A unified synthesis of topologically diverse: Aspidosperma alkaloids through divergent iminium-trapping

Article abstract of DOI:10.1039/c8ob02621a

Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.

Full text of DOI:10.1039/c8ob02621a

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
A unified synthesis of topologically diverse
Aspidosperma alkaloids through divergent
iminium-trapping†
Cite this: Org. Biomol. Chem., 2018,
16, 9409
Marco V. Mijangos* and Luis D. Miranda
*
Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five
Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a
single molecular scaffold, namely indole–valerolactam 6. This common intermediate can be divergently
manipulated, through the incorporation of conformational and electronic constraints that influence the
chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs.
C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct
C(3)–H indole functionalization is reported for the first time in an approach to goniomitine (4), and a fol-
lowing tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The devel-
opment of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to
obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2,
and 3.
Received 22nd October 2018,
Accepted 20th November 2018
DOI: 10.1039/c8ob02621a
rsc.li/obc
Aspidosperma alkaloids aspidospermidine (1),9 vincadifformine
(2),10 1,2-dehydroaspidospermidine (3),9 goniomitine (4),11
Introduction
Given sufficient time and resources, chemists are able to con- and quebrachamine (5)12 can be distributed into three well-
struct almost any given natural product irrespective of struc- differentiated structural topologies, and at the same time, it
tural complexity. However, in recent years there has been can be recognized that the three cores share an indole nucleus
growing concern about minimizing the environmental impact, in conjugation with a 3,3-diethylpiperidine moiety.
effort and man-power needed to successfully complete this
Thus, we devised that the selected targets could divergently
demanding task. Consequently, in the search for optimal syn- arise from indole–valerolactam (6), by chemoselective control
thetic efficiency, concepts such atom,1 redox,2 pot,3 and step4 of the reaction pathways of the iminium ion 7 derived there-
economies have become characteristic features in modern syn-
thetic planning.5 In this context, total synthesis approaches
are steadily moving toward the design of versatile strategies
that divergently and selectively furnish a collection of skeletally
diverse natural products through the chemical manipulation
of a single intermediate,6 whose design is usually guided by
the recognition of shared structure patterns among the desired
targets.7
We selected the structurally intricate Aspidosperma alkaloids
to put this concept into practice. Much attention has been
paid to this family of natural products, in particular for the
remarkable anticancer properties of vinblastine and vincris-
tine, pseudo-dimeric alkaloids, which are already in use for
chemotherapy.8 As shown in Scheme 1, the members of the
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior,
Ciudad Universitaria, Coyoacán, Mexico City, 04510. E-mail: viniciomili@gmail.com,
lmiranda@unam.mx; http://www.iquimica.unam.mx
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Divergent iminium-trapping for a unified synthesis of topo-
logically diverse Aspidosperma alkaloids.
c8ob02621a
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9409–9419 | 9409

View Article Online
Paper
Organic & Biomolecular Chemistry
from. This reasoning gave rise to the three possible fates for
iminium 7 as depicted in Scheme 1. Path A, where the
iminium is trapped by the indole nitrogen cyclizing to the
indolo-naphthyridine system of goniomitine (4); path B, where
the said iminium species 7 reacts with the indole C(3) position
to produce the cis-pyridocarbazole 22 (not shown) which could
be advanced to targets 1, 2 and 3; and path C where the inter-
mediate 6 is completely reduced, setting the stage for the syn-
thesis of target 5.
Under our approach, the judicious selection of R groups in
7 to impose different electronic and conformational con-
straints was found to be crucial for the achievement of success-
ful chemoselection from paths A–C. Our findings are detailed
in the following sections.
Scheme 2 Gram scale synthesis of common intermediate 6.
Results and discussion
prefunctionalization and cross-coupling,6f or multi-step indole
functionalization and further functional group manipula-
tions.20a,b Accordingly, advances in efficiency will result in
direct attachment of the ethylenic chain via indole C–H
functionalization. To this end, we explored a catalytic carbene
insertion21 using commercially available ethyl diazoacetate
(16), whose oxidation state could be adjusted concomitantly
with the planned reductive cyclization.6f,20e
Thus, we reacted intermediate 6 with diazoacetate 16 in the
presence of various catalysts, solvents and temperatures
(Table 1). The use of InBr3,21a Cu(OTf)2 21a or Rh2(OAc)4 21b,c as
catalysts resulted in slow reaction rates and complex reaction
mixtures. In contrast, the use of 0.1 equivalents of Cu(acac)2 in
refluxing benzene21d under microwave irradiation and portion-
wise addition of 3 equivalents of 16 provided the desired C(3)
functionalized indole 17 in 54% yield (Table 1, entry 7).
Our experimentation began with the development of a straight-
forward and efficient route to afford multigram quantities of
the common intermediate indole–valerolactam 6. As we
decided to pursue an alkyne indolization approach,13 we first
addressed the synthesis of terminal alkyne 8 through direct
alkylation, and found that the reaction between various valero-
lactam-enolates with different homopropargyl electrophiles
failed to produce the desired product, probably as these elec-
trophiles are prone to preferential elimination.14 In light of the
above, valerolactam (9) was reacted with 2.1 equivalents of
n-BuLi and the dianion obtained thereby was treated consecu-
tively with ethyl iodide and benzyl chloride to afford N-benzyl
α-ethylvalerolactam 10 in a single synthetic operation and with
excellent yield. The lithium enolate of 10 was then C-alkylated
with allyl bromide yielding alkene 11 in 93%.15 In order to
synthesize the terminal alkyne 8, alkene 11 was treated with
dicyclohexylborane and H2O2 to provide alcohol 12,15 which
was oxidized16 to aldehyde 13 and subsequently homologated
with the Bestmann–Ohira reagent (14)17 to provide the terminal
alkyne 8. Finally, the sequential Sonogashira coupling of 8 with
o-iodoaniline,13b,c and a zinc iodide catalyzed alkyne hydro-
amination18 efficiently furnished the key indole–valerolactam 6
(Scheme 2).
With 2,3-disubstituted indole 17 now in hand, the final
stage for the total synthesis of goniomitine (4) was set. After
some experimentation, we found that 17 could be transformed
Table 1 Relevant conditions for the C–H functionalization of 6 via
catalytic carbene insertion
It is worth mentioning that this synthetic sequence pro-
vided up to six grams of the common intermediate 6 in 36%
overall yield. Moreover, the use of allyl-valerolactam 11 pro-
vides the opportunity for an asymmetric version using Stoltz’s
enantioselective allylation chemistry.19
Entrya
Catalystb
Solventc/temp
Time
% Yield 17
Total synthesis of goniomitine
1
2
3
4
5
6
7
InBr3
CH2Cl2/R.T.
CH2Cl2/−78 °C
MePh/−78 °C
MePh/R.T.
CH2Cl2/R.T.
PhH/refluxd
PhH/refluxe
24 h
0.5 h
0.5 h
6 h
6 h
6 h
12%
35%
32%
24%
25%
52%
54%
To transform indole–valerolactam 6 to the alkaloid goniomi-
tine (4) the iminium ion 7 needs to react through path A and
undergo 6-exo-cyclization via C–N bond formation (Scheme 1).
Using our approach, this could be achieved by blocking the
indole C(3) position first. Our analysis of the previous related
syntheses of this alkaloid showed that a significant increment
of chemical steps was due to the installation of the hydroxy-
ethylene moiety at the indole C(3) position, involving indole
Cu(OTf)2
Cu(OTf)2
Rh2(OAc)4
Rh2(OAc)4
Cu(acac)2
Cu(acac)2
1.5 h
a All reactions were carried out using 3 eq. of 16. b 0.1 eq. of catalyst.
c All solvents were used anhydrous and freshly distilled. d Conventional
heating. e Under microwave assistance.
9410 | Org. Biomol. Chem., 2018, 16, 9409–9419
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
directly into N-benzyl-goniomitine 20 in moderate isolated
yield via a tandem ester reduction/iminium ion generation/
cyclization process using DIBAL at −78 °C. Finally, our first
target alkaloid 4 was secured by N-benzyl hydrogenolysis of 23
in 70% yield (Scheme 3). In this way, goniomitine (4, 82 mg)
was achieved in 10 steps from valerolactam (9) in 5% overall
yield.
Scheme 4 Attempts to cyclize 6 to cis-pyridocarbazole 22a.
Total synthesis of aspidospermidine (1), vincadifformine (2)
and 1,2-dehydroaspidospermidine (3)
Boc-6 in 78% yield. After some experimentation, we found that
the treatment of a solution of di-Boc-6 in anhydrous dichloro-
methane with a slight excess of lithium triethylborohydride at
−78 °C, followed by treatment with trifluoroacetic acid in one
pot, smoothly furnished the desired cis-pyridocarbazole 22b in
excellent yield as a sole diastereoisomer without the need for
chromatographic purification (Scheme 5). With the desired
tetracyclic system 22b in hand, only 2 steps remained to reach
aspidospermidine (1). First, hydroxylamine 23 was obtained
through a known alkylation procedure with 2-bromoethanol as
an electrophile.23 Hereafter, we found that hydroxylamine 23
could be transformed directly into aspidospermidine (1) in
41% yield using a one-pot mesylation/SN2/reduction protocol.
On the other hand, after a mesylation/SN2 protocol,23 isolation
of 1,2-dehydroaspidospermidine (3, 46% yield) was needed, to
transform it to vincadifformine (2) with methyl cyanoformate/
n-BuLi6a albeit in low yield (Scheme 5). In doing so, the syn-
thesis of both aspidospermidine (1, 50 mg) and 1,2-dehydroas-
pidospermidine (3, 114 mg) from valerolactam (9) in 10%
overall yield required 12 steps; and vincadifformine (2, 12 mg)
was obtained in 13 steps in 3% overall yield.
Access to this triad of alkaloids with the flagship pentacyclic
Aspidosperma framework could be guaranteed if we manage to
react iminium ion 7 selectively through reaction path B, which
entails a 6-exo-cyclization via C–C bond formation (Scheme 1).
The synthesis of cis-pyridocarbazole 22 through this discon-
nection is deceptively simple. Our revision indicated that the
vast majority of the related work forges this bond via Bischler–
Napieralski type reactions which, for stereoelectronic reasons,
furnishes a trans-fused pyridocarbazole.22a,d Moreover, the
only directly related effort using
a valerolactam-derived
iminium ion gave a mixture of cis- and trans-pyridocarbazoles
along with the respective compounds derived from C–N bond
formation and over-reduction.22g
Indeed, when we attempted the hemi-reduction/cyclization
of 6 → 22 with DIBAL under the identical conditions to
convert 2,3-disubstituted indole 17 into indolo-naphthyridine
20, the only observable product (even at −78 °C) was the
N-benzylpiperidine 21. The outcome was invariable in spite of
experimental conditions such as solvent (THF/MePH/CH2Cl2),
mode and rate of addition, and reaction temperature. This
observation was later used as a leverage for the total synthesis
of quebrachamine (5) (Scheme 4). The premature over-
reduction of indole–valerolactam 6 could indicate that indole
C-(3) substitution in 17 imposes a necessary conformational
bias for successful iminium trapping.
To solve this problem, we resorted to a lactam electrophilic
activation maneuver that could allow the use of a milder reduc-
tant to control the desired reduction level.14 To this end, the
benzyl group in 6 was interchanged with the electron-with-
drawing tert-butoxycarbonyl group in two steps to afford di-
Total synthesis of quebrachamine (3)
In this unified approach, quebrachamine (3) could be obtained
if iminium ion 7 takes reaction path C, and in this time it
suffers further reduction to the corresponding amine. As
already stated, the unexpected difficulty in controlling the
hemi-reduction of common intermediate 6 was used as an
advantage to access this last topology. Thus, we optimized the
Scheme 5 The
one-pot
hemi-reduction/cyclization/deprotection
process to obtain cis-pyridocarbazole 22b enabled the syntheses of
aspidospermidine (1), vincadifformine (2) and 1,2-dehydroaspidospermi-
dine (3).
Scheme 3 Total synthesis of goniomitine (4) through tandem ester
reduction/iminium generation/cyclization.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9409–9419 | 9411

View Article Online
Paper
Organic & Biomolecular Chemistry
by the indolic nitrogen (path A), the indole C(3) functionali-
zation in 17 was indispensable, whereas indole–valerolactam 6
with the C(3)-position free, reacted through path C leading to
over-reduction under seemingly identical conditions.
Controlling this reactivity was achieved through the lactam
electrophilic activation in di-Boc-6, which allowed the use of a
milder reductant and could also influence the observed selecti-
vity (indole N(1) vs. C(3) cyclization).
Scheme 6 Synthesis of chloroacetamide 25.
For the synthesis of goniomitine (4), a Cu-catalyzed indole
C(3)–H carbene insertion installed an ethoxycarbonylmethyl-
ene moiety which was adjusted to the required hydroxyethyl-
ene motif in tandem with a reductive iminium generation/
cyclization process. On the other hand, a convenient one-pot
hemi-reduction/cyclization/deprotection process to transform
di-Boc-6 in cis-pyridocarbazole 22b directly allowed the syn-
thesis of the pentacyclic Aspidosperma alkaloids 1, 2, and 3.
The convergence of these strategies and methods into common
intermediate 6 effectively increased the chemical efficiency of
all five synthetic targets, as now they share on average 60% of
their synthetic sequence, which allowed the preparation of sig-
nificant quantities (tens of milligrams) of the natural products
with diminished resources and effort.
Scheme 7 Xanthate-based radical-oxidative macrocyclization vs.
Witkop photocyclization for the synthesis of quebrachamine (5).
said reduction and found that the treatment of 6 with Red-Al
in THF at 0 °C furnished the N-benzylpiperidine 21 in quanti-
tative yield. Next, 21 was subjected to hydrogenolysis and the
resulting crude secondary amine was treated with chloroacetyl
chloride resulting in pure chloroacetamide 25 in 72% yield in
the two steps, without the need for any chromatographic oper-
ations (Scheme 6).
Experimental
General information
All reagents and solvents were obtained from Aldrich and
Fluka. Solvents were dried and freshly distilled before use
using appropriate desiccants and nitrogen, unless specified
otherwise. Dichloromethane, acetonitrile, N,N-diisopropyl-
amine, methanol and dimethyl sulfoxide were dried by reflux-
ing them with excess calcium hydride under nitrogen. THF,
toluene and benzene were dried by refluxing them with excess
sodium metal under nitrogen (using benzophenone as an indi-
cator). All laboratory materials were oven dried at 130 °C for
12 hours and cooled under nitrogen prior use. All reactions
were carried out under a positive pressure of nitrogen unless
otherwise specified. All reaction mixtures were magnetically
stirred. All oxygen and/or water sensitive solutions were trans-
ferred via a syringe. The reaction progress was monitored by
analytical thin layer chromatography using GF silica plates.
Visualization was achieved by shortwave UV light (254 nm) and
by phosphomolybdic acid or vanillin TLC-staining. Melting
points were determined on a Fisher apparatus and are uncor-
rected. Flash column chromatography was conducted using
silica gel (230–400 mesh) and mixtures of hexane, ethyl
acetate, methanol or methylene chloride as eluents. 1H and
13C NMR spectra were recorded on Bruker Fourier 300 MHz,
To close the nine-membered ring of quebrachamine,24 we
explored the feasibility of an intramolecular C–C coupling via
a xanthate-based oxidative free radical process.25 Thereupon,
we reacted chloroacetamide 25 with potassium O-ethyl dithio-
carbonate to obtain xanthate 26 in 80% yield, and then pro-
ceeded to test the proposed cyclization. However, under
different oxidative addition conditions,25c,d only complex mix-
tures were obtained in which the desired macrolactam 28
could not be detected. Therefore, we returned to chloroaceta-
mine 25 and executed a Witkop photocyclization mirroring
Pagenkopf’s24d and Gaich’s26 approaches (34% yield). Finally,
reduction of the macrolactam 28 with Red-Al produced quebra-
chamine (5) in 76% yield (Scheme 7). Thus, quebrachamine (5,
42 mg) was synthesized in 12 steps from valerolactam (9) in
6% overall yield
Conclusions
We have developed a unified synthetic approach to five Jeol, Eclipse 300 MHz or Bruker Avance III 400 MHz spec-
Aspidosperma alkaloids distributed within three structurally trometers using CDCl3 or DSMO-d6 as solvents. Chemical
diverse molecular topologies from a single synthetic inter- shifts are reported as parts per million downfield from an
mediate. Chemo-discrimination from the reaction paths A–C internal tetramethylsilane standard (δ = 0.0 for 1H) or from
depicted in Scheme 1 was achieved through the incorporation solvent references. NMR coupling constants are reported in
of electronic and conformational constraints in the common hertz (Hz). High-resolution mass spectra were recorded with
intermediate 6. We found that for successful iminium trapping an AccuTOFLC equipped with an ionSense DART controller
9412 | Org. Biomol. Chem., 2018, 16, 9409–9419
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
1
ionization source. IR spectra were obtained on a Universal (5.6460 g, 93% yield) as a colorless liquid. H NMR (300 MHz,
Diamond ATR top-plate.
chloroform-d) δ 7.34–7.22 (m, 5H), 5.92–5.66 (m, 1H),
5.16–4.93 (m, 2H), 4.58 (d, J = 2.5 Hz, 2H), 3.16 (ddd, J = 8.6,
4.4, 2.7 Hz, 2H), 2.55 (ddt, J = 13.6, 6.8, 1.4 Hz, 1H), 2.22 (ddt, J
1-Benzyl-3-ethylpiperidin-2-one (10)
A dry 500 mL round bottomed flask was charged with valero- = 13.6, 8.0, 1.0 Hz, 1H), 1.89–1.62 (m, 6H), 1.53 (dq, J = 14.7,
lactam (9, 5.0160 g, 50.0942 mmol, 1.0 eq.), and then purged 7.4 Hz, 1H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, chloro-
with nitrogen. Then, 167 mL (0.3 M) of freshly distilled THF form-d) δ 174.5, 137.8, 135.0, 128.6, 128.1, 127.3, 117.8, 50.6,
were injected and valerolactam was readily dissolved. The flask 47.8, 45.3, 43.4, 31.6, 28.9, 19.8, 8.9. IR (cm−1): 2938, 2876,
was cooled in an ice-water bath for 20 minutes and then 11 M 1635, 1490, 1453, 1352, 1196, 913, 737, 701. HRMS: m/z (M + 1)
n-BuLi in hexane (9.6 mL, 105.1971 mmol, 2.1 eq.) was slowly calculated for C17H24NO: 258.18579; found 258.18583.
added via a syringe, and left to react for 1 hour while maintain-
1-Benzyl-3-ethyl-3-(3-hydroxypropyl)piperidin-2-one (12)
ing the ice-water bath. Then, ethyl iodide was injected over a
period of 5 min (11.84 g, 75.1413 mmol, 1.5 eq.) at 0 °C and A solution of BH3·SMe2 (7.9 mL, 6.3547 g, 83.6480 mmol,
allowed to react for 1 hour. The reaction mixture was then 2.5 eq.) in 95 mL of freshly distilled THF was cooled to 0 °C
placed in an acetone/dry-ice bath and left to cool for 15 min. (ice/water bath), and then cyclohexene (17.2 mL, 13.8805 g,
Then benzyl chloride (6.73 g, 52.5989 mmol) was slowly 167.2761 mmol, 5.0 eq.) was slowly injected and left to react
injected, the −78 °C bath was removed after 15 minutes and for 1 hour at 0 °C. Then, a solution of alkene 11 (8.6114 g,
the mixture was allowed to reach room temperature over 33.4592 mmol, 1.0 eq.) in freshly distilled THF (50 mL) was
3 hours. Then, the reaction mixture was treated with 150 mL of slowly injected into the borane solution at 0 °C. The reaction
saturated NH4Cl solution, the phases were separated and the mixture was allowed to reach room temperature overnight. The
aqueous phase was back-extracted two times with EtOAc. All resulting solution was cooled to 0 °C (ice/water bath) and, very
organic phases were put together and dried over Na2SO4 and carefully, 2 M aqueous NaOH (100 mL) was slowly added to the
filtered, and the solvent was removed under reduced pressure reaction flask (CAUTION: very exothermic reaction, gas evol-
and the residue was purified by flash column chromatography ution, use a well vented fume hood), followed by the slow and
(20% EtOAc/hexane r.f. approx. 0.35) to afford 10 (10.4505 g, careful addition of aqueous 30% H2O2 (CAUTION: very
1
98% yield) as a pale yellow liquid. H NMR (300 MHz, chloro- exothermic reaction, gas evolution, use a well vented fume
form-d) δ 7.32–7.13 (m, 5H), 4.54 (s, 2H), 3.13 (dd, J = 7.1, hood). The reaction was allowed to reach room temperature
4.9 Hz, 2H), 2.37–2.16 (m, 1H), 2.93–1.73 (m, 3H), 1.70–1.45 (s, and stirred for 24 hours. Then, the solids were filtered, and
3H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, chloroform-d) the liquid phases were separated. The aqueous phase was
δ 172.7, 137.7, 128.6, 128.0, 127.3, 50.3, 47.5, 43.0, 25.9, 25.0, 21.7, extracted two times with EtOAc. All organic phases were put
11.6. IR (cm−1): 2932, 2868, 1631, 1491, 1447, 699. HRMS: m/z together and dried over Na2SO4 and filtered, and the solvent
(M + 1) calculated for C14H20NO: 218.15448; found: 218.15459.
was removed under reduced pressure and the residue was
purified by flash column chromatography (30 → 70% EtOAc/
hexane, 70% EtOAc/hexane r.f. approx. 0.35) to afford a color-
3-Allyl-1-benzyl-3-ethylpiperidin-2-one (11)
A dry 250 mL round bottomed flask was charged with freshly less liquid which needed to be redissolved in EtOAc and
distilled N,N-diisopropylamine (3.7 mL, 2.6387 g, washed with water, to obtain pure 12 (5.3444 g, 58% yield) as a
25.9463 mmol, 1.1 eq.) and then 13 mL of freshly distilled colorless liquid after drying and removal of the volatiles.
THF (2.0 M) was added and the mixture was cooled to −78 °C 1H NMR (300 MHz, chloroform-d) δ 7.33–7.21 (m, 5H), 4.66
in an acetone/dry ice bath. Then, 11 M n-BuLi in hexane (d, J = 14.5 Hz, 1H), 4.48 (d, J = 14.5 Hz, 1H), 3.59 (m, 2H), 3.18
(2.4 mL, 25.9463 mmol, 1.1 eq.) was slowly added via a syringe. (m, 2H), 1.99–1.38 (m, 6H), 1.37–1.13 (m, 2H), 0.87 (t, J =
The −78 °C bath was replaced with an ice/water bath and the 7.5 Hz, 3H). 13C NMR (75 MHz, chloroform-d) δ 175.4, 137.6,
reaction mixture was stirred for 20 minutes. Then, this LDA 128.7, 128.2, 127.4, 62.9, 50.7, 47.8, 44.9, 35.6, 34.2, 31.9, 29.0,
solution was cooled to −78 °C for 10 minutes and a solution of 27.8, 25.5, 24.2, 19.8, 8.7. IR (cm−1): 3405, 2938, 2868, 1610,
compound 10 (5.1258 g, 23.5875 mmol, 1.0 eq.) in 62 mL of 1491, 1449, 1196, 736, 700. HRMS: m/z (M + 1) calculated for
freshly distilled THF was slowly transferred via a syringe under C17H26NO2: 276.19635; found 276.19698.
nitrogen, and left to react for 45 minutes at −78 °C. Then allyl
bromide (2.3 mL, 3.24 g, 25.9463 mmol, 1.1 eq.) was slowly
3-(1-Benzyl-3-ethyl-2-oxopiperidin-3-yl)propanal (13)
injected, and the reaction mixture was allowed to reach room A solution of anhydrous DMSO (1.51 mL, 1.66 g, 21.00 mmol,
temperature over 3 hours. After the reaction was complete (as 1.1 eq.) in freshly distilled CH2Cl2 (45 mL) was cooled to
judged by TLC), the reaction mixture was treated with 150 mL −78 °C (acetone/dry ice) and oxalyl chloride (1.81 mL, 2.72 g,
of saturated NH4Cl solution, the phases were separated and 21.00 mmol, 1.1 eq.) was slowly added via a syringe. After
the aqueous phase was back-extracted two times with EtOAc. 5 minutes of stirring at −78 °C, a solution of alcohol 12
All organic phases were put together and dried over Na2SO4 (5.2593 g, 19.098 mmol, 1.0 eq.) in freshly distilled CH2Cl2
and filtered, and the solvent was removed under reduced (45 mL) was slowly added to the dimethyl chlorosulphonium
pressure and the residue was purified by flash column chrom- solution while maintaining the system at −78 °C and reacting
atography (10% EtOAc/hexane, r.f. approx. 0.35) to afford 11 for 15 minutes. Then triethylamine (13.4 mL, 9.8 g,
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9409–9419 | 9413

View Article Online
Paper
Organic & Biomolecular Chemistry
95.49 mmol, 5.0 eq.) was slowly added and the reaction thaw method (6 cycles, using an acetone/dry ice bath for freez-
mixture was stirred for a further 10 minutes at −78 °C, and ing, and a room temperature water bath for thawing). Then, a
then left to reach room temperature over 30 minutes. When mixture of Pd(PPh3)2Cl2 (0.2666 g, 0.3723 mmol, 0.03 eq.) and
the reaction was complete (as judged by TLC), the mixture was CuI (0.1688 g, 0.8686 mmol, 0.07 eq.) was added under nitro-
treated with 100 mL of saturated NH4Cl solution, the phases gen, and Et2NH (2.94 mL, 1.3682 g, 18.6127 mmol, 1.5 eq.) was
were separated and the aqueous phase was back-extracted two injected. The reaction mixture was put in a pre-heated oil bath
times with CH2Cl2. All organic phases were put together and at 50–55 °C and stirred for 2 hours. After the reaction was com-
dried over Na2SO4 and filtered, and the solvent was removed plete (as judged by TLC), the mixture was partitioned in EtOAc
under reduced pressure and the residue was purified by flash (150 mL) and saturated NH4Cl (150 mL), and the organic layer
column chromatography (35% EtOAc/hexane, r.f. approx. 0.35) was washed five times with water (100 mL). The organic phase
to afford 13 (4.590 g, 87% yield) as a pale yellow liquid. 1H was dried over Na2SO4 and filtered, and the solvent was
NMR (300 MHz, chloroform-d) δ 9.76 (t, J = 1.6 Hz, 1H), removed under reduced pressure and the residue was purified
7.34–7.20 (m, 5H), 4.64 (d, J = 14.5 Hz, 1H), 4.46 (d, J = 14.5 by flash column chromatography (30% EtOAc/hexane, r.f.
Hz, 1H), 3.18 (m, 2H), 2.67–2.38 (m, 2H), 2.02–1.71 (m, 6H), approx. 0.35) to afford 15 (4.430 g, 97% yield) as a yellow
1.63–1.49 (m, 2H), 0.87 (t, J = 7.5, 3H). 13C NMR (75 MHz, syrup. 1H NMR (300 MHz, chloroform-d, rotamer mixture)
chloroform-d) δ 202.5, 174.1, 137.6, 128.7, 128.1, 127.4, 50.6, δ 7.34–7.20 (m, 12H), 7.09–7.02 (m, 2H), 6.69–6.60 (m, 4H),
47.8, 44.3, 39.8, 31.0, 30.2, 29.8, 19.6, 8.6. IR (cm−1): 2936, 4.68 (d, J = 14.5 Hz, 1H), 4.62 (d, J = 14.5 Hz, 1H), 4.50 (d, J =
2874, 1721, 1625, 1491, 1449, 1351, 1260, 1195, 955, 735, 700. 14.5 Hz, 1H), 4.45 (d, J = 14.5 Hz, 1H), 4.24 (br, 1H), 3.21–3.14
HRMS: m/z (M + 1) calculated for C17H24NO2: 274.18070; (m, 2H), 2.62–2.43 (m, 2H), 2.31 (t, J = 8.0 Hz, 1H), 2.19–2.09
found 274.18065.
(m, 2H), 1.91–1.67 (m, 10H), 1.65–1.50 (m, 2H), 1.28–1.18 (m,
1H), 0.90 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR
(75 MHz, chloroform-d, rotamer mixture) δ 174.2, 174.0, 148.0,
1-Benzyl-3-(but-3-yn-1-yl)-3-ethylpiperidin-2-one (8)
NOTE: Ohira–Bestmann diazophosphonate 14 was prepared 137.7, 132.1, 129.0, 128.7, 128.1, 127.4, 117.8, 114.2, 108.8,
using a literature procedure.1 To a solution of aldehyde 13 95.7, 50.6, 47.8, 45.0, 44.9, 37.8, 37.0, 31.5, 31.1, 29.3, 19.9,
(4.4341 g, 16.2201 mmol, 1.0 eq.) in freshly distilled MeOH 19.7, 15.0, 8.8, 8.7. IR (cm−1): 3449, 3281, 2936, 2873, 1611,
(200 mL), was added anhydrous K2CO3 (4.6741 g, 1490, 1451, 1195, 734, 798. HRMS: m/z (M + 1) calculated for
32.4403 mmol, 2.0 eq.) under nitrogen, and the mixture was C17H24NO2: 361.22799; found 361.22740.
stirred vigorously for 10 minutes. Then, a solution of diazo-
3-(2-(1H-Indol-2-yl)ethyl)-1-benzyl-3-ethylpiperidin-2-one (6)
phosphonate 14 (4.6741 g, 24.3302 mmol, 1.5 eq.) in freshly
distilled MeOH (30 mL) was slowly added via a syringe, and To a solution of alkynylaniline 15 (6.1941 g, 17.1824 mmol,
the reaction mixture was stirred overnight (12 hours approx.). 1.0 eq.) in freshly distilled toluene (80 mL) was added ZnI2
When the reaction was complete (as judged by TLC), the vola- (1.0969 g, 3.4365 mmol) under nitrogen and heated to reflux
tiles were removed under reduced pressure and the residue for 1 hour. After the reaction was complete (as judged by TLC),
was partitioned in EtOAc (150 mL) and water (150 mL), and the reaction mixture was treated with water (100 mL), and the
the aqueous layer was back-extracted two times with EtOAc. All organic layer was dried over Na2SO4 and filtered, and the
organic phases were put together and dried over Na2SO4 and solvent was removed under reduced pressure and the residue
filtered, and the solvent was removed under reduced pressure was purified by flash column chromatography (30% EtOAc/
and the residue was purified by flash column chromatography hexane, r.f. approx. 0.35) to afford indole 6 (5.5747 g, 90%
(15% EtOAc/hexane, r.f. approx. 0.35) to afford 8 (4.110 g, 94% yield) as a yellow syrup. 1H NMR (300 MHz, chloroform-d)
1
yield) as a colorless liquid. H NMR (300 MHz, chloroform-d) δ 8.81 (br, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.36–7.22 (m, 6H),
δ 7.34–7.30 (m, 2H), 7.27–2.23 (m, 3H), 4.62 (d, J = 14.5 Hz, 7.17–6.99 (m, 2H), 6.23 (s, 1H), 4.70 (d, J = 14.6 Hz, 1H), 4.55
1H), 4.53 (d, J = 14.5 Hz, 1H), 3.19 (t, J = 5.7 Hz, 2H), 2.25 (d, J = 14.6 Hz, 1H), 3.23 (m, 2H), 2.88 (ddd, J = 14.4, 10.8,
(dddd, J = 9.1, 6.1, 3.6, 2.7 Hz, 2H), 2.01 (ddd, J = 13.6, 10.0, 6.0 Hz, 1H), 2.69 (ddd, J = 14.8, 10.7, 4.5 Hz, 1H), 2.23 (ddd, J =
6.4 Hz, 1H), 1.94 (t, J = 2.7 Hz, 1H), 1.85–1.71 (m, 6H), 1.56 13.7, 10.9, 4.5 Hz, 1H), 1.94–1.63 (m, J = 32.6 Hz, 8H), 1.28 (m,
(dq, J = 13.7, 7.4 Hz, 1H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR 1H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, chloroform-d)
(75 MHz, chloroform-d) δ 173.9, 137.6, 128.5, 128.0, 127.3, δ 175.1, 140.2, 137.6, 136.3, 128.8, 128.1, 127.5, 120.9, 119.7,
84.8, 68.2, 50.5, 47.6, 44.8, 37.3, 31.0, 29.3, 19.7, 14.1, 8.6. IR 119.4, 110.7, 99.1, 50.8, 47.9, 45.6, 38.2, 31.7, 29.2, 24.0, 19.7,
(cm−1): 3296, 3234, 2937, 2874, 2116, 1626, 1490, 1448, 1352, 8.7. IR (cm−1): 3270, 2939, 2871, 1609, 1491, 1454, 1348, 1286,
1258, 1193, 734, 799, 630. HRMS: m/z (M + 1) calculated for 1198, 781, 738, 698. HRMS: m/z (M + 1) calculated for
C18H24NO: 270.18579; found 270.18650.
C17H24NO2: 361.22799; found 361.22871.
3-(4-(2-Aminophenyl)but-3-yn-1-yl)-1-benzyl-3-ethylpiperidin-2- Ethyl 2-(2-(2-(1-benzyl-3-ethyl-2-oxopiperidin-3-yl)ethyl)-1H-indol-
one (15) 3-yl)acetate (17)
A solution of terminal alkyne 8 (3.3426 g, 12.4085 mmol, 1.0 A solution of common intermediate 6 (0.3105 g, 0.8613 mmol,
eq.) and o-iodoaniline (2.6594 g, 13.6493 mmol, 1.1 eq.) in 1.0 eq.) in freshly distilled benzene (4.5 mL) in a CEM micro-
anhydrous DMF (38 mL) was degassed by the freeze–pump– wave vial was degassed by the freeze–pump–thaw method
9414 | Org. Biomol. Chem., 2018, 16, 9409–9419
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
(5 cycles), then 87% ethyl diazoacetate in CH2Cl2 (0.156 mL, Goniomitine (4)
1.2920 mmol, 1.5 eq.) was added via a syringe, and the reac-
To a solution of N-benzylamine 20 (0.1517 g, 0.3904 mmol,
1.0 eq.) in absolute ethanol (9 mL) and acetic acid (18 mL) was
added Pd(OH)2/C (0.3034 g), then the system was purged with
hydrogen gas and maintained under a hydrogen balloon for
2 hours. When the reaction was complete (as judged by TLC),
the reaction mixture was filtered through a Celite pad, and the
volatiles were removed under reduced pressure. The residue
was redissolved in CH2Cl2 and treated with 1 M aq. NaOH until
pH 10 was reached. The layers were separated and the aqueous
phase was back-extracted twice with CH2Cl2. All organic phases
were put together and dried over Na2SO4 and filtered, and the
solvent was removed under reduced pressure and the residue
was purified by flash column chromatography (r.f. approx. 0.30,
5% MeOH/CH2Cl2) to afford synthetic goniomitine (4) (0.0815 g,
70% yield) as a white semisolid. The analytical data match the
data in the literature.20c 1H NMR (300 MHz, chloroform-d)
δ 7.52 (d, J = 7.9 Hz, 1H), 7.29 (m, 1H), 7.23–7.02 (m, 2H), 4.79
(s, 1H), 3.82 (s, 1H), 3.82 (t, J = 6.5 Hz, 2H), 3.08–2.98 (m, 2H),
2.97–2.90 (m, 2H), 2.90–2.74 (m, 2H), 2.51 (td, J = 12.9, 6.7 Hz,
1H), 1.94–1.84 (m, 1H), 1.84–1.40 (m, 8H), 1.20 (m, 2H),
0.94–0.82 (m, 3H). 13C NMR (75 MHz, chloroform-d) δ 135.5,
132.8, 129.1, 120.6, 119.6, 118.2, 108.3, 106.0, 71.6, 62.7, 45.7,
35.2, 34.1, 28.7, 27.8, 21.7, 21.7, 18.6, 7.2. IR (cm−1): 3300, 2925,
2853, 1460, 1356, 1309, 1190, 1113, 1043, 1014, 735. HRMS: m/z
(M + 1) calculated for C26H33N2O: 299.21234; found: 299.21104.
tion mixture was heated under microwave assistance at 85 °C
for 1 hour. Then, 87% ethyl diazoacetate in CH2Cl2 (0.156 mL,
1.2920 mmol, 1.5 eq.) was added via a syringe, and the reac-
tion mixture was heated under microwave assistance at 85 °C
for another hour. Then the volatiles were removed under
reduced pressure, and the residue was purified by flash
column chromatography (25% EtOAc/hexane r.f. approx. 0.30)
to afford indoleacetate 17 (0.2076 g, 54% yield) as a yellow
syrup. 1H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 7.47 (d,
J = 6.9 Hz, 1H), 7.25–7.15 (m, 6H), 7.05–6.98 (m, 2H), 4.61 (d,
J = 14.6 Hz, 1H), 4.48 (d, J = 14.6 Hz, 1H), 4.03 (q, J = 7.1 Hz,
2H), 3.60 (s, 2H), 3.19–3.16 (m, 2H), 2.86 (ddd, J = 14.4, 10.4,
6.5 Hz, 1H), 2.52 (ddd, J = 14.5, 10.5, 4.4 Hz, 1H), 2.09 (ddd, J =
13.9, 10.4, 4.3 Hz, 1H), 1.81–1.68 (m, 6H), 1.61 (dd, J = 13.8,
7.5 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). 13
C
NMR (100 MHz, chloroform-d) δ 175.1, 172.1, 137.4, 135.3,
128.7, 127.9, 127.4, 121.1, 119.2, 118.2, 110.6, 103.7, 60.6, 50.7,
47.8, 45.8, 37.9, 31.6, 30.6, 29.1, 21.7, 19.6, 14.3, 8.5. IR (cm−1):
3275, 2936, 1729, 1609, 1491, 1458, 1261, 1194, 1160, 1030,
739, 700. HRMS: m/z (M + 1) calculated for C28H35N2O3:
447.26477; found: 447.26410.
N-Benzyl goniomitine (20)
A solution of indoleacetate 17 (0.4039 g, 0.9044 mmol, 1.0 eq.)
in freshly distilled THF (56 mL) was cooled to −78 °C (acetone/
dry ice bath) and then 1 M DIBAL in heptane (5.0 mL,
4.9744 mmol, 5.5 eq.) was added dropwise and left to react for
tert-Butyl 2-(2-(1-(tert-butoxycarbonyl)-3-ethyl-2-oxopiperidin-
3-yl)ethyl)-1H-indole-1-carboxylate (di-Boc-6)
20 min at −78 °C. Then the cryogenic bath was removed and A solution of common intermediate 6 (1.5542 g, 4.3114 mmol,
the reaction mixture was allowed to reach room temperature 1.0 eq.) and anhydrous tBuOH (4.7 mL) in freshly distilled
over 1.5 hours. When the reaction was complete (as judged by THF (110 mL) in a round bottomed two necked flask was
TLC), the reaction mixture was cooled to 0 °C (ice/water bath) cooled to −78 °C (acetone/dry ice bath), and then, freshly con-
and was carefully quenched with aq. sat. potassium sodium densed liquid ammonia (77 mL) was slowly added to the reac-
tartrate (30 mL), the cold bath was removed and the reaction tion flask through one of the mouths under a positive pressure
mixture was stirred vigorously for 1 hour. The layers were sep- of nitrogen, and the system was stirred at −78 °C for
arated and the aqueous phase was back-extracted twice with 10 minutes. Then, sodium metal in small pieces (0.5174 g,
EtOAc. All organic phases were put together and dried over 21.5567 mmol, 5.0 eq.) was added to the reaction flask in a
Na2SO4 and filtered, and the solvent was removed under single operation through one of the mouths of the flask under
reduced pressure and the residue was purified by flash column a positive pressure of nitrogen, and the reaction mixture was
chromatography (r.f. approx. 0.30, 20% EtOAc/hexane) to vigorously stirred for 40 minutes. When 6 was consumed (as
afford N-benzyl goniomitine (20) (0.1410 g, 40% yield) as a judged by TLC), the reaction mixture was treated with solid
colorless syrup. 1H NMR (400 MHz, chloroform-d) δ 7.49 (d, NH4Cl (3.12 g), the cryogenic bath was removed, the reaction
J = 7.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.20–6.98 (m, 7H), mixture was exposed to the atmosphere and allowed to reach
4.33 (s, 1H), 3.78 (t, J = 6.4 Hz, 2H), 3.58 (d, J = 13.4 Hz, 1H), room temperature while the ammonia was evaporated comple-
3.20 (ddd, J = 16.4, 9.5, 5.3 Hz, 1H), 3.00–2.87 (m, 5H), 2.50 tely, under constant stirring in a well vented fume hood. Water
(ddd, J = 13.6, 9.5, 5.8 Hz, 1H), 2.18 (td, J = 12.1, 2.8 Hz, 1H), (50 mL) was added, and the organic layer was separated. The
1.89–1.76 (m, 1H), 1.75–1.67 (m, 1H), 1.54–1.41 (m, 4H), aqueous layer was back-extracted with CH2Cl2 (30 mL × 2). All
1.38–1.23 (m, 2H), 0.98–0.79 (m, 3H), 0.69 (t, J = 7.4 Hz, 3H). organic phases were put together and dried over Na2SO4 and
13C NMR (100 MHz, chloroform-d) δ 140.0, 137.4, 134.3, filtered, and the solvent was removed under reduced pressure
128.4, 128.1, 127.9, 126.4, 120.4, 119.2, 117.9, 108.7, 105.5, and the crude solid (1.1537 g) was used without further purifi-
62.7, 57.7, 52.5, 38.5, 33.8, 30.9, 27.7, 24.2, 21.3, 18.3, 7.6. IR cation in the next step. The crude solid was dissolved in
(cm−1): 3370, 2930, 1460, 1360, 1310, 1199, 1131, 1032, 734, CH2Cl2 (90 mL), then di-tert-butyl dicarbonate (4.04 mL,
698. HRMS: m/z (M + 1) calculated for C26H33N2O: 389.25929; 3.8407 g, 17.2456 mmol, 4.0 eq.) followed by triethylamine
found: 389.25914.
(2.42 mL, 1.763 g, 17.2456 mmol, 4.0 eq.) were added to the
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9409–9419 | 9415

View Article Online
Paper
Organic & Biomolecular Chemistry
reaction flask, and the reaction mixture was heated to reflux overnight with vigorous stirring. When the reaction was com-
without any moisture/oxygen excluding considerations for plete (as judged by TLC), the reaction mixture was allowed to
15 hours. When the reaction was complete (as judged by TLC), reach room temperature, the volatiles were removed under
water (50 mL) was added, the phases were separated and the reduced pressure, and the residue was partitioned between
aqueous phase was back-extracted two times with CH2Cl2. All EtOAc and water. The layers were separated and the aqueous
organic phases were put together and dried over Na2SO4 and phase was back-extracted two times with EtOAc. All organic
filtered, and the solvent was removed under reduced pressure phases were put together and dried over Na2SO4 and filtered,
and the residue was purified by flash column chromatography and the solvent was removed under reduced pressure and the
(10% EtOAc/hexane r.f. approx. 0.40) to afford di-Boc-6 residue was purified by flash column chromatography (r.f.
(1.7388 g, 86% yield in two steps) as a colorless syrup. 1H NMR approx. 0.35, 25% acetone/hexane + 10% NEt3) to afford
(300 MHz, chloroform-d) δ 8.03 (d, J = 8.8 Hz, 1H), 7.45–7.42 hydroxylamine 23 (0.8280 g, 87% yield) as a colorless syrup.
1
(m, 1H), 7.25–7.14 (m, 2H), 6.38 (s, 1H), 3.64 (t, J = 5.2 Hz, 3H), The analytical data match the data in the literature. H NMR
3.15–2.88 (m, 2H), 2.11–1.46 (m, 8H), 1.68 (s, 9H), 1.51 (s, 9H), (300 MHz, chloroform-d) δ 8.48 (s, br, 1H), 7.47–7.44 (m, 1H),
0.92 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, chloroform-d) 7.19–7.16 (m, 1H), 7.10–7.07 (m, 2H), 3.48 (m, 2H), 3.25–3.09
δ 176.8, 154.0, 150.6, 142.5, 136.5, 129.4, 123.3, 122.6, 119.8, (m, 5H), 2.66–2.56 (m, 3H), 2.30–2.21 (m, 2H), 1.90–1.70 (m,
115.6, 106.8, 83.7, 82.5, 48.2, 47.3, 36.5, 30.9, 30.6, 28.4, 28.1, 2H), 1.66–1.57 (m, 1H), 1.50–1.34 (m, 2H), 1.22–1.12 (m, 1H),
24.8, 20.2, 8.6. IR (cm−1): 2974, 2936, 2880, 1765, 1716, 1453, 0.99–0.87 (m, 1H), 0.74 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz,
1326, 1298, 1275, 1253, 1146, 1116, 1085, 851, 741. HRMS: m/z chloroform-d) δ 136.2, 135.8, 129.9, 120.8, 119.3, 117.7, 110.7,
(M + 1) calculated for C27H39N2O5: 471.28590; found: 471.2861. 110.1, 63.1, 56.0, 54.3, 52.5, 37.1, 34.8, 29.7, 24.3, 22.1, 20.3,
8.0. IR (cm−1): 3391, 3056, 2931, 2877, 2793, 1461, 1381, 1330,
4a-Ethyl-2,3,4,4a,5,6,7,11c-octahydro-1H-pyrido[3,2-c]carbazole
1260, 1124, 1040, 742. HRMS: m/z (M + 1) calculated for
(22b)
C19H27N2O: 299.21234; found: 299.21242.
A solution of di-boc-6 (1.7388 g, 3.6949 mmol, 1.0 eq.) in
freshly distilled CH2Cl2 (37 mL) was cooled to −78 °C (acetone/
Aspidospermidine (1)
dry ice bath), and 1 M LiEt3BH in THF (4.44 mL, 4.44 mmol, A solution of hydroxylamine 23 (0.1294 g, 0.4335 mmol,
1.2 eq.) was slowly added via a syringe, and left to react for 1.0 eq.) in freshly distilled CH2Cl2 (3 mL) was cooled to
30 min at −78 °C. Then, the system was opened and CF3CO2H approximately −10 °C (ice/NaCl/water bath), then triethyl-
(37 mL) was added slowly at −78 °C, and when the addition amine (0.122 mL, 0.088 g, 0.8671 mmol, 2.0 eq.) was injected
was complete, the reaction mixture was allowed to reach room followed by methanesulfonyl chloride (0.064 mL, 0.0948 g,
temperature with stirred overnight. Then the volatiles were 0.8237, 1.9 eq.), and stirred at that temperature for
removed under reduced pressure, the residue was redissolved 40 minutes. When the reaction was complete (as judged by
in CH2Cl2 and treated with 1 M NaOH until pH 10–11 was TLC), 1 M t-BuOK in THF was added (2.17 mL, 2.1675 mmol,
achieved. The layers were separated and the aqueous phase 5.0 eq.) and the reaction mixture was allowed to reach room
was back-extracted two times with CH2Cl2. All organic phases temperature over 1.5 hours. When the reaction was complete
were put together and dried over Na2SO4 and filtered, and the (as judged by TLC), the mixture was cooled to 0 °C (ice/water
solvent was removed under reduced pressure to obtain, bath) and
1 M LiEt3BH in THF was added (3.5 mL,
without any further purification, pure carbazole 22b (0.9359 g, 3.468 mmol, 8.0 eq.), and the reaction mixture was allowed to
98%, r.f. approx. 0.35, 25% acetone/hexane + 10% NEt3) as a reach room temperature over 1.0 hour. When the reaction was
white solid. The analytical data match the data in the litera- complete (as judged by TLC), the mixture was quenched with
ture.1 1H NMR (300 MHz, chloroform-d) δ 8.38 (s, br, 1H), 7.56 5 mL of aq. sat. NH4Cl (5 mL), the layers were separated and
(m, 1H), 7.21–7.18 (m, 1H), 7.11–7.05 (m, 2H), 3.71 (s, 1H), the aqueous phase was back-extracted two times with EtOAc.
3.03 (d, J = 12.5 Hz, 1H), 2.76 (td, J = 12.3, 11.7, 3.4 Hz, 2H), All organic phases were put together and dried over Na2SO4
2.57 (dd, J = 8.4, 3.9 Hz, 3H), 2.47–2.13 (m, 1H), 1.81 (d, J = and filtered, and the solvent was removed under reduced
13.0 Hz, 1H), 1.71–1.37 (m, 6H), 1.17–1.03 (m, 1H), 0.84 (t, J = pressure and the residue was purified by flash column chrom-
7.5 Hz, 3H). 13C NMR (75 MHz, chloroform-d) δ 136.3, 134.6, atography (r.f. approx. 0.30, 10% acetone/hexane + 10% NEt3)
127.5, 120.9, 119.2, 117.6, 111.9, 110.7, 56.7, 46.2, 34.6, 34.2, to afford synthetic aspidospermidine 1 (0.0498 g, 41% yield) as
29.6, 24.2, 22.7, 20.1, 7.7. IR (cm−1): 3058, 2926, 2880, 1451, a white solid. The analytical data match the data in the litera-
1304, 1204, 1113, 898, 871, 734. HRMS: m/z (M + 1) calculated ture.22e 1H NMR (400 MHz, chloroform-d) δ 7.07 (d, J = 7.3 Hz,
for C17H17N2: 255.18612; found: 255.18615.
1H), 7.01 (td, J = 7.6, 1.1 Hz, 1H), 6.72 (td, J = 7.4, 1.0 Hz, 1H),
6.63 (d, J = 7.6 Hz, 1H), 3.51 (s, br, 1H), 3.12–3.05 (m, 2H),
2.34–2.18 (m, 2H), 2.01–1.90 (m, 2H), 1.81–1.70 (m, 1H),
1.68–1.60 (m, 3H), 1.53–1.33 (m, 4H), 1.16–1.02 (m, 1H), 0.87
2-(4a-Ethyl-2,3,4,4a,5,6,7,11c-octahydro-1H-pyrido[3,2-c]
carbazol-1-yl)ethan-1-ol (23)
To a solution of pyridocarbazole 22b (0.8111 g, 3.1887 mmol, (dq, J = 14.5, 7.4 Hz, 1H), 0.64 (t, J = 7.5 Hz, 3H). 13C NMR
1.0 eq.) in absolute ethanol (80 mL) was added 2-bromoetha- (100 MHz, chloroform-d) δ 149.4, 135.7, 127.1, 122.8, 119.0,
nol (3.55 mL, 6.2567 g, 47.8299 mmol, 15 eq.), followed by 110.3, 71.3, 65.7, 53.9, 53.4, 53.0, 38.8, 35.7, 34.5, 30.0, 28.1,
Na2CO3 (5.0695 g, 47.8299 mmol, 15 eq.) and was refluxed 23.0, 21.8, 6.8. IR (cm−1): 3362, 3282, 2929, 2859, 2777, 2721,
9416 | Org. Biomol. Chem., 2018, 16, 9409–9419
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
1605, 1480, 1461, 1340, 1257, 1178, 1025, 903, 865, 740. HRMS: 1H), 6.79 (ddd, J = 7.8, 1.0, 0.6 Hz, 1H), 3.76 (s, 3H), 3.16–3.05
m/z (M + 1) calculated for C19H27N2: 283.21742; found: 283.21753. (m, 1H), 3.00–2.83 (m, 1H), 2.71 (d, J = 15.2 Hz, 1H), 2.61–2.49
(m, 1H), 2.48–2.33 (m, 1H), 2.27 (d, J = 15.1 Hz, 1H), 2.11–1.96
Dehydroaspidospermidine (3)
(m, 1H), 1.90–1.75 (m, 1H), 1.74–1.65 (m, 1H), 1.65–1.48 (m,
A solution of hydroxylamine 23 (0.2925 g, 0.9800 mmol, 1.0 2H), 1.33–1.17 (m, 2H), 1.02–0.88 (m, 1H), 0.69–0.48 (m, 4H).
eq.) in freshly distilled CH2Cl2 (7 mL) was cooled to approxi- 13C NMR (75 MHz, chloroform-d) δ 169.1, 167.8, 143.2, 137.9,
mately −10 °C (ice/NaCl/water bath), then triethylamine 127.5, 120.5, 109.3, 92.6, 77.4, 77.2, 77.0, 76.6, 72.7, 55.5, 51.8,
(0.276 mL, 0.2003 g, 1.960 mmol, 2.0 eq.) was injected followed 51.0, 50.6, 45.2, 38.1, 32.8, 29.4, 25.7, 22.1, 7.1. IR (cm−1):
by methanesulfonyl chloride (0.145 mL, 0.2144 g, 3361, 2930, 2768, 1673, 1605, 1477, 1460, 1435, 1278, 1253,
1.8620 mmol, 1.9 eq.), and stirred at that temperature for 1206, 1236, 1155, 1124, 1110, 1043, 747. HRMS: m/z (M + 1)
40 minutes. When the reaction was complete (as judged by calculated for C21H27N2O2: 339.20725; found: 339.20718.
TLC), 1 M t-BuOK in THF was added (4.90 mL, 4.90 mmol,
2-(2-(1-Benzyl-3-ethylpiperidin-3-yl)ethyl)-1H-indole (21)
5.0 eq.) and the reaction mixture was allowed to reach room
temperature over 1.5 hours. When the reaction was complete A solution of common intermediate 6 (1.7181 g, 4.7660 mmol,
(as judged by TLC), the mixture was quenched with 5 mL of 1.0 eq.) in freshly distilled THF (100 mL) was cooled to 0 °C
aq. sat. NH4Cl (10 mL), the layers were separated and the (ice/water bath) and then 60% Red-Al in MePh (10.9 mL,
aqueous phase was back-extracted two times with EtOAc. All 33.3621 mmol, 7.0 eq.) was slowly added through one of the
organic phases were put together and dried over Na2SO4 and necks of the flask, and stirred for 1 hour. When the reaction
filtered, and the solvent was removed under reduced pressure was complete (as judged by TLC), the reaction mixture was
and the residue was purified by flash column chromatography carefully quenched with aq. sat. potassium sodium tartrate
(r.f. approx. 0.30, 10% acetone/hexane + 10% NEt3) to afford (100 mL) at 0 °C, the cold bath was removed and the reaction
synthetic 1,2-dehydroaspidospermidine 3 (0.1143 g, 42% yield) mixture was stirred vigorously for 1 hour. The layers were sep-
as a colorless semisolid. The analytical data match the data in arated and the aqueous phase was back-extracted twice with
the literature.6a 1H NMR (300 MHz, chloroform-d) δ 7.52 (d, J = EtOAc. All organic phases were put together and dried over
7.6 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), Na2SO4 and filtered, and the solvent was removed under
7.17 (t, J = 7.4 Hz, 1H), 3.22–3.15 (m, 2H), 2.77 (t, J = 12.3 Hz, reduced pressure and the residue was purified by flash column
1H), 2.79 (d, J = 10.7 Hz, 1H), 2.60 (ddd, J = 12.2, 8.3, 5.7 Hz, chromatography (r.f. approx. 0.40, 20% acetone/hexane) to
1H), 2.52–2.41 (m, 2H), 2.25–2.11 (m, 3H), 1.98–1.75 (m, 1H), afford N-benzylamine 21 (1.6514 g, 100% yield) as a colorless
1.72–1.27 (m, 3H), 1.03 (dd, J = 13.5, 4.8 Hz, 1H), 0.99 (dd, J = syrup. 1H NMR (300 MHz, chloroform-d) δ 8.10 (s, br, 1H), 7.54
13.5, 4.8 Hz, 1H), 0.78–0.54 (m, 2H), 0.50 (t, J = 7.1 Hz, 3H). (d, J = 9.5 Hz, 1H), 7.39–7.25 (m, 6H), 7.18–7.02 (m, 2H), 6.24
13C NMR (75 MHz, chloroform-d) δ 192.3, 154.5, 147.1, 127.4, (s, 1H), 3.52 (d, J = 13.4 Hz, 2H), 3.44 (d, J = 13.2 Hz, 1H),
125.1, 121.0, 120.1, 79.0, 61.3, 54.6, 52.0, 36.5, 35.2, 33.2, 29.7, 2.66–2.44 (m, 3H), 2.34–2.22 (m, 2H), 2.03–1.89 (m, 2H),
27.2, 23.7, 22.0, 7.3. IR (cm−1): 2929, 2975, 2719, 1575, 1457, 1.74–1.57 (m, 3H), 1.59–1.24 (m, 5H), 0.82 (t, J = 7.6 Hz, 3H).
1323, 1192, 739. HRMS: m/z (M + 1) calculated for C19H25N2: 13C NMR (75 MHz, chloroform-d) δ 140.8, 136.0, 129.1, 129.0,
281.20177; found: 281.20183.
128.3, 127.9, 120.9, 119.8, 119.6, 110.4, 99.1, 63.5, 62.2, 55.1,
35.9, 34.0, 22.1, 22.0, 7.5. IR (cm−1): 3406, 2931, 1455, 1287,
1122, 780, 700, 738, 698. HRMS: m/z (M + 1) calculated for
Vincadifformine (2)
A solution of 1,2-dehydroaspidospermidine (3) (0.0350 g, C24H31N2: 347.24872; found: 347.24881.
0.1248 mmol, 1.0 eq.) in freshly distilled THF (1 mL) was
cooled to −78 °C (dry ice/acetone bath), then 2.5 M n-BuLi in
hexanes (0.2 mL, 0.1977 mmol, 1.6 eq.) was added dropwise
1-(3-(2-(1H-Indol-2-yl)ethyl)-3-ethylpiperidin-1-yl)-2-
chloroethan-1-one (25)
through one of the necks of the reaction flask, and stirred for To a solution of benzylamine 21 (0.500 g, 1.4430 mmol,
30 minutes at −78 °C. Then MeOCOCN (Mander’s reagent) 1.0 eq.) in methanol (16 mL) was added Pd/C (0.500 g), and
was added (0.0160 mL, 0.0172 g, 0.1977 mmol, 1.6 eq.), the then, ammonium formate (0.4550, 7.2147 mmol, 5.0 eq.) was
cryogenic bath was removed, and the reaction mixture was added in portions (CAUTION: use a well vented hood. In some
allowed to reach room temperature over 30 minutes. Then the of the runs, the reaction caught fire at this point, regardless of
reaction mixture was quenched with aq. sat. NH4Cl, the layers the order of addition of the reagents. In the case of fire, the
were separated and the aqueous phase was back-extracted one reaction flask was capped, which caused the fire to be put out
more time with EtOAc. All organic phases were put together quickly). The reaction mixture was heated to reflux for
and dried over Na2SO4 and filtered, and the solvent was 1.5 hours and when the reaction was complete (as judged by
removed under reduced pressure and the residue was purified TLC), the reaction mixture was brought to room temperature,
by preparative TLC (r.f. approx. 0.30, 10% triethylamine/ filtered through a Celite pad, and the clear liquid filtrate was
hexane) to afford synthetic vincadifformine (2) (0.0120 g, 30% concentrated under reduced pressure. This residue was purged
yield) as a colorless syrup. The analytical data match the data with nitrogen, redissolved in anhydrous THF (36 mL), cooled
in the literature.6a 1H NMR (300 MHz, chloroform-d) δ 8.90 (s, to approx. 0 °C (ice/water bath) and triethylamine (0.1770 g,
br, 1H), 7.12 (td, J = 7.7, 1.2 Hz, 1H), 6.85 (td, J = 7.5, 1.0 Hz, 0.244 mL, 1.7316 mmol, 1.2 eq.) was added via a syringe. Then
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9409–9419 | 9417

View Article Online
Paper
Organic & Biomolecular Chemistry
chloroacetyl chloride (0.1995 g, 0.141 mL, 1.7316 mmol, 1.2 this time. However, extended irradiation caused complex mix-
eq.) was added dropwise, and left to react for 30 min at 0 °C. tures and lower isolated yields). The solvent was removed
When the reaction was complete (as judged by TLC), the reac- under reduced pressure and the residue was purified by flash
tion mixture was quenched with aq. sat. NH4Cl (30 mL), the column chromatography (r.f. approx. 0.40, 50% EtOAc/hexane)
layers were separated and the aqueous phase was back- to afford oxoquebrachamine 28 (0.0589 g, 34% yield) as a
extracted twice with EtOAc. All organic phases were put white semisolid. The analytical data match the data in the lit-
together and dried over Na2SO4 and filtered, and the solvent erature.24d 1H NMR (300 MHz, chloroform-d + dimethyl-
was removed under reduced pressure to afford chloroaceta- sulfoxide-d6) δ 9.24 (s, br, 1H), 7.53–7.50 (m, 1H), 7.13–7.09
mide 25 (0.3458 g, 72% yield) as a colorless syrup. The analyti- (m, 1H), 6.94–6.89 (m, 2H), 4.47 (d, J = 12.4 Hz, 1H), 4.32 (d,
cal data match the data in the literature.24d 1H NMR (300 MHz, J = 14.0 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.42 (d, J = 14.0 Hz,
chloroform-d, rotamer mixture: 6* : 1°) δ 8.80* (s, br, 1H), 1H), 2.71–2.44 (m, 4H), 2.32 (td, J = 12.4, 2.8 Hz, 1H),
8.54° (s, br, 1H), 7.54*,° (d, J = 8.2 Hz, 2H), 7.36*,° (d, J = 1.60–0.97 (m, 8H), 0.73 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
7.2 Hz, 2H), 7.16–7.04*,° (m, 4H), 6.26° (s, 1H), 6.23* (s, 1H), chloroform-d + dimethylsulfoxide-d6) δ 170.4, 138.6, 134.5,
4.19–4.04*,° (m, 6H), 3.62–3.52*,° (m, 2H), 3.21–3.12*,° (m, 129.6, 120.7, 119.3, 118.0, 110.4, 104.6, 53.7, 42.8, 38.7, 34.5,
2H), 2.80–2.60*,° (m, 6H), 1.71–1.36*,° (m, 12H), 1.33–1.16*,° 32.1, 30.5, 29.7, 28.7, 20.7, 20.4, 7.3. IR (cm−1): 3234, 2926,
(m, 2H), 0.93* (t, J = 7.5 Hz, 3H), 0.90° (d, J = 7.5 Hz, 3H). 13C 2857, 1599, 1466, 732, 699. HRMS: m/z (M + 1) calculated for
NMR (75 MHz, chloroform-d, rotamer mixture) δ 169.4, 166.2, C19H25N2O: 297.19669; found: 333.17342.
140.6, 139.6, 136.3, 136.2, 128.8, 121.2, 120.8, 119.8, 119.7,
Quebrachamine (5)
suspension of oxoquebrachamine 28 (0.0589 g,
119.3, 110.9, 110.7, 99.3, 98.9, 55.3, 50.5, 47.8, 43.4, 41.4, 41.2,
37.1, 36.4, 34.4, 33.6, 33.1, 31.1, 28.3, 27.0, 22.6, 22.0, 20.7, 7.6,
7.3. IR (cm−1): 3278, 2937, 2861, 1634, 1455, 1283, 1248, 782,
A
0.1957 mmol, 1.0 eq.) in freshly distilled THF (7 mL) was
cooled to 0 °C (ice/water bath) and then Red-Al 60% in MePh
(0.255 mL, 0.7827 mmol, 4.0 eq.) was slowly added through
one of the necks of the flask, and stirred for 2 hours (the start-
ing solid dissolves as it reacts). When the reaction was com-
plete (as judged by TLC), the reaction mixture was carefully
quenched with aq. sat. potassium sodium tartrate (7 mL) at
0 °C, the cold bath was removed and the reaction was stirred
vigorously for 1 hour. The layers were separated and the
aqueous phase was back-extracted twice with EtOAc. All
organic phases were put together and dried over Na2SO4 and
filtered, and the solvent was removed under reduced pressure
and the residue was purified by flash column chromatography
(r.f. approx. 0.35, 5% MeOH/CH2Cl2) to afford synthetic queb-
rachamine (5) (0.0418 g, 76% yield) as a colorless semisolid.
The analytical data match the data in the literature.24d 1H
NMR (300 MHz, chloroform-d) δ 7.75 (s, br, 1H), 7.51–7.48 (m,
1H), 7.30–7.25 (m, 1H), 7.11–7.06 (m, 2H), 3.26 (d, J = 11.7,
1H), 2.99–2.78 (m, 2H), 2.74–2.63 (m, 2H), 2.51–2.20 (m, 4H),
1.97–1.88 (m, 1H), 1.66–1.46 (m, 4H), 1.36–1.95 (m, 5H), 0.85
(d, J = 7.6 Hz, 3H). 13C NMR (75 MHz, chloroform-d) δ 140.0,
134.9, 129.0, 120.3, 118.8, 117.5, 110.1, 108.8, 56.8, 55.2, 53.4,
37.2, 34.9, 33.6, 32.2, 22.8, 22.6, 22.1, 7.9. IR (cm−1): 3234,
2926, 2857, 1466, 732, 699. HRMS: m/z (M + 1) calculated for
C19H27N2: 283.21742; found: 283.21749.
736. HRMS: m/z (M
333.17337; found: 333.17342.
+ 1) calculated for C19H26N2OCl:
S-(2-(3-(2-(1H-Indol-2-yl)ethyl)-3-ethylpiperidin-1-yl)-2-
oxoethyl)-O-ethyl carbonodithioate (26)
A solution of chloroacetamide 25 (0.1000 g, 0.1957 mmol,
1.0 eq.) in acetonitrile (4 mL) was treated with potassium ethyl
xanthogenate (0.0359 g, 0.2153 mmol, 1.1 eq.) and stirred for
3 hours. When the reaction was complete (as judged by TLC),
the reaction mixture was concentrated in vacuo and the residue
was partitioned between ethyl acetate and water. The layers
were separated and the aqueous phase was back-extracted
twice with EtOAc. All organic phases were put together and
dried over Na2SO4 and filtered, and the solvent was removed
under reduced pressure and the residue was purified by flash
column chromatography to afford xanthate (26) (0.0418 g, 76%
yield) as a yellow liquid. 1H NMR (300 MHz, chloroform-d)
δ 8.90 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H),
7.12–7.00 (m, 2H), 6.18 (s, 1H), 4.70–4.62 (m, 1H), 4.61–4.51
(m, 1H), 4.48–4.36 (m, 2H), 4.32 (d, J = 15.4 Hz, 1H), 4.16–4.10
(m, 1H), 4.10 (d, J = 15.4 Hz, 1H), 3.91 (d, J = 13.1 Hz, 1H),
3.27–3.14 (m, 1H), 2.81–2.57 (m, 3H), 1.70–1.47 (m, 5H), 1.39
(t, J = 7.1 Hz, 3H), 1.32–1.12 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz, chloroform-d) δ 214.0, 166.1, 140.6, 136.3,
128.7, 120.6, 119.5, 119.1, 110.9, 98.8, 77.2, 70.9, 50.8, 47.9,
39.7, 37.2, 35.0, 32.9, 28.9, 22.8, 22.4, 13.9, 7.2. HRMS: m/z
(M + 1) calculated for C22H31N2O2S2: 419.18269; found: 419.18278.
Conflicts of interest
Oxoquebrachamine (28)
There are no conflicts to declare.
In a quartz vessel, a solution of chloroacetamide 25 (0.1916 g,
0.5756 mmol, 1.0 eq.) in ethanol (30 mL) and water (5 mL) was
treated with Na2CO3 (0.1220 g, 1.1513 mmol, 2.0 eq.) and then,
nitrogen was bubbled to the solution for 15 minutes with con-
Acknowledgements
stant stirring. Then, the quartz vessel was irradiated at 254 nm Financial support from Programa de Apoyo a Proyectos de
(300 W) for 5 hours (NOTE: the reaction was not complete at Investigación e Innovación Tecnológica (PAPIIT-DGPA No.
9418 | Org. Biomol. Chem., 2018, 16, 9409–9419
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
IN210516) is gratefully acknowledged. We also thank 15 Y. Liu, S. C. Virgil, R. H. Grubbs and B. M. Stoltz, Angew.
B. Quiroz, R. Patiño, A. Peña, E. Huerta, I. Chavez, R. Gabiño, Chem., Int. Ed., 2015, 54, 11800.
L. Velasco, J. Pérez and M. C. García-González for technical 16 C. Taillier, B. Gille, V. Bellosta and J. Cossy, J. Org. Chem.,
support.
2005, 70, 2097.
17 E. Quesada, S. A. Raw, M. Reid, E. Roman and
R. J. K. Taylor, Tetrahedron, 2006, 62, 6673.
18 H. K. Grover and M. A. Kerr, Synlett, 2015, 26, 815.
19 D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D. E. White,
S. C. Virgil and B. M. Stoltz, Nat. Chem., 2012, 4, 130.
20 Selected synthesis of goniomitine: (a) S. Takano, T. Sato,
K. Inomata and K. Ogasawara, J. Chem. Soc., Chem.
Commun., 1991, 462; (b) C. L. Morales and B. L. Pagenkopf,
Org. Lett., 2008, 10, 157; (c) M. Mizutani, F. Inagaki,
T. Nakanishi, C. Yanagihara, I. Tamai and C. Mukai, Org.
Lett., 2011, 13, 1796; (d) S. Zhou and Y. Jia, Org. Lett., 2014,
16, 3416; (e) J. K. Vellucci and C. M. Beaudry, Org. Lett.,
2015, 17, 4558.
21 (a) J. S. Yadav, B. V. S. Reddy and G. Satheesh, Tetrahedron
Lett., 2003, 44, 8331; (b) J. L. Wood, B. M. Stoltz,
H.-J. Dietrich, D. A. Pflum and D. T. Petsch, J. Am. Chem.
Soc., 1997, 119, 9641; (c) R. Gibe and M. A. Kerr, J. Org.
Chem., 2002, 67, 6247; (d) M. B. Johansen and M. A. Kerr,
Org. Lett., 2010, 12, 4956.
Notes and references
1 (a) C. M. Marson, Chem. Soc. Rev., 2012, 41, 7712;
(b) B. M. Trost, Science, 1991, 254, 1471.
2 N. Z. Burns, P. S. Baran and R. W. Hoffmann, Angew.
Chem., Int. Ed., 2009, 48, 2854.
3 (a) Y. Hayashi, S. Koshino, K. Ojima and E. Kwon, Angew.
Chem., Int. Ed., 2017, 56, 11812; (b) L. Albrecht, H. Jiang
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492.
4 (a) P. A. Clarke, S. Santos and W. H. C. Martin, Green
Chem., 2007, 9, 438; (b) H. Xiang, Y. Chen, Q. He, Y. Xie
and C. Yang, RSC Adv., 2013, 3, 5807.
5 (a) T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem.
Soc. Rev., 2009, 38, 3010; (b) T. Gaich and P. S. Baran,
J. Org. Chem., 2010, 75, 4657; (c) I. S. Young and
P. S. Baran, Nat. Chem., 2009, 1, 193.
6 (a) S. B. Jones, B. Simmons, A. Mastracchio and
D. W. C. Macmillan, Nature, 2011, 475, 183; 22 Selected synthesis of the pentacyclic aspidosperma alka-
(b) H. Mizoguchi, H. Oikawa and H. Oguri, Nat. Chem.,
2013, 6, 57; (c) O. Wagnières, Z. Xu, Q. Wang and J. Zhu,
J. Am. Chem. Soc., 2014, 136, 15102; (d) Z. Xu, Q. Wang and
J. Zhu, J. Am. Chem. Soc., 2015, 137, 6712; (e) Y. Yang,
Y. Bai, S. Sun and M. Dai, Org. Lett., 2014, 16, 6216;
(f) B. P. Pritchett, J. Kikuchi, Y. Numajiri and B. M. Stoltz,
Angew. Chem., Int. Ed., 2016, 55, 13529.
7 (a) R. M. Wilson and S. J. Danishefsky, J. Org. Chem., 2007,
72, 4293; (b) S. Krüger and T. Gaich, Angew. Chem., Int. Ed.,
2015, 54, 315; (c) S. Krüger and T. Gaich, Eur. J. Org. Chem.,
2016, 4893; (d) C. K. G. Gerlinger, S. Krüger and T. Gaich,
Chem. – Eur. J., 2018, 24, 3994.
loids aspidospermidine, vincadifformine and 1,2-dehy-
droaspidospermidine: (a) Z. Chen, S. Zhou and Y. Jia,
J. Org. Chem., 2015, 80, 12545; (b) M. Mizutani, S. Yasuda
and C. Mukai, Chem. Commun., 2014, 50, 5782;
(c) S. Blechert, R. Knier, H. Schroers and T. Wirth,
Synthesis, 1995, 592; (d) M. G. Banwell, B. D. Bissett,
S. Busato, C. J. Cowden, D. C. R. Hockless, J. W. Holman,
R. W. Read and A. W. Wu, J. Chem. Soc., Chem. Commun.,
1995, 2551; (e) H. Ma, X. Xie, P. Jing, W. Zhanga and
X. She, Org. Biomol. Chem., 2015, 13, 5255; (f) For an atypi-
cal cyclization of the kind giving a cis-fused pyrido-carba-
zole see: K. C. Nicolaou, M. S. Dalby and U. Majumder,
J. Am. Chem. Soc., 2008, 130, 14942; (g) P. Forns, A. Diez
and M. Rubiralta, J. Org. Chem., 1996, 61, 7882.
8 (a) S. E. Malawista, H. Sato and K. G. Bensch, Science, 1968,
160, 770; (b) M. A. Jordan and L. Wilson, Nat. Rev. Cancer,
2004, 4, 253; (c) B. Gigant, C. Wang, R. B. G. Ravelli, 23 S. A. Kozmin, T. Iwama, Y. Huang and V. H. Rawal, J. Am.
F. Roussi, M. O. Steinmetz, P. Curmi, A. Sobel and
M. Knossow, Nature, 2005, 435, 519.
9 (a) K. Biemann, M. Friedmann-Spiteller and G. Spiteller,
Tetrahedron Lett., 1961, 2, 485; (b) K. Biemann, M. Spiteller-
Friedmann and G. Spiteller, J. Am. Chem. Soc., 1963, 85,
631.
10 C. Djerassi, H. Budzikiewicz, J. M. Wilson, J. Gosset, J. Le
Men and M.-M. Janot, Tetrahedron Lett., 1962, 3, 235.
11 L. Randriambola, J.-C. Quirion, C. Kan-Fan and
H.-P. Husson, Tetrahedron Lett., 1987, 28, 2123.
12 O. Hesse, Ber. Dtsch. Chem. Ges., 1881, 13, 2308.
13 (a) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873;
(b) H. A. Oskooie, M. M. Heravi and F. K. Behbahani,
Molecules, 2007, 12, 1438; (c) L. A. Polindara-García and
L. D. Miranda, Synthesis, 2012, 1051–1056.
Chem. Soc., 2002, 124, 4628.
24 Selected synthesis of quebrachamine: (a) S. Takano,
M. Yonaga and K. Ogasawara, J. Chem. Soc., Chem.
Commun., 1981, 1153; (b) M. Node, H. Nagasawa and
K. Fuji, J. Org. Chem., 1990, 55, 517; (c) M. Amat,
O. Lozano, C. Escolano, E. Molins and J. Bosch, J. Org.
Chem., 2007, 72, 4431; (d) B. Bajtos and B. L. Pagenkopf,
Eur. J. Org. Chem., 2009, 1072; (e) S.-W. Hsu, H.-Y. Cheng,
A.-C. Huang, T.-L. Ho and D.-R. Hou, Eur. J. Org. Chem.,
2014, 3109.
25 (a) B. Quiclet-Sire and S. Z. Zard, Chem. – Eur. J., 2006, 12,
6002; (b) S. Z. Zard, Angew. Chem., Int. Ed. Engl., 1997, 36,
672; (c) Y. M. Osornio, R. Cruz-Almanza, V. Jiménez-
Montaño and L. D. Miranda, Chem. Commun., 2003, 2316;
(d) M. A. Guerrero and L. D. Miranda, Tetrahedron Lett.,
2006, 47, 2517.
14 M. J. Fisher and L. E. Overman, J. Org. Chem., 1990, 55,
1447.
26 C. Leitner and T. Gaich, Chem. Commun., 2017, 53, 7451.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9409–9419 | 9419