An efficient approach to the synthesis of 1,3-diaryl-1,2,3,4-[4H]-tetrahydronaphthalene-2-carboxylic acids

Article abstract of DOI:10.1016/S0968-0896(98)00022-4

A flexible approach to the synthesis of endothelin receptor antagonists of the 1,3-diaryl-1,2,3,4-[4H]-tetrahydronaphthalene-2-carboxylic acid class is described. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00022-4

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 695±700
An Ecient Approach to the Synthesis of 1,3-Diaryl-1,2,3,4-
[4H]-tetrahydronaphthalene-2-carboxylic Acids
Jia-Ning Xiang,* Ponnal Nambi, Eliot H. Ohlstein and John D. Elliott
Research and Development, SmithKline Beecham Pharmaceuticals, P.O. Box 1539, 709 Swedeland Road, King of Prussia,
Pennsylvania 19406-0939, U.S.A.
Received 26 August 1997; accepted 23 November 1997
AbstractÐA ¯exible approach to the synthesis of endothelin receptor antagonists of the 1,3-diaryl-1,2,3,4-[4H]-tetra-
hydronaphthalene-2-carboxylic acid class is described. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
and aryl groups for biological activity. As part of our
e€orts to assess the contribution of the indane ring to
antagonist activity, we decided to prepare the analogous
tetrahydronaphthalene. To this end Compound 3 was
selected as our initial synthetic target in order to com-
pare its biological activities with an earlier lead in the
indane series (2). In this paper we describe an ecient
The endothelins (ETs), discovered in 1988,1 are a family
of three isopeptides (ET-1, ET-2, and ET-3) encoded in
the human genome and each is composed of 21 amino
acids, with disul®de linkages between cysteine residues
at positions 1,15 and 3,11. The ETs elicit their e€ects
through binding to receptors of the G-protein coupled
seven-transmembrane spanning superfamily, and two
receptor sub-types have been fully characterized from
human tissues through molecular cloning and expres-
sion.3±5 Recently, compelling data has become available
with receptor speci®c antagonists to support a role for
the ETs in disease processes.2 Despite extensive animal
model studies, controversy still surrounds the optimal
antagonist selectivity considered necessary for the treat-
ment of human disorders. This critical question will
only be resolved by clinical trials which are now ongo-
ing, and may be dependent upon the disease targeted
(Figure 1).
synthesis
of
trans,trans-1,3-diaryltetrahydronaph-
thalene-2-carboxylic acid (3) and demonstrate that this
approach can be applied to synthesize other members in
this class (Figure 2).
Results and Discussion
Our retrosynthetic analysis for the construction of the
1,3-diaryltetrahydronaphthalene ring system is shown in
Scheme 1. Thus the aryl ring at C-1 was envisioned as
being added through 1,4-addition-elimination of a
Grignard reagent to methyl enol ether (4). The methyl
enol ether (4) would be derived from b-keto ester (5)
which in turn could be obtained via a Dieckmann cycli-
zation. Finally, it was anticipated that the Dieckmann
substrate could be prepared by the ¯uoride ion pro-
moted Michael addition of trimethylsilylmethylbenzoate
(6) to benzylidene malonate (7)7 followed by mono-
deprotection and decarboxylation.
Recently, we reported the rational design and synthesis
of 1,3-diarylindane-2-carboxylic acids as potent endo-
thelin antagonists.6 209670 (1) is a highly potent mem-
ber of this class which inhibits [125I]ET-1 binding to
cloned human ETA and ETB receptors with Ki values of
0.43 and 14.7 nM, respectively. Structure±activity rela-
tionship studies in the indane series highlight the
importance of the all trans relationship of aryl, carboxyl
The synthesis (Scheme 2) began with treatment of
methyl o-trimethylsilylmethylbenzoate (6) with a mix-
ture of a,b-unsaturated esters (7) in the presence of CsF
in dry hexamethylphosphoramide (HMPA), a€ording
the Michael adduct (8) in 60% yield. The mixture of
Key words: Endothelin; endothelin receptor antagonist; G-
protein coupled receptor; 1,4-addition; Dieckmann cyclization.
*Corresponding author.
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00022-4

696
J.-N. Xiang et al./Bioorg. Med. Chem. 6 (1998) 695±700
Our initial attempts to install the remaining phenyl
substituent at C-1 (Scheme 3) through either, cuprate
addition to the methyl enol ether (11)9 or palladium
mediated coupling of a boronic acid with the enol tri-
¯ate (12),10 were unsuccessful. While the major pathway
of Grignard addition (i.e., phenyl-magnesium chloride)
to the methyl enol ether (11) occurred in a 1,2 sense, a
small amount of 1,4-addition product was also isolated.
We then reasoned that a bulkier alcohol in the ester
portion of the molecule should favor the desired 1,4-
addition product. a-Methylbenzyl alcohol was chosen
since it could be readily removed by hydrogenolysis
later in the synthesis. Thus ester exchange with a-
methylbenzyl alcohol in the presence of dimethylamino-
pyridine (DMAP) in re¯uxing toluene,11 (Scheme 4) fol-
lowed by diazomethane treatment of the corresponding
phenethyl ester (13) in ethanol/diethyl ether, provided
methyl enol ether (14) in 67% [three steps from (9)].
Figure 1.
geometric isomers of the arylidene malonate (7) was
derived by condensation of piperonal and benzylmethyl
malonate. Removal of the benzyl protecting group of (8)
by catalytic hydrogenolysis and subsequent decarboxyl-
ation upon heating the mono acid to 150 ꢀC, generated
dimethyl ester (9) in 96% yield. The b-ketoester (10) was
then formed as 1:1 mixture of the two possible diastereo-
mers through Dieckmann cyclization with sodium
methoxide.8
Gratifyingly, addition of 3,4-methylenedioxyphenyl-
magnesium bromide to the methyl enol ether (14) in
THF at 0 ꢀC a€orded the desired 1,4 addition-elimina-
tion product (15) in 69% yield. As shown in Table 1,
Figure 2.
Scheme 1.

J.-N. Xiang et al./Bioorg. Med. Chem. 6 (1998) 695±700
697
Scheme 2. (a) CsF, HMPA, 60 ꢀC; (b) H2, 10% Pd/C; (c) 150 ꢀC; (d) NaOMe/MeOH/THF.
this reaction also proceeds eciently for other sub-
stituted phenyl Grignard reagents as well.
To complete the synthesis of (3), the phenethyl ester (15)
was subjected to hydrogenolysis (10% Pd/C/55 psi-H2,
5 h) to generate the corresponding acid, which was
converted directly to the methyl ester (16) in 66% yield
for the two steps. Reduction of the tetrasubstituted
double bond in (16) was then accomplished by further
hydrogenation (55 psi) for 72 h to provide all cis methyl
ester (17). Epimerization at C-2 and hydrolysis of the
Scheme 3. (a) CH2N2, MeOH/Diethyl ether or (b) Tf2O, pyr-
idine, CH2Cl2.
Scheme 4. Reagents: (a) Ph(Me)CHOH, DMAP, PhMe; (b) CH2N2, EtOH; (c) 3,4-Methylenedioxyphenyl-magnesium bromide THF;
(d) H2 (55 psi), 5 h, EtOAc; (e) CH2N2, MeOH; (f) H2 (55 psi), 72 h, EtOAc; (g) MeONa/MeOH, THF; (h) aq NaOH/MeOH, aq HCl.

698
J.-N. Xiang et al./Bioorg. Med. Chem. 6 (1998) 695±700
Table 1. Addition of phenyl Grignard reagents on enol ether
14
Entry
Grignard reagent
Product
Yield (%)
Figure 3. Overlay of indane 2 (red) and tetrahydronaphthalene
3 (green).
spectra were obtained with a Bruker AM-250 and a
Bruker AM-400 spectrometers and are reported as ppm
down®eld from Me4Si with multiplicity, number of
protons, and coupling constant(s) in Hertz indicated
parenthetically. Elemental analyses were obtained using
a Perkin±Elmer 240C elemental analyzer. Chromato-
graphy refers to ¯ash chromatography using Kiseslgel
60, 230±400 mesh silica gel.
Benzyl-methyl-2-[1-(3,4-methylenedioxyphenyl)-2-(2-meth-
ylcarboxyphenyl)-ethyl] malonate (8). To a solution of
benzyl, methyl-2-(3,4-methylenedioxy-benzyliden)-malo-
nate 7 (2.16 g, 6.35 mmol) and methyl o-trimethylsilyl-
methyl benzoate 6 (2.12 g, 9.53 mmol) in HMPA (6 mL)
at room temperature was added CsF (1.93 g,
12.70 mmol) in one portion. The mixture was heated to
60 ꢀC for 3 h under argon and then quenched with
water, extracted with 1:1 EtOAc:Hexane. The organic
layer was separated and washed with brine and dried
(NaSO4). After removing the solvent, chromatography
of the residue with 4:1 Hexane:EtOAc gave 1.87 g (60%)
of an inseparable 1:1 mixture of title compounds 8 as
methyl ester under basic conditions gave the target
compound (3).
Biological evaluation of (3) indicates that it is an inferior
antagonist by comparison with the indane counterpart (2)
[Ki's ETA 1.4 mM (3) versus 0.1 mM (2); ETB 3.3 mM (3)
versus 0.8 mM (2)]. The weaker binding anity of 3 to the
receptors might be due to a di€erent conformation pre-
sented by the tetrahydronaphthalene ring. Molecular
modeling overlay of 2 and 3 (Figure 3) revealed that to
keep all three substituents which are important for the
binding anity well aligned, the aromatic ring of 3 is
clearly located at a di€erent region compared to that in 2
indicating this aromatic moiety in 2 might also be involved
in participating in the interaction with the receptors.
colorless oil: Rf 0.31 (silica gel, 2:1 n-hexane:EtOAc); IR
1
(neat): 2952, 1755, 1723, 1489, 1442, 1248 cm
;
1H
NMR (CDCl3): d 3.30±3.40 (m, 4H), 3.45 (s, 3H), 3.61
(m, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 3.84 (m,
2H), 4.90 (dd, J=18 Hz, J=12.3 Hz, 2H), 5.18 (d,
J=1.2 Hz, 2H), 5.87 (m, 4H), 6.36±6.57 (m, 6H), 7.00±
7.40 (m, 16H), 7.50 (d, J=1.4 Hz, 2H); 13C NMR
(CDCl3): d 168.9, 168.5, 168.4, 167.9, 147.7, 146.7,
140.7, 135.8, 134.1, 134.0, 132.2, 131.8, 130.7, 129.0,
128.8, 128.6, 128.5, 126.6, 122.3, 122.2, 109.0, 108.2,
101.2, 67.7, 67.4, 58.4, 53.0, 52.7, 52.3, 47.7, 38.5, 38.2;
MS (ES) m/z 491 (MH+); Anal. Calcd for C28H26O8: C,
68.56; H, 5.34. Found: C, 68.53; H, 5.33.
In summary, we have described a ¯exible approach to
trans,trans-1,3-diaryltetrahydronaphthalene-2-carboxylic
acids of type (3) from readily available precursors.
Experimental
General methods
Melting points were measured with a Thomas±Hoover
1
Methyl-3-(3,4-methylenedioxyphenyl)-4-(2-methylcarboxy-
phenyl)butanoate (9). To a solution of triesters 8 (3.30 g,
melting point apparatus and are uncorrected. H NMR

J.-N. Xiang et al./Bioorg. Med. Chem. 6 (1998) 695±700
699
6.73 mmol) in 10 mL of ethyl acetate was added 330 mg
of 10% Pd/C and the mixture was stirred under H2
atmosphere at room temperature for 7 h. Filtration and
concentration gave 2.70 g of the crude acids which were
directly used in the following reaction without further
ethers 14 as colorless oil: Rf 0.56 (silica gel, 3:1 n-hexane:
EtOAc); IR (neat): 2980, 2934, 1709, 1690, 1616, 1502,
1
1487, 1441, 1250, 1197, 1040 cm 1; H NMR (CDCl3):
d 1.44 (d, J=7.3 Hz, 3H), 1.58 (d, J=7.3 Hz, 3H),
2.94 (m, 2H), 3.37 (m, 2H), 3.87 (s, 3H), 3.90 (s, 3H),
4.16 (m, 2H), 5.89 (t, 4H), 5.98 (m, 2H), 6.63 (m, 6H),
7.00±7.70 (m, 18H); MS (ES) m/z 429 (MH+); Anal.
calcd for C27H24O5: C, 75.68; H, 5.65. Found: C, 75.34;
H, 5.49.
1
puri®cation. H NMR (CDCl3): d 3.30 (m, 2H), 3.52 (s,
3H), 3.54 (m, 4H), 3.80 (s, 3H), 3.81 (m, 2H), 3.83 (s,
3H), 3.85 (s, 3H), 5.79 (m, 4H), 6.44 (m, 2H), 6.54 (m,
4H), 7.00 (m, 2H), 7.11-7.30 (m, 4H), 7.76 (m, 2H). The
neat crude acids (2.70 g) were heated to 150 ꢀC for 1 h
and ¯ash chromatography of the residue with 4:1 n-
hexane:ethyl acetate gave 2.30 g (96% over two steps) of
the diester 9 as a colorless oil: Rf 0.46 (silica gel, 2:1 n-
hexane:EtOAc); IR (neat): 2951, 1736, 1721, 1504, 1488,
(RS)-ꢀ-Methylbenzyl-(3SR)-1,3-bis(3,4-methylenedioxy-
phenyl)-3,4-dihydro-2-naphthoate (15). To a mixture of
1-bromo-3,4-methylenedioxy-benzene (423 mg, 2.10 mmol)
and Mg (68 mg, 2.80 mmol) in 3 mL of THF was added
2 uL of MeI and the mixture was irradiated by ultra-
sound for 30 min. To a solution of methyl enol ether 14
(300 mg, 0.70 mmol) in 4 mL of THF at 0 ꢀC under
argon was added dropwise the Grignard reagent in
THF. After 15 min, the reaction was quenched with aq
HCl and the mixture was extracted with 1:1 hex-
ane:EtOAc. The organic extract was washed with brine
and dried (Na2SO4). After removing the solvent, ¯ash
chromatography of the residue with 4:1 hexane:EtOAc
gave 250 mg (69%) of 1:1 mixture of inseparable dia-
stereomers 15 as colorless oil: Rf 0.45 (silica gel, 3:1 n-
hexane:EtOAc); IR (KBr): 2884, 1712, 1692, 1502, 1485,
1
1438, 1254, 1081, 1039, 811 cm 1; H NMR (CDCl3): d
2.67 (d, J=8.3 Hz, 2H), 3.23±3.55 (m, 3H), 3.60 (s, 3H),
3.92 (s, 3H), 5.95 (s, 2H), 6.60 (dd, J=8.0, 1.7 Hz, 1H),
6.70 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 7.08 (dd, J=7.5,
0.8 Hz, 1H), 7.26 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.37
(ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.89 (dd, J=7.8, 1.3 Hz,
1H); 13C NMR (CDCl3): d 173.0, 168.3, 147.9, 146.4,
141.7, 137.8, 132.3, 132.2, 132.1, 131.2, 130.3, 126.7,
121.1, 108.5, 108.2, 101.2, 52.4, 51.9, 44.0, 41.5, 40.9;
MS (ES) m/z 357 (MH+); Anal. Calcd for C20H20O6: C,
67.41; H, 5.66. Found: C, 67.42; H, 5.53.
1
(RS)-ꢀ-Methylbenzyl±(3SR)-1-methoxy-3-(3,4-methylene-
dioxyphenyl)-3,4-dihydro-2-naphthoate (14). To a solu-
tion of diester (800 mg, 2.24 mmol) in 10 mL of THF
was added 3 mL of a solution of 25% wt NaOMe/
MeOH and the mixture was heated to re¯ux for 1 h.
After cooling to room temperature, the mixture was
poured into 1 N HCl and extracted twice with 1:1 hex-
ane:EtOAc. The combined oraginc extract was washed
with brine and dried (Na2SO4). Removal of the solvent
gave the crude b-keto ester 10, which was used in the
next reaction without further puri®cation.
1437, 1233, 1038, 812, 698 cm 1; H NMR (CDCl3): d
1.18 (d, J=7.3 Hz, 3H), 1.24 (d, J=7.3 Hz, 3H), 3.09
(m, 2H), 3.41 (dd, J=17.3, 7.9 Hz, 2H), 4.15 (m, 2H),
5.67 (m, 2H), 5.91 (s, 4H), 6.00 (m, 4H), 6.68±7.27 (m,
30H); 13C NMR (CDCl3): d 167.94, 147.43, 146.98,
146.17, 141.28, 136.33, 134.72, 134.61, 132.52, 132.27,
129.05, 128.95, 128.16, 128.10, 128.01, 127.97, 127.74,
127.56, 127.52, 127.47, 126.63, 126.10, 126.04, 122.42,
120.70, 109.77, 108.17, 108.06, 101.01, 100.76, 72.40,
72.38, 41.54, 41.42, 37.21, 37.17, 21.87, 21.60; MS (ES)
m/z 519 (MH+); Anal. calcd for C33H26O6: C, 76.43; H,
5.05. Found: C, 76.70; H, 5.14.
To a solution of the crude b-keto ester 10 in 10 mL of
toluene was added a-methylbenzyl alcohol (0.41 mL,
3.36 mmol) and DMAP (10 mg) and the mixture was
re¯uxed for 28 h. After cooling to room temperature,
the mixture was poured into water and extracted twice
with 1:1 hexane:EtOAc. The combined organic extract
was washed with brine and dried (Na2SO4). Removal of
the solvent gave the crude b-keto ester 13, which was
used in the next reaction without further puri®cation.
(1RS,2SR,3SR)-Methyl-1,3-bis(3,4-methylenedioxyphen-
yl)-1,2,3,4-tetrahydro-2-naphthoate (17). To a solution
of a-methylbenzylester 15 (454 mg, 0.876 mmol) in 4 mL
of EtOAc was added 60 mg of 10% Pd/C and shaken
under H2 (55 psi) at room temperature for 24 h. After
®ltration and concentration, the residue was dissolved in
ether and added excess of diazomethane solution in
ether. The reaction was quenched with acetic acid and
washed with water, brine and dried (Na2SO4). After
removing the solvent, ¯ash chromatography of the
residue with 4:1 Hexane:EtOAc gave 160 mg (43%) of
the cis±cis methyl ester 17 as a colorless oil: Rf 0.52
(silica gel, 3:1 n-hexane/EtOAc); 1H NMR (CDCl3): d
2.95 (dd, J=16.4, 5.0 Hz, 1H), 3.25 (s, 3H), 3.27 (dd,
J=6.3, 3.7 Hz, 1H), 3.37 (m, 1H), 3.86 (t, J=14.0 Hz,
1H), 4.51 (d, J=6.3 Hz, 1H), 5.94 (m, 4H), 6.60±7.20
(m, 10H).
To a solution of the crude ester 13 in 10 mL of ethanol
at room temperature was added 20 mL of diazomethane
solution (13 mmol) and the mixture was stirred under
argon at room temperature for 17 h. The reaction was
quenched with AcOH and the solution was then con-
centrated. Flash chromatography of the residue with 4:1
hexane:EtOAc gave 647 mg (67% over three steps) of a
1:1 mixture of inseparable diastereomeric methyl eno-

700
J.-N. Xiang et al./Bioorg. Med. Chem. 6 (1998) 695±700
(1RS,2SR,3SR)-1,3-Bis(3,4-methylenedioxyphenyl)-1,2,-
3,4-tetrahydro-2-naphthoic acid (3). To solution of
methyl ester 17 (160 mg, 0.373 mmol) in 3 mL of THF
was added 0.7 mL of 25% NaOMe:MeOH and stirred
at room temperature under argon for 18 h. The mixture
was poured into 1 N HCl and extracted with 1:1 hex-
ane:EtOAc. The organic extract was washed with brine
and dried (Na2SO4). After removing the solvent, ¯ash
chromatography of the residue with 4:1 n-hex-
ane:EtOAc gave 130 mg (81%) of the all trans methyl
ester as a white solid: Rf 0.52 (silica gel, 3:1 n-hex-
ane:EtOAc); 1H NMR (CDCl3): d 3.07 (t, J=11.2 Hz,
1H), 3.10 (dd, J=16.7, 5.6 Hz, 1H), 3.20 (dd, J=16.7,
11.0 Hz, 1H), 3.33 (ddd, J=11.2, 11.0, 5.6 Hz, 1H), 4.42
(d, J=11.2 Hz, 1H), 5.96 (s, 4H), 6.55±6.85 (m, 7H),
7.03±7.18 (m, 3H); 13C NMR (CDCl3): d 173.95, 147.84,
147.62, 146.46, 146.34, 138.07, 137.43, 136.50, 135.70,
129.44, 128.37, 126.28, 122.48, 120.65, 108.98, 108.23,
108.06, 107.71, 100.94, 100.90, 56.98, 51.25, 50.17,
44.14, 38.21; Anal. Calcd for C26H22O6: C, 72.55; H,
5.15. Found: C, 72.52; H, 5.39.
and dried (Na2SO4). After removing the solvent, ¯ash
chromatography of the residue with 4:1 hexane:EtOAc
gave 83 mg (70%) of 1,4-addition product 18. H NMR
(CDCl3): d 1.08 (d, 3H), 1.17 (d, 3H), 3.02±3.10 (m, 2H),
3.33±3.43 (m, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 5.58±5.65
(m, 2H), 5.88 (s, 4H), 6.60±7.22 (m, 32H).
1
(RS)-Phenethyl-(3SR)-1-(2-methoxymethoxy-4-methoxy)-
phenyl-3-(3,4-methylene-dioxyphenyl)-3,4-dihydro-2-naph-
thoate (19). The above procedure was also followed for
preparation of 1,4-addition product. Methyl enol ether
14 (44 mg, 0.10 mmol), 4-methoxy-2-methoxymethoxy-
phenyl megnesium bromide in ether (0.50 mL,
0.10 mmol). Yield 37 mg (64%). 1H NMR (CDCl3): d
1.12 (d, 3H), 1.22 (d, 3H), 3.02 (m, 2H), 3.19 (s, 3H),
3.23 (s, 3H), 3.50 (m, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.25
(m, 2H), 5.00 (m, 2H), 4.93 (d, 1H), 5.05 (d, 1H), 5.68
(m, 2H), 5.86 (m, 4H), 6.60-7.20 (m, 30H).
Acknowledgement
We would like to thank Edith A. Reich for elemental
analyses.
To a solution of all trans methyl ester (110 mg,
0.257 mmol) in 6 mL of 1:1 MeOH:THF was added
2 mL of 10% NaOH and heated to 70 ꢀC for 7 h. The
mixture was poured into water and washed with 1:1
Hexane:EtOAc. The aqeous solution was acidi®ed with
6 N HCl to pH 5 and extracted with EtOAc. The
organic extract was washed with brine and dried
(Na2SO4). Removal of the solvent gave 100 mg (94%) of
the title acid 3 as a white solid: Rf 0.07 (silica gel, 2:1 n-
hexane:EtOAc); 1H NMR (CDCl3): d 3.00±3.25 (m,
3H), 4.38 (d, J=10.8 Hz, 1H), 5.94 (s, 4H), 6.55±7.18
(m, 10H); 13C NMR (CDCl3): d 177.55, 147.89, 147.69,
146.57, 146.47, 137.84, 137.12, 136.21, 135.60, 129.44,
128.36, 126.35, 122.59, 120.78, 108.96, 108.28, 108.11,
107.68, 100.98, 56.53, 50.05, 43.95, 38.19; MS (ES) m/z
416 (M+); HRMS (FAB) Calcd for C25H19O6Na2:
461.0977. Found: 461.0954. Anal. calcd for C25H19
References
1. Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.;
Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T.
Nature (London) 1988, 332, 411.
2. Doherty, A. M. J. Med. Chem. 1992, 35, 1493.
3. Arai, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanashi, S.
Nature (London) 1990, 348, 730.
4. Sakurai, T.; Yanagisawa, M.; Takuwa, Y.; Miyazaki, H.;
Kimura, S.; Goto, K.; Masaki, T. Nature (London) 1990, 348,
732.
5. Karne, S.; Jayawickreme, C. K.; Lerner, M. R. J. Biol.
Chem. 1993, 268, 19126.
6. Elliott, J. D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber,
J. D.; Erhard, K. F.; Nambi, N. A.; Elshourbagy, N. A.;
Kumar, C.; Lee, J. A.; Bean, J. W.; De Brosse, C. W.; Eggle-
ston, D. S.; Brooks, D. P.; Feuerstein, G.; Ru€olo, R. R., Jr.;
Weinstock, J.; Gleason, J. G.; Peisho€, C. E.; Ohlstein, E. H. J.
Med. Chem. 1994, 37, 1553.
.
O6 H2O: C, 69.12; H, 5.10. Found: C, 68.89 H, 5.41.
(RS)-Phenethyl-(3SR)-1-(4-methoxyphenyl)-3-(3,4-methyl-
enedioxyphenyl)-3,4-dihydro-2-naphthoate (18). To
a
7. Aono, M.; Terao, Y.; Achiwa, K. Chem. Lett. 1985, 339.
8. Schaefer and Bloom®eld Org. React. 1967, 15, 1±203.
mixture of 1-bromo-4-methoxy benzene (218 mg,
1.17 mmol) and Mg (28 mg, 1.17 mmol) in 3 mL of THF
was added 2 mL of MeI and the mixture was irradiated
by ultrasound for 30 min. To a solution of methyl enol
ether 14 (100 mg, 0.23 mmol) in 4 mL of THF at 0 ꢀC
under argon was added dropwise the Grignard reagent
solution. After 15 min, the reaction was quenched with
aq HCl and the mixture was extracted with 1:1 hex-
ane:EtOAc. The organic extract was washed with brine
9. Nugent, W. A.; Hobbs, F. W., Jr. J. Org. Chem. 1986, 51,
3376.
10. (a)Yasuda, N.; Xavier, L.; Rieger, D. L.; Li, Y.; DeCamp,
A. E.; Dolling, U.-H. Tetrahedron Lett. 1993, 34, 3211. (b)
Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
11. Taber, D. F.; Amedio, J. C.; Patel, Y. K. J. Org. Chem.
1985, 50, 3618.