ј-H), 4.70 (dd, J_2,3= 2.2, J_3,4= 7.9 Hz, 1 H, 3-H), 4.44 (dd, 1 H,

2-H), 4.30 (dd, J_4,5= 1.5 Hz, 1 H, 4-H), 4.25 (dd, J_{CH2-All,CH2-All}

(1,5-Anhydro-2-deoxy-glucitol-2-yl)(1,2:3,4-di-O-isopropylidene-α-

D

-galactopyranos-6-yl)amine (34) and N-(1,5-Anhydro-2-deoxy-gluc-

itol-2-yl)-6-amino-6-deoxy-1,2:3,4-di-O-isopropylidene- -glycero-

α- -galacto-heptopyranurononitrile (34b): The aldehyde 26 (120 mg,

= 13.2, J_CH2-All,=CH2= 1.6 Hz, 1 H, -CH₂-All), 4.12 (bd, J_5,6a

8.5 Hz, 1 H, 5-H), 4.05 (dd, J_CH2-All,=CH2= 1.3 Hz, 1 H, -CH₂-All),

3.95–3.88, (m, 2 H, 2Ј-H, 5Ј-H), 3.71 (dd, J_2Ј,3Ј= 10.7, J_3Ј,4Ј

=

D,L

D

=

0.46 mmol) and amine 29 (240 mg, 1.20 mmol) were reacted ac-

cording to general procedure 3. After purification by column

chromatography (DCM/MeOH, 14:1) 34 (142 mg, 76%) could be

isolated as a colourless solid. The byproduct 34b (47 mg, 24 %)

could be isolated as a stereoisomeric mixture.

8.8 Hz, 1 H, 3Ј-H), 3.40 (dd, J_5Ј,6aЈ= 3.2, J_6aЈ,6bЈ= 12.9 Hz, 1 H,

6aЈ-H), 3.29–3.24 (m, 2 H, 4Ј-H, 6a-H), 3.21–3.15 (m, 2 H, 6b-H,

6bЈ-H), 2.00 (s, 3 H, NHAc), 1.56 (s, 3 H, -CH₃), 1.44 (s, 3 H,

-CH₃), 1.36 (s, 6 H, 2ϫ -CH₃) ppm. ¹³C NMR (100 MHz, MeOD):

δ = 172.68 (CO-NHAc), 134.15 (CH-All), 116.96 (=CH₂-All),

109.80 [C(CH₃)₂], 109.17 [C(CH₃)₂], 96.79, 96.58 (C-1, C-1Ј), 73.50

(C-4Ј), 71.60, 71.06 (C-3Ј, C-3, C-4), 70.62 (C-2), 68.84 (-CH₂-All),

67.66 (C-5Ј), 64.14 (C-5), 54.05 (C-2Ј), 49.03 (C-6Ј), 47.30 (C-6),

25.24, 25.15, 23.90, 23.32 (4ϫ CH₃), 21.47 (CH₃-NHAc) ppm.

C₂₃H₃₈N₂O₁₀(502.5): FAB-MS: m/z = 503.5 [M + H]⁺.

34: M.p. 169 °C, [α]²_D⁰= –18 (c = 0.25, CH₃OH), R_F= 0.30 (DCM/

MeOH, 6:1). ¹H NMR (500 MHz, MeOD): δ = 5.54 (d, J_1,2

=

5.1 Hz, 1 H, 1-H), 4.66 (dd, J_2,3= 2.2, J_3,4= 7.9 Hz, 1 H, 3-H),

4.39 (dd, 1 H, 2-H), 4.27 (dd, J_4,5= 1.6 Hz, 1 H, 4-H), 4.12 (dd,

J_1Јe,1Јa= 11.4, J_1Јe,2Ј= 4.7 Hz, 1 H, 1eЈ-H), 3.97 (ddd, J_5,6a= 8.5,

J_5,6b= 4.4 Hz, 1 H, 5-H), 3.85 (dd, J_5Ј,6aЈ= 2.2, J_6aЈ,6bЈ= 12.0 Hz,

1 H, 6aЈ-H), 3.65 (dd, J_5Ј,6bЈ= 5.7 Hz, 1 H, 6bЈ-H), 3.36 (dd, J_2Ј,3Ј

= 10.4, J_3Ј,4Ј= 8.5 Hz, 1 H, 3Ј-H), 3.28 (dd, J_4Ј,5Ј= 9.5 Hz, 1 H,

4Ј-H), 3.25–3.19 (m, 2 H, 1Јa-H, 5Ј-H), 2.97 (dd, J_6a,6b= 13.2 Hz,1

H, 6a-H), 2.92 (dd, 1 H, 6b-H), 2.76 (ddd ≈ dt, J_1Јa,2Ј= 10.4 Hz, 1

H, 2Ј-H), 1.52 (s, 3 H, -CH₃), 1.40 (s, 3 H, -CH₃), 1.33 (s, 6 H,

2ϫ -CH₃) ppm. ¹³C NMR (100 MHz, MeOD): δ = 109.43 [C-

(CH₃)₂], 108.89 [C(CH₃)₂], 96.70 (C-1), 81.63 (C-5Ј), 76.45 (C-3Ј),

71.94 (C-4), 71.27 (C-4Ј), 71.12 (C-2), 70.80 (C-3), 67.91 (C-1Ј),

66.33 (C-5), 62.03 (C-6Ј), 59.01 (C-2Ј), 46.88 (C-6), 25.37, 24.17,

23.62 (4ϫ CH₃) ppm. C₁₈H₃₁NO₉(405.4): calcd. C 53.33, H 7.71,

N 3.46; found C 49.78, H 7.78, N 3.34.

35b: R_F= 0.63 (DCM/MeOH, 4:1). ¹H NMR (500 MHz, MeOD):

δ = 5.90 (dddd, J_CH-All,=CH2c= 10.2, J_CH-All,=CH2t= 17.3,

J_{CH-All,CH2-All}= 5.3, J_{CH-All,CH2-All}= 6.1 Hz, 1 H, CH-All), 5.49 (d,

J_1,2= 4.8 Hz, 1 H, 1-H), 5.29 (dddd ≈ dq, 1 H, =CH₂-All), 5.15

(dddd ≈ dq, 1 H, =CH₂-All), 4.74 (d, J_1Ј,2Ј= 3.8 Hz, 1 H, 1Ј-H),

4.69 (dd, J_2,3= 2.3 J_3,4= 7.9 Hz, 1 H, 3-H), 4.41–4.37 (m, 2 H, 2-

H, 4-H), 4.16 (dddd ≈ ddt, J_{CH2-All,CH2-All}= 13.2, J_CH2-All,=CH2

=

1.5 Hz, 1 H, -CH₂-All), 4.00–3.92 (m, 3 H, -CH₂-All, 5-H, 6-H),

3.88 (dd, J_2Ј,3Ј= 8.7 Hz, 1 H, 2Ј-H), 3.71–3.60 (m, 2 H, 3Ј-H, 5Ј-

H), 3.28 (dd, J_3Ј4Ј= 8.7 Hz, 1 H, 4Ј-H), 3.02 (dd, J_5Ј,6aЈ= 3.1,

J_6aЈ,6bЈ= 12.5 Hz, 1 H, 6aЈ-H), 2.94 (dd, J_5Ј,6bЈ= 7.4 Hz, 1 H, 6bЈ-

H), 1.95 (s, 3 H, NHAc), 1.49 (s, 3 H, -CH₃),1.42 (s, 3 H, -CH₃),

1.34 (s, 3 H, -CH₃), 1.32 (s, 3 H, -CH₃) ppm. ¹³C NMR (100 MHz,

MeOD): δ = 134.33 (CH-All), 117.81, 116.77 (=CH₂-All, CN),

110.16 [C(CH₃)₂], 109.29 [C(CH₃)₂], 96.78, 96.52 (C-1, C-1Ј), 73.13

(C-4Ј), 71.53 (C-3Ј), 71.09 (C-2), 70.93 (C-4), 70.70 (C-5Ј), 70.37

(C-3), 68.26 (-CH₂-All), 67.63 (C-5), 54.30 (C-2Ј), 50.66 (C-6),

48.21 (C-6Ј), 25.20, 25.17, 23.95, 23.46 (4ϫ CH₃), 21.46 (CH₃-

NHAc) ppm. C₂₄H₃₇N₃O₁₀(527.5): FAB-MS: m/z = 528.7 [M +

H]⁺.

34b: R_F= 0.46 (DCM/MeOH, 6:1). ¹H NMR (400 MHz, MeOD):

δ = 5.54 (d, J_1,2= 4.8 Hz, 0.6 H, 1-H), 5.51 (d, J_1*,2*= 5.1 Hz, 0.4

H, 1*-H), 4.72 (dd, J_2,3= 2.3, J_3,4= 7.9 Hz, 0.7 H, 3-H), 4.68 (dd,

J_2*,3*= 2.3, J_3*,4*= 7.9 Hz, 0.4 H, 3*-H), 4.47–4.39 (m, 2 H, 2-H,

4-H, 2*-H, 4*-H), 4.10–4.04 (m, 1.3 H, 1Јe-H, 1Јe*-H, 6*-H), 3.99

(d, J_5,6= 8.1 Hz, 0.7 H, 6-H), 3.93–3.89 (m, 1 H, 5-H, 5*-H), 3.82

(dd, J_5Ј6aЈ= J_5Ј*,6aЈ*= 0.5, J_6aЈ,6bЈ= J_6aЈ*,6bЈ*= 11.7 Hz, 1 H, 6aЈ-

H, 6aЈ*-H), 3.62 (dd, J_5Ј,6bЈ= J_5Ј*,6bЈ*= 5.6 Hz, 1 H, 6bЈ-H, 6bЈ*-

H), 3.28–3.08 (m, 4 H, 1Јa-H, 3Ј-H, 4Ј-H, 5Ј-H, 1Јa*-H, 3Ј*-H,

(Benzyl-2-acetamido-2,6-dideoxy-α-

1,2:3,4-di-O-isopropylidene-α- -galactopyranos-6-yl)amine (36), N-

(Benzyl-2-acetamido-2,6-dideoxy-α- -glucopyranoside-6-yl)-6-

amino-6-deoxy-1,2:3,4-di-O-isopropylidene- -glycero-α- -galacto-

heptopyranurononitrile (36b): The aldehyde 26 (93 mg, 0.35 mmol)

D-glucopyranosid-6-yl)(6-deoxy-

4Ј*-H, 5Ј*-H), 2.82 (ddd ≈ dt, J_1Јe,2Ј= 4.6, J_1Јa,2Ј= 9.9, J_2Ј,3Ј

=

D

9.9 Hz, 0.7 H, 2Ј-H), 2.77–2.70 (m, 0.3 H, 2Ј*-H), 1.53 (s, 0.9 H,

-CH₃*), 1.50 (s, 2.6 H, CH₃), 1.33 (s, 4.4 H, 2ϫ -CH₃) ppm. ¹³C

NMR (100 MHz, MeOD): δ = 120.28 (CN*), 118.33 (CN), 110.28

D

D,

L

D

[C(CH₃)₂], 109.84 [C(CH₃)₂], 109.24 [C(CH₃)₂, C(CH₃)₂*], 96.82 and amine 31 (273 mg, 0.88 mmol) were reacted according to gene-

(C-1, C-1*), 81.67 (C-5Ј), 81.39 (C-5Ј*), 78.72 (C-3Ј*), 76.83 (C- ral procedure 3. After purification by column chromatography

Eur. J. Org. Chem. 2007, 1130–1144

www.eurjoc.org

1141

J. Neumann, S. Weingarten, J. Thiem

FULL PAPER

(DCM/MeOH, 12:1) 36 (92 mg, 48%) could be isolated as a colour-

less syrup. The byproduct 36b (57 mg, 28%) could be isolated as a

stereoisomeric mixture.

1 H, O-CH₂-All), 3.82 (dd, J_2,3= 10.7 Hz, 1 H, 2-H), 3.6 (dd, J_3,4

= 8.9 Hz, 1 H, 3-H) 3.58 (dd, J_4,5= 9.9 Hz, 1 H, 5-H), 3.46 (dd, 1

H, 4-H), 1.95 (s, 3 H, CH₃-Ac) ppm. ¹³C NMR (D₂O, 100 MHz):

δ = 133.98 (All-CH), 118.22 (All-CH₂), 96.50 (C-1), 88.32 (C-6),

73.16 (C-5), 71.19 (C-3), 71.12 (C-4), 68.81 (O-CH₂-All), 53.90 (C-

2), 22.20 (CH₃-Ac) ppm. C₁₁H₁₇NO₆(259.3): calcd. C 50.97, H

6.56, N 5.41; found C 48.43, H 6.54, N 4.56; (mixture of 39 and

39-hydrate).

1

36: R_F= 0.20 (DCM/MeOH, 5:1). H NMR (500 MHz, MeOD):

δ = 7.41–7.29 (m, 5 H, CH-Bn), 5.58 (d, J_1,2= 5.1 Hz, 1 H, 1-H),

4.90 (d, J_1Ј,2Ј= 3.5 Hz, 1 H, 1Ј-H), 4.79 (d, J_{CH2-Bn,CH2-Bn}

12.3 Hz, 1 H, -CH₂-Bn), 4.69 (dd, J_2,3= 2.2, J_3,4= 7.9 Hz, 1 H, 3-

H), 4.54 (d, 1 H, -CH₂-Bn), 4.43 (dd, 1 H, 2-H), 4.27 (dd, J_4,5

=

1.9 Hz, 1 H, 4-H), 4.13 (ddd ≈ dt, J_5,6a= 8.8, J_5,6b= 1.9 Hz, 1 H,

5-H), 3.98 (ddd ≈ dt, J_5Ј,6aЈ= 3.2, J_5Ј,6bЈ= 9.1 Hz, 1 H, 5Ј-H), 3.89

Benzyl 2-Acetamido-2-deoxy-α-

D-gluco-hexodialdo-1,5-pyranoside

(40): To a suspension of 37^[37](101 mg, 0.32 mmol) in acetonitrile

(dd, J_2Ј,3Ј= 10.7 Hz, 1 H, 2Ј-H), 3.74 (dd, J_3Ј,4Ј= 9.1 Hz, 1 H, 3Ј- (2.5 mL) was added Dess–Martin periodinane (185 mg, 0.44 mmol)

H), 3.41 (dd, J_6aЈ,6bЈ= 12.9 Hz, 1 H, 6aЈ-H), 3.31 (dd, J_6a,6bin dichloromethane (5 mL). The mixture was stirred at room tem-

13.2 Hz, 1 H, 6a-H), 3.26 (dd ≈ t, 1 H, 4Ј-H), 3.22–3.17 (m, 2 H, perature for 3 h. The reaction was stopped by adding water/dichlo-

=

6b-H, 6bЈ-H), 1.94 (s, 3 H, NHAc), 1.56 (s, 3 H, -CH₃), 1.39 (s, 3

H, -CH₃), 1.36 (s, 3 H, -CH₃), 1.35 (s, 3 H, -CH₃) ppm. ¹³C NMR

(100 MHz, MeOD): δ = 174.07 (CO-NHAc), 139.03 (C-Bn),

romethane (1:1) and the phases were separated. The aqueous phase

was washed with dichloromethane several times, filtered, neutral-

ized with 1  sodium hydroxide solution and concentrated. The

129.94, 129.63, 129.48 (CH-Bn), 111.33 [C(CH₃)₂], 110.71 [C- remaining water was removed by freeze drying and the residue was

(CH₃)₂], 98.11, 98.00 (C-1, C-1Ј), 75.01 (C-4Ј), 73.06 (C-4), 72.56, purified by column chromatography (DCM/MeOH, 12:1). Product

72.43 (C-3Ј, C-3), 72.13 (C-2), 71.21 (-CH₂-Bn), 69.19 (C-5Ј), 65.65 40 (32 mg, 32%) could be isolated as a colourless solid; m.p. 89 °C,

20

(C-5), 55.56 (C-2Ј), 50.38 (C-6Ј), 49.09 (C-6), 26.71, 26.66, 25.39,

24.80 (4ϫ CH₃), 22.93 (CH₃-NHAc) ppm. C₂₇H₄₀N₂O₁₀(552.3):

FAB-MS: m/z = 553.4 [M + H]⁺.

[α]

= +148 (c = 0.23, MeOH), R_F= 0.30 (DCM/MeOH, 5:1).

546

¹H NMR (D₂O, 400 MHz): δ = 7.60–7.56 (m, 5 H, Ar-H), 5.42 (d,

J_5,6= 1.8 Hz, 1 H, 6-H), 5.12 (d, J_1,2= 3.3 Hz, 1 H, 1-H), 4.68 (s,

²J_{Ar-CH2,Ar-CH2}= 11.7 Hz, 1 H, CH₂-Ar), 3.99 (dd, J_2,3= 10.7 Hz,

36b: R_F= 0.60 (DCM/MeOH, 5:1). ¹H NMR (500 MHz, MeOD):

δ = 7.43–7.30 (m, 5 H, CH-Bn), 5.55 (d, J_1,2= 4.7 Hz, 1 H, 2ϫ 1-

1 H, 2-H), 3.89 (dd, J_4,5= 1.0 Hz, 1 H, 5-H), 3.86 (dd, J_3,4

=

8.9 Hz, 1 H, 3-H), 3.69 (dd, 1 H, 4-H), 2.08 (s, 1 H, CH₃-Ac) ppm.

¹³C NMR (D₂O, 100 MHz): δ = 129.1 (CH-Ar), 128.7 (CH-Ar),

96.1 (C-1), 88.2 (C-6), 73.2 (C-5), 71.1 (C-3), 70.9 (C-4), 69.9 (CH₂-

Bn), 53.9 (C-2), 22.1 (CH₃-Ac) ppm.

H), 4.86 (d, J_1Ј,2Ј= 3.8 Hz, 1 H, 1Ј-H), 4.78 (d,J_{CH2-Bn,CH2-Bn}

=

11.7 Hz, 0.5 H, CH₂-Bn), 4.76 (d, 0.5 H, -CH₂-Bn), 4.74 (d, 0.5

H, -CH₂-Bn), 4.69 (dd, J_2,3= 2.5, J_3,4= 7.9 Hz, 0.5 H, 3-H), 4.52

(d, J_{CH2-Bn,CH2-Bn}= 12.0 Hz, 0.5 H, -CH₂-Bn), 4.51 (d, 0.5 H,

-CH₂-Bn), 4.47–4.41 (m, 2 H, 2ϫ 2-H, 2ϫ 4-H), 4.09–4.04 (m, 1

2-Acetamido-1,5-anhydro-2-deoxy-hexodialdo-

suspension of 38 (122 mg, 0.59 mmol) in acetonitrile (3 mL) was

10.7 Hz, 1 H, 2ϫ 2Ј-H), 3.84–3.76 (m, 1 H, 2ϫ 5Ј-H), 3.75–3.70 added pyridine (0.05 mL) and Dess–Martin periodinane (280 mg,

D-glucitol (41): To a

H, 2ϫ 6-H), 4.04–4.00 (m, 1 H, 2ϫ 5-H), 3.94–3.90 (m, J_2Ј,3Ј

=

(m, 2 H, 2ϫ 3Ј-H), 3.42 (dd ≈ t, 0.5 H, 4Ј-H), 3.35 (dd ≈ t, J_3Ј,4Ј

8.9, J_4Ј,5Ј= 9.5 Hz, 0.5 H, 4Ј-H), 3.19 (dd, J_5Ј6aЈ= 2.8, J_6aЈ,6bЈ

12.6 Hz, 0.5 H, 6aЈ-H), 3.09 (dd, 0.5 H, 6aЈ-H), 3.02 (dd, J_5Ј,6bЈ

=

0.7 mmol) in dichloromethane (6 mL). The mixture was stirred at

room temperature for 4 h. The reaction was stopped by adding

dichloromethane/water (1:1) and the phases were separated. The

6.3 Hz, 0.5 H, 6bЈ-H), 2.92 (dd, 0.5 H, 6bЈ-H), 1.92 (s, 3 H, NHAc), aqueous phase was washed with dichloromethane several times, fil-

1.56 (s, 1.5 H, -CH₃), 1.55 (s, 1.5 H, -CH₃), 1.45 (s, 1.8 H, -CH₃), tered, neutralized with 1  sodium hydroxide solution and concen-

1.43 (s, 1.5 H, -CH₃), 1.39 (s, 1.9 H, -CH₃), 1.36 (s, 3.5 H, 2ϫ trated. The remaining water was removed by freeze drying and the

-CH₃), 1.32 (s, 1.4 H, -CH₃) ppm. ¹³C NMR (100 MHz, MeOD): residue was purified by column chromatography (DCM/MeOH,

δ = 173.99 (CO-NHAc), 139.23 (C-Bn), 129.91, 129.61, 129.45

(CH-Bn), 120.50 (CN), 119.37 (CN), 111.66 [C(CH₃)₂], 111.30

6:1) to give 41 (23 mg, 19%) as a colourless solid; m.p. 150 °C,

20

[α] = –17.5 (c = 0.08, MeOH), R_F= 0.33 (DCM/MeOH, 3:1).

546

[C(CH₃)₂], 110.81 [C(CH₃)₂], 98.22 (C-1), 97.77 (C-1Ј), 74.66 (C- ¹H NMR (D₂O, 400 MHz): δ = 5.18 (d, J_5,6= 2.0 Hz, 1 H, 6-H),

4Ј), 72.95 (C-3Ј), 72.59 (C-3), 72.44, 72.20 (C-2, C-4), 72.02 (C-5Ј), 3.90 (dd, J_1a,1b= 11.2 Hz, 1 H, 1a-H), 3.78 (ddd, J_1a,2= 5.1, J_2,3

70.70 (-CH₂-Bn), 69.18 (C-5), 55.79 (C-2Ј), 52.61 (C-6), 49.46 (C-

6Ј), 26.74, 25.51, 25.02, 23.00 (4ϫ CH₃), 21.52 (CH₃-NHAc) ppm.

C₂₈H₃₉N₃O₁₀(577.3): FAB-MS: m/z = 578.5 [M + H]⁺.

= 9.9 Hz, 1 H, 2-H), 3.49–3.44 (m, 2 H, 3-H, 4-H), 3.23 (dd, J_4,5

= 4.8 Hz, 1 H, 5-H), 3.17 (dd, 1 H, 1b-H), 1.96 (s, 3 H, CH₃-Ac)

ppm. ¹³C NMR (D₂O, 100 MHz): δ = 88.1 (C-6), 81.2 (C-5), 75.0

(C-3), 71.0 (C-4), 67.5 (C-1), 51.5 (C-2), 22.3 (CH₃-Ac) ppm.

Allyl 2-Acetamido-2-deoxy-α-D-gluco-hexodialdo-1,5-pyranoside

(39): To a suspension of 15^[36](502 mg, 1.92 mmol) in acetonitrile

(8 mL) was added Dess–Martin periodinane^[39](880 mg,

2.10 mmol) in dichloromethane (10 mL) and the mixture was

stirred at room temperature for 2 h. The reaction was stopped by

adding water/dichloromethane (1:1) and the phases were separated.

The aqueous phase was washed several times with dichlorometh-

ane, filtered, neutralized with 1  sodium hydroxide solution and

concentrated. The remaining water was removed by freeze drying

and the residue was purified by column chromatography (DCM/

Benzyl 2-Amino-2-deoxy-α-D-galactopyranoside (42): Benzyl 2-acet-

amido-2-deoxy-4,6-di-O-pivaloyl-α--galactopyranoside^[44,45]

(550 mg, 1.15 mmol) and barium hydroxide octahydrate (4.8 g,

13.30 mmol) in water (27 mL) were stirred at 100–120 °C for 16 h.

After cooling to room temperature the precipitate was filtered and

the filtrate was treated with dry ice to remove the barium salts. The

solvent was removed by freeze drying to give 42 (580 mg, 100%)

20

as a colourless solid; m.p. 145 °C, [α] = +62.9 (c = 0.55, MeOH),

546

R_F= 0.07 (DCM/MeOH, 5:1). ¹H NMR (400 MHz, D₂O): δ =

MeOH, 12:1). Product 39 (242 mg, 49%) could be isolated as a 7.53–7.43 (m, 5 H, CH-Bn), 5.27 (d, J_1,2= 3.8 Hz, 1 H, 1-H), 4.82

20

colourless solid; m.p. 130 °C, [α] = +147 (c = 0.13, MeOH), R_F

(d, J_{CH2-Bn,CH2-Bn}= 11.5 Hz, 1 H, CH₂-Bn), 4.67 (d, 1 H, CH₂-

Bn), 4.09–3.99 (m, 3 H, 3-H, 4-H, 5-H), 3.78–3.73 (m, J_5,6a= 3.3,

J_5,6b= 4.8 Hz, 2 H, 6a-H, 6b-H), 3.48 (ddd, J_2,3= 10.4 Hz, 1 H,

2-H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 129.0 (CH-Bn), 95.4

546

= 0.31 (DCM/MeOH, 5:1). ¹H NMR (D₂O, 400 MHz): δ = 5.88

(dddd, J_{A l l - C H , - O - C H 2}= 5.4 Hz, 1 H, All-CH), 5.27 (dd,

J_{CH2-All,CH2-All}= 15.8 Hz, 1 H, CH₂-All), 5.19 (d, J_5,6= 1.8 Hz, 1

H, 6-H), 5.17 (dd, 1 H, CH₂-All), 4.87 (d, J_1,2= 3.6 Hz, 1 H, 1- (C-1), 71.7 (C-5), 70.2 (CH₂-Bn), 68.5 (C-3), 67.5 (C-4), 61.3 (C-

H), 4.15 (dd, J_{-O-CH2,-O-CH2}= 12.9 Hz, 1 H, O-CH₂-All), 3.95 (dd, 6), 51.2 (C-2) ppm.

1142

www.eurjoc.org

Eur. J. Org. Chem. 2007, 1130–1144

Saccharide Mimetics with Non-Glycosidic Amino Bridges

FULL PAPER

(Allyl 2-Acetamido-2,6-dideoxy-α-

D

-glucopyranosid-6-yl)(1,5-anhy-

NHAc) ppm. C₂₄H₃₆N₂O₁₀(512.6): MALDI-TOF-MS: m/z =

dro-2-deoxy- -glucitol-2-yl)amine (43): The aldehyde 39 (92.5 g,

D

535.1 [M + Na]⁺, 551.1 [M + K]⁺.

0.36 mmol) in methanol (2.5 mL) and amine 29 (204 mg,

1.02 mmol) in methanol (1.0 mL) were reacted according to general

[Allyl 6-Deoxy-β-

D-galactopyranos-6-yl-(1Ǟ4)-2-acetamido-2-de-

oxy-α- -glucopyranoside](1,5-anhydro-2-deoxy-glucitol-2-yl)amine

D

procedure 4. Compound 43 (112 mg, 78%) could be isolated as a

(46): The disaccharide aldehyde 22 (61 mg, 0.15 mmol) and amine

29 (71 mg, 0.36 mmol) in methanol were reacted according to gene-

ral procedure 3 (1 mL). Purification by gelpermeation chromatog-

raphy on sephadex LH 20 (water/methanol, 1:1) allowed isolation

of compound 46 (61 mg, 73%) as a colourless solid; m.p. 165 °C

20

colourless solid; m.p. 105 °C, [α] = +96 (c = 0.08, MeOH), R_F

=

546

0.65 (iPrOH/NH₃/H₂O, 5:1:2). ¹H NMR (400 MHz, D₂O): δ = 6.03

(dddd, 1 H, =CH-All), 5.41 (dd, J_CH-All,CH2c= 10.4 Hz, 1 H, CH₂-

All), 5.34 (dd, J_CH-All,CH2t= 17.3 Hz, 1 H, CH₂-All), 5.00 (d, J_1,2

= 3.8 Hz, 1 H, 1-H), 4.32 (dd, J_{CH-All,CH2-All}= 5.1 Hz, 1 H, O-

CH₂-All), 4.27 (dd, J_1aЈ1bЈ= 11.2, J_1aЈ,2Ј= 4.8 Hz, 1 H, 1aЈ-H), 4.13

(dd, J_{CH-All,CH2-All}= 6.1 Hz, 1 H, O-CH₂-All), 4.04–3.98 (m, 2 H,

2-H, 5Ј-H), 3.95 (dd, J_5Ј,6aЈ= 2.0, J_6aЈ,6bЈ= 12.3 Hz, 1 H, 6aЈ-H),

(dec.), [α]²_D⁰= +57 (c = 0.35, H₂O), R_F= 0.47 (iPrOH/NH₃/H₂O,

1

5:1:2). H NMR (500 MHz, D₂O): δ = 5.90 (ddd, J_CH-All,=CH2c

10.4, J_CH-All,=CH2t= 17.3, J_{CH-All,CH2-All}= 6.0, J_{CH-All,CH2-All}

=

5.1 Hz, 1 H, CH-All), 5.29 (d, 1 H, =CH₂-All), 5.20 (d, 1 H, =CH₂-

All), 4.87 (d, J_1,2= 3.5 Hz, 1 H, 1-H), 4.46 (d, J_1Ј,2Ј= 7.9 Hz, 1 H,

1Ј-H), 4.20 (d, J_{1aЈЈ,1bЈЈ}= 11.4, J_1aЈЈ,2ЈЈ= 4.7 Hz, 1 H, 1aЈЈ-H), 4.15

(dd, J_{CH2-All,CH2-All}= 12.9 Hz, 1 H, -CH₂-All), 3.98 (dd, 1 H,

-CH₂-All), 3.91 (dd, J_2,3= 10.4, J_5Ј,6aЈ= 2.8, J_5Ј,6bЈ= 10.4 Hz, 2 H,

2-H, 5Ј-H), 3.86 (d, J_3Ј,4Ј= 3.2 Hz, 1 H, 4Ј-H), 3.84–3.76 (m, 6 H,

3-H, 4-H, 5-H, 6a-H, 6b-H, 6aЈЈ-H), 3.68–3.60 (m, 3 H, 3Ј-H, 3ЈЈ-

H, 6bЈЈ-H), 3.52–3.43 (m, 2 H, 2Ј-H, 1bЈЈ-H), 3.40–3.26 (m, 4 H,

6aЈ-H, 6bЈ-H, 4ЈЈ-H, 5ЈЈ-H), 3.18 (dd, J_2ЈЈ,3ЈЈ= 10.7 Hz, 1 H, 2ЈЈ-

H), 1.98 (s, 3 H, NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ =

133.97 (CH-All), 118.41 (=CH₂-All), 102.63 (C-1Ј), 96.38 (C-1),

80.85 (C-5ЈЈ), 76.98 (C-4), 74.04 (C-3ЈЈ), 73.76 (C-3Ј), 72.68, 71.27,

71.21, 70.49, 70.19, 69.46 (C-3, C-5, C-2Ј, C-4Ј, C-5Ј, C-4ЈЈ), 69.00

(-CH₂-All), 65.19 (C-1ЈЈ), 61.10 (C-6ЈЈ), 60.06 (C-6), 57.83 (C-2ЈЈ),

53.82 (C-2), 46.81 (C-6Ј), 22.28 (CH₃-NHAc) ppm.

3.83 (dd, J_2,3= 8.9, J_3,4= 10.7 Hz, 1 H, 3-H), 3.77 (dd, J_5Ј,6bЈ

5.3 Hz, 1 H, 6bЈ-H), 3.65 (dd, J_2Ј3Ј= 8.6, J_3Ј4Ј= 9.2 Hz, 1 H, 3Ј-

H), 3.54–3.42 (m, 4 H, 1bЈ-H, 4Ј-H, 4-H, 5-H), 3.38 (dd, J_5,6a

6.1, J_6a,6b= 13.2 Hz, 1 H, 6a-H), 3.21–3.05 (m, 2 H, 2Ј-H, 6b-H),

2.09 (s, 3 H, CH₃-Ac) ppm. ¹³C NMR (D₂O, 100 MHz): δ = 134.02

(CH-All), 118.24 (=CH₂-All), 96.49 (C-1), 80.86 (C-5), 72.49 (C-

4Ј), 71.03 (C-4), 70.45 (C-3), 69.21 (C-1Ј, -CH₂-All), 61.16 (C-6Ј),

58.07 (C-2Ј), 53.86 (C-2), 47.33 (C-6), 22.19 (CH₃-Ac) ppm.

C₁₇H₃₀N₂O₉(406.4): MALDI-TOF-MS: 407.5 [M + H]⁺, 429.5 [M

+ Na]⁺.

=

(Allyl 2-Acetamido-2,6-dideoxy-α-D-glucopyranosid-6-yl)(allyl-2-de-

oxy-α- -glucopyranos-2-yl)amine (44): The aldehyde 39 (90 mg,

D

0.34 mmol) in methanol (2.2 mL) and amine 28 (220 mg,

1.01 mmol) in methanol (1 mL) were reacted according to general

[Allyl 6-Deoxy-β-

D

-galactopyranos-6-yl-(1Ǟ4)-2-acetamido-2-de-

-gluc-

procedure 4 to give 44 (66 mg, 42%) as a colourless solid; m.p.

oxy-α- -glucopyranoside](benzyl 2-acetamido-2,6-dideoxy-α-

D

20

187 °C, [α]

= +133 (c = 0.03, H₂O), R_F= 0.64 (iPrOH/NH₃/

546

opyranosid-6-yl)amine (47): The disaccharide aldehyde 22 (75 mg,

0.18 mmol) and amine 31 (130 mg, 0.42 mmol) in methanol

(1.2 mL) were reacted according to general procedure 3. Purifica-

tion by gelpermeation chromatography on Sephadex LH 20 (water/

methanol, 1:1) allowed isolation of compound 47 (53 mg, 41%) as

a colourless solid; m.p. 180 °C (dec.), [α]²_D⁰= +33 (c = 0.15, H₂O),

H₂O, 5:1:2). ¹H NMR (400 MHz, D₂O): δ = 5.98–5.84 (m, 2 H,

2ϫ CH-All), 5.35–5.25 (m, 2 H, 2ϫ = CH₂-All), 5.24–5.18 (m, 2

H, =CH₂-All), 5.09 (d, J_1Ј,2Ј= 3.6 Hz, 1 H, 1Ј-H), 4.86 (d, J_1,2

=

3.6 Hz, 1 H, 1-H), 4.23–4.13 (m, 2 H, 2ϫ -CH₂-All), 4.05–3.95 (m,

2 H, 2ϫ -CH₂-All), 3.87 (dd, J_2,3= 10.7 Hz, 1 H, 2-H), 3.84–3.75

(m, 3 H, 5-H, 2Ј-H, 5Ј-H), 3.73–3.59 (m, 6 H, 3-H, 4-H, 6a-H, 3Ј-

H, 4Ј-H, 6aЈ-H), 3.40–3.26 (m, 2 H, 6b-H, 6bЈ-H), 1.97 (s, 3 H,

CH₃-NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ = 117.92 (=CH₂-

All), 97.56 (C-1Ј), 94.95 (C-1), 74.10, 73.41, 71.00 (C-3, C-4, C-5,

C-3Ј, C-4Ј, C5Ј) 69.15 (-CH₂-All) 61.48 (C-6Ј), 54.21 (C-2), 54.02

(C-2Ј), 48.50 (C-6), 22.17 (CH₃-NHAc) ppm. C₂₀H₃₄N₂O₁₀(462.5)

MALDI-TOF-MS: m/z = 463.4 [M + H]⁺, 485.4 [M + Na]⁺.

1

R_F= 0.54 (iPrOH/NH₃/H₂O, 5:1:2). H NMR (400 MHz, D₂O): δ

= 7.35–7.25 (m, 5 H, CH-Bn), 5.82 (ddd, J_CH-All,=CH2c= 10.4,

J_CH-All,=CH2t= 17.3, J_{CH-All,CH2-All}= 6.1, J_{CH-All,CH2-All}= 5.3 Hz,

1 H, CH-All), 5.22 (d, J_=CH2t,=CH2c= 1.5, J_=CH2,CH2-All= 1.5 Hz,

1 H, =CH₂-All), 5.13 (d, 1 H, =CH₂-All), 4.84 (d, J_1,2= 3.8 Hz, 1

H, 1-H), 4.77 (d, J_{1 Ј Ј , 2 Ј Ј}= 2.8 Hz, 1 H, 1ЈЈ-H), 4.68 (d,

J_{CH2-Bn,CH2-Bn}= 12.0 Hz, 1 H, -CH₂-Bn), 4.43 (d, 1 H, -CH₂-Bn),

4.39 (d, J_1Ј,2Ј= 7.9 Hz, 1 H, 1Ј-H), 4.08 (dddd ≈ ddt, 1 H, -CH₂-

All), 3.89 (dddd ≈ ddt, J_{CH2-All,CH2-All}= 13.0 Hz, 1 H, -CH₂-All),

3.84–3.68 (m, 10 H, 2-H, 3-H, 4-H, 5-H, 6a-H, 6b-H, 4Ј-H, 5Ј-H,

2ЈЈ-H, 5ЈЈ-H), 3.64 (dd, J_2ЈЈ,3ЈЈ= 10.7, J_3ЈЈ,4ЈЈ= 8.9 Hz, 1 H, 3ЈЈ-H),

3.58 (dd, J_3Ј,4Ј= 3.3 Hz, 1 H, 3Ј-H), 3.43 (dd, J_2Ј,3Ј= 9.9 Hz, 1 H,

2Ј-H), 3.26 (dd, J_4ЈЈ,5ЈЈ= 9.7 Hz, 1 H, 4ЈЈ-H), 3.19–3.08 (m, 2 H,

6aЈ-H, 6aЈЈ-H), 2.99–2.90 (m, 2 H, 6bЈ-H, 6bЈЈ-H), 1.85 (s, 3 H,

NHAc), 1.82 (s, 3 H, NHAcЈЈ) ppm. ¹³C NMR (100 MHz, D₂O):

δ = 174.68 (CO-NHAc), 137.37 (C-Bn), 133.98 (CH-All), 129.18,

128.88, 128.80 (CH-Bn), 118.37 (=CH₂-All), 102.74 (C-1Ј), 96.30

(C-1, C-1ЈЈ), 77.49 (C-4), 72.78 (C-4ЈЈ), 72.69 (C-3Ј), 71.83, 71.37,

71.20, 70.94, 69.98, 69.70, 69.02 (C-3, C-5, C-2Ј, C-4Ј, C-5Ј, C-3ЈЈ,

C-5ЈЈ), 70.38 (-CH₂-Bn), 68.97 (-CH₂-All), 60.16 (C-6), 53.96 (C-2,

C-2ЈЈ), 49.33, 48.77 (C-6Ј, C-6ЈЈ), 22.23, 22.17 (CH₃-NHAc, CH₃-

NHAcЈЈ) ppm.

(Allyl 2-Acetamido-2,6-dideoxy-α-

D-glucopyranosid-6-yl)(benzyl-2-

deoxy-α- -galactopyranos-2-yl)amine (45): The aldehyde 39

D

(100 mg, 0.39 mmol) in methanol (2.5 mL) and amine 42 (311 mg,

1.16 mmol) in methanol (1.5 mL) were reacted according to general

procedure 4 to give 45 (155 mg, 76%) as a colourless solid; m.p.

20

150 °C, [α]

= +119 (c = 0.32, H₂O), R_F= 0.44 (iPrOH/NH₃/

546

H₂O, 5:1:2). ¹H NMR (400 MHz, D₂O): δ = 7.60–7.48 (m, 5 H,

CH-Bn), 6.01 (dddd, J_{CH-All,CH2-All}= 5.3, J_{CH-All,CH2-All}= 6.1,

J_CH-All,CH2c= 10.4, J_CH-All,CH2t= 17.3 Hz, 1 H, CH-All), 5.39 (dd,

1 H, =CH₂-All), 5.33 (dd, 1 H, =CH₂-All), 5.27 (d, J_1Ј,2Ј= 3.8 Hz,

1 H, 1Ј-H), 4. 96 (d, J_{1 , 2}= 3. 8 Hz, 1 H, 1-H), 4.86 (d,

J_{CH2-Bn,CH2-Bn}= 11.5 Hz, 1 H, CH₂-Bn), 4.68 (d, 1 H, CH₂-Bn),

6.40 (dd, J_{CH2-All,CH2-All}= 12.9 Hz, 1 H, -CH₂-All), 4.11–3.98 (m,

4 H, -CH₂-All, 2-H, 4Ј-H, 5Ј-H), 3.91–3.77 (m, 5 H, 3-H, 5-H, 3Ј-

H, 6aЈ-H, 6bЈ-H), 3.35 (dd, J_3,4= 9.2 Hz, 1 H, 4-H), 3.08–3.00 (m,

2 H, 2Ј-H, 6a-H), 2.79 (dd, J_5,6b= 8.6, J_6a,6b= 12.2 Hz, 1 H, 6b-

H), 2.14 (s, 3 H, CH₃-NHAc) ppm. ¹³C NMR (100 MHz, D₂O): δ

= 129.42, 129.24, 128.93 (CH-Bn), 118.40 (=CH₂-All), 96.42 (C-1Ј),

95.02 (C-1), 73.11 (C-4), 72.21 (C-3), 72.12 (C-4Ј or C-5Ј), 71.37 (C-

3Ј, C-5), 69.98 (CH₂-Bn), 69.06 (CH₂-All), 67.54 (C-4Ј or C-5Ј),

Acknowledgments

Support of this work by the Fonds der Chemischen Industrie and

the Deutsche Forschungsgemeinschaft (SFB 470,A5) is gratefully

61.76 (C-6Ј), 57.87 (C-2Ј), 54.13 (C-2), 47.81 (C-6), 22.33 (CH₃- acknowledged.

Eur. J. Org. Chem. 2007, 1130–1144

www.eurjoc.org

1143

J. Neumann, S. Weingarten, J. Thiem

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Received: November 2, 2006

Published Online: January 19, 2007

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Article Doi

Synthesis of novel di- and trisaccharide mimetics with non-glycosidic amino bridges

DOI: 10.1002/ejoc.200600958

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