Regioselective synthesis of the 1-bromo-4-phenyl-tetrahydro-7-amino- benzocyclohepten-6-one, a subnanomolar aminopeptidase-N/CD13 inhibitor

Article abstract of DOI:10.1016/j.tet.2012.05.121

A regioselective synthesis of the title 1-bromo-4-phenyl-tetrahydro-7- amino-benzocyclohepten-6-one 2 has been pursued and develop in order to allow a large scale synthesis of this highly potent and selective APN inhibitor (K _i 60 pM). The pivo

Full text of DOI:10.1016/j.tet.2012.05.121

Tetrahedron 68 (2012) 6447e6455
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Tetrahedron
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Regioselective synthesis of the 1-bromo-4-phenyl-tetrahydro-7-amino-
benzocyclohepten-6-one, a subnanomolar aminopeptidase-N/CD13 inhibitor
ꢀ
€
Mira Al-Lakkis-Wehbe, Lionel Roux, Cedric Charrier, Sarah Alavi, Didier Le Nouen, Albert Defoin,
Celine Tarnus, Sebastien Albrecht
*
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Organique et Bioorganique, EA4466, Universite de Haute-Alsace, ENSCMu, 3 rue Alfred Werner, Mulhouse 68093 Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2012
Received in revised form 24 May 2012
Accepted 29 May 2012
Available online 4 June 2012
A regioselective synthesis of the title 1-bromo-4-phenyl-tetrahydro-7-amino-benzocyclohepten-6-one 2
has been pursued and develop in order to allow a large scale synthesis of this highly potent and selective
APN inhibitor (Ki 60 pM). The pivotal step in this approach was the desymmetrization of the ketones 6a,b
through regioselective generation of the silyl enol ethers 5a,b. After obtention of the corresponding
enones 13a,b and the ene-amides 4a,be40a,b, it was possible to separate the regioisomers at this step.
Conversion to the desired phenylbromo-amide 17 was achieved from the both isolated major and minor
regioisomers through chemical manipulations including Suzuki coupling and Sandmeyer reaction. The
title compound 2$HCl was finally synthesized after a series of deprotections/protection.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
APN inhibitor
Regioselective synthesis
Silyl enol ethers
Aromatic substitution
1. Introduction
available starting materials) that requires a preparative HPLC sepa-
ration of thetwo regioisomers, method inadequate and not satisfying
APN/CD13 is a membrane bound zinc-dependent homodimeric
enzyme, member of the M1 family of aminopeptidase, which
removes N-terminal aminoacids from unsubstituted oligopeptides,
amide or arylamide, with a broad substrate specificity.1 This en-
zyme is of biological and medical importance,2 indeed studies with
a potent inhibitor as bestatin3e5 indicate that APN/CD13 is an active
player in angiogenesis and tumor metastasis. APN/CD13 is there-
fore an interesting target for possible therapeutic applications in
the domain of cancer therapy, which requires potent and selective
inhibitors. A large number of potent APN/CD13 inhibitors have been
described and recent reviews give an excellent overview of the
work made these last years.6
In recent works we have described the 7-amino-benzocyclo-
heptan-6-one 1 as a nonpeptidic, reversible, competitive, and stable
micromolar aminopeptidase-N/CD13 inhibitor7 and specified that
the 1- or 4-phenyl or bromo substitution enhanced this inhibitory
potency.8 We were delighted to find out that by additive effect the 1-
bromo-4-phenyl derivative 2 is a subnanomolar APN inhibitor8,9 (Ki
60 pM) and is so far the most potent inhibitor of mammalian APN/
CD13. It is interesting to note that it retains a very high selectivity
toward the M1 subfamily of one-zinc aminopeptidases. However, its
synthesis is problematic and gives rise to a regioisomeric mixture (13
steps with an overall yield of 1.1e1.8% from the commercially
for a large quantity synthesis needed to carry out further in vivo
studies. We thuswantedto design a regioselectiveapproachallowing
us to access the 1-bromo-4-phenyl derivative 2 in large scale.
In this present work, we describe different methods of improving
the synthesis of this very potent inhibitor 2 (Scheme 1). At first we
developed an attractive chemistry allowing easy and efficient
modifications of the aniline core to use both regioisomers. Then, we
explored an original method to functionalize the cycloheptene
moiety via an epoxide ring opening reaction. The synthesis started
from the inexpensive 2,3-dimethylaniline 9a to obtain regiose-
lectively the intermediate bromoamido-benzocycloheptanones
3a,b in two ways, depending on whether the aromatic cycle was
brominated in the 4 positionat the endof the synthesis(routea) orat
the start (route b, into the known 9b). The key step involved the
desymmetrization of the ketones 6a,b through regioselective for-
mation of the silyl enol ethers 5a,b. The target compound 2 was then
obtained by appropriate substitution of the amino and bromo
groups. Moreover, the minor isomer 40b was recycled for the same
synthetic purpose with other aromatic transformations.
2. Results and discussion
2.1. Synthesis of the intermediate ene-amides 4a,b
The synthesis of the benzocycloheptane moiety, as depicted
in Scheme 2, started either with the commercially available
* Corresponding author. E-mail address: sebastien.albrecht@uha.fr (S. Albrecht).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.121

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M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
tert-butyldimethylsilyl triflate (2 equiv) according to the litera-
ture11 gave a mixture of regioisomeric N-silylated silylenol ethers
5a,b with a satisfying isomeric excess (80:20 for 6a, 75:25 for 6b)
due to the very bulky silylated amide substituent. The use of the
less steric hindered trimethylsilyl triflate gave a lower regiose-
lectivity (ca. 60:40). The oxidation of these enol ethers with a per-
acid into a silyloxyketone as in the precedent works7,8 was here
impossible due to their instability under these conditions. These
enol ethers were instead successfully oxidized by a-bromination
with N-bromosuccinimide (NBS)12 into the corresponding bromo-
ketones (in mixture with the minor regioisomers). These bromo-
ketones were rather unstable and dehydrohalogened in situ with
DBU7 into the enones 13a,b in good yield, again as an inseparable
mixture with the minor regioisomers. Reductive amination of these
enones according to the Bhattacharyya method13 by reaction with
isopropyl orthotitanate and ammonia in dry methanol, and sub-
sequent sodium borohydride reduction and N-protection gave
a mixture of unsaturated amides, which were then resolved by
crystallization and chromatography to give in 54% yield the major
isomers 4a and 4b and in ca. 10% the minor ones 40a,b from the
ketones 6a,b.
Scheme 1. Chemical structures of APN inhibitors and retrosynthetic analysis.
In order to determine the identity of these regioisomers, NOE
experiments were performed in the case of the major regioisomer
4a by irradiation of H-9 at 6.47 ppm NOE values of ca. 6% were
observed for the aromatic 1-H at 7.01 ppm and 8-H at 5.80 ppm (see
Supplementary data). These effects agreed to a spatial proximity of
these protons, and consequently, assigned unambiguously the
structure of 4a. Furthermore, the bromo derivatives 4b and 40b
were characterized by an important deshielding, ca. 0.3e0.7 ppm
(see bold figures in Table 1), for the proton 9-H and the equatorial
proton 5-H by comparison with the values of the corresponding
proton of the unsubstituted 4a and 40a, respectively. This strong
peri effect indicated the spatial proximity of the electronegative
bromine substituent and was observed for all other derivatives in
the bromoamido series.
2,3-dimethylaniline 9a or its known para-bromo derivative 9b,
which was obtained by bromination of 9a in 75% yield.8 The com-
pounds 9a,b were then N-protected into the tert-butylcarbamates
11a,b in good yield.
Table 1
Chemical shift of ene-amides 4a, 4b and 40a, 40b
Compounds
d (ppm)
5-H
8-H
9-H
4a
2.63/2.82
2.56/2.77
2.64
5.80
6.03
6.05
6.16
6.47
6.75
6.49
6.46
4b
40a
40b
2.57/3.15
Scheme 2. Synthesis of the amines 4/40a,b. Reagents and conditions: (a) Boc2O, MeOH,
Na2CO3, quant. (b) 2 equiv NBS, CCl4, hn, quant. (c) Bu4NBr, CH2Cl2, NaHCO3 5%. (d) 1 N
aqueous NaOH, 100 ꢀC, MeCN, yield for 6a: 44%e55% from 9a, for 6b: 50% from 9b. (e)
Met2BuSiOTf, NEt3, PhMe, 80 ꢀC, 2 h. (f) NBS, MeCN, then DBU (13a and regioisomer:
88%, 13b and regioisomer: 64%). (g) Ti(OiPr)4, 2e3 M NH3 in MeOH, 6 h, then NaBH4,
2 h. (h) ClCO2Bn, Na2CO3, THF.
2.2. Synthesis of the phenyl-bromo amine 2$HCl
The synthetic scheme followed at this point two parallel ways
according as 11a or the bromo derivative 11b were used as starting
material and gave access to the cycloheptene ring in three steps.7,10
Starting from the major isomers 4a,b, the following reaction
sequence led to the key compound 17 (Scheme 3).
Epoxidation with m-chloroperbenzoic acid led to the cis-epox-
ides 14a,b as sole isomer, because of the participation of the amide
function in position 7. Subsequent reduction with Dibal-H14 at the
benzylic position, provided the cis-hydroxy-amides 15a,b. Those cis
configuration resulted from the same J6,7 coupling values as pre-
viously given for similar compounds.6,7 The hydroxy-amides were
then oxidized with DesseMartin periodinane15 in the intermediate
amido-ketones 3a,b with good overall yield from 4a,b (three steps,
64e69%). Attempts to directly isomerize the epoxides 14a,b into
the ketones 3a,b with Lewis acids16 or with Pd-catalysts17 gave no
reaction or only irreproducible results, because principally of
a partial N-deprotection. The oxidation of the alcohol 15a in the
ketone 3a as well as its easily aromatic bromination into the
bromo-amide 3b were already described in a precedent work.18
A photochemical bis-bromination led quantitatively to the
a, -
a0
dibromo derivatives 8a,b. These reactive benzylic bromo com-
pounds were used directly without further purification, but the
crystallized 8b was fully characterized. Then, a double nucleophilic
substitution of 8a,b with the acetonedicarboxylate 7 under phase
transfer catalysis gave the benzocycloheptenones esters 12a,b as
a 1:1 cis/trans isomeric mixture, followed by a subsequent de-
carboxylation in basic medium into the ketones 6a,b with nearly
50% overall yield from the anilines 9a,b, respectively.
We then focused our attention on the functionalization of the
cycloheptene ring as shown in Scheme 2, which involved
a desymmetrization of the molecule to afford a regioisomeric
mixture. Indeed silylation of the enols of the ketone 6a,b with

M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
6449
Scheme 3. Synthesis of the phenyl-bromo amine 2$HCl. Reagents and conditions: (a)
m-CPBA, CH2Cl2, 0 ꢀC, 2 h. (14a: 89%; 14b: 80%). (b) Dibal-H, THF, ꢁ60 ꢀC (15a: 84%;
15b: quant.). (c) DesseMartin periodinane, CH2Cl2, rt (3a: 92% from 15a; 3b: 80% from
15b, lit.18). (d) lit.:18 NBS, MeCN, 4 h, 50 ꢀC, 92%. (e) PhB(OH)2, Pd(PPh3)4, K2CO3, DME,
H2O, 85 ꢀC, 5 h. (f) 1. TFA, 2. tBuONO, CuBr2, MeCN, 30 ꢀC, then 80 ꢀC. (g) 33% HBr,
AcOH. (h) Na2CO3, Boc2O, 0 ꢀC. (i) lit.:8 dry HCl in Et2O.
Scheme 4. Recycling pathway of the minor isomer 40b. Reagents and conditions: (a) 1.
TFA or 30% aqueous H2SO4, 2. NaNO2, KI. (b) PhB(OH)2, Pd(PPh3)4, K2CO3, H2O, THF,
70 ꢀC, 20 h. (c) m-CPBA, CH2Cl2, 0 ꢀC, 2 h. (d) Dibal-H, THF, ꢁ60 ꢀC. (e) DesseMartin
periodinane, CH2Cl2, rt.
3. Conclusion
Thus the amide 3b was obtained, respectively, with 30% and 22%
overall yield from the ketones 6a,b.
We have presented the regioselective synthesis of a selective
and subnanomolar inhibitor of the aminopeptidase APN/CD13. This
synthesis from the commercially available and inexpensive 3,4-
dimethylaniline 9a was effected with an overall yield of 3.9e4.6%
according to the two used synthetic pathways. Despite being longer
than the previously reported synthesis, this regioselective ap-
proach has paved the way to further in vivo studies, which shall be
reported in due course.
In order to obtain the target molecule 2 from the bromoamido
derivative 3b, the aromatic ring substituents were modified as
depicted in Scheme 3. A Suzuki reaction with the phenylboronic
acid gave the 4-phenyl-keto-amide 16. The substitution of the
amido group was carried out, after acidic N-deprotection, by a ‘one
pot’ Sandmeyer reaction through formation of the corresponding
diazonium salt by reaction with tert-butyl nitrite and cupric bro-
mide.19 The bromophenyl amide 17 was then isolated in moderate
yield. The classical Sandmeyer conditions (HBr, NaNO2) gave only
deceptive results (30%). Attempts to deprotect the 7-amido func-
tions by classic hydrogenolysis over palladium led to a complex
mixture with partial loss of the bromine substituent. Finally, the
bromophenyl amine, as hydrobromide salt 2$HBr, was obtained by
acidic deprotection with hydrobromic acid in acetic acid20 with 34%
yield from 3b. This hydrobromide salt was then transformed into
the preferred hydrochloride salt by again N-protection in basic
milieu into the known tert-butylcarbamate 18 whose deprotection
into 2$HCl was already described8 (with dry HCl in ether, 31% yield
from from 3b).
4. Experiment
4.1. General
Flash chromatography (FC): silica gel (Merck 60,
230e400 mesh). TLC: Al-roll silica gel (Merck 60, F254). Mp: Kofler
hot bench, corrected. IR spectra (n
in cmꢁ1): Nicolet 405 FT-IR. 1H
and 13C NMR (400 MHz and 100.6 MHz resp.) spectra: Bruker
Avance 400, at 295 K, tetramethylsilane (TMS), or natrium trime-
thylsilylpropionate-d4 (TSP-d4) in D2O (1H NMR) and CDCl3, or
CD3OD [
d
(CDCl3)¼77.0,
d
(CD3OD)¼49.0 with respect to TMS] (13
C
The regioselective synthesis of the derivative 2$HCl was ach-
ieved via two parallel ways with an overall yield of 4.6% (route a, 17
steps) and 2.6% (route b, 17 steps) from the commercially available
aniline 9a.
NMR) as internal standard at 295 K;
d in parts per million and J in
hertz. High resolution MS were measured on a Bruker MicrOTof
spectrometer in Institut de Chimie, UMR 7177 CNRS, ULP, Stras-
bourg, France, or Agilent Technologies 6510 (QTof) spectrometer in
ꢀ
ENSCMu, Universite de Haute Alsace, Mulhouse, France. Micro-
2.3. Synthesis of the phenyl-bromo compounds from the
minor isomer 40b
analyses were carried out by the Service Central de Microanalyses
du CNRS, Fe69,390 Vernaison or Service de Microanalyse, UMR
ꢀ
ꢀ
7565 CNRS Universite Henri Poincare F-54,506 Vandoeuvre-les-
Nancy.
In order to complete this work, we transformed the minor iso-
lated isomer 40b into the phenylbromo-amide 17 in five steps by
substitution of the amido group with a phenyl moiety followed by
subsequent functionalization of the cycloheptene ring (Scheme 4).
Because of the weak reactivity of the double bond of 40b, due to
the steric effect of the amido group in peri position on the aromatic
ring, this substituent was first transformed (Scheme 4). After acidic
N-deprotection, a classical Sandmeyer reaction in the presence of
potassium iodide21 gave the iodo-bromo derivative 19. A Suzuki
coupling reaction, as above for 16, but at 70 ꢀC in THF, with phe-
nylboronic acid provided the phenylbromo-amide 10 in good yield.
The same reaction sequence as for 4a was used in order to func-
tionalize the aliphatic ring through the cis-epoxide 20 and the cis-
hydroxy-amide 21 to give in three steps the phenylbromo-amide 17
in 54% yield from 40b (4% from 6b). A supplementary 1.3% yield via
this recycling pathway allowed to improve the route b overall yield
to 3.9%.
4.2. Reagents and solvents
Pd/C (5%) were obtained from Fluka, other reactants were pur-
chased from usual provider. DesseMartin periodinane (DMP) was
prepared according to lit.15 Usual solvents were freshly distilled,
dry EtOH and MeOH distilled over Mg/MgI2, dry THF over Na and
benzophenone, dry Et2O or PhMe were distilled and stored over Na,
CH2Cl2 was distilled over P2O5 and kept over Na2CO3. NEt3 was
distilled before use.
4.3. Synthesis of the ketones 6a,b
4.3.1. N-tert-Butyloxycarbonyl-2,3-dimethylaniline (11a). A solution
of 9a (10 g, 82.5 mmol) and Boc2O (21.6 g, 99 mmol, 1.2 equiv) in

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M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
MeOH (80 mL) was stirred at rt with powdered Na2CO3 (10.5 g,
99 mmol, 1.2 equiv) for 1.5 h. The solids were filtered off and the
solution was evaporated, the residue dissolved in AcOEt, the solu-
tion filtrated and evaporated again. The residue was recrystallized
from cyclohexane (30 mL) to obtained by filtration at 0 ꢀC 11a
under Argon for 6e16 h. The organic layer was separated, evaporated
and dissolved in AcOEt (200 mL). The aqueous layer was extracted
with AcOEt (2ꢂ300 mL), the combined organic solutions were
washed with brine (2ꢂ300 mL), dried (MgSO4) and evaporated to
give 12a as a brownish resin which was used without further puri-
fication (33.1 g, quant.). For analytical purpose, a sample was purified
by FC (AcOEt/cyclohexane 2:8).
(18.6 g, quant.) as pink crystals. Mp 104e106 ꢀC. IR (KBr):
2965, 2980, 1692, 1519, 1364, 1242, 1160, 1018, 780 cmꢁ1. 1H NMR
(400 MHz, CDCl3):
¼1.51 (s, 9H, CMe3), 2.15 (s, 3H, Me), 2.29 (s, 3H,
n¼3357,
d
A vigorously stirred biphasic solution of NaOH (33.8 g,
Me), 6.23 (br s, 1H, NH), 6.93 (d, 1H, 4-H), 7.08 (dd, 1H, 5-H), 7.52 (br
0.844 mol, 10 equiv) in 270 mL H2O and 12a (33.1, 84.4 mmol) in
MeCN (140 mL) was refluxed at 85 ꢀC for 2 h. The mixture was left
at rt, neutralized portionwise with NaHCO3 (71.5 g, 0.85 mol) and
extracted twice with AcOEt (200 mL). The organic phase was
washed with brine (2ꢂ200 mL), dried (MgSO4) and evaporated to
give 6a (10.2e12.8 g, 44e55%) after purification by FC (cyclohex-
ane/AcOEt 8:2).
d, 1H, 6-H). J4,5¼7.3, J5,6¼8.0 Hz. 13C NMR (100 MHz, CDCl3):
¼20.8,
d
27.6 (2 CH3); 28.5 (CMe3); 80.4 (CMe3); 120.5 (C-6); 126.0, 126.2 (C-
4, C-5); 127.7 (C-1); 136.1, 137.3 (C-2, C-3); 153.6 (NCO2). Anal. Calcd
for C14H17NO3 (247.30): C 70.56, H 8.65, N 6.33; found: 70.3, H 8.7,
6.2. HRMS (ESI): calcd for C13H19LiNO2 [MþLi]þ: 228.1576; found:
228.1583.
Compound 12a (50:50 cis/trans isomeric mixture): colorless
4.3.2. 4-Bromo-N-tert-butoxycarbonyl-2,3-dimethylaniline (11b).
Same procedure as for 11a with 9b (4 g, 14.2 mmol), MeOH (40 mL),
Boc2O (3.77 g, 17.3 mmol, 1.2 equiv) and Na2CO3 (3.35 g, 31.3 mmol,
2.2 equiv) for 16 h. MeOH was evaporated, the solution of the
residue in AcOEt was washed with H2O, dried (MgSO4) and evap-
orated to give 11b (4.3 g, quant.) as colorless crystals. Mp
resin. IR (KBr):
n
¼1161, 1243, 1367, 1438, 1515, 1720, 1744, 2956,
3367 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
¼1.48, 1.52, 1.53 (3s, 9H,
CMe3), 3.29e3.65 (m, 5H), 3.68e3.80 (m, 6H), 3.80e4.00 (m, 1H),
6.80e7.22 (m, 2H, ArH), 7.80e7.40 (m, 1H, ArH). HRMS (ESI): calcd
for C20H25NNaO7 [MþNa]þ: 414.1523; found: 414.1527.
Compound 6a: yellowish crystals. Mp 99e100 ꢀC. IR (KBr):
117e118 ꢀC. IR (KBr):
1020 cmꢁ1. 1H NMR (400 MHz, CDCl3):
3H, 2-Me), 2.40 (s, 3H, 3-Me), 6.20 (s, 1H, NH), 7.38 (m, 2H, 5-H, 6-
H). 13C NMR (100 MHz, CDCl3):
n
¼3365, 2988, 1695, 1509, 1280, 1244, 1160,
¼1.51 (s, 9H, CMe3), 2.22 (s,
n
¼3363, 2983, 1693, 1500, 1455, 1444, 1243, 1159, 757 cmꢁ1
.
1H
d
NMR (400 MHz, CDCl3):
d
¼1.51 (s, 9H, CMe3), 2.63 (m, 4H, CH2-6,
CH2-8), 2.88 (m, 2H, CH2-9), 2.94 (m, 2H, CH2-5), 6.21 (br s, 1H, NH),
d¼15.1 (2-Me); 20.5 (3-Me); 28.5
7.09 (d, 1H, 4-H), 7.18 (br dd, 1H, 3-H), 7.34 (br d, 1H, 2-H). J3,4¼7.5,
(CMe3); 80.7 (CMe3); 121.0 (C-4); 121.8 (C-6); 129.7 (C-1); 130.1 (C-
5); 135.4, 136.5 (C-3, C-2); 153.4 (NCO). Anal. Calcd for C13H18BrNO2
(300.19): C 52.01, H 6.04, N 4.67; found: C 52.5, H 6.19, N 4.7. HRMS
(ESI): calcd for C15H18BrNNaO2 [MþNa]þ: 322.0413 and 324.0394;
found: 322.0400 and 324.0396.
J2,3¼8.0 Hz. 13C NMR (100 MHz, CDCl3):
¼23.3 (C-9); 28.3 (CMe3);
d
30.7 (C-5); 44.5, 43.5 (C-6, C-8); 80.5 (CMe3); 124.3 (C-2); 126.8 (C-
4); 127.1 (C-3); 127.9 (C-1); 134.9 (C-9a); 142.0 (C-4a); 154.1 (NCO);
211.1 (CO-7). Anal. Calcd for C16H21NO3 (275.35): C 69.79, H 7.69, N
5.09; found: C 69.67, H 7.75, N 4.94.
4.3.3. N-tert-Butyloxycarbonyl-2,3-bis(bromomethyl)aniline (8a). A
solution of 11a (18.3 g, 82 mmol) and finely pulverized NBS (30.9 g,
173 mmol, 2.1 equiv) in CCl4 (800 mL) was irradiated with HPK125
mercury lamp for 1e2 h with stirring. The reaction mixture was
washed with H2O, the aqueous phase extracted with CH2Cl2, and
the combined organic solutions dried (MgSO4) and evaporated to
give 8a (32 g, quant.) as a colorless resin, only characterized by
4.3.6. Dimethyl
4-bromo-1-tert-butoxycarbonylamino-7-oxo-
5,6,8,9-tetrahydro-benzocyclohepten-6,8-dicarboxylate (12b) and 1-
tert-butoxycarbonylamino-4-bromo-5,6,8,9-tetrahydro-benzocyclo-
hepten-7-one (6b). Same procedure as for 12a with 8b (6.1 g,
13.3 mmol), 7 (2.3 mL, 16 mmol, 1.2 equiv), NBu4Br (2.58 g, 8 mmol,
0.6 equiv), 5% aqueous NaHCO3 (50 mL) and CH2Cl2 (50 mL) to give
12b (6.3 g, quant.). The crystallized trans-isomer can be isolated
i
NMR. 1H NMR (400 MHz, CDCl3):
d
¼1.54 (s, 9H, CMe3), 4.56 (s, 2H,
from Pr2O.
CH2Br), 4.67 (s, 2H, CH2Br), 6.61 (br s, 1H, NH), 7.12 (d, 1H, 4-H), 7.30
Compound 12b was hydrolyzed in aqueous 2.5 N NaOH (50 mL)
and MeCN (25 mL) as for 12a for 16 h to give 6b (2.35 g, 50%) after
FC (cyclohexane/AcOEt 8:2) and washing with Pr2O.
(dd, 1H, 5-H), 7.79 (d, 1H, 6-H). J4,5¼7.5, J5,6¼8.1 Hz. 13C NMR
i
(100 MHz, CDCl3):
d
¼25.7 (2-CH2); 28.3 (C(Me)3); 30.3 (3-CH2); 81.3
(C(CH3)3); 124.2 (C-6); 126.5 (C-4); 127.0 (C-1); 129.8 (C-5); 136.8
Compound 12b (50:50 cis/trans isomeric mixture): colorless
(C-2); 137.9 (C-3); 152.9 (NCO2).
resin. 1H NMR (400 MHz, CDCl3):
d¼1.52, 1.53 (2s, 9H), 4.3e3.1 (m,
12H), 7.0e7.5 (m, 2H, ArH), 7.6e7.7 (m, 1H, NH).
4.3.4. 4-Bromo-N-tert-butyloxycarbonyl-2,3-bis(bromomethyl)ani-
line (8b). Same procedure as for 8a, with 11b (4.0 g, 13.3 mmol),
NBS (5 g, 27.9 mmol, 2.1 equiv) in CCl4 (160 mL), to give after re-
crystallization in cyclohexane 8b (6.1 g, quant.) as a cream solid.
trans-12b: colorless crystals. Mp 175e177 ꢀC. IR (KBr):
n¼1167,
1202, 1239, 1281, 1365, 1515, 1693, 1737, 1754, 2950, 3343 cmꢁ1. 1H
NMR (400 MHz, CDCl3):
d¼1.52 (s, 9H, CMe3), 3.19 (dd, 1H, 9-Heq),
3.33 (dd, 1H, 5-Hax), 3.44 (dd, 1H, 9-Heq), 3.63 (dd, 1H, 6-H), 3.74
(dd, 1H, 5-Heq), 3.75, 3.82 (2s, 2ꢂ 3H, 2 OMe), 4.25 (dd, 1H, 8-H),
7.46 (s, 2H, ArH), 7.71 (br s, 1H, NH). J5ax,5eq¼14.5, J5ax,6¼11.3,
J5eq,6¼5.1, J8,9ax¼3.4, J8,9eq¼6.6, J9eq,9ax¼15.6 Hz. HRMS (ESI): calcd
for C20H24BrNNaO7 [MþNa]þ: 492.0628 and 494.0611; found:
492.0625 and 494.0610.
Mp 116e117 ꢀC. IR (KBr):
n
¼547, 829, 1066, 1158, 1206, 1219, 1240,
1365, 1408, 1471, 1497, 1716, 2981, 3412 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
¼1.54 (s, 9H, CMe3), 4.65 (s, 2H, 2-CH2Br), 4.73 (s, 2H, 3-
d
CH2Br), 6.54 (br s, 1H, NH), 7.54 (d, 1H, 5-H), 7.71 (br d, 1H, 6-H).
J5,6¼8.8 Hz. 13C NMR (100 MHz, CDCl3):
¼26.0 (2-CH2Br); 28.2
d
(CMe3); 29.6 (3-CH2Br); 81.6 (CMe3); 120.5 (C-4); 125.0 (C-6);
128.8 (C-1); 134.0 (C-5); 135.8, 137.2 (C-2, C-3); 152.6 (CO). Anal.
Calcd for C13H16Br3NO2 (457.99): C 34.00, H 3.52, N 3.06; found: C
34.2, H 3.5, N 2.9.
Compound 6b: colorless crystals. Mp 135e136 ꢀC. IR (KBr):
n
¼3342, 2978, 2920,1693,1514,1288,1250,1161,1070, 903 cmꢁ1. 1H
NMR (400 MHz, CDCl3):
d¼1.50 (s, 9H, CMe3), 2.62 (m, 4H, CH2-6,
CH2-8), 2.95 (m, 2H, CH2-9), 3.22 (m, 2H, CH2-5), 6.19 (br s, 1H, NH),
7.24 (br d, 1H, 2-H), 7.48 (d, 1H, 3-H). J2,3¼8.6 Hz. 13C NMR
4.3.5. Dimethyl1-tert-butoxycarbonylamino-7-oxo-5,6,8,9-tetrahydro-
(100 MHz, CDCl3):
d
¼24.1 (C-9); 28.4 (CMe3); 29.0 (C-5); 43.5, 43.1
benzocyclohepten-6,8-dicarboxylate
(12a),
and
1-tert-butox-
(C-6, C-8); 81.0 (CMe3); 121.2 (C-4); 125.4 (C-2); 131.3 (C-3); 134.4
(C-9a); 137.2 (C-1); 140.8 (C-4a); 154.0 (NCO); 210.2 (CO-7). HRMS
(ESI): calcd for C16H20BrNNaO3 [MþNa]þ: 316.0524 and 378.0504;
found: 376.0517 and 378.0500. Anal. Calcd for C16H20BrNO3
(354.24): C 54.24, H 5.69, N 3.95; found: C 54.3, H 5.7, N 4.1.
ycarbonylamino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6a). A
vigorously stirred mixture of 8a (32 g, 84.4 mmol), 7 (17.6 g, 14.6 mL,
101.3 mmol, 1.2 equiv), NBu4Br (16.3 g, 50.6 mmol, 0.6 equiv), 5%
aqueous NaHCO3 (380 mL) and CH2Cl2 (270 mL) was heated at 40 ꢀC

M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
6451
4.4. Synthesis of the amido-ketones 3a,b
J5a,5b¼15.0, J8a,8b¼14.0, J8a,9a¼10.4, J8a,9b¼3.4, J8b,9b¼8.4, J8b,9a¼3.2,
J9a,9b¼15.2 Hz.
4.4.1. 4-[(tert-Butoxycarbonyl)-tert-butyldimethylsilylamino]-7-tert-
butyldimethylsilyloxy-6,9-dihydro-5H-benzocycloheptene and 1-
[(tert-butoxycarbonyl)-tert-butyldimethylsilylamino]-7-tert-butyldi-
methylsilyloxy-6,9-dihydro-5H-benzocycloheptene (80:20 isomeric
mixture, 5a). To a solution of 6a (10 g, 36 mmol, dried by evapo-
ration with toluene) in dry CH2Cl2 (50 mL) and NEt3 (12 mL,
86.5 mmol, 2.4 equiv) was added dropwise Met2BuSiOTf (18 mL,
79 mmol, 2.2 equiv) at 0 ꢀC under Ar. The solution was vigorously
stirred at 0 ꢀC for 0.5 h. The solution was hydrolyzed with aqueous
N NaHCO3 (100 mL) and extracted thrice with AcOEt (200 mL). The
organic phases were dried (MgSO4) and evaporated to give crude 5a
(18.1 g, quant.) as green resin, which was directly use for the next
step, only characterized by 1H NMR (80:20 M and m isomers,
Compound 13a: colorless crystals. Mp 108e112 ꢀC. Rf¼0.32
(cyclohexane/AcOEt 80:20). IR (KBr):
n
¼3343, 2985, 2955, 1693,
1655, 1521, 1253, 1163 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼1.51 (s,
9H, CMe3), 2.75 (m, 2H, CH2-6), 2.97 (m, 2H, CH2-5), 6.19 (d, 1H, 8-
H), 6.37 (s, 1H, NH), 7.14 (d, 1H, 9-H), 7.21 (d, 1H, 1-H), 7.27 (dd, 1H,
4
2-H), 7.47 (d, 1H, 3-H). J1,2¼7.6, J1,3¼1.2, J2,3¼8.0, J8,9¼12.6 Hz. 13
C
NMR (100 MHz, CDCl3):
d
¼22.1 (C-5); 28.3 (CMe3); 41.8 (C-6); 80.8
(CMe3); 126.9 (C-2); 127.2 (C-3); 129.3 (C-8); 130.1 (C-1); 134.6 (C-
4a); 135.6 (C-9a); 136.0 (C-4); 142.8 (C-9); 153.9 (NCO); 201.4 (C-7).
Anal. Calcd for C16H19NO3þ1/3H2O (279.33): C 68.8, H 7.10, N 5.01;
found: C 69.0, H 7.1, N 4.93.
Minor regioisomer of 13a, only characterized by 1H NMR
(400 MHz, CDCl3):
d
¼1.52 (s, 9H, CMe3), 2.74 (m, 2H, CH2-6), 2.98
400 MHz, CDCl3):
d
¼ꢁ0.32 (s, 3H, NSiMe), 0.05, 0.06 (2s, 6H,
(m, 2H, CH2-5), 6.27 (d, 1H, 8-H), 6.39 (s, 1H, NH), 7.07 (d, 1H, 4-H),
7.20 (d, 1H, 9-H), 7.30 (dd, 1H, 3-H), 7.61 (d, 1H, 2-H). J2,3¼8.0,
J3,4¼7.5, J8,9¼12.8 Hz.
OSiMe2), 0.39 (s, 3H, NSiMe), 0.87, 1.05 (2s, 2ꢂ 9H, 2 SitBu), 1.43 (s,
9H, OtBu), 2.25 (m, 1H, 6-Hb), 2.36 (m, 1H, 6-Ha), 2.84 (m, 2H, CH2-
5), 3.06 (m, 0.2H, 9-Hb m), 3.17 (dd, J¼16.4, 6.5 Hz, 0.8H, 9-Hb M),
3.27 (m, 0.2H, 9-Ha m), 3.39 (ddt, J¼16.4, 4.8, 2.0 Hz, 0.8H, 9-Ha M),
4.98 (t, J¼6.5 Hz, 0.2H, 8-H m), 5.08 (dd, J¼4.8, 6.8 Hz, 0.8H, 8-H M),
6.94 (m, 2H, ArH), 7.03 (m, 1H, ArH). J4,5¼7.3, J5,6¼8.0 Hz.
4.4.4. 1-Bromo-4-tert-butoxycarbonylamino-5,6-dihydro-benzocy-
clohepten-7-one (13b) and 4-bromo-1-tert-butoxycarbonylamino-
5,6-dihydro-benzocyclohepten-7-one (regioisomer of 13b), 75:25
mixture. Bromo derivative: same procedure as above with 5b (from
6b, 2.0 g, 5.6 mmol) in dry THF (30 mL) and NBS (2.0 g, 11.2 mmol),
for 16 h at rt to give the crude mixture of bromoketone and its
regioisomer (quantitative).
4.4.2. 1-Bromo-4-[(tert-butoxycarbonyl)-tert-butyldimethylsilyl]
amino-7-tert-butyldimethylsilyloxy-6,9-dihydro-5H-benzocyclo-
heptene
and
4-bromo-1-[(tert-butoxycarbonyl)-tert-butyldime-
thylsilyl]amino-7-tert-butyldimethylsilyloxy-5,9-dihydro-5H-benzo-
cycloheptene (75:25 isomeric mixture, 5b). Same procedure as for
5a, with 6b (2.0 g, 5.6 mmol), NEt3 (1.9 mL, 13.5 mmol, 2.4 equiv)
and Met2BuSiOTf (2.85 mL, 12.4 mmol, 2.2 equiv) in CH2Cl2 (50 mL)
for 1 h at 0 ꢀC, to give crude 5b (3.8 g, quant.) as colorless resin,
which was directly use for the next step, only characterized by 1H
Enone: same procedure as above with DBU (1.8 mL, 11.8 mmol)
in THF (30 mL) for 16 h to afford a mixture of enone 13b and
a mixture of different silyl enol ethers.
To this crude solution in dry THF (10 mL) was added dropwise
a solution of TBAF (2.2 g, 8.4 mmol, 1.5 equiv) in dry THF (5 mL) at
0
ꢀC under Ar. The reaction mixture was stirred for 2 h and was
NMR (75:25 M and m isomers, 400 MHz, CDCl3):
d
¼ꢁ0.30 (s, 3H,
quenched with a saturated aqueous solution of NH4Cl (20 mL). The
organic layer was separated, the aqueous layer was extracted with
AcOEt (2ꢂ20 mL) and the combined organic phases were washed
with brine, dried over MgSO4 and evaporated under reduced
pressure. Purification by FC (cyclohexane/AcOEt, 80:20) gave the
75:25 mixture of 13b and its regioisomer (1.28 g, 65% from 6b).
Compound 13b and its regioisomer: colorless resin. IR (KBr):
NSiMe), 0.07, 0.08 (2s, 6H, OSiMe2), 0.39 (s, 3H, NSiMe), 0.87 (s, 9H,
OSitBu), 1.05 (s, 9H, NSitBu), 1.43 (s, 9H, COt2Bu), 2.26, 2.36 (2 m, 2H,
CH2-6), 2.90, 3.13, 3.25 (3 m, 2.5H, CH2-5 Mþm, CH2-9 m), 3.54 (d,
J¼6.5 Hz,1.5H, CH2-9 M), 4.94 (dd, J¼7.3, 5.3 Hz, 0.25H, 8-H m), 5.07
(t, J¼6.5 Hz, 0.75H, 8-H M), 6.80 (d, J¼8.3 Hz, 0.25H, 2-H m), 6.81 (d,
J¼8.6 Hz, 0.75H, 3-H M), 7.35 (d, J¼8.6 Hz, 0.75H, 2-H M), 7.35 (d,
J¼8.3 Hz, 0.25H, 3-H m).
n
¼3343, 2985, 2955, 1693, 1655, 1521, 1253, 1163 cmꢁ1
.
1H NMR
(400 MHz, CDCl3):
d
¼1.52 (s, 9H, CMe3), 2.75 (m, 2H, CH2-6), 2.99
4.4.3. 4-tert-Butoxycarbonylamino-5,6-dihydro-benzocyclohepten-
7-one (13a) and 1-tert-butoxycarbonylamino-5,6-dihydro-benzocy-
clohepten-7-one (regioisomer of 13a), 80:20 isomeric mixture. To
a stirred solution of 5a (from 6a, 10.0 g, 36 mmol) in dry THF
(300 mL) at 0 ꢀC under Ar was added portionwise NBS (6.4 g,
36 mmol, 1 equiv). After further stirring for 1 h at 0 ꢀC and 1 h at rt,
aqueous N NaHCO3 (50 mL) was added, the mixture extracted
thrice with AcOEt (250 mL) and the organic phases washed with
H2O, dried (MgSO4) and evaporated to give a 80:20 mixture of the
corresponding bromoketone and its regioisomer (21 g, quantita-
tive), which was not purified.
(m, 2H, CH2-5), 6.24 (br s, 1H, NH), 6.29 (d, 1H, 8-H), 7.38 (br d, 1H,
3-H), 7.50 (d, 1H, 9-H), 7.55 (d, 1H, 2-H). J2,3¼8.6, J8,9¼12.8 Hz. 13
C
NMR (100 MHz, CDCl3):
d
¼23.2 (C-5); 28.2 (CMe3); 43.2 (C-6); 81.0
(CMe3); 123.2 (C-1); 127.8 (C-3); 130.2 (C-8); 131.5 (C-2); 134.3,
134.9 (C-4a, C-9a); 138.1 (C-4); 140.0 (C-9); 153.7 (NCO2); 201.5 (C-
7). HRMS (ESI): calcd for C16H18BrNNaOþ3 [MþNa]þ: 374.0362;
found: 374.0353.
Minor regioisomer of 13b: 1H NMR (100 MHz, CDCl3):
d
¼1.54 (s,
9H, CMe3), 2.73 (m, 2H, CH2-6), 3.27 (m, 2H, CH2-5), 6.24 (br s, 1H,
NH), 6.31 (d, 1H, 8-H), 7.16 (d, 1H, 9-H), 7.58 (m, 2H, 2-H, 3-H).
J8,9¼12.8 Hz. 13C NMR (100 MHz, CDCl3):
¼28.2 (CMe3); 28.5 (C-5);
d
A solution of the precedent mixture (from 6a (10.0 g 36 mmol))
in Et2O (400 mL) and DBU (11 mL, 75.6 mmol, 2.1 equiv) was stirred
at rt for 30 min to 30 ꢀC. After dilution with AcOEt (300 mL), the
organic phase was washed with brine (20 mL), dried (MgSO4) and
evaporated to give crude enone. Purification by FC (cyclohexane/
AcOEt¼80:20) gave pure 80:20 mixture of 13a and its regioisomer
(8.7 g, 88% in three steps from 6a). Compound 13a can be crystal-
lized from iPr2O.
43.3 (C-6); 81.4 (CMe3); 118.9 (C-4); 122.9 (C-2); 130.8 (C-8); 133.9
(C-3); 134.1 (C-9); 136.8, ca. 138, 141.2 (C-1, C-4a, C-9a); 152.7
(NCO2); 201.9 (C-7).
4.4.5. 4-tert-Butoxycarbonylamino-7-benzyloxycarbonylamino-6,7-
dihydro-5H-benzocycloheptene (4a) and 1-tert-butoxycarbonyl-
amino-7-benzyloxycarbonylamino-6,7-dihydro-5H-benzocyclo-
heptene (40a). A solution of the mixture of 13a and its regioisomer
(8.7 g, 31.8 mmol) in NH3 2e3 M in dry MeOH (200 mL) with
Ti(OiPr)4 (19.7 mL, 66.5 mmol, 2.1 equiv) was stirred at rt under Ar
for 16 h. NaBH4 (1.21 g, 31.8 mmol, 1 equiv) was then added por-
tionwise under further stirring for 4 h. The mixture was evaporated
and the residue vigorously stirred in AcOEt (200 mL) and aqueous
NH4OH 1 N (200 mL) for 2 h. The titanic salts are filtered off, the
Bromoketone: only characterized by 1H RMN, major
regioisomer: 1H NMR (400 MHz, CDCl3):
(dddd, 1H, 8-Hb), 2.74 (ddd, 1H, 9-Hb), 3.07 (ddd, 1H, 9-Ha), 3.20
(ddd, 1H, 8-Ha), 3.30 (dd, 1H, 5-Hb), 3.46 (dd, 1H, 5-Ha), 4.54 (ddd,
1H, 6-H), 6.21 (s, 1H, NH), 7.09 (d, 1H, 4-H), 7.22 (dd, 1H, 3-H), 7.39
d
¼1.50 (s, 9H, CMe3), 2.65
4
(d, 1H, 2-H). J2,3¼8.0, J3,4¼7.6, J5b,6¼8.0, J5a,6¼3.2, J6,8b¼1.6,

6452
M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
solid extracted with the same solvents mixtures, the combined
organic phases were separated and the aqueous solutions extracted
with AcOEt (200 mL). The combined organic phases are dried
(MgSO4) and evaporated to give a 80:20 isomeric mixture of amines
(7.9 g, 90%). A solution of the crude amine mixture (7.9 g,
28.9 mmol) in THF (190 mL) was stirred with NaHCO3 (6.10 g,
57.7 mmol, 2 equiv) and ClCO2Bn (5.0 mL, 34.7 mmol,1.2 equiv) at rt
for 16 h. The solution was evaporated, the residue dissolved in
AcOEt (100 mL) and the solution washed with H2O. The organic
phase was dried (MgSO4) and evaporated to give a 80:20 isomeric
mixture of 4a/40a. First crop of 4a (3.72 g), was obtained by crys-
tallization in iPr2O/AcOEt 4:1. The mother liquor was resolved by FC
(cyclohexane/AcOEt 80:20). Final yield: 4a (7.06 g, 54%) and 40a
(100 MHz, CDCl3):
d
¼24.8 (C-5); 28.3 (CMe3); 38.1 (C-6); 50.2 (C-7);
66.8 (CH2Ph); 80.8 (CMe3); 120.5 (C-1); 124.6 (C-3); 128.1, 128.1,
128.5 (3 CHar); 129.5 (C-9); 130.6 (C-2); 133.8 (C-8); 134.1, 135.9,
136.2, 136.3 (C-4, C-4a, C-9a, Car-s); 153.6 (NCOt2Bu), 155.4
(NCO2Bn). HRMS (ESI): calcd for C24H27BrN2NaO4 [MþNa]þ:
509.1046 and 511.1025; found: 509.1040 and 511.1026.
Compound 40b: colorless crystals. Mp 192 ꢀC. IR (KBr):
2976, 2931, 1691, 1540, 1517, 1291, 1253, 1162, 1028, 779,
695 cmꢁ1 1H NMR (400 MHz, CDCl3):
n
¼3342,
.
d
¼1.51 (s, 9H, CMe3), 1.97
(dddd, 1H, 6-Hb), 2.47 (dddd, 1H, 6-Ha), 2.57 (ddd, 1H, 5-Hb), 3.15
(ddd, 1H, 5-Ha), 4.10 (ddddd, 1H, 7-H), 4.88 (d, 1H, 7-NH), 5.07 (s,
2H, CH2Ph), 6.16 (dd, 1H, 8-H), 6.36 (br s, 1H, 1-NH), 6.46 (dd, 1H,
9-H), 7.34 (s, 5H, ArH), 7.44 (d, 1H, 3-H), 7.70 (d, 1H, 2-H). J2,3¼8.8,
i
(1.63 g, 13%) after washing with Pr2O.
J5a,5b¼13.0,
J5a,6a¼4.7,
J5a,6b¼2.9,
J5b,6a¼13.0,
J5b,6b¼5.8,
Compound 4a: colorless crystals. Mp 172e174 ꢀC. IR (KBr):
J6a,6b¼12.4, J6a,7¼7.0, J6b,7¼10.6, J7,8¼5.0, JNH,7¼8.0, J7,9¼1.5,
n
¼3332, 1691, 1682, 1514, 1249, 1164 cmꢁ1
.
1H NMR (400 MHz,
J8,9¼10.8 Hz. 13C NMR (100 MHz, CDCl3):
¼28.3 (CMe3); 30.2 (C-
d
CDCl3, 323 K):
d
¼1.50 (s, 9H, CMe3), 2.07 (dddd, 1H, 6-Hb), 2.14
5); 39.5 (C-6); 49.6 (C-7); 66.8 (CH2Ph); 80.9 (CMe3); 118.1 (C-4);
120.0 (C-2); 123.4 (C-9); 128.0, 128.2, 128.5 (3 CHar); 130.6 (C-1);
131.9 (C-3); 135.0, 136.4 (Car-s, C-9a), 137.7 (C-8), 139.4 (C-4a),
152.5 (NCOt2Bu), 155.7 (NCO2Bn). HRMS (ESI): calcd for
C24H27BrN2NaO4 [MþNa]þ: 509.1046 and 511.1025; found
509.1047 and 511.1025.
(dddd, 1H, 6-Ha), 2.63 (ddd, 1H, 5-Hb), 2.82 (ddd, 1H, 5-Ha), 4.48
(ddddd, 1H, 7-H), 4.80 (d, 1H, NHCbz), 5.11 (2 d, 2H, OCH2Ph), 5.80
(dd, 1H, 8-H), 6.15 (s, 1H, NH), 6.47 (dd, 1H, 9-H), 7.01 (d, 1H, 1-H),
7.12 (t, 1H, 2-H), 7.30e7.38 (m, 6H, 5 ArH, 3-H). JOCH2Ph¼12.0,
4
J1,2¼J2,3¼7.6, J1,3¼1.2, J5a,5b¼15.2, J5a,6a¼2.4, J5a,6b¼8.0, J5b,6a¼10.0,
J5b,6b¼2.4, J6a,6b¼14.0, J6a,7¼5.2, J6b,7¼7.6, J7,8¼4.4, J7,NH¼8.8,
J7,9¼2.0, J8,9¼12.2 Hz. 13C NMR (100 MHz, CDCl3):
d¼23.9 (C-5); 28.5
4.4.7. cis-1-tert-Butoxycarbonylamino-7-benzyloxycarbonylamino-
5,6-epoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (14a). A solu-
tion of 4a (7.0 g, 17.1 mmol) in CH2Cl2 (300 mL) and m-CPBA
(4.73 g, 26.3 mmol, 1.6 equiv) at 0 ꢀC under Ar was stirred at 0 ꢀC
for 16 h. An aqueous 0.4 M Na2S2O3 in 1 N NaHCO3 solution
(300 mL) was added and the mixture stirred at rt for another
30 min. After elimination of the insolubles, the solution was
extracted with AcOEt (3ꢂ100 mL), the organic phases washed with
aqueous N NaHCO3 solution (2ꢂ100 mL) and brine, dried (MgSO4)
and evaporated to give 14a (6.47 g, 89%) as colorless crystals. Mp
(CMe3); 33.5 (C-6); 51.8 (C-7); 66.9 (OCH2Ph); 80.6 (CMe3); 124.5
(C-3); 126.3 (C-2); 128.3, 128.7 (3 CHar); 129.1 (C-1); 131.4 (C-9);
131.5 (C-8); 134.6 (Car); 135.5 (C-4); 136.3, 136.6 (2 Car); 154.1
(NCOt2Bu); 155.5 (NCO2Bn). HRMS (ESI) calcd for C24H28N2NaO4
[MþNa]þ: 431.1941; found: 431.1938.
Compound 40a: colorless crystals. Mp 188e190 ꢀC. IR(KBr):
n
¼3385, 3258, 1719, 1698, 1557, 1531, 1244, 1164 cmꢁ1
.
1H NMR
(400 MHz, CDCl3):
d
¼1.51 (s, 9H, CMe3), 2.02 (ddt, 1H, 6-Hb),
2.34 (dddd, 1H, 6-Ha), 2.64 (m, 2H, CH2-5), 4.31 (ddddd, 1H, 7-
H), 4.9 (d, 1H, 7-NH), 5.09 (s, 2H, OCH2Ph), 6.05 (dd, 1H, 8-H),
6.36 (s, 1H, NHBoc), 6.49 (dd, 1H, 9-H), 6.92 (d, 1H, 4-H), 7.16
(dd, 1H, 3-H), 7.30e7.38 (m, 5H, ArH), 7.71 (d, 1H, 2-H). J2,3¼8.2,
J3,4¼7.6, J5a,5b¼14.0, J5,6a¼6.4, 9.2, J5,6b¼5.0, J6a,6b¼13.2, J6a,7¼6.4,
J6b,7¼9.2, J7,NH¼7.3, J7,8¼4.8, J7,9¼1.0, J8,9¼11.6 Hz. 13C NMR
188e191 ꢀC. IR (KBr):
n
¼3430, 3283, 2977, 2936, 1686, 1551, 1524,
1258, 1158 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
¼1.48 (s, 9H, Bu),
t
1.68 (dddd, 1H, 8-Hb), 1.96 (ddddd, 1H, 8-Ha), 2.43 (ddd, 1H, 9-Hb),
2.96 (ddd, 1H, 9-Ha), 3.66 (dd, 1H, 6-H), 4.03 (d, 1H, 5-H), 4.42
(dddd, 1H, 7-H), 5.12 (s, 2H, OCH2Ph), 5.14 (br d, 1H, NHCbz), 6.17 (s,
1H, NHBoc), 7.21 (t, J¼7.8 Hz, 1H, 3-H), 7.31e7.42 (m, 7H, ArH).
J5,6¼4.2, J6,7¼3.2, 4J6,8a¼1.2, J7,8a¼4.8, J7,8b¼10.0, J7,NH¼9.2,
(CDCl3):
d
¼28.3 (CMe3); 31.1 (C-5); 38.6 (C-6); 50.4 (C-7); 66.8
(OCH2Ph); 80.6 (CMe3); 119.7 (C-2); 123.9 (C-9); 124.3 (C-4);
128.0 (C-3); 128.2, 128.2, 128.5 (3 CHar); 135.1 (C-4,C-8); 135.7,
136.4, 141.7 (3 Car); 152.9 (NCOt2Bu); 155.5 (NCO2Bn). HRMS
(ESI): calcd for C24H28N2NaO4 [MþNa]þ: 431.1941; found:
431.1940.
J8a,8b¼13.6,
J8a,9a¼8.8,
J8a,9b¼1.6,
J8b,9a¼1.6,
J8b,9b¼10.2,
J9a,9b¼16.0 Hz. 13C NMR (100 MHz, CDCl3):
d
¼23.6 (C-9); 28.5
(CMe3); 30.3 (C-8); 51.7 (C-7); 60.3 (C-5); 60.5 (C-6); 67.0
(OCH2Ph); 80.7 (CMe3); 126.0, 126.7 (C-2, C-4); 128.7, 128.3, 128.2
(3 CHar); 131.4 (C-3); 136.5, 135.9, 135.0, 133.5 (4 Car); 154.0
(NCOt2Bu); 155.8 (NCO2Bn). Anal. Calcd for C24H28N2O5 (424.49): C
67.91, H 6.65, N 6.60; found: C 67.6, H 6.7, N 6.4.
4.4.6. 1-Bromo-4-tert-butoxycarbonylamino-7-benzyloxycarbonyla-
mino-6,7-dihydro-5H-benzocycloheptene (4b) and 4-bromo-1-tert-
butoxycarbonylamino-7-benzyloxycarbonylamino-6,7-dihydro-5H-
benzocycloheptene (40b). Same procedure as for 4a/40a with the
mixture of 13b and its regioisomer (1.28 g, 3.6 mmol) in NH3 2.8 M
in MeOH (20 mL) with Ti(OiPr)4 (2.06 g, 7.2 mmol, 2 equiv) for 16 h,
then reduction with NaBH4 (137 mg, 3.6 mmol, 1 equiv) for 4 h. The
crude amine was protected in THF (12 mL) with ClCO2Bn (0.57 mL,
4.0 mmol, 1.1 equiv) and Na2CO3 (0.77 g, 7.2 mmol, 2 equiv) to give
crude mixture (0.89 g), which was resolved by successive FC (cy-
clohexane/AcOEt 9:1) to give 4b (947 mg, 54%) and 40b (210 mg,
12%).
4.4.8. cis-4-Bromo-1-tert-butoxycarbonylamino-7-benzyloxycarbo-
nylamino-5,6-epoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene
(14b). Same procedure as for 14a with 4b (900 mg, 1.8 mmol), m-
CPBA (0.51 g, 2.95 mmol). After work-up, the crude product was
i
purified by washing with Pr2O to give 14b (743 mg, 80%) as col-
orless crystals. Mp 150 ꢀC. IR (KBr):
n
¼3327, 2976, 2938, 1688, 1530,
1507, 1312, 1276, 1247, 1162, 1066, 1016 cmꢁ1. 1H NMR (400 MHz,
CDCl3, 323 K):
¼1.51 (s, 9H, CMe3), 1.59 (dddd, 1H, 8-Hb), 2.13
d
(dddd, 1H, 8-Ha), 2.49 (ddd, 1H, 9-Hb), 2.91 (ddd, 1H, 9-Ha), 3.69
(dt, 1H, 6-H), 4.26 (d, 1H, 5-H), 4.43 (dddd, 1H, 7-H), 4.81 (br d, 1H,
7-NH), 5.11 (s, 2H, CH2Ph), 6.09 (br s, 1H, 1-NHBoc), 7.31 (d, 1H, 2-
H), 7.33 (m, 5H, ArH), 7.47 (d, 1H, 3-H). J2,3¼8.6, J5,6¼4.0, J6,7¼4.2,
4J6,8a¼1.2, J7,8a¼5.5, J7,8b¼10.0, J7,NH¼7.6, J8a,8b¼13.9, J8a,9a¼7.6,
J8a,9b¼2.3, J8b,9a¼2.3, J8b,9b¼10.2, J9a,9b¼15.3 Hz. 13C NMR
Compound 4b: colorless crystals. Mp 164 ꢀC. IR (KBr):
2974, 2934, 1692, 1545, 1516, 1254, 1163, 1042, 776, 695 cmꢁ1
NMR (400 MHz, CDCl3):
¼1.51 (s, 9H, CMe3), 2.05 (dddd, 1H, 6-Hb),
n
¼3336,
.
1H
d
2.39 (dddd, 1H, 6-Ha), 2.56 (ddd, 1H, 5-Hb), 2.77 (ddd, 1H, 5-Ha),
4.28 (ddddd, 1H, 7-H), 4.80 (d, 1H, 7-NH), 5.11 (s, 2H, CH2Ph), 6.03
(dd, 1H, 8-H), 6.14 (br s, 1H, 4-NH), 6.75 (dd, 1H, 9-H), 7.34 (m,
5H, ArH), 7.32 (d, 1H, 3-H), 7.43 (d, 1H, 2-H). J2,3¼8.6, J5a,5b¼14.3,
J5a,6a¼3.6, J5a,6b¼5.2, J5b,6a¼11.3, J5b,6b¼4.4, J6a,6b¼13.2, J6a,7¼6.8,
J6b,7¼8.4, J7,NH¼7.8, J7,8¼4.6, J7,9¼2.0, J8,9¼11.6 Hz. 13C NMR
(100 MHz, CDCl3):
d
¼22.9 (C-9); 27.3 (CMe3); 29.3 (C-8), 49.7 (C-7),
57.8 (C-5); 58.3 (C-6); 65.7 (CH2Ph); 80.0 (CMe3); 124.2 (C-4);
125.9 (C-2); 126.9, 127.1, 127.5 (3 CHar), 130.2 (C-3); 131.8, 132.8,
135.4 (C-4a, C-9a, Car-s), 137.1 (C-1), 152.6 (NCO-1), 154.6 (NCO-7).

M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
6453
HRMS (ESI): calcd for C24H27BrN2NaO5 [MþNa]þ: 525.1001 and
procedure as for 3a with 15b (700 mg, 1.4 mmol) in CH2Cl2 (20 mL)
and DMP (882 mg, 2.1 mmol, 1.5 equiv) for 2 h at rt. Crude 3b was
purified by FC (AcOEt/cyclohexane 8:2) (560 mg, 80%).
Compound 3b: beige crystals. Mp 174e176 ꢀC (lit.18 176 ꢀC).
Same physical data as in lit.18
527.0981; found 525.0990 and 527.0976.
4.4.9. cis-1-tert-Butoxycarbonylamino-7-benzyloxycarbonylamino-
6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (15a). To a solution of
14a (6.2 g, 14.6 mmol) in THF (180 mL) at ꢁ78 ꢀC was added
dropwise Dibal-H (1 M solution in toluene, 87.5 mL, 87.5 mmol,
6 equiv). The solution was stirred at e30 ꢀC for 1 h. Aqueous sodium
tartrate 1 M (100 mL) and AcOEt (200 mL) was added and the so-
lution stirred for 30 min, the organic phase was washed with brine,
the aqueous phase extracted with AcOEt (100 mL). The combined
organic phases were dried (MgSO4) and evaporated to give 15a,
which was washed with Et2O (5.22 g, 84%) as colorless crystals. Mp
4.5. Syntheses of the amino-ketone 2
4.5.1. 1-tert-Butoxycarbonylamino-4-phenyl-7-benzyloxycarbonyla-
mino-5,7,8,9-tetrahydro-benzocyclohepten-6-one (16). A solution of
3b (4.0 g, 7.9 mmol) (320 mg, 0.64 mmol) in H2O (25 mL) and
DME (112 mL) was stirred with PhB(OH)2 (1.47 g, 11.9 mmol,
1.5 equiv), Pd(PPh3)4 (937 mg, 0.8 mmol) and K2CO3 (1.65 g,
11.9 mmol, 1.5 equiv) at reflux under Ar for 5 h. H2O (100 mL) was
added and the solution extracted with AcOEt (3ꢂ100 mL), the
organic phase washed with brine (100 mL), dried (MgSO4) and
evaporated. The residue was purified by FC (AcOEt/cyclohexane
8:2) to give 16 (3.25 g, 82%) as brownish crystals. Mp 168 ꢀC. IR
180e184 ꢀC (lit.18 174 ꢀC). IR (KBr):
1664, 1541, 1515, 1266, 1250, 1167, 1049 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
¼1.49 (m, 1H, 8-Hb), 1.51 (s, 9H, CMe3), 2.02 (dddt, 1H, 8-
n
¼3429, 3325, 2973, 2935, 1699,
d
Ha), 2.46 (ddd, 1H, 9-Hb), 2.95 (ddd, 1H, 9-Ha), 3.05 (dd, 1H, 5-Hb),
3.10 (dd, 1H, 5-Ha), 3.86 (dddd, 1H, 7-H), 4.10 (dddd, 1H, 6-H), 5.12
(s, 1H, CH2Ph), 5.24 (d, 1H, NHCbz), 6.16 (s, 1H, NHBoc), 7.01 (d, 1H,
4-H), 7.11 (dd, 1H, 3-H), 7.35e7.29 (m, 6H, 5 ArH, 2-H). J2,3¼7.8,
4J2,4¼1.2, J3,4¼7.6, J5a,5b¼14.8, J5b,6¼7.2, J5a,6¼1.6, J6,7¼2.8, 4J6,8a¼1.2,
J7,8a¼4.4, J7,8b¼11.5, J7,NH¼8.8, J8a,8b¼14.0, J8a,9a¼8.2, J8a,9b¼1.2,
J8b,9a¼1.2, J8b,9b¼11.4, J9a,9b¼15.0 Hz. Data in agreement with those
(KBr):
n
¼3331, 2969, 2929, 1718, 1688, 1513, 1367, 1246, 1163,
1015, 756, 710, 696 cmꢁ1
.
1H NMR (400 MHz, CDCl3, 323 K):
d
¼1.54 (s, 9H, CMe3), 1.60 (ddt, 1H, 8-Hb), 2.71 (ddt, 1H, 8-Ha),
3.00 (dd, 2H, CH2-9), 3.71 (d, 1H, 5-Hb), 3.81 (d, 1H, 5-Ha), 4.55
(ddd, 1H, 7-H), 5.07 (s, 2H, CH2Ph), 5.58 (br d, 1H, 7-NH), 6.20 (br
s, 1H, 1-NHBoc), 7.18 (d, 1H, 3-H), 7.28e7.43 (m, 10H, ArH), 7.47 (d,
2-H). J2,3¼8.2, J5a,5b¼16.0, J7,NH¼7.4, J7,8a¼7.0, J7,8b¼11.0, J8a,9¼7.3,
of the lit.18 13C NMR (100 MHz, CDCl3):
d
¼24.6 (C-9); 27.7 (C-8);
28.3 (CMe3); 39.3 (C-5); 57.3 (C-7); 66.6 (CH2Ph); 68.9 (C-6); 80.5
(CMe3); 124.9 (C-2); 126.6 (C-3); 128.1, 128.5, 128.6 (3 CHar); 129.6
(C-4); 134.4, 135.2, 136.5, 136.9 (C-1, C-4a, C-9a, Car-s); 154.2
(NHCOt2Bu); 155.6 (NHCO2Bn). Data in agreement with those of the
lit.18 HRMS (ESI) calcd for C24H31N2O5 [MþH]þ: 427.2227; found:
427.2230.
J8b,9¼5.5, J8a,8b¼13.0 Hz. 13C NMR (100 MHz, CDCl3):
¼24.2 (C-9);
d
28.3 (CMe3); 32.9 (C-8); 43.9 (C-5); 60.3 (C-7); 66.8 (CH2Ph); 80.7
(CMe3); 124.0 (C-2); 127.2, 128.0, 128.1, 128.3, 128.6, 129.8 (6
CHar); 129.3 (C-3); 131.0 (C-9a); 133.7 (C-1); 134.2, 136.2 (C-4, C-
4a); 140.0, 140.5 (2 Car-s); 153.9 (NCO-1); 155.4 (NCO-7); 204.9
(CO-6). HRMS (ESI): calcd for C30H32N2NaO5 [MþNa]þ: 523.2203;
found: 523.2206; calcd for C30H33N2O5 [MþH]þ: 501.2389; found:
501.2390.
4.4.10. cis-4-Bromo-1-tert-Butoxycarbonylamino-7-benzyloxycarbo-
nylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (15b). Same
procedure as for 15a with 14b (700 mg, 1.39 mmol), Dibal-H
(8.4 mL, 8.4 mmol) to give after work-up 15b (705 g, quant) as
4.5.2. 1-Bromo-4-phenyl-7-benzyloxycarbonylamino-5,7,8,9-
tetrahydro-benzocyclohepten-6-one (17). A solution of 16 (3.0 g,
6.0 mmol) in dry CH2Cl2 (110 mL) and CF3CO2H (110 mL) was stirred
at rt for 1 h under Ar. 1 N NaHCO3 aqueous solution (500 mL) was
added, the mixture was extracted with CH2Cl2 (3ꢂ100 mL), the
organic phases washed with brine, dried (MgSO4) and evaporated.
The solution of the crude amine in dry MeCN (110 mL) was stirred
a cream solid. Mp 166 ꢀC. IR (KBr):
n
¼3319, 2926, 1698, 1541, 1509,
1248, 1164, 1045 cmꢁ1. 1H NMR (400 MHz, CDCl3, 323 K):
d
¼1.51 (s,
9H, CMe3), 1.55 (dddd, 1H, 8-Hb), 2.03 (ddddd, 1H, 8-Ha), 2.55 (ddd,
1H, 9-Hb), 3.00 (ddd, 1H, 9-Ha), 3.04 (dd, 1H, 5-Hb), 3.72 (dd, 1H, 5-
Ha), 3.85 (dddd, 1H, 7-H), 4.20 (ddt, 1H, 6-H), 5.12 (s, 2H, CH2Ph),
5.22 (br d, 1H, 7-NH), 6.10 (br s, 1H, 1-NH), 7.25 (d, 1H, 2-H), 7.36 (m,
5H, ArH), 7.44 (d, 1H, 3-H). J2,3¼8.5, J5a,5b¼14.7, J5a,6¼8.2, J5b,6¼1.0,
t
under Ar at rt with CuBr2 (1.35 g, 6 mmol, 1 equiv) and BuONO
4
J6,7¼3.0, J6,8a¼1.0, JNH,7¼8.5, J7,8a¼4.2, J7,8b¼11.5, J8a,8b¼13.5,
(1.46 mL, 12.4 mmol, 2 equiv) for 16 h, then refluxed for 4 h. H2O
(100 mL) was added, the mixture was extracted with AcOEt
(3ꢂ100 mL), the combined organic phases washed with brine, dried
(MgSO4) and evaporated. The residue was purified by FC (AcOEt/
cyclohexane 8:2) to give 17 (1.28 g, 46%) as a brownish solid. Mp
J8a,9a¼8.4, J8a,9b¼1.4, J8b,9a¼1.6, J8b,9b¼10.9, J9a,9b¼15.1 Hz. 13C NMR
(100 MHz, CDCl3):
d
¼25.4 (C-9); 27.6 (C-8); 28.3 (CMe3); 37.5 (C-6);
56.8 (C-7); 66.7 (CH2Ph); 68.4 (C-5); 80.8 (CMe3); 123.6 (C-4); 125.6
(C-2); 128.0, 128.1, 128.5 (3 CHar); 130.9 (C-3); 133.8, 135.0, 136.4
(C-4a, C-9a, Car-s); 138.4 (C-1); 153.79 (NCO-1), 155.63 (NCO-7).
HRMS (ESI): calcd for C24H30BrN2O4 [MþH]þ: 505.1333 and
507.1312; found. 505.1316 and 507.1307.
96 ꢀC. IR (KBr):
1319, 1257, 1017, 1075, 990, 776, 742, 698 cmꢁ1
323 K):
n
¼3315, 2929, 1718, 1677, 1533, 1451, 1384, 1361,
.
1H NMR (CDCl3,
d
¼1.57 (dddd, 1H, 8-Hb), 2.72 (dddd, 1H, 8-Ha), 3.22 (ddd,
1H, 9-Hb), 3.32 (ddd, 1H, 9-Ha), 3.72 (d, 1H, 5-Hb), 3.84 (d, 1H, 5-
Ha), 4.53 (ddd, 1H, 7-H), 5.09 (s, 2H, CH2Ph), 5.53 (br d, 1H, 7-
NH), 7.06 (d, 1H, 3-H), 7.27e7.45 (m, 10H, ArH), 7.55 (d, 1H, 2-H).
J2,3¼8.2, J5a,5b¼16.4, J7,8a¼7.6, J7,8b¼10.8, J7,NH¼8.0, J8a,8b¼12.8,
J8a,9a¼4.5, J8a,9b¼10.6, J8b,9a¼6.4, J8b,9b¼4.3, J9a,9b¼14.8 Hz. 13C NMR
4.4.11. 1-(tert-Butoxycarbonylamino)-7-benzyloxycarbonylamino-
5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one (3a). To a solution of
alcohol 15a (5.0 g, 11.7 mmol) (356 mg, 0.83 mmol) in dichloro-
methane (150 mL), was added DesseMartin periodinane (6.0 g,
14.0 mmol,1.2 equiv). This mixture was stirred at rt for 2 h and then
diluted with water and dichloromethane. After separation, the
aqueous layer was extracted with dichloromethane (ꢂ3). The
combined organic phases were dried over MgSO4 and concentrated
in vacuum. The residue was purified by FC (cyclohexane/AcOEt, 80/
20) yielding 3a (4.56 g, 92%) as a colorless solid. Compound 3a:
colorless crystals. Mp 176e178 ꢀC (lit.18 176e178 ꢀC). Same physical
data as in lit.18
(100 MHz, CDCl3):
d
¼29.7 (C-9); 32.4 (C-8); 44.5 (C-5); 59.6 (C-7);
66.9 (CH2Ph); 123.6 (C-1); 127.6, 128.1, 128.2, 128.4, 128.5, 129.5 (6
CHar); 130.2 (C-3); 131.7 (C-2); 132.2 (C-4a); 136.2 (Car-s(Ph));
139.1, 139.8, 142.1 (C-4, C-9a, Car-s(Bn)); 155.3 (NCO); 205.1 (CO-6).
HRMS (ESI): for C25H23BrNO3 [MþH]þ: 464.0861 and 466.0841;
found: 464.0860 and 466.0838.
4.5.3. 1-Bromo-4-phenyl-7-amino-5,7,8,9-tetrahydro-6H-benzocy-
clohepten-6-one, hydrobromide (2$HBr). A solution of 17 (1.0 g,
2.15 mmol) in 33% HBr solution in AcOH (33 mL) and AcOH (33 mL)
was stirred at rt for 16 h. After evaporation of the solvent, the
4.4.12. 4-Bromo-1-tert-butoxycarbonylamino-7-benzyloxycarbonyl-
amino-5,7,8,9-tetrahydro-benzocyclohepten-6-one
(3b). Same

6454
M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
residue was crystallized and washed with Et2O to give 2$HBr
(795 mg, 90%) as colorless crystals. Mp >200 ꢀC. IR (KBr):
¼794,
770, 825, 1454, 1496, 1507, 1720, 2931, 3423 cmꢁ1 1H NMR
(400 MHz, CD3OD):
1H, 7-H), 4.95 (d, 1H, 7-NH), 5.11 (s, 2H, CH2Ph), 5.90 (dd, 1H, 8-H),
6.33 (d, 1H, 9-H), 7.04 (d, 1H, 2-H), 7.36 (m, 10 ArH), 7.52 (d, 1H, 3-
H). J2,3¼8.2, J5a,5b¼13.8, J5a,6a¼4.1, J5a,6b¼4.1, J5b,6a¼11.7, J5b,6b¼4.6,
J6a,6b¼13.2, J6a,7¼6.9, J6b,7¼9.6, JNH,7¼8.5, J7,8¼4.6, J7,9¼1.5,
n
.
d
¼1.76 (dddd, 1H, 8-Hb), 2.58 (dddd, 1H, 8-Ha),
3.44 (ddd, 1H, 9-Hb), 3.52 (ddd, 1H, 9-Ha), 3.86 (d, 1H, 5-Hb), 4.04
(d, 1H, 5-Ha), 4.32 (dd, 1H, 7-H), 7.12 (d, 1H, 3-H), 7.35e7.45 (m, 5H,
ArH), 7.62 (d, 1H, 2-H). J2,3¼8.3, J5a,5b¼15.3, J7,8a¼7.6, J7,8b¼11.8,
J8,9¼11.3 Hz. 13C NMR (100 MHz, CDCl3):
¼30.3 (C-5); 38.6 (C-6);
d
50.1 (C-7); 66.8 (CH2Ph); 123.4 (C-4); 127.3, 128.1 (3C), 128.5, 129.0
(6 CHar); 129.6 (C-9, C-2); 131.3 (C-3); 133.6 (C-8), 136.3, 136.8
(Car-s, C-9a); 140.0, 141.0 (Car-s, C-4a), 155.5 (NCO). HRMS (ESI):
calcd for C25H23BrNO2 [MþH]þ: 448.0907; found 448.0901.
J8a,8b¼12.8,
J8a,9a¼9.6,
J8a,9b¼3.6,
J8b,9a¼3.6,
J8b,9b¼8.2,
J9a,9b¼15.0 Hz. Same data as for 2$HCl8 HRMS (ESI): calcd for
C17H17BrNO [MþH]þ: 330.0488 and 332.0469, found: 330.0458 and
332.0433.
4.5.7. cis-7-Benzyloxycarbonylamino-1-bromo-5,6-epoxy-4-phenyl-
6,7,8,9-tetrahydro-5H-benzocycloheptene (20). A solution of 10
(90 mg, 0.20 mmol) in CH2Cl2 (20 mL) and m-CPBA (69 mg,
0.4 mmol, 2 equiv) under Ar was stirred at 40 ꢀC for 16 h. An
aqueous 0.4 M Na2S2O3 in 1 N NaHCO3 solution (35 mL) was added
and the mixture stirred at rt for another 30 min. The mixture was
extracted with AcOEt (3ꢂ20 mL), the combined organic phases
were washed with brine (10 mL), dried (MgSO4) and evaporated to
give 20 (87 mg, 94%) as colorless crystals. Mp 104 ꢀC. IR (KBr):
4.5.4. 1-Bromo-4-phenyl-7-tert-butyloxycarbonylamino-5,7,8,9-
tetrahydro-benzocyclohepten-6-one (18). A solution of 2$HBr
(750mg,1.82mmol)inMeOH(40mL)withBoc2O(1.54g,2equiv)and
Na2CO3 (427 mg, 2.2 equiv) was stirred at 0 ꢀC for 1.5 h. The solution
was diluted with H2O 10 mL and extracted with AcOEt (3ꢂ20 mL), the
combinedorganicphaseswerewashedwithbrine,dried(MgSO4)and
evaporated. The obtained crystals were washed with iPr2O to give 18
(745 mg, 95%) as colorless crystals. Mp 144e146 ꢀC (lit.8 144e150 ꢀC).
Same IR (KBr) and NMR data (CDCl3) as in lit.8
n
¼3306, 2930, 1683, 1534, 1307, 1260, 701 cmꢁ1. 1H NMR (400 MHz,
CDCl3):
d
¼1.64 (dddd, 1H, 8-Hb), 2.13 (dddd, 1H, 8-Ha), 2.57 (ddd,
1H, 9-Hb), 3.51 (ddd, 1H, 9-Ha), 3.59 (ddd, 1H, 6-H), 3.77 (d, 1H, 5-
H), 4.42 (dddd, 1H, 7-H), 4.98 (d, 1H, 7-NH), 5.10 (s, 2H, CH2Ph), 7.05
(d, 1H, 3-H), 7.30e7.45 (m, 10H, ArH), 7.61 (d, 1H, 2-H). J2,3¼8.2,
J5,6¼4.2, J6,7¼3.5, 4J6,8a¼1.4, J7,8a¼5.3, J7,8b¼10.4, J7,NH¼9.1,
4.5.5. 4-Bromo-1-iodo-7-benzyloxycarbonylamino-6,7-dihydro-5H-
benzocycloheptene (19). A solution of 40b (200 mg, 0.41 mmol) in dry
CH2Cl2 (5 mL) and CF3CO2H (5 mL) was stirred at 0 ꢀC for 45 min
under Ar. 1 N NaHCO3 aqueous solution (50 mL) was added, the
mixture was extracted with CH2Cl2 (5ꢂ10 mL), the combined organic
phases were washed with brine, dried (MgSO4) and evaporated. Al-
ternatively a stirred solution of 40b (200 mg, 0.41 mmol) in DME
(3 mL) and 30% v/v aqueous H2SO4 solution (3 mL) was warmed at
50 ꢀC for 2 h. The crude amine solution was cooled at 0 ꢀC and a so-
lution of NaNO2 (106 mg,1.54 mmol, 3.5 equiv) in H2O (2.5 mL) were
added. This mixture was stirred for 1 h at 0 ꢀC and a solution of KI
(855 mg, 5.15 mmol,1.25 equiv) in H2O (2.5 mL) was added and after
1 h, another KI solution (855 mg, 5.15 mmol, 1.25 equiv) in H2O
(2.5 mL). After stirring for 1 h, H2O (20 mL) was added and the so-
lution extracted with AcOEt(3ꢂ20mL), the combined organic phases
were washed with brine (10 mL), dried (MgSO4) and evaporated. The
residue was purified by FC (AcOEt/cyclohexane 9:1) to give 19
J8a,8b¼13.7,
J8a,9a¼8.4,
J8a,9b¼1.6,
J8b,9a¼1.6,
J8b,9b¼10.3,
J9a,9b¼15.6 Hz. 13C NMR (100 MHz, CDCl3):
d
¼29.7 (C-9); 30.1 (C-8);
51.4 (C-7); 58.0 (C-5); 60.9 (C-6); 66.8 (CH2Ph); 123.6 (C-1); 127.7,
128.0, 128.1, 128.1, 128.5, 129.5, 129.7 (6 CHar, C-3); 133.0 (C-2);
132.2, 136.3 (C-4, Car-s(Ph)); 139.9 (C-4a); 141.1 (Car-s(Bn)); 146.5
(C-9a); 155.6 (NCO). HRMS (ESI): calcd for C25H23BrNO3 [MþH]þ:
464.0855 and 466.0835; found: 464.0849 and 466.0833.
4.5.8. cis-7-Benzyloxycarbonylamino-1-bromo-4-phenyl-6,7,8,9-
tetrahydro-5H-benzocyclohepten-6-ol (21). To
a solution of 20
(80 mg, 0.172 mmol) in dry THF (4 mL) at ꢁ78 ꢀC was added
dropwise Dibal-H (1.2 mL, 1.2 mmol, 7 equiv) and the solution
stirred at ꢁ30 ꢀC for 1 h. H2O (10 mL) and AcOEt (20 mL) were
added and the mixture stirred for 30 min, the precipitate was fil-
tered and extracted thrice with H2O and AcOEt again. The com-
bined aqueous filtrates were extracted with AcOEt (3ꢂ20 mL), the
combined organic phases were washed with brine (20 mL), dried
(MgSO4) and evaporated to give 21 (80 mg, quant.) as a beige solid.
(149 mg, 73%) as brownish crystals. Mp 158 ꢀC. IR (KBr):
n
¼3315,
2930, 1687, 1542, 1274, 1257, 1032 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼2.00 (dddd,1H, 6-Hb), 2.48 (dddd,1H, 6-Ha), 2.65 (ddd,1H, 5-Hb),
3.17 (ddd,1H, 5-Ha), 4.13 (ddddd,1H, 7-H), 4.90 (d,1H, 7-NH), 5.08 (s,
2H, CH2Ph), 6.02 (dd, 1H, 8-H), 6.54 (dd, 1H, 9-H), 7.15 (d, 1H, 3-H),
7.36 (m, 5H, ArH), 7.56 (d, 1H, 2-H). J2,3¼8.3, J5a,5b¼13.5, J5a,6a¼4.4,
J5a,6b¼3.6, J5b,6a¼12.3, J5b,6b¼5.5, J6a,6b¼13.0, J6a,7¼7.0, J6b,7¼10.4,
J7,NH¼7.8, J7,8¼4.9, J7,9¼2.0, J8,9¼11.2 Hz. 13C NMR (100 MHz, CDCl3):
Mp 150 ꢀC. IR (KBr):
n
¼3582, 3335, 2926, 2854, 1665, 1541, 1451,
1265, 1078, 1046, 1018, 697 cmꢁ1. 1H NMR (400 MHz, CDCl3, 332 K):
d
¼1.59 (ddt, 1H, 8-Hb), 2.07 (dddt, 1H, 8-Ha), 2.80 (ddd, 1H, 9-Hb),
2.88 (dd, 1H, 5-Hb), 3.27 (dd, 1H, 5-Ha), 3.48 (ddd, 1H, 9-Ha), 3.83
(dddd, 1H, 7-H), 4.03 (dddd, 1H, 6-H), 5.11 (s, 2H, CH2Ph), 5.12 (d,
1H, 7-NH), 6.98 (d, 1H, 3-H), 7.30e7.45 (m, 10H, ArH), 7.51 (d, 1H, 2-
d
¼31.0 (C-5); 39.4 (C-6); 49.4 (C-7); 66.9 (CH2Ph); 98.6 (C-1); 124.67
(C-4); 128.2, 128.5,128.5 (3 CHar); 132.7 (C-3); 133.6 (C-9); 135.1 (C-
8); 137.9 (C-2); 136.3, 140.9, 141.2 (Car-s, C-4a, C-9a); 155.5 (NCO).
HRMS (ESI): calcd for C19 H18BrINO2 [MþH]þ: 497.9560 and
499.9539; found: 497.9563 and 499.9541.
4
H). J2,3¼8.2, J5a,5b¼14.6, J5a,6¼8.2, J5b,6¼1.4, J6,7¼2.8, J6,8a¼1.3,
J7,NH¼8.4, J7,8a¼4.5, J7,8b¼11.2, J8a,8b¼13.8, J8a,9a¼8.3, J8a,9b¼1.2,
J8b,9a¼2.0, J8b,9b¼11.2, J9a,9b¼14.7 Hz. 13C NMR (100 MHz, CDCl3):
d
¼27.2 (C-8); 30.6 (C-9); 34.6 (C-5); 57.1 (C-7); 66.8 (CH2Ph); 68.8
4.5.6. 7-Benzyloxycarbonylamino-4-bromo-1-phenyl-6,7-dihydro-
(C-6); 123.6 (C-1); 127.2, 128.1, 128.2, 128.2, 128.5, 129.4 (6 CHar);
129.6 (C-3); 131.1 (C-2); 134.2 (C-4); 136.3 (Car-s(Ph)), 141.0 (Car-
s(Bn)), 141.5 (C-4a), 143.6 (C-9a), 155.5 (NCO). HRMS (ESI): calcd for
C25H25BrNO3 [MþH]þ: 466.1012 and 468.0991; found: 466.0993
and 468.0990.
5H-benzocycloheptene (10). To
a solution of 19 (120 mg,
0.24 mmol) and phenylboronic acid (30 mg, 0.24 mmol) in THF
(8 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and a solution
of K2CO3 (320 mg, 2.4 mmol) in H2O (8 mL). The solution was
stirred under Ar for 20 h at 70 ꢀC. H2O (20 mL) was added and the
solution extracted with AcOEt (3ꢂ20 mL), the combined organic
phases were washed with brine (10 mL), dried (MgSO4) and
evaporated. The residue was purified by FC (AcOEt/cyclohexane
4.5.9. 7-(Benzyloxycarbonyl)amino-1-bromo-4-phenyl-5,7,8,9-
tetrahydro-benzocyclohepten-6-one (17). A solution of 21 (75 mg,
0.16 mmol) and DMP (82 mg, 0.19 mmol, 1.2 equiv) in CH2Cl2
(13 mL) was stirred at rt for 2 h. 1 M aqueous Na2S2O3 solution
(10 mL) and AcOEt (10 mL) were added and the mixture was stirred
for another 2 h. The aqueous phase was extracted with AcOEt
(3ꢂ20 mL), the combined organic phases were washed with brine
9:1) to give 10 (98 mg, 91%) as a beige resin. IR (KBr):
2953, 2924, 2855, 1686, 1542, 1536, 14,520, 1302, 1256, 702 cmꢁ1
1H NMR (400 MHz, CDCl3):
¼2.06 (dddd, 1H, 6-Hb), 2.50 (dddd,
1H, 6-Ha), 2.69 (ddd, 1H, 5-Hb), 3.23 (ddd, 1H, 5-Ha), 4.35 (ddddd,
n
¼3314,
.
d

M. Al-Lakkis-Wehbe et al. / Tetrahedron 68 (2012) 6447e6455
6455
(10 mL), dried (MgSO4) and evaporated. The residue was purified by
References and notes
FC (AcOEt/cyclohexane 8:2) to give 17 (65 mg, 87%). Physical data
described section 3.6.2.
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crystallization in iPrOH/Et2O as a colorless solid. Same IR (KBr) and
NMR data (CD3OD) as in lit.8
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ꢀ
contre le Cancer (Inca) for a grant to M.A.-L., the Region Alsace for
ꢀ
ꢁ
grant to L.R. and the Ministere de l’Education Nationale for a grant
to S.A.. We thank Dr. Cecile Joyeux for HR-mass spectrometry
measurements and the students Azely Mirre, Arnaud Mignatelli
and Pascale Tremel for their participation to this work.
ꢀ
Supplementary data
The copies of 1H NMR and 13C NMR of intermediates and the
final compound 2$HCl are found in the Supplementary data. Sup-
plementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.05.121.
21. Zhu, G.-D.; Staeger, M. A.; Boyd, S. A. Org. Lett. 2000, 3345.