Palladium-mediated domino oxidative amination of cyclohexadienes as an entry to indole alkaloids

Article abstract of DOI:10.1016/j.tet.2018.12.043

A palladium-mediated double oxidative amination reaction on cyclohexa-2,5-dienes has been developed, leading to the tetracyclic indoline skeleton of aspidosperma and strychnos alkaloids. The allyl-palladium intermediate, generated after the double oxidati

Full text of DOI:10.1016/j.tet.2018.12.043

Accepted Manuscript
Palladium-mediated domino oxidative amination of cyclohexadienes as an entry to
indole alkaloids
Dawood Hosni Dawood, Redouane Beniazza, Frédéric Robert, Yannick Landais
PII:
S0040-4020(18)31521-7
https://doi.org/10.1016/j.tet.2018.12.043
TET 30029
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 September 2018
Revised Date: 18 December 2018
Accepted Date: 19 December 2018
Please cite this article as: Dawood DH, Beniazza R, Robert Fréé, Landais Y, Palladium-mediated
domino oxidative amination of cyclohexadienes as an entry to indole alkaloids, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2018.12.043.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Palladium-mediated Domino Oxidative
Amination of Cyclohexadienes as an Entry to
Indole Alkaloids.
Leave this area blank for abstract info.
Dawood Hosni Dawood, Redouane Beniazza, Frédéric Robert and Yannick Landais
University of Bordeaux, Institute of Molecular Sciences (ISM), CNRS-UMR 5255, F-33400 Talence, France.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Palladium-mediated Domino Oxidative Amination of Cyclohexadienes as an Entry to
Indole Alkaloids.
Dawood Hosni Dawooda,b, Redouane Beniazzaa,c, Frédéric Roberta and Yannick Landaisa
a University of Bordeaux, Institute of Molecular Sciences (ISM), CNRS-UMR 5255, F-33400 Talence, France.
b Agricultural Chemistry Department, Faculty of Agriculture, Mansoura University, 35516 Mansoura, Egypt.
c Mohammed VI Polytechnic University, UM6P, 43150 Ben Guerir, Morocco.
Dedicated with respect to Prof. Leon Ghosez
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A palladium-mediated double oxidative amination reaction on cyclohexa-2,5-dienes has been
developed, leading to the tetracyclic indoline skeleton of aspidosperma and strychnos alkaloids.
The allyl-palladium intermediate, generated after the double oxidative amination, could be
trapped by an internal nucleophile to allow the construction of 3 rings in a single step.
Approaches to the synthesis of strychnine and mossambine is finally reported.
Available online
2018 Elsevier Ltd. All rights reserved
.
Keywords:
Palladium oxidative amination
Cascade reactions
Strychnos alkaloids
Cyclohexadiene desymmetrization
———
Dr Frédéric Robert. Tel.: +33 (5) 40 00 64 41; e-mail: frederic.robert@u-bordeaux.fr
Prof. Yannick Landais. Tel.: +33 (5) 40 00 22 89; e-mail: yannick.landais@u-bordeaux.fr

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Cascade (or Domino) reactions constitute a powerful tool for
the construction of complex natural products as several C-C or C-
heteroatom bonds may be created in one pot with an increase of
the structural complexity.1 The desymmetrization of cyclic
dienes,2 when applicable, also constitutes an efficient strategy in
organic synthesis3 as, at least two new stereogenic centers are
formed, including in some cases, the creation of a chiral
quaternary stereocenter.4 Combining these two approaches then
allows a straightforward access to the synthesis of a broad range
of natural products. Applying this strategy to the synthesis of
alkaloids, and especially indole alkaloids, requires the
development of efficient C-N bond forming reactions (Figure 1).
Scheme 2. Pd(II)-catalyzed oxidative amination.
We then attempted a cyclization starting from an aromatic
sulfonamide 5, available in two steps from 2-aminobiphenyl
through a Birch reductive alkylation10 (after the protection of the
aniline). Oxygen concentration was found to be a critical factor,
indicating that Pd0 reoxidation is the turnover limiting step of the
process.11 Inefficient reoxidation of Pd0 into PdII leads to
aggregation of Pd0 and precipitation of Pd metal, a process which
could be prevented by addition of charcoal.12 The presence of
stoichiometric NaOAc as a base also enhanced the yield of these
reactions (Scheme 3).13 It should also be noticed that Zhu et al.
have developed recently an elegant palladium oxidative
amination on cyclohexadienes using chiral ligands, allowing the
extension of our strategy to an enantioselective version.14
Figure 1. Indoles alkaloids sharing a common tetracyclic backbone.
Aza-Michael reactions5 have been successfully used in
asymmetric desymmetrization of cyclohexadienones as an access
to tetracyclic indolines,6 including the Büchi ketone,7 a key
intermediate in the synthesis of aspidosperma and strychnos
alkaloids. Few years ago, our group has also developed a Pd(II)-
catalyzed double oxidative amination of cyclohexadienes with
the trapping of the final allyl-palladium by an acetate forming a
highly functionalized cyclohexene as a single diastereoisomer
(Scheme 1).8
Scheme 3. Oxidative amination of aromatic sulfonamide.
At this stage, a sequential double addition confirmed the
formation of the acetate insertion product as
a unique
Scheme 1. Pd(II)-catalyzed double oxidative amination cascade.
diastereoisomer, identical to that obtained through the one pot
process (Scheme 1 and 4). However, when the reaction was run
with an acrylamide (e.g. 8), instead of an acetate, only the
tetracyclic product 9 was formed with no trace of the desired
pentacyclic system, resulting from an insertion (and elimination)
of the intermediate palladium species into the double bond in a
Heck-type fashion.
We wish to report herein an extension of this methodology
with the formation of a third ring by an intramolecular trapping
of the Pd-π allyl intermediate (Figure 2) and some attempts to
complete the synthesis of mossambine, a strychnos alkaloid.
Figure 2. Triple cascade addition onto cyclohexadienes
2. Results and discussion
Bäckvall et al. first explored the Pd(II)-catalyzed cyclization
of sulfonamides onto cyclohexene in DMSO with dioxygen as a
reoxidant (Scheme 2, eq. 1).9 We demonstrated that the
cyclization could also be performed on a cyclohexa-1,4-diene
with various protecting groups on the nitrogen (Scheme 2, eq. 2).
The somewhat lower yields obtained are due to a partial
overoxidation of the final diene into an enone.
Scheme 4. Sequential double oxidative amination.

3
The double bond of the acrylamide being quite far away from
the palladium center in the putative allyl-Pd intermediate, an
amide 10 with a longer arm was then synthesized (Scheme 5).
Unfortunately, if the desired tricyclic product 11, an advanced
intermediate in the synthesis of iboxyphylline, an aspidosperma
alkaloid,15 was effectively formed, yields were always low and
the reaction difficult to reproduce. The faster oxidation of the
terminal double bond of 10 (through a Wacker type process) or a
competing 6-exo carbopalladation followed by an oxidation of
the exocyclic double bond might explain the low yield of 11, the
only compound stable to overoxidation.
ACCEPTED MANUSCRIPT
When the palladium oxidative amination was performed on
the six amides above, only two cyclized products were observed.
Starting from 17, low amount of tetracyclic acetate 18 was
isolated. However, when the reaction was carried out on
tosylamine 16, pentacyclic 19 could be observed, albeit in very
low yield (Scheme 7).
Scheme 7. Oxidative amination on substrates 16 and 17.
From these failures, it appeared that sulfonamides, stable
under the harsh oxidative conditions, would constitute suitable
nucleophiles. Carbamate 22, formed through addition of a N-
tosyl isocyanate to the corresponding amine, was thus submitted
to the oxidative amination protocol, affording the pentacyclic
compound 23, formed in satisfying yield (Scheme 8).
Scheme 5. Double oxidative amination and insertion.
In the search for a nucleophile that would stand the harsh
oxidative conditions, different acyl groups bearing electron-rich
aromatics, a malonate, a tosylamine... were then introduced on
the primary amine (Scheme 6). Amides 12-16 were thus isolated
in good overall yield (in 2 steps from 6), except amide 17 formed
after sulfone elimination.
Scheme 8. Formation of pentacyclic compound 23.
To demonstrate further the efficiency of the strategy, a one-
pot triple oxidative amination protocol was then attempted with
success on precursor 24, leading to pentacyclic 25 in a
remarkable 72% yield (Scheme 9), in only five steps and 30%
overall yield from commercially available 2-amino biphenyl.
Scheme 9. One-pot triple oxidative amination.
In order to complete the synthesis of indole alkaloids,
including that of strychnine, we also thought using the allylic
acetate 2 formed after the double cyclization (Scheme 1).
Unfortunately, despite extensive efforts and whatever the
organometallic protocol (Pd or Cu) used for the SN2' type
reactions (Scheme 10), only starting material or degradation were
observed. This may be ascribed to the presence of the allylic
sulfonamide which may enter into a competition with the acetate
leaving group in the allylic substitution reaction.
Scheme 6. Acid coupling

4
Tetrahedron
ACCEPTED MANUSCRIPT
NAc
NAc
Pd
Cu
OAc
N
+ Nu
N
Nu
SO2Et
EtO2S
allylic leaving group
Scheme 10. Failures in the intermolecular SN2' reactions
An intramolecular version was then envisaged to avoid the
allylic leaving group problems mentioned above. For this
purpose, precursor 27, having a SES protecting group, was
prepared with the same strategy (Scheme 11).
Scheme 13. Synthesis of the mossambine precursor.
To complete the synthesis of mossambine, the installation of a
carbomethoxy group was then required. A common and general
strategy exploited by many groups,19 for the elaboration of the
aspidosperma skeletons relies on the use of a combination of
LDA (or n-BuLi) and Mander's reagent NCCO2Me,20 a soft
reagent known to favor C- over N-alkylation (Scheme 14).
Scheme 11. Synthesis of the SES-protected precursor.
The aromatic nitrogen was then unprotected with a fluoride
source and coupled with a bromoacryloyl chloride to give 28.
Unfortunately, as before, the various organometallic conditions
tested gave rise to degradation products and no trace of the
desired pentacyclic skeleton 29 (Scheme 12).
OAc
OAc
N
N
LDA, NCCO2Me
-70°C, THF
N
N
H
CO2Me
Scheme 14. Mander's reagent approach to mossambine
Despite extensive efforts to find suitable reaction conditions,
including variation of the amount of base and reagent or of the
temperature, we were not able to adapt this reaction to the
formation of the strychnos skeleton. On similar compounds of the
strychnos family, as for example for the transformation of
dehydrotubifoline into akuammicine (Figure 1), Bonjoch, Bosch
et al. have used the carbomethoxylation of the nitrogen center,
Scheme 12. Failures in the intramolecular SN2' reactions
In the meantime we also envisaged to target mossambine (see
Fig. 1), for which only one total synthesis was achieved by the
group of Kuehne.16 An intramolecular Heck reaction, inspired by
Rawal in his synthesis of dehydrotubifoline,17 was chosen for the
formation of the alkaloid D-ring (Figure 3).
followed
by
a
photochemical
rearrangement.21
N-
carbomethoxylation of substrate 33 was performed to afford 35,
albeit in moderate yield, but the photochemical rearrangement of
the latter never provided the expected rearranged product,
probably due to the presence of the acetoxy group (Scheme 15).
Figure 3. Mossambine retrosynthesis
For that purpose, the derivative 27, bearing appropriate
orthogonal protecting groups on both nitrogens, i.e. Boc and
SEM substituents, was used. An iodo-butenyl chain was then
installed, after Boc removal, on the key intermediate 27 (Scheme
13). The SES protecting group was then removed in order to
direct the Heck reaction on the correct position.17b Compound 33,
which can be seen as an acetoxy-dehydrotubifoline derivative,18
was thus formed in a moderate 44% yield and only 9 steps from
2-amino biphenyl.
Scheme 15. Photochemical rearrangement approach
3. Conclusion
As a summary, our palladium-mediated double oxidative
amination reaction constitutes an attractive and straightforward
strategy for the functionalization of cyclohexa-2,5-dienes,

5
4.2.1. Dimethyl 2-(2-(2-((4aS,9aS)-9-
(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-
yl)ethylamino)-2-oxoethyl)malonate (12)
leading to the tetracyclic and pentacyclic indoline skeletons of
aspidosperma and strychnos alkaloids. Combined with the
enantioselective method developed by Zhu and co-workers,14 this
ACCEPTED MANUSCRIPT
strategy offers
a valuable entry for a rapid access to
Starting from 7 (100 mg, 0.328 mmol, 1 eq.) and 2-
methoxycarbonyl-succinic acid 1-methyl ester, the crude product
was purified by silica gel chromatography (petroleum ether/ethyl
acetate, 70/30) to give 12 (70 mg, 0.1470 mmol, 45% over 2
steps) as a colorless oil. Rf = 0.79 (EtOAc: 100%). IR (film,
NaCl): ν= 2951, 1783, 1707, 1596, 1476, 1346, 1235, 1153, 757
cm-1. 1H NMR (CDCl3, 300 MHz): δ (ppm) = 7.41-7.02 (m, 5H),
6.03 (d, 1H, J = 3 Hz), 5.94-5.89 (m, 1H), 5.70-5.67 (m, 1H),
5.05 (s, 1H), 3.96 (t, 1H, J = 3 Hz), 3.75 (s, 6H), 3.28 (d, 1H, J =
3.4 Hz), 3.20-3.11 (m, 2H), 2.74-2.71 (m, 2H), 2.06-2.02 (m,
2H), 1.89-1.81 (m, 2H), 1.39 (t, 3H, J = 4.14 Hz). 13C NMR
(CDCl3, 75.5 MHz): δ (ppm) = 169.6 (C=O), 169.3 (C=O), 140.7
(C), 136.8 (C), 130.2 (CH), 128.2 (CH), 124.7 CH), 124.1 (CH),
123.5 (CH), 121.3 (CH), 114.3 (CH), 65.4 (CH), 52.9 (CH3), 47.6
(CH), 46.7 (CH2), 45.9 (CH), 41.7 (CH2), 35.7 (CH2), 34.8 (CH2),
7.8 (CH3). MS (ESI) m/z (%):499 [M+Na]+ (100), 477 [M+H]+
(18). HRMS (ESI): [M+Na]+ C23H28N2O7NaS: calcd. 499.1520,
found 499.1520.
aspidosperma and strychnos alkaloids. Finally, we also showed
that the allyl-palladium intermediate, formed after the double
oxidative amination, could also be trapped in an intramolecular
fashion with
construction of 3 rings and 3 C-N bond in a single step.
a third internal sulfonamide to afford the
4. Experimental
4.1. Materials and apparatus
Commercial reagents were used without purification. DMSO,
Acetonitrile, CH2Cl2 and (i-Pr)2NH were distilled under CaH2.
THF and Et2O were distilled from sodium and benzophenone. 1H
NMR and 13C NMR were recorded on Brüker AC-250FT (1H:
250 MHz, 13C: 62.9 MHz), a Brüker Avance-300FT (1H: 300
MHz, 13C: 75.5 MHz) or a Brüker DPX-400FT (1H: 400 MHz,
13C: 100.2 MHz) apparatus using CDCl3 as internal reference.
Mass spectra were recorded on a Nermag R10-10 C. High
resolution mass spectra were recorded on a FT-IRC mass
spectrometer Brüker 4.7T BioApex II. InfraRed (IR) spectra were
4.2.2. N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-
dihydro-4aH-carbazol-4a-yl)ethyl)-3,4,5-
trimethoxybenzamide. (13)
recorded on
a
Perkin-Elmer Paragon 1000 FT-IR
Starting from 7 (100 mg, 0.328 mmol, 1 eq.) and 3,4-
dimethoxy-benzoic acid, the crude product was purified by silica
gel chromatography (petroleum ether/ethyl acetate, 70/30 then
50/50) to give 13 (75 mg, 0.15 mmol, 46% over 2 steps) as a
white solid. M.p. = 74.2-75.9°C. Rf = 0.86 (petroleum ether/ethyl
acetate: 50/50). IR (solid, KBr): ν = 2924, 1638, 1583, 1498,
spectrophotometer. Melting points were not corrected and
determined by using a Büchi-Totolli apparatus and Stuart
Scientific apparatus (SMP3). Compound 1, 2, 6, 7, 8, 9 have
already been described.8
4.2. General protocol for amide synthesis
1
1338, 1234, 1127, 697 cm-1. H NMR (CDCl3, 300 MHz): δ
(ppm) = 7.32 (d, 1H, J = 7.9 Hz), 7.07-7.04 (m, 2H), 6.96-6.87
(m, 3H), 6.27 (t, 1H, J = 3 Hz), 5.97-5.96 (m, 2H), 5.90- 5.84 (s,
1H), 5.69 (d, 1H, J = 9.4 Hz), 5.09 (d, 1H, J = 3 Hz), 3.81 (s,
9H), 3.49-3.35 (m, 2H), 3.12 (q, 2H, J = 7.1 Hz), 2.11-1.95 (m,
2H), 1.33 (t, 3H, J=7.5 Hz). 13C NMR (CDCl3, 75.5 MHz): δ
(ppm) = 167.2 (C), 153.1 (C), 140.5 (CH), 136.8 (CH), 130.4
(C), 129.7 (CH), 128.1 (CH), 124.7 (CH), 123.8 (CH), 123.8
(CH), 123.5 (CH), 121.2 (CH), 114.2 (CH), 104.2 (CH), 65.3
(CH), 60.9 (CH3), 56.2 (CH3), 46.7 (CH), 46.3 (CH2), 41.5 (CH2),
36.1 (CH2), 7.8 (CH3). MS (ESI) m/z (%):521 [M+Na]+ (100),
499 [M+H]+ (45). HRMS (ESI): [M+Na]+ C26H30N2O6NaS: calcd.
521.1716, found 521.1721.
In a two-necked round-bottom flask was introduced AlCl3
(178 mg, 1.33 mmol) in ether (8 mL) at 0°C. A solution of
LiAlH4 (1.0M in ether, 1.33 mL, 1.33 mmol) was added dropwise
and the mixture was allowed to stirr for 30 min at room
temperature. To the solution, was added 9-Ethanesulfonyl-9,9a-
dihydro-carbazol-4a-yl)-acetonitrile 6 (400 mg, 1.33 mmol; in 8
mL of ether) dropwise at 0°C and the media was stirred at room
temperature for an additional 4h. Water (1 mL) was cautiously
added followed by the addition of a 10% aqueous sodium
hydroxide solution and the media was stirred for another 30 min.
Filtration of the solid residue over celite, washing generously
with AcOEt, separation of the two layers, drying of the organic
layer over sodium sulfate and evaporation of the solvent gave 7
as an oily product (350 mg, 87%). The product was, in general,
sufficiently pure to be used in the next step without further
4.2.3. N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-
dihydro-4aH-carbazol-4a-yl)ethyl)furan-3-
carboxamide. (14)
1
purification. H NMR (CDCl3, 300 MHz): δ (ppm) = 7.31-7.28
Starting from 7 (100 mg, 0.328 mmol, 1 eq.) and furan-2-
carboxylic acid, the crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 70/30 then 50/50)
to give 14 (174 mg, 0.4370 mmol, 53% over 2 steps) as a white
solid. M.p. = 52.2-54.5 °C. Rf = 0.48 (petroleum ether/ethyl
acetate: 50/50). IR (solid, KBr): ν = 3370, 2928, 1651, 1528,
(m, 1H), 7.03-7.01 (m, 2H), 6.94-6.91 (m, 1H), 5.88 (m, 2H),
5.78-5.74 (m, 1H), 5.60 (dd, J = 1.6 Hz, 1H), 4.95(d, J = 1.60
Hz), 3.01 (q, J = 7.5 Hz, 2H), 2.68 (m , 2H), 2.95-1.80 (m, 2 H),
1.27 (t, J = 7.50 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): δ (ppm)
= 140.4 (C), 137.2 (C), 130.2 (CH), 127.8 (CH), 124.4 (CH),
123.7 (C), 123.7 (CH), 123.5 (CH), 120.5 (CH), 113.9 (CH),
65.59 (CH), 46.8 (C), 46.5 (CH2), 46.1 (CH2), 45.4 (CH2), 37.4
(CH2), 7.7 (CH3).
1
1476, 1343, 1170, 1009, 722, 697 cm-1. H NMR (CDCl3, 300
MHz): δ (ppm) = .43-7.42 (m, 2H), 7.27-7.15 (m, 2H), 7.09-7.02
(m, 2H), 6.52-6.48 (m, 2H), 6.07-6.06 (s, 2H), 5.97-5.94 (m, 1H),
5.74 (d, 1H, J = 9.4 Hz), 5.10 (s, 1H), 3.50 (q, 2H, J = 7.1 Hz),
3.22-3.12 (m, 2H), 2.23-1.95 (m, 2H), 1.42 (t, 3H, J =7.5 Hz).
13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 158.4 (C), 147.8 (C),
143.9 (CH), 140.7 (C), 136.7 (C), 130.2 (CH), 128.2 (CH), 124.7
(CH), 123.9 (CH), 123.9 (CH), 123.5 (CH), 121.3 (CH), 114.2
(CH), 114.1 (CH), 112.1 (CH), 65.4 (CH), 46.7 (C), 45.8 (CH2),
41.8 (CH2), 35.1 (CH2), 7.8 (CH3). MS (ESI) m/z (%):399
[M+H]+ (100), 421 [M+Na]+ (54). HRMS (ESI): [M+H]+
C21H23N2O4S: calcd. 399.1373, found 399.1380.
Crude amine 7 (1 eq.) was dissolved in CH2Cl2 (0.1M). The
carboxylic acid (1.1 eq.), EDAC (1.5 eq.) and HOBt (1.3 eq.)
were added to this mixture. Finally the base (DIPEA, 0.16 ml, 3
eq.) was added and the reaction mixture was stirred 30h at room
temperature. The reaction was then stopped by addition of
NaHCO3 and extracted with EtOAc. The combined organic
layers were washed with brine, dried over sodium sulfate,
concentrated in vacuo and the product purified by silica gel
chromatography giving amides 12-17.

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.2.4. N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-
123.9 (CH), 123.6 (C), 121.5 (CH), 114.3 (C), 65.4 (CH), 46.7
dihydro-4aH-carbazol-4a-yl)ethyl)-1H-indole-3-
carboxamide. (15)
(C), 46.3 (CH2), 41.2 (CH2), 36.1 (CH2), 7.9 (CH3). MS (ESI) m/z
(%):521 [M+Na]+ (100), 499 [M+H]+ (11). HRMS (ESI):
[M+Na]+ C25H26N2O5NaS2: calcd. 521.1175, found 521.1192.
Starting from 7 (100 mg, 0.328 mmol, 1 eq.) and 1H-indole-3-
carboxylic acid, the crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 70/30 then 50/50)
to give 15 (105 mg, 0.2348 mmol, 48% over 2 steps) as a white
solid. M.p = 126.6-127.7 °C. Rf = 0.65 (petroleum ether/ethyl
acetate: 50/50). IR (solid, KBr): ν = 3401, 1618, 1542, 1457,
4.3. Other amide precursors
4.3.1. 4-methyl-N-(2-((4aS,9aS)-9-(2-
(trimethylsilyl)ethylsulfonyl)-9,9a-dihydro-4aH-
carbazol-4a-yl)ethylcarbamoyl)benzenesulfonamide
(22)
1339, 1150, 1009, 749 cm-1. H NMR (CDCl3, 300 MHz): δ
1
(ppm) = 9.77 (s, 1H), 7.94-7.91 (m, 1H), 7.62 (s, 1H), 7.29-7.25
(m, 2H), 7.09-7.01 (m, 3H), 6.88-6.86 (m, 2H), 6.46-6.42 (t, 1H,
J = 5.3 Hz), 5.84-5.83 (m, 2H), 5.74-5.70 (m, 1H), 5.50 (d, 1H, J
= 9.4 Hz), 5.04-5.03 (s, 1H), 3.34-3.32 (m, 2H), 3.10-2.97 (m,
2H), 2.03-1.79 (m, 2H), 1.21 (t, 3H, J = 7.5 Hz). 13C NMR
(CDCl3, 75.5 MHz): δ (ppm) = 166.1 (C), 140.4 (C), 137.1 (C),
136.5 (C), 130.2 (CH), 128.1 (CH), 127.9 (CH), 125.1 (C), 124.7
(CH), 124.1 (CH), 123.8 (CH), 123.6 (CH), 122.8 (CH), 121.5
(CH), 121.1 (CH), 120.2 (CH), 114.2 (CH), 112.2 (CH), 111.5
(C), 65.5 (CH), 46.8 (C), 45.8 (CH2), 42.2 (CH2), 35.4 (CH2), 7.7
(CH3). MS (ESI) m/z (%): 470 [M+Na]+ (100), 448 [M+H]+ (50).
HRMS (ESI): [M+Na]+ C25H25N3O3NaS: calcd. 470.1662, found
470.1662.
In a 100 ml two-necked round bottom flask, AlCl3 (1.142 g,
8.56 mmol, 3 eq.) was dissolved in Et2O (12 mL) at 0°C, then
LiAlH4 (433 mg, 11.42 mmol, 4 eq.) was added. The reaction
mixture was then stirred at room temperature for 30 min. Nitrile
21 (1.062 g, 2.855 mmol, 1 eq.) was dissolved in Et2O (3 mL)
and THF (3 mL), and added dropwise at 0°C. The reaction
mixture was stirred at room temperature for 18h then the reaction
stopped by addition of ice then NaOH 10% (40 mL) was added
and the reaction mixture was stirred for 1h. Ether was added. The
reaction mixture was filtered through celite and extracted with
DCM. The combined organic layers were washed with brine,
dried over sodium sulfate and concentrated in vacuum affording
the amine as a yellow oil. To a solution of the crude amine (703
mg, 1.869 mmol, 1 eq.) in CH2Cl2 (20 mL) at 0°C was added the
p-toluene sulfonyl isocyanate (368 mg, 1.869 mmol, 1 eq.). The
reaction was warmed to r.t. and stirred while monitoring the
consumption of the amine by TLC (2-16h). The reaction mixture
was evaporated directly without extraction. Purification by silica
gel chromatography (petroleum ether/ethyl acetate, 70/30)
afforded 22 (786 mg, 1.371 mmol, 73% over 2 steps) as a white
solid. M.p. = 86.8-88.1°C. Rf = 0.58 (petroleum ether/ ethyl
acetate: 70/30). IR (solid, KBr): ν = 3353, 2950, 1672, 1547,
4.2.5. N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-
dihydro-4aH-carbazol-4a-yl)ethyl)-2-(4-
methylphenylsulfonamido)acetamide (16)
Starting from 7 (100 mg, 0.328 mmol, 1 eq.) and (toluene-4-
sulfonylamino)-acetic acid, the crude product was purified by
silica gel chromatography (petroleum ether/ethyl acetate, 80/20
then 50/50) afforded 16 (349 mg, 0.6774 mmol, 82 % over 2
steps) as a white solid. M.p. = 143.4-144.0°C. Rf = 0.48
(petroleum ether/ethyl acetate: 50/50). IR (solid, KBr): ν = 2284,
1
1
1345, 1250, 698 cm-1. H NMR (CDCl3, 300 MHz): δ (ppm) =
1658, 1458, 1339, 1152, 763 cm-1. H NMR (CDCl3, 300 MHz):
8.75 (broad s, 1H), 7.77 (d, 2H, J = 8.3 Hz), 7.38 (d, 1H, J = 8.1
Hz), 7.30-7.16 (m, 2H), 7.14-7.09 (m, 2H), 7.02-6.97 (m, 1H),
6.54-6.52 (m, 1H), 6.03(d, 2H, J = 3.4 Hz), 5.93-5.87 (m, 1H),
5.65 (d, 1H, J = 9.6 Hz), 5.00 (s, 1H), 3.28-3.20 (m, 2H), 3.08-
2.99 (m, 2H), 2.40 (s, 3H), 2.12-2.02 (m, 1H), 1.87-1.77 (m, 1H),
1.08-0.99 (m, 2H), -0.01 (s, 9H). 13C NMR (CDCl3, 75.5 MHz):
δ (ppm) = 151.9 (C), 144.9 (C), 141.2 (C), 136.8 (C), 136.2 (C),
130.4 (CH), 130.1 (CH), 128.3 (CH), 127.1 (CH), 125.3 (CH),
123.7 (CH,), 123.6 (CH), 123.3 (CH), 121.4 (CH), 114.1 (CH),
65.2 (CH), 49.2 (C), 46.6 (CH2,), 41.4 (CH2), 36.2 (CH2), 21.8
(CH3), 9.9 (CH2), -1.9 (CH3). MS (ESI) m/z (%): 596 [M+Na]+
(100). HRMS (ESI): [M+Na]+ C27H35N3O5NaSiS2: calcd.
596.1679, found 596.1683.
δ (ppm) = 7.92-7.89 (m, 2H), 7.70 (d, 2H, J= 8.1 Hz), 7.39-7.32
(m, 4H), 7.24 (t, 1H, J= 6.8 Hz), 7.11 (t, 1H, J= 14.8 Hz), 6.06-
6.01 (m, 1H), 5.96-5.85 (m, 3H), 5.10 (d, 1H, J= 3.4 Hz), 3.36
(d, 2H, J= 7.1 Hz), 3.24-3.12 (m, 2H, CH2), 3.09-2.53 (m, 2H),
2.34 (s, 3H), 2.01-1.91 (m), 1.70-1.60 (m), 1.27 (t, 3H, J= 7.3
Hz). 13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 162.1 (C), 140.6
(C), 139.8 (CH), 138.7 (C), 136.6 (C), 134.4 (C), 133.9 (CH),
130.1 (CH), 129.7 (CH), 128.3 (C), 128.2 (CH), 124.8 (C), 124.1
(CH), 123.9 (CH), 123.6 (C), 121.5 (CH), 114.3 (C), 65.4 (CH),
46.7 (C), 46.3 (CH2), 41.2 (CH2), 36.1 (CH2), 7.9 (CH3). MS
(ESI) m/z (%): 538 [M+Na]+ (100), 615 [M+H]+ (56). HRMS
(ESI): [M+Na]+ C25H29N3O5NaS2: calcd. 538.1446, found
538.1452.
4.3.2. N-(2-(1-(2-
(ethylsulfonamido)phenyl)cyclohexa-2,5-
dienyl)ethylcarbamoyl)-4-
4.2.6. (E)-N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-
dihydro-4aH-carbazol-4a-yl)ethyl)-3-
(phenylsulfonyl)acrylamide (17)
methylbenzenesulfonamide (24)
Starting from 7 (100 mg, 0.328 mmol, 1 eq.) and 3,3-bis-
benzenesulfonyl-propionic acid, the crude product was purified
by silica gel chromatography (petroleum ether/ethyl acetate,
80/20 then 50/50) to give 17 (195 mg, 0.3915 mmol, 54 % over 2
steps) as a white solid. M.p. = 147.1-148.9°C. Rf = 0.48
(petroleum ether/ethyl acetate: 50/50). IR (solid, KBr): ν = 3231,
In a 100 ml two-necked round bottom flask, AlCl3 (966 mg,
7.25 mmol, 3 eq.) was dissolved in Et2O (20 mL) at 0°C, then
LiAlH4 (365 mg, 9.64 mmol, 4 eq.) was added. The reaction
mixture was stirred at room temperature for 30 min. Product 5
(700 mg, 2.41 mmol, 1 eq.) was dissolved in Et2O (5 mL) and
THF (5 mL), and added dropwise at 0°C. The reaction mixture
was stirred at room temperature for 18h, then the reaction was
stopped by addition of ice. NaOH 10% (40 mL) was then added
and the reaction mixture stirred for 1h. After addition of ether the
reaction mixture was filtered through celite and extracted with
DCM. The combined organic layers were washed with brine,
dried over sodium sulfate and concentrated in vacuum, affording
the intermediate amine as a viscous oil. To a solution of crude
amine (1 eq.) in DCM (0.1M) at 0°C was added the p-toluene
sulfonyl isocyanate (1 eq.). The reaction was warmed to r.t. and
1
1671, 1476, 1343, 1148, 656 cm-1. H NMR (CDCl3, 300 MHz):
δ (ppm) = 7.55 (d, 2H, J= 7.5 Hz), 7.33-7.30 (m), 7.25-7.20 (m,
2H), 7.04 (d, 1H, J= 8.1 Hz), 6.94-6.82 (m, 2H), 6.80 (t, 1H, J=
8.1 Hz), 6.71-6.67 (m), 6.64-6.58 (m), 6.33 (t, 1H, J= 5.4 Hz),
5.66-5.58 (m, 2H), 5.55-5.53 (m), 5.33 (d, 1H, J= 9.6 Hz), 4.69
(d, 1H, J= 2.6 Hz), 3.06-2.97 (m, 2H), 2.84-2.72 (m, 2), 1.83-
1.69 (m, 1H), 1.58-1.49 (m, 1H), 1.05 (t, 3H, J= 7.3 Hz). 13C
NMR (CDCl3, 75.5 MHz): δ (ppm) = 162.1 (C), 140.6 (C), 139.8
(CH), 138.7 (C), 136.6 (C), 134.4 (C), 133.9 (CH), 130.1 (CH),
129.7 (CH), 128.3 (C), 128.2 (2 CH), 124.8 (C), 124.1 (CH),

7
stirred while monitoring the consumption of the amine by TLC
(2-16h). The reaction mixture was evaporated directly without
extraction. Purification by silica gel chromatography (petroleum
ether/ ethyl acetate, 70/30) afforded 24 (376 mg, 0.747 mmol,
70% over 2 steps) as a white solid. M.p. = 92.1-93.4°C. Rf = 0.26
(petroleum ether/ethyl acetate: 70/30). IR (solid, KBr): ν = 3347,
MHz): δ (ppm) = 7.69-7.64 (m, 2H), 7.57-7.52 (m, 1H), 7.44-
ACCEPTED MANUSCRIPT
7.38 (m, 2H), 7.33-7.26 (m, 3H), 7.03 (t, 1H, J = 7.5 Hz), 6.80
(d, 1H, J = 7.7 Hz), 6.34 (d, 1H, J = 10.3 Hz), 5.84 (d, 1H, J =
7.7 Hz), 3.30 (d, 1H, J = 10.3 Hz), 5.22 (d, 1H, J = 8.6 Hz), 4.65
(s, 1H), 4.11-4.01 (m, 1H), 3.94 (d, 1H, J = 9.03 Hz), 3.75-3.68
(m, 1H), 3.16 (q, 2H, J = 7.3 Hz), 2.40-2.20 (m, 2H), 2.08 (s,
3H), 1.42 (t, 3H, J = 7.3 Hz). 13C NMR (CDCl3, 75.5 MHz): δ
(ppm) = 170.3 (C), 161.9 (C), 141.6 (CH), 140.2 (C), 138.8 (C),
135.2 (C), 134.4 (C), 131.1 (CH), 129.9 (CH), 129.7 (CH), 128.3
(CH), 128.2 (CH), 127.7 (C) 125.1 (CH), 123.1 (C), 114.7 (CH),
70.1 (CH), 65.1 (CH), 64.1 (CH), 52.1 (C), 44.8 (CH2), 43.8
(CH2), 36.3 (CH2), 21.1 (CH3), 7.8 (CH3). MS (ESI) m/z (%): 579
[M+Na]+ (100). HRMS (ESI): [M+Na]+ C27H28N2O7NaS2: calcd.
579.1230, found 579.1244.
1672, 1453, 1335, 1148, 1090, 887 cm-1. H NMR (CDCl3, 300
1
MHz): δ (ppm) = 8.48 (broad s, 1H), 7.45 (d, 2H, J = 8.3 Hz),
7.23 (d, 1H, J = 7.9 Hz), 7.02-6.90 (m, 5H), 6.35 (t, 1H, J= 5.7
Hz), 5.77 (d, 2H, J = 10.2 Hz), 5.15 (d, 2H, J = 10.2 Hz), 3.01-
2.93 (m, 2H), 2.81 (q, 2H, J = 7.3 Hz), 2.65 (ABsystem, 2H, JAB
=
8.3 Hz), 2.08 (s, 3H), 1.75-1.70 (m, 2H), 0.99 (t, 3H, J = 7.3
Hz,). 13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.9 (C), 144.9
(C), 137.6 (C), 136.8 (C), 132.4 (C), 130.1 (CH), 130.1 (CH),
128.6 (CH), 126.9 (CH), 126.8 (CH), 126.2 (CH), 123.9 (CH),
119.3 (CH), 46.5 (CH2), 41.7 (C), 38.8 (CH2), 36.7 (CH2), 25.8
(CH2), 21.7 (CH3), 8.1 (CH3). MS (ESI) m/z (%): 526 [M+Na]+
(100), 504 [M+H]+ (6). HRMS (ESI): [M+Na]+ C24H29N3O5NaS2:
calcd. 526.1440, found 526.1450.
4.4.2. 2-((4aS,9aS)-9-(2-
(trimethylsilyl)ethylsulfonyl)-9,9a-dihydro-4aH-
carbazol-4a-yl)acetonitrile (21)
Starting from 205a (1.8 g, 4.813 mmol, 1 eq.), the reaction was
run 24h at 55°C. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate: 80/20) to give 21
(1.40 g, 3.762 mmol, 78%) as a white solid. M.p. = 92.4-93.3°C.
Rf = 0.16 (petroleum ether/ethyl acetate: 90/10). IR (solid, KBr):
ν = 2958, 1595, 1478, 1342, 1250, 1152, 984, 838, 738, 650 cm-1.
1H NMR (CDCl3, 300 MHz): δ (ppm) = 7.42-7.39 (m, 1H), 7.25-
7.20 (m, 2H), 7.08-7.04 (m, 1H), 6.07 (s, 2H), 6.01-5.97 (m, 1H),
5.74 (d, 1H, J = 9.4 Hz), 5.00 (s, 1H), 3.17-2.97 (m, 2H), 2.82
(ABsystem, 2H, JAB = 25.59 Hz), 1.11-1.04 (m, 2H), 0.0002 (s,
9H). 13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 141.5 (C), 133.2
(C), 129.3 (CH), 127.7 (CH), 124.4 (CH), 124.2 (CH), 123.6
(CH), 123.6 (CH), 122.6 (CH), 116.4 (C), 114.3 (CH), 65.4
(CH), 48.2 (C), 45.6 (CH2), 29.4 (CH2), 9.7 (CH2), -1.9 (CH3).
MS (ESI) m/z (%): 395 [M+Na]+ (100). HRMS (ESI): [M+Na]+
C19H24N2O2NaSiS: calcd. 395.1219, found 395.1224.
4.3.3. Tert-butyl 2-(1-(2-(2-
(trimethylsilyl)ethylsulfonamido)phenyl)cyclohexa-
2,5-dienyl)ethylcarbamate (26)
To a solution of the amine5a (380 mg, 1.005 mmol, 1 eq.) in
THF (10 mL), was added (t-Boc)2O (263 mg, 1.206 mmol, 1.2
eq.). The resulting solution was refluxed at 80°C for 12 h. The
reaction mixture was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over Na2SO4, and
evaporated. Purification by silica gel chromatography (petroleum
ether/ ethyl acetate, 80:20) afforded 26 (275 mg, 0.5750 mmol,
57% over 2 steps) as a white solid. M.p. = 58.3-60.5°C. Rf = 0.51
(petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr): ν = 3350,
1
2954, 1713, 1495, 1336, 1251, 1147, 861, 757 cm-1. H NMR
(CDCl3, 300 MHz): δ (ppm) = 7.58-7.55 (m, 1H), 7.42-7.39 (m,
1H), 7.30-7.25 (m, 1H), 7.15-7.12 (m, 1H), 6.12 (d, 2H, J = 9.4
Hz), 5.55 (d, 2H, J = 9.78 Hz), 4.70 (broad s, 2H), 3.22- 3.20 (m,
2H), 3.07-3.01 (m, 2H), 2.94-2.80 (m, 2H), 2.14-2.09 (m, 2H),
1.47 (s, 9H) 1.04-0.98 (m, 2H), 0.00 (s, 9H). 13C NMR (CDCl3,
75.5 MHz): δ (ppm) = 158.1 (C), 139.8 (C), 134.7 (C), 132.4
(CH), 130.4 (CH), 128.5 (CH), 128.3 (CH), 125.9 (CH), 121.4
(CH), 81.4 (C), 50.5 (CH2), 43.7 (C), 41.3 (CH2), 38.9 (CH2),
30.5 (CH3), 27.8 (CH2), 12.1 (CH2), 0.0 (CH3). MS (ESI) m/z
(%):501 [M+Na]+ (100), 479 [M+H]+ (46), 379 [(M+H)-Boc]+
(73). HRMS (ESI): [M+Na]+ C24H38N2O4NaSSi: calcd. 501.2361,
found 501.2361.
4.4.3. Product (23)
Starting from 22 (152 mg, 0.264 mmol, 1 eq.), the reaction
was run 24h at 55°C. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 90/10), affording
23 (80 mg, 0.140 mmol, 53%) as a white solid. M.p. = 239.3-
241.1°C. Rf = 0.63 (petroleum ether/ ethyl acetate: 80/20). IR
(solid, KBr): ν = 2924, 1737, 1478, 1348, 1164, 840, 663 cm-1.
1H NMR (CDCl3, 300 MHz): δ (ppm) = 7.98 (d, 2H, J = 8.3 Hz),
7.29 (m, 4H), 7.10-7.09 (m, 1H), 7.08-7.06 (m, 1H), 6.10-5.97
(m, 2H), 4.92-4.88 (m, 1H), 4.61 (d, 1H, J = 8.3 Hz), 4.40 (s,
1H), 3.51-3.37 (m, 2H), 3.11-3.05 (m, 2H), 2.47-2.41 (m, 1H),
2.40 (s, 3H), 2.23-1.11 (m, 1H), 1.10-1.04 (m, 2H), 0.02 (s, 9H).
13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.7 (C), 144.8 (C),
140.5 (C), 136.6 (C), 131.7 (C), 130.3 (CH), 129.7 (CH), 129.6
(CH), 128.2 (CH), 124.5 (CH), 124.3 (CH,), 122.9 (CH), 114.8
(CH), 62.7 (CH), 57.4 (CH), 52.1 (CH), 50.2 (C), 49.6 (CH2),
42.8 (CH2), 41.9 (CH2), 21.8 (CH3), 10.3 (CH2), -1.9 (CH3). MS
(ESI) m/z (%): 594 [M+Na]+ (100), 572 [M+H]+ (8). HRMS
(ESI): [M+Na]+ C27H35N3O5NaSiS2: calcd. 594.1523, found
594.1546.
4.4. General procedure for palladium oxidative amination
Starting material (1 eq.) and sodium acetate (2 eq.) were
dissolved in DMSO (0.1M) and the solution was flushed with
dioxygen. Pd(OAc)2 (0.1 eq.) and charcoal (approx. same mass as
Pd(OAc)2) were added and the resulting solution was stirred for
24h at 55-90°C. The reaction mixture was diluted with a large
volume of water and was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure
before purification by silica gel chromatography.
4.4.4. Product (25)
Starting from 24 (150 mg, 0.298 mmol, 1 eq.), the reaction
was run 24h at 55°C. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 90/10), affording
25 (107 mg, 0.214 mmol, 72%) as a white solid. M.p. = 217.7-
219.1°C. Rf = 0.48 (petroleum ether/ ethyl acetate: 50/50). IR
(solid, KBr): ν = 2972, 1734, 1478, 1384, 1154, 763, 663 cm-1.
1H NMR (CDCl3, 300 MHz): δ (ppm) = 7.87 (d, 2H, J = 8.3
Hz), 7.28-7.18 (m, 4H), 7.15-7.10 (m, 1H), 7.04 (t, 1H, J = 7.3
Hz), 6.01 (t, 2H, J = 14.3 Hz), 4.84-4.81 (m, 1H), 4.55 (d, 1H, J
= 8.3 Hz), 4.33 (s, 1H), 3.43-3.29 (m, 2H), 3.16 (q, 2H, J = 7.4
4.4.1. (3aR,4R,6aS,11a1R)-7-(ethylsulfonyl)-3-((E)-
3-(phenylsulfonyl)acryloyl)-2,3,3a,4,6a,7-
hexahydro-1H-pyrrolo[2,3-d]carbazol-4-yl acetate
(18)
Starting from 17 (169 mg, 0.338 mmol, 1 eq.), the reaction
was run 24h at 55°C. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate, 80:20) to give 18
(49 mg, 0.0881 mmol, 26%) as an oily product. Rf = 0.48
(petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr): ν = 2981,
1
1739, 1648, 1420, 1348, 1151, 671 cm-1. H NMR (CDCl3, 300

8
Tetrahedron
ACCEPTED MANUSCRIPT
Hz), 2.40-2.38 (m, 1H), 2.35 (s, 3H), 2.21-2.10 (m, 1H), 1.36 (t,
was removed under vacuum, and the residue was partitioned
3H, J = 7.3 Hz). 13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.6
(C), 144.8 (C), 140.2 (C), 136.7 (C), 131.7 (C), 130.4 (CH),
129.7 (CH), 129.6 (CH), 128.2 (CH), 124.5 (CH), 124.3 (CH),
123.1 (CH), 114.8 (CH), 62.7 (CH), 57.5 (CH), 52.1 (CH), 50.1
(C), 47.2 (CH2), 43.1 (CH2), 41.8 (CH2), 21.7 (CH3), 8.2 (CH3).
MS (ESI) m/z (%): 522 [M+Na]+ (100), 500 [M+H]+ (10). HRMS
(ESI): [M+Na]+ C24H25N3O5NaS2: calcd. 522.1127, found
522.1144.
between H2O and CH2Cl2. The dried organic extracts were
concentrated under vacuum. Purification by silica gel
chromatography (Hexane/ethyl acetate: 8/2) afforded 31 (164
mg, 0.267 mmol, 72% over 2 steps) as a white solid. M.p. =
134.3-135.6°C. Rf = 0.65 (petroleum ether/ ethyl acetate: 80/20).
IR (solid, KBr): ν = 2950, 1731, 1476, 1340, 1232, 1100, 970,
840, 698 cm-1. 1H NMR (CDCl3, 300 MHz): δ (ppm) = 7.33-7.25
(m, 1H), 7.16-7.11 (m, 1H), 7.05-7.00 m, 1H), 6.08-6.04 (m, 1H),
5.90 (q, 1H, J = 6.03 Hz), 5.81-5.76 (m, 1H), 5.23 (s, 1H), 4.59
(s, 1H), 3.93 (AB system, 2H, JAB = 140.1 Hz), 3.29 (d, 1H, J = 3.8
Hz), 3.20-3.12 (m, 1H), 3.09-3.02 (m, 2H), 2.69-2.61 (m, 1H),
2.10-1.91 (m, 2H), 1.85 (s, 3H), 1.77 (d, 3H, J = 6.4 Hz), 1.10-
1.04 (m, 2H), 0.00 (s, 9H). 13C NMR (CDCl3, 75.5 MHz): δ
(ppm) = 170.4 (C), 140.1 (C), 135.8 (C), 130.9 (CH), 130.2
(CH), 128.6 (CH), 125.7 (CH), 123.8 (CH), 123.6 (CH), 114.3
(CH), 109.4 (C), 67.9 (CH), 66.5 (CH), 66.4 (CH2), 66.1 (CH),
51.4 (C), 50.1 (CH2), 48.4 (CH2), 40.1 (CH2), 21.6 (CH3,, 20.9
(CH3) 10.1 (CH2), -1.9 (CH3). MS (ESI) m/z (%):615 [M+H]+
(100), 637 [M+Na]+ (70). HRMS (ESI): [M+H]+ C25H36IN2O4SSi:
calcd. 615.1209, found 615.1216.
4.4.5. (3aR,4R,6aS,11a1R)-tert-butyl 4-acetoxy-7-
(2-(trimethylsilyl)ethylsulfonyl)-3a,4,6a,7-
tetrahydro-1H-pyrrolo[2,3-d]carbazole-3(2H)-
carboxylate (27)
Starting from 26 (1.070 g, 2.248 mmol, 1 eq.), the reaction
was run 24h at 55°C. The crude product was purified by silica gel
chromatography (petroleum ether/ethyl acetate 90:10) to give 27
(0.880 mg, 1.647 mmol, 72%) as a colorless oil. Rf = 0.41
(petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl): ν =
3354, 2814, 1668, 1478, 1171, 1055, 844, 766 cm-1. H NMR
1
(CDCl3, 300 MHz): δ (ppm) = 7.32-7.22 (m, 2H), 7.05-6.99 (m,
2H), 6.27-6.16 (m, 1H), 6.10-6.04 (m, 1H), 5.52 (s, 1H), 4.61 (s,
1H), 4.21 (s, 1H), 3.63 (broad s, 2H), 3.03-2.97 (m, 2H), 2.16-
2.07 (m, 2H), 1.62 (s, 3H), 1.50 (s, 9H), 1.06-1.01 (m, 2H), 0.00
(s, 9H). 13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 169.8 (C),
154.4 (C), 154.1 (C), 141.4 (CH), 137.9 (C), 137.3 (C), 128.8
(CH), 123.9 (CH), 122.3 (C), 113.7 (CH), 80.4 (C), 68.7 (CH),
67.5 (CH), 60.1 (CH), 53.7 (C), 47.8 (CH2), 43.8 (CH2), 40.3
(CH2), 28.5 (CH3), 20.30 (CH3), 9.9 (CH2), -2.0 (CH3). MS (ESI)
m/z (%): 557 [M+Na]+(100). HRMS (ESI): [M+Na]+ C26H38N2O6
NaSSi: calcd.557.2112, found 557.2108.
4.5.3. (3aR,4R,6aS,11a1S)-3-((Z)-2-iodobut-2-
enyl)-2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3-
d] carbazol-4-yl acetate. (32)
CsF (1.854 g, 13.9 mmol, 15 eq.) was added to a solution of
product 31 (0.5 g, 0.814 mmol, 1 eq.) in CH3CN (40 mL). The
resulting suspension was heated at 80°C for 30h. After cooling to
r.t., the solvent was removed under vacuum. Purification by silica
gel chromatography (deactivated silica gel, DCM/methanol:
95/5) afforded 32 (214 mg, 0.475 mmol, 58%) as a brown oil. Rf
= 0.26 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl): ν
4.5. Synthesis of strychnos skeleton
= 3368, 1731, 1606, 1484, 1369, 1238, 1022, 969, 743 cm-1. H
1
NMR (CDCl3, 300 MHz): δ (ppm) = 7.10-7.06 (m, 2H), 6.77 (t,
1H, J = 7.5 Hz), 6.68 (d, 1H, J = 7.8 Hz), 5.97 (q, 1H, J = 6.4
Hz), 5.79-5.70 (m, 2H), 5.30 (s, 1H), 4.01 (s, 1H), 3.95 (d, 1H, J
= 14.3 Hz), 3.89 (s, 1H), 3.51 (d, 1H, J= 14.3 Hz), 3.23 (d, 1H, J
= 4.1 Hz), 3.14-3.07 (m, 1H), 2.72-2.64 (m, 1H), 2.16-2.07 (m,
2H), 1.96 (s, 3H), 1.82 (d, 3H, J= 6.4 Hz). 13C NMR (CDCl3,
75.5 MHz): δ (ppm) = 170.8 (C), 148.7 (C), 133.9 (C), 131.52
(CH), 130.6 (CH), 128.05 (CH), 125.5 (CH), 123.7 (CH), 119
(CH) 110.2 (C), 109.9 (CH), 69.7 (CH), 67.1 (CH), 66.7 (CH2),
62.1 (CH), 52.7 (C), 50.3 (CH2), 38.7 (CH2), 21.7 (CH3), 21.3
(CH3). MS (ESI) m/z (%):451 [M+H]+ (100), 473 [M+Na]+ (12),
391 [(M+H)-OAc]+ (11). HRMS (ESI): [M+H]+ C20H24IN2O2:
calcd. 451.0877, found 451.0882.
4.5.1. (3aR,4R,6aS,11a1S)-tert-butyl 4-acetoxy-7-
((Z)-3-bromoacryloyl)-3a,4,6a,7-tetrahydro-1H-
pyrrolo[2,3-d]carbazole-3(2H)-carboxylate (28)
3-bromoacryloyl chloride (206 mg, 1.216 mmol, 1.5 eq) was
added to the crude amine (300 mg, 0.810 mmol, 1 eq) in CH2Cl2
(10 mL), then triethylamine (1.5 eq), EDAC (1.5 eq) was added
to this mixture. The reaction mixture was stirred for 6h at room
temperature. Then the reaction was stopped by addition of H2O
(20 mL), extracted with EtOAc. The combined organic layers
were washed with brine, dried over sodium sulfate and
concentrated in vacuo. The crude reaction mixture was purified
by silica gel chromatography (petroleum ether/ethyl acetate
70:30) to provide 28 (162 mg, 0.3226 mmol, 40%) as a yellow
solid. M.p. = 92.9-94.6°C. Rf = 0.41 (petroleum ether/ethyl
acetate: 80/20). IR (solid, KBr): 2976, 1739, 1696, 1480, 1391,
4.5.4. Product (33)
A solution of 32 (190 mg, 0.422 mmol, 1 eq.), Pd(OAc)2 (9
mg, 0.0411 mmol, 0.1 eq.), K2CO3 (284 mg, 2.055 mmol, 5 eq.)
and Bu4NCl (1165 mg, 0.419 mmol, 1 eq.) in DMF (4 mL) was
warmed at 60°C for 3 h. After cooling to room temperature, Et2O
was added and the organic layer was washed with brine, dried
over Na2SO4, and concentrated under vacuum. Purification by
silica gel chromatography (Diethyl ether/triethylamine: 98/2)
afforded 33 (60 mg, 0.186 mmol, 44%) as a yellow solid. Rf =
0.48 (Diethyl ether /triethylamine: 95/5). M.p. = 104.7-105.9°C.
IR (solid, KBr): ν = 3368, 1731, 1606, 1484, 1369, 1238, 1022,
1
1239, 1170, 932, 753, 659 cm-1. H NMR (CDCl3, 300 MHz): δ
(ppm) = 7.72 (d, 1H, J = 9.6 Hz), 7.28-7.24 (m, 2H), 7.10-7.02
(m, 3H), 5.92 (s, 2H), 5.50 (s, 1H), 4.72 (s, 1H), 4.06 (s, 1H),
3.76 (s, 1H), 3.50 (s, 1H), 2.16 (s, 2H), 1.94 (s, 3H), 1.48 (s, 9H).
13C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.5 (C), 161.8 (C),
155.2 (C), 140.22 (C), 136.5 (C), 129.4 (CH), 128.9 (CH), 128.6
(C), 126.6 (C), 125.4 (CH), 122.9 (CH), 80.6 (C), 69.03 (CH),
64.02 (CH), 63.3 (CH), 52.1 (C), 45.03 (CH2), 38.7 (CH2), 28.6
(CH3), 21.1 (CH3). HRMS (ESI): [M+Na]+ C24H27N2O5 Br Na:
calcd. 525.1001, found 525.0997.
1
969, 743 cm-1. H NMR (CDCl3, 300 MHz): δ (ppm) = 7.55 (d,
1H, J = 7.9 Hz), 7.32-7.28 (m, 2H), 7.20-7.15 (m, 1H), 5.49 (q,
1H, J = 6.8 Hz), 5.09 (t, 1H, J = 3.4 Hz), 4.17 (d, 1H, J = 2.6
Hz), 3.80 (d, 1H, J = 15.5 Hz), 3.43 (s, 1H), 3.39-3.19 (m, 4H),
2.81 (d, 1H, J = 13.5 Hz), 2.26-2.17 (m, 1H), 2.12-2.03 (m, 1H),
1.69 (d, 3H, J = 6.8 Hz), 1.42 (s, 3H). 13C NMR (CDCl3, 75.5
MHz): δ (ppm) = 187.2 (C), 169.5 (C), 154.5 (C), 144.2 (C),
139.4 (C), 127.4 (CH), 124.9 (CH), 120.9 (CH), 120.6 (CH),
119.6 (CH) 69.2 (CH), 67.2 (CH), 63.2 (C), 55.2 (CH2), 52.9
4.5.2. (3aR,4R,6aS,11a1R)-3-((Z)-2-iodobut-2-
enyl)-7-(2-(trimethylsilyl)ethylsulfonyl)-
2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3-
d] carbazol-4-yl acetate (31)
To a solution of crude 30 (160 mg, 0.37 mmol, 1 eq.) in
CH3CN (6 mL) were added anhydrous K2CO3 (110 mg, 0.74
mmol, 2 eq.) and (Z)-1-bromo-2-iodo-2-butene (193 mg, 0.74
mmol, 2 eq.). The mixture was stirred at r.t. for 3 h. The solvent

9
Heureux, N.; Wouters, J.; Marko, I. E. Org. Lett. 2005, 7, 5245-
5248.
8. Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais Y. Org.
Lett. 2007, 9, 3913-3916.
9. Rönn, M.; Bäckvall, J. E.; Anderson, P. G. Tetrahedron Lett.
1995, 36, 7749-7752.
10. a) Lebeuf, R.; Dunet, J.; Beniazza, R.; Ibrahim, D.; Bose, G.;
Robert, F.; Landais Y. J. Org. Chem. 2009, 74, 6469-6478; b)
Lebeuf, R.; Robert, F.; Landais, Y. Org. Lett. 2005, 7, 4557.
11. a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420;
Angew. Chem., 2004, 116, 3480-3501; b) Gligorich, K. M.;
Sigman, M. S. Angew. Chem., Int. Ed. 2006, 45, 6612-6615;
Angew. Chem., 2006, 118, 6764-6767.
12. a) Mahaim, C.; Carrupt, P.-A.; Hagenbuch, J-P.; Florey, A.;
Vogel, P. Helv. Chim. Acta 1980, 63, 1149; b) Steunenberg, P.;
Jeanneret, V.; Zhu, Y.-H.; Vogel, P. Tetrahedron: Asymmetry
2005, 16, 337.
(CH2), 35.9 (CH2), 34.1 (CH), 33.4 (CH2), 19.8 (CH3), 12.8
(CH3). MS (ESI) m/z (%): 345 [M+Na]+, 323 [M+H]+, 263 [M-
Ac+H]+. HRMS (ESI): [M+Na]+ C20H22N2O2Na: calcd. 345.1579,
found 345.1600.
ACCEPTED MANUSCRIPT
4.5.5. Product (35)
To a solution of NaH (7.5 mg, 0.3105 mmol, 2 eq.) in THF (2
mL) cooled at 0°C was added dropwise a solution of the imine 33
(50 mg, 0.1552 mmol, 1 eq.) in THF (1 mL) over 25 min. After
40 min, methyl chloroformate (0.02 mL, 0.0.465 mmol, 3 eq.)
was added over 5 min. The resulting mixture was stirred at -20°C
for 12h and then poured into brine (20 mL). The organic layer
was separated, and the aqueous layer was extracted with ether.
The combined extracts were washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude reaction mixture
was purified by silica gel chromatography (diethyl
ether/triethylamine 99:1 then 95:5) to provide 35 (26 mg, 0.0686
mmol, 44%) as a white solid. M.p. = 143.4-144.7°C. Rf = 0.41
(petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr) ν= 3456,
13. Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J.
Org. Chem. 1996, 61, 3584-3585.
14. Bao, X.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2018, 57, 1995-
1999; Angew. Chem. 2018, 130, 2013-2017.
15. a) Kuehne, M. E.; Pitner J. B. J. Org. Chem. 1989, 54, 4553-4569;
b) Khuong-Huu, F.; Cesario, F.; Guilhem, J.; Goutarel, R.
Tetrahedron 1976, 32, 2539-2543.
1
2962, 1733, 1474, 1360, 1230, 1059, 757, 603 cm-1. H NMR
(CDCl3, 300 MHz): δ (ppm) = 7.75 (d, 1H, J = 5.85 Hz), 7.07-
7.01 (m, 1H), 7.01 (d, 1H, J = 4.74 Hz), 6.99 (t, 1H, J = 4.74
Hz), 6.07 (d, 1H, J = 6.06 Hz), 5.45-5.39 (q, 1H, J = 5.13 Hz),
5.25 (t, 1H, J = 2.64 Hz), 4.17-4.16 (m, 1H), 3.91 (s, 3H), 3.61
(d, 2H, J = 11.19 Hz), 3.57-2.96 (m, 1H), 2.95-2.93 (m, 1H),
2.82-2.75 (m, 1H), 2.26-2.20 (m, 1H), 1.82-1.75 (m, 1H), 1.70 (d,
3H, J = 5.13 Hz), 1.46 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): δ
(ppm) = 170.4 (C), 153.2 (C), 145.5 (C), 140.7 (C), 135.7 (C),
134.3 (C), 127.3 (C), 123.7 (CH), 121.8 (C), 119.8 (CH), 115.2
(CH), 108.5 (CH), 69.1 (CH), 60.2 (CH), 52.9 (CH3), 52.8 (C),
52.4 (CH2), 52.1 (CH2), 41.1 (CH2), 35.7 (CH), 20.57 (CH3,
OAc), 13.2 (CH3). MS (ESI) m/z (%): 381[M+H]+(100). HRMS
(ESI): [M+H]+ C22H25N2O4: calcd. 381.1808, found 381.1808.
16. a) Kuehne, M. E.; Dai, W.; Li, Y.-L. J. Org. Chem. 2001, 66,
1560-1566; b) Kuehne, M. E.; Bandarage, U. K.; Hammach, A.;
Li, Y.-L.; Wang, T. J. Org. Chem. 1998, 63, 2172-2183; c)
Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61,
7873-7881.
17. a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030-3031; b) Rawal, V. H.; Michoud, C. J. Org.
Chem. 1993, 58, 5583-5584.
18. For dehydrotubifoline synthesis see: He, W.; Hu, J.; Wang, P.;
Chen, L.; Ji, K.; Yang, S.; Li, Y.; Xie, Z.; Xie, W. Angew. Chem.
Int. Ed. 2018, 57, 3806-3809; Angew. Chem. 2018, 130, 3868-
3871 and references cited therein.
19. For recent examples see: a) Kang, T.; White, K. L.; Mann, T. J.;
Hoveyda, A. H.; Movassaghi, M. Angew. Chem. Int. Ed. 2017, 56,
13857-13860; Angew. Chem. 2017, 129, 14045-14048; b) Zhao,
S.; Andrade, R. B. J. Org. Chem. 2017, 82, 521-531; c) Kim, J.-
Y.; Suhl, C.-H.; Lee, J.-H.; Cho, C.-G. Org. Lett. 2017, 19, 6168-
6171.
Acknowledgments
20. Mander, L. N. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 5, pp 3466-
3469.
We thank the CNRS, and MNERT for financial support as
well as UNESCO for a Ph.D. grant to D.H.D.
21. a) Bonjoch, J.; Solé, D.; Garcia-Rubio, S.; Bosch, J. J. Am. Chem.
Soc. 1997, 119, 7230-7240; b) Gràcia, J.; Casamitjana, N.;
Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59, 3939-3951; c)
Amat, A.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299-
6312.
References
1. a) Tietze, L. F.; Domino Reactions: Concepts for Efficient
Organic Synthesis; Eds.; Wiley-VCH: Weinheim, 2014; b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger P. G. Angew. Chem. Int.
Ed. 2006, 45, 7134-7186; c) Fogg, D. E.; dos Santos, E. N. Coord.
Chem. Rev. 2004, 248, 2365-2379; d) Tietze, L. F. Chem. Rev.
1996, 96, 115-136.
2. a) Nakahara, K.; Fujioka, H. Symmetry 2010, 2, 437-454; b)
Studer, A.; Schleth, F. Synlett 2005, 3033-3041; c) Abd Rahman,
N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369-1395.
3. For example see: a) Rousseau, G.; Lebeuf, R.; Schenk, K.; Castet,
F.; Robert, F.; Landais, Y. Chem. Eur. J. 2014, 20, 14771-14782;
b) Dunet, J.; Lebeuf, R.; Bose, G.; Robert, F.; Landais, Y. Org.
Lett. 2010, 12, 2178-2181; c) Lebeuf, R.; Robert, F.; Schenk, K.;
Landais, Y. Org. Lett. 2006, 7, 4755-4758.
4. a) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Chem.
Rev. 2016, 116, 7330-7396; b) Lebeuf, R.; Robert, F.; Landais, Y.
Arkivoc 2014, (iii), 6-17; c) Rousseau, G.; Robert, F.; Landais, Y.
Chem. Eur. J. 2009, 15, 11160-11173; d) Rousseau, G.; Robert,
F.; Schenk, K.; Landais, Y. Org. Lett. 2008, 10, 4441-4444.
5. a) Ibrahim, D. H.; Dunet, J.; Robert, F.; Landais, Y. Heterocycles
2018, 97, DOI: 10.3987/COM-18-S(T)36; b) Gu, Q.; You, S.-L.
Chem. Sci. 2011, 2, 1519-1522; c) Pereira, J.; Barlier, M.; Guillou,
C. Org. Lett. 2007, 9, 3101-3103.
6. Wang, Y.; Xie, Y. F.; Lin, B.; Cheng, M.; Liu, Y. Chem. Eur. J.
2018, DOI: 10.1002/chem.201800775.
7. a) Buchi, G.; Matsumoto, K.; Nishimura, H. J. Am. Chem. Soc.
1971, 93, 3299-3301; b) Ando, M.; Buchi, G.; Ohnuma, T. J. Am.
Chem. Soc. 1975, 97, 6880-6881; c) Winkler, J. D.; Scott, R. D.;
Williard, P. G. J. Am. Chem. Soc. 1990, 112, 9871-8975; d)