Easy and stereoselective approach to α,β-unsaturated γ-lactones fused to pyranoses from furanose scaffolds

Article abstract of DOI:10.1021/ol071351m

The first facile and efficient route to pyranose-fused butenolides from furanose scaffolds, convenient for scaling up production, is described. Wittig olefination of 1,2-O-isopropylidene pentofuranos- or hexofuranos-3-uloses with a resonance-stabilized yl

Full text of DOI:10.1021/ol071351m

ORGANIC
LETTERS
2
007
Vol. 9, No. 17
339-3341
Easy and Stereoselective Approach to
-Unsaturated -Lactones Fused to
Pyranoses from Furanose Scaffolds
3
r
,
â
γ
Nuno M. Xavier and Am e´ lia P. Rauter*
Departamento de Qu ´ı mica e Bioqu ´ı mica/Centro de Qu ´ı mica e Bioqu ´ı mica da
Faculdade de Ci eˆ ncias da UniVersidade de Lisboa, Ed. C8, 5° Piso,
1749-016 Lisboa, Portugal
aprauter@fc.ul.pt
Received June 7, 2007
ABSTRACT
The first facile and efficient route to pyranose-fused butenolides from furanose scaffolds, convenient for scaling up production, is described.
Wittig olefination of 1,2-O-isopropylidene pentofuranos- or hexofuranos-3-uloses with a resonance-stabilized ylide led to the stereoselective
formation of the (Z)-r,â-unsaturated ester. In the presence of acid labile 5-O- or 5,6-di-O-protecting groups, acid hydrolysis of the Wittig
product resulted in isomerization to the pyranose form and spontaneous lactonization to give the target molecules in good overall yield.
The R,â-unsaturated γ-lactone motif is found in many natural
products exhibiting a wide range of biological properties,
namely, phytotoxic, antibacterial, or anti-inflammatory ac-
tivities, with some of those compounds being described as
potential anticancer agents, phospholipase A2 and cyclooxy-
genase inhibitors.1 Furthermore, sugars comprising this
structural moiety have been reported as fungicides or highly
fused R,â-unsaturated γ-lactones, only a few were reported,
and those are fused to six-membered rings at positions 2
2
potent and selective insecticides (Figure 1). This biological
profile encourages the search for efficient and straightforward
approaches leading to new sugar-based butenolides.
Five-membered ring lactones fused to carbohydrate tem-
plates are known mainly in furanose systems. These com-
pounds are useful intermediates for the preparation of
Figure 1. Structure of sugar-based R,â-unsaturated γ-lactones
possessing fungicidal (A) and insecticidal properties (B).
3
nucleosides and branched-chain sugars. Concerning sugar-
4
and 3 of the sugar. However, their synthesis was imple-
(
1) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron 1999, 55, 12137-12148.
mented in a very low global yield using pyranos-2-uloses
as starting materials, which are in general obtained in low
yield by chemical synthesis.
(2) (a) Rauter, A. P.; Ferreira, M. J.; Font, J.; Virgili, A.; Figueredo,
M.; Figueiredo, J. A.; Ismael, M. I.; Canda, T. L. J. Carbohydr. Chem.
995, 14, 929-948. (b) Justino, J.; Rauter, A. P.; Canda, T.; Wilkins, R.;
Matthews, E. Pest Manage. Sci. 2005, 61, 985-990.
3) (a) Velazquez, S.; Jimeno, M. L.; Huss, S.; Balzarini, J.; Camarasa,
1
(
M.-J. J. Org. Chem. 1994, 59, 7661-7670. (b) Gregori, A.; Alib e´ s, R.;
Bourdelande, J. L.; Font, J. Tetrahedron Lett. 1998, 39, 6963-6966. (c)
Alib e´ s, R.; Bourdelande, J. L.; Gregori, A.; Font, J.; Rustullet, A.; Parella,
T. J. Carbohydr. Chem. 2003, 22, 501-111.
(4) (a) Rychlik, M.; Schieberle, P. J. Agric. Food Chem. 1998, 46, 5163-
5169. (b) Bennet, M.; Gill, G. B.; Pattenden, G.; Shuker, A. J.; Stapleton,
A. J. Chem. Soc., Perkin Trans. 1 1991, 1991, 929-937. (c) Liu, H.-M.;
Zhang, F.; Zhang, J.; Shi, L. Carbohydr. Res. 2003, 338, 1737-1743.
1
0.1021/ol071351m CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/26/2007

We report herein an easy and direct method to prepare
pyranose-fused butenolides starting from readily available
pentofuranos- or hexofuranos-3-uloses.
Butenolides fused to hexopyranoses were synthesized as
illustrated in Scheme 1.
chloride at 0 °C. The 6-O-pivaloyl derivative 4 was the major
reaction product, isolated in 57% yield, and the 5,6-di-O-
pivaloyl-protected derivative 5 was obtained in only 27%
yield. However, benzoylation afforded under similar condi-
tions the 5,6-di-O-benzoyl derivative 6 in 83% yield, and
no monoprotection was observed. The 6-O-pivaloyl (Z)-R,â-
unsaturated ester 4 was then submitted to hydrolysis with
aqueous acetic acid (70%) under reflux to give the target
molecule 7 as a mixture of both anomers (R/â ratio 1:0.7)
in 83% yield, resulting from deprotection of the 1,2-
acetonide, furanose ring opening, its closure into the pyranose
form, and intramolecular lactonization, in one single step.
When compound 3b was subjected to similar hydrolytic
conditions, followed by acetylation with acetic anhydride in
pyridine, the triacetate-derived butenolide 9 was obtained
in 78% overall yield (ratio R/â, 2:1). Direct synthesis of the
intermediate deprotected butenolide 8 was successfully and
readily achieved (90% yield) by acid hydrolysis of 2b with
Scheme 1
+
7
IR-120 H resin in refluxing methanol (ratio R/â, 3:1).
Moreover, the butenolide fused to positions 3 and 4 of a
pyranose moiety 10 was successfully obtained by resin acid
hydrolysis of the (E)-R,â-unsaturated ester 2a, which after
acetylation gave the triacetate derivative 11 as a 1:1 mixture
of R,â-anomers in 63% overall yield.
However, no intramolecular cyclization was observed by
removal of the 1,2-O-isopropylidene group of 5, which
comprises a nonacid labile and bulky pivaloyl protecting
group at position 5, being the 1,2-diol 12 isolated in 62%
yield. This result suggests that the formation of butenolides
2
,3-fused to carbohydrates under these experimental condi-
tions is favored in pyranose systems rather than in furanose
forms. Confirmation of this finding was possible when the
8
pentofuranosid-3-ulose 13 (Scheme 2), with the acid-
The 3-keto sugar 1 was obtained by oxidation of com-
mercially available 1,2:5,6-di-O-isopropylidene-R-D-gluco-
furanose with pyridinium dichromate/acetic anhydride in dry
5
a
methylene chloride in nearly quantitative yield, using a
Scheme 2
5
b
different workup than that described in the literature.
It was subjected to Wittig reaction with [(ethoxycarbonyl)-
methylene]triphenylphosphorane in refluxing chloroform,
affording the known (E)- and (Z)-R,â-unsaturated esters 2a
6
and 2b, in 12% yield and 68% yield, respectively. The 5,6-
O-isopropylidene group of 2b was selectively removed by
treatment with aqueous acetic acid (60%) affording the 5,6-
diol 3b in 95% yield.
Selective protection of the primary hydroxyl group of 3b
was successful even when the substrate was treated with
pivaloyl chloride in excess (2.4 equiv) in pyridine/methylene
(5) (a) General experimental procedure for PDC/Ac2O oxidation: A
solution of sugar (3.47 mmol) in dry CH2Cl2 (6 mL) was added to a mixture
of PDC (0.96 g, 2.57 mmol) and Ac2O (1.1 mL, 11.6 mmol) in dry CH2Cl2
(
12 mL) under argon. The resulting mixture was stirred under reflux until
resistant 5-O-pivaloyl group, was used as starting material.
complete conversion, then cooled to rt. The solvent was removed in vacuo.
Diethyl ether (50 mL) was added to the solid residue, and the mixture was
filtered over florisil. The solvent was removed under a vacuum to afford
the 3-keto sugar. (b) Lee, J.-C.; Chang, S.-W.; Liao, C.-C.; Chi, F.-C.; Chen,
C.- S.; Wen, Y.-S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.;
Hung, S.-C. Chem.-Eur. J. 2004, 10, 399-415.
Its synthesis was accomplished by PDC/Ac
2
O oxidation of
9
1,2-O-isopropylidene-5-O-pivaloyl-R-D-xylofuranose in 81%
yield. Wittig olefination of 13 was stereoselective, leading
to the (Z)-R,â-unsaturated ester 14b in 70% yield, with the
(
6) (a) Tronchet, J. M. J.; Gentile, B. Carbohydr. Res. 1975, 44, 23-35.
b) Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987,
2, 1201-1210.
(E)-adduct 14a being isolated in 12% yield. As expected,
(
5
intramolecular lactonization to 16 did not occur by treatment
3340
Org. Lett., Vol. 9, No. 17, 2007

with aqueous acetic acid, resulting in the 1,2-diol 15 in 70%
yield (ratio R/â, 1:0.7), thereby reinforcing that butenolides
are difficult to fuse at positions 2,3 of furanose rings with
this methodology.
The preparation of butenolides 2,3-fused to pentopyranose
units (Scheme 3) was accomplished following a synthetic
the acid labile tert-butyldimethylsilyl group in quantitative
yield, the resulting silyl ether being oxidized to the pento-
1
0
2
furanos-3-ulose derivative 17 with PDC/Ac O for the first
time, in 97% yield. When this 3-keto sugar reacted with
[(ethoxycarbonyl)methylene]triphenylphosphorane in chlo-
roform under reflux, stereoselectivity to the (Z)-R,â-unsatur-
11
ated ester 18b was achieved, with this isomer being isolated
in 81% yield and the (E)-isomer being obtained in 8% yield.
Selective hydrolysis of 18b with aqueous acetic acid (70%)
at 70 °C afforded the desilylated derivative 19 in 85% yield,
Scheme 3
+
and IR-120 H resin promoted total hydrolysis with the
formation of the butenolide 2,3-fused to the pentopyranose
ring 20 in 79% yield in a 1:1 mixture of the R,â-anomers.
In conclusion, a reliable and facile method is described
for the stereoselective synthesis of potentially bioactive
carbohydrate-based butenolides fused to pento- and hexopy-
ranose rings. The synthetic strategy followed herein involves
a short number of steps leading to the target molecules in
good overall yield, with the added value of a possible
regioselective protection for further derivatization. The
readily avaliable starting materials obtained from inexpensive
sugars (D-glucose and D-xylose) and the easy and efficient
experimental procedures make this methodology useful for
the preparation of new sugar derivatives of biological interest.
pathway similar to that described above for the hexopyranose
moieties. The primary hydroxyl group of 1,2-O-isopro-
pylidene-R-D-xylofuranose, easily prepared from D-xylose
and commercially available, was selectively protected with
Acknowledgment. The authors thank Funda c¸ a˜ o para a
Ci eˆ ncia e Tecnologia for the financial support of the project
POCI/AMB/58116/2004.
(
7) Typical experimental procedure for IR-120 H + resin promoted
hydrolysis: To a solution of 3-deoxy-3-C-[(Z)-(ethoxycarbonyl)methylene]-
,2:5,6-di-O-isopropylidene-R-D-ribo-hexofuranose (0.11g, 0.33 mmol) in
Supporting Information Available: New products char-
acterization. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
MeOH (1.8 mL) was added Amberlite IR-120 H + resin (35 mg). The
mixture was moderately stirred under reflux overnight. After filtration of
the resin and evaporation of the solvent, the crude was purified by CC on
silica gel using AcOEt as eluent to afford 8 (60 mg, 90%) as a white solid.
OL071351M
(8) Suhara, Y.; Nihei, K.-i.; Kurihara, M.; Kittaka, A.; Yamaguchi, K.;
Fujishima, T.; Konno, K.; Miyata, N.; Takayama, H. J. Org. Chem. 2001,
(10) Parr, I. B.; Horenstein, B. A. J. Org. Chem. 1997, 62, 7489-7494.
(11) (a) Martinkov a´ , M.; Gonda, J.; Raschmanov a´ , J. Molecules 2006,
11, 564-573. (b) Robins, M. J.; Doboszewski, B.; Victor, A.; Timoshchuk,
V. A.; Peterson, M. A. J. Org. Chem. 2000, 65, 2939-2945.
6
6, 8760-877.
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(
2
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