Addition of organometallics to aldimines, aldoximes

'Recent Research Developments in Organic Chemistry'

Addition of organometallics to aldimines, aldoximes and aldononitriles: a key step towards the synthesis of azasugars

Jean-Bernard Behr*, Richard Plantier-Royon*

Laboratoire Réactions Sélectives et Applications, UMR 6519 CNRS-Université de Reims, Faculté des Sciences, BP 1039, F-51687 Reims Cedex 2, France

Corresponding Authors. Tel.: +33-326-91-32-38; fax: + 33-326-91-31-66; e-mail: [email protected] (J.-B.B.). Tel.: + 33-326-91-33-08; fax: +33-326-91-31-66; e-mail: [email protected] (R.P.-R.)

RUNNING TITLE : N-glyco-additions

ABSTRACT : Glycoconjugates play an essential role in biological events such as intercellular recognition and cell-mediated processes. Azasugars constitute the most interesting class of sugar mimics due to their potent inhibition properties towards glycoprocessing enzymes such as glycosidases and glycosyltransferases. Accordingly, azasugars may find therapeutic applications for various diseases such as diabete, cancers or viral infections. Various synthetic routes have been intensively developed during the past twenty years. This review is focused on the recent advances related to the synthesis of iminosugars by a nucleophilic addition to glycosylamines and related compounds such as glycosylhydroxylamines and glycononitriles.

Keywords: iminosugars, nucleophilic addition, glycosylamines, glycosidases

1

INTRODUCTION Since 40 years, glycobiology investigates the complex mechanisms of carbohydrate-receptor interactions and the structure-function relationships of oligosaccharides involved in molecular recognition [1]. Due to their pivotal role in the biosynthesis of oligo-, polysaccharides and glycoconjugates, glycosidases and glycosyltransferases represent two very important classes of enzymes [2]. Their inhibition was shown to induce important effects on maturation, transport and secretion of glycoproteins as well as cell-cell or cell-virus recognition processes. Therefore, glycosidases or glycosyltransferases have been envisaged as valuable targets for the development of new drugs in different fields such as diabete, viral infection, genetic disorders and cancers [3]. Iminosugars also named azasugarsξ constitute undoubtedly one of the most fascinating class of natural or synthetic carbohydrate mimics [4]. Since the discovery of nojirimycin 1a in 1966 [5], more than one hundred polyhydroxylated alkaloids have been isolated from plants and microorganisms and have shown great potential as drugs. The main representatives of the different classes of naturally occurring iminosugars are represented in Figure 1. HO

HO HO

N

HO

H

HO

R1

HO

R1

OH

OH

1d : R1=CH2CH2OH, miglitol 1e : R1=(CH2)3CH3

1a : R1=OH, nojirimycin (6.3 µM) 1b : R1=H, 1-deoxynojirimycin (8.7 µM) 1c : R1=CH2OH, homonojirimycin

HO

HO HO

HO NH

NH

HO

HO

R1

R1

2a : R1=H, DAB (0.18 µM) 2b : R1=OH, nectrisine (0.08 µM) 2c : R1=CH2OH, DMDP (3.3 µM)

HO N

3a : R1=H, isofagomine (86 µM) 3b : R1=OH, noeuromycine (0.022 µM) HO

HO

OH

HO

N

OH

HO H OH 4 : casuarine (0.7 µM)

HO

HO

N N

CO2H

NHAc 5 : nagstatine (0.01 µM)

N

HO OH 6 : castanospermine (0.015 µM)

Figure 1. Structures of some azasugars and their inhibition properties towards glycosidases.

ξ

Strictly, the term azasugar should relate to compounds in the structure of which a carbon atom has been replaced by nitrogen. However, the terms azasugar, iminosugar or iminoalditol are commonly used to characterize Nitrogen-in-the-ring sugar analogues.

2

The replacement of the ring oxygen atom by nitrogen, that has been designed by Nature itself, confers strong therapeutic potential to the resulting sugar analogues [6]. Indeed, the potent affinity of iminosugars for the active site of glycosidases or glycosyltransferases is generally attributed to their structural resemblance with the carbohydrate moiety of the natural substrate (a polysaccharide or a sugar-nucleotide) [7]. In particular, the protonated nitrogen atom can mimic the positively charged endocyclic oxygen which appears at the transition state of the biocatalytic acidic glycoside hydrolysis. In their protonated form, iminosugars are also believed to interact strongly with a carboxylate group at the enzyme active site [8]. Moreover, the spatial arrangement of the hydroxyl groups in piperidine azasugars closely resemble that of the natural sugars in their ground-state conformation. On the other hand, the flattened structure of pyrrolidine-type or bicyclic azasugars can mimic the half-chair conformation of the oxonium cation (Figure 2). HO HO HO

HO

O HO HO OH

oxocarbenium transition state

H N H OH

protonated DNJ

HO HO HO

H N

H

OH protonated DMDP

Figure 2.

Since glycosyl transfer reactions are thought to proceed through transition states similar to those of glycosidases, iminosugar derivatives have been also targeted as potential glycosyl transferase inhibitors [9]. Interestingly, some recent work has expended the potential of these sugar analogues to other classes of enzymes that utilize sugar derivatives (in particular nucleotides [10]) as substrates like DNA-polymerases [10b], UDP-Gal mutase [10c], MTAphosphorylase [11], glycogen phosphorylase [12], metalloproteases [13] or ricin toxin Achain [14]. In this context, considerable effort has been made recently to develop efficient synthetic routes, not only towards natural iminosugars like DNJ or DMDP or their synthetic derivatives, but also towards new analogues featuring various structural elements (purine or pyrimidine bases, fluorine, phosphonate, cyclopropyl ring). Recently, two N-alkylated compounds derived from 1-deoxynojirimycin have been approved as therapeutic agents: miglitol 1d (Glyset®) is used for the treatment of type-2 diabete and Zavesca® 1e has been approved as a drug for the treatment of Gaucher's disease. There is no doubt that more azasugars of practical use remain to be discovered.

Synthesis of azasugars from carbohydrates: an overview. A variety of approaches have been carried out to assemble azasugars. They can be roughly divided into two main categories : a) Those which utilise non-carbohydrate precursors. Indeed, azasugars were obtained in various manners either from tartaric acid [15] or aminoacids and derivatives like Garner's aldehyde [16] which contain the chiral information that is transferred to the growing C-chain. On the other hand, asymmetric synthesis from non chiral starting materials has also been performed for the construction of optically active polyhydroxypyrrolidines or piperidines.

3

These approaches include enzymatic processes [17], Diels-Alder cycloadditions [18], Sharpless asymmetric epoxidation or aminohydroxylation [19] as key steps. b) Those starting from carbohydrate building blocks. The similar structural features between azasugars and carbohydrates have made them ideal chirons. Actually, these readily available starting compounds, which bear at least two controlled stereocenters were used in most of the synthesis described so far. Due to the multifunctional character of carbohydrates, the iminosugar-core-structure may be reached by multiple ways. The introduction of the essential nitrogen atom is usually performed in the carbon chain in place of a free hydroxyl group, which requires multistep sequences involving fastidious protection/deprotection procedures. This type of chemistry has been comprehensively reviewed [20]. However, the nitrogen atom might also be introduced in the anomeric position, taking advantage of the particular reactivity of aldoses. Indeed, the anomeric center of aldoses can be readily aminated by treatment with either ammonia or a primary amine, to afford a glycosylamine, in equilibrium with the open-chain imine (see next section). As described in Scheme 1, these compounds might be very easily converted to azasugars. Reduction of the imine (Scheme 1, path A) or homologation with an organometallic reagent (path B) affords an aminoalditol which might be cyclized to the corresponding pyrrolidine or piperidine.

OH O

NHR

A

C-1 reduction

NHR

HO

cyclization

n

HO

OH activation

R N

a,b

c

HO

m

n

B

OH NHR

R1M C-1 homologation

HO

OH H

O NR

HO

C

-

R1

n

HO

R=OH

OH

C-1 reduction

NH2 n

HO E

OH NH2

C-1 homologation

m

N

cyclizationc

R1 m

H N

OH activationa,b HO

m

H N

OH activationa,b cyclizationc

HO

R1

HO

HO

HO

N n

c

m

OH D

cyclization

N

R1M

n

cyclization

OH activation

OH

N+

R=OH

R a,b

HO

m

n a

Maybe performed on any -OH group. bhalogenation, sulfonation, oxidation. cUsually spontaneous.

Scheme 1. Synthesis of azasugars from sugar derivatives with nitrogen at C-1.

The introduction of the nitrogen atom at the anomeric position might also be achieved by reaction with hydroxylamines to form the corresponding glycosylhydroxylamines, which are 4

stable and easy to handle azasugar precursors (Scheme 1, path A, B or C : R=OH). In addition, glycosylhydroxylamines can be conveniently dehydrated to glycononitriles, which represent another important class of sugar derivatives with nitrogen at C-1 that might give access to azasugars (Scheme 1, path D and E). However, these synthetic strategies have been scarcely reviewed. In the following sections, the use of glycosylamines, glycosylhydroxylamines and glycononitriles for the synthesis of azasugars will be emphasized, especially their reactions with organometallic nucleophiles.

Preparation and chemical properties of glycosylamines, glycosylhydroxylamines and glycononitriles. Glycosylamines are a long-known and widely exemplified class of carbohydrate-derivatives [21]. Some, such as nucleosides or glycopeptides, are of biological interest. Others are valuable synthetic intermediates in the chemistry of glycoconjugates which play essential roles in biological processes such as cell development, cell adhesion, regulation, infection, metastasis [2a,22]. The stability of glycosylamines is strongly dependent on the basicity of the aglycon, the hybridisation state and degree of substitution of the nitrogen atom, the structure of the sugar moiety, and the pH of the solution [23]. Glycosylamines exhibit mutarotation phenomena and can rearrange into isomeric compounds [21]. Crystallisation of these molecules, for solid compounds, generally occurs with one or several molecules of the solvent. These different properties often complicate the isolation and the structural analysis of glycosylamines. Nevertheless, 1H and 13C NMR have brought valuable informations concerning these molecules. For example, the pyranoid structure is favoured as well as the equatorial orientation of the amino group [24]. Substituted aliphatic or aromatic glycosylamines are easily obtained regio- and stereoselectively (β-anomer is the major isomer) from reducing sugars and primary amines in polar solvents with or without an acidic catalyst (Scheme 2) [21]. R-NH2

O OH (OR)n

∆

O (OR)n

H N

R

Scheme 2.

Other indirect methods such as condensation between amines and acylglycosyl halides, transglycosylation reactions or reduction of imines have also been reported. Synthesis of primary glycosylamines proved to be more difficult to achieve. Reaction of free sugars with aqueous ammonia leads to the formation of several by-products from epimerisation, Amadori-type rearrangement and degradation [25]. Two different synthetic routes to these particular glycosylamines have been explored recently. The carbohydrate amine functionality can be introduced by transformation of hydroxyl-protected sugars in organic solvents as reaction media. Some examples of this approach include the conversion of glycosyl halides with ammonia [26], azide [27], or the Burgess reagent [28]. Other syntheses are based on the transformation of glycals [29] or α-hydroxynitriles [30]. A second approach uses unprotected water-soluble carbohydrates and, in this case, the amination procedure is commonly carried out by the Kochetkov method with the use of a saturated solution of ammonium bicarbonate in water [31]. A new procedure for the selective 5

amination of unprotected sugars was recently introduced using ammonium carbamate in methanol as the reactant and showed a general applicability for a series of mono- and disaccharides (Scheme 3) [32]. NH4COONH2 - CO2 NH3

O OH

(HO)n

NH4COONH2

O NH2

(HO)n

R

- NH3

R

R = OH, NHAc

high vacuum or bases

O NH2

(HO)n

HOOCNH2

O NH2

(HO)n R

R precipitate in methanol Scheme 3.

Glycosylamines are very attractive chiral synthons but their synthetic use is quite scarce due to their low stability. Indeed, these molecules are generally prone to dimerization, hydrolysis and isomerization. These side reactions make the purification of glycosylamines extremely difficult and generally, the separation steps must be carried out later in the syntheses. However, on a practical point of view, glycosylamines are generally used as crude material and their transformations usually occur with high yields. In a same manner, N-benzyl-N-glycosylhydroxylamines derived from carbohydrates are suitable substrates for the synthesis of iminosugars. Synthesis of sugar hydroxylamines is generally carried out, from readily available sugars, by a simple heating with a slight excess of N-alkylhydroxylamine in a high boiling solvent or without any solvent. Purification of these glycosylhydroxylamines can be performed by crystallization or by flash chromatography and therefore demonstrating a better stability than the corresponding glycosylamines. According to their structures, glycosylhydroxylamines can exist in equilibrium with the open-chain tautomer featuring a nitrone function (Scheme 4). O OH

R-NHOH

O

∆

R N OH

R=H

OH

- H2O

OH

R N O

R=H OH N

N

OH

Scheme 4.

6

Finally, glycononitriles can be readily obtained from glycosylhydroxylamines by dehydration with a variety of reagents such as Ac2O [33] or TFA anhydride [34], MsCl [35], benzoyl chloride [36] or (S,S)-dimethyl dithiocarbonate [37]. These compounds are usually very stable and easy to handle. Their reduction or alkylation with subsequent cyclization gives a possible access to azasugars (Scheme 1, path D or E).

Addition of organometallics to glycosylamines. The first reaction of an organometallic reagent with a glycosylamine was described by Nicotra in 1989 as a part of a project towards the synthesis of D-glucosamine derived Cglycosides [38]. The addition of vinylmagnesium bromide to N-benzyl-2,3,5-tri-O-benzyl-Darabinofuranosylamine 8a was attempted by analogy with previous results on the vinylation of aldoses. The aminoalcohol 9a was obtained in good yield and high stereoselectivity and could be transformed to the α-C-glycoside 11 by aminomercuriocyclization (Scheme 5). BnOH2C

O

BnO

OH

i

O

BnOH2C BnO

OBn

NHBn

ii

OH NHBn H

BnOH2C

BnO

OBn

9a

8a

7a

OBn

iii HO O

HO HO

H2N CH 3 11

iv

BnO O

BnO BnO

BnHN CH HgCl 2 10

Scheme 5. Reagents and conditions : (i) BnNH2 (95%); (ii) CH2=CHMgBr, THF (71%); (iii) Hg(OCOCF3)2, THF, then aq. KCl (77%); (iv) NaBH4, EtOH, then H2, Pd-C.

A first application of this reaction to the synthesis of azasugars was described in 1993 by the same authors [39], which opened the route to a new and efficient synthetic procedure towards this type of compounds. The synthetic strategy involves the steroselective introduction of a new substituent at the anomeric center via the nucleophilic addition step and treatment of the so-obtained aminoalcohol with Tf2O or MsCl to give the corresponding pyrrolidine. Diversity may be introduced either at the nitrogen atom by using different Nsubstituted glycosylamines, or at the adjacent carbon by using different organometallic nucleophiles (Scheme 6).

7

RO

O

RO

NHR1

OH H NHR1

R2M n

OR

R1 = Bn, butyl, allyl,hexyl R2 = vinyl, allyl, butyl, octyl, CF2P(O)(OEt)2

R2 n

OR

syn adduct as major isomer

MsCl

RO

or Tf2O

R1 N n

inversion of configuration

R2 OR

cis position of both substituents

Scheme 6. Stereochemical outcome of the synthesis of azasugars via glycosylamines.

The stereochemical outcome of the reaction deserves some comments. As indicated in Scheme 6, the nucleophilic addition to benzyl [40,41a] or isopropylidene [41] protected αalkoxy imines affords generally the syn product as major stereoisomer, which is in agreement with Cram-chelation control models. The formation of a major anti isomer has been observed but was confined to the case in which a stoechiometric amount of BF3.OEt2 was added in the reaction mixture [41b]. Furthermore, during the cyclization procedure, an inversion of the configuration occurs at the stereocenter bearing the leaving group. This was firmly assessed by NOE experiments and has to be taken into account for the construction of azasugars with defined stereochemistry at C-5. This method allows also the introduction of easily functionalizable substituents (vinyl, allyl) for the construction of more elaborated structures. The most representative examples of this type of chemistry will be discussed below. As mentioned above, glycosyltransferases, which catalyse the transfer of a sugar residue from nucleotide-diphosphate glycosides, are believed to proceed via an oxocarbenium like intermediate in a same manner than glycosidases. Several reports suggest that (1,1difluoromethyl) phosphonates act as effective mimics of the phosphate linker [42]. These findings led to consider pyrrolidine azasugars 16 (Scheme 7), which display such a difluoromethylphosphonate substituent in their structures, as potential transition-state analogue inhibitors. The synthesis of these models was accomplished by nucleophilic opening of protected D-arabino-, D-ribo- or L-xylo-furanosylamines 8a-c with diethyl (lithiodifluoromethyl) phosphonate, followed by the cyclization of the amino phosphonate product obtained (Scheme 7) [43]. In each case, the two possible stereoisomers were formed and isolated. Similar results were obtained in the arabino, ribo and xylo series concerning the stereochemical outcome (d.e. between 40% and 70% in favour of the syn adduct) or the yields (52-55%). Deprotection of compounds 15a,b to the monophosphonate esters 16a,b was carried out by Pd(0)-catalysed transfer hydrogenation and subsequent saponification in aqueous ammonia. Both compounds were assayed against chitin synthase [44], a glycosyltransferase involved in the biosynthesis of chitin, which is considered as a valuable antifungal target (IC50 = 1.6 mM for 16a and IC50 = 38 mM for 16b).

8

R3

O

NHBn

R4 BnO

R2

OH H NHBn

R3 i

R1

R4

CF2P(O)(OEt)2

BnO

R2

OH HNBn H

R3 +

R1

R4 BnO

12a-c Major

8a-c a : R1=OBn, R2=R4=H, R3=CH2OBn b : R1=OBn, R2=R3=H, R4=CH2OBn c : R1=R4=H, R2=OBn, R3=CH2OBn

CF2P(O)(OEt)2

13a-c minor

ii

R4

ii

Bn N

CF2P(O)(OEt)2

R3 BnO

R2

R1

R2

R1

Bn N

R4

CF2P(O)(OEt)2

R3 BnO

14a-c

R2

R1

15a-c iii, iv

R4

H N

O CF2P OH OEt

R3 a : R4=H, R3=CH2OH b : R3=H, R4=CH2OH

HO

OH 16a,b

Scheme 7. Reagents and conditions : (i) HCF2P(O)(OEt)2, LDA; (ii) MsCl, pyridine; (iii) Pd-C, NH4+HCO2-, MeOH; (iv) NH4OH.

To improve the inhibitory potencies and the selectivity of compound 16a, the tricomponent bisubstrate inhibitor 22 was synthetized, which contains structural informations from both the donor (UDP-GlcNAc) and the acceptor (a GlcNAc derivative) of the enzymatic reaction [45]. Condensation of lithiodifluoromethylphosphonate was performed on Nallylglycosylamine 17 to obtain pyrrolidine 18 after cyclization (Scheme 8). Standard functional group transformations of the N-allyl moiety to the corresponding aldehyde, followed by reductive amination with N-acetylglucosamine derivative 20 gave the protected transition state analogue 21. Deprotection procedures afforded the hydrosoluble targeted compound 22. Unfortunately, 22 did not inhibit chitin synthase activity at the maximum tested concentration of 500 µΜ.

9

O O

BnO BnO

i,ii

OBn 17

H

N

BnO

NHAll

BnO

CF2P(O)(OEt)2 iii, iv

OBn

N

BnO BnO

R1O HN RO

PMBO O 20

OMe NHAc

N

RO RO

OBn 19

18 minor

H2N BnO

CF2P(O)(OEt)2

v

O OMe NHAc

CF2P(O)(OEt)2 OR

21 : R=Bn, R1=PMB 22 : R=R1=H

vi

Scheme 8. Reagents and conditions : (i) HCF2P(O)(OEt)2, LDA; (ii) MsCl, pyridine; (iii) OsO4, NMO; (iv) NaIO4/SiO2; (v) 20, MgSO4, then NaBH3CN; (vi) TFA, then HCO2NH4, Pd-C.

Grignard reagents, in particular vinyl or allyl derivatives, have been widely used as nucleophiles in the procedure. For instance, the addition of vinylmagnesium bromide to Nbenzyl-2,3,5-tri-O-benzyl-D-arabinofuranosylamine 8a afforded stereoselectively the syn product 9a in 88% d.e. (Scheme 5). The cyclization of 9a with MsCl yielded the unsaturated pyrrolidine 23a (Scheme 9) which was reduced with concomitant debenzylation to afford the alkyl-substituted azasugar 24 [39]. Analogues 25, 26 and 27 (Scheme 9) were synthesized in a same manner, starting from protected D-glucopyranose or D-mannopyranose which were reacted with different amines and Grignard reagents [46]. The alkyl substituent was expected to increase the lipophilicity of the azasugars and improve their biological properties. However, compounds 24-27 did only slightly inhibit α-mannosidase from Jack beans (Ki = 1.2-10.6 mM).

10

R3

O

NHBn

R4 BnO

OH H NHBn

R3

i

R4

8a,b a : R3=CH2OBn, R4=H b : R3=H, R4=CH2OBn

HO

: :

iii

OH H N

HO OH 25 Bu N

ii

HO

R3

BnO

OH 26 H N HO

CH2CH3 OH

OH 27

BnO OBn 30a,b

OBn 23a,b

iv

iv,v H N

R4

Bn N

BnO

OH

HO

OH

Bn N

R4

R3 (CH2)3CH3

29a 29b

6 0

Bn N

R4

(CH2)3CH3 OH

OBn

ii

24

HO

94 100

R3 HO

HO

BnO

OBn 9a 9b

OH HNBn H

R4

+

BnO

OBn

H N

R3

OH

OH BnO

OBn 31

28a,b a : R3=CH2OH, R4=H b : R3=H, R4=CH2OH

vi

NH

Bn N

BnO

O O

BnO

O

O O

N

O

O

OBn 32

HO

OH

Scheme 9. Reagents and conditions: (i) CH2=CH2MgBr, THF (88%); (ii) MsCl, pyr (75%); (iii) H2, Pd-C, H+; (iv) H2SO4, O3, then NaBH4; (v) NH4+HCO2-, Pd-C, MeOH; (v) see ref. [48].

More interestingly, ozonolysis of vinyl pyrrolidine 23a with subsequent reduction and debenzylation afforded 2,5-imino-L-iditol 28a (Scheme 9) [44], a compound featuring C2 symmetry that has been used as chiral auxiliary in asymmetric synthesis [47]. The same sequence was also conducted on N-benzyl-2,3,5-tri-O-benzyl-L-xylofuranosylamine 8b and afforded 2,5-imino-D-glucitol 28b in a very straightforward and stereoselective manner. Azasugar 28b is a potent α-glucosidase inhibitor and was also assayed as chitin synthase inhibitor (IC50 = 5.7 mM) [44]. The minor vinyl pyrrolidine 30a has been exploited for the construction of a new UDP-GlcNAc analogue (Scheme 9). Indeed, the easy transformation to the monodeprotected pyrrolidinol 31 allowed the coupling to an uridinylmalonate derivative, which yielded the transition state analogues 32 [48]. This compound proved to be a potent chitin synthase inhibitor (Ki = 35 µM) and displayed some antifungal activity.

11

As shown above, the use of the L-xylo configurated glycosylamine 8b allows the synthesis of D-configurated polyhydroxypyrrolidines, which are widespread in Nature. Accordingly, the first synthesis of the natural 6-deoxy-homoDMDP 33a and its stereoisomer 33b (isolated in 1998 from Hyacinthus orientalis) has been achieved in a very concise manner starting from 8b via allylmagnesium chloride addition, cyclization, allyl to hydroxyethyl functionalization and debenzylation (Scheme 10). This work permitted to ascertain the absolute configuration of the natural analogues [49].

O

BnO

NHBn

Bn N

BnO

+ BnO

OBn

i,ii

BnO

Bn N

BnO

OBn

BnO

OBn

34

8b

35

iii

iii

Bn N

BnO BnO

Bn HO N

BnO OBn

OH

OH BnO

36

OBn 37

iv,v

iv,v

H N

HO HO

HO

H N

HO OH

33b

OH

OH HO

OH 33a

Scheme 10. Reagents and conditions : (i) AllylMgCl (91%); (ii) MsCl, pyridine (80%); (iii) OsO4, NMO (90%); (iv) NaIO4, EtOH/H2O then NaBH4 (83%); (v) HCO2NH4, Pd-C, MeOH.

In addition, the unsaturated intermediates 34 and 35 were used as building blocks for the synthesis of a new series of polyhydroxypyrrolizidines, structurally related to (+)-casuarine 4 [50]. Bishydroxylation of 34 or 35 gave two pairs of easily separable stereoisomeric diols. The selective activation of the primary alcohol function with TsCl lead to spontaneous ring closure (Scheme 11). Debenzylation of the resulting bicyclic compounds gave the four pyrrolizidines 38a-d which proved to be potent amyloglucosidase inhibitors [51].

12

36

37 i,ii

i,ii

HO HO HO

HO R

N

1

HO

R2 H

R

N

1

R2

HO

H

38c: R1=OH, R2=H 38d: R1=H, R2=OH

38a: R1=OH, R2=H 38b: R1=H, R2=OH

IC50 (amyloglucosidase from Aspergillus niger) 103 µM 120 µM 4.5 µM 3.7 µM

38a 38b 38c 38d

Scheme 11. Reagents and conditions : (i) TsCl, pyridine (40-60%); (ii) HCO2NH4, Pd-C, MeOH (40%).

The unsaturated pyrrolidine 35 also served as precursor of a new family of C-iminoglycosyl α-aminoacids via cross-metathesis with N-Boc-vinyl- and allyl-oxazolidine as described in Scheme 12 [52] .

BocN

Bn N

BnO

0,1 BnO

Bn N

O

OBn

Grubbs' catalyst

BnO

BocN O 0,1

BnO

OBn

34 : R=Bn R=Cbz Scheme 12.

Addition of organometallics to glycosylhydroxylamines and glycononitriles. Dondoni et al. have demonstrated the ability of N-benzyl-N-furanosyl or pyranosylhydroxylamines to act as versatile precursors of 5- or 6-membered ring iminosugars by their reaction with 2-lithio thiazole, as a formyl group equivalent, followed by suitable transformation of the resulting adducts (Scheme 13) [53].

13

O

BnO

OH

BnO

88 %

OBn

O

BnO

i

BnO

7a

BnO

OBn 39a

Bn N+ O-

OH

BnO

N(OH)Bn

OBn 40a

N S

Li

OH OBn BnO

75 %

*

OH OBn ii

Th

78 %

OBn N(OH)Bn

Bn N

Th

iv

42 Bn N

BnO

R

73 % BnO

vi

H N

HO

OH

86 % BnO

OBn 43

65 %

OBn NHBn

41, dr = 9 : 1

BnO

iii

Th

BnO

v 74 %

OBn

R = CHO : 44

HO

OH 28b

R = CH2OH : 45

Scheme 13. Th = 2-thiazolyl. Reagents and conditions : (i) BnNHOH; (ii) Cu(OAc)2, Zn; (iii) Tf2O, pyridine; (iv) TfOMe; then NaBH4; then AgNO3 in MeCN-H2O; (v) NaBH4; (vi) H2, 20% Pd(OH)2/C; then Dowex (OH-).

A range of pyrrolidine homoazasugars have been prepared according to this reaction sequence [54]. In a more recent work, the authors investigated the reactivity of the glycosylhydroxylamines towards other metallic nucleophiles such as 1-trimethylsilylethynyl lithium or allylmagnesium bromide [55]. The so-obtained open-chain hydroxylamines were converted into iminosugar C-glycosides as exemplified with the synthesis of 6-deoxy homoDMDP 33a (scheme 14).

14

O

BnO BnO

OH

82 %

OBn

O

BnO

i

N(OH)Bn

BnO

7b

BnO

OBn 39b

BnO

BnO

85 %

OBn N(OH)Bn

Bn N

H N HO

ref [49]

iv 80 %

47

HO OBn

* OBn NHBn

46, anti / syn = 85 : 15

BnO

OBn

OH OBn iii

*

80 %

Bn N+ O-

40b

OH OBn ii

BnO

OH

BnO

35

OH

OH 33b

Scheme 14. Reagents and conditions : (i) BnNHOH; (ii) AllMgBr, THF, -30°C; (iii) Cu(OAc)2, Zn, AcOH, H2O, 70°C; (iv) MsCl, pyridine, rt.

In contrast with the analogous reaction involving glycosylamines, the reaction of organometallics with glycosylhydroxylamines yields the anti adduct as the major stereoisomer. It is assumed that the addition of the nucleophilic species occurred to the open chain nitrone which can be seen as an alkoxy iminium equivalent. The anti selectivity can be rationalized by a preferential conformation adopted by the nitrone due to metal coordination to both the nitrone oxygen and the free hydroxyl group, as depicted in Figure 3.

OBn O H H RMgBr

Mg N Bn O H +

anti-adduct

H OBn CH OBn 2

Figure 3.

Jäger and co-workers have reported stereoselective syntheses of a series of 3,4dihydroxypyrrolidine 1-oxides 51 by an analogous strategy (Scheme 15), taking advantage of substituent variation in the nitrone addition step and of the Cope-House cyclization of the corresponding unsaturated hydroxylamines 49 derived from D-ribose [56]. Removal of the acetonide protecting group in the so-formed compound 50 using aqueous HCl in methanol gave, after purification with an acidic ion exchange resin, the crystalline pyrrolidine N-oxides.

15

Bn

4 steps

O

N

OH

HO HO

40 %

OH

O

R

i

+

Bn N

O-

OH O

O

O

48

49

R = H, (2S)-Me, (2R)-Me, (2S)-Vinyl, (2S)-Ph, (2R)-Ph -

O N

ii

-

Bn +

O

iii-v

R

Bn N+

R

57-84 % O

O

HO

OH 51

50

Scheme 15. Reagents and conditions : (i) R-M; (ii) CHCl3, rt; (iii) conc. HCl, MeOH/H2O, rt; (iv) Dowex 50W-X8 (H+ form); (v) recrystallization (MeOH/Et2O).

Intermediates 50 were also reduced with acid-activated zinc dust and fully deprotected to the corresponding pyrrolidines 54 (Scheme 16).

Bn

Bn 50

i

N

R

49-84 %

ii

N

H R

78-96 % O

O 52

iii

N

R

50-87 % HO

OH 53

HO

OH 54

R = H, (2S)-Me, (2R)-Me, (2S)-Vinyl, (2S)-Ph, (2R)-Ph Scheme 16. Reagents and conditions : (i) Zn, AcOH, rt; (ii) conc. HCl, MeOH/H2O, rt; (iii) H2 (4 bars), Pd(OH)2/C, MeOH, rt.

The synthesis of proline derivatives using the same methodology has also been described [56]. From the (2S)-2-vinyl pyrrolidine 55, the targeted compounds were accessible through a sequence of bis(hydroxylation), lead tetraacetate cleavage of the diol and reduction or oxidation of the corresponding aldehyde 59 (Scheme 17). The glycosidase inhibition potencies of these compounds were evaluated. Whereas none of the pyrrolidine N-oxides showed significant inhibition, several of the iminopolyols prepared turned out to be weak to moderate glycosidase inhibitors, with Ki in the range from 30 to 500 µM.

16

Bn

Bn i

N

iv

N

83 % O

Z

OH

N

OH

O

O

55 79 % iii

R=H

57

R=Z

58

H

O

O

R = Bn 56

100 % ii

O

O

59 3 steps

3 steps

H

H

N

N

OH

O OR

R = H, Me HO

OH

HO

60

OH 61

Scheme 17. Reagents and conditions : (i) OsO4, NMO, acetone/H2O, rt; (ii) H2 (4 bars), Pd(OH)2/C, MeOH, rt; (iii) BnOCOCl, Na2CO3, dioxane/H2O, rt; (iv) Pb(OAc)4, K2CO3, CH2Cl2, rt.

Recently, O-protected aldoximes have also emerged as powerful synthetic precursors of hydroxylated cyclic nitrones (Scheme 1, path C). These compounds, which can be seen as azasugars in an oxidized form, may be either reduced or may serve as substrates for the preparation of C-2 substituted azasugars via 1,3-dipolar cycloadditions or organometallic additions. Cyclic nitrones were generally prepared in a four-step sequence from the protected sugar [57] as exemplified in Scheme 18. After synthesis of the corresponding oxime, the hydroxyl group of the oxime was protected by a hindered silylated group. Mesylation of the alcohol at C-4 and subsequent O-desilylation with Bu4NF gave the cyclic nitrones (Scheme 18), sometimes in the presence of the corresponding cyclic oxime [58]. i, ii

O

BnO

OH

OH

BnO

OTBDPS N

100 % BnO

BnO

OBn

62

7

iii

OTBDPS

OMs

BnO

OBn

N

70 %

iv 90 %

BnO

OBn 63

ON+

BnO BnO

OBn 64

Scheme 18. Reagents and conditions : (i) NH2OH.HCl, pyridine, rt; (ii) TBDPSi-Cl, pyridine, rt; (iii) MsCl, TEA, CH2Cl2, rt; (iv) TBAF, toluene, ∆.

As the cyclization occurs with an inversion of the configuration at the attacked carbon atom, the formation of the nitrone generally induces an inversion in the D or L-series. An initial 17

conversion of the free hydroxy group to the corresponding iodide by Garegg’s method permitted to retain the D or L-series of the starting sugar, according to the resulting double inversion of the whole procedure (Scheme 19) [57d]. Oi

BnO

62

OTBDPS

I N

48 % BnO

N+

BnO

ii 91 %

BnO

OBn 65

OBn 66

Scheme 19. Reagents and conditions : (i) I2, ImH, Ph3P, toluene, ∆. (ii) TBAF, toluene, ∆.

Such nitrones have shown remarkable reactivity as 1,3-dipoles in cycloadditions towards alkenes [57d, 58, 59] and this reaction has been used in the synthesis of a series of pyrrolizidines [60]. The synthesis of 7-deoxycasuarine 38c and hyacinthacine A2 72 by Goti and co-workers is a representative example of this type of chemistry [61]. OBn

O-

COX

N+

BnO

R BnO

CH2Cl2

+ rt

OBn

BnO BnO

66

OBn

N O H

COX

R

67a-c

+

BnO BnO

N O H

COX

R

68a-c

R = COOMe, X = OMe

78 %

-

R = H, X = OMe

56 %

23 %

R = H, X = NMe2

78 %

-

Scheme 20.

The reaction of nitrone 66 with a range of dipolarophiles afforded mainly the anti isomers 67a-c (Scheme 20), which display the expected relative stereochemistry at C-1 and C-7 in the final target molecules. The N,N-dimethyl amide cycloadduct 67c was then converted into the desired pyrrolizidines 38c and 72 by a simple three- or four-step sequences as described in Scheme 21. Another approach to 7-deoxycasuarine 38c was described using the same methodology based on a 1,3-dipolar cycloaddition of nitrone 66 and allyl alcohol [62].

18

OBn

OBn

N O

BnO

i

N

BnO

CONMe2

O OH

80 % H

BnO

67c

iv OH

OH

iv

N

BnO

N

HO 75 %

76 %

H

OH

OBn

N

BnO

40 %

ii, iii

OBn

N HO

69

75 % iii

OH HO

H

BnO

BnO

38c

H

H

BnO

70

H

HO

71

72

Scheme 21. Reagents and conditions : (i) Zn, CH3COOH/H2O, 50°C; (ii) MsCl, TEA, CH2Cl2, rt; (iii) LiAlH4, THF, ∆; (iv) H2, Pd/C, MeOH, rt.

On the other hand, the addition of organometallic reagents to five-membered enantiopure cyclic nitrones (Scheme 1, path C) has revealed a straightforward approach to substituted chiral pyrrolidines. Recent results have shown that nucleophilic addition to various nitrones proceeded smoothly and with high stereoselectivity [63]. At first, the use of TMSCN was effective, affording the corresponding transhydroxyaminonitriles such as 74a as the only diastereomer. These compounds are direct precursors of 2-aminomethyl pyrrolidines like 76a (Scheme 22) [64].

O-

O-

OH i

+

N

N

100 % O

O

ii

CN

OH

+

iii

CN

N

100 % O

O

73

100 % O

O

74a

O

O

75

74b

100 % iv H N

76a

iv

NH2 . HCl O

O

CN

N

H N

iv

O

NH2 . HCl O

76b

Scheme 22. Reagents and conditions : (i) TMSCN (2.4 equiv), MeOH, rt; (ii) MnO2 (1.2 equiv), CH2Cl2, rt; (iii) NaBH4 (4 equiv), MeOH, 0°C; (iv) H2, 5 % Pd(OH)2/C, conc. HCl/MeOH 1:30, 150 bars, 30°C.

19

Since an inversion of configuration at C-2 can be achieved through an oxidation-reduction sequence, both possible configurations are accessible, starting from a same precursor. Thus, reduction of the hydroxylamine 74a under high hydrogen pressure (150 bars) gave the trans2-aminomethyl pyrrolidine 76a in a quantitative yield. Whereas, oxidation of compound 74a with MnO2 afforded the ketonitrone 75 which was stereoselectively reduced to pyrrolidine 76b featuring the all-cis stereochemistry. The same synthetic strategy was exploited to obtain 2-hydroxymethyl pyrrolidines by using LiCH2OMOM as the synthetic equivalent of the hydroxymethylanion (Scheme 23) [64]. The organolithium derivative reacted with the cyclic nitrone 73 with the usual antistereoselectivity to afford the hydroxylamine 77a (Scheme 23). Direct reduction as well as the oxidation-reduction sequence were performed as previously described to give the fully deprotected enantiopure polyhydroxylated pyrrolidines 78a,b. O-

O-

OH i

+

N

N

R

70 % O

O

ii

OH

+

N

iii

R

65 % O

O

73

O

O

O

79

77b

100 % iv H N

HO

iv

OH OH

78a

R

100 % O

R = OMOM

77a

N

H N

iv

OH OH

HO 78b

Scheme 23. Reagents and conditions : (i) LiCH2OMOM (1.2 equiv), THF, -78°C; (ii) MnO2 (1.2 equiv), CH2Cl2, rt; (iii) NaBH4 (4 equiv), MeOH, 0°C; (iv) H2, 5 % Pd(OH)2/C, conc. HCl/MeOH 1:30, 150 bars, 30°C.

A synthesis of (+)-lentiginosine 86 and structural analogues was based on a highly stereoselective addition of vinylmagnesium bromide on the L-tartaric acid-derived nitrone 80 as the key step (Scheme 24)[65]. The resulting hydroxylamine 81 derived from an anti-attack of the organometallic reagent with respect to the vicinal hindered alkoxy group. After reduction of the hydroxylamine to the corresponding amine 82, the latter was reacted with but-3-enoic acid to give the amide 83. The ring-closure metathesis reaction was performed using the first-generation Grubbs' catalyst and yielded 84, the bicyclic precursor of (+)lentiginosine. Transformation of 84 to (+)-lentiginosine and some structural analogues were carried out using standard methods.

20

O-

O

OH i

N+

ii

N

96 %

iii

84 %

OtBu

tBuO

H N

OtBu

tBuO

80

N

71 % OtBu

tBuO

81

OtBu

tBuO

82

83

O iv

v

N H

60 %

OtBu

tBuO 84

H

62 %

OtBu

tBuO 85

vii

80 %

vi

N

N H

62 %

OH

HO 86

(+)-lentiginosine

O N H OH

HO 87

Scheme 24. Reagents and conditions : (i) CH2CHMgBr, Et2O; (ii) In cat., Zn, MeOH, NH4Cl, ∆; (iii) CH2CHCH2COOH, BtOH, DCC; (iv) (Cl)2(Cy3P)2RuCHPh, CH2Cl2; (v) LiAlH4, THF; (vi) H2, Pd/C, MeOH then TFA; (vii) TFA.

N-glycosylnitrones like 88 were recently found to react as synthetic equivalents of chiral C-1, C-1' bis-nitrone synthons in organometallic additions [66]. Treatment of the C-phenyl-Nerythrosylnitrone 88 with a 3-fold excess of a Grignard reagent gave the expected bis-adducts in good yields (Scheme 25). The stereochemistry of the two newly generated stereocenters was studied. The major bis-adducts 90 appeared to derive from a preferential attack of the Grignard reagent at the re face for the first attack and the si face for the second.

21

O-

O-

N

O

excess

Ph

+

R

HO

N

RMgX

O

O

N

O

Ph

+

OH

+

R

O

O

Ph

O

O

88

90

RMgX

RMgX

O

O

XMg

N

O

Ph

MgX Ph

O

R N+

R O

O

O

O

89 Scheme 25.

From the acetylated bis-allyl adduct 92, the synthesis of azasugar 96 which display a particular pyrrolidinoazepine structure, was carried out through a ring-closure metathesis reaction (Scheme 26). Reduction of the so-formed hydroxylamine with zinc dust and subsequent cyclization with triflic anhydride afforded the pyrrolidinoazepine 95. Final deprotection of the hydroxyl groups was achieved by acidic treatment, which gave the desired product as its hydrochloride salt. OH N

HO

OAc i

Ph

N

AcO

Ph

O

O

92

93

Ph Ph

HO

NH H

90 %

O

O 94

iv

v

N

90 %

H O

O

O

O

91

iii

Ph N H OAc

AcO

98 %

98 % O

ii

O 95

Ph H + Cl- N

80 %

H HO

OH 96

Scheme 26. Reagents and conditions : (i) Ac2O, THF, 65°C; (ii) 2nd generation Grubbs' catalyst 5 %, CH2Cl2, 40°C; (iii) KHCO3, MeOH, rt then Zn, AcOH, rt; (iv) Tf2O, pyridine, rt; (v) conc. HCl, MeOH, rt.

22

Finally, glycononitriles have also been used as precursors of azasugars. The most simple way to reach polyhydroxypyrrolidines from glycononitriles consists in the reduction of the CN triple bond to the corresponding primary amine which can cyclize via an intramolecular nucleophilic displacement (Scheme 1, path D). Such an example was reported some years ago for the stereoselective synthesis of the streptomycetal antibiotic (–)-anisomycin from Dgalactose [67]. Treatment of the oxime 98 with methanesulfonyl chloride in pyridine caused simultaneously dehydration and mesylation, furnishing a good yield of the nitrile mesylate 99 (Scheme 27). The reductive cyclization was performed in 65% yield using diborane in THF at reflux. Debenzylation by transfer hydrogenolysis in the presence of formic acid led to crystalline (–)-deacetylanisomycin 101 in 85% yield. 9 steps D-Galactose

O

4-OMe-Ph

i

OH

OH

4-OMe-Ph

OH N

86 % BnO

OBn

BnO

97 OMs N

ii 4-OMe-Ph

98

BnO

OBn 99

4-OMe-Ph

4-OMe-Ph BnO

OBn 100

H N

iv

H N

iii 65 %

71 %

OBn

(-)-anisomycin

77 % HO

OH 101

Scheme 27. Reagents and conditions : (i) NH2OH.HCl, pyridine, EtOH, ∆; (ii) MsCl, pyridine, rt; (iii) BH3 1M in THF, THF, ∆; (iv) 10 % Pd/C, EtOH, HCOOH, Sonication, 45°C.

Glycononitriles are also valuable precursors of tetrazole derived polyhydroxylated piperidines via intramolecular 1,3-dipolar cycloaddition of 5-azido-5-deoxy-glycononitriles [68]. Accordingly, the nojirimycin-derived tetrazole 110, named nojiritetrazole, was easily obtained from 2,3,4,6-tetra-O-benzyl-D-glucose in 6 steps as described in Scheme 28. Interestingly, the reductive cleavage of the tetrazole functionality can be performed by LiAlH4 to afford, after debenzylation, the well-known deoxynojirimycin. This nojiritetrazole proved to be a good competitive inhibitor of glucosidases. The analogue featuring the D-manno configuration, named mannonojiritetrazole, was synthesized according to the same procedure [69].

23

OBn

BnO OH

O

OBn

BnO

i 99 %

OBn

BnO

OBn

OH

N

OH

OH CN

ii 85 %

104

OBn O CN OBn

OBn OR CN

iv 86 %

OBn

BnO

OBn

OR CN

vi 70 %

BnO

OBn

R = H 106

+

OBn H N

CN

OBn

BnO

OBn

105

92 %

OBn

103

OBn

iii

OBn

BnO

OBn

102

BnO

OBn

OBn 10 %

108

97 % v R = Ts 107 OR R = Bn

109

R=H

110

98 % vii

N N N N OR

RO OR

nojiritetrazole Scheme 28. Reagents and conditions : (i) NH2OH, EtOH, ∆; (ii) PPh3, CBr4, CH3CN, rt; (iii) DMSO, (COCl)2, CH2Cl2, Et3N; (iv) NaBH4, CeCl3.6 H2O, -60°C; (v) TsCl, pyridine, ∆; (vi) NaN3, DMSO, 110-125°C; (vii) H2, Pd-C, MeOH, AcOH.

Recently, reaction of nitriles with organometallic reagents (Scheme 1, path E) has been envisaged in our lab as a new synthetic pathway to unprecedented structures. The conversion of aromatic and aliphatic nitriles into primary cyclopropylamines can readily be achieved using Grignard reagents in the presence of titanium tetraisopropoxide [70]. This method was extended to carbohydrate-derived nitriles, in particular glycononitriles, and proved to be effective with a range of protecting groups [71]. Thus, we performed the first synthesis of a spirocyclopropyl azasugar, based on a straightforward titanium-mediated transformation of protected arabinononitrile 112 into the corresponding cyclopropylamine with concomitant cyclization [72]. The starting nitrile 112 was initially obtained by dehydration of the corresponding oxime and concomitant O-mesylation with methanesulfonyl chloride in 76% yield (Scheme 29). Cyclopropanation was performed in the presence of BF3.Et2O and was followed by the cyclization to give the targeted pyrrolidine 115 in 42% yield. Conventional debenzylation was performed, after protection of the amine function with a Boc group, to afford the polyhydroxylated compound finally deprotected by acidic removal of the N-Boc protection and purification with a Dowex 50W-X8 resin.

24

OBn

OBn O

OH

OH

i

N

OH

76 %

91 % BnO

BnO

OBn 7

iii

OBn

ii

OBn

BnO

111 OBn H N

OBn

Boc

OH H N

v

N

50 %

88 % BnO

OBn 112

iv

42 %

OMs CN

OBn

BnO

113

OBn

HO

114

OH 115

Scheme 29. Reagents and conditions : (i) NH2OH.HCl, NaHCO3; (ii) MsCl (6 equiv), pyridine, rt; (iii) EtMgBr (2.2 equiv), Ti(OiPr)4, -78°C to rt then BF3.Et2O (2 equiv); (iv) Boc2O, Et3N, THF, rt; (v) H2, 10 % Pd/C, MeOH, rt then 1 M HCl, rt and Dowex 50W-X8

The same methodology was applied to other fully protected aldoses as starting materials. Thus, a range of polyhydroxylated pyrrolidines with a spirocyclopropyl group in the 5position were synthesized (Figure 4) [73]. H N

R

OH

H N

2

OH

R1 HO

H

OH

1

HO 2

118

115 : R = CH2OH, R = H 116 : R1 = H, R2 = CH2OH

H N HO

OH

OH 117

OH

H N HO

OH

OH

119

Figure 4.

As five-membered-ring iminosugars featuring a methyl group at C-5 displayed potent Lfucosidase inhibition properties, the replacement of the methyl group by a spirocyclopropane could induce electronical and conformational modifications which might influence the binding interactions towards the biological receptor. These pyrrolidines were analysed for their inhibitory activities towards α-L-fucosidase from bovine kidney and various other commercially available glycosidases [73]. The spirocyclopropyl azasugar 118 proved to be a potent and selective competitive inhibitor of α-L-fucosidase with Ki = 1.6 µM and IC50 = 13 µM. Other pyrrolidines obtained from pentoses are weaker inhibitors of α-L-fucosidase. However, compound 116 displayed potent inhibition of amyloglucosidases from Aspergillus niger (IC50 = 100 µM) and rhizopus mold (IC50 = 47 µM).

25

Conclusion The two-steps sequence nucleophilic addition – cyclization onto carbohydrates bearing a nitrogen atom at the anomeric position proved to be a fast and efficient method for the synthesis of azasugars. Glycosylamines, glycosylhydroxylamines and glycononitriles are effective starting materials allowing a functionalization at the 2-position of the nitrogen heterocycle. A range of polyhydroxylated pyrrolidines, piperidines and indolizidines were synthesized using this methodology. However, this wide-scope reaction has not been exploited extensively yet. According to the increasing interest of iminosugars as potent inhibitors of glycosidases and glycosyl transferases, this straightforward route should give new developments in the future.

References and notes 1. 2. 3.

4. 5. 6.

7. 8. 9. 10.

Davies, G.J., Sinnott, M.L. and Withers, S.G. 1998, Comprehensive Biological Catalysis, Academic Press, London. a) Dwek, R.A. 1996, Chem. Rev., 96, 683. b) Varki, A. 1993, Glycobiology, 3, 97. a) Fiaux, H., Popowycz, F., Favre, S., Schütz, C., Vogel, P., Gerber-Lemaire, S. and Juillerat-Jeanneret, L. 2005, J. Med. Chem., 48, 4237. b) Kim, J. H., Curtis-Long, M. J., Seo, W. D., Ryu, Y. B., Yang, M. S. and Park, K. H. 2005, J. Org. Chem,. 70, 4082. c) Robina, I., Moreno-Vargas, A. J., Carmona, A. T. and Vogel, P. 2004, Curr. Drug Metab., 5, 329-361. d) Greimel, P., Spreitz, J., Stütz, A.E. and Wroddnigg, T.M. 2003, Curr. Top. Med. Chem., 3, 513. e) Butters, T.W., Dwek, R.A. and Platt, F.M. 2000, Chem. Rev., 100, 4683. f) Johnson, P.S., Lebovitz, H.E., Coriff, R.F., Simonson, D.C., Raskin, P. and Munera, C.L. 1998, J. Clin. Endocrinol. Metab., 83, 1515. g) Mehta, A., Zitzmann, N., Rudd, P.M., Block, T.M. and Dwek, R.A. 1998, FEBS Lett., 430, 17. h) Ichikawa, Y., Lin, Y.C., Dumas, D.P., Shen, G.J., Garcia-Junceda, E., Williams, M.A., Bayer, R., Ketcham, C., Walker, L.E., Paulson, J.C. and Wong, C.-H. 1992, J. Am. Chem. Soc., 114, 9283. i) Fleet, G.W.J., Karpas, A., Dwek, R.A., Fellows, L.E., Tyms, A.S., Petursson, S., Namgoong, S.K., Ramsden, S.G., Smith, P.W., Son, J.C., Wilson, F.X., Witty, D.R., Jacob, G.S. and Rademacher, T.W. 1988, FEBS Lett., 237, 128. j) Bernaki, R.J. and Korytnyk, W. 1985, Cancer Metast. Rev., 4, 81. Stütz, A.E. 1999, Iminosugars as glycosidase inhibitors: Nojirimycin and beyond, Wiley-VCH, Weinheim. Inouye, S., Tsuruoka, T. and Niida, T. 1966, J. Antibiot., 19, 288. a) Asano, N., 2003, Glycobiology, 13, 93R. b) Iminosugars : Recent Insights into their Bioactivity and Potential as Therapeutic Agents; Martin, O. R., Compain, P., Eds. Curr. Top. Med. Chem. 2003, 3, N°5. Sinnott, M.L., 1990, Chem. Rev., 90, 1171. a) Heightmann, T.D. and Vasella, A.T. 1999, Angew. Chem. Int. Ed., 38, 288. b) Vasella, A., Davies, G.J. and Böhm, M. 2002, Curr. Opin. Chem. Biol., 6, 619. (a) Behr, J.-B. 2003, Curr. Med. Chem. (Anti Infective Agents), 3, 173. (b) Compain, P., Martin, O.R. 2001 Bioorg. Med. Chem., 9, 3077. (a) Mayer, A., Häberli, A. and Leumann, C.J. 2005, Org. Biomol. Chem., 3, 1653. (b) Mizushina, Y., Xu, X., Asano, N., Kasai, N., Kato, A., Takemura, M., Asahara, H., Linn, S., Sugawara, F., Yoshida, H., Sakaguchi, K. 2003, Biochem. Biophys. Res. Comm., 304, 78. (c) Lee, R.E., Smith, M.D., Nash, R.J., Griffiths, R.C., McNeil, M.,

26

11. 12. 13.

14. 15. 16.

17.

18.

19.

20.

21.

22.

23. 24.

25. 26. 27.

Grewal, R.K., Yan, W., Besra, G.S., Brennan, P.J. and Fleet, G.W.J. 1997, Tetrahedron Lett., 38, 6733. Evans, G.B., Furneaux, R.H., Lenz, D.H., Painter, G.F., Schramm, V.L., Singh, V. and Tyler, P.C. 2005, J. Med. Chem., 48, 4679. Somsak, L., Nagy, V., Hadady, S., Docsa, T. and Gergely, P. 2003, Curr. Pharm. Des., 9, 1177. a) Moriyama, H., Tsukida, T., Inoue, Y., Yokota, K., Yoshino, K., Kondo, H., Miura, N. and Nishimura, S.-I., 2004, J. Med. Chem., 47, 1930. b) Tsukida, T., Moriyama, M., Inoue, Y., Kondo, H., Yoshino, K. and Nishimura, S.-I. 2004, Bioorg. Med. Chem. Lett., 14, 1569. Roday, S., Amukele, T., Evans, G.B., Tyler, P.C., Furneaux, R.H. and Schramm, V.L. 2004, Biochemistry, 43, 4923. Lysek, R. and Vogel, P. 2004, Helv. Chim. Acta, 87, 3167. a) Qiu, X.-L. and Qing, F.-L. 2005, J. Org. Chem., 70, 3826. b) Cooper, S.T., Larigo, A.S., Laurent, P., Moody, C.J. and Takle, A.K. 2005, Org. Biomol. Chem., 3, 1252. c) Pyun, S.-J., Lee, K.-Y., Oh, C.-Y., Joo, J.-E., Cheon, S.-H. and Ham, W.-H. 2005, Tetrahedron, 61, 1413. d) Kim, J.H., Curtis-Long, M.J., Seo, W.D., Ryu, Y.B., Yang, M.S. and Park, K.H. 2005, J. Med. Chem., 70, 4082. e) Huang, Y. and Dalton, D.R. 1997, J. Org. Chem., 62, 372. a) Schuster, M. 1999, Bioorg. Med. Chem. Lett., 9, 615. b) Johns, B.A. and Johnson, C.R. 1998, Tetrahedron Lett., 39, 749. c) Takayama, S., Martin, R., Wu, J., Laslo, K., Siuzdak, G. and Wong, C.-H. 1997, J. Am. Chem. Soc., 119, 8146. a) Osborn, H.M.I. and Coisson, D. 2004, MiniRev. Org. Chem., 1, 41. b) Behr, J.-B., Chevrier, C., Defoin, A., Tarnus, C. and Streith, J. 2003, Tetrahedron, 59, 543. c) Streith, J. and Defoin, A. 1994, Synthesis, 1107. (a) Ayad, T., Génisson, Y. and Baltas, M. 2005, Org. Biomol. Chem., 3, 2626. b) Wang, R.-W. and Qing, F.-L. 2005, Org. Lett., 7, 2189. c) Singh, S. and Han, H. 2004, Tetrahedron Lett., 45, 6349. d) Tang, M. and Pyne, S.G. 2003, J. Org. Chem., 68, 7818. e) Takebayashi, M., Hiranuma, S., Kanie, Y., Kajimoto, T., Kanie, O. and Wong, C.-H. 1999, J. Org. Chem., 64, 5280. a) Afarinkia, K. and Bahar, A. 2005, Tetrahedron: Asymm., 16, 1239. b) Pearson, M.S.M., Mathé-Allainmat, M. Fargeas, V. and Lebreton, J. 2005, Eur. J. Org. Chem., 2159. c) Cipolla, L., La Ferla, B. and Nicotra, F. 2003, Curr. Top. Med. Chem., 3, 485. d) Yoda, H. 2002, Curr. Org. Chem., 6, 223. a) Paulsen, H. and Pflughaupt, K.W., in Pigman, W., Horton, D., Wander, J.D. Eds., The Carbohydrates, Chemistry and Biochemistry, Vol. 1B, 2nd Ed., Academic Press, New York, 1980, pp. 881-927. (b) Ellis, G.P., and Honeyman, J. 1955, Adv. Carbohydr. Chem., 10, 95. (a) Grogan, M.J., Pratt, M.R., Marcaurelle, L.A. and Bertozzi, C.R. 2002, Annu. Rev. Biochem. 71, 593. (b) Arsequell, G. and Valencia, G. 1999, Tetrahedron: Asymmetry 10, 3045. (a) Sokolowski, J. and Walczyna, R. 1976, Rocz. Chem. 50, 437. (b) Pigman, W., Cleveland, E.A., Couch, D.H. and Cleveland, J.H. 1951, J. Am. Chem. Soc. 73, 1976. (a) Lockhoff, O. and Stadler, P. 1998, Carbohydr. Res. 314, 13. (b) Perrin, C.L. and Armstrong, K.B. 1993, J. Am. Chem. Soc. 115, 6825. (c) Chavis, C., De Gourcy, C., Dumont, F. and Imbach, J.-L. 1983, Carbohydr. Res. 113, 1. Kort, M.J. 1970, Adv. Carb. Chem. Biochem. 25, 311. Michael, F., Frier, R., Plate, E. and Hiller, A. 1952, Chem. Ber. 85, 1092. Györdeak, Z., Szilagyi, L. and Paulsen, H. 1993, J. Carbohydr. Chem. 12, 139.

27

28. 29. 30. 31.

32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

42.

43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.

Nicolaou, K.C., Snyder, S.A., Nalbandian, A.Z. and Longbottom, L.A. 2004, J. Am. Chem. Soc. 126, 6234. Danishefsky, S.J. and Bilodeau, M.T. 1996, Angew. Chem., Int. Ed. Eng. 35, 1380. Dorsey, A.D., Barbarow, J.E. and Trauner, D. 2003, Org. Lett. 5, 3237. (a) Lubineau, A., Augé, J. and Drouillat, B. 1995, Carbohydr. Res. 266, 211. (b) Lubineau, A., Drouillat, B., Augé, J. and Mentech, J., 1994, Fr. Demande FR 2695127, CAN 121:158102. (c) Likhosherstov, L.M., Novikova, O.S., Derevitskaja, V.A. and Kochetkov, N.K. 1986, Carbohydr. Res. 146, C1-C5. Hackenberger, C.P.R., O’Reilly, M.K. and Imperiali, B. 2005, J. Org. Chem. 70, 3574. McGinnis, G.D. 1982, Carbohydrate Res. 108, 284. Yokoyama, M., Hirano, S., Matsushita, M., Hachiya, T., Kobayashi, N., Kubo, M. and Seki, H. 1995 J. Chem. Soc. Perkin Trans. 1, 1747. Buchanan, J. G., Lumbard, K. W., Sturgeon, R. J., Thompson, D. K. and Wightman, R. H. 1990, J. Chem. Soc. Perkin Trans. 1, 699. Kampf, A. and Dimant, E. 1972 Carbohydrate Res., 21, 1. Khan, T.A., Peruncheralathan, S., Ila, H. and Junjappa, H. 2004, Synlett, 2019. Carcano, M., Nicotra, F., Panza, L. and Russo, G. 1989, J. Chem. Soc. Chem. Commun., 297. Lay, L., Nicotra, F., Paganini, A., Pangrazio, C. and Panza, L. 1993, Tetrahedron Lett. 34, 4555. Badoney, R., Cativiela, C., Diaz-de-Villegas, M.D., Diez, R. and Galvez, J.A. 2005, Synlett, 1734. (a) Nagai, M., Gaudino, J.J. and Wilcox, C.S. 1992, Synthesis, 163. (b) Matsumoto, T., Kobayashi, Y., Takemoto, Y., Ito, Y., Kamijo, T., Harada, H. and Terashima, S. 1990, Tetrahedron Lett. 31, 4175. (a) Halazy, S., Ehrhard, A., Eggenspiller, A., Berges-Gross, V. and Danzin, C. 1996 Tetrahedron, 52, 177. (b) Caplan, N.A., Pogson, C.I., Hayes, D.J. and Blackburn, G.M. 1998, Bioorg. Med. Chem. Lett., 8, 515. (c) Wang, Q., Huang, Z., Ramachandran, C., Dinaut, A.N. and Taylor, S.D. 1998, Biorg. Med. Chem. Lett., 8, 345. (d) Blackburn, G.M., Kent, D.E. and Kolkmann, F. 1984, J. Chem. Soc. Perkin. Trans. I, 1119. Behr, J.-B., Mvondo-Evina, C., Phung, N. and Guillerm, G. 1997, J. Chem. Soc. Perkin Trans. I, 1597. Gautier-Lefebvre, I., Behr, J.-B., Guillerm, G. and Muzard, M. 2005, Eur. J. Med. Chem., 40, 1255. Gautier-Lefebvre, I., Behr, J.-B., Guillerm, G. and Ryder, N.S. 2000, Bioorg. Med. Chem. Lett., 10, 1483. Cipolla, L., Nicotra, F., Pangrazio, C. and Panza, L. 1995, Tetrahedron 51, 4679. Masaki, Y., Oda, H., Kazuta, K., Usui, A., Itoh, A. and Xu, F. 1992, Tetrahedron Lett., 33, 5089. Behr, J.-B., Gautier-Lefebvre, I., Mvondo-Evina, C., Guillerm, G. and Ryder, N.S. 2001, J. Enz. Inhib., 16, 107. Behr, J.-B. and Guillerm, G. 2002, Tetrahedron: Asymmetry, 13, 111. Behr, J.-B., Erard, A. and Guillerm, G. 2002, Eur. J. Org. Chem., 1256. Behr, J.-B. and Vogel, P. 2003, unpublished results. Dondoni, A., Giovannini, P.P. and Perrone, D. 2005, J. Org. Chem., 70, 5508. Dondoni, A. and Perrone, D. 1999, Tetrahedron Lett. 40, 9375. Dondoni, A., Giovannini, P.P. and Perrone, D. 2002, J. Org. Chem., 67, 7203. Dondoni, A. and Perrone, D. 2003, Tetrahedron, 59, 4261. Palmer, A.M. and Jäger, V. 2001, Eur. J. Org. Chem., 2547.

28

57.

58. 59.

60.

61. 62. 63.

64. 65. 66. 67. 68. 69. 70.

71. 72. 73.

(a) Cicchi, S., Corsi, M., Brandi, A., and Goti, A. 2002, J. Org. Chem., 67, 1678. (b) Tamura, O., Toyao, A. and Ishibashi, H. 2002, Synlett, 1344. (c) Duff, F.J., Vivien, V. and Wightman, R.H. 2000, Chem. Commun., 2127. (d) Holzapfel, C.W. and Crous, R. 1998, Heterocycles 48, 1337. Chevrier, C., LeNouen, D., Neuburger, M., Defoin, A. and Tarnus, C. 2004, Tetrahedron Lett., 45, 5363. (a) Lombardo, M., Fabbroni, S. and Trombini, C. 2001, J. Org. Chem., 66, 1264. (b) Brandi, A., Cicchi, S., Cordero, F.M., Frignoli, R., Goti, A., Picasso, S. and Vogel, P. 1995, J. Org. Chem., 60, 6806. (a) Epperson, M.T. and Gin, D.Y. 2002, Angew. Chem., Int. Ed., 41, 1778. (b) Goti, A., Cicchi, S., Cacciarini, M., Cardona, F., Fedi, V. and Brandi, A. 2001, Org. Lett, 3, 1367. (c) Kuban, J., Kolarovic, A., Fisera, L., Jaeger, V., Humpa, O. and Pronayova, N. 2001, Synlett, 1866. (d) Goti, A., Cicchi, S., Cacciarini, M., Cardona, F., Fedi, V. and Brandi, A. 2000, Eur. J. Org. Chem., 3633. (e) McCaig, A.E., Meldrum, K.P. and Wightman, R.H. 1998, Tetrahedron, 54, 9429. (f) McCaig, A.E. and Wightman, R.H. 1993, Tetrahedron Lett., 34, 3939. Cardona, F., Faggi, E., Liguori, F., Cacciarini, M. and Goti, A. 2003, Tetrahedron Lett., 44, 2315. Carmona, A.T., Wightman, R.H., Robina, I and Vogel, P. 2003, Helv. Chim. Acta, 86, 3066. (a) Merino, P., Tejero, T., Revuelta, J., Romero, P., Cicchi, S., Mannucci, V., Brandi, A. and Goti, A. 2003, Tetrahedron: Asymmetry, 14, 367. (b) Goti, A., Cicchi, S., Mannucci, V., Cardona, F., Guarna, F., Merino, P. and Tejero, T. 2003, Org. Lett, 5 4235. (c) Pulz, R., Cicchi, S., Brandi, A. and Reissig, H.-U. 2003, Eur. J. Org. Chem., 1153. Marradi, M., Cicchi, S., Delso, J.I., Rosi, L., Tejero, T., Merino, P. and Goti, A. 2005, Tetrahedron Lett., 46, 1287. Cardona, F., Moreno, G., Guarna, F., Vogel, P., Schuetz, C., Merino, P. and Goti, A. 2005, J. Org. Chem., 70, 6552. Bonanni, M., Marradi, M., Cicchi, S., Faggi, C., and Goti, A. 2005, Org. Lett., 7, 319. Baer, H.H. and Zamkanei, R. 1988, J. Org. Chem., 53, 4786. Ermert, P. and Vasella, A. 1991, Helv. Chim. Acta, 74, 2043. Ermert, P., Vasella, A., Weber, M., Rupitz, K. and Withers, S.G. 1993, Carbohydr. Res., 250, 113. (a) Laroche, C., Harakat, D., Bertus, P. and Szymoniak, J. 2005, Org. Biomol. Chem., 3, 3482. (b) Bertus, P. and Szymoniak, J. 2003, Synlett, 265. (c) Laroche, C., Bertus, P. and Szymoniak, J. 2003, Tetrahedron Lett., 44, 2485. (d) Bertus, P. and Szymoniak, J. 2003, J. Org. Chem., 68, 7133. (e) Bertus, P. and Szymoniak, J. 2002, J. Org. Chem., 67, 3965. (f) Bertus, P. and Szymoniak, J. 2001, Chem. Commun., 1792. Laroche, C., Behr, J.-B., Szymoniak, J., Bertus, P. and Plantier-Royon, R. 2005, Eur. J. Org. Chem., 5084. Laroche, C., Plantier-Royon, R., Szymoniak, J., Bertus, P. and Behr, J.-B., 2006, Synlett, in press. Laroche, C., Behr, J.-B., Szymoniak, J., Bertus, P., Schütz, C., Vogel, P. and PlantierRoyon, R. 2006, to be published.

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