Synthesis of biphenyls mimicking the structure of the antimitotic rhazinilam

Full text of DOI:10.1021/jo980697v

6414
J . Org. Chem. 1998, 63, 6414-6420
Syn th esis of Bip h en yls Mim ick in g th e
Str u ctu r e of th e An tim itotic Rh a zin ila m
Ce´cile Pascal, J oe¨lle Dubois, Daniel Gue´nard, and
Franc¸oise Gue´ritte*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette Cedex, France
Received April 15, 1998
In tr od u ction
(-)-Rhazinilam 1 is an axially chiral phenylpyrrole
compound which has been isolated from Melodinus
australis,1 Rhazya stricta,2 and Kopsia singapurensis.3
Biological studies have shown that rhazinilam mimics
the cellular effects of paclitaxel (Taxol). It induces both
microtubules bundling in interphase and blocks mitotic
cells in aster-like structure.4 In vitro, this antimitotic
compound induces spiralization of tubulin such as vin-
blastine and inhibits the cold-induced disassembly of
microtubules such as paclitaxel.4 Structurally, (-)-
rhazinilam 1 is characterized by four rings: the phenyl
A-ring, the nine-membered lactam B-ring, the pyrrole
C-ring, and the piperidine D-ring. According to X-ray
data, the A-C dihedral angle of (-)-rhazinilam 1 is 95°
and the amide bond possesses a cis conformation.5
Structure-activity relationship studies suggest that the
presence of the phenylpyrrole unit as well as the lactam
function are indispensable for antitubulin activity.6
Moreover, the good interaction of (-)-diethylphenylpyr-
role 27,8 with tubulin in comparison to the low activity of
phenylpyrrole 38 shows that restricted rotation of the
biaryl and/or the presence of the two ethyl groups plays
a major role in the biological activity.
tubulin assembly.10 Previously, we reported the synthe-
sis of dibenzoazonine 5 from 2-phenylbenzoic acid.11 This
compound does not interact with microtubules, and all
our efforts to replace the dioxolane by alkyl chains
through alkylation of the corresponding ketone were
unsuccessful.12 In this paper we describe the synthesis
of new ortho-substituted bridged biphenyls 4a to 4e, and
we show that the more or less hindered substitution at
carbon 9 affects the interaction with tubulin.
Resu lts a n d Discu ssion
As shown in Scheme 1, our approach is based on a
cross-coupling reaction of a protected aniline derivative
with ortho-substituted phenyl halides A. This would lead
to the key biphenyl intermediate B which would cyclize
into a nine-membered ring after deprotection of the
amine and acid groups followed by intramolecular cy-
clization.
As part of our studies in this series, we considered that
the replacement of the phenylpyrrole by a biphenyl unit
might be an interesting feature to analyze. Indeed,
molecular modeling studies show that biphenyl com-
pounds such as 4 with a quaternary carbon at the 9
position could mimic the conformation of rhazinilam 1
as well as that of phenylpyrrole 2.9 Moreover, the biaryl
unit is an important moiety present in a number of
antimitotic products which act generally as inhibitors of
Sch em e 1
Commercially available 2-bromophenylacetonitrile was
used as starting material to introduce alkyl groups in
the ortho position of the phenyl ring. Monoalkylation and
dialkylation were realized in good yields by reacting 1
or 2 equiv of LDA with the corresponding alkyl halides
in THF. This led to nitriles 6a , 6b,13 6c, 6d , and 6e14
which were reduced into the corresponding aldehydes
7a -e after treatment with diisobutylaluminum hydride
(DIBAH) in toluene and hydrolysis. The unstable alde-
hydes 7a -e were immediately subjected to the Horner-
(1) Linde, H. H. A. Helv. Chim. Acta 1965, 48, 1822,.
(2) Banerji, A.; Majumder, P. L.; Chatterjee, A. Phytochem. 1970,
9, 1491.
(3) Thoison, O.; Gue´nard, D.; Se´venet, T.; Kan-Fan, C.; Quirion, J .-
C.; Husson, H.-P.; Deverre, J .-R.; Chan, K. C.; Potier, P. C. R. Acad.
Sci. Paris II 1987, 304, 157.
(4) David, B.; Se´venet, T.; Morgat, M.; Gue´nard, D.; Moisand, A.;
Tollon, Y.; Thoison, O.; Wright,M. Cell Motil. Cytoskeleton 1994, 28,
317.
(5) Abraham D. J .; Rosenstein, R. D.; Lyon, R. L.; Fong, H. H. S.
Tetrahedron Lett. 1972, 10, 909.
(6) David, B.; Se´venet, T.; Thoison, O.; Awang, K.; Pa¨ıs, M.; Wright,
M.; Gue´nard, D. Biorg. Med. Chem. Lett. 1997, 7, 2155.
(7) Soufyane, M. Ph.D. Universite´ de Reims ChampagnesArdenne,
France, 1993.
(10) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed.
Engl. 1990, 29, 977.
(8) Alazard, J .-P.; Millet-Paillusson, C.; Gue´nard, D.; Thal, C. Bull.
Soc. Chim. Fr. 1996, 133, 251 and earlier reference cited therein.
(9) Molecular modeling studies were performed using MacroModel
(version 5.5) on a Silicon Graphics 4D/25 workstation. For reference
see: Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.
(11) Pascal, C.; Gue´ritte-Voegelein, F.; Thal, C.; Gue´nard, D. Synth.
Commun. 1997, 27, 1501.
(12) Pascal, C. Ph.D. Universite´ Paris XIsOrsay, France, 1997.
(13) Parham, W. E.; J ones, L. D. J . Org. Chem. 1976, 41, 1187.
(14) Mndzhoyan, S. L.; Kramer, M. S.; Akopyan, S. G.; Grigoryan,
M. M.; Ter-Zakharyan, Y. Z.; Agabayan, R. V.; Kazaryan, E. V. Pharm.
Chem. J . 1992, 26, 169.
S0022-3263(98)00697-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/08/1998

Notes
J . Org. Chem., Vol. 63, No. 18, 1998 6415
Sch em e 2
highly dipolar solvent such as DMF does not improve the
Stille coupling (data not shown). LiCl has been reported
to accelerate the cross-coupling reaction of organostan-
nanes and aryl bromides.17 When LiCl was used as an
additive in the coupling reaction of aryl bromide 9d , a
slightly higher yield of 7% was obtained. Likewise,
copper iodide known to improve yield and rate in the
Stille cross-coupling18 had no effect on the reaction. In
all the performed experiments, dimer 12 was also isolated
with a yield ranging from 10% (for the coupling reactions
with 9a and 9c) to about 40% for the coupling reactions
with the aryl bromides having a quaternary carbon in
the ortho position of the phenyl (9b, 9d , and 9e). The
formation of such a homocoupling product was already
mentioned in the literature and found to be due to the
presence of oxygen in the medium.19 However, in our
hands, the coupling reactions performed under argon
after six freeze-thaw cycles as previously described by
Farina et al.19 did not lead to a substantial increase in
the yield of the desired compounds.
This study shows that the structure of aryl bromides
9 decisively affects the yield of the Stille coupling reaction
going from 64% and 56% with the monoalkyl aryl
bromides 9a and 9c to less than 10% with the more
hindered cyclopentanyl (9e) and diethyl (9d ) derivatives.
It should also be noted that the use of the corresponding
aryl iodides instead of the aryl bromides 9a , 9b, and 9c
in the Stille reaction led to a higher yield in the
monoalkylated coupling products 11a (70% isolated yield)
and 11c (66% isolated yield) (data not shown). Unfor-
tunately, the yield in the dimethyl biphenyl 11b could
not be improved and the synthesis of the diethyl aryl
iodide corresponding to 9d was unsuccessful. As Suzuki
couplings are recommended in the case of hindered aryl
halides, we studied the reaction of aryl boronic acid with
the sterically hindered haloarene 9d in the presence of
base such as Cs2CO3 and Ba(OH)2.20 However, no cross-
coupling products could be isolated from the reaction
mixture. Because enough quantities of biphenyl products
11a -e were obtained to carry on the synthesis, no further
attempts were made to improve the yield of the cross
coupling reactions with the hindered aryl halides 9d and
9e.21
Sch em e 3
The NMR spectra of the two coupling products 11a and
11c clearly show the presence of two diastereoisomers
((R,aS/S,aR) and (R,aR/S,aS) configuration)22 whereas
compounds 11b, 11d , and 11e have one element of
asymmetry and are obtained as racemic atropisomers (aR
and aS configuration). Because of a possible diastereo-
selectivity during the final cyclization step, no attempts
have been made to separate the diastereoisomers of 11a
and 11c. Removal of the Boc group under acidic condi-
Wadsworth-Emmons (HWE) conditions.15 Treatment
with triethyl phosphonoacetate and NaH afforded selec-
tively trans-alkenes 8a -e with good yields. Catalytic
hydrogenation with PtO2 in ethanol led to aryl bromides
9a -e (Scheme 2).
We then performed different cross-coupling reactions
with N-(tert-butoxycarbonyl)-2-(trimethylstannyl)aniline
1016 and the aryl bromides 9a -e. From the palladium
catalysts assayed (PdBnCl(PPh3)2, PdCl2(CH3CN)2, or Pd-
(PPh3)4), benzyl[bis(triphenylphosphine)]palladium(II) chlo-
ride (PdBnCl(PPh3)2) was found to give the best yield of
the cross-coupled products. The reactions were carried
out in toluene and were usually complete within 13 h
giving 11a -e in yields ranging from 64% to 3% depend-
ing on the amount of steric hindrance in the arylbromides
9 (Scheme 3). We varied the conditions of the coupling
reaction with the diethyl derivative 9d . The use of a
(16) Salituro, F. G.; McDonald, I. A. J . Org. Chem. 1988, 53, 6138.
(17) Fujita, M.; Oka, H.; Ogura, K. Tetrahedron Lett. 1995, 36,
5247.
(18) Saa, J . M.; Martorell, G. J . Org. Chem. 1993, 58, 1963.
(19) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J . Org.
Chem. 1993, 58, 5434.
(20) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett. 1992, 207.
(21) Among the other methodologies which could be used to improve
the cross-coupling reactions of hindered biaryls is the “ligandless”
palladium-catalyzed reaction (for examples see: (a) Anderson, J . C.;
Namli, H.; Roberts, C. A. Tetrahedron 1997, 53, 15123. (b) Bumagin,
N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437. (c) Wallow, T. I.;
Novak, B. M. J . Org. Chem. 1994, 59, 5034.
(22) Two distinct signals corresponding to the alkyl groups at C-9
are observed at 1.22 and 1.08 ppm (2d, J ) 8 Hz, CH3) in the NMR
spectrum of 11a and at 0.88 and 0.67 ppm (2t, J ) 7 Hz, CH2CH3) in
the NMR spectra of 11c.
(15) For review see: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989,
89, 3.

6416 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
Sch em e 4
gests that bulky groups at carbon 9 make an important
contribution to tubulin binding. The increase in activity
going from compounds 4a , 4b, and 4c to 4d could thus
be due to the decrease of their conformational freedom
along the biphenyl axis. But the fact that the cyclopen-
tanyl derivative 4e is less active than the diethyl bi-
phenyl 4d rather suggests a direct interaction of the alkyl
groups with tubulin. The inactivity of dioxolane 5 in
comparison with the activity of the cyclopentanyl deriva-
tive 4e is consistent with the hypothesis of these hydro-
phobic interactions.
In summary, the synthesis of new ortho-substituted
bridged biphenyls which mimic the structure of rhazi-
nilam 1 was achieved for the first time. This result is of
importance because the stability of biphenyl molecules
in comparison to that of phenylpyrroles make these
compounds good candidates for structure-activity rela-
tionship studies in this series of antimitotic agents. We
will present soon the synthesis of other new biphenyl
analogues more active than rhazinilam 1.
Exp er im en ta l Section
tions led to the corresponding amino derivatives 13a -e
(Scheme 4). Subsequent methanolysis of the ester group
gave the amino acids 14a -e, and the synthesis was
completed by intramolecular cyclization of 14a -e in the
presence of EDCI23 and HOBT24 under high dilution
conditions to yield the five bridged biphenyl lactams 4a -
e.
As expected, cyclization of diastereomeric biphenyls
14a and 14c led with good yields to only one isomer, rac-
4a and rac-4c, respectively. Molecular modeling studies
show that the more favorable situation for intramolecular
cyclization is with the (R,aR/S,aS) isomer which is
therefore cyclized.25 Meanwhile, the unreacted diaste-
reoisomers (R,aS/S,aR) 14a and (R,aS/S,aR) 14c will
interconvert into the (R,aR/S,aS) isomers by rotation
around the phenyl-phenyl bond.
General methods were the same as previously described.26 All
reagents were commercially available except N-(tert-butoxy-
carbonyl)-2-(trimethylstannyl)aniline 10 which was prepared
according to ref 16.
Alk yla t ion of 2-Br om op h en yla cet on it r ile. 2-(2-Br o-
m op h en yl)p r op ion itr ile 6a . To a cold (-78 °C) solution of
LDA prepared from n-BuLi (8.73 mL, 13.9 mmol) and diisopro-
pylamine (2.14 mL, 15.24 mmol) in dry THF (40 mL) under
argon was added a solution of 2-bromophenylacetonitrile (1.65
mL, 12.70 mmol) in dry THF (20 mL). This mixture was stirred
for 20 min, and iodomethane (0.95 mL, 15 mmol) was added.
The solution was allowed to warm to room temperature and
stirred for 2.5 h. Addition of aqueous saturated NH4Cl, extrac-
tion with AcOEt, and drying (Na2SO4) followed by filtration,
concentration, and purification by column chromatography (98:2
heptane-AcOEt) afforded 2.4 g (90%) of 2-(2-bromophenyl)-
propionitrile 6a as a colorless oil: IR (CHCl3) 2250 cm-1 1H
;
NMR (250 MHz, CDCl3) δ 7.57 (m, 2H), 7.36 (t, J ) 7.0 Hz, 1H),
7.19 (t, J ) 7.0 Hz, 1H), 4.33 (q, J ) 7.0 Hz, 1H), 1.61 (d, J )
7.0 Hz, 3H) ppm; 13C NMR (62.5 MHz, CDCl3) δ 136.5, 133.4,
129.8, 128.5, 128.3, 122.6, 121.1, 31.4, 20.2 ppm; CIMS m/z 210-
212 (MH+•). Anal. Calcd for C9H7BrN: C, 51.71; H, 3.37; N,
6.70. Found: C, 51.54; H, 3.27; N, 6.55.
The 13C NMR spectra of 4b and 4d , realized at room
temperature, show the lack of signals corresponding to
some carbons of the B-ring and alkyl groups at C-9. On
the other hand, more signals than expected are present
in the spectra recorded at 263 K. These results clearly
indicate the presence of several conformers, in slow
equilibrium, due to the flexibility of the B-ring.
Besides the synthesis of new tricyclic hindered biphe-
nyl lactams, the aim of this study was to show that a
biphenyl could replace the phenylpyrrole group of rhazi-
nilam 1 in the interaction with tubulin. The activity of
compounds 4a to 4e was evaluated on the cold-induced
disassembly of microtubules as described earlier.6 It
should be noted that all the compounds have been
assayed under their racemic forms and their activities
compared to that of (-)-rhazinilam 1. The results show
that compounds 4b, 4c, 4d , and 4e have the capacity to
interact with tubulin in the same fashion as rhazinilam.
Compounds 4b, 4c, 4d , and 4e were respectively 20, 17,
2-(2-Br om op h en yl)-2-m eth ylp r op ion itr ile13 6b was ob-
tained from 2-bromophenylacetonitrile (1.65 mL, 12.70 mmol)
by the above procedure, but using n-BuLi (16.7 mL, 26.7 mmol),
27.9 mmol of diisopropylamine (3.9 mL) and 31.8 mmol of
iodomethane (2.0 mL). Purified by column chromatography
(96:4 heptane-AcOEt): yield 80% of a colorless oil. 6b: IR
1
(CHCl3) 2240 cm-1; H NMR (250 MHz, CDCl3) δ 7.66 (bd, J )
8.0 Hz, 1H), 7.48 (bd, J ) 8.0, 1H), 7.34 (bt, J ) 8.0 Hz, 1H),
7.19 (bt, J ) 8.0 Hz, 1H), 1.91 (s, 6H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 138.2, 135.7, 129.6, 128.0, 127.3, 123.4, 122.6, 37.4,
27.5 ppm; EIMS m/z 223-225 (M+•), 208-210. Anal. Calcd for
C
10H10BrN: C, 53.57; H, 4.50; N, 6.29. Found: C, 53.84; H, 4.45;
N, 6.19.
2-(2-Br om op h en yl)bu tyr on itr ile 6c was obtained from
2-bromophenylacetonitrile (3.2 mL, 24.6 mmol) by the above
procedure, but using n-BuLi (17.6 mL, 28.1 mmol), 30.6 mmol
of diisopropylamine (4.3 mL), and 51 mmol of iodoethane (4.08
mL). Purified by column chromatography (100:3.5 heptane-
8, and 16 times less active than rhazinilam 1 (IC50
)
AcOEt): yield 88% of a colorless oil. 6c: IR (CHCl3) 2250 cm-1
;
3µΜ) and compound 4a was inactive. Since 4d is a more
active disassembly inhibitor than 4b and 4c, this sug-
1H NMR (250 MHz, CDCl3) δ 7.59 (dd, J ) 8.0 and 1.0 Hz, 1H),
7.58 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.38 (bt, J ) 8.0, 1H), 7.20
(bt, J ) 8.0, 1H), 4.24 (q, J ) 8.0 and 5.0 Hz, 1H), 1.93 (m, 2H),
1.14 (t, J ) 7.0 Hz, 3H) ppm; 13C NMR (62.5 MHz, CDCl3) δ
136.0, 133.4, 129.7, 129.1, 128.2, 123.1, 120.0, 38.7, 27.8, 11.5
(23) Sheehan, J . C.; Cruickshang, P. A.; Boshart, G. L. J . Org. Chem.
1965, 26, 2525.
(24) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
(25) Molecular modeling using MM2 as force field showed that the
transition state for the (R,aR/S,aS) isomer was 3.6 kcal lower in energy
than that of the (R,aS/S,aR) isomer.
(26) Marder, R.; Dubois, J .; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Potier, P. Tetrahedron 1995, 51, 1985.

Notes
J . Org. Chem., Vol. 63, No. 18, 1998 6417
ppm; EIMS m/z 223-225 (M+•). Anal. Calcd for C10H10BrN: C,
53.60; H, 4.50; N, 6.25. Found: C, 54.15; H, 4.62; N, 6.08.
2-(2-Br om op h en yl)-2-eth ylbu tyr on itr ile 6d was obtained
from 2-bromophenylacetonitrile (3.3 mL, 25.5 mmol) by the
above procedure, but using n-BuLi (32 mL, 51 mmol), 51 mmol
of diisopropylamine (7.15 mL), and 102 mmol of iodoethane (8.16
mL). Purified by column chromatography (96:4 heptane-
δ 9.73 (s, 1H), 7.64 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.33 (dd, J )
8.0 and 2.0 Hz, 1H), 7.17 (td, J ) 8.0 and 2.0 Hz, 1H), 7.12 (dd,
J ) 8.0 and 2.0 Hz, 1H, 4.02 (t, J ) 7.0 Hz, 1H), 2.16 (m, 2H),
1.78 (m, 2H), 0.94 (t, J ) 7.0 Hz, 3H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 200.1, 136.4, 133.5, 129.8, 129.1, 128.0, 126.0, 59.1,
22.8, 11.7 ppm; EIMS m/z 227-229 (M+•).
2-(2-Br om op h en yl)-2-eth ylbu tyr a ld eh yd e 7d . Purified by
column chromatography (94:6 heptane-AcOEt): yield 73% of a
AcOEt): yield 94% of a colorless oil. 6d : IR (CHCl3) 2240 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.70 (dd, J ) 8.0 and 1.0 Hz, 1H),
7.62 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.34 (td, J ) 8.0 and 1 Hz,
1H), 7.18 (td, J ) 8.0 and 1.0 Hz, 1H), 2.66 (m, 2H), 2.09 (m,
2H), 0.93 (t, J ) 7.0 Hz, 6H) ppm; 13C NMR (62.5 MHz, CDCl3)
δ 136.1, 134.7, 131.9, 131.2, 129.4, 127.7, 122.6, 118.7, 52.4, 28.6,
colorless oil. 7d : IR (CHCl3) 1725 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 9.87 (s, 1H), 7.62 (d, J ) 8.0 Hz, 1H), 7.38 (m, 2H),
7.19 (m, 1H), 2.10 (m, 4H), 0.77 (t, J ) 7.0 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 204.1, 139.5, 134.9, 130.7, 129.3, 127.8,
123.8, 24.3, 7.9 ppm; CIMS m/z 255-257 (MH+).
2-(2-Br om op h en yl)cyclop en ta n eca r ba ld eh yd e 7e. Puri-
fied by column chromatography (100:3 heptane-AcOEt): yield
73% of a colorless oil. 7e: IR (CHCl3) 1725 cm-1; 1H NMR (250
MHz, CDCl3) δ 9.65 (s, 1H), 7.63 (dd, J ) 8.0 and 2.0 Hz, 1H),
7.41 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.34 (td, J ) 8.0 and 2.0 Hz,
1H), 7.18 (dd, J ) 8.0 and 2.0 Hz, 1H), 2.40 (m, 2H), 2.29 (m,
2H), 1.78 (m, 4H) ppm; 13C NMR (50 MHz, CDCl3) δ 202.1, 141.6,
134.6, 129.1, 128.8, 127.6, 124.6, 35.5, 34.1, 25.1 ppm; EIMS m/z
252-254 (M+•).
P r epar ation of Ester s 8a-e via th e Hor n er -Wadswor th -
Em m on s Rea ction . Gen er a l P r oced u r e. Triethylphospho-
noacetate (8.7 mmol) was added to a stirred suspension of NaH
(4.26 mmol) in dry THF (25 mL). After 10 min the aldehyde
7a , 7b, 7c, 7d , or 7e in dry THF (7 mL) was added. The reaction
mixture was stirred at room temperature for 16 h. After
hydrolysis and extraction with EtOAc, workup, and chromatog-
raphy, the corresponding esters were obtained.
10.4 ppm; CIMS m/z 252-254 (MH+). Anal. Calcd for C12H14
-
BrN: C, 57.16; H, 5.60; N, 5.56. Found: C, 57.29; H, 5.63; N,
5.58.
2-(2-Br om op h en yl)-2cyclop en ta n eca r bon itr ile14 6e was
obtained from 6-bromo-2-(2-bromophenyl)hexanenitrile prepared
from 2-bromophenylacetonitrile (200 µL, 1.54 mmol) by the above
procedure, but using n-BuLi (2.02 mL, 3.2 mmol), 3.39 mmol of
diisopropylamine (475 µL), and 1.54 mmol of 1,4-dibromobutane
(190 µL). The crude extract purified by column chromatography
(8:2 heptane-AcOEt) led to 285 mg of 6-bromo-2-(2-bromo-
phenyl)hexanenitrile: IR (CHCl3) 2240 cm-1; 1H NMR (250 MHz,
CDCl3) δ 7.58 (m, 2H), 7.38 (td, J ) 7.0 and 1 Hz, 1H), 7.21 (td,
J ) 7.0 and 1.0 Hz, 1H), 4.30 (q, J ) 9.0 and 6.0 Hz, 1H), 3.42
(t, J ) 7.0 Hz, 2H), 1.93 (m, 2H), 1.74 (m, 2H), 1.62 (m, 2H)
ppm; 13C NMR (62.5 MHz, CDCl3) δ 135.3, 133.5, 129.9, 129.0,
127.7, 123, 120.3, 37.2, 33.6, 32.8, 25.8 ppm; CIMS m/z 386-
390 ((MH+) + 57).
6-Bromo-2-(2-bromophenyl)hexanenitrile (151 mg, 0.46 mmol)
in dry THF (3 mL) was then added dropwise to a solution of
n-BuLi (0.31 mL) and diisopropylamine (0.80 mL) in dry THF
(10 mL) at -72 °C, and the mixture was stirred for 10 min.
Addition of aqueous saturated NH4Cl, extraction with AcOEt,
and drying (Na2SO4) followed by filtration, concentration and
purification by column chromatography (100:6 heptane-AcOEt)
afforded 106 mg (92%) of 2-(2-bromophenyl)-cyclopentanecar-
4-(2-Br om op h en yl)p en t-2-en oic Acid Eth yl Ester 8a .
Purified by column chromatography (97:3 heptane-AcOEt):
yield 86% of a colorless oil. 8a : IR (CHCl3) 1711 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.58 (dd, J ) 8.0 and 1.0, 1H), 7.29 (td, J )
8.0 and 1.0 Hz, 1H), 7.19 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.12 (dd,
J ) 16.0 and 5.0 Hz, 1H), 7.11 (td, J ) 8 and 1 Hz, 1H), 5.85
(dd, J ) 16 and 2 Hz, 1H), 4.19 (q, J ) 7.0 Hz, 2H), 4.15 (m,
1H), 1.42 (d, J ) 7.0 Hz, 3H), 1.29 (t, J ) 7 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 166.7, 151.0, 142.4, 133.1, 128.3, 127.9,
124.0, 120.9, 60.4, 40.6, 19.2, 14.3 ppm; CIMS m/z 283-285
(MH+).
1
bonitrile 6e as a colorless oil: IR (CHCl3) 2243 cm-1; H NMR
(250 MHz, CDCl3) δ 7.67 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.43 (dd,
J ) 8.0 and 1.0 Hz, 1H), 7.32 (td, J ) 8.0 and 1 Hz, 1H), 7.12
(td, J ) 8 and 1 Hz, 1H), 2.74 (m, 2H), 2.20 (m, 2H), 2.03 (m,
2H), 1.96 (m, 2H) ppm; 13C NMR (62.5 MHz, CDCl3) δ 137.6,
135.3, 129.6, 127.8, 127.6, 123.1, 47.7, 38.3, 23.8 ppm; CIMS m/z
250-252 (MH+).
4-(2-Br om op h en yl)-4-m eth ylp en t-2-en oic Acid Eth yl Es-
ter 8b. Purified by column chromatography (96:4 heptane-
AcOEt): yield 92% of a colorless oil. 8b: IR (CHCl3) 1706 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.58 (dd, J ) 8.0 and 1.0 Hz, 1H),
7.43 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.39 (td, J ) 8.0 and 1.0 Hz,
1H), 7.28 (d, J ) 16.0 Hz, 1H), 7.11 (td, J ) 8.0 and 1.0 Hz, 1H),
5.70 (d, J ) 16 Hz, 1H), 4.11 (q, J ) 7.0 Hz, 2H), 1.61 (s, 6H),
1.29 (t, J ) 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.1,
157.1, 144.0, 135.5, 128.6, 128.0, 127.4, 123.6, 119.2, 60.3, 42.3,
28.3, 14.3 ppm; CIMS m/z 297-299 (MH+).
P r ep a r a tion of Ald eh yd es 7a -e. Gen er a l P r oced u r e. A
solution of 1 M DIBAL-H (19 mmol) in hexane was added
dropwise to a solution of nitriles 6a , 6b, 6c, 6d , or 6e (9.6 mmol)
in toluene (30 mL) at -70 °C. The mixture was first stirred at
-70 °C for 30 min and then at room temperature for 1 h
whereupon ethyl formate was added and stirring was continued
for 15 min. The mixture was poured into a saturated ammonium
chloride solution, and aqueous sulfuric acid was added. The
aqueous phase was extracted with AcOEt, and the organic phase
was dried over Na2SO4 and filtered. Evaporation to dryness
furnished the crude material which was purified by column
chromatography leading to aldehydes 7a , 7b, 7c, 7d , or 7e.
2-(2-Br om op h en yl)p r op ion a ld eh yd e 7a . Purified by col-
umn chromatography (100:3 heptane-AcOEt): yield 44% of a
4-(2-Br om op h en yl)h ex-2-en oic Acid Eth yl Ester 8c. Pu-
rified by column chromatography (100:3 heptane-AcOEt): yield
80% of a colorless oil. 8c: IR (CHCl3) 1709 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.62 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.35 (td, J )
8.0 and 2.0 Hz, 1H), 7.26 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.14 (td,
J ) 8.0 and 1.0 Hz, 1H), 7.07 (dd, J ) 16.0 and 7.0 Hz, 1H),
5.89 (dd, J ) 16 and 1, 1H), 4.24 (q, J ) 8.0, 2H), 4.01 (m, 1H),
1.88 (m, 2H), 1.33 (t, J ) 8.0 Hz, 3H), 0.98 (t, J ) 7.0 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 166.6, 150.1, 141.2, 133.1,
128.5, 128.0, 127.9, 125.1, 121.5, 60.3, 48.0, 27.5, 14.3, 11.9 ppm;
CIMS m/z 297-299 (MH+).
4-(2-Br om op h en yl)-4-eth ylh ex-2-en oic Acid Eth yl Ester
8d . Purified by column chromatography (94:6 heptane-Et2O):
yield 60% of a colorless oil. 8d : IR (CHCl3) 1706 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.58 (d, J ) 8.0 Hz, 1H), 7.30 (m, 2H), 7.25
(d, J ) 16.0 Hz, 1H), 7.09 (td, J ) 8.0 and 2.0 Hz, 1H), 5.70 (d,
J ) 16.0 Hz, 1H), 4.20 (q, J ) 8.0 Hz, 2H), 2.21 (m, 2H), 1.99
(m, 2H), 1.30 (t, J ) 8.0 Hz, 3H), 0.74 (t, J ) 8.0 Hz, 6H) ppm;
13C NMR (75 MHz, CDCl3) δ 167.1, 156.1, 142.8, 135.8, 130.5,
128.2, 127.0, 123.7, 120.0, 60.4, 49.6, 28.5, 14.5, 8.7 ppm; CIMS
m/z 325-327 (MH+). Anal. Calcd for C16H21BrO2: C, 59.09; H,
6.51; O, 9.84. Found: C, 58.94; H, 7.09; O, 9.48.
colorless oil. 7a : IR (CHCl3) 1725 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 9.75 (s, 1H), 7.65 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.34
(dd, J ) 8.0 and 2.0 Hz, 1H), 7.17 (td, J ) 8.0 and 2.0 Hz, 1H),
7.12 (dd, J ) 8.0 and 2.0 Hz, 1H, 4.18 (q, J ) 7.0 Hz, 1H), 1.44
(d, J ) 7.0 Hz, 3H) ppm; 13C NMR (62.5 MHz, CDCl3) δ 200.3,
133.5, 129.3, 129.2, 128.2, 125.2, 52.0, 14.1 ppm; EIMS m/z 212-
214 (M+•).
2-(2-Br om op h en yl)-2-m eth ylp r op ion a ld eh yd e 7b. Puri-
fied by column chromatography (100:3 heptane-AcOEt): yield
80% of a colorless oil. 7b: IR (CHCl3) 1725 cm-1; 1H NMR (250
MHz, CDCl3) δ 9.80 (s, 1H), 7.59 (bd, J ) 8.0 Hz, 1H), 7.42 (dd,
J ) 8.0 and 2.0 Hz, 1H), 7.36 (bt, J ) 8.0 Hz, 1H), 7.18 (td, J )
8.0 and 2.0 Hz, 1H, 1.50 (s, 6H,) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 203.0, 142.3, 134.5, 129.2, 128.7, 127.9, 123.5, 51.8,
23.2 ppm; CIMS m/z 227-229 (MH+).
3-[1-(2-Br om op h en yl)cyclop en tyl]a cr ylic Acid Eth yl Es-
ter 8e. Purified by column chromatography (100:4 heptane-
2-(2-Br om op h en yl)bu tyr a ld eh yd e 7c. Purified by column
chromatography (100:3 heptane-AcOEt): yield 69% of a color-
less oil. 7c: IR (CHCl3) 1725 cm-1; 1H NMR (250 MHz, CDCl3)
AcOEt): yield 78% of a colorless oil. 8e: IR (CHCl3) 1706 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.58 (dd, J ) 8.0 and 1.0 Hz, 1H),

6418 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
7.41 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.28 (td, J ) 8.0 and 1.0 Hz,
1H), 7.18 (d, J ) 16.0 Hz, 1H), 7.10 (td, J ) 8.0 and 1.0 Hz, 1H),
5.52 (d, J ) 16.0 Hz, 1H), 4.15 (q, J ) 7.0 Hz, 2H), 2.33 and
2.14 (2m, 4H), 1.75 (m, 4H), 1.26 (t, J ) 7 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 166.0, 155.0, 144.6, 135.2, 128.7, 128.3,
127.2, 124.4, 119.7, 60.3, 54.7, 38.4, 23.8, 14.3 ppm; CIMS m/z
323-325 (MH+).
Hyd r ogen a tion of Ester s 8a -e. Gen er a l P r oced u r e.
Esters 8a , 8b, 8c, 8d , and 8e (0.27 mmol) in ethanol (5 mL)
were hydrogenated over PtO2 (10 mg) for 16 h. After filtration
and evaporation of the solvent, the crude extract is chromato-
graphed to give respectively compounds 9a , 9b, 9c, 9d , and 9e.
4-(2-Br om op h en yl)p en ta n oic Acid Eth yl Ester 9a . Puri-
fied by column chromatography (9:1 heptane-AcOEt): yield 47%
of a colorless oil. 9a : IR (CHCl3) 1725 cm-1; 1H NMR (250 MHz,
CDCl3) δ 7.56 (d, J ) 8.0 Hz, 1H), 7.30 (d, J ) 8.0 Hz, 1H), 7.27
(t, J ) 8.0 Hz, 1H), 7.06 (m, 1H), 4.10 (q, J ) 7.0 Hz, 2H), 3.32
(m, 1H), 2.25 (m, 2H), 1.97 (q, J ) 7.0 Hz, 2H), 1.23 (d, J ) 7.0
Hz, 3H), 1.22 (t, J ) 7.0 Hz, 3H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 173.6, 145.3, 133.0, 127.8, 127.7, 127.3, 122.9, 60.4,
37.6, 32.4, 21.3, 14.3 ppm; CIMS m/z 285-287 (MH+).
LiCl P r oced u r e. A round-bottom flask containing a solution
of 9c (40 mg, 0.12 mmol in dry THF (4 mL) was degassed under
argon. To this solution was added N-(tert-butoxycarbonyl)-2-
(trimethylstannyl)aniline 10 (43.6 mg, 0.13 mmol), PdBnCl-
(PPh3)2 (4.6 mg, 0.006 mmol), and LiCl (20.6 mg, 0.49 mmol).
The resulting solution was allowed to stir at 110 °C for 16 h.
The reaction was then diluted in AcOEt and washed with NH4-
OH (10%). The organic fraction was dried and concentrated to
give a mixture which was chromatographed.
4-(2′-ter t-Bu toxyca r bon yla m in obip h en yl-2-yl)p en ta n o-
ic Acid Eth yl Ester 11a (R,a S/S,a R a n d R,a R/S,a S). Purified
by preparative thin-layer chromatography (9:1 heptane-AcO-
Et): white amorphous solid (yield 64% from 9a ). 11a : IR
(CHCl3) 3400, 1725 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.19 and
8.11 (2d, J ) 8.0 Hz, 1H), 7.47-7.28 (m, 4H), 7.14 (d, J ) 8.0
Hz, 1H), 7.08 (d, J ) 8.0 Hz, 1H), 6.19 and 6.08 (2s, 1H), 4.04
and 3.99 (2q, J ) 7 Hz, 2H), 2.56 (m, 1H), 2.10 (m, 1H), 1.94 (m,
2H), 1.79 (m, 1H), 1.45 (s, 9H), 1.22 and 1.08 (2d, J ) 7.0 Hz,
3H), 1.19 and 1.17 (2t, J ) 7 Hz, 3H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 173.6, 152.6, 145.3, 137.0, 136.8, 136.1, 130.6, 130.4,
130.2, 129.1, 128.5, 128.4, 126.7, 126.6, 126.4, 126.1, 122.7, 122.5,
118.7, 80.5, 60.3, 35.3, 34.6, 35.0, 34.0, 32.9, 32.5, 28.4, 28.3,
23.6, 22.1, 14.3 ppm; CIMS m/z 398 (MH+). Anal. Calcd for
4-(2-Br om op h en yl)-4-m eth ylp en ta n oic Acid Eth yl Ester
9b . Purified by column chromatography (97:3 heptane-
AcOEt): yield 43% of a colorless oil. 9b: IR (CHCl3) 1730 cm-1
;
C
24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C, 72.71; H, 8.12;
N, 3.51.
4-(2′-ter t-Bu toxyca r bon yla m in obip h en yl-2-yl)-4-m eth yl-
1H NMR (250 MHz, CDCl3) δ 7.62 (dd, J ) 8.0 and 1.0 Hz, 1H),
7.39 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.28 (td, J ) 8.0 and 1.0 Hz,
1H), 7.07 (td, J ) 8.0 and 1.0 Hz, 1H), 4.09 (q, J ) 7.0 Hz, 2H),
2.43 (m, 2H), 2.03 (m, 2H), 1.53 (s, 6H), 1.24 (t, J ) 7.0 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 173.9, 144.0, 135.9, 129.3,
127.9, 125.9, 122.6, 60.3, 39.6, 34.7, 28.8, 28.5, 14.3 ppm; CIMS
m/z 299-301 (MH+).
p en ta n oic Acid Eth yl Ester 11b (a S/a R). Purified by pre-
parative thin-layer chromatography (9:1 heptane-AcOEt): yel-
low oil containing 11b (19% from 9b) and 12. 11b: IR (CHCl3)
1
3418, 1725 cm-1; H NMR (250 MHz, CDCl3) δ 8.08 (d, J ) 8.0
Hz, 1H), 7.41 (d, J ) 8.0 Hz, 1H), 7.35 (m, 3H), 7.08 (m, 3H),
5.99 (bs, 1H), 4.09 (q, J ) 7.0 Hz, 2H), 2.12-1.78 (m, 4H), 1.45
4-(2-Br om op h en yl)h exa n oic Acid Eth yl Ester 9c. Puri-
fied by column chromatography (97:3 heptane-AcOEt): yield
92% of a colorless oil. 9d : IR (CHCl3) 1725 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.62 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.36 (td, J )
8.0 and 2.0 Hz, 1H), 7.26 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.12 (td,
J ) 8.0 and 2.0 Hz, 1H), 4.15 (q, J ) 8.0 Hz, 2H), 3.27 (m, 1H),
2.20 (m, 3H), 1.95 (m, 3H), 1.30 (t, J ) 8.0 Hz, 3H), 0.88 (t, J )
8.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.6, 143.7,
132.8, 128.4, 127.8, 127.5, 126.0, 60.3, 44.5, 32.6, 29.3, 14.3, 11.7
ppm; EIMS m/z 298-300 (M+.).
4-(2-Br om op h en yl)-4-eth ylh exa n oic Acid Eth yl Ester 9d .
Purified by column chromatography (96:4 heptane-AcOEt):
yield 60% of a colorless oil. 9e: IR (CHCl3) 1725 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.60 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.34 (dd,
J ) 8.0 and 2.0 Hz, 1H), 7.25 (td, J ) 8.0 and 2.0 Hz, 1H), 7.03
(td, J ) 8.0 and 2.0 Hz, 1H), 4.08 (q, J ) 8.0, 2H), 2.33 (m, 2H),
1.99 (m, 6H), 1.29 (t, J ) 8, 3H), 0.70 (t, J ) 8.0 Hz, 6H) ppm;
13C NMR (75 MHz, CDCl3) δ 174.0, 143.3, 136.4, 130.2, 127.7,
127.0, 122.6, 60.3, 44.5, 29.9, 28.8, 26.3, 14.3, 8.5 ppm; CIMS
m/z 327-329 (MH+).
(s, 9H), 1.21 (t, J ) 7.0 Hz, 3H), 1.20 and 1.07 (s, 6H) ppm; 13
C
NMR (62.5 MHz, CDCl3) δ 173.9, 152.7, 146.0, 136.6, 136.2,
134.0, 133.4, 132.9, 130.3, 128.9, 128.5, 126.5, 122.0, 119.1, 80.5,
60.4, 39.6, 39.1, 30.7, 29.7, 28.4, 14.3 ppm; CIMS m/z 412 (MH+).
4-(2′-ter t-Bu t oxyca r b on yla m in ob ip h en yl-2-yl)h exa n o-
ic Acid Eth yl Ester 11c (R,a S/S,a R a n d R,a R/S,a S). Purified
by preparative thin-layer chromatography (8:2 heptane-AcO-
Et): yield 56% (from 9c) of a white amorphous solid. 11c: IR
(CHCl3) 3410, 1725 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.17 (t,
J ) 8.0 Hz, 1H), 7.30 (m, 5H), 7.12 (m, 1H), 7.04 (m, 1H), 6.19
and 6.05 (2s, 1H), 4.02 (q, J ) 7.0 Hz, 2H), 2.35 (m, 1H), 2.09-
1.50 (m, 6H), 1.42 (s, 9H), 1.16 (t, J ) 7.0 Hz, 3H), 0.88 and
0.67 (2t, J ) 7.0 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ
180.1, 174.0, 152.5, 144.1, 143.9, 137.6, 136.0, 135.1, 130.6, 129.0,
128.9, 128.4, 126.6 122.4, 122.3, 118.4, 80.4, 60.3, 41.8, 41.7, 32.7,
32.3, 31.8, 30.4, 29.9, 28.9, 28.30, 28.27, 14.3, 12.5, 11.8 ppm;
CIMS m/z 412 (MH+). Anal. Calcd for C25H33NO4: C, 72.96;
H, 8.08; N, 3.40. Found: C, 73.24; H, 8.25; N, 3.35.
4-(2′-ter t-Bu t oxyca r b on yla m in ob ip h en yl-2-yl)-4-et h yl-
h exa n oic Acid Eth yl Ester 11d (a S/a R). LiCl procedure.
Purified by preparative thin-layer chromatography (7:3 hex-
anes-Et2O): yellow oil containing 11d (7% from 9d )) and 12.
3-[1-(2-Br om op h en yl)cyclop en tyl]p r op ion ic Acid Eth yl
Ester 9e. Purified by column chromatography (100:4 heptane-
AcOEt): yield 89% of a colorless oil. 9e: IR (CHCl3) 1725 cm-1
;
1
1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J ) 8.0 and 1.0 Hz, 1H),
7.28 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.22 (td, J ) 8.0 and 1.0 Hz,
1H), 7.04 (td, J ) 8.0 and 1.0 Hz, 1H), 4.02 (q, J ) 7.0 Hz, 2H),
2.23 (m, 3H), 1.97 (m, 5H), 1.73 (m, 4H), 1.21 (t, J ) 7.0 Hz,
3H) ppm; 13C NMR (62.5 MHz, CDCl3) δ 173.8, 145.6, 135.4,
130.1, 127.7, 126.9, 123.2, 60.3, 51.5, 37.5, 23.2, 14.2 ppm; CIMS
m/z 325-327 (MH+).
11d : IR (CHCl3) 3250, 1725 cm-1; H NMR (300 MHz, CDCl3)
δ 8.12 (bd, J ) 8.0 Hz, 1H), 7.51 (bd, J ) 8 Hz, 1H), 7.20 (m,
6H), 6.02 (s, 1H), 4.09 (q, J ) 8.0 Hz, 2H), 1.70 (m, 4H), 1.50
(m, 4H), 1.42 (s, 9H), 1.22 (t, J ) 8.0 Hz, 3H), 0.69 and 0.60 (t,
J ) 8.0 Hz, 6H) ppm; 13C NMR (62.5 MHz, CDCl3) δ 174.1, 153.0,
144.7, 137.2, 133.4, 133.3, 130.6, 130.1, 128.3, 128.2, 126.4, 121.7,
118.6, 80.4, 60.4, 45.9, 31.2, 29.7, 28.5, 28.38, 28.3, 14.4, 8.7 ppm;
CIMS m/z 440 (MH+).
Stille Cou p lin g betw een (2-Tr im eth ylsta n n a n ylp h en yl)-
ca r ba m ic Acid ter t-Bu tyl Ester 10 a n d Br om id es 9a to 9e.
Gen er a l P r oced u r e. In a two-necked round-bottom flask, the
bromide 9a , 9b, 9c, 9d , or 9e (0.31 mmol) and PdBnCl(PPh3)2
(0.016 mmol) were stirred in dry toluene (8 mL) at room
temperature for 10 min. N-(tert-Butoxycarbonyl)-2-(trimethyl-
stannyl)aniline 1014 (0.34 mmol) was then added. The solution
was stirred at 110 °C for 13 h. After cooling, the mixture was
hydrolyzed and extracted with EtOAc. The organic layer was
further dried with Na2SO4 and filtrated. The mixture obtained
after removal of the solvent was chromatographed on silica gel.
Although most of the dimer 12 could be removed by chroma-
tography, some amount of it remains in the purified fraction of
the coupling products 11b, 11c, and 11d . The yield of these
coupling products is thus given taking into account the amount
of 12 calculated from the 1H NMR spectra.
4-[1-(2′-ter t-Bu t oxyca r b on yla m in ob ip h en yl-2-yl)cyclo-
p en tylp r op ion ic Acid Eth yl Ester 11e (a S/a R). Purified by
column chromatography (100:7 heptane-AcOEt): yellow oil
containing 11e (6% from 9e) and 12. 11e: IR (CHCl3) 3419,
1725 cm-1 1H NMR (250 MHz, CDCl3) δ 8.10 (d, J ) 8.0 Hz,
;
1H), 7.30 (m, 4H), 7.15 (bd, J ) 8.0 Hz, 1H), 7.04 (m, 2H), 6.06
(bs, 1H), 4.04 (q, J ) 7.0 Hz, 2H), 2.12-1.40 (m, 12H), 1.42 (s,
9H), 1.22 (t, J ) 7.0 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ
174.0, 152.8, 146.5, 136.9, 136.4, 132.3, 130.5, 130.1, 128.3, 127.9,
126.5, 121.8, 119.1, 80.6, 60.4, 51.8, 37.5, 36.6, 32.8, 30.9, 28.4,
22.7, 21.9, 14.3 ppm; EIMS m/z 437 (M+•).
2,2′-(Bis(N-ter t-bu toxyca r bon yla m in e)bip h en yl 12. Iso-
lated as a white amorphous solid from the above purifications.
yield: 10% from the cross-coupling reaction of 9a with 10, 40%
from the cross coupling reaction of 9b, 9d -9e with 10. 12: IR

Notes
J . Org. Chem., Vol. 63, No. 18, 1998 6419
(CHCl3) 3412, 1725 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.22 (d,
J ) 7.0 Hz, 2H), 7.43 (m, 2H), 7.15 (m, 4H), 6.26 (s, 2H), 1.54 (s,
18H) ppm; 13C NMR (75 MHz, CDCl3) δ 152.9, 136.6, 130.6,
129.6, 129.1, 126.5, 123.4, 120.1, 80.8, 28.4 ppm; EIMS m/z 384
(M+•).
P r ep a r a tion of Am in es 13a -e. Gen er a l P r oced u r e. To
a solution of biaryl 11a , 11b (87%), 11c, 11d (90%), or 11e (96%)
(0.136 mmol) in methylene chloride (1 mL) was added at 0 °C 1
mL of trifluoroacetic acid. The mixture was stirred at 0 °C for
15 min. After neutralization with aqueous saturated Na2CO3
and extraction with AcOEt, the organic phase was dried and
filtered and the solvent was removed to give the crude extract
which was chromatographed.
4-(2′-Am in obip h en yl-2-yl)p en ta n oic Acid Eth yl Ester
13a (R,a S/S,a R a n d R,a R/S,a S). Purified by preparative thin-
layer chromatography (8:2 heptane-AcOEt): yield 86% of a
white amorphous solid. 13a : IR (CHCl3) 3450, 3350, 1725, 1620
cm-1; 1H NMR (250 MHz, CDCl3) δ 7.40-7.19 (m, 6H), 7.09 (d,
J ) 8.0, 1H), 6.95 (t, J ) 8.0, 1H), 4.06 (q, J ) 7.0, 2H), 3.87 (bs,
2H), 2.63 (m, 1H), 2.07-1.82 (m, 4H), 1.15 (m, 6H) ppm; 13C
NMR (62.5 MHz, CDCl3) δ 173.9, 145.4, 144.0, 135.8, 131.2,
130.6, 130.4, 128.4, 126.6, 126.4, 126.3, 126.1, 118.2, 117.9, 115.1,
114.9, 61.1, 60.4, 35.0, 34.8, 33.6, 33.0, 32.6, 32.5, 23.2, 22.3,
14.2, 14.0 ppm; EIMS m/z 297 (M+•).
N HCl. After extraction with AcOEt, the organic layers were
dried over Na2SO4. After removal of the solvent, the crude
extracts were chromatographed if necessary.
4-(2′-Am in obip h en yl-2-yl)p en ta n oic Acid 14a (R,a S/S,a R
a n d R,a R/S,a S). Yield: 100% of a white amorphous solid.
14a : IR (CHCl3) 3488, 3394, 1713, 1612 cm-1 1H NMR (250
;
MHz, CDCl3) δ 7.35-7.25 (m, 5H), 6.98 (d, J ) 8.0 Hz, 1H), 6.64
(m, 2H), 5.12 (bs, 3H), 2.61 (m, 1H), 2.09 (m, 2H), 1.80 (m, 2H),
1.17 and 1.15 (2d, J ) 7.0 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 179.8, 145.1, 144.0, 143.7, 138.4, 130.6, 130.4, 128.5,
127.2, 126.9, 126.3, 126.6, 126.4, 126.1, 118.2, 115.4, 115.0, 34.9,
34.5, 33.4, 32.7, 32.0, 23.2, 22.4 ppm; CIMS m/z 270 (MH+).
4-(2′-Am in obip h en yl-2-yl)-4-m eth ylp en ta n oic Acid 14b
(a S/a R). Purified by preparative thin-layer chromatography
(92:8 CH2Cl2-MeOH): yield 91% of a white amorphous solid.
14b: IR (CHCl3) 3394, 1730, 1612 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 7.47 (d, J ) 8.0 Hz, 1H), 7.32 (J ) 8.0 and 1.0 Hz, 1H),
7.23 (bt, J ) 8.0 Hz, 1H), 7.16 (bt, J ) 8.0 Hz, 1H), 7.03 (2bd, J
) 8.0 Hz, 2H), 6.79 (bt, J ) 8.0 Hz, 1H), 6.73 (bd, J ) 8.0 Hz,
1H), 5.10 (bs, 3H), 2.01 (m, 4H), 1.22 (s, 3H), 1.19 (s, 3H) ppm;
13C NMR (62.5 MHz, CDCl3) δ 181, 146.0, 143.6, 138.1, 133.0,
130.9, 130.6, 128.6, 128.5, 128.0, 126.6, 118.1, 115.6, 50.9, 39.5,
31.3, 30.2, 29.5 ppm; CIMS m/z 284 (MH+).
4-(2′-Am in obip h en yl-2-yl)h exa n oic Acid 14c (R,a S/S,a R
a n d R,a R/S,a S). Purified by preparative thin-layer chroma-
tography (91:9 CH2Cl2-MeOH): yield 96% of a white amorphous
4-(2′-Am in obip h en yl-2-yl)-4-m eth ylp en ta n oic Acid Eth yl
Ester 13b (a S/a R). Purified by column chromatography (6:4
heptane-AcOEt): yield 78% of a white amorphous solid. 13b:
solid. 14c: IR (CHCl3) 3400, 1720, 1600 cm-1 1H NMR (250
;
IR (CHCl3) 3494, 3394, 1725, 1613 cm-1
;
1H NMR (250 MHz,
MHz, CDCl3) δ 7.30 (m, 5H), 7.05 (d, J ) 8.0 Hz, 1H), 6.84 (m,
2H), 6.40 (s, 3H), 2.61 (m, 1H), 2.19 (m, 2H), 1.95 (m, 2H), 1.63
(2q, J ) 7.0 Hz, 2H), 0.84 and 0.82 (2t, J ) 7.0 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 143.5, 138.6, 130.4, 130.3, 130.1,
129.9, 128.0, 127.8, 126.6, 126.0, 125.9, 117.6, 114.9, 114.7, 41.1,
30.9, 30.2, 29.6, 28.5, 12.4, 11.8, 11.5 ppm; CIMS m/z 284 (MH+).
4-(2′-Am in obip h en yl-2-yl)-4-eth ylh exa n oic Acid 14d (a S/
a R). Purified by preparative thin-layer chromatography (92:8
CH2Cl2-MeOH): yield 77% of a white amorphous solid. 14d :
CDCl3) δ 7.49 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.33 (td, J ) 8.0 and
1.0 Hz, 1H), 7.22 (td, J ) 8.0 and 1.0 Hz, 1H), 7.16 (td, J ) 8.0
and 1.0 Hz), 1H, 7.04 (2dd, J ) 8.0 and 1.0 Hz, 2H), 6.78 (td, J
) 8.0 and 1.0 Hz, 1H), 6.72 (bd, J ) 8.0 Hz, 1H), 4.08 (q, J ) 7.0
Hz, 2H), 3.42 (bs, 2H), 2.09 (m, 3H), 1.82 (m, 1H), 1.28 (s, 3H),
1.22 (t, J ) 7.0 Hz, 3H), 1.18 (s, 3H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 174.6, 146.1, 144.1, 138.2, 133.1, 130.7, 130.6, 128.6,
127.8, 126.5, 126.0, 117.5, 115.1, 60.3, 39.5, 38.9, 30.9, 29.9, 29.4,
14.3 ppm; CIMS m/z 312 (MH+).
1
IR (CHCl3) 3400, 1712, 1612 cm-1; H NMR (200 MHz, CDCl3)
4-(2′-Am in obip h en yl-2-yl)h exa n oic Acid Eth yl Ester 13c
(R,a S/S,a R a n d R,a R/S,a S). Purified by column chromatog-
raphy (7:3 heptane-AcOEt): yield 62% of a white amorphous
solid. 13c: IR (CHCl3) 34580, 3400, 1725, 1618 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.30 (m, 5H), 6.98 (m, 1H), 6.79 (m, 2H),
4.02 (2q, J ) 7.0 Hz, 2H), 3.49 (bs, 2H), 2.52 (m, 1H), 2.18-1.58
(m, 6H), 1.20 (2t, J ) 7.0 Hz, 3H), 0.80 (2t, J ) 7.0 Hz, 3H)
ppm; 13C NMR (62.5 MHz, CDCl3) δ 174.0, 144.1, 139.0, 130.9,
130.8, 130.5, 130.4, 128.4, 128.2, 126.8, 126.3, 117.9, 117.8, 115.0,
60.2, 41.6, 32.9, 32.5, 31.5, 30.6, 30.1, 29.1, 14.2, 12.3, 12.0 ppm;
CIMS m/z 312 (MH+).
δ 7.59 (bd, J ) 8.0 Hz, 1H), 7.43 (t, J ) 8.0 Hz, 1H), 7.37 (d, J
) 8.0 Hz, 1H), 7.27 (t, J ) 8.0 Hz, 1H), 7.14 (m, 2H), 6.91 (m,
2H), 5.40 (bs, 3H), 2.12-1.64 (m, 8H), 0.85 and 0.75 (t, J ) 7.0
Hz, 6H) ppm; 13C NMR (60 MHz, CDCl3) δ 144.5, 143.3, 138.3,
133.3, 131.0, 130.4, 129.7, 128.4, 127.8, 126.4, 118.4, 115.9, 45.4,
31.2, 30.8, 27.8, 27.2, 8.5, 8.3 ppm; EIMS m/z 311 (M+•).
3-[1-(2′-Am in obip h en yl-2-yl)cyclop en tyl)]p r op ion ic Acid
14e (a S/a R). Purified by preparative thin-layer chromatogra-
phy (92:8 CH2Cl2-MeOH): yield 84% of a white amorphous
solid. 14e: IR (CHCl3) 3400, 1725 cm-1 1H NMR (250 MHz,
;
CDCl3) δ 7.34 (t, J ) 8.0 Hz, 1H), 7.28 (d, J ) 8.0 Hz, 1H), 7.22
(t, J ) 8.0 Hz, 1H), 7.14 (t, J ) 8.0 Hz, 1H), 7.05 (m, 2H), 6.78
(t, J ) 8.0 Hz, 1H), 6.72 (d, J ) 8.0 Hz, 1H), 5.52 (bs, 3H), 2.01-
1.57 (3m, 12H) ppm; 13C NMR (62.5 MHz, CDCl3) δ 146.5, 143.8,
138.2, 132.4, 131.0, 130.0, 129.8, 128.4, 127.4, 126.5, 118.0, 115.6,
51.7, 38.6, 36.0, 33.0, 31.7, 22.6, 22.4 ppm; CIMS m/z 310 (MH+).
Cycliza tion of Am in o Acid s 14a -e. Gen er a l P r oced u r e.
A solution of 14a , 14b, 14c, 14d , or 14e (0.177 mmol) and NEt3
(0.177 mmol) in dry CH2Cl2 (10 mL) was added dropwise to a
solution of EDCI (0.177 mmol) and HOBT (0.177 mmol) in dry
CH2Cl2 (150 mL) at 0 °C. The mixture was stirred for 84 h.
After evaporation of the solvent, the solid mixture was dissolved
in AcOEt and the solution was washed with aqueous saturated
Na2CO3 and water. After drying over Na2SO4 and filtration, the
organic phase was evaporated. The crude extract was then
chromatographed to give compound 4a , 4b, 4c, 4d , or 4e.
9-Meth yl-5,7,8,9-tetr ah ydr o-5-azadiben zo[a ,c]cyclon on en -
6-on e 4a (R,a R/S,a S). Purified by preparative thin-layer
chromatography (97:3 CH2Cl2-MeOH): yield 71% of a white
amorphous solid. 4a : IR (CHCl3) 3381, 1665 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.40 (m, 7H), 6.96 (d, J ) 8.0 Hz, 1H), 6.60 (bs,
1H), 2.42 (m, 1H), 2.14 (m, 2H), 1.81 (m, 2H), 1.23 (d, J ) 7.0
Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) δ 176.4, 144.0, 129.3,
129.0, 128.7, 127.7, 126.1, 126.0, 37.0, 36.4, 33.9, 23.1 ppm; EIMS
m/z 251 (M+•); HRMS calcd for C17H17NO (MH+) 251.1310, found
251.1319.
4-(2′-Am in obip h en yl-2-yl)-4-eth ylh exa n oic Acid Eth yl
Ester 13d (a S/a R). Purified by column chromatography (8:2
hexanes-Et2O): yield 95% of a white amorphous solid. 13d :
IR (CHCl3) 3488, 3400, 1725, 1613 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.48 (dd, J ) 8.0 and 2.0 Hz, 1H), 7.33 (td, J ) 8.0 and
2.0 Hz, 1H), 7.23 (td, J ) 8.0 and 2.0 Hz, 1H), 7.14 (td, J ) 8.0
and 2.0 Hz, 1H), 7.02 (m, 2H), 6.72 (m, 2H), 4.10 (q, J ) 8.0 Hz,
2H), 3.42 (s, 2H), 1.89 (m, 4H), 1.63 (m, 4H), 1.24 (t, J ) 8.0 Hz,
3H), 0.69 (t, J ) 8.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
174.4, 144.8, 144.3, 139.0, 133.7, 130.5, 129.7, 128.4, 127.7, 126.4,
117.5, 115.3, 60.4, 45.8, 31.2, 30.1, 28.1, 27.8, 14.5, 8.7 ppm;
CIMS m/z 340 (MH+).
4-(2′-Am in obiph en yl-2-yl)cyclopen tylpr opion ic Acid Eth -
yl Ester 13e (a S/a R). Purified by preparative thin-layer
chromatography (8:2 heptane-AcOEt): yield 95% of a white
amorphous solid. 13e: IR (CHCl3) 3488, 3394, 1725, 1612 cm-1
;
1H NMR (250 MHz, CDCl3) δ 7.35 (td, J ) 8.0 and 1.0 Hz, 1H),
7.29 (dd, J ) 8.0 and 1.0 Hz, 1H), 7.24 (td, J ) 8.0 and 1.0 Hz,
1H), 7.17 (td, J ) 8.0 and 1.0 Hz, 1H), 7.08 (m, 2H), 6.78 (td, J
) 8.0 and 1.0 Hz, 1H), 6.72 (bd, J ) 8.0 Hz, 1H), 4.04 (q, J )
8.0, 2H), 3.46 (bs, 2H), 2.10-1.42 (m, 12H), 1.24 (t, J ) 7.0 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.2, 138.0, 130.8, 129.9,
129.7, 128.4, 127.3, 126.4, 117.4, 115.1, 60.3, 51.7, 37.9, 35.9,
32.9, 31.0, 22.7, 22.1, 14.3; CIMS m/z 338 (MH+).
P r ep a r a tion of Acid s 14a -e. Gen er a l P r oced u r e. To a
solution of amine 13a , 13b, 13c, 13d or 13e (0.1 mmol) in
methanol (1 mL) was added an aqueous solution of NaOH (50%).
After refluxing the mixture for 3 h, the solution was extracted
with AcOEt. The aqueous phase was acidified (pH ) 5) with 1
9,9-Dim eth yl-5,7,8,9-tetr a h yd r o-5-a za d iben zo[a ,c]cyclo-
n on en -6-on e 4b (a R/a S). Purified by preparative thin-layer
chromatography (97:3 CH2Cl2-MeOH): yield 78% of a white
amorphous solid. 4b: IR (CHCl3) 3381, 1662 cm-1 1H NMR
;

6420 J . Org. Chem., Vol. 63, No. 18, 1998
Notes
white amorphous solid. 4e: IR (CHCl3) 3378, 1662 cm-1 1H
(250 MHz, CDCl3) δ 7.55 (d, J ) 8.0 Hz, 1H), 7.40 (m, 2H), 7.34
(bt, J ) 8.0 Hz, 1H), 7.23 (m, 2H), 7.20 (t, J ) 8.0 Hz, 1H), 6.88
(d, J ) 8.0 Hz, 1H), 6.84 (bs, 1H), 2.42 (m, 2H), 1.79 (m, 2H),
1.48 (s, 3H), 0.92 (s, 3H) ppm; 13C NMR (50 MHz, CDCl3, 263
K) δ 177.0, 145.5, 135.6, 130.4, 129.1, 128.4, 128.2, 127.9, 127.8,
127.4, 42.3, 39.3-34.7, 29.5-27.5 ppm; CIMS m/z 266 (MH+);
HRMS calcd for C18H19NO (MH+) 265.1467, found 265.1473.
9-Eth yl-5,7,8,9-tetr a h yd r o-5-a za d iben zo[a ,c]cyclon on en -
6-on e 4c (R,a R/S,a S). Purified by preparative thin-layer
chromatography (95:5 CH2Cl2-MeOH): yield 81% of a white
amorphous solid. 4c: IR (CHCl3) 3400, 1662 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.40 (m, 5H), 7.28 (d, J ) 8.0 Hz, 1H), 7.18 (t, J
) 8.0 Hz, 1H), 7.02 (s, 1H), 6.95 (d, J ) 8.0 Hz, 1H), 2.10-1.55
(3m, 7H), 0.65 (t, J ) 7.0 Hz, 3H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 176.5, 143.2-136.5, 129.3-125.9, 45.0, 35.0, 34.2, 29.6,
12.4 ppm; CIMS m/z 266 (MH +); HRMS calcd for C18H19NO
(MH+) 265.1467, found 265.1473
;
NMR (250 MHz, CDCl3) δ 7.40 (m, 4H), 7.32 (td, J ) 8.0 and
1.0 Hz, 1H), 7.32 (td, J ) 8.0 and 1.0 Hz, 1H), 7.23 (d, J ) 8.0
Hz, 1H), 7.17 (bt, J ) 8.0 Hz, 1H), 6.85 (dd, J ) 8.0 Hz, 1H),
6.77 (s, 1H), 2.30-1.08 (m, 12H) ppm; 13C NMR (62.5 MHz,
CDCl3) δ 176.9, 147.7, 145.2, 138.2, 136.2, 131.1, 129.7, 129.3,
128.6, 128.3, 127.7, 125.8, 52.0, 42.5, 36.6, 34.8, 29.7, 23.2, 21.0
ppm; CIMS m/z 292 (MH +); HRMS calcd for C20H21NO (MH+)
291.1623, found 291.1624.
Ack n ow led gm en t. The authors would like to thank
Professor P. Potier for his constant interest in their work
and Dr. C. Thal for stimulating and fruitful discussions.
The authors gratefully acknowledge the contribution of
Professor Queguiner and his team in discussions con-
cerning this work which is part of a collaborative
program on the synthesis of new biaryl compounds of
potential biological interest. Finally, we thank Dr. P.
R. J enkins for carefully reading the manuscript and
making several useful remarks.
9,9-Dieth yl-5,7,8,9-tetr ah ydr o-5-azadiben zo[a ,c]cyclon on -
en -6-on e 4d (a R/a S). Purified by preparative thin-layer chro-
matography (97:3 CH2Cl2-MeOH): yield 74% of a white amor-
phous solid. 4d : IR (CHCl3) 3380, 1662 cm-1 1H NMR (250
;
MHz, CDCl3) δ 7.50 (d, J ) 8.0 Hz, 1H), 7.39 (m, 3H), 7.33 (m,
1H), 7.20 (m, 2H), 6.84 (d, J ) 8.0 Hz, 1H), 6.68 (s, 1H), 2.39-
1.78 (m, 6H), 1.27 (m, 2H), 0.82 (t, J ) 7.0 Hz, 3H), 0.71 (t, J )
7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3, 263 K) δ 177.4,
138.5, 135.7, 130.9, 129.5, 128.7, 128.5, 128.1, 127.9, 127.7, 125.9,
45.3, 38.1-24.1, 8.3, 8.2 ppm; EIMS m/z 293 (M+•); HRMS calcd
for C20H23NO (MH+) 293.1780, found 293.1782.
9,9-Tetr a m eth ylen e-5,7,8,9-tetr a h yd r o-5-a za d iben zo[a ,c]-
cyclon on en -6-on e 4e (a R/a S). Purified by preparative thin-
layer chromatography (97:3 CH2Cl2-MeOH): yield 79% of a
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 6a -e to 11a -e, 12, 13a -e, 14a -e, and 4a -e (42
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O980697V