Synthesis and biological evaluation of sugars containing α,β-unsaturated γ-lactones

Article abstract of DOI:10.1002/ejoc.200800763

The stereocontrolled synthesis of new sugar derivatives carrying the α,β-unsaturated δ-lactone (butenolide) moiety is described. Sugar-fused or sugar-linked butenolides can be constructed by an efficient reaction sequence involving Wittig olefination of 3- or 5-keto sugars and intramolecular cyclization of the intermediate γ-hydroxy α,β-unsaturated esters. The antimicrobial activities of the products and that of a known sugar-derived pyranoid α,β-unsaturated δ-lactone were investigated against six pathogenic bacteria and six fungi. The pyranoid α,β-unsaturated δ-lactone 29 proved to be the most active compound in this series towards the plant pathogenic fungi Colletotrichum coffeanum (coffee berry disease) and Pyricularia oryzae (rice blast disease). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800763

FULL PAPER
DOI: 10.1002/ejoc.200800763
Synthesis and Biological Evaluation of Sugars Containing α,β-Unsaturated
γ-Lactones
Nuno M. Xavier,[a] Sandrina Silva,[a] Paulo J. A. Madeira,[a] M. Helena Florêncio,[a]
Filipa V. M. Silva,[b] Jorge Justino,[b] Joachim Thiem,[c] and Amélia P. Rauter*[a]
Keywords: Wittig reaction / Lactones / Carbohydrates
The stereocontrolled synthesis of new sugar derivatives car-
were investigated against six pathogenic bacteria and six
rying the α,β-unsaturated δ-lactone (butenolide) moiety is de-
fungi. The pyranoid α,β-unsaturated δ-lactone 29 proved to
scribed. Sugar-fused or sugar-linked butenolides can be con- be the most active compound in this series towards the plant
structed by an efficient reaction sequence involving Wittig
olefination of 3- or 5-keto sugars and intramolecular cycliza-
tion of the intermediate γ-hydroxy α,β-unsaturated esters.
The antimicrobial activities of the products and that of a
known sugar-derived pyranoid α,β-unsaturated δ-lactone
pathogenic fungi Colletotrichum coffeanum (coffee berry dis-
ease) and Pyricularia oryzae (rice blast disease).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
their efficacy as potent and selective insecticides
aginst Drosophila melanogaster Meig (fruitfly), and proved
to be much more active than imidacloprid, the insecticide
that is already commercially used.[8] The fungicidal lactones
were synthesized via Reformatsky-type reaction with a dial-
dofuranose as starting material.[7,9] The approach described
for the synthesis of the insecticidal compounds relies on the
reaction of sugar epoxides with the dianion of phenylsele-
noacetic and -propionic acids, or their thioanalogues, fol-
lowed by oxidation and elimination.[7,10] Various routes
leading to sugar-C-linked butenolides have also been re-
ported, including Wittig and iodo-lactonization reactions
starting from a dialdofuranose and recently, ring-closing
metathesis via sugar-derived Baylis–Hillman adducts.[11,12]
With respect to sugar-fused α,β-unsaturated γ-lactones,
some literature reports describe their use for the prepara-
tion of bioactive natural products and branched-chain
sugars.[13,14]
Introduction
α,β-Unsaturated γ-lactones are abundant in both natu-
rally occurring and synthetic products and are known to
show a variety of antimicrobial[1] or cytotoxic[2] properties.
Some of these compounds were reported to be potential
antitumor agents,[3] cyclooxygenase or phospholipase A2
inhibitors,[4] or antibiotics.[5]
In particular sugars bearing this moiety have become im-
portant molecular targets with respect to their significant
biological profile and their functionalized nature, which
make them suitable intermediates of distinct synthetic ver-
satility.[6]
The practice of incorporating unsaturated lactones into
carbohydrates has been achieved with success in our labora-
tory. Some of these compounds (exocyclic unsaturated γ-
lactones, compounds of type A, Figure 1) show significant
antifungal activity and are particularly effective against
Puccinia recondita (wheat), Botrytis cinerea (pepper) and
Plasmopara viticola (gravepine). They are considered poten-
tial wheat-, pepper-, or wine-protective agents.[7] Moreover,
sugar-linked butenolides (endocyclic unsaturated γ-lac-
tones, compounds of type B, Figure 1) have demonstrated
[a] Centro de Química e Bioquímica/Departamento de Química e
Bioquímica, Faculdade de Ciências da Universidade de Lisboa,
Ed. C8,
5° Piso, Campo Grande, 1749-016 Lisboa, Portugal
Fax: +351-21-7500088
E-mail: aprauter@fc.ul.pt
[b] Escola Superior Agrária-Instituto Politécnico de Santarém,
Complexo Andaluz,
Apartado 279, 2001-904, Santarém, Portugal
[c] Faculty of Science, Department of Chemistry, University of
Hamburg,
Figure 1. Structure of sugar-linked α,β-unsturated-γ-lactones pos-
sessing fungicidal (A) and insecticidal (B) properties.
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
6134
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6134–6143

Carbohydrates Containing α,β-Unsaturated γ-Lactones
We have recently demonstrated an effective route to ac- pounds. In addition, we compared these results with related
cess various butenolides fused to pento- and hexopyr- data for known antifungal α-methylene γ-butyrolactones in
anoses.[15] The strategy is based on the Wittig olefination order to rationalize, in terms of structure, the influence of
of furanos-3-uloses containing acid-labile 5-O- or 5,6-di-O- the lactone system on the observed bioactivities. For this
protecting groups, followed by acid hydrolysis. According purpose we especially want to emphasize a possible rela-
to our previous findings and as part of our ongoing search tionship between the Michael-accepting ability of the tested
for strategies to insert these structural motifs into carbo- compounds and their biological activities.
hydrate templates for the design of new potentially biolo-
gically active substances, we have planned the synthesis of
Results and Discussion
analogues of the described insecticidal butenolides (com-
pounds type B, Figure 1).
The developed methodology makes use of the Wittig re-
action of 5-keto sugars with a resonance-stabilized ylide to
give α,β-unsaturated esters. The latter are spontaneously
converted into the corresponding lactones in the presence
1. Chemistry
1.1. C–C-Linked Sugar-Butenolides
The synthesis of 5-keto sugars 5–8 (Scheme 1) was
of a γ-hydroxy group, by controlling the stereochemistry of achieved by regioselective oxidation of the secondary hy-
the Wittig products. Derivatives which differ in the steric droxy group of the 5,6-diol precursors 1–4 with the system
bulk of the substituent at C-3 or in the C-3 configuration Bu2SnO/NBS[17] in 90, 78, 60 and 61% yield, respectively.
were synthesized in order to investigate the influence of The 1H NMR spectra of the α-hydroxy ketone products
these structural factors on the stereoselectivity. Moreover, show AB-system patterns for 6a-H, 6b-H, with geminal
to broaden the structural diversity of these sugar deriva- coupling constants from 20.2 to 20.5 Hz. The carbonyl
tives, we explored our recently reported methodology for groups of 5–8 give rise to characteristic signals in the 13C-
the synthesis of new butenolides fused to pento- and hexo- NMR spectra (δ = 208.2, 208.2, 207.1, and 207.3, respec-
pyranoses. One of the prospective applications of these bi- tively) and show IR band absorptions at 1725 and
cyclolactones is the synthesis of fused-disaccharides by diol 1730 cm–1. The lower yield obtained for the ribo derivatives
addition.
may result from dimerization of the α-hydroxy ketones,
The results of the antimicrobial activity evaluation per- which must depend on the stereochemistry at C-3, as sug-
formed on the newly synthesized C–C-linked sugar-buteno- gested in the literature.[17] Hence dimerization occurs to a
lides as well as on the previously reported bicyclic fused larger extent in ribo than in xylo compounds in which the
derivatives are presented here. To extend the range of the orientation of the C-3 substituent results on increased steric
sugar-based unsaturated lactones tested, a pyranoid α,β-un- hindrance to the formation of dimers. The 5-keto substrates
saturated γ-lactone[16] was included in our set of com- were subjected to Wittig reaction with [(ethoxycarbonyl)-
Scheme 1. Reactions and conditions: a) Bu2SnO, toluene, reflux overnight, then NBS, CH2Cl2, 5 min; b) Ph3P=CHCO2Et, CHCl3, reflux;
c) BrCH2CO2Et, Zn, THF, 50 °C.
Eur. J. Org. Chem. 2008, 6134–6143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6135

A. P. Rauter et al.
FULL PAPER
methylene]triphenylphosphorane in refluxing chloroform to tonization, depends on the orientation of the C-3 substitu-
give compounds 9–12. Starting from 3-O-benzyl- and ent. A possible steric hindrance due to C-3 configuration in
3-O-allyl-1,2-O-isopropylidene-α--xylo-hexofuranos-5- xylo-hexofuranose derivatives with a bulky benzyloxy group
ulose (5, 6), the (Z)-α,β-unsaturated esters 9, 10 were ob- or with allyl ether protection at position 3 may be envis-
tained in 74% and 60% yield, respectively, and no cycliza- aged. The 5-keto sugars 5, 6 were also used as precursors
1
tion was observed. In the H NMR spectra, the signals of for a Reformatsky reaction with ethyl bromoacetate to af-
the olefinic protons appear at δ = 6.02 and 6.08, respec- ford the sugar-linked β-hydroxy lactones 15, 16, formed in
tively, as broad singlets. Diagnostic signals for the configu- low yield (16 and 19%, respectively), together wih a com-
ration assignment of these molecules are the 4-H protons, plex mixture of degradation products. A salient feature of
1
which are relatively downfield shifted (δ = 5.83 and the H NMR spectra of 15 and 16 is the two separate sets
5.84 ppm), thus reflecting the orientation of the ethoxycar- of AB systems for the five-membered ring lactone unit, as-
bonyl group. Furthermore, the (Z)-configuration around signed for 5Јa-H, 5Јb-H, and 6a-H, 6b-H, the latter shifted
the double bond could be confirmed by NOESY experi- upfield. The presence of the signals at 174.8 and 175.1 for
ments, due to the correlations of 3-H and 4-H with CH3 the carbonyl groups of 15 and 16, respectively, in their 13C
(Et) protons and those of 6-H with 5Јa-H, 5Јb-H. However, NMR spectra confirmed the lactone skeleton. Our pro-
when the ribo-hexofuranos-5-ulose derivatives 7–8 were posed configuration for the stereogenic centre (C-5) of the
used as starting materials, the corresponding Wittig reac- formed lactone is based on the assumption that the nucleo-
tion provided mainly the formation of the (E) adducts, the philic attack of the Reformatsky reagent to 5–6 should oc-
spontaneous cyclization of which gave the α,β-unsaturated- cur from the less hindered face of the carbonyl group.
γ-lactones 13, 14 in 47% and 49% yield, respectively. The
1.2. Sugar-Fused Butenolides
carbonyl groups of the butenolide moeties were confirmed
by the signals at δ = 173.3 in their 13C NMR spectra. In
The synthesis of sugar-fused butenolides was ac-
the 1H NMR spectra, olefinic protons give rise to signals at complished following the approach previously reported by
δ = 6.06 and 6.12, respectively, and as a consequence of us, starting from readily available furanos-3-uloses.[15] Thus,
lactonization, chemical shifts values for 4-H around δ = Wittig reaction of 1,2;5,6-di-O-isopropylidene-α--ribo-
4.85 are much smaller than those observed for their acyclic hexofuranosid-3-ulose[9] with [(ethoxycarbonyl)methylene]-
(Z)-aducts 11 and 12, which were isolated in only 12 and triphenylphosphorane in refluxing chloroform afforded the
11% yield, respectively. These results suggest that the known (E)- and (Z)-α,β-unsaturated esters 17a,b[18]
stereoselectivity of the Wittig reaction to the formation of (Scheme 2) in 12% yield and 68% yield, respectively. The
the (E)-isomers and consequently, to their spontaneous lac- (E) adduct 17b was partially hydrolysed at the primary ace-
Scheme 2. Reactions and conditions: a) AcOH 60% aq., room temp.; b) PivCl, CH2Cl2/py, 0 °C; c) AcOH 70% aq., reflux; d) Amberlite
IR-120 H+, MeOH, reflux overnight; e) DOWEX 50W H+, MeOH, reflux, 2 h; f) DOWEX 50W H+, MeOH, reflux, overnight; g) Ac2O,
py, room temp., 5 min; OsO4, py, room temp.
6136
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6134–6143

Carbohydrates Containing α,β-Unsaturated γ-Lactones
tonide with aq. acetic acid (60%) to the corresponding diol dation step: pyridinium chlorochromate (PCC) as in the
18b which was subsequently treated with pivaloyl chloride original procedure and pyridinium dichromate (PDC). In
in pyridine/dichloromethane at 0 °C. The mono-pivaloyl de- both cases, after reaction completion, the mixture was fil-
rivative 19, selectively obtained in 81% yield, was submitted tered through a short Florisil plug, which efficiently re-
to hydrolysis with aqueous acetic acid (70%) under reflux tained the green CrIII species, facilitating the purification of
to provide the hexopyranose-fused butenolide 21 as a mix- the enonolactone 29 by column chromatography. However
ture of α,β-anomers in 58% yield. Noteworthy in this step, the first oxidizing methodology provided the best result in
in which cleavage of the acetal, isomerization to the pyr- this one-pot, two-step procedure, forming the target com-
anose form, and accompanying intramolecular lactoniza- pound in 43% overall yield, when compared to 31% yield
tion occur, is that the pivaloyl group unexpectedly remains using PDC.
in the final product and no migration was observed. This
feature could indeed be confirmed by the observed HMBC
correlation between 6a,b-H and the carbonyl carbon of the
pivaloyl group. On the other hand, conversion of the (Z)-
α,β-unsaturated ester 17a to the butenolide 22 in one single
step was initially performed by treatment with IR-120 H+
resin in refluxing methanol overnight in 90% yield. Manip-
ulation of the reaction conditions using an ion-exchange
resin with stronger acidic properties, Dowex-50W, the reac-
tion time was reduced to 2 h, whereas the corresponding
methyl glycoside 24 was formed in 57% yield after over-
night stirring. Dihydroxylation of the triacetate-derived but-
enolide 23 with osmium tetroxide gave the α/β-cis-diols
25a,b which could be separated by column chromatography
and isolated in 33 and 23% yield, respectively. The (S)-con-
figuration of the new stereocenter could be assigned by 2D-
NOESY analysis of the β-anomer, with the detection of
NOEs between 3Ј-H-5-H and 3Ј-H-1-H (Scheme 2). These
compounds constitute non-natural fused disaccharides
which comprise a butyrolactone and a pyranose system.
Similarly to the hexofuranose derivatives, the (E)-α,β-un-
saturated ester 26b, a minor stereoisomer, prepared by Wit-
tig olefination of 1,2-O-isopropylidene-5-O-tert-butyldime-
thylsilyl-α--erythro-furan-3-ulose,[15] was subjected to an
analogous acid hydrolysis, which was followed by acety-
lation (Scheme 3). The bicyclolactone 27, the structure of
which comprises the butenolide moiety fused to a pentopyr-
anose unit at positions 3 and 4, was obtained in 74% overall
yield.
Scheme 4. Reactions and conditions: a) NBS, H2O/THF; b) PCC,
molecular sieves (3 Å), CH2Cl2, room temp.; c) PDC, Ac2O,
CH2Cl2, room temp.
2. Antibacterial and Antifungal Screening
The antimicrobial activities of sugar-linked butenolides
13, 14, sugar-fused butenolides 22, 23, 30[15] and 31[15] (Fig-
ure 2) and pyranoid α,β-unsaturated δ-lactone 29 were in-
vestigated using the paper disk diffusion method.[19,20]
These compounds were evaluated for their in vitro anti-
bacterial activity against pathogens such as Bacillus cereus,
Bacillus subtilis, Enterococcus faecalis, Escherichia coli,
Pseudomonas aeruginosa and Staphylococcus aureus. Their
antifungal activity was studied on a panel of plant patho-
genic fungi which may also cause human allergies including
Botrytis spp., Colletotrichum coffeanum, Fusarium culmo-
rum, Pyricularia oryzae, and Rhizopus spp., and the human
fungal pathogen Candida albicans. The results are presented
in Table 1. The sugar-linked butenolide 14 exhibited weak
effects toward Bacillus subtilis and Candida albicans while
the 3-O-benzyl counterpart 13, showed virtually no activity
at all. Regarding these results and in contrast with those of
the analogues possessing an α-methylene-γ-lactone moiety
(compounds type B, Figure 1), particularly against Botrytis
spp., Fusarium culmorum and Pyricularia oryzae, it is clear
that the exocylic double bond in the lactone enhances the
antifungal activity of these compounds. Given their struc-
ture, the exocyclic α,β-unsaturated γ-lactones have greater
ability than the endocyclic derivatives to act as Michael ac-
ceptors, which is commonly related to the bioactivity of
α,β-unsaturated carbonyl compounds.[21] Hence, the pres-
Scheme 3. Reactions and conditions: a) AcOH 70%, reflux; b)
Ac2O, py, room temp., 5 min.
1.3. Synthesis of a Sugar Pyranoid α,β-Unsaturated
δ-Lactone
The hex-2-enono-1,5-lactone 29 was synthesized by reac-
tion of 1,5-anhydro-3,4,6-tri-O-acetyl-2-deoxy--arabino-
hex-1-enitol (28) (non-preferred trivial name: 3,4,6-tri-O-
acetyl--glucal) with N-bromosuccinimide (NBS) and water
followed by oxidation of the 2-bromolactol formed, accord-
ing to the approach previously reported (Scheme 4).[16] Two
Figure 2. Structure of sugar-fused butenolides 30, 31 submitted to
different chromium-based reagents were used at the oxi- bioactivity tests.
Eur. J. Org. Chem. 2008, 6134–6143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6137

A. P. Rauter et al.
FULL PAPER
Table 1. Antimicrobial activities of compounds 13, 14, 22, 23, 29, 30 and 31.[a]
13
14
22
23
29
30
31
Control[b]
I
Microbes and bacteria
II
Bacillus cereus
Bacillus subtilis
Enterococcus faecalis
Escherichia coli
Pseudomonas aeruginosa
Staphylococcus aureus
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
9
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
10
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
16
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
11
Ͻ6.4
9
9
9
9
Ͻ6.4
10
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
24
30
26
28
Ͻ6.4
27
38
46
40
42
22
40
Fungi
Botrytis spp.
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
9
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
8
8
8
8
11
10
16
Ͻ6.4
15
Ͻ6.4
8
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
8
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
16
12
39
20
16
24
18
63
18
Candida albicans
Colletotrichum coffeanum
Fusarium culmorum
Pyricularia oryzae
Rhizopus spp.
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
Ͻ6.4
11
[a] Compound solutions tested [300 µg compound in DMSO (15 µL)]. [b] Chloramphenicol was used for all bacteria and for C. albicans,
whereas actidione was used for the filamentous fungi; a solution of the control (I: 30 µg, II: 300 µg) in DMSO (15 µL) was used.
ence of the quaternary hindered β-carbon in the lactone step. Hence, butenolides were prepared from ribo-furanos-
system of 13 and 14, considerably reduces their propensity 5-ulose derivatives, while olefination of xylo-5-uloses did
to a nucleophilic attack, especially by sulfhydryl groups of not afford the appropriate stereoisomer for spontaneous cy-
enzymes.
clization. The synthesis of sugar-fused butenolides was ac-
Sugar-fused butenolides 22, 23 and 30 display selective complished starting from pento- and hexofuranos-3-uloses,
antibacterial activity against Bacillus subtilis; the highest ac- using our previously reported Wittig olefination–acid hy-
tivity was observed for the triacetate derivative 23 with drolysis approach.[15] The biological evaluation performed
moderate effect. The antibacterial effect of compound 31 is on some of the new targets suggests that the presence of a
practically negligible. With respect to the antifungal activity non-hindered double bond in the conjugated system is es-
assays, all the butenolide derivatives show similar and weak sential for the biological activity. The low molecular flexibil-
activities toward Candida albicans. Compounds 22 and 23 ity of the new sugar-linked and sugar-fused butenolides
exhibit weak activities against Botrytis spp., although but- possessing a quaternary Cβ does not allow their expression
enolides 30 and 31 are inactive against these pathogens. The as Michael acceptors and probably explains the weak anti-
results of the antimicrobial evaluation made on this series microbial effect observed for these compounds. The pyr-
may be also related to the presence of the hindered double anoid α,β-unsaturated δ-lactone 29, which is undoubtedly
bond in the lactone conjugated system, which is now fused more susceptible to Michael addition, displays activity
to a six-membered ring, making the system less susceptible against most of the bacteria studied and moderate antifun-
to Michael addition. The pyranoid α,β-unsaturated δ-lac- gal effect toward Colletotrichum coffeanum and Pyricularia
tone 29 proved to be the most active compound of this set; oryzae, confirming therefore the above disclosed assump-
29 is active against all the bacteria tested, except for Bacillus tions.
subtilis, for which no effect was detected. Regarding the
tested fungi, lactone 29 shows weak activities against Botry-
tis spp. and Candida albicans and moderate activity against
Experimental Section
Colletotrichum coffeanum (coffee berry disease) and Pyricul-
General Methods: Melting points were determined with a Stuart
aria oryzae (rice blast disease). The greater Michael-ac-
Scientific SMP 3 apparatus or a Leitz apparatus and are uncor-
cepting ability of 29 when compared to that of the previous
rected. Optical rotations were measured on a Perkin–Elmer 343
polarimeter at 20 °C. IR spectra were acquired using a Hitachi 270–
lactones, due to the electron-withdrawing influence of the
bromine atom and absence of steric hindrance in the reac-
tive double bond, may indeed contribute to the biological
results obtained.
50 spectrometer. 1H and 13C NMR spectra were recorded with a
Bruker Avance 400 or a Bruker AMX-400 spectrometer, both op-
erating at 400.13 MHz for 1H or 100.62 MHz for 13C. Chemical
shifts are expressed in parts per million and are referenced either
to TMS as internal standard for H or to the solvent signal (13C
1
NMR: δ = 77.16 for CDCl3). Assignments were made, when
needed, with the help of DEPT, COSY, HMQC, NOESY and
HMBC experiments. HRMS spectra were acquired in an Apex Ul-
tra FTICR Mass Spectrometer equipped with an Apollo II Dual
ESI/MALDI ion source, from Bruker Daltonics, and a 7T actively
shielded magnet from Magnex Scientific.
Conclusions
A series of novel sugar-containing butenolides was syn-
thesized. C–C-Linked sugar-butenolides were prepared by
Wittig olefination of hexofuranos-5-uloses followed by in-
tramolecular lactonization of the intermediate γ-hydroxy
α,β-unsaturated esters. The configuration at C-3 seems to
All reactions were followed by TLC on Merck 60 F254 silica gel
be an important structural factor to control the cyclization aluminum plates. UV at 254 nm and a solution of 10% H2SO4 in
6138 Eur. J. Org. Chem. 2008, 6134–6143
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Carbohydrates Containing α,β-Unsaturated γ-Lactones
3
EtOH were used for detection. Column chromatography was car-
ried out on silica gel 60 G (0.040–0.063 mm, from Merck).
=CH2 allylic), 4.67 (br. t, 1 H, 2-H), 4.60 (d, J3,4 = 9.1 Hz, 1 H,
2
4-H), 4.51, 4.46 (part A of AB system, J6a,6b = 20.5 Hz, 6a-H),
4.46, 4.41 (part B of AB system, 6b-H), 4.23, 4.22, 4.20, 4.19 (part
General Procedure for the Synthesis of Hexofuranos-5-uloses 5–8:
Dibutyltin oxide (0.221 g, 0.89 mmol) was added to a solution of
5,6-diol (0.81 mmol) in toluene (5.4 mL). The mixture was stirred
under reflux with a Dean–Stark apparatus. The solvent was evapo-
rated and the residue was dried in vacuum for 30 min. The crude
was then taken up in dry CHCl3 (5.4 mL) and N-bromosuccinimide
(NBS, 0.158 g, 0.89 mmol) was added. The resulting solution was
stirred for 5 min. The solvent was removed in vacuum, and the
residue was purified by column chromatography (CC) on silica gel.
2
3
AX of ABX system, Ja,b = 12.6, Ja,H-all = 5.8 Hz, a-H, OCH2
3
allylic), 4.14, 4.13, 4.11, 4.10 (part BX of ABX system, Jb,H-all
=
3
5.8 Hz, b-H, OCH2 allylic), 3.83 (dd, J2,3 = 4.0 Hz, 1 H, 3-H),
3.09 (br. s, 1 H, OH), 1.59 (s, 3 H, Me), 1.38 (s, 3 H, Me) ppm.
13C NMR (100 MHz, CDCl3): δ = 207.3 (CO), 133.8 (CH allylic),
119.1 (=CH2 allylic), 113.9 (Cq, isopr.), 104.6 (C-1), 80.3 (C-4),
79.8 (C-3), 77.8 (C-2), 72.0 (OCH2 allylic), 66.7 (C-6), 26.9 (Me),
26.6 (Me) ppm. HRMS: calcd. for [M + Na]+ 281.0996, found
281.0996.
3-O-Benzyl-1,2-O-isopropylidene-α-
D
-xylo-hexofuranos-5-ulose (5):
3-O-Benzyl-1,2-O-isopropylidene-α--glucofuranose[22]
(0.250 g,
General Procedure for the Preparation of the α,β-Unsaturated Esters
9–12 and Butenolides 13–14: [(Ethoxycarbonyl)methylene]triphenyl-
phosphorane (0.153 g, 0.44 mmol) was added to a solution of hex-
ofuranos-5-ulose (0.26 mmol) in dry CHCl3 (2.1 mL). The mixture
was stirred under reflux until complete conversion, as indicated by
TLC. The solvent was removed and the residue was purified by
column chromatography (CC) on silica gel.
0.81 mmol) gave 5 (0.220 g, 90%) as a white solid, after purification
by CC (EtOAc/ petroleum ether, 3:7). NMR spectroscopic data was
in full agreement with those reported in the literature.[17]
3-O-Allyl-1,2-O-isopropylidene-α-
D
-xylo-hexofuranos-5-ulose
(6):
3-O-Allyl-1,2-O-isopropylidene-α--glucofuranose[23]
(0.374 g,
1.44 mmol) gave 6 (0.291 g, 78%) as a colorless oil, after purifica-
tion by CC (EtOAc/cyclohexane, 3:7). Rf = 0.28 (EtOAc/petroleum
Ethyl (5Z)-3-O-Benzyl-5,6-dideoxy-5-C-hydroxymethyl-1,2-O-iso-
propylidene-α-D-xylo-5-enoheptofuranuronate (9): Wittig olefination
of 3-O-benzyl-1,2-O-isopropylidene-α--xylo-hexofuranos-5-ulose
(0.080 g, 0.26 mmol) was completed within 4 h to give 9 (0.073 g,
75%) as a colorless syrup after purification by CC (EtOAc/petro-
ether, 1:9). [α]2D0 = –70 (c = 1, in CH Cl ). IR (neat): ν = 1725
˜
2
2
(C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.05 (d, J1,2
=
3
3.5 Hz, 1 H, 1-H), 5.80–5.71 (m, 1 H, CH allylic), 5.25–5.17 (m, 2
3
H, =CH2 allylic), 4.80 (d, J3,4 = 3.5 Hz, 1 H, 4-H), 4.58 (d, 1 H,
leum ether, 1:4). Rf = 0.47 (EtOAc/petroleum ether, 1:4). [α]2D0
=
2-H), 4.57, 4.56, 4.52, 4.51 (part AX of ABX system, 2J6a,6b = 20.2,
JOH,H-6b = 4.3 Hz, 6a-H), 4.49, 4.48, 4.44, 4.43 (part BX of ABX
1
–91 (c = 0.6, in CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.32–
3
3
7.21 (m, 5 H, Ph), 6.02 (s, 1 H, 6-H), 6.00 (d, J1,2 = 3.6 Hz, 1 H,
system, JOH,H-6b = 4.0 Hz, 6b-H), 4.25 (d, 1 H, 3-H), 4.07, 4.06,
2
3
4.05, 4.03 (part AX of ABX system, 2Ja,b = 12.6, Ja,H-all = 5.3 Hz,
1-H), 5.83 (s, 1 H, 4-H), 4.65–4.59 (m, Ja,b = 11.6 Hz, 2 H, a-H,
OCH2Ph, 2-H), 4.45–4.40 (m, 2 H, b-H, OCH2Ph, 3-H), 4.35 (br.
s, 2 H, 5Јa-H, 5Јb-H), 4.08 (q, 3J = 7.2 Hz, 2 H, CH2CH3), 1.52 (s,
3 H, Me), 1.34 (s, 3 H, Me), 1.25 (t, 3 H, CH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.0 (CO), 156 (C-5), 137.1 (Cq, Ph),
128.4, 128.0, 127.9, (CH, Ph), 117.0 (C-6), 112.1 (Cq, isopr.), 104.9
(C-1), 83.2 (C-3), 82.5 (C-2), 80.0 (C-4), 72.4 (OCH2Ph), 64.5 (C-
5Ј), 60.2 (CH2CH3), 26.9 (Me), 26.4 (Me), 14.2 (CH2CH3) ppm.
HRMS: calcd. for C20H26O7 [M + H]+ 379.1751, found 379.1754;
calcd. for [M + Na]+ 401.1571, found 401.1574; calcd. for
[M + K]+ 417.1310, found 417.1314.
a-H, OCH2 allylic), 3.95, 3.94, 3.92, 3.91 (part BX of ABX system,
3Jb,H-all = 5.8 Hz, b-H, OCH2 allylic), 2.93 (t, 1 H, OH), 1.48 (s, 3
H, Me), 1.34 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
208.2 (CO), 133.3 (CH allylic), 118.2 (=CH2 allylic), 112.7 (Cq,
isopr.), 106.0 (C-1), 84.6 (C-4), 83.2 (C-3), 81.9 (C-2), 71.5 (OCH2
allylic) 68.3 (C-6), 27.0 (Me), 26.3 (Me) ppm. HRMS: calcd. for
C12H18O6 [M
+
H]+ 259.1176, found 259.1177; calcd. for
[M + Na]+ 281.0996, found 281.0996; calcd. for [M + K]+ 297.0735,
found 297.0735.
3-O-Benzyl-1,2-O-isopropylidene-α-
D
-ribo-hexofuranos-5-ulose (7):
3-O-Benzyl-1,2-O-isopropylidene-α--allofuranose[24]
(1.00 g,
Ethyl (5Z)-3-O-Allyl-5,6-dideoxy-5-C-hydroxymethyl-1,2-O-isopro-
pylidene-α-
D-xylo-5-enoheptofuranuronate (10): Wittig olefination
3.22 mmol) gave 7 (0.595 g, 60%) as a colorless syrup after after
purification by CC (EtOAc/petroleum ether, 2:3). Rf = 0.36
(EtOAc/petroleum ether, 2:3). [α]2D0 = +24 (c = 0.4, in CH2Cl2). IR
of 3-O-allyl-1,2-O-isopropylidene-α--xylo-hexofuranos-5-ulose
(0.184 g, 0.71 mmol) was completed within 4 h and gave 10
(0.139 g, 60%) as a colorless syrup, after purification by CC
(EtOAc/cyclohexane, 1:4). Rf = 0.28 (EtOAc/petroleum ether, 1:4).
(neat): ν = 1730 cm–1 (C=O). 1H NMR (400 MHz, CDCl3): δ =
˜
3
7.37–7.27 (m, 5 H, Ph), 5.81 (d, J1,2 = 3.4 Hz, 1 H, 1-H), 4.76,
4.73 (part A of AB system, Ja,b = 11.9 Hz, a-H, OCH2Ph), 4.64–
[α]2D0 = –31 (c = 0.4, in CH2Cl2). H NMR (400 MHz, CDCl3): δ
1
2
3
= 6.08 (br. s, 1 H, 6-H), 5.99 (d, J1,2 = 3.8 Hz, 1 H, 1-H), 5.84 (s,
1 H, 4-H), 5.82–5.72 (m, 1 H, CH allylic), 5.26–5.13 (m, 2 H, =CH2
4.59 (m, 2 H, b-H, 4-H), 4.57 (br. t, 1 H, 2-H), 4.45, 4.40, (part A
2
of AB system, J6a,6b = 20.2 Hz, 6a-H), 4.38, 4.33, (part B of AB
3
3
3
allylic), 4.57 (d, 1 H, 2-H), 4.38 (d, J3,4 = 3.3 Hz, 1 H, 3-H), 4.34
system, 6b-H), 3.81 (dd, J2,3 = 4.4, J3,4 = 9.3 Hz, 1 H, 3-H), 1.59
(s, 3 H, Me), 1.36 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3):
δ = 207.1 (CO), 136.7 (Cq, Ph), 128.6, 128.3, 128.1, (CH, Ph), 113.8
(Cq, isopr.), 104.6 (C-1), 80.4 (C-4), 79.4 (C-3), 77.6 (C-2), 72.5
(OCH2Ph), 66.5 (C-6), 26.9 (Me), 26.5 (Me) ppm. HRMS: calcd.
for C16H20O6 [M + H]+ 309.1333, found 309.1335; calcd. for [M +
Na]+ 331.1152, found 331.1159; calcd. for [M + K]+ 347.0891,
found 347.0884.
(br. d, 2 H, 5Јa-H, 5Јb-H), 4.19 (q, 3J = 7.1 Hz, 2 H, CH2CH3),
2
4.08, 4.06, 4.05, 4.03 (part AX of ABX system, Ja,b = 12.9,
3Ja,H-all = 5.3 Hz, a-H, OCH2 allylic), 3.95, 3.94, 3.92, 3.91 (part
3
BX of ABX system, Jb,H-all = 5.8 Hz, OCH2 allylic), 2.54 (t, J =
5.8 Hz, 1 H, OH), 1.53 (s, 3 H, Me), 1.34 (s, 3 H, Me), 1.29 (t, 3
H, CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9 (CO),
156.3 (C-5), 133.8 (CH allylic), 117.9 (=CH2 allylic), 117.1 (C-6),
112.1 (Cq, isopr.), 105.0 (C-1), 83.6 (C-3), 82.9 (C-2), 79.9 (C-4),
71.5 (OCH2 allylic) 64.5 (C-5Ј), 60.4 (CH2CH3), 27.0 (Me), 26.5
(Me), 14.4 (CH2CH3) ppm. HRMS: calcd. for C16H24O7
[M + H]+ 329.1595, found 329.1593; calcd. for [M + Na]+ 351.1414,
found 351.1410; calcd. for [M + K]+ 367.1154, found 367.1152.
3-O-Allyl-1,2-O-isopropylidene-α-
D
-ribo-hexofuranos-5-ulose
(8):
3-O-Allyl-1,2-O-isopropylidene-α--allofuranose[25]
(0.473 g,
1.82 mmol) gave 8 (0.289 g, 61%) as a colorless oil after purifica-
tion by CC (EtOAc/cyclohexane, 3:7). Rf = 0.23 (EtOAc/cyclohex-
ane, 2:3). [α]2D0 = +56 (c = 0.7, in CH Cl ). IR (neat): ν = 1725
˜
2
2
(C=O) cm–1. H NMR (400 MHz, CDCl3): δ = 6.00–5.87 (m, 1 H, Ethyl (5Z)-3-O-Benzyl-5,6-dideoxy-5-C-hydroxymethyl-1,2-O-iso-
1
3
CH allylic), 5.87 (d, J1,2 = 3.6 Hz, 1 H, 1-H), 5.37–5.24 (m, 2 H,
propylidene-α-
D
-ribo-5-enoheptofuranuronate (11) and 3-O-Benzyl-
Eur. J. Org. Chem. 2008, 6134–6143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6139

A. P. Rauter et al.
FULL PAPER
5,6-dideoxy-1,2-O-isopropylidene-α-
D
-ribo-5-enoheptofuranurono-
system, 2J5Јa,5Јb = 18.2 Hz, 5Јa-H), 4.87–4.79 (m, 2 H, 4-H, 5Јb-H),
7,5Ј-lactone (13): Wittig olefination of 3-O-benzyl-1,2-O-isopro-
pylidene-α--ribo-hexofuranos-5-ulose (0.187 g, 0.61 mmol) was
completed within 1 h 30 min and gave 11 (0.027 g, 12%) as a color-
less syrup and 13 (0.096 g, 47%) as a white solid, after purification
by CC (EtOAc/petroleum ether, 1:4). Data for 11: Rf = 0.45
4.70 (t, 1 H, 2-H), 4.27, 4.26, 4.24, 4.22 (part AX of ABX system,
3
2Ja,b = 12.4, Ja,H-all = 5.6 Hz, a-H, OCH2 allylic), 4.09, 4.07, 4.06,
3
4.04 (part BX of ABX system, Jb,H-all = 6.3 Hz, b-H, OCH2 al-
3
3
lylic), 3.66 (dd, J2,3 = 4.1, J3,4 = 9.4 Hz, 1 H, 3-H), 1.61 (s, 3 H,
Me), 1.39 (s, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
173.3 (C-7), 166.4 (C-5), 133.6 (CH allylic), 119.3 (=CH2 allylic),
1
(EtOAc/petroleum ether, 2:3). [α]2D0 = +6 (c = 0.9, in CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m, 5 H, Ph), 6.06 (s, 1 115.8 (C-6), 113.8 (Cq, isopr.), 104.5 (C-1), 82.0 (C-3), 77.0 (C-2),
3
3
H, 6-H), 5.85 (d, J3,4 = 9.9 Hz, 1 H, 4-H), 5.74 (d, J1,2 = 3.3 Hz,
74.5 (C-4), 71.9 (OCH2 allylic), 71.0 (C-5Ј), 26.8 (Me), 26.5 (Me)
1 H, 1-H), 4.70, 4.66 (part A of AB system, Ja,b = 11.9 Hz, a-H, ppm. HRMS: calcd. for C14H18O6 [M + H]+ 283.1176, found
2
OCH2Ph), 4.58 (t, 1 H, 2-H), 4.56, 4.53 (part B of AB system, b- 283.1181.
H, OCH2Ph), 4.28–4.09 (m, 3 H, 5Јa-H, CH2CH3), 4.03, 4.01, 3.99,
General Procedure for the Synthesis of β-Hydroxy Lactones 15–16:
To a mixture of previously activated granulated zinc 20 mesh
(78 mg, 1.2 mmol) and hexofuranos-5-ulose (0. 8 mmol) in anhy-
drous THF (0.6 mL) was added a solution of ethyl bromoacetate
(0.13 mL, 1.1 mmol) in THF (0.7 mL) under argon. The mixture
was stirred at 50 °C for 1 h 30 min. After cooling to room temp., a
10% HCl solution (8 mL, cooled to 0 °C) was added. The mixture
was extracted with CH2Cl2 (3ϫ4 mL), the organic phase was neu-
tralized with a diluted NaHCO3 solution, washed with water and
dried with anhydrous MgSO4. The solvent was evaporated and the
residue was purified by column chromatography (CC) on silica gel.
2
3
3.97 (part BX of AB system, J5a,5b = 14.9, J5b,OH = 7.1 Hz, 5Јb-
3
H), 3.81 (dd, J2,3 = 3.8 Hz, 1 H, 3-H), 1.65 (s, 3 H, Me), 1.37 (s,
3 H, Me), 1.26 (t, 3 H, CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3) δ = 165.9 (CO), 152.2 (C-5), 137.6 (Cq, Ph), 128.5, 128.1,
128.0 (CH, Ph), 120.0 (C-6), 113.6 (Cq, isopr.), 104.2 (C-1), 81.0
(C-3), 77.8 (C-2), 75.0 (C-4), 72.3 (OCH2Ph), 62.5 (C-5Ј), 60.4
(CH2CH3), 27.0 (Me), 26.9 (Me), 14.3 (CH2CH3) ppm. HRMS:
calcd. for C20H26O7 [M + H]+ 379.1751, found 379.1757; calcd. for
[M + Na]+ 401.1571, found 401.1577; calcd. for [M + K]+ 417.1310,
found 417.1319. Data for 13: Rf = 0.21 (EtOAc/petroleum ether,
1
1:3); m.p. 158–159 °C. [α]2D0 = +35 (c = 0.4, in CH2Cl2). H NMR
3-O-Benzyl-6-deoxy-5-C-hydroxymethyl-1,2-O-isopropylidene-α-L-
(400 MHz, CDCl3): δ = 7.41–7.30 (m, 5 H, Ph), 6.06 (br. d, 1 H,
ido-heptofuranurono-7,5Ј-lactone (15): 3-O-Benzyl-1,2-O-isopro-
pylidene-α--xylo-hexofuranos-5-ulose (0.25 g, 0. 8 mmol) gave 15
(0.041 g, 15%) as a colorless oil, after purification by CC (EtOAc/
petroleum, 3:7). Rf = 0.44 (EtOAc/petroleum ether, 2:3). [α]2D0 = –51
3
3
6-H), 5.83 (d, J1,2 = 3.6 Hz, 1 H, 1-H), 4.87 (d, J3,4 = 9.2 Hz, 1
H, 4-H), 4.84, 4.80 (part AX of ABX system, 2J5Јa,5Јb = 18.2, 3J5Јa,6
= 1.6 Hz, 5Јa-H), 4.81, 4.78 (part A of AB system, Ja,b = 11.6 Hz,
2
a-H, OCH2Ph), 4.72, 4.68 (part BX of ABX system, 5Јb-H), 4.66
(t, 1 H, 2-H), 4.56, 4.53 (part B of AB system, b-H, OCH2Ph), 3.65
1
(c = 0.9, in CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.42–7.31
3
(m, 5 H, Ph), 6.01 (s, J1,2 = 3.8 Hz, 1 H, 1-H), 4.76, 4.73 (part A
3
(dd, J2,3 = 4.1 Hz, 1 H, 3-H), 1.62 (s, 3 H, Me), 1.39 (s, 3 H, Me)
2
of AB system, Ja,b = 11.7 Hz, a-H, OCH2Ph), 4.67 (d, 1 H, 2-H),
ppm. 13C NMR (100 MHz, CDCl3): δ = 173.3 (C-7), 166.2 (C-5),
136.5 (Cq, Ph), 128.9, 128.7, 128.4 (CH, Ph), 116.1 (C-6), 113.8
(Cq, isopr.), 104.5 (C-1), 81.5 (C-3), 76.9 (C-2), 74.6 (C-4), 72.6
(OCH2Ph), 70.9 (C-5Ј), 26.8 (Me), 26.5 (Me) ppm. HRMS: calcd.
for C18H20O6 [M + H]+ 333.1333, found 333.1333.
4.49, 4.46 (part B of AB system, b-H, OCH2Ph), 4.42, 4.39 (part
A of AB system, J5Јa,5Јb = 10.4 Hz, 5Јa-H, CH2OCO), 4.25, 4.22
(part B of AB system, 5Јb-H, CH2OCO), 4.21 (d, 1 H, 3-H), 4.14
3
(d, J3,4 = 3.8 Hz, 1 H, 4-H), 2.68, 2.64 (part A of AB system,
3J6a,6b = 17.5 Hz, 6a-H), 2.46, 2.42 (part B of AB system, 6b-H),
1.49 (s, 3 H, Me), 1.34 (s, 3 H, Me) ppm. 13C NMR (100 MHz,
CDCl3): δ = 174.8 (CO), 135.8 (Cq, Ph), 129.1, 128.9, 128.5 (CH,
Ph), 112.2 (Cq, isopr.), 105.2 (C-1), 82.3 (C-3), 81.8 (C-2), 81.0 (C-
4), 76.9 (C-5Ј), 76.6 (C-5), 72.2 (OCH2Ph), 40.6 (C-6), 26.8 (Me),
26.2 (Me) ppm. HRMS: calcd. for C18H22O7 [M + H]+ 351.1438,
found 351.1439.
Ethyl (5Z)-3-O-Allyl-5,6-dideoxy-5-C-hydroxymethyl-1,2-O-isopro-
pylidene-α-
D-ribo-5-enoheptofuranuronate (12) and 3-O-Allyl-5,6-di-
deoxy-1,2-O-isopropylidene-α-
D-ribo-5-enoheptofuranurono-7,5Ј-lac-
tone (14): Wittig olefination of 3-O-allyl-1,2-O-isopropylidene-α--
ribo-hexofuranos-5-ulose (0.163 g, 0.63 mmol) was completed
within 2 h and gave 12 (0.023 g, 11%) as a colorless syrup and 14
(0.087 g, 49%) as a white solid, after purification by CC (EtOAc/
cyclohexane, 1:4). Data for 12: Rf = 0.34 (EtOAc/petroleum ether,
3-O-Allyl-6-deoxy-5-C-hydroxymethyl-1,2-O-isopropylidene-α-L-
ido-heptofuranurono-7,5Ј-lactone (16): 3-O-Allyl-1,2-O-isopropyl-
idene-α--xylo-hexofuranos-5-ulose (0.22 g, 0.86 mmol) gave 16
(0.048 g, 19%) as a colorless oil, after purification by CC (EtOAc/
1
2:3). [α]2D0 = +3 (c = 0.3, in CH2Cl2). H NMR (CDCl3): δ = 6.10
(s, 1 H, 6-H), 5.92–5.81 (m, 1 H, CH allylic), 5.80–5.74 (m, 2 H,
cyclohexane, 1:4). Rf = 0.22 (EtOAc/petroleum ether, 1:4). [α]2D0
=
3
1-H, 4-H), 5.30–5.17 (m, 2 H, =CH2 allylic), 4.64 (t, J1,2 = 3J2,3
=
–21 (c = 1.1, in CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 6.00
4.80 Hz, 1 H, 2-H), 4.35, 4.34, 4.31, 4.30 (part AX of ABX system,
2J5Јa,5Јb = 15.2, 3J5Јa,OH = 3.8 Hz, 5Јa-H), 4.22–4.10 (m, 3J = 7.1 Hz,
3 H, 5Јb-H, CH2CH3), 4.16, 4.14, 4.12, 4.11 (part AX of ABX
3
(s, J1,2 = 3.8 Hz, 1 H, 1-H), 5.94–5.82 (m, 1 H, CH allylic), 5.38–
5.28 (m, 2 H, =CH2 allylic), 4.60 (d, 1 H, 2-H), 4.48, 4.46 (part A
of AB system, J5Јa,5Јb = 10.4 Hz, 5Јa-H, CH2OCO), 4.32, 4.29 (part
2
3
system, Ja,b = 13.4, Ja,H-all = 6.1, a-H, OCH2 allylic), 4.06, 4.04,
3
3
B of AB system, 5Јb-H, CH2OCO), 4.26 (d, J3,4 = 3.5 Hz, 1 H, 3-
4.02, 4.01 (part BX of ABX system, Jb,H-all = 5.6, b-H, OCH2
allylic), 3.81 (dd, J3,4 = 9.1, 1 H, 3-H), 3.36 (t, 1 H, OH), 1.64 (s,
2
3
H), 4.24, 4.22, 4.21, 4.19 (part AX of ABX system, Ja,b = 12.6,
3Ja,H-all = 5.3 Hz, a-H, OCH2 allylic), 4.11 (d, 1 H, 4-H), 4.03, 4.01,
3 H, Me), 1.37 (s, 3 H, Me), 1.29 (t, 3 H, CH2CH3) ppm. 13C NMR
(100 MHz, CDCl3) δ = 165.9 (CO), 151.4 (C-5), 134.4 (CH allylic),
120.3 (C-6), 118.1 (=CH2 allylic), 113.7 (Cq, isopr.), 104.1 (C-1),
81.4 (C-3), 77.9 (C-2), 75.2 (C-4), 71.8 (OCH2 allylic), 63.1 (C-5Ј),
60.5 (CH2CH3), 27.0 (Me), 26.8 (Me), 14.3 (CH2CH3) ppm.
HRMS: calcd. for C16H24O7 [M + H]+ 329.1595, found 329.1610;
calcd. for [M + Na]+ 351.1414, found 351.1403. Data for 14: Rf =
0.18 (EtOAc/petroleum ether, 1:3); m.p. 64–66 °C. [α]2D0 = +65 (c =
1.2, in CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 6.12 (br. s, 1 H,
3
4.00, 3.98 (part BX of ABX system, Jb,H-all = 6.6 Hz, b-H, OCH2
2
allylic), 2.85, 2.81 (part A of AB system, J6a,6b = 17.4 Hz, 6a-H),
2.61, 2.57 (part B of AB system, 6b-H), 1.50 (s, 3 H, Me), 1.34 (s,
3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.1 (CO),
132.7 (CH allylic), 119.8 (=CH2 allylic), 112.3 (Cq, isopr.), 105.2
(C-1), 82.7 (C-4), 81.9 (C-2), 81.2 (C-3), 77.2 (C-5Ј), 76.8 (C-5),
71.2 (OCH2 allylic), 40.8 (C-6), 26.9 (Me), 26.3 (Me) ppm. HRMS:
calcd. for C14H20O7 [M + H]+ 301.1282, found 301.1287.
3
6-H), 5.98–5.86 (m, 1 H, CH allylic), 5.85 (d, J1,2 = 3.5 Hz, 1 H,
3-Deoxy-3-C-[(E)-(ethoxycarbonyl)methylene]-1,2-O-isopropylidene-
1-H), 5.37–5.25 (m, 2 H, =CH2 allylic), 4.94, 4.89 (part AX of ABX 5,6-di-O-pivaloyl-α-
D-ribo-hexofuranose (19a) and 3-Deoxy-3-C-
6140
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6134–6143

Carbohydrates Containing α,β-Unsaturated γ-Lactones
[(E)-(ethoxycarbonyl)methylene]-1,2-O-isopropylidene-6-O-pivaloyl-
furanose[18] (0.11 g, 0.33 mmol) in MeOH (1.8 mL) was added Am-
berlite IR-120 H+ resin (35 mg). The mixture was moderately
stirred under reflux overnight. After filtration of the resin and evap-
α-
D-ribo-hexofuranose (19b): To a solution of 3-deoxy-3-C-[(E)-
(ethoxycarbonyl)methylene]-1,2-O-isopropylidene-α--ribo-hexofu-
ranose (66 mg, 0.23 mmol) in dry pyridine (1 mL) at 0 °C was oration of the solvent, the crude was purified by CC on silica gel
added a solution of pivaloyl chloride (0.25 mmol, 0.03 mL) in dry
CH2Cl2 (0.4 mL), under N2. The whole solution was kept whilst
stirring at 0 °C for 1 h. The solvent was then removed under vac-
uum. The residue was poured into water (10 mL) and extracted
with CH2Cl2 (3ϫ5 mL). Combined organic layers were washed
with a sat. aq. NaHCO3 solution, water and brine, and dried with
MgSO4. After filtration and evaporation of the solvent, the residue
was purified by column chromatography (EtOAc/petroleum ether,
1:4) to afford the mono-O-pivaloyl derivative 19 (69 mg, 81%) and
the di-O-pivaloyl derivative 20 (6.5 mg, 6.8%) derivatives as color-
less oils. Data for 19: Rf = 0.16 (EtOAc/petroleum ether, 1:4).
using AcOEt as eluent to afford 22 (60 mg, 90%) as a white solid.
Method B: Alternatively, an analogous procedure using Dowex-
50W (H+ form) resin led the reaction to completion within 2 h.
After filtration of the resin and evaporation of the solvent, com-
pound 22 was crystallized from AcOEt (yield 57 %), Rf = 0.22
(EtOAc), m.p. 168–174 °C. [α]2D0 = +192 (c = 0.9, MeOH). 1H
3
NMR (400 MHz, [D6]DMSO) δ = 7.56 (d, J = 5.6, 1β-OH), 7.04
3
(d, 3J = 4.6, 1α-OH), 6.00 (d, J = 5.8, 4β-OH), 5.95–5.87 (m, 3Јα-
3
H, 3Јβ-H, 4α-OH), 5.47 (t, 1α-H), 4.96 (d, J1,2(α) = 4.1, 2α-H),
4.89 (t, 6β-OH), 4.79 (t, 6α-OH), 4.65 (d, 3J1,2(β) = 7.1, 2β-H), 4.37–
3
2
4.30 (m, 1β-H, 4α-H, 4β-H), 3.79–3.52 (m, J5,6a(β) = 5.3, J6a,6b(β)
1
[α]2D0 = +189 (c = 1.0, CH2Cl2). H NMR (400 MHz, CDCl3): δ =
3
2
= 12.1, J5,6a(α) = 5.3, J6a,6b(α) = 11.6, 6aα-H, 6aβ-H, 6bα-H, 6bβ-
H, 5α-H), 3.12 (ddd, 5β-H) ppm. 13C NMR (100 MHz, [D6]-
DMSO) δ = 172.9 (CO), 171.1 (C-3α), 111.7 (C-3Јα, C-3Јβ), 98.7
(C-1β), 90.4 (C-1α), 82.0 (C-2β), 80.2 (C-5β), 78.6 (C-2α), 74.4 (C-
5α), 66.1 (C-4β), 65.7 (C-4α), 60.1 (C-6a, C-6β) ppm. HRMS:
calcd. for C8H10O6 [M + H]+ 203.0550, found 203.0550; calcd. for
[M + Na]+ 225.0370, found 225.0369; calcd. for [M + K]+ 241.0109,
found 241.0109. C8H10O6 (202.16): C 47.53, H 4.99; found C 47.60,
H 4.90.
3
6.25 (t, J2,3Ј ≈ J3Ј,4 ≈ 1.9, 1 H, 3Ј-H), 5.91 (d, J1,2 = 4.8, 1-H), 5.66
4
4
3
(dt, J2,4 ≈ J3Ј,4, J4,5 = 5.9, 1 H, 4-H), 5.16 (dt, 1 H, 2-H), 4.27–
4.16 (m, 3J5,6a = 3.6, 2J6a,6b = 11.7, 3 H, 6a-H, CH2CH3), 4.06 (dd,
3J5,6b = 6.1, 1 H, 6b-H), 3.89 (dddd, 1 H, 5-H), 1.43 (s, 3 H, Me),
3
1.40 (s, 3 H, Me), 1.31 (t, J = 7.1, 3 H, CH2CH3), 1.22 (br. s, 9
H, Me, piv.). 13C NMR (100 MHz, CDCl3) δ = 178.8 (CO, piv.),
166.6 (CO), 158.0 (C-3), 118.9 (C-3Ј), 113.9 (Cq, isopr.), 103.7 (C-
1), 81.8 (C-2), 80.7 (C-4), 73.0 (C-5), 65.3 (C-6), 61.3 (CH2CH3),
39.0 (Cq, piv.), 28.0 (Me, isopr.), 27.9 (Me, isopr.), 27.3 (Me, piv.),
14.2 (CH2CH3) ppm. HRMS: calcd. for C18H28O8 [M + Na]+
395.1677, found 395.1687. Data for 20: Rf = 0.61 (EtOAc/petro-
leum ether, 2:3). [α]2D0 = +18 (c = 0.3, CH2Cl2). 1H NMR
1,4,6-Tri-O-acetyl-3-C-(carboxymethylene)-3-deoxy-α,β-D-ribo-
hexopyranose-3Ј,2-lactone (23): To a solution of 3-C-(carboxy-
methylene)-3-deoxy--ribo-hexopyranose-3Ј,2-lactone (68 mg,
0.34 mmol) in pyridine (2 mL), was added acetic anhydride (1 mL)
and the mixture was stirred at room temp. for 5 min. After coevap-
oration with toluene (3ϫ), the crude was purified by column
chromatography on silica gel (EtOAc/petroleum ether, 1:1) to af-
ford 23 (94 mg, 85%) as a colorless oil. Rf = 0.32 (EtOAc/petro-
leum ether, 1:1). [α]2D0 = +178 (c = 1.2, CH2Cl2). 1H NMR
4
4
(400 MHz, CDCl3) δ = 6.19 (t, J2,3Ј ≈ J3Ј,4 ≈ 1.9, 1 H, 3Ј-H), 5.89
3
4
4
3
(d, J1,2 = 4.7, 1-H), 5.79 (dt, J2,4 ≈ J3Ј,4, J4,5 = 4.1, 1 H, 4-H)
3
5.25 (ddd, 5-H), 5.12 (dt, 1 H, 2-H), 4.29–4.17 (m, J5,6a = 3.8,
2J6a,6b = 11.7, 3 H, 6a-H, CH2CH3), 4.10, 4.08, 4.07, 4.05 (part BX
of ABX system, 3J5,6b = 7.6, 1 H, 6b-H), 1.42 (s, 3 H, Me), 1.38 (s,
3
3 H, Me), 1.29 (t, 3 H, J = 7.1, CH2CH3), 1.24 (br. s, 9 H, Me,
piv.), 1.18 (br. s, 9 H, Me, piv.) ppm. 13C NMR (100 MHz, CDCl3)
δ = 177.6 (CO, piv.), 165.0 (CO), 156.4 (C-3), 119.3 (C-3Ј), 113.8
(Cq, isopr.), 103.9 (C-1), 81.6 (C-2), 79.5 (C-4), 72.9 (C-5), 62.8 (C-
6), 61.0 (CH2CH3), 38.9 (Cq, piv.), 38.6 (Cq, piv.), 28.0 (Me, isopr.),
27.9 (Me, isopr.), 27.3 (Me, piv.), 27.2 (Me, piv.), 14.2 (CH2CH3)
ppm. HRMS: calcd. for C23H36O9 [M + H]+ 457.2432, found
457.2446; calcd. for [M + Na]+ 479.2252, found 479.2267.
3
(400 MHz,CDCl3) δ = 6.60 (d, H-1α, J1,2 = 4.6), 6.02–5.96 (m,
3
3
3Јα-H, 3Јβ-H), 5.71 (dd, J3Ј,4(α) = 1.52, J4,5(α) = 9.6, 4α-H), 5.66
3
3
3
(dd, J3Ј,4(β) = 1.52, J4,5(β) = 9.6, 4α-H), 5.40 (d, J1,2(β) = 7.6, 1β-
3
3
H), 5.10 (dd, J2,3Ј(α) = 1.5, 2α-H), 4.90 (dd, J2,3Ј(β) = 1.5, 2β-H),
4.40–4.32 (m, 6aα-H, 6aβ-H) 4.24 (t, 6bα-H, 6bβ-H), 4.00 (ddd,
5α-H), 3.77 (ddd, 5β-H), 2.22 (s, Me, Ac, α, Me, Ac, β), 2.21 (s,
Me, Ac, β), 2.11 (s, Me, Ac, α, Me, Ac, β), 2.09 (s, Me, Ac, α)
ppm.13C NMR (100 MHz CDCl3) δ = 171.0 (CO, Ac, α), 170.6
(CO, Ac, β, CO, lact., α, CO, lact., β), 169.1 (CO, Ac, β), 169.1
(CO, Ac, α), 168.7 (CO, Ac, β), 168.2 (CO, Ac, α), 163.2 (C-3β),
161.6 (C-3α), 115.3 (C-3Јα), 114.7 (C-3Јβ), 95.4 (C-1β), 88.8 (C-
1α), 78.9 (C-2β), 76.4 (C-2α), 76.2 (C-5β), 71.9 (C-5α), 66.4 (C-4β),
66.0 (C-4α), 61.4 (C-6α), 61.3 (C-6β), 20.8, 20.7, 20.7, 20.5 (Me,
Ac) ppm. HRMS: calcd. for C14H16O9 [M + H]+ 329.0867, found
329.0864; calcd. for [M + Na]+ 351.0687, found 351.0690; calcd.
for [M + K]+ 367.0426, found 367.0417.
3-C-(Carboxymethylene)-3-deoxy-6-O-pivaloyl-α-D-ribo-hexo-
pyranose-3Ј,4-lactone (21): A solution of 3-deoxy-3-C-[(E)-(ethoxy-
carbonyl)methylene]-1,2-O-isopropylidene-6-O-Piv-α--ribo-hexo-
furanose (62 mg, 0.17 mmol) in 70% aq. AcOH (1.46 mL) was
stirred under reflux for 1 h 45 min. The solvent was coevaporated
with toluene (3ϫ) and the crude was purified by column
chromatography on silica gel (EtOAc/petroleum ether, 3:2) to af-
ford 21 (28 mg, 58%) as a colorless oil. Rf = 0.21 (EtOAc/petro-
leum ether, 4:1). [α]2D0 = –5 (c = 0.8, CH2Cl2). 1H NMR (400 MHz,
3
CDCl3, α anomer) δ = 6.15 (br. s, 3Ј-H), 5.50 (d, J1,2 = 3.8, 1-H),
Methyl 3-C-(Carboxymethylene)-3-deoxy-α,β-D-ribo-hexopyrano-
4.76 (d, J4,5 = 9.2, 4-H), 4.59 (br. d, 2-H), 4.54, 4.53, 4.51, 4.50
side-3Ј,2-lactone (24): To a solution of 3-deoxy-3-C-[(Z)-(ethoxy-
carbonyl)methylene]-1,2:5,6-di-O-isopropylidene-α--ribo-hexofur-
anose[18] (0.14 g, 0.43 mmol) in MeOH (2 mL) was added Dowex-
50W (H+ form) resin (42 mg). The mixture was stirred under reflux
overnight. After filtration of the resin and evaporation of the sol-
vent, the crude was purified by CC on silica gel (EtOAc/petroleum
ether, 7:3) to afford 24 (52 mg, 57%) as a colorless oil. Rf = 0.15
(EtOAc/petroleum ether, 7:3). [α]2D0 = +14 (c = 0.5, CH2Cl2). 1H
3
2
(part AX of ABX system, J5,6a = 2.5, J6a,6b = 12.2, 6a-H), 4.30,
3
4.29, 4.27, 4.26 (part BX of ABX system, J5,6b = 4.6, 6b-H), 3.93
(ddd, 5-H), 1.22 (s, Me, piv.). 13C NMR (100 MHz, CDCl3, α an-
omer) δ = 178.7 (CO, piv.), 172.4 (CO, lact.), 168.8 (C-3), 114.8 (C-
3Ј), 92.9 (C-1), 76.9 (C-4), 71.4 (C-5), 69.1 (C-2), 62.9 (C-4β), (C-
6), 39.2 (Cq, piv.), 27.3 (Me, piv.) ppm. HRMS: calcd. for
C13H18O7 [M + H]+ 287.1125, found 287.1134; calcd. for
[M + Na]+ 309.0945, found 309.0953.
4
NMR (400 MHz, [D6]acetone) δ = 5.98 (t, 1 H, 3Јβ-H), 5.92 (t, J
3
3-C-(Carboxymethylene)-3-deoxy-
D-ribo-hexopyranose-3Ј,2-lactone
= 1.5, 1 H, 3Јα-H), 5.24 (d, J = 6.3, 1 H, 4β-OH), 5.18–5.12 (m,
3
(22). Method A: To a solution of 3-deoxy-3-C-[(Z)-(ethoxy-
carbonyl)methylene]-1,2:5,6-di-O-isopropylidene-α--ribo-hexo-
1α-H, 4α-OH), 4.97 (dd, J1,2(α) = 4.5, 1 H, 2α-H), 4.66–4.57 (m,
3J1,2(β) = 7.3, 4α-H, 4β-H, 2β-H), 4.24 (d, 1β-H), 3.96–3.77 (m, 6aα-
Eur. J. Org. Chem. 2008, 6134–6143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6141

A. P. Rauter et al.
FULL PAPER
H, 6aβ-H, 6bα-H, 6bβ-H), 3.54–3.48 (m, Meβ, 5α-H), 3.41 (s,
5bβ-H) 2.20, 2.16, 2.16, 2.12 (4s, Me, Ac, α,β) ppm. 13C NMR
(CDCl3, 100.62 MHz): δ = 114.9 (C-3Јβ), 114.8 (C-3Јα), 94.7 (C-
Meα), 3.29 (ddd, 5β-H). 13C NMR ([D6]acetone, 100.62 MHz): δ =
173.1 (COα), 172.6 (COβ), 171.9 (C-3β), 170.3 (C-3α), 113.3 (C- 1β), 89.3 (C-1α), 76.0 (C-4β), 75.6 (C-4α), 69.7 (C-2β), 68.5 (C-5β),
3Јβ), 112.8 (C-3Јα), 106.3 (C-1β), 98.5 (C-1α), 81.5 (C-2β), 79.0 (C-
68.3 (C-2α), 65.4 (C-5α), 20.9, 20.8, 20.6, 20.5 (Me, Ac) ppm.
2α), 75.8 (C-5α), 67.6 (C-4β), 67.0 (C-4α), 61.9 (C-6β), 61.8 (C-6α). HRMS: calcd. for C11H12O7 [M + Na]+ 279.0475, found 279.0469.
56.9 (Meβ), 55.3 (Meα) ppm. HRMS: calcd. for C9H12O6
4,6-Di-O-acetyl-2-bromo-2,3-dideoxy-D-erythro-hex-2-enono-1,5-lac-
tone (29)
[M + H]+ 217.0707, found 217.0700; calcd. for [M + Na]+ 239.0526,
found 239.0518.
Method A: The protocol described in ref.[16] was used, except the
number of equivalents of PCC, which was reduced to 2.5, and slight
modifications concerning the work-up procedure. After total con-
sumption of 28, as indicated by TLC, the solvent was evaporated
under reduced pressure. Ethyl ether was added to the residue, in
order to precipitating the CrIII species and the resulting mixture
was filtered through a short Florisil pad. The filtrate was concen-
trated in vacuo and the crude was purified by column chromatog-
raphy on silica gel (EtOAc/petroleum ether, 3:7) to afford 29 in
1,4,6-Tri-O-acetyl-3-C-[(R)-(carboxy)hydroxymethyl]-α-
pyranose-3Ј,2-lactone (25a) and 1,4,6-Tri-O-acetyl-3-C-[(R)-(car-
boxy)hydroxymethyl]-β- -glucopyranose-3Ј,2-lactone (25b): To a
D-gluco-
D
solution of 1,4,6-tri-O-acetyl-3-C-(carboxymethylene)-3-deoxy-α,β-
-ribo-hexopyranose-3Ј,2-lactone (94 mg, 0.29 mmol) in pyridine
(2.3 mL), was added osmium tetroxide (97 mg, 0.38 mmol) and the
mixture was stirred at room temp. for 15 min. Saturated NaHSO3
solution (9 mL) and pyridine (3 mL) were added and the whole
mixture was kept on stirring within 5 min to cleave the osmium
complex. After extraction with CHCl3 (3ϫ15 mL), the combined
organic layers were washed with water and dried with Na2SO4. Af-
ter filtration and evaporation of the solvent, the residue was puri-
fied by column chromatography (EtOAc/, petroleum ether, 2:3) to
afford the α-anomer 25a (33 mg, 33 %) and the β-anomer 25b
(23 mg, 23%) as white solids. Data for 25a: Rf = 0.27 (EtOAc/
petroleum ether, 2:3); m.p. 181.1–183.2 °C. [α]2D0 = +87 (c = 2.0,
1
43% yield (0.24 g, starting from 0.5 g of 28) as a colorless oil. H
NMR spectroscopic data was in fully agreement with that re-
ported.[16]
Method B: The oxidation step was carried out as follows. To the
residue obtained from the first step in dichloromethane (6 mL), was
added a mixture of pyridinium dichromate (1.38 g, 3.66 mmol) and
acetic anhydride (1.4 mL, 14.8 mmol) in dichloromethane (15 mL)
at room temp. under argon. The whole mixture was stirred at room
temp. for 30 h. After a similar work up than that described above
and purification by column chromatography, compound 29 was ob-
tained in 31% yield (345 mg starting from 1 g of 28).
1
3
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 6.43 (d, J1,2 = 5.3, 1
3
H, 1-H), 5.03 (d, J4,5 = 10.4, 1 H, 4-H), 4.69 (s, 1 H, OH), 4.67–
4.63 (m, 2 H, 2-H, 3Ј-H), 4.37, 4.36, 4.35, 4.33 (part AX of ABX
system, 3J5,6a = 4.1, 2J6a,6b = 12.5, 1 H, 6a-H), 4.24, 4.24, 4.22, 4.21
Biological Assays
3
(part BX of ABX system, J5,6b = 2.3, 1 H, 6b-H), 4.07 (ddd, 1 H,
The susceptibility of microorganisms to the unsaturated lactones
13, 14, 22, 23, 29, 30 and 31 was evaluated by the disk diffusion
method according to the standard procedure CLSI (Clinical Labo-
ratory Standards Institute/National Committee for Clinical Labo-
ratory Standards).[19,20] The microorganisms used in the tests be-
long to the American Type Culture Collection (ATCC) and Cen-
traalbureau voor Schimmelcultures (CBS) collections, from United
States and The Netherlands, respectively. Additional fungi kept in
our lab were also used. The group of bacteria chosen for the study
consisted of Gram-negative strains such as Escherichia coli (ATCC
8739) and Pseudomonas aeruginosa (ATCC 27853) and the follow-
ing Gram-positive bacteria: Bacillus cereus (ATCC 11778), Bacillus
subtilis (ATCC 6633), Enterococcus faecalis (ATCC 29212) and
Staphylococcus aureus (ATCC 25923). For the antifungal bioassays,
six fungi were tested: Botrytis spp., Candida albicans (ATCC
10231), Colletotrichum coffeanum (CBS 396.67), Fusarium culmo-
rum (CBS 129.73), Pyricularia oryzae (CBS 433.70), and Rhizopus
spp. The culture medium and incubation temperature used for fun-
gal growth was Potato Dextrose Agar and 25 °C, whereas for bacte-
ria, Nutrient Agar incubated at 37 °C was used. Paper disks of
6.4 mm were placed on the agar and the solution of each substance
(300 µg) in DMSO (15 µL) was applied on each disk. Chloram-
phenicol was used as control for all bacteria tested and C. albicans,
whereas actidione was used for the filamentous fungi. After incu-
bation, the nearest diameter of the inhibition zone was measured.
Zones less than 15 mm in diameter and uniform growth in the dish
were considered indicative of weak antimicrobial activity; 15–20,
moderate activity. Each sample was tested in three equivalent ex-
periments.
5-H), 2.72–2.67 (m, 1 H, OH), 2.17 (s, 3 H, Ac), 2.14 (s, 3 H, Ac),
2.11 (s, 3 H, Ac),13C NMR (100 MHz, CDCl3) δ = 87.5 (C-1), 77.7
(C-2), 72.6 (C-4), 69.6 (C-3Ј), 67.0 (C-5), 61.9 (C-6), 20.9, 20.8, 20.7
(3 ϫ CH3, Ac) ppm. HRMS: calcd. for C1 4H18 O1 1 [M +
Na]+ 385.0741, found 385.0753. Data for 25b: Rf = 0.33 (EtOAc/
petroleum ether, 2:3); m.p. 139–140.7 °C. [α]2D0 = +35 (c = 1.1,
1
3
CH2Cl2). H NMR (400 MHz, CDCl3) δ = 5.54 (d, J1,2 = 8.4, 1
3
H, 1-H), 5.00 (d, J4,5 = 10.4, 1 H, 4-H), 4.63 (s, 1 H, OH), 4.52
(d, 1 H, 3Ј-H), 4.46 (d, 1 H, 2-H), 4.36, 4.35, 4.34, 4.33 (part AX
3
2
of ABX system, J5,6a = 4.8, J6a,6b = 12.5, 1 H, 6a-H), 4.27, 4.25
3
(part BX of ABX system, J5,6b = 2.3, 1 H, 6b-H), 3.90 (ddd, 1 H,
5-H), 2.81–2.76 (m, 1 H, OH), 2.18 (s, 3 H, Ac), 2.16 (s, 3 H, Ac),
2.11 (s, 3 H, Ac) ppm. 13C NMR (100 MHz, CDCl3, DEPT) δ =
92.6 (C-1), 81.0 (C-2), 73.1 (C-4), 72.7, (C-5), 69.4 (C-3Ј), 62.0 (C-
6), 20.9, 20.8, 20.7 (3ϫCH3, Ac) ppm. HRMS: calcd. for
C14H18O11 [M + Na]+ 385.0741, found 385.0740.
1,2-Di-O-Acetyl-3-C-(carboxymethylene)-3-deoxy-α,β-D-erythro-
pentopyranose-3Ј,2-lactone (27): A solution of 5-O-TBDMS-3-de-
oxy-3-C-[(E)-(ethoxycarbonyl)methylene]-1,2-O-isopropylidene-α-
-erythro-pentofuranose[15] (51 mg, 0.14 mmol) in 70% aq. AcOH
(1.1 mL) was stirred under reflux for 1h 30 min. The solvent was
then removed under vacuum. Acetic anhydride (0.4 mL) and pyr-
idine (0.8 mL) were added to the residue and the mixture was
stirred for 5 min. After coevaporation with toluene, the crude was
purified by column chromatography on silica gel (EtOAc/petroleum
ether, 1:3) to afford the title compound (26.3 mg, 74%) as a color-
less oil. Rf = 0.23 (EtOAc/petroleum ether, 1:3). [α]2D0 = –12 (c =
1
3
0.5, CH2Cl2). H NMR (400 MHz, CDCl3) δ = 6.47 (d, J1,2(α)
=
≈
4
4
4
4.5, 1α-H), 6.05 (t, J2,3Ј(α) ≈ J3Ј,4(α) ≈ 2, 3Јα-H), 5.97 (t, J2,3Ј(β)
4J3Ј,4(β) ≈ 2.0, 3Јβ-H), 5.78 (ddd, 4J2,3Ј(α) = 2.0, 4J2,4(α) = 0.5, 2α-H),
5.69 (ddd, 3J1,2(β) = 7.6, 4J2,3Ј(β) = 2.0, 3J2,4(β) = 0.5, 2β-H), 5.49 (d,
1β-H), 5.02–4.96 (m, 4α-H, 4β-H), 4.57 (dd, 3J4,5a(β) = 6.8, 2J5a,5b(β)
Acknowledgments
3
2
= 10.8, 5aβ-H), 4.36 (dd, J4,5a(α) = 6.8, J5a,5b(α) = 10.8, 5aα-H),
The authors thank Fundação para a Ciência e Tecnologia (FCT)
for financial support of project POCI/AMB/58116/2004, PhD
3.56 (t, 3J4,5b(α) ≈ 2J5a,5b(α) = 10.5, 5bα-H), 3.28 (dd, 3J4,5b(β) = 10.0,
6142
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6134–6143

Carbohydrates Containing α,β-Unsaturated γ-Lactones
[12] P. Radha Krishna, M. Narsingam, J. Comb. Chem. 2007, 9, 62–
69.
[13] M. Bennet, G. B. Gill, G. Pattenden, A. J. Shuker, A. Stapleton,
J. Chem. Soc. Perkin Trans. 1 1991, 929–937.
[14] H.-M. Liu, F. Zhang, J. Zhang, L. Shi, Carbohydr. Res. 2003,
338, 1737–1743.
grants SFRH/BD/39251/2007 (to N. M. X.), SFRH/BD/27614/
2006 (to P. J. A. M.) and network (REDE/1501/REM/2005). The
Deutsche Forschungsgemeinschaft (DFG) (SFB 470, A5) is also
gratefully acknowledged for the support of the collaborative re-
search (N. M. X., A. P. R., J. T.).
[15] N. M. Xavier, A. P. Rauter, Org. Lett. 2007, 9, 3339–3341.
[16] A. P. Rauter, T. Canda, J. Justino, M. I. Ismael, J. A. Figuei-
redo, J. Carbohydr. Chem. 2004, 23, 239–251.
[17] X. Kong, T. B. Grindley, J. Carbohydr. Chem. 1993, 12, 557–
571.
[18] K. Tadano, Y. Idogaki, H. Yamada, T. Suami, J. Org. Chem.
1987, 52, 1201–1210.
[19] A. W. Bauer, W. M. M. Kirby, J. C. Sherris, M. Turck, Am. J.
Clinic. Pathol. 1966, 45, 493–496.
[20] Methods for antimicrobial susceptibility tests for bacteria that
grow aerobically: approved standard, 2nd ed. National Com-
mittee for Clinical Laboratory Standards, document M7-A3,
1993,Villanova, PA.
[21] L. S. Favier, A. O. M. Maria, G. H. Wendel, E. J. Borkowski,
O. S. Giordano, L. Pelzer, C. E. Tonn, J. Ethnopharmacol. 2005,
100, 260–267.
[22] O. Schmidt, Methods Carbohydr. Chem. 1963, 2, 318–325.
[23] A. B. Smith III, R. A. Riviero, K. J. Hale, H. V. Vaccaro, J. Am.
Chem. Soc. 1991, 113, 2092–2112.
[1] A. Husain, S. M. Hasan, S. Lal, M. M. Alam, Indian J. Pharm.
Sci. 2006, 68, 536–538.
[2] D.-H. Li, T.-J. Zhu, H.-B. Liu, Y.-C. Fang, Q.-Q. Gu, W.-M.
Zhu, Arch. Pharm. Res. 2006, 29, 624–626.
[3] F. Cateni, J. Zilic, M. Zacchigna, P. Bonivento, F. Frausin, V.
Scarcia, Eur. J. Med. Chem. 2006, 41, 192–200.
[4] S. Ma, Z. Shi, Z. Yu, Tetrahedron 1999, 55, 12137–12148.
[5] T. Anke, W. Watson, B. Giannetti, W. Steglich, J. Antibiot.
1981, 34, 1271–1277.
[6] N. M. Xavier, A. P. Rauter, Carbohydr. Res. 2008, 343, 1523–
1539.
[7] A. P. Rauter, M. J. Ferreira, J. Font, A. Virgili, M. Figueredo,
J. A. Figueiredo, M. I. Ismael, T. L. Canda, J. Carbohydr.
Chem. 1995, 14, 929–948.
[8] J. Justino, A. P. Rauter, T. Canda, R. Wilkins, E. Matthews,
Pest. Manag. Sci. 2005, 61, 985–990.
[9] A. P. Rauter, J. A. Figueiredo, M. I. Ismael, M. S. Pais, A. G.
Gonzalez, J. Dias, J. B. Barrera, J. Carbohydr. Chem. 1987, 6,
259–272.
[10] A. P. Rauter, J. Figueiredo, M. Ismael, T. Canda, J. Font, M.
Figueredo, Tetrahedron: Asymmetry 2001, 12, 1131–1146.
[11] G. V. M. Sharma, T. Rajendra Prasad, P. Radah Krishna,
M. H. V. Ramana Rao, A. C. Kunwar, J. Carbohydr. Chem.
2002, 21, 501–511.
[24] A. P. Rauter, J. A. Figueiredo, M. I. Ismael, Carbohydr. Res.
1989, 188, 19–24.
[25] T. K. M. Shing, W.-C. Fung, C.-H. Wong, J. Chem. Soc., Chem.
Commun. 1994, 449–450.
Received: August 3, 2008
Published Online: November 10, 2008
Eur. J. Org. Chem. 2008, 6134–6143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6143