Iodine(III)-mediated ring expansion: An efficient and green pathway in the synthesis of a key precursor for the design of aminopeptidase (APN or CD13) inhibitors

Article abstract of DOI:10.1016/j.tet.2010.09.005

Iodine(III)-mediated ring expansion of a methylidenebenzocyclohexane derivative into the corresponding benzosuberone was used as a key reaction for the obtention of an important precursor for the design of aminopeptidase (APN or CD13) inhibitors. It represents the first application of this environmentally friendly rearrangement to medicinal chemistry.

Full text of DOI:10.1016/j.tet.2010.09.005

Tetrahedron 66 (2010) 8722e8728
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iodine(III)-mediated ring expansion: an efficient and green pathway in the
synthesis of a key precursor for the design of aminopeptidase (APN or CD13)
inhibitors
*
*
Lionel Roux, Cédric Charrier, Albert Defoin, Philippe Bisseret , Céline Tarnus
FRE 3253, Laboratoire de Chimie Organique et Bioorganique, associé au CNRS, ENSCMu, 3 rue A. Werner, 68093 Mulhouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2010
Received in revised form 27 August 2010
Accepted 3 September 2010
Available online 15 September 2010
Iodine(III)-mediated ring expansion of a methylidenebenzocyclohexane derivative into the corre-
sponding benzosuberone was used as a key reaction for the obtention of an important precursor for the
design of aminopeptidase (APN or CD13) inhibitors. It represents the first application of this environ-
mentally friendly rearrangement to medicinal chemistry.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Aminopeptidase
Hypervalent iodine chemistry
Ring expansion
APN or CD13 inhibitors
1. Introduction
particular in angiogenesis-dependent pathologies.2 Structural
requirements for APN inhibition were previously determined4,5 and
Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is an ectopepti-
dase that belongs to the class of metalloenzymes from the M1
family with a zinc ion essential for catalysis.1 The expression of
this ubiquitous proteolytic enzyme has been shown to be dys-
regulated in many diseases and is known to play an important
led to the discovery of (ꢀ)-7-amino-6-benzosuberone scaffold 1 as
a lead structure, showing a remarkable inhibitory potency and
selectivity toward APN, with a Ki value of 1 m
M.5 In view of its
minimal size, this compound displayed an excellent ligand effi-
ciency of 0.63 according to the definition by Hopkins et al.6
role in tumor angiogenesis and metastasis.1b,2 Although many
inhibitors of aminopeptidases are available, most of them are
poorly selective.3 The development of highly specific and potent
inhibitors remains a challenge since most aminopeptidases are
zinc-dependent enzymes that share a broad substrate specificity.1
Specific inhibitors would be undoubtely crucial biological tools
since little is known about the precise role and mechanism of
action of APN in the physiological and pathological processes, in
This scaffold therefore appeared as an excellent candidate for
further chemical elaboration and derivatization and we already
pointed out the outstanding inhibitory activity and selectivity
toward APN of the racemic 4-phenyl and 1-bromo derivatives 2 and
3, paving thus the way to the elaboration of (ꢀ)-1,4-difunctional-
ized derivatives 4. Our synthesis of 2 and 3 started from ortho-
xylenic precursors and relied on a non-regioselective step of
modest yield.5 We present here a straightforward synthesis of the
(ꢀ)-1,4-disubstituted aminobenzosuberone 5, which potentially
represents an ideal precursor to compounds of the series 4.7 As
indicated Fig. 1, our synthesis started from natural -tryptophane 10
L
* Corresponding authors. E-mail address: philippe.bisseret@uha.fr (P. Bisseret).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.005

L. Roux et al. / Tetrahedron 66 (2010) 8722e8728
8723
and was based on the transformation in two steps of the 1-tetra-
lone derivative 8 into the corresponding -benzosuberone 6. This
saponification and protection of the primary amine function as
a trifluoroacetamide.
b
overall transformation, which is based in a first step on the con-
version of a six-membered ring ketone into the corresponding
exomethylene derivative followed by a step of oxidative rear-
rangement, has been originally reported from 1-tetralone and some
of its methyl or methoxy derivatives, using thallium nitrate in
methanol for the ring expansion.8 More recently, after a first report
that implied non-cyclic ketones,9a Justik and Koser published,
again from simple 1-tetralones, an analogous sequence in which
[hydroxy(tosyloxy)iodo]benzene (HTIB) was employed as an
excellent green alternative to the very toxic thallium salt in the
rearrangement step.9b As reported here, this latter procedure
proved very convenient for the preparation of the functionalized
benzosuberone 6 from its exomethylenic precursor 7. To the best of
our knowledge, this represents the first application of Koser’s
procedure to medicinal chemistry.10
The preparation of 1-oxo-tetrahydronaphthalenic compound 8
required at first the tricky reduction of the carbonyl function in
trifluoroacetaniline 9. As shown in Scheme 2, this could be achieved
by prolonged hydrogenation in acetic acid at 110 ꢁC. Under these
conditions, both the N-trifluoroacetyl and the N-ethoxycarbonyl
protecting groups were preserved.11 The acid chloride derivative of
15 was then submitted to a AlCl3-mediated FriedeleCrafts reac-
tion12 yielding 8 and the lactam derivative 16 arising from prior
AlCl3-induced partial deprotection of the NHCOCF3 moiety.
Access to the precursor 7 of the rearranged compound implied
the methylenation of the oxo derivative 8. This step required
extensive trials as a Wittig reaction13 or the use of a Tebbe
reagent14 proved quite unsatisfactory. Finally, a two-steps pro-
cedure implying the addition of methylmagnesium bromide fol-
lowed by the dehydratation of the tertiary alcohol appeared much
Fig. 1. Retrosynthesis of 4-bromo-1-tert-butylbenzyloxycarbonylamino benzosuberone derivative 5.
2. Results and discussion
more suitable and allowed us to obtain the desired intermediate
in 55% overall yield.
Our synthesis started with the preparation of the 4-phenyl-
butanoic acid derivative 9. This compound was readily obtained
Methylenic derivative 7 was then submitted to HTIB in metha-
nol at rt according to Koser and Justik.9 Under these conditions, we
with an overall yield of 62% from natural
L
-tryptophane as in-
were pleased to isolate after 1 h the desired b-benzocycloalkanone
dicated Scheme 1. After protection as a methyl ester and as
a N-ethoxycarbonyl derivative, intermediate 12 was submitted to
ozonolysis leading to an equimolar mixture of the expected
N-formyl compound 14 and its deprotected partner 13. A full access
to 13 was possible by the treatment of 14 with methanolic HCl.
The aniline derivative 13 was finally converted into 9 after
6 in a good yield as shown in Scheme 3.
Our key-precursor 5 carrying bromo- and NHBoc subtituents for
further chemical derivatization on the aromatic ring was finally
prepared from 6 according to Scheme 4.
Switching the trifluoroacetyl protection of 6 to a tert-butyloxy-
carbonyl was easily accomplished using mild basic conditions to
Scheme 1. Synthesis of 2-ethoxycarbonylamino-4-oxo-4-[2-(2,2,2-trifluoroacetylamino)-phenyl]-butanoic acid 9.

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L. Roux et al. / Tetrahedron 66 (2010) 8722e8728
Scheme 2. Synthesis of ethyl [1-oxo-5-(2,2,2-trifluoroacetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamate 8.
Scheme 3. Synthesis of 1-(2,2,2-trifluoroacetylamino)-7-ethoxycarbonylamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one 6.
Scheme 4. Synthesis of 1-(tert-butoxycarbonylamino)-4-bromo-7-benzyloxycarbonylamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one 5.
free the aniline moiety.15 In spite of the mildness of this trans-
formation, the integrity of the asymmetric center next to the
carbonyl function could not be preserved and yielded 17 as a race-
mic mixture. Removal of the ethoxycarbonyl protection could not
be accomplished easily: indeed, strong acidic or basic conditions
like HBr or HCl at reflux in acetic acid,16 use of TMSI17 or methanolic
Ba(OH)2 at reflux failed to give the desired compound. Neverthe-
less, after reduction of the carbonyl function of 17 into a secondary
alcohol, this latter basic condition worked perfectly.18 The resulting
amine was purified as a benzyloxycarbonyl derivative and easily
further converted with excellent yield into its para-bromo
derivative by action of NBS in acetonitrile.
3. Conclusion
In conclusion, we have performed the synthesis of a key
2-benzosuberone precursor 5 required for the preparation of
a series of APN inhibitors of type 4. This synthesis, which starts

L. Roux et al. / Tetrahedron 66 (2010) 8722e8728
8725
from natural
L
-tryptophane, relies on the first utilization in
2H, H3a), 3.76 (dd, J¼17.8, 4.2 Hz, 2H, H3b), 3.75 (s, 3H, HOMe), 4.12 (q,
J¼7.0 Hz, 2H, ethyl-CH2), 4.28 (ddd, J¼8.8, 4.2, 3.8 Hz, 1H, H2), 5.78
(d, J¼8.8 Hz, 1H, NH), 6.67 (dd, J¼8.3, 1.5 Hz, 1H, H3), 6.67 (ddd,
J¼8.3, 7.8, 0.8 Hz, 1H, H4), 7.28 (ddd, J¼8.3, 7.8, 1.5 Hz, 1H, H5), 7.67
(dd, J¼8.3, 0.8 Hz, 1H, H6aro).
medicinal chemistry of a rearrangement mediated by the Koser’s
reagent HTIB between a methylidenebenzocyclohexane derivative
and the corresponding ring expanded benzosuberone.
4. Experimental
To a solution of the preceeding butyrate 13 (23.42 g, 0.11 mol) in
THF (300 mL) were added water (300 mL), methanol (15 mL), and
LiOH (50 g). The mixture was stirred at rt for 14 h. Aqueous 6 N HCl
was then added dropwise to obtain pH¼3. After separation, the
aqueous layer was extracted with ethyl acetate (ꢃ5). The combined
organic phases were dried over MgSO4 and concentrated in vacuo.
Trifluoroacetic anhydride (18.2 mL, 0.13 mol) was then added and
the mixture was stirred at rt for 2 h. Water was added at this stage
to hydrolyze excess of trifluoroacetic anhydride. After extraction
with dichloromethane (ꢃ4), the organic phases were dried over
MgSO4 and concentrated in vacuo to give an orange oil. The residue
was purified by FC (cyclohexane/AcOEt/AcOH, 70/28/2) yielding the
butanoic acid derivative 9 in 78% yield. 1H NMR: (CDCl3, 400 MHz,
4.1. General methods
TLC chromatography was performed with silica gel (Merck 60
F254). Flash chromatography was performed on silica gel (Merck 60,
230e400 mesh). Melting points were recorded on a Kofler hot
bench and are corrected. IR spectra were measured with a Nicolet
405 FT-IR spectrometer. Optical rotations were measured on
a SchmidteHaensch Polartronic Universal or a PerkineElmer 341
LC polarimeter. NMR spectra were recorded on a Bruker AV 400
spectrometer. High resolution MS were measured on a Waters
Micromass Q-Tof Ultima API spectrometer. MeOH was distilled over
Mg/MgI2, THF over Na and benzophenone; CH2Cl2 was distilled
over P2O5 and kept over Na2CO3.
295 K):
d
1.26 (t, J¼7.0 Hz, 3H, ethyl-CH3), 3.71 (dd, J¼18.4, 4.0 Hz,
2H, H3a), 3.80 (dd, J¼18.4, 4.0 Hz, 2H, H3b), 4.13 (q, J¼7.0 Hz, 2H,
ethyl-CH2), 4.82 (dt, J¼8.1, 4.0 Hz,1H, H2), 5.76 (d, J¼8.1 Hz,1H, NH),
7.31 (t, J¼7.8 Hz, 1H, H4), 7.68 (t, J¼8.1 Hz, 1H, H5), 7.99 (d, J¼7.8 Hz,
1H, H3), 8.72 (d, J¼8.1 Hz, 1H, H6ar), 12.57 (s, 1H, Hacid). 13C NMR
4.1.1. N-(Ethoxycarbonyl)tryptophane methyl ester (12)19. To a solu-
tion of -tryptophane 10 (50 g, 0.245 mol) in methanol (600 mL),
L
was added dropwise thionyl chloride (19.6 mL, 0.269 mol) at 0 ꢁC
under Ar. The mixture was heated under Ar at reflux for 2 h 30.
After evaporation of methanol, we obtained the crude methyl ester
(CDCl3, 100.6 MHz, 295 K): d 14.43 (eCH2eCH3), 41.94 (C3), 49.59
(C2), 61.64 (eCH2eCH3), 117.7 (q, J¼286 Hz, eCF3), 121.29 (C4ar),
121.69 (C2ar), 124.82 (C5ar), 131.21 (C3ar), 136.12 (C6ar), 138.6 (C1ar),
156.39 (Ccarbamate), 158.1 (q, J¼37 Hz, eCamide), 177.32 (C1), 202.18
11 in quantitative yield. 1H NMR (CD3OD, 400 MHz, 295 K):
d 3.36
(dd, J¼15.1, 7.0 Hz,1H, H3b), 3.42 (dd, J¼15.1, 5.5 Hz,1H, H3a), 3.72 (s,
3H, HOMe), 4.28 (dd, J¼7.0, 5.5 Hz, 1H, H2), 7.03 (t, J¼7.9 Hz, 1H,
H5indol), 7.10 (t, J¼7.9 Hz, 1H, H6indol), 7.21 (s, 1H, H2indol), 7.38 (d,
J¼7.9 Hz, 1H, H7indol), 7.51 (d, J¼7.9 Hz, 1H, H4indol).
(C4). 19F NMR: (CDCl3, 376.5 MHz, 295 K):
d
ꢂ76.4. IR (cmꢂ1, KBr):
3357, 3314.8, 3112, 2986, 2935, 1717.6, 1703, 1653, 1590.9, 1535.9,
25
1455.8, 1285.6, 1157.7. [
a]
þ71.5 (c 1.0, CHCl3). Mp¼100e102 ꢁC.
D
The latter compound (53.43 g, 0.245 mol) was dissolved into
water (300 mL) containing sodium carbonate decahydrate
(210.31 g, 0.735 mol). To this solution were added dichloromethane
(300 mL) and ethyl chloroformate (23.3 mL, 0.245 mol). After stir-
ring at rt for 14 h, the aqueous and organic phases were separated.
The aqueous layer was extracted with dichloromethane. The com-
bined organic phases were dried over MgSO4 and concentrated in
vacuo to give the N-(ethoxycarbonyl)tryptophane methylic ester 12
4.1.3. 2-Ethoxycarbonylamino-4-[2-(2,2,2-trifluoroacetylamino)-phe-
nyl]-butanoic acid (15). 2-Ethoxycarbonylamino-4-oxo-4-[2-(2,2,
2-trifluoroacetylamino)-phenyl]-butanoic acid 9 (25 g, 66.44 mmol)
was dissolved in acetic acid (120 mL). This solution was added
dropwise under H2 at rt to a suspension of Pd/C (5 g) in acetic acid
(300 mL). The mixture was heated at reflux (110 ꢁC) under strirring
for 30 h. This solution was filtered off on Celite and acetic acid was
evaporated to give a brown oil, which was purified by FC (cyclo-
hexane/AcOEt/AcOH, 70/28/2) to give 2-ethoxycarbonylamino-4-
[2-(2,2,2-trifluoroacetylamino)-phenyl]-butanoic acid 15 with
in quantitative yield. 1H NMR (CDCl3, 400 MHz, 295 K):
d 1.27 (t,
J¼7.0 Hz, 3H, CH3 ethyl), 3.31 (d, J¼5.3 Hz, 2H, H3), 3.69 (s, 3H,
HOMe), 4.12 (q, J¼7.0 Hz, 2H, ethyl-CH2), 4.28 (dt, J¼7.8, 5.3 Hz, 1H,
H2), 7.02 (s, 1H, H2indol), 7.13 (t, J¼7.8 Hz, 1H, H5indol), 7.21 (t,
J¼7.8 Hz, 1H, H6indol), 7.37 (d, J¼7.8 Hz, 1H, H7indol), 7.56 (d, J¼7.8 Hz,
1H, H4indol), 8.10 (s, 1H, H1indol). 13C NMR (CDCl3, 100.6 MHz, 295 K):
a yield of 67%. 1H NMR (CDCl3, 400 MHz, 295 K):
d
1.25 (t, J¼7.2 Hz,
3H, ethyl-CH3), 1.91 (m, 1H, H3a), 2.10 (m, 1H, H3b), 2.69 (t, J¼7.7 Hz,
2H, H4), 4.10 (q, J¼7.2 Hz, 2H, ethyl-CH2), 4.10 (m, 1H), 7.24e7.36 (m,
4H, Har). 13C NMR (CDCl3, 100.6 MHz, 295 K):
d 15.03 (eCH2eCH3),
d
14.52 (ethyl-CH3), 27.94 (C3), 52.31 (OCH3), 54.33 (C2), 61.11
28.7 (C4), 33.49 (C3), 54.95 (C2), 62.18 (eCH2eCH3), 117.7 (q,
J¼286 Hz, eCF3), 128.38 (C4ar), 128.54 (C2ar), 128.95 (C6ar), 129.54
(C5ar), 130.74 (C1ar), 131.31 (C3ar), 158.1 (q, J¼37 Hz, Camide), 159.07
(Ccarbamate), 175.73 (C1). 19F NMR: (CD3OD, 376.5 MHz, 295 K):
(ethyl-CH2), 109.93 (Cq), 111.20 (C7indol), 118.58 (C4indol), 119.64
(C5indol), 122.21 (C6indol), 122.75 (C2indol), 127.52(Cq), 136.10 (Cq),
156.03 (eNHeCOeOEt), 172.56 (CeCOeOMe). IR (cmꢂ1, KBr):
3319.2, 3058, 2986, 1753.6, 1724.1, 1685.9, 1550.7, 1462, 1434.2,
d
ꢂ76.4 ppm. IR (cmꢂ1, KBr): 3302, 3061, 2993, 1711.5, 1689, 1541.2,
25
25
1375.3, 1289.8, 1218.7, 1067.5.
[a
]
þ47.0 (c 1.0, CHCl3).
1285, 1258.1, 1202, 1164.6, 1055.7. [
a]
ꢂ10.2 (c 1.0, CHCl3).
D
D
Mp¼92e94 ꢁC. HRMS (ESI) calcd for [C15H18N2O4, Na]þ: 313.1159;
Mp¼112e115 ꢁC. HRMS calcd for [C15H17N2O5F3, H]þ¼363.1162;
found 313.1160.
found 363.1162.
4.1.2. 2-Ethoxycarbonylamino-4-oxo-4-[2-(2,2,2-trifluoroacetylamino)-
phenyl]-butanoic acid (9). A solution of N-(ethoxycarbonyl)trypto-
phane methyl ester 12 (71.12 g, 0.245 mol) in methanol (700 mL)
was stirred under a flux of ozone at ꢂ60 ꢁC during 10 h and gave
a mixture of 4-oxo-butyrates 13 and 14 as checked in 1H NMR on
a sample. After concentration to 1/4, 4 N aqueous HCl (100 mL) was
added. The mixture was stirred at rt for 1 h, extracted with ethyl
acetate (4ꢃ200 mL) and the combined organic solvents were
evaporated, dried over MgSO4, and concentrated in vacuo to give
the crude methyl 4-(2-amino-phenyl)-2-ethoxycarbonylamino-4-
oxo-butyrate 13 in quantitative yield. 1H NMR: (CDCl3, 400 MHz,
4.1.4. Ethyl [1-oxo-5-(2,2,2-trifluoroacetylamino)-1,2,3,4-tetrahydro-
naphthalen-2-yl]-carbamate (8) and ethyl [2-oxo-2,3,4,5-tetrahydro-
1H-benzo[b]azepin-3-yl]-carbamate (16). To a solution of butanoic
acid derivative 15 (16.15 g, 0.044 mol) in dichloromethane
(100 mL) was added dropwise thionyl chloride (3.6 mL, 0.049 mol)
at 0 ꢁC under Ar. This mixture was heated at reflux for 1 h 30 min
to give a solution of an acyl chloride, which was added dropwise
for 2 h to a solution of AlCl3 (23.79 g, 0.18 mol) in dichloro-
methane (200 mL) at rt. The mixture was stirred for 2 h and then
quenched with ice. After separation, the aqueous layer was
extracted with dichloromethane (ꢃ4). The organic phases were
dried over MgSO4 and concentrated in vacuo to give a brownish
295 K):
d
1.25 (t, J¼7.0 Hz, 3H, ethyl-CH3), 3.53 (dd, J¼17.8, 3.8 Hz,

8726
L. Roux et al. / Tetrahedron 66 (2010) 8722e8728
oil. The residue was purified by FC (dichloromethane/AcOEt, 95/5)
to give the ethyl [1-oxo-5-(2,2,2-trifluoroacetylamino)-1,2,3,
4-tetrahydro-naphthalen-2-yl]-carbamate 8 in 56% yield and the
trifluoroacetylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]-carba-
mate 7 with a yield of 55%. 1H NMR (CDCl3, 400 MHz, 295 K):
d
1.26 (t, J¼7.1 Hz, 3H, ethyl-CH3), 2.01(m, 1H, H3a), 2.10(m, 1H,
ethyl
[2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]-carba-
H3b), 2.78 (br t, J¼12.2 Hz, 2H, H4), 4.15 (q, J¼7.1 Hz, 2H, ethyl-
CH2), 4.51 (m, 1H, H2), 4.8 (d, J¼8.1 Hz, 1H, NH carbamate), 5.27
(s, 1H, Halkene a), 5.62 (s, 1H, Halkene b), 7.27 (dd, J¼8.0, 7.8 Hz, 1H,
H7), 7.57 (d, J¼8.0 Hz, 1H, H6), 7.66 (d, J¼7.8 Hz, 1H, H8), 7.82 (br
mate 16 (20% yield).
Compound 8: (CDCl3, 400 MHz, 295 K):
d
1.29 (t, J¼7.0 Hz, 3H,
ethyl-CH3), 1.95 (dddd, J¼4.8, 12.4, 12.9, 13.8 Hz, 1H, H3axial), 2.85
(m, 1H, H3eq), 2.94 (ddd, J¼2.3, 4.8, 17.1 Hz, 1H, H4eq), 3.07 (ddd,
J¼5.0, 12.4, 17.1 Hz, 1H, H4a), 4.18 (q, J¼7.0 Hz, 2H, ethyl-CH2), 4.10
(ddd, J¼4.8, 5.3, 13.8 Hz, 1H, H2axial), 5.84 (br s, J¼5.3 Hz, 1H, NH
carbamate), 7.46 (t, J¼7.5 Hz, 1H, H7), 7.84 (br s, 1H, NH amide), 7.95
(d, J¼7.8 Hz, 1H, H6), 8.03 (d, J¼7.3 Hz, 1H, H8). 13C NMR (CDCl3,
s, 1H, NH amide). 13C NMR (CDCl3, 100.6 MHz, 295 K):
d 14.6
(eCH2eCH3), 22.22 (C4), 28.7 (C3), 51.1 (C2), 61.0 (eCH2eCH3),
110.2 (Cdu methylene), 116.0 (q, J¼289 Hz, eCF3), 118.9 (C1), 122.6
(Cq), 123.6 (C6), 124.5 (C8), 127.1 (C7), 128.3 (Cq), 134.8 (Cq), 142.9
(Ccarbamate), 155.6 (q, J¼37.4 Hz, eCamide). 19F NMR: (CDCl3,
100.6 MHz, 295 K):
d
14.55 (eCH2eCH3), 23.57 (C4), 29.53 (C3),
376.5 MHz, 295 K):
d
ꢂ76.5. IR (cmꢂ1, KBr): 3314, 3266.0, 3072,
56.97 (C2), 61.20 (eCH2eCH3), 117.7 (q, J¼286 Hz, eCF3), 126.91
2982, 2943, 1707.3, 1685, 1540.8, 1258.9, 1188, 1158.7.
Mp¼168e172 ꢁC. HRMS calcd for [C16H17N2O3F3, Na]þ¼365.1083;
found 365.1086.
(C4ar), 127.69 (C2ar), 129.96 (C6ar), 132.34 (C5ar), 132.62 (C1ar), 136.47
(C3ar), 155.6 (q, J¼37 Hz, Camide), 156.35 (Ccarbamate), 194.32 (C1). 19
F
NMR: (CDCl3, 376.5 MHz, 295 K):
d
ꢂ76.4. IR (cmꢂ1, KBr): 3309.3,
3263, 3065, 2993, 1716, 1684, 1540.8, 1319.7, 1270.3, 1238.5, 1196.3,
4.1.6. 1-(2,2,2-Trifluoroacetylamino)-7-ethoxycarbonylamino-5,7,8,9-
tetrahydro-6H-benzocyclohepten-6-one (6). After dissolution of
carbamate 7 (1.71 g, 5.0 mmol) into methanol (100 mL), Koser’s re-
agent (PhI(OH)OTs) (2.94 g, 7.5 mmol, 1.5 equiv) was added. The
mixture was stirred at rt for 1 h. This solution was concentrated and
diluted with water and ethyl acetate. After separation, the aqueous
layer was extracted with ethyl acetate (3ꢃ100 mL). The organic
phase was dried over MgSO4 and concentrated in vacuo to give
a brown solid. The residue was purified by recristallisation in diiso-
propylether to give the 1-(2,2,2-trifluoroacetylamino)-7-ethox-
1164.6. [
a
]
25 þ30.0 (c 1.0, CDCl3). Mp¼181e182 ꢁC. HRMS calcd for
D
[C15H15N2O4F3, H]þ¼345.1057; found 345.1066.
Compound 16: 1H NMR (CDCl3, 400 MHz, 295 K):
d 1.22 (t,
J¼7.0 Hz, 3H, ethyl-CH3), 2.01 (ddd, J¼7.5, 11.6, 12.0 Hz, 1H, H4b),
2.65e2.76 (m, 2H, H5be4a), 2.96 (dd, J¼8.3, 12.3 Hz, 1H, H5a), 4.08 (q,
J¼7.0 Hz, 2H, ethyl-CH2), 4.30 (dd, J¼7.1, 12.0 Hz, 1H, H3), 5.60 (br s,
1H, NH carbamate), 7.00 (d, J¼7.5 Hz, 1H, H6), 7.17 (t, J¼7.5 Hz, 1H,
H7), 7.23 (m, 2H, H8e9), 7.73 (s, 1H, NHamide). 13C NMR (CDCl3,
100.6 MHz, 295 K): d 14.94 (eCH2eCH3), 28.89 (C5), 37.09 (C4), 51.20
(C3), 61.39 (eCH2eCH3), 122.82 (C6), 126.69 (Cq), 126.93 (C7), 128.21
(C8e9), 130.28 (C8e9), 134.35 (Cq), 156.16 (Ccarbamate), 173.29 (Camide).
IR (cmꢂ1, KBr): 3266.5, 3220, 3058, 2982, 2932, 2871,1724.3,1675.5,
ycarbonylamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one
6
with a yield of 70%. 1H NMR (CDCl3, 400 MHz, 295 K):
d
1.24 (t,
J¼7.4 Hz, 3H, ethyl-CH3), 1.57(dddd, J¼4.8, 6.8, 10.3, 12.2 Hz, 1H, H8a),
2.67(br dd, J¼8.5, 12.2 Hz, 1H, H8b), 2.90 (m, 2H, H9aþb), 3.71(d,
J¼15.0 Hz, 1H, H5a), 3.97(d, J¼15.0 Hz, 1H, H5b), 4.10 (q, J¼7.4 Hz, 2H,
ethyl-CH2), 4.55 (ddd, J¼5.6, 8.5, 10.3 Hz, 1H, H7), 5.56 (d, J¼5.6 Hz,
1H, NH carbamate), 7.22 (d, J¼7.3 Hz, 1H, H2), 7.28 (t, J¼7.3 Hz, 1H,
H3), 7.37 (d, J¼7.3 Hz, 1H, H4), 7.84 (br s, 1H, NH amide). 13C NMR
1542.1, 1258.5, 1053.5. [
a
]
25 þ85.1 (c 1.0, CHCl3). Mp¼144 ꢁC. HRMS
D
calcd for [C13H16N2O3, H]þ¼249.1239; found 249.1234.
4.1.5. Ethyl[1-methylen-5-(2,2,2-trifluoroacetylamino)-1,2,3,4-tetra-
hydro-naphthalen-2-yl]-carbamate (7). To a solution of carbamate
8 (2.2 g, 6.4 mmol) in THF (100 mL) were added successively
HMPA (1.1 mL, 6.4 mmol, 1 equiv) and MeMgBr 3 M in dieth-
ylether (15.3 mL, 0.045 mol, 7 equiv) under Ar at 0 ꢁC. This
mixture was stirred at 0 ꢁC for 3 h. After quenching with ice and
an aqueous saturated solution of NH4Cl, extraction with Et2O
(ꢃ3), the organic phase was dried over MgSO4, and concentrated
in vacuo to give a brown solid with a quantitative yield. The
crude product was introduced in the next reaction without pu-
(CDCl3, 100.6 MHz, 295 K):
d 14.5 (eCH2eCH3), 24.1 (C9), 32.7 (C8),
48.1 (C5), 60.3 (C7), 61.1 (eCH2eCH3), 116.0 (q, J¼288.9 Hz, eCF3),
125.9 (C4), 128.0 (C3), 129.8 (C2), 131.6 (C4’), 134.3 (C1’), 135.2 (C1),
155.6 (q, J¼38.2 Hz, eCamide),155.71 (Ccarbamate), 203.16 (C6). 19F NMR:
(CDCl3, 376.5 MHz, 295 K): ꢂ76.5. IR (cmꢂ1, KBr): 3327.6, 3274,
3076,2989, 2939, 1710.4, 1674.6, 1532.4, 1254.6, 1199, 1164.7.
Mp¼197e199 ꢁC. HRMS calcd for [C16H17N2O4F3, Na]þ¼381.1033;
found 381.1030.
rification. 1H NMR (CDCl3, 400 MHz, 295 K):
d
1.28 (t, J¼7.1 Hz,
3H, ethyl-CH3), 1.38 (s, 3H, methyl-CH3), 1.81 (ddd, J¼10.3, 12.2,
12.8 Hz, 1H, H3ax), 2.10 (m, 1H, H3eq), 2.79 (m, 2H, H4), 3.89 (ddd,
J¼3.3, 7.8, 12.2 Hz, 1H, H2), 4.18 (q, J¼7.1 Hz, 2H, ethyl-CH2), 5.86
(d, J¼7.8 Hz, 1H, NH carbamate), 7.28 (t, J¼7.8 Hz, 1H, H7), 7.50
(d, J¼7.8 Hz, 1H, H8), 7.59 (d, J¼8.0 Hz, 1H, H6), 8.04 (br s, 1H,
4.1.7. 1-(tert-Butoxycarbonylamino)-7-ethoxycarbonylamino-
5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one (17). To a solution of
1-(2,2,2-trifluoroacetylamino)-7-ethoxycarbonylamino-5,7,8,9-tet-
rahydro-6H-benzocyclohepten-6-one 6 (1.00 g, 2.79 mmol) in
methanol (60 mL) and water (25 mL), was added K2CO3 (3.86 g,
27.9 mol, 10 equiv). This mixture was heated at 110 ꢁC for 14 h, and
then diluted with water and ethyl acetate. After separation, the
aqueous layer was extracted with ethyl acetate (ꢃ5). The combined
organic phases were dried over MgSO4 and concentrated in vacuo
NH amide). 13C NMR (CDCl3, 100.6 MHz, 295 K):
d 14.5
(eCH2eCH3), 23.5 (C4), 25.4 (Cmethyl), 25.8 (C3), 56.3 (C2), 61.6
(eCH2eCH3), 74.0 (C1), 116.0 (q, J¼289 Hz, eCF3), 123.5 (C8),
123.7 (Cq), 126.0 (C6), 127.3 (Cq), 127.4 (C7), 131.4 (Cq), 155.4 (q,
J¼37.4 Hz, eCamide), 157.8 (Ccarbamate). 19F NMR: (CDCl3,
to give a brown oil. 1H NMR (CD3OD, 400 MHz, 295 K):
d 1.22 (t,
376.5 MHz, 295 K):
d
ꢂ76.4. IR (cmꢂ1, KBr): 3317.5, 2986, 1718.0,
J¼7.1 Hz, 3H, ethyl-CH3), 1.65(m, 1H, H8a), 2.48 (m, 1H, H8b), 3.04
(ddd, J¼3.4, 9.4, 15.1 Hz, 1H, H9a), 3.11 (ddd, J¼3.3, 7.3, 15.1 Hz, 1H,
H9b), 3.70 (d, J¼15.1 Hz,1H, H5a), 4.08(d, J¼15.1 Hz, 1H, H5b), 4.06 (q,
J¼7.1 Hz, 2H, ethyl-CH2), 4.50 (dd, J¼6.8, 11.3 Hz, 1H, H7), 7.35 (m,
3H, H2, H3, H4). To a solution of the latter compound (178 mg,
0.68 mmol) in methanol (20 mL), were added successively K2CO3
(722 mg, 6.81 mmol,10 equiv) and di-tert-butyl dicarbonate (1.49 g,
6.81 mol, 10 equiv). This mixture was stirred at rt for 14 h, and then
diluted with water and ethyl acetate. After separation, the aqueous
layer was extracted with ethyl acetate (ꢃ5). The combined organic
phases were dried over MgSO4 and concentrated in vacuo to give
a brown solid. The residue was purified by FC (cyclohexane/AcOEt,
1680, 1541.3, 1418, 1261.7, 1213. Mp¼80e85 ꢁC. HRMS calcd for
[C16H19N2O4F3, Na]þ¼383.1189; found 383.1188. To a solution of
this tertiary alcohol (2.2 g, 6.4 mmol) in dichloromethane
(100 mL), were added successively mesyl chloride (2.5 mL,
0.032 mol, 5 equiv) and triethylamine (4.4 mL, 0.032 mol,
5 equiv). This mixture was heated at reflux for 14 h, and then
diluted with water. After separation, the aqueous layer was
extracted with dichloromethane (ꢃ3). The combined organic
phases were dried over MgSO4 and concentrated in vacuo to
give a brown solid. The residue was purified by FC (cyclohexane/
AcOEt, 70/30) to give the ethyl [1-methylene-5-(2,2,2-

L. Roux et al. / Tetrahedron 66 (2010) 8722e8728
8727
80/20) yielding 1-(tert-butoxycarbonylamino)-7-ethoxycarbony-
lamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one 17 with
residue was purified by FC (cyclohexane/AcOEt, 80/20) to give the
1-(tert-butoxycarbonylamino)-7-benzyloxycarbonylamino-5,7,8,9-
tetrahydro-6H-benzocyclohepten-6-ol 19 with a yield of 70%. 1H
a yield of 52%. 1H NMR (CDCl3, 400 MHz, 295 K):
d
1.24 (t, J¼7.1 Hz,
3H, ethyl-CH3), 1.52 (br s, 10H, H8a, 9HBoc), 2.65(dddd, J¼4.5, 7.1, 9.3,
13.1 Hz, 1H, H8b), 2.94 (m, 2H, H9aþb), 3.65 (d, J¼15.4 Hz, 1H, H5a),
3.91 (d, J¼15.4 Hz, 1H, H5b), 4.10 (q, J¼7.1 Hz, 2H, ethyl-CH2), 4.53
(ddd, J¼7.1, 7.1, 11.1 Hz, 1H, H7), 5.48 (d, J¼7.1 Hz, 1H, NH from
carbamate), 6.23 (br s, 1H, amide NH), 7.01 (d, J¼7.6 Hz, 1H, H4), 7.17
(t, J¼7.8 Hz, 1H, H3), 7.42 (d, J¼7.8 Hz, 1H, H2). 13C NMR (CDCl3,
NMR (CDCl3, 400 MHz, 323 K): d 1.52 (br s, 10H, H8b, 9HBoc), 2.04
(ddd, J¼4.3, 8.0, 13.3 Hz, 1H, H8a), 2.48 (dd, J¼11.3 Hz, 1H, H9b), 2.98
(dd, J¼8.0 Hz, 1H, H9a), 3.04 (dd, J¼7.2, 14.3 Hz, 1H, H5b), 3.13(d,
J¼14.3 Hz, 1H, H5a), 3.88 (dddd, J¼2.0, 4.3, 8.0, 11.4 Hz, 1H, H7), 4.12
(dd, J¼2.0, 7.2 Hz, 1H, H6), 5.13 (s, 2H, CH2 from Cbz), 5.24 (d,
J¼8.0 Hz, 1H, NH from Cbz), 6.15 (br s, 1H, NH from Boc), 7.03 (d,
J¼7.8 Hz, 1H, H4), 7.13 (t, J¼7.5 Hz, 1H, H3), 7.37 (m, 6H, H2þ5HCbz).
100.6 MHz, 295 K):
d 14.5 (eCH2eCH3), 23.8 (C9), 28.3 (9H from
Boc), 33.3 (C8), 48.15 (C5), 60.52 (C7), 60.99 (eCH2eCH3), 80.61 (Cq
13C NMR (CDCl3, 100.6 MHz, 295 K):
d 24.61 (C9), 27.74 (C8), 28.30
from Boc), 124.59 (C2), 127.07 (C4), 127.39 (C3), 135.0, 133.58, 133.43
(9H from Boc), 39.35 (C5), 57.29 (C7), 66.67 (CH2 from Cbz), 68.93
(C6), 80.53 (Cq from Boc), 124.97 (C2), 125.5 (Cq from Cbz), 126.64
(Cq), 153.88 (Ccarbamate), 155.64 (Ccarbamate), 204.44 (C6). IR (cmꢂ1
,
KBr): 3324.6, 2982, 2935, 2856, 1718, 1686.9, 1588, 1521.6, 1447,
1379, 1249.5, 1162.0. Mp¼140e142 ꢁC. HRMS calcd for [C19H26N2O5,
Na]þ¼385.1734; found 385.1739.
(C3), 128.09 (2
*
C from Cbz), 128.51 (2 C from Cbz), 129.62 (C4),
*
134.42, 135.18, 136.95 (Cq), 136.5 (C from Cbz), 154.34 (Ccarbamate),
155.91 (Ccarbamate). IR (cmꢂ1, KBr): 3433, 3323.9, 2993, 2971, 2926.1,
1698.9, 1671, 1541, 1441, 1368, 1251.3, 1166, 1046.2. Mp¼174 ꢁC.
HRMS calcd for [C19H26N2O5, H]þ¼427.2227; found 427.2228.
4.1.8. 1-(tert-Butoxycarbonylamino)-7-ethoxycarbonylamino-
5,7,8,9-tetrahydro-6H-benzocyclohepten-6-ol (18). To a solution of
1-(tert-butoxycarbonylamino)-7-ethoxycarbonylamino-5,7,8,9-tetra-
hydro-6H-benzocyclohepten-6-one 17 (180 mg, 0.497 mmol) in
anhydrous THF (20 mL) at ꢂ78 ꢁC, was added dropwise DIBAL
(3.5 mL, 3.48 mmol, 7 equiv). This mixture was stirred at ꢂ78 ꢁC
for 1 h, and at rt for 1 h, and then diluted with a aqueous solution
1 N of sodium tartrate and ethyl acetate. After separation, the
aqueous layer was extracted with ethyl acetate (ꢃ5). The combined
organic phases were dried over MgSO4 and concentrated in
vacuo to give a white solid. 1-(tert-Butoxycarbonylamino)-7-
ethoxycarbonylamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-
ol 18 is obtained with a quantitative yield. 1H NMR (CDCl3,
4.1.10. 1-(tert-Butoxycarbonylamino)-7-benzyloxycarbonylamino-
5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one (20). To a solution of
1-(tert-butoxycarbonylamino)-7-benzyloxycarbonylamino-5,7,8,9-
tetrahydro-6H-benzocyclohepten-6-ol (356 mg, 0.83 mmol) in
dichloromethane (10 mL), was added DesseMartin periodinane
(424 mg, 1 mmol, 1.2 equiv). This mixture was stirred at rt for 2 h
and then diluted with water and dichloromethane. After separa-
tion, the aqueous layer was extracted with dichloromethane (ꢃ3).
The combined organic phases were dried over MgSO4 and
concentrated in vacuo to give a white solid. The residue was puri-
fied by FC (cyclohexane/AcOEt, 80/20) yielding 1-(tert-butoxy-
carbonylamino)-7-benzyloxycarbonylamino-5,7,8,9-tetrahydro-6H-
benzocyclohepten-6-one 20 with a yield of 92%. 1H NMR (CDCl3,
400 MHz, 323 K):
d
1.26 (t, J¼7.3 Hz, 3H, ethyl-CH3), 1.52 (br s, 10H,
H8b, 9HBoc), 1.99 (ddd, J¼4.0, 8.1, 13.4 Hz, 1H, H8a), 2.47 (dd,
J¼11.3 Hz, 1H, H9b), 2.98 (dd, J¼8.1 Hz, 1H, H9a), 3.04 (dd, J¼7.1,
14.1 Hz, 1H, H5b), 3.09 (d, J¼14.1 Hz, 1H, H5a), 3.82 (ddd, J¼4.0, 7.3,
11.8 Hz, 1H, H7), 4.08 (d, J¼7.1 Hz, 1H, H6), 4.14 (q, J¼7.3 Hz, 2H,
ethyl-CH2), 5.16 (d, J¼7.3 Hz,1H, NH from carbamate), 6.23 (br s,1H,
NH from Boc), 7.02 (d, J¼7.3 Hz, 1H, H4), 7.11 (t, J¼7.6 Hz, 1H, H3),
400 MHz, 323 K):
d
1.50 (s, 9H, Boc), 1.54 (m, J¼4.4, 7.2, 11.2, 12.8 Hz,
1H, H8b), 2.66 (dddd, J¼4.4, 7.6, 9.2, 12.5 Hz, 1H, H8a), 2.89 (ddd,
J¼4.4, 7.2, 15.0 Hz, 1H, H9b), 2.95 (ddd, J¼4.4, 9.2, 15.0 Hz, 1H, H9a),
3.64 (d, J¼15.2 Hz, 1H, H5b), 3.92 (d, J¼15.2 Hz, 1H, H5a), 4.55 (ddd,
J¼6.8, 7.6, 11.2 Hz, 1H, H7a), 5.07 (s, 2H, CH2 from Cbz), 5.69 (d, 1H,
NHCbz), 6.25 (br s, 1H, NHBoc), 7.02 (d, J¼7.6 Hz, 1H, H2), 7.17 (t,
J¼8.0 Hz, 1H, H3), 7.30e7.36 (m, 6H, HCbzþH2), 7.43 (d, J¼8.0 Hz, 1H,
7.33 (d, J¼8.1 Hz, 1H, H2). 13C NMR (CDCl3, 100.6 MHz, 295 K):
d 14.6
(eCH2eCH3), 24.63 (C9), 27.63 (C8), 28.28 (9H from Boc), 39.36 (C5),
57.1 (C7), 60.71 (eCH2eCH3), 69.01 (C6), 80.46 (Cq from Boc), 125.04
(C2), 126.48 (C3), 129.64 (C4), 134.3, 135.6, 137.1 (Cq), 154.34 (Ccar-
bamate), 155.91 (Ccarbamate). IR (cmꢂ1, KBr): 3494, 3364, 3316.9, 2982,
2921.3, 2853, 1697.2, 1699.9, 1521.9, 1443.1, 1367.4, 1250.7, 1166.0,
1059.9. Mp¼138e140 ꢁC. HRMS calcd for [C19H26N2O5,
H]þ¼365.2057; found 365.2060.
H2). 13C NMR (CDCl3, 100.6 MHz, 295 K):
d 204.2 (C6), 155.3
t
(NCO2Bn), 153.8 (NCO2 Bu), 136.3 (C9a), 135.0, 133.4 (C4a, Ph), 131.8
(C1), 128.5, 128.1, 128.0 (5C, Ph), 127.4 (C3), 127.1 (C4), 124.5 (C2),
80.6 (CMe3), 66.8 (OBn), 60.6 (C7), 48.1 (C5), 33.2 (C8), 28.3 (3C,
CMe3), 23.8 (C9). IR (cmꢂ1, KBr): 3353.5, 3326.7, 2971.8, 2940.5,
1720.8, 1689.2, 1519.4, 1248.1, 1241.1, 1163.3. HRMS calcd for
C24H28N2O5 [MþNa]þ: 447.1890; found: 447.1886.
4.1.9. 1-(tert-Butoxycarbonylamino)-7-benzoxycarbonylamino-
5,7,8,9-tetrahydro-6H-benzocyclohepten-6-ol (19). To a solution of
1-(tert-butoxycarbonylamino)-7-ethoxycarbonylamino-5,7,8,9-tet-
rahydro-6H-benzocyclohepten-6-ol 18 (30 mg, 0.082 mmol) in
methanol (1 mL) and water (2 mL), was added Ba(OH)2 (130 mg,
0.412 mmol, 5 equiv). This mixture was heated at 100 ꢁC for 16 h,
and then diluted with water and ethyl acetate. After separation, the
aqueous layer was extracted with ethyl acetate (5ꢃ10 mL). The
combined organic phases were dried over MgSO4 and concentrated
4.1.11. 1-(tert-Butoxycarbonylamino)-4-bromo-7-benzyloxy-
carbonylamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one
(5). To a solution of 1-(tert-butoxycarbonylamino)-7-benzyloxy-
carbonylamino-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one
(20 mg, 0.05 mmol) in acetonitrile (2 mL), was added N-bromo-
succinimide (11.6 mg, 0.06 mmol, 1.3 equiv). This mixture was
stirred at 50 ꢁC for 4 h and then diluted with aqueous solution of
ammonium chloride 1 N and ethyl acetate. After separation, the
organic phase was dried over MgSO4 and concentrated in vacuo
in vacuo to give white solid. 1H NMR (CDCl3, 400 MHz, 323 K):
d 1.51
i
(s, 9H, 9HBoc),1.78 (br s,1H), 2.12 (br s, 3H), 2.48 (br s,1H), 2.90 (br s,
2H), 3.11 (br s, 1H), 3.89 (br s, 1H), 6.32 (br s, 1H, NH from Boc), 7.04
(d, J¼7.3 Hz, 1H, H4), 7.11 (t, J¼7.3 Hz, 1H, H3), 7.31 (d, J¼7.3 Hz, 1H,
H2). To a solution of this latter compound (0.082 mmol) in THF
(5 mL), were added successively Na2CO3 (17.4 mg, 0.164 mmol,
to give a white solid. The residue was crystallized in Pr2O to give
1-(tert-butoxycarbonylamino)-4-bromo-7-benzyloxycarbonylamino-
5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one 5 with a yield of 92%.
1H NMR (CDCl3, 400 MHz, 323 K):
d
1.51 (s, 9H, Boc), 1.57 (dddd, J¼4.7,
5.2,10.6,12.5 Hz,1H, H8b), 2.66 (dddd, J¼5.2, 7.5,11.6,12.5 Hz,1H, H8a),
2.86(ddd, J¼4.7,11.6,15.5 Hz,1H, H9b), 2.96(ddd, J¼5.2, 5.2,15.5 Hz,1H,
H9a), 3.95 (d, J¼17.4 Hz,1H, H5b), 4.24 (d, J¼17.4 Hz,1H, H5a), 4.54 (ddd,
J¼6.5, 7.5, 10.6 Hz, 1H, H7a), 5.07 (s, 2H, CH2 from Cbz), 5.69 (d, 1H,
NHCbz), 6.22 (brs,1H, NHBoc), 7.36 (m, 6H, HCbzþH2), 7.44 (d, J¼8.6 Hz
2 equiv) and benzyl chloroformate (17.5 mL, 0.123 mmol, 1.5 equiv).
This mixture was stirring at rt for 14 h, and then diluted with water
and ethyl acetate. After separation, the aqueous layer was extracted
with ethyl acetate (ꢃ5). The combined organic phases were dried
over MgSO4 and concentrated in vacuo to give a brown solid. The
1H, H3). 13C NMR (CDCl3, 100.6 MHz, 295 K):
d 24.57 (C9), 28.24

8728
L. Roux et al. / Tetrahedron 66 (2010) 8722e8728
5. Dérivés d’aminobenzocycloheptène, leurs procédés de préparation et leur
utilisation en thérapeutique. Albrecht, S.; Maiereanu, A.; Faux, N.; Tarnus-
Rondeau, C.; Defoin, A.; Pale, P. WO2008059141 (A1).
6. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discvery Today 2004, 9, 430e431.
7. 4-Bromobenzosuberone derivative 2 is in particular ideally substituted for
further pallado-catalyzed coupling experiments.
8. Taylor, E. C.; Chiang, C.-S. Tetrahedron Lett. 1977, 21, 1827e1830.
9. (a) Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45, 6159e6163; (b) Justik,
M. W.; Koser, G. F. Molecules 2005, 10, 217e225.
10. Iodine(III)-promoted ring expansion of 1-vinylcycloalkanols was recently used
for the synthesis of seven-membered ring methoxylated ketones: Silva, L. F., Jr.;
Vasconcelos, R. S.; Nogueira, M. A. Org. Lett. 2008, 10, 1017e1020 Although
closely related to our approach, this latter work did not imply methylidene
derivatives as in our case but vinylcycloalkanols.
11. De Lombaert, S.; Blanchard, L.; Stamford, L. B.; Sperbeck, D. M.; Grim, M. D.;
Jenson, T. M.; Rodriguez, H. R. Tetrahedron Lett. 1994, 35, 7513e7516.
12. Carr, M. A.; Creviston, P. E.; Hutchison, D. R.; Kennedy, J. H.; Khau, V. V.; Kress,
T. J.; Leanna, M. R.; Marshall, J. D.; Martinelli, M. J.; Peterson, B. C.; Varie, D. L.;
Wepsiec, J. P. J. Org. Chem. 1997, 62, 8640e8653.
13. Lin, K.-Y.; Matteucci, M. D. J. Am. Chem. Soc. 1998, 120, 8531e8532.
14. Hartley, R. C.; Li, J.; Main, C. A.; McKiernan, G. J. Tetrahedron 2007, 63,
4825e4864.
(eNHCOOC(CH3)3), 32.44 (C8), 47.00 (C6), 59.08 (C7), 66.66 (CH2 du
Cbz), 81.04 (eNHCOOC(CH3)3), 121.03 (Cq), 125.42 (C3),128.05, 128.15,
and 128.50 (5 CH from Cbz),131.36 (C3),133.82 (Cq),134.61 (Cq),136.16
(Cq), 138.38 (Cq), 153.53 (eNHCOOe), 155.29 (eNHCOOe), 204.20
(C5). IR (cmꢂ1, KBr): 3315.7, 2926.8, 1686.8, 1527.3, 1506.1, 1250.3,
1160.6, 995.0, 697.3 Mp¼176 ꢁC. HRMS calcd for [C24H27BrN2O5,
H]þ¼503.1176; found 503.1170.
Acknowledgements
The support of the Centre National de la Recherche Scientifique
(FRE-3253) and the Ecole Nationale Supérieure de Chimie de
Mulhouse is gratefully acknowledged. We also wish to thank the
Region Alsace for a Ph.D. Grant to L.R. We thank the students Jean-
Baptiste Deslandes, Yannick Bidal and Mathieu Lesieur for their
participation to this work.
15. Park, C. H.; Brittelli, D. R.; Wang, C. L. J.; Marsh, F. D.; Gregory, W. A.; Wuonola,
M. A.; McRipley, R. J.; Eberly, V. S.; Slee, A. M.; Forbes, M. J. Med. Chem. 1992, 35,
1156e1165.
16. Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867e870.
17. Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442e445.
18. Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41, 3455e3462.
19. Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson, R. J. Synth. Commun. 1995, 25,
561e568.
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