Efficient preparation of 3-substituted-furan-2(5H)-ones and their direct vinylogous aldol addition

Article abstract of DOI:10.1016/S0040-4020(01)00331-3

The deprotonation of 3-substituted-furan-2(5H)-ones 1, obtained via the hydrolysis of 3-substituted-2,5-dihydro-2,5-dimethoxyfurans, affords in the reaction with both aromatic and aliphatic aldehydes regioselectively the unsaturated 3-substituted 5-(1′-hydroxy)-γ-butyrolactones, such as 4, 5, 6, 7, 8, 9 and 10. The use of Lewis acids allows modulation of the diastereoisomeric ratios. The subsequent reduction, carried out with nickel boride, gives rise to the formation of the corresponding saturated 5-(1′-hydroxy)-γ-butyrolactones, such as 11, 12 and 13.

Full text of DOI:10.1016/S0040-4020(01)00331-3

TETRAHEDRON
Pergamon
Tetrahedron 57 %2001) 4429±4436
Ef®cient preparation of 3-substituted-furan-2ꢀ5H)-ones and their
direct vinylogous aldol addition
Marco Bella,a,b,p Giovanni Piancatellia,p and Antonella Squarciaa
a
Á
Dipartimento di Chimica, Universita `La Sapienza', Piazzale Aldo Moro 5, Box No. 34-Roma 62, 00185 Rome, Italy
bCentro CNR di Studio per la Chimica delle Sostanze Organiche Naturali, Piazzale Aldo Moro 5, Box No. 34-Roma 62, 00185 Rome, Italy
Received 25 October 2000; revised 1 March 2001; accepted 15 March 2001
AbstractÐThe deprotonation of 3-substituted-furan-2%5H)-ones 1, obtained via the hydrolysis of 3-substituted-2,5-dihydro-2,5-dimeth-
oxyfurans, affords in the reaction with both aromatic and aliphatic aldehydes regioselectively the unsaturated 3-substituted 5-%10-hydroxy)-g-
butyrolactones, such as 4, 5, 6, 7, 8, 9 and 10. The use of Lewis acids allows modulation of the diastereoisomeric ratios. The subsequent
reduction, carried out with nickel boride, gives rise to the formation of the corresponding saturated 5-%10-hydroxy)-g-butyrolactones, such as
11, 12 and 13. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
the desired product in low yield, presumably due to the
formation of regioisomers. Employing aromatic aldehydes,
the reaction is reported to be regioselective.5 The anions of
particular butenolides, suitably substituted as methyl
tetronate, 4-methoxyfuran-2%5H)-one, undergo prevalently
functionalization on the C5 with electrophiles.6
Unsaturated and saturated 5-%10-hydroxy)-g-butyrolactones
comprise a very important class of organic compounds both
existing in natural products and in synthetic bioactive
molecules.1
Herein we describe a method for the easy synthesis of
3-substituted-furan-2%5H)-ones 1 %Fig. 1) in which the
phenylselenyl group and halogen atoms act as `protective
groups' for the C3 position that allow speci®c functional-
ization at the C5 position and could then be easily removed
having performed the aldol addition. Butenolides with
halogen substituents on the double bond have been
developed as cytostatics7 and are present in some naturally
occurring rubrolides.8 Furthermore, the preparation of
4-halo- and pseudo-halofuran-2%5H)-ones is described9 as
well as their functionalization with aromatic and vinylic
moieties %Suzuki and Stille coupling),10 but there is a
paucity of general methods which allows us to obtain the
corresponding 3-furan-2%5H)-ones.11,12
Owing to the growing interest in these substances, both
syntheses involving de novo construction of the lactone
ring or the functionalization of butenolides are continously
published in the literature; particularly, there is the
monumental work of Casiraghi and Rassu exploiting the
condensation
of
trimethylsilyloxyfuran
%synthetic
equivalent of the anion of furan-2%5H)-one) with chiral
aldehydes to obtain a large number of useful intermediates
in organic synthesis.2
In strict contrast, only a few authors report the direct
addition of aldehydes to the readily available metal enolates
of furan-2%5H)-ones. This is probabily due to the relatively
low-yielding and time-consuming synthesis of these
systems, but mainly due to the formation of both the C5
and C3 functionalized products in the reaction with electro-
philes. To date, it is known that enolate formation of furan-
2%5H)-one and its condensation with aliphatic aldehydes
gives predominantly %3:1) the C3 functionalized products
as major regioisomer together with the C5 functionalized
product %as a 1:1 syn/anti mixture of diastereoisomers).3
This methodology was employed only once in the literature
in the key step for the preparation of melondrinol,4 affording
Keywords: regioselective aldol reaction; furanones.
Corresponding authors. Tel.: 139-6-4991-3861; fax: 139-6-490631;
e-mail: Giovanni.Piancatelli@uniroma1.it
p
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020%01)00331-3

4430
M. Bella et al. / Tetrahedron 57 62001) 4429±4436
Scheme 1. i: 1 M HClaq, acetone, 2 h, rt, 66%; ii: 63% HBraq, acetone, 2 h, rt, 80%; iii: 37% HClaq, acetone, 2 h, rt, 1cˆ70%, 1bˆ12%.
2. Results and discussion
prefer the use of acetone instead of CH3CN because despite
the lower yield %66% instead of 81%) the only by-product is
the easily separable 1-phenylselenylacetone 3.14
3-Phenylselenylfuran-2%5H)-one 1a was prepared as
previously described13 %acetone, 1 M HCl, 66%) from
3-phenylselenyl-2,5-dihydro-2,5-dimethoxyfuran 2a; we
Compound 1b was obtained as a single product in the
Scheme 2. i: LHMDS, 1.5 equiv., THF, 1 h, 2788C, then Lewis acid, PhCHO, 15 min.
Table 1. Vinylogous aldol condensation of 3-substituted-furan-2%5H)-ones 1 with benzaldehyde
Entry
Starting
materials
Lewis acid
5 syn: 4 anti ratio
Temp. of
addition of the
aldehyde %8C)
Yield %%)
4, 5
6
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
None
1:2
6:1
1:4
1:3.5
1:1
1:6
278
278
278
278
278
278
278
278
20
40
83
70
70
95
70
±
65
70
±
±
±
±
±
±
±
30
15
4
20
15
±
BF3´Et2Oa
Zn%OTf)2
Sn%OTf)2
c
c
BF3´Et2Oa,b
Zn%OTf)2
b,c
None
±
BF3´Et2Oa
BF3´Et2Oa
None
.20:1
.20:1
±
.20:1
3:1
9
10
11
12
278
278
20
BF3´Et2Oa
BF3´Et2Oa
65
70
a
20 equiv. of BF3´Et2O were employed.
1.5 equiv. were used.
Toluene instead of THF was employed as solvent.
c
b

M. Bella et al. / Tetrahedron 57 62001) 4429±4436
4431
Scheme 3. i: LHMDS, 1.5 equiv., THF, 2788C 1 h, then BF3´Et2O, 20 equiv., RCHO: CH3CHyCHCHO and C12H25CHO, 15 min.
Table 2. Vinylogous aldol condensation of furan-2%5H)-ones 1 with crotonaldehyde and tridecyl aldehyde
Entry
Starting materials
Products
Aldehyde
Anti/syn ratio
Yield %%)
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
7a, 8a
9a, 10a
7b, 8b
9b, 10b
7c, 8c
Crotonaldehyde
n-C12H25CHO
Crotonaldehyde
n-C12H25CHO
Crotonaldehyde
n-C12H25CHO
1:1
1:1
1:1
1:2
1:1
1:1
90
90
90
70
85
85
9c, 10c
reaction of 2b with concentrated HBr %acetone, 63% HBraq,
rt, 80%). Using concentrated HCl %acetone, 37% HClaq, rt),
surprisingly we isolated instead 3-chlorofuran-2%5H)-one 1c
%70%) and only in low yields %12%) the desired 3-bromo-
furan-2%5H)-one 1b. This may be due to the formation of 2c
as key intermediate, through an addition of HCl/elimination
of HBr, prior to lactonization %Scheme 1).
7, 10). The presence of BF3´Et2O as Lewis acid in the
reaction medium made it possible to isolate the desired
isomers anti-4b, 4c and syn-5b, 5c. The enolate of the
3-phenylselenylfuran-2%5H)-one 1a is unstable at rt as the
lithiated furan-2%5H)-one,5 while the enolates derived from
3-bromo- and 3-chlorofuran-2%5H)-ones 1b and 1c could be
warmed up to rt without signi®cant decomposition. Adding
benzaldehyde to the lithium enolates of 1b and 1c in the
presence of BF3´Et2O both at rt and at 2788C, the products
were the expected compounds 4b, 4c and 5b, 5c, showing an
excellent diastereoselectivity with a .20:1 syn/anti ratio
%Table 1, entries 8, 9, 11).
Noteworthy, even if the transformation of the 3-substituted-
2,5-dihydro-2,5-dimethoxyfurans into the 3-substituted-
furan-2%5H)-ones has been occasionally reported,15 these
are the only examples in which a single regioisomer is
obtained in such a reaction.
With the long-chain aliphatic aldehyde tridecanal as
electrophile in order to mimic the structure of the natural
The reaction of compound 1a with aromatic aldehydes
%LHMDS, THF, then Lewis acids, PhCHO; Scheme 2 and
Table 1), gave only the C5 functionalization products anti-
4a, and syn-5a; no traces of dialkylated products were
detected even if the reaction was performed with an excess
of base.16 Lewis acids made it possible both to increase
yields and to modulate the diastereoselectivity %from 1:6
anti/syn ratio up to 6:1; Table 1, entries 2, 6).
Table 3. Reduction of unsaturated 3-substituted-5-%10-hydroxy)-g-butyro-
lactones to 5-%10-hydroxy)-g-butyrolactones 11, 12, 13
Entry
Starting material
Products
Yield %%)
1
2
3
4
5
6
7
8
9
4a, 5a
4b, 5b
4c, 5c
7a, 8a
7b, 8b
7c, 8c
9a, 10a
9b, 10b
9c, 10c
11a, 11b
11a, 11b
11a, 11b
12a, 12b
12a, 12b
12a, 12b
13a, 13b
13a, 13b
13a, 13b
90
90
85
70
70
70
80
70
90
In contrast, halogenated compounds 1b and 1c in the reac-
tion without Lewis acids gave only the isomeric 5-%10-
hydroxy)-furan-2%3H)-ones 6b and 6c as an inseparable
3:1 mixture of diastereoisomers %20±30%, Table 1, entries
Scheme 4. i: NiCl2, NaBH4, THF/MeOH, 10 min, 08C.

4432
M. Bella et al. / Tetrahedron 57 62001) 4429±4436
via direct vinylogous aldol condensation of furan-2%5H)-
ones is an alternative methodology with respect to the
Lewis acid-mediated silyloxyfuran condensation with
aldehydes. The diastereoselectivity could be effectively
modulated employing Lewis acids and selecting the experi-
mental conditions; we also describe a new regioselective
method for the preparation of halogenated furan-2%5H)-
ones 1b and 1c. Work is in progress in our group to apply
this reactivity to other electrophiles in light of the greater
nucleophilicity of our lithium enolates compared to the silyl
enol ethers generally used up to now.
4. Experimental
4.1. General experimental
Figure 2. .20:1 syn/anti mixture of 3-chloro-5-%10hydroxy)-furan-2%5H)-
ones: resonance of proton on the C10 after D2O addition.
1H-NMR and 13C-NMR spectra were recorded on a Varian
Gemini 200 spectrometer with CDCl3 as the solvent and as
the internal standard. Coupling constants are quoted in
Hertz %Hz). IR spectra were obtained with a Shimazu IR
435 grating infrared spectrophotometer. Melting points
were determined on a Mettler FP apparatus and are
uncorrected. Yields are given for isolated products after
column chromatography showing a single spot on the
substance muricatacin,17 we obtained a mixture of only the
C5 functionalized compounds with little or no diastereo-
isomeric excesses albeit in good yields %Scheme 3 and
Table 2, entries 2, 4, 6). Employing crotonaldehyde %the
recently isolated sapinofuranones show a similar structural
moiety),18 only the desired 1,2 functionalization products
are formed with no detectable trace of 1,4-conjugate
addition compounds %Table 2, entries 1, 3, 5).
1
TLC plate and no detectable impurities in the H-NMR
spectrum. Compounds 2a,22 2b23 were prepared according
to literature; spectra of compounds 12a, 12b,24 and 13a,
13b25 are in agreement with those previously reported.
LHMDS %1 M solution in hexane), benzaldehyde, tri-
decanal, crotonaldehyde, boron tri¯uoride etherate, zinc%II)
tri¯ate, and tin%II) tri¯ate were used as purchased %Aldrich).
THF and toluene were dried over sodium wire and distilled
prior to use. Hexane, acetone, ethyl acetate, methanol,
diethyl ether, acetic anhydride, pyridine, 63% HBr and
37% HCl solution are analytical grade reagents purchased
from Carlo Erba. Silica gel %230±400 mesh) was purchased
from Merck.
The removal of the double bond and the phenylselenyl
group was accomplished by reaction with NiCl2/NaBH4
%Scheme 4 and Table 3, entries 1, 4, 7). Although it is
already reported that this reagent combination removes
the phenylselenyl group and the conjugate double bonds
separately,19 the one pot procedure applied on all
compounds including halogenated ones %entries 2, 3, 5, 6,
8, 9) gave rise to the desired g-butyrolactones in good
yields. In addition, the side chain double bond of
compounds 7a, 8a, 7b, 8b and 7c, 8c was also hydrogenated
in this procedure %entries 4, 5, 6).
4.1.1. 3-Phenylselenylfuran-2ꢀ5H)-one 1a. To a solution
of 3-phenylselenyl-2,5-dihydro-2,5-dimethoxyfuran 2a
%1.00 g, 3.51 mmol) in acetone %30 mL) placed in an
open-air round-bottomed ¯ask with vigorous stirring, 1 M
HCl solution %1 mL) was added dropwise. The colour of the
solution changed from colourless to light yellow then again
to colourless. The reaction mixture was stirred until no start-
ing material was detectable on TLC %2 h). The reaction
mixture was diluted with ethyl acetate, washed once with
water, the organic layer was dried over anhydrous Na2SO4
and solvent evaporated in vacuo to give an oil that was
puri®ed via ¯ash chromatography on silica gel %15 g, eluant
hexane/ethyl acetate 9:1, then hexane/ethyl acetate 2:1) to
give 553 mg of compound 1a %2.32 mmol, 66%) as pale
Relative syn/anti stereochemistry was assigned on the
analysis of 1H-NMR spectra; the syn diastereoisomers
have a larger value of the coupling constant J5±1' between
the protons on the C5 and the C10 and a lower chemical shift
of the protons on the C1 and C3 if compared with the corre-
sponding anti isomers %Fig. 2).20 A con®rmation of our
assignments is also the chemical correlation of the
compound syn-5b with the known syn-14 %Scheme 5).21
3. Conclusions
Our synthesis of 10-hydroxysubstituted-g-butyrolactones
Scheme 5. i: NiCl2, NaBH4, THF/MeOH, 10 min, rt, 90%; ii: Ac2O, Py, 24 h, rt, 85%.

M. Bella et al. / Tetrahedron 57 62001) 4429±4436
4433
yellow solid [mpˆ55±588C %ether/hexane). Lit.14: 57±
588C], and 80 mg of compound 326 %10%) as an oil.
171.28 %CO). IR n %CHCl3)/cm21: 3350; 3110; 1756;
1630; 1210. HRMS %FAB) 346.0100 %C17H14O3Se requires
346.0108).
4.1.2. 3-Bromofuran-2ꢀ5H)-one 1b. The same experimental
procedure for the preparation of 1a, starting from 2b %1.00 g,
4.78 mmol) gave 1b %3.83 mmol, 624 mg, 80%) employing
63% HBr solution %7 mL). White solid, mpˆ54±588C %ether/
hexane). Lit.11a: 56±588C. 1H-NMR, d %CDCl3): 4.86 %2H, d,
Jˆ2 Hz, CH2CHy); 7.62 %1H, t, Jˆ2 Hz, CHyC).13C-NMR,
d %CDCl3): 71.90 %CH2CHy); 113.70 %CHyC); 149.59
%CHyC); 169.39 %CO).
4.2.3. syn-ꢀ10Rp, 5Rp)-3-Bromo-10-hydroxybenzylfuran-
2ꢀ5H)-one 5b. White solid, mpˆ100±1028C %ether/
hexane): [Found: C, 49.32; H, 3.16. C11H9O3Br requires
1
C, 49.26; H, 3.38%]. H-NMR, d %CDCl3): 3.0 %1H, br,
disappears after D2O addition, CHOH); 4.76 %1H, d,
Jˆ6.8 Hz, CHOH); 5.11 %1H, dd, J1ˆ6.8 Hz, J2ˆ1.8 Hz,
CHCHy); 7.24 %1H, d, Jˆ1.8 Hz, CHCHy); 7.4 %5H, m,
Ph). 13C-NMR,
d
%CDCl3): 73.12 %CHOH); 86.12
4.1.3. 3-Chlorofuran-2ꢀ5H)-one 1c. The same experimental
procedure for the preparation of 1a starting from 2b %1.00 g
4.78 mmol) gave 1c as a white solid %3.35 mmol, 360 mg,
70%) and 1b %0.57 mmol, 93 mg, 12%) employing 37% HCl
solution %7 mL). Mpˆ23±268C %ether/hexane). Lit.11b: 25±
278C. 1H-NMR, d %CDCl3): 4.89 %2H, d, Jˆ2 Hz, CH2CHy);
7.41 %1H, t, Jˆ2 Hz, CHyC). 13C-NMR, d %CDCl3): 70.24
%CH2CHy); 125.25 %CHyC); 144.99 %CHyC); 168.79 %CO).
%CHCHy); 114.47; 126.83; 128.98; 129.27 %Ph); 137.40
%CHyC); 149.92 %CHyC); 168.17 %CO). IR n %CHCl3)/
cm21: 3615; 3100; 1775; 1625; 1200. HRMS %FAB)
267.97355 %C11H9O3Br requires 267.97350).
4.2.4. 3-Bromo-10-hydroxybenzylfuran-2ꢀ3H)-one 6b.
Inseparable 3:1 mixture of diastereoisomers. Colourless
oil: [Found: C, 49.36; H, 3.51. C11H9O3Br requires C,
1
49.26; H, 3.38%]. H-NMR, d %CDCl3): %major diastero-
isomer) 2.5 %1H, br, disappears after D2O addition,
CHOH); 5.10 %2H, s,); 7.4 %6H, m). 13C-NMR, d %CDCl3):
%major diasteroisomer) 73.11; 85.90; 114.40; 126.16;
128.82; 129.00; 137.86; 149.50; 168.16 %CO). IR n
%CHCl3)/cm21: 3640; 3010; 1770; 1645; 1210. HRMS
%FAB) 267.97353 %C11H9O3Br requires 267.97350).
4.2. General procedure for the direct aldol condensation
of 1 with aldehydes
To a cooled %2788C) solution of 1a %0.31 mmol) in dry THF
%2 mL) under argon, LHMDS %0.32 mL, 1 M solution in
THF, 1.05 equiv.) was added dropwise. The reaction
mixture was stirred at this temperature for 45 min. A THF
%1 mL) solution of Lewis acid %see Table 1) was added also
at 2788C under argon and after 10 min a THF %1 mL)
solution of aldehyde %1.5 equiv.). After 5 min, NH4Cl
%2 M solution, 5 mL) was added dropwise and the mixture
diluted with ethyl acetate %10 mL). The organic layer was
washed with brine %3 mL), dried %Na2SO4) and solvent
evaporated in vacuo to give an oil. This was puri®ed by
¯ash chromatography on silica gel %3 g, eluant hexane/
ethyl acetate 9:1 then hexane/ethyl acetate 6:1) to give
pure compounds as depicted in Table 1.
4.2.5. anti-ꢀ10Rp, 5Sp)-3-Chloro-10-hydroxybenzylfuran-
2ꢀ5H)-one 4c. Dense pale yellow oil: [Found: C, 58.95;
H, 4.23. C11H9O3Cl requires C, 58.81; H, 4.04%]. 1H-
NMR, d %CDCl3): 2.5 %1H, br, disappears after D2O
addition, CHOH); 4.90 %1H, d, Jˆ2 Hz, CHOH); 5.10
%1H, dd, J1ˆ2 Hz, J2ˆ1.8 Hz, CHCHy); 7.37 %1H, d,
Jˆ1.8 Hz, CHCHy); 7.4 %5H, m, Ph). 13C-NMR, d
%CDCl3):): 75.37 %CHOH); 84.30 %CHCHy); 126.09;
127.80; 128.98; 129.27 %Ph); 140.36 %CHyC); 145.81
%CHyC); 170.01 %CO). IR n %CHCl3)/cm21: 3615; 3120;
1770; 1635; 1090. HRMS %FAB) 224.02406 %C11H9O3Cl
requires 224.02402).
4.2.1. anti-ꢀ10Rp, 5Sp)-10-Hydroxybenzyl-3-phenylselenyl-
furan-2ꢀ5H)-one 4a. Dense pale yellow oil: [Found: C,
58.90; H, 4.13. C17H14O3Se requires C, 58.96; H, 4.08%].
1H-NMR, d %CDCl3): 3.0 %1H, br, disappears after D2O
addition, CHOH); 4.97 %1H, d, Jˆ4.4 Hz, CHOH); 5.03
%1H, dd, J1ˆ4.4 Hz, J2ˆ1.8 Hz, CHCHy); 6.73 %1H, d,
Jˆ1.8 Hz, CHCHy); 7.2±7.5 %8H, m, Ph); 7.5±7.6 %2H,
m, Ph). 13C-NMR, d %CDCl3): 73.91 %CHOH); 87.28
%CHCHy); 126.0, 126.7, 127.0, 127.5, 127.7, 128.3,
128.7, 130.0 %2 Ph); 135.56 %CHyC); 148.65 %CHyC);
171.28 %CO). IR n %CHCl3)/cm21: 3350; 3110; 1756;
1630; 1210. HRMS %FAB) 346.01076 %C17H14O3Se requires
346.01081).
4.2.6. syn-ꢀ10Rp, 5Rp)-3-Chloro-10-hydroxybenzylfuran-
2ꢀ5H)-one 5c. White solid, mpˆ87±898C %ether/hexane):
[Found: C, 58.79; H, 4.13. C11H9O3Cl requires C, 58.81;
1
H, 4.04%]. H-NMR, d %CDCl3): 2.5 %1H, br, disappears
after D2O addition, CHOH); 4.74 %1H, d, Jˆ6.8 Hz,
CHOH); 5.13 %1H, dd, J1ˆ6.8 Hz, J2ˆ1.8 Hz, CHCHy);
7.05 %1H, d, Jˆ1.8 Hz, CHCHy); 7.4 %5H, m, Ph). 13C-
NMR, d %CDCl3): 73.12 %CHOH); 84.36 %CHCHy);
126.09; 126.80; 128.98; 129.27 %Ph); 137.36 %CHyC);
144.81 %CHyC); 167.50 %CO). IR n %CHCl3)/cm21: 3615;
3120; 1770; 1635; 1090. HRMS %FAB) 224.02406
%C11H9O3Cl requires 224.02402).
4.2.2. syn-ꢀ10Rp, 5Rp)-10-Hydroxybenzyl-3-phenylselenyl-
furan-2ꢀ5H)-one 5a. Dense pale yellow oil: [Found: C,
58.98; H, 4.03. C17H14O3Se requires C, 58.96; H, 4.08%].
1H-NMR, d %CDCl3): 3.0 %1H, br, disappears after D2O
addition, CHOH); 4.69 %1H, d, Jˆ6.4 Hz, CHOH); 5.01
%1H, dd, J1ˆ6.4 Hz, J2ˆ1.8 Hz, CHCHy); 6.52 %1H, d,
Jˆ1.8 Hz, CHCHy); 7.2±7.5 %8H, m, Ph); 7.5±7.6 %2H,
m, Ph). 13C-NMR, d %CDCl3): 75.67 %CHOH); 87.45
%CHCHy); 126.0, 126.5, 127.1, 128.2, 128.8, 129.3,
129.8, 130.0 %2 Ph); 135.73 %CHyC); 146.99 %CHy);
4.2.7. 3-Chloro-10-hydroxybenzylfuran-2ꢀ3H)-one 6c.
Inseparable 3:1 mixture of diastereoisomers. Colourless
oil: [Found: C, 58.72; H, 4.20. C11H9O3Cl requires C,
1
58.81; H, 4.04%]. H-NMR, d %CDCl3): %minor diastero-
isomer): 3.0 %1H, br, disappears after D2O addition,
CHOH); 5.07 %1H, s, CHOH); 5.13 %1H, d, Jˆ1.8 Hz,
CHCHy); 7.21 %1H, d Jˆ1.8 Hz, CHyC); 7.4 %5H, m,
Ph); %major diasteroisomer): 3.0 %1H, br, disappears after
D2O addition, CHOH); 5.09 %1H, s, CHOH); 5.11 %1H, d,

4434
M. Bella et al. / Tetrahedron 57 62001) 4429±4436
Jˆ1.8 Hz, CHCHy); 7.21 %1H, d, Jˆ1.8 Hz, CHyC); 7.4
%5H, m, Ph). 13C-NMR, d %CDCl3): %major diasteroisomer):
75.37 %CHOH); 84.26 %CHCHy); 126.09; 126.80; 128.98;
129.27 %Ph); 137.36 %CHyC); 144.84 %CHyC); 167.50
%CO). IR n %CHCl3)/cm21: 3620; 3115; 1777; 1650; 1110.
HRMS %FAB) 224.02416 %C11H9O3Cl requires 224.02402).
d, Jˆ1.8 Hz, CHyCBr). 13C-NMR, d %CDCl3): 18.00 %CH3);
73.15 %CHOH); 85.32 %CHCHy); 114.19 %CHyCHMe);
126.98 %CHyCHMe); 132.34 %CHyCBr); 150.37
%CHyCBr); 168.47 %CO). IR n %CHCl3)/cm21: 3815;
3150; 2900; 1811; 1650; 1625; 1100. HRMS %FAB)
231.97355 %C8H9O3Br requires 231.97350).
4.2.8. anti-ꢀ10Rp, 5Sp)-10-Hydroxycrotyl-3-phenylselenyl-
furan-2ꢀ5H)-one 7a and syn-ꢀ10Rp, 5Rp)-10-hydroxy-
crotyl-3-phenylselenylfuran-2ꢀ5H)-one 8a. Inseparable
mixture 1:1 of diastereoisomers. Dense pale yellow oil:
[Found: C, 54.28; H, 4.68. C14H14O3Se requires C, 54.38;
4.2.11. syn-ꢀ10Rp, 5Rp)-3-Bromo-10-hydroxycrotylfuran-
2ꢀ5H)-one 8b. Dense colourless oil: [Found: C, 41.18; H,
3.75. C8H9O3Br requires C, 41.38; H, 3.91%]. H-NMR, d
1
%CDCl3): 1.73 %3H, dd, J1ˆ1 Hz, J2ˆ6.6 Hz, CH3); 3.0 %1H,
br, disappears after D2O addition, CHOH); 4.25 %1H, t,
Jˆ6.6 Hz, CHOH); 4.93 %1H, dd, J1ˆ1.8 Hz, J2ˆ5.8 Hz,
CHCHy); 5.4±5.5 %1H, m, CHyCHMe); 5.8±6.0 %1H, m,
CHyCHMe); 7.51 %1H, d, Jˆ1.8 Hz, CHyCBr). 13C-NMR,
d %CDCl3): 18.00 %CH3); 72.03 %CHOH); 85.26 %CHCHy);
114.12 %CHyCHMe); 127.18 %CHyCHMe); 131.36
%CHyCBr); 150.21 %CHyCBr); 168.66 %CO). IR n
%CHCl3)/cm21: 3815; 3150; 2900; 1811; 1650; 1625;
1100. HRMS %FAB) 231.97352 %C8H9O3Br requires
231.97350).
1
H, 4.56%]. H-NMR, d %CDCl3), syn/anti mixture: 1.70
%6H, m, 2CH3); 3.0 %2H, br, disappears after D2O addition,
CHOH); 4.0±4.1 %1H, m, CHOH); 4.2±4.3 %1H, m, CHOH);
4.85 %1H, dd, J1ˆ2 Hz, J2ˆ2.4 Hz, CHCy); 4.88 %1H, dd,
J1ˆ1.4Hz, J2ˆ1.6 Hz, CHCy); 5.35±5.40 %1H, m,
CHyCHMe); 5.4±5.5 %1H, m, CHyCHMe); 5.7±5.8 %1H,
m, CHyCHMe); 5.8±5.9 %1H, m, CHyCHMe); 6.75 %1H, d,
Jˆ1.8 Hz, CHyCSePh); 6.84 %1H, d, Jˆ1.8 Hz, CHyC-
SePh); 7.4 %5H, m. Ph); 7.65±7.70 %5H, m, Ph). 13C-NMR,
d %CDCl3), syn/anti mixture: 18.37 %2CH3); 72.98 %CHOH);
73.95 %CHOH); 86.61 %CHCy); 86.79 %CHCy); 127.73;
127.97; 129.30; 129.54; 129.65; 129.72; 129.75; 130.37;
130.39; 130.42; 131.43; 132.04; 135.78 %CHyCSePh);
135.86 %CHyCSePh); 146.79 %CHyCSePh); 146.90
%CHyCSePh); 171.35 %CO); 171.56 %CO). IR n %CHCl3)/
cm21: 3520; 3100; 1756; 1650; 1630; 1200. HRMS %FAB)
310.01088 %C14H14O3Se requires 310.01081).
4.2.12. anti-ꢀ10Rp, 5Sp)-3-Bromo-10-hydroxytridecylfuran-
2ꢀ5H)-one 9b. White solid, mpˆ68±708C %ether/hexane):
[Found: C, 56.89; H, 7.46. C17H27O3Br requires C, 56.97; H,
7.60%]. 1H-NMR, d %CDCl3): 0.87 %3H, t, Jˆ6.8 Hz,
CH3CH2); 1.25 %22H, bs, CH3%CH2)11); 3.0 %1H, br,
disappears after D2O addition, CHOH); 3.8±3.9 %1H, m,
CHOH); 4.88 %1H, dd, J1ˆ1.8 Hz, J2ˆ4.5 Hz, CHCHy);
7.61 %1H, d, Jˆ1.8 Hz, CHCHy). 13C-NMR, d %CDCl3):
13.15 %CH3); 21.69; 24.42; 28.25; 28.36; 28.53; 28.60;
28.64; 28.67; 30.92; 32.02; 34.32 %11 CH2); 70.37
%CHOH); 84.29 %CHCHy); 113.05 %CHyCBr); 148.99
%CHyCBr); 167.19 %CO). IR n %CHCl3)/cm21: 3150;
2930; 1772; 1630; 1150. HRMS %FAB) 358.11438
%C17H27O3Br requires 358.11436).
4.2.9. anti-ꢀ10Rp, 5Sp)-10-Hydroxytridecyl-3-phenylsele-
nylfuran-2ꢀ5H)-one 9a and syn-ꢀ10Rp, 5Rp)-10-hydroxy-
tridecyl-3-phenylselenylfuran-2ꢀ5H)-one 10a. Inseparable
mixture 1:1 of diastereoisomers. Dense pale yellow oil:
[Found: C, 63.26; H, 7.36. C23H32O3Se requires C, 63.28;
H, 7.39%]. 1H-NMR, d %CDCl3): %anti) 0.86 %3H, t,
Jˆ6.6 Hz, CH3CH2); 1.24 %22H, bs, CH3%CH2)11); 3.0 %1H,
br, disappears after D2O addition, CHOH); 3.7±3.8 %1H, m,
CHOH); 4.85 %1H, dd, J2ˆ1.8 Hz, J3ˆ5.2 Hz, CHCHy);
6.88 %1H, d, J1ˆ1.8 Hz, CHCHy); 7.3±7.5 %3H, m, Ph);
4.2.13. syn-ꢀ10Rp, 5Rp)-3-Bromo-10-hydroxytridecylfuran-
2ꢀ5H)-one 10b. White solid, mpˆ70±738C %ether/hexane):
[Found: C, 56.79; H, 7.56. C17H27O3Br requires C, 56.97; H,
7.60%]. 1H-NMR, d %CDCl3): 0.87 %3H, t, Jˆ6.8 Hz,
CH3CH2); 1.25 %22H, bs, CH3%CH2)11); 3.0 %1H, br,
disappears after D2O addition, CHOH); 3.7±3.9 %1H, m,
CHOH); 4.92 %1H, dd, J1ˆ1.8 Hz, J2ˆ4.8 Hz, CHCHy);
7.52 %1H, d, J2ˆ1.8 Hz, CHCHy). 13C-NMR, d %CDCl3):
14.22 %CH3); 22.87; 25.53; 29.46; 29.50; 29.59; 29.66;
29.73; 29.76; 29.80; 32.05; 33.17 %11 CH2); 71.95
%CHOH); 85.69 %CHCHy); 114.10 %CHyCBr); 150.44
%CHyCBr); 168.44 %CO). IR n %CHCl3)/cm21: 3150;
2930; 1772; 1630; 1150. HRMS %FAB) 358.11426
%C17H27O3Br requires 358.11436).
1
7.5±7.7 %2H, m, Ph). H-NMR, d %CDCl3): %syn) 0.86 %3H,
t, Jˆ6.6 Hz, CH3CH2); 1.24 %22H, s, CH3%CH2)11); 3.0 %1H,
br, disappears after D2O addition, CHOH); 3.6±3.7 %1H, m,
CHOH); 4.82 %1H, dd, J1ˆ1.8 Hz, J2ˆ7.0 Hz, CHCHy);
6.77 %1H, d, Jˆ1.8 Hz, CHCHy); 7.3±7.5 %3H, m, Ph);
7.5±7.7 %2H, m, Ph). 13C-NMR, d %CDCl3), syn/anti mixture:
14.62 %2 peaks, CH3); 23.18; 25.98; 26.03; 29.71; 29.85;
29.92; 30.00; 30.07; 30.15; 32.40; 33.4 %11 peaks, CH2);
72.13 %CHOH); 72.29 %CHOH); 87.16 %CHCHy); 87.23
%CHCHy); 126.14; 126.19; 129.69; 129.82; 129.90;
130.41; 135.78; 135.83; 136.11; 136.96; 147.32 %CHyC-
SePh); 147.41 %CHyCSePh); 171.64 %CO); 171.69 %CO).
IR n %CHCl3)/cm21, syn/anti mixture: 3100; 2930; 1754;
1625; 1150. HRMS %FAB) 436.15160 %C23H32O3Se requires
436.15167).
4.2.14. anti-ꢀ10Rp, 5Sp)-3-Chloro-10-hydroxycrotylfuran-
2ꢀ5H)-one 7c. Dense colourless oil: [Found: C, 51.13; H,
4.95. C8H9O3Cl requires C, 51.06; H, 4.82%]. H-NMR, d
1
%CDCl3): 1.75±1.80 %3H, m, CH3); 3.0 %1H, br, disappears
after D2O addition, CHOH); 4.3±4.4 %1H, m, CHOH); 4.94
%1H, dd, J1ˆ1.8 Hz, J2ˆ4.6 Hz, CHCHy); 5.4± 5.5 %1H, m,
CHyCHMe); 5.8±6.0 %1H, m, CHyCHMe); 7.39 %1H, d,
Jˆ1.8 Hz, CHyCCl). 13C-NMR, d %CDCl3): 17.98 %CH3);
73.37 %CHOH); 83.50 %CHCHy); 126.10 %CHyCHMe);
126.95 %CHyCHMe); 132.45 %CHyCCl); 145.22
%CHyCCl); 167.65 %CO). IR n %CHCl3)/cm21: 3815;
4.2.10. anti-ꢀ10Rp, 5Sp)-3-Bromo-10-hydroxycrotylfuran-
2ꢀ5H)-one 7b. Dense colourless oil: [Found: C, 41.36; H,
3.79. C8H9O3Br requires C, 41.38; H, 3.91%]. H-NMR, d
%CDCl3): 1.7±1.8 %3H, m, CH3); 3.0 %1H, br, disappears after
D2O addition, CHOH); 4.39 %1H, t, Jˆ5.4, CHOH); 4.91
%1H, dd, J1ˆ1.8 Hz, J2ˆ4.6 Hz, CHCHy); 5.4±5.5 %1H,
m, CHyCHMe), 5.8±6.0 %1H, m, CHyCHMe), 7.57 %1H,
1

M. Bella et al. / Tetrahedron 57 62001) 4429±4436
4435
3120; 2920, 1816; 1635; 1650; 1090. HRMS %FAB)
188.02409 %C8H9O3Cl requires 188.02402).
cm21: 3615; 2900; 1772; 1200. HRMS %FAB) 192.07857
%C11H12O3 requires 192.07864).
4.2.15. syn-ꢀ10Rp, 5Rp)-3-Chloro-10-hydroxycrotylfuran-
2ꢀ5H)-one 8c. Dense colourless oil: [Found: C, 51.3; H,
4.9. C8H9O3Cl requires C, 51.06; H, 4.82%]. H-NMR, d
4.3.2. syn-ꢀ10Rp, 5Rp)-10-Acetoxybenzyl-g-butyrolactone
14. Compound 11b %40 mg, 0.21 mmol) in acetic anhydride
%1 mL) and pyridine %0.1 mL) was stirred at rt for 24 h. The
resulting solution was then diluted with ethyl acetate
%10 mL) and washed with a CuSO4 saturated solution
%3£10 ml), the solvent was then evacuated in vacuo to
1
%CDCl3): 1.7±1.8 %3H, m, CH3); 3.0 %1H, br, disappears after
D2O addition, CHOH); 4.40±4.45 %1H, m, CHOH); 4.97
%1H, dd, J1ˆ1.8 Hz, J2ˆ5.7 Hz, CHCHy); 5.4±5.5 %1H,
m, CHyCHMe); 5.9±6.0 %1H, m, CHyCHMe); 7.31 %1H,
d, Jˆ1.8 Hz, CHyCCl). 13C-NMR, d %CDCl3): 17.83 %CH3);
72.22 %CHOH); 83.44 %CHCHy); 125.95 %CHyCHMe);
127.17 %CHyCHMe); 131.36 %CHyCCl); 145.65
%CHyCCl); 168.44 %CO). IR n %CHCl3)/cm21: 3815;
3120; 2920, 1816; 1635; 1650; 1090. HRMS %FAB)
188.02410 %C8H9O3Cl requires 188.02402).
1
give 41 mg of product 14 as a viscous oil %85%). The H-
NMR of the product was identical to the one reported in
literature.21
1
14: H-NMR, d %CDCl3): 2.0 %2H, m, CH2CH2CO); 2.12
%3H, s, CH3CO); 2.4±2.5 %2H, m, CH2CH2CO); 4.79 %1H,
q, Jˆ6.6 Hz, CHCHOAc); 5.80 %1H, d, Jˆ6.6 Hz, CHOAc);
7.3±7.4 %5H, m, Ph). 13C-NMR, d %CDCl3): 21.02
%CH2CH2CO); 24.13 %CH3CO); 28.06 %CH2CH2CO); 76.36
%CHCHOAc); 80.51 %CHOAc); 127.32; 128.78; 128.98;
135.41 %Ph); 169.69 %CO); 176.37 %CO).
4.2.16. anti-ꢀ10Rp, 5Sp)-3-Chloro-10-hydroxytridecylfuran-
2ꢀ5H)-one 9c and syn-ꢀ10Rp, 5Rp)-3-chloro-10-hydroxy-
tridecylfuran-2ꢀ5H)-one 10c. Inseparable mixture %syn/
anti 1:1) of diastereoisomers. White solid, mpˆ61±648C:
[Found: C, 64.79; H, 8.59. C17H27O3Cl requires C, 64.93; H,
8.67%]. 1H-NMR, d %CDCl3): %anti) 0.87 %3H, t, Jˆ6.2 Hz,
CH3CH2); 1.25 %22H, bs, CH3%CH2)11); 3.5 %1H, br, dis-
appears after D2O addition, CHOH); 3.8±3.9 %1H, m,
CHOH); 4.97 %1H, dd, J1ˆ1.8 Hz, J2ˆ4.4 Hz, CHCHy);
Acknowledgements
We wish to thank MURST COFIN 98 for ®nancial
support.
1
7.43 %1H, d, Jˆ1.8 Hz, CHCHy). H-NMR, d %CDCl3)
%syn) 0.87 %3H, t, Jˆ6.2 Hz, CH3CH2); 1.25 %22H, s,
CH3%CH2)11); 3.5 %1H, br, disappears after D2O addition,
CHOH); 3.7±3.8 %1H, m, CHOH); 4.93 %1H, dd,
J1ˆ1.8 Hz, J2ˆ4.7 Hz, CHCHy); 7.34 %1H, d, J2ˆ1.8 Hz,
CHCHy). 13C-NMR, d %CDCl3): %syn/anti mixture): 14.22
%2 peaks, CH3); 22.78; 25.58; 29.45; 29.48; 29.57; 29.56;
29.72; 29.75; 29.72; 32.03; 33.12 %22 peaks, CH2); 71.51
%CHOH); 71.75 %CHOH); 83.83 %CHCHy); 83.76
%CHCHy); 125.67 %CHyCCl); 125.84 %CHyCCl); 135.42
%CHyCCl); 145.78 %CHyCCl); 167.92 %CO); 167.94 %CO).
IR n %CHCl3)/cm21: %syn/anti mixture): 3120; 2930; 1775;
1630; 1170. HRMS %FAB) 314.16495 %C17H27O3Cl requires
314.16487).
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