A Convenient Synthesis of Protoanemonin

Article abstract of DOI:10.1081/SCC-120025181

A new convenient synthesis of protoanemonin (1) starting from 2-deoxy-D-ribose (3) is described. A key step in the sequence is the successive β- and δ-eliminations of 3,5-di-O-p-toluoyl-2-deoxy-D-ribono-1,4-lactone (6).

Full text of DOI:10.1081/SCC-120025181

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A Convenient Synthesis of Protoanemonin
Caroline Crey a , Pascal Dumy a , Jean Lhomme a & Mitsuharu Kotera a
a LEDSS-UMR5616 Associé au CNRS, BP53, Université Joseph Fourier, Grenoble, France
Published online: 16 Aug 2006.
To cite this article: Caroline Crey , Pascal Dumy , Jean Lhomme & Mitsuharu Kotera (2003) A Convenient Synthesis of
Protoanemonin, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:21, 3727-3732, DOI: 10.1081/SCC-120025181
To link to this article: http://dx.doi.org/10.1081/SCC-120025181
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3727–3732, 2003
A Convenient Synthesis of Protoanemonin
Caroline Crey, Pascal Dumy, Jean Lhomme,
*
and Mitsuharu Kotera
LEDSS-UMR5616 Associe au CNRS, BP53, Universite
´ ´
Joseph Fourier, Grenoble, France
ABSTRACT
A new convenient synthesis of protoanemonin (1) starting from 2-
deoxy-D-ribose (3) is described. A key step in the sequence is the
successive b- and ꢀ-eliminations of 3,5-di-O-p-toluoyl-2-deoxy-D-
ribono-1,4-lactone (6).
Key Words: Protoanemonin; Synthesis; b- and ꢀ-eliminations.
Protoanemonin [5-methylene-2-(5H )-furanone 1] is the antibacterial
principle of many plants belonging to Ranunculaceae family (e.g., butter-
cup).[1] This dieno g-lactone is not stable and dimerizes spontaneously to
´
*Correspondence: Mitsuharu Kotera, LEDSS-UMR5616 Associe au CNRS,
BP53, Universite Joseph Fourier, 38041 Grenoble, France; Fax:
´
33.4.76.51.49.46; E-mail: mitsu.kotera@ujf-grenoble.fr.
3727
DOI: 10.1081/SCC-120025181
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3728
Crey et al.
Scheme 1.
Scheme 2.
anemonin 2 via a head to head [2 þ 2] cycloaddition in a regio and stereo-
specific manner.[2,3] Protoanemonin 1 has also shown to be synthetically
useful as a C5 synthon for its reactivity particularly as a dienophile in
Diels-Alder cycloadditions[4–7] (Sch. 1).
On the other hand, protoanemonin [5-methylene-2-(5H )-furanone 1]
is the by-product resulting from the cleavage of the 2-deoxyribonolactone
lesion in DNA.[8–11] This abasic lesion is produced in a variety of DNA
oxidative damaging processes including UV light and g-irradiation or the
action of chemical agents such as the ene-diyne antibiotic neocarzino-
statin or metal complexes. This lactone lesion is alkali labile and is subject
to successive b- and ꢀ-elimination reactions leading to strand cleavage
and formation of protoanemonin 1 (Sch. 2).
Several synthetic methods to prepare protoanemonin (1) have been
reported in the literature.[12–16] In the two methods described earlier,
levulinic acid was used as starting material. Although these methods
have been widely used, they involve several tedious separation steps
and some problems of reproducibility have been reported. More recently,
Font and co-workers developed a method using photo-oxygenation of
5-hydroxymethylfurfuril.

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Synthesis of Protoanemonin
3729
Scheme 3.
In the course of our study of the 2-deoxyribonolactone lesion in
DNA, protoanemonin 1 was required repeatedly as an authentic
sample for analysis.[17,18] Because of the unstability of 1, none of the
above preparative methods was appropriate in this context, we thus
devised a new efficient method to prepare protoanemonin 1 starting
from 2-deoxy-D-ribose 3 (Sch. 3).
The lactone 6 was prepared from 3 using a three step procedure
carried out successively without purification in a 58% overall yield. In
the first stage of the transformation (3–4), glycosilation was achieved with
methanolic hydrogen chloride prepared by adding acetyl chloride to
methanol. The resulting mixture of the methylfuranoside anomers (4)
was acylated by treatment with p-toluoyl chloride in pyridine to give 5.
The lactone 6 was obtained by oxidation of the methoxy sugar 5 by
m-chloroperbenzoic acid in the presence of a catalytic amount of boron
trifluoride etherate. This lactone 6 is a stable crystalline solid and can be
stored at room temperature without special precaution.
Upon treatment of lactone 6 with 5 equiv. of NEt3 at room tempera-
ture overnight, successive b- and ꢀ-eliminations took place cleanly to
afford protoanemonin 1 with 80% yield. The IR and NMR spectra of
1 were identical to those described in the literature.
In summary, we developed a new safe, convenient, and rapid
synthetic entry to protoanemonin 1 by successive b- and ꢀ-eliminations
from the stable lactone 6.
EXPERIMENTAL
All chemicals and solvents were used as purchased. All preparations
were carried out in a hood. Melting points were measured on a

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3730
Crey et al.
REICHERT THERMOVAR apparatus. 1H NMR and 13C NMR
spectra were recorded on BRUKER AV300 spectrometers. NMR
spectra were referenced to the residual solvent peak; chemical shifts ꢀ
in ppm; apparent scalar coupling constants J in Hz. IR spectra were
recorded on Nicolet Impact 400. Elemental analyses were performed by
‘‘Service central d’analyse du CNRS.’’
3,5-Di-O-p-toluoyl-2-deoxy-D-ribono-1,4-lactone (6)
To a solution of 5.0 g (37.0 mmol) of 2-deoxy-D-ribose 3 in MeOH
(60 mL) was added 1% methanolic hydrogen chloride (10 mL; prepared
by adding 1.7 mL of acetyl chloride to 100 mL of MeOH). The reaction
mixture was stirred at room temperature for 25 min and neutralized by
adding solid sodium bicarbonate (2 g). After filtration, the methanol was
removed by repeated coevaporation with pyridine (1 ꢀ 25 mL and
2 ꢀ 10 mL) under reduced pressure. The residual syrup was dissolved in
pyridine (30 mL), cooled to 0ꢁC and p-toluoylchloride (11 mL; 80 mmol)
was added dropwise. The solution was stirred under argon at room
temperature overnight. The reaction mixture was evaporated and diluted
with NaHCO3 saturated aqueous solution and extracted three times with
CH2Cl2. The combined organic layers were washed with NH4Cl
saturated aqueous solution, then with KH2PO4 (5% aqueous solution),
dried on MgSO4 and evaporated.
To the resulting syrup in CH2Cl2 (60 mL) was added BF3-Et2O
(1.6 mL, 10.9 mmol) and mCPBA (13.8 g, 80.0 mmol). The mixture was
stirred overnight under argon. The solution was diluted in NaHCO3
0.5 M and stirred during 15 min. The mixture was extracted with
CH2Cl2 (1 ꢀ 100 mL and 2 ꢀ 50 mL). The combined organic layers were
washed with NaHCO3 0.5 M (50 mL) and dried on MgSO4. After
evaporation and recrystallization from hot AcOEt/cyclohexane (20:80;
v/v) (100 mL), the lactone (6) was obtained as a white crystal in 52%
yield. M.p.: 110–112ꢁC. IR (KBr): ꢁ ¼ 1792, 1719, 1610, 1269, 1174, 1100,
1
753 cmꢂ1. H NMR (300 MHz, CDCl3): ꢀ ¼ 7.89 (m, 4H), 7.25 (m, 4H),
5.59 (m, 1H, H-3), 4.95 (m, 1H, H-4), 4.61 (m, 2H, H-5), 3.18 (dd, 1H,
H-2, J ¼ 18 and 7 Hz), 2.81 (dd, 1H, H-20, J ¼ 18 and 2 Hz), 2.42 (s, 6H,
CH3). 13C NMR (75 MHz, CDCl3): ꢀ ¼ 21.7 (two peaks, CH3), 35.1 (C-2),
63.7 (C-5), 71.7 (C-3), 82.6 (C-4), 125.9, 126.3, 128.4, 129.4 (two peaks),
129.7, 129.8, 144.4, 144.8 (arom C), 165.8, 165.9 (C¼O), 174.0 (C¼O
lactone). Anal. calcd. for C21H20O6: C, 68.47; H, 5.47. Found: C,
68.14; H, 5.58.

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Synthesis of Protoanemonin
3731
Protoanemonin (1)
To a solution of (6) (2.0 g; 5.0 mmol) in CH2Cl2 (25 mL), was added
NEt3 (2.73 g; 27.0 mmol). The mixture was stirred at room temperature
overnight, washed with Na2CO3 1 M (4 ꢀ 20 mL) and dried on molecular
sieves 4 A. Column chromatography on silica gel (pentane/CH2Cl2; 1/2 as
eluent) of the residual syrup afforded pure protoanemonin in 80% yield.
IR (KBr): ꢁ ¼ 1781, 1750, 1647, 1561, 1285, 1122, 1069, 972, 874, 823,
1
727 cmꢂ1. H NMR (300 MHz, CDCl3): ꢀ ¼ 7.41 (d, 1H, H-3, J ¼ 5 Hz),
6.24 (d, 1H, H-2, J ¼ 5 Hz), 5.24 (m, 1H, ¼CHEHZ), 4.90 (d, 1H,
¼CHEHZ, J ¼ 3 Hz). 13C NMR (75 MHz, CDCl3): ꢀ ¼ 98.4 (¼CH2),
122.0 (C-4), 143.9 (C-3), 155.3 (C-5), 170.1 (C-2). Anal. calcd. for
(C5H4O2): C, 62.50; H, 4.20. Found: C, 61.72; H, 4.18.
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Received in the UK November 19, 2002