Stereoselective dihydroxylation reaction of alkenyl β- D -hexopyranosides: A methodology for the synthesis of glycosylglycerol derivatives and 1-O-Acyl-3-O-β- D -glycosyl-sn-glycerol analogues

FULL PAPER

DOI: 10.1002/ejoc.201101539

Stereoselective Dihydroxylation Reaction of Alkenyl β-

D

-Hexopyranosides:

A Methodology for the Synthesis of Glycosylglycerol Derivatives and 1-O-

Acyl-3-O-β- -glycosyl-sn-glycerol Analogues

D

José M. Vega-Pérez,*^[a]Carlos Palo-Nieto,^[a]Ignacio Periñán,^[a]Margarita Vega-Holm,^[a]

José M. Calderón-Montaño,^[b]Miguel López-Lázaro,^[b]and Fernando Iglesias-Guerra*^[a]

Keywords: Synthetic methods / Asymmetric synthesis / Carbohydrates / Diastereoselectivity / Biological activity /

Dihydroxylation

A variety of new glycosylglycerol derivatives have been pre-

pared by stereoselective dihydroxylation of a range of alk-

NHAc) at the 2-position of the sugar moiety is required to

obtain high levels of stereofacial discrimination. New 1-O-

enyl β-

D-hexopyanosides under Donohoe’s conditions. We

acyl-3-O-β-D-glycosyl-sn-glycerol analogues were obtained

have studied the relationship between the diastereoisomeric

excess and the structural features of the precursor (sugar and

alkenyl moieties). The stereochemical yields demonstrated

that the presence of a hydrogen-bond donor group (OH,

by functionalisation of the primary hydroxy group with a

fatty acid. Preliminary cytotoxic activity assays of both glyco-

sylglycerol and glycoglycerolipid analogues are also pre-

sented.

Introduction

Osmium-mediated dihydroxylation is one of the most

synthetically useful reactions and is tolerant of a wide array

of functional groups. The basic premise of the reaction is

the syn addition of the hydroxy groups across a C=C bond

to produce 1,2-glycols.^[1–6]The utility of this reaction in the

field of organic synthesis is enhanced by the easy transfor-

mation of the 1,2-diol products into other synthetically use-

ful intermediates. This becomes more important when these

synthetic intermediates are the precursors of products with

biological activity.^[7]

In the field of diastereoselective dihydroxylation of sub-

stituted alkenes, the most useful compounds that have been

subjected to these protocols are cyclic allylic alcohols and

amides. In 1983, Kishi and co-workers reported a thorough

study of the dihydroxylation of allylic alcohols and showed

that the double bond is oxidised from the face opposite the

hydroxy group under standard conditions (OsO₄/NMO),

being driven by steric factors^[8](Scheme 1).

Scheme 1. Hydroxy-directed dihydroxylation.

sequence of a hydrogen bond formed between the hydroxy

group of the allylic alcohol and the oxo ligands, which act

as efficient hydrogen-bonding acceptors, and thus the dihy-

droxylation occurs on the same face as the hydroxy group

of the allylic alcohol.^[9]They also reported the direct dihy-

droxylation of a range of cyclic allylic amides with this sys-

tem, describing the same hydrogen-bonding control leading

to the syn stereoisomer^[10](Scheme 2).

Donohoe et al. disclosed the use of an osmium tetroxide–

tetramethylethylenediamine (TMEDA) complex for the

synthesis of the syn diol. The product is obtained as a con-

[a] Departamento de Química Orgánica y Farmacéutica, Facultad

de Farmacia, Universidad de Sevilla,

Scheme 2. TMEDA-stereocontolled reaction.

c/ Profesor García González 2, 41012 Sevilla, Spain

E-mail: vega@us.es

Our research group has a long-term interest in the use of

carbohydrates in asymmetric processes. In this sense, we

have employed carbohydrate derivatives as chiral templates

for the stereoselective synthesis of different compounds: di-

amino sugars, chiral oxazolidines, highly functionalised new

iglesias@us.es

[b] Departamento de Farmacología, Facultad de Farmacia,

Universidad de Sevilla,

c/ Profesor García González 2, 41012 Sevilla, Spain

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201101539.

Eur. J. Org. Chem. 2012, 1237–1252

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J. M. Vega-Pérez, F. Iglesias-Guerra et al.

FULL PAPER

β-enamino ketones and compounds with potential anti-can- ids have been found to have biological and pharmacological

cer activity.^[11]

activities, including antitumour, HIV-1 infection inhibitory

On the other hand, searching for new methods for the and antiinflammatory activities.^[18]

stereoselective synthesis of relevant functions such as cyclo-

Natural acyl mono- and diglycosylglycerols, generally ga-

propanes^[12]and oxiranes, our research involves the use of lactolipids in which the sugar is linked to the 3-position of

carbohydrates as chiral inducers in asymmetric transforma- sn-glycerol, have attracted attention as antitumour-promot-

tions of olefins, with the olefinic chain joined to different ing compounds.^[19]The search for effective chemo-pre-

positions of the sugar moiety through various functions.

venting agents is focused on the synthesis of new glycogly-

Focusing on the development of epoxidation reactions cerolipid analogues and biological evaluation to clarify the

of olefins with high stereocontrol (diastereoselectivity), our structural features necessary for the antitumour-promoting

group has described the stereoselective epoxidation of olefin activity.^[20]In this context we have started a research pro-

moieties linked through various functionalities (glyco- gram based on the synthesis of new glycoglycerolipid ana-

side,^[13,14]amide^[15]and acetal^[16]) to different positions of logues. We present herein new glycosylglycerol analogues 6,

carbohydrate residues with m-chloroperoxybenzoic acid as obtained by an easy and efficient dihydroxylation of alkenyl

oxidant under mild conditions. The different types of chiral β-d-gluco- and β-d-galacto-pyranoside derivatives (Fig-

epoxides obtained (epoxy glycosides, epoxy amides and ep- ure 2). Finally the lipophilic chain was linked to the glycos-

oxy acetals) can be transformed into a variety of com- ylglycerol skeleton through an ester and/or amide function,

pounds.

Herein we present our research focused on the develop-

producing new glycoglycerolipid analogues.

ment of stereoselective osmium-mediated dihydroxylation

reactions employing carbohydrate derivatives as chiral tem-

plates. To prepare the compounds to be dihydroxylated,

first we decided to join the alkenyl moiety to the sugar resi-

due through a glycosidic bond. Previously we have de-

scribed the stereoselective epoxidation reactions of a variety

of alkenyl β-d-gluco- and β-d-galacto-pyranoside deriva-

tives as an efficient methodology for obtaining new chiral

epoxyalkyl-β-d-hexopyranoside derivatives.^[13,14,17]We at-

tempted to assess the behaviour of alkenyl glycosides as chi-

ral templates in osmium-mediated dihydroxylation reac-

tions. Secondly, we had to decide on the appropriate sugar

residue to act as chiral inductor. We have chosen β-d-gala-

cto- and β-d-gluco-pyranoside derivatives with different

substitution patterns at the 2- and 3-positions of the sugar

moiety. Thirdly, a range of allylic alcohols were used in the

glycosylation reaction to explore both the stereoselectivity

and the substrate scope of the reaction.

Figure 2. General structure of the new glycosylglycerol analogues.

Biological tests of both glycosylglycerol and glyco-

glycerolipid analogues are in an initial state and preliminary

results are presented.

Results and Discussion

With a view to addressing this goal, we present herein

our choice of scaffold, namely structure 5,^[13]to act as pre-

cursor as it fulfils all the requirements stated above (Fig-

ure 1).

Development of Stereoselective Osmium-Mediated

Dihydroxylation Reactions: Synthesis of New

Glycosylglycerol Analogues

To synthesise the new glycosylglycerol analogues we have

developed a highly diastereoselective osmium-mediated di-

hydroxylation reaction of alkenyl β-d-hexopyranoside de-

rivatives. We have employed d-galactose, d-glucose and 2-

acetamido-2-deoxy-d-glucose as sugar precursors. Our ob-

jective was to achieve a set of functionalised substances

with a well-defined stereochemistry that differ in the type

of incorporated alkenyl moiety as well as in the sugar resi-

due and its substituents.

Figure 1. General structure of the alkenyl β-d-hexopyranosides.

Glycolipids are glycoconjugates that are widespread in

The alkenyl β-d-galactopyranosides were prepared fol-

bacteria, plants and animals. They serve a variety of func- lowing a short synthetic sequence that starts from the com-

tions in nature. Glycoglycerolipids are one of a class of gly- mercially available α-d-acetobromogalactose 7. These alk-

colipids that are common constituents of plant cell mem- enyl 4,6-O-(S)-benzylidene-d-galactopyranosides 8–13 have

branes and bacterial cell walls. They consist of one or more been described previously by our group and were obtained

monosaccharide units and fatty acid residues linked by a in good chemical yields (87–92%) as a single diastereoiso-

glycerol moiety. A large number of natural glycoglycerolip- mer^[13](Scheme 3).

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Eur. J. Org. Chem. 2012, 1237–1252

Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

19, 20 and 22–23 have previously been synthesised by our

group.^[14]

With the alkenyl β-d-hexopyranoside derivatives in hand,

we performed assays to develop an effective stereoselective

dihydroxylation of the double bond. First, we tried stan-

dard catalytic conditions (OsO₄catalytic/NMO) with com-

pounds 12 (galacto derivative) and 15 (gluco derivative), but

the reactions showed no stereoselectivity. We then looked

at the work of Donohoe and co-workers, who reported the

direct dihydroxylation of a range of cyclic allylic alcohols

and amides with the formation of the syn stereoisomer with

high stereocontrol.^[9,10]

The 2,3-dihydroxyalkyl β-d-hexopyranosides 24–37 were

synthesised by employing Donohoe’s conditions: sugar de-

rivatives (1.0 mmol), TMEDA (1.1 mmol) and OsO₄

(1.05 mmol). Compounds 8–13, 15, 16 and 18–23 were used

as precursors. This is the first report of the dihydroxylation

of alkenyl sugar derivatives employing these conditions

(Scheme 6). The dihydroxylated derivatives were isolated in

satisfactory chemical yields (50–90%). Stereochemical

Scheme 3. Reagents and conditions: (i) HOCH₂CR¹=CR²R³,

MeNO₂/PhMe, Hg(CN)₂, 50 °C, 2–3 h; (ii) NaMeO, MeOH;

(iii) PhCH(OMe)₂, MeCN, CSA, 87–92%.

In all the NMR spectra the proton of the 4,6-O-(S)-

benzylidene acetal appears as a singlet between 5.55 and

5.57 ppm, and the anomeric proton as a doublet at around

4.30 ppm in those cases in which its signal is resolved.

1

yields (des) were established by H NMR spectroscopy and

are summarised in Table 1.

By

using

2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl

bromide (14) as the starting material and employing the

same methodology we prepared alkenyl β-d-glucopyrano-

side derivatives 15^[21]and 16 in good yields (Scheme 4).

Scheme 4. Reagents and conditions: (i) HOCH₂CR¹=CR²R³,

MeNO₂/PhMe (1:1), Hg(CN)₂, 50 °C, 2–3 h; (ii) NaMeO, MeOH;

(iii) PhCH(OMe)₂, MeCN, CSA (10 mg), 81%.

The reaction of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-

α-d-glucopyranosyl chloride (17)^[22]with the corresponding

unsaturated alcohols gave the corresponding acetylated in-

termediates, which were subjected to deacetylation, and

subsequent reaction with benzaldehyde dimethyl acetal gave

compounds 18–23 (Scheme 5). Compound 18 has pre-

viously been described in the literature^[23]and compounds

Scheme 6. Reagents and conditions: TMEDA, OsO₄, CH₂Cl₂,

–78 °C, 2 h.

The diastereoisomeric excesses of the products from the

dihydroxylation of d-galactose derivatives were low (en-

tries 1–6) with the exception of compounds 24 and 28,

which were obtained with high de (60 and 78%, respectively,

entries 1 and 5). The presence of the methyl group at the 2-

position of the olefin seems to slightly increase the dia-

stereoisomeric excess [compare entry 1 (R¹= H) vs. entry 5

(R¹= Me) and entry 3 (R¹= H) vs. entry 6 (R¹= Me)].

Scheme 5. Reagents and conditions: (i) HOCH₂CR¹=CR²R³,

MeNO₂/PhMe (1:1), Hg(CN)₂, 1–2 d; (ii) NaMeO, MeOH;

(iii) PhCH(OMe)₂, MeCN, CSA (10 mg), 80–90%.

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J. M. Vega-Pérez, F. Iglesias-Guerra et al.

FULL PAPER

Table 1. Asymmetric osmium-mediated dihydroxylation of alkenyl

β-d-galactopyranosides derivatives 8–13 and β-d-glucopyranosides

derivatives 15, 16 and 18–23.

Entry Compd. R¹

R²

R³

R⁴

Yield^[a]

[%]

de^[b]

[%]

1

2

3

4

5

6

7

8

24

25

26

27

28

29

30

31

32

33

34

35

36

37

H

Me

H

Me

H

Me

H

Me

H

Me

Ph

n-C₇H₁₅

H

Ph

H

Me

Ph

–

88

53

52

80

91

66

60

72

92

75

82

65

81

63

60

9

–

9

78

13

–

43

Ͼ99

50

OH

NHAc

9

10

11

12

13

14

n-C₇H₁₅NHAc

H

Me

NHAc

Scheme 7. Reagents and conditions: (i) KOH, 18-crown-6, BnBr,

THF, 3 h, 58%; (ii) KOH, 18-crown-6, BnBr, THF, 20 min, 88%.

[a] Yields after column chromatography. [b] Diastereoisomeric ex-

cesses were determined by relative integration of the ¹H NMR spec-

tra of the reaction mixtures.

employ both ether (benzyl) and ester (acetyl and capriloyl)

functions. Compounds 41–44^[14]were synthesised in high

yields (Scheme 8).

In the case of the d-glucose derivatives, as for the d-gal-

acto derivatives, the diastereoselectivity increased when a

methyl group is present at the 2-position of the olefin moi-

ety [entry 7 (R¹= H) vs. entry 8 (R¹= Me)].

The alkenyl 2-acetamido-2-deoxy-d-glucopyranoside de-

rivatives reacted in virtually all cases with practically com-

plete stereoselectivity (entries 9–14). The diastereomeric ex-

cess was only moderate (50%) in the reaction of the 3,3-

disubstituted olefin, compound 37 (entry 14).

In view of the results presented in Table 1, we can con-

clude that the best chiral inductor is the residue of 2-acet-

amido-2-deoxy-d-glucopyranoside, which provided total

stereoselectivity regardless of the structure of the alkenyl

moiety. For the same alkenyl residue, the d-galactose deriv-

atives gave lower levels of stereoselectivity (compare en-

tries 1–5 vs. entries 9–13) with moderate-to-good de values

obtained with terminal olefins. For the d-glucopyranoside

derivatives the diastereomeric excess decreased even more.

To have a higher number of substrates to subject to dihy-

droxylation and focusing primarily on analysing the influ-

ence of hydroxy groups at the 2- and 3-positions of the

sugar on the stereochemical yields, we also prepared mono-

and diprotected derivatives. We chose those substrates that

yielded diols in high diastereoisomeric excesses, that is,

those derived from d-galactose and 2-acetamido-2-deoxy-

d-glucose.

Scheme 8. Reagents and conditions: (i) KOH, 18-crown-6, BnBr,

THF, 3 h, 70%; (ii) DAMP, acid chloride, CH₂Cl₂, 0 °C, 3 h, 60–

80%.

Compounds 38–44 were then subjected to osmium-medi-

ated dihydroxylation under the same conditions as de-

scribed above (Scheme 9). The chemical and stereochemical

yields are presented in Table 2.

We carried out dibenzylation and selective monobenzyl-

ation reactions (selective at the 3-position) with the galacto

derivatives 8^[24]and 12. In both cases we employed the same

method but with rigorous control of the amounts of rea-

gents and of the reaction time (3 h and 20 min, respectively)

according to a method previously described^[13]for the prep-

aration of monoprotected derivatives (Scheme 7).

The alkenyl 2-acetamido-2-deoxy-β-d-glucopyranoside

derivatives 18 and 22 were also subjected to the 3-O-protec-

Scheme 9. Reagents and conditions: TMEDA, OsO₄, CH₂Cl₂,

tion reaction. To protect the hydroxy group we decided to –78 °C, 2 h.

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Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

Table 2. Asymmetric osmium-mediated dihydroxylation of alkenyl

β-d-hexopyranosides derivatives 38–44.

Entry Compd. R¹R⁴

R⁵

Sugar

Yield^[a]de^[b]

[%]

1

2

3

4

5

6

7

45

46

47

48

49

50

51

H

OBn Bn

galacto

gluco

82

70

66

78

75

81

82

–

20

68

Ͼ99

43

Me OBn Bn

H

Me NHAc Bn

H

OH

Bn

NHAc Bn

NHAc COCH₃

NHAc CO(CH₂)₆CH₃gluco

[a] Yields after column chromatography. [b] Diastereoisomeric ex-

cesses were determined by relative integration of the ¹H NMR spec-

tra of the reaction mixtures.

As can be seen from Table 2, 2,3-di-O-benzyl galacto de-

rivatives 45 and 46 were obtained with low de values (en-

tries 1 and 2). Compounds 24 and 28, galacto derivatives

with the same alkenyl moiety but with the 2- and 3-posi-

tions unprotected, gave high de values (60 and 78%, respec-

tively, Table 1, entries 1 and 5). Compound 47, the 3-O-

benzyl galacto derivative, was obtained in high stereochemi-

cal yield (68%). Based on this result it can be concluded

that the presence of a OH group at the 2-position of the

sugar is determinant for the stereoselectivity of the reaction,

attributed to the formation of a hydrogen bridge.^[9,10]

However, the 3-O-protection of 2-acetamido-2-deoxy

gluco derivatives (benzyl ether and acetyl ester) did not af-

fect the stereochemical yield. Compounds 48–50 were es-

sentially obtained as one diastereoisomer (entries 4–6). This

suggests that the amide function at the 2-position also acts

as a hydrogen-bond donor and directs the stereochemical

course of the reaction. When a capriloyl ester is present at

the 3-position the de falls (43%, entry 7), probably due to

steric interactions.

Scheme 10. Reagents and conditions: (i) TMEDA, OsO₄, CH₂Cl₂,

–78 °C, 2 h, 75%; (ii) DAMP, tosyl chloride, CH₂Cl₂, 0 °C, 5 h,

82%; (iii) NaN₃, DMF, 70 °C, 18 h, 82%; (iv) m-CPBA (Aldrich

57–86%), CH₂Cl₂, –15 °C, 1 month, 83%; (v) NaN₃, LiClO₄,

CH₃CN, 80 °C, 10 h, 82%.

studies led us to assign the R configuration to the glycol

formed and, by extension, the Re notation to the most reac-

tive face. We tentatively propose the mechanism shown in

Figure 3.

Table 3. NMR spectroscopic data for characteristic protons in com-

pound 53 obtained by two routes.^[a]

Entry Compd.

δ [ppm]

3-H

NH

1-H

CH₃CON de^[b][%]

M/m

1

2

53^[c]

53^[d]

5.32

4.77

3.92

1.88

Ͼ99

71

5.32/5.38 4.77/4.83 3.92/4.02 1.88/1.89

Stereochemical Assignment

[a] M/m represents major/minor diastereomer. [b] Diastereoiso-

meric excesses were determined by relative integration of the ¹H

NMR spectra of the reaction mixtures. [c] Compound 53 obtained

from compound 49 as precursor. [d] Compound 53 obtained from

compound 54 as precursor.

Our next objective was the assignment of the configura-

tions of the new stereogenic centres in the glycol moieties

formed in the dihydroxylation reactions. With this goal in

mind we prepared the azide derivative 53 from two different

compounds through short synthetic sequences. We em-

ployed compound 49, a new glycosylglycerol analogue ob-

tained by the dihydroxylation reaction, and the appropriate

epoxyalkyl derivative 54 as precursors (Scheme 10). Note

that this epoxide has previously been prepared in high dia-

stereomeric yield from the alkenyl glucopyranoside 42 by a

stereoselective epoxidation reaction; it was assigned an R

configuration.^[14]

Figure 3. Mechanism tentatively proposed to explain the Re face

attack favored.

We compared the chemical shifts of the easily identifiable

protons and carbons of compound 53, obtained by each of

Synthesis of New Glycoglycerolipid Analogues

1

the two routes. The H and ¹³C NMR spectra of 53 pre-

pared from glycol 49 present a single set of signals (deϾ

In the design of new glycoglycerolipids, the structural

99%). In contrast, compound 53 was obtained as a dia- features usually taken into consideration are the nature of

stereomeric mixture (70% de) from the epoxyalkyl deriva- the saccharidic residue, the anomeric configuration of the

tive 54. The chemical shifts of the protons of the major glycosidic linkage and the length and position of the acyl

diastereoisomer were identical to the single signals of com- residue situated on one of the primary hydroxy groups of

pound 53 obtained from 49 (Table 3). These correlation the glycerol moiety.^[20]

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J. M. Vega-Pérez, F. Iglesias-Guerra et al.

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Three key issues must be addressed in our planned syn- to the β-hexopyranoside residue (the β configuration is

thesis of glycoglycerolipds. First, the glycerol moiety must present in natural bioactive glycosylglycerols)^[19]through

be attached to the sugar. Our synthetic approach involved the stereoselective dihydroxylation of alkenyl β-d-hexopyr-

the preparation of an optically active glycerol moiety linked anosides. Other synthetic approaches involve glycosylation

with an optically active glycerol component yielding dif-

ferent α/β stereoselectivities.^[25]Secondly, O-acylation of the

primary hydroxy group with a fatty acid must be per-

formed. We have employed capriloyl and palmitoyl moieties

as examples of short and medium fatty acid residues and,

with the objective of expanding the acyl residues on the

primary OH, the oleyl residue was also used. Thirdly, the

protecting groups must be eliminated. In this way, com-

pounds 58–60 were obtained in high yields (Scheme 11).

Finally, we planned the synthesis of analogues in which

the lipophilic chain is linked to the glycosylglycerol skeleton

through bonds chemically and enzymatically more stable

than an ester. The designed analogue should be an isoster

of our acylglycosylglycerol. We chose the amide function

taking advantage of the azido derivative 53 prepared for the

stereochemical study and performed its selective reduction

to the amino group and subsequent acylation (Scheme 12).

Evaluation of Cytotoxic Activity

To examine the cytotoxic activity of our compounds

against cancer cells they were tested in vitro against A549

human lung cancer cells by using the MTT method. To

evaluate the selectivity of our compounds towards tumour

and normal cells, they were also tested in an MTT assay

against MRC5 human non-malignant lung fibroblasts (for

conditions of the MTT assay, see the Exptl. Sect.). We car-

ried out these early biological tests to evaluate both the

cytotoxicity and selectivity of the glycosylglycerol and gly-

coglycerolipid analogues.

Scheme 11. Reagents and conditions: (i) DAMP, acid chloride,

CH₂Cl₂, 0 °C, 3 h, 50–78%; (ii) H₂/Pd-C, 4 bar; (iii) 80% acetic

acid/water, 60 °C, 5 h, 85%.

First, we evaluated the 1-O-acyl-3-O-2-acetamido-2-de-

oxy-β-d-glucopyranosyl-sn-glycerol derivatives 58–60 and

the analogue 63 with an amide function. As reference com-

pound we employed cisplatin, a drug with cytotoxic activity,

to truly gauge the effectiveness of our compounds.

The viability of human lung cancer cells A549 and hu-

man non-malignant lung fibroblasts MRC5 treated for 48 h

with several concentrations of each compound is shown in

Figures 4–7.

Figure 4 shows the results for compound 58, the capriloyl

derivative, which showed low cytotoxic activity (IC₅₀Ͼ

1000 μm).

Figure 5 and Figure 7 show the results for compounds

59 and 63, both palmitoyl derivatives with an ester or amide

function. As can be seen, in spite of showing cytotoxic ac-

tivity (IC₅₀= 44.80 and 81.97 μm, respectively, for the refer-

ence compound IC₅₀= 11.67), these compounds did not

show selective activity towards the cancer cell line.

However, compound 60 showed an intermediate situa-

tion. Its activity was less than those of 59 and 63 (IC₅₀

= 362.00 μm), but in this case the cancer cells were more

susceptible than normal cells to its cytotoxic activity (Fig-

ure 6).

Scheme 12. Reagents and conditions: (i) H₂/Pd-C, 1 bar, 4 h;

(ii) DAMP, acyl chloride, CH₂Cl₂, 0 °C, 3 h, 71%; (iii) H₂/Pd-C,

4 bar, 24 h, 80%.

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Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

Figure 4. Percentage cell viability (Ϯ SEM) in A549 and MRC5

cells exposed to compound 58 for 48 h determined by the MTT

assay.

Figure 7. Percentage cell viability (Ϯ SEM) in A549 and MRC5

cells exposed to compound 63 for 48 h determined by the MTT

assay.

These four compounds have the same sugar and glycerol

moieties. The only different structural feature between them

is the acyl group at the 1-position of the glycerol. The pres-

ence of the oleyl group in compound 60 increases the selec-

tivity against cancer cells in this kind of compounds.

We also evaluated the glycosylglycerol analogues 27 and

36, galacto and gluco derivatives, respectively (Figures 8 and

9).

Figure 5. Percentage cell viability (Ϯ SEM) in A549 and MRC5

cells exposed to compound 59 for 48 h determined by the MTT

assay.

Figure 8. Percentage cell viability (Ϯ SEM) in A549 and MRC5

cells exposed to compound 27 for 48 h determined by the MTT

assay.

Figure 8 shows the results of compound 27. In addition

to showing cytotoxic activity (IC₅₀= 63.58 μm), this com-

pound also showed selectivity; the viability of normal cells

MRC-5 was higher than the viability of cancer cells A549.

Compound 36 was chosen for cytotoxicity testing be-

cause it is the glycol precursor of the acyl glycerol analogues

that were tested. As shown in Figure 9, it was neither biolo-

gically active nor selective.

Figure 6. Percentage cell viability (Ϯ SEM) in A549 and MRC5

cells exposed to compound 60 for 48 h determined by the MTT

assay.

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J. M. Vega-Pérez, F. Iglesias-Guerra et al.

FULL PAPER

Alkenyl β-D-Glucopyranosides 16 and 21: Mercury cyanide (2.54 g,

10.0 mmol), 4 Å molecular sieves (5 g) and the corresponding un-

saturated alcohol (10.0 mmol) were added to a solution of 2,3,4,6-

tetra-O-acetyl-α-d-glucopyranosyl bromide (14; 2.06 g, 5.0 mmol)

in nitromethane/toluene (1:1, 30 mL). The mixture was heated at

50 °C with stirring until TLC showed that all the starting material

had reacted (2–3 h). The solid was filtered through Celite and

washed with toluene. The organic layer was washed with an aque-

ous saturated solution of sodium hydrogen carbonate and brine,

then dried (MgSO₄), evaporated to dryness and purified by column

chromatography. For compound 21, with 2-acetamido-3,4,6-tri-O-

acetyl-2-deoxy-d-glucopyranosyl chloride as starting material, the

glycosidation reaction was carried out at room temperature for 1–

2 d. A solution of sodium methoxide (1 mmol) in methanol (5 mL)

was added to a solution of the corresponding acetylated alkenyl

β-d-glucopyranoside in methanol (50 mL). After 30 min at room

temperature, the solution was neutralised by the addition of Dowex

50 resin (H⁺form), filtered and the solvents evaporated to dryness.

Benzaldehyde dimethyl acetal (10.0 mmol) and camphorsulfonic

acid (10 mg) were added to a solution of the corresponding alkenyl

β-d-glucopyranoside in acetonitrile (30 mL). The mixture was

stirred at room temperature until TLC showed that all the starting

material had reacted. Then triethylamine was added until pH 7.

The reaction mixture was evaporated and the compound obtained

was purified by column chromatography to give compounds 16 and

21 in good yields.

Figure 9. Percentage cell viability (Ϯ SEM) in A549 and MRC5

cells exposed to compound 36 for 48 h determined by the MTT

assay.

Conclusions

We have described the stereoselective dihydroxylation of

alkenyl β-d-hexopyranosides under Donohoe’s conditions.

We have demonstrated the decisive role of a hydrogen-bond

donor group (OH, NHAc) at the 2-position of the sugar

moiety in the stereochemical control of the reaction. We

have also studied the influence of the sugar residue on the

stereoselectivity of the reaction. The 2-acetamido-2-deoxy-

β-d-glucopyranoside derivative was found to be the best

chiral inductor, giving Ͼ99% de irrespective of the structure

of the alkene. The chiral agent capability of the d-galactose

residue was lower and dependent on the structure of the

alkene moiety.

By using different sugar moieties and allylic alcohols this

becomes an efficient methodology for the stereoselective

synthesis of a wide variety of new glycosylglycerol ana-

logues and, by their use as precursors, of new 1-O-acyl-3-

O-β-d-glycosyl-sn-glycerol analogues.

2-Methyl-2-propenyl

4,6-O-(R)-Benzylidene-β-D-glucopyranoside

(16): Purification by column chromatography using hexane/ethyl

acetate (1.5:1) as eluent gave the compound as a white solid; yield

1.30 g (81%); m.p. 98–99 °C. [α]_D= –52.0 (c = 1.0, CH₂Cl₂). ¹H

NMR (500 MHz, CDCl₃): δ = 1.79 [s, 3 H, OCH₂C(CH₃)=CH],

3.45 (m, 1 H, 5-H), 3.53–3.59 (m, 2 H, 2-H, 3-H), 3.79 (t, J =

10.3 Hz, 1 H, 6_a-H), 3.84 (t, J = 9.1 Hz, 1 H, 4-H), 4.07, 4.28 [2 d,

J = 12.4 Hz, 2 H, OCH₂C(CH₃)=CH₂], 4.35 (dd, J = 5.0, 10.4 Hz,

1 H, 6_e-H), 4.44 (d, J = 7.8 Hz, 1 H, 1-H), 4.96, 5.04 [2 m, 2 H,

OCH₂C(CH₃)=CH₂], 5.57 (s, 1 H, PhCH), 7.3–7.5 (m, 5 H,

Ph) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ

=

19.5

[OCH₂C(CH₃)=CH₂], 66.4 (C-5), 68.7 (C-6), 73.2 (C-4), 73.3

[OCH₂C(CH₃)=CH₂], 74.6 (C-2), 80.6 (C-3), 101.9 (C-1), 102.0

(PhCH), 113.5 [OCH₂C(CH₃)=CH₂], 126.3–137.0 (Ph), 140.8

[OCH₂C(CH₃)=CH₂] ppm. MS (FAB): m/z (%) = 345 (60) [M +

Na]⁺. HRMS (FAB): calcd. for C₁₇H₂₂O₆Na [M + Na]⁺345.1314;

found 345.1320. C₁₇H₂₂O₆(322.14): calcd. C 63.34, H 6.88; found

C 63.21, H 6.62.

We have also presented our preliminary results on cyto-

toxicity assays.

At present we are preparing more compounds by this

methodology and studying the relationship between the

structural features of our compounds (sugar, alkenyl and

acyl moieties) and their cytotoxic activity and selectivity.

(E)-2-Decenyl 2-Acetamido-4,6-O-(R)-benzylidene-2-deoxy-β-D-glu-

copyranoside (21): Purification by column chromatography using

dichloromethane/methanol (20:1) as eluent gave a white solid; yield

1

1.60 g (72%); m.p. 230–231 °C. [α]_D= –31.0 (c = 0.5, MeOH). H

Experimental Section

NMR (500 MHz, [D₆]DMSO): δ = 0.85 [t, J = 6.9 Hz, 3 H,

OCH₂CH=CH(CH₂)₆CH₃], 1.20–1.35 [m, 10 H, OCH₂CH=

CHCH₂(CH₂)₅CH₃], 1.80 (s, 3 H, CH₃CON), 1.98 [m, 2 H,

OCH₂CH=CHCH₂(CH₂)₅CH₃], 3.30 (m, 1 H, 5-H), 3.41 (t, J =

9.3 Hz, 1 H, 4-H), 3.49 (m, 1 H, 2-H), 3.61 (m, 1 H, 3-H), 3.71 (t,

J = 10.2 Hz, 1 H, 6_a-H), 3.93 [dd, J = 6.0, 12.5 Hz, 1 H,

OCH_AH_BCH=CH(CH₂)₆CH₃], 4.11 [dd, J = 5.5, 12.5 Hz, 1 H,

OCH_AH_BCH=CH(CH₂)₆CH₃], 4.18 (dd, J = 4.8, 9.8 Hz, 1 H, 6_e-

H), 4.49 (d, J = 8.4 Hz, 1 H, 1-H), 5.23 (d, J = 5.6 Hz, 1 H, OH),

5.58 (s, 1 H, PhCH), 5.43 [m, 1 H, OCH₂CH=CH(CH₂)₆CH₃], 5.63

[m, 1 H, OCH₂CH=CH(CH₂)₆CH₃], 7.3–7.5 (m, 5 H, Ph), 7.78 (d,

J = 9.0 Hz, 1 H, NH) ppm. ¹³C NMR (125 MHz, [D₆]DMSO):

δ = 13.8 [OCH₂CH=CH(CH₂)₆CH₃], 22.0 (CH₃CON), 23.0–31.6

[OCH₂CH=CH(CH₂)₆CH₃], 56.2 (C-2), 65.9 (C-5), 67.9 (C-6), 68.9

[OCH₂CH=CH(CH₂)₆CH₃], 70.4 (C-3), 81.3 (C-4), 100.6 (PhCH),

Materials and General Methods: Evaporations were conducted un-

der reduced pressure. Preparative chromatography was performed

on silica gel 60 (E. Merck). Kieselgel 60 F254 (E. Merck) was used

for TLC. Melting points were obtained with an SMP 10 Stuart

Melting Point apparatus. Optical rotations were obtained with a

Perkin–Elmer Polarimeter Model 341 at 25 °C. Mass spectra were

recorded with a Micromass AUTOSPECQ mass spectrometer: EI

at 70 eV and CI at 150 eV, HR measurements with resolutions of

10000. FAB-MS were recorded by using a thioglycerol matrix.

NMR spectra were recorded at 25 °C with a Bruker AMX500 and

AV500 spectrometers at 500 MHz for ¹H and 125 MHz for ¹³C.

The chemical shifts are reported in ppm on the δ scale relative to

TMS. COSY, HSQC and NOESY experiments were performed to

assign the signals in the NMR spectra.

1244

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Eur. J. Org. Chem. 2012, 1237–1252

Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

100.8 (C-1), 126.0 [OCH₂CH=CH(CH₂)₆CH₃], 133.2 [OCH₂CH= OCH_AH_BCH(OH)CH₂OH minor], 4.91 (d, J = 6.1 Hz, 1 H, 2-

CH(CH₂)₆CH₃], 126.0–137.7 (Ph), 169.1 (C=O) ppm. MS (FAB): OH), 4.99 (d, J = 4.4 Hz, 1 H, 3-OH), 5.57 (s, 1 H, PhCH), 7.3–

m/z (%) = 470 (100) [M + Na]⁺. HRMS (FAB): calcd. for 7.5 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 63.4

C₂₅H₃₇NO₆Na [M + Na]⁺470.2519; found 470.2504. C₂₅H₃₇NO₆

(459.26): calcd. C 67.09, H 8.33, N 3.13; found C 66.83, H 8.51, N

3.39.

(C-5 minor), 63.4 (C-5 major), 66.4 [OCH₂CH(OH)CH₂OH], 69.1

(C-6), 70.5 [OCH₂CH(OH)CH₂OH], 70.8 (C-2 major), 71.0 (C-2

minor), 71.6 (C-3 major), 71.8 (C-3 minor), 72.2 (C-4 minor), 72.3

(C-4 major), 76.5 [OCH₂CH(OH)CH₂OH], 100.2 (C-1), 104.1

(PhCH), 126.8–139.1 (Ph) ppm. MS (FAB): m/z (%) = 365 (100)

[M + Na]⁺. HRMS (FAB): calcd. for C₁₆H₂₄O₈Na [M + Na]⁺

365.1212; found 365.1224.

Allyl 2-Acetamido-4,6-O-(R)-benzylidene-3-O-capriloyl-2-deoxy-β-

D-glucopyranoside (44): DAMP (2 mmol) and capriloyl chloride

(1 mmol) were added to a solution of 18 (0.5 mmol) in dry dichlo-

romethane (30 mL) precooled to 0 °C. The reaction mixture was

stirred at 0 °C until TLC showed that all the starting material had

reacted (3 h). The organic phase was successively washed with di-

luted hydrochloric acid, water and an aqueous saturated solution

of sodium hydrogen carbonate, dried (MgSO₄), filtered and the fil-

trate was evaporated to dryness. The compound was obtained as a

white solid by column chromatography using hexane/ethyl acetate

(2S,3S)-2,3-Dihydroxybutyl 4,6-O-(S)-Benzylidene-β-D-galactopyr-

anoside (25): Two stereoisomers were obtained in a 1.2:1 ratio (9%

de). The pure diastereomeric mixture was obtained as a pale-yellow

syrup by column chromatography using dichloromethane/methanol

(10:1) as eluent; yield 0.19 g (53%). [α]_D= –21.2 (c = 0.5, CH₂Cl₂).

¹H NMR (500 MHz, CDCl₃): δ = 1.19, 1.21 [2 d, J = 6.4 Hz, 3 H,

OCH₂CH(OH)CH(OH)CH₃], 3.46 (m, 1 H, 5-H), 3.55–3.85 [m, 5

(2:1) as eluent; yield 0.26 g (54%); m.p. 201–202 °C. [α]_D= –63.0

1

(c = 0.3, CH₂Cl₂). H NMR (500 MHz, CDCl₃): δ = 0.85 [t, J = H, 2-H, 3-H, OCH_AH_BCH(OH)CH(OH)CH₃], 3.95 [dd, J = 5.8,

7.0 Hz, 3 H, CH₃(CH₂)₅CH₂CO₂], 1.2–1.6 [m, 10 H, CH₃(CH₂)₅- 11.1 Hz, 0.45 H, OCH_AH_BCH(OH)CH(OH)CH₃minor], 4.0–4.1

CH₂CO₂], 1.95 (s, 3 H, CH₃CON), 2.32 [m, 2 H, CH₃(CH₂)₅-

CH₂CO₂], 3.51 (m, 1 H, 5-H), 3.70 (t, J = 9.4 Hz, 1 H, 4-H), 3.80 (t,

[m, 1.55 H, 6_a-H, OCH_AH_BCH(OH)CH(OH)CH₃major], 4.17 (m,

1 H, 4-H), 4.30 (d, J = 12.4 Hz, 1 H, 6_e-H), 4.34, 4.35 (2 d, J =

J = 10.3 Hz, 1 H, 6_a-H), 4.02 (m, 1 H, OCH_AH_BCH=CH₂), 4.17 (m, 7.7 Hz, 1 H, 1-H), 5.52 (s, 1 H, PhCH), 7.2–7.5 (m, 5 H, Ph) ppm.

1 H, 2-H), 4.30–4.35 (m, 2 H, 6_e-H, OCH_AH_BCH=CH₂), 4.55 (d, J

¹³C NMR (125 MHz, CDCl₃): δ = 19.3, 19.4 [OCH₂CH(OH)-

= 8.5 Hz, 1 H, 1-H), 5.15–5.30 (m, 2 H, 3-H, OCH₂CH=CH₂), 5.51 CH(OH)CH₃], 66.8 (C-5), 68.0, 68.1 (C-2), 69.0 (C-6), 71.6 [OCH₂-

(s, 1 H, PhCH), 5.58 (d, J = 9.4 Hz, 1 H, NH), 5.85 (m, 1 H,

OCH₂CH=CH₂), 7.35–7.45 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 14.0 [CH₃(CH₂)₆CO₂], 23.3 (CH₃CON), 22.6–34.3

CH(OH)CH(OH)CH₃], 72.7 (C-3), 74.0 [OCH₂CH(OH)CH(OH)-

CH₃], 75.2 (C-4), 101.4 (PhCH), 103.5, 103.6 (C-1), 126.4–137.4

(Ph) ppm. MS (FAB): m/z (%) = 379 (100) [M + Na]⁺. HRMS

[CH₃(CH₂)₆CO₂], 54.6 (C-2), 66.6 (C-5), 68.7 (C-6), 70.0 (FAB): calcd. for C₁₇H₂₄O₈Na [M + Na]⁺379.1369; found

(OCH₂CH=CH₂), 71.5 (C-3), 78.7 (C-4), 101.2 (C-1), 101.4 (PhCH),

117.6 (OCH₂CH=CH₂), 126.1–137.0 (Ph), 133.6 (OCH₂CH=CH₂),

170.0 (CH₃CON), 174.2 [CH₃(CH₂)₆CO₂] ppm. MS (FAB): m/z (%)

= 498 (30) [M + Na]⁺. HRMS (FAB): calcd. for C₂₆H₃₇NO₇Na [M

+ Na]⁺498.2468; found 498.2480. C₂₆H₃₇NO₇(475.26): calcd. C

65.66, H 7.84, N 2.95; found C 65.66, H 8.03, N 3.04.

379.1356.

2,3-Dihydroxy-3-phenylpropyl 4,6-O-(S)-Benzylidene-β-D-galactopy-

ranoside (26): Two stereoisomers were obtained in a 1:1 ratio. The

pure diastereomeric mixture was obtained as a pale-yellow solid by

column chromatography using dichloromethane/methanol (7:1) as

eluent; yield 0.22 g (52%); m.p. 130–131 °C. [α]_D= –17.0 (c = 0.5,

CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 3.32, 3.34 (2 s, 1 H, 5-

H), 3.51 [dd, J = 6.6, 10.7 Hz, 0.5 H, OCH_AH_BCH(OH)CH(OH)-

Ph], 3.60–3.65 [m, 1.5 H, 3-H, OCH_AH_BCH(OH)CH(OH)Ph],

3.75–3.90 [m, 3 H, 2-H, OCH_AH_BCH(OH)CH(OH)Ph], 3.98 (m, 1

H, 6_a-H), 4.10 (m, 1 H, 4-H), 4.22 (d, J = 12.4 Hz, 1 H, 6_e-H),

4.26, 4.28 (2 d, J = 7.8 Hz, 1 H, 1-H), 4.64, 4.77 [2 d, J = 6.6 Hz,

1 H, OCH₂CH(OH)CH(OH)Ph], 5.47, 5.49 (2 s, 1 H, PhCH), 7.0–

7.5 (m, 10 H, 2 Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 66.6,

66.7 (C-5), 69.0 (C-6), 70.7 (C-2), 71.3 [OCH₂CH(OH)CH(OH)Ph],

71.5 (C-3), 72.6 [OCH₂CH(OH)CH(OH)Ph], 74.9 [OCH₂CH(OH)-

CH(OH)Ph], 75.4 (C-4), 101.3 (PhCH), 103.1, 103.6 (C-1), 137.6–

126.4 (2 Ph) ppm. MS (FAB): m/z (%) = 441 (100) [M + Na]⁺.

HRMS (FAB): calcd. for C₂₂H₂₆O₈Na [M + Na]⁺441.1525; found

441.1536. C₂₂H₂₆O₈(418.16): calcd. C 63.15, H 6.26; found C

63.24, H 6.30.

2,3-Dihydroxyalkyl β-D-Hexopyranosides 24–37 and 45–51: A solu-

tion of 0.5 m OsO₄(1.05 mmol) in dichloromethane was added to

a solution of sugar derivatives 8–13, 15, 16, 18–23 and 38–44

(1.0 mmol) and TMEDA (1.1 mmol) in dry dichloromethane pre-

cooled to –78 °C (50 mL). The solution turned brown-black and

was stirred at –78 °C until TLC showed that all the starting mate-

rial had reacted (2 h). Ethylenediamine (5.0 mmol) was added to

the crude reaction mixture at room temperature and the resulting

solution stirred for 48 h, during which time a brown precipitate

formed. The solution was concentrated under reduced pressure and

the resulting residue dissolved in methanol/ethyl acetate (1:4) and

filtered through Celite. The organic phase was evaporated to dry-

ness and the compounds obtained were purified by flash

chromatography on silica gel. The diastereomeric excesses (de) were

1

determined by H NMR spectroscopy.

(2R)-2,3-Dihydroxypropyl

4,6-O-(S)-Benzylidene-β-

D-galactopyr-

(2S,3S)-2,3-Dihydroxydecenyl 4,6-O-(S)-Benzylidene-β-D-galactopy-

anoside (24): Two diastereoisomers were obtained in a 4:1 ratio

(60% de). The pure diastereomeric mixture was obtained as a white

solid by column chromatography using dichloromethane/methanol

(7:1) as eluent; yield 0.33 g (88%); m.p. 141–142 °C. [α]_D= +7.0 (c

= 0.5, MeOH). ¹H NMR (500 MHz, [D₆]DMSO): δ = 3.36–3.51

ranoside (27): Two stereoisomers were obtained in a 1.2:1 ratio (9%

de). The pure diastereomeric mixture was obtained as a pale-yellow

syrup by column chromatography using dichloromethane/methanol

(20:1) as eluent; yield 0.35 g (80%). [α]_D= –14.1 (c = 0.6, CH₂Cl₂).

¹H NMR (500 MHz, CDCl₃): δ = 0.88 [t, J = 7.0 Hz, 3 H, OCH_2-

[m, 6 H, 2-H, 3-H, OCH_AH_BCH(OH)CH₂OH], 3.63 (m, 1 H, 5- CH(OH)CH(OH)(CH₂)₆CH₃], 1.25–1.30 [m, 12 H, OCH₂CH(OH)-

H), 3.71 [dd, J = 5.4, 9.7 Hz, 0.8 H, OCH_AH_BCH(OH)CH₂OH

major], 3.84 [dd, J = 4.3, 10.1 Hz, 0.2 H, OCH_AH_BCH(OH)-

CH(OH)(CH₂)₆CH₃], 1.75 (s, 1 H, OH), 3.39 (m, 0.45 H, 5-H

minor), 3.41 (m, 0.55 H, 5-H major), 3.6–3.7 [m, 3 H, 3-H, OCH₂-

CH₂OH minor], 4.06–4.08 (m, 3 H, 4-H, 6_a-H, 6_e-H), 4.22 (d, J = CH(OH)CH(OH)(CH₂)₆CH₃], 3.75–3.80 [m, 2 H, 2-H, OCH_A-

7.6 Hz, 0.8 H, 1-H major), 4.24 (d, J = 7.3 Hz, 0.2 H, 1-H minor), H_BCH(OH)CH(OH)(CH₂)₆CH₃], 4.00 [m, 1 H, OCH_AH_BCH(OH)

4.51 [m, 1 H, OCH_AH_BCH(OH)CH₂OH], 4.63 [d, J = 5.2 Hz, 0.8 CH(OH)(CH₂)₆CH₃], 4.02 (m, 1 H, 6_a-H), 4.11 (m, 1 H, 4-H), 4.27

H, OCH_AH_BCH(OH)CH₂OH major], 4.67 [d, J = 4.3 Hz, 0.2 H, (m, 1 H, 6_e-H), 4.32, 4.33 (2 d, J = 7.8 Hz, 1 H, 1-H), 5.49 (s, 0.45

Eur. J. Org. Chem. 2012, 1237–1252

www.eurjoc.org

1245

J. M. Vega-Pérez, F. Iglesias-Guerra et al.

FULL PAPER

H, PhCH minor), 5.50 (s, 0.55 H, PhCH major), 7.3–7.5 (m, 5 H,

[OCH₂C(CH₃)(OH)CH(OH)Ph minor], 65.9 (C-5 major), 66.0 (C-

5 minor), 68.6 (C-6), 70.2 (C-2 minor), 70.3 (C-2 major), 71.7 (C-

Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.0 [OCH₂CH(OH)-

CH(OH)(CH₂)₆CH₃],

22.6–33.6

[OCH₂CH(OH)CH(OH)(C- 3),

73.6

[OCH₂C(CH₃)(OH)CH(OH)Ph

minor],

73.7

H₂)₆CH₃], 66.7 (C-5 minor), 66.8 (C-5 major), 69.1 (C-6), 71.3 (C- [OCH₂C(CH₃)(OH)CH(OH)Ph major], 73.9 [OCH₂C(CH₃)(OH)-

2), 71.8 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃minor], 72.1 [OCH₂- CH(OH)Ph major], 74.3 [OCH₂C(CH₃)(OH)CH(OH)Ph minor],

CH(OH)CH(OH)(CH₂)₆CH₃major], 72.4 [OCH₂CH(OH)CH- 75.4 [OCH₂C(CH₃)(OH)CH(OH)Ph major], 75.7 [OCH₂C-

(OH)(CH₂)₆CH₃minor], 72.5 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃

minor], 72.6 (C-3), 72.7 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃99.8 (PhCH major), 103.9 (C-1 major), 104.1 (C-1 minor), 126.2–

major], 72.8 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃major], 75.4 (C-

142.1 (2 Ph) ppm. MS (FAB): m/z (%) = 455 (100) [M + Na]⁺.

(CH₃)(OH)CH(OH)Ph minor], 75.9 (C-4), 99.7 (PhCH minor),

4), 101.3 (PhCH), 103.3 (C-1 major), 103.5 (C-1 minor), 126.5– HRMS (FAB): calcd. for C₂₃H₂₈O₈Na [M + Na]⁺455.1682; found

137.5 (Ph) ppm. MS (FAB): m/z (%) = 463 (100) [M + Na]⁺.

HRMS (FAB): calcd. for C₂₃H₃₆O₈Na [M + Na]⁺463.2308; found

463.2323.

455.1676. C₂₃H₂₈O₈(432.18): calcd. C 63.88, H 6.53; found C

63.81, H 6.60.

2,3-Dihydroxypropyl

4,6-O-(R)-Benzylidene-β-D-glucopyranoside

(2R)-2,3-Dihydroxy-2-methylpropyl 4,6-O-(S)-Benzylidene-β-D-gal-

(30): Two stereoisomers were obtained in a 1:1 ratio. Purification by

column chromatography using dichloromethane/methanol (10:1) as

eluent gave a white solid; yield 0.20 g (60%); m.p. 182–183 °C.

actopyranoside (28): Two diastereoisomers were obtained in an

8.1:1 ratio (78% de). The pure diastereomeric mixture was obtained

as a pale-yellow syrup by column chromatography using dichloro-

methane/methanol (7:1) as eluent; yield 0.33 g (91%). [α]_D= +5.0

1

[α]_D= –21.0 (c = 0.5, MeOH). H NMR (500 MHz, [D₆]DMSO):

δ = 3.10 (m, 1 H, 2-H), 3.28–3.42 [m, 5.5 H, 3-H, 4-H, 5-H,

OCH_AH_BCH(OH)CH₂OH], 3.49 [dd, J = 4.6, 9.8 Hz, 0.5 H, OCH-

_AH_BCH(OH)CH₂OH], 3.60–3.70 [m, 2.5 H, 6_a-H, OCH_AH_B-

CH(OH)CH₂OH], 3.77 [dd, J = 4.4, 10.0 Hz, 0.5 H, OCH_AH_B-

CH(OH)CH₂OH], 4.18 (dd, J = 4.0, 10.6 Hz, 1 H, 6_e-H), 4.34, 4.35

(2 d, J = 7.5 Hz, 1 H, 1-H), 4.46 [m, 1 H, OCH₂CH(OH)CH₂OH],

4.58, 4.61 [2 d, J = 3.0, 3.8 Hz, 1 H, OCH₂CH(OH)CH₂OH], 5.25

(s, 2 H, 2-OH, 3-OH), 5.55 (s, 1 H, PhCH), 7.35–7.45 (m, 5 H,

Ph) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 62.7, 62.8 [OCH₂-

CH(OH)CH₂OH], 65.8 (C-5), 67.9 (C-6), 70.3, 70.4 [OCH₂-

CH(OH)CH₂OH], 71.2, 71.5 [OCH₂CH(OH)CH₂OH], 72.6, 72.7

(C-3), 74.3, 74.4 (C-2), 80.6 (C-4), 100.6 (PhCH), 103.8, 103.9 (C-

1), 126.3–137.7 (Ph) ppm. MS (FAB): m/z (%) = 365 (100) [M +

Na]⁺. HRMS (FAB): calcd. for C₁₆H₂₂O₈Na [M + Na]⁺365.1212;

found 365.1202. C₁₆H₂₂O₈(342.34): calcd. C 56.13, H 6.48; found

C 56.24, H 6.41.

1

(c = 0.5, CH₂Cl₂). H NMR (500 MHz, CDCl₃): δ = 1.10 [s, 2.67

H, OCH₂C(CH₃)(OH)CH₂OH major], 1.12 [s, 0.33 H,

OCH₂C(CH₃)(OH)CH₂OH minor], 3.39 (m, 1 H, 5-H), 3.43 [d, J

= 11.4 Hz, 0.89 H, OCH₂C(CH₃)(OH)CH_AH_BOH major], 3.47 [d,

J = 11.3 Hz, 0.11 H, OCH₂C(CH₃)(OH)CH_AH_BOH minor], 3.52

[d, J = 10.5 Hz, 1 H, OCH_AH_BC(CH₃)(OH)CH₂OH], 3.61 [d, J =

11.4 Hz, 1 H, OCH₂C(CH₃)(OH)CH_AH_BOH], 3.65 (dd, J = 9.7,

3.7 Hz, 1 H, 3-H), 3.75 (dd, J = 7.7, 9.7 Hz, 1 H, 2-H), 3.80 [d, J =

10.4 Hz, 0.11 H, OCH_AH_BC(CH₃)(OH)CH₂OH minor], 4.00 (dd, J

= 1.7, 12.6 Hz, 1 H, 6_a-H), 3.92 [d, J = 10.5 Hz, 0.89 H, OCH-

_AH_BC(CH₃)(OH)CH₂OH major], 4.10 (d, J = 3.6 Hz, 1 H, 4-H),

4.25 (dd, J = 1.2, 12.5 Hz, 1 H, 6_e-H), 4.32 (d, J = 7.8 Hz, 0.11 H,

1-H minor), 4.34 (d, J = 7.7 Hz, 0.89 H, 1-H major), 5.48 (s, 1 H,

PhCH), 7.3–7.6 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ

= 21.3 [OCH₂C(CH₃)(OH)CH₂OH major], 22.7 [OCH₂C-

(CH₃)(OH)CH₂OH minor], 66.8 (C-5), 67.8 [OCH₂C(CH₃)(OH)-

CH₂OH minor], 67.9 [OCH₂C(CH₃)(OH)CH₂OH major], 69.1 (C-

6), 71.3 (C-2 minor), 71.4 (C-2 major), 72.3 (C-3), 72.6

[OCH₂C(CH₃)(OH)CH₂OH], 75.5 (C-4), 75.9 [OCH₂C(CH₃)(OH)-

CH₂OH], 101.3 (PhCH), 103.7 (C-1), 126.4–137.6 (Ph) ppm. MS

(FAB): m/z (%) = 379 (100) [M + Na]⁺. HRMS (FAB): calcd. for

C₁₇H₂₄O₈Na [M + Na]⁺379.1369; found 379.1390.

(2R)-2,3-Dihydroxy-2-methylpropyl 4,6-O-(R)-Benzylidene-β-D-glu-

copyranoside (31): Two stereoisomers were obtained in a 2.5:1 ratio

(43% de). The pale-yellow syrup was purified by column

chromatography using dichloromethane/methanol (10:1) as eluent;

yield 0.26 g (72%). [α]_D= –18.0 (c = 0.5, MeOH). ¹H NMR

(500 MHz, [D₆]DMSO):

δ = 1.00 [s, 2.1 H, OCH₂C(CH₃)-

(OH)CH₂OH major], 1.03 [s, 0.9 H, OCH₂C(CH₃)(OH)CH₂OH

minor], 3.13 (m, 1 H, 2-H), 3.20 [m, 1 H, OCH₂C(CH₃)(OH)-

CH_AH_B(OH)], 3.26–3.32 [m, 2 H, OCH_AH_BC(CH₃)(OH)CH_A-

H_BOH], 3.35–3.45 (m, 3 H, 3-H, 4-H, 5-H), 3.62, 3.63 [2 d, J =

9.8 Hz, 1 H, OCH_AH_BC(CH₃)(OH)CH₂OH], 3.69 (m, 1 H, 6_a-H),

(2S,3S)-2,3-Dihydroxy-2-methyl-3-phenylpropyl 4,6-O-(S)-Benzyl-

idene-β-D-galactopyranoside (29): Two stereoisomers were obtained

in a 1.3:1 ratio (13% de). The pure diastereomeric mixture was

obtained as a white solid by column chromatography using dichlo-

romethane/methanol (20:1) as eluent; yield 0.4 g (66%); m.p. 150–

4.18 (dd,

OCH₂C(CH₃)(OH)CH₂OH

J

=

4.5, 10.6 Hz,

1

H, 6_e-H), 4.23 [s, 0.7 H,

4.24 [s, 0.3 H,

1

151 °C. [α]_D= –9.5 (c = 0.5, CH₂Cl₂). H NMR (500 MHz, [D₆]-

major],

DMSO): δ = 0.90 [s, 1.71 H, OCH₂C(CH₃)(OH)CH(OH)Ph

major], 0.97 [s, 1.29 H, OCH₂C(CH₃)(OH)CH(OH)Ph minor], 3.15

[d, J = 9.7 Hz, 0.43 H, OCH_AH_BC(CH₃)(OH)CH(OH)Ph minor],

3.4–3.5 [m, 3.57 H, 2-H, 3-H, 5-H, OCH_AH_BC(CH₃)(OH)CH-

(OH)Ph major], 3.52 [d, J = 9.8 Hz, 0.57 H, OCH_AH_BC(CH₃)-

(OH)CH(OH)Ph major], 3.81 [d, J = 9.8 Hz, 0.43 H, OCH_A-

H_BC(CH₃)(OH)CH(OH)Ph minor], 4.0–4.1 (m, 3 H, 4-H, 6_e-H, 6_a-

H), 4.18 (d, J = 7.4 Hz, 0.43 H, 1-H minor), 4.25 (d, J = 7.4 Hz,

0.57 H, 1-H major), 4.55 [s, 1 H, OCH₂C(CH₃)(OH)CH(OH)Ph],

4.55 [d, J = 4.7 Hz, 0.43 H, OCH₂C(CH₃)(OH)CH(OH)Ph minor],

4.62 [d, J = 4.7 Hz, 0.57 H, OCH₂C(CH₃)(OH)CH(OH)Ph major],

4.88 (d, J = 5.6 Hz, 1 H, 2-OH), 4.99 [d, J = 4.8 Hz, 0.57 H,

OCH₂C(CH₃)(OH)CH₂OH minor], 4.34, 4.35 (2 d, J = 7.7 Hz, 1

H, 1-H), 4.45 [m, 1 H, OCH₂C(CH₃)(OH)CH₂OH], 5.25 (m, 1.2

H, 2-OH, 3-OH), 5.29 (d, J = 4.5 Hz, 0.7 H, 2-OH), 5.56 (s, 1 H,

PhCH), 7.40–7.45 (m, 5 H, Ph) ppm. ¹³C NMR (125 MHz, [D₆]-

DMSO): δ = 21.5 [OCH₂C(CH₃)(OH)CH₂OH], 65.8 (C-5), 66.0

[OCH₂C(CH₃)(OH)CH₂OH], 67.9 (C-6), 71.5 [OCH₂C(CH₃)-

(OH)CH₂OH], 72.6 (C-3), 74.1 [OCH₂C(CH₃)(OH)CH₂OH], 74.5

(C-2), 80.6 (C-4), 100.6 (PhCH), 104.2 (C-1), 137.8–126.3

(Ph) ppm. MS (FAB): m/z (%) = 379 (100) [M + Na]⁺. HRMS

(FAB): calcd. for C₁₇H₂₄O₈Na [M + Na]⁺379.1369; found

379.1366.

OCH₂C(CH₃)(OH)CH(OH)Ph major], 5.03, 5.04 (2 d, J = 3.9 Hz, (2R)-2,3-Dihydroxypropyl 2-Acetamido-4,6-O-(R)-benzylidene-2-de-

1 H, 3-OH), 5.11 [d, J = 4.8 Hz, 0.43 H, OCH₂C(CH₃)(OH)- oxy-β- -glucopyranoside (32): Only one stereoisomer was obtained

D

CH(OH)Ph minor], 5.55 (s, 0.43 H, PhCH minor), 5.56 (s, 0.57 H, (Ͼ99% de). A white solid was obtained after column chromatog-

PhCH major), 7.2–7.5 (m, 10 H, 2 Ph) ppm. ¹³C NMR (125 MHz, raphy by using dichloromethane/methanol (10:1) as eluent; yield

1

[D₆]DMSO): δ = 20.6 [OCH₂C(CH₃)(OH)CH(OH)Ph major], 21.4

0.35 g (92%); m.p. 201–202 °C. [α]_D= –23.6 (c = 0.5, MeOH). H

1246

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Eur. J. Org. Chem. 2012, 1237–1252

Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

NMR (500 MHz, [D₆]DMSO): δ = 1.80 (s, 3 H, CH₃CON), 3.38 3.56–3.61 [m, 2 H, 3-H, OCH_AH_BCH(OH)CH(OH)(CH₂)₅CH₃],

(m, 1 H, 3-H), 3.49–3.52 [m, 3 H, 2-H, 4-H, OCH_AH_BCH(OH)- 3.70 (t, J = 10.1 Hz, 1 H, 6_a-H), 4.20 (dd, J = 5.0, 10.1 Hz, 1 H,

CH₂OH], 3.57–3.60 [m, 2 H, 5-H, OCH_AH_BCH(OH)CH₂OH], 3.72 6_e-H), 4.31 [d, J = 5.8 Hz, 1 H, OCH₂CH(OH)CH(OH)(CH₂)₆-

(t, J = 10.0 Hz, 1 H, 6_a-H), 4.19 (dd, J = 5.0, 10.1 Hz, 1 H, 6_e-H),

4.46 (d, J = 8.4 Hz, 1 H, 1-H), 5.58 (s, 1 H, PhCH), 7.35–7.55 (m,

CH₃], 4.46 (d, J = 8.4 Hz, 1 H, 1-H), 5.22 (d, J = 5.5 Hz, 1 H, 3-

OH), 5.58 (s, 1 H, PhCH), 7.34–7.45 (m, 5 H, Ph), 7.76 (d, J =

5 H, Ph), 7.81 (d, J = 8.8 Hz, 1 H, NH) ppm. ¹³C NMR (125 MHz, 8.9 Hz, 1 H, NH) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ =

[D₆]DMSO): δ = 23.0 (CH₃CON), 48.6 (C-2), 56.2 (C-5), 62.9 (C-

13.9 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃], 23.0 (CH₃CON), 22.0–

6), 65.9 (C-3), 70.2 [OCH₂CH(OH)CH₂OH], 70.4 [OCH₂CH- 32.6 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃], 56.2 (C-2), 65.9 (C-5),

(OH)CH₂OH], 70.8 [OCH₂CH(OH)CH₂OH], 81.2 (C-4), 100.6 67.8 (C-6), 70.2 [OCH₂CH(OH)CH(OH)(CH₂)₆CH₃], 70.5 [OCH₂-

(PhCH), 102.1 (C-1), 126.3–137.7 (Ph), 169.3 (C=O) ppm. MS

(FAB): m/z (%) = 406 (80) [M + Na]⁺. HRMS (FAB): calcd. for

C₁₈H₂₅NO₈Na [M + Na]⁺406.1478; found 406.1493. C₁₈H₂₅NO₈

(383.16): calcd. C 56.39, H 6.57, N 3.65; found C 56.74, H 6.70, N

3.54.

CH(OH)CH(OH)(CH₂)₆CH₃], 70.7 (C-3), 71.4 [OCH₂CH(OH)-

CH(OH)(CH₂)₆CH₃], 81.3 (C-4), 100.6 (PhCH), 102.1 (C-1),

126.3–137.7 (Ph), 169.2 (C=O) ppm. MS (FAB): m/z (%) = 504

(100) [M + Na]⁺. HRMS (FAB): calcd. for C₂₅H₃₉NO₈Na [M +

Na]⁺504.2573; found 504.2574. C₂₅H₃₉NO₈(481.58): calcd. C

62.35, H 8.16, N 2.91; found C 61.97, H 8.27, N 2.86.

(2S,3S)-2,3-Dihydroxybutyl 2-Acetamido-4,6-O-(R)-benzylidene-2-

deoxy-β-D-glucopyranoside (33): Only one stereoisomer was ob-

tained (Ͼ99% de). Purification by column chromatography using

(2R)-2,3-Dihydroxy-2-methylpropyl 2-Acetamido-4,6-O-(R)-benzyl-

idene-2-deoxy-β-D-glucopyranoside (36): Only one stereoisomer was

obtained (Ͼ99% de). A white solid was obtained after column

chromatography using dichloromethane/methanol (10:1) as eluent;

yield 0.32 g (81%); m.p. 218–219 °C. [α]_D= –22.2 (c = 0.5, MeOH).

¹H NMR (500 MHz, [D₆]DMSO): δ = 0.9 [s, 3 H, OCH₂C-

(OH)(CH₃)CH₂OH], 1.80 (s, 3 H, CH₃CON), 3.16 [m, 2 H, OCH₂-

C(OH)(CH₃)CH₂OH], 3.28 [d, J = 10.5 Hz, 1 H, OCH_AH_B-

C(OH)(CH₃)CH₂OH], 3.42–3.47 (m, 2 H, 3-H, 4-H), 3.48 [d, J =

10.5 Hz, 1 H, OCH_AH_BC(OH)(CH₃)CH₂OH], 3.54–3.58 (m, 2 H,

2-H, 5-H), 3.72 (t, J = 10.1 Hz, 1 H, 6_a-H), 4.12 [s, 1 H, OCH₂-

C(OH)(CH₃)CH₂OH], 4.20 (dd, J = 4.9, 10.1 Hz, 1 H, 6_e-H), 4.39

[t, J = 6.0 Hz, 1 H, OCH₂C(OH)(CH₃)CH₂OH], 4.42 (d, J =

7.9 Hz, 1 H, 1-H), 5.26 (d, J = 5.2 Hz, 1 H, 3-OH), 5.58 (s, 1 H,

PhCH), 7.2–7.5 (m, 5 H, Ph), 7.79 (d, J = 8.4 Hz, 1 H, NH) ppm.

¹³C NMR (125 MHz, [D₆]DMSO): δ = 21.4 [OCH₂C(OH)(CH₃)-

CH₂OH], 23.0 (CH₃CON), 56.1 (C-2), 65.9 [OCH₂C(OH)(CH₃)-

CH₂OH], 66.2 (C-3), 67.9 (C-6), 70.3 (C-5), 71.5 [OCH₂C-

(OH)(CH₃)CH₂OH], 73.9 [OCH₂C(OH)(CH₃)CH₂OH], 81.3 (C-4),

100.7 (PhCH), 102.6 (C-1), 126.4–137.8 (Ph), 169.3 (C=O) ppm.

MS (FAB): m/z (%) = 420 (100) [M + Na]⁺. HRMS (FAB): calcd.

dichloromethane/methanol (10:1) as eluent gave a white solid; yield

0.30 g (75%); m.p. 221–222 °C. [α]_D= –34.2 (c = 0.5, MeOH). H

1

NMR (500 MHz, [D₆]DMSO): δ = 1.00 [d, J = 6.5 Hz, 3 H, OCH₂-

CH(OH)CH(OH)CH₃], 1.80 (s, 3 H, CH₃CON), 3.25–3.35 (m, 2

H, 3-H, 5-H), 3.40 (d, J = 9.0 Hz, 1 H, 4-H), 3.46 [m, 1 H, OCH-

_AH_BCH(OH)CH(OH)CH₃], 3.50 (m, 1 H, 2-H), 3.55–3.65 [m, 3 H,

OCH_AH_BCH(OH)CH(OH)CH₃], 3.70 (t, J = 10.1 Hz, 1 H, 6_a-H),

4.12 [m, 1 H, OCH₂CH(OH)CH(OH)CH₃], 4.20 (dd, J = 5.0 Hz,

1 H, 6_e-H), 4.36 [m, 1 H, OCH₂CH(OH)CH(OH)CH₃], 4.47 (d, J

= 8.5 Hz, 1 H, 1-H), 5.23 (m, 1 H, 3-OH), 5.58 (s, 1 H, PhCH),

7.4–7.5 (m, 5 H, Ph), 7.7 (d, J = 8.9 Hz, 1 H, NH) ppm. ¹³C NMR

(125 MHz, [D₆]DMSO): δ = 18.9 [OCH₂CH(OH)CH(OH)CH₃],

23.0 (CH₃CON), 56.2 (C-2), 65.9 (C-5), 66.7 [OCH₂CH-

(OH)CH(OH)CH₃], 67.8 (C-6), 70.4 (C-3), 70.6 [OCH₂CH(OH)-

CH(OH)CH₃], 72.8 [OCH₂CH(OH)CH(OH)CH₃], 81.2 (C-4),

100.6 (PhCH), 101.9 (C-1), 126.3–137.7 (Ph), 169.3 (C=O) ppm.

MS (FAB): m/z (%) = 420 (100) [M + Na]⁺. HRMS (FAB): calcd.

for C₁₉H₂₇NO₈Na [M

+

Na]⁺420.1634; found 420.1644.

C₁₉H₂₇NO₈(397.17): calcd. C 57.42, H 6.85, N 3.52; found C

57.39, H 6.46, N 3.14.

for C₁₉H₂₇NO₈Na [M

C₁₉H₂₇NO₈(397.17): calcd. C 57.42, H 6.85, N 3.52; found C

57.42, H 7.01, N 3.41.

+

Na]⁺420.1634; found 420.1624.

(2S,3S)-2,3-Dihydroxy-3-phenylpropyl

2-Acetamido-4,6-O-(R)-

benzylidene-2-deoxy-β- -glucopyranoside (34): Only one stereoiso-

D

(2S)-2,3-Dihydroxy-3-methylbutyl 2-Acetamido-4,6-O-(R)-benzyl-

idene-2-deoxy-β-D-glucopyranoside (37): Two stereoisomers were ob-

mer was obtained (Ͼ99% de). Purification by column chromatog-

raphy using dichloromethane/methanol (15:1) as eluent gave a

white solid; yield 0.38 g (82%); m.p. 205–206 °C. [α]_D= –37.0 (c =

tained in a 3:1 ratio (50% de). The pure diastereomeric mixture was

obtained as a white solid by column chromatography using dichloro-

methane/methanol (12:1) as eluent; yield 0.26 g (63%); m.p. 202–

1

0.5, MeOH). H NMR (500 MHz, [D₆]DMSO): δ = 1.81 (s, 3 H,

CH₃CON), 3.41 (t, J = 9.0 Hz, 1 H, 4-H), 3.70 (t, J = 10.1 Hz, 1

H, 6_a-H), 4.16 (dd, J = 5.0, 10.1 Hz, 1 H, 6_e-H), 4.48 (d, J = 8.0 Hz,

1 H, 1-H), 4.54 (d, J = 3.9 Hz, 1 H, 3-OH), 5.58 (s, 1 H, PhCH),

7.20–7.45 (m, 10 H, Ph), 7.78 (d, J = 8.7 Hz, 1 H, NH) ppm. ¹³C

NMR (125 MHz, [D₆]DMSO): δ = 23.0 (CH₃CON), 56.2 (C-2),

65.8 (C-5), 67.8 (C-6), 73.4 (C-3), 81.2 (C-4), 100.6 (PhCH), 102.1

(C-1), 126.3–143.3 (Ph), 169.2 (C=O) ppm. MS (CI): m/z (%) = 460

(20) [M + H]⁺. HRMS (CI): calcd. for C₂₄H₃₀NO₈[M + H]⁺

460.1971; found 460.1969. C₂₄H₂₉NO₈(459.19): calcd. C 62.73, H

6.36, N 3.05; found C 62.55, H 6.51, N 3.47.

1

203 °C. [α]_D= –15.0 (c = 0.5, MeOH). H NMR (500 MHz, [D₆]-

DMSO): δ = 1.04, 0.98 [2 s, 6 H, OCH₂CH(OH)C(CH₃)₂OH], 1.80

(s, 0.75 H, CH₃CON minor), 1.81 (s, 2.25 H, CH₃CON major), 3.42

(t, J = 9.2 Hz, 1 H, 4-H), 3.48 (m, 1 H, 2-H), 3.60 (m, 1 H, 3-H),

3.71 (t, J = 10.1 Hz, 1 H, 6_a-H), 3.84 [d, J = 7.4 Hz, 1 H, OCH_A-

H_BCH(OH)C(CH₃)₂OH], 4.09 [m, 1 H, OCH₂CH(OH)C(CH₃)₂OH],

4.20 (m, 1 H, 6_e-H), 4.32 [m, 1 H, OCH₂CH(OH)C(CH₃)₂OH], 4.48

(d, J = 8.3 Hz, 0.25 H, 1-H minor), 4.51 (d, J = 8.3 Hz, 0.75 H, 1-

H major), 5.23 (m, 1 H, 3-OH), 5.58 (s, 1 H, PhCH), 7.2–7.5 (m, 5

H, Ph), 7.77 (d, J = 8.7 Hz, 0.75 H, NH major), 7.80 (d, J = 8.9 Hz,

(2S,3S)-2,3-Dihydroxydecyl 2-Acetamido-4,6-O-(R)-benzylidene-2- 0.25 H, NH minor) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ =

deoxy-β-

D

-glucopyranoside (35): Only one stereoisomer was ob-

23.1 (CH₃CON), 24.7, 26.7 [OCH₂CH(OH)C(CH₃)₂OH], 56.3 (C-2),

65.9 (C-5), 67.9 (C-6), 70.6, 70.8, 70.5 [OCH₂CH(OH)C(CH₃)₂OH,

C-3], 76.1 [OCH₂CH(OH)C(CH₃)₂OH], 81.3 (C-4), 100.7 (PhCH),

tained (Ͼ99% de). Purification by column chromatography using

dichloromethane/methanol (15:1) as eluent gave a white solid; yield

0.31 g (65%); m.p. 232–233 °C. [α]_D= –39.0 (c = 0.5, MeOH). H 101.7 (C-1 minor), 102.1 (C-1 major), 126.3–137.7 (Ph), 169.5

NMR (500 MHz, [D₆]DMSO): δ = 0.85 [t, J = 7.0 Hz, 3 H, OCH₂- (C=O) ppm. MS (FAB): m/z (%) = 434 (60) [M + Na]⁺. HRMS

CH(OH)CH(OH)(CH₂)₆CH₃], 1.23–1.38 [m, 10 H, OCH₂CH(OH)- (FAB): calcd. for C₂₀H₂₉NO₈Na [M + Na]⁺434.1791; found

1

CH(OH)CH₂(CH₂)₅CH₃], 1.80 (s, 3 H, CH₃CON), 3.29–3.539 [m,

434.1781. C₂₀H₂₉NO₈(411.19): calcd. C 58.38, H 7.10, N 3.40; found

8 H, 2-H, 4-H, 5-H, OCH_AH_BCH(OH)CH(OH)CH₂(CH₂)₅CH₃], C 58.74, H 6.74, N 3.43.

Eur. J. Org. Chem. 2012, 1237–1252

www.eurjoc.org

1247

J. M. Vega-Pérez, F. Iglesias-Guerra et al.

FULL PAPER

2,3-Dihydroxypropyl 2,3-Di-O-benzyl-4,6-O-(S)-benzylidene-β-

D

-ga-

(s, 1 H, PhCH), 7.25–7.45 (m, 10 H, 2 Ph) ppm. ¹³C NMR

(125 MHz, [D₆]DMSO): δ = 62.9 [OCH₂CH(OH)CH₂OH], 65.8

(C-5), 68.7 (C-6), 69.2 (C-2 major), 69.3 (C-2 minor), 70.3

(PhCH₂O), 70.5 [OCH₂CH(OH)CH₂OH], 71.1 [OCH₂CH(OH)-

CH₂OH], 72.5 (C-4), 79.1 (C-3), 99.7 (PhCH), 103.4 (C-1 major),

103.5 (C-1 minor), 126.1–138.8 (2 Ph) ppm. MS (FAB): m/z (%) =

lactopyranoside (45): Two stereoisomers were obtained in a 1:1 ra-

tio. Purification by column chromatography using hexane/ethyl

acetate (1:2) as eluent gave a white solid; yield 0.43 g (82%); m.p.

1

134–135 °C. [α]_D= +17.0 (c = 0.5, CH₂Cl₂). H NMR (500 MHz,

CDCl₃): δ = 1.26 [m, 1 H, OCH₂CH(OH)CH₂OH], 1.55 [s, 1 H,

OCH₂CH(OH)CH₂OH], 3.36 (s, 1 H, 5-H), 3.58 (dd, J = 9.5, 455 (100) [M + Na]⁺. HRMS (FAB): calcd. for C₂₃H₂₈O₈Na [M +

3.4 Hz, 1 H, 3-H), 3.6–3.7 [m, 3 H, OCH_AH_BCH(OH)CH_AH_BOH, Na]⁺455.1682; found 455.1680. C₂₃H₂₈O₈(432.18): calcd. C 63.88,

2-H], 3.80–3.90 [m,

3

H, OCH_AH_BCH(OH)CH₂OH, OCH₂-

H 6.53; found C 63.59, H 6.89.

CH(OH)CH_AH_BOH], 4.02 (d, J = 12.4, J = 1.7 Hz, 1 H, 6_a-H),

4.13 (d, J = 3.4 Hz, 1 H, 4-H), 4.27 (d, J = 12.3 Hz, 1 H, 6_e-H),

4.30 (d, J = 7.8 Hz, 0.5 H, 1-H), 4.40 (d, J = 7.8 Hz, 0.5 H, 1-H),

4.75 (s, 2 H, PhCH₂O-3), 4.80 (m, 2 H, PhCH₂O-2), 5.49 (s, 1 H,

PhCH), 7.3–7.6 (m, 15 H, 3 Ph) ppm. ¹³C NMR (125 MHz,

[D₆]DMSO): δ = 21.2 [OCH₂C(OH)(CH₃)CH₂OH], 62.4 [OCH₂-

C(OH)(CH₃)CH₂OH], 66.6 (C-5), 67.4 (C-6), 69.1 (PhCH₂O), 71.8

[OCH₂C(OH)(CH₃)CH₂OH], 72.5 (C-4), 73.6 [OCH₂C(OH)(CH₃)-

CH₂OH], 74.4 (PhCH₂O), 75.2 (C-2), 78.8 (C-3), 101.4 (PhCH),

104.1 (C-1), 126.4–138.4 (3 Ph) ppm. MS (FAB): m/z (%) = 545

(80) [M + Na]⁺. HRMS (FAB): calcd. for C₃₀H₃₄O₈Na [M +

Na]⁺545.2151; found 545.2132.

(2R)-2,3-Dihydroxypropyl

benzylidene-2-deoxy-β-D-glucopyranoside (48): Only one stereoiso-

2-Acetamido-3-O-benzyl-4,6-O-(R)-

mer was obtained (Ͼ99% de). Purification by column chromatog-

raphy using dichloromethane/methanol (15:1) as eluent gave a

white solid; yield 0.37 g (78%); m.p. 274–275 °C. [α]_D= –13.0 (c =

1

0.5, MeOH). H NMR (500 MHz, [D₆]DMSO): δ = 1.81 (s, 3 H,

CH₃CON), 3.52 (m, 1 H, 3-H), 3.61 [m, 1 H, OCH_AH_BCH(OH)-

CH₂OH], 3.67–3.69 (m, 2 H, 2-H, 4-H), 3.76 (t, J = 10.1 Hz, 1 H,

6_a-H), 7.95 (d, J = 7.8 Hz, 1 H, NH), 4.23 (dd, J_5,6e= 5.0, J_6e,6a

=

10.1 Hz, 1 H, 6_e-H), 4.44 [t, J = 5.2 Hz, 1 H, OCH₂CH(OH)-

CH₂OH], 4.53 (d, J = 7.5 Hz, 1 H, 1-H), 4.56–4.58 [m, 2 H,

PhCH_AH_BO, OCH₂CH(OH)CH₂OH], 4.70 (d, J = 12.1 Hz, 1 H,

PhCH_AH_BO), 5.69 (s, 1 H, PhCH), 7.2–7.5 (m, 10 H, 2 Ph) ppm.

¹³C NMR (125 MHz, [D₆]DMSO): δ = 23.0 (CH₃CON), 54.6 (C-

2), 62.8 [OCH₂CH(OH)CH₂OH], 65.6 (C-5), 67.8 [OCH₂CH(OH)-

CH₂OH], 70.2 (C-6), 70.9 [OCH₂CH(OH)CH₂(OH)], 73.1

(PhCH₂O), 78.7 (C-3), 80.9 (C-4), 100.1 (PhCH), 101.9 (C-1),

126.0–144.4 (2 Ph), 169.1 (C=O) ppm. MS (FAB): m/z (%) = 496

(100) [M + Na]⁺. HRMS (FAB): calcd. for C₂₅H₃₁NO₈Na [M +

Na]⁺496.1947; found 496.1944. C₂₅H₃₁NO₈(473.20): calcd. C

63.41, H 6.60, N 2.96; found C 63.35, H 6.71, N 2.76.

(2R)-2,3-Dihydroxy-2-methylpropyl

2,3-Di-O-benzyl-4,6-O-(S)-

benzylidene-β- -galactopyranoside (46): Two diastereoisomers were

D

obtained in a 1.5:1 ratio (20% de). The pure diastereomeric mixture

was obtained as a white solid by column chromatography using

hexane/ethyl acetate (1:2) as eluent; yield 0.37 g (70%); m.p. 136–

137 °C. [α]_D= +22.0 (c = 0.5, CH₂Cl₂). ¹H NMR (500 MHz,

CDCl₃): δ = 1.13 [s, 1.8 H, OCH₂C(OH)(CH₃)CH₂OH major], 1.15

[s, 1.2 H, OCH₂C(OH)(CH₃)CH₂OH minor], 2.40 [m, 1 H, OCH₂-

C(OH)(CH₃)CH₂OH], 3.02, 3.03 [2 s, 1 H, OCH₂C(OH)(CH₃)-

CH₂OH], 3.36 (s, 1 H, 5-H), 3.43 (m, 1 H, 3-H), 3.5–3.6 [m, 2.6

H, OCH_AH_B(OH)C(CH₃)CH₂OH, OCH₂(OH)C(CH₃)CH_AH_BOH

major, 2-H], 3.66 [d, J = 10.4 Hz, 0.4 H, OCH₂(OH)C(CH₃)CH_A-

H_BOH minor], 3.77 [d, J = 10.4 Hz, 0.4 H, OCH₂C(OH)(CH₃)-

CH_AH_BOH minor], 3.85–3.90 [m, 1.6 H, OCH_AH_BC(OH)-

(CH₃)CH₂OH, OCH₂C(OH)(CH₃)CH_AH_BOH major], 4.02 (d, J =

10.7 Hz, 1 H, 6_a-H), 4.13 (d, J = 3.5 Hz, 1 H, 4-H), 4.27 (d, J =

12.3 Hz, 1 H, 6_e-H), 4.44 (d, J = 7.8 Hz, 0.4 H, 1-H minor), 4.46

(d, J = 7.8 Hz, 0.6 H, 1-H major), 4.75 (s, 2 H, PhCH₂O-3), 4.85

(m, 2 H, PhCH₂O-2), 5.49 (s, 1 H, PhCH), 7.2–7.6 (m, 15 H, 3

Ph) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 63.6 [OCH₂-

CH(OH)CH₂OH], 66.6 (C-5), 69.2 (C-6), 70.7 (PhCH₂O), 71.9

[OCH₂CH(OH)CH₂OH], 72.4 (C-4), 73.7 [OCH₂CH(OH)-

CH₂OH], 75.5 (PhCH₂O), 78.3 (C-2), 79.7 (C-3), 101.3 (PhCH),

104.4 (C-1), 126.4–129.0 (3 Ph) ppm. MS (FAB): m/z (%) = 559

(80) [M + Na]⁺. HRMS (FAB): calcd. for C₃₁H₃₆O₈Na [M + Na]

(2R)-2,3-Dihydroxy-2-methylpropyl 2-Acetamido-3-O-benzyl-4,6-O-

(R)-benzylidene-2-deoxy-β-D-glucopyranoside (49): Only one stereo-

isomer was obtained (Ͼ99% de). A white solid was obtained after

purification by column chromatography using dichloromethane/

methanol (15:1) as eluent; yield 0.36 g (75%); m.p. 263–265 °C.

1

[α]_D= –43.5 (c = 0.5, MeOH). H NMR (500 MHz, CDCl₃): δ =

1.10 [s, 3 H, OCH₂C(CH₃)(OH)CH₂OH], 1.89 (s, 3 H, CH₃CON),

2.53 [m,

1 H, OCH₂C(CH₃)(OH)CH₂OH], 2.98 [s, 1 H,

OCH₂C(CH₃)(OH)CH₂(OH)], 3.39 [dd, J = 6.9, 11.3 Hz, 1 H,

OCH₂C(CH₃)(OH)CH_AH_BOH], 3.45–3.50 [m,

OCH_AH_BC(CH₃)(OH)CH₂OH], 3.55–3.62 [m,

2

H, 5-H,

H, 2-H,

OCH₂C(CH₃)(OH)CH_AH_BOH], 3.72 (t, J = 9.3 Hz, 1 H, 4-H), 3.79

(t, J = 10.3 Hz, 1 H, 6_a-H), 3.84 [d, J = 10.0 Hz, 1 H,

OCH_AH_BC(CH₃)(OH)CH₂OH], 3.89 (t, J = 9.5 Hz, 1 H, 3-H), 4.35

(dd, J = 5.0, 10.4 Hz, 1 H, 6_e-H), 4.65 (d, J = 12.0 Hz, 1 H,

PhCH_AH_BO), 4.75 (d, J = 8.3 Hz, 1 H, 1-H), 4.90 (d, J = 12.0 Hz,

1 H, PhCH_AH_BO), 5.37 (d, J = 7.8 Hz, 1 H, NH), 5.58 (s, 1 H,

PhCH), 7.25–7.55 (m, 10 H, Ph) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 21.2 [OCH₂C(CH₃)(OH)CH₂OH], 23.5 (CH₃CON),

56.5 (C-2), 66.2 [OCH₂C(CH₃)(OH)CH₂OH], 67.8 (C-5), 68.6 (C-

6), 71.6 [OCH₂C(CH₃)(OH)CH₂OH], 74.1 (PhCH₂O), 75.8

[OCH₂C(CH₃)(OH)CH₂OH], 76.5 (C-3), 82.5 (C-4), 101.3 (PhCH),

102.2 (C-1), 126.0–138.2 (Ph), 171.0 (C=O) ppm. MS (FAB): m/z

+

559.2308; found 559.2345. C₃₁H₃₆O₈(536.24): calcd. C 69.39, H

6.76; found C 69.34, H 6.76.

(2R)-2,3-Dihydroxypropyl 3-O-Benzyl-4,6-O-(S)-benzylidene-β-D-

galactopyranoside (47): Two stereoisomers were obtained in a 5.2:1

ratio (68% de). The pure diastereomeric mixture was obtained as

a white solid by column chromatography using dichloromethane/

methanol (10:1) as eluent; yield 0.28 g (66%); m.p. 138–139 °C.

[α]_D= +13.0 (c = 0.4, CH₂Cl₂). ¹H NMR (500 MHz, [D₆]DMSO):

δ = 3.35 [m, 2 H, OCH₂CH(OH)CH₂OH], 3.45–3.50 [m, 4 H, 2-H,

3-H, 5-H, OCH_AH_BCH(OH)CH₂OH], 3.62 [m, 1 H, OCH₂CH-

(OH)CH₂OH], 3.68 [dd, J = 5.9, 10.0 Hz, 1 H, OCH_AH_BCH-

(OH)CH₂OH], 4.0–4.1 (m, 2 H, 6_e-H, 6_a-H), 4.25 (d, J = 7.8 Hz,

0.84 H, 1-H major), 4.35 (d, J = 3.1 Hz, 1 H, 4-H), 4.51 [t, J =

(%)

= 510 (100) [M +

Na]⁺. HRMS (FAB): calcd. for

C₂₆H₃₃NO₈Na [M + Na]⁺510.2104; found 510.2120. C₂₆H₃₃NO₈

(487.22): calcd. C 64.05, H 6.82, N 2.87; found C 63.89, H 6.72, N

2.80.

(2R)-2,3-Dihydroxypropyl

2-Acetamido-3-O-Acetyl-4,6-O-(R)-

5.8 Hz, 1 H, OCH₂CH(OH)CH₂OH], 4.60 (d, J = 12.2 Hz, 1 H, benzylidene-2-deoxy-β-

D-glucopyranoside (50): Only one stereoiso-

OCH_AH_BPh), 4.64 [d, J = 5.3 Hz, 1 H, OCH₂CH(OH)CH₂OH], mer was obtained (Ͼ99% de). Purification by column chromatog-

4.68 (d, J = 12.2 Hz, 1 H, OCH_AH_BPh), 4.98 (d, J = 4.2 Hz, 0.16 raphy using dichloromethane/methanol (15:1) as eluent gave a

H, 2-OH minor), 5.19 (d, J = 4.2 Hz, 0.84 H, 2-OH major), 5.58 white solid; yield 0.34 g (81%); m.p. 237–238 °C. [α]_D= –5.2 (c =

1248

www.eurjoc.org

Eur. J. Org. Chem. 2012, 1237–1252

Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

1

0.5, MeOH). H NMR (500 MHz, [D₆]DMSO): δ = 1.78 (s, 3 H, 4.34 (dd, J = 5.0, 10.4 Hz, 1 H, 6_e-H), 4.65 (d, J = 12.0 Hz, 1 H,

CH₃CON), 1.94 (s,

OCH₂CH(OH)CH₂OH], 3.42 [dd,

3

H, CH₃COO), 3.25–3.30 [m,

5.8, 9.8 Hz,

2

1

H, PhCH_AH_BO), 4.73 (d, J = 8.4 Hz, 1 H, 1-H), 4.89 (d, J = 12.0 Hz,

H, 1 H, PhCH_AH_BO), 5.40 (d, J = 7.7 Hz, 1 H, NH), 5.59 (s, 1 H,

J

=

OCH_AH_BCH(OH)CH₂OH], 3.50–3.55 [m, 2 H, 5-H, OCH₂CH- PhCH), 7.30–7.80 (m, 14 H, Ar) ppm. ¹³C NMR (125 MHz,

(OH)CH₂OH], 3.60 [dd, J = 5.8, 9.8 Hz, 1 H, OCH_AH_BCH(OH)-

CDCl₃): δ = 21.1 [OCH₂C(CH₃)(OH)CH₂OTs], 21.6 (C₆H₄CH₃),

CH₂OH], 3.70–3.80 (m, 3 H, 2-H, 4-H, 6_a-H), 4.23 (dd, J = 5.0, 23.5 (CH₃CON), 56.4 (C-2), 66.1 (C-5), 68.7 (C-6), 70.8

10.2 Hz, 1 H, 6_e-H), 4.64 (d, J = 8.5 Hz, 1 H, 1-H), 5.10 (t, J = [OCH₂C(CH₃)(OH)CH₂OTs], 72.9 [OCH₂C(CH₃)(OH)CH₂OTs],

10.0 Hz, 1 H, 3-H), 5.62 (s, 1 H, PhCH), 7.30–7.35 (m, 5 H, Ph),

73.3 [OCH₂C(CH₃)(OH)CH₂OTs], 74.2 (PhCH₂O), 76.5 (C-3), 82.4

7.91 (d, J = 9.2 Hz, 1 H, NH) ppm. ¹³C NMR (125 MHz, [D₆]- (C-4), 101.3 (PhCH), 101.8 (C-1), 126.0–145.1 (3 Ar), 170.6

DMSO): δ = 20.5 (CH₃CONH), 22.7 (CH₃COO), 53.7 (C-2), 62.8

(C=O) ppm. MS (FAB): m/z (%) = 664 (30) [M + Na]⁺. HRMS

[OCH₂CH(OH)CH₂OH], 65.7 (C-5), 67.6 (C-6), 70.1 [OCH₂CH- (FAB): C₃₂H₃₅NO₁₁SNa [M + Na]⁺664.1829; found 664.1840.

(OH)CH₂OH], 71.1 [OCH₂CH(OH)CH₂OH], 71.9 (C-3), 78.0 (C- C₃₂H₃₅NO₁₁S (641.19): calcd. C 59.90, H 5.50, N 2.18, S 5.00;

4), 100.2 (PhCH), 101.4 (C-1), 126.1–137.3 (Ph), 169.2 (CH₃CON),

found C 60.24, H 5.82, N 2.01.

169.7 (CH₃COO) ppm. MS (FAB): m/z (%)

= 448 (100)

Synthesis of (2R)-3-Azido-2-hydroxy-2-methylpropyl 2-Acetamido-

3-O-benzyl-4,6-O-(R)-benzylidene-2-deoxy-β-D-glucopyranoside (53)

[M + Na]⁺. HRMS (FAB): calcd. for C₂₀H₂₇NO₉Na [M + Na]⁺

448.1584; found 448.1573. C₂₀H₂₇NO₉(425.17): calcd. C 56.46, H

6.40, N 3.29; found C 56.47, H 6.36, N 3.09.

From 52: Sodium azide (2.0 mmol) was added to a solution of the

tosyl derivative 52 (1.0 mmol) in dry DMF (20 mL) and the reac-

tion was heated at 70 °C (18 h). The reaction mixture was diluted

with dichloromethane, successively washed with water and brine,

and the organic phase was evaporated to dryness. Only one stereo-

isomer was obtained (100% de). Purification by flash chromatog-

raphy on silica gel using hexane/ethyl acetate (1:2) as eluent gave a

white solid; yield 0.42 g (82%); m.p. 192–193 °C. [α]_D= +2.0 (c

= 0.5, MeOH). ¹H NMR (500 MHz, CDCl₃): δ = 1.17 [s, 3 H,

OCH₂C(CH₃)(OH)CH₂N₃], 1.88 (s, 3 H, CH₃CON), 3.27 [s, 2 H,

(2R)-2,3-Dihydroxypropyl

2-Acetamido-3-O-capriloyl-4,6-O-(R)-

benzylidene-2-deoxy-β- -glucopyranoside (51): Two stereoisomers

D

were obtained in a 2.5:1 ratio (43% de). Purification by column

chromatography using dichloromethane/methanol (10:1) as eluent

gave a pale-yellow syrup; yield 0.53 g (82%). [α]_D= –30.0 (c = 1.0,

MeOH). ¹H NMR (500 MHz, [D₆]DMSO): δ = 0.81 [t, J = 7.0 Hz,

3 H, CH₃(CH₂)₅CH₂CO₂], 1.1–1.5 [m, 10 H, CH₃(CH₂)₅CH₂CO₂],

1.74 (s, 0.9 H, CH₃CON minor), 2.20 [m, 2 H, CH₃(CH₂)₅-

CH₂CO₂], 1.75 (s, 2.1 H, CH₃CON major), 3.3–3.6 [m, 4 H, 5-

H, OCH₂CH(OH)CH₂OH], 3.70–3.85 [m, 5 H, 2-H, 4-H, 6_a-H,

OCH₂CH(OH)CH₂OH], 4.26 (m, 1 H, 6_e-H), 4.62 (d, J = 8.5 Hz,

0.3 H, 1-H minor), 4.76 (d, J = 8.5 Hz, 0.7 H, 1-H major), 5.04 (t,

J = 9.9 Hz, 0.7 H, 3-H major), 5.12 (t, J = 9.9 Hz, 0.3 H, 3-H

minor), 5.62 (s, 1 H, PhCH), 7.34 (m, 5 H, Ph), 7.78 (d, J = 9.4 Hz,

0.7 H, NH major), 7.92 (d, J = 9.4 Hz, 0.3 H, NH minor) ppm.

¹³C NMR (125 MHz, [D₆]DMSO): δ = 13.9 [CH₃(CH₂)₆CO₂], 22.6

(CH₃CON), 22.0–33.5 [CH₃(CH₂)₆CO₂], 53.4 (C-2 major), 53.6 (C-

2 minor), 65.9 (C-5), 67.7 (C-6), 68.9 [OCH₂CH(OH)CH₂OH], 70.1

[OCH₂CH(OH)CH₂OH], 71.0 [OCH₂CH(OH)CH₂OH], 71.7 (C-

3), 78.2 (C-4), 100.2 (PhCH), 101.6 (C-1 minor), 102.0 (C-1 major),

126.0–137.4 (Ph), 169.1 (CH₃CON), 172.3 [CH₃(CH₂)₅CH₂-

CO₂] ppm. MS (FAB): m/z (%) = 532 (60) [M + Na]⁺. HRMS

(FAB): calcd. for C₂₆H₃₉NO₉Na [M + Na]⁺532.2523; found

532.2507.

OCH₂C(CH₃)(OH)CH₂N₃], 3.39 [d,

J

=

9.9 Hz,

1

H,

OCH_AH_BC(CH₃)(OH)CH₂N₃], 3.48 (m, 1 H, 5-H), 3.57 (m, 1 H,

2-H), 3.72 (t, J = 9.2 Hz, 1 H, 4-H), 3.77–3.82 [m, 2 H, 6_a-H,

OCH_AH_BC(CH₃)(OH)CH₂N₃], 3.92 (t, J = 9.5 Hz, 1 H, 3-H), 4.35

(dd, J = 5.0, 10.5 Hz, 1 H, 6_e-H), 4.66 (d, J = 12.0 Hz, 1 H,

PhCH_AH_BO), 4.77 (d, J = 8.3 Hz, 1 H, 1-H), 4.90 (d, J = 12.0 Hz,

1 H, PhCH_AH_BO), 5.32 (d, J = 7.8 Hz, 1 H, NH), 5.58 (s, 1 H,

PhCH), 7.3–7.5 (m, 10 H, 2 Ph) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 22.0 [OCH₂C(CH₃)(OH)CH₂N₃], 23.6 (CH₃CON),

56.7 (C-2), 57.6 [OCH₂C(CH₃)(OH)CH₂N₃], 66.1 (C-5), 68.7 (C-

6), 72.2 [OCH₂C(CH₃)(OH)CH₂N₃], 74.2 (PhCH₂O), 74.5

[OCH₂C(CH₃)(OH)CH₂N₃], 76.5 (C-3), 82.5 (C-4), 101.3 (PhCH),

101.9 (C-1), 126.0–138.2 (2 Ph), 170.7 (C=O) ppm. MS (FAB): m/z

(%)

= 535 (50) [M +

Na]⁺. HRMS (FAB): calcd. for

C₂₆H₃₂N₄O₇Na [M + Na]⁺535.2169; found 535.2153. C₂₆H₃₂N₄O₇

(512.23): calcd. C 60.93, H 6.29, N 10.93; found C 60.66, H 6.51,

N 10.97.

Stereochemical Assignment

Synthesis of (2S)-2-Hydroxy-2-methyl-3-tosyloxypropyl 2-Acet-

amido-3-O-benzyl-4,6-O-(R)-benzylidene-2-deoxy-β-D-glucopyrano-

From 54: Lithium perchlorate (2.0 mmol) and sodium azide

(4.0 mmol) were added to a solution of the oxirane derivative 54

side (52): DAMP (2.0 mmol) and tosyl chloride (1.1 mmol) were (1.0 mmol) in dry CH₃CN (70 mL) and the reaction was heated at

added to a solution of the glycol derivative 49 (1.0 mmol) in dry

dichloromethane (50 mL) cooled to 0 °C. The mixture was stirred

at 0 °C until TLC showed that all the starting material had reacted

(ca. 5 h). The organic phase was washed with diluted hydrochloric

acid, water and saturated sodium hydrogen carbonate, and the or-

ganic layer was evaporated to dryness. Only one stereoisomer was

obtained (100% de). A white solid was obtained after purification

80 °C (10 h). The reaction mixture was poured into water and the

compound was extracted with ethyl acetate (50 mL). The reaction

mixture was diluted with CH₂Cl₂(50 mL). The organic phase was

washed with water (2ϫ40 mL), dried and the solvents evaporated

to dryness. A white solid was obtained after purification by column

chromatography using hexane/ethyl acetate (1:2) as eluent. Two

stereoisomers were obtained in a 6:1 ratio (71% de); yield 0.42 g

by column chromatography using hexane/ethyl acetate (1:2) as elu- (82%). ¹H NMR (500 MHz, CDCl₃): δ = 1.16 [s, 0.42 H,

ent; yield 0.53 g (82%); m.p. 234–235 °C. [α]_D= –8.0 (c = 0.3, OCH₂C(CH₃)(OH)CH₂N₃minor], 1.17 [s, 2.58 H,

CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.12 [s, 3 H, OCH₂C(CH₃)(OH)CH₂N₃major], 1.88 (s, 2.58 H, CH₃CON

OCH₂C(CH₃)(OH)CH₂OTs], 1.88 (s, 3 H, CH₃CON), 2.45 (s, 3 H, major), 1.89 (s, 0.42 H, CH₃CON minor), 3.27 [s, H,

2

C₆H₄CH₃), 3.41 [d, J = 10.0 Hz, 1 H, OCH_AH_BC(CH₃)(OH)- OCH₂C(CH₃)(OH)CH₂N₃], 3.39 [d, J = 9.9 Hz, 1 H, OCH_AH_BC-

CH₂OTs], 3.46 (m, 1 H, 5-H), 3.56 (m, 1 H, 2-H), 3.70 (t, J = (CH₃)(OH)CH₂N₃], 3.48 (m, 1 H, 5-H), 3.57 (m, 1 H, 2-H), 3.70

9.4 Hz, 1 H, 4-H), 3.75 [d, J = 10.0 Hz, 1 H, OCH_AH_BC(CH₃)-

(OH)CH₂OTs], 3.79 (t, J = 10.3 Hz, 1 H, 6_a-H), 3.84 [d, J = 9.5 Hz,

(t, J = 9.1 Hz, 0.14 H, 4-H minor), 3.72 (t, J = 9.3 Hz, 0.86 H, 4-

H major), 3.78–3.82 [m, 2 H, 6_a-H, OCH_AH_BC(CH₃)(OH)CH₂N₃],

1 H, OCH₂C(CH₃)(OH)CH_ACH_BOTs], 3.90 (t, J = 9.6 Hz, 1 H, 3- 3.92 (t, J = 9.5 Hz, 0.86 H, 3-H major), 4.02 (t, J = 9.5 Hz, 0.14

H), 3.95 [d, J = 9.5 Hz, 1 H, OCH₂C(CH₃)(OH)CH_ACH_BOTs], H, 3-H minor), 4.35 (dd, J = 5.0, 10.5 Hz, 0.86 H, 6_e-H major),

Eur. J. Org. Chem. 2012, 1237–1252

www.eurjoc.org

1249

J. M. Vega-Pérez, F. Iglesias-Guerra et al.

4.40 (dd, J = 4.9, 10.5 Hz, 0.14 H, 6_e-H minor), 4.66 (d, J = OCH_AH_BC(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 3.69 (t, J = 9.2 Hz,

FULL PAPER

12.0 Hz, 1 H, PhCH_AH_BO), 4.77 (d, J = 8.3 Hz, 0.86 H, 1-H

major), 4.83 (d, J = 8.3 Hz, 0.14 H, 1-H minor), 4.90 (d, J =

12.0 Hz, 1 H, PhCH_AH_BO), 5.32 (d, J = 7.8 Hz, 0.86 H, NH

major), 5.38 (d, J = 7.9 Hz, 0.14 H, NH minor), 5.58 (s, 1 H,

PhCH), 7.3–7.5 (m, 10 H, 2 Ph) ppm. MS (FAB): m/z (%) = 535

(40) [M + Na]⁺. HRMS (FAB): calcd. for C₂₆H₃₂N₄O₇Na [M +

Na]⁺535.2169; found 535.2191.

1 H, 4-H), 3.76–3.80 [m, 2 H, 6_a-H, OCH_AH_BC(CH₃)(OH)CH₂O-

CO(CH₂)₁₄(CH₃)], 3.94 [d, J = 11.2 Hz, 1 H, OCH₂C(CH₃)(OH)-

CH_AH_BOCO(CH₂)₁₄CH₃], 4.03 (t, J = 9.5 Hz, 1 H, 3-H), 4.08 [d, J

= 11.2 Hz, 1 H, OCH₂C(CH₃)(OH)CH_AH_BOCO(CH₂)₁₄CH₃], 4.34

(dd, J = 5.0, 10.2 Hz, 1 H, 6_e-H), 4.64 (d, J = 11.9 Hz, 1 H,

PhCH_AH_BO), 4.86 (d, J = 8.4 Hz, 1 H, 1-H), 4.90 (d, J = 11.9 Hz,

1 H, PhCH_AH_BO), 5.52 (d, J = 7.8 Hz, 1 H, NH), 5.57 (s, 1 H,

PhCH), 7.3–7.5 (m, 10 H, 2 Ph) ppm. ¹³C NMR (125 MHz,

DMSO): δ = 14.1 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 21.4

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 23.5 (CH₃CON), 24.7–

34.2 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 57.2 (C-2), 66.1

(C-5), 67.8 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 68.7 (C-6),

Synthesis of Glycoglycerolipid Analogues

Selective Acylation Reaction: DAMP (1 mmol) and acid chloride

(0.5 mmol) were added to a solution of 49 and 61 (0.5 mmol) in

dry dichloromethane (30 mL) precooled to 0 °C. The reaction mix-

ture was stirred at 0 °C until TLC showed that all the starting mate-

rial had reacted (3 h). The organic phase was successively washed

with diluted hydrochloric acid, water and an aqueous saturated

solution of sodium hydrogen carbonate, dried (MgSO₄), filtered

and the filtrate was evaporated to dryness. The compounds ob-

tained were purified by flash chromatography on silica gel.

71.2

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃],

173.7

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 74.3 (PhCH₂O), 74.4

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 76.6 (C-3), 82.6 (C-4),

101.3 (PhCH), 101.7 (C-1), 126.0–129.0 (2 Ph), 170.7

(CH₃CON) ppm. MS (FAB): m/z (%) = 748 (30) [M + Na]⁺.

HRMS (FAB): calcd. for C₄₂H₆₃NO₉Na [M + Na]⁺748.4401;

found 748.4405. C₄₂H₆₃NO₉(725.45): calcd. C 69.49, H 8.75, N

1.93; found C 69.69, H 8.97, N 1.80.

(2S)-3-Capriloyloxy-2-hydroxy-2-methylpropyl 2-Acetamido-3-O-

benzyl 4,6-O-(R)-benzylidene-2-deoxy-β-D-glucopyranoside (55): A

white solid was obtained by column chromatography using hexane/

ethyl acetate (1:3) as eluent; yield 0.31 g (50%); m.p. 150–151 °C.

[α]_D= –2.0 (c = 0.5, CH₂Cl₂). H NMR (500 MHz, [D₆]DMSO):

(2R)-2-Hydroxy-2-methyl-3-palmitamidopropyl 2-Acetamido-3-O-

benzyl-4,6-O-(R)-benzylidene-2-deoxy-β-D-glucopyranoside (62): A

1

white solid was obtained after purification by column chromatog-

raphy using dichloromethane/methanol (80:1) as eluent; yield

δ = 0.87 [t, J = 7.1 Hz, 3 H, OCH₂C(CH₃)(OH)CH₂OCO-

(CH₂)₆CH₃], 1.16 [s, 3 H, OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆-

CH₃], 1.25–1.70 [m, 10 H, OCH₂C(CH₃)(OH)CH₂OCOCH₂-

(CH₂)₅CH₃], 1.88 (s, 3 H, CH₃CON), 2.34 [t, J = 7.5 Hz, 2 H,

OCH₂C(CH₃)(OH)CH₂OCOCH₂(CH₂)₅CH₃], 3.40 [d, J = 9.8 Hz,

1 H, OCH_AH_BC(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 3.47–3.51 (m, 2

H, 2-H, 5-H), 3.69 (t, J = 9.3 Hz, 1 H, 4-H), 3.76–3.81 [m, 2 H,

6_a-H, OCH_AH_BC(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 3.93 [d, J =

11.2 Hz, 1 H, OCH₂C(CH₃)(OH)CH_AH_BOCO(CH₂)₆CH₃], 4.01 (t,

1

0.51 g (71%); m.p. 195–196 °C. [α]_D= –12.0 (c = 0.5, MeOH). H

NMR (500 MHz, DMSO): δ = 0.85 [t, J = 6.8 Hz, 3 H,

OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄CH₃], 0.98 [s,

OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄CH₃], 1.15–1.30 [m, 26 H,

OCH₂C(CH₃)(OH)CH₂NHCOCH₂(CH₂)₁₃CH₃], 1.83 (s, H,

NCH₃CO), 2.12 [t, 7.7 Hz, H, OCH₂C(CH₃)(OH)-

3

H,

3

J

=

2

CH₂NHCOCH₂(CH₂)₁₃CH₃], 3.1–3.8 [m, 7 H, 2-H, 3-H, 4-H, 5-

H, 6_a-H, OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄CH₃], 4.22 (dd, J

= 5.0, 10.1 Hz, 1 H, 6_e-H), 4.47 (d, J = 8.2 Hz, 1 H, 1-H), 4.55

[s, 1 H, OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄CH₃], 4.59 (d, J =

J

= 9.5 Hz, 1 H, 3-H), 4.10 [d, J = 11.2 Hz, 1 H,

OCH₂C(CH₃)(OH)CH_AH_BOCO(CH₂)₆CH₃], 4.34 (dd, J = 5.0,

10.2 Hz, 1 H, 6_e-H), 4.64 (d, J = 11.9 Hz, 1 H, PhCH_AH_BO), 4.85

(d, J = 8.4 Hz, 1 H, 1-H), 4.90 (d, J = 11.9 Hz, 1 H, PhCH_AH_BO),

5.47 (d, J = 7.8 Hz, 1 H, NH), 5.57 (s, 1 H, PhCH), 7.26–7.55

(m, 10 H, 2 Ph) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = 14.1

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 21.4 [OCH₂C(CH₃)-

11.9 Hz,

1 H, PhCH_AH_BO), 4.71 (d, J = 11.9 Hz, 1 H,

PhCH_AH_BO), 5.68 (s, 1 H, PhCH), 7.20–7.43 (m, 5 H, Ph), 7.52 [t,

J = 5.85 Hz, 1 H, OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄CH₃],

7.92 (d, J = 8.6 Hz, 1 H, CH₃CONH) ppm. MS (FAB): m/z (%) =

747 (30) [M + Na]⁺. HRMS (FAB): calcd. for C₄₂H₆₄N₂O₈Na [M

+ Na]⁺747.4560; found 747.4544. C₄₂H₆₄N₂O₈(724.47): calcd. C

69.58, H 8.90, N 3.86; found C 69.42, H 8.89, N 3.66.

(OH)CH₂OCO(CH₂)₆CH₃],

22.6

(CH₃CON),

24.9–34.2

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 57.1 (C-2), 66.1 (C-5),

67.8 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 68.7 (C-6), 71.2

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 74.4 [OCH₂C(CH₃)-

(OH)CH₂OCO(CH₂)₆CH₃], 74.3 (PhCH₂O), 76.5 (C-3), 82.6 (C-4),

101.3 (PhCH), 101.7 (C-1), 126.0–138.2 (2 Ph), 170.7 (CH₃CON),

173.8 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃] ppm. MS (FAB):

m/z (%) = 636 (80) [M + Na]⁺. HRMS (FAB): calcd. for

C₃₄H₄₇NO₉Na [M + Na]⁺636.3149; found 636.3135. C₃₄H₄₇NO₉

(613.33): calcd. C 66.54, H 7.72, N 2.28; found C 66.39, H 7.32, N

2.63.

Deprotection Reactions: Solutions of compounds 55, 56 and 62

(0.5 mmol) in dry methanol (10 mL) were each subjected to hydro-

genolysis over 10% Pd/C (50 mg) at room temperature under hy-

drogen (4 bar) for 24 h. The mixture was diluted with methanol

and the catalyst filtered off and washed with methanol. The filtrate

was concentrated to dryness under reduced pressure.

(2S)-3-Capriloyloxy-2-hydroxy-2-methylpropyl 2-Acetamido-2-de-

oxy-β-D-glucopyranoside (58): Purification by column chromatog-

(2S)-2-Hydroxy-2-methyl-3-palmitoyloxypropyl 2-Acetamido-3-O-

raphy using dichloromethane/methanol (10:1) as eluent gave a pale-

yellow syrup; yield 0.37 g (85%). [α]_D= –11.0 (c = 0.3, MeOH).

¹H NMR (500 MHz, [D₆]DMSO): δ = 0.85 [t, J = 7.1 Hz, 3 H,

benzyl-4,6-O-(R)-benzylidene-2-deoxy-β-

D-glucopyranoside

(56):

Only one stereoisomer was obtained (Ͼ99% de). A white solid was

obtained after purification by column chromatography using

OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃],

OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 1.2–1.6 [m, 10 H,

H,

CH₃CON), 2.29 [t, J = 7.4 Hz, 2 H, OCH₂C(CH₃)(OH)CH₂OC-

OCH₂(CH₂)₅CH₃], 3.00 (m, 2 H, 4-H, 5-H), 3.26 [d, J = 9.6 Hz, 1

H, OCH_AH_BC(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 3.30–3.45 (m, 3

1.01

[s,

3

H,

dichloromethane/methanol (20:1) as eluent; yield 0.56 g

1

(78%); m.p. 142–143 °C. [α]_D= –5.0 (c = 0.5, CH₂Cl₂). H NMR OCH₂C(CH₃)(OH)CH₂OCOCH₂(CH₂)₅CH₃], 1.75 (s,

3

(500 MHz, CDCl₃): δ = 0.88 [t, J = 6.9 Hz, 3 H, OCH₂C-

(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 1.16 [s, H, OCH₂C-

(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 1.25–1.29 [m, 26 H,

OCH₂C(CH₃)(OH)CH₂OCOCH₂(CH₂)₁₃CH₃], 1.88 (s,

CH₃CON), 2.33 [t, J = 7.7 Hz, 2 H, OCH₂C(CH₃)(OH)CH₂- (CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 3.66 (m, 1 H, 6_B-H), 3.80 [d, J

OCOCH₂(CH₂)₁₃CH₃], 3.42–3.51 [m, H, 2-H, 5-H, = 10.9 Hz, 2 H, OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 4.23 (d,

3

H, H, 2-H, 3-H, 6_A-H), 3.52 [d, J = 9.6 Hz, 1 H, OCH_AH_BC-

3

1250

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Eur. J. Org. Chem. 2012, 1237–1252

Stereoselective Dihydroxylation of Alkenyl Hexopyranosides

J = 8.4 Hz, 1 H, 1-H), 4.51 (t, J = 5.8 Hz, 1 H, 6-OH), 4.60 [s, 1

H,OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 4.88 (d, J = 5.3 Hz, 1

(CH₃CON),

173.0

[OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄-

CH₃] ppm. MS (FAB): m/z (%) = 569 (100) [M + Na]⁺. HRMS

H, 3-OH), 4.98 (d, J = 4.1 Hz, 1 H, 4-OH), 7.64 (d, J = 8.9 Hz, 1 (FAB): calcd. for C₂₈H₅₄N₂O₈Na [M + Na]⁺569.3778; found

H, NH) ppm. ¹³C NMR (125 MHz, [D₆]DMSO):

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 21.7 [OCH₂C(CH₃)-

(OH)CH₂OCO(CH₂)₆CH₃], 22.9 (CH₃CON), 22.0–33.4

δ

=

13.9 569.3795.

Synthesis of (2S)-2-Hydroxy-2-methyl-3-oleoyloxypropyl 2-Acet-

amido-2-deoxy-β- -glucopyranoside (60): A solution of compound

D

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 55.4 (C-2), 61.0 (C-6),

67.9 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₃], 69.9 (C-5), 70.6

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₅CH₃], 73.4 [OCH₂C(CH₃)-

(OH)CH₂OCO(CH₂)₆CH₃], 73.9 (C-3), 76.9 (C-4), 101.9 (C-1),

169.1 (CH₃CON), 172.8 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆-

CH₃] ppm. MS (FAB): m/z (%) = 458 (100) [M + Na]⁺. HRMS

(FAB): calcd. for C₂₀H₃₇NO₉Na [M + Na]⁺458.2366; found

458.2383.

57 (0.4 mmol) in 80% acetic acid/water (20 mL) was heated at

60 °C. The reaction was monitored until TLC showed that all the

starting material had reacted (5 h). Then the reaction mixture was

cooled to room temperature. The pH of the solution was adjusted

to 7.5 with saturated aqueous sodium hydrogen carbonate solution

and the aqueous solution was extracted with dichloromethane. The

organic layer was washed with water and saturated aqueous sodium

chloride solution, dried with MgSO₄and concentrated under re-

duced pressure. The syrup was purified by column chromatography

using dichloromethane/methanol (10:1) as eluent; yield 0.46 g

(85%). [α]_D= –22.0 (c = 0.3, MeOH). ¹H NMR (500 MHz,

[D₆]DMSO): δ = 0.85 [t, J = 7.0 Hz, 3 H, OCH₂C(CH₃)(OH)-

(2S)-2-Hydroxy-2-methyl-2-palmitoyloxypropyl 2-Acetamido-2-de-

oxy-β-D-glucopyranoside (59): The pure compound was obtained as

a white solid by column chromatography using dichloromethane/

methanol (10:1) as eluent; yield 0.46 g (85%); m.p. 112–113 °C.

1

[α]_D= –8.0 (c = 0.5, CH₂Cl₂). H NMR (500 MHz, [D₆]DMSO):

CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃], 1.02 [s,

(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃], 1.20–1.55 [m, 22

H, OCH₂C(CH₃)(OH)CH₂OCOCH₂(CH₂)₅CH₂CH=CHCH₂-

(CH₂)₆CH₃], 1.76 (s, H, CH₃CON), 1.95–2.00 [m, H,

OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₆CH₂CH=CHCH₂(CH₂)₆CH₃],

2.28 [t, 7.3 Hz, H, OCH₂C(CH₃)(OH)CH₂OCOCH₂-

3 H, OCH₂C-

δ = 0.84 [t, J = 7.0 Hz, 3 H, OCH₂C(CH₃)(OH)CH₂OCO-

(CH₂)₁₄CH₃], 1.01 [s,

3

H, OCH₂C(CH₃)(OH)CH₂OCO-

(CH₂)₁₄CH₃], 1.2–1.6 [m, 28 H, OCH₂C(CH₃)(OH)CH₂OCO-

(CH₂)₁₄CH₃], 1.75 (s, 3 H, CH₃CON), 2.28 [t, J = 7.5 Hz, 2 H,

OCH₂C(CH₃)(OH)CH₂OCOCH₂(CH₂)₁₃CH₃], 3.04–3.06 (m, 2 H,

3

4

J

=

2

4-H, 5-H), 3.25–3.30 [m,

CH₂OCO(CH₂)₁₄CH₃], 3.36 (m, 1 H, 2-H), 3.44 (m, 1 H, 6_A-H),

3.52 [d, 9.7 Hz, H, OCH_AH_BC(CH₃)(OH)CH₂OCO-

2 H, 3-H, OCH_AH_BC(CH₃)(OH)-

(CH₂)₆CH=CH(CH₂)₇CH₃], 3.04–3.08 (m, 2 H, 4-H, 5-H), 3.25–

3.50 [m, 4 H, 2-H, 3-H, 6_A-H, OCH_AH_BC(CH₃)(OH)CH₂OCO-

J

=

1

(CH₂)₇CH=CH(CH₂)₇CH₃], 3.53 [d,

J

=

9.6 Hz,

1

H,

(CH₂)₁₄CH₃], 3.67 (m, 1 H, 6_B-H), 3.81 [dd, J = 10.9 Hz, 2 H,

OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 4.24 (d, J = 8.4 Hz, 1

H, 1-H), 4.47 (t, J = 5.8 Hz, 1 H, 6-OH), 4.56 [s, 1 H,

OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 4.84 (d, J = 5.3 Hz, 1

H, 3-OH), 4.93 (d, J = 4.9 Hz, 1 H, 4-OH), 7.61 (d, J = 9.4 Hz, 1

OCH_AH_BC(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃], 3.66

(m, 1 H, 6_B-H), 3.81 [dd, J = 11.0 Hz, 2 H, OCH₂C(CH₃)(OH)-

CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃], 4.25 (d, J = 8.2 Hz, 1 H, 1-

H), 4.48 (t,

J = 5.8 Hz, 1 H, 6-OH), 4.56 [s, 1 H,

OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃], 4.85 (d,

J = 5.1 Hz, 1 H, 3-OH), 4.94 (d, J = 4.7 Hz, 1 H, 4-OH), 5.31

[m, 2 H, OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃],

7.61 (d, J = 8.9 Hz, 1 H, NH) ppm. ¹³C NMR (125 MHz,

H, NH) ppm. ¹³C NMR (125 MHz, [D₆]DMSO):

δ = 13.9

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 21.7 (CH₃CON), 22.9

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 22.0–33.5 [OCH₂C-

(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 55.4 (C-2), 61.0 (C-6), 67.9

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄CH₃], 69.9 [OCH₂C(CH₃)-

(OH)CH₂OCO(CH₂)₁₄CH₃], 70.6 (5-C), 73.4 [OCH₂C(OH)(CH₃)-

CH₂OCO(CH₂)₁₄CH₃], 73.9 (C-3), 76.9 (C-4), 101.9 (C-1), 170.7

[D₆]DMSO):

δ

=

13.9 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇-

CH=CH(CH₂)₇CH₃], 21.7 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇-

CH=CH(CH₂)₇CH₃], 22.9 (CH₃CON), 22.0–33.4 [OCH₂C-

(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃], 55.4 (C-2), 60.9

(CH₃CON),

172.8

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₁₄-

(C-6),

67.9

[OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH-

CH₃] ppm. MS (FAB): m/z (%) = 570 (100) [M + Na]⁺. HRMS

(FAB): calcd. for C₂₈H₅₃NO₉Na [M + Na]⁺570.3618; found

570.3583. C₂₈H₅₃NO₉(547.37): calcd. C 61.40, H 9.75, N 2.56;

found C 61.59, H 9.62, N 2.55.

(CH₂)₇CH₃], 69.9 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH-

(CH₂)₇CH₃], 70.6 (C-5), 73.5 [OCH₂C(CH₃)(OH)CH₂OCO-

(CH₂)₇CH=CH(CH₂)₇CH₃], 73.9 (C-3), 76.9 (C-4), 101.9 (C-1),

129.6 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇CH=CH(CH₂)₇CH₃],

169.0 (CH₃CON), 172.7 [OCH₂C(CH₃)(OH)CH₂OCO(CH₂)₇-

CH=CH(CH₂)₇CH₃] ppm. MS (FAB): m/z (%) = 596 (100) [M +

(2R)-2-Hydroxy-2-methyl-3-palmitamidopropyl 2-Acetamido-2-de-

oxy-β-D-glucopyranoside (63): A pale-yellow syrup was obtained af-

ter column chromatography using dichloromethane/methanol

(10:1) as eluent; yield 0.43 g (80%). [α]_D= –14.3 (c = 0.3, MeOH).

¹H NMR (500 MHz, [D₆]DMSO): δ = 0.84 [t, J = 6.8 Hz, 3 H,

Na]⁺. HRMS (FAB): calcd. for C₃₀H₅₅NO₉Na [M

596.3775; found 596.3795.

+

Na]⁺

Synthesis of (2R)-3-Amino-2-hydroxy-2-methylpropyl 2-Acetamido-

3-O-benzyl-4,6-O-(R)-benzylidene-2-deoxy-β- -glucopyranoside

OCH₂C(CH₃)(OH)CH₂NHCOCH₂(CH₂)₁₃CH₃], 0.96 [s,

3 H,

D

OCH₂C(CH₃)(OH)CH₂NHCOCH₂(CH₂)₁₃CH₃], 1.20–1.27 [m, 26

H, OCH₂C(CH₃)(OH)CH₂NHCOCH₂(CH₂)₁₃CH₃], 1.82 (s, 3 H,

NHCOCH₃), 2.12 [t, J = 7.4 Hz, 2 H, OCH₂C(CH₃)(OH)-

CH₂NHCOCH₂(CH₂)₁₃CH₃], 4.20 (d, J = 8.5 Hz, 1 H, 1-H), 7.54

(61): A solution of compound 53 (0.5 mmol) in dry methanol

(10 mL) was subjected to hydrogenolysis over 10% Pd/C (50 mg)

at room temperature under hydrogen (1 bar) for 4 h. The mixture

was diluted with methanol and the catalyst was filtered off and

washed with methanol. The filtrate was concentrated to dryness

under reduced pressure. The compound was detected by MS and

used without purification in the deprotection reaction. MS (FAB):

m/z (%) = 569 (40) [M + Na]⁺. HRMS (FAB): calcd. for

C₂₆H₃₄N₂O₇Na [M + Na]⁺509.2264; found 509.2258.

[t,

J = 5.80 Hz, 1 H, OCH₂C(CH₃)(OH)CH₂NHCOCH₂-

(CH₂)₁₃CH₃], 7.71 (d, J = 8.9 Hz, 1 H, NH) ppm. ¹³C NMR

(125 MHz, [D₆]DMSO): δ = 13.9 [OCH₂C(OH)(CH₃)CH₂OCO-

(CH₂)₁₄CH₃], 22.5 [OCH₂C(OH)(CH₃)CH₂NHCO(CH₂)₁₄CH₃],

22.9 (CH₃CON), 22.0–33.5 [OCH₂C(CH₃)(OH)CH₂NHCO-

(CH₂)₁₄CH₃], 45.8 [OCH₂C(CH₃)(OH)CH₂NHCO(CH₂)₁₄CH₃],

55.4 (C-2), 61.0 (C-6), 70.5 [OCH₂C(CH₃)(OH)CH₂NHCO-

Bioactivity

(CH₂)₁₄CH₃],

71.0

(C-5),

74.4

[OCH₂C(CH₃)(OH)- Cell Culture: The human A549 lung cancer cell line and the human

CH₂NHCO(CH₂)₁₄CH₃], 74.7 (C-3), 77.0 (C-4), 102.0 (C-1), 169.5 lung fibroblastic MRC-5 cell line were maintained in DMEM sup-

Eur. J. Org. Chem. 2012, 1237–1252

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1251

J. M. Vega-Pérez, F. Iglesias-Guerra et al.

FULL PAPER

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Cell Proliferation Assay: The MTT assay is a colorimetric tech-

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bation period of 48 h, the medium was removed and MTT (125 μL,

1 mg/mL in medium) was added to each well for 5 h. Then 20%

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[13]

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Supporting Information (see footnote on the first page of this arti-

1

cle): H NMR spectra for the reported new compounds.

Acknowledgments

[17]

[18]

The authors thank the Junta de Andalucía, the Spanish Ministerio

de Educación y Ciencia (MEC), and the Fondos Europeos para

el Desarrollo Regional (FEDER) program (P06-FQM-01885 and

CTQ2007-61185) for financial support. I.P. thanks the Junta de

Andalucía for a predoctoral grant. C. P.-N. thanks the Junta de

Andalucía (P09-AGR4597) and the Ministerio de Asuntos Exteri-

ores y Cooperación (AECID) (grant number A/023577/09) for fin-

ancial support.

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Received: October 20, 2011

Published Online: December 29, 2011

1252

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Eur. J. Org. Chem. 2012, 1237–1252

Article Doi

Stereoselective dihydroxylation reaction of alkenyl β- D -hexopyranosides: A methodology for the synthesis of glycosylglycerol derivatives and 1-O-Acyl-3-O-β- D -glycosyl-sn-glycerol analogues

DOI: 10.1002/ejoc.201101539

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