Enantioselective synthesis of the spirotryprostatin A scaffold

Article abstract of DOI:10.1016/j.tet.2011.04.056

The pentacyclic spirotryprostatin scaffold embodies an oxindole with an all-carbon quaternary stereocenter. The scaffold can efficiently be accessed in a one-pot reaction sequence consisting of a highly enantioselective 1,3-dipolar cycloaddition, N-acylat

Full text of DOI:10.1016/j.tet.2011.04.056

Tetrahedron 67 (2011) 10195e10202
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective synthesis of the spirotryprostatin A scaffold
,
,
b
c
c
Andrey P. Antonchick a, Hannah Schuster a b, Hanna Bruss a , Markus Schurmann , Hans Preut ,
€
,b,
Daniel Rauh b, Herbert Waldmann a
*
a
€
Max-Planck-Institut fur Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Technische Universitat Dortmund, Fakultat Chemie, Chemische Biologie, Otto-Hahn-Strasse 6, 44221, Dortmund, Germany
Technische Universitat Dortmund, Fakultat Chemie, Anorganische Chemie, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
b
c
€
€
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
The pentacyclic spirotryprostatin scaffold embodies an oxindole with an all-carbon quaternary stereo-
center. The scaffold can efficiently be accessed in a one-pot reaction sequence consisting of a highly
enantioselective 1,3-dipolar cycloaddition, N-acylation of the resulting stereochemically complex 3,30-
pyrrolidinyl-spirooxindole core with Fmoc-proline and spontaneous ring closure upon N-deprotection.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 February 2011
Received in revised form 11 April 2011
Accepted 14 April 2011
Available online 21 April 2011
Keywords:
Spirotryprostatin A
All-carbon quaternary spirocenter
[3þ2] Cycloaddition
1,3-Dipolar cycloaddition
Biology-oriented synthesis
1. Introduction
MeO
N
N
O
H
O
H
CO2Me
NH
H
O
H
O
MeO
MeO
Natural products (NPs) are a rich source of evolutionary vali-
dated scaffold structures endowed with biological activity. Com-
pound collections inspired by natural products often serve as
valuable starting points for medicinal chemistry and chemical bi-
ology research.1 Based on this rationale, we introduced biology-
oriented synthesis (BIOS) for the design and synthesis of natural
product-based compound libraries with focused structural di-
versity.2 Given the structural complexity and richness in stereo-
genic centres of natural products and compound collections
inspired by them, the development of efficient asymmetric
methods for their synthesis is in high demand.
N
N
OBn
O
O
O
Br
N
H
N
H
N
H
MeO
1
spirotryprostatin A ( )
2
3
Fig. 1. Structures of 3,30-pyrrolidinyl-spirooxindoles. Bn¼benzyl.
The key structural feature of spirotryprostatins is a pentacycle
with an all-carbon quaternary spirostereocenter embedded in the
oxindole core. The need to construct this centre stereospecifically
makes the synthesis of these molecules a challenging task and
subject to significant interest.7,8 Recently developed asymmetric
approaches include oxidative rearrangement of chiral tetrahydro-
The 3,30-pyrrolidinyl-spirooxindole motif is an important het-
erocyclic scaffold that forms the core of numerous alkaloids in-
cluding spirotryprostatin AeE, which display a broad range of
biological activities.3,4 Studies on the synthesis of spirotryprostatin
A (1) resulted in the discovery of analogue 2, which shows higher
activity than the natural product itself (Fig. 1).5 In the development
of a natural product-inspired compound collection with spiroox-
indole scaffold, we recently discovered 3,30-pyrrolidinyl-spiroox-
indole 3 that arrests mitosis, causes chromosome congression
defects and inhibits tubulin re-growth in cells.6
b
-carbolins,5,9 an iminium ion intramolecular cyclization,10 [3þ2]11
and [5þ2]12 cycloadditions, intramolecular Heck reactions,13
a nitroolefination strategy,14 magnesium iodide catalyzed ring-ex-
pansion15 and
a
Pd-catalyzed prenylation.16 In all cases di-
astereomers were formed. Given the lack of knowledge on the
mechanism of action of spirotryprostatins in biological systems, the
design and development of methodology allowing for the synthesis
of a focused compound collection for subsequent chemical biology
research is in high demand.
* Corresponding author. Fax: þ49 231 133 2499; e-mail address: herbert.wald-
mann@mpi-dortmund.mpg.de (H. Waldmann).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.056

10196
A.P. Antonchick et al. / Tetrahedron 67 (2011) 10195e10202
Table 1
2. Results and discussion
Evaluation of different reaction conditions for the 1,3-dipolar cycloaddition
CO2Me
N
Our initial studies were focused on a linear approach based on
MeO2C
the oxidative rearrangement of tetrahydro-
hydro- -carboline 4 was obtained from -tryptophan in four steps
b
-carbolines.5,9 Tetra-
1)Cu(CH3CN)4PF6
NAc
O
7a-g
ligand
, Et3N
b
L
O
using a diastereoselective PicteteSpengler cyclization as key step
(Scheme 1). Attempts to rearrange 4 to the spirotryprostatin ana-
logue 5 using various oxidative conditions were not successful and
selective formation of the acylindole derivative 6 was observed.
Br
2) Ac2O
N
H
N
H
8a
9a
10a
Br
Ph
S-t-Bu
PPh2
NMe2
PPh2
NH2
PPh2
NH2
PPh2
N
O
H
H
O
Fe
Fe
Fe
Fe
oxidation
N
7a
7b
7c
7d
O
H
O
N
Br
H
NH2
N
H
PPh2
5
HO2C
H
O
PPh2
N
NMe2
4 steps
PCy2
PPh2
N
Fe
O
H
PPh2
Ph2P
Me2N
Ph
Fe
Fe
N
H
N
N
H
Ph
HN
Br
O
4
O
7e
7g
7f
N
H
NBS,H3O+
68%
Entrya
Ligand
Solvent
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7d
7d
7d
7d
7d
7d
7d
7d
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
1.5
1
1
1
1
1
2
3
12
12
1
0.8
3
60
51
72
56
63
63
78
33
Traces
Traces
53
52
45
1/20
1/6
1/20
1/15
1/20
1/5
1/20
1/10
n.d.
88
56e
65
6
Br
91e
62e
69
Scheme 1. Oxidation of tetrahydro-b-carboline 4.
Given this failure we developed a new approach for the prepa-
ration of a collection of compounds with the 3,30-pyrrolidinyl-spi-
rooxindole scaffold embodied in the spirotryprostatins (Scheme 2).
Here we report the first example of a catalytic enantioselective
45e
95e
n.d.
n.d.
90e
94e
71e
95e
95e
9
Toluene
Et2O
10
11f
12g
13h
14i
15j
n.d.
DCM
DCM
DCM
DCM
DCM
1/15
1/15
1/12
1/18
1/18
cycloaddition of azomethine ylides17,18 to
a,a-disubstituted alkenes
giving access to the 3,30-pyrrolidinyl-spirooxindole core with an
all-carbon quaternary spirostereocenter and two tertiary centres in
a one-pot transformation from readily accessible starting materials.
Spiropyrrolidines with an additional stereocenter (see e.g., 3) have
been synthesized by dipolar cycloadditions employing arylidene-
or alkylidene indolinones as dipolarophiles.6 However, due to their
4
2
51
56
n.d.¼not determined.
a
Reaction conditions: iminoester 9a (1.0 equiv) was reacted with 3-methyl-
eneoxindole 8a (1.5 equiv), Cu(CH3CN)4PF6 (5 mol %), ligand 7aeg (5 mol %) in
dichloromethane (0.1 M) at ambient temperature for the given time. Then acetic
anhydride (1.05 equiv) was added.
pronounced reactivity
a,a
-disubstituted alkenes19 have not been
used successfully in this enantioselective catalytic [3þ2] cycload-
dition, and the spirotryprostatin core has not been accessible with
this methodology so far.
b
Isolated yields of the major diastereomer after column chromatography.
c
Determined by 1H NMR analysis.
d
Determined by HPLC analysis.
Opposite enantiomer.
10 mol % of ligand 7d was used.
10 mol % of Cu(CH3CN)4PF6 and 10 mol % of ligand 7d were used.
e
f
g
R3O2C
N
h
O
R2
N
CO2R3
3 mol % of Cu(CH3CN)4PF6 and 3 mol % of ligand 7d were used.
i
Performed at 0 ꢀC.
NH
R2
O
j
Performed for 30 min at 0 ꢀC and then the reaction mixture was allowed to warm
N
to ambient temperature.
R2
O
R1
O
R1
R1
N
H
O
N
H
N
H
enantiomeric excess, diastereoselectivity and yield when the S,P-
ferrocenyl ligand 7d was used in dichloromethane (Table 1, entry 4).
To further optimize the reaction conditions, we varied the solvent,
concentration of the reactants, reaction temperature, ligand/catalyst
ratio and catalyst loading. We found that cycloaddition in tetrahy-
drofuran leads to the product with comparable enantioselectivity but
lower yields. Similar trends were observed at lower reaction tem-
perature and higher ligand/catalyst loading (Table 1, entries 11 and
14). Nonpolar solvents such as toluene led to the formation of only
trace amounts of product most likely due to low solubility of the 3-
methyleneoxindole. The reduction of ligand/catalyst loading to
3 mol % (Table 1, entry 13) compromised chemical yield and enan-
tioselectivity. Best results were obtained when the reaction was
started at 0 ꢀC for 30 min and continued at ambient temperature until
the iminoester 9a was consumed (Table 1, entry 15).21
Scheme 2. Retrosynthesis of spirotryprostatin A analogues.
The synthesis of 3,30-pyrrolidinyl-spirooxindoles commenced
with the cycloaddition of N-(4-bromobenzylidene)glycine methyl
ester 9a with 3-methyleneoxindole 8a using ferrocene-based li-
gands 7aeg and Cu(CH3CN)4PF6 (Table 1). The reaction proceeded
smoothly at ambient temperature in the presence of 5 mol % of the
Cu(I)/ligand complex. The nitrogen of the pyrrolidine was selectively
protected prior to workup to prevent isomerisation of the 3,30-pyr-
rolidinyl-spirooxindoles due to retro-Mannich/Mannich20 equili-
bration. Initial screening of various ligands revealed that the best
results were obtained for the formation of 10a with regard to

A.P. Antonchick et al. / Tetrahedron 67 (2011) 10195e10202
Table 2 (continued )
10197
With the optimized reaction conditions in hand, we investigated
the substrate scope of the 1,3-dipolar cycloaddition with regard to
the substitution on the azomethine ylides and 3-methyleneox-
indoles (Table 2). A variety of mono- and polysubstituted benzyli-
dene glycine derivatives bearing electron-withdrawing and
Entry
Product
Yielda (%)
drb
eec (%)
MeO2C
NAc
electron-donating
substituents
reacted
with
excellent
9
10i
MeO
55
1/20
97
Br
O
Table 2
N
Scope of the catalytic enantioselective cycloaddition of azomethine ylides to 3-
methyleneoxindoles
H
CO2Me
MeO2C
1)Cu(CH3CN)4PF6
(5 mol%),
MeO2C
R1
NAc
O
N
NAc
7d (5 mol%), Et3N
O
10
10j
40
45
1/20
93
96
Cl
2) Ac2O
R1
N
H
Br
O
R2
N
N
H
R2
H
8
9
10
MeO2C
NAc
Entry
1
Product
Yielda (%)
drb
eec (%)
11
10k
1/2
MeO
O
Cl
MeO2C
N
Cl
H
NAc
O
10a
10b
10c
10d
10e
10f
56
1/18
1/20
1/2
95
84
93
87
92
92
96
Br
a
Isolated yields of the single diastereomer after column chromatography.
Determined by 1H NMR analysis.
N
b
c
H
Determined by HPLC analysis.
MeO2C
NAc
enantioselectivity. Except for ortho-substituted azomethine ylides
the diastereoselectivity was high. The products were isolated as
single diastereomers in high yields after two steps. Excellent results
independent of the electronic nature of the substituent were
obtained for the different 3-methyleneoxindoles. Interestingly, the
reactionworked well in the presence of acidic groups such as phenol
(Table 2, entry 3) and did notrequireprotection of the nitrogen of the
3-methyleneoxindoles. The absolute configuration of the major
stereoisomer was unambiguously determined by crystal structure
analysis (Fig. 2).
Following the one-pot procedure developed for azomethine
ylides and 3-methyleneoxindoles 8, we next applied this method-
ology to the enantioselective construction of the biologically rele-
vant but stereochemically complex spirotryprostatin A analogues
11. The one-pot synthesis included an enantioselective 1,3-dipolar
cycloaddition, acylation of the hindered amine with (L)-FmocProCl
and deprotection of the Fmoc-group, which resulted immediately
2
3
4
5
6
7
53
41
40
41
69
51
OMe
OMe
O
N
H
MeO2C
NAc
O
Br
N
H
OH
MeO2C
NAc
1/2
O
Cl
N
Cl
H
MeO2C
NAc
1/2
CN
O
N
H
MeO2C
NAc
O
1/20
1/20
CF3
N
H
MeO2C
NAc
O
10g
Br
N
Br
H
MeO2C
NAc
O
8
10h
60
1/20
95
F
Br
N
Fig. 2. ORTEP plot of 10k at 50% probability level.
H

10198
A.P. Antonchick et al. / Tetrahedron 67 (2011) 10195e10202
Table 3
chromatography were technical grade and distilled prior to use. Dry
solvents (CH2Cl2, toluene and THF) were purified by the Solvent
Purification System M-BRAUN Glovebox Technology SPS-800. An-
alytical thin-layer chromatography (TLC) was performed on Merck
silica gel aluminium plates with F-254 indicator, visualised by ir-
radiation with UV light. Column chromatography was performed
using silica gel Merck 60 (particle size 0.040e0.063 mm). Solvent
mixtures are understood as volume/volume.
Spirotryprostatin A analogues obtained by the one-pot procedure
N
1) Cu(CH3CN)4PF6
O
H
CO2Me
H
O
(5 mol%),
7d (5 mol%), Et3N
N
R1
N
R2
9
O
R2
2) (L)-FmocProCl
N
H
R1
O
3) Piperidine
N
H
1H NMR and 13C NMR were recorded on a Bruker DRX400
(400 MHz) or DRX500 (500 MHz) spectrometer in CDCl3, (CD3)2SO or
8
11
Product, yield (%)a
Product, yield (%)a
CD3OD. Data are reported in the following order: chemical shift (d) in
parts per million; multiplicities are indicated brs (broadened singlet),
s (singlet), d (doublet), t (triplet), m (multiplet); coupling constants (J)
are given in Hertz (Hz). High resolution mass spectra were recorded
on an LTQ Orbitrap mass spectrometer coupled to an Accela HPLC-
N
N
O
H
O
H
H
O
H
O
N
O
N
O
System (HPLC column: Hypersyl GOLD, 50 mmꢁ1 mm, 1.9
mm).
F
F
Fourier transform infrared spectroscopy (FTIR) spectra were obtained
with a Bruker Tensor 27 spectrometer (ATR, neat) and are reported in
terms of frequency of absorption (cmꢂ1). Optical rotations were
measured in a SchmidtþHaensch Polartronic HH8 polarimeter.
The enantiomeric excesses were determined by HPLC analysis
using a chiral stationary phase column (column: CHIRALCEL IA,
eluent: isohexane/(ethanol/DCM¼1/100)). The chiral HPLC
methods were calibrated with the corresponding racemic mixtures.
Chemical yields refer to pure isolated substances. The yields and
enantiomeric excesses are given in Table 2.
OMe
N
H
N
H
11a, 60%
11b, 63%
N
N
O
H
O
H
H
O
H
O
N
N
O
F
O
Br
OMe
N
N
H
Br
H
4.2. Synthetic protocols
11c, 18%
11d, 55%
4.2.1. General procedure for the enantioselectively catalyzed 1,3-di-
polar cycloaddition. To a solution of iminoester (0.10 mmol), (Rp)-
2-(tert-butylthio)-1-(diphenylphosphino)ferrocene (5 mol %,
N
N
O
H
O
H
H
O
5
m
mol) and tetrakis(acetonitrile)copper(I) hexafluorophosphate
H
O
mol) in dichloromethane (1 mL) at 0 ꢀC under argon
N
N
O
(5 mol %, 5
m
were added triethylamine (1.1 equiv, 0.11 mmol) and 3-methyl-
eneoxindole (1.5 equiv, 0.15 mmol). The reaction mixture was
allowed to stir for 30 min at 0 ꢀC and then at ambient tempera-
ture. Acetic anhydride (1.05 equiv, 0.105 mmol) was added to the
reaction mixture when the iminoester was consumed. The re-
action was stirred additionally at ambient temperature for 2 h.
The solvent was removed in vacuo and purification of the crude
product by column chromatography on silica gel (ethyl acetate/
pentane) afforded the pure product.
O
Br
Br
N
H
N
H
Br
11e, 21%
11f, 45%
a
Isolated yields after column chromatography.
in triggering of a diketopiperazine cyclization to form the penta-
cyclic scaffold (Table 3). The desired products 11 were obtained in
a one-pot procedure from readily accessible compounds. Notably,
the approach developed here gives access to spirotryprostatin an-
alogues that could not be obtained by application of known
methods (see above).
4.2.2. Methyl (20S,3R,50S)-10-acetyl-20-(4-bromophenyl)-2-oxo-1,2-
dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate (10a). 1H NMR
(400 MHz, CDCl3, # denotes major-, * minor rotamer signals)
d
¼9.08# (s, 1H), 8.52
*
(s, 1H), 7.40e7.05 (m, 7H), 6.85# (d, J¼7.7, 1H),
6.69
*
(d, J¼7.7, 2H), 5.29
*
(s, 1H), 5.07# (dd, J¼8.1, 7.9, 1H), 5.00# (s,
1H), 4.86
*
(m, 1H), 3.92
*
(s, 3H), 3.86# (s, 3H), 2.93
*
(d, J¼13.4, 1H),
2.79
*
(dd, J¼13.4, 9.4, 1H), 2.71# (dd, J¼13.0, 7.7, 1H), 2.45# (dd,
3. Conclusion
J¼13.0, 8.1, 1H), 2.24
*
(s, 3H), 1.83# ppm (s, 3H); 13C NMR (101 MHz,
In conclusion, we have developed a highly enantioselective and
high yielding synthesis of the polycyclic spirotryprostatin scaffold
embodying the 3,30-pyrrolidinyl-spirooxindole core by means of
a catalytic [3þ2] cycloaddition of azomethine ylides. The synthesis
is efficient and highly practical and should give ready access to
a natural product-inspired compound collection based on the spi-
rotryprostatin structure.
CDCl3, major rotamer)
d
¼176.88, 171.75, 171.37, 140.55, 136.81,
132.08, 131.93, 131.26, 129.82, 129.22, 127.93, 123.79, 122.81, 122.61,
~
n
110.99, 71.72, 59.83, 59.04, 52.99, 36.52, 22.92 ppm; FTIR: ¼2951,
1718,1651,1615,1489,1472,1434,1399,1375,1337,1297,1240,1204,
1181, 1130, 1102, 1071, 1043, 1010 cmꢂ1; HRMS: calcd for [MþH]þ
C21H2079BrN2O4: 443.06010, found: 443.05997; HRMS: calcd for
[MþH]þ C21H2081BrN2O4: 445.05805, found: 445.05768;
½ ꢃ
a RDT
ꢂ81.8 (CHCl3, c 1.0); HPLC conditions: CHIRALCEL IA column, iso-
hexane/(ethanol/DCM¼1/100)¼2/3, flow rate¼0.5 mL minꢂ1, major
enantiomer: tR¼24.5 min; minor enantiomer: tR¼31.0 min.
4. Experimental section
4.1. General
4.2.3. Methyl (20S,3R,50S)-10-acetyl-20-(4-methoxyphenyl)-2-oxo-1,2-
Unless otherwise noted, all commercially available compounds
dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate (10b). 1H NMR
were used as provided without further purification. Solvents for
(500 MHz, CDCl3)
d¼8.67 (s, 1H), 7.38e7.21 (m, 4H), 7.13 (t, J¼7.5,

A.P. Antonchick et al. / Tetrahedron 67 (2011) 10195e10202
10199
1H), 6.84 (d, J¼7.7, 1H), 6.76 (d, J¼8.4, 2H), 5.08 (dd, J¼8.2, 7.4, 1H),
4.98 (s, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 2.76 (dd, J¼13.0, 7.4, 1H), 2.45
(dd, J¼13.0, 8.2, 1H), 1.83 ppm (s, 3H); 13C NMR (126 MHz, CDCl3)
rate¼0.5 mL minꢂ1, major enantiomer: tR¼28.3 min; minor en-
antiomer: tR¼31.1 min.
d¼176.93, 171.78, 171.51, 159.70, 140.75, 132.47, 129.54, 129.49,
4.2.7. Methyl
(20S,3R,50S)-10-acetyl-2-oxo-20-[4-(trifluoromethyl)
128.61, 123.51, 122.81, 114.12, 110.74, 72.20, 59.85, 59.14, 55.42,
phenyl]-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
52.84, 36.44, 22.85 ppm; FTIR:
n
¼3215, 2955, 1720, 1617, 1513, 1472,
(10f). 1H NMR (400 MHz, CDCl3, # denotes major-, * minor rotamer
~
1437, 1400, 1339, 1289, 1246, 1205, 1177, 1108, 1032 cmꢂ1; HRMS:
signals)
d
¼8.77# (s, 1H), 8.18
*
(s, 1H), 7.64e7.07# (m, 7H), 6.83# (d,
*
calcd for [MþH]þ C22H22N2O5: 395.16015, found: 395.15964; ½a RDT
ꢃ
J¼7.7, 1H), 6.68
*
(d, J¼7.7, 1H), 5.38
*
(s, 1H), 5.09# (dd, J¼8.1, 7.8, 1H),
ꢂ49.8 (CHCl3, c 1.0); HPLC conditions: CHIRALCEL IA column, iso-
hexane/(ethanol/DCM¼1/100)¼2/3, flow rate¼0.5 mL minꢂ1, major
enantiomer: tR¼27.5 min; minor enantiomer: tR¼31.4 min.
5.06# (s,1H), 4.88
1H), 2.86e2.77
8.1, 1H), 2.26
mixture of the rotamers)
*
(m,1H), 3.92
*
(s, 3H), 3.87# (s, 3H), 2.94
*
(d, J¼13.3,
*
(m, 1H), 2.73# (dd, J¼13.0, 7.8, 1H), 2.46# (dd, J¼13.0,
*
(s, 3H), 1.81# ppm (s, 3H); 13C NMR (101 MHz, CDCl3,
d¼178.60, 176.41, 171.71, 171.46, 171.25,
4.2.4. Methyl (20R,3R,50S)-10-acetyl-20-(2-bromo-3-hydroxy-4-me-
thoxyphenyl)-2-oxo-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-car-
171.15, 141.75, 141.46, 141.05, 140.41, 131.97, 129.92, 129.86, 129.32,
127.87, 126.46, 125.77, 125.19, 125.16, 123.88, 123.70, 123.32, 122.82,
110.83, 110.61, 71.61, 71.15, 61.62, 59.82, 59.03, 57.90, 53.18, 53.02,
~
boxylate (10c). 1H NMR (400 MHz, CD3OD)
d
¼7.87 (d, J¼8.6, 1H),
7.36e7.29 (m, 1H), 7.21 (d, J¼7.2, 1H), 7.17e7.09 (m, 1H), 7.03 (d,
J¼8.6, 1H), 6.97 (d, J¼7.7, 1H), 5.49 (s, 1H), 4.92e4.85 (m, 1H), 3.93
(s, 3H), 3.85 (s, 3H), 2.64e2.55 (m, 1H), 2.36e2.30 (m, 1H),
38.50, 36.75, 23.26, 22.87 ppm; FTIR:
n
¼2953, 1721, 1654, 1619, 1473,
1399, 1323, 1272, 1205, 1163, 1112, 1066, 1018 cmꢂ1; HRMS: calcd for
[MþH]þ C22H19F3N2O4: 433.13697, found: 433.13667; ½a RDT
ꢂ39.1
ꢃ
1.82 ppm (s, 3H); 13C NMR (101 MHz, CD3OD)
d¼175.75, 172.18,
(CHCl3, c 1.0); HPLC conditions: CHIRALCEL IA column, isohexane/
(ethanol/DCM¼1/100)¼2/3, flow rate¼0.5 mL minꢂ1, major enan-
tiomer: tR¼19.5 min; minor enantiomer: tR¼21.9 min.
172.08, 148.31, 144.03, 141.05, 133.46, 129.09, 129.03, 123.02,
122.35, 120.07, 110.71, 110.20, 110.03, 70.36, 59.35, 57.55, 55.67,
~
n
51.99, 37.36, 21.00 ppm; FTIR: ¼2953, 1719, 1642, 1619, 1490,
1471, 1439, 1401, 1369, 1333, 1276, 1203, 1151, 1106, 1079,
1031 cmꢂ1; HRMS: calcd for [MþH]þ C22H2179BrN2O6: 489.06558,
found: 489.06517; HRMS: calcd for [MþH]þ C22H2181BrN2O6:
4.2.8. Methyl (20S,3R,50S)-10-acetyl-6-bromo-20-(4-bromophenyl)-2-
oxo-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
(10g). 1H NMR (500 MHz, CDCl3, # denotes major-, * minor rotamer
491.06353, found: 491.06298; ½a DRT
ꢃ
ꢂ26.7 (CHCl3, c 1.0); HPLC
signals)
d
¼8.44# (s, 1H), 7.95
*
(s, 1H), 7.48e6.83#
*
(m, 7H), 5.27
(m, 1H), 3.92
*
(s,
(s,
conditions: CHIRALCEL IA column, isohexane/(ethanol/DCM¼1/
1H), 5.06# (dd, J¼8.4, 7.0 1H), 4.97# (s, 1H), 4.85
*
*
100)¼1/3, flow rate¼0.5 mL minꢂ1
,
major enantiomer:
3H), 3.88# (s, 3H), 2.93
*
(d, J¼13.0, 1H), 2.80e2.74
*
(m, 1H), 2.74#
tR¼18.3 min; minor enantiomer: tR¼35.5 min.
(dd, J¼13.0, 7.0, 1H), 2.45# (dd, J¼13.0, 8.4, 1H), 2.24
*
(s, 3H),
1.83# ppm (s, 3H); 13C NMR (126 MHz, CDCl3, major rotamer)
4.2.5. Methyl (20R,3R,50S)-10-acetyl-20-(2,3-dichlorophenyl)-2-oxo-
d
¼176.13, 171.48, 171.26, 141.81, 136.37, 132.09, 131.44, 130.85,
1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
(10d). 1H
129.11, 127.83, 126.65, 124.21, 123.36, 122.95, 114.15, 71.69, 59.80,
~
NMR (500 MHz, CDCl3)
d
¼8.45 (dd, J¼7.8, 1.2, 1H), 8.32 (s, 1H), 7.49
58.84, 53.02, 36.55, 22.88 ppm; FTIR:
n
¼2951, 1726, 1645, 1610,
(dd, J¼7.9, 1.4, 1H), 7.42 (t, J¼7.9, 1H), 7.35 (td, J¼7.6, 1.2, 1H),
7.20e7.11 (m, 2H), 6.92 (d, J¼7.8, 1H), 5.46 (s, 1H), 4.94 (dd, J¼11.5,
7.0, 1H), 3.88 (s, 3H), 2.67e2.58 (m, 1H), 2.32 (dd, J¼12.7, 7.0, 1H),
1484, 1435, 1403, 1331, 1202, 1180, 1118, 1059, 1041, 1010 cmꢂ1
;
HRMS: calcd for [MþH]þ C21H1879Br2N2O4: 520.97061, found:
520.97035; HRMS: calcd for [MþH]þ C21H1879Br81BrN2O4:
522.96856, found: 522.96805; HRMS: calcd for [MþH]þ
1.88 ppm (s, 3H); 13C NMR (126 MHz, CDCl3)
d¼174.91, 172.06,
171.05, 139.89, 137.55, 133.10, 133.00, 131.60, 130.54, 129.64, 128.46,
128.33, 123.78, 122.65, 110.69, 68.63, 59.26, 57.34, 53.05, 37.69,
C21H1881Br2N2O4: 524.96652, found: 524.96593;
½
a RDT
ꢃ
ꢂ106.8
(CHCl3, c 1.0); HPLC conditions: CHIRALCEL IA column, isohexane/
(ethanol/DCM¼1/100)¼2/3, flow rate¼0.5 mL minꢂ1, major enan-
tiomer: tR¼28.2 min; minor enantiomer: tR¼40.0 min.
~
22.48 ppm; FTIR:
n
¼3235, 2925, 2853, 1745, 1721, 1639, 1619, 1471,
1444, 1424, 1367, 1330, 1293, 1241, 1204, 1186, 1159, 1107, 1080,
1043, 1009 cmꢂ1; HRMS: calcd for [MþH]þ C21H1835Cl2N2O4:
433.07164, found: 433.07153; HRMS: calcd for [MþH]þ
4.2.9. Methyl (20S,3R,50S)-10-acetyl-20-(4-bromophenyl)-5-fluoro-2-
oxo-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
(10h). 1H NMR (500 MHz, CDCl3, # denotes major-, * minor
C21H1835Cl37ClN2O4: 435.06869, found: 435.06849;
½
a RDT
ꢃ
þ7.1
(CHCl3, c 1.0); HPLC conditions: CHIRALCEL IA column, isohexane/
(ethanol/DCM¼1/100)¼1/1, flow rate¼0.5 mL minꢂ1, major enan-
tiomer: tR¼21.7 min; minor enantiomer: tR¼25.8 min.
rotamer signals)
d
¼8.66# (s, 1H), 8.11
*
(s, 1H), 7.45e6.88#
(s, 1H), 5.06#
(m, 1H), 3.92 (s, 3H),
(m, 1H), 2.74# (dd,
*
(m,
6H), 6.80# (dd, J¼8.3, 4.0, 1H), 6.66
*
(m, 1H), 5.26
*
(dd, J¼8.2, 7.2, 1H), 4.99# (s, 1H), 4.86
*
*
4.2.6. Methyl (20S,3R,50S)-10-acetyl-20-(4-cyanophenyl)-2-oxo-1,2-
dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate (10e). 1H NMR
(500 MHz, CDCl3, # denotes major-, * minor rotamer signals)
3.87# (s, 3H), 2.95
*
(d, J¼13.8, 1H), 2.80e2.74
*
J¼13.1, 7.2, 1H), 2.46# (dd, J¼13.0, 8.2, 1H), 2.24
*
(s, 3H),
1.84# ppm (s, 3H); 13C NMR (126 MHz, CDCl3, major rotamer)
d
¼8.41# (s, 1H), 7.87
*
(s, 1H), 7.66e7.51#
*
(m, 2H), 7.43e7.09#
*
(m,
d
¼176.56, 171.53, 171.15, 136.57, 136.42, 133.35, 132.02, 131.35,
5H), 6.86# (d, J¼7.7, 1H), 6.73
*
(d, J¼7.7, 1H), 5.35# (s, 1H),
129.24, 129.19, 127.93, 122.80, 116.37, 116.19, 111.59, 111.53, 111.51,
5.15e5.02#
*
(m, 2H), 4.88
*
(d, J¼8.9, 1H), 3.92
*
(s, 3H), 3.88# (s,
111.13, 110.93, 71.66, 59.77, 59.57, 52.97, 36.51, 22.88 ppm; FTIR:
(dd, J¼13.4, 9.4, 1H), 2.72# (dd,
¼3206, 2927, 1742, 1722, 1639, 1622, 1484, 1447, 1433, 1402,
~
n
3H), 2.94
*
(d, J¼13.4, 1H), 2.82
*
J¼13.0, 8.0, 1H), 2.47# (dd, J¼13.0, 8.1, 1H), 2.26
*
(s, 3H), 1.83# ppm
1370, 1301, 1280, 1240, 1211, 1175, 1134, 1073, 1031, 1009 cmꢂ1
;
(s, 3H); 13C NMR (126 MHz, CDCl3, mixture of the rotamers)
HRMS: calcd for [MþH]þ C21H1879BrFN2O4: 461.05067, found:
d
¼178.09, 175.84, 171.73, 171.38, 171.05, 171.00, 143.20, 142.56,
431.05052; HRMS: calcd for [MþH]þ C21H1881BrFN2O4:
141.34, 140.27, 132.67, 132.07, 131.98, 130.08, 129.99, 129.21, 128.33,
126.99, 124.01, 123.82, 123.36, 122.89, 119.24, 118.86, 112.59, 111.37,
110.80, 110.52, 71.64, 71.18, 61.55, 59.82, 59.07, 57.86, 53.19, 53.03,
~
463.04863, found: 463.04832; ½a DRT
ꢂ73.0 (CHCl3, c 1.0); HPLC
ꢃ
conditions: CHIRALCEL IA column, isohexane/(ethanol/DCM¼1/
100)¼2/3, flow rate¼0.5 mL minꢂ1
,
major enantiomer:
38.61, 36.91, 23.11, 22.84 ppm; FTIR:
n
¼2955, 1721, 1646, 1619,
tR¼28.4 min; minor enantiomer: tR¼35.2 min.
1504, 1472, 1436, 1402, 1339, 1273, 1205, 1177, 1107, 1067, 1040,
1019 cmꢂ1; HRMS: calcd for [MþH]þ C22H19N3O4: 390.14483,
4.2.10. Methyl (20S,3R,50S)-10-acetyl-20-(4-bromophenyl)-5-methoxy-
2-oxo-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
(10i). 1H NMR (400 MHz, CDCl3, # denotes major-, * minor rotamer
found: 390.14501; ½a DRT
ꢂ40.4 (CHCl3, c 1.0); HPLC conditions:
ꢃ
CHIRALCEL IA column, isohexane/(ethanol/DCM¼1/100)¼2/3, flow

10200
A.P. Antonchick et al. / Tetrahedron 67 (2011) 10195e10202
signals)
d
¼8.81# (s, 1H), 8.21
*
(s, 1H), 7.40e6.80#
*
(m, 6H), 6.76# (d,
chromatography on silica gel (ethyl acetate/pentane¼1/3/ethyl
J¼8.4, 1H), 6.62
*
(d, J¼8.5, 1H), 5.27
*
(s, 1H), 5.07# (dd, J¼8.2, 7.4,
acetate) afforded the pure product.
1H), 4.99# (s, 1H), 4.85
*
(m, 1H), 3.91
*
(s, 3H), 3.86# (s, 3H), 3.85
(s,
*
3H), 3.84# (s, 3H), 2.93
*
(d, J¼13.5, 1H), 2.81e2.72
*
(m, 1H), 2.71#
4.2.14. (2R,3S,5aS,10aS)-50-Fluoro-3-(4-methoxyphenyl)-5a,6,7,8-
tetrahydro-1H,5H-spiro[dipyrrolo[1,2-a:10,20-d]pyrazine-2,30-indole]-
(dd, J¼13.1, 7.4, 1H), 2.45# (dd, J¼13.1, 8.2, 1H), 2.25
*
(s, 3H),
1.83# ppm (s, 3H); 13C NMR (101 MHz, CDCl3, major rotamer)
20,5,10(10H,10aH)-trione (11a). 1H NMR (400 MHz, DMSO)
d¼10.35
d
¼176.75, 171.72, 171.22, 156.81, 136.84, 133.83, 133.28, 131.91,
(s, 1H), 7.48 (dd, J¼8.7, 2.5, 1H), 7.08 (td, J¼9.6, 2.5, 1H), 6.83 (dd,
J¼8.5, 4.5,1H), 6.76 (s, 4H), 5.05 (dd, J¼10.0, 7.9,1H), 4.92 (s,1H), 4.66
(t, J¼7.4,1H), 3.71 (s, 3H), 3.63e3.51 (m,1H), 3.51e3.39 (m,1H), 2.63
(dd, J¼13.0,10.6,1H), 2.24e2.08 (m, 2H),1.99e1.78 ppm (m, 3H); 13C
131.25, 129.19, 127.94, 122.60, 113.66, 111.31, 110.45, 71.80, 59.84,
~
n
59.54, 56.35, 52.97, 36.54, 22.94 ppm; FTIR:
¼2952, 1716, 1650,
1490, 1437, 1400, 1328, 1301, 1273, 1242,1202, 1179, 1157, 1102, 1071,
1032, 1010 cmꢂ1
;
HRMS: calcd for [MþH]þ C22H2179BrN2O5:
NMR (101 MHz, DMSO)
d
¼174.44, 167.31, 166.21, 158.41, 158.34 (d,
473.07066, found: 473.07041; HRMS: calcd for [MþH]þ
J¼238.7), 137.12, 135.42 (d, J¼8.2), 129.35, 127.34, 114.61 (d, J¼23.9),
C22H2181BrN2O5: 475.06861, found: 475.06844; ½a RDT
ꢃ
ꢂ101.2 (CHCl3,
113.14,111.21 (d, J¼24.5),110.20 (d, J¼8.2), 68.04, 60.47, 58.69, 56.85,
~
c 1.0); HPLC conditions: CHIRALCEL IA column, isohexane/(ethanol/
DCM¼1/100)¼2/3, flow rate¼0.5 mL minꢂ1, major enantiomer:
tR¼33.2 min; minor enantiomer: tR¼47.1 min.
54.93, 44.86, 33.05, 26.84, 23.39 ppm; FTIR:
n
¼3321, 2936, 2894,
1729, 1647, 1611, 1511, 1485, 1455, 1427, 1302, 1285, 1243, 1224, 1172,
1137, 1031 cmꢂ1; HRMS: calcd for [MþH]þ C24H23O4N3F: 436.16671,
found: 436.16626; ½a DRT
ꢂ270.5 (DMSO, c 0.5).
ꢃ
4.2.11. Methyl (20S,3R,50S)-10-acetyl-20-(4-bromophenyl)-5-chloro-2-
oxo-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
(10j). 1H NMR (400 MHz, CDCl3, # denotes major-, * minor
4.2.15. (2R,3S,5aS,10aS)-50-Fluoro-3-phenyl-5a,6,7,8-tetrahydro-
1H,5H-spiro[dipyrrolo[1,2-a:10,20-d]pyrazine-2,30-indole]-
rotamer signals)
d
¼8.98# (s, 1H), 8.43
*
(s, 1H), 7.44e7.16#
(s, 1H), 5.05# (dd,
*
(m, 6H),
20,5,10(10H,10aH)-trione (11b). 1H NMR (500 MHz, DMSO)
d¼10.40
6.77# (d, J¼8.3, 1H), 6.63
*
(d, J¼8.2, 1H), 5.26
*
(s, 1H), 7.53 (dd, J¼8.7, 2.5 Hz, 1H), 7.26e7.18 (m, 3H), 7.12 (td, J¼9.3,
2.5 Hz, 1H), 6.89e6.84 (m, 3H), 5.11 (dd, J¼10.4, 7.7 Hz, 1H), 4.99 (s,
1H), 4.70 (t, J¼7.5 Hz, 1H), 3.61 (dt, J¼14.5, 7.2 Hz, 1H), 3.52e3.45
(m, 1H), 2.65 (dd, J¼13.1, 10.4 Hz, 1H), 2.23 (dd, J¼13.1, 7.7 Hz, 1H),
2.20e2.13 (m, 1H), 2.01e1.83 ppm (m, 3H); 13C NMR (126 MHz,
J¼8.2, 7.4, 1H), 4.99# (s, 1H), 4.85
*
(m, 1H), 3.90
(s, 3H), 3.86# (s,
*
3H), 2.92
*
(d, J¼13.4, 1H), 2.81e2.73
*
(m, 1H), 2.72# (dd, J¼13.1,
7.4, 1H), 2.45# (dd, J¼13.1, 8.2, 1H), 2.23
*
(s, 3H), 1.82# ppm (s, 3H);
13C NMR (101 MHz, CDCl3, major rotamer)
d
¼176.50, 171.59,
171.27, 139.13, 136.55, 133.54, 132.02, 131.35, 129.87, 129.16, 129.07,
127.89, 123.33, 122.79, 111.99, 71.52, 59.82, 59.35, 53.05, 36.50,
DMSO)
d
¼174.27, 167.33, 166.10, 158.30 (d, J¼237.0 Hz), 137.29,
137.05, 135.35 (d, J¼8.8 Hz), 127.69, 127.24, 114.61 (d, J¼23.0 Hz),
~
n
22.96 ppm; FTIR:
¼2951, 1723, 1649, 1621, 1480, 1435, 1400, 1327,
111.18 (d, J¼24.9 Hz), 110.19 (d, J¼6.5 Hz), 68.39, 60.42, 58.74, 56.82,
1301, 1204, 1180, 1119, 1073, 1034, 1011 cmꢂ1; HRMS: calcd for
[MþH]þ C21H1879Br35ClN2O4: 477.02116, found: 477.02076; HRMS:
calcd for [MþH]þ C21H1879Br37ClN2O4: 479.01817, found:
479.01823; HRMS: calcd for [MþH]þ C21H1881Br37ClN2O4:
44.81, 33.18, 26.78, 23.33 ppm; FTIR:
n
¼3296, 2926, 2854, 1731,
~
1656, 1488, 1458,1425, 1301,1272,1224, 1180, 1139, 1030, 977 cmꢂ1
;
HRMS: calcd for [MþH]þ C23H20FN3O3: 406.15615, found:
406.15592; ½a RDT
ꢂ158.50 (DMSO, c 1.00).
ꢃ
481.01613, found: 481.01543; ½a DRT
ꢂ126.3 (CHCl3, c 1.0); HPLC
ꢃ
conditions: CHIRALCEL IA column, isohexane/(ethanol/DCM¼1/
4.2.16. (2R,3S,5aS,10aS)-3-(4-Bromophenyl)-50-fluoro-5a,6,7,8-tetra-
hydro-1H,5H-spiro[dipyrrolo[1,2-a:10,20-d]pyrazine-2,30-indole]-
100)¼2/3, flow rate¼0.5 mL minꢂ1
,
major enantiomer:
tR¼25.9 min; minor enantiomer: tR¼33.9 min.
20,5,10(10H,10aH)-trione (11c). 1H NMR (500 MHz, DMSO)
d
¼10.43
(s, 1H), 7.53 (dd, J¼8.5, 2.1 Hz, 1H), 7.42 (d, J¼8.2 Hz, 2H), 7.14e7.08
(m, 1H), 6.90e6.79 (m, 3H), 5.09 (dd, J¼10.1, 7.9 Hz,1H), 5.01 (s, 1H),
4.68 (t, J¼7.4 Hz,1H), 3.64e3.56 (m,1H), 3.51e3.43 (m,1H), 2.61 (dd,
J¼13.1, 10.1 Hz, 1H), 2.25 (dd, J¼13.1, 7.9 Hz, 1H), 2.21e2.13 (m, 1H),
4.2.12. Methyl (20R,3R,50S)-10-acetyl-20-(2,3-dichlorophenyl)-5-me-
thoxy-2-oxo-1,2-dihydrospiro[indole-3,30-pyrrolidine]-50-carboxylate
(10k). 1H NMR (400 MHz, CDCl3)
d
¼8.89 (s, 1H), 8.44 (dd, J¼7.9, 1.3,
1H), 7.47 (dd, J¼7.9, 1.3, 1H), 7.40 (t, J¼7.9, 1H), 6.86 (dd, J¼8.5, 2.3,
1H), 6.80e6.74 (m, 2H), 5.44 (s, 1H), 4.91 (dd, J¼11.4, 7.0, 1H), 3.87
(s, 3H), 3.82 (s, 3H), 2.65e2.54 (m, 1H), 2.31 (dd, J¼12.7, 7.0, 1H),
2.05e1.83 ppm (m, 3H); 13C NMR (126 MHz, DMSO)
d
¼174.39,
167.38, 165.95, 158.33 (d, J¼236.3 Hz), 137.07, 136.84, 135.07
(d, J¼8.3 Hz), 130.61, 129.61, 120.38, 114.70 (d, J¼23.5 Hz), 111.25
(d, J¼24.8 Hz), 110.28 (d, J¼8.2 Hz), 67.60, 60.39, 58.78, 56.66, 44.81,
~
1.87 ppm (s, 3H); 13C NMR (101 MHz, CDCl3)
d¼175.17, 171.89,
170.77, 156.54, 137.46, 134.00, 133.19, 132.80, 131.41, 130.20, 128.20,
128.09, 113.13, 111.00, 110.10, 68.31, 58.98, 57.69, 56.06, 52.88, 37.35,
33.48, 26.80, 23.29 ppm; FTIR:
n
¼3293, 2924, 2854,1727,1650,1486,
1457, 1427, 1299, 1218, 1174, 1136, 1105, 1071, 1008 cmꢂ1; HRMS:
22.30 ppm; FTIR:
¼2995, 2947, 2826, 1748, 1718, 1629, 1483, 1454,
calcd for [MþH]þ C23H1979BrFN3O3: 484.06666, found: 484.06546;
~
n
1423, 1309, 1199, 1044 cmꢂ1; ½a DRT
ꢃ
þ5.1 (CHCl3, c 1.0); HPLC con-
HRMS: C23H1981BrFN3O3: 486.06461, found: 486.06327;
½ ꢃ
a RDT
ditions: CHIRALCEL IA column, isohexane/(ethanol/DCM¼1/100)¼
1/1, flow rate¼0.5 mL minꢂ1, major enantiomer: tR¼25.6 min; mi-
nor enantiomer: tR¼28.0 min.
ꢂ143.33 (DMSO, c 0.63).
4.2.17. (2R,3S,5aS,10aS)-60-Bromo-3-(4-methoxyphenyl)-5a,6,7,8-
tetrahydro-1H,5H-spiro[dipyrrolo[1,2-a:10,20-d]pyrazine-2,30-indole]-
4.2.13. General procedure for the one-pot synthesis of spiro-
tryprostatin A inspired compounds. To a solution of iminoester 7a
(1 equiv), (Rp)-2-(tert-butylthio)-1-(diphenylphosphino)ferrocene
(5 mol %) and tetrakis (acetonitrile)copper(I) hexafluorophosphate
(5 mol %) in dichloromethane (0.1 M) at 0 ꢀC under argon were
added triethylamine (1.1 equiv) and 3-methyleneoxindole
(1.5 equiv). The reaction mixture was allowed to stir for 30 min at
20,5,10(10H,10aH)-trione (11d). 1H NMR (400 MHz, DMSO)
d¼10.49
(s, 1H), 7.46 (d, J¼8.0, 1H), 7.20 (dd, J¼8.0, 1.8, 1H), 6.99 (d, J¼1.8,
1H), 6.76 (s, 4H), 5.02 (dd, J¼10.4, 7.5, 1H), 4.92 (s, 1H), 4.61 (t, J¼7.3,
1H), 3.71 (s, 3H), 3.62e3.52 (m, 1H), 3.49e3.40 (m, 1H), 2.61 (dd,
J¼13.1, 10.5, 1H), 2.22e2.09 (m, 2H), 1.98e1.79 ppm (m, 3H); 13C
NMR (101 MHz, DMSO)
133.21, 129.24, 127.39, 124.93, 124.27, 121.09, 113.15, 112.34, 67.94,
d
¼174.35, 167.19, 166.16, 158.42, 142.73,
0
ꢀC and then 2 h at ambient temperature. A solution of (L)-
60.46, 58.78, 56.11, 54.93, 44.85, 33.05, 26.86, 23.38 ppm; FTIR:
~
FmocProCl in dichloromethane (0.14 M, 1.05 equiv) was added, the
reaction mixture was stirred at ambient temperature for 3 h and
piperidine (25 equiv) was added. The reaction mixture was stirred
at ambient temperature for 5 h and the solvents were removed in
vacuo. Purification of the crude product by column
n
¼3252, 2923, 2851, 1733, 1655, 1610, 1512, 1482, 1448, 1418, 1326,
1303, 1245, 1210, 1174, 1117, 1035; ½a DRT
ꢃ
ꢂ215.2 (CHCl3, c 0.5).
4.2.18. (2R,3S,5aS,10aS)-60-Bromo-3-(4-bromophenyl)-5a,6,7,8-tet-
rahydro-1H,5H-spiro[dipyrrolo[1,2-a:10,20-d]pyrazine-2,30-indole]-

A.P. Antonchick et al. / Tetrahedron 67 (2011) 10195e10202
10201
20,5,10(10H,10aH)-trione (11e). 1H NMR (500 MHz, DMSO)
d
¼10.57 (s,
Waldmann, H. Angew. Chem., Int. Ed. 2009, 48, 3224e3242; Renner, S.; van
Otterlo, W. A. L.; Seoane, M. D.; Mocklinghoff, S.; Hofmann, B.; Wetzel, S.;
Schuffenhauer, A.; Ertl, P.; Oprea, T. I.; Steinhilber, D.; Brunsveld, L.; Rauh, D.;
Waldmann, H. Nat. Chem. Biol. 2009, 5, 585e592; (n) Wetzel, S.; Klein, K.;
Renner, S.; Rauh, D.; Oprea, T. I.; Mutzel, P.; Waldmann, H. Nat. Chem. Biol. 2009,
5, 581e583; (o) Wetzel, S.; Wilk, W.; Chammaa, S.; Sperl, B.; Roth, A. G.; Yek-
taoglu, A.; Renner, S.; Berg, T.; Arenz, C.; Giannis, A.; Oprea, T. I.; Rauh, D.;
Kaiser, M.; Waldmann, H. Angew. Chem., Int. Ed. 2010, 49, 3666e3670; (p)
Dekker, F. J.; Rocks, O.; Vartak, N.; Menninger, S.; Hedberg, C.; Balamurugan, R.;
Wetzel, S.; Renner, S.; Gerauer, M.; Scholermann, B.; Rusch, M.; Kramer, J. W.;
Rauh, D.; Coates, G. W.; Brunsveld, L.; Bastiaens, P. I. H.; Waldmann, H. Nat.
Chem. Biol. 2010, 6, 449e456; (q) Bon, R. S.; Waldmann, H. Acc. Chem. Res. 2010,
1H), 7.51 (d, J¼8.0 Hz,1H), 7.43 (d, J¼8.6 Hz, 2H), 7.24 (dd, J¼8.0,1.8Hz,
1H), 7.02 (d, J¼1.8 Hz, 1H), 6.85 (d, J¼6.5 Hz, 2H), 5.07 (dd, J¼10.2,
7.7 Hz, 1H), 5.01 (s, 1H), 4.64 (t, J¼7.4 Hz, 1H), 3.65e3.56 (m, 1H),
3.51e3.44 (m, 1H), 2.60 (dd, J¼13.2, 10.2 Hz, 1H), 2.24 (dd, J¼13.2,
7.7 Hz, 1H), 2.22e2.13 (m, 1H), 2.00e1.83 ppm (m, 3H); 13C NMR
(126 MHz, DMSO)
130.61,124.96,124.33,121.17,120.40,112.39, 67.49, 60.36, 58.85, 55.94,
d
¼174.30, 167.26, 165.89, 142.68, 136.74, 132.87,
~
44.80, 33.46, 26.81, 23.27 ppm; FTIR:
n
¼3064, 2926, 2852,1723,1650,
€
1611, 1483, 1452, 1409, 1328, 1301, 1273, 1261, 1216, 1155, 1117, 1069,
1025, 1008 cmꢂ1; HRMS: calcd for [MþH]þ C23H1979Br2N3O3:
543.98659, found: 543.98625; HRMS: C23H1981Br2N3O3: 547.98250,
43, 1103e1114; (r) Basu, S.; Ellinger, B.; Rizzo, S.; Deraeve, C.; Schurmann, M.;
Preut, H.; Arndt, H.-D.; Waldmann, H. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
6805e6810.
3. (a) Bindra, J. S. In The Alkaloids; Manske, R. H. F., Ed.; Academic: New York, 1973;
Vol. 14, pp 84e121; (b) Sakai, S.; Aimi, N.; Yamaguchi, K.; Ohhira, H.; Hori, K.;
Haginiwa, J. Tetrahedron Lett. 1975, 16, 715e718; (c) Aimi, N.; Yamaguchi, K.;
Sakai, S.; Haginiwa, J.; Kubo, A. Chem. Pharm. Bull. 1978, 26, 3444e3449; (d)
Sakai, S.; Aimi, N.; Yamaguchi, K.; Yamanaka, E.; Haginiwa, J. J. Chem. Soc., Perkin
Trans. 1 1982, 1257e1262; (e) Wong, W. H.; Lim, P. B.; Chuah, C. H. Phyto-
chemistry 1996, 41, 313e315; (f) Pellegrini, C.; Weber, M.; Borschberg, H. J. Helv.
Chim. Acta 1996, 79, 151e168; (g) Anderton, N.; Cockrum, P. A.; Colegate, S. M.;
Edgar, J. A.; Flower, K.; Vit, I.; Willing, R. I. Phytochemistry 1998, 48, 437e439;
(h) Reyes-Chilpa, R.; Rivera, J.; Oropeza, M.; Mendoza, P.; Amekraz, B.; Jan-
kowski, C.; Campos, M. Biol. Pharm. Bull. 2004, 27, 1617e1620; (i) Kam, T. S.;
Choo, Y. M. Tetrahedron 2000, 56, 6143e6150; (j) Ma, J.; Hecht, S. M. Chem.
Commun. 2004, 1190e1191; (k) Pandey, R.; Singh, S. C.; Gupta, M. M. Phyto-
chemistry 2006, 67, 2164e2169.
found: 547.98191; ½a DRT
ꢂ184.62 (CHCl3, c 0.65).
ꢃ
4.2.19. (2R,3S,5aS,10aS)-3-(4-Bromophenyl)-5a,6,7,8-tetrahydro-
1H,5H-spiro[dipyrrolo[1,2-a:10,20-d]pyrazine-2,30-indole]-
20,5,10(10H,10aH)-trione (11f). 1H NMR (500 MHz, DMSO)
d
¼10.39
(s, 1H), 7.50 (d, J¼7.4, 1H), 7.39 (d, J¼8.4, 2H), 7.24 (t, J¼7.7, 1H), 7.02
(dd, J¼7.7, 7.4, 1H) 6.85 (d, J¼7.7, 1H), 6.79 (d, J¼8.4, 2H), 5.06 (dd,
J¼10.6, 8.1, 1H), 4.93 (s, 1H), 4.62 (t, J¼7.5, 1H), 3.62e3.52 (m, 1H),
3.48e3.40 (m, 1H), 2.59 (dd, J¼13.0, 10.6, 1H), 2.22e2.08 (m, 2H),
1.98e1.78 ppm (m, 3H); 13C NMR (126 MHz, DMSO)
d
¼175.35,
4. (a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651e12666; (b) Cui,
C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832e835; (c) Wang, F. Z.; Fang,
Y. C.; Zhu, T. J.; Zhang, M.; Lin, A. Q.; Gu, Q. Q.; Zhu, W. M. Tetrahedron 2008, 64,
7986e7991.
168.22, 166.93, 141.70, 137.86, 134.56, 131.51, 129.46, 123.90, 122.87,
121.23, 110.52, 68.79, 61.27, 59.85, 57.01, 45.71, 34.55, 27.73,
~
24.19 ppm; FTIR:
n
¼3254, 2946, 2887, 1724, 1652, 1617, 1486, 1470,
1429, 1334, 1294, 1212, 1149, 1105, 1073, 1008 cmꢂ1; HRMS: calcd
for [MþH]þ C23H2079BrN3O3: 466.07608, found: 466.07583; HRMS:
calcd for [MþH]þ C23H2081BrN3O3: 468.07403, found: 468.07365;
5. Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc.
1999, 121, 2147e2155.
€
6. Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.; Preut,
H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735e740.
7. For a review on the challenge of developing catalytic asymmetric methods for
the synthesis of quaternary all-carbon centers, see: (a) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388e401; (b) Douglas, C. J.; Overman, L.
E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363e5367; (c) Trost, B. M.; Jiang, C. H.
Synthesis 2006, 369e396; (d) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2007, 5969e5994; (e) Steven, A.; Overman, L. E. Angew. Chem., Int.
Ed. 2007, 46, 5488e5508; (f) Trost, B. M.; Brennan, M. K. Synthesis 2009,
3003e3025.
½
a RDT
ꢃ
ꢂ9.8 (CHCl3, c 1.0).
Acknowledgements
Our research was supported by the Max Planck Gesellschaft, the
BMBF (NGFN-Plus 01GS08102) and the European Research Council
under the European Union’s Seventh Framework Programme (FP7/
2007-2013)/ERC Grant agreement no. 268309.
8. For excellent reviews on the synthesis of 3,30-pyrrolidinyl-spirooxindoles, see:
(a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209e2219; (b) Galliford,
C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748e8758.
9. (a) Edmondson, S. D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37,
1138e1140; (b) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 8003e8010; (c) Wearing, X. Z.; Cook, J. M. Org. Lett. 2002,
4, 4237e4240; (d) Takayama, H.; Fujiwara, R.; Kasai, Y.; Kitajima, M.; Aimi, N.
Org. Lett. 2003, 5, 2967e2970; (e) Li, C. M.; Chan, C.; Heimann, A. C.; Dani-
shefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 1444e1447.
10. (a) von Nussbaum, F.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39,
2175e2178; (b) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Angew. Chem., Int. Ed.
2004, 43, 5357e5360.
Supplementary data
Copies of 1H NMR- and 13C NMR-spectra and HPLC traces are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2011.04.056.
11. (a) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666e5667;
(b) Sebahar, P. R.; Osada, H.; Usui, T.; Williams, R. M. Tetrahedron 2002,
58, 6311e6322; (c) Onishi, T.; Sebahar, P. R.; Williams, R. M. Org. Lett.
2003, 5, 3135e3137; (d) Lo, M. M. C.; Neumann, C. S.; Nagayama, S.;
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mun. 2007, 631e633.
12. Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 4083e4086.
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better results.
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