Synthesis of imidazolo-piperidinopentoses as nagstatine analogues

FULL PAPER

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues^[‡]

[a]

[b]

´

Francois Gessier, Theophile Tschamber,* Celine Tarnus, Markus Neuburger,

¸

Walter Huber,^[c]and Jacques Streith*^[a]

Keywords: Azasugars / Circular dichroism / Enzyme inhibitors / Nitrogen heterocycles

The syntheses of the four imidazolo-piperidino-pentoses and [α]_Dvalues, in conjunction with single-crystal X-ray dif-

3−6, which belong to the -series, and of their -enanti- fraction analyses of the -arabino and -lyxo azasugars ent-

omers, ent-3 to ent-6, are reported. Ascorbic acid and isoasc- 3 and 6. Although lacking the hydroxymethylene group in

orbic acid were converted over several steps into the -threo/ the C(5) position, the overall structure of these eight ste-

-erythro- and the -erythro/ -threo-configured aldot- reomers strongly resembles that of the natural product nags-

etroses, respectively, which are the key building blocks for tatine (1), a potent inhibitor of N-acetyl-β- -glucosaminid-

D

L

D

L

D

the eight target imidazolo-pentoses cited above. Nucleo-

philic addition of a metallated imidazole to any one of these

four aldotetroses gave the corresponding two diastereomeric

ase. As a matter of fact, after examination of the inhibitory

properties of these imidazolo-piperidinoses against six com-

monly encountered glycosidases, we observe that the L-arab-

adducts, intramolecular cyclisation of which provided the ex- ino imidazolo-sugar ent-3 is a potent inhibitor in this series,

pected bicyclic target molecules, with some protection and

deprotection steps being unavoidable prerequisites. The

with K_i= 1 µ

tosidase. The

M

both with a β-glucosidase and with a β-galac-

-ribo and -xylo stereomers 4 and 5 proved to

D

structures and configurations of all eight piperidinoses in be inhibitors of a β-glucosidase of similar magnitude (4: K_i=

Scheme 1 were determined unambiguously, by a combina- 20 µ ; 5: K_i= 17 µ ), the other stereomers being either mod-

tion of ¹H/¹³C NMR spectroscopy, circular dichroism (CD) est to poor inhibitors, or showing no inhibition at all.

M

Introduction

of the substrate Ϫ in its flattened transition state Ϫ and the

enzyme’s active site.^[5,6]Once protonated at the most basic

nitrogen atom Ϫ by ‘‘lateral protonation’’ of the pseudo-

anomeric N-atom inside the enzyme’s active site^[4]Ϫ 1 gives

rise to an imidazolium cation that mimics the postulated

oxocarbonium ion-type transition states rather well. The of-

ten higher potency displayed by 1 and by similar artificial

bicyclic mimics has been attributed to their greater rigidity,

the polyhydroxylated heterocyclic moiety being effectively

locked in a conformation that favours inhibition.^[4,7Ϫ9]In

fact, several nonnatural azole-piperidinoses have been syn-

thesized,^[4,7,8]some of which have shown remarkably strong

inhibition properties.^[10]

The mechanism of polysaccharide hydrolases (i.e., of gly-

cosidases) is thought to produce transition states with pro-

nounced oxocarbonium characters, both with retaining and

with inverting glycosidases.^[1]Since most natural oligo- and

polysaccharides are chair conformer pyranoses, the ensuing

oxocarbonium-type transition states appear as flattened,

half-chair, conformations.

In 1992, Aoyagi, Aoyama and co-workers published the

structure of the natural product nagstatine (1), and showed

that this imidazole-sugar is a very potent inhibitor of some

glucosaminidases, with a K_ivalue of 4 nM for the bovine

kidney enzyme N-acetyl-β--glucosaminidase, for ex-

ample.^[2,3]The discovery of 1 heralded a new era for investi-

gation of glycosidase-catalysed polysaccharide hydrolysis

mechanisms.^[4]The imidazole ring forces the six-membered

piperidinose ring of 1 to occupy a half-chair conformation.

As a result, azasugar 1 would seem to mimic the ‘‘activated

complex’’ of the sugar moiety in the enzyme-substrate com-

plex. Therefore, its stereostructure should be in agreement

with Pauling’s prediction of close similarity in the structure

In a preceding publication we reported the synthesis of

all eight imidazolo-piperidinose stereomers Ϫ such as -

arabino-azasugar 2 (three asymmetric centres) Ϫ the overall

structures of which are similar to those of Scheme 1, except

for the basic nitrogen atom, which appears in the 2-position

(heterocyclic numbering) in azasugar 2,^[11]while occupying

the pseudoanomeric N(1) position in the series at hand.

Similarities with nagstatine (1) in this latter series are hence

rather obvious. For that reason, we surmised that some of

the eight stereomers of Scheme 1 might show reasonably

potent glycosidase inhibitory properties. As we see below,

this assumption proved to be correct, at least for some of

the eight target azasugars, as determined by

MichaelisϪMenten kinetics with six commonly encoun-

tered glycosidases. Single-crystal X-ray diffraction experi-

ments with the -arabino and -lyxo stereomers ent-3 and

[‡]

Carbohydrate Transition State Mimics, I

[a]

´

Ecole Nationale Superieure de Chimie, Universite de Haute-

Alsace,

3, rue Alfred Werner, 68093 Mulhouse, France

Fax: (internat.) ϩ 33-389/336875

E-mail: J.Streith@univ-mulhouse.fr

Institut für anorganische Chemie, Universität Basel,

Spitalstrasse 51, 4056 Basle, Switzerland

Optical Spectroscopy, F. Hoffmann-La Roche AG,

Grenzacherstrasse, 4070 Basle, Switzerland

[b]

[c]

1

6, in combination with H and ¹³C NMR spectra, together

Eur. J. Org. Chem. 2001, 4111Ϫ4125

WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001

1434Ϫ193X/01/1121Ϫ4111 $ 17.50ϩ.50/0

4111

F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

FULL PAPER

with the chiroptical data of all eight imidazolo-piperid-

The primary starting materials, -ethyl threonate and -

inoses, allowed their absolute configurations to be deter- ethyl erythronate derivatives, were obtained from the easily

mined unambiguously. It should be noted in particular that available and inexpensive ascorbic acid and isoascorbic

the circular dichroism (CD) spectra were in perfect agree- acid, respectively, according to known methodology based

ment with the expected mirror-image relationships of the on the oxidative cleavage of the ene-diol double bond of the

four pairs of opposite enantiomers 3/ent-3, 4/ent-4, 5/ent-5 corresponding monoacetonides (see below). Walden inver-

and 6/ent-6.

sions were performed, by which -ethyl threonate (from as-

corbic acid) provided -ethyl erythronate, and -ethyl er-

ythronate (from isoascorbic acid) -ethyl threonate.

Arabinose Series 3 and Ribose Series 4

Retrosynthetic analyses of the -arabino 3 and -ribo 4

target molecules suggested isoascorbic acid (-erythro con-

figuration) in its monoacetonide form as the starting mat-

erial (see Scheme 2). Oxidative cleavage of the ene-diol

double bond of this starting material, followed by ester-

ification of the ensuing carboxylate to the corresponding

ethyl -erythronate 7, had already been described by Abu-

shanab and co-workers,^[12]and Demuynck and co-

workers.^[13]O-Benzylation of 7 (BnBr/Ag₂O/KI/4A MS/

˚

toluene) gave 8 (83%), which was quantitatively reduced

(DIBAH/toluene at Ϫ78 °C) to aldehyde 9, a compound

that readily condenses with water to afford the hydrated

form of the aldehyde. In order to avoid the formation of

that (undesired) hydrate, the very dry aldehyde 9 was care-

fully prepared (see Exp. Sect.) and used directly in the next

step without purification. C(2)-Lithiated N-trityl-imidazole

was added under argon to aldehyde 9, to give a mixture of

adducts 10, as the minor and less polar diastereomer, and

14 (major and most polar diastereomer). These stereomers

could be separated to a large extent by chromatography. O-

Benzylation (NaH/BnBr/toluene) of minor adduct 10 gave

fully protected derivative 11 in good yield, but with small

amounts of impurities. Partial deprotection of 11 in acidic

medium (Dowex H^ϩ/EtOH/H₂O) produced pure and crys-

talline -arabino diol 12 (69%). A similar sequence of reac-

tions, starting from the major and not entirely homogenous

adduct 14, gave dibenzyl ether 15, and thence pure crystal-

line -ribo diol 16. Compound 12 was N- and O-tosylated

(TsCl/NEt₃/DMAP/CH₂Cl₂) to direct the sulfonylation pro-

cess toward the primary alcohol. The expected N,O-ditosyl

derivative, without being purified, dissolved slowly in a

Scheme 1. Nagstatine (1) and the imidazolo-piperidinoses

Results

Synthesis of Imidazolo-piperidinoses

In order to prepare all eight stereomers in Scheme 1, we NaOH/MeOH solution at room temp. for 12 h, and af-

decided to use a classical approach, starting from -er- forded bicyclic compound 13 (45%) in crystalline form. Hy-

ythrose 9 and -erythrose (ent-9), and from -threose 20 drogenolysis of 13 (H₂/Pd(OH)₂/C/AcOH) gave the ex-

and -threose (ent-20) Ϫ all four aldotetroses provided with pected -arabino target molecule 3 (45%) as a crystalline

appropriate protection groups Ϫ by nucleophilic addition compound (Scheme 2). The chiroptical properties of 3 are

of an N-protected and C(2)-metallated imidazole derivative shown in Figure 1 (CD spectrum) and in Table 1 ([α]_D). A

to the aldehyde double bond, using a known method.^[7]We similar sequence of reactions, starting from the linear -ribo

expected that each of the four aldotetrose derivatives would derivative 16, afforded di-O-benzyl--ribo-piperidinose 17,

afford a pair of diastereomeric imidazolo-pentoses, the nu- and then -ribo-piperidinose 4, the chiroptical data of

cleophilic addition process having little chance of being di- which are also shown in Figure 1 and in Table 1.

astereoselective. This did indeed turn out to be the outcome

Retrosynthetic analyses of the -arabino and -ribo target

of these nucleophilic coupling reactions, and resulted in the enantiomers ent-3 and ent-4 suggested -erythro aldehyde

expected eight linear imidazolo stereomers in toto. These ent-9 as the starting material (see Scheme 3). A multi-step

could be cyclised to the corresponding imidazolo-piperidi- synthesis of this compound had been described by us previ-

nose derivatives, deprotection of which produced the target ously, starting from an -threonate ethyl ester derivative

imidazolo-sugars shown in Scheme 1.

(from ascorbic acid), followed by a Walden inversion at

4112

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

FULL PAPER

Scheme 2. Synthesis of the imidazolo -arabino and -ribo piperid-

inoses 3 and 4.

˚

a) BnBr, KI, Ag₂O, MS (4 A), toluene, reflux; b) toluene, Ϫ78 °C,

DIBAH; c) 1. N-tritylimidazole in THF, nBuLi, Ϫ5 °C; 2. ϩ 9 in

THF at Ϫ5 °C, then stirring at 0 °C; 3. H₂O; d) NaH, THF, BnBr,

nBu₄NI, 40 °C; e) EtOH/H₂O, Dowex 50WX8, 60 °C; f) 1. CH₂Cl₂,

TsCl, NEt₃, DMAP, 0 °C, 24 h; 2. 2  NaOH/MeOH, room temp.,

12 h; g) H₂, Pd(OH)₂/C, AcOH

C(2) to give the corresponding ethyl -erythronate, the O-

benzyl derivative of which had been quantitatively reduced

to ent-9.^[11]Treatment of C(2)-lithiated N-trityl-imidazole

with anhydrous aldehyde ent-9 gave a mixture of the two

expected diastereomeric adducts ent-10 (minor and less po-

lar compound) and ent-14 (more polar and major adduct)

which could be separated to a large extent by column chro-

matography. The chromatographic fraction containing the

minor and almost pure -arabino diastereomer ent-10 was

O-benzylated (NaH/BnBr/nBu₄NI/THF) to produce the

Figure 1. Circular dichroism of the eight imidazolo-piperidinoses

homogenous derivative ent-11. This was deprotected in ent-15, followed by the crystalline -ribo diol ent-16 (87%).

acidic medium (Dowex H^ϩ/EtOH/H₂O) to give the crystal- Intramolecular cyclisation of ent-12 to the -arabino piper-

line -arabino diol ent-12 (83%). A similar reaction se- idinose ent-13 was performed (as above for 13) by way of

quence, starting from the major and almost pure -ribo ad- the N,O-ditosyl intermediate. Hydrogenolysis of ent-13 (H₂/

duct ent-14, provided the homogenous bis-benzyl derivative Pd/C/MeOH) gave ent-3 (63%). The absolute configuration

Eur. J. Org. Chem. 2001, 4111Ϫ4125

4113

F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

Table 1. Rotatory power data ([α]²_D⁰values) of the eight stereomers of Scheme 1.

FULL PAPER

-arabino (3)

Ϫ23

(c ϭ 1.0, H₂O)

-arabino (ent-3)

ϩ28

-ribo (4)

Ϫ32

(c ϭ 1.0, H₂O)

-ribo (ent-4)

ϩ32

-xylo (5)

-lyxo (6)

Ϫ56

Ϫ42

(c ϭ 1.0, MeOH)

-xylo (ent-5)

ϩ55

(c ϭ 1.0, MeOH)

-lyxo (ent-6)

ϩ42

(c ϭ 1.0, H₂O)

(c ϭ 1.0, MeOH)

of ent-3 could be determined from its chiroptical properties

(CD spectrum: Figure 1; optical rotatory power: Table 1)

and by a single-crystal X-ray diffraction experiment (Figure

3). Comparison of chiroptical data clearly proved the mir-

ror image relationship between 3 and ent-3. A similar reac-

tion sequence with ent-16 gave piperidinose derivative ent-

17, which was deprotected to the -ribo target molecule ent-

4. This proved to be the enantiomer of the -ribo com-

pound 4 (Figure 1 and Table 1).

Xylose Series 5 and Lyxose Series 6

Retrosynthetic analysis of the -xylo and -lyxo target

molecules 5 and 6 suggested -threo aldehyde 20 as the

starting material (see Scheme 4). This could be obtained

from the known -erythronate ethyl ester 7 (from isoascor-

bic acid)^[12,13]by Walden inversion at C(2) and semireduc-

tion of the ensuing -threonate ester 19 to the aldehyde 20

as follows. Sequential treatment of 7 with triflic anhydride

and pyridine, followed by an S_N2 reaction between the cor-

responding triflate and a nitrite salt (NaNO₂/CH₂Cl₂/H₂O),

produced the -threo diastereomer 18 (74% from 7). O-

Benzylation (BnBr/Ag₂O/KI/toluene) gave 19 (77%), which

was reduced (DIBAH/toluene; Ϫ78 °C) to the correspond-

ing -threose derivative 20 (85%). Treatment of C(2)-

lithiated N-trityl-imidazole with anhydrous aldehyde 20 un-

der argon atmosphere produced the diastereomeric adducts

21 (less polar and minor adduct) and 25 (more polar and

major adduct), which were separated to a large extent by

column chromatography, accompanied by some unchanged

N-trityl-imidazole. The minor -xylo isomer 21 was O-

benzylated (NaH/Bu₄NI/BnBr/toluene) to give 22, which

was at once deprotected with acid (4  HCl) to yield the

key intermediate 23 as a crystalline compound. A similar

sequence of reactions, starting from the major diastereomer

25, enabled the linear -lyxo diol 27 to be obtained as a

crystalline compound, by way of intermediate 26. Intramo-

lecular cyclisations of the linear imidazolosugar derivatives

23 and 27 were performed as follows. Compound 23 was

N- and O-tosylated (TsCl/Et₃N/CH₂Cl₂in the presence of

Bu₂SnO as a catalyst) in order to direct the sulfonylation

process toward the primary alcohol. The expected N,O-di-

Scheme 3. Synthesis of the imidazolo -arabino and -ribo piperid-

inoses ent-3 and ent-4. a) 1. N-Tritylimidazole in THF, nBuLi, Ϫ5

°C; 2. ϩ ent-9 in THF at Ϫ5 °C, then stirring at 0 °C; 3. H₂O; b)

NaH, THF, BnBr, nBu₄NI, 40 °C; c) EtOH/H₂O, Dowex 50 WX8,

60 °C; d) 1. TsCl, NEt₃, DMAP, CH₂Cl₂, 0 °C; 2. 2  NaOH/

MeOH, room temp.; e) 1. Bu₂SnO, NEt₃,TsCl, CH₂Cl₂; 2. 2 

NaOH/MeOH, room temp.; f) H₂, Pd/C, 30 bar, MeOH.

tosyl derivative, without being purified, dissolved slowly in lute configuration of 6 were determined by a single-crystal

2  NaOH/MeOH and afforded piperidinose derivative 24 X-ray diffraction experiment (Figure 2).

(87%). A similar reaction sequence with the linear -lyxo

Retrosynthetic analyses of the -xylo and -lyxo target

derivative 27 gave 28 (90%). Both 24 and 28 were depro- molecules ent-5 and ent-6 suggested -threo aldehyde ent-20

tected (H₂/Pd(OH)₂/C), to afford the -xylo and -lyxo ste- (ex vitamin C) as the starting material (see Scheme 5). The

reomers 5 and 6, respectively. The stereostructure and abso- preparation of ent-20 had already been described by us in

4114

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

FULL PAPER

˚

Figure 2. Molecular structure of 6; selected bond lengths [A), bond

angles [°] and torsion angles [°]: N(1)ϪC(1) 1.385(2), N(1)ϪC(7)

1.325(2), C(1)ϪC(2) 1.353(2), C(2)ϪN(2) 1.375(2), N(2)ϪC(3)

1.464(2), N(2)ϪC(7) 1.356(2), C(3)ϪC(4) 1.521(2), C(4)ϪO(1)

1.426(2), C(4)ϪC(5) 1.534(2), C(5)ϪO(2) 1.421(2), C(5)ϪC(6)

1.532(2),

C(6)ϪO(3)

1.425(2),

C(6)ϪC(7)

1.500(2);

110.3(1),

127.3(1),

125.0(1),

110.6(1),

110.7(1),

127.0(1).

C(1)ϪN(1)ϪC(7),

C(1)ϪC(2)ϪN(2)

C(2)ϪN(2)ϪC(7)

N(2)ϪC(3)ϪC(4)

C(4)ϪC(5)ϪC(6)

N(1)ϪC(7)ϪN(2)

105.2(1),

106.0(1),

107.4(1),

110.2(1),

109.5(1),

111.1(1),

N(1)ϪC(1)ϪC(2)

C(2)ϪN(2)ϪC(3)

C(3)ϪN(2)ϪC(7)

C(3)ϪC(4)ϪC(5)

C(5)ϪC(6)ϪC(7)

N(1)ϪC(7)ϪC(6)

N(2)ϪC(7)ϪC(6) 121.3(1); N(1)ϪC(7)ϪN(2)ϪC(3) Ϫ174.5,

C(2)ϪN(2)ϪC(7)ϪC(6) Ϫ172.3, C(6)ϪC(7)ϪN(2)ϪC(3) 13.6,

C(1)ϪN(1)ϪC(7)ϪN(2)

0.3,

N(2)ϪC(3)ϪC(4)ϪC(5)

48.9,

C(6)ϪC(5)ϪC(4)ϪC(3) Ϫ63.7, C(7)ϪC(6)ϪC(5)ϪC(4) 49.5,

C(7)ϪN(2)ϪC(3)ϪC(4) Ϫ24.9, N(1)ϪC(1)ϪC(2)ϪN(2) 0.0,

C(7)ϪN(1)ϪC(1)ϪC(2) Ϫ0.2, C(7)ϪN(2)ϪC(2)ϪC(1) 0.2

(Scheme 5). The chiroptical properties of these imidazolo-

piperidinoses proved their mirror image relationship with

respect to the -xylo 5 and -lyxo 6 stereomers, respectively

(Table 1 and Figure 1).

Scheme 4. Synthesis of the imidazolo -xylo and -lyxo piperid-

inoses 5 and 6. a) 1) Tf₂O, CH₂Cl₂, pyridine, Ϫ10 °C to room

Spectral Properties and Structure Analyses

˚

temp., 2. NaNO₂, DMF; b) Ag₂O, KI, MS 4A, BnBr toluene, re-

flux; c) DIBAH, toluene, Ϫ78 °C; d) N-tritylimidazole in THF,

nBuLi, Ϫ5 °C, 2. ϩ 20 in THF at Ϫ5 °C then stirring at 0 °C; e)

NaH, nBu₄NI, THF, BnBr, 40 °C; f) 4  HCl, reflux; g) 1. NEt₃,

The structures and absolute configurations of imidazolo-

sugars 3 to 6 and ent-3 to ent-6 could be assigned without

1

Bu₂SnO, CH₂Cl₂, TsCl, 2. 2  NaOH/MeOH; h) H₂, Pd(OH)₂/C, any ambiguity, thanks to a combination of H/¹³C NMR

EtOH/AcOH

spectroscopy and circular dichroism (CD) and rotatory

power data, in conjunction with the single-crystal X-ray dif-

a previous publication.^[11]Anhydrous aldehyde ent-20 was fraction analyses of the -arabino and -lyxo imidazolosu-

treated with C(2)-lithiated N-trityl-imidazole, under reac- gars ent-3 and 6, as shown below.

tion conditions similar to those used for the coupling reac-

X-ray diffraction analysis of ent-3 clearly demonstrated

tions described above. This resulted in a mixture of the two its absolute -arabino configuration, as shown in Figure 3.

expected diastereomeric adducts ent-21 (minor and less po- Let us now consider a ‘‘configuration retro-analysis’’ for the

lar compound), and ent-25 (major and more polar com- synthetic sequence of that azasugar (Scheme 3). Since ent-3

pound) which were separated to a large extent by chromato- has the -arabino configuration, it follows that:

graphy. O-Benzylation of ent-21 and ent-25 produced the

i) its precursor, minor adduct ent-10, exists in the same

fully protected compounds ent-22 and ent-26, respectively. -arabino configuration,

Partial deprotection of these compounds in acidic media

ii) as a consequence, the major adduct ent-14 has the di-

gave the corresponding crystalline diols ent-23 and ent-27. astereomeric -ribo configuration, and so does the corres-

Intramolecular cyclisation of the respective N,O-ditosyl de- ponding target azasugar ent-4, as shown in Scheme 3,

rivatives of these two compounds in NaOH/MeOH solution

iii) the Walden inversion we had described previously

gave the expected imidazolo-piperidinoses ent-24 and ent- with the -threo ester derivative obtained from ascorbic

28, which were deprotected by hydrogenolysis to give target acid^[11]ultimately affords the -erythro intermediate ent-9,

molecules -xylo ent-5 and -lyxo ent-6, respectively which is the immediate precursor of both ent-10 and ent-14,

Eur. J. Org. Chem. 2001, 4111Ϫ4125

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F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

FULL PAPER

˚

Figure 3. Molecular structure of ent-3; selected bond lengths [A],

bond angles[°] and torsion angles[°]:

N(1)ϪC(1) 1.384(2),

N(1)ϪC(7) 1.325(1), C(1)ϪC(2) 1.359(2), C(2)ϪN(2) 1.377(1),

N(2)ϪC(3) 1.465(1), N(2)ϪC(7) 1.358(1), C(3)ϪC(4) 1.524(1),

C(4)ϪC(5) 1.521(1), C(5)ϪO(2) 1.419(1), C(5)ϪC(6) 1.528(1),

C(6)ϪC(7) 1.500(1); C(1)ϪN(1)ϪC(7) 105.43(9), N(1)ϪC(1)ϪC(2)

110.3(1), C(1)ϪC(2)ϪN(2) 105.7(1), C(2)ϪN(2)ϪC(3) 127.11(9),

C(2)ϪN(2)ϪC(7)

N(2)ϪC(3)ϪC(4)

C(4)ϪC(5)ϪC(6)

N(1)ϪC(7)ϪN(2)

107.64(9),

110.05(8),

113.34(8),

110.99(9),

C(3)ϪN(2)ϪC(7)

C(3)ϪC(4)ϪC(5)

C(5)ϪC(6)ϪC(7)

N(1)ϪC(7)ϪC(6)

125.18(9),

109.78(8),

111.51(8),

126.74(8),

N(2)ϪC(7)ϪC(6) 122.23(8); N(1)ϪC(7)ϪN(2)ϪC(3) 177.4,

C(2)ϪN(2)ϪC(7)ϪC(6) 178.1, C(6)ϪC(7)ϪN(2)ϪC(3) Ϫ4.8,

C(1)ϪN(1)ϪC(7)ϪN(2) Ϫ0.5, N(2)ϪC(3)ϪC(4)ϪC(5) 50.5,

C(6)ϪC(5)ϪC(4)ϪC(3) 60.5, C(7)ϪC(6)ϪC(5)ϪC(4) Ϫ39.2,

C(7)ϪN(2)ϪC(3)ϪC(4)

24.7,

N(1)ϪC(1)ϪC(2)ϪN(2)Ϫ0.3,

C(7)ϪN(1)ϪC(1)ϪC(2) 0.5, C(7)ϪN(2)ϪC(2)ϪC(1) 0.0

centre C(3) modified, in the laboratory: i.e. in vitro. Only

asymmetric centre C(4) has been left untouched and occurs

in target molecule ent-3 as created in vivo in nature (in vit-

amin C).

If we consider the X-ray diffraction analysis of stereomer

6, which is in perfect agreement with its configuration as

Scheme 5. Synthesis of the imidazolo -xylo and -lyxo piperid-

inoses ent-5 and ent-6. a) N-tritylimidazole in THF, nBuLi, Ϫ5 °C,

2. ϩ ent-20 in THF at Ϫ5 °C, then stirring at 0 °C; b) NaH, being -lyxo (Figure 2), use of this in conjunction with the

¹H/¹³C NMR and CD spectra (Figure 1) of all four ste-

nBu₄NI, THF, BnBr, 40 °C; c) 2  HCl, reflux; cЈ) EtOH/H₂O,

Dowex Hϩ, 60 °C; d) 1. CH₂Cl₂, DMAP, NEt₃, TsCl, 0 °C, 2. 2 

reomers 6, ent-6, 5 and ent-5 unambiguously gives their as-

signments as -lyxo, -lyxo, -xylo and -xylo, respectively.

The arguments are similar to those outlined above for the

- and -arabino and - and -ribo stereomers.

NaOH/MeOH; dЈ) 1. NEt₃, Bu₂SnO, CH₂Cl₂, TsCl, 2. 2  NaOH/

MeOH; e) H₂, Pd/C, MeOH, 20Ϫ30 bar.

1

iv) since the H and ¹³C NMR spectra of azasugar 3 are

identical to and superimposable on those of -arabino ent-

3, and since the CD spectra of these two stereomers are

mirror images (Figure 1), it may be concluded that 3 has

the -arabino configuration,

The chiroptical properties proved to be of great interest.

The rotatory power data Ϫ in terms both of magnitude and

sign Ϫ agreed rather well with the mirror image relation-

ships between opposite enantiomers (Table 1). It is worth

noting that all the -configured imidazolosugars were levo-

rotatory, and the -stereomers dextrorotatory ([α]²_D⁰values).

Furthermore, the magnitudes of the [α]_Dvalues of opposite

enantiomers were identical, or at least very similar. Last but

not least, the circular dichroism (CD) spectra of all eight

stereomers are definite testimony to the mirror image rela-

tionship between the pairs of opposite enantiomers 3/ent-3,

4/ent-4, 5/ent-5, and 6/ent-6 (Figure 1).

1

v) since the H and ¹³C NMR spectra of azasugar 4 are

identical to and superimposable on those of -ribo ent-4,

and since the CD spectra of these two stereomers are mirror

images (Figure 1), it may be concluded that 4 has the -

ribo configuration.

That is to say that the X-ray diffraction analysis of -

1

arabino stereomer ent-3, taken in conjunction with the H/

¹³C NMR and CD spectra of 3, ent-4 and 4, permits the -

arabino, -ribo and -ribo configurations, respectively, to be

assigned to these three stereomers. When considering the

absolute 3D structure of ent-3, it is worth noting that the

Enzymatic Assays

The eight imidazolo-piperidinopentoses from Scheme 1

asymmetric centre C(2) has been created, and asymmetric were evaluated as potential inhibitors of six commercially

4116

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

FULL PAPER

available glycosidases. A number of these stereomers be noted that manmade -galacto imidazolo-piperidinose

showed some interesting inhibitory and selectivity proper- 29 Ϫ the (-galacto) homologue of (-arabino) ent-3

ties, as reported in Table 2.

(Scheme 6) Ϫ is the most powerful β--galactosidase inhib-

The -arabino derivative 3 was inactive towards the pool itor known so far (K_ica. 2 nM), since Tatsuta and co-

of enzymes evaluated, whereas its -arabino enantiomer ent- workers demonstrated that it was ca. five hundred times

3 was quite potent with respect to β-glucosidase from al-

monds and β-galactosidase from E. coli, with K_ivalues of

1µM in both cases. These are the most potent inhibitory

effects observed for the whole series. This is most probably

due to the chiral 3D structure of ent-3, since i) the three

asymmetric carbon atoms C(2), C(3), and C(4) in ent-3

(carbohydrate numbering, see: Scheme 1) have the same ab-

solute configurations as the corresponding carbon atoms in

β--galacto-pyranose; ii) the carbon atoms C(2) and C(3)

of ent-3 have the same absolute configurations as the cor-

responding carbon atoms in β--gluco-pyranose. It should azolo-piperidinose ent-3

Scheme 6. -galacto-imidazolo-piperidinose 29 and -arabino-imid-

Table 2. Inhibition constants (K_i) in µ measured at 22 °C. NI ϭ no inhibition at [I] ϭ 1 m. ([S] ϭ K_M)

Eur. J. Org. Chem. 2001, 4111Ϫ4125

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F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

FULL PAPER

more active than ent-3 with the same β--galactosidase Experimental Section

(from E. coli).^[7]Comparison of the K_ivalues of ent-3 and

29 clearly shows that the CH₂OH ‘‘handle’’ is of great im-

portance for strong docking of an imidazolo-piperidinose

in the active site of the corresponding enzyme.

General: ؊ Flash chromatography (FC): silica gel (Merck 60;

230Ϫ400 mesh). Ϫ TLC: aluminium sheets precoated with silica

gel (Merck 60 F₂₅₄); spots were viewed by UV or by heating with

a thermogun 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). Ϫ M.p.: Kofler hot-bench or Mettler FP-51

apparatus; corrected. Ϫ Optical rotations were all measured at ϩ20

°C: Schmidt-Haensch Polartronic Universal polarimeter. Ϫ CD

spectra were measured in H₂O solution between 185 and 400 nm

under nitrogen atmosphere on a Jobin Yvon CD6 Dichrographe

(∆ε values). Ϫ ¹H and ¹³C NMR spectra: 250 MHz and 400 MHz,

and 62.9 and 100.6 MHz, respectively; Bruker ACF 250 and Bruker

DSX 400 spectrometers at 300 K. Internal references for ¹H NMR:

Si(Me)₄, CDCl₃(δ ϭ 7.26), CD₃OD (δ ϭ 3.30), dioxane (δ ϭ 3.75)

for spectra in D₂O (δ ϭ 0.00); for ¹³C NMR: CDCl₃(δ ϭ 77.03),

CD₃OD (δ ϭ 49.02); δ in ppm and J in Hz. Ϫ Microanalyses were

carried out by the Service Central de Microanalyses of the CNRS,

F-69390 Vernaison or by the Institut de Chimie des Substances

Naturelles du CNRS, F-91198 Gif-sur-Yvette. MeOHϪNH₃stands

for a solution of pure MeOH saturated with NH₃(gas) at room

temp.

The -xylo stereomer 5 is a good example of configura-

tional fit with respect to a particular glycosidase (almond

β-glucosidase ), with a K_ivalue of 17 µM. Indeed, in terms

of absolute configuration, the three asymmetric centres

C(2), C(4) and C(5) in 5 are identical to those in -gluco-

pyranose. The -xylo enantiomer ent-5 was a weak inhibitor

(K_iϭ 280 µ) of α--mannosidase from Jack beans, never-

theless showing an interesting selectivity for this particular

enzyme.

The -ribo stereomer 4 proved to be as potent (K_iϭ 20

µ) as 5 with the almond β-glucosidase. To interpret this

result, it may be argued that C(2) and C(4) of 4 have the

same absolute configurations as the corresponding carbon

atoms in β--gluco-pyranose. The -ribo stereomer ent-4

only weakly inhibited the α-mannosidase of Jack beans

(K_iϭ 285 µ). Nevertheless, ent-4 is selective for this par-

ticular hydrolytic enzyme. Once again we note that C(2) and

C(3) of ent-4 have the same absolute configurations as the

corresponding carbon atoms in α--manno-pyranose.

Enzymatic Assays

Glycosidases [α-mannosidase (EC 3.2.1.24) from jack beans, β-

mannosidase (EC 3.2.1.25) from snails, α-glucosidase (EC 3.2.1.20)

from bakers’ yeast, β-glucosidase (EC 3.2.1.21) from almonds, α-

galactosidase (EC 3.2.1.22) from green coffee beans, β-galactosid-

Finally, the -lyxo stereomer 6 was shown to have moder-

ate inhibitory effects on α-glucosidase from bakers’ yeast

(K_iϭ 80 µ) and β-galactosidase from E. coli (K_iϭ 65 µ), ase from E. coli (EC 3.2.1.23)] and their corresponding substrates

were purchased from Sigma Co.

again with some 3D complementarities. If configurational

complementarity were to be operative throughout the whole

series, 6 would be expected to be an inhibitor of α- or β-

mannosidase. This is indeed observed but only to a moder-

Spectrophotometric assays were performed at the optimum pH for

each enzyme^[14]with p-nitrophenyl-α--mannopyranoside as a sub-

strate for α-mannosidase (K_mϭ 2 m, pH ϭ 4.5), p-nitrophenyl-

ate extent, since 6 is an (albeit rather poor) inhibitor of α- β--mannopyranoside for β-mannosidase (K_mϭ 1.3 m, pH ϭ

4.0), p-nitrophenyl-α--glucopyranoside for α-glucosidase (K_m

0.3 m, pH ϭ 7.0), p-nitrophenyl-β--glucopyranoside for β-gluco-

sidase (K_mϭ 2 m, pH ϭ 5.0), p-nitrophenyl-β--galactoside

ϭ

-mannosidase of Jack beans. As for -lyxo stereomer ent-

6, it had no significant effect at a concentration of 1 m on

any of the enzymes studied.

(K_mϭ 0.3 , pH ϭ 7.0) and p-nitrophenyl-α--galactoside (K_m

ϭ

In a preceding publication we described the syntheses

and enzymatic assays of all eight imidazolo-piperidinose

stereomers, of which -arabino compound 2 in Scheme 1 is

representative.^[11]Note that the basic nitrogen atom occu-

pies a different position in these compounds, all other struc-

tural parameters being identical. When comparing the in-

hibition properties of azasugars 3؊6 and ent-3؊ent-6, with

those previously described for their type 2 N-positional iso-

mers, several characteristic differences are evident:

0.3 m, pH ϭ 6.5) as substrates for the corresponding galactosid-

ases. The release of p-nitrophenol was measured continuously at

405 nm to determine initial velocities. All kinetics studies were per-

formed at 25 °C and the reaction was started by addition of enzyme

in a 1 mL assay medium (acetate buffer 50 m, or phosphate buffer

20 m according to the desired pH value) using substrate concen-

trations around the K_mvalue of each enzyme. The K_ivalues were

determined for the most potent inhibitors, by use of the Dixon

graphical procedure.^[15,16]

Ethyl

D-Erythronate Derivative 8: A mixture of freshly prepared

i) the half-chair inhibiting imidazolo-sugars described

here are configurationally selective and seem to be true

transition state analogue inhibitors of glycosidases

(Table 2), whereas active type 2 imidazolo-sugars as a rule

inhibit quite different glycosidases,^[11]

anhydrous Ag₂O (10.21 g; 44.1 mmol), powdered molecular sieves

˚

(4A, 3.7 g), and KI (570 mg) was heated under vacuum at 300 °C.

After the mixture had cooled to room temp., a solution of 7 (6.00 g;

29.4 mmol)^[12,13]in anhydrous toluene (230 mL) and BnBr

(3.80 mL, 31.8 mmol) were added. The resulting suspension was

heated under reflux for 2 h. After cooling to room temp., the sus-

pension was filtered, the resulting solution was evaporated to dry-

ness under vacuum, and the residue was purified by chromato-

graphy (AcOEt/cyclohexane, 2:8) to yield 8 (7.14 g, 83%) as a

ii) the active azasugars described here inhibit β-glycosid-

ases to a greater extent than they inhibit α-glycosidases,

whereas active type 2 azasugars as a rule inhibit α-glycosid-

ases, albeit rather poorly,

1

slightly yellow syrup. Ϫ [α]²_D⁰

؍

؉37 (c ϭ 2, CHCl₃). Ϫ H NMR

and ¹³C NMR spectra were identical to those we had reported

previously for the ent-8 enantiomer.^[11]Ϫ C₁₆H₂₂O₅(294.34): calcd.

C 65.29, H 7.53; found C 65.3, H 7.5.

iii) the pseudoanomeric N(1) atom appears to represent

a key factor in the Ϫ most probably lateral^[4]Ϫ binding of

the inhibiting imidazolo-sugars described here.

4118

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

FULL PAPER

D-Erythrose Derivative 9: A solution of DIBAH (1.6 , 8.5 mL, 1.21 (s, 3 H,CH₃isoprop.), 1.27 (s, 3 H, CH₃isoprop.), 3.56 (dd, 1

12.7 mmol; 1.5 equiv.) in toluene was added dropwise at Ϫ78 °C

to a stirred solution of 8 (2.50 g, 8.49 mmol) in anhydrous toluene

H, 2-H), 3.61 (dd, 1 H, 4-H_b), 3.66 (dd, 1 H, 4-H_a), 3.80 (td, 1 H,

3-H), 3.93 and 4.13 (AB, J ϭ 11.6, 2 H, OCH₂Ph), 4.06 (d, 1 H,

(55 mL). The reaction was complete after 15 min at Ϫ78 °C, excess 1-H), 4.43 and 4.48 (AB, J ϭ 11.5, 2 H, OCH₂Ph), 6.91 (d, 1 H,

DIBAH was slowly neutralised with MeOH (25 mL), and the solu- 4Ј-H or 5Ј-H), 7.12 (d, 1 H, 4Ј-H or 5Ј-H), 7.10 to 7.30 (m, 25 H,

tion was allowed to warm to room temp. The solution was treated CH phenyl); J_1,2ϭ 5.2, J_2,3ϭ 3.6, J_3,4aϭ 6.7, J_3,4bϭ 6.9, J_4a,4bϭ

sequentially with a saturated aq. Seignette salt (K and Na tartrate)

solution (2 mL) and some brine (4 mL), resulting in the precipita-

tion of the aluminium salts, which were filtered and washed with

AcOEt (ca. 70 mL). The filtrates were dried (MgSO₄), filtered and

concentrated to dryness. The resulting syrup was dissolved in an-

hydrous toluene and the solution concentrated in vacuo; this pro-

cedure was repeated three times in order to obtain the free aldehyde

instead of the hydrate. The final syrup was kept under vacuum over

P₂O₅in a dessicator for 20 h to yield 9 as an oil (2.07 g, 97%). Ϫ

The ¹H NMR spectrum was superimposable on the one that we

had reported in a preceding publication for the -erythrose derivat-

ive ent-9.^[11]

8.0, J_4Ј,5Јϭ 1.4.

Imidazole- -ribo Derivative 15: The same procedure as above was

D

applied, starting from the major adduct 14 (3.66 g, ca 6.5 mmol) in

THF (65 mL), Bu₄NI (ca. 30 mg), NaH (920 mg, ca 19 mmol), and

BnBr (940 µL, 7.9 mmol). Workup as above, followed by chromato-

graphy, gave 15 (4.44 g, overall yield from the aldehyde 9: ca. 48%).

Compound 15 was used without any further purification in the

deprotection step. Ϫ ¹H NMR (CDCl₃): δ ϭ 1.32 (s, 3 H, CH₃

isoprop.), 1.36 (s, 3 H, CH₃isoprop.), 3.77 (dd, 1 H, 2-H), 3.81 (t,

1 H, 4-H_b), 3.91 (dd, 1 H, 4-H_a), 3.95 and 4.31 (AB, J ϭ 11.7,

OCH₂Ph), 4.01 and 4.56 (AB, J ϭ 11.0, OCH₂Ph), 4.25 (d, 1 H,

1-H), 5.12 (td, 1 H, 3-H), 6.80 (d, 1 H, 4Ј-H or 5Ј-H), 7.10 to 7.34

(m, 26 H, CH phenyl, and 4Ј-H or 5Ј-H); J_1,2ϭ 4.8, J_2,3ϭ 1.4,

J_3,4aϭ 7.0, J_3,4bϭ 7.9, J_4a,4bϭ 7.9, J_4Ј,5Јϭ 1.3.

Coupling Reaction Between a Lithio-imidazole and D-Erythrose De-

rivative 9: (Scheme 2). A solution of BuLi in hexane (1.6 ,

10.8 mL, 17.2 mmol) was added dropwise under argon atmosphere

at Ϫ5 °C over a period of 15 min to a stirred solution of N-trityl-

imidazole (4.71 g, 15.8 mmol) in anhydrous THF (180 mL). A solu-

tion of aldehyde 9 (3.58 g, 14.3 mmol) in THF (14 mL) was added

dropwise to this stirred mixture, which was further stirred for 2 h

at 0 °C. The reaction was quenched with ice, the mixture was con-

centrated in vacuo and dissolved in AcOEt (160 mL), and the aque-

ous phase was extracted several times with AcOEt. The combined

organic extracts were dried (MgSO₄) and filtered, and the solvents

were evaporated to dryness. The resulting crude oil (yellow) was

separated by careful column chromatography (AcOEt/cyclohexane,

4:6 then 1:1), which produced two fractions, the first one con-

taining mostly the minor adduct 10 (1.90 g), the second one con-

taining mainly the major adduct 14 (3.66 g).

Imidazolo-D-arabino Derivative 12: A stirred solution of 11 (1.79 g,

2.76 mmol) in EtOH (20 mL) and water (20 mL), containing some

Dowex (50WX8) beads, was heated to 60 °C for 3 h. After filtra-

tion, the resin was washed several times with ether and extracted,

with the aid of ultrasound, with MeOH saturated with ammonia

(3 ϫ 20 mL). The combined extracts were evaporated to dryness

and the residue was purified by chromatography (ether/cyclohex-

ane/MeOHϪNH₃, 20:15:5) to provide compound 12 (702 mg, 69%)

as a colourless powder. A small amount of 12 was recrystallised

(CH₂Cl₂/pentane), m.p. 112Ϫ113 °C, [α]²_D⁰ϭ Ϫ39 (c ϭ 2, MeOH).

1

Ϫ H NMR (CDCl₃): δ ϭ 3.67 (dd, 1 H, 4-H_b), 3.77 (dd, 1 H, 4-

H_a), 3.81 (dd, 1 H, 2-H), 3.89 (ddd, 1 H, 3-H), 4.14 and 4.39 (AB,

J ϭ 11.0, 2 H, OCH₂Ph), 4.48 and 4.56 (AB, J ϭ 11.6, 2 H,

OCH₂Ph), 5.04 (d, 1 H, 1-H), 7.05 (s, 2 H, 4Ј-H and 5Ј-H), 7.15 to

7.33 (m, 10 H, H from phenyl); J_1,2ϭ 3.3, J_2,3ϭ 7.5, J_3,4aϭ 3.6,

Compound 10: ¹H NMR (CDCl₃): δ ϭ 1.22 (s, 3 H, CH₃isoprop.),

1.28 (s, 3 H, CH₃isoprop.), 2.30 (dd, 1 H, 2-H), 3.39 (ddd, 1 H, 3- J_3,4bϭ 4.6, J_4a,4bϭ 11.5. Ϫ ¹³C NMR (CDCl₃): δ ϭ 63.4 (C-4),

H), 3.41 (d, 1 H, OH), 3.66 (t, 1 H, 4-H_b), 3.73 (dd, 1 H, 4-H_a), 71.2 (C-3), 72.7 (OCH₂Ph), 74.2 (OCH₂Ph), 75.4 (C-1), 81.2 (C-2),

4.13 (dd, 1 H, 1-H), 4.26 and 4.34 (AB, J ϭ 10.7, 2 H, OCH₂Ph), 128.1 to 128.6 (C_o,m,pof Ph, C-4Ј and C-5Ј), 137.1 and 137.5 (C_s

6.82 (d, 1 H, 4Ј-H or 5Ј-H), 7.07 (d, 1 H, 4Ј-H or 5Ј-H), 7.11 to

of phenyl), 146.6 (C-2Ј). Ϫ C₂₁H₂₄N₂O₄(368.42): calcd. C 68.46,

7.36 (m, 20 H, CH phenyl); J_1,OHϭ 10.4, J_1,2ϭ 1.3, J_2,3ϭ 3.3, H 6.57, N 7.60; found C 68.4, H 6.5, N 7.6.

J_3,4aϭ 6.6, J_3,4bϭ 8.1, J_4a,4bϭ 8.1, J_4Ј,5Јϭ 1.3.

Imidazolo-D-ribo Derivative 16: The same procedure as above was

1

Compound 14: H NMR (CDCl₃): δ ϭ 0.86 (d, 1 H, OH), 1.26 (s, applied, starting from 15 (4.44 g, 6.82 mmol) in EtOH (40 mL) and

3 H, CH₃isoprop.), 1.36 (s, 3 H, CH₃isoprop.), 3.61 (d, 2 H, 4-H_awater (40 mL), and some Dowex (50WX8) beads. Workup fol-

and 4-H_b), 3.96 (dd, 1 H, 1-H), 4.11 (dd, 1 H, 2-H), 4.47 (td, 1 H, lowed by chromatography as above provided 16 (1.39 g, 55%),

3-H), 4.44 and 4.68 (AB, J ϭ 10.3, 2 H, OCH₂Ph), 6.76 (d, 1 H, which was crystallised (CH₂Cl₂/pentane), m.p. 109Ϫ110 °C. Ϫ

1

4Ј-H or 5Ј-H), 7.05 (d, 1 H, 4Ј-H or 5Ј-H), 7.08 to 7.28 (m, 20 [α]²_D⁰ϭ ϩ65 (c ϭ 2, MeOH). Ϫ H NMR (CDCl₃): δ ϭ 3.31 (ddd,

H, CH phenyl); J_1,OHϭ 4.5, J_1,2ϭ 8.1, J_2,3ϭ 2.2, J_3,4ϭ 7.3,

J_4Ј,5Јϭ 1.3.

1 H, 3-H), 3.59 (dd, 1 H, 4-H_b), 3.71 (dd, 1 H, 4-H_a), 4.05 (dd, 1

H, 2-H), 4.48 and 4.55 (AB, J ϭ 11.7, 2 H, OCH₂Ph), 4.71 and

4.92 (AB, J ϭ 11.0, 2 H, OCH₂Ph), 5.08 (d, 1 H, 1-H), 6.96 (s, 2

Imidazolo-D-arabino Derivative 11: Bu₄NI (catalytic amount, ca.

H, 4Ј-H and 5Ј-H), 7.28 to 7.34 (m, 10 H, H from phenyl); J_1,2

ϭ

15 mg) and NaH (50% in oil) in excess (480 mg, ca 10 mmol) were

added at room temp under argon atmosphere to a stirred solution

of the minor adduct 10 (1.90 g, ca 3.4 mmol) in anhydrous THF

(35 mL). Once hydrogen formation had ceased, BnBr (485 µL,

4.10 mmol) was added, and the mixture was heated at 40 °C for

12 h. MeOH (2 mL) was then added and the resulting clear solu-

tion was evaporated to dryness in vacuum. The residue was dis-

solved in AcOEt (60 mL), and the solution was washed with water

and brine, dried (MgSO₄) and filtered, and the solvents were evap-

orated off. The residue was purified by chromatography (AcOEt/

cyclohexane, 2:8) and compound 11 (1.79 g, overall yield from the

aldehyde 9: 19%) was obtained pure. Ϫ ¹H NMR (CDCl₃): δ ϭ

2.8, J_2,3ϭ 8.8, J_3,4aϭ 3.4, J_3,4bϭ 5.3, J_4a,4bϭ 11.3. Ϫ ¹³C NMR

(CDCl₃): δ ϭ 63.7 (C-4), 70.4 (C-3), 71.6 (OCH₂Ph), 75.4

(OCH₂Ph), 76.4 (C-1), 81.1 (C-2), 127.6 to 128.6 (C_o,m,pof phenyl,

and C-4Ј and C-5Ј), 137.8 and 138.1 (C_sof phenyl), 145.7 (C-2Ј).

Ϫ C₂₁H₂₄N₂O₄(368.42): calcd. C 68.46, H 6.57, N 7.60; found C

68.4, H 6.6, N 7.6.

Imidazolo-D-arabino-piperidinose Derivative 13: DMAP (catalytic

amounts, ca. 5 mg) and TsCl (355 mg, 1.86 mmol, 2.7 equiv.) were

added at 0 °C to a stirred solution of 12 (254 mg, 0.69 mmol) and

freshly distilled Et₃N (265 µL, 1.86 mmol, 2.7 equiv.) in CH₂Cl₂

(11 mL). After 24 h stirring at 0 °C, the reaction was quenched

Eur. J. Org. Chem. 2001, 4111Ϫ4125

4119

F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

with H₂O (5 mL) and the aqueous phase was extracted with Workup and separation by chromatography followed by lyophilis-

FULL PAPER

CH₂Cl₂. The combined organic solutions were evaporated to give

ation gave 4 (50 mg, 69%) as a colourless crystalline powder.

a crude mixture, which was dissolved in MeOH (9 mL) and 2  M.p._dec190 °C. ؊ [α]²_D⁰ϭ Ϫ32 (c ϭ 1, H₂O). Ϫ CD (H₂O): Fig-

1

NaOH (10 mL). The resulting solution was stirred for 12 h at room ure 1. Ϫ H NMR (CD₃OD, 400 MHz): δ ϭ 4.04 (dd, 1 H, 5-H_b),

temp., and then diluted with H₂O (30 mL) and extracted with 4.07 (dd, 1 H, 5-H_a), 4.12 (dd, 1 H, 7-H), 4.17 (ddd, 1 H, 6-H),

CH₂Cl₂. The combined organic solutions were dried (MgSO₄) and

the solvents were evaporated off. The crude residue was purified by

4.71 (d, 1 H, 8-H), 6.97 (d, 1 H, 2-H or 3-H), 6.98 (d, 1 H, 2-H or

3-H); J_5a,5bϭ 12.0, J_5a,6ϭ 5.3, J_5b,6ϭ 7.7, J_6,7ϭ 1.8, J_7,8ϭ 3.9,

chromatography (CHCl₃/THF/MeOHϪNH₃, 6:3.5:0.5) and pro- J_2,3ϭ 1.2. Ϫ ¹³C NMR (CD₃OD, 100.6 MHz): δ ϭ 48.0 (C-5),

vided crystalline compound 13 (110 mg, 45%), m.p. 115Ϫ117 °C

66.9 (C-8), 68.5 (C-6), 72.1 (C-7), 120.0 (C-3), 129.2 (C-2), 147.1

(toluene). Ϫ [α]²_D⁰ϭ Ϫ63 (c ϭ 2, CHCl₃). Ϫ ¹H NMR (CDCl₃): (C-8a). Ϫ HR-MS [M ϩ H]^ϩ(C₇H₁₁O₃N₂): calcd. 171.0770;

δ ϭ 2.36 (sl, 1 H, OH), 3.94 (dd, 1 H, 5-H_b), 4.05 (dd, 1 H, H-7), found 171.0771.

4.14 (dd, 1 H, 5-H_a), 4.53 (ddd,1 H, 6-H), 4.54 and 4.70 (AB, J ϭ

Coupling Reaction Between a Lithio-imidazole and L-Erythrose De-

11.8, OCH₂Ph), 4.75 and 4.92 (AB, J ϭ 11.9, OCH₂Ph), 4.78 (d, 1

H, 8-H), 6.84 (d, 1 H, 3-H), 7.10 (d, 1 H, 2-H), 7.20 to 7.37 (m, 10

H, CH phenyl); J_2,3ϭ 1.3, J_5a,5bϭ 12.0, J_5a,6ϭ 5.8, J_5b,6ϭ 8.9,

J_6,7ϭ 2.4, J_7,8ϭ 3.9. Ϫ ¹³C NMR (CDCl₃): δ ϭ 46.7 (C-5), 64.8

(C-6), 70.0 (C-8), 71.7 (OCH₂Ph), 72.5 (OCH₂Ph), 78.7 (C-7), 119.0

(C-3), 127.7 to 128.6 (C_o,m,pof phenyl), 129.6 (C-2), 137.4 and 138.0

(C_sof phenyl), 142.4 (C-8a). Ϫ HR-MS [M ϩ H]^ϩ(C₂₁H₂₃N₂O₃):

calcd. 351.1709; found 351.1711.

rivative ent-9: (Scheme 3). Ϫ The same procedure as used for the

preparation of 9 was applied, starting from N-trityl-imidazole

(6.69 g, 21.6 mmol) in THF (300 mL) and a solution of BuLi in

hexane (1.6 , 14.7 mL, 23.5 mmol, 1.2 equiv.), under argon atmo-

sphere. Aldehyde ent-9^[11](4.91 g, 19.6 mmol) in anhydrous THF

(20 mL) was added slowly and the reaction mixture was stirred for

1 h at 0 °C. After workup and chromatography (AcOEt/ cyclohex-

ane, 4:6, then 1:1), two fractions were obtained, the first one con-

taining mainly adduct ent-10 (minor and less polar compound,

2.23 g) and the second one adduct ent-14 (major and more polar

compound, 8.35 g). Each of the two fractions was used for benzyl-

ation without further purification.

D-ribo-Imidazolo-piperidinose Derivative 17: The same procedure as

above was applied, starting from 16 (400 mg, 1.08 mmol), Et₃N

(415 µL, 2.93 mmol, 2.7 equiv.), DMAP (ca. 15 mg) and TsCl

(516 mg, 2.71 mmol, 2.5 equiv.), in CH₂Cl₂(20 mL) under argon.

The crude di-tosyl ester in MeOH (13 mL) solution was treated as

above with 2  NaOH (14 mL). Workup and separation by chro-

matography provided 17 (176 mg, 46%) as colourless crystals. Ϫ

The ¹H NMR and ¹³C NMR spectra of ent-10 and ent-14 were

superimposable on those of 10 and 14, respectively.

1

M.p. 128 Ϫ129 °C. Ϫ [α]²_D⁰ϭ ϩ115 (c ϭ 2, CHCl₃). Ϫ H NMR

Imidazolo L-arabino Derivative ent-11: The same procedure as for

(C₆D₆): δ ϭ 2.95 (dd, 1 H, 5-H_b), 3.19 (dd, 1 H, 7-H), 3.75 (dd, 1

H, 5-H_a), 4.03 (sl, 1 H, OH), 4.23 and 4.41 (AB, J ϭ 12.0,

OCH₂Ph), 4.55 (m, 1 H, 6-H), 4.82 (dd, 1 H, 8-H), 4.89 and 4.98

(AB, J ϭ 12.1, OCH₂Ph), 6.29 (d, 1 H, 3-H), 7.04 to 7.48 (m, 11

H, CH phenyl and 2-H); J_2,3ϭ 1.1, J_5a,5bϭ 12.9, J_5a,6ϭ 2.8,

J_5b,6ϭ 3.8, J_6,7ϭ 2.3, J_6,8ϭ 1.1, J_7,8ϭ 3.8. Ϫ ¹³C NMR (C₆D₆):

δ ϭ 50.6 (C-5), 67.2 (C-6), 69.6 (C-8), 70.4 (OCH₂Ph), 71.3

(OCH₂Ph), 75.8 (C-7), 119.3 (C-3), 127.7 to 129.0 (C_o,m,pof

phenyl), 130.2 (C-2), 138.1 and 138.5 (C_sof Ph), 142.9 (C-8a). Ϫ

C₂₁H₂₂N₂O₃(350.40): calcd. C 71.98, H 6.33, N 8.00; found C 71.9,

H 6.4, N 8.0

the preparation of 11 was used, starting from ent-10 (2.23 g) in

anhydrous THF (60 mL), a catalytic amount of Bu₄NI (10 mg) and

a 50% suspension of NaH in oil (760 mg, ca. 16 mmol). After 15

min, H₂evolution had ceased, the reaction mixture was heated at

40 °C, BnBr (1.3 mL, 11.0 mmol) was added and the solution was

stirred at 40 °C for 12 h. After workup and chromatography (Ac-

OEt/cyclohexane, 2:8), ent-11 was obtained (1.98 g, 16% overall

yield from aldehyde ent-9) as a solid beige foam. Its ¹H NMR spec-

trum was superimposable on that of 11.

Imidazolo L-ribo Derivative ent-15: The same procedure as for the

preparation of 11 (see above) was used, starting from impure ent-

14 (8.35 g) in THF (100 mL), Bu₄NI (catalytic amount), NaH (ca

50% in oil) (2.1 g, ca. 44 mmol) and BnBr (3.4 mL, 29 mmol). After

workup and purification by chromatography, compound ent-15

(6.85 g, 54% overall yield from aldehyde ent-9) was obtained as a

solid beige foam. Its ¹H NMR spectrum was superimposable on

that of 15.

D-arabino-Imidazolo-piperidinose (3): A stirred solution of 13

(97 mg, 0.277 mmol) in AcOH (19 mL) was placed under H₂atmo-

sphere (1 bar) at room temp. in the presence of Pd(OH)₂/C

(‘‘Pearlman’s catalyst’’, 100 mg). After 24 h the suspension was

centrifuged and the catalyst was washed several times with AcOH.

The solution was evaporated to dryness in vacuum, the residue was

dissolved in MeOH and the resulting solution was percolated

through Amberlist IRA 400 (OH^Ϫ) beads to eliminate residual

AcOH. The solution was evaporated to dryness and separated by

chromatography (CHCl₃/MeOH/NH₄OH_aq, 7:2.5:0.5); a second

chromatographic separation (AcOEt/MeOH, 7:3) was necessary,

giving compound 3 (21.5 mg, 45%) in crystalline form. Ϫ M.p._dec

157Ϫ158 °C. Ϫ [α]²_D⁰ϭ Ϫ23 (c ϭ 1, H₂O). Ϫ CD (H₂O): Figure 1.

Imidazolo L-arabino Derivative ent-12:- The same procedure as for

the preparation of 12 was used, starting from ent-11 (1.98 g,

3.00 mmol) in EtOH/H₂O, 1:1 (60 mL) containing some Dowex

(50WX8) beads. After workup and chromatography (CHCl₃/THF/

MeOHϪNH₃, 6:3.5:0.5), ent-12 (930 mg, 83%) was obtained as a

colourless solid, which was recrystallised. M.p. 111Ϫ113 °C (tolu-

ene). Ϫ [α]²_D⁰ϭ ϩ38 (c ϭ 2, MeOH) (12: [α]²_D⁰ϭ Ϫ39, see above).

Its ¹H NMR and ¹³C NMR spectra were superimposable on those

of 12. Ϫ HR-MS [M ϩ H]^ϩ(C₂₁H₂₅N₂O₄): calcd. 369.1816;

found 369.1817.

1

Ϫ H NMR (CD₃OD, 400 MHz): δ ϭ 3.97 (dd, 1 H, 5-H_b), 4.00

(dd, 1 H, 7-H), 4.13 (dd, 1 H, 5-H_a), 4.38 (ddd, 1 H, 6-H), 4.71 (d,

1 H, 8-H), 6.98 (s, 2 H, 2-H and 3-H); J_5a,5bϭ 12.3, J_5a,6ϭ 5,

J_5b,6ϭ 7.7, J_6,7ϭ 2.1, J_7,8ϭ 5.1. Ϫ ¹³C NMR (CD₃OD,

100.6 MHz): δ ϭ 47.8 (C-5), 66.7 (C-6), 67.8 (C-8), 74.4 (C-7),

120.2 (C-3), 129.3 (C-2), 146.4 (C-8a). Ϫ HR-MS [M ϩ H]^ϩ

(C₇H₁₁O₃N₂): calcd. 171.0770; found 171.0772.

Imidazolo L-ribo Derivative ent-16: The same procedure as above

was used, starting from ent-15 (6.85 g, 10.5 mmol) in EtOH/H₂O,

1:1 (140 mL), and some Dowex (50WX8) beads. Workup pro-

vided ent-16 (3.37 g, 87%) as a colourless solid, which was recrys-

tallised. M.p. 111Ϫ112 °C (toluene). Ϫ [α]²_D⁰ϭ Ϫ68 (c ϭ 2, MeOH)

D-ribo-Imidazolo-piperidinose (4): The same procedure as above was

applied, starting from 17 (150 mg, 0.428 mmol) and Pd(OH)₂/C

(150 mg) in AcOH (28 mL) under H₂atmosphere (1 bar) for 15 h. (16: [α]²_D⁰ϭ ϩ65, see above). Ϫ Its ¹H NMR and ¹³C NMR spectra

4120

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

were superimposable on those of 16. Ϫ HR-MS: [M ϩ H]^ϩdiluted with DMF (6 mL). Excess CH₂Cl₂was evaporated in va-

FULL PAPER

(C₂₁H₂₅N₂O₄): calcd. 369.1816; found 369.1816.

cuum at room temp., NaNO₂(1.02 g, 14.8 mmol, 5.0 equiv.) was

added, the resulting mixture was stirred for 1 h at room temp., the

salt that precipitated was filtered, the filtrate was evaporated in

vacuum to dryness, and the crude residue was separated by chro-

matography (AcOEt/cyclohexane, 3:7). Compound 18 (4.53 g, 74%)

was obtained as a pale yellow oil. Ϫ [α]²_D⁰ϭ Ϫ21 (c ϭ 2, CHCl₃).

Ϫ ¹H NMR (CDCl₃): δ ϭ 1.30 (t, J ϭ 7.0, 3 H, CH₂CH₃), 1.34 (s,

3 H, CH₃isopr.), 1.41 (s, 3 H, CH₃isopr.), 2.98 (d, 1 H, OH), 4.00

(dd, 1 H, 4-H_b), 4.08 (dd, 1 H, 4-H_a), 4.09 (dd, 1 H, 2-H), 4.27 (q,

J ϭ 7.0, 1 H, CHHЈCH₃), 4.28 (q, J ϭ 7.0, 1 H, CHHЈCH₃), 4.37

(td, 1 H, 3-H); J_2,OHϭ 7.9, J_2,3ϭ 2.7, J_3,4aϭ 6.7, J_3,4bϭ 7.0,

L

-arabino-Imidazolo-piperidinose Derivative ent-13: The same pro-

cedure as for 13 (see above) was used, starting from ent-12 (267 mg,

0.72 mmol), freshly distilled Et₃N (400 µL, 2.88 mmol, 4.0 equiv.),

DMAP (8 mg, 0.07 mmol, 0.1 equiv.) and TsCl (410 mg,

2.16 mmol, 3.0 equiv.) in anhydrous CH₂Cl₂(15 mL), followed by

treatment with 2  aq. NaOH/MeOH, 1:1 (10 mL). Workup fol-

lowed by chromatography as above for 13 provided ent-13 (173 mg,

68%) as a colourless oil, which was crystallised. Ϫ M.p. 117Ϫ118

°C (toluene). Ϫ [α]²_D⁰ϭ ϩ63.5 (c ϭ 2, CHCl₃) (13: [α]²_D⁰ϭ Ϫ63, see

above). Ϫ Its ¹H NMR and ¹³C NMR spectra were superimposable

on those of 13. HR-MS: [M ϩ H]^ϩ(C₂₁H₂₃N₂O₃): calcd. 351.1709;

found 351.1706. Ϫ C₂₁H₂₂N₂O₃(350.42): calcd. C 71.98, H 6.33,

N 7.99; found C 72.1, H 6.3, N 7.9.

J

_4a,4bϭ 8.2. Ϫ ¹³C NMR (CDCl₃): δ ϭ 14.1 (CH₂CH₃), 25.3 (CH₃

isopr.), 26.1 (CH₃isopr.), 62.0 (CH₂CH₃), 65.6 (C-4), 70.3 (C-2),

76.3 (C-3), 109.9 [C(CH₃)₂], 172.1 (C-1). The ¹H NMR and ¹³C

NMR spectra were identical to those of the -ethyl threonate en-

antiomer described in the literature.^[13]Ϫ C₉H₁₆O₅(204.22): calcd.

C 52.93, H 7.90; found C 52.7, H 7.5.

L

-ribo-Imidazole-piperidinose Derivative ent-17: A solution of ent-

16 (100 mg, 0.27 mmol), Et₃N (80 µL, 0.57 mmol, 2.1 equiv.),

Bu₂SnO (ca. 3 mg) as catalyst and TsCl (114 mg, 0.59 mmol, 2.2

equiv.) in anhydrous CH₂Cl₂(6 mL) was stirred for 12 h at room

temp. The mixture was diluted with CH₂Cl₂(20 mL), washed with

a saturated aq. solution of NH₄Cl (20 mL), and concentrated in

vacuo without being dried. The resulting residue was added as a

suspension to a 2  NaOH/MeOH (1:1) solution (20 mL), stirred

for 8 h at room temp., diluted with H₂O (30 mL) and extracted

with CHCl₃(3 ϫ 30 mL). The combined organic solutions were

dried (MgSO₄) and filtered and the solvents were evaporated off in

vacuo. The crude residue was purified by chromatography (CH₂Cl₂/

MeOHϪNH₃, 98:2) to give ent-17 (91 mg, 95%) as a colourless

Ethyl D-Threonate Derivative 19: A mixture of freshly prepared an-

hydrous Ag₂O (26.72 g, 114.9 mmol, 1.5 equiv.), powdered molecu-

˚

lar sieves (4A, 21 g) and KI (687 mg, 4.14 mmol, 0.05 equiv.) was

heated under vacuum at 300 °C. After this had cooled to room

temp., a solution of 18 (15.66 g, 76.7 mmol) in anhydrous toluene

(150 mL) was added and the mixture was heated at 50 °C. BnBr

(10.5 mL, 82.2 mmol, 1.15 equiv.) was added, and the stirred solu-

tion was heated to reflux for 1 h and left to cool to room temp. The

suspension was filtered and the solids were washed with AcOEt

(300 mL). The combined organic solutions were evaporated to dry-

ness in vacuo and the residue was separated by chromatography

(AcOEt/cyclohexane, 1:9). Compound 19 (13.32 g, 77%) was ob-

tained as a pale yellow oil. Ϫ [α]²_D⁰ϭ Ϫ54 (c ϭ 2, CHCl₃) (see also

ent-19: [α]²_D⁰ϭ ϩ59 (c ϭ 2, CHCl₃), cf. ref.^[11]). Ϫ ¹H NMR

(CDCl₃): δ ϭ 1.29 (t, J ϭ 7.1, 3 H, CH₂CH₃), 1.35 (s 3 H, CH₃

isopr.), 1.39 (s, 3 H, CH₃isopr.), 3.95 (dd, 1 H, 4-H_b), 3.98 (d, 1

H, 2-H), 4.01 (dd, 1 H, 4-H_a), 4.22 (q, J ϭ 7.1, 2 H, CH₂CH₃),

4.39 (q, 1 H, 3-H), 4.52 and 4.78 (AB, J ϭ 11.9, 2 H, OCH₂Ph),

solid, which was recrystallised. M.p. 130 °C (toluene). Ϫ [α]²_D⁰

ϭ

1

Ϫ123 (c ϭ 2, CHCl₃) (17: [α]²_D⁰ϭ ϩ115, see above). Its H NMR

and ¹³C NMR spectra were superimposable on those of 17. Ϫ

C₂₁H₂₂N₂O₃(350.42): calcd. C 71.98, H 6.33, N 7.99; found C

72.0, H 6.2, N 7.8.

L

-arabino-Imidazole-piperidinose (ent-3): A stirred solution of ent-

13 (147 mg, 0.42 mmol) in MeOH (5 mL) was placed under H₂

atmosphere (30 bar) at room temp. in the presence of moist 10%

Pd/C (containing 50% water). After 8 days, the suspension was

centrifuged and the catalyst was washed several times with warm

MeOH. The combined organic fractions were evaporated to dry-

ness and the residue was purified by chromatography (AcOEt/

MeOH, 7:3) to give ent-3 (45 mg, 63%) as a pale yellow powder

after lyophilization. Recrystallisation from H₂O provided some

monocrystals, one of which was used for X-ray diffraction analysis

(Figure 3). Ϫ M.p._dec.120Ϫ125 °C. ؊ [α]²_D⁰ϭ ϩ28 (c ϭ 1, H₂O).

Ϫ CD (H₂O): Figure 1. Ϫ ¹H NMR and ¹³C NMR spectra were

superimposable on those of 3. Ϫ HR-MS [M ϩ H]^ϩ(C₇H₁₁N₂O₃):

calcd. 171.0770; found 171.0772.

7.28 to 7.38 (m, 5 H, H of phenyl); J_2,3ϭ 5.9, J_3,4aϭ 6.5, J_3,4b

ϭ

6.4, J_4a,4bϭ 8.7. Ϫ ¹³C NMR (CDCl₃): δ ϭ 14.2 (CH₂CH₃), 25.3

(CH₃isopr.), 26.3 (CH₃isopr.), 61.2 (CH₂CH₃), 65.5 (C-4), 72.8

(OCH₂Ph), 75.9 (C-3), 78.6 (C-2), 109.9 [C(CH₃)₂], 128.0 to 128.4

(C_o,m,pof phenyl), 137.1 (C_sof phenyl), 170.1 (C-1).

D-Threose Derivative 20: A solution of DIBAH (1.2 , 28.3 mL,

34.0 mmol, 2.5 equiv.) in toluene was added dropwise at Ϫ78 °C

to a stirred solution of 19 (4.00 g, 13.6 mmol) in anhydrous toluene

(92 mL). After ca. 1 h, excess DIBAH was slowly neutralised with

MeOH (ca. 40 mL), and the solution was allowed to warm to room

temperature. The solution was treated sequentially with saturated

aq. Seignette salt (K and Na tartrate) solution (3 mL) and some

brine (6 mL), resulting in the precipitation of aluminium salts,

which were filtered and washed with AcOEt. The stirred filtrates

were dried (MgSO₄) and filtered and the solvents were removed.

The resulting syrup was dissolved in anhydrous toluene and the

solution was concentrated in vacuo; this procedure was repeated

three times in order to obtain the free aldehyde instead of the hy-

drate. The final syrup was placed under vacuum over fresh P₂O₅in

L

-ribo-Imidazole-piperidinose (ent-4): The same procedure as above

was used, starting from ent-17 (281 mg, 0.88 mmol) and moist 10%

Pd/C (containing 50% water). After 4 days at room temp., workup

as above provided ent-4 (92 mg, 68%) as colourless crystals. M.p._dec.

215 °C. Ϫ [α]²_D⁰ϭ ϩ32 (c ϭ 1, H₂O). Ϫ CD (H₂O): Figure 1. Ϫ

The ¹H NMR and ¹³C NMR spectra were superimposable on those

of 4. Ϫ HR-MS [M ϩ H]^ϩ(C₇H₁₁N₂O₃): calcd. 171. 0770; found

171.0770.

a dessicator for 20 h to yield 20 as a yellow oil (3.39 g, quant. yield).

1

Ethyl

equiv.) was added slowly at Ϫ10 °C to a stirred solution of 7

(6.12 g, 30 mmol)^[12,13]and anhydrous pyridine (3.63 mL, 45 mmol, H, 4-H_a), 4.38 (q, 1 H, 3-H), 4.66 and 4.79 (AB, J ϭ 11.9, 2 H,

1.5 equiv.) in anhydrous CH₂Cl₂(140 mL). After 1 h at room temp., OCH₂Ph), 7.34 to 7.38 (m, 5 H, H of phenyl), 9.72 (d, 1 H, 1-H);

some H₂O was added and the solution was extracted with CH₂Cl₂. J_1,2ϭ 1.5, J_2,3ϭ 5.4, J_3,4aϭ 6.6, J_3,4bϭ 5.9, J_4a,4bϭ 8.8. Ϫ ¹³C

D-Threonate Derivative 18: Tf₂O (6.43 mL, 39 mmol, 1.3 Ϫ H NMR (CDCl₃): δ ϭ 1.35 (s, 3 H, CH₃isopr.), 1.43 (s, 3 H,

CH₃isopr.), 3.86 (dd, 1 H, 2-H), 3.95 (dd, 1 H, 4-H_b), 4.06 (dd, 1

The combined organic solutions were evaporated to ca. 5 mL and

NMR (CDCl₃): δ ϭ 25.1 (CH₃isopr.), 26.1 (CH₃isopr.), 65.3 C-

Eur. J. Org. Chem. 2001, 4111Ϫ4125

4121

F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

FULL PAPER

4), 73.3 (OCH₂Ph), 75.3 (C-3), 82.8 (C-2), 109.8 [C(CH₃)₂], 128.1 to 130.1 (C_o,m,pof phenyl), 138.7 and 138.8 (2 ϫ C_sof phenyl),

to 128.6 (C_o,m,pof phenyl), 136.9 (C_sof phenyl), 202.1 (C-1). 142.4 (3 ϫ C_sof phenyl), 147.6 (C-2Ј).

Coupling Reaction Between a Lithio-imidazole and D-Threose Deriv-

Imidazolo-D-xylo Derivative 23: A stirred solution of 22 (3.30 g,

ative 20: (Scheme 4). A similar procedure to that used for the coup-

ling reaction with aldehyde 9 (see above) was employed, starting

from N-trityl-imidazole (5.61 g, 18.1 mmol) in anhydrous THF

(225 mL) under argon atmosphere at Ϫ5 °C, with a solution of

BuLi in hexane (1.6 , 12.3 mL, 19.7 mmol, 1.2 equiv.) and alde-

hyde 20 (4.11 g, 16.4 mmol) in THF (10 mL). After workup and

chromatography (AcOEt/cyclohexane, 7:3), an impure fraction

containing mainly 21 (2.68 g) was obtained, followed by a second

fraction containing 25 (2.29 g) and some N-trityl-imidazole. The

two fractions were benzylated separately without further purifica-

tion. This coupling reaction was not optimised.

5.06 mmol) in HCl (4 , 19 mL) was heated at reflux for 4 h. The

mixture was cooled to room temp., then washed twice with Et₂O.

The organic fractions were extracted with HCl (2 , 30 mL). The

combined acidic aqueous fractions were basified (aq. K₂CO₃) to

pH ϭ 10 and extracted with CH₂Cl₂. The combined organic frac-

tions were dried (MgSO₄) and filtered, and the solvents were evap-

orated. The crude residue was purified by chromatography (CHCl₃/

THF/MeOHϪNH₃, 6:3.5:0.5) to provide 23 (1.69 g, 91%) as a crys-

talline compound. M.p. 103Ϫ104 °C (EtOH/H₂O, 7:3). Ϫ [α]²_D⁰

ϭ

ϩ51 (c ϭ 2, MeOH). Ϫ ¹H NMR (CDCl₃): δ ϭ 2.57 (sl, 1 H, OH),

3.51 (dd, 1 H, 4-H_b), 3.60 (dd, 1 H, 4-H_a), 3.74 (m, 1 H, 3-H), 3.77

(1 H, 2-H), 4.46 and 4.54 (AB, J ϭ 11.6, 2 H, OCH₂Ph), 4.49 and

4.56 (AB, J ϭ 11.2, 2 H, OCH₂Ph), 4.96 (d, 1 H, 1-H), 7.03 (sl, 2

H, 4Ј-H and 5Ј-H), 7.21 to 7.37 (m, 10 H, H of phenyl), 9.79 (sl, 1

H, N-H). Ϫ ¹³C NMR: δ ϭ 63.5 (C-4), 71.3 (C-3), 72.4 (OCH₂Ph),

74.6 (OCH₂Ph), 76.7 (C-1), 81.2 (C-2), 116.2 (C-4Ј and C-5Ј), 128.1

to 128.6 (C_o,m,pof phenyl), 137.1 and 137.6 (2 ϫ C_sof phenyl),

145.7 (C-2Ј). Ϫ C₂₁H₂₄N₂O₄ϩ 1/2 H₂O (377.44): calcd. C 66.83,

H 6.68, N 7.42; found C 66.8, H 6.6, N 7.5.

Compound 21: ¹H NMR (CDCl₃): δ ϭ 1.21 (s, 3 H, CH₃isopr.),

1.24 (s, 3 H, CH₃isopr.), 2.53 (dd, 1 H, 2-H), 2.88 (d, 1 H, OH),

3.08 (t, 1 H, 4-H_b), 3.45 (dd, 1 H, 4-H_a), 3.79 (q, 1 H, 3-H), 4.12

(dd, 1 H, 1-H), 4.43 and 4.49 (AB, J ϭ 11.3, OCH₂Ph), 6.80 (d, 1

H, 4Ј-H or 5Ј-H), 7.08 (d, 1 H, 4Ј-H or 5Ј-H), 7.13 to 7.35 (m, 20

H, H of phenyl); J_1,OHϭ 8.5, J_1,2ϭ 3.2, J_2,3ϭ 6.4, J_3,4aϭ 6.4,

J_3,4bϭ 7.9, J_4a,4bϭ 8.1, J_4Ј,5Јϭ 1.4.

1

Compound 25: H NMR (CDCl₃): δ ϭ 0.82 (d, 1 H, OH), 1.30 (s,

Imidazolo-D-lyxo Derivative 27: The same procedure as above was

6 H, 2 ϫ CH₃isopr.), 3.69 (dd, 1 H, 4-H_b), 3.86 (dd, 1 H, 4-H_a),

3.92 (dd, 1 H, 2-H), 4.22 (q, 1 H, 3-H), 4.24 (dd, 1 H, 1-H), 4.54

and 4.63 (AB, J ϭ 10.2, OCH₂Ph), 6.82 (d, 1 H, 4Ј-H or 5Ј-H),

used, starting from 26 (3.36 g, 5.17 mmol) in HCl (4 , 20 mL) at

reflux. Workup provided 27 (1.385 g, 73%) as a colourless foam,

which was recrystallised. M.p._dec.161 °C (EtOH/H₂O, 7:3). Ϫ

7.07 to 7.35 (m, 21 H, H of phenyl, and 4Ј-H or 5Ј-H); J_1,OH

ϭ

1

[α]²_D⁰ϭ Ϫ34 (c ϭ 2, MeOH). Ϫ H NMR (CDCl₃): δ

؍

3.53 (d, 2

4.2, J_1,2ϭ 8.3, J_2,3ϭ 5.9, J_3,4aϭ 6.6, J_3,4bϭ 7.1, J_4a,4bϭ 8.7,

J_4Ј,5Јϭ 1.3.

H, 4-H_aand 4-H_b), 3.66 (q, 1 H, 3-H), 4.05 (dd, 1 H, H-2), 4.47

and 4.53 (AB, J ϭ 11.6, OCH₂Ph), 4.59 and 4.70 (AB, J ϭ 11.2, 2

H, OCH₂Ph), 4.87 (d, 1 H, H-1), 7.01 (s, 2 H, 4Ј-H and 5Ј-H), 7.24

to 7.35 (m, 10 H, CH phenyl); J_1,2ϭ 3.3, J_2,3ϭ 4.8, J_3,4ϭ4.7. Ϫ

¹³C NMR (CDCl₃): δ ϭ 62.1 (C-4), 71.0 (C-3), 71.6 (OCH₂Ph),

74.7 (OCH₂Ph), 75.5 (C-1), 81.1 (C-2), 127.7 to 128.5 (C_o,m,pof

phenyl), 137.3 and 137.7 (2 ϫ C_sof phenyl), 145.8 (C-2Ј). Ϫ

C₂₁H₂₄N₂O₄(368.43): calcd. C 68.46, H 6.57, N 7.60; found C 68.6,

H 6.5, N 7.7.

Imidazolo-D-xylo Derivative 22: The same procedure as for the pre-

paration of 11 was used, starting from impure adduct 21 (2.68 g) in

anhydrous THF (50 mL) under argon atmosphere, with a catalytic

amount of Bu₄NI (ca. 20 mg), NaH (ca 50% in oil, 810 mg, ca.

17 mmol), and BnBr (1.1 mL, 9.6 mmol). After workup and chro-

matography (AcOEt/cyclohexane, 1:9), 22 (1.53 g, overall yield

1

from aldehyde 20: 14%) was isolated as a beige foam. Ϫ H NMR

(CDCl₃): δ ϭ 1.27 (s, 6 H, 2 ϫ CH₃isoprop.), 3.38 (m, 3 H, 3-H,

4-H_aand 4-H_b), 3.74 (t, 1 H, 2-H), 3.79 and 4.22 (AB, 2 H, J ϭ

11.7, 2 H, OCH₂Ph), 4.16 (d, 1 H, 1-H), 4.65 (s, 2 H, OCH₂Ph),

6.89 (d, 1 H, 4Ј-H or 5Ј-H), 7.08 to 7.27 (m, 26 H, H of phenyl,

and 4Ј-H or 5Ј-H); J_1,2ϭ 5.8, J_2,3ϭ 5.8, J_4Ј,5Јϭ 1.4. Ϫ ¹³C NMR

(CDCl₃): δ ϭ 26.2 (CH₃isoprop.), 26.9 (CH₃isoprop.), 66.7 (C-4),

70.2 (OCH₂Ph), 73.7 (C-1), 73.9 (OCH₂Ph), 75.7 [C(Ph)₃], 77.2 (C-

3), 80.2 (C-2), 108.5 [C(CH₃)₃], 123.0 (C-4Ј), 126.0 (C-5Ј), 126.7 to

130.0 (C_o,m,pof phenyl), 139.0 (C_sof phenyl), 139.1 (C_sof phenyl),

142.4 (3 ϫ C_sphenyl), 146.3 (C-2Ј).

D

-xylo-Imidazolo-piperidinose Derivative 24: Bu₂SnO (catalytic

amounts, ca. 5 mg) and TsCl (194 mg, 1.02 mmol, 2.5 equiv.) were

added at room temp. to a stirred solution of 23 (150 mg,

0.40 mmol) and Et₃N (170 µL; 1.22 mmol; 3.0 equiv.) in anhydrous

CH₂Cl₂(9 mL). After 12 h at room temp., the reaction mixture was

diluted with CH₂Cl₂(30 mL), washed with a saturated aqueous

solution of NH₄Cl (40 mL), evaporated to near dryness in vacuum

and taken up in 2  NaOH/MeOH (1:1, 20 mL), and the resulting

reaction mixture was stirred for 12 h at room temp. The solution

was diluted with water (30 mL) and extracted several times with

CH₂Cl₂. The organic solution was dried (MgSO₄) and filtered, and

Imidazolo-D-lyxo Derivative 26: The same procedure as above was

used, starting from impure adduct 25 (2.29 g), Bu₄NI (20 mg) in the solvents were removed. The crude residue was purified by chro-

THF (40 mL), NaH (ca. 50% in oil, 680 mg, ca. 14 mmol), and matography (Et₂O/MeOHϪNH₃, 98:2) to provide 24 (124 mg,

BnBr (0.97 mL, 8.1 mmol). Workup as above followed by chroma-

tography provided 26 (1.94 g, overall yield from the aldehyde 20: Ϫ [α]²_D⁰ϭ ϩ31 (c ϭ 2, CHCl₃). Ϫ H NMR (C₆D₆): δ ϭ 3.62 (dd,

18%) as a colourless foam. Ϫ ¹H NMR (CDCl₃): δ ϭ 1.28 (s, 3 H,

1 H, 5-H_b), 3.73 (dd, 1 H, 5-H_a), 3.93 (dd, 1 H, H-7), 3.96 (m, 1

CH₃isoprop.), 1.31 (s, 3 H, CH₃isoprop.), 3.65 (dd, 1 H, 4-H_b), H, 6-H), 4.11 and 4.27 (AB, J ϭ 11.9, 2 H, OCH₂Ph), 4.84 (d, 1

3.84 and 4.01 (AB, J ϭ 12.5, 2 H, OCH₂Ph), 3.90 (d, 1 H, 4-H_a), H, 8-H), 4.89 and 4.99 (AB, J ϭ 11.9, OCH₂Ph), 6.34 (d, 1 H, 3-

87%) as a crystalline solid. M.p. 101Ϫ101.5 °C (EtOH/H₂O, 7:3).

1

4.02 (dd, 1 H, 2-H), 4.25 (td, 1 H, 3-H), 4.34 (d, 1 H, 1-H), 4.45 H), 6.97 to 7.16 (m, 8 H, CH phenyl), 7.26 (d, 1 H, H-2), 7.31 to

and 4.59 (AB, J ϭ 10.4, 2 H, OCH₂Ph), 6.85 (d, 1 H, 4ЈH or 5Ј- 7.35 (m, 2 H, CH phenyl); J_2,3ϭ 1.1, J_5a,5bϭ 12.7, J_5a,6ϭ 3.0,

H), 7.02 to 7.32 (m, 26 H, H of phenyl, and 4Ј-H or 5Ј-H); J_1,2

8.1, J_2,3ϭ 5.0, J_3,4aϭ 6.4, J_3,4bϭ 7.6, J_4a,4bϭ 8.2, J_4Ј,5Јϭ 1.4. Ϫ (C-5), 66.6 (C-6), 71.0 (C-8), 71.7 (OCH₂Ph), 72.5 (OCH₂Ph), 75.8

¹³C NMR: δ ϭ 25.8 (CH₃isoprop.), 26.4 (CH₃isoprop.), 66.6 (C-

(C-7), 119.5 (C-3), 127.8 to 128.5 (C_o,m,pof phenyl), 129.1 (C-2),

ϭ

J_5b,6ϭ 3.0, J_6,7ϭ 5.1, J_7,8ϭ 3.4. Ϫ ¹³C NMR (CDCl₃): δ ϭ 48.8

4), 68.9 (OCH₂Ph), 72.9 (C-1), 74.9 (OCH₂Ph), 75.8 [C(Ph)₃], 76.9 137.1 and 137.2 (2 ϫ C_sof phenyl), 141.4 (C-8a). Ϫ C₂₁H₂₂N₂O₃

(C-3), 80.8 (C-2), 108.5 [C(CH₃)₂], 123.1 (C-4Ј), 125.4 (C-5Ј), 126.7 (350.42): calcd. C 71.98, H 6.33, N 7.99; found C 71.9, H 6.2, N 8.1.

4122

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

-lyxo-Imidazolo-piperidinose Derivative 28: The same procedure as

FULL PAPER

D

cyclohexane, 3:7, then 6:4), which provided two fractions. The less

above was used, starting from 27 (200 mg, 0.54 mmol), Et₃N (230 polar one contained a mixture (5.18 g) of the -xylo adduct ent-21

µL, 1.62 mmol, 3.0 equiv.), Bu₂SnO (ca. 10 mg) and TsCl (259 mg,

1.35 mmol, 2.5 equiv.) in CH₂Cl₂(12 mL). Workup as above fol-

lowed by chromatography provided 28 (169 mg, 90%) as a crystal-

and some unchanged trityl-imidazole; the more polar one con-

tained almost pure -lyxo compound ent-25 (4.80 g). Both fractions

were used as such for the next reaction step. The ¹H NMR and ¹³

C

line compound. M.p. 146Ϫ147 °C (EtOH/H₂O, 7:3). [α]²_D⁰ϭ Ϫ191 NMR spectra of ent-21 and ent-25 superimposable on those of 21

(c ϭ 2, CHCl₃). Ϫ ¹H NMR (CDCl₃): δ ϭ 3.65 (dd, 1 H, 7-H), and 25.

3.72 (dd, 1 H, 5-H_b), 4.41 (dd, 1 H, 5-H_a), 4.43 and 4.65 (AB, J ϭ

Imidazolo-L-xylo Derivative ent-22: Bu₄NI (catalytic amount, ca.

11.8, 2 H, OCH₂Ph), 4.69 (td, 1 H, 6-H), 4.70 and 4.79 (AB, J ϭ

12.0, 2 H, OCH₂Ph), 4.83 (d, 1 H, 8-H), 6.88 (d, 1 H, H-3), 7.11

(d, 1 H, H-2), 7.30 to 7.47 (m, 10 H, CH phenyl); J_2,3ϭ 1.1,

J_5a,5bϭ 12.1, J_5a,6ϭ 6.6, J_5b,6ϭ 9.4, J_6,7ϭ9.7, J_7,8ϭ 3.5. Ϫ

¹³C NMR (CDCl₃): δ ϭ 48.4 (C-5), 64.2 (C-6), 67.2 (C-8), 70.7

(OCH₂Ph), 71.2 (OCH₂Ph), 79.5 (C-7), 119.3 (C-3), 127.7 to 128.6

(C_o,m,pof phenyl),129.8 (C-2), 137.2 and 137.8 (2 ϫ C_sof phenyl),

143.1 (C-8a). Ϫ C₂₁H₂₂N₂O₃(350.42): calcd. C 71.98, H 6.33, N

7.99; found C 72.1, H 6.2, N 8.0.

15 mg) and NaH (ca 50% in oil, 1.3 g, ca. 27 mmol) were added at

room temperature under argon atmosphere to a stirred solution of

the impure minor adduct ent-21 (5.18 g) in anhydrous THF

(80 mL). Once hydrogen formation had ceased, BnBr (2.2 mL,

18.6 mmol) was added, and the mixture was heated at 40 °C for

12 h. MeOH (2 mL) was added and the resulting clear solution was

evaporated to dryness in vacuo. The residue was dissolved in Ac-

OEt (150 mL), the solution was washed with water (80 mL) and

brine, then dried (MgSO₄) and filtered, and the solvents were re-

moved. The residue was purified by chromatography (AcOEt/cyclo-

hexane, 2:8) to provide pure ent-22 (2.97 g, overall yield from the

aldehyde ent-20: 25%) as a beige foam. The ¹H NMR and ¹³C

NMR spectra were superimposable on those of 22.

D-xylo-Imidazolo-piperidinose (5): A stirred solution of 24 (233 mg,

0.66 mmol) in EtOH/AcOH, 1:1 (10 mL) was placed under H₂at-

mosphere (1 bar) at room temp. in the presence of moist (20%

H₂O) Pd(OH)₂/C (‘‘Pearlman’s catalyst’’, 400 mg). After 12 h the

suspension was centrifuged and the catalyst was rinsed several

times with hot MeOH. The combined organic solutions were evap-

orated to dryness in vacuo, the crude residue was taken up again

in MeOH, and the resulting solution was passed through Amberlist

IRA 400 (OH^Ϫ) (15 mL) beads in order to eliminate the last traces

of AcOH. After evaporation of the solvent, the residue was purified

by chromatography (AcOEt/MeOH, 8:2) to give 5 (75 mg, 66%) as

colourless crystals. M.p._dec.175 °C. Ϫ [α]²_D⁰ϭ Ϫ56 (c ϭ 1, MeOH).

Ϫ CD (H₂O): Figure 1. Ϫ ¹H NMR (CD₃OD, 400 MHz): δ ϭ 3.91

(dd, 1 H, 7-H), 3.92 (dd, 1 H, 5-H_b), 4.07 (ddd, 1 H, 6-H), 4.27

(dd, 1 H, 5-H_a), 4.56 (d, 1 H, 8-H), 7.01 (d, 1 H, 2-H or 3-H),7.02

Imidazolo-L-lyxo Derivative ent-26: The same procedure as above

was used, starting from ent-25 (4.80 g) in THF (80 mL), Bu₄NI (ca.

20 mg), NaH (50% in oil, 1.2 g, ca. 25 mmol) and BnBr (2.0 mL,

16.9 mmol). Workup as above followed by chromatography pro-

vided compound ent-26 (5.10 g, overall yield from the aldehyde ent-

20: 43%). Its ¹H NMR and ¹³C NMR spectra were superimposable

on those of 26.

Imidazolo-L-xylo Derivative ent-23: A solution of ent-22 (2.90 g,

4.46 mmol) in aq. HCl (2 , 70 mL) was heated at reflux for 4 h,

cooled to room temp., and washed with Et₂O (2 ϫ 50 mL). The

organic fractions were extracted with HCl (2 , 30 mL). The com-

bined aqueous phases were basified with aq. ammonia to ca. pH

10 and extracted with AcOEt (4 ϫ 80 mL). The combined organic

fractions were dried (MgSO₄) and filtered, and the solvents were

removed. The crude residue was purified by chromatography

(CHCl₃/THF/MeOHϪNH₃, 6:3:1) to provide ent-23 (877 mg, 53%)

as a colourless foam, which was recrystallised. Ϫ M.p. 99Ϫ100 °C

(CHCl₃). Ϫ [α]²_D⁰ϭ Ϫ53 (c ϭ 2, CH₃OH) (23: [α]²_D⁰ϭ ϩ 51). Ϫ

The ¹H NMR and ¹³C NMR spectra were superimposable on those

of 23. Ϫ HR-MS [M ϩ H]^ϩ(C₂₁H₂₅N₂O₄): calcd. 369.1815; found

369.1816). Ϫ C₂₁H₂₄N₂O₄ϩ 1/2 H₂O (377.44): calcd. C 66.83, H

6.68, N 7.42; found C 66.8, H 6.6, N 7.4.

(d, 1 H, 2-H or 3-H); J_5a,5bϭ 12.6, J_5a,6ϭ 4.6, J_5b,6ϭ 6.5, J_6,7

ϭ

7.5, J_7,8ϭ 5.6, J_2,3ϭ 1.3. Ϫ ¹³C NMR (CD₃OD, 100.6 MHz): δ ϭ

49.2 (C-5), 68.9 (C-6), 69.4 (C-8), 75.2 (C-7), 120.0 (C-3), 129.3 (C-

2), 146.8 (C-8a). Ϫ C₇H₁₀N₂O₃(170.17): calcd. C 49.40, H 5.92, N

16.46; found C 49.5, H 5.9, N 16.4.

D-lyxo-Imidazolo-piperidinose (6): The same procedure as above

was used, starting from 28 (283 mg, 0.81 mmol) and moist

Pd(OH)₂/C (400 mg), under H₂atmosphere (1 bar). After workup

as above, the crude final product was purified by chromatography

(CHCl₃/MeOH, 8:2) to provide 6 (122 mg, 89%) as a slightly yel-

low, crystalline solid. M.p._dec.182 °C (H₂O/EtOH); one of the mon-

ocrystals was used for X-ray diffraction analysis (Figure 2). Ϫ

1

[α]²_D⁰ϭ Ϫ 42 (c ϭ 1, MeOH). Ϫ CD (H₂O): Figure 1. Ϫ H NMR

Imidazolo-L-lyxo Derivative ent-27: The same procedure as em-

(CD₃OD, 400 MHz): δ ϭ 3.83 (dd, 1 H, 5-H_b, 3.99 (dd, 1 H, 7-H),

4.28* and 4.29* (m, 2 H, 6-H and 5-H_arespectively), 4.85 (d, 1 H,

8-H), 6.98 (d, 1 H, 2-H or 3-H), 6.99 (d, 1 H, 2-H or 3-H); J_5a,5bϭ

ployed for the preparation of 12 was used, starting from ent-26

(5.10 g, 7.84 mmol) in EtOH/H₂O (1:1, 80 mL), containing some

Dowex (50WX8) beads. After workup and chromatography

(CHCl₃/THF/MeOHϪNH₃, 6:3.5:0.5), ent-27 (2.32 g, 80%) was

obtained as a colourless solid, which was recrystallised. M.p._dec.

161 °C (toluene). Ϫ [α]²_D⁰ϭ ϩ33 (c ϭ 2, MeOH) (27: [α]²_D⁰ϭ Ϫ34,

12.7*, J_5a,6ϭ 4.4*, J_5b,6ϭ 5.1*, J_6,7ϭ 6.8*, J_7,8ϭ 3.7*, J_2,3

ϭ

1.3. (*These values for second order signals were calculated with

the NUTS Program from Acorn NMR). Ϫ ¹³C NMR (CD₃OD,

100.6 MHz): δ ϭ 48.0 (C-5), 65.4 (C-8), 67.8 (C-6), 72.2 (C-7),

120.2 (C-3), 128.7 (C-2), 147.0 (C-8a). C₇H₁₀N₂O₃(170.17): calcd.

C 49.40, H 5.92, N 16.46; found C 49.0, H 5.9, N 16.3.

1

see above). Ϫ The H NMR and ¹³C NMR spectra were superim-

posable on those of 27. Ϫ HR-MS [M ϩ H]^ϩ(C₂₁H₂₅N₂O₄) calcd.

369.1815; found 369.1816. Ϫ C₂₁H₂₄N₂O₄(368.43): calcd. C 68.46,

H 6.57, N 7.60; found C 68.2, H 6.6, N 7.7.

Coupling Reaction Between a Lithiated Imidazole and L-Threose De-

rivative ent-20: (Scheme 5). A procedure similar to that for the

coupling reaction with aldehyde 9 (see above) was used, starting

from N-trityl-imidazole (6.18 g, 19.9 mmol) in anhydrous THF

L-xylo-Imidazolo-piperidinose Derivative ent-24: DMAP (catalytic

amounts, ca. 10 mg) and TsCl (387 mg, 2.03 mmol, 2.5 equiv.) were

added at 0 °C to a stirred solution of ent-23 (300 mg, 0.81 mmol)

(250 mL) under argon atmosphere at Ϫ5 °C, with a solution of and Et₃N (310 µL, 2.23 mmol, 2.7 equiv.) in CH₂Cl₂(12 mL) .

BuLi in hexane (1.6 , 13.6 mL, 21.7 mmol, 1.2 equiv.) and alde-

After 24 h the reaction mixture was diluted with CH₂Cl₂(30 mL),

washed with a saturated aqueous solution of NH₄Cl (40 mL) and

hyde ent-20 (4.53 g, 18.1 mmol)^[11]in THF (20 mL). After workup,

the resulting crude oil was separated by chromatography (AcOEt/ evaporated to near dryness, and the residue was taken up in 2 

Eur. J. Org. Chem. 2001, 4111Ϫ4125 4123

F. Gessier, T. Tschamberg, C. Tarnus, M. Neuburger, W. Huber, J. Streith

FULL PAPER

NaOH/MeOH (1:1, 20 mL), the resulting suspension being stirred (containing 50% water; 440 mg) at room temp. for 64 h. The cata-

at room temp. for 12 h. The reaction medium was diluted with H₂O lyst was removed by centrifugation and washed several times with

(30 mL) and extracted with CH₂Cl₂(3 ϫ 30 mL). The combined

organic fractions were dried (MgSO₄), filtered and evaporated to

dryness, and the crude residue was purified by chromatography

hot MeOH, and the combined organic solutions were evaporated

to dryness in vacuo. The crude residue was purified by chromato-

graphy (AcOEt/MeOH, 7:3) to provide ent-5 (79 mg, 75%) as a

(CHCl₃/THF/MeOHϪNH₃, 7:2.5:0.5) to provide ent-24 (142 mg) colourless oil that solidified spontaneously and was recrystallised.

as a colourless oil that crystallised spontaneously, together with

M.p._dec.192 °C (EtOH). Ϫ [α]²_D⁰ϭ ϩ55 (c ϭ 1, MeOH) (5: [α]²_D⁰

ϭ

recovered ent-23 (104 mg). Yield of ent-24 from consumed ent-23:

Ϫ56, see above). CD (H₂O): Figure 1. Ϫ The ¹H NMR and ¹³C

NMR spectra were superimposable on those of 5. Ϫ HR-MS [M

ϩ H]^ϩ(C₇H₁₁N₂O₃): calcd. 171.0770; found 171.0772.

69%. Ϫ M.p. 99 °C. Ϫ [α]²_D⁰ϭ Ϫ33 (c ϭ 2, CHCl₃) (24: [α]²_D⁰

ϭ

ϩ31, see above). Ϫ The ¹H NMR and ¹³C NMR were superimpos-

able on those of 24. Ϫ HR-MS [M ϩ H]^ϩ(C₂₁H₂₃N₂O₃): calcd.

351.1709; found 351.1710).

L

-lyxo-Imidazolo-piperidinose (ent-6): The same procedure as above

was used, starting from ent-28 (439 mg, 1.25 mmol) and Pd/C

(10%) (containing 50% water; 450 mg) in MeOH (15 mL) under H₂

pressure (20 bar) at room temp. for 4 days. Workup as above fol-

lowed by chromatography (CHCl₃/MeOH/NH₄OH, 7:3:0.5) pro-

vided ent-6 (113 mg, 53%) as colourless crystals, which were recrys-

tallised. M.p._dec.201Ϫ202 °C (EtOH). Ϫ [α]²_D⁰ϭ ϩ42 (c ϭ 1,

MeOH) (6: [α]²_D⁰ϭ Ϫ42, see above). Ϫ CD (H₂O): Figure 1. Ϫ The

¹H NMR and ¹³C NMR spectra were superimposable on those of

6. ؊ HR-MS for [M ϩ H]^ϩ(C₇H₁₁N₂O₃): calcd. 171.0770; found

171.0770.

L

-lyxo-Imidazolo-piperidinose Derivative ent-28: A procedure sim-

ilar to the one employed for the synthesis of 24 was used, starting

from ent-27 (200 mg, 0.54 mmol), Et₃N (230 µL, 1.65 mmol),

Bu₂SnO (ca 5 mg) and TsCl (260 mg, 1.36 mmol, 2.5 equiv.) in

CH₂Cl₂(12 mL) and 2  NaOH/MeOH (1:1, 30 mL). Chromato-

graphy provided ent-28 (145 mg, 76%) as a colourless solid, which

was recrystallised. Ϫ M.p. 146Ϫ147 °C (toluene). Ϫ [α]²_D⁰ϭ ϩ196

(c ϭ 2, CHCl₃) (28: [α]²_D⁰ϭ Ϫ191, see above). Ϫ The ¹H NMR and

¹³C NMR spectra were superimposable on those of 28. ؊ HR-

MS [M ϩ H]^ϩ(C₂₁H₂₃N₂O₃): calcd. 351.1709; found 351.1707. Ϫ

C₂₁H₂₂N₂O₃(350.42): calcd. C 71.98, H 6.33, N 7.99; found C 71.8,

H 6.2, N 8.0.

X-ray Diffraction Analysis of ent-3 and 6. Experimental Details

Compound ent-3 crystallised with one molecule H₂O, not shown

in the diagram.

L-xylo-Imidazolo-piperidinose (ent-5): A vigorously stirred solution

of ent-24 (219 mg, 0.62 mmol) in MeOH (8 mL) was placed under

H₂pressure (30 bar) in an autoclave in the presence of Pd/C (10%)

Table 3. Crystal data and parameter collection for ent-3 and 6.

Table 3. Crystal data and data collection parameters for ent-3 and for 6.

ent-3

6

formula

C₇H₁₀H₂O₃, H₂O

C₇H₁₀N₂O₃

170.17

mol. weight

crystal system

Space group

188.18

orthorhombic

P2₁2₁2₁

6.7413(2)

7.9980(2)

15.3798(3)

90

829.23

4

orthorhombic

P2₁2₁2₁

6.6823(3)

7.3559(4)

15.165(1)

90.000

745.41

4

˚

a [A]

˚

b [A]

˚

c [A]

α [°]

β [°]

γ [°]

V [A ]

Z

3

˚

F(000)

400

1.51

0.12

360

1.52

0.11

d_calcd.[gcm^Ϫ3

]

µ [mm^Ϫ1

]

crystal size [mm]

T [K]

radiation

0.10 ϫ 0.14 ϫ 0.40

293

Mo-K_α

(λ ϭ 0.71073)

CCD

0.11 ϫ 0.14 ϫ 0.21

293

Mo-K_α

(λ ϭ 0.71073)

CCD

measurement method

Θ_max[deg]

32.03

30.03

no. of measured reflections

no. of independent reflections

no. of reflns in refinement

no. of variables

final R

final R_w

11063

2782

2586

139

0.0335

0.0387

Chebychev

7884

2149

1783

122

0.0388

0.0390

Chebychev

polynomial

weighting scheme

[19]

polynomial

last max/min. in

difference map

0.33/Ϫ0.38

0.36/Ϫ0.40

4124

Eur. J. Org. Chem. 2001, 4111Ϫ4125

Synthesis of Imidazolo-Piperidinopentoses as Nagstatine Analogues

FULL PAPER

T. Aoyagi, H. Suda, K. Uotani, F. Kojima, T. Aoyama, K.

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750Ϫ770.

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[2]

The usual corrections were applied. The structure was solved by

direct methods using the SIR92 program.^[17]Anisotropic least-

squares, full-matrix refinement was carried out on all non-hydrogen

atoms using the program CRYSTALS.^[18]Scattering factors were

taken from the International Tables, Vol. IV, Table 2.2 B.

[3]

[4]

For ent-3: The positions of the hydrogen atoms were determined

geometrically. The refinement of 139 parameters including 2586

reflections with I Ͼ 2.00 σ(I) resulted in a residual of 0.0335 (R_wϭ

0.0387). Chebychev polynomial weights^[19]were used to complete

the refinement. The density maximum in the last difference map

[5]

[6]

[7]

[8]

3

˚

was 0.33 e/A , the last minimum was Ϫ0.38 e/A

For 6: The hydrogen atoms are in calculated positions or were loc-

ated in the difference Fourier map and refined using appropriate

restraints. The refinement of 122 parameters including 1783

reflections with I Ͼ 2.00 σ(I) resulted in a residual of 0.0388 (R_wϭ

0.0390). Chebychev polynomial weights^[19]were used to complete

the refinement. The density maximum in the last difference map

[9]

[10]

[11]

[12]

3

˚

was 0.36 e/A , the last minimum was Ϫ0.40 e/A .

E. Abushanab, P. Vemishetti, R. W. Leiby, H. K. Singh, A. B.

Mikkilineni, D. C. J. Wu, R. Saibaba, R. P. Panzica, J. Org.

Chem. 1988, 53, 2598Ϫ2602.

Crystallographic data have been deposited at the Cambridge Crys-

tallographic Data Centre under the numbers CCDC 165612 for ent-

3 and CCDC 165613 for 6. Copies of the data can be obtained free

of charge on application to CCDC, 12 Union Road, Cambridge

CB2 1EZ, UK [E-mail: deposit@ccdc.cam.ac.uk].

[13]

[14]

´

C. Andre, J. Bolte, C. Demuynck, Tetrahedron: Asymmetry

1998, 9, 1359Ϫ1367.

M. Ichikawa, Y. Igarashi, Y. Ichikawa, Tetrahedron Lett. 1995,

36, 1767Ϫ1770.

[15]

[16]

Y.-T. La, J. Biol. Chem. 1967, 242, 5474Ϫ5480.

I. H. Segel, Enzyme Kinetics, John Wiley & Sons, New-York,

1975, pp109Ϫ144.

A. Altomare, G. Cascarano, G. Giacovazzo, A. Guagliardi, M.

C. Burla, G. Polidori, M. Camalli, J. Appl. Cryst. 1994, 27, 435

(SIR92 Ϫ a program for automatic solution of crystal struc-

tures by direct methods).

D. J. Watkin, R. J. Carruthers, P. Betteridge, Program CRYS-

TALS (1985), Chemical Crystallography Laboratory, Oxford,

UK.

Acknowledgments

[17]

We wish to thank the Fondation pour l’Ecole de Chimie de Mul-

house for a PhD grant to Franc¸ois Gessier. We are indebted to

Estelle Dubost and to Jeffery Newsome, who worked out some of

the organic synthetic steps, and to Josiane Kohler for the CD spec-

tral measurements. And, last but not least, the support of the

Centre National de la Recherche Scientifique (UPRES-A 7015) is

gratefully acknowledged.

[18]

[19]

J. R. Carruthers, D. J. Watkin, Acta Crystallogr., Sect. A 1979,

35, 698Ϫ699.

Received April 20, 2001

[1]

D. E. Zechel, S. G. Withers, Acc. Chem. Res. 2000, 33, 11Ϫ18.

[O01194]

Eur. J. Org. Chem. 2001, 4111Ϫ4125

4125

Article Doi

Synthesis of imidazolo-piperidinopentoses as nagstatine analogues

DOI: 10.1002/1099-0690(200111)2001:21<4111::AID-EJOC4111>3.0.CO;2-7

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