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Cite this: Org. Chem. Front., 2018, 5,
273

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Total syntheses of pyrroloazocine indole alkaloids:
challenges and reaction discovery
Mariia S. Kirillova,

a

Fedor M. Miloserdov

a

and Antonio M. Echavarren

*a,b

Lapidilectines, grandilodines, lundurines and tenuisines are indole alkaloids, isolated from plants of Kopsia
genus. They feature a common indole-fused pyrroloazocine core, whose construction poses a significant
Received 31st August 2017,
Accepted 23rd October 2017
DOI: 10.1039/c7qo00786h
rsc.li/frontiers-organic

1.

synthetic challenge. In this review, we discuss the reported strategies for the total synthesis of this family
of alkaloids with a focus on the different methods used for the construction of spiro[cyclohexane-2-indoline] and indole-pyrroloazocine intermediates, introduction of indole-fused cyclopropane as well as other
new methodologies uncovered in the course of the total syntheses. In closing, the existing hypothesis of
the biosynthetic origin and relationships of the pyrroloazocine indole alkaloids are presented.

Introduction

Pyrroloazocine indole alkaloids is a family comprising sixteen
natural compounds isolated from two closely related plant
species, Kopsia grandifolia1–3 and Kopsia tenuis4–6 (Scheme 1).
Kopsia grandifolia as a species was described in 2004 in the
D. J. Middleton classification,7 and was previously known as

a

Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institut of Science
and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain.
E-mail: aechavarren@iciq.es
b
Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili,
C/Marcel·li Domingo s/n, 43007 Tarragona, Spain

Mariia S. Kirillova was born in
Bryansk (Russia) in 1988 and
graduated in chemistry from the
Gubkin Russian State University
of Oil and Gas in Moscow
(Russia) in 2011. She was
awarded a pre-doctoral fellowship from the Government of
Catalonia to work on the synthesis of complex natural products at the Institute of
Chemical Research of Catalonia
(ICIQ) with Prof. Antonio
Mariia S. Kirillova
M. Echavarren and obtained her
Ph.D. in 2016. She continued as a post-doctoral associate until
the summer of 2017. In 2015, she worked with the group of Prof.
Corey R. J. Stephenson (University of Michigan) as a summer
exchange student. Recently, she joined the University of Zurich as
a post-doctoral researcher in the group of Prof. Cristina Nevado.

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Kopsia lapidilecta.1,2 In the modern classification,7 Kopsia lapidilecta describes another plant that grows on Natuna islands
in Indonesia, while Kopsia grandifolia is distributed over peninsular Malaysia, and Kopsia tenuis is endemic to the Sarawak
region on the North of the Borneo island.
All sixteen pyrroloazocine indole alkaloids have a common
pyrroloazocine core and they are biosynthetically related by a
series of decarboxylation events8 (Scheme 1). These natural
compounds can be further divided into three subcategories
based on their key structural features: diester, lactone or cyclopropane. Diester natural compounds were isolated from the
Kopsia grandifolia plant as both epimers at the C16 position2,3
(here and further in the manuscript we will use the numbering

Fedor Miloserdov was born in
Moscow in 1990 and started to
work in the research laboratory
while at high school (Moscow
Chemical Lyceum). He graduated
from the Mendeleev University of
Chemical Technology of Russia
(Moscow), in 2012. During his
university study, he made a
series of short stays with the
group of Prof. Vladimir Grushin
(Institute of Chemical Research
of Catalonia, ICIQ, Tarragona,
Fedor M. Miloserdov
Spain). He continued his education with Vladimir Grushin at ICIQ, and obtained his Ph.D.
degree in 2015. After that he became a Postdoctoral Fellow in the
group of Prof. Antonio Echavarren (ICIQ), where he is currently
working in the areas of total synthesis and gold catalysis.

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defined in the isolation reports).1–6 Cyclopropane-containing
lundurines were obtained from Kopsia tenuis,4,5 and lactones
were isolated from both Kopsia tenuis and Kopsia grandifolia.1,3,4,6 Initially, the structure of tenuisines was wrongly
assigned to be dimeric,6 and later corrected4 to monomeric
structures with a lactone moiety. Interestingly, all members of
this alkaloid family isolated from the Kopsia tenua plant
feature methoxylation at the indole ring.
Only preliminary studies of biological activities of pyrroloazocine indole alkaloids have been reported. Lundurines B
and D showed cytotoxicity toward B15 melanoma cells,4 and
lundurines B, D, grandilodines A, C and lapidilectine B were
capable of reversing multidrug resistance in vincristineresistant KB (VJ300) cells.3,4
In recent years, pyrroloazocine indole alkaloids attracted
considerable attention from the synthetic community, and the
total syntheses of lundurines A–C, grandilodines B, C and

Antonio M. Echavarren received
his PhD from the Universidad
Autónoma de Madrid (UAM,
1982) with Prof. Francisco
Fariña. After a postdoctoral stay
in
Boston
College
with
Prof. T. Ross Kelly, he joined the
UAM as an Assistant Professor.
Following a two year period as a
NATO-fellow with Prof. John
K. Stille in Fort Collins
(Colorado State University), he
joined the Institute of Organic
Antonio M. Echavarren
Chemistry of the CSIC in
Madrid. In 1992, he returned to the UAM as a Professor of
Organic Chemistry and in 2004, he moved to Tarragona as a
Group Leader at the Institute of Chemical Research of Catalonia
(ICIQ). He has been a Liebig Lecturer (Organic Division, German
Chemical Society, 2006), an Abbot Lecturer in Organic Chemistry
(University of Illinois at Urbana-Campaign, 2009), a Schulich
Visiting Professor (Technion, Haifa, 2011), Sir Robert Robinson
Distinguished Lecturer (University of Liverpool, 2011), a Novartis
Lecturer in Organic Chemistry (Massachusetts Institute of
Technology, 2015) and a Kurt Alder Lecturer 2017 (University of
Cologne). In 2012, he got a European Research Council Advanced
Grant and in 2014, he became the president of the 49th EUCHEM
Conference on Stereochemistry (Bürgenstock conference). Prof.
Echavarren is a member of the International Advisory Board of
Organic & Biomolecular Chemistry, Chemical Society Reviews,
Advanced Synthesis and Catalysis, and Organic Letters, a member
of the Editorial Board of Chemistry European Journal, and an
Associate Editor of Chemical Communications. He is a Fellow of
the Royal Society of Chemistry. He received the 2004 JanssenCylag Award in Organic Chemistry and the 2010 Gold Medal of
the Royal Spanish Chemical Society and an Arthur C. Cope
Scholar Award from the ACS.

274 | Org. Chem. Front., 2018, 5, 273–287

Scheme 1 Pyrroloazocine indole alkaloids and their biosynthetic
relationship.

lapidilectine B have been reported. For lundurines A–C,
grandilodine C and lapidilectine B, asymmetric approaches
were developed as well. Depending on how the rigid indolefused azabicyclo[4,2,2] skeleton is constructed, syntheses of
pyrroloazocine indole alkaloids fall into two categories: via
spiro[cyclohexane-2-indoline] and via azocine-containing intermediates (Scheme 2). The use of the latter pathway for the
synthesis of lundurines requires another difficult step – the
cyclopropanation of an indole moiety.
In this review, we discuss the reported methods to achieve
the synthesis of the key spiro[cyclohexane-2-indoline] and
azocino-indole intermediates, as well as other important transformations that were necessary to complete the synthesis of
the natural products. In the context of lundurine syntheses,9
the indole cyclopropanation, and some key transformations of
the cyclopropane moiety will be discussed in more detail.
Finally, the current biosynthetic proposal for the origin of
pyrroloazocine indole alkaloids will be presented.

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Scheme 2 Retrosynthetic approaches to the indole-fused 2-azabicyclo
[4,2,2]-skeleton. Cyclopropanation of indole for the synthesis of
lundurines.

2. Synthesis via spiro[cyclohexane-2indoline] intermediates
Indolines containing a 2-spiro fused cyclohexane ring are well
known compounds. This moiety is presented in numerous
indole alkaloids isolated from plants of genus Kopsia8 (Fig. 1),
including kopsamine, isolated for the first time by Gorter in
1920.10 To the best of our knowledge, the first spiro[cyclohexane-2-indoline] was synthesized nine decades ago, by
thermal alkali-mediated cyclization of an amino acid obtained
by means of Strecker synthesis (Scheme 3).11 Nowadays there
are several well-established routes to spiro[cyclohexane-2-indolines], and some of them were successfully utilized in the synthesis of pyrroloazocine indole alkaloids.
One of these methods is Smalley cyclization (Scheme 3a).
Enolizable aryl ketones bearing an ortho-azido group can be
involved in base-induced cyclization that constructs the indoline ring, and in case of a cyclohexyl substituent, this leads to
the formation of spiro[cyclohexane-2-indolines].12,13 This

Fig. 1 Examples of natural compounds with the highlighted spiro
[cyclohexane-2-indoline] part.

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Review

Scheme 3 The first synthesis of spiro[cyclohexane-2-indolines],11 and
retrosynthetic approaches to indole spirofused cyclohexanes applied to
the total synthesis of pyrroloazocine indole alkaloids.

transformation was employed in the total synthesis of lapidilectine B, developed by Pearson et al.14,15 A similar reaction
was later applied to enamine-bearing substrates,16 and recently
a practical Cu-catalyzed cascade of ortho-bromoarene azidation/Smalley cyclization has been reported.17
Another method of assembly of spiro[cyclohexane-2-indoline] compounds relays on the construction of a C–C bond
between an ortho-bromo aryl moiety and a cyano-group in
Strecker type intermediates (Scheme 3b). This transformation
was initially developed as a radical cyclization method.18
However such conditions were not suitable for the application
in the total synthesis, and an alternative protocol utilizing
i-PrMgCl was developed.19 A similar transformation from a retrosynthetic perspective is the acid-catalyzed Ugi condensation/
Hoesh reaction cascade between electron-rich anilines, cyclohexanone and t-BuNC20 (Scheme 4).
The Diels–Alder cycloaddition reaction is one of the most
useful synthetic tools for the construction of cyclohexane
rings, including the one presented in spiro[cyclohexane-2indolines]. In such transformations, the indoline-containing
part can play the role of a diene or dienophile. For the latter,
several examples of cycloaddition reactions involving indoleylidenes and dimethyl butadiene were reported,21 and,
recently, this strategy was applied for the total synthesis of

Scheme 4 Ugi condensation/Hoesh reaction cascade in the synthesis
of spiro[cyclohexane-2-indolines].20

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racemic grandilodine B22 (Scheme 3c). The Diels–Alder reaction between an indoline-containing diene and a dienophile
has also been widely used in the synthesis of indole alkaloids23 (Scheme 5).
An alternative approach to spiro[indoline-cyclohexanes] is
based on C6 ring-closing transformations (Scheme 3d), such
as aldol-type reactions,24,25 olefin metathesis,26 and
Dieckmann condensation.27,28 The last two approaches were
developed by the group of Nishida in the course of the total
synthesis of lundurines.
Several other methods for the synthesis of spiro[cyclohexane-2-indoline] were reported, including an alkylation/
oxidative rearrangement of cyclohepta[b]indoles29 (Scheme 6,
eqn (1)), addition of iodonium ylides to ortho-chloromethyl
aryl amides30 (Scheme 6, eqn (2)), and spirocyclization of conjugated dienes with protonated indoles31 (Scheme 6, eqn (3)).
The platinum-catalyzed formal [4 + 3] cycloaddition can also
give rise to cyclohexane-2-indoline spirocyclic products containing an additional cyclopropyl moiety32 (Scheme 7).
Although these products resemble the lundurines, the [4 + 3]
cycloaddition reaction has not yet been applied to the synthesis of these natural compounds.
2.1

Scheme 7 Cyclopropane-containing spiro[cyclohexane-2-indoline] as
a product in Pt-catalyzed formal [4 + 3] cycloaddition.32

Total synthesis of racemic lapidilectine B by Pearson et al.

The very first total synthesis of pyrroloazocine indole alkaloid,
racemic lapidilectine B, was accomplished by the group of
Pearson in 200114,15 (Scheme 8). The spiro[cyclohexane-2-indoline] fragment was constructed by Smalley cyclization of the
substituted cyclohexyl ketone. Because of the unsymmetrical

Scheme 8
Scheme 5 [4 + 2]-cycloaddition reaction between indoline-containing
diene and vinyl sulfone in the total synthesis of indole alkaloids.23a

Scheme 6

Examples of spiro[cyclohexane-2-indoline] synthesis.29–31

276 | Org. Chem. Front., 2018, 5, 273–287

Total synthesis of racemic lapidilectine B by Pearson et al.14,15

nature of the cyclohexyl substituent, the product was obtained
as a 2.2 : 1 mixture of two diastereomers, and the major one
was further used in the synthesis. The functionalization of
3-oxiindole and the cleavage of a double bond led to the lactol
ether intermediate bearing a keto group. This ketone became
the source of 2-azaallyllithium species that were subsequently
introduced into the [3 + 2] cycloaddition reaction with phenyl
vinyl sulfide, providing the pyrrolidine core of the molecule
with the correct relative configuration at C20. The elimination
of the sulfoxide moiety provided the required unsaturation in
the pyrroline. The lactole ether fragment was oxidized to the
lactone, and finally an intramolecular alkylation of the pyrroline nitrogen with alkyl mesylate closed the azocine ring,
leading to lapidilectine B. The approach developed by Pearson
et al. required ca. 25 steps with ca. 0.5% overall yield,14 which
was further improved to ca. 1%.15

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2.2 Total synthesis of lundurines by Nishida et al.,
1st generation

carbamate, completing the synthesis of racemic lundurine B,
in 29 steps and ca. 1% overall yield.

The first total synthesis of lundurines was developed by the
group of Nishida, and was reported in 2014.26 First the synthesis of racemic lundurine B was accomplished, and shortly
after the initial publication, the same group published another
approach to racemic lundurines A and B,27 that will be discussed separately, as a 2nd generation synthesis. The primary
synthetic approach featured an early construction of a cyclopropane motif (Scheme 9). The indole ring was assembled at
one side of cyclopropane by a copper-mediated aromatic amination, and the lactone ring at the other side of a cyclopropane
was opened. The side chains were elongated by means of a
Wittig olefination providing a precursor for ring-closing metathesis. The ring closing metathesis was performed under standard conditions producing the spiro[cyclohexane-2-indoline].
After several steps, an amino-ethanol moiety was attached to a
side chain of a molecule, and an N,O-acetal of cyclohexanone
was generated, building the azocine ring. The pyrroline ring
was constructed by another ring closing metathesis step, and
finally the Boc protecting group was converted into the methyl

2.3 Total synthesis of lundurines by Nishida et al.,
2nd generation

Scheme 9 Total synthesis of racemic lundurine B by Nishida et al.,
1st generation.26

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The second generation synthesis of the lundurine by the group
of Nishida27,28 retrosynthetically resembles the synthesis of
lapidilectine B by Pearson et al.14,15 First, the spiro[cyclohexane-2-indoline] was constructed by Dieckmann condensation (Scheme 10). The unsaturated ethyl ester was introduced by the ethoxyacetylene addition/Meyer–Schuster
rearrangement sequence, and the silyl enol ether precursor for
the Saegusa-Ito oxidation was generated, desymmetrizing the
molecule. It was previously reported that 4-t-Bu-cyclohexanone
can be desymmetrized upon treatment with chiral lithium
amides.33 The application of this methodology to the Boc-protected spiro[cyclohexane-2′-indoline]-4-one provided the corresponding chiral product with 88% ee, that was employed for
the asymmetric synthesis of (−)-lundurine B.28 The obtained
1,4-diene was further treated with SmI2, that triggered radical
cyclization thereby producing the cyclopropane-containing
product.34,35 The modification of functional groups resulted in
the formation of allylic acetate, containing an amino-group,
which was cyclized in the presence of a Pd-catalyst producing

Scheme 10
et al.27,28

2nd generation total synthesis of lundurines by Nishida

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an azocine ring. Like in their 1st generation of synthesis,
Nishida and coworkers constructed a pyrroline ring at the last
stage by ring-closing metathesis, providing racemic lundurines
A and B in 31 steps and ca. 1.5% overall yield.27 An asymmetric
synthesis of (−)-lundurine B was accomplished following a
similar synthetic strategy, where the Boc-protecting group was
converted into methyl carbamate in the last steps (total 30
steps, ca. 1% overall yield, 88% ee).28
2.4 Total synthesis of (+)-grandilodine C and (+)-lapidilectine B
by Nishida et al.
The group of Nishida further elaborated their approach to pyrroloazocine indole alkaloids in the course of the asymmetric
total synthesis of lactone-containing grandilodine C and lapidilectine B.19 Similar to their 2nd generation synthesis of the
lundurines, the desymmetrization of spiro[cyclohexane-2′indoline]-4-one was the first key step. The synthetic sequence
to this starting material was shortened from 11 steps27 to only
3, and the indole ring was constructed by i-PrMgCl-mediated
cyclization in the Strecker adduct (Scheme 11). In this study,
the desymmetrization reaction could be performed directly on
the diketone substrate, containing additionally the methyl carbamate protecting group on the indole nitrogen, instead of
Boc (see above), with good 76% ee, which could be increased
to 91% ee by crystallization. The next copper-mediated conjugated vinylation occurred with high diastereoselectivity, providing an unsaturated side-chain, that after ozonolysis and oxidation, it became a part of a lactone ring. The modification of
functional groups resulted in the formation of allylic acetate,
containing an amino-group. An analogous intermediate was
involved in the total synthesis of lundurines.27 Similarly the
Pd-catalyzed allylic substitution was employed to assemble an
azocine moiety, and the metathesis reaction was used for the
formation of unsaturated pyrrolidone in (+)-grandilodine C. A
further reduction of amide gave (+)-lapidilectine B. The
described synthesis of (+)-grandilodine A (76% ee)36 has 18
steps and ca. 8.5% overall yield.19
2.5

Total synthesis of racemic grandilodine B by Zu et al

More recently, the first total synthesis of a diester-type pyrroloazocine indole alkaloid, grandilodine B, has been developed
by Zu and coworkers (Scheme 12).22 Their approach has similarities with the above-mentioned synthesis of lapidilectine B
by Pearson et al.14,15 The spiro[cyclohexane-2-indoline] tricycle
was efficiently constructed in only two steps taking advantage
of the Diels–Alder reaction that proceeded with an excellent
yield and a good level of diastereoselectivity (4 : 1 α/β ratio).
The major diastereomer was further functionalized, the 3-oxyindole moiety was allylated, and the benzylic hydroxyl group
was substituted with cyanide, which was later transformed
into a methyl ester. Similar to Pearson et al., the pyrroline ring
was introduced by [3 + 2] cycloaddition, and the azocine ring
was closed by N-alkylation reactions. The 4-cyclohexanone presented in the molecule was transformed into a nitrone, which
reacted with methyl acrylate thereby providing an isoxazolidine.37 The N–O bond and the benzyl group were cleaved in

278 | Org. Chem. Front., 2018, 5, 273–287

Scheme 11 Total synthesis of (+)-grandilodine C and (+)-lapidilectine B
by Nishida et al.19

the course of hydrogenation leading to the formation of a
lactam ring.38 The intramolecular N-alkylation of the lactam
led to the azocine ring. Finally, cyano- and ethyl ester-groups
were transformed into methyl esters, thereby completing the
synthesis of racemic grandilodine B with a total of 19 steps
and ca. 2.5% overall yield.

3. Synthesis via fused
pyrroloazocine-indole intermediates
As an alternative to the spiro-fused indoline strategy, the construction of indole-containing an 8-membered ring followed
by late-stage indole cyclopropanation has been explored by
several groups. Diverse methodologies have been developed
for the synthesis of indoloazocine tricyclic scaffolds.
Palladium-mediated dihydroindoloazocine cyclization of
N-prenyl-(S)-tryptophan derivatives has been used as a key step
in the synthesis of (+)-austamide and related alkaloids by

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Scheme 13

Examples of indoloazocine synthesis.

Scheme 14 Retrosynthetic approaches to indoloazocine applied in the
total synthesis of pyrroloazocine indole alkaloids.
Scheme 12

Total synthesis of racemic grandilodine B by Zu et al.22

Corey (Scheme 13, eqn (1)).39 Nishida and co-workers reported
the formation of the azocino-indole subunit from o-halophenylenaminoester by deconjugation of a double bond followed by
intramolecular Heck reactions (Scheme 13, eqn (2)).40 Lewis
acid-mediated epoxide opening of tryptamine-derived transepoxyamides followed by 8-exo-tet cyclization have been
applied as a key step in the syntheses of (+)-balasubramide41
and its derivatives (Scheme 13, eqn (3)).42
A number of methods have been developed for the assembly of indoloazocines to build up the rigid polycyclic skeleton
of Kopsia alkaloid. One of the first syntheses of the lapidilectine tetracyclic core developed by Sarpong et al. relies on
Friedel–Crafts (or Friedel–Crafts-type) reactions (Scheme 14,
path a).43 Similar indole acylation was reported in the synthesis of substituted indoloazocines from tryptamine-derived
(sulfonamido)methyl acrylic acid.44

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In the synthesis of lundurine A by the group of Qin, the azocinoindole ring system was assembled by intramolecular alkylation of imine by primary iodide (Scheme 14, path b).45
Intramolecular hydroarylation of alkynes with electron-rich
heteroarenes, such as indoles, provide a fast access to the azocinoindole skeleton. Due to the remarkable affinity of gold(I)
towards alkynes, gold salts demonstrate high efficiency in catalyzing these processes.46 Mercury salts are also competent in
catalyzing hydroarylation reactions.47
3.1 Synthesis of the lapidilectine tetracyclic core by Sarpong
et al., 8-membered ring via Friedel–Crafts acylation
An 11-step synthesis of the tetracyclic core of Kopsia indole
alkaloid was developed by Sarpong based on the Friedel–Crafts
acylation of indole to form the 8-membered ring
(Scheme 15).43 The synthesis commenced with a four-component Ugi reaction between tryptamine, isocyanocyclohexene,
a substituted cyclohexanone, and acetic acid to form the coup-

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Scheme 15

Organic Chemistry Frontiers

Synthesis of lapidilectine tetracyclic core by Sarpong et al.43

ling adduct that was converted into the key spiro-fused lactam.
This intermediate was further opened in 3 steps: formation of
TBS enol ether, its oxidative cleavage and subsequent formation
of dimethyl acetal, furnishing the precursor for the Friedel–
Crafts-type transformation. The cyclization was promoted by
Amberlyst-15, as a source of acid, to afford indoloazocine in
54% yield. Preliminary studies of enantioselective deprotonation
of spiro-fused ketone with chiral amine bases demonstrated the
possibility of stereoselective desymmetrization, although only
moderate enantiomeric excess (up to 39%) was achieved.
3.2 Total synthesis of (−)-lundurine A by Qin et al.,
8-membered ring via imine alkylation
In 2015, Qin’s group reported the asymmetric synthesis of
(−)-lundurine A and determined its absolute configuration
(Scheme 16).45a The primary iodide intermediate, required to
construct the polyhydropyrroloazocine scaffold, was prepared
from N-protected pyrrolidinone in 7 steps. The pyrrolidinone
fragment was allowed to react with vinylmagnesium bromide,
followed by palladium-catalyzed Heck coupling of resulting
enone with 2-bromoindole to give the 2-alkenyl substituted
indole. The manipulation of the functional group yielded the
desired cyclic imine, the precursor for the indoloazocine synthesis. Intramolecular N-alkylation led to the 8-membered ring
and formation of iminium cation that sets the stage for the
diastereoselective generation of tetrasubstituted carbon stereocenter C20. The addition of allylmagnesium bromide from the
less hindered face of the iminium cation allowed the generation of stereocenter C20, providing the product as a
5 : 1 mixture of diastereomers. The hexacyclic core of lundurine A was efficiently constructed by employing a late stage
Simmons–Smith cyclopropanation. Simple functional group
modification provided the natural product (−)-lundurine A in
approximately 2% overall yield.

280 | Org. Chem. Front., 2018, 5, 273–287

Scheme 16

Total synthesis of (−)-lundurine A by Qin et al.45

However, the lengthy preparation of pyrrolidinone was a significant issue in this first approach.45a The second asymmetric
synthesis of (−)-lundurine A by Qin et al. relied on a diazo
cyclopropanation strategy (Scheme 16).45b The intermediate
aldehyde was converted into tosyl hydrazone, that underwent a
one-pot Bamford-Stevens diazotization/diazo decomposition/
cyclopropanation cascade promoted by Cu(TBS)2 to yield the
corresponding hexacycle.
3.3 Construction of the 8-membered ring via alkyne
hydroarylation
The hydroarylation of alkynes with indoles is a facile and convenient method for the synthesis of alkenyl heteroarenes and
polycyclic skeletons from easily accessible precursors.48 The
group of Echavarren demonstrated that alkenylation of indole
with terminal alkynes results in the formation of indoloazocines in the presence of a catalytic amount of AuCl or AuCl3 by

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Scheme 19
et al.50

3.4

Scheme 17 Cycloisomerization of propargylated tryptamine derivatives
by spirocyclic indolenine intermediates.

7-endo-dig cyclization and a subsequent 1,2-alkene shift
(Scheme 17).46 In contrast, the use of an electrophilic
[JohnPhosAu(NCMe)]SbF6 catalyst leads to 7-membered azepinoindoles presumably through an initial 6-exo-pathway. The
cycloisomerization of propargylated 2-substituted tryptamine
derivatives results in the formation of isolable spirocyclic
2-methyleneindoline, which supported the initial hypothesis
that the reaction proceeds through an initial attack by the
most nucleophilic 3-position of indole onto alkyne.
The mechanism and selectivity of gold-catalyzed cyclization
of indole-ynes yielding indoloazocines have been studied by
DFT calculations and experimentally.49 These studies suggest
that reaction pathways bifurcate after the formation of the
alkyne–gold complex, leading to α- or β-alkenylation routes
(Scheme 18).
The potential utility of gold-catalyzed cyclization of propargylated indole derivatives has been tested in model studies for
the synthesis of pyrroloazocine Kopsia alkaloids by Echavarren
and co-workers. An enantiopure precursor for the hydroarylation step was obtained from methyl 2-(1H-indol-3-yl) acetate in
7 steps (Scheme 19).50 The formation of the tetracycle was
achieved in 55% yield using AuCl3 as the catalyst. A similar
outcome was obtained with AuCl suggesting that gold(III)
might be reduced to gold(I) under the reaction conditions.

Scheme 18

Bifurcation point of cycloisomerization pathways.

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Synthesis of lapidilectine tetracyclic core by Echavarren

Total synthesis of (−)-lundurine A–C by Echavarren et al

A unified approach towards racemic and enantioselective total
syntheses of the natural products lundurines A–C has been
developed, based on a previously elaborated method for the
construction of the 8-membered ring by gold-catalyzed hydroheteroarylation (Scheme 20).51
The indole pyrroloazocine ring system of lundurines was
constructed in 3 steps starting from commercially available
5-methoxytryptamine and an allyl oxoester by a tandem condensation/lactamization/[3,3]-sigmatropic Claisen rearrangement, followed by Seyferth–Gilbert homologation and gold(I)mediated cycloisomerization of the resulting indole-yne
precursor. The latter transformation proceeded with perfect
8-endo selectivity and high yields, enabling the fastest and

Scheme 20

Total synthesis of lundurines A–C by Echavarren et al.51

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Review

Scheme 21 Generation of tetrasubstituted carbon stereocenter C20 in
the total synthesis of lundurines A–C by Echavarren et al.51

most efficient synthesis of the tetracyclic core of the pyrroloazocine indole alkaloids. The protection of indole nitrogen with
methyl carbamate, followed by the oxidative cleavage of an exocyclic double bond and condensation with tosyl hydrazide
yielded a diazo precursor for a Lewis acid-mediated intramolecular indole cyclopropanation. The desired hexacycle was
obtained in 80% yield when tosyl hydrazone was treated with
BF3·OEt2 at 80 °C. The migration of the double bond to the opposite side of the hexahydroazocine ring was achieved by simple
heating through vinyl cyclopropane retro-ene/ene rearrangement
providing enamide. Hydride reductions of the olefin under acidic
conditions led to an advanced cyclopropyl-fused indoline intermediate. This common intermediate was ultimately converted
into lundurines A–C within a few additional steps.51
For the asymmetric synthesis of lundurines A–C, the generation of the stereocenter C20 was achieved by the implementation of a practical chirality transfer from the chiral auxiliary on
the allyl fragment (Scheme 21). The enantiopure oxoester was
condensed with 5-methoxytryptamine under basic conditions to
prevent Pictet-Spendler type reactions. The resulting imine undergoes lactamization to form a mixture of E- and Z-enamides, following the Claisen rearrangement of allylvinyl ether thereby
leading to the desired aldehyde in an 89 : 11 enantiomeric ratio.51

Organic Chemistry Frontiers

cyclopropanation strategy is well illustrated from the work of
Qin’s group.45b An extensive investigation of the transition
metal-catalyzed intramolecular cyclopropanation of indole
pyrroloazocine ring systems closely related to the lundurines
revealed an unexpected reactivity of metalo-carbene species. In
the presence of copper or rhodium salts, the decomposition of
α-diazocarboxylates resulted in the formation of C–H insertion
products (at C3 and C5 positions) instead of the anticipated
reaction of the carbene with an indole double bond
(Scheme 22). In case of α-diazocyanide, the insertion at C15–H
was predominant leading to a cyclobutanone product. The
steric hindrance, conformational features of the 8-membered
ring, as well as the presence of electron-withdrawing groups
stabilizing the diazo compound could possibly explain the preferential formation of the insertion products. Ultimately, the
successful application of the diazocyclopropanation strategy
was achieved using a less stable alkyl diazo compound generated in situ from the corresponding tosyl hydrazone. Cascade
Bamford–Stevens diazotization/diazo decomposition/cyclopropanation mediated by Cu(TBS)2 occurred with a similar
efficiency in comparison with the previously used Simmons–
Smith reaction and afforded cyclopropyl-fused indoline in a
64% yield (Scheme 23).
In our model studies towards the synthesis of lundurines,
we have considered the use of Bamford–Stevens diazotization/
a transition metal-catalyzed diazo decomposition/indole cyclopropanation strategy (Scheme 24, eqn (1)).54 Despite our
efforts in the systematic screening of bases, catalysts, and
temperatures, an undesired vinyl-substituted tetracycle was

4. Synthesis and reactivity of
indoline-fused cyclopropanes
The construction of the cyclopropyl-fused indoline core of the
lundurines poses a significant synthetic challenge. A number
of methods have been developed for both inter- and intramolecular cyclopropanation by transition metal-catalyzed
decomposition of diazo compounds, typically employing
rhodium or coper salts.52 For some systems, enantioselective
versions have also been developed.53
4.1 Undesired reactivity in indoles cyclopropanation step in
the course of lundurines total syntheses
The challenge of constructing a hexacyclic lundurine core with
a cyclopropyl moiety fused to an indoline by using a diazo

282 | Org. Chem. Front., 2018, 5, 273–287

Scheme 22 Transition metal-catalyzed intramolecular C–H functionalizations of indole pyrroloazocine ring systems by Qin et al.45

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Review

a metal catalyst, the vinyl derivative was obtained as the only
product. Interestingly, when transition metal-free conditions
were used for the system featuring a partially unsaturated hexahydroazocine ring system, the cyclopropane-containing hexacycle was obtained in low yield with a concomitant migration
of the double bond to the opposite side of the hexahydroazocine ring (Scheme 24, eqn (2)).
4.2 Lewis acid-mediated [3 + 2] cycloaddition of tosyl
hydrazones to alkenes as a cyclopropanation strategy

Scheme 23 The construction of the hexacyclic lundurine core by
cyclopropanation by Qin et al.45

Less known Lewis acid-mediated 1,3-dipolar cycloaddition of
tosyl hydrazones to olefins yielding corresponding pyrazolines
followed by a loss of dinitrogen is a very interesting alternative
to diazotization/transition metal catalyzed cyclopropanation.
Thus, when o-(trans-2-butenyl)benzaldehyde tosylhydrazone
was treated with BF3·OEt2, indenopyrazole was obtained as the
only product (Scheme 25).55 This transformation was proposed
to begin by the coordination of boron trifluoride to the imine
nitrogen atom of the hydrazone, followed by a stepwise formal
1,3-dipolar cycloaddition. The chromatography purification of
indenopyrazole resulted in the loss of p-toluenesulphenic acid,
thereby yielding the corresponding indenopyrazoline. The
latter, upon thermolysis or photolysis, is converted into a
cyclopropane with the loss of dinitrogen.
The formation of pyrazolines by 1,3-dipolar cycloaddition
between hydrazones and olefins was also reported in the
context of steroid systems (Scheme 26).56 Various aryl substituted hydrazones were shown to successfully undergo stereoselective cycloaddition reactions providing androstene-fused
pyrazoline derivatives. In the case of o,p-dinitrophenyl hydrazones, pyrazolidines were obtained instead. This finding
shows that the reaction rate is dependent on the electronic
characteristic of the substituent and supports the proposed
stereochemical model of cycloaddition. Additionally, computational studies on the mechanism of the pyrazoline formation
have been disclosed.56
Moreover, in 1986, the group of Schultz demonstrated that
a vinylcyclopropane can be generated by BF3-mediated [3 + 2]
cycloaddition/thermal pyrazoline decomposition (Scheme 27).57
Thermally induced dinitrogen extrusion resulted in a tricyclic
product. The irradiation of the vinylcyclopropane with Pyrexfiltered light in methanol provided a 1 : 2 : 1 mixture of starting
materials and a mixture of isomeric l,3- and 1,7-cyclooctadienes.

Scheme 24 Transition metal-catalyzed intramolecular cyclopropanation of indole pyrroloazocine ring systems vs. C–H insertion or
elimination.51,54

obtained as the major product in all cases. An unexpected
formal C–H insertion at the C5 position was occurring in the
presence of transition metal salts. However, in the absence of

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Scheme 25 Proposed mechanism of indenopyrazoline formation by
Lewis acid-mediated [3 + 2]-cycloaddition of hydrazones to olefins.55

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Review

Organic Chemistry Frontiers

Scheme 26 Formation of androstene-fused pyrazolines by Lewis acidmediated [3 + 2] cycloaddition of hydrazones to olefins.56
Scheme 28 The construction of the hexacyclic lundurine core by
cyclopropanation by Echavarren et al.51

Scheme 27 Formation of cyclooctadienes by Lewis acid-mediated
[3 + 2] cycloaddition and photochemical cleavage.57

Longer irradiation of the mixture resulted in the formation of
1,7-cyclooctadiene in an almost quantitative yield.
4.3 [3 + 2] cycloaddition of tosyl hydrazones to alkenes in
total synthesis of lundurines. Unexpected isomerization of
vinyl cyclopropane and similar literature precedents
Lewis acid-mediated [3 + 2] cycloaddition/thermal pyrazoline
decomposition was found to be the most efficient strategy for
the key indole cyclopropanation step in the course of the lundurine synthesis by Echavarren et al (Scheme 28).51 Under
similar to the above mentioned acidic conditions (BF3·OEt2 in
CH2Cl2, at 80 °C), the desired hexacycle was obtained in 80%
yield. The isolated pyrazoline intermediate was converted to
indoline-fused cyclopropane upon heating or slowly while
being stored.
Interestingly, the product of direct cyclopropanation undergoes a puzzling thermal isomerization upon which the double
bond migrates to the opposite side of the hexahydroazocine
ring (Scheme 28). This transformation was proposed to
proceed by a homodienyl retro-ene rearrangement followed by
the reverse process. DFT calculations (Scheme 29), demonstrated that a 1,5-hydrogen shift leads to the formation of an
1,4-diene intermediate, which undergoes intramolecular ene

284 | Org. Chem. Front., 2018, 5, 273–287

Scheme 29 Olefin migration by homodienyl retro-ene rearrangement/
ene-reaction.51

reactions to form a new vinyl cyclopropane moiety. The formation of a more stable conjugated N-acylenamine is a driving
force of this transformation. Both transition states for 1,5hydrogen shifts were found to be similar in energy (ca.
29.5 kcal mol−1). The computed barrier for an alternative

Scheme 30 Thermal isomerization of 1,4-diene into vinyl cyclopropane
by an ene-reaction.

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mechanism proceeding by direct dyotropic rearrangement was
found to be unaccessibly high (>80 kcal mol−1). Additionally, a
similar ene-reaction was observed separately in a pyrroloazocine diene substrate (Scheme 30).58
An irreversible formation of skipped dienes from vinylcyclopropane has been previously reported in the context of cyclic
and bicyclic systems.59 A mechanistic study of intramolecular
dienyl and homodienyl 1,5-hydrogen shifts in the context of

Review

cyclic (5- to 9-membered rings) and open chain systems has
been performed.60 The isomerization of bicyclo[6.1.0]octen-2ene through homodienyl retro-ene rearrangement takes place
at 150–170 °C, with an activation energy of ca. 33 kcal mol−1.
Only one precedent for the reverse process, the rearrangement
of skipped dienes into vinyl cyclopropanes under thermal conditions, has been reported for the oxy-homodienyl substrate
(Scheme 31), and requires temperatures of around 260 °C (activation energies of 41–43.5 kcal mol−1).61

5. Biosynthesis of pyrroloazocine
indole alkaloids

Scheme 31 The rearrangement of skipped dienes into vinyl cyclopropanes under thermal conditions.

Scheme 32

A hypothesis for the origin of pyrroloazocine indole alkaloids
and the biosynthetic relationships within this family has been
reported.8 The pyrroloazocine indole alkaloids belong to a
broader class of monoterpene indole alkaloids, which are
derivatives of iridoid terpene secologanin. Secologanin is first
condensed with tryptamine in a Pictet–Spengler reaction providing strictosidine (Scheme 32).62 Deglycosylation of strictosidine then provides 4,21-dehydrogeissoschizine, which after a

Proposed biosynthesis of pyrroloazocine indole alkaloids.

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Review

series of rearrangements gives aspidosperma type alkaloids,
such as tabersonine or minovincine.62 The latter was proposed63 to be a precursor for aspidofractinines, alkaloids that
are predominant in Kopsia species.8 For example, grandilodines and lapidilectines were isolated from Kopsia grandifolia
together with aspidofractinine alkaloids venalstonine2 and
kopsinine.3 Further oxidation at C21 provides alkaloids like
kopsidasine, and its N-oxide, that were proposed to be a
source of pauciflorine type alkaloids, such as kopsijasminilam.8 Pauciflorines were considered as precursors for diestertype pyrroloazocine indole alkaloids, such as lapidilectine A.8
subsequent oxidative decarboxylation of benzylic methyl ester
and lactonization would lead to alkaloids like lapidilectine B
and tenuisine A. Next, the decarboxylation of the lactone
would result in the formation of cyclopropane-containing lundurines, which was proposed to proceed by a heterolytic
Krapcho-type mechanism. It is worth noting that both decarboxylations of quaternary methyl ester and a lactone are rather
unusual, and no experimental support for these transformations has been disclosed yet.

Conflicts of interest
There are no conflicts to declare.

Acknowledgements
We acknowledge the funding from MINECO/FEDER, UE
(CTQ2016-75960-P),
MINECO-Severo
Ochoa
Excellence
Acreditation 2014–2018, (SEV-2013-0319), the European
Research Council (Advanced Grant No. 321066), the AGAUR
(2014 SGR 818 and FI fellowship to MSK), and CERCA
Programme/Generalitat de Catalunya.

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