Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity

Article abstract of DOI:10.1016/S0968-0896(03)00295-5

The synthesis of 5- and 3-(1′-hydroxyalkyl)-substituted 5H-furan-2-ones 4a-d and 8a-d as well as 5-alkylidene-5H-furan-2-ones 5a-d is described. A study of the structure-activity relationship of these furanone-based natural product analogues towards two different quorum sensing systems is reported. Although the synthesized compounds are not as potent quorum sensing inhibitors as some natural counterparts and a synthetic analogue hereof, interesting structure-activity relationships are seen.

Full text of DOI:10.1016/S0968-0896(03)00295-5

Bioorganic & Medicinal Chemistry 11 (2003) 3261–3271
Synthesis of Furanone-Based Natural Product Analogues with
Quorum Sensing Antagonist Activity
Thomas Hjelmgaard,b Tobias Persson,a,b Thomas B. Rasmussen,c Michael Givskovc
and John Nielsena,*
aDepartment of Chemistry, The Royal Veterinary and Agricultural University, Thorvaldsensvej 40, DK-1871 Frederiksberg C, Denmark.
bDepartment of Chemistry, Organic Chemistry, Bld. 201, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark
cDepartment of Molecular Microbiology, BioCentrum-DTU, Bld. 301, Technical University of Denmark,
DK-2800 Kgs. Lyngby, Denmark
Received 18October 2002; accepted 23 April 2003
Abstract—The synthesis of 5- and 3-(10-hydroxyalkyl)-substituted 5H-furan-2-ones 4a–d and 8a–d as well as 5-alkylidene-5H-furan-
2-ones 5a–d is described. A study of the structure–activity relationship of these furanone-based natural product analogues towards
two different quorum sensing systems is reported. Although the synthesized compounds are not as potent quorum sensing inhibitors
as some natural counterparts and a synthetic analogue hereof, interesting structure–activity relationships are seen.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
least in part, controlled by the swr quorum sensing sys-
tem.5 The function of this system is dependent on the
synthesis and excretion of the signal molecules N-buta-
noyl homoserine lactone (BHL) and N-hexanoyl homo-
serine lactone (HHL). With increasing cell density the
lactone signals accumulate in the culture medium. At a
certain threshold value the signals are thought to ago-
nize the receptor molecule SwrR, which then in turn
induces expression of a number of quorum sensing tar-
get genes, among them the swrA gene.6,7 The swrA
encodes a lipopeptide synthase, which catalyzes the
production of serrawettin W1, a compound which
reduces the surface tension of the medium and enables
the dense bacterial culture to expand on the surface of
semi-solid media.7 The system is thought to work in a
manner similar to the N-3-oxohexanoyl homoserine
lactone (OHHL) dependent luxR, luxI quorum sensor
of Vibrio fischieri, which controls the expression of
bioluminescence in response to high cell density.5
For centuries, natural products have been a reliable and
valuable source for drug discovery. Over the last dec-
ade, combinatorial chemistry and parallel synthesis of
compound arrays or focused libraries have been estab-
lished for discovery and development of new medicinal
drugs. Moreover, the combination of natural products
and combinatorial chemistry has broken new ground in
the continuous effort toward novel therapeutics, as nat-
ural products continue to deliver both new drug
approvals and significant numbers for the sales statis-
tics.1 Thus, in our pursuit of identifying new non-toxic
inhibitors of interbacterial communication and organi-
zation termed quorum sensing,2 we have investigated a
series of furanone-type natural products as templates
for small combinatorial libraries and evaluated their
biological activities with respect to quorum sensing.
The bacterium Serratia liquefaciens MG1 is able to per-
form rapid surface translocation on semi-solid surfaces,
a process termed swarming.3 Formation of a swarming
culture requires co-ordination between the bacterial
cells.4 In S. liquefaciens MG1, this coordination is, at
Previously, we have reported the synthesis and quorum
sensing modulating effects of 4- and 5-modified acylated
homoserine lactones.8 Furthermore, halogenated fur-
anones isolated from the algae Delisea pulchra and their
synthetic analogues (see Scheme 1) are able to antag-
onize quorum sensing controlled gene expression
including swarming motility of S. liquefaciens MG16,9,10
and biofilm formation and expression of virulence
*Corresponding author. Tel.: +45-3528-2428; fax: +45-3528-2398;
e-mail: jn@kvl.dk
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00295-5

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T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
in situ isomerization with Et3N gave 5H-furan-2-one 2
in 46% yield.19 Reacting 2 with trimethylchlorosilane
and Et3N has been reported to yield pure 2-(tri-
methylsilyloxy)furan 3 in 82% yield after only two dis-
tillations.20 Several distillations were needed, though, in
order to obtain pure 3,21 reducing the yield to 42%.
However, it was found that stirring the first obtained
crude distillate at room temperature under N2 for 30
min followed by filtration and distillation yielded pure 3
in 58% yield, a clear improvement. Vinyloguous
Mukaiyama aldol condensations between 3 and alipha-
tic aldehydes in the presence of the Lewis acid triethyl-
silyltriflate (TESOTf) then gave the target molecules
erythro-4a–d and threo-4a–d with threo as the major
isomer.13,18,22À26 See Table 1 for yields and diastereo-
meric ratios. Erythro/threo-ratios were determined by
NMR.25
Scheme 1. Structures of some naturally occurring halogenated fur-
anones, 1a–b, and a synthetic analogue 1c, all antagonists in quorum
sensing systems.
factors in Pseudomonas aeruginosa.11 Likewise, these
halogenated furanones have been shown to promote
rapid proteolytic degradation of the LuxR receptor.12
Recently, two new natural products sharing structural
similarities with furanones 1a–c (Scheme 1), have been
isolated. These natural products, iso-cladospolide B13
and acaterin, shown in Scheme 2, were isolated from a
marine sponge14 and from Pseudomonas sp. A92,15À17
respectively. Analogues of iso-cladospolide B have been
shown to be cytotoxic against different types of tumor
cell lines,18 whereas acaterin has been shown to be an
inhibitor of acyl-CoA (cholesterol acyltransferase).15
Acetylation of 4a–d in the presence of Et3N and DMAP
resulted in elimination, yielding 5-((E)/(Z)-alkylidene)-
5H-furan-2-ones 5a–d, as shown in Scheme 5.26 See
Table 2 for yields and (E)/(Z)-ratios, which were deter-
mined by NMR.27 The products were, however, very
reactive and had to be stored under N2 and even then
the shelf stability was limited. Thus, a compound tenta-
tively assigned to be 5a was isolated but decomposed
Thus, taking these biological activities (albeit unrelated
to quorum sensing) and structural similarities with the
halogenated furanones 1a–c into account, these two
natural products serve as structural templates for the
target scaffolds of this study, 5- and 3-(10-hydroxyalkyl)-
substituted 5H-furan-2-ones (4a–d and 8a–d) and
5-alkylidene-5H-furan-2-ones (5a–d), shown in Scheme 3.
Hence, the aim of this study is to determine the influ-
ences of relative configurations of stereogenic centres,
the length and position of the hydroxyalkyl chain as
well as the presence of g,d-unsaturation on the
antagonistic activity.
Chemistry
5-(10-hydroxyalkyl)-5H-furan-2-ones erythro-4a–d and
threo-4a–d were synthesized by the sequence shown in
Scheme 4.
Scheme 4. (a) HCOOH, H2O2, Na2SO4, K2CO3, H2O, CH2Cl2, reflux
to rt; then Et3N, toluene, rt; (b) TMSCl, Et3N, 0ꢀC to rt; (c)
CH3(CH2)n–CHO, TESOTf, CH2Cl2, À78 ꢀC; then 1M HCl, rt.
Oxidation of furfural with 30% H2O2 in the presence of
formic acid in a salted two-phase system followed by an
Table 1. Yields and diastereomeric ratios for the synthesis of erythro-
and threo-4a–d from 3
Compd
Yield (%)
erythro/threoa
erythro/threo-4a
erythro/threo-4b
erythro/threo-4c
erythro/threo-4d
11
51
89
77
18:82b
35:65c
30:70c
23:77c
Scheme 2. Natural products iso-cladospolide B and acaterin.
aErythro/threo-ratios were determined by NMR.
bErythro/threo-isomers not separated.
cErythro/threo-isomers separated by flash chromatography.
Scheme 3. Target scaffolds, derived from iso-cladospolide B (4a–d and
5a–d) and acaterin (8a–d), respectively.
Scheme 5. (a) Ac2O, Et3N, DMAP, CH2Cl2, rt.

T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
3263
Table 2. Yields and diastereomeric ratios for the synthesis of (E)/(Z)-
5a–d from erythro/threo-4a–d
Table 3. Yields and diastereomeric ratios for the synthesis of 7a–d,
dia. A/dia. B/dia. C/dia. D from 6, dia. A/dia. B
Compd
Yield (%)
(E)/(Z)b
Compd
Yield
(%)
dia. A/dia.
B/dia. C/dia. Db
(E)/(Z)-5aa
(E)/(Z)-5b
(E)/(Z)-5c
(E)/(Z)-5d
—
54
86
65
—
50:50c
50:50c
50:50c
7a, dia. A/dia. B/dia. C/dia. D
7b, dia. A/dia. B/dia. C/dia. D
7c, dia. A/dia. B/dia. C/dia. D
7d, dia. A/dia. B/dia. C/dia. D
75
23:26:40:11c
39:28:15:18d
28:27:35:10d
45:20:15:20d
92a
97a
72a
aDecomposed too rapidly to be fully characterized.
b(E)/(Z)-ratios were determined by NMR.
c(E)/(Z)-isomers not separated.
aA content of up to approximately 8% of 6 was determined by NMR.
bDia. A/dia. B/dia. C/dia. D-ratios were determined by NMR.
cDia. A, dia. D and a mixture of dia. B and dia. C were separated by
flash chromatography.
dMixtures of dia. A and dia. B were be separated from mixtures of dia.
C and dia. D by flash chromatography.
Table 4. Yields and diastereomeric ratios for the synthesis of 8a–d,
dia. A/dia. B from 7a–d, dia. A/dia. B/dia. C/dia. D
Compd
Yield (%)
dia. A/dia. Ba
b
8a, dia. A/dia. B
8b, dia. A/dia. B
8c, dia. A/dia. B
8d, dia. A/dia. B
66
76
8
—
—
5
c
c
c
73
—
aDia. A/dia. B-ratios were determined by NMR.
bDia. A/dia. B-isomers not separated.
cDiastereomers dia. A and dia. B could be separated by flash chroma-
tography, but since NMR spectra of dia. A and dia. B were almost
identical and the diastereomers could not be separated by GC–MS,
accurate diastereomeric ratios could not be determined. Based on iso-
lated fractions after flash chromatography a dia. A/dia. B ratio of
approximately 1:3 was determined.
Scheme 6. (a) i-Pr2NH, n-BuLi, THF, À78 ꢀC; then PhSSPh, THF,
À78 ꢀC; (b) i-Pr2NH, n-BuLi, THF, À78 ꢀC; then CH3(CH2)n–CHO,
THF, À50 ꢀC; (c) m-CPBA, CH2Cl2, 0 ꢀC; then toluene, reflux.
too rapidly to be fully characterized. An explanation
could be that these compounds might dimerize.28
assays showing the antagonistic effects of the com-
pounds on different quorum sensing systems. The
results obtained are listed in Table 5.
The two diastereomers, dia. A and dia. B, of 3-(10-
hydroxyalkyl)-5-methyl-5H-furan-2-ones 8a–d were
synthesized by the sequence shown in Scheme 6.
Firstly, using the luxR, PluxI-gfp(ASV) based monitor
Escherichia coli (pJBA89)32 in which fluorescent Gfp
expression can be induced by exogenous OHHL, an
inhibitory concentration, IC50, of the synthesized com-
pounds was found. IC50 describes the moles of inhibitor
molecules required per mole OHHL to reduce
expression of fluorescence to 50% of the untreated
control. Thus, the lower the IC50 value the stronger the
antagonist.
Reacting the lithium enolate of g-valerolactone with
diphenyldisulfide in THF at À78 ꢀC,29 gave the a-sulfa-
nylated product 5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one 6 in 49% yield with a diasteromeric ratio
dia. A/dia. B of 34:66. Condensation of the lithium
enolate of 6 with aliphatic aldehydes in THF at
À50 ꢀC,30 gave the products 3-(10-hydroxyalkyl)-5-
methyl-3-phenylsulfanyl-dihydro-furan-2-ones 7a–d in
the yields and diastereomeric ratios shown in Table 3.
For 7b–d, separating the products from starting materi-
als proved difficult so a content of up to approximately
8 % of6 was determined by NMR, which did not,
however, represent a problem in the subsequent step.
The measured antagonistic effects of this assay are
shown in Table 5 compared to one of the D. pulchra fur-
anones, 1b, and a synthetic analogue, 1c (see Scheme 1).
As seen in general, the compounds with the shorter
alkyl chains showed a greater antagonistic effect than
the compounds with the longer alkyl chains. Thus, ery-
thro/threo-4a was the strongest antagonist of the ery-
thro/threo-4a–d series, whereas no effect was observed
for threo-4c, erythro-4d and threo-4d. The same was seen
for 5b–d where 5b was the most effective of these com-
pounds and 5d showed no activity. For these com-
pounds, however, the limited shelf stability could be a
source of inaccurate results.
Oxidation of 7a–d with m-CPBA followed by reflux in
toluene leading to elimination,30,31 gave the target
molecules
3-(10-hydroxyalkyl)-5-methyl-5H-furan-2-
ones 8a–d, dia. A and dia. B. See Table 4 for yields and
diastereomeric ratios.
Biological Results and Discussion
For 8a–d the most active compound was 8b, dia. A,
which was also the most active compound in general for
the IC50 assay. This result is in good accordance with
The synthesized compounds erythro/threo-4a–d, (E)/
(Z)-5b–d and 8a–d, dia. A/dia. B were subjected to two

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T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
Table 5. Antagonistic effects of compounds erythro/threo-4a–d, 5b–d
and 8a–d, dia. A and dia. B in the two assays IC50 (compared to 1b and
1c) and swarming (compared to the untreated control)
chains. Thus, only erythro/threo-4a, erythro, threo-4b
and 5b of the erythro/threo-4a–d series and 5b–d series
showed an effect. It is notable that the most active
compound of the swarming assay, erythro-4b, also has
an alkyl chain of butyl length, this time however, in the
5-position. Except for 8d, dia. A, the compounds 8a–d
showed little effect in this assay. Likewise, it is interest-
ing that the antagonistic effect of these compounds see-
mingly increased with increasing lengths of the alkyl
chain. Again, differences in the activities of the different
diastereomers were observed.
d
Compd
IC50
(mol antagonist)
Swarmingh
(mm/4 h)
Erythro/threo-4aa
Erythro-4b
Threo-4b
Erythro-4c
Threo-4c
139
231
151
277
25
12
23
40
40
40
40
27
40
40
50
40
40
e
—
—
—
e
Erythro-4d
Threo-4d
e
(E)/(Z)-5bb
(E)/(Z)-5cb
(E)/(Z)-5db
8a, dia. A/dia. Bc
8b, dia. A
8b, dia. B
8c, dia. A
8c, dia. B
125
210
In conclusion, several biologically active compounds
were found. From the IC50 results, it is evident that 5H-
furan-2-ones substituted with short alkyl chains are in
general more active quorum sensing antagonists than
the longer alkyl chain counterparts. Furthermore, dif-
ferences in the activities between the different diaster-
eoisomers were observed. Much the same pattern was
observed in the swarming assay, however, without any
coherence between the relative activities for the different
compounds in the two assays. Interestingly though, the
most active antagonists synthesized in this study both
had an alkyl chain substituent of butyl length in the 3-
or 5-position, which is consistent with the striking bio-
logical activity observed from 1b and analogues hereof.
We anticipate that this new structural information will
allow us to design new potentially active compounds in
our commitment to develop quorum sensing inhibitors.
e
—
141
95
229
21835
133
194
37
25
40
NAg
NAg
40
8d, dia. A
8d, dia. B
1b
1c
Untreated control
e
—
11.9f
8.2f
NAg
aErythro/threo=18:82.
b(E)/(Z)=50:50.
cdia. A/dia. B not determined.
dIC50 describes the moles of inhibitor molecules required per mole
OHHL to reduce expression of fluorescence to 50% of the untreated
control, measured at 25 nM OHHL.
eNo effect observed.
fMeasured at 5 nM OHHL.
gNot available.
hDescribes the ability of the synthesised compounds to inhibit quorum
sensing swarming motility of S. liquefaciens MG1, measured as colony
expansion in 4h (mm/h).
Experimental
Chemistry
structures of the D. pulchra furanones 1a–b, since these
compounds as well as 8b have an alkyl chain of butyl
length in the 3-position. Interestingly, the different
diastereomers showed different effects.
All chemicals were purchased from Aldrich or Fluka
and were, unless otherwise stated, used without further
purification. All solvents were distilled immediately
prior to use. THF and Et2O were distilled under N2
from Na-benzophenone. Toluene, CH2Cl2, Et3N,
i-Pr2NH were dried over CaH2 and distilled under N2.
Furfural, aldehydes and g-valerolactone were also dis-
tilled prior to use. n-BuLi in hexanes was titrated prior
to use.33 IR spectra were recorded on a Perkin–Elmer
It is notable that the synthesized compounds were much
less efficient as quorum sensing antagonists in this assay
compared to 1b and 1c. This suggests that the action of
the halogenated furanones can be attributed to the pre-
sence of reactive groups that cause nucleophilic sub-
stitutions on the receptor site, which in turn makes the
protein prone to degradation.12
1
1600 Series FTIR (n expressed in cmÀ1). 200 MHz H-
and 50.3 MHz 13C NMR spectra were recorded with a
Bruker AC 200 spectrometer whereas 300 MHz 1H- and
75.4 MHz 13C NMR spectra were recorded with a Var-
ian Mercury 300 spectrometer. Chemical shifts are
referenced to the residual solvent peak. Mass spectra
(MS/GC–MS) have been recorded on a 5809A Hewlett-
Packard Gas Chromatograph and Trio 2 VG Masslab
in EI mode at 70 eV or in NH3–CI mode. Numbers in
parentheses in MS spectra are relative abundances.
Flash chromatography was performed with Merck silica
gel 60, 0.040–0.063 mm (230–400 mesh ASTM) or silica
gel 60, 0.035–0.070 mm, Amicon 85040. TLC was per-
formed on Merck TLC aluminum sheets, silicagel 60,
F254. Melting points are uncorrected.
The ability of the synthesized compounds to inhibit
quorum sensing dependent swarming motility of S.
liquefaciens MG1 was also measured. Thus, reduced
colony expansions of S. liquefaciens MG1 indicates a
stronger antagonist. All the compounds were dissolved
in the growth medium at 100 mM, a concentration
which was found to be non-toxic to the bacteria (data
not shown). The increase in diameter of the expanding,
swarming colonies was measured from 22 to 26-h post-
inoculation and expressed as mm/4 h. The results
obtained are also listed in Table 5. The colony of the
untreated control expanded with 40 mm/4 h.
Again, for erythro/threo-4a–d and 5b–d, the compounds
with the shorter alkyl chains showed a greater antag-
onistic effect than the compounds with the longer alkyl
5H-Furan-2-one (2). 2 (19.6 g, 46%) as a yellowish
liquid was prepared from furfural following a procedure
described in the literature.19 Bp=89–91ꢀC/15 mm Hg,

T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
3265
80–82 ꢀC/11 mm Hg (lit.19: 95–96 ꢀC/19 mmHg, 79–
81 ꢀC/9 mmHg); 13C NMR (50.3 MHz, CDCl3): d 173.6
(1C, C-2), 152.8(1C, C-4), 121.5 (1C, C-3), 72.1 (1C, C-
5); 1H NMR19 (200 MHz, CDCl3): d 7.59 (1H, ddd,
J=5.5 Hz, J=1.5 Hz, J=1.5 Hz, H-4), 6.17 (1H, ddd,
J=5.5 Hz, J=2.0 Hz, J=2.0 Hz, H-3), 4.91 (2H, dd,
J=2.0 Hz, J=1.5 Hz, 2ÂH-5); IR34 (neat): 3098(w),
2936 (w), 1773 and 1741 (2Âs, split C¼O), 1600 (m),
1448 (m), 1348 (m), 1159 (m), 1094 (m), 1035 (m), 881
(m), 810 (m), 692 (w); GC–MS35 (EI): m/z 84 (51, M+),
55 (100), 54 (24), 39 (16), 29 (11), 27 (31), 26 (17).
(5S,10R)/(5R,10S)-5-(10 -Hydroxyethyl)-5H-furan-2-one
(erythro-4a) and (5S,10S)/(5R,10R)-5-(10-hydroxyethyl)-
5H-furan-2-one (threo-4a). Colorless oil; Erythro/
threo=18:82; Rf (hexane/EtOAc 1:1)=0.13; 13C
NMR37,38 (50.3 MHz, CDCl3): d 173.0 (2C, 2ÂC-2),
153.7 (2C, 2ÂC-4), 122.7 (2C, 2ÂC-3), 87.1, 86.9, 68.0
1H NMR24,37,38 (200 MHz, CDCl3): d 7.57 (0.18H, dd,
J=5.5 Hz, J=1.5 Hz, H-4, erythro), 7.47 (0.82H, dd,
J=5.5 Hz, J=1.5 Hz, H-4, threo), 6.17 (1H, dd, J=5.5
Hz, J=2.0 Hz, H-3), 4.93 (1H, ddd, J=5.0 Hz, J=2.0
Hz, J=1.5 Hz, H-5), 4.05 (0.18H, m, H-10, erythro),
3.94 (0.82H, m, H-10, threo), 2.9 (1H, s, OH), 1.29
0
and 67.5 (4C, 2ÂC-5 and 2ÂC-10), 18.7 (2C, 2ÂCH3 );
2-(Trimethylsilyloxy)furan (3). A mixture of TMSCl
(18.8 mL, 16.1 g, 0.149 mol) and Et3N (21.6 mL, 15.7 g,
0.155 mol) was added to 2 (10.0 mL, 12.0 g, 0.142 mol)
at 0 ꢀC under N2. A colorless precipitate formed. The
reaction mixture was stirred at room temperature for 20
h. Fractional distillation of the reaction mixture under
reduced pressure afforded a crude product containing a
small amount of a colorless precipitate. The crude pro-
duct was stirred for 30 min under N2 at room tempera-
ture, whereby more colorless precipitate formed.
Filtration of this mixture through silica gel and washing
of the solids with dry Et2O gave a clear filtrate, to which
4 A molecular sieves were added. Fractional distillation
under reduced pressure of the mixture yielded 3 (13.0 g,
58%) as a yellowish liquid. Bp=41–42 ꢀC/15 mmHg
(lit.20,21: 44–46 ꢀC/17 mmHg); 13C NMR (50 MHz,
CDCl3): d 156.7 and 132.4 (2C, C-2 and C-5), 111.0 and
83.2 (2C, C-3 and C-4), À0.3 (3C, 3ÂSi–CH3); 1H
NMR20 (200 MHz, CDCl3): d 6.82 (1H, dd, J=2.0 Hz,
J=1.0 Hz, H-5), 6.21 (1H, dd, J=3.0 Hz, J=2.0 Hz, H-
4), 5.10 (1H, dd, J=3.0 Hz, J=1.0 Hz, H-3), 0.30 (9H,
s, 9ÂSi–CH3); IR (neat): 3134 (w), 2964 (m), 2903 (w),
1780 (m), 1618 (s), 1524 (m), 1383 (m), 1256 (s), 1214
0
(0.18Â3H, d, J=6.5 Hz, 3ÂCH3 , erythro), 1.28
0
(0.82Â3H, d, J=6.5 Hz, 3ÂCH3 , threo); IR37 (neat):
3442 (m, br, O–H), 3095 (w), 2980 (m), 2936 (m), 1752 (s,
C¼O), 1600 (w), 1458(w), 1380 (w), 1169 (m), 1101 (m),
990 (m), 898 (w), 852 (m), 821 (m), 709 (w); MS39 (EI): m/
+
.
z 110 (1, MÀH2O), 84 (100, HO(CH )CH¼CHCꢁO ),
+
+
.
56 (8, HO(CH )CH¼CH ), 55 (14, HO–(C3H2) ), 45
(38).
(5S,10R)/(5R,10S)-5-(10 -Hydroxybutyl)-5H-furan-2-one
(erythro-4b). Colorless oil; Rf (hexane/EtOAc
2:1)=0.22; 13C NMR (50.3 MHz, CDCl3): d 172.9 (1C,
C-2), 153.4 (1C, C-4), 122.9 (1C, C-3), 86.0 and 71.2
0
(2C, C-5 and C-10), 35.0 and 18.7 (2C, 2ÂCH2 ), 13.8
0
1
(1C, CH3 ); H NMR (200 MHz, CDCl3): d 7.55 (1H,
dd, J=6.0 Hz, J=1.5 Hz, H-4), 6.20 (1H, dd, J=6.0
Hz, J=2.0 Hz, H-3), 4.97 (1H, ddd, J=4.5 Hz, J=2.0
Hz, J=1.5 Hz, H-5), 3.90 (1H, m, H-10), 2.2 (1H, 0s,
0
OH), 1.8–1.3 (4H, m, 4ÂCH2 ), 0.95 (3H, t, 3ÂCH3 );
IR (neat): 3448(m, br, O–H), 3097 (w), 2962 (m), 2933
(m), 2874 (m), 1752 (s, C¼O), 1600 (m), 1458(m), 1333
(m), 1165 (m), 1101 (m), 1033 (m), 913 (m), 825 (m); MS
(EI): m/z 156 (1, M+), 138(1, M ÀH2O), 84 (100,
(m), 1148(m), 1070 (m), 1010 (m), 958(m), 853 (s),
36
+
.
764 (m), 712 (m), 658(m); GC–MS
(EI): m/z 156
HO(CH )CH¼CHCꢁO ), 73 (28), 55 (65, HO–
(27, M+), 113 (22), 75 (12), 74 (15), 73 (100,
Si(CH3)3).
(C3H2)+), 43 (26), 31 (10), 29 (11).
(5S,10S)/(5R,10R)-5-(10 -Hydroxybutyl)-5H-furan-2-one
(threo-4b). Colorless solid; Mp=32–36 ꢀC; Rf (hexane/
EtOAc 2:1)=0.17; 13C NMR (50.3 MHz, CDCl3): d
173.1 (1C, C-2), 154.0 (1C, C-4), 122.5 (1C, C-3), 86.2
and 71.3 (2C, C-5 and C-10), 35.1 and 18.6 (2C,
General procedure for (5S,10R)/(5R,10S)-5-(10-hydroxy-
alkyl)-5H-furan-2-ones (erythro-4a–d) and (5S,10S)/
(5R,10R)-5-(10-hydroxyalkyl)-5H-furan-2-ones (threo-4a–
d). 3 (0.27 mL, 257 mg, 1.64 mmol) and aldehyde (1.38
mmol) were dissolved in CH2Cl2 (2.5 mL) under N2 at
À78 ꢀC with stirring. TESOTf (0.06 mL, 0.27 mmol)
was added and the reaction mixture was stirred at
À78 ꢀC for 2 h under N2. 1M HCl (0.8mL) was then
added and the reaction mixture was allowed to heat to
room temperature under stirring. The mixture was then
stirred for 30 min at room temperature. The reaction
mixture was diluted with CH2Cl2 (2.0 mL) and water
(1.0 mL). The organic phase was isolated and washed
with water (2Â1.0 mL). The combined aqueous phases
were extracted with CH2Cl2 (1.0 mL) and the combined
organic phases were dried over MgSO4, filtered and
concentrated. Flash chromatography (4a: hexane/
EtOAc 1:1; 4b–d: hexane/EtOAc 2:1) of the residue gave
the desired products in the following yields: 4a: 11%,
4b: 51%, 4c: 89%, 4d: 77% and the following erythro/
threo ratios: 4a: 18:82, 4b: 35:65, 4c: 30:70, 4d: 23:77.
Except for 4a, erythro- and threo-isomers could be
separated.
0
0
2ÂCH2 ), 13.8(1C, CH3 ); 1H NMR (200 MHz, CDCl3):
d 7.48(1H, dd, J=6.0 Hz, J=1.5 Hz, H-4), 6.17 (1H,
dd, J=6.0 Hz, J=2.0 Hz, H-3), 4.99 (1H, ddd, J=4.5
0
Hz, J=2.0 Hz, J=1.5 Hz, H-5), 3.78(1H, m, H-1 ), 2.6
0
(1H, s, OH), 1.7–1.3 (4H, m, 4ÂCH2 ), 0.95 (3H, t,
0
3ÂCH3 ); IR (KBr): 3404 (m, br, O–H), 3083 (w), 2959
(m), 2872 (w), 1752 (s, C¼O), 1601 (w), 1467 (w), 1170
(m), 1095 (m), 1033 (m), 917 (w), 850 (w), 826 (m); MS
(EI): m/z 156 (1, M+), 138(1, M ÀH2O), 84 (100,
+
.
HO(CH )CH¼CHCꢁO ), 73 (23), 55 (63, HO–
(C3H2)+), 43 (24).
(5S,10R)/(5R,10S)-5-(10 -Hydroxyhexyl)-5H-furan-2-one
(erythro-4c). Colorless oil; Rf (hexane/EtOAc
2:1)=0.25; 13C NMR (50.3 MHz, CDCl3): d 173.2 (1C,
C-2), 153.7 (1C, C-4), 122.7 (1C, C-3), 86.2 and 71.4
(2C, C-5 and C-10), 303.0, 31.5, 25.2 and 22.5 (4C,
0
4ÂCH2 ), 13.9 (1C, CH3 ); 1H NMR (200 MHz, CDCl3):
d 7.56 (1H, dd, J=5.5 Hz, J=1.5 Hz, H-4), 6.19 (1H,

3266
T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
dd, J=5.5 Hz, J=2.0 Hz, H-3), 4.96 (1H, ddd, J=4.5
Hz, J=2.0 Hz, J=1.5 Hz, H-5), 3.87 (1H, m, H-10), 3.2
General procedure for 5-((E)/(Z)-alkylidene)-5H-furan-
2-ones (5a–d). 4a–d 0.543 mmol) was dissolved in
CH2Cl2 (3.0 mL) under N2. Et3N (0.22 mL, 160 mg,
1.58mmol) and acetic anhydride (0.12 mL, 130 mg, 1.27
mmol) followed by DMAP (6.0 mg, 0.049 mmol) were
then added. The mixture was stirred at room tempera-
ture under N2 for 2 h. TLC of the reaction mixture
showed no trace of starting materials. The reaction
mixture was diluted with CH2Cl2 (2.0 mL) and the
organic phase was washed with saturated aqueous
NaHCO3 (1.0 mL) and water (1.0 mL). The organic
phase was dried over MgSO4, filtered and concentrated.
Flash chromatography (hexane/EtOAc 9:1) of the resi-
due gave the desired products in the following yields: 5b:
54%, 5c: 86%, 5d: 64%, all with (E)/(Z)-ratios 50:50. 5a
was presumably isolated but decomposed too rapidly to
be fully characterized. The (E)/(Z)-isomers were not
separated. The products were stored under N2.
0
(1H, s, OH), 1.7–1.1 (8H, m, 8ÂCH2 ), 0.85 (3H, t,
0
3ÂCH3 ); IR (neat): 3448(m, br, O–H), 3097 (w), 2930
(m), 2861 (m), 1752 (s, C¼O), 1600 (w), 1466 (m), 1337
(m), 1170 (m), 1105 (m), 1031 (m), 897 (w), 712 (w); MS
(EI): m/z 184 (1, M+), 166 (1, MÀH2O), 84 (100,
+
+
.
HO(CH )CH¼CHCꢁO ), 83 (28), 55 (52, HO–(C3H2) ),
43 (11), 41 (19), 29 (12).
(5S,10S)/(5R,10R)-5-(10 -Hydroxyhexyl)-5H-furan-2-one
(threo-4c). Colorless solid; Mp=53–57 ꢀC; Rf (hexane/
EtOAc 2:1)=0.23; 13C NMR (50.3 MHz, CDCl3): d
173.1 (1C, C-2), 154.0 (1C, C-4), 122.5 (1C, C-3), 86.2
and 71.6 (2C, C-5 and C-10), 33.1, 31.5, 25.1 and 22.4
0
0
1
(4C, 4ÂCH2 ), 13.9 (1C, CH3 ); H NMR (200 MHz,
CDCl3): d 7.47 (1H, dd, J=6.0 Hz, J=1.5 Hz, H-4),
6.16 (1H, dd, J=6.0 Hz, J=2.0 Hz, H-3), 4.99 (1H,
ddd, J=4.5 Hz, J=2.0 Hz, J=1.5 Hz, H-5), 3.76 (1H,
m, H-10), 2.6 (1H, s, OH), 1.7–1.1 (8H, m, 8ÂCH2 ),
5-((E)/(Z)-Butylidene)-5H-furan-2-one (5b). Colorless
oil; (E)/(Z)=50:50; Rf (hexane/EtOAc 9:1)=0.25/0.23;
13C NMR (50.3 MHz, CDCl3): d 170.1 (2C, 2ÂC-2),
150.0, 149.7, 143.6, 139.4, 119.9, 118.8, 117.5 and 116.6
(8C, 2ÂC-3, 2ÂC-4, 2ÂC-5 and 2ÂC-10), 28.4, 28.3,
0
0
0.85 (3H, t, 3ÂCH3 ); IR (KBr): 3390 (m, br, O–H),
3095 (w), 2928(m), 2858(w), 1723 (s, C ¼O), 1603 (w),
1468(w), 1177 (w), 1097 (w), 1027 (w), 920 (w), 864 (w),
826 (w), 800 (w), 659 (w); MS (EI): m/z 184 (1, M+),
+
0
.
166 (1, MÀH2O), 84 (100, HO(CH )CH¼ CHCꢁO ),
83 (28), 57 (10), 56 (10), 55 (55, HO–(C3H2)+), 43 (11),
41 (18).
22.7 and 22.1 (4C, 4ÂCH2 ), 13.6 and 13.4 (2C,
0
1
2ÂCH3 ); H NMR (200 MHz, CDCl3): d 7.64 (0.50H,
dd, J=5.5 Hz, J=1.0 Hz, H-4, E), 7.33 (0.50H, d,
J=5.5 Hz, H-4, Z), 6.18(0.50H, dd, J=5.5 Hz, J=2.0
Hz, H-3, E), 6.13 (0.50H, dd, J=5.5 Hz, J=0.5 Hz, H-
3, Z), 5.76 (0.50H, dddd, J=8.5 Hz, J=8.5 Hz,
J=2.0 Hz, J=1.0 Hz, H-10, E), 5.30 (0.50H, ddd,
J=8.0 Hz, J=8.0 Hz, J=0.5 Hz, H-100, Z), 2.3 (2H,
(5S,10R)/(5R,10S)-5-(10 -Hydroxyoctyl)-5H-furan-2-one
(erythro-4d). Colorless oil; Rf (hexane/EtOAc
2:1)=0.30; 13C NMR (50.3 MHz, CDCl3): d 173.1 (1C,
C-2), 153.6 (1C, C-4), 122.8(1C, C-3), 86.1 and 71.4
(2C, C-5 and C-10), 33.0, 31.7, 029.3, 29.1, 25.5 and 22.6
0
m, 2ÂC¼C-CH2 ), 1.5 (2H, m, 2ÂCH2 ), 0.93 (3H, t,
0
1
0
(6C, 6ÂCH2 ), 14.0 (1C, CH3 ); H NMR (200 MHz,
CDCl3): d 7.55 (1H, dd, J=5.5 Hz, J=1.5 Hz, H-4),
6.18(1H, dd, J=5.5 Hz, J=2.0 Hz, H-3), 4.96 (1H,
ddd, J=4.5 Hz, J=2.0 Hz, J=1.5 Hz, H-5), 3.87 (1H,
3ÂCH3 ).
5-((E)/(Z)-Hexylidene)-5H-furan-2-one (5c). Colorless
oil; (E)/(Z)=50:50; Rf (hexane/EtOAc 9:1)=0.25/0.24;
13C NMR (50.3 MHz, CDCl3): d 171.7 (2C, 2ÂC-2),
151.5, 151.2, 145.2, 140.9, 121.6, 120.5, 119.4 and 118.5
(8C, 2ÂC-3, 2ÂC-4, 2ÂC-5 and 2ÂC-10), 32.9, 32.7,
m, H-10), 2.8(1H, s, O H), 1.7–1.1 (12H, m, 12ÂCH2 ),
0
0
0.90 (3H, t, 3ÂCH3 ); IR (neat): 3424 (m, br, O–H),
3104 (w), 2925 (s), 2856 (m), 1752 (s, C¼O), 1600
(w), 1466 (m), 1332 (m), 1170 (m), 1106 (m),
1043 (m), 897 (m), 826 (m), 706 (w); MS (EI): m/z 212 (1,
0
30.8, 30.1, 28.1, 28.0 and 23.9 (8C, 8ÂCH2 ), 15.5 (2C,
0
1
2ÂCH3 ); H NMR (200 MHz, CDCl3): d 7.64 (0.50H,
dd, J=5.5 Hz, J=0.5 Hz, H-4, E), 7.33 (0.50H, d,
J=5.5 Hz, H-4, Z), 6.20 (0.50H, dd, J=5.5 Hz, J=2.0
Hz, H-3, E), 6.14 (0.50H, dd, J=5.5 Hz, J=0.5 Hz, H-
3, Z), 5.79 (0.50H, dddd, J=8.5 Hz, J=8.5 Hz, J=2.0
Hz, J=0.5 Hz, H-10, E), 5.31 (0.50H, ddd, J=8.0 Hz,
J=8.0 Hz, J=0.5 Hz, H-10, Z), 2.3 (2H, m, 2ÂC¼C–
M+), 194 (1, MÀH2O), 84 (100, HO(CH )CH¼
.
CHCꢁO+), 69 (47), 57 (11), 55 (33, HO–(C3H2)+), 43
(15), 41 (14).
(5S,10S)/(5R,10R)-5-(10 -Hydroxyoctyl)-5H-furan-2-one
(threo-4d). Colorless solid; Mp=72.5–74 ꢀC; Rf (hex-
ane/EtOAc 2:1)=0.26; 13C NMR (50.3 MHz, CDCl3): d
172.9 (1C, C-2), 153.8(1C,0 C-4), 122.7 (1C, C-3), 86.1
and 71.8(2C, C-5 and C-1 ), 33.2, 31.7, 29.3, 29.1, 25.4
0
0
0
CH2 ), 1.7–1.2 (6H, m, 6ÂCH2 ), 0.9 (3H, t, 3ÂCH3 ).
5-((E)/(Z)-Octylidene)-5H-furan-2-one (5d). Colorless
oil; (E)/(Z)=50:50; Rf (hexane/EtOAc 9:1)=0.27/0.25;
13C NMR (50.3 MHz, CDCl3): d 170.2 and 170.0 (2C,
2ÂC-2), 149.9, 149.6, 143.6, 139.3, 120.0, 118.9, 117.8
and 117.0 (8C, 2ÂC-3, 2ÂC-4, 2ÂC-5 and 2ÂC-10),
31.7, 29.6, 29.2, 29.0, 26.60, 26.4 and 22.6 (12C,
0
0
and 22.6 (6C, 6ÂCH2 ), 14.0 (1C, CH3 ); 1H NMR
(200 MHz, CDCl3): d 7.47 (1H, dd, J=5.5 Hz, J=1.5
Hz, H-4), 6.18(1H, dd, J=5.5 Hz, J=2.0 Hz, H-3),
4.99 (1H, ddd, J=4.5 Hz, J=2.0 Hz, J=1.5 Hz, H-5),
3.76 (1H, m, H-10), 2.2 (1H, s, OH), 1.7–1.1 (12H, m,
0
0
0
12ÂCH2 ), 0.85 (3H, t, 3ÂCH3 ); IR (KBr): 3378(m, br,
O–H), 3102 (w), 2925 (m), 2853 (m), 1723 (s, C¼O),
1603 (w), 1470 (w), 1431 (w), 1328(w), 1177 (m), 1101
(w), 1019 (w), 922 (w), 863 (w), 832 (m), 799 (w), 661
(w); MS (EI): m/z 212 (1, M+), 194 (1, MÀH2O), 84
12ÂCH2 ), 14.0 (2C, 2ÂCH3 ); 1H NMR (200 MHz,
CDCl3): d 7.63 (0.50H, dd, J=5.5 Hz, J=0.5 Hz, H-4,
E), 7.33 (0.50H, d, J=5.5 Hz, H-4, Z), 6.20 (0.50H, dd,
J=5.5 Hz, J=2.0 Hz, H-3, E), 6.14 (0.50H, dd, J=5.5
Hz, J=0.5 Hz, H-3, Z), 5.78(0.50H, dddd, J=8.5 Hz,
J=8.5 Hz, J=2.0 Hz, J=0.5 Hz, H-10, E), 5.31 (0.50H,
ddd, J=8.0 Hz, J=8.0 Hz, J=0.5 Hz, H-10, Z), 2.4
+
.
(100, HO(CH )CH¼CHCꢁO ), 69 (45), 57 (13), 55 (37,
HO–(C3H2)+), 45 (16), 43 (16), 41 (16).

T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
3267
0
0
(2H, m, 2ÂC¼C–CH2 ), 1.7–1.2 (10H, m, 10ÂCH2 ), 0.9
General procedure for 3-(10-hydroxyalkyl)-5-methyl-3-
phenylsulfanyl-dihydro-furan-2-ones (7a–d, dia. A, dia.
B, dia. C and dia. D). i-Pr2NH (0.18mL, 129 mg, 1.27
mmol) was dissolved in THF (0.8mL) under N 2 and the
mixture was cooled to À78 ꢀC. 1.52 M n-BuLi in hex-
anes (0.85 mL, 1.29 mmol) was added and the mixture
was stirred for 30 min at À78 ꢀC under N2. A solution
of 6 (224 mg, 1.08mmol) in THF (1.1 mL) was added
dropwise whereupon the temperature was raised to
À50 ꢀC. The reaction mixture was stirred for 1 h at this
temperature under N2, whereupon a solution of alde-
hyde (1.30 mmol) in THF (0.8mL) was added. The
reaction mixture was stirred for 2 h at À50 ꢀC under N2.
The reaction mixture was poured into cold saturated
aqueous NH4Cl (6.5 mL). The mixture was extracted
with Et2O (4Â3.5 mL) and the combined organic phases
were dried over MgSO4, filtered and concentrated.
Flash chromatography (7a: hexane/EtOAc 3:1; 7b: hex-
ane/EtOAc 6:1; 7c–d: hexane/EtOAc 9:1) of the residue
gave the desired products in the following yields: 7a:
75%, 7b: 92%, 7c: 97%, 7d: 72% and the following dia.
A/dia. B/dia. C/dia. D-ratios: 7a: 23:26:40:11, 7b:
39:28:15:18, 7c: 28:27:35:10, 7d: 45:20:15:20. For 7b–d,
mixtures of dia. A and dia. B could be separated from
mixtures of dia. C and dia. D. For 7a, dia. A, dia. D and
a mixture of dia. B and dia. C were separated. For 7b–d,
separating the products from starting materials proved
difficult so a content of up to approximately 8% of 6
was determined by NMR, which did not, however,
represent a problem in the subsequent step.
0
(3H, t, 3ÂCH3 ).
5-Methyl-3-phenylsulfanyl-dihydro-furan-2-one (6, dia. A
and dia. B). i-Pr2NH (0.76 mL, 554 mg, 5.38mmol)
was dissolved in THF (20 mL) under N2 and the mix-
ture was cooled to À78 ꢀC. 1.52 M n-BuLi in hexanes
(3.54 mL, 5.38mmol) was added and the mixture was
stirred for 30 min at À78 ꢀC under N2. A solution of g-
valerolactone (0.46 mL, 485 mg, 4.84 mmol) in THF (10
mL) was added and the reaction mixture was stirred for
30 min at À78 ꢀC under N2. A solution of diphenyldi-
sulfide (1.270 g, 5.81 mmol) in THF (10 mL) was then
added dropwise and the reaction mixture was stirred for
3 h at À78 ꢀC under N2. The reaction mixture was
quenched by adding a 1:1:1 solution of AcOH/MeOH/
THF (2.0 mL). The reaction mixture was diluted with
CHCl3 (20 mL) and water (10 mL) and the organic
phase was isolated, washed with water (3Â10 mL), dried
over MgSO4, filtered and concentrated. Flash chroma-
tography (hexane/EtOAc 9:1) of the residue yielded 6
(491 mg, 49%) as a colorless oil with dia. A/dia.
B=0.34:0.66. The diastereomers could be separated by
flash chromatography. Also isolated was 266 mg (17%)
of the a-disulfanylated product.
5-Methyl-3-phenylsulfanyl-dihydro-furan-2-one (6, dia.
A). Colorless oil; Rf (hexane/EtOAc 9:1)=0.15; 13C
NMR40 (75.4 MHz, CDCl3): d 174.6 (1C, C-2), 133.6,
132.1, 129.4 and 128.8 (6C, 6ÂS–C6H5), 75.6 (1C, C-5),
1
45.7 and 37.8(2C, C-3 and C-4), 21.0 (1C, CH3-5); H
NMR40,41 (300 MHz, CDCl3): d 7.59–7.52 and 7.38–
7.31 (2H and 3H, 2Âm, 5ÂS–C6H5), 4.56 (1H, ddq,
J=7.8Hz, J=6.1 Hz, J=6.0 Hz, H-5), 3.91 (1H, dd,
J=8.4 Hz, J=3.7 Hz, H-3), 2.39 (1H, ddd, J=13.8Hz,
J=6.0 Hz, J=3.7 Hz, H-4a), 2.27 (1H, ddd, J=13.8
Hz, J=8.4 Hz, J=7.8Hz, H-4 b), 1.38(3H, d, J=6.1
Hz, 3ÂCH3-5); IR (neat): 3060 (w), 2980 (m), 2932 (m),
1766 (s, C¼O), 1582 (w), 1479 (m), 1440 (m), 1386 (m),
1341 (m), 1297 (m), 1184 (s), 1087 (m), 1026 (m), 944
(m), 744 (m), 692 (m); MS (EI): m/z 209 (10, M+1), 208
(71, M+), 164 (11), 149 (33), 135 (17), 116 (18), 110 (71,
Ph–SH), 109 (32), 91 (14), 77 (14), 69 (11), 65 (24), 55
(100), 51 (13), 45 (10), 43 (16), 39 (16), 29 (11), 27 (21).
3-(10-Hydroxyethyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7a, dia. A). Colorless oil; Rf (hexane/
EtOAc 3:1)=0.27; 13C NMR (75.4 MHz, CDCl3): d
175.2 (1C, C-2), 137.2, 130.3, 129.2 and 128.7 (6C, 6ÂS–
C6H5), 74.5, 67.0 and 60.6 (3C, C-3, C-5 an0d C-10), 36.7,
1
20.7 and 16.9 (3C, C-4, CH3-5 and CH3 ); H NMR
(300 MHz, CDCl3): d 7.56–7.49 and 7.45–7.30 (2H and
3H, 2Âm, 5ÂS–C6H5), 4.67 (1H, m, H-5), 4.07 (1H, q,
J=6.4 Hz, H-10), 2.37 (1H, ddd, J=13.6 Hz, J=10.0
Hz, J=0.8Hz, H-4 a), 2.29 (1H, s, OH), 2.10 (1H, dd,
J=13.6 Hz, J=5.6 Hz, H-4b), 1.41 (3H, dd, J=6.1 Hz,
J=0.8Hz, 3 ÂCH3-5), 1.38(3H, dd, J=6.4 Hz, J=1.1
0
Hz, 3ÂCH3 ); IR (neat): 3460 (m, br, O–H), 3057 (w),
2978(m), 2933 (m), 1752 (s, C ¼O), 1573 (w), 1474 (m),
1440 (s), 1385 (m), 1348 (m), 1297 (m), 1199 (s), 1100
(m), 1057 (m), 994 (m), 941 (m), 890 (m), 756 (m), 694
(m), 652 (w); MS (EI): m/z 252 (6, M+), 208(100,
MÀCH3CHO), 163 (10), 149 (11), 147 (10), 136 (17),
135 (24), 131 (25), 130 (11), 129 (40), 121 (18), 110 (52,
Ph–SH), 109 (39), 105 (59), 91 (24), 85 (36), 77 (17), 69
(10), 65 (18), 55 (56), 45 (14), 43 (22).
5-Methyl-3-phenylsulfanyl-dihydro-furan-2-one (6, dia.
B). Colorless oil; Rf (hexane/EtOAc 9:1)=0.12; 13C
NMR40 (75.4 MHz, CDCl3): d 174.8(1C, C-2), 133.5,
132.6, 129.4 and 128.6 (6C, 6ÂS–C6H5), 75.1 (1C, C-5),
1
46.8and 37.7 (2C, C-3 and C-4), 21.3 (1C, CH3-5); H
NMR40,41 (300 MHz, CDCl3): d 7.58–7.51 and 7.37–
7.29 (2H and 3H, 2Âm, 5ÂS–C6H5), 4.53 (1H, ddq,
J=9.0 Hz, J=6.2 Hz, J=6.1 Hz, H-5), 3.97 (1H, dd,
J=10.6 Hz, J=9.0 Hz, H-3), 2.74 (1H, ddd, J=13.1
Hz, J=9.0 Hz, J=6.1 Hz, H-4a), 1.85 (1H, ddd,
J=13.1 Hz, J=10.6 Hz, J=9.0 Hz, H-4b), 1.35 (3H, d,
J=6.2 Hz, 3ÂCH3-5); IR (neat): 3058(w), 2978(w),
2933 (w), 1770 (s, C¼O), 1583 (w), 1476 (m), 1440 (m),
1387 (m), 1342 (m), 1175 (s), 1121 (m), 1054 (m), 951
(m), 744 (m), 692 (m); MS (EI): m/z 209 (11, M+1), 208
(95, M+), 164 (13), 149 (36), 135 (17), 116 (18), 110 (61,
Ph–SH), 109 (31), 91 (16), 77 (13), 65 (21), 55 (100), 51
(15), 45 (14), 43 (15), 39 (18), 29 (11), 27 (18).
3-(10-Hydroxyethyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7a, dia. B/dia. C). Colorless oil; Dia. B/
dia. C=37:63; Rf (hexane/EtOAc 3:1)=0.24; 13C NMR
(75.4 MHz, CDCl3): d 177.2 and 175.0 (2C, 2ÂC-2),
137.6, 137.2, 130.5, 130.1, 129.6, 129.3, 129.2 and 128.8
(12C, 12ÂS–C6H5), 74.5, 68.6, 68.6, 61.3 and 60.2 (6C,
2ÂC-3, 2ÂC-5 and 2ÂC-10), 39.0, 34.7, 21.9, 20.7, 17.7
0
and 17.1 (6C, 2ÂC-4, 2ÂCH3-5 and 2ÂCH3 ); 1H NMR
(300 MHz, CDCl3): d 7.60–7.49 and 7.44–7.29 (2H and
3H, 2Âm, 5ÂS–C6H5), 4.54 (1H, m, H-5), 4.08(0.63H,

3268
T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
q, J=6.2 Hz, H-10, dia. C), 3.99 (0.37H, q, J=6.2 Hz,
H-10, dia. B), 3.30 (0.37H, s, OH, dia. B), 2.87 (0.63H,
dd, J=13.9 Hz, J=8.5 Hz, H-4a, dia. C), 2.82 (0.63H, s,
OH, dia. C), 2.20 (0.37H, dd, J=14.1 Hz, J=5.6 Hz, H-
4a, dia. B), 2.05 (0.37H, dd, J=14.1 Hz, J=10.0 Hz, H-
4b, dia B), 1.75 (0.63H, dd, J=13.9 Hz, J=4.8Hz, H-
4b, dia C), 1.37 (3H, d, J=6.2 Hz, 3ÂCH3), 1.24 (3H, d,
J=6.2 Hz, 3ÂCH3); IR (neat): 3435 (m, br, O–H), 3060
(w), 2976 (m), 2931 (m), 1751 (s, C¼O), 1574 (w), 1474
(m), 1440 (s), 1384 (m), 1349 (m), 1297 (m), 1198 (s),
1100 (m), 1093 (s), 1055 (m), 991 (m), 941 (m), 897 (m),
755 (m), 694 (m), 642 (w); MS (EI): m/z 252 (3, M+),
208(100, M ÀCH3CHO), 149 (17), 147 (10), 136 (12),
135 (22), 131 (21), 129 (29), 121 (16), 116 (13), 110 (66,
Ph–SH), 109 (43), 105 (43), 91 (23), 85 (29), 77 (17), 69
(10), 65 (20), 55 (37), 45 (10), 43 (17).
(s), 1117 (m), 1064 (m), 1026 (m), 1006 (m), 959 (m), 939
(m), 854 (w), 752 (m), 693 (m), 641 (w); MS (EI): m/z
280 (5, M+), 208(82, M ÀCH3(CH2)2CHO), 149 (22),
135 (16), 131 (11), 116 (14), 110 (69, Ph–SH), 109 (37),
105 (17), 91 (18), 85 (15), 77 (16), 72 (20), 71 (22), 69
(19), 65 (27), 57 (14), 56 (11), 55 (100), 45 (10), 44 (18),
43 (38), 41 (22), 39 (20), 29 (28), 28 (18), 27 (33).
3-(10-Hydroxybutyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7b, dia. C/dia. D). Colorless oil; Dia. C/
dia. D=46:54; Rf (hexane/EtOAc 6:1)=0.16; 13C NMR
(75.4 MHz, CDCl3): d 177.0 and 175.8(2C, 2 ÂC-2),
137.2, 137.1, 130.2, 130.0, 129.5, 129.3, 129.2 and 129.0
(12C, 12ÂS–C6H5), 74.4, 74.3, 73.0, 72.2, 61.5 and 59.8
(6C, 2ÂC-3, 2ÂC-5 and 2ÂC-10), 36.8, 35.1, 34.1, 33.0,
21.9, 21.9, 19.8, 19.4, 14.0 and 13.9 (10C, 2ÂC-4,
0
0
1
4ÂCH2 , 2ÂCH3-5 and 2ÂCH3 ); H NMR (300 MHz,
CDCl3): d 7.59–7.48and 7.45–7.29 (2H and 3H, 2 Âm,
5ÂS–C6H5), 4.55 (1H, m, H-5), 3.85 (0.54H, dd, J=10.3
3-(10-Hydroxyethyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7a, dia. D). Colorless oil; Rf (hexane/
EtOAc 3:1)=0.16; 13C NMR (75.4 MHz, CDCl3): d
175.6 (1C, C-2), 137.3, 130.3, 129.3 and 129.2 (6C, 6ÂS–
C6H5), 74.4, 69.1 and 61.1 (3C, C-3, C-5 an0d C-10), 36.4,
0
Hz, J=1.8Hz, H-1 , dia. D), 3.74 (0.46H, dd, J=10.1
Hz, J=2.0 Hz, H-10, dia. C), 2.87 (0.54H, dd, J=14.1
Hz, J=8.6 Hz, H-4a, dia. D), 2.77 (0.46H, dd, J=14.4
Hz, J=8.3 Hz, H-4a, dia. C), 2.62 (1H, s, OH), 1.79
(0.46H, dd, J=14.4 Hz, J=6.1 Hz, H-4b, dia. C), 1.74
(0.54H, dd, J=14.1 Hz, J=4.7 Hz, H-4b, dia. D), 1.68–
1
22.1 and 17.7 (3C, C-4, CH3-5 and CH3 ); H NMR
(300 MHz, CDCl3): d 7.62–7.54 and 7.47–7.32 (2H and
3H, 2Âm, 5ÂS–C6H5), 4.57 (1H, m, H-5), 4.00 (1H, q,
J=6.2 Hz, H-10), 2.78(1H, dd, J=14.6 Hz, J=8.3 Hz,
H-4a), 2.69 (1H, s, OH), 1.80 (1H, dd, J=14.6 Hz,
J=5.8Hz, H-4 b), 1.29 (3H, d, J=6.2 Hz, 3ÂCH3), 1.25
(3H, d, J=6.2 Hz, 3ÂCH3); IR (neat): 3410 (m, br, O–
H), 3059 (w), 2978(m), 2932 (m), 1750 (s, C ¼O), 1583
(w), 1439 (s), 1384 (m), 1349 (m), 1271 (m), 1196 (s),
1118(s), 1046 (s), 969 (m), 904 (m), 755 (m), 694 (m);
MS (EI): m/z 252 (2, M+), 208(100, M ÀCH3CHO),
163 (10), 149 (17), 147 (11), 136 (15), 135 (23), 131 (24),
130 (10), 129 (36), 121 (17), 116 (11), 110 (61, Ph–SH),
109 (41), 105 (52), 91 (24), 85 (30), 77 (14), 65 (13), 55
(23), 43 (16).
0
1.22 (4H, m, 4ÂCH2 ), 1.27 (0.54Â3H, d, J=6.6 Hz,
3ÂCH3-5, dia. D), 1.17 (0.46Â3H, d, J=6.3 Hz,
0
3ÂCH3-5, dia. C), 0.97–0.86 (3H, 2Ât, 3ÂCH3 ); IR
(neat): 3437 (m, br, O–H), 3060 (w), 2960 (m), 2873 (m),
1752 (s, C¼O), 1573 (w), 1440 (m), 1384 (m), 1348 (m),
1194 (s), 1111 (m), 1067 (m), 1000 (m), 964 (m), 941 (m),
866 (w), 753 (m), 694 (m), 640 (w); MS (EI): m/z 280 (1,
M+), 208(100, M ÀCH3(CH2)2CHO), 164 (11), 149
(30), 147 (10), 135 (22), 131 (17), 129 (11), 121 (13), 116
(22), 115 (11), 110 (91, Ph–SH), 109 (51), 105 (24), 91
(23), 85 (21), 77 (17), 72 (26), 69 (17), 65 (25), 55 (89), 51
(13), 45 (13), 44 (29), 43 (43), 41 (24), 39 (24), 29 (28), 27
(29).
3-(10-Hydroxybutyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7b, dia. A/dia. B). Colorless oil; Dia. A/
dia. B=60:40; Rf (hexane/EtOAc 6:1)=0.23; 13C NMR
(75.4 MHz, CDCl3): d 175.2 and 174.8(2C, 2 ÂC-2),
137.4, 137.2, 130.3, 130.2, 129.1, 129.0, 128.8 and 128.7
(12C, 12ÂS–C6H5), 74.3, 74.3, 72.4, 70.3, 61.4 and 60.2
(6C, 2ÂC-3, 2ÂC-5 and 2ÂC-10), 39.4, 36.9, 33.9, 32.2,
20.8, 20.6, 19.8, 19.4, 14.0 and 14.0 (10C, 2ÂC-4,
3-(10-Hydroxyhexyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7c, dia. A/dia. B). Colorless oil; Dia. A/dia.
B=59:41; Rf (hexane/EtOAc 9:1)=0.23; 13C NMR
(75.4 MHz, CDCl3): d 175.2 and 174.8(2C, 2 ÂC-2),
137.5, 137.2, 130.3, 130.2, 129.2, 129.1, 128.8 and 128.6
(12C, 12ÂS–C6H5), 74.4, 72.7, 70.7, 61.5 and 60.3 (6C,
2ÂC-3, 2ÂC-5 and 2ÂC-10), 39.5, 36.9, 31.8, 30.1, 26.3,
26.0, 22.7, 22.7, 20.8, 20.6, 14.2 and 14.1 (14C, 2ÂC-4,
0
0
1
4ÂCH2 , 2ÂCH3-5 and 2ÂCH3 ); H NMR (300 MHz,
CDCl3): d 7.60–7.49 and 7.45–7.29 (2H and 3H, 2Âm,
5ÂS–C6H5), 4.65 (0.40H, ddq, J=10.1 Hz, J=6.2 Hz,
J=5.5 Hz, H-5, dia. B), 4.48(0.60H, ddq, J=9.7 Hz,
J=6.1 Hz, J=5.5 Hz, H-5, dia. A), 3.83 (0.40H, dd,
J=10.4 Hz, J=1.3 Hz, H-10, dia. B), 3.77 (0.60H, dd,
J=9.8Hz, J=2.0 Hz, H-10, dia. A), 3.27 (1H, s, OH),
2.36 (0.40H, dd, J=13.5 Hz, J=10.1 Hz, H-4a, dia. B),
2.23 (0.60H, dd, J=14.1 Hz, J=5.5 Hz, H-4a, dia. A),
2.08(0.40H, dd, J=13.5 Hz, J=5.5 Hz, H-4b, dia. B),
2.05 (0.60H, dd, J=14.1 Hz, J=9.7 Hz, H-4b, dia. A),
0
0
1
8ÂCH2 , 2ÂCH3-5 and 2ÂCH3 ); H NMR (300 MHz,
CDCl3): d 7.60–7.49 and 7.45–7.30 (2H and 3H, 2Âm,
5ÂS–C6H5), 4.65 (0.41H, ddq, J=10.1 Hz, J=6.0 Hz,
J=6.2 Hz, H-5, dia. B), 4.50 (0.59H, ddq, J=9.9 Hz,
J=6.2 Hz, J=5.8Hz, H-5, dia. A), 3.82 (0.41H, dd,
J=10.4 Hz, J=1.5 Hz, H-10, dia. B), 3.75 (0.59H, dd,
J=9.7 Hz, J=1.7 Hz, H-10, dia. A), 3.25 (1H, s, OH),
2.36 (0.41H, dd, J=13.5 Hz, J=10.1 Hz, H-4a, dia. B),
2.24 (0.59H, dd, J=14.1 Hz, J=5.8Hz, H-4 a, dia. A),
2.08(0.41H, dd, J=13.5 Hz, J=6.2 Hz, H-4b, dia. B),
2.06 (0.59H, dd, J=14.1 Hz, J=9.9 Hz, H-4b, dia. A),
0
1.72–1.19 (4H, m, 4ÂCH2 ), 1.39 (0.40Â3H, d, J=6.2
0
Hz, 3ÂCH3-5, dia. B), 1.36 (0.60Â3H, d, J=6.1 Hz,
1.71-1.19 (8H, m, 8ÂCH2 ), 1.40 (0.41Â3H, d, J=6.0
0
3ÂCH3-5, dia. A), 0.97 (0.40Â3H, t, 3ÂCH3 , dia. B),
Hz, 3ÂCH3-5, dia. B), 1.37 (0.59Â30H, d, J=6.2 Hz,
3ÂCH3-5, dia. A), 0.90 (3H, m, 3CH3 ); IR (neat): 3482
(m, br, O–H), 3059 (w), 2930 (m), 2858 (m), 1762 (s,
C¼O), 1574 (w), 1440 (m), 1386 (m), 1344 (m), 1296
0
0.91 (0.60Â3H, t, 3ÂCH3 , dia. A); IR (neat): 3480 (m,
br, O–H), 3059 (w), 2961 (m), 2873 (m), 1760 (s, C¼O),
1574 (w), 1440 (m), 1386 (m), 1344 (m), 1295 (m), 1194

T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
3269
(m), 1193 (s), 1121 (m), 1056 (m), 1025 (m), 940 (m), 879
(w), 751 (m), 692 (m), 641 (w); MS (EI): m/z 308(1,
M+), 208(100, M ÀCH3(CH2)4CHO), 164 (10), 149
(24), 136 (10), 135 (16), 131 (17), 129 (11), 121 (10), 116
(14), 110 (57, Ph–SH), 109 (34), 105 (23), 91 (14), 77
(10), 65 (11), 57 (10), 56 (13), 55 (36), 43 (11), 39 (5).
MS (EI): m/z 208(70, M ÀCH3(CH2)6CHO), 149 (17),
135 (13), 131 (11), 116 (11), 110 (51, Ph–SH), 109 (28),
105 (13), 91 (13), 85 (17), 84 (26), 82 (13), 81 (12), 77
(10), 69 (26), 68(13), 67 (13), 65 (22), 57 (36), 56 (32), 55
(100), 51 (12), 45 (17), 44 (29), 43 (54), 42 (17), 41 (39),
39 (21), 29 (20), 27 (15).
3-(10-Hydroxyhexyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7c, dia. C/dia. D). Colorless oil; Dia. C/
dia. D=25:75; Rf (hexane/EtOAc 9:1)=0.11; 13C NMR
(75.4 MHz, CDCl3): d 177.1 (2C, 2ÂC-2), 137.1, 137.1,
130.1, 130.0, 129.5, 129.2, 129.2 and 129.0 (12C, 12ÂS–
C6H5), 74.4, 74.3, 73.3, 72.6, 61.5 and 60.0 (6C, 2ÂC-3,
2ÂC-5 and 2ÂC-10), 36.8, 35.2, 32.0, 31.7, 31.7, 30.9,
26.2, 205.9, 22.7, 21.9, 14.1 a0nd 14.1 (14C, 2ÂC-4,
3-(10-Hydroxyoctyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7d, dia. C/dia. D). Colorless oil; Dia. C/
dia. D=34:66; Rf (hexane/EtOAc 9:1)=0.16; 13C NMR
(75.4 MHz, CDCl3): d 177.2 and 175.9 (2C, 2ÂC-2),
137.3, 137.2, 130.3, 130.2, 129.6, 129.4, 129.3 and 129.2
(12C, 12ÂS–C6H5), 74.5, 74.4, 73.4, 72.7, 61.6 and 60.0
(6C, 2ÂC-3, 2ÂC-5 and 2ÂC-10), 36.9, 35.3, 32.2, 32.1,
32.0, 31.1, 29.7, 29.6, 29.5, 29.4, 26.8, 026.4, 22.9, 22.8,
14.3 and 14.3 (18C, 2ÂC-4, 12ÂCH2 , 2ÂCH3-5 and
1
8ÂCH2 , 2ÂCH3-5 and 2ÂCH3 ); H NMR (300 MHz,
0
CDCl3): d 7.59–7.48and 7.44–7.28(2H and 3H, 2 Âm,
5ÂS–C6H5), 4.54 (1H, m, H-5), 3.83 (0.75H, dd, J=10.1
Hz, J=1.5 Hz, H-10, dia. D), 3.74 (0.25H, dd, J=9.9
Hz, J=2.2 Hz, H-10, dia. C), 2.87 (0.75H, dd, J=14.0
Hz, J=8.4 Hz, H-4a, dia. D), 2.76 (0.25H, dd, J=14.5
Hz, J=8.3 Hz, H-4a, dia. C), 2.57 (1H, s, OH), 1.78
(0.25H, dd, J=14.5 Hz, J=6.3 Hz, H-4b, dia. C), 1.74
(0.75H, dd, J=14.0 Hz, J=4.7 Hz, H-4b, dia. D), 1.65–
2ÂCH3 ); 1H NMR and H–H-COSY (300 MHz,
CDCl3): d 7.59–7.48and 7.45–7.28(2H and 3H, 2 Âm,
5ÂS–C6H5), 4.55 (1H, m, H-5), 3.83 (0.66H, d, J=10.0
Hz, H-10, dia. D), 3.64 (0.34H, dd, J=9.8Hz, J=1.9
Hz, H-10, dia. C), 2.87 (0.66H, dd, J=14.0 Hz, J=8.4
Hz, H-4a, dia. D), 2.77 (0.34H, dd, J=14.4 Hz, J=8.3
Hz, H-4a, dia. C), 2.50 (1H, s, OH), 1.79 (0.34H, dd,
J=14.4 Hz, J=6.3 Hz, H-4b, dia. C), 1.75 (0.66H, dd,
J=14.0 Hz,0 J=4.7 Hz, H-4b, dia. D), 1.65–1.20 (12H,
m, 12ÂCH2 ), 1.27 (0.66Â3H, d, J=6.5 Hz, 3ÂCH3-5,
dia. D), 1.17 (0.34Â3H, d, J=6.4 Hz, 3ÂCH3-5, dia. C),
0
1.22 (8H, m, 8ÂCH2 ), 1.25 (0.75Â3H, d, J=6.3 Hz,
3ÂCH3-5, dia. D), 1.17 (0.25Â3H, d, J=6.4 Hz,
0
3ÂCH3-5, dia. C), 0.88 (3H, m, 3ÂCH3 ); IR (neat):
0
3452 (m, br, O–H), 3059 (w), 2929 (m), 2858 (m), 1749
(s, C¼O), 1584 (w), 1440 (m), 1384 (m), 1348 (m), 1198
(s), 1113 (m), 1055 (m), 1026 (m), 950 (m), 862 (w), 749
(m), 694 (m); MS (EI): m/z 308(1, M +), 208(100,
MÀCH3(CH2)4CHO), 164 (16), 149 (40), 147 (11), 135
(22), 131 (13), 116 (22), 115 (11), 110 (79, Ph–SH), 109
(42), 105 (13), 91 (17), 82 (10), 77 (10), 65 (15), 57 (20),
56 (29), 55 (62), 44 (23), 43 (21), 41 (21), 39 (13), 29 (15),
27 (15).
0.88 (3H, m, 3CH3 ); IR (neat): 3467 (m, br, O–H), 3060
(w), 2927 (m), 2856 (m), 1756 (s, C¼O), 1584 (w), 1440 (m),
1384 (m), 1347 (m), 1195 (s), 1117 (m), 1068 (m), 992 (m),
950 (m), 750 (m), 693 (m), 644 (w); MS (NH3-CI): m/z 354
(1, M+NH+4 ), 226 (100, MÀCH3(CH2)6CHO+NH+4 ),
208(15, M ÀCH3(CH2)6CHO).
General procedure for 3-(10-hydroxyalkyl)-5-methyl-5H-
furan-2-ones (8a–d, dia. A and dia. B). 7a–d (0.749
mmol) was dissolved in CH2Cl2 (5.0 mL) at 0 ꢀC.
m-CPBA (80%, 178 mg, 0.824 mmol) was added and
the reaction mixture was stirred at 0 ꢀC for 30 min. TLC
of the reaction mixture showed no presence of starting
materials. The reaction mixture was then washed with
water (1.5 mL), saturated aqueous NaHCO3 (1.5 mL)
and saturated aqueous NaCl (1.5 mL), dried over
MgSO4, filtered and concentrated. The residue (sulfox-
ide, colorless solid) was dissolved in toluene (5.0 mL)
and the mixture was refluxed at 110 ꢀC for 30 min. TLC
of the reaction mixture showed no presence of the sulf-
oxides. The mixture was hereafter concentrated. Flash
chromatography (8a: hexane/EtOAc 1:1; 8b–d: hexane/
EtOAc 3:1) of the residue gave the desired products in
the following yields: 8a: 66%, 8b: 76%, 8c: 85%, 8d:
73%. Except for 8a, the diastereomers dia. A and dia. B
could be separated, but since NMR spectra of dia. A
and dia. B were almost identical and the diastereomers
could not be separated by GC–MS, accurate diaster-
eomeric ratios could not be determined. Based on iso-
lated fractions after flash chromatography a dia. A/dia.
B ratio of approximately 1:3 was determined for 8b–d.
3-(10-Hydroxyoctyl)-5-methyl-3-phenylsulfanyl-dihydro-
furan-2-one (7d, dia. A/dia. B). Colorless oil; Dia. A/
dia. B=75:25; Rf (hexane/EtOAc 9:1)=0.24; 13C NMR
(75.4 MHz, CDCl3): d 175.4 and 174.9 (2C, 2ÂC-2),
137.6, 137.3, 130.4, 130.3, 129.3, 129.2, 128.9 and 128.7
(12C, 12ÂS–C6H5), 74.5, 72.9, 70.8, 61.6 and 60.5 (6C,
2ÂC-3, 2ÂC-5 and 2ÂC-10), 39.6, 37.1, 32.1, 32.0, 29.7,
29.7, 29.5, 29.4, 26.8, 26.5, 22.9, 22.08, 20.9, 20.7, 14.4
and 14.3 (18C, 2ÂC-4, 12ÂCH2 , 2ÂCH3-5 and
0
2ÂCH3 ); 1H NMR and H–H-COSY (300 MHz,
CDCl3): d 7.60–7.49 and 7.44–7.29 (2H and 3H, 2Âm,
5ÂS–C6H5), 4.64 (0.25H, ddq, J=10.0 Hz, J=6.0 Hz,
J=6.0 Hz, H-5, dia. B), 4.49 (0.75H, ddq, J=10.0 Hz,
J=6.0 Hz, J=6.0 Hz, H-5, dia. A), 3.81 (0.25H, d,
J=10.5 Hz, H-10, dia. B), 3.75 (0.75H, d, J=9.7 Hz, H-
10, dia. A), 3.28(1H, s, O H), 2.36 (0.25H, dd, J=13.5
Hz, J=10.0 Hz, H-4a, dia. B), 2.23 (0.75H, dd, J=14.1
Hz, J=6.0 Hz, H-4a, dia. A), 2.08(0.25H, dd, J=13.5
Hz, J=6.0 Hz, H-4b, dia. B), 2.06 (0.75H, dd, J=14.1
Hz, J=10.0 Hz, H-4b, dia. A), 1.72–1.18(12H, m,
0
12ÂCH2 ), 1.39 (0.25Â3H, d, J=6.0 Hz, 3ÂCH3-5, dia.
B), 1.36 (0.75Â3H, d, J=6.0 Hz, 3ÂCH3-5, dia. A), 0.87
0
(3H, m, 3ÂCH3 ); IR (neat): 3496 (m, br, O–H), 3060
3-(10-Hydroxyethyl)-5-methyl-5H-furan-2-one (8a, dia.
A/dia. B). Colorless oil; Rf (hexane/EtOAc 1:1)=0.21;
13C NMR (75.4 MHz, CDCl3): d 172.9 and 172.9 (2C,
2ÂC-2), 149.2, 149.2, 137.5 and 137.4 (4C, 2ÂC-3 and
(w), 2923 (m), 2857 (m), 1762 (s, C¼O), 1575 (w), 1440
(m), 1386 (m), 1344 (m), 1295 (m), 1193 (s), 1125 (m),
1058(m), 1003 (m), 937 (w), 750 (m), 692 (m), 640 (w);

3270
T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
2ÂC-4), 78.2, 63.2 and 63.1 (4C, 2ÂC-5 and 2ÂC-100),
21.8, 21.8, 19.1 and 19.0 (4C, 2ÂCH3-5 and 2ÂCH3 );
1H NMR (300 MHz, CDCl3): d 7.19 (1H, m, H-4), 5.03
(1H, ddq, J=6.9 Hz, J=1.4 Hz, J=1.4 Hz, H-5), 4.62
(1H, ddq, J=6.7 Hz, J=1.4 Hz, J=1.4 Hz, H-10), 3.01
3440 (m, br, O–H), 3086 (w), 2932 (m), 2860 (m), 1740
(s, C¼O), 1654 (w), 1458(m), 1376 (m), 1320 (m), 1202
(m), 1116 (m), 1084 (s), 1028 (m), 951 (w), 922 (w), 873
(w), 789 (w), 669 (w); MS (EI): m/z 199 (1, M+1), 180 (3,
MÀH2O), 128(13), 127 (100, M À(CH2)4CH3), 110 (28),
99 (22), 82 (21), 81 (11), 71 (17), 55 (14), 43 (49), 41 (11).
0
(1H, s, OH), 1.42 (3H, d, J=6.7 Hz, 3ÂCH3 ), 1.40 (3H,
dd, J=6.9 Hz, J=0.9 Hz, 3ÂCH3-5); IR (neat): 3451
(m, br, O–H), 3090 (w), 2981 (m), 3935 (m), 1750 (s,
C¼O), 1654 (w), 1451 (m), 1372 (m), 1322 (m), 1205
(m), 1115 (m), 1090 (s), 1061 (m), 1004 (m), 952 (w), 875
(m), 788 (m), 635 (w); MS (EI): m/z 143 (2, M+1), 127
(76, MÀCH3), 124 (8, MÀH2O), 99 (57), 98(17), 82
(13), 81 (35), 71 (22), 55 (16), 53 (24), 45 (15), 43 (100),
39 (10), 27 (10).
3-(10-Hydroxyhexyl)-5-methyl-5H-furan-2-one (8c, dia.
B). Colorless oil; Rf (hexane/EtOAc 3:1)=0.12; 13C
NMR (75.4 MHz, CDCl3): d 172.8(1C, C-2), 149.7 and
136.5 (2C, C-3 and C-4), 78.2 and 67.1 (2C, C-5 and C-
0
10), 35.7, 31.8, 25.1, 22.8, 19.2 and 14.2 (6C, 4ÂCH2 ,
0
1
CH3-5 and CH3 ); H NMR (300 MHz, CDCl3): d 7.18
(1H, dd, J=1.4 Hz, J=1.4 Hz, H-4), 5.03 (1H, ddq,
J=6.6 Hz, J=1.4 Hz, J=1.4 Hz, H-5), 4.45 (1H, dddd,
J=7.9 Hz, J=4.8Hz, J=1.4 Hz, J=1.40Hz, H-10), 2.80
(1H, s, OH), 1.82-1.19 (8H, m, 8ÂCH2 ), 1.41 (3H, d,
3-(10-Hydroxybutyl)-5-methyl-5H-furan-2-one (8b, dia.
A). Colorless oil; Rf (hexane/EtOAc 3:1)=0.12; 13C
NMR (75.4 MHz, CDCl3): d 172.7 (1C, C-2), 149.4 and
136.4 (2C, C-3 and C-4), 78.1 and 67.0 (2C, C-5 and C-
0
J=6.6 Hz, 3ÂCH3-5), 0.86 (3H, t, 3ÂCH3 ); IR (neat):
3462 (m, br, O–H), 3089 (w), 2934 (m), 2860 (m), 1743
(s, C¼O), 1654 (w), 1458(m), 1376 (m), 1320 (m), 1202
(m), 1116 (m), 1080 (s), 1028 (m), 950 (w), 922 (w), 876
(w), 787 (w), 733 (w), 667 (w); MS (EI): m/z 199 (1,
M+1), 180 (3, MÀH2O), 128(12), 127 (100,
MÀ(CH2)4CH3), 110 (28), 99 (20), 82 (20), 71 (16), 55
(16), 53 (11), 43 (61), 41 (16).
0
10), 37.7, 19.1, 18.7 and 14.0 (4C, 2ÂCH2 , CH3-5 and
0
1
CH3 ); H NMR (300 MHz, CDCl3): d 7.18(1H, dd,
J=1.4 Hz, J=1.4 Hz, H-4), 5.05 (1H, ddq, J=6.9 Hz,
J=1.4 Hz, J=1.4 Hz, H-5), 4.48(1H, dddd, J=7.9 Hz,
J=4.8Hz, J=1.4 Hz, J=1.4 Hz, H-10), 2.63 (1H, s,
0
OH), 1.83-1.30 (4H, m, 4ÂCH2 ), 1.43 (3H, d, J=6.9
0
Hz, 3ÂCH3-5), 0.95 (3H, t, 3ÂCH3 ); IR (neat): 3426
(m, br, O–H), 3087 (w), 2961 (m), 2873 (m), 1735 (s,
C¼O), 1654 (w), 1458(m), 1377 (m), 1322 (m), 1200
(m), 1114 (m), 1082 (s), 1028 (m), 949 (w), 870 (w), 788
(w), 669 (w); GC–MS (EI): m/z 152 (6, MÀH2O), 127
(95, MÀ(CH2)2CH3), 110 (14), 99 (23), 82 (20), 81 (17),
71 (25), 55 (18), 53 (20), 43 (100), 41 (21), 39 (16), 29
(11), 28(13), 27 (15).
3-(10-Hydroxyoctyl)-5-methyl-5H-furan-2-one (8d, dia.
A). Colorless oil; Rf (hexane/EtOAc 3:1)=0.14; 13C
NMR17 (75.4 MHz, CDCl3): d 172.7 (1C, C-2), 149.4
and 136.4 (2C, C-3 and C-4), 78.1 and 67.2 (2C, C-5 and
C-10), 35.6, 31.9, 29.5, 29.3, 25.4, 22.7, 19.1 and 14.2
0
0
1
(8C, 6ÂCH2 , CH3-5 and CH3 ); H NMR17 and H–H-
COSY (300 MHz, CDCl3): d 7.18(1H, dd, J=1.3 Hz,
J=1.3 Hz, H-4), 5.05 (1H, ddq, J=6.9 Hz, J=1.3 Hz,
J=1.3 Hz, H-5), 4.47 (1H, dddd, J=7.9 Hz, J=4.8Hz,
J=1.3 Hz, J=1.3 0Hz, H-10), 2.80 (1H, s, OH), 1.85–1.19
(12H, m, 12ÂCH2 ), 01.43 (3H, d, J=6.9 Hz, 3ÂCH3-5),
0.87 (3H, t, 3ÂCH3 ); IR (neat): 3447 (m, br, O–H),
3089 (w), 2926 (m), 2856 (m), 1735 (s, C¼O), 1654 (w),
1458(m), 1376 (m), 1320 (m), 1201 (m), 1116 (m), 1085
(s), 1025 (m), 949 (w), 872 (w), 790 (w), 669 (w); MS
(EI): m/z 227 (1, M+1), 208(2, M ÀH2O), 128(14), 127
(100, MÀ(CH2)6CH3), 110 (32), 99 (17), 82 (16), 81 (11),
57 (11), 55 (10), 43 (22).
3-(10-Hydroxybutyl)-5-methyl-5H-furan-2-one (8b, dia.
B). Colorless oil; Rf (hexane/EtOAc 3:1)=0.10; 13C
NMR (75.4 MHz, CDCl3): d 172.8(1C, C-2), 149.5 and
136.4 (2C, C-3 and C-4), 78.1 and 66.8 (2C, C-5 and C-
0
10), 37.7, 19.0, 18.6 and 13.9 (4C, 2ÂCH2 , CH3-5 and
0
1
CH3 ); H NMR (300 MHz, CDCl3): d 7.18(1H, dd,
J=1.4 Hz, J=1.4 Hz, H-4), 5.03 (1H, ddq, J=6.8Hz,
J=1.4 Hz, J=1.4 Hz, H-5), 4.47 (1H, dddd, J=7.9 Hz,
J=4.7 Hz, J=1.4 Hz, J=1.4 Hz, H-10), 2.75 (1H, s,
0
OH), 1.81–1.30 (4H, m, 4ÂCH2 ), 10.41 (3H, d, J=6.8
Hz, 3ÂCH3-5), 0.93 (3H, t, 3ÂCH3 ); IR (neat): 3448
(m, br, O–H), 3089 (w), 2960 (m), 2874 (m), 1736 (s,
C¼O), 1654 (w), 1458(m), 1377 (m), 1322 (m), 1200
(m), 1115 (m), 1074 (s), 1023 (m), 960 (w), 872 (w), 789
(w), 663 (w); GC–MS (EI): m/z 152 (6, MÀH2O), 127
(100, MÀ(CH2)2CH3), 110 (21), 99 (22), 82 (20), 81 (16),
71 (23), 55 (16), 53 (18), 43 (93), 41 (14), 39 (14), 27 (11).
3-(10-Hydroxyoctyl)-5-methyl-5H-furan-2-one (8d, dia.
B). Colorless oil; Rf (hexane/EtOAc 3:1)=0.12; 13C
NMR17 (75.4 MHz, CDCl3): d 172.9 (1C, C-2), 149.7
and 136.6 (2C, C-3 and C-4), 78.2 and 67.1 (2C, C-5 and
C-10), 35.7, 32.0, 29.6, 29.4, 25.5, 22.8, 19.1 and 14.3
0
0
1
(8C, 6ÂCH2 , CH3-5 and CH3 ); H NMR17 (300 MHz,
CDCl3): d 7.18(1H, dd, J=1.4 Hz, J=1.4 Hz, H-4),
5.02 (1H, ddq, J=6.9 Hz, J=1.4 Hz, J=1.4 Hz, H-5),
4.45 (1H, dddd, J=7.9 Hz, J=4.9 Hz, J=1.4 Hz,
J=1.4 Hz, H-10), 2.92 (1H, s, OH), 1.81–1.19 (12H, m,
3-(10-Hydroxyhexyl)-5-methyl-5H-furan-2-one (8c, dia.
A). Colorless oil; Rf (hexane/EtOAc 3:1)=0.16; 13C
NMR (75.4 MHz, CDCl3): d 172.7 (1C, C-2), 149.5 and
136.4 (2C, C-3 and C-4), 78.1 and 67.2 (2C, C-5 and C-
0
12ÂCH2 ), 1.40 (3H, d, J=6.9 Hz, 3ÂCH3-5), 0.85 (3H,
0
0
10), 35.6, 31.6, 25.1, 22.7, 19.1 and 14.1 (6C, 4ÂCH2 ,
t, 3ÂCH3 ); IR (neat): 3434 (m, br, O–H), 3091 (w),
0
1
CH3-5 and CH3 ); H NMR (300 MHz, CDCl3): d 7.18
(1H, dd, J=1.4 Hz, J=1.4 Hz, H-4), 5.05 (1H, ddq,
J=6.7 Hz, J=1.4 Hz, J=1.4 Hz, H-5), 4.47 (1H, dddd,
J=7.9 Hz, J=4.8Hz, J=1.4 Hz, J=1.40Hz, H-10), 2.77
(1H, s, OH), 1.84–1.19 (8H, m, 8ÂCH2 ), 1.42 (3H, d,
2931 (m), 2856 (m), 1752 (s, C¼O), 1654 (w), 1458(m),
1376 (m), 1320 (m), 1200 (m), 1117 (m), 1083 (s), 1025
(m), 949 (w), 871 (w), 789 (w), 669 (w); MS (EI): m/z 227
(1, M+1), 208(1, M ÀH2O), 128(14), 127 (100,
MÀ(CH2)6CH3), 110 (29), 99 (15), 82 (13), 57 (11), 55
(11), 43 (29).
0
J=6.7 Hz, 3ÂCH3-5), 0.87 (3H, t, 3ÂCH3 ); IR (neat):

T. Hjelmgaard et al. / Bioorg. Med. Chem. 11 (2003) 3261–3271
3271
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The Technical University of Denmark, the Danish
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the Villum Kann Rasmussen Foundation are gratefully
acknowledged for financial support. Dr. J. Øgaard
Madsen is thanked for his assistance with recording and
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