Fischer indole synthesis applied to the total synthesis of natural products

Abstract

One of the oldest and most useful reactions in organic chemistry is the Fischer indole synthesis (FIS). It is known to have a wide variety of applications including the synthesis of indole rings, often present as the framework in the total synthesis of natural products, particularly those found in the realm of alkaloids, which comprise a ring system known as an indole alkaloid. In this review, we are trying to emphasize the applications of FIS as an old reaction, which is currently applied to the total synthesis of biologically active natural products and some other complex targets.

Full text

Fischer indole synthesis applied to the total
synthesis of natural products
Majid M. Heravi, *Sahar Rohani, Vahideh Zadsirjan*and Nazli Zahedi
One of the oldest and most useful reactions in organic chemistry is the Fischer indole synthesis (FIS). It is
known to have a wide variety of applications including the synthesis of indole rings, often present as the
framework in the total synthesis of natural products, particularly those found in the realm of alkaloids,
which comprise a ring system known as an indole alkaloid. In this review, we are trying to emphasize the
applications of FIS as an old reaction, which is currently applied to the total synthesis of biologically
active natural products and some other complex targets.
1. Introduction
Nowadays, there has been increasing attention on the total
synthesis of bioactive natural products and their synthetic
analogues in the arena of organic chemistry. Novel synthetic
approaches and strategies are available that permit formation
of novel complex molecules or already structurally known
naturally occurring compounds which can be used as
prescribed drugs or medications.
1
Remarkably, the name indole
is a combination of the words indigo and oleum because
initially, indole was prepared and identied from the reaction
of the indigo dye with oleum.
2
As a matter of fact, one of the
most plentiful heterocyclic systems found in nature is indole. It
is a vital functional nucleus in the structures of different dyes,
fragrances, pharmaceuticals and agricultural chemicals.
3,4
Indole ring moieties became important structural components
in diverse natural pharmaceutical agents, hence their synthesis
and functionalization is a key eld in heterocyclic chemistry,
which has attracted the attention of synthetic organic chemists.
5
Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran.
E-mail: mmheravi@alzahra.ac.ir; z_zadsirjan@yahoo.com
Majid M Heravi was born in
1952 in Mashhad, Iran. He
received his B. Sc. degree from
the National University of Iran
in 1975 and his M. Sc. and Ph.
D. degrees from Salford Univer-
sity, England in 1977 and 1980,
respectively. He completed his
doctoral thesis under the super-
vision of the late Jim Clarck in
Salford University, England. He
started his career as a research
fellow in Daroupakhsh (a phar-
maceutical company) in 1981 Tehran, Iran and joined as an
assistant professor to Ferdowsi University of Mashhad, Iran in
1983, and was promoted to associate professor in 1993 and full
professor in 1997 in the aforementioned university. In 1999 he
moved to Alzahra University of Tehran, Iran as professor of
chemistry where he still works. He has previously been a visiting
professor at UC Riverside, California, USA and Hamburg Univer-
sity, Hamburg, Germany. His research interests focus on hetero-
cyclic chemistry, catalysis, organic methodology and green
synthetic organic chemistry.
Sahar Rohani was born in 1987
in Shiraz, Iran. She received her
B.Sc. degree in pure Chemistry
from the Kharazmi University,
Tehran, Iran, in 2009 and her
MSc. degree in Organic Chem-
istry at Kashan University, Iran
(2012) under the supervision of
Dr Abdolhamid Bamoniri. She is
currently working towards her
PhD in Organic chemistry at
Alzahra University under the
supervision of Dr Ghodsi
Mohammadi Ziarani. Her research eld is synthesis of various
nanocatalysts and their application in coupling reactions.
Cite this: RSC Adv.,2017,7,52852
Received 27th September 2017
Accepted 3rd November 2017
DOI: 10.1039/c7ra10716a
rsc.li/rsc-advances
52852 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances
REVIEW

Therefore, in the last century, different strategies for producing
an indole moiety have been established
6
and among them, the
FIS is the most well-established and practical strategy.
7
Pd-promoted reaction is also a perfect approach for the
synthesis of indoles. In this approach o-haloaniline is usually
used as starting material, which upon treatment with appropriate
unsaturated units, generates new carbon–carbon and carbon–
nitrogen bonds for the construction of the indole core.
8–12
Buchwald et al. presented an approach for the syntheses of FIS
precursors. They developed a Pd-catalyzed cross coupling reac-
tion for the synthesis of N-aryl benzophenone hydrazones, which
are used as common precursors in the typical FIS.
13
The same
group also reported a facile, efficient and general Pd-catalyzed
approach for the synthesis of a wide range of arylhydrazines or
arylhydrazones, which are typical precursors for the FIS.
14
FIS which is rarely called Fischer indolization, has been
accomplished rst by Emil Fischer and Friedrich Jourdan in
1883.
15
FIS is signicant among the well-established classical
methods which efficiently results in the synthesis of the bioactive
indole scaffold that is usually found in alkaloids and in different
valuable medicament.
16,17
The FIS usually gives a facile, effective
protocol for the conversion of enolizable N-arylhydrazones into
indoles using an acid as catalyst.
18
In FIS, the selection of acid
catalyst is very decisive. Brønsted acids such as HCl, H
2
SO
4
and
PTS were frequently employed effectively in this reaction.
19,20
Lewis acids such BF
3
/etherate, ZnCl
2
,FeCl
3
, and AlCl
3
are also
benecial catalysts for this reaction.
21,22
Several reviews have been
reported the selected examples of FIS acid catalysis.
23
A few arylhydrazines are commercially available; they are
generally synthesized by reduction of aryl diazonium salts, which
in turn can be provided from the appropriate aniline derivatives.
Alternatively, aryl diazonium salts can directly be transformed to
hydrazones via the Japp–Klingemann reaction.
24
The Japp–Klin-
gemann reaction involves the reaction of the aryl diazonium salt
with an active methylenyl or methinyl compound in the presence
of an appropriate either acid or base to afford an azo compound,
which under either basic or acidic, or even thermal conditions
can be transformed into the corresponding hydrazone.
24
Indole is the most powerful pharmacodynamic core known
in several naturally occurring compounds.
12–25
Indoles are
known as privileged structures due to their unique roles in
different biochemical procedures.
26,27
Fig. 1 Biologically potent molecules containing indole as a moiety.
Vahideh Zadsirjan was born in
Shiraz, Iran in 1979. She
received her B. Sc. in Pure
Chemistry from Kharazmi
University in 2002, and her M.
Sc by course in 2007 and Ph. D
degree in organic chemistry in
2016 under the supervision of
Professor Majid M. Heravi from
Alzahra University Tehran, Iran.
Her research is focused on
heterocyclic chemistry, catalysis,
organic methodology and green
synthetic organic chemistry.
Nazli Zahedi was born in Teh-
ran, Iran in 1987. She received
her M.D. (G.P) from Medical
School, Islamic Azad University,
Tehran, Iran, in 2014. She is
working towards, taking a place
as resident in a Medical School.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52853
Review RSC Advances

In the group of molecules having biological properties that
were known for a long period of time, melatonin 3as a common
cycle of circadian, tryptophan as a vital amino acid utilized in
sleep disorders and depressive states treatment, tryptamine 1
like serotonin 2realized as growth factors in plants, are
important neurotransmitter. Furthermore, strychnine 5is
a potent stimulant of central nervous system (CNS), LSD 6is
a powerful hallucinogen, and also reserpine was applied as
antihypertensive (Fig. 1).
28
Esrine appears in the Physostigma venenosums seeds has
been suggested for the curing of Alzheimer's disease. Serotonin,
the vasoconstrictor hormone, serves as a neurotransmitter in
animals. Dimeric vinca alkaloids including vincristine and
vinblastine extracted from Catharanthus roseus, which are
utilized in cancer and Hodgkin's diseases treatment.
28
Due to the importance of indole derivatives,
29
it has been
published different reviews in the synthesis of indoles and their
applications in the total synthesis of natural product.
25,30–33
Because of the large number of biologically fascinating natural
products containing poly-substituted indole moieties, FIS has
attained signicant synthetic attention.
34
In continuation of our interest in applications of name
reactions in the total synthesis of natural products
35–47
and in
the synthesis of heterocyclic systems,
48–52
in this review, we try to
highlight the applications of FIS in total synthesis of biologi-
cally active natural products.
2. Applications of Fischer indole
synthesis in the total synthesis of
natural products using
2.1. Aryl hydrazines
Strychnine 5is the chief molecule of the strychnos alkaloids
group, one of the most crowded groups of indole alkaloids.
Initially, strychnine since 1818 was extracted from the Strychnos-
nux vomica's bark and seeds by Pelletier also Caventou and its
essential form has been recognized by Regnault, about 20 years
later.
53,54
In 1954 the historic strychnine's total synthesis 5by
Woodward
55
signied a milestone in the arena of organic
chemistry. Strychnine 5(C
21
H
22
N
2
O
2
) has a complex structure. It
contains six adjacent stereocenters, which ve of them are posi-
tioned in the cyclohexane ring's center and includes merely 24
skeletal atoms, closely packed and organized in seven rings.
Specied its complicated construction, coupled with its highly
toxic activities and pharmacological, strychnine 5has attracted
organic chemists much attention. It is a disreputable poison that
50 mg of it can be deadly for an adult human. That obstructs
postsynaptic hindrance in the spinal cord where it irritates the
transmitter glycine. These effects have made strychnine more
valuable and useful in trial pharmacology.
56
The starting materials for the total synthesis of strychnine 5
was the 2-veratrylindole 10 that was synthesized by FIS from
phenylhydrazine 8and acetoveratrone 9. The rst steps in this
methodology involves the introduction of the 2-aminoethyl
chain to the b-position of 2-veratrylindole 10.Aer several steps,
compound 10 was transformed to strychnine 5(Scheme 1).
57,58
Aspidospermidine is a member of aspidosperma alkaloids
including a pentacyclic ring system, which was separated from
Aspidosperma (a genus of owering plant in the family Apoc-
ynaceae) quebracho blanco and other aspidosperma species.
59,60
The total synthesis of alkaloids aspidospermine 11 was rst
achieved and reported in 1963 by Stork and Dolni.
61
It was
used in the treatment of erectile impotence, and decreasing the
benign prostatic hyperplasia (BPH) symptoms, in guinea pig
and also in rabbit corpus spongiosum and cavernosum due to
its inhibition of smooth muscle contractions.
The parent indole is an achiral molecular unit; the formation
of chiral products by using a FIS is by no means unusual. The
application of a-branched carbonyl molecules for example can
result in the synthesis of indolenine derivatives having
a quaternary stereocenter in the 3-position. For the total
synthesis of ()-aspidospermine 11, Stork and co-workers
acquired merit of this reactivity. This method was started from
butyraldehyde 12, which transformed into complex cyclohexa-
none 13 upon several steps. The FIS of the cyclohexanone 13
and hydrazine 14 afforded the indolenine 15 that has been
transformed into the desired 11 via imine reduction and
N-acetylation (Scheme 2).
61
Remarkably, in chemistry of alkaloid, attention in carbazole
alkaloids has raised signicantly throughout the past years
because of the desired ability of novel kinds of pharmacologi-
cally active compounds. Therefore, for example various carba-
zoles, oxotetrahydrocarbazoles, tetrahydrocarbazoles,
mukonine and glycozoline isomers, prenylcarbazoles, carbazo-
mycins, amino-and nitrocarbazoles as well as pyrido[b]carba-
zole derivatives (such as ellipticines 16 and analogues) contain
anti-convulsant, anti-tumour, anti-inammatory, anti-
histamine, psychotropic, antibiotic and fungistatic activities.
62
The tetracyclic natural product ellipticine (5,11-dimethyl-6H-
pyrido[4,3-b]carbazole) 16 has been extracted in 1959 from the
Ochrosia elliptica Labill plant material.
63
This small tropical
evergreen tree goes to the Apocynaceae family and included
various other alkaloids, involving 9-methoxyellipticine. As
ellipticine 16 was extracted from various other Apocynaceae
plants class (Ochrosia acuminate,Ochrosia moorei and Ochrosia
vieillardii) and from strychnos dinkagei of the Loganiaceae
class. The ellipticine class of complexes use their biological
Scheme 1 Total synthesis of strychnine 5.
52854 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

property through various styles of action, the most well-
developed of that are insertion with topoisomerase II inhibi-
tion and DNA. Recently, other types of action were demon-
strated, involving kinase inhibition, communication with bio-
oxidation, p53 transcription factor and adduct formation.
64
As depicted in Scheme 3, the total synthesis of ellipticine 16
initiated from the allylic alcohol 17. A [3,3]-sigmatropic rear-
rangement with propionic anhydride 18 gave the carboxylic acid
19. Next, the carboxylic acid 19 treated with phenylhydrazine 8
to provide phenylhydrazone 20 continued by the FIS to provide
indole 21. The latter afforded the corresponding natural
product ellipticine 16 in several reaction steps.
65
A series of 11-alkylbenzo[a]carbazole derivatives 22 and their
dihydro analogues have been prepared and examined for their
binding attraction for the estrogen receptor and their anti-
estrogenic and estrogenic effects in the immature mouse. They
also showed mammary tumor inhibiting property. Further-
more, benzo[a]-carbazole derivatives are at polycycles, which
contain the intercalating potential into the DNA. In 1986 von
Angerer and Prekajac described the total synthesis of the 11-
alkyl-11H-benzo[a]carbazoles 22. In this approach, the FIS of the
arylhydrazine hydrochlorides 23 and the tetralones 24 gave the
5,6-dihydro-11H-benzo[a]carbazoles 25. Next, the latter has
been transformed into the corresponding natural product 22b
through subjection to different chemical reactions (Scheme 4).
66
The Strychnos alkaloids are obtained from preakuammicine
and appearently generated from secologanin and tryptophan
through geissoschizine and strictosidine which is actually
a monoterpenoid indole alkaloids biosynthetic pathway. Several
mechanisms have been presupposed to interconnect those of
the Strychnos type with the Corynanthe alkaloid geissoschizine,
but the main features of the rearrangement to preakuammicine
and dehydropreakuammicine stay still unknown. The Strychnos
alkaloids have obtained less attention from synthetic stand-
point than other kinds of indole alkaloids such as Yohimbe,
Iboga,Aspidosperma and Corynanthe.
67
Scheme 3 Total synthesis of ellipticine 16.
Scheme 2 Total synthesis of ()-aspidospermine 11.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52855
Review RSC Advances

The indole alkaloids bearing a nonrearranged secologanin
scaffold contain different structural varieties. Among these, the
alkaloids of the uleine family (dasycarpidan stereoparent) and
the Strychnos alkaloids along with the Aspidospermatan bioge-
netic subtype (condyfolan stereoparent) are identied by the
presence of a 1,5-methanoazocino[4,3-b] indole moiety having
two-carbon chain, typically an ethyl group, at the bridge carbon.
An asymmetric total synthesis of the alkaloids of the uleine
family, nordasycarpidone 26, dasycarpidol 27, dasycarpidone 28
and tubotaiwin 29 were achieved via formation of the tetracyclic
Scheme 5 Total synthesis of, nordasycarpidone 26, dasycarpidone 27, dasycarpidol 28 and tubotalwine 29.
Scheme 4 Total synthesis of 11-alkyl-11H-benzo[a]carbazoles 22.
52856 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

intermediate 34, that were synthesized through FI reaction. This
approach was initiated from 4-piperidineacetates cis-31 and trans-
31, which formed from l-benzyl-3-ethyl-4-piperidone 30 and their
transformation to the desired 4-acetonylpiperidines 32.Then,the
conversion of piperidine cis-32 into the bridged 2-azabicyclo
[3.3.1]-nonane 33 and the FIS of the latter afforded the desired
compound 34. The FIS of ketone 33 has been examined by
applying different acid catalysts. The best consequence has been
provided once the phenylhydrazone from 33 has been reuxed in
acetic acid. Based on these reaction conditions the desired tet-
racycle 34 has been produced as the only isolable product, but in
satisfactory yield. The methanoazocinoindole 34 as a usual main
intermediate. This tetracyclic compound includes a C-20 ethyl
group equatorial with respect to the piperidine ring, namely, with
the identical relative stereochemistry as uleine, dasycarpidone,
and the Aspidospermatan alkaloids. Therefore, aer several steps,
tetracycle 34 afforded the alkaloids nordasycarpidone 26 and
dasycarpidone 27 in 73% and 76% yields, respectively. Lastly,
NaBH
4
reduction of dasycarpidone 27 resulted in the alkaloid
dasycarpidol 28. On the other hand, methanoazocinoindole 34,
afforded ()-tubotaiwin 29 upon several steps (Scheme 5).
68,69
Archer and co-workers employed an identical approach for the
synthesis of 5,11-demethylellipticines (9-hydroxy-6H-pyrido[4,3-b]
carbazole).
68
In the current method, initially, the reaction of
enamine 36 and methyl vinyl ketone 37 afforded a mixture of
trans-andcis-ketones 38 that have individually transformed into
indole 40 through FI reaction. Some of the nonlinear pyrido[3,4-c]
carbazole (17%) have been synthesized from the cis-ketone. Next,
dehydrogenation and demethylation gave the corresponding
natural product 9-hydroxy-6H-pyrido[4,3-b]carbazole 35
(Scheme 6).
70
Indolocarbazole alkaloids exhibit an increasing gure of
natural products extracted from slime molds, marine sources
and soil organisms. Several of them exhibited signicant bio-
logical property. For example, staurosporine and rebeccamycin
are known as antitumor, protein kinase C and topoisomerase I
inhibitors, respectively. Arcyriaavin A 41 is proven to be an
inhibitor of human cytomegalovirus replication. Particularly,
a synthetic derivative, NB-506, is now under clinical trials as
antitumor agents.
71
Similarly, a concise and extremely signicant synthesis of
indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives like arcyriaavin
A41 via a double FIS has been effectively demonstrated by
Bergman and Pelcman in 1989.
70,71
This approach is based on
a double FIS of the bis(phenylhydrazone) 45. The latter was
synthesized through Diels–Alder reaction of market purchas-
able 2,3-bis(trimethylsilyloxy) butadiene 42 with the dien-
ophiles 43,affording the cycloadducts 44. This cycloadduct was
treated with phenylhydrazine 8in acetic acid and MeOH to
afford 45. The double FIS of 45 using polyphosphoric acid tri-
methylsilyl ester (PPSE) as the cyclization agent, led to arcyria-
avin A 41 in 68% yield (Scheme 7). The novel method gave
a concise and very signicant synthesis of indolo[2,3-a]pyrrolo
[3,4-c]carbazole derivatives and appropriate in the synthesis of
a large range of functionalized products and does not need
expensive or in available starting compounds.
72
A novel synthetic method to the synthesis of natural product
arcyriaavin-A 41 and unsymmetrical analogs was demonstrated
by Tom´
e and co-workers in 2000.
73
The method relied on
consecutive Diels–Alder cycloaddition, FI and formal nitrene
insertion procedures. This total synthesis was initiated from the
market purchasable 2-nitrobenzaldehyde 46.Uponvarioussteps,
2-nitrobenzaldehyde 46 transformed into the perhydroisoindole-
1,3,5-trione 47a. Then, trione 47a has been exposed to a FIS with
p-methoxyphenylhydrazine 48,providingamixtureof
compounds 49a and 50a in a 2 : 1 ratio. This ratio looks to
depend on the stability of the ene-hydrazine intermediate. Upon
two steps, the corresponding compound 50a gave the pure
arcyriaavin-A analogue 41a and the parent natural product
arcyriaavin-A 41b in 55% yield (Scheme 8).
73
Physostigmine is an alkaloid which is extracted from the seeds
of Physostigma venenosum (Calabal beans) and it is clinically
effective as a anticholinergic drug. In addition, its enantiomer
protects against organophosphate poisoning. Physostigmine's
analogous have indicated a therapeutic power in Alzheimer's
disease,
2
and recently is in phase II efficacy trials. Additionally,
Scheme 6 Synthesis of 9-hydroxy-6H-pyrido[4,3-b]carbazole 35.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52857
Review RSC Advances

physostigmine has an important role in neuroscience such as
a powerful potent morphine-like narcotic agonist activity of
()-eserine in vivo.
74
Remarkably, there is signicant attention in molecules bearing
central stimulatory property including the anti-cholinergic Cala-
bar bean alkaloids because of their therapeutic in cholinergic
disorders and Alzheimer's disease. Enantioselective total
synthesis of the Calabar bean alkaloid ()-physostigmine 53 and
()-physovenine 54 were accomplished in a short method in 1991
by using FIS under nonacidic conditions as the main stage.
75
The
total synthesis was initiated from the optically active tricyclic
enone 56, which synthesized from racemic dicyclopentadiene 55
in four-steps. Then, alkylation reaction of the latter gave the
monomethyl ketone 57 in 86% yields as a mixture of epimers.
Polycyclic ketone 57 was as a stereochemical control parameter in
the major FI step. Once monomethyl ketone 57 has been reuxed
by using p-methoxyphenylhydrazine hydrochloride 39 in aqueous
pyridine (1 : 10), a simple diastereoselective reaction happened to
supply the carbinolamine 60 as a single product, in 82% chemical
yield. Then, lactol 61 under reux in MeOH with a trace of HCl
produced concomitant deacetylation and cyclization to provide
the tricyclic amino acetal 62. The reaction of 62 with boron
Scheme 8 Total synthesis of arcyriaflavin-A 41.
Scheme 7 Total synthesis of arcyriaflavin A 41.
52858 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

tribromide continued by carbamylation of the obtained phenol 63
gave ()-physovenine 54. This method created the rst enantio-
selective synthesis of the natural products.
On the other hand, in another route, the lactol 61 upon
several steps provided ()-esermethole 51. Since 51 has
formerly been converted into natural ()-physostigmine 53 in
Scheme 9 Total synthesis of ()-esermethole 51,()-eseroline 52,()-physostigmine 53 and ()-physovenine 54.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7,52852–52887 | 52859
Review RSC Advances

two steps through ()-eseroline 52, these reactions are consid-
ered as steps of a formal synthesis of the natural product
(Scheme 9).
75
Bioactivity-directed isolation of the obtain of the cyanophyte
Tolypothrix tjipanasensis has resulted in the isolation of novel N-
glycosides of indolo[2,3-a]carbazole derivatives planned tjipa-
nazole derivatives Al, A2, B, Cl, C2, C3, C4, D, E, Fl, F2, Gl, G2, I
and J. Tjipanazoles are known as novel antifungal agents
extracted from the blue-green alga Tolyporix tjipanasensis.
They showed moderate fungicidal property (strain DB-l-l)
against Aspergillus avus,Trichophyton mentagrophytes and
Candida albicans.
76
The total synthesis of tjipanazole D 64 and E 65 has been
achieved by Bonjouklian and co-workers in 1991,
75
which relied
on FIS reaction. Initially, under air, two equivalents of p-chlor-
ophenylhydrazine hydrochloride 66 and 1,2-cyclohexanedione
67 provided 6-chloro-1-(2-(4-chlorophenyl)hydrazono)-2,3,4,9-
tetrahydro-1H-carbazole 68. The latter based on a FIS gave tji-
panazole D 64 in 54% yield. Subsequently, tjipanazole E 65 has
been extracted as a minor component through coupling reac-
tion of 64 and 1-bromo-a-D-glucopyranosyl-2,3,4,6-tetraacetate
69 aer elimination of the masking substituents (Scheme 10).
76
A novel and efficient synthesis of the pyrrolo[4,3,2-d,e]
quinoline system was accomplished. It is a typical class of
marine alkaloids contains the discorhabdins, prianosins and
other antineoplastic. These include the discorhabdins, priano-
sins, damirones, iso-batzellines and batzellines which are
extracted from wakayin and sponges, isolated from the Fijian
ascidian Clauelina sp. Makaluvamine is a member of the pyr-
roloiminoquinone family and synthesis of makaluvamine D 70,
a mammalian topoisomerase II inhibitor is discovered by the
sponge Zyzzya cf. marsailis. They also showed power in vitro
cytotoxicity in the direction of the human colon tumor cell line
HCT 116 and lead into cancer chemotherapy.
77
The present method to the total synthesis of makaluvamine
D70, a pyrroloiminoquinone containing a tyramine side chain
at C7, was started from a FIS by applying (2,3-dimethoxyphenyl)
hydrazine 72 and dihydrofuran 73. By this route, a pyrroloimi-
noquinone containing a tyramine side chain at C7 undergoes
FIS that instantaneously developed two-carbon side chains.
That prevents the requirement for lengthy synthetic approach at
the indole 3-position, providing reasonably direct pathway to
obtain an appropriate precursor for cyclization to 70. As a result,
the starting material for this method was 2,3-dimethoxybenzoic
acid 71 that has been transformed to crystalline (3,4-dime-
thoxyphenyl)hydrazine 72 upon several steps. Then, this
hydrazine has been reacted with dihydrofuran 73 according to
a procedure established by McKittrick
78
and gave a 1 : 1 mixture
of the tetrahydrofuran 74 and the hydrazone 75 (an E/Z
mixture). The mixture has been exposed to FIS by using ZnCl
2
to afford the desired tryptophol 76. Lastly, aer several steps
makaluvamine D 70 has been isolated as its triuoroacetate 77
that was identical through comparison of its
l
H and
13
C NMR
spectra, mass spectrum and IR spectrum, and with an example
of natural makaluvamine D triuoroacetate (Scheme 11).
77
The ibophyllidine alkaloids compose a small group of indole
alkaloids of the ibogan type which is explored during the last
twenty years and identied by the presence of the structurally
unusual pyrrolizino [l,7-c,d] carbazole ring system. It actually
containes a pyrrolidine D-nor ring instead of the piperidine ring
that usually existed in the monoterpenoid indole alkaloids.
Much research has been typieded the synthesis of alkaloids
with the former feature, by the Strychnos alkaloids and Aspido-
sperma although less attention has been performed to ibo-
phyllidine alkaloids
5
but deethylibophyllidine is chosen as the
synthetic target.
79
The total synthesis of ()-deethylibophyllidine 78 was
accomplished in eight steps starting from O-methyltyramine 79
Scheme 10 Total synthesis of tjipanazole D 64 and E 65.
52860 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

in 5.5% overall yield in that regioselective FIS to a tetracyclic
ring system as a main step. The synthesis was initiated by
market purchasable O-methyltyramine (4-methoxyphenethyl-
amine) 79 that has transformed into cis-octahydroindolone 80
by an enantioselective method in 54% overall yield in several
steps. The FIS of the phenylhydrazone and ketone 80 occurred
regioselectively in acetic acid as an acid catalyst and solvent to
give the tetracyclic 81 in 60% yield. It is remarkable that the
sulfoxide substituent did not endure Pummerer rearrangement
in the presence of the acidic conditions needed for both the
hydrolytic elimination of the enol ether and the FIS. b-Amino
sulfoxide scaffold is more reactive than those sulfoxides bearing
an electron-withdrawing group at the a-position. Thus, b-amino
sulfoxide is useful from the synthetic point of view, thus
employed in initial step of the synthesis with the requisite
oxidation level at the methylene carbon linked to the nitrogen
atom. In the following, aer several steps the tetracyclic 81 was
transformed into ()-deethylibophyllidine 78 in 50% yield
(Scheme 12).
80,81
Murrayafoline A 82, extracted from the root of various
species of the genus Glycosmis,Murraya and Clausena (Ruta-
ceae), displays potent fungicidal property against Cladosporium
cucumerinum and growth inhibitory property on cell cycle M-
phase inhibitory, human brosarcoma HT-1080 cells and
apoptosis inducing properties on mouse tsFT210 cells.
82
In 1998, Murakami and co-workers described the six-step
total synthesis of murrayafoline A 82 with 40% yield.
83
The
current method initiated by the treatment of aminophenol 83
through the 2-hydrazino-5-methylphenol 84 to give the O-
methanesulfonyl (mesyl) derivative 86. Then, the provided O-
mesylphenylhydrazone 86 has been exposed to FIS to give the
tetrahydrocarbazole derivatives 87 and 88 in 63% and 3% yield,
respectively. Lastly, aer multi reactions the mesyloxy
compound 87 gave murrayafoline A 82 (Scheme 13).
83
A catalytic enantioselective synthesis of 20-deethyltubifoli-
dine 89 by using the heterobimetallic enantioselective catalyst
(ALB-KO-t-Bu-MS 4A) has been achieved in 1998.
84
Initially, the
catalytic enantioselective Michael addition of cyclohexenone 90
Scheme 12 Total synthesis of deethylibophyllidine 78.
Scheme 11 Total synthesis of makaluvamine D 70.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52861
Review RSC Advances

and dimethyl malonate 91, by utilizing AlLibis(binaphthoxide)
complex (ALB) as catalyst, provided optically pure 92 in 99% ee
and 94% yield even at ambient temperature. Then, optically
pure compound 92 transformed into the indole derivative 93 in
92% yield, via an extremely regioselective FI approach
continued through decarbalkoxylation (the ee of 93 has been
shown to be 99%). Then, the latter has been transformed to 20-
deethyltubifolidine 89, through a multi-step reaction with an
overall yield of 27% (Scheme 14).
84
A catalytic enantioselective synthesis of the strychnos alkaloid
tubifolidine 94, was extracted from the leaves of pleiocarpa tubi-
cina, has been accomplished in an extremely stereocontrolled
method.
84
This total synthesis based on the chiral indoles 93 as
a main intermediate to put the remaining enantioselective
centers by using substrate control. This compound has been
provided through an extremely regioselective FIS between ketone
92, which has been provided through enantioselective Michael
reaction, and phenylhydrazine hydrochloride in AcOH at 80 C.
The latter has lastly converted to the tubifolidine 94 via amulti-
step synthesis in 24% overal yield (Scheme 15).
84
Several indole alkaloids contain the basic tetracyclic frame-
work with eventually groups for example a methyl substituent
on nitrogen 5 or 12 and/or hydroxy or methoxy substituents on
carbon 1, 2, 3 or 4. A 9-azabicyclo [3.3.1] nonanone was applied
during a tried synthesis of ajmaline via a FI reaction. (endo,
endo)-9-benzyl-9-azabicyclo [3.3.1] nonane-2,6-diol 96 that
already gave a simple admittance to enantioselective synthesis
of indolizidine and quinolizidine alkaloids, can also be applied
Scheme 13 Total synthesis of murrayafoline A 132.
Scheme 14 Total synthesis of 20-deethyltubifolidine 89.
52862 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

in principle for the formation of macroline/sarpagine type
alkaloids. Ketone 97 has been produced in 37% yield from
readily accessible (endo,endo)-9-benzyl-9-azabicyclo [3.3.1]
nonane-2,6-diol 96 aer several steps.
Next, ketone 97 was treated with functionalized phenyl-
hydrazines 98 under reux in hydrochloric acid-saturated
MeOH. The desired derivatives 99 were readily provided via an
abnormal FI. Then two intermediates 95a and 95b were directly
produced through Swern oxidation of 99a and 99b, respectively.
These two intermediates can be utilized for the formation of
macroline/sarpagine kind alkaloids (Scheme 16).
85
Next, in another route, ketone 97 has been treated with meta-
functionalized phenylhydrazine derivatives 101 noticeably
should result in a mixture of 1- and 3-functionalized
compounds: for example, with meta-tolylhydrazine a 1 : 1
mixture of 102a and 102b has been provided. To create this FIS
regioselective, a transitory substitution by bromine at one ortho-
position has been employed. Aer FI and hydrogenolysis by
using Pd/C and potassium carbonate, the 1- or 3-functionalized
100a and 100b, respectively were provided (Scheme 17).
85
These
consequences exhibit that (endo,endo)-9-benzyl-9-azabicyclo
[3.3.1]nonane-2,6-diol 96 provided a simple condition to enan-
tioselective synthesis of quinolizidine and indolizidine
alkaloids. This method can also basically apply for the synthesis
of macroline/sarpagine alkaloids.
The Aspidosperma group demonstrates one of the widest
class of indole alkaloids, having more than 250 products
extracted from different biological sources. An important
member of this group is tabersonine 103 that exhibits a main
role in the synthetic chemistry of Aspidosperma alkaloids and
biosynthesis. Initially, tabersonine has been extracted from
Amsonia tabernaemontana in 1954 by Le Men and co-workers.
86
Soon upon the rst report, the alkaloid has been extracted from
various other natural sources, demonstrating its relative bio-
logical abundance.
In 2001, Rawal and his group described the twelve-step
enantioselective total synthesis of ()-tabersonine 103 with
overall yield of 70–80%.
87
The enantioselective total synthesis of
racemic tabersonine was initiated from market purchasable
monoacetal 104. Upon several steps, carbamate 105 has been
provided in 88% yield. Subsequent, reaction of the silyl enol
ether 105 with dilute HCl provided a clean hydrolysis to bicyclic
ketone 106, with the cis stereochemistry intact. This trans-
formation, sacriced the double bond position, which has been
accomplished via the rst cycloaddition. In providing for FIS,
ketone 106 has been transformed into the phenylhydrazone via
heating it with phenylhydrazine hydrochloride 23a by using
Scheme 16 Total synthesis of basic teracyclic skeleton of macroline/sarpagine type alkaloids.
Scheme 15 Total synthesis of tubifolidine 94.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7,52852–52887 | 52863
Review RSC Advances

Na
2
CO
3
. In the following, the crude hydrazone has been reuxed
at 95 C in glacial AcOH. A weakly acidic medium found to favor
idolization toward the more functionalized carbon. Based on
these reaction conditions, the indolization provided efficiently
and in satisfactory yield (93% overall) but gave both possible
indole isomers in roughly equal quantities. The two isomers have
been easily isolated via column chromatography. Hence, by using
FI reaction, this reaction didn't have stereocontrol. Next, the
tetracyclic indole 107, upon several steps, afforded ()-taber-
sonine (rac-103), in 70–80% yield (Scheme 18).
87
Peduncularine 109 is a member of the indole alkaloids class
with a monoterpene unit like the aliphatic portion, which rstly
was extracted by Bick and co-workers in 1971, from the
Tasmanian shrub Aristotelia peduncularis.
88
Alkaloids have been
derived from some of other elaeocarpaceous plants from A.
serrata (New Zealand), A. chilensis (Chile) and also mostly from
New Guinea. Its conguration associated alkaloids aristoteline,
peduncularine, tasmanine, aristoserratine, sorelline and
hobartine. That is also re-divided biogenetically pattern with
a rearranged geranyl and tryptamine subunit. These natural
productions such as peduncularine have indicated cytotoxic
activity against cell lines of breast cancer and other biological
activities.
In 2002, Roberson and co-workers achieved a relatively short
total synthesis of ()-peduncularine 109 in sixteen steps from
market purchasable 1,4-cyclohexadiene 110.
89
This compound
Scheme 18 Total synthesis of ()-tabersonine 103.
Scheme 17 Total synthesis of basic tetracyclic of indole alkaloids 100.
52864 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

could provide acetate 111,aer several steps. The latter has
been exposed to FIS to supply alcohol 112 with concomitant
deprotection of the C-8 alcohol. The latter upon several steps
produced ()-peduncularine 109 with appropriate yield. The
main step of in the current total synthesis is the [3 + 2] annu-
lation reaction of an allylic silane by using chlorosulfonyl
isocyanate, that transported the desired bicyclic nucleus of the
naturally occurring compounds (Scheme 19).
89
A novel group of 5-heteroaryl-functionalized 1-(4-uo-
rophenyl)-3-(4-piperidinyl)-1H-indoles as enormously selective
and potentially CNS-active a
1
-adrenoceptor antagonists was
shown by Eilbracht and co-workers.
90
The corresponding
products were provided from the antipsychotic sertindole 113.
The structure–affinity relationships of the 5-heteroaryl substit-
uents and the groups on the piperidine nitrogen atom were
optimized with respect to affinity for a
1
adrenoceptors and
selectivity in respect to dopamine (D
1–4
) and serotonin (5-HT
1A–
1B
and 5-HT
2A,2C
) receptors.
91
A usual aspect of unusual antipsychotics for example clozapine,
olanzapine, sertindole 113 and seroquel is nanomolar attraction
for a
1
adrenoceptors additionally to their attractions for serotonin
5-HT
2A
and dopamine D
2
and receptors. The real balanced
attractions for these receptors might underlie the enhanced form
of these drugs (enhanced rate between doses containing antipsy-
chotic property and extrapyramidal side effects) as contrasted to
classical antipsychotic drugs, for example haloperidol. The phe-
nylindole framework of sertindole 113 is a promising pattern for
thegrowthofmainactinga
1
antagonists. Replacing of the 5-
chloro atom in sertindole 113 with polar substituents including
functionalized aminomethyl and carbamoyl groups provided
Scheme 20 Total synthesis of sertindole 113.
Scheme 19 Total synthesis of ()-peduncularine 109.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7,52852–52887 | 52865
Review RSC Advances

a novel group of particular a
1
adrenoceptor antagonists. This
research demonstrated that 5-substituents mixing hydrogen bond
acceptor possessions with steric bulk in the plane of the indole
core are necessary to provide high affinity for adrenergic a
1
receptors mixed with satisfactory selectivity in respect to dopa-
mine D
2
and serotonin 5-HT
2A
and 5-HT
2C
receptors.
Tryptamine imitative is specically included in many biolog-
ical processes, such as melatonin in serotonin in neurological
processes or in the circadian rhythm control. Therefore, trypt-
amine containing the nucleus indole and its imitative were
employed for the reaction of various diseases such as migraine
(for example Sumatriptan), schizophrenia (e.g. Sertindole) and
depression (e.g. D-tryptophan). In this approach, rstly, tandem
hydroformylation-FIS gave appropriate admittance to indole 116
initiating from the readily accessible olen114 through trans-
formation with market purchasable 4-bromophenylhydrazine
115 and afforded indole 116 in 39% yield. The latter has been
then transformed into the corresponding sertindole 113,upon
several reactions (Scheme 20).
90,91
Meridianins are brominated 3-(2-aminopyrimidine)-indoles,
which are puried from Aplidium meridianum, an Ascidian from
the South Atlantic (South Georgia Islands). Meridianins prevent
cell proliferation and induce apoptosis, a demonstration of their
ability to enter cells and to interfere with the activity of kinases
important for cell division and cell death. These results suggest
that meridianins constitute a promising scaffold from which more
potent and selective protein kinase inhibitors could be designed.
92
The compounds, except meridianin G and the related iso-
meridianins C, were found to inhibit CDKs, GSK-3, PKA and
other protein kinases in the low micromolar range. Meridianins
B and meridianin E were the most potent inhibitors while
meridianin G, isomeridianin C and G were essentially inactive.
Meridianins B and E were selected for further studies on
selectivity and cellular effects.
93
Franco and co-workers described synthesis of iso-meridianin
derivatives 117 via microwave irradiation (MWI).
93
The
synthetic method contains six steps, in which FIS is considered
as the main reaction. This group selected isocytosine 118 as
a suitable starting compound, since the hydroxyl group at posi-
tion 4 permits an appropriate functionalization and introduction
of the requisite C-2 carbonyl group.In this procedure, isocytosine
118 has been transformed into the corresponding methyl ketone
119 upon different steps. The latter based on normal conditions
afforded the desired phenylhydrazone derivatives 120a and 120b
in 90% yield. The desired products 120a and 120b have been
employed without more purication. The FIS was the main step
of this method, so many efforts by utilizing various catalysts,
solvents and heating conditions were attempted. As a result, the
usage of zinc chloride and MWI provided a quick, clean and
quantitative elimination of the Boc group. Although, addition of
a small amount of dimethylformamide prior to MWI with zinc
chloride into 120a and 120b provided the desired iso-meridianin
G117a and iso-meridianin C 117b in satisfactory yields, respec-
tively (Scheme 21).
93
The total synthesis of 8-desbromohinckdentine A 121 has
been effectively achieved and described by Liu and co-workers
in 2003.
94
In this route, 2-(2-bromophenyl)-indole 123, has
been formed through the FIS from phenylhydrazine hydro-
chloride 23a and 2-bromoacetophenone 122. Upon several
steps, indole 123 has been converted into the corresponding
single dibrominated natural product 121 (Scheme 22).
94
()-Aspidospermidine 124 is one of the aspidosperma alka-
loidsfamily.Aspidospermaalkaloidsstructurallyhavepentacyclic
[6.5.6.6.5] ABCDE ring system skeleton with a common structural
feature which is cis-stereocenters at C-7, C-21, and C-20 (all carbon
quaternary). Some parts of this kind of alkaloids like vinblastine
and vincristine have been used as cancer chemotherapy medica-
tions. Additionally tabersonine (possess inhibitory effect against
SK-BR-3 human cancer cell lines which is better than cisplatin),
jerantinine-E (more potent in vitro cytotoxicity against human KB
cells, IC50 <1 mgmL
1
), and vincadifformine (cytotoxic), are
pharmacologically important alkaloids.
95
Total synthesis of (+)-aspidospermidine 124 has been
described by Aube and co-workers in 2005.
96
The main reactions
Scheme 21 Total synthesis of iso-meridianins G 117a and C 117b.
52866 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

used in the total synthesis of this pentacyclic Aspidosperma
alkaloid contain a deracemizing imine alkylation/Robinson
annulation sequence, a selective “redox ketalization”, and also
an intramolecular Schmidt reaction. A FIS happened on
a tricyclic ketone similar to the sequence described in their
aspidospermine synthesis. The synthetic method utilized 2-
ethylcyclopentanone 125 as the precursor. The latter provided
tricyclic lactam 126 as a single diastereomer in 82% chemical
yield and 84% enantioselectivity. Compound 126 did not show
amenable to a direct FIS reaction and so has been reduced in
a three-step procedure to the desired ketoamine 13 by using of
selective protection of the ketone carbonyl continued through
a reduction/deprotection reaction. The reaction of ketoamine
13 with phenylhydrazine 8, acid and lastly lithium aluminium
hydride gave the target (+)-aspidospermidine (124, 51% yield
from 13) along with 13% of a by-product 127. This by-product
probably arose through the FI of the less-functionalized
enamine isomer (Scheme 23).
96
Another approach has been described by Canesi and co-
workers for the synthesis of ()-aspidospermidine 124 in 12
steps.
97
This method, relied on ‘‘aromatic ring umpolung’’ was
initiated from a polyfunctionalized phenol 128. Upon diverse
steps, this compound can be transformed into main interme-
diate 13. In the following, FIS of tricycle 13 and phenylhydrazine
8under reux condition resulted in the hydrazone 129 that is
transformed to imine 130 in AcOH. The latter is reduced in the
same pot by using lithium aluminium hydride to provide
()-aspidospermidine 124, in 43% yield (Scheme 24).
97
Also, in another method, for the total synthesis of (+)-aspi-
dospermidine 124, 1-(p-methoxy benzyl)piperidin-2-one 131
upon several steps provided tricyclic core 13. The latter is
a privileged tricyclic nucleus having the crucial C-20 all-carbon
quaternary stereocenter would be a signicant issue in
providing enantioselective synthesis of 124 and structurally
related bisindole alkaloids. Also, FI cyclization reaction of 13
produced dehydroaspidospermidine that on reduction by using
lithium aluminium hydride afforded corresponding naturally
occurring compound (+)-aspidospermidine 124 in 50% yield
(Scheme 25).
95
Cryptosanguinolentine 132 or called isocryptolepine is the
most important member of indoloquinoline alkaloids, which
was separated from the roots of the West African plant
Scheme 23 Total synthesis of (+)-aspidospermidine 124.
Scheme 22 Total synthesis of 8-desbromohinckdentine A 121.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52867
Review RSC Advances

Cryptolepis sanguinolenta. In traditional folk medicine was used
for treatment of fevers such as fever of malaria. Various types of
hetero-aromatic alkaloids have potential applications in the
medicinal eld. Many such alkaloids intercalate in the DNA
double helix resulting in changes in DNA conformation so they
can inhibit DNA transcription and replication. X-ray analysis
and spectroscopy can investigate the mode and strength of
binding of these alkaloids to DNA. In addition, some N-methyl
derivatives of these ring systems exhibit important cytotoxic and
antimicrobial activities.
98
A novel and appropriate synthesis of cryptosanguinolentine
132, have been described by Dhanabal and co-workers in 2005.
99
In this total synthesis, an improved FI cyclization reaction has
been employed in the initial step. 4-Hydroxy-1-methyl-1H-
quinolin-2-one 133 and phenylhydrazine hydrochloride 23a
reacted by using a mixture of glacial AcOH and concentrated
HCl in the ratio of 4 : 1 to afford the indoloquinoline scaffold
134 in a single step. Then, the corresponding compound 134 in
several steps gave cryptosanguinolentine 132 in high yields
(Scheme 26).
99
Haplophytine 135 (C
27
H
31
O
5
N
3
), the important indole alka-
loid, and cimicidine (C
23
H
28
O
5
N
2
) were isolated from the
Mexican plant Haplophyton cimicidum's dried leaves, rst time
in 1952 by Snyder and co-workers.
100
Huplophyton cimicidum
produces the aspidospermine and the biogenetically related
eburnamine kinds of alkaloids. Haplophytine 135 is constituted
of two parts that are joined by the forming of a quaternary
carbon center. The right-half part is a hexacyclic aspidosperma
class of alkaloid, known as aspidophytine, which is acquired by
the acidic degradation of (+)-haplophytine. The le-half part has
an unique structure, that includes a bicyclo[3.3.1] framework
which possesses bridged aminal and ketone activities. Both
alkaloids are toxic to insects, but most of the toxicity is owed by
the haplophytine conLent (I) also they are toxic to German
roaches on contact, injection and ingestion. The LD/50 dosage
of cimicidine is about 60 g/g (contact, 48 h) and for hap-
lophytine is 18 g/g. Haplophytine caused extended paralysis at
dosage levels under the LD/50 value. The total crude alkaloid
has been discovered to be toxic to an extensive range of insects
containing Mexican bean beetle larvae, European corn borers,
egg-plant lace bugs, Colorado potato beetle larvae and adults,
codling moths and grasshoppers.
101
The rst total synthesis of (+)-haplophytine 135 has been
reported by using several key steps including intramolecular
Mannich reaction, oxidative rearrangement, the FIS and Frie-
del–Cras alkylation reaction.
102
Ueda and co-workers demon-
strated the rst total synthesis of (+)-haplophytine 135 in 2009
via an effective method.
102
Haplophytine is contained of two
segments that are linked by the construction of a quaternary
carbon center. Total synthesis of (+)-haplophytine 135 was
initiated from market purchasable 7-benzyloxyindole 136 and
upon various steps afforded 137 as the main precursor of the FI
reaction. The reaction of hydrazine 137 with tricyclic ketone
138, synthesized by d’Angelo and co-workers by using 50%
Scheme 25 Total synthesis of (+)-aspidospermidine 124.
Scheme 24 Total synthesis of ()-aspidospermidine 124.
52868 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

H
2
SO
4
provided the desired hydrazone.
103
Upon widespread
optimization, this group ultimately known that cautious control
of the reaction temperature and the suitable selection of solvent
and acid were necessary to favorably attain the corresponding
indolenine 139 over the indole 140 in satisfactory yield. There-
fore, the reaction with p-toluenesulfonic acid in tert-butanol at
80 C provided indolenine 139 in 47% yield accompanied with
indole 140 in 29% yield. Lastly, imine 139 aer different steps
provided (+)-haplophytine 218 (Scheme 27).
102
Minensine is an indole alkaloid which is extracted from the
African plant named Strychnos minensis by Massiot and co-
workers in 1989.
104
Minensine has signicant biological
functions containing anticancer activities. Additionally, various
types of the Strychnos indole alkaloids have interesting anti-
cancer functions too.
104
In 2011, a short total synthesis of minensine 141 was
accomplished in ten steps.
105
The assembly of minensine 141
started with the FIS. Therefore, the reaction of cheap and
market purchasable phenylhydrazine 8and 1,4-cyclo-
hexanedione monoethylene acetal 142 at ambient temperature
continued by heating at 190 C provided the corresponding
indole product 143 in 89% yield. Next, the corresponding indole
aer several steps afforded ()-minensine 141 in 95% yield
(Scheme 28).
105
(+)-Aspidoalbidine (or (+)-fendleridine) is an Aspidosperma
alkaloid separated from the seeds of Aspidosperma fendleri. The
Scheme 27 Total synthesis of (+)-haplophytine 135.
Scheme 26 Total synthesis of cryptosanguinolentine 132.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52869
Review RSC Advances

name fendleridine was related to the name of the tree, by Bur-
nell and co-workers in 1966.
106
Brown found (+)-N-acetylaspi-
doalbidine in 1963,
107
they gave the name “aspidoalbidine”to
the postulated simplest member by analogy to aspidospermi-
dine, discovered by Biemann two years before. Acetylaspi-
doalbidine is a member of Aspidosperma family, which is
isolated from the Venezuelan tree species and Aspidosperma
rhombeosignatum markgraf and Aspidosperma fendleri woodson.
The Aspidosperma family is one of the indole alkaloid families
also many of them have signicant biological activities.
108
The total synthesis of acetylaspidoalbidine 144, an alkaloid
isolated from the Aspidosperma family, has been achieved by
Guerard and co-workers in 2012.
109
As depicted in Scheme 29,
the total synthesis of 144 was initiated from different benzylic
alcohol systems 145, that has been converted into alcohol 146
through a multi-step synthesis. Then, the pentacyclic scaffold
has been generated by using a FIS method followed by treat-
ment with lithium aluminium hydride. This approach resulted
in a mixture of the indoline nucleus 147 and an unanticipated
indole, in a 2 : 1 ratio favoring the corresponding 147. The
corresponding compound 147 upon several steps transformed
into acetylaspidoalbidine 144. A signicant enantioselective
form of this procedure is the ability to rapidly convert a cheap
and simple phenol into an extremely substituted nucleus
including a prochiral dienone in the form of a quaternary
carbon center linked to different sp
2
carbons. The provided
structures are current in various naturally occurring
compounds containing imperative biological properties. A fast
method to diverse polycyclic molecules, involving the main
tricyclic or tetracyclic systems of alkaloids belonging to the
Aspidosperma group and a novel formal synthesis of acetylas-
pidoalbidine have been demonstrated. The consequences
exhibit the potential of these oxidative transposition methods
and the efficacy of the “aromatic ring Umpolung”concept. The
reaction happens in valuable yields by using allyl groups (up to
67%) and is less signicant with phenyl, vinyl, or alkyl substit-
uents (Scheme 29).
109
In 2004, Kam and co-workers isolated Mersicarpine 148 from
the stem-bark of the Kopsia arborea and Kopsia fruticosa.
110
The
tetracyclic dihydroindole mersicarpine was exhibited in another
kind of Kopsia,viz.,K. singapurensis too, which has a typical
seven-membered cyclic imine joined with indoline and d-lac-
tam. The Kopsia has intriguing biological activities. Additionally
other alkaloids were obtained from kopsia such as mersi-
carpine, pericidine, arboricinine, valparicine, arboorine,
arboricine and arboloscine.
111
In 2013, Iwama and co-workers accomplished an extremely
signicant enantioselective total synthesis of ()-mersicarpine
148 by using an 8-pot/11-step sequence in 21% chemical yield
that initiated from market purchasable 2-ethyl-
cyclohexanone.
112
The features of this procedure were FIS,
simple admittance to the azepinoindole framework, the short-
step and signicant synthesis. This method was started with
the FIS by utilizing optically active ketoester 149, which
synthesized in 99% enantioselectivity based on the procedure
by d’Angelo and Desma¨
ele.
113
The latter has been reacted with
phenylhydrazine 8in AcOH at 120 C to provide the desired
tetracyclic tetrahydrocarbazole 150 in excellent yield without
isolation of the transient tricyclic tetrahydrocarbazole 151.Aer
several steps by using various routes, the corresponding
compounds 150 and 151 produced benzyloxycarbonyl (Cbz)
carbamate 152, that is as a main intermediate to form
()-mersicarpine 148. This group tried to examine the reaction
Scheme 29 Total synthesis of acetylaspidoalbidine 144.
Scheme 28 Total synthesis of minfiensine 141.
52870 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

conditions of FIS reaction that afforded tricyclic tetrahy-
drocarbazole 150 without the production of the lactam ring.
Relied on the previous observation, using phenylhydrazine
hydrochloride in MeOH and in the presence of acetic acid
afforded the corresponding tricyclic tetrahydrocarbazole 150,
selectively. The effect of acid on the ratio of 150 to 151 was
examined. As a result, methanesulfonic acid was found as
a suitable acid for the improvement in selectivity of the FIS.
More outstandingly, it was found that the product ratio was
extremely sensitive to the quantity of acid employed. Therefore,
the reaction in the presence of phenylhydrazine 8and meth-
anesulfonic acid afforded 151 in excellent yield and selectivity.
Finally, the ()-mersicarpine 148 was synthesized in 21% yield
(Scheme 30).
112
The Aspidosperma alkaloids own a main place in natural
chemistry inventions due to their different biological activities
and extensive range of compound structural variations. Acid
cleavage of haplophytine (a dimeric indole alkaloid was found
Scheme 31 Total synthesis of ()-aspidophytine 153 and (+)-cimicidine 154.
Scheme 30 Total synthesis of ()-mersicarpine 148.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52871
Review RSC Advances

in the Haplophyton cimicidum's leaves) guided to aspidophytine,
a lactonic aspidospermine member of alkaloid that has been
recommended to be used in its synthesis and be a biosynthetic
pioneer of haplophytine.
114
In 2013 Satoh and co-workers described a total synthesis of
()-aspidophytine 153 and also the initial total synthesis of its
congeners, (+)-cimicidine 154 and (+)-cimicine 155, have been
achieved in a divergent method. Preparation of the aspido-
sperma scaffold has been performed via FIS.
115
The regio-
chemistry of the FIS was powerfully reliant on the type of acid,
and a weak acid, including AcOH gave the corresponding
indolenine isomer in satisfactory selectivity. In this method,
total synthesis of ()-aspidophytine 153 and (+)-cimicidine 154
was initiated from market purchasable ketoester 156, which has
been provided from optically active tricyclic aminoketone 138
upon several steps.
102
The latter compound 138 treated with
functionalized phenylhydrazine 72 via FIS under reux in
benzene to afford hydrazone 157 which has been exposed to
different acidic conditions. Finally, this group provided the
corresponding indolenine 158 in 48% accompained with 5% of
indole 159 once reaction has been completed in AcOH at 100 C.
Pentacyclic indolenine 158 provided ()-aspidophytine 153
aer several steps. Subsequent, they demonstrated the total
synthesis of (+)-cimicidine 154 by using the usual intermediate
158 through diverse reactions (Scheme 31).
115
The efficacy of the convergent synthetic approach has been
shown by achievement of the rst total synthesis of (+)-cimicine
155. Therefore, FIS through 2-methoxyphenylhydrazine 14 and
aminoketone 138 provided hydrazine 160 which provided 41%
of the corresponding indolenine compound 161 in satisfactory
regioselectivity and 6% of compound 162 Next, upon different
steps, imine 161 gave (+)-cimicine 155 (Scheme 32).
115
The efficiency of this synthetic approach for manufacturing
extremely substituted aspidosperma alkaloids has been
completely exhibited via the divergent synthesis of these three
aspidosperma alkaloids from the usual tricyclic aminoketone
intermediate. Furthermore, in this research, the regiochemistry
of the FIS has been powerfully affected by acidity of acids, which
produced the corresponding indolenine isomer in satisfactory
selectivity (Scheme 32).
115
Akuammilines have an indolenine or indoline core, which is
combined to a polycyclic framework. The complicated struc-
tures of these molecules have biosynthetic source and biological
efficacy that can show activities for combating plasmodial, viral,
and cancerous diseases. The alkaloids fraction of alstonia
scholarisleaf, vallesamine, picrinine and scholaricine, may
make the analgesic and anti-inammatory effects based on in
vivo and in vitro screening. Picrinine is a component of the
akuammiline family of alkaloids, which has six stereogenic
centers, ve of them are contiguous, and includes two N,O-
acetal linkages within its polycyclic skeleton. Picrinine 163
reveals anti-inammatory activity via inhibition of the 5-lip-
oxygenase enzyme.
17
Picrinine was rstly extracted from the
leaves of Alstonia scholaris in 1965.
116
The plant Alstonia schol-
aris, also called the Dita Bark tree, has been a rich origin of
alkaloids. They can be extracted from its owers, bark, seeds,
leaves, fruitpods and roots. These alkoldes have been used to
treat chronic respiratory diseases, for treatment of malaria and
dysentery in Southeast Asia, and have been used as traditional
medicines to treat various ailments in livestock and humans for
the centuries. Even in china it is used for their antitussive and
antiasthmatic properties also to release tracheitis and cold
symptom. In addition to picrinine and scholaricine, three new
indole alkaloids, 5-epi-nareline ethyl ether, nareline ethyl ether
and scholarine-V(4)-oxide were separated from the leaf extract
of Alstonia scholaris.
117
Smith and co-workers described the rst total synthesis of
the akuammiline alkaloid picrinine 163 in which a main step of
their total synthesis was FIS.
118
Synthesis of this natural product
has been initiated from sulfonamide 164, which is available
from market purchasable or can be easily synthesized. Then,
sulfonamide 164 upon various steps produced carbonate 165
that was an appropriate initiating compound for FIS. In the
critical FI, triuoroacetic acid stimulated reaction of carbonate
Scheme 32 Total synthesis of (+)-cimicine 155.
Scheme 33 Total synthesis of picrinine 163.
52872 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

165 and phenylhydrazine 8gave the hexacyclic indolenine 166
with complete diastereoselectivity. This conversion is identied
as one of the most complex cases of the FIS. It should be
mentioned that indolenine 166 is in equilibrium with its
hydrate, hence, purication and 2D NMR analysis were essen-
tial to assist structure clarication. However, upon numerous
steps picrinine 163 has been provided. This synthetic method
shows short assembly of a main FIS to forge the natural prod-
uct's carbon scaffold, and a number of delicate late-stage
conversions to furnish the total synthesis (Scheme 33).
118
Family of the Vinca class of alkaloid was the subject of
synthetic studies with attendant and important biological
properties. For example the pentacyclic vindoline 167, which is
the main alkaloid, isolated from the plant Catharanthus roseus.
Due to its antimitotic properties compound 167 has been
recently being used in the clinical treatment of different human
cancers.
119
Members of the Vinca group of alkaloid have been the topic of
extensive synthetic studies. The total synthesis of 167 was initi-
ated from phenylhydrazine 8and cyclohexane-1,4-dione
monoethylene ketal 142 as precursor for the rst FIS to provide
product 143 (94%). Next, the latter has beentransformed into the
pentacyclic compound 167 by using different steps in chiral, non-
racemic form and in ca. 33% yield (Scheme 34).
120
The spiroindimicins are a member of structurally alkaloids
extracted from the deep-sea-derived marine actinomycete Strep-
tomyces sp. SCSIO 03032. Marine actinomycete Streptomyces
SCSIO 03032 can produce polyketide macrolactam heronamides,
a-pyridone antibiotic piericidins, lynamicins and polyketide
macrolactam heronamides. Deep-sea organisms have survived
under their hard environment by adjusting an extensive range of
their metabolic pathways and biochemical processes. The deep-
-sea-derived marine actinomycete Streptomyces sp. SCSIO 03032,
that causes a range of structurally unprecedented natural prod-
ucts such as spiroindimicins A–D, dichlorinated bisindole alka-
loids possessing unique heteroaromatic frameworks featuring or
spiro-rings. Some analogues of bisindole alkaloids are DNA-
topoisomerase I inhibitors and protein kinase inhibitors which
have been used in cancer clinical trials.
121
Sperry and co-workers in 2016 exhibited effective usage of the
FIS to generate a pentacyclic spirobisindole.
122
In this synthetic
method, rstly, requisite spiroindolinyl pentanone 172 has been
produced from the treatment of iodoaniline 170 and bromide
171 in high yield. Then, with the spiroindolinyl pentanone 172,
the stage was set for the critical FI reaction. Aer heating a solu-
tion of 172 in hand, and 4-chlorophenylhydrazine in AcOH under
reux, the spirobisindole 174 has been provided in high yield,
representing the timeless efficacy of this classic reaction in
complex natural product synthesis. Subsequent, the latter
transformed into the natural products ()-spiroindimicin C 168,
that aer reductive amination produced ()-spiroindimicin B
169 (Scheme 35).
122
Montamine isolated from the seeds of Centaurea montana.
The genus Centaurea have been applied in folk medicine for the
treatment of different diseases. Centaurea montana, known as
the mountain cornower, is a native plant in Australia and
Europe. Montamine has a unique dimeric N,N0-diacyl hydrazide
Scheme 34 Total synthesis of Vinca group of alkaloid 167.
Scheme 35 Synthesis of spiroindimicins B 169 and C 168.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52873
Review RSC Advances

structure and shows cytotoxicity against CaCo-2 colon cancer
cells (IC
50
¼43.9l M).
123
In 2015, Xu and co-workers described the total synthesis of
alkaloid natural product montamine analogue 175 in 55%
yield.
124
As depicted in Scheme 36, this group provided 3-(2-
hydroxyethyl)-5-methoxyindole (usually found as 5-methoxy-
tryptophol, 176) through the FIS with p-methoxyphenylhy-
drazine hydrochloride 39 and 2,3-dihydrofuran 73. Whereas the
yield of this treatment was modest, it nevertheless gave
a reasonable, one-step method to an indole suitably substituted
having an oxygen group at the 5-position and ethyl alcohol
scaffold at the 3-position. Alcohol 176 gave the advanced
montaine analogue 175 in several steps (Scheme 36).
124
The monoterpene indole alkaloids are an extremely different
group of naturally occurring compounds, which were provided
in a widespread series of medicinal plants. They have natural
structural complication and a number of signicant biological
properties, which qualies a gure of them to be principle
candidates for anti-arrhythmic, anti-malarial and anti-cancer
agents.
125
Dixon and co-workers, in 2016, achieved a novel
method for the difference total synthesis of ()-vinca-
difformine, ()-vincaminorine, ()-quebrachamine, ()-N-
methylquebrachamine and ()-minovine and, each in slighter
than 10 linear steps in perfect diastereoselectivities.
126
Initially, for the synthesis of ()-minovine 177, this route was
started with the formation of aldehyde 183 from 3-ethyl-2-
piperidone 182 upon two steps. The production of the indole
functionality continued effectively by Stork's modication of the
FIS of aldehyde 183 with phenylhydrazine hydrochloride 23a
which produced indole 184 in 62% yield. The latter aer different
steps produced the desired alkaloid, ()-minovine 177 in 52%
yield. Another skeletally distinct alkaloid, ()-vincaminorine 178
has been provided as a single diastereomer in the reaction vessel
in 31% yield, which could be more transformed into N-methyl-
quebrachamine 179 in 61% yield. Moreover, in another route,
indole 184 can produce ()-vincadifformine 180 and ()-que-
brachamine 181 with 84% and 71% yields, respectively.
126
This
approach that gives a concise and different synthetic method to
various vincadifformine-type, quebrachamine-type and iboga-
type alkaloids. Strategically, the novel method shows a key late-
stage formation of reactive enamine functionality from stable
indole-linked d-lactam through an extremely chemoselective Ir(I)
mediated reduction (Scheme 37).
126
Ergot alkaloids were in the group of the rst fungal-derived
naturally occurring compounds recognized, inspiring pharma-
ceutical requests in infective diseases, CNS disorders, cancer
and migraine. Aurantioclavine 185 has been rst extracted from
the fungus Penicillium aurantiovirens in 1981. It has become an
striking target for whole synthesis campaigns because of the
interesting synthetic challenge presented by the fused azepi-
noindole nucleus and its jub as a biosynthetic pioneer to the
communesin alkaloids, that show cytotoxicity against leukemia
cell rules.
127
In 2016, total synthesis of ()-aurantioclavine has been
accomplished by Cho and co-workers.
128
However, the signi-
cant step of this total synthesis was the production of 3,4-fused
tricyclic indole derivatives via intramolecular FIS of aryl
hydrazides, that contain a carbonyl group including a side
chain connected to the meta-position of the aromatic ring. The
intramolecular FIS approach does not need cumbersome pre-
functionalization, and therefore, it may act to simplify the
formation of polycyclic indole alkaloids. The novel approach
initiated with market purchasable (S)-b-amino-3-iodo-benzene
ethanol 186. The latter aer several steps gave aryl hydrazide
187 in 70% yield that exposed to the standard intramolecular
FIS conditions and treated to generate the corresponding indole
derivatives 188 in 72% yield. The latter underwent several
chemical synthetic conversions to make the corresponding
()-aurantioclavine 185 (Scheme 38).
128
Scheme 36 Total synthesis of montamine analogue 175.
52874 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

2.2. Japp–Klingemann reaction
The Japp–Klingemann reaction presents a very useful alterna-
tive synthetic route to a number of arylhydrazones, employed in
the Fischer indolization process. In 1969, Dutta and co-workers
reported the total synthesis of ()-mahanimbine 189 extracted
from the stem bark of Murraya koenigii Spreng.
129
This
whole synthesis initiated by Japp–Klingemann of 2-hydrox-
ymethylenecyclohexanone 191 and the diazoaryl complex 190,
which afforded phenylhydrazone 192. Next, FIS of hydrazone 33
in the presence of acetic acid/hydrochloric acid under reux
gave 7-hydroxy-6-methoxy-2,3,4,9-tetrahydro-1H-carbazole-1-
one 193. Then, the latter has been transformed into
()-mahanimbine 189 in several steps (Scheme 39).
129
The rst naturally occurring carbazole alkaloid extracted
from Murraya koenigii Spreng (Rutaceae) was Murrayanine 194.
However, later from other species of the genus Clausena and
Murraya and displays important biological property. For
example, it has exhibited to powerfully prevent the aggregation
of platelet, serve as an antifungal and antibacterial agent, and
contain cytotoxic property.
130
Chakraborty and co-workers reported total synthesis of mur-
rayanine 194 in 1968.
131
In this approach, initial Japp–Klingemann
Scheme 38 Total synthesis of ()-aurantioclavine 185.
Scheme 37 Total synthesis of ()-minovine 177,()-vincaminorine 178,()-N-methylquebrachamine 179,()-vincadifformine 180 and
()-quebrachamine 181.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52875
Review RSC Advances

reaction between phenyldiazonium chloride 195 and 2-
hydroxymethylene-5-methylcyclohexanone 196 led to hydrazone
197.Next,FISofhydrazone197 in the presence of acetic acid/
hydrochloric acid under reux afforded 1-oxo-3-methyl-1,2,3,4-
tetrahydrocarbazole 198. Finally, the latter was then transformed
into the corresponding natural product murrayanine 194 upon
different chemical reactions (Scheme 40).
131
Murrayacine 199, that is an alkaloid extracted from Murraya
koenigii stem bark and Clausena heptaphylla, is known in spices,
herbs and (curryleaf tree).
132
The total synthesis of murrayacine
199, has been demonstrated by Chakraborty and co-workers in
1973.
133
7-Hydroxy-6-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-
carbazol-1-one 202. Lastly, the latter has been transformed to the
corresponding murrayacine 199 (Scheme 41).
133
Carbazole derivatives contain a signicant group of hetero-
cycles that are found for their powerful antibacterial, antitumor,
anti-inammatory, antihistamine and psychotropic, activities.
Natural 1-oxygenated carbazole alkaloids are principally
Scheme 40 Total Synthesis of murrayanine 194.
Scheme 39 Total synthesis of ()-mahanimbine 189.
Scheme 41 Total synthesis of murrayacine 199.
52876 |RSC Adv.,2017,7,52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

isolated from the genera Clausena and Murraya species, and in
the case of 2- and 3-functionalized classes, their biogenesis were
developed.
134
The total synthesis of natural products mukolidine 203 and
mukoline 204 has been achieved by Chakraborty and co-workers
in 1982.
135
As depicted in Scheme 42, this total synthesis initiated
through a Japp–Klingemann reaction of toluenediazonium
chloride 205 and 2-hydroxymethylenecyclohexanone 191 to give
hydrazone 206. Next, FIS of the latter afforded the 1-oxotetrahy-
drocarbazole 207. Subsequent, the desired 1-oxotetrahydro-
carbazole 207 has been transformed into mukolidine 203 that
reduced with NaBH
4
, to provide mukoline 204.
135
The total synthesis of heptazolidine 208, a carbazole alkaloid
extracted from Clausena heptaphylla, has been achieved by
Chakraborty and co-workers in 1985.
136
In this approach, the
main intermediate is 2-hydroxy-3-methoxy-6-methyltetrahydro-
carbazole 215b. Initially, diazoaryl derivative 209 reacted with 2-
hydroxymethylene-5-methylcyclohexanone 196 via Japp–Klinge-
mann reaction to give the corresponding phenylhydrazone 210.
The latter was then subjected into FIS to afford drocarbazole 211,
which upon Wolff–Kishner reduction provided the tetrahy-
drocarbazole 215b. The tetrahydrocarbazole 215b has been
produced via reaction between 4-methylcyclohexanone 213 and
3-acetoxy-4-methoxyphenylhydrazine hydrochloride 212 to the
phenylhydrazone 214, FI reaction, and ester removal. The latter
has been transformed into the corresponding natural product
heptazolidine 208 through subjection to various chemical reac-
tions (Scheme 43).
136
Scheme 42 Total synthesis of mukolidine 203 and mukoline 204.
Scheme 43 Total synthesis of heptazolidine 208.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52877
Review RSC Advances

The carbazole alkaloids exhibit a big and constructional rich
group of naturally occurring compounds, which are provided by
a range of terrestrial plants. Especially, plants inside the Ruta-
ceae group are remarkable producers of these products, with
the genus Murraya affording the maximum gure of distinctive
structures. Usually known in the external Himalayas and on the
Indian peninsula, the leaves of M. koenigii (L.) Spreng are with
other things, broadly used as a spice avoring and giving it the
name “curry-leaf tree”by the people of these areas. Extracts
obtained of the plant are employed in local medicine due to
their antimicrobial property.
137
The rst total synthesis of a natural dimeric carbazole alka-
loid, ()-bismurrayaquinone-A 216 was demonstrated by
Bringmann and co-workers in 1995.
138
In this synthetic method,
rstly, the desired hydrazone 197 has been produced from
phenyldiazonium chloride 195 and 2-hydroxymethylene-5-
methylcyclohexanone 196 through Japp–Klingemann reaction.
Then, the desired hydrazone 197 has been exposed to FIS by
using acetic acid/hydrochloric acid to give 1-oxo-3-methyl-
1,2,3,4-tetrahydrocarbazole 198. Subsequent, the latter has
been transformed into the desired 216 in 73% yield, aer
several steps. Through chromatography on a chiral phase, the
two enantiomers of ()-bismurrayaquinone-A 216 have been
separated (Scheme 44).
138
Indole alkaloids are signicant natural products due to their
structural association to the important amino acid, tryptophan
and the important metabolites of tryptophan, for instance the
neurotransmitter serotonin. One class of indole alkaloids was
extracted from Alstonia species.
139
Tryprostatin A 217 was
extracted as secondary metabolites of a marine fungal strain
BM939 and depicted to entirely prevent respectively cell cycle
progression of tsFT210 cells in the G2/M phase at a nal
concentration of 50 mgmL
1
of 217. Tryprostatins A 217 include
a 2-isoprenyltryptophan scaffold and a proline residue that
include the diketopiperazine unit.
140
The rst stereoselective total synthesis of tryprostatin A 217
has been described by Gan and co-workers in 1997.
141
The
synthesis was started by using the FI cyclization reaction
through a Japp–Klingemann azo-ester intermediate. Once m-
anisidine 218 has been reacted with NaNO
2
and concentrated
aqueous hydrochloric acid, continued by the addition of the
anion of ethyl a-ethylacetoacetate, the Japp–Klingemann azo-
ester intermediate has been synthesized. Once this interme-
diate has been heated in a solution of ethanolic hydrochloric
acid, a mixture of ethyl 6-methoxy-3-methylindole-2-carboxylate
219a and its 4-methoxy isomer 219b has been provided in a ratio
of 10 : 1. The corresponding 6-methoxyindole isomer 219a has
been isolated from the mixture by simple crystallization. While
this reaction was exothermic, this approach was far safer to
Scheme 44 Total synthesis of ()-bismurrayaquinone-A 216.
Scheme 45 Total synthesis of tryprostatin A 217.
52878 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

execute on large scale than the Moody azide pyrolysis. Then,
compound 219a was transformed into the corresponding indole
alkaloid tryprostatin A 217 in 50% yield (Scheme 45).
141
Chowdhury and co-workers extracted two novel carbazole
alkaloids planned as koenigine-quinone A and koenigine-
quinone B from the alcoholic extract of the stem bark of Mur-
raya koenigii Spreng.
142
In 1998, they have demonstrated the
structures given for koeniginequinone A 220a and B 220b using
a FI of the desired phenylhydrazones 222a,b as the main step.
The phenylhydrazone derivatives 222 have been provided via
a Japp–Klingemann reaction between 2-hydroxymethylene 5-
methylcyclohexanone 196 and the aryldiazonium chloride
derivatives 221a and 221b, respectively and transform into the
1-oxotetrahydrocarbazole 223a and 223b in the presence of acid.
Next, koeniginequinone A 220a A and 220b B have been
produced in 65.5% and 72% yield, respectively, through a multi-
step reaction (Scheme 46).
142
Melatonin (N-acetyl-5-methoxy tryptamine) 3(darkness
hormone) is an indolamine hormone which is made by the
photoreceptor cells of the retina and the pineal gland in verte-
brates, additionally it was rst isolated in 1958 by Lerner and
Case at Yale University.
143
They found the light-related features
within the skin cells of amphibians. The molecule produced the
collection of the pigment melanin inside the melanocytes which
is causing the skin to lighten. The hormone is increased at night
and has been conducting as a time signal for an organism's
annual (circannual) and daily (circadian) biological rhythms.
Melatonin regulates sleep/wake patterns and also synchronizes
the release of other hormone. Furthermore, melatonin has been
displayed medicinally functions as inhibitor of the onset of
Alzheimer's disease, treatment of sleep disorders and in
protection against oxudative stress.
143
In recent years, much was appealed about the therapeutic
possessions of the hormone melatonin. This interest has
resulted in the of publication of two general scientic books
preserving that the hormone can cure the symptoms of some
kinds of cancer, acting as hypertensive in case of high blood
pressure, treating Alzheimer's disease, AIDS, and coronary heart
disease as well as being used as sleep aid, sexual vivacity, and
durability. Therefore, making it a phenomenon drug of the
1990s. Melatonin is mostly formed in the pineal gland, a pea-
sized organ placed in the center of the brain, and to a minor
extent in the retina. Melatonin is found valuable in some
problems for example coronary heart disease and aging.
144
Scheme 46 Total synthesis of koeniginequinone A 220a and B 220b.
Scheme 47 Total synthesis of melatonin 3.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52879
Review RSC Advances

The total synthesis of melatonin 3needed phenylhydrazone
226, which is synthesized through coupling diazotized 4-
methoxyaniline 224 and 2-oxopiperidine-3-carboxylic acid 225.
This has been continued via FI cyclization reaction to give 6-
methoxy-1-oxotetrahydro-b-carboline 227. The latter afforded
the corresponding melatonin 3in several reaction steps in 41%
yield (Scheme 47).
145
The rst asymmetric total synthesis of ()-gilbertine 228,
a member of the uleine type indole alkaloids, has been
demonstrated in 2004 by Blechert and Jiricek in a seventeen-
steps reaction with a 5.5% yield.
146
The uleine alkaloid ()-gil-
bertine 228 has been extracted by Miranda and Blechert in 1982
from the Brazilian tree Aspidosperma gilbertii (A. P. Duarte).
147
This method was initiated from 2-allylcyclohexenone 229, that
could be readily synthesized from o-anisic acid through Birch
conditions on a large scale, and dimethylmalonate as a market
purchasable starting compound. Upon a multi-step reaction, 2-
allylcyclohexenone 229 has been converted into compound 230,
which was an appropriate precursor for FIS. That products have
been isolated from the FIS depended powerfully on both the
solvent and the pK
a
of the acid promoter. Pivalic acid afforded
no transformation, and formic acid reaction led to deprotection
of the alcohol and production of the formylester 231b, while
triuoracetic acid afforded the deprotected hydroxyindole 231a.
Also, p-TsOH in tetrahydrofuran afforded only decomposition;
although, in toluene the corresponding indole 231c could be
provided in 72% yield. The Japp–Klingemann FI procedure has
been utilized effectively as a convergent synthetic method for
the formation of the corresponding tetrahydrocarbazole 231c.
Then, the latter has been transformed into the corresponding
natural product ()-gilbertine 228 (Scheme 48).
147
3. Miscellaneous
Another approach for the synthesis of ellipticine 232 has been
advanced by Stillwell and Woodward with the key B-ring
production through FIS.
73,79
In this synthetic method, rstly,
the requisite phenylhydrazone derivative 235 has been synthe-
sized from the reaction of (Z)-pent-3-en-2-one 233 and 1-methyl-
4-piperidone 234 and next exposed to FI reaction to give 2-
methyl-1,2,3,4,5,5a,11,11a-octahydroellipticine 236 (82%).
Lastly, dehydrogenation by using Pd on carbon afforded ellip-
ticine 232 in a very poor yield of 0.3% (Scheme 49).
62,66
Alkaloids, for example manzamines and lamellarins, having
diversely structures and signicant biological properties provided
by marine plants, microbes and invertebrates importantly
encouraged interdisciplinary studies by biologists and chemists
worldwide. Among the marine alkaloids, the structurally and
discorhabdins associated alkaloids are a special group of nitrog-
enous pigments belonging to the pyrroloiminoquinone-kind
alkaloids family. This class of naturally occurring compounds
Scheme 48 Total synthesis of ()-gilbertine 228.
Scheme 49 Total synthesis of ellipticine 232.
52880 |RSC Adv.,2017,7,52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

contains a typical nucleus pyrrolo[2,3,4-d,e]quinoline tetracyclic
framework linked to a spiro-substituent at the C-6 location.
148
The pyrroloquinoline alkaloids, found as the discorhabdins,
are known in the sponges of the genus Latrunculia du Bocage
along the New Zealand coast. These quinonimine alkaloids are
responsible for the pigmentation possessed by the sponges, and
several of the compounds in this group, together with the
structurally related makaluvamines, prianosins, and epi-
nardins, show antitumor activity.
149
In 1997, Heathcock and co-workers revealed the approach
relied on the FIS to make 7-hydroxy-indole derivatives in
satisfactory yield.
150
The unusual FIS is a common problem
once an ortho group is current on the phenylhydrazone.
Mixtures of indole derivatives are constantly provided, and
yields of the corresponding indole are commonly low. They
could evade this problem by using constrain the hydrazine
that it could merely endure electrocyclization in the expected
way. Such a limitation would result if the oxygen and nitrogen
atoms could be connected by a short tether. Finally, this
group examined the formation and usage of an appropriately-
substituted benzoxazine. The requisite phenylhydrazine 242
has been formed in four steps from 2-amino-4-nitrophenol
241 in 60% yield. Next, the reaction with 4-benzyloxybutanal
243 gave hydrazone 244 in 93% yield. There are several
formerly found instances of employing hydrazones of 4-
aminobenzoxazines identical to hydrazone 244 in the FI
reaction. In each of these cases, two carbon tether was an
essential structural part in the desired compound. In this
approach, they explored to employ the tether to suppress the
unusual FI reaction, then eliminated it when the indole had
been synthesized. The similar approach has been employed to
form other indole derivatives containing different groups on
the benzene ring. In each situation, no proof of contami-
nating indole products has been realized. Since the
dimethylene chain is easily provided and then cleaved, this
“tether”approach may show to be an important approach for
overpowering the unusual FI reaction. Next, aer several
steps, indole 245 afforded the pyrrolo[2,3,4-d,e]quinoline core
246, that is a structural part known in a range of naturally
occurring compounds involving the discorhabdin alkaloids,
the isobatzellines, and wakayin, batzellines, the makaluv-
amines, damir ones A and B, and terrestrially-obtained hae-
matopodin.
150
The latter aer several steps afforded
discorhabdins C 237,E238,D239 and the dethia analogue
240 (Scheme 50).
149
Eudistomidin-A is an alkaloid separated from Okinawan
tunicate, Eudistoma glaucus, which has a calmodulin antago-
nistic effect. Recently, calmodulin antagonists have been
effective as device for investigating physiological activities of
calmodulin, a ubiquitous Ca
2+
-binding protein that acts as
Scheme 50 Total synthesis of discorhabdins C 237,E238,D239 and the dethia analogue 240.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52881
Review RSC Advances

a main mediator regulating cellular function and a difference of
cellular enzyme system.
151
In 1998, the initial total synthesis of the marine alkaloid
eudistomidin-A 247 in 72% yield presented a FIS as a key step
has been described by Murakami and co-workers.
152,153
This
synthetic method was started from 2-amino-5-bromophenol 248
that has been transformed into ethyl pyruvate 2-(4-bromo-2-
tosyloxyphenyl)hydrazone 249. FIS of the hydrazone 249 has
effectively occurred with polyphosphoric acid (PPA) to give the
desired ethyl 5-bromo-7-tosyloxyindole-2-carboxylate 250 as the
only separable product (41% yield). The latter afforded
eudistomidin-A 247 aer several steps (Scheme 51).
152,153
seco-Duocarmycins show a great guarantee as ultrapotent
cytotoxins but due to poverty of therapeutic index, they are
unsuccessful in advance clinical. seco-Duocarmycins include
spirocyclization of a deep-embedded chloromethylindoline
fragment to prompt production of an N3-adenine covalent. This
spiracyclization can be stopped by blocking the seco-duo-
carmycins OH group.
154
The natural antibiotic (+)-duocarmycin
SA 251 is a powerful cytostatic agent (Scheme 52). (+)-Duo-
carmycin SA with an IC
50
of 10 pM (cancer line L1210) shows
high cytotoxicity power, which is candidate for cancer treat-
ment. The cytotoxicity of 251, the biologically and structurally of
related (+)-CC-1065 are created by an alkylation of N-3 of
adenine in AT-rich parts of the minor groove of the DNA by
reaction with the spiro-[cyclopropane-cyclohexadienone] moiety
in 251 and (+)-CC-1065. Duocarmycin SA 251 looks better than
CC-1065 because it hasn't deadly hepatotoxic side effect which
is appeared with (+)-CC-1065. Besides (+)-duocarmycin SA 251 is
a strongest one in cytotoxic potency and solvolytic stability and
the most stable part is this class agents additionally glycosylated
seco analogues of duocarmycin and CC-1065 are extremely
encouraging for the critical cancer's treatment in an antibody-
directed enzyme prodrug therapy.
155
A concise and signicant synthesis of seco-duocarmycin SA
251, an extremely strong cytostatic agent and direct precursor of
the natural product duocarmycin SA 251, was accomplished in
2003 by Tietze and co-workers.
155
The synthetic procedure
includes a FIS to show the heterocyclic moiety as a main reac-
tion. The total synthesis of seco-duocarmycin SA 251 was initi-
ated by diazotation of market purchasable 2-methoxy-4-
nitroaniline 251, which upon two steps produced the hydra-
zone 253 extremely easily with an overall yield of 69%. Then, FI
reaction happened by heating at 120 C by using of poly-
phosphoric acid and xylene as co-solvent to provide methyl 7-
methoxy-5-nitro-1H-indole-2-carboxylate 254 in 64% yield. In
the following, upon several steps seco-duocarymcin SA 251 has
been synthesized in 91% yield (Scheme 52).
155
Scheme 51 Total synthesis of eudistomidin-A 247.
Scheme 52 Total synthesis of seco-duocarmycin SA 251.
52882 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

Such as Evodia officinalis and Evodia rutaecarpa, rutaecarpine
255 is the major of indoloquinazoline alkaloid, which is extracted
from Rutaceous plants. Traditional medicinal has long used this
plant for treatment of inammation-related symptoms. Studies
currently shows this anti-inammatory function is related to its
component rutaecarpine, exhibiting a selective and powerful
COX-2 inhibited activity. Furthermore, rutaecarpine has other
functions such as the analgesic, antianoxic, vasorelaxing, cyto-
toxic and antiplatelet.
156
A wide range of quinazolinone alkaloids were extracted from
numerous animals, plants, and microorganisms and formed
because of their well-developed pharmacological properties.
The dried fruits of Evodia rutaecarpa were employed in tradi-
tional Chinese medicine under the name Wu-Chu-ru and Shih-
Hu as a treatment for cholera, dysentery, headache, postpartum
and worm infections. The extracted drug includes quinazoli-
nocarboline alkaloid rutaecarpine 255.
156
In year 2004, the total
synthesis of rutaecarpine 255 has been accomplished in several
steps through FIS as a main step by Argade and co-workers.
157
The treatment of anthranilamide 256 and glutaric anhydride
257 in benzene/1,4-dioxane (2 : 1) at ambient temperature gave
the desired o-amidoglutaranilic acid 258 in quantitative yield.
Upon various steps, 6-phenylhydrazono-6,7,8,9-tetrahydro-11H-
pyrido-[2,1-b]quinazolin-11-one 259 has been produced in 98%
yield from 258. The corresponding hydrazone 259 on zeolite (H-
Mordenite) through FIS under reux in glacial AcOH afforded
the biologically active natural product rutaecarpine 255 in 82%
yield (Scheme 53).
157
Thiopeptide antibiotics are extremely strong and structurally
complex secondary metabolites from soil bacteria (Actinomy-
cetes), and they are provided by ribosomal peptide biosyn-
thesis.
158
The antibiotic nosiheptide 260 (RP9671) has been
initially extracted by French and co-workers in the early 1960s
from Streptomyces actuous 40 037.
159
Nosiheptide, that is equal
to multhiomycin extracted from Streptomyces antibioticus
8446CC, is a part of the thiopeptide antibiotics. They have been
topic of comprehensive biosynthetic studies. Some thiopeptides
have known biological property against anaerobes and Gram-
positive bacteria, involving pathogens resistant to antibiotics.
The total synthesis of nosiheptide 260 was achieved by
Bentley and co-workers and reported in 2004. This approach has
been accomplished through a FIS as a main step.
160
The starting
hydrazine was synthesized from the market purchasable 3-
amino-4-chlorobenzoic acid 261 via diazotisation and reduction
with SnCl
2
, and has been instantaneously reacted with methyl 2-
oxobutanoate to provide the hydrazone 262. In the following, FI
cyclisation reaction of hydrazone 262 by using PPA in AcOH
produced the indole 263 in 87% yield. The corresponding
indole 263 has been transformed into the nosiheptide 260 via
several chemical transformations (Scheme 54).
160
Sempervirine 264, an alkaloid isolated from the roots of Gel-
semium sempervirens, in 1916 is known as an antiproliferative
agent both in vitro and in vivo.
161
Earlier in a high throughput
screening (HTS) campaign of natural products, sempervirine was
discovered as a MDM2 E3 ubiquitin ligase inhibitor. Sempervir-
ine is known to stabilize p53 tumor suppressor protein levels by
blocking its proteasomal degradation via an ubiquitin-dependent
pathway. It inhibits both murine double minutes-2 (MDM2)
dependent p53 ubiquitinylation and MDM2 auto-
ubiquitinylation. Thus, cancer cells carrying wild-type p53 when
treated with this compound induce stabilization of p53 leading to
apoptosis. Sempervirine is also known to intercalate DNA, and
inhibits DNA topoisomerase I; therefore, it is considered as
a potential lead in anticancer therapeutics. Some of the known
members of this family such as avopereirine, serpentine and
alstonine exhibit a variety of biological activities, for example
anti-HIV, antipsychotic, sedative and immunostimulant activities
together with notable cytostatic effects.
162
In 2006, Lipinska and co-workers reported a unied
synthetic approach for the total synthesis of zwitterionic indolo
[2,3-a]quinolizine alkaloid in ve steps via FIS as one of the
main steps.
1
This total synthesis was initiated from the acces-
sible 5-acetyl-3-methylthio-1,2,4-triazine 268 that has been
synthesized in 40% yield in two-step reaction from 3-
methylthio-1,2,4-triazine 267 which can be provided on a large
laboratory-scale by using the glioxal 265 and S-methyl-
thiosemicarbazide hydroiodide 266. In the following, the cor-
responding compound 268, was transformed into 3-acetyl-1-
methylthiocycloalka[c]pyridine 270 via various stages. The
Scheme 53 Total synthesis of rutaecarpine 255.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52883
Review RSC Advances

acetyl substituent stays in compound 270 that affords admit-
tance to the synthesis of the indole scaffold through the FIS. The
FIS of the phenylhydrazone 270 into 271 requisite MWI of the
reaction mixture (substrate with zinc chloride (ZnCl
2
) solution
in triethylene glycol (TEG)). The latter can then be converted
into the sempervirine 264 (Scheme 55).
1
4. Conclusion
Indole derivatives exhibit a very imperative family of
compounds that show a key role in cell biology and are potential
natural products. There has been a growing attention in the
usage of indoles and their derivatives as bioactive molecules
against microbes, cancer cells, and different types of disorder in
the human body. The FIS is possibly the most widespread and
extremely explored method to indole derivatives. It gives
a signicant and useful approach for manufacturing indole
derivatives, a group of molecules with much signicance in
biological chemistry. The reaction's greatest application lies in
the production of commercialized antimigraine drugs and in
pharmaceutical chemistry. Parallelly, with the renement of the
synthetic methods the isolation of novel molecules from natural
sources containing indole scaffolds is another continuing and
increasing investigation eld. The study of these novel
compounds and the examination of their properties and
potential usage in the reaction of different diseases is another
synergistic aspect of the importance of the organic synthesis of
indoles. This review highlights the signicance and importance
of applicability of FIS as a key step in total synthesis of natural
products, particularly those showing biological activities.
Scheme 55 Total synthesis of sempervirine 211.
Scheme 54 Total synthesis of nosiheptide 206.
52884 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

Conflicts of interest
The author has conrmed there are no conicts to declare.
References
1 T. M. Lipi´
nska, Tetrahedron, 2006, 62, 5736–5747.
2 D. R. Stuart, M. Bertrand-Laperle, K. M. Burgess and
K. Fagnou, J. Am. Chem. Soc., 2008, 130, 16474–16475.
3 F. Zhan and G. Liang, Angew. Chem., Int. Ed., 2013, 52, 1266–
1269.
4 D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev.,
2003, 103, 893–930.
5 N. K. Kaushik, N. Kaushik, P. Attri, N. Kumar, C. H. Kim,
A. K. Verma and E. H. Choi, Molecules, 2013, 18, 6620–6662.
6 D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67,
7195–7210.
7 E. Fischer and O. Hess, Eur. J. Inorg. Chem., 1884, 17, 559–
568.
8 R. Larock, E. Yum and M. Refvik, J. Org. Chem., 1998, 63,
7652–7662.
9 C.-y. Chen, D. R. Lieberman, R. D. Larsen, T. R. Verhoeven
and P. J. Reider, J. Org. Chem., 1997, 62, 2676–2677.
10 Y. Dong and C. A. Busacca, J. Org. Chem., 1997, 62, 6464–
6465.
11 T. Sakamoto, Y. Kondo and H. Yamanaka, Heterocycles,
1988, 27, 2225–2249.
12 L. S. Hegedus, Angew. Chem., Int. Ed., 1988, 27, 1113–1126.
13 S. Wagaw, B. H. Yang and S. L. Buchwald, J. Am. Chem. Soc.,
1998, 120, 6621–6622.
14 S. Wagaw, B. H. Yang and S. L. Buchwald, J. Am. Chem. Soc.,
1999, 121, 10251–10263.
15 E. Fischer and F. Jourdan, Eur. J. Inorg. Chem., 1883, 16,
2241–2245.
16 M. Shiri, M. A. Zolgol, H. G. Kruger and Z. Tanbakouchian,
Chem. Rev., 2009, 110, 2250–2293.
17 P. A. Roussel, J. Chem. Educ., 1953, 30, 122.
18 B. Robinson, The Fischer indole synthesis, John Wiley & Sons
Inc, New York, Chichester, 1982, pp. 48–59.
19 D. Q. Xu, W. L. Yang, S. P. Luo, B. T. Wang, J. Wu and
Z. Y. Xu, Eur. J. Org. Chem., 2007, 2007, 1007–1012.
20 D.-Q. Xu, J. Wu, S.-P. Luo, J.-X. Zhang, J.-Y. Wu, X.-H. Du
and Z.-Y. Xu, Green Chem., 2009, 11, 1239–1246.
21 G. L. Rebeiro and B. M. Khadilkar, Synthesis, 2001, 2001,
0370–0372.
22 T. M. Lipi´
nska and S. J. Czarnocki, Org. Lett., 2006, 8, 367–
370.
23 G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 7, 1045–
1075.
24 R. R. Phillips, Org. React., 1959, 10, 143–178.
25 T. Sravanthi and S. Manju, Eur. J. Pharm. Sci., 2016, 91,1–
10.
26 Z. Bian, C. C. Marvin, M. Pettersson and S. F. Martin, J. Am.
Chem. Soc., 2014, 136, 14184–14192.
27 E. V. Mercado-Marin, P. Garcia-Reynaga, S. Romminger,
E. F. Pimenta, D. K. Romney, M. W. Lodewyk,
D. E. Williams, R. J. Andersen, S. J. Miller and
D. J. Tantillo, Nature, 2014, 509, 318–234.
28 V. Sharma, P. Kumar and D. Pathak, J. Heterocycl. Chem.,
2010, 47, 491–502.
29 M. Shiri, Chem. Rev., 2012, 112, 3508–3549.
30 G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
2875–2911.
31 G. W. Gribble, Indole ring synthesis: From natural products to
drug discovery, WileyVCH, 2016, p. 704.
32 B. Robinson, Chem. Rev., 1963, 63, 373–401.
33 M. Inman and C. J. Moody, Chem. Sci., 2013, 4,29–41.
34 D. L. Hughes, Org. Prep. Proced. Int., 1993, 25, 607–632.
35 M. M. Heravi, S. Khaghaninejad and N. Nazari, Adv.
Heterocycl. Chem., 2015, 112, 183–226.
36 M. M. Heravi, S. Khaghaninejad and M. Mosto,Adv.
Heterocycl. Chem., 2014, 112,1–50.
37 S. Sadjadi, M. M. Heravi and N. Nazari, RSC Adv., 2016, 6,
53203–53272.
38 M. M. Heravi, E. Hashemi and N. Nazari, Mol. Diversity,
2014, 18, 441–472.
39 M. M. Heravi, E. Hashemi and F. Azimian, Tetrahedron,
2014, 70,7–21.
40 M. M Heravi, E. Hashemi and N. Ghobadi, Curr. Org. Chem.,
2013, 17, 2192–2224.
41 M. M. Heravi and E. Hashemi, Tetrahedron, 2012, 68, 9145–
9178.
42 M. M. Heravi, A. Bakhtiari and Z. Faghihi, Curr. Org. Chem.,
2014, 11, 787–823.
43 M. M. Heravi and V. Zadsirjan, Tetrahedron: Asymmetry,
2013, 24, 1149–1188.
44 M. M. Heravi and V. F. Vavsari, RSC Adv., 2015, 5, 50890–
50912.
45 M. M. Heravi and N. Nazari, Curr. Org. Chem., 2015, 19,
2358–2408.
46 M. M. Heravi, T. Ahmadi, A. Fazeli and N. M. Kalkhorani,
Curr. Org. Synth., 2015, 12, 328–357.
47 M. M. Heravi and A. Fazeli, Heterocycles, 2010, 81, 1979–2026.
48 M. M. Heravi, B. Baghernejad and H. A. Oskooie, Curr. Org.
Chem., 2009, 13, 1002–1014.
49 M. Heravi and S. Sadjadi, J. Iran. Chem. Soc., 2009, 6,1–54.
50 M. M. Heravi and P. Hajiabbasi, Monatsh. Chem., 2012, 143,
1575–1592.
51 M. M Heravi, H. Hamidi and V. Zadsirjan, Curr. Org. Chem.,
2014, 11, 647–675.
52 M. M. Heravi and E. Hashemi, Monatsh. Chem., 2012, 143,
861–880.
53 P. Pelletier and J. B. Caventou, Ann. Chim. Phys., 1818, 104,
323–324.
54 P. Pelletier and J. B. Caventou, Ann. Chim. Phys., 1819, 10,
142–177.
55 R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger,
H. U. Daeniker and K. Schenker, J. Am. Chem. Soc., 1954,
76, 4749–4751.
56 J. Bonjoch and D. Sol´
e, Chem. Rev., 2000, 100, 3455–3482.
57 R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger,
H. U. Daeniker and K. Schenker, Tetrahedron, 1963, 19,
247–288.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52885
Review RSC Advances

58 S. M. Babu and S. Ranganathan, Resonance, 2014, 19, 641–
644.
59 K. Biemann, M. Spiteller-Friedmann and G. Spiteller, J. Am.
Chem. Soc., 1963, 85, 631–638.
60 J.D.MedinaandJ.A.Hurtado,Planta Med., 1977, 32,130–132.
61 G. Stork and J. E. Dolni, J. Am. Chem. Soc., 1963, 85, 2872–
2873.
62 M. Sainsbury, Synthesis, 1977, 1977, 437–448.
63 S. Goodwin, A. F. Smith and E. C. Horning, J. Am. Chem.
Soc., 1959, 81, 1903–1908.
64 V. K. Kansal and P. Potier, Tetrahedron, 1986, 42, 2389–2408.
65 Y. Langlois, N. Langlois and P. Potier, Tetrahedron Lett.,
1975, 16, 955–958.
66 E. Von Angerer and J. Prekajac, J. Med. Chem., 1986, 29, 380–
386.
67 M. Amat, A. Linares and J. Bosch, J. Org. Chem., 1990, 55,
6299–6312.
68 J. Bonjoch, N. Casamitjana, J. Quirante, M. Rodriguez and
J. Bosch, J. Org. Chem., 1987, 52, 267–275.
69 J. Gracia, N. Casamitjana, J. Bonjoch and J. Bosch, J. Org.
Chem., 1994, 59, 3939–3951.
70 S. Archer, B. S. Ross, L. Pica-Mattoccia and D. Cioli, J. Med.
Chem., 1987, 30, 1204–1210.
71 G. W. Gribble and S. J. Berthel, Studies in natural products
chemistry, Atta-ur-Rahman, Ed., Elsevier, Amsterdam, 1993,
vol. 12, pp. 365–409.
72 M. Adeva, F. Buono, E. Caballero, M. Medarde and F. Tom´
e,
Synlett, 2000, 2000, 0832–0834.
73 J. Bergman and B. Pelcman, J. Org. Chem., 1989, 54, 824–
828.
74 R. Tsuji, M. Nakagawa and A. Nishida, Heterocycles, 2002,
58, 587–593.
75 S. Takano, M. Moriya and K. Ogasawara, J. Org. Chem., 1991,
56, 5982–5984.
76 R. Bonjouklian, T. A. Smitka, L. E. Doolin, R. M. Molloy,
M. Debono, S. A. Shaffer, R. E. Moore, J. B. Stewart and
G. M. Patterson, Tetrahedron, 1991, 47, 7739–7750.
77 J. D. White, K. M. Yager and T. Yakura, J. Am. Chem. Soc.,
1994, 116, 1831–1838.
78 B. Mckittrick, A. Failli, R. J. Steffan, R. M. Soll, P. Hughes,
J. Schmid, A. A. Asselin, C. Shaw, R. Noureldin and
G. Gavin, J. Heterocycl. Chem., 1990, 27, 2151–2163.
79 J.-C. Fern`
andez, N. Valls, J. Bosch and J. Bonjoch, J. Chem.
Soc., Chem. Commun., 1995, 22, 2317–2318.
80 J. Bonjoch, J. Catena and N. Valls, J. Org. Chem., 1996, 61,
7106–7115.
81 J. Catena, N. Valls, J. Bosch and J. Bonjoch, Tetrahedron
Lett., 1994, 35, 4433–4436.
82 T. T. T. Thuy, N. M. Cuong, T. Q. Toan, N. N. Thang,
B. H. Tai, N. X. Nhiem, H.-J. Hong, S. Kim, S. Legoupy
and Y. S. Koh, Arch. Pharmacal Res., 2013, 36, 832–839.
83 Y. Murakami, H. Yokoo and T. Watanabe, Heterocycles,
1998, 49, 127–132.
84 S. Shimizu, K. Ohori, T. Arai, H. Sasai and M. Shibasaki, J.
Org. Chem., 1998, 63, 7547–7551.
85 D. Gennet, P. Michel and A. Rassat, Synthesis, 2000, 2000,
447–451.
86 M. M. Janot, H. Pourrat and M. J. Le, Bull. Soc. Chim. Fr.,
1954, 707–708.
87 S. A. Kozmin, T. Iwama, Y. Huang and V. H. Rawal, J. Am.
Chem. Soc., 2002, 124, 4628–4641.
88 I. Bick, J. Bremner, N. Preston and I. Calder, J. Chem. Soc.,
Chem. Commun., 1971, 19, 1155–1156.
89 C. W. Roberson and K. Woerpel, J. Am. Chem. Soc., 2002,
124, 11342–11348.
90 A. M. Schmidt and P. Eilbracht, Org. Biomol. Chem., 2005, 3,
2333–2343.
91 T. Balle, J. Perregaard, M. T. Ramirez, A. K. Larsen,
K. K. Søby, T. Liljefors and K. Andersen, J. Med. Chem.,
2003, 46, 265–283.
92 M. Gompel, M. Leost, E. B. D. K. Joffe, L. Puricelli,
L. H. Franco, J. Palermo and L. Meijer, Bioorg. Med. Chem.
Lett., 2004, 14, 1703–1707.
93 L. H. Franco and J. A. Palermo, Chem. Pharm. Bull., 2003, 51,
975–977.
94 Y. Liu and W. W. McWhorter, J. Am. Chem. Soc., 2003, 125,
4240–4252.
95 G. Pandey, S. K. Burugu and P. Singh, Org. Lett., 2016, 18,
1558–1561.
96 R. Iyengar, K. Schildknegt, M. Morton and J. Aub´
e, J. Am.
Chem. Soc., 2005, 70, 10645–10652.
97 C. Sabot, K. C. Gu´
erard and S. Canesi, Chem. Commun.,
2009, 20, 2941–2943.
98 K. Cimanga, T. De Bruyne, L. Pieters, M. Claeys and
A. Vlietinck, Tetrahedron Lett., 1996, 37, 1703–1706.
99 T. Dhanabal, R. Sangeetha and P. Mohan, Tetrahedron Lett.,
2005, 46, 4509–4510.
100 E. F. Rogers, H. Snyder and R. F. Fischer, J. Am. Chem. Soc.,
1952, 74, 1987–1989.
101 J. E. Saxton, Alkaloids: Chemistry and Physiology, 1965, vol. 8,
pp. 673–678.
102 H. Ueda, H. Satoh, K. Matsumoto, K. Sugimoto,
T. Fukuyama and H. Tokuyama, Angew. Chem., 2009, 121,
7736–7739.
103 J. d'Angelo, D. Desma¨
ele, F. Dumas and A. Guingant,
Tetrahedron: Asymmetry, 1992, 3, 459–505.
104 G. Massiot, P. Th´
epenier, M.-J. Jacquier, L. Le Men-Olivier
and C. Delaude, Heterocycles, 1989, 29, 1435–1438.
105 P. Liu, J. Wang, J. Zhang and F. G. Qiu, Org. Lett., 2011, 13,
6426–6428.
106 R. Burnell, J. Medina and W. Ayer, Can. J. Chem., 1966, 44,
28–31.
107 K. Brown Jr, H. Budzikiewicz and C. Djerassi, Tetrahedron
Lett., 1963, 4, 1731–1736.
108 E. L. Campbell, A. M. Zuhl, C. M. Liu and D. L. Boger, J. Am.
Chem. Soc., 2010, 132, 3009–3012.
109 K. C. Gu´
erard, A. Gu´
erinot, C. Bouchard-Aubin,
M.-A. M´
enard, M. Lepage, M. A. Beaulieu and S. Canesi, J.
Org. Chem., 2012, 77, 2121–2133.
110 T.-S. Kam, G. Subramaniam, K.-H. Lim and Y.-M. Choo,
Tetrahedron Lett., 2004, 45, 5995–5998.
111 K.-H. Lim, O. Hiraku, K. Komiyama, T. Koyano, M. Hayashi
and T.-S. Kam, J. Nat. Prod., 2007, 70, 1302–1307.
52886 |RSC Adv.,2017,7, 52852–52887 This journal is © The Royal Society of Chemistry 2017
RSC Advances Review

112 Y. Iwama, K. Okano, K. Sugimoto and H. Tokuyama,
Chem.–Eur. J., 2013, 19, 9325–9334.
113 D. Desmaeele and J. d'Angelo, J. Org. Chem., 1994, 59, 2292–
2303.
114 J. M. Lopchuk, Recent advances in the synthesis of
aspidosperma-type alkaloids, Prog. Heterocycl. Chem., Eds,
Elsevier Science, New York, 2011, vol. 23, pp. 1–25.
115 H. Satoh, H. Ueda and H. Tokuyama, Tetrahedron, 2013, 69,
89–95.
116 A. Chatterjee, B. Mukherjee, A. Ray and B. Das, Tetrahedron
Lett., 1965, 6, 3633–3637.
117 J. M. Smith, J. Moreno, B. W. Boal and N. K. Garg, J. Org.
Chem., 2015, 80, 8954–8967.
118 J. M. Smith, J. Moreno, B. W. Boal and N. K. Garg, J. Am.
Chem. Soc., 2014, 136, 4504–4507.
119 J. D. White and Y. Li, Heterocycles, 2014, 88, 899–910.
120 L. V. White, M. G. Banwell and A. C. Willis, Heterocycles,
2015, 90, 298–315.
121 W. Zhang, Z. Liu, S. Li, T. Yang, Q. Zhang, L. Ma, X. Tian,
H. Zhang, C. Huang and S. Zhang, Org. Lett., 2012, 14,
3364–3367.
122 L. M. Blair and J. Sperry, Chem. Commun., 2016, 52, 800–
802.
123 M. Shoeb, S. M. MacManus, M. Jaspars, J. Trevidu,
L. Nahar, P. Kong-Thoo-Lin and S. D. Sarker, Tetrahedron,
2006, 62, 11172–11177.
124 M. B. Freitas, K. A. Simollardes, C. M. Rufo, C. N. McLellan,
G. J. Dugas, L. E. Lupien and E. A. C. Davie, Tetrahedron
Lett., 2013, 54, 5489–5491.
125 B. Gigant, C. Wang, R. B. Ravelli and F. Roussi, Nature,
2005, 435, 519–522.
126 P. W. Tan, J. Seayad and D. J. Dixon, Angew. Chem., Int. Ed.,
2016, 55, 13436–13440.
127 S. R. McCabe and P. Wipf, Org. Biomol. Chem., 2016, 14,
5894–5913.
128 J. Park, D.-H. Kim, T. Das and C.-G. Cho, Org. Lett., 2016, 18,
5098–5101.
129 N. L. Dutta, C. Quasim and M. S. Wadia, Indian J. Chem.,
1969, 7, 1061–1062.
130 P. Bernal and J. Tamariz, Helv. Chim. Acta, 2007, 90, 1449–
1454.
131 D. P. Chakraborty and B. Chowdhury, J. Org. Chem., 1968,
33, 1265–1268.
132 S. Ray and D. P. Chakraborty, Phytochemistry, 1976, 15, 356–
360.
133 D. P. Chakraborty, A. Islam and P. Bhattacharyya, J. Org.
Chem., 1973, 38, 2728–2729.
134 K. Prabakaran and K. J. Rajendra Prasad, Synth. Commun.,
2012, 42, 2966–2980.
135 S. Roy, L. Bhattacharyya and D. P. Chakraborty, J. Indian
Chem. Soc., 1982, 59, 1369–1371.
136 S. Roy, L. Bhattacharyya and D. P. Chakraborty, J. Indian
Chem. Soc., 1985, 62, 673–680.
137 L. C. Konkol, F. Guo, A. A. Sarjeant and R. J. Thomson,
Angew. Chem., Int. Ed., 2011, 50, 9931–9934.
138 G. Bringmann, A. Ledermann, M. Stahl and K. P. Gulden,
Tetrahedron, 1995, 51, 9353–9360.
139 Y. Bi, L. K. Hamaker and J. M. Cook, Studies in Natural
Products Chemistry, Bioactive Natural Products, Part A, ed.
F. Z. Basha and A. Rahman, Elsevier Science, Amsterdam,
1993, vol. 13, p. 383.
140 C. B. Cui, H. Kakeya and H. Osada, J. Antibiot., 1996, 49,
534–540.
141 T. Gan, R. Liu, P. Yu, S. Zhao and J. M. Cook, J. Org. Chem.,
1997, 62, 9298–9304.
142 C. Saha and B. Chowdhury, Phytochemistry, 1998, 48, 363–
366.
143 C. Prabhakar, N. V. Kumar, M. R. Reddy, M. Sarma and
G. O. Reddy, Org. Process Res. Dev., 1999, 3, 155–160.
144 J. Arendt, Melatonin and the Mammalian Pineal Gland,
Chapman & Hall, London, 1st edn, 1995, vol. 60, pp. 17–109.
145 R. A. Abramovitch and D. Shapiro, J. Chem. Soc., 1956,
4589–4592.
146 J. Jiricek and S. Blechert, J. Am. Chem. Soc., 2004, 126, 3534–
3538.
147 F. Tang, M. G. Banwell and A. C. Willis, J. Org. Chem., 2016,
81, 10551–10557.
148 J.-F. Hu, H. Fan, J. Xiong and S.-B. Wu, Chem. Rev., 2011,
111, 5465–5491.
149 K. M. Aubart and C. H. Heathcock, J. Org. Chem., 1999, 64,
16–22.
150 B. G. Szczepankiewicz and C. H. Heathcock, Tetrahedron,
1997, 53, 8853–8870.
151 J. i. Kobayashi, H. Nakamura, Y. Ohizumi and Y. Hirata,
Tetrahedron Lett., 1986, 27, 1191–1194.
152 Y. Murakami, H. Takahashi, Y. Nakazawa, M. Koshimizu,
T. Watanabe and Y. Yokoyama, Tetrahedron Lett., 1989,
30, 2099–2100.
153 Y. Murakami, T. Watanabe, H. Takahashi, H. Yokoo,
Y. Nakazawa, M. Koshimizu, N. Adachi, M. Kurita,
T. Yoshino and T. Inagaki, Tetrahedron, 1998, 54,45–64.
154 H. M. Sheldrake, S. Travica, I. Johansson, P. M. Loadman,
M. Sutherland, L. Elsalem, N. Illingworth, A. J. Cresswell,
T. Reuillon and S. D. Shnyder, J. Med. Chem., 2013, 56,
6273–6277.
155 L. F. Tietze, F. Haunert, T. Feuerstein and T. Herzig, Eur. J.
Org. Chem., 2003, 2003, 562–566.
156 J.-F. Liao, W.-F. Chiou, Y.-C. Shen, G.-J. Wang and
C.-F. Chen, Chin. Med., 2011, 6,6–13.
157 S. B. Mhaske and N. P. Argade, Tetrahedron, 2004, 60, 3417–
3420.
158 K. P. Wojtas, M. Riedrich, J. Y. Lu, P. Winter, T. Winkler,
S. Walter and H. D. Arndt, Angew. Chem., Int. Ed., 2016,
55, 9772–9776.
159 F. Benazet, M. Cartier, J. Florent, C. Godard, G. Jung,
J. Lunel, D. Mancy, C. Pascal, J. Renaut and P. Tarridec,
Experientia, 1980, 36, 414–416.
160 D. J. Bentley, J. Fairhurst, P. T. Gallagher, A. K. Manteuffel,
C. J. Moody and J. L. Pinder, Org. Biomol. Chem., 2004, 2,
701–708.
161 T. Lipi´
nska, Tetrahedron Lett., 2002, 43, 9565–9567.
162 T. C. Rao, S. Saha, G. B. Raolji, B. Patro, P. Risbood,
M. J. Dilippantonio, J. E. Tomaszewski and
S. V. Malhotra, Tetrahedron Lett., 2013, 54, 487–490.
This journal is © The Royal Society of Chemistry 2017 RSC Adv.,2017,7, 52852–52887 | 52887
Review RSC Advances