A consecutive Diels-Alder approach toward a Tet repressor directed combinatorial library

Article abstract of DOI:10.1016/j.tet.2006.04.092

A combinatorial library of 180 tetracycline analogs was generated by solution phase parallel synthesis applying a consecutive Diels-Alder strategy. Chemical methodology suitable for three-dimensional solution phase parallel synthesis was developed that en

Full text of DOI:10.1016/j.tet.2006.04.092

Tetrahedron 62 (2006) 6899–6908
A consecutive Diels–Alder approach toward a Tet repressor
directed combinatorial library
Christian Kormann,a Frank W. Heinemannb and Peter Gmeinera,
*
aDepartment of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19,
D-91052 Erlangen, Germany
bDepartment of Inorganic Chemistry, Friedrich Alexander University, Egerlandstrasse 1, D-91058 Erlangen, Germany
Received 7 March 2006; revised 21 April 2006; accepted 27 April 2006
Available online 23 May 2006
Abstract—A combinatorial library of 180 tetracycline analogs was generated by solution phase parallel synthesis applying a consecutive
Diels–Alder strategy. Chemical methodology suitable for three-dimensional solution phase parallel synthesis was developed that enabled
us to generate a collection of potential TetR inducers. The synthesis was built on cross-conjugated trienes as central building blocks facilitating
two consecutive cycloaddition processes with different dienophiles. Upon sequential exposure to naphthoquinone and maleimide derivatives,
the generation of a carbocyclic skeleton of type 2 incorporating the diversity elements R1–R5 was envisaged.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives, the generation of a carbocyclic skeleton of type
2 incorporating the diversity elements R1–R5 was envisaged.
Linking chemical synthesis of natural product derivatives
with genetic evolution of biologically active proteins creates
an effective bridge between a basic understanding of func-
tional proteins and the discovery of highly potent and selec-
tive modulators for gene regulation in prokaryotes and
eukaryotes.1,2 Following this approach, we constructed a
mutant of the tetracycline-inducible repressor protein
TetR3,4 displaying specificity for the tetracycline analog 1
(Scheme 1) preventing both antibiotic activity and induction
of the wild-type Tet repressor.5 As a complement to our re-
cent efforts on solid-phase supported combinatorial synthe-
sis,6,7 we herein present a solution phase parallel synthesis8
of a tetracycline related compound library of type 2.
According to preliminary studies, the tetracycline mimetic
core structure of 2 could be docked into the binding pocket
of TetR crystal structure.9 To provide an efficient approach
to the identical four-ring carbocyclic structure as a basic
skeleton, our forward directed plan of synthesis was built
on a homo-Diels–Alder (HDA) approach allowing an
efficient and stereospecific construction of multiple carbon–
carbon bonds. Our strategy involved cross-conjugated
trienes as central building blocks facilitating two consecu-
tive cycloaddition processes with different dienophiles.10,11
Upon sequential exposure to naphthoquinone and maleimide
HO
N
H
H
H
OH
OH
O
O
OH
OH
OH
OH
O
O
NH2
OH
O
O
NH2
OH
tetracycline
1
R4
R4
O
R2
O
O
R2
R3
O
O
R3
2
O
N
R1
R1
N
O
O
R5
R5
Scheme 1. Lead compounds and plan of synthesis.
2. Results and discussion
2.1. Elaboration of the key reactions
Keywords: Solution phase parallel synthesis; Diels–Alder; Tetracycline;
TetR.
* Corresponding author. Tel.: +49 9131 8529383; fax: +49 9131 8522585;
e-mail: gmeiner@pharmazie.uni-erlangen.de
The usage of Diels–Alder reactions represents a particularly
efficient strategy for the parallel synthesis of complex
molecular structures.12 Since we aimed to generate a
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.092

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C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
combinatorial compound collection of suitable purity and
yield, appropriate reaction conditions for the consecutive
Diels–Alder processes have to be elaborated by investigating
a model reaction sequence. As a representative central build-
ing block, we chose the cross-conjugated triene B1 that was
expected to provide sufficient chemical stability and effi-
cient accessibility. The preparation of B110,11 was done by
g-pentadienylation of benzaldehyde using 5-bromo-1,3-
pentadiene13 in the presence of indium dust followed by
sulfonylation of the formed secondary alcohol and b-elimi-
nation. Our initial synthetic investigations were directed to
the HDA reaction of the triene B1 with 5-hydroxynaphtho-
quinone (A0) when heating both components in toluene at
40–60 ꢀC gave a hardly separable mixture of regioisomers
together with the respective dehydro-derivatives, which were
obviously produced by intermolecular electron transfer.
Performing the transformation under Lewis acid-catalyzed
conditions at ꢁ60 ꢀC produced the cycloaddition product 3
as apureregioisomer. However, theformationof asubstantial
amount of the oxidation product 6 was observed after chro-
matography. To exclude this side reaction, we subjected the
2-methyl substituted hydroxynaphthoquinone A1 (plumba-
gin) as well as the 2,3-dimethyl derivative A214,15 being de-
voidof an activating 5-hydroxy group to the above mentioned
reaction conditions resulting in the formation of the tricyclic
products 4 and 5, respectively. Besides the thermally induced
HDA processes, we investigated Lewis acid-mediated condi-
tions at low temperature (ꢁ60 ꢀC) using scandium trifluoro-
methanesulfonate16 and, alternatively, boron trifluoride
diethyl etherate17 when pure cycloaddition products could
be isolated in 70–85% yield. Due to economic reasons, we
chose the BF3 promoted variant as the method of choice.
To accommodate conditions in a parallel reactor, the reaction
temperature was raised to ꢁ30 ꢀC which proved to be possi-
ble without significant loss of yield and purity. For the trans-
formation of the hydroxynaphthoquinone derivative A1,
complete regioselectivity was observed, which is obviously
due to secondary orbital interactions. The regiochemical out-
come of the reaction could be unambiguously determined by
NMR spectroscopy when HMBC experiments clearly indi-
cated that the carbonyl carbon located in b-position to the
hydroxy substituent showed cross-peaks to both methylene
hydrogens whereas the C]O with the remote hydroxyl
group displaying coupling via three bonds with an aromatic
hydrogen interacted with the proton adjacent to the phenyl
substituent. Since the sterically demanding phenyl group of
B1 was expected to predominantly adopt a trans-orientation
with respect to the reactive diene substructure and substantial
endo-selectivity was assumed for the Diels–Alder process,
we anticipated a trans-disposition between the phenyl and
the vicinally positioned methyl group, which was confirmed
at the final product stage.
opposite to the phenyl substituent to avoid steric inter-
actions. The molecular structure of the racemic pentacyclic
target compound 8 could be elucidated by X-ray crystallo-
graphy (Fig. 1). Interestingly, the pentacyclic scaffold shows
a concave shape when the phenyl moiety is located in a
sandwich-like manner over the aromatic system of the former
naphthoquinone.
O
O
OH
6
O
O
O
Y
Z
Y
Z
+
O
X
X
A0-2
B1
3: X = OH, Y, Z = H
4: X = OH, Y = CH3, Z = H
5: X = H; Y, Z = CH3
O
N
O
O
O
O
H
Z
X
N
C5
O
7: X = OH, Y = CH3, Z = H
8: X = H; Y, Z = CH3
Scheme 2. Representative model reactions.
Based on our model studies, reaction conditions could be
found that seemed to be robust and reproducible and,
thus, suitable for an efficient production of a liquid organic
phase supported 3D-library. Since the parallelization of the
conventional heating requires substantially less technical
sophistication than parallel microwave assisted synthesis,
we decided to perform the library production without micro-
wave technology.
An efficient approach of the pentacyclic model compounds
7 and 8 by cycloaddition of the synthetic intermediates 4
and 5, respectively, with N-phenylmaleimide (C5) was in-
vestigated employing both microwave technology (80 ꢀC
for 20 min without use of a solvent) and conventional
heating (toluene at 68 ꢀC for 3 days). In fact, application
of both techniques resulted in the formation of the final
products 7 and 8 in >80% yield (Scheme 2). According to
diagnostic NOEs, complete diastereospecifity was observed
indicating a cis-selective endo-approach of the dienophile
Figure 1. Crystal structure of (3aS,6R,6aS,12aR,13aS,13bR)-8.

C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
6901
2.2. Library production
Thus, each of the quinones A1–3 was reacted with the set of
cross-conjugated trienes B1–6 in the presence of boron tri-
fluoride diethyl etherate at ꢁ30 ꢀC. After extraction with
water, the organic layer had to be separated. This could be
done in a very practical manner by adding n-hexane to
convey the organic layer to the top followed by freezing
the aqueous layer at ꢁ60 ꢀC and sucking off the liquid or-
ganic part. After removal of nonpolar impurities on a short
pad of silica gel, each of the 18 tricyclic compounds {A1–
3B1–6} was distributed to 10 reaction vessels and stirred
with the maleimides {C1–10} in toluene to afford the 180
tetracycline analogs 7–186 {A1–3B1–6C1–10}. After
preparative HPLC, the members of the compound collection
were obtained in 26.7–86.4% yield. Ninety-five percent
of the final products showed purities higher than 90%
(Table 1).
Following the procedure described above, 180 tetracycline
analogs should be prepared starting from the naphthoqui-
nones A1–3, the cross-conjugated trienes B1–6 and the
maleimides C1–10 (Scheme 3, Fig. 2).
O
Y
C 1 - 10
B 1 - 6
A 1 - 3
(a)
(b)
O
H
Z
O
X
N
O
7 - 186
Scheme 3. Solution phase parallel synthesis. (a) B1–6, BF3$Et2O, CH2Cl2,
ꢁ30 ꢀC, 16 h. (b) C1–10, toluene, 68 ꢀC, 3 days.
Quinones:
O
O
O
O
O
Br
O
OH
A3
OH
A1
A2
Cross-conjugated trienes:
Cl
F
Br
B1
B2
B3
B4
B5
B6
Maleimides:
O
O
O
O
O
N
N
N
N
N
O
H
O
O
O
O
C1
C2
C3
C4
C5
O
O
O
O
O
N
N
N
N
O
N
O
O
O
O
COOH
O
Br
C6
Figure 2. Building blocks.
C7
C8
C9
C10

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C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
Table 1. Purities and yields of library products
No.
Building blocks
Purity
(LC–MS) (%)
Yield (over
two steps) (%)
No.
Building blocks
Purity
(LC–MS) (%)
Yield (over
two steps) (%)
9
A1B1C1
A1B1C2
A1B1C3
A1B1C4
A1B1C5
A1B1C6
A1B1C7
A1B1C8
A1B1C9
A1B1C10
A1B2C1
A1B2C2
A1B2C3
A1B2C4
A1B2C5
A1B2C6
A1B2C7
A1B2C8
A1B2C9
A1B2C10
A1B3C1
A1B3C2
A1B3C3
A1B3C4
A1B3C5
A1B3C6
A1B3C7
A1B3C8
A1B3C9
A1B3C10
A1B4C1
A1B4C2
A1B4C3
A1B4C4
A1B4C5
A1B4C6
A1B4C7
A1B4C8
A1B4C9
A1B4C10
A1B5C1
A1B5C2
A1B5C3
A1B5C4
A1B5C5
A1B5C6
A1B5C7
A1B5C8
A1B5C9
A1B5C10
A1B6C1
A1B6C2
A1B6C3
A1B6C4
A1B6C5
A1B6C6
A1B6C7
A1B6C8
A1B6C9
A1B6C10
A2B1C1
A2B1C2
A2B1C3
A2B1C4
A2B1C5
A2B1C6
A2B1C7
A2B1C8
A2B1C9
A2B1C10
A2B2C1
>99.0
>99.0
>99.0
>99.0
>99.0
89.1
>99.0
>99.0
>99.0
94.0
62.4
84.0
86.4
83.5
73.5
82.6
76.6
73.8
70.4
77.2
61.7
70.1
72.2
71.8
67.9
43.4
61.1
57.4
71.0
57.8
69.5
85.2
76.1
61.2
81.7
76.8
75.9
58.8
72.3
56.6
68.6
60.6
74.1
60.5
69.6
40.3
58.3
84.3
73.7
71.4
80.2
75.7
53.8
66.6
55.8
43.1
41.0
83.2
61.8
60.9
58.7
49.5
63.4
76.5
72.3
59.6
76.3
68.1
79.4
73.5
61.3
65.4
68.0
63.4
52.4
63.7
62.2
59.3
73.3
71.1
58.9
97
98
99
A2B4C1
A2B4C2
A2B4C3
A2B4C4
A2B4C5
A2B4C6
A2B4C7
A2B4C8
A2B4C9
A2B4C10
A2B5C1
A2B5C2
A2B5C3
A2B5C4
A2B5C5
A2B5C6
A2B5C7
A2B5C8
A2B5C9
A2B5C10
A2B6C1
A2B6C2
A2B6C3
A2B6C4
A2B6C5
A2B6C6
A2B6C7
A2B6C8
A2B6C9
A2B6C10
A3B1C1
A3B1C2
A1B1C3
A3B1C4
A3B1C5
A3B1C6
A3B1C7
A3B1C8
A3B1C9
A3B1C10
A3B2C1
A3B2C2
A3B2C3
A3B2C4
A3B2C5
A3B2C6
A3B2C7
A3B2C8
A3B2C9
A3B2C10
A3B3C1
A3B3C2
A3B3C3
A3B3C4
A3B3C5
A3B3C6
A3B3C7
A3B3C8
A3B3C9
A3B3C10
A3B4C1
A3B4C2
A3B4C3
A3B4C4
A3B4C5
A3B4C6
A3B4C7
A3B4C8
A3B4C9
A3B4C10
A3B5C1
89.9
>99.0
>99.0
>99.0
>99.0
98.6
55.9
29.8
54.1
55.1
56.9
59.2
69.9
59.2
42.8
65.2
54.6
65.9
59.9
49.4
38.0
67.1
55.7
57.0
48.8
58.9
64.2
52.0
61.7
57.6
47.7
54.7
53.5
56.9
68.4
62.9
33.0
47.9
58.6
45.7
53.9
41.1
31.7
26.7
43.5
48.2
45.8
33.5
31.1
27.3
35.8
28.2
25.4
30.8
38.3
43.3
31.4
32.3
28.4
38.5
27.7
30.1
40.2
37.1
31.8
20.5
42.2
35.8
38.2
32.2
38.1
37.6
48.1
39.2
32.2
46.5
38.7
10
11
12
7
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
8
81.7
>99.0
>99.0
93.8
98.0
88.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
97.7
>99.0
>99.0
98.9
>99.0
>99.0
88.7
>99.0
>99.0
91.0
98.9
94.7
>99.0
>99.0
>99.0
97.1
>99.0
>99.0
>99.0
98.4
91.1
>99.0
96.0
94.6
>99.0
>99.0
>99.0
97.4
>99.0
>99.0
96.6
>99.0
>99.0
>99.0
87.3
>99.0
98.4
>99.0
>99.0
>99.0
96.7
>99.0
>99.0
>99.0
82.0
>99.0
97.1
>99.0
>99.0
>99.0
95.7
>99.0
>99.0
>99.0
88.6
>99.0
>99.0
>99.0
>99.0
98.9
95.4
>99.0
>99.0
95.6
95.5
96.1
97.3
96.7
97.4
95.7
93.6
92.3
95.1
98.2
93.3
96.5
>99.0
94.6
93.4
96.5
96.0
97.7
95.9
98.7
92.1
97.6
95.4
98.0
96.3
97.4
>99.0
96.6
90.6
92.7
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
95.6
72
73
74
75
76
77
94.9
>99.0
>99.0
>99.0
>99.0
86.0
93.9
95.2
(continued)

C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
6903
Table 1. (continued)
No.
Building blocks
Purity
(LC–MS) (%)
Yield (over
two steps) (%)
No.
Building blocks
Purity
(LC–MS) (%)
Yield (over
two steps) (%)
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
A2B2C2
A2B2C3
A2B2C4
A2B2C5
A2B2C6
A2B2C7
A2B2C8
A2B2C9
A2B2C10
A2B3C1
A2B3C2
A2B3C3
A2B3C4
A2B3C5
A2B3C6
A2B3C7
A2B3C8
A2B3C9
A2B3C10
>99.0
98.5
94.4
35.2
80.0
56.8
57.2
54.7
58.4
61.4
47.3
55.1
64.7
64.5
44.4
57.0
59.7
54.3
41.0
58.2
55.2
53.9
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
A3B5C2
A3B5C3
A3B5C4
A3B5C5
A3B5C6
A3B5C7
A3B5C8
A3B5C9
A3B5C10
A3B6C1
A3B6C2
A3B6C3
A3B6C4
A3B6C5
A3B6C6
A3B6C7
A3B6C8
A3B6C9
A3B6C10
>99.0
>99.0
>99.0
96.9
>99.0
>99.0
>99.0
>99.0
94.2
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
>99.0
98.5
36.0
44.5
34.4
43.2
37.1
43.8
36.3
38.7
33.7
40.3
36.2
33.4
37.9
37.6
29.6
32.1
38.3
42.2
39.6
98.2
>99.0
>99.0
>99.0
98.7
94.1
>99.0
>99.0
>99.0
>99.0
>99.0
95.1
96.1
>99.0
97.1
>99.0
3. Summary
4.2. Preparation of the quinones A1–3
In summary, a consecutive Diels–Alder approach was ex-
ploited for a highly regio- and stereoselective two-step syn-
thesis of a TetR directed library of carbocyclic scaffolds in
racemic form. Chemical methodology suitable for three-
dimensional solution phase parallel synthesis was developed
that enabled us to generate a collection of 180 potential TetR
inducers.
A2 was readily prepared by a chromium-(VI)-oxide cata-
lyzed oxidation of 2,3-dimethylnaphthalene with periodic
acid.14 A3 was obtained by the bromination of commercially
available A1.18
4.3. Preparation of the cross-conjugated trienes
B1–610,11,19
Indium powder (100 mesh, 282 mg, 2.46 mmol) was added
in portions to a solution of 5-bromo-1,3-pentadiene
(657 mg, 4.47 mmol) and aromatic aldehyde (2.23 mmol)
in DMF (2.23 mL) at 0 ꢀC. After stirring for 5 h at 0 ꢀC, tem-
perature was allowed to rise to 10 ꢀC. The mixture was
diluted with CH2Cl2 (15 mL) and poured into diethyl ether
(190 mL). The resulting turbid mixture was filtered through
a pad of silica gel and washed with an additional amount of
ether. Evaporation of the solvent and purification of the
crude intermediate by flash chromatography on silica gel
using n-hexane/ethyl acetate (10:1) resulted in the desired
secondary alcohol. Mesyl chloride (1.35 mL, 17.5 mmol)
was added dropwise to a solution of this intermediate
(13.1 mmol) and triethylamine (2.74 mL, 19.7 mmol) in
CH2Cl2 (100 mL) at ꢁ50 ꢀC. The resulting mixture was
allowed to warm to ꢁ30 ꢀC over 45 min and poured into a
half saturated aqueous solution of NaHCO3 (100 mL).
Subsequent extraction with diethyl ether (3ꢂ100 mL), treat-
ment with Na2SO4, filtration and evaporation of the solvent
resulted in the crude methane sulfonate, which was dis-
solved in dry benzene (100 mL), treated with 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (2.4 mL, 15.7 mmol) and gently
heated at 44 ꢀC for 3 h. Flash column chromatography of
the concentrated crude mixture employing n-hexane fur-
nished the trienes B1–6 in 54–66% overall yield.
4. Experimental
4.1. General
Absolute solvents (over molecular sieves) and starting mate-
rials obtained from commercial source were used without
1
further purification. H NMR and 13C NMR spectra were
determined on a BRUKER AVANCE 360 or a BRUKER
AVANCE 600 spectrometer in solution. COSY, HSQC,
HMBC and NOE spectra (600 MHz) spectra were deter-
mined in solution using instrument BRUKER AVANCE
600. LC–MS analyses were conducted using an Agilent
Binary Gradient System in combination with ChemStation
Software (MeOH/0.1 N aq HCOOH 10/90–90/10) applying
a Zorbax SB-C8 (4.6 mmꢂ150 mm, 5 mm) column, UV
detection at 254 nm and a flow rate of 0.5 mL/min. Mass
detection was pointed out with a Bruker Esquire 2000 ion-
trap-mass spectrometer using an APC ionization source.
EIMS spectra were recorded on FINNIGAN MAT TSQ
700 spectrometer. HRMS were determined on a JOEL
GCmateII at a resolution of M/DM>5000. CHN elementary
analyses were done at the laboratory of Ilse Beetz, Kronach.
Silica gel (40–63 mm) was used for a purification step. Pre-
parative HPLC was conducted using an Agilent 1100 Series
system applying a Eurospher-C18 (4.6 mmꢂ250 mm, 7 mm)
with H2O and acetonitrile both containing 0.1% of trifluoro-
acetic acid (gradient 0–80% acetonitrile) with a flow rate of
20 mL/min.
4.3.1. 1-Isopropyl-4-(2-vinylbuta-1,3-dienyl)benzol B3.
1
MS m/z 198 (M+). H NMR (600 MHz, CDCl3): d 1.29
(d, J¼7.0 Hz, 6H), 2.94 (sept, J¼7.0 Hz, 1H), 5.22 (d,

6904
C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
J¼10.7 Hz, 1H), 5.37 (d, J¼11.1 Hz, 1H), 5.47 (d, J¼
17.7 Hz, 1H), 5.55 (d, J¼17.3 Hz, 1H), 6.58 (dd,
J¼17.3 Hz, 10.7 Hz, 1H), 6.65 (br s, 1H), 6.76 (dd, J¼
17.7 Hz, 11.1 Hz, 1H), 7.20–7.25(m, 2H), 7.32–7.36(m, 2H).
128.1, 129.2 (2C), 135.0, 135.2, 135.6, 138.2, 138.5,
159.7, 199.2, 203.2.
4.4.2. (1RS,4aRS,9aSR)-4a,9a-Dimethyl-1-phenyl-2-
vinyl-1,4,4a,9a-tetrahydroanthracene-9,10-dione 5. MS
m/z 342 (M+). 1H NMR (360 MHz, CDCl3): d 1.16 (s,
3H), 1.65 (s, 3H), 2.10 (m, 1H), 3.62 (br dd, J¼19.8 Hz,
4.8 Hz, 1H), 3.84 (s, 1H), 4.65 (d, J¼17.6 Hz, 1H), 4.78
(d, J¼11.0 Hz, 1H), 6.15 (m, 1H), 6.26 (dd, J¼17.6 Hz,
11.0 Hz, 1H), 6.68–6.83 (m, 5H), 7.39 (m, 2H), 7.55–7.61
(m, 1H), 7.77–7.81 (m, 1H).
4.3.2. 1-Brom-4-(2-vinylbuta-1,3-dienyl)benzol B4. MS
1
m/z 234 (M+ 79Br). H NMR (360 MHz, CDCl3): d 5.26
(dd, J¼10.8 Hz, 1.0 Hz, 1H), 5.41 (dt, J¼11.0 Hz, 1.4 Hz,
1H), 5.49 (d, J¼17.7 Hz, 1.5 Hz, 1H), 5.57 (dd, J¼
17.3 Hz, 1.4 Hz, 1H), 6.56 (ddd, J¼17.3 Hz, 10.8 Hz,
1.0 Hz, 1H), 6.57 (br s, 1H), 6.66 (dd, J¼17.7 Hz,
11.1 Hz, 1H), 7.24–7.29 (m, 2H), 7.41–7.46 (m, 2H).
4.5. General procedure for synthesis of pentacyclic
compounds {A1–3/B1–6/C1–10}
4.3.3. 1-Chlor-4-(2-vinylbuta-1,3-dienyl)benzol B5. MS
1
m/z 190 (M+). H NMR (360 MHz, CDCl3): d 5.26 (dd,
J¼10.7 Hz, 1.0 Hz, 1H), 5.41 (dt, J¼11.0 Hz, 0.9 Hz, 1H),
5.49 (dd, J¼17.6 Hz, 1.6 Hz, 1H), 5.57 (dd, J¼17.4 Hz,
1.5 Hz, 1H), 6.57 (ddd, J¼17.4 Hz, 10.7 Hz, 1.0 Hz, 1H),
6.60 (br s, 1H), 6.66 (ddd, J¼17.6 Hz, 11.1 Hz, 0.9 Hz,
1H), 7.31–7.35 (m, 4H).
Each of the compounds {A1–3/B1–6} was divided into 10
parts. Every part was placed in a sealed glass tube with
the maleimides C1–10 (5 equiv) under nitrogen. Toluene
(1 mL) was added to each reaction vessel. The solution
was stirred for 3 days at 68 ꢀC. Removal of the solvent under
reduced pressure and further purification by HPLC afforded
the pentacyclic compounds {A1–3/B1–6/C1–10}.
4.3.4. 1-Fluor-4-(2-vinylbuta-1,3-dienyl)benzol B6. MS
1
m/z 174 (M+). H NMR (CDCl3): d 5.23 (br d, J¼10.6 Hz,
1H), 5.38 (br d, J¼11.1 Hz, 1H), 5.47 (dd, J¼17.8 Hz,
1.3 Hz, 1H), 5.54 (dd, J¼17.2 Hz, 1.3 Hz, 1H), 6.55 (br
dd, J¼17.2 Hz, 10.6 Hz, 1H), 6.60 (br s, 1H), 6.65 (br dd,
J¼17.8 Hz, 11.1 Hz, 1H), 7.01–7.06 (m, 2H), 7.33–7.37
(m, 2H).
4.5.1. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-11-
Hydroxy-6a-methyl-6-phenyl-3a,4,6,6a,12a,13,13a,13b-
octahydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-
tetrone 9 {A1,B1,C1}. MS m/z 441 (M+). 1H NMR
(600 MHz, CDCl3): d 1.45 (s, 3H), 2.16 (m, 1H), 2.57–
2.62 (2H), 2.85 (m, 1H), 2.99 (ddd, J¼14.4 Hz, 10.0 Hz,
6.0 Hz, 1H), 3.18 (ddd, J¼10.1 Hz, 8.3 Hz, 1.4 Hz, 1H),
3.24–3.27 (2H), 3.53 (br s, 1H), 5.46 (m, 1H), 6.99–7.03
(m, 2H), 7.04–7.07 (m, 1H), 7.07–7.11 (m, 2H), 7.10 (br
d, J¼8.2 Hz, 1H), 7.33 (br d, J¼7.5 Hz, 1H), 7.49 (dd, J¼
8.2 Hz, 7.5 Hz, 1H), 7.97 (br s, 1H), 11.92 (s, 1H). 13C
NMR (150 MHz, CDCl3): d 22.9, 24.9, 25.2, 32.6, 41.2,
45.2, 52.8, 53.2, 56.1, 117.2, 118.6, 122.9, 124.1, 127.1,
127.9 (2C), 130.6 (2C), 135.8, 136.6, 139.3, 140.3, 160.7,
178.2, 179.1, 199.4, 204.4. Exact mass (EI+) m/z calcd for
C27H23NO5: 441.1576. Found: 441.1577.
4.4. General procedure for synthesis of tricyclic
compounds {A1–3/B1–6}
A solution of quinone A1–3 (1.5 mmol) and cross-conju-
gated triene B1–6 (1.5 mmol) in dichloromethane (6 mL)
was cooled to ꢁ30 ꢀC under inert atmosphere. Boron trifluor-
ide diethyl etherate (0.5 mL) was added dropwise within
5 min. After stirring for 1 h, the reaction mixture was treated
with an additional amount of B1–6 (0.75 mmol). The solu-
tion was allowed to stir overnight. After addition of H2O
(6 mL) the reaction mixture was allowed to warm to 0 ꢀC
under vigorous stirring. Treatment with n-hexane (6 mL)
followed by cooling to ꢁ60 ꢀC resulted in freezing of the
aqueous layer. The supernatant organic phase was removed
by pipetting and evaporated under reduced pressure. Crude
purification of the resulting residue was performed by ad-
sorption to silica gel, whereas the un-reacted triene and non-
polar side-products were removed by washing with n-hexane
(500 mL). Elution using dichloromethane (500 mL) and
subsequent evaporation of the solvent afforded the tricyclic
compounds {A1–3/B1–6}, which were used for the next
step without further purification.
4.5.2. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Ethyl-
11-hydroxy-6a-methyl-6-phenyl-3a,4,6,6a,12a,13,13a,
13b-octahydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-
tetrone 11 {A1,B1,C3}. MS m/z 469 (M+). 1H NMR
(600 MHz, CDCl3): d 1.11 (t, J¼7.2 Hz, 3H), 1.45 (s, 3H),
2.13 (m, 1H), 2.63 (br dd, J¼15.8 Hz, 7.4 Hz, 1H), 2.66
(ddd, J¼14.0 Hz, 8.0 Hz, 5.7 Hz, 1H), 2.84 (m, 1H), 3.01–
3.14 (2H), 3.17 (dd, J¼8.5 Hz, 5.4 Hz, 1H), 3.29 (dd,
J¼5.7 Hz, 5.7 Hz, 1H), 3.45 (br s, 1H), 3.52 (q, J¼7.2 Hz,
2H), 5.39 (m, 1H), 6.98–7.13 (m, 5H), 7.13 (dd, J¼8.4 Hz,
8.0 Hz, 1H), 7.33 (dd, J¼7.6 Hz, 1.0 Hz, 1H), 7.53 (dd,
J¼8.4 Hz, 7.6 Hz, 1H), 11.97 (s, 1H). 13C NMR
(150 MHz, CDCl3): d 13.1, 23.2, 25.2 (2C), 33.0, 33.7,
40.0, 44.1, 52.9, 53.4, 56.2, 117.2, 118.7, 122.9, 123.9,
127.2, 127.9 (2C), 130.8 (2C), 136.0, 136.8, 139.0, 140.4,
160.8, 178.3, 179.3, 199.6, 204.6. Exact mass (EI+) m/z
calcd for C29H27NO5: 469.1889. Found: 469.1890.
4.4.1. (1RS,4aRS,9aSR)-5-Hydroxy-9a-methyl-1-phenyl-
2-vinyl-1,4,4a,9a-tetrahydroanthracene-9,10-dione 4.
MS m/z 344 (M+). 1H NMR (360 MHz, acetone-d6): d 1.65
(s, 3H), 2.53 (m, 1H), 3.42 (br d, J¼8.2 Hz, 1H), 3.62 (br
dd, J¼20.3 Hz, 4.5 Hz, 1H), 3.79 (s, 1H), 4.77 (d,
J¼10.7 Hz, 1H), 4.78 (d, J¼17.7 Hz, 1H), 6.21 (m, 1H),
6.34 (dd, J¼17.7 Hz, 10.7 Hz, 1H), 6.76–6.87 (m, 5H),
6.91 (dd, J¼8.1 Hz, 1.2 Hz, 1H), 7.34 (dd, J¼7.7 Hz,
1.2 Hz, 1H), 7.42 (dd, J¼8.1 Hz, 7.7 Hz, 1H), 11.72 (s,
1H). 13C NMR (90 MHz, acetone-d6): d 20.1, 23.4, 47.6,
49.8, 52.0, 112.1, 117.6, 117.9, 122.0, 127.0, 127.6 (2C),
4.5.3. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-11-Hydroxy-
6a-methyl-2,6-diphenyl-3a,4,6,6a,12a,13,13a,13b-octa-
hydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone 7
{A1,B1,C5}. MS m/z 517 (M+). 1H NMR (600 MHz,
CDCl3): d 1.44 (s, 3H), 2.24 (m, 1H), 2.66–2.76 (2H), 2.93

C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
6905
79
32
(m, 1H), 3.04 (ddd, 15.0 Hz, 9.5 Hz, 6.0 Hz, 1H), 3.29–3.33
(2H), 3.39 (dd, J¼8.6 Hz, 5.5 Hz, 1H), 3.50 (br s, 1H), 5.50
(m, 1H), 7.03–7.07 (m, 2H), 7.08–7.19 (6H), 7.35 (br d,
J¼7.5 Hz, 1H), 7.40–7.44 (m, 1H), 7.45–7.51 (m, 2H),
7.54 (dd, J¼8.1 Hz, 7.5 Hz, 1H), 11.98 (s, 1H). 13C NMR
(150 MHz, CDCl3): d 23.5, 25.2, 25.5, 33.1, 40.3, 44.4,
52.9, 53.5, 56.5, 117.1, 118.6, 122.9, 123.9, 126.5 (2C),
127.2, 128.0 (2C), 128.8 (2C), 129.3 (2C), 130.7, 131.8,
136.0, 136.8, 138.8, 140.6, 160.8, 177.6, 178.5, 199.4,
204.5. Exact mass (EI+) m/z calcd for C33H27NO5:
517.1889. Found: 517.1884. Anal. Calcd for C33H27NO5:
C, 76.58; H, 5.26; N, 2.71. Found: C, 76.58; H, 5.43; N, 2.40.
Exact mass (EI+) m/z calcd for C36H BrNO5 (M+):
637.1464. Found: 637.1464.
4.5.7. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Bromophenyl)-2-cyclohexyl-11-hydroxy-6a-methyl-
3a,4,6,6a,12a,13,13a,13b-octahydro-1H-anthra[2,3-e]iso-
indole-1,3,7,12(2H)-tetrone 46 {A1,B4,C9}. MS m/z 601
1
(M+ 79Br). H NMR (600 MHz, CDCl3): d 1.19–1.34 (m,
3H), 1.36 (s, 3H), 1.42–1.48 (m, 2H), 1.65–1.69 (m, 1H),
1.80–1.85 (m, 2H), 2.01–2.16 (m, 3H), 2.51–2.61 (m, 2H),
2.71 (m, 1H), 2.96 (ddd, J¼14.5 Hz, 8.5 Hz, 6.1 Hz, 1H),
3.04–3.11 (m, 2H), 3.28–3.32 (m, 2H), 3.86–3.93 (m, 1H),
5.30 (m, 1H), 6.95–7.01 (m, 2H), 7.19 (dd, J¼8.3 Hz,
0.9 Hz, 1H), 7.23–7.27 (m, 2H), 7.33 (dd, J¼7.7 Hz,
0.9 Hz, 1H), 7.58 (dd, J¼8.3 Hz, 7.7 Hz, 1H), 11.97 (s,
4.5.4. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Ethyl-11-
hydroxy-6a-methyl-6-(4-methylphenyl)-3a,4,6,6a,12a,
13,13a,13b-octahydro-1H-anthra[2,3-e]isoindole-1,3,7,
12(2H)-tetrone 20 {A1,B2,C3}. MS m/z 483 (M+). 1H NMR
(600 MHz, CDCl3): d 1.09 (t, J¼7.2 Hz, 3H), 1.43 (s, 3H),
2.11 (m, 1H), 2.22 (s, 3H), 2.61 (br dd, J¼15.5 Hz, 7.2 Hz,
1H), 2.65 (ddd, J¼14.4 Hz, 7.9 Hz, 5.7 Hz, 1H), 2.80 (m,
1H), 3.04 (ddd, J¼14.4 Hz, 9.8 Hz, 5.8 Hz, 1H), 3.09 (br
dd, J¼8.6 Hz, 7.7 Hz, 1H), 3.15 (dd, J¼8.6 Hz, 5.7 Hz,
1H), 3.27 (dd, J¼5.8 Hz, 5.7 Hz, 1H), 3.40 (br s, 1H), 3.50
(q, J¼7.2 Hz, 2H), 5.38 (m, 1H), 6.85–6.89 (m, 2H), 6.89–
6.94 (m, 2H), 7.14 (br d, J¼8.2 Hz, 1H), 7.32 (br d,
J¼7.6 Hz, 1H), 7.53 (dd, J¼8.2 Hz, 7.6 Hz, 1H), 12.00 (s,
1H). 13C NMR (150 MHz, CDCl3): d 13.1, 20.9, 23.3, 25.2,
25.3, 33.1, 33.7, 40.0, 44.0, 52.9, 53.4, 55.8, 117.2, 118.6,
122.7, 123.7, 126.5, 128.6 (2C), 130.5 (2C), 135.6, 136.1,
136.7, 136.8, 140.5, 160.8, 178.3, 179.2, 199.6, 204.6.
Exact mass (EI+) m/z calcd for C30H29NO5: 483.2046.
Found: 483.2045.
1H). Exact mass (EI+) m/z calcd for C33H BrNO5 (M+):
79
32
601.1464. Found: 601.1464.
4.5.8. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Chlorophenyl)-2-ethyl-11-hydroxy-6a-methyl-3a,4,6,6a,
12a,13,13a,13b-octahydro-1H-anthra[2,3-e]isoindole-
1,3,7,12(2H)-tetrone 50 {A1,B5,C3}. MS m/z 503 (M+). 1H
NMR (600 MHz, CDCl3): d 1.08 (t, J¼7.1 Hz, 3H), 1.37 (s,
3H), 2.11 (m, 1H), 2.54–2.65 (m, 2H), 2.74 (m, 1H), 3.03
(ddd, J¼14.6 Hz, 9.0 Hz, 6.2 Hz, 1H), 2.99–3.06 (m, 1H),
3.11–3.15 (m, 1H), 3.30 (dd, J¼6.4 Hz, 6.2 Hz, 1H), 3.36
(br s, 1H), 3.49 (q, J¼7.1 Hz, 2H), 5.32 (m, 1H), 6.99–7.03
(m, 2H), 7.09–7.13 (m, 2H), 7.18 (br d, J¼8.4 Hz, 1H),
7.32 (br d, J¼7.6 Hz, 1H), 7.56 (dd, J¼8.4 Hz, 7.6 Hz,
1H), 11.96 (s, 1H). Exact mass (EI+) m/z calcd for
C29H26ClNO5: 503.1499. Found: 503.1499.
4.5.9. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Benzyl-6-
(4-fluorophenyl)-11-hydroxy-6a-methyl-3a,4,6,6a,12a,
13,13a,13b-octahydro-1H-anthra[2,3-e]isoindole-1,3,7,
12(2H)-tetrone 65 {A1,B6,C8}. MS m/z 549 (M+). 1H NMR
(600 MHz, CDCl3): d 1.25 (s, 3H), 2.12 (m, 1H), 2.52 (ddd,
J¼14.6 Hz, 6.6 Hz, 6.4 Hz, 1H), 2.64 (br dd, J¼15.3 Hz,
7.6 Hz, 1H), 2.74 (m, 1H), 2.94 (ddd, J¼14.6 Hz, 9.0 Hz,
6.2 Hz, 1H), 3.11–3.18 (3H), 3.24 (dd, J¼6.4 Hz, 6.2 Hz,
1H), 4.58 (d, J¼14.2 Hz, 1H), 4.63 (d, J¼14.2 Hz, 1H),
5.28 (m, 1H), 6.77–6.82 (m, 2H), 6.87–6.91 (m, 2H), 7.16
(br d, J¼8.3 Hz, 1H), 7.24–7.32 (m, 5H), 7.29 (br d,
J¼7.6 Hz, 1H), 7.54 (dd, J¼8.3 Hz, 7.6 Hz, 1H), 11.94 (s,
1H). Exact mass (EI+) m/z calcd for C34H28FNO5:
549.1952. Found: 549.1951.
4.5.5. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-11-
Hydroxy-6a-methyl-6-(4-methylphenyl)-2-phenyl-
3a,4,6,6a,12a,13,13a,13b-octahydro-1H-anthra[2,3-e]iso-
indole-1,3,7,12(2H)-tetrone 22 {A1,B2,C5}. MS m/z 531
(M+). 1H NMR (600 MHz, CDCl3): d 1.43 (s, 3H), 2.21 (m,
1H), 2.25 (s, 3H), 2.65–2.75 (2H), 2.90 (m, 1H), 3.02 (m,
1H), 3.25–3.32 (2H), 3.37 (dd, J¼8.5 Hz, 5.7 Hz, 1H), 3.46
(br s, 1H), 5.49 (m, 1H), 6.69–6.94 (m, 2H), 6.94–6.99 (m,
2H), 7.12–7.20 (3H), 7.34 (br d, J¼7.6 Hz, 1H), 7.39–7.45
(m, 1H), 7.45–7.51 (m, 2H), 7.54 (dd, J¼8.3 Hz, 7.6 Hz,
1H), 12.01 (s, 1H). 13C NMR (150 MHz, CDCl3): d 20.9,
23.7, 25.3, 25.5, 33.2, 40.3, 44.4, 53.0, 53.4, 56.0, 117.2,
118.6, 122.8, 123.6, 126.5 (2C), 128.7 (2C), 128.8, 129.3
(2C), 130.6 (2C), 131.8, 135.4, 136.1, 136.8, 136.9, 140.8,
160.8, 177.6, 178.5, 199.6, 204.6. Exact mass (EI+) m/z calcd
for C34H29NO5: 531.2046. Found: 531.2039.
4.5.10. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6a,12a-
Dimethyl-6-phenyl-3a,4,6,6a,12a,13,13a,13b-octahydro-
1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone 68
{A2,B1,C1}. MS m/z 439 (M+). 1H NMR (600 MHz,
CDCl3): d 1.22 (s, 3H), 1.59 (s, 3H), 2.17 (m, 1H), 2.54–
2.60 (2H), 2.78 (dd, J¼13.9 Hz, 12.3 Hz, 1H), 3.19 (m,
1H), 3.21 (ddd, J¼8.6 Hz, 8.3 Hz, 2.1 Hz, 1H), 3.31 (dd,
J¼8.6 Hz, 6.1 Hz, 1H), 3.74 (br s, 1H), 5.46 (m, 1H), 6.60–
6.65 (m, 2H), 6.82–6.87 (m, 3H), 7.47 (ddd, J¼7.5 Hz,
7.5 Hz, 1.1 Hz, 1H), 7.52 (ddd, J¼7.5 Hz, 7.5 Hz, 1.1 Hz,
1H), 7.60 (br d, J¼7.5 Hz, 1H), 7.82 (br d, J¼7.5 Hz, 1H),
8.25 (br s, 1H). 13C NMR (150 MHz, CDCl3): d 20.8, 25.1,
26.9, 29.4, 33.8, 41.3, 44.5, 51.7, 56.9, 57.3, 125.3, 125.9,
126.8, 126.8, 127.7 (2C), 130.1 (2C), 133.3, 133.6, 133.8,
135.7, 139.7, 141.1, 178.6, 179.5, 200.5, 201.2. Exact mass
(EI+) m/z calcd for C28H25NO4: 439.1784. Found: 439.1784.
4.5.6. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-
(4-Bromophenyl)-11-hydroxy-6-(4-isopropylphenyl)-
6a-methyl-3a,4,6,6a,12a,13,13a,13b-octa-hydro-1H-
anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone 34 {A1,
B3,C7}. MS m/z 637 (M+ 79Br). 1H NMR (600 MHz,
CDCl3): d 1.12 (d, J¼6.8 Hz, 3H), 1.13 (d, J¼6.8 Hz, 3H),
1.46 (s, 3H), 2.27 (m, 1H), 2.67–2.77 (m, 3H), 2.94–3.05
(2H), 3.24 (dd, J¼5.5 Hz, 4.8 Hz, 1H), 3.33 (ddd, J¼
10.4 Hz, 8.6 Hz, 2.0 Hz, 1H), 3.40 (br dd, J¼8.6 Hz,
5.5 Hz, 1H), 3.52 (br s, 1H), 5.54 (m, 1H), 6.85–6.87 (m,
2H), 6.89–6.92 (m, 2H), 7.07 (br d, J¼8.3 Hz, 1H), 7.08–
7.11 (m, 2H), 7.32 (br d, J¼7.6 Hz, 1H), 7.47 (dd, J¼
8.3 Hz, 7.6 Hz, 1H), 7.60–7.63 (m, 2H), 11.89 (s, 1H).

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C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
4.5.11. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Ethyl-
6a,12a-dimethyl-6-phenyl-3a,4,6,6a,12a,13,13a,13b-octa-
hydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone
2.1 Hz, 1H), 3.41 (dd, J¼8.4 Hz, 5.9 Hz, 1H), 3.63 (br s,
1H), 5.47 (m, 1H), 6.49–6.53 (m, 2H), 6.70–6.74 (m, 2H),
7.13–7.17 (m, 2H), 7.38–7.43 (m, 1H), 7.44–7.49 (m, 2H),
7.53 (ddd, J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.57 (ddd, J¼
7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.65 (br dd, J¼7.5 Hz, 1.2 Hz,
1H), 7.87 (br dd, J¼7.5 Hz, 1.2 Hz, 1H). Exact mass (EI+)
m/z calcd for C35H31NO4: 529.2253. Found: 529.2253.
1
70 {A2,B1,C3}. MS m/z 467 (M+). H NMR (600 MHz,
CDCl3): d 1.10 (t, J¼7.2 Hz, 3H), 1.23 (s, 3H), 1.57 (s,
3H), 2.13 (m, 1H), 2.55–2.61 (2H), 2.86 (dd, J¼14.0 Hz,
12.2 Hz, 1H), 3.13 (ddd, J¼8.5 Hz, 8.4 Hz, 1.6 Hz, 1H),
3.14 (m, 1H), 3.20 (dd, J¼8.5 Hz, 5.9 Hz, 1H), 3.51 (q,
J¼7.2 Hz, 1H), 3.63 (br s, 1H), 5.37 (m, 1H), 6.57–6.61
(m, 2H), 6.85–6.91 (m, 3H), 7.50 (ddd, J¼7.5 Hz, 7.5 Hz,
1.2 Hz, 1H), 7.54 (ddd, J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H),
7.61 (br d, J¼7.5 Hz, 1H), 7.85 (br d, J¼7.5 Hz, 1H). 13C
NMR (150 MHz, CDCl3): d 13.1, 20.9, 25.3, 26.7, 29.4,
33.6, 34.3, 40.1, 43.2, 51.8, 56.9, 57.2, 125.3, 126.0, 126.9,
126.9, 127.6 (2C), 130.1 (2C), 133.4, 133.6, 133.8, 135.9,
139.8, 140.6, 178.4, 179.3, 200.4, 201.1. Exact mass (EI+)
m/z calcd for C30H29NO4: 467.2097. Found: 467.2098.
4.5.15. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-(4-
Acetylphenyl)-6-(4-isopropylphenyl)-6a,12a-dimethyl-
3a,4,6,6a,12a,13,13a,13b-octahydro-1H-anthra[2,3-e]iso-
indole-1,3,7,12(2H)-tetrone 92 {A2,B3,C6}. MS m/z 599
1
(M+). H NMR (600 MHz, CDCl3): d 1.02 (d, J¼6.8 Hz,
6H), 1.19 (s, 3H), 1.57 (s, 3H), 2.31 (m, 1H), 2.57–2.67
(2H), 2.65 (s, 3H), 2.68 (ddd, J¼16.0 Hz, 6.8 Hz, 2.2 Hz,
1H), 2.76 (dd, J¼14.1 Hz, 12.1 Hz, 1H), 3.33 (m, 1H), 3.36
(ddd, J¼8.5 Hz, 8.3 Hz, 2.2 Hz, 1H), 3.47 (dd, J¼8.5 Hz,
6.0 Hz, 1H), 3.73 (br s, 1H), 5.55 (m, 1H), 6.52–6.57 (m,
2H), 6.65–6.70 (m, 2H), 7.36–7.40 (m, 2H), 7.44 (ddd,
J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.48 (ddd, J¼7.5 Hz,
7.5 Hz, 1.2 Hz, 1H), 7.63 (br dd, J¼7.5 Hz, 1.2 Hz, 1H),
7.78 (br dd, J¼7.5 Hz, 1.2 Hz, 1H), 8.06–8.09 (m, 2H).
Exact mass (EI+) m/z calcd for C39H37NO5: 599.2672.
Found: 599.2672.
4.5.12. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6a,12a-
Dimethyl-2,6-diphenyl-3a,4,6,6a,12a,13,13a,13b-octa-
hydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone 8
{A2,B1,C5}. MS m/z 515 (M+). 1H NMR (600 MHz,
CDCl3): d 1.23 (s, 3H), 1.58 (s, 3H), 2.26 (m, 1H), 2.64 (dd,
J¼13.9 Hz, 7.4 Hz, 1H), 2.67 (ddd, J¼16.0 Hz, 6.8 Hz,
1.9 Hz, 1H), 2.86 (dd, J¼13.9 Hz, 12.3 Hz, 1H), 3.25 (m,
1H), 3.33 (ddd, J¼8.5 Hz, 8.3 Hz, 1.9 Hz, 1H), 3.43 (dd,
J¼8.5 Hz, 5.9 Hz, 1H), 3.70 (br s, 1H), 5.49 (m, 1H),
6.63–6.67 (m, 2H), 6.88–6.93 (m, 3H), 7.16–7.19 (m, 2H),
7.39–7.44 (m, 1H), 7.45–7.50 (m, 2H), 7.52 (ddd, J¼
7.5 Hz, 7.5 Hz, 1.1 Hz, 1H), 7.56 (ddd, J¼7.5 Hz, 7.5 Hz,
1.1 Hz, 1H), 7.65 (br d, J¼7.5 Hz, 1H), 7.87 (br d,
J¼7.5 Hz, 1H). 13C NMR (150 MHz, CDCl3): d 20.9,
25.5, 26.8, 29.7, 34.3, 40.3, 43.5, 51.8, 57.0, 57.6, 125.2,
126.0, 126.5 (2C), 126.9, 127.0, 127.7 (2C), 128.7, 129.2
(2C), 130.1 (2C), 133.4, 133.7, 133.8, 135.8, 139.9, 140.5,
177.5, 178.6, 200.4, 201.1. Exact mass (EI+) m/z calcd for
C34H29NO4: 515.2097. Found: 515.2097. Anal. Calcd for
C34H29NO4: C, 79.20; H, 5.67; N, 2.72. Found: C, 79.20;
H, 5.64; N, 2.78.
4.5.16. 3-[(3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Isopropylphenyl)-6a,12a-dimethyl-1,3,7,12-tetraoxo-1,3,
3a,4,6,6a,7,12,12a,13,13a,13b-dodecahydro-2H-an-
thra[2,3-e]isoindol-2-yl]propanoic acid 96 {A2,B3,C10}.
1
MS m/z 553 (M+). H NMR (600 MHz, CDCl3): d 1.01 (d,
J¼6.8 Hz, 6H), 1.19 (s, 3H), 1.56 (s, 3H), 2.18 (m, 1H),
2.54–2.63 (3H), 2.64 (t, J¼7.2 Hz, 2H), 2.79 (dd, J¼
14.1 Hz, 12.0 Hz, 1H), 3.17 (ddd, J¼8.4 Hz, 8.2 Hz, 2.1 Hz,
1H), 3.21 (m, 1H), 3.25 (dd, J¼8.4 Hz, 5.9 Hz, 1H), 3.71 (br
s, 1H), 3.80 (m, 2H), 5.43 (m, 1H), 6.49–6.53 (m, 2H), 6.62–
6.66 (m, 2H), 7.42 (ddd, J¼7.6 Hz, 7.6 Hz, 1.2 Hz, 1H), 7,45
(ddd, J¼7.6 Hz, 7.6 Hz, 1.2 Hz, 1H), 7.59 (br dd, J¼7.6 Hz,
1.2 Hz, 1H), 7.75 (br dd, J¼7.6 Hz, 1.2 Hz, 1H). Exact mass
(EI+) m/z calcd for C34H35NO6: 553.2464. Found: 553.2463.
4.5.13. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6a,12a-
Dimethyl-6-(4-methylphenyl)-2-propyl-3a,4,6,6a,12a,
13,13a,13b-octahydro-1H-anthra-[2,3-e]isoindole-1,3,7,
12(2H)-tetrone 80 {A2,B2,C4}. MS m/z 495 (M+). 1H NMR
(600 MHz, CDCl3): d 0.82 (t, J¼7.4 Hz, 3H), 1.22 (s, 3H),
1.46–1.56 (2H), 1.54 (s, 3H), 2.14 (m, 1H), 2.53–2.59
(2H), 2.86 (dd, J¼14.1 Hz, 12.1 Hz, 1H), 3.08 (m, 1H),
3.12 (ddd, J¼8.4 Hz, 8.2 Hz, 1.8 Hz, 1H), 3.18 (dd,
J¼8.6 Hz, 5.8 Hz, 1H), 3.42 (m, 2H), 3.58 (br s, 1H), 5.36
(m, 1H), 6.43–6.47 (m, 2H), 6.65–6.69 (m, 2H), 7.51 (ddd,
J¼8.6 Hz, 7.6 Hz, 1.1 Hz, 1H), 7.55 (ddd, J¼8.6 Hz,
7.6 Hz, 1.1 Hz, 1H), 7.60 (br dd, J¼7.6 Hz, 1.1 Hz, 1H),
7.85 (br dd, J¼7.6 Hz, 1.1 Hz, 1H). Exact mass (EI+) m/z
calcd for C32H33NO4: 495.2410. Found: 495.2410.
4.5.17. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Bromophenyl)-2,6a,12a-trimethyl-3a,4,6,6a,12a,13,13a,
13b-octahydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-
1
tetrone 98 {A2,B4,C2}. MS m/z 531 (M+ 79Br). H NMR
(600 MHz, CDCl3): d 1.23 (s, 3H), 1.56 (s, 3H), 2.15 (m,
1H), 2.54–2.61 (2H), 2.85 (dd, J¼14.1 Hz, 12.0 Hz, 1H),
2.95 (s, 3H), 3.13 (m, 1H), 3.17 (ddd, J¼8.4 Hz, 8.2 Hz,
2.1 Hz, 1H), 3.23 (dd, J¼8.4 Hz, 5.9 Hz, 1H), 3.65 (br s,
1H), 5.36 (m, 1H), 6.44–6.50 (m, 2H), 6.93–6.99 (m, 2H),
7.53 (ddd, J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.57 (ddd,
J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.60 (br dd, J¼7.5 Hz,
1.2 Hz, 1H), 7.82 (br dd, J¼7.5 Hz, 1.2 Hz, 1H). Exact
mass (EI+) m/z calcd for C29H BrNO4 (M+): 531.1045.
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26
Found: 531.1041.
4.5.14. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6a,12a-
Dimethyl-6-(4-methylphenyl)-2-phenyl-3a,4,6,6a,12a,13,
13a,13b-octahydro-1H-anthra-[2,3-e]isoindole-1,3,7,12
4.5.18. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Bromophenyl)-2-cyclohexyl-6a,12a-dimethyl-3a,4,6,6a,
12a,13,13a,13b-octahydro-1H-anthra[2,3-e]isoindole-
1,3,7,12(2H)-tetrone 105 {A2,B4,C9}. MS m/z 599 (M+
1
(2H)-tetrone 81 {A2,B2,C5}. MS m/z 529 (M+). H NMR
1
(600 MHz, CDCl3): d 1.22 (s, 3H), 1.54 (s, 3H), 2.11 (s,
3H), 2.23 (m, 1H), 2.61 (dd, J¼14.1 Hz, 7.2 Hz, 1H), 2.67
(ddd, J¼15.9 Hz, 6.8 Hz, 2.1 Hz, 1H), 2.84 (dd, J¼14.1 Hz,
12.1 Hz, 1H), 3.19 (m, 1H), 3.31 (ddd, J¼8.4 Hz, 8.2 Hz,
79Br). H NMR (600 MHz, CDCl3): d 1.18–1.36 (m, 3H),
1.23 (s, 3H), 1.42–1.50 (m, 2H), 1.55 (s, 3H), 1.62–1.71 (m,
1H), 1.78–1.88 (m, 2H), 2.00–2.17 (3H), 2.52–2.58 (2H),
2.80 (dd, J¼14.1 Hz, 12.1 Hz, 1H), 3.06 (m, 1H), 3.08

C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
6907
(ddd, J¼15.9 Hz, 6.8 Hz, 2.1 Hz, 1H), 3.14 (dd, 8.4 Hz,
5.9 Hz, 1H), 3.56 (br s, 1H), 3.90 (m, 1H), 5.33 (m, 1H),
6.42–6.49 (m, 2H), 6.97–7.03 (m, 2H), 7.56 (ddd,
J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.60 (ddd, J¼7.5 Hz,
7.5 Hz, 1.2 Hz, 1H), 7.63 (br dd, J¼7.5 Hz, 1.2 Hz, 1H),
7.87 (br dd, J¼7.5 Hz, 1.2 Hz, 1H). Exact mass (EI+) m/z
12.0 Hz, 1H), 3.12 (m, 1H), 3.18 (ddd, J¼8.4 Hz, 8.2 Hz,
2.1 Hz, 1H), 3.23 (dd, J¼8.4 Hz, 5.9 Hz, 1H), 3.41 (br s,
1H), 4.58 (d, J¼14.0 Hz, 1H), 4.65 (d, J¼14.0 Hz, 1H),
5.32 (m, 1H), 6.41–6.47 (m, 2H), 6.47–6.53 (m, 2H),
7.25–7.32 (m, 5H), 7.50 (br dd, J¼7.6 Hz, 7.6 Hz, 1H),
7.55 (br dd, J¼7.6 Hz, 7.6 Hz, 1H), 7.55 (br d, J¼7.6 Hz,
1H), 7.83 (br d, J¼7.6 Hz, 1H). Exact mass (EI+) m/z calcd
for C35H30FNO4: 547.2159. Found: 547.2159.
calcd for C34H BrNO4 (M+): 599.1671. Found: 599.1675.
79
34
4.5.19. 3-[(3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Bromophenyl)-6a,12a-dimethyl-1,3,7,12-tetra-oxo-1,3,3a,
4,6,6a,7,12,12a,13,13a,13b-dodeca-hydro-2H-anthra-
[2,3-e]isoindol-2-yl]propanoic acid 106 {A2,B4,C10}. MS
m/z 589 (M+ 79Br). 1H NMR (600 MHz, CDCl3): d 1.23 (s,
3H), 1.56 (s, 3H), 2.14 (m, 1H), 2.54–2.60 (2H), 2.61 (dd,
J¼7.2 Hz, J¼7.2 Hz, 2H), 2.84 (dd, J¼14.1 Hz, 12.1 Hz,
1H), 3.12 (m, 1H), 3.16 (ddd, J¼8.5 Hz, 8.3 Hz, 1.6 Hz,
1H), 3.22 (dd, J¼8.5 Hz, 5.7 Hz, 1H), 3.64 (br s, 1H), 3.78
(m, 2H), 5.35 (m, 1H), 6.45–6.50 (m, 2H), 6.95–6.99 (m,
2H), 7.54 (ddd, J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.56–7.62
(2H), 7.84 (dd, J¼7.5 Hz, 1.2 Hz, 1H). Exact mass (EI+)
4.5.23. 3-[(3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-10-
Bromo-11-hydroxy-6a,12a-dimethyl-1,3,7,12-tetraoxo-
6-phenyl-1,3,3a,4,6,6a,7,12,12a,13,13a,13b-dodeca-
hydro-2H-anthra[2,3-e]isoindol-2-yl]propanoic acid 136
{A3,B1,C10}. MS m/z 591 (M+ 79Br). 1H NMR (600 MHz,
CDCl3): d 1.46 (s, 3H), 2.16 (m, 1H), 2.61 (t, J¼7.2 Hz,
2H), 2.61 (dd, 1H), 2.65 (ddd, J¼14.5 Hz, 8.1 Hz, 5.4 Hz,
1H), 2.86 (m, 1H), 3.05 (ddd, J¼14.5 Hz, 10.0 Hz, 6.0 Hz,
1H), 3.15 (ddd, J¼8.5 Hz, 8.3 Hz, 1.3 Hz, 1H), 3.20 (dd,
J¼8.5 Hz, 5.4 Hz, 1H), 3.29 (dd, J¼6.0 Hz, 5.4 Hz, 1H),
3.50 (br s, 1H), 3.78 (t, J¼7.2 Hz, 2H), 5.42 (m, 1H),
6.94–7.00 (m, 2H), 7.04–7.12 (m, 3H), 7.21 (d, J¼8.1 Hz,
1H), 7.76 (d, J¼8.1 Hz, 1H), 12.61 (s, 1H). Exact mass
m/z calcd for C31H BrNO6 (M+): 589.1100. Found:
79
28
589.1098.
(EI+) m/z calcd for C30H BrNO7 (M+): 591.0893. Found:
79
26
4.5.20. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-6-(4-
Chlorophenyl)-6a,12a-dimethyl-2-phenyl-3a,4,6,6a,12a,
13,13a,13b-octahydro-1H-anthra-[2,3-e]isoindole-
1,3,7,12(2H)-tetrone 111 {A2,B5,C5}. MS m/z 549 (M+).
1H NMR (600 MHz, CDCl3): d 1.23 (s, 3H), 1.56 (s, 3H),
2.25 (m, 1H), 2.62 (dd, J¼14.1 Hz, 7.2 Hz, 1H), 2.69 (ddd,
J¼15.9 Hz, 6.8 Hz, 2.1 Hz, 1H), 2.85 (dd, J¼14.1 Hz,
12.1 Hz, 1H), 3.22 (m, 1H), 3.33 (ddd, J¼8.4 Hz, 8.2 Hz,
2.1 Hz, 1H), 3.42 (dd, J¼8.4 Hz, 5.9 Hz, 1H), 3.68 (br s,
1H), 5.46 (m, 1H), 6.54–6.59 (m, 2H), 6.84–6.88 (m, 2H),
7.14–7.18 (m, 2H), 7.39–7.43 (m, 1H), 7.44–7.50 (m, 2H),
7.56 (ddd, J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.60 (ddd,
J¼7.5 Hz, 7.5 Hz, 1.2 Hz, 1H), 7.65 (br dd, J¼7.5 Hz,
1.2 Hz, 1H), 7.87 (br dd, J¼7.5 Hz, 1.2 Hz, 1H). Exact
mass (EI+) m/z calcd for C34H28ClNO4: 549.1707. Found:
549.1705.
591.0896.
4.5.24. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-10-
Bromo-2-ethyl-11-hydroxy-6a,12a-dimethyl-6-(4-methyl-
phenyl)-3a,4,6,6a,12a,13,13a,13b-octahydro-1H-anthra-
[2,3-e]isoindole-1,3,7,12(2H)-tetrone 139 {A3,B2,C3}.
MS m/z 561 (M+ 79Br). 1H NMR (600 MHz, CDCl3):
d 1.10 (t, J¼7.2 Hz, 3H), 1.45 (s, 3H), 2.13 (m, 1H), 2.19
(s, 3H), 2.62 (ddd, J¼15.7 Hz, 7.2 Hz, 1.4 Hz, 1H), 2.67
(ddd, J¼14.4 Hz, 8.1 Hz, 5.2 Hz, 1H), 2.86 (m, 1H), 3.05
(ddd, J¼14.4 Hz, 10.1 Hz, 6.0 Hz, 1H), 3.12 (ddd, J¼
9.4 Hz, 8.1 Hz, 1.4 Hz, 1H), 3.17 (dd, J¼8.5 Hz, 5.8 Hz,
1H), 3.27 (dd, J¼6.0 Hz, 5.2 Hz, 1H), 3.44 (br s, 1H), 3.51
(q, J¼7.2 Hz, 2H), 5.42 (m, 1H), 6.75–6.79 (m, 2H), 6.85–
6.89 (m, 2H), 7.21 (d, J¼8.1 Hz, 1H), 7.76 (d, J¼8.1 Hz,
1H), 12.64 (s, 1H). Exact mass (EI+) m/z calcd for
C30H BrNO5 (M+): 561.1151. Found: 561.1151.
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28
4.5.21. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Ethyl-6-
(4-fluorophenyl)-6a,12a-dimethyl-3a,4,6,6a,12a,13,13a,
13b-octahydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-
tetrone 119 {A2,B6,C3}. MS m/z 485 (M+). 1H NMR
(600 MHz, CDCl3): d 1.09 (t, J¼7.2 Hz, 3H), 1.22 (s, 3H),
2.55 (s, 3H), 2.12 (m, 1H), 2.57 (dd, J¼14.2 Hz, 7.6 Hz,
1H), 2.59 (ddd, J¼15.8 Hz, 6.8 Hz, 2.1 Hz, 1H), 2.85 (dd,
J¼14.2 Hz, 12.0 Hz, 1H), 3.10 (m, 1H), 3.13 (ddd,
J¼8.4 Hz, 8.2 Hz, 2.1 Hz, 1H), 3.19 (dd, J¼8.4 Hz,
5.7 Hz, 1H), 3.51 (q, J¼7.2 Hz, 2H), 3.63 (br s, 1H), 5.35
(m, 1H), 6.51–6.59 (m, 4H), 7.53 (ddd, J¼7.5 Hz, 7.5 Hz,
1.1 Hz, 1H), 7.57 (ddd, J¼7.5 Hz, 7.5 Hz, 1.1 Hz, 1H),
7.62 (br dd, J¼7.5 Hz, 1.1 Hz, 1H), 7.85 (br dd, J¼7.5 Hz,
1.1 Hz, 1H). Exact mass (EI+) m/z calcd for C30H28FNO4:
485.2002. Found: 485.1999.
4.5.25. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-10-
Bromo-2-(4-bromophenyl)-11-hydroxy-6-(4-isopropyl-
phenyl)-6a,12a-dimethyl-3a,4,6,6a,12a,13,13a,13b-octa-
hydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone
1
153 {A3,B3,C7}. MS m/z 717 (M+ 79Br/81Br). H NMR
(600 MHz, CDCl3): d 1.10 (d, J¼6.8 Hz, 3H), 1.10 (d,
J¼6.8 Hz, 3H), 1.51 (s, 3H), 2.29 (m, 1H), 2.66–2.79
(3H), 3.01 (ddd, J¼14.7 Hz, 10.5 Hz, 6.0 Hz, 1H), 3.11
(m, 1H), 3.25 (dd, J¼5.5 Hz, 4.4 Hz, 1H), 3.35 (ddd,
J¼8.5 Hz, 8.5 Hz, 2.1 Hz, 1H), 3.43 (dd, J¼8.7 Hz,
6.0 Hz, 1H), 3.60 (br s, 1H), 5.59 (m, 1H), 6.75–6.79 (m,
2H), 6.83–6.87 (m, 2H), 7.10–7.14 (m, 2H), 7.21 (d,
J¼8.2 Hz, 1H), 7.60–7.64 (m, 5H), 7.68 (d, J¼8.2 Hz,
1H), 12.50 (s, 1H). Exact mass (EI+) m/z calcd for
C36H Br2NO5 (M+): 715.0569. Found: 715.0570.
79
31
4.5.22. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Benzyl-
6-(4-fluorophenyl)-6a,12a-dimethyl-3a,4,6,6a,12a,13,13a,
13b-octahydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-
tetrone 124 {A2,B6,C8}. MS m/z 547 (M+). 1H NMR
(600 MHz, CDCl3): d 1.16 (s, 3H), 1.37 (s, 3H), 2.13 (m,
1H), 2.51 (dd, J¼14.1 Hz, 7.6 Hz, 1H), 2.62 (ddd, J¼
15.8 Hz, 7.1 Hz, 2.1 Hz, 1H), 2.69 (dd, J¼14.1 Hz,
4.5.26. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Benzyl-
10-bromo-11-hydroxy-6-(4-isopropylphenyl)-6a,12a-
dimethyl-3a,4,6,6a,12a,13,13a,13b-octahydro-1H-anthra-
[2,3-e]isoindole-1,3,7,12(2H)-tetrone 154 {A3,B3,C8}.
MS m/z 651 (M+ 79Br). 1H NMR (600 MHz, CDCl3):
d 1.08 (d, J¼6.8 Hz, 3H), 1.09 (d, J¼6.8 Hz, 3H), 1.32

6908
C. Kormann et al. / Tetrahedron 62 (2006) 6899–6908
(s, 3H), 2.17 (m, 1H), 2.63–2.71 (3H), 2.94 (m, 1H), 2.99
(m, 1H), 3.17 (dd, J¼5.9 Hz, 4.4 Hz, 1H), 3.20 (ddd,
J¼9.4 Hz, 8.1 Hz, 1.4 Hz, 1H), 3.24 (dd, J¼8.7 Hz,
5.8 Hz, 1H), 3.42 (br s, 1H), 4.62 (d, J¼14.0 Hz, 1H), 4.67
(d, J¼14.0 Hz, 1H), 5.48 (m, 1H), 6.64–6.68 (m, 2H),
6.78–6.82 (m, 2H), 7.16 (d, J¼8.2 Hz, 1H), 7.24–7.32 (m,
5H), 7.65 (d, J¼8.2 Hz, 1H), 12.49 (s, 1H). Exact mass
(s, 3H), 2.13 (m, 1H), 2.25 (ddd, J¼14.7 Hz, 8.6 Hz, 6.4 Hz,
1H), 2.65 (br dd, J¼15.8 Hz, 7.3 Hz, 1H), 2.75 (m, 1H), 2.95
(ddd, J¼14.7 Hz, 8.8 Hz, 6.1 Hz, 1H), 3.13–3.19 (3H), 3.27
(dd, J¼6.4 Hz, 6.1 Hz, 1H), 4.59 (d, J¼14.1 Hz, 1H), 4.63
(d, J¼14.1 Hz, 1H), 5.30 (m, 1H), 6.77–6.82 (m, 2H),
6.84–6.88 (m, 2H), 7.19 (d, J¼8.1 Hz, 1H), 7.25–7.31 (m,
5H), 7.81 (d, J¼8.1 Hz, 1H), 12.62 (s, 1H). Exact mass
(EI+) m/z calcd for C37H BrNO5 (M+): 651.1620. Found:
(EI+) m/z calcd for C34H BrFNO5 (M+): 627.1057.
79
34
79
27
651.1624.
Found: 627.1059.
4.5.27. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-10-
Bromo-6-(4-bromophenyl)-11-hydroxy-6a,12a-dimethyl-
3a,4,6,6a,12a,13,13a,13b-octahydro-1H-anthra[2,3-e]iso-
indole-1,3,7,12(2H)-tetrone 157 {A3,B4,C1}. MS m/z 599
Acknowledgements
This work was supported by the Deutsche Forschungsge-
meinschaft (SFB-473). Dr. Stefan Lober is acknowledged
¨
for helpful discussions.
1
(M+ 79Br/81Br). H NMR (600 MHz, CDCl3): d 1.41 (s,
3H), 2.16 (m, 1H), 2.56 (ddd, J¼14,8 Hz, 8.3 Hz, 6.1 Hz,
1H), 2.62 (ddd, J¼16.1 Hz, 7.2 Hz, 1.4 Hz, 1H), 2.78 (m,
1H), 3.00 (ddd, J¼14.8 Hz, 9.3 Hz, 6.4 Hz, 1H), 3.19
(ddd, J¼8.4 Hz, 8.3 Hz, 1.4 Hz, 1H), 3.24 (dd, J¼8.7 Hz,
5.5 Hz, 1H), 3.31 (dd, J¼6.4 Hz, 6.1 Hz, 1H), 3.45 (br s,
1H), 5.44 (m, 1H), 6.93–6.97 (m, 2H), 7.23 (d, J¼8.1 Hz,
1H), 7.24–7.27 (m, 2H), 7.67 (br s, 1H), 7.83 (d, J¼
8.1 Hz, 1H), 12.60 (s, 1H). Exact mass (EI+) m/z calcd for
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.04.092.
C27H Br2NO5 (M+): 596.9786. Found: 596.9783.
79
21
4.5.28. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-(4-
Acetylphenyl)-10-bromo-6-(4-chlorophenyl)-11-hy-
droxy-6a,12a-dimethyl-3a,4,6,6a,12a,13,13a,13b-octa-
hydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone
172 {A3,B5,C6}. MS m/z 673 (M+ 81Br). 1H NMR
(600 MHz, CDCl3): d 1.38 (s, 3H), 2.27 (m, 1H), 2.62 (m,
1H), 2.64 (s, 3H), 2.74 (br dd, J¼15.9 Hz, 7.1 Hz, 1H),
2.87 (m, 1H), 3.02 (ddd, J¼14.9 Hz, 8.8 Hz, 6.2 Hz, 1H),
3.29 (ddd, J¼9.0 Hz, 8.6 Hz, 1.9 Hz, 1H), 3.34 (dd,
J¼6.4 Hz, 6.2 Hz, 1H), 3.39 (dd, J¼8.6 Hz, 5.3 Hz, 1H),
3.42 (br s, 1H), 5.48 (m, 1H), 6.99–7.04 (m, 2H), 7.23–7.26
(m, 2H), 7.25 (d, J¼8.1 Hz, 1H), 7.30–7.34 (m, 2H), 7.84
(d, J¼8.1 Hz, 1H), 8.05–8.08 (m, 2H), 12.62 (s, 1H). Exact
References and notes
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mass (EI+) m/z calcd for C35H BrClNO6 (M+): 671.0710.
79
27
7. Rodriguez Loaiza, P.; Lober, S.; Hubner, H.; Gmeiner, P.
¨
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4.5.29. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-10-
Bromo-2-(4-bromophenyl)-6-(4-fluorophenyl)-11-hy-
droxy-6a,12a-dimethyl-3a,4,6,6a,12a,13,13a,13b-octa-
hydro-1H-anthra[2,3-e]isoindole-1,3,7,12(2H)-tetrone
1
183 {A3,B6,C7}. MS m/z 693 (M+ 79Br/81Br). H NMR
(600 MHz, CDCl3): d 1.38 (s, 3H), 2.25 (m, 1H), 2.62 (ddd,
J¼14.8 Hz, 8.3 Hz, 6.4 Hz, 1H), 2.73 (ddd, J¼15.8 Hz,
7.1 Hz, 1.4 Hz, 1H), 2.87 (m, 1H), 3.02 (ddd, J¼14.8 Hz,
9.0 Hz, 6.1 Hz, 1H), 3.30 (ddd, J¼9.1 Hz, 8.4 Hz, 1.4 Hz,
1H), 3.34 (dd, J¼6.4 Hz, 6.1 Hz, 1H), 3.36 (dd, J¼8.4 Hz,
5.3 Hz, 1H), 3.43 (br s, 1H), 5.46 (m, 1H), 6.83–6.89 (m,
2H), 7.00–7.05 (m, 2H), 7.04–7.08 (m, 2H), 7.25 (d, J¼
8.1 Hz, 1H), 7.58–7.63 (m, 2H), 7.83 (d, J¼8.1 Hz, 1H),
12.63 (s, 1H). Exact mass (EI+) m/z calcd for
12. For a very recent example, see: Messer, R.; Pell, X.; Marzinzik,
A. L.; Lehmann, H.; Zimmermann, J.; Haner, R. Synlett 2005,
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2441–2444.
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C33H Br2FNO5 (M+): 691.0005. Found: 691.0019.
79
24
17. Motoyoshiya, J.; Masue, Y.; Iwayama, G.; Yoshioka, S.; Nishii,
Y.; Aoyama, H. Synthesis 2004, 2099–2102.
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21, 3889–3896.
4.5.30. (3aRS,6SR,6aRS,12aSR,13aRS,13bSR)-2-Benzyl-
10-bromo-6-(4-fluorophenyl)-11-hydroxy-6a,12a-di-
methyl-3a,4,6,6a,12a,13,13a,13b-octahydro-1H-an-
thra[2,3-e]isoindole-1,3,7,12(2H)-tetrone 184 {A3,B6,C8}.
MS m/z 627 (M+ 79Br). 1H NMR (600 MHz, CDCl3): d 1.25