In search of glycogen phosphorylase inhibitors: 5-Substituted 3-C-glucopyranosyl-1,2,4-oxadiazoles from β-D-Glucopyranosyl cyanides upon cyclization of O-acylamidoxime intermediates

FULL PAPER

DOI: 10.1002/ejoc.200600073

In Search of Glycogen Phosphorylase Inhibitors: 5-Substituted 3-C-

Glucopyranosyl-1,2,4-oxadiazoles from β- -Glucopyranosyl Cyanides upon

D

Cyclization of O-Acylamidoxime Intermediates

Mahmoud Benltifa,^[a,c]Sébastien Vidal,^[a]Bernard Fenet,^[b]Moncef Msaddek,^[c]

Peter G. Goekjian,^[a]Jean-Pierre Praly,*^[a]Attila Brunyánszki,^[d]Tibor Docsa,^[e]and

Pál Gergely^[d]

Keywords: Cyanides / C-Glycosides / Heterocycles / 1,2,4-Oxadiazoles / Glycogen phosphorylase (GP)

Upon treatment with hydroxylamine-, benzyl- and benzoyl-

protected β- -glucopyranosyl cyanides efficiently afforded

a “one-pot” procedure (benzylated series), or in two steps

(benzoylated series). The twelve 5-substituted 1,2,4-oxadi-

azoles obtained upon debenzoylation were assayed against

D

the corresponding amidoximes. They reacted by O-acylation

in the presence of carboxylic acids or acyl chlorides to pro-

vide benzyl- and benzoyl-protected O-acylamidoximes. The

latter were isolated and fully characterized. Thermal cycliza-

tion of O-acylamidoximes yielded the corresponding 5-sub-

glycogen phosphorylase (GP). 3-C-(β-

(2-naphthyl)-1,2,4-oxadiazole was the best inhibitor of rabbit

muscle glycogen phosphorylase b (K_i= 38.4 3.0 µ ).

D-Glucopyranosyl)-5-

M

Germany, 2006)

stituted 3-C-β-D-glucopyranosyl-1,2,4-oxadiazoles, either in

lism, several potential therapeutic approaches to diabetes

are currently receiving much attention.^[4]

Introduction

The increasing world-wide prevalence of both metabolic

disorders and diabetes^[1](mostly the non-insulin-dependent

type-2 diabetes mellitus) calls for better insight into the ori-

gin(s) of glucose metabolic disorders and for more effective

therapeutic approaches.^[2]For example, α-glucosidase inhib-

itors^[3]have attracted much attention since they were found

to be effective in lowering the post-prandial glycaemic rise

after carbohydrate ingestion, as shown in particular for sal-

acinol, a sulfur-containing natural compound isolated from

an antidiabetic traditional medicine.^[3a]Based on infor-

mation at the molecular level, gained by studying insulin

signal transduction, regulation of glucose uptake and other

insulin signalling effects, in particular on glycogen metabo-

Being responsible for glycogenolysis with the release of

glucose-1-phosphate (Glc-1-P) from glycogen, glycogen

phosphorylase (GP) intervenes by providing glucose for the

glycolytic pathway in muscles and to the bloodstream in the

liver. In an advanced stage of type-2 diabetes, hepatic glu-

cose production is excessive,^[4,5]due to changes in insulin

signalling and in particular, insulin’s inability to inhibit he-

patic gluconeogenesis. Hepatic glucose production repre-

sents the net contribution of gluconeogenesis, glycogenesis

and glycogenolysis, three interrelated processes sharing Glc-

1-P as a common intermediate. It is therefore reasonable

to assume that inhibiting hepatic GP would reduce hepatic

glucose production, as indicated by experiments based on

the administration of potent GP inhibitors (e.g. glucose an-

alogs, azasugars) to animals.^[6,7]Another recent work con-

cluded that GP inhibition, aimed at attenuating hypergly-

caemia, is unlikely to negatively impact the metabolic and

functional muscle capacity.^[8]These data support the idea

that GP inhibition^[9]might offer opportunities for an inter-

vention in the treatment of glucose metabolic disorders.

We have contributed to such investigations by preparing

β--glucopyranosyl-hydroquinone derivatives^[10]found to

be weak inhibitors of GP^[11]and N-acyl-NЈ-β--glucosyl-

ureas which were studied enzymatically and crystallographi-

cally and mainly found to bind at the active site of GP.^[12]

This result, as well as the fact that glucopyranosyl–

[a] Laboratoire de Chimie Organique 2, UMR-CNRS 5181, Uni-

versité Claude Bernard Lyon 1,

43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne,

France

Fax: +33-4-72-44-83-49

E-mail: jean-pierre.praly@univ-lyon1.fr

[b] Centre Commun de RMN, UMR-CNRS 5012, Université

Claude Bernard Lyon 1,

43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne,

France

[c] Laboratoire de Synthèse Hétérocyclique, Photochimie et Com-

plexation, Faculté des Sciences de Monastir,

Avenue de l’Environnement, Monastir 5000, Tunisie

[d] Department of Medical Chemistry, Medical and Health Science

Centre, University of Debrecen,

Nagyerdei krt. 98, 4012 Debrecen, Hungary

[e] Signalling and Apoptosis Research Group of the Hungarian

Academy of Sciences, Research Centre for Molecular Medicine,

Medical and Health Science Centre, University of Debrecen,

Nagyerdei krt. 98, 4012 Debrecen, Hungary

spiro(thio)hydantoins,^[9]

glucopyranosyl–benzimidazole,

–benzothiazole, –1,3,4-oxadiazoles^[13]and glucopyranosyl–

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5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

FULL PAPER

spirooxathiazoles^[12a,14]were GP inhibitors, encouraged fur-

ther developments towards 5-substituted 3-C-β--glucopyr-

anosyl-1,2,4-oxadiazoles. 1,2,4-Oxadiazoles^[15]are consid-

ered as bioisosteres of esters and amides^[16]and have vari-

ous biological activities such as muscarinic agonists,^[17]

benzodiazepine receptor antagonists,^[18]antirhinovirals,^[19]

anthelmintics,^[20]inhibitors of tyrosine kinase,^[21]angioten-

sin-II receptor antagonists^[22]and histamine H3 receptor

antagonists.^[23]We now disclose a general access to novel,

hydrolytically stable 5-substituted 3-C-β--glucopyranosyl-

1,2,4-oxadiazoles and their evaluation from enzymatic stud-

ies as potential inhibitors of GP.

Treatment of amidoxime 3 with carboxylic acids or acyl

chlorides with subsequent heating at 100 °C in 1,4-dioxane

afforded the 1,2,4-oxadiazoles 7 as stable materials in good

yields. The reaction was achieved in a one-pot two-step pro-

cedure (Scheme 1) presumably via O-acylamidoxime inter-

mediates. O-Acylamidoximes can be obtained by using

either an acid in the presence of an activating agent, an acyl

chloride, or an anhydride.^[15b]We did not use anhydrides

due to the limited number of commercially available rea-

gents and we observed that acyl chlorides were more ef-

ficient than carboxylic acids for preparing the oxadiazoles

7 (Table 1). Unfortunately, the attempted hydrogenolysis of

the benzyl protecting groups of 7 under various conditions

[EtOH, H₂(5 atm); MeOH with cat. HCO₂H, H₂(3 atm);

cyclohexene/EtOH] with Pd(OH)₂/C (20%) as the catalyst

were not encouraging as judged by TLC (complex mixture

of UV-active spots) and spectroscopy (NMR, MS). Hydro-

genolysis [EtOH, H₂(3 atm), Pd(OH)₂/C (20%), 3 d] of

benzylated amidoxime 3 afforded in low yield (22%) a mix-

ture of partially deprotected amidoxime isomers.

Therefore, we turned our attention to the benzoylated

series where final deprotections were presumed uneventful,

the readily prepared -glucopyranosyl cyanide 2^[25]was

treated with hydroxylamine, liberated from its hydrochlo-

ride with sodium methoxide in MeOH, as reported.^[34]We

observed partial debenzoylation of the products, resulting

in a complex mixture, presumably because of the presence

of nucleophilic species and/or use of NaOMe in slight ex-

cess. However, when pyridine was used both as solvent and

base to liberate hydroxylamine from its hydrochloride salt,

2 was efficiently converted into the benzoylated amidoxime

4 (90% yield) without cleavage of the benzoate esters

(Scheme 1). Acylation of amidoxime 4 was achieved using

either an acyl chloride or an acid in conjunction with an

activating system (EDCI, HOBt) to afford the O-acylamid-

oximes 6 in good yields (Table 1). Acylation occurred

Results and Discussion

A possible route to 3-C-glycosyl-1,2,4-oxadiazoles in-

volves dehydrative cyclization of O-acyl-amidoxime inter-

mediates. Developing such an approach from benzyl- or

benzoyl-protected -glucopyranosyl cyanides 1^[24]and 2^[25]

required the synthesis of the amidoxime precursors 3 and

4, respectively, to be subsequently subjected to acylation,

followed by cyclization. Recently improved methodologies

such as solid-phase synthesis,^[26]microwave irradiation^[27]

and applications to amino acids^[28]have demonstrated the

feasibility of this approach. A literature survey revealed ex-

amples of sugar derivatives displaying an amidoxime group

in furanose (positions 1^[29]and 3^[30]) and pyranose rings

(positions 1,^[31]2,^[32]and 6^[33]), prepared typically from cya-

nosugars upon reaction with hydroxylamine.

Use of benzyl ether protection on the carbohydrate moi-

ety was presumed to be advantageous since hydrogenolysis

of these ethers should provide the desired 3-C-glycosyl-

1,2,4-oxadiazoles after a simple purification step. The ben-

zylated amidoxime 3 was prepared from β--glucopyranos-

yl cyanide 1^[24]in MeOH by reaction with hydroxylamine,

freshly prepared from its hydrochloride in the presence of chemoselectively at the OH group of amidoxime 4 since the

sodium methoxide^[34](Scheme 1).

NH₂nitrogen atom has a decreased nucleophilicity, com-

Scheme 1. a) NH₂OH, MeOH (R = Bn) or NH₂OH/HCl, C₅H₅N (R = Bz), 50 °C; b) R¹COCl or R¹CO₂H, EDCI, HOBt, 1,4-dioxane;

c) 1,4-dioxane, 100 °C; d) NaOMe, MeOH; e) Ac₂O, C₅H₅N.

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Table 1. Isolated yields for the preparations of O-acylamidoximes 6 and 1,2,4-oxadiazoles 7–9.

R¹

3Ǟ7

4Ǟ6

6Ǟ8

100 °C

8Ǟ9

NaOMe

Reagents/conditions

(1) R¹CO₂H (1) R¹COCl R¹COCl

R¹CO₂H

(2) 100 °C

a

b

c

d

e

f

g

h

i

CH₃

C₆H₅

4-MeO-C₆H₄

4-Me-C₆H₄

4-O₂N-C₆H₄

3-Cl-C₆H₄

3-pyridyl

2-furyl

2-thienyl

61

88

87

67

100

93

72

79

90

62

50

64

87

60

87

88

60

58

68

78

98

89

80

85

95

94

60

93

70

89

98

31

57

69

76

97

j

k

l

1-naphthyl

2-naphthyl

(E)-styryl

55

47

m

n

o

p

(1S)-N-Fmoc-1-amino-2-methylprop-1-yl

(1S)-1-amino-2-methylprop-1-yl

tetra-O-benzoyl-β--glucopyranosyl

1,5-anhydro-2-deoxy--arabino-hex-1-enitolyl

75

50

51

88^[a]

95

25

45^[b]

[a] 8n was obtained upon treatment of the Fmoc-protected precursor 8m with piperidine in CH₂Cl₂. [b] 9p was obtained upon treatment

of the benzoyl-protected precursor 8o with NaOMe in MeOH.

pared to a typical NH₂amino group, due to the possibility HSQC and HMBC correlations. For molecules 6h–i, 8h–i

of mesomerism to form an iminium cation (C–NH₂to and 9h–i, assignment of proton and carbon resonances was

C=NH₂⁺).^[30b,35]Such a mesomerism would increase the achieved by careful analysis of the spectra in order to distin-

electron density of the OH group, thereby enhancing its nu- guish 3-H, 4-H and 5-H in furan and thiophene rings, based

cleophilicity. Refluxing the O-acylamidoximes 6 in 1,4-diox- on literature data for 2-substituted furans^[38](deshielding of

3

ane afforded the desired benzoylated 1,2,4-oxadiazoles 8 by nuclei at α-positions to the oxygen atom; J_3,4Ϸ 3.5 Hz Ͼ

dehydration in 50–98% yields (Table 1). Interestingly, con- ³J_4,5Ϸ 1.9 Hz) and thiophenes^[39](³J_4,5Ϸ 5.0–5.8 Hz Ͼ

4

densation with more elaborate acid derivatives [FmocVal- ³J_3,4Ϸ 3.6–4.0 Hz Ͼ J_2,5Ϸ 2.5–4.0 Hz). These assign-

OH (Entry 8m) or glycoheptonic acid^[36](Entry 8o)] were ments were supported by the HMBC correlations observed

also high-yielding.

for the C-5 atoms of the oxadiazole ring with the furan and

Deprotection of the benzoylated oxadiazoles 8 under thiophene 3-H and 5-H protons, by the respective ³J and ⁴J

3

Zemplén conditions was generally achieved in good yields couplings. In connection with the larger magnitude of J,

(60–98%) to afford the fully deprotected oxadiazoles 9. All correlations involving the 3-H protons appeared stronger.

oxadiazoles 8 and 9, as well as the acetylated 1-naphthyl

Assignment of the stereochemistry for the C=N double

derivative 10j, were obtained as stable white crystalline ma- bond in the benzoylated amidoxime 4 was examined. Vari-

terials. It is worth mentioning that, upon piperidine-cata- ous reports based on dipole moments^[40]concluded that pri-

lyzed cleavage of the Fmoc group, amino acid based oxadi- mary amidoximes [R¹–C(=NOH)NH₂] exist predominantly

azole 8m afforded deprotected oxadiazole 8n in 88% yield, in the (Z) configuration, whereas tertiary amidoximes [R¹–

but with partial racemization of the 1-amino-2-methylprop- C(=NOH)NR²R³] exist only in the (E) configuration. Not

1-yl residue. ¹H NMR spectroscopy clearly indicated the surprisingly, secondary amidoximes [R¹–C(=NOH)NHR²]

presence of a 87:13 mixture of diastereoisomers as calcu- are found as (E) and/or (Z) isomers. Other studies reported

lated from the integrals of the α-H doublets at δ = 3.91 and changes in chemical shifts for the hydroxy group of tertiary

3.84 ppm, respectively. The 3,5-bis(C-glycosyl)-1,2,4-oxadi- amidoximes from δ Ϸ 9.05 ppm for the (E) isomer to δ Ϸ

azole 8o underwent, under Zemplén conditions, regioselec- 9.70 ppm for the (Z) isomer mainly due to intramolecular

tive 1,2-elimination of benzoic acid in the pyranosyl ring hydrogen bonding.^[40c,41]Furthermore, the crystal structure

attached at the 5-position of the oxadiazole ring to afford of a primary amidoxime at the 3-position of an α--gluco-

9p. Base-induced elimination has been previously reported furanose ring^[30b]unambiguously displayed a (Z)-config-

for a similar compound.^[37]The electron-withdrawing ef- ured C=N bond. These data suggest a (Z) configuration for

fects exerted by the 1,2,4-oxadiazole ring and a possible 4, which was confirmed by NMR spectroscopy at 500 MHz.

tautomeric form involving an exocyclic double bond at C- A solution of 4 in CD₃COCD₃was subjected to a 1D gradi-

5oxa and an H–N-4 group might explain the acidity of the ent ROESY experiment. Low temperature (193 K) was re-

proton linked to the carbon atom vicinal to C-5oxa and quired in order to obtain a sharp signal for the OH proton

therefore the racemization of 8n, or 1,2-elimination in 8o to resonating at δ = 9.39 ppm. When this signal was selected,

yield 9p.

a ROESY effect was observed for NH₂(0.74%). A false

The structures of the products obtained were deduced peak was also observed for 1-H (0.89%) due to a transfer

from 1D NMR and 2D NMR spectroscopy which allowed, of magnetization during the spin lock (200 ms) due to the

in most cases, complete signal assignments based on COSY, scalar coupling between 1-H and the NH₂group. Of par-

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5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

FULL PAPER

ticular interest is the fact that no significant interaction was ation and dehydrative cyclization of the O-acylamidoximes

observed between the 2-H and the OH proton of amid- afforded, by one-pot or stepwise processes, the correspond-

oxime 4, as expected for a (Z)-configured C=N double ing 3-C-β--glucopyranosyl-1,2,4-oxadiazoles with various

bond. Analysis of the same solution of 4 by 2D NOESY at groups at the 5-position of the 1,2,4-oxadiazole ring (alkyl,

298 K displayed interactions between the NH₂and both the aryl, aminoalkyl and glycosyl). Deprotected 5-substituted

2-H (strong) and 1-H (weak) protons. This was interpreted 3-C-β--glucopyranosyl-1,2,4-oxadiazoles were obtained by

as a consequence of the free rotation about the C-glycosidic cleavage of the benzoyl protecting groups. Compound 9k

bond under these conditions. A positive exchange crosspeak displaying a 2-naphthyl residue was the best inhibitor of

was also observed between the OH and NH₂protons in- RMGPb with a K_ivalue of 38.4 3.0 µ. We are currently

dicative of a fast exchange rate of protons in these groups. preparing, by another route, the regioisomeric 3-substituted

No interaction could be evidenced between either the OH 5-C-β--glucopyranosyl-1,2,4-oxadiazoles for comparative

and 1-H or the OH and 2-H protons, therefore indicating a evaluation of the inhibition of glycogen phosphorylase.

distal disposition of these groups and a (Z)-configured

C=N double bond in 4.

Deprotected β--glucosyl formamidoxime 5 and twelve

Experimental Section

3-β--glucopyranosyl-1,2,4-oxadiazoles with different R¹

General Methods: Thin-layer chromatography (TLC) was carried

out using aluminium sheets coated with silica gel 60 F₂₅₄(Merck).

substituents at the 5-position of the oxadiazole ring were

evaluated as inhibitors of rabbit muscle glycogen phospho-

TLC plates were inspected with UV light and developed by treat-

rylase b (RMGPb). Amidoxime 5 and oxadiazoles 9a, 9e–j

ment with a mixture of 5% H₂SO₄in EtOH followed by heating.

and 9p (R¹= Me, p-nitrophenyl, m-chlorophenyl, 3-pyridyl,

Silica gel column chromatography was performed with Geduran^®

2-furyl, 2-thienyl, 1-naphthyl and 1,5-anhydro-2-deoxy--

silica gel Si 60 (40–63 µm) purchased from Merck (Darmstadt,

arabino-hex-1-enitolyl) showed no inhibition at a maximum

concentration of 625 µ. This threshold was selected in re-

lation to the IC₅₀values determined for a series of glucose-

based inhibitors.^[9]The IC₅₀and K_ivalues obtained for 9b–

d and 9k are listed in Table 2.

Germany). Preparative reversed-phase chromatography (RP-18)

was performed using a 15×150 mm column of fully endcapped sil-

ica gel 100 C₁₈(Ͼ400 mesh, Fluka). ¹H and ¹³C NMR spectra

were recorded at 23 °C using Bruker AC200, DRX300 or DRX500

spectrometers with the residual solvent as the internal standard.

The following abbreviations are used to explain the observed multi-

plicities: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet

of doublets of doublets; t, triplet; td, triplet of doublets; q, quadru-

plet; m, multiplet; br, broad; p, pseudo. 1D ROESY experiments

(200 ms) were performed using the Bruker selrogp sequence and

the 2D NOESY experiments (800 ms) with the noesygpph sequence.

NMR solvents were purchased from Euriso-Top (Saint Aubin,

France). HRMS (LSIMS) data were recorded in the positive mode

(unless stated otherwise) using a Thermo Finnigan Mat 95 XL

spectrometer. MS (ESI) data were recorded in the positive mode

using a Thermo Finnigan LCQ spectrometer. Optical rotations

were measured using a Perkin–Elmer polarimeter. Elemental analy-

ses were performed at the Service Central d’Analyses du CNRS

(Vernaison, France). EDCI stands for 1-[3-(dimethylamino)propyl]-

3-ethylcarbodiimide hydrochloride. HOBt stands for 1-hydroxy-

benzotriazole. Carbon atoms in the -gluco-pyranosyl ring and the

R¹substituent are numbered by simple figures and primed figures,

respectively, while those of the oxadiazole ring have the oxa suffix.

Table 2. Inhibition of RMGPb by some 5-aryl-3-(β--glucopyran-

osyl)-1,2,4-oxadiazoles.

9b

9c

9d

9k

R¹

phenyl

625^[a]

–

p-methoxyphenyl p-tolyl 2-naphthyl

IC₅₀[µ]

550 15

350 11

Ͻ300

38.4 3.0

K_i[µ]^[b]

–

[a] 10% Inhibition was observed at this concentration. [b] K_ivalues

were determined when IC₅₀values were Ͻ300 µ.

These data show that the presence of a heteroatom or a

polar group in R¹is not favourable in terms of inhibition

of GP, leading to inactive or less active (compare 9c and

9d) molecules. For the active oxadiazoles, the inhibition in-

creased according to the sequence R¹= phenyl Ͻ p-meth-

oxyphenyl Ͻ p-tolyl Ͻ 2-naphthyl, the 2-naphthyl derivative

9k being the most potent inhibitor of RMGPb in this series

with a K_ivalue of 38.4 µ. This again shows^[9,12a]that the

Preparation of Benzylated 1,2,4-Oxadiazoles 7 using Carboxylic Ac-

2-naphthyl group is quite favourable for the inhibition of ids (Procedure A): A solution of carboxylic acid (1 equiv.), amid-

oxime 3 (0.08 mmol, 1.2 equiv.) and EDCI (2 equiv.) in 1,4-dioxane

(2 mL) was stirred at 50 °C for 16 h. The mixture was then heated

to reflux (100 °C) for an additional 3 h. The crude mixture was

concentrated to afford, after silica gel column chromatography, the

desired 1,2,4-oxadiazoles 7 (yield calculated based on the acid

used).

GP, in sharp contrast with the isomeric 1-naphthyl group

which confers no inhibitory activity.

Conclusions

Inhibition of hepatic glycogen phosphorylase has been

proposed as a new therapeutic approach for the treatment

of type-2 diabetes with inhibitors usually based on glucos-

idic or heterocyclic scaffolds. C-Glucosyl-1,2,4-oxadiazoles,

with such features, appeared to deserve attention and syn-

thetic efforts. To this end, benzyl- and benzoyl-protected β-

-glucopyranosyl cyanides were converted into the corre-

Preparation of Benzylated 1,2,4-Oxadiazoles 7 using Acyl Chlorides

(Procedure B): A solution of acyl chloride (1 equiv.) and amidoxime

3 (0.08 mmol, 1 equiv.) in 1,4-dioxane (2 mL) was stirred at room

temperature for 16 h. The mixture was heated to reflux for 3 h and

processed as indicated for procedure A.

Preparation of O-Acylamidoximes 6 using Acyl Chlorides (Procedure

C): Acyl chloride (1.1 equiv.) was added to a suspension of amid-

sponding C-glycosylformamidoximes. Subsequent O-acyl- oxime 4 (0.2 mmol, 1 equiv.) in 1,4-dioxane (3 mL). After the mix-

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J.-P. Praly et al.

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ture was stirred at room temperature for 16 h, the solvent was evap-

orated. The desired O-acylamidoximes 6 were purified from the

crude mixture by silica gel column chromatography.

J_5,6b= 2.6 Hz, J_6a,6b= 12.4 Hz, H-6b), 4.76 (s, 2 H, NH₂), 5.69 (t,

1 H, J_1,2= 9.8 Hz, J_2,3= 9.7 Hz, H-2), 5.73 (t, 1 H, J_3,4= 9.6 Hz,

J_4,5= 9.7 Hz, H-4), 5.96 (t, 1 H, J_3,4= 9.6 Hz, J_2,3= 9.7 Hz, H-3),

7.24–7.43 (m, 10 H, Harom), 7.47–7.57 (m, 2 H, Harom), 7.81–8.04

(m, 8 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.4 (C-

6), 69.6 (C-4), 70.2 (C-2), 74.3 (C-3), 76.7 (C-1), 76.8 (C-5), 128.7,

128.7, 128.9, 129.1 (C^IVarom), 129.2 (C^IVarom), 129.4 (C^IVarom),

129.9 (C^IVarom), 130.1, 130.2, 130.3, 133.6, 133.7, 133.7, 134.0,

149.9 (H₂NC=NOH), 165.6, 165.7, 166.2, 166.6 (4 OCOPh) ppm.

C₃₅H₃₀N₂O₁₀(638.62): calcd. C 65.83, H 4.73, N 4.39, O 25.05;

found C 65.05, H 4.79, N 4.37, O 24.60.

Preparation of O-Acylamidoximes 6 using Carboxylic Acids (Pro-

cedure D): HOBt (1.2 equiv.) and EDCI (1.2 equiv.) were added at –

10 °C to a solution of carboxylic acid (1 equiv.) and amidoxime 4

(0.25 mmol, 1.2 equiv.) in CH₂Cl₂/DMF (9:1, 2 mL). The solution,

stirred at –10 °C for 20 min and at room temperature for an ad-

ditional 8 h, was processed as indicated for procedure C (yield cal-

culated based on the acid used).

Preparation of Benzoylated 1,2,4-Oxadiazoles 8 (Procedure E): A

solution of O-acylamidoxime 6 (0.08 mmol) in 1,4-dioxane (2 mL)

was heated to reflux (100 °C). The reaction was monitored by TLC

and the crude mixture separated by silica gel column chromatog-

raphy to provide the desired 1,2,4-oxadiazoles 8.

C-(β-D-Glucopyranosyl)formamidoxime (5): A solution of amid-

oxime 4 (135 mg, 0.21 mmol) was treated according to method F

to obtain 5 (14 mg, 30%) as a colourless gum. R_f= 0.50 (EtOAc/

MeOH, 4:1). [α]²_D⁰= +15 (c = 1, MeOH). ¹H NMR (300 MHz,

D₂O): δ = 3.45 (m, 2 H, H-4, H-5), 3.49 (br. t, 1 H, J Ϸ 9.0 Hz,

H-3), 3.59 (dd, 1 H, J_1,2= 9.5 Hz, J_2,3Ϸ 9 Hz, H-2), 3.70 (d, 1 H,

J_1,2= 9.5 Hz, H-1), 3.71 (dd, 1 H, J_5,6a= 3.5 Hz, J_6a,6b= 11.8 Hz,

H-6a), 3.84 (dd, 1 H, J_6a,6b= 11.8 Hz, J_5,6bϷ 1 Hz, H-6b) ppm.

¹³C NMR (75 MHz, D₂O): δ = 61.0 (C-6), 69.6 (C-4), 71.3 (C-2),

77.2 (C-3), 77.9 (C-1), 80.1 (C-5), 154.0 (H₂NC=NOH) ppm. MS

(LSIMS, glycerol): m/z = 223.0 [M+H]⁺. HRMS (LSIMS, glyc-

erol): m/z = C₇H₁₅N₂O₆[M+H]⁺calcd. 223.0930, found 223.0929.

Zemplén Deprotection of Benzoylated C-Glycosides (Procedure F):

NaOMe (1  in MeOH, 50 µL) was added to a solution of benzoyl-

ated C-glycosides (0.15 mmol) in MeOH (2 mL). The mixture was

stirred at room temperature for 3 h and then neutralized with a

cation exchange resin (Dowex 50WX2, H⁺form). The resin was

filtered off and washed with MeOH (3×10 mL). The filtrate was

concentrated and the crude mixture separated by silica gel column

chromatography (PE/EtOAc, 3:2, then EtOAc, then EtOAc/MeOH,

95:5 to 9:1) to provide the deprotected 1,2,4-oxadiazoles.

5-Phenyl-3-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1,2,4-

oxadiazole (7b). a): A solution of benzoic acid (16 mg, 0.13 mmol),

benzylated amidoxime 3 (89.3 mg, 0.15 mmol, 1.2 equiv.) and

EDCI (49 mg, 0.25 mmol, 2 equiv.) was treated according to pro-

cedure A, to afford 7b (26 mg, 31%), purified by silica gel column

chromatography (PE/EtOAc, 4:1). b) A solution of benzoyl chloride

(11 µL, 0.09 mmol) and benzylated amidoxime 3 (54 mg,

0.09 mmol, 1 equiv.) was treated according to procedure B. Silica

gel column chromatography (PE/EtOAc, 4:1) afforded 7b (35 mg,

57%) as a white solid. R_f= 0.75 (PE/EtOAc, 4:1). M.p. 78–79 °C

(CH₂Cl₂/PE). [α]²_D⁰= –32 (c = 1, CHCl₃). ¹H NMR (300 MHz,

CDCl₃): δ = 3.68 (m, 1 H, H-5), 3.75 (m, 2 H, H-6a, H-6b), 3.79–

3.88 (m, 2 H, H-3, H-4), 4.10 (dd, 1 H, J_1,2= 9.5 Hz, J_2,3= 9.0 Hz,

H-2), 4.45 (d, 1 H, J = 10.9 Hz, CH₂Ph), 4.51 (d, 1 H, J = 12.4 Hz,

CH₂Ph), 4.59 (d, 1 H, J = 12.4 Hz, CH₂Ph), 4.60 (d, 1 H, J =

10.7 Hz, CH₂Ph), 4.61 (d, 1 H, J_1,2= 9.5 Hz, H-1), 4.70 (d, 1 H, J

= 10.9 Hz, CH₂Ph), 4.85 (d, 1 H, J = 10.7 Hz, CH₂Ph), 4.94 (s, 2

H, CH₂Ph), 7.01–7.18 (m, 7 H, Harom), 7.27–7.54 (m, 13 H,

Harom), 7.57–8.09 (m, 3 H, Harom), 8.11 (d, 2 H, J = 7.0 Hz,

Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 69.2 (C-6), 73.6

(C-1), 73.9, 75.3, 75.6, 76.1 (4×CH₂Ph), 78.3 (C-4), 80.2 (C-2), 80.3

(C-5), 87.3 (C-3), 124.5 (C^IVarom), 128.0, 128.1, 128.1, 128.2, 128.3,

128.37, 128.45, 128.6, 128.7, 128.8, 128.9, 129.4, 133.3, 138.1 (C^IVa-

rom), 138.3 (C^IVarom), 138.4 (C^IVarom), 138.9 (C^IVarom), 168.7 (C-

3oxa), 176.4 (C-5oxa) ppm. MS (LSIMS, NBA/AcONa): m/z =

669.2 [M+H]⁺, 691.1 [M+Na]⁺. HRMS (LSIMS, NBA/AcONa):

m/z = C₄₂H₄₀N₂O₆[M+Na]⁺calcd. 691.2784, found 691.2782.

C-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)formamidoxime (3):

Hydroxylamine hydrochloride (103 mg, 1.48 mmol) was dissolved

in the minimum amount of MeOH with gentle heating; then the

mixture was allowed to reach room temperature. A drop of phenol-

phthalein was added and the solution was treated with NaOMe

(1  in MeOH) until a pink colour persisted. The precipitated NaCl

was eliminated by filtration to afford a solution of free hydroxyl-

amine. The freshly prepared solution of free hydroxylamine

(1.48 mmol) was added to a solution of 2,3,4,6-tetra-O-benzyl-β--

glucopyranosyl cyanide (1)^[24](215 mg, 0.39 mmol) in MeOH

(30 mL). The mixture was heated (50 °C) and TLC monitoring (PE/

EtOAc, 3:2) indicated completion of the reaction after 12 h. The

solvent was evaporated; then silica gel column chromatography

(PE/EtOAc, 3:2) afforded the benzylated amidoxime 3 (212 mg,

93%) as a white solid. R_f= 0.63 (PE/EtOAc, 1:1). M.p. 47–48 °C

(CH₂Cl₂/PE). [α]²_D⁰= +29 (c = 1, CHCl₃). ¹H NMR (300 MHz,

CD₃COCD₃): δ = 3.40–3.48 (m, 1 H, H-5), 3.54–3.68 (m, 4 H),

3.75–3.82 (m, 2 H), 4.40–4.86 (m, 8 H, 4 CH₂Ph), 5.26 (br. s, 2 H,

NH₂), 7.10–7.32 (m, 20 H, 4 CH₂Ph), 8.95 (br. s, 1 H, OH) ppm.

¹³C NMR (75 MHz, CD₃COCD₃): δ = 70.3 (C-6), 74.3, 75.4, 75.8,

76.4 (4 CH₂Ph), 79.1, 79.6, 81.4, 87.5 (C-1 to C-4), 80.2 (C-5),

128.62, 128.66, 128.8, 128.9, 129.1, 129.2, 129.4, 129.5, 129.6, 129.7

(CHarom), 139.9, 140.1, 140.2, 140.6 (C^IVarom), 152.4

(H₂NC=NOH) ppm. C₃₅H₃₈N₂O₆(582.69): calcd. C 72.14, H 6.57,

N 4.81, O 16.47; found C 71.65, H 6.52, N 4.87, O 16.36. MS

(LSIMS, glycerol): m/z = 583 [M+H]⁺. HRMS (LSIMS, glycerol):

m/z = C₃₅H₃₉N₂O₆[M+H]⁺calcd. 583.2808, found 583.2801.

5-(p-Nitrophenyl)-3-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-

C-(2,3,4,6-Tetra-O-benzoyl-β-

D

-glucopyranosyl)formamidoxime (4):

1,2,4-oxadiazole (7e). a) A solution of p-nitrobenzoic acid (11 mg,

0.065 mmol), benzylated amidoxime 3 (46 mg, 0.08 mmol,

1.2 equiv.) and EDCI (30 mg, 0.16 mmol, 2 equiv.) was treated ac-

cording to procedure A, to afford 7e (32 mg, 69%) after silica gel

column chromatography (PE/EtOAc, 7:3). b) A solution of p-nitro-

benzoyl chloride (15 mg, 0.08 mmol) and benzylated amidoxime 3

(48 mg, 0.08 mmol, 1 equiv.) was treated according to procedure

B. Silica gel column chromatography (PE/EtOAc, 7:3) afforded 7e

(45 mg, 76%) as a pale yellow solid. R_f= 0.73 (PE/EtOAc, 7:3).

M.p. 88–89 °C (CH₂Cl₂/PE). [α]²_D⁰= –42 (c = 0.75, CHCl₃). ¹H

NMR (300 MHz, CDCl₃): δ = 3.70 (m, 1 H, H-5), 3.76 (m, 2 H,

A solution of 2,3,4,6-tetra-O-benzoyl-β--glucopyranosyl cyanide

(2)^[25](4.32 g, 7.13 mmol) and hydroxylamine hydrochloride

(1.24 g, 17.83 mmol, 2.5 equiv.) in pyridine (10 mL) was heated at

50 °C for 8 h. The solvent was evaporated; then the mixture was

separated by silica gel column chromatography (PE/EtOAc, 1:1) to

obtain 4 (4.13 g, 90%) as a white solid. R_f= 0.48 (PE/EtOAc, 1:1).

M.p. 99–100 °C (CH₂Cl₂/PE). [α]²_D⁰= +17 (c = 1, CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 4.21 (ddd, 1 H, J_4,5= 9.7 Hz, J_5,6a

5.1 Hz, J_5,6b= 2.8 Hz, H-5), 4.31 (d, 1 H, J_1,2= 9.8 Hz, H-1), 4.47

(dd, 1 H, J_5,6a= 5.0 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.62 (dd, 1 H,

=

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Eur. J. Org. Chem. 2006, 4242–4256

5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

FULL PAPER

H-6a, H-6b), 3.81 (dd, 1 H, J_3,4= 8.9 Hz, J_4,5= 9.2 Hz, H-4), 3.87

(dd, 1 H, J_2,3= 8.7 Hz, J_3,4= 8.9 Hz, H-3), 4.07 (dd, 1 H, J_1,2

9.7 Hz, J_2,3= 8.7 Hz, H-2), 4.46 (d, 1 H, J = 11.5 Hz, CH₂Ph),

(C-1Ј), 135.7 (C-2Ј), 138.1 (C^IVarom), 138.3 (C^IVarom), 138.4

(C^IVarom), 138.9 (C^IVarom), 168.8 (C-3oxa), 176.6 (C-5oxa) ppm.

MS (ESI): m/z = 719.2 [M + H]⁺, 741.3 [M + Na]⁺, 1436.7

=

4.50 (d, 1 H, J = 12.2 Hz, CH₂Ph), 4.58 (d, 1 H, J = 12.2 Hz, [2 M+H]⁺, 1459.9 [2 M+Na]⁺. HRMS (LSIMS, NBA/AcONa):

CH₂Ph), 4.61 (d, 1 H, J = 10.7 Hz, CH₂Ph), 4.63 (d, 1 H, J_1,2

=

m/z = C₄₆H₄₂N₂O₆Na [M+Na]⁺calcd. 741.2941, found 741.2945.

9.7 Hz, H-1), 4.74 (d, 1 H, J = 11.5 Hz, CH₂Ph), 4.87 (d, 1 H, J =

10.7 Hz, CH₂Ph), 4.96 (s, 2 H, CH₂Ph), 6.93–7.37 (m, 20 H, 4

5-[(E)-Styryl]-3-C-(2,3,4,6-tetra-O-benzyl-β- -glucopyranosyl)-

D

1,2,4-oxadiazole (7l): A solution of cinnamoyl chloride (13 mg,

0.076 mmol) and benzylated amidoxime 3 (45 mg, 0.076 mmol,

1 equiv.) was treated according to procedure B. Silica gel column

chromatography (PE/EtOAc, 7:3) afforded 7l (25 mg, 47%) as a

white solid. R_f= 0.83 (PE/EtOAc, 7:3). M.p. 106–107 °C (CH₂Cl₂/

4

3

CH₂Ph), 8.24 (dt, 2 H, J_m= 2.0 Hz, J_o= 9.0 Hz, PhNO₂), 8.36

(dt, 2 H, ⁴J_m= 2.0 Hz, ³J_o= 9.0 Hz, PhNO₂) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 69.2 (C-6), 73.4 (C-1), 73.9, 75.2, 75.6, 76.2

(4 CH₂Ph), 78.2 (C-4), 79.9 (C-2), 80.3 (C-5), 87.4 (C-3), 124.7

(PhNO₂), 128.10, 128.14, 128.2, 128.32, 128.37, 128.41, 128.6,

128.8, 128.91, 128.92 (C^IVarom), 129.7 (PhNO₂), 138.1, 138.3,

138.4, 138.8 (C^IVarom), 150.6 (C-NO₂), 169.2 (C-3oxa), 174.3 (C-

5oxa) ppm. MS (ESI): m/z = 714.0 [M + H]⁺. HRMS (LSIMS,

NBA/AcONa): m/z = C₄₂H₃₉N₃O₈Na [M+Na]⁺calcd. 736.2635,

found 736.2637.

PE). [α]²_D⁰= –42 (c = 0.76, CHCl₃). H NMR (300 MHz, CDCl₃):

1

δ = 3.65–3.78 (m, 4 H, H-4, H-5, H-6a, H-6b), 3.84 (dd, 1 H, J_2,3

= 9.0 Hz, J_3,4= 8.7 Hz, H-3), 4.04 (dd, 1 H, J_1,2= 9.6 Hz, J_2,3

=

9.0 Hz, H-2), 4.43 (d, 1 H, J = 10.9 Hz, CH₂Ph), 4.51 (d, 1 H, J =

12.1 Hz, CH₂Ph), 4.56–4.59 (m, 3 H, H-1, CH₂Ph), 4.70 (d, 1 H, J

= 10.9 Hz, CH₂Ph), 4.85 (d, 1 H, J = 10,9 Hz, CH₂Ph), 4.93 (s, 2

H, CH₂Ph), 6.96 (d, 1 H, J = 16.5 Hz, CH = CHPh), 7.00–7.10

(m, 2 H, Harom), 7.12–7.23 (m, 5 H, Harom), 7.27–7.35 (m, 13 H,

Harom), 7.41–7.44 (m, 3 H, Harom), 7.56–7.61 (m, 2 H, Harom),

7.80 (d, 1 H, J = 16.5 Hz, CH=CHPh) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 69.3 (C-6), 73.5 (C-1), 73.9, 75.3, 75.6, 76.1 (4 CH₂Ph),

78.3 (C-4), 80.2, 80.3 (C-2, C-5), 87.2 (C-3), 110.5 (CH = CHPh),

128.0, 128.1, 128.1, 128.2, 128.3, 128.4, 128.4, 128.7, 128.8, 128.9,

129.5, 131.0, 134.7 (C^IVarom), 138.1 (C^IVarom), 138.3 (C^IVarom),

138.4 (C^IVarom), 138.8 (C^IVarom), 143.4 (CH = CHPh), 168.4 (C-

3oxa), 175.9 (C-5oxa) ppm. MS (ESI): m/z = 695.2 [M+H]⁺, 717.3

[M+Na]⁺, 1388.6 [2 M+H]⁺, 1410.8 [2 M+Na]⁺. HRMS (LSIMS,

NBA/AcONa): m/z = C₄₄H₄₂N₂O₆Na [M+Na]⁺calcd. 717.2941,

found 717.2938.

5-(3-Pyridyl)-3-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1,2,4-

oxadiazole (7g): A solution of nicotinoyl chloride hydrochloride

(15 mg, 0.08 mmol) and benzylated amidoxime 3 (50 mg,

0.08 mmol, 1 equiv.) was treated according to procedure B. Silica

gel column chromatography (PE/EtOAc, 2:3) afforded 7 g (58 mg,

97%) as a pale yellow solid. R_f= 0.63 (PE/EtOAc, 2:3). M.p. 98–

99 °C (CH₂Cl₂/PE). [α]²_D⁰= –41 (c = 0.67, CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 3.67 (m, 1 H, H-5), 3.75 (m, 2 H, H-6a,

H-6b), 3.80 (dd, 1 H, J_3,4= 8.7 Hz, J_4,5= 9.2 Hz, H-4), 3.87 (dd,

1 H, J_2,3= 9.0 Hz, J_3,4= 8.7 Hz, H-3), 4.08 (dd, 1 H, J_1,2= 9.4 Hz,

J_2,3= 9.0 Hz, H-2), 4.47 (d, 1 H, J = 11.0 Hz, CH₂Ph), 4.54 (d, 1

H, J = 12.1 Hz, CH₂Ph), 4.57 (d, 1 H, J = 12.1 Hz, CH₂Ph), 4.60

(d, 1 H, J = 10.7 Hz, CH₂Ph), 4.63 (d, 1 H, J_1,2= 9.4 Hz, H-1),

4.74 (d, 1 H, J = 11.0 Hz, CH₂Ph), 4.86 (d, 1 H, J = 10.7 Hz,

CH₂Ph), 4.95 (s, 2 H, CH₂Ph), 6.96–7.35 (m, 20 H, CH₂Ph), 7.46

(br. s, 1 H, Hpyr), 8.32 (d, 1 H, J = 7,8 Hz, Hpyr), 8.82 (br. s, 1 H,

Hpyr), 9.30 (br. s, 1 H, Hpyr) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 69.2 (C-6), 73.4 (C-1), 73.9, 75.2, 75.6, 76.2 (4 CH₂Ph), 78.3

(C-4), 80.0 (C-2), 80.3 (C-5), 87.4 (C-3), 128.1, 128.2, 128.2, 128.3,

128.4, 128.5, 128.6, 128.8, 128.9 (CHarom, CHpyr), 135.7 (CHpyr),

138.1, 138.3, 138.4, 138.8 (C^IVarom), 149.6 (CHpyr), 153.7 (CHpyr),

168.9 (C-3oxa), 174.3 (C-5oxa) ppm. MS (ESI): m/z = 670.1

[M+H]⁺, 1360.8 [2 M+Na]⁺. HRMS (LSIMS, NBA/AcONa): m/z

= C₄₁H₃₉N₃O₆Na [M+Na]⁺calcd. 692.2737, found 692.2730.

O-Acetyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamid-

oxime (6a): A solution of acetyl chloride (40 µL, 0.56 mmol) and

benzoylated amidoxime 4 (300 mg, 0.47 mmol) was treated accord-

ing to procedure C. Silica gel column chromatography (CH₂Cl₂/

EtOAc, 95:5) afforded 6a (193 mg, 61%) as a white solid. R_f= 0.38

(CH₂Cl₂/EtOAc, 95:5). M.p. 96–98 °C (CH₂Cl₂/PE). [α]²_D⁰= +0.3 (c

= 0.7, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.94 (s, 3 H,

CH₃), 4.27 (ddd, 1 H, J_4,5= 9.8 Hz, J_5,6a= 5.3 Hz, J_5,6b= 2.7 Hz,

H-5), 4.49 (d, 1 H, J_1,2= 9.8 Hz, H-1), 4.54 (dd, 1 H, J_5,6a= 5.3 Hz,

J_6a,6b12.4 Hz, H-6a), 4.65 (dd, 1 H, J_5,6b= 2.7 Hz, J_6a,6b= 12.4 Hz,

H-6b), 5.22 (s, 2 H, NH₂), 5.73 (t, 1 H, J_1,2= 9.8 Hz, J_2,3= 9.7 Hz,

H-2), 5.77 (t, 1 H, J_3,4= 9.7 Hz, J_4,5= 9.8 Hz, H-4), 5.98 (t, 1 H,

J_2,3= 9.7 Hz, J_3,4= 9.7 Hz, H-3), 7.22–7.83 (m, 11 H, Harom),

7.92–8.05 (m, 9 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

19.8 (CH₃), 63.4 (C-6), 69.6 (C-4), 70.3 (C-2), 74.1 (C-3), 76.1 (C-

1), 77.0 (C-5), 128.7, 128.8, 128.9, 128.9, 128.9 (C^IVarom), 129.1

(C^IVarom), 129.2 (C^IVarom), 129.8 (C^IVarom), 130.1, 130.2, 130.3,

130.4, 133.7, 133.8, 134.0, 153.6 (H₂NC = NOH), 165.7, 165.9,

166.0, 166.6 (4 OCOPh), 168.7 (NOCO) ppm. MS (LSIMS, NBA):

m/z = 681 [M+H]⁺. HRMS (LSIMS, NBA): m/z = C₃₇H₃₃N₂O₁₁

[M+H]⁺calcd. 681.2084, found 681.2089.

5-(2-Naphthyl)-3-C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-

1,2,4-oxadiazole (7k): A solution of 2-naphthoyl chloride (17 mg,

0.09 mmol) and benzylated amidoxime 3 (52 mg, 0.09 mmol,

1 equiv.) was treated according to procedure B. Silica gel column

chromatography (PE/EtOAc, 4:1) afforded 7k (35 mg, 55%) as a

white solid. R_f= 0.71 (PE/EtOAc, 4:1). M.p. 112–113 °C (CH₂Cl₂/

1

PE). [α]²_D⁰= –44 (c = 0.88, CHCl₃). H NMR (300 MHz, CDCl₃):

δ = 3.68 (m, 1 H, H-5), 3.77 (m, 2 H, H-6a, H-6b), 3.82 (dd, 1 H,

J_3,4= 8.9 Hz, J_4,5= 9.0 Hz, H-4), 3.88 (dd, 1 H, J_2,3= 8.8 Hz, J_3,4

= 8.9 Hz, H-3), 4.13 (dd, 1 H, J_1,2= 9.7 Hz, J_2,3= 8.8 Hz, H-2),

4.49 (d, 1 H, J = 10.9 Hz, CH₂Ph), 4.56 (d, 1 H, J = 12.2 Hz,

CH₂Ph), 4.60 (d, 1 H, J = 12.2 Hz, CH₂Ph), 4.61 (d, 1 H, J =

10.7 Hz, CH₂Ph), 4.65 (d, 1 H, J_1,2= 9.7 Hz, H-1), 4.73 (d, 1 H, J

= 10.9 Hz, CH₂Ph), 4.87 (d, 1 H, J = 10.7 Hz, CH₂Ph), 4.95 (s, 2

H, CH₂Ph), 6.96–7.12 (m, 5 H, Harom), 7.15–7.18 (m, 2 H,

O-Benzoyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formami-

doxime (6b): A solution of benzoyl chloride (39 µL, 0.34 mmol) and

benzoylated amidoxime 4 (200 mg, 0.31 mmol) was treated accord-

ing to procedure C. Silica gel column chromatography (PE/EtOAc,

Harom), 7.27–7.36 (m, 13 H, Harom), 7.55–7.56 (m, 2 H, H-6Ј, H- 3:2) afforded 6b (204 mg, 88%) as a white solid. R_f= 0.47 (PE/

7Ј), 7.87–7.99 (m, 3 H, H-4Ј, H-5Ј, H-8Ј), 8.12 (dd, 1 H, J_1Ј,3Ј

=

EtOAc, 3:2). M.p. 98–100 °C (CH₂Cl₂/PE). [α]²_D⁰= –47 (c = 1,

1

1.7 Hz, J_3Ј,4Ј= 8.7 Hz, H-3Ј), 8.67 (pd, 1 H, J_1Ј,3Ј= 1,7 Hz, H-1Ј)

CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.29 (ddd, 1 H, J_4,5

=

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 69.2 (C-6), 73.6 (C-1), 73.9, 9.6 Hz, J_5,6a= 5.4 Hz, J_5,6b= 2.7 Hz, H-5), 4.53 (dd, 1 H, J_5,6a

75.3, 75.6, 76.1 (4 CH₂Ph), 78.2 (C-4), 80.2, 80.3 (C-2, C-5), 87.3

(C-3), 121.7, 133.1 (C-4Јa, C-8Јa), 124.3 (C-3Ј), 127.6, 128.1, 128.1,

128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 128.9, 129.4, 129.6, 129.8

5.4 Hz, J_6a,6b= 12.3 Hz, H-6a), 4.60 (d, 1 H, J_1,2= 9.9 Hz, H-1),

4.65 (dd, 1 H, J_5,6b= 2.7 Hz, J_6a,6b= 12.3 Hz, H-6b), 5.24 (s, 2 H,

NH₂), 5.75 (t, 1 H, J_1,2= 9.9 Hz, J_2,3= 9.6 Hz, H-2), 5.78 (t, 1 H,

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FULL PAPER

J_3,4= 9.6 Hz, J_4,5= 9.6 Hz, H-4), 5.99 (t, 1 H, J_2,3= 9.6 Hz, J_3,4

0.25 mmol) and benzoylated amidoxime 4 (135 mg, 0.21 mmol) was

= 9.6 Hz, H-3), 7.23–7.58 (m, 15 H, Harom), 7.82 (dd, 2 H, J = treated according to procedure C. Silica gel column chromatog-

1.4 Hz, J = 8.5 Hz, Harom), 7.90–7.96 (m, 6 H, Harom), 8.04 (dd, raphy (PE/EtOAc, 3:2) afforded 6e (166 mg, 100%) as a white solid.

2 H, J = 1.4 Hz, J = 8.5 Hz, Harom) ppm. ¹³C NMR (75 MHz,

R_f= 0.54 (PE/EtOAc, 3:2). M.p. 114–115 °C (CH₂Cl₂/PE). [α]²_D⁰

=

1

CDCl₃): δ = 63.4 (C-6), 69.6 (C-4), 70.4 (C-2), 74.1 (C-3), 76.3 (C- –57 (c = 1, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.35 (ddd,

1), 77.1 (C-5), 128.7, 128.8, 128.9, 128.9, 129.1 (C^IVarom), 129.2

(C^IVarom), 129.5 (C^IVarom), 129.8 (C^IVarom), 129.9, 130.1, 130.2,

130.3, 130.4, 133.4, 133.7, 133.8, 154.6 (H₂NC=NO), 163.7

1 H, J_4,5= 9.8 Hz, J_5,6a= 5.2 Hz, J_5,6b= 2.7 Hz, H-5), 4.58 (dd, 1

H, J_5,6a= 5.2 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.64 (d, 1 H, J_1,2

9.8 Hz, H-1), 4.66 (dd, 1 H, J_5,6b= 2.7 Hz, J_6a,6b= 12.4 Hz, H-6b),

=

(NOCO), 165.7, 166.0, 166.1, 166.6 (4 OCOPh) ppm. C₄₂H₃₄N₂O₁₁5.47 (s, 2 H, NH₂), 5.81 (t, 1 H, J_1,2= 9.8 Hz, J_2,3= 9.6 Hz, H-2),

(742.73): calcd. C 67.92, H 4.61, N 3.77, O 23.70; found C 67.66,

H 4.92, N 3.79, O 23.41. MS (LSIMS, NBA): m/z = 743.6

[M+H]⁺. HRMS (LSIMS, NBA): m/z = C₄₂H₃₅N₂O₁₁[M+H]⁺

calcd. 743.2241, found 743.2243.

5.83 (t, 1 H, J_3,4= 9.6 Hz, J_4,5= 9.8 Hz, H-4), 6.04 (t, 1 H, J_2,3=

9.6 Hz, J_3,4= 9.6 Hz, H-3), 7.21–7.54 (m, 12 H, Harom), 7.80–8.13

(m, 12 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = (ppm)

63.5 (C-6), 69.6 (C-4), 70.5 (C-2), 74.0 (C-3), 76.0 (C-1), 77.1 (C-5),

123.9, 128.7, 128.8, 128.9, 128.9, 129.0 (C^IVarom), 129.1 (C^IVarom),

129.7 (C^IVarom), 130.1, 130.2, 130.3, 130.4, 130.9, 133.8, 133.9,

134.1, 134.9 (C^IVarom), 150.7 (C^IVarom), 155.4 (H₂NC=NO), 162.0

(NOCO), 165.7, 166.0, 166.2, 166.6 (4 OCOPh) ppm. C₄₂H₃₃N₃O₁₃

(787.72): calcd. C 64.04, H 4.22, N 5.33, O 26.40; found C 63.60,

H 4.18, N 5.31, O 25.68.

O-(p-Anisoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)form-

amidoxime (6c): A solution of p-anisoyl chloride (58 µL,

0.43 mmol) and benzoylated amidoxime 4 (250 mg, 0.39 mmol) was

treated according to procedure C. Silica gel column chromatog-

raphy (PE/EtOAc, 3:2) afforded 6c (262 mg, 87%) as a pale yellow

solid. R_f= 0.52 (PE/EtOAc, 1:1). M.p. 100–101 °C (CH₂Cl₂/PE).

[α]²_D⁰= –62 (c = 0.56, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ =

3.80 (s, 3 H, OCH₃), 4.28 (ddd, 1 H, J_4,5= 9.9 Hz, J_5,6a= 5.3 Hz,

J_5,6b= 2.7 Hz, H-5), 4.53 (dd, 1 H, J_5,6a= 5.3 Hz, J_6a,6b= 12.5 Hz,

O-(m-Chlorobenzoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-D-gluco-

pyranosyl)formamidoxime (6f): A solution of m-chlorobenzoyl chlo-

ride (54 µL, 0.42 mmol) and benzoylated amidoxime 4 (223 mg,

0.35 mmol) was treated according to procedure C. Silica gel column

chromatography (PE/EtOAc, 3:2) afforded 6f (253 mg, 93%) as a

white solid. R_f= 0.55 (PE/EtOAc, 3:2). M.p. 96–97 °C (CH₂Cl₂/

H-6a), 4.59 (d, 1 H, J_1,2= 9.9 Hz, H-1), 4.65 (dd, 1 H, J_5,6b

=

2.7 Hz, J_6a,6b= 12.5 Hz, H-6b), 5.19 (s, 2 H, NH₂), 5.76 (m, 2 H,

H-2, H-4), 5.98 (t, 1 H, J_2,3= 9.6 Hz, J_3,4= 9.6 Hz, H-3), 6.84 (d,

2 H, J = 8.9 Hz, H-2Ј, H-6Ј), 7.24–7.58 (m, 12 H, Harom), 7.81–

7.96 (m, 6 H, Harom), 7.88 (d, 2 H, J = 8.9 Hz, H-3Ј, H-5Ј), 8.04

(m, 2 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 55.4

(OCH₃), 63.0 (C-6), 69.2 (C-4), 69.9 (C-2), 73.7 (C-3), 75.9 (C-1),

76.7 (C-5), 113.6 (C-2Ј, C-6Ј), 121.3 (C-4Ј), 128.3, 128.4, 128.47,

128.51 (C^IVarom), 128.7 (C^IVarom), 128.8 (C^IVarom), 129.4

(C^IVarom), 129.7, 129.8, 129.9, 130.0, 131.5 (C-3Ј, C-5Ј), 133.27 (2

C), 133.33, 133.6, 153.8 (H₂NC=NO), 163.1 (NOCO), 163.4 (C-1Ј),

165.3, 165.6, 165.7, 166.2 (4 OCOPh) ppm. C₄₃H₃₆N₂O₁₂(772.75):

calcd. C 66.83, H 4.70, N 3.63, O 24.85; found C 66.63, H 4.83, N

3.48, O 24.90.

PE). [α]²_D⁰= –48 (c = 0.95, CHCl₃). H NMR (300 MHz, CDCl₃):

1

δ = 4.28 (ddd, 1 H, J_4,5= 9.8 Hz, J_5,6a= 5.4 Hz, J_5,6b= 2.6 Hz, H-

5), 4.53 (dd, 1 H, J_5,6a= 5.4 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.57 (d,

1 H, J_1,2= 9.8 Hz, H-1), 4.66 (dd, 1 H, J_5,6b= 2.6 Hz, J_6a,6b

=

12.4 Hz, H-6b), 5.21 (s, 2 H, NH₂), 5.72 (t, 1 H, J_1,2= 9.8 Hz, J_2,3

= 9.6 Hz, H-2), 5.77 (t, 1 H, J_3,4= 9.6 Hz, J_4,5= 9.8 Hz, H-4), 5.98

(t, 1 H, J_2,3= 9.6 Hz, J_3,4= 9.6 Hz, H-3), 7.25–7.60 (m, 14 H,

Harom), 7.78–7.84 (m, 3 H, Harom), 7.88 (t, 1 H, J = 1.7 Hz,

Harom), 7.92–7.96 (m, 4 H, Harom), 8.03–8.06 (m, 2 H, Harom)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.3 (C-6), 69.5 (C-4), 70.4

(C-2), 74.0 (C-3), 76.2 (C-1), 77.2 (C-5), 128.0, 128.8, 128.9, 129.1

(C^IVarom), 129.8 (C^IVarom), 129.9, 130.1, 130.2, 130.3, 130.4, 131.2

(C^IVarom), 133.5, 133.7, 133.8, 134.1, 135.0 (C^IVarom), 154.7

(H₂NC=NO), 162.5 (NOCO), 165.7, 166.0, 166.1, 166.6 (4 OC-

OPh) ppm. MS (ESI): m/z = 777.0 [M + H]⁺, 799.1 [M + Na]⁺,

1554.7 [2 M + H]⁺, 1574.6 [2 M + Na]⁺. HRMS (LSIMS, NBA/

AcONa): m/z = C₄₂H₃₃ClN₂O₁₁Na [M + Na]⁺calcd. 799.1671,

found 799.1680.

C-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-O-(p-toluoyl)form-

amidoxime (6d): A solution of p-toluoyl chloride (45 µL,

0.34 mmol) and benzoylated amidoxime 4 (200 mg, 0.31 mmol) was

treated according to procedure C. Silica gel column chromatog-

raphy (PE/EtOAc, 7:3) afforded 6d (160 mg, 67%) as a white solid.

R_f= 0.38 (PE/EtOAc, 7:3). M.p. 105–107 °C (CH₂Cl₂/PE). [α]²_D⁰

=

–56 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 2.30 (s, 3

H, CH₃), 4.30 (ddd, 1 H, J_4,5= 9.7 Hz, J_5,6a= 5.5 Hz, J_5,6b

O-Nicotinoyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)form-

=

amidoxime (6g): A solution of nicotinoyl chloride hydrochloride

(58 mg, 0.33 mmol) and benzoylated amidoxime 4 (150 mg,

0.23 mmol) was treated according to procedure C. The mixture was

diluted with saturated aqueous NaHCO₃(20 mL) and the aqueous

layer extracted with CHCl₃(3×20 mL). Organic layers were com-

bined, dried (Na₂SO₄), filtered and the solvents evaporated. Silica

gel column chromatography (PE/EtOAc, 3:7) afforded 6g (156 mg,

93%) as a white solid. R_f= 0.45 (PE/EtOAc, 3:7). M.p. 115–116 °C

(CH₂Cl₂:PE). [α]²_D⁰= –43 (c = 1, CHCl₃). ¹H NMR (300 MHz,

2.7 Hz, H-5), 4.54 (dd, 1 H, J_5,6a= 5.5 Hz, J_6a,6b= 12.3 Hz, H-6a),

4.63 (d, 1 H, J_1,2= 9.8 Hz, H-1), 4.65 (dd, 1 H, J_5,6b= 2.7 Hz,

J_6a,6b= 12.3 Hz, H-6b), 5.30 (s, 2 H, NH₂), 5.80 (t, 1 H, J_2,3

=

9.5 Hz, J_1,2= 9.8 Hz, H-2), 5.81 (t, 1 H, J_3,4= 9.5 Hz, J_4,5= 9.7 Hz,

H-4), 6.01 (t, 1 H, J_2,3= 9.5 Hz, J_3,4= 9.5 Hz, H-3), 7.10 (d, 2 H,

J = 8.0 Hz, Htol), 7.21–7.55 (m, 12 H, Harom), 7.81 (m, 4 H, J =

8.4 Hz, J = 8.1 Hz, Htol, Harom), 7.92–7.96 (m, 4 H, Harom), 8.03

(m, 2 H, J = 8.4 Hz, J = 1.4 Hz, Harom) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 22.0 (CH₃), 63.5 (C-6), 69.7 (C-4), 70.4 (C-2), 74.2 (C-

3), 76.4 (C-1), 77.1 (C-5), 126.7 (C^IVarom), 128.7, 128.8, 128.9,

129.0 (C^IVarom), 129.1 (C^IVarom), 129.2 (C^IVarom), 129.5, 129.8

(C^IVarom), 129.9, 130.1, 130.2, 130.3, 130.4, 133.7, 133.8, 134.1,

144.1 (C^IVtol), 154.5 (H₂NC=NO), 163.8 (NOCO), 165.7, 166.1,

166.2, 166.6 (4 OCOPh) ppm. MS (LSIMS, glycerol): m/z = 779

[M + Na]⁺. HRMS (LSIMS, glycerol): m/z = C₄₃H₃₆N₂NaO₁₁

[M+Na]⁺calcd. 779.2217, found 779.2220.

CDCl₃): δ = 4.36 (ddd, 1 H, J_4,5= 9.7 Hz, J_5,6a= 5.2 Hz, J_5,6b

=

2.8 Hz, H-5), 4.58 (dd, 1 H, J_5,6a= 5.2 Hz, J_6a,6b= 12.4 Hz, H-6a),

4.65 (d, 1 H, J_1,2= 9.7 Hz, H-1), 4.68 (dd, 1 H, J_5,6b= 2.8 Hz,

J_6a,6b= 12.4 Hz, H-6b), 5.61 (s, 2 H, NH₂), 5.84 (t, 1 H, J_3,4

=

9.6 Hz, J_4,5= 9.7 Hz, H-4), 5.85 (t, 1 H, J_1,2= 9.7 Hz, J_2,3= 9.6 Hz,

H-2), 6.05 (t, 1 H, J_2,3= 9.6 Hz, J_3,4= 9.6 Hz, H-3), 7.21–7.57 (m,

13 H, Harom), 7.83–8.18 (m, 9 H, Harom), 8.68 (d, 1 H, J = 3.0 Hz,

Harom), 9.13 (s, 1 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃):

O-(p-Nitrobenzoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-

formamidoxime (6e): A solution of p-nitrobenzoyl chloride (47 mg,

D

-glucopyranosyl)- δ = 63.5 (C-6), 69.6 (C-4), 70.4 (C-2), 74.1 (C-3), 76.2 (C-1), 77.1

(C-5), 123.8, 125.7 (C^IVarom), 128.7, 128.8, 128.9, 129.1 (C^IVarom),

4248

www.eurjoc.org

Eur. J. Org. Chem. 2006, 4242–4256

5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

FULL PAPER

129.2 (C^IVarom), 129.7 (C^IVarom), 130.1, 130.2, 130.3, 130.4, 133.7, 5.37 (s, 2 H, NH₂), 5.85 (t, 1 H, J_3,4= 9.6 Hz, J_4,5= 9.7 Hz, H-4),

133.8, 133.9, 134.1, 137.5, 150.7, 153.7, 155.2 (H₂NC=NO), 162.5 5.86 (t, 1 H, J_1,2= 9.8 Hz, J_2,3= 9.6 Hz, H-2), 6.09 (t, 1 H, J_2,3

(NOCO), 165.7, 166.1, 166.2, 166.6 (4 OCOPh) ppm. C₄₁H₃₃N₃O₁₁9.6 Hz, J_3,4= 9.6 Hz, H-3), 7.17–7.50 (m, 15 H, Harom), 7.73–8.04

=

(743.71): calcd. C 66.21, H 4.47, N 5.65, O 23.66; found C 65.54,

H 4.63, N 5.71, O 23.47.

(m, 11 H, Harom), 8.44 (dd, 1 H, J = 1.1 Hz, J = 9.1 Hz, Harom)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.6 (C-6), 69.8 (C-4), 70.6

(C-2), 74.2 (C-3), 76.4 (C-1), 77.1 (C-5), 124.8, 126.0, 126.8, 127.2

(C^IVarom), 128.2, 128.8, 128.8, 128.9, 129.0, 129.2 (C^IVarom), 129.3

(C^IVarom), 129.5, 129.8 (C^IVarom), 130.1, 130.2, 130.4, 130.5, 131.6

(C^IVarom), 133.4, 133.7, 133.8, 133.9, 134.0 (C^IVarom), 134.1, 154.7

(H₂NC=NO), 165.0 (NOCO), 165.8, 166.2, 166.3, 166.7 (4 OC-

OPh) ppm. C₄₆H₃₆N₂O₁₁(792.78): calcd. C 69.69, H 4.58, N 3.53,

O 22.20; found C 69.12, H 4.62, N 3.46, O 21.55.

O-(2-Furoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)form-

amidoxime (6h): A solution of 2-furoyl chloride (32 µL, 0.33 mmol)

and benzoylated amidoxime 4 (200 mg, 0.31 mmol) was treated ac-

cording to procedure C. Silica gel column chromatography (PE/

EtOAc, 3:2) afforded 6h (165 mg, 72%) as a white solid. R_f= 0.32

(PE/EtOAc, 3:2). M.p. 104–106 °C (CH₂Cl₂/PE). [α]²_D⁰= –48 (c =

0.68, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.30 (ddd, 1 H,

J_4,5= 9.4 Hz, J_5,6a= 5.2 Hz, J_5,6b= 2.8 Hz, H-5), 4.54 (dd, 1 H,

J_5,6a= 5.2 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.61 (d, 1 H, J_1,2= 10.2 Hz,

H-1), 4.65 (dd, 1 H, J_5,6b= 2.8 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.41 (s,

2 H, NH₂), 5.81 (m, 2 H, H-2, H-4), 6.00 (t, 1 H, J_2,3= 9.6 Hz,

J_3,4= 9.6 Hz, H-3), 6.35 (dd, 1 H, J_3Ј,4Ј= 3.3 Hz, J_4Ј,5Ј= 1.7 Hz,

H-4Ј), 7.11 (d, 1 H, J_3Ј,4Ј= 3.3 Hz, H-3Ј), 7.20–7.55 (m, 11 H,

Harom), Ϸ 7.46 (d, 1 H, J_4Ј,5Ј= 1.7 Hz, H-5Ј), 7.81–8.04 (m, 9 H,

Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.5 (C-6), 69.6,

70.4 (C-2, C-4), 74.2 (C-3), 76.2 (C-1), 77.1 (C-5), 112.2 (C-4Ј),

118.8 (C-3Ј), 128.7, 128.8, 128.8, 128.9, 128.9 (C^IVarom), 129.1

(C^IVarom), 129.8 (C^IVarom), 130.1, 130.2, 130.3, 130.4, 133.7, 133.8,

134.1, 143.5 (C-2Ј), 146.8 (C-5Ј), 154.8 (H₂NC=NO), 156.1

(NOCO), 165.7, 166.1, 166.2, 166.6 (4 OCOPh) ppm. MS (LSIMS,

NBA/AcONa): m/z = 755 [M + Na]⁺. HRMS (LSIMS, NBA/

AcONa): m/z = C₄₀H₃₂N₂O₁₂Na [M+Na]⁺calcd. 755.1853, found

755.1858.

O-(2-Naphthoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-

formamidoxime (6k): A solution of 2-naphthoyl chloride (89 mg,

0.47 mmol) and benzoylated amidoxime 4 (200 mg, 0.31 mmol) was

treated according to procedure C. Silica gel column chromatog-

raphy (PE/EtOAc, 3:2) afforded 6h (154 mg, 62%) as a white solid.

R_f= 0.63 (PE/EtOAc, 3:2). M.p. 105–106 °C (CH₂Cl₂/PE). [α]²_D⁰

–72 (c = 1, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.29 (ddd,

1 H, J_4,5= 9.7 Hz, J_5,6a= 5.4 Hz, J_5,6b= 2.6 Hz, H-5), 4.54 (dd, 1

=

1

H, J_5,6a= 5.4 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.62 (d, 1 H, J_1,2

=

9.9 Hz, H-1), 4.67 (dd, 1 H, J_5,6b= 2.6 Hz, J_6a,6b= 12.4 Hz, H-6b),

5.25 (s, 2 H, NH₂), 5.75 (t, 1 H, J_1,2= 9.9 Hz, J_2,3= 9.6 Hz, H-2),

5.78 (t, 1 H, J_3,4= 9.6 Hz, J_4,5= 9.7 Hz, H-4), 6.00 (t, 1 H, J_2,3

=

9.6 Hz, J_3,4= 9.6 Hz, H-3), 7.26–7.59 (m, 14 H, Harom), 7.82–7.97

(m, 10 H, Harom), 8.06 (m, 2 H, Harom), 8.49 (br. s, 1 H, Harom)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.4 (C-6), 69.5 (C-4), 70.4

(C-2), 74.1 (C-3), 76.3 (C-1), 77.2 (C-5), 125.4, 126.7, 127.2, 128.2,

128.6 128.7, 128.9, 128.9, 129.2 (C^IVarom), 129.7, 129.8 (C^IVarom),

130.1, 130.2, 130.3, 130.4, 131.4, 132.8 (C^IVarom), 133.7, 133.8,

134.1, (C arom), 135.9 (C^IVarom), 154.5 (H₂NC = NOH), 163.9

(NOCO), 165.7, 166.0, 166.2, 166.6 (4 OCOPh) ppm. C₄₆H₃₆N₂O₁₁

(792.78): calcd. C 69.69, H 4.58, N 3.53, O 22.20; found C 68.19,

H 4.57, N 3.48, O 21.68.

C-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-O-(2-thienoyl)form-

amidoxime (6i): A solution of 2-thienoyl chloride (35 µL,

0.33 mmol) and benzoylated amidoxime 4 (200 mg, 0.31 mmol) was

treated according to procedure C. Silica gel column chromatog-

raphy (PE/EtOAc, 3:2) afforded 6i (186 mg, 79%) as a white solid.

R_f= 0.37 (PE/EtOAc, 3:2). M.p. 102–103 °C (CH₂Cl₂/PE). [α]²_D⁰

=

O-[(1S)-N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}valinoyl]-C-

(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamidoxime (6m):

–44 (c = 0.55, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 4.31 (ddd,

1 H, J_4,5= 9.8 Hz, J_5,6a= 5.4 Hz, J_5,6b= 2.8 Hz, H-5), 4.55 (dd, 1

HOBt (52 mg, 0.39 mmol), EDCI (75 mg, 0.39 mmol), Fmoc-Val-

OH (111 mg, 0.33 mmol) and amidoxime 4 (250 g, 0.39 mmol) in

CH₂Cl₂/DMF (9:1, 10 mL) were treated according to procedure D.

The solvent was evaporated and the crude product dissolved in

EtOAc (50 mL). The organic layer was washed with saturated aque-

ous NaHCO₃(2×50 mL), water (50 mL), 0.5  aqueous KHSO₄

(2×50 mL) and brine (50 mL), dried (MgSO₄), filtered and concen-

trated to dryness. Silica gel column chromatography (PE/EtOAc,

7:3) afforded 6m (235 mg, 75%) as a white solid. R_f= 0.26 (PE/

EtOAc, 7:3). M.p. 173–175 °C (CH₂Cl₂/hexane). [α]²_D⁰= –8 (c =

H, J_5,6a= 5.4 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.61 (d, 1 H, J_1,2

9.9 Hz, H-1), 4.66 (dd, 1 H, J_5,6b= 2.8 Hz, J_6a,6b= 12.4 Hz, H-6b),

5.35 (s, 2 H, NH₂), 5.81 (t, 1 H, J_1,2= 9.9 Hz, J_2,3= 9.5 Hz, H-2),

5.82 (t, 1 H, J_3,4= 9.5 Hz, J_4,5= 9.8 Hz, H-4), 6.01 (t, 1 H, J_2,3

9.5 Hz, J_3,4= 9.5 Hz, H-3), 6.95 (dd, 1 H, J_4Ј,5Ј= 4.9 Hz, J_3Ј,4Ј

3.8 Hz, H-4Ј), 7.20–7.54 (m, 12 H, Harom), 7.43 (dd, 1 H, J_4Ј,5Ј

4.9 Hz, J_3Ј,5Ј= 1.2 Hz, H-5Ј), 7.72 (dd, 1 H, J_3Ј,4Ј= 3.8 Hz, J_3Ј,5Ј

=

1.2 Hz, H-3Ј), 7.80–8.05 (m, 8 H, Harom) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 63.5 (C-6), 69.7 (C-4), 70.4 (C-2), 74.2 (C-

3), 76.2 (C-1), 77.1 (C-5), 128.1 (C-4Ј), 128.8, 128.9, 128.9, 129.0

(C^IVarom), 129.2, 129.2 (C^IVarom), 129.8, 130.1, 130.2, 130.3, 130.4,

132.0 (C^IVarom), 132.9 (C-5Ј), 133.7, 133.8, 134.1 (C-3Ј), 134.2,

154.5 (H₂NC=NO), 159.4 (NOCO), 165.7, 166.1, 166.2, 166.6 (4

OCOPh) ppm. MS (LSIMS, NBA): m/z = 749.9 [M+H]⁺. HRMS

(LSIMS, NBA): m/z = C₄₀H₃₃N₂O₁₁S [M+H]⁺calcd. 749.1805,

found 749.1809.

1

0.92, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 0.81 (d, 3 H, J =

6.7 Hz, CH₃), 0.86 (d, 3 H, J = 6.7 Hz, CH₃), 2.04 (m, 1 H, J_Hα,Hβ

= 5.1 Hz, H-β), 4.17 (t, 1 H, J = 6.8 Hz, J = 6.8 Hz, HFmoc), 4.23

(ddd, 1 H, J_4,5= 9.9 Hz, J_5,6a= 5.2 Hz, J_5,6b= 2.8 Hz, H-5), 4.30

(dd, 1 H, J_Hα,Hβ= 5.1 Hz, J_Hα,NH= 9.5 Hz, H-α), 4.38 (d, 2 H, J

= 6.8 Hz, CH₂Fmoc), 4.46 (d, 1 H, J_1,2= 9,7 Hz, H-1), 4.50 (dd, 1

H, J_5,6a= 5.2 Hz, J_6a,6b= 12.2 Hz, H-6a), 4.65 (dd, 1 H, J_5,6b

=

O-(1-Naphthoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-

D

-glucopyranosyl)-

2.8 Hz, J_6a,6b= 12.2 Hz, H-6b), 5.20 (s, 2 H, NH₂), 5.23 (d, 1 H,

J_Hα,NH= 9.5 Hz, NH), 5.67 (t, 1 H, J_1,2= 9.7 Hz, J_2,3= 9.6 Hz,

H-2), 5.76 (t, 1 H, J_3,4= 9.6 Hz, J_4,5= 9.9 Hz, H-4), 5.95 (t, 1 H,

J_2,3= 9.6 Hz, J_3,4= 9.6 Hz, H-3), 7.23–7.58 (m, 18 H, Harom),

7.75 (d, 2 H, J = 9.0 Hz, Harom), 7.80 (m, 2 H, Harom), 7.88–

7.95 (m, 4 H, Harom), 8.02–8.05 (m, 2 H, Harom) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 17.9 (CH₃), 19.3 (CH₃), 31.7 (C-β), 47.6

formamidoxime (6j): A solution of 1-naphthoyl chloride (225 mg,

1.18 mmol) and benzoylated amidoxime 4 (420 mg, 0.66 mmol) was

treated according to procedure C. Silica gel column chromatog-

raphy (PE/EtOAc, 3:2) afforded 6j (465 mg, 90%) as a white solid.

R_f= 0.47 (PE/EtOAc, 3:2). M.p. 90–92 °C (CH₂Cl₂/PE). [α]²_D⁰

=

1

–39 (c = 1, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.35 (ddd,

1 H, J_4,5= 9.7 Hz, J_5,6a= 5.4 Hz, J_5,6b= 2.6 Hz, H-5), 4.56 (dd, 1 (CHFmoc), 58.5 (C-α), 63.3 (C-6), 67.4 (CH₂Fmoc), 69.4 (C-4), 70.3

H, J_5,6a= 5.4 Hz, J_6a,6b= 12.3 Hz, H-6a), 4.66 (dd, 1 H, J_5,6b

2.6 Hz, J_6a,6b= 12.3 Hz, H-6b), 4.71 (d, 1 H, J_1,2= 9.8 Hz, H-1),

=

(C-2), 73.9 (C-3), 76.0 (C-1), 77.2 (C-5), 120.4, 125.4, 127.5, 128.1,

128.6 128.7, 128.9, 129.0 (C^IVarom), 129.2 (C^IVarom), 129.8

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4249

J.-P. Praly et al.

FULL PAPER

(C^IVarom), 130.1, 130.2, 130.3, 130.4, 133.7, 134.0, 141.7 7.93 (d, 2 H, J = 7.8 Hz, Harom), 8.01–8.08 (m, 4 H, Harom) ppm.

(2 C^IVarom), 144.1 (C^IVarom), 144.3 (C^IVarom), 154.6 (H₂NC=NO),

156.6 (COFmoc), 165.7, 166.0, 166.0, 166.6 (4 OCOPh), 169.2

(NOCO) ppm. MS (LSIMS, NBA): m/z = 960 [M+H]⁺. HRMS

¹³C NMR (75 MHz, CDCl₃): δ = 63.7 (C-6), 69.8 (C-4), 71.0 (C-

2), 73.0 (C-1), 74.6 (C-3), 77.5 (C-5), 124.1 (C^IVarom), 128.7, 128.8,

128.9, 129.1 (C^IVarom), 129.2 (C^IVarom), 129.2 (C^IVarom), 129.4,

(LSIMS, NBA): m/z = C₅₅H₅₀N₃O₁₃[M+ H]⁺calcd. 960.3344, 129.9 (C^IVarom), 130.2, 130.3, 133.4, 133.5, 133.7, 133.9, 165.1,

found 960.3350.

165.6, 166.3 166.6 (4 OCOPh), 167.3 (C-3oxa), 177.0 (C-5oxa)

ppm. MS (LSIMS, NBA): m/z = 725.2 [M+H]⁺. HRMS (LSIMS,

NBA): m/z = C₄₂H₃₃N₂O₁₀[M + H]⁺calcd. 725.2135, found

725.2138.

C-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-O-[(2,3,4,6-tetra-

O-benzoyl-β-D-glucopyranosyl)formyl]formamidoxime (6o): HOBt

(52 mg, 0.39 mmol), EDCI (74 mg, 0.39 mmol), C-(2,3,4,6-tetra-O-

benzoyl-β--glucopyranosyl)formic acid^[36](200 mg, 0.32 mmol)

and amidoxime 4 (250 g, 0.39 mmol) in CH₂Cl₂/DMF (9:1, 10 mL)

were treated according to procedure D. The solvent was evaporated

and the crude product dissolved in EtOAc (50 mL). The organic

layer was washed with saturated aqueous NaHCO₃(2×50 mL),

water (50 mL), 0.5  aqueous KHSO₄(2 × 50 mL) and brine

(50 mL), dried (MgSO₄), filtered and concentrated to dryness. Sil-

ica gel column chromatography (PE/EtOAc, 3:2) afforded 6o

(200 mg, 50%) as a white solid. R_f= 0.42 (PE/EtOAc, 3:2). M.p.

95–96 °C (CH₂Cl₂/hexane). [α]²_D⁰= –7 (c = 0.65, CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 4.14 (m, 1 H, H-5), 4.22 (m, 1 H, H-5Ј),

4.42–4.56 (m, 4 H, H-1, H-1Ј, H-6a, H-6Јa), 4.63–4.72 (m, 2 H, H-

6b, H-6Јb), 5.45 (br. s, 2 H, NH₂), 5.63–5.99 (m, 6 H, H-2, H-2Ј,

5-(p-Methoxyphenyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-gluco-

pyranosyl)-1,2,4-oxadiazole (8c): A solution of 6c (213 mg,

0.28 mmol) was treated according to procedure E for 17 d. Silica

gel column chromatography (PE/EtOAc, 3:2) afforded 8c (180 mg,

87%) as a pale yellow solid. R_f= 0.45 (PE/EtOAc, 3:2). M.p. 88–

89 °C (CH₂Cl₂/PE). [α]²_D⁰= –56 (c = 1, CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 3.86 (s, 3 H, OCH₃), 4.37 (ddd, 1 H, J_4,5

= 9.7 Hz, J_5,6a= 5.2 Hz, J_5,6b= 3.0 Hz, H-5), 4.56 (dd, 1 H, J_5,6a

= 5.2 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.67 (dd, 1 H, J_5,6b= 3.0 Hz,

J_6a,6b= 12.4 Hz, H-6b), 5.15 (d, 1 H, J_1,2= 9.4 Hz, H-1), 5.87 (t,

1 H, J_3,4= 9.4 Hz, J_4,5= 9.7 Hz, H-4), 6.05 (t, 1 H, J_2,3= 9.4 Hz,

J_3,4= 9.4 Hz, H-3), 6.11 (t, 1 H, J_1,2= 9.4 Hz, J_2,3= 9.4 Hz, H-2),

6.95 (d, 2 H, J = 8.9 Hz, H-2Ј, H-6Ј), 7.26–7.55 (m, 12 H, Harom),

H-3, H-3Ј, H-4, H-4Ј), 7.21–7.61 (m, 23 H, Harom), 7.82–8.09 (m, 7.84 (m, 4 H, Harom), 7.93 (d, 2 H, J = 8.9 Hz, H-3Ј, H-5Ј), 8.01

17 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 62.7 (C-6), (m, 4 H, Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 55.5

62.8 (C-6Ј), 68.9 (2 C), 69.4, 69.7, 73.5, 73.7, 75.3, 76.5, 76.6, 76.7, (OCH₃), 63.3 (C-6), 69.4 (C-4), 70.5 (C-2), 72.6 (C-1), 74.2 (C-3),

128.1–129.8 (12 signals for 40 Carom), 133.0–133.6 (6 signals for 8

CHarom), 154.9 (H₂NC=NO), 162.9 (NOCO), 165.0, 165.1, 165.3,

165.4, 165.5, 165.6, 166.0, 166.1 (8 OCOPh) ppm. MS (LSIMS,

NBA): m/z = 1245.1 [M + H]⁺. HRMS (LSIMS, NBA): m/z =

C₇₀H₅₇N₂O₂₀[M+H]⁺calcd. 1245.3505, found 1245.3509.

77.0 (C-5), 114.4 (C-2Ј, C-6Ј), 116.3 (C-4Ј), 128.3 (2 C), 128.4, 128.7

(C^IVarom), 128.8 (C^IVarom), 128.9 (C^IVarom), 129.5 (C^IVarom),

129.79 (2 C), 129.82, 129.9, 130.3 (C-3Ј, C-5Ј), 133.1, 133.2 (2 C),

133.5, 163.3 (C-1Ј), 164.7, 165.2, 165.8, 166.2 (4 OCOPh), 166.7

(C-3oxa); 176.5 (C-5oxa) ppm. C₄₃H₃₄N₂O₁₁(754.74): calcd. C

68.43, H 4.54, N 3.71, O 23.32; found C 67.15, H 4.73, N 3.29, O

21.98.

5-Methyl-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-1,2,4-

oxadiazole (8a): A solution of 6a (192 mg, 0.28 mmol) was treated

according to procedure E for 2 d. Silica gel column chromatog-

3-C-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-(p-tolyl)-1,2,4-

raphy (CH₂Cl₂/EtOAc, 95:5) afforded 8a (89 mg, 50%) as a white oxadiazole (8d): A solution of 6d (125 mg, 0.16 mmol) was treated

solid. R_f= 0.87 (CH₂Cl₂/EtOAc, 95:5). M.p. 60–61 °C (CH₂Cl₂/

according to procedure E for 5 d. Silica gel column chromatog-

1

PE). [α]²_D⁰= +6 (c = 0.5, CHCl₃). H NMR (300 MHz, CDCl₃): δ

raphy (PE/EtOAc, 7:3) afforded 8d (73 mg, 60%) as a white solid.

= 2.55 (s, 3 H, CH₃), 4.36 (ddd, 1 H, J_4,5= 9.6 Hz, J_5,6a= 5.2 Hz,

J_5,6b= 3.1 Hz, H-5), 4.54 (dd, 1 H, J_5,6a= 5.2 Hz, J_6a,6b= 12.4 Hz, –47 (c = 0.51, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 2.39 (s,

R_f= 0.39 (PE/EtOAc, 7:3). M.p. 74–76 °C (CH₂Cl₂/PE). [α]²_D⁰

=

1

H-6a), 4.65 (dd, 1 H, J_5,6b= 3.1 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.10

(d, 1 H, J_1,2= 9.4 Hz, H-1), 5.83 (t, 1 H, J_3,4= 9.6 Hz, J_4,5

9.6 Hz, H-4), 5.98 (t, 1 H, J_1,2= 9.4 Hz, J_2,3= 9.4 Hz, H-2), 6.05

3 H, CH₃), 4.39 (ddd, 1 H, J_4,5= 9.5 Hz, J_5,6a= 5.2 Hz, J_5,6b=

3.0 Hz, H-5), 4.57 (dd, 1 H, J_5,6a= 5.2 Hz, J_6a,6b= 12.3 Hz, H-6a),

4.68 (dd, 1 H, J_5,6b= 3.0 Hz, J_6a,6b= 12.3 Hz, H-6b), 5.17 (d, 1 H,

=

(t, 1 H, J_2,3= 9.4 Hz, J_3,4= 9.4 Hz, H-3), 7.24–7.54 (m, 12 H, J_1,2= 9.5 Hz, H-1), 5.88 (t, 1 H, J_3,4= 9.5 Hz, J_4,5= 9.5 Hz, H-4),

Harom), 7.82–8.09 (m, 8 H, Harom) ppm. ¹³C NMR (75 MHz,

6.06 (dd, 1 H, J_2,3= 9.5 Hz, J_3,4= 9.5 Hz, H-3), 6.12 (dd, 1 H, J_1,2

CDCl₃): δ = 12.9 (CH₃), 63.8 (C-6), 69.9 (C-4), 71.0 (C-2), 72.8 (C- = 9.5 Hz, J_2,3= 9.5 Hz, H-2), 7.24–7.55 (m, 14 H, Harom), 7.84

1), 74.5 (C-3), 77.4 (C-5), 128.7, 128.8, 128.8, 128.9, 129.0 (m, 4 H, Harom), 7.93 (m, 4 H, Harom), 8.02 (m, 2 H, Harom)

(C^IVarom), 129.1 (C^IVarom), 129.2 (C^IVarom), 129.9 (C^IVarom), ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 22.1 (CH₃), 63.7 (C-6), 69.8

130.2, 130.2, 130.3, 133.5, 133.7, 133.8, 133.9, 165.1, 165.6, 166.2

(C-4), 71.0 (C-2), 73.0 (C-1), 74.7 (C-3), 77.5 (C-5), 121.4

166.6 (4 OCOPh), 166.8 (C-3oxa), 178.1 (C-5oxa) ppm. MS (C^IVarom), 128.7, 128.8, 129.1 (C^IVarom), 129.2 (C^IVarom), 129.3

(LSIMS, NBA): m/z = 663 [M + H]⁺. HRMS (LSIMS, NBA): m/z

(C^IVarom), 129.6 (C^IVarom), 129.9 (C^IVarom), 130.1, 130.2, 130.3,

133.5, 133.7 (2 C), 133.9, 144.3 (C^IVarom), 165.1, 165.6, 166.3,

166.6 (4 OCOPh), 167.2 (C-3oxa), 177.2 (C-5oxa) ppm. MS

(LSIMS, NBA): m/z = 739 [M+H]⁺. HRMS (LSIMS, NBA): m/z

= C₄₃H₃₅N₂O₁₀[M+H]⁺calcd. 739.2292, found 739.2296.

= C₃₇H₃₁N₂O₁₀[M+H]⁺calcd. 663.1979, found 663.1977.

5-Phenyl-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-1,2,4-

oxadiazole (8b): A solution of 6b (255 mg, 0.34 mmol) was treated

according to procedure E for 10 d. Silica gel column chromatog-

raphy (PE/EtOAc, 3:2) afforded 8b (158 mg, 64%) as a white solid.

5-(p-Nitrophenyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-

1,2,4-oxadiazole (8e): A solution of 6e (244 mg, 0.31 mmol) was

treated according to procedure E for 16 h. Silica gel column

R_f= 0.56 (PE/EtOAc, 3:2). M.p. 136–137 °C (CH₂Cl₂/PE). [α]²_D⁰

–36 (c = 1, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.38 (ddd,

=

1

1 H, J_4,5= 9.3 Hz, J_5,6a= 5.2 Hz, J_5,6b= 2.8 Hz, H-5), 4.56 (dd, 1 chromatography (PE/EtOAc, 3:2) afforded 8e (207 mg, 87%) as a

H, J_5,6a= 5.2 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.68 (dd, 1 H, J_5,6b

2.8 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.17 (d, 1 H, J_1,2= 9.1 Hz, H-1),

5.88 (dd, 1 H, J_3,4= 9.4 Hz, J_4,5= 9.4 Hz, H-4), 6.06 (t, 1 H, J_2,3

=

pale yellow solid. R_f= 0.61 (PE/EtOAc, 3:2). M.p. 98–100 °C

(CH₂Cl₂/PE). [α]²_D⁰= –58 (c = 1, CHCl₃). ¹H NMR (300 MHz,

CDCl₃): δ = 4.40 (ddd, 1 H, J_4,5= 9.5 Hz, J_5,6a= 5.1 Hz, J_5,6b

=

= 9.4 Hz, J_3,4= 9.4 Hz, H-3), 6.11 (t, 1 H, J_1,2= 9.1 Hz, J_2,3

9.4 Hz, H-2), 7.25–7.59 (m, 15 H, Harom), 7.85 (m, 4 H, Harom),

=

2.7 Hz, H-5), 4.56 (dd, 1 H, J_5,6a= 5.0 Hz, J_6a,6b= 12.4 Hz, H-6a),

4.70 (dd, 1 H, J_5,6b= 2.7 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.23 (m, 1

4250

www.eurjoc.org

Eur. J. Org. Chem. 2006, 4242–4256

5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

H, H-1), 5.89 (m, 1 H, H-4), 6.07 (m, 2 H, H-2, H-3), 7.25–7.56 H, J_5,6a= 5.4 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.67 (dd, 1 H, J_5,6b

FULL PAPER

=

(m, 12 H, Harom), 7.84–8.04 (m, 8 H, Harom), 8.28 (m, 4 H, 3.0 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.17 (m, 1 H, J_1,2Ϸ 9,5 Hz,H-1),

Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63,2 (C-6), 69.2

(C-4), 70.6 (C-2), 72.4 (C-1), 74.0 (C-3), 77.0 (C-5), 124.2, 128.3,

128.4, 128.4, 128.6 (C^IVarom), 128.7 (C^IVarom), 128.9 (C^IVarom),

5.86 (m, 1 H, H-4), 6.06 (m, 1 H, H-3), 6.08 (m, 1 H, H-2), 6.57

(dd, 1 H, J_3Ј,4Ј= 3.6 Hz, J_4Ј,5Ј= 1.7 Hz, H-4Ј), 7.28 (dd, 1 H, J_3Ј,4Ј

= 3.6 Hz, J_3Ј,5Ј= 0.7 Hz, H-3Ј), 7.30–7.54 (m, 12 H, Harom), 7.64

129.3, 129.5 (C^IVarom), 129.7, 129.8, 133.1, 133.3, 133.4, 133.5, (dd, 1 H, J_3Ј,5Ј0.7 Hz, J_4Ј,5Ј= 1.7 Hz, H-5Ј), 7.82–8.02 (m 8 H,

150.3 (C^IVarom), 164.7, 165.1, 165.7, 166.1 (4 OCOPh), 167.4 (C- Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63,7 (C-6), 69.8

3oxa), 174.5 (C-5oxa) ppm. C₄₂H₃₁N₃O₁₂(769.71): calcd. C 65.54,

H 4.06, N 5.46, O 24.94; found C 64.65, H 4.21, N 5.43, O 24.21.

(C-4), 71.0 (C-2), 72.8 (C-1), 74.6 (C-3), 77.4 (C-5), 113.0 (C-4Ј),

117.8 (C-3Ј), 128.7, 128.9, 129.1 (C^IVarom), 129.2 (2 C^IVarom),

129.9 (C^IVarom), 130.2, 130.3, 133.5, 133.7, 133.7, 133.9, 140.1 (C-

2Ј), 147.4 (C-5Ј), 165.1, 165.6, 166.2, 166.6 (4 OCOPh), 167.1 (C-

3oxa), 168.7 (C-5oxa) ppm. MS (LSIMS, NBA): m/z = 715.1

[M+H]⁺. HRMS (LSIMS, NBA): m/z = C₄₀H₃₁N₂O₁₁[M+H]⁺

calcd. 715.1928, found 715.1933.

5-(m-Chlorophenyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyran-

osyl)-1,2,4-oxadiazole (8f): A solution of 6f (222 mg, 0.28 mmol)

was treated according to procedure E for 10 d. Silica gel column

chromatography (PE/EtOAc, 7:3) afforded 8f (190 mg, 88%) as a

white solid. R_f= 0.68 (PE/EtOAc, 7:3). M.p. 80–81 °C (CH₂Cl₂/

1

PE). [α]²_D⁰= –44 (c = 1.25, CHCl₃). H NMR (300 MHz, CDCl₃):

3-C-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-(2-thienyl)-

δ = 4.40 (m, 1 H, J_4,5= 9.9 Hz, J_5,6a= 5.2 Hz, J_5,6b= 2.9 Hz, H-

5), 4.57 (dd, 1 H, J_5,6a= 5.2 Hz, J_6a,6b= 12.3 Hz, H-6a), 4.70 (dd,

1,2,4-oxadiazole (8i): A solution of 6i (139 mg, 0.19 mmol) was

treated according to procedure E for 6 d. Silica gel column

1 H, J_5,6b= 2.9 Hz, J_6a,6b= 12.3 Hz, H-6b), 5.19 (m, 1 H, H-1), chromatography (PE/EtOAc, 7:3) afforded 8i (92 mg, 68%) as a

5.90 (m, 1 H, H-4), 6.09 (m, 1 H, H-3), 6.10 (m, 1 H, H-2), 7.25– white solid. R_f= 0.41 (PE/EtOAc, 7:3). M.p. 79–80 °C (CH₂Cl₂/

7.52 (m, 14 H, Harom), 7.83–7.87 (m, 4 H, Harom), 7.92–7.95 (m, PE). [α]²_D⁰= –40 (c = 0.54, CHCl₃). H NMR (300 MHz, CDCl₃):

3 H, Harom), 8.02 (m, 3 H, Harom) ppm. ¹³C NMR (75 MHz,

δ = 4.37 (ddd, 1 H, J_4,5= 9.7 Hz, J_5,6a= 5.2 Hz, J_5,6b= 3.0 Hz, H-

CDCl₃): δ = 63.7 (C-6), 69.7 (C-4), 71.1 (C-2), 72.9 (C-1), 74.5 (C- 5), 4.56 (dd, 1 H, J_5,6a= 5.2 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.67 (dd,

3), 77.5 (C-5), 125.7 (C^IVarom), 126.7, 128.7, 128.8, 128.9, 129.1

1 H, J_5,6b= 3.0 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.15 (m, 1 H, H-1),

(C^IVarom), 129.2 (C^IVarom), 129.4 (C^IVarom), 129.9 (C^IVarom), 5.86 (m, 1 H, H-4), 6.02–6.12 (m, 2 H, H-2, H-3), 7.12 (dd, 1 H,

1

130.2, 130.3, 130.8, 133.5, 133.6, 133.7, 133.8, 133.9, 135.6

(C^IVarom), 165.2, 165.6, 166.3, 166.6 (4 OCOPh), 167.6 (C-3oxa),

175.8 (C-5oxa) ppm. MS (LSIMS, NBA/AcONa): m/z = 781.7

J_3Ј,4Ј= 4.0 Hz, J_4Ј,5Ј= 5.0 Hz, H-4Ј), 7.24–7.54 (m, 12 H, Harom),

7.58 (dd, 1 H, J_3Ј,5ЈϷ 1.0 Hz, J_4Ј,5Ј= 5.0 Hz, H-5Ј), 7.83 (dd, 1 H,

J_3Ј,4Ј= 4.0 Hz, J_3Ј,5ЈϷ 1.0 Hz, H-3Ј), 7.83–7.86 (m, 4 H, Harom),

[ M + N a ] ⁺. H R M S ( L S I M S , N B A / A c O N a ) : m / z = 7.92 (m, 2 H, Harom), 8.01 (m, 2 H, Harom) ppm. ¹³C NMR

C₄₂H₃₁ClN₂O₁₀Na [M+Na]⁺calcd. 781.1565, found 781.1567.

(75 MHz, CDCl₃): δ = 63.7 (C-6), 69.7 (C-4), 71.0 (C-2), 72.9 (C-

1), 74.6 (C-3), 77.5 (C-5), 125.6 (C-2Ј), 128.7, 128.9 (C-4Ј), 129.1

(C^IVarom), 129.2 (C^IVarom), 129.3 (C^IVarom), 129.9 (C^IVarom),

130.2, 130.3, 132.8, 133.0 (C-3Ј, C-5Ј), 133.5, 133.7, 133.7, 133.9,

165,1, 165.6, 166.3, 166.6 (4 OCOPh), 167.2 (C-3oxa), 172.6 (C-

5oxa) ppm. MS (LSIMS, NBA): m/z = 731 [M + H]⁺. HRMS

(LSIMS, NBA): m/z = C₄₀H₃₁N₂O₁₀S [M+H]⁺calcd. 731.1699,

found 731.1698.

5-(3-Pyridyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β- -glucopyranosyl)-

D

1,2,4-oxadiazole (8 g): A solution of 6 g (250 mg, 0.39 mmol) was

treated according to procedure E for 2 d. The crude mixture was

diluted with saturated aqueous NaHCO₃(20 mL) and the aqueous

layer extracted with CHCl₃(3×20 mL). The organic layers were

combined, dried (Na₂SO₄), filtered and the solvents were evapo-

rated. Silica gel column chromatography (PE/EtOAc, 1:1) afforded

8 g (73 mg, 60%) as a white solid. R_f= 0.33 (PE/EtOAc, 1:1). M.p.

88–90 °C (CH₂Cl₂/PE). [α]²_D⁰= –34 (c = 0.5, CHCl₃). ¹H NMR

5-(1-Naphthyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-

1,2,4-oxadiazole (8j): A solution of 6j (451 mg, 0.57 mmol) was

treated according to procedure E for 7 d. Silica gel column

chromatography (PE/EtOAc, 7:3) afforded 8j (339 mg, 78%) as a

(300 MHz, CDCl₃): δ = 4.39 (ddd, 1 H, J_4,5= 9.8 Hz, J_5,6a

5.2 Hz, J_5,6b= 2.8 Hz, H-5), 4.56 (dd, 1 H, J_5,6a= 5.2 Hz, J_6a,6b

=

12.4 Hz, H-6a), 4.69 (dd, 1 H, J_5,6b= 2.8 Hz, J_6a,6b= 12.4 Hz, H-

white solid. R_f= 0.56 (PE/EtOAc, 7:3). M.p. 66–67 °C (CH₂Cl₂/

6b), 5.19 (m, 1 H, H-1), 5.89 (m, 1 H, H-4), 6.08 (m, 2 H, H-2, H- PE). [α]²_D⁰= –33 (c = 0.78, CHCl₃). H NMR (300 MHz, CDCl₃):

1

3), 7.29–7.58 (m, 13 H, 12 Harom, H-5Ј), 7.84 (m, 4 H, Harom),

7.93 (dd, 2 H, J = 1.3 Hz, J = 7.2 Hz, Harom), 8.02 (dd, 2 H, J =

1.3 Hz, J = 7.2 Hz, Harom), 8.33 (dt, 1 H, J_2Ј,4Ј= J_4Ј,6Ј1.9 Hz,

δ = 4.47 (ddd, 1 H, J_4,5= 9.6 Hz, J_5,6a= 5.1 Hz, J_5,6b= 2.8 Hz, H-

5), 4.61 (dd, 1 H, J_5,6a= 5.1 Hz, J_6a,6b= 12.3 Hz, H-6a), 4.74 (dd,

1 H, J_5,6b= 2.8 Hz, J_6a,6b= 12.3 Hz, H-6b), 5.33 (d, 1 H, J_1,2

=

J_4Ј,5Ј8.0 Hz, H-4Ј), 8.79 (dd, 1 H, J_4Ј,6Ј= 1.9 Hz, J_5Ј,6Ј= 4.9 Hz, 9.8 Hz, H-1), 5.97 (t, 1 H, J_3,4= 9.6 Hz, J_4,5= 9.6 Hz, H-4), 6.17

H-6Ј), 9.29 (d, 1 H, J_2Ј,4Ј= 1.9 Hz, H-2Ј) ppm. ¹³C NMR (75 MHz, (t, 1 H, J_2,3= 9.5 Hz, J_3,4= 9.6 Hz, H-3), 6.30 (t, 1 H, J_1,2= 9.8 Hz,

CDCl₃): δ = 63.6 (C-6), 69.7 (C-4), 71.0 (C-2), 72.9 (C-1), 74.5 (C- J_2,3= 9.5 Hz, H-2), 7.22–7,59 (m, 15 H, Harom), 7.81–8.05 (m, 10

3), 77.5 (C-5), 120.7 (C-3Ј), 124.2 (C-5Ј), 128.7, 128.8, 128.8, 128.9,

129.0 (C^IVarom), 129.1 (C^IVarom), 129.1 (C^IVarom), 129.9

(C^IVarom), 130.2, 130.3, 133.6, 133.7, 133.8, 133.9, 135.9 (C-4Ј),

149.6 (C-2Ј), 153.9 (C-6Ј), 165.1, 165.5, 166.2, 166.5 (4 OCOPh),

H, Harom), 8.21 (dd, 1 H, J = 1.0 Hz, J = 7.3 Hz, H-2Ј), 9.02 (d,

1 H, J = 8.4 Hz, H-8Ј) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.8

(C-6), 69.9 (C-4), 71.2 (C-2), 73.1 (C-1), 74.7 (C-3), 77.5 (C-5),

120.7 (C^IVarom), 125.2, 126.1, 127.2, 128.8, 128.9, 129.1, 129.2

167.5 (C-3oxa), 175.0 (C-5oxa) ppm. MS (LSIMS, NBA): m/z = (C^IVarom), 129.3 (C^IVarom), 129.3 (C^IVarom), 130.0 (C^IVarom),

726 [M + H]⁺. HRMS (LSIMS, NBA): m/z = C₄₁H₃₂N₃O₁₀

130.2, 130.3, 130.5 (C^IVarom), 130.6, 133.6, 133.7, 133.8, 134.0,

134.1, 134.3, 165.2, 165.7, 166.4, 166.6 (4 OCOPh), 167.3 (C-3oxa),

177.2 (C-5oxa) ppm. MS (LSIMS, NBA): m/z = 775 [M + H]⁺.

HRMS (LSIMS, NBA): m/z = C₄₆H₃₅N₂O₁₀[M + H]⁺calcd.

775.2292, found 775.2290.

[M+H]⁺calcd. 726.2088, found 726.2088.

5-(2-Furyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-1,2,4-

oxadiazole (8h): A solution of 6h (143 mg, 0.19 mmol) was treated

according to procedure E for 13 d. Silica gel column chromatog-

raphy (PE/EtOAc, 3:2) afforded 8h (81 mg, 58%) as a white solid.

5-(2-Naphthyl)-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-

1,2,4-oxadiazole (8k): A solution of 6k (106 mg, 0.13 mmol) was

treated according to procedure E for 16 h. Silica gel column

R_f= 0.60 (PE/EtOAc, 3:2). M.p. 76–78 °C (CH₂Cl₂/PE). [α]²_D⁰

–47 (c = 1, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4,37 (ddd,

=

1

1 H, J_4,5= 9.6 Hz, J_5,6a= 5.4 Hz, J_5,6b= 3.0 Hz, H-5), 4.56 (dd, 1 chromatography (PE/EtOAc, 7:3) afforded 8k (101 mg, 98%) as a

4251

Eur. J. Org. Chem. 2006, 4242–4256

www.eurjoc.org

J.-P. Praly et al.

FULL PAPER

white solid. R_f= 0.52 (PE/EtOAc, 7:3). M.p. 93–95 °C (CH₂Cl₂/

3), 77.5 (C-5), 128.7, 128.8, 128.9, 129.0 (C^IVarom), 129.1 (C^IVa-

rom), 129.1 (C^IVarom), 129.9 (C^IVarom), 130.1, 130.2, 130.3, 133.5,

133.7, 133.8, 133.9, 165.0, 165.6, 166.2, 166.4 (4 OCOPh), 166.6

(C-3oxa), 184.1 (C-5oxa) ppm. MS (LSIMS, NBA): m/z = 720.2

[M+H]⁺. HRMS (LSIMS, NBA): m/z = C₄₀H₃₈N₃O₁₀[M+H]⁺

calcd. 720.2557, found 720.2559.

1

PE). [α]²_D⁰= –40 (c = 0.25, CHCl₃). H NMR (300 MHz, CDCl₃):

δ = 4.43 (ddd, 1 H, J_4,5= 9.7 Hz, J_5,6a= 5.1 Hz, J_5,6b= 3.0 Hz, H-

5), 4.60 (dd, 1 H, J_5,6a= 5.1 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.72 (dd,

1 H, J_5,6b= 3.0 Hz, J_6a,6b= 12.4 Hz, H-6b), 5.24 (d, 1 H, J_1,2

=

9.4 Hz, H-1), 5.93 (t, 1 H, J_3,4= 9.4 Hz, J_4,5= 9.7 Hz, H-4), 6.12

(t, 1 H, J_2,3= 9.4 Hz, J_3,4= 9.4 Hz, H-3), 6.18 (t, 1 H, J_1,2= 9.4 Hz,

J_2,3= 9.4 Hz, H-2), 7.23–7.56 (m, 14 H, Harom), 7.81–8.05 (m, 12

H, Harom), 8.60 (s, 1 H, H-1Ј) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 63.8 (C-6), 69.8 (C-4), 71.1 (C-2), 73.1 (C-1), 76.6 (C-3), 77.5

(C-5), 121.3, 124.2, 127.6, 128.4, 128.8, 128.9, 129.0, 129.1

(C^IVarom), 129.2, 129.3 (C^IVarom), 129.4, 129.6, 129.9 (C^IVarom),

130.0 (C-1Ј), 130.2, 130.3, 133.0 (C^IVarom), 133.6, 133.7, 133.8,

134.0, 135.7 (C^IVarom), 165.2, 165.7, 166.3, 166.6 (4 OCOPh), 167.5

(C-3oxa), 177.2 (C-5oxa) ppm. MS (LSIMS, NBA): m/z = 775.2

[M+H]⁺. HRMS (LSIMS, NBA): m/z = C₄₆H₃₅N₂O₁₀[M+H]⁺

calcd. 775.2292, found 775.2287.

3,5-Bis[C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)]-1,2,4-oxa-

diazole (8o): A solution of 6o (162 mg, 0.13 mmol) was treated ac-

cording to procedure E for 2 d. Silica gel column chromatography

(PE/EtOAc, 3:2) afforded 8o (151 mg, 95%) as a white solid. R_f=

0.60 (PE/EtOAc, 3:2). M.p. 182–184 °C (CH₂Cl₂/PE). [α]²_D⁰= –3 (c

1

= 0,72, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 4.31 (m, 2 H,

H-5, H-5Ј), 4.51–4.67 (m, 4 H, H-6a, H-6b, H-6Јa, H-6Јb), 5.11 (d,

1 H, J_1,2= 9.9 Hz, H-1), 5.23 (d, 1 H, J_1Ј,2Ј= 9.8 Hz, H-1Ј), 5.75

(t, 1 H, J = 9.7 Hz, H-4 or H-4Ј), 5.79 (t, 1 H, J = 9.7 Hz, H-2),

5.81 (t, 1 H, J = 9.7 Hz, H-4 or H-4Ј), 5.88 (t, 1 H, J = 9.7 Hz, H-

2Ј), 6.02 (t, 1 H, J = 9.4 Hz, H-3 or H-3Ј), 6.04 (t, 1 H, J = 9.4 Hz,

H-3 or H-3Ј), 7.20–7.52 (m, 24 H, Harom), 7.68–8.02 (m, 16 H,

Harom) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 63.5, 63.8 (C-6, C-

6Ј), 69.4, 69.7 (C-4, C-4Ј), 71.0, 71.1 (C-2, C-2Ј), 72.8 (C-1), 73.0

(C-1Ј), 74.2, 74.4 (C-3, C-3Ј), 77.3, 77.6 (C-5, C-5Ј), 128.7, 128.7,

128.8, 128.8, 128.9, 128.9, 129.0 (C^IVarom), 129.0 (C^IVarom), 129.0

(C^IVarom), 129.1 (C^IVarom), 129.2 (C^IVarom), 129.8 (C^IVarom),

129.9 (C^IVarom), 130.2, 130.2, 130.3, 133.5, 133.6 (2 C), 133.7,

133.8 (2 C), 133.9, 134.0, 164.9, 165.1, 165.5, 165.6, 166.1, 166.2,

166.6 (2 C) (8 OCOPh), 167.0 (C-3oxa), 174.8 (C-5oxa) ppm. MS

(LSIMS, NBA): m/z = 1227.0 [M+H]⁺. HRMS (LSIMS, NBA):

m/z = C₇₀H₅₅N₂O₁₉[M+H]⁺calcd. 1227.3399, found 1227.3386.

5-[(1S)-1-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-methyl-

propyl]-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-1,2,4-oxa-

diazole (8m): A solution of 6m (198 mg, 0.21 mmol) was treated

according to procedure E for 6 d. Silica gel column chromatog-

raphy (PE/EtOAc, 7:3) afforded 8m (98 mg, 51%) as a white solid.

R_f= 0.58 (PE/EtOAc, 7:3). M.p. 78–80 °C (CH₂Cl₂/hexane). [α]²_D⁰

1

= –33 (c = 1, CHCl₃). H NMR (300 MHz, CDCl₃): δ = 0.82 (d,

6 H, J Ϸ 6.5 Hz, 2 CH₃), 2.15 (m, 1 H, J Ϸ 6.5 Hz, H-β), 4.20 (t,

1 H, J = 6.9 Hz, J = 6.9 Hz, HFmoc), 4.34 (ddd, 1 H, J_4,5= 9.7 Hz,

J_5,6a= 5.5 Hz, J_5,6b= 2.9 Hz, H-5), 4.41 (m, 2 H, J = 6.9 Hz,

CH₂Fmoc), 4.49 (dd, 1 H, J_5,6a= 5.5 Hz, J_6a,6b= 12.3 Hz, H-6a),

4.64 (dd, 1 H, J_5,6b= 2.9 Hz, J_6a,6b= 12.3 Hz, H-6b), 4.95 (dd, 1

3-C-(β-D-Glucopyranosyl)-5-methyl-1,2,4-oxadiazole (9a): A solu-

H, J_Hα,Hβ= 6.1 Hz, J_Hα,NH= 9.4 Hz, H-α), 5.08 (d, 1 H, J_1,2

9.3 Hz, H-1), 5.48 (d, 1 H, J_Hα,NH= 9.4 Hz, NH), 5.81 (t, 1 H, J_3,4

= 9.5 Hz, J_4,5= 9.7 Hz, H-4), 5.98 (t, 1 H, J_1,2= 9.3 Hz, J_2,3

=

tion of 8a (77 mg, 0.12 mmol) was treated according to procedure

F to obtain 9a (25 mg, 89%) as a hygroscopic solid. R_f= 0.30

(EtOAc/MeOH, 4:1). [α]²_D⁰= +16 (c = 0,9, MeOH). ¹H NMR

(300 MHz, CD₃OD): δ = 2.62 (s, 3 H, CH₃), 3.44 (m, 2 H, H-4, H-

5), 3.49 (m, 1 H, H-3), 3.67 (m, 2 H, H-2, H-6a), 3.86 (dd, 1 H,

J_5,6b= 1.3 Hz, J_6a,6b= 12.0 Hz, H-6b) 4.41 (d, 1 H, J_1,2= 9.7 Hz,

H-1) ppm. ¹³C NMR (75 MHz, CD₃OD): δ = 12.1 (CH₃), 62.9 (C-

6), 71.3 (C-4), 73.4 (C-2), 74.9 (C-1), 79.2 (C-3), 82.6 (C-5), 169.3

(C-3oxa), 179.1 (C-5oxa) ppm. MS (LSIMS, glycerol): m/z = 247

[M + H]⁺. HRMS (LSIMS, glycerol): m/z = C₉H₁₅N₂O₆[M+H]⁺

calcd. 247.0930, found 247.0931.

=

9.5 Hz, H-2), 6.04 (t, 1 H, J_2,3= 9.5 Hz, J_3,4= 9.5 Hz, H-3), 7.25–

7.63 (m, 18 H, Harom), 7.75–7.99 (m, 10 H, Harom) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 18.3 (CH₃), 18.6 (CH₃), 33.3 (C-β),

47.5 (CHFmoc), 54.3 (C-α), 63.7 (C-6), 67.7 (CH₂Fmoc), 69.8 (C-

4), 71.0 (C-2), 72.7 (C-1), 74.3 (C-3), 77.5 (C-5), 120.4, 125.5, 127.5,

128.2, 128.7, 128.8, 128.8, 128.9 (C^IVarom), 129.0 (C^IVarom), 129.1

(C^IVarom), 129.9 (C^IVarom), 130.1, 130.2, 130.3, 133.5, 133.7, 133.9,

133.9, 141.7, 143.9, 144.2 (4 C^IVarom-Fmoc), 156.3 (COFmoc),

165.1, 165.6, 166.2, 166.5 (4 OCOPh), 166.6 (C-3oxa), 180.2 (C-

5oxa) ppm. MS (LSIMS, NBA): m/z = 942.1 [M+H]⁺. HRMS

(LSIMS, NBA): m/z = C₅₅H₄₈N₃O₁₂[M+ H]⁺calcd. 942.3238,

found 942.3250.

3-C-(β-D-Glucopyranosyl)-5-phenyl-1,2,4-oxadiazole (9b): A solu-

tion of 8b (117 mg, 0.16 mmol) was treated according to procedure

F to obtain 9b (41 mg, 80%) as a pale yellow solid. R_f= 0.17

(EtOAc/MeOH, 4:1). M.p. 52–54 °C (MeOH/hexane). [α]²_D⁰= +9 (c

5-[(1S)-1-amino-2-methylpropyl]-3-C-(2,3,4,6-tetra-O-benzoyl-β-D-

1

= 1, MeOH). H NMR (300 MHz, D₂O): δ = 3.56 (m, 2 H, H-4,

glucopyranosyl)-1,2,4-oxadiazole (8n): A solution of 8m (89 mg,

0.09 mmol) in CH₂Cl₂/piperidine (9:1, 3 mL) was stirred at room

temp. for 45 min. Silica gel chromatography (PE/EtOAc, 7:3) af-

forded 8n (59 mg, 88%) as a white solid, shown to be a 87:13 diaste-

reoisomeric mixture (NMR). The minor diastereoisomer gave a

H-5), 3.63 (t, 1 H, J Ϸ 8.5 Hz, H-3), 3.71 (dd, 1 H, J_1,2= 9.5 Hz,

J_2,3= 8.5 Hz, H-2), 3.75 (dd, 1 H, J_5,6a= 5.4 Hz, J_6a,6b= 12.5 Hz,

H-6a), 3.88 (dd, 1 H, J_5,6b= 1.6 Hz, J_6a,6b= 12.5 Hz, H-6b), 4.58

(d, 1 H, J_1,2= 9.5 Hz, H-1), 7.47 (m, 2 H, Harom), 7.59 (m, 1 H,

Harom), 7.93 (m, 2 H, Harom) ppm. ¹³C NMR (75 MHz, D₂O): δ

= 61.1 (C-6), 69.6 (C-4), 72.2 (C-2), 73.4 (C-1), 77.2 (C-3), 80.7 (C-

5), 123.0 (C^IVarom), 128.4 (2 C), 129.7 (2 C), 134.2, 168.1 (C-3oxa),

177.3 (C-5oxa) ppm. MS (LSIMS, thioglycerol): m/z = 309 [M +

H]⁺. HRMS (LSIMS, thioglycerol): m/z = C₁₄H₁₇N₂O₆[M+H]⁺

calcd. 309.1087, found 309.1088.

1

doublet (δ = 3.84 ppm, J = 5.8 Hz) in the H NMR spectrum. R_f

= 0.27 (PE/EtOAc, 7:3). Major isomer: ¹H NMR (300 MHz,

CDCl₃): δ = 0.84 (d, 3 H, J = 6.8 Hz, CH₃), 0.85 (d, 3 H, J =

6.8 Hz, CH₃), 1.66 (br. s, 2 H, NH₂), 2.05 (m, 1 H, J = 6.8 Hz, H-

β), 3.91 (d, 1 H, J_Hα,Hβ= 5.7 Hz, H-α), 4.34 (ddd, 1 H, J_4,5

9.8 Hz, J_5,6a= 5.2 Hz, J_5,6b= 3.0 Hz, H-5), 4.54 (dd, 1 H, J_5,6a

=

5.2 Hz, J_6a,6b= 12.4 Hz, H-6a), 4.65 (dd, 1 H, J_5,6b= 3.0 Hz, J_6a,6b

= 12.4 Hz, H-6b), 5.08 (d, 1 H, J_1,2= 9.5 Hz, H-1), 5.84 (t, 1 H,

J_3,4= 9.5 Hz, J_4,5= 9.8 Hz, H-4), 5.99 (t, 1 H, J_1,2= 9.5 Hz, J_2,3

3-C-(β-D-Glucopyranosyl)-5-(p-methoxyphenyl)-1,2,4-oxadiazole

(9c): A solution of 8c (155 mg, 0.46 mmol) was treated according

to procedure F to obtain 9c (60 mg, 85%) as a white solid. R_f=

= 9.5 Hz, H-2), 6.05 (t, 1 H, J_2,3= 9.5 Hz, J_3,4= 9.5 Hz, H-3), 0.59 (EtOAc/MeOH, 4:1). M.p. 182–183 °C (CH₂Cl₂/PE). [α]²_D⁰

=

7.25–7.56 (m, 12 H, Harom), 7.79–8.02 (m, 8 H, Harom) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 17.9 (CH₃), 18.9 (CH₃), 33.9 (C-β),

+10 (c = 0.75, MeOH). H NMR (300 MHz, CD₃OD): δ = 3.46–

1

3.55 (m, 3 H, H-3, H-4, H-5), 3.70 (dd, 1 H, J_5,6a= 5.0 Hz, J_6a,6b

55.2 (C-α), 63.7 (C-6), 69.8 (C-4), 71.1 (C-2), 72.8 (C-1), 74.3 (C- = 12.1 Hz, H-6a), 3.78 (t, 1 H, J_1,2= 9.7 Hz, J_2,3= 8.7 Hz, H-2),

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Eur. J. Org. Chem. 2006, 4242–4256

5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

FULL PAPER

3.89 (s, 3 H, OCH₃), 3.90 (d, 1 H, J_6a,6b= 12.1 Hz, H-6b), 4.48 (d,

1 H, J_1,2= 9.7 Hz, H-1), 7.11 (d, 2 H, J = 9.0 Hz, H-2Ј, H-6Ј), 8.08

5.2 Hz, J_6a,6b= 12.1 Hz, H-6a), 3.83 (dd, 1 H, J_1,2= 9.7 Hz, J_2,3

=

8.7 Hz, H-2), 3.92 (dd, 1 H, J_5,6a= 1.5 Hz, J_6a,6b= 12.1 Hz, H-6b),

(d, 2 H, J = 9.0 Hz, H-3Ј, H-5Ј) ppm. ¹³C NMR (75 MHz, 4.54 (d, 1 H, J_1,2= 9.7 Hz, H-1), 7.70 (ddd, 1 H, J_2Ј,5ЈϷ 0.5 Hz,

CD₃OD): δ = 56.2 (OCH₃), 62.9 (C-6), 71.4 (C-4), 73.5 (C-2), 75.1 J_4Ј,5Ј= 8.0 Hz, J_5Ј,6Ј= 4.9 Hz, H-5Ј), 8.57 (dt, 1 H, J_2Ј,4Ј= J_4Ј,6Ј

=

(C-1), 79.3 (C-3), 82.7 (C-5), 115.9 (C-2Ј, C-6Ј), 117.4 (C-4Ј), 131.1 1.9 Hz, J_4Ј,5Ј= 8.0 Hz, H-4Ј), 8.84 (dd, 1 H, J_4Ј,6Ј= 1.9 Hz, J_5Ј,6Ј

(C-3Ј, C-5Ј), 165.2 (C-1Ј), 169.8 (C-3oxa); 177.5 (C-5oxa) ppm.

C₁₅H₁₈N₂O₇(338.31): calcd. C 53.25, H 5.36, N 8.28, O 33.10; CD₃OD): δ = 61.9 (C-6), 70.5 (C-4), 72.4 (C-2), 74.0 (C-1), 78.2

=

4.9 Hz, H-6Ј), 9.33 (br. s, 1 H, H-2Ј) ppm. ¹³C NMR (75 MHz,

found C 53.37, H 5.57, N 8.06, O 33.38.

(C-3), 81.8 (C-5), 121.3 (C-3Ј), 124.8 (C-5Ј), 136.2 (C-4Ј), 148.5 (C-

2Ј), 153.2 (C-6Ј), 169.2 (C-3oxa), 174.4 (C-5oxa) ppm. MS (LSIMS,

glycerol): m/z = 310.1 [M+H]⁺. HRMS (LSIMS, glycerol): m/z =

C₁₃H₁₆N₃O₆[M+H]⁺calcd. 310.1039, found 310.1037.

3-C-(β- -Glucopyranosyl)-5-(p-tolyl)-1,2,4-oxadiazole (9d): A solu-

D

tion of 8d (60 mg, 0.08 mmol) was treated according to procedure

F to obtain 9d (22 mg, 85%) as a white solid. R_f= 0.60 (EtOAc/

MeOH, 4:1). M.p. 67–69 °C (MeOH/hexane). [α]²_D⁰= +7 (c = 1,

MeOH). ¹H NMR (300 MHz, CD₃OD): δ = 2.46 (s, 3 H, CH₃),

3.48–3.60 (m, 3 H, H-3, H-4, H-5), 3.72 (dd, 1 H, J_5,6a= 4.2 Hz,

J_6a,6b= 12.2 Hz, H-6a), 3.81 (t, 1 H, J_1,2= 9.6 Hz, J_2,3= 8.7 Hz,

H-2), 3.91 (br. d, 1 H, J_5,6bϽ 1.0 Hz, J_6a,6b= 12.2 Hz, H-6b), 4.51

(d, 1 H, J_1,2= 9.6 Hz, H-1), 7.42 (d, 2 H, J = 8.2 Hz, Harom), 8.04

5-(2-Furyl)-3-C-(β-D-glucopyranosyl)-1,2,4-oxadiazole (9h): A solu-

tion of 8h (68 mg, 0.09 mmol) was treated according to procedure

F to obtain 9h (26 mg, 93%) as a hygroscopic solid. R_f= 0.60

(EtOAc/MeOH, 4:1). [α]²_D⁰= +8 (c = 0.74, MeOH). ¹H NMR

(300 MHz, CD₃OD): δ = 3.50 (m, 2 H, H-4, H-5), 3.54 (t, 1 H, J

Ϸ 9 Hz, H-3), 3.72 (br. dd, 1 H, J_5,6a= 4.9 Hz, J_6a,6b= 12.1 Hz,

(d, 2 H, J 8.2 Hz, Harom) ppm. ¹³C NMR (75 MHz, CD₃OD): δ H-6a), 3.76 (dd, 1 H, J_1,2= 9.7 Hz, J_2,3Ϸ 9 Hz, H-2), 3.90 (dd, 1

= 20.7 (CH₃), 61.8 (C-6), 70.4 (C-4), 72.5 (C-2), 74.1 (C-1), 78.3 H, J_5,6a= 1.1 Hz, J_6a,6b= 12.1 Hz, H-6b), 4.51 (d, 1 H, J_1,2

=

(C-3), 81.7 (C-5), 121.4 (C^IVarom), 128.1 (2 C), 130.1 (2 C), 144.6 9.7 Hz, H-1), 6.77 (dd, 1 H, J_3Ј,4Ј= 3.6 Hz, J_4Ј,5Ј= 1.8 Hz, H-4Ј),

(C^IVarom), 168.9 (C-3oxa), 176.7 (C-5oxa) ppm. MS (LSIMS, glyc-

erol): m/z = 323 [M + H]⁺. HRMS (LSIMS, glycerol): m/z =

C₁₅H₁₉N₂O₆[M+H]⁺calcd. 323.1243, found 323.1242.

7.48 (dd, 1 H, J_3Ј,4Ј= 3.6 Hz, J_3Ј,5Ј= 0.7 Hz, H-3Ј), 7.93 (dd, 1 H,

J_3Ј,5Ј= 0.7 Hz, J_4Ј,5Ј= 1.8 Hz, H-5Ј) ppm. ¹³C NMR (75 MHz,

CD₃OD): δ = 61.8 (C-6), 70.3 (C-4), 72.4 (C-2), 73.8 (C-1), 78.2

(C-3), 81.7 (C-5), 112.8 (C-4Ј), 117.4 (C-3Ј), 140.1 (C-2Ј), 148.1 (C-

5Ј), 168.4 (C-5oxa), 168.6 (C-3oxa) ppm. MS (LSIMS, glycerol):

m/z = 299.0 [M + H]⁺. HRMS (LSIMS, glycerol): m/z =

C₁₂H₁₅N₂O₇[M+H]⁺calcd. 299.0879, found 229.0877.

3-C-(β-D-Glucopyranosyl)-5-(p-nitrophenyl)-1,2,4-oxadiazole (9e): A

solution of 8e (139 mg, 0.18 mmol) was treated according to pro-

cedure F to obtain 9e (60 mg, 95%) as a white solid. R_f= 0.20

(EtOAc/MeOH, 4:1). M.p. 92–94 °C (MeOH/hexane). [α]²_D⁰= +9 (c

1

= 0.72, MeOH). H NMR (300 MHz, CD₃OD): δ = 3.44–3.53 (m,

3-C-(β-

D-Glucopyranosyl)-5-(2-thienyl)-1,2,4-oxadiazole (9i): A

2 H, H-4, H-5), 3.56 (t, 1 H, J Ϸ 9 Hz, H-3), 3.72 (dd, 1 H, J_5,6a

solution of 8i (95 mg, 0.13 mmol) was treated according to pro-

= 5.2 Hz, J_6a,6b= 12.1 Hz, H-6a), 3.84 (dd, 1 H, J_1,2= 9.7 Hz, J_2,3cedure F to obtain 9i (28 mg, 70%) as a colourless oil. R_f= 0.54

= 8.7 Hz, H-2), 3.92 (dd, 1 H, J_5,6b= 1.5 Hz, J_6a,6b= 12.1 Hz, H- (EtOAc/MeOH, 4:1). [α]²_D⁰= +6 (c = 1, MeOH). ¹H NMR

6b), 4.56 (d, 1 H, J_1,2= 9.7 Hz, H-1), 8.93–8.48 (m, 4 H, J Ϸ 9 Hz,

Harom) ppm. ¹³C NMR (75 MHz, CD₃OD): δ = 61.9 (C-6), 70.4

(300 MHz, CD₃OD): δ = 3.41 (m, 2 H, H-4, H-5), 3.45 (t, 1 H, J

Ϸ 9 Hz, H-3), 3.63 (dd, 1 H, J_5,6a= 4.6 Hz, J_6a,6b= 12.0 Hz, H-

(C-4), 72.5 (C-2), 74.0 (C-1), 78.2 (C-3), 81.8 (C-5), 124.6 (2 C), 6a), 3.70 (dd, 1 H, J_1,2= 9.7 Hz, J_2,3Ϸ 9 Hz, H-2), 3.82 (br. d, 1

129.4 (C^IVarom), 129.4 (2 C), 150.9 (C^IVarom), 169.5 (C-3oxa),

174.7 (C-5oxa) ppm. MS (LSIMS, negative mode, NBA): m/z =

352 [M – H]^–. HRMS (LSIMS, negative mode, NBA): m/z =

C₁₄H₁₄N₃O₈[M–H]^–calcd. 352.0781, found 352.0785.

H, J_6a,6b= 12.0 Hz, H-6b), 4.41 (d, 1 H, J_1,2= 9.7 Hz, H-1), 7.22

(dd, 1 H, J_3Ј,4Ј= 3.7 Hz, J_4Ј,5Ј= 5.0 Hz, H-4Ј), 7.83 (br. d, 1 H,

J_4Ј,5Ј= 5.0 Hz, H5Ј), 7.91 (br. d, 1 H, J_3Ј,4Ј= 3.7 Hz, H-3Ј) ppm.

¹³C NMR (75 MHz, CD₃OD): δ = 61.8 (C-6), 70.3 (C-4), 72.4 (C-

2), 73.9 (C-1), 78.2 (C-3), 81.7 (C-5), 125.3 (C-2Ј), 129.0 (C-4Ј),

132.6 (C-3Ј), 133.3 (C-5Ј), 168.8 (C-3oxa), 172.2 (C-5oxa) ppm. MS

(LSIMS, glycerol): m/z = 315.1 [M+H]⁺. HRMS (LSIMS, glyc-

erol): m/z = C₁₂H₁₄N₂NaO₆S [M+Na]⁺calcd. 337.0470, found

337.0470.

5-(m-Chlorophenyl)-3-C-(β-D-glucopyranosyl)-1,2,4-oxadiazole (9f):

A solution of 8f (150 mg, 0.19 mmol) was treated according to pro-

cedure F to obtain 9f (63 mg, 94%) as a white solid. R_f= 0.47

(EtOAc/MeOH, 4:1). M.p. 99–101 °C (MeOH/hexane). [α]²_D⁰= +8

1

(c = 0.85, MeOH). H NMR (300 MHz, CD₃OD): δ = 3.46–3.55

(m, 2 H, H-4, H-5), 3.57 (t, 1 H, J Ϸ 9 Hz, H-3), 3.74 (dd, 1 H, 3-C-(β-D-Glucopyranosyl)-5-(1-naphthyl)-1,2,4-oxadiazole (9j): A

J_5,6a= 5.0 Hz, J_6a,6b= 12.1 Hz, H-6a), 3.83 (dd, 1 H, J_1,2= 9.6 Hz,

J_2,3= 8.7 Hz, H-2), 3.92 (dd, 1 H, J_5,6b= 0.8 Hz, J_6a,6b= 12.1 Hz,

solution of 8j (220 mg, 0.28 mmol) was treated according to pro-

cedure F to obtain 9j (90 mg, 89%) as a colourless oil. R_f= 0.51

(EtOAc/MeOH, 4:1). [α]²_D⁰= +10 (c = 0.86, MeOH). ¹H NMR

(300 MHz, CD₃OD): δ = 3.59 (m, 2 H, H-4, H-5), 3.64 (t, 1 H, J

H-6b), 4.54 (d, 1 H, J_1,2= 9.6 Hz, H-1), 7.60 (dd, 1 H, J_4Ј,5Ј

=

8.0 Hz, J_5Ј,6Ј= 7.8 Hz, H-5Ј), 7.68 (ddd, 1 H, J_2Ј,4Ј= 2.0 Hz, J_4Ј,5Ј

= 8.0 Hz, J_4Ј,6Ј= 1.2 Hz, H-4Ј), 8.07 (dt, 1 H, J_2Ј,6Ј= 1.5 Hz, J_4Ј,6ЈϷ 9 Hz, H-3), 3.79 (br. d, 1 H, J Ϸ 12 Hz, J Ϸ 5 Hz, H-6a), 3.97

= 1.2 Hz, J_5Ј,6Ј= 7.8 Hz, H-6Ј), 8.13 (t, 1 H, J_2Ј,4Ј= 2.0 Hz, J_2Ј,6Ј(d, 1 H, J_6a,6b= 12.5 Hz, H-6b), 3.99 (t, 1 H, J_1,2= 9.7 Hz, J_2,3

= 1.5 Hz, H-2Ј) ppm. ¹³C NMR (75 MHz, CD₃OD): δ = 61.9 (C- 9.0 Hz, H-2), 4.65 (d, 1 H, J_1,2= 9.7 Hz, H-1), 7.54–7.66 (m, 3 H,

=

6), 70.4 (C-4), 72.5 (C-2), 74.0 (C-1), 78.3 (C-3), 81.7 (C-5), 125.9

Hnaph), 7.93 (br. d, 1 H, J = 7.9 Hz, H-5Ј), 8.09 (br. d, 1 H, J =

8.2 Hz, H-4Ј), 8.26 (dd, 1 H, J = 1.0 Hz, J = 7.3 Hz, H-2Ј), 8.99

(C^IVarom), 126.4 (C-6Ј), 127.8 (C-2Ј), 131.2 (C-5Ј), 133.2 (C-4Ј),

135.4 (C^IVarom), 169.1 (C-3oxa), 175.2 (C-5oxa) ppm. MS (LSIMS, (br. d, 1 H, J = 8.0 Hz, H-8Ј) ppm. ¹³C NMR (75 MHz, CD₃OD):

glycerol): m/z = 343 [M+H]⁺. HRMS (LSIMS, glycerol): m/z =

δ = 60.7 (C-6), 69.2 (C-4), 71.3 (C-2), 73.0 (C-1), 77.1 (C-3), 80.5

(C-5), 119.3 (C^IVnaph), 123.8, 124.2 (C-8Ј), 125.7, 127.1, 127.7 (C-

5Ј), 128.8 (C-2Ј), 129.0 (C^IVnaph), 132.7 (C-4Ј), 133.0 (C^IVnaph),

167.6 (C-3oxa), 175.4 (C-5oxa) ppm. MS (LSIMS, glycerol): m/z =

359 [M + H]⁺. HRMS (LSIMS, glycerol): m/z = C₁₈H₁₉N₂O₆

[M+H]⁺calcd. 359.1243, found 359.1251.

C₁₄H₁₆ClN₂O₆[M+H]⁺calcd. 343.0697, found 343.0695.

3-C-(β-D-Glucopyranosyl)-5-(3-pyridyl)-1,2,4-oxadiazole (9g): A

solution of 8g (75 mg, 0.1 mmol) was treated according to pro-

cedure F to obtain 9g (18 mg, 60%) as a white solid. R_f= 0.20

(EtOAc/MeOH, 4:1). M.p. 162–164 °C (MeOH/PE). [α]²_D⁰= +11 (c

1

= 0.55, MeOH). H NMR (300 MHz, CD₃OD): δ = 3.50 (m, 2 H,

3-C-(β-

D-Glucopyranosyl)-5-(2-naphthyl)-1,2,4-oxadiazole (9k): A

H-4, H-5), 3.55 (t, 1 H, J = 8.9 Hz, H-3), 3.71 (dd, 1 H, J_5,6a

=

solution of 8k (89 mg, 0.11 mmol) was treated according to pro-

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J.-P. Praly et al.

FULL PAPER

cedure F to obtain 9k (40 mg, 98%) as a white solid. R_f= 0.50

7:3). M.p. 142–143 °C (CH₂Cl₂/PE). [α]²_D⁰= –32 (c = 0,94, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 1.94 (CH₃), 2.06 (CH₃), 2.08

(EtOAc/MeOH, 4:1). M.p. 98–100 °C (MeOH/hexane). [α]²_D⁰= +5

1

(c = 0.82, MeOH). H NMR (500 MHz, CD₃OD, 60 °C): δ = 3.55 (CH₃), 2.09 (CH₃), 3.96 (ddd, 1 H, J_4,5= 9.8 Hz, J_5,6a= 2.2 Hz,

(m, 2 H, H-4, H-5), 3.59 (t, 1 H, J Ϸ 9 Hz, H-3), 3.77 (br. dd, 1

J_5,6b= 5.0 Hz, H-5), 4.22 (dd, 1 H, J_5,6a= 2.2 Hz, J_6a,6b= 12.5 Hz,

H-6a), 4.34 (dd, 1 H, J_5,6b= 5.0 Hz, J_6a,6b= 12.5 Hz, H-6b), 4.90

H, J_5,6a= 5,1 Hz, J_6a,6b= 12.1 Hz, H-6a), 3.89 (dd, 1 H, J_1,2

=

9.7 Hz, J_2,3= 8.8 Hz, H-2), 3.93 (dd, 1 H, J_5,6b= 1.1 Hz, J_6a,6b

12.1 Hz, H-6b), 4.57 (d, 1 H, J_1,2= 9.7 Hz, H-1), 7.60–7.67 (m, 2

=

(d, 1 H, J_1,2= 10.0 Hz, H-1), 5.32 (t, 1 H, J_3,4= 9.4 Hz, J_4,5

9.8 Hz, H-4), 5.43 (t, 1 H, J_2,3= 9.4 Hz, J_3,4= 9.4 Hz, H-3), 5.74

H, H-6Ј, H-7Ј), 7.96 (d, 1 H, J = 8.0 Hz, H-8Ј), 8.03 (d, 1 H, J_5Ј,6Ј(dd, 1 H, J_1,2= 10.0 Hz, J_2,3= 9.4 Hz, H-2), 7.59 (dd, 1 H, J_3Ј,4Ј

=

= 8.0 Hz, H-5Ј), 8.04 (d, 1 H, J_3Ј,4Ј= 8.6 Hz, H-4Ј), 8.14 (dd, 1 H,

J_1Ј,3Ј= 1.5 Hz, J_3Ј,4Ј= 8.6 Hz, H-3Ј), 8.72 (br. s, 1 H, H-1Ј) ppm.

¹³C NMR (125 MHz, CD₃OD): δ = 62.1 (C-6), 70.6 (C-4), 72.6 (C-

= 8.2 Hz, J_2Ј,3Ј= 7.3 Hz, H-3Ј), 7.60 (ddd, 1 H, J_5Ј,6Ј= 8.0 Hz, J_6Ј,7Ј

= 6.7 Hz, J_6Ј,8Ј= 1.5 Hz, H-6Ј), 7.72 (ddd, 1 H, J_6Ј,7Ј= 6.7 Hz, J_7Ј,8Ј

= 8.5 Hz, J_5Ј,7Ј= 1.4 Hz, H-7Ј), 7.93 (dm, 1 H, J_5Ј,6Ј= 8.0 Hz, J_5Ј,7Ј

2), 74.3 (C-1), 78.5 (C-3), 81.7 (C-5), 121.4 (C-2Ј), 123.5 (C-3Ј), = 1.4 Hz, J_5Ј,8Ј= 1.0 Hz, H-5Ј), 8.09 (br. d, 1 H, J_3Ј,4Ј= 8.2 Hz, H-

127.5, 128.0 (C-8Ј), 128.8, 129.2 (C-1Ј), 129.3, 129.3, 133.2 (C-4Јa),

135.8 (C-8Јa), 169.2 (C-3oxa), 176.7 (C-5oxa) ppm. NMR spectra

were recorded at 60 °C due to poor solubility of the compound in

CD₃OD. MS (ESI): m/z = 359.0 [M+H]⁺, 381.1 [M+Na]⁺, 716.8

[2 M + H]⁺, 738.9 [2 M + Na]⁺. HRMS (LSIMS, NBA): m/z =

C₁₈H₁₈N₂NaO₆[M+Na]⁺calcd. 381.1063, found 381.1066.

4Ј), 8.34 (dd, 1 H, J_2Ј,3Ј= 7.3 Hz, J_2Ј,4Ј= 1.2 Hz, H-2Ј), 9.11 (dm,

1 H, J_5Ј,8ЈϷ 1.0 Hz, J_6Ј,8Ј= 1.5 Hz, J_7Ј,8Ј= 8.5 Hz, H-8Ј) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 20.9, 21.0, 21.1, 21.2 (4 CH₃), 62.5

(C-6), 68.5 (C-4), 70.3 (C-2), 72.5 (C-1), 74.4 (C-3), 77.1 (C-5),

120.6 (C-8Јa), 125.2 (C-3Ј), 126.1 (C-8Ј), 127.2 (C-6Ј), 128.9 (C-7Ј),

129.2 (C-5Ј), 130.5 (C-1Ј), 130.6 (C-2Ј), 134.2 (C-4Јa), 134.4

(C-4 Ј), 167.1 (C-3oxa), 169.4, 169.8, 170.8, 171.1 (4 COCH₃), 177.2

(C-5oxa) ppm. MS (LSIMS, NBA): m/z = 527.1 [M+H]⁺. HRMS

(LSIMS, NBA): m/z = C₂₆H₂₇N₂O₁₀[M+H]⁺calcd. 527.1666,

found 527.1662.

5-[(1S)-1-Amino-2-methylpropyl]-3-C-(β-D-glucopyranosyl)-1,2,4-

oxadiazole (9n): A solution of 8n (58 mg, 0.08 mmol) was treated

according to procedure F to obtain 9n (6 mg, 25%) as a colourless

oil. R_f= 0.35 (EtOAc/MeOH, 4:1). [α]²_D⁰= +24 (c = 0.45, H₂O).

¹H NMR (500 MHz, D₂O): δ = 0.93 (d, 3 H, J = 6.8 Hz, CH₃),

1.02 (d, 3 H, J = 6.8 Hz, CH₃), 2.40 (m, 1 H, H-β), 3.47 (t, 1 H, J

= 9.5 Hz, H-4), 3.57 (m, 2 H, H-3, H-5), 3.67 (m, 2 H, H-2, H-6a),

3.83 (br. d, 1 H, J = 11.7 Hz, H-6b), 4.62 (d, 1 H, J_1,2= 9.8 Hz,

H-1), 4.70 (m, 1 H, H-α) ppm. ¹³C NMR (125 MHz, D₂O): δ =

19.9 (CH₃), 20.3 (CH₃), 33.7 (C-β), 56.2 (C-α), 63.5 (C-6), 72.2 (C-

4), 74.5 (C-2), 75.6 (C-1), 79.7, 83.4 (C-3, C-5), 170.4 (C-3oxa),

178.8 (C-5oxa) ppm. MS (LSIMS, glycerol): m/z = 304

[M+H]⁺. HRMS (LSIMS, glycerol): m/z = C₁₂H₂₂N₃O₆[M+H]⁺

calcd. 304.1509, found 304.1507.

Enzyme Assays: Glycogen phosphorylase b was prepared from rab-

bit skeletal muscle according to the method of Fischer and

Krebs^[42]using 2-mercaptoethanol instead of -cysteine and recrys-

tallized at least three times before use. The kinetic studies with

glycogen phosphorylase were performed as described previously.^[43]

Kinetic data for the inhibition of rabbit skeletal muscle glycogen

phosphorylase b by monosaccharide compounds was collected

using different concentrations of α--glucose-1-phosphate (4, 6, 8,

10, 12, and 14 m) and constant concentrations of glycogen (1%,

w/v) and AMP (1 m). Compounds were dissolved in DMSO in

a final concentration of 250 m then diluted in a buffer for the

phosphorylase inhibition assay so that the DMSO concentration

would not be higher than 0.25%. Consequently, the highest inhibi-

tor concentration applied was 625 µ. The enzymatic activities are

presented in the form of double-reciprocal plots (Lineweaver–Burk)

applying a nonlinear data-analysis program. The inhibition con-

stants (K_i) were determined whenever lower than about 300 µ,

according to Dixon by replotting the slopes from the Lineweaver–

Burk plots against the inhibitor concentrations. The means of stan-

dard errors for all calculated kinetic parameters averaged to less

than 10%.^[44]Otherwise, IC₅₀values were determined in the pres-

ence of 4 m α--glucose-1-phosphate, 1 m AMP, 1% glycogen

and varying concentrations of the inhibitor.

5-C-(2-Deoxy-D-arabino-hex-1-enopyranosyl)-3-C-(β-D-gluco-

pyranosyl)-1,2,4-oxadiazole (9p): A solution of 8o (138 mg,

0.11 mmol) was treated according to procedure F to obtain 9p

(19 mg, 45 %) as a hygroscopic solid after RP-18 column

chromatography (H₂O, then H₂O/MeOH, 4:1). R_f= 0.15 (EtOAc/

MeOH, 4:1). M.p. 118–120 °C. [α]²_D⁰= +16 (c = 0.56, D₂O). ¹H

NMR (300 MHz, D₂O): δ = 3.53 (t, 1 H, J Ϸ 9 Hz, H-4), 3.62

(ddd, 1 H, J_4,5Ϸ 9 Hz, J_5,6a= 5.3 Hz, J_5,6b= 1.8 Hz, H-5), 3.63 (t,

1 H, J_2,3= J_3,4Ϸ 9 Hz, H-3), 3.70 (t, 1 H, J_1,2= 9.3 Hz, J_2,3

Ϸ

9 Hz, H-2), 3.74 (dd, 1 H, J_5,6a= 5.3 Hz, J_6a,6b= 12.5 Hz, H-6a),

3.81 (dd, 1 H, J_3Ј,4Ј= 7.4 Hz, J_4Ј,5Ј= 9.7 Hz, H-4Ј), 3.90 (dd, 1 H,

J_5,6b= 1.8 Hz, J_6a,6b= 12.5 Hz, H-6b), 3.94 (dd, 1 H, J_5Ј,6Јa

5.2 Hz, J_6Јa,6Јb= 12.8 Hz, H-6Јa), 4.02 (dd, 1 H, J_5Ј,6Јa= 2.4 Hz,

J_6Јa,6Јb= 12.8 Hz, H-6Јb), 4.19 (ddd, 1 H, J_4Ј,5Ј= 9.7 Hz, J_5Ј,6Јa

=

5.2 Hz, J_5Ј,6Јb= 2.4 Hz, H-5Ј), 4.45 (dd, 1 H, J_2Ј,3Ј= 2.8 Hz, J_3Ј,4Ј

= 7.4 Hz, H-3Ј), 4.64 (d, 1 H, J_1,2= 9.3 Hz, H-1), 6.16 (d, 1 H,

J_2Ј,3Ј= 2.8 Hz, H-2Ј) ppm. ¹³C NMR (75 MHz, D₂O): δ = 60.4 (C-

6Ј), 61.2 (C-6), 68.2 (C-4Ј), 68.7 (C-3Ј), 69.7 (C-4), 72.2 (C-2), 73.2

(C-1), 77.1 (C-3), 80.3 (C-5Ј), 80.7 (C-5), 112.4 (C-2Ј), 139.6 (C-

1Ј), 167.9 (C-3oxa), 172.4 (C-5oxa) ppm. MS (ESI): m/z = 377.0

[M+H]⁺, 399.1 [M+Na]⁺, 774.9 [2 M+ Na]⁺. HRMS (LSIMS,

glycerol): m/z = C₁₄H₂₁N₂O₁₀[M + H]⁺calcd. 377.1196, found

377.1192.

Acknowledgments

Generous financial support of this research was provided by the

Région Rhône-Alpes (funds from MIRA Recherche 2001 and sti-

pends to M. B. L. as a co-tutored student) and in part by a Euro-

pean Integrated Project (FP6-IP 503467) and is gratefully acknowl-

edged. Other support was provided by the University Claude-Ber-

nard Lyon 1 (to co-tutored Ph.D. Thesis), CNRS, French Ministry

of Education and Research, French Ministry of Foreign Affairs

(PAI Balaton no. 11061PE with Pr. László Somsák, University of

Debrecen, Hungary). This work was also supported by the Hung-

arian Research Fund (OTKA K60620 to P. G.). Prof. M. Srivastava

(Federal University of Pernambuco, Recife, Brazil) is thanked for

helpful discussions. C-(2,3,4,6-Tetra-O-benzoyl-β--glucopyrano-

syl)formic acid was kindly provided by Prof. László Somsák.

5-(1-Naphthyl)-3-C-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-

1,2,4-oxadiazole (10j): A solution of 9j (36 mg, 0.1 mmol) in pyri-

dine/Ac₂O (9:1, 3 mL) was stirred at room temp. for 16 h. The mix-

ture was poured into saturated aqueous NaHCO₃(25 mL) and the

aqueous layer was extracted with CHCl₃(3×25 mL). The organic

layers were combined, dried (MgSO₄), filtered and concentrated to

afford 10j (53 mg, 100%) as a white solid. R_f= 0.56 (PE/EtOAc,

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5-Substituted 3-C-Glucopyranosyl-1,2,4-oxadiazoles from β--Glucopyranosyl Cyanides

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Article Doi

In search of glycogen phosphorylase inhibitors: 5-Substituted 3-C-glucopyranosyl-1,2,4-oxadiazoles from β-D-Glucopyranosyl cyanides upon cyclization of O-acylamidoxime intermediates

DOI: 10.1002/ejoc.200600073

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