Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors

Article abstract of DOI:10.1016/j.bmc.2006.06.050

Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C. 3.4.11.1), aminopeptidase-N (E.C. 3.4.11.2), Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10), and the aminopeptidase activity of leukotriene A₄ hydrolase (E.C. 3.3.2.6). Several compounds showed K_i values in the low micromolar range against the 'one-zinc' aminopeptidases, while most of them were rather poor inhibitors of the 'two-zinc' enzymes. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.

Full text of DOI:10.1016/j.bmc.2006.06.050

Bioorganic & Medicinal Chemistry 14 (2006) 7241–7257
Synthesis and structure activity relationships of novel non-peptidic
metallo-aminopeptidase inhibitors
a
a,
a
a,
*
*
´
´
Sebastien Albrecht, Albert Defoin, Emmanuel Salomon, Celine Tarnus,
Anders Wetterholmb and Jasper Z. Haeggstro¨mb
aLaboratoite de Chimie Organique et Bioorganique, UMR 7015, ENSCMu, F-68093 Mulhouse Cedex, France
bDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden
Received 22 March 2006; revised 15 June 2006; accepted 23 June 2006
Available online 17 July 2006
Abstract—Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopep-
tidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as het-
erocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase
(E.C. 3.4.11.1), aminopeptidase-N (E.C. 3.4.11.2), Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10), and the aminopeptidase
activity of leukotriene A4 hydrolase (E.C. 3.3.2.6). Several compounds showed Ki values in the low micromolar range against the
‘one-zinc’ aminopeptidases, while most of them were rather poor inhibitors of the ‘two-zinc’ enzymes. This interesting selectivity
profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
utmost importance in order to gain a deeper under-
standing of the biological functions of APs and to assess
their potential as drug targets. In the present study, we
focus on APs that prefer an hydrophobic residue in po-
sition P1. Many of these enzymes show a similar broad
specificity, except for a few ones which are highly specif-
ic. Although many AP inhibitors are already available,9–12
most of them are poorly selective. Moreover, the vast
majority of these compounds are amino acid or peptide
analogues, with a few notable exceptions such as the nat-
ural products curcumin and psammaplin A, and synthetic
flavonoid derivatives, notably 20,3-dinitroflavone-8-acetic
acid.12,13
Metallo-aminopeptidases (APs) remove amino acids
from unblocked N-termini of peptides and proteins.
This family of exopeptidases is widely distributed in nat-
ure, with representative members present in animal cells,
plants, bacteria and fungi. Although some APs are
secreted, the vast majority are either cytosolic or mem-
brane-bound enzymes.1–4
All metallo-aminopeptidases catalyse the same chemical
reaction. Generally cleavage of the scissile peptide bond
is dependent upon the chemical structure and composi-
tion of amino acid residues that flank the cleavage site
(P1 ꢀ P01).5 They can be broadly classified into two sub-
families on the basis of the number of their active site
zincs. While some of these enzymes contain only one-
zinc, others possess a binuclear metal centre, usually
referred to as a co-catalytic unit.5
Unfortunately, since all these APs are zinc-dependent
enzymes sharing a broad substrate specificity, the devel-
opment of specific inhibitors is undoubtedly a daunting
task. In the present study, we report on the design and
synthesis of 3-amino-2-tetralone derivatives, as well as
on their inhibitory activities against a panel of ‘one-zinc’
and ‘two zincs’ APs. 3-Amino-2-tetralone 1 has been de-
scribed as a selective inhibitor of the ‘one-zinc’ AP-N.14
We have found that 1 is not stable under physiological
conditions. In an attempt to identify more stable deriv-
atives of 1 and to gain insights into the selectivity-deter-
mining features, we have investigated a number of
structural modifications in positions 1–3 of 3-amino-2-
tetralone. A comprehensive list of the compounds
These APs are believed to play an important role in
many normal or pathophysiological processes.6–8 There-
fore, the design of highly specific, potent inhibitors is of
Keywords: Tetralone derivatives; Aminopeptidase inhibitors.
*
Corresponding authors. Tel.: +33 389336864; fax: +33 389336875;
e-mail addresses: Albert.Defoin@uha.fr; Celine.Tarnus@uha.fr
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.06.050

7242
S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
synthesised during the course of this work is provided in
Scheme 1.
carries an epoxide hydrolase activity that catalyses the
final step in the biosynthesis of leukotriene B4, a potent
chemotactic and immune modulating lipid mediator.14
All compounds were evaluated against the following en-
zymes: the mammalian cytosolic leucine aminopeptidase
(LAPc, E.C. 3.4.11.1) and the secreted, bacterial amino-
peptidase from Aeromonas proteolytica (APaero, E.C.
3.4.11.10) were used as representative members of the
‘two-zinc’ sub-family. The biological role of the ubiqui-
tous LAPc is not well-understood, nevertheless altered
activity is observed with a number of physiological pro-
cesses.7 The membrane-bound aminopeptidase M (also
referred to as or AP-N, E.C. 3.4.11.2) and the aminopep-
tidase activity of leukotriene A4 hydrolase (LTA4H, E.C.
3.3.2.6) were selected as representative of the ‘one-zinc’
sub-family. Both enzymes belong to the M1 family of
zinc-dependent metallopeptidases.4 AP-N is widely ex-
pressed at the surface of mammalian cells and up-regulat-
ed in a number of pathological processes including cell
migration and tumour growth.12 The precise function of
the LTA4H AP activity is currently not known but it also
Therefore, inhibitors of this family of enzymes may
prove to be interesting biological tools.
In this study, the parent compound 3-amino-2-tetralone
1 and bestatin, a well-known aminopeptidase inhibitor,
were used as reference inhibitors.
2. Chemistry
2.1. Tetralone-oxime derivatives (2a–g)
Preparation of amino-tetralone 115,16 has already been
described from 1,4-dihydronaphthalene 617 by epoxida-
tion, opening of this epoxide with ammonia, N-protec-
tion as Boc-derivative 7a, alcohol oxidation in ketone
8a and finally acidic N-deprotection (Scheme 2).
N
R
OR
NH2,HCl
2a R = H
NH2,HCl
3a R = H
b R = Me
c R = Bn
d R = CH2CH2Ph
e R = (CH2)3Ph
b R = CO-Me
c R = CO-NHOH
d R = P(O)(OH)2
1
O
2
A
B
3
NH2,HCl
f R = (CH2)4Ph
g R = (CH2)5Ph
1
H
N
O
X
O
NH2,HI
4a X = O
5
b X = S
c X = NOH
d X = NNH2
e X = CH2
Scheme 1.
HCl,H2N
(CH2)n-Ph
O
X
9a-g
NHZ
6
a Z = CO2tBu
7a,b X = H,OH
8a,b X = O
periodinane
HCl (a)
1
X = O,
b Z = CO2Bn or H2/Pd-C, HCl(b)
Z = H,HCl
N
N
a R = H
b R = Me
c R = Bn
H2/Pd-C
HCl
OR
OR
NHCO2Bn
NH2,HCl
d R = CH2CH2Ph
e R = (CH2)3Ph
10a-g
2a-g
f
R = (CH2)4Ph
g R = (CH2)5Ph
Scheme 2.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7243
For the synthesis of oximes 2a–g, the same initial reac-
NEt3, HNROR'
Pd(PPh3)4
CO, DMF
1. LiHMDS
THF, -78˚C
2. PhNTf2
tions were followed but N-protection was best carried
out as benzyloxycarbonyl derivative 7b, to prevent par-
tial hydrolysis of the oxime function to the correspond-
ing ketone, which otherwise occurred during the final
acidic deprotection of Boc-derivatives.
OTf
8a,b
70-80%
NHZ
a Z = CO2tBu
b Z = CO2Bn
12a,b
Quantitative oxidation of 7b to ketone 8b with Dess–
Martin periodinane18 followed with condensation with
hydroxylamine 9a or O-substituted hydroxylamines
9b–g19 provided N-protected oximes 10a–g, which were
quantitatively deprotected to yield final amino-oximes
2a–g by hydrogenolysis over Pd–C 5% in aqueous HCl
and ethanol (Scheme 2).
O
O
H2/Pd-C
NROR'
NHZ
NHOH
NH2
for 13b
13a R = R' = Me, Z = CO2tBu
b R = H, R' = Bn, Z = CO2Bn
3c
H2/PtO2 for 13a
2.2. Aminotetraline (3a)
O
O
MeMgCl
THF, 0˚C
The known amine 3a20–22 was prepared according to the
Bhattacharyya’s method23 (Scheme 3) by treatment of
b-tetralone 11 with ammonia in ethanol and titanium
(IV) isopropoxide, followed by in situ sodium borohy-
dride reduction in ca. 40% yield from 11.
NMeOMe
36%
NHCO2tBu
NHZ
15 Z = CO2tBu
3b Z = H, HCl
14
conc. HCl
EtOH/H2O
Scheme 4.
2.3. Amino-tetralinecarbonyl derivatives (3b–d)
The synthesis of these compounds is presented in
Scheme 4, starting from the aminoketones 8a and b
which were transformed into the triflate enol ethers
12a and b according to described method.24 Their
palladium-catalysed carbonylation under CO atmo-
sphere25,26 with the Weinreb hydroxylamine for the
Boc-derivative 12a or with O-benzyl-hydroxylamine
for the benzyloxycarbonyl derivative 12b provided the
crystalline dihydro-naphthalene-2-amides 13a and b,
respectively, in 68–80% yield from 8a or b. Hydrogena-
tion on Pd–C of the benzyl derivative 13b led directly to
a 60/40 isomeric mixture of hydroxamic acid 3c with
hydrogenolysis of the diverse protecting groups in 71%
yield. Hydrogenation over PtO2 of the Boc-derivative
13a give quantitatively a 80/20 isomeric mixture of tetra-
hydronaphthalene 14.
with HBr in AcOH led to amino phosphonic acid 3d as
70/30 isomeric mixture in 70% overall yield from 16.
2.4. Hetero-naphthalenones (4a–d)
Isochromanone 4a,29,30 isothiochromanone 4b29,31 and
dihydro-isoquinolinones 4d32 are known compounds.
Synthesis of isochromanone 4a was carried out from
homophthalic acid 18a. Monoesterification by SOCl2
in MeOH33 and reduction with borane34 gave easily a
variable mixture of alcohol-ester 19 and isochromanone
4a which provided pure 4a by heating in toluene at 80 ꢁC
in the presence of p-TsOH35 (Scheme 6).
Isothiochromanone 4b was synthesised by acidic opening
of isochromanone 4a with HBr in bromo-acid 20a,29 but
the cyclisation of the corresponding acid chloride with
sulfide ion gave unsatisfactory results and was therefore
realised via another route (Scheme 6). The bromo-acid
20a was reacted with thiourea and the thiouronium salt
was directly saponified with NaOH into the thiol-acid
21. Esterification of 21 with SOCl2/MeOH or with dia-
zomethane and cyclisation with AlMe336,37 provided iso-
thiochromanone 4b in 46 % overall yield from 4a.
Addition of the methylmagnesium onto 14 at 0 ꢁC gave
a 20/80 mixture of cis and trans isomers of methylketone
15 in moderate yield (36%) which was then quantitative-
ly acidic N-deprotected into the amino-ketone 3b (5/95
mixture of cis and trans isomers).
The triflate enol ether 12a was phosphonylated (Scheme
5) by palladium catalysed coupling of dimethyl phos-
phite27,28 to provide the dihydro-naphthalene-2-phos-
phonate 16 in 61% yield. Hydrogenation over PtO2
and acidic hydrolysis of the obtained phosphonate 16
N-Substituted isoquinolinones 4c and d were obtained
more simply by the method described for 4d32 by action
OTi(OiPr)3
NH2.HCl
O
NH2
1.NaBH4
2. HCl. Et2O
NH3-EtOH
Ti(OiPr)4
3a
11
Scheme 3.

7244
S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
1. LiHMDS
iPr2NEt, HP(O)(OMe)2
THF, -78˚C
Pd(OAc)2, dppf
OTf
2. PhNTf2
DMF
8a
t
NHCO2 Bu
12a
O
O
OMe
OR
P
P
H2/PtO2
OMe
OR
NHCO2tBu
NHZ
16
17 Z = CO2tBu, R=Me
3d Z = H, HBr, R=H
33 % HBr, AcOH
Scheme 5.
O
BH3
CO2R
CO2H
CO2Me
+
O
OH
18a R = H
18b R = Me
SOCl2
MeOH
4a
19
pTsOH, PhMe 80˚C
NH2OH
or NH2NH2
K2CO3
O
X
HBr/AcOH
CO2R
20b
N
Br
4c X = OH
4d X = NH2
20a R = H
20b R = Me
HCl
MeOH
1. thiourea
2. NaOH
1. CH2N2
2. AlMe3
O
CO2H
20a
S
SH
4b
21
Scheme 6.
of hydroxylamine for 4c or hydrazine for 4d with
bromo-ester 20b in ethanol.
3.1. Structural requirements for 3-amino-2-tetralone
activity
2.5. Aminoquinolinone (5)
The bicyclic structure 1, which may be described as a
conformationally constrained, cyclised phenylalanine
derivative, has previously been reported as a selective
inhibitor of the ‘one-zinc’ AP-N. Furthermore, it has
been proposed that the amino-tetralone scaffold acts as
a bidentate ligand, with both its amino and carbonyl
groups contributing to the coordination sphere of the
catalytic zinc.15 The primary amine function in position
3 is clearly an essential feature for inhibitory activity
since all N-protected derivatives reported herein were
inactive up to 1 M concentration. This result is also in
line with the well-known requirement for a free N-termi-
nus in peptide substrates of APs.15 Hence, the primary
amino group of 1 is likely to mimic the aminoterminal
amino group of an AP substrate. The carbonyl group
in position 2 also appears to be critical, presumably as
Amine 5 was prepared according to the lit.38,39 in two
steps (Scheme 7), by condensation of ortho-nitrobenzal-
dehyde (22) with N-acetylglycine (23) into aryl-isoxazo-
lone 24 which was then reduced and hydrolysed to 5 as
hydroiodide with red phosphor and HI in ca. 40% yield
from 22.
3. Aminopeptidase inhibition and discussion
All compounds were evaluated as racemic mixtures. All
active compounds behaved as competitive inhibitors of
the panel aminopeptidases. The inhibitory parameters
(Ki or IC50) are reported in Table 1.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7245
H
N
AcOH, 100˚C
AcONa
NO2
O
NO2
P/HI
NHAc
+
CO2H
NH2,HI
O
O
24
NH
5
23
22
O
Scheme 7.
Table 1. Inhibition of aminopeptidase activity
Compound
LAPc (E.C. 3.4.11.1)
APaero (E.C. 3.4.11.10)
AP-N (E.C. 3.4.11.2)
LTA4H (E.C. 3.3.2.6)
Bestatin
1
0.0005
120
0.0016
130
3.5
0.5
0.5
>1000
>1000
>1000
>1000
500
2a
2b
2c
>1000
>1000
>1000
>100
>1000
800
210
1800
130a
790
2d
2e
170
300
260a
110a
55a
>1000
>100
>100
6a
2f
110
130
8a
2g
3a
3b
3c
80a
30a
>1000
>1000
10a
>1000
500
4a
150
>1000
>1000
4a
>1000
750
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
3d
4a
4b
4c
>1000
>1000
>1000
>1000
1000
500
>1000
4a
4a
740
>1000
>1000
>1000
>1000
>1000
>1000
4d
4e
>1000
>1000
>1000
80a
5
All substances were evaluated as racemic mixtures. IC50 (lM) values were determined from Dixon plots at a substrate concentration set to the Km
value for the corresponding enzyme (see Section 5). Inactive compounds were tested up to their solubility limit under the assay conditions. Ki (lM, in
boldface) were also determined from Dixon plots. LAPc, cytosolic leucine aminopeptidase (E.C. 3.4.11.1); AP-N, aminopeptidase-N (E.C. 3.4.11.2);
APaero, Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10) and LTA4H, the aminopeptidase activity of leukotriene A4 hydrolase (E.C. 3.3.2.6).
a Ki (lM).
a surrogate of the carbonyl group of the scissile peptide
bond in AP substrates. In support of this view, alcohol
derivatives, which have been obtained by reduction of
the carbonyl function, have been shown to be very weak
inhibitors.15 The lack of binding affinity of compounds
3a and 4e, bearing either the primary amino or the car-
bonyl functionality, respectively, further corroborates
this hypothesis. Thus, our design strategy was focused
on analogues bearing new functionalities in positions 2
and 3, with the potential to display bidentate zinc-che-
lating properties. The primary amine was conserved in
most, but not all, cases.
‘two-zinc’ AP sub-family. Its bacterial twin sister from
A. proteolytica was only weakly inhibited, with IC50
values ranging from 110 to 210 lM, for the best com-
pounds, depending on the length of the alkyl spacer
between the oxime-oxygen and the phenyl ring. There
was no clear correlation between the chain length and
the observed inhibitory potency. By contrast, the
selected members of the ‘one-zinc’ enzymes (AP-N
and LTA4H aminopeptidase activity) seemed to be
more sensitive to this series of compounds, again
depending on the spacer length. AP-N was inhibited
by 2f and g with Ki values of 55 and 80 lM, respec-
tively. With such spacers of four to five carbon atoms
the phenyl ring might be able to reach the S1 hydro-
phobic binding pocket, simultaneously allowing opti-
mal positioning of the zinc chelating groups. Finally,
LTA4H was inhibited more selectively by 2e and f,
with remarkably low Ki values of 6 and 8 lM, respec-
tively. A chain length of at least three carbon atoms
was necessary to observe this level of inhibitory poten-
cy. Other inhibitors of LTA4H bearing such an alkyl-
phenyl group have already been reported.40 The lack
of inhibitory activity of the free oxime and its O-
methyl derivative strongly suggests that, in these struc-
tures, the O-substituted oxime function is not involved
in zinc-chelation.
3.2. Modifications of the carbonyl group
In a first series, the replacement of the carbonyl group
with potential zinc-chelating functions was investigated.
3.2.1. Oxime and O-substituted derivatives. Com-
pounds in the 2 series appeared to be rather poor
inhibitors of most APs evaluated. The free oxime
was unfortunately not an interesting chelating function
in our case, since derivative 2a was inactive on all
four AP enzymes. O-Substituted derivatives 2b–g were
totally inactive on the cytosolic porcine kidney leucine
aminopeptidase (LAPc), an important member of the

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S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
3.2.2. Other modifications in position 2. Derivative 3b
bearing a methyl ketone in position 2 was essentially
inactive on all sub-classes of aminopeptidases evaluated,
with IC50 values higher than or equal to 0.5 mM for
APaero.
against the bacterial enzyme from A. proteolytica. Thus,
this cyclised hydroxamic acid compound turned out to
be as active as the exocyclic hydroxamic acid 3c against
APaero. Furthermore, the isothiochromanone deriva-
tive 4b was also a good inhibitor of this enzyme
(Ki = 4 lM), equipotent to the hydroxamic acids 4c
and 3c.
The introduction of an hydroxamic acid, a potent zinc-
chelating function widely used for the design of metallo-
protease inhibitors,41–43 led to compound 3c which
inhibited most of the panel enzymes, with Ki values in
the low micromolar range. Interestingly, and in sharp
contrast to the more typical APs, LTA4H was not inhib-
ited by this particular structure, again suggesting that
zinc-chelation is more difficult to achieve for LTA4H
than for the more typical APs. This may be explained
by the distinct shape of the LTA4H active site, a long
and narrow hydrophobic cleft with a deeply buried zinc
ion.44 The active sites of known APs are more open and
their zinc ion(s) thus more accessible.9,45,46
3.3. Stability of 3-amino-2-tetralone (1) and its active
analogues
Enzyme assays were run at 25 ꢁC in 20 mM Tris–HCl
buffer pH 7.5, with leucine-para-nitroanilide (0.2 mM)
as substrate, in a total reaction volume of 1 mL. The for-
mation of para-nitroaniline was followed at 405 nm
(e = 10,800 molꢁ1 l cmꢁ1). The reaction was started by
addition of 3 mU of porcine kidney AP-N. Under these
experimental conditions linear kinetics were observed
for at least 10 h. Dotted line A corresponds to control
(no inhibitor; Vo = 4.3 nmol hꢁ1). In experiments B
and C 1 lM of 1 and 200 lM of 2b, respectively, were
used. In experiment B, 40% of inhibition
(Vi = 2.4 nmol hꢁ1) was observed during the first hour.
After 4 h, the enzyme activity was back to control
(Vi = Vo = 4.25 nmol hꢁ1). In contrast, 50% inhibition
(Vi = 2.1 nmol hꢁ1)was observed throughout experi-
ment C.
Phosphonate and phosphinate derivatives have been
widely used as transition states analogues for peptidom-
imetic inhibitors of proteolytic enzymes.47–49 The appli-
cation of this concept to the tetralone scaffold led to the
design of derivative 3d. This compound inhibited
APaero with a Ki value of 150 lM and was thus equipo-
tent to the parent 3-amino-2-tetralone 1 on this bacterial
enzyme. Against the mammalian enzymes, however,
compound 3d was found to be 1000-fold less active than
1 on AP-N, and totally inactive on LAPC and LTA4H
up to 1 mM concentration.
We found that the stability of the 3-amino-2-tetralone 1
in aqueous solution at physiological pH is limited, with
an approximate half life of 2 h. This prompted us to
devise a simple experimental approach to evaluate
compound stability under our assay conditions. By con-
tinuously monitoring AP-N reaction rates over a period
of 10 h we were able to assess and compare the stability
of the various compounds reported herein. An example
is shown in Figure 1, where 1 is compared to the more
stable analogue 2b. While inhibition of AP-N activity
by the oxime analogue 2b remained constant during at
3.2.3. Modification of the B cycle. Finally, we have car-
ried out modifications of the B cycle of 1 in an attempt
to increase stability at physiological pH. The heterocy-
clic compounds in the 4 and 5 series were synthesised
and evaluated. None of them inhibited the mammalian
aminopeptidases, up to 1 mM concentration. Interest-
ingly, however, compound 4c exhibited a Ki of 4 lM
C (nmol/ml)
50
A
B
Control
40
30
20
10
0
O
NH2
1
C
N
OCH3
NH2
2b
0
1
2
3
4
5
6
7
8
9
10
Time (hours)
Figure 1. Enzyme assays were run at 25 ꢁC in 20 mM Tris–HCl buffer, pH 7.5, with leucine-para-nitroanilide (0.2 mM) as substrate, in a total
reaction volume of 1 mL. The formation of para-nitroaniline was followed at 405 nm (e = 10,800 molꢁ1 l cmꢁ1). The reaction was started by addition
of 3 mU of porcine kidney AP-N. Under these experimental conditions linear kinetics were observed for at least 10 h. Dotted line A corresponds to
control (no inhibitor; Vo = 4.3 nmol hꢁ1). In experiments B and C 1 lM of 1 and 200 lM of 2b, respectively, were used. In experiment B, 40% of
inhibition (Vi = 2.4 nmol hꢁ1) was observed during the first hour. After 4 h, the enzyme activity was back to control (Vi = Vo = 4.25 nmol hꢁ1). In
contrast, 50% inhibition (Vi = 2.1 nmol hꢁ1) was observed throughout experiment C.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7247
least 10 h, inhibition by 1 levelled off after about 2 h, the
observed reaction rate returning slowly to control values
after this period of time. Similar results were observed
with all active compounds, which were all stable for at
least 10 h under our assay conditions.
Pharmaceuticals, Basel. Microanalyses were carried
out by the Service Central de Microanalyses du CNRS,
F-69390 Vernaison.
5.2. Reagents and solvents
1,4-Dihydronaphthalene (6) was synthesised according
to Ref. 17, 2,3-epoxy-1,2,3,4-tetrahydronaphthalene
according to Refs. 16 and 17, 2-methyl-4-(2-nitro-ben-
zylidene)-4H-oxazol-5-one (24) according to Ref. 38
and 3-amino-3,4-dihydro-1 H-quinolin-2-one (5)
according to Ref. 39. Dess–Martin periodinane was ob-
tained as 1 M solution in CH2Cl2 from Aldrich or syn-
thesised according to Refs. 18 and 53. O-Substituted
hydroxylamines 9d–g were prepared according to Ref.
19. Commercial products were purchased from usual
suppliers, 1,1’-bis(diphenylphosphino) ferrocene (dppf)
from Alfa Aesar. Usual solvents were freshly distilled,
dry EtOH and MeOH distilled over Mg/MgI2, dry
THF over Na and benzophenone, dry Et2O was distilled
and stored over Na, CH2Cl2 was distilled over P2O5 and
kept over Na2CO3. NEt3 was distilled before use.
4. Conclusion
The development of novel metallo-protease inhibitors in
general represents an important scientific endeavour be-
cause of the pharmaceutical relevance of many of these
enzymes. While this work was concentrated on amino-
peptidases and the 3-amino-2-tetralone scaffold, recent
published work on matrix metallo-protease inhibitors
illustrates the need to explore novel chemotypes with
zinc binding properties.50 Although 3-amino-2-tetralone
and bestatin remain the best inhibitors to date, both in
terms of specificity and potency, against the ‘one-zinc’
and ‘two-zinc’ aminopeptidase sub-families, respective-
ly, we successfully identified 3-amino-2-tetralone deriva-
tives with improved stability. Moreover, O-substituted
oxime derivatives with large hydrophobic groups were
shown to be micromolar inhibitors of the ‘one-zinc’
AP-N and LTA4H aminopeptidase activities. These
compounds were inactive against the mammalian LAPc,
a member of the ‘two-zinc’ sub-family, and, hence, may
have an interesting selectivity profile for the further
development of inhibitors of mammalian aminopepti-
dases with only one active site zinc. Not unexpectedly,
hydroxamic acid derivatives were devoid of specificity,
but LTA4H was found to be surprisingly insensitive to
such inhibitors. During this study, we also identified
three compounds, the cyclised hydroxamic acid 4c, the
isothiochromanone 4b and aminoquinolinone 5, which
were selective, micromolar inhibitors of the bacterial,
‘two-zinc’ APaero. Although these compounds failed
to inhibit LAPc, the mammalian representative of the
‘two-zinc’ sub-family, they might, nevertheless, prove
useful in the future for the inhibition of other metallo-
enzymes with a co-catalytic unit.
5.3. trans-3-tert-Butoxycarbonyl-amino-1,2,3,4-tetra-
hydronaphthalen-2-ol (7a)
A suspension of 2,3-epoxy-1,2,3,4-tetrahydronaphtha-
lene16,17 (2.9 g, 19.9 mmol) in MeOH (40 mL) and 25%
concd ammonia (50 mL) was heated at 95 ꢁC in a bomb-
enrohr for 18 h. The solvent was evaporated to give the
crude amino-alcohol.
To a solution of the crude amino-alcohol in MeOH
(40 mL) was added Boc2O (5.2 g, 23.9 mmol, 1.2 equiv)
and the mixture was stirred under Ar at rt 16 h. The sol-
vent was evaporated, and the residue purified by FC
(cyclohexane/AcOEt, 8/2–6/4) to give 7a (2.84 g, 54%).
Colorless crystals, mp 122–4 ꢁC (lit.16 149–150 ꢁC).
1H NMR (CDCl3): 7.20–7.05 (m, 4Har); 4.72 (d, J = ca.
6.0, NH); 3.88 (m, H–C(2), H–C(3)); 3.25 (dd, J = 16.4,
5.0 Hz, 1H); 3.20 (dd, J = 16.4, 4.8 Hz, 1H); 2.86 (dd,
J = 16.4, 8.3 Hz, 1H); 2.71 (dd, J = 16.4, 8.7 Hz, 1H);
1.47 (s, CMe3).
5. Experimental
5.1. General
5.4. 3-Benzyloxycarbonyl-amino-1,2,3,4-tetra-
hydronaphthalen-2-ol (7b)
Flash chromatography (FC), silica gel (Merck 60, 230–
400 mesh). TLC, Al-roll silica gel (Merck 60, F254).
Mp, Kofler hot bench, corrected. IR spectra (m, cmꢁ1),
Nicolet 405 FT-IR. [a]D, Schmidt–Haensch Polartronic
Universal or Perkin-Elmer 341 LC polarimeter. 1H,
31P and 13C NMR (400, 161.9 and 100.6 MHz, respec-
tively). Spectra: Bruker Avance 400, or in some cases
Bruker AC-F 250, tetramethylsilane (TMS), or sodium
(D4)-trimethylsilylpropionate (D4-TSP) in D2O (1H
NMR), extern 80% aqueous PO4H3 (31P NMR) and
CDCl3, or (in D2O) dioxane [d(CDCl3) = 77.0, in D2O
d(dioxane) = 67.4 with respect to TMS] (13C NMR) as
internal references; d in parts per million and J in Hertz.
High resolution MS were measured in Spectroscopy
Laboratory of Strasbourg University or on a Waters
Micromass Q-Tof Ultima API spectrometer in Basilea
To a solution of the crude above amino-alcohol (prepared
2,3-epoxy-1,2,3,4-tetrahydronaphthalene,16,17
from
1.0 g, 6.84 mmol) in THF (10 mL) and water (2 mL) were
successively added at 0 ꢁC Na2CO3 (1.6 g, 15 mmol) and
benzyl chloroformate (1.4 mL, 9.81 mmol, 1.5 equiv)
and the mixture was stirred under Ar at rt for 1 h. Water
and Et2O were added and the precipitated 7b was filtered
and washed with iPr2O (1.6 g, 79%).
Colorless needles, mp 143–5 ꢁC (toluene).
IR (KBr), m: 3369, 3308, 3063, 2926, 2895, 2840, 1687,
1548, 1453, 1435, 1316, 1303, 1255, 1212, 1108, 1067,
1049, 1022, 747, 726, and 694 cmꢁ1
.

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S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
1H NMR (CDCl3): 7.37–7.33 (m, 5Har); 7.16–7.06 (m,
4Har); 5.14 (s, CH2Ph); 4.91 (s, NH); 3.94 (m, H–C(2),
H–C(3)); 3.29 (dd, Ha–C(4)); 3.21 (dd, Ha–C(3); 2.87
(dd, Hb–C(1)); 2.72 (dd, Hb–C(4)); 2.60 (s, OH).
1H NMR (CDCl3): 7.22 (s, 3Har); 7.12 (m, 1Har); 5.63
(br s, NH), 4.47 (m, H–C(3)); 3.78 (d, Ha–C(1)); 3.77 (d,
Hb–C(1)); 3.62 (dd, Ha–C(4)); 2.89 (t, Hb–C(4)), 1.47 (s,
OtBu). J(1a,1b) = 21.4, J(3,4a) = 5.8, J(3,4b) = 12.5,
J(3,NH) = ca. 7.0, J(4a,4b) = 15.5 Hz.
J(1a,1b) = 16.8,
J(3,4a) = 3.6, J(3,4b) = 8.6, J(4a,4b) = 16.4 Hz.
J(1a,2) = 4.6,
J(1b,2) = 7.6,
5.7. General procedure for the synthesis of 3-benzyloxy-
carbonylamino-3,4-dihydro-1H-naphthalen-2-one
O-substituted-oximes (10a–g)
13C NMR (CDCl3): 157.2 (NCO2); 136.4 (Cs(Bn));
133.8, 133.4 (C(4a), C(8a)); 129.1, 128.8, 128.7, 128.4,
128.3, 126.6, 126.4 (7Car); 70.7 (C(2)); 67.2 (OCH2Ph);
53.5 (C(3)); 37.2 (C(1)); 34.6 (C(4)).
To a solution of 8b in dry pyridine (15 mL/mmol) was
added O-substituted-hydroxylamine hydrochloride 9a–g
(1.2 equiv) and the mixture was stirred under Ar at rt
for 1–9 h. The reaction was monitored by TLC. The reac-
tion mixture was diluted with AcOEt, washed successively
with 2 N aq NH4Cl and brine and dried over MgSO4.
After evaporation of the solvent, the title product crystal-
lised in cool iPr2O or iPrOH and washed with cool iPr2O.
Anal. Calcd for C18H19NO3 (297.35): C, 72.71; H, 6.44;
N, 4.71. Found: C, 72.6; H, 6.5; N, 4.7.
5.5. 3-Benzyloxycarbonyl-amino-3,4-dihydro-1H-
naphthalen-2-one (8b)
To a solution of 7b (1.0 g, 3.36 mmol) in wet CH2Cl2
(60 mL) was added Dess–Martin periodinane (3.14 g,
7.4 mmol) and the mixture was stirred at rt for 3 h.
The reaction mixture was diluted with AcOEt
(100 mL), reduced with Na2S2O3 Æ 5H2O (9.2 g,
37 mmol, 5 equiv) and 1 N aq NaHCO3 and stirred at
room temperature for 1 h. The organic solution was
washed successively with 1 N aq NaHCO3 and brine,
and dried over MgSO4. The solvent was evaporated,
and the residue purified by FC (cyclohexane/AcOEt, 9/
1 then 8/2) to give 8b (0.80 g, 80%).
5.7.1. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one oxime (10a). From 8b (300 mg) was ob-
tained 10a (256 mg, 81%).
Colorless crystals, mp 171–2 ꢁC (iPrOH).
IR (KBr), m: 3302, 3065, 3033, 2955, 2897,
1701,1685,1667, 1534, 1496, 1456, 1363, 1327, 1309,
1283, 1233, 1262, 1070, 996, 939, 741, and 696 cmꢁ1
.
1H NMR (CD3OD): 7.35–7.28 (m, 5 Har); 7.19–7.14 (m,
4 Har); 5.09 (s, OCH2Ph); 4.45 (dd, H–C(3)); 3.93 (d,
Ha–C(1)); 3.78 (d, Hb–C(1)); 3.14 (dd, Ha–C(4)); 2.91
Colorless needles, mp 89–90 ꢁC (iPr2O).
IR (KBr), m: 3325, 2934, 1730, 1693, 1517, 1494, 1384,
1360, 1300, 1238, 1071, 998, 779, 753, 744, and
(dd,
J(3,4b) = 9.6, J(4a,4b) = 15.0 Hz.
Hb–C(4)).
J(1a,1b) = 21.6,
J(3,4a) = 4.5,
696 cmꢁ1
.
13C NMR (CD3OD): 158.2 (C(2)); 156.0 (NCO2); 138.3
(Cs(Bn)); 135.4, 134.1 (C(4a), C(8a)); 129.8, 129.6,
129.5, 129.0, 128.8, 128.1, 127.4 (7Car); 67.5 (CH2Ph);
51.5 (C(3)); 37.2 (C(4)); 29.1(C(1)).
1H NMR (CDCl3): 7.38–7.31 (m, 5Har); 7.24 (m, 3Har);
7.12 (m, 1Har); 5.89 (br s, NH); 5.14 (s, OCH2Ph); 4.52
(m, H–C(3)); 3.79, 3.78 (2 d, CH2C(1)); 3.64 (dd, Ha–
C(4));
2.91
(dd,
Hb–C(4)).
J(1a,1b) = 21.6,
J(3,4a) = ca. 6.0, J(3,4b) = 13.0, J(3,NH) = ca. 6.0,
J(4a,4b) = 14.9 Hz.
Anal. Calcd for C18H18N2O3 (310.35): C, 69.66; H, 5.85;
N 9.03. Found: C, 69.4; H, 5.9; N, 9.0.
13C NMR (CDCl3): 205.5 (C(2)); 156.0 (NCO2); 136.4
(Cs(Bn)); 133.6, 132.3 (C(4a),C(8a)); 128.9, 128.7,
128.5, 128.4, 128.3, 127.5, 127.3 (7Car); 67.1 (OCH2Ph);
57.6 (C(3)); 42.9 (C(1)); 36.3 (C(4)).
5.7.2. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one O-methyloxime (10b). From 8b (300 mg)
was obtained 10b (260 mg, 66%).
Colorless crystals, mp 115-7 ꢁC (iPrOH).
Anal. Calcd for C18H17NO3 (295.33): C, 73.20; H, 5.80;
N, 4.74. Found: C, 73.1; H, 5.9; N, 4.7.
IR (KBr), m: 3295, 3062, 3033, 2953, 2896, 1688, 1545,
1356, 1307, 1283, 1261, 1072, 1046, 991, 891, 744, and
5.6. 3-tert-Butoxycarbonyl-amino-3,4-dihydro-1H-
naphthalen-2-one (8a)
696 cmꢁ1
.
1H NMR (CD3OD): 7.38–7.29 (m, 5 Har); 7.20–7.12 (m,
4 Har); 5.11 (s, OCH2Ph); 4.45 (dd, H–C(3)); 3.89 (s,
NOMe), 3.89 (d, Ha–C(1)); 3.74 (d, Hb–C(1)); 3.13
(dd, Ha–C(4)); 2.92 (dd, Hb–C(4)). J(1a,1b) = 21.6,
J(3,4a) = 4.6, J(3,4b) = 9.8, J(4a,4b) = 15.1 Hz.
Same procedure as 8b with 7a (2.733 g, 10.38 mmol) in
CH2Cl2 (90 mL) and Dess–Martin periodinane (6.6 g,
15.57 mmol). The crude crystallised 8a was washed three
i
times with Pr2O (2.23 g, 82%).
Colorless needles, mp 100–4 ꢁC (iPr2O) (lit.16 104–5 ꢁC).
13C NMR (CD3OD): 158.1 (C(2)); 156.5 (NCO2); 138.4
(Cs(Bn)); 135.3, 133.8 (C(4a), C(8a)); 129.8, 129.6,
129.5, 129.0, 128.8, 128.1, 127.5 (7Car); 67.4 (CH2Ph);
62.3 (OMe); 51.5 (C(3)); 37.0 (C(4)); 29.7 (C(1)).
IR (KBr), m: 3327, 3012, 2981, 1733, 1679, 1528, 1366,
1311, 1163, 1020, and 744 cmꢁ1
.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7249
Anal. Calcd for C19H20N2O3 (324.37): C, 70.35; H, 6.21;
N, 8.64. Found: C, 70.4; H, 6.4; N, 8.6.
1H NMR (CDCl3): 7.40–7.14 (m, 14Har); 5.84 (br
d, NH); 5.12 (s, OCH2Ph); 4.48 (m, H–C(3));
4.13 (t, CH2(10)); 3.97 (d, Ha–C(1)); 3.63 (d, Hb–
C(1)); 3.46 (dd, Ha–C(4)); 2.75 (dd, Hb–C(4));
5.7.3. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one O-benzyloxime (10c). From 8b (100 mg)
was obtained 10c (66 mg, 50%).
2.70
(t,
CH2(30));
2.00
(quint,
CH2(20)).
J(1a,1b) = 22.4, J(3,4a) = ca. 5.0, J(3,4b) = 10.5,
J(3,NH) = ca. 6.0, J(4a,4b) = 15.0, J(10,20) = 6.6,
J(20,30) = 7.6 Hz.
Colorless crystals, mp 116–8 ꢁC (iPrOH).
IR (KBr), m: 3305, 3032, 2923, 2462, 1685, 1537, 1494,
1438, 1351, 1254, 1071, 1040, 1008, 875, 741, and
13C NMR (CDCl3): 155.9 (C(2)); 154.3 (NCO2); 141.9
(Cs(Bn)); 136.5 (Cs(Ph)); 133.9, 132.4 (C(4a), C(8a));
129.1, 128.7, 128.6, 128.6, 128.5, 128.4, 127.3, 126.7,
126.0 (10Car); 73.8 (C(10)); 67.0 (CH2Ph); 50.5 (C(3));
36.7 (C(4)); 32.4 (C(30)); 30.7 (C(20); 29.2 (C(1)).
695 cmꢁ1
.
1H NMR (CDCl3): 7.36–7.27 (m, 10Har); 7.19–709 (m,
4Har); 5.85 (br d, NH), 5.13–5.10 (m, 2OCH2Ph); 4.48
(dd, H–C(3)); 4.03 (d, Ha–C(1)); 3.68 (d, Hb–C(1));
Anal. Calcd for C27H28N2O3 (428.52): C, 75.68; H, 6.59;
N, 6.54. Found: C, 75.6; H, 6.7; N, 6.5.
3.41
J(1a,1b) = 21.9,
J(3,NH) = ca. 5.0, J(4a,4b) = 14.8 Hz.
(dd,
Ha–C(4)),
2.74
(dd, Hb–C(4)).
J(3,4b) = 10.4,
J(3,4a) = 4.6,
5.7.6. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one O-(4-phenylbutyl)oxime (10f). From 8b
(85 mg) was obtained 10f (105 mg, 83%).
13C NMR (CDCl3): 155.9 (C(2)); 155.1 (NCO2); 137.5
(Cs(Bn)); 136.4 (Cs(NOBn)); 133.8, 132.2 (C(4a),
C(8a)); 129.0, 128.6, 128.5, 128.3, 128.1, 127.2, 126.7
(Car); 76.5, 67.0 (2CH2Ph); 50.5 (C(3)); 36.5 (C(4));
29.4 (C(1)).
Colorless crystals, mp 115–7 ꢁC (iPrOH).
IR (KBr), m: 3317, 2937, 1688, 1530, 1453, 1362, 1281,
1260, 1069, 961, 921, 748, 733, and 697 cmꢁ1
.
Anal. Calcd for C25H24N2O3 (400.47): C, 74.98; H, 6.04;
N, 7.00. Found: C, 75.1; H, 6.2; N, 6.9.
1H NMR (CDCl3): 7.40–7.12 (m, 14Har); 5.83 (br d,
NH); 5.14 (s, OCH2Ph); 4.48 (m, H–C(3)); 4.12 (br t,
CH2(10)); 4.01 (d, Ha–C(1)); 3.65 (d, Hb–C(1)); 3.48
(dd, Ha–C(4)); 2.73 (dd, Hb–C(4)); 2.65 (t, CH2(40));
5.7.4. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one O-(2-phenylethyl)oxime (10d). From 8b
(50 mg) was obtained 10d (66 mg, 83%).
1.71
(m,
CH2(20),
CH2(30)).
J(1a,1b) = 22.0,
J(3,4a) = 4.6, J(3,4b) = 11.0, J(3,NH) = ca. 6.0,
J(4a,4b) = 15.2 Hz.
Colorless crystals, mp 96–8 ꢁC (iPrOH).
IR (KBr), m: 3321, 3027, 2935, 1686, 1534, 1495, 1455,
1439, 1282, 1259, 1065, 1043, 1027, 986, 897, 745, and
13C NMR (CDCl3): 155.8 (C(2)); 154.1 (NCO2); 142.4
(Cs(Bn)); 136.6 (Cs(Ph)); 134.0, 132.4 (C(4a), C(8a));
129.1, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 127.3,
126.7, 125.9 (10Car); 74.3 (C(10)); 67.0 (CH2Ph); 50.5
(C(3)); 36.7 (C(4)); 35.8 (C(40)); 29.3 (C(1)); 28.8, 27.9
(C(20), (C(30)).
697 cmꢁ1
.
1H NMR (CDCl3): 7.40–7.11 (m, 14 Har); 5.74 (br
s, NH); 5.14 (s, OCH2Ph); 4.49 (m, H–C(3)); 4.33
(t, CH2(10)); 3.96 (d, Ha–C(1)); 3.63 (d, Hb–C(1)); 3.47
(dd, Ha–C(4)); 2.99 (t, CH2(20)); 2.74 (dd, Hb–C(4)).
Anal. Calcd for C28H30N2O3 (442.55): C, 75.99; H, 6.83;
N, 6.33. Found: C, 76.1; H, 7.0; N, 6.3.
J(1a,1b) = 21.8,
J(3,4a) = 4.6,
J(3,4b) = 10.6,
J(3,NH) = ca. 6.0, J(4a,4b) = 15.0, J(10,20) = 6.8 Hz.
5.7.7. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one O-(5-phenylpentyl)oxime (10g). From 8b
(90 mg) was obtained 10g (121 mg, 87%).
13C NMR (CDCl3): 155.8 (C(2)); 154.7 (NCO2); 138.8
(Cs(Bn)); 136.6 (Cs(Ph)); 133.9, 132.4 (C(4a), C(8a));
129.1, 128.7, 128.6, 128.5, 128.3, 127.3, 126.7, 126.4
(Car); 75.0 (C(10)); 67.0 (CH2Ph); 50.5 (C(3)); 36.7
(C(4)); 36.0 (C(20); 29.4 (C(1)).
Colorless crystals, mp 78–80 ꢁC (iPrOH).
IR (KBr), m: 3329, 2959, 2936, 2882, 1692, 1529, 1494,
1451, 1361, 1307, 1281, 1069, 998, 931, 749, 733, and
Anal. Calcd for C26H26N2O3 (414.50): C, 75.34; H, 6.32;
N 6.76. Found: C, 75.2; H, 6.4; N 6.7.
697 cmꢁ1
.
5.7.5. 3-Benzyloxycarbonylamino-3,4-dihydro-1H-naph-
thalen-2-one O-(3-phenylpropyl)oxime (10e). From 8b
(84 mg) was obtained 10e (72 mg, 60%).
1H NMR (CDCl3): 7.40–7.12 (m, 14Har), 5.85 (br d,
NH); 5.13 (s, OCH2Ph); 4.48 (m, H–C(3)); 4.10 (t,
CH2(10)); 3.99 (d, Ha–C(1)); 3.63 (d, Hb–C(1)); 3.48
(dd, Ha–C(4)); 2.75 (dd, Hb–C(4)); 2.62 (t, CH2(50));
1.68 (m, CH2(20), CH2(40)), 1.41 (quint, CH2
(30)). J(1a,1b) = 21.8, J(3,4a) = 4.6, J(3,4b) = 11.2,
Colorless crystals, mp 93–5 ꢁC (iPrOH).
IR (KBr), m: 3326, 2949, 1685, 1533, 1261, 1041, 914,
J(3,NH) = 5.8,
J(4a,4b) = 14.8,
J(10,20) = 6.4,
746, and 697 cmꢁ1
.
J(20,30) = J(30,40) = 7.7, J(40,50) = 7.6 Hz.

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S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
13C NMR (CDCl3): 155.8 (C(2)); 154.1 (NCO2); 142.7
(Cs(Bn)); 136.6 (Cs(Ph)); 134.0, 132.4 (C(4a), C(8a));
129.1, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 127.2,
126.7, 125.8 (10Car); 74.5 (C(10)); 67.0 (CH2Ph); 50.5
(C(3)); 36.7 (C(4)); 36.0 (C(50)); 31.4 (C(20)); 29.3
(C(1)); 29.0 (C(40)); 25.7 (C(30)).
5.8.3. 3-Amino-3,4-dihydro-1H-naphthalen-2-one O-ben-
zyloxime hydrochloride (2c). From oxime 10c 49 mg) was
obtained 2c (27 mg, 73%).
Colorless crystals, mp 230 ꢁC (dec) (iPrOH/Et2O).
IR (KBr), m: 3450, 3030, 2856, 2616, 1584, 1514, 1495,
Anal. Calcd for C29H32N2O3 (456.58): C, 76.29; H, 7.06;
N, 6.14. Found: C, 76.5; H, 7.3; N, 6.0.
1356, 983, 980, 758, 752, 739, and 697 cmꢁ1
.
1H NMR (CD3OD): 7.42–7.20 (m, 9H), 5.24 (s,
OCH2Ph), 4.19 (dd, H–C(3)), 4.10 (d, Ha–C(1)), 3.82
(d, Hb–C(1)), 3.27 (dd, Ha–C(4)), 3.04 (dd, Hb–C(4)).
5.8. General procedure for the synthesis of 3-amino-3,4-
dihydro-1H-naphthalen-2-one O-phenylalkyloximes
hydrochloride (2a–g)
J(1a,1b) = 22.1,
J(4a,4b) = 14.6 Hz.
J(3,4a) = 5.0,
J(3,4b) = 11.8,
Oxime 10a–g was hydrogenolysed in EtOH (20 mL/
mmol) and 1 N aq HCl (1.0 equiv) over 5% Pd–C
(20 mg/mmol) at rt. The reaction was monitored by
TLC. Pd–C was centrifuged off and the solvent evapo-
rated. The obtained compound was recrystallised in
iPrOH/Et2O.
13C NMR (CD3OD): 154.4 (C(2)); 138.8 (Car-s); 133.1,
133.0 (C(4a),C(8a)); 129.8, 129.7, 129.5, 129.3, 129.1,
128.9, 128.0 (7Car); 77.8 (CH2Ph); 50.3 (C(3)); 34.7
(C(4)); 29.8 (C(1)).
HR-MS (FAB+) calcd for C17H19N2O, [M+H]+:
267.1497; found: 267.1483.
5.8.1. 3-Amino-3,4-dihydro-1H-naphthalen-2-one oxime
hydrochloride (2a). From oxime 10a (50 mg) was ob-
tained 2a (26 mg, 76%).
5.8.4. 3-Amino-3,4-dihydro-1H-naphthalen-2-one O-(2-
phenylethyl)oxime hydrochloride (2d). From oxime 10d
(58 mg) was obtained 2d (30 mg, 68%).
Colorless crystals, mp 230–40 ꢁC (dec) (iPrOH/Et2O).
IR (KBr), m: 3240, 3000, 1586, 1494, 1457, 1422, 978,
Colorless crystals, mp 182–6 ꢁC (iPrOH/Et2O).
757, and 739 cmꢁ1
.
IR (KBr), m: 3430, 3026, 2865, 1578, 1496, 1454, 1066,
1H NMR (CD3OD): 7.25–7.21 (m, 4Har); 4.14 (dd, H–
C(3)); 4.08 (d, Ha–C(1)); 3.76 (d, Hb–C(1)); 3.24 (dd,
Ha–C(4)); 3.03 (dd, Hb–C(4)). J(1a,1b) = 22.0,
J(3,4a) = 4.6, J(3,4b) = 11.8, J(4a,4b) = 14.6 Hz.
1021, 755, and 699 cmꢁ1
.
1H NMR (CD3OD): 7.29–7.19 (m, 9Har), 4.39 (t,
CH2(10)), 4.18 (dd, H–C(3)), 3.99 (d, Ha–C(1)), 3.73
(d, Hb–C(1)), 3.26 (dd, Ha–C(4)), 3.03 (m, Hb–C(4),
CH2(20)). J(1a,1b) = 22.0, J(3,4a) = 5.0, J(3,4b) = 11.6,
J(4a,4b) = 14.8, J(10,20) = 6.8 Hz.
13C NMR (CD3OD): 152.6 (C(2)); 133.5, 133.2
(C(4a),C(8a)); 129.9, 129.7, 128.8, 127.9 (4Car); 50.4
(C(3)); 34.9 (C(4)); 28.9 (C(1)).
13C NMR (CD3OD): 154.0 (C(2)); 139.9 (Car-s); 133.2,
133.0 (C(4a),C(8a)); 130.0 (Car-m); 129.8, 129.7 (2Car);
129.4 (Car-o); 128.9, 128.0, 127.3 (3Car); 76.5 (C(10));
50.3 (C(3)); 36.5 (C(20)); 34.8 C(4)); 29.7 C(1)).
HR-MS (FAB+) calcd for C10H13N2O, [M+H]+:
177.1028; found: 177.1034.
5.8.2. 3-Amino-3,4-dihydro-1H-naphthalen-2-one O-meth-
yloxime hydrochloride (2b). From oxime 10b (50 mg) was
obtained 2b (26 mg, 74%).
HR-MS (ESI-Q-Tof) calcd for C18H20N2O, [M]+:
280.1576; found: 280.1588.
Colorless crystals, mp 200–10 ꢁC (dec) (iPrOH/Et2O).
IR (KBr) m: 3506, 3426, 3006, 2928, 1605, 1522, 1493,
5.8.5. 3-Amino-3,4-dihydro-1H-naphthalen-2-one O-(3-
phenylpropyl)oxime hydrochloride (2e). From oxime 10e
(49 mg) was obtained 2e (26 mg, 68%).
1458, 1411, 1055, 919, and 756 cmꢁ1
.
1H NMR (CD3OD): 7.23–7.21 (m, 4Har); 4.18 (dd, H–
C(3)); 4.05 (d, Ha–C(1)); 4.00 (s, NOMe); 3.76 (d,
Hb–C(1)); 3.27 (dd, Ha–C(4)); 3.04 (dd, Hb–C(4)).
J(1a,1b) = 22.0, J(3,4a) = 5.0, J(3,4b) = 11.8, J(4a,4b)
= 14.8 Hz.
Colorless crystals, mp 162–70 ꢁC (iPrOH/Et2O).
IR (KBr), m: 3450, 3027, 2865, 1583, 1505, 1496, 1454,
1408, 1384, 1066, 1032, 1013, 918, 757, 743, and
700 cmꢁ1
.
13C NMR (CD3OD): 153.6 C(2); 133.1, 133.0
(C(4a),C(8a));129.8, 129.7, 128.9, 128.0 (4Car); 62.9
(OCH3); 50.2 (C(3)); 34.7 (C(4)); 29.5 (C(1)).
1H NMR (CD3OD): 7.27–7.20 (m, 8Har), 7.15 (m,
1Har), 4.22 (t, CH2(10)), 4.17 (dd, H–C(3)), 4.00
(d, Ha–C(1)), 3.73 (d, Hb–C(1)), 3.27 (dd, Ha–C(4)),
3.03 (dd, Hb–C(4)), 2.75 (t, CH2(30)), 2.07 (quint,
CH2(20)). J(1a,1b) = 22.0, J(3,4a) = 5.0, J(3,4b) = 11.9,
J(4a,4b) = 14.8, J(10,20) = 6.4, J(20,30) = 7.6 Hz.
HR-MS (FAB+) calcd for C11H15N2O, [M+H]+:
191.1184; found: 191.1184.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7251
13C NMR (CD3OD): 153.5 C(2); 143.1 (Car-s); 133.2,
5.9. 1,2,3,4-Tetrahydronaphthalen-2-amine, hydrochlo-
ride (3a)
133.0 (C(4a),C(8a)); 129.9, 129.7 (2Car);129.5, 129.4
(Car-m,Car-o); 128.9, 128.0, 126.9 (3Car); 75.2 (C(10));
50.3 (C(3)); 34.8 (C(4)); 33.3 (C(30)); 31.7 (C(20)); 29.6
(C(1)).
A mixture of b-tetralone 11 (1 mL, 10 mmol), Ti(OiPr)4
(5.85 mL, 20 mmol, 2 equiv) and saturated ammonia in
EtOH (10 mL) was stirred under Ar at rt for 16 h.
NaBH4 (0.46 mg, 12 mmol, 1.2 equiv) was then added
and the resulting mixture was stirred at rt for an addi-
tional 3 h. The solvents were evaporated, the residue
diluted with AcOEt and treated with 1 N aq NH4OH
(20 mL). The inorganic precipitate was filtered off and
washed with AcOEt (3· 20 mL). The organic layer was
separated and the remaining aqueous layer was extract-
ed with AcOEt (3· 20 mL). The combined organic phas-
es were dried over MgSO4 and concentrated in vacuo.
HCl, 2.2 M, in dry Et2O (5 mL) was added and the pre-
cipitated hydrochloride 3a was filtered and recrystallised
HR-MS. (FAB+) calcd for C19H23N2O, [M+H]+:
295.1810; found: 295.1802.
5.8.6. 3-Amino-3,4-dihydro-1H-naphthalen-2-one O-(4-
phenylbutyl)oxime hydrochloride (2f). From oxime 10f
(88 mg) was obtained 2f (54 mg, 78%).
Colorless crystals, mp 150–4 ꢁC (iPrOH/Et2O).
IR (KBr), m: 3450, 3025, 2858, 2616, 1578, 1512, 1495,
1453, 1406, 1384, 1025, 1018, 756, 741, and 698 cmꢁ1
.
i
in PrOH/Et2O (0.75 g, 40%).
1H NMR (CD3OD): 7.26–7.14 (m, 9Har); 4.22
(t, CH2(10)); 4.17 (dd, H–C(3)); 4.04 (d, Ha–C(1));
3.77 (d, Hb–C(1)); 3.26 (dd, Ha–C(4)); 3.03 (dd,
Hb–C(4)); 2.67 (t, CH2(40)); 1.80–1.70 (m,
Colorless crystals, mp 230–2 ꢁC (iPrOH/Et2O) (lit.20
236–8 ꢁC).
CH2(20),
CH2(40)).
J(1a,1b) = 22.0,
J(3,4a) =
IR (KBr), m: 3432, 3055, 2990, 2895, 1605, 1498, 1477,
5.0, J(3,4b) = 12.0, J(4a,4b) = 14.6, J(10,20) = 6.0,
J(30,40) = 6.8 Hz.
and 744 cmꢁ1
.
Same 1H NMR and 13C NMR spectra (D2O) as in
lit.21,22
13C NMR (CDCl3): 150.9, 142.5, 132.1, 131.8, 129.0,
128.8, 128.5, 128.4, 127.8, 127.0, 125.8, 75.0, 49.7,
35.7, 34.1, 29.0, 28.6, 27.9.
5.10. 2-Trifluoromethylsulfonyloxy-3-benzyloxycarbon-
ylamino-3,4-dihydronaphthalene (12b) and O-benzyl
3-benzyloxycarbonylamino-3,4-dihydronaphthalene-2-
carbohydroxamate (13b)
1H NMR (CDCl3): 7.27–7.17 (m, 9Har), 4.23 (m,
H–C(10)), 4.20 (m, H–C(3)), 4.03 (d, J = 22.1 Hz,
Ha–C(1)); 3.70 (d, J = 22.1 Hz, Hb–C(1)); 3.63 (dd,
J = 4.0, 15.1 Hz, Ha–C(4)); 3.34 (t, J = 13.5 Hz, Hb–
C(4)); 2.66 (t, J = 7.1 Hz, CH2(40)).
To a solution of LiHMDS (prepared from HMDS and
BuLi, 0.57 mmol, 2.2 equiv) in dry THF (1 mL) was
added dropwise a solution of 8b (78 mg, 0.26 mmol) in
THF (1 mL) and the mixture was stirred under Ar at
ꢁ78 ꢁC for 45 min, then PhNTf2 (223 mg, 0.62 mmol,
2.4 equiv) in THF (1 mL) was added at ꢁ78 ꢁC and
the reaction mixture was stirred at 0 ꢁC for 2.5 h. The
reaction mixture was quenched with 2 M aq NH4Cl,
extracted with Et2O and washed with brine. The organic
solution was dried over MgSO4 and the solvent was
evaporated to give crude 12b which was used without
purification.
HR-MS (ESI-Q-Tof) calcd for C20H24N2O, [M]+:
308.1889; found: 308.1906.
5.8.7. 3-Amino-3,4-dihydro-1H-naphthalen-2-one O-(5-
phenylpentyl)oxime hydrochloride (2g). From oxime 10g
(62 mg) was obtained 2g (37 mg, 76%).
Colorless crystals, mp 152–5 ꢁC (iPrOH/Et2O).
IR (KBr), m: 3450, 2936, 2854, 2614, 1578, 1509, 1495,
1459, 1451, 1051, 1039, 1004, 743, 739, and 697 cmꢁ1
.
A solution of crude 12b (0.26 mmol), Et3N (220 lL,
1.58 mmol,
6 equiv),
BnONH2 Æ HCl
(210 mg,
1H NMR (CD3OD): 7.27–7.08 (m, 9Har), 4.20 (t,
CH2(10)), 4.16 (dd, H–C(3)), 4.00 (d, Ha–C(1)), 3.72
(d, Hb–C(1)), 3.26 (dd, Ha–C(4)), 3.02 (dd, Hb–C(4)),
2.63 (t, CH2(50)), 1.77 (quint, CH2(20)), 1.68 (quint,
1.32 mmol, 5 equiv), Pd(PPh3)4 (22 mg) in DMF
(5 mL) was purged with CO and stirred under CO
(1 atm) at 60 ꢁC for 4 h. The reaction mixture was
diluted with Et2O, quenched with 2 M aq NH4Cl
and washed with brine. The organic solution was
dried over MgSO4, the solvent was evaporated and
the residue purified by FC (cyclohexane/AcOEt, 7/3)
to give 13b (90 mg, 80%).
CH2(40)),
1.44
(quint,
CH2(30)).
J(1a,1b) =
22.0, J(3,4a) = 5.0, J(3,4b) = 11.8, J(4a,4b) = 14.8,
J(10,20) = 6.5, J(20,30) = J(30,40) = J (40,50)=7.6 Hz.
13C NMR (CD3OD): 153.3, 143.7, 133.2, 133.0, 129.8,
129.7, 129.4, 129.3, 128.9, 128.0, 126.7, 75.8, 50.3,
36.7, 34.8, 32.4, 29.8, 29.6, 26.5.
1
Compound 12b, only characterised by NMR: H NMR
(CDCl3): 7.40–7.17 (m, 9Har); 6.64 (s, H–C(1)); 5.11 (s,
OCH2Ph); 5.01 (d, NH); 4.79 (m, H–C(3)); 3.33 (dd,
Ha–C(4));
J(3,4b) = 3.5, J(4a,4b) = 16.6 Hz.
HR-MS (ESI-Q-Tof) calcd for C22H26N2O, [M]+:
322.2045; found: 322.2041.
3.13
(dd,
Hb–C(4)).
J(3,4a) = 6.5,

7252
S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
Compound 13b: Colorless crystals, mp 150–2 ꢁC
5.12. 3-Amino-1,2,3,4-tetrahydronaphthalene-2-carbohy-
droxamic acid (3c)
(iPrOH).
IR (KBr), m: 3304, 3196, 1689, 1655, 1626, 1541, 1257,
Compound 13b (54 mg, 0.126 mmol) was hydrogenoly-
sed in EtOH (3 mL) over 5% Pd–C (10 mg) at rt 8 h.
Then Pd–C was centrifuged off and the solution was
concentrated. The crude compound was recrystallised
in PrOH/Et2O to give 3c as (40/60) mixture of cis and
trans isomers (22 mg, 71%).
1047, 746, 736, and 697 cmꢁ1
.
1H NMR (CDCl3): 10.75 (s, NHOBn); 7.71 (s, H–C(1));
7.50–7.21 (m, 14Har); 5.27 (d, NH); 5.04–4.91 (m, 2
OCH2Ph); 4.52 (m, H–C(3)); 3.20 (dd, Ha–C(4)); 2.93
i
(dd,
J(3,4b) = 1.5, J(4a,4b) = 16.3 Hz.
Hb–C(4)).
J(3,NH) = 9.6,
J(3,4a) = 5.9,
Colorless crystals, mp 130–5 ꢁC (dec) (iPrOH/Et2O).
13C NMR (CDCl3): 164.3 (CON–C(2)); 156.9 (NCO2);
135.8, 135.6, 132.2, 131.7, 130.0, 129.5, 129.2, 129.1,
128.9, 128.7, 128.6, 128.5, 128.4, 127.9 (14Car); 78.0
(NOCH2Ph); 67.8 (OCH2Ph); 43.3 (C(3)); 35.1 (C(4)).
IR (KBr), m: 3418, 3171, 3025, 2927, 1665, 1496, 1455,
1043, and 748 cmꢁ1
.
1H NMR (CD3OD): 7.19–7.17 (m, 8Har); 3.96 (m, H–
C(3), isomer 1); 3.82 (dt, J = 5.2, 10.6 Hz, H–C(3), iso-
mer 2); 3.30–2.75 (m, 5H, isomer 1, 4H, isomer 2);
2.71 (dt, J = 5.6, 10.8 Hz, H–C(2), isomer 2).
Anal. Calcd for C26H24N2O4 (428.48): C, 72.88; H, 5.65;
N, 6.54. Found: C, 72.6; H, 5.5; N, 6.3.
5.11. 2-Trifluoromethylsulfonyloxy-3-tert-butoxycarbon-
ylamino-3,4-dihydronaphthalene (12a) and N,O-Dimethyl
3-tert-butoxycarbonyl-amino-3,4-dihydronaphthalene-2-
carbohydroxamate (13a)
13C NMR (CD3OD): 172.4, 171.0, 134.5, 133.9, 132.8,
131.6, 130.6, 130.2, 129.8, 129.4, 128.1, 128.0, 127.9,
127.8, 49.8, 48.8, 43.1, 38.8, 34.1, 34.1, 31.1, 28.7.
HR-MS (ESI-Q-Tof) calcd for C11H14N2O2, [M]+:
206.1055; found: 206.1054.
Same procedure as for 13b with 8a (50 mg,
0.19 mmol) to give crude 12a which was used without
purification.
5.13. N,O-Dimethyl 3-tert-butoxycarbonylamino-1,2,3,
4-tetrahydronaphthalene-2-carbohydroxamate (14)
Same procedure as for 13b with crude 12a (0.19 mmol),
HCl Æ HN(OMe)Me (93 mg, 0.95 mmol), Et3N (140 lL,
0.95 mmol) and Pd(PPh3)4 (22 mg, 10% mol) in DMF
(5 mL). The reaction mixture was stirred under CO
(1 atm) at 60 ꢁC for 24 h. The reaction mixture was
diluted with Et2O, quenched with 2 M aq NH4Cl and
washed with brine. The organic solution was dried over
MgSO4 and the solvent was evaporated and the residue
purified by FC (cyclohexane/AcOEt, 7/3) to give 13a
(40 mg, 68%).
Amide 13a (154 mg, 0.46 mmol) was hydrogenated in
EtOH (3.5 mL) over PtO2 (5 mg) at rt for 48 h. PtO2
was centrifuged off and the solution was concentrated
to give 14 as a 80/20 isomeric mixture (155 mg, quant.).
Colorless resin.
1H NMR (CDCl3): 7.14–7.07 (m, 4Har); 4.91 (d,
J = 8.0 Hz, NH); 4.50 (m, H–C(3)); 3.73 (s, OMe);
3.30–3.28 (m, Ha–C(1), H–C(2)); 3.21 (s, NMe); 3.08
1
Compound 12a, only characterised by NMR: H NMR
t
(m, 2H–C(4)); 2.84 (m, Hb–C(1)); 1.40 (s, Bu).
(CDCl3): 7.40–7.17 (m, 4Har); 6.62 (s, H–C(1)); 4.75 (m,
NH, H–C(3)); 3.31 (dd, Ha–C(4)), 3.11 (d, Hb–C(4));
1.26 (s, CMe3). J(3,4a) = 6.3, J(4a,4b) = 16.8 Hz.
13C NMR (CDCl3): 162.6 (CON–C(2)); 155.7 (NCO2);
134.2, 133.2 (C(4a), C(8a)); 129.6, 129.1, 126.3, 126.3
(4Car); 79.4 (CMe3); 61.6 (OMe); 45.9 (C(3)); 39.2
(C(2)); 35.2 (C(4)); 32.9 (NMe); 28.5 (CMe3); 27.2
(C(1)).
Compound 13a: Colorless crystals, mp 70–4 ꢁC (iPrOH).
IR (KBr), m: 3282, 3266, 2981, 2972, 1700, 1696, 1642,
1531, 1364, 1164, 1049, 1018, and 764 cmꢁ1
.
HR-MS (ESI-Q-Tof) calcd for C18H26N2O4, [M]+:
334.1849; found: 334.1853.
1H NMR (CDCl3): 7.25–7.20 (m, 4 Har); 6.97 (s, H–
C(1)); 4.83 (m, NH, H–C(3)); 3.69 (s, OMe); 3.31 (s,
NMe); 3.10 (m, 2H–C(4)).
5.14. 3-tert-Butoxycarbonylamino-1,2,3,4-tetrahydro-
naphthalene-2-ethanone (15)
13C NMR (CDCl3): 169.4 (CON–C(2)); 155.2 (NCO2);
133.7, 133.5 (C(4a), C(8a)); 131.6 (C(2)); 131.5 (C(1));
129.3, 129.0, 128.1, 127.3 (4Car); 79.7 (CMe3); 61.4
(OMe); 45.1 (C(3)); 35.0 (NMe); 33.5 (C(4)); 28.5
(CMe3).
To a solution of amide 14 (0.46 mmol) in dry THF
(4 mL) was added 3 M MeMgCl in THF (710 lL,
2.13 mmol) under Ar at 0 ꢁC. The reaction mixture
was stirred at rt for 4 h, diluted with Et2O, quenched
with 2 M aq NH4Cl, washed with brine and dried over
MgSO4. The organic solution was concentrated and
purified by FC (cyclohexane/ethyl acetate, 8/2) to give
15 as a 80/20 diastereoisomeric mixture (36 mg, 27%).
Anal. Calcd for C18H24N2O4, 1/2H2O: C, 63.32; H, 7.23;
N, 8.21. Found: C, 63.3; H, 7.3; N, 8.3.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7253
Colorless crystals, mp 130–6 ꢁC (iPrOH).
5 equiv), Pd(OAc)2 (17 mg, 0.2 equiv) and dppf
(85 mg, 0.4 equiv) in DMF (5 mL) was stirred under
Ar at 100 ꢁC for 24 h. The reaction mixture was dilut-
ed with Et2O, quenched with 2 M aq NH4Cl and
washed with brine. The organic solution was dried
over MgSO4 and the solvent was evaporated and the
residue purified by FC (cyclohexane/AcOEt, 3/7) to
give 16 (82 mg, 61%).
IR (KBr), m: 3447, 3345, 2975, 2930, 1713, 1686, 1502,
1367, 1344, 1253, 1167, 1060, and 760 cmꢁ1
.
1
Major isomer. H NMR (CDCl3): 7.15–7.07 (m, 4Har);
4.83 (d, J = 8.5 Hz, NH); 4.61 (m, H–C(3)); 3.21–3.15
(m, Ha–C(1)), Ha–C(4)); 2.97–2.92 (m, Hb–C(1), Hb–
t
C(4), H–C(2),); 2.31 (s, Me); 1.39 (s, Bu).
Brownish oil.
13C NMR (CDCl3): 209.0 (C@O); 155.6 (NCO2); 133.7,
132.9 (C(4a), C(8a)); 129.8, 129.3, 126.6, 126.5 (4Car);
79.8 (CMe3); 50.3 (C(2)); 46.4 (C(3)); 35.7 (C(4)); 28.9
(Me); 28.4 (CMe3); 26.6 (C(1)).
IR (KBr), m: 3440, 2976, 2956, 1702, 1636, 1522, 1366,
1246, 1168, 1053, 1028, 829, 765, and 531 cmꢁ1
.
1H NMR (CDCl3): 7.50 (d, J = 19.6 Hz, H–C(1)); 7.33–
7.22 (m, 4Har); 4.70 (m, NH, H–C(3)); 3.79 (d,
J = 10.1 Hz, OMe); 3.77 (d, J = 10.1 Hz, OMe); 3.06
1
Minor isomer. H NMR (CDCl3): 7.15–7.07 (m, 4Har);
4.83 (d, J = 8.5 Hz, NH); 4.24 (m, H–C(3)); 3.12–3.04
(m, Ha–C(1), Ha–C(4)); 2.92–2.87 (m, Hb–C(1), H–
C(2)); 2.73 (dd, J = 8.1, 16.4 Hz, Hb–C(4)); 2.26 (s,
t
(m, 2H–C(4)); 1.41 (s, Bu).
t
Me); 1.43 (s, Bu).
31P NMR (CDCl3): 22.2.
13C NMR (CDCl3): 209.0 (C@O); 155.3 (NCO2); 133.9,
133.6 (C(4a), C(8a)); 129.2, 128.6, 126.6, 126.5 (4Car);
79.8 (CMe3); 53.5 (C(2)); 47.9 (C(3)); 35.0 (C(4)); 30.0
(C(1)); 28.4 (CMe3); 28.1 (Me).
13C NMR (CDCl3): 154.8 (NCO2); 143.0 (d, J = 11 Hz,
C(1)); 134.1 (C(4a)); 130.8 (d, J = 18 Hz, C(8a)); 130.5,
129.3, 128.7, 127.5 (4Car); 125.3 (d, J = 188 Hz, C(2));
79.7 (CMe3); 52.8, 52.8 (2OMe); 43.0 (d, J = 8.5 Hz,
C(3)); 35.0 (d, J = 8.5 Hz, C(4)), 28.4 (CMe3).
HR-MS (ESI-Q-Tof) calcd for C17H23NO3, [M]+:
289.1678; found: 289.1672.
HR-MS (ESI-microTof) calcd for C17H24NNaO5P,
[M]+: 376.1284; found: 376.1289.
5.15. 3-Amino-1,2,3,4-tetrahydronaphthalene-2-ethanone
hydrochloride (3b)
5.17. Dimethyl 3-tert-butoxycarbonylamino-1,2,3,4-tet-
rahydronaphthalene-2-phosphonate (17)
A mixture of 15 (26 mg, 90 lmol) and concd HCl
(75 lL, 900 lmol, 10 equiv) in EtOH (1.2 mL) and water
(55 lL) was stirred at rt under Ar for 16 h. The solvent
was evaporated and the solid recrystallised in PrOH/
Et2O to give 3b as a 5/95 mixture of cis and trans isomers
(16 mg, 80%).
The phosphonate 16 (80 mg, 0.22 mmol) was hydroge-
nated in MeOH (3.5 mL) over PtO2 (5 mg) at rt for
48 h. PtO2 was centrifuged off and the solution concen-
trated to give 17 as a 70/30 diastereoisomeric mixture
(80 mg, quant.).
i
Colorless crystals, mp 198–200 ꢁC (iPrOH/Et2O).
Colorless oil.
1
Major isomer. H NMR (CDCl3): 7.15–7.07 (m, 4Har);
IR (KBr), m: 3435, 3220, 3165, 2977, 2935, 2897, 2846,
2823, 1703, 1593, 1490, 1398, 1175, and 747 cmꢁ1
.
5.15 (br s, NH); 4.12 (m, H–C(3)); 3.79 (d,
J = 10.6 Hz, OMe); 3.74 (d, J = 10.6 Hz, OMe); 3.30
(br d, Ha–C(4)); 3.16–2.97 (m, 2H–C(1)); 2.74 (dd,
J = 8.0, 16.1 Hz, Hb–C(4)); 2.41 (m, H–C(2)); 1.45 (s,
CMe3).
1
Major isomer. trans, H NMR (CD3OD): 7.19–7.16 (m,
4Har); 3.83 (dt, H–C(3)); 3.39 (dd, Ha–C(1)); 3.22 (dd,
Ha–C(4)); 3.11 (dt, H–C(2)); 2.89 (dd, Hb–C(4)); 2.84
(dd, Hb–C(1)); 2.35 (s, Me). J(1a,1b) = 16.0,
J(1a,2) = 5.4, J(1b,2) = 11.4, J(2,3) = 8.6, J(3,4a) =
5.6, J(3,4b) = 10.7, J(4a,4b) = 15.7 Hz.
31P NMR (CDCl3): 33.2.
13C NMR (CDCl3): 155.1 (NCO2); 134.0, 133.7 (d,
J = 12 Hz, (C(4a), C(8a)); 129.2, 128.3, 126.5 (2)
(4Car); 79.5 (CMe3); 53.0 (d, J = 7 Hz), 52.8 (d,
J = 7 Hz) (2 OMe)); 46.8 (C(3)); 36.6 (d, J = 143 Hz,
C(2)); 35.9 (d, J = 10 Hz, C(4)); 28.3 ((C(1), CMe3).
13C NMR (CD3OD): 210.3 (C@O); 134.6, 133.1 (C(4a),
C(8a)); 129.7, 129.5, 128.1, 127.9 (4Car); 51.6 (C(2));
48.9 (C(3)); 33.8 (C(4)); 32.0 (C(1)); 28.6 (Me).
HR-MS (ESI-Q-Tof) calcd for C12H16NO, [M]+:
189.1154; found: 189.1182.
1
Minor isomer. H NMR (CDCl3): 7.15–7.07 (m, 4Har);
5.42 (br d, NH); 4.42 (m, H–C(3)); 3.76 (d,
J = 10.6 Hz, OMe); 3.61 (d, J = 10.6 Hz, OMe); 3.16–
2.97 (m, 2H–C(1), 2H–C(4)); 2.52 (ddt, J = 19.2, 2.8,
5.16. Dimethyl 3-tert-butoxycarbonylamino-3,4-dihydro-
naphthalene-2-phosphonate (16)
t
7.0 Hz, H–C(2); 1.44 (s, Bu).
A mixture of 12a (0.38 mmol), iPr2EtN (210 lL,
2.29 mmol, 6 equiv), HP(OMe)2 (175 lL, 1.91 mmol,
31P NMR (CDCl3): 33.7.

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S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
13C NMR (CDCl3): 155.1 (NCO2); 133.5, 133.1 (d,
J = 10 Hz, (C(4a), C(8a)); 130.0, 128.7, 126.4 (2)
(4Car); 79.5 (CMe3); 52.8 (d, J = 7 Hz), 52.6 (d,
J = 7 Hz) (2 OMe); 45.2 (C(3)); 35.5 (d, J = 143 Hz,
C(2)); 35.2 (d, J = 8 Hz, C(4)); 28.3 (CMe3); 27.0 (C(1)).
3.71 (s, OMe). J(3,4) = 7.8, J(3,5) = 1.2, J(4,5) = 7.6,
J(4,6) = 1.4, J(5,6) = 7.6 Hz.
5.20. Isochroman-3-one (4a) and methyl 2-hydroxy-
methylphenylacetate (19)
HR-MS (ESI-microTof) calcd for C17H26NNaO5P,
[M]+: 378.1441; found: 378.1442.
A solution of BH3 1 M in THF (60 mL, 60 mmol) was
slowly added to a solution of 18b (10.8 g, 55.5 mmol)
in dry THF (80 mL) at ꢁ15 ꢁC and the mixture was stir-
red under Ar at ꢁ15 ꢁC to rt for 16 h. The reaction mix-
ture was diluted with Et2O, washed successively with
1 N aq NaHCO3 and brine and dried over MgSO4.
The solvent was evaporated to give a variable mixture
of 19 and 4a (10.1 g).
5.18. 3-Amino-1,2,3,4-tetrahydronaphthalene-2-phos-
phonic acid, hydrobromide (3d)
Compound 17 (45 mg, 0.12 mmol) was heated with an
excess of 33% HBr in AcOH (2 mL) at 100 ꢁC for 2 h.
The mixture was evaporated to dryness and the solid
i
recrystallised in PrOH/Et2O to give 3d as a 70/30 iso-
meric mixture (26 mg, 70%).
A solution of this crude mixture in toluene (20 mL) and
p-TsOH (0.5 g, 2.5 mmol) was heated at 80 ꢁC for 3 h.
The reaction mixture was diluted with Et2O, washed
with brine and dried over MgSO4. After evaporation
4a was crystallised in toluene (5.36 g, 66%).
Colorless crystals, mp 144–6 ꢁC (iPrOH/Et2O).
IR (KBr), m: 3408, 3217, 3025, 2934, 1620, 1604, 1496,
1234, 1210, 1154, 985, 958, 948, 909, 753, and 525 cmꢁ1
.
Compound 19: Colorless resin, only characterised by 1H
NMR (CDCl3): 7.41 (m, 1Har); 7.30 (m, 2Har); 7.24 (m,
1Har); 4.69 (s, 2H–C(2)); 3.78 (s, 2H–C(1)); 3.71 (s,
OMe).
Major isomer. 1H NMR (CD3OD): 7.25–7.15 (m, 4Har);
4.03 (m, H–C(3)); 3.26–3.10 (m, 2H–C(1), 2H–C(4));
2.59 (m, H–C(2)).
Compound 4a: Colorless crystals, mp 82–4 ꢁC (toluene)
(lit.52 82–3 ꢁC).
31P NMR (CD3OD): 26.3.
13C NMR (CD3OD): 134.1 (d, J = 10.6 Hz, C(8a));
131.7 (C(4a)); 130.6, 130.2, 128.1, 127.8 (Car); 47.7 (d,
J = 5.0 Hz, C(3)); 35.2 (d, J = 139.2 Hz, C(2)); 33.5 (d,
J = 10.6 Hz, C(4)); 26.0 (C(1)).
IR (KBr), m: 3020, 2990, 2893, 1749, 1486, 1458, 1406,
1392, 1252, 1225, 1187, 1148, 1037, 1028, 992, 959,
819, 777, 762, 743, 693, 551, and 458 cmꢁ1
1H NMR (CDCl3): same data as in lit.30
5.21. 2-Bromomethylphenylacetic acid (20a)
.
Minor isomer. 1H NMR (CD3OD): 7.25–7.15 (m, 4Har);
3.77 (m, H–C(3)); 3.26–3.10 (m, 2H–C(1),Ha–C(4)); 2.95
(dd, J = Hb–C(4)); 2.31 (m, H–C(2)).
Same procedure as in the literature.30 A solution of 4a
(1 g, 6.7 mmol) in 33% HBr in acetic acid (9.1 mL)
was stirred at rt for 2 h and then at 70 ꢁC for 1 h. Dilu-
tion with cold water and filtration affords 20a which was
31P NMR (CD3OD): 25.7.
13C NMR (CD3OD): 134.9 (d, J = 11.3 Hz, C(1a));
132.8 (C(8a)); 129.8, 129.4, 128.2, 127.8 (Car); 48.9
(C(3)); 37.3 (d, J = 140.6 Hz, C(2)); 34.3 (d,
J = 13.6 Hz, C(4)); 29.0 (d, J = 3.5 Hz, C(1)).
i
recrystallised in Pr2O (1.35 g, 88%).
Colorless crystals, mp 133–4 ꢁC (iPr2O); (lit.29 139–
140 ꢁC, lit.51 129–132 ꢁC)).
HR-MS (ESI-Q-Tof) calcd for C10H14NO3P, [M]+:
227.0711; found: 227.0669.
IR (KBr), m: 2923, 2954, 2740, 2637, 1694, 1425, 1415,
1338, 1248, 1226, 936, 918, 769, 675, 618, and 601 cmꢁ1
1H NMR (CDCl3): same data as in lit.51
.
5.19. Methyl 2-carboxyphenylacetate (18b)
SOCl2 (1 mL, 13.8 mmol) was slowly added to a
solution of homophthalic acid (10 g, 55.5 mmol) in
dry methanol (100 mL) and the solution was stirred
under Ar at rt for 6 h. The reaction mixture was
poured in brine (30 mL), extracted with CH2Cl2
and the organic phase washed with water, dried over
MgSO4, and the solvent was evaporated to give 18b
(10.8 g, quant.).
5.22. Methyl 2-bromomethylphenylacetate (20b)
A solution of 2.1 N HCl in Et2O (1 mL, 2.1 mmol) was
slowly added to a solution of 20a (1 g, 4.4 mmol) in
MeOH (10 mL). The reaction mixture was stirred at rt
for 12 h and the solvent evaporated to give the crude
product as a 66/33 mixture of 20b and the corresponding
chloro-derivative (540 mg, quant.).
Colorless crystals, mp 96–8 ꢁC (lit.33 96–8 ꢁC).
1
Only characterised by H NMR (CDCl3): 7.37–7.36 (m,
1Har); 7.30–7.20 (m, 3Har); 4.68 (s, CH2Cl); 4.58 (s,
CH2Br); 3.81 (s, 2H–C(1)); 3.71 (s, OMe).
1H NMR (CDCl3): 8.15 (d, H–C(3)), 7.54 (t, H–C(5)),
7.41 (t, H–C(4)), 7.29 (d, H–C(6)), 4.06 (s, 2H–C(1)),

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7255
5.23. Isothiochroman-3-one (4b)
1H NMR (CDCl3): 7.29–7.26 (m, 2Har); 7.20–7.16
(m, 2Har); 4.88 (s, 2H–C(1)); 3.79 (s, 2H–C(4)).
Thiourea (0.20 g, 2.61 mmol, 1.2 equiv) was added to a
stirred solution of 20a (500 mg, 2.18 mmol) in dry ace-
tone (5.5 mL) under Ar at rt for 0.5 h. The precipitate
of thiouronium salt was filtered and washed with dry
acetone (0.544 g, 83%).
13C NMR (CDCl3): 162.6 (C(3)); 129.9, 128.8 (C(4a),
C(8a)); 128.1, 128.0, 127.2, 125.9 (4Car); 51.3 (C(1));
34.6 (C(4)).
Anal. Calcd for C9H9NO: (163.17): C, 66.25; H, 5.56; N,
8.58. Found: C, 66.3; H, 5.7; N, 8.5.
The crude thiouronium salt was hydrolysed in water
(3 mL) and aqueous 1 N aq NaOH (2.5 mL) at 100 ꢁC
for 2 h. The solution was acidified with aqueous 1 N
HCl (pH ꢂ1) and extracted with CH2Cl2. The organic
solution was dried over MgSO4, and the solvent was
evaporated to give crude thiol-acid 21. Esterification of
21 with an excess of solution of diazomethane in THF
gave the crude methyl ester after evaporation. To a solu-
tion of this crude methyl ester in dry toluene (20 mL)
was slowly added a solution of 2 M AlMe3 (1.1 mL,
2.18 mmol) in toluene. The reaction mixture was stirred
under Ar at rt for 16 h, hydrolysed at 0 ꢁC with aqueous
1 N HCl and extracted with AcOEt. The organic solu-
tion was washed with brine, dried over MgSO4 and
the solvent was evaporated. The crude product was puri-
fied by sublimation (60 ꢁC, 20 Torr) to give 4b (165 mg,
46% from 20a).
HR-MS (FAB+) calcd for C9H10NO2, [M+H]+:
164.0711; found: 164.0712.
5.25. 2-Amino-1,4-dihydro-2-isoquinolin-3-one (4d)
A solution of 20b (215 mg, 0.87 mmol) in MeOH (5 mL)
was stirred with Na2CO3 (376 mg, 3.55 mmol, 4 equiv)
and NH2NH2 Æ 2HCl (102 mg, 0.98 mmol, 1.2 equiv) un-
der Ar at 80 ꢁC for 48 h. The hot solution was filtered
and the filtrate concentrated, diluted with CH2Cl2 and
washed with 1 N aq NaOH (0.9 mL), and brine. The
organic solution was dried over MgSO4 and the solvent
was evaporated. The crude product was purified by sub-
limation (100 ꢁC, 20 Torr) to give 4 d (100 mg, 70%).
Yellowish crystals, mp 115–7 ꢁC (subl.) (lit.32 114–
117 ꢁC).
Compound 4b: Colorless crystals, mp 102–4 ꢁC (subl.)
(lit.29 105–6 ꢁC).
IR (KBr), m: 3305, 3200, 2894, 1652, 1632, 1609, 1493,
IR (KBr), m: 1662, 1652, 1051, 773, 744, and 644 cmꢁ1
.
and 739 cmꢁ1
.
1
Same H NMR and 13C NMR spectra (CDCl3) as in
1H NMR (CDCl3): 7.25–7.17 (m, 4Har); 4.73 (s, 2H–
C(1)); 4.59 (s, NH2); 3.71 (s, 2H–C(4)).
lit.29,31
Anal. Calcd for C9H8OS (164.23): C, 65.82; H, 4.91; S,
19.53. Found: C, 65.6; H, 5.1; S, 19.5.
13C NMR (CDCl3): 167.5 (C(3)); 131.2, 130.7 (C(4a),
C(8a)); 127.7, 127.6, 126.9, 125.5 (4Car); 54.3 (C(1));
36.3 (C(4)).
HR-MS (FAB+) calcd for C9H9OS, [M+H]+: 165.0374;
found: 165.0377.
Anal. Calcd for C9H10N2O (162.19): C, 66.65; H, 6.21;
N, 17.27. Found: C, 66.6; H, 5.7; N, 16.1.
1
Thiouronium salt, H NMR (CD3OD): 7.45 (m, 1Har);
7.32 (m, 3Har); 4.52 (s, 2H); 3.79 (s, 2H).
HR-MS (FAB+) calcd for C9H11N2O, [M+H]+:
163.0871; found: 163.0871.
Compound 21, only characterised by 1H NMR (CDCl3):
7.31–7.23 (m, 4Har); 3.82 (s, 2H); 3.79 (d, 2H); 1.72 (t,
SH). J(CH2,SH) = 7.0 Hz.
5.26. Enzyme assays
Enzyme source: Bovine kidney LAPc and A. proteolytica
aminopeptidase were purchased from Sigma Chemical
Co. Porcine kidney AP-N was purified as a soluble form
according to a published procedure.54 Human recombi-
nant LTA4H was provided by our collaborator J. Z.
Haeggstro¨m.
5.24. 2-Hydroxy-1,4-dihydro-2H-isoquinolin-3-one (4c)
A solution of crude 20b (400 mg, 1.64 mmol) in MeOH
(15 mL) was stirred with Na2CO3 (523 mg, 4.93 mmol)
and NH2OH Æ HCl (138 mg, 1.97 mmol, 1.2 equiv) un-
der Ar at 80 ꢁC for 22 h. The hot solution was filtered
and the filtrate concentrated, acidified with 1 N aq
HCl (pH ꢂ1), and extracted with CH2Cl2. The organic
solution was dried over MgSO4, and the solvent was
evaporated. The crude product was purified by sublima-
tion (140 ꢁC, 20 Torr) to give 4c (188 mg, 75%).
Typical assay conditions: Spectrophotometric assays
were performed with L-leucine-para-notroanilide
as
a
substrate for LAPc (Km = 2 mM), AP-N
(Km = 0.2 mM), and APaero (Km = 0.03 mM), alanine-
para-nitroanilide was used for LTA4H (Km = 2 mM).
All kinetic studies were performed at 30 ꢁC and the reac-
tions were started by the addition of enzyme in 1 mL as-
say medium: LAPc, 5 U in 10 mM Tris–HCl, 0.1 mM
ZnCl2, 5 mM MnCl2, 1 M KCl, pH 8.0; APaero, 3 mU
in 10 mM Tris–HCl, 0.05 mM ZnCl2, pH 8.0; AP-N,
Colorless crystals, mp 198–200 ꢁC (subl.).
IR (KBr), m: 3037, 2810, 1656, 1620, 1530, 1503, 1331,
755, and 745 cmꢁ1
.

7256
S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
22. Dupeau, P.; Hay, A.-E.; Bruneau, C.; Dixneuf, P. H.
Tetrahedron: Asymmetry 2001, 12, 863–867.
23. Miriyala, B.; Bhattacharyya, S.; Williamson, J. . Tetrahe-
dron 2004, 60, 1463–1471.
24. MacMurry, J. E.; Scott, W. J. Tetrahedron Lett 1983, 24,
979–982.
25 mU in10 mM Tris–HCl, pH 7.5, and LTA4H, 5 lg in
10 mM Tris–HCl, 0.1 mM KCl, pH 7.5.
The release of para-nitroaniline (e = 10,800 Mꢁ1cmꢁ1) at
405 nm was measured to determine initial velocities. Ki
values were determined using a Dixon plot.55
25. Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985,
26, 1109–1112.
´
26. Szarka, Z.; Skoda-Fo¨ldes, R.; Kollar, L.; Berente, Z.;
Horvath, J.; Tuba, Z. Tetrahedron 2000, 56, 5253–
Acknowledgments
´
5257.
27. Schwan, A. L. Chem. Soc. Rev. 2004, 33, 218–224.
28. Abbas, S.; Bertram, R. D.; Hayes, C. Org. Lett. 2001, 3,
3365–3367.
29. Lemaire, C.; Luxen, A.; Christiaens, L.; Guillaume, M.
J. Heterocycl. Chem. 1983, 20, 811–812.
30. Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1995, 51,
3351–3364.
31. Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1996, 61,
1859–1862.
32. Odasso, G.; Winters, G.; Schiatti, P.; Selva, D. Farmaco.
Ed. Sci. 1983, 38, 199–204.
33. (a) Ram, R. N.; Meher, N. K. J. Chem. Res., Synop. 2000,
6, 282–283; (b) Silverman, R. B.; Levy, M. A. J. Org.
Chem. 1980, 45, 815–818.
The support of the Centre National de la Recherche Sci-
entifique (UMR 7015) and the Swedish Research Coun-
cil (10350) is gratefully acknowledged. We also wish to
´
´
thank the Fondation of the Ecole Nationale Superieure
de Chimie de Mulhouse and the Ville of Mulhouse for a
Ph.D. Grant to S. Albrecht. We thank Prof. Vandorssel-
ear of Strasbourg University and Dr. Mathias Wind of
Basilea Pharmaceuticals (Basel) for HR-mass spectrom-
etry measurements. We thank the students Christine
Venard, Yves Muller and Arnaud Mignatelli for their
participation in this work.
34. Yoon, N. M.; Pak, C. S.; Brown, H. C.; Khrishnamur-
thy, S.; Stocky, T. P. J. Org. Chem. 1973, 38, 2786–
2792.
35. Phillips, D. D.; Hill, T. B. J. Am. Chem. Soc. 1958, 80,
3663–3667.
36. Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1973, 95,
5829–5831.
37. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 48, 4171–4174.
References and notes
1. McDonald, J. K.; Barrett, A. J.. In Mammalian Protease,
A glossary and Bibliography; Academic Press: New York,
1986; Vol. 2.
2. Hooper, N. M. FEBS Lett. 1994, 28, 1–6.
3. Rawling, N. D.; Barrett, A. J. Enzymology 1995, 248, 183–
228.
4. Taylor, A. FASEB J. 1993, 7, 290–298.
5. Lowther, W. T.; Matthews, B. W. Chem. Rev. 2002, 102,
4581–4607.
6. Amoscato, A. A.; Sramkoski, R. M.; Babcock, G. F.;
Alexander, J. W. Biochem. Biophys. Acta 1990, 1041, 317–
319.
7. Grembecka, J.; Kafarski, P. Mini-Rev. Med. Chem. 2001,
1, 133–144.
8. Sato, Y. Biol. Pharm. Bull. 2004, 27, 772–776.
9. Stra¨ter, N.; Lipscomb, W. N. Biochemistry 1995, 34,
14792–14800.
38. Johnson, J. R. Org. React. 1942, 1, 253.
39. Weichert, R. Liebigs Ann. Chem. 1963, 662, 161–164.
40. Penning, T. D.; Chandrakumar, N. S.; Chen, B. B.;
Chen, H. Y.; Desai, B. N.; Djuric, S. W.; Docter, S. H.;
Gasiecki, A. F.; Haack, R. A.; Miyashiro, J. M.;
Russell, M. A.; Yu, S. S.; Corley, D. G.; Durley, R.
C.; Kilpatrick, B. F.; Parnas, B. L.; Askonas, L. J.;
Gierse, J. K.; Harding, E. I.; Highkin, M. K.; Kachur,
J. F.; Kim, S. H.; Krivi, G. G.; Villani-Price, D.; Pyla,
E. Y.; Smith, W. G.; Ghoreishi-Haack, N. S. J. Med.
Chem. 2000, 43, 721–735.
10. Flipo, M.; Florent, I.; Grellier, P.; Sergheraert, C.;
Deprez-Polain, R. Bioorg. Med. Chem. Lett. 2003, 13,
2659–2662.
11. Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P.
J. Med. Chem. 2003, 46, 2641–2655.
12. Xu, W.; Li, Q. Curr. Med. Chem. – Anti-Cancer Agents
2005, 5, 281–301.
13. Bauvois, B.; Dauzonne, D. Med. Res. Rev. 2006, 26, 88–
130.
41. Chan, W. W.-C.; Dennis, P.; Demmer, W.; Brand, K.
J. Bio. Chem. 1982, 257, 7955–7957.
´
42. Fournie-Zaluski, M.-C.; Coric, P.; Turcaud, S.; Bruetschy,
L.; Lucas, E.; Noble, F.; Roques, B. P. J. Med. Chem.
1992, 35, 1259–1266.
43. Hu, X.; Zhu, J.; Srivathsan, S.; Pei, D. Bioorg. Med.
Chem. Lett. 2004, 14, 77–79.
44. Thunnissen, M. M.; Nordlund, P. N.; Haeggstro¨m, J. Z.
Nat. Struct. Biol. 2001, 8, 131–135.
14. Haeggstro¨m, J. Z. J. Biol. Chem. 2004, 279, 50639–50642.
15. Schalk, C.; d’Orchymont, H.; Jauch, M.-F.; Tarnus, C.
Arch. Biochem. Biophys. 1994, 311, 42–46.
16. d’Orchymont, H.; Tarnus, C. Eur. Patent 0378456 A1,
1990.
17. Cook, E. S.; Hill, A. J. J. Chem. Soc. 1940, 1995–1998.
18. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–
4156.
19. Albrecht, S.; Defoin, A.; Tarnus, C. Synthesis 2006, 1635–
1638.
20. Kametani, T.; Sugahara, H.; Yagi, H. J. Chem. Soc. C
1966, 717–722.
45. Kim, H.; Lipscomb, W. N. Biochemistry 1993, 32, 8465–
8478.
46. Chevrier, B.; Schalk, C.; d’Orchymont, H.; Rondeau, J.-M.;
Moras, D.; Tarnus, C. Structure 1994, 2, 283–291.
47. Lipscomb, W. N.; Stra¨ter, N. Chem. Rev. 1996, 96, 2375–
2433.
´
48. Chen, H.; Roques, B. P.; Fournie-Zaluski, M.-C. Bioorg.
Med. Chem. Lett. 1999, 9, 1511–1516.
´
49. Chen, H.; Noble, F.; Roques, B. P.; Fournie-Zaluski, M.-C.
J. Med. Chem. 2001, 44, 3523–3530.
50. Puerta, D. T.; Lewis, J. A.; Cohen, S. M. J. Am. Chem.
Soc. 2004, 126, 8388–8389.
51. Leroy Chauffe; Andrews, L. J.; Keefer, R. M. J. Org.
Chem. 1966, 31, 3758–3764.
21. deJong, A. P.; Fesik, S. W.; Makriyannis, A. J. Med.
Chem. 1982, 25, 1438–1441.

S. Albrecht et al. / Bioorg. Med. Chem. 14 (2006) 7241–7257
7257
52. Heilbron, I.; Cook, A. H.; Bunbury, H. M.; Hey, D. H. In
Dictionnary of organic compounds; Eyre and Spottiswoode
Ltd: London, 1965; Vol. 5.
54. Wacker, H.; Lecky, P.; Fischer, E. H.; Stein, E. A. Helv.
Chim. Acta 1971, 54, 473–484.
55. Segel, I. H. In Enzyme Kinetics; Wiley: New York, 1975;
pp 109–144.
53. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.