Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase

Article abstract of DOI:10.1021/jm9701942

The first successful preparation of mono- and disubstituted 3,7- dihydroxytropolone involves a four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by permethylation of the resultant products furnished gram quantities of intermediates 13-18. Single or double Suzuki coupling reactions between these permethylated monobromo- and dibromodihydroxytropolone derivatives and a variety of boronic acids delivered the expected products whose deprotection yielded the desired compounds 1a-u and 26a-n, usually in fair to good yields. Tropolones 1 and 26 were found to be potent inhibitors of inositol monophosphatase with IC₅₀ values in the low-micromolar range. The results are discussed in the context of the recently described novel mode of inhibition of the enzyme by 3,7- dihydroxytropolones.

Full text of DOI:10.1021/jm9701942

4208
J . Med. Chem. 1997, 40, 4208-4221
Mon oa r yl- a n d Bisa r yld ih yd r oxytr op olon es a s P oten t In h ibitor s of In ositol
Mon op h osp h a ta se†
Serge R. Piettre,* Catherine Andre´, Marie-Christine Chanal, J ean-Bernard Ducep, Brigitte Lesur,
Franc¸ois Piriou, Pierre Raboisson, J ean-Michel Rondeau, Charles Schelcher, Pascale Zimmermann, and
Axel J . Ganzhorn
Marion Merrell Research Institute, 16 rue d’Ankara, F-67080 Strasbourg, France‡
Received March 21, 1997X
The first successful preparation of mono- and disubstituted 3,7-dihydroxytropolone involves a
four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by
permethylation of the resultant products furnished gram quantities of intermediates 13-18.
Single or double Suzuki coupling reactions between these permethylated monobromo- and
dibromodihydroxytropolone derivatives and a variety of boronic acids delivered the expected
products whose deprotection yielded the desired compounds 1a -u and 26a -n , usually in fair
to good yields. Tropolones 1 and 26 were found to be potent inhibitors of inositol monophos-
phatase with IC50 values in the low-micromolar range. The results are discussed in the context
of the recently described novel mode of inhibition of the enzyme by 3,7-dihydroxytropolones.
In tr od u ction
ies have been conducted, thus refining both the knowl-
edge of the active site and the mechanistic features of
substrate hydrolysis.8 IMPase is a homodimer of 30-
kDa subunits, each of them requiring at least two
magnesium ions for activation.8 The active site is rather
large and potentially able to accommodate bulky mol-
ecules, a proposal that has been experimentally con-
firmed.9 It is believed that hydrolysis of the phosphate
occurs through the direct attack of a molecule of water
via activation by a glutamic acid residue.7b An alterna-
tive mechanism of hydrolysis, involving in-line attack
of another water molecule, has also been discussed.8e
Among the noncompetitive or competitive inhibitors
of the enzyme reported in the literature, the most potent
are the bisphosphonic acids.5a However, these com-
pounds do not efficiently cross the blood-brain barrier,
and their prodrugs are characterized by a very low
bioavailability.10
Inositol monophosphatase (IMPase, EC 3.1.3.25) hy-
drolyzes all inositol monophosphates produced by the
dephosphorylation of inositol polyphosphates in the
phosphoinositide cycle or by the de novo synthesis from
glucose-6-phosphate.1 The past decade has witnessed
an upsurge of interest in the enzyme following the
discovery that it is inhibited by lithium at concentra-
tions similar to those used in the treatment of manic
depressive patients and the suggestion by Berridge that
it might be the actual target of lithium therapy.2
Lithium is remarkable as a drug in that it acts on the
manic phase of the illness by normalizing the mood of
patients rather than sedating them. It is perhaps the
only drug for which clear prophylaxis has been demon-
strated in the central nervous system.3 However,
despite the undisputable value of lithium as a drug, a
number of issues detract from its utility.4 It has a
narrow therapeutic window, and various side effects
ranging from mild to serious have been reported over
the years. These include weight gain, tremor, and
memory impairment, as well as kidney failure, decom-
pensation of cardiac status, and transient leukocytosis.
In addition, for reasons unclear at the present time, it
takes between 7 and 10 days for lithium to exert its
antimanic effect; as a result, other antipsychotic drugs
are needed during that period of time. The narrow
therapeutic window of lithium requires monitoring
plasma drug concentration, a costly procedure. Hence,
several laboratories have searched for other inhibitors
of IMPase in the hope of developing a drug which would
lack the spectrum of side effects associated with lithium
therapy.5
We recently reported that 3,7-dihydroxytropolone (1,
R ) H) is the foremost representative of a new class of
potent, competitive inhibitors of inositol monophos-
phatase.11 These compounds interact with the active
site in such a way that three oxygens of the seven-
membered ring are effective chelators of the two mag-
nesium ions. Modeling studies carried out on the
structure of the enzyme-substrate complex showed that
three contiguous oxygens of the ring superimpose
perfectly with the ester oxygen of inositol monophos-
phate, the phosphate oxygen which chelates both metal
ions M1 and M2, and a molecule of water believed to be
the nucleophile responsible for the hydrolysis of the
phosphate function (Figure 1). The finding that analo-
gous six-membered rings were inactive demonstrates
the uniqueness of hydroxytropolones as inhibitors of
IMPase. Attempts to increase the potency of the parent
dihydroxytropolone would require derivatizing it. The
The human enzyme has been cloned and expressed.6
Several structures, determined by X-ray crystallogra-
phy, have been published,7 and numerous kinetic stud-
† Dedicated to the memory of Dr. Zdenek J anousek.
* Address for correspondence: University of Rouen, Faculte´ des
Sciences, IRCOF-UPRES A 6014, rue Tesnie`re, F-76821 Mont Saint
Aignan, France. Phone: (33) 235-52-29-70. Fax: (33) 235-52-24-11.
E-mail: Serge.Piettre@osiris.univ-rouen.fr.
‡ Now Synthe´labo Biomole´culaire, same address.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
S0022-2623(97)00194-5 CCC: $14.00 © 1997 American Chemical Society

Potent Inhibitors of Inositol Monophosphatase
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4209
Sch em e 1
Sch em e 2
size of the active site of the enzyme is large enough to
accommodate bulky groups, and additional interactions5
with the amino acid residues can be expected. On the
basis of modeling studies, we were especially interested
in preparing and testing diverse functionalized aryldihy-
droxytropolones (1, R ) aryl). In this paper, we describe
the chemistry developed to prepare 4-mono- and 4,6-
disubstituted 3,7-dihydroxytropolones and their activity
as inhibitors of IMPase.
Ch em istr y
Work describing the use of 2 in Suzuki coupling
reactions suggested it could be a convenient means to
reach our target molecules.12,16 This would be possible
only if the additional hydroxyl groups can be efficiently
introduced. Such a transformation is in principle pos-
sible through sequential bromination of the aryltropolo-
ne, acetolysis of the resultant bromo derivative using
Takeshita’s reagent (ATA; see below),17 and hydrolysis
of the subsequent polyacetate, as shown in Scheme 1
(steps C-E). Only one hydroxyl group at a time can be
introduced since direct dibromination of tropolones is
known to occur in R and γ positions.18 Thus, six steps
are needed to introduce the two hydroxyl groups.
sequence of reactions was needed for the introduction
of the fourth oxygen led us to consider an alternative
route.
Thus, reversing the synthetic sequence (i.e., introduc-
ing the hydroxyl groups on the seven-membered ring
first and carrying out the Suzuki coupling reaction at
the end) would not only shorten the synthesis but also
make the preparation more convergent (Scheme 2).19
The known and readily available 3,7-dihydroxytropolone
(8) was chosen as the ideal starting material for the
sequence. This compound is easily prepared in three
steps from commercially available tropolone by double
bromination, acetolysis, and hydrolysis of the resultant
triacetates.11,17b,20
The feasibility of this synthetic route was tested on
the 7-phenyl and 7-(p-methoxyphenyl) derivatives 3a,b.16
Demethylation was achieved with HCl in methanol to
give tropolones 4a (86% yield) and 4b (99% yield),
respectively. Bromination using N-bromosuccinimide
furnished a 4:1 to 3:2 mixture of the expected bro-
motropolones 5a ,b and the corresponding 3,5-dibro-
mides. The desired monobromo derivatives were iso-
lated in only 32% and 45% yield after chromatographic
purification. Treatment with a 20:2:1 mixture of acetic
anhydride/trifluoroacetic acid/acetic acid (ATA)17 led to
the isolation of diacetates 6a ,b (57% and 50% yield,
respectively). Hydrolysis of the acetate functions in hot
aqueous acetic acid produced the hydroxytropolones
7a ,b (51% and 39% yield, respectively). The low overall
yield of the sequence (8% from 3a to 7a and 9% from
3b to 7b) coupled with the fact that a second, similar
Bromination of 8 proved to be more challenging than
expected. It was soon discovered that the desired
4-bromo-3,7-dihydroxytropolone (9) was more reactive
toward brominating agents than the starting material
8, thus yielding significant amounts of dibromide 10.
Considerable effort was spent to find conditions which
would maximize the amount of 9 at the expense of 10.
In the end it was found that slow addition (5.5 h) of an
acetone solution of N-bromosuccinimide (NBS) to a
cooled (-15 °C) solution of 3,7-dihydroxytropolone (8)
in dry dimethylformamide (DMF) and stirring at the
same temperature for an additional 16 h reproducibly
led to a 47:43:10 mixture of unconsumed starting
material 8/monobromo derivative 9/dibromo derivative
10 (Scheme 3).

4210 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Piettre et al.
Sch em e 3a
a
(i) NBS (slow addition), -20 °C; (ii) CH2N2, 0 °C.
Permethylation of model 3,7-dihydroxytropolone (8)
was next studied. Classical methylation reactions (e.g.,
using methyl iodide under basic conditions) led to
unreproducible results and low yields of isolated per-
methylated products. On the other hand, reaction with
freshly prepared diazomethane at 0 °C proceeded
smoothly to produce the desired compounds (two iso-
mers) in 89% isolated yield. Thus, reaction of the crude
mixture from bromination as described above with
excess diazomethane at 0 °C furnished, after workup,
a mixture of permethylated isomeric trimethoxytropones
11 and 12, bromotrimethoxytropones 13-16, and di-
bromotrimethoxytropones 17 and 18 (Scheme 3).21
Chromatographic separation led to the isolation of all
eight products in the pure form. Trimethoxytropones
11 and 12 could be deprotected (vide infra) and recycled.
This somewhat tedious procedure nevertheless permit-
ted the preparation of the desired monobromo and
dibromo compounds in gram quantities. Structural
The relative reactivity of all four isomeric monobromo
derivatives 13-16 in the Suzuki coupling reaction was
next studied in parallel experiments using p-(trifluo-
romethyl)phenylboronic acid. Isomers 13-15 displayed
essentially identical behavior under standard conditions
(10% Pd[P(Ph)3]4, toluene-ethanol, Na2CO3, 110 °C, 16
h), affording the desired products 19d , 20c, and 21b
(85-90% isolated yields). Isomer 16, however, yielded
1
assignment of all eight isomers was achieved using H
and 13C NMR in 1-D and 2-D modes at 500 and 125
MHz, respectively. Heteronuclear multiple quantum
correlation (HMQC) and heteronuclear multiple bond
correlation (HMBC) were run to establish direct and
long-range 13C-1H connectivities.22 These studies re-
sulted in the unambiguous assignment of all isomers
to the structures depicted in Scheme 3 and are exempli-
fied by the monobromo derivatives 13 to 16. Thus, the
proton in the R position to the brominated carbon was
always found at a lower field than the other proton, due
to the combined effects of the Br and OMe substituents
(or CO in structure 16); in addition both were charac-
terized by a geminal H-H coupling (3J ) 13 Hz). The
patterns obtained from the HMBC spectra clearly
indicated the geminal (2J ) and vicinal (3J ) couplings. For
instance, the 2-D spectrum of compound 14 was the only
one displaying no coupling pattern for carbon 1 (CdO);
in addition it showed 3J couplings for two C-OMe
the expected coupled product 22b in much lower yield
(37%) along with the biphenyl derivative 23 (9% yield),
the result of a nucleophilic addition reaction of ethanol
followed by ring contraction. In another analogous
experiment, the ratio was reversed (26% yield of 23 and
5% yield of 22b).24 The structure of compound 23 was
determined by the method used for tropones 11-18, as
described above. Carrying out the experiment in the
absence of ethanol yielded the desired product 22b in
83% yield. These experiments demonstrate that all four
regioisomeric tropones 13-16 possess virtually identical
reactivities in the Suzuki coupling reaction.
A number of coupling reactions between either the
model compound 2, or any of the four monobrominated
compounds 13-16, and diversely functionalized boronic
acids, or boranes, were carried out using the standard
conditions described above to produce the corresponding
aryl derivatives 3, 19, 20, 21, or 22. The yields were in
most cases fair to good, thus demonstrating the flex-
ibility of the synthetic method (Table 1).25 It should be
2
3
(carbons 2 and 7) and J and J couplings for the C-Br
(carbon 6) and only one C-OMe (carbon 3). An analo-
gous analysis was carried out for each compound.
Attempts to selectively monodebrominate the isomeric
permethylated dibromo derivatives 17 and 18 using a
variety of reagents did not succeed.23

Potent Inhibitors of Inositol Monophosphatase
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4211
Ta ble 1. Yields of the Suzuki Coupling Reactions and of the Deprotection Step
starting Suzuki yields deprotected
yields
(%)
material reaction product
R
(%)
product
R
2
14
2
3a
20a
3c
C6H5
C6H5
C6H5-C6H4
94
67
78
91
50
69
70
69
50
62
50
83
88
89
37c
64
95
75
59
70
87
76
57
42
42
28
64
55
52
4a
1a
4c
4b
1b
1b
4d
1b
1c
1d
1e
1f
C6H5
C6H5
C6H5-C6H4
86a
79
b
2
3b
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-BnO-C6H4
p-BnO-C6H4
o,m′-(MeO)2-C6H3
o-F-C6H4
m-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
m,m-(F3C)2-C6H3
o-OHC-C6H4
m-OHC-C6H4
m-OHC-C6H4
m-OHC-C6H4
m-OHC-C6H4
m-NC-C6H4
m-NC-C6H4
m-MeCONH-C6H4
m-BocNH-CH2-C6H4
p-[(C6H5)2CdNd(CH2)2]-C6H4
m-NO2-C6H4
1-naphthyl
2-naphthyl
m-[5-(2-naphthyl)-2-oxadiazolyl]phenyl 38
m-[7-(2-methoxy)troponyl]-C6H4
2-benzofuryl
2-thienyl
3-thienyl
p-MeO-C6H4
p-HO-C6H4
p-HO-C6H4
p-HO-C6H4
p-HO-C6H4
o,m-(HO)2-C6H3
o-F-C6H4
m-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
p-F3C-C6H4
m,m-(F3C)2-C6H3
o-OHC-C6H4
m-OHC-C6H4
m-OHC-C6H4
m-OHC-C6H4
m-OHC-C6H4
m-NC-C6H4
m-NC-C6H4
m-MeCONH-C6H4
m-NH2-CH2-C6H4
95a
49
b
13
15
2
19a
21a
3d
78
95
40
88
70
b
80
b
b
68
d
82
63
b
14
13
13
16
13
14
15
16
14
2
20b
19b
19c
22a
19d
20c
21b
22b
20d
3e
1f
1f
1f
1g
4e
4f
1h
1h
1h
4g
1i
1j
1k
1l
1m
1n
1o
1p
4h
1q
1r
2
3f
13
15
16
2
14
14
13
13
14
14
14
14
2
13
13
13
2
14
2
19e
21c
22c
3g
20e
20f
19f
19g
20g
20h
20i
20j
3h
19h
19i
19j
3i
19k
3j
b
96
74
49
d
82
52
82
98
p-[H2N-(CH2)2]-C6H4
m-NO2-C6H4
1-naphthyl
2-naphthyl
m-[5-(2-naphthyl)-2-oxadiazolyl]phenyl 92
45
46
19
88
30
37
38
31
31
m-[7-(2-methoxy)troponyl]-C6H4
2-benzofuryl
2-thienyl
3-thienyl
5-pyrimidyl
5-pyrimidyl
n-C8H17
HO-(CH2)4-
HO-(CH2)5-
b
63
81
58
85
25
b
1s
4i
1t
4j
1u
1v
5-pyrimidyl
5-pyrimidyl
n-C8H17
t-BuMe2SiO-(CH2)4-
t-Bu(C6H5)2SiO-(CH2)5-
14
14
20k
20l
30
d
a
b
d
HCl or MeONa in methanol (see Experimental Section). Not carried out. c A byproduct was also isolated (see text). Not successful.
noted that careful chromatographic purification at this
stage is very important since the dihydroxytropolones
produced in the next step proved to be very difficult to
purify by any means (vide infra).
functions. Deprotection of the benzylidenimine moiety
present in 19g also occurred as expected, thereby
delivering the amine. Compound 4e (R ) o-CHO-C6H4)
was not observed, and the tricyclic product that would
presumably form during the last step could not be
isolated, or even detected.27 Product 1k (R ) H2NCH2-
C6H4) was formed but could not be purified.28
The aldehyde group of product 3f was reacted with
hydroxylamine and benzylhydroxylamine to give the
expected oximes 3k (R ) m-HO-NdCH-C6H4) and 3l (R
) m-BnO-NdCH-C6H4) in excellent yields (93% and
96% yield, respectively). However, deprotection of the
tropolonic methyl ether functions with TMSI simulta-
neously resulted in the transformation of the oxime into
a nitrile group, thus producing product 4g instead (72%
and 77% isolated yield, respectively). Reaction between
tropolone 4f and hydroxylamine hydrochloride under
basic conditions slowly converted the starting aldehyde
into the corresponding oxime 4k (R ) m-HO-NdCH-
C6H4) in quantitative yield. Application of this proce-
dure to dihydrotropolone derivative 1h also resulted in
the formation of the desired oxime 1w (R ) m-HO-
NdCH-C6H4) along with a byproduct. However puri-
fication was not readily achieved.
Introduction of only one aryl group (using p-meth-
oxyboronic acid) on a dibromotropolone derivative (2-
methoxy-3,7-dibromotropone, 24a ) was attempted but
resulted instead in the isolation of the bisaryl derivative
24b as the major product (30% yield), the desired
monoaryl derivative 24c being isolated in only 7% yield.
The deprotection step was worked out on a mixture
of isomeric permethylated dihydroxytropolones 11 and
12. It was found that treatment with an excess of
trimethylsilyl iodide in dry acetonitrile at 80 °C, evapo-
ration of the volatiles (including any HI that might have
formed), and hydrolysis of the crude material thereby
formed resulted in the isolation of the desired 3,7-
dihydroxytropolone (8) in virtually quantitative yield.26
These conditions were successfully used in most of the
cases described in Table 1 and show the tolerance for
many functional groups. The reported isolated yields
are unoptimized. The deprotection step usually works
well; however, the compounds produced are character-
ized by low solubility in most organic solvents or water
and crystallization proved to be very difficult in many
cases. As expected, compounds incorporating additional
methoxy (19a ,b), benzyloxy (3d and 20b), or silyloxy
(20k ) groups underwent complete cleavage of all ether
Reduction of aldehyde 3f was achieved using sodium
triacetoxyborohydride and yielded the desired alcohol
3m (R ) m-HOCH2-C6H4) in 91% yield. Similar condi-
tions applied to aldehydes 21c and 22c furnished the

4212 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Piettre et al.
Ta ble 2. Yields of the Double Suzuki Coupling Reactions and
of the Deprotection Step
Ta ble 3. IC50 Values of Tropolone Derivatives as Inhibitors of
IMPasea
Suzuki
product
IC50 (µM)
product
IC50 (µM)
reaction
product
yield
(%)
deprotected
product
yield
(%)
L-690,330a
8
0.8
10
1q
1r
7
15
R
p-MeO-C6H4
o-F-C6H4
m-F3C-C6H4
p-F3C-C6H4
m,m-(F3C)2-C6H3
m-OHC-C6H4
m-NC-C6H4
m-MeCONH-C6H4
m-NO2-C6H4
1-naphthyl
25a
25b
25c
25d
25e
25f
25g
25h
25i
25j
25k
25l
77
89
90
93
81
71
68
41
68
100
81
45
26a a
26b
26c
26d
26e
26f
26g
26h
26i
99
53
30
76
86
87
70
27
35
79
76
25
7a
27d
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1l
200
>200
10
1s
1t
1u
25
10
5
10
20
10
7
65
10
130
10
20
4
20
90
8
20
26a
26b
26c
26d
26e
26f
26g
26h
26i
26j
26k
26l
26m
26n
>200
>200
200
70
>100
26j
26k
26l
30
65
20
2-naphthyl
m-[5-(2-naphthyl)-2-
oxadiazolyl]phenyl
2-benzofuryl
3-thienyl
>100
>100
>200
40
25m
25n
15
60
26m
26n
73
98
1m
1n
1o
1p
a
R ) p-HO-C6H4.
>100
35
40
corresponding alcohols 21d and 22d (R ) m-HOCH2-
C6H4) in 66% and 50% yield, respectively.
a
See ref 5a. Rates were determined in duplicate using six
concentrations of compound in addition to a control without
inhibitor and fitted by the equation v ) V0/(1 + [I]/IC50) for
competitive inhibition, where V0 is the uninhibited rate and [I] is
the concentration of inhibitor. Standard deviations for the fitted
parameters were below 20%. IC50 values from separate experi-
ments differed by less then 2-fold.
We next focused our attention on the possibility of
carrying out a double Suzuki coupling reaction on the
dibromo derivatives 17 and 18, with the intention of
producing 4,6-disubstituted-3,7-dihydroxytropolones (26).
Dibromination of 3,7-dihydroxytropolone (8) could be
achieved by using NBS in refluxing CCl4. Several
washings of the crude solid with water afforded 4,6-
dibromo-3,7-dihydroxytropolone (10) with an overall
yield of 75%. Permethylation was readily achieved
using a slight excess of diazomethane to furnish a 1:4
mixture of compounds 17 and 18, identical with the
compounds isolated before (vide supra). Double Suzuki
coupling reaction was performed on 18 using the same
conditions as above, but with 2.2 equiv of boronic acid,
and was found to deliver the expected bisaryl derivatives
25 in generally good isolated yields. It has to be noted
consider it as a possible entry into the field of ben-
zotropolones characterized by a polyhydroxylated seven-
membered ring (of the type 27c). In addition, the six-
membered ring bromine would potentially be usable for
further diversification via additional Suzuki coupling
reactions. Thus, purpurogallin30 was treated with 2
equiv of bromine in acetic acid to produce 27b (55%
isolated yield). Attempts to transform this material into
the desired hydroxytropolone derivative 27c using clas-
sical methodology (NaOH, copper, sodium â-naphtha-
lenesulfonate in water) yielded only purpurogallin.31
Treatment of 27b with ATA at 100 °C for 24 h provided
tetraacetate 28a and pentaacetate 28b in 20% and 43%
isolated yield, respectively, thus leaving the six-mem-
bered ring bromine untouched. Here again, the struc-
1
ture of the compound was ascertained by using H and
13C NMR in 1-D and 2-D modes at 500 and 125 MHz,
respectively. HMQC and HMBC were also run to
establish direct and long-range 13C-1H connectivities.22
However, hydrolysis of 28b in a mixture of acetic acid
and water at 100 °C furnished 3-hydroxypurpurogallin
(27d ) in 36% isolated yield, the result of concomitant
acetate hydrolysis and brominolysis of 28b.
Biologica l Activities
Table 3 summarizes the IC50 values for tropolone
derivatives as inhibitors of IMPase. The bisphosphonic
acid L-690,330, a known competitive inhibitor, was also
tested and is included in the table as a reference
compound. Its IC50 value of 0.8 µM agrees well with
the published Ki of 0.33 µM.5a The parent compound,
dihydroxytropolone (8), had an IC50 value of 10 µM and
was previously shown to be a competitive inhibitor with
respect to the substrate, inositol 1-phosphate, with a Ki
value of 5 µM.11 Some of the compounds listed in Table
3 were also tested for their mechanism of inhibition.
These included 1e,f as derivatives with meta and para
substituents on the aromatic ring and 1m and 26i as
examples for mono- versus bissubstituted dihydrox-
that compound 25j was isolated as a 1:1 mixture of
rotamers; this mixture was observed even at 353 K.
Deprotection of compounds 25 was achieved in a similar
manner and furnished the target bisaryldihydroxytropo-
lones 26. Here again, the two p-methoxy substituents
(present in compound 25a ) underwent concomitant
deprotection, leading to the isolation of the desired bis-
(p-hydroxyphenyl) derivative 26a . Results are compiled
in Table 2.
Reports29 that commercially available purpurogallin
(27a ) could be dibrominated to produce 27b led us to

Potent Inhibitors of Inositol Monophosphatase
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4213
F igu r e 1. Stereoview of the active site of the inositol monophosphatase complex with Ca2+ and D-inositol 1-phosphate.7d M1,
M2, and M3 are the positions of the three Ca2+ ions. W2 is the potential nucleophilic water molecule.7b Glu-70, Asp-90, Asp-93,
and Asp-220 are metal ion ligands. In our model for the binding of 3,7-dihydroxytropolone, oxygen 2 (superimposed on a phosphate
oxygen) chelates both M1 and M2, oxygen 1 (superimposed on the phosphoester oxygen) chelates M2, and oxygen 3, by displacing
W2, chelates M1 and makes a hydrogen bond with Glu-70. A hydrogen bond between the fourth oxygen and Leu-42 also participates
in the binding. The plane of the molecule was estimated to be around 70° from the mean plane of the inositol ring of D-Ins(1)P,
thereby precluding the third metal ion (M3) from positioning itself in the active site.11
ytropolones. The rate of substrate hydrolysis was
measured in a coupled spectrophotometric assay8g by
varying the concentration of inositol 1-phosphate at
different fixed concentrations of the inhibitor. Plots of
1/rate versus 1/[inositol 1-phosphate] always gave a
series of straight lines that intersected in a common
point on the y-axis, indicating competitive inhibition
with respect to the substrate. Kinetic constants were
determined using the equation for competitive inhibition
and the computer program COMP.32 The following Ki
values were obtained: 5 ( 1 µM (1e), 40 ( 5 µM (1f),
10 ( 1 µM (1m ), 20 ( 2 µM (26i). Equations for
noncompetitive or uncompetitive inhibition could not be
fitted to the experimental data. These results indicate
that the derivatives of dihydroxytropolone described in
this paper follow the same mechanism of inhibition as
their parent compound, i.e., they compete with the
substrate inositol 1-phosphate for binding to the active
site of IMPase.
According to our model of dihydroxytropolone binding
to IMPase, three contiguous oxygen atoms of the seven-
membered ring chelate two active site Mg2+ ions (Figure
1).11 The fourth oxygen makes an interaction with the
main chain carbonyl group of Leu-42. If correct, this
model predicts that substituents in position 4 of the
cycle, as in our series of derivatives, point into a space
that is occupied by inositol in enzyme-substrate com-
plexes. We therefore anticipated that an increase in
affinity may be achieved through the interaction of side
chains in this position with Glu-213, a residue that
contributes a factor of about 20 to the binding interac-
tion with inositol 1-phosphate.7c In particular, a hy-
droxyphenyl side chain, as in 1b, appeared to have
about the right length to reach Glu-213 and form a
hydrogen bond. The lack of any improvement in affinity
as compared to 8 perhaps indicates that our original
model may have to be modified. For example, since
there are four contiguous oxygens, the seven-membered
ring could be rotated by 51° without losing any interac-
tion with the two magnesium ions. In this case, the side
chain in position 4 of the ring would no longer point
toward Glu-213. However, through this rotation the
postulated interaction of the fourth oxygen atom in 8
with Leu-42 would be lost, and another explanation for
the 8-fold increase in affinity of dihydroxytropolone as
compared to monohydroxytropolone would be needed.11
It is not immediately apparent how the enzyme can
accommodate a second aromatic side chain in the active
site (as in 26a ). Our model predicts that an additional
substituent in position 7 would interfere with a enzyme
loop comprising amino acids 36-41. However, residues
30-40 were shown to be completely disordered in the
crystal structure of the apoenzyme, indicating some
flexibility in this area.7c
None of the derivatives synthesized displayed any
significant improvement in affinity as compared to 8.
Some additional observations can be made. Aromatic
side chains are easily accommodated as single substitu-
tions, whereas in most cases some affinity is lost with
the bissubstituted derivatives. This is not always true
though; for example, 26a is just as potent as 1b,
indicating that, in principle, the topology of the active
site allows two aromatic side chains. However, at least
for the symmetrical compounds of this work, there was
no advantage of the bissubstituted over the monosub-
stituted derivatives. It should also be noted that in
many cases of the 26 series, for example 26d or 26l,
solubility problems were encountered above 100 mM.
Another observation is related to the effect of substit-
uents on the phenyl side chain. Substituents in the
meta position (compounds 1e,h ,i,m ) have no effect,
whereas para substituents decrease the affinity, as in
1f. We believe that this is a steric rather than an
electronic effect, since the small hydroxyl group in 1b
does not change the efficacy of inhibition as compared
to 1a .
Con clu sion
A short synthetic scheme has been worked out that
allows for the first time an easy access to diversely
functionalized mono- and disubstituted 3,7-dihydroxy-
tropolones.33,34 These compounds are inhibitors of IM-

4214 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Piettre et al.
Addition of water (40 µL), warming, and a usual workup
furnished an orange oily residue which was subjected to
chromatography. Elution (H/A ) 4:1) afforded 22 mg of
tropone iii (16% yield); this was followed by 28 mg (27%) of
unconsumed starting material. iii: 1H NMR (360 MHz) δ 1.34
Pase with moderate to good affinities. Clearly, more
derivatives will be needed to more thoroughly explore
the structure-activity relationship of these tropolones
as inhibitors of this enzyme. In addition, a more
detailed comprehension of the precise binding mode in
the active site would be greatly helped by a high-
resolution X-ray structure of an enzyme-inhibitor
complex.
3
3
(d, 12H, J ) 6.9), 2.29 (s, 3H), 3.83 (s, 3H), 4.11 (sept, 2H, J
3
3
) 6.8), 6.20 (d, 1H, J ) 10.7), 6.40 (d, 1H, J ) 10.4), 6.75 (t,
1H, 3J ) 10.5); 13C NMR (125 MHz) δ 20.65, 22.97, 49.53,
51.98, 109.83, 123.51, 132.72, 143.61, 155.40, 169.21, 182.53.
Bor on ic Acid s. Gen er a l P r oced u r e. To a vigorously
stirred solution of the starting bromide (10 mmol) in THF (50
mL) cooled at -78 °C was added dropwise n-butyllithium
(6.875 mL of a 1.6 N solution in hexanes). Stirring was
continued for 15 min, and triisopropylborate (5.64 g, 6.92 mL,
30 mmol) was rapidly added. After 1 h of additional stirring
at -78 °C, the mixture was warmed to room temperature and
stirring was continued overnight. A usual workup and evapo-
ration of the dried combined organic phases delivered the crude
material which was subjected to purification when needed.
p-(Ben zyloxy)p h en ylbor on ic Acid . The crude material
(2.28 g) was pure enough to be used in the next step (99%
Exp er im en ta l Section
Unless otherwise stated, materials were obtained from
commercial sources and used without further purification.
Tetrahydrofuran was distilled under nitrogen from sodium/
benzophenone immediately prior to use. Diisopropylamine
and triethylamine were distilled from calcium hydride and
stored under nitrogen over 3-Å molecular sieves. Reactions
involving LDA and TMSI were conducted under an inert
atmosphere. Drying of the organic extract was carried out
using NaSO4. Chromatography was performed using Merck
60 (230-400 ASTM) silica gel according to the procedure
published by Still (abbreviations for the elution solvents are
as follows: H ) heptane, C ) methylene chloride, A ) ethyl
acetate, E ) diethyl ether, T ) toluene).35 Unless otherwise
3
yield): 1H NMR δ 5.18 (s, 2H), 7.12 (d, 2H, J ) 8.4), 7.32-
7.54 (m, 5H), 8.20 (d, 2H, J ) 8.4); MS (TSP+) 246 (MNH4+).
3
o,m ′-Dim eth oxyp h en ylbor on ic Acid . The crude mate-
rial was dissolved in diethyl ether (15 mL), and n-heptane (10
mL) was added. The resultant solution was placed in the cold
for 16 h. Filtration gave the compound in 37% yield (651
mg): 1H NMR δ 3.83 (s, 3H), 3.91 (s, 3H), 6.91 (d, 1H, 3J )
1
stated, H and 19F NMR spectra were recorded in deuterated
chloroform at 200 and 188 MHz, and proton-decoupled 13C
NMR spectra were recorded at 50 MHz; chemical shifts are
expressed in ppm downfield from internal or external tetram-
ethylsilane, hexafluorobenzene, and deuterated chloroform,
respectively; coupling constants (J ) are expressed in hertz (Hz).
Low-resolution mass spectra were recorded using the positive
or negative ion thermospray method, and high-resolution mass
spectra were obtained from FAB methodology.
4
3
4
9.4), 6.99 (dd, 1H, J ) 3.9, J ) 9.4), 7.42 (d, 1H, J ) 3.9).
p -[2-[(D i p h e n y lm e t h y le n e )a m i n o ]e t h y l]p h e n y l-
bor on ic Acid . Chromatography and elution (H/A ) 1:1)
delivered 1.09 g of the desired boronic acid (33% yield): 1H
3
3
NMR δ 3.07 (t, 2H, J ) 7.2), 3.69 (t, 2H, J ) 7.2), 6.89-7.68
3
(m, 12H), 7.98 (d, 2H, J ) 6.1).
2-Ca r b om et h oxy-3-m et h yl-7-m et h oxyt r op on e
(i).13
m -[5-(2-Na p h th yl)-2-oxa d ia zolyl]p h en ylbor on ic Acid .
Chromatography and sequential elution with H/A (1:1) and
pure ethyl acetate led to the isolation of the boronic acid in
60% yield (1.90 g): 1H NMR δ 7.17-8.30 (badly defined
multiplet, 10H), 8.67 (s, 1H); MS (TSP+) 317 (MH+).
Methyl iodide (170 mg, 1.2 mmol) was added to a mixture of
7-carboxy-6-methyltropolone (180 mg, 1 mmol) and cesium
carbonate (359 mg, 1.1 mmol) in anhydrous DMF (5 mL) at
room temperature. Stirring was continued overnight. The
crude mixture was then concentrated, and the residue was
subjected to a standard workup. Chromatography and elution
with H/A (9:1) yielded the desired product as an amber oil (152
mg, 73% yield): 1H NMR δ 2.31 (s, 3H), 3.90 (s, 6H), 6.62 (d,
m -[[N -(t er t -B u t o x y c a r b o n y l)a m in o ]m e t h y l]p h e n -
ylbor on ic Acid . Chromatography and elution (H/A ) 3:2)
gave the compound in 10% yield (250 mg): 1H NMR δ 1.49 (s,
3
3
9H), 4.99 (d, 2H, J ) 9.7), 7.47 (t, 1H, J ) 7.2), 7.53 (d, 1H,
3
3
3
1H, J ) 9.9), 6.75 (d, 1H, J ) 10.8), 6.96 (dd, 1H, J ) 9.9,
3J ) 7.3), 8.09 (s, 1H), 8.13 (d, 1H, J ) 7.3).
3
10.8); MS (TSP+) 209 (MH+).
Br om in ation of Tr opolon es. 3-Br om o-7-ph en yltr opolo-
n e (5a ). A mixture of starting tropolone 4a (198 mg, 1 mmol),
N-bromosuccinimide (178 mg, 1 mmol), and benzene (3 mL)
was refluxed for 3 h. The solution was cooled and worked up.
The crude orange solid was purified by crystallization in hot
toluene (1 mL). After separation the crystals were washed
1
with some n-pentane: yield, 89 mg (32%); H NMR δ 6.88 (t,
1H, 3J ) 10.5), 7.42-7.62 (m, 6H), 8.10 (d, 1H, 3J ) 10.6); MS
(TSP+) 277, 279 (MH+), 294, 296 (MNH4+). 3,5-Dibromo-7-
phenyltropolone was also isolated as a byproduct of the
reaction (32 mg, 9%): 1H NMR δ 7.35-7.52 (m, 5H), 7.83 (d,
2-Car bom eth oxy-3-m eth yl-7-ter t-bu tyltr opon e (ii).12 To
a solution of ester i (104 mg, 0.5 mmol) in dry THF (1 mL)
cooled to -78 °C was added dropwise tert-butyllithium (294
µL of a 1.7 N solution in hexanes, 0.5 mmol). The dark-red
solution was stirred at the same temperature for 0.5 h and
quenched with water (40 µL). The solution was warmed, and
a usual workup led to the isolation of a brown oil. Chromato-
graphic separation using H/E (9:1) as eluent gave 26 mg (22%)
of tropone ii and 22 mg of a byproduct of unidentified
structure. ii: 1H NMR (500 MHz) δ 1.30 (s, 9H), 2.26 (s, 3H),
4
4
1H, J ) 2.0), 8.37 (d, 1H, J ) 2.0).
3-Br om o-7-(p-m eth oxyph en yl)tr opolon e (5b). The same
procedure was used. A 10 mmol scale crude product purified
by double crystallization from hot CCl4 yielded 1.23 g (40%)
of desired bromotropolone 5b; this yield was raised to 45%
when purification was achieved by chromatography (eluent:
3
H/E/A ) 700:300:5): 1H NMR δ 3.86 (s, 3H), 6.87 (t, 1H, J )
10.5), 6.99 (d, 2H, 3J ) 8.8), 7.46 (d, 2H, 3J ) 8.8), 7.54 (d, 1H,
3J ) 10.8), 8.05 (d, 1H, 3J ) 10.8); MS (TSP+) 307, 309 (MH+),
324, 326 (MNH4+).
3
3
3.85 (s, 3H), 6.69 (dd, 1H, J ) 1.3, 11.5), 6.80 (dd, 1H, J )
7.9, 11.5), 7.06 (dd, 1H, J ) 1.3, 7.9); 13C NMR (125 MHz) δ
3
3,5-Dibromo-7-(p-methoxyphenyl)tropolone was also isolated
in 10% yield (385 mg): 1H NMR δ 3.86 (s, 3H), 6.99 (d, 2H, 3J
18.98, 30.11, 37.83, 52.19, 128.69, 131.88, 135.35, 138.48,
141.39, 160.26, 168.19, 187.91; MS (TSP+) 235 (MH+), 252
(MNH4+).
3
4
) 8.7), 7.46 (d, 2H, J ) 8.7), 7.86 (d, 1H, J ) 1.9), 8.34 (d,
1H, J ) 1.9); MS (TSP+) 385, 387, 389 (MH+).
4
2-C a r b o m e t h o x y -3-m e t h y l-7-(d iis o p r o p y la m in o )-
tr op on e (iii).12 To a cooled (-78 °C) solution of LDA freshly
prepared from diisopropylamine (50.6 mg, 70 µL, 0.5 mmol)
in dry THF (1 mL) and n-butyllithium (312.5 µL of a 1.6 N
solution in hexanes, 0.5 mmol) was added a solution of
compound i (104 mg, 0.5 mmol) in THF (0.5 mL). Stirring of
the resultant deep-red solution was continued for 30 min.
1,7-Dibr om o-2,3,4,6-tetr a h yd r oxy-5H-ben zocycloh ep -
ta d ien -5-on e (27b). A solution of bromine (1.6 g, 0.515 mL)
in acetic acid (5 mL) was added dropwise at room temperature
to a solution of purpurogallin (27a ) (1.10 g, 5 mmol) in acetic
acid (35 mL). The mixture was stirred at the same temper-
ature for 10 days and filtered. The solid was washed with CH2-
Cl2 and recrystallized from acetone (three crops): yield, 1.046

Potent Inhibitors of Inositol Monophosphatase
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4215
1
3
3
g (55%); H NMR δ 7.25 (d, 1H, J ) 13.0), 7.85 (d, 1H, J )
13.0); MS (TSP-) 375, 377, 379 (M - H), 297, 299 (M - H -
Br).
methanol was stirred for 40 h at room temperature. The pH
was raised to 7 by adding 1 N HCl, the mixture was
evaporated, and dry THF (6 mL) was added to the residue.
Filtration and addition of CH2Cl2 (1.5 mL) induced a precipi-
tate which was filtered to give 95 mg of the pure compound
Br om in a tion of 3,7-Dih yd r oxytr op olon e. In a four-
neck, 1-L flask equipped with a mechanical stirrer, a ther-
mometer and an addition funnel designed for slow addition
were added 3,7-dihydroxytropolone11,17b (6.16 g, 40 mmol) and
anhydrous DMF (400 mL) under argon. The solution was
cooled to -15 °C by using an acetone bath and a cryostat.
N-Bromosuccinimide (7.12 g, 40 mmol) was dissolved in
acetone (400 mL), and the resultant solution was placed in
the addition funnel. This solution was then added dropwise
over a period of time of 5.5-6 h, and stirring was continued
overnight at the same temperature. This produced a red-
brown solution which was evaporated under reduced pressure
(DMF was removed by using an oil pump) until a dark, oily
solid was obtained (18.91 g). Water (520 mL) was added to
this residue, and the mixture was stirred for 20 h. Filtration
and drying of the precipitate yielded 6.1 g of creamy powder
whose 1H NMR indicated a 47:43:10 mixture of 9/8/10.
4-Br om o-3,7-d ih yd r oxytr op olon e (9): 1H NMR (CD3OD)
3
(39% yield): 1H NMR δ 3.82 (s, 3H), 5.83 (d, 1H, J ) 12.4),
6.94 (d, 2H, 3J ) 9.0), 7.03 (t, 1H, 3J ) 11.7), 7.45 (d, 2H, 3J )
3
8.9), 7.97 (d, 1H, J ) 12.1); MS (TSP+) 245 (MH+).
2,3,4,6,7-P e n t a h yd r oxy-5H -b e n zocycloh e p t a d ie n -5-
on e (27d ). The procedure was the same as for compound 8a .
The crude material was sublimed at 160-215 °C: 0.01 mbar
1
3
(yield, 85 mg (36%)); H NMR δ 6.71 (d, 1H, J ) 12.4), 6.80
(s, 1H), 7.25 (d, 1H, J ) 12.4); MS (TSP+) 237 (MH+). Anal.
(C11H8O6‚0.25H2O) C, H.
3
P er m et h yla t ion of t h e 9/8/10 Mixt u r e. The 9/8/10
mixture (5 g) was dissolved in dry tetrahydrofuran (700 mL)
and the solution was cooled to 0 °C. Freshly prepared
diazomethane (CAUTION) (320 mL of a 0.4 M solution in
ether, 4 equiv) was added slowly, and the mixture was stirred
overnight at 0 °C. Excess diazomethane was cautiously
destroyed by adding acetic acid (2 mL), and the solution was
warmed and evaporated. This was run several times (total
amount of starting 9/8/10 mixture: 17.59 g), and a total of
23.76 g was obtained. Purification of the residue was achieved
by chromatography on silical gel and elution with solvents of
increasing polarities. Thus heptane/ethyl acetate (8:2) deliv-
ered dibromo derivatives 17 and 18; this was followed by mono
bromoderivatives 16, 14, 13, and 15 by increasing the amount
of ethyl acetate (6:4 to 1:4). Compounds 11 and 12 were
isolated using pure ethyl acetate and a 9:1 mixture of ethyl
acetate/methanol, respectively. Further purification is some-
times achieved by performing a second chromatography and
using a mixture of ethyl acetate and methylene chloride as
eluent.
3
3
δ 6.82 (d, 1H, J ) 12.2), 7.57 (d, 1H, J ) 12.2).
4,6-Dibr om o-3,7-dih ydr oxytr opolon e (10): 1H NMR (CD3-
OD) δ 8.24 (s, 1H).
Compound 10 was also obtained in the pure form by direct
bisbromination of 3,7-dihydroxytropolone. Thus refluxing for
6 h a mixture of N-bromosuccinimide (178 mg, 1 mmol) and
3,7-dihydroxytropolone (75 mg, 0.5 mmol) in benzene (2 mL)
and evaporating the solvent left a crude, creamy solid which
was stirred in water (4 mL) for 2 h to give the pure compound
(72 mg). Evaporation of the filtrate and repetition of the
process with 2 mL of water yielded another crop (50 mg): total
yield, 122 mg (78%); MS (TSP-) 309, 311, 313 (M - H). Anal.
(C7H4Br2O4) C, H.
5,7-Dibr om o-2,3,4-tr im eth oxytr op on e (17): 200 mg; 1H
NMR (500 MHz) δ 3.90 (s, 3H), 3.92 (s, 3H), 3.97 (s, 3H), 7.93
(s, 1H); 13C NMR (125 MHz) δ 60.5, 60.9, 61.8, 123.4, 124.0,
133.9, 154.1, 156.1, 160.3, 173.3; MS (TSP+) 355, 357, 359
(MH+).
ATA Rea ction s. Gen er a l P r oced u r e. The required
starting material (1 mmol) was dissolved in a 20:2:1 mixture
of acetic anhydride/trifluoroacetic acid/acetic acid (ATA;17
4
mL) and heated at 90 °C for the requisite time. The mixture
was then allowed to cool to room temperature and worked up.
Chromatographic purification of the crude material led to the
isolation of the desired product.
3-P h en yl-2,7-d ia cetoxytr op on e (6a ): heating time, 16 h;
eluent, H/A (3:2); yield, 170 mg (57%); 1H NMR δ 2.10 (s, 3H),
2.37 (s, 3H), 6.99-7.45 (m, 8H); MS (TSP+) 299 (MH+), 256
(MH+ - Ac).
3-(p-Meth oxyp h en yl)-2,7-d ia cetoxytr op on e (6b): heat-
ing time, 4.5 h; eluent, H/E (7:3); yield, 164 mg (50%); 1H NMR
δ 2.14 (s, 3H), 2.37 (s, 3H), 3.85 (s, 3H), 6.90-7.33 (m, 7H);
MS (TSP+) 329 (MH+), 346 (MNH4+). Further elution gave
2-acetoxy-7-bromo-3-(p-methoxyphenyl)tropone as a byproduct
(14 mg, 4% yield): 1H NMR δ 2.22 (s, 3H), 3.85 (s, 3H), 6.83
(t, 1H, 3J ) 10.5), 6.94 (d, 2H, 3J ) 8.9), 7.22 (d, 1H, 3J )
10.6), 7.31 (d, 2H, 3J ) 8.7), 7.92 (d, 1H, 3J ) 10.1); MS (TSP+)
349, 351 (MH+).
4,6-Dibr om o-2,3,7-tr im eth oxytr op on e (18): 1.928 g; 1H
NMR (500 MHz) δ 3.87 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 8.37
(s, 1H); 13C NMR (125 MHz) δ 60.3, 61.0, 62.0, 116.0, 133.7,
139.5, 154.7, 157.1, 163.1, 174.3; MS (TSP+) 355, 357, 359
(MH+).
7-Br om o-2,3,4-tr im eth oxytr op on e (13): 2.081 g; 1H NMR
(500 MHz) δ 3.86 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 6.77 (d,
3
3
1H, J ) 13.2), 7.38 (d, 1H, J ) 13.2); 13C NMR (125 MHz) δ
60.5, 60.9, 61.8, 119.2, 134.0, 137.1, 155.2, 157.0, 158.7, 180.3;
MS (TSP+) 275, 277 (MH+).
6-Br om o-2,3,7-tr im eth oxytr op on e (14): 2.668 g; 1H NMR
(500 MHz) δ 3.90 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H), 6.68 (d,
3
3
1H, J ) 12.9), 7.28 (d, 1H, J ) 12.9); 13C NMR (125 MHz) δ
56.4, 59.5, 59.8, 120.6, 124.2, 132.2, 153.7, 157.5, 162.1, 173.5;
MS (TSP+) 275, 277 (MH+).
4-Br om o-2,3,7-tr im eth oxytr op on e (15): 1.75 g; 1H NMR
(500 MHz) δ 3.86 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 6.13 (d,
1-Br om o-2,3,4,6,7-p en ta a cetoxy-5H-ben zocycloh ep ta -
d ien -5-on e (28b) a n d 1,7-Dibr om o-2,3,4,6-tetr a a cetoxy-
5H-ben zocycloh ep ta d ien -5-on e (28a ): heating time, 24 h;
eluent, H/A (3:2); yield 28b, 231 mg (44%); 1H NMR δ 2.26 (s,
3
3
1H, J ) 11.0), 7.92 (d, 1H, J ) 11.1); 13C NMR (125 MHz) δ
56.4, 60.2, 61.5, 104.1, 131.2, 136.0, 153.2, 157.5, 160.7, 174.3;
MS (TSP+) 275, 277 (MH+).
3
3H), 2.29 (s, 3H), 2.30 (s, 6H), 2.38 (s, 3H), 6.56 (d, 1H, J )
13.0), 7.70 (d, 1H, J ) 13.0); 13C NMR δ 20.04, 20.05, 20.35,
5-Br om o-2,3,4-tr im eth oxytr op on e (16): 1.974 g; 1H NMR
(500 MHz) δ 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 6.45 (d,
3
20.55, 118.1, 124.4, 130.2, 130.5, 131.6, 138.4, 140.2, 142.2,
143.7, 144.7, 166.2, 166.7, 167.7, 180.7; MS (TSP+) 542, 544
(MNH4+). More elution delivered 28a (109 mg, 20% yield): 1H
NMR δ 2.28 (s, 3H), 2.30 (s, 3H), 2.32 (s, 3H), 2.38 (s, 3H),
6.91 (d, 1H, 3J ) 12.8), 7.48 (d, 1H, 3J ) 12.8); MS (TSP+)
562, 564, 566 (MNH4+).
3
3
1H, J ) 11.1), 7.50 (d, 1H, J ) 11.1); 13C NMR (125 MHz) δ
56.5, 59.9, 61.2, 109.6, 122.9, 130.1, 156.3, 156.5, 163.0, 173.8;
MS (TSP+) 275, 277 (MH+).
2,3,4-Tr im eth oxytr op on e (11): 5.40 g; 1H NMR (500 MHz)
δ 3.83 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 6.26 (d, 1H, 3J ) 11.6),
6.86 (d, 1H, 3J ) 12.1), 7.00 (dd, 1H, 3J ) 11.6, 12.1); 13C NMR
(125 MHz) δ 56.2, 59.5, 61.2, 106.0, 131.7, 133.1, 153.9, 159.6,
Hyd r olysis of P olya ceta te Com p ou n d s. 3-P h en yl-7-
h yd r oxytr op olon e (7a ). The bisacetate 6a (298 mg, 1 mmol)
was dissolved in a 2:1 mixture of acetic acid/water, heated at
100 °C for 8 h, cooled, and evaporated. Crystallization from
hot CCl4 gave the product in 26% yield (56 mg): 1H NMR δ
7.16-7.30 (m, 2H), 7.42-7.57 (m, 5H); MS (TSP+) 215 (MH+),
232 (MNH4+). Anal. (C13H10O3) C, H.
3-(p-Meth oxyp h en yl)-7-h yd r oxytr op olon e (7b). A solu-
tion of tropone 6b (65 mg, 0.2 mmol) in methanol (0.6 mL)
and 0.4 mL of a 1 M solution of sodium methanolate in
160.5, 180.9; MS (TSP
+) 197 (MH+).
2,3,7-Tr im eth oxytr op on e (12): 3.47 g; 1H NMR (500 MHz)
3
δ 3.84 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 6.61 (d, 1H, J ) 9.3),
6.84 (d, 1H, J ) 10.9), 6.93 (dd, 1H, J ) 9.3, 10.9); 13C NMR
(125 MHz) δ 56.4, 57.9, 59.4, 109.6, 118.3, 127.9, 153.1, 160.0,
164.8, 173.7; MS (TSP+) 197 (MH+).
3
3
3,7-Dibr om o-2-m eth oxytr op on e (24a ). To a slurry of the
3,7-dibromotropolone (1.87 g, 6.7 mmol) in THF (28 mL) at 0

4216 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Piettre et al.
°C was added slowly a freshly prepared solution of diazo-
methane (CAUTION) (56 mL of a 0.4 M solution in diethyl
ether, 18.09 mmol), and stirring was continued overnight at
room temperature. Acetic acid (2 mL) was added slowly to
the stirring mixture cooled at 0 °C. Evaporation of the
volatiles, chromatography of the residue, and elution (H/A )
9:1) delivered the desired compound (296 mg, 15% yield): 1H
7-(o,m ′-Dim e t h oxyp h e n yl)-2,3,4-t r im e t h oxyt r op on e
(19b): H/A ) 3:7; 66 mg; 1H NMR δ 3.72 (s, 3H), 3.79 (s, 3H),
3
3.89 (s, 3H), 3.91 (s, 3H), 3.95 (s, 3H), 6.28 (d, 1H, J ) 10.4),
3
6.81-6.86 (m, 3H), 7.18 (d, 1H, J ) 10.3), (CD3CN) 3.68 (s,
3
3H), 3.78 (s, 3H), 3.83 (s, 3H), 3.87 (s, 6H), 6.48 (d, 1H, J )
3
10.6), 6.84-6.94 (m, 3H), 7.20 (d, 1H, J ) 10.8).
7-(o-F lu or op h en yl)-2,3,4-tr im eth oxytr op on e (19c): H/A
) 9:1; 61 mg; 1H NMR δ 3.94 (s, 6H), 3.98 (s, 3H), 6.33 (d, 1H,
3J ) 10.5), 7.16-7.36 (m, 5H); 19F NMR δ 49.01-49.13 (m,
1F); MS (TSP+) 249 (MH+).
3
NMR δ 4.01 (s, 3H), 6.49 (dd, 1H, J ) 9.4, 11.7), 7.52 (d, 1H,
3J ) 11.7), 8.03 (d, 1H, 3J ) 9.4); MS (TSP+) 293, 295, 297
(MH+), 310, 312, 314 (MNH4+).
P er m eth yla tion of 3,7-Dih yd r oxytr op olon e. The same
procedure was applied to 3,7-dihydroxytropolone using an
excess (6 equiv) of diazomethane solution (CAUTION). A 55:
45 mixture of isomeric trimethoxytropones 11 and 12 was
obtained and purified by chromatography using pure ethyl
acetate as eluent (yield: 89%).
7-[p -(T r iflu o r o m e t h y l)p h e n y l]-2,3,4-t r im e t h o x y -
1
tr op on e (19d ): H/A ) 7:3; 113 mg; H NMR δ 3.92 (s, 3H),
3
3.93 (s, 3H), 3.94 (s, 3H), 6.34 (d, 1H, J ) 10.7), 7.26 (d, 1H,
3J ) 10.7), 7.56 (d, 2H, 3J ) 8.5), 7.64 (d, 2H, 3J ) 8.5); 19F
NMR δ 99.17 (s, 3F); MS (TSP+) 341 (MH+).
7-(m-For m ylph en yl)-2,3,4-tr im eth oxytr opon e (19e): H/A
) 3:2; 71 mg; 1H NMR δ 3.93 (s, 3H), 3.94 (s, 6H), 6.36 (d, 1H,
3J ) 10.8), 7.31 (d, 1H, 3J ) 10.6), 7.56 (t, 1H, 3J ) 7.7), 7.74-
7.88 (m, 2H), 7.96-7.98 (m, 1H), 10.04 (s, 1H), (CD3CN) 3.83
Su zu k i Cou p lin g Rea ction . Gen er a l P r oced u r e for
th e Mon osu bstitu ted Tr op on es. In a flask flushed with
argon were placed the requisite isomer of permethylated
monobromotropolone derivative (2, 13, 14, 15, or 16; 110 mg,
0.4 mmol), toluene (8 mL), and palladium tetrakistriph-
enylphosphine (46 mg, 0.04 mmol, 0.1 equiv). A 2 M aqueous
solution of sodium carbonate (0.4 mL, 0.8 mmol, 2 equiv) and
the boronic acid (0.44 mmol, 1.1 equiv) dissolved36 in absolute
ethanol (0.4 mL) were then sequentially added, and the
mixture was heated at 100 °C for 16 h. Evaporation of the
volatiles left a residue which was purified by chromatography
on silica gel. Elution gave the desired products in yields
described in Table 1. The eluents and the isolated masses are
given first.
3
(s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 6.49 (d, 1H, J ) 10.8), 7.35
(d, 1H, 3J ) 10.7), 7.58 (t, 1H, 3J ) 7.6), 7.73 (d, 1H, 3J ) 7.6),
3
7.85 (d, 1H, J ) 7.6), 7.95 (s, 1H), 10.02 (s, 1H); MS (TSP+)
301 (MH+).
7-[m -[[N-(ter t-Bu toxyca r bon yl)a m in o]m eth yl]p h en yl]-
2,3,4-tr im eth oxytr op on e (19f): H/A ) 7:3; 67 mg; 1H NMR
3
δ 1.46 (s, 9H), 3.92 (s, 6H), 3.93 (s, 3H), 4.35 (d, 2H, J ) 7.8),
6.33 (d, 1H, 3J ) 8.7), 7.23-7.40 (m, 5H), (CD3CN) 1.42 (s,
3
9H), 3.82 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 4.24 (d, 2H, J )
6.2), 6.45 (d, 1H, 3J ) 10.4), 7.20-7.36 (m, 5H); MS (TSP+)
402 (MH+), 419 (MNH4+).
1
7-P h en yl-2-m eth oxytr op on e (3a ): E; 80 mg; H NMR δ
7-[p-[2-[(Diph en ylm eth ylen e)am in o]eth yl]ph en yl]-2,3,4-
tr im eth oxytr op on e (19g): H/A ) 2:3; 53 mg; 1H NMR δ 3.04
(t, 2H, 3J ) 7.6), 3.67 (t, 2H, 3J ) 7.6), 3.92 (s, 6H), 3.94 (s,
3H), 6.32 (d, 1H, 3J ) 10.9), 7.00-7.65 (m, 15H), (CD3CN) 2.98
(t, 2H, 3J ) 6.8), 3.59 (t, 2H, 3J ) 6.8), 3.81 (s, 3H), 3.82 (s,
3
3.95 (s, 3H), 6.74 (d, 1H, J ) 9.4), 6.83-6.94 (m, 1H), 6.99-
7.10 (m, 1H), 7.29-7.90 (m, 6H); MS (TSP+) 213 (MH+).
7-(p-Meth oxyp h en yl)-2-m eth oxytr op on e (3b): E; 88 mg;
1H NMR δ 3.83 (s, 3H), 3.94 (s, 3H), 6.73 (d, 1H, 3J ) 9.4),
6.81-7.06 (m, 4H), 7.41-7.47 (m, 3H); MS (TSP+) 243 (MH+).
7-(p-P h en ylp h en yl)-2-m eth oxytr op on e (3c): H/A ) 1:1;
3
3H), 3.86 (s, 3H), 6.43 (d, 1H, J ) 11.2), 6.95-7.02 (m, 2H),
7.14 (d, 2H, 3J ) 7.2), 7.24-7.62 (m, 11H); MS (TSP+) 480
(MH+).
1
3
90 mg; H NMR δ 3.96 (s, 3H), 6.77 (d, 1H, J ) 9.6), 6.88-
6.98 (m, 1H), 7.03-7.11 (m, 1H), 7.40-7.73 (m, 10H); MS
(TSP+) 289 (MH+), 311 (MNa+).
7-(2-Ben zofu r yl)-2,3,4-tr im eth oxytr op on e (19h ): H/A )
1
1:1; 57 mg; H NMR δ 3.90 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H),
3
3
7-[p-(Ben zyloxy)p h en yl]-2-m eth oxytr op on e (3d ): H/A
6.47 (d, 1H, J ) 11.2), 7.18-7.34 (m, 2H), 7.46 (d, 1H, J )
7.8), 7.63 (d, 1H, 3J ) 7.1), 8.02 (s, 1H), 8.19 (d, 1H, 3J ) 11.1);
MS (TSP+) 313 (MH+), 330 (MNH4+).
) 1:9, then pure A; 89 mg; 1H NMR δ 3.94 (s, 3H), 5.11 (s,
4
3
2H), 6.98-7.46 (m, 12H), 7.59 (dd, 1H, J ) 1.2, J ) 8.1).
7-(o-F or m ylp h en yl)-2-m eth oxytr op on e (3e): H/A ) 4:1;
7-(2-Th ien yl)-2,3,4-tr im eth oxytr op on e (19i): H/A ) 1:1;
21 mg; 1H NMR δ 3.92 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 6.47
(d, 1H, 3J ) 11.1), 7.13 (dd, 1H, 3J ) 4.2, 5.6), 7.47 (dd, 1H, 4J
1
3
91 mg; H NMR δ 3.96 (s, 3H), 6.84 (d, 1H, J ) 9.7), 6.88-
4
3
6.98 (m, 1H), 7.11-7.22 (m, 1H), 7.26 (dd, 1H, J ) 1.4, J )
4
3
3
4
3
7.5), 7.42 (dd, 1H, J ) 1.1, J ) 8.7), 7.45-7.69 (m, 2H), 7.95
) 2.8, J ) 5.6), 7.54 (dd, 1H, J ) 2.8, J ) 4.2), 7.82 (d, 1H,
4
3
(dd, 1H, J ) 1.5, J ) 7.6), 9.81 (s, 1H).
3J ) 11.1), (CD3CN) 3.83 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H),
3
3
7-(m -F or m ylp h en yl)-2-m eth oxytr op on e (3f): H/A ) 7:3,
6.59 (d, 1H, J ) 11.2), 6.94 (dd, 1H, J ) 4.4, 6.1), 7.15 (dd,
4 3 4 3
then pure A; 72 mg; 1H NMR δ 3.98 (s, 3H), 6.80 (d, 1H, J )
1H, J ) 1.2, J ) 6.1), 7.52 (dd, 1H, J ) 1.2, J ) 4.4), 7.60
3
3
9.6), 6.88-6.98 (m, 1H), 7.07-7.18 (m, 1H), 7.48-7.60 (m, 2H),
(d, 1H, J ) 11.2).
4
3
4
3
7.77 (dt, 1H, J ) 1.5, J ) 7.8), 7.88 (dt, 1H, J ) 1.3, J )
7.5), 7.98 (t, 1H, 4J ) 1.6), 10.04 (s, 1H); MS (TSP+) 241 (MH+).
7-(m -Cya n op h en yl)-2-m eth oxytr op on e (3g): C/E ) 9:1;
7-(3-Th ien yl)-2,3,4-tr im eth oxytr op on e (19j): H/A ) 1:1;
98 mg; 1H NMR δ 3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H), 6.32
3
(d, 1H, J ) 10.7), 7.28-7.48 (m, 3H), 7.83 (s, 1H), (CD3CN)
1
3
3
72 mg; H NMR δ 3.99 (s, 3H), 6.82 (d, 1H, J ) 10.6), 6.89-
6.99 (m, 1H), 7.10-7.21 (m, 1H), 7.41-7.54 (m, 2H), 7.61-
7.77 (m, 3H), (CD3CN) 3.93 (s, 3H), 6.90-7.00 (m, 2H), 7.19
(dd, 1H, 3J ) 8.7, 10.6), 7.45-7.58 (m, 2H), 7.63-7.71 (m, 2H),
7.77 (s, 1H); MS (TSP+) 238 (MH+), 255 (MNH4+).
3.83 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.44 (d, 1H, J ) 10.6),
7.37-7.44 (m, 2H), 7.53 (d, 1H, 3J ) 10.6), 7.85-7.89 (m, 1H);
MS (TSP+) 279 (MH+).
6-(5-P yr im id yl)-2,3,7-tr im eth oxytr op on e (19k ): pure A,
then M/A ) 5:95; 40 mg; 1H NMR δ 3.91 (s, 3H), 3.94 (s, 3H),
3.95 (s, 3H), 6.38 (d, 1H, 3J ) 10.6), 7.26 (d, 1H, 3J ) 10.6),
8.85 (s, 2H), 9.15 (s, 1H); MS (TSP+) 275 (MH+).
6-P h en yl-2,3,7-tr im eth oxytr op on e (20a ): H/A ) 3:2; 73
7-[m -[7-(2-Me t h oxyt r op olon yl)]p h e n yl]-2-m e t h oxy-
1
tr op on e (3h ): C/A ) 1:1, the M/A ) 1:9; 62 mg; H NMR δ
3
3.95 (s, 6H), 6.76 (d, 2H, J ) 9.4), 6.84-6.94 (m, 2H), 6.99-
7.11 (m, 2H), 7.40-7.51 (m, 3H), 7.55-7.60 (m, 3H); MS (TSP+)
mg; H NMR δ 3.74 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 6.95 (s,
1
347 (MH+), 364 (MNH4+).
2H), 7.31-7.48 (m, 5H), (CD3CN) 3.69 (s, 3H), 3.83 (s, 3H),
3.94 (s, 3H), 6.94 (d, 1H, 3J ) 12.4), 7.06 (d, 1H, 3J ) 12.5),
7.30-7.46 (m, 5H); MS (TSP+) 273 (MH+).
7-(5-P yr im id yl)-2-m eth oxytr op on e (3i): M/A ) 1:9; 26
1
3
mg; H NMR δ 4.00 (s, 3H), 6.85 (d, 1H, J ) 9.7), 6.93-7.04
4
3
(m, 1H), 7.15-7.26 (m, 1H), 7.48 (dd, 1H, J ) 1.0, J ) 8.9),
6-[p-(Ben zyloxy)ph en yl]-2,3,7-tr im eth oxytr opon e (20b):
8.87 (s, 2H), 9.18 (s, 1H); MS (TSP+) 215 (MH+).
H/A ) 1:1; 104 mg; H NMR δ 3.76 (s, 3H), 3.98 (s, 6H), 4.00
1
1
3
3
7-n -Octyl-2-m eth oxytr op on e (3j): H/A ) 1:1; 38 mg; H
(s, 3H), 5.13 (s, 2H), 6.91 (d, 1H, J ) 12.6), 6.99 (d, 1H, J )
12.5), 7.04 (d, 2H, 3J ) 8.4), 7.30-7.51 (m, 7H), (CD3CN) 3.68
(s, 3H), 3.82 (s, 6H), 3.92 (s, 3H), 5.13 (s, 2H), 6.89-7.09 (m,
NMR δ 0.86 (t, 3H, 3J ) 6.9), 1.18-1.90 (m, 12H), 2.74 (t, 2H,
3J ) 7.6), 3.91 (s, 3H), 6.70 (d, 1H, 3J ) 9.6), 6.72-6.83 (m,
1H), 6.93-7.00 (m, 1H), 7.34 (d, 1H, 3J ) 8.8); MS (TSP+) 249
(MH+).
3
4H), 7.39 (d, 2H, J ) 8.8), 7.36-7.55 (m, 5H).
6-[p -(T r iflu o r o m e t h y l)p h e n y l]-2,3,7-t r im e t h o x y -
1
7-(p-Meth oxyp h en yl)-2,3,4-tr im eth oxytr op on e (19a ):
H/A ) 1:1; 60 mg; 1H NMR δ 3.73 (s, 3H), 3.86 (s, 3H), 3.96 (s,
3H), 3.99 (s, 3H), 6.86-7.02 (m, 4H), 7.27-7.34 (m, 2H).
tr op on e (20c): H/A ) 2:3; 119 mg; H NMR δ 3.92 (s, 3H),
3
3.94 (s, 3H), 3.95 (s, 3H), 6.35 (d, 1H, J ) 10.6), 7.26 (d, 1H,
3
3
3J ) 10.6), 7.56 (d, 2H, J ) 8.4), 7.65 (d, 2H, J ) 8.4), (CD3-

Potent Inhibitors of Inositol Monophosphatase
CN) 3.83 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 6.46 (d, 1H, J )
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4217
3
4-(m-For m ylph en yl)-2,3,7-tr im eth oxytr opon e (21c): H/A
) 1:1, then pure A; 71 mg; 1H NMR δ 3.64 (s, 3H), 3.94 (s,
3H), 3.98 (s, 3H), 6.74 (d, 1H, 3J ) 10.6), 6.98 (d, 1H, 3J )
10.6), 7.55-7.67 (m, 2H), 7.88-7.93 (m, 2H), 10.07 (s, 1H).
5-[m -(T r iflu o r o m e t h y l)p h e n y l]-2,3,4-t r im e t h o x y -
tr op on e (22a ): H/A ) 7:3; 68 mg; 1H NMR δ 3.57 (s, 3H),
3.95 (s, 3H), 4.02 (s, 3H), 7.02 (d, 1H, 3J ) 9.4), 7.10 (d, 1H, 3J
) 9.4), 7.53-7.67 (m, 4H), (CD3CN) 3.53 (s, 3H), 3.88 (s, 3H),
3
3
10.6), 7.31 (d, 1H, J ) 10.4), 7.58 (d, 2H, J ) 8.4), 7.68 (d,
2H, 3J ) 8.4); 19F NMR δ 99.15 (s, 3F); MS (TSP+) 341 (MH+).
6-[m ,m -Bis(t r iflu or om e t h yl)p h e n yl]-2,3,7-t r im e t h -
oxytr op on e (20d ). A first chromatography was run (H/A )
3:2) to give a slightly impure material which was subjected to
a second chomatography (T/A ) 7:3): 104 mg; 1H NMR δ 3.83
3
(s, 3H), 3.87 (s, 3H), 3.92 (s, 3H), 6.50 (d, 1H, J ) 11.2), 7.41
3
3
3
(d, 1H, J ) 11.2), 7.96 (s, 1H), 8.03 (s, 2H), (CD3CN) 3.95 (s,
3.91 (s, 3H), 6.89 (d, 1H, J ) 12.7), 7.141 (d, 1H, J ) 12.7),
7.61-7.71 (m, 4H); 19F NMR δ 99.14 (s, 3F); MS (TSP+) 341
(MH+).
3H), 3.98 (s, 6H), 6.41 (d, 1H, 3J ) 10.8), 7.30 (d, 1H, 3J )
10.8), 7.84 (s, 1H), 7.94 (s, 2H); 19F NMR δ 99.17 (s, 6F).
6-(m -Cya n op h en yl)-2,3,7-tr im eth oxytr op on e (20e): C/E
) 4:1; 68 mg; 1H NMR δ 3.80 (s, 3H), 3.99 (s, 3H), 4.02 (s,
3H), 6.85 (d, 1H, 3J ) 12.6), 6.98 (d, 1H, 3J ) 12.6), 7.51-7.71
(m, 4H), (CD3CN) 3.71 (s, 3H), 3.85 (s, 3H), 3.94 (s, 3H), 6.88
5-[p -(T r iflu o r o m e t h y l)p h e n y l]-2,3,4-t r im e t h o x y -
tr op on e (22b): H/A ) 7:3; 50 mg; 1H NMR δ 3.57 (s, 3H),
3
3.95 (s, 3H), 4.03 (s, 3H), 7.05 (s, 2H), 7.48 (d, 2H, J ) 8.2),
7.69 (d, 2H, 3J ) 8.2); 19F NMR δ 99.14 (s, 3F); MS (TSP+)
341 (MH+).
3
3
(d, 1H, J ) 12.6), 7.06 (d, 1H, J ) 12.6), 7.53-7.72 (m, 4H);
MS (TSP+) 298 (MH+).
E t h yl 4-[p -(t r iflu or om et h yl)p h en yl]-2,3-d im et h oxy-
ben zoa te (23): eluted first as a byproduct of the reaction (13
6-(m -Aceta m id op h en yl)-2,3,7-tr im eth oxytr op on e (20f):
1
3
A/M ) 95:5; 55 mg; H NMR δ 2.19 (s, 3H), 3.71 (s, 3H), 3.94
mg, 9% yield); 1H NMR δ 1.42 (t, 3H, J ) 7.10), 3.66 (s, 3H),
3
3
3
(s, 3H), 3.98 (s, 3H), 6.92 (s, 2H), 7.02 (d, 1H, J ) 7.6), 7.33
4.00 (s, 3H), 4.41 (q, 2H, J ) 7.1), 7.13 (d, 1H, J ) 8.2), 7.59
(d, 1H, 3J ) 8.2), 7.60-7.72 (m, 4H); 13C NMR δ 14.3, 60.9,
61.2, 61.7, 123.9, 125.1, 125.2, 125.4, 126.5, 129.5, 138.6, 141.0,
151.6, 153.7, 165.8; 19F NMR δ 99.20 (s, 3F); MS (TSP+) 355
(MH+).
3
3
(t, 1H, J ) 7.6), 7.54 (s, 1H), 7.56 (d, 1H, J ) 7.6), (CD3CN)
2.07 (s, 3H), 3.68 (s, 3H), 3.82 (s, 3H), 3.91 (s, 3H), 6.89 (d,
1H, J ) 12.5), 6.98 (d, 1H, J ) 8.3), 7.02 (d, 1H, J ) 12.5),
7.35 (t, 1H, J ) 8.3), 7.51-7.55 (m, 2H).
3
3
3
3
6-(m -Nitr op h en yl)-2,3,7-tr im eth oxytr op on e (20g): H/A
) 3:2; 81 mg; 1H NMR δ 3.81 (s, 3H), 3.98 (s, 3H), 4.01 (s,
3H), 6.87 (d, 1H, 3J ) 12.5), 6.98 (d, 1H, 3J ) 12.5), 7.56-7.73
(m, 2H), 8.22-8.26 (m, 2H), (CD3CN) 3.73 (s, 3H), 3.84 (s, 3H),
3.95 (s, 3H), 6.93 (d, 1H, 3J ) 12.6), 7.10 (d, 1H, 3J ) 12.6),
7.60-7.77 (m, 2H), 8.17-8.26 (m, 2H); MS (ES+) 318 (MH+).
6-(1-Na p h th yl)-2,3,7-tr im eth oxytr op on e (20h ): H/A )
5-(m-For m ylph en yl)-2,3,4-tr im eth oxytr opon e (22c): H/A
1
) 7:3; 104 mg; H NMR δ 3.56 (s, 3H), 3.95 (s, 3H), 4.03 (s,
3H), 7.03 (d, 1H, 3J ) 12.7), 7.11 (d, 1H, 3J ) 12.7), 7.51-7.72
(m, 2H), 7.88-7.93 (m, 2H), 10.07 (s, 1H).
P r ep a r a tion of Oxim es. Oxim e of 7-(m -F or m ylp h en -
yl)-2-m eth oxytr op on e (3k ). To a suspension of aldehyde 3f
(50 mg, 0.22 mmol) in ethanol (2 mL) were sequentially added
pyridine (70 mg, 72 µL, 0.88 mmol) and a solution of hydroxyl-
amine hydrochloride (15.3 mg, 0.24 mmol) in ethanol (1 mL).
The mixture was stirred for 48 h and evaporated. Methylene
chloride (5 mL) was added to the residue, and the organic
phase was washed with water (3 × 5 mL) and dried. Chro-
matography using ethyl acetate as eluent furnished the pure
1
2:3; 71 mg; H NMR δ 3.65 (s, 3H), 4.04 (s, 6H), 6.89 (d, 1H,
3J ) 12.6), 6.98 (d, 1H, 3J ) 12.6), 7.32 (dd, 1H, 4J ) 1.0, 3J )
7.0), 7.39-7.60 (m, 4H), 7.87-7.95 (m, 2H).
6-(2-Na p h th yl)-2,3,7-tr im eth oxytr op on e (20i): H/A )
1
3:7; 67 mg; H NMR δ 3.76 (s, 3H), 3.99 (s, 3H), 4.00 (s, 3H),
3
3
6.94 (d, 1H, J ) 12.6), 7.06 (d, 1H, J ) 12.6), 7.46-7.55 (m,
3H), 7.80-7.91 (m, 4H), (CD3CN) 3.68 (s, 3H), 3.84 (s, 3H),
3.92 (s, 3H), 7.00 (s, 2H), 7.39-7.53 (m, 3H), 7.78 (s, 1H), 7.83-
7.92 (m, 3H).
oxime in 93% yield (52 mg):
1H NMR δ 3.94 (s, 3H), 6.82 (d,
1H, 3J ) 9.5), 6.85-6.95 (m, 1H), 7.05-7.15 (m, 1H), 7.28-
7.48 (m, 4H), 7.59 (s, 1H), 8.09 (s, 1H); MS (TSP+) 256 (MH+).
Ben zyloxim e of 7-(m-For m ylph en yl)-2-m eth oxytr opon e
(3l). The same procedure was used with N-benzylhydroxyl-
amine (15.3 mg, 0.24 mmol): yield, 96% (73 mg): 1H NMR δ
3.98 (s, 3H), 5.24 (s, 2H), 6.77 (d, 1H, 3J ) 9.5), 6.86-6.96 (m,
1H), 7.03-7.12 (m, 1H), 7.28-7.62 (m, 9H), 7.71 (s, 1H), 8.18
(s, 1H); MS (TSP+) 346 (MH+).
6-[m -[5-(2-Na p h t h yl)-2-oxa d ia zolyl]p h en yl]-2,3,7-t r i-
1
m eth oxytr op on e (20j): H/A ) 1:4, then pure A; 71 mg; H
NMR δ 3.82 (s, 3H), 4.02 (s, 3H), 4.04 (s, 3H), 7.02 (s, 2H),
7.55-7.68 (m, 4H), 7.90-8.03 (m, 3H), 8.19-8.26 (m, 3H), 8.66
(s, 1H), (CD3CN) 3.78 (s, 3H), 3.89 (s, 3H), 3.98 (s, 3H), 6.99
(d, 1H, 3J ) 12.2), 7.12 (d, 1H, 3J ) 12.2), 7.55-8.26 (m, 10H),
8.73 (s, 1H); MS (TSP+) 467 (MH+).
R ed u ct ion of Ald eh yd es 4f, 22c, a n d 23b . Gen er a l
P r oced u r e. The requisite aldehyde (0.3 mmol) was dissolved
in benzene (3 mL), and sodium triacetoxyborohydride (127 mg,
0.6 mmol) was added. The mixture was then refluxed for 1 h,
cooled, and evaporated. Chromatography of the residue and
elution with ethyl acetate furnished the desired alcohol.
7-[m-(Hydr oxym eth yl)ph en yl]-2-m eth oxytr opon e (3m ):
66 mg, 91% yield; 1H NMR δ 3.96 (s, 3H), 4.70 (s, 2H), 6.77 (d,
1H, 3J ) 9.5), 6.85-6.95 (m, 2H), 7.02-7.13 (m, 1H), 7.34-
7.50 (m, 5H); MS (TSP+) 243 (MH+).
6-[4-[(t er t -Bu t yld im e t h ylsilyl)oxy]b u t yl]-2,3,7-t r i-
1
m eth oxytr op on e (20k ): H/A ) 7:3; 47 mg; H NMR δ 0.46
3
(s, 6H), 0.89 (s, 9H), 1.58-1.68 (m, 4H), 2.65 (t, 2H, J ) 7.2),
3
3.63 (t, 2H, J ) 5.5), 3.91 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H),
6.84 (s, 2H); (CD3CN) 0.45 (s, 6H), 0.91 (s, 9H), 1.50-1.68 (m,
4H), 2.51-2.58 (m, 2H), 3.53-3.59 (m, 2H), 3.79 (s, 3H), 3.84
3
3
(s, 3H), 3.89 (s, 3H), 6.90 (d, 1H, J ) 10.9), 6.97 (d, 1H, J )
10.9); MS (TSP+) 269 (MH+ - t-BuMe2Si).
6-[5-[(t er t -Bu t yld ip h e n ylsilyl)oxy]p e n t yl]-2,3,7-t r i-
m eth oxytr op on e (20l): C/A ) 9:1; 64 mg; 1H NMR δ 1.39 (s,
4-[m -(H y d r o x y m e t h y l)p h e n y l]-2,3,7-t r i m e t h o x y -
3
3
9H), 1.40-1.66 (m, 6H), 2.61 (t, 2H, J ) 7.5), 3.66 (t, 2H, J
) 6.3), 3.90 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 6.81 (s, 2H),
7.35-7.42 (m, 6H), 7.64-7.67 (m, 4H); (CD3CN) 1.03 (s, 9H),
1.42-1.63 (m, 6H), 2.61 (t, 2H, 3J ) 7.5), 3.69 (t, 2H, 3J )
tr op on e (21d ): 60 mg, 66% yield; 1H NMR δ 3.62 (s, 3H), 3.91
3
(s, 3H), 3.95 (s, 3H), 4.77 (s, 2H), 6.70 (d, 1H, J ) 10.7), 6.96
3
(d, 1H, J ) 10.7), 7.25-7.41 (m, 4H), (CD3CN) 3.57 (s, 3H),
3
3.83 (s, 3H), 3.88 (s, 3H), 4.65 (s, 2H), 6.82 (d, 1H, J ) 10.5),
3
3
6.2), 3.79 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 6.85 (d, 1H, J )
6.95 (d, 1H, J ) 10.5), 7.22-7.40 (m, 4H).
12.5), 6.93 (d, 1H, 3J ) 12.5), 7.38-7.46 (m, 6H), 7.66-7.70
(m, 4H); MS (TSP+) 521 (MH+).
5-[m -(H y d r o x y m e t h y l)p h e n y l]-2,3,4-t r i m e t h o x y -
tr op on e (22d ): 45 mg, 50% yield; 1H NMR δ 3.55 (s, 3H),
3
4-(p-Meth oxyp h en yl)-2,3,7-tr im eth oxytr op on e (21a ):
3.93 (s, 3H), 4.00 (s, 3H), 4.76 (s, 2H), 7.00 (d, 1H, J ) 12.7),
H/A ) 1:1; 83 mg; 1H NMR δ 3.85 (s, 3H), 3.92 (s, 6H), 3.94 (s,
7.12 (d, 1H, J ) 12.7), 7.25-7.47 (m, 4H), (CD3CN) 3.53 (s,
3
3
3
3H), 6.34 (d, 1H, J ) 10.6), 6.94 (d, 2H, J ) 8.6), 7.27 (d, 1H,
3H), 3.88 (s, 3H), 3.93 (s, 3H), 4.66 (s, 2H), 6.90 (d, 1H, J )
3
3
3J ) 10.6), 7.44 (d, 2H, J ) 8.7), (CD3CN) 3.68 (s, 3H), 3.82
12.7), 7.11 (d, 1H, J ) 12.7), 7.23-7.47 (m, 4H); MS (TSP+)
3
(s, 3H), 3.83 (s, 3H), 3.93 (s, 3H), 6.95 (d, 1H, J ) 12.6), 6.99
303 (MH+).
(d, 2H, 3J ) 8.8), 7.04 (d, 1H, 3J ) 12.6), 7.29 (d, 2H, 3J )
8.8); MS (TSP+) 303 (MH+).
Attem p ted Sin gle Su zu k i Rea ction on 3,7-Dibr om o-2-
Meth oxytr op on e. In a flask flushed with argon were placed
3,7-dibromo-2-methoxytropone (24a ) (100 mg, 0.34 mmol),
THF (22 mL), and palladium tetrakistriphenylphosphine (39
mg, 0.034 mmol, 0.1 equiv). A 1.8 M aqueous solution of
potassium hydroxide (0.75 mL, 1.36 mmol, 4 equiv) and
p-methoxyphenylboronic acid (73 mg, 0.48 mmol, 1.4 equiv)
4-[p -(T r iflu o r o m e t h y l)p h e n y l]-2,3,7-t r im e t h o x y -
1
tr op on e (21b): H/A ) 7:3; 121 mg; H NMR δ 3.65 (s, 3H),
3
3.94 (s, 3H), 3.98 (s, 3H), 6.72 (d, 1H, J ) 10.6), 6.93 (d, 1H,
3J ) 10.6), 7.47 (d, 2H, 3J ) 8.2), 7.67 (d, 2H, 3J ) 8.2); 19F
NMR δ 99.22 (s, 3F); MS (TSP+) 341 (MH+).

4218 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Piettre et al.
were then sequentially added, and the mixture was stirred at
room temperature for 16 h. Evaporation of the volatiles left
a residue which was purified by chromatography on silica gel
to give 3-br om o-7-(p-m eth oxyp h en yl)-2-m eth oxytr op on e
(24c): eluent, H/E ) 4:1; yield, 8 mg (7%); 1H NMR δ 3.84 (s,
4,6-Di(2-ben zofu r yl)-2,3,7-tr im eth oxytr opon e (25m ): H/A
) 7:3; 13 mg; 1H NMR δ 3.98 (s, 3H), 4.06 (s, 3H), 4.13 (s,
3H), 7.25-7.48 (m, 5H), 7.58-7.74 (m, 5H), 8.64 (s, 1H), (CD3-
CN) 3.88 (s, 3H), 3.99 (s, 3H), 4.03 (s, 3H), 7.33-7.44 (m, 5H),
7.56-7.72 (m, 5H), 8.65 (s, 1H); MS (TSP+) 429 (MH+).
4,6-Di(3-th ien yl)-2,3,7-tr im eth oxytr op on e (25n ): H/A )
3
3
3H), 3.96 (s, 3H), 6.67 (dd, 1H, J ) 9.0, 11.6), 6.94 (d, 2H, J
3
) 8.8), 7.27-7.39 (m, 2H), 7.46 (d, 2H, J ) 8.8); MS (TSP+)
1
3:2; 43 mg; H NMR δ 3.69 (s, 3H), 3.82 (s, 3H), 4.01 (s, 3H),
321, 323 (MH+), 338, 340 (MNH4+). More elution furnished
3,7-bis(p-m eth oxyp h en yl)-2-m eth oxytr op on e (24b): yield,
35 mg (30%); 1H NMR δ 3.70 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H),
7.20-7.51 (m, 7H), (CD3CN) 3.63 (s, 3H), 3.78 (s, 3H), 3.92 (s,
3H), 7.19-7.33 (m, 3H), 7.40-7.58 (m, 4H); MS (TSP+) 361
(MH+).
3
6.84-7.06 (m, 6H), 7.33-7.40 (m, 3H), 7.53 (d, 2H, J ) 8.8);
Dep r otection Rea ction s u n d er Acid ic Con d ition s.
7-P h en yltr op olon e (4a ). The starting methoxytropone 3a
(2.12 g, 10 mmol) was dissolved in methanol (30 mL), and
concentrated aqueous HCl (30 mL) was added. The resultant
solution was refluxed for 6 h and allowed to cool slowly. The
pure product crystallized out overnight in 86% yield (1.70 g):
1H NMR δ 7.02-7.12 (m, 1H), 7.31-7.54 (m, 7H), 7.58 (d, 1H,
3J ) 10.2); MS (TSP+) 199 (MH+), 216 (MNH4+).
MS (TSP+) 349 (MH+), 366 (MNH4+).
Dou ble Su zu k i Cou p lin g Rea ction . The procedure fol-
lowed for the preparation of bisaryldihydroxytropolones is the
same as the one for the monosubstituted derivatives on a 0.2-
mmol scale (dibromotropolone derivative 18), but with 2.2
equiv of boronic acid (0.44 mmol) and 4 equiv of sodium
carbonate (0.2 mL, 0.4 mmol). Yields are given in Table 2.
The eluents and isolated masses are given first.
4,6-Bis(p -m e t h oxyp h e n yl)-2,3,7-t r im e t h oxyt r op on e
(25a ): H/A ) 1:1; 63 mg; 1H NMR δ 3.65 (s, 3H), 3.78 (s, 3H),
3.86 (s, 3H), 3.87 (s, 3H), 4.02 (s, 3H), 6.90-7.01 (m, 5H), 7.28-
7.38 (m, 4H), (CD3CN) 3.56 (s, 3H), 3.70 (s, 3H), 3.80 (s, 3H),
3.82 (s, 3H), 3.90 (s, 3H), 6.87-6.99 (m, 5H), 7.27-7.32 (m,
4H); MS (TSP+) 409 (MH+).
4,6-Bis(o-flu or op h en yl)-2,3,7-tr im eth oxytr op on e (25b):
H/A ) 7:3; 68 mg; 1H NMR δ 3.67 (s, 3H), 3.80 (s, 3H), 3.94 (s,
3H), 6.85 (s, 1H), 7.09-7.46 (m, 8H); 19F NMR δ 48.78-48.90
(br s, 1F), 49.13-49.26 (br s, 1F); MS (TSP+) 385 (MH+).
4,6-B is [m -(t r iflu o r o m e t h y l)p h e n y l]-2,3,7-t r im e t h -
oxytr op on e (25c): H/A ) 7:3; 87 mg; 1H NMR δ 3.70 (s, 3H),
3.83 (s, 3H), 4.03 (s, 3H), 6.88 (s, 1H), 7.53-7.63 (m, 8H), (CD3-
CN) 3.63 (s, 3H), 3.76 (s, 3H), 3.94 (s, 3H), 6.89 (s, 1H), 7.57-
7.70 (m, 8H); 19F NMR δ 99.35 (s, 3F), 99.38 (s, 3F); MS (TSP+)
485 (MH+).
7-(p-Meth oxyp h en yl)tr op olon e (4b). Application of the
same procedure to 3b led to the isolation of the corresponding
tropolone 4b in 95% yield (2.17 g): 1H NMR δ 3.86 (s, 3H),
3
6.96-7.03 (m, 2H), 7.20 (t, 1H, J ) 9.5), 7.42-7.52 (m, 3H),
7.65-7.73 (m, 2H); MS (TSP+) 229 (MH+).
Dep r otection Rea ction s w ith TMSI. Gen er a l P r oce-
d u r e. The permethylated monosubstituted or disubstituted
tropolone (0.15 mmol) was dissolved in dry acetonitrile (5 mL),
and TMSI (freshly distilled over copper wire, 120 mg, 85 µL,
0.6 mmol, 4 equiv for the monosubstituted tropolone deriva-
tives and twice this amount for the disubstituted tropolones
derivatives) was added via syringe (as reaction times may vary
from one compound to another it may be advisable to conduct
the experiment in an NMR tube, thereby allowing the moni-
toring of the reaction by 1H NMR spectroscopy). The mixture
was then heated at 80 °C for a period of time ranging from 15
min to 3 h. Evaporation left an oily residue. Toluene (4 mL)
was added and evaporated. This step was repeated twice to
ensure complete removal of any excess TMSI and any hydri-
odic acid that might have formed. The oily residue was
dissolved in acetonitrile, and water was then added to hydro-
lyze the silyloxy functions. After 2 h at room temperature the
solution was evaporated, and the above treatment with toluene
was applied (3 × 4 mL) to give a solid. This was dissolved in
ethyl acetate (40 mL) and washed rapidly with a saturated
Na2S2O3 aqueous solution (10 mL). The organic phase was
washed with water (2 × 10 mL), dried over sodium sulfate,
and evaporated to furnish the tropolones in yields reported in
Table 3.
4,6-Bis[p -(t r iflu or om et h yl)p h en yl]-2,3,7-t r im et h oxy-
tr op on e (25d ): H/A ) 7:3; 90 mg; 1H NMR δ 3.68 (s, 3H),
3
3.81 (s, 3H), 4.02 (s, 3H), 6.84 (s, 1H), 7.46 (d, 4H, J ) 8.1),
7.62-7.70 (m, 4H), (CD3CN) 3.63 (s, 3H), 3.76 (s, 3H), 3.94 (s,
3H), 6.85 (s, 1H), 7.54 (d, 4H, 3J ) 8.2), 7.66-7.78 (m, 4H);
19F NMR δ 99.09 (s, 3F), 99.11 (s, 3F); MS (TSP+) 485 (MH+).
4,6-Bis[m ,m -b is(t r iflu or om e t h yl)p h e n yl]-2,3,7-t r i-
m eth oxytr op on e (25e): pure C, then C/A ) 99:1; 100 mg;
1H NMR δ 3.75 (s, 3H), 3.88 (s, 3H), 4.05 (s, 3H), 6.79 (s, 1H),
7.82 (s, 4H), 7.92 (s, 2H); 19F NMR δ 99.14 (s, 6F), 99.17 (s,
6F).
4,6-Bis(m-for m ylph en yl)-2,3,7-tr im eth oxytr opon e (25f):
H/A ) 1:1; 57 mg; 1H NMR δ 3.66 (s, 3H), 3.81 (s, 3H), 4.02 (s,
3H), 6.89 (s, 1H), 7.54-7.66 (m, 4H), 7.86-7.90 (m, 4H), 10.04
(s, 1H), 10.05 (s, 1H); MS (TSP+) 405 (MH+).
3,7-Dih yd r oxytr op olon e (8): obtained quantitatively as
a creamy powder, identical in every respect with an authentic
sample.
7-(p-Hyd r oxyp h en yl)tr op olon e (4d ): 25 mg; 1H NMR
4,6-Bis(m-cya n op h en yl)-2,3,7-tr im eth oxytr op on e (25g):
H/A ) 4:1; 54 mg; 1H NMR δ 3.68 (s, 3H), 3.83 (s, 3H), 4.03 (s,
3H), 6.76 (s, 1H), 7.47-7.69 (m, 8H); MS (TSP+) 399 (MH+).
4 ,6 -B i s (m -a c e t a m i d o p h e n y l )-2 ,3 ,7 -t r i m e t h o x y -
tr op on e (25h ): H/A ) 1:1; 38 mg; 1H NMR δ 2.15 (s, 3H),
3.59 (s, 3H), 3.70 (s, 3H), 3.92 (s, 3H), 6.88 (s, 1H), 6.98 (d,
2H, J ) 7.5), 7.18-7.26 (m, 2H), 7.38-7.62 (m, 4H).
4,6-Bis(m -n itr op h en yl)-2,3,7-tr im eth oxytr op on e (25i):
H/A ) 3:2; 59 mg; 1H NMR δ 3.72 (s, 3H), 3.86 (s, 3H), 4.03 (s,
3H), 6.85 (s, 1H), 7.54-7.72 (m, 4H), 8.22-8.27 (m, 4H), (CD3-
CN) 3.63 (s, 3H), 3.76 (s, 3H), 3.94 (s, 3H), 6.87 (s, 1H), 7.52-
3
(CD3OD) δ 6.84 (d, 2H, J ) 8.6), 7.20-7.57 (m, 5H), 7.75 (d,
1H, J ) 10.0); MS (TSP+) 215 (MH+), 232 (MNH4+).
3
7-(m -F or m ylp h en yl)tr op olon e (4f): 28 mg; 1H NMR δ
7.08-7.21 (m, 1H), 7.40-7.49 (m, 2H), 7.60-7.70 (m, 2H), 7.83
3
3
(d, 1H, J ) 7.8), 7.94 (d, 1H, J ) 7.6), 8.05 (s, 1H), 10.08 (s,
1H); MS (TSP+) 227 (MH+), 244 (MNH4+). This compound,
when left in deuterated methanol, slowly transformed into the
3
hemiketal: 1H NMR (CD3OD) δ 5.41 (s, 1H), 7.19 (t, 1H, J )
3
10.1), 7.40-7.57 (m, 6H), 7.66 (d, 1H, J ) 10.0).
7-(m -Cya n op h en yl)tr op olon e (4g): 32 mg; 1H NMR δ
7.11-7.22 (m, 1H), 7.46-7.49 (m, 2H), 7.55-7.63 (m, 2H), 7.72
3
7.78 (m, 4H), 8.12 (d, 2H, J ) 7.6), 8.18 (s, 2H); MS (TSP+)
3
3
(d, 1H, J ) 7.7), 7.79 (d, 1H, J ) 7.8), 7.84 (s, 1H); 13C NMR
(90 MHz) δ 112.61, 118.57, 120.99, 127.51, 129.09, 131.73,
132.97, 133.81, 137.36, 137.53, 140.28, 141.06, 169.80, 171.98;
IR (KBr) ν: 3204 (OH), 2227 (CN), 1598 (CO) cm-1; MS (TSP+)
241 (MNH4+).
439 (MH+).
4,6-Di(1-n a p h th yl)-2,3,7-tr im eth oxytr op on e (25j): H/A
1
) 7:3; 89 mg; isolated as a 1:1 mixture of rotamers; H NMR
δ 3.63 (s, 3H), 3.76 (s, 3H), 4.12 (s, 3H), 7.00 and 7.03 (s, 1H),
7.37-7.90 (m, 14H).
The same compound was isolated from the reaction between
TMSI and oximes 3k ,l using the above procedure, in 72% yield
(24 mg) and 77% yield (25 mg), respectively.
7-(5-P yr im id yl)tr op olon e (4i). This was carried out on
a 0.112-mmol scale. The general procedure was followed up
to the hydrolysis step. After evaporation of the volatile and
treatment with toluene as above, the crude solid material was
dissolved in 10 mL of water and 6 mL of methanol. To this
stirring solution was slowly added a solution of silver nitrate
4,6-Di(2-n a p h th yl)-2,3,7-tr im eth oxytr op on e (25k ): H/A
) 7:3; 73 mg; 1H NMR δ 3.68 (s, 3H), 3.84 (s, 3H), 4.10 (s,
3H), 7.27 (s, 1H), 7.45-7.60 (m, 6H), 7.70-7.94 (m, 8H).
4,6-Bis[m -[5-(2-n a p h th yl)-2-oxa d ia zolyl]p h en yl]-2,3,7-
tr im eth oxytr op on e (25l): H/A ) 1:1; 66 mg; 1H NMR δ 3.78
(s, 3H), 3.90 (s, 3H), 4.11 (s, 3H), 7.09 (s, 1H), 7.45-7.72 (m,
8H), 7.88-8.03 (m, 6H), 8.19-8.28 (m, 6H), 8.66 (s, 2H); MS
(TSP+) 737 (MH+).

Potent Inhibitors of Inositol Monophosphatase
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4219
(18.7 mg, 0.112 mmol) in water (10 mL), and stirring was
continued for 15 min. Filtration through a Millipore mem-
brane and evaporation yielded 19 mg of the desired tropolone
as a yellow powder (85% yield): 1H NMR (CD3OD) δ 7.20 (td,
1H, J ) 1.4, J ) 9.7), 7.38-7.58 (m, 2H), 7.75 (d, 1H, J )
9.1), 8.97 (s, 2H), 9.14 (s, 1H); MS (TSP+) 201 (MH+).
6-P h en yl-3,7-d ih yd r oxytr op olon e (1a ): 27 mg; 1H NMR
(CD3OD) δ 7.07 (d, 1H, 3J ) 11.8), 7.15 (d, 1H, 3J ) 11.8),
7.31-7.48 (m, 5H); 13C NMR (CD3OD) δ 119.62, 128.61, 129.07,
130.44, 131.68, 132.82, 141.49, 151.73, 155.94, 158.07, 163.29;
MS (TSP-) 229 (MH-). Anal. (C13H10O4) C, H.
8.2), 7.82-7.92 (m, 4H); MS (TSP+) 281 (MH+). Anal.
(C17H12O4) C, H.
6-[m -[5-(2-Na p h t h yl)-2-oxa d ia zolyl]p h en yl]-3,7-d ih y-
d r oxytr op olon e (1p ): 58 mg; 1H NMR (CD3OD) δ 7.13 (d,
1H, 3J ) 11.9), 7.19 (d, 1H, 3J ) 11.9), 7.50-7.69 (m, 4H),
7.84-7.98 (m, 3H), 8.12-8.23 (m, 2H), 8.24 (s, 1H), 8.59 (s,
1H); MS (TSP+) 425 (MH+). Anal. (C25H16N2O5‚0.5H2O) C,
H; N: calcd, 6.46; found, 5.90.
4
3
3
6-(2-Ben zofu r yl)-3,7-d ih yd r oxytr op olon e (1q): 25 mg;
3
1H NMR (DMSO-d6) δ 7.01 (d, 1H, J ) 12.2), 7.22-7.37 (m,
3
3
2H), 7.61 (d, 1H, J ) 8.3), 7.72 (d, 1H, J ) 8.4), 7.78 (s, 1H),
7.96 (d, 1H, 3J ) 12.2); HR-MS (FAB) calcd for C15H11O5
271.0605, found 271.0606. Anal. (C15H10O5‚2.5H2O) C; H:
calcd, 4.79; found, 4.04.
6-(p-Hyd r oxyp h en yl)-3,7-d ih yd r oxytr op olon e (1b): 18
1
mg from 19a and 35 mg from 20b; H NMR (CD3OD) δ 6.83
(d, 2H, 3J ) 8.4), 7.05 (d, 1H, 3J ) 11.9), 7.15 (d, 1H, 3J )
11.9), 7.31 (d, 2H, 3J ) 8.3); MS (TSP+) 247 (MH+). Anal.
(C13H10O5‚H2O) C, H.
6-(2-Th ien yl)-3,7-d ih yd r oxytr op olon e (1r ): 28 mg; 1H
NMR (DMSO-d6) δ 6.93 (d, 1H, 3J ) 12.2), 7.17 (t, 1H, 3J )
5.5), 7.62-7.82 (m, 3H); MS (TSP+) 237 (MH+); HR-MS (FAB)
calcd for C11H9O4S 237.0221, found 237.0219.
6-(o,m′-Dih ydr oxyph en yl)-3,7-dih ydr oxytr opolon e (1c):
16 mg; 1H NMR (CD3OD) δ 6.60-6.76 (m, 3H), 7.01 (d, 1H, 3J
6-(3-Th ien yl)-3,7-d ih yd r oxytr op olon e (1s): 20 mg; 1H
3
) 10.8), 7.12 (d, 1H, J ) 10.8); MS (TSP+) 263 (MH+). Anal.
3
NMR (360 MHz/DMSO-d6) δ 6.96 (d, 1H, J ) 12.0), 7.29 (d,
(C13H10O6‚0.33H2O) C, H.
3
3
3
1H, J ) 12.0), 7.44 (d, 1H, J ) 4.9), 7.58 (dd, 1H, J ) 3.0,
4.9), 7.82 (d, 1H, 3J ) 3.0); MS (TSP+) 237 (MH+). Anal.
(C11H8O4S) C, H.
6-(o-Flu or oph en yl)-3,7-dih ydr oxytr opolon e (1d): 35 mg;
1H NMR (CD3OD) δ 7.05 (s, 2H), 7.08-7.42 (m, 4H); 19F NMR
(CD3OD) δ 49.1-49.3 (m, 1F); MS (TSP+) 271 (MH+). Anal.
(C13H9O4F) C, H.
6-(5-P yr im id yl)-3,7-d ih yd r oxytr op olon e (1t): 29 mg;
procedure was the same as for compound 5i; 1H NMR (DMSO-
6-[m -(Tr iflu or om et h yl)p h en yl]-3,7-d ih yd r oxyt r op o-
lon e (1e): 31 mg; 1H NMR (CD3OD) δ 7.12 (s, 2H), 7.57-7.77
(m, 4H); 19F NMR (CD3OD) δ 101.80 (s, 3F); MS (TSP+) 299
(MH+), 316 (MNH4+). Anal. (C14H9O4F3) C, H.
6-[p -(Tr iflu or om e t h yl)p h e n yl]-3,7-d ih yd r oxyt r op o-
3
3
d6) δ 7.02 (d, 1H, J ) 11.6), 7.17 (d, 1H, J ) 11.6), 8.90 (s,
2H), 9.17 (s, 1H); MS (TSP+) 233 (MH+); HR-MS (FAB) calcd
for C11H9N2O4 233.0562, found 233.0567.
6-(4-Hyd r oxybu tyl)-3,7-d ih yd r oxytr op olon e (1u ): 10
1
3
mg; H NMR (CD3OD) δ 1.55-1.78 (m, 4H), 2.80 (t, 2H, J )
7.5), 3.58 (t, 2H, 3J ) 6.3), 6.99 (d, 1H, 3J ) 11.7), 7.09 (d, 1H,
3J ) 11.7); MS (TSP+) 209 (MH+ - H2O), 227 (MH+); HR-MS
(FAB) calcd for C11H9N2O4 227.0919, found 227.0916.
1
lon e (1f): 36 mg from 20c; H NMR (CD3OD) δ 7.06 (d, 1H,
3
3
3J ) 11.6), 7.17 (d, 1H, J ) 11.6), 7.64 (d, 2H, J ) 8.4), 7.72
(d, 2H, 3J ) 8.4); 19F NMR (CD3OD) δ 101.00 (s, 3F); MS (TSP+)
299 (MH+), 316 (MNH4+). Anal. (C14H9O4F3‚0.25H2O) C, H.
6-[m ,m -Bis(t r iflu or om e t h yl)p h e n yl]-3,7-d ih yd r oxy-
4,6-Bis(p-h ydr oxyph en yl)-3,7-dih ydr oxytr opolon e (26a):
50 mg; after treatment with sodium thiosulfate, the product
tr op olon e (1g): 37 mg; 1H NMR (CD3OD) δ 7.08 (d, 1H, J )
3
1
was washed with diethyl ether; H NMR (CD3OD) δ 6.82 (d,
12.2), 7.17 (d, 1H, 3J ) 12.2), 7.96 (s, 1H), 8.06 (s, 2H); 19F
NMR (CD3OD) δ 101.77 (s, 6F); MS (TSP+) 367 (MH+). Anal.
(C15H8O4F6) C, H.
3
3
4H, J ) 8.9), 7.17 (s, 1H), 7.30 (d, 4H, J ) 8.9); MS (TSP+)
339 (MH+). Anal. (C19H14O6‚0.5Et2O‚H2O) C, H.
4,6-Bis[o-(flu or om et h yl)p h en yl]-3,7-d ih yd r oxyt r op o-
6-(m -F or m ylp h en yl)-3,7-d ih yd r oxytr op olon e (1h ): 21
1
lon e (26b): 27 mg; H NMR δ 7.13-7.26 (m, 6H), 7.34-7.44
1
3
mg; H NMR (CD3OD) δ 7.09 (d, 1H, J ) 11.6), 7.17 (d, 1H,
(m, 3H); 19F NMR δ 48.34 (br s, 2F); MS (TSP+) 343 (MH+).
Anal. (C19H12O4F2‚0.25H2O) C, H.
3J ) 11.6), 7.64 (t, 1H, J ) 7.7), 7.79 (d, 1H, J ) 7.8), 7.92
(d, 1H, 3J ) 7.5), 8.01 (s, 1H), 10.04 (s, 1H); MS (TSP+) 259
(MH+), 276 (MNH4+). Anal. (C14H10O5) C, H. This compound,
when left in deuterated methanol, slowly transformed into the
hemiketal: 1H NMR (CD3OD) δ 5.43 (s, 1H), 7.12-7.52 (m,
6H).
3
3
4,6-Bis[m -(t r iflu or om e t h yl)p h e n yl]-3,7-d ih yd r oxy-
tr op olon e (26c): 20 mg; 1H NMR (360 MHz/DMSO-d6) δ 7.04
3
3
(s, 1H), 7.64 (t, 2H, J ) 8.6), 7.72 (d, 2H, J ) 8.6), 7.78 (d,
2H, 3J ) 8.6), 7.84 (s, 2H); 19F NMR (338 MHz/DMSO-d6) δ
101.71 (s, 6F); MS (TSP+) 443 (MH+). Anal. (C21H12
-
6-(m -Cya n op h en yl)-3,7-d ih yd r oxytr op olon e (1i): 28 mg;
O4F6‚0.25H2O) C, H.
3
1H NMR (CD3OD) δ 7.10 (s, 2H), 7.60 (t, 1H, J ) 7.7), 7.72
4,6-Bis[p -(t r iflu or om e t h yl)p h e n yl]-3,7-d ih yd r oxy-
tr op olon e (26d ): 50 mg; 1H NMR (360 MHz/DMSO-d6) δ 7.09
(s, 1H), 7.68-7.74 (m, 8H); 19F NMR (338 MHz/DMSO-d6) δ
101.75 (s, 6F); MS (TSP+) 443 (MH+); HR-MS (FAB) calcd for
C21H13O4F6 443.0718, found 443.0705.
(d, 1H, 3J ) 7.8), 7.76 (d, 1H, 3J ) 7.8), 7.84 (s, 1H); MS (TSP-)
255 (MH-). Anal. (C14H9NO4‚0.25H2O) C, H, N.
6-(m -Aceta m id op h en yl)-3,7-d ih yd r oxytr op olon e (1j):
21 mg; 1H NMR (CD3OD) δ 2.12 (s, 3H), 7.03 (d, 1H, 3J ) 11.7),
7.13 (d, 1H, 3J ) 11.7), 7.18 (d, 1H, 3J ) 8.2), 7.37 (t, 1H, 3J )
8.3), 7.58 (d, 1H, 3J ) 8.3), 7.63 (s, 1H); MS (TSP+) 288 (MH+),
305 (MNH4+). Anal. (C15H13NO5‚0.33H2O) C, H; N: calcd,
4.72; found, 3.93.
4,6-Bis[m ,m -b is(t r iflu or om et h yl)p h en yl]-3,7-d ih yd r -
1
oxytr op olon e (26e): 74 mg; H NMR δ 7.19 (s, 1H), 7.7 (s,
2H), 7.96 (s, 4H); 19F NMR δ 99.07 (s, 12F); MS (TSP+) 579
(MH+). Anal. (C23H10O4F12) C, H.
6-[p-(2-Am in oeth yl)ph en yl]-3,7-dih ydr oxytr opolon e (1l):
4,6-Bis(m -for m ylp h en yl)-3,7-d ih yd r oxytr op olon e (26f):
47 mg; one of the aldehyde functions was found to have
3
33 mg; 1H NMR (CD3OD) δ 3.00 (t, 2H, J ) 7.8), 3.23 (t, 2H,
3
3
3J ) 7.8), 7.06 (d, 1H, J ) 11.8), 7.13 (d, 1H, J ) 11.8), 7.34
(d, 2H, 3J ) 8.2), 7.46 (d, 2H, 3J ) 8.2); MS (TSP-) 272 (MH-);
HR-MS (FAB) calcd for C15H16NO4 274.1079, found 271.1091.
Anal. (C15H15NO4‚HI‚1.5H2O) H, N; C: calcd, 42.07; found,
41.28.
1
transformed into a hemiketal; H NMR δ 5.44 (s, 1H), 7.23-
7.30 (m, 1H), 7.44-7.48 (m, 3H), 7.57 (s, 1H), 7.62-7.66 (m,
3
3
1H), 7.77 (d, 1H, J ) 7.9), 7.92 (d, 1H, J ) 7.6), 7.99 (s, 1H),
10.08 (s, 1H); MS (TSP+) 363 (MH+), 380 (MNH4+). Anal.
(C21H16O7‚0.75H2O) C, H.
6-(m-Nitr oph en yl)-3,7-dih ydr oxytr opolon e (1m ): 21 mg;
4,6-Bis(m -cya n op h en yl)-3,7-d ih yd r oxytr op olon e (26g):
3
3
1H NMR (CD3OD) δ 7.12 (d, 1H, J ) 11.6), 7.19 (d, 1H, J )
11.6), 7.72 (t, 1H, 3J ) 7.9), 7.91 (d, 1H, 3J ) 7.6), 8.27 (d, 1H,
3J ) 8.4), 8.37 (s, 1H); MS (TSP-) 274 (MH-); HR-MS (FAB)
calcd for C13H10NO6 276.0508, found 276.0504.
1
37 mg; H NMR (DMSO-d6) δ 7.03 (s, 1H), 7.61 (t, 2H, 3J )
7.6), 7.78-7.88 (m, 4H), 7.97 (s, 2H); MS (TSP+) 357 (MH+),
374 (MNH4+). Anal. (C21H12N2O4‚0.5H2O) C, H, N.
4,6-Bis(m -a cet a m id op h en yl)-3,7-d ih yd r oxyt r op olon e
(26h ): 17 mg; 1H NMR (CD3OD) δ 2.12 (s, 3H), 6.82 (d, 4H, 3J
) 8.9), 7.17 (s, 1H), 7.30 (d, 4H, 3J ) 8.9); MS (TSP+) 421
(MH+), 438 (MNH4+); HR-MS (FAB) calcd for C23H21N2O6
421.1400, found 421.1402. Anal. (C23H20N2O6‚2.5H2O) C, N;
H: calcd, 5.46; found, 4.83.
6-[(1-Na p h th yl)p h en yl]-3,7-d ih yd r oxytr op olon e (1n ):
1
34 mg; H NMR (CD3OD) δ 7.03 (d, 1H, 3J ) 12.2), 7.12 (d,
1H, 3J ) 12.2), 7.29-7.58 (m, 5H), 7.85-7.94 (m, 2H); MS
(TSP+) 281 (MH+). Anal. (C17H12O4‚1.33H2O) C, H.
6-[(2-Na p h th yl)p h en yl]-3,7-d ih yd r oxytr op olon e (1o):
41 mg; 1H NMR δ (CD3OD/CDCl3): 7.10 (d, 1H, 3J ) 12.2),
4,6-Bis(m -n itr op h en yl)-3,7-d ih yd r oxytr op olon e (26i):
3
3
1
7.24 (d, 1H, J ) 12.2), 7.44-7.52 (m, 2H), 7.59 (d, 1H, J )
21 mg; H NMR (DMSO-d6) δ 7.10 (s, 1H), 7.70 (t, 2H, 3J )

4220 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26
Piettre et al.
3
3
1,2,4,6-tetraol. J . Chem. Soc., Chem. Commun. 1995, 2353-
2356. (d) Schnetz, N.; Gue´dat, Ph.; Spiess, B.; Schlewer, G.
Synthesis of Thioanalogues of myo-Inositol-1-monophosphate as
Possible Inhibitors of myo-Inositol Monophosphatase. Bull. Soc.
Chim. Fr. 1996, 133, 205-208.
7.6), 7.94 (d, 4H, J ) 7.8), 8.21 (d, 2H, J ) 7.4), 8.31 (s, 2H);
MS (TSP-) 395 (MH-); HR-MS (FAB) calcd for C19H13N2O8
397.0672, found 397.0667. Anal. (C19H13N2O8‚0.75H2O) C;
H: calcd, 3.32; found, 2.83.
4,6-Di(1-n aph th yl)-3,7-dih ydr oxytr opolon e (26j): 48 mg;
isolated as a 1:1 mixture of rotamers; 1H NMR δ 6.93 and 6.98
(s, 1H), 7.48-7.70 (m, 10H), 7.88-7.99 (m, 4H); MS (TSP+)
407 (MH+); HR-MS (FAB) calcd for C27H19O4 407.1277, found
407.1283. Anal. (C27H18O4‚2H2O) C; H: calcd, 5.01; found,
4.24.
4,6-Di(2-n a p h th yl)-3,7-d ih yd r oxytr op olon e (26k ): 46
mg; 1H NMR δ 7.48-7.60 (m, 6H), 7.68 (d, 2H, 3J ) 8.3), 7.85-
7.99 (m, 7H); MS (TSP+) 407 (MH+). Anal. (C27H18O4) C, H.
4,6-Bis[m -[5-(2-n a p h th yl)-2-oxa d ia zolyl]p h en yl]-3,7-d i-
h yd r oxytr op olon e (26l): 26 mg; 1H NMR (DMSO-d6) δ 7.17
(s, 1H), 7.57-7.82 (m, 9H), 7.99-8.22 (m, 9H), 8.31 (s, 2H),
8.80 (s, 2H). Anal. (C43H26N4O6‚H2O) C, H; N: calcd, 7.86;
found, 7.05.
4,6-Di(2-ben zofu r yl)-3,7-d ih yd r oxytr op olon e (26m ): 42
mg; 1H NMR (CD3OD) δ 7.20-7.40 (m, 4H), 7.61-7.69 (m, 4H),
7.78 (s, 2H), 9.20 (s, 1H); MS (TSP+) 387 (MH+); HR-MS (FAB)
calcd for C23H15O6 387.0868, found 387.0875. Anal. (C23H14O6‚
1.25H2O) C, H.
4,6-Di(3-th ien yl)-3,7-d ih yd r oxytr op olon e (26n ): 46 mg;
1H NMR δ 7.40-7.48 (m, 4H), 7.55-7.65 (m, 2H), 7.68 (s, 1H);
MS (TSP+) 319 (MH+); HR-MS (FAB) calcd for C15H11O4S2
319.0098, found 319.0087. Anal. Calcd for C15H10O4S2: C,
56.59; H, 3.17. Found: C, 57.18; H, 3.69.
Oxim e of 7-(m -F or m ylp h en yl)tr op olon e (3k ). The pro-
cedure used for the preparation of oximes 3k ,l was followed
using aldehyde 4f (50 mg, 0.22 mmol), pyridine (70 mg, 72
µL, 0.88 mmol), and hydroxylamine hydrochloride (15.3 mg,
0.24 mmol) in ethanol. Evaporation of the organic extract
furnished 52 mg of the pure oxime 3k (98% yield): 1H NMR δ
7.03-7.48 (dt, 1H, 4J ) 2.0, 3J ) 10.4), 7.49 (m, 4H), 7.58-
7.66 (m, 3H), 8.13 (s, 1H); MS (TSP+) 242 (MH+), 259 (MNH4+).
In h ibition of IMP a se by Tr op olon e Der iva tives. The
human recombinant enzyme was produced in Escherichia coli
and purified to homogeneity as previously described.8f,g IC50
values were determined at 37 °C in 50 mM TrisCl, 250 mM
KCl, pH 7.5, using a radiochemical assay with 0.2 mM DL-
myo-inositol 1-phosphate (2 × Km), 0.2 µCi/µmol D-[3H]inositol
1-phosphate, 2 mM MgCl2, and varying concentrations of
inhibitor.37 Ki values were determined at 37 °C and pH 7.5
by measuring the release of inorganic phosphate in a coupled
spectrophotometric assay.8f,g The concentrations of substrate
were varied between 0.05 and 0.5 mM at different fixed
concentrations of inhibitor with 0.5 mM MgCl2. For all
experiments the amount of enzyme was adjusted so that no
more than 10% of the substrate was utilized during the
reaction.
(6) McAllister, G.; Whiting, P.; Hammond, E. A.; Knowles, M. R.;
Atack, J . R.; Bailey, F. J .; Maigetter, R.; Ragan, C. I. cDNA
Cloning of Human and Rat Brain myo-Inositol Monophos-
phatase. Biochem. J . 1992, 284, 749-754.
(7) (a) Bone, R.; Springer, J . P.; Atack, J . R. Structure of Inositol
Monophosphatase, the Putative Target of Lithium Therapy.
Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 10031-10035. (b) Bone,
R.; Frank, L.; Springer, J . P.; Pollack, S. J .; Osborne S.; Atack,
J . R.; Knowles, M. R.; McAllister, G.; Ragan, C. I.; Broughton,
H. B.; Baker, R.; Fletcher, S. R. Structural Analysis of Inositol
Monophosphatase Complexes with Substrates. Biochemistry
1994, 33, 9460-9467. (c) Bone, R.; Frank, L.; Springer, J . P.;
Atack, J . R. Structural Studies of Metal Binding by Inositol
Monophosphatase: Evidence for two-Metal Ion Catalysis. Bio-
chemistry 1994, 33, 9468-9476. (d) Ganzhorn, A. J .; Rondeau,
J .-M. Structure of an Enzyme-Substrate Complex and the
Catalytic Mechanism of Human Brain myo-Inositol Monophos-
phatase. Protein Eng. 1997, 10 (Suppl.), 61.
(8) (a) Ganzhorn, A. J .; Chanal, M.-Ch. Kinetic Studies with myo-
Inositol Monophosphatase from Bovine Brain. Biochemistry
1990, 29, 6065-6071. (b) Greasley, P. J .; Gore, M. G. Bovine
Inositol Monophosphatase. Studies on the Binding Interactions
of Magnesium, Lithium and Phosphate Ions. FEBS Lett. 1993,
331, 114-118. (c) Leech, A. P.; Baker, R.; Shute, J . K.; Cohen,
M. A.; Gani, D. Chemical and Kinetic Mechanisms of the Inositol
Monophosphatase Reaction and its Inhibition by Li+. Eur. J .
Biochem. 1993, 212, 693-704. (d) Pollack, J . S.; Atack, J . R.;
Knowles, M. R.; McAllister, G.; Ragan, C. I.; Baker, R.; Fletcher,
S. R.; Iversen, L. L.; Broughton, H. B. Mechanism of Inositol
Monophosphatase, the putative Target of Lithium Therapy. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 5766-5770. (e) Wilkie, J .; Cole,
A. G.; Gani, D. 3-Dimensional Interactions between Inositol
Monophosphatase and its Substrates, Inhibitors and Metal Ion
Cofactors. J . Chem. Soc., Perkin Trans. 1 1995, 2709-2727. (f)
Ganzhorn, A. J .; Lepage, P.; Pelton, P. D.; Strasser, F.; Vincen-
don, P.; Rondeau, J .-M. The contribution of Lysine-36 to
Catalysis by Human myo-Inositol Monophosphatase. Biochem-
istry 1996, 35, 10957-10966. (g) Strasser, F.; Pelton, P. D.;
Ganzhorn, A. J . Kinetic Characterization of Enzyme Forms
Involved in Metal Ion Activation and Inhibition of Myo-inositol
Monophosphatase. Biochem. J . 1995, 307, 585-593.
(9) (a) Baker, R.; Carrick, C.; Leeson, P. D.; Lennon, I. C.; Liverton,
N. J . Design and Synthesis of 6R-Substituted 2â,4R-Dihydroxy-
1-phosphoryloxycyclohexanes, Potent Inhibitors of Inositol Mono-
phosphatase. J . Chem. Soc., Chem. Commun. 1991, 298-300.
(b) Fletcher, S. R.; Baker, R.; Ladduwhahetty, T.; Sharpe, A.;
Teall, M.; Atack, J . R. 4-Hydroxyphenoxymethylene Bisphos-
phonic Acid Derivatives: Potent, Non-hydrolysable Inhibitors
of myo-Inositol Monophosphatase. Bioorg. Med. Chem. Lett.
1993, 3, 141-146.
(10) (a) Atack, J . R.; Cook, S. M.; Watt, A. P.; Fletcher, S. R.; Ragan,
C. I. In Vitro and In Vivo Inhibition of Inositol Monophosphatase
by the Bisphosphonate L-690,330. J . Neurochem. 1993, 60, 652-
658. (b) Atack, J . R.; Prior, A. M.; Fletcher, S. R.; Quirk, K.;
McKernan, R.; Ragan, C. I. Effects of L-690,488, a Prodrug of
the Bisphosphonate Inositol Monophosphatase Inhibitor L-690,
330, on Phosphatidylinositol Markers. J . Pharmacol. Exp. Ther.
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Refer en ces
(1) Billington, D. C. The Inositol Phosphates. Chemical Synthesis
and Biological Significance; VCH Publisher: Wheinheim, 1991;
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(11) Piettre, S. R.; Ganzhorn, A.; Hoflack, J .; Islam, K.; Hornsperger,
J .-M. R-Hydroxytropolones: A New Class of Potent Inhibitors
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Am. Chem. Soc. 1997, 119, 3201-3204.
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and Other Agents on the Activity of myo-Inositol Monophos-
phatase from Bovine Brain. J . Biol. Chem. 1980, 255, 10896-
10901. (b) Berridge, M. J .; Downes, P. F.; Hanley, M. R. Lithium
Amplifies Agonist-Dependent Phosphatidylinositol Responses in
Brain and Salivary Glands. Biochem. J . 1982, 206, 587-595.
(c) Nahorski, S. R.; Ragan, C. I.; Challiss, R. A. J . Lithium and
the Phosphoinositide Cycle: An Example of Uncompetitive
Inhibition and its Pharmacological Consequences. Trends Phar-
macol. Sci. 1991, 12, 297-303.
(12) Methyltropone i was first briefly considered for derivatization
because of the possibility of bromination of the methyl group.13
However a variety of conditions led only to the bromine being
introduced on the cycle. On the other hand, reactions between i
and tert-butyllithium or freshly prepared lithium diisopropyl-
amide (LDA) provided products ii and iii in low yields (see
Experimental Section), resulting from substitution of the seven-
membered ring methoxy group (as demonstrated by 1H and 13C
NMR experiments in 1-D and 2-D modes at 500 and 125 MHz).
Moreover attempts to substitute the bromine atom of 7-bromo-
2-methoxytropone (3) with alcohols under basic or acidic condi-
tions gave either untractable mixtures or, again, compounds
arising from replacement of the methoxy group (low yields).15
(13) 2-Carbomethoxy-3-methyl-7-methoxytropone was obtained by
methylation of 6-methyl-7-carboxytropolone, a byproduct of the
preparation of 6-carboxymethyl-7-carboxytropolone;14 see Ex-
perimental Section.
(3) Mitchell, P. B.; Parker, G. B. Treatment of Bipolar Disorders.
Med. J . Aust. 1991, 151, 488-493.
(4) Peet, M.; Pratt, J . P. Lithium. Current Status in Psychiatric
Disorders. Drugs 1993, 46, 7-17.
(5) (a) Atack, J . R.; Fletcher, S. R. Inhibitors of Inositol Monophos-
phatase. Drugs Future 1994, 19, 857-866 and references therein
(review article). (b) van Steijn, A. M. P.; Willems, H. A. M.; de
Boer, Th.; Geurts, J . L. T.; van Boeckel, C. A. A. Synthesis of
myo-Inositol-1-Phosphatase Inhibitors in which the Phosphate
Group is Replaced by Less Polar Groups. Bioorg. Med. Chem.
Lett. 1995, 5, 469-474. (c) Schulz, J .; Wilkie, J .; Lightfoot, Ph.;
Rutherford, T.; Gani, D. Synthesis and Properties of Mechanism-
based Inhibitors and Probes for Inositol Monophosphatase
Derived from 6-O-(2′-Hydroxyethyl)-(1R,2R,4R,6R)-cyclohexane-
(14) Haworth, R. D.; Hobson, J . D. Purpurogallin. Part IV. Some
Properties of Tropolones. J . Chem. Soc. 1951, 561-568.
(15) Pietra, F. Revival of Troponoid Chemistry. Acc. Chem. Res 1979,
12, 132-138.

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(16) Suri, S. C.; Nair, V. Palladium(0)-Catalysed Reaction of 2-Bromo-
7-methoxytropone with Arylboronic Acids: An Efficient Synthe-
sis of 2-Aryl-7-methoxytropones. Synthesis 1990, 695-696.
(17) (a) Takeshita, H.; Mori, A.; Kusaba, T. An Improved Synthesis
of 2,7-Dihydroxytropone (3-Hydroxytropolone). Synthesis 1986,
578-579. (b) Takeshita, H.; Mori, A.; Kusaba, T.; Watanabe, H.
Preparation of Polyacetoxytropones and Polyhydroxytropolones
by Acetolysis and Hydrolysis of Halotroponoids by Acetyl Tri-
fluoroacetate with Exhaustive Displacement of Halogens on the
Tropone Ring. Predominant Formation of Reductive Acetolysates
from Fully-Substituted Tropones. Bull. Chem. Soc. J pn. 1987,
60, 4325-4333.
(27) This speculative hemiketal would result from the interaction
between the tropolonic oxygen adjacent to the o-CHO-phenyl and
the aldehyde group; no aldehyde signal could be observed by 1
NMR spectroscopy.
H
(28) Deprotection of the permethylated tropolone derivative resulted
in the formation of the desired amino compound (as shown by
1H NMR spectroscopy); however, this material was highly
impure, and efforts to purify it did not succeed. The methods
used to attempt purification include classical chromatography
or HPLC on silica gel (reverse-phase), cellulose, and resins as
well as crystallization in various solvents.
(29) Horner, L.; Go¨wecke, S. o-Quinones. XVI. Addition Reactions of
3-Methoxy-o-quinone. Chem. Ber. 1961, 94, 1267-1276.
(30) Commercially available purpurogallin was sublimed (200 °C/
0.001 mbar) before use.
(31) Nozoe, T.; Doi, K.; Hashimoto, T. Synthesis of Puberulonic Acid.
Bull. Chem. Soc. J pn. 1960, 33, 1071-1074.
(32) Cleland, W. W. Statisitical Analysis of Enzyme Kinetic Data.
In Methods in Enzymology; Purich, D. L., Ed.; Academic Press:
New York, 1979; Vol. 63, pp 103-138.
(33) Only 10 compounds encompassing the 3,7-dihydroxytropolonic
unit have been reported so far in the literature, among which
are the parent compound 8, 3,5,7-trihydroxytropolone, and the
natural products puberulonic acid and puberulic acid.
(34) It should be noted that the results described in this paper are
adaptable to solid-phase synthesis; Piettre, S. R.; Baltzer, S. A
New Approach to the Solid-Phase Suzuki Reaction. Tetrahedron
Lett. 1997, 38, 1197-2000.
(35) Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic
Technique for Preparative Separation with Moderate Resolution.
J . Org. Chem. 1978, 43, 2923-2924.
(36) The boronic acid and ethanol can also be added sequentially
(cases of poor solubility).
(18) Nozoe, T. Recent Advances in the Chemistry of Troponoids and
Related Compounds in J apan. Pure Appl. Chem. 1971, 28, 239-
280.
(19) Preparation of boronic acids was needed in several cases.
(20) An improved procedure for the preparation of 3,7-dibromotropo-
lone was worked out.11
(21) Permethylated mono- and dibromodihydroxytropolones display
a tendency to react with excess diazomethane to form pyrazo-
lotropolone derivatives; precedents for this kind of reactivity
have been reported in the past.18
(22) (a) Davis, A. L.; Keeler, J .; Lane, E.; Moskau, D. Experiments
for Recording Pure Absorption Heteronuclear Correlation Spec-
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216. (b) Bax, A.; Summers, M. F. 1H and 13C Assignments from
Sensitivity-Enhanced Detection of Heteronuclear Multiple-Bond
Connectivity by 2-D Multiple Quantum NMR. J . Am. Chem. Soc.
1986, 108, 2093-2094.
(23) These included treatment with tert-butyllithium, tributyltin
hydride, and tris(trimethylsilyl)silane.
(24) The two experiments were carried out by the same person using
the same experimental procedure; the results thus demonstrate,
in this precise case, the extreme sensitivity of the reaction to
minute variations in experimental conditions. This is the only
example of ring contraction observed in this study; it is of note
that it is also the only example of a reaction between isomer 16
and
a boronic acid substituted in the para position by an
(37) Ragan, C. I.; Watling, K. J .; Gee, N. S.; Aspley, S.; J ackson, R.
G.; Reid, G. G.; Baker, R.; Billington, D. C.; Barnaby, R. J .;
Leeson, P. D. The Dephosphorylation of Inositol 1,4-Bisphos-
phate to Inositol in Liver and Brain Involves Two Distinct Li+-
sensitive Enzymes ans Proceeds via Inositol 4-Phosphate. Bio-
chem. J . 1988, 249, 143-148.
electron-withdrawing substituent. The results may be indicative
of an activation of the tropolone ring by the p-(trifluoromethyl)-
phenyl group toward nucleophilic species.
(25) The direct introduction of a nucleophile on the tropolone ring
resulted in the substitution of a methoxy substituent, leaving
the bromine untouched; S. R. Piettre, C. Schelcher, unpublished
results.
(38) Modeling experiments were carried out as described in ref 11.
(26) Treatment of permethylated dihydroxytropolones with TMSI at
room temperature resulted in the rapid cleavage of two of the
three ether functions; removal of the third methoxy group was
much slower (20% unconsumed after 24 h at room temperature)
and required heating.
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