Synthesis of γ-lactones and ascorbic acid analogues by diastereoselective hydrogenation of α-hydroxy-γ-alkylidenebutenolides

Article abstract of DOI:10.1002/1099-0690(200205)2002:9<1566::AID-EJOC1566>3.0.CO;2-2

The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride afforded functionalized γ-alkylidene-α-hydroxybutenolides, which were transformed into cis-configured γ-lactones by diastereoselective hydrogenation. Wiley-VCH Verlag GmbH,

Full text of DOI:10.1002/1099-0690(200205)2002:9<1566::AID-EJOC1566>3.0.CO;2-2

FULL PAPER
Synthesis of γ-Lactones and Ascorbic Acid Analogues by Diastereoselective
Hydrogenation of α-Hydroxy-γ-alkylidenebutenolides
[
a]
[a]
[a]
Peter Langer,* Nehad N. R. Saleh, and Valentin Köhler
Keywords: Butenolides / Hydrogenations / Lactones / Silyl enol ethers / Stereoselectivity
The cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes
with oxalyl chloride afforded functionalized γ-alkylidene-α-
hydroxybutenolides, which were transformed into cis-config-
ured γ-lactones by diastereoselective hydrogenation.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
stegane, (ϩ)- and (Ϫ)-steganacin,[10] (Ϫ)-verrucarinolac-
[
9]
Introduction
tone,[ and chrysanthemic acid analogues.
11]
[12]
Saturated γ-lactones are present in a variety of biologic-
Although a number of syntheses of γ-lactones and buten-
[1]
[13]
ally relevant natural products. Examples include goniofu- olides are known, they are in many cases limited to spe-
[
2a,2b]
furone,
a styryl lactone that proved cytotoxic to cific substitution patterns. The development of alternative
[2c]
[2d]
human tumour cells, aplasmomycin, boromycin,
mus- strategies for the preparation of these important hetero-
and erythroskyri- cycles is therefore of considerable importance. We have re-
ne. In addition, functionalized γ-lactones represent useful cently reported a new synthesis of γ-alkylidene-α-hy-
[
2e,2f]
[2g]
[2h]
carine,
palytoxin,
C-glycosides,
[
2i]
[3]
precursors for the synthesis of polyketide structures. Un- droxybutenolides by means of a Lewis acid catalysed
saturated γ-lactones (butenolides) are also present in many cyclization of 1,3-bis(trimethylsilyoxy)-1,3-butadienes with
biologically relevant ring systems:[ lactone A, for example, oxalyl chloride.
4]
[14]
Here we report an efficient approach to
was isolated from the marine sponge Xestospongia,[ (ϩ)- racemic γ-lactones, based on diastereoselective hydrogena-
leptosphaerin is a metabolite of the marine ascomycete Lep- tion of γ-alkylidene-α-hydroxybutenolides.[
tosphaeria oraemaris,[ and compound WF-3681 is an al-
5]
15]
6a]
dose reductase inhibitor produced by Chaetomella raphig-
[
6b]
[7]
era. Ascorbic acid analogues have been used as key in- Results and Discussion
[8]
termediates in the synthesis of (ϩ)- and (Ϫ)-eldanolide,
the antileukaemic lignans (ϩ)-trans-burseran,[9] (Ϫ)-iso-
The Pd/C-catalysed hydrogenation[16] of γ-alkylidenebut-
enolide 3a, which was efficiently prepared by Me SiOTf-
3
catalysed cyclization of bis(silyl enol ether) 1a with oxalyl
chloride,[
14b]
afforded the γ-lactone 4a in good yield and
with very good cis diastereoselectivity. Treatment of dienes
1
3
bϪg with oxalyl chloride afforded the novel butenolides
bϪg in good yields. Hydrogenation of 3bϪe gave the cis-
[
a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstr. 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551/399475
E-mail: planger@gwdg.de
New address: Institut für Chemie und Biochemie der Ernst-
Moritz-Arndt-Universität Greifswald, Soldmannstr. 16/17,
17487 Greifswald, Germany
Scheme 1. Synthesis of γ-butyrolactones 4a؊g
1566
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0509Ϫ1566 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 1566Ϫ1572

Synthesis of γ-Lactones and Ascorbic Acid Analogues
FULL PAPER
Table 1. Synthesis of butenolides 3 and lactones 4
nals were assigned by H,H- and C,H-COSY experiments.
Protons 6-H and 6-HЈ both coupled with two protons (AB
Yield of 3 (%)[a]
[a]
Yield of 4 (%)[a] system), two signals were detected for the diastereotopic
3/4
R
protons 4-H (δ ϭ 3.06) and 4-HЈ (δ ϭ 2.16), which coupled
a
b
c
d
e
f
OEt
OMe
O(tBu)
O(iBu)
OCH
OCH
tBu
74
72
73
56
55
50
84
74
72
85
87
82
0
2
with each other ( J4 ϭ 12.8 Hz) and with hydrogen atoms
Ј,4
3
-H and 5-H. The greater chemical shift for 4-H than for
4-HЈ can be explained by the influence of the neighbouring
2
CH
Ph
2
OMe
ester groups. As was to be expected, high values were ob-
3
3
2
served for the coupling constants J3 (10.3 Hz) and J
,4Ј
4Ј,5
g
63
(
10.3 Hz), indicating a cis relationship between the respect-
[
a]
ive hydrogen atoms. In contrast, lower values were observed
for J4,5 (5.6 Hz) and J3,4 (8.5 Hz). Related chemical shifts
and coupling constants were observed for the correspond-
ing resonances of lactones 4 (Table 2). In addition, NOESY
experiments were helpful in establishing the relative config-
uration independently.
Isolated yield.
configured γ-lactones 4bϪe with very good diastereoselec-
tivities (Scheme 1, Table 1). A complex mixture was ob-
tained in the hydrogenation of benzyl ester 3f, whilst hydro-
genation of the ketone-derived butenolide 3g once more af-
forded the γ-lactone 4g with very good cis diastereoselectiv-
ity.
The cis diastereoselectivity can be explained by the fol-
lowing observation: only the exocyclic double bond was hy-
drogenated when (a) the reaction time was shortened to 1 h,
Inversion of configuration at the C-3 carbon atoms in
lactones 4a and 4b was studied next. Treatment of the mes-
ylate of 4a with KOH resulted in decomposition. Treatment
of 4a with sodium benzoate afforded the desired products,
but with only moderate stereoselectivity. We eventually
found that application of the Mitsunobu procedure[ with
benzoic acid resulted in complete inversion of the config-
uration and formation of the trans-configured lactones 7a
and 7b in good yields (Scheme 3). The configurations of the
products were established by comparison of the spectro-
scopic data with those of lactone 6 (vide infra).
18]
(
b) the partial hydrogen pressure was reduced, or (c) the
solution was not properly flushed with hydrogen. These re-
sults suggest that the exocyclic double bond was hydrogen-
ated first, to give intermediate A, and this was diastereo-
selectively hydrogenated from the sterically less encumbered
side of the molecule (Scheme 2).
[
17]
The hydroxy group at carbon atom C-3 allowed an effi-
cient functionalization of the γ-lactone through SN reac-
2
tions with non-oxygen nucleophiles. Lactone 4a was con-
verted in high yield under standard conditions[ into the
mesylate 8 (Scheme 4). Treatment of 8 with sodium azide
afforded lactone 9 with complete inversion of configura-
tion.[ Treatment of 8 with lithium bromide gave the brom-
19]
19]
[20]
ide 10a in high yield. Unfortunately, the stereoselectivity
here was rather low (ds ϭ 2:1) and could not be improved
by modification of the conditions. A slightly better selectiv-
ity (ds ϭ 3:1) was observed on treatment of 8 with sodium
iodide, which afforded the corresponding lactone 10b in
good yield. Treatment of 10a with DBU resulted in the
formation of the open-chain ester 11 rather than in the
formation of a butenolide.[ Product 11 was presumably
21]
formed by initial deprotonation of the CH group adjacent
2
to the ester, cleavage of the C5ϪO bond and subsequent
elimination of HBr. The configuration of 11 was established
1
by comparison of the H NMR spectroscopic data with
those reported in the literature.[
22]
1
It seems appropriate to briefly compare the H NMR
spectroscopic features of lactones 4, 6, 7, and 8 (Table 2).
Thanks to the identical relative configurations of their sub-
stituents, lactones 4 all exhibited similar chemical shifts for
Scheme 2. Synthesis and structure elucidation of lactone 6
The relative configurations of the γ-lactones were studied protons 4-H, 4-HЈ, 3-H, and 5-H. Hydrogen atoms 4-H and
spectroscopically. In fact, the benzoyl-protected derivative 6 4-HЈ were assigned on the basis of the observed coupling
proved to be an excellent candidate for NMR experiments, constants (vide supra). Hydrogen atoms 4-H were de-
due to the absence of any signal overlap. Lactone 6 was shielded relative to 4-HЈ, due to through-space electronic
prepared in good yield and with very good diastereoselec- effects of the adjacent hydroxy and ester groups. Because
tivity from γ-alkylidenebutenolide 5, which was obtained by of the enhanced electron-withdrawing effect of the benzoyl
1
protection of 3a with benzoyl chloride. The H NMR sig- group, larger chemical shifts were observed for protons 4-
Eur. J. Org. Chem. 2002, 1566Ϫ1572
1567

P. Langer, N. N. R. Saleh, V. Köhler
FULL PAPER
1
Table 2. Characteristic chemical shifts ( H NMR)
Compd.
δ (4-HЈ)[a]
δ (4-H)[a]
δ (3-H)
δ (5-H)
4
4
4
4
4
4
6
7
7
8
9
a
b
c
d
e
g
2.00 (ddd, 12.5, 10.6, 10.6)
1.98 (ddd, 12.5, 10.5, 10.5)
1.96 (ddd, 12.5, 10.5, 10.5)
1.95 (m)
1.98 (ddd, 12.5, 10.5, 10.5)
1.86 (ddd, 12.6, 10.4, 10.4)
2.16 (ddd, 12.8, 10.3, 10.3)
2.60 (dd, 8.0, 7.8)
2.90 (m)
2.82 (m)
2.80 (ddd, 12.5, 8.5, 5.5)
2.60Ϫ2.95 (m)
2.80 (m)
2.82 (ddd, 12.6, 8.4, 5.4)
3.06 (ddd, 12.8, 8.5, 5.6)
2.60 (dd, 8.0, 7.8)
2.57 (dd, 8.0, 7.6)
2.95 (ddd, 12.5, 8.5, 5.5)
2.32 (t, 7.0)
4.58
4.58
4.57
4.55
4.60
4.57
5.73
5.67
5.65
5.36
4.40
4.82
4.82
4.77
4.80
4.80
4.86
4.94
5.12
4.58
4.83
4.95
a
b
2.57 (dd, 8.0, 7.6)
1.86 (ddd, 12.5, 10.5, 10.5)
2.32 (t, 7.0)
[a]Chemical shifts (CDCl
) in ppm and coupling constants in Hz.
3
ca. 8 Hz. For mesylate 8 and lactones 4, similar spectro-
scopic features were observed, except for a significant de-
shielding of hydrogen atom 3-H, located next to the mesyl-
ate group. The relative trans configuration of the substitu-
ents in azide 9 was supported by the deshielding and shield-
ing of hydrogen atoms 4-HЈ and 4-H, respectively.
Hydrogenation reactions of γ-alkylidenebutenolides con-
taining an additional substituent were studied next
Scheme 3. Mitsunobu reactions of 4a and 4b
(
Scheme 5, Table 3). The Pd/C-catalysed hydrogenation of
methoxy-substituted γ-alkylidenebutenolide 12a[
14b]
af-
forded the ascorbic acid analogue 13a. Only the exocyclic
double bond was hydrogenated, with very good chemoselec-
tivity. The product was isolated in 58% yield when the reac-
tion was carried out under a hydrogen pressure of p ϭ 75
bar. A better yield (70%) was obtained with hydrogen at
atmospheric pressure. The yield could be further improved
from 70 to 82% by use of the less polar, benzoyl-protected
derivative 12b, which was prepared from 12a in good yield.
The hydrogenation of the methyl- and ethyl-substituted de-
rivatives 12c and 12d was equally efficient, and afforded the
butenolides 13c and 13d, respectively, in good yields.
Scheme 4. Functionalization reactions of lactone 4a
H, 4-HЈ, 3-H, and 5-H in 6 than for their counterparts in
lactones 4. In particular, the resonance of hydrogen atom
3
-H was shifted downfield by more than 1 ppm, since it was
Scheme 5. Hydrogenation of butenolides 12a؊d
Table 3. Synthesis of ascorbic acid analogues 13a؊d
directly influenced by the benzoyl group. In the case of the
benzoyl derivatives 7a and 7b, similar shifts were observed
for 3-H. Because of the inversion of configuration in the
latter compound, the chemical shifts and coupling con-
stants of 4-H, 4-HЈ, and 5-H differed significantly from
those of lactones 4 and 6. The hydrogen atoms 4-HЈ and 4-
H were deshielded and shielded, respectively, relative to the
respective atoms of lactone 6. This can be explained by the
fact that both hydrogen atoms were both located next to a
hydrogen atom (3-H or 5-H) and next to the ester or the
benzoyloxy group. Therefore, dd signals were observed for
both 4-HЈ and 4-H, with coupling constants in the range of
R1
R2
R3
Yield (%)[a]
1
3
p [bar]
Solvent
a
a
b
c
H
H
Bz
H
H
OMe
OMe
OMe
Me
Me
Me
Me
Me
Et
75
1
1
1
1
MeOH
MeOH
CH Cl
2 2
MeOH
EtOH
58
70
82
71
61
d
Et
[a]
Isolated yields.
1568
Eur. J. Org. Chem. 2002, 1566Ϫ1572

Synthesis of γ-Lactones and Ascorbic Acid Analogues
In conclusion, we report a new approach to racemic cis- (m), 1620 (s), 1394 (m), 1228 (m), 1208 (m), 1140 (m), 1056 (s). MS
FULL PAPER
ϩ
(
EI, 70 eV): m/z (%) ϭ 214 (2) [M ], 184 (3), 139 (100); the exact
configured γ-lactones by diastereoselective hydrogenation
of functionalized γ-alkylidenebutenolides. Our current work
is directed towards the development of an enantioselective
version of this methodology.
ϩ
9 10 6
molecular mass m/z ϭ 214.0477Ϯ2 mD [M ] for C H O was con-
firmed by HRMS (EI, 70 eV).
Benzyl [4-Hydroxy-5-oxofuran-2(5H)-ylidene]acetate (3f): Starting
from 1f (2.00 g, 5.94 mmol), 3f was isolated as a colourless solid
1
(
726 mg, 50%). H NMR ([D
6
]acetone, 250 MHz): δ ϭ 5.20 (s, 2
), 7.15 (s, 1 H, ring-CH), 7.25Ϫ7.50
]acetone, 62.5 MHz): δ ϭ 66.61 (OCH ), 98.43
), 108.74 (ring-CH), 128.83, 128.88, 129.19 (CH, Ph),
36.98 (C, Ph), 150.34, 161.03, 164.09, 165.91 (C). IR (KBr): ν˜ ϭ
H, OCH
(
2
), 5.74 (s, 1 H, CHCO
Ph). C NMR ([D
(CHCO
2
Experimental Section
1
3
6
2
General: See ref.[14b]
2
1
Ϫ1
General Procedure for the Preparation of γ-Alkylidenebutenolides by
3222 (br) cm , 3148 (m), 1776 (s), 1694 (s), 1631 (s), 1621 (s), 1402
Reaction of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with Oxalyl
(m), 1269 (s), 1244 (m), 1090 (m). MS (EI, 70 eV): m/z (%) ϭ 246
ϩ
Chloride: A CH
2
Cl
2
solution (7 mL) of Me
Cl
1.5 mmol, 0.13 mL) and the 1,3-bis(trimethylsiloxy)-1,3-butadiene HRMS (EI, 70 eV).
3
SiOTf (0.45 mmol) was
[M ] (22), 201 (19), 140 (60), 91 (100); the exact molecular mass
ϩ
added at Ϫ78 °C to a CH
2
2 10 5
solution (30 mL) of oxalyl chloride m/z ϭ 246.0528Ϯ2 mD [M ] for C13H O was confirmed by
(
3
6
(1.5 mmol). The temperature was allowed to rise to 20 °C over
h. After the mixture had been stirred for 2Ϫ6 h at 20 °C, a satur-
(
(
5E)-5-(3,3-Dimethyl-2-oxobutylidene)-3-hydroxyfuran-2(5H)-one
3g): The synthesis of 3g has previously been reported.[
14b]
ated solution of NaCl was added, the organic layer was separated,
and the aqueous layer was repeatedly extracted with ether. The
combined organic extracts were dried (MgSO ) and filtered, and pension of Pd/C (20 mol %) in EtOH/CH Cl (1:1; 35 mL) was
Ethyl (4-Hydroxy-5-oxo-2,5-dihydrofuran-2-yl)acetate (4a): A sus-
4
2 2
the solvent was removed in vacuo. The residue was purified by col-
umn chromatography (silica gel; ether/petroleum ether, 1:10 Ǟ 1:3).
saturated with hydrogen (1 bar). To this suspension was added a
solution of 3a (185 mg, 1.00 mmol). After stirring for 72 h, the so-
lution was filtered and the filtrate was concentrated in vacuo. The
Ethyl [4-Hydroxy-5-oxofuran-2(5H)-ylidene]acetate (3a): The syn-
thesis of 3a has been reported previously.[
residue was purified by filtration through a short pad of silica gel
14b]
1
to give 4a as a colourless solid (139 mg, 74%). H NMR (CDCl
3
,
2
1
50 MHz): δ ϭ 1.27 (t, J ϭ 7.0 Hz, 3 H, CH
2.5 Hz, J4,3 ϭ J4,5 ϭ 10.6 Hz, 1 H, 4-HЈ), AB signal (δ
3
), 2.00 (ddd, J4,4Ј
ϭ
Methyl [4-Hydroxy-5-oxofuran-2(5H)-ylidene]acetate (3b): Starting
from methyl acetoacetate (175 mg, 1.50 mmol), 3b was isolated as
A
ϭ 2.70,
1
δB ϭ 2.85, JA,B ϭ 17.6 Hz, JA,5 ϭ JB,5 ϭ 6.5 Hz, 2 H, 6-H, 6-HЈ),
partly overlapped by 2.90 (m, 1 H, 4-H), 4.18 (q, J ϭ 7.0 Hz, 2 H,
OCH ), 4.58 (dd, J ϭ 10.5 Hz, J3,4Ј ϭ 8.5 Hz, 1 H, 3-H), 4.82
2 3,4
a
2
colourless solid (184 mg, 72%).
H
NMR ([D
6
]acetone,
Me), 7.24
]acetone, 62.5 MHz): δ ϭ 51.00
50 MHz): δ ϭ 3.81 (s, 3 H, OCH
3
), 5.79 (s, 1 H, CHCO
2
s, 1 H, ring-CH). 1 C NMR ([D
3
(
(
6
(
dddd, J5,4 ϭ 10.5 Hz, J5,6 ϭ J5,6Ј ϭ 6.5 Hz, J5,4Ј ϭ 5.5 Hz, 1 H,
OCH
3
), 97.59 (CHCO
63.40, 165.75 (C). IR (KBr): ν˜ ϭ 3230 cm , 3147, 3080, 2983,
775, 1696, 1382, 1146, 1088, 1038. MS (EI, 70 eV): m/z (%) ϭ 170
2
Me), 108.00 (ring-CH), 149.53, 160.05,
1
3
Ϫ1
3 3
5-H). C NMR (CDCl , 62.9 MHz): δ ϭ 13.92 (CH ), 36.33, 39.75
1
1
(
(
2 2
CH ), 61.01 (OCH ), 68.09, 72.76 (CH), 169.47, 177.16 (C). IR
Ϫ1
ϩ
(neat): ν˜ ϭ 3437 (br) cm , 2984 (m), 2938 (m), 1779 (s), 1732 (s),
1651 (m), 1449 (s), 1409 (m), 1388 (s), 1371 (s), 1316 (s), 1284 (s),
15) [M ], 142 (10); the exact molecular mass m/z ϭ 170.0215Ϯ2
mD [M ] for C H O was confirmed by HRMS (EI, 70 eV).
7 6 5
ϩ
1
262 (s), 1189 (s), 1130 (s), 1026 (s). MS (DCI): m/z (%) ϭ 394 (22)
tert-Butyl [4-Hydroxy-5-oxofuran-2(5H)-ylidene]acetate (3c): The
synthesis of 3c has been reported previously.[
ϩ
ϩ
[2 M ϩ NH
4
], 206 [M ϩ NH
4
] (100).
14b]
Methyl
(4-Hydroxy-5-oxo-2,5-dihydrofuran-2-yl)acetate
(4b):
Isobutyl [4-Hydroxy-5-oxofuran-2(5H)-ylidene]acetate (3d): Starting
Methylidenefuranone 3b (170 mg, 1.00 mmol) was treated with hy-
from 1d (1.00 g, 3.30 mmol), 3d was isolated as a colourless solid drogen (1 bar) and Pd/C (20 mol %) in 5 mL of EtOH/CH Cl
2
2
1
(
390 mg, 56%). H NMR ([D
6
]acetone, 250 MHz): δ ϭ 0.94 (d, J ϭ (1:1). The solution was filtered and the filtrate was concentrated in
), 2.04 [nonuplet, J ϭ 7.0 Hz, 1 H, CH(CH ],
vacuo. The residue was purified by filtration through a short pad
.93 (d, J ϭ 7.0 Hz, 2 H, CH ), 5.70 (d, J ϭ 1.0 Hz, 1 H, CHCO ), of silica gel to give 4b as a colourless oil (125 mg, 72%). H NMR
.24 (d, J ϭ 1.0 Hz, 1 H, ring-CH). C NMR ([D
2.5 MHz): δ ϭ 19.25 (CH ), 28.44 [CH(CH ], 70.98 (CH
7
3
7
6
.0 Hz, 6 H, CH
3
3 2
)
1
2
2
13
6
]acetone,
), 98.74 10.5 Hz, 1 H, 4-HЈ), AB signal (δA ϭ 2.70, δB ϭ 2.90, JA,B
(CDCl , 250 MHz): δ ϭ 1.98 (ddd, J
3
4,4Ј
ϭ 12.5 Hz, J4,3 ϭ J4,5
ϭ
ϭ
3
3
)
2
2
(
CHCO
2
), 108.83 (ring-CH), 150.34, 160.74, 164.19, 166.14 (C). 17.5 Hz, JA,5 ϭ JB,5 ϭ 6.5 Hz, 2 H, 6-H, 6-HЈ), partly overlapped
Ϫ1
IR (KBr): ν˜ ϭ 3238 (br) cm , 3084 (w), 2965 (m), 1777 (s), 1692 by 2.82 (m, 1 H, 4-H), 3.73 (s, 3 H, OCH ), 4.58 (dd, J
3,4
ϭ
3
(
7
s), 1632 (s), 1621 (s), 1408 (m), 1275 (m), 1092 (m). MS (EI, 10.5 Hz, J3,4Ј ϭ 8.5 Hz, 1 H, 3-H), 4.82 (dddd, J ϭ 10.5 Hz,
5,4
ϩ
13
0 eV): m/z (%) ϭ 212 (4) [M ], 157 (49), 139 (100); the exact
J5,6 ϭ J5,6Ј ϭ 6.5 Hz, J5,4Ј ϭ 5.5 Hz, 1 H, 5-H). C NMR (CDCl3,
62.9 MHz): δ ϭ 36.41, 39.59 (CH ), 52.05 (OCH ), 68.16, 72.75
ϩ
12 5
molecular mass m/z ϭ 212.0684Ϯ2 mD [M ] for C10H O was
2
3
confirmed by HRMS (EI, 70 eV). C10
H 5.70; found C 56.77, H 5.74.
H
12
O
5
(212.2): calcd. C 56.60, (CH), 169.89, 177.02 (C). MS (DCI): m/z (%) ϭ 192 (100) [M ϩ
ϩ
NH4 ].
2
-Methoxyethyl [4-Hydroxy-5-oxofuran-2(5H)-ylidene]acetate (3e):
tert-Butyl (4-Hydroxy-5-oxo-2,5-dihydrofuran-2-yl)acetate (4c):
Methylidenefuranone 3c (210 mg, 0.99 mmol) was treated with hy-
drogen (1 bar) and Pd/C (20 mol %) in 36 mL of CH Cl (1:1). The
2 2
Starting from methoxyethyl acetoacetate (1.00 g, 3.28 mmol), 3e
1
was isolated as a colourless solid (386 mg, 55%). H NMR ([D
cetone, 250 MHz): δ ϭ 3.31 (s, 3 H, OCH ), 3.60, 4.26 (2 ϫ t, J ϭ solution was filtered and the filtrate was concentrated in vacuo.
.0 Hz, 2 ϫ 2 H, OCH ), 5.66 (d, J ϭ 1.0 Hz, 1 H, CHCO ), 7.13 The residue was purified by filtration through a short pad of silica
d, J ϭ 1.0 Hz, 1 H, ring-CH). 13C NMR ([D ]acetone, 62.5 MHz): gel to give 4c as a colourless solid (182 mg, 85%). 1H NMR
δ ϭ 58.65 (OCH ), 64.03, 70.90 (OCH ), 98.53 (CHCO ), 108.82 (CDCl , 250 MHz): δ ϭ 1.45 (s, 9 H, CH ), 1.96 (ddd, J4,4Ј
ring-CH), 150.38, 160.93, 164.18, 166.01 (C). IR (KBr): ν˜ ϭ 3141 12.5 Hz, J4,3 ϭ J4,5 ϭ 10.5 Hz, 1 H, 4-HЈ), AB signal (δ
ϭ 2.60,
6
]a-
3
5
(
2
2
6
3
2
2
3
3
ϭ
(
(
A
Ϫ1
br) cm , 3097 (w), 3001 (w), 2963 (w), 1811 (s), 1716 (s), 1652
δ
B
ϭ 2.78, JA,B ϭ 17.5 Hz, JA,5 ϭ JB,5 ϭ 6.5 Hz, 2 H, 6-H, 6-HЈ),
Eur. J. Org. Chem. 2002, 1566Ϫ1572
1569

P. Langer, N. N. R. Saleh, V. Köhler
partly overlapped by 2.80 (ddd, J4Ј,4 ϭ 12.5 Hz, J4Ј,3 ϭ 8.5 Hz, ide (0.41 mL, 1.1 equiv.), pyridine (0.39 mL, 1.5 equiv.), and
FULL PAPER
J
1
5
3
1
1
1
4Ј,5 ϭ 5.5 Hz, 1 H, 4-H), 4.57 (dd, J3,4 ϭ 10.5 Hz, J3,4Ј ϭ 8.5 Hz,
H, 3-H), 4.77 (dddd, J5,4 ϭ 10.5 Hz, J5,6 ϭ J5,6Ј ϭ 6.5 Hz, J5,4Ј
.5 Hz, 1 H, 5-H). 13C NMR (CDCl
, 62.9 MHz): δ ϭ 27.99 (CH
6.48, 41.10 (CH ), 68.28, 73.14 (CH), 81.85 [OC(CH
], 168.63, layers were dried (MgSO
4
DMAP (catalytic amount) was stirred at 0 °C for 24 h. Water was
added to the solution, the organic layer was separated, and the
), aqueous layer was extracted with ether. The combined organic
) and filtered, and the filtrate was concen-
77.23 (C). IR (neat): ν˜ ϭ 3436 (br) cm , 2980 (m), 2933 (m), trated in vacuo. The residue was purified by chromatography (silica
ϭ
3
3
2
3
)
3
Ϫ1
779 (s), 1729 (s), 1476 (m), 1457 (m), 1395 (m), 1370 (s), 1315 (m), gel, ether/petroleum ether, 1:1) to give 5 as a colourless solid
1
288 (m), 1257 (m), 1159 (s), 1026 (m). MS (DCI): m/z (%) ϭ 450 (820 mg, 88%). H NMR (CDCl
3
, 250 MHz): δ ϭ 1.35 (t, J ϭ
), 4.30 (q, J ϭ 7.0 Hz, 2 H, OCH ), 6.00 (s, 1 H,
Me), 8.55 (t, J ϭ 8.0 Hz, 2 H, Ph), 8.65 (t, J ϭ 8.0 Hz, 1
ϩ
4
ϩ
4
(6) [2 M ϩ NH
], 234 (100) [M ϩ NH
].
7.0 Hz, 3 H, CH
CHCO
3
2
2
Isobutyl
(4-Hydroxy-5-oxo-2,5-dihydrofuran-2-yl)acetate
(4d):
H, Ph), 8.20 (d, J ϭ 8.0 Hz, 2 H, Ph), 8.40 (s, 1 H, ring-CH).
Methylidenefuranone 3d (163 mg, 0.77 mmol) was treated with hy-
drogen (1 bar) and Pd/C (20 mol %) in 24 mL of CH Cl . The
solution was filtered and the filtrate was concentrated in vacuo.
The residue was purified by filtration through a short pad of silica
gel to give 4d as a colourless oil (144 mg, 87%). H NMR (CDCl
2
2
Ethyl [4-(Benzyloxy)-5-oxo-2,5-dihydrofuran-2-yl]acetate (6): Com-
pund 5 (426 mg, 1.5 mmol) was treated with hydrogen (1 bar) and
Pd/C (20 mol %) in EtOH/CH Cl (1:1, 50 mL). The solution was
2 2
1
3
,
filtered and the filtrate was concentrated in vacuo. The residue was
2
3
50 MHz): δ ϭ 0.90 (d, J ϭ 7.0 Hz, 6 H, CH ), 1.95 [m, 2 H, 4-
purified by chromatography (silica gel; ether/petroleum ether, 1:5)
HЈ, CH(CH
3
)
2
], 2.60Ϫ2.95 (m, 3 H, 6-H, 6-HЈ, 4-H), 3.88 (d, J ϭ
1
to give 6 as a colourless solid (315 mg, 73%). H NMR (CDCl
3
,
1
3
7
.0 Hz, 2 H, OCH
2
), 4.55 (m, 1 H, 3-H), 4.80 (m, 1 H, 5-H).
, 62.9 MHz): δ ϭ 18.92 (CH ), 27.49 [CH(CH
), 68.23 (CH), 71.14 (OCH ), 72.86 (CH), 169.47,
77.11 (C). IR (neat): ν˜ ϭ 3441 (br) cm , 2963 (s), 2896 (m), 2876
C
2
1
δ
50 MHz): δ ϭ 1.28 (t, J ϭ 7.1 Hz, 3 H, CH
2.8 Hz, J4Ј,5 ϭ J4Ј,3 ϭ 10.3 Hz, 1 H, 4-HЈ), AB signal (δ
3
), 2.16 (ddd, J4Ј,4
ϭ
NMR (CDCl
3
1
3
3
3 2
) ],
A
ϭ 2.75,
6.48, 39.85 (CH
2
2
B
ϭ 2.94, JA,B ϭ 16.4 Hz, JA,5 ϭ 6.2 Hz, JB,5 ϭ 6.8 Hz, 2 H, 6-
Ϫ1
H, 6-HЈ), 3.06 (ddd, J4,4Ј ϭ 12.8 Hz, J4,3 ϭ 8.5 Hz, J4,5 ϭ 5.6 Hz,
H, 4-H), 4.20 (q, J ϭ 7.1 Hz, 2 H, CH CH ), 4.94 (m, not com-
pletely resolved dddd, J5,4Ј ϭ 10.3 Hz, J5,6(B) ϭ 6.8 Hz, J5,6(A)
(m), 1780 (s), 1735 (s), 1471 (m), 1408 (s), 1390 (m), 1371 (m), 1315
1
3
2
(m), 1284 (m), 1255 (m), 1188 (s), 1130 (s). MS (DCI): m/z (%) ϭ
ϭ
ϭ
ϩ
ϩ
4 4 16 5
450 (40) [2 M ϩ NH ], 234 (100) [M ϩ NH ]. C10H O (216.2):
6
8
6
.2 Hz, J5,4 ϭ 5.6 Hz, 1 H, 5-H), 5.73 (dd, J3,4Ј ϭ 10.3 Hz, J3,4
calcd. C 55.55, H 7.46; found C 55.59, H 7.32.
-Methoxyethyl (4-Hydroxy-5-oxo-2,5-dihydrofuran-2-yl)acetate
4e): Methylidenefuranone 3e (126 mg, 0.59 mmol) was treated
with hydrogen (1 bar) and Pd/C (20 mol %) in 18 mL of CH Cl
13
.5 Hz, 1 H, 3-H), 7.43Ϫ8.09 (m, 5 H, Ar). C NMR (CDCl
2.9 MHz): δ ϭ 14.11 (CH ), 34.76, 40.07 (C-4, C-6), 61.25
O), 68.80, 72.80 (C-3, C-5), 128.53 (CH, Ph), 130.01, 130.08
CH, Ph; C, Ph), 133.79 (CH, Ph), 165.35, 168.98, 171.59 (PhCO
3
,
2
(
3
(
(
CH
2
2
.
2
,
2
ϩ
2
C-2, CO Et). MS (70 eV, EI): m/z (%) ϭ 292 (25) [M ]; the exact
molecular mass m/z ϭ 292.0947Ϯ2 mD [M ] for C15H O was
16 6
The solution was filtered and the filtrate was concentrated in vacuo.
The residue was purified by filtration through a short pad of silica
gel to give 4e as a colourless oil (105 mg, 82%). H NMR (CDCl
ϩ
1
confirmed by HRMS (EI, 70 eV).
3
,
2
1
J
3
4
J
50 MHz): δ ϭ 1.98 (ddd, J4,4Ј ϭ 12.5 Hz, J4,3 ϭ J4,5 ϭ 10.5 Hz,
H, 4-HЈ), AB signal (δ ϭ 2.75, δ ϭ 2.89, JA,B ϭ 17.5 Hz, JA,5
B,5 ϭ 6.5 Hz, 2 H, 6-H, 6-HЈ), overlapped by 2.80 (m, 1 H, 4-H),
.39 (s, 3 H, OCH ), 3.60, 4.25 (2 ϫ t, J ϭ 5.0 Hz, 2 ϫ 2 H, OCH ),
.60 (dd, J3,4 ϭ 10.5 Hz, J3,4Ј ϭ 8.5 Hz, 1 H, 3-H), 4.80 (dddd,
Synthesis of γ-Lactones 7a and 7b: A toluene solution (1 mL) of
DEAD (0.133 mL, 0.85 mmol) was added at 0 °C to a degassed
toluene solution (10 mL) of 4a (154 mg, 0.82 mmol), benzoic acid
A
B
ϭ
3
2
(
3
104 mg, 0.85 mmol), and PPh (322 mg, 1.23 mmol). The solution
was stirred at 20 °C for 14 h. The solvent was removed in vacuo,
and the residue was purified by chromatography (silica gel; ether/
petroleum ether, 1:3) to give 7a as a slightly yellow oil (172 mg,
1
3
5,4 ϭ 10.5 Hz, J5,6 ϭ J5,6Ј ϭ 6.5 Hz, J5,4Ј ϭ 5.5 Hz, 1 H, 5-H).
, 62.9 MHz): δ ϭ 36.29, 39.63 (CH ), 58.81 (OCH
), 68.17 (CH), 70.06 (OCH ), 72.68 (CH), 169.40,
C
NMR (CDCl
3
2
3
),
6
1
1
3.84 (OCH
2
2
Ϫ1
7
2%).
77.00 (C). IR (neat): ν˜ ϭ 3404 (br) cm , 2929 (m), 2854 (m),
778 (s), 1737 (s), 1658 (m), 1454 (m), 1412 (m), 1378 (m), 1316
Ethyl [4-(Benzyloxy)-5-oxotetrahydrofuran-2-yl]acetate (7a): Start-
(
(
m), 1284 (m), 1259 (m), 1184 (s), 1128 (s), 1100 (s), 1030 (s). MS
DCI): m/z (%) ϭ 454 (8) [2 M ϩ NH
ing from 4a (154 mg, 0.82 mmol), 7a was isolated as a slightly yel-
ϩ
4
ϩ
], 236 (100) [M ϩ NH
4
].
1
low oil (177 mg, 74%). H NMR (CDCl
3
, 250 MHz): δ ϭ 1.28 (t,
J ϭ 7.0 Hz, 3 H, CH
HЈ), 2.80 (m, 2 H, 6-H, 6-HЈ), 4.20 (q, J ϭ 7.0 Hz, 2 H, OCH
3
), 2.60 (dd, J ϭ 8.0, J ϭ 7.8, 2 H, 4-H, 4-
),
.12 (quint, J ϭ 6.8 Hz, 5-H), 5.67 (t, J ϭ 8.0 Hz, 1 H, 3-H),
5
-(3,3-dimethyl-2-oxobutyl)-3-hydroxyfuran-2(5H)-one (4g): (5E)-5-
(
(
(
3,3-Dimethyl-2-oxobutylidene)-3-hydroxyfuran-2(5H)-one
50 mg, 0.26 mmol) was treated with hydrogen (1 bar) and Pd/C
20 mol %) in 5 mL of EtOH/CH Cl (1:1). The solution was fil-
2 2
(3g)
2
5
7
1
3
.40Ϫ7.60 (m, 3 H, Ph), 8.07 (dt, J ϭ 6.3, J ϭ 1.2, 2 H, Ph).
, 62.9 MHz): δ ϭ 13.98 (CH ), 33.40, 39.36 (CH
), 68.41, 73.96 (CH), 128.37 (CH, Ph), 128.48 (C, Ph),
129.80, 133.61 (CH, Ph), 165.22, 169.09, 172.16 (C). IR (neat): ν˜ ϭ
C
NMR (CDCl
1.00 (OCH
3
3
2
),
tered and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel; ether/petroleum ether, 1:4)
to give 4g as a colourless solid (33 mg, 63%). H NMR (CDCl
6
2
1
3
,
Ϫ1
3
441 (br) cm , 2963 (s), 2896 (m), 2876 (m), 1780 (s), 1735 (s),
250 MHz): δ ϭ 1.14 [s, 9 H, C(CH
J4,3 ϭ J4,5 ϭ 10.4 Hz, 1 H, 4-HЈ), AB signal (δ
3.15, JA,B ϭ 17.7 Hz, JA,5 ϭ JB,5 ϭ 6.4 Hz, 2 H, 6-H, 6-HЈ), partly
3
)
3
], 1.86 (ddd, J4,4Ј ϭ 12.6 Hz,
1
471 (m), 1408 (s), 1390 (m), 1371 (m), 1315 (m), 1284 (m), 1255
A
ϭ 2.76, δ
B
ϭ
ϩ
(
m), 1188 (s), 1130 (s). MS (EI, 70 eV): m/z (%) ϭ 292 (4) [M ],
ϩ
1
05 (100); the exact molecular mass m/z ϭ 292.0946Ϯ2 mD [M ]
overlapped by 2.82 (ddd, J4Ј,4 ϭ 12.6 Hz, J4Ј,3 ϭ 8.4 Hz, J4Ј,5
.4 Hz, 1 H, 4-H), 4.57 (dd, J3,4 ϭ 10.6 Hz, J3,4Ј ϭ 8.4 Hz, 1 H, 3-
H), 4.86 (dddd, J5,4 ϭ 10.4 Hz, J5,6 ϭ J5,6Ј ϭ 6.4 Hz, J5,4Ј ϭ 5.4 Hz,
ϭ
for C15H
16
O
6
was confirmed by HRMS (EI, 70 eV).
5
Methyl
[4-(Benzyloxy)-5-oxotetrahydrofuran-2-yl]acetate
(7b):
1
3
1
H, 5-H). 13C NMR (CDCl
6.85, 42.03 (C-4, C-6), 44.17 [C(CH
77.27 (C-2), 212.16 (OϭCtBu). MS (70 eV, DCI): m/z (%) ϭ 418
3
, 50 MHz): δ ϭ 25.99 [C(CH
3 3
) ],
Starting from 4a (174 mg, 1.00 mmol), 7b was isolated as a slightly
3 3
) ], 68.27, 73.21 (C-3, C-5),
1
yellow oil (200 mg, 72%). H NMR (CDCl
dd, J ϭ 8.0, J ϭ 7.6, 2 H, 4-H, 4-HЈ), 2.78 (m, 2 H, 6-H, 6-HЈ),
.69 (s, 3 H, OCH ), 4.58 (quint, J ϭ 6.3 Hz, 5-H), 5.65 (t, J ϭ
7.7 Hz, 1 H, 3-H), 7.35Ϫ7.60 (m, 3 H, Ph), 8.02 (d, J ϭ 7.4 Hz, 2
3
, 250 MHz): δ ϭ 2.57
(
ϩ
ϩ
(
12) [2 M ϩ NH
Ethyl (4-Benzyloxy-5-oxo-2,5-dihydrofuran-2-yl)acetate (5):
CH Cl (70 mL) solution of 3a (591 mg, 3.21 mmol), benzoyl chlor-
4 4
], 235 (24), 218 (100) [M ϩ NH ].
3
3
A
1
3
2
2
H, Ph). C NMR (CDCl
3
, 62.9 MHz): δ ϭ 33.45, 39.14 (CH
2
),
1570
Eur. J. Org. Chem. 2002, 1566Ϫ1572

Synthesis of γ-Lactones and Ascorbic Acid Analogues
FULL PAPER
5
1
3
1
7
1.98 (OCH
3
), 68.42, 73.93 (CH), 128.40 (CH, Ph), 128.48 (C, Ph),
H, 4-H, 6-H), 4.20 (q, J ϭ 6.5 Hz, 2 H, OCH
), 4.58 (dd, J ϭ 6.6,
2
29.83, 133.64 (CH, Ph), 165.24, 169.57, 172.14 (C). IR (KBr): ν˜ ϭ J ϭ 1.0, 3-H, major isomer), 4.72 (t, J ϭ 7.0 Hz, 3-H, minor iso-
Ϫ1
13
441 (br) cm , 2953 (s), 1781 (s), 1724 (s), 1450 (m), 1439 (m), mer), 5.05 (m, 1 H, 5-H, both isomers). C NMR (CDCl
362 (m), 1340 (m), 1328 (m), 1285 (s), 1188 (m), 1126 (s). MS (EI, 62.9 MHz): δ ϭ 7.45, 10.40 (CH, C-3), 14.01 (CH , both isomers),
, both isomers),
3
,
3
ϩ
0 eV): m/z (%) ϭ 278 (16) [M ], 105 (100); the exact molecular
2 2
38.58, 39.31, 39.80, 40.67 (CH ), 61.324 (OCH
ϩ
mass m/z ϭ 278.0790Ϯ2 mD [M ] for C14
HRMS (EI, 70 eV).
H
14
O
6
was confirmed by 75.33, 76.09 (CH, C-5), 169.04, 169.09, 173.80, 173.91 (C). IR
Ϫ1
(neat): ν˜ ϭ 3521 (br) cm , 2983 (m), 2936 (m), 1780 (s), 1732 (s),
1
1
630 (m), 1465 (m), 1403 (s), 1386 (s), 1349 (m), 1325 (s), 1314 (s),
Ethyl
(
(
{4-[(Methylsulfonyl)oxy]-5-oxotetrahydrofuran-2-yl}acetate
8): A CH Cl solution (40 mL) of 4a (130 mg, 0.69 mmol), NEt
0.143 mL, 1.03 mmol), and mesyl chloride (0.080 mL, 1.03 mmol)
283 (s), 1264 (s), 1173 (s), 1097 (s). MS (DCI): m/z (%) ϭ 298 (44)
2
2
3
ϩ
[M ], 253 (41), 210 (42), 171 (100); the exact molecular mass m/
ϩ
z ϭ 297.9702Ϯ2 mD [M ] for C
8 11 4
H O I was confirmed by HRMS
was stirred at 0 °C for 1 h. Water was added to the solution, the
organic layer was separated, and the aqueous layer was extracted
(
EI, 70 eV).
with ether. The combined organic layers were dried (MgSO
4
) and
6-Ethoxy-6-oxohexa-2,4-dienoic Acid (11): A THF solution (5 mL)
of lactone 10 (80 mg, 0.32 mmol) and DBU (100 mg, 0.66 mmol)
filtered, and the filtrate was concentrated in vacuo to give 8 as a
1
3
colourless solid (176 mg, 96%). H NMR (CDCl , 250 MHz): δ ϭ was stirred at 20 °C for 24 h. The solution was worked up in the
1
J
1
1
.21 (t, J ϭ 7.0 Hz, 3 H, CH
4,5 ϭ 10.5 Hz, 1 H, 4-HЈ), AB signal (δ
7.5 Hz, JA,5 ϭ JB,5 ϭ 6.5 Hz, 2 H, 6-H, 6-HЈ), 2.95 (ddd, J4Ј,4
3
), 1.86 (ddd, J4,4Ј ϭ 12.5 Hz, J4,3
ϭ
ϭ
ϭ
usual way. Product 11 was isolated by chromatography (silica gel;
ether); yield: 43 mg, 78%. The configuration of 11 was established
A
ϭ 2.65, δ ϭ 2.80, JA,B
B
1
by comparison of its H NMR spectroscopic data with those re-
[
22]
2.5 Hz, J4Ј,3 ϭ 8.5 Hz, J4Ј,5 ϭ 5.5 Hz, 1 H, 4-H), 3.10 (s, 3 H, ported in the literature for the (E,Z) and (Z,Z) isomers.
), 4.11 (q, J ϭ 7.0 Hz, 2 H, OCH ), 4.83 (dddd, J5,4 product was obtained as a 2.5:1 mixture of (E,E) and (E,Z) iso-
0.5 Hz, J5,6 ϭ J5,6Ј ϭ 6.5 Hz, J5,4Ј ϭ 5.5 Hz, 1 H, 5-H), 5.36 (dd, mers. H NMR (CDCl
3,4 ϭ 10.5 Hz, J3,4Ј ϭ 8.5 Hz, 1 H, 3-H). 13C NMR (CDCl
CH both isomers), 4.25 (q, J ϭ 6.5 Hz, 2 H, OCH
2.9 MHz): δ ϭ 13.87 (CH ), 34.48 (CH ), 39.32 (SCH ), 39.37 6.01 (d, J ϭ 14.0 Hz, 1 H, CH minor isomer), 6.18 (d, J ϭ 16.0 Hz,
), 61.02 (OCH ), 72.93, 73.74 (CH), 168.77, 170.69 (C). IR 1 H, CH minor isomer), 6.22 (m, 2 H, CH major isomer), 6.75 (t,
neat): ν˜ ϭ 3334 (br) cm , 3027 (m), 2985 (m), 2942 (m), 1793 (s), J ϭ 14.0 Hz, 1 H, CH minor isomer), 7.35 (m, 2 H, CH major
The
SCH
3
2
ϭ
1
1
J
6
3
, 250 MHz): δ ϭ 1.30 (t, J ϭ 6.5 Hz, 3 H,
both isomers),
3
,
3
2
3
2
3
(
(
CH
2
2
Ϫ1
1
1
5
732 (s), 1656 (m), 1449 (m), 1411 (s), 1361 (s), 1290 (m), 1264 (s), isomer), 8.35 (dd, J ϭ 14.0, J ϭ 16.0 Hz, 1 H, CH minor isomer).
1
3
178 (s), 1097 (s), 1061 (s), 1029 (s), 1003 (s). MS (DCI): m/z (%) ϭ
C NMR (CDCl
60.90, 60.99 (OCH
40.33, 142.56, 142.90 (CH), 165.76, 166.03, 170.04, 170.59 (C).
3
, 62.9 MHz): δ ϭ 14.17 (CH
3
, both isomers),
ϩ
ϩ
50 (100) [2 M ϩ NH
4
], 284 (87) [M ϩ NH
4
].
2
), 123.72, 127.41, 129.32, 129.90, 138.15,
1
Ethyl (4-Azido-5-oxotetrahydrofuran-2-yl)acetate (9): A DMF solu-
tion (1 mL) of 8 (105 mg, 0.39 mmol) and NaN (38 mg,
ϩ
MS (DCI): m/z (%) ϭ 170 (19) [M ], 152 (19), 125 (63), 97 (100).
3
0
.59 mmol) was stirred for 12 h at 20 °C. The solution was filtered,
Synthesis of γ-Alkylidenebutenolides 12a, 12c, and 12d: The syn-
and the filtrate was concentrated in vacuo to give 9 as a colourless thesis of these compounds has been reported.[
14b]
1
oil (76 mg, 92%). H NMR (CDCl
3
, 250 MHz): δ ϭ 1.28 (t, J ϭ
Methyl [4-(Benzyloxy)-3-methoxy-5-oxofuran-2(5H)-ylidene]acetate
12b): A CH Cl (40 mL) solution of 12a (200 mg, 1.00 mmol),
6
2
7
.3 Hz, 3 H, CH
H, 6-H, 6-HЈ), 4.15 (q, J ϭ 6.3 Hz, 2 H, OCH
.2 Hz, 1 H, 3-H), 4.95 (quint, J ϭ 6.5 Hz, 5-H). C NMR
, 62.9 MHz): δ ϭ 14.02 (CH ), 33.33, 39.18 (CH ), 56.88
CH, C-3), 61.16 (OCH ), 74.52 (CH, C-5), 169.02, 172.66 (C). MS
DCI): m/z (%) ϭ 231 (100) [M ϩ NH
3
), 2.32 (t, J ϭ 7.0 Hz, 2 H, 4-H, 4-HЈ), 2.73 (m,
(
2
2
2
), 4.40 (t, J ϭ
13
benzoyl chloride (0.13 mL, 1.1 equiv.), pyridine (0.12 mL, 1.5
equiv.), and DMAP (catalytic amount) was stirred at 0 °C for 24 h.
Water was added to the solution, the organic layer was separated,
and the aqueous layer was extracted with ether. The combined or-
(
(
(
CDCl
3
3
2
2
ϩ
4
].
ganic layers were dried (MgSO
concentrated in vacuo. The residue was purified by chromato-
lution (2.5 mL) of 8 (106 mg, 0.40 mmol) and LiBr (69 mg, graphy (silica gel; ether/petroleum ether, 1:1) to give 12b as a col-
4
) and filtered, and the filtrate was
Ethyl (4-Bromo-5-oxotetrahydrofuran-2-yl)acetate (10a): A THF so-
1
0
.80 mmol) was stirred for 20 h at 20 °C. The solution was filtered, ourless solid (255 mg, 84%). H NMR (CDCl
and the filtrate was concentrated in vacuo to give 10a as a colour- 3.81 (s, 3 H, OCH ), 4.13 (s, 3 H, OCH ), 5.72 (s, 1 H, CHCO
, 250 MHz): δ ϭ 7.40Ϫ7.75 (m, 3 H, Ph), 8.12 (m, 2 H, Ph). C NMR (CDCl
), 2.25Ϫ3.25 (m, 4 H, 4-H, 6-H), 4.15 62.5 MHz): δ ϭ 51.16, 59.49 (OCH ), 97.80 (CHCO Me), 126.97
3
, 250 MHz): δ ϭ
3
3
2
Me),
1
13
less oil (82 mg, 82%, ds ϭ 2:1). H NMR (CDCl
.25 (t, J ϭ 6.5 Hz, 3 H, CH
q, J ϭ 6.5 Hz, 2 H, OCH ), 4.45 (dd, J ϭ 6.6, J ϭ 1.0, 3-H, major
isomer), 4.55 (t, J ϭ 7.0 Hz, 3-H, minor isomer), 4.92 (quint, J ϭ
3
3
,
1
(
3
3
2
2
(C), 128.90, 130.61 (CH, Ph), 133.68 (C), 134.75 (Ph, CH), 149.71,
153.23, 161.78, 163.31, 163.44 (C). MS (EI, 70 eV): m/z (%) ϭ 305
1
3
ϩ
ϩ
6
.5 Hz, 5-H, minor isomer), 5.10 (m, 5-H, major isomer).
NMR (CDCl , 62.9 MHz): δ ϭ 14.01 (CH , both isomers), 37.03, z ϭ 304.0583Ϯ2 mD [M ] for C15
8.07 (CH, C-3), 38.28, 38.62, 38.92, 39.53 (CH ), 61.12 (OCH ), (EI, 70 eV).
4.93, 75.18 (CH, C-5), 168.93, 168.97 (C), 172.66 (C, both iso-
C
(3) [M ϩ 1], 304 [M ], 105 (100); the exact molecular mass m/
ϩ
3
3
12 7
H O was confirmed by HRMS
3
7
2
2
ϩ
Methyl (4-Hydroxy-3-methoxy-5-oxo-2,5-dihydrofuran-2-yl)acetate
(13a): Pd/C (20 mol %) was added to a methanol solution (10 mL)
of 12a (100 mg, 0.50 mmol). The solution was treated with hydro-
gen (75 bar) for 48 h at 20 °C. The solution was filtered, and the
filtrate was concentrated in vacuo. The residue was purified by
mers). MS (DCI): m/z (%) ϭ 251, 249 (4) [M ], 204, 206 (25), 162,
ϩ
164 (25); the exact molecular mass m/z ϭ 249.9840Ϯ2 mD [M ]
for C Br was confirmed by HRMS (EI, 70 eV).
8 11 4
H O
Ethyl (4-Iodo-5-oxotetrahydrofuran-2-yl)acetate (10b): A THF solu-
tion (2.5 mL) of 8 (105 mg, 0.40 mmol) and NaI (120 mg, chromatography (silica gel; ether/petroleum ether, 1:3) to give 14a
.80 mmol) was stirred for 20 h at 20 °C. The solution was filtered, as a colourless solid (58 mg, 58%). The product was isolated in 70%
and the filtrate was concentrated in vacuo. The residue was purified yield (70 mg) when the reaction was carried out under a hydrogen
0
1
by chromatography (silica gel; ether/petroleum ether, 1:3) to give pressure of 1 bar. H NMR (CDCl
3
, 250 MHz): δ ϭ AB signal
1
1
0b as a colourless oil (88 mg, 74%, ds ϭ 3:1). H NMR (CDCl
3
,
(δ ϭ 2.53, δ ϭ 2.87, JA,B ϭ 16.4 Hz, JA,5 ϭ 8.8 Hz, JB,5 ϭ 3.7 Hz,
A B
2
50 MHz): δ ϭ 1.25 (t, J ϭ 6.5 Hz, 3 H, CH ), 2.30Ϫ3.20 (m, 4 2 H, 6-H), 3.73 (s, 3 H, OCH
3
3
), 4.18 (s, 3 H, CO
2
3
CH ), 5.07 (dd,
Eur. J. Org. Chem. 2002, 1566Ϫ1572
1571

P. Langer, N. N. R. Saleh, V. Köhler
FULL PAPER
[
2] [2a]
J
5,6H(A) ϭ 8.8 Hz, J5,6H(B) ϭ 3.7 Hz, 1 H, 5-H), 5.67 (s, 1 H, OH).
C. Cagnolini, M. Ferri, P. R. Jones, P. J. Murphy, B. Ayres,
[
2b]
1
3
B. Cox, Tetrahedron 1997, 53, 4815.
P. J. Murphy, J. Chem.
C NMR (CDCl
COCϭC, CO CH
69.52, 171.07 (C-2, CO
.99; found C 47.67, H 5.02.
3
, 50 MHz): δ ϭ 37.10 (C-6), 52.19, 59.53
), 72.62 (C-5), 118.63, 151.67 (C-3, C-4),
Me). C (202.2): calcd. C 47.53, H
Soc., Chem. Commun. 1992, 1096. [ E. J. Corey, D. H. Hua,
2c]
(H
3
2
3
[
2d]
B.-C. Pan, S. P. Seitz, J. Am. Chem. Soc. 1982, 104, 6818.
M. A. Avery, S. C. Choudhry, O. P. Dhingra, M. Kang, J. D.
1
4
2
8 10 6
H O
[2e]
White, A. J. Whittle, J. Am. Chem. Soc. 1983, 105, 6517.
R.
341. [ M. Chmielewski, P. Guzik, Heterocycles 1984, 22, 7.
[2g]
Amouroux, B. Gerin, M. Chastrette, Tetrahedron Lett. 1982,
Methyl [4-(Benzyloxy)-3-methoxy-5-oxo-2,5-dihydrofuran-2-yl]acet-
ate (13b): Pd/C (20 mol %) was added to a CH Cl solution (10
mL) of 12b (80 mg, 0.26 mmol). The suspension was treated with
hydrogen (1 bar) for 48 h at 20 °C and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromato-
2f]
4
2
2
Y. Kishi, S. S. Ko, L. L. Klein, K.-P. Pfaff, Tetrahedron Lett.
[2h]
1982, 4415.
1
M. Lakhrissi, Y. Chapleur, Angew. Chem. 1996,
[2i]
08, 833; Angew. Chem. Int. Ed. Engl. 1996, 35, 750Ϫ752.
L. Herrera, M. S. Pino Gonzalez, M. Nieto Sampedro, R. M.
graphy (silica gel; ether/petroleum ether, 1:3) to give 13b as a col-
Dominguez Aciego, Tetrahedron 1989, 45, 269.
1
[3] [3a]
6
ourless solid (66 mg, 82%). H NMR ([D ]acetone, 250 MHz): δ ϭ
S. Hanessian, P. J. Murray, S. P. Sahoo, Tetrahedron Lett.
[
3b]
1
985, 5623. For hydrogenations of butenolides, see:
G.
AB signal (δ
B,5 ϭ 3.6 Hz, 2 H, 6-H), 3.65 (s, 3 H, OCH
CO CH ), 5.27 (dd, J5,6H(A) ϭ 8.8 Hz, J5,6H(B) ϭ 3.6 Hz, 1 H, 5-
H), 7.50Ϫ7.60 (m, 2 H, Ph), 7.70Ϫ7.80 (m, 1 H, Ph), 8.12 (m, 2
H, Ph). 13C NMR ([D
]acetone, 75 MHz): δ ϭ 37.35 (C-6), 52.19,
), 73.21 (CH, C-5), 114.50, 128.83 (C), 129.82, 130.98,
A
ϭ 2.70, δ
B
ϭ 3.08, JA,B ϭ 16.5 Hz, JA,5 ϭ 8.7 Hz,
Stork, S. D. Rychnovsky, J. Am. Chem. Soc. 1987, 109, 1564.
J
3
), 4.18 (s, 3 H,
[4]
[4a]
[4b]
Reviews:
Y. S. Rao, Chem. Rev. 1976, 76, 625.
G. Pat-
2
3
[4c]
tenden, Prog. Chem. Nat. Prod. 1978, 35, 133.
Contemp. Org. Synth. 1994, 1, 287.
[5]
D. W. Knight,
6
E. Quino a` , E. Kho, L. V. Manes, P. Crews, G. Bakus, J. Org.
Chem. 1986, 51, 4260.
6] [6a]
6
1
7
0.33 (CH
3
[
35.23 (CH, Ph), 163.90, 164.44, 166.81, 169.75 (C). MS (EI,
0 eV): m/z (%) ϭ 306 (3) [M ], 105 (100); the exact molecular
A. J. Pallenberg, J. D. White, Tetrahedron Lett. 1986, 5591.
T. Namiki, M. Nishikawa, Y. Itoh, I. Uchida, M. Hashim-
ϩ
[6b]
ϩ
mass m/z ϭ 306.0740Ϯ2 mD [M ] for C15
H
14
O
7
was confirmed by
oto, Tetrahedron Lett. 1987, 1400.
J. A. J. M. Vekemans, G. A. M. Franken, C. W. M. Dapperens,
E. F. G. Godefroi, J. Org. Chem. 1988, 53, 627.
[
[
7]
8]
HRMS (EI, 70 eV).
Methyl
(4-Hydroxy-3-methyl-5-oxo-2,5-dihydrofuran-2-yl)acetate
J. P. Vigneron, R. Meric, M. Larcheveque, A. Debal, J. Y. Lalle-
mand, G. Kunesch, P. Zagetti, M. Gallois, Tetrahedron 1984,
(13c): A methanol suspension (5 mL) of Pd/C (20 mol %) was re-
4
0, 3521.
peatedly flushed with hydrogen (1 bar). Methyl (2Z)-[4-hydroxy-3-
methyl-5-oxofuran-2(5H)-ylidene]acetate (12c; 63 mg, 0.34 mmol)
was added, and the suspension was again flushed with hydrogen.
The reaction mixture was stirred for 48 h at 20 °C (1 bar) and
filtered, and the filtrate was concentrated in vacuo. The residue was
[9]
K. Tomioka, T. Ishiguro, K. Koga, J. Chem. Soc., Chem. Com-
mun. 1979, 652.
K. Tomioka, T. Ishiguro, Y. Iitaka, K. Koga, Tetrahedron 1984,
[10]
4
0, 1303.
[11]
K. Tomioka, F. Sato, K. Koga, Heterocycles 1982, 17, 311.
purified by chromatography (silica gel; ether/petroleum ether, 1:3)
[12] J. Mann, A. Thomas, J. Chem. Soc., Chem. Commun. 1985,
1
to give 13c as a colourless solid (45 mg, 71%). H NMR ([D
6
]ace-
ϭ 2.46,
ϭ 2.98, JA,B ϭ 16.2 Hz, JA,5 ϭ 8.8 Hz, JB,5 ϭ 3.5 Hz, 2 H, 6-H),
737.
[13]
tone, 250 MHz): δ ϭ 1.90 (s, 3 H, 4-CH
3
), AB signal (δ
A
For recent syntheses, see: C. Harcken, R. Brückner, Angew.
Chem. 1997, 109, 2866; Angew. Chem. Int. Ed. Engl. 1997, 36,
2750, and references cited therein.
δ
3
5
5
B
3 3
.66 (s, 3 H, CH ,
O), 5.09Ϫ5.18 (m, 1 H, 5-H). 13C NMR (CDCl
), 37.52 (C-6), 52.29 (CH O), 77.73 (C-
), 130.53, 137.88 (C-3, C-4), 169.70, 169.89 (C-2, CO Me). MS
70 eV, EI): m/z (%) ϭ 186 (22) [M ]; the exact molecular mass
8 10 5
m/z ϭ 186.0528Ϯ2 mD [M ] for C H O was confirmed by
[
14] [14a]
P. Langer, M. Stoll, Angew. Chem. 1999, 111, 1919; Angew.
0.3 MHz): δ ϭ 9.25 (CH
3
3
Chem. Int. Ed. 1999, 38, 1803. [
Stoll, Chem. Eur. J. 2000, 6, 3204.
For related hydrogenations of butenolides, see:
14b]
P. Langer, T. Schneider, M.
2
ϩ
(
[15]
[15a]
C. Marino,
ϩ
O. Varela, R. M. de Lederkremer, Carbohydr. Res. 1990, 220,
HRMS (EI, 70 eV).
145. [15b] L. O. Jerocic, O. J. Varela, A. F. Cirelli, R. M. de
Lederkremer, Tetrahedron 1984, 40, 1425.
Ethyl (3-Ethyl-4-hydroxy-5-oxo-2,5-dihydrofuran-2-yl)acetate (13d):
Methylidenefuranone 12d (56 mg, 0.26 mmol) was treated with hy-
drogen (1 bar) and Pd/C (20 mol %) in 5 mL of EtOH. The solution
was filtered, the filtrate was concentrated in vacuo, and the residue
[16]
[17]
A. J. Poss, M. S. Smyth, Tetrahedron Lett. 1988, 29, 5723.
This assumption is also supported by the selective hydrogena-
tion of the exocyclic double bond of 3-(benzoyloxy)-5-ethyl-
[
17a]
idene-2(5H)-furanone with Pd/BaSO
4
as the catalyst:
O. J.
was purified by chromatography (silica gel; ether/petroleum ether,
Varela, A. F. Cirelli, R. M. de Lederkremer, Carbohydr. Res.
1982, 100, 424. [
17b]
C. Marino, O. Varela, R. M. de Leder-
1
1
:3) to give 13d as a colourless solid (35 mg, 61%). H NMR
kremer, Carbohydr. Res. 1991, 220, 145.
J. Mulzer, N. Salimi, Liebigs Ann. Chem. 1986, 1172.
O. Mitsunobu, Synthesis 1981, 1.
(
(
2
CDCl
t, J ϭ 7.6 Hz, 3 H, CH
.18, JA,B ϭ 7.6 Hz, JA,X ϭ JB,X ϭ 7.6 Hz, 2 H, CH
signal (δ ϭ 2.48, δ ϭ 2.80, JA,B ϭ 16.1 Hz, JA,5 ϭ 8.6 Hz, JB,5
.9 Hz, 2 H, 6-H), 4.18 (q, J ϭ 7.1 Hz, 2 H, CH CH O), 5.26 (dd,
5,6H(A) ϭ 8.6 Hz, J5,6H(B) ϭ 3.9 Hz, 1 H, 5-H). 13C NMR (CDCl
5.5 MHz): δ ϭ 11.55, 14.09 (CH CH CϭC, CH CH O), 17.80
CϭC), 37.94 (C-6), 61.31 (CH O), 76.78 (C-5), 134.82, 137.27
C-3, C-4), 169.25, 169.89 (C-2, CO Et). MS (70 eV, EI): m/z (%) ϭ
14 (32) [M ]. A small amount of an unknown impurity could not
be separated.
3
, 250 MHz): δ ϭ 1.27 (t, J ϭ 7.1 Hz, 3 H, CH
CH CϭC), AB signal (δ ϭ 2.13, δ
CϭC), AB
3 2
CH O), 1.67
[
18] [18a]
[18b]
3
2
A
B
ϭ
2
[19]
J. A. J. M. Vekemans, R. G. M. de Bruyn, R. C. H. M. Caris,
A. J. P. M. Kokx, J. J. H. G. Konings, E. F. Godefroi, J. Org.
Chem. 1987, 52, 1093.
A
B
ϭ
3
J
7
3
2
[20] [20a]
3
,
J. Gharbi-Benarous, M. S. Morales-Rios, G. Dana, Can. J.
Chem. 1985, 63, 2384. [
Chem. 1999, 1407.
21]
20b]
C. Herdeis, J. Telser, Eur. J. Org.
3
2
3
2
(
(
CH
2
2
[
[
S. Kanemasa, N. Nakagawa, H. Suga, O. Tsuge, Bull. Chem.
Soc. Jpn. 1989, 62, 171.
2
ϩ
2
22] [22a]
B. J. Adger, C. Barrett, J. Brennan, P. McGuigan, M. A.
McKervey, B. Tarbit, J. Chem. Soc., Chem. Commun. 1993,
220. [
22b]
M. M. Rogic, T. R. Demmin, J. Am. Chem. Soc.
1
1
1
[22c]
978, 100, 5472.
949, 32, 1017.
A. Funke, P. Karrer, Helv. Chim. Acta
[
1]
For a review, see: U. Ravid, R. M. Silverstein, L. R. Smith,
Received November 19, 2001
[O01539]
Tetrahedron 1978, 34, 1449.
1572
Eur. J. Org. Chem. 2002, 1566Ϫ1572