Hydroarylation of bicyclic, unsaturated dicarboximides: access to aryl-substituted, bridged perhydroisoindoles

Article abstract of DOI:10.1016/j.tetlet.2008.02.171

The C-C coupling of the two bicyclic, unsaturated dicarboximides 6 and 8 with aryl and hetaryl halides gave under reductive Heck conditions the 5-substituted N-phenylbicyclo[2.2.1]heptane-2,3-dicarboximides 7 and 9. Reduction of these imides opens a new a

Full text of DOI:10.1016/j.tetlet.2008.02.171

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2685–2688
Hydroarylation of bicyclic, unsaturated dicarboximides:
access to aryl-substituted, bridged perhydroisoindoles
a
a
a,
b,
*
*
¨
Go¨kce Go¨ksu , Melek Gul , Nuket Ocal , Dieter E. Kaufmann
¨
¨
a Yildiz Technical University, Faculty of Art and Sciences, Davutpasa Campus, 34210 Esenler-Istanbul, Turkey
b Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
Received 11 February 2008; revised 26 February 2008; accepted 29 February 2008
Available online 6 March 2008
Abstract
The C–C coupling of the two bicyclic, unsaturated dicarboximides 6 and 8 with aryl and hetaryl halides gave under reductive Heck
conditions the 5-substituted N-phenylbicyclo[2.2.1]heptane-2,3-dicarboximides 7 and 9. Reduction of these imides opens a new access to
the bridged perhydroisoindole derivatives 12 and 14 with prospective biological activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Palladium; Homogenous catalysis; C–C coupling; Reduction; Amine; Aromatics
N-Substituted imides, such as maleimides 1,1 isohemat-
inic acids 22 and especially bicyclic derivatives such as tan-
dospirone 3 derivatives3,4 (Fig. 1) are known for their
broad spectrum of pharmacological properties, thus show-
ing antibiotic, fungicidal, analgesic, anxiolytic, and cyto-
static effects.
Derivatives of the exo-5,6-dehydronorcantharidin 5
(Fig. 2) are also pharmacologically active.5 Norcantharidin
shows a comparable activity with cantharidin 4 (Fig. 2)
which is the major effective ingredient in pharmaceuticals
for the treatment of certain malignant tumors in China.
Compound 5 has been widely employed in clinical practice,
as it is less toxic and much easier to synthesize.6,7 Further-
more, in connection with an additional imide unit this type
of structure has recently become a topic in heterocyclic
chemistry because of its anti-tumor, anti-virus, analgesic,
sedative, and fungicidal activities.7
We therefore became interested in the synthesis of bio-
active cantharidin analogues that represent aryl-modified
bicyclic imide systems, too. We first synthesized endo-N-
phenylbicyclo[2.2.1]hept-5-ene-2,3-dicarboximide 6 from
cyclopentadiene and N-phenylmaleimide and exo-N-
phenyl-7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboximide, 8
O
OH
O
O
O
O
N
R
N
R
1
2
O
N
N
N
(CH2)4
N
N
O
3
O
O
O
O
O
O
Fig. 1. Maleimides 1, isohematinic acids 2 and tandospirone 3.
Me
Me
4
H
*
O
O
Corresponding authors. Tel.: +90 212 449 17 50; fax: +90 212 449 15
H
5
¨
14 (N.O.).
E-mail addresses: nocal@yildiz.edu.tr, ocal20002000@yahoo.com (N.
¨
Fig. 2. Cantharidin 4 and exo-5,6-dehydronor-cantharidin 5.
Ocal), dieter.kaufmann@tu-clausthal.de (D. E. Kaufmann).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.171

2686
G. Go¨ksu et al. / Tetrahedron Letters 49 (2008) 2685–2688
Table 1
from furan and N-phenylmaleimide as starting compounds
according to the literature.8,9
Selected 1H NMR data for compounds 7a–d
7a
7s
Kaufmann and co-workers have a long-standing experi-
ence in palladium-catalyzed hydroarylation10 and domino
reactions of heterobicyclic and tricyclic systems11 toward
bioactive compounds such as epibatidine12 and ana-
logues,13 diazanorbornanes14 and N-aminoimides.15 In
reductive arylation reactions triphenylarsine has proved
to be superior to triphenylphosphine and carbenes as
ligands in both selectivity and yield.12
Treatment of 6 with iodobenzene, 2-iodothiophene, o-
chloroiodobenzene and p-chloroiodobenzene under reduc-
tive Heck conditions16 gave the pure products 7a–d after
chromatographic separation on silica gel as single dias-
tereomers in isolated yields of 51–89%17 (Scheme 1). The
stereochemistry was inferred from their NMR spectra
including diagnostic spin–spin interactions.
Ar
6x
O
4
3
1
2
5n
N
Ph
6n
O
7a
7b
1.68–1.72, d
1.95–2.05, m
3.02, br s
7c
7d
H7a
H7s
H1
1.64–1.67, d
1.94–1.98, dt
3.00–3.08, m
3.00–3.08, m
1.69–1.80, m
1.69–1.80, m
3.13–3.15, d
3.00–3.03, br d
1.64–1.67, d
1.88–1.91, dt
2.95–2.97, br d
3.00–3.05, m
H4
3.02, br s
O
O
Ar
O
N
O
Pd(OAc)2, AsPh3,
DMF
N
The exo-position of the C-5 substituent was confirmed
by the fact that H5 showed no significant interaction with
H1 but did show a cross-peak as a result of W-coupling
to H7-syn. The geminal protons on C-6 were identified by
vicinal coupling to H1 and W-coupling to H3-exo, respec-
Ar(Hetar)I, HCO2H,
NEt3, 65 ºC
O
O
8
9a-f
Cl
Cl
1
Ar (Hetar) =
tively. In addition, Table 1 shows selected H NMR data
N
S
of the hydroarylation products 7a–d.
Cl
Cl
d
Cl
e
The same reductive Heck arylation conditions were suc-
cessfully applied to the reaction of 8 with iodobenzene, 2-
iodothiophene, 4-chloro-1-iodobenzene, 2,4-dichloro-1-
iodobenzene, and 2-chloro-5-iodopyridine to give the new
exo-arylated heterocycles 9a–f in good yields after chro-
matographic separation18 (Scheme 2). Again, a characteris-
tic coupling pattern between the bridgehead and the H5
a
b
c
f
Scheme 2.
O
1
and H6 protons appeared in the H NMR spectra. Addi-
N
N
R
R
tionally, H–H COSY spectra showed cross peaks between
H2 and H3 and between H5 and H6, respectively.
10
11
In addition to the 13C NMR and FTIR spectral data
which were in agreement with the proposed structures,
the mass spectra of all new compounds showed the
expected molecular ion peaks.
Fig. 3. Alkyl substituted perhydroisoindoles 10 and 11.
associated with typical antipsychotic agents.20,21 Some di-
alkylaminoalkyl perhydroisoindole derivatives, being simi-
lar to 10 and 11, are also displaying hypotensive activities
(Fig. 3). The compounds were prepared by reduction of
the corresponding imides.22,23 Thus, it also seemed interest-
ing to obtain perhydroisoindoles from new 5,6-dehydro-
norcantharidin derivatives.
A number of structurally related bicyclic amines have
proved to be useful in the treatment of physiologically or
drug induced psychosis or dyskinesia in mammals.19 Per-
hydroisoindoles are selective sigma receptor antagonists,
and have a low potential for movement disorder side effects
As a part of our continuing study to obtain new perhyd-
roisoindole derivatives, we reduced compounds 7a,b,d
using an excess of LiAlH4 in refluxing diethyl ether. After
regular workup the crude product was purified by column
chromatography to yield 12a,b,d in 50–60% (Scheme 3).
Ar
Pd(OAc)2, AsPh3,
DMF
O
O
N
N
Ar(Hetar)I, HCO2H,
NEt3, 65 ˚C
O
O
6
7a-d
Ar
Ar
O
Cl
LiAlH4
Ar (Hetar) =
N
N
Diethyl ether
S
Cl
d
a
b
c
7a, b, d
12a,b,d
Scheme 1.
Scheme 3.

G. Go¨ksu et al. / Tetrahedron Letters 49 (2008) 2685–2688
2687
8. William, J. B.; William, B. L. J. Am. Chem. Soc. 1957, 79, 1444–1447.
9. Anderson, W. K.; Milowsky, A. S. J. Org. Chem. 1985, 50, 5423–
O
O
Ar
ArI, [Pd]
5424.
N
N
Red. Heck conditions
10. Namyslo, J. C.; Kaufmann, D. E. Chem. Ber. Recl. 1997, 130, 1327–
1331.
13
14a,b
¨
11. Yolacan, C.; Bagdatli, E.; Ocal, N.; Kaufmann, D. E. Molecules 2006,
11, 603–614.
Scheme 4.
12. Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 804–806.
13. Otten, A.; Namyslo, J. C.; Stoermer, M.; Kaufmann, D. E. Eur. J.
Org. Chem. 1998, 9, 1997–2001.
The structural identification of the new reduced
compounds 12a,b,d succeeded.24 In the FTIR spectra the
characteristic C@O band (1702–1710 cmÀ1) of 7a,b,d was
absent. NMR and MS/EI spectra were also in agreement
with the proposed structures.
Additionally, we tried the reduction of 9a,b by LiAlH4
under the same reaction conditions. Yields were very low
after workup, though, probably due to opening of the oxy-
gen bridge. Therefore, we first reduced precursor 8 at room
temperature (2 h), then worked up at 0 °C by dropwise
addition of ethyl acetate, and then water. The crude prod-
uct was purified by column chromatography (SiO2, hexane/
ethyl acetate 1:2) to yield 13 in 84%. Reductive arylation of
13 with iodobenzene and 2-iodothiophene under Heck con-
ditions gave the pure products 14a,b after chromatographic
separation on silica in isolated yields of 50% and 37%,
respectively25 (Scheme 4).
In conclusion, in the presence of triphenylarsine as a
ligand, the palladium-catalyzed hydroarylation of the
easily accessible tricyclic N-phenyl derivatives of the unsat-
urated imides 6 and 8 has been proven to be a
stereoselective, versatile, and high-yield approach for the
synthesis of aryl and heteroaryl derivatives. Our results
have also demonstrated that the reductive access to aryl-
substituted bridged perhydroisoindoles will be useful for
the construction of novel heterocycles of potential pharma-
cological interest.
14. Storsberg, J.; Nandakumar, M. V.; Sankaranarayanan, S.; Kauf-
mann, D. E. Adv. Synth. Catal. 2001, 343, 177–180.
¨
15. Bagdatli, E.; Ocal, N.; Kaufmann, D. E. Helv. Chim. Acta 2007, 90,
2380–2385.
16. Reductive Heck reactions, general procedure: A solution of Pd(OAc)2
(5.6 mg, 0.025 mmol) and AsPh3 (33.7 mg, 0.11 mmol) in anhydrous
DMF or DMSO (3 mL) was stirred under nitrogen at 65 °C for
15 min. Then, compound 6 (239 mg, 1 mmol) or 8 (241 mg, 1 mmol),
respectively, Et3N (488 lL, 3.5 mmol), aryl(heteroaryl) iodide
(1.5 mmol) and HCOOH (138 mg, 3 mmol) were added. The reaction
mixture was stirred for 8–24 h. After cooling to room temperature
EtOAc and brine were added, the organic layer was separated, dried
(MgSO4), filtered, and the solvent evaporated. The residue was
purified by column chromatography (SiO2).
17. Compound (7a): Colorless crystals, mp 125–8 °C (89% from hexane/
ethyl acetate (3:2)), 1H NMR (400 MHz, CDCl3 d: 1.64–1.67 (d,
J = 13.2 Hz, 1H, H7a); 1.94–1.98 (dt, J = 1.5; 10.4 Hz, 1H, H7s); 2.01–
2.04 (m, 2H, H6x and H6n); 3.00–3.08 (m, 3H, H5n, H1 and H4); 3.32–
3.36 (dd, J = 5.01; 9.65 Hz, 1H, H2); 3.38–3.42 (dd, J = 5.01; 9.65 Hz,
1H, H3); 7.21–7.25 (m, 3H, ar); 7.30–7.35 (m, 4H, ar); 7.42–7.46 (m,
1H, ar); 7.50–7.55 (m, 2H, ar). 13C NMR (100 MHz, CDCl3 d): 32.4;
39.3; 40.1; 42.0; 46.4; 48.3; 48.8; 117.5; 126.2; 126.6; 127.1; 128.5;
128.8; 129.3; 131.7; 144.2; 177.1; 177.2. GC–MS (EI, 70 eV): 317
(M+); 175; 129; 119; 104; 77. Compound (7b): Colorless crystals, mp
91 °C (51% from hexane/ethyl acetate (3:1)), 1H NMR (400 MHz,
CDCl3 d): 1.68–1.72 (d, J = 14.4 Hz, 1H, H7a); 1.95–2.05 (m, 2H, H7s
and H6x); 2.09–2.15 (m, 1H, H6n); 3.02 (2H, br s, 2H, H1 and H4);
3.24–3.28 (dd, J = 5.38; 8.56 Hz, 1H, H2); 3.31–3.35 (m, 1H, H5n);
3.37–3.41 (dd, J = 5.50; 9.90 Hz, 1H, H3); 6.84–6.85 (dt, J = 2.20;
4.52 Hz, 1H, ar); 6.94–6.96 (dd, J = 3.55; 5.13 Hz, 1H, ar); 7.17–7.18
(dd, J = 1.1; 5.13 Hz, 1H, ar); 7.29–7.32 (m, 2H, ar); 7.41–7.46 (m,
1H, ar); 7.49–7.54 (m, 2H, ar). 13C NMR (100 MHz, CDCl3 d): 34.9;
38.1; 39.7; 39.8; 47.7; 48.0; 48.4; 123.5; 123.6; 126.6; 126.8; 128.8;
129.3; 131.7; 149.1; 176.8; 176.9. MS (EI, 70 eV): 324 (M+); 323; 175;
147; 119; 77. Compound (7c): Colorless crystals, mp 174–5 °C (63%
from hexane/ethyl acetate (2:1)), 1H NMR (400 MHz, CDCl3 d):
1.69–1.80 (m, 2H, H7a and H7s); 2.00–2.04 (dt, J = 1.46; 11.98 Hz, 1H,
Acknowledgment
We gratefully acknowledge the financial support of this
work by the Yildiz Technical University Scientific Research
Projects Coordination Department (Project No. 24-01-02-
04).
H
6x); 2.23–2.29 (ddd, J = 2.56; 9.17; 11.61 Hz, 1H, H6n); 3.00–3.03 (br
s, 1H, H4); 3.13–3.15 (br d, J = 6.23 Hz, 1H, H1); 3.32–3.38 (m, 2H,
H2 and H3); 3.41–3.45 (dd, J = 5.26; 9.65 Hz, 1H, H5n); 7.15–7.20 (m,
1H, ar); 7.23–7.30 (m, 1H, ar); 7.33–7.47 (m, 4H, ar); 7.50–7.55 (m,
2H, ar). 13C NMR (100 MHz, CDCl3 d): 34.3; 39.8; 40.5; 40.6; 44.4;
48.7; 49.2; 126.5; 127.1; 127.3; 127.9; 129.3; 129.8; 130.4; 132.3; 134.9;
142.4; 177.3; 177.5. MS (EI, 70 eV): 352 (M+), 351; 175; 147; 119; 77.
Compound (7d): Colorless crystals, mp 167–8 °C (62% from hexane/
ethyl acetate (2:1)). 1H NMR (400 MHz, CDCl3 d): 1.64–1.67 (d,
J = 14.3 Hz, 1H, H7a); 1.88–1.91 (dt, J = 1.46; 12.10 Hz, 1H, H7s);
1.92–2.05 (m, 2H, H6n and H6x); 2.95–2.97 (br d, J = 6.4 Hz, 1H, H1);
3.00–3.05 (m, 2H, H2 and H4); 3.31–3.35 (m, 1H, H3); 3.38–3.42 (dd,
J = 5.26; 9.65 Hz, 1H, H5n); 7.14–7.18 (m, 2H, ar); 7.27–7.33 (m, 4H,
ar); 7.42–7.46 (m, 1H, ar); 7.49–7.54 (m, 2H, ar). 13C NMR
(100 MHz, CDCl3 d): 32.5; 39.2; 40.1; 41.5; 46.3; 48.1; 48.7; 126.6;
128.4; 128.5; 128.8; 129.3; 131.7; 132.0; 142.6; 177.0; 177.1. MS (EI,
70 eV): 353 (M+), 351; 175; 147; 119; 77.
References and notes
1. Zentz, F.; Valla, A.; Le Guillou, R.; Labia, R.; Mathot, A.; Sirot, D.
Il Farmaco 2002, 57, 421–442.
2. DiPardo, R. M.; Patane, M. A.; Newton, R. C.; Price, R.; Broten, T.
P.; Chang, R. S. L.; Ransom, R. W.; Di Salvo, J.; Freidinger, R. M.;
Bock, M. G. Bioorg. Med. Chem. Lett. 2001, 11, 1959–1962.
3. Kossakowski, J.; Jarocka, M. Il Farmaco 2001, 56, 785–789.
4. Stack, G. P.; Abou-Gharbia, M. A.; Podlesny, E. J. U.S. Patent
4,748,240, American Home Products Corporation NY, 1988; Chem.
Abstr. 1988, 109, 211085.
5. Hart, M. E.; Chamberlin, A. R.; Walkom, C.; Sakoff, J. A.;
McCluskey, A. Bioorg. Med. Chem. Lett 2004, 14, 1969–1973.
6. Deng, L.; Yongzhou, H. J. Heterocycl. Chem. 2007, 44, 597–601.
7. Deng, L.-P.; Liu, F.-M.; Wang, H.-Y. J. Heterocycl. Chem. 2005, 42,
13–18.
18. Compound (9a): Colorless crystals, mp 148 °C (70% from hexane/
ethyl acetate (3:1)), 1H NMR (200 MHz, CDCl3 d): 1.96–1.99 (m, 1H,
H
6n); 2.01–2.03 (dd, J = 8.96; 11.86 Hz, 1H, H6x); 3.05–3.09
(dd, J = 5.06; 8.84 Hz, 1H, H5n); 3.14–3.18 (d, J = 7.20 Hz, 1H,

2688
G. Go¨ksu et al. / Tetrahedron Letters 49 (2008) 2685–2688
H2); 3.20–3.23 (d, J = 7.20, 1H, H3); 4.91 (s, 1H, H4); 5.13–5.16 (d,
J = 5.30 Hz, 1H, H1); 7.24–7.25 (m, 2H, ar); 7.26–7.47 (m, 8H, ar).
22. Rice, L. M.; Grogan, C. H.; Reid, E. E. J. Am. Chem. Soc. 1953, 75,
4911–4915.
13C NMR (50 MHz, CDCl3 d): 40.0; 47.4; 49.8; 50.2; 79.6; 85.2; 12.5–
127.1; 128.7; 129.2; 131.7; 133.1; 143.9; 176.2; 175.9. GC–MS (EI,
70 eV): 319 (M+); 290; 174; 128; 117; 91. Compound (9b): Colorless
crystals, mp 174.6 °C (40% from hexane/ethyl acetate (3:1)), 1H NMR
(400 MHz, CDCl3 d): 2.09–2.16 (m, 1H, H6n); 2.31–2.36 (dd, J = 8.80;
12.83 Hz, 1H, H6x); 3.16–3.18 (d, J = 7.09 Hz; 1H, H2); 3.23–3.25 (d,
J = 7.09 Hz; 1H, H3); 3.47–3.50 (dd, J = 4.52; 8.92 Hz, 1H, H5n); 4.95
(s, 1H, H1); 5.18–5.19 (d, J = 5.38 Hz, 1H, H4); 6.92–6.98 (m, 1H,
thienyl); 6.96–6.98 (dd, J = 3.55; 5.14 Hz, 1H, thienyl); 7.20–7.22 (dd,
J = 0.89; 5.13 Hz, 1H, thienyl); 7.29–7.32 (m, 2H, Ph); 7.42–7.53 (m,
3H, Ph). 13C NMR (100 MHz, CDCl3 d): 40.9; 43.4; 49.9; 49.9; 79.9;
85.8; 124.4–126.9; 127.2; 129.3; 129.7; 132.1; 147.4; 176.2; 176.4. GC–
MS (EI, 70 eV): 325 (M+); 297; 175; 160; 149; 77. Compound (9c):
Colorless crystals, mp 189 °C (41% from hexane/ethyl acetate (3:1)).
1H NMR (400 MHz, CDCl3 d): 1.96–2.02 (m, 1H, H6n); 2.31–2.36
(dd, J = 9.05; 12.96 Hz, 1H, H6x); 3.08–3.12 (dd, J = 4.89; 9.05 Hz,
1H, H5n); 3.18–3.20 (d, J = 7.09 Hz, 1H, H2); 3.23–3.25 (d,
J = 7.09 Hz, 1H, H3); 4.91 (s, 1H, H4); 5.17–5.18 (d, J = 5.25 Hz,
1H, H1); 7.26–7.23 (m, 2H, ar); 7.29–7.32 (m, 4H, ar); 7.53–7.42 (m,
3H, aromatic). 13C NMR (100 MHz, CDCl3 d): 40.6; 47.2; 50.1; 50.5;
79.9; 85.5; 126.9–128.9; 129.2; 129.3; 129.7; 132.0; 133.1; 142.9; 176.2;
176.5. GC–MS (EI, 70 eV): 354 (M+1+); 325; 175; 139; 103.
Compound (9d): Colorless crystals, mp 179 °C (45% from hexane/
ethyl acetate (3:1)). 1H NMR (400 MHz, CDCl3 d): 1.92–1.98 (m, 1H,
H6n);2.38–2.40 (dd, J = 9.05; 12.84 Hz, 1H, H6x); 3.24–3.26 (d,
J = 7.09 Hz, 1H, H2); 3.30–3.32 (d, J = 7.09 Hz, 1H, H3); 3.66–3.70
(dd, J = 0.01; 8.92 Hz, 1H, H5n); 5.06 (s, 1H, H4); 5.18–5.19 (d,
J = 5.38 Hz, 1H, H1); 7.19–7.23 (m, 1H, ar); 7.27–7.33 (m, 3H, ar);
7.39–7.54 (m, 5H, ar). 13C NMR (100 MHz, CDCl3 d): 39.6; 43.4;
50.2; 50.5; 80.1; 85.5; 126.3–127.9–128.4; 129.6–129.7; 132.1; 133.6;
141.5; 176.2; 176.5. GC–MS (EI, 70 eV): 353 (M+); 325; 175; 191; 102.
Compound (9e): Colorless crystals, mp 170.2 °C (56% from hexane/
ethyl acetate (3:1)), 1H NMR (400 MHz, CDCl3 d): 1.85–1.91 (m, 1H,
23. Otzenberger, R. D.; Lipkowitz, K. B.; Mundy, B. P. J. Org. Chem.
1974, 39, 319–321.
24. Compound (12a): Yellow oil, (60% from hexane/ethyl acetate (2:1)),
1H NMR (400 MHz, CDCl3 d): 1.57–1.60 (m, 2H, H10a and H10b);
1.83–1.86 (d, J = 9.90 Hz, 1H, H9x); 2.09–2.15 (dt, J = 2.44; 12.16 Hz,
1H, H9n); 2.44 (br s, 1H, H1); 2.51–2.52 (br d, J = 4.52 Hz, 1H, H7);
2.72–2.86 (m, 2H, H2 and H6); 2.95–3.03 (AB, J = 8.31 Hz, 2H, H5);
3.07–3.11 (dd, J = 5.13; 8.80 Hz, 1H, H8n); 3.57–3.60 (d, J = 11.6 Hz,
1H, H3); 3.66–3.69 (d, J = 10 Hz, 1H, H3); 6.76–6.80 (m, 3H, ar);
7.15–7.18 (m, 1H, ar); 7.22–7.24 (m, 2H, ar); 7.28–7.32 (m, 4H, ar).
13C NMR (100 MHz, CDCl3 d): 32.2; 39.6; 40.3; 42.4; 43.2; 44.5; 47.9;
49.5; 49.6; 113.9; 117.1; 125.7; 127.6; 128.6; 129.5; 147.7; 149.2. MS
(EI, 70 eV): 289 (M+); 144; 106; 77. Compound (12b): Yellow oil,
(50% from hexane/ethyl acetate (2:1)), 1H NMR (400 MHz, CDCl3
d): 1.43–1.47 (m, 2H, H10a and H10b); 1.71–1.75 (d, J = 10.00 Hz, 1H,
H
9x); 2.04–2.13 (dt, J = 2.46; 12.15 Hz, 1H, H9n); 2.35 (br s, 1H, H1);
2.43–2.45 (br d, J = 4.53 Hz, 1H, H7); 2.64–2.83 (m, 2H, H2 and H6);
3.12–3.17 (AB, J = 8.48 Hz, 2H, H5); 3.37–3.41 (dd, J = 5.22; 9.57
1H,
H8n); 3.74–3.78 (d, J = 11.6 Hz, 1H, H3); 3.97–4.00 (d,
J = 8.93 Hz, 1H, H3); 6.69 (m, 1H, ar); 6.75–6.76 (d, J = 3.44 Hz,
1H, ar); 6.83–6.92 (m, 1H, ar); 7.05–7.11 (m, 2H, ar); 7.14–7.28 (m,
3H, ar). 13C NMR (100 MHz, CDCl3 d): 30.1; 34.2; 36.2; 40.6; 42.1;
42.9; 44.2; 47.2; 48.6; 114.0; 117.6; 122.5; 122.6; 126.5; 127.6; 129.2;
130.4; 148.7; 152.5. MS (EI, 70 eV): 295 (M+); 211; 179; 165; 149; 110;
83. Compound (12c): Yellow oil, (50% from hexane/ethyl acetate
(2:1)), 1H NMR (250 MHz, CDCl3 d): 1.45–1.53 (m, 2H, H10a and
H
10b), 1.72–1.75 (d, J = 9.45 Hz, 1H, H9x), 2.02–2.10 (m, 1H, H9n),
2.30 (br s, 1H, H1), 2.35–2.42 (m, 1H, H7), 2.65–2.79 (m, 2H, H2 and
H6), 2.87–2.91 (AB, J = 10 Hz, 2H, H5), 2.95–3.02 (dd, J = 5.10;
8.68 Hz, 1H, H8n), 3.50–3.53 (d, J = 11.5 Hz, 1H, H3), 3.57–3.60 (d,
J = 11.6 Hz, 1H, H3), 6.68–6.74 (m, 3H, ar), 7.05–7.10 (d,
J = 12.50 Hz, 2H, ar), 7.15–7.25 (m, 4H, ar). 13C NMR (62.5 MHz,
CDCl3 d): 30.2; 31.7; 38.8; 39.7; 41.8; 42.6; 43.9; 48.9; 49.1; 113.3;
116.6; 125.2; 127.8; 128.1; 128.2; 128.8; 145.3; 148.4. MS (EI, 70 eV):
323 (M+); 289; 213; 172; 136; 96; 77.
H6n); 2.36–2.41 (dd, J = 9.05; 12.96 Hz, 1H, H6x); 3.21–3.23 (d,
J = 7.09 Hz, 1H, H2); 3.27–3.29 (d, J = 7.09 Hz, 1H, H3); 3.59–3.63
(dd, J = 4.89; 9.05 Hz, 1H, H5n); 5.00 (s, 1H, H4); 5.16–5.17 (d,
J = 5.25 Hz, 1H, H1); 7.26–7.28 (dd, J = 2.20; 8.56 Hz, 1H, ar); 7.30–
7.32 (m, 2H, ar); 7.42–7.43 (m, 2H, ar); 7.45–7.46 (m, 1H, ar); 7.49–
7.54 (m, 2H, ar). 13C NMR (100 MHz, CDCl3 d): 39.6; 43.0; 50.1;
50.4; 80.1; 84.4; 126.9–128.2–128.9; 129.3; 129.5; 129.5; 132.1; 133.4;
134.2–140.2; 176.1; 176.1. GC–MS (EI, 70 eV): 388 (M+); 325; 175;
191; 103. Compound (9f): Colorless crystals, mp 152 °C (97% from
hexane/ethyl acetate (3:1)), 1H NMR (200 MHz, CDCl3 d): 1.89–1.96
(m, 1H, H6n); 2.30–2.40 (dd, J = 10.00; 13.00 Hz, 1H, H6x); 3.08–3.11
(dd, J = 5.02; 9.11 Hz, 1H, H5n); 3.17–3.20 (d, J = 7.08, 1H, H2);
3.22–3.25 (d, J = 7.09 Hz, 1H, H3); 4.87 (s, 1H, H4); 5.16–5.19 (d,
J = 5.30 Hz, 1H, H1); 7.26–7.48 (m, 6H, ar); 7.61–7.66 (dd, J = 2.52;
8.34 Hz, 1H, ar); 8.27–8.28 (d, J = 2.26 Hz, 1H, ar). 13C NMR
(50 MHz, CDCl3 d): 40.1; 44.1; 49.6; 49.8; 79.5; 84.8; 126.4; 128.9–
129.2; 131.3; 131.5; 138.4; 150.2; 175.4; 175.7. GC–MS (EI, 70 eV):
354 (M+); 325; 139; 119; 117; 91; 68.
25. Compound (14a). Colorless crystals, mp 142 °C (47% from hexane/
ethyl acetate (1:2)), 1H NMR (400 MHz, CDCl3 d): 1.68–1.73 (m, 1H,
H
9n); 1.99–2.03 (dd, J = 9.27; 12.69 Hz, 1H, H9x); 2.62–2.64 (m, 2H,
H2 and H3); 2.80–2.83 (m, 1H, H8n); 2.87–2.90 (AB, J = 4.88 Hz, 2H,
H5); 3.55–3.64 (td, J = 10.74; 18.06 Hz, 2H, H3); 4.22 (s, 1H, H1);
4.43–4.45 (d, J = 4.50 Hz, 1H, H7); 6.52–6.55 (dd, J = 7.82; 8.78 Hz,
2H, ar); 6.62–6.64 (m, 1H, ar); 7.10–7.11 (m, 2H, ar); 7.12–7.13 (m,
2H, ar); 7.18–7.19 (m, 2H, ar); 7.21–7.22 (m, 1H, ar). 13C NMR
(100 MHz, CDCl3 d): 40.5; 47.5; 48.1; 48.7; 53.1; 54.0; 81.1; 87.2;
113.3–117.2; 126.5; 127.5–128.7; 129.3–129.6; 130.2; 131.7–132.4;
146.3; 148.6. GC–MS (EI, 70 eV): 291 (M+); 172; 144; 91; 77.
Compound (14b). Colorless crystals, mp 149 °C (37% from hexane/
ethyl acetate (1:2)), 1H NMR (400 MHz, CDCl3 d): 1.80–1.82 (m, 1H,
H9n); 2.02–2.04 (dd, J = 8.78; 13.05 Hz, 1H, H9x); 2.59–2.65 (td,
J = 5.85; 8.30 Hz, 2H, H2 and H6); 2.84–2.89 (m, 2H, H3); 3.18–3.21
(dd, J = 5.05; 9.12 Hz, 1H, H8n); 3.59–3.64 (td, J = 3.06; 7.20 Hz, 2H,
H5); 4.25 (s, 1H, H1); 4.46–4.47 (d, J = 5.37 Hz, 1H, H7); 6.51–6.55
(dd, J = 7.85; 8.82 Hz, 2H, ar); 6.63–6.64 (m, 2H, ar); 6.67–6.78 (m,
1H, ar); 6.81–6.82 (m, 2H, ar); 7.03–7.05 (m, 1H, ar). 13C NMR
(100 MHz, CDCl3 d): 40.9; 43.0; 47.9; 48.0; 53.8; 54.0; 80.9; 87.5;
113.8; 117.2; 123.4–123.7; 126.7; 128.4–128.0; 129.2–129.0; 148.5;
149.5. GC–MS (EI, 70 eV): 297 (M+); 184; 144; 83; 77.
19. de Costa, B. R.; He, X. S.; Linders, J. T.; Dominguez, C.; Gu, Z. Q.;
Williams, W.; Bowen, W. D. J. Med. Chem. 1993, 36, 2311–2320.
20. Ciganek, E. U.S. Patent 5,216,018, Du Pont Merck Pharmaceutical
Company, 1993; Chem. Abstr. 1993, 119, 225816.
21. Gilligan, P. J. U.S. Patent 5532243, Du Pont Merck Pharmaceutical
Company, 1996; Chem. Abstr. 1994, 120, 134304.