Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: Structure-activity relationship study directed toward the improvement of metabolic stability

Article abstract of DOI:10.1021/jm960301c

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5- 1ipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8- dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC₅₀ = 190 nM) and the formation of leukotriene B₄ in human polymorphonuclear leukocytes (IC₅₀ = 3 nM) as well as in human whole blood (IC₅₀ = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

Full text of DOI:10.1021/jm960301c

J . Med. Chem. 1996, 39, 3951-3970
3951
Dioxa bicycloocta n yl Na p h th a len en itr iles a s Non r ed ox 5-Lip oxygen a se
In h ibitor s: Str u ctu r e-Activity Rela tion sh ip Stu d y Dir ected tow a r d th e
Im p r ovem en t of Meta bolic Sta bility
Daniel Delorme,† Yves Ducharme,* Christine Brideau, Chi-Chung Chan, Nathalie Chauret, Sylvie Desmarais,
Daniel Dube´, J ean-Pierre Falgueyret, Re´jean Fortin, J ocelyne Guay, Pierre Hamel, Tom R. J ones, Carole Le´pine,
Chun Li, Malia McAuliffe, Cyril S. McFarlane, Deborah A. Nicoll-Griffith, Denis Riendeau,
J ames A. Yergey, and Yves Girard
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Que´bec, Canada H9R 4P8
Received April 23, 1996X
Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO)
inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone
rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity
relationship study aimed toward the improvement of metabolic stability in this series. The
best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement
of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the
pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor
9a c (L-708,780). Compound 9a c inhibits the oxidation of arachidonic acid to 5-hydroperoxy-
eicosatetraenoic acid by 5-LO (IC50 ) 190 nM) and the formation of leukotriene B4 in human
polymorphonuclear leukocytes (IC50 ) 3 nM) as well as in human whole blood (IC50 ) 150
nM). The good inhibitory profile shown by naphthalenenitrile 9a c is accompanied by an
improved resistance to oxidative metabolism. In addition, 9a c is orally active in the functional
model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at
0.1 mg/kg).
In tr od u ction
Unfortunately, compound 2 is extensively metabolized
in vivo. In rats for example, methyl ether 2 is rapidly
demethylated to the tertiary alcohol derivative 3a (L-
702,539) (Chart 1).6 Furthermore, in vivo, the major
metabolite 3a is itself the subject of extensive oxidative
metabolism occurring at two different sites:7 first, on
the lactone ring with the formation of the hydroxylac-
tone 3b and, second, on the tetrahydropyran ring with
the formation of the hydroxypyran metabolite 3c which
undergoes further oxidation to the hydroxy acid 4, a
species in equilibrium with pyranone 5. This extensive
metabolism reduces the potential of development for
this class of inhibitors. In this paper we will describe
the synthesis and the biological activity of the different
metabolites. We will also present the results of the
structure-activity relationship (SAR) study that was
directed toward the improvement of metabolic stability
as well as the optimization of the in vitro potency.
Leukotrienes are important biological mediators de-
rived from arachidonic acid through the action of 5-li-
poxygenase (5-LO).1 Leukotriene B4 (LTB4) is a potent
chemotactic agent and is involved in leukocyte activa-
tion.2 The peptidoleukotrienes LTC4, LTD4, and LTE4
are powerful spasmogenic agents and have been shown
to be implicated in the pathology of several diseases.3
Thus, selective inhibitors of 5-LO could form a new class
of therapeutic agents for the treatment of disease states
such as asthma4 and rheumatoid arthritis.
Recently, we have reported a new class of selective
and orally active inhibitors of 5-lipoxygenase, the naph-
thalenic lignan lactones.5a Compounds of this class
interact with the arachidonic acid binding site of 5-LO
and inhibit the enzymatic reaction by a nonredox
mechanism.5b A representative example of this class
is compound 2 (Chart 1) which exhibits excellent in vitro
activity with an IC50 of 14 nM for the inhibition of
arachidonic acid oxidation by human recombinant 5-LO
and IC50’s of 1.5 and 50 nM for the inhibition of LTB4
production in human polymorphonuclear leukocytes and
human whole blood, respectively. Carboxylate 1, the
open form of lactone 2, is well absorbed in rats and
readily converted in vivo to the active species 2. Car-
boxylate 1 is orally active in inhibiting LTB4 biosyn-
thesis in a rat pleurisy model with an ED50 of 0.6 mg/
kg. A functional model of antigen-induced broncho-
constriction in allergic squirrel monkeys also revealed
the high potency of this inhibitor with 95% inhibition
of the increase in airway resistance (RL) at a dose of
0.3 mg/kg.
Ch em istr y
The modifications on lead structure 2 were directed
at three specific sites on the molecule: the lactone ring,
the tetrahydropyran ring, and the pendant phenyl ring.
The majority of naphthalenic lactones 3a -v (Table
1) were prepared by the alkylation of lactonic naphthols
7a -m with the appropriate benzylic derivatives 6a -f
according to one of the three following methods: treat-
ment with potassium carbonate in dimethylformamide
(method A), treatment with cesium carbonate in di-
methylformamide (method B), or Mitsunobu reaction
(method C). Most substituted naphthalenes 9a -a c
(Table 2) were prepared by the treatment of naphthols
8a -w with alkylating agents 6a ,e following the same
methods. Saponification of naphthalenic lactones
3a ,f,h ,u by ethanolic sodium hydroxide afforded the
corresponding sodium carboxylates 10a ,f,h ,u (Table 3).
* Corresponding author: Dr. Yves Ducharme. Phone: 514-428-8621.
Fax: 514-695-0693.
† Present address: Astra Research, 275 Blvd. Armand-Frappier,
Laval, Que´bec, Canada H7V 4A7.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
S0022-2623(96)00301-9 CCC: $12.00 © 1996 American Chemical Society

3952 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
Ch a r t 1. Metabolism of Tetrahydropyranyl Naphthalenic Lignan Lactones
Ta ble 1. Physical and Synthetic Data for Naphthalenic Lactones 3a -v
compd
3
6
a
7
R1
R2
R3
R4
X
R5
R6
Ar
methoda
A
formula
anal.b
yield (%)c
75
a
a
H
H
H
H
H
H
H
H
H
H
Br
H
OH
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C30H26O5‚0.2EtOAc
30H26O6
30H26O6
C31H28O5‚0.5CH2Cl2
C32H30O5‚0.6CH2Cl2
C32H30O5
32H26O5‚1.2EtOAc
C32H28O5
C31H28O6‚0.1C6H14
C31H26O6
30H25FO5
30H25ClO5‚0.7EtOAc C,H
31H28O6
30H25FO5‚0.4EtOAc
30H25ClO5
31H28O6
29H25NO5
C,H
d
d
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
C
OH
H
a
a
c
d
l
Br
Br
Br
Cl
B
B
B
A
C,H
C,H
d
C,H
C,H
C,H
C,H,O
C,H,F
34
78
16
77
m
a
a
H
H
HC)CH
C
H2C-CH2
b
e
a
a
a
a
a
a
a
a
a
a
e
f
a
a
g
h
i
OCH3
H
Br
OH
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
OH
OH
A
C
B
B
B
B
B
B
B
B
B
B
C
C
41
61
75
39
42
56
45
68
26
15
51
76
73
29
O-CH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-FPh
4-ClPh
4-MeOPh
2-FPh
2-ClPh
3-MeOPh
3-Py
2-Fu
3-Fu
3-Th
3-Fu
C
C
C
C
C
C
C
C
C
C
C,H
C,H
C,H,Cl
C,H
d
C,H
C,H
C,H,S
C,H
C,H
j
k
b
c
d
e
f
28H24O6
28H24O6‚0.2EtOAc
28H24O5S
C29H24O7‚0.2EtOAc
C29H24O7‚0.8EtOAc
s
t
u
v
H
H
H
H
e
e
O-CH2
H2C-O
3-Fu
a
b
Method A, K2CO3/DMF; method B, Cs2CO3/DMF; method C, Mitsunobu reaction. Elemental analyses were within (0.4% of the
calculated value. c Isolated yield of the final step. High-resolution mass spectrum was obtained for this compound.
d
The following compounds were prepared by different
methods. The hydroxylactone metabolite 3b was ob-
tained by the pyridinium dichromate oxidation of so-
dium carboxylate 10a . Acid-catalyzed hydrolysis of
methyl glycoside 3i afforded the hydroxypyran metabo-
lite 3c, which upon treatment with silver carbonate on
Celite8 afforded pyranone 5. Bicyclic derivative 3h was
obtained by catalytic hydrogenation of unsaturated
analog 3g. Reduction of methyl ester 9h with diisobu-
tylaluminum hydride gave access to primary alcohol 9b
which was methylated (NaH, MeI) to deliver ether 9e.
Ester 9h was also saponified with lithium hydroxide to
afford carboxylic acid 9j. Furthermore, treatment of
methyl ester 9h with methyllithium gave tertiary
alcohol 9d . Secondary alcohol 9c was obtained by
sodium borohydride reduction of acetyl derivative 9g.
Methylation of alcohol 9c then provided ether 9f.
Treatment of chloromethyl derivative 9a a with imida-
zole produced analog 9n , while phenyl ketone 9u was
prepared by the addition of phenylmagnesium bromide
to aldehyde 9a b followed by pyridinium chlorochromate
oxidation.
Ben zylic Der iva tives 6. The required benzyl ha-
lides and benzyl alcohols 6a -f were prepared in the
following ways. Radical bromination of toluene 115a
yielded benzyl bromide 6a (Scheme 1). The preparation
of methyl glycoside 6b involved in situ formation of
3-lithiotoluene (Scheme 2) by lithium-bromine ex-
change on 3-bromotoluene followed by the addition of
2,3-dihydro-4H-pyran-4-one9 to afford tertiary alcohol
12. Successive methoxybromination, tributyltin hy-
dride-mediated reduction, and radical bromination com-

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3953
Ta ble 2. Physical and Synthetic Data for Naphthalenes 9a -a c
compd
9
6
a
8
R1 R2 R3 R4
X
R5
Ar
methoda
formula
anal.b yield (%)c
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
CH2CH3
CH2OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
B
C30H30O3‚0.2EtOAc
C29H28O4‚0.3CHCl3
C30H30O4
C31H32O4‚0.35CHCl3
C30H30O4‚0.25CHCl3
C31H32O4‚0.3EtOAc
C30H28O4‚0.8EtOAc
C30H28O5‚0.5EtOAc
C,H
C,H
C,H
C,H
C,H
C,H
C,H
C,H
C,H,N
C,H
d
94
CH(CH3)OH
C(CH3)2OH
CH2OCH3
CH(CH3)OCH3
COCH3
f
g
h
i
a
a
a
e
a
b
Br
Br
Br
B
B
B
74
91
44
CO2CH3
CN
COOH
CN4H
C
C
29H25NO3‚0.1EtOAc
29H26O5‚0.2CHCl3
j
k
l
a
a
a
i
k
l
Br
Br
Br
NaH/DMF C29H26N4O3
B
B
10
64
76
CN4(3-CH3)
CN4(2-CH3)
CH2(1-imidazole)
CN
CN4(3-CH3)
2-oxazoline
2-thiazoline
2-(4,4-dimethyloxazoline) 3-Fu
2-benzothiazole
COPh
C30H28N4O3‚0.2EtOAc C,H,N
C30H28N4O3‚1.2H2O C,H,N
C32H30N2O3‚0.3EtOAc C,H,N
27H23NO4 C,H,N
C28H26N4O4‚0.3EtOAc C,H,N
m
n
o
p
q
r
a
a
a
a
a
a
g
m
o
q
p
r
Br
Br
Br
Br
Br
Br
3-Fu
3-Fu
3-Fu
3-Fu
B
B
B
B
B
B
C
73
54
83
81
87
67
C
C
C
C
C
C
C
29H27NO5‚0.8EtOAc
29H27NO4S‚0.3EtOAc C,H,N
31H31NO5‚1.1EtOAc C,H,N
C,H,N
s
t
3-Fu
3-Fu
3-Fu
3-Fu
33H27NO4S‚0.5EtOAc C,H,N
u
v
w
x
y
z
a a
a b
a c
33H28O5‚0.5CH2Cl2
C,H,N
d
a
a
a
a
a
a
a
e
s
t
Br
Br
Br
Br
Br
Br
Br
CO(3-pyridine)
CO(2-thiazole)
CH2(2-thiazole)
CO2CH3
B
B
B
B
B
B
B
C
32H27NO5
52
81
81
64
91
95
86
83
30H25NO5S‚0.9EtOAc C,H,N
u
v
w
d
h
g
3-Fu
C30H27NO4S‚1.4EtOAc C,H,N
(CH2)3CH3
CH2Ph
Ph
3-Fu
3-Fu
C28H32O5‚0.2EtOAc
C31H30O5‚0.4EtOAc
C,H
C,H
CO2CH3
CH2Cl
CHO
O-CH2 OH CN
C28H23NO5‚0.4EtOAc
C,H,N
a
b
Method A, K2CO3/DMF; method B, Cs2CO3/DMF; method C: Mitsunobu reaction. Elemental analyses were within (0.4% of the
calculated value. c Isolated yield of the final step. High-resolution mass spectrum was obtained for this compound.
d
Ta ble 3. Physical and Synthetic Data for Carboxylates 10a ,f,h ,u
compd
3
10
R1
R2
R3
R4
Ar
Ph
Ph
Ph
formula
anal.a
a
f
h
u
a
f
h
u
H
CH3
H
H
CH3
H
H
H
H
H
C30H27O6Na‚0.5NaOH
C32H31O6Na‚1.2NaOH
C32H29O6Na‚2.0NaOH
C29H25O8Na‚0.6NaOH
C,H
C,H
C,H
C,H
H2C-CH2
O-CH2
H
H
3-Fu
a
Elemental analyses were within (0.4% of the calculated value.
Sch em e 1
A practical procedure for the medium scale enantio-
selective synthesis of (1S,5R)-6,8-dioxabicyclo[3.2.1]-
octan-3-one (15e) was elaborated by modifying already
reported preparations12 (Scheme 3). Sequential treat-
ment of D-glucose in pyridine with p-toluenesulfonyl
chloride (1 equiv), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 2 equiv), and additional p-toluenesulfonyl chlo-
ride (2 equiv) delivered 2,4-bis(O-p-tolylsulfonyl)-1,6-
anhydro-â-D-glucose (17) in a one-pot fashion. Reduc-
tion with lithium triethylborohydride followed by
oxidation of the intermediate secondary alcohol with
pyridinium chlorochromate yielded bicyclic ketone 15e.
The scarcity of L-glucose incited the search of a different
pleted the synthetic sequence. A slightly modified
approach was used to prepare benzylic derivatives 6c-f
(Table 4). Addition of protected 3-lithiobenzyl alcohols
to tetrahydropyran-4-one derivatives 15c,10d ,11e,f gave
access to tertiary alcohols 16c-f. Alcohol deprotection
and halogenation, if necessary, yielded the desired
benzylic derivatives 6c-f.

3954 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
Sch em e 2
finally produced lactone 27, which upon catalytic hy-
drogenation was debenzylated to the desired lactonic
naphthol 7l. Preparation of gem-dimethyllactone 7m
started with methyllithium addition on naphthofura-
none 2817 followed by a permanganate oxidation to
afford the intermediate 2-naphthoic acid derivative.
Addition of methylmagnesium bromide followed by acid-
catalyzed debenzylation gave access to dimethyllactone
7m .
Na p h th ols 8. Naphthols 8a -f were derived from
7-methoxy-4-phenyl-2-naphthoic acid20 (29) (Scheme 8).
Demethylation to naphthol 30 was accomplished by
treatment with pyridine hydrochloride at 175 °C. Stan-
dard esterification gave methyl ester 8a which in turn
was converted to nitrile 8b by the method of Weinreb.21
Methyl ester 8a was also reduced to primary alcohol
8c which was transformed into chloromethyl derivative
8d . Treatment of acid 30 with methyllithium gave
access to acetylnaphthalene 8e, which upon hydrogena-
tion was transformed into ethyl derivative 8f.
The synthesis of (3-furyl)naphthalenenitrile 8g is
presented in Scheme 9. Palladium-catalyzed coupling
of 3-furoyl chloride with ethyl 3-iodopropionate followed
by hydrolysis produced carboxylic acid 31. Acetic
anhydride-mediated conversion of acid 31 to the corre-
sponding lactone and condensation with 3-methoxyben-
zaldehyde then yielded intermediate 32, which upon
acid treatment rearranged to naphthalene 33.20 The
preparation of naphthol 8g was completed by a Weinreb
reaction to transform the ester into a nitrile21 followed
by a pyridine hydrochloride-promoted demethylation.
Aldehyde 8h was prepared by diisobutylaluminum
hydride reduction of nitrile 8g.
Reaction of nitriles 8b,g with tributyltin azide af-
forded tetrazoles 8i,j (Scheme 10), which after methy-
lation were separated into their 2-methyl (8k ,m ) and
1-methyl (8l,n ) isomers. Acid-catalyzed condensation
of naphthalenenitrile 8g with ethanolamines gave ox-
azoline derivatives 8o,p ; condensation with 2-amino-
ethanethiol gave thiazoline 8q, and condensation with
2-aminothiophenol gave benzothiazole 8r (Scheme 11).
Addition of 3-lithiopyridine and 2-lithiothiazole to naph-
thalenenitrile 8g afforded acylated naphthalenes 8s,t
respectively. Wolff-Kishner reduction of 8t gave access
to analog 8u (Scheme 12).
approach for the stereoselective synthesis of enantio-
meric (1R,5S)-6,8-dioxabicyclo[3.2.1]octan-3-one (15f).
Thus, addition of the anion of 2-(2,2-dimethoxyethyl)-
1,3-dithiane13 to the tert-butyldimethylsilyl ether of (S)-
(-)-glycidol14 afforded secondary alcohol 18 (Scheme 4).
Desilylation with tetrabutylammonium fluoride followed
by acid-catalyzed cyclization gave glycoside 19. Closure
to the dioxabicyclo system 20 was effected by selective
tosylation of the primary alcohol and DBU-promoted
cyclization.12a Enantiomerically pure bicyclic ketone 15f
was finally obtained by mercury perchlorate cleavage
of the 1,3-dithiane moiety.15
La cton ic Na p h th ols 7. The required lactonic naph-
thols 7a -f bearing different aromatic rings were pre-
pared according to the general method16 shown in
Scheme 5. Appropriate aryl carboxaldehydes were
converted to thioacetals 21a -f by treatment with
thiophenol in the presence of boron trifluoride etherate.
Conjugate addition of the anion of these thioacetals on
2(5H)-furanone followed by enolate trapping with 3-(ben-
zyloxy)benzaldehyde yielded intermediates 22a -f in-
corporating a completely assembled carbon framework.
Treatment with boiling trifluoroacetic acid in the pres-
ence of thioanisole efficiently performed the cyclization
to lactonic naphthols 7a -f with concomitant debenzy-
lation. (4-Fluorophenyl)naphthol 7g was prepared by
an intramolecular Diels-Alder reaction as described
previously.17
The preparation of naphthols 8v,w bearing nonaro-
matic substituents in place of the pendant phenyl ring
is presented in Scheme 13. The synthetic sequence
involves addition of n-butyl or benzyl Grignard reagents
on 3-carbethoxy-6-methoxy-1-tetralone22 (34) followed
by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation,
dehydration, pyridinium hydrochloride demethylation,
and diazomethane esterification.
Lactonic naphthols 7h -k were prepared by the
method presented in Scheme 6. Lithium-halogen
exchange on aryl bromide 2318 followed by the addition
of appropriate aromatic aldehydes gave benzyl alcohols
24a ,h -k which upon heating with maleic anhydride19
yielded lignans 25a ,h -k . Reduction of the cyclic an-
hydrides by zinc borohydride followed by debenzylation
afforded naphthols 7h -k .
The syntheses of the 3-methylated naphthofuranones
7l,m are highlighted in Scheme 7. Reduction of the
anhydride moiety of compound 25a with lithium alu-
minum hydride to the corresponding diol followed by
selective silylation of the 3-hydroxymethyl function
permitted side chain differentiation. Subsequent pyri-
dinium chlorochromate oxidation and methylmagne-
sium bromide treatment afforded alcohol 26. Protection
of the secondary alcohol as an acetate was followed by
fluoride desilylation and permanganate oxidation of the
resulting primary alcohol to the corresponding carboxy-
lic acid. Methanolysis of the acetate and acid treatment
Str u ctu r e-Activity Rela tion sh ip
All of the compounds prepared were evaluated for
their potency to inhibit (a) oxidation of arachidonic acid
by recombinant human 5-LO (H5-LO),5b (b) production
of LTB4 in human peripheral blood polymorphonuclear
leukocytes (HPMN),23 and (c) production of LTB4 in
human whole blood (HWB).23
Meta bolite Eva lu a tion . As previously mentioned,
naphthalenic lignan lactone 2 is extensively metabolized
when administered orally to rats as its bioavailable
carboxylate form 1.6 The major metabolite detected in

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3955
Ta ble 4. Synthesis of Benzylic Derivatives 6c-f
entry
R1
R2
R3
H
R4
H
P
reagents
X
c
d
e
f
CH3
H
H
CH3
H
H
THP
THP
TBDPS
TBDPS
(1) p-TsOH, (2) DIPHOS/CBr4
(1) p-TsOH, (2) PPh3/CCl4
Br
Cl
OH
OH
HCdCH
O-CH2
CH2-O
TBAF
TBAF
H
H
Sch em e 3
Sch em e 6
Sch em e 4
Sch em e 7
Sch em e 5
the plasma of dosed animals is demethylated lactone
3a . The chemical synthesis of alcohol 3a was performed
and its biological activity evaluated in vitro. Despite a
8-fold loss of potency in the enzymatic H5-LO assay,
alcohol 3a was equipotent to methyl ether 2 in the
cellular HPMN assay and only 3-fold less potent in the
HWB assay (Table 5). Globally, 3a presents a very good
in vitro inhibitory profile. Unfortunately, this com-
pound is also extensively metabolized when adminis-
tered orally as its bioavailable carboxylate form 10a in
rats and rhesus monkeys. The metabolic pathway
followed by lignan lactone 3a (Chart 1) was elucidated
with the help of in vitro studies using hepatic mi-
crosomes from rat, rhesus monkey, and human.
A
qualitative correlation between in vitro and in vivo
biotransformations was established as reported by

3956 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
Sch em e 8
Sch em e 9
Sch em e 10
Sch em e 11
Chauret et al.7a The major metabolites, hydroxylactone
3b, hydroxypyran 3c, and pyranone 5, were synthesized
and evaluated in vitro. They all showed poor inhibitory
activity or none at all. These results triggered our
search for metabolically stable naphthalenic lignan
lactone analogs. The elucidation of the metabolic
pathway followed by lactone 3a early in the drug
discovery process proved to be extremely useful in
directing our SAR studies to critical areas of the lead
structure.
La ct on e R in g Mod ifica t ion s. (a ) Met a b olism
Block a d e. In principle, oxidative metabolism on the
lactone ring of compound 3a could be prevented by
substituting the benzylic methylene hydrogen atoms. In
this respect, gem-dimethyllactone 3e was prepared.
Unfortunately, the introduction of two methyl groups
on the lactone ring resulted in a major loss of in vitro
activity (Table 6). In fact, even substitution by a single
methyl unit also has a detrimental effect on the potency
of analog 3d . A possible explanation for this loss of
activity involves the conformation of the pendant phenyl
ring. The presence of substituents on the lactone ring
forces the pendant phenyl ring to adopt an orthogonal
position toward the naphthalene unit, and this confor-
mation seems unfavorable for efficient enzyme binding.
The fact that ortho substitution of the pendant phenyl
ring also reduces potency (vide infra) is consistant with
this hypothesis. Since metabolism blockade on the
lactone ring did not prove to be promising, we next
considered lactone replacement.
(b) La cton e Rep la cem en t. Replacement of the
lactone ring of inhibitor 3a by a simple ethyl (9a ) or
hydroxymethyl (9b) side chain results in compounds
approximately 5 times less potent in the HPMN assay
(Table 7), while replacement by a methoxymethyl (9e)
side chain produces a nearly equipotent inhibitor. This
result indicates the importance of incorporating a non-
polar binding site in the lactone surrogate side chain

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3957
Ta ble 7. In Vitro Potency of Naphthalenes 9a -x
Sch em e 12
IC50 (nM)a
R
Ar H5-LO HPMN
HWB
9a CH2CH3
9b CH2OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
760
260
520
1500
160
1200
130
70
10*
9*
28
59*
4*
41*
2
>1000
9c CH(CH3)OH
9d C(CH3)2OH
9e CH2OCH3
9f CH(CH3)OCH3
9g COCH3
675
200
>1000
90
9h CO2CH3
3
100
9i CN
Ph
120
3
100
9j COOH
Ph
190*
9k CN4H
Ph
Ph
Ph
Ph
3-Fu
3-Fu
3-Fu
3-Fu
>6000 >700*
>3000
Sch em e 13
9l CN4(2-CH3)
9m CN4(1-CH3)
9n CH2(1-imidazole)
9o CN
9p CN4(2-CH3)
9q 2-oxazoline
9r 2-thiazoline
120
3000
640
30
4
310
>67* >10000*
40*
2
10
80
50
80
2
70
3
50
2
75
9s 2-(4,4-dimethyloxazoline) 3-Fu
190
17
2900*
9t 2-benzothiazole
9u COPh
9v CO(3-pyridine)
9w CO(2-thiazole)
9x CH2(2-thiazole)
3-Fu >6000
>62*
Ta ble 5. In Vitro Potency of Naphthalenic Lignan Lactone 2
and Metabolites 3a -c and 5
3-Fu
3-Fu
3-Fu
3-Fu
70
120
50
1
7
2
1
200*
370*
130
IC50 (nM)a
140
660*
H5-LO
HPMN
HWB
a
Each IC50 value corresponds to an average of at least two
independant determinations, except those identified with an
asterisk, which are the result of a single titration.
2
14
115
1.5
2
50
140
>3000
1600
3a
3b
3c
5
>6000
>700
810
15
35
390
>3000
surrogates for the lactone ring. Furthermore, the
drastic difference of potency between 1-methyltetrazole
9m (IC50 ) 3 µM in H5-LO assay) and 2-methyltetrazole
9l (IC50 ) 120 nM in H5-LO assay) indicates that the
lactone surrogate needs to be coplanar to the naphtha-
lene ring (a high-energy conformation for 9m ) for
efficient enzyme binding. Other heterocycles may be
used as surrogates. In the (3-furyl)naphthalene series,
2-oxazolyl (9q) and 2-thiazolyl (9r ) analogs are equipo-
tent to 2-methyltetrazole 9p . Once again, increasing
bulkiness by incorporating methyl substituents on the
oxazoline ring (9s) results in a loss of potency. Hetero-
cycles can be linked to the naphthalene ring by a
carbonyl group (9u -w ) or a methylene unit (9x) to
produce analogs practically equipotent to 2-methyltet-
razole 9p . Therefore, the lactone ring of the naphtha-
lenic lignan inhibitors can be efficiently replaced by a
variety of planar functional groups and heterocycles
without losing the in vitro activity.
a
Each IC50 value is an average of at least two independant
determinations.
Ta ble 6. In Vitro Potency of the Methylated Lactones 3d ,e
IC50 (nM)a
R1
R2
H5-LO
HPMN
HWB
3d
3e
CH3
CH3
H
CH3
1300
>6000
150
80
>3000
>3000
a
Each IC50 value is an average of at least two independant
determinations.
There was nevertheless a potential drawback with
the lactone replacement approach, and it concerned
pharmacokinetics. Previous studies5a have shown that
lactones such as 2 are not absorbed when administered
orally to rats while their open carboxylate form (e.g.,
1) are. By removing the lactone moiety, we obviously
lose the ability to use this method for improving
bioavailability. This concern was however alleviated
when naphthalenenitrile 9i was detected in rat plas-
ma samples (0.7 µM at 6 h) after oral dosing at 20 mg/
kg. Furthermore, naphthalenenitrile 9i showed im-
proved metabolic stability compared to lactone 3a in an
in vitro rat hepatic microsome assay. Under standard
for efficient enzyme inhibition. Substitution on the
hydroxymethyl (9c,d ) or methoxymethyl (9f) side chains
by methyl groups led to a reduction in activity. It is
therefore apparent that increasing bulkiness in this
region is unfavorable. In consequence, replacement of
the lactone ring by planar functional groups was
investigated. Naphthalene derivatives bearing an acetyl
(9g), methoxycarbonyl (9h ), or nitrile (9i) function were
equipotent to lactone 3a , while carboxylic acid 9j, a
potential metabolite of ester 9h , and tetrazole 9k were
essentially inactive in the HPMN assay. Thus, non-
acidic planar electron-withdrawing groups are efficient

3958 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
Ta ble 8. In Vitro Metabolism by Rat Hepatic Microsomes of
Derivatives 3a ,j and 9i,a c
Ta ble 9. In Vitro Potency of Tetrahydropyran Derivatives 3f-j
a
Each IC50 value corresponds to an average of at least two
independant determinations, except the one identified with an
asterisk, which is the result of a single titration.
rahydropyran ring might occur in a stereospecific axial
fashion. If that is the case, axial substituents would
be expected to show a better ability to block metabolism.
With this in mind, 8-oxabicyclo[3.2.1]octen-6-yl deriva-
tive 3g and its saturated analog 3h were prepared.
While 3g is 14-fold less potent than compound 3a in
the HPMN assay, saturated 3h is only 3-fold less potent
in the H5-LO and HPMN assays. The 8-oxabicyclo-
[3.2.1]octanyl system showed improved efficacy in block-
ing metabolism. Only one major metabolite besides the
expected hydroxylactone could be detected in plasma
samples when oxabicyclo 3h was administered orally
to rats as a solution of its carboxylate 10h .
a
Peak areametabolites/(peak areametabolites + peak areaparent).
microsomal incubation conditions (see Experimental
Section), lactone 3a was transformed into four observ-
able metabolites to the extent of 6-7%, while naphtha-
lenenitrile 9i was transformed into three observable
metabolites to the extent of 4-5% (Table 8). For this
encouraging pharmacokinetic behavior and owing to its
improved metabolic stability, the nitrile moiety was
selected as a preferred lactone surrogate for further SAR
studies.
A further modification on the bicyclic ring system was
inspired by the discovery that methyl glycoside 3i, an
intermediate in the synthesis of hydroxypyran metabo-
lite 3c, was remarquably active in vitro (IC50 ) 23 nM
in H5-LO assay). This observation suggested that the
introduction of a second oxygen atom in the bicyclo-
[3.2.1]octane ring system could increase the potency of
the bicyclic inhibitors. The 6,8-dioxabicyclo[3.2.1]-
octanyl analog 3j was then prepared and showed indeed
a 2-fold increase of potency in the HWB assay in
comparison with monooxygenated 3h . Even more sig-
nificantly, the incorporation of a second oxygen atom
in the bicyclic system improved further the metabolic
stability as shown in vitro by the rat hepatic microsome
assay. Following standard microsomal incubation, com-
pound 3j was metabolized to the extent of 1-2% only
(Table 8). The 6,8-dioxabicyclo[3.2.1]octanyl ring sys-
tem efficiently blocked oxidative metabolism and was
selected as an efficient tetrahydropyranyl surrogate for
further SAR studies.
Tetr a h yd r op yr a n Rin g Mod ifica tion s. Meta bo-
lism Block a d e. To prevent the oxidative metabolism
process leading from naphthalenic lignan lactone 3a to
hydroxypyran 3c, a blockade approach similar to the
one described previously for the lactone ring protection
was undertaken on the tetrahydropyran ring. Introduc-
tion of two equatorial24 methyl groups flanking the
tetrahydropyran ring oxygen atom gave compound 3f
(Table 9). Despite a 6-fold loss of potency in the HWB
assay, this analog is equipotent to 3a in the enzymatic
H5-LO and the cellular HPMN assays. However, HPLC
analysis of plasma samples revealed the formation of
at least four major metabolites when 2,6-dimethyltet-
rahydropyran 3f was administered orally to rats as a
solution of its carboxylate 10f. The inability of equato-
rial substituents to significantly reduce metabolism
suggests that enzymatic R-hydroxylation on the tet-

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3959
Ta ble 10. In Vitro Potency of Naphthalenic Lactones 3k -t
Ta ble 12. In Vitro Potency of 6,8-Dioxabicyclo[3.2.1]octanyl
Derivatives 3u ,v and 9a c
IC50 (nM)a
Ar
H5-LO
HPMN
HWB
3k
3l
4-FPh
4-ClPh
4-MeOPh
2-FPh
2-ClPh
3-MeOPh
3-Py
2-Fu
3-Fu
3-Th
140
5500
6000
360
380
80
720*
280
26
3
26*
89*
18
11*
4
25
5*
2
410
>3000
3m
3n
3o
3p
3q
3r
1800
1100
260
1200
450
100
50
3s
3t
27
2
a
Each IC50 value corresponds to an average of at least two
independant determinations, except those identified with an
asterisk, which are the result of a single titration.
Ta ble 11. In Vitro Potency of Naphthalenes 9y,z
a
Each IC50 value corresponds to an average of at least two
independant determinations, except the one identified with an
asterisk, which is the result of a single titration.
LO and HWB assays (Table 12) with an improved
metabolic stability. After oral administration of the
naphthalenic lactone analog 3u in rats as a solution of
its carboxylate 10u (20 mg/kg), no major metabolites
were detected in plasma samples besides the expected
hydroxylactone. Compound 3u is a chiral inhibitor, and
since it was synthesized from D-glucose, it consists of a
single enantiomer. In order to investigate the enanti-
oselectivity of 5-LO inhibition25 in the dioxabicyclo[3.2.1]-
octanyl series, enantiomer 3v was prepared. Enanti-
omer 3v was 2-3-fold less potent than 3u in the H5-
LO and HPMN assays and more than 10-fold less active
in the HWB assay.
The best modifications, i.e., replacement of the lactone
ring by a nitrile group, replacement of the tetrahydro-
pyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety,
and replacement of the pendant phenyl ring by a 3-furyl
ring, were next incorporated in a single molecule to
produce inhibitor 9a c. This compound is equipotent to
naphthalenic lignan lactone 3a in the three in vitro
assays. The good inhibitory profile shown by naphtha-
lenenitrile 9a c is accompanied by a strong resistance
to oxidative metabolism. Under the standard rat mi-
crosomal incubation of compound 9a c, a single metabo-
lite was observed to the extent of only 0.4% (Table 8).
This behavior was translated in vivo since no major
metabolites were detected in rat plasma samples after
oral dosing of naphthalenenitrile 9a c (20 mg/kg), while
the plasma concentration of the parent compound
reached 2.5 µM 6 h after administration. Thus, the
combination of the best modifications effectively re-
sulted in the production of a potent and metabolically
stable inhibitor with enhanced pharmacokinetic proper-
ties, naphthalenenitrile 9a c.
IC50 (nM)a
R
H5-LO
HPMN
HWB
9y
9z
(CH2)3CH3
CH2Ph
2200
>6000
15*
>70*
a
Each IC50 value corresponds to an average of at least two
independant determinations, except those identified with an
asterisk, which are the result of a single titration.
P h en yl Rin g Mod ifica tion s: In Vitr o P oten cy
Op tim iza tion . A variety of analogs bearing differently
substituted pendant phenyl rings was evaluated (Table
10). Substitution by a fluorine atom at the para position
resulted in analog 3k , an inhibitor equipotent to phenyl
3a in the H5-LO assay. Larger substituents, either elec-
tron-withdrawing (chloro 3l) or electron-donating (meth-
oxy 3m ), were not tolerated at this position. m-
Methoxyphenyl derivative 3p is equipotent to compound
3a . Ortho substitution by fluorine (3n ) or chlorine (3o)
atoms results in a 3-10-fold loss of activity. Replace-
ment of the phenyl ring by a 6-membered heteroaro-
matic moiety was detrimental to activity as exemplified
by 3-pyridyl analog 3q. On the other hand, substitution
by 5-membered heterocycles was favorable. Even though
2-furyl analog 3r is 3-fold less active than phenyl
substituted 3a , 3-furyl derivative 3s is more potent in
each of the three assays used to evaluate the inhibitor
potencies. The same trend was observed with the
3-thienyl analog 3t. The requirement for an aromatic
ring at this position is illustrated by the major loss of
potency observed for naphthalenic esters 9y,z bearing
a butyl group and a benzyl group, respectively, in place
of the pendant phenyl ring (Table 11).
Compound 9a c (L-708,780) was found to be more
potent in vitro than Zileuton26 and MK-059123 (Table
13). When compared to Zeneca’s inhibitor D2138,27
inhibitor 9a c is 2-3-fold more potent in the H5-LO and
HPMN assays while it is 2-fold less potent in the HWB
assay.
Com bin a tion of th e Best Mod ifica tion s. Replace-
ment of the pendant phenyl ring of dioxabicyclic analog
3j by a 3-furyl moiety gave rise to compound 3u , an
inhibitor equipotent to tetrahydropyran 3a in both H5-

3960 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
Ta ble 13. Comparison of in Vitro Potency of Zileuton,
MK-0591, D-2138, and 9a c
and soluble extracts from sf9 cells overexpressing H5-LO as
described by Falgueyret et al.5b Where more than two IC50
values have been determined, the 95% confidence limits were
(<80% of the mean value.
Leu k otr ien e Biosyn th esis in Ra t P leu r a l Ca vity. LTB4
levels in rat pleural exudates following interpleural injection
of carrageenan followed 16-20 h later by ionophore A23187
were determined as previously described.23
Asca r is-In du ced Br on ch ocon str iction in Squ ir r el Mon -
k eys. Naturally sensitized male squirrel monkeys were
challenged with an aerosol of Ascaris antigen. Changes in
pulmonary mechanics (airway resistance, RL, and dynamic
compliance, CDyn) were monitored in conscious animals using
airflow measurements from a face mask and measurements
of pleural pressure as previously described.23
IC50 (nM)a
H5-LO
HPMN
HWB
Zileuton
MK-0591
D-2138
9a c
3700
5000
330
1100
3
10
3
2000
500
80
190
150
a
Each IC50 value is an average of at least two independant
determinations.
In Vivo Stu d ies
In spite of its excellent in vitro potency, 9a c showed
only modest activity in inhibiting LTB4 biosynthesis in
vivo in a rat pleurisy model.23 Using a 3 h oral
pretreatment with a dose of 3 mg/kg, no inhibition was
observed. For comparison, the FLAP inhibitor MK-
059123 presents an ED50 of 0.5 mg/kg after a 2 h
pretreatment in the same model. When rats were
submitted to a longer pretreatment of 6 h, the same dose
of 9a c gave rise to 50% inhibition of the LTB4 biosyn-
thesis. This result correlates with the slow absorption
of naphthalenenitrile 9a c observed in rat after oral
administration.
The effect of 9a c on antigen-induced bronchoconstric-
tion in allergic squirrel monkeys23 was also measured.
A 4 h pretreatment at 0.1 mg/kg oral dose followed by
a challenge with an aerosol of Ascaris antigen produced
a 95% inhibition of the increase in airway resistance
(RL) and a 100% inhibition of decrease in dynamic
compliance (Cdyn). For MK-0591, the values obtained
Ra t Hep a tic Micr osom a l In cu ba tion s. Incubations were
conducted as described previously by Chauret et al.7a Briefly,
the incubations were conducted with rat liver microsomal
protein (1 mg in a 50 µL sucrose solution (0.25 M)), a premixed
cofactor buffer containing 2.5 mM MgCl2, 2.5 mM NADP, and
25 mM glucose-6-phosphate in a 125 mM phosphate buffer (pH
7.4 (400 µL)), and the drug candidate (12.5 µL of an 8 mM
solution in DMSO). After a 2 min preincubation, 2 units of
glucose-6-phosphate dehydrogenase (25 µL of a solution con-
taining 80 units/mL in water) were added to give a total
volume of 500 µL. The final drug concentration was 200 µM.
Incubations were conducted at 37 °C for 1 h, and reactions
were quenched by the addition of acetonitrile (500 µL). After
centrifugation to remove precipitated proteins, the supernatant
was analyzed by reverse phase HPLC. For analytical HPLC,
the system consisted of Waters components: a 600-MS pump,
a 715 Ultra WISP injector, a 994 photodiode array detector
controlled by Powerline software, and a Nova Pak C18 column
(3.9 × 150 mm). Eluent A was 20 mM ammonium acetate
adjusted to pH 5.4 with acetic acid, and eluent B was
methanol. A linear gradient was run from 47% to 87%
methanol over 40 min. The detection wavelength was 245 nm.
Mea su r em en t of P la sm a Level a n d Bioa va ila bility.
Male Sprague-Dawley rats (2) were starved overnight and
dosed orally with the compound as a solution in 0.5% methocel
(1 mL/100 g). Blood was taken from the jugular vein at 0,
0.5, 1, 2, 4, 6, and 8 h after dosing. In the intravenous studies,
compounds were dissolved in 5% dextrose and injected intra-
venously in the jugular vein (dose volume ) 0.1 mL/100 g).
Blood was taken from the jugular vein at 0, 5, 15, and 30 min
and 1, 2, 4, and 6 h after dosing. Blood was centrifuged and
plasma collected. To 100 µL of each plasma sample was added
an equal volume of acetonitrile to precipitate proteins. An
aliquot (30 µL) of the supernatant after centrifugation was
subjected to reverse phase HPLC. The parent compound was
quantitated from the area of the corresponding peak, relative
to the standard (plasma sample at time 0 min, spiked with
varying concentrations of the compound).
at a higher dose of 0.3 mg/kg were RL) 44% and Cdyn
)
46%.23 Thus, 9a c is more potent than MK-0591 in this
functional model.
Con clu sion
Elucidation of the metabolic pathways of naphthalenic
lignan lactone 3a early in the drug discovery process
proved very useful in directing our SAR study toward
critical areas of the lead structure. Replacement of the
lactone and tetrahydropyran rings by a nitrile group and
a 6,8-dioxabicyclo[3.2.1]octanyl moiety efficiently im-
proves the metabolic stability of inhibitors in this series.
Furthermore, replacing the pendant phenyl ring by a
3-furyl heterocycle leads to a major gain of in vitro
activity. Combination of these three features in a single
compound produces the highly potent 5-LO inhibitor
9a c. Following oral administration of 9a c in rats, no
circulating metabolites were observed. Compound 9a c
is orally active in the functional model of antigen-
induced bronchoconstriction in allergic squirrel mon-
keys. Thus, the further development of this series of
nonredox inhibitors may result in the identification of
novel antiasthma and antiinflammation agents.
Ch em istr y. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on Bruker AM 250 and 300 and AMX
300 spectrometers, and proton chemical shifts are reported
relative to tetramethylsilane as internal standard. Infrared
spectra were measured on a Perkin-Elmer 681 spectropho-
tometer, and only the largest or most characteristic absorp-
tions are reported. Melting points were obtained on either a
Buchi 510 or Electrothermal 9100 apparatus in open capillary
tubes and are uncorrected. Elemental analyses were per-
formed by Galbraith Laboratories Inc., Knoxville, TN, Oneida
Research Services, Whitesboro, NY, or Guelph Chemical
Laboratories Ltd., Guelph, Ontario. Where reported only by
symbols, the results were within 0.4% of theoretical values.
High-resolution mass spectra were recorded at the Biomedical
Mass Spectrometry Unit, McGill University, Montreal, Quebec.
P r ep a r a tion of Ben zylic Ha lid es a n d Alcoh ols 6. 3-(4-
Hyd r oxytetr a h yd r o-2H-p yr a n -4-yl)ben zyl Br om id e (6a ).
A mixture of toluene 115 (16 g, 77 mmol), N-bromosuccinimide
(14.6 g, 82 mmol), and azoisobutyronitrile (AIBN) (127 mg,
0.8 mmol) in CCl4 (250 mL) was refluxed for 1.5 h. Filtration
and evaporation of the filtrate followed by chromatography on
silica gel (hexane/EtOAc, 65:35) afforded the desired benzyl
bromide as a yellow solid (19 g, 89%): 1H NMR (300 MHz,
Exp er im en ta l Section
Biology. Gen er a tion of LTB4 in Hu m a n P er ip h er a l
Blood P olym or p h on u clea r Leu k ocytes (HP MN) a n d Hu -
m a n Wh ole Blood (HWB). The generation of LTB4 in human
peripheral blood polymorphonuclear leukocytes and human
whole blood was measured as previously described by Brideau
et al.23 Where more than two IC50 values have been deter-
mined, the 95% confidence limits (cl) were (<120% of the
mean value for HPMN and (<90% of the mean value for
HWB.
Activity of Hu m a n 5-Lip oxygen a se (H5-LO). The activ-
ity of 5-LO was measured using a spectrophotometric assay

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3961
CDCl3) δ 1.65 (m, 2H), 2.20 (m, 2H), 3.90 (m, 5H), 4.55 (s, 2H),
7.40 (m, 3H), 7.55 (br s, 1H).
(400 mg, 1.25 mmol) in EtOH (5 mL). The reaction mixture
was stirred at room temperature for 90 min before the volatiles
were evaporated. The residue was then partitioned between
water and ether, and the organic phase was dried (MgSO4)
and evaporated. Chromatography on silica gel (hexane/EtOAc,
1:1) afforded the desired alcohol (100 mg, 34%) which was used
as such in the next step.
Step 4: 3-(4r-Hyd r oxy-2,6-d im eth yltetr a h yd r o-2H-p y-
r a n -4-yl)ben zyl Br om id e (6c). To a solution of alcohol from
step 3 (80 mg, 0.34 mmol) in CH2Cl2 (4 mL) was added CBr4
(118 mg, 0.35 mmol). The mixture was cooled to -30 °C, and
DIPHOS (124 mg, 0.34 mmol) was added. After 10 min, there
was added a 1:10 mixture of EtOAc and hexane (10 mL), and
the mixture was filtered. The filtrate was chromatographed
on silica gel (EtOAc/hexane, 3:7) to afford the title product (83
mg, 82%): 1H NMR (250 MHz, CDCl3) δ 1.25 (d, 6H), 1.40-
1.90 (m, 5H), 4.0 (m, 2H), 4.50 (s, 2H), 7.20-7.50 (m, 3H), 7.53
(s, 1H).
3-(3r-H yd r oxy-8-oxa b icyclo[3.2.1]oct -6-e n -3-yl)b e n -
zyl Ch lor ide (6d). Step 1: 2-[[3-(3r-Hydr oxy-8-oxabicyclo-
[3.2.1]oct-6-en -3-yl)ben zyl]oxy]tetr ah ydr o-2H-pyr an (16d).
Following the procedure described in step 1 for the preparation
of 6b, but using ketone 15d 11 and 2-[(3-bromobenzyl)oxy]-
tetrahydro-2H-pyran as starting materials, the expected de-
rivative 16d was obtained in 52% yield as an oil: 1H NMR
(250 MHz, CDCl3) δ 1.50-1.75 (m, 6H), 1.90 (d, 2H), 2.50 (m,
2H), 3.03 (s, 1H), 3.55 (m, 1H), 3.90 (m, 1H), 4.49 (d, 1H), 4.72
(m, 1H), 4.80 (d, 1H), 4.93 (d, 2H), 6.59 (s, 2H) 7.25-7.45 (m,
3H), 7.48 (s, 1H).
3-(4-Hydr oxy-2-m eth oxytetr ah ydr o-2H-pyr an -4-yl)ben -
zyl Br om id e (6b). Step 1: 3-(4-Hyd r oxy-3,4-d ih yd r o-2H-
p yr a n -4-yl)tolu en e (12). To a solution of 3-bromotoluene
(12.2 g, 71.4 mmol) in THF (80 mL), cooled to -78 °C, was
added n-butyllithium in hexane (2.2 M, 32.4 mL, 71.4 mmol).
The resulting white suspension was stirred for 30 min; then
there was added a solution of 2,3-dihydro-4H-pyran-4-one9 (7.0
g, 71 mmol) in THF (40 mL). The resulting amber solution
was stirred at -78 °C for 4 h and then allowed to warm up to
room temperature, and the reaction was quenched with
saturated aqueous NH4Cl (250 mL), and the mixture was
extracted three times with EtOAc. Extracts were washed
twice with brine, dried, and evaporated to an oily residue
which was chromatographed on silica gel (hexane/EtOAc, 85:
15) to afford 12 as a yellow liquid (7.4 g, 54%): 1H NMR (250
MHz, CDCl3) δ 2.03 (m, 3H), 2.38 (s, 3H), 4.11 (m, 2H), 4.97
(d, 1H), 6.62 (d, 1H), 7.08 (dd, 1H), 7.19-7.35 (m, 3H).
Step 2: 3-(3-Br om o-4-h yd r oxy-2-m eth oxytetr a h yd r o-
2H-p yr a n -4-yl)tolu en e (13). To a solution of bromide 12
(4.03 g, 21.2 mmol) in methanol (30 mL) cooled to 0 °C was
added slowly a suspension of N-bromosuccinimide (3.77 g, 21.2
mmol) in methanol (15 mL). After 1 h of stirring in the cold,
the reaction was quenched with pH 7 phosphate buffer (100
mL) and the mixture extracted three times with CH2Cl2. The
extracts were dried and evaporated, and the residue was
chromatographed on silica gel (hexane/EtOAc, 4:1) to afford
the desired product as an amber oil (3.85 g, 60%) and as a
mixture of diastereomers which was used as such.
Step 2: 3-(3r-Hyd r oxy-8-oxa bicyclo[3.2.1]oct-6-en -3-
yl)ben zyl Ch lor id e (6d ). A solution of tetrahydropyranyl
ether 16d (6.63 g, 21.0 mmol) and p-toluenesulfonic acid
monohydrate (5.15 g, 27.1 mmol) in methanol (250 mL) was
stirred at room temperature for 1 h. The mixture was
neutralized with aqueous NaHCO3 and extracted with CH2-
Cl2 three times. The extracts were dried and evaporated, and
the crude benzyl alcohol was dried by dissolving in benzene
and evaporating twice. It was then dissolved in acetonitrile
(100 mL), there were added triphenylphosphine (4.73 g, 18.0
mmol) and CCl4 (18 mL, 166 mmol), and the mixture was
stirred at room temperature for 4 h. The volatiles were
evaporated, and the residue was chromatographed on silica
gel (hexane/EtOAc, 65:35) to afford 6d (2.42 g, 50%) as an
amber oil: 1H NMR (250 MHz, CDCl3) δ 1.89 (d, 2H), 2.50
(dd, 2H), 3.07 (s, 1H), 4.60 (s, 2H), 4.93 (d, 2H), 6.60 (s, 2H),
7.26 (m, 1H), 7.34 (t, 1H), 7.43 (m, 1H), 7.53 (s, 1H).
(1S,5R)-3-(3r-Hyd r oxy-6,8-d ioxa bicyclo[3.2.1]octa n -3-
yl)ben zyl Alcoh ol (6e). Step 1: 2,4-Bis(O-p-tolylsu lfon yl)-
Step 3: 3-(4-Hyd r oxy-2-m eth oxytetr a h yd r o-2H-p yr a n -
4-yl)tolu en e (14). A mixture of bromide 13 (3.85 g, 12.8
mmol), tributyltin hydride (3.72 g, 12.8 mmol), and AIBN (10
mg) in toluene (25 mL) was refluxed for 1.5 h and then
evaporated. The residue was chromatographed on silica gel
(hexane/EtOAc, 85:15) to afford the product as an oil (2.16 g,
76%): 1H NMR (250 MHz, CDCl3) δ 1.72 (d, 1H), 1.96 (d, 1H),
2.13 (dd, 1H), 2,25 (m, 1H), 2.37 (s, 3H), 3.46 (s, 3H), 3.77 (m,
1H), 4.16 (m, 1H), 4.67 (s, 1H), 4.93 (d, 1H), 7.09 (m, 1H), 7.26
(m, 2H), 7.35 (s, 1H).
Step 4: 3-(4-Hyd r oxy-2-m eth oxytetr a h yd r o-2H-p yr a n -
4-yl)ben zyl Br om id e (6b). Following the radical bromina-
tion procedure described above in the preparation of 6a , using
the product from step 3 as starting material, the title product
was obtained as an amber oil which was used crude: 1H NMR
(250 MHz, CDCl3) δ 1.70 (d, 1H), 2.00 (d, 1H), 2.10 (dd, 1H),
2.25 (m, 1H), 3.45 (s, 3H), 3.80 (m, 1H), 4.15 (m, 1H), 4.50 (s,
2H), 4.75 (s, 1H), 4.95 (d, 1H), 7.30-7.45 (m, 3H), 7.60 (s, 1H).
3-(4r-Hyd r oxy-2,6-d im eth yltetr a h yd r o-2H-p yr a n -4-yl)-
ben zyl Br om id e (6c). Step 1: 2-[(3-Br om oben zyl)oxy]-
tetr a h yd r o-2H-p yr a n . To a solution of 3-bromobenzyl alco-
hol (11.5 g) and p-toluenesulfonic acid monohydrate (116 mg)
in CH2Cl2 (100 mL) at 0 °C was added 3,4-dihydro-2H-pyran
(6.2 mL). The resulting solution was stirred at room temper-
ature for 3 h; then the reaction was quenched with aqueous
NH4OAc. The aqueous phase was extracted with CH2Cl2, and
the combined organic phases were washed with brine, dried,
and evaporated. Chromatography on silica gel (hexane/EtOAc,
9:1) afforded the desired protected alcohol (72%) as an oil: 1H
NMR (250 MHz, CDCl3) δ 1.5-2.0 (m, 6H), 3.55 (dt, 1H), 3.90
(dq, 1H), 4.70 (t, 1H), 4.75 (d, 1H), 7.20 (q, 2H), 7.40 (dd, 1H),
7.53 (s, 1H).
1,6-a n h yd r o-â-D-glu cose (17). A solution of p-toluenesulfo-
nyl chloride (233 g, 1.22 mol) in pyridine (350 mL) was added
over 20 min to a cooled (0 °C) suspension of D-glucose (200 g,
1.11 mol) in pyridine (750 mL), and the resulting mixture was
stirred at room temperature for 25 h. Dichloromethane (1.0
L) was added, and the mixture was cooled to 0 °C; then 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (332 mL, 2.22 mol) was
added over 15 min. After stirring at room temperature for 2
days, the mixture was again cooled to 0 °C and p-toluenesulfo-
nyl chloride (448 g, 2.35 mol) was added. Stirring was
continued at room temperature for 2 days; then the volatiles
were evaporated, CH2
Cl2 (1.5 L) was added, and the organic
phase was washed with 1 N aqueous HCl (3 × 1.5 L) and then
with brine, dried, and evaporated. The residue was chromato-
graphed on silica gel (EtOAc) to afford ditosylate 17 (252 g,
48%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 2.45 (s,
6H), 2.75 (d, 1H), 3.70 (dd, 1H), 3.95 (m, 1H), 4.00 (d, 1H),
4.20 (d, 1H), 4.35 (d, 1H), 4.65 (d, 1H), 5.30 (s, 1H), 7.35 (m,
4H), 7.80 (m, 4H).
Step 2: (1S,3S,5R)-6,8-Dioxa bicyclo[3.2.1]octa n -3-ol.
To a solution of ditosylate 17 (107 g, 0.228 mol) in THF (1.6
L) at -40 °C was added 1 M lithium triethylborohydride in
THF (800 mL, 0.8 mol). The mixture was stirred at room
temperature overnight and then cannulated into cold water
(226 mL) with external cooling. There were added 3 N aqueous
NaOH (640 mL, 1.92 mol) and then 30% H2O2 (490 mL, 4.3
mol). The reaction mixture was stirred at room temperature
for 1 h, and the supernatant THF layer was collected and
Step 2: 2-[[3-(4r-Hyd r oxy-2,6-d im eth yltetr a h yd r o-2H-
pyr an -4-yl)ph en yl]m eth yl]tetr ah ydr o-2H-pyr an (16c). Fol-
lowing the procedure of step 1 in the preparation of 6b, but
using 2,6-dimethyltetrahydro-4H-pyran-4-one (15c)10 and the
benzyl ether from step 1 as starting materials, 16c was
obtained (65%) as a mixture of R and â isomers. The isomers
were separated by chromatography on silica gel (hexane/
EtOAc, 6:4). The R isomer is the least polar isomer: 1H NMR
(250 MHz, CDCl3) δ 1.23 (d, 6H), 1.59-1.95 (m, 10H), 3.50-
3.60 (m, 2H), 3.90-4.20 (m, 3H), 4.50 (d, 1H), 4.70 (t, 1H),
4.80 (d, 1H), 7.20-7.45 (m, 3H), 7.50 (s, 1H).
Step 3: 3-(4r-Hyd r oxy-2,6-d im eth yltetr a h yd r o-2H-p y-
r a n -4-yl)ben zyl Alcoh ol. p-Toluenesulfonic acid monohy-
drate (12 mg, 63 mmol) was added to a solution of ether 16c

3962 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
concentrated. The resulting residue was recombined with the
aqueous layer and extracted with CH2Cl2 using a continuous
extractor for several hours. The organic layer was dried and
evaporated, affording an oily residue which was chromato-
graphed on silica gel (hexane/EtOAc, 1:1) to yield the desired
product as an oil (25 g, 86%): 1H NMR (250 MHz, CDCl3) δ
1.80-2.40 (m, 4H), 3.73 (t, 1H), 4.05 (t, 1H), 4.33 (d, 1H), 4.55
(t, 1H), 5.65 (s, 1H).
Step 3: (1S,5R)-6,8-Dioxabicyclo[3.2.1]octan -3-on e (15e).
A solution of alcohol from step 2 (16.6 g, 89 mmol) in CH2Cl2
(200 mL) was added slowly to a suspension of pyridinium
chlorochromate (38.4 g, 178 mmol) and Celite (22 g) in CH2-
Cl2 (400 mL), and the mixture was stirred at room temperature
for 1 h. After dilution with ether (600 mL), the mixture was
filtered through Celite and the filtrate evaporated. The
residue was distilled using a Ku¨gelrohr apparatus (100 °C,
1.8 mmHg) to afford the desired ketone as a colorless oil (8.2
g, 50%): 1H NMR (250 MHz, CDCl3) δ 2.45 (s, 1H), 2.50 (d,
1H), 2.60 (s, 2H), 3.88 (s, 2H), 4.85 (t, 1H), 5.81 (s, 1H).
Step 4: (1S,5R)-3-(3r-Hyd r oxy-6,8-d ioxa bicyclo[3.2.1]-
octa n -3-yl)]ben zyl Alcoh ol (6e). Following the procedure
described in step 1 of the preparation of 6b, but using ketone
15e and 3-bromo-O-(tert-butyldiphenylsilyl)benzyl ether as
starting materials, the expected silylated derivative 16e was
obtained. The crude product was treated with Bu4NF in THF
at room temperature for 1.5 h. After evaporation of the sol-
vent, the crude product was chromatographed on silica gel
(hexane/EtOAc, 4:1) to yield the alcohol 6e as a colorless oil
(92%): 1H NMR (250 MHz, CDCl3) δ 2.00 (dd, 2H), 2.22 (d,
1H), 2.40 (dd, 1H), 2.70 (br s, 1H), 3.75 (t, 1H), 3.95 (s, 1H),
4.45 (d, 1H), 4.65 (m, 3H), 5.70 (s, 1H), 7.30 (m, 2H), 7.50 (s,
1H).
(1R,5S)-3-(3r-Hyd r oxy-6,8-d ioxa bicyclo[3.2.1]octa n -3-
yl)ben zyl Alcoh ol (6f). Step 1: Dith ia n e Silyl Eth er 18.
To a solution of 2-(2,2-dimethoxyethyl)-1,3-dithiane13 (10.4 g,
50 mmol) in THF (50 mL) at -30 °C was added, over 30 min,
n-butyllithium (1.3 M) in hexane (38.5 mL, 50 mmol). After 1
h, there was added a solution of (S)-(-)-glycidol tert-butyldi-
methylsilyl ether14 (9.42 g, 50 mmol) in THF (10 mL) and
stirring was continued at -30 °C for 2 h. The reaction was
quenched with saturated aqueous NH4Cl and the mixture par-
titioned between ether and water. The organic residue was
chromatographed on silica gel (hexane/EtOAc, 4:1) to yield 18
(16.0 g, 80%) as a yellow liquid: 1H NMR (300 MHz, CDCl3) δ
0.08 (s, 6H), 0.91 (s, 9H), 1.97 (m, 2H), 2.08 (dd, 1H), 2.20 (dd,
1H), 2.30 (dd, 1H), 2.46 (dd, 1H), 2.85 (m, 4H), 3.29 (d, 1H),
3.34 (s, 3H), 3.38 (s, 3H), 3.53 (dd, 2H), 4.01 (m, 1H), 4.73 (dd,
1H).
Step 2: Dith ia n e 19. A solution of Bu4NF (1 M) in THF
(26.5 mL, 26.5 mmol) was added to a solution of dithiane silyl
ether 18 (9.94 g, 25 mmol) in THF (50 mL). After 2 h at room
temperature the mixture was evaporated and the residue
chromatographed on silica gel (hexane/EtOAc, 1:3), affording
the expected diol (6.64 g, 94%) as an amber oil. A portion of
this material (3.11 g, 11.0 mmol) was dissolved in THF (40
mL), and 5% aqueous HCl (25 mL) was added. This mixture
was stirred at 60 °C for 15 h and then refluxed for 3 h. After
partitioning between water and EtOAc, the organic residue
was evaporated to give 19 (2.05 g, 79%) as a mixture of R and
â epimers which was used as such.
Step 3: Dioxa bicyclo Dith ia n e 20. p-Toluenesulfonyl
chloride (1.98 g, 10.4 mmol) was added to a cold (0 °C) solution
of dithiane 19 in pyridine (10 mL). After stirring for 90 min
at room temperature, methanol (1 mL) was added followed by
chloroform (50 mL). The mixture was washed with water
twice, dried, and evaporated to a residue which was chromato-
graphed on silica gel (hexane/EtOAc, 3:2) to afford the expected
primary tosylate (2.22 g, 65%) as an amber solid. A solution
of this material (1.95 g, 5.0 mmol) in CH2Cl2 (30 mL) was
treated with DBU (1.5 mL, 10 mmol) and the resulting mixture
stirred at room temperature for 60 h. After evaporation of
the volatiles, the residue was chromatographed on silica gel
(hexane/EtOAc, 3:1) yielding dioxabicyclo dithiane 20 (0.77 g,
71%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 1.90-
2.10 (m, 2H), 2,10 (dd, 1H), 2.50 (m, 2H), 2.65 (d, 1H), 2.84
(m, 2H), 2.99 (m, 2H), 3.68 (m, 1H), 4.50 (d, 1H), 4.54 (m, 1H),
5.59 (s, 1H).
Step 4: (1R,5S)-6,8-Dioxabicyclo[3.2.1]octan -3-on e (15e).
A solution of mercury(II) perchlorate trihydrate (1.73 g, 3.81
mmol) in water (1 mL) was added over 10 min to a vigorously
stirred mixture of 20 (757 mg, 3.47 mmol) and calcium
carbonate (420 mg, 4.20 mmol) in THF (12 mL). After 40 min
at room temperature more mercury perchlorate (0.56 g, 1.2
mmol) in water (0.2 mL) was added. After another 30 min at
room temperature, ether was added, the mixture was stirred
vigorously, and the ether phase was decanted, dried, and
evaporated to deliver ketone 15f (324 mg, 73%) as a colorless
liquid: 1H NMR (300 MHz, CDCl3) δ 2.48 (d, 1H), 2.60 (d, 2H),
2.80 (m, 1H), 3.88 (m, 2H), 4.86 (m, 1H), 5.83 (s, 1H).
Step 5: (1R,5S)-3-(3r-Hyd r oxy-6,8-d ioxa bicyclo[3.2.1]-
octa n -3-yl)ben zyl Alcoh ol (6f). Following the procedure
described in step 1 for the preparation of 6b, but using ketone
15f and 3-bromo-O-(tert-butyldiphenylsilyl)benzyl ether as
starting materials, the expected silylated derivative 16f was
obtained in 43% yield. The crude product was treated with
Bu4NF in THF at room temperature for 1.5 h. After evapora-
tion of the solvent, the crude product was chromatographed
on silica gel (hexane/EtOAc, 4:1) to yield the alcohol 6f as a
colorless oil (93%): 1H NMR (250 MHz, CDCl3) δ 1.80 (br s,
1H), 2.00 (m, 2H), 2.25 (d, 1H), 2.45 (dd, 1H), 3.80 (m, 1H),
3.85 (s, 1H), 4.50 (d, 1H), 4.70 (m, 3H), 5.75 (s, 1H), 7.25 (m,
1H), 7.30-7.45 (m, 2H), 7.55 (s, 1H).
P r ep a r a tion of La cton ic Na p h th ols 7. 7-Hyd r oxy-4-
p h en yln a p h th o[2,3-c]fu r a n -1(3H)-on e (7a ). Step 1: Ben -
za ld eh yd e Dip h en yl Dith ioa ceta l (21a ). To a solution of
benzaldehyde (31.8 g, 300 mmol) and thiophenol (69.2 g, 629
mmol) in isopropyl acetate (300 mL) cooled to 0 °C was added
slowly boron trifluoride etherate (42.6 g, 300 mmol). The
mixture was stirred in the cold for 1 h; then the reaction was
quenched slowly with 10% aqueous K2CO3. The phases were
separated, and the aqueous phase was extracted with EtOAc.
Combined organic phases were washed with aqueous carbon-
ate and then three times with water, dried, and evaporated
to an oil which solidified. The solid was triturated with
pentane (250 mL) and filtered to afford the dithioacetal as a
white solid (35.8 g). A further crop was obtained by crystal-
lization of filtrate material (total 75.7 g, 82%).
Step 2: 7-Hydr oxy-4-ph en yln aph th o[2,3-c]fu r an -1(3H)-
on e (7a ). To a solution of benzaldehyde diphenyl dithioacetal
(23.5 g, 76 mmol) in THF (250 mL), cooled to -70 °C, was
added slowly n-butyllithium in hexane (2.1 M, 37 mL, 77.7
mmol), and a yellow suspension resulted. After 20 min, there
was added slowly 2(5H)-furanone (7.64 g, 91 mmol), and the
mixture was stirred in the cold for 30 min, becoming a light
yellow solution. There was added slowly a solution of 3-(ben-
zyloxy)benzaldehyde (16.5 g, 77.7 mmol) in THF (75 mL), and
stirring was continued at -70 °C for 1 h. Acetic acid (9 g, 150
mmol) was added slowly; then the mixture was allowed to
warm up to room temperature. After dilution with an equal
volume of ether, the mixture was washed four times with
brine, dried, and evaporated to an oil which was the interme-
diate 22a . This material was dissolved in thioanisole (75 mL),
and there was added trifluoroacetic acid (190 mL). This
mixture was heated at 60 °C for 1 h; then the trifluoroacetic
acid was evaporated and the residual slurry was triturated
with ether (200 mL) and filtered to afford the desired lactone
7a as a cream-colored solid (12.7 g, 60%): mp >225 °C; 1H
NMR (300 MHz, acetone-d6) δ 5.28 (s, 2H), 7.30 (dd, 1H), 7.47-
7.64 (m, 6H), 7.68 (d, 1H), 8.31 (s, 1H), 9.08 (s, 1H); IR (KBr)
3240 (br), 1740, 1620, 1225 cm-1
.
The same method was followed, using the appropriate
aromatic aldehyde as starting material, to prepare the follow-
ing lactonic naphthols.
7-Hyd r oxy-4-(3-m eth oxyp h en yl)n a p h th o[2,3-c]fu r a n -
1(3H)-on e (7b): mp >225 °C; 30% yield; 1H NMR (300 MHz,
DMSO-d6) δ 3.79 (s, 3H), 5.32 (q, 2H), 7.03 (m, 3H), 7.25 (dd,
1H), 7.49 (m, 2H), 7.64 (d, 1H), 8.39 (s, 1H).
7-H yd r oxy-4-(3-p yr id yl)n a p h t h o[2,3-c]fu r a n -1(3H )-
on e (7c). In this case, the product obtained after the TFA-
thioanisole treatment was debenzylated but had not cyclized.
This product (380 mg, 0.74 mmol) was stirred at room

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3963
temperature in TFA (3 mL) containing methanesulfonic acid
(0.5 mL, 7.7 mmol) for 2 h. The TFA was evaporated and the
residue diluted with ether and neutralized with 1 N aqueous
NaOH. After several extractions with ether, the combined
extracts were washed with brine, dried, and evaporated to a
solid which was triturated with ether and filtered to afford
the desired lactone 7c (25% combined yield) as a pale yellow
solid: 1H NMR (250 MHz, DMSO-d6) δ 4.50 (m, 2H), 6.45 (dd,
1H), 6.65-6.80 (m, 3H), 7.10 (d, 1H), 7.60 (s, 1H), 7.90 (m,
2H), 9.40 (s, 1H).
The same method was followed, using the appropriately
substituted benzaldehyde as starting material, to prepare the
following naphthalenic lactones.
7-H yd r oxy-4-(4-ch lor op h e n yl)n a p h t h o[2,3-c]fu r a n -
1(3H)-on e (7h ). In this case the final debenzylation was done
as follows: The intermediate benzylated lactone (1.3 g) was
heated in a mixture of acetic acid (20 mL) and 6 N aqueous
HCl (5 mL) at 100 °C for 18 h. After cooling, the mixture was
diluted with water and extracted with EtOAc, the extracts
were washed with water, dried, and evaporated, and the
residue was stirred with ether at room temperature for 1 h
and filtered to afford 7h (870 mg, 86%) as a white solid: mp
7-H yd r oxy-4-(2-fu r yl)n a p h t h o[2,3-c]fu r a n -1(3H )-on e
1
(7d ): tan solid; mp 218 °C dec; H NMR (300 MHz, acetone-
1
>235 °C; H NMR (400 MHz, acetone-d6) δ 5.30 (d, 2H), 7.31
d6) δ 5.55 (s, 2H), 6.73 (m, 1H), 6.98 (d, 1H), 7.40 (dd, 1H),
7.51 (d, 1H), 7.87 (s, 1H), 8.25 (s, 1H), 8.39 (d, 1H), 9.06 (br s,
1H).
(dd, 1H), 7.50-7.58 (m, 3H), 7.60-7.66 (m, 2H), 7.70 (d, 1H),
8.33 (s, 1H), 9.05 (br s, 1H).
7-Hyd r oxy-4-(4-m eth oxyp h en yl)n a p h th o[2,3-c]fu r a n -
1(3H)-on e (7i). In this case the final debenzylation was done
as follows: The intermediate benzylated lactone (225 mg) was
stirred in a mixture of TFA (3 mL) and methanesulfonic acid
(1 mL) at room temperature for 30 min. After evaporation of
the TFA, the residue was dissolved in EtOAc, washed several
times with water, dried, and evaporated. The residue was
stirred with ether at room temperature for 30 min and filtered
to yield 7i (146 mg, 84%) as a beige solid.
7-H yd r oxy-4-(2-ch lor op h e n yl)n a p h t h o[2,3-c]fu r a n -
1(3H)-on e (7k ): obtained as a mixture of isomeric lactones
which could not be separated; used as such in the coupling
step.
7-H yd r oxy-4-(3-fu r yl)n a p h t h o[2,3-c]fu r a n -1(3H )-on e
1
(7e): tan solid; mp >225 °C; 37% yield; H NMR (300 MHz,
acetone-d6) δ 5.43 (s, 2H), 6.80 (d, 1H), 7.35 (dd, 1H), 7.51 (d,
1H), 7.86 (m, 1H), 7.98 (m, 1H), 8.03 (d, 1H), 8.28 (s, 1H), 9.25
(br s, 1H); IR (KBr) 3340 (br), 1740, 1622, 1225 cm-1
.
7-H yd r oxy-4-(3-t h ie n yl)n a p h t h o[2,3-c]fu r a n -1(3H )-
on e (7f): yellow solid; mp >235 °C; 1H NMR (300 MHz,
acetone-d6) δ 5.35 (s, 2H), 7.30 (m, 2H), 7.50 (d, 1H), 7.69 (m,
1H), 7.73 (m, 1H), 7.85 (d, 1H), 8.28 (s, 1H), 9.0 (br s, 1H).
7-H yd r oxy-4-(2-flu or op h e n yl)-n a p h t h o[2,3-c]fu r a n -
1(3H)-on e (7j). Step 1: 5-(Ben zyloxy)-2-(r-h yd r oxy-2-
flu or oben zyl)ben za ld eh yd e Dim eth yl Aceta l (24j). To a
solution of 5-(benzyloxy)-2-bromobenzaldehyde dimethyl acetal
(23)18 (10.1 g, 30 mmol) in THF (150 mL) at -70 °C was added
slowly n-butyllithium in hexane (2.1 M, 15 mL, 31.5 mmol).
After 15 min, there was slowly added a solution of 2-fluo-
robenzaldehyde (3.97 g, 32 mmol) in THF (10 mL). The cooling
bath was removed and the mixture allowed to warm up to 10
°C, whereupon the reaction was quenched with saturated
aqueous NH4Cl (100 mL) and the mixture extracted twice with
ether. The extracts were washed three times with brine, dried,
and evaporated, and the residue was chromatographed on
silica gel (hexane/EtOAc, 3:1) to afford 24j as an oil (8.93 g,
78%).
Step 2: 7-(Ben zyloxy)-4-(2-flu or op h en yl)n a p h th o[2,3-
c]fu r a n -1,3-d ion e (25j). A mixture of acetal 24j (8.9 g, 23.3
mmol), maleic anhydride (9.13 g, 93 mmol), and camphorsul-
fonic acid (1 g) in toluene (100 mL) was refluxed for 24 h. The
solvent was evaporated and the residue diluted with ether (200
mL), stirred for 30 min, and filtered to afford the anhydride
25j as an off-white solid (4.41 g, 48%): 1H NMR (300 MHz,
CDCl3) δ 5.29 (s, 2H), 7.27-7.63 (m, 11H), 7.78 (d, 1H), 8.43
(s, 1H).
Step 3: 7-(Ben zyloxy)-4-(2-flu or op h en yl)n a p h th o[2,3-
c]fu r a n -1(3H)-on e. To a solution of anhydride 25j (1.19 g, 3
mmol) in DMF (20 mL) at 0 °C were added zinc chloride (820
mg, 6 mmol) and then, in portions, sodium borohydride (171
mg, 4.5 mmol). The mixture was warmed up to room tem-
perature, more NaBH4 was added (171 mg), and stirring was
continued for 30 min. The mixture was diluted with water
and acidified with 1 N aqueous HCl, and the precipitate was
filtered (1.29 g). This solid was refluxed in benzene (50 mL)
containing p-toluenesulfonic acid (50 mg) with azeotropic
removal of water for 24 h. The solvent was evaporated and
the residue boiled in EtOAc (25 mL) for 30 min, cooled, and
filtered. The filtrate material was chromatographed on silica
gel (hexane/EtOAc, 3:1) to afford the desired lactone as a white
solid (438 mg, 38%): mp 179-182 °C; 1H NMR (300 MHz,
CDCl3) δ 5.23 (dd, 2H), 7.29-7.53 (m, 11H), 7.63 (d, 1H), 8.42
(s, 1H).
Step 4: 7-Hyd r oxy-4-(2-flu or op h en yl)n a p h th o[2,3-c]-
fu r a n -1(3H)-on e (7j). A mixture of the lactone from step 3
(240 mg) and palladium hydroxide (20%) on carbon (80 mg)
in EtOAc (40 mL) was stirred under an atmosphere of
hydrogen at room temperature for 18 h. After filtration,
evaporation of the filtrate afforded a solid residue which was
triturated in ether to yield the desired naphthol 7j as a white
solid (162 mg, 88%): mp >230 °C; 1H NMR (300 MHz, acetone-
d6) δ 5.27 (q, 2H), 7.33 (dd, 1H), 7.42 (m, 2H), 7.52-7.68 (m,
4H), 8.37 (s, 1H), 9.15 (br s, 1H).
7-Hydr oxy-3-m eth yl-4-ph en yln aph th o[2,3-c]fu r an -1(3H)-
on e (7l). Step 1: 6-(Ben zyloxy)-2,3-bis(h yd r oxym eth yl)-
1-p h en yln a p h th a len e. To a suspension of lithium aluminum
hydride (2.5 g, 65.8 mmol) in THF (100 mL) at 0 °C was added
anhydride 25a (5.0 g, 13.1 mmol) in portions. The resulting
mixture was refluxed for 2 h and then stirred at room
temperature for 18 h. After cooling to 0 °C there was added
slowly 6 N aqueous HCl until all the aluminum salts had
dissolved. The mixture was diluted with EtOAc; the organic
phase was washed several times with brine, dried, and
evaporated. The residue was crystallized from EtOAc/hexane
to afford the desired diol (1.4 g, 29%) as a white solid: 1H NMR
(250 MHz, CDCl3) δ 3.0 (br s, 1H), 4.60 (s, 2H), 4.95 (s, 2H),
5.20 (s, 2H), 7.10 (dd, 1H), 7.25-7.50 (m, 13H), 7.80 (s, 1H).
Step 2: 6-(Ben zyloxy)-3-[[(ter t-bu tyld ip h en ysilyl)oxy]-
m eth yl]-2-(h yd r oxym eth yl)-1-p h en yln a p h th a len e. To a
solution of diol from step 1 (1.02 g) in DMF (15 mL) was added
imidazole (410 mg) and then tert-butylchlorodiphenylsilane
(0.79 mL). After 1 h of stirring at room temperature, the
mixure was diluted with ether, washed three times with water
and then brine, dried, and evaporated. Chromatography on
silica gel (hexane/EtOAc, 95:5) yielded the desired monosily-
lated compound as an oil (1.23 g, 73%): 1H NMR (250 MHz,
CDCl3) δ 1.03 (s, 9H), 3.30 (t, 1H), 4.55 (d, 2H), 5.0 (s, 2H),
5.20 (s, 2H), 7.10 (m, 2H), 7.40 (m, 18H), 7.75 (m, 4H).
Step 3: 6-(Ben zyloxy)-3-[[(ter t-bu tyld ip h en ysilyl)oxy]-
m eth yl]-2-for m yl-1-p h en yln a p h th a len e. To a solution of
alcohol from step 2 (1.2 g, 2 mmol) in CH2Cl2 (25 mL) was
added dry powdered 4 Å molecular sieves (1 g) and pyridinium
chlorochromate (1 g, 4.6 mmol). After stirring at room
temperature for 1 h, the mixture was filtered through a short
column of silica gel, eluting with ether. The eluate was
evaporated to afford the desired aldehyde as an oil (1.1 g,
92%): 1H NMR (250 MHz, CDCl3) δ 1.2 (s, 9H), 5.20 (s, 2H),
5.35 (s, 2H), 7.15 (dd, 1H), 7.35 (m, 18H), 7.75 (m, 4H), 8.35
(s, 1H), 9.80 (s, 1H).
Step 4: 6-(Ben zyloxy)-3-[[(ter t-bu tyld ip h en ysilyl)oxy]-
m et h yl]-2-(1-h yd r oxyet h yl)-1-p h en yln a p h t h a len e (26).
To a solution of aldehyde from step 3 (1.1 g, 1.8 mmol) in THF
(15 mL) at -78 °C was added dropwise 1.4 M methylmagne-
sium bromide in toluene-THF (2.8 mL, 3.9 mmol). After 10
min the cooling bath was removed and the reaction was
quenched with saturated aqueous NH4Cl. After dilution with
ether, the organic phase was washed with water and brine,
dried, and evaporated to afford the desired product as a foam
(1.1 g, 98%): 1H NMR (250 MHz, CDCl3) δ 1.10 (s, 9H), 1.35
(d, 3H), 3.25 (d, 1H), 4.45 (m, 1H), 5.00 (d, 1H), 5.20 (s, 2H),
5.40 (d, 1H), 7.00-7.50 (m, 19H), 7.75 (m, 5H).

3964 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
Step 5: 2-(1-Acetoxyeth yl)-6-(ben zyloxy)-3-(h yd r oxy-
m eth yl)-1-p h en yln a p h th a len e. To a solution of naphtha-
lene 26 (300 mg, 0.5 mmol) in acetic anhydride (2 mL) were
added pyridine (0.3 mL) and 4-(dimethylamino)pyridine (10
mg). After 2 h at room temperature, the mixture was diluted
with ether, washed with water and then with aqueous CuSO4,
dried, and evaporated to afford a crude intermediate which
was dissolved in THF (10 mL). At 0 °C there was added acetic
acid (0.1 mL) followed by 1 M tetrabutylammonium fluoride
in THF (1.4 mL). The mixture was stirred in the cold for 2 h,
the reaction quenched with saturated aqueous NH4Cl, and the
mixture diluted with ether. The organic phase was washed
with brine, dried, and evaporated and the residue chromato-
graphed on silica gel (hexane/EtOAc, 7:3) to afford the desired
alcohol as an oil (115 mg, 56% combined yield): 1H NMR (250
MHz, CDCl3) δ 1.50 (d, 3H), 2.00 (s, 3H), 2.30 (s, 1H), 5.05 (m,
2H), 5.20 (s, 2H), 6.00 (q, 1H), 7.00-7.55 (m, 13H), 7.90 (s,
1H).
St ep 6: 3-(1-Acet oxyet h yl)-7-(ben zyloxy)-4-p h en yl-2-
n a p h th oic Acid . To a solution of the alcohol from step 5 (110
mg, 0.26 mmol) in tert-butyl alcohol (6 mL) were added pH 7
aqueous phosphate buffer (4 mL) and a solution of KMnO4 (90
mg, 0.57 mmol) in water (2 mL). After stirring for 3 h at room
temperature, the mixture was diluted with EtOAc and aqueous
sodium sulfite. It was then acidified to pH 2 with 10% aqueous
HCl; the organic phase was collected, washed with water,
dried, and evaporated to give the desired acid as an oil (104
mg, 91%): 1H NMR (250 MHz, CDCl3) δ 1.60 (d, 3H), 2.00 (s,
3H), 5.10 (br s, 1H), 5.15 (s, 2H), 5.90 (q, 1H), 7.10-7.55 (m,
13H), 8.00 (s, 1H).
Step 7: 7-(Ben zyloxy)-3-m eth yl-4-p h en yln a p h th o[2,3-
c]fu r a n -1(3H)-on e (27). To a solution of acid from step 6 (100
mg, 0.23 mmol) in methanol (3 mL) was added sodium
methoxide (5 mg), and the mixture was stirred at room
temperature for 24 h and then evaporated. The residue was
dissolved in EtOAc (3 mL), and 6 N aqueous HCl (2 drops)
was added. After stirring at room temperature for 20 min,
the mixture was washed three times with brine, dried, and
evaporated to afford lactone 27 as a foam (86 mg, 100%): 1H
NMR (250 MHz, CDCl3) δ 1.20 (s, 3H), 5.20 (s, 2H), 5.70 (q,
1H), 7.30-7.70 (m 13H), 8.30 (s, 1H).
Step 8: 7-Hyd r oxy-3-m eth yl-4-p h en yln a p h th o[2,3-c]-
fu r a n -1(3H)-on e (7l). A solution of lactone 27 (86 mg) in
EtOAc (3 mL) containing 10% palladium on carbon (26 mg)
was stirred under an atmosphere of hydrogen at room tem-
perature for 48 h. After filtration the filtrate was evaporated
to afford lactonic naphthol 7l as a solid (55 mg, 83%): 1H NMR
(250 MHz, CD3OD) δ 1.15 (d, 3H), 5.70 (q, 1H), 7.20-7.70 (m,
8H), 8.30 (s,1H).
7-Hyd r oxy-3,3-d im eth yl-4-p h en yln a p h th o[2,3-c]fu r a n -
1(3H)-on e (7m ). Step 1: 2-Acetyl-6-(ben zyloxy)-3-(h y-
d r oxym eth yl)-1-p h en yln a p h th a len e. To a suspension of
lactone 2817 (500 mg, 1.36 mmol) in THF (25 mL) at -78 °C
there was added 1 M methyllithium in ether (2 mL, 2 mmol).
The mixture was warmed slowly until a homogeneous solution
was obtained; then the reaction was quenched with aqueous
saturated NH4Cl and the mixture partitioned between ether
and water. Evaporation of the organic phase yielded the title
compound as a foam which was used as such in the next step.
Step 2: 3-Acetyl-7-(ben zyloxy)-4-p h en yl-2-n a p h th oic
Acid . To a solution of the alcohol from step 1 in tert-butyl
alcohol (10 mL) were added pH 7 aqueous phosphate buffer
(4 mL) and then a solution of potassium permanganate (500
mg, 3.16 mmol) in water (2 mL). After stirring at room
temperature for 3 h, the mixture was diluted with EtOAc and
aqueous sodium sulfite and acidified to pH 2 with 10% aqueous
HCl. The organic phase was collected, washed with water,
dried, and evaporated to give the desired acid (150 mg) as an
oil.
with brine, dried, and evaporated. Chromatography on silica
gel (hexane/EtOAc/CH2Cl2, 85:15:30) afforded the desired
lactone (76 mg, 14% for three steps) as a foam: 1H NMR (250
MHz, CDCl3) δ 1.45 (s, 6H), 5.20 (s, 2H), 7.20-7.55 (m, 13H),
8.35 (s, 1H).
Step 4: 7-Hyd r oxy-3,3-d im eth yl-4-p h en yln a p h th o[2,3-
c]fu r a n -1(3H)-on e (7m ). A solution of benzyloxy lactone
from step 3 (70 mg, 0.18 mmol) in acetic acid (2 mL) and 6 N
aqueous HCl (0.8 mL) was heated at 120 °C for 4 h. After
cooling, the mixture was diluted with EtOAc, and the organic
phase was collected, washed with water and brine, dried, and
evaporated to yield the phenol 7m (52 mg, 97%) as a pale
yellow foam.
P r ep a r a tion of Na p h th ols 8. Meth yl 7-Hyd r oxy-4-
p h en yl-2-n a p h th oa te (8a ). Step 1: 7-Hyd r oxy-4-p h en yl-
2-n a p h th oic Acid (30). A mixture of 7-methoxy-4-phenyl-
2-naphthoic acid20 (29) (55 g, 0.20 mol) and pyridine
hydrochloride (400 g, 3.46 mol) was heated at 175 °C for 10 h.
After cooling to room temperature, water (2 L) was added and
after stirring for 15 min, the mixture was filtered. The solid
was dissolved in water (1.5 L) containing 10 N aqueous NaOH
(35 mL), and the solution was filtered. Acidification of the
filtrate with 1 N aqueous HCl and filtration afforded the
desired naphthol as a tan solid (28.5 g, 55%): mp >250 °C;
1H NMR (300 MHz, acetone-d6) δ 7.26 (dd, 1H), 7.43 (d, 1H),
7.48-7.58 (m, 5H), 7.78 (m, 2H), 8.46 (s, 1H).
Step 2: Meth yl 7-Hyd r oxy-4-p h en yl-2-n a p h th oa te (8a ).
To a suspension of acid 30 (5 g) in methanol (60 mL) was added
dropwise thionyl chloride (1.52 mL, 1.5 equiv). The mixture
was stirred at room temperature for 18 h, and the solvent was
evaporated. Chromatography of the residue on silica gel
(hexane/EtOAc, 1:1) afforded the ester 8a (4.51 g, 81%) as a
tan solid: mp 192-195 °C; 1H NMR (300 MHz, CDCl3) δ 3.98
(s, 3H), 5.32 (s, 1H), 7.18 (dd, 1H), 7.34 (d, 1H), 7.49 (m, 5H),
7.84 (m, 2H), 8.45 (s, 1H).
7-Hyd r oxy-4-p h en yl-2-n a p h th a len en itr ile (8b). To a
suspension of naphthoate 8a (890 mg, 2.19 mmol) in toluene
(50 mL) was added 1 M dimethylaluminum amide in toluene21
(9.59 mL), and the mixture was refluxed for 16 h. After cooling
to 0 °C, there was added carefully 1 N aqueous HCl in excess,
and after 15 min in the cold, the mixture was extracted four
times with CH2Cl2. The extracts were washed three times
with brine, dried, and evaporated to a solid which was
chromatographed on silica gel (hexane/EtOAc, 3:7) to afford
nitrile 8b as a yellow solid (437 mg, 56%): 1H NMR (300 MHz,
CDCl3) δ 5.30 (s, 1H); 7.15 (d, 1H), 7.25 (d, 1H), 7.40-7.55 (m,
6H), 7.82 (d, 1H), 8.06 (s, 1H); IR (KBr) 3500-3200, 2200 cm-1
.
6-H yd r oxy-3-(h yd r oxym et h yl)-1-p h en yln a p h t h a len e
(8c). To a solution of ester 8a (2.5 g, 9.0 mmol) in THF (50
mL) at 0 °C was added diisobutylaluminum hydride (3.83 g,
26.9 mmol), and the mixture was stirred at 0 °C for 2 h. The
reaction was quenched with methanol; then the mixture was
evaporated to dryness and partitioned between 1 N aqueous
HCl and EtOAC. The organic phase was washed three times
with water, dried, and evaporated to a residue which was
stirred in ether (20 mL) for 1 h and filtered to afford alcohol
8c as a white solid (1.46 g, 65%).
3-(Ch lor om eth yl)-6-h ydr oxy-1-ph en yln aph th alen e (8d).
A mixture of alcohol 8c (1.46 g, 5.84 mmol), triphenylphos-
phine (3.0 g, 11.7 mmol), and CCl4 (10 g, 58.4 mmol) in CH2-
Cl2 was refluxed for 2 h. The mixture was evaporated and
the residue chromatographed on silica gel (hexane/EtOAc, 4:1)
to yield 8d as a white solid (1.40 g, 89%): 1H NMR (400 MHz,
acetone-d6) δ 4.88 (s, 2H), 7.13 (dd, 1H), 7.30 (m, 2H), 7.42-
7.58 (m, 5H), 7.73 (d, 1H), 7.80 (s, 1H), 8.72 (s, 1H).
3-Acetyl-6-h yd r oxy-1-p h en yln a p h th a len e (8e). To a
solution of naphthoic acid 30 (12 g, 45.4 mmol) in ether (150
mL) at 0 °C was added slowly 1.4 M methyllithium in ether
(160 mL, 224 mmol). The mixture was then stirred at room
temperature for 24 h, the reaction quenched with chlorotri-
methylsilane until pH 1, and the mixture diluted with water
(100 mL). After 2 h of stirring, the organic phase was collected,
washed with water, aqueous saturated K2CO3, and brine,
dried, and evaporated. The residue was triturated in ether
and filtered to afford ketone 8e as a beige solid (6.76 g, 57%):
Step 3: 7-(Ben zyloxy)-3,3-d im eth yl-4-p h en yln a p h th o-
[2,3-c]fu r a n -1(3H)-on e. To a solution of acid from step 2 (150
mg) in THF (10 mL) at -8 °C was added dropwise 1.4 M
methylmagnesium bromide in ether (0.8 mL). After 2 h at -8
°C, the reaction was quenched with 10% aqueous HCl and the
mixture diluted with ether. After stirring for a further 2 h,
the organic phase was collected, washed with water and then

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3965
1H NMR (250 MHz, CDCl3) δ 2.75 (s, 3H), 5.61 (s, 1H), 7.15-
7.85 (m, 9H), 8.30 (s, 1H).
preparation of compound 30, the desired naphthol 8g was
obtained in 57% yield as a light yellow solid: mp 198-199
°C; 1H NMR (300 MHz, acetone-d6) δ 6.84 (s, 1H), 7.34 (dd,
1H), 7.39 (s, 1H), 7.46 (s, 1H), 7.77 (s, 1H), 7.94 (s, 1H), 8.09
(d, 1H), 8.17 (s, 1H).
4-(3-F u r y l)-7-h y d r o x y -2-n a p h t h a le n e c a r b o x a ld e -
h yd e (8h ). To a solution of nitrile 8g (1.5 g, 6.4 mmol) in
THF (30 mL) at -78 °C was added dropwise 1.5 M diisobu-
tylaluminum hydride in toluene (9.3 mL, 14 mmol). The
mixture was stirred for 1 h at 0 °C and then at room
temperature for 1 h and the reaction quenched with 10%
aqueous HCl at 0 °C. The mixture was partitioned between
EtOAc and water. The organic phase yielded aldehyde 8h
(1.35 g, 90%) as a pale yellow solid which was used as such:
1H NMR (250 MHz, acetone-d6) δ 6.80 (s, 1H), 7.35 (dd, 1H),
7.50 (s, 1H), 7.70 (s, 1H), 7.80 (s, 1H), 7.90 (s, 1H), 8.10 (d,
1H), 8.30 (s, 1H), 9.05 (s, 1H), 10.15 (s, 1H).
6-Hyd r oxy-1-p h en yl-3-(tetr a zol-5-yl)n a p h th a len e (8i).
Following the procedure for the preparation of 8j but using
nitrile 8b as starting material, the desired tetrazole was
obtained in 61% yield as a brown solid which was used as such.
1-(3-Fu r yl)-6-h ydr oxy-3-(tetr azol-5-yl)n aph th alen e (8j).
To a solution of nitrile 8g (134 mg, 0.57 mmol) in 1,2-
dichlorobenzene (13 mL) was added tributyltin azide (663 mg,
1.7 mmol), and the mixture was stirred at 150 °C for 2 h. After
cooling, the reaction was quenched with acetic acid (0.7 mL,
12 mmol), and 15 min later the insolubles were filtered to
afford the expected tetrazole (158 mg) as a dark solid which
was used as such.
3-Eth yl-6-h yd r oxy-1-p h en yln a p h th a len e (8f). A mix-
ture of ketone 8e (167 mg) and palladium hydroxide (20%) on
carbon (50 mg) in EtOAc (30 mL) was stirred under an
atmosphere of hydrogen at room temperature for 24 h. After
filtration, evaporation of the filtrate and chromatography on
silica gel (hexane/EtOAc/CH2Cl2, 9:1:5) afforded the desired
naphthol 8f as a foamy solid (165 mg, 100%): 1H NMR (250
MHz, CDCl3) δ 1.35 (t, 3H), 2.80 (q, 2H), 5.40 (s, 1H), 6.95-
7.80 (m, 10H).
4-(3-F u r yl)-7-h yd r oxy-2-n a p h th a len en itr ile (8g). Step
1: Eth yl 4-(3-F u r yl)-3-oxobu ta n oa te. To a solution of ethyl
3-iodopropanoate (96 g, 0.42 mol) in benzene (800 mL) and
N,N-dimethylacetamide (80 mL), mechanically stirred, was
added zinc-copper couple (50 g, 0.77 mol), and the mixture
was stirred at 65 °C for 1.5 h. After cooling to 30 °C, there
was added tetrakis(triphenylphosphine)palladium(0) (2 g), and
then a solution of 3-furoyl chloride (50 g, 0.38 mol) in benzene
(50 mL) was added at such a rate that the temperature did
not exceed 55 °C. After the addition, the mixture was stirred
until the temperature had dropped to 30 °C; then it was
filtered. The filtrate was washed with 10% aqueous HCl (250
mL) and then three times with water, dried, and evaporated
to an oil which solidified. The solid was triturated with
hexane/ether (2:1) and filtered, affording the desired product
(60.4 g, 80%): mp 55-57 °C; 1H NMR (300 MHz, CDCl3) δ
1.26 (t, 3H), 2.72 (t, 2H), 3.09 (t, 2H), 4.15 (q, 2H), 6.78 (d,
1H), 7.44 (t, 1H), 8.07 (d, 1H).
Step 2: 4-(3-F u r yl)-3-oxobu ta n oic Acid (31). To a
suspension of ester from step 1 (60 g, 0.31 mol) in methanol
(300 mL) and THF (70 mL) was added 2.5 N aqueous NaOH
(130 mL), and the mixture was stirred at room temperature
for 1 h. The resulting solution was diluted with water (250
mL) and then concentrated to a volume of 300 mL. Water was
added (100 mL), and the mixture was filtered. The yellow
filtrate was acidified with 6 N aqueous HCl and the resulting
precipitate filtered to afford the desired acid 31 (47.2 g, 92%)
6-Hyd r oxy-3-(2-m eth yltetr a zol-5-yl)-1-p h en yln a p h th a -
len e (8k ) a n d 6-H yd r oxy-3-(1-m et h ylt et r a zol-5-yl)-1-
p h en yln a p h th a len e (8l). Following the procedure for the
preparation of 8m but using tetrazole 8i as starting material,
a
mixture of two methylated isomers was obtained and
separated by chromatography on silica gel (hexane/EtOAc, 7:3).
1
8k : beige solid (44%); H NMR (250 MHz, acetone-d6) δ 4.45
(s, 3H), 7.20 (dd, 1H), 7.40 (m, 1H), 7.50 (m, 5H), 7.75 (d, 1H),
7.90 (d, 1H), 8.45 (s, 1H), 9.00 (s, 1H). 8l: beige solid (10%);
1H NMR (250 MHz, acetone-d6) δ 4.40 (s, 3H), 7.25 (dd, 1H),
7.40 (m, 1H), 7.50 (m, 5H), 7.60 (s, 1H), 7.80 (d, 1H), 8.20 (s,
1H), 9.05 (s, 1H).
1
as a tan solid: mp 148-149 °C; H NMR (300 MHz, acetone-
d6) δ 2.64 (t, 2H), 3.10 (t, 2H), 6.78 (d, 1H), 7.65 (t, 1H), 8.42
(d, 1H).
Step 3: F u r a n on e 32. A mixture of acid from step 2 (47
g, 0.28 mol), sodium acetate (25.4 g, 0.31 mol), m-anisaldehyde
(42.2 g, 0.31 mol), and acetic anhydride (158 mL, 1.67 mol)
was mechanically stirred and heated at 70 °C for 4.5 h. After
cooling, the mixture was poured onto cold water (1 L), and
after stirring for 20 min, the mixture was filtered. When dry,
the solid was stirred in ether (300 mL) at room temperature
for 30 min and filtered again affording furanone 32 as a gold-
colored solid (43.8 g, 58%): mp 135-136 °C; 1H NMR (300
MHz, CDCl3) δ 3.87 (s, 3H), 6.62 (s, 1H), 6.68 (d, 1H), 6.96
(dd, 1H), 7.11 (s, 1H), 7.21 (d, 1H), 7.40 (m, 2H), 7.53 (t, 1H),
7.88 (d, 1H).
St ep 4: Met h yl 4-(3-F u r yl)-7-m et h oxy-2-n a p h t h oa t e
(33). To a suspension of furanone 32 (32.6 g, 0.122 mol) in
methanol (250 mL), mechanically stirred, was slowly added
sulfuric acid (24.5 g, 0.25 mol), and the resulting mixture was
refluxed for 2 days. Some methanol was distilled off (100 mL),
and the resulting suspension was cooled to room temperature
and filtered, affording a solid (20.2 g) greatly enriched in the
desired regioisomer. The solid was stirred in methanol (50
mL) at room temperature for 1 h and filtered, affording
naphthoate 33 (19 g, 55%) as a grayish solid: mp 95-96 °C;
1H NMR (300 MHz, CDCl3) δ 3.94 (s, 3H), 3.99 (s, 3H), 6.70
(s, 1H), 7.25 (m, 2H), 7.58 (s, 1H), 7.69 (s, 1H), 7.91 (s, 1H),
8.07 (d, 1H), 8.48 (s, 1H).
1-(3-F u r yl)-6-h yd r oxy-3-(2-m et h ylt et r a zol-5-yl)n a p h -
th a len e (8m ). To a solution of tetrazole 8j (158 mg, 0.57
mmol) in DMF (3 mL) were added cesium carbonate (203 mg,
0.62 mmol) and iodomethane (0.039 mL, 0.62 mmol). The
mixture was stirred at room temperature overnight, then the
reaction was quenched with water, and the mixture was
extracted with EtOAc. The product from the organic phase
was chromatographed on silica gel (hexane/EtOAc, 7:3) to yield
methyltetrazole 8m (67 mg, 40%) as a cream-colored solid: 1H
NMR (250 MHz, CDCl3) δ 4.45 (s, 3H), 6.75 (s, 1H), 7.30 (m,
2H), 7.60 (s, 1H), 7.70 (s, 1H), 8.10 (m, 2H), 8.50 (s, 1H).
6-Hydr oxy-1-(3-fu r yl)-3-(2-oxazolin yl)n aph th alen e (8o).
This compound was prepared in the same manner as 8p using
ethanolamine as starting material, in 51% yield: 1H NMR (250
MHz, DMSO-d6) δ 4.00 (t, 2H), 4.45 (t, 2H), 6.80 (s, 1H), 7.20
(dd, 1H), 7.30 (d, 1H), 7.70 (d, 1H), 7.85 (s, 1H), 7.95 (d, 1H),
8.00 (s, 1H), 8.20 (s, 1H), 9.30 (br s, 1H).
6-Hydr oxy-1-(3-fu r yl)-3-(4,4-dim eth yl-2-oxazolin yl)n aph -
th a len e (8p ). A mixture of nitrile 8g (300 mg, 1.27 mmol),
2-amino-2,2-dimethylethanol (0.74 mL, 7.8 mmol), and zinc
chloride (20 mg) was heated at reflux in chlorobenzene (20 mL)
for 3 days. The mixture was concentrated and chromato-
graphed on silica gel (hexane/EtOAc, 3:2) to yield naphthol
8p (293 mg, 75%) as a white solid: 1H NMR (250 MHz,
acetone-d6) δ 1.35 (s, 6H), 4.20 (s, 2H), 6.80 (d, 1H), 7.25 (dd,
1H), 7.35 (d, 1H), 7.75 (t, 1H), 7.80 (d, 1H), 7.90 (s, 1H), 8.05
(d, 1H), 8.20 (s, 1H), 8.90 (s, 1H).
Step 5: 4-(3-F u r yl)-7-m eth oxy-2-n a p h th a len en itr ile.
Following the procedure described above for the preparation
of nitrile 8b, using ester 33 as starting material and 2 equiv
of dimethylaluminum amide, the desired nitrile was obtained
in 75% yield as a light yellow solid: 1H NMR (400 MHz,
acetone-d6) δ 3.98 (s, 3H), 6.86 (s, 1H), 7.37 (dd, 1H), 7.52 (d,
1H), 7.55 (s, 1H), 7.79 (s, 1H), 7.96 (s, 1H), 8.14 (d, 1H), 8.30
(s, 1H).
6-Hydr oxy-1-(3-fu r yl)-3-(2-th iazolin yl)n aph th alen e (8q).
A mixture of nitrile 8g (500 mg, 2.1 mmol) and 2-aminoet-
hanethiol hydrochloride (1.2 g, 10 mmol) in chlorobenzene (30
mL) was refluxed for 24 h. After cooling, the mixture was
diluted with EtOAc, washed twice with saturated NaHCO3 and
then with brine, dried, and evaporated. The solid residue was
stirred vigorously with ether for 1 h at room temperature and
filtered to afford naphthol 8q (379 mg, 60%) as a pale yellow
Step 6: 4-(3-Fu r yl)-7-h ydr oxy-2-n aph th alen en itr ile (8g).
Following the demethylation procedure described above in the

3966 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
solid: 1H NMR (250 MHz, acetone-d6) δ 3.50 (t, 2H), 4.45 (t,
2H), 6.70 (s, 1H), 7.25 (dd, 1H), 7.40 (d, 1H), 7.75 (t, 1H), 7.80
(d, 1H), 7.90 (s, 1H), 8.05 (m, 2H), 8.90 (s, 1H).
8w and the product esterified with diazomethane to afford
naphthol 8v (95%) as a brown oil.
Meth yl 4-Ben zyl-7-h yd r oxy-2-n a p h th oa te (8w ). Step
1: Meth yl 4-Ben zyl-7-m eth oxy-1,2-dih ydr o-2-n aph th oate.
To a solution of 3-carbethoxy-6-methoxy-1-tetralone (34)22 (1.5
g) in THF (30 mL) at 0 °C was added 2.0 M benzylmagnesium
chloride in THF until no more 34 remained, as monitored by
TLC. The reaction was quenched with 10% aqueous HCl and
extracted with ether. The extract was washed three times
with water and brine, dried, and evaporated to afford a residue
which was refluxed in benzene (30 mL) containing camphor-
sulfonic acid (20 mg) for 4 h with azeotropic removal of water.
After evaporation of the solvent, the crude product (dihy-
dronaphthoic acid) was esterified with ethereal diazomethane
and the product chromatographed on silica gel (hexane/EtOAc,
95:5) to afford the desired methyl ester (1.29 g, 76%) as an oil
which was used as such in the next step.
Step 2: Meth yl 4-Ben zyl-7-m eth oxy-2-n a p h th oa te. A
mixture of ester from step 1 (1.29 g, 4.2 mmol) and DDQ (950
mg, 4.2 mmol) in benzene (25 mL) was stirred at room
temperature for 30 min. The mixture was diluted with ether,
washed with aqueous NH4Cl, water, and brine, dried, and
evaporated. The residue was chromatographed on silica gel
(hexane/EtOAc, 90:10) to afford the expected product as an
oil (800 mg, 62%): 1H NMR (250 MHz, CDCl3) δ 3.90 (s, 3H),
3.95 (s, 3H), 4.45 (s, 2H), 7.30 (m, 7H), 7.80 (d, 1H), 7.90 (d,
1H), 8.45 (s, 1H).
Step 3: Meth yl 4-Ben zyl-7-h yd r oxy-2-n a p h th oa te (8w ).
A mixture of ester from step 2 (770 mg, 2.5 mmol) and
pyridine‚HCl (6.0 g, 52 mmol) was heated at 180-200 °C for
30 min. After cooling the mixture was partitioned between
EtOAc (50 mL) and 3% aqueous HCl (10 mL). The organic
phase was washed with water and then brine, dried, and
evaporated to afford the naphthoic acid which was esterified
with ethereal diazomethane. The ester was chromatographed
on silica gel (hexane/EtOAc, 85:15) to afford naphthol 8w as
a foamy solid (456 mg, 62%): 1H NMR (250 MHz, acetone-d6)
δ 3.90 (s, 3H), 4.45 (s, 2H), 7.25 (m, 6H), 7.40 (m, 1H), 7.70
(m, 1H), 8.00 (m, 1H), 8.30 (m, 1H), 8.90 (s, 1H).
3-(2-Be n zot h ia zolyl)-6-h yd r oxy-1-(3-fu r yl)n a p h t h a -
len e (8r ). To a saturated solution of HCl in 1,2-dichloroben-
zene (12 mL) was added 2-aminothiophenol (0.5 mL, 4.7
mmol). To the resulting suspension was added nitrile 8g (200
mg, 0.85 mmol), and the mixture was refluxed for 3 days. The
cooled mixture was chromatographed as such on silica gel
(hexane/EtOAc, 9:1), affording a solid which was triturated
in a small volume of ether at room temperature for 30 min
and filtered to yield naphthol 8r (115 mg, 39%) as a pale yellow
solid: 1H NMR (300 MHz, acetone-d6) δ 6.90 (s, 1H), 7.30 (dd,
1H), 7.45 (m, 2H), 7.55 (t, 1H), 7.80 (t, 1H), 8.00 (s, 1H), 8.10
(m, 4H), 8.45 (s, 1H).
6-H yd r oxy-1-(3-fu r yl)-3-(3-p yr id ylca r b on yl)n a p h t h a -
len e (8s). To a solution of 3-bromopyridine (0.4 mL, 4.15
mmol) in ether (25 mL) at -78 °C was added dropwise 2.06 M
n-butyllithium in hexane (2.0 mL, 4.12 mmol), and the
resulting yellow mixture was stirred at -78 °C for 20 min.
There was added a solution of nitrile 8g (250 mg, 1.06 mmol)
in THF (5 mL), and the mixture was warmed to 0 °C and
stirred for 15 min. The reaction was quenched with saturated
aqueous NH4Cl, and the mixture was stirred at room temper-
ature for 30 min and partitioned between EtOAc and water.
Chromatography of the organic residue on silica gel (hexane/
EtOAc, 1:9) afforded naphthol 8s as a yellow solid (161 mg,
48%): 1H NMR (250 MHz, CDCl3) δ 6.70 (m, 1H), 7.10 (d, 1H),
7.20 (dd, 1H), 7.45-7.70 (m, 5H), 8.05 (d, 1H), 8.15 (m, 1H),
8.75 (m, 1H), 8.85 (s, 1H).
6-Hyd r oxy-1-(3-fu r yl)-3-(2-th ia zolylca r bon yl)n a p h th a -
len e (8t). To a solution of thiazole (0.3 mL, 4.2 mmol) in THF
(20 mL) at -78 °C was added 1.1 M n-butyllithium in hexane
(3.8 mL, 4.2 mmol). After 30 min, there was added a solution
of nitrile 8g (250 mg, 1.06 mmol) in THF (5 mL). The reaction
mixture was warmed to -20 °C and then the reaction
quenched with 10% aqueous HCl. The mixture was stirred
at room temperature for 1 h and extracted with ether. The
extracts were washed with brine, dried, and evaporated, and
the residue was chromatographed on silica gel (hexane/EtOAc,
85:15) to afford ketone 8t (195 mg, 57%) as an orange solid:
1H NMR (250 MHz, acetone-d6) δ 6.85 (s, 1H), 7.35 (dd, 1H),
7.50 (d, 1H), 7.80 (s, 1H), 7.95 (s, 1H), 8.15 (m, 5H), 9.10 (s,
1H).
6-H yd r oxy-1-(3-fu r yl)-3-(2-t h ia zolylm et h yl)n a p h t h a -
len e (8u ). To a mixture of ketone 8t (420 mg, 1.3 mmol) and
potassium carbonate (1.4 g, 10 mmol) in diethylene glycol (10
mL) was added hydrazine (0.1 mL, 3.2 mmol). The mixture
was stirred at 190 °C for 2 h, cooled down, and diluted with
EtOAc and pH 7 buffer solution. The organic phase was
washed with buffer and then with brine, dried, and evaporated.
Chromatography on silica gel (hexane/EtOAc, 3:2) gave naph-
thol 8u (221 mg, 55%) as a yellow oil: 1H NMR (250 MHz,
CDCl3) δ 4.50 (s, 2H), 6.65 (m, 1H), 7.05 (m, 2H), 7.15 (br s,
1H), 7.25 (m, 2H), 7.45 (s, 1H), 7.55 (t, 1H), 7.60 (s, 1H), 7.75
(d, 1H), 7.90 (d, 1H).
P r ep a r a tion of F in a l P r od u cts 3. Meth od A: 7-[[3-(4-
H yd r oxyt et r a h yd r o-2H -p yr a n -4-yl)p h en yl]m et h oxy]-4-
p h en yln a p h th o[2,3-c]fu r a n -1(3H)-on e (3a ). A mixture of
lactonic naphthol 7a (800 mg, 2.89 mmol), benzylic halide 6a
(1.02 g, 3.76 mmol), and potassium carbonate (1.03 g, 7.44
mmol) in DMF (10 mL) was stirred at room temperature for
21 h. The mixture was diluted with water (50 mL) and
extracted three times with EtOAc; the extracts were washed
with 1 N NaOH and then twice with brine, dried, and
evaporated. Chromatography on silica gel (CHCl3/EtOAc, 1:1)
afforded the desired product as a yellow solid (1.02 g, 75%):
1
mp 191-192 °C; H NMR (250 MHz, CDCl3) δ 1.70 (m, 3H),
2.20 (m, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 5.25 (s, 2H), 7.35-
7.60 (m, 10H), 7.65 (s, 1H), 7.75 (d, 1H), 8.45 (s, 1H).
Meth od B: 7-[[3-(4-Hyd r oxytetr a h yd r o-2H-p yr a n -4-yl)-
p h en yl]m eth oxy]-4-(3-m eth oxyp h en yl)n a p h th o[2,3-c]fu -
r a n -1(3H)-on e (3p ). A mixture of lactonic naphthol 7b (204
mg, 0.67 mmol), benzylic halide 6a (218 mg, 0.80 mmol), and
cesium carbonate (343 mg, 1.33 mmol) in DMF (8 mL) was
stirred at room temperature for 3 h. The mixture was diluted
with water and acidified with 1 N aqueous HCl and the
precipitate filtered. Purification by chromatography on silica
gel (hexane/EtOAc) afforded the desired product as a white
solid (225 mg, 68%): mp 182-184 °C; 1H NMR (250 MHz,
CDCl3) δ 1.71 (d, 2H), 2.22 (m, 2H), 3.86 (s, 3H), 3.90 (m, 4H),
5.24 (s, 2H), 5.26 (s, 2H), 6.92 (m, 2H), 7.03 (dd, 1H), 7.33 (dd,
1H), 7.45 (m, 5H), 7.67 (s, 1H), 7.77 (d, 1H), 8.38 (s, 1H).
Meth od C: 7-[[3-(1R,5S)-(3r-Hyd r oxy-6,8-d ioxa bicyclo-
[3.2.1]oct a n -3-yl)p h en yl]m et h oxy]-4-(3-fu r yl)n a p h t h o-
[2,3-c]fu r a n -1(3H)-on e (3v). Diethyl azodicarboxylate (0.052
mL, 0.33 mmol) was added to a solution of triphenylphosphine
(87 mg, 0.33 mmol) in THF (2 mL). After 5 min, there were
added naphthol 7e (88 mg, 0.33 mmol) and, 5 min later, alcohol
6f (71 mg, 0.30 mmol). The mixture was stirred at room
temperature for 16 h, diluted with EtOAc (20 mL), and washed
with 1 N aqueous NaOH, water, and brine, and the organic
phase was evaporated. The residue was chromatographed
Meth yl 4-n -Bu tyl-7-h yd r oxy-2-n a p h th oa te (8v). Step
1: 4-n -Bu tyl-7-m eth oxy-1,2-d ih yd r o-2-n a p h th oic Acid . To
a suspension of anhydrous CeCl3 (520 mg, 2.1 mmol) in THF
(25 mL) at 0 °C was added tetralone 3422 (400 mg, 2.1 mmol)
followed by n-butylmagnesium bromide (2.0 M) in ether (1.05
mL, 2.1 mmol). The mixture was stirred at 0 °C for 2 h; then
the reaction was quenched with 1 N aqueous HCl and the
mixture extracted with ether. The extracts were washed with
1 N HCl and then with brine, dried, and evaporated. Chro-
matography on silica gel (hexane/EtOAc, 4:1) yielded the
dihydronaphthoic acid as an oil (263 mg, 72%).
Step 2: 4-n -Bu tyl-7-m eth oxy-2-n a p h th oic Acid . The
acid from step 1 was dehydrogenated as described in step 2 of
the preparation of naphthol 8w to afford the desired naphthoic
acid as a white solid (64%): 1H NMR (250 MHz, CDCl3) δ 1.00
(t, 3H), 1.50 (m, 2H), 1.75 (m, 2H), 3.10 (m, 2H), 3.95 (s, 3H),
7.30 (m, 2H), 7.80 (s, 1H), 8.00 (d, 1H), 8.50 (s, 1H).
Step 3: Meth yl 4-n -Bu tyl-7-h yd r oxy-2-n a p h th oa te (8v).
The acid from step 2 was demethylated with pyridine hydro-
chloride as described in step 3 of the preparation of naphthol

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3967
twice on silica gel (CHCl3/EtOAc, 3:1, and then toluene/EtOAc,
4:1) to afford 3v (42 mg, 29%) as a white solid: 1H NMR (300
MHz, CDCl3) δ 2.05 (m, 2H), 2.30 (d, 1H), 2.50 (dd, 1H), 3.80
(m, 1H), 3.91 (s, 1H), 4.50 (d, 1H), 4.70 (m, 1H), 5.22 (s, 2H),
5.33 (s, 2H), 5.78 (s, 1H), 6.60 (m, 1H), 7.35-7.50 (m, 5H), 7.65
(m, 3H), 8.01 (d, 1H), 8.33 (s, 1H).
3u : white solid; 1H NMR (250 MHz, CDCl3) δ 2.06 (m, 1H),
2.12 (d, 1H), 2.34 (d, 1H), 2.50 (dd, 1H), 3.80 (dd, 1H), 3.95 (s,
1H), 4.52 (d, 1H), 4.72 (t, 1H), 5.22 (s, 2H), 5.36 (s, 2H), 5.80
(s, 1H), 6.60 (s, 1H), 7.30-7.50 (m, 5H), 7.60-7.70 (m, 3H),
8.00 (d, 1H), 8.36 (s, 1H).
7-[[3-(4-H yd r oxyt e t r a h yd r o-2H -p yr a n -4-yl)p h e n yl]-
m eth oxy]-3-h yd r oxy-4-p h en yln a p h th o[2,3-c]fu r a n -1(3H)-
on e (3b). A mixture of carboxylate 10a (271 mg, 0.43 mmol)
and pyridinium dichromate (487 mg, 1.3 mmol) in acetone
(25 mL) was stirred at room temperature for 5 h and then
filtered through Celite. The filtrate was evaporated and
the residue chromatographed on silica gel (CHCl3/MeOH,
9:1) to afford 3b (40 mg, 19%) as a white solid: mp 219-
The following compounds were prepared according to analo-
gous procedures. Synthetic and physical data for final com-
pounds 3a -v are presented in Table 1.
3d : glassy solid; 1H NMR (250 MHz, CDCl3) δ 1.15 (d, 3H),
1.70 (m, 2H), 2.20 (m, 2H), 3.90 (m, 4H), 5.25 (s, 2H), 5.70 (q,
1H), 7.27-7.70 (m, 12H), 8.35 (s, 1H); HRMS (C31H28O5 + H+)
calcd 481.2017, found 481.2015.
1
1
3e: white foamy solid; H NMR (250 MHz, CDCl3) δ 1.49
220 °C; H NMR (250 MHz, acetone-d6) δ 1.60 (d, 2H), 2.10
(s, 6H), 1.70 (m, 2H), 2.22 (m, 2H), 3.93 (m, 4H), 5.23 (s, 2H),
7.21-7.58 (m, 11H), 7.67 (s, 1H), 8.35 (s, 1H); HRMS (C32H30O5
+ H+) calcd 495.2172, found 495.2172.
(m, 2H), 3.75 (dd, 2H), 3.90 (m, 2H), 4.10 (s, 1H), 5.30 (s, 2H),
6.70 (s, 1H), 7.35-7.60 (m, 9H), 7.65 (d, 1H), 7.80 (m, 2H),
8.35 (s, 1H); HRMS (C30H26O6 + H+) calcd 483.1807, found
483.1809.
1
3f: white solid; H NMR (250 MHz, CDCl3) δ 1.24 (d, 6H),
1.65-1.80 (m, 5H), 4.05 (m, 2H), 5.25 (m, 4H), 7.30-7.80 (m,
12H), 8.40 (s, 1H); HRMS (C32H30O5 + H+) calcd 495.2172,
found 495.2170.
3c. To a solution of methyl glycoside 3i (103 mg, 0.21 mmol)
in THF (3 mL) was added 10% aqueous HCl (1.5 mL), and the
mixture was stirred at room temperature for 24 h. Saturated
aqueous NaHCO3 (25 mL) was added, and the mixture was
extracted with EtOAc. Chromatography of the organic residue
on silica gel (CHCl3/EtOAc, 1:1) gave 3c (68 mg, 68%) as a
colorless gum and as a mixture of R and â epimers: 1H NMR
(500 MHz, acetone-d6) assignments done on mixture, R epimer
δ 1.70 (d, 1H), 1.90 (d, 1H), 2.10 (dd, 1H), 2.25 (m, 1H), 3.65
(m, 1H), 4.35 (m, 1H), 5.30 (d, 1H), 5.30 (s, 2H), 5.35 (s, 2H),
5.90 (d, 1H), 7.35-7.45 (m, 3H), 7.45-7.55 (m, 4H), 7.58 (m,
2H), 7.72 (m, 2H), 7.80 (s, 1H), 8.40 (s, 1H); â-epimer, δ 1.60
(d, 1H), 1.80 (dd, 1H), 1.95 (m, 1H), 2.05 (m, 1H), 3.80 (dd,
1H), 3.95 (d, 1H), 5.10 (dd, 1H), 5.30 (s, 2H), 5.35 (s, 2H), 7.35-
7.45 (m, 3H), 7.45-7.55 (m, 4H), 7.58 (m, 2H), 7.72 (m, 2H),
7.80 (s, 1H), 8.40 (s, 1H); HRMS (C30H26O6 + H+ - 2H2O) calcd
447.1596, found 447.1595.
3g: white solid; mp 171-173 °C; 1H NMR (250 MHz, CDCl3)
δ 1.90 (d, 2H), 2.55 (dd, 2H), 3.10 (s, 1H), 4.95 (d, 2H), 5.70 (s,
2H), 5.75 (s, 2H), 6.60 (s, 2H), 7.30-7.60 (m, 10H), 7.65 (s,
1H), 7.70 (d, 1H), 8.40 (s, 1H).
3i: white solid; mp 179-180 °C; 1H NMR (250 MHz, CDCl3)
δ 1.75 (d, 1H), 1.99 (d, 1H), 2.16 (dd, 1H), 2.27 (m, 1H), 3.47
(s, 3H), 3.79 (dd, 1H), 4.18 (m, 1H), 4.76 (s, 1H), 4.95 (d, 1H),
5.23 (s, 2H), 5.24 (s, 2H), 7.30-7.60 (m, 10H), 7.72 (m, 2H),
8.38 (s, 1H).
3j: white solid; 1H NMR (300 MHz, CDCl3) δ 2.05 (m, 2H),
2.30 (dd, 1H), 2.45 (dd, 1H), 3.80 (m, 1H), 3.90 (s, 1H), 4.50
(d, 1H), 4.70 (m, 1H), 5.20 (s, 2H), 5.25 (s, 2H), 5.75 (s, 1H),
7.25-7.70 (m, 12H), 8.35 (s, 1H).
3k : cream-colored solid; mp 167-169 °C; 1H NMR (300
MHz, CDCl3) δ 1.65 (s, 1H), 1.72 (d, 2H), 2.23 (m, 2H), 3.94
(m, 4H), 5.23 (s, 4H), 7.18-7.52 (m, 9H), 7.67 (s, 1H), 7.70 (d,
1H), 8.38 (s, 1H).
3h . A mixture of alkene 3g (52 mg, 1.1 mmol) and 10%
palladium on carbon (22 mg) in EtOAc (3 mL) was stirred at
room temperature under hydrogen for 45 min. After filtration,
the filtrate was evaporated and the residue chromatographed
on silica gel (CHCl3/hexane, 4:1) to yield compound 3h (38 mg,
3l: white solid; mp 125-127 °C; 1H NMR (400 MHz,
acetone-d6) δ 1.64 (d, 2H), 2.10 (m, 2H), 3.74 (m, 2H), 3.90 (m,
2H), 4.08 (s, 1H), 5.33 (s, 6H), 7.36-7.46 (m, 3H), 7.55 (d, 3H),
7.66 (d, 2H), 7.72-7.82 (m, 3H), 8.41 (s, 1H).
1
73%) as a white solid: mp 125-127 °C; H NMR (250 MHz,
CDCl3) δ 1.80 (d, 2H), 2.00 (m, 2H), 2.40 (m, 4H), 4.50 (m,
2H), 5.65 (s, 2H), 5.70 (s, 2H), 7.25-7.60 (m, 10H), 7.65 (s,
1H), 7.70 (d, 1H), 8.35 (s, 1H).
3m : white solid; mp 220-223 °C; 1H NMR (400 MHz,
acetone-d6) δ 1.63 (d, 2H), 2.11 (m, 2H), 3.74 (m, 2H), 3.88 (m,
2H), 3.92 (s, 1H), 5.30 (s, 2H), 5.34 (s, 2H), 7.15 (d, 2H), 7.38-
7.45 (m, 5H), 7.55 (d, 1H), 7.78 (m, 3H), 8.38 (s, 1H).
3n : white solid; mp 194-196 °C; 1H NMR (300 MHz, CDCl3)
δ 1.66 (s, 1H), 1.70 (d, 2H), 2.22 (m, 2H), 3.93 (m, 4H), 5.22 (s,
2H), 5.24 (s, 2H), 7.30-7.49 (m, 9H), 7.64 (d, 1H), 7.67 (s, 1H),
8.42 (s, 1H).
7-[[3-(4-H y d r o x y -2-o x o t e t r a h y d r o -2H -p y r a n -4-y l)-
p h en yl]m et h oxy]-4-p h en yln a p h t h o[2,3-c]fu r a n -1(3H )-
on e (5). A mixture of hydroxypyran 3c (152 mg, 0.31 mmol)
and silver carbonate on Celite8 (1.60 g) in benzene (25 mL)
was refluxed for 4 h. The mixture was filtered and the filtrate
evaporated. Chromatography on silica gel (CHCl3/EtOAc, 3:2)
yielded lactone 5 (59 mg, 39%) as a white solid: mp 192-195
3o: lactonic naphthol used (7k ) was a mixture of isomeric
lactones; purification achieved on the mixture of coupled
products by chromatography on silica gel (hexane/EtOAc, 1:1)
to afford 3o as a white solid; mp 198-200 °C dec; 1H NMR
(300 MHz, CDCl3) δ 1.68 (s, 1H), 1.72 (d, 2H), 2.22 (m, 2H),
3.93 (m, 4H), 5.18 (q, 2H), 5.24 (s, 2H), 7.30 (m, 2H), 7.39-
7.55 (m, 7H), 7.62 (dd, 1H), 7.66 (s, 1H), 8.43 (s, 1H).
3q: yellow solid; 1H NMR (250 MHz, DMSO-d6) δ 1.55 (m,
2H), 2.00 (m, 2H), 3.75 (m, 4H), 5.10 (s, 1H), 5.30 (s, 2H), 5.40
(m, 2H), 7.40 (m, 4H), 7.65 (m, 3H), 7.90 (s, 1H), 8.00 (m, 1H),
8.55 (s, 1H), 8.75 (m, 2H); HRMS (C29H25NO5 + H+) calcd
468.1811, found 468.1812.
1
°C; H NMR (250 MHz, CDCl3) δ 2.15 (m, 1H), 2.40 (m, 1H),
2.95 (q, 2H), 4.40 (m, 1H), 4.75 (m, 1H), 5.25 (s, 4H), 7.30-
7.55 (m, 10H), 7.60 (s, 1H), 7.75 (d, 1H), 8.40 (s, 1H). Anal.
(C30H24O6‚0.4EtOAc) C,H.
P r ep a r a tion of F in a l P r od u cts 9. The following com-
pounds were prepared by one of the three methods described
previously for the preparation of compounds 3. Synthetic and
physical data for final compounds 9a -a c are presented in
Table 2.
9a : white solid; mp 121-122.5 °C; 1H NMR (250 MHz,
CDCl3) δ 1.35 (t, 3H), 1.60 (s, 1H), 1.70 (m, 2H), 2.20 (m, 2H),
2.80 (q, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 7.10-7.55 (m, 12H),
7.65 (s, 1H), 7.80 (d, 1H); HRMS (C30H30O3+H+) calcd 539.2274,
found 539.2273.
9g: pale yellow solid; 1H NMR (250 MHz, CDCl3) δ 1.70
(m, 3H), 2.20 (m, 2H), 2.70 (s, 3H), 3.90 (m, 4H), 5.20 (s, 2H),
7.25 (m, 1H), 7.40-7.50 (m, 10H), 7.65 (s, 1H), 7.85 (m, 2H),
8.35 (s, 1H); HRMS (C30H28O4 + H+) calcd 453.2065, found
453.2066.
9h : white solid; mp 98-100 °C; 1H NMR (250 MHz, CDCl3)
δ 1.70 (m, 3H), 2.20 (m, 2H), 3.90 (m, 4H), 3.95 (s, 3H), 5.20
(s, 2H), 7.25 (m, 1H), 7.35-7.50 (m, 9H), 7.65 (s, 1H), 7.85 (m,
2H), 8.50 (s, 1H); HRMS (C30H28O5 + H+) calcd 469.201 47,
found 469.201 49.
3r : white solid; mp 164-166 °C; 1H NMR (400 MHz,
acetone-d6) δ 1.63 (d, 2H), 2.10 (m, 2H), 3.25 (m, 2H), 3.90 (m,
2H), 4.08 (s, 1H), 5.33 (s, 2H), 5.60 (s, 2H), 6.78 (m, 1H), 7.02
(m, 1H), 7.39-7.48 (m, 2H), 7.50-7.58 (m, 2H), 7.70 (m, 2H),
7.79 (s, 1H), 8.39 (s, 1H), 8.47 (d, 1H).
3s: cream-colored solid; mp 181-183 °C; 1H NMR (300 MHz,
CDCl3) δ 1.62 (s, 1H), 1.67 (d, 2H), 2.22 (m, 2H), 3.94 (m, 4H),
5.24 (s, 2H), 5.35 (s, 2H), 6.61 (d, 1H), 7.42 (m, 5H), 7.65 (m,
3H), 8.03 (d, 1H), 8.35 (s, 1H).
3t: white solid; mp 172-175 °C; 1H NMR (400 MHz,
acetone-d6) δ 1.65 (d, 2H), 2.12 (m, 2H), 3.77 (m, 2H), 3.93 (m,
2H), 4.09 (s, 1H), 5.33 (s, 2H), 5.40 (s, 2H), 7.36 (m, 1H), 7.40-
7.48 (m, 3H), 7.57 (d, 1H), 7.74 (m, 1H), 7.80 (m, 3H), 7.93 (d,
1H), 8.40 (s, 1H).

3968 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Delorme et al.
9i: yellow solid; IR (KBr) 3600-3200, 2220, 1640, 1600
cm-1; 1H NMR (250 MHz, CDCl3) δ 1.65 (dd, 2H), 2.20 (m, 2H),
3.90 (m, 4H), 5.20 (s, 2H), 7.80-8.10 (m, 14H).
2H), 7.15 (dd, 1H), 7.25 (d, 1H), 7.40-7.50 (m, 9H), 7.65 (s,
1H), 7.70 (s, 1H), 7.80 (d, 1H); HRMS (C29H28O4 + H+) calcd
441.2067, found 441.2066.
9l: white solid; mp 185 °C; 1H NMR (250 MHz, CDCl3) δ
1.70 (m, 2H), 2.20 (m, 2H), 3.90 (m, 4H), 4.40 (s, 3H), 5.20 (s,
2H), 7.25 (dd, 1H), 7.35-7.60 (m, 9H), 7.65 (s, 1H), 7.85 (d,
1H), 8.00 (d, 1H), 8.55 (s, 1H).
9c. To a solution of ketone 9g (275 mg, 0.61 mmol) in
ethanol (10 mL) was added NaBH4 (45 mg, 1.2 mmol), and
the mixture was stirred at room temperature for 3 h. After
the reaction was quenched with 10% aqueous NaOH, the
mixture was extracted with ether. After evaporation of the
solvent, the crude product was stirred in a small volume of
ether and filtered to afford 9c (248 mg, 90%) as a white solid:
mp 138.5-140.5 °C; 1H NMR (250 MHz, CDCl3) δ 1.60 (d, 3H),
1.70 (m, 2H), 2.00 (d, 1H), 2.20 (m, 2H), 3.90 (m, 4H), 5.10 (m,
1H), 5.20 (s, 2H), 7.15 (dd, 1H), 7.30 (m, 2H), 7.45 (m, 8H),
7.65 (s, 1H), 7.75 (s, 1H), 7.80 (d, 1H); HRMS (C30H30O4 + H+)
calcd 455.2224, found 455.2222.
9d . To a solution of ester 9h (200 mg, 0.43 mmol) in THF
(10 mL) at -78 °C was added 1.4 M methyllithium in ether
(1.45 mL, 2.03 mmol). After 2 h at -78 °C. the reaction was
quenched with saturated aqueous NH4Cl and the mixture
extracted with ether. The extracts were washed with brine,
dried, and evaporated, and the residue was chromatographed
on silica gel (hexane/EtOAc/CH2Cl2, 1:1:1) to yield 9d as a
white foam (100 mg, 50%): 1H NMR (250 MHz, CDCl3) δ 1.65-
1.75 (m, 3H), 1.70 (s, 6H), 1.90 (s, 1H), 2.20 (m, 2H), 3.90 (m,
4H), 5,20 (s, 2H), 7.15 (dd, 1H), 7.30 (d, 1H), 7.35-7.50 (m,
9H), 7.65 (s, 1H), 7.80 (d, 1H), 7.85 (d, 1H); HRMS (C31H32O4
+ H+) calcd 469.2379, found 469.2379.
9e. To a solution of alcohol 9b (148 mg, 0.34 mmol) in THF
(10 mL) at 0 °C were added NaH (10 mg, 0.417 mmol) and
then iodomethane (30 mL, 0.48 mmol). The mixture was
stirred at room temperature for 18 h; then the reaction was
quenched with saturated aqueous NH4Cl and the mixture
extracted with ether. The crude product was chromatographed
on silica gel (hexane/EtOAc, 3:2) to afford 9e as a white foam
(122 mg, 80%): 1H NMR (250 MHz, CDCl3) δ 1.60 (s, 1H), 1.70
(m, 2H), 2.20 (m, 2H), 4.45 (s, 3H), 3.90 (m, 4H), 4.65 (s, 2H),
5.20 (s, 2H), 7.15 (dd, 1H), 7.25 (m, 1H), 7.40-7.50 (m, 9H),
7.65 (s, 1H), 7.70 (s, 1H), 7.80 (d, 1H); HRMS (C30H30O4 + H+)
calcd 455.2224, found 455.2222.
9f. To a solution of alcohol 9c (60 mg, 0.13 mmol) in THF
(3 mL) were added 80% NaH dispersed in oil (10 mg, 0.33
mmol) followed by iodomethane (0.02 mL, 0.32 mmol). The
mixture was stirred at room temperature for 24 h; the reaction
was quenched with saturated aqueous NH4Cl and the mixture
partitioned between water and ether. The organic residue was
chromatographed on silica gel (hexane/EtOAc/CH2Cl2, 3:2:2)
to afford 9f (50 mg, 81%) as a white foam: 1H NMR (250 MHz,
CDCl3) δ 1.50 (d, 3H), 1.70 (m, 3H), 2.20 (m, 2H), 3.25 (s, 3H),
3.90 (m, 4H), 4.45 (q, 1H), 5.15 (s, 2H), 7.15 (dd, 1H), 7.30 (m,
2H), 7.45 (m, 8H), 7.65 (s, 2H), 7.85 (d, 1H).
9j. To a solution of ester 9h (300 mg) in THF-methanol-
water (3:1:1, 10 mL) was added LiOH‚H2O (50 mg). After
stirring at room temperature for 18 h, the mixture was
acidified to pH 3 with 10% aqueous HCl and extracted with
ether. The extracts were washed with brine, dried, and
evaporated, and the residue was chromatographed on silica
gel (CH2Cl2/MeOH, 9:1) to afford acid 9j as a white solid (218
mg, 75%): mp 202-205 °C; 1H NMR (300 MHz, CDCl3) δ 1.71
(d, 2H), 2.22 (m, 2H), 3.50 (s, 1H), 3.75 (br s, 1H), 3.92 (m,
4H), 5.23 (s, 2H), 7.29 (dd, 1H), 7.37-7.54 (m, 9H), 7.67 (s,
1H), 7.88 (d, 1H), 7.93 (s, 1H), 8.59 (s, 1H); HRMS (C29H26O5
+ H+) calcd 455.1860, found 455.1858.
9k . To a solution of tetrazole 8i (175 mg, 0.61 mmol) in
DMF (4 mL) were added 80% NaH dispersed in oil (38 mg,
1.5 mmol) and, 30 min later, benzylic halide 6a (182 mg, 0.67
mmol), and the mixture was stirred at room temperature for
18 h. The mixture was partitioned between water and EtOAc
and the mixture of alkylated products chromatographed on
silica gel (hexane/EtOAc, 1:1, + 0.5% AcOH) to afford the
desired 9k (31 mg, 10%) as a white solid: mp 205-206 °C; 1H
NMR (250 MHz, acetone-d6) δ 1.65 (m, 2H), 2.10 (m, 2H), 3.85
(m, 4H), 5.30 (s, 2H), 7.35 (dd, 1H), 7.40-7.60 (m, 8H), 7.65
(d, 1H), 7.75 (s, 1H), 7.85 (d, 1H), 7.95 (d, 1H), 8.60 (s, 1H);
HRMS (C29H26N4O3 + H+) calcd 479.2083, found 479.2082.
9n . To a suspension of 60% NaH dispersed in oil (218 mg,
5.45 mmol) in DMF (10 mL) were added (chloromethyl)-
9m : white solid; mp 209-210 °C; 1H NMR (250 MHz, CDCl3)
δ 1.70 (m, 2H), 1.80 (s, 1H), 2.20 (m, 2H), 3.90 (m, 4H), 4.25
(s, 3H), 5.20 (s, 2H), 7.30 (dd, 1H), 7.35-7.50 (m, 9H), 7.60 (d,
1H), 7.65 (s, 1H), 7.90 (d, 1H), 8.15 (s, 1H).
9o: cream-colored solid; mp 144-145 °C; IR (KBr) 3480,
2230, 1625, 1500 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.54 (m,
2H), 2.18 (m, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 6.65 (s, 1H), 7.28
(m, 2H), 7.34-7.55 (m, 5H), 7.65 (m, 2H), 8.08 (m, 2H).
9p : white solid; mp 155-157 °C; 1H NMR (250 MHz, CDCl3)
δ 1.70 (m, 2H), 1.85 (s, 1H), 2.20 (m, 2H), 3.90 (m, 4H), 4.45
(s, 3H), 5.20 (s, 2H), 6.75 (s, 1H), 7.25 (dd, 1H), 7.30-7.50 (m,
4H), 7.60 (t, 1H), 7.65 (s, 1H), 7.70 (s, 1H), 8.10 (m, 2H), 8.50
(s, 1H).
9q: pale yellow foam; 1H NMR (250 MHz, DMSO-d6) δ 1.55
(m, 2H), 2.00 (m, 2H), 3.75 (m, 4H), 4.15 (t, 2H), 4.80 (t, 2H),
5.30 (s, 2H), 6.90 (s, 1H), 7.40 (m, 4H), 7.65 (s, 1H), 7.75 (d,
1H), 7.90 (m, 2H), 8.10 (m, 2H), 8.50 (s, 1H).
1
9r : yellow solid; H NMR (250 MHz, DMSO-d6) δ 1.55 (m,
2H), 2.00 (m, 2H), 3.50 (t, 2H), 3.75 (m, 4H), 4.45 (t, 2H), 5.10
(s, 1H), 5.25 (s, 2H), 6.85 (s, 1H), 7.30-7.50 (m, 4H), 7.65 (s,
1H), 7.75 (m, 2H), 7.90 (t, 1H), 8.00 (m, 2H), 8.15 (s, 1H).
9s: yellow foam; 1H NMR (250 MHz, CDCl3) δ 1.40 (s, 6H),
1.70 (m, 2H), 2.20 (m, 2H), 3.90 (m, 4H), 4.20 (s, 2H), 5.20 (s,
2H), 6.70 (s, 2H), 7.30 (m, 2H), 7.45 (m, 3H), 7.55 (t, 1H), 7.65
(m, 2H), 7.90 (s, 1H), 8.05 (d, 1H), 8.30 (s, 1H).
9t: white solid; mp 165-167 °C; 1H NMR (250 MHz, CDCl3)
δ 1.70 (m, 3H), 2.20 (m, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 6.75
(s, 1H), 7.25 (dd, 1H), 7.35-7.50 (m, 6H), 7.60 (t, 1H), 7.65 (s,
1H), 7.75 (s, 1H), 7.95 (d, 1H), 8.10 (m, 3H), 8.40 (s, 1H).
9v: pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 1.75
(m, 3H), 2.20 (m, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 6.70 (s, 1H),
7.25-7.80 (m, 11H), 8.10 (d, 1H), 8.75 (m, 1H), 8.85 (m, 1H);
HRMS (C32H27NO5 + H+) calcd 506.1968, found 506.1970.
9w : yellow foam; 1H NMR (250 MHz, CDCl3) δ 1.70 (m,
2H), 2.20 (m, 2H), 3.90 (m, 4H), 5.25 (s, 2H), 6.75 (s, 1H), 7.35
(dd, 1H), 7.45 (m, 3H), 7.60 (t, 1H), 7.68 (s, 1H), 7.72 (s, 1H),
7.75 (d, 1H), 8.10 (m, 3H), 8.22 (d, 1H), 9.10 (s, 1H).
9x: pale yellow foam; 1H NMR (250 MHz, CDCl3) δ 1.65
(m, 2H), 2.20 (m, 2H), 3.90 (m, 4H), 4.50 (s, 2H), 5.20 (s, 2H),
6.70 (s, 1H), 7.25 (m, 5H), 7.40-7.70 (m, 7H), 8.00 (d, 1H).
9y: yellow foam; 1H NMR (250 MHz, CDCl3) δ 1.00 (t, 3H),
1.45 (m, 2H), 1.75 (m, 4H), 2.20 (m, 2H), 3.05 (m, 2H), 3.90
(m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 7.30-7.50 (m, 5H), 7.65 (s,
1H), 7.75 (s, 1H), 7.95 (d, 1H), 8.30 (s, 1H).
9z: pale yellow solid; 1H NMR (250 MHz, CDCl3) δ 1.70 (m,
2H), 1.75 (s, 1H), 2.20 (m, 2H), 3.90 (m, 4H), 3.95 (s, 3H), 4.45
(s, 2H), 5.20 (s, 2H), 7.15-7.50 (m, 10H), 7.60 (s, 1H), 7.80 (d,
1H), 7.90 (d, 1H), 8.40 (s, 1H).
9a a : yellow solid; 1H NMR (250 MHz, CDCl3) δ 1.70 (m,
2H), 2.20 (m, 2H), 3.15-4.00 (m, 4H), 4.75 (s, 2H), 5.20 (s, 2H),
7.20 (dd, 1H), 7.25-7.85 (m, 13H).
1
9a b: yellow foam; H NMR (250 MHz, CDCl3) δ 1.70 (m,
3H), 2.20 (m, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 6.70 (s, 1H), 7.40
(m, 4H), 7.50 (m, 1H), 7.60 (t, 1H), 7.65 (s, 1H), 7.70 (s, 1H),
7.80 (s, 1H), 8.10 (d, 1H), 8.20 (s, 1H), 10.2 (s, 1H).
1
9a c: pale yellow solid; H NMR (250 MHz, CDCl3) δ 2.05
(dd, 2H), 2.30 (d, 1H), 2.50 (dd, 1H), 3.80 (m, 1H), 3.95 (s, 1H),
4.50 (d, 1H), 4.70 (m, 1H), 5.20 (m, 1H), 5.80 (s, 1H), 6.65 (s,
1H), 7.20-7.70 (m, 9H), 8.10 (m, 2H); HRMS (C28H23NO5
+
H+) calcd 454.1654, found 454.1655.
9b. To a solution of ester 9h (500 mg, 1.07 mmol) in THF
(20 mL) at -78 °C was added 1 M diisobutylaluminum hydride
in toluene (3.5 mL). The mixture was stirred at -78 °C for 1
h; then the reaction was quenched with 10% aqueous HCl and
the mixture extracted with ether. The extracts were washed
with aqueous HCl and then water, dried, and evaporated.
Chromatography on silica gel (hexane/EtOAc, 2:3) gave 9b as
a white foam (385 mg, 82%): 1H NMR (250 MHz, CDCl3) δ
1.90 (t, 1H), 2.20 (m, 2H), 3.90 (m, 4H), 4.85 (d, 2H), 5.20 (s,

Naphthalenenitriles as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3969
Drazen, J . M. The Pivotal Role of 5-Lipoxygenase Products in
the Reaction of Aspirin-sensitive Asthmatics to Aspirin. Am. Rev.
Respir. Dis. 1993, 148, 1447-1451. (c) Israel, E.; Dermarkarian,
R.; Rosenberg, M.; Sperling, R.; Taylor, G.; Rubin, P.; Drazen,
J . F. The Effects of a 5-Lipoxygenase Inhibitor on Asthma
Induced by Cold, Dry Air. N. Engl. J . Med. 1990, 323, 1740-
1744. (d) Bel, E. H.; Tanaka, W.; Spector, R.; Friedman, B.; von
de Veer, H.; Diijkman, J . H.; Sterk, P. J . MK-886, an Effective
Oral Leukotriene Biosynthesis Inhibitor on Antigen-Induced
Early and Late Asthmatic Reactions in Man. Am. Rev. Respir.
Dis. 1990, 141, A31.
naphthalene 9a a (250 mg, 0.54 mmol) and imidazole (186 mg,
2.73 mmol). The mixture was stirred at room temperature
for 18 h and then partitioned between water and EtOAc. The
residue obtained from the organic phase was chromatographed
on silica gel (CH2Cl2/MeOH, 95:5) to afford 9n (171 mg, 64%)
as a white solid: mp 172-174 °C; 1H NMR (400 MHz, acetone-
d6) δ 1.64 (d, 2H), 2.10 (m, 2H), 3.76 (m, 2H), 3.90 (m, 2H),
4.10 (s, 1H), 5.29 (s, 2H), 5.44 (s, 2H), 6.95 (s, 1H), 7.17-7.27
(m, 3H), 7.37-7.56 (m, 9H), 7.66 (s, 1H), 7.75 (m, 3H).
9u . Step 1. To a solution of aldehyde 9a b (250 mg, 0.58
mmol) in THF at -78 °C was added 2 M phenylmagnesium
bromide in ether (0.8 mL, 1.6 mmol). The mixture was stirred
at -78 °C for 20 min; then the reaction was quenched with
saturated aqueous NH4Cl and the mixture partitioned between
ether and water. Chromatography of the organic residue on
silica gel (hexane/EtOAc, 2:3) afforded the desired tertiary
alcohol as an oil (244 mg, 82%): 1H NMR (250 MHz, CDCl3) δ
1.6 (s, 1H), 1.70 (m, 2H), 2.20 (m, 2H), 2.35 (d, 1H), 3.90 (m,
4H), 5.20 (s, 2H), 6.00 (d, 1H), 6.65 (s, 1H), 7.20 (dd, 1H), 7.25-
7.50 (m, 10H), 7.55 (t, 1H), 7.60 (s, 1H), 7.65 (s, 1H), 7.75 (s,
1H), 8.00 (d, 1H).
Step 2. To a solution of alcohol from step 1 (230 mg, 0.45
mmol) in CH2Cl2 (15 mL) at room temperature were added
dry powdered 4 Å molecular sieves (500 mg) and pyridinium
chlorochromate (300 mg, 1.4 mmol). After stirring for 30 min,
the mixture was filtered through a short pad of silica gel,
eluting with ether. The eluate was chromatographed on silica
gel (hexane/EtOAc, 2:3) to afford 9u as a pale yellow foam (180
mg, 78%): 1H NMR (250 MHz, CDCl3) δ 1.6 (s, 1H), 1.70 (m,
2H), 2.20 (m, 2H), 3.90 (m, 4H), 5.20 (s, 2H), 6.70 (s, 1H), 7.35-
7.65 (m, 10H), 7.70 (s, 1H), 7.80 (d, 1H), 7.90 (m, 2H), 8.10
(m, 2H).
(5) (a) Ducharme, Y.; Brideau, C.; Dube´, D.; Chan, C.-C.; Falgueyret,
J .-P.; Gillard, J . W.; Guay, J .; Hutchinson, J . H.; McFarlane, C.
S.; Riendeau, D.; Scheigetz, J .; Girard, Y. Naphthalenic Lignan
Lactones as Selective, Non-redox 5-Lipoxygenase Inhibitors.
Synthesis and Biological Activity of (Methoxyalkyl) thiazole and
Methoxytetrahydropyran Hybrids. J . Med. Chem. 1994, 37, 512-
518. (b) Falgueyret, J .-P.; Denis, D.; Macdonald, D.; Hutchinson,
J . H.; Riendeau, D. Characterization of the Arachidonate and
ATP Binding Sites of Human 5-Lipoxygenase Using Photoaf-
finity Labeling and Enzyme Immobilization. Biochemistry 1995,
34, 13603-13611.
(6) Following oral administration of lignan lactone 2 to rats as a
solution of its bioavailable carboxylate form 1 in 0.5% methocel
at a dose of 50 mg/kg, HPLC analysis of plasma samples revealed
that the maximum concentration (Cmax) reached by parent
compound 2 was 4 µM (1 h postdosage). Alcohol 3a was detected
in the same samples with a Cmax of 14 µM at 2 h postdosage.
(7) (a) Chauret, N.; Li, C.; Ducharme, Y.; Trimble, L. A.; Yergey, J .
A.; Ramachandran, C.; Nicoll-Griffith, D. A. In Vitro and In Vivo
Biotransformations of the Naphthalenic Lignan Lactone 5-Li-
poxygenase Inhibitor, L-702,539. Drug. Metab. Dispos. 1995, 23,
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P r ep a r a t ion of Sod iu m Ca r b oxyla t es 10. 10a .
A
mixture of lactone 3a (401 mg, 0.86 mmol) and 1 N aqueous
sodium hydroxide (0.95 mL, 0.95 mmol) was refluxed in
ethanol (7 mL) for 2 h. Evaporation of the resulting solution
afforded a residue which was dissolved in water (5 mL).
Lyophilization yielded the desired carboxylate 10a (443 mg)
as an off-white solid: 1H NMR (250 MHz, DMSO-d6) δ 1.56
(m, 2H), 1.98 (m, 2H), 3.75 (m, 4H), 4.17 (d, 2H), 5.09 (s, 1H),
5.21 (s, 2H), 7.0-7.6 (m, 11H), 7.65 (s, 1H), 7.95 (br s, 1H),
8.05 (s, 1H).
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The following compounds were prepared according to an
analogous procedure Synthetic and physical data for carboxy-
lates 10 are presented in Table 3.
10f: white solid; 1H NMR (250 MHz, DMSO-d6) δ 1.1 (d,
6H), 1.4-1.7 (m, 4H), 3.8 (m, 2H), 4.2 (d, 2H), 5.1 (m, 1H), 5.2
(s, 2H), 7.1 (q, 1H), 7.2 (d, 1H), 7.3-7.7 (m, 8H), 7.9 (d, 1H),
8.0 (s, 1H), 8.5 (s, 1H).
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10h : pale yellow solid; 1H NMR (250 MHz, DMSO-d6) δ 1.75
(m, 4H), 2.10 (dd, 2H), 2.33 (d, 2H), 4.17 (d, 2H), 4.37 (br s,
2H), 4.99 (s, 1H), 5.19 (s, 2H), 7.03-7.54 (m, 12H), 7.87 (t,
1H), 8.06 (s, 1H).
1
10u : white solid; H NMR (300 MHz, DMSO-d6) δ 1.8 (d,
1H), 2.0 (dq, 2H), 2.2 (dd, 1H), 3.6 (t, 1H), 4.3 (br s, 2H), 4.4
(d, 1H), 4.6 (t, 1H), 5.1 (s, 1H), 5.2 (s, 2H), 5.6 (s, 1H), 6.6 (s,
1H), 7.1 (dd, 1H), 7.3-7.4 (m, 3H), 7.4 (d, 1H), 7.5 (d, 1H), 7.6
(s, 1H), 7.7 (s, 1H), 7.9 (t, 1H), 8.0 (s, 1H).
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