General synthesis and biological evaluation of α-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-α-C-glycosides)

Bioorganic & Medicinal Chemistry 13 (2005) 2313–2324

General synthesis and biological evaluation of a-1-C-substituted

derivatives of fagomine (2-deoxynojirimycin-a-C-glycosides)

Jean-Yves Goujon,^aDavid Gueyrard,^aPhilippe Compain,^a,*Olivier R. Martin,^a,*

Kyoko Ikeda,^bAtsushi Kato^cand Naoki Asano^b

a

´ ´ ´

Institut de Chimie Organique et Analytique, CNRS, Universite d’Orleans, rue de Chartres, BP 6759, 45067 Orleans, France

^bFaculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan

^cDepartment of Hospital Pharmacy, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan

Received 2 June 2004; accepted 22 December 2004

Available online 19 January 2005

Abstract—A general synthesis of a-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-a-C-glycosides) by ring-opening

reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate, is

described. The nine-step reaction sequence proceeded in an overall yield of 14–28% from tri-O-benzyl-^D-glucal. Biological evalu-

ation of a-1-C-substituted derivatives of fagomine, of the 2-deoxy analog of a-homonojirimycin 19 and its 1,N-anhydro derivative

22 as glycosidase inhibitors is reported. The glycosyl phosphate mimetic 15k was found to display no inhibitory activity towards

glycogen phosphorylase b and phosphoglucomutase.

1. Introduction

OH

Me

Since the discovery of their occurrence in 1966¹and of

their biological activity as glycosidase inhibitors by

Bayer chemists ten years later, iminosugars have been

the subject of intense studies.²Recently, the scope of

their biological activity has been extended to the inhibi-

tion of a number of enzymes such as glycosyltransfer-

ases,³metalloproteinases,⁴glycogen phosphorylases,⁵a

sugar nucleotide mutase⁶and nucleoside-processing en-

zymes.⁷These ﬁndings have triggered renewed interest

in iminosugars. Since these enzymes are involved in

numerous fundamental biological processes, carbohy-

drate mimetics with nitrogen instead of the ring oxygen

constitute leads for the development of new therapeutic

agents in a wide range of diseases.^8,9Two iminosugar

derivatives have already been approved as drugs: N-

hydroxyethyl-1-deoxynojirimycin (Glyset^TM1¹⁰) to treat

complications associated with type II diabetes and N-

butyl-1-deoxynojirimycin 2¹¹(Zavesca^TM) for the treat-

ment of GaucherÕs disease, a severe lysosomal storage

disorder (Scheme 1). Further exciting applications are

being uncovered: N-alkyliminosugars have been found

OH

N

HO

OH

2

1

OH

H

N

H

N

HO

Me

3

4

Scheme 1.

to reversibly induce infertility in male mice, opening

the way to a nonhormonal approach to male contracep-

tion.¹²Considering the high potential of ÔazasugarsÕ for

drug discovery, diversity-oriented synthesis of stable

derivatives, such as iminosugars C-glycosides, is still

needed to accelerate the exploration of new biological

targets and the ﬁnding of more selective/potent inhibi-

tors. To achieve this goal and as part of our continuing

studies on iminosugars,¹³we have designed a ﬂexible

strategy for the general synthesis of a-1-C-substituted

derivatives of fagomine (1,2-dideoxynojirimycin, 3).

*

Corresponding authors. Fax: + 33 (0) 2 38 41 72 81; e-mail addresses:

philippe.compain@univ-orleans.fr; olivier.martin@univ-orleans.fr

doi:10.1016/j.bmc.2004.12.043

2314

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

tri-O-benzyl-^D-glucal (7) (Scheme 3). Hydration of 7

H

OBn

by a mild one-pot procedure²³provided the correspond-

ing 2-deoxysugar 8, which was further transformed into

alkene 9²⁴by Wittig methylenation. Introduction of the

amino group at C-6 of the ^D-arabino heptenitol 9 was

performed by way of a double Mitsunobu reaction.

The conﬁguration at C-6 of 9 was inverted eﬃciently

in 79% yield by reaction with p-nitrobenzoic acid in

the presence of Ph₃P and DIAD to provide 10,^20a

followed by debenzoylation under basic conditions to

give ^L-xylo heptenitol 11. A second Mitsunobu reaction

using phthalimide aﬀorded the expected ^D-arabino amino

sugar 13 in 72% yield after removal of the phthalimido

group. The amino-heptenitol 13 was then cyclized using

NIS to produce the relatively unstable 1-C-iodomethyl

derivatives of fagomine 14 with a good diastereoselectiv-

ity in favour of the a-diastereoisomer (70% de). The

two epimers could be separated by ﬂash chromato-

graphy, even though partial decomposition occurred.

By contrast, the NIS-promoted cyclization of the tetra-

O-benzyl-^D-gluco analogue of 14²⁵is completely

diastereoselective: this comparison conﬁrms the impor-

tant role of the 3-O-benzyl group in the stereochemical

outcome of the cyclization of the latter heptenitol. To

avoid degradation, the mixture of the two stereoisomers

14 was engaged without puriﬁcation, in the subsequent

cyclization promoted by DBU. The aziridine 5 was iso-

lated in 74% yield from 13 after puriﬁcation by ﬂash

chromatography.

Nu-H

N

BnO

Nu

6

5

Scheme 2.

Recently, fagomine (3) was found to have potent antihy-

perglycemic eﬀect in streptozocin-induced diabetic mice

and to enhance glucose-induced insulin secretion.¹⁴To

our knowledge, only one example of a natural fagomine

C-glycoside (compound 4)¹⁵has been reported to date.

Our synthetic strategy hinges on the ring-opening reac-

tions of the bicyclic aziridine 5, which allows the intro-

duction of structural diversity at the ÔanomericÕ

position by using the wide library of nucleophiles avail-

able (Scheme 2). This point is crucial if one wants to

explore the aﬃnity of the aglycon binding site within a

range of carbohydrate-processing enzymes. In addition,

the key intermediate in our strategy, iminosugar-derived

aziridine 5,¹⁶once deprotected, is of biological interest

as a potential irreversible inhibitor of glycosidases.

In a previous communication,²¹we have reported the

ﬁrst synthesis of 1,N-anhydro derivative of fagomine 5,

its deprotection and its use as an advanced intermediate

for the synthesis of a-1-C-substituted derivatives by way

of regioselective opening of the aziridine ring.²²Herein,

we wish to described the full details of theses studies as

well as the biological evaluation of the compounds

synthesized.

2.2. Ring opening reactions of aziridine 5

Baeyer strain combined with the electronegativity of the

nitrogen atom explain the ability of aziridines to under-

go ring opening under relatively mild conditions.²⁶

However, this process still remains challenging in com-

parison with the corresponding reaction of epoxides

due to diminished electronegativity of the nitrogen atom

and the presence of an additional valency.^26aIn addi-

tion, there have been few investigations on the ring-

2. Results and discussion

2.1. Synthesis of the bicyclic aziridine 5

The synthesis of the key aziridine intermediate 5 was

performed in eight steps and 34% overall yield from

OBn

OH

OBn

O

a

O

b

c

BnO

OH

7

8

9

OBn

6

OBn

NPht

f

e

d

BnO

OpNbz

OH

11

12

10

OBn

NH₂

OBn

H

N

h

g

N

BnO

I

14 de 70%

5

13

Scheme 3. Reagents and conditions: (a) (i) NIS (1.1 equiv), CH₃CN/H₂O (95:5), 0 ꢁC, 15 min; (ii) Na₂S₂O₄(4 equiv), NaHCO₃(10 equiv), DMF/

H₂O (1:1), 5 h; (b) Ph₃P⁺CH₃Br^ꢀ(3.5 equiv), n-BuLi (3.5 equiv), THF, 0 ꢁC to rt, 24 h, 81% (three steps); (c) PPh₃(3 equiv), p-nitrobenzoic acid

(3 equiv), DIAD (3 equiv), toluene, 0 ꢁC to rt, 16 h; (d) Na (0.2 equiv), MeOH, 1 h, 79% (two steps); (e) phthalimide (3 equiv), PPh₃(3 equiv), DIAD

(3 equiv), toluene, 0 ꢁC to rt, 16 h; (f) ethylenediamine (10 equiv), EtOH, 80 ꢁC, 5 h, 72% (two steps); (g) NIS (1.2 equiv), CH₂Cl₂, 1 h; (h) DBU

(10 equiv), THF, D, 6 h, 74% (two steps).

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

2315

OBn

H

N

OBn

H

N

BnO

15b

NHPh

SPh

15a

PhNH₂, LiClO₄cat.

CH₃CN, ∆, 2h

63%

PhSH, Et₃N

CH₂Cl₂, 3h

81%

OBn

H

N

H

N

OBn

RCO₂H

BnO

CH₂Cl₂, 16h

CSA cat.

O

N

BnO

MeOH, 16h

O

R

OMe

40%

15e

5

15f R = Ph 75%

15g R = propyl 82%

15h R = CH₂NHCbz 74%

15i R = p-nitrophenyl 79%

Morpholine, LiClO₄cat.

Diallylamine, LiClO₄cat.

CH₃CN, ∆, 2h

81%

CH₃CN, ∆, 2h

84%

OBn

H

OR

H

N

BnO

RO

N

O

15c R =Bn

15l R =H

15d

Scheme 4.

OBn

N

opening of N-alkylated aziridines in contrast to

aziridines N-activated by sulfonyl, phosphoryl or

carbonyl groups.^27,19

OBn

H

N

a

BnO

O

P

O

OBn

We ﬁrst investigated the reactions of aziridine 5 with

various heteroatomic nucleophiles including thiol,

amine, alcohol, carboxylate and phosphate (Scheme 4).

We were pleased to ﬁnd that the corresponding ring-

opening products 15 could be obtained in good yields

and with a high degree of regioselectivity (the seven-

membered cyclic was not detected by NMR spectro-

scopy). Bicyclic iminosugar 5 was readily opened with

thiophenol in the presence of triethylamine at room tem-

perature. In the presence of a catalytic amount of lith-

ium perchlorate, aziridine 5 underwent cleavage by

primary or secondary amines under the mild conditions

recently developed by Yadav et al. for N-tosyl azir-

idines.²⁸The best yields were obtained with secondary

amines. The ring opening proceeded much less satisfac-

torily with alcohols: aziridine 5 was opened by MeOH in

the presence of camphorsulfonic acid to give 15e in 40%

yield whereas the reactions with phenol or butanol led to

an untractable mixture of products.

5

15j

OBn

OH

H

N

b

HO

O

P

O

OH

15k

OH

Scheme 5. Reagents and conditions: (a) (BnO)₂P(O)OH (1.3 equiv),

CH₂Cl₂, 16 h, 78%; (b) H₂, Pd/C, MeOH/HCl 4 N cat, 24 h, 85%.

is the ﬁrst example of a ring-opening reaction of an

N-alkylated aziridine by a phosphate.²⁹Compound

15k is a promising precursor of novel UDP-Glc analogs

that could display interesting activity as glycosyltrans-

ferase inhibitors.³

We then turned our attention to organometallic nucleo-

philes in order to synthesize inter alia a-1-C-ethyl-fago-

mine 4, a fagomine C-glycoside recently isolated from

Adenophora triphylla var. japonica.^15aThe reaction of

aziridine 5 with various organometallic reagents (MeLi,

Me₂CuLi, MeCeCl₂) failed to give the desired product

16 under various conditions. However, 16 could be ob-

tained in 65% yield by the reaction of Me₂CuLi with

the mixture of the two stereoisomers 14 (Scheme 6).³⁰

The same process performed with Pr₂CuLi furnished

the expected compound 17 in a less satisfactory yield

of 32%. Removal of the benzyl groups in 16 provided

a-1-C-ethyl fagomine 4 in 88% yield.

Regioselective ring opening occurred readily with vari-

ous carboxylic acids in dichloromethane to provide the

corresponding 2-deoxy-a-homonojirimycin derivatives

15f–i in 74% to 82% yield.¹⁹No migration of the acyl

group to the endocyclic nitrogen occurred as established

unambiguously by IR and NMR spectral data. Under

the same experimental conditions, the reaction with di-

benzyl phosphate aﬀorded protected iminosugar phos-

phate 15j, which was debenzylated by hydrogenolysis

to furnish the corresponding glycosyl phosphate mime-

tic 15k in 85% yield (Scheme 5). To our knowledge, this

2316

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

OBn

OH

H

N

H

N

OBn

H

N

a or b

N

I

a, b

BnO

HO

BnO

( )_n

Me

16 n =1

17 n =3

I

14-α,β

22

14α

OH

H

N

c

Scheme 8. Reagents and conditions: (a) TMSI (8.5 equiv), CH₂Cl₂,

0 ꢁC to rt, 16 h, 84%; (b) K₂CO₃(1.8 equiv), H₂O, 4 h, 90%.

HO

Me

4

cleaved the benzyl groups at the stage of the a-1-C-

iodomethyl derivative 14a. The deprotection step was

performed using a large excess of TMSI in dichloro-

methane. The expected bicyclic iminosugar 22 was then

generated by intramolecular nucleophilic substitution

promoted by K₂CO₃in water in 75% yield for the two

steps (Scheme 8).

Scheme 6. Reagents and conditions: (a) Me₂CuLi (1.1 equiv), THF,

ꢀ50 ꢁC to rt, 6 h, 65%; (b) n-Pr₂CuLi (1.3 equiv), THF, ꢀ60 ꢁC to rt,

16 h, 32%; (c) H₂, Pd/C, EtOH, HCl 4 N cat, 24 h, 88%.

2.3. Access to 2-deoxy analogs of a-homonojirimycin

The 2-deoxy analog of a-homonojirimycin (19) was ob-

tained by alkaline saponiﬁcation of ester 15f and

hydrogenolysis of the resulting alcohol 18 under classi-

cal conditions (Scheme 7); the spectral parameters of

19 were found to be identical to those of naturally occur-

2.5. Conformational analysis

¹H NMR Analysis (Table 1) of the 2-deoxy-a-homo-

nojirimycin derivatives indicated that the molecules hav-

ing free OH groups (4, 15l, 19 as well as 21) adopt in

ring 2-deoxy-a-homonojirimycin recently isolated.³¹

A

4

similar strategy was used to prepare the 2-deoxy analog

of N-butyl-a-homonojirimycin 21. The ester 15g was

ﬁrst N-alkylated by reductive amination using butyr-

aldehyde and NaBH₃CN to provide 20 in 78% yield.

Removal of the benzyl groups in 20 followed by sapon-

iﬁcation of the ester group using an ion-exchange resin

[Dowex 1-X2, (OH^ꢀform)] aﬀorded the expected analog

of N-butyl-a-homonojirimycin 21 in 88% yield for the

two steps. Deprotection of the morpholino derivative

15c by hydrogenolysis provided the corresponding pipe-

ridinol 15l in 85% yield (Scheme 4).

D₂O a nondistorted C₁(D) conformation in which the

C-1 substituent is in axial position. The benzylated

derivatives (15a–j) exhibit however smaller values of

J_2ax,3, J_3,4and J_4,5coupling constants, which indicate

the existence of a conformational equilibrium with the

alternate ¹C₄(D) conformation or of a nonchair confor-

mation. The free 1-phosphate 15k has a conformation

more closely related to that of the protected derivatives

15a–j than to the free iminoalditols.

2.6. Screening of carbohydrate-processing enzymes

2.4. Synthesis of the 1,N-anhydro derivative of fagomine

22

The inhibitory eﬀect of fagomine analogs 15l, 19, 21, 22

on various glycosidases has been examined (Tables 2

and 3). For comparison purposes, the IC₅₀values of

fagomine (3), 1-deoxynojirimycin (24), N-butyl 1-deoxy-

nojirimycin (26), a-homonojirimycin (23) and its N-butyl

derivative 25 were also included in the tables. The aziri-

dine 22 is a weak inhibitor of glycosidases but displays

slightly better inhibitory activity than fagomine (3). This

result may be explained by the ﬂattened structure of the

bicyclic aziridine 22 that may partially mimic the half

Finally, we investigated the deprotection of aziridine 5

in order to obtain the 1,N-anhydro derivative of fago-

mine 22. Under usual debenzylation conditions, the

reaction led to an untractable mixture of products (using

Na/NH₃) or to the cleavage of the aziridine ring to give

the a-1-C-methyl analogue of 4 in quantitative yield

(using H₂, Pd/C). To overcome this diﬃculty, we ﬁrst

OBn

H

N

OBn

18

OH

H

N

H

N

b

a

O

BnO

HO

O

Ph

OH

15f

19

OBn

OH

H

N

OBn

N

b,d

N

c

O

BnO

HO

O

BnO

O

OH

O

21

20

15g

Scheme 7. Reagents and conditions: (a) MeONa (0.2 equiv), MeOH, 4 h, 86%; (b) H₂, Pd/C, MeOH, HCl 1 N cat, 16 h, 87%; (c) C₃H₇CH@O

(2 equiv), NaBH₃CN (1.2 equiv), CH₃COOH (3 equiv), molecular sieves 4 A, MeOH, 16 h, 78%. (d) Dowex 1-X2, (OH^ꢀform), 1 h, 88% (from 20).

˚

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

2317

Table 1. Coupling constants in 2-deoxy-a-homonojirimycin deriva-

tives

analog 21 with the exception of the rat intestinal maltase

(Table 3). The homoazasugar 19 and its N-butyl analog

21 were designed in part to verify if a hydroxymethyl

group at the pseudo-anomeric position could compen-

sate for the missing OH group at C-2. Comparison of

the inhibition constants between nojirimycin analogs

24 and 26 and the homoazasugars 19 and 21 demon-

strates that the insertion of a hydroxymethyl group at

C-1 is not suﬃcient to reinstate potent biological activity

as a-glucosidase inhibitors (Tables 2 and 3).

H₄

OR

H_2ax

N

H

H₁

RO

H_2eq

H₅

H₃

X

J (Hz)

R = Bn

15a–j

R = H

4, 15l, 19

J_1,2ax

J_1,2eq

J_2ax,3

J_2eq,3

J_3,4

4.5–5.0

4.1–5.0

8.3–9.2

4.1–5.0

6.6–7.5

5.2–6.0

1.8–2.3

11.9–13.0

5.0

Interconversion of the terminal hydroxyl group in 19 by

a morpholino group does not change signiﬁcantly the

biological proﬁle of the 2-deoxynojirimycin analogs as

inhibitors of glucosidases (Tables 2 and 3).

9.2–9.8

J_4,5

Fagomine analogs 15l, 19, 21 and 22 did not display any

signiﬁcant inhibitory activity toward b-glucosidases and

a-fucosidases. In addition, 15l and 19 did not inhibit an

a-^L-rhamnosidase (Penicillium decumbens).

chair structure of the glycosyl cation involved in the

mechanism of the enzymatic hydrolysis.^2a,36There is

however no indication of irreversible inhibition of the

enzymes listed by compound 22.

Compound 15k was designed as a potential inhibitor of

enzymes processing glucose 1-phosphate such as glyco-

gen phosphorylase or phosphoglucomutase. Recent

studies have demonstrated the interest of glycogen phos-

phorylase inhibitors as potential new hypoglycemic

agents for the treatment of complications associated with

type II diabetes.^5,38Unfortunately, the glucose 1-phos-

phate mimetic 15k did not display any inhibitory activity

toward glycogen phosphorylase b nor towards phospho-

glucomutase (Table 4). Further biological studies on

a-glucosidases indicated that 15k was a modest but selec-

tive inhibitor of rat intestinal isomaltase and sucrase.

Comparison of the IC₅₀values between a-homonojiri-

mycin (23) and its 2-deoxy analog 19 indicated that

the a-glucosidase active sites can discriminate by over

two or three orders of magnitude inhibitors diﬀering

by the absence of the hydroxyl group at C-2.³⁷Interest-

ingly, in the case of N-alkylated iminosugars, the ab-

sence of an OH group at C-2 does not seem to be

detrimental for the inhibitory activity towards a-glucosi-

dases. IC₅₀values found for N-butyl a-homonojirimycin

(25) are indeed similar to those obtained for its 2-deoxy

Table 2. IC₅₀values for 19, 22 and related compounds towards selected glycosidases

Enzyme

IC₅₀(lM)

OH

H

N

OH

H

N

OH

H

N

HO

OH

19

3

23

24

22

a-Glucosidase

Rice

Yeast

320^a

(10.4)^d

NI

380

0.04^b

340

0.05^e

190^f

0.36^b

0.30^b

0.21^b

88

880

820^b

460^b

90

NI

150

9.2

45

Rat intestinal maltase

Rat intestinal isomaltase

Rat intestinal sucrase

0.34^b

0.70

100

(22.3)

0.17^b

b-Glucosidase

Sweet almond

Caldocellum saccharolyticum

NI^a,c

NI

(28.9)

NI

81^f

55

NI

a-Fucosidase

Bovine epididymis

Human placenta

140^b

NI

^aTaken from Ref. 32.

^bTaken from Ref. 33.

^cNI: less than 50% inhibition at 1000 lM.

^d% Inhibition at 1000 lM.

^eTaken from Ref. 34.

^fTaken from Ref. 35.

2318

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

Table 3. IC₅₀values for 21, 15l and related compounds towards selected glycosidases

Enzyme

IC₅₀(lM)

C₄H₉

OH

H

N

C₄H₉

OH

C₄H₉

OH

N

HO

OH

N

O

OH

21

26

25

15l

a-Glucosidase

Rice

Yeast

4.2^a

NI^b

4.8^a

100^a

3.0^a

0.42

NI

2.1^a

2.7^a

58^a

6.6

NI

145

NI

195

25

Rat intestinal maltase

Rat intestinal isomaltase

Rat intestinal sucrase

500

120

12.5

48

b-Glucosidase

Sweet almond

NI

1000

NI

Caldocellum saccharolyticum

(pH 5.0)

a-Fucosidase

Bovine epididymis

Human placenta

NI

^aTaken from Ref. 33.

^bNI: less than 50% inhibition at 1000 lM.

Table 4. IC₅₀values for 15k towards selected enzymes

toward glycogen phosphorylase b or phosphogluco-

mutase. These results may be explained in part by the

absence of the hydroxyl group corresponding to HO-2

in the parent glucosides. Interestingly, 15k was found

to be a modest but selective inhibitor of rat intestinal

isomaltase and sucrase. Future work will focus on the

extension of our synthetic strategy to other iminosugar

C-glycosides bearing an OH group at C-2.

Enzyme

IC₅₀(lM)

H

N

OH

+

H

HO

_

O

P

O

15k

NI^a

OH

a-Glucosidase

Rat intestinal maltase

Rat intestinal isomaltase

Rat intestinal sucrase

Rat trehalase

4. Experimental

4.1. General

39

48

NI

Rat lactase

Rat cellobiase

Unless otherwise stated, all reactions requiring anhy-

drous conditions were carried out under argon. Tetra-

hydrofuran was freshly distilled from sodium/

benzophenone under argon prior to use. Dichloro-

methane and toluene were distilled from calcium

hydride. Infrared spectra were recorded using ﬁlms on

NaCl windows or KBr pellets. Low-resolution mass

spectra (MS) were recorded with a Perkin–Elmer Sciex

API 3000 in the ion spray (IS) mode. Speciﬁc rotations

were measured at room temperature (20 ꢁC) in a 1 dm

cell with a Perkin–Elmer 241 polarimeter. Analytical

thin layer chromatography was performed using silica

gel 60F₂₅₄precoated plates (Merck). Flash Chromato-

graphy was performed on silica gel 60 (230-400 mesh)

with ethyl acetate (AcOEt) and petroleum ether (PE)

Glycogen phosphorylase b

NI

Phosphoglucomutase

^aNI: less than 50% inhibition at 1000 lM.

3. Conclusion

In conclusion we have demonstrated that iminosugar-

derived aziridine 5 was a versatile intermediate for the

synthesis of fagomine C-glycosides and related com-

pounds bearing a diverse range of functional groups at

the ÔanomericÕ position. The nine-step reaction sequence

proceeded in an overall yield of 14–28% from tri-O-benz-

yl-^D-glucal (7). In the course of this study, the synthesis

of a natural product, a-1-C-ethyl-fagomine (4), has been

also achieved. The 1-C-substituted derivatives of fago-

mine 15l, 19 and 21 were found to be modest inhibitors

of a-glucosidases whereas the 1,N-anhydro derivatives

of fagomine 22 displayed weak reversible inhibition

values towards glycosidases. The glycosyl phosphate

mimetic 15k was found to have no inhibitory activity

1

as eluants. H and ¹³C NMR spectra were recorded at

25 ꢁC on Bruker DPX 250 Advance (250 MHz) and

JEOL ECP-500 (500 MHz) spectrometers with Me₄Si

as internal reference unless otherwise stated and J values

are quoted in Hertz. Carbon multiplicities were assigned

by distortionless enhancement by polarization transfer

(DEPT) experiments. Elemental analyses were carried

out at the Service Central of Microanalyse du CNRS

(Vernaison, France).

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

2319

4.2. Chemistry

1H), 2.55 (d, 1H, J = 7.9 Hz), 3.44 (m, 2H), 3.61 (dd,

1H, J = 3.0, 5.9 Hz), 3.72 (m, 1H), 3.95 (m, 1H),

4.45–4.65 (m, 5H), 4.75 (d, 1H, J = 11.2 Hz), 5.05–

5.14 (m, 2H), 5.86 (m, 1H), 7.26–7.32 (m, 15H); ¹³C

NMR (62.9 MHz, CDCl₃): d_C35.0, 69.6, 71.3, 72.5,

73.1, 74.5, 79.1, 79.4, 117.2, 127.5–128.3, 134.7, 137.9,

138.2, 138.3; MS-IS m/z 455 [M + Na]⁺. Anal. Calcd

for C₂₈H₃₂O₄: C, 77.75; H, 7.45. Found: C, 77.15; H,

7.63.

4.2.1. 4,5,7-Tri-O-benzyl-1,2,3-trideoxy-^D-arabino-hept-

1-enitol (9).²⁴To a solution of methyltriphenylphospho-

nium bromide (8.62 g, 24.15 mmol) in THF (45 mL) was

added dropwise at 0 ꢁC 1.6 M BuLi in hexane (14.2 mL,

22.7 mmol). The reaction was stirred for 30 min at 0 ꢁC

and then for 30 min at room temperature. In another

ﬂask, a solution of BuLi in hexane (1.6 M, 4 mL,

6.5 mmol) was added dropwise at 0 ꢁC to a solution of

2-deoxy sugar 8²³(3.0 g, 6.9 mmol) in THF (30 mL)

and stirred for 30 min. The resulting solution was then

cannulated into the THF solution of phosphorane.

The reaction mixture was stirred for 24 h at room tem-

perature, then quenched with a saturated aqueous solu-

tion of NH₄Cl (50 mL) and extracted with AcOEt

(3 · 60 mL). The combined organic layers were dried

over MgSO₄, evaporated under reduced pressure and

the residue was puriﬁed by column chromatography

4.2.4. 4,5,7-Tri-O-benzyl-1,2,3,6-tetradeoxy-6-phthalim-

ido-^D-arabino-hept-1-enitol (12). To a solution of alcohol

11 (1.03 g, 2.38 mmol) in dry toluene (50 mL) were

added triphenylphosphine (4.19 g, 7.15 mmol) and

phthalimide (1.05 g, 7.15 mmol). The reaction was

cooled at 0 ꢁC and then DIAD (1.44 g, 7.15 mmol)

was added slowly. The reaction was stirred overnight

at room temperature and the solvent was then

removed under reduce pressure. The crude product

was puriﬁed by column chromatography (9:1, PE/

AcOEt) to give the desired compound 12 as a colour-

(9:1, PE/AcOEt) to give the desired compound 9 as a

20

colourless oil (2.56 g, 86%); ½aꢁ ꢀ0.8 (c = 1.7, CHCl₃);

D

20

D

¹H NMR (250 MHz, CDCl₃): d_H2.46 (m, 2H), 3.03 (d,

1H, J = 4.9 Hz), 3.61 (m, 2H), 3.72 (m, 1H), 4.02 (m,

1H), 4.50–4.62 (m, 6H), 5.02–5.11 (m, 2H), 5.78 (m,

1H), 7.26–7.31 (m, 15H); ¹³C NMR (62.9 MHz, CDCl₃):

d_C34.4, 70.2, 71.0, 72.3, 73.2, 73.3, 78.0, 78.8, 117.1,

127.5–128.1, 134.8, 137.7, 137.9, 138.0; MS-IS m/z 455

[M + Na]⁺, 432 [M + H]⁺.

less oil (1.61 g, 78%); ½aꢁ +42.5 (c = 1.5, CHCl₃); H

1

NMR (250 MHz, CDCl₃): d_H2.42 (m, 2H), 3.54

(ddd, 1H, J = 3.2, 4.7, 8.0 Hz), 3.89 (dd, 1H, J = 4.0,

10 Hz), 4.11 (t, 1H, J = 10 Hz), 4.31–4.66 (m, 7H),

4.83 (ddd, 1H, J = 4, 9.7, 10 Hz), 4.98–5.10 (m, 2H),

5.77 (m, 1H), 7.11–7.29 (m, 15H), 7.55–7.67 (m, 4H);

¹³C NMR (62.9 MHz, CDCl₃): d_C33.6, 50.1, 67.2,

72.2, 73.3, 74.7, 78.4, 116.5, 122.6, 127.0–128.1, 131.9,

133.5, 135.3, 137.7, 137.8, 138.0, 168.4; IR (ﬁlm) m

1711 cm^ꢀ1(C@O). Anal. Calcd for C₃₆H₃₅NO₅: C,

76.98; H, 6.28; N, 2.49. Found: C, 76.39; H, 6.28; N,

2.74.

4.2.2.

4,5,7-Tri-O-benzyl-1,2,3-trideoxy-6-O-(4-nitro-

benzoyl)-^L-xylo-hept-1-enitol (10). To a solution of alco-

hol 9 (2.3 g, 5.3 mmol) in dry toluene (100 mL) were

added triphenylphosphine (4.19 g, 15.9 mmol) and 4-

nitrobenzoic acid (2.67 g, 15.9 mmol). The reaction

was cooled to 0 ꢁC and then DIAD (15.9 mmol,

3.22 g) was added slowly. The reaction mixture was stir-

red overnight at room temperature and the solvent was

then removed under reduced pressure. The crude prod-

uct was puriﬁed by column chromatography (9:1, PE/

AcOEt) to give the desired compound 10 as a pale yel-

4.2.5.

(2R,3R,4R,6S)-3,4-Di(benzyloxy)-2-benzyloxy-

methyl-1-azabicyclo[4.1.0]heptane (5). To a solution of

compound 12 (530 mg, 0.94 mmol) in EtOH (30 mL)

was added ethylenediamine (0.39 mL, 9.4 mmol). The

reaction was heated at 80 ꢁC overnight and, after cool-

ing, the solvent was removed under reduced pressure.

The crude product was dissolved in CH₂Cl₂(20 mL)

and then NIS (254 mg, 1.12 mmol) was added. After

1 h at room temperature, a saturated aqueous solution

of Na₂S₂O₃was added (10 mL). The reaction was ex-

tracted with CH₂Cl₂(2 · 30 mL), the combined organic

layers were dried over MgSO₄and evaporated under re-

duced pressure. The crude iodomethyl derivative {14: ¹H

NMR (250 MHz, CDCl₃): d_H1.81 (ddd, 1H, J = 4.4,

9.0, 13.2 Hz), 2.14 (dt, 1H, J = 4.7, 4.7, 13.4 Hz), 3.10

(m, 1H), 3.28–3.33 (m, 4H), 3.55–3.71 (m, 3H), 4.44–

4.55 (m, 5H), 4.77 (d, 1H, J = 11.5 Hz), 7.25–7.28 (m,

5H); ¹³C NMR (62.9 MHz, CDCl₃): d_C11.8, 32.6,

50.5, 53.8, 69.9, 71.2, 72.9, 73.6, 76.6, 77.6, 127.3–

128.6, 138.0, 138.1, 138.2; MS-IS m/z 558.5 [M + H]⁺}

was dissolved in THF (25 mL) and then DBU

(1.40 mL, 9.4 mmol) was added. The reaction was

reﬂuxed for 5 h and, after cooling, the solvent was

removed under reduced pressure. The crude product

was puriﬁed by column chromatography (PE/AcOEt

20

1

low oil (2.67 g, 87%); ½aꢁ +3.6 (c = 1.9, CHCl₃); H

D

NMR (250 MHz, CDCl₃): d_H2.41 (m, 1H), 2.53 (m,

1H), 3.66 (m, 2H), 3.74 (dd, 1H, J = 4.2, 10.8 Hz),

3.95 (t, 1H, J = 4.9 Hz), 4.39–4.81 (m, 6H), 5.09–5.13

(m, 2H), 5.64 (ꢂq, 1H, J = 6.0 Hz), 5.80 (m, 1H),

7.26–7.32 (m, 15H), 8.13 (d, 2H, J = 9.0 Hz), 8.24 (d,

2H, J = 9.0 Hz); ¹³C NMR (62.9 MHz, CDCl₃): d_C

33.8, 67.8, 71.4, 72.5, 73.5, 74.2, 77.5, 77.6, 117.1,

122.9, 127.1–127.8, 130.3, 133.8, 135.0, 137.2, 137.5,

137.6, 149.9, 163.5; IR (ﬁlm) m 1710 cm^ꢀ1(C@O). Anal.

Calcd for C₃₅H₃₅NO₇: C, 72.27; H, 6.07; N, 2.41.

Found: C, 72.17; H, 6.18; N, 2.33.

4.2.3. 4,5,7-Tri-O-benzyl-1,2,3-trideoxy-^L-xylo-hept-1-

enitol (11). To a solution of ester 10 (1.28 g, 2.2 mmol)

in dry MeOH under argon (75 mL) was added sodium

(11 mg, 0.44 mmol). The reaction mixture was stirred

for 4 h at room temperature and the solvent was then

removed under reduced pressure. The crude product

was puriﬁed by column chromatography (9:1, PE/

AcOEt) to give the desired compound 11 as a colour-

20:80 to 0:100) to give the aziridine 5 as a colourless

20

D

oil (274 mg, 68% for the three steps); ½aꢁ +10.6

20

D

1

less oil (0.86 g, 91%); ½aꢁ +5.2 (c = 1.1, CHCl₃); H

(c = 1.1, CHCl₃); ¹H NMR (250 MHz, CDCl₃): d_H

1.40 (d, 1H, J = 3.4 Hz), 1.97–2.22 (m, 4H), 2.54

NMR (250 MHz, CDCl₃): d_H2.35 (m, 1H), 2.47 (m,

2320

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

(m, 1H), 3.56–3.72 (m, 4H), 4.39 (d, 1H, J = 11.2 Hz),

4.53–4.66 (m, 5H), 7.12–7.33 (m, 15H); ¹³C NMR

(62.9 MHz, CDCl₃): d_C26.8, 30.4, 35.4, 64.8, 71.0,

72.3, 73.3, 73.4, 77.6, 79.5, 127.5–128.4, 138.3, 138.5,

138.6; MS-IS m/z 430.5 [M + H]⁺; HRMS-CI m/z

430.2384 [M + H]⁺(C₂₈H₃₁NO₃required 430.2382).

77.9, 78.6, 112.9, 117.3, 127.4–129.3, 138.1, 138.5,

148.3. HRMS-ESI m/z 523.2962

[M + H]⁺

(C₃₄H₃₉N₂O₃required 523.2961).

4.2.9. 4,5,7-Tri-O-benzyl-1,2,3,6-tetradeoxy-2,6-imino-1-

morpholino-^D-manno-heptitol (15c). To a solution of azi-

ridine 5 (50 mg, 0.116 mmol) in acetonitrile (3 mL) were

added morpholine (13.2 mg, 0.15 mmol) and LiClO₄

(2 mg, 0.011 mmol). The reaction was heated at 80 ꢁC

for 4 h and after cooling, the solvent was removed under

reduced pressure. The crude product was puriﬁed by col-

4.2.6.

(2R,3R,4R,6S)-2-Hydroxymethyl-1-azabicyclo-

[4.1.0]heptane-3,4-diol (22). To a solution of crude iodo-

methyl derivative 14 (100 mg, 0.18 mmol) in CH₂Cl₂

(4 mL) was added slowly at 0 ꢁC iodotrimethylsilane

(154 lL, 1.08 mmol). The reaction mixture was allowed

to warm up to room temperature and stirred for 24 h.

Water (10 mL) and diethylether (10 mL) were then

added, the organic layer was separated and the aqueous

layer was extracted with diethylether (10 mL). The aque-

ous layer was concentrated to a volume of 1 mL and

K₂CO₃(44.7 mg, 0.32 mmol) was added. After 3 h, the

solvent was removed under reduced pressure and the

crude product was puriﬁed on Dowex 1-X2 (OH^ꢀ) ion

exchange resin (elution with water). The combined frac-

umn chromatography using AcOEt as eluant to give 15c

20

as a pale yellow oil (50 mg, 84%); ½aꢁ +22.6 (c = 0.6,

D

CHCl₃); ¹H NMR (250 MHz, CDCl₃): d_H1.67 (m,

1H), 1.90 (m, 1H), 2.15 (m, 2H), 2.30–2.52 (m, 5H),

3.09–3.25 (m, 2H), 3.35 (dd, 1H, J = 6.6 Hz), 3.55–3.73

(m, 7H), 4.42–4.62 (m, 5H), 4.77 (d, 1H, J = 11.4 Hz),

7.26–7.30 (m, 15H); ¹³C NMR (62.5 MHz, CDCl₃): d_C

31.9, 45.0, 53.9, 61.0, 67.0, 70.1, 71.3, 73.1, 73.7, 78.0,

127.5–128.3, 138.3, 138.5, 138.6; MS-IS m/z 539

[M + Na]⁺, 517 [M + H]⁺.

tions were lyophilized to aﬀord compound 22 as a white

20

D

foam (21 mg, 75%); ½aꢁ +57.7 (c = 0.4, H₂O); ¹H NMR

4.2.10.

1,2,3,6-Tetradeoxy-2,6-imino-1-morpholino-^D-

(500 MHz, D₂O–TSP:³⁹) d_H1.66 (br d, 1H), 1.97 (ddd,

1H, J = 6.0, 9.6, 14.2 Hz), 2.02 (br d, 1H), 2.23 (m,

1H), 2.44 (ddd, 1H, J = 2.3, 3.5, 14.2 Hz), 2.57 (ddd,

1H, J = 3.2, 6.0, 9.6 Hz), 3.34 (dd, 1H, J = 8.7,

9.6 Hz), 3.76 (dd, 1H, J = 6.0, 11.5 Hz), 3.89 (dd,

1H, J = 3.2, 11.5 Hz); ¹³C NMR (125 MHz, D₂O–

TSP³⁹): d_C32.1, 34.9, 36.8, 66.4, 69.5, 71.3, 74.7;

HRMS-CI m/z 160.0976 [M + H]⁺(C₇H₁₄NO₃required

160.0973).

manno-heptitol (15l). To a solution of 15c (20 mg,

0.038 mmol) in MeOH (1 mL) were added 1 N HCl

(0.1 equiv) and 10% Pd/C (0.2 equiv). The reaction mix-

ture was stirred under H₂(1 atm) overnight and then the

solids were removed by ﬁltration on a pad of Celite. The

solvent was removed under reduced pressure and the

residue was puriﬁed on Dowex 1-X2 (OH^ꢀ) ion ex-

change resin (elution with water). The combined frac-

tions were lyophilized to aﬀord compound 15l as a

20

1

white foam (8 mg, 85%); ½aꢁ +23.6 (c = 0.5, H₂O); H

D

4.2.7. 4,5,7-Tri-O-benzyl-2,3,6-trideoxy-2,6-imino-1-S-

phenyl-1-thio-^D-manno-heptitol (15a). To a solution of

aziridine 5 (50 mg, 0.116 mmol) in CH₂Cl₂(1 mL) were

added triethylamine (21 lL, 0.15 mmol) and thiophenol

(17 lL, 0.15 mmol). After 2 h at room temperature, the

solvent was removed under reduced pressure. The crude

product was puriﬁed by column chromatography (8:2,

NMR (500 MHz, D₂O–TSP³⁹): d_H1.67 (ddd, 1H,

J = 6.0, 11.9, 13.3 Hz), 1.99 (ddd, 1H, J = 2.3, 5.0,

13.3 Hz), 2.50 (m, 1H), 2.57 (m, 2H), 2.64 (m, 2H),

2.73 (m, 1H), 2.82 (ddd, 1H, J = 2.8, 7.3, 9.2 Hz), 3.18

(dd, 1H, J = 9.2 Hz), 3.38 (m, 1H), 3.61 (dd, 1H,

J = 7.3, 11.5 Hz), 3.73 (ddd, 1H, J = 4.6, 9.2, 11.9 Hz),

3.79 (t, 4H, J = 5.0 Hz), 3.91 (dd, 1H, J = 2.8,

11.5 Hz); ¹³C NMR (125 MHz, D₂O–TSP³⁹): d_C36.9,

49.9, 55.9, 58.0, 61.7, 64.8, 68.8, 72.2, 76.2; MS-IS m/z

247.5 [M + H]⁺; HRMS-FAB m/z 247.1660 [M + H]⁺

(C₁₁H₂₃N₂O₄required 247.1658).

PE/AcOEt) to give 15a as a pale yellow oil (50.6 mg,

20

D

81%); ½aꢁ

+18.2 (c = 1.0, CHCl₃); ¹H NMR

(250 MHz, CDCl₃): d_H1.72 (ddd, 1H, J = 4.6, 9.7,

13.2 Hz), 2.02 (br s, 1H), 2.12 (dt, 1H, J = 4.2, 4.2,

13.4 Hz), 2.94–3.09 (m, 3H), 3.21 (m, 1H), 3.33 (t, 1H,

J = 7.5 Hz), 3.59 (d, 2H, J = 5.1 Hz), 3.65 (m, 1H),

4.41–4.57 (m, 5H), 4.79 (d, 1H, J = 11.2 Hz), 7.24–7.29

(m, 20H); ¹³C NMR (62.9 MHz, CDCl₃): d_C33.0,

37.5, 49.0, 54.2, 70.2, 71.4, 73.2, 74.2, 77.6, 78.9, 126.4,

127.5, 127.6, 127.7, 128.0, 128.3, 129.0, 130.1, 135.7,

138.2, 138.4; HRMS-ESI m/z 540.2575 [M + H]⁺

(C₃₄H₃₈NO₃S required 540.2572).

4.2.11. 4,5,7-Tri-O-benzyl-1,2,3,6-tetradeoxy-1-diallyl-

amino-2,6-imino-^D-manno-heptitol (15d). To a solution

of aziridine 5 (30 mg, 0.07 mmol) in acetonitrile (2 mL)

were added diallylamine (11 lL, 0.14 mmol) and LiClO₄

(0.007 mmol, 1.2 mg). The reaction was heated at 80 ꢁC

for 2 h and, after cooling, the solvent was removed

under reduced pressure. The crude product was puriﬁed

by column chromatography using AcOEt as eluant to

20

4.2.8. 4,5,7-Tri-O-benzyl-1,2,3,6-tetradeoxy-2,6-imino-1-

phenylamino-^D-manno-heptitol (15b). To a solution of

aziridine 5 (30 mg, 0.07 mmol) in acetonitrile (2 mL)

were added aniline (13 lL, 0.14 mmol) and LiClO₄

(0.007 mmol, 1.2 mg). The reaction was heated at

80 ꢁC for 2 h and after cooling, the solvent was removed

under reduced pressure. The crude product was puriﬁed

by column chromatography (1:9, PE/AcOEt) to give 15b

as a pale yellow oil (22 mg, 63%); ¹³C NMR (62.9 MHz,

CDCl₃): d_C33.3, 45.5, 48.8, 54.1, 69.5, 71.6, 73.2, 74.1,

give 15d as a pale yellow oil (23 mg, 81%); ½aꢁ +9.6

D

(c = 0.2, CHCl₃); ¹H NMR (250 MHz, CDCl₃): d_H

1.75 (ddd, 1H, J = 4.9, 8.7, 13.7 Hz), 2.00 (dt, 1H,

J = 4.6, 4.6, 13.4 Hz), 2.36 (dd, 1H, J = 5.1, 13.1 Hz),

2.63 (dd, 1H, J = 9.9, 13.1 Hz), 3.01–3.21 (m, 3H),

3.28 (m, 1H), 3.32 (t, 1H, J = 7.4 Hz), 3.64 (m, 3H),

4.50–4.62 (m, 5H), 4.76 (d, 1H, J = 11.5 Hz), 5.14 (m,

4H), 5.73 (m, 2H), 7.24–7.33 (m, 15H); ¹³C NMR

(62.9 MHz, CDCl₃): d_C30.6, 47.3, 54.2, 54.3, 57.1,

71.5, 73.2, 74.0, 77.2, 118.3, 127.5–128.4, 134.8, 138.1,

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

2321

138.4, 138.5; HRMS-ESI m/z 527.3252 [M + H]⁺

(C₃₄H₄₃N₂O₃required 527.3274).

48.1, 54.4, 65.9, 67.2, 70.0, 71.7, 73.2, 74.0, 77.3, 78.2,

127.7–128.6, 136.3, 138.3, 138.5, 156.3, 169.9; HRMS-

ESI m/z 661.2883 [M + Na]⁺(C₃₈H₄₂N₂O₇Na required

661.2890).

4.2.12.

1-O-Benzoyl-4,5,7-tri-O-benzyl-2,3,6-trideoxy-

2,6-imino-^D-manno-heptitol (15f). To a solution of aziri-

dine 5 (30 mg, 0.07 mmol) in CH₂Cl₂(3 mL) was added

benzoic acid (11.1 mg, 0.09 mmol). The reaction was

stirred overnight at room temperature and then the

solvent was removed under reduced pressure. The

crude product was puriﬁed by column chromatography

4.2.15. 4,5,7-Tri-O-benzyl-2,3,6-trideoxy-1-O-(4-nitro-

benzoyl)-2,6-imino-D-manno-heptitol (15i). To a solution

of aziridine 5 (30 mg, 0.070 mmol) in CH₂Cl₂(2 mL)

was added 4-nitrobenzoic acid (15.2 mg, 0.091 mmol).

The reaction was stirred overnight at room temperature

and then the solvent was removed under reduced pres-

sure. The crude product was puriﬁed by column chro-

(2:8, PE/AcOEt) to give 15f as a white solid (29 mg,

20

D

75%); ½aꢁ

+25.4 (c = 0.5, CHCl₃); ¹H NMR

(250 MHz, CDCl₃): d_H1.79 (ddd, 1H, J = 4.7, 9.0,

13.5 Hz), 2.06 (dt + br s, 2H, J = 4.7, 4.7, 13.4 Hz),

3.21 (dt, 1H, J = 5.3, 7.1 Hz), 3.38 (t, 1H, J = 7.1 Hz),

3.48 (m, 1H), 3.66 (d, 2H, J = 5.3 Hz), 3.77 (m, 1H),

4.34 (m, 2H), 4.46–4.60 (m, 5H), 4.82 (d, 1H,

J = 11.4 Hz), 7.25–7.43 (m, 17H), 7.54 (m, 1H), 8.05

(m, 2H); ¹³C NMR (62.9 MHz, CDCl₃): d_C30.8, 48.2,

54.4, 65.5, 70.3, 71.6, 73.2, 73.9, 77.3, 78.3, 127.5–

128.4, 129.6, 130.0, 133.0, 138.2, 138.4, 138.5, 166.2;

MS-IS m/z 552 [M + H]⁺. IR (ﬁlm) m 1712 (C@O),

matography (2/8, PE/AcOEt) to give 15i as a solid

20

D

(33 mg, 79%); ½aꢁ +28.2 (c = 0.5, CHCl₃); d_H1.79

(ddd, 1H, J = 4.7, 8.8, 13.7 Hz), 2.01 (dt, 1H, J = 4.6,

4.6, 13.7 Hz), 2.16 (br s, 1H), 3.20 ( ꢂ q, 1H), 3.38 (t,

1H, J = 7.1 Hz), 3.48 (m, 1H), 3.66 (d, 2H,

J = 5.5 Hz), 3.76 (m, 1H), 4.29–4.55 (m, 5H), 4.59 (s,

2H), 4.80 (d, 1H, J = 11.5 Hz), 7.27–7.30 (m, 15H),

8.10 (s, 4H); ¹³C NMR (62.9 MHz, CDCl₃): d_C30.7,

47.8, 54.3, 66.2, 70.2, 71.6, 73.2, 73.9, 77.1, 78.1, 123.5,

127.5–128.3, 130.6, 135.2, 138.1, 138.3, 150.4, 164.3;

3346 (NH) cm^ꢀ1

.

IR (ﬁlm) m 1717 (C@O), 3352 (NH) cm^ꢀ1

.

4.2.13. 4,5,7-Tri-O-benzyl-1-O-butanoyl-2,3,6-trideoxy-

2,6-imino-^D-manno-heptitol (15g). To a solution of aziri-

dine 5 (30 mg, 0.07 mmol) in CH₂Cl₂(3 mL) was added

butanoic acid (7.9 mg, 0.09 mmol). The reaction was

stirred overnight at room temperature and then the sol-

vent was removed under reduced pressure. The crude

product was puriﬁed by column chromatography (7:3

to 5:5: PE/AcOEt) to give 15g as a pale yellow oil

4.2.16. 4,5,7-Tri-O-benzyl-1-O-(dibenzyloxyphosphoryl)-

2,3,6-trideoxy-2,6-imino-^D-manno-heptitol (15j). To a

solution of aziridine 5 (20 mg, 0.046 mmol) in CH₂Cl₂

(1 mL) was added dibenzyl phosphate (15.5 mg,

0.056 mmol). The reaction was stirred overnight at room

temperature and then the solvent was removed under

reduced pressure. The crude product was puriﬁed by

column chromatography using AcOEt as eluant to give

20

D

1

(29.5 mg, 82%); ½aꢁ +19.6 (c = 0.9, CHCl₃); H NMR

15j as a colourless oil (25 mg, 78%); ½aꢁ +16.1 (c = 1.3,

D

1

(250 MHz, CDCl₃): d_H0.90 (t, 3H, J = 7.4 Hz), 1.61

(m, 2H, J = 7.4 Hz), 1.71 (ddd, 1H, J = 5.0, 8.9,

13.6 Hz), 1.95 (dt, 1H, J = 5.0, 5.0, 13.5 Hz), 2.26 (t,

2H, J = 7.4 Hz), 2.45 (br, 1H, NH), 3.10 (dt, 1H,

J = 5.1, 5.1, 7 Hz), 3.30 (m, 1H), 3.35 (t, 1H,

J = 7.3 Hz), 3.61 (d, 2H, J = 5.1 Hz), 3.70 (m, 1H),

4.00 (dd, 1H, J = 5.4, 11.0 Hz), 4.14 (dd, 1H, J = 8.5,

11.0 Hz), 4.41–4.62 (m, 5H), 4.78 (d, 1H, J = 11.3 Hz),

7.24–7.28 (m, 15H); ¹³C NMR (62.9 MHz, CDCl₃): d_C

13.6, 18.4, 30.8, 36.0, 48.1, 54.2, 64.7, 70.1, 71.6, 73.1,

73.9, 77.3, 78.3, 127.5–128.4, 138.2, 138.4, 173.4;

MS-IS m/z 540 [M + Na]⁺, 518 [M + H]⁺; IR (ﬁlm) m

CHCl₃); H NMR (250 MHz, CDCl₃): d_H1.66 (ddd,

1H, J = 4.8, 9.2, 13.6 Hz), 1.90 (dt, 1H, J = 4.7, 4.7,

13.5 Hz), 2.27 (br s, 1H), 3.02 (m, 1H), 3.24 (m, 1H),

3.32 (t, 1H, J = 7.2 Hz), 3.56 (m, 2H), 3.61 (m, 1H),

3.85 (dt, 1H, J = 6.0, 6.0, 11.6 Hz), 4.02 ( ꢂ q, 1H),

4.37–4.57 (m, 5H), 4.76 (d, 1H, J = 11.2 Hz), 5.00 (d,

4H, J = 8.4 Hz), 7.25–7.29 (m, 25H); ¹³C NMR

(62.9 MHz, CDCl₃): d_C30.1, 49.0 (d, J = 7.8 Hz), 54.0,

67.8 (d, J = 6.0 Hz), 69.2 (d, J = 5.4 Hz), 70.0, 71.3,

73.0, 73.8, 77.1, 78.1, 127.4–128.4, 135.6 (d,

J = 6.7 Hz), 138.0, 138.3 (2C); HRMS-ESI m/z

708.3097 [M + H]⁺(C₄₂H₄₇NO₇P required 708.3090).

1735 (C@O), 3352 (NH) cm^ꢀ1

.

4.2.17.

phosphate (15k). To

2,3,6-Trideoxy-2,6-imino-^D-manno-heptitol-1-

solution of 15j (35 mg,

4.2.14. 4,5,7-Tri-O-benzyl-1-O-(benzyloxycarbonylamino-

acetyl)-2,3,6-trideoxy-2,6-imino-^D-manno-heptitol (15h).

To a solution of aziridine 5 (25 mg, 0.058 mmol) in

CH₂Cl₂(3 mL) was added Z-glycine (18.2 mg,

0.087 mmol). The reaction was stirred overnight at room

temperature and then the solvent was removed under

reduced pressure. The crude product was puriﬁed by

a

0.049 mmol) in MeOH (1 mL) were added 1 N HCl

(0.1 equiv) and the ﬁltrate was 10% Pd/C (0.2 equiv).

The reaction mixture was stirred under H₂(1 atm) over-

night and then the catalyst was removed by ﬁltration on

a pad of Celite and neutralized with a minimal amount

of Dowex 1-X2 (OH^ꢀ) ion exchange resin. The solvent

column chromatography using AcOEt as eluant to give

was removed under reduced pressure to aﬀord com-

20

D

15h as a pale yellow oil (27 mg, 74%); ½aꢁ +20.4

pound 15k as a colourless oil (10.8 mg, 85%); ½aꢁ

D

(c = 1.2, CHCl₃); ¹H NMR (250 MHz, CDCl₃): d_H

1.72 (m, 1H), 1.92 (m, 1H), 2.07 (br s, 1H), 3.05 (m,

1H), 3.35 (m, 2H), 3.59–3.65 (m, 3H), 3.93 (m, 2H),

4.06 (dd, 1H, J = 5.6, 10.7 Hz), 4.22 (t, 1H,

J = 9.6 Hz), 4.40–4.56 (m, 5H), 4.77 (d, 1H,

J = 11.4 Hz), 5.11 (s, 2H), 5.21 (m, 1H), 7.25–7.33 (m,

20H); ¹³C NMR (62.9 MHz, CDCl₃): d_C30.9, 42.8,

+25.5 (c = 0.2, H₂O); H NMR (250 MHz, D₂O; ref.

AcOH d = 2.04): d_H1.89 (ddd, 1H, J = 5.3, 9.7,

14.7 Hz), 2.22 (dt, 1H, J = 4.2, 4.2, 14.7 Hz), 3.44 (m,

1H), 3.63 (t, 1H, J = 8.2 Hz), 3.86–3.98 (m, 3H), 4.04

(m, 1H), 4.13 (m, 2H); ¹³C NMR (62.9 MHz, D₂O–

TSP³⁹): d_C28.3 (CH₂), 50.3 (CH, d, J = 7.8 Hz), 56.0

(CH), 56.04 (CH₂), 61.9 (CH₂, d, J = 7.8 Hz), 66.2

1

2322

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

(CH), 67.6 (CH); HRMS-FAB m/z 258.0741 [M + H]⁺

(C₇H₁₇NO₇P required 258.0743).

3H), 2.01 (ddd, 1H, J = 2.0, 5.0, 13.1 Hz), 2.79 (ddd,

1H, J = 3.0, 7.2, 10.0 Hz), 2.95 (m, 1H), 3.12 (t, 1H,

J = 9.5 Hz), 3.55 (dd, 1H, J = 7.1, 11.9 Hz), 3.73 (ddd,

1H, J = 5.1, 9.1, 11.9 Hz), 3.89 (dd, 1H, J = 3.1,

11.9 Hz); ¹³C NMR (62.9 MHz, D₂O–TSP³⁹): d_C11.0,

24.0, 35.4, 53.1, 55.3, 62.9, 70.3, 74.5; MS-IS m/z 176.5

[M + H]⁺; HRMS-CI m/z 176.1281 [M + H]⁺

(C₈H₁₈NO₃required 176.1286).

4.2.18. (2R,3R,4R,6R)-3,4-Di(benzyloxy)-2-benzyloxy-

methyl-6-ethylpiperidine (16). A solution of 1.4 M methyl-

lithium (0.189 mmol, 0.135 mL) in diethylether was

added at ꢀ50 ꢁC to a slurry of CuI (0.117 mmol,

22.3 mg) in dry THF (1 mL). After 1 h a solution of

crude iodomethyl derivative 14 (0.09 mmol, 50.1 mg) in

THF (0.5 mL) was added slowly. The reaction was stir-

red overnight at room temperature, quenched with a sat-

urated aqueous solution of NH₄Cl (2 mL) and extracted

with EtOAc (3 · 5 mL). The combined organic layers

were dried over MgSO₄, concentrated under reduced

pressure and the residue was puriﬁed by column chroma-

4.2.21.

4,5,7-Tri-O-benzyl-2,3,6-trideoxy-2,6-imino-^D-

manno-heptitol (18). To a solution of ester 15f (24 mg,

0.44 mmol) in dry MeOH under argon (2 mL) was

added sodium (2.2 mg, 0.088 mmol). The reaction was

stirred 4 h at room temperature and the solvent was

removed under reduced pressure. The crude product was

puriﬁed by column chromatography using AcOEt as

tography (100% AcOEt) to give the desired compound 16

20

D

as a colourless oil (16.9 mg, 65%); ½aꢁ +24.1 (c = 1.4,

eluant to give the desired compound 18 as a colourless

20

D

1

CHCl₃); H NMR (250 MHz, CDCl₃): d_H0.87 (t, 3H,

J = 7.5 Hz), 1.35–1.50 (m, 2H), 1.65 (ddd, 1H), 1.93

(m, 2H), 2.90 (m, 1H), 3.00 (m, 1H), 3.34 (t, 1H,

J = 7.9 Hz), 3.62 (d, 2H, J = 4.7 Hz), 3.70 (m, 1H),

4.41–4.60 (m, 5H), 4.82 (d, 1H, J = 11.0 Hz), 7.24–7.31

(m, 15H); ¹³C NMR (62.9 MHz, CDCl₃): d_C11.1, 25.5,

34.0, 51.5, 54.0, 70.4, 71.4, 73.1, 74.2, 78.0, 79.3, 127.5–

128.3, 138.3, 138.6, 138.7; HRMS-CI m/z 446.2699

[M + H]⁺(C₂₉H₃₆NO₃required 446.2695).

oil (16.9 mg, 86%); ½aꢁ +29.5 (c = 0.4, CHCl₃); ¹H

NMR (250 MHz, CDCl₃): d_H1.67 (ddd, 1H, J = 5.5,

9.5, 13.7 Hz), 1.92 (dt, 1H, J = 4.2, 4.2, 13.5 Hz), 2.62

(br s, 2H), 2.89 (m, 1H), 3.14 (m, 1H), 3.36–3.69 (m,

5H), 3.81 (dd, 1H, J = 4.6, 9.0 Hz), 4.41–4.64 (m, 5H),

4.80 (d, 1H, J = 11.1Hz), 7.24–7.30 (m, 15H); ¹³C

NMR (62.9 MHz, CDCl₃): d_C31.5, 51.0, 53.7, 61.7,

69.1, 71.5, 73.2, 74.2, 77.7, 78.5, 127.5–128.3, 138.0,

138.4 (2C); MS-IS m/z 448.5 [M + H]⁺. HRMS-ESI

m/z 448.2484 [M + H]⁺(C₂₈H₃₄NO₄required 448.2488).

4.2.19. (2R,3R,4R,6R)-3,4-Di(benzyloxy)-2-benzyloxy-

methyl-6-butylpiperidine (17). A solution of 2.0 M

propylmagnesium chloride (0.094 mL, 0.189 mmol) in

diethylether was added at ꢀ50 ꢁC to a slurry of CuI

(22.3 mg, 0.117 mmol) in dry THF (1 mL). After 1 h a

solution of crude iodomethyl derivative 14 (50.1 mg

0.09 mmol) in THF (0.5 mL) was added dropwise. The

reaction was stirred overnight at room temperature,

quenched with saturated aqueous NH₄Cl (2 mL) and

extracted with EtOAc (3 · 5 mL). The combined organic

layers were dried over MgSO₄, concentrated under

reduced pressure and the residue was puriﬁed by column

4.2.22. 2,3,6-Trideoxy-2,6-imino-^D-manno-heptitol (19).

To a solution of 18 (30 mg, 0.067 mmol) in MeOH

(2 mL) were added 1 N HCl (0.1 equiv) and 10% Pd/C

(0.2 equiv). The reaction mixture was stirred under H₂

(1 atm) overnight and then ﬁltered on a pad of Celite.

The solvent was removed under reduced pressure and

the residue was puriﬁed on Dowex 1-X2 (OH^ꢀ) ion

exchange resin (elution with water). The combined frac-

tions were lyophilized to aﬀord compound 19 as a col-

20

1

ourless oil (10 mg, 87%); ½aꢁ +29.1 (c = 0.4, H₂O); H

D

NMR (500 MHz, D₂O–TSP³⁹): d_H1.66 (ddd, 1H,

J = 6.0, 11.9, 13.3 Hz), 2.01 (ddd, 1H, J = 1.8, 5.0,

13.3 Hz), 2.82 (ddd, 1H, J = 2.8, 7.8, 9.2 Hz), 3.18 (dd,

1H, J = 9.2 Hz), 3.16–3.21 (m, 1H), 3.60 (dd, 1H,

J = 7.8, 11.5 Hz), 3.61 (dd, 1H, J = 6.0, 11.5 Hz), 3.69

(ddd, 1H, J = 5.0, 9.2, 11.9 Hz), 3.79 (dd, 1H, J = 9.2,

11.5 Hz), 3.91 (dd, 1H, J = 2.8, 11.5 Hz); ¹³C NMR

(125 MHz, D₂O–TSP³⁹): d_C34.8, 54.8, 57.7, 63.1, 64.9,

72.3, 76.3; [Natural 2,3,6-trideoxy-2,6-imino-^D-manno-

heptitol³¹(same conditions): d_C34.9, 54.9, 57.7, 63.2,

65.0, 72.4, 76.4.]; MS-IS m/z 200 [M + Na]⁺, 178

[M + H]⁺; HRMS-FAB m/z 178.1078 [M + H]⁺

(C₇H₁₆NO₄required 178.1079).

chromatography (5:5, PE/AcOEt) to give the desired

20

D

compound 17 as a pale yellow oil (14 mg, 32%); ½aꢁ

1

+21.6 (c = 0.7, CHCl₃); H NMR (250 MHz, CDCl₃):

d_H0.88 (t, 3H, J = 6.3 Hz), 1.16–1.52 (m, 6H), 1.64

(m, 1H), 1.92 (m, 2H), 3.01 (m, 2H), 3.34 (t, 1H,

J = 7.9 Hz), 3.63 (d, 2H, J = 4.7 Hz), 3.69 (m, 1H),

4.41–4.60 (m, 5H), 4.82 (d, 1H, J = 11.3 Hz), 7.25–7.31

(m, 15H); ¹³C NMR (62.9 MHz, CDCl₃): d_C14.1,

22.7, 28.9, 32.2, 34.3, 50.0, 54.1, 70.3, 71.5, 73.2, 74.3,

77.9, 79.4, 127.5–128.3, 138.3, 138.6, 138.7; MS-IS

m/z 474.8 [M + H]⁺.

4.2.20. (2R,3R,4R,6R)-2-Hydroxymethyl-6-ethylpiper-

idine-3,4-diol (4). To a solution of 16 (40 mg, 0.09 mmol)

in MeOH (3 mL) were added 1 N HCl (0.1 equiv) and

10% Pd/C (0.2 equiv). The reaction mixture was stirred

under H₂(1 atm) overnight and the solids were removed

by ﬁltration on a pad of Celite. The solvent was removed

under reduced pressure and the residue was puriﬁed on

Dowex 1-X2 (OH^ꢀ) ion exchange resin (elution with

water). The combined fractions were lyophilized to

aﬀord compound 4 as a white foam (13.8 mg, 88%);

4.2.23. 4,5,7-Tri-O-benzyl-1-O-butanoyl-N-butyl-2,3,6-

trideoxy-2,6-imino-^D-manno-heptitol (20). To a mixture

of iminosugar 15g (120 mg, 0.23 mmol), butanal

(42 lL, 0.46 mmol), glacial acetic acid (40 lL, 0.7 mmol)

˚

and powdered 3 A molecular sieves (125 mg) in

anhydrous MeOH, was added NaBH₃CN (18 mg,

0.28 mmol). The reaction mixture was stirred overnight

at room temperature and then the solids were removed

by ﬁltration through a pad of Celite. The solids were

washed with EtOAc (20 mL), the organic solvent was

removed under reduced pressure and the residue was

20

1

½aꢁ +42.3 (c = 0.4, H₂O); H NMR (250 MHz, D₂O–

D

MeOH³⁹): d_H0.88 (t, 3H, J = 7.5 Hz), 1.49–1.63 (m,

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

2323

puriﬁed by column chromatography (5:5, PE/AcOEt) to

give the desired compound 20 as colourless oil (102 mg,

References and notes

20

D

78%); ½aꢁ ꢀ18.0 (c = 0.1, CHCl₃); ¹H NMR (250 MHz,

1. (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1966, 78, 495;

(b) Inouye, S.; Tsuruoka, T.; Niida, T. J. Antibiot., Ser. A

1966, 19, 288.

2. (a) Iminosugars as Glycosidase Inhibitors Nojirimycin and

Beyond; Stutz, A. E., Ed.; Wiley-VCH: New York, 1999.

CDCl₃): d_H0.89 (t, 3H, J = 7.5 Hz), 0.94 (t, 3H,

J = 7.5 Hz), 1.23–1.77 (m, 8H), 2.02 (m, 1H), 2.26 (t,

2H, J = 7.3 Hz), 2.68 (m, 2H), 2.85 (m, 1H), 3.24 (m,

1H), 3.58–3.75 (m, 4H), 4.06 (dd, 1H, J = 7.3,

11.1 Hz), 4.19 (dd, 1H, J = 5.5, 11.1 Hz), 4.46–4.62 (m,

5H), 4.83 (d, 1H, J = 11.1 Hz), 7.22–7.25 (m, 15H);

¹³C NMR (62.9 MHz, CDCl₃): d_C13.6, 14.0, 18.3,

20.6, 29.1, 30.8, 36.1, 37.1, 48.7, 53.0, 59.4, 62.2, 67.2,

71.3, 73.1, 74.1, 78.0, 78.1, 127.4–128.2, 138.0, 138.6,

138.7, 173.4; MS-IS m/z 574.5 [M + H]⁺; IR (ﬁlm) m

¨

For a historical background, see Chapter 1 by Paulsen, H.

ÔThe Early Days of Monosaccharides Containing Nitrogen

in the RingÕ; (b) Asano, N.; Nash, R. J.; Molyneux, R. J.;

Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.

3. (a) Compain, P.; Martin, O. R. Curr. Top. Med. Chem.

2003, 3, 541; (b) Compain, P.; Martin, O. R. Bioorg. Med.

Chem. 2001, 9, 3077; (c) Sears, P.; Wong, C.-H. Angew.

Chem., Int. Ed. 1999, 38, 2300.

4. (a) Moriyama, H.; Tsukida, T.; Inoue, Y.; Kondo, H.;

Yoshino, K.; Nishimura, S.-I. Bioorg. Med. Chem. Lett.

2003, 13, 2737; (b) Moriyama, H.; Tsukida, T.; Inoue, Y.;

Yokota, K.; Yoshino, K.; Kondo, H.; Miura, N.;

Nishimura, S.-I. J. Med. Chem. 2004, 47, 1930.

5. Jakobsen, P.; Lundbeck, J. M.; Kristiansen, M.; Breinholt,

J.; Demuth, H.; Pawlas, J.; Torres Candela, M. P.;

Andersen, B.; Westergaard, N.; Lundgren, K.; Asano,

N. Bioorg. Med. Chem. 2001, 9, 733.

6. (a) Lee, R. E.; Smith, M. D.; Pickering, L.; Fleet, G. W. J.

Tetrahedron Lett. 1999, 39, 8689; (b) Lee, R. E.; Smith, M.

D.; Nash, R. J.; Griﬃths, R. C.; McNeil, M.; Grewal, R.

K.; Yan, W.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J.

Tetrahedron Lett. 1997, 38, 6733.

7. (a) Schramm, V. L.; Tyler, P. C. Curr. Top. Med. Chem.

2003, 3, 525; (b) Evans, G. B.; Furneaux, R. H.;

Lewandowicz, A.; Schramm, V. L.; Tyler, P. C. J. Med.

Chem. 2003, 46, 5271; (c) Fedorov, A.; Shi, W.; Kicska,

G.; Fedorov, E.; Tyler, P. C.; Furneaux, R. H.; Hanson, J.

C.; Gainsford, G. J.; Larese, J. Z.; Schramm, V. L.; Almo,

S. C. Biochemistry 2001, 40, 853; (d) Miles, R. W.; Tyler,

P. C.; Furneaux, R. H.; Bagdassarian, C.; Schramm, V. L.

Biochemistry 1998, 37, 8615; (e) Kline, P. C.; Schramm, V.

L. Biochemistry 1993, 32, 13212.

1737 (C@O) cm^ꢀ1

.

4.2.24. N-Butyl-2,3,6-trideoxy-2,6-imino-^D-manno-hepti-

tol (21). To a solution of 20 (23 mg, 0.040 mmol) in

MeOH (2 mL) were added 1 N HCl (0.1 equiv) and

10% Pd/C (0.2 equiv). The reaction mixture was stirred

under H₂(1 atm) overnight and the solids were removed

by ﬁltration on a pad of Celite. Dowex 1-X2 (OH^ꢀ)

resin was added to the ﬁltrate and after 1 h, the reaction

mixture was ﬁltered. The solvent was removed under

reduced pressure to aﬀord compound 21 as a colour-

20

less oil (8.2 mg, 88%); ½aꢁ ꢀ7.1 (c = 0.5, H₂O); ¹H

NMR (250 MHz, D₂O): d^D_H0.91 (t, 3H, J = 7.0 Hz),

1.24–1.56 (m, 4H), 1.65 (dt, 1H, J = 5.2, 13.0,

13.0 Hz), 2.05 (ddd, 1H, J = 2.2, 5.0, 13.5 Hz), 2.55–

2.75 (m, 3H), 3.17 (m, 1H), 3.40 (t, 1H, J = 9.8 Hz),

3.61–3.94 (m, 5H); ¹³C NMR (62.5 MHz, D₂O): d_C

15.5, 22.5, 31.7, 32.2, 50.1, 57.6, 60.0, 61.0, 63.5, 72.1,

73.8. HRFABMS m/z 234.1707 [M + H]⁺(C₁₁H₂₄NO₄

required 234.1705).

4.3. Biochemical assays

8. Iminosugars: Recent Insights Into Their Bioactivity and

Potential As Therapeutic Agents in Curr. Top. Med. Chem.;

Martin, O. R.; Compain, P. Eds.; Bentham, Neth., 2003,

3, issue 5.

Brush border membranes prepared from rat small intes-

tine according to the method of Kessler et al.⁴⁰were

used as the enzyme source of rat intestinal a-glucosid-

ases. Other enzymes were purchased from Sigma Chemi-

cal Co. The activities of rice a-glucosidase and rat

intestinal a-glucosidases were determined using an

appropriate disaccharide as substrate. The released ^D-

glucose was determined colourimetrically using glucose

B-test Wako (Wako Pure Chemical Ind.). Other glycosid-

ase activities were determined using an appropriate

p-nitrophenyl glycoside as substrate. The reaction was

stopped by adding 400 mM Na₂CO₃. The released p-

nitrophenol was measured spectrometrically at 400 nm.

Glycogen phosphorylase activity was assayed in the

direction of glycogen breakdown from the photometri-

cal determination of the rate of NADPH formation in

an assayed coupled to phosphoglucomutase and glucose

6-phosphate dehydrogenase according to the method of

Maddaiah and Madsen.⁴¹

9. Alper, J. Science 2001, 291, 2338.

10. Mitrakou, A.; Tountas, N.; Raptis, A. E.; Bauer, R. J.;

Schulz, H.; Raptis, S. A. Diabetes Med. 1998, 15, 657.

11. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top.

Med. Chem. 2003, 3, 561; (b) Butters, T. D.; Dwek, A.;

Platt, F. M. Chem. Rev. 2000, 100, 4683; (c) Cox, T.;

Lachmann, R.; Hollak, C.; Aerts, J.; van Weely, S.;

Hrebicek, M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.;

Gow, I.; Elstein, D.; Zimran, A. The Lancet 2000, 355,

1481.

12. Van der Spoel, A. C.; Jeyakumar, M.; Butters, T. D.;

Charlton, H. M.; Moore, H. D.; Dwek, R. A.; Platt, F. M.

Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 17173.

13. (a) For selected recent references see: Godin, G.; Garnier,

E.; Compain, P.; Martin, O. R.; Ikeda, K.; Asano, N.

Tetrahedron Lett. 2004, 45, 579; (b) Godin, G.; Compain,

P.; Martin, O. R. Org. Lett. 2003, 5, 3269; (c) Godin, G.;

Compain, P.; Masson, G.; Martin, O. R. J. Org. Chem.

2002, 67, 6960.

14. (a) Nojima, H.; Kimura, I.; Fu-Jin, C.; Sugihara, Y.;

Haruno, M.; Kato, A.; Asano, N. J. Nat. Prod. 1998, 61,

397; (b) Taniguchi, S.; Asano, N.; Tomino, F.; Miwa, I.

Horm. Metab. Res. 1998, 30, 679.

15. (a) Asano, N.; Nishida, M.; Miyauchi, M.; Ikeda, K.;

Yamamoto, M.; Kizu, H.; Kameda, Y.; Watson, A. A.;

Nash, R. J.; Fleet, G. W. J. Phytochemistry 2000, 53, 379;

Acknowledgements

Financial support of this study by grants from CNRS

and the association ÔVaincre les Maladies LysosomalesÕ

is gratefully acknowledged.

2324

J.-Y. Goujon et al. / Bioorg. Med. Chem. 13 (2005) 2313–2324

(b) For synthesis of a close analog of 4, (+)-5-deoxyaden-

Becker, R.; Brunner, E. J. Am. Chem. Soc. 1989, 111,

7500; (f) Concellon, J. M.; Riego, E.; Suarez, J. R. J. Org.

Chem. 2003, 68, 9242.

ophorine [(2R,3S,4S,6R)-2-hydroxymethyl-6-ethylpiperi-

dine], see: Felpin, F.-X.; Boubekeur, K.; Lebreton, J. J.

Org. Chem. 2004, 69, 1497.

28. Yadav, J. S.; Subba Reddy, B. V.; Parimala, G.; Venka-

tram Reddy, P. Synthesis 2002, 16, 2383.

29. For an example of opening of an N-activated aziridine by

a phosphate see: Misiura, K.; Kinas, R. W.; Stec, W. J.;

Kusnierczyk, H.; Radzikowski, C.; Sonoda, A. J. Med.

Chem. 1988, 31, 226.

16. To our knowledge, four examples of iminosugar-derived

aziridines having the 1-azabicyclo[4.1.0]heptane skeleton

have been reported to date: one independently by

Ganem,¹⁷and its enantiomer by Paulsen,¹⁸one by

Vasella,¹⁹and two by our group²⁰.

17. Tong, M. K.; Ganem, B. J. Am. Chem. Soc. 1988, 110,

312.

18. Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter,

W. Liebigs Ann. Chem. 1990, 10, 953.

19. Bernet, B.; Bulusu Murty, A. R. C.; Vasella, A. Helv.

Chim. Acta 1990, 73, 940.

20. (a) Martin, O. R.; Xie, F.; Liu, L. Tetrahedron Lett. 1995,

36, 4027; (b) Martin, O. R.; Saavedra, O. Tetrahedron

Lett. 1995, 36, 799.

21. Goujon, J.-Y.; Gueyrard, D.; Compain, P.; Martin, O. R.;

Asano, N. Tetrahedron: Asymmetry 2003, 14, 1969.

22. For ring-opening reactions of a bicyclic aziridine having

the 1-azabicyclo[4.1.0]heptan-2-one skeleton see: Wu, X.;

Toppet, S.; Compernolle, F.; Hoornaet, G. J. Tetrahedron

2003, 59, 1483.

30. Jeﬀord, C. W.; Wang, J. Tetrahedron Lett. 1993, 34,

1111.

31. Unpublished results.

32. Kato, A.; Asano, N.; Kizu, H.; Matsui, K. J. Nat. Prod.

1997, 60, 312.

33. (a) Asano, N.; Oseki, K.; Kizu, H.; Matsui, K. J. Med.

Chem. 1994, 37, 3701; (b) Asano, N.; Kizu, H.; Oseki, K.;

Tomioka, E.; Matsui, K.; Okamoto, M.; Baba, M. J. Med.

Chem. 1995, 38, 2349; (c) Asano, N.; Nishida, M.; Kato,

A.; Kizu, H.; Matsui, K.; Shimada, Y.; Itoh, T.; Baba, M.;

Watson, A. A.; Nash, R. J.; de Q. Lilley, P. M.; Watkin,

D. J.; Fleet, G. W. J. J. Med. Chem. 1998, 41, 2565.

34. Asano, N.; Oseki, K.; Kaneko, E.; Matsui, K. Carbohydr.

Res. 1994, 258, 255.

35. Evans, S. V.; Fellows, L. E.; Shing, T. K. M.; Fleet, G. W.

J. Phytochemistry 1985, 24, 1953.

36. Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319–

384.

37. It is well-known that the 2-OH group plays an important

role in the transition-state stabilization of glycosidase-

mediated glycoside hydrolyses.

38. (a) Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely,

P. Curr. Pharm. Des. 2003, 9, 1177; (b) Treadway, J. L.;

Mendys, P.; Hoover, D. J. Exp. Opin. Invest. Drugs 2001,

10, 439; (c) Ross, A. S.; Gulve, E. A.; Wang, M. Chem.

Rev. 2004, 104, 1255–1282.

23. Costantino, V.; Imperatore, C.; Fattorusso, E.; Mangoni,

A. Tetrahedron Lett. 2000, 41, 9177.

´

24. (a) Desire, J.; Dransﬁeld, P. J.; Gore, P. M.; Shipman, M.

Synlett 2001, 1329; (b) Tius, M. A.; Busch-Petersen, J.

Tetrahedron Lett. 1994, 35, 5181.

25. (a) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett.

1996, 37, 1991; (b) Boschetti, A.; Nicotra, F.; Panza, L.;

Russo, G. J. Org. Chem. 1988, 53, 4181.

26. (a) For recent reviews see: Hu, X. E. Tetrahedron 2004, 60,

2701; (b) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247; (c)

McCoull, W.; Davis, F. A. Synthesis 2000, 10, 1347.

27. (a) For selected references see: Hayes, J. F.; Shipman, M.;

Twin, H. J. Org. Chem. 2002, 67, 935; (b) Eis, J.; Ganem,

B. Tetrahedron Lett. 1985, 26, 1153; (c) Sekar, G.; Singh,

V. K. J. Org. Chem. 1999, 64, 2537; (d) Caiazzo, A.; Dalili,

S.; Yudin, A. K. Org. Lett. 2002, 4, 2597; (e) Mulzer, J.;

39. MeOH or TSP are used as internal reference.

40. Kessler, M.; Acuto, O.; Strelli, C.; Murer, H.; Semenza,

G. A. Biochem. Biophys. Acta 1978, 506, 136.

41. Maddaiah, V. T.; Madsen, N. B. J. Biol. Chem. 1966, 241,

3873.

Article Doi

General synthesis and biological evaluation of α-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-α-C-glycosides)

DOI: 10.1016/j.bmc.2004.12.043

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.bmc.2004.12.043

Full text of DOI:10.1016/j.bmc.2004.12.043

Products guided by the article

R&D Labs maybe for 605675-65-8

Relevant to this article

Hot Product