Scholarly article on 2,3,5-tri-O-benzyl-4-O-tert-butyldimethylsilyl-L-arabinose ethylenedithioacetal 613234-28-9 from Tetrahedron p. 6503

Tetrahedron 59 (2003) 6503–6520

Stereocontrolled synthesis of imidazolo[1,5]hexopiperidinoses and

imidazol-4(5)-yl-C-glycosides

a

b

a

Andrzej Frankowski,^aDariusz Deredas, Estelle Dubost, Franc¸ois Gessier, Stefan Jankowski,

,

*

c

Markus Neuburger, Czesława Seliga, Theophile Tschamber and Kamil Weinberg

a

b

a

´

^aInstitute of Organic Chemistry, Technical University of Lodz, ul. Zwirki 36, 90924 Lodz, Poland

b

´

Ecole Nationale Superieure de Chimie, Universite de Haute-Alsace, 3 rue Alfred Werner, 68093 Mulhouse, France

¨ ¨

Institut fur anorganische Chemie, Universitat Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland

c

Received 29 January 2003; revised 20 June 2003; accepted 3 July 2003

Dedicated to Professor Jacques Streith on the occasion of his 70th birthday

Abstract—The syntheses of imidazolo[1,5]hexopiperidinoses 2–6 and imidazol-4(5)-yl C-glycosides 7–9 are reported. The crucial step of

this approach relies upon the S_N2-type cyclisation of selectively protected C(1), C(2), C(3) and C(5)-substituted 1-[imidazol-4(5)-yl]pentitols

in which the imidazole nitrogen or the C(1)-connected oxygen are involved as the competitive nucleophilic centers, respectively. Six selected

imidazolosugars were evaluated as potential inhibitors of glycosidases.

1. Introduction

The mechanism of oligo- and polysaccharide hydrolysis by

glycosidases is thought to involve a cyclic oxocarbonium ion

as an intermediate, in which the pyranose ring adopts a half-

chair conformation.¹Imidazolosugars are ﬂattened azasugar

analogues which mimicthe transitionstate forglycosidicbond

hydrolysis and are therefore potential glycosidase inhibitors.

Only one imidazolosugar, nagstatine (1), has been isolated

from natural sources so far, and this has proved to be a potent

inhibitor of N-acetyl-b-^D-glucosaminidase.^2,3

Imidazolosugars can be considered as 1,2- or 1,5-disubsti-

tuted imidazole derivatives, depending on the mode of

imidazole annelation to the azasugar ring. The synthesis of

imidazolo[1,2]-azasugars has been the subject of interest of

several research groups.^4–11Some of these compounds have

proven to be potent glycosidase inhibitors, mainly of

b-glycosidases, in accordance with the postulated (and

proved) mechanism of lateral protonation of imidazole

nitrogen by retentive b-glycosidases.¹²Our previous

research has been concerned with syntheses and

transformations of imidazolo[1,5]azapentoses,^13–17some

of which are moderately active as inhibitors of a-glyco-

sidases. In this paper we present syntheses of imida-

zolo[1,5] hexopiperidinoses 2–6 containing the exo-

hydroxymethyl group, which are close analogues of the

Keywords: imidazolohexapiperidinoses; imidazolyl-C-glycosides;

corresponding hexopyranoses, and imidazole C-glyco-

glycosidase inhibition.

sides 7–9 formed in competitive reactions (see our

preliminary paper²³).

*

Corresponding author. Tel.: þ48-426313144; fax: þ48-426365530;

e-mail: andfrank@ck-sg.p.lodz.pl

doi:10.1016/S0040-4020(03)01055-X

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A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

2. Results and discussion

perchlorate and CaCO₃to give the aldehyde 14 in 90%

yield. A mixture of epimeric imidazolyl-pentitols 15a

(^D-altro) and 15b (D-allo) was prepared by nucleophilic

addition of the 5-lithiated imidazole 10 to aldehyde 14. The

epimers were obtained in a 1:2 ratio, determined by

2.1. Synthesis of imidazolo[1,5]hexopiperidinoses and

1[imidazol-4(5)-yl]-C-glycosides

1

We present herein the syntheses of ﬁve imidazolo[1,5]hexo-

piperidinoses: 2–6. These products have been obtained

from 1-[4(5)-imidazolyl]pentitols, which have been

activated towards intramolecular S_N2 attack at C(4) of the

pentitol moiety. The N–cyclisation competes with a

nucleophilic attack of O(1) at C(4). The latter reaction

initiates the formation of imidazole C-glycosides 7, 8 and 9.

We have observed this course of reaction in the ^L-talo series

where only C-glycoside 7 was formed. In the ^D-gluco series,

where two C-glycosides 8 and 9 were obtained, the

imidazolopiperidinose 6 was isolated as a minor product.

comparison of integration of H–C(1) protons in H NMR

spectra. They were chromatographically separated and

subjected to analogous reaction sequences. Thus, benzyl-

ation of 15a under standard conditions (NaH, BnBr, Bu₄NI,

THF) resulted in the formation of tetrabenzyl derivative

16a. The silyl group on 16a was removed by treatment with

Bu₄NF and then the imidazole ring was deprotected under

acidic conditions (HCl, THF, reﬂux) to give 1,2,3,5-tetra-O-

benzyl-1[4(5)-imidazolyl]-^D-altro-pentitol (17a) in 60%

yield (2 steps). The same reaction sequence starting from

imidazolyl-^D-allo-pentitol (15b) led to the formation of

1,2,3,5-tetra-O-benzyl-1[4(5)-imidazolyl]-^D-allo-pentitol

(17b) in 82% overall yield (Scheme 1).

The imidazolyl-pentitols were obtained by addition of the

lithiated derivative of the 1,2-disubstituted imidazole 10¹⁸

to protected pentoses. Each of these reactions resulted in

two epimeric imidazolyl-pentitols. Each pair of products

was chromatographically separated and they were separ-

ately subjected to sequences of analogous reactions leading

to the target structures.

The compound 17a was subsequently mesylated and

immediately treated with acetic anhydride in pyridine at

808C to give the cyclised product 18 in 67% yield. Its

subsequent hydrogenolysis in the presence of Pd(OH)₂

(Pearlman’s catalyst) yielded imidazolo[1,5]-L-galacto-

piperidinose (2) in 78% yield.

2.1.1. ^L-galacto and L-talo series. Tri-O-benzyl-D-ribo-

furanose¹⁹11, used as a chiral precursor, and treated with

1,2-dithioethane in anhydrous HCl/dioxane, to give the 1,2-

dithioacetal 12 in 85% yield. The remaining OH group on

C-4 was protected with a TBDMS group under standard

conditions to give compound 13 in 84% yield. The

dithioacetal function in 13 was removed with mercury

The latter compound 17b, treated with triﬂic anhydride and

pyridine in CH₂Cl₂at 2208C, was converted into the

ditriﬂated derivative 19 which was gradually transformed

into the N-triﬂated imidazolyl-C-glycoside 20. It was

immediately N-deprotected with NaOH in methanol to

yield the tribenzylated derivative of imidazolyl-C-glycoside

Scheme 1. Reagents and conditions: (a) HSCH₂CH₂SH, dioxane/HCl, room temp., 12 h; (b) TBDMSCl, imidazole, DMF, room temp. 24 h; (c) Hg(ClO₄)₂,

CaCO₃, THF/H₂O, room temp. 2 h; (d) 10, n-BuLi, THF, 2708C; (e) NaH, BnBr, Bu₄NI cat., THF, room temp., 12 h; (f) Bu₄NF, room temp.; (g) 1.5 M HCl,

reﬂux, 2 h.

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6505

Figure 1. Molecular structure of 7 with the atom-numbering scheme

(ORTEP plot. Displacement elipsoids are drown at the 50% probability

level); Selected torsion angles [8]: O(1)–C(4)–C(5)–C(6)¼29.5, O(1)–

C(7)–C(6)–C(5)¼30.1, C(4)–C(5)–C(6)–C(7)¼235.7.

Scheme 3. Steric interactions in the transition states.

We believe the different outcomes of both the above

cyclisations result from different steric interactions in the

transition states of those reactions (Scheme 3).

In the ^L-talo series the transition state leading to N-cyclisa-

tion of the ^D-allo-pentitol 19 (with formation of the

piperidinose ring) in both possible conformations has

unfavourable 1,3-interactions of the pseudoaxial C(1)–

OBn with the axial C(3)–OBn and the axial C(2)–OBn with

the pseudoaxial C(4)–CH₂OBn (Scheme 3a). The situation

in the ^L-galacto series is the opposite. One of the two

possible conformations of the transition state leading to the

piperidine ring formation has no 1,3-diaxial interactions

(Scheme 3b).

2.1.2. ^D-gulo and D-ido series. Following the reaction

pathway shown in Scheme 4, dithioacetal 24 was obtained

from tri-O-benzyl-^L-arabino-furanose 23²⁰in 62% yield

and was subsequently silylated to give its 4-O-TBDMS

derivative 25 in 82% yield. The thioacetal function of 25

was cleaved in conditions described by Fetizon (CH₃I,

Na₂CO₃, acetone/water, 608C)²¹to give 2,3,5-tri-O-benzyl-

4-O-t-butyldimethylsilyl-^L-arabinose 26 in 49% yield. As a

result of addition of the 5-lithiated imidazole 10 to aldehyde

26 a mixture of ^L-gluco-27a and L-manno-imidazolyl-

pentitols 27b was obtained in 97% yield. The epimers 27a

and 27b were chromatographically separated and isolated in

a 1:2 ratio (31 and 66% yields, respectively). They were

subjected to analogous reaction sequences. Benzylation of

the epimers 27a and 27b resulted in the tetrabenzyl

derivatives 28a and 28b, respectively. They were sub-

sequently deprotected from acid-labile groups (including

TBDMS) with 1.5 M HCl in reﬂuxing THF to give

tetrabenzyl-imidazolyl-pentitols 29a (63% yield from 27a)

and 29b (64% yield from 27b), respectively. Their

mesylation and subsequent treatment with acetic anhydride

in pyridine at 808C resulted in cyclisation with formation of

Scheme 2. Reagents and conditions: (a) (1) MsCl, Py, room temp.; 1 h. (2)

Ac₂O, Py, 808C, 24 h (b) H₂, Pd(OH)₂/C, EtOH, AcOH; (c) Tf₂O, Py,

CH₂Cl₂, 2208C then room temp., 5 h; (d) 4 M NaOH, MeOH, room temp.;

(e) H₂, Pd(OH)₂/C, room temp., 48 h.

21, which was subsequently debenzylated by hydro-

genolysis in the presence of palladium hydroxide to give

4,5-(a-^L-lyxofuranosyl)-1H-imidazole 7 in 81% yield.

Structure of the furanoside 7 was clearly demonstrated by

the X-ray diffraction analysis as shown in Figure 1. The

expected formation of imidazolo[1,5]-^L-talo-piperidinose

22 was not observed at all (Scheme 2).

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A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

Scheme 4. Reagents and conditions: (a) HSCH₂CH₂SH, dioxane/HCl, room temp., 24 h; (b) TBDMSCl, imidazole, DMAP, DMF, room temp. 20 h; (c) CH₃I,

acetone/H₂O, 608C, 24 h; (d) 10, n-BuLi, THF, 2708C, 2.5 h; (e) NaH, BnBr, Bu₄NI cat., THF, room temp., 12 h; (f) 1.5 M HCl, reﬂux, 2 h; (g) (1) MsCl, Py,

08C to room temp., 1 h. (2) Ac₂O, 808C, 20 h; (h) H₂, Pd/C, room temp., 48 h.

tetrabenzyl-imidazolo[1,5]piperidinoses with D-ido (30a,

20% yield) and ^D-gulo (30b, 51% yield) conﬁgurations,

respectively. They were both debenzylated by hydrogeno-

lysis to produce the target compounds imidazolo[1,5]-^D-

ido-piperidinose 3 and imidazolo[1,5]-^D-gulo-piperidinose

4 in 48 and 51% yields, respectively. In both cases the steric

conditions do not disfavour N-cyclisation with formation of

imidazolopiperidinoses 3 and 4. In the ^D-gulo series both

conformations of the transition state leading to N-cyclisa-

tion are free from 1,3-diaxial interactions (Scheme 3c). In

the ^D-ido series one of the conformations of the transition

state leading to N-cyclisation is free from such interactions

(Scheme 3d).

under acidic conditions without isolation to give imidazolyl-

furanoses 34a (60% yield from 32a) and 34b (65% yield

from 32b), respectively, both as mixtures of anomers.

Reduction of 34a and 34b by NaBH₄resulted in 1,3-di-O-

benzyl-^L-gulo- (35a) and 1,3-di-O-benzyl-L-ido-imidazo-

lyl-pentitol (35b) in 87 and 88% yields, respectively. These

were tritylated to form ditrityl derivatives 36a (48%) and

36b (56%). Their monobenzylation afforded mixtures of

1,2,3- and 1,3,4-tri-O-benzyl-pentitols: 37a (47%) and 38a

(27%) in the ^L-gulo and 37b (37%) and 38b (23%) in the L-

ido series, respectively. Compounds 37a and 37b were used

in further reactions (Scheme 5).

Treatment of 37a and 37b with phenylmethanesulphonyl

chloride gave epimeric sulphonates 39a and 39b, respect-

ively. As a result of their heating in pyridine and subsequent

acidic cleavage of the trityl groups, different ways of

cyclisation in both series were observed. ^L-gulo-Pentitol

39a afforded N-cyclisation with formation of tribenzyl-

imidazolo-^D-manno-piperidinose 40a, which after hydro-

genolytic cleavage of benzyl groups gave imidazolo[1,5]-^D-

manno-piperidinose (5) in 75% yield. ^L-ido-Pentitol 39b

2.1.3. ^D-manno and D-gluco series. Dialdofuranose 31,

readily available from ^D-glucose,²²under treatment with

lithiated imidazole 10 gave a mixture of the two epimeric

imidazolyl-pentoses 32a and 32b in 78% yield. These two

diastereomers were chromatographically separated and

isolated in a 3:2 ratio. They were subiected to analogous

reaction sequences. Thus, benzylation of 32a and 32b

yielded compounds 33a and 33b, which were deprotected

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6507

Scheme 5. Reagents and conditions: (a) 10, n-BuLi, THF, 2708C; (b) BnBr, NaH, DMF, room temp.; (c) HCl aq, THF, reﬂux; (d) NaBH₄, MeOH, 08C to room

temp.; (e) TrCl, Py, DMAP, 80–908C; (f) BnBr, NaH, Bu₄NI cat., THF, 08C to room temp.

under the same experimental conditions gave mainly

O-cyclisationproducts—4(5)(a-^D-arabinopyranosyl)imidazole

41 and 4(5)(b-^D-arabinopyranosyl)imidazole 42. Tribenzyl-

conﬁguration on the C-1 stereogenic centre in both epimeric

series ^D-manno and D-gluco was also determined inde-

pendently by chemical means according to our previously

described results.²³

imidazolo-^D-gluco-piperidinose 40b,

a

result of

N-cyclisation, was a minor product (41:42:40b¼7:4:1).

Hydrogenolytic cleavage of the benzyl groups in 41, 42

and 40b resulted in the C-pyranosides 8 and 9 and

imidazolo[1,5]-^D-gluco-piperidinose (6) in 87, 57 and

88%, respectively, (Scheme 6). Structures of both pyrano-

Phenylmethanesulphonylation of both OH groups in

imidazolyl-pentitol 36a and subsequent acidic cleavage of

the trityl groups afforded a mixture of the disulphonate

derivative 43a and imidazolo-^D-manno-piperidinose 44 in a

2:1 ratio. Under treatment with NaNH₂, compound 44, as a

result of trans-elimination, afforded an unsaturated deriva-

tive 46, which was catalytically hydrogenated to give the

imidazolopiperidinose 48. Pentitol 43a under the same

reaction conditions (NaNH₂) yielded an unsaturated azepa-

nose 45. Its hydrogenolytic debenzylation and reduction

resulted in formation of imidazoloazepanose 47. Both of the

above reaction pathways involve trans-elimination and

prove R conﬁguration on C-1 in the epimer 32a and ^L-gulo

conﬁguration in all imidazolyl-pentitols originating from it.

Thus, the target imidazolopiperidinose 5 has the ^D-manno

conﬁguration. The epimeric imidazolyl-pentitol 36b in a

sequence of analogous reactions gave, via disulphonate 43b,

a tricyclic structure 49, which was catalytically hydrogen-

ated to afford imidazolopyrrolydinose 50 (Scheme 8). The

stereochemical outcome of these reactions, involving a

contraction of the intermediately formed piperidinose

ring,²³is only possible with an antiperiplanar position for

the C(8)–C(8a) bond relative the sulphonyloxy leaving

group, proving ^L-ido conﬁguration in the epimer 32b and all

1

sides 8 and 9 were deduced from their H and ¹³C NMR

spectra (vide infra).

The formation of two anomeric pyranosides 41 and 42, each

with three benzyl groups, together with a transfer of one

such group from C(1) to C(4) and a conﬁguration change on

C(4), may be tentatively explained in the following way:

Firstly, the C(1) benzyloxyl group oxygen attacks at C(4)

inducing phenylmethanesulphonoxyl anion departure,

inversion of conﬁguration on C(4) and formation of a

furanose oxonium ion. The subsequent opening of this

cation involves the departure of a benzyloxyl group and

formation of a resonance-stabilised allyl-type cation. Then,

nucleophilic attack of the C(5) oxygen on the C(1) atom of

the cation results in the formation of two anomeric

pyranosides as trityl oxonium ions. The departure of a

stabilised trityl carbocation then affords the pyranosides 41

and 42 (Scheme 7).

In addition to spectroscopic analysis (vide infra) the

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A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

Scheme 6. Reagents and conditions: (a) BnSO₂Cl, Py, 2308C to room

temp.; (b) Py, 60–808C; (c) 6 M HCl aq, THF, reﬂux; (d) H₂, Pd/C, EtOH,

room temp.

imidazolyl-pentitols originating from it. Thus, imidazolo-

piperidinose 6 has the ^D-gluco conﬁguration.

2.2. Structure analysis

Scheme 8. Reagents and conditions: (a) BnSO₂Cl, Py, 2308C to room

temp.; (b) 6 M HCl aq, THF, reﬂux; (c) NaNH₂, DMF, room temp.; (d) H₂,

Pd/C, EtOH, room temp.

The structural and conﬁgurational assignments of imida-

zolo-hexopiperidinoses and imidazolyl-C-glycosides were

1

determined from the H and ¹³C NMR spectroscopic data.

The structures of imidazolopiperidinoses 2–6 were asigned

from ¹³C NMR data analysis. The chemical shifts of C-5 in

imidazolopiperidinoses 2–6 and their benzyl derivatives are

within the range of 55–58 ppm. This range is diagnostic for

carbons bonded to the imidazole ring nitrogen. The ^D-gulo

conﬁguration of tetrabenzyl-imidazolo[1,5]piperidinose

30b was conﬁrmed by application of the nuclear Overhauser

effect (NOE). Irradiation of H-8 generated NOE enhance-

ment at H-7 (5.3%) and when H-7 was irradiated, the 9.0%

NOE at H-8 was observed. The same conﬁguration was

conﬁrmed in 4 after debenzylation: irradiation of H-8

generated nuclear Overhauser enhancement at H-7 (10.5%).

The additional splitting observed for H-8 (0.9 Hz) in 4 can

be explained by the allylic proton–proton coupling with

H-1.

The compound 30b was assigned the ^D-gulo conﬁguration,

therefore the isomer 30a should have the ^D-ido conﬁgur-

ation. For both isomers 30a and 30b the vicinal coupling

constants between H-8 and H-7 or H-7 and H-6 are

similar (around 3.5 and 7 Hz, respectively). This can be

Scheme 7. Proposed reaction pathway to the pyranosides 41 and 42.

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6509

Table 1. Inhibition values of the compounds 2, 4, 5, 47, 48, 50 against six commercially available glycosidases. The percentage of inhibition was measured at

1 mM. NI¼no inhibition at [I]¼1 mM

2

4

5

a-^D-Glucosidase (baker’s yeast)

b-^D-Glucosidase (almonds)

a-^D-Galactosidase (green coffee beans)

b-^D-Galactosidase (Escherichia coli)

a-^D-Mannosidase (Jack beans)

NI

47

NI

10%

K_i¼230 mM

K_i¼90 mM

NI

K_i¼100 mM

NI

17%

NI

50

b-^D-Mannosidase (acetone snail powder)

48

a-^D-Glucosidase (baker’s yeast)

b-^D-Glucosidase (almonds)

a-^D-Galactosidase (green coffee beans)

b-^D-Galactosidase (Escherichia coli)

a-^D-Mannosidase (Jack beans)

NI

22%

14%

NI

33%

16%

NI

13%

b-^D-Mannosidase (acetone snail powder)

explained by the conformations of 30a and 30b in

which benzyloxy groups attached to C-6 and C-7 are axial

and exo-benzyloxymethyl group occupies the pseudo-

equatorial position.

mesh). TLC: silica gel on plastic sheets (Merck 60 HF₂₅₄);

the spots were viewed under UV or by heating with a

termogun after spraying with a solution of KMnO₄(20 g)

and Na₂CO₃(40 g) in H₂O (1 L) or a solution of

phosphomolybdic acid (5 in 96% EtOH). Mp Koﬂer hot-

bench or Bu¨chi-SMP-30 aparatus; corrected values. Optical

rotations were measured at 208C: Schmidt–Haensch

Polartronic Universal and Perkin–Elmer 241 polarimeters.

¹H and ¹³C NMR spectra: Bruker ACF 250 and Avance

DPX 250 spectrometers at 300 K. Internal references for ¹H

NMR: SiMe₄(d¼0.00), CDCl₃(d¼7.26), CD₃OD

(d¼3.30), [D₄]TSP for spectra in D₂O (d¼0.00); for ¹³C

NMR: CDCl₃(d¼77.03), CD₃OD (d¼49.02); d in ppm and

J in Hz. HR-MS on Finnigan MAT 95 (Finnigan MAT

GmbH, Germany) and ZabSpec TOF Micromass

spectometers at 8Kv (source temp. 408C). Elemental

analysis were carried out by the Microanalysis Service of

CNRS (Verneson, France).

In the ^D-gluco series the two major products 41 and 42 are

tribenzyl-C-pyranosides. As was proved by HMBC experi-

ment, only the proton assigned as ₀H-1 has the heteronuclear

shift correlation with C-2⁰and C-5 atoms. The conﬁguration

at the C-1 atom can be deduced from the analysis of the

vicinal coupling constants. Their signiﬁcant difference

between H-1 and H-2: 9.77 Hz (8) and 1.71 Hz (9)

undoubtedly provides evidence for equatorial (8) and

axial (9) position for the imidazole ring.

2.3. Enzymatic assays

The compounds 2, 4, 5, 47, 48, 50 have been evaluated as

potential inhibitors of six commercially available glycosi-

dases, and the results compiled in Table 1. The imidazolo

derivatives which do show some activity proved to be

competitive inhitors, but only moderate inhibitions could be

measured. The ^D-gulo 4 inhibits the a-D-galactosidase

(green coffee beans) and the b-^D-galactosidase (Escherichia

coli) with K_ivalues of 90 and 100 mM, respectively. This

stereoisomer 4 has an identical conﬁguration with the

D-galactose in the C(8), C(6), C(5) positions. The D-manno

5 inhibits the b-^D-glucosidase (almonds) with a K_iof

230 mM. In the stereoisomer 5 the three conﬁgurations C(7),

C(6) and C(5) are identical with those of the asymmetric

centres of the ^D-glucose. Unexpectedly D-manno 5

inhibits very weakly a-^D-mannosidase (Jack bean)

neverthless that all stereogenic centers have the same

conﬁguration as ^D-mannose. The previously described²³

compounds 47, 48, 50 show a very weak inhibition

when tested with a concentration of 1 mM. It appears

therefore that these compounds are very poor inhibitors.

The ^L-galacto 2 was inactive towards the pool of evaluated

D-glycosidases.

3.2. X-Ray diffraction analysis

Single crystals of 7, suitable for X-ray crystallography, were

grown by crystallization from methanol. Data were

collected at 293 K on a Bruker-Nonius KappaCCD area

detector using Mo Ka radiation (l¼0.71073). The com-

pound with the chemical formula of C₈H₁₂N₂O₄crystallized

in the orthorhombic space group P2₁2₁2₁.The dimensions of

the unit-cell are: a¼6.9605(3), b¼8.0701(4), c¼16.5064(7),

a¼b¼g¼908. The usual corrections were applied. The

structure was solved using the program SIR 92.²⁴Aniso-

tropic reﬁnement on all non-hydrogen atoms was carried out

using the program CRYSTALS.²⁵Scattering factors were

taken from the International Tables Vol. IV table 2.2B.. The

plots were created using ORTEP-3 for Windows.²⁶

3.3. Enzymatic assays

Glycosidases [a-mannosidase (EC 3.2.1.24) from Jack

beans, b-mannosidase (EC 3.2.1.25) from snail acetone

powder, a-glucosidase (EC 3.2.1.20) from baker’s yeast,

b-glucosidase (EC 3.2.1.21) from almonds, a-galactosidase

(EC 3.2.1.22) from green coffee beans, b-galactosidase

from Escherichia coli (EC 3.2.1.23)], and their correspond-

ing substrates were purchased from Sigma Co. Spectro-

photometric assays were performed at the optimum pH for

each enzyme,²⁷with p-nitrophenyl-a-D-mannopyranoside

3. Experimental

3.1. General

Flash chromatography: silica gel (Merck 60; 230–400

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A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

as a substrate for a-mannosidase (K_m¼2 mM, pH¼4.5),

p-nitrophenyl-b-^D-mannopyranoside for b-mannosidase

(K_m¼1.33 mM, pH¼4.0), p-nitrophenyl-a-D-glucopyrano-

side for a-glucosidase (K_m¼0.3 mM, pH¼7), p-nitro-

phenyl-b-^D-glucopyranoside for b-glucosidase (K_m¼

1.3 mM, pH¼5.0), p-nitrophenyl-a-^D-galactopyranoside

for a-^D-galactosidase (K_m¼0.25 mM, pH¼6.5) and p-nitro-

phenyl-b-^D-galactopyranoside for b-D-galactosidase

(K_m¼0.4 mM, pH¼7). The release of p-nitrophenol was

measured continuously at 405 nm to determine initial

velocities. All kinetics were performed at 258C and the

reaction was started by the addition of enzyme in a 1 mL

assay medium (acetate buffer 50 mM, or phosphate buffer

20 mM according to the desired pH value) using substrate

concentrations around the K_mvalue of each enzyme. The K_i

values were determined for the most potent inhibitors, by

the Dixon graphical procedure.^28,29

4.1 Hz, C(2)H), 3.74 (1H, dd, J¼6.9, 3.0 Hz, C(3)H), 3.68

(1H, dd, J¼9.8, 4.4 Hz, C(5)H_aH_b), 3.54 (1H, dd, J¼9.8,

6.0 Hz, C(5)H_aH_b), 3.31–3.11 (4H, m, S(CH₂)₂), 0.92

(9H, s, SiC(CH₃)₃), 0.09 and 0.07 (6H, 2 p s, Si(CH₃)₂);

d_C(60 MHz, CDCl₃) 138.5, 138.4, 138.2 (C s-arom.),

128.3, 127.4 (CH arom.), 83.1 (C-3), 83.0 (C-2), 75.1

(OCH₂Ph), 73.7 (OCH₂Ph), 73.2 (OCH₂Ph), 72.6 (C-4),

72.3 (C-5), 54.9 (C-1), 38.8, 38.4, (S(CH₂)₂), 25.9

((CH₃)₃CSi), 18.1 ((CH₃)₃CSi), 24.55,-4.66 ((CH₃)₂Si);

HRMS (Cl, NH₃) MH^þ, 611.2685. C₃₄H₄₇O₄S₂Si requires

611.2685.

3.3.3. 2,3,5-Tri-O-benzyl-4-O-tert-butyldimethylsilyl-^D-

ribose (14). To a stirred mixture of compound 13 (1.29 g,

2.1 mmol), CaCO₃(630 mg, 6.3 mmol) and water (4 mL) in

THF (15 mL) was added dropwise a solution of Hg(ClO₄)₂.

H₂O (2.26 g, 4.6 mmol) in water (4 mL) at room tempera-

ture. The mixture was vigorously stirred at room tempera-

ture for 2 h and ﬁltered. The ﬁltrate was diluted with Et₂O

(100 mL) and washed with brine (2£60 mL). The organic

layer was dried (MgSO₄), ﬁltered and evaporated. The

residue was puriﬁed by ﬂash chromatography (AcOEt/

cyclohexane 1:9) to yield the title compound 14 (1.01 g,

90%) as a colourless oil. [a]²_D⁰¼þ4.0 (c¼3.0; CHCl₃); d_H

(250 MHz, CDCl₃) 9.67 (1H, d, J¼0.9 Hz, C(1)H), 7.33–

7.21 (15H, m, 3Ph), 4.64 and 4.57 (2H, AB, J¼11.9 Hz,

OCH₂Ph), 4.68 and 4.56 (2H, AB, J¼11.9 Hz, OCH₂Ph),

4.46 and 4.41 (2H, AB J¼12.1 Hz, OCH₂Ph), 4.13 (2H, m,

C(2)H, C(4)H), 3.95 (1H, dd, C(3)H), 3.54 (2H, d,

J¼4.4 Hz, C(5)H_aH_b), 0.86 (9H, s, SiC(CH₃)₃), 0.06 and

0.05 (6H, 2 p s Si(CH₃)₂); d_C(60 MHz, CDCl₃) 201.8 (C-1),

138.1, 137.8, 137.4 (C s-arom.), 128.4–127.6 (CH arom.),

82.5 (C-2), 81.4 (C-3), 73.3 (OCH₂Ph), 73.2 (OCH₂Ph),

72.8 (OCH₂Ph), 71.4 (C-5), 71.3 (C-4), 25.9 ((CH₃)₃CSi),

18.1 ((CH₃)₃CSi), 24.5 ((CH₃)₂Si); HRMS (Cl, NH₃)

MH^þ, 535.2880. C₃₂H₄₃O₅Si requires 535.2879.

3.3.1. 2,3,5-Tri-O-benzyl-D-ribose ethylenedithioacetal

(12). A solution of 2,3,5-tri-O-benzyl-^D-ribofuranose 11¹⁹

(520 mg, 1.24 mmol) and ethanedithiol (0.16 mL,

1.8 mmol) in dioxane saturated with HCl (5 mL) was stirred

at room temperature overnight. The mixture was treated

with CHCl₃(20 mL) and washed with a saturated aq.

solution of NaHCO₃and water. The organic layer was dried

(MgSO₄), ﬁltered and evaporated. The residue was puriﬁed

by ﬂash chromatography (AcOEt/cyclohexane 1:9 to 2:8) to

give the title compound 12 (520 mg, 85%) as a pale yellow

oil. [Found: C 67.5, H 6.4, S 12.9 C₂₈H₃₂O₄S₂requires C

67.71, H 6.49, S 12.91%]; [a]²_D⁰¼þ11 (c¼3.0; CHCl₃); n_max

(ﬁlm): 3030, 3018, 2920, 1485, 1436, 1186, 1092, 900, 736,

696, 620 cm²¹; d_H(250 MHz, CDCl₃) 7.40– 7.25 (15H, m,

3Ph), 4.96 (1H, d, J¼7.5 Hz, C(1)H), 4.84 and 4.77 (2H,

AB, J¼11.0 Hz, OCH₂Ph), 4.69 and 4.54 (2H, AB,

J¼11.4 Hz, OCH₂Ph), 4.52 and 4.45 (2H, AB, J¼11.9 Hz,

OCH₂Ph), 4.15 (1H, m, C(4)H), 3.81 (1H, dd, J¼7.5,

3.1 Hz, C(2)H), 3.77 (1H, dd, J¼7.0, 3.1 Hz, C(3)H), 3.65

(1H, dd, J¼9.7, 3.0 Hz, C(5)H_aH_b), 3.56 (1H, dd, J¼9.7,

6.3 Hz, C(5)H_aH_b), 3.12–3.23 (4H, m, S(CH₂)₂), 2.62 (1H,

exhange with D₂O, d, J¼4.7 Hz, C(4)OH); d_C(60 MHz,

CDCl₃) 138.0–138.2 (3 p C s-arom.), 128.4–127.7 (CH

arom), 84.6 (C-2). 81.1 (C-3), 75.2 (OCH₂Ph), 73.4

(OCH₂Ph), 73.2 (OCH₂Ph), 71.3 (C-5), 70.7 (C-4), 54.7

(C-1), 38.7 and 38.1 (S(CH₂)₂); HRMS (Cl, NH₃) MH^þ,

497.1818. C₂₈H₃₃O₄S₂requires 497.1820.

3.3.4. Coupling reaction between the C(5)-lithio deriva-

tive of imidazole 10 and 14: synthesis of ^D-altro (15a) and

D-allo (15b) epimers. A solution of n-BuLi in hexanes

(2.5 M, 4.5 mL, 11.2 mmol) was added under argon at

2788C to a stirred solution of imidazole derivative 10

(1.80 g, 10.3 mmol) in anhydrous THF (50 mL). After

30 min the TBDMSCl (1.85 g, 12.2 mmol) was added at

once and the mixture was stirred at room temperature for

2 h, then cooled again to 2788C and treated with n-BuLi in

hexane (2.5 M, 4.9 mL, 12.2 mmol). After 30 min, a

solution of ribose derivative 14 (3.65 g, 6.8 mmol) in

anhydrous THF (5 mL) was added dropwise and the stirring

was continued at 2788C for 30 min and then at room

temperature for 12 h. The reaction mixture was quenched

with water (1 mL) and concentrated under reduced pressure.

The residue was diluted with Et₂O (100 mL) and washed

with brine (80 mL). The organic layer was dried (MgSO₄),

ﬁltered and evaporated. The two epimers were separated by

careful chromatography (AcOEt/cyclohexane 1:9, 2:8, then

1:1) to give the ^D-altro epimer 15a (1.24 g, 22%) as an

orange-coloured oil and the ^D-allo epimer 15b (2.84 g,

50%) as a yellow oil. 15a d_H(250 MHz, CDCl₃) 7.37–7.14

(16H, m, C(4⁰)H, 3Ph), 5.33 (1H, d, J¼1.2 Hz, C(1)H), 4.88

and 4.58 (2H, AB, J¼11.0 Hz, OCH₂Ph), 4.47 (2H, s,

OCH₂Ph), 4.42 and 3.80 (2H, AB, J¼10.4 Hz, OCH₂Ph),

4.24 (1H, ddd, J¼6.1, 5.2, 1.8 Hz, C(4)H), 4.07 (1H, dd,

3.3.2. 2,3,5-Tri-O-benzyl-4-O-tert-butyldimethylsilyl-^D-

ribose ethylenedithioacetal (13). A solution of thioacetal

12 (1.25 g, 2.5 mmol), anhydrous imidazole (514 mg,

7.5 mmol) and TBDMSCl (760 mg, 5.0 mmol) in anhydrous

DMF (10 mL) was stirred at room temperature for 24 h. The

mixture was treated with saturated aq. solution of NH₄Cl

(80 mL) and extracted with cyclohexane. The extracts were

dried (MgSO₄), ﬁltered and evaporated. The residue was

puriﬁed by ﬂash chromatography (AcOEt/cyclohexane 5:

95) to give the title compound 13 (1.29 g, 84%) as a

colourless oil. [a]_D²⁰¼25.0 (c¼1.0; CHCl₃); n_max(ﬁlm):

3046, 2910, 2856, 1498, 1456, 1360, 1252, 1100, 838, 776,

736, 696 cm²¹; d_H(250 MHz, CDCl₃) 7.33–7.25 (15H, m,

3Ph), 4.97 (1H, d, J¼4.1 Hz, C(1)H), 4.88 and 4.76 (2H,

AB, J¼10.9 Hz, OCH₂Ph), 4.76 and 4.59 (2H, AB,

J¼11.2 Hz, OCH₂Ph),4.47 (2H, s, OCH₂Ph), 4.24 (1H,

ddd, J¼6.0, 4.4, 3.0 Hz, C(4)H), 3.88 (1H, dd, J¼6.9,

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6511

J¼8.5, 1.2 Hz, C(2)H), 3.84 (1H, dd, J¼8.5, 1.2 Hz,

C(3)H), 3.74 (1H, dd, J¼9.8, 5.2 Hz, C(5)H_aH_b), 3.56

(1H, dd, J¼9.8, 6.1 Hz, C(5)H_aH_b), 2.59 (6H, s, N(CH₃)₂),

0.98 (9H, s, SiC(CH₃)₃), 0.90 (9H, s, SiC(CH₃)₃), 0.40 (6H,

s, Si(CH₃)₂) 0.08 (6H, s, Si(CH₃)₂); HRMS (Cl, NH₃) MH^þ,

found 824.4178. C₄₃H₆₆N₃O₇Si₂S requires 824.4160.15b

d_H(250 MHz, CDCl₃) 7.49 (1H, s, C(4⁰)H), 7.33–7.11

(15H, m, 3Ph), 5.28 (1H, dd, J¼6.1, 4.3 Hz, C(1)H), 4.69

and 4.51 (2H, AB, J¼11.3 Hz, OCH₂Ph), 4.61 and 4.42 (2H,

AB, J¼1.3 Hz, OCH₂Ph), 4.51 and 4.45 (2H, AB,

J¼11.9 Hz, OCH₂Ph), 4.26 (1H, ddd, J¼5.8, 4.9, 3.7 Hz,

C(4)H), 4.05 (1H, t, J¼5.5 Hz, C(2)H), 3.81 (1H, dd, J¼5.5,

3.7 Hz, C(3)H), 3.67 (1H, dd, J¼9.8, 4.9 Hz, C(5)H_aH_b),

3.56 (1H, dd, J¼9.8, 5.8 Hz, C(5)H_aH_b), 3.84 (1H, dd,

J¼8.5, 1.2 Hz, C(3)H), 3.49 (1H exchange with D₂O, d,

J¼4.3 Hz, C(1)OH), 2.60 (6H, s, N(CH₃)₂), 0.98 (9H, s,

SiC(CH₃)₃), 0.90 (9H, s, SiC(CH₃)₃), 0.37 (6H, s, Si(CH₃)₂)

0.09 (6H, s, Si(CH₃)₂); HRMS (Cl, NH₃) MH^þ, found

824.4179. C₄₃H₆₆N₃O₇Si₂S requires 824.4160.

3.3.6. 5,6,7,8-Tetra-O-benzyl-imidazolo[1,5]-^L-galacto-

piperidinose (18). To a stirred solution of compound 17a

(230 mg, 0.4 mmol) in dry pyridine (5 mL) at 08C was

added MsCl (0.125 mL, 1.6 mmol). After stirring for 1 h at

room temperature, followed by addition of Ac₂O (0.25 mL),

the mixture was heated at 808C for 20 h, and neutralised at

room temperature with EtOH (1 mL). The reaction mixture

was diluted with AcOEt (25 mL) and washed with brine

(3£20 mL). The organic layer was dried (MgSO₄), ﬁltered

and evaporated. The residue was puriﬁed by ﬂash

chromatography (Et₂O/MeOH-NH₃98:2) to yield the title

compound 18 (150 mg, 67%) as a yellow oil. [a]²_D⁰¼256

(c¼1.0; CHCl₃), d_H(250 MHz, CDCl₃) 8.06 (1H, s, C(1)H),

7.42–7.06 (20H, m, 4Ph), 7.42 (1H, s, C(3)H), 4.75 (1H, d,

J¼4.5 Hz, C(8)H), 4.53 and 4.31 (2H, AB, J¼11.8 Hz,

OCH₂Ph), 4.42 (2H, s, OCH₂Ph),4.24 (1H, ddd, J¼8.4, 2.3,

1.8 Hz, C(5)H), 4.19 (1H, dd, J¼6.3, 1.8 Hz, C(6)H), 4.12

and 4.03 (2H, AB, J¼11.8 Hz, OCH₂Ph), 3.98 (1H, dd,

J¼9.9, 2.3 Hz, C(9) H_aH_b), 3.97 (1H, dd, J¼6.3, 4.5 Hz,

C(7)H), 3.77 (1H, dd, J¼9.9, 8.4 Hz, C(9)H_aH_b); d_C

(60 MHz, CDCl₃) 137.7–137.4 (C s-arom.), 136.8 (C-3),

127.4–128.4 (CH arom., C-1), 124.9 (C-8a), 77.3 (C-7),

73.5 (C-6), 73.3 (OCH₂Ph), 72.6 (OCH₂Ph), 72.3

(OCH₂Ph), 70.8 (C-9), 70.7 (OCH₂Ph), 69.6 (C-8), 56.3

(C-5); HRMS (Cl, NH₃) MH^þ, found 561.2754.

C₃₆H₃₇N₂O₄requires 561.2753.

3.3.5. 1,2,3,5-Tetra-O-benzyl-1-[1H-imidazol-4(5)yl]-^D-

altro-pentitol (17a). To a stirred solution of epimer 15a

(1.20 g 1.46 mmol) and Bu₄NI (catalytic amount) in

anhydrous THF (50 mL) was added portionwise 50% NaH

in oil (210 mg, ca. 4.4 mmol) at room temperature. When

the evolution of H₂ceased, BnBr (0.3 mL, 2.50 mmol) was

added at room temperature. Stirring was continued at room

temperature for 12 h. The mixture was quenched with

MeOH (10 mL) and the solvents were evaporated. The

residue was diluted with Et₂O (100 mL), washed with water

(50 mL) and brine (50 mL). The organic layer was dried

(MgSO₄), ﬁltered and evaporated. The residue was puriﬁed

by ﬂash chromatography (AcOEt/cyclohexane 1:9) to

obtain the benzylated product 16a (1.07 g, 1.17 mmol

80%) as a yellow oil. This compound 16a was dissolved

in anhydrous THF (16 mL) and treated with the solution of

TBAF in THF (1 M, 4 mL, 4.0 mmol, 3 equiv.). The

mixture was stirred at room temperature for 12 h and

concentrated in vacuo. The residue was diluted with Et₂O

(60 mL), washed with a saturated aq. solution of NH₄Cl

(30 mL) and the organic layer was evaporated without

drying. The residue was dissolved in aq. HCl (1.5 M,

30 mL) and the solution was reﬂuxed for 2 h. The reaction

mixture was neutralised with NH₄OH and extracted with

CHCl₃(2£30 mL). The organic layers were dried (MgSO₄),

ﬁltered and evaporated. The residue was puriﬁed by ﬂash

chromatography (CH₂Cl₂/MeOH-NH₃96:4) to give the title

compound 17a (507 mg, 60% from 15a) as a light yellow

resin. [a]²_D⁰¼23 (c¼1.0; CHCl₃); d_H(250 MHz, CDCl₃)

7.44 (1H, s, C(2⁰)H), 7.36–7.08 (20H, m, 4Ph), 6.97 (1H, s,

C(5⁰)H), 5.87 (1H, d, J¼7.3 Hz, C(1)H), 4.75 and 4.66 (2H,

AB, J¼11.4 Hz, OCH₂Ph), 4.50 and 4.38 (2H, AB,

J¼11.6 Hz, OCH₂Ph), 4.47 and 4.42 (2H, AB, J¼11.9 Hz,

OCH₂Ph), 4.52 and 4.34 (2H, AB, J¼11.3 Hz, OCH₂Ph),

4.10 (1H, dd, J¼7.3, 2.4 Hz, C(2)H), 3.89 (1H, ddd, J¼7.6,

5.8, 2.4 Hz, C(4)H), 3.63 (1H, dd, J¼9.8, 2.4 Hz,

C(5)H_aH_b), 3.61 (1H, dd, J¼7.6, 2.4 Hz, C(3)H), 3.51

(1H, dd, J¼9.8, 5.8 Hz, C(5)H_aH_b); d_C(60 MHz, CDCl₃):

138.0–138.6 (C s-arom.), 135.5 (C-2⁰), 128.3–127.5 (CH

arom.), 82.7 (C-4), 79.3 (C-3), 75.9 (C-1), 75.0 (OCH₂Ph),

73.3 (OCH₂Ph), 72.7 (OCH₂Ph), 71.7 (OCH₂Ph), 71.0

(C-5), 70.3 (C-2); HRMS (Cl, NH₃) MH^þ, found 579.2863.

C₃₆H₃₉N₂O₅requires 579.2859.

3.3.7. Imidazolo[1,5]-^L-galacto-piperidinose (2). A sus-

pension of piperidinose 18 (130 mg, 0.23 mmol) and 10%

Pd(OH)₂/C (Pearlman’s catalyst) (250 mg) in EtOH/AcOH

(4 mL, 1:1) was vigorously stirred under H₂(ca. 2 atm.) at

room temperature for 24 h. The suspension was centrifuged

and the catalyst was washed several times with MeOH. The

solution was evaporated to dryness in vacuo and the residue

was dissolved in MeOH and passed over an Amberlyst IRA

400 (OH²) column (elution with MeOH). The combined

fractions were evaporated and the residue was puriﬁed by

ﬂash chromatography (CHCl₃/MeOH/NH₄OH 5:4:1) to

give the title compound 2 (36 mg, 78%) as a pale yellow

powder. [a]²_D⁰¼þ12 (c¼0.5; H₂O); d_H(400 MHz; D₂O)

7.83 (1H, s, C(3)H), 6.98 (1H, s, C(1)H), 4.80 (1H, d,

J¼8.6 Hz, C(8)H), 4.33 (1H, t, J¼2.5 Hz, C(6)H), 4.25 (1H,

ddd, J¼6.7, 5.3, 2.5 Hz, C(5)H), 4.08 (1H, dd, J¼11.7,

6.7 Hz, C(9)H_aH_b), 3.99 (1H, dd, J¼11.7, 5.3 Hz,

C(9)H_aH_b), 3.81 (1H, dd, J¼8.6, 2.2 Hz, C(7)H); d_C

(100.6 MHz; D₂O): 135.5 (C-3), 130.5 (C-8a), 124.6

(C-1), 73.4 (C-7), 69.6 (C-6), 65.2 (C-8), 61.1 (CH₂OH),

d¼58.1 (C-5); HRMS (Cl, NH₃) MH^þ, found 201.0877.

C₈H₁₃N₂O₄requires 201.0875.

3.3.8. 1,2,3,5-Tetra-O-benzyl-[1H-imidazol-4(5)-yl]-^D-

allo-pentitol (17b). The same procedure as described for

the preparation of 17a (see above) was used, starting from

15b (2.68 g, 3.25 mmol) in THF (40 mL), Bu₄NI (catalytic

amount) and a 50% suspension of NaH in oil (468 mg,

ca.10 mmol) and BnBr (0.5 mL, 4.19 mmol) to give after

workup 16b, which without puriﬁcation was treated with a

solution of TBAF in THF (1 M, 10 mL, 10.0 mmol) and

after workup as above, was reﬂuxed in aq. HCl (1.5 M,

40 mL). After workup and chromatography (CH₂Cl₂/

MeOH-NH₃96:4) the title compound 17b was given

(1.54 g, 82%) as a yellow resin. [a]²_D⁰¼þ46 (c¼1.0;

CHCl₃); d_H(400 MHz, CDCl₃) 7.48 (1H, s, C(2⁰)H),

6512

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

7.34–7.13 (20H, m, 4Ph), 6.92 (1H, s, C(4⁰,5⁰)H), 4.85 (1H,

d, J¼4.3 Hz, C(1)H), 4.75 and 4.63 (2H, AB, J¼11.0 Hz,

OCH₂Ph), 4.48 (2H, s, OCH₂Ph), 4.54 and 4.44 (2H, AB,

J¼11.1, OCH₂Ph), 4.48 and 4.33 (2H, AB, J¼11.8,

OCH₂Ph), 4.15 (1H, dd, J¼5.9, 4.3 Hz, C(2)H), 4.14 (1H,

ddd, J¼6.6, 4.9, 3.2 Hz, C(4)H), 3.60 (1H, dd, J¼9.8,

6.6 Hz, C(5)H_aH_b), 3.57 (1H, dd, J¼9.8, 3.2 Hz, C(5)H_aH_b),

3.55 (1H, t, J¼4.9 Hz, C(3)H); d_C(100.6 MHz; CDCl₃)

138.0–137.9 (C s-arom.), 135.7 (C-2⁰), 128.5–127.6 (CH

arom.), 81.3 (C-4), 79.1 (C-3), 74.6 (OCH₂Ph), 73.7 (C-1),

73.4 (OCH₂Ph), 73.3 (OCH₂Ph), 71.1 (C-2), 71.0 (C-5),

70.4 (OCH₂Ph); HRMS (Cl, NH₃) MH^þ, found 579.2860.

C₃₆H₃₉N₂O₅requires 579.2859.

73.2 (C-1), 62.1 (C-5); HRMS (Cl, NH₃) MH^þ, found

201.0878. C₈H₁₃N₂O₄requires 201.0875.

3.3.11. 2,3,5-Tri-O-benzyl-^L-arabinose ethylenedithio-

acetal (24). The same procedure as for the preparation of

12 was used, starting from 2,3,5-tri-O-benzyl-^L-arabino-

furanose 23²⁰(5.65 g, 13.4 mmol) and ethanedithiol (1.9 g,

20 mmol) in dioxane saturated with HCl (60 mL). After

workup as for 12, the crude product was puriﬁed by ﬂash

chromatography (AcOEt/hexane 1:3) to give the title

compound 24 (4.1 g, 61.5%) as a pale yellow oil.

[a]²_D⁰¼223.1 (c¼1.4; CHCl₃); n_max(ﬁlm): 3030, 3016,

2920, 1484, 1436, 1188, 1092, 900, 736, 696, 620; d_H

(250 MHz, CDCl₃) 7.40–7.25 (15H, m, 3Ph), 4.91 (1H, d,

J¼8.1 Hz, C(1)H), 4.96 and 4.74 (2H, AB, J¼11.6 Hz,

OCH₂Ph), 4.65 and 4.53 (2H, AB, J¼11.0 Hz, OCH₂Ph),

4.54 and 4.49 (2H, AB, J¼11.9 Hz, OCH₂Ph), 3.98 (1H, m,

C(4)H), 3.85 (1H, dd, J¼8.1, 2.4 Hz, C(2)H), 3.78 (1H, dd,

J¼8.8, 2.4 Hz, C(3)H), 3.67 (1H, dd, J¼9.5, 3.3 Hz,

C(5)H_aH_b), 3.59 (1H, dd, J¼9.7, 4.9 Hz, C(5)H_aH_b),

3.30–3.14 (4H, m, S(CH₂)₂), 2.59 (1H, exhange with

D₂O, d, J¼4.7 Hz, C(4)OH); d_C(60 MHz, CDCl₃) 138.2–

137.7 (3 p C s-arom.), 128.4–127.5 (CH arom), 83.7 (C-2),

79.8 (C-3), 75.3 (OCH₂Ph), 74.2 (OCH₂Ph), 73.4

(OCH₂Ph), 71.0 (C-5), 70.1 (C-4), 54.4 (C-1), 38.7 and

37.8 (S(CH₂)₂); HRMS (Cl, NH₃) MH^þ, 497.1817.

C₂₈H₃₃O₄S₂requires 497.1820.

3.3.9. 2,3,5-Tri-O-benzyl-1[1H-imidazol-4(5)-yl]a-^L-

lyxo-furanoside (21). To a stirred solution of 17b

(480 mg, 0.83 mmol) and dry pyridine (0.27 mL,

3.32 mmol) in dry CH₂Cl₂(40 mL) Tf₂O (0.42 mL,

2.5 mmol) was added dropwise at 2208C. Stirring was

continued at 2208C for 2 h and for another 3 h at room

temperature. The reaction mixture was washed with

saturated aq. NaHCO₃solution. The organic layer was

evaporated without drying. The residue was dissolved in

MeOH (20 mL) and NaOH aq. solution (4 M, 10 mL) was

added. The mixture was stirred at room temperature for

30 min and concentrated under reduced pressure. The

residue was diluted with CH₂Cl₂(50 mL), washed with

H₂O (40 mL) and extracted with CH₂Cl₂(2£20 mL). The

organic layers were dried (MgSO₄), evaporated and the

residue puriﬁed by ﬂash chromatography (CH₂Cl₂/MeOH-

NH₃95:5) to give the title compound 21 (233 mg, 60%) as a

colourless resin. [a]_D²⁰¼229 (c¼1.0; CHCl₃); d_H(400 MHz,

CDCl₃) 7.34–7.16 (16H, m, CH arom. and C(2⁰)H), 6.67

(1H, s, C(4⁰, 5⁰)H), 5.03 (1H, d, J¼7.1 Hz, C(1)H), 4.76 and

4.54 (2H, AB, J¼11.7, OCH₂Ph), 4.54 and 4.47 (2H, AB,

J¼12.1, OCH₂Ph), 4.45 (2H, s, OCH₂Ph), 4.44 (1H, m,

C(4)H), 4.38 (1H, dd, J¼7.1, 4.2 Hz, C(2)H), 4.19 (1H, t,

J¼4.3 Hz, C(3)H), 3.78 (1H, dd, J¼9.9, 6.8 Hz, C(5)H_aH_b),

3.75 (1H, dd, J¼9.9, 5.4 Hz, C(5)H_aH_b); d_C(100.6 MHz,

CDCl₃) 138.2–137.8 (3 p C s-arom.), 137.6 (C-5⁰), 135.8

(C-2⁰), 127.5–128.4 (CH arom.), 116.5 (C-4⁰), 83.0 (C-2),

78.6 (C-4), 77.7 (C-3), 75.6 (C-1), 73.4 (2 p OCH₂Ph), 72.4

(OCH₂Ph), 69.4 (C-5); HRMS (Cl, NH₃) MH^þ, found

471.2282. C₂₉H₃₁N₂O₄requires 471.2284.

3.3.12. 2,3,5-Tri-O-benzyl-4-O-tert-butyldimethylsilyl-^L-

arabinose ethylenedithioacetal (25). To a stirred solution

of compound 24 (4.65 g, 9.4 mmol) in anhydrous DMF was

added anhydrous imidazole (1.92 g, 28 mmol) and

TBDMSCl (4.23 g, 28 mmol) and stirring was continued

at 808C for 20 h. The reaction mixture was poured into ice-

water (150 mL) and extracted with cyclohexane. The

extracts were dried (MgSO₄), ﬁltered and evaporated. The

residue was puriﬁed by ﬂash chromatography (AcOEt/

hexane 4:1) to gove the title compound 25 (4.7 g, 82%) as a

pale yellow oil. [a]_D²⁰¼þ1.5 (c¼1.0; CHCl₃); n_max(ﬁlm):

3048, 2912, 2856, 1496, 1456, 1360, 1252, 1100, 836, 776,

736, 696; d_H(250 MHz, CDCl₃) 7.33–7.25 (15H, m, 3Ph),

4.86 (1H, d, J¼5.5 Hz, C(1)H), 4.83 and 4.74 (2H, AB,

J¼11.6 Hz, OCH₂Ph), 4.77 and 4.66 (2H, AB, J¼11.1 Hz,

OCH₂Ph), 4.47 (2H, s, OCH₂Ph), 4.09 (1H, ddd, J¼5.4, 4.7,

3.7 Hz, C(4)H), 3.83 (1H, dd, J¼5.5, 3.7 Hz, C(3)H), 3.79

(1H, dd, J¼9.7, 4.7 Hz, C(5)H_aH_b), 3.76 (1H, t, J¼5.5 Hz,

C(2)H), 3.52 (1H, dd, J¼9.7, 5.4 Hz, C(5)H_aH_b), 3.31–3.10

(4H, m, S(CH₂)₂), 0.91 (9H, s, SiC(CH₃)₃), 0.11 and 0.10

(6H, 2 p s, Si(CH₃)₂); d_C(60 MHz, CDCl₃) 138.8, 138.6,

138.1 (C s-arom.), 128.3–127.3 (CH arom.), 84.3 (C-3),

84.1 (C-2), 75.8 (OCH₂Ph), 75.0 (OCH₂Ph), 73.3

(OCH₂Ph), 73.1 (C-4), 71.5 (C-5), 54.6 (C-1), 38.8, 38.7,

(S(CH₂)₂), 25.9 ((CH₃)₃CSi), 18.1 ((CH₃)₃CSi), 24.33,

24.63 ((CH₃)₂Si); HRMS (Cl, NH₃) MH^þ, 611.2684.

C₃₄H₄₇O₄S₂Si requires 611.2685.

3.3.10. 4,5-(a-^L-Lyxofuranosyl)-H-imidazole (7).

A

mixture of furanoside 21 (297 mg, 0.63 mmol), 10%

Pd(OH)₂/C (350 mg) and PdO (50 mg) in EtOH (10 mL)

was vigorously stirred under H₂(ca. 2 atm) at room

temperature for 48 h. The suspension was centrifuged and

the catalyst was washed several times with EtOH. The

combined organic solutions were evaporated and the residue

was puriﬁed by ﬂash chromatography (CHCl₃/MeOH/H₂O)

5:4.5:0.5) to give the title compound 7 (102 mg, 81%) as a

colourless oil which was crystallised (MeOH) mp 197–

1988C (dec.). [Found: C 48.1, H 6.2, N 13.7 C₈H₁₂N₂O₄

requires C 48.00, H 6.04, N 13.99%]. [a]²_D⁰¼257 (c¼1.0;

D₂O); d_H(250 MHz, CD₃OD) 8.04 (1H, s, C(2⁰)H), 7.22

(1H, s, C(4⁰, 5⁰)H), 4.87 (1H, d, J¼6.9 Hz, C(1)H), 4.36–

4.24 (3H, m, C(2)H, C(3)H and C(4)H), 3.84 (1H, dd,

J¼11.6, 4.6 Hz, C(5)H_aH_b), 3.77 (1H, dd, J¼11.6, 5.8 Hz,

C(5)H_aH_b); d_C(60 MHz, CD₃OD) 137.7 (C-4⁰), 136.8

(C-2⁰), 118.0 (C-5⁰), 82.2 (C-2), 78.0 (C-4), 77.7 (C-3),

3.3.13. 2,3,5-Tri-O-benzyl-4-O-tert-butyldimethylsilyl-^L-

arabinose (26). To a stirred solution of thioacetal 25 (4 g,

6.5 mmol) in a mixture of acetone and water (100 mL, 4:1)

were added Na₂CO₃(4.8 g, 45 mmol) and MeI (10 mL) and

the mixture was stirred at reﬂux under argon atmosphere for

16 h. Additional portions (2£2.5 mL) of MeI were added

during heating. After evaporation of the acetone, residue

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6513

was diluted with H₂O and extracted with cyclohexane. The

organic layer was dried (MgSO₄), ﬁltered and evaporated.

The residue was puriﬁed by ﬂash chromatography (AcOEt/

hexane 1:10) to give the title compound 26 (1.7 g, 48.6%) as

a pale yellow thick oil; d_H(250 MHz, CDCl₃) 9.78 (1H, d,

J¼1.1 Hz, C(1)H), 7.39–7.28 (15H, m, 3Ph), 4.79 and 4.63

(2H, AB, J¼11.8 Hz, OCH₂Ph), 4.66 and 4.58 (2H, AB,

J¼11.9, OCH₂Ph), 4.54 (2H, s, OCH₂Ph), 4.23 (1H, ddd,

J¼5.1, 4.7, 4.6 Hz C(4)H), 4.13 (2H, dd, J¼4.4, 1.1 Hz,

C(2)H), 4.07 (1H, dd, J¼4.4, 4.6 Hz, C(3)H), 3.80 (2H, dd,

J¼9.9, 4.7 Hz, C(5)H_aH_b),), 3.66 (2H, dd, J¼9.9, 5.1 Hz,

C(5)H_aH_b), 0.95 (9H, s, SiC(CH₃)₃), 0.13 and 0.12 (6H,

2 p s Si(CH₃)₂); d_C(60 MHz, CDCl₃) 201.7 (C-1), 138.1,

137.8, 137.4 (C s-arom.), 128.4–127.5 (CH arom.), 83.3

(C-2), 80.3 (C-3), 73.5 (OCH₂Ph), 73.2 (OCH₂Ph), 73.1

(OCH₂Ph), 72.0 (C-4), 71.3 (C-5), 25.8 ((CH₃)₃CSi), 18.1

((CH₃)₃CSi), 24.4 ((CH₃)₂Si); HRMS (Cl, NH₃) MH^þ,

535.2881. C₃₂H₄₃O₅Si requires 535.2879.

(9H, s, SiC(CH₃)₃), 0.81 (9H, s, SiC(CH₃)₃), 0.36 (3H, s,

Si(CH₃)₂), 20.06 (3H, s, Si(CH₃)₂), 20.24 (6H, s,

Si(CH₃)₂)); d_C(60 MHz, CDCl₃) 155.7 (C-2⁰), 138.9,

138.7, 138.2 (C s-arom.), 133.1 (C-4⁰), 132.3 (C-5⁰),

128.4–127.4 (CH arom.), 85.7 (C-3), 83.7 (C-2), 77.2

(C-4), 75.9 (OCH₂Ph), 75.6 (OCH₂Ph), 73.4 (OCH₂Ph),

70.8 (C-5), 62.9 (C-1), 36.9 (CH₃)₂N, 27.1 ((CH₃)₃CSi),

25.7 ((CH₃)₃CSi), 18.5 ((CH₃)₃CSi), 17.8 ((CH₃)₃CSi),

23.7, 23.9, 25.2, ((CH₃)₂Si); HRMS (Cl, NH₃) MH^þ,

found 824.4179. C₄₃H₆₆N₃O₇Si₂S requires 824.4160.

3.3.15. 1,2,3,5-Tetra-O-benzyl-1-[1H-imidazol-4(5)-yl]-

L-manno-pentitol (29b). To a stirred solution of compound

27b (0.68 g, 0.826 mmol) in anhydrous DMF (7.5 mL) was

added portionwise 50% NaH in oil (80 mg, ca. 3.3 mmol) at

108C. When the evolution of H₂ceased, BnBr (0.24 mL,

1.98 mmol) was added at 08C. Stirring was continued at

room temperature overnight. The mixture was neutralised

with a saturated aq. NaHCO₃solution (5 mL) and extracted

with AcOEt. The organic layer was dried (MgSO₄), ﬁltered

and evaporated. The crude product 28b was dissolved in the

mixture of THF (24 mL)/aq. HCl solution (1.5 M, 12 mL)

and reﬂuxed for 2 h, then stirred at room temperature

overnight. The reaction mixture was neutralised with

saturated aq. K₂CO₃solution, extracted with CHCl₃, dried

(MgSO₄) and evaporated. The residue was puriﬁed by ﬂash

chromatography (CHCl₃/EtOH 10:1) to give the title

compound 29b (306 mg, 64% from 27b) as a pale yellow

oil. [a]²_D⁰¼þ6.4 (c¼0.55; CHCl₃).); d_H(400 MHz, CDCl₃)

7.57 (1H, s, C(2⁰)H), 7.34–7.13 (20H, m, 4Ph), 7.11 (1H, s,

C(4⁰,5⁰)H), 4.74 (1H, d, J¼5.7 Hz, C(1)H), 4.44 (2H, s,

OCH₂Ph), 4.48 (2H, s, OCH₂Ph), 4.57 and 4.41 (2H, AB,

J¼10.7, OCH₂Ph), 4.46 and 4.25 (2H, AB, J¼11.7,

OCH₂Ph), 4.22 (1H, dd, J¼5.7, 4.7 Hz, C(2)H), 3.94 (1H,

ddd, J¼7.5, 5.5, 3.7 Hz, C(4)H), 3.71 (1H, dd, J¼7.5,

4.7 Hz, C(3)H), 3.66 (1H, dd, J¼9.6, 3.7 Hz, C(5)H_aH_b),

3.57 (1H, dd, J¼9.6, 5.5 Hz, C(5)H_aH_b); d_C(100.6 MHz;

CDCl₃), 138.2, 138.1, 138.0, 137.8 (4 p C s-arom.), 135.5

(C-2⁰), 133.7 (C-4⁰), 128.4–127.6 (CH arom.), 124.5 (C-5⁰),

82.0 (C-2), 79.2 (C-3), 75.1 (OCH₂Ph), 74.4 (OCH₂Ph),

73.5 (C-1), 73.4 (OCH₂Ph), 71.1 (C-5), 71.0 (C-4), 70.1

(OCH₂Ph); HRMS (Cl, NH₃) MH^þ, found 579.2861.

C₃₆H₃₉N₂O₅requires 579.2859.

3.3.14. Coupling reaction between the C(5)-lithio deriva-

tive of imidazole 10 and 26: synthesis of ^L-gluco (27a)

and ^L-manno (27b) epimers. To a stirred solution of

imidazole 10 (1.23 g, 4.26 mmol) in anhydrous THF

(15 mL) was added dropwise a solution of BuLi in hexane

(1.6 M, 2.9 mL, 4.65 mmol) under Ar at 2708C and the

stirring was continued at 2508C for 20 min. To the mixture

cooled again to 2708C was added dropwise a solution of 26

(1.32 g, 2.46 mmol) in anhydrous THF (15 mL) and the

stirring was continued at 2708C for 30 min and then at

room temperature for 2.5 h. The reaction mixture was

diluted with H₂O, THF was evaporated under reduced

pressure and the residue was extracted with CH₂Cl₂. The

organic layer was dried (MgSO₄), ﬁltered and evaporated.

The two epimers were separated by careful chromatography

(AcOEt/hexane 1:2) to give the ^L-gluco epimer 27a (0.63 g,

31%, R_f¼0.5) and the L-manno epimer 27b (1.35 g, 66.5%,

R_f¼0.7) both as a pale yellow oils. 27a [a]²_D⁰¼219.7 (c¼1.2

CHCl₃); d_H(250 MHz, CDCl₃) 7.47 (1H, s, C(4⁰)H), 7.41–

7.18 (15H, m, 3Ph), 5.25 (1H, d, J¼5.8 Hz, C(1)H), 4.71

(2H, s, OCH₂Ph), 4.53 (2H, s, OCH₂Ph), 4.52 and 4.24 (2H,

AB, J¼10.8 Hz, OCH₂Ph), 4.07 (1H, ddd, J¼7.0, 6.5,

5.8 Hz, C(4)H), 3.98 (1H, dd, J¼5.8, 1.5 Hz, C(2)H), 3.84

(1H, dd, J¼6.5, 1.5 Hz, C(3)H), 3.86 (1H, dd, J¼10.1,

5.8 Hz, C(5)H_aH_b), 3.85 (1H, dd, J¼6.5, 1.5 Hz, C(3)H),

3.71 (1H, dd, J¼10.1, 7.0 Hz, C(5)H_aH_b), 2.78 (6H, s,

N(CH₃)₂), 1.01 (9H, s, SiC(CH₃)₃), 0.90 (9H, s, SiC(CH₃)₃),

0.47 (3H, s, Si(CH₃)₂), 0.46 (3H, s, Si(CH₃)₂), 0.16 (3H, s,

Si(CH₃)₂), 0.15 (3H, s, Si(CH₃)₂), d_C(60 MHz, CDCl₃)

155.7 (C-2⁰), 138.3, 137.6, 135.0, (C s-arom.), 132.2 (C-5⁰),

128.3–127.4 (CH arom.), 81.6 (C-3), 80.1 (C-2), 77.2 (C-4),

74.9 (OCH₂Ph), 74.1 (OCH₂Ph), 73.1 (OCH₂Ph), 72.0 (C-

5), 64.9 (C-1), 37.6 (CH₃)₂N, 27.4 ((CH₃)₃CSi), 25.9

((CH₃)₃CSi), 18.32 ((CH₃)₃CSi), 18.21 ((CH₃)₃CSi),

23.22, 23.43, 24.49, 24.76, ((CH₃)₂Si); HRMS (Cl,

NH₃) MH^þ, found 824.4179. C₄₃H₆₆N₃O₇Si₂S requires

824.4160. 27b [a]²_D⁰¼þ20.3 (c¼0.8 CHCl₃); d_H(250 MHz,

CDCl₃) 7.65 (1H, s, C(4⁰)H), 7.39–7.16 (15H, m, 3Ph), 5.08

(1H, dd, J¼10.3, 4.5 Hz, C(1)H), 4.56 and 4.48 (2H, AB,

J¼11.8 Hz, OCH₂Ph), 4.19 (1H, dd, J¼7.5, 4.5 Hz, C(2)H),

3.93 (1H, dd, J¼12.6, 4.8 Hz, C(5)H_aH_b), 3.91 (1H, ddd,

J¼8.2, 4.8, 0.8 Hz, C(4)H), 3.85 (1H, dd, J¼7.5, 0.8 Hz,

C(3)H), 3.48 (1H, dd, J¼12.6, 8.2 Hz, C(5)H_aH_b), 2.70

(6H, s, N(CH₃)₂), 2.57 (1H, d, J¼10.3 Hz, C(1)OH), 1.06

3.3.16. 1,2,3,5-Tetra-O-benzyl-1-[1H-imidazol-4(5)-yl]-

L-gluco-pentitol (29a). The same procedure as for the

preparation of 29b was used, starting from 27a (0.68 g,

0.826 mmol) in anhydrous DMF (7.5 mL), 50% NaH in oil

(80 mg, ca. 3.3 mmol) and BnBr (0.24 mL, 1.98 mmol).

Acid hydrolysis of the crude 28a and workup followed by

chromatography gave the title compound 29a (300 mg, 63%

from 27a) as a pale yellow oil. [a]²_D⁰¼226.0 (c¼0.45;

CHCl₃); d_H(400 MHz, CDCl₃) 7.43 (1H, s, C(2⁰)H), 7.39–

7.08 (20H, m, 4Ph), 6.90 (1H, s, C(4⁰,5⁰)H), 4.84 (1H, d,

J¼5.7 Hz, C(1)H), 4.56 and 4.50 (2H, AB, J¼10.9 Hz

OCH₂Ph), 4.71 and 4.48 (2H, AB, J¼10.3, OCH₂Ph), 4.46

(2H, s, OCH₂Ph), 4.53 and 4.29 (2H, AB, J¼11.8,

OCH₂Ph), 4.08–3.98 (2H, m, C(2)H and C(4)H), 3.75

(1H, dd, J¼6.3, 4.2 Hz, C(3)H), 3.63 (1H, dd, J¼9.4,

3.8 Hz, C(5)H_aH_b), 3.61 (1H, dd, J¼9.4, 6.4 Hz, C(5)H_aH_b);

d_C(100.6 MHz; CDCl₃) 138.1, 138.0, 137.9, 137.7 (4 p C

s-arom.), 132.4 (C-2⁰), 128.8–126.7 (CH arom.), 121.5

(C-5⁰), 81.4 (C-2), 78.2 (C-3), 74.8 (OCH₂Ph), 74.5

6514

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

(OCH₂Ph), 73.6 (C-1), 73.2 (OCH₂Ph), 71.1 (C-2), 73.6 (C-

5), 70.8 (OCH₂Ph), 70.7 (C-4); HRMS (Cl, NH₃) MH^þ,

found 579.2864. C₃₆H₃₉N₂O₅requires 579.2859.

(400 MHz; CD₃OD) 7.76 (1H, s, C(3)H), 7.01 (1H, s,

C(1)H), 4.70 (1H, overlaps with HDO signal, C(8)H), 4.50–

4.40 (1H, m, C(5)H), 4.20 (1H, dd, J¼5.5, 2.5 Hz, C(6)H),

4.10 (1H, dd, J¼9.6, 5.5 Hz, C(7)H), 4.00 (1H, dd, J¼12.2,

3.7 Hz, C(9)H_aH_b), 3.79 (1H, dd, J¼12.2, 6.8 Hz,

C(9)H_aH_b); d_C(100.6 MHz; D₂O): 131.9 (C-3), 129.0

(C-8a), 123.7 (C-1), 72.7 (C-7), 69.2 (C-6), 67.6 (C-9),

61.1 (C-8), 58.9 (C-5); HRMS (Cl, NH₃) MH^þ, found

201.0878. C₈H₁₃N₂O₄requires 201.0875.

3.3.17. 5,6,7,8-Tetra-O-benzyl-imidazolo[1,5]-^L-ido-

piperidinose (30a). The same procedure as for the

preparation of 18 was used, starting from 29a (200 mg,

0.346 mmol), in anhydrous pyridine (4.5 mL), MsCl

(0.11 mL, 1.385 mmol) and Ac₂O (0.22 mL) to give after

workup and chromatography (CH₂Cl₂/acetone 2.5:1) the

title compound 30a (39 mg, 20%) as an yellow oil.

[a]²_D⁰¼þ36.0 (c¼0.95; CHCl₃); d_H(250 MHz, CDCl₃)

7.69 (1H, s, C(3)H), 7.39–7.15 (20H, m, 4Ph), 7.10 (1H,

s, C(1)H), 4.80 and 4.70 (2H, AB, J¼11.8 Hz, OCH₂Ph),

4.59 and 4.53 (2H, AB, J¼11.9 Hz, OCH₂Ph), 4.69 (1H, d,

J¼3.5 Hz, C(8)H), 4.67 (s, 2H, OCH₂Ph), 4.52–4.45 (1H,

bd, from COSY obscured by OCH₂Ph, C(5)H), 4.47 (2H, s,

OCH₂Ph), 4.12 (1H, dd, J¼7.5, 3.5 Hz, C(7)H), 3.92 (1H,

dd, J¼10.1, 3.4 Hz, C(9) H_aH_b), 3.86 (1H, dd, J¼7.5,

5.0 Hz, C(6)H), 3.84 (1H, dd, J¼10.1, 4.2 Hz, C(9)H_aH_b);

d_C(60 MHz, CDCl₃) 137.8 (C-8a), 137.5–137.4 (C

s-arom.), 136.3 (C-3), 128.2–127.6 (CH arom.), 125.5

(C-1), 78.8 (C-7), 76.8 (C-6), 73.5 (OCH₂Ph), 73.3

(OCH₂Ph), 73.2 (OCH₂Ph), 71.7 (C-9), 70.9 (OCH₂Ph),

69.5 (C-8), 55.0 (C-5); HRMS (Cl, NH₃) MH^þ, found

561.2754. C₃₆H₃₇N₂O₄requires 561.2753.

3.3.20. Imidazolo[1,5]-^D-gulo-piperidinose (4). The same

procedure as for the preparation of 3 was used staring from

30b (170 mg, 0.43 mmol) to give after workup 4 (31 mg,

51%) as a pale yellow powder. [a]²_D⁰¼246.9 (c¼1.15;

CH₃OH); d_H(400 MHz; CD₃OD) 8.20 (1H, s, C(3)H), 7.15

(1H, s, C(1)H), 4.98 (1H, dd, J¼4.0, 0.9 Hz, C(8)H), 4.45–

4.39 (1H, m, C(5)H), 4.37 (1H, dd, J¼7.1, 6.3 Hz, C(6)H),

4.17 (1H, dd, J¼6.3, 4.0 Hz, C(7)H), 4.03 (1H, dd, J¼12.1,

4.1 Hz, C(9)H_aH_b), 3.95 (1H, dd, J¼12.1, 6.4 Hz,

C(9)H_aH_b); d_C(100.6 MHz; D₂O): 133.5 (C-3), 128.5

(C-8a), 120.6 (C-1), 66.5 (C-7), 65.8 (C-6), 60.1 (C-9),

59.2 (C-8), 54.3 (C-5); HRMS (Cl, NH₃) MH^þ, found

201.0878. C₈H₁₃N₂O₄requires 201.0875.

3.3.21. Coupling reaction between the C(5)-lithio deriva-

tive of imidazole 10 and 3-O-benzyl-1,2-O-isopropyl-

idene-1,5-^D-xylo-dialdofuranose 31: synthesis of L-gulo

(32a) and ^L-ido (32b) epimers. To a stirred solution of

imidazole 10 (8.8 g, 30.4 mmol) in anhydrous THF (65 mL)

was added dropwise a solution of n-BuLi in hexane (1.6 M,

19 mL, 30.4 mmol) under argon at 2708C. After 15 min a

solution of 31 (4.7 g, 16.9 mmol) in anhydrous THF

(70 mL) was added dropwise at 2608C. After another

15 min the acetone-dry ice bath was removed and the

mixture was stirred for 2.5 h at room temperature. The

reaction was quenched with cold water, evaporated under

reduced pressure and the residue was diluted with water,

extracted with CH₂Cl₂, dried (MgSO₄), ﬁltered and

evaporated. The two epimers were separated by careful

chromatography (CH₂Cl₂/acetone 12:1) to give the L-gulo

epimer 32a (4.5 g, 7.9 mmol, 47%, R_F¼0.48) and the L-ido

epimer 32b (3.0 g, 5.3 mmol, 31%, R_f¼0.3) both as a yellow

foams. 32a [a]_D²⁰¼234 (c¼1.4; CHCl₃); n_max(ﬁlm): 3384,

2928, 2856, 1460, 1380, 1252, 1160, 1076, 1028, 844, 832,

780, 728, 700 cm²¹; d_H(250 MHz, CDCl₃) 7.37–7.27 (5H,

m, Ph), 7.26 (1H, s, C(4⁰)H), 5.89 (1H, d, J¼3.6 Hz, C(5)H),

5.25 (1H, dd, J¼8.5, 4.8 Hz, C(1)H), 4.64 (1H, d, J¼3.6 Hz,

C(4)H), 4.74 and 4.62 (2H, AB, J¼11.2 Hz, OCH₂Ph), 4.52

(1H, dd, J¼8.5, 3.0 Hz, C(2)H), 4.22 (1H, d, J¼3.0 Hz,

C(3)H), 3.15 (1H, d, J¼4.8 Hz, OH), 2.75 (6H, s, N(CH₃)₂),

1.51 and 1.33 (6H, 2s, C(CH₃)₂), 1.01 (9H, s, SiC(CH₃)₃),

0.38 (6H, s, Si(CH₃)₂); d_C(60 MHz, CDCl₃) 153.3 (C-2⁰),

136.6 (C s-arom.), 129.5 (C-4⁰), 128.5–126.9 (CH arom.,

C-5⁰), 112.6 (C(CH₃)₂), 105.1 (C-5), 82.2 (C-3), 81.4 (C-4),

79.5 (C-2), 72.4 (OCH₂Ph), 63.7 (C-1), 38.1 (N(CH₃)₂),

27.0 (Si(C(CH₃)₃), 26.4 and 25.7 (C(CH₃)₂), 14.5

(C(CH₃)₃), 23.7 (Si(CH₃)₂); FAB-MS: 568 (MH^þ);

HRMS (Cl, NH₃) MH^þ, found 568.2512. C₂₆H₄₂N₃O₇SSi

requires 568.2513. 32b [a]²_D⁰¼235 (c¼1.1; CHCl₃); n_max

(ﬁlm): 3472, 2936, 2856, 1460, 1376, 1252, 1160, 1076,

1020, 844, 832, 784, 728, 696 cm²¹; d_H(250 MHz, CDCl₃)

7.37–7.16 (5H, m, Ph), 7.21 (1H, s, C(4⁰)H), 6.04 (1H, d,

J¼3.8 Hz, C(5)H), 5.26 (1H, dd, J¼5.7, 2.6 Hz, C(1)H),

3.3.18. 5,6,7,8-Tetra-O-benzyl-imidazolo[1,5]-^D-gulo-

piperidinose (30b). The same procedure as for the

preparation of 30a was used, starting from 29b (200 mg,

0.346 mmol), in anhydrous pyridine (4.5 mL), MsCl

(0.11 mL, 1.385 mmol) and Ac₂O (0.22 mL). Workup

followed by chromatography (CH₂Cl₂/acetone 2.5:1) gave

the title compound 30b (99 mg, 51%) as a yellow oil.

[a]²_D⁰¼þ4.3 (c¼0.7; CHCl₃); d_H(250 MHz, CDCl₃) 7.73

(1H, s, C(3)H), 7.41–7.11 (20H, m, 4Ph), 7.01 (1H, s,

C(1)H), 4.79 (1H, d, J¼3.3 Hz, C(8)H), 4.71 and 4.58 (2H,

AB, J¼12.0 Hz, OCH₂Ph), 4.67 and 4.54 (2H, AB,

J¼12.4 Hz, OCH₂Ph), 4.64–4.56 (1H, bd, from COSY

obscured by OCH₂Ph, C(5)H), 4.62–4.50 (2H, AB,

J¼11.7 Hz, OCH₂Ph), 4.54–4.48 (2H, AB, J¼11.8 Hz,

OCH₂Ph), 4.23 (1H, dd, J¼6.9, 4.8 Hz, C(6)H), 3.98 (1H,

dd, J¼6.9, 3.3 Hz, C(7)H), 3.81 (2H, d, J¼5.9 Hz,

C(9)H_aH_b); d_C(60 MHz, CDCl₃) 138.0 (C-8a), 137.9–

137.5 (C s-arom.), 136.3 (C-3), 129.8–127.7 (CH arom.),

126.9 (C-1), 77.2 (C-7), 75.1 (OCH₂Ph), 74.7 (C-6), 73.5

(OCH₂Ph), 73.4 (OCH₂Ph), 72.6 (C-9), 70.8 (OCH₂Ph),

68.6 (C-8), 54.9 (C-5); HRMS (Cl, NH₃) MH^þ, found

561.2755. C₃₆H₃₇N₂O₄requires 561.2753.

3.3.19. Imidazolo[1,5]-^D-ido-piperidinose (3). A suspen-

sion of piperidinose 30a (65 mg, 0.115 mmol) and 10%

Pd(OH)₂/C (Pearlman’s catalyst) (150 mg) in EtOH/AcOH

(4 mL, 1:1) was vigorously stirred under H₂(ca. 2 atm) at

room temperature for 24 h. The suspension was centrifuged

and the catalyst was washed several times with MeOH. The

solution was evaporated under reduced pressure and the

residue was dissolved in MeOH and passed over an

Amberlyst IRA 400 (OH²) column (elution with MeOH).

The combined fractions were evaporated and the residue

was puriﬁed by ﬂash chromatography (CHCl₃/MeOH/

NH₄OH 5:4:1) to yield the title compound 3 (11 mg, 48%)

as a pale yellow powder. [a]²_D⁰¼þ8.0 (c¼0.25; CH₃OH); d_H

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6515

4.57 (1H, d, J¼3.8 Hz, C(4)H),4.57 (1H, dd, J¼5.7, 3.7 Hz,

C(2)H), 4.54 and 4.38 (2H, AB, J¼11.8 Hz, OCH₂Ph), 4.03

(1H, d, J¼3.7 Hz, C(3)H), 3.20 (1H, d, J¼2.6 Hz, OH), 2.77

(6H, s, N(CH₃)₂), 1.49 and 1.33 (6H, 2s, C(CH₃)₂), 1.00

(9H, s, SiC(CH₃)₃), 0.40 and 0.39 (6H, 2s, Si(CH₃)₂); d_C

(60 MHz, CDCl₃) 156.1 (C-2⁰), 137.0 (C s-arom.), 130.9

(C-4⁰), 128.5–127.6 (CH arom., C-5⁰), 111.6 (C(CH₃)₂),

104.9 (C-5), 82.5 (C-3), 82.3 (C-4), 80.1 (C-2), 71.8

(OCH₂Ph), 62.7 (C-1), 37.3 (N(CH₃)₂), 27.2 (Si(C(CH₃)₃),

26.7 and 26.2 (C(CH₃)₂), 18.3 (C(CH₃)₃), 23.6 and 23.7

(Si(CH₃)₂); HRMS (Cl, NH₃) MH^þ, found 568.2512.

C₂₆H₄₂N₃O₇SSi requires 568.2513.

129.0–128.0 (CH arom.), 120.6 (C-5⁰), 79.5 (C-3), 75.3

(C-1), 74.9 (OCH₂Ph), 73.7 (C-4), 73.5 (C-2), 70.6

(OCH₂Ph), 63.6 (C-5); HRMS (Cl, NH₃) MH^þ, found

399.1919. C₂₂H₂₇N₂O₅requires 399.1920.

3.3.25. 1,3-Di-O-benzyl-1-[1H-imidazol-4(5)-yl]-^L-ido-

pentitol (35b). The same procedure as for the preparation

of 35a was used starting from 34b (0.34 g, 0.86 mmol) to

give after workup the title compound 35b (0.30 g,

0.75 mmol, 88%) as a yellow foam. [a]²_D⁰¼þ288 (c¼0.9;

MeOH); n_max(ﬁlm): 3240, 2872, 1496, 1456, 1224, 1088,

788, 700 cm²¹; d_H(60 MHz, acetone-d₆) 7.79 (1H, bs,

C(2⁰)H), 7.40–7.20 (10H, m, 2Ph), 7.15 (1H, bs, C(5⁰)H),

4.79 (1H, d, J¼6.5 Hz, C(1)H), 4.69 and 4.61 (2H, AB,

J¼11.8 Hz, OCH₂Ph), 4.50 and 4.41 (2H, AB, J¼11.8 Hz,

OCH₂Ph), 4.28 (1H, dd, J¼6.5, 3.8 Hz, C(2)H), 3.94 (1H,

dt, J¼5.5, 4.5 Hz, C(4)H), 3.66 (2H, bd, J¼5.5 Hz,

C(5)H_aH_b), 3.59 (1H, dd, J¼4.5, 3.8 Hz, C(3)H); d_C

(60 MHz, acetone-d₆) 140.2, 139.5 (C s-arom.), 136.6

(C-4⁰₀), 136.1 (C-2⁰), 128.9–128.0 (CH arom.), 119.5

(C-5 ), 80.2 (C-3), 76.1 (C-1), 74.6 (OCH₂Ph), 74.4 (C-2),

73.2 (C-4), 70.8 (OCH₂Ph), 63.7 (C-5); HRMS (Cl,

NH₃) MH^þ, found 399.1919. C₂₂H₂₇N₂O₅requires

399.1920.

3.3.22. (5R)-3,5-Di-O-benzyl-5-[1H-imidazol-4(5)-yl]-^D-

xylofuranose (34a). To a stirred solution of compound

32a (2.54 g, 4.47 mmol) in anhydrous DMF (40 mL) was

added portionwise 50% NaH in oil (0.44 g, ca 9.1 mmol) at

room temperature. After 30 min the mixture was cooled to

08C and BnBr (1.3 mL, 10.8 mmol) was added dropwise.

Stirring was continued at room temperature overnight. The

mixture was neutralised with saturated aq. NaHCO₃

solution (50 mL) and extracted with AcOEt. The organic

layer was dried (MgSO₄), ﬁltered and evaporated. The crude

product 33a was dissolved in THF (12.5 mL) and aq. HCI

solution (1.5 M, 20 mL) was added. The mixture was

reﬂuxed for 1.5 h, neutralised with saturated aq. K₂CO₃

solution, evaporated under reduced pressure and coevapo-

rated several times with dry ethanol to remove water.

Residue was extracted a few times with dry ethanol and

chromatographed after evaporation (CHCl₃/EtOH 5:1) to

give the title compound 34a (1.06 g, 2.67 mmol, 60% from

32a) as a yellow oil containing mixture of anomers (two

3.3.26. 1,3-Di-O-benzyl-1-(1-triphenylmethyl-1H-imida-

zol-4-yl)-5-O-triphenylmethyl-^L-gulo-pentitol (36a). The

solution of compound 35a (0.42 g, 1.05 mmol), TrCl

(0.88 g, 3.14 mmol) and DMAP (18 mg) in dry pyridine

(6 mL) was stirred under argon atmosphere at 80–908C for

48 h. The mixture was evaporated under reduced pressure,

coevaporated several times with toluene to remove pyridine

and puriﬁed by chromatography (AcOEt/hexane 2:1) to

yield the title compound 36a (0.45 g, 0.51 mmol, 48%) as a

white foam. [a]_D²⁰¼232 (c¼0.85; CHCl₃); n_max(ﬁlm):

3064, 3048, 3032, 2984, 2880, 1596, 1492, 1448, 1216,

1072, 788, 704 cm²¹; d_H(250 MHz, CDCl₃) 7.49 (1H, d,

J¼1.3 Hz, C(2₀⁰)H), 7.45–7.00 (40H, m, 8Ph), 6.86 (1H, d,

J¼1.3 Hz, C(5 )H), 4.50 (1H, d, J¼8 Hz, C(1)H), 4.44 and

4.22 (2H, AB, J¼12.0 Hz, OCH₂Ph), 4.42 (2H, s, OCH₂Ph),

4.20–4.12 (3H, m, C(2)H, C(3)H, C(4)H), 3.36 (1H, dd,

J¼8.0, 5.0 Hz, C(5)H_aH_b), 3.19 (1H, dd, J¼8.0, 6.0 Hz,

C(5)H_aH_b); d_C(60 MHz, CDCl₃) 139.1 (C-2⁰), 130.0–127.0

(m, CH arom., C-4⁰), 121.4 (C-5⁰), 77.1 (C-3), 75.5 (C-1),

75.3 (C-2), 74.8 (OCH₂Ph), 72.9 (C-4), 70.4 (OCH₂Ph),

64.5 (C-5); HRMS (Cl, NH₃) MH^þ, found 883.4110.

C₆₀H₅₅N₂O₅requires 883.4111.

1

pairs of imidazole signals on H NMR spectrum); HRMS

(Cl, NH₃) MH^þ, found 397.1764. C₂₂H₂₅N₂O₅requires

397.1763.

3.3.23. (5S)-3,5-Di-O-benzyl-5-[1H-imidazol-4(5)-yl]-^D-

xylofuranose (34b). The same procedure as for the

preparation of 34a was used starting from 32b (5.58 g,

9.815 mmol) to give after workup the title compound 34b

(2.53 g, 6.38 mmol, 65% from 32b) as a yellow oil

containing mixture of anomers (two pairs of imidazole

1

signals on H NMR spectrum); HRMS (Cl, NH₃) MH^þ,

found 397.1764. C₂₂H₂₅N₂O₅requires 397.1763.

3.3.24. 1,3-Di-O-benzyl-1-[1H-imidazol-4(5)-yl]-^L-gulo-

pentitol (35a). To a stirred solution of compound 34a

(0.33 g, 0.83 mmol) in anhydrous methanol (5 mL) was

added portionwise NaBH₄(0.16 g, 4.2 mmol) at 08C. The

mixture was stirred at 08C for 30 min and stirring was

continued at room temperature overnight. The reaction was

quenched with saturated aq. NH₄Cl solution, evaporated to

dryness and puriﬁed by chromatography (CHCl₃/EtOH 1:1)

to give the title compound 35a (0.29 g, 0.73 mmol, 87%) as

a yellow foam. [a]_D²⁰¼249 (c¼0.8; MeOH); n_max(ﬁlm):

3288, 2872, 1496, 1456, 1228, 1064, 756, 700 cm²¹; d_H

(60 MHz, acetone-d₆) 7.78 (1H, bs, C(2⁰)H), 7.40–7.20

(10H, m, 2Ph), 7.19 (1H, bs, C(5⁰)H), 4.77 and 4.62 (2H,

AB, J¼11.5 Hz, OCH₂Ph), 4.69 (1H, d, J¼7.3 Hz, C(1)H),

4.47 and 4.33 (2H, AB, J¼11.5 Hz, OCH₂Ph), 4.24 (1H, dd,

J¼7.3, 2.0 Hz, C(2)H), 3.95–3.85 (2H, m, C(3)H, C(4)H),

3.66 (2H, bd, J¼4.8 Hz, C(5)H_aH_b); d_C(60 MHz, acetone-

d₆) 140.1, 139.3 (C s-arom.), 136.7 (C-2⁰), 135.9 (C-4⁰),

3.3.27. 1,3-Di-O-benzyl-1-(1-triphenylmethyl-1H-imida-

zol-4-yl)-5-O-triphenylmethyl-^L-ido-pentitol (36b). The

same procedure as for the preparation of 36a was used

starting from 35b (0.39 g, 0.98 mmol) to give after workup

the title compound 36b (0.48 g, 0.54 mmol, 56%) as white

foam. [a]_D¼þ18 (c¼0.8; CHCl₃); n_max(ﬁlm): 3064, 3048,

3032, 2984, 2880, 1596, 1492, 1448, 1216, 1072, 788,

704₀cm²¹; d_H(250 MHz, CDCl₃) 7.40 (1H, d, J¼1.3 Hz,

C(2₀)H), 7.35–7.00 (40H, m, 8Ph), 6.73 (1H, d, J¼1.3 Hz,

C(5 )H), 4.58 (1H, d, J¼6.0 Hz, C(1)H), 4.55 and 4.31 (2H,

AB, J¼11.5 Hz, OCH₂Ph), 4.53 and 4.35 (2H, AB,

J¼11.0 Hz, OCH₂Ph), 4.22 (1H, dd, J¼6.0, 4.0 Hz,

C(2)H,), 4.08 (1H, ddd, J¼7.0, 6.0, 2.5 Hz, C(4)H), 3.84

(1H, dd, J¼4.0, 2.5 Hz, C(3)H), 3.34 (1H, dd, J¼9.0,

6.0 Hz, C(5)H_aH_b), 3.18 (1H, dd, J¼9.0, 7.0 Hz, C(5)H_aH_b);

6516

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

d_C(60 MHz, CDCl₃) 139.1 (C-2⁰), 130.0–127.0 (m, C

arom., C-4⁰), 121.4 (C-5⁰), 77.1 (C-3), 75.5 (C-1), 75.3

(C-2), 74.8 (OCH₂Ph), 72.9 (C-4), 70.4 (OCH₂Ph), 64.5

(C-5); HRMS (Cl, NH₃) MH^þ, found 883.4110.

C₆₀H₅₅N₂O₅requires 883.4111.

white foams. 37b [a]²_D⁰¼21 (c¼1.4; CH₂Cl₂); n_max(ﬁlm):

3064, 3048, 3032, 2984, 1600, 1492, 1448, 1216, 1072, 908,

788, 700 cm²¹; d_H(250 MHz, CDCl₃) 7.45 (1H, d,

J¼1.3 Hz, C(2⁰)H), 7.42–6.88 (45H, m, 9Ph), 6.86 (1H, d,

J¼1.3 Hz, C(5⁰)H), 4.81 (1H, d, J¼5.3 Hz, C(1)H), 4.60 and

4.53 (2H, AB, J¼11.3 Hz, OCH₂Ph), 4.53 and 4.41 (2H,

AB, J¼11.5 Hz, OCH₂Ph), 4.45 and 4.25 (2H, AB,

J¼11.0 Hz, OCH₂Ph), 4.14 (1H, dd, J¼6.3, 5.3 Hz,

C(2)H), 4.05 (1H, ddd, J¼8.0, 6.0, 1.8 Hz, C(4)H), 3.95

(1H, dd, J¼6.3, 1.8 Hz, C(3)H),3.31 (1H, dd, J¼9.0, 6.0 Hz,

C(5)H_aH_b), 3.04 (1H, dd, J¼9.0, 8.0 Hz, C(5)H_aH_b); d_C

(60 MHz, CDCl₃) 143.8, 142.3 (CPh₃), 139.1–138.0 (m,

C-2⁰, C-4⁰, C s-arom.), 129.6–126.8 (m, CH arom.), 120.7

(C-5⁰), 82.1 (C-2), 78.5 (C-3), 76.7 (C-1), 75.1 (OCH₂Ph),

74.2 (OCH₂Ph), 71.1 (OCH₂Ph), 70.1 (C-4), 64.4 (C-5);

HRMS (Cl, NH₃) MH^þ, found 973.4579. C₆₇H₆₁N₂O₅

requires 973.4580. 38b [a]²_D⁰¼þ13 (c¼0.9; CH₂Cl₂). IR

(ﬁlm): 3064, 3048, 3032, 2984, 2872, 1600, 1492, 1448,

1216, 1068, 908, 740, 700 cm²¹; d_H(250 MHz, CDCl₃)

7.50–7.00 (46H, m, 9Ph, C(2⁰)H), 6.51 (1H, d, J¼1.3 Hz,

C(5⁰)H), 4.65 and 4.43 (2H, AB, J¼11.3 Hz, OCH₂Ph), 4.62

and 4.43 (2H, AB, J¼11.0 Hz, OCH₂Ph), 4.49 and 4.20 (2H,

AB, J¼12.0 Hz, OCH₂Ph), 4.36 (1H, d, J¼6.8 Hz, C(1)H),

4.06 (1H, dd, J¼6.8, 3.5 Hz, C(2)H), 3.90 (1H, ddd, J¼5.8,

5.5, 3.5 Hz, C(4)H), 3.73 (1H, dd, J¼5.5, 3.5 Hz, C(3)H),

3.44 (1H, dd, J¼10.3, 3.5 Hz, C(5)H_aH_b), 3.30 (1H, dd,

J¼10.3, 5.8 Hz, C(5)H_aH_b); d_C(60 MHz, CDCl₃) 144.1,

142.2 (CPh₃), 138.8–138.0 (m, C-2⁰, C-4⁰, C s-arom.),

129.6–126.7 (m, CH arom.), 121.3 (C-5⁰), 79.7 (C-4), 78.4

(C-3), 74.9 (C-1), 74.5 (OCH₂Ph), 73.5 (C-2), 72.7

(OCH₂Ph), 70.0 (OCH₂Ph), 63.5 (C-5); HRMS (Cl, NH₃)

MH^þ, found 973.4581. C₆₇H₆₁N₂O₅requires 973.4580.

3.3.28. 1,2,3-Tri-O-benzyl-1-(1-triphenylmethyl-1H-imi-

dazol-4-yl)-5-O-triphenylmethyl-^L-gulo-pentitol (37a)

and 1,3,4-Tri-O-benzyl-1-(1-triphenylmethyl-1H-imida-

zol-4-yl)-5-O-triphenylmethyl-^L-gulo-pentitol (38a). To a

stirred solution of 36a (120 mg, 0.14 mmol) in anhydrous

THF (2 mL) was added portionwise 50% NaH in oil (10 mg,

ca. 0.2 mmol) at 08C. After 30 min a catalytic amount of

Bu₄NI was added and then BnBr (0.025 mL, 0.21 mmol)

was added dropwise. The reaction mixture was stirred

overnight at room temperature, quenched with MeOH and

evaporated to dryness. Residue was diluted with water and

extacted with CHCl₃. The organic layer was dried (MgSO₄),

ﬁltered and evaporated. The residue was puriﬁed by ﬂash

chromatography (AcOEt/hexane 3:2) to give title com-

pounds 37a (62 mg, 0.064 mmol, 47%, R_f¼0.55) and 38a

(36 mg, 0.037 mmol, 27%, R_f¼0.48) both as a white foams.

37a [a]²_D⁰¼29 (c¼1.1; CH₂Cl₂); n_max(ﬁlm): 3064, 3048,

3032, 2984, 2872, 1600, 1496, 1448, 1212, 1068, 788,

700₀cm²¹; d_H(250 MHz, CDCl₃) 7.40 (1H, d, J¼1.3 Hz,

C(2₀)H), 7.38–6.80 (45H, m, 9Ph), 6.77 (1H, d, J¼1.3 Hz,

C(5 )H), 4.77 (1H, d, J¼5.5 Hz, C(1)H), 4.52 and 4.30 (2H,

AB, J¼11.0 Hz, OCH₂Ph), 4.47 and 4.33 (2H, AB,

J¼11.5 Hz, OCH₂Ph), 4.46 (2H, s, OCH₂Ph), 4.22 (1H,

ddd, J¼7.5, 6.0, 2.0 Hz, C(4)H), 4.17 (1H, t, J¼2.0 Hz,

C(3)H), 4.02 (1H, dd, J¼5.5, 2.0 Hz, C(2)H), 3.33 (1H, dd,

J¼9.0, 6.0 Hz, C(5)H_aH_b), 3.12 (1H, dd, J¼9.0, 7.5 Hz,

C(5)H_aH_b); d_C(60 MHz, CDCl₃) 143.0, 141.3 (CPh₃),

137.7–137.3 (m, C-2⁰, C-4⁰, C s-arom.), 128.7–125.8 (m,

C-arom.), 120.6 (C-5⁰), 81.2 (C-2), 77.9 (C-3), 74.4 (C-1),

73.7 (OCH₂Ph), 73.0 (OCH₂Ph), 69.4 (OCH₂Ph), 69.1

(C-4), 62.5 (C-5); HRMS (Cl, NH₃) MH^þ, found 973.4580.

C₆₇H₆₁N₂O₅requires 973.4580. 38a [a]²_D⁰¼215 (c¼1.8;

CH₂Cl₂); n_max(ﬁlm): 3064, 3048, 3032, 2984, 2872, 1600,

1492, 1448, 1240, 1068, 756, 700 cm²₀¹; d_H(250 MHz,

CDCl₃) 7.58–6.90 (46H, m, 9Ph, C(2 )H), 6.78 (1H, d,

J¼1.3 Hz, C(5⁰)H), 4.69 and 4.36 (2H, AB, J¼11.3 Hz,

OCH₂Ph), 4.68 and 4.60 (2H, AB, J¼11.8 Hz, OCH₂Ph),

4.44 (1H, d, J¼3.3 Hz, C(1)H), 4.42 and 4.13 (2H, AB,

J¼12.5 Hz, OCH₂Ph), 4.16 (1H, dd, J¼6.3, 65.3 Hz,

C(3)H), 4.00 (1H, dd, J¼6.3, 3.3 Hz, C(2)H), 3.94 (1H,

dt, J¼5.3, 3.3 Hz, C(4)H), 3.45 (1H, dd, J¼10.5, 3.3 Hz,

C(5)H_aH_b), 3.29 (1H, dd, J¼10.5, 5.3 Hz, C(5)H_aH_b); d_C

(60 MHz, CDCl₃) 144.0, 142.3 (CPh₃), 139.8–138.3 (m,

C-2⁰, C-4⁰, C s-arom.), 129.7–126.7 (m, C-arom.), 120.8

(C-5⁰), 80.2 (C-4), 77.9 (C-3), 75.8 (C-1), 74.3 (OCH₂Ph),

73.0 (C-2), 72.9 (OCH₂Ph), 70.0 (OCH₂Ph), 63.5 (C-5);

HRMS (Cl, NH₃) MH^þ, found 973.4581. C₆₇H₆₁N₂O₅

requires 973.4580.

3.3.30. 6,7,8-Tri-O-benzyl-imidazolo[1,5]-^D-manno-

piperidinose (40a). To a stirred solution of BnSO₂Cl

(53 mg, 0.27 mmol) in dry pyridine (1.25 mL) was added

dropwise under argon atmosphere a solution of 37a (86 mg,

0.088 mmol) in dry pyridine (1.25 mL) at 2308C. After

30 min the acetone-dry ice bath was removed and the

reaction was stirred overnight at room temperature. The

mixture was evaporated under reduced pressure, coevapo-

rated several times with toluene to remove pyridine and

puriﬁed by ﬂash chromatography (hexane/AcOEt 2:1) to

give the title compound 39a (R_f¼0.50) which was dried,

dissolved in dry pyridine (7.5 mL) and stirred at 60–808C

for 3 days, until 39a disappeared (TLC). The mixture was

evaporated under reduced pressure and the residue was

dissolved in THF (7.5 mL). To this solution aq. HCl (6 M,

2.5 mL) was added and the mixture was reﬂuxed for 1.5 h.

THF was evaporated under reduced pressure and the residue

was neutralised with saturated aq. solution of K₂CO₃and

extracted with CHCl₃. The organic layer was dried

(MgSO₄), ﬁltered, evaporated and the residue was puriﬁed

by ﬂash chromatography (CHCl₃/MeOH 9:1) to give 40a

(22 mg, 0.047 mmol, 53% from 37a) as a white foam.

[a]²_D⁰¼262 (c¼0.9; CHCl₃); n_max(ﬁlm): 3064, 3048, 3032,

2928, 2864, 1496, 1456, 1360, 1228, 1112, 936, 788, 696,

664 cm²¹; d_H(250 MHz, CDCl₃): 7.69 (1H, bs, C(3)H),

7.37–7.27 (15H, m, 3Ph), 6.96 (1H, bs, C(1)H), 4.97 and

4.73 (2H, AB, J¼11.3 Hz, OCH₂Ph), 4.70 (1H, d,

J¼3.0 Hz, C(8)H), 4.68 and 4.60 (2H, AB, J¼12.0,

OCH₂Ph), 4.63 and 4.32 (2H, AB, J¼12.3 Hz, OCH₂Ph),

4.27 (1H, dd, J¼8.5, 5.8 Hz, C(6)H), 4.19 (1H, ddd, J¼6.5,

3.3.29. 1,3,4-Tri-O-benzyl-1-(1-triphenylmethyl-1H-imi-

dazol-4-yl)-5-O-triphenylmethyl-^L-ido-pentitol (37b)

and 1,3,4-tri-O-benzyl-1-(1-triphenylmethyl-1H-imida-

zol-4-yl)-5-O-triphenylmethyl-^L-ido-pentitol (38b). The

same procedure as for the preparation of 37a and 38a was

used starting from 36b (120 mg, 0.14 mmol) to give after

workup title compounds 37b (49 mg, 0.05 mmol, 37%,

R_f¼0.50) and 38b (31 mg, 0.032 mmol, 23%, R_f¼0.58) as a

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6517

5.8, 3.5 Hz, C(5)H), 3.93 (1H, dd, J¼11.5, 3.5 Hz,), 3.80

(1H, dd, J¼11.5, 6.5 Hz, C(5)H_aH_b), 3.80 (1H, dd, J¼8.5,

3.0 Hz, C(7)H); d_H(60 MHz, CDCl₃) 137.8, 137.6 and

137.4 (C s-arom.), 136.9 (C-3), 135.8 (C-8a), 125.6 (C-1),

80.3 (C-7), 74.8 (C-6), 74.2 (OCH₂Ph), 71.8 (OCH₂Ph),

69.5 (OCH₂Ph), 65.7 (C-8), 63.7 (C-9), 61.5 (C-5); HRMS

(Cl, NH₃) MH^þ, found 471.2281. C₂₉H₃₁N₂O₄requires

471.2283.

C₂₉H₃₁N₂O₄requires 471.2283. 41 [a]²_D⁰¼237 (c¼0.4;

CHCl₃); n_max(ﬁlm): 3064, 3048, 3032, 2928, 2864, 1496,

1456, 1356, 1312, 1208, 1088, 912, 7₀88, 740, 696 cm²¹; d_H

(250 MHz, CDCl₃) 7.61 (1H, s, C(2 )H), 7.45–7.08 (15H,

m, 3Ph), 7.08 (1H, s, C(5⁰)H), 4.81 and 4.72 (2H, AB,

J¼12.5 Hz, OCH₂Ph), 4.73 and 4.25 (2H, AB, J¼11.5 Hz,

OCH₂Ph), 4.69 and 4.64 (2H, AB, J¼12.0 Hz, OCH₂Ph),

4.30 (1H, d, J¼9.3 Hz, C(1)H), 4.14 (1H, dd, J¼12.5,

2.3 Hz, C(5)H_aH_b), 4.09 (1H, t, J¼9.3 Hz, C(2)H), 3.83

(1H, ddd, J¼3.3, 2.3, 1.0 Hz, C(4)H), 3.66 (1H, dd, J¼9.3,

3.3 Hz, C(3)H), 3.43 (1H, dd, J¼12.5, 1.0 Hz, C(5)H_aH_b);

d_C(60 MHz, CDCl₃) 138.3, 138.2 (C s-arom.), 135.1 (C-3⁰),

129.0–127.6 (m, CH arom.), 127.6 (C-1⁰), 118.5 (C-5⁰),

82.4 (C-3), 78.5 (C-2), 75.3 (C-1), 75.1 (OCH₂Ph), 73.0

(C-4), 72.0 (OCH₂Ph), 71.5 (OCH₂Ph), 67.3 (C-5); HRMS

(Cl, NH₃) MH^þ, found 471.2281. C₂₉H₃₁N₂O₄requires

471.2283. 42 [a]_D²⁰¼26 (c¼0.7; CHCl₃); n_max(ﬁlm): 3064,

3048, 3032, 2928, 2864, 1496, 1456, 1352, 1304, 1208,

1092, 912, 752, 700 cm²¹; d_H(250 MHz, acetone-d₆): 7.57

(1H₀, s, C(2⁰)H), 7.44–7.10 (15H, m, 3Ph), 6.96 (1H, s,

C(5 )H), 4.89 (1H, d, J¼1.5 Hz, C(1)H), 4.81 and 4.73 (2H,

AB, J¼11.8 Hz, OCH₂Ph), 4.61 (2H, s, OCH₂Ph), 4.37 and

4.29 (2H, AB, J¼11.5 Hz, OCH₂Ph), 4.14 (1H, dd, J¼4.0,

2.5 Hz, C(3)H), 3.96 (1H, dt, J¼4.8, 2.5 Hz, C(4)H), 3.92

(1H, dd, J¼4.0, 1.5 Hz, C(2)H), 3.84 (1H, dd, J¼10.3,

4.8 Hz, C(5)H_aH_b), 3.78 (1H, dd, J¼10.3, 2.5 Hz,

C(5)H_aH_b); d_C(60 MHz, CDCl₃) 138.3, 138.2, 137.6 (C

s-arom.), 134.6 (C-3⁰), 129.8 (C-1⁰), 128.5–127.6 (m, CH

arom.), 119.5 (C-5⁰), 77.9 (C-2), 73.3 (C-4), 73.0 (OCH₂Ph),

72.6 (OCH₂Ph), 72.4 (C-3), 71.3 (OCH₂Ph), 70.4 (C-1),

64.6 (C-5); HRMS (Cl, NH₃) MH^þ, found 471.2281.

C₂₉H₃₁N₂O₄requires 471.2283.

3.3.31. Imidazolo[1,5]-^D-manno-piperidinose (5). To a

solution of piperidinose 40a (22 mg, 0.047 mmol) in 95%

ethanol (2 mL) was added 10% Pd/C catalyst (50 mg) and

the mixture was stirred at room temperature overnight under

H₂atmosphere. The presence of substrate was still

monitored (TLC). Addition of a new portion of the catalyst

(50 mg) and additional time (24 h) was necessary for

substrate disappearance. Then mixture was ﬁltered through

celite pad, evaporated and puriﬁed by ﬂash chromatography

(EtOH/NH₃aq. 6:1) to give the title compound 5 (7 mg,

0.035 mmol, 75%) as a brown foam. [a]²_D⁰¼225 (c¼0.35;

MeOH); d_H(250 MHz, D₂O) 8.22 (1H, bs, C(3)H), 7.27

(1H, bs, C(1)H), 5.14 (1H, d, J¼3.5 Hz, C(8)H), 4.35 (1H,

dd, J¼12.3, 2.5 Hz, C(9)H_aH_b), 4.30 (1H, dd, J¼9.5,

8.0 Hz, C(6)H), 4.18 (1H, ddd, J¼8.0, 4.3, 2.5 Hz,

C(5)H), 4.12 (1H, dd, J¼12.3, 4.3 Hz, C(9)H_aH_b), 4.02

(1H, dd, J¼9.5, 3.5 Hz, C(7)H); d_C(60 MHz, D₂O) 133.8

(C-8a), 128.2 (C-3), 122.4 (C-1), 69.0 (C-7), 63.2 (C-6),

59.9 (C-8), 59.4 (C-5), 58.3 (C-9); HRMS (Cl, NH₃) MH^þ,

found 201.0878. C₈H₁₃N₂O₄requires 201.0875.

3.3.32. 6,7,8-Tri-O-benzyl-imidazolo[1,5]-^D-gluco-piper-

idinose (40b), 4,5-(2,3,4-tri-O-benzyl-a-^D-arabinopyra-

nosyl)-1H-imidazole (41) and 4,5-(2,3,4-tri-O-benzyl-b-

D-arabinopyranosyl)1H-imidazole (42). The same

procedure as for the preparation of 40a was used starting

from 37b (230 mg, 0.24 mmol) to give ﬁrst after ﬂash

chromatography (hexane/AcOEt 2:1) 39b. According to

farther procedure the ditrityl derivative 39b was stirred in

pyridine at 60–808C until substrate disappeared (TLC) and

subsequently after evaporation of pyridine the residue was

reﬂuxed in the mixture THF/aq. HCl (6 M). After workup as

for 40a, as a result of three subsequent chromatographies

(CHCl₃/MeOH 9:1; acetone/CH₂Cl₂3:1; AcOEt/CHCl₃/

EtOH 6:3:1) three products were isolated: 41 (36 mg,

0.076 mmol, 32% from 37b, R_f¼0.29), 42 (21 mg,

0.044 mmol, 19% from 37b R_f¼0.20) and 40b (7 mg,

0.015 mmol, 6% from 37b, R_f¼0.15) as a white foams. (R_f

values in AcOEt/CHCl₃/EtOH 6:3:1). 40b [a]²_D⁰¼þ9

(c¼0.25; CHCl₃); n_max(ﬁlm): 3064, 3048, 3032, 2928,

2864, 1496, 1456, 1364, 1264, 1152, 1200, 1108, 944, 784,

696, 648 cm²¹; d_H(250 MHz, CDCl₃) 7.66 (1H, bs, C(3)H),

7.37–7.26 (15H, m, 3Ph), 7.05 (1H, bs, C(1)H), 4.84 and

4.62 (2H, AB, J¼11.5 Hz, OCH₂Ph), 4.78 and 4.71 (2H,

AB, J¼11.5 Hz, OCH₂Ph), 4.70 (1H, d, J¼5.0 Hz, C(8)H),

4.69 and 4.60 (2H, AB, J¼11.8 Hz, OCH₂Ph), 4.15 (1H,

ddd, J¼7.8, 5.3, 3.0 Hz, C(5)H), 4.13 (1H, dd, J¼12.8,

3.0 Hz, C(9)H_aH_b), 4.10 (1H, dd, J¼6.8, 5.0 Hz, C(7)H),

3.98 (1H, dd, J¼12.8, 5.3 Hz, C(9)H_aH_b), 3.81 (1H, dd,

J¼7.8, 6.8 Hz, C(6)H); d_C(60 MHz, CDCl₃) 136.0–135.6

(m, C s-arom.), 132.6 (C-3), 129.8 (C-8a), 127.5–126.0 (m,

CH arom., C-1), 82.7 (C-7), 77.3 (C-6), 73.8 (OCH₂Ph),

73.5 (OCH₂Ph), 72.0 (C-8), 71.4 (OCH₂Ph), 60.5 (C-9),

60.5 (C-5); HRMS (Cl, NH₃) MH^þ, found 471.2280.

3.3.33. 4,5-(a-^D-Arabinopyranosyl)1H-imidazole (8). To

a solution of compound 41 (66 mg, 0.098 mmol) in 95%

EtOH (4 mL) was added 10% Pd/C catalyst 105 mg) and the

mixture was stirred overnight in H₂atmosphere at room

temperature. The new portion of catalyst (120 mg) was

added and the stirring was continued for the next 24 h until

substrate disappeared (TLC). The mixture was ﬁltered

through celite, evaporated and puriﬁed by ﬂash chromato-

graphy (EtOH/NH₃aq. 6:1) to give the title compound 8

(17 mg, 0.085 mmol, 87%, R_f¼0.35) as a colourless ﬁlm.

[a]²_D⁰¼242 (c¼0.26; CH₃OH); d_H(250 MHz, CD₃OD) 7.88

(1H, br s, C(2⁰)H), 7.16 (1H, br s, C(5⁰)H), 4.19 (1H, d,

J¼9.8 Hz, C(1)H), 3.98 (1H, dd, J¼3.5, 1.8 Hz, C(4)H),

3.95 (1H, dd, J¼9.8, 9.6 Hz, C(2)H), 3.89 (1H, dd, J¼12.8,

1.8 Hz, C(5)H_aH_b), 3.72 (1H, dd, J¼12.8, 1.8 Hz,

C(5)H_aH_b), 3.68 (1H, dd, J¼9.6, 3.5 Hz, C(3)H); d_C

(60 MHz, CD₃OD) 135.5 (br, C-3⁰), 129.2 (C-1⁰), 118.3

(br, C-5⁰), 76.2 (C-2), 73.9 (C-4), 70.5 (C-6), 70.19 (C-3),

69.5 (C-5); HRMS (Cl, NH₃) MH^þ, found 201.0878.

C₈H₁₃N₂O₄requires 201.0875.

3.3.34. 4,5-(b-^D-Arabinopyranosyl)1H-imidazole (9).

The same procedure as for the preparation of 8 was used

starting from 42 (29 mg, 0.062 mmol) to give after workup

the title compound 9 (7 mg, 0.035 mmol, 57%, R_f¼0.15 in

EtOH/NH₃aq. 6:1) as a colourless ﬁlm. [a]²_D⁰¼þ5.4

(c¼0.21; CH₃OH); d_H(250 MHz, CD₃OD) 7.75 (1H, br s,

C(2⁰)H), 7.15 (1H, br s, C(5⁰)H), 4.90 (1H, d, J¼1.7 Hz,

C(1)H), 4.14 (1H, dd, J¼4.4, 3.3 Hz, C(3)H), 4.09 (1H, dd,

J¼5.1, 3.3 Hz, C(4)H), 4.04 (1H, dd, J¼4.4, 1.7 Hz,

6518

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

C(2)H), 3.84 (1H, dd, J¼10.3, 5.1 Hz, C(5)H_aH_b), 3.73 (1H,

dd, J¼10.3, 5.1 Hz, C(5)H_aH_b); d_C(60 MHz, CD₃OD)

133.6 (C-3⁰), 131.8 (C-1⁰), 115.1 (C-5⁰), 70.5 (C-6), 69.0

(C-2), 68.8 (C-1), 67.6 (C-3), 63.6 (C-5), 62.2 (C-4); HRMS

(Cl, NH₃) MH^þ, found 201.0878. C₈H₁₃N₂O₄requires

201.0875.

J¼8.7, 3.0 Hz, C(7)H), 4.73 and 4.63 (2H, AB, J¼11.5 Hz,

OCH₂Ph), 4.61 (1H, d, J¼3.0 Hz, C(8)H), 4.48 and 4.33

(2H, AB, J¼11.8 Hz, OCH₂Ph), 4.31 and 4.20 (2H, AB,

J¼14.0 Hz, OSO₂CH₂Ph), 4.29 (1H, dd, J¼8.7, 3.5 Hz,

C(6)H), 4.18 (1H, ddd, J¼6.2, 4.6, 3.5 Hz, C(5)H), 3.86

(1H, dd, J¼11.9, 4.6 Hz, C(9)H_aH_b), 3.72 (1H, dd, J¼11.9,

6.2 Hz, C(9)H_aH_b); d_C(60 MHz, CDCl₃) 137.0 (C-3),

129.0–127.5 (m, CH arom.), 127.2 (C-1), 124.7 (C-8a),

80.4 (C-7), 74.3 (OCH₂Ph), 73.2 (C-6), 70.3 (OCH₂Ph),

68.1 (C-8), 63.0 (C-9), 61.4 (C-5), 57.4 (OSO₂CH₂Ph);

HRMS (Cl, NH₃) MH^þ, found 535.1904. C₂₉H₃₁N₂O₆S

requires 535.1902.

3.3.35. Imidazolo[1,5]-^D-gluco-piperidinose (6). The same

procedure as for the preparation of 8 was used starting from

40b (8 mg, 0.017 mmol) to give after workup the title

compound 6 (3 mg, 0.015 mmol, 88%, R_f¼0.30 in EtOH/

NH₃aq. 6:1) as a colourless ﬁlm. [a]²_D⁰¼26.5 (c¼0.13;

CH₃OH); d_H(400 MHz, D₂O) 7.93 (1H, s, C(3)H), 6.76

(1H, s, C(1)H), 4.86 (1H, d, J¼6.2 Hz, C(8)H), 4.47–4.38

(1H, m, C(5)H), 4.31 (1H, dd, J¼9.2, 7.8 Hz, C(6)H), 4.07

(1H, dd, J¼12.2, 4.5 Hz, C(9)H_aH_b), 3.96 (1H, dd, J¼12.2,

3.1 Hz, C(9)H_aH_b), 3.89 (1H, dd, J¼9.2, 6.2 Hz, C(7)H); d_C

(100.6 MHz, D₂O) 131.5 (C-8a), 130.9 (C-3), 121.6 (C-1),

70.3 (C-7), 60.9 (C-9), 60.3 (C-8), 58.8 (C-5); HRMS (Cl,

NH₃) MH^þ, found 201.0877. C₈H₁₃N₂O₄requires

201.0875.

3.3.37. 1,3-Di-O-benzyl-2,4-di-O-phenylmethanesul-

phonyl-1-[1H-imidazol-4(5)-yl]-^L-ido-pentitol (43b). The

same procedure as for the preparation of 43a and 44 was

used starting from 36b (100 mg, 0.11 mmol) to give after

workup the title compound 43b (56 mg, 0.08 mmol, 70%,

R_f¼0.35 in CH₂Cl₂/acetone 1:1) as a white foam. [a]²_D⁰¼þ4

(c¼0.6; CHCl₃); n_max(ﬁlm): 3328, 2944, 1496, 1448, 1352,

1172, 1064, 788, 696, 652 cm²¹; d_H(250 MHz, CDCl₃)

7.72 (1H, s, C(2⁰)H), 7.35–7.15 (20H, m, 4Ph), 6.81 (1H, s,

C(5⁰)H), 5.27 (1H, dd, J¼6.7, 3.9 Hz, C(2)H), 4.92 (1H, d,

J¼6.7 Hz, C(1)H), 4.80 (1H, ddd, J¼7.8, 4.3, 2.8 Hz,

C(4)H), 4.58 and 4.41 (2H, AB, J¼11.3 Hz, OCH₂Ph), 4.44

and 4.29 (2H, AB, J¼11.5 Hz, OCH₂Ph), 4.36 and 4.23 (2H,

AB, J¼14.0 Hz, OSO₂CH₂Ph), 4.26 (2H, s, OSO₂CH₂Ph),

3.94 (1H, dd, J¼13.3, 4.3 Hz, C(5)H_aH_b), 3.88 (1H, dd,

J¼7.8, 3.9 Hz, C(3)H), 3.75 (1H, dd, J¼13.3, 2.8 Hz,

C(5)H_aH_b); d_C(60 MHz, CDCl₃) 137.5–137.0 (m, C

s-arom.), 136.5 (C-4⁰), 133.0 (C-2⁰), 129.0–127.0 (m, CH

arom), 118.6 (C-5⁰), 83.2 (C-4), 82.0 (C-2), 75.5 (C-3), 74.9

(OCH₂Ph), 70.5 (OCH₂Ph), 73.1 (C-1), 60.7 (C-5), 57.3

(OSO₂CH₂Ph), 57.0 (OSO₂CH₂Ph); HRMS (Cl, NH₃)

MH^þ, found 706.1938. C₃₆H₃₈N₂O₉S₂requires 706.1940.

3.3.36. 1,3-Di-O-benzyl-2,4-di-O-phenylmethanesul-

phonyl-1-[1H-imidazol-4(5)yl]-^L-gulo-pentitol (43a) and

6,8-di-O-benzyl-7-O-phenylmethanesulphonyl-imida-

zolo[1,5]-^D-manno-piperidinose (44). To a stirred solution

of BnSO₂Cl (225 mg, 1.18 mmol) in anhydrous pyridine

(2.5 mL) was added portionwise a solution of 36a (250 mg,

0.28 mmol) in anhydrous pyridine (3.75 mL) at 2308C.

After 30 min the dry ice-acetone bath was removed and the

mixture was stirred at room temperature overnight then

evaporated under reduced pressure and co-evaporated

several times with toluene to remove pyridine. The residue

was dissolved in THF (11.25 mL)/aq. HCl (6 M, 3.75 mL)

mixture and reﬂuxed for 75 min THF was evaporated and

the remaining mixture was neutralised with saturated aq.

K₂CO₃solution and extracted with CHCl₃. The organic

layer was dried (MgSO₄), ﬁltered and evaporated. The

residue was twofold ﬂash-chromatographed (CHCl₃/MeOH

9:1; CH₂Cl₂/acetone 1:1) to give title compounds 43a

(69 mg, 0.10 mmol, 34%, R_f¼0.35 in CH₂Cl₂/acetone 1:1)

and 44 (28 mg, 0.05 mmol, 18%, R_f¼0.15 in CH₂Cl₂/

acetone 1:1) as a white foams. 43a [a]²_D⁰¼235 (c¼0.5;

CH₂Cl₂); n_max(ﬁlm): 3328, 2928, 1496, 1448, 1356, 1172,

1072, ₀788, 696, 644 cm²¹; d_H(250 MHz, CDCl₃) 7.69 (1H,

s, C(2 )H), 7.45–7.15 (20H, m, 4Ph), 6.97 (1H, s, C(5⁰)H),

5.35 (1H, dd, J¼5.0, 4.5 Hz, C(2)H), 4.96–4.81 (2H, m,

C(1)H, C(4)H), 4.64 and 4.48 (2H, AB, J¼10.5 Hz,

OCH₂Ph), 4.44 and 4.36 (2H, AB, J¼10.8 Hz, OCH₂Ph),

4.38 and 4.31 (2H, AB, J¼13.5 Hz, OSO₂CH₂Ph), 4.22 and

4.13 (2H, AB, J¼14.1 Hz, OSO₂CH₂Ph), 4.04 (1H, t,

J¼5.0 Hz, C(3)H), 3.80 (1H, dd, J¼12.5, 5.0 Hz,

C(5)H_aH_b), 3.70 (1H, dd, J¼12.5, 3.8 Hz, C(5)H_aH_b); d_C

(60 MHz, CDCl₃) 138.0–136.5 (m, C s-arom.), 135.9

(C-4⁰₀), 133.3 (C-2⁰), 131.5–126.0 (m, CH arom.), 119.3

(C-5 ), 82.4 (C-4), 81.1 (C-2), 75.6 (C-3), 74.3 (OCH₂Ph),

71.9 (OCH₂Ph), 73.0 (C-1), 60.8 (C-5), 57.9 (OSO₂CH₂Ph),

57.5 (OSO₂CH₂Ph); HRMS (Cl, NH₃) MH^þ, found

706.1938. C₃₆H₃₈N₂O₉S₂requires 706.1940. 44

[a]²_D⁰¼232 (c¼1.25; CHCl₃); n_max(ﬁlm): 3064, 3048,

3032, 2992, 2864, 1528, 1496, 1456, 1356, 1172, 1084, 984,

788, 696 cm²¹; d_H(250 MHz, CDCl₃) 7.60 (1H, s, C(3)H),

7.35–7.15 (15H, m, 3Ph), 6.80 (1H, s, C(1)H), 4.85 (1H, dd,

3.3.38. (6R,7S)-7,9-Dibenzyloxy-6,7-dihydro-5H-imi-

dazo[1,5-a]azepin-6-ol (45). To a stirred solution of

compound 43a (69 mg, 0.10 mmol) in anhydrous DMF

(1.5 mL) was added under argon atmosphere NaNH₂

(10 mg, 0.26 mmol) and the mixture was stirred at room

temperature overnight. The mixture was quenched with

MeOH, neutralised with AcOH and evaporated to dryness.

The residue was diluted with 5% aq. K₂CO₃solution and

extracted with CHCl₃. The organic layer was dried

(MgSO₄), ﬁltered and evaporated. The residue was puriﬁed

by ﬂash chromatography (CHCl₃/MeOH 9:1) to give the

title compound 45 (30 mg, 0.08 mmol, 85%) as a colourless

amorphous solid). [a]²_D⁰¼þ57 (c¼1.5; CHCl₃); n_max(ﬁlm):

3112, 2992, 2928, 1708, 1656, 1492, 1452, 1356, 1256,

1216, 1152, 1144, 1136, 1128, 1096, 1028, 760, 696 cm²¹

;

d_H(250 MHz, CDCl₃þC₆D₆) 7.46 (1H, s, C(3)H), 7.30–

7.00 (10H, m, 2Ph), 7.00 (1H, s, C(1)H), 4.70 (1H, d,

J¼6.0 Hz, C(8)H), 4.61 and 4.58 (2H, AB, J¼12 Hz,

OCH₂Ph), 4.36 and 4.21 (2H, AB, J¼11.5 Hz, OCH₂Ph),

3.88 (1H, dd, J¼6.0, 3.1 Hz, C(7)H), 3.83 (1H, dd, J¼13.2,

9.0 Hz, C(5)H_aH_b), 3.74 (1H, ddd, J¼9.0, 3.1, 2.6 Hz,

C(6)H), 3.51 (1H, dd, J¼13.2, 2.6 Hz, C(5)H_aH_b); d_C

(250 MHz, CDCl₃þC₆D₆) 147.8 (C-9), 140.0 (C-1), 138.0

(C-9a), 139.4, 137.7 (C s-arom.), 131.0 (C-3), 129.0–127.5

(m, CH arom.), 95.8 (C-8), 76.4 (C-7), 71.2 (OCH₂Ph), 70.3

(OCH₂Ph), 69.9 (C-6), 47.9 (C-5); HRMS (Cl, NH₃) MH^þ,

found 363.1706. C₂₂H₂₃N₂O₃requires 363.1708.

A. Frankowski et al. / Tetrahedron 59 (2003) 6503–6520

6519

3.3.39. (5R,6S)-6,8-Dibenzyloxy-5,6-dihydro-5-hydroxy-

methyl-imidazo[1,5-a]pyridine (46). The same procedure

as for the preparation of 45 was used staring from 44

(49 mg, 0.09 mmol) to give after workup and ﬂash

chromatography (acetone/CH₂Cl₂) 6:1) the title compound

46 (28 mg, 0.08 mmol, 84%) as a colourless amorphous

solid. [a]²_D⁰¼þ172 (c¼0.9; CHCl₃); n_max(ﬁlm): 3128,

3032, 2856, 1648, 1560, 1492, 1456, 1392, 1364, 1292,

1256, 1212, 1088, 1068, 1052, 748, 696, 656 cm²¹; d_H

(250 MHz, CDCl₃) 7.50 (1H, s, C(3)H), 7.40–7.20 (10H, m,

2Ph), 6.94 (1H, s, C(1)H), 4.95 (2H, s, OCH₂Ph), 4.88 (1H,

d, J¼6.3 Hz, C(7)H), 4.47 and 4.42 (2H, AB, J¼12.3 Hz,

OCH₂Ph), 4.41 (1H, ddd, J¼8.8, 5.0, 1.3 Hz, C(5)H), 4.24

(1H, dd, J¼6.3, 1.3 Hz, C(6)H), 3.60 (1H, dd, J¼11.3,

1.0 Hz, C(9)H_aH_b), 3.47 (1H, dd, J¼11.3, 8.8 Hz,

C(9)H_aH_b); d_C(60 MHz, CDCl₃) 140.0 (C-8), 139.2

(C-8a), 138.3 (C-3), 129.0–127.5 (m, CH arom.), 124.8

(C-1), 89.8 (C-7), 71.2 (C-6), 69.3 (OCH₂Ph), 69.2

(OCH₂Ph), 62.8 (C-9), 60.5 (C-5); HRMS (Cl, NH₃)

MH^þ, found 363.1707. C₂₂H₂₃N₂O₃requires 363.1708.

3.3.42. (2R,5R,6R,11S)-5,11-Dibenzyloxy-4-oxa-1,9-dia-

zatricyclo[5,3,0,1^2,6]-7(8),9-undecadiene (49). The same

procedure as for the preparation of 45 was used starting

from 43b (35 mg, 0.05 mmol) to give after workup and ﬂash

chromatography (CHCl₃/MeOH 9:1) the title compound 49

(10 mg, 0.03 mmol, 56%) as a white foam. [a]²_D⁰¼282

(c¼1.75; CHCl₃); n_max(ﬁlm): 2928, 2856, 1496, 1460,

1360, 1248, 1216, 1124, 1044, 960, 912, 788, 756, 696,

656 cm²¹; d_H(250 MHz, CDCl₃) 7.51 (1H, s, C(3)H),

7.42–7.19 (10H, m, 2Ph), 6.86 (1H, s, C(1)H), 4.89 (1H, s,

C(6)H), 4.88 (1H, d, J¼2.5 Hz, C(8)H), 4.73 and 4.51 (2H,

AB, J¼12 Hz, OCH₂Ph), 4.62 and 4.54 (2H, AB,

J¼11.5 Hz, OCH₂Ph), 4.40 (1H, d, J¼3.3 Hz, C(5)H),

3.85 (1H, dd, J¼11.3, 3.3 Hz, C(9)H_aH_b), 3.60 (1H, d,

J¼11.3 Hz, C(9)H_aH_b), 3.48 (1H, bd, J¼2.5 Hz, C(7)H); d_C

(60 MHz, CDCl₃) 138.9, 138.8 (C s-arom.), 135.2 (C-7a),

131.1 (C-3), 129.0–128.0 (m, CH arom.), 121.2 (C-1), 98.6

(C-8), 85.2 (C-6), 70.7 (OCH₂Ph), 69.5 (OCH₂Ph), 63.5

(C-9), 59.2 (C-5), 43.5 (C-7); HRMS (Cl, NH₃) MH^þ, found

363.1708. C₂₂H₂₃N₂O₃requires 363.1709.

3.3.40. (6S,7R,9R)-6,7,8,9-Tetrahydro-5H-imidazo[1,5-

a]azepin-6,7,9-triol (47). To a solution of compound 45

(66 mg, 0.18 mmol) in 95% ethanol (6 mL) was added 10%

Pd/C catalyst (135 mg) and the mixture was stirred over-

night under H₂atmosphere at room temperature. The

stirring was continued for next 4 days under H₂after

addition of the two new portions of the catalyst (2£100 mg)

until complete disappearance of the substrate (TLC). The

mixture was ﬁltered through celite, evaporated and puriﬁed

by chromatography (EtOH/aq. NH₃11:1) to give the title

compound 47 (8 mg, 0.043 mmol, 24%) as a white foam.

[a]²_D⁰¼217 (c¼0.4; MeOH); d_H(250 MHz, D₂O) 7.73 (1H,

s, C(3)H), 6.95 (1H, s, C(1)H), 4.89 (1H, dd, J¼10.5,

3.0 Hz, C(9)H), 4.37 (1H, dd, J¼15.0, 6.5 Hz, C(5)H_aH_b),

4.15 (1H, dd, J¼6.5, 1.8 Hz, C(6)H), 4.06 (1H, ddd, J¼10.8,

4.0, 1.8 Hz, C(7)H), 3.99 (1H, d, J¼15.0 Hz, C(5)H_aH_b),

2.14 (1H, ddd, J¼12.5, 10.8, 3.0 Hz, C(8)H_aH_b), 2.03 (1H,

ddd, J¼12.5, 10.5, 4.0 Hz, C(8)H_aH_b); d_C(60 MHz, D₂O)

134.1 (C-9a), 126.8 (C-3), 120.6 (C-1), 69.4 (C-6), 66.9

(C-7), 61.6 (C-9), 45.3 (C-5), 35.8 (C-8); HRMS (Cl, NH₃)

MH^þ, found 185.09289. C₈H₁₃N₂O₃requires 185.092617.

3.3.43. (5R,6S,7S)-6,7-Dihydro-5,7-dihydroxymethyl-

5H-pyrrolo[1,2-c]imidazole-6-ol (50). To a solution of

compound 49 (39 mg, 0.11 mmol) in 95% ethanol (4 mL)

was added 10% Pd/C catalyst (80 mg) and the mixture was

stirred at room temperature overnight in H₂atmosphere. A

new portion of catalyst (90 mg) was added and mixture was

stirred for the next 2 days. After workup as for 47 and

chromatography (EtOH/NH₃aq. 9:1) the title compound 50

(16 mg, 0.09 mmol, 81%) was given as a white foam.

[a]²_D⁰¼216 (c¼0.3; MeOH); d_H(250 MHz, D₂O) 8.61 (1H,

s, C(3)H), 7.24 (1H, s, C(1)H), 4.61 (1H, t, J¼6.6 Hz,

C(6)H), 4.50 (1H, dt, J¼6.6, 3.7 Hz, C(7)H), 4.22 (1H, dd,

J¼5.8, 3.7 Hz, C(8)H_aH_b), 4.00 (1H, dd, J¼11.3, 5.1 Hz,

C(9)H_aH_b), 3.90 (1H, dd, J¼6.6, 5.8 Hz, C(8)H_aH_b), 3.85

(1H, dd, J¼11.3, 6.2 Hz, C(9)H_aH_b), 3.43 (1H, ddd, J¼6.6,

6.2, 5.1 Hz, C(5)H), d_C(60 MHz, D₂O) 134.6 (C-7a), 127.0

(C-3), 111.6 (C-1), 75.0 (C-6), 65.5 (C-7), 58.3 (C-9), 58.2

(C-8), 45.0 (C-5); HRMS (Cl, NH₃) MH^þ, found

185.09256. C₈H₁₃N₂O₃requires 185.092617.

Acknowledgements

3.3.41. (5S,6S,8R)-5,6,7,8,-Tetrahydro-5-hydroxy-

methyl-imidazo[1,5-a]pyridin-6,8-diol (48). To a solution

of compound 46 (39 mg, 0.11 mmol) in 95% ethanol (4 mL)

was added 10% Pd/C catalyst (80 mg) and the mixture was

stirred at room temperature overnight in H₂atmosphere. A

new portion of catalyst (80 mg) was added and mixture was

stirred for the next 2 days. After workup as for 47 and

chromatography (CHCl₃/MeOH 2:1) the title compound 48

(7 mg, 0.038 mmol, 35%) was given as a white foam.

[a]²_D⁰¼232 (c¼0.35; MeOH); d_H(250 MHz, D₂O) 7.73

(1H, s, C(3)H), 6.95 (1H, s, C(1)H), 4.89 (1H, dd, J¼7.5,

5.8 Hz, C(8)H), 4.12 (1H, ddd, J¼8.8, 6.5, 3.0 Hz, C(6)H),

4.03 (1H, ddd, J¼6.5, 4.3, 3.5 Hz, C(5)H), 3.90 (1H, dd,

J¼12.3, 3.5 Hz, C(9)H_aH_b), 3.78 (1H, dd, J¼12.3, 4.3 Hz,

C(9)H_aH_b), 2.32 (1H, ddd, J¼13.0, 5.8, 3.0 Hz, C(7)H_aH_b),

1.86 (1H, ddd, J¼13.0, 8.8, 7.5 Hz, C(7)H_aH_b); d_C

(250 MHz, D₂O) 143.0 (C-8a), 131.2 (C-3), 64.0 (C-6),

124.0 (C-1), 61.0 (C-5), 60.3 (C-8), 60.2 (C-9), 35.9 (C-7);

HRMS (Cl, NH₃) MH^þ, found 185.09231. C₈H₁₃N₂O₃

requires 185.092617.

We thank the EU PECO Copernicus program (ERBCI-

PACT930232), andtheFranco-PolishPoloniumprogram(No.

98249) for having furthered the bilateral scientiﬁc exchange

endeavours by the Lodz and the Mulhouse research groups.

We also wish to thank the Polish State Committee for

Scientiﬁc Research (KBN) for ﬁnancial support (grant 3T09A

09817). CCDC 201211 contains the supplementary crystal-

lographic data for this paper. This data can be obtained free of

charge at www.ccdc.cam. ac.uk/conts/retrieving.html [or

from the Cambridge Crystallographic Data Centre, 12,

Union Road, Cambridge CB2 1EZ, UK; fax: þ44-1223/336-

033; E-mail: deposit@ccdc. cam.ac.uk].

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Article Doi

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DOI: 10.1016/S0040-4020(03)01055-X

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