Design, synthesis, and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid

Article abstract of DOI:10.1021/jm970034q

An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-butenyl]- 2(5H)-furanone (12d). This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5- (3-butynyl)-3,4-dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d) followed by Lindlar catalyzed hydrogenation produces 12d. Butynyl intermediate 7 is prepared from 2-(benzyloxy)-5-deoxyascorbic acid (15) by iodination (I₂, PPh₃, Imd), iodo substitution with lithium acetylide ethylenediamine complex (LiAEDA, HMPA, -5 °C), and benzyl group cleavage (Ac₂O, Pyr, BCl₃). The utility of this synthetic method was demonstrated by the synthesis of analogues 10e-k. Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5- LO) with comparable efficacy as reported for aspirin and zileuton, respectively. The antioxidant activity of these aci-reductones, measured as a function of their inhibitory effect on CCl₄-induced lipid peroxidation of hepatic microsomes, exceeds that produced by α-tocopherol. Synthetic routes and initial structure-activity relationships (SAR) for these novel mixed functioning antioxidants are presented.

Full text of DOI:10.1021/jm970034q

420
J . Med. Chem. 1998, 41, 420-427
Articles
Design , Syn th esis, a n d Biologica l Eva lu a tion of Con for m a tion a lly Con str a in ed
a ci-Red u cton e Mim ics of Ar a ch id on ic Acid 1
Allen T. Hopper,*,† Donald T. Witiak,‡ and J ohn Ziemniak†
OXIS International, Inc., 6040 North Cutter Circle, Portland, Oregon 97217, and School of Pharmacy, University of Wisconsin,
Madison, Wisconsin 53706
Received J anuary 16, 1997
An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-
5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-butenyl]-2(5H)-furanone (12d ). This hydrophobic antioxi-
dant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its
respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-
dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d ) followed by Lindlar
catalyzed hydrogenation produces 12d . Butynyl intermediate 7 is prepared from 2-(benzyloxy)-
5-deoxyascorbic acid (15) by iodination (I2, PPh3, Imd), iodo substitution with lithium acetylide
ethylenediamine complex (LiAEDA, HMPA, -5 °C), and benzyl group cleavage (Ac2O, Pyr,
BCl3). The utility of this synthetic method was demonstrated by the synthesis of analogues
10e-k . Biological testing revealed that certain of these antioxidants inhibit both cyclooxy-
genase (COX) and 5-lipoxygenase (5-LO) with comparable efficacy as reported for aspirin and
zileuton, respectively. The antioxidant activity of these aci-reductones, measured as a function
of their inhibitory effect on CCl4-induced lipid peroxidation of hepatic microsomes, exceeds
that produced by R-tocopherol. Synthetic routes and initial structure-activity relationships
(SAR) for these novel mixed functioning antioxidants are presented.
Ch a r t 1. Conformationally Constrained Mimics of AA
In tr od u ction
The development of dual antioxidant arachidonic acid
(AA) metabolism inhibitors may provide added benefits
over existing drugs for the treatment of diseases as-
sociated with oxidative stress and inflammation. Nu-
merous conditions, which are currently treated by the
administration of antiinflammatory agents, including
asthma, rheumatoid arthritis,2 irritable bowel disease
(IBD),3,4 adult respiratory distress syndrome (ARDS),5
atherosclerosis,6,7 ischemia/reperfusion injury,8,9 res-
tenosis,10,11 neurodegenerative disorders,12-14 and ini-
tiation and promotion of carcinogenesis,15 correlate with
abnormally high levels of reactive oxygen species (ROS).
Antioxidant-based therapies through the administration
of both natural antioxidants (e.g., vitamin E, vitamin
C, and superoxide dismutase, SOD) and synthetic
antioxidants (e.g., 4-aryl-2-hydroxytetronic acids,16 2-O-
alkylascorbic acids,17 probucol,18 and tirilazad mesyl-
ate19) have been or are currently being investigated for
the management of a number of these conditions.
Previously, S-AA aci-reductone analogue (2) (Chart
1) was identified as a stereoselective and potent AA
metabolic inhibitor synthesized in our laboratories.20
This compound inhibits both PGE2 and LTB4 production
in stimulated macrophages (IC50 ) 20 µM) and blocks
AA-induced platelet aggregation (AAIPA) with an IC50
< 10 µM. Dual cyclooxygenase (COX) and lipoxygenase
(LO) activity could be important in preventing substrate
shunting in the AA cascade and therefore provide an
improved class of antiinflammatory agents. Although
2 demonstrates an encouraging biological profile, both
its instability and labored synthesis render this com-
pound less than satisfactory as a pharmaceutical.
To provide compounds which retain the biological
properties observed in 2, possess increased stability, and
have a simplified synthesis, conformationally con-
strained analogues of the type 3 (Chart 1) were envis-
aged. The 2-hydroxytetronic acid moiety is a stable
carboxylic acid bioisostere with a redox potential suf-
ficient to protect lipid membranes against oxidative
damage. The phenyl ring is proposed to mimic the C8
and C11 cis skipped double bonds of AA (1). The ortho
† OXIS International, Inc.
‡ University of Wisconsin.
S0022-2623(97)00034-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/23/1998

aci-Reductone Mimics of Arachidonic Acid
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 421
Sch em e 1
Sch em e 2
substituent, which contains the relative C13 through
C20 portion of AA, functions to maintain the suspected
COX-bound conformation of the fatty acid. 2-Hexenyl-
benzene analogue 12d was identified as the synthetic
target in favor of 2-octenyl derivative 3, because of the
lower cost of starting materials.
which COX catalyzes the conversion of AA into PGG2
by way of tyrosyl-385 radical abstraction.24 Synthetic
routes and initial structure-activity relationships (SAR)
for these novel mixed functioning AA metabolic inhibi-
tors are discussed.
Resu lts a n d Discu ssion
Others have synthesized constrained analogues of AA
which display promising biological activities. Nicolaou
and Webber21 prepared cis- and trans-7,13-bridged AA
4, reported to be potent and selective 5-LO inhibitors.
Buckle and Fenwick22 synthesized ortho-substituted
phenyl-5-octenoic acid derivative 5. This compound has
little effect against 5-LO but inhibits phospholipase A2
by 70% at 20 µM. 2-Hydroxytetronic acid analogue 12d
is ionized at physiological pH and has a biologically
relevant redox potential similar to that observed for
ascorbic acid.23 Such a redox function is proposed to
interfere with the active site of LO and COX enzymes
and to scavenge ROS in lipid membranes. Further, the
ortho substituent in 12d presents a benzylic hydrogen
in the same relative position as the C13 pro-S hydrogen
of AA. This hydrogen is involved in the mechanism by
Target compound 12d and related analogues
10a ,b,d -k were anticipated to be available in a con-
vergent synthesis by coupling 5-(3-butynyl)tetronic acid
6 or 7 with substituted iodobenzenes 8a -k followed by
Lindlar catalyzed hydrogenation (Scheme 1).
Butynyltetronic acid 6 was prepared in four steps
from commercially available R-hydroxylactone 13a by
the method of Stork and Rychnovsky (Scheme 2).25
Intermolecular condensation of the lithium hexameth-
yldisilazide (LiHMDA)-produced anion of ethyl (benzyl-
oxy)acetate with [(trimethylsilyl)oxy]lactone 13b fol-
lowed by treatment with anhydrous K2CO3 in MeOH
at 0 °C provides 5-deoxyascorbic acid derivative 15 in
75% yield. Initial attempts to synthesize 15 by in-
tramolecular Claisen cyclization26 of (benzyloxy)acetate

422 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Hopper et al.
Sch em e 3
pressure resulted in the formation of monoolefin 11c
after consumption of 1 equiv of H2. Utilization of a
second equivalent of H2 resulted in reduction of the
freshly formed double bond without effecting the triple
bond of the hexynyl side chain to produce monoalkyne
20d . Attempted debenzylation of intermediate 11c by
acetylation and treatment with BCl3 was unsuccessful
and resulted in the isolation of a compound lacking vinyl
1
protons in the H NMR spectrum.32
To circumvent problems with benzyl group deprotec-
tion and partial alkyne reduction, coupling of 2-((2Z)-
hexenyl)iodobenzene (8d ) with 2-hydroxytetronic acid
7 was investigated. Hexenylbenzene 8d was obtained
in 78% yield by dicyclohexylborane reduction of hexyne
8c. Pd(PPh3)4-catalyzed coupling in pyrrolidine pro-
vided enyne 10d in better than 70% yield. Lindlar
catalyzed reduction yielded target diene 12d .
14 (LiHMDA, THF, -78 f 0 °C) failed; only starting
material could be isolated. Iodination (I2, PPh3, Imd,
93%) of benzyl-protected tetronic acid 15 provided iodo
species 16, which underwent reaction with 3 equiv of
lithium acetylide ethylenediamine (LiAEDA) complex
in HMPA at -5 °C to give 2-(benzyloxy)tetronic acid 6
as a yellow solid in 85% crude yield.27 Benzyl group
cleavage28 to provide intermediate 7 was effected in 80%
yield and in one pot by acetylation of the vinylogous acid
6 (Ac2O, Pyr) followed by treatment of the crude residue
with BCl3. Alternatively, benzyl group cleavage of iodo
compound 16 (Ac2O, Pyr, BCl3) provides 2-hydroxy-
tetronic acid 17 in 90% yield. However, reaction of 17
with LiAEDA gives 7 in only 30% yield.
In a model study, palladium tetrakis(triphenylphos-
phine)-catalyzed coupling29 between 2-(benzyloxy)-
tetronic acid 6 and iodobenzene in pyrrolidine at room
temperature for 3 h produced benzyl-protected aryl-
ethynyl analogue 9a in 90% isolated yield (Scheme 1).
Attempted direct Lindlar catalyzed reduction of inter-
mediate 9a to the desired 2-hydroxytetronic acid olefin
12a failed. Saturated compound 18a formed after 1 h,
and after 3 h at atmospheric pressure, debenzylated
compound 19a was isolated. Alternatively, Lindlar
reduction of intermediate 9a (1 equiv of H2 at 1 atm) to
the cis olefin 11a and benzyl group cleavage (Ac2O, Pyr,
BCl3) gave the desired cis olefinic 2-hydroxytetronic acid
12a .
This convergent reaction sequence was utilized for the
production of compounds 10e-k , which were designed
for the exploration of structure-activity relationships.
Initial biological screening data against COX-1,33 COX-
2,33 5-LO,34 and LPO35 for these analogues and related
derivatives (10a ,b,d and 12d ) are summarized in Table
1. All compounds at a test concentration of 300 µM
effectively inhibited CCl4-induced LPO of polyunsatu-
rated fatty acids from guinea pig liver microsomes as
quantified by spectrophotometric analysis of MDA
formation, with equivalent or better potency than that
produced by R-tocopherol. Generally, poor to modest
inhibitory activity against COX-1 and COX-2 was
observed by all test compounds. Test compounds were
screened at 300 µM against both COX-1, which was
isolated from ram seminal vesicle, and COX-2, which
was obtained from sheep placenta. COX activity was
determined by measuring the formation of thiobarbitu-
rate-reactive substances photospectrometrically at 530
nm. Enyne 10d and pentylthiomethyl analogue 10i
were the most potent COX inhibitors in this series, with
potencies similar to that of aspirin. Precursor enyne
10d is a slightly more effective inhibitor of COX-1 (55%
at 300 µM) than designed AA mimic 12d (37% at 300
µM). 2-Methylphenyl and phenyl compounds 10a ,b,
respectively, are ineffective inhibitors of both isoforms
of COX. These data suggest that the ortho substituent
is important for biological activity.
Iodobenzene 8c was prepared by a BF3-Et2O-assisted
reductive iodonio-Claisen rearrangement30 reaction of
iodobenzene diacetate with 1-(trimethylsilyl)-2-hexyne31
(22) (Scheme 3). Coupling of (benzyloxy)tetronic acid
6 with iodobenzene 8c produced diyne 9c in approxi-
mately 50% yield. Lindlar reduction at atmospheric
Ta ble 1. Biological Evaluation of Compounds 10a -k and 12d for Inhibition of COX-1-, COX-2-, 5-LO-, and CCl4-Induced LPO of
Hepatic Microsomes
compd
COX-1 (300 µM)a
5b
COX-2 (300 µM)
5-LO (30 µM)
LPO (300 µM)
10a
10b
10d
10e
10f
10g
10h
10i
13
18
58
43
62
59
8
55
25
8
34
38
67
28
15
23
22
20
45
81, IC50 ) 0.4 µM
72
61
75
73
72
62
100, IC50 ) 0.3 µM
81
97, IC50 ) 0.3 µM
82
90
10j
25
12
30
60
10k
12d
NT
37
NT
NT
NT
28
NT
NT
100, IC50 ) 0.16 µM
NT
68
99
R-tocopherolc
BW755Cc
NT
IC50 ) 280 µM
NT
4
IC50 ) 5.6 µM
0
NT
aspirinc
76, IC50 ) 240 µM
IC50 ) 1.7 µM
0, IC50 ) 660 µM
IC50 ) 2.4 µM
indomethacinc
NT
a
b
The test concentrations at which compounds were screened are in parentheses. NT, not tested. Percent inhibition values are provided
unless otherwise indicated as an IC50 value. All experiments were performed in duplicate by Panlabs, Inc., Bothell, WA. c For comparison
purposes, data are provided for R-tocopherol, BW755C, aspirin, and indomethacin.

aci-Reductone Mimics of Arachidonic Acid
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 423
both H2O2- and LPS-induced NF-κB nuclear transloca-
tion, thus further implicating ROS involvement in the
signal transduction pathway which regulates NF-κB
activity. Naphthyl-substituted derivative 10g inhibits
LPS-induced NF-κB nuclear translocation by 90% at 30
nM. The potency of this analogue is unprecedented. The
internal standards, antioxidant PDTC and glucocorti-
coid steroid dexamethasone, inhibit NF-κB nuclear
translocation by 50% at 10 000 nM and 60% at 1000
nM, respectively. The mechanism of action of naphthyl
derivative 10g is unknown but may be linked to its
antioxidant activity. Compounds capable of controlling
the production of inflammatory proteins and their
products at the gene level are anticipated to lack the
undesirable side effects associated with steroids but to
produce similar antiinflammatory activity.38 The mixed
functioning antioxidant AA metabolism inhibitors de-
scribed here may provide superior antiinflammatory
activity over conventional therapies in vivo by inhibiting
both NF-κB nuclear translocation and inflammatory
eicosanoid biosynthesis. Studies designed to determine
the mechanisms by which these compounds inhibit 5-LO
and NF-κB activation and also to identify important
structure-activity relationships are in progress.
F igu r e 1. Comparison of the N-hydroxyurea 5-LO inhibitors
zileuton and ABT-761 with the 2-hydroxytetronic acid ana-
logues 10g,k . The IC50 values are for inhibition of 5-LO in the
broken RBL-1 cell assay.
Exp er im en ta l Section
Most of the compounds produce greater than 80%
inhibition of 5-LO in a crude enzyme preparation from
rat basophilic leukemia cells (broken RBL-1) at a test
concentration of 30 µM. The observed activity of these
agents against 5-LO is likely due primarily to the
antioxidant properties associated with the 2-hydroxy-
tetronic acid moiety and, to a lesser degree, the struc-
ture of the lipophilic arylbutyne substituent. Not
surprisingly, initial studies from our laboratories indi-
cate that removal of the 2-hydroxyl group from the aci-
reductone ring provides tetronic acids which are devoid
of both LPO and 5-LO activity. Note, however, that
structural activity relationships for this series of aci-
reductones exist; the substituents in the aromatic ring
influence the inhibitory activity against 5-LO. For
example, sulfone 10j inhibits 5-LO by 30% at 30 µM,
while benzenesulfonamide 10f produces 80% inhibition
at 30 µM. IC50 values for thiophenol 10e, enyne 10d ,
and naphthylyne derivative 10g range between 300 and
500 nM, and this is in the range reported for Abbott’s
5-LO inhibitor zileuton.36 The close structural resem-
blance and similar 5-LO inhibitory activity of the aci-
reductones 10e-j and the N-hydroxyurea class of 5-LO
inhibitors suggest that the 2-hydroxytetronic acid func-
tionality may in fact act as a bioisostere for the N-
hydroxyurea moiety (Figure 1). Interestingly, benzyl-
thiophene derivative 10k , a close structural analogue
of ABT-761, which has an IC50 of 23 nM in the broken
RBL-1 assay,36 was the most potent 5-LO inhibitor of
this series with an IC50 of 160 nM.
Gen er a l Meth od s. Melting points were determined in
open capillaries with a Thomas-Hoover Uni-Melt apparatus
and are uncorrected. Unless otherwise noted all reagents were
purchased from commercial suppliers and used as received.
Preparative scale separations were carried out by column
chromatography using 70-240 mesh silica gel 60A. 1H and
13C NMR spectra were recorded on either a Bruker AM 300
MHz or Varian 200 MHz spectrometer. Elemental analyses
were performed by Quantitative Technologies, Inc., White-
house, NJ .
Assa y for NF -KB Nu clea r Tr a n sloca tion . Experiments
were performed with transformed rat alveolar macrophages
(NR8383 cells). Cells were treated simultaneously with LPS
(1 µg/mL) and the test compounds. Untreated control cells
and cells treated with LPS alone were tested in each experi-
ment. Cells were harvested 6 h after treatment, and nuclear
proteins were extracted, frozen, and quantified using the
Bradford assay. Electrophoretic mobility shift assays (EMSA)
were subsequently performed using a radiolabeled NF-κB
probe. Following reaction of the nuclear proteins with the
radiolabeled probe and separation on a 5% polyacrylamide gel,
the bands were assayed by autoradiography. NF-κB binding
selectivity was assayed by cold and nonspecific competition
using the LPS-treated sample in each experiment. All EMSA
were repeated at least once to verify results. Laser densito-
metry of NF-κB bands was done on autoradiographs to
quantify NF-κB binding activity and compare treatment
groups
3-(Ben zyloxy)-4-h yd r oxy-5-(2-h yd r oxyeth yl)-2(5H)-fu r -
a n on e (15).25 A solution of 10.0 g (98 mmol) of 13a in 100
mL of anhydrous THF under argon and with magnetic stirring
was cooled to 0-5 °C. Addition of 14 mL (110 mmol) of TMSCl
and 16 mL (115 mmol) of TEA immediately produced a white
precipitate. The suspension was warmed to room temperature
and stirred for 4 h. The suspension was poured into a
separatory funnel containing 100 mL of H2O and 500 mL of
ether. The organic layer was washed with 50 mL of H2O and
50 mL of brine, dried (MgSO4), and concentrated. Purification
(Kugelrohr distillation) provided 14.7 g (90%) of the (silyloxy)-
lactone 13b: bp 80-100 °C (8 mmHg).
ROS are important pathogenic mediators in numer-
ous diseases due to their effect on cellular membranes,
which apparently results in the activation of transcrip-
tion factors such as AP1 and NF-κB.7 The inflammatory
response element NF-κB is upregulated by H2O2, oxi-
datively modified low-density lipoproteins (LDL), lipo-
polysaccharide (LPS), UV radiation, and certain cyto-
kines in vitro.37 Antioxidants including pyrrolidine-
dithiocarbamate (PDTC) and N-acetylcysteine block
To a 500-mL two-necked flask, flame-dried under argon and
equipped with a magnetic stir bar, were added 200 mL of THF
and 18.7 mL (89 mmol) of HMDS. The flask was cooled to
-78 °C, and 55.4 mL (89 mmol) of a 1.6 M n-BuLi solution in

424 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Hopper et al.
hexanes was added with stirring over 15 min. The light-yellow
solution was stirred for an additional 15 min, and 16.7 g (86
mmol) of ethyl (benzyloxy)acetate was added over 5 min. The
solution was stirred for 20 min at -78 °C, and 14.7 g (84.4
mmol) of 13b was added via syringe. The reaction was
quenched after 30 min by pouring into a mixture of 100 mL of
10% concentrated HCl solution and 500 mL of ether. The
aqueous layer was separated and washed with 2 × 100 mL of
ether. The combined ether extracts were washed with 50 mL
of brine, dried (MgSO4), and concentrated.
1H NMR (acetone-d6) δ 4.80 (dd, 1H, J ) 3.5, 8.0 Hz), 3.50-
3.25 (m, 2H), 2.60-2.35 (m, 1H), 2.20-1.95 (m, 1H). Anal.
(C6H7O4I) C, H.
3-(Ben zyloxy)-5-(3-b u t yn yl)-4-h yd r oxy-2(5H )-fu r a n -
on e (6).27 To a flame-dried, three-necked round-bottom flask
with magnetic stir bar, argon inlet, and septum containing 5.7
g (55.8 mmol) of 90% LAEDA complex was added 20 mL of
HMPA. The suspension was stirred for 15 min at room
temperature and cooled in an ice bath (acetone/CO2) to between
-5 and -10 °C, and 6.7 g (18.6 mmol) of 16 dissolved in 15
mL of HMPA was added over a 2-min period. A dark-brown-
orange slurry formed, and the temperature was maintained
between 0 and -5 °C for 30 min. The reaction was quenched
by the careful addition of 150 mL of 10% concentrated HCl
solution, which was immediately extracted with 2 × 200 mL
of ether. The combined ether extracts were washed with 2 ×
50 mL of 5% aqueous HCl solution and extracted with 4 × 50
mL of NaHCO3 solution. The combined bicarbonate extracts
were washed with 50 mL of ether, acidified with 20% concen-
trated HCl solution to pH 1, and extracted with 3 × 150 mL
of Et2O. The combined Et2O extracts were washed with 50
mL of brine, dried (MgSO4), and concentrated leaving 4.1 g
(85% crude yield) of a yellow solid. This material was used
without further purification in subsequent steps: mp 85-88
°C; 1H NMR (CDCl3) δ 7.38-7.26 (m, 5H), 5.06, (q, J ab ) 11.6
Hz, 2H), 4.75 (dd, J ) 3.5, 8.1 Hz, 1H), 2.27-2.20 (m, 2H),
2.12-2.01 (m, 1H), 1.98 (t, J ) 2.6 Hz, 1H), 1.73-1.62 (m, 1H);
13C NMR (CDCl3) δ 169.93, 160.90, 136.39, 128.77, 128.73,
128.64, 120.13, 82.31, 74.30, 73.43, 69.71, 30.78, 13.72.
The yellow oil was dried in vacuo for 15 h and placed under
argon, and 400 mL of MeOH was added. The solution was
cooled to 0 °C with stirring, and 11.7 g (85 mmol) of anhydrous
K2CO3 was added. After 30 min, the suspension was concen-
trated to about 75 mL, diluted with 100 mL of H2O and 50
mL of saturated bicarbonate solution, and washed with 2 ×
100 mL of ether. The aqueous phase was acidified with
concentrated HCl to a pH near 1 and extracted with 10 × 150
mL of ether. The combined ether extracts were washed with
100 mL of brine, dried (MgSO4), and concentrated to a yellow
oil (18.7 g, 86%) which solidified upon standing. Recrystalli-
zation from benzene and hexanes provided 15.8 g (75%) of a
white solid: mp 98-99 °C; 1H NMR (acetone-d6) δ 0.7.46-
7.27 (m, 5H), 5.06 (s, 2H), 4.83 (t, J ) 6.3 Hz, 1H), 3.85-3.69
(m, 2H), 2.05-1.95 (m, 1H), 1.89-1.76 (m, 1H). Anal.
(C13H14O5) C, H.
3-(Ben zyloxy)-4-h yd r oxy-5-(2-iod oeth yl)-2(5H)-fu r a n -
on e (16).39 To an oven-dried, 250-mL round-bottom flask
flushed with argon were added 5.8 g (22 mmol) of PPh3, 1.5 g
(22 mmol) of imidazole, and 80 mL of Et2O-CH3CN (3:1). The
mixture was cooled in an ice water bath with magnetic stirring,
and 5.6 g (22 mmol) of iodine was added in four equal portions
with vigorous stirring. The resulting slurry was warmed at
room temperature for 20 min and cooled to 0 °C, 5.0 g (20
mmol) of 15 dissolved in 20 mL of CH3CN-Et2O (1:1) was
added in one portion, and the remainder was rinsed in with 5
mL of Et2O. The mixture was stirred at 0 °C for 10 min and
then at room temperature for 30 min, and the reaction was
quenched by pouring into 150 mL of 10% HCl solution and
extracting with 500 mL of Et2O-hexanes (1:1). The aqueous
layer was separated and extracted with 100 mL of Et2O. The
combined organic fractions were washed with 50 mL of H2O
and extracted with 5 × 50 mL of saturated NaHCO3 solution.
The combined bicarbonate extracts were washed with 50 mL
of Et2O-hexanes (1:1), acidified to pH below 2, and extracted
with 3 × 200 mL of Et2O. The combined ether extracts were
washed with 100 mL of brine, dried (MgSO4), and concentrated
to 6.7 g (93%) of a white solid which was not further purified:
5-(3-Bu tyn yl)-3,4-d ih yd r oxy-2(5H)-fu r a n on e (7).28 An
oven-dried, 250-mL one-necked flask equipped with a magnetic
stir bar was flushed with argon and attached to an argon inlet,
and 2.6 g (10.0 mmol) of 6 and 50 mL of anhydrous CH2Cl2
were added. The solution was cooled in an ice bath to 5 °C
with magnetic stirring, and 1.9 mL (20.0 mmol) of acetic
anhydride was added followed by 1.7 mL (21 mmol) of pyridine.
The ice bath was removed after 1 h, and the mixture was
concentrated on a rotary evaporator and dried at 0.5 mmHg
at room temperature for 12 h. Argon was introduced followed
by 100 mL of dry CH2Cl2. The solution was cooled to -78 °C
with stirring, and 25 mL (25 mmol) of 1.0 M BCl3 in CH2Cl2
was added. The reaction mixture was allowed to gradually
warm to 10 °C over about 2 h and maintained at 10 °C for 1
h. The mixture was poured into 50 mL of brine and extracted
with 4 × 100 mL of Et2O. The combined Et2O fractions were
extracted with 3 × 25 mL of saturated NaHCO3 solution. The
combined bicarbonate extracts were washed with 25 mL of
Et2O, acidified to pH 1 with concentrated HCl solution, and
extracted with 5 × 100 mL of Et2O. The combined Et2O
washes were dried (MgSO4), filtered through 100 g of silica
gel (remove polar impurity), and washed with 1 L of ether.
Removal of solvent in vacuo left 1.4 g (80%) of analytically
1
mp 101-104 °C; H NMR (CDCl3) δ 7.40-7.27 (m, 5H), 5.06
(dd, J ) 11.4 Hz, 2H), 4.69 (dd, J ) 3.4, 8.0 Hz, 1H), 3.06 (t,
J ) 7.3 Hz, 2H), 2.41-2.29 (m, 1H), 2.02-1.90 (m, 1H); 13C
NMR (CDCl3) δ 170.33, 160.61, 136.32, 128.77, 128.69, 128.58,
120.11, 75.76, 73.39, 35.77, -2.03. Anal. (C13H13O4I) Calcd:
C, 43.35; H, 3.64. Found: C, 43.94; H, 3.69.
1
pure off-white solid: mp 124-128 °C dec; H NMR (acetone-
d6) δ 4.79 (dd, J ) 3.4, 8.3 Hz, 1H) 2.42 (t, J ) 2.6 Hz, 1H),
2.37-2.30 (m, 2H), 2.20-2.09 (m, 1H), 1.81-1.67 (m, 1H); 13
C
3,4-Dih yd r oxy-5-(2-iod oeth yl)-2(5H)-fu r a n on e (17). To
a dry flask flushed with argon were added 0.72 g (2.0 mmol)
of 16 and 10 mL of CH2Cl2. The solution was cooled with
stirring in an ice-water bath, and 0.38 mL (4.0 mmol) of acetic
anhydride and 0.34 mL (4.2 mmol) of pyridine were added.
The ice bath was removed, and the solution was stirred for 1
h. All volatile substances were removed in vacuo (2 h at 1
mmHg, 25 °C). Argon was introduced to the reaction flask,
the residue was taken up in 20 mL of dry CH2Cl2 and cooled
to -78 °C, and 5.2 mL (2.6 mmol) of 1.0 M BCl3 in CH2Cl2
was added with stirring. The reaction mixture was kept at
-78 °C for 1 h and at room temperature for 30 min. The
mixture was poured into 50 mL of brine and extracted with 3
× 30 mL of Et2O. The combined Et2O extracts were washed
with 5 mL of H2O and extracted into NaHCO3 (3 × 15 mL).
The bicarbonate fractions were pooled and washed with 15 mL
of ether, acidified to pH 1 with 25% concentrated HCl solution,
and extracted into Et2O (3 × 30 mL). The Et2O extracts were
washed with 15 mL of brine, dried (MgSO4), and concentrated
to 360 mg (67%) of a white crystalline solid: mp 150-151 °C;
NMR (acetone-d6) δ 170, 153.7, 119, 83.4, 74.7, 70.9, 32.4, 14.4.
Anal. (C8H8O4) C, H.
2-((2Z)-Hexen yl)iod oben zen e (8d ).40 A dry, 25-mL two-
necked flask equipped with a magnetic stir bar, argon inlet,
and septum was cooled to 0 °C, and 3 mL of 1.0 M BH3 in
THF was added. Cyclohexene (607 µL, 6 mmol) was added
via syringe, and the suspension stirred at 0-5 °C for 35 min.
Iodobenzene 8c30 (0.852 g, 3.0 mmol) was added to the reaction
mixture dropwise over 5 min. The ice bath was removed, and
the yellow reaction mixture stirred at room temperature for 1
h. The solution that formed was cooled in an ice bath, and
1.4 mL (25 mmol) of glacial AcOH was added. The solution
stirred at room temperature for 1 h, was poured into 75 mL of
H2O, and was extracted with 3 × 30 mL of hexanes. The
combined hexane fractions were washed with 25 mL of H2O,
25 mL of saturated NaHCO3 solution, 25 mL of H2O, and 2 ×
20 mL of brine, dried (MgSO4), and concentrated to an oil (do
not warm above 30 °C to avoid isomerization of the double
bond). Purification over 40 g of silica gel using hexanes as

aci-Reductone Mimics of Arachidonic Acid
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 425
eluant provided 670 mg (78%) of a colorless oil: 1H NMR
(CDCl3) δ 7.82 (d, J ) 7.8 Hz, 1H), 7.30-7.20 (m, 2H), 6.91-
6.86 (m, 1H), 5.62-5.46 (m, 2H), 3.47 (d, J ) 6.5 Hz, 2H),
2.17-2.10 (m, 2H), 1.49-1.37 (m, 2H), 0.94 (t, J ) 7.3 Hz, 3H);
13C NMR (CDCl3) δ 143.8, 139.3, 131.8, 129.2, 128.3, 127.7,
126.6, 100.8, 38.8, 29.6, 22.7, 13.9. Anal. (C12H15I) C, H.
Gen er a l P r oced u r e for Cou p lin g Rea ction s.29 Pd-
(PPh3)4 (58 mg, 0.05 mmol), an iodobenzene 8a -k (2.0 mmol),
butynyltetronic acid 6 or 7 (1.0 mmol), 2 mL of pyrrolidine,
and 19 mg (0.1 mmol) of CuI were added to a flame-dried
reaction flask fitted with an argon inlet, septum, and magnetic
stir bar. The flask was protected from light (foil), and the
yellow mixture was stirred at room temperature until starting
material was not visible by TLC analysis (CHCl3-MeOH, 9:1).
The reaction mixture was poured into 50 g of ice and 10 mL
of concentrated HCl and extracted with 2 × 50 mL of Et2O.
The Et2O extracts were combined and washed with 2 × 20
mL of 10% HCl solution, 20 mL of H2O, and 20 mL of brine,
dried (MgSO4), and concentrated.
3-(Ben zyloxy)-4-h yd r oxy-5-(4-p h en yl-3-bu tyn yl)-2(5H)-
fu r a n on e (9a ). This was prepared by coupling 6 with
iodobenzene 8a on a 2.0-mmol scale by the general coupling
method described above to yield 600 mg (90%) of 9a . Purifica-
tion: The residue was diluted with pentanes and extracted
with 5 × 20 mL of NaHCO3 solution. The combined extracts
were washed with 25 mL of 1:1 pentane-Et2O solution,
acidified to pH 1 with 20% concentrated HCl solution, and
extracted into 2 × 50 mL of Et2O. The ether extracts were
washed with 30 mL of H2O and 30 mL of brine, dried (MgSO4),
and concentrated: 1H NMR (CDCl3) δ 7.38-7.19 (m, 10H), 5.06
(s, 2H), 4.78 (dd, J ) 3.5, 8.0 Hz, 1H), 3.75 (dt, J ) 3.9, 8.1
Hz, 2H), 2.22-2.12 (m, 1H), 1.81-1.71 (m, 1H); 13C NMR
(CDCl3) δ 171.2, 161.7, 136.4, 131.6, 128.6, 128.5, 128.5, 128.3,
127.9, 123.5, 120.0, 87.8, 81.9, 74.9, 73.4, 31.0, 14.7.
3,4-Dih yd r oxy-5-(4-p h e n yl-3-b u t yn yl)-2(5H )-fu r a n -
on e (10a ). Iodobenzene 8a and 2-hydroxytetronic acid 7 were
coupled using the general procedure. Compound 10a was
purified by dissolving in 30 mL of Et2O and extracting into
saturated NaHCO3 solution (3 × 15 mL). The bicarbonate
extracts were pooled and washed with 10 mL of Et2O, acidified
to pH 2 with 10% HCl solution, and extracted into Et2O (2 ×
25 mL). The Et2O extracts were combined and washed with
10 mL of H2O, 3 mL of 10% saturated NaHCO3 in H2O (i.e., 1
mL of saturated NaHCO3 solution in 9 mL of H2O) in order to
remove highly polar acidic impurities, 10 mL of H2O, and 10
mL of brine, dried (MgSO4), and concentrated to a white
solid: mp 145-146 °C; 1H NMR (acetone-d6) δ 7.35-7.15 (m,
5H), 4.75 (dd, J ) 3.4, 8.2 Hz, 1H), 2.50-2.40 (m, 2H), 2.20-
2.05 (m, 1H), 1.75-1.60 (m, 1H); 13C NMR (acetone-d6) δ 170.2,
153.8, 132.3, 129.2, 128.7, 124.6, 119.0, 89.3, 82.1, 74.9, 32.4,
15.3.
3,4-Dih yd r oxy-5-[4-(2-((p h en ylth io)m eth yl)p h en yl)-3-
bu tyn yl]-2(5H)-fu r a n on e (10e). This was synthesized by
coupling 350 mg (1.1 mmol) of 2-[(phenylthio)methyl]-1-
iodobenzene (8e)41 with 120 mg (0.71 mmol) of 2-hydroxy-
tetronic acid 7 following the general coupling procedure
described above. Purification over silica gel using CHCl3-
MeOH-AcOH (96:3:1) as eluant provided 180 mg (69%) of a
light-yellow oil, which was dried at 0.05 mmHg at 58 °C for 2
h: 1H NMR (acetone-d6) δ 7.44-7.19 (m, 9H), 4.90 (dd, J )
3.3, 8.3 Hz, 1H), 4.36 (s, 2H), 2.63 (t, J ) 7.6 Hz, 2H), 2.28-
2.21 (m, 1H), 1.90-1.81 (m, 1H). Anal. (C21H18O4S) C, H.
3,4-Dih yd r oxy-5-[4-(N-bu tyl-2-ben zen esu lfon a m id o)-3-
bu tyn yl]-2(5H)-fu r a n on e (10f). This was synthesized by
coupling 400 mg (1.2 mmol) of N-butyl-2-iodobenzenesulfon-
amide (8f) with 168 mg (1.0 mmol) of 2-hydroxytetronic acid
7 following the general coupling procedure described above.
Purification over silica gel using CHCl3-MeOH-AcOH (500:
16:0.5) as eluant provided a light-yellow oil, which was dried
at 0.05 mmHg at 58 °C for 2 h: 1H NMR (acetone-d6) δ 8.00-
7.96 (m, 1H), 7.59-7.55 (m, 1H), 7.33-7.24 (m, 2H), 6.66 (s,
1H), 4.82 (dd, J ) 3.4, 8.3 Hz, 1H), 3.44-3.36 (m, 2H), 3.23-
3.14 (m, 2H), 2.52-2.45 (m, 1H), 2.00-1.94 (m, 1H), 1.69-
1.53 (m, 2H), 1.43-1.29 (m, 2H), 0.81 (t, J ) 7.2 Hz, 3H); 13
C
NMR (acetone-d6) δ 169.8, 153.5, 141.6, 137.6, 130.0, 124.2,
123.8, 120.9, 118.6, 114.4, 108.7, 74.8, 53.6, 32.0, 24.9, 24.1,
20.9, 12.9. Anal. (C18H21NO6S) C, H, N.
3,4-Dih yd r oxy-5-[4-(2-n a p h th yl)-3-bu tyn yl]-2(5H)-fu r -
a n on e (10g). This was synthesized by coupling 300 µL (2.0
mmol) of 2-iodonaphthalene (8g) with 175 mg (1.0 mmol) of
2-hydroxytetronic acid 7 following the general coupling pro-
cedure described above. Purification over silica gel using
CHCl3-MeOH-AcOH (96:3:1) as eluant provided 230 mg
(75%) of a viscous yellow oil, which solidified after drying at
0.05 mmHg at 58 °C for 2 h: 1H NMR (acetone-d6) δ 8.4-8.3
(m, 1H), 7.96-7.88 (m, 2H), 7.70-7.43 (m, 4H), 4.98 (dd, J )
3.4, 8.3 Hz, 1H), 2.82-2.75 (m, 2H), 2.48-2.29 (m, 1H), 2.00-
1.85 (m, 1H). Anal. (C18H14O4‚0.5H2O) C, H.
3,4-Dih yd r oxy-5-[4-(2-((p r op ylt h io)m et h yl)p h en yl)-3-
bu tyn yl]-2(5H)-fu r a n on e (10h ). This was synthesized by
coupling 440 mg (1.5 mmol) of 2-[(propylthio)methyl]iodoben-
zene (8h ) with 170 mg (1.0 mmol) of 2-hydroxytetronic acid 7
following the general coupling procedure described above.
Purification over silica gel using CHCl3-MeOH-AcOH (500:
16:0.5) as eluant provided 240 mg (72%) of a yellow oil, which
1
was dried at 0.05 mmHg at 58 °C for 2 h: H NMR (acetone-
d6) δ 7.44-7.21 (m, 4H), 4.90 (dd, J ) 3.4, 8.3 Hz, 1H), 3.89
(s, 2H), 2.70-2.63 (m, 2H), 2.48-2.41 (m, 2H), 2.26-2.21 (m,
1H), 1.90-1.81 (m, 1H), 1.64-1.53 (m, 2H), 0.93 (t, J ) 7.3
Hz, 3H). Anal. (C18H20O4S) Calcd: C, 65.05; H, 6.07.
Found: C, 64.51; H, 6.28.
3,4-Dih yd r oxy-5-[4-(2-((p en t ylt h io)m et h yl)p h en yl)-3-
bu tyn yl]-2(5H)-fu r a n on e (10i). This was synthesized by
coupling 240 mg (0.75 mmol) of 2-methyl(1-pentyl sulfide)-
iodobenzene (8i) with 84 mg (0.5 mmol) of 2-hydroxytetronic
acid 7 following the general coupling procedure described
above. Purification over silica gel using CHCl3-MeOH-AcOH
(500:16:0.5) as eluant provided a yellow oil, which was dried
at 0.05 mmHg at 58 °C for 2 h: 1H NMR (acetone-d6) δ 7.43-
7.21 (m, 4H), 4.95 (dd, J ) 3.4, 8.4 Hz, 1H), 3.89 (s, 2H), 2.70-
2.63 (m, 2H), 2.50-2.43 (m, 2H), 2.26-2.21 (m, 1H), 2.00-
1.81 (m, 1H), 1.66-1.45 (m, 2H), 1.43-1.20 (m, 4H), 0.87 (t, J
) 7.2 Hz, 3H). Anal. (C20H24O4S‚0.5H2O) C, H.
3,4-Dih yd r oxy-5-[4-(2-m eth ylp h en yl)-3-bu tyn yl]-2(5H)-
fu r a n on e (10b). This was synthesized by coupling 2-hydroxy-
tetronic acid 7 with 2-iodotoluene (8b) following the general
coupling method above. Purification over silica gel using
CHCl3-MeOH (96:4) as eluant provided aci-reductone 10b as
a light-yellow solid: mp 111-112 °C; 1H NMR (CDCl3) δ 7.37-
7.07 (m, 4H), 5.01 (dd, J ) 3.5, 8.5 Hz, 1H), 2.69-2.65 (m,
2H), 2.40 (s, 3H), 2.39-2.27 (m, 1H), 1.97-1.86 (m, 1H); 13C
NMR (CDCl3) δ 173.6, 155.8, 140.0, 131.9, 129.3, 127.9, 125.5,
123.1, 117.5, 91.5, 80.9, 76.4, 31.3, 20.7, 15.3. Anal. (C15H14O4)
C, H.
3,4-Dih ydr oxy-5-[4-(2-((2Z)-h exen yl)ph en yl)-3-bu tyn yl]-
2(5H)-fu r a n on e (10d ). This was synthesized by coupling 0.34
g (2.0 mmol) of 2-hydroxytetronic acid 7 with 1.1 g (4.0 mmol)
of 2-iodo-1-[(2Z)-hexenyl]benzene (8d ) following the general
coupling procedure described above. Purification over silica
gel using CHCl3-MeOH (96:4) as eluant provided 100 mg
(17%) of a yellow oil, which was dried at 0.05 mmHg at 58 °C
for 2 h: 1H NMR (acetone-d6) δ 7.43-7.15 (m, 4H), 5.70-5.45
(m, 2H), 4.91 (dd, 1H, J ) 3.4, 8.3 Hz), 3.57 (d, 2H, J ) 5.9
Hz), 2.66 (t, 2H, J ) 7.0 Hz), 2.37-2.11 (m, 3H), 2.00-1.85
(m, 1H), 1.48-1.29 (m, 2H), 0.93 (t, 3H, J ) 7.3 Hz). Anal.
(C20H22O4‚0.2H2O) C, H.
3,4-Dih ydr oxy-5-[4-(2-((pr opylsu lfon yl)m eth yl)ph en yl)-
3-bu tyn yl]-2(5H)-fu r a n on e (10j). This was synthesized by
coupling 600 mg (1.5 mmol) of 2-methyl(1-propyl sulfone)-
iodobenzene (8j) with 236 mg (1.2 mmol) of 2-hydroxytetronic
acid 7 following the general coupling procedure described
above. Purification over silica gel using CHCl3-MeOH-AcOH
(500:16:0.5) as eluant provided 250 mg (50%) of a light-yellow
oil, which was dried at 0.05 mmHg at 58 °C for 2 h: 1H NMR
(acetone-d6) δ 7.56-7.34 (m, 4H), 4.96 (dd, J ) 3.4, 8.2 Hz,
1H), 4.57 (s, 2H), 3.03-2.95 (m, 2H), 2.71-2.64 (m, 2H), 2.35-
2.26 (m, 1H), 1.94-1.70 (m, 3H), 1.02 (t, J ) 7.4 Hz, 3H); 13
NMR (acetone-d6) δ 169.9, 153.5, 132.9, 132.1, 131.0, 128.9,
C

426 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Hopper et al.
128.5, 125.3, 118.6, 94.0, 79.6, 74.4, 57.2, 54.0, 31.5, 15.7, 14.8,
12.7. Anal. (C18H20O6S) Calcd: C, 59.34; H, 5.53. Found: C,
58.93; H, 5.76.
(CDCl3) δ 7.34-7.14 (m, 5H), 6.46 (d, J ) 11.5 Hz, 1H), 5.65-
5.57 (m, 1H), 4.77 (dd, J ) 3.5, 8.0 Hz, 1H), 2.49 (dd, J ab ) 7.6
Hz, 2H), 2.16-2.09 (m, 1H), 1.80-1.70 (m, 1H); 13C NMR
(CDCl3) δ 173.4, 155.9, 137.1, 130.4, 130.3, 128.7, 128.3, 128.3,
126.8, 117.5, 77.2, 31.8, 23.5.
3,4-Dih yd r oxy-5-[2-(4-((4-flu or op h en yl)m et h yl)t h io-
p h en eyl)-3-bu tyn yl]-2(5H)-fu r a n on e (10k ). This was syn-
thesized by coupling 750 mg (4.5 mmol) of 6 with 2.6 g (8.2
mmol) of 4-[(4-fluorophenyl)methyl]-2-iodothiophene42 follow-
ing the general coupling procedure described above. The
residue was purified over silica gel using CHCl3-MeOH-
AcOH (500:15:0.5) as eluant and dried at 0.05 mmHg at 58
°C for 2 h to provide 1.2 g (75% yield) of 10k as a brown wax:
3,4-Dih yd r oxy-5-[4-(2-m et h ylp h en yl)-(3Z)-b u t en yl]-2-
(5H)-fu r a n on e (12b). This was synthesized by Lindlar
catalyzed reduction of alkyne 10b using the general hydroge-
nation procedure above to produce an oil containing only the
1
cis isomer as observed by H NMR spectra: 1H NMR (CDCl3)
δ 7.34-7.20 (m, 4H), 6.59 (d, J ) 11.4 Hz, 1H), 5.81-5.73 (m,
1H), 4.81 (dd, J ) 3.4, 8.2 Hz, 1H), 2.49-2.35 (m, 2H), 2.33 (s,
3H), 2.17-2.13 (m, 1H), 1.81-1.75 (m, 1H); 13C NMR (CDCl3)
δ 173.6, 156.0, 136.2, 136.2, 130.2, 129.9, 129.6, 128.8, 127.1,
125.5, 117.4, 77.3, 31.9, 23.4, 19.9.
3,4-Dih yd r oxy-5-[4-(2-((2Z)-h exen yl)p h en yl)-(3Z)-b u -
ten yl]-2(5H)-fu r a n on e (12d ). This was synthesized by Lind-
lar catalyzed reduction of alkyne 10d using the general
hydrogenation procedure described above to produce an oil
containing only the cis isomer as observed by 1H NMR spectra.
Less than 5% of starting material remained, which was not
separable from the product: 1H NMR (acetone-d6) δ 7.25-7.15
(m, 4H), 6.59 (d, 1H, J ) 11.4 Hz), 5.81-5.76 (m, 1H), 5.51-
5.43 (m, 2H), 4.71 (dd, 1H, J ) 3.5, 7.6 Hz), 3.44-3.25 (m,
2H), 2.40-1.90 (m, 5H), 1.76-1.58 (m, 1H), 1.50-1.32 (m, 2H),
0.94 (t, 3H, J ) 7.3 Hz). Anal. (C20H24O4‚0.5H2O) C, H.
1
mp 119-121 °C; H NMR (acetone-d6) δ 7.38-7.25 (m, 2H),
7.13-6.99 (m, 3H), 6.78-6.74 (m, 1H), 4.84 (dd, J ) 3.3, 8.1
Hz, 1H), 4.14 (s, 2H), 2.59 (t, J ) 7.1 Hz, 2H), 2.38-2.14 (m,
1H), 1.90-1.69 (m, 1H); 13C NMR (acetone-d6) δ 169.19, 164.04,
157.29, 152.78, 145.79, 136.74, 131.80, 130.80, 130.47, 125.54,
122.74, 118.84, 115.89, 115.03, 92.44, 74.90, 74.31, 35.14,
31.84, 15.02. Anal. (C19H15FO4S) C, H.
Gen er a l Meth od for Lin d la r Hyd r ogen a tion . Quinoline
(70 µL, 0.6 mmol), 5% Pd/BaSO4 (15 mg), and 0.25 mmol of
the acetylene were combined in 20 mL of ethanol and hydro-
genated at atmospheric pressure until 6 mL (0.25 mmol) of
H2 was consumed as measured by a H2O filled buret. The
catalyst was removed by filtration through two fluted filter
papers, and the solution was concentrated to about 5 mL,
taken up in 50 mL of ether, washed with 3 × 15-mL portions
of 5% aqueous HCl, 20 mL of H2O, and 20 mL of brine, dried
(MgSO4), and concentrated.
Refer en ces
3-(Ben zyloxy)-5-(4-p h en ylb u t a n yl)-4-h yd r oxy-2(5H )-
fu r a n on e (18a ). Hydrogenation of alkyne 9a using 50 mg of
5% Pd/BaSO4 and 70 µL of quinoline under a hydrogen-filled
balloon for a period of 1 h provided saturated compound 18a .
Workup was performed as described in the general hydrogena-
tion procedure: 1H NMR (acetone-d6) δ 7.46-7.12 (m, 10H),
5.04 (dd, J ab ) 11.4 Hz, 2H), 4.64 (dd, J ) 3.5, 7.2 Hz, 1H),
2.58 (t, J ) 7.8 Hz, 2H), 2.00-1.89 (m, 1H), 1.66-1.53 (m, 3H),
1.39-1.29 (m, 2H); 13C NMR (acetone-d6) δ 170.4, 163.8, 143.2,
138.4, 129.1, 129.0, 129.0, 129.0, 128.6, 126.4, 119.8, 76.2, 73.3,
36.2, 32.3, 32.0, 24.2. Anal. (C21H22O4‚0.25H2O) C, H.
3,4-Dih yd r oxy-5-(4-p h e n ylb u t a n yl)-2(5H )-fu r a n on e
(19a ). Alkyne 9a was hydrogenated for 3 h as described for
saturated compound 18a . Workup was performed as described
in the general hydrogenation procedure: 1H NMR (acetone-
d6) δ 7.28-7.13 (m, 5H), 4.66 (dd, J ) 3.4, 7.2 Hz, 1H), 2.62 (t,
J ) 7.7 Hz, 2H), 2.00-1.93 (m, 1H), 1.69-1.42 (m, 5H); 13C
NMR (acetone-d6) δ 170.7, 154.9, 143.3, 129.2, 129.1, 126.5,
118.6, 76.2, 36.3, 32.7, 32.1, 24.6. Anal. (C14H16O4‚0.25H2O)
C, H.
3,4-Dih yd r oxy-5-(4-p h en yl-(3Z)-bu ten yl)-2(5H)-fu r a n -
on e (12a ). Meth od A. 3-(Benzyloxy)furanone 11a (55 mg,
0.17 mmol) in a dry, 10-mL round-bottom flask under argon
with a magnetic stir bar was taken up in 2.5 mL of CH2Cl2
and cooled to 0 °C, and 31.2 µL (0.33 mmol) of acetic anhydride
and 26.1 µL (0.34 mmol) of pyridine were added with stirring.
The ice bath was removed, and the solution was stirred at room
temperature for 2 h. All volatile materials were removed in
vacuo, and the residue was dried at 0.2 mmHg, 25 °C, for 2 h.
The residue was placed under argon, dissolved in 1.7 mL of
CH2Cl2, and cooled to -78 °C with stirring. BCl3 (1.0 M) in
CH2Cl2 (0.88 mL, 0.88 mmol) was added, and the mixture
stirred while slowly warming to 15 °C over 2 h. The reaction
mixture was poured into 25 mL of H2O and extracted with 2
× 25 mL of Et2O. The Et2O extracts were washed with 10
mL of H2O and extracted with 3 × 15 mL of saturated NaHCO3
solution. The bicarbonate extracts were combined, acidified
to pH 2, and extracted with 2 × 25 mL of Et2O. The Et2O
extracts were combined, washed with 10 mL of H2O and 10
mL of brine, dried (MgSO4), and concentrated to a light-yellow
oil as a 4:1 mixture of unsaturated 12a and saturated 19a as
estimated by 13C NMR.
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