Isomaltulose Oxidation and Dehydration Products as Starting Materials Towards Fine Chemicals

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1768 Current Organic Chemistry, 2014, 18, 1768-1787

Isomaltulose Oxidation and Dehydration Products as Starting Materials Towards Fine Chemicals

Jia-Neng Tana,b, Mohammed Ahmara,b and Yves Queneaua,b,*

a INSA Lyon, ICBMS, Bâtiment J. Verne, 20 av A. Einstein, F 69621 Villeurbanne, France; bCNRS, UMR 5246, ICBMS, Université Lyon 1; INSA-Lyon; CPE-Lyon; Bâtiment CPE, 43 bd du 11 novembre 1918, F 69622 Villeurbanne, France

Abstract: Chemical reactions using isomaltulose as the starting material leading to advanced functional carbohydrate derivatives are re-viewed. A focus is made notably on the synthesis and application of different kinds of carboxylic acids and lactones obtained by oxida-tion of isomaltulose and the strategies using its triply dehydrated derivative, glycosyloxymethylfurfural.

Keywords: Baylis-Hillman, biobased chemistry, dehydration, glucosyloxymethylfurfural, isomaltitol (palatinit), isomaltulose (Palatinose®),oxidation.

1. INTRODUCTION

Carbohydrates are ubiquitous in Nature and show extremely high chemical interest, either with respect to biological issues or to their possible use as starting materials for the synthesis of chemical intermediates and fine chemicals. Due to different reasons which relate to the shortage of cheap fossil resources, the necessity to integrate renewable carbon in chemicals for lowering their carbon footprint, or the search for added-value products from agricultural crops or by-products, many research groups have in the past decades focused their work on finding new ways and methods for transforming carbohydrates (either small sugars or polysaccharides) into useful functional molecules of valuable chemical intermediates [1-9].

The structural complexity exhibited by carbohydrates is at the same time a gift and a challenge to chemists, allowing a wide range of innovation and applications, but also requiring methods showing selectivity and able to adapt to the peculiar chemical sensitivity of sugars. Many applications have however reached the industrial level thus demonstrating how sugars offer opportunities as renewable raw materials, such as the well-known alkylpolygl-ucosides (APG) in the field of surfactants [10, 11] or, more recently, Pro-Xylane® in the area of cosmetic applications [12-16].

Among sugars which are widely available, isomaltulose 1 is an interesting disaccharide. Isomaltulose (6-O-�-D-glucopyranosyl-D-fructofuranose, also referred to as Palatinose®), is synthesized from sucrose by bioconvesion on the industrial scale [17, 18]. It has been used as a food in Japan since 1985 [19].

Depending on the microorganism used for the biochemical isomerisation, different glucose-fructose disaccharides can be obtained [20-25]. Analogous fructose-containing disaccharides can also be produced either by degradation of naturally occurring oligosaccharides [26, 27] or by chemical isomerisation using sodium aluminate (Scheme 1) [28].

In solution (DMSO, water, pyridine), isomaltulose is mainly present in the form of its fructofuranose, with the � anomer as the major one [29]. In this � form, an intramolecular H-bond with

�Address correspondence to this author at the INSA Lyon, ICBMS, Bâtiment J. Verne, 20 av A. Einstein, F 69621 Villeurbanne, France ; Tel 00 33 4 72 43 61 69; Fax 00 33 4 72 43 88 96; E-mail: [email protected]

OH-2 of the glucose moiety is evidenced in the crystalline state [29, 30]. In DMSO, the open chain form was also identified by NMR in a 3 to 5% ratio. A recent review covers the main biological routes to sucrose analogs, in particular using enzymatic processes [31].

The chemistry of isomaltulose, in part schematized in (Scheme 2), has been intensely studied since late 1980’s notably by the groups of Lichtenthaler and Kunz who reported very sensible routes towards various kinds of derivatives [32-38]. Main strategies are those based on the hydrogenation (to 12) or reductive amination of the ketone function (to 13 or 14), on the oxidative degradation to glucosylated carboxylic acids such as 15 or 16, in which the fructo-syl moiety has been partly cleaved, and on the triple dehydration product of the fructosyl moiety, glucosyloxymethylfurfural 17(GMF).

In this article, after a brief overview of some aspects of isomaltulose chemistry, we will focus on two types of reactions and products, those derived from carboxylic derivatives such as the ones obtained by different oxidation methods, and those which concern glucosyloxymethylfurfural (GMF), obtained by the triple dehydration under methods similar to those used for the synthesis of hydroxymethyl furfural (HMF) from fructose. After highlighting the work by other groups, we will notably overview our recent results related to these two types of approaches from isomaltulose, achieved in the context of our work dedicated to application of carbohydrates as organic raw materials [5, 6, 39-41].

2. BACKGROUND ON ISOMALTULOSE CHEMISTRY

Isomaltulose, like sucrose, is a disaccharide made of glucose and fructose, however having its glycosidic bond connecting C-1 of the glucosyl moiety and O-6 of the fructosyl one. Therefore, iso-maltulose possesses a hemiketalic function (the masked ketone function of the fructose moiety) which can be discriminated from the other hydroxyl groups, whereas the chemistry of sucrose mostly relies on selective OH group transformations because both ano-meric carbons are connected together [39, 41].

Of course, like any other reducing sugar, isomaltulose can also undergo glucosidation reactions. Either simple alkyl glycosides can be obtained by treatment with alcohols in the presence of acidic catalysts [42], or dimeric spirodioxanyl tetrasaccharides such as those found in mixtures of oligosaccharides obtained by treatment

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Isomaltulose Oxidation and Dehydration Products as Starting Materials Towards Fine Chemicals Current Organic Chemistry, 2014, Vol. 18, No. 13 1769

OHOHO

HO

OH

O O

OH

OH OH

OH

OHOHO

HO

OH

O

O OH

HO

OHHO

OHOHO

HO

OH

O

O OH

HO

OHO

H

OH

H

a

b

ab

Agrobacteriumradiobacter

Protaminobacterrubrum

4 trehalulose

2 sucrose

R6O

OR5

OR4

OR3

OR1

R1 R3 R4 R5 R6

H H H H H�-Glu H H H H

H H H HH H H HH H H �-Glu HH H H H

fructose (3)trehalulose (4)turanose (5)maltulose (6)leucrose (7)isomaltulose (1)

�-Glu�-Glu

�-GluH H H H �-Gal melibiulose (8)H H �-Gal H lactulose(9)H H H H �-Glu gentiobiulose (10)H H H H �-Xyl primeverulose (11)

H

1 isomaltulose

OHOHO

HO

OH

HOO

OH

HO

HO

O

O

Scheme 1.

OHOHO

HO

OH

OO

OH

OH OH

OH

OHOHO

HO

OH

O

OH

OH

OH

OH

OH

OHOHO

HO

OH

O

OH

OH

OH

NH2

OH

hydrogenation

reductive amination

OHOHO

HO

OH

O

OH

OH

OH

CO2H

OHOHO

HO

OH

OCO2H

oxidation

1 isomaltulose

12 isomaltitol

13 secondary isomaltamines

15 glucosyl-arabinonic acid 16 CMG

17 GMF

dehydration

OHOHO

HO

OH

O

OH

OH

OH

OH

NH2

OO CHO

14 primary isomaltamines

OHOHO

HO

OH

Scheme 2.

1770 Current Organic Chemistry, 2014, Vol. 18, No. 13 Tan et al.

OHOHO

HO

OH

OO

OH

OH OR

OH

18 alkyl isomaltulosides, � anomer as major product

1 isomaltuloseROH, acid catalyst

OHOHO

HO

OH

OO

OH

OH

O

O OH

OHHO

OHO

OOH

HO

O

19 cyclic bis isomaltulosides

OHOO

HO

OH

OO

OH

OH OH

OH

O

OH

HOHO

OH

20 3-O-�-D-galactosyl isomaltuloseScheme 3.

OHOHO

HO

OH

OO

HO

OH OH

OH

1 isomaltulose

OHOHO

HO

O

OO

HO

OH OH

OH

OHOHO

HO

OH

OO

HO

OH OH

O

O

R

O

R

enzymatic esterification

21 1-O-acyl isomaltulose (major)

22 6'-O-acyl isomaltulose (minor)

+

Scheme 4.

with citric acid [43] or more selectively synthesized by activation with hydrogen fluoride (Scheme 3) [44-46].

As any other sugar, isomaltulose can be functionalized by reaction of its non anomeric hydroxyl groups. For example, enzymatic ga-lactosylation at the OH-3’ can be achieved by treatment of iso-maltulose with �-galactosidase [47].

Enzymatic esterification of isomaltulose leads to amphiphilic esters. In a comprehensive study on acylation of various disaccha-rides using the protease subtilisin as catalyst, the OH-1 of isomaltu-lose was found to be more reactive than the other primary hydroxyl,

OH-6’ [48]. More recently, the lipase from Candida antarctica was used to form different disaccharidic esters including isomaltulose myristate (Scheme 4) [49].

By reaction with amines, isomaltulose can be transformed to several types of nitrogen containing heterocycles (Scheme 5). For example, the synthesis of imidazoles such as 23 by reaction of formamidine acetate with isomaltulose in the presence of hydrazine was reported by Lichtenthaler and co-workers [50]; it was recently revisited using a melt of ammonium carbonate as ammonia source and medium [51]. Pyrazoles were also synthesized from isomaltulose by reaction with phenylhydrazine. An intermediate bis


phenylhydrazone 24 evolves to the pyrazole 25 upon acetylation, which then can lead to variously functionalized glucosylated pyrazoles 26 and 27 (Scheme 5) [52]. Another reaction involving the ketone group of isomaltulose with an amine is the Heyns rearrangement which leads to N-acetyl-(6-O-�-D-glucopyranosyl) glucosamine 28 in 40% yield (Scheme 6) [53].

Preparation of isomaltitol 12 (also referred to as isomalt or palatinit), obtained by hydrogenation of the carbonyl group, used as a food additive and in many other applications is the main industrial application of isomaltulose [8, 34, 54]. Isomaltulose or isomaltitol can be used as polyols for preparing amphiphilic derivatives such as 29 via ester or ether linkages by reaction with esters, acylhalides or alkylhalides [55]. Other amphiphilic isomalt ethers: 30 and 31 were prepared by palladium catalyzed telomerisation of butadiene [56] or base catalyzed fatty epoxide ring-opening (Scheme 7) [57]. Reduc-tive amination of Palatinose® offers also various routes from 13 towards surfactants or monomers such as compounds 32 to 36,following classical strategies applied to glucose or other available reducing sugars (Scheme 8) [35-38, 58-61].

3. OXIDATION OF ISOMALTULOSE

Oxidation products of carbohydrates are useful in the context of the design of biobased chemical intermediates and products, since polyhydroxycarboxylates have potential industrial applications due to their cation sequestering properties [62, 63]. They have received considerable interest in recent years, with methodological studies in all fields of chemical [64, 65] and biochemical oxidation [66, 67]. This applies to polysaccharides (starch, cellulose, chitin…) and also to smaller sugars, and in particular sucrose and isomaltulose which are available on the industrial scale. In this section, several oxida-tion methods will be discussed especially in the context of iso-maltulose chemistry: 1) oxidation of primary alcohols to carboxylic acids using oxygen in the presence of platinum or using the TEMPO hypochlorite oxidizing system, 2) biochemical oxidation to 3’-oxo isomaltulose and their derivatives, 3) oxidative degradation of the fructosyl moiety of isomaltulose to glucosyl arabinonic or 4) glycolic acids, leading also to lactones which serve as synthons towards various types of neoglycoconjugates.

OHOHO

HO

OH

O

OH

OH

OH

N

23

HN

R

OHOHO

HO

OH

O

OH

CHON N

Ph OHOHO

HO

OH

O

OH

N NPh

R

R = H; Me, Ph

R = OH, NH2, NHAc26 27

OAcOAcO

AcO

OAc

O

OAc

N NPh

NNAcPh

H

OHOHO

HO

OH

O

OH

OH

OH

NNHPh

NNHPh

H

OHOHO

HO

OH

OO

OH

OH OH

OH

1 isomaltulose

24 25

PhNHNH2

Ac2O

NaOMe

RH2N

HN

(NH4)2CO3

65~80 oC

Scheme 5.

OHOHO

HO

OH

OO

OH

OH OH

OH

1 isomaltulose

"one-pot" Yield = 40%

OHOHO

HO

OH

HOO

OHNHAcHO

O

28 N-acetyl-6-O-(�-D-glucopyranosyl)-D-glucosamine

1. BnNH2then AcOH

2. H2, Pd(OH)23. Ac2O, NaHCO3

Scheme 6.


OHOHO

HO

OH

O

OH

OH

OH

OH

OH

12 isomalt

OHOHO

HO

OH

O

OH

OH

OH

OH

O

HOC10H21

+ isomers

ORORO

OR

OR

O

OR

OR

OR

OR

OR

29 R = alkyl chain, acyl chain, polyoxyethylenic ether

30 R =

31 hydroxyalkylethers

Scheme 7.

OHOHO

HO

OH

O

OH

OH

OH

NH2

OH

13 isomaltamine

OHOHO

HO

OH

O

OH

OH

OH

NH

OH

33 polymerisable isomaltamide

O

OHOHO

HO

OH

O

OH

OH

OH

NH

OH

O

32 amphiphilic isomaltamide

OHOHO

HO

OH

O

OH

OH

OH

OH

NH

OHOHO

HO

OH

O

OH

OH

OH

OH

N

OH

O

35 amphiphilic N-alkyl isomaltamine

36 polymerisable N,N-dialkyl isomaltamine

OHOHO

HO

OH

O

OH

OH

OH

NH

OH

O

NH

34 amphiphilic isomalturea

Scheme 8.

3.1. Oxidation with the Pt/O2 and TEMPO Systems The Pt/O2 and the TEMPO oxidizing systems are normally used

for selective oxidation of primary alcohols to carboxylic acids. For example, this method has been applied to sucrose, leading to de-rivatives with carboxyl groups at the primary positions [68-72]. In the case of the Pt/O2 method, the issue is to get defined products among the mono-, di-, and tricarboxy-derivatives, with difficulties related with catalyst poisoning which prevent to reach polycarboxy-lated products. Continuous extraction of the monocarboxylated

derivatives from the medium by electrodialysis was reported [73, 74]. Heyns [75, 76] and van Bekkum [77] have thoroughly investi-gated the field of catalytic oxidation of carbohydrates and estab-lished some general rules which are: 1) aldehyde function of al-doses is readily oxidized; 2) the alcohol functions require more aggressive reaction conditions, with primary ones reacting faster than secondary ones; 3) primary alcohols adjacent to the carbonyl group in ketoses react faster, nearly as fast as an aldose. Therefore, it was expected that OH-1 of isomaltulose would be oxidized more


rapidly (to provide 15) than OH-6’ (leading to 37), but it was found by Kunz and coworkers that both positions actually underwent oxi-dation in similar rates, forming compound 38. The carboxylated derivatives of isomaltulose can undergo reductive amination pro-viding aminoacids 39, 40, 41 (Scheme 9) [37, 78]. Such products were further used for the synthesis of monomers by reaction with isocyanatoethyl methacrylate [79] or by simple methacryloylation leading to monomers which were used in various polymerisation conditions [38].

The hypochlorite-TEMPO system has found successful applica-tions in the oxidation of polysaccharides [80, 81] and unprotected small carbohydrates [82-86]. Oxidation of isomaltulose [87] how-ever, is not selective and leads to a mixture of four methyl esters (characterized as their peracetylated derivatives: 42, 43, 44, and 45)differing by the length of the chain arising from the fructose moi-ety, associated with a glucose moiety which is either unchanged or oxidized at the C-6 (Scheme 10). The presence of products 42 and 44, not oxidized at the C-6, and the absence of any product with the

OHOHO

HO

HO2C

O

OH

OH

OH

O

CO2H

OHOHO

HO

OH

O

OH

OH

OH

O

CO2H

OHOHO

HO

HO2C

O

OH

OH

OH

O

OH

OHOHO

HO

OH

O

OH

OH

OH

NH2

CO2H

OHOHO

HO

HO2C

O

OH

OH

OH

NH2

OH

OHOHO

HO

HO2C

O

OH

OH

OH

NH2

CO2H

37 15 glucosyl-arabinonic acid 38

39 40 41

Scheme 9.

OHOHO

HOO

O

OH

OH OH

OH

OH

OAcOAcO

OAc

OAc

O

OAc

OAc

OAc

CO2Me

OAcOAcO

OAc

OAc

OCO2Me

OAc

OAc14%

OAcOAcO

OAc

MeO2C

O CO2Me

OAc

OAcOAcO

OAc

MeO2C

O

OAc

OAc

OAc

CO2Me

10%

5% 3%

1) TEMPO2) MeOH, Acid3) Ac2O, Py

MeOH, acid

OHOHO

HOO

O

OH

OH OMe

OH

OH 1) TEMPO2) MeOH, Acid3) Ac2O, Py

1) O2, Pt2) MeOH, Acid3) Ac2O, Py

OAcOAcO

OAc

MeO2C

OO

OAc

OAc OMe

CO2Me

80%

OAcOAcO

OAc

MeO2C

OO

OAc

OAc OMe

OAc

OAcOAcO

OAc

MeO2C

O CO2Me

OAc

23% 5%

1 isomaltulose

46

42

44

43

45

47 43

48

Scheme 10.


unchanged fructose part and oxidized at the C-6, confirm that the oxidative cleavage occurring on the fructose ring is always faster compared to the primary alcohol oxidation, as already observed in the case of inulin [80]. Applied to methyl isomaltuloside 46, a mix-ture of products is also obtained in which the major ones were char-acterized as their peracetylated methyl ester derivatives 43 and 47.Alternatively, the Pt/O2 oxidation of methyl isomaltuloside proved to be much more efficient and led selectively to 6’-mono-carboxylated methyl isomaltuloside 48 in good yield.

3.2. Microbial Oxidation to 3-keto Isomaltulose

Microbial oxidation of disaccharides to 3-keto products was originally reported by De Ley et al. [88]. The active catalyst of the reaction was found to be the D-glucoside 3-dehydrogenase of Agro-bacterium tumefaciens. Being very selective and rather efficient, this bioconversion was further investigated by the groups of De Ley and Buchholz. It was, in particular, applied in the synthesis of 3-keto-sucrose, from which several interesting new sucrose deriva-tives, such as sucrose 3-epimer or amino derivatives could be ob-tained [89-92]. The reaction was found to be even more efficient when applied to isomaltulose, which led to 3-ketoisomaltulose (49)in good yield. Careful kinetic investigations of the reaction condi-tions with respect to oxygen concentration and pH were performed [93]. 3-Ketoisomaltulose could be further transformed to aminated derivatives 50 by reductive amination, after careful optimization of the reaction conditions for preventing base-catalyzed retro aldol degradation of the starting 3-keto compound. The resulting diamino product 50 was used in poly-addition reactions with diisocyantes leading to carbohydrate containing polyurethanes or in polyconden-sation reactions with dicarboxylic acid dichlorides [37, 38, 94]. The oxidation reaction catalyzed with D-glucoside 3-dehydrogenase is thus rather general and highly selective in terms of regiochemistry with respect to the OH-3 of the glucose moiety. However, impor-tant variations in the structure of the substrate are acceptable, as illustrated by the ability to oxidize also 6-O-(�-D-glucopyranosyl)-D-2-amino-2-deoxy-mannitol 13, obtained by reductive amination from isomaltulose, which led the corresponding 3-keto analogue, or glucopyranosylmannitol 51 (Scheme 11) [95].

3.3. 5-Glucosyl Arabinonic Acid and Derivatives

Under strongly alkaline conditions, the reaction of isomaltulose with oxygen provides glucosyl arabinonic acid (15), isolated by crystallization of its potassium salt in 80-90% yield. This reaction is

particularly efficient as compared to other substrates such as fruc-tose itself or other fructosyl disaccharides. It results probably from easier formation of the enediolate precursor when the substrate is predominantly in the furanosyl form [29, 37]. Several studies by Lichtenthaler and Kunz groups have demonstrated the usefulness of glucosyl arabibonic acid. Notably, it could be transformed to the methyl ester 52 then reduced to the arabinitol analog 53 or isomalti-tol 12. By reaction with amines, the amides 54 and 55 are formed, and when fatty amine is used, the products exhibit surfactant prop-erties. The liquid crystalline properties of a series of fatty amides such as 55 were investigated, showing smectic A mesophases (Scheme 12) [96].

Glucosyl arabinonic acid is transformed to its lactone 56 by simple treatment with strongly acidic resin. While DIBAL reduc-tion of this lactone afforded the 5-O-glucosyl arabinose disaccha-ride (characterized as its peracetate 57), many other interesting synthons could be also prepared. Notably, once the lactone was perbenzoylated to 58, base catalyzed elimination led to compound 59, in which the carbon-carbon double bond could be specifically hydrogenated to 3-deoxy-D-threo-pentonic acid lactone 60 in high yield. Alternatively, SmI2 reduction of lactone led to furanone 61which could also be further hydrogenated to its saturated counter-part 62 [97, 98]. Such carbohydrate based lactones are extremely useful synthons for grafting sugars on other chemical architectures (Scheme 12) [99, 100].

3.4. Carboxymethyl Glycoside (CMG) and Carboxymethyl Gly-coside Lactones (CMGLs)

Carboxymethyl �-D-glucopyranoside (CMG, 16) can be ob-tained by simple oxidation of isomaltulose by hydrogen peroxide in acidic media. This one-step process, using cheap reagents and sim-ple reaction conditions, is an attractive alternative to previous syn-theses despite rather low yield (ca. 35%) [101]. Another alternative is simple Fischer glycosylation of glycolic acid with glucose in the presence of hydrochloric acid, described by Petersson et al., but the yield is even lower 6% yield), and it leads to a 70:30 �/� mixture [102].

CMG was also obtained from trehalulose or from isomalt. The addition of sodium tungstate, known to promote the oxidative clea-vage of glycols via peroxotungstate species [103-106], was indis-pensable in the case of isomaltulose [107] whereas for isomaltulose and trehalulose led only to slightly higher yields. CMG could be obtained on a 5-10 g scale. The product obtained by acetylation of

OHO

OHO

OH

OO

OH

OH OH

OH

49 3-oxo isomaltulose

OHOH2N

HO

OH

O

OH

OH

OH

NH2

OH

OHO

OHO

OH

O

OH

OH

OH

NH2

OH

diisocyanates or

diacid chlorides

polyurethanes or polyamides

51 3-oxo isomaltamines

50

Scheme 11.


OHOHO

HO

OH

O

OH

OH

OH

CO2H

15 glucosyl-arabinonic acid

OHOHO

HO

OH

O

OH

OH

OH

O

OMe

OHOHO

HO

OH

O

OH

OH

OH

O

NH2

OHOHO

HO

OH

O

OH

OH

OH

O

NH

OHOHO

HO

OH

O

OH

OH

OH

OH

OHOHO

HO

OH

OO

HO OH

O

OBzOBzO

OBz

OBz

OO

O

OBzOBzO

OBz

OBz

OO

O

OBzOBzO

OBz

OBz

OO

O

OBzOBzO

BzOOBz

OBz

OO

O

OBzOBzOBzO

OBz

OBz

OO

BzO OBz

O

OAcOAcO

OAc

OAc

OO

AcO OAc

OAc

56

58 59

61

60

62

5755

5352

54

H+

1. DiBAL2. Ac2O

BzCl

DBU/THF

-78 oC

SmI2

Pd/H2

Pd/H2

Scheme 12.

acylation conditions(RCO)2O, Py

or RCOCl, NEt31

isomaltulose

O

O

CO2HHO

HOHO

OHH2O2, H+

NaWO4 ORORO

O

OR

O

O

63 R = Ac 64 R = ClCH2CO 65 R = Bz 66 R = Piv

ORORO

OH

OR

O

O

OEt

EtOH

ORORO

OH

OR

O

O

NHR'

R'NH2

OAcOAcO

AcO

OAc

OOH

O

OAcOAcO

AcO

OAc

O

O

AcO OAc

O

OAcOAcO

HO

OAc

OOH

O

7157 70

O

O

O

O

O

ROH

OAcOAcO

AcO

OAc

OAc

16 CMG67

68

69

OH

HOHO

Scheme 13.

CMG is its 2-O-lactone (CMGluL, 63) which was found to be eas-ily opened with alcohols or amines leading to esters or amides 67and 68 [99, 108-120].

Among side products after acetylation were found: lactone 57 (Scheme 13), resulting from incomplete oxidation to glycosyl arabinonic acid, glucose pentaacetate 69 arising from CMG hy-drolysis, tetraacetyl carboxymethyl glucoside 70 or its analog hav-ing free OH-2 71 reflecting the opening of the lactone during the reaction or at the work-up stages. Other acylating reagents (chloroacetyl chloride, pivaloyl anhydride or benzoyl chloride) can be used in order to tune the stability of the protecting groups in 64-66. Similar lactones with variations in the sugar type, the anomeric configuration, mono- or disaccharides were also prepared by the

oxidation of allyl glycosides or anomeric alkylation with tert-butylbromoacetate [107, 111, 112].

The reactivity of these lactones, and in particular of gluco-CMGL arising from isomaltulose, was studied in different condi-tions. Reaction with alcohols in either basic or acidic media lead to the corresponding esters having a free 2-OH while all three other positions: 3, 4 and 6 were acetylated. As shown in (Scheme 14), the scope of the reaction with amines is wider, because the amides formed are more stable and can be used further. The reaction with amines proved to be very general giving good to excellent yields of a wide range of pseudoglycoconjugates such as: glycoaminoacids hybrids such as 72 [108], pseudooligosaccharides such as 73 [109], amphiphilic compounds arising from fatty amines (74) or amino-


cholesterol (75) [110, 111]; some of them were investigated with respect to their liquid crystalline properties in the context of a more general study of liquid crystalline glycolipids [114]. Bolaam-phiphiles (76) were obtained by reaction with diamines [108].

Glucosylated porphyrins such as 77, potentially useful for can-cer photochemotherapy, were prepared by reaction of CMGL with amino functionalized porphyrins [115, 116] and found to exhibit

clearly improved photoactivity as compared to the non-glycosylated ones. Original membrane imaging probes exhibiting non-linear optical properties were also prepared [117].

One advantage of CMGL synthons is the possible subsequent functionalisation at the position 2 which readily yields 1,2-bis-functionalized carbohydrates derivatives. Several examples of such systems are depicted in (Scheme 15), including diyne and

OAcOAcO

HO

OAc

ONH

OCO2Me

72

OHOHO

O

HOO

OH

NH

OH

HO

HO

O

HO

NH

OHOHO

HO

HO

O

O

OHOHO

HO

OH

ONH

O

OHOHO

OH

OH

OOHOHO

HO

OH

ONH

O

NH On

n

n = 4, 6

n = 5, 7, 9, 11, 13, 15

76

N

NH HN

N

O

OHOHO

HO

OH

OO

NH

o,pHO O

HOHO

O

OH

O

N N

ON

ON

Et

Et

Et

Et

HN

HN

HO OHO

HOO

OH

O

73

74

75

77

78

Scheme 14.

AcOAcO

O

O

OAc

OHN

O

AcOAcO

O

OAc

OHN

O

O

79 80

OAcO

AcOO

O

NHRCO2Et

81 R =

85 R = Bn

86 R = C12H25

84 R =

OAcO

AcOO

O

O

NHR

82 R = Bn

83 R = C12H25

CH2 C CH CH2 C CH

Scheme 15.


N

N

N

NH

HOHO

HO

OHN

O

O

N3

HOHO

HO

O

OO

n

Cu(I)

�-gluco-CMGL

AcOAcO

OH

OAc

OHN

O

O

AcOAcO

TfO

AcO

O

HN

O

O

RORO

N3RO

O

HN

O

O

Tf2O, Py

NaN3

NEt3, MeOH, H2O89 R = Ac90 R = H

87

88

91

63

OHOHO

OHO

OH

NH

HN

O

O

OAcOAcO

HOO

AcO

NH

HN O

O

O

OHOHO

O

N3OH

NH

HN

O

O

HO S S

O S

O

OHHO

OHO

OH

HN

NH

O

O

n HO S S

O S

O

OHOH

O

N3

OH

HN

NH

O

O

n

70°C 30°C

92

93 94

95 96

63

Scheme 16.


OHO

CHO

Fructose (3)

ORO

CHO

Isomaltulose (1)

Cat.

-3H2O

17 GMF, Glucosyloxymethylfurfural

99 HMF

OH

CH2OHHOH2C

HO

OHO - H2O CHOH

HOH2C

HO

OHO

97

CHO

HOH2C

OH

O

98

- H2O - H2O

OHOHO

HO

OH

O O

OH

OH OH

OH

Scheme 17.

enyne 79, 80, and unsaturated derivatives 81-83 (obtained after oxidation of the OH-2 and concomittant elimination) further elon-gated to compounds 84 by Wittig olefination. Interesting antifungal and antibacterial activities were found for these two last types of products [118]. This method was applied to the synthesis of two new types of carbohydrate-based monomers. The first example represents a series of azido-alkynes prepared from 87 by formation of the triflate 88 followed by sodium azide substitution to 89, de-protected to the bifunctional 2-deoxy-2-azido manno derivative 90which underwent copper(I)-catalyzed azide-alkyne polyaddition [119]. The second type of monomers are acrylamides which were used in RAFT (reversible addition fragmentation chain-transfer) polymerization reactions. Monomers were prepared by acryloyla-tion of the intermediate aminoethylamide derivative 92. Whereas the 2-OH gluco monomer 93 readily polymerized to 95 as expected, reaction of the 2-N3-manno monomer 94 was more difficult, and was only able to produce 96 at a lower temperature, thus necessitat-ing a more reactive initiator (Scheme 16) [120].

Overall, a number of products can be designed by exploiting isomaltulose oxidation products. Besides carboxy-isomaltulose and glucosylarabinonic acid derivatives offering easy accesses to many different targets, the CMG 2-O-lactone which arises from car-boxymethyl glucoside appears also as an interesting synthon, pro-viding an original way towards 1,2-bisfunctionalized carbohydrate derivatives.

4. DEHYDRATION OF ISOMALTULOSE TO GMF

Dehydration of isomaltulose to �-D-glucosyloxymethylfurfural (GMF 17), a glycosylated hydroxymethylfurfural, is another inter-esting option towards biobased derivatives (Scheme 17). Formation of GMF broadens the scope of hydroxymethylfurfural (HMF 99),which appears as one of the most attractive bio-based chemicals established by Bozell and Petersen in the “Top 10 + 4 chemicals” list [7, 121-123]. The higher polarity of the products might be use-ful in various aspects such as novel hydrophilic polymers, surfac-tants, liquid crystals and other functionalized materials.

Compared to dehydration of monosaccharides (fructose or glu-cose) or selected polysaccharides [123], the conditions to generate GMF from isomaltulose required to carefully prevent undesired cleavage of the intersaccharide linkage. Dehydration of isomaltu-lose under aqueous acidic conditions led mostly to glucose and HMF, after hydrolysis of GMF glycosidic bond, or after prior iso-maltulose hydrolysis and further fructose dehydration to HMF. Therefore, anhydrous systems should be used. Compared to organic

solvents commonly used to convert fructose to HMF, like dimethyl-formamide (DMF), acetonitrile and quinoline, dimethyl sulfoxide (DMSO) shows the best results for the dehydration of isomaltulose. As reported by Lichtenthaler et al. [124], GMF can be obtained in up to 70% yield by heating isomaltulose in DMSO in the presence of a strongly acidic ion-exchange resin (Dowex 50 WX4, H+ form) and freshly desiccated molecular sieves, along with dimeric iso-maltulose anhydrides (l0%), HMF, glucose (5-10%), and the start-ing material (10%). This procedure can be adapted from the batch into a continuous process using a flow reactor [125] making GMF available on possibly larger scale thus more attractive as a bio-based building block. This protocol has been further applied to access several other hydrophilic HMF analogues [28] that are: �-GalMF 100, �-GMF 101, and �-XylMF 102. Their preparation from the respective disaccharides: glycosyl-(1-6)-glucoses meli-biose, gentiobiose, and primeverose, involves a simple two-step process, aluminate-promoted isomerization of their reducing glu-cose moiety to fructose, then acid-induced dehydration of the fruc-tose unit (Scheme 18).

Koenig and co-workers [126] recently developed a novel method to prepare GMF, by using isomatulose-choline chloride melts with different acidic catalysts under mild reaction conditions (Scheme 19). The best yield (52% yield of GMF 17 in 1 hour) was reported for ZnCl2 as a catalyst. Montmorillonite also showed cata-lytic activity in this reaction, giving 46% of GMF within 15 min-utes. Due to the fact that it is nontoxic and recyclable, use of Montmorillonite as a catalyst is attractive. Although the yield are lower than in the DMSO solution protocol, such dehydration of isomaltulose in a neat melt system, without addition of any organic solvents, is a convenient and nontoxic alternative for GMF synthesis.

As described by Urashima et al. [127], a series of glycosylated HMF can be generated by heating HMF with galactose (103) in 1,4-dioxane (Scheme 20). Under catalyst-free conditions, four different types of HMF-galactosides were detected, namely HMF �-D-galactofuranoside 104, HMF �-D-galactofuranoside 105,HMF-�-D-galactopyranoside 100 and HMF �-D-galactopyranoside 106. Heating HMF with glucose (107) gives HMF �-D-gluco-furanoside 108, HMF �-D-glucofuranoside 109, HMF �-D-gluco-pyranoside (GMF, 17) and HMF �-D-glucopyranoside respectively 101. Major product are the pyranosidic forms, as expected for glucose or galactose glycosidations. HMF D-galactopyranoside and HMF D-glucopyranoside were also detected under direct heating of galactose and glucose at 215°C in the absence of any catalysts or solvents.


ROO OH

OHHO

OHRO

O OH

OHHO

OH Dowex 50 WX4 (H+)

DMSO, 120 °C

NaAl(OH)4

H+

100: R = �-Gal, Yield = 65%101: R = �-Glc, Yield = 63% 102: R = �-Xyl, Yield = 58%

ORO

CHO

4A, 3 hYield = 70~80%

(6 eq) (2 mol %)

Scheme 18.

Cat. 100 °C

HONCl

Cat. Time (min)� Yield (%)ZnCl2� 60� 52Montmorillonite� 15 46Amberlyst� 15 34p-TsOH 15 35FeCl3� 15 27

OHOHO

HO

OH

OO

HO

OH OH

OH1 isomaltulose 17 GMF

OO CHO

OHOHO

HO

OH

Scheme 19.

O

OH

HOOHOH

OH

HOO CHO

HMF (99)

OO CHO

104

O

HO

HOOH

OH

OO CHO

OHO

HOOH

OH

OO CHO

OOH

OH

HOOH

OO CHOO

OH

OH

HOOH

OO CHO

OHOHO

OH

OH

OO CHO

OHOHO

OH

OH

OO CHO

OHO

OH

OHHO

OO CHO

OHO

OH

OHHO

galactose (103)

105

100 106

OHOHO

OHOH

OH

HOO CHO

HMF (99)

glucose (107)

108 109

17, GMF 101

�

�

+

+

Scheme 20.


Table 1. Condensation between glucose derivatives and the furanic alcohols.

+ ROO R1

OAcO

OAc

OAc

O CHOO

AcOOAcO

OAc

OAcAcO

Y

Cat.

110 111 112

Y R R1 Condition Yield (%)

Br (a) H CHO Ag2O, rt 11

Br (a) H CH(OMe)2 Ag2O, I2, CaSO4 , rt 8

O-C(NH)CCl3 (a ��b) H CHO BF3.Et2O,-20°C - rt 32

O-C(NH)CCl3 (a ��b) TBDMS CHO BF3.Et2O,-20°C - rt 0

OAc (b) TBDMS CHO BF3.Et2O,-20°C - rt 33

O

OH

HO

OOH

OH

O

OH

HOOH

OO CHO

O

OOH

OH

O

HOOH

OO CHO

HO

HOHO

OH

O

HOOH

ONH

CHO

OH OH

O

HOOH

O

OH

N

OHRO

O CHO

113 R = Sorbitol114 R = Mannitol

115116

117 118Scheme 21.

In keeping with glycosylations of HMF, Cottier et al. [128] in-vestigated preparation of peracetylated �-GMF 112 (the corre-sponding � anomer of GMF) by glycosylation of HMF or its sily-lated derivative (Table 1). This reaction was studied using differ-ently activated glucosyl donors 110 and differently substituted furanoic alcohols 111. Direct condensation of HMF with a glucosyl donor gave only moderate yield of 112 (32%).

It is important to note that GMF (17) and some of its analogs (100, 101, 106, 113-118) have been also found in different natural products, plants, and foods (Scheme 20 and 21), such as Rehman-niae Radix (Di Huang) [129-131], the kernel of Prinsepia uniflora [132], the fruit of Amelanchier Canadensis [133], and in commer-cial caramel and caramel candy [127].

Many reactions have been performed on GMF, involving either the aldehyde group or the furan unit [124]. A series of interesting derivatives have thus been synthesized (Scheme 22). Reduction of GMF by NaBH4 gives the respective GMF-alcohol 122 (85%), while reductive amination provides GMF-amine 127 (97%). Selec-tive oxidation of GMF by chlorite gives the corresponding furan-carboxylic acid 119 (89%). Both GMF-amine 127 and the furancar-boxylic acid 119 can be transformed to a series of non-ionic am-phiphilic compounds 120, 121, 128-130 by esterification with long-chain alcohols or by N-acylation with fatty acid chlorides, respec-tively (Scheme 22). Such compounds can be regarded as surfactants

and also exhibit liquid crystalline properties [96]. Heating GMF with hydroxylammonium chloride provides nitrile 123 (61%), which can be further transformed to tetrazolide 124 (90%) by a 1,3-dipolar cycloaddition with sodium azide in DMF. Also GMF read-ily undergoes base-catalyzed aldol-type reaction with nitromethane and acetophenone leading to the corresponding 2-nitrovinyl and 2-benzoylvinyl compounds (125 and 126) in good yields.

Lichtenthaler et al. [134, 136] reported an efficient protocol for the conversion of GMF (17), GMF-alcohol (122), and GMF-amine (127) into N-heterocycles such as: pyrrole, pyridazine, pyridinol, pyridazinone, and benzodiazepinone. Oxidation of the furan moiety of GMF or per-acetylated-GMF generated three different reactive �-keto-carboxylic acid intermediates, namely 131 (85%), 132 (93%) and 133 (98%) under different reaction conditions (Scheme 23).The reaction between glucosylated hydroxybutenolide 131 and o-phenylenediamine (134) led to the formation of glucosylated benzodiazepinone 135 (65%). This product could be further dehydrogenated with 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ), to glucosylated benzodiazepinone 136 (50%). Treatment of 133 with phenyl hydrazine (137) afforded pyridazinone 138 (70%), whereas with 1,2-diaminobenzene (134) or 1,2-diamino-4,5-dichloro-benzene (139) gave benzodiaze-pinones 140 (55%) and 141 (48%) respectively.


122

NH2OH/HCl (1 equiv)

DMSO

Yield = 61% 123

O

OHOHO

HO

OH

O CN110 OC, 0.5 h

RCH3

NaOH solution (10%)

0 OC, 0.5 h

NaN3 (2 equiv)

DMF

Yield = 90%

O

OHOHO

HO

OH

O100 OC, 3 h N N

NN

Na+

O

OHOHO

HO

OH

O R

125: R = NO2, Yield = 71%126: R = COPh, Yield = 70%

Raney Ni

NH3 solution

60 °C, 1 hO

OHOHO

HO

OH

ONH2

127

H2, 100 atm

Yield = 97%

119

O

OHOHO

HO

OH

O COOH

O

OHOHO

HO

OH

OOH

NaBH4 (2 equiv)

CH3OH

Yield = 85%

r.t. 2 h

NaClO2 (1 equiv)

H2O

Yield = 89%

DCC

Fat alcoholO

OHOHO

HO

OH

O

acry chloride

OR

O

120: R =C6H13, Yield = 71%

121: R = C10H21, Yield = 70%

O

OHOHO

HO

OH

O

HN

R

128: R = C4H9, Yield = 71%

129: R = C6H13, Yield = 70%

O

130: R = C8H17, Yield = 70%

17 GMF

124

Scheme 22.

Reaction between GMF-alcohol (122) and bromine in water generates glucosyloxy-cis-hexenedione 148, which spontaneously cyclized to dihydropyranone 149 (95%) through Achmatowicz reaction [135] (Scheme 24). Further treatment of the dihydro-pyranone with hydrazine gives glucosylated 3,6-dihydroxy-methyl-pyridazine 150 (68%). Oxidation of perbenzylated GMF-alcohol with 3-chloroperbenzoic acid gave glucosylated cis-hexenediones 140 (79%). Further reduction of the olefinic double bond followed by N-cyclizations with ammonium acetate, aniline, benzylamine, and dodecylamine provided glucosylated pyrroles 144(70%), 145 (75%), 146 (84%), 147 (83%) respectively [136].

The aza-Achmatowicz reaction [137] of GMF-amine 127 with bromine in water gives the 6-(glucosyloxymethyl)-3-pyridinol 151(75%) (Scheme 25). When the terminal group was changed to a

secondary amino group, this oxidation provided N-alkyl pyridinium betaines 154 (71%) and 155 (70%), thus affording original cationic surface-active compounds. Through selective carbamoylation, 155can also be converted into a hydrophilic pyridostigmine 156 (86%), exhibiting cholinesterase inhibitory activity [138].

In keeping with reaction on the furanic moiety of GMF, Cottier et al. [128] reported that hydroxy butenolides 131� and 131� could be easily generated from per-acetylated GMF or �-GMF by pho-tooxygenation (Scheme 26). Reduction of the same intermediate led to the acetylated diastereoisomers of acetylated diastereoisomers of ranunculin 157 (60~80%) in moderate to good yield. Alternatively, via a hydrogen transfer reaction, this intermediate gave access to �-keto esters 158 (75%) and 159 (70%), which can be further trans-formed to glycosyl �-aminobutyric acid derivatives.


O

OHOHO

HO

OH

O CHO

140: R = H, Yield = 55%

O

OAcOAcO

AcO

OAc

O

HO

O

NH2

NH2

O

OAcOAcO

AcO

OAc

O

NH

HN

O

O

OAcOAcO

AcO

OAc

O

NH

HN

O

O

OHOHO

HO

OH

COOHO

O

OHOHO

HO

OH

COOHO

O

OHOHO

HO

OH

N N

O

O

OHOHO

HO

OH

O

NH

HN

OR

R

NH2

NH2

R

RNH-NH2

1. Ac2O/Pyridine2. mCPBA/CH2Cl2

Yield = 85%

Yield = 65%

Yield = 98%

H2O2

DDQ

Yield = 50%

1O2MeOH

Yield = 93%

132

131 133

138

135

136

Yield = 70%

141: R = Cl, Yield = 48%

17 GMF

134137

134: R = H139: R = Cl

Scheme 23.

O

OHOHO

HO

OH

O

O

OBnOBnO

BnO

OBn

O

OHOHO

HO

OH

1. BnBr/KOH/Dioxane2. mCPBA/CH2Cl2

Yield = 79%

Yield = 70%

Br2/H2O

148142O OOBn

O

OBnOBnO

BnO

OBn

N

R

OBn

144: R = H, Yield = 70% 145: R = Ph, Yield = 75%

O

OHOHO

HO

OH

O OOH

O

O

HO

O

OHOHO

HO

OH

NN

OH

Yield = 95%

Yield = 68%

149

150

O

OBnOBnO

BnO

OBn

143O OOBn

N2H4

Zn/HOAc

RNH2/H+

OH

146: R = Bn, Yield = 84% 147: R = n-C12H25, Yield = 83%

122

Scheme 24.


127

Br2/H2O

Br2/H2O

154: R = Me, Yield = 71%155: R = (CH2)13Me, Yield = 70%

ON

O

Me

NMe2

O

Cl-

151

156152: R = Me, Yield = 71%153: R = (CH2)13Me, Yield = 70%

Yield = 75%

Yield = 86%

Yield = 97%

OH

O

HOOH

O

HO

17 GMF

OO

NH2

OH

O

HOOH

HO

N

OH

OH

O

HOOH

HO

OH

O

HOOH

O

HO

N

O

R

OO

NHR

OH

O

HOOH

HO

Scheme 25.

OAcO

AcO

OAc

O CHOO

AcO

OAcO

AcO

OAc

O CHOO

AcO

HO

OAcO

AcO

OAc

O CHOO

AcO

H

OAcO

AcO

OAc

OAcO O

OMe

O

1: HCOOK/Pd(OAc)2/DMF

Reduction

Yield = 60~80%

157

[O2]

2: K2CO3/Me2SO4/Acetone

158: � epimer, Yield = 75%159: � epimer, Yield = 70%

131

Scheme 26.

161Solvent, 36 h

OO

OH O

OMeDABCO

OMe

O

Solvent Yield (%)H2O 331,4-Dioxane� 0DMI� <5CH3CN/H2O 311,4-Dioxane/H2O 35DMI/H2O 56

160

17 GMF

OH

O

HOOH

OO CHO

HO

OH

O

HOOH

HO

Scheme 27.

Recently, Queneau et al. [139] have reported new carbohydrate containing acrylates arising from an aqueous Baylis-Hillman reac-tion of GMF with various acrylates (Scheme 27). Different solvent conditions were compared and the best yields were found when a 1:1 (v/v) ratio of dimethylisosorbide (DMI) and water was used, leading to 56% yield of the Baylis-Hillman adducts 161. It is im-

portant to note that the reaction also proceeds in pure water, though in a lower isolated yield (33%), but a significant amount of starting material (30%) was recovered. The reaction of GMF and some of its analogues were then investigated with various acrylates differing in their ester group and the results are listed in (Scheme 28). This new approach towards totally biobased functional compounds (po-


tential monomers, surfactants) appears very attractive when consid-ering the fact that this reaction can take place in water or other bio-based solvents.

5. CONCLUSION

Isomaltulose offers a wide range of strategies for designing new biobased chemicals. Besides its interest as precursor of the industri-ally relevant product isomalt, hydroxy groups transformations such as glycosidation, glycosylation, etherification, esterification, oxida-tion to carboxylated derivatives, and reactions of the fructose car-bonyl with aminated reagents have demonstrated its extremely ver-satile usefulness as a starting chemical. Through the fascinating triple dehydration to GMF, the fructose structure offers additional ways towards carbohydrate-based functional compounds and mate-rials. GMF can be further transformed in three directions, either by reaction of the OH groups, the furanic moiety or the isolated alde-hyde function. Taking into account the importance of HMF in biobased chemistry nowadays, GMF finds a renewed interest as exemplified by some recent results reported above.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Authors thank the Ministère de l’Enseignement Supérieur et de la Recherche (MESR) and CNRS for the financial support, as well as the Chinese Scholarship Council (UT-INSA-CSC call) for a fellowship to JNT.

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162 (63%)

165 (56%)164 (60%)

167 (57%)

172 (51%)

163 (35%)

168 (63%) 169 (62%)

166 (50%)

OO

OH O

OEt

OH

O

HOOH

HO

OO

OH O

OBu

OH

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HOOH

HO

OO

OH O

O

OH

O

HOOH

HO

OO

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OOO

OH O

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OO

OH O

OMeO

HOOH

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Scheme 28.


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Received: January 17, 2014 Revised: March 15, 2014 Accepted: May 25, 2014

Isomaltulose Oxidation and Dehydration Products as Starting Materials Towards Fine Chemicals

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