Diastereodivergence and appendage diversity in the multicomponent synthesis of aryl-pyrrolo-tetrahydrocarbazoles

Article abstract of DOI:10.1016/j.tet.2008.07.045

A one-pot approach using a subsequent Cu(II)/Cu(I) catalysis and a highly diastereodivergent three-component reaction allow an easy access to various aryl-pyrrolo-tetrahydrocarbazoles with the control of up to four variable fragments and two different diastereoselectivities.

Full text of DOI:10.1016/j.tet.2008.07.045

Tetrahedron 64 (2008) 9607–9618
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereodivergence and appendage diversity in the multicomponent synthesis
of aryl-pyrrolo-tetrahydrocarbazoles
,
b
,
b
c
a
a
Daniel Royer a, Yung-Sing Wong a , Sophie Ple , Angele Chiaroni , Khalid Diker , Jean Levy
*
´
`
´
a Laboratoire d’Isolement, Structure, Transformations et Synthe`se de Substances Naturelles, Universite´ de Reims-Champagne-Ardennes/CNRS FRE 2715,
Facult´e de Pharmacie, IFR53 Biomole´cules, 51 rue de Cognacq-Jay, 51096 Reims Cedex, France
b
´
´
´
ˆ
´
Departement de Pharmacochimie Moleculaire, Universite de Grenoble/CNRS UMR 5063, CNRS/ICMG FR 2607, Bat. Andre Rassat, 470 rue de la Chimie,
38041 Grenoble Cedex 9, France
c Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot approach using a subsequent Cu(II)/Cu(I) catalysis and a highly diastereodivergent three-
component reaction allow an easy access to various aryl-pyrrolo-tetrahydrocarbazoles with the control
of up to four variable fragments and two different diastereoselectivities.
Received 27 March 2008
Received in revised form 11 July 2008
Accepted 14 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 18 July 2008
1. Introduction
aryl-pyrrolo-tetrahydrocarbazole structure have been reported to
be cytotoxic against cancer cell lines.9
Multicomponent reactions (MCR) are powerful approaches for
the rapid access to large libraries of compounds,1 in particular for
those involving many variable reactants. Each variable reactant can
introduce a new appendage that, combined with each other, would
greatly increase the potentiality of fragment combinations. When
these reactions create and control multiple stereogenic centres,2
complex three-dimensional architectures can be made. Among
multistereogenic MCR, the multicomponent [4þ2] cycloaddition
reactions can potentially generate up to four stereogenic sp3 carbon
centres in a single step and have proven to be highly diaster-
eoselective.3 According to the Diversity-Oriented Synthesis (DOS)
concept,4 reactions that would be able to diverge towards a new
diastereoselection should thus extend the libraries into new three-
dimensional molecular diversities.5
Several years ago, an efficient three-component [4þ2] cyclo-
addition reaction involving a 2-substituted indole 1 with an aro-
matic aldehyde 2 and a maleimide 3 was described to yield a single
diastereomeric aryl-pyrrolo-tetrahydrocarbazole 4 in racemic form
(Scheme 1).6,7 Only one relative configuration was accessible. The
central rigid core can be regarded as a suitable scaffold for elabo-
rating a small molecules library that mimics podophyllotoxin,
a natural product well-known as an inhibitor of protein–protein
interaction at tubulin level.8 Moreover, molecules having an
To meet the practice-oriented synthesis criteria and to rapidly
expand our chemical library, we now report reaction optimisations
that allow two distinct configurations to be selectively obtained. In
addition, we will describe the beneficial use of CuSO4$5H2O as the
catalyst of choice in this MCR approach. Indeed, a subsequent
Huisgen 1,3-dipolar cycloaddition (‘click’ methodology10) can be
performed in the same flask by the ability of Cu(II) to be regen-
erated in situ to Cu(I).11,12 These processes have the potential to
extensively increase the diversification of the chemical library.
2. Results and discussion
We began our study by the preparation of various 2-substituted
indoles 1a–h, readily obtained in two steps from 6 (Scheme 2) using
an improved Moody’s approach.13
The three-component coupling of 1, 2 and 3 (Scheme 3) requires
a catalyst (Table 1, entry 1), presumably to activate the initial
Friedel–Crafts addition of the indole 1 to the aldehyde 2. The
thermal condition should favour a subsequent 1,4-elimination
process, generating the reactive indole-2,3-quinodimethane
species.14
Our initial study used the Brønsted acid 10-camphorsulfonic
acid (CSA) as catalyst. However, a low yield was observed with the
electron-donating aromatic aldehyde 2a (entry 2). We found that
the unexpensive Lewis acid CuSO4$5H2O (10 mol %) proved to be
more efficient (entry 3) and allowed through combination of
various indoles 1a–h with the aldehydes 2a–d and the maleimides
3a–c the synthesis of a wide range of new cycloadduct 4 or 5
ranging from 44% to 90% yield. Remarkably, for each combination
* Corresponding author at present address. De´partement de Pharmacochimie
Mole´culaire, Universite´ de Grenoble/CNRS UMR 5063, CNRS/ICMG FR 2607, Baˆt.
´
Andre Rassat, 470 rue de la Chimie, 38041 Grenoble Cedex 9, France. Tel.: þ33 476
63 53 10; fax: þ33 476 63 53 95.
E-mail address: yung-sing.wong@ujf-grenoble.fr (Y.-S. Wong).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.045

9608
D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
R3
R3
OMe
R2
R4
O
R2
R4
MeO
OMe
R1
R1
O
O
O
2
O
O
O
N R5
N R5
N
H
N
H
O
multicomponent
[4+2] réaction
O
OH
podophyllotoxin
O
Y
3
O
Y
1
( )-4
Scheme 1. Le´vy-3CR for the synthesis of indolo-podophyllotoxin analogues.
a : R1 = H; Y = OEt
Y
R1
O
O
b : R1 = H; Y =
c : R1 = H; Y =
d : R1 = H; Y =
O
O
N
N
O
O
O Bn
O
NO2
HY
Zn
NH4Cl
N
H
O
O
OH
NO2
Δ
O
Y
R1
R4
O
O
1a-h
R1
7a-h
6
R3
R2
O
e : R1 = H; Y =
N
N
R5
f : R1 = OBn; Y = OEt
O
O
O
2a : R2 = R3 = R4 = OMe
g : R1 = H; Y = N
O
O
3a : R5 = Ph
2b : R2 = R4 = OMe, R3 = OH
2c : R2 = R3 = H, R4 = NO2
2d : R2 = R4 = H, R3 = OMe
3b : R5 = H
O
3c : R5
=
h : R1 = H; Y =
N
Scheme 2. Synthesis of 2-substituted indoles 1a–h.
R1
single diastereomer
R3
single diastereomer
R3
N
1
H
R2
R4
R2
R4
O
+
R3
Y
R1
R1
O
O
R2
R4
N R5
Δ
Δ
N R5
catalyst
N
H
catalyst
N
H
O
O
2
O
O
O
+
O
Y
Y
( )-5
( )-4
N R5
Y = 5 membered-ring
Y = linear substituent
3
O
´
Scheme 3. Highly diastereodivergent [4þ2] Levy-3CR.
with the indoles 1a–f, only one diastereomer in racemic form was
isolated, either 4 or 5. It is noteworthy that every indole having
an acyclic Y-substituent (1a–c) gives the configuration 4 (entries
2–11), whereas those having a five-membered ring at the Y-sub-
stituent position (1d,e) end up with the configuration 5 (entries
12–17). The only detectable and competing side product was the
self-condensed indole-2,3-quinodimethane dimer.15
This reaction condition was tolerant with the unprotected
phenol 2b, the simple maleimide 3b and the terminal alkynes
(entries 10 and 11). It was easy from the 1H NMR spectra to dis-
tinguish the diastereomers 4 from 5 by their typical chemical shifts
and by their coupling constants from the protons set on the
cyclohexene. Interestingly, when the reaction was carried out with
the indole 1g having a six-membered ring at the Y-substituent
position (entry 18), the diastereoselection was less efficient and
both configurations 5g and 4g were obtained as an inseparable
mixture in 59% yield. The configuration of the major diastereomer
remains the cycloadduct 5g in the ratio of 9:1 compared with 4g as
shown by the 1H NMR spectra.
At the Y-substituent position, we also evaluated the impact of
the chiral N-acyl-benzyloxazolidinone (five-membered ring) in
discriminating the facial selectivity (Scheme 4). The reaction of

D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
9609
Table 1
were stirred overnight at room temperature to yield two new aryl-
pyrrolo-tetrahydrocarbazoles 12 (68%) and 13 (62%).20 This ap-
proach extends truly the diversification potential of our product in
a very short and efficient way.
Two products 14 and 15 (Fig. 2) gave additional examples of
possible variations on this scaffold using this stereoselective and
stereodivergent one-pot route.
Stereoselectives [4þ2] Le´vy-3CR
Entry
Reactantsa
Conditionb
No catalystc
Product
Yield (%)
1
2
3
4
5
6
7
8
1aþ2aþ3a
1aþ2aþ3a
1aþ2aþ3a
1aþ2bþ3a
1aþ2aþ3b
1aþ2bþ3b
1fþ2aþ3a
1cþ2aþ3a
1aþ2cþ3a
1aþ2dþ3c
1bþ2bþ3a
1dþ2aþ3a
1eþ2aþ3a
1dþ2bþ3a
1dþ2aþ3b
1dþ2bþ3b
1dþ2cþ3a
1gþ2aþ3a
d
0
38
74
65
52
44
47
56
90
76
69
73
68
63
66
54
77
59
A
B
B
B
C
B
B
B
B
B
B
B
B
B
C
B
B
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
3. Conclusion
9
In summary, an one-pot approach can selectively unite in one
molecular entity four different and variable fragments with two
kinds of diastereoselectivities, using the copper catalyst twice in
two different oxidation degrees. The high stereoselectivity ob-
served in the formation of 4 (with acyclic Y-substituents) and 5
(with five-membered ring Y-substituents) is still unclear consid-
ering that it cannot be ascribed to the hindrance of the Y-sub-
stituent, nor be related to their functional moieties. Further
investigations are now underway to clarify the highly selective
formation of these two distinct diastereomers 4 and 5. Their
potency to inhibit protein–protein interactions are now under
evaluation. These results will be reported shortly.
10
11
12
13
14
15
16
17
18
5g/4g (9:1)
a
Reactants: 1 (1 equiv)þ2 (1.5 equiv)þ3 (3 equiv).
b
Condition A: 10 mol % CSA, reflux in toluene for 20 h. Condition B: 10 mol %
CuSO4$5H2O, reflux in toluene for 16–36 h. Condition C: 10 mol % CuSO4$5H2O,
reflux in chlorobenzene for 16–36 h.
c
Reflux in toluene for 18 h.
4. Experimental
indole (þ)-1h with the aldehyde 2b and the phenylmaleimide 3a
gave two separable products (ꢀ)-8 (27%) and (þ)-9 (45%), albeit
with a weak facial selectivity (2:3).
4.1. General informations
Melting points were performed on Reichert Thermovar hot-
stage apparatus. IR (film and KBr) spectra were measured with
a Bormem FTIR instrument. UV spectra were obtained with a UNI-
CAM 8700 UV/Vis spectrophotometer in MeOH. 1H NMR (300 MHz
and 400 MHz) and 13C NMR (75 MHz and 100 MHz) spectra were
acquired on a Bruker AC 300 and AC 400 spectrometer with TMS
Gratifyingly, compounds (ꢁ)-4a and (þ)-9 formed single crys-
tals suitable for X-ray diffraction (Fig. 1).16,17 Hence, the relative
configurations of products 4 and 5 and the absolute stereochem-
istries for (ꢀ)-8 and (þ)-9 were unambiguously assigned. The
cycloadduct (þ)-9 is a typical Diels–Alder endo-isomer, whereas
cycloadduct 4a shows an inversion on the stereogenic centre
bearing the acyl-Y-substituent.18 In addition, the reduction of the
imide group of 5a with 6 equiv of LiEt3BH in THF (Scheme 5) gave
regioselectively the hydroxy lactam 10 (71%), whereas the re-
duction of 4a in the same condition led to the isolation of the di-
astereomeric product 11 (74%). Interestingly, the resulting hydroxy
lactam group holds potential for further transformations into var-
ious substructures.19
To circumvent the need for extensive purifications and to rapidly
increase the diversity of our library, we thought that the Cu(II) cat-
alyst used for our MCR, i.e., CuSO4$5H2O, could be ‘recycled’ into
Cu(I) catalyst by simple addition of sodium ascorbate to promote
a subsequentHuisgen 1,3-dipolarcycloadditionin a one-potprocess.
As proof of concept, the indole 1a, the aldehyde 2d and the
maleimide 3c (only 1.5 equiv of 3c was used) were first heated in
toluene with 10 mol % CuSO4$5H2O for 24 h (Scheme 6). The
resulting mixture containing the newly formed product 4i was split
into two equal parts. From each vessel were added sodium ascor-
bate and a new fragment having an azide group. Both mixtures
as internal standard or relative to the deuterated solvent [13C:
d
(CDCl3)¼77 ppm,
d
(DMSO-d6)¼39.51 ppm,
d
(CD3OD)¼49.2 ppm].
Optical rotations were recorded on a Perkin–Elmer 341. Mass
spectra (LRMS and HRMS) were recorded with a VG Autospec,
Micromass GCT and apparatus NERMAG R1010C (EI, CI, DCI, FAB).
ESI mass spectra were recorded with ZQ Waters and MALDI,
Autoflex, Bruker. Elemental analyses were carried out by the
Microanalysis Service of the University of Reims. Flash chroma-
tography was performed on silica gel (Merck, 40–63 mm). Reactions
were monitored by Thin-layer chromatography, with Merck TLC
aluminium sheets (Silica gel 60F254). Zinc dust (<325 mesh) was
purchased from Aldrich Chemical. CuSO4$5H2O was crushed as
a powder prior to use.
4.2. 1-Prop-2-ynylpyrrole-2,5-dione (3c)21
Triphenylphosphine (2.7 g, 10.3 mmol) in dry THF (70 mL) was
cooled to ꢀ78 ꢂC. DEAD (1.63 mL) was injected dropwise over
OH
OH
MeO
OMe
MeO
OMe
O
N
O
N
•
10 mol% CuSO H2O
+
(+)-1h+ 2b + 3a
Ph
Ph
toluene, reflux, 24 h
N
H
N
H
O
O
O
O
O
O
N
N
Bn
(−)-8
Bn
(+)-9
O
O
27%
45%
Scheme 4. Weak diastereoselectivity induced by the chiral N-acyl-benzyloxazolidinone in [4þ2] 3CR.

9610
D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
OH
OMe
MeO
OMe
MeO
OMe
O
N
O
N
O
Ph
Ph
N
H
N
H
O
O
O
O
N
OEt
( )-4a
Bn
O
(+)-9
Figure 1. ORTEP drawing of molecules 4a (left hand side) and 9 (right hand side). Displacement ellipsoids are shown at the 30% probability level.
OMe
OMe
MeO
OMe
MeO
OMe
O
O
LiEt3BH
THF, − 78 °C
71%
LiEt3BH
THF, − 78 °C
74%
5a
4a
N
Ph
N
Ph
N
H
N
H
OH
OH
OH
OH
11
10
Scheme 5. Regioselective reduction of 5a and 4a.
OMe
1a
+
2d
+
3c
EtO
O
(1 equiv.) (1.5 equiv.) (1.5 equiv.)
10% mol CuSO4.5H2O
toluene, reflux, 24 h
N
N
O
N
OMe
N
N
H
O
O
O
12
N3
OEt
OEt
O
OMe
split
68%
N
+Na ascorbate
N
H
O
N3
N
N
N
O
O
OEt
4i
N
N
H
13
62%
O
O
OEt
Scheme 6. Dual Cu(II)/Cu(I) catalysis in the one-pot, four-component assembling.
2 min. The yellow mixture was stirred for 5 min after which the
propargyl alcohol (633 mg, 11.3 mmol) was added over 1 min. After
stirring for 5 min, the maleimide 3b (1.0 g, 10.3 mmol) was poured
in one portion. The resulting mixture was stirred for 5 min at
ꢀ78 ꢂC and at ambient temperature overnight. The solvent was
removed in vacuo and the product directly purified by flash chro-
matography (silica gel, 1:4 EtOAc/cyclohenaxe) to give the product
3c (722 mg, 52%) as
a
colourless oil; Rf¼0.14 (1:4 EtOAc/

D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
9611
OMe
J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
¼26.8 (2ꢃCH3), 42.1
OH
MeO
OMe
(CH2), 70.7 (CH2), 91.4 (C), 105.6 (C), 114.0 (CH), 119.9 (CH), 127.5
(2ꢃCH), 128.2 (CH), 128.6 (CH), 128.8 (2ꢃCH), 132.1 (C), 135.2
(C), 141.4 (C), 160.6 (C), 162.7 (C), 170.7 (C), 193.1 (C); LRMS (DCI,
NH3þisobutane): m/z (%): 414 (4) [MþH]þ, 370 (72), 286 (100);
HRMS (ESI) calcd for C21H18O8NNa2 [MꢀHþ2Na]þ: 458.0828,
found: 458.0815.
O
O
N
O
O
OEt
N
Ph
N
N
N
N
H
N
H
N
O
O
O
O
N
O
4.5. 4-(2-Nitrophenyl)-3-oxobutyric acid ethyl ester (7a)13
N
O
N
14
66%
15
56%
Compound 6a (10.0 g, 32.6 mmol) in absolute ethanol
(100 mL) was refluxed for 5 h (oil bath: T¼130 ꢂC). Ethanol was
evaporated in vacuo and the resulting solid was purified by flash
chromatography (silica gel, 1:4 EtOAc/cyclohenaxe) to give the
ester 7a (7.36 g, 90%) as a white crystals, mp 53–54 ꢂC; Rf¼0.34
(CH2Cl2); IR: nmax (KBr): 3439, 3073, 2992, 2942, 1749,
Figure 2. Additional examples of product obtained in the one-pot diastereodivergent
[4þ2] MCR/[3þ2] cycloaddition.
cyclohexane); IR: nmax (film): 3054, 1718, 1428, 1265, 1153,
1724 cmꢀ1; UV: 260, 208 nm; 1H NMR (300 MHz, CDCl3):
d¼1.30
738 cmꢀ1; UV: 328, 296, 285, 205 nm; 1H NMR (400 MHz, CDCl3):
(t, J¼7.2 Hz, 3H), 3.62 (s, 2H), 4.23 (q, J¼7.2 Hz, 2H), 4.25 (s, 2H),
7.30 (d, J¼7.6 Hz, 1H), 7.47 (dd, J¼8.2, 7.6 Hz, 1H), 7.50 (dd, J¼7.6,
7.6 Hz, 1H), 8.11 (d, J¼7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d
¼2.31 (t, J¼2.6 Hz, 1H), 4.29 (d, J¼2.6 Hz, 2H), 6.83 (s, 2H); 13C
NMR (100 MHz, CDCl3):
d
¼26.6 (CH2), 71.4 (C), 76.9 (CH), 134.3
(2ꢃCH), 169.1 (2ꢃC); LRMS (EI, 70 eV): m/z (%): 135 (37) [M]þ, 107
(72), 54 (100); HRMS (EI): calcd for C7H5N2O2: 135.0320, found:
135.0319.
d
¼14.0 (CH3), 47.7 (CH2), 49.2 (CH2), 61.5 (CH2), 125.2 (CH), 128.6
(CH), 129.6 (C), 133.6 (CH), 133.7 (CH), 148.4 (C), 166.9 (C), 198.1
(C); LRMS (DCI, NH3þisobutane): m/z (%): 269 (20) [MþNH4]þ,
252 [MþH]þ (100), 206 (41), 164 (90). Elemental analysis calcd
(%) for C12H13O5N: C 57.37, H 5.22, N 5.58; found: C 57.21, H 5.10,
N 5.51.
4.3. 2-[1-Hydroxy-2-(2-nitrophenyl)-ethylidene]-malonic
acid dimethyl ester (6a)13
To a solution of 2-nitrophenyl-acetic acid (25.0 g, 0.138 mol) in
dry CH2Cl2 (250 mL) under N2 was injected oxalyl chloride (COCl)2
(15 mL, 1.25 equiv) via syringe followed by six drops of DMF (gas
evolution). The mixture was stirred at rt for 4 h. Then, the solvent
and excess of (COCl)2 were evaporated in vacuo to give the corre-
sponding acyl chloride as a clear brown oil. In meantime, Hu¨nig’s
base (47 mL, 2 equiv) was added dropwise to a solution of Mel-
drum’s acid (19.9 g, 0.138 mol, 1 equiv) in dry CH2Cl2 (150 mL)
cooled with an ice bath. The previous freshly prepared acyl chloride
in dry CH2Cl2 (50 mL) was added dropwise to the mixture at 0 ꢂC.
After stirring for 1 h at 0 ꢂC and 30 min at rt, the mixture was
acidified with an aqueous solution of HCl (1 M). The two layers
were separated and the compound was extracted from the aqueous
layer with CH2Cl2. The combined organic solution was dried
(MgSO4) and evaporated. The resulting yellow solid was suspended
in ethanol (minimum volume) and placed in fridge overnight. After
quick filtrations and washings with cold ethanol and with cold
ether, the product 6a (36.85 g, 87%) was obtained as a white solid,
mp 114–116 ꢂC (ether/cyclohexane); Rf¼0.13 (2.5% MeOH/CH2Cl2);
IR nmax (KBr): 3451, 2999, 1736 cmꢀ1; UV: 260, 240 nm; 1H NMR
4.6. 4-(2-Nitrophenyl)-3-oxobutyric acid prop-
2-ynyl ester (7b)
A solution of compound 6a (1.5 g, 4.9 mmol) and propargyl al-
cohol (410 mg, 7.32 mmol) in dry THF (10 mL) was warmed at
100 ꢂC for 3 h. THF was evaporated in vacuo and the resulting solid
was purified by flash chromatography (silica gel, 3:7 EtOAc/hep-
tane) to give the ester 7b (1.23 g, 96%) as a colourless crystal, mp
54–55 ꢂC; Rf¼0.27 (3:7 EtOAc/cyclohexane); IR: nmax (film): 2949,
1751, 1722, 1525, 1408, 1347, 1313, 1196, 1151, 1067, 1000, 730 cmꢀ1
;
UV: 260, 205 nm; 1H NMR (400 MHz, CDCl3):
d¼2.55 (t, J¼2.4 Hz,
1H), 3.70 (s, 2H), 4.25 (s, 2H), 4.74 (d, J¼2.4 Hz, 2H), 7.31 (dd, J¼7.6,
1.2 Hz, 1H), 7.47 (ddd, J¼7.6, 7.6, 1.2 Hz, 1H), 7.59 (ddd, J¼7.6, 7.6,
1.2 Hz, 1H), 8.09 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
¼47.5 (CH2), 48.5 (CH2), 52.5 (CH2), 75.4 (C), 76.9 (CH), 125.0 (CH),
128.5 (CH), 129.3 (C), 133.6 (CH), 133.7 (CH), 148.1 (C), 165.9 (C),
197.6 (C); LRMS (FABþ): m/z (%): 262 (100) [MþH]þ, 206 (75). Ele-
mental analysis calcd (%) for C13H11O5N: C 59.77, H 4.24, N 5.36;
found: C 59.55, H 4.21, N 5.35.
(300 MHz, CDCl3):
d
¼1.69 (s, 6H), 4.55 (s, 2H), 7.29 (d, J¼6.7 Hz,1H),
7.40 (dd, J¼8.0, 6.6 Hz, 1H), 7.54 (dd, J¼6.7, 6.6 Hz, 1H), 8.00 (d,
J¼8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):
¼26.7 (2ꢃCH3), 41.2
d
4.7. [4-(2-Nitrophenyl)-3-oxobutyryl]-carbamic acid
benzyl ester (7c)
(CH2), 91.4 (C), 105.5 (C), 125.3 (CH), 129.0 (CH), 129.1 (C), 133.7
(CH), 133.8 (CH), 148.4 (C), 160.4 (C), 170.7 (C), 193.0 (C); LRMS
(FABþ): m/z (%): 308 (100) [MþH]þ, 292 (45). Elemental analysis
calcd (%) for C14H13O7N: C 54.71, H 4.27, N 4.56; found: C 54.53, H
4.06, N 4.49.
Starting from 6a (502 mg, 3.32 mmol) and following the same
condition as described for 7b, the product 7c (1.06 g, 89%) was
isolated as a white solid, mp 98 ꢂC; Rf¼0.18 (3:7 EtOAc/cyclo-
hexane); IR: nmax (film): 3288, 2965, 1757, 1729, 1703, 1524, 1346,
1202, 1069 cmꢀ1; UV: 291, 266, 205 nm; 1H NMR (400 MHz,
4.4. 5-[2-(5-Benzyloxy-2-nitrophenyl)-1-hydroxy-
ethylidene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (6f)
CDCl3):
d
¼4.03 (s, 2H), 4.24 (s, 2H), 4.25 (s, 2H), 5.15 (s, 2H),
7.31–737 (m, 5H), 7.46 (dd, J¼8.0, 7.6 Hz, 1H), 7.59 (dd, J¼7.6,
Following the same condition as described for 6a, the prod-
uct 6f (15.2 g, 67%) was obtained as a white solid, mp 100 ꢂC
(ether/cyclohexane); Rf¼0.24 (1:1 EtOAc/CH2Cl2); IR: nmax (film):
3435, 1735, 1661, 1579, 1511, 1420, 1332, 1261, 1028, 918,
7.6 Hz, 1H), 8.10 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
¼47.8 (CH2), 50.6 (CH2), 68.1 (CH2), 125.2 (CH), 128.3 (CH),
128.6 (4ꢃCH), 129.4 (C), 133.6 (CH), 133.8 (CH), 134.6 (C), 148.5
(C), 151.7 (C), 167.2 (C), 198.9 (C); LRMS (DCI, NH3þisobutane):
m/z (%): 374 [MþNH4]þ (18), 357 [MþH]þ (100), 152 (63); HRMS
733 cmꢀ1
CDCl3):
1H), 7.02 (dd, J¼9.2, 2.8 Hz, 1H), 7.35–7.43 (m, 5H), 8.24 (d,
;
UV: 309, 255, 240, 210 nm; 1H NMR (400 MHz,
d
¼1.8 (s, 6H), 4.77 (s, 2H), 5.17 (s, 2H), 6.93 (d, J¼2.8 Hz,
(ESI) calcd for
379.0906.
C
18H16O6N2Na [MþNa]þ: 379.0906, found:

9612
D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
4.8. 4-(2-Nitrophenyl)-1-(2-oxo-oxazolidin-3-yl)-butane-1,3-
dione (7d)
7.37 (d, J¼7.6 Hz, 1H), 7.45 (dd, J¼8.2, 7.6 Hz, 1H), 7.59 (dd, J¼7.6,
7.6 Hz, 1H), 8.07 (d, J¼8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d¼21.2 (CH2), 42.3 (CH2), 47.2 (CH2), 52.9 (CH2), 67.6 (CH2), 124.8
Starting from 6a (2.0 g, 6.5 mmol) and 2-oxazolidinone (567 mg,
6.5 mmol) and following the same condition as described for 7b,
the product 7d (1.56 g, 82%) was obtained as white needles, mp
110 ꢂC (EtOAc/cyclohexane); Rf¼0.28 (1:1 EtOAc/cyclohexane); IR:
nmax (KBr): 3435, 3387, 2978, 2928, 1771, 1723, 1699, 1522, 1391,
(CH), 128.3 (CH), 129.5 (C), 133.5 (CH), 133.7 (CH), 148.4 (C), 151.6
(C), 168.9 (C), 198.9 (C); LRMS (ESI): m/z (%): 329 (85) [MþNa]þ, 124
(100); HRMS (ESI): calcd for C14H14N2O6Na [MþNa]þ: 329.0750,
found: 329.0746.
1341 cmꢀ1; UV: 260, 212 nm; 1H NMR (300 MHz, CDCl3):
d¼4.01 (t,
4.12. (S)-(D)-1-(4-Benzyl-2-oxo-oxazolidin-3-yl)-4-
(2-nitrophenyl)-butane-1,3-dione (7h)
J¼7.8 Hz, 2H), 4.16 (s, 2H), 4.26 (s, 2H), 4.40 (t, J¼7.8 Hz, 2H), 7.37
(dd, J¼7.6, 1.3 Hz, 1H), 7.47 (ddd, J¼8.2, 7.6 Hz, 1.3, 1H), 7.60 (ddd,
J¼7.6, 7.6, 1.3 Hz, 1H), 8.08 (dd, J¼8.2, 1.3 Hz, 1H); 13C NMR (75 MHz,
Starting from 6a (3.46 g, 11.3 mmol) and (S)-(þ)-4-benzylox-
azolidin-2-one (1.6 g, 9.0 mmol) and following the same condition
as described for 7b, the product 7h (2.6 g, 75%) was isolated as
CDCl3):
d
¼41.9 (CH2), 47.3 (CH2), 49.9 (CH2), 62.2 (CH2), 124.9 (CH),
128.4 (CH), 129.2 (C), 133.5 (CH), 133.6 (CH), 148.4 (C), 153.7 (C),
165.7 (C), 198.6 (C); LRMS (EI, 70 eV): m/z (%): 292 (1) [M]þ, 156
(100). Elemental analysis calcd (%) for C12H12O6N2: C 53.43, H 4.14,
N 9.59; found: C 53.14, H 4.01, N 9.47.
a white amorphous solid, mp 92–93 ꢂC; Rf¼0.28 (1:1 EtOAc/cyclo-
28
hexane); [
a
]
þ38.0 (c 1.0, CHCl3); IR: nmax (KBr): 3412, 3032, 2981,
D
2924, 1782, 1726, 1701, 1528, 1395, 1356, 1202 cmꢀ1; UV: 204, 261,
231, 210 nm; 1H NMR (300 MHz, CDCl3):
d¼2.74 (dd, J¼13.5, 9.8 Hz,
4.9. 4-(2-Nitrophenyl)-1-(2-oxopyrrolidin-1-yl)-butane-1,3-
dione (7e)
1H), 3.25 (dd, J¼13.5, 3.3 Hz, 1H), 4.06–4.20 (m, 4H), 4.24 (s, 2H),
4.64 (m, 1H), 7.12–7.32 (m, 5H), 7.38 (dd, J¼7.6, 1.2 Hz, 1H), 7.52 (dd,
J¼8.2, 8.0 Hz, 1H), 7.61 (dd, J¼8.2, 7.6 Hz, 1H), 8.02 (d, J¼8.0 Hz, 1H);
Starting from 6a (700 mg, 2.28 mmol) and pyrrolidin-2-one
(233 mg, 2.74 mmol) and following the same condition as de-
scribed for 7b, the product 7e (500 mg, 76%) was obtained as yellow
solid, mp 102 ꢂC; Rf¼0.19 (1:1 EtOAc/cyclohexane); IR: nmax (film):
2950, 1733, 1691, 1525, 1402, 1346, 1248, 1198, 1068, 732 cmꢀ1; UV:
13C NMR (75 MHz, CDCl3):
d¼37.0 (CH2), 47.2 (CH2), 50.1 (CH2), 54.5
(CH), 66.1 (CH2), 124.7 (CH), 126.9 (CH), 128.3 (CH), 128.5 (2ꢃCH),
129.1 (2ꢃCH), 129.2 (C), 133.4 (CH), 133.5 (CH), 134.8 (C), 148.2 (C),
153.5 (C), 165.6 (C), 198.8 (C); LRMS (EI, 70 eV): m/z (%): 382 (66)
[M]þ, 246 (63), 178 (100). Elemental analysis calcd (%) for
290, 260, 207 nm; 1H NMR (400 MHz, CDCl3):
d
¼1.95 (tt, J¼8.0,
C20H18O6N2: C 62.82, H 4.74, N 7.33; found: C 62.69, H 4.90, N 7.30.
7.5 Hz, 2H), 2.48 (t, J¼8.0 Hz, 2H), 3.74 (t, J¼7.5 Hz, 2H), 4.04 (s, 2H),
4.20 (s, 2H), 7.29 (dd, J¼7.6, 1.3 Hz, 1H), 7.37 (ddd, J¼7.9, 7.6, 1.3 Hz,
4.13. (1H-Indol-2-yl)-acetic acid ethyl ester (1a)13
2H), 7.51 (ddd, J¼7.6, 7.6, 1.3 Hz, 1H), 8.00 (dd, J¼7.9, 1.3 Hz, 1H); 13
C
NMR (100 MHz, CDCl3):
d
¼16.8 (CH2), 33.1 (CH2), 45.1 (CH2), 47.5
To a biphasic solution of compound 7a (925 mg, 3.68 mmol) in
THF (40 mL) and an aqueous solution of saturated NH4Cl (39 mL)
was added zinc dust (21 g) under vigorous stirring. The reaction
mixture was stirred for 2 h and then quenched with an aqueous
solution of saturated KHCO3. The solid residue was removed by
filtration (Celite). The product was extracted with EtOAc and dried
(MgSO4). After evaporation and flash chromatography (silica gel,
CH2Cl2), the product 1a (710 mg, 95%) was isolated as an oil, which
solidified by standing in fridge, mp 32 ꢂC; Rf¼0.70 (CH2Cl2); IR: nmax
(KBr): 3399, 3055, 2982, 1726 cmꢀ1; UV: 289, 281, 272, 221 nm; 1H
(CH2), 51.3 (CH2), 124.9 (CH), 128.4 (CH), 129.5 (C), 133.5 (CH), 133.7
(CH), 148.5 (C), 166.4 (C), 175.7 (C), 198.9 (C); LRMS (DCI,
NH3þisobutane): m/z (%): 308 (7) [MþNH3]þ, 291 (100) [MþH]þ,
246 (7), 154 (14). Elemental analysis calcd (%) for C14H14O5N2: C
57.93, H 4.86, N 9.65; found: C 57.75, H 4.63, N 9.55.
4.10. 4-(5-Benzyloxy-2-nitrophenyl)-3-oxobutyric acid
ethyl ester (7f)
Starting from 6f (2.0 g, 4.8 mmol) in absolute ethanol (38 mL)
and following the same condition as described for 7a, the product
7f (1.67 g, 97%) was obtained as a white amorphous solid, mp 96 ꢂC;
Rf¼0.21 (CH2Cl2); IR: nmax (film): 2982, 2943, 1732, 1715, 1604, 1592,
1521,1412,1333,1252,1073,1034, 842, 743 cmꢀ1; UV: 308, 397, 231,
NMR (400 MHz, CDCl3):
d
¼1.27 (t, J¼7.2 Hz, 3H), 3.78 (s, 2H), 4.19
(q, J¼7.2 Hz, 2H), 6.33 (m, 1H), 7.07 (dd, J¼8.0, 7.5 Hz, 1H), 7.12 (dd,
J¼8.2, 8.0 Hz, 1H), 7.29 (d, J¼8.2 Hz, 1H), 7.54 (d, J¼7.5 Hz, 1H); 13
C
NMR (100 MHz, CDCl3):
d¼14.1 (CH3), 33.9 (CH2), 61.3 (CH2), 101.7
(CH), 110.8 (CH), 119.7 (CH), 120.0 (CH), 121.6 (CH), 128.1 (C), 130.6
(C), 136.3 (C), 170.6 (C); LRMS (FABþ): m/z (%): 204 (25) [MþH]þ,
203 (40), 130 (100). Elemental analysis calcd (%) for C12H13O2N: C
70.92, H 6.45, N 6.89; found: C 70.67, H 6.63, N 6.90.
211 nm; 1H NMR (400 MHz, CDCl3):
d
¼1.29 (t, J¼7.2 Hz, 3H), 3.64 (s,
2H), 4.21 (s, 2H), 4.22 (q, J¼7.2 Hz, 2H), 5.11 (s, 2H), 6.83 (d,
J¼2.8 Hz, 1H), 6.95 (dd, J¼9.2, 2.8 Hz, 1H), 7.33–7.42 (m, 5H), 8.17 (d,
J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼14.0 (CH3), 48.3 (CH2),
d
49.3 (CH2), 61.4 (CH2), 70.5 (CH2), 113.8 (CH), 119.6 (CH), 127.5
(2ꢃCH), 128.0 (CH), 128.4 (CH), 128.7 (2ꢃCH), 132.7 (C), 135.3 (C),
141.2 (C),162.6 (C),167.0 (C),198.2 (C); LRMS (DCI, NH3þisobutane):
m/z (%): 375 [MþNH4]þ (63), 358 [MþH]þ (100), 312 (30), 266 (9);
HRMS (TOF EIþ): calcd for C19H19O6N: 357.1212, found: 357.1214.
4.14. (1H-Indol-2-yl)-acetic acid prop-2-ynyl ester (1b)
Starting from compound 7b (845 mg, 3.23 mmol) and following
the same condition as described for 1a, except vigorous stirring
with zinc dust only for 30 min, the product 1b (521 mg, 76%) was
isolated as an oil, which solidified by standing in fridge, mp 55 ꢂC;
Rf¼0.14 (1:4 ether/cyclohexane); IR: nmax (film): 3400, 3286, 3058,
2925, 1738, 1456, 1289, 1158, 1024, 748, 640 cmꢀ1; UV: 289, 272,
4.11. 4-(2-Nitrophenyl)-1-(2-oxo-[1,3]oxazinan-3-yl)-butane-
1,3-dione (7g)
218 nm; 1H NMR (400 MHz, CDCl3):
d¼2.47 (t, J¼2.6 Hz,1H), 3.76 (s,
Starting from 6a (4.0 g, 13 mmol) and [1,3]oxazinan-2-one
(1.3 g, 13 mmol) and following the same condition as described for
7b, the product 7g (2.4 g, 61%) was obtained as a white solid, mp
104 ꢂC; Rf¼0.25 (1:1 EtOAc/cyclohexane); IR: nmax (film): 3425,
2921, 1730, 1700, 1523, 1478, 1407, 1347, 1276, 1170, 1070, 989,
727 cmꢀ1; UV: 300, 265, 210 nm; 1H NMR (400 MHz, CDCl3):
2H), 4.28 (d, J¼2.6 Hz, 2H), 6.32 (m, 1H), 7.07 (ddd, J¼7.6, 7.6, 1.2 Hz,
1H), 7.12 (ddd, J¼7.6, 7.6, 1.2 Hz, 1H), 7.24 (dd, J¼7.6, 1.2 Hz, 1H), 7.52
(dd, J¼7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼33.5 (CH2),
d
52.6 (CH2), 75.4 (C), 77.1 (CH), 102.0 (CH), 110.8 (CH), 119.8 (CH),
120.1 (CH), 121.7 (CH), 128.0 (C), 129.7 (C), 136.3 (C), 169.6 (C); LRMS
(DCI, NH3þisobutane): m/z (%): 214 (32) [MþH]þ, 144 (45), 131
(100). Elemental analysis calcd (%) for C13H11O2N: C 73.23, H 5.20, N
6.57; found: C 72.93, H 5.17, N 6.50.
d
¼2.06 (m, 2H), 3.76 (t, J¼6.4 Hz, 2H), 4.26 (s, 2H), 4.29 (t, J¼5.4 Hz,
2H), 6.42 (s, 1H); 7.37 (d, J¼7.6 Hz, 1H), 7.45 (dd, J¼8.2, 7.6 Hz, 1H),

D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
9613
4.15. (2-1H-Indol-2-yl-acetyl)-carbamic acid benzyl ester (1c)
4.19. 3-(2-1H-Indol-2-yl-acetyl)-[1,3]oxazinan-2-one (1g)
Starting from 7c (474 mg, 1.33 mmol) and following the same
condition as described for 1a, the product 1c (352 mg, 86%) was
isolated as a white solid, mp 135 ꢂC; Rf¼0.30 (1:19 EtOAc/CH2Cl2);
IR: nmax (film): 3345, 2930, 1765, 1693, 1513, 1499, 1455, 1204,
1028 cmꢀ1; UV: 288, 289, 274 nm; 1H NMR (400 MHz, CDCl3):
Starting from 7g (1.8 g, 5.9 mmol) and following the same
condition as described for 1a, the product 1g (1.03 g, 68%) was
isolated as a white solid, mp 144 ꢂC; Rf¼0.26 (1:1 EtOAc/cyclo-
hexane); IR: nmax (film): 1735, 1700, 1548, 1478, 1458, 1422, 1266,
1175, 994, 742 cmꢀ1; UV: 287, 272, 217, 200 nm; 1H NMR (400 MHz,
d
¼4.24 (s, 2H), 5.19 (s, 2H), 6.41 (s, 1H), 7.08 (ddd, J¼8.0, 7.0, 0.8 Hz,
CDCl3):
d
¼2.03 (m, 2H), 3.70 (t, J¼6.5 Hz, 2H), 4.27 (t, J¼5.4 Hz, 2H),
1H), 7.15 (ddd, J¼7.0, 7.0, 1.2 Hz, 1H), 7.31 (dd, J¼8.0, 1.2 Hz, 1H),
4.45 (s, 2H), 6.42 (s, 1H), 7.05 (dd, J¼7.8, 7.8 Hz, 1H), 7.12 (dd, J¼8.0,
7.35–7.38 (m, 5H), 7.55 (dd, J¼7.0, 0.8 Hz, 1H); 13C NMR (100 MHz,
7.8, 1H), 7.31 (d, J¼8.0 Hz, 1H), 7.53 (d, J¼7.8 Hz, 1H); 13C NMR
CDCl3):
d¼35.6 (CH2), 68.2 (CH2), 102.6 (CH), 110.9 (CH), 119.8 (CH),
(100 MHz, CDCl3):
d
¼21.6 (CH2), 37.5 (CH2), 42.9 (CH2), 67.6 (CH2),
120.2 (CH), 121.9 (CH), 128.1 (C), 128.5 (2ꢃCH), 128.7 (2ꢃCH), 128.8
(CH), 130.1 (C), 134.6 (C), 136.3 (C), 151.6 (C), 170.8 (C); LRMS (ESI):
m/z (%): 331 (100) [MþNa]þ, 309 (40) [MþH]þ, 265 (35), 220 (35);
HRMS (TOF EIþ) calcd for C18H16O3N2: 308.1161, found: 308.1160.
102.4 (CH), 110.8 (CH), 119.6 (CH), 120.1 (CH), 121.6 (CH), 128.1 (C),
131.4 (C),136.1 (C),152.0 (C), 172.9 (C); LRMS (ESI): m/z (%): 281 (28)
[MþNa]þ, 216 (38), 102 (100); HRMS (ESI): calcd for C14H14N2O3Na
[MþNa]þ: 281.0902, found: 281.0894.
4.16. 3-[1H-Indol-2-yl-acetyl]-oxazolidin-2-one (1d)
4.20. (S)-(D)-4-Benzyl-3-[1H-indol-2-yl-acetyl]-
oxazolidin-2-one (1h)
Starting from 7d (865 mg, 2.96 mmol) and following the same
condition as described for 1a, the product 1d (614 mg, 85%) was
isolated as white crystals, mp 174 ꢂC; Rf¼0.19 (CH2Cl2); IR: nmax
(KBr): 3353, 3000, 2934, 1765, 1686, 1404, 1391, 1294, 1225,
1125 cmꢀ1; UV: 289, 286, 271, 219 nm; 1H NMR (300 MHz, CDCl3):
Starting from 7h (2.34 g, 6.13 mmol) and following the same
condition as described for 1a, the product 1h (1.59 g, 78%) was
isolated as an amorphous white solid, mp 112 ꢂC; Rf¼0.39 (CH2Cl2);
28
[a
]
þ119.5 (c 1.0, CHCl3); IR: nmax (KBr): 3390, 3316, 3028, 2976,
D
d
¼4.02 (dd, J¼8.4, 7.8 Hz, 2H), 4.42 (dd, J¼8.4, 7.8 Hz, 2H), 4.45 (s,
2924, 1767, 1699, 1456, 1395, 1362, 1217, 1186 cmꢀ1; UV: 289, 282,
2H), 6.46 (m, 1H), 7.07 (ddd, J¼8.0, 7.0, 0.8 Hz, 1H), 7.15 (ddd, J¼7.0,
7.0, 1.2 Hz, 1H), 7.34 (dd, J¼8.0, 1.2 Hz, 1H), 7.55 (dd, J¼7.0, 0.8 Hz,
274, 217 nm; 1H NMR (300 MHz, CDCl3):
d¼2.80 (dd, J¼13.6, 8.5 Hz,
1H), 3.09 (dd, J¼13.6, 3.2 Hz, 1H), 4.10–4.20 (m, 2H), 4.37 (d,
J¼15.0 Hz, 1H), 4.52 (d, J¼15.0 Hz, 1H), 4.65 (m, 1H), 6.49 (m, 1H),
6.98 (d, J¼7.1 Hz, 2H), 7.05–7.22 (m, 4H), 7.34 (d, J¼8.0 Hz, 1H), 7.57
1H); 13C NMR (75 MHz, CDCl3):
d
¼34.3 (CH2), 42.7 (CH2), 62.2
(CH2), 102.7 (CH), 110.8 (CH), 119.8 (CH), 120.2 (CH), 121.9 (CH),
128.2 (C), 130.2 (C), 136.2 (C), 153.9 (C), 169.6 (C); LRMS (EI, 70 eV):
m/z (%): 244 (27) [M]þ, 189 (26), 157 (95), 130 (100). Elemental
analysis calcd (%) for C13H12O3N (244): C 63.91, H 4.95, N 11.47;
found: C 63.51, H 4.96, N 11.27.
(d, J¼7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3):
¼34.8 (CH2), 37.3
d
(CH2), 55.0 (CH), 66.2 (CH2), 102.6 (CH), 110.9 (CH), 119.8 (CH), 120.2
(CH), 121.8 (CH), 127.3 (CH), 128.2 (C), 128.8 (2ꢃCH), 129.3 (2ꢃCH),
130.2 (C), 134.5 (C), 136.1 (C), 153.9 (C), 169.4 (C); LRMS (EI, 70 eV):
m/z (%): 334 (24) [M]þ, 157 (73), 130 (100). Elemental analysis calcd
(%) for C20H18O3N2 (334): C 71.83, H 5.43, N 8.38; found: C 71.81, H
5.47, N 8.37.
4.17. 1-(2-1H-Indol-2-yl-acetyl)-pyrrolidin-2-one (1e)
Starting from 7e (360 mg, 1.24 mmol) and following the same
condition as described for 1a, the product 1e (224 mg, 75%) was
isolated as a white powder, mp 183 ꢂC; Rf¼0.19 (CH2Cl2); IR: nmax
(film): 3345, 1724, 1682, 1452, 1355, 1293, 1226, 743 cmꢀ1; UV: 289,
4.21. General procedure for the three-component coupling
reaction
281, 273, 218, 210 nm; 1H NMR (400 MHz, acetone-d6):
d
¼2.05 (m,
Method A. The indole 1 (1 mmol), the aldehyde 2 (1.5 mmol), the
2H), 2.61 (t, J¼8.0 Hz, 2H), 3.78 (t, J¼7.2 Hz, 2H), 4.40 (s, 2H), 6.30
(m, 1H), 6.96 (ddd, J¼7.0, 7.0, 1.2 Hz,1H), 7.04 (ddd, J¼7.0, 7.0, 1.2 Hz,
1H), 7.37 (dd, J¼7.0, 1.2 Hz, 1H), 7.46 (dd, J¼7.0, 1.2 Hz, 1H); 13C NMR
dienophile 3 (3 mmol) and
D
-(þ)-10-camphorsulfonic acid (23 mg,
0.1 mmol) in dry toluene (15 mL) were warmed up to 130 ꢂC for
20 h under N2. After cooling, the black solution was neutralised
with saturated aqueous NaHCO3. The compound was extracted
with EtOAc and dried (MgSO4). After evaporation, the product was
applied to flash chromatography (silica gel).
(100 MHz, acetone-d6):
d
¼17.8 (CH2), 34.1 (CH2), 36.4 (CH2), 46.4
(CH2),102.2 (CH),111.8 (CH),119.9 (CH),120.5 (CH),121.7 (CH),129.6
(C), 133.2 (C), 137.7 (C), 170.8 (C), 176.6 (C); LRMS (DCI,
NH3þisobutane): m/z (%): 243 (100) [MþH]þ, 157 (62). Elemental
analysis calcd (%) for C14H14O2N2: C 69.41, H 5.82, N 11.56; found: C
69.24, H 5.57, N 11.43.
Method B. The indole 1 (1 mmol), the aldehyde 2 (1.5 mmol), the
dienophile 3 (3 mmol) and CuSO4$5H2O (25 mg, 0.1 mmol) in dry
toluene (15 mL) were warmed up to 130 ꢂC for 16–36 h under N2.
The mixture was filtered (paper filter) to remove the catalyst, which
was washed once with CH2Cl2 or methanol. After evaporation, the
product was applied to flash chromatography (silica gel).
4.18. (5-Benzyloxy-1H-indol-2-yl)-acetic acid ethyl ester (1f)
Starting from 7f (2.19 g, 6.13 mmol) and following the same
condition as described for 1a, the product 1g (1.75 g, 92%) was
isolated as a white solid, mp 92 ꢂC; Rf¼0.28 (CH2Cl2); IR: nmax (film):
3393, 2982, 1729, 1589, 1485, 1453, 1179, 1026, 736 cmꢀ1; UV: 305,
Method C. Same condition as method B by using chlorobenzene
instead of toluene and by warming up to 150 ꢂC for 16–36 h.
4.21.1. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-1,3-Dioxo-2-phenyl-10-(3,4,5-
*
294, 287, 274, 212 nm; 1H NMR (400 MHz, CDCl3):
d
¼1.28 (t,
trimethoxyphenyl)-1,2,3,3a,4,5,10,10a-octahydropyrrolo-
J¼7.2 Hz, 3H), 3.78 (s, 2H), 4.19 (q, J¼7.2 Hz, 2H), 5.08 (s, 2H), 6.25
(br s, 1H), 6.89 (dd, J¼8.6, 2.4 Hz), 7.08 (d, J¼2.4 Hz, 1H), 7.21 (d,
J¼8.6 Hz, 1H), 7.29 (m, 1H), 7.36 (m, 2H), 7.45 (m, 2H); 13C NMR
[3,4-b]carbazole-4-carboxylic acid ethyl ester (4a)
Method A, 24 h, 210 mg (38%), method B, 24 h, 410 mg (74%),
flash chromatography with eluent 2:3 EtOAc/cyclohexane, isolated
as clear yellow needles, mp 263 ꢂC (yellow needles, EtOAc/cyclo-
hexane); Rf¼0.37 (1:1 EtOAc/cyclohexane); IR: nmax (KBr): 3360,
2940, 1736, 1717, 1589, 1503, 1387, 1198, 1125 cmꢀ1; UV: 291, 283,
(100 MHz, CDCl3):
d
¼14.1 (CH3), 35.7 (CH2), 62.4 (CH2), 72.6 (CH2),
101.6 (CH), 103.7 (CH), 111.5 (CH), 112.5 (2ꢃCH), 127.5 (CH), 127.7
(CH), 128.4 (2ꢃCH), 128.6 (C),131.4 (C), 131.7 (C), 138.2 (C), 154.0 (C),
171.0 (C); LRMS (DCI, NH3þisobutane): m/z (%): 310 (100) [MþH]þ,
218 (33); HRMS (TOF EIþ); calcd for C19H19N03: 309.1365, found:
309.1342.
271, 219, 209 nm; 1H NMR (300 MHz, CDCl3):
3H), 3.64 (s, 6H), 3.75 (s, 3H), 3.82 (dd, J¼8.7, 7.6 Hz, 1H), 4.38 (dd,
J¼8.7, 3.0 Hz, 1H), 4.44 (q, J¼7.1 Hz, 2H), 4.83 (d, J¼3.0 Hz, 1H), 4.91
d
¼1.46 (t, J¼7.1 Hz,

9614
D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
(d, J¼7.6 Hz, 1H), 6.22 (s, 2H), 6.57 (m, 2H), 7.05 (dd, J¼7.5, 7.5 Hz,
1H), 7.20 (dd, J¼7.5, 7.5 Hz, 1H), 7.25–7.33 (m, 3H), 7.34 (d, J¼7.5 Hz,
J¼8.0, 7.6 Hz, 1H), 7.05 (dd, J¼8.0, 7.6 Hz, 1H), 7.18 (d, J¼8.0 Hz, 1H),
7.48 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6, TMS):
¼14.1
d
1H), 7.38 (d, J¼7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d¼14.4 (CH3),
(CH3), 36.9 (CH), 37.9 (CH), 42.6 (CH), 45.9 (CH), 55.8 (2ꢃCH3), 61.8
(CH2), 106.4 (2ꢃCH), 111.5 (CH), 111.7 (C), 118.5 (CH), 118.7 (CH),
121.6 (CH), 125.5 (C), 128.5 (C), 130.6 (C), 134.5 (C), 136.7 (C), 147.3
(2ꢃC), 171.2 (C), 177.8 (C), 179.5 (C); LRMS (FABþ): m/z (%): 465 (15)
[MþH]þ, 265 (100). Elemental analysis calcd (%) for C25H24O7N2: C
64.65, H 5.21, N 6.03; found: C 64.46, H 5.26, N 5.87.
36.4 (CH), 38.9 (CH), 41.0 (CH), 45.3 (CH), 56.0 (2ꢃCH3), 60.7 (CH3),
63.0 (CH2),106.0 (2ꢃCH),111.0 (CH),112.1 (C),118.6 (CH),120.1 (CH),
123.0 (CH), 125.8 (C), 126.0 (2ꢃCH), 127.1 (C), 128.6 (CH), 128.9
(2ꢃCH), 131.3 (C), 134.8 (C), 136.3 (C), 137.4 (C), 153.2 (2ꢃC), 170.4
(C),175.7 (C),177.1 (C); LRMS (EI, 70 eV): m/z (%): 554 (27) [M]þ, 508
(100), 308 (20), 167 (25). Elemental analysis calcd (%) for
C
32H30O7N2: C 69.30, H 5.45, N 5.05; found: C 68.95, H 5.67, N 4.83.
4.21.5. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-8-Benzyloxy-1,3-dioxo-2-phenyl-
*
10-(3,4,5-trimethoxyphenyl)-1,2,3,3a,4,5,10,10a-octahydro-
pyrrolo[3,4-b]carbazole-4-carboxylic acid ethyl ester (4e)
4.21.2. (ꢁ)-(4S
*
,5S ,10S ,10aS )-10-(4-Hydroxy-3,5-dimethoxy-
*
*
*
phenyl)-1,3-dioxo-2-phenyl-1,2,3,3a,4,5,10,10a-octahydro-
Method B, 48 h, 200 mg (47%) as an amorphous solid, mp
239 ꢂC, Rf¼0.17 (3:7 EtOAc/cyclohexane); IR: nmax (film): 2953, 1711,
1592, 1498, 1459, 1390, 1182, 1123 cmꢀ1; UV: 308, 277, 222, 210 nm;
pyrrolo[3,4-b]carbazole-4-carboxylic acid ethyl ester (4b)
Method A, 24 h, 243 mg (45%), method B, 24 h, 350 mg, (65%),
flash chromatography with eluent 2:3 EtOAc/cyclohexane, isolated
as an amorphous white solid, mp 254 ꢂC (EtOAc/cyclohexane);
Rf¼0.32 (1:1 EtOAc/cyclohexane); IR: nmax (film): 3395, 2940, 1713,
1614, 1517, 1500, 1459, 1356, 1299, 1214, 1196, 1112, 1027 cmꢀ1; UV:
1H NMR (400 MHz, CDCl3):
d
¼1.43 (t, J¼7.2 Hz, 3H), 3.66 (s, 6H),
3.76 (s, 3H), 3.78 (dd, J¼8.8, 7.6 Hz, 1H), 4.36 (dd, J¼8.8, 2.8 Hz, 1H),
4.40 (q, J¼7.2 Hz, 2H), 4.81 (d, J¼2.8 Hz, 1H), 4.82 (d, J¼7.6 Hz, 1H),
5.0 (s, 2H), 6.20 (s, 2H), 6.55 (m, 2H), 6.84 (s, 1H), 6.92 (d, J¼8.8 Hz,
1H), 7.23–7.30 (m, 5H), 7.33 (dd, J¼8.2, 7.2 Hz, 2H), 7.39 (d, J¼7.2 Hz,
290, 279, 270, 216 nm; 1H NMR (400 MHz, DMSO-d6, TMS):
d¼1.33
(t, J¼7.0 Hz, 3H), 3.52 (s, 6H), 3.75 (dd, J¼8.7, 8.0 Hz, 1H), 4.32 (m,
2H), 4.38 (dd, J¼8.7, 3.2 Hz, 1H), 4.65 (d, J¼3.2 Hz, 1H), 4.84 (d,
J¼8.0 Hz, 1H), 6.19 (s, 2H), 6.54 (m, 2H), 6.90 (dd, J¼8.0, 7.5 Hz, 1H),
7.07 (dd, J¼8.0, 7.5 Hz, 1H), 7.25 (d, J¼8.0 Hz, 1H), 7.27–7.33 (m, 3H),
7.40 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6, TMS): 13C
2H); 13C NMR (100 MHz, CDCl3):
d
¼14.3 (CH3), 36.4 (CH), 38.8 (CH),
41.0 (CH), 45.3 (CH), 56.0 (2ꢃCH3), 60.7 (CH3), 62.9 (CH2), 70.8
(CH2), 102.5 (CH), 105.9 (2ꢃCH), 111.7 (CH), 113.2 (CH), 126.0
(2ꢃCH), 126.2 (C), 127.5 (2ꢃCH), 127.8 (CH), 128.4 (2ꢃCH), 128.5
(CH), 128.9 (2ꢃCH), 131.2 (C), 131.6 (C), 134.7 (C2), 137.2 (C9), 137.4
(C), 153.1 (2ꢃC), 153.4 (C), 170.3 (C), 175.7 (C), 177.1 (C); LRMS
(FABþ): m/z (%): 661 (25) [MþH]þ, 614 (100); HRMS (ESI): calcd for
NMR (100 MHz, DMSO-d6, TMS):
d¼14.0 (CH3), 36.7 (CH), 37.8 (CH),
41.6 (CH), 44.7 (CH), 55.9 (2ꢃCH3), 61.9 (CH2), 106.7 (2ꢃCH), 111.0
(C, CH), 118.3 (CH), 118.7 (CH), 121.7 (CH), 125.3 (C), 126.4 (2ꢃCH),
128.2 (C, CH), 128.6 (2ꢃCH), 130.3 (C), 131.9 (C), 135.0 (C), 136.7 (C),
147.5 (2ꢃC), 171.1 (C), 175.4 (C), 177.3 (C); LRMS (EI, 70 eV): m/z (%):
540 (7) [M]þ, 495 (32), 294 (51), 57 (100). Elemental analysis calcd
(%) for C31H28O7N2: C 68.88, H 5.22, N 5.18; found: C 68.60, H 5.20, N
5.00.
C
39H36O8Na [MþNa]þ: 683.2369, found: 683.2359.
4.21.6. (ꢁ)-(4S
*
,5S
*
*
,10S ,10aS )-[1,3-Dioxo-2-phenyl-10-(3,4,5-
*
trimethoxyphenyl)-1,2,3,3a,4,5,10,10a-octahydropyrrolo[3,4-b]-
carbazole-4-carbonyl]-carbamic acid benzyl ester (4f)
Method B,18 h,163 mg (56%), as an amorphous solid, mp 218 ꢂC;
Rf¼0.21 (2:3 EtOAc/cyclohexane); IR: nmax (film): 3353, 2958, 1783,
1714, 1590, 1504, 1456, 1385, 1327, 1188, 1124 cmꢀ1; UV: 291, 282,
4.21.3. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-1,3-Dioxo-10-(3,4,5-
*
trimethoxyphenyl)-1,2,3,3a,4,5,10,10a-octahydropyrrolo-
274, 220, 211 nm; 1H NMR (400 MHz, CDCl3):
d¼3.59 (s, 6H), 3.76 (s,
[3,4-b]carbazole-4-carboxylic acid ethyl ester (4c)
3H), 3.77–3.30 (m, 2H), 4.83 (m,1H), 4.94 (m,1H), 5.16 (d, J¼11.8 Hz,
Method A, 24 h, 120 mg (25%), method C, 24 h, 249 mg (52%),
flash chromatography with eluent 1:1 EtOAc/cyclohexane, isolated
as an amorphous white solid, mp 235 ꢂC; Rf¼0.19 (1:1 EtOAc/cy-
clohexane); IR: nmax (film): 3263, 2939, 1777, 1718, 1591, 1506, 1459,
1330, 1234, 1125, 1019 cmꢀ1; UV: 292, 279, 270, 219 nm; 1H NMR
1H), 5.22 (d, J¼11.8 Hz, 1H), 6.22 (s, 2H), 6.64 (m, 2H), 7.04 (dd,
J¼7.6, 7.6 Hz, 1H), 7.16 (dd, J¼7.6, 7.6 Hz, 1H), 7.30–7.37 (m, 8H); 13
C
NMR (100 MHz, CDCl3):
d
¼38.7 (CH), 39.1 (CH), 43.0 (CH), 47.0 (CH),
56.1 (2ꢃCH3), 60.7 (CH3), 68.2 (CH2), 106.0 (2ꢃCH), 111.6 (CH), 113.1
(C), 118.4 (CH), 120.0 (CH), 122.9 (CH), 125.4 (C), 126.1 (2ꢃCH), 128.1
(C),128.7 (2ꢃCH),128.8 (2ꢃCH),128.8 (CH),129.1 (2ꢃCH),130.8 (C),
134.0 (C), 134.6 (C), 136.8 (C), 137.5 (C), 151.0 (C), 153.3 (2ꢃC), 170.2
(C), 175.3 (C), 179.0 (C); LRMS (ESI): m/z (%): 682 (100) [MþNa]þ;
HMRS (ESI): calcd for C38H33N3O8Na [MþNa]þ: 682.2165, found:
682.2168.
(400 MHz, DMSO-d6, TMS):
d
¼1.31 (t, J¼7.2 Hz, 3H), 3.56 (dd, J¼8.8,
8.4 Hz, 1H), 3.58 (s, 3H), 3.63 (s, 6H), 4.08 (dd, J¼8.8, 3.6 Hz, 1H),
4.28 (m, 2H), 4.52 (d, J¼3.6 Hz, 1H), 4.76 (d, J¼8.4 Hz, 1H), 6.23 (s,
2H), 6.89 (dd, J¼8.0, 7.6 Hz, 1H), 7.06 (dd, J¼8.0, 7.6 Hz, 1H), 7.22 (d,
J¼8.0 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6,
TMS):
d
¼14.1 (CH3), 36.9 (CH), 38.1 (CH), 42.6 (CH), 45.6 (CH), 55.6
(2ꢃCH3), 59.9 (CH3), 61.8 (CH2), 106.1 (2ꢃCH), 111.4 (CH), 111.5 (C),
118.4 (CH), 118.8 (CH), 121.7 (CH), 125.5 (C), 128.5 (C), 136.2 (C),
136.5 (C), 136.6 (C), 152.2 (2ꢃC), 171.1 (C), 177.8 (C), 179.4 (C); LRMS
(EI, 70 eV): m/z (%): 478 (19) [M]þ, 432 (100), 308 (62). Elemental
analysis calcd (%) for C26H26O7N2: C 65.27, H 5.48, N 5.86; found: C
65.36, H 5.76, N 5.66.
4.21.7. (ꢁ)-(4S
*
,5S
*
*
,10S ,10aS )-10-(3-Nitrophenyl)-1,3-dioxo-2-
*
phenyl-1,2,3,3a,4,5,10,10a-octahydropyrrolo[3,4-b]carbazole-4-
carboxylic acid ethyl ester (4g)
Method B, 18 h, 338 mg, 90%, flash chromatography with eluent
3:7 EtOAc/cyclohexane, isolated as a white solid, mp 225 ꢂC;
Rf¼0.21 (3:7 EtOAc/cyclohexane); IR: nmax (film): 3413, 3057, 1713,
1528, 1382, 1349, 1184, 736 cmꢀ1; UV: 289, 282, 267, 218, 196 nm;
4.21.4. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS
*
)-10-(4-Hydroxy-3,5-dimethoxy-
1H NMR (400 MHz, CDCl3):
d
¼1.46 (t, J¼7.2 Hz, 3H), 3.93 (dd, J¼8.6,
phenyl)-1,3-dioxo-1,2,3,3a,4,5,10,10a-octahydro-
8.2 Hz, 1H), 4.41 (dd, J¼8.6, 3.2 Hz, 1H), 4.44 (q, J¼7.2 Hz, 2H), 4.89
(d, J¼3.2 Hz, 1H), 5.07 (d, J¼8.2 Hz, 1H), 6.50 (m, 2H), 7.02 (dd,
J¼8.0, 7.6 Hz, 1H), 7.16 (d, J¼8.0 Hz, 1H), 7.20 (dd, J¼7.6, 7.6 Hz, 1H),
7.25–7.27 (m, 3H), 7.33–7.42 (m, 3H), 7.90 (br s, 1H), 8.05 (br d,
pyrrolo[3,4-b]carbazole-4-carboxylic acid ethyl ester (4d)
Method C, 36 h, 204 mg (44%), flash chromatography with elu-
ent 1:1 EtOAc/cyclohexane, isolated as an amorphous white solid,
mp 296 ꢂC; Rf¼0.16 (3:1 EtOAc/cyclohexane); IR: nmax (KBr): 3377,
3182, 3064, 1779, 1712, 1617, 1518, 1460, 1364, 1334, 1300, 1276,
1213, 1192, 1114, 746 cmꢀ1; UV: 328, 296, 285, 205 nm; 1H NMR
J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼14.4 (CH3), 36.5 (CH),
d
38.3 (CH), 40.9 (CH), 44.5 (CH), 63.1 (CH2),110.6 (C),111.3 (CH),118.3
(CH), 120.3 (CH), 122.6 (CH), 123.2 (CH), 123.7 (CH), 125.4 (C), 125.5
(2ꢃCH), 127.8 (C), 128.6 (CH), 128.9 (2ꢃCH), 129.5 (CH), 130.9 (C),
135.0 (CH), 136.4 (C), 141.8 (C), 148.3 (C), 170.1 (C), 175.1 (C), 176.4
(C); LRMS (ESI): m/z (%): 548.1 (15) [MþK]þ, 532 (100) [MþNa]þ;
(400 MHz, DMSO-d6, TMS):
d
¼1.30 (t, J¼7.2 Hz, 3H), 3.53 (dd, J¼8.8,
8.4 Hz, 1H), 3.61 (s, 6H), 4.04 (dd, J¼8.8, 3.2 Hz, 1H), 4.28 (m, 2H),
4.50 (d, J¼3.2 Hz, 1H), 4.69 (d, J¼8.4 Hz, 1H), 6.17 (s, 2H), 6.88 (dd,

D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
9615
HRMS (ESI): calcd for C29H30N3O6Na [MþNa]þ: 532.1485, found:
(ESI): m/z (%): 595 (100) [MþH]þ, 131 (87). Elemental analysis calcd
(%) for C33H29O8N3: C 66.53, H 4.91, N 7.06; found: C 66.18, H 4.75, N
6.86.
532.1483.
4.21.8. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-10-(4-Methoxyphenyl)-1,3-dioxo-
*
2-prop-2-ynyl-1,2,3,3a,4,5,10,10a-octahydropyrrolo[3,4-b]-
carbazole-4-carboxylic acid ethyl ester (4h)
4.21.11. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR )-4-(2-Oxopyrrolidine-1-carbonyl)-
*
2-phenyl-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydro-3aH-
pyrrolo[3,4-b]carbazole-1,3-dione (5b)
Method B, 24 h, 205 mg (76%), flash chromatography eluent 1:4
EtOAc/cyclohexane, isolated as an amorphous white solid, mp
148 ꢂC; Rf¼0.27 (3:7 EtOAc/cyclohexane); IR: nmax (film): 3390,
3300, 2992, 1713, 1510, 1460, 1395, 1251, 1178, 1030, 735 cmꢀ1; UV:
Method B, 18 h, 81 mg (68%), flash chromatography (silica gel)
with eluent 1:1 EtOAc/cyclohexane, isolated as an amorphous
white powder, mp 224 ꢂC; Rf¼0.18 (3:2 EtOAc/cyclohexane); IR:
nmax (film): 3346, 2938, 1715, 1697, 1590, 1503, 1461, 1383, 1248,
1197, 1123 cmꢀ1; UV: 292, 280, 220, 211 nm; 1H NMR (400 MHz,
330, 290, 281, 221, 202 nm; 1H NMR (400 MHz, CDCl3):
d
¼1.39 (t,
J¼7.2 Hz, 3H), 2.01 (t, J¼2.4 Hz, 1H), 3.59 (dd, J¼17.4, 2.4 Hz, 1H),
3.64 (s, 3H), 3.67 (dd, J¼17.4, 2.4 Hz,1H), 3.68 (dd, J¼8.8, 7.6 Hz,1H),
4.15 (dd, J¼8.8, 3.2 Hz, 1H), 4.36 (q, J¼7.2 Hz, 2H), 4.76 (d, J¼3.2 Hz,
1H), 4.80 (d, J¼7.6 Hz, 1H), 6.61 (d, J¼8.4 Hz, 2H), 6.79 (d, J¼8.4 Hz,
2H), 6.97 (dd, J¼7.8, 7.6 Hz, 1H), 7.12 (dd, J¼8.2, 7.6 Hz, 1H), 7.19 (d,
J¼7.6 Hz, 1H), 7.34 (d, J¼8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
CDCl3):
d
¼2.00 (m, 2H), 2.62 (t, J¼8.0 Hz, 2H), 3.67 (s, 6H), 3.75 (s,
3H), 3.80 (dd, J¼7.5, 7.1 Hz, 1H), 3.90 (t, J¼7.8 Hz, 2H), 4.44 (dd,
J¼10.6, 7.1 Hz, 1H), 4.89 (d, J¼7.5 Hz, 1H), 5.55 (d, J¼10.6 Hz, 1H),
6.50 (m, 2H), 6.62 (s, 2H), 7.04 (dd, J¼7.5, 7.5 Hz, 1H), 7.17 (dd, J¼7.5,
7.5 Hz, 1H), 7.22–7.28 (m, 3H), 7.30 (d, J¼7.5 Hz, 1H), 7.35 (d,
d
¼14.2 (CH3), 26.9 (CH2), 36.2 (CH), 37.6 (CH), 40.7 (CH), 45.4 (CH),
J¼7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼16.9 (CH2), 33.7 (CH2),
d
54.9 (CH3), 62.7 (CH2), 71.1 (C), 76.2 (CH), 110.9 (CH), 111.9 (C), 113.5
(2ꢃCH), 118.5 (CH), 119.8 (CH), 122.6 (CH), 125.6 (C), 127.0 (C), 129.4
(2ꢃCH), 130.8 (C), 136.2 (C), 158.7 (C), 170.3 (C), 175.4 (C), 176.5 (C);
LRMS (DCI, NH3þisobutane): m/z (%): 474 (8) [MþNH4]þ, 457 (100)
[MþH]þ, 410 (81), 349 (68). Elemental analysis calcd (%) for
38.6 (CH), 39.0 (CH), 39.6 (CH), 46.2 (CH2), 46.7 (CH), 56.3 (2ꢃCH3),
60.6 (CH3), 106.7 (2ꢃCH), 110.9 (CH), 112.8 (C), 118.4 (CH), 119.7
(CH), 122.8 (CH), 125.5 (C), 126.2 (2ꢃCH), 128.6 (CH), 128.9 (2ꢃCH),
130.0 (C), 131.0 (C), 134.8 (C), 137.0 (2ꢃC), 153.0 (2ꢃC), 171.3 (C),
175.1 (C), 175.8 (C), 176.5 (C); LRMS (FABþ): m/z (%): 616 (25)
[MþNa]þ, 594 (95) [MþH]þ, 508 (100). Elemental analysis calcd (%)
for C34H31O7N3: C 68.79, H 5.26, N 7.08; found: C 68.40, H 5.18, N
6.91.
C
27H24O5N2: C 71.04, H 5.30, N 6.14; found: C 70.87, H 5.11, N 6.05.
4.21.9. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-10-(4-Hydroxy-3,5-
*
dimethoxyphenyl)-1,3-dioxo-2-phenyl-1,2,3,3a,4,5,10,10a-
octahydropyrrolo[3,4-b]carbazole-4-carboxylic
4.21.12. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR )-10-(4-Hydroxy-3,5-
*
acid prop-2-ynyl ester (4i)
dimethoxyphenyl)-4-(2-oxo-oxazolidine-3-carbonyl)-2-phenyl-
4,5,10,10a-tetrahydro-3aH-pyrrolo[3,4-b]carbazole-1,3-dione (5c)
Method A, 24 h, 99 mg, 17%, method B, 24 h, 366 mg, 63%, flash
chromatography with eluent 3:2 EtOAc/cyclohexane, isolated as an
amorphous solid, mp 232 ꢂC; Rf¼0.14 (3:2 EtOAc/heptane); IR: nmax
(film): 3351, 2958, 2920, 1762, 1708, 1515, 1459, 1389, 1202, 1110,
1031 cmꢀ1; UV: 291, 283, 274, 208 nm; 1H NMR (400 MHz, DMSO-
Method B, 20 h, 103 mg, (69%), flash chromatography eluent
1:49 EtOAc/CH2Cl2, isolated as an amorphous white solid, mp
231 ꢂC; Rf¼0.23 (2:3 EtOAc/cyclohexane); IR: nmax (film): 3420,
1744, 1713, 1617, 1517, 1459, 1386, 1273, 1214, 1112, 735 cmꢀ1; UV:
289, 281, 217, 207 nm; 1H NMR (400 MHz, CDCl3):
d¼2.62 (t,
J¼2.6 Hz, 1H), 3.64 (s, 6H), 3.81 (dd, J¼8.6, 7.1 Hz, 1H), 4.33 (dd,
J¼8.6, 3.0 Hz, 1H), 4.88 (dd, J¼15.7, 2.3 Hz, 1H), 4.89 (d, J¼3.0 Hz,
1H), 4.90 (d, J¼7.1 Hz, 1H), 6.21 (s, 2H), 6.53 (m, 2H), 7.03 (dd, J¼8.0,
7.9 Hz, 1H), 7.19 (dd, J¼8.1, 7.9 Hz, 1H), 7.23–7.33 (m, 4H), 7.38 (d,
d6, TMS):
d
¼3.69 (s, 6H), 3.44–3.80 (m, 4H), 4.22 (ddd, J¼9.6, 9.6,
9.2 Hz, 1H), 4.10 (m, 1H), 4.52 (m, 1H), 4.58 (m, 1H), 4.76 (d,
J¼7.6 Hz, 1H), 5.53 (d, J¼11.6 Hz, 1H), 6.43 (m, 2H), 6.62 (s, 2H), 6.90
(dd, J¼8.0, 7.2 Hz, 1H), 7.06 (dd, J¼8.0, 7.2 Hz, 1H), 7.24–7.33 (m,
J¼8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼36.3 (CH), 38.6 (CH),
d
41.0 (CH), 45.4 (CH), 53.9 (CH2), 56.3 (2ꢃCH3), 76.5 (CH), 76.6 (C),
105.8 (2ꢃCH), 111.1 (CH), 112.5 (C), 118.6 (CH), 120.1 (CH), 123.1
(CH), 125.7 (C), 126.0 (2ꢃCH), 126.4 (C), 128.5 (CH), 128.9 (2ꢃCH),
129.9 (C), 131.1 (C), 134.4 (C), 136.4 (C), 146.9 (2ꢃC), 169.8 (C), 175.7
(C), 176.9 (C); LRMS (DCI, NH3þisobutane): m/z (%): 551 (4)
[MþH]þ, 494 (21), 316 (54), 288 (100). Elemental analysis calcd (%)
for C32H26O7N2: C 69.81, H 4.76, N 5.09; found: C 69.53, H 4.60, N
5.01.
5H); 13C NMR (100 MHz, DMSO-d6, TMS):
d¼36.5 (CH), 38.5 (CH),
39.3 (CH), 43.3 (CH2), 46.8 (CH), 56.4 (2ꢃCH3), 63.0 (CH2), 107.5
(2ꢃCH), 111.2 (CH), 112.1 (C), 118.4 (CH), 118.7 (CH), 121.9 (CH), 125.6
(C), 127.0 (2ꢃCH), 128.5 (CH), 128.8 (2ꢃCH), 130.5 (C), 131.0 (C),
132.0 (C), 135.1 (C), 136.8 (C), 147.8 (2ꢃC), 154.3 (C), 171.8 (C), 175.2
(C), 176.7 (C); LRMS (DCI, NH3þisobutane): m/z (%): 599 (2)
[MþNH4]þ, 581 (2) [M]þ, 428 (4), 183 (100); HRMS (ESI): calcd for
C
32H27N3O8Na [MþNa]þ: 604.1696, found: 604.1695.
4.21.10. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR
*
)-4-(2-Oxo-oxazolidine-3-
4.21.13. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR )-4-(2-Oxo-oxazolidine-3-
*
carbonyl)-2-phenyl-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-
tetrahydro-3aH-pyrrolo[3,4-b]carbazole-1,3-dione (5a)
carbonyl)-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydro-
3aH-pyrrolo[3,4-b]carbazole-1,3-dione (5d)
Method B, 24 h, 434 mg, 73%, flash chromatography with eluent
3:2 EtOAc/cyclohexane, isolated as needles, mp 233 ꢂC (EtOAc/cy-
clohexane); Rf¼0.18 (3:2 EtOAc/cyclohexane); IR: nmax (film): 3340,
2958, 2928, 1775, 1714, 1591, 1504, 1461, 1389, 1237, 1123 cmꢀ1; UV:
Method B, 24 h, 343 mg, 66%, flash chromatography with eluent
3:1 EtOAc/cyclohexane, isolated as an amorphous solid, mp 253 ꢂC
(EtOAc/cyclohexane); Rf¼0.20 (3:1 EtOAc/cyclohexane); IR: nmax
(film): 3350, 2945, 2920, 1772, 1701, 1589, 1506, 1457, 1357, 1320,
1224, 1123, 1036 cmꢀ1; UV: 291, 281, 270, 213 nm; 1H NMR
290, 284, 279, 216 nm; 1H NMR (400 MHz, DMSO-d6, TMS):
d¼3.57
(s, 9H), 3.78 (dd, J¼8.0, 7.8 Hz, 1H), 3.98 (ddd, J¼9.6, 9.6, 9.0 Hz, 1H),
4.10 (m,1H), 4.49–4.56 (m, 2H), 4.61 (dd, J¼11.6, 8.0 Hz,1H), 4.82 (d,
J¼7.6 Hz, 1H), 5.55 (d, J¼11.6 Hz, 1H), 6.43 (m, 2H), 6.69 (s, 2H), 6.92
(dd, J¼7.6, 7.6 Hz, 1H), 7.07 (dd, J¼7.6, 7.6 Hz, 1H), 7.26–7.31 (m, 3H),
7.33 (d, J¼7.6 Hz, 1H), 7.34 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
(400 MHz, DMSO-d6, TMS):
d
¼3.54 (dd, J¼8.8, 7.6 Hz, 1H), 3.55 (s,
3H), 3.63 (s, 6H), 4.00 (ddd, J¼10.8, 9.2, 9.2 Hz, 1H), 4.10 (ddd,
J¼10.8, 8.8, 5.2 Hz, 1H), 4.28 (dd, J¼11.8, 8.8 Hz, 1H), 4.51 (dd, J¼9.2,
8.8 Hz, 1H), 4.55 (ddd, J¼9.2, 8.8, 5.2 Hz, 1H), 4.69 (d, J¼7.6 Hz, 1H),
5.39 (d, J¼11.8 Hz, 1H), 6.61 (s, 2H), 6.89 (dd, J¼8.0, 7.2 Hz, 1H), 7.04
(dd, J¼8.0, 7.2 Hz, 1H), 7.30 (dd, J¼8.0, 7.2 Hz, 2H); 13C NMR
DMSO-d6, TMS):
d
¼36.2 (CH), 38.4 (CH), 39.0 (CH), 43.0 (CH2), 46.2
(CH), 56.0 (2ꢃCH3), 59.8 (CH3), 62.7 (CH2), 107.0 (2ꢃCH), 110.9 (CH),
111.5 (C), 118.1 (CH), 118.5 (CH), 121.6 (CH), 125.3 (C), 126.6 (2ꢃCH),
128.3 (CH), 128.6 (2ꢃCH), 130.8 (C), 131.7 (C), 136.2 (C), 136.4 (C),
136.5 (C), 152.5 (2ꢃC), 154.0 (C), 171.5 (C), 174.8 (C), 176.4 (C); LRMS
(100 MHz, DMSO-d6, TMS):
d¼36.0 (CH), 38.2 (CH), 39.7 (CH), 43.1
(CH2), 47.3 (CH), 55.8 (2ꢃCH3), 59.8 (CH3), 62.7 (CH2), 106.7 (2ꢃCH),
110.9 (CH), 111.7 (C), 118.1 (CH), 118.4 (CH), 121.5 (CH), 125.3 (C),
130.8 (C), 136.0 (C), 136.3 (C), 136.5 (C), 152.1 (2ꢃC), 154.0 (C), 171.7

9616
D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
(C), 177.1 (C), 178.6 (C); LRMS (DCI, NH3þisobutane): m/z (%): 520
(53) [MþH]þ, 352 (100); HRMS (ESI): calcd for C27H25N3O8Na:
542.1539 [MþNa]þ, found: 542.1539.
4.21.17. (ꢀ)-(4S,5S,10S,10aS,40S)-4-(4-Benzyl-2-oxo-oxazolidine-3-
carbonyl)-10-(4-hydroxy-3,5-dimethoxyphenyl)-2-phenyl-
4,5,10,10a-tetrahydro-3aH-pyrrolo[3,4-b]carbazole-1,3-dione (8)
28
As a white powder, mp 180 ꢂC, [
a
]
D
ꢀ32.2 (c 1.5, CHCl3);
4.21.14. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR
*
)-10-(4-Hydroxy-3,5-
Rf¼0.16 (2:3 EtOAc/cyclohexane); IR: nmax (film): 3364, 2920, 1770,
dimethoxyphenyl)-4-(2-oxo-oxazolidine-3-carbonyl)-4,5,10,10a-
tetrahydro-3aH-pyrrolo[3,4-b]carbazole-1,3-dione (5e)
1712, 1516, 1461, 1389, 1217, 1112, 740 cmꢀ1; UV: 292, 283, 210,
206 nm; 1H NMR (400 MHz, DMSO-d6, TMS):
d
¼3.00 (dd, J¼13.6,
Method C, 36 h, 273 mg, 54%, flash chromatography with eluent
3:2 EtOAc/cyclohexane, isolated as an amorphous solid, mp >325 ꢂC
(ether/CH2Cl2); Rf¼0.1 (3:1 EtOAc/cyclohexane); IR: nmax (film):
8.8 Hz, 1H), 3.38 (dd, J¼13.6, 3.2 Hz, 1H), 3.60 (s, 6H), 3.77 (dd,
J¼8.4, 7.2 Hz, 1H), 4.27 (dd, J¼9.2, 4.0 Hz, 1H), 4.37 (dd, J¼9.2,
8.8 Hz, 1H), 4.57 (dd, J¼11.4, 8.4 Hz, 1H), 4.70 (m, 1H), 4.80 (d,
J¼7.2 Hz, 1H), 5.64 (d, J¼11.4 Hz, 1H), 6.45 (m, 2H), 6.66 (s, 2H),
6.94 (dd, J¼8.0, 7.2 Hz, 1H), 7.10 (dd, J¼8.0, 7.2 Hz, 1H), 7.25–7.40
3362, 2941,1772,1718,1610,1513,1463,1392,1329,1217,1112 cmꢀ1
;
UV: 330, 291, 285, 210 nm; 1H NMR (400 MHz, DMSO-d6, TMS):
d
¼3.50 (dd, J¼8.8, 7.6 Hz, 1H), 3.61 (s, 6H), 4.01 (ddd, J¼9.6, 9.2,
(m, 10H); 13C NMR (100 MHz, DMSO-d6, TMS):
d¼36.8 (CH), 37.8
9.2 Hz, 1H), 4.10 (m, 1H), 4.25 (dd, J¼11.6, 8.8 Hz, 1H), 4.50 (m, 1H),
4.56 (m, 1H), 4.64 (d, J¼7.6 Hz, 1H), 5.36 (d, J¼11.6 Hz, 1H), 6.57 (s,
2H), 6.88 (dd, J¼8.0, 7.2 Hz, 1H), 7.04 (dd, J¼8.0, 7.2 Hz, 1H), 7.30 (d,
(CH2), 38.2 (CH), 38.9 (CH), 46.6 (CH), 55.6 (CH), 56.1 (2ꢃCH3),
66.6 (CH2), 107.3 (2ꢃCH), 111.0 (CH), 112.1 (C), 118.1 (CH), 118.5
(CH), 121.6 (CH), 125.3 (C), 126.7 (2ꢃCH), 126.9 (CH), 128.2 (CH),
128.6 (2ꢃCH), 128.7 (2ꢃCH), 129.4 (2ꢃCH), 130.2 (C), 130.6 (C),
131.7 (C), 134.9 (C), 136.2 (C), 136.7 (C), 148.1 (2ꢃC), 154.1 (C), 171.6
(C), 174.9 (C), 176.6 (C); LRMS (DCI, NH3þisobutane): m/z (%): 689
[MþNH4]þ, 672 (15) [MþH]þ, 518 (46), 494 (65), 178 (100); HRMS
J¼8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6, TMS):
¼36.1 (CH),
d
38.0 (CH), 39.8 (CH), 43.1 (CH2), 47.6 (CH), 55.9 (2ꢃCH3), 62.7 (CH2),
106.8 (2ꢃCH),110.9 (CH),112.0 (C),118.1 (CH),118.3 (CH),121.5 (CH),
125.4 (C), 130.5 (C), 130.8 (C), 134.2 (C), 136.5 (C), 147.2 (2ꢃC), 171.7
(C),177.2 (C),178.6 (C); LRMS (FABþ): m/z (%): 506 (10) [MþH]þ, 277
(90), 244 (100). Elemental analysis calcd (%) for C26H23O8N3: C 61.78,
H 4.59, N 8.32; found: C 61.34, H 4.80, N 7.91.
(ESI): calcd for
694.2170.
C
39H33N3O8Na [MþNa]þ: 694.2164, found:
4.21.18. (þ)-(4R,5R,10R,10aR,40S)-4-(4-Benzyl-2-oxo-oxazolidine-
4.21.15. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR
*
)-10-(3-Nitrophenyl)-4-(2-oxo-
3-carbonyl)-10-(4-hydroxy-3,5-dimethoxyphenyl)-2-phenyl-
oxazolidine-3-carbonyl)-2-phenyl-4,5,10,10a-tetrahydro-3aH-
pyrrolo[3,4-b]carbazole-1,3-dione (5f)
4,5,10,10a-tetrahydro-3aH-pyrrolo[3,4-b]carbazole-1,3-dione (9)
28
As a white powder, mp 185 ꢂC, [
a]
þ23.7 (c 1.0, acetone);
D
Method B, 18 h, 260 mg, 77%, flash chromatography with eluent
1:1 EtOAc/cyclohexane, isolated as a white solid, mp 217–218 ꢂC;
Rf¼0.25 (3:2 EtOAc/cyclohexane); IR: nmax (film): 3372, 3045, 1766,
1697, 1523, 1393, 1350, 1258, 734 cmꢀ1; UV: 290, 284, 268, 219,
Rf¼0.10 (2:3 EtOAc/cyclohexane); IR: nmax (film): 3362, 1770, 1713,
1517, 1457, 1388, 1213, 1111, 741 cmꢀ1; UV: 290, 282, 205 nm; 1H
NMR (400 MHz, DMSO-d6, TMS):
d
¼2.77 (dd, J¼13.6, 10.8 Hz, 1H),
3.41 (dd, J¼13.6, 4.2 Hz, 1H), 3.59 (s, 6H), 3.78 (dd, J¼8.2, 7.8 Hz,
1H), 4.30 (dd, J¼8.8, 2.0 Hz, 1H), 4.42 (dd, J¼8.8, 8.0 Hz, 1H), 4.66
(dd, J¼11.4, 8.2 Hz, 1H), 4.68 (m, 1H), 4.78 (d, J¼7.8 Hz, 1H), 5.49
(d, J¼11.4 Hz, 1H), 6.45 (m, 2H), 6.74 (s, 2H), 6.92 (dd, J¼8.0,
7.2 Hz, 1H), 7.07 (dd, J¼8.0, 7.2 Hz, 1H), 7.22–7.35 (m, 10H); 13C
198 nm; 1H NMR (400 MHz, DMSO-d6):
d
¼3.95 (dd, J¼8.6, 8.2 Hz,
1H), 4.00–4.16 (m, 2H), 4.47–4.66 (m, 2H), 5.17 (d, J¼8.2 Hz, 1H),
5.67 (d, J¼11.6 Hz,1H), 6.37 (m, 2H), 6.89 (dd, J¼7.6, 7.6 Hz,1H), 7.07
(dd, J¼7.6, 7.6 Hz, 1H), 7.24–7.30 (m, 4H), 7.35 (d, J¼8.0 Hz, 1H), 7.49
(dd, J¼8.0, 8.0 Hz, 1H), 7.89 (d, J¼8.0 Hz, 1H), 8.04 (br d, J¼8.0 Hz,
NMR (100 MHz, DMSO-d6, TMS):
d¼36.3 (CH), 36.4 (CH2), 38.3
1H), 8.32 (br s, 1H); 13C NMR (100 MHz, DMSO-d6):
d
¼35.9 (CH),
(CH), 40.5 (CH), 46.5 (CH), 55.9 (2ꢃCH3), 56.2 (CH), 66.8 (CH2),
107.3 (2ꢃCH), 110.9 (CH), 111.8 (C), 118.1 (CH), 118.4 (CH), 121.6
(CH), 125.3 (C), 126.7 (2ꢃCH), 126.8 (CH), 128.2 (CH), 128.6
(2ꢃCH), 128.7 (2ꢃCH), 129.2 (2ꢃCH), 130.2 (C), 131.0 (C), 131.8 (C),
134.8 (C), 136.4 (C), 136.6 (C), 147.6 (2ꢃC), 153.6 (C), 171.4 (C),
175.0 (C), 176.3 (C); LRMS (FABþ): m/z (%): 672 (100) [MþH]þ.
Elemental analysis calcd (%) for C39H33O8N3: C 69.72, H 4.95, N
6.26; found: C 69.32, H 4.97, N 6.12.
37.3 (CH), 38.9 (CH), 43.0 (CH2), 45.3 (CH), 62.7 (CH2),110.4 (C),111.1
(CH), 117.9 (CH), 118.7 (CH), 121.8 (CH), 122.0 (CH), 124.1 (CH), 125.0
(C), 126.2 (2ꢃCH), 128.3 (CH), 128.6 (2ꢃCH), 129.3 (CH), 131.3 (C),
131.4 (C), 136.0 (CH), 136.5 (C), 143.2 (C), 147.6 (C), 154.0 (C), 171.5
(C), 174.7 (C), 175.9 (C); LRMS (ESI): m/z (%): 573 (100) [MþNa]þ;
HRMS (ESI): calcd for C30H29N4O7Na [MþNa]þ: 573.1386, found:
573.1390.
4.21.16. 4-(2-Oxo-[1,3]oxazinane-3-carbonyl)-2-phenyl-10-(3,4,5-
trimethoxyphenyl)-4,5,10,10a-tetrahydro-3aH-pyrrolo-
4.21.19. (ꢁ)-(4S
*
,5R
*
,10S
*
,10aR )-3-Hydroxy-4-hydroxymethyl-2-
*
phenyl-10-(3,4,5,-trimethoxyphenyl)-3,3a,4,5,10,10a-hexahydro-
[3,4-b]carbazole-1,3-dione (5g/4g)
2H-pyrrolo[3,4-b]carbazol-1-one (10)
Method B, 36 h, 100 mg, 59%, flash chromatography with eluent
1:1 EtOAc/cyclohexane, isolated as a white solid; Rf¼0.12 (1:1
EtOAc/cyclohexane); IR: nmax (film): 3345, 2931, 1715, 1591, 1505,
1458, 1386, 1274, 1184, 1123, 1004, 738 cmꢀ1; UV: 291, 285, 217,
203 nm; LRMS (ESI): m/z (%): 632 (100) [MþNa]þ, 341 (50); HRMS
To a suspension of 5a (50 mg, 84 mmol) in dry CH2Cl2 (2 mL)
cooled at ꢀ78 ꢂC was injected dropwise LiEt3BH (0.59 mL, 1 M in
THF, 0.59 mmol, 7 equiv) under argon. The solution was stirred for
6 h at ꢀ78 ꢂC. After addition of MeOH (2 mL), the solution was
warmed up to rt. The solvent was removed in vacuo and brine was
added. The product was extracted with EtOAc and the combined
organic solvent was dried over MgSO4. After evaporation and flash
chromatography (3:97 MeOH/CH2Cl2), the product 10 (32 mg, 74%)
was isolated as yellow solid, mp 180–182 ꢂC; Rf¼0.28 (5:95 MeOH/
CH2Cl2); IR: nmax (film): 3054, 1704, 1588, 1423, 1267, 1124,
890 cmꢀ1; UV: 290, 283, 277, 221, 196 nm; 1H NMR (400 MHz,
(ESI): calcd for
632.2003.
C
34H31N3O8Na [MþNa]þ: 632.2009, found:
NMR data for the major diastereomer 5g: 1H NMR (400 MHz,
CDCl3):
d
¼1.82–2.04 (m, 2H), 3.68 (s, 6H), 3.74 (s, 3H), 3.74–3.82 (m,
3H), 4.15 (m, 1H), 4.23 (m, 1H), 4.48 (dd, J¼10.8, 8.5 Hz, 1H), 4.89 (d,
J¼7.6 Hz, 1H), 5.66 (d, J¼10.8 Hz, 1H), 6.50 (m, 2H), 6.67 (s, 2H), 7.03
(dd, J¼7.5, 7.5 Hz, 1H), 7.15 (dd, J¼7.5, 7.5 Hz, 1H), 7.20–7.30 (m, 4H),
DMSO-d6):
d
¼2.92 (dd, J¼8.0, 7.4 Hz, 1H), 3.37 (s, 3H), 3.49 (s, 6H),
7.35 (d, J¼7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d¼21.4 (CH2),
3.58 (m, 1H), 3.88 (dd, J¼7.6, 7.4 Hz, 1H), 4.35 (m, 1H), 4.41 (m, 1H),
4.58 (d, J¼8.0 Hz,1H), 5.27 (d, J¼7.2 Hz,1H), 6.40 (br s, 2H), 6.77 (dd,
J¼7.6, 7.6 Hz, 1H), 6.90 (d, J¼7.6 Hz, 1H), 6.96 (dd, J¼8.0, 7.6 Hz, 1H),
7.02 (m, 2H), 7.16 (m, 2H), 7.34 (d, J¼8.0 Hz, 1H); 13C NMR (75 MHz,
39.0 (CH), 39.9 (CH), 40.4 (CH), 43.3 (CH2), 46.7 (CH), 56.3 (2ꢃCH3),
60.6 (CH3), 67.6 (CH2), 106.7 (2ꢃCH), 110.9 (CH), 112.5 (C), 118.3
(CH), 119.6 (CH), 122.7 (CH), 125.5 (C), 126.2 (2ꢃCH), 128.6 (CH),
128.9 (2ꢃCH), 130.7 (C), 131.1 (C), 135.1 (C), 136.9 (C), 151.8 (C), 152.9
(2ꢃC), 174.3 (C), 175.1 (C), 176.1 (C).
CDCl3):
d
¼35.6 (CH), 39.2 (CH), 41.4 (CH), 44.7 (CH), 56.0 (2ꢃCH3),
60.7 (CH3), 63.0 (CH2), 86.4 (CH), 106.6 (2ꢃCH), 110.9 (CH), 111.3 (C),

D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
9617
118.6 (CH), 119.2 (CH), 121.9 (CH), 122.5 (2ꢃCH), 126.2 (CH), 126.3
(C), 128.8 (2ꢃCH), 133.3 (C), 136.4, 136.7 (4ꢃC), 152.9 (2ꢃC), 175.3
(C); LRMS (FABþ): m/z (%): 537 (10) [MþNa]þ, 515 (100) [MþH]þ,
497 (45) [MꢀOH], 484 (45); HRMS (ESI): calcd for C30H30N2O6Na
[MþNa]þ: 537.2002; found: 537.2003.
1.77 mmol, 1.5 equiv) and CuSO4$5H2O (29 mg, 0.12 mmol) in tol-
uene (5 mL) was stirred and refluxed for 24 h. After cooling, CHCl3
(1 mL), EtOH (1 mL) and water (1 mL) were added. The mixture was
checked for homogenisation and split into equal shares. To the first
flask, the azido-acetic acid ethyl ester (168 mg, 1.18 mmol, 2 equiv)
in CHCl3 (1 mL) and the
L-ascorbic acid sodium salt (14 mg,
4.21.20. (ꢁ)-(4S
*
,5R
*
,10S
*
,10aS
*
)-3-Hydroxy-4-hydroxymethyl-2-
0.07 mmol) were added and the mixture was stirred for 18 h at rt.
To the second flask, the benzyl azide (160 mg,1.18 mmol, 2 equiv) in
phenyl-10-(3,4,5,-trimethoxyphenyl)-3,3a,4,5,10,10a-hexahydro-
2H-pyrrolo[3,4-b]carbazol-1-one (11)
CHCl3 (1 mL) and the
L-ascorbic acid sodium salt (14 mg,
Following the same condition as described for 10 and starting
from 4a (156 mg, 0.28 mmol), the product 11 (102 mg, 71%) was
isolated as a white amorphous solid, mp 214–215 ꢂC; Rf¼0.25 (5:95
MeOH/CH2Cl2); IR: nmax (film): 3444, 3055, 1705, 1584, 1420, 1258,
0.07 mmol) were added and the mixture was stirred for 18 h at rt.
The solvent of each flask was removed in vacuo. EtOAc was added
and the resulting solution was dried (MgSO4) and filtered. The
solvent was removed in vacuo prior to flash chromatography.
1124, 890 cmꢀ1
;
UV: 291, 283, 276, 223, 207 nm; 1H NMR
(400 MHz, DMSO-d6):
d
¼2.89 (dd, J¼7.8, 7.5 Hz, 1H), 3.30 (m, 3H),
4.22.1. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-2-(1-Ethoxycarbonylmethyl-1H-
*
3.50 (s, 6H), 3.60 (dd, J¼7.8, 2.0 Hz, 1H), 3.67 (m, 1H), 3.78 (m, 1H),
3.91 (m, 1H), 4.57 (d, J¼7.5 Hz, 1H), 5.30 (d, J¼6.7 Hz, 1H), 6.27 (br s,
2H), 6.80 (dd, J¼8.0, 7.5 Hz, 1H), 6.97 (dd, J¼8.0, 7.5 Hz, 1H), 7.00
(dd, J¼8.0, 7.5 Hz, 1H), 7.04–7.08 (m, 3H), 7.13–7.18 (m, 2H), 7.31 (d,
[1,2,3]triazol-4-ylmethyl)-10-(4-methoxyphenyl)-1,3-dioxo-
1,2,3,3a,4,5,10,10a-octahydropyrrolo[3,4-b]carbazole-4-
carboxylic acid ethyl ester (12)
Flash chromatography eluent 3:2 EtOAc/cyclohexane, 234 mg
(68%), isolated as an amorphous white solid, mp 160 ꢂC; Rf¼0.3 (4:1
EtOAc/cyclohexane); IR: nmax (film): 3380, 2992, 1738, 1708, 1510,
1445, 1400, 1250, 1236, 1216, 1180, 1027, 734 cmꢀ1; UV: 290, 280,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
¼33.5 (CH), 38.1
d
(CH), 40.6 (CH), 43.1 (CH), 55.6 (2ꢃCH3), 59.7 (CH3), 64.6 (CH2), 85.3
(CH), 106.3 (2ꢃCH), 110.9 (CH), 117.7 (CH), 118.1 (CH), 120.6 (2ꢃCH),
124.2 (CH), 125.9 (C), 128.1 (2ꢃCH), 134.4 (C), 135.8 (C), 136.4 (C),
137.8 (C),138.0 (C),152.1 (2ꢃC),174.8 (C); LRMS (FABþ): m/z (%): 537
(10) [MþNa]þ, 515 (100) [MþH]þ, 496 (20) [MꢀH2O]þ; HRMS (TOF
EIþ): calcd for C30H30N2O6: 514.2104, found: 514.2144.
276, 226, 208 nm; 1H NMR (400 MHz, CDCl3):
d¼1.27 (t, J¼7.2 Hz,
3H), 1.39 (t, J¼7.2 Hz, 3H), 3.64 (s, 3H), 3.68 (dd, J¼9.0, 7.6 Hz, 1H),
4.16 (dd, J¼9.0, 3.4 Hz,1H), 4.22 (q, J¼7.2 Hz, 2H), 4.25 (d, J¼14.4 Hz,
1H), 4.36 (q, J¼7.2 Hz, 2H), 4.37 (d, J¼14.4 Hz, 1H), 4.73 (d, J¼3.4 Hz,
1H), 4.80 (d, J¼7.6 Hz, 1H), 5.03 (s, 2H), 6.50 (dd, J¼7.6 Hz, 2H), 6.76
(d, J¼7.6 Hz, 2H), 6.95 (dd, J¼8.0, 7.6 Hz, 1H), 7.13 (dd, J¼8.0, 7.6 Hz,
1H), 7.18 (d, J¼8.0 Hz, 1H), 7.27 (s, 1H), 7.33 (d, J¼8.0 Hz, 1H); 13C
4.21.21. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-10-(4-Hydroxy-3,5-
*
dimethoxyphenyl)-1,3-dioxo-2-phenyl-1,2,3,3a,4,5,10,10a-
octahydropyrrolo[3,4-b]carboxylic acid 1-benzyl-1H-
NMR (100 MHz, CDCl3):
d
¼13.9 (CH3), 14.2 (CH3), 33.2 (CH2), 36.5
[1,2,3]triazol-4-ylmethyl ester (14)
(CH), 37.5 (CH), 40.7 (CH), 45.0 (CH), 50.6 (CH2), 54.9 (CH3), 62.2
(CH2), 62.7 (CH2), 110.9 (CH), 112.2 (C), 113.2 (2ꢃCH), 118.4 (CH),
119.7 (CH), 122.6 (CH), 124.5 (CH), 125.6 (C), 127.2 (C), 129.5 (2ꢃCH),
130.9 (C), 136.2 (C), 141.7 (C), 158.2 (C), 166.2 (C), 170.4 (C), 176.1 (C),
177.2 (C); LRMS (FABþ): m/z (%): 586 (65) [MþH]þ, 539 (78), 512
(40), 307 (100); HRMS (TOF EIþ): calcd for C32H35N5O6: 585.2223,
found: 585.2206.
A solution of indole 1g (95 mg, 0.45 mmol), 3,5-dimethoxy-4-
hydroxy-benzaldehyde 2b (121 mg, 0.67 mmol, 1.5 equiv), N-phe-
nylmaleimide 3a (231 mg, 1.3 mmol, 3 equiv) and CuSO4$5H2O
(11 mg, 0.045 mmol) in toluene (5 mL) was stirred and refluxed for
24 h. After cooling, CHCl3 (0.5 mL), EtOH (0.5 mL) and water
(0.5 mL) were added followed by benzyl azide (77 mg, 0.58 mmol)
in CHCl3 (0.5 mL) and the L-ascorbic acid sodium salt (10 mg,
0.049 mmol) and the mixture was stirred for 18 h at rt. EtOAc was
added (10 mL) and the mixture was dried over MgSO4. After fil-
tration and solvent evaporation, flash chromatography (silica gel,
45:55 EtOAc/cyclohexane) gave the product 14 (201 mg, 66%) as
yellow solid, mp 211 ꢂC; Rf¼0.11 (1:1 EtOAc/cyclohexane); IR: nmax
(KBr): 3465, 3375, 1734, 1707, 1614, 1519, 1499, 1459, 1428, 1384,
1330, 1214, 1176, 1117, 734 cmꢀ1; UV: 300, 292, 218, 207 nm; 1H
4.22.2. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aS )-2-(1-Benzyl-1H-[1,2,3]triazol-4-
*
ylmethyl)-10-(4-methoxyphenyl)-1,3-dioxo-1,2,3,3a,4,5,10,10a-
octahydropyrrolo[3,4-b]carbazole-4-carboxylic acid ethyl ester (13)
Flash chromatography eluent 2:3 EtOAc/cyclohexane, 215 mg
(62%), isolated as an amorphous white solid, mp 188–190 ꢂC;
Rf¼0.22 (1:1 EtOAc/cyclohexane); IR: nmax (film): 3392, 2989, 2937,
1750, 1713, 1506, 1458, 1241, 1180, 1030, 1024 cmꢀ1; UV: 290, 284,
NMR (400 MHz, CDCl3):
d
¼3.65 (s, 6H), 3.75 (dd, J¼8.6, 7.5 Hz, 1H),
279, 214, 193 nm; 1H NMR (400 MHz, CDCl3):
d¼1.40 (t, J¼7.2 Hz,
4.31 (dd, J¼8.6, 3.9 Hz, 1H), 4.86 (d, J¼3.9 Hz, 1H), 4.91 (d, J¼7.5 Hz,
1H), 5.28 (d, J¼13.0 Hz, 1H), 5.51 (d, J¼14.8 Hz, 1H), 5.56 (d,
J¼14.8 Hz, 1H), 5.73 (d, J¼13.0 Hz, 1H), 6.24 (s, 2H), 6.52 (m, 2H),
7.05 (dd, J¼7.5, 7.5 Hz, 1H), 7.20 (dd, J¼7.5, 7.5 Hz, 1H), 7.24–7.38 (m,
9H), 7.50 (s,1H), 7.51 (d, J¼7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):
3H), 3.66 (m, 1H), 3.67 (s, 3H), 4.11 (m, 1H), 4.12 (d, J¼15.2 Hz, 1H),
4.28 (d, J¼15.2 Hz, 1H), 4.38 (q, J¼7.2 Hz, 2H), 4.72 (d, J¼2.4 Hz, 1H),
4.79 (d, J¼7.6 Hz, 1H), 5.41 (s, 2H), 6.56 (d, J¼8.0 Hz, 2H), 6.77 (d,
J¼8.0 Hz, 2H), 6.97 (dd, J¼7.6, 7.2 Hz, 1H), 7.10–7.40 (m, 9H); 13C
NMR (100 MHz, CDCl3):
d
¼14.3 (CH3), 33.2 (CH2), 36.4 (CH), 37.6
d¼36.9 (CH), 38.7 (CH), 41.1 (CH), 45.9 (CH), 54.4 (CH2), 56.3
(CH), 40.7 (CH), 45.2 (CH), 53.9 (CH2), 55.0 (CH3), 62.8 (CH2), 110.9
(CH), 112.2 (C), 113.3 (2ꢃCH), 118.5 (CH), 119.9 (CH), 122.7 (CH),
122.9 (CH), 125.7 (C), 127.2 (C), 128.01 (2ꢃCH), 128.6 (CH), 129.0
(2ꢃCH), 129.6 (2ꢃCH), 130.8 (C), 134.5 (C), 136.2 (C), 158.4 (C), 170.4
(C), 176.2 (C), 177.2 (C); LRMS (ESI): m/z (%): 612 (10) [MþNa]þ, 590
(100) [MþH]þ; HRMS (ESI): calcd for C34H32N5O5[MþH]þ:
590.2403, found: 590.2404.
(2ꢃCH3), 59.0 (CH2), 105.6 (2ꢃCH), 111.6 (CH), 112.1 (C), 118.2 (CH),
119.8 (CH), 122.5 (CH), 122.8 (CH), 125.6 (C), 126.1 (2ꢃCH), 126.7
(CH), 127.0 (C), 128.1 (2ꢃCH), 128.5 (CH), 128.7 (CH), 129.0 (2ꢃCH),
129.2 (2ꢃCH), 129.9 (C), 131.2 (C), 134.0 (C), 134.3 (C), 136.7 (C),
142.3 (C), 146.9 (2ꢃC), 170.3 (C), 175.9 (C), 177.2 (C); LRMS (DCI,
NH3þisobutane): m/z (%): 684 (53) [MþH]þ, 174 (100). Elemental
analysis calcd (%) for C39H33O7N5: C 68.51, H 4.86, N 10.24; found: C
68.36, H 4.75, N 9.91.
4.22.3. (ꢁ)-(4S
*
,5S
*
,10S
*
,10aR )-{4-[10-(4-Methoxyphenyl)-1,3-
*
dioxo-4-(2-oxo-oxazolidine-3-carbonyl)-3,3a,4,5,10,10a-
hexahydro-1H-pyrrolo[3,4-b]carbazol-2-ylmethyl]-[1,2,3]-
triazol-1-yl}-acetic acid ethyl ester (15)
4.22. Procedure for the ‘one flask’ Cu(II)/CuI catalysed
reactions
A solution of indole 1a (200 mg, 0.8 mmol), 4-anisaldehyde 2d
(166 mg, 1.2 mmol, 1.5 equiv), N-propynyl-maleimide 3c (166 mg,
1.2 mmol,1.5 equiv)and CuSO4$5H2O (20 mg, 0.08 mmol) in toluene
A solution of indole 1a (240 mg, 1.18 mmol), 4-anisaldehyde 2c
(241 mg, 1.77 mmol, 1.5 equiv), N-propynylmaleimide 3c (240 mg,

9618
D. Royer et al. / Tetrahedron 64 (2008) 9607–9618
Org. Lett. 2005, 7, 4321–4324; (f) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4,
2913–2916; (g) Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.; Lee, J. Org. Lett. 2003, 5,
3439–3442.
4. (a) Schreiber, S. L. Science 2000, 287, 1964–1969; (b) Spring, D. R. Org. Biomol.
Chem. 2003, 1, 3867–3870; (c) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2004, 43, 46–58; (d) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9,
248–258; (e) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2007, 47,
48–56.
5. (a) For recent and efficient examples of diastereodivergent reactions, see
Rondot, C.; Zhu, J. Org. Lett. 2005, 7, 1641–1644; (b) Kumagai, N.; Muncipinto,
G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006, 45, 3635–3638; (c) Luo, S.; Xu, H.;
Zhang, L.; Li, J.; Cheng, J.-P. Org. Lett. 2008, 10, 653–656.
6. Diker, K.; Do¨e´ de Maindreville, M.; Royer, D.; Le Provost, F.; Le´vy, J. Tetrahedron
Lett. 1999, 40, 7463–7467.
7. For other examples of indoles involved in MCR [4þ2] cycloaddition reactions
see: Sapi, J.; Laronze, J.-Y. ARKIVOC 2004, 7, 208–222 and the references therein.
8. (a) Gordaliza, M.; Garcı´a, P. A.; Miguel del Corral, J. M.; Castro, M. A.; Go´mez-
Zurita, M. A. Toxicon 2004, 44, 441–459; (b) Apers, S.; Vlietinck, A.; Pieters, L.
Phytochem. Rev. 2003, 2, 201–207; (c) Sellars, J. D.; Steel, P. G. Eur. J. Org. Chem.
2007, 3815–3828.
(5 mL) was stirred and refluxed for 24 h. After cooling, CHCl3 (1 mL),
EtOH (1 mL) and water (1 mL) were added followed by the azido-
acetic acid ethyl ester (234 mg, 1.81 mmol) in CHCl3 (1 mL) and the
L-ascorbic acid sodium salt (18 mg, 0.09 mmol) and the mixture was
stirred for 18 h at rt. EtOAc was added (15 mL) and the mixture was
dried over MgSO4. After filtration and solvent evaporation, flash
chromatography (silica gel,1:99 MeOH/CH2Cl2) gave the product 15
(288 mg, 56%) as an amorphous white solid, mp 203 ꢂC; Rf¼0.17 (1:1
EtOAc/cyclohexane); IR: nmax (film): 3400, 2985, 1770, 1706, 1510,
1426, 1391, 1245, 1223, 1115, 1029, 738 cmꢀ1; UV: 291, 282, 220,
205 nm; 1H NMR (400 MHz, CDCl3):
d
¼1.25 (t, J¼7.2 Hz, 3H), 3.61 (s,
3H), 3.64 (dd, J¼9.0, 8.2 Hz, 1H), 3.92 (m, 1H), 4.04 (m, 1H), 4.12 (dd,
J¼10.3, 9.0 Hz,1H), 4.19 (q, J¼7.2 Hz, 2H), 4.20–4.34 (m, 2H), 4.25 (d,
J¼15.0 Hz,1H), 4.37 (d, J¼15.0 Hz,1H), 4.80 (d, J¼8.2 Hz,1H), 4.92 (s,
2H), 5.57 (d, J¼10.3 Hz, 1H), 6.54 (d, J¼8.9 Hz, 2H), 6.91 (dd, J¼7.8,
7.2 Hz, 2H), 7.03–7.15 (m, 5H), 7.27 (d, J¼8.8 Hz, 1H); 13C NMR
´
´
´
9. Caballero, E.; Adeva, M.; Calderon, S.; Sahagun, H.; Tome, F.; Medarde, M.;
Ferna´ndez, J. L.; Lo´pez-La´zaro, M.; Ayuso, M. J. Bioorg. Med. Chem. 2003, 11,
3413–3421.
(100 MHz, CDCl3):
d¼13.9 (CH3), 33.2 (CH2), 37.2 (CH), 37.6 (CH), 40.3
(CH), 43.0 (CH2), 45.7 (CH), 50.5 (CH2), 54.9 (CH3), 62.2 (CH2), 62.7
(CH2), 111.1 (CH), 112.8 (C, 2ꢃCH), 118.3 (CH), 119.5 (CH), 122.5 (CH),
124.4 (CH), 125.3 (C), 129.1 (C), 130.7 (2ꢃCH), 131.0 (C), 136.7 (C),
141.8 (C), 154.4 (C), 158.1 (C), 166.3 (C), 170.9 (C), 175.7 (C), 176.2 (C);
LRMS (DCI, NH3þisobutane): m/z (%): 627 (11) [MþH]þ, 344 (17), 512
(40),105 (100). Elemental analysis calcd (%) for C32H30O8N6: C 61.34,
H 4.83, N 13.41; found: C 61.38, H 4.63, N 13.35.
10. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021; (b) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006,
51–68.
11. (a) For a one-pot approach using two reactions of which both reactions were
catalysed by Cu(I) and involving
a Huigens 1,3-dipolar cycloaddition, see
Mantovani, G.; Ladmiral, V.; Tao, L.; Haddleton, D. M. Chem. Commun. 2005,
2089–2091; (b) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505–4507.
12. (a) For a one-pot sequence using two reactions of which only one reaction was
catalysed by Cu(I) and involving
a Huigens 1,3-dipolar cycloaddition, see
Ramachary, D. B.; Barbas, C. F., III. Chem.dEur. J. 2004, 10, 5323–5331; (b) Pirali,
T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8, 4145–4148.
13. Moody, C. J.; Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1 1990, 673–679.
14. (a) Pindur, U.; Erfanian-Abdoust, H. Chem. Rev. 1989, 89, 1681–1689; (b)
Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc. Chem. Res. 1984, 17,
35–41.
15. Diker, K.; Do¨e´ de Maindreville, M.; Le´vy, J. Tetrahedron Lett. 1999, 40, 7459–
7462.
16. Crystal data for 4a: C32H30N2O7, M¼554.58, triclinic, a¼9.191(4), b¼11.293(4),
c¼13.688(7) Å, U¼1403.2(11) Å3, T¼293(2) K, space group Pꢀ1, Z¼2, Dc¼1.
311 Mg mꢀ3, reflection collected/unique 12,271/6406 [Rint¼0.0392, wR2¼0.1492
for all data]; CCDC 651345.
Acknowledgements
We thank the University of Reims-Champagne-Ardennes, the
University of Grenoble, and the CNRS for financial support. Spec-
troscopic measurements by C. Petermann (NMR) and P. Sigaut (MS)
are gratefully acknowledged.
References and notes
17. Crystal data for 9: C39H33N3O8$2H2O, M¼707.72, monoclinic, a¼19.516(8), b¼9.
894(4), c¼20.266(8) Å, U¼3510(2) Å3, T¼293(2) K, space group C2, Z¼4, Dc¼
1.339 Mg mꢀ3, reflection collected/unique 15,516/6753[Rint¼0.0310, wR2¼0.1672
for all data]; CCDC 651346.
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2005; (b) Do¨mling, A. Chem. Rev. 2006, 106, 17–89.
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´
18. The relative configuration for products 4 was erroneously assigned from our
initial report (Ref. 6).
19. (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856; (b)
Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431–1628.
20. As the initial mixture was splitted into two equal parts, each yield is referred to
0.5 equiv of indole 1a.
21. Walker, M. A. J. Org. Chem. 1995, 60, 5352–5355.
lena, G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693–700.
3. (a) Wender, P. A.; Gamber, G. G.; Scanio, M. J. C. Angew. Chem., Int. Ed. 2001, 40,
3895–3897; (b) Neumann, H.; Jacobi von Wangelin, A.; Klaus, S.; Go¨rdes, D.;
Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2001, 123, 8398–8399; (c) Hu¨ bner,
S.; Michalik, D.; Jiao, H.; Neumann, N.; Klaus, S.; Stu¨bing, D.; Spannenberg, A.;
Beller, M. Chem. Asian J. 2007, 2, 720–733; (d) Hu¨bner, S.; Jiao, H.; Michalik, D.;
Neumann, H.; Klaus, S.; Stru¨bing, D.; Spannenberg, A.; Beller, M. Chem. Asian J.
2007, 2, 734–746; (e) Stru¨bing, D.; Neumann, H.; Hu¨bner, S.; Klaus, S.; Beller, M.