A Photoredox Catalysis Approach for the Synthesis of Both the ABDE and the ABCD Cores of Tronocarpine

Article abstract of DOI:10.1055/s-0039-1690208

A general strategy for the facile construction of both the ABDE and ABCD cores of tronocarpine, chippiine and dippinine alkaloids through the retrosynthetic disconnection of the polycyclic motifs into an indole or tryptamine fragment and a suitably functionalized alkyl chain is presented. The approach is enabled by an efficient Ir(III)-catalyzed, photoredox-mediated radical addition of tetramethyl 1-bromopentane-1,1,3,5-tetracarboxylate and dimethyl 2-bromopentanedioate selectively at C-2 of the indole. Subsequent intramolecular cyclization events furnish the desired ABDE and ABCD polycyclic cores in good preparative yields.

Full text of DOI:10.1055/s-0039-1690208

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
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en
D. A. Contreras-Cruz et al.
Paper
Synthesis
A Photoredox Catalysis Approach for the Synthesis of Both the
ABDE and the ABCD Cores of Tronocarpine
David A. Contreras-Cruza,b
Mario Castañón-Garcíaa
Enrique Becerril-Rodrígueza
Luis D. Miranda*a
0
0
0
0-
0
0
0
2-9
7
6
5-7
0
9
7
CO2Me
Photoredox
C-2 selective alkylation
B
OH
A
D
NH
N
A
R
C
E
B
N
O
CO2Me
R1
CO2Me
O
or
Br
MeO2C
H
D
NH
C
E
N
HO
a Instituto de Química, Universidad Nacional Autónoma de
México, Ciudad Universitaria, Ciudad de México, 04510,
México
O
H
B
A
O
D
N
R2
Tronocarpine
O
lmiranda@unam.mx
Three-step protocol
b Facultad de Estudios Superiores Zaragoza, Universidad
Nacional Autónoma de México, Ciudad de México, 09230,
Mexico
Dedicated to Dr. Joseph M. Muchowski on the occasion of his
82nd birthday
Received: 09.08.2019
Accepted after revision: 12.09.2019
Published online: 08.10.2019
iboga alkaloids. Several contributions to the syntheses of
the ABCD core of tronocarpine (1) have been reported to
date.9 On the other hand, the tetracyclic ABDE substructure
5 was achieved in 2009 by Sapeta and Kerr using an intra-
molecular Mn(III)-mediated malonate oxidative cyclization
as the pivotal step.10 In 2014, Martínez et al. reported the
most advanced approach towards the full tronocarpine
framework, featuring an intermolecular oxidative xanthate-
based radical addition to N-Boc-tryptamine to install a
malonate unit, which was linearly elaborated further into
the ABCDE pentacycle 6.11 Recently, in 2019, Han’s group
reported the semi-synthesis of the pentacyclic alkaloid (+)-
dippinine B (3) from commercially available (+)-catha-
ranthine via a biosynthetically inspired route.12
DOI: 10.1055/s-0039-1690208; Art ID: ss-2019-m0446-op
Abstract A general strategy for the facile construction of both the
ABDE and ABCD cores of tronocarpine, chippiine and dippinine alkaloids
through the retrosynthetic disconnection of the polycyclic motifs into
an indole or tryptamine fragment and a suitably functionalized alkyl
chain is presented. The approach is enabled by an efficient Ir(III)-cata-
lyzed, photoredox-mediated radical addition of tetramethyl 1-bro-
mopentane-1,1,3,5-tetracarboxylate and dimethyl 2-bromopen-
tanedioate selectively at C-2 of the indole. Subsequent intramolecular
cyclization events furnish the desired ABDE and ABCD polycyclic cores
in good preparative yields.
Key words indoles, alkaloids, radicals, photoredox catalysis, trono-
carpine
NH
NH
E
NH
C
D
O
A
C
C
D
B
N
Tabernaemontana (Apocynaceae) is a genus of plants
with more than one hundred species known, which are dis-
tributed throughout the tropical regions, mainly in Ameri-
ca, Africa, and Asia, where they have been used in tradition-
al medicine for the treatment of hypertension, sore throats
and abdominal pain.1,2 Among monoterpene indole alka-
loids isolated from this species (Tabernaemontana sp.) are
tronocarpine (1),3 10,11-demethoxychippiine (2),4 dip-
pinine B (3) and dippinine C (4),5,6 which are presumably
biosynthesized from iboganes.7 In vitro assays showed ap-
preciable cytotoxic activity of 2 against KB cells, while com-
pounds 3 and 4 were able to reverse multidrug resistance in
vincristine-resistant KB cells.8 These four alkaloids share a
very similar pentacyclic ABCDE ring system, with the main
difference between 1 and 2–4 being a rearranged junction
of the E ring (Figure 1). Other important shared structural
features are the presence of a hemiaminal function in the D
ring and a quaternary carbon fusing the CDE rings. These
intriguing structures have motivated some research groups
to develop synthetic approaches to such monomeric post-
B
N
A
O
B
N
A
D
E
H
CO2Me
E
CO2Me
O
HO
HO
H
2
HO
1
3
NH
N
O
C
C
D
A
B
N
O
O
A
B
N
D
B
E
A
D
E
N
CO2Me
CO2Me
E
O
CO2Me
6
H
HO
5
4
Figure 1 Tronocarpine (1), 10,11-demethoxychippiine (2), dippinine B
(3), dippinine C (4) and advanced intermediates reported for trono-
carpine
Closer examination of compounds 1–4, and many other
related indole monoterpenoid alkaloids, reveals a C-2 al-
kylated tryptamine basic structure (Figure 1, highlighted in
red). Accordingly, a direct C–H alkylation (C–C bond forma-
tion) at C-2 of the indole nucleus (e.g., tryptamine) with a
suitably functionalized alkyl skeleton would yield valuable
synthetic intermediates for practical entries into this type
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. A. Contreras-Cruz et al.
Paper
Synthesis
of molecules (see Scheme 1). Incidentally, the innate C-2 in-
stallation of selected alkyl moieties via direct radical oxida-
tive addition onto the indole nucleus, either with or with-
out substitution at C-3, has been well documented.13 This
issue is in sharp contrast with the classic electrophilic sub-
stitution at C-3. In 2003, we reported an efficient xanthate-
based radical oxidative addition for the direct installation of
an acetate moiety at C-2 of the indole nucleus.13c Extension
to malonyl radicals to functionalize N-Boc-tryptamine was
further described by us in 2009.9e In the last decade pho-
toredox catalysis has become a powerful and promising tool
that makes feasible several reactions that were once consid-
ered difficult to achieve.14 In this context, the research
group of Stephenson reported the catalytic photoredox C-2
selective functionalization of indoles employing bromom-
alonates as the source of secondary15 and tertiary16 malonyl
radicals.
Based on these precedents, the present study was de-
signed to test the hypothesis that indole derivatives 9 might
be homolytically alkylated with dimethyl 2-bromoglutarate
derivatives 10 under photocatalytic conditions. Should this
hypothesis prove to be realizable, the resulting adducts 11
will contain the complete basic functionality to be ad-
vanced to either the common ABDE skeleton (through a
Dieckmann condensation/lactamization sequence) or to the
ABCD framework (via a double lactamization sequence)
present in the alkaloids 1–4, as depicted retrosynthetically
in Scheme 1.
CO2Me
CO2Me
13
n-Bu3P
CH3CN
r.t.
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
NaH
NBS
THF
MeO2C
MeO2C
Br
CO2Me
MeO2C
CO2Me
0 °C to r.t.
99%
84%
14
12
10a
Scheme 2 Synthetic route to bromomalonate 10a
cent to the position 2 of the heterocyclic ring, as shown in
Table 1. The source of monochromatic visible light was a 30
W hand-made apparatus constructed with an array of blue
LEDs (450–452 nm), which kept the irradiation chamber at
a constant temperature of 28 °C with the aid of a fan.20 The
reactions were carried out in 4 mL glass vials and indole
(9a) was used in excess with the intention to efficiently
trap the fleeting malonyl radical (Table 1, entries 1 and 3).
Gratifyingly, when Ru(bpy)3Cl2·6H2O was used, the expect-
ed 2-substitued indole 11a was obtained in 79% yield (Table
1, entry 1); however, a dramatic drop in the yield (33%) was
observed when the reaction was scaled up (Table 1, entry
2), probably due to decreased photon penetration into the
round-bottomed flask in comparison to the vials, which
hampered the excitation of the photocatalyst and therefore
the formation of the malonyl radical. Finally, when Ir(ppy)3
was used as the photocatalyst, the desired product 11a was
obtained in quantitative yield (Table 1, entry 3). It is im-
portant to note that the excess starting indole could be re-
covered by flash column chromatography to be reused with
no detriment to the observed yields. On the contrary, at-
tempts to carry out this photoredox radical addition failed
with 3-substituted indoles such as N-Boc-tryptamine (9b)
and N-Cbz-tryptamine (9c).
R
CO2Me
Br
R1
H
+
N
MeO2C
H
R2
9a R = H
9b R = CH2CH2NHBoc
9c R = CH2CH2NHCbz
10a R1 = CO2Me
R2 = CH2CH2CO2Me
10b R1 = H, R2 = H
Dieckmann
condensation
Table 1 Screened Conditions for the Photoredox-Initiated Radical Ad-
dition of 10a to Indole
Homolytic
substitution
CO2Me
OH
N
O
CO2Me
R
CO2Me
R1
7
Lactamization
N
H
N
H
NH
O
9a (5 equiv)
Photocatalyst (1 mol%)
2,6-Lutidine (1 equiv)
CH3CN (2.6 M)
+
MeO2C
3
CO2Me
CO2Me
R2
2
CO2Me
CO2Me
N
N
1H
MeO2C
11a
Br
Lactamization
11a–c
O
CO2Me
30 W Blue LEDs
(450 nm)
8
CO2Me
MeO2C
28 °C
Scheme 1 Retrosynthesis of the polycyclic systems 7 and 8
10a (1 equiv)
Thus, our work commenced with the synthesis of bro-
momalonate 10a by a phosphine-catalyzed Michael addi-
tion of dimethyl malonate (13) to the ,-unsaturated ester
12.17,18 Next, bromination of the elongated-chain malonate
14 with N-bromosuccinimide in a basic medium furnished
the desired bromomalonate 10a on gram scale and in prac-
tically quantitative yield (Scheme 2).
Entry
Catalyst
Time (h)
Yield (%)
1
2
3
Ru(bpy)3Cl2·6H2O
Ru(bpy)3Cl2·6H2O
Ir(ppy)3
17
20
17
79a
33b
100a
a Indole (9a) (0.26 mmol) was used.
b Indole (9a) (13 mmol) was used.
The visible-light photoredox radical addition to indole
(9a) employing bromomalonate 10a as a radical precursor
proved to be a very efficient route for generating the (gen-
erally regarded as challenging19) quaternary carbon adja-
With the quaternary indolyl-malonate 11a in hand, ex-
perimentation towards the construction of the title alkaloid
polycyclic substructures was carried out. To this end, intra-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

C
D. A. Contreras-Cruz et al.
Paper
Synthesis
molecular cyclization of coupled indole 11a promoted by
potassium carbonate gave the indole-lactam 15 in 89% yield
(Scheme 3). This compound was unambiguously character-
ized by NMR spectroscopy and single-crystal X-ray analy-
sis.21
dine, blue LEDs] (Scheme 5). Again, only the products 11b
and 11c of C-2 indole alkylation were observed, and only in
moderate yields. To our delight, cyclization of the coupled
indoles 11b and 11c in basic medium furnished the pyrido-
indoles 16b and 16c, respectively, in excellent yields. Final-
ly, removal of the protecting group in 16b or 16c led to
spontaneous lactamization to yield the desired ABCD tetra-
cycle 8 in moderate isolated yields. Moreover, a single crys-
tal of 8 was secured allowing its unequivocal structural as-
sessment by X-ray crystallography.21
CO2Me
CO2Me
K2CO3
CH3CN
CO2Me
CO2Me
N
H
N
Reflux
89%
CO2Me
CO2Me
MeO2C
O
15
11a
In conclusion, we have demonstrated our retrosynthetic
concept that dissects the Tabernaemontana and related al-
kaloids into an indole fragment and a designed hydrocar-
bon fragment suitable to accommodate the monoterpenoid
skeleton through judicious application of posterior intra-
molecular cyclizations. Iridium(III) photoredox catalysis
proved to be an amenable method for the direct coupling of
indole derivatives and the elaborated bromo esters 10. In
the first case, the coupling of indole with bromomalonate
10a yielded the quaternary indolyl-malonate 11a, which
led to the construction of ABDE core 7 in 42% overall yield
via just two further cyclization events. In the second case,
the tetracycle ABCD 8 was also straightforwardly synthe-
sized in yields of 24–33% from the coupled diester-trypt-
amines 11b,c by way of two successive lactamizations. Fur-
ther investigation towards the total synthesis of indole
monoterpenoid alkaloids using this approach is currently
underway.
15
Scheme 3 Synthesis and X-ray crystal structure of intermediate 15
Subsequently, to complete the target ABDE system, an
intramolecular Dieckmann condensation on the tricycle 15
mediated by TiCl4/Et3N was performed (Scheme 4). In this
way, the desired tetracycle 7 was obtained as a unique dias-
tereomer in moderate yield after flash column chromatog-
raphy. Interestingly, the presence of a single signal in the 1H
NMR spectrum at 12.15 ppm confirmed that the tetracycle
7 was found mostly as the enol tautomer, since the keto
tautomer was unidentifiable in the spectrum.
In order to explore the capacity of this strategy to con-
struct the ABCD core of tronocarpine (1), we reacted N-Boc-
tryptamine (9b)22a and N-Cbz-tryptamine (9c)22b with the
L-glutamic acid derived bromoester 10b23 using the previ-
ously optimized conditions [see Table 1: Ir(ppy)3, 2,6-luti-
Moisture-sensitive reactions were performed under an argon atmo-
sphere and glassware was flame-dried in an oven. THF was dried over
sodium metal (benzophenone as indicator) and distilled prior to use.
CH2Cl2 was dried over calcium hydride and distilled prior to use. Un-
less otherwise noted, all reagents were obtained commercially and
used without further purification. The reactions were monitored by
TLC using Kieselgel 60 GF254 plates, eluting with hexane/EtOAc solvent
systems. Chromatographic spots were detected by irradiation of the
TLC plates with UV light (254 nm), followed by exposure to vanillin,
phosphomolybdic acid or potassium permanganate stains with
CO2Me
CO2Me
CO2Me
O
TiCl4
Et3N
H
N
O
N
O
CH2Cl2
0 °C
47%
CO2Me
O
7
OMe
15
Scheme 4 Synthesis of tetracycle 7
O
O
O
O
Br 10b
NHGP
CO2Me
Ir(ppy)3 (1 mol%)
2,6-Lutidine
CH3CN
NHGP
NHPG
K2CO3
CH3CN
NH
Method a (24%)
C
D
or
B
A
O
CO2Me
N
N
H
N
H
Reflux
N
30 W Blue LEDs
450 nm
Method b (33%)
O
O
16b, 97%
16c, 98%
8
9b, PG = Boc
9c, PG = Cbz
11b, 38%
11c, 53%
28 °C
CO2Me
8
Scheme 5 Synthesis and X-ray crystal structure of 8. Method a (for 16b): (1) CF3COOH, CH2Cl2, r.t.; (2) K2CO3, MeOH, 40 °C. Method b (for 16c): Pd/C
(10%), H2, MeOH, r.t.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

D
D. A. Contreras-Cruz et al.
Paper
Synthesis
further careful heating. Column chromatography was performed with
Sigma-Aldrich silica gel (200–300 mesh) under positive pressure. The
melting points were measured on a Fisher-Johns apparatus and are
uncorrected. Infrared spectra were obtained with a Bruker Tensor 27
FT-IR spectrophotometer, as thin films held between KBr cells. 1H and
13C NMR spectra were recorded on Jeol Eclipse-300 MHz and Bruker
Avance III-400 MHz spectrometers in CDCl3. Chemical shift data are
reported in ppm with TMS (0 ppm, 1H), CDCl3 (76.9 ppm, 13C) and
DMSO-d6 (39.5 ppm, 13C) as internal standards. Standard abbrevia-
tions are used to report signal splitting patterns. Coupling constants
(J) are reported in hertz (Hz). High-resolution mass spectrometry was
performed using a Jeol JMS-T100LC spectrometer employing the
DART+ technique in positive ion mode. X-ray diffraction studies were
performed on a Bruker AXS diffractometer. CIF files were processed
using Mercury software provided by the CCDC. For the photoredox
experiments, a handmade 30 W reactor was used; this device emits
1536 lumens of monochromatic blue light (450–452 nm).20
1H NMR (400 MHz, CDCl3/TMS):  = 3.81 (s, 3 H), 3.78 (s, 3 H), 3.67 (s,
6 H), 2.90 (dd, J1 = 15.1 Hz, J2 = 9.0 Hz, 1 H), 2.76–2.70 (m, 1 H), 2.40–
2.33 (m, 3 H), 2.00–1.84 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 174.7, 172.8, 167.2, 166.8, 60.6, 54.0,
51.9, 51.7, 41.7, 39.7, 31.2, 28.7.
HRMS (DART+): m/z [M + H]+ calcd for C13H20BrO8: 383.03415; found:
383.03404.
Tetramethyl 1-(1H-Indol-2-yl)pentane-1,1,3,5-tetracarboxylate
(11a)
Bromomalonate 10a (0.1 g, 0.26 mmol), indole (9a) (0.15 g, 1.3
mmol), 2,6-lutidine (0.028 g, 0.03 mL, 0.26 mmol) and Ir(ppy)3 (1.7
mg, 0.0026 mmol) were added to a 4 mL vial equipped with a stir bar
under an argon atmosphere. Afterwards, deoxygenated CH3CN (0.5
mL) was added to the vial and degassing was performed using the
freeze-pump-thaw technique. The vial was irradiated in a blue LED
photoreactor for 17 h at a constant temperature of 28 °C. After that
time, the solution was adsorbed on silica gel. Purification by flash col-
umn chromatography using hexane/EtOAc (7:3) gave 11a (0.109 g,
0.259 mmol, 100%) as an orange oil which crystallized slowly as a
slightly brown solid.
Tetramethyl Pentane-1,1,3,5-tetracarboxylate (14)
Unsaturated ester 12 (3.41 g, 19.8 mmol), dimethyl malonate (13)
(7.84 g, 59.41 mmol), CH3CN (46 mL) and n-tributylphosphine (0.41 g,
0.51 mL, 1.98 mmol) were placed into a round-bottomed flask. The
solution was stirred under an argon atmosphere for 23 h at room
temperature followed by evaporation of CH3CN under reduced pres-
sure. The resulting greenish oil was purified by column chromatogra-
phy using hexane/EtOAc (8:2) to elute the excess of dimethyl
malonate (13), followed by hexane/EtOAc (8:2) to give malonate 14
(5.04 g, 16.55 mmol, 84%) as a clear oil.
Mp 93–96 °C; Rf = 0.2 (hexane/EtOAc, 7:3).
IR (film): 3407, 3002, 2954, 2847, 1735, 1454, 1436, 1233, 1207,
1169, 1091, 1071, 751 cm–1
.
1H NMR (300 MHz, CDCl3/TMS):  = 9.52 (s, 1 H), 7.47 (d, J = 7.8 Hz, 1
H), 7.31 (d, J = 7.6 Hz, 1 H), 7.13–7.07 (m, 1 H), 7.03–6.97 (m, 1 H),
6.29–6.28 (m, 1 H), 3.68 (s, 6 H), 3.51 (s, 3 H), 3.28 (s, 3 H), 2.85 (dd,
J1 = 14.4 Hz, J2 = 9.7 Hz, 1 H), 2.45–2.30 (m, 2 H), 2.17 (t, J = 7.7 Hz, 2
H), 1.88–1.69 (m, 2 H).
13C NMR (75 MHz, CDCl3):  = 175.0, 172.9, 170.1, 169.9, 135.7, 132.7,
127.5, 122.2, 120.4, 119.9, 111.3, 101.8, 57.3, 53.3, 51.6, 40.8, 38.7,
31.2, 28.8.
Rf = 0.1 (hexane/EtOAc, 8:2).
IR (film): 3456, 3002, 2956, 2848, 1735, 1437, 1330, 1246, 1203,
1159, 1046 cm–1
.
1H NMR (400 MHz, CDCl3/TMS):  = 3.72 (s, 3 H), 3.71 (s, 3 H), 3.66 (s,
3 H), 3.64 (s, 3 H), 3.42 (dd, J1 = 9.0 Hz, J2 = 5.9 Hz, 1 H), 2.48–2.41 (m,
1 H), 2.34–2.30 (m, 2 H), 2.23–2.15 (m, 1 H), 2.11–2.04 (m, 1 H), 1.97–
1.79 (m, 2 H).
HRMS (DART+): m/z [M + H]+ calcd for C21H26NO8: 420.16584; found:
420.16500.
13C NMR (100 MHz, CDCl3):  = 174.6, 173.0, 169.2, 169.2, 52.7, 52.6,
51.8, 51.6, 49.5, 42.2, 31.3, 30.6, 27.2.
Dimethyl 7-(3-Methoxy-3-oxopropyl)-6-oxo-7,8-dihydropyrido-
HRMS (DART+): m/z [M + H]+ calcd for C13H21O8: 305.12364; found:
[1,2-a]indole-9,9(6H)-dicarboxylate (15)
305.12373.
Tetramethyl 1-(1H-indol-2-yl)pentane-1,1,3,5-tetracarboxylate (11a)
(1.42 g, 3.4 mmol) and potassium carbonate (95%, 1.9 g, 13.6 mmol)
were placed into a round-bottomed flask under argon. The mixture
was dissolved in CH3CN (170 mL) and heated at reflux for 18 min, af-
ter which the solution was allowed to cool to room temperature. The
CH3CN was evaporated under reduced pressure and distilled H2O (130
mL) was added to the resulting brown oil. The aqueous phase was ex-
tracted with CH2Cl2 (2 × 130 mL) and the combined organic phases
were dried over Na2SO4. The solvent was evaporated under reduced
pressure and the residue was adsorbed on silica gel. Purification by
column chromatography using hexane/EtOAc (8:2) gave N-acylated
indole 15 (1.17 g, 3.04 mmol, 89%) as an orange crystalline solid.
Tetramethyl 1-Bromopentane-1,1,3,5-tetracarboxylate (10a)
A solution of malonate 14 (5.03 g, 16.55 mmol) dissolved in anhy-
drous THF (120 mL) was placed into a round-bottomed flask under ar-
gon. The solution was cooled with an ice–water bath followed by the
addition of NaH (95%, 0.5 g, 19.86 mmol). The bubbling suspension
was vigorously stirred for 15 min whilst maintaining cooling with the
ice bath. Subsequently, recrystallized N-bromosuccinimide (3.24 g,
18.21 mmol) was added in one portion and the mixture was stirred at
0 °C for 5 min. The suspension was warmed to room temperature and
stirred for an additional 30 min, after which distilled H2O (180 mL)
was added. The resulting mixture was extracted with EtOAc (2 × 180
mL) and the combined organic phases were dried over Na2SO4. The
solvent was evaporated under reduced pressure and the residue was
adsorbed on silica gel. Purification by column chromatography using
hexane/EtOAc (7:3) gave bromomalonate 10a (6.32 g, 16.49 mmol,
99%) as an orange oil.
Mp 88–90 °C; Rf = 0.24 (hexane/EtOAc, 8:2).
IR (film): 3451, 3007, 2954, 1748, 1734, 1695, 1452, 1437, 1383,
1327, 1276, 1233, 1194, 1069, 766 cm–1
.
1H NMR (400 MHz, CDCl3/TMS):  = 8.39 (d, J = 8.2 Hz, 1 H), 7.49–7.44
(m, 1 H), 7.30–7.25 (m, 1 H), 7.22–7.18 (m, 1 H), 6.62 (s, 1 H), 3.83 (s,
3 H), 3.71 (s, 3 H), 3.62 (s, 3 H), 2.76–2.56 (m, 2 H), 2.54–2.41 (m, 3 H),
2.38–2.29 (m, 1 H), 1.97–1.88 (m, 1 H).
Rf = 0.3 (hexane/EtOAc, 7:3).
13C NMR (100 MHz, CDCl3):  = 173.3, 169.8, 169.2, 168.5, 135.2,
132.4, 129.2, 125.5, 124.3, 120.7, 116.6, 109.2, 55.5, 39.1, 33.7, 31.3,
25.3.
IR (film): 3654, 3457, 3003, 2954, 2848, 2599, 2042, 1735, 1435,
1380, 1249, 1198, 1164, 1092, 1051, 1022, 987, 836 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

E
D. A. Contreras-Cruz et al.
Paper
Synthesis
HRMS (DART+): m/z [M + H]+ calcd for C20H22NO7: 388.13963; found:
Dimethyl 2-{3-[2-(Benzyloxycarbonylamino)ethyl]-1H-indol-2-
388.13973.
yl}pentanedioate (11c)
Dimethyl 2-bromopentanedioate (10b) (0.1199 g, 0.5015 mmol), N-
Cbz-tryptamine (9c) (0.3476 g, 1.1809 mmol), 2,6-lutidine (0.6 mL,
0.555 g, 5.1795 mmol) and Ir(ppy)3 (4 mg, 0.0051 mmol) were added
to a 4 mL vial equipped with a stir bar under an argon atmosphere.
Afterwards, deoxygenated CH3CN (2.2 mL) was added to the vial and
degassing was performed with the freeze-pump-thaw technique. The
vial was irradiated in a blue LED photoreactor for 12 h at a constant
temperature of 28 °C. After that time, the solution was adsorbed on
silica gel. Purification by flash column chromatography using
hexane/EtOAc (85:15) gave 11c (0.1216 g, 0.2687 mmol, 53%) as a yel-
low oil.
Dimethyl 10-Hydroxy-6-oxo-6,7,8,11-tetrahydro-7,11-methano-
azocino[1,2-a]indole-9,11-dicarboxylate (7)
A solution of N-acylated indole 15 (0.056 g, 0.146 mmol) dissolved in
anhydrous CH2Cl2 (9 mL) was placed into a round-bottomed flask un-
der argon. The solution was cooled to about 0 °C in an ice–water bath
followed by dropwise addition of titanium tetrachloride (0.083 g,
0.048 mL, 0.439 mmol); the solution acquired an orange color imme-
diately. Subsequent dropwise addition of triethylamine (0.052 g,
0.072 mL, 0.512 mmol) led to the solution turning gray. After stirring
for 4 h at 0 °C, the now black solution was quenched by adding dis-
tilled H2O (40 mL). The mixture was extracted twice with CH2Cl2
(2 × 15 mL) and the combined organic phase was dried over Na2SO4.
The solvent was evaporated under reduced pressure and the resulting
oil was adsorbed on silica gel. Purification by column chromatogra-
phy using hexane/EtOAc (8:2) gave tetracyclic indole 7 (0.024 g,
0.0683 mmol, 47%) as a yellow oil.
Rf = 0.06 (hexane/EtOAc, 85:15).
IR (film): 3376, 3344, 3059, 3030, 2950, 1697, 1517, 1455, 1436,
1236, 1201, 1155, 1068, 986, 741, 697, 599 cm–1
.
1H NMR (300 MHz, CDCl3/TMS):  = 8.52 (s, 1 H), 7.54 (d, J = 8.9 Hz, 1
H), 7.32–7.29 (m, 7 H), 7.19–7.06 (m, 2 H), 5.09–5.05 (m, 3 H), 4.05–
4.00 (m, 1 H), 3.59–3.56 (m, 6 H), 3.53–3.42 (m, 2 H), 3.04–2.82 (m, 2
H), 2.28–2.20 (m, 3 H).
Rf = 0.3 (hexane/EtOAc, 8:2).
IR (film): 3014, 2952, 2855, 1749, 1700, 1659, 1616, 1438, 1349,
13C NMR (75 MHz, CDCl3):  = 173.5, 173.1, 156.5, 136.8, 136.0, 130.9,
128.6, 128.24, 128.21, 127.8, 122.5, 119.8, 118.7, 111.1, 109.4, 66.7,
52.6, 51.8, 41.6, 31.2, 28.1, 24.6, 14.2.
HRMS (DART+): m/z [M + H]+ calcd for C25H29N2O6: 453.20256; found:
453.20117.
1322, 1229, 1072, 746 cm–1
.
1H NMR (300 MHz, CDCl3/TMS):  = 12.15 (s, 1 H), 8.43 (d, J = 7.9 Hz, 1
H), 7.57–7.54 (m, 1 H), 7.36–7.25 (m, 2 H), 7.12 (s, 1 H), 3.90 (s, 3 H),
3.74 (s, 3 H), 3.32 (q, J = 3.8 Hz, 1 H), 2.81 (d, J = 4.2 Hz, 2 H), 2.62 (d,
J = 3.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 172.1, 170.4, 169.3, 166.8, 134.8, 129.7,
125.5, 123.5, 110.6, 108.4, 99.9, 95.7, 95.6, 53.0, 51.1, 47.9, 32.8, 26.7.
HRMS (DART+): m/z [M + H]+ calcd for C19H18NO6: 356.11341; found:
356.11340.
Methyl 10-[2-(tert-Butoxycarbonylamino)ethyl]-6-oxo-6,7,8,9-
tetrahydropyrido[1,2-a]indole-9-carboxylate (16b)
Dimethyl
2-{3-[2-(tert-butoxycarbonylamino)ethyl]-1H-indol-2-
yl}pentanedioate (11b) (0.2684 g, 0.6414 mmol) and potassium car-
bonate (95%, 0.54 g, 3.907 mmol) were placed into a round-bottomed
flask under argon. The mixture was dissolved in CH3CN (32 mL) and
heated at reflux for 6 h, after which the solution was allowed to cool
to room temperature. The CH3CN was evaporated under reduced pres-
sure and distilled H2O (30 mL) was added to the resulting brown oil.
The aqueous phase was extracted with EtOAc (2 × 30 mL) and the
combined organic phases were dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford N-acylated indole 16b
(0.24 g, 0.621 mmol, 97%) as a yellow oil. The crude product was used
in the following reaction without further purification.
Dimethyl 2-{3-[2-(tert-Butoxycarbonylamino)ethyl]-1H-indol-2-
yl}pentanedioate (11b)
Dimethyl 2-bromopentanedioate (10b) (0.08 g, 0.33 mmol), N-Boc-
tryptamine (9b) (0.13 g, 0.50 mmol), 2,6-lutidine (0.038 mL, 0.032 g,
0.33 mmol) and Ir(ppy)3 (2 mg, 0.064 mmol) were added to a 4 mL
vial equipped with a stir bar under an argon atmosphere. Afterwards,
deoxygenated CH3CN (1 mL) was added to the vial and degassing was
performed using the freeze-pump-thaw technique. The vial was irra-
diated in a blue LED photoreactor for 12 h at a constant temperature
of 28 °C. After that time, the solution was adsorbed on silica gel. Puri-
fication by flash column chromatography using hexane/EtOAc (85:15)
gave 11b (0.0528 g, 0.126 mmol, 38%) as a yellow oil.
IR (film): 3287, 3053, 2928, 2853, 1716, 1648, 1535, 1454, 1434,
1263, 1175, 736, 699 cm–1
.
1H NMR (300 MHz, CDCl3/TMS):  = 8.49 (dd, J1 = 7.3 Hz, J2 = 1.2 Hz, 1
H), 7.60–7.53 (m, 1 H), 7.38–7.27 (m, 3 H), 4.18–4.16 (m, 1 H), 3.74 (s,
3 H), 3.50–3.33 (m, 2 H), 3.07–2.92 (m, 2 H), 2.86–2.76 (m, 2 H), 2.41–
2.20 (m, 2 H), 1.43 (s, 9 H).
13C NMR (75 MHz, CDCl3):  = 171.6, 168.3, 155.9, 134.9, 130.8, 129.6,
125.2, 124.0, 118.6, 116.7, 79.3, 52.9, 45.7, 39.9, 37.3, 30.9, 28.4, 24.2.
Rf = 0.11 (hexane/EtOAc, 85:15).
IR (film): 3385, 3323, 2951, 2863, 1735, 1677, 1524, 1453, 1436,
1277, 1149, 962, 745, 619 cm–1
.
1H NMR (300 MHz, CDCl3/TMS):  = 8.42 (s, 1 H), 7.57–7.55 (m, 1 H),
7.34–7.31 (m, 1 H), 7.21–7.08 (m, 2 H), 4.75 (s, 1 H), 4.06–4.01 (m, 1
H), 3.72 (s, 3 H), 3.71–3.67 (m, 2 H), 3.62 (s, 3 H), 2.97–2.76 (m, 2 H),
2.40–2.19 (m, 4 H), 1.43 (s, 9 H).
HRMS (DART+): m/z [M + H]+ calcd for C21H27N2O5: 387.19200; found:
387.19218.
13C NMR (75 MHz, CDCl3):  = 173.5, 173.0, 155.9, 135.9, 130.7, 127.8,
122.3, 119.6, 118.8, 111.3, 110.9, 52.6, 51.7, 46.9, 45.7, 41.5, 41.1,
31.1, 28.4, 28.1.
Methyl 10-[2-(Benzyloxycarbonylamino)ethyl]-6-oxo-6,7,8,9-
tetrahydropyrido[1,2-a]indole-9-carboxylate (16c)
HRMS (DART+): m/z [M + H]+ calcd for C22H31N2O6: 419.21821; found:
419.21638.
Dimethyl 2-{3-[2-(benzyloxycarbonylamino)ethyl]-1H-indol-2-yl}-
pentanedioate (11c) (0.2753 g, 0.6084 mmol) and potassium carbon-
ate (95%, 0.5046 g, 3.46 mmol) were placed into a round-bottomed
flask under an argon atmosphere. The mixture was dissolved in
CH3CN (31 mL) and heated at reflux for 6 h, after which the solution
was allowed to cool to room temperature. The CH3CN was evaporated
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

F
D. A. Contreras-Cruz et al.
Paper
Synthesis
under reduced pressure and distilled H2O (30 mL) was added to the
resulting brown oil. The aqueous phase was extracted with EtOAc
(2 × 30 mL) and the combined organic phases were dried over Na2SO4.
The solvent was evaporated under reduced pressure to afford N-acyl-
ated indole 16c (0.25 g, 0.5945 mmol, 98%) as a yellow oil. The crude
product was used in the following reaction without further purifica-
tion.
13C NMR (75 MHz, DMSO-d6):  = 172.8, 169.7, 134.1, 130.5, 130.0,
125.1, 124.2, 118.7, 116.3, 116.2, 38.5, 37.8, 32.8, 26.3, 22.5.
HRMS (DART+): m/z [M + H]+ calcd for C15H15N2O2: 255.11335; found:
255.11277.
Funding Information
IR (film): 3375, 2953, 2921, 2850, 1732, 1697, 1511, 1455, 1365,
1317, 1245, 1159, 1170, 1037, 989, 751, 558 cm–1
.
D.A.C. thanks the Consejo Nacional de Ciencia y Tecnología (CONA-
CYT) for a Ph.D. scholarship (Grant No. 271165). Financial support
from Dirección General de Asuntos del Personal Académico, Universi-
dad Nacional Autónoma de México (DGAPA-UNAM) (PAPIIT Nos.
1H NMR (300 MHz, CDCl3/TMS):  = 8.48 (d, J = 8.0 Hz, 1 H), 7.53 (d, J =
7.4 Hz, 1 H), 7.37–7.28 (m, 8 H), 5.14–5.04 (m, 2 H), 4.97 (br s, 1 H),
3.68 (s, 3 H), 3.53–3.43 (m, 2 H), 3.04–2.72 (m, 4 H), 2.51–2.45 (m, 1
H), 2.24–2.14 (m, 1 H).
IN210516 and IN208719) is gratefully acknowledged.
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37.5, 31.0, 24.9, 24.2, 14.3.
Acknowledgment
HRMS (DART+): m/z [M + H]+ calcd for C24H25N2O5: 421.17635; found:
421.17589.
We thank R. Patiño-Maya, Ma. P. Orta-Pérez, E. García-Ríos, A. Peña, E.
Huerta, Ma. C. García-González, B. Quiroz, I. Chávez, L. Velasco and J.
Pérez for technical support. The authors also extend their gratitude to
Simón Hernández-Ortega for X-ray crystallography. In addition, we
thank Marco V. Mijangos for his helpful comments.
2,3,5,6-Tetrahydroazepino[3,4,5-hi]benzo[b]indolizine-
4,7(1H,4aH)-dione (8)
Method a
N-Acylated indole 16b (0.1332 g, 0.3447 mmol) was placed into a
round-bottomed flask under argon. Trifluoroacetic acid (1.028 mL,
1.53 g, 13.424 mmol) and CH2Cl2 (6 mL) were added and the mixture
was stirred at room temperature for 1 h. The solvent was evaporated
under reduced pressure followed by the addition of potassium car-
bonate (95%, 0.06 g, 0.4124 mmol) and anhydrous MeOH (6 mL). The
suspension was heated at 40 °C for 2 h and then distilled H2O (10 mL)
was added. The aqueous phase was extracted with EtOAc (2 × 10 mL)
and the combined organic phases were dried over Na2SO4. The solvent
was evaporated under reduced pressure and the oily residue was ad-
sorbed on silica gel. Purification by flash column chromatography us-
ing EtOAc/hexane (9:1) gave tetracycle 8 (0.0214 g, 0.0841 mmol,
24%) as a transparent crystalline solid.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690208.
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References
(1) (a) Silveira, D.; Felipe de Melo, A. M. M.; Magalhães, P. O.;
Fonseca-Bazzo, Y. M. Tabernaemontana Species: Promising
Sources of New Useful Drugs, In Studies in Natural Products
Chemistry, Vol. 54; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
2017, 227. (b) Athipornchai, A. Asian J. Pharm. Clin. Res. 2018,
11, 45. (c) Boligon, A. A.; Piana, M.; Kubiça, T. F.; Mario, D. N.;
Dalmolin, T. V.; Bonez, P. C.; Weiblen, R.; Lovato, L.; Alves, S. H.;
Campos, M. M. A.; Athayde, M. L. J. Appl. Biomed. 2015, 13, 7.
(2) (a) Shrikanth, V. M.; Janardhan, B.; Veena, S. M.; Dhananjaya, B.
L.; Muddapura, U. M.; More, S. L. Int. J. Pharm. Pharm. Sci. 2015,
7, 66. (b) Medeiros, M. R.; Prado, L. A.; Fernandes, V. C.;
Figuereido, S. S.; Coppede, J.; Martins, J.; Fiori, G. M.; Martinez-
Rossi, N. M.; Beleboni, R. O.; Contini, S. H.; Pereira, P. S.; Fachin,
A. L. Nat. Prod. Commun. 2011, 6, 193. (c) Batina, M. de F. C.;
Cintra, A. C. O.; Veronese, E. L. G.; Lavrador, M. A. S.; Giglio, J. R.;
Pereira, P. S.; Dias, D. A.; França, S. Z.; Sampaio, S. V. Planta Med.
2000, 66, 424. (d) Noguchi, Y.; Hirose, T.; Ishiyama, A.; Iwatsuki,
M.; Otoguro, K.; Sunazuka, T.; Ōmura, S. J. Nat. Med. 2016, 70,
302.
Mp 223–224 °C; Rf = 0.25 (hexane/EtOAc, 9:1).
Method b
N-Acylated indole 16c (0.0389 g, 0.0925 mmol) was placed into a
round-bottomed flask followed by the addition of Pd/C (10%, 0.003 g)
and MeOH (2.5 mL). A balloon containing hydrogen equipped with a
syringe was fitted to the septum and the gas was bubbled into the
suspension. The mixture was stirred at room temperature for 10 min
and then filtered over Celite. The solvent was evaporated under re-
duced pressure and the residue transferred to a round-bottomed
flask. Potassium carbonate (95%, 0.0382 g, 0.2626 mmol) and CH3CN
(3 mL) were added and the resulting suspension was heated at 40 °C
for 2.5 h. Distilled H2O (10 mL) was added and the aqueous phase was
extracted with EtOAc (2 × 10 mL). The organic phases were combined
and dried over Na2SO4. The solvent was evaporated under reduced
pressure and the oily residue was adsorbed on silica gel. Purification
by flash column chromatography using EtOAc/hexane (9:1) gave tet-
racycle 8 (0.0077 g, 0.0302 mmol, 33%) as a transparent crystalline
solid.
(3) Kam, T.-S.; Sim, K.-M.; Lim, T. M. Tetrahedron Lett. 2000, 41,
2733.
(4) (a) Nielsen, H. B.; Hazell, A.; Hazell, R.; Ghia, F.; Torssell, K. G. B.
Phytochemistry 1994, 37, 1729. (b) Kam, T.-S.; Pang, H.-S.; Choo,
Y. M.; Komiyama, K. Chemistry & Biodiversity 2004, 1, 646.
(5) Kam, T.-S.; Sim, K.-M. Heterocycles 2001, 55, 2405.
(6) Kam, T.-S.; Sim, K.-M. Heterocycles 1999, 51, 345.
(7) (a) Hájíček, J. Collect. Czech. Chem. Commun. 2011, 76, 2023.
(b) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532.
(c) Pfaffenbach, M.; Gaich, T. The Rhazinilam-Leuconoxine-
IR (film): 3310, 3222, 2958, 2921, 1697, 1656, 1607, 1454, 1378,
1323, 1175, 1132, 764, 589, 547, 428 cm–1
.
1H NMR (300 MHz, DMSO-d6/TMS):  = 8.33–8.30 (m, 1 H), 8.09–8.05
(m, 1 H), 7.49–7.46 (m, 1 H), 7.34–7.26 (m, 2 H), 4.44–4.37 (m, 1 H),
3.82–3.68 (m, 1 H), 3.41–3.39 (m, 1 H), 2.89–2.67 (m, 4 H), 2.20–2.09
(m, 2 H).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

G
D. A. Contreras-Cruz et al.
Paper
Synthesis
Mersicarpine Triad of Monoterpenoid Indole Alkaloids, In The
Alkaloids: Chemistry and Biology, Vol. 77; Knölker, H.-J., Ed.; Aca-
demic Press: Cambridge (USA), 2017, 2.
(15) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J. W.;
Stephenson, C. R. J. Org. Lett. 2010, 12, 3104.
(16) Swift, E. C.; Williams, T. M.; Stephenson, C. R. J. Synlett 2016, 27,
754.
(17) (a) Rauhut, M. M.; Currier, H. (American Cyanamid Co.) US
Patent 3,074,999, 1963; Chem. Abstr. 1963, 58, 11224a.
(b) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron 2009, 65,
4069. (c) Jenner, G. Tetrahedron Lett. 2000, 41, 3091.
(18) Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Mañas, M.;
Sebastián, R. M.; Vallribera, A. Tetrahedron 2005, 61, 8598.
(19) Yamane, Y.; Yoshinaga, K.; Sumimoto, M.; Nishikata, T. ACS
Catal. 2019, 9, 1757.
(8) Kam, T.-S.; Sim, K.-M.; Pang, H.-S.; Koyano, T.; Hayashi, M.;
Komiyama, K. Bioorg. Med. Chem. Lett. 2004, 14, 4487.
(9) (a) Mahboobi, S.; Burgemeister, T.; Kastner, F. Arch. Pharm.
1995, 328, 29. (b) Mahboobi, S.; Bernauer, K. Helv. Chim. Acta
1988, 71, 2034. (c) Du, D.; Li, L.; Wang, Z. J. Org. Chem. 2009, 74,
4379. (d) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561.
(e) Reyes-Gutiérrez, P. E.; Torres-Ochoa, R. O.; Martínez, R.;
Miranda, L. D. Org. Biomol. Chem. 2009, 7, 1388. (f) Nidhiry, J. E.;
Prasad, K. R. Synlett 2014, 25, 2585.
(10) Sapeta, K.; Kerr, M. A. Org. Lett. 2009, 11, 2081.
(11) Torres-Ochoa, R. O.; Reyes-Gutiérrez, P. E.; Martínez, R. Eur. J.
Org. Chem. 2014, 48.
(20) For more information on the construction of the reactor, see:
Contreras-Cruz, D. A.; Cantú-Reyes, M.; García-Sánchez, J. M.;
Peña-Ortíz, D.; Sánchez-Carmona, M. A.; Miranda, L. D. J. Chem.
Educ. 2019, 9, 2015.
(12) Seong, S.; Lim, H.; Han, S. Chem 2018, 5, 1.
(13) (a) Ziegler, F. E.; Jeroncic, L. O. J. Org. Chem. 1991, 56, 3479.
(b) Artis, D. R.; Cho, I.-S.; Jaime-Figueroa, S.; Muchowski, J. M.
J. Org. Chem. 1994, 59, 2456. (c) Osornio, Y. M.; Cruz-Almanza,
R.; Jiménez-Montaño, V.; Miranda, L. D. Chem. Commun. 2003,
2316. (d) Guerrero, M. A.; Miranda, L. D. Tetrahedron Lett. 2006,
47, 2517.
(14) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
40, 102. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem.
Rev. 2013, 113, 5322. (c) Romero, N. A.; Nicewicz, D. A. Chem.
Rev. 2016, 116, 10075. (d) Matsui, J. K.; Lang, S. B.; Heitz, D. R.;
Molander, G. A. ACS Catal. 2017, 7, 2563. (e) López-Mendoza, P.;
Díaz, J. E.; Loaiza, A. E.; Miranda, L. D. Tetrahedron 2018, 74,
5494.
(21) CCDC 1892843 (15) and 1893953 (23) contain the supplemen-
tary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
(22) (a) Bang, D.; Chopra, N.; Kent, S. J. Am. Chem. Soc. 2004, 126,
12888. (b) Kandukuri, S. R.; Schiffner, J. A.; Oestreich, M. Angew.
Chem. Int. Ed. 2012, 51, 1265.
(23) (a) Henig, J.; Tóth, É.; Engelmann, J.; Gottschalk, S.; Mayer, H. A.
Inorg. Chem. 2010, 49, 6124. (b) Mulla, R. S.; Walden, M. T.;
Yufit, D. S.; Desa, T.; Lurie-Luke, E.; Williams, J. A. G. Tetrahedron
2017, 73, 6410.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G